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InWeb_InBioMap (InWeb_IM for short) is a scored, integrated human protein–protein interaction network resource aggregated from public, experimentally determined protein–protein interactions. The resource enables functional interpretation of large-scale genomics data. Genome-scale human protein–protein interaction networks are critical to understanding cell biology and interpreting genomic data, but challenging to produce experimentally. Through data integration and quality control, we provide a scored human protein–protein interaction network (InWeb_InBioMap, or InWeb_IM) with severalfold more interactions (>500,000) and better functional biological relevance than comparable resources. We illustrate that InWeb_InBioMap enables functional interpretation of >4,700 cancer genomes and genes involved in autism.

This paper describes a novel homotopy method to compute fuel-optimal trajectories starting from a time-optimal solution. The time-optimal problem is proposed to serve as a gateway for solving the minimum thrust problem. Homotopy is used to link the original low-thrust fuel-optimal problem with the minimum thrust problem. Two new variables are introduced in the dynamic model. The first is a logarithm of mass variable and the second is an acceleration magnitude variable. The analytic expression of the logarithm of mass co-state is solved. For the time-optimal problem, initial co-state of logarithm of mass can be expressed by thrust magnitude and transfer time. Then, the number of unknown initial co-states decreased. The effectiveness and optimality of the proposed method is validated through simulations of two rendezvous missions.

The thalamic reticular nucleus (TRN), the major source of thalamic inhibition, regulates thalamocortical interactions that are critical for sensory processing, attention and cognition 1 – 5 . TRN dysfunction has been linked to sensory abnormality, attention deficit and sleep disturbance across multiple neurodevelopmental disorders 6 – 9 . However, little is known about the organizational principles that underlie its divergent functions. Here we performed an integrative study linking single-cell molecular and electrophysiological features of the mouse TRN to connectivity and systems-level function. We found that cellular heterogeneity in the TRN is characterized by a transcriptomic gradient of two negatively correlated gene-expression profiles, each containing hundreds of genes. Neurons in the extremes of this transcriptomic gradient express mutually exclusive markers, exhibit core or shell-like anatomical structure and have distinct electrophysiological properties. The two TRN subpopulations make differential connections with the functionally distinct first-order and higher-order thalamic nuclei to form molecularly defined TRN–thalamus subnetworks. Selective perturbation of the two subnetworks in vivo revealed their differential role in regulating sleep. In sum, our study provides a comprehensive atlas of TRN neurons at single-cell resolution and links molecularly defined subnetworks to the functional organization of thalamocortical circuits. A study integrating single-cell RNA-sequencing and electrophysiology data shows that in mouse, the cellular repertoire of the thalamic reticular nucleus is characterized by a transcriptomic gradient defined at its extremes by mutually exclusive expression of Spp1 and Ecel1 , providing insights into the organizational principles underlying the divergent functions of this brain region.

Schlemm’s canal (SC) is central in intraocular pressure regulation but requires much characterization. It has distinct inner and outer walls, each composed of Schlemm’s canal endothelial cells (SECs) with different morphologies and functions. Recent transcriptomic studies of the anterior segment added important knowledge, but were limited in power by SEC numbers or did not focus on SC. To gain a more comprehensive understanding of SC biology, we performed bulk RNA sequencing on C57BL/6 J SC, blood vessel, and lymphatic endothelial cells from limbal tissue (~4,500 SECs). We also analyzed mouse limbal tissues by single-cell and single-nucleus RNA sequencing (C57BL/6 J and 129/Sj strains), successfully sequencing 903 individual SECs. Together, these datasets confirm that SC has molecular characteristics of both blood and lymphatic endothelia with a lymphatic phenotype predominating. SECs are enriched in pathways that regulate cell-cell junction formation pointing to the importance of junctions in determining SC fluid permeability. Importantly, and for the first time, our analyses characterize three molecular classes of SECs, molecularly distinguishing inner wall from outer wall SECs and discovering two inner wall cell states that likely result from local environmental differences. Further, and based on ligand and receptor expression patterns, we document key interactions between SECs and cells of the adjacent trabecular meshwork (TM) drainage tissue. Also, we present cell type expression for a collection of human glaucoma genes. These data provide a new molecular foundation that will enable the functional dissection of key homeostatic processes mediated by SECs as well as the development of new glaucoma therapeutics.

Background Understanding the genetic causes underlying variability in chromatin accessibility can shed light on the molecular mechanisms through which genetic variants may affect complex traits. Thousands of ATAC-seq samples have been collected that hold information about chromatin accessibility across diverse cell types and contexts, but most of these are not paired with genetic information and come from distinct projects and laboratories. Results We report here joint genotyping, chromatin accessibility peak calling, and discovery of quantitative trait loci which influence chromatin accessibility (caQTLs), demonstrating the capability of performing caQTL analysis on a large scale in a diverse sample set without pre-existing genotype information. Using 10,293 profiling samples representing 1454 unique donor individuals across 653 studies from public databases, we catalog 24,159 caQTLs in total. After joint discovery analysis, we cluster samples based on accessible chromatin profiles to identify context-specific caQTLs. We find that caQTLs are strongly enriched for annotations of gene regulatory elements across diverse cell types and tissues and are often linked with genetic variation associated with changes in expression (eQTLs), indicating that caQTLs can mediate genetic effects on gene expression. We demonstrate sharing of causal variants for chromatin accessibility across human traits, enabling a more complete picture of the genetic mechanisms underlying complex human phenotypes. Conclusions Our work provides a proof of principle for caQTL calling from previously ungenotyped samples and represents one of the largest, most diverse caQTL resources currently available, informing mechanisms of genetic regulation of gene expression and contribution to disease.

MicroRNA (miRNA) dysregulation is implicated in testicular germ cell tumor (TGCT) pathogenesis. Here, we characterized miRNA expression profiles across TGCT histologic subtypes using miRNA-sequencing on 43 formalin-fixed paraffin-embedded (FFPE) tissue samples (31 primary, 12 metastases) from 29 patients to identify diagnostic markers and their regulatory functions. From 20 seminomas (SEM), 14 non-seminomatous germ cell tumors (N-SEM), and 9 teratomas, we profiled a total of 2606 miRNAs. Compared to teratomas, 154 miRNAs (targeting 657 genes) were enriched in SEM, and 141 miRNAs (targeting 358 genes) in N-SEM. miR-200-3p, targeting the DNA methyltransferase DNMT3B, was enriched in N-SEM versus SEM. Our findings showed high concordance with The Cancer Genome Atlas (TCGA)-TGCT data (Pearson R > 0.66, p  < 1e−10). miRNA expression was largely similar between primary and metastatic tissues and between chemotherapy-treated and untreated teratomas, reflecting teratoma chemo-resistance. Using novel candidates, miRNA-based logistic regression classifiers distinguished viable GCT (SEM/N-SEM) from teratoma (Area Under the Curve [AUC] > 0.96) and SEM from N-SEM (AUC = 0.81), outperforming well-known miRNA markers. Target gene analysis implicated FOXO and RUNX1 regulation, somatotroph signaling, and height-related pathways. Overall, our comprehensive tissue-level miRNA profiling in TGCTs identified potential diagnostic biomarkers for histologic subtypes, offering insights into miRNA-mediated transcriptional dysregulation.

Since the trabecular meshwork (TM) is central to intraocular pressure (IOP) regulation and glaucoma, a deeper understanding of its genomic landscape is needed. We present a multimodal, single-cell resolution analysis of mouse limbal cells (includes TM). In total, we sequenced 9,394 wild-type TM cell transcriptomes. We discovered three TM cell subtypes with characteristic signature genes validated by immunofluorescence on tissue sections and whole-mounts. The subtypes are robust, being detected in datasets for two diverse mouse strains and in independent data from two institutions. Results show compartmentalized enrichment of critical pathways in specific TM cell subtypes. Distinctive signatures include increased expression of genes responsible for (1) extracellular matrix structure and metabolism (TM1 subtype), (2) secreted ligand signaling to support Schlemm’s canal cells (TM2), and (3) contractile and mitochondrial/metabolic activity (TM3). ATAC-sequencing data identified active transcription factors in TM cells, including LMX1B. Mutations in LMX1B cause high IOP and glaucoma. LMX1B is emerging as a key transcription factor for normal mitochondrial function, and its expression is much higher in TM3 cells than other limbal cells. To understand the role of LMX1B in TM function and glaucoma, we single-cell sequenced limbal cells from Lmx1b V265D/+ mutant mice (2491 TM cells). In Lmx1b V265D/+ mice, TM3 cells were uniquely affected by pronounced mitochondrial pathway changes. Mitochondria in TM cells of Lmx1b V265D/+ mice are swollen with a reduced cristae area, further supporting a role for mitochondrial dysfunction in the initiation of IOP elevation in these mice. Importantly, treatment with vitamin B3 (nicotinamide), which enhances mitochondrial function and metabolic resilience in other contexts, significantly protected Lmx1b mutant mice from IOP elevation.

BRAF mutations are a significant driver of disease in pediatric low-grade glioma, but the implications of BRAF alterations on the clinical course and treatment response in adult glioma remain unclear. Here, we characterize a multi-institutional cohort of more than 300 patients (>200 adults) with BRAF -mutated glioma using clinical, pathological/molecular, and outcome data. We observed that adult and pediatric BRAF -mutant gliomas harbor distinct clinical and molecular features, with a higher prevalence of BRAF V600E (Class I) and BRAF fusions in pediatric tumors. BRAF V600E alterations were associated with improved survival in adults with glioma overall, though not in glioblastoma. Other genomic alterations observed within functional classes were consistent with the putative roles of those BRAF mutation classes in glioma pathogenesis. In our adult cohort, BRAF V600E alterations conferred sensitivity to targeted therapies. Overall, this large cohort of BRAF -altered adult gliomas demonstrates a broad range of molecular alterations with implications for treatment sensitivity and survival.

Background Asian American (AsAm) representation is lacking in conversations surrounding cultural humility in healthcare. We aimed to investigate US medical student perspectives on AsAm patient inclusion in cultural humility training in medical education. Methods This qualitative study analyzed free-text responses to an optional, open-ended question presented at the conclusion of an online survey assessing medical student experiences with and perceptions regarding AsAm patients in their medical education. This survey was distributed to a convenience sample of nine US medical schools. Medical students who completed at least one clinical rotation were eligible to participate in the survey. Qualitative analysis of free-text responses was conducted in an iterative process to generate emergent themes. Results There was a total of 195 optional free-text responses from 688 participants (28%). Motivation to learn about AsAm population included shared identity and desire to better serve the AsAm population in their local community and future careers. Topics of interest included healthcare-related cultural preferences, healthcare delivery strategies, and health disparities for the AsAm population and other minority patients. Students reported that they drew on personal experiences and some pre-clinical or clinical exposures to learn about AsAm patients. Respondents cited the lack of exposure in the medical school curriculum and clinical experiences as the main challenge to learning about AsAm health and provided suggestions for the delivery of this education in their pre-clinical and clinical education. Respondents emphasized that AsAms are treated as a monolith in medical education and healthcare, despite their heterogeneity. Conclusions Medical students identified a need and interest for greater inclusion of AsAm topics in medical education on cultural humility and minority health.

Parkinson’s disease (PD) is a progressive neurodegenerative disease characterized by mitochondrial dysfunction and accumulation of alpha-synuclein (α-Syn)-containing protein aggregates known as Lewy bodies (LB). Here, we investigated the entry of α-Syn into mitochondria to cause mitochondrial dysfunction and loss of cellular fitness in vivo. We show that α-Syn expressed in yeast and human cells is constitutively imported into mitochondria. In a transgenic mouse model, the level of endogenous α-Syn accumulation in mitochondria of dopaminergic neurons and microglia increases with age. The imported α-Syn is degraded by conserved mitochondrial proteases, most notably NLN and PITRM1 (Prd1 and Cym1 in yeast, respectively). α-Syn in the mitochondrial matrix that is not degraded interacts with respiratory chain complexes, leading to loss of mitochondrial DNA (mtDNA), mitochondrial membrane potential and cellular fitness decline. Importantly, enhancing mitochondrial proteolysis by increasing levels of specific proteases alleviated these defects in yeast, human cells, and a PD model of mouse primary neurons. Together, our results provide a direct link between α-synuclein-mediated cellular toxicity and its import into mitochondria and reveal potential therapeutic targets for the treatment of α-synucleinopathies.