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• W4233156629 abstract "EditorialIn pursuit of scientific excellence: sex mattersVirginia M. MillerVirginia M. MillerDepartments of Surgery and Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MinnesotaPublished Online:01 May 2012https://doi.org/10.1152/ajpregu.00105.2012This is the final version - click for previous versionMoreSectionsPDF (47 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat the year 2012 marks the 125th anniversary of the American Physiological Society (APS). Throughout its history, APS has been a leader in innovation and excellence in scientific technology, discovery, education, and publication. Consistent with this history, APS is leading the scientific publication community by requiring the reporting of the sex of experimental animals and material derived from experimental animals or humans, as well as the sex (or gender where appropriate) of humans used in studies published in their journals. Upon reading this statement, your reaction might be, “How can this change in policy be a groundbreaking action? Sex is such a basic biological variable that influences physiology and disease. Hasn't it been obvious for a long time that it should be reported in the Methods section of scientific papers?” Well, it has been obvious that sex is a biological variable affecting experimental outcomes, but it has been far from obvious to journals and investigators that it should be routinely reported in the scientific literature!Recent reviews of basic science journals (3), of studies of cells in culture from high-impact cardiovascular journals (18), and of basic and clinical scientific literature (5, 22) suggest that sex of experimental material is not consistently reported in the scientific literature. Indeed, overall less than 40% of studies using experimental animals and only about 25% of studies using cells in culture identified the sex of the experimental material. This percentage is low given the growing knowledge base that physiology and pathophysiology differ between male and female animals and humans beyond reproductive function to include all physiological systems [i.e., cardiovascular, respiratory, musculoskeletal, immunological, gastrointestinal, neurological, renal (23)]. Furthermore, intracellular signaling pathways may be differentially expressed in cells, tissues, and animals, including humans, depending on their sex and hormonal status (1, 2, 4, 6–11, 14–17, 19–21, 24, 25), to mention only a few studies.In the era of physiological genomics and individualized medicine, the presence of an XX or XY chromosomal complement is fundamental to the genome of an individual person, animal, tissue, or cell. Every cell has a sex.Therefore, based on existing knowledge, it is inappropriate to assume that results from studies conducted on only one sex apply to the other (13). For some studies of neonates and embryos, cells derived from males and females are mixed in a single culture and should be reported as such. The scientific community needs to determine whether this technique is valid by providing sufficient data to control and confirm survival, differentiation, and function of cells of each sex. Similarly, cell-based therapies need to validate survival and function of the cell graft in the same- and opposite-sexed recipients.Validation through replication of results is one hallmark of excellent science. For other investigators to reproduce your experiments, information regarding the type of experimental material that was used in the original experiment is required. Sex of the experimental material is a critical piece of that information.How then should the sex of experimental material be reported? Use of the terms “sex” and “gender” has evolved over the last decade. According to definitions proposed by the Institute of Medicine (23), “sex” is a biological construct dictated by the presence of sex chromosomes and in animals and humans the presence of functional reproductive organs. “Gender” is a cultural construct and refers to behaviors that might be directed by specific stimuli (visual, olfactory, etc.) or by psychosocial expectations that result from assigned or perceived sex. Gender, thus, can influence biological outcomes. In most studies conducted on isolated cells, tissues can be classified as male or female by the sex chromosomal complement and for experimental animals by the sex chromosomal complement and anatomical features. Similar information may be available for humans. However, humans may self-report their sex according to gender and some studies in animals can be designed to address influences of psychosocial (gender) constructs on physiological outcomes (12). The new editorial policy for all APS journals requires the reporting of sex for cells, tissues, and experimental animals and humans (i.e., male and female) or gender where appropriate. The investigator must decide based on the experimental design which terms are most appropriate for a given study.As a member of the APS for over 30 years, I am pleased that our professional society is a leader in instituting and enforcing a policy for reporting sex of experimental material. As President of the Organization for the Study of Sex Differences, I am honored to help educate my colleagues on the importance of sex as a biological variable in our collective efforts to strive for scientific excellence. This new editorial policy for APS journals will lead the way for changes in editorial policies of other scientific journals. Implementation of the new policy by reviewers, associate editors, and editors will improve communication of scientific results and perhaps assist in more rapid translation of information from basic science to clinical medicine. Yes, in our pursuit of scientific excellence, sex matters.DISCLOSURESNo conflicts of interest, financial or otherwise, are declared by the author(s).REFERENCES1. Antoniucci D , Miller VM , Sieck GC , Fitzpatrick LA. Gender-related differences in proliferative responses of vascular smooth muscle cells to endothelin-1. Endothelium 8: 137–145, 2001.Crossref | PubMed | Google Scholar2. Avner P , Heard E. X-chromosome inactivation: counting, choice and initiation. Nat Rev Genet 2: 59–67, 2001.Crossref | PubMed | ISI | Google Scholar3. Beery AK , Zucker I. Sex bias in neuroscience and biomedical research. Neurosci Biobehav Rev 35: 565–572, 2011.Crossref | PubMed | ISI | Google Scholar4. Csaba G , Torok O , Kovacs P. Permanence of the cell-to-cell transmission of insulin induced hormonal imprinting. Acta Physiol Hung 75: 111–116, 1990.PubMed | Google Scholar5. Geller SE , Koch A , Pellettieri B , Carnes M. Inclusion, analysis and reporting of sex and race/ethnicity in clinical trials: have we made progress? J Womens Health 20: 315–320, 2011.Crossref | PubMed | ISI | Google Scholar6. Hager R , Cheverud JM , Leamy LJ , Wolf JB. Sex dependent imprinting effects on complex traits in mice. BMC Evol Biol 8: 303, 2008.Crossref | PubMed | ISI | Google Scholar7. Isensee J , Ruiz Noppinger P. Sexually dimorphic gene expression in mammalian somatic tissue. Gend Med 4, Suppl B: S75–S95, 2007.Crossref | PubMed | Google Scholar8. Isensee J , Witt H , Pregla R , Hetzer R , Regitz-Zagrosek V , Noppinger PR. Sexually dimorphic gene expression in the heart of mice and men. J Mol Med 86: 61–74, 2008.Crossref | PubMed | ISI | Google Scholar9. Ivanova T , Beyer C. Estrogen regulates tyrosine hydroxylase expression in the neonate mouse midbrain. J Neurobiol 54: 638–647, 2003.Crossref | PubMed | Google Scholar10. Liao YC , Lin HF , Guo YC , Yu ML , Liu CK , Juo SH. Sex-differential genetic effect of phosphodiesterase 4D (PDE4D) on carotid atherosclerosis. BMC Med Genet 11: 93, 2010.Crossref | PubMed | ISI | Google Scholar11. McEwen BS. Invited review: Estrogens effects on the brain: multiple sites and molecular mechanisms. J Appl Physiol 91: 2785–2801, 2001.Link | ISI | Google Scholar12. Miller VM , Kaplan JR , Schork NJ , Ouyang P , Berga SL , Wenger NK , Shaw LJ , Webb RC , Mallampalli M , Steiner M , Taylor DA , Bairey Merz CN , Reckelhoff JF. Strategies and methods to study sex differences in cardiovascular structure and function: a guide for basic scientists. Biol Sex Differ 2: 14, 2011.Crossref | PubMed | Google Scholar13. Nieuwenhoven L , Klinge I. Scientific excellence in applying sex- and gender-sensitive methods in biomedical and health research. J Womens Health 19: 313–321, 2010.Crossref | PubMed | ISI | Google Scholar14. Ober C , Loisel DA , Gilad Y. Sex-specific genetic architecture of human disease. Nat Rev Genet 9: 911–922, 2008.Crossref | PubMed | ISI | Google Scholar15. Ostrer H. Sex-based differences in gene transmission and gene expression. Lupus 8: 365–369, 1999.Crossref | PubMed | ISI | Google Scholar16. Pierce JP , Kievits J , Graustein B , Speth RC , Iadecola C , Milner TA. Sex differences in the subcellular distribution of angiotensin type 1 receptors and NADPH oxidase subunits in the dendrites of C1 neurons in the rat rostral ventrolateral medulla. Neuroscience 163: 329–338, 2009.Crossref | PubMed | ISI | Google Scholar17. Rzewuska-Lech E , Jayachandran M , Fitzpatrick LA , Miller VM. Differential effects of 17β-estradiol and raloxifene on VSMC phenotype and expression of osteoblast-associated proteins. Am J Physiol Endocrinol Metab 289: E105–E112, 2005.Link | ISI | Google Scholar18. Taylor KE , Vallejo-Giraldo C , Schaible NS , Zakeri R , Miller VM. Reporting of sex as a variable in cardiovascular studies using cultured cells. Biol Sex Differ 2: 11, 2011.Crossref | PubMed | Google Scholar19. van Nas A , Ingram-Drake L , Sinsheimer JS , Wang SS , Schadt EE , Drake T , Lusis AJ. Expression quantitative trait loci: replication, tissue- and sex-specificity in mice. Genetics 185: 1059–1068, 2010.Crossref | PubMed | ISI | Google Scholar20. Wang S , Yehya N , Schadt EE , Wang H , Drake TA , Lusis AJ. Genetic and genomic analysis of a fat mass trait with complex inheritance reveals marked sex specificity. PLoS Genet 2: e15, 2006.Crossref | PubMed | ISI | Google Scholar21. Waxman DJ , Dannan GA , Guengerich FP. Regulation of rat hepatic cytochrome P-450: age-dependent expression, hormonal imprinting, and xenobiotic inducibility of sex-specific isoenzymes. Biochemistry (Mosc) 24: 4409–4417, 1985.Crossref | ISI | Google Scholar22. Wizemann TM Institute of Medicine. Sex-Specific Reporting of Scientific Research: A Workshop Summary. Washington, DC: National Academies Press, 2012.Google Scholar23. Wizemann TM , Pardue ML. Exploring the Biological Contributions to Human Health: Does Sex Matter? Board on Health Sciences Policy. Washington, DC: National Academy Press, 2001, p. 288.Google Scholar24. Yang X , Schadt EE , Wang S , Wang H , Arnold AP , Ingram-Drake L , Drake TA , Lusis AJ. Tissue-specific expression and regulation of sexually dimorphic genes in mice. Genome Res 16: 995–1004, 2006.Crossref | PubMed | ISI | Google Scholar25. Yao J , Hamilton RT , Cadenas E , Brinton RD. Decline in mitochondrial bioenergetics and shift to ketogenic profile in brain during reproductive senescence. Biochim Biophys Acta 1800: 1121–1126, 2010.Crossref | PubMed | ISI | Google ScholarAUTHOR NOTESAddress for reprint requests and other correspondence: V. M. Miller, Medical Science 4-62, Mayo Clinic, 200 First St. SW, Rochester, MN 55905 (e-mail: miller.[email protected]edu). Download PDF Back to Top Next FiguresReferencesRelatedInformation Collections Cited ByIs there sufficient evidence to explain the cause of sexually dimorphic behaviour in force steadiness?Applied Physiology, Nutrition, and Metabolism, Vol. 43, No. 11Maternal protein‐energy malnutrition during early pregnancy in sheep impacts the fetal ornithine cycle to reduce fetal kidney microvascular development30 July 2014 | The FASEB Journal, Vol. 28, No. 11Sex and basic science. A Title IX positionKathryn Sandberg, Joseph G. Verbalis, Gina L. C. Yosten, and Willis K. Samson15 August 2014 | American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, Vol. 307, No. 4Female mice liberated for inclusion in neuroscience and biomedical researchNeuroscience & Biobehavioral Reviews, Vol. 40Role of Proopiomelanocortin Neuron Stat3 in Regulating Arterial Pressure and Mediating the Chronic Effects of LeptinHypertension, Vol. 61, No. 5Sex, hormones, and stress: How they impact development and function of the carotid bodies and related reflexesRespiratory Physiology & Neurobiology, Vol. 185, No. 1 More from this issue > Volume 302Issue 9May 2012Pages R1023-R1024 Copyright & PermissionsCopyright © 2012 the American Physiological Societyhttps://doi.org/10.1152/ajpregu.00105.2012PubMed22422666History Published online 1 May 2012 Published in print 1 May 2012 Metrics" @default.
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