The differential regulation of Lck kinase phosphorylation sites by CD45 is critical for T cell receptor signaling responses

SummaryThe molecular mechanisms whereby the CD45 tyrosine phosphatase (PTPase) regulates T cell receptor (TCR) signaling responses remain to be elucidated. To investigate this question, we have reconstituted CD45 (encoded by Ptprc)-deficient mice, which display severe defects in thymic development, with five different expression levels of transgenic CD45RO, or with mutant PTPase null or PTPase-low CD45R0. Whereas CD45 PTPase activity was absolutely required for the reconstitution of thymic development, only 3% of wild-type CD45 activity restored T cell numbers and normal cytotoxic T cell responses. Lowering the CD45 expression increased CD4 lineage commitment. Peripheral T cells with very low activity of CD45 phosphatase displayed reduced TCR signaling, whereas intermediate activity caused hyperactivation of CD4+ and CD8+ T cells. These results are explained by a rheostat mechanism whereby CD45 differentially regulates the negatively acting pTyr-505 and positively acting pTyr-394 p56lck tyrosine kinase phosphorylation sites. We propose that high wild-type CD45 expression is necessary to dephosphorylate p56lck pTyr-394, suppressing CD4 T+ cell lineage commitment and hyperactivity

Ancestral roles of atypical cadherins in planar cell polarity

Fat, Fat-like, and Dachsous family cadherins are giant proteins that regulate planar cell polarity (PCP) and cell adhesion in bilaterians. Their evolutionary origin can be traced back to prebilaterian species, but their ancestral function(s) are unknown. We identified Fat-like and Dachsous cadherins in Hydra, a member of phylum Cnidaria a sister group of bilaterian. We found Hydra does not possess a true Fat homolog, but has homologs of Fat-like (HyFatl) and Dachsous (HyDs) that localize at the apical membrane of ectodermal epithelial cells and are planar polarized perpendicular to the oral-aboral axis of the animal. Using a knockdown approach we found that HyFatl is involved in local cell alignment and cell-cell adhesion, and that reduction of HyFatl leads to defects in tissue organization in the body column. Overexpression and knockdown experiments indicate that the intracellular domain (ICD) of HyFatl affects actin organization through proline-rich repeats. Thus, planar polarization of Fat-like and Dachsous cadherins has ancient, prebilaterian origins, and Fat-like cadherins have ancient roles in cell adhesion, spindle orientation, and tissue organization

Smokeless Tobacco in Uganda:Perceptions among Tobacco Control Stakeholders

The use and sale of smokeless tobacco (SLT) is prohibited in Uganda under the Tobacco Control Act (TCA), 2015. Nonetheless, SLT products remain available, and there are limited and inconsistent data on SLT users. Additionally, the perceptions of tobacco control stakeholders on SLT are unknown, making it difficult to determine barriers to enforcing the ban. This study examined perceptions of tobacco control stakeholders regarding SLT in Uganda. Qualitative semi-structured interviews were conducted with stakeholders who were purposively selected from ministries, semi-autonomous government agencies and Civil Society Organizations. Interviews explored knowledge, attitudes, perceptions of SLT appeal, and user demographics. Data were analysed using Nvivo V.12 software. Participants demonstrated a general lack of awareness of SLT product types and the extent of their use. They believed SLT use was increasing among females and minors and was as harmful to health and the economy as smoking. SLT products were thought to be cheaper than cigarettes and to appeal to minors. Discreet use was thought to help users overcome the cultural aversion towards tobacco use among women and youth in Uganda. There is an urgent need to strengthen the implementation of the SLT ban whilst also increasing efforts to reduce tobacco smoking

Parasite-stress promotes in-group assortative sociality: the cases of strong family ties and heightened religiosity

Throughout the world people differ in the magnitude with which they value strong family ties or heightened religiosity. We propose that this cross-cultural variation is a result of a contingent psychological adaptation that facilitates in-group assortative sociality in the face of high levels of parasite-stress while devaluing in-group assortative sociality in areas with low levels of parasite-stress. This is because in-group assortative sociality is more important for the avoidance of infection from novel parasites and for the management of infection in regions with high levels of parasite-stress compared with regions of low infectious disease stress. We examined this hypothesis by testing the predictions that there would be a positive association between parasite-stress and strength of family ties or religiosity. We conducted this study by comparing among nations and among states in the United States of America. We found for both the international and the interstate analyses that in-group assortative sociality was positively associated with parasite-stress. This was true when controlling for potentially confounding factors such as human freedom and economic development. The findings support the parasite-stress theory of sociality, that is, the proposal that parasite-stress is central to the evolution of social life in humans and other animals

Acidity and the multiphase chemistry of atmospheric aqueous particles and clouds

The acidity of aqueous atmospheric solutions is a key parameter driving both the partitioning of semi-volatile acidic and basic trace gases and their aqueous-phase chemistry. In addition, the acidity of atmospheric aqueous phases, e.g., deliquesced aerosol particles, cloud, and fog droplets, is also dictated by aqueous-phase chemistry. These feedbacks between acidity and chemistry have crucial implications for the tropospheric lifetime of air pollutants, atmospheric composition, deposition to terrestrial and oceanic ecosystems, visibility, climate, and human health. Atmospheric research has made substantial progress in understanding feedbacks between acidity and multiphase chemistry during recent decades. This paper reviews the current state of knowledge on these feedbacks with a focus on aerosol and cloud systems, which involve both inorganic and organic aqueous-phase chemistry. Here, we describe the impacts of acidity on the phase partitioning of acidic and basic gases and buffering phenomena. Next, we review feedbacks of different acidity regimes on key chemical reaction mechanisms and kinetics, as well as uncertainties and chemical subsystems with incomplete information. Finally, we discuss atmospheric implications and highlight the need for future investigations, particularly with respect to reducing emissions of key acid precursors in a changing world, and the need for advancements in field and laboratory measurements and model tools

Mediterranean-type diet and brain structural change from 73 to 76 years in a Scottish cohort

STUDY FUNDING The data were collected by a Research into Ageing programme grant; research continues as part of the Age UK–funded Disconnected Mind project. The work was undertaken by The University of Edinburgh Centre for Cognitive Ageing and Cognitive Epidemiology, part of the cross-council Lifelong Health and Wellbeing Initiative (MR/K026992/1), with funding from the BBSRC and Medical Research Council. Imaging and image analysis was performed at the Brain Research Imaging Centre (sbirc.ed.ac.uk/), Edinburgh, supported by the Scottish Funding Council SINAPSE Collaboration. Derivation of mean cortical thickness measures was funded by the Scottish Funding Council’s Postdoctoral and Early Career Researchers Exchange Fund awarded by SINAPSE to David Alexander Dickie. L.C.A.C. acknowledges funding from the Scottish Government's Rural and Environment Science and Analytical Services (RESAS) division.Peer reviewedPublisher PD

Expanded directly binds conserved regions of Fat to restrain growth via the Hippo pathway

The Hippo pathway is a conserved and critical regulator of tissue growth. The FERM protein Expanded is a key signaling hub that promotes activation of the Hippo pathway, thereby inhibiting the transcriptional co-activator Yorkie. Previous work identified the polarity determinant Crumbs as a primary regulator of Expanded. Here, we show that the giant cadherin Fat also regulates Expanded directly and independently of Crumbs. We show that direct binding between Expanded and a highly conserved region of the Fat cytoplasmic domain recruits Expanded to the apicolateral junctional zone and stabilizes Expanded. In vivo deletion of Expanded binding regions in Fat causes loss of apical Expanded and promotes tissue overgrowth. Unexpectedly, we find Fat can bind its ligand Dachsous via interactions of their cytoplasmic domains, in addition to the known extracellular interactions. Importantly, Expanded is stabilized by Fat independently of Dachsous binding. These data provide new mechanistic insights into how Fat regulates Expanded, and how Hippo signaling is regulated during organ growth