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Research articles

Salivary analysis to unveil the paradigma of stress of domestic horses reared in the wild

• A. Marchegiani

Photorefractivity and photocurrent dynamics of triphenylamine-based polymer composites

• Naoto Tsutsumi
• Takafumi Sassa
• Wataru Sakai

Prevalence of hepatitis B and C viruses among migrant workers in Qatar

• Gheyath K. Nasrallah
• Hiam Chemaitelly
• Laith J. Abu-Raddad

Luminal androgen receptor subtype and tumor-infiltrating lymphocytes groups based on triple-negative breast cancer molecular subclassification

• Tae-Kyung Yoo

Data mining and safety analysis of avatrombopag: a retrospective pharmacovigilance study based on the US food and drug administration’s adverse event reporting system

Faults locating of power distribution systems based on successive PSO-GA algorithm

• Wenzhang Xu

Multisensory-inspired modeling and neural correlates for two key binocular interactions

• Vincent A. Billock
• Kacie Dougherty
• Marc D. Winterbottom

Multidrug-resistant phenotypes of genetically diverse Escherichia coli isolates from healthy domestic cats

• Virginia Núñez-Samudio
• Gumercindo Pimentel-Peralta
• Iván Landires

Preference of position in the proximity of various sugars revealed by location analysis of Drosophila melanogaster

• Haruki Kato
• Hiroyuki Nakagawa
• Kazuhiko Kume

Basal forebrain volume and metabolism in carriers of the Colombian mutation for autosomal dominant Alzheimer’s disease

• Stefan Teipel
• Alice Grazia
• Nunzio Pomara

Dual FDG/PSMA PET imaging to predict lesion-based progression of mCRPC during PSMA-RLT

• Florian Rosar
• Caroline Burgard
• Samer Ezziddin

Examining the unsustainable relationship between SDG performance, ecological footprint and international spillovers

• Mustafa Moinuddin
• Simon Høiberg Olsen

Investigation of rank order centroid method for optimal generation control

• T. Varshney
• A. V. Waghmare
• Ibrahim A. Hameed

Effects of plyometric training on health-related physical fitness in untrained participants: a systematic review and meta-analysis

• Nuannuan Deng
• Kim Geok Soh

Association of OPRM1 rs1799971, HTR1B rs6296 and COMT rs4680 polymorphisms with clinical phenotype among women with fibromyalgia

• César Fernández-de-las-Peñas
• Silvia Ambite-Quesada
• Lars Arendt-Nielsen

Molecular modeling and simulation approaches to characterize potential molecular targets for burdock inulin to instigate protection against autoimmune diseases

• Huma Farooque Hashmi
• Mohammed Bourhia

Nucleobindin 2 inhibits senescence in gastric carcinoma

• Yu Ishibashi
• Takashi Itoh
• Makoto Saegusa

5-MeO-DMT induces sleep-like LFP spectral signatures in the hippocampus and prefrontal cortex of awake rats

• Annie C. Souza
• Bryan C. Souza
• Sidarta Ribeiro

Identification of cancer risk groups through multi-omics integration using autoencoder and tensor analysis

• Ali Braytee
• Ali Anaissi

Chemogenetic activation or inhibition of histaminergic neurons bidirectionally modulates recognition memory formation and retrieval in male and female mice

• Alessia Costa
• Eva Ducourneau
• M. Beatrice Passani

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Formatting guide

This guide describes how to prepare contributions for submission. We recommend you read this in full if you have not previously submitted a contribution to Nature . We also recommend that, before submission, you familiarize yourself with Nature ’s style and content by reading the journal, either in print or online, particularly if you have not submitted to the journal recently.

Formats for Nature contributions

Articles are the main format for original research contributions to Nature . In addition, Nature publishes other submitted material as detailed below.

Articles are original reports whose conclusions represent a substantial advance in understanding of an important problem and have immediate, far-reaching implications. In print, physical sciences papers do not normally exceed 6 pages on average, and biological, clinical and social-sciences papers do not normally exceed 8 pages on average. However, the final print length is at the editor’s discretion.

Articles start with a fully referenced summary paragraph, ideally of no more than 200 words, which is separate from the main text and avoids numbers, abbreviations, acronyms or measurements unless essential. It is aimed at readers outside the discipline. This summary paragraph should be structured as follows: 2-3 sentences of basic-level introduction to the field; a brief account of the background and rationale of the work; a statement of the main conclusions (introduced by the phrase 'Here we show' or its equivalent); and finally, 2-3 sentences putting the main findings into general context so it is clear how the results described in the paper have moved the field forwards. Please refer to our annotated example   to see how the summary paragraph should be constructed.

The typical length of a 6-page article with 4 modest display items (figures and tables) is 2500 words (summary paragraph plus body text). The typical length of an 8-page article with 5-6 modest display items is 4300 words. A ‘modest’ display item is one that, with its legend, occupies about a quarter of a page (equivalent to ~270 words). If a composite figure (with several panels) needs to occupy at least half a page in order for all the elements to be visible, the text length may need to be reduced accordingly to accommodate such figures. Keep in mind that essential but technical details can be moved into the Methods or Supplementary Information.

As a guideline, articles typically have no more than 50 references. (There is no such constraint on any additional references associated with Methods or Supplementary Information.)

Sections are separated with subheadings to aid navigation. Subheadings may be up to 40 characters (including spaces).

Word counts refer to the text of the paper. Title, author list, acknowledgements and references are not included in total word counts.

Matters Arising and Corrections

Matters Arising are exceptionally interesting or important comments and clarifications on original research papers or other peer-reviewed material published within the past 18 months in Nature . They are published online but not in print.

For further details of and instructions for how to submit such comments on peer-reviewed material published in Nature — or to notify editors of the potential need for a correction — please consult our Matters Arising page.

Other contributions to Nature

Please access the other submitted material pages for further details on any of the contribution types below:

News and Comment

Correspondence

Books & Arts

News & Views

Insights, Reviews and Perspectives

Technology Features

The editorial process

See this section for an explanation of Nature 's editorial criteria for publication, refereeing policy and how editors handle papers after submission. Submission to a Nature journal is taken by the journal to mean that all the listed authors have agreed to all of the contents. See authorship policy for more details.

Presubmission enquiries

If you wish to enquire whether your Article might be suitable for consideration by Nature , please use our online presubmission enquiry service . All presubmission enquiries must include a cover paragraph to the editor stating the interest to a broad scientific readership, a fully referenced summary paragraph, and a reference list.

Readability

Nature is an international journal covering all the sciences. Contributions should therefore be written clearly and simply so that they are accessible to readers in other disciplines and to readers for whom English is not their first language. Thus, technical jargon should be avoided as far as possible and clearly explained where its use is unavoidable. Abbreviations, particularly those that are not standard, should also be kept to a minimum. The background, rationale and main conclusions of the study should be clearly explained. Titles and abstracts in particular should be written in language that will be readily intelligible to any scientist. Essential but specialized terms should be explained concisely but not didactically.

For gene, protein and other specialized names authors can use their preferred terminology so long as it is in current use by the community, but they must give all known names for the entity at first use in the paper. Nature prefers authors to use internationally agreed nomenclature. Papers containing new or revised formal taxonomic nomenclature for animals, whether living or extinct, are accepted conditional on the provision of LSIDs (Life Science Identifiers) by means of registration of such nomenclature with ZooBank, the proposed online registration system for the International Code of Zoological Nomenclature (ICZN).

Even though no paper will be rejected because of poor language, non–native English speakers occasionally receive feedback from editors and reviewers regarding language and grammar usage in their manuscripts. You may wish to consider asking colleagues to read your manuscript and/or to use a professional editing service such as those provided by our affiliates Nature Research Editing Service or American Journal Experts . You can also get a fast, free grammar check of your manuscript that takes into account all aspects of readability in English. Please note that the use of a language editing service is not a requirement for publication in Nature .

Nature 's editors provide detailed advice about the expected print length when asking for the final version of the manuscript. Nature 's editors often suggest revised titles and rewrite the summary paragraphs of Articles so the conclusions are clear to a broad readership.

After acceptance, Nature 's subeditors (copyeditors) ensure that the text and figures are readable and clear to those outside the field, and edit papers into Nature 's house style. They pay particular attention to summary paragraphs, overall clarity, figures, figure legends and titles.

Proofs are sent before publication; authors are welcome to discuss proposed changes with Nature 's subeditors, but Nature reserves the right to make the final decision about matters of style and the size of figures.

A useful set of articles providing general advice about writing and submitting scientific papers can be found on the SciDev.Net website.

Format of Articles

Contributions should be double-spaced and written in English (spellings as in the Oxford English Dictionary ).

Contributions should be organized in the sequence: title, authors, affiliations (plus present addresses), bold first paragraph, main text, main references, tables, figure legends, methods (including separate data and code availability statements), methods references, acknowledgements, author contributions, competing interest declaration, additional information (containing supplementary information line (if any) and corresponding author line), extended data figure/table legends. In order to facilitate the review process, for initial submissions we encourage authors to present the manuscript text and figures together in a single file (Microsoft Word or PDF, up to 30 MB in size). The figures may be inserted within the text at the appropriate positions or grouped at the end, and each figure legend should be presented together with its figure. Also, please include line numbers within the text.

Titles do not exceed two lines in print. This equates to 75 characters (including spaces). Titles do not normally include numbers, acronyms, abbreviations or punctuation. They should include sufficient detail for indexing purposes but be general enough for readers outside the field to appreciate what the paper is about.

An uninterrupted page of text contains about 1250 words.

A typical 6-page Article contains about 2,500 words of text and, additionally, 4 modest display items (figures and/or tables) with brief legends, reference list and online-only methods section if applicable. A composite figure (with several panels) usually needs to take about half a page, equivalent to about 600 words, in order for all the elements to be visible (see section 5.9 for instructions on sizing figures).

A typical 8-page Article contains about 4300 words of text and, additionally, 5-6 modest display items (figures and/or tables) with brief legends, reference list and online-only methods section if applicable. A composite figure (with several panels) usually needs to take about half a page, equivalent to about 600 words, in order for all the elements to be visible (see section 5.9 for instructions on sizing figures).

Authors of contributions that significantly exceed the limits stated here (or as specified by the editor) will have to shorten their papers before acceptance, inevitably delaying publication.

Nature requires authors to specify the contribution made by their co-authors in the end notes of the paper (see section 5.5). If authors regard it as essential to indicate that two or more co-authors are equal in status, they may be identified by an asterisk symbol with the caption ‘These authors contributed equally to this work’ immediately under the address list. If more than three co-authors are equal in status, this should be indicated in the author contributions statement. Present addresses appear immediately below the author list (below the footnote rule at the bottom of the first page) and may be identified by a dagger symbol; all other essential author-related explanation is placed in the acknowledgements.

Our preferred format for text is Microsoft Word, with the style tags removed.

TeX/LaTeX: If you have prepared your paper using TeX/LaTeX, we will need to convert this to Word after acceptance, before your paper can be typeset. All textual material of the paper (including references, tables, figure captions, online methods, etc.) should be included as a single .tex file.

We prefer the use of a ‘standard’ font, preferably 12-point Times New Roman. For mathematical symbols, Greek letters and other special characters, use normal text or Symbol font. Word Equation Editor/MathType should be used only for formulae that cannot be produced using normal text or Symbol font.

The ‘Methods’ section is in the main text file, following the figure legends. This Methods section will appear in the PDF and in the full-text (HTML) version of the paper online, but will not appear in the printed issue. The Methods section should be written as concisely as possible but should contain all elements necessary to allow interpretation and replication of the results. As a guideline, the Methods section does not typically exceed 3,000 words. To increase reproducibility, authors are encouraged to deposit a detailed description of protocols used in their study in a protocol sharing platform of their choice. Springer Nature’s protocols.io is a free and open service designed to help researchers share experimental know-how. Protocols deposited by the authors in www.protocols.io will be linked to the online Methods section upon publication

Detailed descriptions of methods already published should be avoided; a reference number can be provided to save space, with any new addition or variation stated.

The Methods section should be subdivided by short bold headings referring to methods used and we encourage the inclusion of specific subsections for statistics, reagents and animal models. If further references are included in this section their numbering should continue from the end of the last reference number in the rest of the paper and they are listed after the Methods section.

Please provide separate Data Availability and Code Availability statements after the main text statements and before the Extended Data legends; detailed guidance can be found in our data availability and data citations policy . Certain data types must be deposited in an appropriate public structured data depository (details are available here ), and the accession number(s) provided in the manuscript. Full access is required at the time of publication. Should full access to data be required for peer review, authors must provide it.

The Methods section cannot contain figures or tables (essential display items should be included in the Extended Data or exceptionally in the Supplementary Information).

References are each numbered, ordered sequentially as they appear in the text, tables, boxes, figure legends, Methods, Extended Data tables and Extended Data figure legends.

When cited in the text, reference numbers are superscript, not in brackets unless they are likely to be confused with a superscript number.

Do not use linked fields (produced by EndNote and similar programs). Please use the one-click button provided by EndNote to remove EndNote codes before saving your file.

As a guideline, Articles allow up to 50 references in the main text if needed and within the average page budget. Only one publication can be listed for each number. Additional references for Methods or Supplementary Information are not included in this count.

Only articles that have been published or accepted by a named publication, or that have been uploaded to a recognized preprint server (for example, arXiv, bioRxiv), should be in the reference list; papers in preparation should be mentioned in the text with a list of authors (or initials if any of the authors are co-authors of the present contribution).

Published conference abstracts, numbered patents, preprints on recognized servers, papers in press, and research datasets that have been assigned a digital object identifier may be included in reference lists, but text, grant details and acknowledgements may not. (An exception is the highlighted references which we ask authors of Reviews, Perspectives and Insights articles to provide.)

All authors should be included in reference lists unless there are more than five, in which case only the first author should be given, followed by ‘et al.’.

Please follow the style below in the published edition of Nature in preparing reference lists.

Authors should be listed surname first, followed by a comma and initials of given names.

Titles of all cited articles are required. Titles of articles cited in reference lists should be in upright, not italic text; the first word of the title is capitalized, the title written exactly as it appears in the work cited, ending with a full stop. Book titles are italic with all main words capitalized. Journal titles are italic and abbreviated according to common usage. Volume numbers are bold. The publisher and city of publication are required for books cited. (Refer to published papers in Nature for details.)

Research datasets may be cited in the reference list if they have been assigned digital object identifiers (DOIs) and include authors, title, publisher (repository name), identifier (DOI expressed as a URL). Example: Hao, Z., AghaKouchak, A., Nakhjiri, N. & Farahmand, A. Global Integrated Drought Monitoring and Prediction System (GIDMaPS) data sets. figshare http://dx.doi.org/10.6084/m9.figshare.853801 (2014).

Recognized preprints may be cited in the reference list. Example: Babichev, S. A., Ries, J. & Lvovsky, A. I. Quantum scissors: teleportation of single-mode optical states by means of a nonlocal single photon. Preprint at http://arXiv.org/quant-ph/0208066 (2002).

References to web-only journals should give authors, article title and journal name as above, followed by URL in full - or DOI if known - and the year of publication in parentheses.

References to websites should give authors if known, title of cited page, URL in full, and year of posting in parentheses.

End notes are brief and follow the Methods (or Methods References, if any).

Acknowledgements should be brief, and should not include thanks to anonymous referees and editors, inessential words, or effusive comments. A person can be thanked for assistance, not “excellent” assistance, or for comments, not “insightful” comments, for example. Acknowledgements can contain grant and contribution numbers.

Author Contributions: Authors are required to include a statement to specify the contributions of each co-author. The statement can be up to several sentences long, describing the tasks of individual authors referred to by their initials. See the authorship policy page for further explanation and examples.

Competing interests  statement.

Additional Information: Authors should include a set of statements at the end of the paper, in the following order:

Papers containing Supplementary Information contain the statement: “Supplementary Information is available for this paper.”

A sentence reading "Correspondence and requests for materials should be addressed to XX.” Nature expects this identified author to respond to readers’ enquiries and requests for materials, and to coordinate the handling of any other matters arising from the published contribution, including corrections complaints. The author named as corresponding author is not necessarily the senior author, and publication of this author’s name does not imply seniority. Authors may include more than one e-mail address if essential, in which event Nature will communicate with the first-listed address for any post-publication matters, and expect that author to coordinate with the other co-authors.

Peer review information includes the names of reviewers who agree to be cited and is completed by Nature staff during proofing.

A sentence reading “Reprints and permissions information is available at www.nature.com/reprints.”

Life sciences and behavioural & social sciences reporting guidelines

To improve the transparency of reporting and the reproducibility of published results, authors of life sciences and behavioural & social sciences Articles must provide a completed Reporting Summary that will be made available to editors and reviewers during manuscript assessment. The Reporting Summary will be published with all accepted manuscripts.

Please note: because of the advanced features used in these forms, you must use Adobe Reader to open the documents and fill them out.

Guidance and resources related to the use and reporting of statistics are available here .

Tables should each be presented on a separate page, portrait (not landscape) orientation, and upright on the page, not sideways.

Tables have a short, one-line title in bold text. Tables should be as small as possible. Bear in mind the size of a Nature page as a limiting factor when compiling a table.

Symbols and abbreviations are defined immediately below the table, followed by essential descriptive material as briefly as possible, all in double-spaced text.

Standard table formats are available for submissions of cryo-EM , NMR and X-ray crystallography data . Authors providing these data must use these standard tables and include them as Extended Data.

Figure legends

For initial submissions, we encourage authors to present the manuscript text and figures together in a single Word doc or PDF file, and for each figure legend to be presented together with its figure. However, when preparing the final paper to be accepted, we require figure legends to be listed one after the other, as part of the text document, separate from the figure files, and after the main reference list.

Each figure legend should begin with a brief title for the whole figure and continue with a short description of each panel and the symbols used. If the paper contains a Methods section, legends should not contain any details of methods. Legends should be fewer than 300 words each.

All error bars and statistics must be defined in the figure legend, as discussed above.

Nature requires figures in electronic format. Please ensure that all digital images comply with the Nature journals’ policy on image integrity .

Figures should be as small and simple as is compatible with clarity. The goal is for figures to be comprehensible to readers in other or related disciplines, and to assist their understanding of the paper. Unnecessary figures and parts (panels) of figures should be avoided: data presented in small tables or histograms, for instance, can generally be stated briefly in the text instead. Avoid unnecessary complexity, colouring and excessive detail.

Figures should not contain more than one panel unless the parts are logically connected; each panel of a multipart figure should be sized so that the whole figure can be reduced by the same amount and reproduced on the printed page at the smallest size at which essential details are visible. For guidance, Nature ’s standard figure sizes are 90 mm (single column) and 180 mm (double column) and the full depth of the page is 170 mm.

Amino-acid sequences should be printed in Courier (or other monospaced) font using the one-letter code in lines of 50 or 100 characters.

Authors describing chemical structures should use the Nature Research Chemical Structures style guide .

Some brief guidance for figure preparation:

Lettering in figures (labelling of axes and so on) should be in lower-case type, with the first letter capitalized and no full stop.

Units should have a single space between the number and the unit, and follow SI nomenclature or the nomenclature common to a particular field. Thousands should be separated by commas (1,000). Unusual units or abbreviations are defined in the legend.

Scale bars should be used rather than magnification factors.

Layering type directly over shaded or textured areas and using reversed type (white lettering on a coloured background) should be avoided where possible.

Where possible, text, including keys to symbols, should be provided in the legend rather than on the figure itself.

Figure quality

At initial submission, figures should be at good enough quality to be assessed by referees, preferably incorporated into the manuscript text in a single Word doc or PDF, although figures can be supplied separately as JPEGs if authors are unable to include them with the text. Authors are advised to follow the initial and revised submissions guidelines with respect to sizing, resolution and labelling.

Please note that print-publication quality figures are large and it is not helpful to upload them at the submission stage. Authors will be asked for high-quality figures when they are asked to submit the final version of their article for publication.At that stage, please prepare figures according to these guidelines .

Third party rights

Nature discourages the use or adaptation of previously published display items (for example, figures, tables, images, videos or text boxes). However, we recognize that to illustrate some concepts the use of published data is required and the reuse of previously published display items may be necessary. Please note that in these instances we might not be able to obtain the necessary rights for some images to be reused (as is, or adapted versions) in our articles. In such cases, we will contact you to discuss the sourcing of alternative material.

Figure costs

In order to help cover some of the additional cost of four-colour reproduction, Nature Portfolio charges our authors a fee for the printing of their colour figures. Please contact our offices for exact pricing and details. Inability to pay this charge will not prevent publication of colour figures judged essential by the editors, but this must be agreed with the editor prior to acceptance.

Production-quality figures

When a manuscript is accepted in principle for publication, the editor will ask for high-resolution figures. Do not submit publication-quality figures until asked to do so by an editor. At that stage, please prepare figures according to these guidelines .

Extended Data

Extended Data figures and tables are online-only (appearing in the online PDF and full-text HTML version of the paper), peer-reviewed display items that provide essential background to the Article but are not included in the printed version of the paper due to space constraints or being of interest only to a few specialists. A maximum of ten Extended Data display items (figures and tables) is typically permitted. See Composition of a Nature research paper .

Extended Data tables should be formatted along similar lines to tables appearing in print (see section 5.7) but the main body (excluding title and legend, which should be included at the end of the Word file) should be submitted separately as an image rather than as an editable format in Word, as Extended Data tables are not edited by Nature’s subediting department. Small tables may also be included as sub-panels within Extended Data figures. See Extended Data Formatting Guide .

Extended Data figures should be prepared along slightly different guidelines compared to figures appearing in print, and may be multi-panelled as long as they fit to size rules (see Extended Data Formatting Guide ). Extended Data figures are not edited or styled by Nature’s art department; for this reason, authors are requested to follow Nature style as closely as possible when preparing these figures. The legends for Extended Data figures should be prepared as for print figures and should be listed one after the other at the end of the Word file.

If space allows, Nature encourages authors to include a simple schematic, as a panel in an Extended Data figure, that summarizes the main finding of the paper, where appropriate (for example, to assist understanding of complex detail in cell, structural and molecular biology disciplines).

If a manuscript has Extended Data figures or tables, authors are asked to refer to discrete items at an appropriate place in the main text (for example, Extended Data Fig. 1 and Extended Data Table 1).

If further references are included in the Extended Data tables and Extended Data figure legends, the numbering should continue from the end of the last reference number in the main paper (or from the last reference number in the additional Methods section if present) and the list should be added to the end of the list accompanying the additional Methods section, if present, or added below the Extended Data legends if no additional Methods section is present.

Supplementary Information

Supplementary Information (SI) is online-only, peer-reviewed material that is essential background to the Article (for example, large data sets, methods, calculations), but which is too large or impractical, or of interest only to a few specialists, to justify inclusion in the printed version of the paper. See the Supplementary Information page for further details.

Supplementary Information should not contain figures (any figures additional to those appearing in print should be formatted as Extended Data figures). Tables may be included in Supplementary Information, but only if they are unsuitable for formatting as Extended Data tables (for example, tables containing large data sets or raw data that are best suited to Excel files).

If a manuscript has accompanying SI, either at submission or in response to an editor’s letter that requests it, authors are asked to refer to discrete items of the SI (for example, videos, tables) at an appropriate point in the main manuscript.

Chemical structures and characterization of chemical materials

For guidelines describing Nature ’s standards for experimental methods and the characterization of new compounds, please see the information sheet on the characterization of chemical materials .

We aim to produce chemical structures in a consistent format throughout our articles. Please use the Nature Portfolio Chemical Structures Guide and ChemDraw template to ensure that you prepare your figures in a format that will require minimal changes by our art and production teams. Submit final files at 100% as .cdx files.

Registered Reports

Registered Reports are empirical articles testing confirmatory hypotheses in which the methods and proposed analyses are pre-registered and peer reviewed prior to research being conducted. For further details about Registered Reports and instructions for how to submit such articles to Nature please consult our Registered Reports page.

All contributions should be submitted online , unless otherwise instructed by the editors. Please be sure to read the information on what to include in your cover letter as well as several important content-related issues when putting a submission together.

Before submitting, all contributors must agree to all of Nature's publication policies .

Nature authors must make data and materials publicly available upon publication. This includes deposition of data into the relevant databases and arranging for them to be publicly released by the online publication date (not after). A description of our initiative to improve the transparency and the reproducibility of published results is available here . A full description of Nature’s publication policies is at the Nature Portfolio Authors and Referees website .

Other Nature Research journals

An account of the relationship between all the Nature journals is provided at the Nature family page . 

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Authorship and authors’ responsibilities

• Principles of authorship
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• Knowledge check: Describe authorship
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Selecting a journal for publication

• Poll: Your criteria for selecting a journal
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• Case study: Bohannon’s sting
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Submitting your paper

• Submitting your manuscript
• Presubmission enquiries at scientific journals
• Scientific cover letters
• An editor's experience: The submission process
• What constitutes a conflict of interest?
• Knowledge check: Conflicts of interest
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Understanding peer review

• A brief history of peer review
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• How to think like a peer reviewer when you read a paper
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Study Suggests Genetics as a Cause, Not Just a Risk, for Some Alzheimer’s

People with two copies of the gene variant APOE4 are almost certain to get Alzheimer’s, say researchers, who proposed a framework under which such patients could be diagnosed years before symptoms.

By Pam Belluck

Scientists are proposing a new way of understanding the genetics of Alzheimer’s that would mean that up to a fifth of patients would be considered to have a genetically caused form of the disease.

Currently, the vast majority of Alzheimer’s cases do not have a clearly identified cause. The new designation, proposed in a study published Monday, could broaden the scope of efforts to develop treatments, including gene therapy, and affect the design of clinical trials.

It could also mean that hundreds of thousands of people in the United States alone could, if they chose, receive a diagnosis of Alzheimer’s before developing any symptoms of cognitive decline, although there currently are no treatments for people at that stage.

The new classification would make this type of Alzheimer’s one of the most common genetic disorders in the world, medical experts said.

“This reconceptualization that we’re proposing affects not a small minority of people,” said Dr. Juan Fortea, an author of the study and the director of the Sant Pau Memory Unit in Barcelona, Spain. “Sometimes we say that we don’t know the cause of Alzheimer’s disease,” but, he said, this would mean that about 15 to 20 percent of cases “can be tracked back to a cause, and the cause is in the genes.”

The idea involves a gene variant called APOE4. Scientists have long known that inheriting one copy of the variant increases the risk of developing Alzheimer’s, and that people with two copies, inherited from each parent, have vastly increased risk.

The new study , published in the journal Nature Medicine, analyzed data from over 500 people with two copies of APOE4, a significantly larger pool than in previous studies. The researchers found that almost all of those patients developed the biological pathology of Alzheimer’s, and the authors say that two copies of APOE4 should now be considered a cause of Alzheimer’s — not simply a risk factor.

The patients also developed Alzheimer’s pathology relatively young, the study found. By age 55, over 95 percent had biological markers associated with the disease. By 65, almost all had abnormal levels of a protein called amyloid that forms plaques in the brain, a hallmark of Alzheimer’s. And many started developing symptoms of cognitive decline at age 65, younger than most people without the APOE4 variant.

“The critical thing is that these individuals are often symptomatic 10 years earlier than other forms of Alzheimer’s disease,” said Dr. Reisa Sperling, a neurologist at Mass General Brigham in Boston and an author of the study.

She added, “By the time they are picked up and clinically diagnosed, because they’re often younger, they have more pathology.”

People with two copies, known as APOE4 homozygotes, make up 2 to 3 percent of the general population, but are an estimated 15 to 20 percent of people with Alzheimer’s dementia, experts said. People with one copy make up about 15 to 25 percent of the general population, and about 50 percent of Alzheimer’s dementia patients.

The most common variant is called APOE3, which seems to have a neutral effect on Alzheimer’s risk. About 75 percent of the general population has one copy of APOE3, and more than half of the general population has two copies.

Alzheimer’s experts not involved in the study said classifying the two-copy condition as genetically determined Alzheimer’s could have significant implications, including encouraging drug development beyond the field’s recent major focus on treatments that target and reduce amyloid.

Dr. Samuel Gandy, an Alzheimer’s researcher at Mount Sinai in New York, who was not involved in the study, said that patients with two copies of APOE4 faced much higher safety risks from anti-amyloid drugs.

When the Food and Drug Administration approved the anti-amyloid drug Leqembi last year, it required a black-box warning on the label saying that the medication can cause “serious and life-threatening events” such as swelling and bleeding in the brain, especially for people with two copies of APOE4. Some treatment centers decided not to offer Leqembi, an intravenous infusion, to such patients.

Dr. Gandy and other experts said that classifying these patients as having a distinct genetic form of Alzheimer’s would galvanize interest in developing drugs that are safe and effective for them and add urgency to current efforts to prevent cognitive decline in people who do not yet have symptoms.

“Rather than say we have nothing for you, let’s look for a trial,” Dr. Gandy said, adding that such patients should be included in trials at younger ages, given how early their pathology starts.

Besides trying to develop drugs, some researchers are exploring gene editing to transform APOE4 into a variant called APOE2, which appears to protect against Alzheimer’s. Another gene-therapy approach being studied involves injecting APOE2 into patients’ brains.

The new study had some limitations, including a lack of diversity that might make the findings less generalizable. Most patients in the study had European ancestry. While two copies of APOE4 also greatly increase Alzheimer’s risk in other ethnicities, the risk levels differ, said Dr. Michael Greicius, a neurologist at Stanford University School of Medicine who was not involved in the research.

“One important argument against their interpretation is that the risk of Alzheimer’s disease in APOE4 homozygotes varies substantially across different genetic ancestries,” said Dr. Greicius, who cowrote a study that found that white people with two copies of APOE4 had 13 times the risk of white people with two copies of APOE3, while Black people with two copies of APOE4 had 6.5 times the risk of Black people with two copies of APOE3.

“This has critical implications when counseling patients about their ancestry-informed genetic risk for Alzheimer’s disease,” he said, “and it also speaks to some yet-to-be-discovered genetics and biology that presumably drive this massive difference in risk.”

Under the current genetic understanding of Alzheimer’s, less than 2 percent of cases are considered genetically caused. Some of those patients inherited a mutation in one of three genes and can develop symptoms as early as their 30s or 40s. Others are people with Down syndrome, who have three copies of a chromosome containing a protein that often leads to what is called Down syndrome-associated Alzheimer’s disease .

Dr. Sperling said the genetic alterations in those cases are believed to fuel buildup of amyloid, while APOE4 is believed to interfere with clearing amyloid buildup.

Under the researchers’ proposal, having one copy of APOE4 would continue to be considered a risk factor, not enough to cause Alzheimer’s, Dr. Fortea said. It is unusual for diseases to follow that genetic pattern, called “semidominance,” with two copies of a variant causing the disease, but one copy only increasing risk, experts said.

The new recommendation will prompt questions about whether people should get tested to determine if they have the APOE4 variant.

Dr. Greicius said that until there were treatments for people with two copies of APOE4 or trials of therapies to prevent them from developing dementia, “My recommendation is if you don’t have symptoms, you should definitely not figure out your APOE status.”

He added, “It will only cause grief at this point.”

Finding ways to help these patients cannot come soon enough, Dr. Sperling said, adding, “These individuals are desperate, they’ve seen it in both of their parents often and really need therapies.”

Pam Belluck is a health and science reporter, covering a range of subjects, including reproductive health, long Covid, brain science, neurological disorders, mental health and genetics. More about Pam Belluck

The Fight Against Alzheimer’s Disease

Alzheimer’s is the most common form of dementia, but much remains unknown about this daunting disease..

How is Alzheimer’s diagnosed? What causes Alzheimer’s? We answered some common questions .

A study suggests that genetics can be a cause of Alzheimer’s , not just a risk, raising the prospect of diagnosis years before symptoms appear.

Determining whether someone has Alzheimer’s usually requires an extended diagnostic process . But new criteria could lead to a diagnosis on the basis of a simple blood test .

The F.D.A. has given full approval to the Alzheimer’s drug Leqembi. Here is what to know about i t.

Alzheimer’s can make communicating difficult. We asked experts for tips on how to talk to someone with the disease .

Cultural Relativity and Acceptance of Embryonic Stem Cell Research

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There is a debate about the ethical implications of using human embryos in stem cell research, which can be influenced by cultural, moral, and social values. This paper argues for an adaptable framework to accommodate diverse cultural and religious perspectives. By using an adaptive ethics model, research protections can reflect various populations and foster growth in stem cell research possibilities.

INTRODUCTION

Stem cell research combines biology, medicine, and technology, promising to alter health care and the understanding of human development. Yet, ethical contention exists because of individuals’ perceptions of using human embryos based on their various cultural, moral, and social values. While these disagreements concerning policy, use, and general acceptance have prompted the development of an international ethics policy, such a uniform approach can overlook the nuanced ethical landscapes between cultures. With diverse viewpoints in public health, a single global policy, especially one reflecting Western ethics or the ethics prevalent in high-income countries, is impractical. This paper argues for a culturally sensitive, adaptable framework for the use of embryonic stem cells. Stem cell policy should accommodate varying ethical viewpoints and promote an effective global dialogue. With an extension of an ethics model that can adapt to various cultures, we recommend localized guidelines that reflect the moral views of the people those guidelines serve.

Stem cells, characterized by their unique ability to differentiate into various cell types, enable the repair or replacement of damaged tissues. Two primary types of stem cells are somatic stem cells (adult stem cells) and embryonic stem cells. Adult stem cells exist in developed tissues and maintain the body’s repair processes. [1] Embryonic stem cells (ESC) are remarkably pluripotent or versatile, making them valuable in research. [2] However, the use of ESCs has sparked ethics debates. Considering the potential of embryonic stem cells, research guidelines are essential. The International Society for Stem Cell Research (ISSCR) provides international stem cell research guidelines. They call for “public conversations touching on the scientific significance as well as the societal and ethical issues raised by ESC research.” [3] The ISSCR also publishes updates about culturing human embryos 14 days post fertilization, suggesting local policies and regulations should continue to evolve as ESC research develops. [4]  Like the ISSCR, which calls for local law and policy to adapt to developing stem cell research given cultural acceptance, this paper highlights the importance of local social factors such as religion and culture.

I.     Global Cultural Perspective of Embryonic Stem Cells

Views on ESCs vary throughout the world. Some countries readily embrace stem cell research and therapies, while others have stricter regulations due to ethical concerns surrounding embryonic stem cells and when an embryo becomes entitled to moral consideration. The philosophical issue of when the “someone” begins to be a human after fertilization, in the morally relevant sense, [5] impacts when an embryo becomes not just worthy of protection but morally entitled to it. The process of creating embryonic stem cell lines involves the destruction of the embryos for research. [6] Consequently, global engagement in ESC research depends on social-cultural acceptability.

a.     US and Rights-Based Cultures

In the United States, attitudes toward stem cell therapies are diverse. The ethics and social approaches, which value individualism, [7] trigger debates regarding the destruction of human embryos, creating a complex regulatory environment. For example, the 1996 Dickey-Wicker Amendment prohibited federal funding for the creation of embryos for research and the destruction of embryos for “more than allowed for research on fetuses in utero.” [8] Following suit, in 2001, the Bush Administration heavily restricted stem cell lines for research. However, the Stem Cell Research Enhancement Act of 2005 was proposed to help develop ESC research but was ultimately vetoed. [9] Under the Obama administration, in 2009, an executive order lifted restrictions allowing for more development in this field. [10] The flux of research capacity and funding parallels the different cultural perceptions of human dignity of the embryo and how it is socially presented within the country’s research culture. [11]

b.     Ubuntu and Collective Cultures

African bioethics differs from Western individualism because of the different traditions and values. African traditions, as described by individuals from South Africa and supported by some studies in other African countries, including Ghana and Kenya, follow the African moral philosophies of Ubuntu or Botho and Ukama , which “advocates for a form of wholeness that comes through one’s relationship and connectedness with other people in the society,” [12] making autonomy a socially collective concept. In this context, for the community to act autonomously, individuals would come together to decide what is best for the collective. Thus, stem cell research would require examining the value of the research to society as a whole and the use of the embryos as a collective societal resource. If society views the source as part of the collective whole, and opposes using stem cells, compromising the cultural values to pursue research may cause social detachment and stunt research growth. [13] Based on local culture and moral philosophy, the permissibility of stem cell research depends on how embryo, stem cell, and cell line therapies relate to the community as a whole. Ubuntu is the expression of humanness, with the person’s identity drawn from the “’I am because we are’” value. [14] The decision in a collectivistic culture becomes one born of cultural context, and individual decisions give deference to others in the society.

Consent differs in cultures where thought and moral philosophy are based on a collective paradigm. So, applying Western bioethical concepts is unrealistic. For one, Africa is a diverse continent with many countries with different belief systems, access to health care, and reliance on traditional or Western medicines. Where traditional medicine is the primary treatment, the “’restrictive focus on biomedically-related bioethics’” [is] problematic in African contexts because it neglects bioethical issues raised by traditional systems.” [15] No single approach applies in all areas or contexts. Rather than evaluating the permissibility of ESC research according to Western concepts such as the four principles approach, different ethics approaches should prevail.

Another consideration is the socio-economic standing of countries. In parts of South Africa, researchers have not focused heavily on contributing to the stem cell discourse, either because it is not considered health care or a health science priority or because resources are unavailable. [16] Each country’s priorities differ given different social, political, and economic factors. In South Africa, for instance, areas such as maternal mortality, non-communicable diseases, telemedicine, and the strength of health systems need improvement and require more focus [17] Stem cell research could benefit the population, but it also could divert resources from basic medical care. Researchers in South Africa adhere to the National Health Act and Medicines Control Act in South Africa and international guidelines; however, the Act is not strictly enforced, and there is no clear legislation for research conduct or ethical guidelines. [18]

Some parts of Africa condemn stem cell research. For example, 98.2 percent of the Tunisian population is Muslim. [19] Tunisia does not permit stem cell research because of moral conflict with a Fatwa. Religion heavily saturates the regulation and direction of research. [20] Stem cell use became permissible for reproductive purposes only recently, with tight restrictions preventing cells from being used in any research other than procedures concerning ART/IVF.  Their use is conditioned on consent, and available only to married couples. [21] The community's receptiveness to stem cell research depends on including communitarian African ethics.

c.     Asia

Some Asian countries also have a collective model of ethics and decision making. [22] In China, the ethics model promotes a sincere respect for life or human dignity, [23] based on protective medicine. This model, influenced by Traditional Chinese Medicine (TCM), [24] recognizes Qi as the vital energy delivered via the meridians of the body; it connects illness to body systems, the body’s entire constitution, and the universe for a holistic bond of nature, health, and quality of life. [25] Following a protective ethics model, and traditional customs of wholeness, investment in stem cell research is heavily desired for its applications in regenerative therapies, disease modeling, and protective medicines. In a survey of medical students and healthcare practitioners, 30.8 percent considered stem cell research morally unacceptable while 63.5 percent accepted medical research using human embryonic stem cells. Of these individuals, 89.9 percent supported increased funding for stem cell research. [26] The scientific community might not reflect the overall population. From 1997 to 2019, China spent a total of $576 million (USD) on stem cell research at 8,050 stem cell programs, increased published presence from 0.6 percent to 14.01 percent of total global stem cell publications as of 2014, and made significant strides in cell-based therapies for various medical conditions. [27] However, while China has made substantial investments in stem cell research and achieved notable progress in clinical applications, concerns linger regarding ethical oversight and transparency. [28] For example, the China Biosecurity Law, promoted by the National Health Commission and China Hospital Association, attempted to mitigate risks by introducing an institutional review board (IRB) in the regulatory bodies. 5800 IRBs registered with the Chinese Clinical Trial Registry since 2021. [29] However, issues still need to be addressed in implementing effective IRB review and approval procedures.

The substantial government funding and focus on scientific advancement have sometimes overshadowed considerations of regional cultures, ethnic minorities, and individual perspectives, particularly evident during the one-child policy era. As government policy adapts to promote public stability, such as the change from the one-child to the two-child policy, [30] research ethics should also adapt to ensure respect for the values of its represented peoples.

Japan is also relatively supportive of stem cell research and therapies. Japan has a more transparent regulatory framework, allowing for faster approval of regenerative medicine products, which has led to several advanced clinical trials and therapies. [31] South Korea is also actively engaged in stem cell research and has a history of breakthroughs in cloning and embryonic stem cells. [32] However, the field is controversial, and there are issues of scientific integrity. For example, the Korean FDA fast-tracked products for approval, [33] and in another instance, the oocyte source was unclear and possibly violated ethical standards. [34] Trust is important in research, as it builds collaborative foundations between colleagues, trial participant comfort, open-mindedness for complicated and sensitive discussions, and supports regulatory procedures for stakeholders. There is a need to respect the culture’s interest, engagement, and for research and clinical trials to be transparent and have ethical oversight to promote global research discourse and trust.

d.     Middle East

Countries in the Middle East have varying degrees of acceptance of or restrictions to policies related to using embryonic stem cells due to cultural and religious influences. Saudi Arabia has made significant contributions to stem cell research, and conducts research based on international guidelines for ethical conduct and under strict adherence to guidelines in accordance with Islamic principles. Specifically, the Saudi government and people require ESC research to adhere to Sharia law. In addition to umbilical and placental stem cells, [35] Saudi Arabia permits the use of embryonic stem cells as long as they come from miscarriages, therapeutic abortions permissible by Sharia law, or are left over from in vitro fertilization and donated to research. [36] Laws and ethical guidelines for stem cell research allow the development of research institutions such as the King Abdullah International Medical Research Center, which has a cord blood bank and a stem cell registry with nearly 10,000 donors. [37] Such volume and acceptance are due to the ethical ‘permissibility’ of the donor sources, which do not conflict with religious pillars. However, some researchers err on the side of caution, choosing not to use embryos or fetal tissue as they feel it is unethical to do so. [38]

Jordan has a positive research ethics culture. [39] However, there is a significant issue of lack of trust in researchers, with 45.23 percent (38.66 percent agreeing and 6.57 percent strongly agreeing) of Jordanians holding a low level of trust in researchers, compared to 81.34 percent of Jordanians agreeing that they feel safe to participate in a research trial. [40] Safety testifies to the feeling of confidence that adequate measures are in place to protect participants from harm, whereas trust in researchers could represent the confidence in researchers to act in the participants’ best interests, adhere to ethical guidelines, provide accurate information, and respect participants’ rights and dignity. One method to improve trust would be to address communication issues relevant to ESC. Legislation surrounding stem cell research has adopted specific language, especially concerning clarification “between ‘stem cells’ and ‘embryonic stem cells’” in translation. [41] Furthermore, legislation “mandates the creation of a national committee… laying out specific regulations for stem-cell banking in accordance with international standards.” [42] This broad regulation opens the door for future global engagement and maintains transparency. However, these regulations may also constrain the influence of research direction, pace, and accessibility of research outcomes.

e.     Europe

In the European Union (EU), ethics is also principle-based, but the principles of autonomy, dignity, integrity, and vulnerability are interconnected. [43] As such, the opportunity for cohesion and concessions between individuals’ thoughts and ideals allows for a more adaptable ethics model due to the flexible principles that relate to the human experience The EU has put forth a framework in its Convention for the Protection of Human Rights and Dignity of the Human Being allowing member states to take different approaches. Each European state applies these principles to its specific conventions, leading to or reflecting different acceptance levels of stem cell research. [44]

For example, in Germany, Lebenzusammenhang , or the coherence of life, references integrity in the unity of human culture. Namely, the personal sphere “should not be subject to external intervention.” [45]  Stem cell interventions could affect this concept of bodily completeness, leading to heavy restrictions. Under the Grundgesetz, human dignity and the right to life with physical integrity are paramount. [46] The Embryo Protection Act of 1991 made producing cell lines illegal. Cell lines can be imported if approved by the Central Ethics Commission for Stem Cell Research only if they were derived before May 2007. [47] Stem cell research respects the integrity of life for the embryo with heavy specifications and intense oversight. This is vastly different in Finland, where the regulatory bodies find research more permissible in IVF excess, but only up to 14 days after fertilization. [48] Spain’s approach differs still, with a comprehensive regulatory framework. [49] Thus, research regulation can be culture-specific due to variations in applied principles. Diverse cultures call for various approaches to ethical permissibility. [50] Only an adaptive-deliberative model can address the cultural constructions of self and achieve positive, culturally sensitive stem cell research practices. [51]

II.     Religious Perspectives on ESC

Embryonic stem cell sources are the main consideration within religious contexts. While individuals may not regard their own religious texts as authoritative or factual, religion can shape their foundations or perspectives.

The Qur'an states:

“And indeed We created man from a quintessence of clay. Then We placed within him a small quantity of nutfa (sperm to fertilize) in a safe place. Then We have fashioned the nutfa into an ‘alaqa (clinging clot or cell cluster), then We developed the ‘alaqa into mudgha (a lump of flesh), and We made mudgha into bones, and clothed the bones with flesh, then We brought it into being as a new creation. So Blessed is Allah, the Best of Creators.” [52]

Many scholars of Islam estimate the time of soul installment, marked by the angel breathing in the soul to bring the individual into creation, as 120 days from conception. [53] Personhood begins at this point, and the value of life would prohibit research or experimentation that could harm the individual. If the fetus is more than 120 days old, the time ensoulment is interpreted to occur according to Islamic law, abortion is no longer permissible. [54] There are a few opposing opinions about early embryos in Islamic traditions. According to some Islamic theologians, there is no ensoulment of the early embryo, which is the source of stem cells for ESC research. [55]

In Buddhism, the stance on stem cell research is not settled. The main tenets, the prohibition against harming or destroying others (ahimsa) and the pursuit of knowledge (prajña) and compassion (karuna), leave Buddhist scholars and communities divided. [56] Some scholars argue stem cell research is in accordance with the Buddhist tenet of seeking knowledge and ending human suffering. Others feel it violates the principle of not harming others. Finding the balance between these two points relies on the karmic burden of Buddhist morality. In trying to prevent ahimsa towards the embryo, Buddhist scholars suggest that to comply with Buddhist tenets, research cannot be done as the embryo has personhood at the moment of conception and would reincarnate immediately, harming the individual's ability to build their karmic burden. [57] On the other hand, the Bodhisattvas, those considered to be on the path to enlightenment or Nirvana, have given organs and flesh to others to help alleviate grieving and to benefit all. [58] Acceptance varies on applied beliefs and interpretations.

Catholicism does not support embryonic stem cell research, as it entails creation or destruction of human embryos. This destruction conflicts with the belief in the sanctity of life. For example, in the Old Testament, Genesis describes humanity as being created in God’s image and multiplying on the Earth, referencing the sacred rights to human conception and the purpose of development and life. In the Ten Commandments, the tenet that one should not kill has numerous interpretations where killing could mean murder or shedding of the sanctity of life, demonstrating the high value of human personhood. In other books, the theological conception of when life begins is interpreted as in utero, [59] highlighting the inviolability of life and its formation in vivo to make a religious point for accepting such research as relatively limited, if at all. [60] The Vatican has released ethical directives to help apply a theological basis to modern-day conflicts. The Magisterium of the Church states that “unless there is a moral certainty of not causing harm,” experimentation on fetuses, fertilized cells, stem cells, or embryos constitutes a crime. [61] Such procedures would not respect the human person who exists at these stages, according to Catholicism. Damages to the embryo are considered gravely immoral and illicit. [62] Although the Catholic Church officially opposes abortion, surveys demonstrate that many Catholic people hold pro-choice views, whether due to the context of conception, stage of pregnancy, threat to the mother’s life, or for other reasons, demonstrating that practicing members can also accept some but not all tenets. [63]

Some major Jewish denominations, such as the Reform, Conservative, and Reconstructionist movements, are open to supporting ESC use or research as long as it is for saving a life. [64] Within Judaism, the Talmud, or study, gives personhood to the child at birth and emphasizes that life does not begin at conception: [65]

“If she is found pregnant, until the fortieth day it is mere fluid,” [66]

Whereas most religions prioritize the status of human embryos, the Halakah (Jewish religious law) states that to save one life, most other religious laws can be ignored because it is in pursuit of preservation. [67] Stem cell research is accepted due to application of these religious laws.

We recognize that all religions contain subsets and sects. The variety of environmental and cultural differences within religious groups requires further analysis to respect the flexibility of religious thoughts and practices. We make no presumptions that all cultures require notions of autonomy or morality as under the common morality theory , which asserts a set of universal moral norms that all individuals share provides moral reasoning and guides ethical decisions. [68] We only wish to show that the interaction with morality varies between cultures and countries.

III.     A Flexible Ethical Approach

The plurality of different moral approaches described above demonstrates that there can be no universally acceptable uniform law for ESC on a global scale. Instead of developing one standard, flexible ethical applications must be continued. We recommend local guidelines that incorporate important cultural and ethical priorities.

While the Declaration of Helsinki is more relevant to people in clinical trials receiving ESC products, in keeping with the tradition of protections for research subjects, consent of the donor is an ethical requirement for ESC donation in many jurisdictions including the US, Canada, and Europe. [69] The Declaration of Helsinki provides a reference point for regulatory standards and could potentially be used as a universal baseline for obtaining consent prior to gamete or embryo donation.

For instance, in Columbia University’s egg donor program for stem cell research, donors followed standard screening protocols and “underwent counseling sessions that included information as to the purpose of oocyte donation for research, what the oocytes would be used for, the risks and benefits of donation, and process of oocyte stimulation” to ensure transparency for consent. [70] The program helped advance stem cell research and provided clear and safe research methods with paid participants. Though paid participation or covering costs of incidental expenses may not be socially acceptable in every culture or context, [71] and creating embryos for ESC research is illegal in many jurisdictions, Columbia’s program was effective because of the clear and honest communications with donors, IRBs, and related stakeholders.  This example demonstrates that cultural acceptance of scientific research and of the idea that an egg or embryo does not have personhood is likely behind societal acceptance of donating eggs for ESC research. As noted, many countries do not permit the creation of embryos for research.

Proper communication and education regarding the process and purpose of stem cell research may bolster comprehension and garner more acceptance. “Given the sensitive subject material, a complete consent process can support voluntary participation through trust, understanding, and ethical norms from the cultures and morals participants value. This can be hard for researchers entering countries of different socioeconomic stability, with different languages and different societal values. [72]

An adequate moral foundation in medical ethics is derived from the cultural and religious basis that informs knowledge and actions. [73] Understanding local cultural and religious values and their impact on research could help researchers develop humility and promote inclusion.

IV.     Concerns

Some may argue that if researchers all adhere to one ethics standard, protection will be satisfied across all borders, and the global public will trust researchers. However, defining what needs to be protected and how to define such research standards is very specific to the people to which standards are applied. We suggest that applying one uniform guide cannot accurately protect each individual because we all possess our own perceptions and interpretations of social values. [74] Therefore, the issue of not adjusting to the moral pluralism between peoples in applying one standard of ethics can be resolved by building out ethics models that can be adapted to different cultures and religions.

Other concerns include medical tourism, which may promote health inequities. [75] Some countries may develop and approve products derived from ESC research before others, compromising research ethics or drug approval processes. There are also concerns about the sale of unauthorized stem cell treatments, for example, those without FDA approval in the United States. Countries with robust research infrastructures may be tempted to attract medical tourists, and some customers will have false hopes based on aggressive publicity of unproven treatments. [76]

For example, in China, stem cell clinics can market to foreign clients who are not protected under the regulatory regimes. Companies employ a marketing strategy of “ethically friendly” therapies. Specifically, in the case of Beike, China’s leading stem cell tourism company and sprouting network, ethical oversight of administrators or health bureaus at one site has “the unintended consequence of shifting questionable activities to another node in Beike's diffuse network.” [77] In contrast, Jordan is aware of stem cell research’s potential abuse and its own status as a “health-care hub.” Jordan’s expanded regulations include preserving the interests of individuals in clinical trials and banning private companies from ESC research to preserve transparency and the integrity of research practices. [78]

The social priorities of the community are also a concern. The ISSCR explicitly states that guidelines “should be periodically revised to accommodate scientific advances, new challenges, and evolving social priorities.” [79] The adaptable ethics model extends this consideration further by addressing whether research is warranted given the varying degrees of socioeconomic conditions, political stability, and healthcare accessibilities and limitations. An ethical approach would require discussion about resource allocation and appropriate distribution of funds. [80]

While some religions emphasize the sanctity of life from conception, which may lead to public opposition to ESC research, others encourage ESC research due to its potential for healing and alleviating human pain. Many countries have special regulations that balance local views on embryonic personhood, the benefits of research as individual or societal goods, and the protection of human research subjects. To foster understanding and constructive dialogue, global policy frameworks should prioritize the protection of universal human rights, transparency, and informed consent. In addition to these foundational global policies, we recommend tailoring local guidelines to reflect the diverse cultural and religious perspectives of the populations they govern. Ethics models should be adapted to local populations to effectively establish research protections, growth, and possibilities of stem cell research.

For example, in countries with strong beliefs in the moral sanctity of embryos or heavy religious restrictions, an adaptive model can allow for discussion instead of immediate rejection. In countries with limited individual rights and voice in science policy, an adaptive model ensures cultural, moral, and religious views are taken into consideration, thereby building social inclusion. While this ethical consideration by the government may not give a complete voice to every individual, it will help balance policies and maintain the diverse perspectives of those it affects. Embracing an adaptive ethics model of ESC research promotes open-minded dialogue and respect for the importance of human belief and tradition. By actively engaging with cultural and religious values, researchers can better handle disagreements and promote ethical research practices that benefit each society.

This brief exploration of the religious and cultural differences that impact ESC research reveals the nuances of relative ethics and highlights a need for local policymakers to apply a more intense adaptive model.

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[5] Concerning the moral philosophies of stem cell research, our paper does not posit a personal moral stance nor delve into the “when” of human life begins. To read further about the philosophical debate, consider the following sources:

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[7] Socially, at its core, the Western approach to ethics is widely principle-based, autonomy being one of the key factors to ensure a fundamental respect for persons within research. For information regarding autonomy in research, see: Department of Health, Education, and Welfare, & National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (1978). The Belmont Report. Ethical principles and guidelines for the protection of human subjects of research.; For a more in-depth review of autonomy within the US, see: Beauchamp, T. L., & Childress, J. F. (1994). Principles of Biomedical Ethics . Oxford University Press.

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[9] Stem Cell Research Enhancement Act of 2005, H. R. 810, 109 th Cong. (2001). https://www.govtrack.us/congress/bills/109/hr810/text ; Bush, G. W. (2006, July 19). Message to the House of Representatives . National Archives and Records Administration. https://georgewbush-whitehouse.archives.gov/news/releases/2006/07/20060719-5.html

[10] National Archives and Records Administration. (2009, March 9). Executive order 13505 -- removing barriers to responsible scientific research involving human stem cells . National Archives and Records Administration. https://obamawhitehouse.archives.gov/the-press-office/removing-barriers-responsible-scientific-research-involving-human-stem-cells

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[13] Source for further reading: Tangwa G. B. (2007). Moral status of embryonic stem cells: perspective of an African villager. Bioethics , 21(8), 449–457. https://doi.org/10.1111/j.1467-8519.2007.00582.x , see also Mnisi, F. M. (2020). An African analysis based on ethics of Ubuntu - are human embryonic stem cell patents morally justifiable? African Insight , 49 (4).

[14] Jecker, N. S., & Atuire, C. (2021). Bioethics in Africa: A contextually enlightened analysis of three cases. Developing World Bioethics , 22 (2), 112–122. https://doi.org/10.1111/dewb.12324

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[18] Oosthuizen, H. (2013). Legal and Ethical Issues in Stem Cell Research in South Africa. In: Beran, R. (eds) Legal and Forensic Medicine. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-32338-6_80 , see also: Gaobotse G (2018) Stem Cell Research in Africa: Legislation and Challenges. J Regen Med 7:1. doi: 10.4172/2325-9620.1000142

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[21] Kooli, C. Review of assisted reproduction techniques, laws, and regulations in Muslim countries.  Middle East Fertil Soc J   24 , 8 (2020). https://doi.org/10.1186/s43043-019-0011-0 ; Gaobotse, G. (2018) Stem Cell Research in Africa: Legislation and Challenges. J Regen Med 7:1. doi: 10.4172/2325-9620.1000142

[22] Pang M. C. (1999). Protective truthfulness: the Chinese way of safeguarding patients in informed treatment decisions. Journal of medical ethics , 25(3), 247–253. https://doi.org/10.1136/jme.25.3.247

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[36] Association for the Advancement of Blood and Biotherapies.  https://www.aabb.org/regulatory-and-advocacy/regulatory-affairs/regulatory-for-cellular-therapies/international-competent-authorities/saudi-arabia

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Culturally, autonomy practices follow a relational autonomy approach based on a paternalistic deontological health care model. The adherence to strict international research policies and religious pillars within the regulatory environment is a great foundation for research ethics. However, there is a need to develop locally targeted ethics approaches for research (as called for in Alahmad, G., Aljohani, S., & Najjar, M. F. (2020). Ethical challenges regarding the use of stem cells: interviews with researchers from Saudi Arabia. BMC medical ethics, 21(1), 35. https://doi.org/10.1186/s12910-020-00482-6), this decision-making approach may help advise a research decision model. For more on the clinical cultural autonomy approaches, see: Alabdullah, Y. Y., Alzaid, E., Alsaad, S., Alamri, T., Alolayan, S. W., Bah, S., & Aljoudi, A. S. (2022). Autonomy and paternalism in Shared decision‐making in a Saudi Arabian tertiary hospital: A cross‐sectional study. Developing World Bioethics , 23 (3), 260–268. https://doi.org/10.1111/dewb.12355 ; Bukhari, A. A. (2017). Universal Principles of Bioethics and Patient Rights in Saudi Arabia (Doctoral dissertation, Duquesne University). https://dsc.duq.edu/etd/124; Ladha, S., Nakshawani, S. A., Alzaidy, A., & Tarab, B. (2023, October 26). Islam and Bioethics: What We All Need to Know . Columbia University School of Professional Studies. https://sps.columbia.edu/events/islam-and-bioethics-what-we-all-need-know

[39] Ababneh, M. A., Al-Azzam, S. I., Alzoubi, K., Rababa’h, A., & Al Demour, S. (2021). Understanding and attitudes of the Jordanian public about clinical research ethics.  Research Ethics ,  17 (2), 228-241.  https://doi.org/10.1177/1747016120966779

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[43] The EU’s definition of autonomy relates to the capacity for creating ideas, moral insight, decisions, and actions without constraint, personal responsibility, and informed consent. However, the EU views autonomy as not completely able to protect individuals and depends on other principles, such as dignity, which “expresses the intrinsic worth and fundamental equality of all human beings.” Rendtorff, J.D., Kemp, P. (2019). Four Ethical Principles in European Bioethics and Biolaw: Autonomy, Dignity, Integrity and Vulnerability. In: Valdés, E., Lecaros, J. (eds) Biolaw and Policy in the Twenty-First Century. International Library of Ethics, Law, and the New Medicine, vol 78. Springer, Cham. https://doi.org/10.1007/978-3-030-05903-3_3

[44] Council of Europe. Convention for the protection of Human Rights and Dignity of the Human Being with regard to the Application of Biology and Medicine: Convention on Human Rights and Biomedicine (ETS No. 164) https://www.coe.int/en/web/conventions/full-list?module=treaty-detail&treatynum=164 (forbidding the creation of embryos for research purposes only, and suggests embryos in vitro have protections.); Also see Drabiak-Syed B. K. (2013). New President, New Human Embryonic Stem Cell Research Policy: Comparative International Perspectives and Embryonic Stem Cell Research Laws in France.  Biotechnology Law Report ,  32 (6), 349–356. https://doi.org/10.1089/blr.2013.9865

[45] Rendtorff, J.D., Kemp, P. (2019). Four Ethical Principles in European Bioethics and Biolaw: Autonomy, Dignity, Integrity and Vulnerability. In: Valdés, E., Lecaros, J. (eds) Biolaw and Policy in the Twenty-First Century. International Library of Ethics, Law, and the New Medicine, vol 78. Springer, Cham. https://doi.org/10.1007/978-3-030-05903-3_3

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[47] Regulation of Stem Cell Research in Germany . Eurostemcell. (2017, April 26). https://www.eurostemcell.org/regulation-stem-cell-research-germany

[48] Regulation of Stem Cell Research in Finland . Eurostemcell. (2017, April 26). https://www.eurostemcell.org/regulation-stem-cell-research-finland

[49] Regulation of Stem Cell Research in Spain . Eurostemcell. (2017, April 26). https://www.eurostemcell.org/regulation-stem-cell-research-spain

[50] Some sources to consider regarding ethics models or regulatory oversights of other cultures not covered:

Kara MA. Applicability of the principle of respect for autonomy: the perspective of Turkey. J Med Ethics. 2007 Nov;33(11):627-30. doi: 10.1136/jme.2006.017400. PMID: 17971462; PMCID: PMC2598110.

Ugarte, O. N., & Acioly, M. A. (2014). The principle of autonomy in Brazil: one needs to discuss it ...  Revista do Colegio Brasileiro de Cirurgioes ,  41 (5), 374–377. https://doi.org/10.1590/0100-69912014005013

Bharadwaj, A., & Glasner, P. E. (2012). Local cells, global science: The rise of embryonic stem cell research in India . Routledge.

For further research on specific European countries regarding ethical and regulatory framework, we recommend this database: Regulation of Stem Cell Research in Europe . Eurostemcell. (2017, April 26). https://www.eurostemcell.org/regulation-stem-cell-research-europe   

[51] Klitzman, R. (2006). Complications of culture in obtaining informed consent. The American Journal of Bioethics, 6(1), 20–21. https://doi.org/10.1080/15265160500394671 see also: Ekmekci, P. E., & Arda, B. (2017). Interculturalism and Informed Consent: Respecting Cultural Differences without Breaching Human Rights.  Cultura (Iasi, Romania) ,  14 (2), 159–172.; For why trust is important in research, see also: Gray, B., Hilder, J., Macdonald, L., Tester, R., Dowell, A., & Stubbe, M. (2017). Are research ethics guidelines culturally competent?  Research Ethics ,  13 (1), 23-41.  https://doi.org/10.1177/1747016116650235

[52] The Qur'an  (M. Khattab, Trans.). (1965). Al-Mu’minun, 23: 12-14. https://quran.com/23

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[54] Aksoy, S. (2005). Making regulations and drawing up legislation in Islamic countries under conditions of uncertainty, with special reference to embryonic stem cell research. Journal of Medical Ethics , 31: 399-403.; see also: Mahmoud, Azza. "Islamic Bioethics: National Regulations and Guidelines of Human Stem Cell Research in the Muslim World." Master's thesis, Chapman University, 2022. https://doi.org/10.36837/ chapman.000386

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[58] Lecso, P. A. (1991). The Bodhisattva Ideal and Organ Transplantation.  Journal of Religion and Health ,  30 (1), 35–41. http://www.jstor.org/stable/27510629 ; Bodhisattva, S. (n.d.). The Key of Becoming a Bodhisattva . A Guide to the Bodhisattva Way of Life. http://www.buddhism.org/Sutras/2/BodhisattvaWay.htm

[59] There is no explicit religious reference to when life begins or how to conduct research that interacts with the concept of life. However, these are relevant verses pertaining to how the fetus is viewed. (( King James Bible . (1999). Oxford University Press. (original work published 1769))

Jerimiah 1: 5 “Before I formed thee in the belly I knew thee; and before thou camest forth out of the womb I sanctified thee…”

In prophet Jerimiah’s insight, God set him apart as a person known before childbirth, a theme carried within the Psalm of David.

Psalm 139: 13-14 “…Thou hast covered me in my mother's womb. I will praise thee; for I am fearfully and wonderfully made…”

These verses demonstrate David’s respect for God as an entity that would know of all man’s thoughts and doings even before birth.

[60] It should be noted that abortion is not supported as well.

[61] The Vatican. (1987, February 22). Instruction on Respect for Human Life in Its Origin and on the Dignity of Procreation Replies to Certain Questions of the Day . Congregation For the Doctrine of the Faith. https://www.vatican.va/roman_curia/congregations/cfaith/documents/rc_con_cfaith_doc_19870222_respect-for-human-life_en.html

[62] The Vatican. (2000, August 25). Declaration On the Production and the Scientific and Therapeutic Use of Human Embryonic Stem Cells . Pontifical Academy for Life. https://www.vatican.va/roman_curia/pontifical_academies/acdlife/documents/rc_pa_acdlife_doc_20000824_cellule-staminali_en.html ; Ohara, N. (2003). Ethical Consideration of Experimentation Using Living Human Embryos: The Catholic Church’s Position on Human Embryonic Stem Cell Research and Human Cloning. Department of Obstetrics and Gynecology . Retrieved from https://article.imrpress.com/journal/CEOG/30/2-3/pii/2003018/77-81.pdf.

[63] Smith, G. A. (2022, May 23). Like Americans overall, Catholics vary in their abortion views, with regular mass attenders most opposed . Pew Research Center. https://www.pewresearch.org/short-reads/2022/05/23/like-americans-overall-catholics-vary-in-their-abortion-views-with-regular-mass-attenders-most-opposed/

[64] Rosner, F., & Reichman, E. (2002). Embryonic stem cell research in Jewish law. Journal of halacha and contemporary society , (43), 49–68.; Jafari, M., Elahi, F., Ozyurt, S. & Wrigley, T. (2007). 4. Religious Perspectives on Embryonic Stem Cell Research. In K. Monroe, R. Miller & J. Tobis (Ed.),  Fundamentals of the Stem Cell Debate: The Scientific, Religious, Ethical, and Political Issues  (pp. 79-94). Berkeley: University of California Press.  https://escholarship.org/content/qt9rj0k7s3/qt9rj0k7s3_noSplash_f9aca2e02c3777c7fb76ea768ba458f0.pdf https://doi.org/10.1525/9780520940994-005

[65] Schenker J. G. (2008). The beginning of human life: status of embryo. Perspectives in Halakha (Jewish Religious Law).  Journal of assisted reproduction and genetics ,  25 (6), 271–276. https://doi.org/10.1007/s10815-008-9221-6

[66] Ruttenberg, D. (2020, May 5). The Torah of Abortion Justice (annotated source sheet) . Sefaria. https://www.sefaria.org/sheets/234926.7?lang=bi&with=all&lang2=en

[67] Jafari, M., Elahi, F., Ozyurt, S. & Wrigley, T. (2007). 4. Religious Perspectives on Embryonic Stem Cell Research. In K. Monroe, R. Miller & J. Tobis (Ed.),  Fundamentals of the Stem Cell Debate: The Scientific, Religious, Ethical, and Political Issues  (pp. 79-94). Berkeley: University of California Press.  https://escholarship.org/content/qt9rj0k7s3/qt9rj0k7s3_noSplash_f9aca2e02c3777c7fb76ea768ba458f0.pdf https://doi.org/10.1525/9780520940994-005

[68] Gert, B. (2007). Common morality: Deciding what to do . Oxford Univ. Press.

[69] World Medical Association (2013). World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA , 310(20), 2191–2194. https://doi.org/10.1001/jama.2013.281053 Declaration of Helsinki – WMA – The World Medical Association .; see also: National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. (1979).  The Belmont report: Ethical principles and guidelines for the protection of human subjects of research . U.S. Department of Health and Human Services.  https://www.hhs.gov/ohrp/regulations-and-policy/belmont-report/read-the-belmont-report/index.html

[70] Zakarin Safier, L., Gumer, A., Kline, M., Egli, D., & Sauer, M. V. (2018). Compensating human subjects providing oocytes for stem cell research: 9-year experience and outcomes.  Journal of assisted reproduction and genetics ,  35 (7), 1219–1225. https://doi.org/10.1007/s10815-018-1171-z https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6063839/ see also: Riordan, N. H., & Paz Rodríguez, J. (2021). Addressing concerns regarding associated costs, transparency, and integrity of research in recent stem cell trial. Stem Cells Translational Medicine , 10 (12), 1715–1716. https://doi.org/10.1002/sctm.21-0234

[71] Klitzman, R., & Sauer, M. V. (2009). Payment of egg donors in stem cell research in the USA.  Reproductive biomedicine online ,  18 (5), 603–608. https://doi.org/10.1016/s1472-6483(10)60002-8

[72] Krosin, M. T., Klitzman, R., Levin, B., Cheng, J., & Ranney, M. L. (2006). Problems in comprehension of informed consent in rural and peri-urban Mali, West Africa.  Clinical trials (London, England) ,  3 (3), 306–313. https://doi.org/10.1191/1740774506cn150oa

[73] Veatch, Robert M.  Hippocratic, Religious, and Secular Medical Ethics: The Points of Conflict . Georgetown University Press, 2012.

[74] Msoroka, M. S., & Amundsen, D. (2018). One size fits not quite all: Universal research ethics with diversity.  Research Ethics ,  14 (3), 1-17.  https://doi.org/10.1177/1747016117739939

[75] Pirzada, N. (2022). The Expansion of Turkey’s Medical Tourism Industry.  Voices in Bioethics ,  8 . https://doi.org/10.52214/vib.v8i.9894

[76] Stem Cell Tourism: False Hope for Real Money . Harvard Stem Cell Institute (HSCI). (2023). https://hsci.harvard.edu/stem-cell-tourism , See also: Bissassar, M. (2017). Transnational Stem Cell Tourism: An ethical analysis.  Voices in Bioethics ,  3 . https://doi.org/10.7916/vib.v3i.6027

[77] Song, P. (2011) The proliferation of stem cell therapies in post-Mao China: problematizing ethical regulation,  New Genetics and Society , 30:2, 141-153, DOI:  10.1080/14636778.2011.574375

[78] Dajani, R. (2014). Jordan’s stem-cell law can guide the Middle East.  Nature  510, 189. https://doi.org/10.1038/510189a

[79] International Society for Stem Cell Research. (2024). Standards in stem cell research . International Society for Stem Cell Research. https://www.isscr.org/guidelines/5-standards-in-stem-cell-research

[80] Benjamin, R. (2013). People’s science bodies and rights on the Stem Cell Frontier . Stanford University Press.

Mifrah Hayath

SM Candidate Harvard Medical School, MS Biotechnology Johns Hopkins University

Olivia Bowers

MS Bioethics Columbia University (Disclosure: affiliated with Voices in Bioethics)

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• Volume 16, issue 5
• ESSD, 16, 2385–2405, 2024
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Brazilian Atmospheric Inventories – BRAIN: a comprehensive database of air quality in Brazil

Leonardo hoinaski, robson will, camilo bastos ribeiro.

Developing air quality management systems to control the impacts of air pollution requires reliable data. However, current initiatives do not provide datasets with large spatial and temporal resolutions for developing air pollution policies in Brazil. Here, we introduce the Brazilian Atmospheric Inventories (BRAIN), the first comprehensive database of air quality and its drivers in Brazil. BRAIN encompasses hourly datasets of meteorology, emissions, and air quality. The emissions dataset includes vehicular emissions derived from the Brazilian Vehicular Emissions Inventory Software (BRAVES), industrial emissions produced with local data from the Brazilian environmental agencies, biomass burning emissions from FINN – Fire INventory from the National Center for Atmospheric Research (NCAR), and biogenic emissions from the Model of Emissions of Gases and Aerosols from Nature (MEGAN) ( https://doi.org/10.57760/sciencedb.09858 , Hoinaski et al., 2023a; https://doi.org/10.57760/sciencedb.09886 , Hoinaski et al., 2023b). The meteorology dataset has been derived from the Weather Research and Forecasting Model (WRF) ( https://doi.org/10.57760/sciencedb.09857 , Hoinaski and Will, 2023a; https://doi.org/10.57760/sciencedb.09885 , Hoinaski and Will, 2023c). The air quality dataset contains the surface concentration of 216 air pollutants produced from coupling meteorological and emissions datasets with the Community Multiscale Air Quality Modeling System (CMAQ) ( https://doi.org/10.57760/sciencedb.09859 , Hoinaski and Will, 2023b; https://doi.org/10.57760/sciencedb.09884 , Hoinaski and Will, 2023d). We provide gridded data in two domains, one covering the Brazilian territory with 20×20  km spatial resolution and another covering southern Brazil with 4×4  km spatial resolution. This paper describes how the datasets were produced, their limitations, and their spatiotemporal features. To evaluate the quality of the database, we compare the air quality dataset with 244 air quality monitoring stations, providing the model's performance for each pollutant measured by the monitoring stations. We present a sample of the spatial variability of emissions, meteorology, and air quality in Brazil from 2019, revealing the hotspots of emissions and air pollution issues. By making BRAIN publicly available, we aim to provide the required data for developing air quality policies on municipal and state scales, especially for under-developed and data-scarce municipalities. We also envision that BRAIN has the potential to create new insights into and opportunities for air pollution research in Brazil.​​​​​​​

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Hoinaski, L., Will, R., and Ribeiro, C. B.: Brazilian Atmospheric Inventories – BRAIN: a comprehensive database of air quality in Brazil, Earth Syst. Sci. Data, 16, 2385–2405, https://doi.org/10.5194/essd-16-2385-2024, 2024.

It is consensus that air pollution threatens public health (OECD, 2024), economic progress (OECD, 2016), and climate (US EPA, 2023a). The negative outcomes associated with air pollution are not uniform within populations, and the impacts may be greater for more susceptible and exposed individuals (Makri and Stilianakis, 2008). Due to their social vulnerability and increasing emissions, developing countries urgently require reliable databases to provide information for designing air quality management systems to control air pollution (Sant'Anna et al., 2021).

Brazil has continental dimensions, is the seventh most populous country in the world, and has the 12th largest gross domestic product (IBGE, 2024). The combination of poorly planned development and the huge socioeconomic discrepancy has led to air quality impacts in Brazil. Air-pollution-related problems are not only restricted to great Brazilian cities and industrialized areas. Vehicular fleets and fuel consumption have also increased in small municipalities (CEIC, 2021; MME, 2023), posing a challenge to controlling vehicular emissions. In preserved and rural areas, large fire emissions have occurred due to illegal deforestation and poor soil management (Escobar, 2019; Rajão et al., 2020).

Following the practices of developed countries, Brazilian air quality policies have been enforced through legislative laws, using air quality standards as key components. However, the air quality management system remains incomplete in Brazil, with policies falling short of effectiveness due to a lack of air quality monitoring data across much of the country, primarily limited to well-developed areas (Sant'Anna et al., 2021). Moreover, Brazilian environmental agencies have not provided enough data and guidance to permit progress. Air quality consultants are still struggling to find mandatory inputs to understand and predict air quality for regulatory purposes. Efforts toward the permanent improvement of high-spatiotemporal-resolution emissions inventories and of meteorological and air quality data are needed.

An effective air quality management system must provide data to determine what emission reductions are needed to achieve the air quality standards (US EPA, 2023b). It requires air quality monitoring, a robust and detailed emissions inventory, reliable meteorological datasets, and methodologies to adapt the state-of-the-art air quality models to Brazil's reality. Moreover, it is crucial to undertake ongoing evaluation and to fully understand the air quality problem to design and implement the programs for pollution control. Currently, available initiatives including reanalysis and satellite products are still not providing datasets with large spatial and temporal resolutions for developing air pollution policies in Brazil. Global reanalyses such as the Copernicus Atmospheric Monitoring Service (CAMS) (Inness et al., 2019) and the second version of the Modern-Era Retrospective Analysis for Research and Applications (MERRA-2) (GMAO, 2015a, b) can provide estimates of air pollutants by combining chemical transport models (CTMs) with satellite and ground-based observations and physical information, assimilating data to constrain the results. However, the currently available reanalysis products do not provide data with high spatial resolution (up to 0.75°  ×  0.75° and 0.5°  ×  0.625°) and could be biased toward representing local and regional air quality (Arfan Ali et al., 2022). Moreover, they provide data for only a small list of air pollutants. Satellite-based products such as Sentinel-5P TROPOMI (Veefkind et al., 2012) and the Moderate-Resolution Imaging Spectroradiometer (MODIS) (Levy et al., 2015; Platnick et al., 2015) are still challenging due to their low temporal resolution, data gaps due to cloud coverage, and uncertainties (Shin et al., 2020). Besides, satellites rely on total tropospheric column measurements, which do not represent surface concentrations (Shin et al., 2019).

In this article, we present the Brazilian Atmospheric Inventories (BRAIN), the first comprehensive database to elaborate upon air quality management systems in Brazil. BRAIN combines local inventories, consolidated datasets, and the usage of internationally recommended models to provide hourly emissions and meteorological and air quality data covering the entire country.

Figure 1 Spatial distribution of CO emissions from (a) vehicles, (b) industries, (c) biomass burning, and (d) biogenic sources, as provided by BRAIN.

BRAIN contains three types of hourly datasets: emissions, meteorology, and air quality. The emissions inventories include vehicular, industrial, biogenic, and biomass burning emissions. We provide meteorological data derived from the Weather Research and Forecasting (WRF) model. Coupling emissions, WRF, and the Community Multiscale Air Quality Modeling System (CMAQ) version 5.3.2, we provide air quality gridded data. All datasets are available on two spatial resolutions: the largest (Fig. S1 in the Supplement – d01) covers the entire country, while the smallest covers southern Brazil (Fig. S1 – d02). The BRAIN datasets in d01 are freely available at https://doi.org/10.57760/sciencedb.09858 (Hoinaski et al., 2023a), https://doi.org/10.57760/sciencedb.09857 (Hoinaski and Will, 2023a), and https://doi.org/10.57760/sciencedb.09859 (Hoinaski and Will, 2023b). The BRAIN datasets in d02 are available at https://doi.org/10.57760/sciencedb.09886 (Hoinaski et al., 2023b), https://doi.org/10.57760/sciencedb.09885 (Hoinaski and Will, 2023c), and https://doi.org/10.57760/sciencedb.09884 (Hoinaski and Will, 2023d). The Federal University of Santa Catarina (UFSC) institutional repository, https://brain.ens.ufsc.br/ (last access: 8 May 2024​​​​​​​), and the web platform, https://hoinaski.prof.ufsc.br/BRAIN/ (last access: 8 May 2024​​​​​​​), have served the BRAIN database since 2019. We envision making available more detailed datasets for other Brazilian regions, especially in the southeast, where the anthropogenic emission effects are more prominent. Future versions will also provide more detailed modeling outputs to properly cover medium- and small-sized cities.

BRAIN is intended to fill the gaps in those cases where adequately representative monitoring data to characterize the air quality are not available. BRAIN would be useful in providing background concentrations for a good procedure for licensing new sources of air pollution.

2.1  Emissions inventory

The BRAIN emissions inventory allows the spatiotemporal analysis of vehicular, industrial, biomass burning, and biogenic emissions in Brazil. The present version of this database does not account for other South American countries' emissions, apart from biomass burning and biogenic sources. We envision implementing other sources and a more detailed emissions inventory from other South American countries in a future version. Figure 1 presents a sample of the inventory, showing the annual carbon monoxide (CO) emissions by source. Section S2 in the Supplement (Table S1) summarizes the species in each emission source inventory. More information on each emissions dataset can be found in Sect. 2.1.1 to 2.1.5.

We observed higher vehicular emission rates of CO in urban areas with large population and vehicle fleet densities, mainly in the south and southeast (Fig. 1a). High industrial emission rates have been detected in the Brazilian regions, with large stationary sources such as refining units, thermoelectric power plants, and cement and paper industries (Fig. 1b) (Kawashima et al., 2020). In general, the north shows a higher concentration of biogenic and fire emissions. While the hotspots of biogenic emissions are predominately in the extreme north, the hotspots of fire emissions turn up in the midwestern, northern, and southern regions, as well as on the Brazilian western border (Fig. 1c–d).

2.1.1  Vehicular emissions

BRAIN uses the multispecies and high-spatiotemporal-resolution database of vehicular emissions from the Brazilian Vehicular Emission Inventory Software (BRAVES) (Hoinaski et al., 2022; Vasques and Hoinaski, 2021). The BRAVES database disaggregates municipality-aggregated emissions using the road density approach and temporal disaggregation based on vehicular flow profiles. SPECIATE 5.1 (Eyth et al., 2020) from the United States Environmental Protection Agency (USEPA, https://www.epa.gov/air-emissions-modeling/speciate , last access: 8 May 2024) speciates conventional pollutants in 41 species. BRAVES considers local studies (Nogueira et al., 2015) and data from Companhia Ambiental do Estado de São Paulo (CETESB) ( https://cetesb.sp.gov.br/veicular/relatorios-e-publicacoes/ , last access: 8 May 2024) to speciate acetaldehydes, formaldehyde, ethanol, and aldehydes in order to account for biofuel particularities in Brazil.

In BRAVES, vehicular activity is defined by fuel consumption in each municipality using data provided by the Brazilian National Agency for Oil, Natural Gas and Biofuel (ANP) ( https://www.gov.br/anp/pt-br/centrais-de-conteudo/dados-abertos/vendas-de-derivados-de-petroleo-e-biocombustiveis , last access: 8 May 2024). A fraction of fuel consumed by road transportation is based on data from the National Energy Balance (BEN) ( https://www.epe.gov.br/pt/publicacoes-dados-abertos/publicacoes/balanco-energetico-nacional-ben , last access: 8 May 2024), and MMA (2014). BRAVES calculates the weighted emission factor (EF) to address the effect of the fleet composition in terms of category, model year, and fuel utilization.

Vasques and Hoinaski (2021) compared BRAVES with different vehicular emission inventories from a local to national scale. On a national scale, vehicular emission rates from BRAVES underestimate the Emission Database for Global Atmospheric Research (EDGAR) and are slightly higher for CO (14 %) and non-methane volatile organic compounds (NMVOCs) (9 %) compared with the national inventory from Ministério do Meio Ambiente (MMA). The differences between estimates from BRAVES and from well-developed state inventories vary from −1  % to 35 % in São Paulo and from −2  % to 52 % in Minas Gerais. In addition, a relatively small bias between BRAVES and the Vehicular Emission Inventory (VEIN) was observed in São Paulo and Vale do Paraiba (Vasques and Hoinaski, 2021).

2.1.2  Industrial emissions

We derived the industrial emissions inventory by combining data from the state environmental agencies of Espírito Santo, Minas Gerais, and Santa Catarina. The emission rates of point sources from Espírito Santo and Minas Gerais are publicly provided by Instituto de Meio Ambiente e Recursos Hídricos do Espírito Santo (IEMA-ES) ( https://iema.es.gov.br/qualidadedoar/inventariodefontes , last access: 8 May 2024) and Fundação Estadual de Meio Ambiente (FEAM) ( http://www.feam.br/qualidade-do-ar/emissao-de-fontes-fixas , last access: 8 May 2024). Data from IEMA-ES contain emissions from the metropolitan region of Vitória from 2015, compiling measurements from regulatory procedures and emissions estimates. We did not convert the emissions inventory to the current modeling year since the data are not continuously updated. Therefore, we assumed that all emissions from these sources occurred in 2019.

In Santa Catarina, industrial emission data have been provided by Instituto de Meio Ambiente (IMA) ( https://www.ima.sc.gov.br/index.php , last access: 8 May 2024). These data are collected in the licensing process of potentially polluting industries. The base year of emission rates varies according to the availability. Summary information about the industrial sector types, the number of industries, and the respective emission rates in Santa Catarina can be found in Hoinaski et al. (2020) and at https://github.com/leohoinaski/IND_Inventory/blob/main/Inputs/BR_Ind.xlsx (last access: 8 May 2024​​​​​​​). Emissions from large stationary sources (refining units, thermoelectric power plants, cement, and paper industries) provided by Kawashima et al. (2020) have been included when not encountered in the environmental agencies' inventories.

We chemically speciated the industrial emission rates by adopting the following steps: (i) grouping each point source using the same categories as in the Emission Database for Global Atmospheric Research (EDGAR) (Crippa et al., 2018) and the Intergovernmental Panel on Climate Change (IPCC) industrial segments, (ii) selecting compatible profiles in SPECIATE 5.1 for each group (Eyth et al., 2020), (iii) averaging the speciation factor by group and pollutant, and (iv) applying the speciation factor for the targeted pollutant (PM, NO x , VOCs). The SPECIATE 5.1 profiles used in this work are listed at https://github.com/leohoinaski/IND_Inventory/tree/main/IndustrialSpeciation (last access: 8 May 2024​​​​​​​). The speciation factors by industrial group and pollutant are available at https://github.com/leohoinaski/IND_Inventory/blob/main/IndustrialSpeciation/IND_speciation.csv (last access: 8 May 2024​​​​​​​).

We also vertically allocate the industrial emissions according to the plume's effective height, estimated by the sum of the geometric height and the superelevation of the plume. The plume superelevation was estimated by the Briggs method (Briggs, 1975, 1969). The initial vertical distribution of the plume has been estimated by disaggregating the emissions using a Gaussian approach, as proposed in the Sparse Matrix Operator Kernel Emissions (SMOKE) model (Bieser et al., 2011; Gordon et al., 2018; Guevara et al., 2014). Python code to estimate the plume's effective height and the initial vertical disaggregation of industrial emissions is available at https://doi.org/10.5281/zenodo.11167115 (Hoinaski, 2024a​​​​​​​).

Figure 2 Annual average of meteorological variables in 2019, simulated by the WRF with 20  ×  20 km resolution. (a) Atmospheric pressure, (b) planetary boundary layer height, (c) specific humidity, (d) annual accumulated precipitation, (e) temperature, (f) wind intensity and direction. All variables are annual averages except for precipitation, which represents the annual accumulated total.

2.1.3  Biomass burning emissions

The Fire INventory from NCAR (FINN) version 1.5 (Wiedinmyer et al., 2011) provides data on biomass burning emissions in BRAIN. FINN outputs contain daily emissions of trace gas and particle emissions from wildfires, agricultural fires, and prescribed burnings and do not include biofuel use and trash burning. Datasets have a 1 km spatial resolution and are available at https://www.acom.ucar.edu/Data/fire/ (last access: 8 May 2024​​​​​​​).

Since CMAQ requires hourly emissions, a Python code ( https://github.com/barronh/finn2cmaq , last access: 8 May 2024) temporally disaggregates daily emissions into hourly emissions. The same code vertically splits the fire emissions to consider the plume rise effect and represents the vertical distribution (Henderson, 2022), converting text files into hourly 3D netCDF files.

Pereira et al. (2016) suggest that fire emissions estimated by FINN are strongly related to deforestation in many Brazilian regions. FINN estimates have a high correlation with both the Brazilian Biomass Burning Emission Model (3BEM) (0.86) and the Global Fire Assimilation System (GFAS) (0.84). The emissions estimated from FINN are commonly overestimated in comparison to other biomass burning emission inventories. An overestimation also occurs when FINN is used in air quality models and compared with observations. However, the use of FINN as input in air quality models can capture the temporal variability of pollutants emitted by biomass burning (Vongruang et al., 2017).

We have implemented the FINN v1.5 in this first version of BRAIN. However, FINN version 2.5 (Wiedinmyer et al., 2023) will be included in our emissions inventory in future work; this version uses an updated algorithm for determining fire size based on MODIS and Visible Infrared Imaging Radiometer Suite (VIIRS) satellite instruments. We also provide data from 2020 with the same modeling grid upgraded to FINN v2.5.

Figure 3 Spatial distribution of air pollutant concentration (a, c, e) and number of violations of air quality standards (b, d, f) for NO 2 (a–b) , O 3 (c–d) , and PM 10 (e–f) .

2.1.4  Biogenic emissions

We derived the biogenic emissions using the Model of Emissions of Gases and Aerosols from Nature (MEGAN) version 3.2 (Guenther et al., 2012; Silva et al., 2020). MEGAN is based on the leaf area index and plant functional groups. The model estimates emissions of gases and aerosols for different meteorological conditions and land cover types (Guenther et al., 2012). The leaf-level temperature and photosynthetically active radiation, as well as the vegetative stress conditions implemented in MEGAN, provide more physically realistic parameterizations for biosphere–atmosphere interactions (Silva et al., 2020). Input datasets, emission factor processors, and emission estimation modules are available at https://bai.ess.uci.edu/megan/data-and-code (last access: 8 May 2024​​​​​​​). Data from WRF and the Meteorology-Chemistry Interface Processor (MCIP) have been used in MEGAN simulations.

MEGAN is commonly adopted to estimate emissions from biogenic fluxes, which constitute an important input for air quality modeling in many regions worldwide (Hogrefe et al., 2011; Kitagawa et al., 2022; Kota et al., 2015). Although MEGAN overestimates nighttime biogenic fluxes, the modeled emissions are correlated with measurements in the Amazon during both wet and dry seasons. The model is capable of capturing relatively well the seasonal variability of important organic pollutants in tropical forests (Sindelarova et al., 2014).

2.1.5  Sea spray aerosol emissions

Sea spray aerosol (SSA) is an important source of particles in the atmosphere. Due to its properties, SSA influences gas–particle partitioning in coastal environments (Gantt et al., 2015). SSA has been implemented in CMAQ as an inline source and requires the input of an ocean mask file (OCEAN) to identify the fractional coverage in each model grid cell allocated to the open ocean (OPEN) or surf zone (SURF). CMAQ uses this coverage information to calculate sea spray emission fluxes from the model's grid cells (US EPA, 2022). Detailed information on the mechanism of sea spray aerosol emissions and its implementation in CMAQ can be found in Gantt et al. (2015).

We provide a Python code ( https://github.com/leohoinaski/CMAQrunner/blob/master/hoinaskiSURFZONEv2.py , last access: 8 May 2024) to reproduce the OCEAN time-independent Input/Output Applications Programming Interface (I/O API) ( https://www.cmascenter.org/ioapi/ , last access: 8 May 2024) file so that it is ready to use in CMAQ. This code uses a shoreline Environmental Systems Research Institute (ESRI) shapefile from the National Oceanic and Atmospheric Administration (NOAA), available at https://www.ngdc.noaa.gov/mgg/shorelines/ (last access: 8 May 2024​​​​​​​).

Figure 4 Spearman rank, bias, root mean squared error (RMSE), and mean absolute error (MAE) of O 3 dataset of BRAIN vs. observed values. Box plots of statistical metric by Brazilian state (considering only states with monitoring stations with representative data in 2019).

2.2  Meteorology

The WRF model has been used in this work to produce inputs for CMAQ and for meteorology characterization in Brazil. We provide hourly simulations in netCDF files. WRF has been set up to reproduce 36 h simulations, where the initial 12 h have been dedicated to model stabilization; these are excluded from the analysis. Thirty-three vertical levels have been employed, spaced at 50 hPa intervals. The parameterizations used in this work are described in Sect. S3. The remaining vertical levels followed a hybrid modeling scheme, accounting for terrain in the lower layers and gradually minimizing its influence at the higher levels. Details of WRF outputs can be found in Sect. S4 (Table S2).

The Global Forecast System (GFS) from the National Center for Atmospheric Research (NCAR) provided inputs with a spatial resolution of 0.25°  ×  0.25° and a temporal resolution of 6 h for the WRF simulations (Skamarock et al., 2008). Land use data and classification parameters are from the United States Geological Survey's (USGS) Moderate Resolution Imaging Spectroradiometer (MODIS).

Figure 5 Time series of O 3 and PM 10 modeled and measured at Limeira  (a, c, e) and CIPP  (b, d, f) monitoring stations.

Figure 6 Annual average concentration of CO from BRAIN with its original resolution (a) , from BRAIN regridded to MERRA-2 resolution (b) , and from MERRA-2 (c) and the difference between MERRA-2 and BRAIN (d) .

Table 1 BRAIN datasets freely available.

Download Print Version | Download XLSX

The Brazilian regions (north, northeast, midwest, southeast, and south) encompass three distinct climatic zones, namely the equatorial, tropical, and subtropical zones. The climatic diversity in Brazil is also shaped by topographical variations, landscape or vegetation, and the coastal areas. The temperature in Brazil follows a latitudinal pattern, increasing from south to north (Fig. 2e). The highest average temperatures are observed in the Amazon region, matching the historic data (Cavalcanti, 2016). The southern region exhibits the lowest average temperatures, which is also consistent with historical data (Cavalcanti, 2016).

The highest values of atmospheric pressure occurred in the northern region and in the extreme south of the country, and the lowest values were between the southeastern and southern regions (Fig. 2a). The planetary boundary layer height (PBLH) reaches the highest levels in the northeastern region and the lowest levels at the southern and southeastern coasts (Fig. 2b). The highest values of wind speed occurred in part of the northern and southern region. The Amazon region presented the lowest values of surface wind speed (Fig. 2f).

Humidity and precipitation exhibit similar patterns in the northern and northeastern regions (Fig. 2c, d) due to the trade winds that transport moisture from the tropical Atlantic (Mendonça and Danni-Oliveira, 2017). Except for the coast, the northeastern region is characterized by low humidity and drought during half of the year. The southern and southeastern regions have well-distributed rainfall throughout the year, as well as intermediate levels of humidity, except for the northern coast of the southern region, which has an elevated level of precipitation and humidity throughout the year.

The WRF model demonstrated the ability to reproduce diurnal and seasonal variability in winds in the Brazilian northeastern region (Souza et al., 2022a), although it underestimated the height of the planetary boundary layer (PBLH) by up to 20 %, as well as the temperature and humidity at 4 °C and 15 %, respectively. Pedruzzi et al. (2022) tested several model configurations, including an alternative land use scheme, and found a WRF tendency to overestimate temperature and humidity in the Brazilian southeastern region. Macedo et al. (2016) also evaluated the model's ability to predict extreme precipitation events. Although the WRF reasonably predicts the main meteorological aspects of the Brazilian southern region, the precipitation extremes were underestimated. A wind mapping study (Souza et al., 2022b) using WRF indicated that the average errors presented by the model in Brazil are minor, with an average bias of 2 m s −1 at 200 m in terms of wind intensity and errors at temperatures of 2 °C and humidity of approximately 10 %. Winds at lower levels tended to be overestimated, whereas PBLH was generally underestimated during the day.

Figure 7 Concentration of CO from BRAIN vs. MERRA-2 in Brazil (a) , northern Brazil (b) , northeastern Brazil (c) , midwestern Brazil (d) , southeastern Brazil (e) , and southern Brazil (f) .

2.3  Air quality

We coupled emissions inventories, WRF, and CMAQ to produce the BRAIN air quality dataset for Brazil. CMAQ version 5.3.2 was set up using the third version of the Carbon Bond 6 chemical mechanism (cb6r3_ae7_aq) (Yarwood et al., 2010; Emery et al., 2015) with AERO7 treatment of secondary organic aerosol for standard cloud chemistry (Appel et al., 2021). The other model configurations used in this work can be found in Sect. S5 and at https://github.com/leohoinaski/CMAQrunner (last access: 8 May 2024​​​​​​​). The pollutant list in CMAQ outputs, containing 216 species, can be found in Sect. S6 (Table S3).

The CMAQ standard profile of boundary conditions is used in the larger domain (d01), which provides the boundary conditions for the smaller one (d02). Further improvements to the database could include the boundary conditions derived from the GEOS-Chem model (Bey et al., 2001) ( https://geoschem.github.io/ , last access: 8 May 2024) or other better alternatives for the largest domain. The simulations have 24 h length and a time step interval of 1 h. The last hour of the previous simulation has been set up as the initial condition of the next one. We used the standard profile for the first hour of the first simulation (00:00:00 GMT on 1 January 2019). The figures with the spatial distribution and violations of criteria pollutants can be found in Sect. S7. Section S8 also presents the time series of criteria pollutants in Brazilian cities.

Using the BRAIN air quality dataset, we can observe the highest concentrations of NO 2 (Fig. 3a–b), O 3 (Fig. 3c–d), and PM 10 (Fig. 3e–f) in southeastern and southern Brazil. The concentration of O 3 violates the World Health Organization (WHO) air quality standards in multiple locations all over the country, while for NO 2 and PM 10 , this occurred mostly in southeastern and southern Brazil.

Figure 8 Annual average concentration of CO and NO 2 from BRAIN at its original resolution (a, c) and from Sentinel-5P TROPOMI spatially aligned to the BRAIN resolution (b, d) .

2.3.1  Models' performance

We sampled pixels around the monitoring station using a buffer of 0.5° to calculate the Spearman rank, bias, root mean squared error (RMSE), and mean absolute error (MAE) of the sampled pixels. We selected the highest Spearman rank of each pixel to demonstrate the model's performance in Figs. 4 and 5. Section S10 presents the box plots with overall statistical metrics for all stations. Section S11 presents statistical metrics by means of a monitoring station and pollutant, considering the pixel with the highest Spearman rank around each monitoring station. Section S12 presents the scatter plots comparing the BRAIN air quality dataset and the observations of each monitoring station. We used the simulations with domain d01 in the statistical analysis.

We observed the highest Spearman rank (0.72) in the state of São Paulo for O 3 concentration. Bias analysis revealed an underestimation in the São Paulo metropolitan area, while an overestimation occurred in Minas Gerais, Santa Catarina, Rio Grande do Sul, and the interior of São Paulo. In the northeast and in the state of Espírito Santo, bias is closer to zero. In Rio de Janeiro, the model over- and underestimated the observations. Regarding RMSE and MAE, the model performed better in coastal areas (maps in Fig. 4).

Comparing the states with air quality monitoring stations, the Spearman correlation of the O 3 dataset of BRAIN is higher in São Paulo, Minas Gerais, and Rio de Janeiro. However, these states also have a higher range of bias values, which could be negative and positive in São Paulo and Rio de Janeiro and are only positive in Minas Gerais (box plots in Fig. 4).

The heterogeneity in the stations' types and the insufficient spatial representativeness of observations in the Brazilian states must be considered while evaluating the model performance. According to the IEMA (2022), the strategic planning for the implementation of air quality monitoring stations, the financing and political efforts, and the technical characteristics (from installation to calibration and maintenance) vary significantly between Brazilian states. The lack of data quality assurance may compromise the credibility of the available air quality observations in Brazil.

BRAIN reproduced well the concentrations in moderately urbanized areas, such as Limeira and Piracicaba (Sect. S12). The database reached moderate performance in highly urbanized areas such as Copacabana and Rio de Janeiro (RJ) and at Marginal Tietê in the megacity of São Paulo (Sect. S12). Regarding the temporal profiles of O 3 and PM 10 , the seasonal and daily profiles are captured for both modeled pollutants, showing a suitable fit with the observations at the Limeira and Pecém Industrial and Port Complex (CIPP) air quality monitoring stations (Fig. 5). This reveals that the database can capture temporal patterns of air pollutant concentrations in urbanized and industrialized areas.

Figures with statistical metrics for other pollutants can be found in Sect. S13. Figures of modeled and observed time series for all monitoring stations can be found in Sect. S14.

Figure 9 Concentration of CO from BRAIN vs. Sentinel-5P TROPOMI in Brazil (a) , northern Brazil (b) , northeastern Brazil (c) , midwestern Brazil (d) , southeastern Brazil (e) , and southern Brazil (f) .

Overall, the average concentrations are well simulated by CMAQ in BRAIN, with fair to good correlations (up to ∼  0.7) between modeling and local measurements in São Paulo. Similar results have been reported by Albuquerque et al. (2018). Kitagawa et al. (2021) simulated PM 2.5 in a Brazilian coastal–urban area and showed that the CMAQ results commonly overestimated the observations, which agrees with the BRAIN air quality dataset. In another comparison between observations and CMAQ simulations (Kitagawa et al., 2022), the model overestimated the PM and NO 2 concentrations in the metropolitan region of Vitória (MRV) and underestimated O 3 . The authors suggest that the CMAQ simulations are suitable over the MRV, even though the model could not capture some local variabilities in air pollutant concentrations. It is already reported that the short-time abrupt variations are difficult to reproduce by means of air quality models (Albuquerque et al., 2018). The complex task of predicting air quality is associated with multiple error factors, including the lack of an emissions inventory, meteorology parameterizations, initial and boundary conditions, chemical mechanisms, numerical routines, etc. (Cheng et al., 2019; Albuquerque et al., 2018; Park et al., 2006; Pedruzzi et al., 2019).

Figure 10 Annual average and hourly time series of CO from BRAIN (a) , MERRA-2 (b) , and Sentinel-5P TROPOMI (daily averages) (c)  in Porto Velho, Brazil.

We analyzed the performances of 4×4  km simulations for CO, NO 2 , O 3 , and SO 2 , drawing a buffer of 0.5° degrees around monitoring station positions in southern Brazil. Our findings indicated higher Spearman values for the spatial resolution of 20×20  km for CO, O 3 , and SO 2 . Specifically, for O 3 , the best result at 20×20  km was 0.76, whereas the same point at 4×4  km resolution showed a correlation of 0.46. This pattern was also observed for CO, with the best result at 20×20  km being a Spearman value of 0.47 and 0.23 at the same point at 4×4  km resolution. The smallest differences in Spearman rank were observed for SO 2 (0.22: 20×20 , 0.19: 4×4 ). Even though improving the spatial resolution did not increase the correlation with measured data, we found the best results for bias, RMSE, and MAE for almost all pollutants at a 4×4  km resolution, except for CO. Please refer to Sect. S15 for the complete statistical analysis of 4×4  km simulations.

BRAIN captures seasonal patterns and the absolute magnitude of PM 2.5 in the northwest of the Amazonas state (near the Amazon Tall Tower Observatory – ATTO), as presented by Artaxo et al. (2013). This shows that our database can reproduce the concentrations in background areas (far from highly urbanized centers). Comparing BRAIN with observations at heavily biomass-burning-impacted sites in southwestern Amazonia (Porto Velho) (Artaxo et al., 2013) revealed that BRAIN can capture seasonal variations caused by wet and dry seasons, as well as the magnitude of average and peak concentrations. However, BRAIN PM 2.5 estimates are closer to the coarse mode of the time series rather than the fine mode shown in Artaxo et al. (2013). Even though BRAIN has captured the O 3 pattern observed by Artaxo et al. (2013), the estimates are around 2.7 times higher than the observations in the dry season and a factor of 2 higher for the wet season. It is worth mentioning that BRAIN uses 2019 data, while the study by Artaxo et al. (2013) consists of a sampling campaign from 2008 to 2012.

Figure 11 Scatter plot and daily time series of CO (a) , O 3 (b) , and NO 2 (c) from BRAIN and Sentinel-5P TROPOMI at T0a (GoAmazon reference). Values extracted using a buffer of 0.2° around the site.

Figure 12 Scatterplot and daily time series of CO, O 3 , and NO 2 from BRAIN and Sentinel-5P TROPOMI at T0t/TT34 (GoAmazon reference). Values extracted using a buffer of 0.2° around the site.

BRAIN has a similar spatial pattern compared with MERRA-2 (GMAO, 2015a b), capturing hotspots in higher populated areas located in the southeast, south, and midwest. In the Amazon region, BRAIN can also capture hotspots similarly to MERRA-2 (Fig. 6). BRAIN estimates for carbon monoxide are lower than those of MERRA-2, except in the southern region and in some urban centers in the southeast and midwest (Fig. 6). Carbon monoxide concentrations estimated by BRAIN are moderately correlated with MERRA-2, mainly in the south (0.57) and southeast (0.55), while in the midwest, north, and northeast, the correlation is weaker (Fig. 7). Compared with the consolidated MERRA-2 database, BRAIN has the advantage since it uses local and more refined information and provides data at a higher spatial resolution for multiple species. We provide a detailed comparison between the MERRA-2 and BRAIN datasets for PM 2.5 , SO 2 , O 3 , and CO in Sect. S16.

We also compare our database with Sentinel-5P TROPOMI (Veefkind et al., 2012) data to demonstrate BRAIN's ability to capture the spatiotemporal variability of air pollutants in unmonitored areas (Fig. 8). We spatially realign Sentinel-5P TROPOMI products to the BRAIN resolution ( 20×20  km) using data from the NASA Goddard Earth Sciences Data and Information Services Center (GES-DISC) ( https://disc.gsfc.nasa.gov/ , last access: 8 May 2024). We merged all layers of the same day and interpolated them to match the BRAIN resolution. We computed the daily averages for both datasets. In this evaluation, we must consider the differences between the datasets since Sentinel-5P TROPOMI relies on tropospheric column measurements and BRAIN surface concentrations. BRAIN captured the hotspots of CO and NO 2 similarly to Sentinel-5P TROPOMI products, especially in southeastern Brazil. However, the hotspots of CO are dislocated towards the ocean in Sentinel-5P TROPOMI. NO 2 estimates from BRAIN present a higher number of hotspots. We emphasize that surface concentration data are more suitable than tropospheric column data in representing air quality. In this analysis, we removed negative values from Sentinel-5P TROPOMI products since they represent low-quality measurements (Eskes et al., 2022).

When we compared CO daily datasets from BRAIN and Sentinel-5P TROPOMI by Brazilian regions, we observed a moderate correlation in the north (0.41), midwest (0.32), and south (0.3). This analysis shows that BRAIN can reasonably detect temporal and spatial patterns of air pollutants. The complete comparison of CO and NO 2 from Sentinel-5P TROPOMI and BRAIN can be found in Sect. S17.

Figure 13 Scatter plot and daily time series of CO (a) , O 3 (b) , and NO 2 (c) from BRAIN and Sentinel-5P TROPOMI at T1 (GoAmazon reference). Values extracted using a buffer of 0.2° around the site.

We highlight that BRAIN, MERRA-2, and Sentinel-5P TROPOMI can capture similar temporal patterns of air pollutant concentrations in heavily biomass-burning-impacted sites such as Porto Velho in Rondônia (Fig. 10) and in urban areas such as São Paulo. We provide time series (minimum–maximum and average) of BRAIN, MERRA-2, and Sentinel-5P TROPOMI data spatially averaged within Brazilian capitals in Sect. S18. Section S19 contains time series (only average) of BRAIN data in Brazilian capitals.

To analyze BRAIN's performance in background regions (with low anthropogenic influence), we extracted data from two forested sites in the Brazilian northern region. As reference, we used the sampling sites of the GoAmazon experiment (Martin et al., 2016), named T0a (forested site situated 154.1 km from the Manaus urban area) and T0t/TT34 (a broken-canopy forested site situated 60.9 km from the city of Manaus). Sentinel-5P TROPOMI data spatially aligned to the BRAIN resolution were also extracted for comparison. A buffer of 0.2° around the sites selected the data of CO, O 3 , and NO 2 from both datasets. The results revealed that BRAIN captured the seasonal profile at T0a (Fig. 11), showing a moderate correlation with the tropospheric column measurements of Sentinel-5P TROPOMI, especially for CO and O 3 .

BRAIN estimates are slightly higher than the observed concentrations in background areas of CO, O 3 , and NO 2 in TT34 (Fig. 12) and T0a (Fig. 11). While O 3 concentrations simulated by BRAIN range around 18 ppb (average in 2019) at the TT34 site, observed concentrations in 2013 (Artaxo et al., 2013) were around 8.5 ppb  ±  1.9 ppb. In T0a, BRAIN simulated concentrations around 16 ppb, overestimating the observations (7 ppb  ±  2 ppb during the wet season from March to April 2013–2020) (Nascimento et al., 2022). Concerning CO, the concentrations simulated by BRAIN are slightly lower, ranging around 73 ppb (average) at TT34 compared to the 130 ppb observed during the GoAmazon experiment from 2010 to 2011 (Artaxo et al., 2013). We emphasize that the BRAIN and GoAmazon datasets are reported in different periods and, consequently, are influenced by different emission rates. For instance, fire emissions have changed significantly since 2011 in the Amazon (Copernicus, 2022; Naus et al., 2022).

We also analyzed BRAIN results in the Manaus urban area. We adopted the sampling site of the GoAmazon experiment (Martin et al., 2016) named T1 (INPA campus in Manaus). Compared with Sentinel-5P TROPOMI data, BRAIN reproduced fairly the temporal pattern of CO, O 3 , and NO 2 in the T1 site (Fig. 13). Abou Rafee et al. (2017) reported mean concentrations of 88.7 ppb for NO x and 382.6 pbb for CO in the Manaus urban area, while BRAIN reached 79 and 99 ppb (maximum of 383 ppb), revealing an underestimation in this area. Again, the sampling campaign presented by Abou Rafee et al. (2017) and the BRAIN simulations use different base years. Comparing BRAIN at T0a/TT34 (background sites) and T1 (urbanized), the database has reached consistent results, with lower concentration levels in preserved areas.

The inability to better predict the observations is mostly due to the quality of the emissions inventory. The lack of information on industrial emissions and their temporal variability is an important source of errors. Moreover, the vehicular emissions inventory also needs improvements to properly disaggregate the emissions in high-flow roads. Future versions of BRAIN could address these issues and incorporate other emission sources.

Emission data are available at https://doi.org/10.57760/sciencedb.09858 (Hoinaski et al., 2023a) and https://doi.org/10.57760/sciencedb.09886 (Hoinaski et al., 2023b). Meteorology data are available at https://doi.org/10.57760/sciencedb.09857 (Hoinaski and Will, 2023a) and https://doi.org/10.57760/sciencedb.09885 (Hoinaski and Will, 2023c). Air quality data are available at https://doi.org/10.57760/sciencedb.09859 (Hoinaski and Will, 2023b) and https://doi.org/10.57760/sciencedb.09884 (Hoinaski and Will, 2023d).

Code to generate the database, statistics, and figures is available at https://github.com/leohoinaski/CMAQrunner (last access: 8 May 2024) or https://doi.org/10.5281/zenodo.11166975 (Hoinaski, 2024b) and https://github.com/leohoinaski/IND_Inventory (last access: 8 May 2024) or https://doi.org/10.5281/zenodo.11167115 (Hoinaski, 2024a).

In this paper, we present BRAIN, the first comprehensive database for air quality management in Brazil. BRAIN provides emissions, meteorology, and air quality datasets for the entire country at a reliable spatiotemporal resolution. The BRAIN database covers a wide range of pollutant species (emissions and ambient concentrations) and atmospheric variables. So far, Brazil has lacked a comprehensive and easily accessible database for developing air quality management systems in urbanized and rural areas. This work contributes to overcoming this gap. BRAIN is a step forward toward a good procedure for licensing new sources of air pollution in Brazil.

Using a sample of BRAIN, we observed several violations of WHO air quality recommendations. The violations are not restricted to densely populated areas but also occur in rural ones. This reinforces the need for better air quality policies and a deep restructuring of the environmental agencies' procedures and data management in Brazil.

Compared with observations, the BRAIN air quality dataset has achieved good overall performance in predicting the criteria pollutants. However, there is plenty of room for improvement, mainly in relation to the quality of the emissions inventory. The lack of information on industrial emissions and their temporal variability is an important source of error. Moreover, the vehicular emissions inventory also needs improvements to properly disaggregate the emissions in high-flow roads. Improvements in boundary conditions and the inclusion of emission sources from other Latin American countries could also enhance the CMAQ performance. The influence of long-range transport will be addressed in a future version of the database by implementing boundary contributions from GEOSCHEM and other tools. Future versions of BRAIN could address these issues, incorporate other emission sources, and provide CMAQ outputs using different chemical mechanisms. We envision providing enough data to reproduce the historical pattern and future scenarios of air pollution in Brazil through a web platform to facilitate the access and usage of our database. We believe in an ongoing process that will improve the database.

The supplement related to this article is available online at:  https://doi.org/10.5194/essd-16-2385-2024-supplement .

LH designed the methodology and developed the software. LH, RW, and CBR processed the data curation, conducted the formal analysis, and created the figures. LH, RW, and CBR prepared the original draft and revised the paper. LH is the project administrator and laboratory supervisor.

The contact author has declared that none of the authors has any competing interests.

Publisher’s note: Copernicus Publications remains neutral with regard to jurisdictional claims made in the text, published maps, institutional affiliations, or any other geographical representation in this paper. While Copernicus Publications makes every effort to include appropriate place names, the final responsibility lies with the authors.

The authors would like to thank the Secretaria de Estado do Desenvolvimento Econômico Sustentável do governo de Santa Catarina. The authors are grateful for the doctoral scholarships provided by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brasil (CAPES).

This research has been supported by the Fundação de Amparo à Pesquisa e Inovação do Estado de Santa Catarina (grant no. 2018/TR/499; “Avaliação do impacto das emissões veiculares, queimadas, industriais e naturais na qualidade do ar em Santa Catarina”).

This paper was edited by Jing Wei and reviewed by two anonymous referees.

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• Introduction
• BRAIN database
• Data availability
• Code availability
• Author contributions
• Competing interests
• Acknowledgements
• Financial support
• Review statement