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Noisy matrix completion aims at estimating a low-rank matrix given only partial and corrupted entries. Despite remarkable progress in designing efficient estimation algorithms, it remains largely unclear how to assess the uncertainty of the obtained estimates and how to perform efficient statistical inference on the unknown matrix (e.g., constructing a valid and short confidence interval for an unseen entry). This paper takes a substantial step toward addressing such tasks. We develop a simple procedure to compensate for the bias of the widely used convex and nonconvex estimators. The resulting debiased estimators admit nearly precise nonasymptotic distributional characterizations, which in turn enable optimal construction of confidence intervals/regions for, say, the missing entries and the low-rank factors. Our inferential procedures do not require sample splitting, thus avoiding unnecessary loss of data efficiency. As a byproduct, we obtain a sharp characterization of the estimation accuracy of our debiased estimators in both rate and constant. Our debiased estimators are tractable algorithms that provably achieve full statistical efficiency.

The gut microbiota is crucial in the pathogenesis of type 2 diabetes mellitus (T2DM). However, the metabolism of T2DM patients is not well-understood. We aimed to identify the differences on composition and function of gut microbiota between T2DM patients with obesity and healthy people. In this study, 6 T2DM patients with obesity and 6 healthy volunteers were recruited, and metagenomic approach and bioinformatics analysis methods were used to understand the composition of the gut microbiota and the metabolic network. We found a decrease in the abundance of Firmicutes, Oribacterium, and Paenibacillus; this may be attributed to a possible mechanism and biological basis of T2DM; moreover, we identified three critical bacterial taxa, Bacteroides plebeius, Phascolarctobacterium sp. CAG207, and the order Acidaminococcales that can potentially be used for T2DM treatment. We also revealed the composition of the microbiota through functional annotation based on multiple databases and found that carbohydrate metabolism contributed greatly to the pathogenesis of T2DM. This study helps in elucidating the different metabolic roles of microbes in T2DM patients with obesity.

The transition of the Munc18-1/syntaxin-1 complex to the SNARE complex, a key step involved in exocytosis, is regulated by Munc13-1, SNAP-25 and synaptobrevin-2, but the underlying mechanism remains elusive. Here, we identify an interaction between Munc13-1 and the membrane-proximal linker region of synaptobrevin-2, and reveal its essential role in transition and exocytosis. Upon this interaction, Munc13-1 not only recruits synaptobrevin-2-embedded vesicles to the target membrane but also renders the synaptobrevin-2 SNARE motif more accessible to the Munc18-1/syntaxin-1 complex. Afterward, the entry of SNAP-25 leads to a half-zippered SNARE assembly, which eventually dissociates the Munc18-1/syntaxin-1 complex to complete SNARE complex formation. Our data suggest that Munc18-1 and Munc13-1 together serve as a functional template to orchestrate SNARE complex assembly. Synaptic exocytosis depends on formation of the SNARE complex but its assembly mechanism is still under debate. Here, the authors identify an interaction between Munc13-1 and synaptobrevin-2 that is critical for the transition of the Munc18-1/syntaxin-1 complex to the SNARE complex.

Emerging spatial technologies, including spatial transcriptomics and spatial epigenomics, are becoming powerful tools for profiling of cellular states in the tissue context 1 , 2 , 3 , 4 – 5 . However, current methods capture only one layer of omics information at a time, precluding the possibility of examining the mechanistic relationship across the central dogma of molecular biology. Here, we present two technologies for spatially resolved, genome-wide, joint profiling of the epigenome and transcriptome by cosequencing chromatin accessibility and gene expression, or histone modifications (H3K27me3, H3K27ac or H3K4me3) and gene expression on the same tissue section at near-single-cell resolution. These were applied to embryonic and juvenile mouse brain, as well as adult human brain, to map how epigenetic mechanisms control transcriptional phenotype and cell dynamics in tissue. Although highly concordant tissue features were identified by either spatial epigenome or spatial transcriptome we also observed distinct patterns, suggesting their differential roles in defining cell states. Linking epigenome to transcriptome pixel by pixel allows the uncovering of new insights in spatial epigenetic priming, differentiation and gene regulation within the tissue architecture. These technologies are of great interest in life science and biomedical research. The authors present two technologies for spatially resolved, genome-wide, joint profiling of the epigenome and transcriptome by cosequencing chromatin accessibility and gene expression, or histone modifications and gene expression on the same tissue section at near-single-cell resolution.

Synaptotagmin-1 (Syt1) acts as a Ca2+ sensor for neurotransmitter release through its C2 domains. It has been proposed that Syt1 promotes SNARE-dependent fusion mainly through its C2B domain, but the underlying mechanism is poorly understood. In this study, we show that the C2B domain interacts simultaneously with acidic membranes and SNARE complexes via the top Ca2+-binding loops, the side polybasic patch, and the bottom face in response to Ca2+. Disruption of the simultaneous interactions completely abrogates the triggering activity of the C2B domain in liposome fusion. We hypothesize that the simultaneous interactions endow the C2B domain with an ability to deform local membranes, and this membrane-deformation activity might underlie the functional significance of the Syt1 C2B domain in vivo. Information travels around the nervous system along cells called neurons, which communicate with each other via connections called synapses. When a signal travelling along one neuron reaches a synapse, it triggers the release of molecules known as neurotransmitters. These molecules are then taken up by the next neuron to pass the signal on. Neurotransmitters are stored in compartments called synaptic vesicles and their release from the first neuron depends on the synaptic vesicles fusing with the membrane that surrounds the cell. This “membrane fusion” process is driven by a group of proteins called the SNARE complex. Membrane fusion is triggered by a sudden increase in the amount of calcium ions in the cell, which leads to an increase in the activity of a protein called synaptotagmin-1. A region of this protein known as the C2B domain is able to detect calcium ions, and it can also bind to the cell membrane and SNARE complex proteins. However, it is not clear what roles these interactions play in driving the release of neurotransmitters. Wang, Li et al. have used a variety of biophysical techniques to study these interactions in more detail using purified proteins and other cell components. The experiments show that all three interactions occur at the same time and are all required for synaptotagmin-1 to trigger membrane fusion. Wang, Li et al. propose that these interactions allow synaptotagmin-1 to bend a section of the cell membrane in response to calcium ions. The experiments also show that the C2B domain interacts more strongly with the SNARE complex than previously thought. A future challenge is to observe whether synaptotagmin-1 works in the same way in living cells.

A central step in synaptic vesicle priming is the transition of syntaxin-1 between two very stable complexes: with Munc18 and with the other SNARE complex components. How this transition is promoted is now explored by NMR and FRET studies, revealing that the MUN domain of Munc13 uses weak interactions to pry open the closed syntaxin-1 in complex with Munc18. During the priming step that leaves synaptic vesicles ready for neurotransmitter release, the SNARE syntaxin-1 transitions from a closed conformation that binds Munc18-1 tightly to an open conformation within the highly stable SNARE complex. Control of this conformational transition is important for brain function, but the underlying mechanism is unknown. NMR and fluorescence experiments now show that the Munc13-1 MUN domain, which plays a central role in vesicle priming, markedly accelerates the transition from the syntaxin-1–Munc18-1 complex to the SNARE complex. This activity depends on weak interactions of the MUN domain with the syntaxin-1 SNARE motif, and probably with Munc18-1. Together with available physiological data, these results provide a defined molecular basis for synaptic vesicle priming, and they illustrate how weak protein-protein interactions can play crucial biological roles by promoting transitions between high-affinity macromolecular assemblies.

Neurotransmitter release by Ca2+‐triggered synaptic vesicle exocytosis is essential for information transmission in the nervous system. The soluble N‐ethylmaleimide sensitive factor attachment protein receptors (SNAREs) syntaxin‐1, SNAP‐25, and synaptobrevin‐2 form the SNARE complex to bring synaptic vesicles and the plasma membranes together and to catalyze membrane fusion. Munc18‐1 and Munc13‐1 regulate synaptic vesicle priming via orchestrating neuronal SNARE complex assembly. In this review, we summarize recent advances toward the functions and molecular mechanisms of Munc18‐1 and Munc13‐1 in guiding neuronal SNARE complex assembly, and discuss the functional similarities and differences between Munc18‐1 and Munc13‐1 in neurons and their homologs in other intracellular membrane trafficking systems. Munc18‐1 and Munc13‐1 regulate synaptic vesicle exocytosis via orchestrating neuronal SNARE complex (syntaxin‐1, SNAP‐25, and synaptobrevin‐2) assembly. In this review, we summarized recent advances towards the molecular mechanisms of Munc18‐1 and Munc13‐1 in guiding neuronal SNARE complex assembly and discussed the similarities and differences between Munc18‐1 and Munc13‐1 in neurons and their homologs in other intracellular membrane trafficking systems.

Magnetic resonance imaging (MRI) contrast agents are categorised according to the following specific features: chemical composition including the presence or absence of metal atoms, route of administration, magnetic properties, effect on the magnetic resonance image, biodistribution and imaging applications. The majority of these agents are either paramagnetic ion complexes or superparamagnetic magnetite particles and contain lanthanide elements such as gadolinium (Gd3+) or transition metal manganese (Mn2+). These elements shorten the T1 or T2 relaxation time, thereby causing increased signal intensity on T1-weighted images or reduced signal intensity on T2-weighted images. Most paramagnetic contrast agents are positive agents. These agents shorten the T1, so the enhanced parts appear bright on T1-weighted images. Dysprosium, superparamagnetic agents and ferromagnetic agents are negative contrast agents. The enhanced parts appear darker on T2-weighted images. MRI contrast agents incorporating chelating agents reduces storage in the human body, enhances excretion and reduces toxicity. MRI contrast agents may be administered orally or intravenously. According to biodistribution and applications, MRI contrast agents may be categorised into three types: extracellular fluid, blood pool and target/organ-specific agents. A number of contrast agents have been developed to selectively distinguish liver pathologies. Some agents are also capable of targeting other organs, inflammation as well as specific tumors.

Neurotransmitter release depends critically on Munc18-1, Munc13, the Ca 2+ sensor synaptotagmin-1, and the soluble N-ethylmaleimide—sensitive factor (NSF) attachment protein (SNAP) receptors (SNAREs) syntaxin-1, synaptobrevin, and SNAP-25. In vitro reconstitutions have shown that syntaxin-1—SNAP-25 liposomes fuse efficiently with synaptobrevin liposomes in the presence of synaptotagmin-1—Ca 2+ , but neurotransmitter release also requires Munc18-1 and Munc13 in vivo. We found that Munc18-1 could displace SNAP-25 from syntaxin-1 and that fusion of syntaxin-1—Munc18-1 liposomes with synaptobrevin liposomes required Munc13, in addition to SNAP-25 and synaptotagmin-1-Ca 2+ . Moreover, when starting with syntaxin-1—SNAP-25 liposomes, NSF—α-SNAP disassembled the syntaxin-1—SNAP-25 heterodimers and abrogated fusion, which then required Munc18-1 and Munc13. We propose that fusion does not proceed through syntaxin-1—SNAP-25 heterodimers but starts with the syntaxin-1—Munc18-1 complex; Munc18-1 and Munc13 then orchestrate membrane fusion together with the SNAREs and synaptotagmin-1-Ca 2+ in an NSF- and SNAP-resistant manner.

Transfer RNA (tRNA)‐derived fragments are the non‐coding single‐stranded RNAs involved in several physiological and pathological processes. Herein, we investigated the role of tRF‐1020, a tRNA fragment, in diabetes‐induced retinal microvascular complications. The results showed that the levels of tRF‐1020 expression were down‐regulated in diabetic retinal vessels and retinal endothelial cells following high glucose or H2O2 stress. Overexpressing tRF‐1020 led to decreased endothelial cell viability, proliferation, migration, and tube formation and alleviated retinal vascular dysfunction as shown by decreased retinal acellular capillaries, vascular leakage, and inflammation. By contrast, tRF‐1020 silencing displayed the opposite effects. tRF‐1020 regulated endothelial angiogenic functions and retinal vascular dysfunction by targeting Wnt signalling. Moreover, the levels of tRF‐1020 expression were reduced in aqueous humour and vitreous samples of the patients with diabetic retinopathy. Collectively, tRF‐1020 is a potential target for the diagnosis and treatment of diabetic retinopathy.