A genetic basis for sex differences in Xp11 translocation renal cell carcinoma.

Xp11 translocation renal cell carcinoma (tRCC) is a rare, female-predominant cancer driven by a fusion between the transcription factor binding to IGHM enhancer 3 (TFE3) gene on chromosome Xp11.2 and a partner gene on either chromosome X (chrX) or an autosome. It remains unknown what types of rearrangements underlie TFE3 fusions, whether fusions can arise from both the active (chrXa) and inactive X (chrXi) chromosomes, and whether TFE3 fusions from chrXi translocations account for the female predominance of tRCC. To address these questions, we performed haplotype-specific analyses of chrX rearrangements in tRCC whole genomes. We show that TFE3 fusions universally arise as reciprocal translocations and that oncogenic TFE3 fusions can arise from chrXi:autosomal translocations. Female-specific chrXi:autosomal translocations result in a 2:1 female-to-male ratio of TFE3 fusions involving autosomal partner genes and account for the female predominance of tRCC. Our results highlight how X chromosome genetics constrains somatic chrX alterations and underlies cancer sex differences.

Progressive Pulmonary Fibrosis Is Caused by Elevated Mechanical Tension on Alveolar Stem Cells.

Fibrosis can develop in most organs and causes organ failure. The most common type of lung fibrosis is known as idiopathic pulmonary fibrosis, in which fibrosis starts at the lung periphery and then progresses toward the lung center, eventually causing respiratory failure. Little is known about the mechanisms underlying the pathogenesis and periphery-to-center progression of the disease. Here we discovered that loss of Cdc42 function in alveolar stem cells (AT2 cells) causes periphery-to-center progressive lung fibrosis. We further show that Cdc42-null AT2 cells in both post-pneumonectomy and untreated aged mice cannot regenerate new alveoli, resulting in sustained exposure of AT2 cells to elevated mechanical tension. We demonstrate that elevated mechanical tension activates a TGF-ß signaling loop in AT2 cells, which drives the periphery-to-center progression of lung fibrosis. Our study establishes a direct mechanistic link between impaired alveolar regeneration, mechanical tension, and progressive lung fibrosis.

Stellar initial mass function varies with metallicity and time.

Most structural and evolutionary properties of galaxies strongly rely on the stellar initial mass function (IMF), namely the distribution of the stellar mass formed in each episode of star formation1-4. The IMF shapes the stellar population in all stellar systems, and so has become one of the most fundamental concepts of modern astronomy. Both constant and variable IMFs across different environments have been claimed despite a large number of theoretical5-7 and observational efforts8-15. However, the measurement of the IMF in Galactic stellar populations has been limited by the relatively small number of photometrically observed stars, leading to high uncertainties12-16. Here we report a star-counting result based on approximately 93,000 spectroscopically observed M-dwarf stars, an order of magnitude more than previous studies, in the 100-300 parsec solar neighbourhood. We find unambiguous evidence of a variable IMF that depends on both metallicity and stellar age. Specifically, the stellar population formed at early times contains fewer low-mass stars compared with the canonical IMF, independent of stellar metallicities. In more recent times, however, the proportion of low-mass stars increases with stellar metallicity. The variable abundance of low-mass stars in our Milky Way establishes a powerful benchmark for models of star formation and can heavily affect results in Galactic chemical-enrichment modelling, mass estimation of galaxies and planet-formation efficiency.

Morphometric brain organization across the human lifespan reveals increased dispersion linked to cognitive performance.

The human brain is organized as segregation and integration units and follows complex developmental trajectories throughout life. The cortical manifold provides a new means of studying the brain's organization in a multidimensional connectivity gradient space. However, how the brain's morphometric organization changes across the human lifespan remains unclear. Here, leveraging structural magnetic resonance imaging scans from 1,790 healthy individuals aged 8 to 89 years, we investigated age-related global, within- and between-network dispersions to reveal the segregation and integration of brain networks from 3D manifolds based on morphometric similarity network (MSN), combining multiple features conceptualized as a "fingerprint" of an individual's brain. Developmental trajectories of global dispersion unfolded along patterns of molecular brain organization, such as acetylcholine receptor. Communities were increasingly dispersed with age, reflecting more disassortative morphometric similarity profiles within a community. Increasing within-network dispersion of primary motor and association cortices mediated the influence of age on the cognitive flexibility of executive functions. We also found that the secondary sensory cortices were decreasingly dispersed with the rest of the cortices during aging, possibly indicating a shift of secondary sensory cortices across the human lifespan from an extreme to a more central position in 3D manifolds. Together, our results reveal the age-related segregation and integration of MSN from the perspective of a multidimensional gradient space, providing new insights into lifespan changes in multiple morphometric features of the brain, as well as the influence of such changes on cognitive performance.

Two-billion-year-old volcanism on the Moon from Chang'e-5 basalts.

The Moon has a magmatic and thermal history that is distinct from that of the terrestrial planets1. Radioisotope dating of lunar samples suggests that most lunar basaltic magmatism ceased by around 2.9-2.8 billion years ago (Ga)2,3, although younger basalts between 3 Ga and 1 Ga have been suggested by crater-counting chronology, which has large uncertainties owing to the lack of returned samples for calibration4,5. Here we report a precise lead-lead age of 2,030 ± 4 million years ago for basalt clasts returned by the Chang'e-5 mission, and a 238U/204Pb ratio (µ value)6 of about 680 for a source that evolved through two stages of differentiation. This is the youngest crystallization age reported so far for lunar basalts by radiometric dating, extending the duration of lunar volcanism by approximately 800-900 million years. The µ value of the Chang'e-5 basalt mantle source is within the range of low-titanium and high-titanium basalts from Apollo sites (µ value of about 300-1,000), but notably lower than those of potassium, rare-earth elements and phosphorus (KREEP) and high-aluminium basalts7 (µ value of about 2,600-3,700), indicating that the Chang'e-5 basalts were produced by melting of a KREEP-poor source. This age provides a pivotal calibration point for crater-counting chronology in the inner Solar System and provides insight on the volcanic and thermal history of the Moon.

The Arabidopsis Rab protein RABC1 affects stomatal development by regulating lipid droplet dynamics.

Lipid droplets (LDs) are evolutionarily conserved organelles that serve as hubs of cellular lipid and energy metabolism in virtually all organisms. Mobilization of LDs is important in light-induced stomatal opening. However, whether and how LDs are involved in stomatal development remains unknown. We show here that Arabidopsis thaliana LIPID DROPLETS AND STOMATA 1 (LDS1)/RABC1 (At1g43890) encodes a member of the Rab GTPase family that is involved in regulating LD dynamics and stomatal morphogenesis. The expression of RABC1 is coordinated with the different phases of stomatal development. RABC1 targets to the surface of LDs in response to oleic acid application in a RABC1GEF1-dependent manner. RABC1 physically interacts with SEIPIN2/3, two orthologues of mammalian seipin, which function in the formation of LDs. Disruption of RABC1, RABC1GEF1, or SEIPIN2/3 resulted in aberrantly large LDs, severe defects in guard cell vacuole morphology, and stomatal function. In conclusion, these findings reveal an aspect of LD function and uncover a role for lipid metabolism in stomatal development in plants.

Divergent suicidal symptomatic activations converge on somato-cognitive action network in depression.

Individuals with depression have the highest lifetime prevalence of suicide attempts (SA) among mental illnesses. Numerous neuroimaging studies have developed biomarkers from task-related neural activation in depressive patients with SA, but the findings are inconsistent. Empowered by the contemporary interconnected view of depression as a neural system disorder, we sought to identify a specific brain circuit utilizing published heterogeneous neural activations. We systematically reviewed all published cognitive and emotional task-related functional MRI studies that investigated differences in the location of neural activations between depressive patients with and without SA. We subsequently mapped an underlying brain circuit functionally connecting to each experimental activation using a large normative connectome database (n = 1000). The identified SA-related functional network was compared to the network derived from the disease control group. Finally, we decoded this convergent functional connectivity network using microscale transcriptomic and chemo-architectures, and macroscale psychological processes. We enrolled 11 experimental tasks from eight studies, including depressive patients with SA (n = 147) and without SA (n = 196). The heterogeneous SA-related neural activations localized to the somato-cognitive action network (SCAN), exhibiting robustness to little perturbations and specificity for depression. Furthermore, the SA-related functional network was colocalized with brain-wide gene expression involved in inflammatory and immunity-related biological processes and aligned with the distribution of the GABA and noradrenaline neurotransmitter systems. The findings demonstrate that the SA-related functional network of depression is predominantly located at the SCAN, which is an essential implication for understanding depressive patients with SA.

TWAS Atlas: a curated knowledgebase of transcriptome-wide association studies.

Transcriptome-wide association studies (TWASs), as a practical and prevalent approach for detecting the associations between genetically regulated genes and traits, are now leading to a better understanding of the complex mechanisms of genetic variants in regulating various diseases and traits. Despite the ever-increasing TWAS outputs, there is still a lack of databases curating massive public TWAS information and knowledge. To fill this gap, here we present TWAS Atlas (https://ngdc.cncb.ac.cn/twas/), an integrated knowledgebase of TWAS findings manually curated from extensive literature. In the current implementation, TWAS Atlas collects 401,266 high-quality human gene-trait associations from 200 publications, covering 22,247 genes and 257 traits across 135 tissue types. In particular, an interactive knowledge graph of the collected gene-trait associations is constructed together with single nucleotide polymorphism (SNP)-gene associations to build up comprehensive regulatory networks at multi-omics levels. In addition, TWAS Atlas, as a user-friendly web interface, efficiently enables users to browse, search and download all association information, relevant research metadata and annotation information of interest. Taken together, TWAS Atlas is of great value for promoting the utility and availability of TWAS results in explaining the complex genetic basis as well as providing new insights for human health and disease research.

GMFB/AKT/TGF-ß3 in Müller cells mediated early retinal degeneration in a streptozotocin-induced rat diabetes model.

Retinal degeneration, characterized by Müller cell gliosis and photoreceptor apoptosis, is considered an early event in diabetic retinopathy (DR). Our previous study proposed that GMFB may mediate diabetic retinal degeneration. This study identified GMFB as a sensitive and functional gliosis marker for DR. Compared to the wild type (WT) group, Gmfb knockout (KO) significantly improved visual function, attenuated gliosis, reduced the apoptosis of neurons, and decreased the mRNA levels of tumor necrosis factor α (Tnf-α) and interleukin-1ß (Il-1ß) in diabetic retinas. Tgf-ß3 was enriched by hub genes using RNA sequencing in primary WT and KO Müller cells. Gmfb KO significantly upregulated the transforming growth factor (TGF)-ß3 protein level via the AKT pathway. The protective effect of TGF-ß3 in the vitreous resulted in significantly improved visual function and decreased the number of apoptotic cells in the diabetic retina. The protection of Gmfb KO in primary Müller cells against high glucose (HG)-induced photoreceptor apoptosis was partially counteracted by TGF-ß3 antibody and administration of TGFBR1/2 inhibitors. Nuclear receptor subfamily 3 group C member 1 (NR3C1) binds to the promoter region of Gmfb and regulates Gmfb mRNA at the transcriptional level. NR3C1 was increased in the retinas of early diabetic rats but decreased in the retinas of late diabetic rats. N'-[(1E)-(3-Methoxyphenyl)Methylene]-3-Methyl-1H-Pyrazole-5-Carbohydrazide (DS-5) was identified as an inhibitor of GMFB, having a protective role in DR. We demonstrated that GMFB/AKT/TGF-ß3 mediated early diabetic retinal degeneration in diabetic rats. This study provides a novel therapeutic strategy for treating retinal degeneration in patients with DR.

Novel humanized monoclonal antibodies against ROR1 for cancer therapy.

BACKGROUND: Overexpression of receptor tyrosine kinase-like orphan receptor 1 (ROR1) contributes to cancer cell proliferation, survival and migration, playing crucial roles in tumor development. ROR1 has been proposed as a potential therapeutic target for cancer treatment. This study aimed to develop novel humanized ROR1 monoclonal antibodies and investigate their anti-tumor effects. METHODS: ROR1 expression in tumor tissues and cell lines was analyzed by immunohistochemistry and flow cytometry. Antibodies from mouse hybridomas were humanized by the complementarity-determining region (CDR) grafting technique. Surface plasmon resonance spectroscopy, ELISA assay and flow cytometry were employed to characterize humanized antibodies. In vitro cellular assay and in vivo mouse experiment were conducted to comprehensively evaluate anti-tumor activity of these antibodies. RESULTS: ROR1 exhibited dramatically higher expression in lung adenocarcinoma, liver cancer and breast cancer, and targeting ROR1 by short-hairpin RNAs significantly inhibited proliferation and migration of cancer cells. Two humanized ROR1 monoclonal antibodies were successfully developed, named h1B8 and h6D4, with high specificity and affinity to ROR1 protein. Moreover, these two antibodies effectively suppressed tumor growth in the lung cancer xenograft mouse model, c-Myc/Alb-cre liver cancer transgenic mouse model and MMTV-PyMT breast cancer mouse model. CONCLUSIONS: Two humanized monoclonal antibodies targeting ROR1, h1B8 and h6D4, were successfully developed and exhibited remarkable anti-tumor activity in vivo.

High resolution crystal structure of BRD4-BD1 in complex with a novel inhibitor precursor.

The inhibition of BRD4 bromodomain is an effective therapeutic strategy for a variety of diseases in which BRD4 are implicated. Herein, we identified a small-molecule BRD4 inhibitor hit named compound 3 using high-throughput screening. The 1.6 Å resolution co-crystal structure confirmed that the compound occupies the KAc recognition pockets of BRD4 by forming key hydrogen bonds with Asn140 and engaging in hydrophobic interactions, thus impedes the binding of acetylated lysine to BRD4. These findings suggest compound 3 can be a lead compound to develop a structurally novel BRD4 inhibitors.

Antimicrobial efficacy of aloe-emodin mediated photodynamic therapy against antibiotic-resistant Pseudomonas aeruginosa in vitro.

Multidrug-resistant Pseudomonas aeruginosa is a common pathogen that causes topical infections following burn injuries. Antimicrobial photodynamic therapy (aPDT) has emerged as a promising approach for treating antibiotic-resistant bacterial infections. The objective of this study was to evaluate the aPDT efficacy of aloe-emodin (AE), which is a photosensitizer extracted from traditional Chinese herbs, on antibiotic-sensitive and antibiotic-resistant P. aeruginosa in vitro. In this study, we confirmed the effectiveness of AE-mediated aPDT against both standard and MDR P. aeruginosa, explored the effects of irradiation time and AE concentration on bacterial survival in AE-mediated aPDT, and observed the structural damage of P. aeruginosa by using transmission electron microscope. Our results showed that neither AE nor light irradiation alone caused cytotoxic effects on P. aeruginosa. However, AE-mediated aPDT effectively inactivated both antibiotic-sensitive and antibiotic-resistant P. aeruginosa. The transmission electron microscope investigation showed that aPDT mediated by AE primarily caused damage to the cytoplasm and cell membrane. Our findings suggest that AE is a photosensitizer in the aPDT of MDR P. aeruginosa-caused topical infections following burn injuries. Future investigations will concentrate on the safety and efficacy of AE-mediated aPDT in animal models and clinical trials.

An efficient curriculum learning-based strategy for molecular graph learning.

Computational methods have been widely applied to resolve various core issues in drug discovery, such as molecular property prediction. In recent years, a data-driven computational method-deep learning had achieved a number of impressive successes in various domains. In drug discovery, graph neural networks (GNNs) take molecular graph data as input and learn graph-level representations in non-Euclidean space. An enormous amount of well-performed GNNs have been proposed for molecular graph learning. Meanwhile, efficient use of molecular data during training process, however, has not been paid enough attention. Curriculum learning (CL) is proposed as a training strategy by rearranging training queue based on calculated samples' difficulties, yet the effectiveness of CL method has not been determined in molecular graph learning. In this study, inspired by chemical domain knowledge and task prior information, we proposed a novel CL-based training strategy to improve the training efficiency of molecular graph learning, called CurrMG. Consisting of a difficulty measurer and a training scheduler, CurrMG is designed as a plug-and-play module, which is model-independent and easy-to-use on molecular data. Extensive experiments demonstrated that molecular graph learning models could benefit from CurrMG and gain noticeable improvement on five GNN models and eight molecular property prediction tasks (overall improvement is 4.08%). We further observed CurrMG's encouraging potential in resource-constrained molecular property prediction. These results indicate that CurrMG can be used as a reliable and efficient training strategy for molecular graph learning. Availability: The source code is available in https://github.com/gu-yaowen/CurrMG.

Integrative multi-omics analysis identifies genetically supported druggable targets and immune cell specificity for myasthenia gravis.

BACKGROUND: Myasthenia gravis (MG) is a chronic autoimmune disorder characterized by fluctuating muscle weakness. Despite the availability of established therapies, the management of MG symptoms remains suboptimal, partially attributed to lack of efficacy or intolerable side-effects. Therefore, new effective drugs are warranted for treatment of MG. METHODS: By employing an analytical framework that combines Mendelian randomization (MR) and colocalization analysis, we estimate the causal effects of blood druggable expression quantitative trait loci (eQTLs) and protein quantitative trait loci (pQTLs) on the susceptibility of MG. We subsequently investigated whether potential genetic effects exhibit cell-type specificity by utilizing genetic colocalization analysis to assess the interplay between immune-cell-specific eQTLs and MG risk. RESULTS: We identified significant MR results for four genes (CDC42BPB, CD226, PRSS36, and TNFSF12) using cis-eQTL genetic instruments and three proteins (CTSH, PRSS8, and CPN2) using cis-pQTL genetic instruments. Six of these loci demonstrated evidence of colocalization with MG susceptibility (posterior probability > 0.80). We next undertook genetic colocalization to investigate cell-type-specific effects at these loci. Notably, we identified robust evidence of colocalization, with a posterior probability of 0.854, linking CTSH expression in TH2 cells and MG risk. CONCLUSIONS: This study provides crucial insights into the genetic and molecular factors associated with MG susceptibility, singling out CTSH as a potential candidate for in-depth investigation and clinical consideration. It additionally sheds light on the immune-cell regulatory mechanisms related to the disease. However, further research is imperative to validate these targets and evaluate their feasibility for drug development.

Multi-feature sparse representation based on adaptive graph constraint for cropland delineation.

Cropland delineation is the basis of agricultural resource surveys and many algorithms for plot identification have been studied. However, there is still a vacancy in SRC for cropland delineation with the high-dimensional data extracted from UAV RGB photographs. In order to address this problem, a new sparsity-based classification algorithm is proposed. Firstly, the multi-feature association sparse model is designed by extracting the multi-feature of UAV RGB photographs. Next, the samples with similar characteristics are hunted with the breadth-first principle to construct a shape-adaptive window for each test. Finally, an algorithm, multi-feature sparse representation based on adaptive graph constraint (AMFSR), is obtained by solving the optimal objective iteratively. Experimental results show that the overall accuracy (OA) of AMFSR reaches 92.3546% and the Kappa is greater than 0.8. Furthermore, experiments have demonstrated that the model also has a generalization ability.

Intravoxel incoherent motion imaging to assess the acute effects of moderate-intensity continuous training and high-intensity interval training on thigh muscles.

This study investigated the use of intravoxel incoherent motion imaging (IVIM) to compare skeletal muscle perfusion during and after high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) to determine the impact on fat oxidation outcomes. Twenty overweight volunteers were recruited for the study. Each participant received one HIIT intervention and one MICT intervention using a cycling ergometer. Participants underwent a magnetic resonance imaging scan before, immediately after, and 1 and 2 h after each intervention. The IVIM parameters (D, fD*) of the rectus femoris, vastus lateralis, and biceps femoris long head were obtained. Changes in IVIM parameters of these muscles after both exercise interventions were compared using a two-factor repeated measures analysis of variance. In the rectus femoris, the fD* increased immediately after exercise intervention (d = 0.69 × 10-3  mm2 /s, p < 0.0083) and 2 h after exercise intervention (d = 0.64 × 10-3  mm2 /s, p < 0.0083) compared with before exercise. The increase in the fD* in the HIIT group was greater than that in the MICT group (d = 0.32, p = 0.023). In the vastus lateralis, the fD* increased immediately after the exercise intervention (d = 0.53 × 10-3  mm2 /s, p < 0.001) and returned to the pre-exercise level 1 h after exercising. The increase in the fD* in the HIIT group was lower than that in the MICT group (d = -0.21, p = 0.015). For the biceps femoris long head, the fD* was not significantly different between the two exercise interventions before and after exercise. Furthermore, the fD* 60 min after the HIIT intervention correlated with maximal oxygen consumption (VO2max), whereas fD* immediately after the MICT intervention correlated with VO2max. In summary, IVIM parameters can be used to evaluate differences in muscle perfusion between HIIT and MICT, and show a correlation with VO2max.

Abnormal dermal microvascular endothelial cells in psoriatic excessive angiogenesis.

Psoriasis is characterized by excessive angiogenesis, with increased distortion and dilation of the dermal blood vessels. These vascular alterations are ascribed, at least in part, to the changes in dermal microvascular endothelial cell functions. However, despite the recognition of vascular normalization as an emerging strategy for the treatment of psoriasis, in-depth studies of human dermal microvascular endothelial cells (HDMECs) have been missing. The difficulty of isolation and culture of HDMECs has impeded the study of endothelial dysfunction in psoriasis. Researchers have done a great deal of work to study the abnormal characteristics of keratinocytes, fibroblasts, and leukocytes in psoriatic skin tissue. Recently, with successful isolation of HDMECs from psoriasis, great progress has been made in the elucidation of the pathogenic role of these cells in psoriasis. It is of great therapeutic significance to study the molecular mechanism of HDMECs in psoriasis. We review here the abnormalities of HDMECs in psoriasis.

Conversion chemoradiotherapy combined with nab-paclitaxel plus cisplatin in patients with locally advanced borderline-resectable or unresectable esophageal squamous cell carcinoma: a phase i/ii prospective cohort study.

BACKGROUND: To evaluate the efficacy and safety of nab-paclitaxel plus cisplatin as the regimen of conversional chemoradiotherapy (cCRT) in locally advanced borderline resectable or unresectable esophageal squamous cell carcinoma (ESCC). METHODS: Patients with locally advanced ESCC (cT3­4, Nany, M0­1, M1 was limited to lymph node metastasis in the supraclavicular area) were enrolled. All the patients received the cCRT of nab-paclitaxel plus cisplatin. After the cCRT, those resectable patients received esophagectomy; those unresectable patients continued to receive the definitive chemoradiotherapy (dCRT). The locoregional control (LRC), overall survival (OS), event-free survival (EFS), distant metastasis free survival (DMFS), pathological complete response (pCR), R0 resection rate, adverse events (AEs) and postoperative complications were calculated. RESULTS: 45 patients with ESCC treated from October 2019 to May 2021 were finally included. The median follow-up time was 30.3 months. The LRC, OS, EFS, DMFS at 1 and 2 years were 81.5%, 86.6%, 64.3%, 73.2 and 72.4%, 68.8%, 44.8%, 52.7% respectively. 21 patients (46.7%) received conversional chemoradiotherapy plus surgery (cCRT+S). The pCR rate and R0 resection rate were 47.6 and 84.0%. The LRC rate at 1 and 2 years were 95.0%, 87.1% in cCRT+S patitents and 69.3%, 58.7% in dCRT patients respectively (HR, 5.14; 95%CI, 1.10-23.94; P = 0.021). The toxicities during chemoradiotherapy were tolerated, and the most common grade 3-4 toxicitiy was radiation esophagitis (15.6%). The most common postoperative complication was pleural effusion (38.1%) and no grade ≥ IIIb complications were observed. CONCLUSION: nab-paclitaxel plus cisplatin are safe as the regimen of conversional chemoradiotherapy of ESCC.

Frequency-domain terahertz optoacoustics for non-contact quantitative detection of gas, liquid, and solid samples.

Terahertz optoacoustics (THz-OA) combines the advantages of abundant molecular characteristic absorptions in a terahertz band and the low attenuation through ultrasonic detection. Frequency-domain THz-OA, benefiting from the compact and the low cost of a continuous-wave THz source, has been used in gas detection and sensing. However, liquid and solid detections are hard to achieve due to the sensitivity limitation of existing technologies. Here we present a high-sensitivity frequency-domain THz-OA system with customized optoacoustic cells to accomplish non-contact quantitative detection of gas, liquid, and solid samples. The relationships between signal amplitudes and sample concentration, volume and temperature are discussed separately, revealing a potential application of this technology.