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Abstract The objective of the present study was to characterize non-classical class I major histocompatibility complex (MHC) genes in buffaloes and evaluate the expression of these genes in different tissue components of the placenta of buffaloes during pregnancy and in trophoblastic cells after stimulation using lipopolysaccharide (LPS). To do this, DNA was extracted from the blood of buffaloes and was subjected to PCR testing and sequencing of the genes NC3 and MICB. The RNA extracted from the placentome and intercotyledonary region of buffaloes in their first (n = 6), second (n = 6) and third (n = 6) trimesters of gestation was subjected to real-time PCR. Explants were created using the chorioallantoic membrane and two experimental groups were established: control and stimulated with LPS for four hours to evaluate the gene expression profile. Analysis on the sequences obtained showed that the genes NC3 and MICB of buffaloes were homologous with those of cattle, with high similarity in the analysis on the sequence variation pattern. The gene expression analysis showed that the genes assessed were transcribed at stages and in placental tissue that differed from what was seen in cattle. The transcription of these genes varied in the tissues studied, with greater transcription of MICB in the intercotyledonary region over the first third of gestation, while the genes studied in the placentome presented low rates of transcription. The trophoblastic cells of the chorioallantoic membrane stimulated with LPS for six hours did not present non-classic MFC-I transcription alterations. The present study therefore provides additional knowledge regarding the immune regulation of placental tissues of buffaloes. Resumo O objetivo do presente estudo foi caracterizar genes não clássicos do complexo principal de histocompatibilidade (MHC) de classe I em búfalas e avaliar a expressão desses genes em diferentes componentes teciduais da placenta de búfalas durante a gestação e em células trofoblásticas após estimulação com lipopolissacarídeo (LPS). Para isso, o DNA foi extraído do sangue de búfalos e submetido a testes de PCR e sequenciamento dos genes NC3 e MICB. O RNA extraído do placentônio e região intercotiledonar de búfalas no primeiro (n = 6), segundo (n = 6) e terceiro (n = 6) trimestres de gestação foi submetido à PCR em tempo real. Explantes foram criados usando a membrana corioalantóide e dois grupos experimentais foram estabelecidos: controle e estimulado com LPS por quatro horas para avaliar o perfil de expressão gênica. A análise das sequências obtidas mostrou que os genes NC3 e MICB de búfalos foram homólogos aos de bovinos, com alta similaridade na análise do padrão de variação de sequência. A análise da expressão gênica mostrou que os genes avaliados foram transcritos em estágios e em tecido placentário diferentes do observado em bovinos. A transcrição desses genes variou nos tecidos estudados, com maior transcrição de MICB na região intercotiledonar ao longo do primeiro terço da gestação, enquanto os genes estudados no placentoma apresentaram baixas taxas de transcrição. As células trofoblásticas da membrana corioalantóide estimuladas com LPS por seis horas não apresentaram alterações não clássicas na transcrição da MFC-I. O presente estudo, portanto, fornece conhecimento adicional sobre a regulação imune de tecidos placentários de búfalos.

Stem cells have indefinite self-renewable capability; however, factors that modulate their pluripotency/function are not fully identified. Here we show that store-dependent Ca2+ entry is essential for modulating the function of bone marrow-derived mesenchymal stem cells (MSCs). Increasing external Ca2+ modulated cell cycle progression that was critical for MSCs survival. Additionally, Ca2+ was critical for stem proliferation, its differentiation, and maintaining stem cell potential. Ca2+ channel characterization, including gene silencing, showed two distinct Ca2+ entry channels (through Orai1/TRPC1 or via Orai3) that differentially regulate the proliferation and viability of MSCs. Importantly, NFκB translocation, but not JNK/ERK into the nucleus, was observed upon store depletion, which was blocked by the addition of Ca2+ channel inhibitors. Radiation lead to a decrease in saliva secretion, decrease in acinar cell number, and enlarged ducts were observed, which were restored by the transplantation of stem cells that were propagated in higher Ca2+. Finally radiation showed a decrese in TRPC1 expression along with a decrese in AQP5, which was again restored upon MSC tranplantation. Together these results suggest that Ca2+ entry is essential for stem cell function that could be critical for regenerative medicine.

TROY, N. Y. LAST winter, in the process of teaching a thirteen-week course in Spanish, I proved for myself the superiority of a direct conversational method of teaching languages by television.

Mobile genes, which can be transferred between bacterial species in the microbiome to impart properties such as antibiotic resistance, are reflective of human activity and local diets. Recent work has underscored the importance of the microbiome in human health, and has largely attributed differences in phenotype to differences in the species present among individuals 1 , 2 , 3 , 4 , 5 . However, mobile genes can confer profoundly different phenotypes on different strains of the same species. Little is known about the function and distribution of mobile genes in the human microbiome, and in particular whether the gene pool is globally homogenous or constrained by human population structure. Here, we investigate this question by comparing the mobile genes found in the microbiomes of 81 metropolitan North Americans with those of 172 agrarian Fiji islanders using a combination of single-cell genomics and metagenomics. We find large differences in mobile gene content between the Fijian and North American microbiomes, with functional variation that mirrors known dietary differences such as the excess of plant-based starch degradation genes found in Fijian individuals. Notably, we also observed differences between the mobile gene pools of neighbouring Fijian villages, even though microbiome composition across villages is similar. Finally, we observe high rates of recombination leading to individual-specific mobile elements, suggesting that the abundance of some genes may reflect environmental selection rather than dispersal limitation. Together, these data support the hypothesis that human activities and behaviours provide selective pressures that shape mobile gene pools, and that acquisition of mobile genes is important for colonizing specific human populations.

The Global Coupled 3 (GC3) configuration of the Met Office Unified Model is presented. Among other applications, GC3 is the basis of the United Kingdom's submission to the Coupled Model Intercomparison Project 6 (CMIP6). This paper documents the model components that make up the configuration (although the scientific descriptions of these components are in companion papers) and details the coupling between them. The performance of GC3 is assessed in terms of mean biases and variability in long climate simulations using present‐day forcing. The suitability of the configuration for predictability on shorter time scales (weather and seasonal forecasting) is also briefly discussed. The performance of GC3 is compared against GC2, the previous Met Office coupled model configuration, and against an older configuration (HadGEM2‐AO) which was the submission to CMIP5. In many respects, the performance of GC3 is comparable with GC2, however, there is a notable improvement in the Southern Ocean warm sea surface temperature bias which has been reduced by 75%, and there are improvements in cloud amount and some aspects of tropical variability. Relative to HadGEM2‐AO, many aspects of the present‐day climate are improved in GC3 including tropospheric and stratospheric temperature structure, most aspects of tropical and extratropical variability and top‐of‐atmosphere and surface fluxes. A number of outstanding errors are identified including a residual asymmetric sea surface temperature bias (cool northern hemisphere, warm Southern Ocean), an overly strong global hydrological cycle and insufficient European blocking. Key Points Description of the Global Coupled 3 (GC3) configuration of the Met Office Unified Model A cross‐time‐scale evaluation of the GC3 configuration is presented Overall, GC3 is an improvement on previous configurations

To examine barriers to initiation and continuation of mental health treatment among individuals with common mental disorders. Data were from the World Health Organization (WHO) World Mental Health (WMH) surveys. Representative household samples were interviewed face to face in 24 countries. Reasons to initiate and continue treatment were examined in a subsample (n = 63,678) and analyzed at different levels of clinical severity. Among those with a DSM-IV disorder in the past 12 months, low perceived need was the most common reason for not initiating treatment and more common among moderate and mild than severe cases. Women and younger people with disorders were more likely to recognize a need for treatment. A desire to handle the problem on one's own was the most common barrier among respondents with a disorder who perceived a need for treatment (63.8%). Attitudinal barriers were much more important than structural barriers to both initiating and continuing treatment. However, attitudinal barriers dominated for mild-moderate cases and structural barriers for severe cases. Perceived ineffectiveness of treatment was the most commonly reported reason for treatment drop-out (39.3%), followed by negative experiences with treatment providers (26.9% of respondents with severe disorders). Low perceived need and attitudinal barriers are the major barriers to seeking and staying in treatment among individuals with common mental disorders worldwide. Apart from targeting structural barriers, mainly in countries with poor resources, increasing population mental health literacy is an important endeavor worldwide.

On its own, a single cell cannot exert more than a microscopic influence on its immediate surroundings. However, via strength in numbers and the expression of cooperative phenotypes, such cells can enormously impact their environments. Simple cooperative phenotypes appear to abound in the microbial world, but explaining their evolution is challenging because they are often subject to exploitation by rapidly growing, non-cooperative cell lines. Population spatial structure may be critical for this problem because it influences the extent of interaction between cooperative and non-cooperative individuals. It is difficult for cooperative cells to succeed in competition if they become mixed with non-cooperative cells, which can exploit the public good without themselves paying a cost. However, if cooperative cells are segregated in space and preferentially interact with each other, they may prevail. Here we use a multi-agent computational model to study the origin of spatial structure within growing cell groups. Our simulations reveal that the spatial distribution of genetic lineages within these groups is linked to a small number of physical and biological parameters, including cell growth rate, nutrient availability, and nutrient diffusivity. Realistic changes in these parameters qualitatively alter the emergent structure of cell groups, and thereby determine whether cells with cooperative phenotypes can locally and globally outcompete exploitative cells. We argue that cooperative and exploitative cell lineages will spontaneously segregate in space under a wide range of conditions and, therefore, that cellular cooperation may evolve more readily than naively expected.

Several organic–inorganic hybrid materials from the metal–organic framework (MOF) family have been shown to form stable liquids at high temperatures. Quenching then results in the formation of melt-quenched MOF glasses that retain the three-dimensional coordination bonding of the crystalline phase. These hybrid glasses have intriguing properties and could find practical applications, yet the melt-quench phenomenon has so far remained limited to a few MOF structures. Here we turn to hybrid organic–inorganic perovskites—which occupy a prominent position within materials chemistry owing to their functional properties such as ion transport, photoconductivity, ferroelectricity and multiferroicity—and show that a series of dicyanamide-based hybrid organic–inorganic perovskites undergo melting. Our combined experimental–computational approach demonstrates that, on quenching, they form glasses that largely retain their solid-state inorganic–organic connectivity. The resulting materials show very low thermal conductivities (~0.2 W m−1 K−1), moderate electrical conductivities (10−3–10−5 S m−1) and polymer-like thermomechanical properties.A series of dicyanamide-based hybrid organic–inorganic perovskite structures has been shown to melt at temperatures below 300 °C. On melt-quenching, they form glasses that possess coordination bonding and show very low thermal conductivities and moderate electrical conductivities as well as polymer-like thermomechanical properties.

Multigene diseases Inflammatory bowel diseases (IBDs) — a broad classification that includes Crohn's disease and ulcerative colitis — are multigenic disorders that are also linked to various environmental components. Despite this complexity, considerable progress has been made in unravelling their pathogenesis. Ramnik Xavier and Daniel Podolsky review recent developments in the field. The genetics of IBDs point to roles for epithelial barrier function, innate and adaptive immunity in pathogenesis, while key environmental factors include commensal bacteria which may provoke dysregulated immune responses in the susceptible host. The advances made in understanding IBDs show what is possible in dissecting the pathogenesis of complex disorders: similar unbundling may be possible in heart disease, diabetes and other multigenic disorders. The cover shows an image of an activated human macrophage, one of several cell populations key to the pathogenesis of IBD. Recently, substantial advances in the understanding of the molecular pathogenesis of inflammatory bowel disease (IBD) have been made owing to three related lines of investigation. First, IBD has been found to be the most tractable of complex disorders for discovering susceptibility genes, and these have shown the importance of epithelial barrier function, and innate and adaptive immunity in disease pathogenesis. Second, efforts directed towards the identification of environmental factors implicate commensal bacteria (or their products), rather than conventional pathogens, as drivers of dysregulated immunity and IBD. Third, murine models, which exhibit many of the features of ulcerative colitis and seem to be bacteria-driven, have helped unravel the pathogenesis/mucosal immunopathology of IBD.

The latest coupled configuration of the Met Office Unified Model (Global Coupled configuration 2, GC2) is presented. This paper documents the model components which make up the configuration (although the scientific description of these components is detailed elsewhere) and provides a description of the coupling between the components. The performance of GC2 in terms of its systematic errors is assessed using a variety of diagnostic techniques. The configuration is intended to be used by the Met Office and collaborating institutes across a range of timescales, with the seasonal forecast system (GloSea5) and climate projection system (HadGEM) being the initial users. In this paper GC2 is compared against the model currently used operationally in those two systems. Overall GC2 is shown to be an improvement on the configurations used currently, particularly in terms of modes of variability (e.g. mid-latitude and tropical cyclone intensities, the Madden–Julian Oscillation and El Niño Southern Oscillation). A number of outstanding errors are identified with the most significant being a considerable warm bias over the Southern Ocean and a dry precipitation bias in the Indian and West African summer monsoons. Research to address these is ongoing.