In this review, we provide an overview of the dynamic changes within the microbiota and its metabolites that are implicated in establishing and maintaining gastrointestinal homeostasis during various stages of microbial colonization. The gradual conversion of the gut microbiota toward a mutualistic microbial community involves replacement of pioneer gut colonizers with bacterial taxa that are characteristic for the adult gut. An important microbial signature of homeostasis in the adult gut is the prevalence and activity of a diverse spectrum of bacterial (...) species that produce beneficial metabolites through metabolic interactions between microbial groups. Deciphering these microbial signatures and their metabolites that govern short and long‐term equilibrium, as well as imbalances in host‐microbial relationships, may provide novel diagnostic tools and/or therapeutic targets for specific disorders associated with intestinal dysbiosis and loss of homeostasis. (shrink)

This article considers the role of the adult epithelial stem cell, with particular reference to the intestinal epithelial stem cell. Although the potential of adult stem cells has been revealed in a number of recent publications, the organization and control of the stem cell hierarchy in epithelial tissues is still not fully understood. The intestinal epithelium is an excellent model in which to study such hierarchies, having a distinctive polarity and high rate of cell proliferation and migration. Studies on the (...) small intestinal crypt provide insight into the characteristics of the stem cells in normal and regenerating circumstances and demonstrate why a thorough understanding of these cells is an essential pre‐requisite for stem cell based therapeutic approaches. BioEssays 24:91–98, 2002. © 2002 John Wiley & Sons, Inc. (shrink)

In this paper the scientific trajectory of Spanish influential biochemist Alberto Sols (1917–1989) is presented in comparative perspective. His social and academic environment, his research training under the Cori's in the US in the early 1950s and his works when coming back to Spain to develop his own scientific career are described in order to present the central argument of this paper on his path from physiological research to research on enzymatic regulation. Sols' main contributions were both scientific and academic. (...) He and his collaborators not only contributed to biological knowledge on the biochemistry of metabolic regulation but to the active reception of biochemistry in the Spanish academia and to update of Spanish medical education. -/- . (shrink)

Interactions between the host and its associated microbiota differ spatially and the local cross talk determines organ function and physiology. Animals and their organs are not uniform but contain several functional and cellular compartments and gradients. In the intestinal tract, different parts of the gut carry out different functions, tissue structure varies accordingly, epithelial cells are differentially distributed and gradients exist for several physicochemical parameters such as nutrients, pH, or oxygen. Consequently, the microbiota composition also differs along the length of (...) the gut, but also between lumen and mucosa of the same intestinal segment, and even along the crypt‐villus axis in the epithelium. Thus, host‐microbiota interactions are highly site‐specific and the local cross talk determines intestinal function and physiology. Here we review recent advances in our understanding of site‐specific host‐microbiota interactions and discuss their functional relevance for host physiology. (shrink)

필자는 본 논문을 통해 서구 형이상학이 제시하는 몸의 위상을 분석한 뒤 새로운 몸 개념을 통해 기존의 몸의 도식의 전복 가능성을 고찰해 보고자 한다. 데카르트에 의해 수립된 몸의 도식은 몸-자동기계(body-mecanic)와 의식조정-자동기계라는 이중의 층위로 분절화되어 있는데 우리는 논증을 통해 이것을 비판적으로 분석하도록 할 것이다. 기존의 몸 도식이 ‘메카닉(mecanic)’이라는 정합적이고 기능주의적인 유기체 논리에서 벗어나지 못하고 있다는 점에 주목하여, 필자는 들뢰즈와 가따리의 “기관 없는 신체(Corps sans organes)” 개념의 프리즘을 통해 “장기-몸(intestins-corps)”이라는 새로운 몸 개념을 제시하고자 한다. 장기-몸(intestins-corps)은 일련의 정합적이고 유기체적인 질서로부터 적출되어 나와 카오스적인 에너지로 (...) 들끓으며 이질적 요소들과의 무한연접으로 열려있는, 새로운 차원의 몸이다. 이러한 장기-몸의 봉기를 가장 잘 나타내주는 사태는 다름 아닌 극한고통이 도래하는 출산이라고 본다. 필자는 출산이 어떤 의미에서 ‘장기-몸’이 실질적으로 가동되는 상태인지를 지젝의 논의의 분석을 통해 심도 있게 고찰할 것이다. 또한 출산을 거친 자들이 상징질서로 편입되지 않고 금기를 깨고 되돌아오는, 살아있는 망자(the living dead)임을 지젝의 논의로부터 분석해 보겠다. 이로서 출산과 같은 극한고통의 체험이 갖는 카오스적 파괴의 힘이 어떤 측면에서 상징적 질서에 균열을 가할 수 있는지도 발터 벤야민의 ‘신적 폭력’ 개념을 착안해 고찰할 것이다. (shrink)

The human pathogen Vibrio cholerae exhibits two distinct lifestyles: one in the aquatic environment where it often associates with chitinous surfaces and the other as the causative agent of the disease cholera. While much of the research on V. cholerae has focused on the host‐pathogen interaction, knowledge about the environmental lifestyle of the pathogen remains limited. We recently showed that the polymer chitin, which is extremely abundant in aquatic environments, induces natural competence as a mode of horizontal gene transfer and (...) that this competence regulon also includes the type VI secretion system (T6SS), a molecular killing device. Here, I discuss the putative consequences that chitin‐induced T6SS activation could have on intestinal colonization and how the transmission route might influence disease outcome. Moreover, I propose that common infant animal models for cholera might not sufficiently take into account T6SS‐mediated interbacterial warfare between V. cholerae and the intestinal microbiota. (shrink)

Unraveling molecular and functional heterogeneity of niche cells within the developing endoderm could resolve mechanisms of tissue formation and maturation. Here, we discuss current unknowns in molecular mechanisms underlying key developmental events in pancreatic islet and intestinal epithelial formation. Recent breakthroughs in single‐cell and spatial transcriptomics, paralleled with functional studies in vitro, reveal that specialized mesenchymal subtypes drive the formation and maturation of pancreatic endocrine cells and islets via local interactions with epithelium, neurons, and microvessels. Analogous to this, distinct intestinal (...) niche cells regulate both epithelial development and homeostasis throughout life. We propose how this knowledge can be used to progress research in the human context using pluripotent stem cell‐derived multilineage organoids. Overall, understanding the interactions between the multitude of microenvironmental cells and how they drive tissue development and function could help us make more therapeutically relevant in vitro models. (shrink)

Previous work has suggested that many stem cells can be found in microanatomic niches, where adjacent somatic cells of the niche control the differentiation and proliferation states of their resident stem cells. Recently published work examining intestinal stem cells (ISCs) in the adult Drosophila midgut suggests a new paradigm where some stem cells actively control the cell fate decisions of their daughters. Here, we review recent literature(1) demonstrating that, in the absence of a detectable stem cell niche, multipotent Drosophila ISCs (...) modulate the Notch signaling pathway in their adjacent daughter cells in order to specify the differentiated lineages of their descendants. These observations made in Drosophila are challenging and advancing our understanding of stem cell biology. BioEssays 30:107–109, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

Maintaining intestinal homeostasis is a key prerequisite for a healthy gut. Recent evidence points out that microRNAs (miRNAs) act at the epicenter of the signaling networks regulating this process. The fine balance in the interaction between gut microbiota, intestinal epithelial cells, and the host immune system is achieved by constant transmission of signals and their precise regulation. Gut microbes extensively communicate with the host immune system and modulate host gene expression. On the other hand, sensing of gut microbiota by the (...) immune cells provides appropriate tolerant responses that facilitate the symbiotic relationships. While the role of many regulatory proteins, receptors and their signaling pathways in the regulation of the intestinal homeostasis is well documented, the involvement of non‐coding RNA molecules in this process has just emerged. This review discusses the most recent knowledge about the contribution of miRNAs in the regulation of the intestinal homeostasis. (shrink)

Background Intestinal transplant in infants with severe short bowel syndrome (SBS) is an emerging therapy, yet without sufficient long-term data or established guidelines, resulting in possible variation in practice. Objectives To assess current attitudes and counselling practices among physicians regarding intestinal transplant in infants with SBS, and to determine whether counselling and management vary between subspecialists or centres. Methods A national sample of practicing paediatric surgeons and neonatologists was surveyed via the American Academy of Paediatrics listserves. Results were analysed by (...) physician subspecialty and again by presence or absence of intestinal transplant at respondent's centre. Results The survey was completed by 433 respondents, consisting of 363 neonatologists and 70 paediatric surgeons. Fifty-seven respondents (13.2%) practiced at a centre that performed intestinal transplants in children. The vast majority of respondents (91% for preterm, 95% for term neonates) felt that maintaining a neonate with SBS on total parenteral nutrition for intestinal transplant was ethically optional (neither impermissible nor obligatory), and that parents should be given an informed choice whether to pursue that option. However, only 33% indicated they often/always offer intestinal transplant as a treatment option to families in this situation. Conclusions There is a marked disparity between individual physicians’ beliefs regarding the acceptability of intestinal transplant for severe SBS and their reported practice. Wide variability exists among physicians with respect to their knowledge, beliefs and practice regarding severe SBS, raising concerns about transparency and justice. Survival data prior to transplant, currently unavailable, are essential to rational decision making and informed parental permission. (shrink)

Regulators of G protein signaling (RGS) proteins provide timely termination of G protein‐coupled receptor (GPCR) responses. Serving as a central control point in GPCR signaling cascades, RGS proteins are promising targets for drug development. In this review, we discuss the involvement of RGS proteins in the pathophysiology of the gastrointestinal inflammation and their potential to become a target for anti‐inflammatory drugs. Specifically, we evaluate the emerging evidence for modulation of selected receptor families: opioid, cannabinoid and serotonin by RGS proteins. We (...) discuss how the regulation of RGS protein level and activity may modulate immunological pathways involved in the development of intestinal inflammation. Finally, we propose that RGS proteins may serve as a prognostic factor for survival rate in colorectal cancer. The ideas introduced in this review set a novel conceptual framework for the utilization of RGS proteins in the treatment of gastrointestinal inflammation, a growing major concern worldwide. (shrink)

Clonal studies of adult chimaeric mouse epithelium have demonstrated the monoclonal composition of crypts of Lieberkühn(1). In neonatal life, however, polyclonal crypts have been found, indicating that crypts are of polyclonal origin(2). We here relate these findings to studies of mosaic tissues which have addressed the question whether solid tumours are of monoclonal or polyclonal origin (ref. 3 for review, 4). The issues has so far remained unresolved because the expected frequencies of polyclonal tumours, given polyclonal origins, have not previously (...) been estimated. A general approach for the calculation of such expected values is suggested. The consistent reports of tumours with polyclonal components suggest that autocrine or paracrine mechanisms play an important role during tumorigenesis. (shrink)

The aim of this article is to explore bodily changes following weight loss surgery. Our empirical material is based on individual interviews with 22 Norwegian women. To further analyze their experiences, we build primarily on the phenomenologist Drew Leder`s distinction between bodily dis-appearance and dys-appearance. Additionally, our analysis is inspired by Simone de Beauvoir, Merleau-Ponty and Julia Kristeva. Although these scholars have not directed their attention to obesity operations, they occupy a prime framework for shedding light on different dimensions of (...) bodily change. In doing so, we were able to identify two main themes: The felt “inner” body versus the visible “surface” body and the “old” body versus the “new” body. In different, though interconnected ways, these main themes encompass tensions between changes the women experienced as contributing to a more “normal” and active life, feeling more accepted, and changes that generated ambivalence. In particular, their skin became increasingly problematic because it did not “shrink” like the rest of the body. On the contrary, it became looser and looser. Moreover, badsmelling folds of skin that wobbled, sweated and chafed at the smallest movement, aprons of fat hanging in front of their stomachs, batwing arms, thick flabby thighs and sagging breasts were described as a huge contrast to the positive response they received to their changed body shape when they were out and about with their clothes on. At the same time, they expressed ambivalence with regards to removing the excess skin by means of plastic surgery. Through their own and other women`s experiences they learned removing the excess skin by means of surgery could be a double-edged sword. By illuminating the experiences of the ones undergoing such changes our article offers new insight in a scholarly debate predominated by medical research documenting the positive outcomes of weight loss surgery. (shrink)

In humans, the intestine is the major reservoir of microbes. Although the intestinal microbial community exists in a state of homeostasis called eubiosis, environmental and genetics factors can lead to microbial perturbation or dysbiosis, a state associated with various pathologies including inflammatory bowel diseases (IBD) and colorectal cancer (CRC). Dysbiotic microbiota is thought to contribute to the initiation and progression of CRC. At the opposite end of the spectrum, two recently published studies inSciencereveal that the microbiota is essential for (...) chemotherapeutic drug efficacy, suggesting a beneficial microbial function in cancer management. The dichotomy between the beneficial and detrimental roles of the microbiota during cancer initiation, progression, and treatment emphasize the interwoven relationship between bacteria and cancer. Moreover, these findings suggest that the microbiota could be considered as a therapeutic target, not only at the level of cancer prevention, but also during management, i.e. by enhancing the efficacy of chemotherapeutics. (shrink)

The human intestines are constantly under the influence of numerous pathological factors: enteropathogenic microorganisms, food antigens, physico‐chemical stress associated with digestion and bacterial metabolism, therefore it must be provided with a system of protection against adverse impact. Recent studies have shown that Paneth cells play a crucial role in maintaining homeostasis of the small intestines. Paneth cells perform many vital functions aimed at maintaining a homeostatic balance between normal microbiota, infectious pathogens and the human body, regulate the qualitative composition and (...) number of intestinal microorganisms, prevent the introduction of potentially pathogenic species, and protect stem cells from damage. Paneth cells take part in adaptive and protective‐inflammatory reactions. Paneth cells maintain dynamic balance between microbial populations, and the macroorganism, preventing the development of intestinal infections and cancer. They play a crucial role in gastrointestinal homeostasis and may be key factors in the etiopathological progression of intestinal diseases. (shrink)

Apoptotic pathways have always been regarded as a key‐player in preserving tissue and organ homeostasis. Excessive activation or resistance to activation of cell death signaling may indeed be responsible for several mechanisms of disease, including malignancy and chronic degenerative diseases. Therefore, targeting apoptotic factors gained more and more attention in the scientific community and novel strategies emerged aimed at selectively blocking or stimulating cell death signaling. This is also the case for the TMEM219 death receptor, which is activated by a (...) circulating ligand, the Insulin‐like growth factor binding protein 3 (IGFBP3) and induces a caspase‐8‐dependent apoptosis of the target cells. Interestingly, stimulation of the IGFBP3/TMEM219 axis exerts an anti‐proliferative effect, while blockade of the TMEM219 deleterious signal protects TMEM219‐expressing cells of the endocrine pancreas, lung, and intestine from damage and death. Here, we summarize the most updated reports on the role of the IGFBP3/TMEM219 apoptotic axis in disease conditions, including intestinal disorders and diabetes, and we describe the advancements in designing and testing novel TMEM219‐based targeting approaches in emerging potential clinical applications. (shrink)

The human intestinal ecosystem, previously called the gut microflora is now known as the Human Gut Microbiota. Microbiome research has emphasized the potential role of this ecosystem in human homeostasis, offering unexpected opportunities in therapeutics, far beyond digestive diseases. It has also highlighted ethical, social and commercial concerns related to the gut microbiota. As diet factors are accepted to be the major regulator of the gut microbiota, the modulation of its composition, either by antibiotics or by food intake, should be (...) regarded as a fascinating tool for improving the human health. Scientists, the food industry, consumers and policymakers alike are involved in this new field of nutrition. Defining how knowledge about the HGM is being translated into public perception has never been addressed before. This raises the question of metaphors associated with the HGM, and how they could be used to improve public understanding, and to influence individual decision-making on healthcare policy. This article suggests that a meeting of stakeholders from the social sciences, basic research and the food industry, taking an epistemological approach to the HGM, is needed to foster close, innovative partnerships that will help shape public perception and enable novel behavioural interventions that would benefit public health. (shrink)

Organoids are three-dimensional biological structures grown in vitro from different kinds of stem cells that self-organise mimicking real organs with organ-specific cell types. Recently, researchers have managed to produce human organoids which have structural and functional properties very similar to those of different organs, such as the retina, the intestines, the kidneys, the pancreas, the liver and the inner ear. Organoids are considered a great resource for biomedical research, as they allow for a detailed study of the development and pathologies (...) of human cells; they also make it possible to test new molecules on human tissue. Furthermore, organoids have helped research take a step forward in the field of personalised medicine and transplants. However, some ethical issues have arisen concerning the origin of the cells that are used to produce organoids and their properties. In particular, there are new, relevant and so-far overlooked ethical questions concerning cerebral organoids. Scientists have created so-called mini-brains as developed as a few-months-old fetus, albeit smaller and with many structural and functional differences. However, cerebral organoids exhibit neural connections and electrical activity, raising the question whether they are or will one day be somewhat sentient. In principle, this can be measured with some techniques that are already available, which are used for brain-injured non-communicating patients. If brain organoids were to show a glimpse of sensibility, an ethical discussion on their use in clinical research and practice would be necessary. (shrink)

The organism is one of the fundamental concepts of biology and has been at the center of many discussions about biological individuality, yet what exactly it is can be confusing. The definition that we find generally useful is that an organism is a unit in which all the subunits have evolved to be highly cooperative, with very little conflict. We focus on how often organisms evolve from two or more formerly independent organisms. Two canonical transitions of this type—replicators clustered in (...) cells and endosymbiotic organelles within host cells—demonstrate the reality of this kind of evolutionary transition and suggest conditions that can favor it. These conditions include co-transmission of the partners across generations and rules that strongly regulate and limit conflict, such as a fair meiosis. Recently, much attention has been given to associations of animals with microbes involved in their nutrition. These range from tight endosymbiotic associations like those between aphids and Buchnera bacteria, to the complex communities in animal intestines. Here, starting with a reflection about identity through time, we consider the distinctions between these kinds of animal–bacteria interactions and describe the criteria by which a few can be considered jointly organismal but most cannot. (shrink)

How much bacterial evolution occurs in our intestines and which factors control it are currently burning questions. The formation of new ecotypes, some of which capable of coexisting for long periods of time, is highly likely in our guts. Horizontal gene transfer driven by temperate phages that can perform lysogeny is also widespread in mammalian intestines. Yet, the roles of mutation and especially lysogeny as key drivers of gut bacterial adaptation remain poorly understood. The mammalian gut contains hundreds of bacterial (...) species, each with many strains and ecotypes, whose abundance varies along the lifetime of a host. A continuous high input of mutations and horizontal gene transfer events mediated by temperate phages drives that diversity. Future experiments to study the interaction between mutations that cause adaptation in microbiomes and lysogenic events with different costs and benefits will be key to understand the dynamic microbiomes of mammals. Also see the video abstract here: https://youtu.be/Zjqsiyb5Pk0. (shrink)

Democracy is both an obvious and dubious idea. Here's why democracy is an obvious idea: For most of history, most governments divided people into the few who rule and the many who obey. The few then used the state to advance their own private interests at the expense of the many. Rulers were less like noble protectors appointed by God and more like intestinal parasites. The obvious solution is to eliminate the distinction between those who rule and those who obey. (...) Make every citizen both a ruler and a subject of that rule. This ensures government promotes everyone's interests. Thus, democracy is the best form of government. It's too bad it took most of civilized history to realize this-and too bad that the world isn't more democratic than it is. Here's why democracy is a dubious idea. Government decisions are high stakes. It decides matters of war and peace, prosperity and poverty, freedom or oppression. Yet we let incompetent people steer the ship of state. Most voters are ignorant and process what little information they have in biased and irrational ways. They fall prey to propaganda and demagogues. They are conformists and don't even try to vote their interests. Democracy is the political equivalent of drunk driving. Thus, democracy is a defective form of government. Democracy is a method by which the masses shoot themselves in their feet. Philosophy students often start essays by writing, "Since the dawn of time, humanity has pondered..." In this case, these arguments and concerns are old, if not dawn-of-time old. We find laypeople, pundits, social scientists, and philosophers making these two arguments today. But in ancient Athens, Socrates, Plato, and Aristotle said similar things. (shrink)

Recent work in the philosophy of biology argues that we must rethink the biological individual beyond the boundary of the species, given that a key part of our essential functioning is carried out by the bacteria in our intestines in a way that challenges any strictly genetic account of what is involved for the biological human. The gut is a kind of ambiguous other within our understanding of ourselves, particularly when we also consider the status of gastro-intestinal disorders. Hegel offers (...) us theoretical tools to describe and understand our relationship to our gut. His description of our selves as continually mediated through otherness is strikingly compatible with the kind of structure contemporary biology presents us with. His accounts of digestion and habit, contextualized by his logic, help point toward an understanding of selfhood as porous and yet still capable of being sufficiently unified for us to make sense of ourselves, one which allows us to acknowledge otherness within us while still having enough unity for agency. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:MIMETIC SADISM IN THE FICTION OF YUKIO MISHIMA Jerry Piven New York University Mishima Yukio (1925-1970) was one ofthe mostenigmatic authors of the 20th century. Novelist, playwright, actor, exhibiionist —his novels are rife with homoerotic and violent imagery, while his fanatical and nihilistic philosophy calls for a return to a Samurai ethos. Mishima thus attained infamy in Japan and in the West, as his shocking novels inspired hordes ofyoung (...) Japanese into a cult ofMishima worship, while critics who acknowledge his genius are still nervous about his sadistic homosexuality and his suicide. Mishima's works are suffused with erotic bloodshed and misogyny, and Mishima finally ended his life by ritually disemboweling himself. I will make the case that Mishima was incessantly plagued by torturous mimetic frustrations, and that his final act of spilling his blood and intestines can be interpreted as the result of mimetic hatred against his rivals. I also argue that Mishima was fundamentally schizoidal; in Girardian terms, a man whose hypocrisy for the sakeofdesire rendered him an exhibitionistic maskdisguisingmimetic rage and fear. Having previously written about Mishima from a psychoanalytic perspective, I believe that a Girardian approach would often yield drastically different interpretations of identical biographical and literary materials. ' 1I initially wrote on Mishima for several diagnostic assignments at my psychoanalytic institute, the National Psychological Association for Psychoanalysis (NPAP). After considering the psychoanalytic and Girardian approaches, I expanded these original essays using identical material to determine whetherthe interpretations orconclusions would differ; I was struck by the way the same details could provide both remarkable congruences and vast divergences ofperspective. Read side by side, one can find compatible conclusions, but one also finds perceptions ofthe same details that would be difficultto conceive or articulate 70Jeremy Piven Mimesis, misogyny, and maculacy Kimitake Hiraoka was a frail, sickly child before he became the muscular and exhibitionistic novelist Yukio Mishima. His brutal and helpless childhood inaugurated his mimetic complexes: his need to escape the suffocating and diseased environment of his grandmother, his rivalry with her, and his mimetic ideal ofbeauty and muscular invulnerability. Mishima was an unhealthy youth, taken from the arms of his mother before he was two months old, and confined to the sickroom of his grandmother for the first twelve years ofhis life. Under the auspices ofhis tyrannical and ostensively psychotic grandmother, Mishima lived in the dark, could play only female friends (becausetheywere deemed harmless), and could eat only gentle foods. He thus lived an imprisoned life away from his parents, amid the excrescences of his sick and hysterical grandmother until adolescence, when his father "reclaimed him." Mishima later rebelled against this sickly nature, sculpting himself into a statuesque ideal of masculine beauty. He became obsessed with martial arts and the eroticism ofhis own engraved body. His fiction and philosophy were permeated by misogyny, glorification ofGrecian male sexuality and aesthetics, and the repudiation ofanything weak or feminine. He finally killed himselfbefore age could wither his masculine beauty. Mishima's fiction prominently features protagonists who mirror his sickly youth. The autobiographical Confessions of a Mask (Kamen no Kokuhaku) describes the homoerotic development ofthis frail child. Such fraiIcharacters inMishima'sfiction arealwaysdrawneroticallytobeautiful males as both mimetic rivals and models. The narrator of Confessions describes his sexual attraction to a sewage collector, a "ladler of excrement"(8). Thehandsomemanwith "ruddycheeks" and "shiningeyes" fascinates the narrator, and he is filled with desire lookingathistightjeans. using psychoanalytic perspectives andjargon. Two ofthe original essays will be published inthePsychoanalyticReview in comingmonths: "PhallicNarcissism, Anal Sadism, and Oral Discord: The Case ofYukio Mishima (part I)," and "Narcissistic Revenge and Suicide: The Case ofYukio Mishima (part H)." I am currently translating these articles for publication in Japan. I included a brief discussion of Mishima in the introduction to Psychological Undercurrents ofHistory (Piven and Lawton, eds.), to explore the complex methodological and psychological dynamics of the field of psychohistory. A commentary on Mishima's traumaticchildhood entitled "The Pathology ofGenius," will appearin aforthcomingedition ofTapestry: TheJournalofHistoricalMotivations andtheSocialFabric, and afinal article, "Voyeurism and Rage in The Sailor Who Fellfrom Grace with the Sea," will appear in Psychological Undercurrents ofHistory, Volume II (2002). Mimetic Sadism in the Fiction ofYukio Mishima71 The narrator thus emerges into a burgeoning homosexuality, but he also fantasizes about dying dramatically. His... (shrink)

Microbiota-gut-brain research is a fast-growing field of inquiry with important implications for how human brain function and behaviour are understood. Researchers manipulate gut microbes to reveal connections between intestinal microbiota and normal brain functions or pathological states. Many claims are made about causal relationships between gut microbiota and human behaviour. By uncovering these relationships, MGB research aims to offer new explanations of mental health and potential avenues of treatment. So far, limited evaluation has been made of MGB's methods and its (...) core experimental findings, many of which are extensively reiterated in copious reviews of the field. These factors, plus the self-help potential of MGB, have combined to encourage uncritical public uptake of MGB discoveries. Both social and professional media focus on the potential for dietary intervention in mental health, and causal relationships are assumed to be established. Our target article has two main aims. One is to examine critically the core practices and findings of experimental MGB research and to raise questions about them for brain and behavioural scientists who may not be familiar with the field. The other is to challenge the way in which MGB findings are presented. Our positive goal is to suggest how current problems and weaknesses may be addressed, in order for both scientific and public audiences to gain a clearer picture of MGB research and its strengths and limitations. (shrink)

Hirschsprung disease and the multiple endocrine neoplasia type 2 syndromes are hereditary disorders related to the abnormal migration, proliferation or survival of neural crest cells and their derivatives. Hirschsprung disease is a frequent disorder of the enteric nervous system, resulting in intestinal obstruction. The multiple endocrine neoplasia type 2 syndromes predispose to cancers of neural crest derivatives. Both diseases are associated with heterozygous mutations in the RET proto‐oncogene. RET encodes a transmembrane receptor tyrosine kinase expressed in neural crest lineages and (...) whose ligand, glial‐cell‐line‐derived neurotrophic factor, has been very recently identified. In vitro expression studies demonstrate that while Hirschsprung disease mutations result in loss of function of the mutant RET tyrosine kinase, multiple endocrine neoplasia type 2 mutations lead to its constitutive activation. Thus, the two ‘faces’ of RET, gain of function and loss of function, each lead to a different syndrome, respectively: multiple endocrine neoplasia type 2, a cancer syndrome, or Hirschsprung disease, a developmental defect. (shrink)

The early evolutionary history of echinoderms was reconstructed on the basis of structural-functional considerations and application of the quasi-engineering approach of ‘Konstruktions-Morphologie’. According to the presented evolutionary scenario, a bilaterally symmetrical ancestor, such as an enteropneust-like organism, became gradually modified into a pentaradial echinoderm by passing through an intermediate pterobranch-like stage. The arms of a pentaradial echinoderm are identified as hydraulic outgrowths from the central coelomic cavity of the bilateral ancestor which developed due to a shortening of the body in (...) length but widening in the diameter. The resulting pentaradial symmetry is a consequence of mechanical laws that dictate minimal contact surface areas among hydraulic pneumatic entities. These developed in the coelomic cavity (metacoel) in the bilaterally symmetrical ancestor, when from the already U-shaped mesentery with the intestinal tract two additional U-shaped bows developed directly or subsequently. During the subsequent development tensile chords of the mesentery ‘sewed’ the gut with the body wall first in three and secondly in five ‘seams’. During the direct development five ‘seams’ between tensile chords and body wall developed straightly. These internal tensile chords subdivide the body coelom into five hydraulic subsystems (‘pneus’), which eventually arrange in a pentaradial pattern. The body could then enlarge only between the tensile chords, which means that five hydraulic bulges developed. These bulges initially supported the tentacles and finally each of them enclosed the tentacle until only the feather-like appendages of the tentacles projected over the surface. The tentacles with their feathers were transformedinto the ambulacral system, and the bulges become the arms. These morphological transformations were accompanied and partly determined by specific histological modifications, such as the development of mutable connective tissues and skeletal elements that fused to ossicles and provided shape stabilization in form of a calcareous skeleton in the body wall. The organism resulted was an ancestral echinoderm (‘Ur-Echinoderm’) with an enlarged metacoel, stabilized by hydraulic pressure working againsta capsule of mutable connective tissue, skeletal elements and longitudinal muscles. In regard to these reconstructions, the body structure of echinoderms can be understood as a hydraulic skeletal capsule. (shrink)

Galectin-3 and LTB4 are pro-inflammatory molecules recently shown to directly cause insulin resistance in mouse and human cells. They are highly expressed in the obese state, and can be targeted both genetically and pharmacologically to improve insulin sensitivity in vivo. This expands on previous research showing that targeting inflammatory cytokines can be insulin sensitizing in animal models. However, translating these potential therapies into the human setting remains challenging. Here we review this latest research, and discuss how balancing their pleiotropic functions, (...) the action of the microbiome, and the ability to identify relevant patient populations are vital considerations for successful anti-inflammatory insulin sensitizing therapy. Recent advances have indicated that a diverse range of inflammatory molecules, including leukotriene B4 and Galectin-3 can cause insulin resistance. Key challenges for translating these new targets into therapies include their pleiotropic effects and likely patient heterogeneity, such as is caused by the intestinal microbiome. (shrink)

This paper asks if there any hope today, in the midst of the pulls and tugs of current globalizing and counter-globalizing forces, of differing theological outlooks and intestine tensions, that the world Church can constitute a politics of reconciliation instead of one characterized by polarized confrontation. Employing the metaphor of “hands,” it proposes some needed steps towards the realization of that hope. Hands can join in reconciliation when they are open in confession and emptied of the manipulation of money, (...) when all hands are welcome at the table, wounded as they are, and when they are raised in communal praise and supplication. (shrink)

Actin is a protein that plays an important role in cell structure, cell motility, and the generation of contractile force in both muscle and nonmuscle cells. In many organisms, multiple forms of actin, or isoactins, are found. These are products of different genes and have different, although very similar, amino acid sequences. Furthermore, these isoactins are expressed in a tissue specific fashion that is conserved across species, suggesting that their presence is functionally important and their behavior can be distinguished quantitatively (...) from one another in vitro. In muscle cells, they are differentially distributed within the cell and some are specifically associated with structures such as costameres, mitochondria, and neuromuscular junctions. There is also good evidence for specific isoactin function in microvascular pericytes and in the intestinal brush border. However, the necessity of specific isoactins for various functions has not yet been conclusively demonstrated. (shrink)

Graphical AbstractIdentifying the properties and molecules of the intestinal microbiome may help our understanding of various diseases and therefore facilitate their treatment; from excluding pathogens to manipulation of the immune system and regulation of non-intestinal sites.

The accumulation of potentially toxic elements (PTEs) has raised public awareness due to harmful contamination to both human and marine creatures. This study was designed to determine the concentration of copper (Cu), zinc (Zn), cadmium (Cd), and nickel (Ni) in the intestine, kidney, muscle, gill, and liver tissues of local commercial edible fish, fourfinger threadfin (Eleutheronema tetradactylum), and black pomfret (Parastromateus niger) collected from Morib (M) and Kuala Selangor (KS). Among the studied PTEs, Cu and Zn were essential elements (...) to regulate body metabolism with certain dosages required while Cd and Ni were considered as non-essential elements that posed chronic and carcinogenic risk. The concentration of PTEs in fish tissue samples was analyzed using flame atomic absorption spectrometry (F-AAS). By comparing the concentration of PTEs in fish tissues as a bioindicator, the environmental risk of Morib was more serious than Kuala Selangor because both fish species collected from Morib resulted in a higher PTEs concentration. For an average 62 kg adult with a fish ingestion rate (FIR) of 0.16 kg/person/day in Malaysia, the estimated weekly intake (EWI) of Cd from the consumption of E. tetradactylum (M: 0.0135 mg/kg; KS: 0.0134 mg/kg) and P. niger (M: 0.0140 mg/kg; KS: 0.0132 mg/kg) had exceeded the provisional tolerable weekly intake (Cd: 0.007 mg/kg) established by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) and oral reference dose (ORD) values of Cd (0.001 mg/kg/day) as provided by the United States Environmental Protection Agency (USEPA) regional screening level, thus it posed chronic risks for daily basis consumption. Besides, the value of the carcinogenic risk of Cd (0.7−3 to 0.8−3) and Ni (0.5−3 to 0.6−3) were in between the acceptable range (10−6 to 10−4) of the health index that indicates a relatively low possibility cancer occurrence to the consumers in both Morib and Kuala Selangor. This study recommended FIR to be 0.80 kg/person/day to reduce the possibility of posing chronic and carcinogenic risks while at the same time obtaining the essential nutrients from the fish. (shrink)

I hypothesize here that the ability of probiotics to synthesize neuroactive compounds provides a unifying microbial endocrinology‐based mechanism to explain the hitherto incompletely understood action of commensal microbiota that affect the host's gastrointestinal and psychological health. Once ingested, probiotics enter an interactive environment encompassing microbiological, immunological, and neurophysiological components. By utilizing a trans‐disciplinary framework known as microbial endocrinology, mechanisms that would otherwise not be considered become apparent since any candidate would need to be shared among all three components. The range (...) of neurochemicals produced by probiotics includes neurochemicals for which receptor‐based targets on immune and neuronal elements (intestinal and extra‐intestinal) have been well characterized. Production of neurochemicals by probiotics therefore allows for their consideration as delivery vehicles for neuroactive compounds. This unifying microbial endocrinology‐based hypothesis, which may facilitate the selection and design of probiotics for clinical use, also highlights the largely unrecognized role of neuroscience in understanding how microbes may influence health.Editor's suggested further reading in BioEssays Harvesting the biological potential of the human gut microbiome Abstract. (shrink)

Importance Informed consent is essential to ethical, rigorous research and is important to recruitment and retention in cancer trials.Objective To examine cancer clinical trial (CCT) participants’ perceptions of informed consent processes and variations in perceptions by cancer type.Design and Setting and Participants Cross-sectional survey from mixed-methods study at National Cancer Institute–designated Northeast comprehensive cancer center. Open-ended and forced-choice items addressed: (1) enrollment and informed consent experiences and (2) decision-making processes, including risk-benefit assessment. Eligibility: CCT participant with gastro-intestinal or genitourinary, hematologic-lymphatic (...) malignancies, lung cancer, and breast or gynecological cancer (N = 334).Main Outcome Measures Percentages satisfied with consent process and information provided; and assessing participation’s perceptions of risks/benefits. Multivariable logistic or ordinal regression examined differences by cancer type.Results Most patient-participants felt well informed by the consent process (more than 90% overall and by cancer type) and. most (87.4%) reported that the consent form provided all the information they wanted, although nearly half (44.8%) reported that they read the form somewhat carefully or less. More than half (57.9%) said that talking to research staff (i.e., the consent process) had a greater impact on participation decisions than reading the consent form (2.1%). A third (31.1%) were very sure of joining in research studies before the informed consent process (almost half of lung cancer patients did—47.1%). Most patients personally assessed the risks and benefits before consenting. However, trust in physicians played an important role in the decision to enroll in CCT.Conclusions and Relevance Cancer patients rely less on written features of the informed consent process than on information obtained from the research staff and their own physicians. Research should focus on information and communication strategies that support informed consent from referring physicians, researchers, and others to improve patient risk-benefit assessment and decision-making. (shrink)

: The film "Who Should Survive?: One of the Choices on Our Conscience" contains a dramatization of the death of an infant with Down syndrome as the result of the parents' decision not to have a congenital intestinal obstruction surgically corrected. The dramatization was based on two similar cases at The Johns Hopkins Hospital and was financed by the Joseph P. Kennedy, Jr., Foundation. When "Who Should Survive?" was exhibited in 1971, the public reaction was generally critical of the parents' (...) decision and the physicians' inaction. Although technological developments in medicine were a necessary condition for the production of this film and its unanticipated reception, they were not a sufficient condition. The proximate cause was a changed understanding of the capabilities of individuals with Down syndrome. Part of the impetus for this change was data showing the adverse effects of institutionalization on normal children. (shrink)

The human microbiome is the bacteria, viruses, and fungi that cover our skin, line our intestines, and flourish in our body cavities. Work on the human microbiome is new, but it is quickly becoming a leading area of biomedical research. What scientists are learning about humans and our microbiomes could change medical practice by introducing new treatment modalities. This new knowledge redefines us as superorganisms comprised of the human body and the collection of microbes that inhabit it and reveals how (...) much we are a part of our environment. The understanding that microbes are not only beneficial but sometimes necessary for survival recasts our interaction with microbes from adversarial to neighborly. This volume explores some of the science that makes human microbiome research possible. It then considers ethical, legal, and social concerns raised by microbiome research. Chapters explore issues related to personal identity, property rights, and privacy. The authors reflect on how human microbiome research challenges reigning views on public health and research ethics. They also address the need for thoughtful policies and procedures to guide the use of the biobanked human samples required for advancing this new domain of research. In the course of these explorations, they introduce examples from the history of biomedical science and recent legal cases that shed light on the issues and inform the policy recommendations they offer at the end of each topic's discussion.This volume is the product of an NIH Human Microbiome Project grant. It represents three years of conversations focused on consensus formation by the twenty-seven members of the interdisciplinary Microbiome Working Group. (shrink)

Abstract. The American dream of the “self-made man” is as central to the functioning of our capitalist society as Wall Street and as familiar as the Statue of Liberty. According to this dream, the tired masses have a shot at making it on their own if they have the will power, stamina, and intestinal fortitude to survive and compete. What do we do now that we are faced with scientific evidence that this very strategy is driving society into disconnection, despair, (...) and even poor health? Relational-cultural theory states that growth happens through and toward relationships not toward increased separation and autonomy. Relational-cultural theory describes empathy and mutuality as key components to healthy relationships. This essay will focus on the latest research in the neuroscience of relationships—the development of the capacity to connect within relationships, the systems that help us read and empathize with others, the adaptability and plasticity of the central nervous system, and the destructive nature of isolation. (shrink)

Members of the CAR group of Ig‐like type I transmembrane proteins mediate homotypic cell adhesion, share a common overall extracellular domain structure and are closely related at the amino acid sequence level. CAR proteins are often found at tight junctions and interact with intracellular scaffolding proteins, suggesting that they might modulate tight junction assembly or function. However, impairment of tight junction integrity has not been reported in mouse knockout models or zebrafish mutants of CAR members. In contrast, in the same (...) knockout models deficits in gap junction communication were detected in several organ systems, including the atrioventricular node of the heart, smooth muscle cells of the intestine and the ureter and in Sertoli cells of the testes. Possible interactions between BT‐IgSF and connexin41.8 on the disturbed pattern of pigment stripes found in zebrafish mutants and between ESAM and connexin43 during hematopoiesis in the mouse are also discussed. On the basis of the combined data and phenotypic similarities between CAR member mutants and connexin mutants I hypothesize that they primarily play a role in the organization of gap junction communication. Also see the video abstract here: https://youtu.be/i0yq2KhuDAE. (shrink)

The chronologic age classically used in demography is often unable to give useful information about which exact stage in development or aging processes has reached an organism. Hence, we propose here to explain in some applications for what reason the chronologic age fails in explaining totally the observed state of an organism, which leads to propose a new notion, the biological age. This biological age is essentially determined by the number of divisions before the Hayflick’s limit the tissue or mitochondrion (...) in a critical organ (in the sense where its loss causes the death of the whole organism) has already used for its development and adult phases. We give a precise definition of the biological age of an organ based on the Hayflick’s limit of its cells and we introduce a desynchronization index (the cell entropy) for some critical tissues or membranes, which are mainly skin, intestinal endothelium, alveoli epithelium and mitochondrial inner membrane. In these actively metabolising interface tissues or membranes, there is a rapid turnover of cells, of their cytoplasmic constituents such as proteins, and of membrane lipids. The boundaries corresponding to these tissues, cells or membranes have vital functions of interface with the environment (protection, homeothermy, nutrition and respiration) and have a rapid turnover (the total cell renewal time is in mice equal to 3 weeks for the skin, 1.5 day for the intestine, 4 months for the alveolae and 11 days for mitochondrial inner membrane) conditioning their biological age. The biological age of a tissue is made of two major components: (1) first, its embryonic age based on the distance (in number of divisions) between the birth date of its first differentiated cell and the time until it reaches its final boundary at the end of its development and (2) second, its adult age whose complement until its death is just the lapse of time made of the sum of remaining cell cycle durations authorized by its Hayflick’s limit. From this definition, we calculate the global biological lifespan of an organism and revisit notions like demographic survival curves, duration and synchrony of cell cycles, living boundaries from proto-cells to organs, and embryonic and adult phases duration. (shrink)

Microfilament interactions with the plasma membranes of animal cells appear to vary with cell type and localization. In the erythrocyte, actin oligomers are associated with the membrane via spectrin and ankyrin. The ends of stress fibers in cultured cells, such as fibroblasts, are attached to the plasma membrane at focal adhesion sites and may involve the protein vinculin as a linking protein. In intestinal brush border microvilli a 110,000 dalton protein links the microfilament bundles to sites on the microvillus. A (...) transmembrane complex containing actin stably associated with a cell surface glycoprotein can be isolated from ascites tumor cell microvilli and can be obtained still associated with microfilaments by gentle extraction and gradient centrifugation of the microvilli. These varied interaction mechanisms are believed to be needed to satisfy the different structural and dynamic requirements of the particular systems. (shrink)

. The subject of this paper is Georg Ernst Stahl's reflections on epilepsy. In the German physician's work, the concept of disease is stratified: it is the morbid idea which causes dysfunctions in the animal economy, as well as irregular motion, overabundance and ultimately an alteration of the corporeal humours. In particular, epilepsy is an affection deriving from an altered functioning of the bodily motions, caused by abnormal blood flow, intestinal worms, anatomical defects, foreign bodies, and the passions of the (...) soul. While a certain medical tradition attributed a nervous origin to epilepsy, Stahl, giving it a humoural genesis, openly shows the theoretical premises on which his physiology rests. So, Stahlian physiology appears to be a non-mechanistic, teleological-inspired, hydraulicism. (shrink)

Recently, Quyn et al. demonstrated that cells within the stem cell zone of human and mouse intestinal crypts tend to align their mitotic spindles perpendicular to the basal membrane of the crypt. This is associated with asymmetric division, whereby particular proteins and individual chromatids are preferentially segregated to one daughter cell. In colonic mucosa containing a heterozygous adenomatous polyposis coli gene (APC) mutation the asymmetry is lost. Here, we discuss asymmetric stem cell division as an anti‐tumourigenic mechanism. We describe how (...) hierarchical tissue structures suppress somatic evolution, and discuss the relative merits of template strand retention to limit the accumulation of DNA replication errors. We suggest experiments to determine whether somatic mutations resulting in loss of spindle alignment confer an advantage within the stem cell niche. Finally, we discuss whether lack of spindle alignment constitutes an oncogenic event per se, with particular reference to studies in model organisms, and the timing of chromosomal instability in human cancers. (shrink)

Homeobox genes play essential roles in specifying the fates of different cell types during embryogenesis. In Drosophila, the homeotic gene caudal is important for the generation of posterior structures. In the mouse, the caudal homologue Cdx2 has been implicated in directing early processes in intestinal morphogenesis and in the maintenance of the differentiated phenotype. A recent study showed that Cdx2 null mutation was embryonically lethal, whereas Cdx2+/− mice developed multiple intestinal polyps in the proximal colon in addition to developmental defects(1). (...) There are striking phenotypic similarities and differences between Cdx2+/− and other mice predisposed to intestinal neoplasia. The possible role of Cdx2 in human colorectal tumorigenesis is discussed. (shrink)