Targeting TrkB-PSD-95 coupling to mitigate neurological disorders.

Tropomyosin receptor kinase B (TrkB) signaling plays a pivotal role in dendritic growth and dendritic spine formation to promote learning and memory. The activity-dependent release of brain-derived neurotrophic factor at synapses binds to pre- or postsynaptic TrkB resulting in the strengthening of synapses, reflected by long-term potentiation. Postsynaptically, the association of postsynaptic density protein-95 with TrkB enhances phospholipase Cγ-Ca2+/calmodulin-dependent protein kinase II and phosphatidylinositol 3-kinase-mechanistic target of rapamycin signaling required for long-term potentiation. In this review, we discuss TrkB-postsynaptic density protein-95 coupling as a promising strategy to magnify brain-derived neurotrophic factor signaling towards the development of novel therapeutics for specific neurological disorders. A reduction of TrkB signaling has been observed in neurodegenerative disorders, such as Alzheimer's disease and Huntington's disease, and enhancement of postsynaptic density protein-95 association with TrkB signaling could mitigate the observed deficiency of neuronal connectivity in schizophrenia and depression. Treatment with brain-derived neurotrophic factor is problematic, due to poor pharmacokinetics, low brain penetration, and side effects resulting from activation of the p75 neurotrophin receptor or the truncated TrkB.T1 isoform. Although TrkB agonists and antibodies that activate TrkB are being intensively investigated, they cannot distinguish the multiple human TrkB splicing isoforms or cell type-specific functions. Targeting TrkB-postsynaptic density protein-95 coupling provides an alternative approach to specifically boost TrkB signaling at localized synaptic sites versus global stimulation that risks many adverse side effects.

Prospective study of urinary incontinence recovery following endoscopic enucleation of the prostate.

OBJECTIVE: To investigate the clinical trajectories and identify risk factors linked to post-enucleation urinary incontinence (UI). PATIENTS AND METHODS: In this prospective study (April 2020 to March 2022) at a single institution, 316 consecutive patients receiving endoscopic enucleation due to benign prostatic enlargement were included. Patient information and perioperative details were collected. Follow-ups, from 1 to 6 months, assessed postoperative UI using International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form and a four-item pad questionnaire, classified per International Continence Society definitions. Logistic regression analysed predictors at 1 week, while generalised estimating equation assessed risk factors from 1 to 3 months postoperatively. RESULTS: Patients with a median prostate volume of 57 mL underwent enucleation, with 22.5% experiencing postoperative UI at 1 week, 5.6% at 3 months, decreasing to 1.9% at 6 months. Multivariable analysis identified age (>80 years), specimen weight (>70 g), en bloc with anteroposterior dissection, and anal tone (Digital Rectal Examination Scoring System score <3) as potential factors influencing UI. Subgroup analysis revealed that specimen weight was associated with both continuous and stress UI. Anal tone was related to both other types and stress UI, while overactive bladder symptoms were associated with urge UI. CONCLUSION: In summary, our study elucidates transient risk factors contributing to temporary post-enucleation UI after prostatectomy. Informed decisions and personalised interventions can effectively alleviate concerns regarding postoperative UI.

Cigarette smoke promotes IL-6-dependent lung cancer migration and osteolytic bone metastasis.

Lung cancer stands as a major contributor to cancer-related fatalities globally, with cigarette smoke playing a pivotal role in its development and metastasis. Cigarette smoke is also recognized as a risk factor for bone loss disorders like osteoporosis. However, the association between cigarette smoke and another bone loss disorder, lung cancer osteolytic bone metastasis, remains largely uncertain. Our Gene Set Enrichment Analysis (GSEA) indicated that smokers among lung cancer patients exhibited higher expression levels of bone turnover gene sets. Both The Cancer Genome Atlas (TCGA) database and our clinic samples demonstrated elevated expression of the osteolytic factor IL-6 in ever-smokers with bone metastasis among lung cancer patients. Our cellular experiments revealed that benzo[α]pyrene (B[α]P) and cigarette smoke extract (CSE) promoted IL-6 production and cell migration in lung cancer. Activation of the PI3K, Akt, and NF-κB signaling pathways was involved in cigarette smoke-augmented IL-6-dependent migration. Additionally, cigarette smoke lung cancer-secreted IL-6 promoted osteoclast formation. Importantly, blocking IL-6 abolished cigarette smoke-facilitated lung cancer osteolytic bone metastasis in vivo. Our findings provide evidence that cigarette smoke is a risk factor for osteolytic bone metastasis. Thus, inhibiting IL-6 may be a valuable therapeutic strategy for managing osteolytic bone metastasis in lung cancer patients who smoke.

Cross-species single-cell landscapes identify the pathogenic gene characteristics of inherited retinal diseases.

Introduction: Inherited retinal diseases (IRDs) affect ∼4.5 million people worldwide. Elusive pathogenic variants in over 280 genes are associated with one or more clinical forms of IRDs. It is necessary to understand the complex interaction among retinal cell types and pathogenic genes by constructing a regulatory network. In this study, we attempt to establish a panoramic expression view of the cooperative work in retinal cells to understand the clinical manifestations and pathogenic bases underlying IRDs. Methods: Single-cell RNA sequencing (scRNA-seq) data on the retinas from 35 retina samples of 3 species (human, mouse, and zebrafish) including 259,087 cells were adopted to perform a comparative analysis across species. Bioinformatic tools were used to conduct weighted gene co-expression network analysis (WGCNA), single-cell regulatory network analysis, cell-cell communication analysis, and trajectory inference analysis. Results: The cross-species comparison revealed shared or species-specific gene expression patterns at single-cell resolution, such as the stathmin family genes, which were highly expressed specifically in zebrafish Müller glias (MGs). Thirteen gene modules were identified, of which nine were associated with retinal cell types, and Gene Ontology (GO) enrichment of module genes was consistent with cell-specific highly expressed genes. Many IRD genes were identified as hub genes and cell-specific regulons. Most IRDs, especially the retinitis pigmentosa (RP) genes, were enriched in rod-specific regulons. Integrated expression and transcription regulatory network genes, such as congenital stationary night blindness (CSNB) genes GRK1, PDE6B, and TRPM1, showed cell-specific expression and transcription characteristics in either rods or bipolar cells (BCs). IRD genes showed evolutionary conservation (GNAT2, PDE6G, and SAG) and divergence (GNAT2, MT-ND4, and PDE6A) along the trajectory of photoreceptors (PRs) among species. In particular, the Leber congenital amaurosis (LCA) gene OTX2 showed high expression at the beginning of the trajectory of both PRs and BCs. Conclusion: We identified molecular pathways and cell types closely connected with IRDs, bridging the gap between gene expression, genetics, and pathogenesis. The IRD genes enriched in cell-specific modules and regulons suggest that these diseases share common etiological bases. Overall, mining of interspecies transcriptome data reveals conserved transcriptomic features of retinas across species and promising applications in both normal retina anatomy and retina pathology.

Long Noncoding RNA CRNDE Promotes Gastric Cancer Progression through Targeting miR-136-5p/MIEN1.

Background: Long noncoding RNAs (lncRNAs) contribute to the initiation and progression of gastric cancer (GC). The purpose of this study is to examine the potential role of lncRNA colorectal neoplasia differentially expressed (CRNDE) in modulating the expression of migration and invasion enhancer 1 (MIEN1) through the suppression of miR-136-5p in GC. Methods: The biological roles of CRNDE, miR-136-5p, and MIEN1 in GC were assessed both in laboratory settings and through the examination of clinical samples. Results: CRNDE was found to be significantly increased in GC tissues, and this upregulation was associated with an unfavorable prognosis of GC patients. In vitro experiments showed that inhibiting cell growth and migration, along with promoting apoptosis in GC cells, could be achieved by either disabling CRNDE or MIEN1, or by increasing the expression of miR-136-5p. MIEN1 is a specific recipient of miR-136-5p, and the anticancer effects of miR-136-5p can be counteracted by the increased expression of MIEN1. Through the examination of clinical specimens, it has been observed that there is a significant positive correlation between the expression of MIEN1 and CRNDE. In contrast, miR-136-5p expression in GC tissues shows a negative correlation. Conclusion: A previously unexplored therapeutic target for GC involves the CRNDE/miR-136-5p/MIEN1 signal transduction cascade.

Systematic transcriptome profiling of hPSC-derived osteoblasts unveils CORIN's mastery in governing osteogenesis through CEBPD modulation.

The commitment of stem cells to differentiate into osteoblasts is a highly regulated and complex process that involves the coordination of extrinsic signals and intrinsic transcriptional machinery. While rodent osteoblastic differentiation has been extensively studied, research on human osteogenesis has been limited by cell sources and existing models. Here, we systematically dissect human pluripotent stem cell-derived osteoblasts to identify functional membrane proteins and their downstream transcriptional networks involved in human osteogenesis. Our results reveal an enrichment of type II transmembrane serine protease CORIN in humans but not rodent osteoblasts. Functional analyses demonstrated that CORIN depletion significantly impairs osteogenesis. Genome-wide chromatin immunoprecipitation enrichment and mechanistic studies show that p38 MAPK-mediated CCAAT enhancer binding protein delta (CEBPD) upregulation is required for CORIN-modulated osteogenesis. Contrastingly, the type I transmembrane heparan sulfate proteoglycan SDC1 enriched in mesenchymal stem cells exerts a negative regulatory effect on osteogenesis through a similar mechanism. Chromatin immunoprecipitation-seq, bulk and single-cell transcriptomes, and functional validations indicated that CEBPD plays a critical role in controlling osteogenesis. In summary, our findings uncover previously unrecognized CORIN-mediated CEBPD transcriptomic networks in driving human osteoblast lineage commitment.

Astrocyte-secreted C3 signaling impairs neuronal development and cognition in autoimmune diseases.

Neuromyelitis optica (NMO) arises from primary astrocytopathy induced by autoantibodies targeting the astroglial protein aquaporin 4 (AQP4), leading to severe neurological sequelae such as vision loss, motor deficits, and cognitive decline. Mounting evidence has shown that dysregulated activation of complement components contributes to NMO pathogenesis. Complement C3 deficiency has been shown to protect against hippocampal neurodegeneration and cognitive decline in neurodegenerative disorders (e.g., Alzheimer's disease, AD) and autoimmune diseases (e.g., multiple sclerosis, MS). However, whether inhibiting the C3 signaling can ameliorate cognitive dysfunctions in NMO remains unclear. In this study, we found that the levels of C3a, a split product of C3, significantly correlate with cognitive impairment in our patient cohort. In response to the stimulation of AQP4 autoantibodies, astrocytes were activated to secrete complement C3, which inhibited the development of cultured neuronal dendritic arborization. NMO mouse models exhibited reduced adult hippocampal newborn neuronal dendritic and spine development, as well as impaired learning and memory functions, which could be rescued by decreasing C3 levels in astrocytes. Mechanistically, we found that C3a engaged with C3aR to impair neuronal development by dampening ß-catenin signalling. Additionally, inhibition of the C3-C3aR-GSK3ß/ß-catenin cascade restored neuronal development and ameliorated cognitive impairments. Collectively, our results suggest a pivotal role of the activation of the C3-C3aR network in neuronal development and cognition through mediating astrocyte and adult-born neuron communication, which represents a potential therapeutic target for autoimmune-related cognitive impairment diseases.

ScRNA-Seq Analyses Define the Role of GATA3 in iNKT Cell Effector Lineage Differentiation.

While the transcription factor GATA-3 is well-established for its crucial role in T cell development, its specific influence on invariant natural killer T (iNKT) cells remains relatively unexplored. Using flow cytometry and single-cell transcriptomic analysis, we demonstrated that GATA-3 deficiency in mice leads to the absence of iNKT2 and iNKT17 cell subsets, as well as an altered distribution of iNKT1 cells. Thymic iNKT cells lacking GATA-3 exhibited diminished expression of PLZF and T-bet, key transcription factors involved in iNKT cell differentiation, and reduced production of Th2, Th17, and cytotoxic effector molecules. Single-cell transcriptomics revealed a comprehensive absence of iNKT17 cells, a substantial reduction in iNKT2 cells, and an increase in iNKT1 cells in GATA-3-deficient thymi. Differential expression analysis highlighted the regulatory role of GATA-3 in T cell activation signaling and altered expression of genes critical for iNKT cell differentiation, such as Icos, Cd127, Eomes, and Zbtb16. Notably, restoration of Icos, but not Cd127, expression could rescue iNKT cell development in GATA-3-deficient mice. In conclusion, our study demonstrates the pivotal role of GATA-3 in orchestrating iNKT cell effector lineage differentiation through the regulation of T cell activation pathways and Icos expression, providing insights into the molecular mechanisms governing iNKT cell development and function.

Interlinked destinies: How ubiquitin-proteasome and autophagy systems underpin neurocognitive outcomes.

The protein homeostasis, or proteostasis, is maintained through the coupling of two pivotal systems: the ubiquitin-proteasome and autophagy. Cumulative evidence has suggested E3 ubiquitin ligases specifically play a central role in this coupling, ensuring the regulation of synaptic and cognitive functions. Defects in these ligases have been identified as hallmarks in a range of neurodevelopmental and neurodegenerative disorders. Recent literature has spotlighted the E3 ubiquitin ligase, UBE3A, as a key player in this domain. Dysregulation or loss of UBE3A function has been linked to disrupted proteostasis, leading to synaptic and cognitive anomalies. Notably, such defects are prominently observed in conditions like Angelman syndrome, a neurodevelopmental disorder characterized by severe cognitive impairments. The emerging understanding of UBE3A's role in bridging the ubiquitin-proteasome and autophagy systems offers a promising therapeutic avenue. Targeting the defective pathways caused by UBE3A loss could pave the way for innovative treatments, potentially ameliorating the cognitive deficits observed in neurological disorders like Angelman syndrome. As the scientific community delves deeper into the molecular intricacies of E3 ubiquitin ligases, there is burgeoning hope for devising effective interventions for associated neurological conditions.

A comparative study of an advanced skin imaging system in diagnosing facial pigmentary and inflammatory conditions.

Visual assessment, while the primary method for pigmentation and erythema evaluation in clinical practice, is subjective, time-consuming, and may lead to variability in observations among clinicians. Objective and quantitative techniques are required for a precise evaluation of the disease's severity and the treatment's efficacy. This research examines the precision and utility of a newly developed skin imaging system in assessing pigmentation and erythema. Sixty participants were recruited, and their facial images were analyzed with the new OBSERV 520 x skin imaging system, compared to DERMACATCH for regional analysis and VISIA for full-face examination. The degree of skin pigmentation was clinically graded using the MASI scores evaluated by dermatologists. The data revealed positive correlations between the novel skin imaging system and the two conventional instruments in quantifying pigmentation and erythema, whether in regional or full-face analysis. Furthermore, the new skin imaging system positively correlated with the clinical MASI scores (r = 0.4314, P < 0.01). In contrast, our study found no significant correlation between the traditional system and clinical assessment, indicating a more substantial capacity for hyperpigmentation assessment in the new system. Our study validates the innovative skin imaging system's accuracy in evaluating pigmentation and erythema, demonstrating its feasibility for quantitative evaluation in both clinical and research purposes.

Peptidomimetic inhibitors targeting TrkB/PSD-95 signaling improves cognition and seizure outcomes in an Angelman Syndrome mouse model.

Angelman syndrome (AS) is a rare genetic neurodevelopmental disorder with profoundly debilitating symptoms with no FDA-approved cure or therapeutic. Brain-derived neurotrophic factor (BDNF), and its receptor TrkB, have a well-established role as regulators of synaptic plasticity, dendritic outgrowth, dendritic spine formation and maintenance. Previously, we reported that the association of PSD-95 with TrkB is critical for intact BDNF signaling in the AS mouse model, as illustrated by attenuated PLCγ and PI3K signaling and intact MAPK pathway signaling. These data suggest that drugs tailored to enhance the TrkB-PSD-95 interaction may provide a novel approach for the treatment of AS and a variety of NDDs. To evaluate this critical interaction, we synthesized a class of high-affinity PSD-95 ligands that bind specifically to the PDZ3 domain of PSD-95, denoted as Syn3 peptidomimetic ligands. We evaluated Syn3 and its analog D-Syn3 (engineered using dextrorotary (D)-amino acids) in vivo using the Ube3a exon 2 deletion mouse model of AS. Following systemic administration of Syn3 and D-Syn3, we demonstrated improvement in the seizure domain of AS. Learning and memory using the novel object recognition assay also illustrated improved cognition following Syn3 and D-Syn3, along with restored long-term potentiation. Finally, D-Syn3 treated mice showed a partial rescue in motor learning. Neither Syn3 nor D-Syn3 improved gross exploratory locomotion deficits, nor gait impairments that have been well documented in the AS rodent models. These findings highlight the need for further investigation of this compound class as a potential therapeutic for AS and other genetic NDDs.

A social-ecological approach for identifying and mapping ecosystem service trade-offs and conservation priorities in peri-urban areas.

Considering both ecological and social dimensions in the assessment of ecosystem services (ESs) can facilitate acceptable and inclusive management strategies, especially in peri-urban areas characterized by intricate human-ecosystem interactions. A limited body of research, however, has mapped the plural values of ESs and their different types of trade-offs in such areas. This research aimed to execute an interdisciplinary analysis of the biophysical and social values of ESs in peri-urban Shanghai, China, through a social-ecological approach that integrates spatial biophysical assessment with participatory mapping. Trade-off analysis in both ES types and ES valuations were then conducted, and multicriteria decision-making was applied for conservation. Our results reveal that trade-off intensities were lower within the social values compared to the biophysical values. Within both value dimensions, relatively stronger trade-offs were found between food production and other ESs. Areas with both high biophysical and social values were infrequently observed across ESs. Based on the characteristics of diverse values, our study identified priority conservation areas and provided management implications. We argue that adopting the integrated social-ecological perspective in sustainable environmental management contributes to the realization of harmonious coexistence between people and nature in peri-urban areas.

Astrocyte-derived CHI3L1 signaling impairs neurogenesis and cognition in the demyelinated hippocampus.

Cognitive dysfunction is a feature in multiple sclerosis (MS), a chronic inflammatory demyelinating disorder. A notable aspect of MS brains is hippocampal demyelination, which is closely associated with cognitive decline. However, the mechanisms underlying this phenomenon remain unclear. Chitinase-3-like (CHI3L1), secreted by activated astrocytes, has been identified as a biomarker for MS progression. Our study investigates CHI3L1's function within the demyelinating hippocampus and demonstrates a correlation between CHI3L1 expression and cognitive impairment in patients with MS. Activated astrocytes release CHI3L1 in reaction to induced demyelination, which adversely affects the proliferation and differentiation of neural stem cells and impairs dendritic growth, complexity, and spine formation in neurons. Our findings indicate that the astrocytic deletion of CHI3L1 can mitigate neurogenic deficits and cognitive dysfunction. We showed that CHI3L1 interacts with CRTH2/receptor for advanced glycation end (RAGE) by attenuating ß-catenin signaling. The reactivation of ß-catenin signaling can revitalize neurogenesis, which holds promise for therapy of inflammatory demyelination.

A Mettl16/m6A/mybl2b/Igf2bp1 axis ensures cell cycle progression of embryonic hematopoietic stem and progenitor cells.

Prenatal lethality associated with mouse knockout of Mettl16, a recently identified RNA N6-methyladenosine (m6A) methyltransferase, has hampered characterization of the essential role of METTL16-mediated RNA m6A modification in early embryonic development. Here, using cross-species single-cell RNA sequencing analysis, we found that during early embryonic development, METTL16 is more highly expressed in vertebrate hematopoietic stem and progenitor cells (HSPCs) than other methyltransferases. In Mettl16-deficient zebrafish, proliferation capacity of embryonic HSPCs is compromised due to G1/S cell cycle arrest, an effect whose rescue requires Mettl16 with intact methyltransferase activity. We further identify the cell-cycle transcription factor mybl2b as a directly regulated by Mettl16-mediated m6A modification. Mettl16 deficiency resulted in the destabilization of mybl2b mRNA, likely due to lost binding by the m6A reader Igf2bp1 in vivo. Moreover, we found that the METTL16-m6A-MYBL2-IGF2BP1 axis controlling G1/S progression is conserved in humans. Collectively, our findings elucidate the critical function of METTL16-mediated m6A modification in HSPC cell cycle progression during early embryonic development.

Improvement Performance of p-GaN Gate High-Electron-Mobility Transistors with GaN/AlN/AlGaN Barrier Structure.

This study demonstrates a particular composited barrier structure of high-electron-mobility transistors (HEMTs) with an enhancement mode composed of p-GaN/GaN/AlN/AlGaN/GaN. The purpose of the composite barrier structure device is to increase the maximum drain current, reduce gate leakage, and achieve lower on-resistance (Ron) performance. A comparison was made between the conventional device without the composited barrier and the device with the composited barrier structure. The maximum drain current is significantly increased by 37%, and Ron is significantly reduced by 23%, highlighting the synergistic impact of the composite barrier structure on device performance improvement. This reason can be attributed to the undoped GaN (u-GaN) barrier layer beneath p-GaN, which was introduced to mitigate Mg diffusion in the capping layer, thus addressing its negative effects. Furthermore, the AlN barrier layer exhibits enhanced electrical properties, which can be attributed to the critical role of high-energy-gap properties that increase the 2DEG carrier density and block leakage pathways. These traps impact the device behavior mechanism, and the simulation for a more in-depth analysis of how the composited barrier structure brings improvement is introduced using Synopsys Sentaurus TCAD.

Combining wireless radar sleep monitoring device with deep machine learning techniques to assess obstructive sleep apnea severity.

STUDY OBJECTIVES: The gold standard for diagnosing obstructive sleep apnea (OSA) is polysomnography (PSG). However, PSG is a time-consuming method with clinical limitations. This study aimed to create a wireless radar framework to screen the likelihood of two levels of OSA severity (i.e., moderate-to-severe and severe OSA) in accordance with clinical practice standards. METHODS: We conducted a prospective, simultaneous study using the wireless radar system and PSG in a Northern Taiwan sleep center, involving 196 patients. The wireless radar sleep monitor, incorporating hybrid models such as deep neural decision trees, estimated the respiratory disturbance index relative to the total sleep time established by PSG (RDIPSG_TST), by analyzing continuous-wave signals indicative of breathing patterns. Analyses were performed to examine the correlation and agreement between the RDIPSG_TST and apnea-hypopnea index (AHI), results obtained through PSG. Cut-off thresholds for RDIPSG_TST were determined using Youden's index, and multiclass classification was performed, after which the results were compared. RESULTS: A strong correlation (ρ = 0.91) and agreement (average difference of 0.59 events/h) between AHI and RDIPSG_TST were identified. In terms of the agreement between the two devices, the average difference between PSG-based AHI and radar-based RDIPSG_TST was 0.59 events/h, while 187 out of 196 cases (95.41%) fell within the 95% confidence interval of differences. A moderate-to-severe OSA model achieved an accuracy of 90.3% (cut-off threshold for RDIPSG_TST: 19.2 events/h). A severe OSA model achieved an accuracy of 92.4% (cut-off threshold for RDIPSG_TST: 28.86 events/h). The mean accuracy of multiclass classification performance using these cut-off thresholds was 83.7%. CONCLUSIONS: The wireless-radar-based sleep monitoring device, with cut-off thresholds, can provide rapid OSA screening with acceptable accuracy, and also alleviate the burden on PSG capacity. However, to independently apply this framework, the function of determining the radar-based total sleep time requires further optimizations and verification in future work.

Sensitization of cancer cells to paclitaxel-induced apoptosis by canagliflozin.

Cancer cells consume more glucose and usually overexpress glucose transporters which have become potential targets for the development of anticancer drugs. It has been demonstrated that selective SGLT2 inhibitors, such as canagliflozin and dapagliflozin, display anticancer activity. Here we demonstrated that canagliflozin and dapagliflozin synergistically enhanced the growth inhibitory effect of paclitaxel in cancer cells including ovarian cancer and oral squamous cell carcinoma cells. Canagliflozin also inhibited glucose uptake via GLUTs. The combination of paclitaxel and WZB117, a GLUT inhibitor, exhibited a strong synergy, supporting the notion that inhibition of GLUTs by canagliflozin may also account for the synergy between canagliflozin and paclitaxel. Mechanistic studies in ES-2 ovarian cancer cells revealed that canagliflozin potentiated paclitaxel-induced apoptosis and DNA damaging effect. Paclitaxel in the nanomolar range elevated abnormal mitotic cells as well as aneuploid cells, and canagliflozin further enhanced this effect. Furthermore, canagliflozin downregulated cyclin B1 and phospho-BUBR1 upon spindle assembly checkpoint (SAC) activation by paclitaxel, and may consequently impair SAC. Thus, paclitaxel disturbed microtubule dynamics and canagliflozin compromised SAC activity, together they may induce premature mitotic exit, accumulation of aneuploid cells with DNA damage, and ultimately apoptosis.

The splicing factor Prpf31 is required for hematopoietic stem and progenitor cell expansion during zebrafish embryogenesis.

Pre-mRNA splicing is a precise regulated process and is crucial for system development and homeostasis maintenance. Mutations in spliceosomal components have been found in various hematopoietic malignancies (HMs) and have been considered as oncogenic derivers of HMs. However, the role of spliceosomal components in normal and malignant hematopoiesis remains largely unknown. Pre-mRNA processing factor 31 (PRPF31) is a constitutive spliceosomal component, which mutations are associated with autosomal dominant retinitis pigmentosa. PRPF31 was found to be mutated in several HMs, but the function of PRPF31 in normal hematopoiesis has not been explored. In our previous study, we generated a prpf31 knockout (KO) zebrafish line and reported that Prpf31 regulates the survival and differentiation of retinal progenitor cells by modulating the alternative splicing of genes involved in mitosis and DNA repair. In this study, by using the prpf31 KO zebrafish line, we discovered that prpf31 KO zebrafish exhibited severe defects in hematopoietic stem and progenitor cell (HSPC) expansion and its sequentially differentiated lineages. Immunofluorescence results showed that Prpf31-deficient HSPCs underwent malformed mitosis and M phase arrest during HSPC expansion. Transcriptome analysis and experimental validations revealed that Prpf31 deficiency extensively perturbed the alternative splicing of mitosis-related genes. Collectively, our findings elucidate a previously undescribed role for Prpf31 in HSPC expansion, through regulating the alternative splicing of mitosis-related genes.

Combined bioinformatics and machine learning methodologies reveal prognosis-related ceRNA network and propose ABCA8, CAT, and CXCL12 as independent protective factors against osteosarcoma.

BACKGROUND: Aberrant circular RNA (circRNA) acts as an oncogene or suppressor during neoplasm initiation and development. However, the functions of most circRNAs in osteosarcoma (OS) remain unclear. OBJECTIVES: We aimed to investigate the expression, molecular functions and mechanisms underlying circRNAs in OS. MATERIAL AND METHODS: Network interaction, pathway enrichment and regression analyses were performed to determine differentially expressed (DE) circRNAs, microRNAs (miRNAs) and messenger RNAs (mRNAs). We constructed competitive endogenous RcodeNA (ceRNA) networks and integrated patient clinical data to analyze the relationship between the networks and prognosis. The circRNA, miRNA and mRNA data were retrieved from Gene Expression Omnibus (GEO) microarray datasets. A circRNA-miRNA-mRNA interaction network was established and visualized using miRNet. Protein interactions were investigated using STRING and Cytoscape, and hub genes were identified using the MCODE plug-in. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes (KEGG) and Reactome pathway analyses were performed to determine the DEmRNAs. LIMMA and RobustRankAggreg were used to screen for DERNAs. Node genes in the interaction network were analyzed using least absolute shrinkage and selection operator (LASSO) and Cox regression to obtain OS-related ceRNA networks. RESULTS: We identified 9 DEcircRNAs, 243 DEmiRNAs and 211 DEmRNAs. We found that a ceRNA subnetwork, based on 1 circRNA, 1 miRNA and 8 mRNAs, was closely associated with OS prognosis. Integrating the proportional hazards model and survival analysis revealed 3 independent protective factors: adenosine triphosphate (ATP)-binding cassette sub-family A member 8 (ABCA8), catalase (CAT) and C-X-C motif chemokine ligand 12 (CXCL12). CONCLUSIONS: Our study provides novel insights into circRNA-related ceRNA networks and identifies potential prognostic biomarkers of OS.

Photocatalytic selective synthesis of (E)-ß-aminovinyl sulfones and (E)-ß-amidovinyl sulfones using Ru(bpy)3Cl2 as the catalyst.

Selectively producing a variety of valuable compounds using controlled chemical reactions starting from a common material is an appealing yet complex concept. Herein, a photocatalytic approach for the selective synthesis of (E)-ß-aminovinyl sulfones and (E)-ß-amidovinyl sulfones from allenamides and sodium sulfinates was established. This reaction exhibits the traits of an eco-friendly solvent and adjustable amide cleavage, and can accommodate a diverse range of substrates with exceptional functional group tolerance. Based on control experiments and deuterium labeling experiments, a plausible radical reaction pathway is proposed.