Activation of the Lck Tyrosine Kinase Targets Cell Surface T Cell Antigen Receptors for Lysosomal Degradation

AbstractThe mechanism by which TCR expression is regulated was explored by expressing a constitutively active form of the tyrosine kinase Lck (Lck505F) in T cells. Expression of Lck505F down-regulated TCR levels, an effect that was even more pronounced in CD45− T cells, in which the activity of this tyrosine kinase is further enhanced. Cells expressing Lck505F synthesized all TCR subunits, but lysosomal degradation of assembled receptors was enhanced. TCRs were rapidly internalized and degraded after removal of a tyrosine kinase inhibitor that had permitted cell surface expression. Finally, TCR levels on thymocytes were increased by an Lck inhibitor, and activation- but not phorbol ester–induced internalization of TCRs on Jurkat cells was prevented by inhibition or loss of Lck. These studies identify a regulated nonreceptor tyrosine kinase–mediated pathway for targeting cell surface receptors for lysosomal degradation

Zoonotic Pathogens From Illegally Traded Wildlife Justify Adopting the One Health Perspective in Disease Response

Recent studies have described a direct relationship between the illegal wildlife trade (IWT) and the prevalence of zoonotic pathogens in human populations. In the Philippines, the Philippine Integrated Disease Surveillance and Response (PIDSR) framework outlines the monitoring, response, and management of disease outbreaks, but needs to be updated in the wake of zoonoses from IWT. Here, we identified zoonotic pathogens that may be introduced to human populations through the IWT, pinpointed potential outbreak hotspots, and provided recommendations on how to improve the Philippines’ public health response while considering One Health. Using seizure data from the Biodiversity Management Bureau (DENR-BMB) covering the period from 2010 to 2016, we found that birds (32.3% of volume) and reptiles (63.3% of volume) were the most frequently seized by law enforcement in terms of incidence and volume. About 54% of seized wildlife could potentially host zoonotic pathogens with bacteria (78.3%), protozoa (34.8%), and viruses (27.5%) being the most represented pathogen groups. Three cities in Metro Manila together accounted for 30% of all seizures in the country followed by Palawan province which accounted for about 28% of seizures. Of the twelve epidemic prone diseases identified in the PIDSR, five diseases were found to have causative agents that could potentially be hosted by the traded wildlife. These findings will not only enhance the approach to surveillance in the PIDSR but will also aid in identifying opportunities to improve policies on agriculture and food security, public health and disease surveillance, and biodiversity conservation

Relative replication capacity of phenotypic SIV variants during primary infections differs with route of inoculation

BACKGROUND: Previous studies of human and simian immunodeficiency virus (HIV and SIV) have demonstrated that adaptive mutations selected during the course of infection alter viral replicative fitness, persistence, and pathogenicity. What is unclear from those studies is the impact of transmission on the replication and pathogenicity of the founding virus population. Using the SIV-macaque model, we examined whether the route of infection would affect the establishment and replication of two SIVmne variants of distinct in vitro and in vivo biological characteristics. For these studies, we performed dual-virus inoculations of pig-tailed macaques via intrarectal or intravenous routes with SIVmneCl8, a miminally pathogenic virus, and SIVmne027, a highly pathogenic variant that replicates more robustly in CD4(+ )T cells. RESULTS: The data demonstrate that SIVmne027 is the dominant virus regardless of the route of infection, indicating that the capacity to replicate efficiently in CD4(+ )T cells is important for fitness. Interestingly, in comparison to intravenous co-infection, intrarectal inoculation enabled greater relative replication of the less pathogenic virus, SIVmneCl8. Moreover, a higher level of SIVmneCl8 replication during primary infection of the intrarectally inoculated macaques was associated with lower overall plasma viral load and slower decline in CD4(+ )T cells, even though SIVmne027 eventually became the dominant virus. CONCLUSIONS: These results suggest that the capacity to replicate in CD4(+ )T cells is a significant determinant of SIV fitness and pathogenicity. Furthermore, the data also suggest that mucosal transmission may support early replication of phenotypically diverse variants, while slowing the rate of CD4(+ )T cell decline during the initial stages of infection

On the logical structure of Bell theorems without inequalities

Bell theorems show how to experimentally falsify local realism. Conclusive falsification is highly desirable as it would provide support for the most profoundly counterintuitive feature of quantum theory - nonlocality. Despite the preponderance of evidence for quantum mechanics, practical limits on detector efficiency and the difficulty of coordinating space-like separated measurements have provided loopholes for a classical worldview; these loopholes have never been simultaneously closed. A number of new experiments have recently been proposed to close both loopholes at once. We show some of these novel designs fail in the most basic way, by not ruling out local hidden variable models, and we provide an explicit classical model to demonstrate this. They share a common flaw, which reveals a basic misunderstanding of how nonlocality proofs work. Given the time and resources now being devoted to such experiments, theoretical clarity is essential. Our explanation is presented in terms of simple logic and should serve to correct misconceptions and avoid future mistakes. We also show a nonlocality proof involving four participants which has interesting theoretical properties.Comment: 8 pages, text clarified, explicit LHV model provided for flawed nonlocality tes

Amplification of simian retroviral sequences from human recipients of baboon liver transplants

Investigations into the use of baboons as organ donors for human transplant recipients, a procedure called xenotransplantation, have raised the specter of transmitting baboon viruses to humans and possibly establishing new human infectious diseases. Retrospective analysis of tissues from two human transplant recipients with end-stage hepatic disease who died 70 and 27 days after the transplantation of baboon livers revealed the presence of two simian retroviruses of baboon origin, simian foamy virus (SFV) and baboon endogenous virus (BaEV), in multiple tissue compartments. The presence of baboon mitochondrial DNA was also detected in these same tissues, suggesting that xenogeneic 'passenger leukocytes' harboring latent or active viral infections had migrated from the xenografts to distant sites within the human recipients. The persistence of SFV and BaEV in human recipients throughout the posttransplant period underscores the potential infectious risks associated with xenotransplantation

Low birthweight is associated with a higher incidence of type 2 diabetes over two decades independent of adult BMI and genetic predisposition

Aims/hypothesis: Low birthweight is a risk factor for type 2 diabetes. Most previous studies are based on cross-sectional prevalence data, not designed to study the timing of onset of type 2 diabetes in relation to birthweight. We aimed to examine associations of birthweight with age-specific incidence rate of type 2 diabetes in middle-aged to older adults over two decades. Methods: Adults aged 30–60 years enrolled in the Danish Inter99 cohort in 1999–2001 (baseline examination), with information on birthweight from original birth records from 1939–1971 and without diabetes at baseline, were eligible. Birth records were linked with individual-level data on age at diabetes diagnosis and key covariates. Incidence rates of type 2 diabetes as a function of age, sex and birthweight were modelled using Poisson regression, adjusting for prematurity status at birth, parity, polygenic scores for birthweight and type 2 diabetes, maternal and paternal diabetes history, socioeconomic status and adult BMI. Results: In 4590 participants there were 492 incident type 2 diabetes cases during a mean follow-up of 19 years. Type 2 diabetes incidence rate increased with age, was higher in male participants, and decreased with increasing birthweight (incidence rate ratio [95% CI per 1 kg increase in birthweight] 0.60 [0.48, 0.75]). The inverse association of birthweight with type 2 diabetes incidence was statistically significant across all models and in sensitivity analysis. Conclusions/interpretation: A lower birthweight was associated with increased risk of developing type 2 diabetes independent of adult BMI and genetic risk of type 2 diabetes and birthweight

Repositioning of special schools within a specialist, personalised educational marketplace - the need for a representative principle

This paper considers how notions of inclusive education as defined in the United Nations Educational, Scientific and Cultural Organization (UNESCO) Salamanca Agreement (1994) have become dissipated, and can be developed and reframed to encourage their progress. It analyses the discourse within a range of academic, legal and media texts, exploring how this dissipation has taken place within the UK. Using data from 78 specialist school websites it contextualises this change in the use of the terms and ideas of inclusion with the rise of two other constructs, the 'specialist school' and 'personalisation'. It identifies the need for a precisely defined representative principle to theorise the type of school which inclusion aims to achieve, which cannot be subsumed by segregated providers. It suggests that this principle should not focus on the individual, but draw upon a liberal/democratic view of social justice, underlining inclusive education's role in removing social barriers that prevent equity, access and participation for all

Low CAIX expression and absence of VHL gene mutation are associated with tumor aggressiveness and poor survival of clear cell renal cell carcinoma.

International audienceWe attempted to describe, in a series of clear cell renal cell carcinoma (RCC), the relationship between CAIX expression, VHL gene mutations, tumor characteristics and outcome. Radical nephrectomy was performed in 100 patients. Genomic DNA was extracted from frozen tumor samples. Four amplimers covering the whole coding sequence of the VHL gene were synthesized by PCR and sequenced. The monoclonal antibody M75 was used to evaluate CAIX protein expression immunohistochemically. VHL mutations were identified in 58 patients (58%) and high CAIX expression (>85%) was observed in 78 (78%). Tumors with VHL mutation showed higher CAIX expression than those without (p = 0.02). Low CAIX expression and absence of VHL mutation were associated with a more advanced tumors e.g., higher T stages and presence of metastases. VHL mutation and high CAIX expression predicted longer progression-free survival (p = 0.037) and disease-specific survival (p = 0.001), respectively. In combination, they defined three prognostic groups (p = 0.002): (i) good prognosis, defined as VHL mutation and high CAIX (2-year survival: 86%), (ii) intermediate prognosis with either VHL mutation or high CAIX (69%), and (iii) poor prognosis with no VHL mutation and low CAIX (45%, median survival 18 months). CAIX expression, but not VHL mutational status, was an independent prognostic factor in multivariate analysis. Taken together, CAIX expression and VHL mutational status are able to stratify patients with clear cell RCC into distinct groups with regards to clinicopathological variables and prognosis, with low CAIX expression and absence of VHL mutation being associated with a poor clinicopathological phenotype and diminished survival