The maturation of young neurons is regulated by complex mechanisms and dysregulation of this process is frequently found in neurodevepmental disorders. MicroRNAs have been implicated in several steps ...of neuronal maturation including dendritic and axonal growth, spine development, and synaptogenesis. We demonstrate that one brain‐enriched microRNA, miR‐137, has a significant role in regulating neuronal maturation. Overexpression of miR‐137 inhibits dendritic morphogenesis, phenotypic maturation, and spine development both in brain and cultured primary neurons. On the other hand, a reduction in miR‐137 had opposite effects. We further show that miR‐137 targets the Mind bomb one (Mib1) protein through the conserved target site located in the 3′ untranslated region of Mib1 messenger RNA. Mib1 is an ubiquitin ligase known to be important for neurodevelopment. We show that exogenously expressed Mib1 could partially rescue the phenotypes associated with miR‐137 overexpression. These results demonstrate a novel miRNA‐mediated mechanism involving miR‐137 and Mib1 that function to regulate neuronal maturation and dendritic morphogenesis during development. STEM Cells 2010;28:1060–1070
Genomic studies of lung adenocarcinoma (LUAD) have advanced our understanding of the disease’s biology and accelerated targeted therapy. However, the proteomic characteristics of LUAD remain poorly ...understood. We carried out a comprehensive proteomics analysis of 103 cases of LUAD in Chinese patients. Integrative analysis of proteome, phosphoproteome, transcriptome, and whole-exome sequencing data revealed cancer-associated characteristics, such as tumor-associated protein variants, distinct proteomics features, and clinical outcomes in patients at an early stage or with EGFR and TP53 mutations. Proteome-based stratification of LUAD revealed three subtypes (S-I, S-II, and S-III) related to different clinical and molecular features. Further, we nominated potential drug targets and validated the plasma protein level of HSP 90β as a potential prognostic biomarker for LUAD in an independent cohort. Our integrative proteomics analysis enables a more comprehensive understanding of the molecular landscape of LUAD and offers an opportunity for more precise diagnosis and treatment.
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•Discovery of prognosis-associated proteins and pathways at early stage of LUAD•Proteomics revealed three subtypes related to clinical and molecular features•Identification of subtype-specific kinases and cancer-associated phosphoproteins•Identification of potential prognostic biomarkers and drug targets in LUAD
Integrative proteomic characterization of lung adenocarcinoma in 103 Chinese patients identifies three subtypes related to clinical and molecular features and nominates potential prognostic biomarkers and drug targets.
Traumatic brain injury (TBI) is a significant risk factor for neurodegenerative disorders, and patients often experience varying degrees of motor impairment. MiR-137, a broadly conserved and ...brain-enriched miRNA, is a key regulator in neural development and in various neurological diseases. Following TBI, the expression of miR-137 is dramatically downregulated. However, whether miR-137 is a therapeutic target for TBI still remains unknown. Here, for the first time, we demonstrate that intranasal administration of miR-137 agomir (a mimic) in the early stage (0-7 days) of TBI effectively inhibits glial scar formation and improves neuronal survival, while early-stage administration of miR-137 antagomir (an inhibitor) deteriorates motor impairment. This study elucidates the therapeutic potential of miR-137 mimics in improving locomotor recovery following motor cortex injury.
Genetic analyses have linked microRNA-137 (MIR137) to neuropsychiatric disorders, including schizophrenia and autism spectrum disorder. miR-137 plays important roles in neurogenesis and neuronal ...maturation, but the impact of miR-137 loss-of-function in vivo remains unclear. Here we show the complete loss of miR-137 in the mouse germline knockout or nervous system knockout (cKO) leads to postnatal lethality, while heterozygous germline knockout and cKO mice remain viable. Partial loss of miR-137 in heterozygous cKO mice results in dysregulated synaptic plasticity, repetitive behavior, and impaired learning and social behavior. Transcriptomic and proteomic analyses revealed that the miR-137 mRNA target, phosphodiesterase 10a (Pde10a), is elevated in heterozygous knockout mice. Treatment with the Pde10a inhibitor papaverine or knockdown of Pde10a ameliorates the deficits observed in the heterozygous cKO mice. Collectively, our results suggest that MIR137 plays essential roles in postnatal neurodevelopment and that dysregulation of miR-137 potentially contributes to neuropsychiatric disorders in humans.
Enamine and iminium ion-mediated asymmetric organocatalysis was not successful in achieving highly stereoselective α-chlorination of acyclic α,α-disubstituted carbonyls. To address this limitation, ...an alternative method was developed, which involved the use of geometry-defined persubstituted enesulfinamides to intercept the electrophilic chlorinating reagent. This approach enables the asymmetric construction of challenging acyclic α,α-disubstituted α-chlorinated ketimines with a high degree of stereoselectivity. The use of chloramine-T, a cost-effective and stable chlorine source rarely utilized in asymmetric electrophilic chlorination, plays a crucial role in achieving superior stereocontrol.
Dimethylsulfoniopropionate (DMSP) is a marine organosulfur compound with important roles in stress protection, marine biogeochemical cycling, chemical signalling and atmospheric chemistry. Diverse ...marine microorganisms catabolize DMSP via DMSP lyases to generate the climate‐cooling gas and info‐chemical dimethyl sulphide. Abundant marine heterotrophs of the Roseobacter group (MRG) are well known for their ability to catabolize DMSP via diverse DMSP lyases. Here, a new DMSP lyase DddU within the MRG strain Amylibacter cionae H‐12 and other related bacteria was identified. DddU is a cupin superfamily DMSP lyase like DddL, DddQ, DddW, DddK and DddY, but shares <15% amino acid sequence identity with these enzymes. Moreover, DddU proteins forms a distinct clade from these other cupin‐containing DMSP lyases. Structural prediction and mutational analyses suggested that a conserved tyrosine residue is the key catalytic amino acid residue in DddU. Bioinformatic analysis indicated that the dddU gene, mainly from Alphaproteobacteria, is widely distributed in the Atlantic, Pacific, Indian and polar oceans. For reference, dddU is less abundant than dddP, dddQ and dddK, but much more frequent than dddW, dddY and dddL in marine environments. This study broadens our knowledge on the diversity of DMSP lyases, and enhances our understanding of marine DMSP biotransformation.
Histone lysine crotonylation (Kcr), an evolutionarily conserved and widespread non‐acetyl short‐chain lysine acylation, plays important roles in transcriptional regulation and disease processes. ...However, the genome‐wide distribution, dynamic changes, and associations with gene expression of histone Kcr during developmental processes are largely unknown. In this study, we find that histone Kcr is mainly located in active promoter regions, acts as an epigenetic hallmark of highly expressed genes, and regulates genes participating in metabolism and proliferation. Moreover, elevated histone Kcr activates bivalent promoters to stimulate gene expression in neural stem/progenitor cells (NSPCs) by increasing chromatin openness and recruitment of RNA polymerase II (RNAP2). Functionally, these activated genes contribute to transcriptome remodeling and promote neuronal differentiation. Overall, histone Kcr marks active promoters with high gene expression and modifies the local chromatin environment to allow gene activation.
Synopsis
Histone lysine crotonylation (Kcr) is an active epigenetic mark with diverse functions during neural development. Kcr regulates neural stem cell fate decisions by activating developmentally primed bivalent promoters.
Histone crotonylation marks active promoters of genes participating in metabolism and proliferation.
Histone crotonylation also activates bivalent promoters to stimulate gene expression in neural stem/progenitor cells.
Crotonate promotes differentiation of neural stem/progenitor cells by increasing histone crotonylation.
Histone lysine crotonylation (Kcr) is an active epigenetic mark with diverse functions during neural development. Kcr regulates neural stem cell fate decisions by activating developmentally primed bivalent promoters.
Aftershock events may immediately follow mainshock events. In liquefiable deposits, the excess pore pressure caused by mainshock events may not dissipate completely in a short time interval between ...the mainshock and the aftershock. Sandy soil with different reconsolidation degrees (Ur) may present different reliquefaction resistances during the aftershock, which was not fully considered into the previous studies of reliquefaction. In this study, discrete element method (DEM) was employed to simulate a series of cyclic triaxial tests to evaluate the effects of Ur on reliquefaction resistance under mainshock–aftershock seismic sequence. The initially liquefied specimen was reconsolidated from two states with small and large residual shear strain respectively. Reconsolidated specimens reliquefied under different cyclic stress ratios (CSRs). Simulation results show that reliquefaction resistance increased gradually with increasing Ur, which was closely related to the previous residual shear strain during the first liquefaction event. Specimens that having large residual shear strain reliquefied easily, and the reliquefaction resistance of those specimens increased slightly with increasing Ur. On the contrary, reliquefaction resistance of the specimens that having small residual shear stain increased obviously with increasing Ur. The ratio of initial mechanical average coordination number to initial mesoscopic fabric anisotropy of reconsolidated specimens had a good correlation to the contraction potential and increased gradually with increasing Ur.
An array of signals regulating the early stages of postnatal subventricular zone (SVZ) neurogenesis has been identified, but much less is known regarding the molecules controlling late stages. Here, ...we investigated the function of the activity-dependent and morphogenic microRNA miR-132 on the synaptic integration and survival of olfactory bulb (OB) neurons born in the neonatal SVZ. In situ hybridization revealed that miR-132 expression occurs at the onset of synaptic integration in the OB. Using in vivo electroporation we found that sequestration of miR-132 using a sponge-based strategy led to a reduced dendritic complexity and spine density while overexpression had the opposite effects. These effects were mirrored with respective changes in the frequency of GABAergic and glutamatergic synaptic inputs reflecting altered synaptic integration. In addition, timely directed overexpression of miR-132 at the onset of synaptic integration using an inducible approach led to a significant increase in the survival of newborn neurons. These data suggest that miR-132 forms the basis of a structural plasticity program seen in SVZ-OB postnatal neurogenesis. miR-132 overexpression in transplanted neurons may thus hold promise for enhancing neuronal survival and improving the outcome of transplant therapies.
SUMMARY
In the exploration and development of carbonate reservoirs, borehole azimuthal acoustic reflection imaging can be used to survey the near-borehole geological structures such as fractures, ...faults or caves in the formation, but the accuracy of azimuth measurement and imaging quality are usually deteriorated due to the amplitudes of event signals being often much weaker than those of borehole mode waves. This study proposes a data processing method for borehole azimuthal acoustic reflection imaging to improve the accuracy of azimuth measurement and imaging quality of the near-borehole geological structures. First, three adjacent receiving sensors in the vertical plane closest to the given azimuth are selected to form a linear phased array receiver subarray, and the elevation angle of the event signals can be obtained by comparing the amplitudes of the stacked waveforms in the vertical plane for different elevation angles. Further, three receiving sensors, closest to the given azimuth, are selected from the arcuate phased array receiver, where the central sensor of the linear phased array receiver subarray is located, to form an arcuate phased array receiver subarray, and the 3-D stacked waveforms with the known elevation and azimuth angle can be calculated. In the incident direction of the event signals, the event signals will be significantly enhanced because the event signals in waveforms of each sensor in the subarray satisfy the in-phase stack condition, so as to improve the migration image quality and interpretation accuracy fundamentally. We confirmed this method by processing azimuth reflection acoustic data from a field experiment including two adjacent fluid-filled artificial boreholes. The comparison of the field data processing results with and without 3-D waveform stacking demonstrated that 3-D waveform stacking significantly improves the accuracy of azimuth interpretation and imaging quality.
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