Notes

Acid-base as well as lipophilic attributes involving peptide nucleic chemical p derivatives.
The HIV intasome is a large nucleoprotein assembly that mediates the integration of a DNA copy of the viral genome into host chromatin. Intasomes are targeted by the latest generation of antiretroviral drugs, integrase strand-transfer inhibitors (INSTIs). Challenges associated with lentiviral intasome biochemistry have hindered high-resolution structural studies of how INSTIs bind to their native drug target. Here, we present high-resolution cryo-electron microscopy structures of HIV intasomes bound to the latest generation of INSTIs. These structures highlight how small changes in the integrase active site can have notable implications for drug binding and design and provide mechanistic insights into why a leading INSTI retains efficacy against a broad spectrum of drug-resistant variants. The data have implications for expanding effective treatments available for HIV-infected individuals. read more Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.Aroma contributes to the unique flavors of fruits and is important for fruit quality evaluation. Among the many volatiles in peach (Prunus persicus) fruits, γ-decalactone has the greatest contribution to the characteristic peach aroma. Some peach cultivars have γ-decalactone contents that are too low to detect. Comparison of the transcriptomes and metabolomes of a high-aroma cultivar, 'Fenghuayulu', and a low-aroma cultivar, 'Achutao', suggested that amino acid substitutions in ALCOHOL ACYLTRANSFERASE (PpAAT1) are responsible for the undetectable levels of γ-decalactone in 'Achutao' fruit. Modeling and molecular docking analysis of PpAAT1 indicated that the substituted residues might determine substrate recognition or act as control channels to the active site. In vitro enzyme assays on PpAAT1 heterologously expressed and purified from Escherichia coli, and in vivo assays using transient PpAAT1 expression in Nicotiana benthamiana or the oleaginous yeast Yarrowia lipolytica indicated that PpAAT1 from high-aroma cultivars was more efficient than PpAAT1 from low-aroma cultivars in catalyzing the conversion of 4-hydroxydecanoyl-CoA into γ-decalactone. Examination of loss-of-function mutations of PpAAT1 generated by CRISPR/Cas9 in 'Fenghuayulu' showed that fruits with PpAAT1 mutations had significantly lower γ-decalactone contents. Expression of the version of PpAAT1 from 'Fenghuayulu' in 'Achutao' restored γ-decalactone levels to those measured in 'Fenghuayulu', confirming the specific contribution of PpAAT1 to the formation of this key aroma compound. These results show how the biosynthesis of the peach aroma compound γ-decalactone is compromised in some low-aroma cultivars and illustrate the physiological role of PpAAT1 in plant lactone biosynthesis. copyright, serif 2020 American Society of Plant Biologists. All rights reserved.BACKGROUND Despite reported injury rates of up to 3 per 1000 hours exposure, there are no evidence-based prevention programmes in tennis. PURPOSE To evaluate the effectiveness of an e-health prevention programme for reducing tennis injury prevalence. STUDY DESIGN Two-arm, researcher-blinded randomised controlled trial. METHODS Adult tennis players of all playing levels were randomised in an unsupervised programme lasting 12 weeks (TennisReady group or control group). The primary outcome was the overall injury prevalence over a 16-week period, measured at 2 weekly intervals with the Oslo Sports and Trauma Research Centre questionnaire. Estimates for the primary outcome and associated 95% CIs were obtained using generalised estimating equation models. Secondary outcome scores included prevalence of substantial injuries, overall incidence, adherence and time-loss injuries. RESULTS A total of 579 (83%) (TennisReady n=286, control n=293) participants were included in the primary analysis. The mean injury prevalence was 37% (95% CI 33% to 42%) in the TennisReady vs 38% (95% CI 34% to 42%) in the control group (adjusted p-value 0.93). The prevalence of substantial injuries was 11% (95% CI 9% to 14%) in the TennisReady vs 12% (95% CI 9% to 15%) in the control group (p value of 0.79). Analysis of the secondary outcome scores showed no difference between groups. The mean prevalence rates between high (8%) and low (92%) adherent groups were 32% (95% CI 23% to 44%) and 37% (95% CI 33% to 42%), respectively (p value 0.36). CONCLUSION Providing an unsupervised e-health tennis-specific exercise programme did not reduce the injury rates and should not be implemented. TRIAL REGISTRATION NUMBER NTR6443. © Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.Primary resistance to CD19-directed chimeric antigen receptor T cell therapy (CART19) occurs in 10-20% of patients with acute lymphoblastic leukemia (ALL), however the mechanisms of this resistance remain elusive. Using a genome-wide loss-of-function screen, we identified that impaired death receptor signaling in ALL led to rapidly progressive disease despite CART19 treatment. This was mediated by an inherent resistance to T cell cytotoxicity which permitted antigen persistence and was subsequently magnified by the induction of CAR T cell functional impairment. These findings were validated using samples from two CAR T cell clinical trials in ALL, where we found that reduced expression of death receptor genes was associated with worse overall survival and reduced T cell fitness. Our findings suggest that inherent dysregulation of death receptor signaling in ALL directly leads to CAR T cell failure by impairing T cell cytotoxicity and promoting progressive CAR T cell dysfunction. Copyright ©2020, American Association for Cancer Research.OBJECTIVES Alzheimer disease (AD) shows a broad array of clinical presentations, but the mechanisms underlying these phenotypic variants remain elusive. Aging-related astrogliopathy (ARTAG) is a relatively recent term encompassing a broad array of tau deposition in astroglia outside the range of traditional tauopathies. White matter thorn-shaped astrocyte (WM-TSA) clusters, a specific ARTAG subtype, has been associated with atypical language presentation of AD in a small study lacking replication. To interrogate the impact of WM-TSA in modifying clinical phenotype in AD, we investigated a clinicopathologic sample of 83 persons with pure cortical AD pathology and heterogeneous clinical presentations. METHODS We mapped WM-TSA presence and density throughout cortical areas and interrogated whether WM-TSA correlated with atypical AD presentation or worse performance in neuropsychological testing. RESULTS WM-TSA was present in nearly half of the cases and equally distributed in typical and atypical AD presentations. Worsening language and visuospatial functions were correlated with higher WM-TSA density in language-related and visuospatial-related regions, respectively. These findings were unrelated to regional neurofibrillary tangle burden. Next, unsupervised clustering divided the participants into 2 groups a high-WM-TSA (n = 9) and low-WM-TSA (n = 74) pathology signature. The high-WM-TSA group scored significantly worse in language but not in other cognitive domains. CONCLUSIONS The negative impact of WM-TSA pathology to language and possibly visuospatial networks suggests that WM-TSA is not as benign as other ARTAG types and may be explored as a framework to understand the mechanisms and impact of astrocytic tau deposition in AD in humans. © 2020 American Academy of Neurology.In Arabidopsis thaliana, the cold-induced epigenetic regulation of FLOWERING LOCUS C (FLC) involves distinct phases of Polycomb repressive complex 2 (PRC2) silencing. During cold, a PHD-PRC2 complex metastably and digitally nucleates H3K27me3 within FLC On return to warm, PHD-PRC2 spreads across the locus delivering H3K27me3 to maintain long-term silencing. Here, we studied natural variation in this process in Arabidopsis accessions, exploring Lov-1, which shows FLC reactivation on return to warm, a feature characteristic of FLC in perennial Brassicaceae This analysis identifies an additional phase in this Polycomb silencing mechanism downstream from H3K27me3 spreading. In this long-term silencing (perpetuated) phase, the PHD proteins are lost from the nucleation region and silencing is likely maintained by the read-write feedbacks associated with H3K27me3. A combination of noncoding SNPs in the nucleation region mediates instability in this long-term silencing phase with the result that Lov-1 FLC frequently digitally reactivates in individual cells, with a probability that diminishes with increasing cold duration. We propose that this decrease in reactivation probability is due to reduced DNA replication after flowering. Overall, this work defines an additional phase in the Polycomb mechanism instrumental in natural variation of silencing, and provides avenues to dissect broader evolutionary changes at FLC. © 2020 Qüesta et al.; Published by Cold Spring Harbor Laboratory Press.Oncogenic mutations in the RNA splicing factors SRSF2, SF3B1, and U2AF1 are the most frequent class of mutations in myelodysplastic syndromes and are also common in clonal hematopoiesis, acute myeloid leukemia, chronic lymphocytic leukemia, and a variety of solid tumors. They cause genome-wide splicing alterations that affect important regulators of hematopoiesis. Several mRNA isoforms promoted by the various splicing factor mutants comprise a premature termination codon (PTC) and are therefore potential targets of nonsense-mediated mRNA decay (NMD). In light of the mechanistic relationship between splicing and NMD, we sought evidence for a specific role of mutant SRSF2 in NMD. We show that SRSF2 Pro95 hot spot mutations elicit enhanced mRNA decay, which is dependent on sequence-specific RNA binding and splicing. SRSF2 mutants enhance the deposition of exon junction complexes (EJCs) downstream from the PTC through RNA-mediated molecular interactions. This architecture then favors the association of key NMD factors to elicit mRNA decay. Gene-specific blocking of EJC deposition by antisense oligonucleotides circumvents aberrant NMD promoted by mutant SRSF2, restoring the expression of PTC-containing transcript. Our study uncovered critical effects of SRSF2 mutants in hematologic malignancies, reflecting the regulation at multiple levels of RNA metabolism, from splicing to decay. © 2020 Rahman et al.; Published by Cold Spring Harbor Laboratory Press.Chromatin barriers prevent spurious interactions between regulatory elements and DNA-binding proteins. One such barrier, whose mechanism for overcoming is poorly understood, is access to recombination hot spots during meiosis. Here we show that the chromatin remodeler HELLS and DNA-binding protein PRDM9 function together to open chromatin at hot spots and provide access for the DNA double-strand break (DSB) machinery. Recombination hot spots are decorated by a unique combination of histone modifications not found at other regulatory elements. HELLS is recruited to hot spots by PRDM9 and is necessary for both histone modifications and DNA accessibility at hot spots. In male mice lacking HELLS, DSBs are retargeted to other sites of open chromatin, leading to germ cell death and sterility. Together, these data provide a model for hot spot activation in which HELLS and PRDM9 form a pioneer complex to create a unique epigenomic environment of open chromatin, permitting correct placement and repair of DSBs. © 2020 Spruce et al.
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