Modulation of TCR signalling components occurs prior to positive selection and lineage commitment in iNKT cells

iNKT cells play a critical role in controlling the strength and character of adaptive and innate immune responses. Their unique functional characteristics are induced by a transcriptional program initiated by positive selection mediated by CD1d expressed by CD4+CD8+ (double positive, DP) thymocytes. Here, using a novel Vα14 TCR transgenic strain bearing greatly expanded numbers of CD24hiCD44loNKT cells, we examined transcriptional events in four immature thymic iNKT cell subsets. A transcriptional regulatory network approach identified transcriptional changes in proximal components of the TCR signalling cascade in DP NKT cells. Subsequently, positive and negative selection, and lineage commitment, occurred at the transition from DP NKT to CD4 NKT. Thus, this study introduces previously unrecognised steps in early NKT cell development and separates, the events associated with modulation of the T cell signalling cascade prior to changes associated with positive selection and lineage commitment

Gender and Perceptions of Romantic Partners’ Sexual Risk

Research shows that in most situations, women perceive themselves to be at greater risk of harm than do men. Gustafson's gender role perspective on risk perception suggests that this is because women are socialized to feel that they need protection, especially from men.Based on Gustafson's gender role perspective on sex differences in risk perception, we predicted that in at least one context, perception of romantic partners’ sexual risk, this gender difference would be reversed. Specifically, women should rate boyfriends as having lower risk for sexually transmitted infections (STIs) than boyfriends rate themselves having.In two studies, we examined heterosexual couples and compared women's perceptions of their boyfriends’ sexual risk level with the boyfriend's self-perception of sexual risk.Self-reported measures of risk for STIs, perception of romantic partners’ risk for STIs.On multiple measures, women rated their boyfriends as having a lower risk for STIs than the men rated themselves. Men did not show this pattern and, in some cases, showed the reverse pattern of perceiving their girlfriends to have a greater level of risk than girlfriends themselves believed they had.Consistent with Gustafson's gender role perspective on risk perception, heterosexual women perceived their romantic partners as relatively less risky in terms of STI risk than men perceived themselves. One potential implication of this finding is that women may be less likely to protect themselves against disease in close romantic relationships because they believe that their partners are low risk, regardless of the partners’ actual risk levels. Conley TD, and Peplau LA. Gender and perceptions of romantic partners’ sexual risk. J Sex Med 2010;7:794–802.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/78632/1/j.1743-6109.2009.01598.x.pd

Multiple Sclerosis risk variants regulate gene expression in innate and adaptive immune cells

At least 200 single-nucleotide polymorphisms (SNPs) are associated with multiple sclerosis (MS) risk. A key function that could mediate SNP-encoded MS risk is their regulatory effects on gene expression. We performed microarrays using RNA extracted from purified immune cell types from 73 untreated MS cases and 97 healthy controls and then performed Cis expression quantitative trait loci mapping studies using additive linear models. We describe MS risk expression quantitative trait loci associations for 129 distinct genes. By extending these models to include an interaction term between genotype and phenotype, we identify MS risk SNPs with opposing effects on gene expression in cases compared with controls, namely, rs2256814 MYT1 in CD4 cells (q = 0.05) and rs12087340 RF00136 in monocyte cells (q = 0.04). The rs703842 SNP was also associated with a differential effect size on the expression of the METTL21B gene in CD8 cells of MS cases relative to controls (q = 0.03). Our study provides a detailed map of MS risk loci that function by regulating gene expression in cell types relevant to MS

A multi-disciplinary commentary on preclinical research to investigate vascular contributions to dementia

Although dementia research has been dominated by Alzheimer's disease (AD), most dementia in older people is now recognised to be due to mixed pathologies, usually combining vascular and AD brain pathology. Vascular cognitive impairment (VCI), which encompasses vascular dementia (VaD) is the second most common type of dementia. Models of VCI have been delayed by limited understanding of the underlying aetiology and pathogenesis. This review by a multidisciplinary, diverse (in terms of sex, geography and career stage), cross-institute team provides a perspective on limitations to current VCI models and recommendations for improving translation and reproducibility. We discuss reproducibility, clinical features of VCI and corresponding assessments in models, human pathology, bioinformatics approaches, and data sharing. We offer recommendations for future research, particularly focusing on small vessel disease as a main underpinning disorder

A Multi-disciplinary Commentary on Preclinical Research to investigate Vascular Contributions to Dementia

Although dementia research has been dominated by Alzheimer's disease (AD), most dementia in older people is now recognised to be due to mixed pathologies, usually combining vascular and AD brain pathology. Vascular cognitive impairment (VCI), which encompasses vascular dementia (VaD) is the second most common type of dementia. Models of VCI have been delayed by limited understanding of the underlying aetiology and pathogenesis. This review by a multidisciplinary, diverse (in terms of sex, geography and career stage), cross-institute team provides a perspective on limitations to current VCI models and recommendations for improving translation and reproducibility. We discuss reproducibility, clinical features of VCI and corresponding assessments in models, human pathology, bioinformatics approaches, and data sharing. We offer recommendations for future research, particularly focusing on small vessel disease as a main underpinning disorder.</p

Differential antimicrobial activity in response to the entomopathogenic fungus Cordyceps in six Australian bee species

Microbial pathogens were important in the evolution of insect societies and remain a major cause of colony death. The differential effects are reported of antimicrobial compounds extracted from six species of Australian native bees on the spores and hyphae of the entomopathogenic fungus Cordyceps bassiana. The bee species were: Amegilla bombiformis, A. asserta, Exoneura robusta, E. nigrescens, Exoneurella tridentata and Trigona carbonaria. The fungus was isolated from E. robusta and it was this species that showed the greatest activity against both Cordyceps spore germination and hyphal growth. One explanation is that anti-Cordyceps activity may have been under greatest selection in this bee species, but its congener, E. nigrescens, showed only slightly weaker activity against the pathogen. In contrast, A. bombiformis, A. asserta, E. tridentata and T. carbonaria showed considerable variation in anti-Cordyceps activity. Nevertheless, there was a trend of greater activity against Cordyceps spore germination than hyphal growth. On the basis of this result, a mechanism whereby fungal pathogens may have been important drivers of social evolution is suggested

Modulation of TCR signalling components occurs prior to positive selection and lineage commitment in iNKT cells

iNKT cells play a critical role in controlling the strength and character of adaptive and innate immune responses. Their unique functional characteristics are induced by a transcriptional program initiated by positive selection mediated by CD1d expressed by CD4+CD8+ (double positive, DP) thymocytes. Here, using a novel Vα14 TCR transgenic strain bearing greatly expanded numbers of CD24hiCD44loNKT cells, we examined transcriptional events in four immature thymic iNKT cell subsets. A transcriptional regulatory network approach identified transcriptional changes in proximal components of the TCR signalling cascade in DP NKT cells. Subsequently, positive and negative selection, and lineage commitment, occurred at the transition from DP NKT to CD4 NKT. Thus, this study introduces previously unrecognised steps in early NKT cell development, and separates the events associated with modulation of the T cell signalling cascade prior to changes associated with positive selection and lineage commitment

Dependence of colorectal cancer risk on the parent-of-origin of mutations in DNA mismatch repair genes

Genetic diseases associated with dynamic mutations in microsatellite DNA often display parent-of-origin effects (POEs) in which the risk of disease depends on the sex of the parent from whom the disease allele was inherited. Carriers of germline mutations in mismatch repair (MMR) genes have high risks of colorectal carcinoma (CRC). We investigated whether these risks depend on the parent-of-origin of the mutation. We studied 422 subjects, including 89 MMR gene mutation carriers, from 17 population-based families who were each recruited via a CRC case diagnosed before age 45 years and found to carry a MMR gene mutation. The POE hazard ratio (HRPOE), defined to be the CRC incidence for carriers with maternally derived mutations divided by the corresponding paternal incidence, was estimated using a novel application of modified segregation analysis. HRPOE (95% confidence interval) was estimated to be 3.2 (1.1–9.8) for males (P = 0.03) and 0.8 (0.2–2.8) for females (P = 0.5) and the corresponding cumulative risks to age 80 years were 88% (54%–100%) for male carriers with maternally derived mutations and 38–48% for all other carriers. If confirmed by larger studies, these results will have important implications for the etiology of CRC and for the clinical management of MMR gene mutation carriers