In vitro and in vivo evaluation of 6-aminopyrazolyl-pyridine-3-carbonitriles as JAK2 kinase inhibitors

Synthesis and biological evaluation of a series of 6-aminopyrazolyl-pyridine-3-carbonitriles as JAK2 kinase inhibitors was reported. Biochemical screening, followed by profile optimization, resulted in JAK2 inhibitors exhibiting good kinase selectivity, pharmacokinetic properties, physical properties and pharmacodynamic effects.     

Differential gene expression in ovaries of pregnant pigs with high and low prolificacy levels and identification of candidate genes for litter size

Previous results from a genome scan in an F(2) Iberian × Meishan pig intercross showed several chromosome regions associated with litter size traits in this species. In order to identify candidate genes underlying these quantitative trait loci (QTL), we performed an ovary gene expression analysis during the sow's pregnancy. F(2) sows were ranked by their estimated breeding values for prolificacy: six sows with the highest estimated breeding value (EBV) (i.e., high prolificacy) and six sows with the lowest EBV (low prolificacy) were selected. Samples were hybridized using an Affymetrix GeneChip porcine genome array. Statistical analysis with a mixed model approach identified 221 differentially expressed probes, representing 189 genes. These genes were functionally annotated in order to identify genetic pathways overrepresented in this list. Among the functional groups most represented was, in first position, immune system response activation against external stimulus. The second group consisted of integrated genes that regulate maternal homeostasis by complement and coagulation cascades. A third group was involved in lipid and fatty acid enzymes of metabolic processes, which participate in the steroidogenesis pathway. In order to identify powerful candidate genes for prolificacy, the second approach of this study was to merge microarray data with the QTL positional information affecting litter size, previously detected in the same experimental cross. As a result, we have identified 27 differentially expressed genes colocalizing with QTL for litter size traits, which fulfill the biological, positional, and functional criteria.     

Intra- and interspecific density-dependent dispersal in an aquatic prey-predator system

1. Dispersal intensity is a key process for the persistence of prey-predator metacommunities. Consequently, knowledge of the ecological mechanisms of dispersal is fundamental to understanding the dynamics of these communities. Dispersal is often considered to occur at a constant per capita rate; however, some experiments demonstrated that dispersal may be a function of local species density. 2. Here we use aquatic experimental microcosms under controlled conditions to explore intra- and interspecific density-dependent dispersal in two protists, a prey Tetrahymena pyriformis and its predator Dileptus sp. 3. We observed intraspecific density-dependent dispersal for the prey and interspecific density-dependent dispersal for both the prey and the predator. Decreased prey density lead to an increase in predator dispersal, while prey dispersal increased with predator density. 4. Additional experiments suggest that the prey is able to detect its predator through chemical cues and to modify its dispersal behaviour accordingly. 5. Density-dependent dispersal suggests that regional processes depend on local community dynamics. We discuss the potential consequences of density-dependent dispersal on metacommunity dynamics and stability.     

Contrasting effects of low-dose IL-2 on vaccine-boosted simian immunodeficiency virus (SIV)-specific CD4+ and CD8+ T cells in macaques chronically infected with SIVmac251

IL-2, the first cytokine discovered with T cell growth factor activity, is now known to have pleiotropic effects on T cells. For example, it can promote growth, survival, and differentiation of Ag-selected cells, or facilitate Ag-induced cell death of T cells when Ag persists, and in vivo, it is thought to contribute to the regulation of the size of adaptive T cell response. IL-2 is deficient in HIV-1 infection and has been used in the management of HIV-1-infected individuals undergoing antiretroviral therapy. In this study, we investigated how continuous low-dose IL-2 affected the CD4+ and CD8+ T cell response induced by two inoculations of a canarypox recombinant SIV-based vaccine candidate in healthy macaques chronically infected with SIVmac251. These macaques had normal levels of CD4+ T cells at the beginning of antiretroviral therapy treatment. Vaccination in the presence of IL-2 significantly augmented Gag-specific CD8+ T cell responses, but actually reduced Gag-specific CD4+ T cell responses. Although IL-2 at low doses did not change the overall concentration of circulating CD4+ or CD8+ T cells, it expanded the frequency of CD4+CD25+ T cells. Depletion of the CD4+CD25+ T cells in vitro, however, did not result in a reconstitution of Gag-specific CD4+ responses or augmentation of SIV-specific CD8+ T cell responses. Thus, we conclude that the decrease in virus-specific CD4+ T cell response may be due to IL-2-promoted redistribution of cells from the circulation, or due to Ag-induced cell death, rather than suppression by a T regulatory population.     

Production of xylanases from rice bran by Streptomyces actuosus A-151

In this study, the agricultural waste was used to screen for an organism that is capable of producing enzymes for degrading xylan and cellulose. Results showed that Streptomyces actuosus A-151, isolated from northern Taiwan, produced β-xylanase when rice bran was used as the sole carbon source. Four xylanases, designated as FI-A, FI-B, FII-A, FII-B, were identified and purified from the culture filtrate of S. actuosus A-151. Their specific activities after purification were 41.3, 86.2, 20.4, 85.2 U/mg, respectively. The pH stability of the four enzymes was: FI-A, 5–8; FI-B, 3–8; FII-A, 5–9; and FII-B, 3–9. The optimum pH for FII-B was 4, and the others were near 5–6. The optimum temperatures for enzyme activities were 60 °C for FII-B, and 70 °C for the others. The thermal stability for all four enzymes were up to 60 °C. The molecular weights of FI-A, FI-B, FII-A, and FII-B xylanases were 30,000, 45,000, 26,000, and 20,000, respectively, by sodium dodecylsulfate–polyacrylamide gel electrophoresis and 30,000, 43,000, 25,000, and 21,000, respectively, by gel filtration. Addition of xylan, shrimp and crab shell powder, and orange peel to the culture medium was found to enhance the production of xylanase.     

Medical Student Attitudes Towards People with Mental Illness in China: A Qualitative Study

Stigma towards people with mental illness is a worldwide concern. A five-nation survey of medical student attitudes towards people with mental illness recently reported far lower levels of social acceptance among Chinese medical students compared to those from the US, Brazil, Ghana, and Nigeria. This qualitative study presented recent Chinese medical school graduates with probes based on questions used in the aforementioned cross-national study to elicit their views of factors underlying the negative attitudes towards social acceptance of people with mental illness. One-hour interviews were conducted with twenty psychiatry residents in June, 2016. Of 241 coded responses concerning negative attitudes, 51.5% were coded as reflecting fear of violent behavior, 22.8% as loss of face (i.e. shame from interpersonal associations), 17.0% lowered social status, 4.98% nonconforming social behavior, and 3.73% the heritability of mental illness. Low levels of social acceptance of individuals with mental illness among medical students in China are largely related to fears of violence of and loss of face. Understanding the attitudes of medical students may inform efforts to reduce stigma through educational initiatives targeted at both medical students and the general public.     

Reassessment of the status of Lymantria albescens and Lymantria postalba (Lepidoptera: Erebidae: Lymantriinae) as distinct ‘Asian gypsy moth’ species,using both mitochondrial and nuclear sequence data

For regulatory purposes, the name ‘Asian gypsy moth’ refers to a group of closely related Asian Lymantria species and subspecies whose female moths display flight capability, a trait believed to confer enhanced invasiveness relative to the European gypsy moth, Lymantria dispar dispar, whose females are flightless. Lymantria albescens and Lymantria postalba are Asian gypsy moths occurring in the southern Ryukyu Islands and in the northern Ryukyu and adjacent Kyushu and Shikoku Islands of Japan, respectively. Although once considered subspecies of L. dispar, their status as distinct species, relative to the latter, is now well established. While postalba was subsequently considered a subspecies of L. albescens, largely on the basis of differences in forewing ground colour in males, both taxa were later given distinct species status by Pogue & Schaefer (2007) following their revision of the genus Lymantria. Here, we re-examined the validity of this revised status through the sequencing of a large portion of the mitochondrial genome (c. 60%) and multiple nuclear marker genes [elongation factor 1-alpha (Ef-1α), wingless (Wgl), internal transcribed spacer 2 (ITS-2), ribosomal protein S5 (RpS5)] in representative specimens of both taxa and other Lymantria species, including L. monacha, L. xylina, L. mathura and members of the L. dispar + L. umbrosa clade. A comparison of the number of substitutions in these genomic regions among the taxa we considered showed lower or equivalent variation between L. albescens and L. postalba compared with subspecies of L. dispar, for mitochondrial and nuclear sequences, respectively. This finding was reflected in the maximum likelihood trees generated independently for mitochondrial and nuclear data, where L. albescens and L. postalba formed, in both analyses, a short-branch sister clade basal to the L. dispar + L. umbrosa clade. We further sequenced three markers [cytochrome c oxydase 1 (COI), EF-1α, Wgl] in multiple L. albescens–L. postalba specimens collected along a south-to-north transect across the Ryukyu Arc and observed no clear distinction among the sampled specimens as a function of taxonomic designation. We conclude that L. albescens and L. postalba form a single species, with postalba representing a darker-winged morph along an apparent south-to-north wing colour cline. Accordingly, L. postalba is relegated to synonymy under L. albescens ( syn.n. ).     

Non-human primate token use shows possibilities but also limitations for establishing a form of currency

Non-human primates evaluate choices based on quantitative information and subjective valuation of options. Non-human primates can learn to value tokens as placeholders for primary rewards (such as food). With those tokens established as a potential form of ‘currency’, it is then possible to examine how they respond to opportunities to earn and use tokens in ways such as accumulating tokens or exchanging tokens with each other or with human experimenters to gain primary rewards. Sometimes, individuals make efficient and beneficial choices to obtain tokens and then exchange them at the right moments to gain optimal reward. Sometimes, they even accumulate such rewards through extended delay of gratification, or through other exchange-based interactions. Thus, non-human primates are capable of associating value to arbitrary tokens that may function as currency-like stimuli, but there also are strong limitations on how non-human primates can integrate such tokens into choice situations or use such tokens to fully ‘symbolize’ economic decision-making. These limitations are important to acknowledge when considering the evolutionary emergence of currency use in our species.This article is part of the theme issue ‘Existence and prevalence of economic behaviours among non-human primates’.     

Emergence of dengue virus serotype 2 in Mauritania and molecular characterization of its circulation in West Africa

The number of sporadic and epidemic dengue fever cases have reportedly been increasing in recent years in some West African countries, such as Senegal and Mali. The first epidemic of laboratory-confirmed dengue occurred in Nouakchott, the capital city of Mauritania situated in the Saharan desert, in 2014. On-site diagnosis of dengue fever was established using a rapid diagnostic test for dengue. In parallel, the presence of Aedes aegypti mosquitoes in the city was confirmed. The initial diagnosis was confirmed by RT-PCR, which showed that all samples from the 2014 dengue epidemic in Nouakchott were dengue virus serotype 2 (DENV-2). The whole genome or envelope protein gene of these strains, together with other DENV-2 strains obtained from travelers returning from West African countries to France between 2016 and 2019 (including two Mauritanian strains in 2017 and 2018), were sequenced. Phylogenetic analysis suggested a recent emergence of an epidemic strain from the cosmopolitan genotype belonging to West African cosmopolitan lineage II, which is genetically distinct from African sylvatic genotype. The origin of this DENV-2 lineage is still unknown, but our data seem to suggest a recent and rapid dispersion of the epidemic strain throughout the region. More complete genome sequences of West African DENV-2 are required for a better understanding of the dynamics of its circulation. Arboviral surveillance and outbreak forecasting are urgently needed in West Africa.     

Childhood adversity and epigenetic modulation of the leukocyte glucocorticoid receptor: preliminary findings in healthy adults

Background

A history of early adverse experiences is an important risk factor for adult psychopathology. Changes in stress sensitivity and functioning of the hypothalamic-pituitary-adrenal (HPA) axis may underlie the association between stress and risk for psychiatric disorders. Preclinical work in rodents has linked low levels of maternal care to increased methylation of the promoter region of the glucocorticoid receptor (GR) gene, as well as to exaggerated hormonal and behavioral responses to stress. Recent studies have begun to examine whether early-life stress leads to epigenetic modifications of the GR gene in humans.

Methods

We examined the degree of methylation of a region of the promoter of the human GR gene (NR3C1) in leukocyte DNA from 99 healthy adults. Participants reported on their childhood experiences of parental behavior, parental death or desertion, and childhood maltreatment. On a separate day, participants completed the dexamethasone/corticotropin-releasing hormone (Dex/CRH) test, a standardized neuroendocrine challenge test.

Results

Disruption or lack of adequate nurturing, as measured by parental loss, childhood maltreatment, and parental care, was associated with increased NR3C1 promoter methylation (p<.05). In addition, NR3C1 promoter methylation was linked to attenuated cortisol responses to the Dex/CRH test (p<.05).

Conclusions

These findings suggest that childhood maltreatment or adversity may lead to epigenetic modifications of the human GR gene. Alterations in methylation of this gene could underlie the associations between childhood adversity, alterations in stress reactivity, and risk for psychopathology.