Our sense of taste begins with taste buds and ends in the brain. Researchers are beginning to unravel the mechanisms and connections that lie in between The ability to taste food is a life-and-death matter. Failure to recognise food with a high enough caloric content could mean a slow death from malnutrition. Failure to detect a poison could result in near-instant expiration. And now, as researchers begin to understand some of the nuts and bolts of taste perception, it seems that the sense of taste may also have more subtle effects on health.At the front line of the taste sensory system are the taste buds—onion-shaped structures on the tongue and elsewhere in the mouth . Up to 1Taste is the sense by which the chemical qualities of food in the mouth are distinguished by the brain, based on information provided by the taste buds. Quality or ‘basic taste’, explains Bernd Lindemann, now retired but an active taste researcher in Germany for many years, is a psychophysical term. Large numbers of people describe different tastants and then statistical analyses are used to define the important tastes. ‘The number of taste qualities has varied over the years’, says Lindemann. ‘We are now settling at around five, though I would not be surprised if some additional qualities pop up’.The five qualities that Lindemann refers to are salty, sour, bitter, sweet, and umami, the last being the Japanese term for a savoury sensation. Salty and sour detection is needed to control salt and acid balance. Bitter detection warns of foods containing poisons—many of the poisonous compounds produced by plants for defence are bitter. The quality sweet provides a guide to calorie-rich foods. And umami (the taste of the amino acid glutamate) may flag up protein-rich foods. Our sense of taste has a simple goal, explains Lindemann: ‘Food is already in the mouth. We just have to decide whether to swallow or spit it out. It's an extremely important decision, but it can be made based on a few taste qualities’.Taste has been actively researched for many decades. During the 20th century, electrophysiologists and other researchers worked hard to understand this seemingly simple sense system. Then, in 1991, the first olfactory receptors were described. These proteins, which are exposed on the surface of cells in the nose, bind to volatile chemicals and allow us to detect smells. This landmark discovery, in part, encouraged many established taste researchers to investigate the molecular aspects of taste.The olfaction results also enticed researchers from other disciplines into the taste field, including collaborators Charles Zuker  and Nick Ryba . About six years ago, explains Zuker, who previously worked on other sensory systems in flies, ‘there was a disconnect between our understanding of sensations in the case of photoreception, mechanoreception, touch, and so on and what we knew about taste’. There was evidence, says Ryba, that a class of protein receptors called G-protein-coupled receptors (GPCRs) were involved in sweet and bitter taste, ‘but the receptors weren't known, so we started to look for them …. These molecules are intrinsically interesting, but more importantly, they provide tools with which we can dissect out how taste works’.The bitter receptors fell first to the onslaught of the UCSD–NIDCR team and other molecular biologists. In 1999, the ability to taste propylthiouracil, a bitter tasting compound, had been linked to a locus on human Chromosome 5p15. Reasoning that this variation might be due to alterations in the coding sequence for a bitter receptor, the UCSD–NIDCR researchers used the draft of the human genome to search for sequences that resembled GPCRs on Chromosome 5p15. ‘That was how we found T2R1, the first bitter receptor, and, subsequently, a whole family of T2Rs’, says Zuker.Researchers want to know: how is taste coded?All these receptors, says Zuker, are coexpressed in bitter taste receptor cells, a result that contradicts other research showing that different bitter-responsive cells react to different bitter molecules. ‘To me’, says Zuker, ‘it makes sense that all the bitter receptors would be expressed in each bitter taste cell. We just need to know if something is bitter to avoid death’, not the exact identity of the bitter tastant.Sac locus, which determines the ability of mice to detect saccharin, and T1R3, a third member of the T1R family. The UCSD–NIDCR team subsequently showed that the T1R2 and T1R3 heterodimer (a complex of one T1R2 and one T1R3 molecule) forms a broadly tuned sweet receptor, responsive to natural sugars and artificial sweeteners, and that a homodimer of two T1R3 molecules forms a low-affinity sugar receptor that responds to high concentrations of natural sugars only. All sweet detection, concludes Zuker, is via the T1R2 and T1R3 receptors.The sweet receptor story started in 1999 with the identification of two putative mammalian taste receptors, GPCRs now known as T1R1 and T1R2. In early 2001, four groups reported an association between the mouse And umami? A truncated glutamate receptor was identified as an umami receptor by researchers at the University of Miami  School of Medicine in 2000. Zuker, however, believes that the one and only umami receptor is a heterodimer of T1R1 and T1R3. In October 2003, Zuker and his coworkers reported that mice in which either T1R1 or T1R3 has been knocked out show no preference for monosodium glutamate (MSG), an umami tastant. However, other researchers reported in August 2003 that T1R3 knockouts retain some preference for MSG. ‘We believe this is due either to the truncated glutamate receptor or another unknown receptor’, says lead author Sami Damak . Damak says he does not know why the two sets of T1R3 knockout mice behaved differently, but the UCSD–NIDCR researchers suggest that the residual response to MSG seen by Damak et al. is a response to the sodium content of MSG. Damak is not alone, however, in thinking there may be more than one umami receptor .Commenting on these recent discoveries, taste expert Linda Bartoshuk  says that ‘it is lovely to see all these details, especially as they confirm what we already believed conceptually’. For example, she says, it is no surprise that there are many bitter receptors but probably only one sweet receptor. ‘There are so many poisons and it makes perfect sense to have lots of receptors feeding into a common transduction pathway. Sweet is a different problem. In nature, there are many molecules with structures similar to sugar that we must not eat because we cannot metabolise them. So I would have predicted one or at most a few highly specific sweet receptors’.The salty and sour receptors may be very different from the GPCRs involved in bitter, sweet, and umami perception, which bind complex molecules on the outside of the cell and transmit a signal into the cell. For salty and sour perception, the taste cell only needs to detect simple ions. One way to do this may be to use ion channels—proteins that form a channel through which specific inorganic ions can diffuse. Changes in cellular ion concentrations could then be detected and transmitted to the nervous system.Physiologist John DeSimone  says there are at least two ion channel receptors for salt in rodent taste receptor cells. The first of these is the epithelial sodium channel, a widely expressed channel that can be blocked specifically with the drug amiloride. In rats, says DeSimone, only 75% of the nerve response to salt can be blocked by amiloride, so there is probably a second receptor. This, he says, seems to be a generalist salt receptor—the amiloride-sensitive channel only responds to sodium chloride—and may be the more important receptor in people.Sour tastants are acids, often found in spoiled or unripe food. DeSimone's current idea is that strong acids enter taste cells through a proton channel (probably a known channel present on other cell types) while weak acids, like acetic acid (vinegar), enter as neutral molecules and then dissociate to lower intracellular pH. DeSimone believes that he has identified the proton channel involved in sour taste as well as an ion channel that could be the second salt receptor, and he plans to do knockout experiments on both. If these channels are essential elsewhere in the body, as DeSimone suspects, to avoid lethality he will need to construct conditional knockouts in which the channel is lost only in the taste receptor cells.Zuker, meanwhile, is not convinced that the current ion channel candidates for salt and sour perception are correct. And, he says, GPCRs could also be involved in these modalities. ‘There is a precedent for that’, he claims, noting that extracellular calcium is sensed by a GPCR.With many taste receptors now identified, researchers are turning to a long-standing question in taste perception: how is taste coded? When we eat, our tongue is bombarded with tastants. How is their detection and transduction of information organised so that the appropriate response is elicited? Taste physiologist Sue Kinnamon  explains the two theories of taste-coding. In the ‘labelled-line’ model, sweet-sensitive cells, for example, are hooked up to sweet-sensitive nerve fibres that go to the brain and code sweet. If you stimulate that pathway, says Kinnamon, ‘you should elicit the appropriate behavioural response without any input from other cell types’. In the ‘cross-fibre’ model, the pattern of activity over many receptors codes taste. This model predicts that taste receptor cells are broadly tuned, responding to many tastants. Support for this theory, says Kinnamon, comes from electrical recordings from receptor cells and from nerves innervating the taste buds that show that one cell can respond to more than one taste quality.Zuker and Ryba's recent work strongly suggests that taste-coding for bitter, sweet, and umami fits the labelled-line model in the periphery of the taste system. Their expression data show that receptors for these qualities are expressed in distinct populations of taste cells. In addition, in early 2003, they reported that, as in other sensory systems, a single signalling pathway involving the ion channel TRPM5 and PLCβ2, a phospholipase that produces a TRPM5 activator, lies downstream of the bitter, sweet, and umami receptors. When the UCSD–NIDCR researchers took PLCβ2 knockout mice, which did not respond to bitter, sweet, or umami, and engineered them so that PLCβ2 was only expressed in bitter receptor-expressing cells, only the ability to respond to bitter tastants was regained. These data, says Zuker, support the labelled-line model.The latest data supporting the labelled-line model came last October when Zuker and colleagues described mice in which a non-taste receptor—a modified κ-opioid receptor that can only be activated by a synthetic ligand—was expressed only in cells expressing T1R2, sweet-responsive cells. The mice were attracted to the synthetic ligand, which they normally ignore, indicating that dedicated pathways mediate attractive behaviours. The researchers plan similar experiments to see whether the same is true for aversive behaviours.Even with all these molecular data, the cross-fibre model of taste-coding still has its supporters—just how many depends on whom one talks to. Both Damak and Kinnamon, for example, believe that there is at least some involvement of cross-fibre patterning even in the taste receptor cells. But, says neurobiologist and olfaction expert Lawrence C. Katz , ‘the onus is now on people who believe otherwise [than the labelled-line model] to provide compelling proof for the cross-fibre theory because now, at least at the periphery, the evidence is compelling for a labelled line for bitter, sweet, and umami’. Bartoshuk also says the debate is decided in favour of the labelled-line model in the periphery. The crossfibre model is an interesting historical footnote, she comments.Whether this putative link between taste perception and health can be confirmed and whether it will be possible to manipulate food preferences to improve health remain to be seen. However, it seems certain that, as in the past five years, the next five years will see large advances in our knowledge of many aspects of taste, a fascinating and important sensory system.The periphery of the taste sensory system has yielded many of its secrets, but relatively little is known about the transduction pathways in taste, how taste cells talk to the nervous system, or about events further downstream in the brain. How are signals from taste receptors integrated with those from olfactory receptors to form a representation of complex food flavours, for example? With their expanding molecular toolbox, researchers can now delve deeper into these aspects of taste perception. This may tell us not only about taste but about how the nervous system in general is put together, says Ryba.But understanding taste is not just an academic exercise. It has practical uses too. DeSimone suggests that by understanding salt receptors, it may be possible to design artificial ligands to help people lower their salt intake. As Kinnamon succinctly puts it, ‘Can you imagine eating potato chips and not having the salty component?’ An artificial salt receptor ligand could make salt-free foods a palatable option for people with high blood pressure. Lindemann also sees a great future in artificial ligands for taste receptors. The sense of taste is partly lost in elderly people, he says, so better tastants—effectively ‘chemical spectacles’—might give them back their pleasure of eating and thereby improve their quality of life.Finally, some aspects of taste may be inextricably tied up with general health, says Bartoshuk. Many people who can taste propylthiouracil are also ‘supertasters’—they have more fungiform papillae, structures containing taste buds, on their tongues than non-tasters . Superta


The European Union recently awarded 12 million Euros to the ZF-MODELS research consortium to study zebrafish models for human development and disease Danio rerio) in 1822, would be astounded to see the scientific attention now afforded to this two-inch-long native of Indian rivers. A fish with no economic worth was how he described this little creature. Yet recently, the European Union awarded 12 million Euros to the ZF-MODELS research consortium to study zebrafish models for human development and disease. When and why did zebrafish swim from home aquaria into research labs, and what can we learn about our biology from this surprising source?Francis Hamilton, the Briton who first described zebrafish , ‘who laid the groundwork for the use of zebrafish as a developmental model’.Xenopus neural development but soon became attracted to zebrafish as a model organism. By the early 1980s, she explains, Streisinger had worked out many of the genetic tricks needed to tackle zebrafish development. What's more, the fish had ‘wonderful embryology’. The embryo, which develops outside its mother, is transparent. ‘You can see different cell types, watch individual cells develop, do transplantation experiments’, Eisen enthuses, ‘and development is quick but not too quick’. Being able to watch individual neurons developing in real time opened up whole new avenues of research for Eisen and other neurobiologists.Eisen, who now heads her own research group, went to Oregon in 1983 to work on The properties of zebrafish that attracted Eisen soon attracted people interested in other aspects of vertebrate development to the stripy tiddler . As EiseDevelopment was dedicated to the mutants that had been isolated and characterised. These screens, says Ralf Dahm , project manager of the ZF-MODELS consortium, ‘were the first major zebrafish projects, and they showed that zebrafish was a model organism to be reckoned with’.The speedy expansion was driven in great part by two genetic screens initiated in 1992–1993 by Christiane Nüsslein-Volhard in Tübingen, Germany, and Wolfgang Driever and Mark Fishman in Boston, Massachusetts. The aim of both screens was to identify genes with unique and essential functions in zebrafish development, and in 1996 an issue of the journal ‘That was a fantastic time’, says Derek Stemple, then a postdoc with Driever but now a group leader at the Wellcome Trust Sanger Institute  and a ZF-MODELS participant. ‘From Wolfgang's lab, I was able to take the mutations that affected notochord development, and have been studying them ever since’. The notochord is an embryonic structure that forms the primitive axial skeleton of the developing embryo, and because mutations affecting notochord development result in shortened embryos, seven of the affected genes have been named after the dwarves in Snow White—zebrafish, like some other developmental models, have many imaginatively named mutants. Stemple now knows the identity of six of these mutated genes, all of which lead to disruption of basement membrane around the notochord.Many mutants from those first two screens are still used by developmental biologists, but another set of mutants has recently been isolated by Nancy Hopkins, Amgen Professor of Biology at the Massachusetts Institute of Technology . About ten years ago, Hopkins started to develop insertional mutagenesis in zebrafish . In thisThe Tübingen researchers did another chemical mutagenesis screen between 2000 and 2001, and are now starting a third screen of 6,000 genomes as part of the ZF-MODELS project. ‘Each of our screens has built on the previous one by including more specific assays’, explains Dahm. Mutagenesis for the third screen is underway, but the assays, which include looking for defects that specifically affect adults, are still at the pilot stage; this autumn, the project's executive committee, which is headed by Nüsslein-Volhard, will decide which assays to use in the full-scale screen. ‘Just over half the 17 partners in the consortium will come to Tübingen to do screens’, predicts Dahm. ‘By bringing in expertise in different systems in this way we should greatly increase the efficiency of the screen’.The ZF-MODELS consortium, which is funded under the European Union's Sixth Framework Programme, aims to establish zebrafish models for human diseases, discover genes that will lead to the identification of new drug targets, and gain fundamental insights into human development. ‘We will mainly focus on using advanced technologies that have recently become available’, says scientific coordinator Robert Geisler . For example, Geisler's lab will use DNA chip technology to investigate gene expression patterns in zebrafish mutants and so provide increased knowledge of the regulatory pathways that act in zebrafish development.Consortium members will also use ‘reverse genetics’ to investigate these pathways. In reverse genetics, researchers start with a gene of interest and investigate the phenotypic effect of altering its activity; by contrast, in ‘forward genetics’ the starting point is to look for a particular phenotype and then hunt out the altered gene that is causing it. Two reverse genetics approaches will be used by the consortium. Gene expression will be transiently knocked down with morpholinos, short segments of the gene that block its function. In addition, a recently developed technique known as TILLING  will be used to knock out gene activity permanently.The first step in TILLING is to mutagenise male zebrafish and mate them with untreated female fish, explains Stemple, whose group is one of three ZF-MODELS partners who will use this approach. Offspring are raised to adulthood, and the DNA of each individual is then genotyped for the exon of interest. The consortium already has a collection of 6,000 such individuals, and once a fish carrying a mutation in the gene of interest has been identified, it will be outcrossed to produce offspring, half of which will carry the desired mutation on one of their chromosomes. ‘It is then a matter of identifying these heterozygote fish and incrossing them to get homozygous fish in which you can see the phenotype that correlates with that mutation’, says Stemple.As well as helping to produce knock-outs for other researchers, Stemple is also using the TILLING technique to develop zebrafish models for muscular dystrophy. Among the genes that are important in notochord development are those that encode laminins. This led Stemple into studying muscular dystrophy because laminins are involved in the human disease. ‘When we used morpholinos to disrupt [the production of] dystroglycan, a laminin receptor, we got a good model for muscular dystrophy’, he explains. Now, he plans to use TILLING to disrupt up to 30 other genes known to be involved in human muscular dystrophy. ‘In particular, we will look for hypomorphic mutants, fish that are viable but on the edge of falling apart’. These mutants can be used to identify small molecules that push the fish into muscular dystrophy. Finding molecules that can cause a disease in this way ‘might give us a handle on something to fix the disease’, says Stemple.In another strand of the ZF-MODELS project, zebrafish expressing green fluorescent protein (GFP) in specific cells or tissues will be generated and characterised . In suchWilson's own interest is in neuroanatomy. Together with Jon Clarke, another developmental neurobiology group leader at University College London, he plans to analyse GFP lines in which small groups of neurons or particular parts of neurons are labelled, and in this way start to build a detailed reconstruction of early brain neuroanatomy. This, in combination with other work on zebrafish carrying mutations affecting neural development, will give the team ‘a better picture of how a vertebrate brain is built’.A final, important aspect of the ZF-MODELS project, adds Dahm, is database construction. ‘We will be developing a set of databases that will integrate all of the project data’, he explains. ‘In addition, we hope to integrate our data with that of ZFIN in the United States to make one central zebrafish resource’.The researchers of the ZF-MODELS consortium are understandably excited about participating in what will, says Geisler, bring an already strong European zebrafish community closer together. But zebrafish researchers in the United States are also excited by the ZF-MODELS project. ‘We need big lab models like ZF-MODELS in developmental biology’, says Hopkins, noting that the days of small groups working in isolation are long gone. This consortium, adds Howard Hughes Medical Institute Investigator Leonard Zon , ‘will not only have an effect on European zebrafish science but also on how it is done in the United States’.But how much can zebrafish tell us about human development and disease? A lot, say zebrafish researchers. ‘Fish really are just little people with fins’, says Hopkins. ‘Of course, there are developmental differences between people and fish, and no one pretends that we can answer every question about human development in zebrafish’. Nevertheless, zebrafish studies can provide valuable clues to the genes involved in human diseases and to potential targets for therapeutic interventions. Hopkins provides the following illustration: ‘We have been doing “shelf screens”, in which we go back to our collection of mutants to find all those that affect the development of a single organ. When Zhaoxia Sun, a postdoc in my lab who now has an independent position at Yale Medical School, screened three-day-old fish for cystic kidney disease, she found 12 different genes. Two were known to cause human cystic kidney disease, so we knew we were in the human disease pathway somewhere, but we had no idea what the other genes were’. Hopkins and Sun have since identified the remaining genes, and these point to a single pathway being involved in the human disease.Developmental geneticist Didier Stainier  is also using zebrafish to study organ development, in particular, heart development. The zebrafish heart is like the early human heart—a tube with an atrium, ventricle, and valves. ‘Everything we have found in the fish is relevant to the human heart’, says Stainier. ‘Obviously, there are additional processes involved in humans, but the basic outline of heart development in fish and people is largely similar’. Stainier has a collection of zebrafish in which valve formation is faulty. ‘Some of the genes we have found will be involved in human congenital valve defects’, he predicts. Knowing the identity of these genes will be useful diagnostically, but, in addition, zebrafish studies can reveal exactly what has gone wrong at a cellular level. The ability to follow individual cells as organs develop is key to this, says Stainier, who reported in March that fibronectin is required for heart development because, by regulating the polarisation of epithelial cells, fibronectin ensures the correct migration of myocardial cells. And in this issue of PLoS Biology, Stainier's lab have identified another zebrafish gene that is involved in heart development—cardiofunk, which encodes a special type of muscle protein.Many researchers are now recognising the value of zebrafish models of human disease. Over the past three to four years, says Zon, this area of research has become a growth industry. The interest in disease models has grown hand-in-hand with the development of morpholinos to knock out specific genes, and the advent of TILLING, says Zon, ‘has set off a whole new fury. There are now large numbers of investigators who will try to knock out their favourite gene and come up with a model’.Zon has worked on disease models for blood , blood vBigger and bigger seems to be the consensus. Chemical screens like Zon's for anticancer drugs can be set up for other human diseases such as muscular dystrophy. Work like Stainier's on organ development may have applications in tissue engineering. ‘If we can find out what drives differentiation in zebrafish’, he suggests, ‘we might be able to do the same for human cells’, making human tissue replacement therapy a practical possibility. And while many zebrafish researchers will continue to study development, others are now moving into the realms of physiology and behavioural studies.Geisler sums up zebrafish developmental research past, present, and future as follows: ‘No other [vertebrate] organism offers the same combination of transparent and accessible embryos, cost-effective mutagenesis screening, and, more recently, a sequenced genome, [DNA] chip, GFP, and knockout technology’. Add to that the potential of zebrafish embryos as a screening platform for small molecule libraries and the new technologies that allow forward and reverse genetics, and it is clear that zebrafish are not about to revert to being pretty pets swimming in small tanks in the corner of the living room.ZF-MODELShttp://www.zf-models.orgMore details of the work included in this European Union Integrated Project can be found at ZFINhttp://z.n.org/ZFIN, provides an extensive database for the zebrafish community including genetic, genomic, and developmental information; search engines for zebrafish researchers and laboratories; listings of meetings; and links to many other zebrafish sites, including sites with movies of zebrafish development.The ZFIN Web site, at Development  on the first two mutagenesis screens contains 37 research articles and can be freely accessed at http://dev.biologists.org/content/vol123/issue1/index.shtmlThe special issue of


During menopause, women experience major changes, including the onset of aging as a natural and inevitable event. The present study aimed to explore and explain the process of aging perception during menopausal transition. This study was a qualitative grounded theory research, which was going to be implemented in 2019–2020 on 18 Baluch women settled in the Sistan & Baluchestan province in South-East Iran and among midlife or older menopause experienced women. Sampling was started first by Purposive sampling, and then it was performed with theoretic sampling. Data analysis was performed according to Corbin and Straus’s approach (2015) in four phases: (1) identifying and developing concepts; (2) analyzing data for the context; (3) entering the process stage into analysis; and (4) integrating categories to build a theory. In this study, seven main categories were obtained: “Sunset of youth”, “aging as the other side of the coin of menopause”, “Weaving a cocoon”, “aging as a mental trap”, “social acceptance”, “aging domino”, and “feeling of transcendence”. It seems that menopause plays an important role in Baluch women’s view toward aging. The practical results of this study can be applied to better understand the middle-aged and older Baluch women’s attitudes toward aging. Also study shows a new evolutionary and situational perspective on the lives of middle-aged menopausal Baluch women. Baluch women in menopause accept the sunset of youth and look forward to experiencing the Feeling of transcendence. Identify and respond to their needs by developing and establishing health policies to change their negative attitudes. Aging is a natural process in an individual’s life. Changes associated with old age can form a new self-perception in an individual, known as “aging perception”. The aging perception is a measure of an individual’s satisfaction with the process of aging, reflecting one’s adaptation to age-related changes. This perception depends on the persons’ understanding of the aging process in their sociocultural context . It seemThe life of every individual consists of different periods . GeneralDuring menopause, women experience major changes, including the onset of aging as a natural and inevitable event , 9. NearDelyser and LockeAccording to the 2016 census, 7.4 million elderly people live in Iran, 50.6% of them are females . Iran isLiving in a patriarchal community, Baluch women face numerous gender-related problems that make their journey through life cycles complicated. Menopause as a transitional stage from middle age to aging may have special impact on the aging perception among women. As mentioned earlier, the aging perception is influenced by the person’s mentality based on cultural context ; therefoMost previous studies on the relationship between menopause and aging have employed quantitative approaches, which cannot explain the nature of the process. Few qualitative studies, while highlighting the importance of examining the nature of the phenomenon, used the content analysis approach , 26, 27 This qualitative study aimed to construct theory grounded in data. The method used in this study reflects Corbin and Straus’s approach to grounded theory analysis . The stuThe inclusion criteria were as follows: Iranian Baluch women who could understand/speak Persian and have logical verbal communications (to ensure the adequacy of cognitive ability); experiencing menopause(complete cessation of menstruation for one year or more) or in peri-menopausal stage (irregular menstruation/cessation of menstruation for at least 60 days or more); or having clinical symptoms of menopause , as approved by a physician or a midwife. The exclusion criteria were as follows: women with menopause due to surgery (hysterectomy or oophorectomy), medication use, chemotherapy, and having a psychiatric diagnosis.In-depth semi-structured, face to face, individual interviews were conducted to collect the data until reaching data saturation (no new codes were formed) The interviews were conducted in comprehensive community health centers or in women’s place of residence (participants’ preferences) and each lasted about 30–60 minutes.The first author  began the interviews by introducing herself, clarifying the goals of the study, and obtaining informed consent. Some of the main interview open- ended questions were as follows: “Can you explain your menopause and reproductive aging?”, “How did you find out you were going through menopause?”, “How did you feel when you find out it?”, “How did you your life changed during this time (in family and among other people)?”, and “What do you think has changed?”The main questions were followed-up by “why”, “when”, “what”, “where”, and “how” questions. If the participant referred to aging when describing her aging experiences, it would be explored by follow-up exploratory questions. Most of the interviews with female participants were conducted individually and recorded by a cell phone. After listening to the recordings several times, they were transcribed in Persian.Data analysis was performed according to Corbin and Straus’s approach (2015) in four phases: (1) identifying and developing concepts; (2) analyzing data for the context; (3) entering the process stage into analysis; and (4) integrating categories to build a theory. The statistic methods used in order to analyze and identify the data which were the context, process and consequences based on paradigm analytic tools such as asking questions from the data , and comparing . In this study, each interview was recorded, typed and transcribed, and initial code and then initial concept by researcher identified. In analyzing the data for context, concepts linked in order to establish between categories, and linked them together in a new concept through ongoing comparison. In the stage of process of the analysis, the relationships between intra-categories systematically and integrating the categories (subject labels based on integrated memo titles used to name concepts). In the stage of integrating the categories, the study’s storyline, core concept, hypothesis emerged by way of the relationship formed between the categories and clarification. In this Statistical analysis was not used any analytical app and it was done manually. Moreover, the criteria of credibility, dependability, conformability, and transferability, approved by Corbin, were used to meet the acceptability/validity criteria. The analysis was done by researcher and it was evaluated by two co-worker who were an expert in qualitative research.To increase acceptability, a combination of semi-structured interviews with note-taking at the scene and reminders was used along with other strategies, such as long-term engagement with the data and spending enough time on collecting, analyzing, and reviewing the data. Although the researcher was immersed in the subject under study for months, the supervisors, consultants, and participants’ opinions and feedbacks were also considered . MoreoveThe study was approved by the Research Ethics Committee at the Welfare and Rehabilitation Sciences University in Iran . The participants were informed about the study verbally and were assured of confidentiality and anonymity. They were informed that they could withdraw from the study at any time. The participants provided written informed consent before the interviews.In the present study, 2311 primary codes were obtained, yielding in 14 subcategories after comparing similarities and differences in the analysis stage. A total of seven main categories were obtained after continuous and theoretical comparisons of subcategories. According to the paradigm analytic tool, the results showed that during the event of menopause, women based on the conditions , chose the strategy of weaving a cocoon and waiting within it for the consequences  to appear .The sunset of youth is one of the main categories of the present study and a part of the structural and contextual conditions of the aging perception process in Baluch women. Advancing age or waning youth was the main concern stated by the participants. As soon as women faced menopause, they started to experience a feeling of becoming old and threatening by the aging challenges, such as Physical, sexual, and psychological declines. Therefore, they were entering a fearful stage, waited each month for menstruation to come and by losing their hope, they gradually started to feel that they are old. This main category included the subcategories of “fear of aging and hope for rejuvenation”, “threats of aging”, “physical manifestations of aging”, and “psychological manifestations of aging”.his subcategory referred to a feeling of being old in the women due to the possible challenges brought about by menopause, suggesting the importance of the menstrual cycles in the lives of these women. Despite the emergence of menopausal symptoms, Baluch women waited for the occurrence of menstruation each month and were focused on their menstrual signs and symptoms in the absence of bleeding. At first, women hoped that these changes are not related to menopause, but later, they were inevitably faced with the truth. Most of the participants stated that they were preoccupied with menstruation before menopause. In this regard, one of the participants said:“…When it was the time, my body, my back, and my abdomen ached; I got heavy and felt down…I felt like this for 4–5 days a month for several years. I was preoccupied with it.” Women who bear children at the age of 50 or 60 years are still considered young. I saw someone on TV who gave birth to a child at this age.” “Women believed that they were young as long as they had their menstrual periods. They considered menopause as the end of fertility and called it “Drought out” due to the emergent weakness and dryness of female reproductive system. They talked about it with sadness and regret and asked about its nature and inappropriate timing:I got completely dried out. I think I got old; and it was over.” “This participant also stated:The end of menstruation is related to aging and becoming dry. As we age, the uterus gets drier, and the dirty blood is dried in it; this is aging.” “Moreover, regarding the "non-excretion of dirty blood" during menopause, one of the participants said:I think when I menstruate, my body becomes lighter, and my eyesight improves. We think that during menstruation, the blood that comes out is poisonous by itself; I want this poison to leave my body. Although I am in so much pain during menstruation, I am willing to take it, without a single Hyoscine tablet, like my sisters and many other women in my family, because we believe that this poison must leave the body…” “The participants believed that the accumulation of dirty blood causes negative physical signs and symptoms:“Immediately after menopause, our eyesight is reduced, our hands and legs feel painful, and we get headaches…We start to have a poor vision…” The Baluch women’s perspective, with the loss of ovarian function, other organs will also undergo changes. It even affects the individual’s activities and psychological status . In this regard, one of the participants said:“For this reason, I feel old…I experience mood swings constantly since menopause; I became nervous; I am not who I was before.” It is one of the main categories of the current study and one of the structural and contextual requirements for understanding the process of aging perception in Baluch women. This category refers to the existence of a set of prevailing beliefs, attitudes, and opinions in the Baluch community regarding menopause, which is rooted in their cultural context and reminds people of the aging process. This main category included the following subcategories: “cultural importance of fertility” and “menopause-related environmental stress”.Due to the cultural importance of fertility in Baluch people , women do not discuss of their menopause and hide it as long as possible. These women attributed this secrecy between infertility and being old. One of the participants said:I had a party two nights ago. I asked someone about how many years had passed since her menopause; she told me that she was not so old and that she was still young! This is how it is; if we tell the truth, people say that we are old, or our husbands think that we cannot have any more children; so, they leave us and remarry.” “Baluch women also considered infertility to be synonymous with disease "Menopause is a disease”:Because your body is too disturbed in every possible way, you feel that you are not alive anymore, you just breathe ! Now, I have severe arthritis; I have pain in my legs, severe pain; I did not have it before, I became like this after menopause; I feel pain in all my bones; I have a heart disease; I feel very dizzy, and my eyes become blurred…”“Some women considered menopause as a form of “bad aging”:“We (women) do not have a good aging; it is very difficult. We become discouraged and disappointed with the world. Our weaknesses lead to sickness; we may go blind, or we may go deaf. Things have gotten worse since my menopause; now, I am completely worn out.” The menopausal experiences of family members and relatives stated as an influential factor in creating a feeling of becoming old by the participants. Regarding the negative consequences of menopause in her mother, one of the participants said:My mother had too much pain in her legs and her lower back; she had many problems. She used to say that when menopause starts, all diseases attack on your body, and you become powerless.” “It is one of the main categories, indicating the interaction between the aging perception and menopausal transition among women. In the Baluch community, women do not directly discuss of their menopause. Instead, they express it in covert ways such as changing their lifestyle and clothing; they wear darker colors, with simple designs, and limit the level of their activities. A woman’s alienation from the society begins by avoiding her partner. Because she feels old and unattractive, she refuses to have sex with her husband; therefore, she suppresses her sexual desire to show her reaction to her aging. This category consisted of the following subcategories: “changes in self-concept”, “reduced level of activity”, “ending the sexual relation”, and “acceptance of one’s fate”.This subcategory implied that Baluch women indirectly expose their menstrual transition by changing their image in the society and for themselves. One of the participants stated:This dress that I am wearing right now, although it has decorated by small flowers, not big ones, is not suitable for me; it does not suit my age. Its color should be darker, because I think I’ve gotten old…People believe that it’s unsuitable to wear some clothes as you get older, because you seem too flashy; the darker your clothes are, the more respectable you look…” “Moreover, about hiding menopause, one of the participants said:When my menstruation stopped, I did not tell my husband or anyone else. There was no need to say it; we did not have sex anymore, and we slept in separate beds. He also did not know if I was menstruating or not.” “This subcategory implied that women somehow deliberately reduced the level of their activities. One of the participants said:Sometimes, I go for a walk; I walk a little and then I have to sit down again. The cars stop by and offer me a ride as if I cannot walk on my own; I really hate this. They think I am miserable, poor, and lonely and have no one; that’s why I am not walking alone! I hate walking the streets like this.” “This subcategory involved women’s suppression of their sexual desires. In this regard, a participant said:We used to have sex for a while, but not anymore; I mean, I have become more masculine. I have become someone else; at first, I wanted him to come to me, but not anymore; I did not care about our marital relations at all.” “The participant women turned to religion to distract and calm themselves. In this regard, one of the participants said:The positive thing about menopause is that you can pray as much as you want. You can go to Quran sessions and touch the Quran . When menstruating, you cannot do these things; you can only recite God’s name, but now, if you do not pray, you will regret it.” “It is one of the main categories, related to the women’s reaction to aging process, and refers to feelings of confusion and uncertainty, which come along with changes in their social status. Permanent cessation of menstruation is the end of a stage in a woman’s life, and menopause is the beginning of a new phase in her body. So that with the onset of premenstrual symptoms each month, they suspected of still being young, and when the symptoms were over, they felt old again. These cycles were repeated even for several years, creating a feeling of entrapment in the women and the image that they have reached to the end of youth and “There is no way out”, for them.At first, I did not notice it; of course, I suspected it as my body was in pain. When my menstruation stopped, I asked myself what is happening to me?” “I am both middle-aged and old! I mean I think so.” “Regarding the feeling of change in status, one of the participants stated:They say that I’m always sitting and that I always fall behind things; I hate it. Some women get old at the age of 50 years, while some like me start to age from 37, women who have worked hard and faced many problems, tolerating their husbands’ constant nagging. In the end, the husband and children will blame you for it.” “It is one of the main categories, suggests that family support and respect can lead to acceptance of menopause by the women during transition from middle age to old age. The supportive behavior of the family and specially the spouse, which mostly occur over time, can lead to the acceptance of menopausal women by themselves and by the society. Regarding family support and respect, one of the participants stated:Thank God I have a child at home who does the house works. I felt confident at that time; I did not feel depressed at home at all.” “Finally, the spouse’s support was introduced as a determinant factor:My husband told me that he did not know what had happened to me; my poor husband did not tell me anything about it anymore…” “This main category indicates women’s feelings about their physical, functional, and psychological declines, causing them to socially isolate themselves. This category included the two subcategories of “Sunset of youth agility” and “insecurity and boredom”.Before transition to menopausal and experiencing the process of aging, women are interested to do difficult activities, as they feel proud of their energy of youth and fearlessness. With the onset of aging and menopause, they feel that their physical strength starts to decline. So feeling frustrated, they lose their courage to do many of their previous activities:“…When we are young, we feel proud of ourselves, and do not feel hardships of life…When we get older, we avoid everything; we get closer to God because we are weaker and have less power. I feel like this…Yes, we lose our sense of pride.” The Baluch women reported that they are feeling boredom after menopause:After the end of menstruation, I felt worse day by day. As you get older, you get depressed; I do not know what you call it. You get Alzheimer’s disease; I got Alzheimer’s. I swear to God I cannot remember the names of my children. For example, if I want to call my own child, sometimes, I call the names of all my daughters-in-law, first; I call all of them until I can remember the name of my own child.” “Although some of the participants had many children, they were upset and felt sorry that they could not have children anymore. As if, having the ability to give birth to another child made them more secure. One of the single participants, at the age of transition to menopause, expressed their fears of insecurity due to her possible future loneliness:Maybe those who have husbands and children will not be so affected, but I wonder who will help me; how my future will turn out; or what will happen to me.”“With the onset of postmenopausal changes, women start to have a more negative view of this transition:Look, my face has wrinkles, and my skin is dark…This started since menopause…” “The Baluch women believed that they could reach high levels of knowledge and rationality after the cessation of menstruation; in other words, these women hoped to reach to the higher ranks of their society and gradually assume an advisory role in major affairs as they get older, in a way people around them think of them differently. Also, because of their religious beliefs, women who were no longer menstruating felt closer to God, as they could focus on their religious practice. This main category included the subcategories of “feeling of superiority” and “Spiritual maturity”.Well, now that I am three years older since the start of menopause, my husband respects me more. The longer you live, the more respect you receive from your husband, your children, your family, and everyone else. The older you get, the more valuable you become. Well, aging can be good too; your family will think highly of you. They respect you very much.” “The other participant said:For example, when my old mother-in-law passed away, it was very difficult for us; it felt as if something very important was missing from our lives. “In the patriarchal society of Baluch, with advancing age, women find the opportunity to reach a social status similar to that of men:It is said that a woman who has stopped menstruating can go to a mosque to pray like a man does. The Baluch people believe in this. For example, my menstruation stopped 10–12 years ago; so, I can stand right behind the Mowlavi (mulla) to pray; I am pure now like a man!” “core category of this study was “Weaving a cocoon on the way to aging transcendence”. The Baluch women, during early phases of menopause and when they were entering a new developmental stage, mostly felt aging as a threat because of their cultural context and society which worshipped fertilization. They were experienced their sunset of youth accompanied by physical, functional, and psychological declines and felt disappointed. Moreover, they stated that they had developed various age-related diseases by the end of fertility and called it “bad aging”.The They adopt a secretive approach toward menopause to avoid being labeled by the society; they changed their clothing and are more inclined to stay at home. Since they found themselves vulnerable, they reduced their level of functional activities to prevent further harm. They even avoid sexual relations and somehow tried to end their marital life. As they hided themselves from the society, their inclination toward spirituality increased.By moving away from worldly preoccupations, women aimed to achieve spiritual growth and stop focusing on their physical, psychological, and functional problems. It seems that women, by losing some abilities, need to acquire a variety of other abilities. They believed that they can get closer to God, using the postmenopausal period to worship God and elevate their spiritual life. Meanwhile, the society, also, accepted them and gave them a higher position due to their developed intellectual and spiritual powersThe results of this study aimed to explore the aging perception of Baluch women during the menopausal transition. The Baluch women in our study remarked that the occurrence of menopause was associated with a feeling of becoming old, which was accompanied by physical, sexual, functional, and psychological declines in them, emerging in the cultural context of their society. They also felt that despite the decline in their physical strength and the related social stress, during their menopause period, they felt that they are closer to God. They rather consciously tried to avoid many social activities and waited for a time point that they could obtain a high l status as a respected and wise person enable to instruct others in the community. Therefore, the context, actions/ interactions and consequences are discussed in this section.context of Baluch society revealed that as soon as menstruation stops, middle-aged Baluch women start to feel older; this suggests the importance of menstruation and fertility in Baluch community. These women believed that with vaginal drying, their eyesight began to dim and this is a sign onset of aging. In their opinion, other organs in their body were also gradually declined, indicating the end of life as a youth and the onset of limitations in the person’s movements and many other activities. In this study, women used phrases, such as “getting dried out”, to describe the end of the reproductive period.Exploring the According to the studies by Ramakuela , Araya , YazdkhaIn the present study, menopause and aging were assumed to be two sides of the same coin. In Baluch culture, “Menopause is a disease” which means that aging itself is a disease, too. In this study, since most participants described menopause as a disease, the onset of aging which considers as a time for disease was also strongly felt. They believed that the lack of blood excretion led to the accumulation of toxins in the body and resulted in the onset of diseases. On the other hand, lost fertility was considered as a defect by these women and made them avoid discussing it. In a study aging has been compared to disease and death, too . AccordiOne of the most important reasons why women began to hide themselves from the society was the onset of perceived aging, which was associated with menopause and losing their fertility power. In other words, women, by menopause, felt that they gradually lose their beauty and vigor and experienced the signs and symptoms of aging. It seems reasonable as an individual’s sense of purpose and meaning in life is influenced by the intrinsic values of the culture that she/he lives in , where wAction/interaction in the present study, “Weaving a cocoon” was a major approach in Baluch menopausal woman. The first behavioral changes observed in these women based on the informal norms of the society, were those which obliged them to behave according to their family role and age; therefore, women made some changes in their appearance including clothing because of both the social expectations and their own feelings of necessity. Similarly, non-verbal signs in other cultures regarding clothing and even jewelry and accessories were found https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. </div> While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool,  15 Sep 2022rebuttal letter Dear Reviewer #2:1. In the inclusion criteria, isn't 60 days a short period of time to experience menopausal symptoms in terms of the perception of menopause? Is there any literature on this?Response:Participants were experiencing of the transition of menopause & post menopause and they selected Based on STRAW Staging System (1)https://doi.org/10.1210/jc.2011-33621) Siobán D. Harlow, Margery Gass, Janet E. Hall, Roger Lobo, Pauline Maki, Robert W. Rebar, Sherry Sherman, Patrick M. Sluss, Tobie J. de Villiers, for the STRAW + 10 Collaborative Group, Executive Summary of the Stages of Reproductive Aging Workshop + 10: Addressing the Unfinished Agenda of Staging Reproductive Aging, The Journal of Clinical Endocrinology & Metabolism, Volume 97, Issue 4, 1 April 2012, Pages 1159–1168, 2. • It would be appropriate to include "having a psychiatric diagnosis" in the exclusion criteria.Response:Thanks. This criteria considered in the research, thus added3. • It is not clear exactly how the sample was determined, it should be detailed.Response:Add: . The first step Purposive Sampling was performed based on inclusion criteria with maximum diversity in sampling  by researcher in the comprehensive health service centers, in Zahedan in the southeast of Iran and contacted the participants and conducted interviews at the center or at home , at their request. purposefully to recruit the participants. In the next step, theoretical sampling was performed, and based on the results of data analysis the main concepts were formed, and the relationships between these concepts were explained.4. • Statistical methods used in data analysis should be written clearly. Information about content analysis should be given.Response:Data analysis was performed according to Corbin and Straus’s approach (2015) in the grounded theory in four phases: (1) identifying and developing concepts; (2) analyzing data for the context; (3) entering the process stage into analysis; and (4) integrating categories to build a theory. . The statistic methods used in order to analyze and identify the data which were the context, process and consequences based on paradigm analytic tools such as asking questions from the data , and comparing . In this study, each interview was recorded, typed and transcribed, and initial code and then initial concept by researcher identified. In analyzing the data for context, concepts linked in order to establish between categories, and linked them together in a new concept through ongoing comparison. In the stage of process of the analysis, the relationships between intra-categories systematically and integrating the categories (subject labels based on integrated memo titles used to name concepts). In the stage of integrating the categories, the study’s storyline, core concept, hypothesis emerged by way of the relationship formed between the categories and clarification • How and by whom was content analysis evaluated?Response:Add: . The analysis was done by researcher and it was evaluated by two co-worker who were an expert in qualitative research.5. • In which program were the records analysed?Response:Add: . In this Statistical analysis was not used any analytical app and it was done manually.• The writing of the Discussion section is disorganized. Adding the results of your study first, then the literature findings, and then the comments will make it more organized. Commentary sentences should be placed at the end of the paragraph.Response:6. It checked &corrected7. • Reference spelling rules and punctuation should be paid attention to.Response: It checked &correctedList of references completed & corrected : ref(8-14-16-17-19-20-21-23-24-25-30-31-32-33-34-35-36-39-40-41-42-44)There are not any retracted articles.AttachmentResponse to Reviewers.docSubmitted filename: Click here for additional data file. 14 Oct 2022Weaving a Cocoon on the Way to Aging Transcendence: Grounded Theory Study on Aging perception during Menopause TransitionPONE-D-21-38238R1 <span style="color: rgb; font-family: verdana, geneva, arial, helvetica, sans-serif; font-size: 11.2px; background-color: rgb;"> Farahnaz Mohammadi-Shahboulaghi, </span> Dear Dr. We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at onepress@plos.org.If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact Kind regards,Nülüfer Erbil, Ph.D, Prof.Academic EditorPLOS ONE 20 Oct 2022PONE-D-21-38238R1 Weaving a Cocoon on the Way to Aging Transcendence: Grounded Theory Study on Aging perception during Menopause Transition Dear Dr. Mohammadi-Shahboulaghi:I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. onepress@plos.org.If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact plosone@plos.org. If we can help with anything else, please email us at Thank you for submitting your work to PLOS ONE and supporting open access. 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Carl Bergmann was an astute naturalist and physiologist. His ideas about animal size and shape were important advances in the pre-Darwinian nineteenth century. Bergmann’s rule claims that that in cold climates, large body mass increases the ratio of volume-to-surface area and provides for maximum metabolic heat retention in mammals and birds. Conversely, in warmer temperatures, smaller body mass increases surface area relative to volume and allows for greater heat loss. For humans, we now know that body size and shape are regulated more by social-economic-political-emotional (SEPE) factors as well as nutrition-infection interactions. Temperature has virtually no effect. Bergmann’s rule is a “just-so” story and should be relegated to teaching and scholarship about the history of science. That “rule” is no longer acceptable science and has nothing to tell us about physiological anthropology. Just So Stories by Rudyard Kipling . He formulated his hypothesis that “…if we could find two animal species which only differed in size…the geographic distribution of these two species should be relatively determined by their size; which absolutely taken would be their homeland, the smaller one should ask for a warmer, the larger one for a colder climate.” Bergmann found support for his hypothesis by comparing body size and wingspan of various birds known to him, of different species but the same family, and showed that in many species, the volume-to-surface ratio is associated with their geographic distribution. Using an approach that may be considered statistical, he found that a majority of species are subject to what is known today as Bergmann’s rule.Bergmann particularly considered the extremes as he believed they represented the upper and lower possible limits for size in endotherms. Bergmann believed that hummingbirds are close to this lowest possible limit for size in endotherms. He then asked, “…whether in all places extremes in size have been reached or not…” and looked for the “largest and smallest homeotherm creatures.” He realized, “…that in the temperate and cold regions, extreme sizes even though possible according to this law, have not been reached…,” and he concluded that “…nature did not fully complete its limits which would have been offered according to this law…The largest animals of the cooler zones have for whatever reasons not been created.” Almost modern in his thinking, he further stated that it “…is not understandable, and rather looks like random particularly when remembering the large distribution of elephant-like and other very large animals Bergmann’s rule is popular since more than 170 years and belongs to the list of what German-speaking people call “Lieschen MüllerBergmann’s 1848 book was published in an old-style German orthography that makes reading his book difficult, even for contemporary native speakers of German. There does not appear to be an English-language translation of the entire book. Consequently, few people have read the original, even those who cite the book in their own research and teaching. This has led to considerable misunderstanding about what Bergmann wrote in his book. As noted by Salewski and Watt , “…BergmOrigin of Species was published. Even so, Allen continued with Bergmann’s pre-evolutionary thinking. Allen cited Darwin’s Origin of Species and discussed natural selection but rejected it. Allen wrote, “…that other influences than natural selection operate powerfully in the differentiation of specific forms, and that geographical causes share more largely in the work than naturalists have heretofore been prepared to admit” [th century American view that much evolutionary change came about through the direct action of the environment, and not natural selection” [Similar admonitions apply to Allen’s rule. Joel Asaph Allen (1838–1921) published his most famous work in an English-language article titled, “The influence of physical conditions in the genesis of species” . As noteo admit” . Smith election” .interspecific. The application of Bergmann’s rule to human beings is intraspecific. In addition, while Bergmann analyzed more than 300 species of birds, belonging to 86 genera, he did not discuss human size. This was done some 100 years later by Derek Roberts (1925–2016) who was interested in the heat production of people according to the climate of their habitats [One of the most common misunderstandings about Bergmann’s research is that he compared what he called “closely related species” living at different latitudes. Biological “species” was a poorly understood concept in 1848, but even so, Bergmann’s comparisons were s 1925–20 who was The human adult phenotype is distinguished from that of the nonhuman primates by proportions of the arms and legs and by the size and shape of the cranium relative to the face and to total body length. These species-specific adult differences develop during the ontogeny of the individual. One classic example was provided by Adolf Schultz , who skeThe human fetus and neonate have a leg length that never exceeds ~33% of total body length, but legs grow relatively quickly after birth to become, on average, 48% of body length by adulthood. This remarkable change in body proportions was illustrated by Stratz , whose oThe ape-human differences in the pattern of body proportion development from fetus to adult may be explained in large part by the evolution of human bipedalism and by the large and complex human brain. Bipedal locomotion places a biomechanical premium on having legs longer than arms. In contrast, the nonhuman apes practice brachiation, which places that premium on having arms longer than legs. The role of the brain in human biological and behavioral evolution is amply discussed elsewhere . Human nThis pattern of fetal circulation is common to most mammals and is likely to be evolutionarily ancient. Because energy and other growth requirements are limited, there is a trade-off between growth of the upper body and the legs, which results in the mammalian fetal pattern of body proportion of large head relative to short legs. To grow and maintain the larger human fetal brain, there is an amplification of the preferential flow of blood to the ascending aorta. The ancient circulatory pattern may leave the human fetal legs with a more acute reduced supply of oxygen and nutrients than other mammals, further slowing fetal leg growth and development compared with more cephalic regions of the body and compared with the fetuses of our smaller-brained primate cousins.SHR = 47.3 for men and 48.1 for women, to the maximum SHR values, i.e., relatively shortest legs, for Guatemala Maya men and Peruvian women (SHR = 54.6 and 55.8).Relative to total body length, boys and men tend to have longer legs and arms than girls and women, although much variation exists. Discrete populations of living humans present a diversity of body sizes and shapes. Mean stature for populations of adults varies from minimum values for the Efe Pygmies of Africa at 144.9 cm for men and 136.1 cm for women  to the mMaking sense of these worldwide comparisons is difficult because of the differences in lifestyle, environment, migration events, and genomics. Despite the plethora of possible factors, most anthropological, human biology, and human physiology research resorts to Bergmann’s and Allen’s rules as primary causes for the global patterns of human body shape variation.Perhaps, the first researcher to carefully assess Bergmann’s rule as applied to humans was Derek Roberts, as mentioned above. He published an analysis showing a significant relationship between body mass and latitude, with groups of people living at higher latitudes having greater body mass than those living closer to the equator . Twenty-r = −0.59. Robert’s 1953 illustration of the data is presented here as Fig. In his famous compilation of studies, Roberts synthesized data from different ethnic groups living at mean annual temperatures between 10 and 80 °F and with adult men weighing between 40 and 77 kg. He found a negative relationship between body weight and mean environmental temperature with correlation value of r = −0.5 to −0.6. Correlations cannot prove causality or, even, the direction of association. It is, of course, absurd to claim that greater body mass of a mammalian species “causes” lower temperature. The reverse, however, is exactly Bergmann’s rule, but does this “rule” make a better explanation? In statistics, the square of the correlation value is often taken as an indication of the percentage of explained variance between two variables. Doing so for Bergmann’s rule means that climate “explains,” at maximum, about 36% of variation in human body mass. Other factors explain the other 64% of the variance.These climate relationships, however, are only correlations, with values in the range of r = −0.3 or less in both sexes. Statistically, the variance explained has dropped to only 9%, which is not a biologically meaningful percentage. Similar findings were reported by Foster and Collard [2), the ratio of surface area to body mass (SA/BM), and the ponderal index (kg/ht3). The percent of variance explained  in these associations varied from a minimum of 0.07 for latitude and ponderal index to a maximum of 0.33 for latitude and body mass. Most of the other R2 values were ~0.20. Again, these values have little biological meaning.A reanalysis of the Roberts’ data by Katzmarzyk and Leonard  modified Collard  based onThe mean annual temperature data for different latitudes used in the analysis by Katzmarzyk and Leonard were taken from sources published between 1970 and 1981. Today, we know that there was a trend of mean global temperature increase during the twentieth century, by about +0.35 °C between 1950 and 1990. Katzmarzyk and Leonard did not consider this trend, and it is just as well that they did not. It is unlikely that the small rise in average global temperature can account for the reduced correlation between body shape and temperature across some 20–30° of latitude between arctic and tropical climates. Katzmarzyk and Leonard reported that the primary reason for the lower correlation was the increase in body mass of the tropical latitude populations, that is, from those regions of the world with a mean average annual temperature ≥ 15 °C. The authors proposed that changes in nutrition and health were the likely reasons for the rapid increases in body mass. Subsequent research confirms the epidemic rise of overweight and obesity of tropical latitude peoples around the world, especially in the current lower-income nations that were colonial era territories of Europe and the USA , 37. KatThe hypothesis that food more than temperature underlies Bergmann’s rule was proposed previously by Geist , who staBuilding on these previous analysis, Pomeroy and colleagues  analyzedThe belief in the fundamental truth that Bergmann’s rule applies to humans is based on the accidental association of height, weight, and average temperature variation by latitude that existed at the time of Robert’s analysis. Before and after that time, that is, before and after 1953, the situation was different, and Bergmann’s rule did not apply. Roberts was, in a sense, lucky when he did his 1953 analysis because he was really describing the effect of secular trends for increased height in the rich northern nations versus the stagnation or decline in height of people in the lower-income colonial era southern nations. In 1953, this difference in average adult stature was at its maximum. The height difference had everything to do with differences in the standard of living and the quality of the social-economic-political-emotional (SEPE) environment . The difDuring the years between Bergmann’s work and Roberts’ compilation, average body height of populations of many nations, and particularly of the industrialized countries, significantly increased. In a meticulous collection of global height changes between the mid-nineteenth and the mid-twentieth century, Kenntner  showed tAs discussed above, in 1998, Katzmarzyk and Leonard  publisheShort or tall adult stature can no longer be considered a simple synonym of nutrition history. It is shown in several recent analyses that height variation within several equatorial and temperate latitude groups of people is quite independent of diet , such as nesting space, food, and mating partners, is influenced by the dominance hierarchy  and/or degree of aggressiveness versus affiliation  of individuals within the group. In humans, growth and final height appear to have causal associations to peer groups, social networks, and dominance within the group [Recent research with social mammals shows that the regulation of growth does not follow some simple genetic program but is strongly regulated by SEPE factors , 54, 55.he group –69. Humahe group .Improvements in SEPE factors leading to social mobility, higher wages, greater democratization, and greater feelings of security have given rise to the exuberant increase in height within a few generations in the contemporary industrial world. The shortness in height currently observed in the low- and middle-income countries may indicate their delay in SEPE modernization when compared to the Western world, but it must not be mistaken as an example of Bergmann’s rule. There is no evidence that Bergmann’s rule applies in these studies of present-day humans.Elsewhere , 70, addThe phrase “political climate” is used here as an analogy and contrast to the meteorological climate. This example describes the political weather of the last 35 years in Germany. This was a period of notable modification of anthropometric parameters during the breakup of the former Soviet Union and the transition of the political, socioeconomic, and emotional circumstances. There was a stark contrast in the economic and political situation between the former German Democratic Republic  and West Germany prior to reunification and during the early 1990s. At the time of reunification in 1989, the body height of school children of East Germany was significantly shorter than that of same-age school children in West Germany, but the difference nearly disappeared within 4–5 years. Pelvic and elbow breadth of all the children decreased at the beginning of 2000, and their fat distribution pattern became more “feminine” after 1997, that is, relatively more fat on hips and lower extremities . The incTwo additional examples add support to the interpretation that population variation in body shape is primarily related to nutritional and SEPE influences, but not to temperature. The first is based on studies conducted since the 1960s with Guatemala Maya people. The rural Maya often lives at altitudes above 1500 m and experience cold temperatures. Their short stature with particularly short legs has been cited as an example of Bergmann’s rule. It was known, however, that the rural Maya consumed only about 80% of the total energy needed for healthy growth, and most of the population suffered much infectious disease and intestinal parasites. In addition, 20.4% of primary school children were also iodine deficient . Iodine These examples emphasize that the small body size and body shape of the Maya and native Peruvians is an unhealthy response to dietary and infectious disease stress and poor SEPE conditions. These examples negate Bergmann’s rule. It is clear from these examples that body size and shape are not beneficial adaptations to the temperature climate. Maya and native Peruvians suffer from an unhealthy emotional climate due to insecurities in education, health care, employment, and housing. The insecurities are associated with adverse childhood experiences and chronic toxic stress that are known to delay skeletal growth, especially in the legs .Carl Bergmann was an astute naturalist and physiologist. His ideas about animal size and shape were important advances in the pre-Darwinian nineteenth century. Today, Bergmann’s rule is a “just-so” story and should be relegated to teaching and scholarship about the history of science. That “rule” is no longer acceptable science and has nothing to tell us about physiological anthropology.