African ancestry neurodegeneration risk variant disrupts an intronic branchpoint in GBA1.

Recently, an African ancestry-specific Parkinson disease (PD) risk signal was identified at the gene encoding glucocerebrosidase (GBA1). This variant ( rs3115534 -G) is carried by ~50% of West African PD cases and imparts a dose-dependent increase in risk for disease. The risk variant has varied frequencies across African ancestry groups but is almost absent in European and Asian ancestry populations.

A Second-Generation Oral SARS-CoV-2 Main Protease Inhibitor Clinical Candidate for the Treatment of COVID-19.

Despite the record-breaking discovery, development and approval of vaccines and antiviral therapeutics such as Paxlovid, coronavirus disease 2019 (COVID-19) remained the fourth leading cause of death in the world and third highest in the United States in 2022. Here, we report the discovery and characterization of PF-07817883, a second-generation, orally bioavailable, SARS-CoV-2 main protease inhibitor with improved metabolic stability versus nirmatrelvir, the antiviral component of the ritonavir-boosted therapy Paxlovid. We demonstrate the pan-human coronavirus antiviral activity and off-target selectivity profile of PF-07817883.

Endocrine Responses to Triptorelin in Healthy Women, Women With Polycystic Ovary Syndrome, and Women With Hypothalamic Amenorrhea.

Context: Limited data exist regarding whether the endocrine response to the gonadotropin-releasing hormone receptor agonist (GnRHa) triptorelin differs in women with polycystic ovary syndrome (PCOS) compared with healthy women or those with hypothalamic amenorrhea (HA).

Objective: We compared the gonadotropin response to triptorelin in healthy women, women with PCOS, or those with HA without ovarian stimulation, and in women with or without polycystic ovaries undergoing oocyte donation cycles after ovarian stimulation.

Methods: The change in serum gonadotropin levels was determined in (1) a prospective single-blinded placebo-controlled study to determine the endocrine profile of triptorelin (0.

Role of Sex on the Genetic Susceptibility to Childhood Asthma in Latinos and African Americans.

Asthma is a respiratory disease whose prevalence changes throughout the lifespan and differs by sex, being more prevalent in males during childhood and in females after puberty. In this study, we assessed the influence of sex on the genetic susceptibility to childhood asthma in admixed populations. Sex-interaction and sex-stratified genome-wide association studies (GWAS) were performed in 4291 Latinos and 1730 African Americans separately, and results were meta-analyzed.

Heterogeneity in PD-L1 expression in malignant peritoneal mesothelioma with systemic or intraperitoneal chemotherapy.

Programmed death-ligand 1 (PD-L1) expression has been described in patients with malignant peritoneal mesothelioma (MPM), but treatment strategies utilising immune checkpoint inhibition are yet to be defined. Here, we examine levels of PD-L1 expression in MPM patients treated with systemic and/or intraperitoneal chemotherapy using tissue from patient tumour biopsies or resections at multiple time points. We found the mean PD-L1 expression was higher in those with a germline mutation and/or those with a higher somatic mutation burden.

Transcriptome-scale super-resolved imaging in tissues by RNA seqFISH.

Imaging the transcriptome in situ with high accuracy has been a major challenge in single-cell biology, which is particularly hindered by the limits of optical resolution and the density of transcripts in single cells. Here we demonstrate an evolution of sequential fluorescence in situ hybridization (seqFISH+). We show that seqFISH+ can image mRNAs for 10,000 genes in single cells-with high accuracy and sub-diffraction-limit resolution-in the cortex, subventricular zone and olfactory bulb of mouse brain, using a standard confocal microscope.

Personal Mutanomes Meet Modern Oncology Drug Discovery and Precision Health.

Recent remarkable advances in genome sequencing have enabled detailed maps of identified and interpreted genomic variation, dubbed "mutanomes." The availability of thousands of exome/genome sequencing data has prompted the emergence of new challenges in the identification of novel druggable targets and therapeutic strategies. Typically, mutanomes are viewed as one- or two-dimensional.

Effect of Genetic Diagnosis on Patients with Previously Undiagnosed Disease.

Background: Many patients remain without a diagnosis despite extensive medical evaluation. The Undiagnosed Diseases Network (UDN) was established to apply a multidisciplinary model in the evaluation of the most challenging cases and to identify the biologic characteristics of newly discovered diseases. The UDN, which is funded by the National Institutes of Health, was formed in 2014 as a network of seven clinical sites, two sequencing cores, and a coordinating center.

Macroautophagy is dispensable for growth of KRAS mutant tumors and chloroquine efficacy.

Macroautophagy is a key stress-response pathway that can suppress or promote tumorigenesis depending on the cellular context. Notably, Kirsten rat sarcoma (KRAS)-driven tumors have been reported to rely on macroautophagy for growth and survival, suggesting a potential therapeutic approach of using autophagy inhibitors based on genetic stratification. In this study, we evaluated whether KRAS mutation status can predict the efficacy to macroautophagy inhibition.