Insertive condom-protected and condomless vaginal sex both have a profound impact on the penile immune correlates of HIV susceptibility.

The penis is the primary site of HIV acquisition in heterosexual men. Elevated penile inflammatory cytokines increase sexual acquisition risk, and topically applied cytokines enhance foreskin HIV susceptibility in an explant model. However, the impact of penile-vaginal sex on these immune parameters is undefined. Heterosexual couples were recruited to the Sex, Couples and Science (SECS) Study, with the collection of penile swabs, semen, cervico-vaginal secretions, and blood after a period of abstinence, and repeated sampling up to 72 hours after either condomless (n = 30) or condom-protected (n = 8) penile-vaginal sex. Soluble immune parameters were quantified by multiplex immunoassay. Co-primary immune endpoints were penile levels of IL-8 and MIG, cytokines previously linked to penile HIV acquisition. One hour after sex there were dramatic increases in penile IL-8 and MIG levels, regardless of condom use, with a gradual return to baseline by 72 hours; similar patterns were observed for other chemoattractant chemokines. Penile cytokine changes were similar in circumcised and uncircumcised men, and repeated measures ANOVA and ANCOVA models demonstrated that the degree of change after condomless sex was explained by cytokine levels in their partners' cervico-vaginal secretions. This may have important implications for the biology of penile HIV acquisition.

Schistosoma mansoni infection and socio-behavioural predictors of HIV risk: a cross-sectional study in women from Uganda.

BACKGROUND: Schistosoma mansoni infection has been associated with increased risk of HIV transmission in African women. This association might be causal or mediated through shared socio-behavioural factors and associated co-infections. We tested the latter hypothesis in a cross-sectional pilot study in a cohort of women from a S. mansoni endemic region of Uganda. To validate the immunological effects of S. mansoni in this cohort, we additionally assessed known schistosomiasis biomarkers. METHODS: HIV-uninfected non-pregnant adult women using public health services were tested for schistosomiasis using the urine circulating cathodic antigen test, followed by serology and Schistosoma spp.-specific PCR. Blood was obtained for herpes simplex virus (HSV)-2 serology, eosinophil counts and cytokine analysis. Samples collected from the genitourinary tract were used to test for classical sexually transmitted infections (STI), for bacterial vaginosis and to assess recent sexual activity via prostate-specific antigen testing. Questionnaires were used to capture a range of socio-economic and behavioral characteristics. RESULTS: Among 58 participants, 33 (57%) had schistosomiasis, which was associated with elevated levels of interleukin (IL)-10 (0.32 vs. 0.19 pg/ml; p = 0.038) and a trend toward increased tumour necrosis factor (TNF) (1.73 vs. 1.42 pg/ml; p = 0.081). Eosinophil counts correlated with levels of both cytokines (r = 0.53, p = 0.001 and r = 0.38, p = 0.019, for IL-10 and TNF, respectively); the association of eosinophilia with schistosomiasis was not significant (OR = 2.538, p = 0.282). Further, schistosomiasis was associated with lower age (per-year OR = 0.910, p = 0.047), being unmarried (OR = 0.263, p = 0.030), less frequent hormonal contraceptive (HC) use (OR = 0.121, p = 0.002, dominated by long acting injectable contraceptives) and a trend to longer time since penile-vaginal sex (OR = 0.350, p = 0.064). All women infected by Chlamydia trachomatis (n = 5), were also positive for schistosomiasis (Fisher's exact p = 0.064). CONCLUSIONS: Intestinal schistosomiasis in adult women was associated with systemic immune alterations, suggesting that associations with immunological correlates of HIV susceptibility warrant further investigation. S. mansoni associations with socio-behavioral parameters and C. trachomatis, which may alter both genital immunity and HIV exposure and/or acquisition risk, means that future studies should carefully control for potential confounders. These findings have implications for the design and interpretation of clinical studies on the effects of schistosomiasis on HIV acquisition.

Rethinking refugia: Tree topology, divergence dates, and demographic history trace the distribution of the endangered Plymouth gentian (Sabatia kennedyana) from the Pleistocene glaciation to present day.

PREMISE OF STUDY: Molecular population genetics is a powerful tool to infer how species responded to past environmental change. In the northern hemisphere, interest is increasing in how species responded to changes in ice coverage and temperature during the last glaciation maximum (LGM, between 18000-21000 yr ago) with a common assumption that glacial refugia were located at the southern edge of a species range. METHODS: We reconstructed the glacial and postglacial phylogeography of Sabatia kennedyana, a member of the Atlantic Coastal Plains Flora with a current distribution from Nova Scotia (NS) to South Carolina, using both cpDNA and nuclear markers. We also examined clinal variation in morphological traits, in particular relative investment in asexual vs sexual growth. KEY RESULTS: We find strong evidence that the species did not reside in southern glacial refugia, but rather in primary glacial refugia off the exposed continental shelf extending from Cape Cod and that this area was responsible for the founding of modern populations across the range from Nova Scotia (NS) to the United States. Additionally, based on the finding of higher cpDNA diversity and older cpDNA lineages in NS, we propose that multiple founder events occurred in NS, while only a single lineage gave rise to current populations in the United States. CONCLUSIONS: By understanding how S. kennedyana responded to past shifts in climate and by identifying areas of high genetic diversity in the northern range edge, we discuss the potential response of the species to future climate change scenarios.

Pollen limitation and reduced reproductive success are associated with local genetic effects in Prunus virginiana, a widely distributed self-incompatible shrub.

BACKGROUND AND AIMS: A vast quantity of empirical evidence suggests that insufficient quantity or quality of pollen may lead to a reduction in fruit set, in particular for self-incompatible species. This study uses an integrative approach that combines field research with marker gene analysis to understand the factors affecting reproductive success in a widely distributed self-incompatible species, Prunus virginiana (Rosaceae). METHODS: Twelve patches of P. virginiana distributed within three populations that differed in degree of disturbance were examined. Two of the sites were small (7-35 km(2)) remnants of forest in an intensively used agricultural landscape, while the third was continuous (350 km(2)) and less disturbed. Field studies (natural and hand cross-pollinations) were combined with marker gene analyses (microsatellites and S-locus) in order to explore potential factors affecting pollen delivery and consequently reproductive success at landscape (between populations) and fine scales (within populations). KEY RESULTS: Reductions in reproductive output were found in the two fragments compared with the continuous population, and suggest that pollen is an important factor limiting fruit production. Genetic analyses carried out in one of the fragments and in the continuous site suggest that even though S-allele diversity is high in both populations, the fragment exhibits an increase in biparental inbreeding and correlated paternity. The increase in biparental inbreeding in the fragment is potentially attributable to variation in the density of individuals and/or the spatial distribution of genotypes among populations, both of which could alter mating dynamics. CONCLUSIONS: By using a novel integrative approach, this study shows that even though P. virginiana is a widespread species, fragmented populations can experience significant reductions in fruit set and pollen limitation in the field. Deatiled examination of one fragmented population suggests that these linitations may be explained by an increase in biparental inbreeding, correlated paternity and fine-scale genetic structure. The consistency of the field and fine-scale genetic analyses, and the consistency of the results within patches and across years, suggest that these are important processes driving pollen limitation in the fragment.

The relaxin family peptide receptors and their ligands: new developments and paradigms in the evolution from jawless fish to mammals.

Relaxin family peptide receptors (Rxfps) and their ligands, relaxin (Rln) and insulin-like (Insl) peptides, are broadly implicated in the regulation of reproductive and neuroendocrine processes in mammals. Most placental mammals harbour genes for four receptors, namely rxfp1, rxfp2, rxfp3 and rxfp4. The number and identity of rxfps in other vertebrates are immensely variable, which is probably attributable to intraspecific variation in reproductive and neuroendocrine regulation. Here, we highlight several interesting, but greatly overlooked, aspects of the rln/insl-rxfp evolutionary history: the ancient origin, recruitment of novel receptors, diverse roles of selection, differential retention and lineage-specific loss of genes over evolutionary time. The tremendous diversity of rln/insl and rxfp genes appears to have arisen from two divergent receptors and one ligand that were duplicated by whole genome duplications (WGD) in early vertebrate evolution, although several genes, notably relaxin in mammals, were also duplicated via small scale duplications. Duplication and loss of genes have varied across lineages: teleosts retained more WGD-derived genes, dominated by those thought to be involved in neuroendocrine regulation (rln3, insl5 and rxfp 3/4 genes), while eutherian mammals witnessed the diversification and rapid evolution of genes involved in reproduction (rln/insl3). Several genes that arose early in evolutionary history were lost in most mammals, but retained in teleosts and, to a lesser extent, in early diverging tetrapods. To elaborate on their evolutionary history, we provide updated phylogenies of the Rxfp1/2 and Rxfp3/4 receptors and their ligands, including new sequences from early diverging vertebrate taxa such as coelacanth, skate, spotted gar, and lamprey. We also summarize the recent progress made towards understanding the functional biology of Rxfps in non-mammalian taxa, providing a new conceptual framework for research on Rxfp signaling across vertebrates.

Corrigendum: Geographical and life-history traits associated with low and high species richness across angiosperm families.

[This corrects the article DOI: 10.3389/fpls.2023.1276727.].

Interindividual behavioural variation in response to elevated CO2 predicts mRNA transcript abundance of genes related to acid-base regulation in medaka (Oryzias latipes).

Rising carbon dioxide (CO2) in aquatic ecosystems due to climate change is a challenge for aquatic ectotherms. We examined whether interindividual variation in behavioural responses to CO2 could predict how a teleost fish would respond to elevated CO2 for multiple phenotypic and molecular traits. To this end, we first quantified behavioural responses of individuals exposed to acute elevated CO2, and used these to assign individuals as either high or low responders relative to the population mean. Subsequently, we exposed both high and low responders to elevated CO2 for 6 weeks and quantified the effect on body condition, behaviour, and mRNA transcript responses of gill and liver genes associated with relevant physiological processes. Generally, we found few relationships between the phenotypic groups and body condition and behaviour following the CO2 exposure period; however, stark differences between the phenotypic groups with respect to gene transcripts from each tissue related to various processes were found, mostly independent of CO2 exposure. The most pronounced changes were in the gill transcripts related to acid-base regulation, suggesting that the observed behavioural variation used to assign fish to phenotypic groups may have an underlying molecular origin. Should the link between behaviour and gene transcripts be shown to have a fitness advantage and be maintained across generations, interindividual variation in behavioural responses to acute CO2 exposure may be a viable and non-invasive tool to predict future population responses to elevated aquatic CO2.

Geographical and life-history traits associated with low and high species richness across angiosperm families.

Introduction: The phenomenal expansion of angiosperms has prompted many investigations into the factors driving their diversification, but there remain significant gaps in our understanding of flowering plant species diversity. Methods: Using the crown age of families from five studies, we used a maximum likelihood approach to classify families as having poor, predicted or high species richness (SR) using strict consensus criteria. Using these categories, we looked for associations between family SR and i) the presence of an inferred familial ancestral polyploidization event, ii) 23 life history and floral traits compiled from previously published datasets and papers, and iii) sexual system (dioecy) or genetically determined self-incompatibility (SI) mating system using an updated version of our own database and iv) geographic distribution using a new database describing the global distribution of plant species/families across realms and biomes and inferred range. Results: We find that more than a third of angiosperm families (65%) had predicted SR, a large proportion (30.2%) were species poor, while few (4.8%) had high SR. Families with poor SR were less likely to have undergone an ancestral polyploidization event, exhibited deficits in diverse traits, and were more likely to have unknown breeding systems and to be found in only one or few biomes and realms, especially the Afrotropics or Australasia. On the other hand, families with high SR were more likely to have animal mediated pollination or dispersal, are enriched for epiphytes and taxa with an annual life history, and were more likely to harbour sporophytic SI systems. Mapping the global distribution of georeferenced taxa by their family DR, we find evidence of regions dominated by taxa from lineages with high vs low SR. Discussion: These results are discussed within the context of the literature describing "depauperons" and the factors contributing to low and high biodiversity in angiosperm clades.

Self-sterility in flowering plants: preventing self-fertilization increases family diversification rates.

BACKGROUND AND SCOPE: New data are presented on the distribution and frequency of self-sterility (SS) - predominantly pre-zygotic self-incompatibility (SI) systems - in flowering plants and the hypothesis is tested that families with self-sterile taxa have higher net diversification rates (DRs) than those with exclusively self-compatible taxa using both absolute and relative rate tests. KEY RESULTS: Three major forms of SI systems (where pollen is rejected at the stigmatic, stylar or ovarian interface) are found to occur in the oldest families of flowering plants, with times of divergence >100 million years before the present (mybp), while post-fertilization SS and heterostyly appear in families with crown ages of 81 and 87 mybp, respectively. It is also founnd that many (22) angiosperm families exhibit >1 SI phenotype and that the distribution of different types of SS does not show strong phylogenetic clustering, collectively suggesting that SS and SI systems have evolved repeatedly de novo in angiosperm history. Families bearing self-sterile taxa have higher absolute DRs using all available calibrations of the angiosperm tree, and this affect is caused mostly by the high DR of families with homomorphic SI systems (in particular stigmatic SI) or those in which multiple SS/SI phenotypes have been observed (polymorphic). Lastly, using sister comparisons, it is further demonstrated that in 29 of 38 sister pairs (including 95 families), the self-sterile sister group had higher species richness and DR than its self-compatible sister based on either the total number of taxa in the clade with SS or only the estimated fraction to harbour SS based on literature surveys. CONCLUSIONS: Collectively, these analyses point to the importance of SS, particularly pre-zygotic SI in the evolution of flowering plants.

Reviewing the physiological roles of the novel hormone-receptor pair INSL5-RXFP4: a protective energy sensor?

There is no common consensus on the physiological role of insulin-like peptide 5 (INSL5) and its cognate receptor, relaxin family peptide receptor 4 (RXFP4). The experimental data for INSL5-RXFP4 expression and function point to a potential role of the peptide hormone and receptor pair in linking energy availability, homeostasis, and inflammation. In this review, we summarize studies on the INSL5-RXFP4 system and propose that the current findings from diverse experimental settings point broadly to a role as a protective energy sensor (PES). Specifically, we review the evidence that (1) INSL5-RXFP4 could regulate immune response by decreasing the production of proinflammatory cytokines and may be involved in the stress response via the HPA axis; (2) INSL5-RXFP4 may signal through sensory neurons on the vagus nerve, transmitting signals to the CNS; and (3) INSL5-RXFP4 could have local autocrine/paracrine roles within the intestinal tract and immune cells. Further investigation and clarification of these proposed roles of INSL5-RXFP4 may prove a greater physiological relevance for the pair and add to existing evidence of INSL5-RXFP4 role as a PES.

Pervasive male-biased expression throughout the germline-specific regions of the sea lamprey genome supports key roles in sex differentiation and spermatogenesis.

Sea lamprey undergo programmed genome rearrangement (PGR) in which ∼20% of the genome is jettisoned from somatic cells during embryogenesis. Although the role of PGR in embryonic development has been studied, the role of the germline-specific region (GSR) in gonad development is unknown. We analysed RNA-sequence data from 28 sea lamprey gonads sampled across life-history stages, generated a genome-guided de novo superTranscriptome with annotations, and identified germline-specific genes (GSGs). Overall, we identified 638 GSGs that are enriched for reproductive processes and exhibit 36x greater odds of being expressed in testes than ovaries. Next, while 55% of the GSGs have putative somatic paralogs, the somatic paralogs are not differentially expressed between sexes. Further, putative orthologs of some the male-biased GSGs have known functions in sex determination or differentiation in other vertebrates. We conclude that the GSR of sea lamprey plays an important role in testicular differentiation and potentially sex determination.

Immune parameters of HIV susceptibility in the female genital tract before and after penile-vaginal sex.

Background: In women, most HIV infections are acquired through penile-vaginal sex. Inflammation in the female genital tract (FGT) increases the risk of HIV acquisition and transmission, likely through recruitment of HIV target cells and disruption of epithelial barrier integrity. Although sex may have important immune and epithelial effects, the impact of receptive penile-vaginal sex on the immune correlates of HIV susceptibility in the female genital tract is not well described. Methods: STI-free heterosexual couples were recruited to the Sex, Couples and Science (SECS) Study, with the serial collection of cervical secretions (CVS), endocervical cytobrushes, blood and semen before and up to 72 h after either condomless (n = 29) or condom-protected (n = 8) penile-vaginal sex. Immune cells were characterized by flow cytometry, and immune factors including cytokines and soluble E-cadherin (sE-cad; a marker of epithelial disruption) were quantified by multiplex immunoassay. Co-primary endpoints were defined as levels of IP-10 and IL-1α, cytokines previously associated with increased HIV susceptibility. Results: Here we show that cervicovaginal levels of vaginal IP-10, sE-cad and several other cytokines increase rapidly after sex, regardless of condom use. The proportion of endocervical HIV target cells, including Th17 cells, activated T cells, and activated or mature dendritic cells (DCs) also increase, particularly after condomless sex. Although most of these immune changes resolve within 72 h, increases in activated cervical CD4 + T cells and Tcm persist beyond this time. Conclusions: Penile-vaginal sex induces multiple genital immune changes that may enhance HIV susceptibility during the 72 h post-sex window that is critical for virus acquisition. This has important implications for the mucosal immunopathogenesis of HIV transmission.

Associations between food allergy, country of residence, and healthcare access.

BACKGROUND: To date, little consideration has been given to access to allergy-related care, despite the fact that food allergy affects a considerable proportion of children. As such, the current study aimed to describe access to food allergy-related services in Canada and the United States (US). METHODS: Participants were recruited via social media from March-July 2021 and were asked to complete an online survey focused on food allergy-related medical care. Participants were Canadian and US residents who live with a child < 18 years old, with ≥ 1 food allergy. A series of logistic regressions were used to assess the associations between country of residence and type of allergy testing utilized during diagnosis. RESULTS: Fifty-nine participants were included in the analysis (Canadian: 32/59; 54.2%; US residents: 27/59; 45.8%). Relative to Canadian participants, US respondents were less likely to be diagnosed using an oral food challenge (OFC; OR 0.16; 95% CI 0.04; 0.75: p < 0.05). Compared to children diagnosed by age 2 years, those diagnosed at age 3 years and older were less likely to have been diagnosed using an OFC (OR 0.12; 95% CI 0.01; 1.01; p = 0.05). CONCLUSIONS: Access to food allergy-related services, varies between Canada and the US. We speculate that this variation may reflect differences in clinical practice and types of insurance coverage. Findings also underscore the need for more research centered on food allergy-related health care, specifically diagnostic testing, among larger and more diverse samples.

Transcriptomic analysis of gonadal development in parasitic and non-parasitic lampreys (Ichthyomyzon spp.), with a comparison of genomic resources in these non-model species.

Lampreys are jawless fishes that diverged ∼550 million years ago from other vertebrates. Sequencing of the somatic and the germline genomes of the sea lamprey (Petromyzon marinus) in 2013 and 2018, respectively, has helped to improve our understanding of the genes and gene networks that control many aspects of lamprey development. However, little is known about the genetic basis of gonadal differentiation in lampreys, partly due to the prolonged period during which their gonads remain sexually indeterminate. We performed RNA-sequencing on gonadal samples from four chestnut lamprey (Ichthyomyzon castaneus) and six northern brook lamprey (I. fossor) to identify differentially expressed genes (DEG's) and pathways associated with transcriptomic differences in: (1) larvae during early gonadal differentiation versus definitive females (i.e., with oocytes in the slow cytoplasmic growth phase); and (2) females versus definitive males undergoing spermatogonial proliferation. We compared the mapping percentages of these transcriptomes to the two available sea lamprey reference genomes and three annotation files (Ensembl and UCSC for the somatic genome and SIMRbase for the germline genome). We found that mapping the RNA-seq reads to the germline genome gave superior results and, using Trinotate, we provided new putative annotations for 8161 genes in the somatic assembly and 880 genes for the germline assembly. We identified >2000 DEG's between stages and sexes, as well as biological pathways associated with each. Interestingly, some of the upregulated genes (e.g., DEG's associated with spermiation) suggest that changes in gene expression can precede morphological changes by several months. In contrast, only 81 DEG's were evident between the chestnut lamprey (that remains sexually immature during an extended post-metamorphic parasitic feeding phase) and the nonparasitic northern brook lamprey (that undergoes sexual maturation near the end of metamorphosis), but few replicates were available for comparable stages and sexes. This work lays the foundation for identifying and confirming the orthology and the function of genes involved in gonadal development in these and other lamprey species across more developmental stages.

Epidemiology, clinical characteristics, and virologic features of COVID-19 patients in Kazakhstan: A nation-wide retrospective cohort study.

BACKGROUND: The earliest coronavirus disease-2019 (COVID-19) cases in Central Asia were announced in March 2020 by Kazakhstan. Despite the implementation of aggressive measures to curb infection spread, gaps remain in the understanding of the clinical and epidemiologic features of the regional pandemic. METHODS: We did a retrospective, observational cohort study of patients with laboratory-confirmed COVID-19 hospitalized in Kazakhstan between February and April 2020. We compared demographic, clinical, laboratory and radiological data of patients with different COVID-19 severities on admission. Logistic regression was used to assess factors associated with disease severity and in-hospital death. Whole-genome SARS-CoV-2 analysis was performed in 53 patients. FINDINGS: Of the 1072 patients with laboratory-confirmed COVID-19 in March-April 2020, the median age was 36 years (IQR 24-50) and 484 (45%) were male. On admission, 683 (64%) participants had asymptomatic/mild, 341 (32%) moderate, and 47 (4%) severe-to-critical COVID-19 manifestation; 20 in-hospital deaths (1•87%) were reported by 5 May 2020. Multivariable regression indicated increasing odds of severe disease associated with older age (odds ratio 1•05, 95% CI 1•03-1•07, per year increase; p<0•001), the presence of comorbidities (2•34, 95% CI 1•18-4•85; p=0•017) and elevated white blood cell count (WBC, 1•13, 95% CI 1•00-1•27; p=0•044) on admission, while older age (1•09, 95% CI 1•06-1•13, per year increase; p<0•001) and male sex (5•63, 95% CI 2•06-17•57; p=0•001) were associated with increased odds of in-hospital death. The SARS-CoV-2 isolates grouped into seven phylogenetic lineages, O/B.4.1, S/A.2, S/B.1.1, G/B.1, GH/B.1.255, GH/B.1.3 and GR/B.1.1.10; 87% of the isolates were O and S sub-types descending from early Asian lineages, while the G, GH and GR isolates were related to lineages from Europe and the Americas. INTERPRETATION: Older age, comorbidities, increased WBC count, and male sex were risk factors for COVID-19 disease severity and mortality in Kazakhstan. The broad SARS-CoV-2 diversity suggests multiple importations and community-level amplification predating travel restriction. FUNDING: Ministry of Education and Science of the Republic of Kazakhstan.

Genetic Relationship Among the Kazakh People Based on Y-STR Markers Reveals Evidence of Genetic Variation Among Tribes and Zhuz.

Ethnogenesis of Kazakhs took place in Central Asia, a region of high genetic and cultural diversity. Even though archaeological and historical studies have shed some light on the formation of modern Kazakhs, the process of establishment of hierarchical socioeconomic structure in the Steppe remains contentious. In this study, we analyzed haplotype variation at 15 Y-chromosomal short-tandem-repeats obtained from 1171 individuals from 24 tribes representing the three socio-territorial subdivisions (Senior, Middle and Junior zhuz) in Kazakhstan to comprehensively characterize the patrilineal genetic architecture of the Kazakh Steppe. In total, 577 distinct haplotypes were identified belonging to one of 20 haplogroups; 16 predominant haplogroups were confirmed by SNP-genotyping. The haplogroup distribution was skewed towards C2-M217, present in all tribes at a global frequency of 51.9%. Despite signatures of spatial differences in haplotype frequencies, a Mantel test failed to detect a statistically significant correlation between genetic and geographic distance between individuals. An analysis of molecular variance found that ∼8.9% of the genetic variance among individuals was attributable to differences among zhuzes and ∼20% to differences among tribes within zhuzes. The STRUCTURE analysis of the 1164 individuals indicated the presence of 20 ancestral groups and a complex three-subclade organization of the C2-M217 haplogroup in Kazakhs, a result supported by the multidimensional scaling analysis. Additionally, while the majority of the haplotypes and tribes overlapped, a distinct cluster of the O2 haplogroup, mostly of the Naiman tribe, was observed. Thus, firstly, our analysis indicated that the majority of Kazakh tribes share deep heterogeneous patrilineal ancestries, while a smaller fraction of them are descendants of a founder paternal ancestor. Secondly, we observed a high frequency of the C2-M217 haplogroups along the southern border of Kazakhstan, broadly corresponding to both the path of the Mongolian invasion and the ancient Silk Road. Interestingly, we detected three subclades of the C2-M217 haplogroup that broadly exhibits zhuz-specific clustering. Further study of Kazakh haplotypes variation within a Central Asian context is required to untwist this complex process of ethnogenesis.

Immune System Effects of Insulin-Like Peptide 5 in a Mouse Model.

Introduction: Insulin-like peptide 5 (INSL5) is a peptide hormone with proposed actions in glucose homeostasis and appetite regulation via its cognate receptor, relaxin family peptide receptor 4 (RXFP4). Here, we look for evidence for their involvement in the immune system using a mouse model. Methods: In silico analyses: we queried public databases for evidence of expression of INSL5-RXFP4 in immune system tissues/cells (NCBI's SRA and GeoProfiles) and disorders (EMBO-EBI) and performed phylogenetic footprinting to look for evidence that they are regulated by immune-associated transcription factors (TFs). Experimental analyses: We characterized the expression and correlation of INSL5/RXFP4 and other immune system markers in central and peripheral immune organs from C57/bl6 mice in seven cohorts. We tested whether fluctuations in circulating INSL5 induce an immune response, by injecting mice with 30 µg/kg of INSL5 peptide in the peritoneum, and examining levels of immune markers and metabolic peptides in plasma. Lastly, we quantified the expression of Rxfp4 in T-cells, dendritic cells and cell lines derived from human and mouse and tested the hypothesis that co-incubation of ANA-1 cells in INSL5 and LPS alters cytokine expression. Results: We find Insl5 expression only in thymus (in addition to colon) where its expression was highly correlated with Il-7, a marker of thymocyte development. This result is consistent with our in silico findings that Insl5 is highly expressed in thymic DP, DN thymocytes and cortical TEC's, and with evidence that it is regulated by thymocyte-associated TF's. We find Rxfp4 expression in all immune organs, and moderately high levels in DCs, particularly splenic DCs, and evidence that it is regulated by immune-associated TF's, such as STAT's and GATA. Systemic effects: We observed significantly elevated concentrations of blood GLP-1, GIP, GCG and PYY following intraperitoneal injection of INSL5, and significantly altered expression of cytokines IL-5, IL-7, M-CSF, IL-15, IL-27 and MIP-2. Immune cell effects: Incubation of ANA-1 cells with INSL5 impeded cell growth and led to a transient elevation of IL-15 and sustained reduction in IL-1ß, IL-6 and TNFα. Conclusion: We propose that INSL5-RXFP4 play a novel role in both central and peripheral immune cell signaling.

Psoriasis Is Associated With Elevated Gut IL-1α and Intestinal Microbiome Alterations.

Background: Psoriasis is a chronic inflammatory condition that predominantly affects the skin and is associated with extracutaneous disorders, such as inflammatory bowel disease and arthritis. Changes in gut immunology and microbiota are important drivers of proinflammatory disorders and could play a role in the pathogenesis of psoriasis. Therefore, we explored whether psoriasis in a Central Asian cohort is associated with alterations in select immunological markers and/or microbiota of the gut. Methods: We undertook a case-control study of stool samples collected from outpatients, aged 30-45 years, of a dermatology clinic in Kazakhstan presenting with plaque, guttate, or palmoplantar psoriasis (n = 20), and age-sex matched subjects without psoriasis (n = 20). Stool supernatant was subjected to multiplex ELISA to assess the concentration of 47 cytokines and immunoglobulins and to 16S rRNA gene sequencing to characterize microbial diversity in both psoriasis participants and controls. Results: The psoriasis group tended to have higher concentrations of most analytes in stool (29/47 = 61.7%) and gut IL-1α was significantly elevated (4.19-fold, p = 0.007) compared to controls. Levels of gut IL-1α in the psoriasis participants remained significantly unaltered up to 3 months after the first sampling (p = 0.430). Psoriasis was associated with alterations in gut Firmicutes, including elevated Faecalibacterium and decreased Oscillibacter and Roseburia abundance, but no association was observed between gut microbial diversity or Firmicutes/Bacteroidetes ratios and disease status. Conclusions: Psoriasis may be associated with gut inflammation and dysbiosis. Studies are warranted to explore the use of gut microbiome-focused therapies in the management of psoriasis in this under-studied population.

Japanese medaka as a model for studying the relaxin family genes involved in neuroendocrine regulation: Insights from the expression of fish-specific rln3 and insl5 and rxfp3/4-type receptor paralogues.

The goal of this paper is to establish Japanese medaka (Oryzias latipes) as a model for relaxin family peptide research, particularly for studying the functions of RLN3 and INSL5, hormones playing roles in neuroendocrine regulation. Medaka, like other teleosts, retained duplicate copies of rln3, insl5 and their rxfp3/4-type receptors following fish-specific whole genome duplication (WGD) and paralogous copies of these genes may have sub-functionalised providing an intuitive model for teasing apart the pleiotropic roles of the corresponding genes in mammals. To this end, we provide experimental evidence for the expression of the relaxin family genes in medaka that had previously only been identified in-silico, confirm the gene structure of five of the ligand genes, characterise gene expression across multiple tissues and during embryonic development, perform in situ hybridization with anti-sense insl5a on embryos and in adult brain and intestinal samples, and compare these results to the data available in zebrafish. We find broad similarities but also some differences in the expression of relaxin family genes in zebrafish versus medaka, and find support for the hypothesis that the rln3a/rln3b and insl5a/insl5b paralogues have been subfunctionalized. Given that medaka has a suite of relaxin family genes more similar to other teleosts, and has retained the gene for rxfp4 (which is lost in zebrafish), our results suggest that O. latipes may be a good model for delineating the ancestral function of the relaxin family genes involved in neuroendocrine regulation.

Impact of Endemic Infections on HIV Susceptibility in Sub-Saharan Africa.

Human immunodeficiency virus (HIV) remains a leading cause of global morbidity with the highest burden in Sub-Saharan Africa (SSA). For reasons that are incompletely understood, the likelihood of HIV transmission is several fold higher in SSA than in higher income countries, and most of these infections are acquired by young women. Residents of SSA are also exposed to a variety of endemic infections, such as malaria and various helminthiases that could influence mucosal and systemic immunology. Since these immune parameters are important determinants of HIV acquisition and progression, this review explores the possible effects of endemic infections on HIV susceptibility and summarizes current knowledge of the epidemiology and underlying immunological mechanisms by which endemic infections could impact HIV acquisition. A better understanding of the interaction between endemic infections and HIV may enhance HIV prevention programs in SSA.