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The Janus tyrosine kinase (JAK) family of non-receptor tyrosine kinases includes four isoforms (JAK1, JAK2, JAK3, and TYK2) and is responsible for signal transduction downstream of diverse cytokine receptors. JAK inhibitors have emerged as important therapies for immun(onc)ological disorders, but their use is limited by undesirable side effects presumed to arise from poor isoform selectivity, a common challenge for inhibitors targeting the ATP-binding pocket of kinases. Here we describe the chemical proteomic discovery of a druggable allosteric cysteine present in the non-catalytic pseudokinase domain of JAK1 (C817) and TYK2 (C838), but absent from JAK2 or JAK3. Electrophilic compounds selectively engaging this site block JAK1-dependent trans-phosphorylation and cytokine signaling, while appearing to act largely as ‘silent’ ligands for TYK2. Importantly, the allosteric JAK1 inhibitors do not impair JAK2-dependent cytokine signaling and are inactive in cells expressing a C817A JAK1 mutant. Our findings thus reveal an allosteric approach for inhibiting JAK1 with unprecedented isoform selectivity.Chemical proteomics identified covalent ligands targeting an isoform-restricted allosteric cysteine in JAK1. The compounds inhibit JAK1-dependent signaling in immune cells with unprecedented selectivity.

The JAK family of non-receptor tyrosine kinases includes four subtypes (JAK1, JAK2, JAK3, and TYK2) and is responsible for signal transduction downstream of diverse cytokine receptors. JAK inhibitors have emerged as important therapies for immuno(onc)ological disorders, but their use is limited by undesirable side effects presumed to arise from poor subtype selectivity, a common challenge for inhibitors targeting the ATP-binding pocket of kinases. Here, we describe the chemical proteomic discovery of a druggable allosteric cysteine present in the non-catalytic pseudokinase domain of JAK1 (C817) and TYK2 (C838), but absent from JAK2 or JAK3. Electrophilic compounds selectively engaging this site block JAK1-dependent transphosphorylation and cytokine signaling, while appearing to act largely as “silent” ligands for TYK2. Importantly, the allosteric JAK1 inhibitors do not impair JAK2-dependent cytokine signaling and are inactive in cells expressing a C817A JAK1 mutant. Our findings thus reveal an allosteric approach for inhibiting JAK1 with unprecedented subtype selectivity.

Background Neoadjuvant dual human epidermal growth factor receptor (HER2) blockade with trastuzumab and pertuzumab plus paclitaxel leads to an overall pathologic complete response (pCR) rate of 46%. Dual HER2 blockade with ado-trastuzumab emtansine (T-DM1) and lapatinib plus nab-paclitaxel has shown efficacy in patients with metastatic HER2-positive breast cancer. To test neoadjuvant effectiveness of this regimen, an open-label, multicenter, randomized, phase II trial was conducted comparing T-DM1, lapatinib, and nab-paclitaxel with trastuzumab, pertuzumab, and paclitaxel in patients with early-stage HER2-positive breast cancer. Methods Stratification by estrogen receptor (ER) status occurred prior to randomization. Patients in the experimental arm received 6 weeks of targeted therapies (T-DM1 and lapatinib) followed by T-DM1 every 3 weeks, lapatinib daily, and nab-paclitaxel weekly for 12 weeks. In the standard arm, patients received 6 weeks of trastuzumab and pertuzumab followed by trastuzumab weekly, pertuzumab every 3 weeks, and paclitaxel weekly for 12 weeks. The primary objective was to evaluate the proportion of patients with residual cancer burden (RCB) 0 or I. Key secondary objectives included pCR rate, safety, and change in tumor size at 6 weeks. Hypothesis-generating correlative assessments were also performed. Results The 30 evaluable patients were well-balanced in patient and tumor characteristics. The proportion of patients with RCB 0 or I was higher in the experimental arm (100% vs. 62.5% in the standard arm, p  = 0.0035). In the ER-positive subset, all patients in the experimental arm achieved RCB 0-I versus 25% in the standard arm ( p  = 0.0035). Adverse events were similar between the two arms. Conclusion In early-stage HER2-positive breast cancer, the neoadjuvant treatment with T-DM1, lapatinib, and nab-paclitaxel was more effective than the standard treatment, particularly in the ER-positive cohort. Trial registration Clinicaltrials.gov NCT02073487 , February 27, 2014.

Background The attenuation of cellular phenotypic switchingdriving PAH vascular remodeling remains an unmet therapeutic need. As eNAMPT (nicotinamide phosphoribosyltransferase)/TLR4 signaling significantly contributes to PH pathobiology, an eNAMPT-neutralizing ALT-100 mAb was utilized to rescue monocrotaline (MCT) and hypoxia/Sugen (Hy/Su) preclinical PH rat models and to evaluate eNAMPT/TLR4 involvement in endothelial cell (EC), smooth muscle cell (SMC) and monocyte/macrophage phenotypic switching. Methods MCT-PH or Hy/Su-PH rats received IgG or ALT-100 mAb (subQ, beginning week 4) with measurements of PH severity and lung tissue scRNAseq at day 42. Results PH severity indices (hemodynamic, histologic, vascular remodeling) were significantly attenuated in MCT-PH and Hy/Su-PH rats receiving ALT-100 mAb. scRNAseq studies revealed Hy/Su exposure increased populations of ECs undergoing EC-to-mesenchymal cell transition (EndMT), proliferating SMCs, and monocytes undergoing macrophage differentiation. Cellular phenotypic switching was ameliorated in Hy/Su-mAb rats. Conclusions Autocrine/paracrine eNAMPT/TLR4 signaling contributes to accelerated cellular phenotypic switching, a druggable strategy to reverse vascular remodeling.

Embodied/modality-specific theories of semantic memory propose that sensorimotor representations play an important role in perception and action. A large body of evidence supports the notion that concepts involving human motor action (i.e., semantic-motor representations) are processed in both language and motor regions of the brain. However, most studies have focused on perceptual tasks, leaving unanswered questions about language-motor interaction during production tasks. Thus, we investigated the effects of shared semantic-motor representations on concurrent language and motor production tasks in healthy young adults, manipulating the semantic task (motor-related vs. nonmotor-related words) and the motor task (i.e., standing still and finger-tapping). In Experiment 1 (n = 20), we demonstrated that motor-related word generation was sufficient to affect postural control. In Experiment 2 (n = 40), we demonstrated that motor-related word generation was sufficient to facilitate word generation and finger tapping. We conclude that engaging semantic-motor representations can have a reciprocal influence on motor and language production. Our study provides additional support for functional language-motor interaction, as well as embodied/modality-specific theories.

Hispanic/Latino populations are underrepresented in Alzheimer Disease (AD) genetic studies. Puerto Ricans (PR), a three-way admixed (European, African, and Amerindian) population is the second-largest Hispanic group in the continental US. We aimed to conduct a genome-wide association study (GWAS) and comprehensive analyses to identify novel AD susceptibility loci and characterize known AD genetic risk loci in the PR population. Our study included Whole Genome Sequencing (WGS) and phenotype data from 648 PR individuals (345 AD, 303 cognitively unimpaired). We used a generalized linear-mixed model adjusting for sex, age, population substructure, and genetic relationship matrix. To infer local ancestry, we merged the dataset with the HGDP/1000G reference panel. Subsequently, we conducted univariate admixture mapping (AM) analysis. We identified suggestive signals within the and genes on chromosome 12q13. This region overlaps with an area of linkage of AD in previous studies (12q13) in independent data sets further supporting. Univariate African AM analysis identified one suggestive ancestral block (  = 7.2×10 ) located in the same region. The ancestry-aware approach showed that this region has both European and African ancestral backgrounds and both contributing to the risk in this region. We also replicated 11 different known AD loci -including - identified in mostly European studies, which is likely due to the high European background of the PR population. PR GWAS and AM analysis identified a suggestive AD risk locus on chromosome 12, which includes the and genes. Our findings demonstrate the importance of designing GWAS and ancestry-aware approaches and including underrepresented populations in genetic studies of AD.

Hispanic/Latino populations are underrepresented in Alzheimer Disease (AD) genetic studies. The Puerto Rican (PR) population, a three-way admixed (European, African, and Amerindian) population is the second-largest Hispanic group in the continental US. We performed a genome-wide association study (GWAS) in the PR population to identify novel AD susceptibility loci and characterize known AD genetic risk loci. 652 individuals (349 AD; 303 cognitively unimpaired), ascertained through the Puerto Rico Alzheimer Disease Initiative (PRADI), were included in the analyses. We performed GWAS on the Whole Genome Sequencing (WGS) dataset with a generalized linear-mixed model adjusting for sex, age, and population substructure as fixed effects and genetic relationship matrix as a random effect. To infer local ancestry, we merged the target PR dataset with appropriate population samples from the HGDP and 1000G reference panels. Subsequently, we conducted univariate admixture mapping (AM) analysis. We also assessed the polygenic risk score (PRS) using the effect sizes from summary statistics from the non-Hispanic White (NHW) study. We identified a suggestive significant (p<5 × 10 ) signal (rs11183403; P = 4 × 10 ) within the SLC38A1 gene on chromosome 12. Univariate African AM analysis identified one suggestive (p<4 × 10 ) ancestral block located in the same region on chromosomes 12q13.1 (p = 7.2 × 10 ). We replicated eight known AD loci- APOE, ABCA7, CLU, FERMT2, GRN, PRDM7, SEC61G, and TREM2. Admixture analysis revealed proportions of 68% European, 20% African, and 12% Amerindian in the PR cohort. NHW-derived PRS has a good prediction power (AUC = 0.62) in the PR dataset. PR GWAS and AM identified a suggestive AD risk locus in the SLC38A1 gene. This region overlaps with an area of linkage of AD in previous studies (12q13). The SLC38A1 gene is associated with ischemic brain damage and its transcription is affected by amyloid-beta peptide. Our study replicated 8 known AD loci previously identified in European studies and showed good predictive power with NHW-derived PRS which is likely due to the high European background of the PR population. Including underrepresented populations in genetic studies is important for identifying health disparities and developing effective treatments for AD in all groups.

Female Aedes aegypti mosquitoes infect more than 400 million people each year with dangerous viral pathogens including dengue, yellow fever, Zika and chikungunya. Progress in understanding the biology of mosquitoes and developing the tools to fight them has been slowed by the lack of a high-quality genome assembly. Here we combine diverse technologies to produce the markedly improved, fully re-annotated AaegL5 genome assembly, and demonstrate how it accelerates mosquito science. We anchored physical and cytogenetic maps, doubled the number of known chemosensory ionotropic receptors that guide mosquitoes to human hosts and egg-laying sites, provided further insight into the size and composition of the sex-determining M locus, and revealed copy-number variation among glutathione S -transferase genes that are important for insecticide resistance. Using high-resolution quantitative trait locus and population genomic analyses, we mapped new candidates for dengue vector competence and insecticide resistance. AaegL5 will catalyse new biological insights and intervention strategies to fight this deadly disease vector. An improved, fully re-annotated Aedes aegypti genome assembly (AaegL5) provides insights into the sex-determining M locus, chemosensory systems that help mosquitoes to hunt humans and loci involved in insecticide resistance and will help to generate intervention strategies to fight this deadly disease vector.

While genome-wide association studies (GWAS) have primarily examined populations of European ancestry, more recent studies often involve additional populations, including admixed populations such as African Americans and Latinos. In admixed populations, linkage disequilibrium (LD) exists both at a fine scale in ancestral populations and at a coarse scale (admixture-LD) due to chromosomal segments of distinct ancestry. Disease association statistics in admixed populations have previously considered SNP association (LD mapping) or admixture association (mapping by admixture-LD), but not both. Here, we introduce a new statistical framework for combining SNP and admixture association in case-control studies, as well as methods for local ancestry-aware imputation. We illustrate the gain in statistical power achieved by these methods by analyzing data of 6,209 unrelated African Americans from the CARe project genotyped on the Affymetrix 6.0 chip, in conjunction with both simulated and real phenotypes, as well as by analyzing the FGFR2 locus using breast cancer GWAS data from 5,761 African-American women. We show that, at typed SNPs, our method yields an 8% increase in statistical power for finding disease risk loci compared to the power achieved by standard methods in case-control studies. At imputed SNPs, we observe an 11% increase in statistical power for mapping disease loci when our local ancestry-aware imputation framework and the new scoring statistic are jointly employed. Finally, we show that our method increases statistical power in regions harboring the causal SNP in the case when the causal SNP is untyped and cannot be imputed. Our methods and our publicly available software are broadly applicable to GWAS in admixed populations.