Heterodimerization of Munc13 C2A domain with RIM regulates synaptic vesicle docking and priming

The presynaptic active zone protein Munc13 is essential for neurotransmitter release, playing key roles in vesicle docking and priming. Mechanistically, it is thought that the C2A domain of Munc13 inhibits the priming function by homodimerization, and that RIM disrupts the autoinhibitory homodimerization forming monomeric priming-competent Munc13. However, it is unclear whether the C2A domain mediates other Munc13 functions in addition to this inactivation–activation switch. Here, we utilize mutations that modulate the homodimerization and heterodimerization states to define additional roles of the Munc13 C2A domain. Using electron microscopy and electrophysiology in hippocampal cultures, we show that the C2A domain is critical for additional steps of vesicular release, including vesicle docking. Optimal vesicle docking and priming is only possible when Munc13 heterodimerizes with RIM via its C2A domain. Beyond being a switching module, our data suggest that the Munc13-RIM heterodimer is an active component of the vesicle docking, priming and release complex

A review of historical reconstruction methods of land use/land cover

Understanding long-term human-environment interactions requires historical reconstruction of past land-use and land-cover changes. Most reconstructions have been based primarily on consistently available and relatively standardized information from historical sources. Based on available data sources and a retrospective research, in this paper we review the approaches and methods of the digital reconstruction and analyze their advantages and possible constraints in the following aspects: (1) Historical documents contain qualitative or semi-quantitative information about past land use, which also usually include land-cover data, but preparation of archival documents is very time-consuming. (2) Historical maps and pictures offer visual and spatial quantitative land-cover information. (3) Natural archive has significant advantages as a method for reconstructing past vegetation and has its unique possibilities especially when historical records are missing or lacking, but it has great limits of rebuilding certain land-cover types. (4) Historical reconstruction models have been gradually developed from empirical models to mechanistic ones. The method does not only reconstruct the quantity of land use/cover in historical periods, but it also reproduces the spatial distribution. Yet there are still few historical land-cover datasets with high spatial resolution. (5) Reconstruction method based on multiple-source data and multidisciplinary research could build historical land-cover from multiple perspectives, complement the missing data, verify reconstruction results and thus improve reconstruction accuracy. However, there are challenges that make the method still in the exploratory stage. This method can be a long-term development goal for the historical land-cover reconstruction. Researchers should focus on rebuilding historical land-cover dataset with high spatial resolution by developing new models so that the study results could be effectively applied in simulations of climatic and ecological effects

Munc13-1 is a Ca2+-phospholipid-dependent vesicle priming hub that shapes synaptic short-term plasticity and enables sustained neurotransmission

During ongoing presynaptic action potential (AP) firing, transmitter release is limited by the availability of release-ready synaptic vesicles (SVs). The rate of SV recruitment (SVR) to release sites is strongly upregulated at high AP frequencies to balance SV consumption. We show that Munc13-1-an essential SV priming protein-regulates SVR via a Ca2+-phospholipid-dependent mechanism. Using knockin mouse lines with point mutations in the Ca2+-phospholipid-binding C2B domain of Munc13-1, we demonstrate that abolishing Ca2+-phospholipid binding increases synaptic depression, slows recovery of synaptic strength after SV pool depletion, and reduces temporal fidelity of synaptic transmission, while increased Ca2+-phospholipid binding has the opposite effects. Thus, Ca2+-phospholipid binding to the Munc13-1-C2B domain accelerates SVR, reduces short-term synaptic depression, and increases the endurance and temporal fidelity of neurotransmission, demonstrating that Munc13-1 is a core vesicle priming hub that adjusts SV re-supply to demand

GPR158 in pyramidal neurons mediates social novelty behavior via modulating synaptic transmission in male mice

Impairment in social communication skills is a hallmark feature of autism spectrum disorder (ASD). The role of G-protein-coupled receptor 158 (GPR158) in ASD remains largely unexplored. In this study, we observed that both constitutive and cell-/tissue-specific knockouts of Gpr158 in pyramidal neurons or the medial prefrontal cortex (mPFC) result in impaired novelty preference, while sociability remains unaffected in male mice. Notably, the loss of GPR158 leads to a significant decline in excitatory synaptic transmission, characterized by a reduction in glutamate vesicles, as well as the expression and phosphorylation of GluN2B in the mPFC. We successfully rescue the phenotype of social novelty deficits either by reintroducing GPR158 in the mPFC of Gpr158 deficient mice or by chemogenetic activation of pyramidal neurons where Gpr158 is specifically ablated. Our findings indicate that GPR158 in pyramidal neurons plays a specific role in modulating social novelty and may represent a potential target for treating social disorders

Efficacy and patient-reported outcomes in advanced non-small cell lung cancer patients receiving aumolertinib as first-line therapy: a real-world study

BackgroundAumolertinib demonstrated superior progression-free survival (PFS) and a well-tolerated toxicity profile compared to gefitinib in front-line treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in the AENEAS trial. However, patient-reported outcomes (PROs) of aumolertinib have not been published.MethodsIn this real-world study, the efficacy was evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) 1.0. PROs were evaluated using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (QLQ-C30) and the EORTC Quality of Life lung cancer-specific module (QLQ-LC13) in advanced NSCLC patients receiving aumolertinib as initial therapy. Pre-specified key symptoms were cough, hemoptysis, dyspnea, sore mouth or tongue, dysphagia, hair loss, tingling in hands or feet, chest pain, arm or shoulder pain, and pain at other sites.ResultsA total of 33 patients were included, 23 of whom had efficacy information up to January 2024. The median follow-up time was 264 days (interval: 36–491 days). The objective response rate and disease control rate were 65.2% and 91.3%, respectively. The EORTC QLQ-LC30 general health status scale showed that functional scales increased and symptom scales decreased during aumolertinib treatment. Symptom scales assessed by the EORTC QLQ-LC13 showed that improvements in cough, sore mouth or tongue, tingling in hands or feet, chest pain, arm or shoulder pain, and other pain sites were both clinically and statistically significant after 6 months of aumolertinib treatment (p < 0.05).ConclusionIn this real-world study, aumolertinib showed comparable disease control and objective response rates as reported in the AENEAS trial for advanced NSCLC patients with EGFR-sensitizing mutations. Aumolertinib treatment improved PROs, further supporting it in first-line clinical practice

The gut metabolite indole-3-propionic acid activates ERK1 to restore social function and hippocampal inhibitory synaptic transmission in a 16p11.2 microdeletion mouse model

Background: Microdeletion of the human chromosomal region 16p11.2 (16p11.2+/−) is a prevalent genetic factor associated with autism spectrum disorder (ASD) and other neurodevelopmental disorders. However its pathogenic mechanism remains unclear, and efective treatments for 16p11.2+/− syndrome are lacking. Emerging evidence suggests that the gut microbiota and its metabolites are inextricably linked to host behavior through the gut-brain axis and are therefore implicated in ASD development. Despite this, the functional roles of microbial metabo‑ lites in the context of 16p11.2+/− are yet to be elucidated. This study aims to investigate the therapeutic potential of indole-3-propionic acid (IPA), a gut microbiota metabolite, in addressing behavioral and neural defcits associated with 16p11.2+/−, as well as the underlying molecular mechanisms. // Results: Mice with the 16p11.2+/− showed dysbiosis of the gut microbiota and a signifcant decrease in IPA levels in feces and blood circulation. Further, these mice exhibited signifcant social and cognitive memory impairments, along with hyperactivation of hippocampal dentate gyrus neurons and reduced inhibitory synaptic transmission in this region. However, oral administration of IPA efectively mitigated the histological and electrophysiological alterations, thereby ameliorating the social and cognitive defcits of the mice. Remarkably, IPA treatment signifcantly increased the phosphorylation level of ERK1, a protein encoded by the Mapk3 gene in the 16p11.2 region, with‑ out afecting the transcription and translation of the Mapk3 gene. // Conclusions: Our study reveals that 16p11.2+/− leads to a decline in gut metabolite IPA levels; however, IPA supple‑ mentation notably reverses the behavioral and neural phenotypes of 16p11.2+/− mice. These fndings provide new insights into the critical role of gut microbial metabolites in ASD pathogenesis and present a promising treatment strategy for social and cognitive memory defcit disorders, such as 16p11.2 microdeletion syndrome

Uni-SMART: Universal Science Multimodal Analysis and Research Transformer

In scientific research and its application, scientific literature analysis is crucial as it allows researchers to build on the work of others. However, the fast growth of scientific knowledge has led to a massive increase in scholarly articles, making in-depth literature analysis increasingly challenging and time-consuming. The emergence of Large Language Models (LLMs) has offered a new way to address this challenge. Known for their strong abilities in summarizing texts, LLMs are seen as a potential tool to improve the analysis of scientific literature. However, existing LLMs have their own limits. Scientific literature often includes a wide range of multimodal elements, such as tables, charts, and molecule, which are hard for text-focused LLMs to understand and analyze. This issue points to the urgent need for new solutions that can fully understand and analyze multimodal content in scientific literature. To answer this demand, we present \textbf{Uni-SMART} (Universal Science Multimodal Analysis and Research Transformer), an innovative model designed for in-depth understanding of multimodal scientific literature. Through rigorous quantitative evaluation across several domains, Uni-SMART demonstrates superior performance over other text-focused LLMs. Furthermore, our exploration extends to practical applications, including patent infringement detection and nuanced analysis of charts. These applications not only highlight Uni-SMART's adaptability but also its potential to revolutionize how we interact with scientific literature

Emerging roles and potential application of PIWI-interacting RNA in urological tumors

The piRNA (PIWI-interacting RNA) is P-Element induced wimpy testis (PIWI)-interacting RNA which is a small molecule, non-coding RNA with a length of 24-32nt. It was originally found in germ cells and is considered a regulator of germ cell function. It can interact with PIWI protein, a member of the Argonaute family, and play a role in the regulation of gene transcription and epigenetic silencing of transposable factors in the nucleus. More and more studies have shown that piRNAs are abnormally expressed in a variety of cancer tissues and patient fluids, and may become diagnostic tools, therapeutic targets, staging markers, and prognostic evaluation tools for cancer. This article reviews the recent research on piRNA and summarizes the structural characteristics, production mechanism, applications, and its role in urological tumors, to provide a reference value for piRNA to regulate urological tumors