Recent progress in cancer immunotherapy emphasizes the importance of understanding immune-regulatory pathways in tumours. Dysfunction of antitumour T cells may be due to mechanisms that are ...evolutionarily conserved or acquired by somatic mutations. The dysfunctional state of T cells has been termed 'exhaustion', on the basis of similarities to dysfunctional T cells in chronic infections. However, despite shared properties, recent studies have identified marked differences between T cell dysfunction in cancer and chronic infection. In this Review, we discuss T cell-intrinsic molecular alterations and metabolic communication in the tumour microenvironment. Identification of the underlying molecular drivers of T cell dysfunction is essential for the continued progress of cancer research and therapy.
Pluripotency is a central, well-studied feature of embryonic development, but the role of pluripotent cell regulation in somatic tissue regeneration remains poorly understood. In planarians, ...regeneration of entire animals from tissue fragments is promoted by the activity of adult pluripotent stem cells (cNeoblasts). We utilized transcriptional profiling to identify planarian genes expressed in adult proliferating, regenerative cells (neoblasts). We also developed quantitative clonal analysis methods for expansion and differentiation of cNeoblast descendants that, together with RNAi, revealed gene roles in stem cell biology. Genes encoding two zinc finger proteins, Vasa, a LIM domain protein, Sox and Jun-like transcription factors, two candidate RNA-binding proteins, a Setd8-like protein, and PRC2 (Polycomb) were required for proliferative expansion and/or differentiation of cNeoblast-derived clones. These findings suggest that planarian stem cells utilize molecular mechanisms found in germ cells and other pluripotent cell types and identify genetic regulators of the planarian stem cell system.
► Expression profiling identifies regulatory genes expressed in neoblasts ► Clonal stem cell assay and RNAi identify stem cell expansion/differentiation genes ► Planarian stem cells share molecular features with embryonic and germ cells
Ensuring the accuracy and consistency of highly decentralized and discretionary decisionmaking is a core challenge for the administrative state. The widely influential school of "democratic ...experimentalism" posits that peer review—the direct and deliberative evaluation of work product by peers in the discipline—provides a way forward, but systematic evidence remains limited. This Article provides the first empirical study of the feasibility and effects of peer review as a governance mechanism based on a unique randomized controlled trial conducted with the largest health department in Washington State (Public Health—Seattle and King County). We randomly assigned half of the food safety inspection staff to engage in an intensive peer review process for over four months. Pairs of inspectors jointly visited establishments, separately assessed health code violations, and deliberated about divergences on health code implementation. Our findings are threefold. First, observing identical conditions, inspectors disagreed 60% of the time. These joint inspection results in turn helped to pinpoint challenging code items and to develop training and guidance documents efficiently during weekly sessions. Second, analyzing over 28,000 independently conducted inspections across the peer review and control groups, we find that the intervention caused an increase in violations detected and scored by 17% to 19%. Third, peer review appeared to decrease variability across inspectors, thereby improving the consistency of inspections. As a result of this trial, King County has now instituted peer review as a standard practice. Our study has rich implications for the feasibility, promise, practice, and pitfalls of peer review, democratic experimentalism, and the administrative state.
MatchIt implements the suggestions of Ho, Imai, King, and Stuart (2007) for improving parametric statistical models by preprocessing data with nonparametric matching methods. MatchIt implements a ...wide range of sophisticated matching methods, making it possible to greatly reduce the dependence of causal inferences on hard-to-justify, but commonly made, statistical modeling assumptions. The software also easily fits into existing research practices since, after preprocessing data with MatchIt, researchers can use whatever parametric model they would have used without MatchIt, but produce inferences with substantially more robustness and less sensitivity to modeling assumptions. MatchIt is an R program, and also works seamlessly with Zelig.
The putative Plasmodium translocon of exported proteins (PTEX) is essential for transport of malarial effector proteins across a parasite-encasing vacuolar membrane into host erythrocytes, but the ...mechanism of this process remains unknown. Here we show that PTEX is a bona fide translocon by determining structures of the PTEX core complex at near-atomic resolution using cryo-electron microscopy. We isolated the endogenous PTEX core complex containing EXP2, PTEX150 and HSP101 from Plasmodium falciparum in the 'engaged' and 'resetting' states of endogenous cargo translocation using epitope tags inserted using the CRISPR-Cas9 system. In the structures, EXP2 and PTEX150 interdigitate to form a static, funnel-shaped pseudo-seven-fold-symmetric protein-conducting channel spanning the vacuolar membrane. The spiral-shaped AAA+ HSP101 hexamer is tethered above this funnel, and undergoes pronounced compaction that allows three of six tyrosine-bearing pore loops lining the HSP101 channel to dissociate from the cargo, resetting the translocon for the next threading cycle. Our work reveals the mechanism of P. falciparum effector export, and will inform structure-based design of drugs targeting this unique translocon.
COVID-19 exposed and exacerbated health disparities, and a core challenge has been how to adapt pandemic response and public health in light of these disproportionate health burdens. Responding to ...this challenge, the County of Santa Clara Public Health Department designed a model of "high-touch" contact tracing that integrated social services with disease investigation, providing continued support and resource linkage for clients from structurally vulnerable communities. We report results from a cluster randomized trial of 5,430 cases from February to May 2021 to assess the ability of high-touch contact tracing to aid with isolation and quarantine. Using individual-level data on resource referral and uptake outcomes, we find that the intervention, randomized assignment to the high-touch program, increased the referral rate to social services by 8.4% (95% confidence interval, 0.8%-15.9%) and the uptake rate by 4.9% (-0.2%-10.0%), with the most pronounced increases in referrals and uptake of food assistance. These findings demonstrate that social services can be effectively combined with contact tracing to better promote health equity, demonstrating a novel path for the future of public health.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
X-ray crystallography often requires non-native constructs involving mutations or truncations, and is challenged by membrane proteins and large multicomponent complexes. We present here a bottom-up ...endogenous structural proteomics approach whereby near-atomic-resolution cryo electron microscopy (cryoEM) maps are reconstructed ab initio from unidentified protein complexes enriched directly from the endogenous cellular milieu, followed by identification and atomic modeling of the proteins. The proteins in each complex are identified using cryoID, a program we developed to identify proteins in ab initio cryoEM maps. As a proof of principle, we applied this approach to the malaria-causing parasite Plasmodium falciparum, an organism that has resisted conventional structural-biology approaches, to obtain atomic models of multiple protein complexes implicated in intraerythrocytic survival of the parasite. Our approach is broadly applicable for determining structures of undiscovered protein complexes enriched directly from endogenous sources.
IMPORTANCE: Data are limited regarding statin therapy for primary prevention of atherosclerotic cardiovascular disease (ASCVD) in adults 75 years and older. OBJECTIVE: To evaluate the role of statin ...use for mortality and primary prevention of ASCVD in veterans 75 years and older. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study that used Veterans Health Administration (VHA) data on adults 75 years and older, free of ASCVD, and with a clinical visit in 2002-2012. Follow-up continued through December 31, 2016. All data were linked to Medicare and Medicaid claims and pharmaceutical data. A new-user design was used, excluding those with any prior statin use. Cox proportional hazards models were fit to evaluate the association of statin use with outcomes. Analyses were conducted using propensity score overlap weighting to balance baseline characteristics. EXPOSURES: Any new statin prescription. MAIN OUTCOMES AND MEASURES: The primary outcomes were all-cause and cardiovascular mortality. Secondary outcomes included a composite of ASCVD events (myocardial infarction, ischemic stroke, and revascularization with coronary artery bypass graft surgery or percutaneous coronary intervention). RESULTS: Of 326 981 eligible veterans (mean SD age, 81.1 4.1 years; 97% men; 91% white), 57 178 (17.5%) newly initiated statins during the study period. During a mean follow-up of 6.8 (SD, 3.9) years, a total 206 902 deaths occurred including 53 296 cardiovascular deaths, with 78.7 and 98.2 total deaths/1000 person-years among statin users and nonusers, respectively (weighted incidence rate difference IRD/1000 person-years, –19.5 95% CI, –20.4 to –18.5). There were 22.6 and 25.7 cardiovascular deaths per 1000 person-years among statin users and nonusers, respectively (weighted IRD/1000 person-years, –3.1 95 CI, –3.6 to –2.6). For the composite ASCVD outcome there were 123 379 events, with 66.3 and 70.4 events/1000 person-years among statin users and nonusers, respectively (weighted IRD/1000 person-years, –4.1 95% CI, –5.1 to –3.0). After propensity score overlap weighting was applied, the hazard ratio was 0.75 (95% CI, 0.74-0.76) for all-cause mortality, 0.80 (95% CI, 0.78-0.81) for cardiovascular mortality, and 0.92 (95% CI, 0.91-0.94) for a composite of ASCVD events when comparing statin users with nonusers. CONCLUSIONS AND RELEVANCE: Among US veterans 75 years and older and free of ASCVD at baseline, new statin use was significantly associated with a lower risk of all-cause and cardiovascular mortality. Further research, including from randomized clinical trials, is needed to more definitively determine the role of statin therapy in older adults for primary prevention of ASCVD.
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