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Genealogy is for Nietzsche a way of doing philosophy that shows not only the inadequacy of traditional metaphysics or “first philosophy,” but also the prospects for nonmetaphysical philosophy. In the preface to the Genealogy of Morals (§4) he says his own adaptation of the method of genealogy was motivated by his reaction to Paul Ree’s Origin of the Moral Sensations. This “upside-down and perverse species of genealogical hypothesis, the genuinely English type” is criticized for being too unhistorical, haphazard, or random. What is perverse is Ree’s social-Darwinian hypothesis that the most recent product of human evolution is, because of the survival of the fittest, also the highest product of human evolution. Nietzsche parodies Ree cruelly in laughing at the idea that the fittest and highest human type is the modern “moral milksop” (Moral-Zartling, GM Preface 7) who thinks of morality as “selflessness, self-sacrifice, or sympathy and pity” (GS 345). Equally perverse and “English” is Ree’s own “refined indolence,” his inability to take the problems of morality seriously.

The polemic in the discussion of women's domestic and public roles is the inaccurate interpretation of gender in the perspective of social, economic, legal, political and religious construction. As a result, one of the sexes is marginalized and subordinated. Women and men are not placed as human beings who have equal opportunities. The error in interpreting the two roles of the human type is called gender bias. It is a must to carry out reinterpretation so that there is a shared awareness that there are equal opportunities and treatment in carrying out their duties as servants of God.

Autografts and allografts are currently considered the gold standard for grafting surgery; however, to meet the growing demand in fast-aging societies, synthetic biomaterials will play an increasingly important role. Here we report a biodegradable scaffold material composed of recombinant polypeptide based on the human type I collagen alpha 1 chain (RCPhC1) as a source of hydrogel-based graft materials. The flexibility to engineer ideal characteristics for bone grafts was demonstrated. The critical internal isotropic pore structure was generated through a designed thin-layer freeze casting process. The optimized biodegradation rate was controlled by dehydrothermal crosslinking by adjusting the amino acid composition of RCPhC1. As a result, RCPhC1 bone grafts manufactured by a highly scalable streamlined production protocol induced robust regeneration of mature bone tissue while being completely resorbed in pre-clinical animal models. Synthetic bone graft materials are needed due to aging societies. Here, biodegradable and versatile recombinant collagen polypeptide scaffolds are engineered to induce bone regeneration in pre-clinical animal models.

The goal of this article is to propose a radical reform of the today’s financial accounting system of businesses accompanied by a corresponding reform of the system of national accounts. It transforms them into genuine ecological and human systems of accounts that can systematically conserve the three main types of capitals which are necessary for the functioning of any economic system. This is a radical means of overcoming the dramatic ecological and human crisis in which the humanity is buried today. This can be done by applying traditional weapons of capital conservation, invented at the end of the Middle Ages by big capitalists for the protection of their financial investments, to human and natural capital. We notably use the famous double entry accounting depicted by Werner Sombart and Max Weber like certain martial arts use the force of the adversary against him. As a result, we come to a complete redefinition of the main concepts of the economics, especially the concepts of capital, profit and market, and to the possibility of a new type of firm management that allows us to get out of the capitalist system.

Kaposi's sarcoma (KS) is a multifocal systemic disease originating from vascular structures, associated with human type 8 herpesvirus and mainly affecting elderly men (male: female ratio, 10-15: 1)1,2 . Dermoscopy and reflectance confocal microscopy (RCM) are two non-invasive diagnostic methods that could improve the accuracy of KS detection2 - 4 . We carried out a review of the current English-language literature regarding dermoscopy and reflectance confocal microscopy as non-invasive diagnostic tools for Kaposi sarcoma lesions. Results are reported in Table 15 - 9 . Patients written informed consents were collected for images publication. Morphological variations of KS and its similarity with other angiomatous conditions often lead to difficulties to make a correct diagnosis only with clinical examination10 . Histological examination represents the gold standard for KS diagnosis3 . Dermoscopy and RCM are two non-invasive high- resolution techniques useful to add additional features in order to help clinicians making the correct diagnosis and also to address the choice for the biopsy-site4 .

SUMMARY Recombinant human type I collagen, identical in structure and functionality to human type I collagen, was successfully expressed and extracted from genetically modified tobacco plants. Contrarily to tissue extracted protein, rhCollagen is not immunogenic and not allergenic and has an intact triple helix structure showing superior biological functionality. A photocurable rhCollagen was developed by chemically modifying the protein to allow cross-linking under illumination at various wavelengths, maintaining the protein structural and biological functions. The use of the photocurable rhCollagen in aesthetic medicine, especially as a dermal filler and as a bioink for 3D-printed breast implant is discussed in this article.

Remission of type 2 diabetes (T2D) may occur after very low-calorie diets or bariatric surgery, and is associated with improved pancreatic beta cell function. Here, we evaluated if T2D beta cell dysfunction can be rescued ex-vivo and which are the molecular mechanisms involved. Islets from 19 T2D donors were studied after isolation (“basal”) and following culture at 5.5 or 11.1 mmol/l glucose (“cultured”). We evaluated glucose-stimulated insulin secretion (GSIS) and transcriptomes by RNA sequencing, correlated insulin secretion changes (“cultured” vs “basal”) to global gene expression, and searched for potential therapeutic gene targets and compounds that mimic gene signatures of recovered beta cell function in T2D islets. GSIS improved in 12 out of 19 islet preparations from T2D donors after culture at 5.5 mmol/l glucose (insulin stimulation index increased from 1.4±0.1 to 2.3±0.2, p

Rationale—Angiotensin converting enzyme (ACE) 2 and the transmembrane protease serine 2 (TMPRSS2) are key for cellular entry of the type 2 coronavirus that causes severe acute respiratory syndrome (SARS-CoV2), the etiological agent of coronavirus-19 disease (COVID-19). There has been a growing concern that renin-angiotensin system (RAS) blockade with ACE inhibitors (ACEIs) or type 1 angiotensin (Ang II) receptor blockers (ARBs) increases ACE2 expression and then elevate patient susceptibility to SARS-CoV-2. However, evidence about RAS blockade and ACE2 in human lung are lacking.Objective– To investigate RAS blockade on ACE2 and TMPRSS2 in type II pneumocytes of human lung parenchymal of untreated and ACEI/ARB-treated hypertensive subjects.Methods and Results– ACE2 and TMPRSS2 protein expression were measured by immunohistochemistry. We found that smoking and RAS blockade influence on the percentage of human ACE2-expressing type II pneumocytes (p= 0.026). Smokers subjects under RAS blockade treatment exhibited higher percentage of ACE2-expressing type II pneumocytes than normotensive ones. Within the ACEI/ARB-treated group, the percentage of ACE2-expressing type II pneumocytes was higher in smokers than never smokers. A significant association between ACE2 immunostaining intensity and smoking on subjects over 60 years old was found (p= 0.05): older smokers exhibited higher ACE2 protein levels compared to youngers. The percentage of TMPRSS2-expressing type II pneumocytes was greater in men than women (p= 0.026) and in subjects under 60 years old (p= 0.040) and trend to be higher in ACEI/ARB-treated subjects than normotensives (p= 0.060). A significant association between TMPRSS2 immunostaining intensity with smoking and age or with RAS blockade and age or with RAS blockade and smoking was observed. Older or smokers subjects under ACEI/ARB treatment exhibited higher TMPRSS2 protein levels than youngers or never smokers.Conclusions—ACE2 and TMPRSS2 are influenced by smoking and ACEI/ARB treatment. These findings help explain the increased susceptibility to COVID-19 in subjects with treated cardiovascular-related pathologies.

—The receptor specificity for the A/rook/Chany/32/2015 (H5N1), A/common gull/Saratov/1676/2018 (H5N6), and A/chicken/PrimorskyKrai/03/2018 (Н9N2) strains of avian influenza virus has been studied. Using the method of surface plasmon resonance for the selected strains we obtained the values ​​of the equilibrium dissociation constants with analogues of receptors such as α2-3 and α2-6. It was found that for strains A/rook/Chany/32/2015 (H5N1) and A/common gull/Saratov/1676/2018 (H5N6), a binding with the human type of receptor (α2-6) is determined, in contrast to the strain A/chicken/PrimorskyKrai/03/2018 (H9N2), which is specific only for avian type receptors (α2-3).

A number of natural products with medicinal properties increase DNA cleavage mediated by type II topoisomerases. In an effort to identify additional natural compounds that affect the activity of human type II topoisomerases, a blind screen of a library of 341 Mediterranean plant extracts was conducted. Extracts from Nuphcir lutea, the yellow water lily, were identified in this screen. N. lutea has been used in traditional medicine by a variety of indigenous populations. The active compound in N. lutea, 6,6’-dihydroxythiobinupharidine, was found to enhance DNA cleavage mediated by human topoisomerase IIα and IIβ ~8-fold and ~3-fold, respectively. Mechanistic studies with topoisomerase IIα indicate that 6,6’-dihydroxythiobinupharidine is a “covalent poison” that acts by adducting the enzyme outside of the DNA cleavage-ligation active site and requires the N-terminal domain of the protein for its activity. Results suggest that some of the medicinal properties of N. lutea may result from the interactions between 6,6’-dihydroxythiobinupharidine and the human type II enzymes.

In the article views of antique authors of human aspect of a phenomenon of slavery are considered. The author recognizes that the importance of a similar research is connected with existence of archetypic layers in the most various cultures causing reproduction of a phenomenon of slave model of the personality and corresponding to it behavior forms. The attention to three aspects in understanding of the bases of existence of the slave as special human type, recorded by antique authors is paid. It, first, slavery “under the law” according to which the captured captives are on sale in slavery. Secondly, this slavery caused by the human nature connected with ethnic origin on a formula “the barbarian and the slave by the concept nature identical”. Thirdly, this slavery in spiritual sense generated by the nature of activity in which the person is engaged. The types of activity forming the free person is for them philosophical reflection as disinterested search of the truth and also, according to Aristotle, political activity. Views of antique authors correspond in the article to views of the Russian religious philosophers proceeding from other paradigm of the activity basis of free existence implanted in Christian outlook. Its essence is that the aspiration to the truth which is implemented in occupations by philosophy has to be directed deep valuable installation, which sense in aspiration to connection of the person good luck.

IL-17 family cytokines are critical to host defense responses at cutaneous and mucosal surfaces. Whereas IL-17A, IL-17F, and IL-17C induce overlapping inflammatory cascades to promote neutrophil-mediated immunity, IL-17E/IL-25 drives type 2 immune pathways and eosinophil activity. Genetic and pharmacological studies reveal the significant contribution these cytokines play in antimicrobial and autoimmune mechanisms. However, little is known about the related family member, IL-17B, with contrasting reports of both pro- and anti-inflammatory function in rodents. We demonstrate that in the human immune system, IL-17B is functionally similar to IL-25 and elicits type 2 cytokine secretion from innate type 2 lymphocytes, NKT, and CD4+ CRTH2+ Th2 cells. Like IL-25, this activity is dependent on the IL-17RA and IL-17RB receptor subunits. Furthermore, IL-17B can augment IL-33–driven type 2 responses. These data position IL-17B as a novel component in the regulation of human type 2 immunity.

The pathophysiology of type 1 diabetes is a complex process involving tightly controlled microenvironments, a number of highly specific immune cell - islet cell interactions, and the eventual breaking of immune tolerance leading to beta cell death. Modeling this process can provide researchers with powerful insights into how and when to best provide treatment, but has proven difficult to accurately model due to its complex nature and differences between animal models and humans. Much progress has been made in determining the genetic, molecular, and cellular mechanisms of type 1 diabetes, yet translating that knowledge to clinical treatments remains challenging. Thus, there exists a capabilities gap between understanding the disease pathophysiology and engineering effective clinical treatment strategies. Biomimetic modeling of human type 1 diabetes is a valuable tool to study and manipulate islet function and can be employed to address immunological aspects of type 1 diabetes. This article will review recent advances in this field, and will suggest ways to synergize systems to model and observe the pathophysiology of autoimmune diabetes with bioengineered therapeutic strategies.

Human type 2 innate lymphoid cells (ILC2) are the only ILC subset that shows heterogeneous expression of the SCF receptor c-Kit (CD117). Despite its use as surface marker to distinguish ILC populations, its influence on ILC2 biology has not been investigated. Here, we show that c-Kit expression of peripheral blood ILC distinguishes two functionally distinct ILC2 subsets (c-Kithi and c-Kitlo ). When examined for their potential for functional plasticity we found that c-Kitlo ILC2 displayed greater potential to produce type 2 cytokines, possibly representing fully mature and lineage committed ILC2. On the other hand, c-Kithi ILC2 coexpressed the ILC3-marker and chemokine receptor CCR6 and were able to mount a significant IL-17A response under ILC3-promoting conditions. In addition, c-Kithi ILC2 produced higher levels of IFN-γ than c-Kitlo ILC2 under ILC1-conditions. Although costimulation with SCF did not further influence ILC2 plasticity, it augmented type 2 cytokine production. We conclude that c-Kit marks distinct subpopulations of ILC2, which has therapeutic implications for conditions in which ILC2 are involved, such as allergy and asthma.

Exploring the accurate structure ensembles are critical to understand the functions of intrinsically disordered proteins (IDPs). As a well-known IDP, islet amyloid polypeptide (IAPP) plays important roles in the development of human type II diabetes (T2D). The toxicity of human IAPP (hIAPP) is induced by the amyloidosis of the peptide, however, its aggregation mechanism remains ambiguous. The characterization of structure ensemble of hIAPP, as well as the differences between hIAPP and its non-amyloidogenic homologous such as rat IAPP (rIAPP), would greatly help to illuminate the amyloidosis mechanism of IAPP. In this study, the atomic structure ensembles of hIAPP and rIAPP were characterized by all-atom molecular dynamics (MD) simulations combined with enhanced sampling technology and experiment data restraints. The obtained structure ensembles were firstly compared with those determined by the conventional MD (cMD) and enhanced sampling without experiment data restraints. The results showed that the enhanced sampling and experiment data restraints would improve the simulation accuracy. The transient N-terminal α-helix structures were adopted by the sub-states of both hIAPP and rIAPP, however, the C-terminal helical structures were only present on hIAPP. The hydrophobic residues in the amyloid-core region of hIAPP are exposed to the solvent. The structure ensemble differences between hIAPP and rIAPP revealed in this work provide potential explain to the amyloidogenic mechanism and would be helpful for the design of drugs to combat T2D.

Vastatin, a fragment derived from type VIII collagen, is one of the least studied collagen-derived matrikines. Vastatin can be detected in serum but little is known regarding the relevance of serum vastatin in colorectal cancer (CRC). In this study, serum vastatin was measured (ELISA) in 67 healthy controls and 48 CRC patients prior to resection and compared to clinicopathological parameters and serum biomarkers of stromal reactivity (C3M, VICM). Impact of resection and chemotherapy were evaluated by comparing baseline values with a 3-month follow-up sample (n = 23). Serum vastatin was detectable in 114 of 115 subjects. At baseline vastatin was elevated in CRC compared to controls (P

The H3N2 influenza viruses became widespread in humans during the 1968 H3N2 pandemic and have been a major cause of influenza epidemics ever since. Different lineages of H3N2 influenza viruses are also commonly found in animals. If a different lineage of H3N2 virus jumps to humans, a human influenza pandemic could occur with devastating consequences. Here, we studied the genetics, receptor-binding properties, and replication and transmission in mammals of 15 H3N2 avian influenza viruses detected in live poultry markets in China. We found that the H3N2 avian influenza viruses are complicated reassortants with distinct replication phenotypes in mice. Five viruses replicated efficiently in mice and bound to both human-type and avian-type receptors. These viruses transmitted efficiently to direct-contact guinea pigs, and three of them also transmitted among guinea pigs and ferrets via respiratory droplets. Moreover, ferret antiserum induced by human H3N2 viruses did not react with any of the H3N2 avian influenza viruses. Our study demonstrates that the H3N2 avian influenza viruses pose a clear threat to human health and emphasizes the need for continued surveillance and evaluation of the H3N2 influenza viruses circulating in nature.

The article analyses a problem of empiric data mining related to psychological features of intersubject cooperation. It is specified that the reliable methodological basis of scientific search is an important pre-condition of empiric research efficiency in intersubject co-operation psychology. It is argued that intersubject co- operation must be studied by psychological science as fundamentally different domain from phenomenology of a separate individual. It is justified that exactly in cultural-historical psychology there is the foundation for cognition of consciousness of man, psychical life of man, and thus - and to the world of mutual relations of people, and phenomenon of intersubjetness. It is proven that by means of various concepts and ideas, introduced by L. S. Vygotsky (proximal development zone, interiorization, theory of experiencing, psychology of instruments and signs, correlation of sense and value), we can have deeper understanding of intersubject co-operation as specifically human type of interaction, aimed at development of agency and connections of a person with the world, other people and his/her inner self. Research of intersubject cooperation is described by means of modified checkers game. The main hypothesis of experimental research is that intersubjectly modified variant of checkers will display fundamentally different psychological features of cooperation, related to strategies of collaboration, positive emotional experiencing and taking into account points of view of the other human being. The article proves that intersubject cooperation is a specific modality of interaction, which in a situation of playing activity can be characterized by orientation on the common aim and cooperative strategies. Authors specify, that strategies of collaboration within intersubject gaming cooperation are various enough, from strictly rationalized to highly emotional. The accounting of other person’s position was demonstrated in many behavioral and verbal acts during sessions of intersubject variant of checkers game. To achieve common result participants had to operate coherently, that needed positions of the other participant to be taken into account. Intersubject variant of checkers became a heuristic research model, using which we made a step forward to deeper understanding of psychological essence of agency., У статті аналізується проблема отримання емпіричних даних щодо психологічних особливостей інтерсуб’єктної взаємодії. Описується дослідження інтерсуб’єктної взаємодії за допомогою модифікованої гри в шашки. Гіпотеза експериментального дослідження полягала в тому, що інтерсуб’єктний варіант гри в шашки буде проявлятися в принципово інших психологічних особливостях взаємодії, пов’язаних з стратегіями співробітництва, позитивними емоційними переживаннями та врахуванням позиції іншої людини. Доведено, що інтерсуб’єктна взаємодія є специфічним різновидом інтеракції, яка в ситуації ігрової діяльності може характеризуватися спрямованістю на спільну мету та кооператив- ними стратегіями. Вказується, що стратегії співробітництва при ігровій інтерсуб’єктній взаємодії є досить різноманітними – від інтелектуалізованих до емоційних.

Pancreatic islet β-cell failure is key to the onset and progression of type 2 diabetes (T2D). The advent of single-cell RNA sequencing (scRNA-seq) has opened the possibility to determine transcriptional signatures specifically relevant for T2D at the β-cell level. Yet, applications of this technique have been underwhelming, as three independent studies failed to show shared differentially expressed genes in T2D β-cells. We performed an integrative analysis of the available datasets from these studies to overcome confounding sources of variability and better highlight common T2D β-cell transcriptomic signatures. After removing low-quality transcriptomes, we retained 3046 single cells expressing 27 931 genes. Cells were integrated to attenuate dataset-specific biases, and clustered into cell type groups. In T2D β-cells (

In 2016 Delong et al. discovered a new type of neoepitope formed by the fusion of two unrelated peptide fragments. Remarkably these neoepitopes, called hybrid insulin peptides, or HIPs, are recognized by pathogenic CD4+ T cells in the NOD mouse and human pancreatic islet-infiltrating T cells in people with type 1 diabetes. Current data implicates CD4+ T-cell responses to HIPs in the immune pathogenesis of human T1D. Because of their role in the immune pathogenesis of human T1D it is important to identify new HIPs that are recognized by CD4+ T cells in people at risk of, or with, T1D. A detailed knowledge of T1D-associated HIPs will allow HIPs to be used in assays to monitor changes in T cell mediated beta-cell autoimmunity. They will also provide new targets for antigen-specific therapies for T1D. However, because HIPs are formed by the fusion of two unrelated peptides there are an enormous number of potential HIPs which makes it technically challenging to identify them. Here we review the discovery of HIPs, how they form and discuss approaches to identifying new HIPs relevant to the immune pathogenesis of human type 1 diabetes.

Angiotensin converting enzyme 2 (ACE2) acts as the receptor for the type 2 coronavirus that causes severe acute respiratory syndrome (SARS-CoV2), the etiological agent of coronavirus-19 disease (COVID-19). There has been a growing concern that renin-angiotensin (RAS) blockade increases the expression of ACE2 and then elevate patient susceptibility to SARS-CoV-2. Here, we report that age, smoking and RAS blockade influence on the percentage of human ACE2-expressing type II pneumocytes. These findings may explain the increased susceptibility to COVID-19 with age and in subjects with treated cardiovascular-related pathologies. Enhanced ACE2-expressing type II pneumonocytes would facilitate SARS-CoV2 infection, thus increasing patient susceptibility to acute respiratory distress syndrome development because of an unbalance between the pressor and depressor axis of the RAS due to ACE2 sequestration by the virus.

Since the establishment of the network for pancreatic organ donors with diabetes (nPOD), we have gained unprecedented insight into the pathology of human type 1 diabetes. Many of the pre-existing “dogmas”, mostly derived from studies of animal models and sometimes limited human samples, have to be revised now. For example, we have learned that autoreactive CD8 T cells are present even in healthy individuals within the exocrine pancreas. Furthermore, their “attraction” to islets probably relies on beta-cell intrinsic events, such as the over-expression of MHC class I and resulting presentation of autoantigens such as (prepro)insulin. In addition, we are discovering other signs of beta-cell dysfunction, possibly at least in part due to stress, such as the over-expression of certain cytokines. This review summarizes the latest developments focusing on cytokines and autoreactive CD8 T cells in human type 1 diabetes pathogenesis.

Type 2 transglutaminase (TGM2) is a multifunctional ubiquitous protein, involving in protein cross-linking, apoptosis, and cell differentiation. Recently, some reports have suggested that TGM2 expression is a potential prognostic marker, and often associates with advanced stages of disease, metastatic spread, as well as drug resistance in many cancer cell lines although its primary function is unknown. To elucidate the role of TGM2 in cancer, the expression profile of the TGM2 need to be examined. In this study, new polyclonal antibodies detecting four TGM2 variants encoding protein from ENSEMBL database are produced and their specificities are confirmed by western blot analysis with E.coli overexpressing TGM2-002 protein, HEK293T cells overexpressing TGM2-S protein and human colon cancer samples. Western blot data showed that these antibodies could detect not only TGM2-002 in E. coli overexpressing TGM2-002 but also smaller molecular weight protein (about 62 kDa) in HEK293T overexpressing TGM2-S cells which was further confirmed by MALDI-TOF analysis. We found that both TGM2-1 and TGM2-4 antibodies could detect the full length TGM2-002 protein in colon cancer samples. Furthermore, in normal sample, we found that majority of TGM2-002 protein existed in membrane fraction but not in total lysate whereas TGM2-002 protein was found in both total lysate and membrane fraction in colon cancer samples.

Bacterial type II phosphopantetheinyl transferases (PPTases), required for the activation of many cellular mega-synthases, have been validated as promising drug targets in several pathogens. Activation of the blue-pigment-synthesizing nonribosomal peptide synthetase BpsA by a target PPTase can be used to screen in vitro for new antibiotic candidates from chemical libraries. For a complete screening platform, there is a need to also counter-screen inhibitors for cross-reactivity with the endogenous human Type II PPTase (hPPTase), as this is a likely source of toxicity. As hPPTase is unable to recognize the PCP-domain of native BpsA, we used a combination of directed evolution and rational engineering to generate a triple-substitution variant that is able to be efficiently activated by hPPTase. Our engineered BpsA variant was able to readily detect inhibition of both hPPTase and the equivalent rat PPTase by broad-spectrum PPTase inhibitors, demonstrating its potential for high-throughput counter-screening of novel antibiotic candidates.

Accumulating evidence suggests that the human embryonic thymus produces distinct waves of innate effector γδ T cells. However, it is unclear whether this process comprises a dedicated subset of IL-17-producing γδ T (γδT17) cells, like reported in mice. Here we present a novel protocol for high-throughput paired γδ TCR-sequencing, which in combination with single-cell RNA-sequencing revealed a high heterogeneity of effector γδ T cell clusters. While immature γδ T cell clusters displayed mixed and diverse TCR, effector cell types in neonatal and adult blood segregated according to γδTCR usage. In adult samples, mature Vδ1+ T cells segregated into exhausted PD-1hi and active PD-1low clusters. Among Vγ9Vδ2+ T cell subsets, we identified distinct PLZF-positive effector γδ T cell clusters with innate type-1 and type-3 T cell signatures that were already detectable in a public dataset of early embryonic thymus organogenesis. Together, this suggests that functionally distinct waves of human innate effector γδ T cells including CCR6+ γδT17 cells develop in the early fetal thymus and persist into adulthood.

Summary Understanding the root causes of autoimmune diseases is hampered by the inability to access relevant human tissues and identify the time of disease onset. To examine the interaction of immune cells and their cellular targets in type 1 diabetes, we differentiated human induced pluripotent stem cells into pancreatic endocrine cells, including β cells. Here, we describe an in vitro platform that models features of human type 1 diabetes using stress-induced patient-derived endocrine cells and autologous immune cells. We demonstrate a cell-type-specific response by autologous immune cells against induced pluripotent stem cell-derived β cells, along with a reduced effect on α cells. This approach represents a path to developing disease models that use patient-derived cells to predict the outcome of an autoimmune response., Graphical Abstract, Highlights • β cell-specific response is achieved using iPSC-β cells and autologous immune cells • An in vitro immune response to iPSC-β cells requires ER stress • T cell activation is restricted to autologous iPSC-β cells • T cell activation is mediated by TCR engagement of peptide-HLA complexes on iPSC-β, Leite et al. describe an in vitro platform that models features of autoimmune type 1 diabetes using patient-derived endocrine cells and autologous immune cells. This represents a path to developing a model with patient-derived cells to predict and analyze the autoimmune response.

Iodothyronine deiodinases (Ds) mediate thyroid hormone (TH) action. They catalyze triiodothyronine (T3) production and degradation via, respectively; outer (ORD) and inner (IRD) ring deiodination. Type 1 D (D1) has a relatively high Km for substrates thyroxine (T4) and reverse T3 (rT3), catalyzes both ORD and IRD and is inhibited by propylthiouracil (PTU). Although no mutations in DIO1 gene have been reported so far in humans, based on the D1-deficient C3H mouse and the heterozygous Dio1 knockout mice, the expected phenotype of D1 loss-of-function is higher serum rT3 and slightly elevated T4. Our objective was to identify new gene defects causing unexplained and discrepant thyroid function tests using whole-exome sequencing (WES). Exons and splice sites are captured with Agilent SureSelectXT and sequenced in Illumina HiSeq2500. Data are analyzed with BWA, GATK, and ANNOVAR applications for alignment, variant calling and annotation, respectively. Sanger sequencing is used to confirm and segregate WES variants in families. A heterozygous pathogenic missense variant in the DIO1 gene (c.282C>A:p.N94K; N-linker) was identified in four family members with relatively higher serum rT3, T4, and free T4 than unaffected relatives, and normal TSH. We identified a second heterozygous pathogenic mutation in the DIO1 (c.603G>A:p.M201I; thioredoxin-fold) in a second family. Two affected individuals presented slightly elevated TSH, higher serum rT3, normal T4 levels, while the T3/T4 ratio was lower compared to unaffected members. To assess the functional activity of the mutant D1 protein, human embryonic kidney epithelial cells (HEK293) were transiently co-transfected with pcDNA3 plasmids expressing pD1-WT, pD1-N94K or pD1-M201I, and pGFP as transfection control. In assays performed with 1μM 125I-T4, the catalytic activities of pD1-N94K and pD1-M201I were 44.7% and 54.1% lower as compared to pD1-WT, respectively. To study the enzyme kinetics, the D1 assay was repeated in the presence of increasing 125I-T4 concentrations (0.1-20μM). The enzymatic activity assays revealed similar Vmax for pD1-N94K and pD1-M201I mutants compared to pD1-WT (VmaxpD1-N94K=53.7 vs VmaxpD1-WT=40.9 and VmaxpD1-M201I=58.8 vs VmaxpD1-WT=42), but higher Michaelis constant (Km) than pD1-WT (KmpD1-N94K=16.4 vs KmpD1-WT=6 and KmpD1-M201I=21.4 vs KmpD1-WT=6.9), which demonstrates a reduced affinity for T4. In conclusion, we report the first DIO1 mutations in humans with serum thyroid tests suggestive of TH metabolism defects. These mutations affect the catalytic activity of the D1, demonstrating impaired functional activity of the mutant enzymes and consequently altering TH metabolism.

In vitro studies have shown that alterations in redox state can cause a range of opposing effects on the properties of the contractile apparatus in skeletal muscle fibers. To test whether and how redox changes occurring in vivo affect the contractile properties, vastus lateralis muscle fibers from seven healthy young adults were examined at rest (PRE) and following (POST) high-intensity intermittent cycling exercise. Individual mechanically skinned muscle fibers were exposed to heavily buffered solutions at progressively higher free [Ca(2+)] to determine their force-Ca(2+) relationship. Following acute exercise, Ca(2+) sensitivity was significantly decreased in type I fibers (by 0.06 pCa unit) but not in type II fibers (0.01 pCa unit). Specific force decreased after the exercise in type II fibers (−18%) but was unchanged in type I fibers. Treatment with the reducing agent dithiothreitol (DTT) caused a small decrease in Ca(2+)-sensitivity in type II fibers at PRE (by ∼0.014 pCa units) and a significantly larger decrease at POST (∼0.035 pCa units), indicating that the exercise had increased S-glutathionylation of fast troponin I. DTT treatment also increased specific force (by ∼4%), but only at POST. In contrast, DTT treatment had no effect on either parameter in type I fibers at either PRE or POST. In type I fibers, the decreased Ca(2+) sensitivity was not due to reversible oxidative changes and may have contributed to a decrease in power production during vigorous exercises. In type II fibers, exercise-induced redox changes help counter the decline in Ca(2+)-sensitivity while causing a small decline in maximum force. NEW & NOTEWORTHY This study identified important cellular changes occurring in human skeletal muscle fibers following high-intensity intermittent exercise: 1) a decrease in contractile apparatus Ca(2+) sensitivity in type I but not type II fibers, 2) a decrease in specific force only in type II muscle fibers, and 3) a redox-dependent increase in Ca(2+) sensitivity occurring only in type II fibers, which would help maintain muscle performance by countering the normal metabolite-induced decline in Ca(2+) sensitivity.

Helminth infections induce strong type 2 and regulatory responses, but the degree of heterogeneity of such cells is not well characterized. Using mass cytometry, we profiled these cells in Europeans and Indonesians not exposed to helminths and in Indonesians residing in rural areas infected with soil-transmitted helminths. To assign immune alteration to helminth infection, the profiling was performed before and 1 year after deworming. Very distinct signatures were found in Europeans and Indonesians, showing expanded frequencies of T helper 2 cells, particularly CD161+ cells and ILC2s in helminth-infected Indonesians, which was confirmed functionally through analysis of cytokine-producing cells. Besides ILC2s and CD4+ T cells, CD8+ T cells and γδ T cells in Indonesians produced type 2 cytokines. Regulatory T cells were also expanded in Indonesians, but only those expressing CTLA-4, and some coexpressed CD38, HLA-DR, ICOS, or CD161. CD11c+ B cells were found to be the main IL-10 producers among B cells in Indonesians, a subset that was almost absent in Europeans. A number of the distinct immune profiles were driven by helminths as the profiles reverted after clearance of helminth infections. Moreover, Indonesians with no helminth infections residing in an urban area showed immune profiles that resembled Europeans rather than rural Indonesians, which excludes a major role for ethnicity. Detailed insight into the human type 2 and regulatory networks could provide opportunities to target these cells for more precise interventions.

Rat models of human type 1 diabetes have been shown to be of great importance for the elucidation of the mechanisms underlying the development of autoimmune diabetes. The three major well-established spontaneous rat models are the BioBreeding (BB) diabetes-prone rat, the Komeda diabetes-prone (KDP) rat, and the IDDM (LEW.1AR1-iddm) rat. Their distinctive features are described with special reference to their pathology, immunology, and genetics and compared with the situation in patients with type 1 diabetes mellitus. For all three established rat models, a distinctive genetic mutation has been identified that is responsible for the manifestation of the diabetic syndrome in these rat strains.

Type 1 diabetes is increasing in incidence in many parts of the world and it might be imagined that the pathological processes that underlie disease progression are firmly understood. However, this is not the case; rather, our collective understanding is still surprisingly rudimentary. There are various reasons for this but one of the most important is that the target organ (the pancreas) has been examined at, or soon after, diagnosis in only a small number of cases worldwide over the past half a century. This review provides a summary of some of the insights gained from these studies and highlights areas of ongoing uncertainty. In particular, it considers the process of insulitis (a form of islet inflammation that occurs characteristically in type 1 diabetes) and discusses the factors that may influence the access of immune cells to the beta cells. Attention is also drawn to recent evidence implying that two distinct profiles of insulitis exist, which occur differentially in people who develop type 1 diabetes at increasing ages. Emphasis is also placed on the emerging (and somewhat surprising) consensus that the extent of beta cell loss is variable among people with type 1 diabetes and that many (especially those who are older at onset) retain significant numbers of insulin-producing cells long after diagnosis. We conclude by emphasising the importance of renewed efforts to study the human pancreas at disease onset and consider how the current insights may inform the design of future strategies to slow or halt the rate of beta cell loss. Electronic supplementary material The online version of this article (10.1007/s00125-018-4731-y) contains a slideset of the figures for download, which is available to authorised users.

Este texto visa pensar a educação enquanto processo artístico de formação do humano e da existência humana. Na esteira das críticas que apontam o processo formativo como homogeneização e redução do tipo humano a uma única formação, este ensaio vislumbra a possibilidade de uma educação para a singularidade. Pensando com Nietzsche, metodologicamente se situa para além de um elencar premissas e defender argumentos, intentando explicitar, narrar e propor pensamentos radicais sobre educação e vida. Assim, arregimenta a arte enquanto um elemento que permite pensar a educação para além das necessidades imediatas, a arte enquanto instrumento que autoriza pensar uma educação para a vida, não para um ofício nem para um acúmulo de conhecimento. Uma formação para tornar-se o que se é, sem um juízo prévio do que deveríamos ser, mas sim uma abertura para as múltiplas perspectivas de configuração do humano. Provocado pelo tema, projeta algumas características de uma educação, de um educador e de um educando imbuídos em um processo artístico, no qual a vida é a obra de arte. Pressupõe que a vida é devir e que nossas teorias pedagógicas não dão conta deste mover existencial, então provoca pensar uma educação como processo artístico, sem finalidades últimas, mas um constante tornar-se o que se é.

Binding exclusively to human-type receptors is a prerequisite for avian influenza viruses to transmit from human to human. We previously reported that 34% of H6 avian influenza viruses recognize the human-type receptor, but their affinity for the avian-type receptor remains higher than that for the human-type receptor. Here, we found that a single amino acid change from glutamine to leucine at position 226 of hemagglutinin caused a switch in receptor-binding preference from avian-type to human-type receptors and rendered A/chicken/Guangdong/S1312/2010(H6N2) capable of respiratory droplet transmission in guinea pigs.

Intranuclear rodlets (INRs) are rod-shaped intranuclear bodies of unknown function present in the nuclei of pancreatic beta cells. Previous studies have demonstrated a significant depletion of INRs from beta cells in mouse models of type II diabetes, suggesting that they may have pathological significance. The objective of the present study was to determine whether beta cell INRs show quantitative alterations in human type II diabetes. In sections of non-neoplastic pancreas from 23 diabetic patients and 23 controls who had undergone complete or partial pancreatectomy, we detected a significant reduction in the proportion of INRs in insulin-immunoreactive beta cells. In addition, we showed that beta cell INRs are immunoreactive for the RNA-binding protein HuR. The results of this study confirm and extend our previous study and implicate this enigmatic nuclear structure in the cellular pathophysiological mechanisms underlying the development of type II diabetes in humans.

Human type III collagen has been suggested to play vital roles in a series of pathophysiological conditions. Sequence analysis among major fibril-forming collagens (types I, II, and III) revealed that Gly-Gly pairs are a distinct sequence feature in type III collagen. This motif occurs more than five times as often in type III compared to type I and II collagens. We used an integrated computational modeling and biophysical approach to analyze the glycine pair motifs to understand how they govern the structure of type III collagen at the molecular level. Triple helical peptides to model the regions of type III collagen containing GG motifs were used to analyze structural and thermodynamic effects of GG incorporation into the collagen sequence. We found that when amino acids adjacent to a GG motif are charged, the collagen adopts a more flexible, random conformation. The GG motif led to altered hydrogen bond patterns and decreased global melting temperatures of the triple helical peptides. The local entropic destabilization effect of the glycine pair helps explain the difference in the flexibility between types I and III collagen fibrils. This finding reveals potential physiological roles of type III collagen in regulating the mechanical properties of collagen fibrils and may enable the design of future collagen-like materials with tunable mechanical properties.