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.
Dysregulation of the balance between cell proliferation and cell death is a central feature of malignances. Death-associated protein kinase 3 (DAPK3) regulates programmed cell death including ...apoptosis and autophagy. Our previous study showed that DAPK3 downregulation was detected in more than half of gastric cancers (GCs), which was related to tumor invasion, metastasis, and poor prognosis. However, the precise molecular mechanism underlying DAPK3-mediated tumor suppression remains unclear. Here, we showed that the tumor suppressive function of DAPK3 was dependent on autophagy process. Mass spectrometry, in vitro kinase assay, and immunoprecipitation revealed that DAPK3 increased ULK1 activity by direct ULK1 phosphorylation at Ser556. ULK1 phosphorylation by DAPK3 facilitates the ULK1 complex formation, the VPS34 complex activation, and autophagy induction upon starvation. The kinase activity of DAPK3 and ULK1 Ser556 phosphorylation were required for DAPK3-modulated tumor suppression. The coordinate expression of DAPK3 with ULK1 Ser556 phosphorylation was confirmed in clinical GC samples, and this co-expression was correlated with favorable survival outcomes in patients. Collectively, these findings indicate that the tumor-suppressor roles of DAPK3 in GC are associated with autophagy and that DAPK3 is a novel autophagy regulator, which can directly phosphorylate ULK1 and activate ULK1. Thus, DAPK3 might be a promising prognostic autophagy-associated marker.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
A series of novel indole‐1,2,4‐triazole derivatives have been designed, synthesized, and evaluated as potential tubulin polymerization inhibitors. The top hit 12, bearing the 3,4,5‐trimethoxyphenyl ...moiety, exhibited substantial anti‐proliferative activity against HepG2, HeLa, MCF‐7, and A549 cells in vitro with IC50 values of 0.23 ± 0.08 μM, 0.15 ± 0.18 μM, 0.38 ± 0.12 μM, and 0.30 ± 0.13 μM, respectively. It also inhibited tubulin polymerization with the IC50 value of 2.1 ± 0.12 μM, which was comparable with that of the positive controls. Furthermore, compound 12 regulated the expression of cell cycle‐related proteins (Cyclin B1, Cdc25c, and Cdc2) and apoptosis‐related proteins (Bcl‐2, Bcl‐x, and Mcl‐1). Mechanistically, compound 12 could arrest cell cycle at the G2/M phase, thus induce an increase of apoptotic cell death. In addition, molecular docking hinted the possible interaction mode of compound 12 into the colchicine binding site of tubulin heterodimers. According to the applications of microtubule‐targeting agents in both direct and synergistic cancer therapies, we hope this work might be of significance for future researches.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The coronavirus disease 2019 (COVID‐19) pandemic underlines a persistent threat of respiratory tract infectious diseases and warrants preparedness for a rapid response. At present, COVID‐19 has had a ...serious social impact and imposed a heavy global burden on public health. The exact pathogenesis of COVID‐19 has not been fully elucidated. Since the outbreak of COVID‐19, a renewed attention has been brought to Toll‐like receptors (TLRs). Available data and new findings have demonstrated that the interaction of human TLRs and SARS‐CoV‐2 is a vital mediator of COVID‐19 immunopathogenesis. TLRs such as TLR2, 4, 7 and 8 are potentially important in viral combat and activation of immunity in patients with COVID‐19. Therapeutics targeting TLRs are currently considered promising options against the pandemic. A number of TLR‐targeting immunotherapeutics are now being investigated in preclinical studies and different phases of clinical trials. In addition, innovative vaccines based on TLRs under development could be a promising approach for building a new generation of vaccines to solve the current challenges. In this review, we summarize recent progress in the role of TLRs in COVID‐19, focusing the new candidate drugs targeting TLRs, the current technology and potential paths forward for employing TLR agonists as vaccine adjuvants.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Narrow therapeutic window limits treatments with thrombolysis and neuroprotection for most stroke patients. Widening therapeutic window remains a critical challenge. Understanding the key mechanisms ...underlying the pathophysiological events in the peri-infarct area where secondary injury coexists with neuroplasticity over days to weeks may offer an opportunity for expanding the therapeutic window. Here we show that ischemia-induced histone deacetylase 2 (HDAC2) upregulation from 5 to 7 d after stroke plays a crucial role. In this window phase, suppressing HDAC2 in the peri-infarct cortex of rodents by HDAC inhibitors, knockdown or knock-out of
promoted recovery of motor function from stroke via epigenetically enhancing cells survival and neuroplasticity of surviving neurons as well as reducing neuroinflammation, whereas overexpressing HDAC2 worsened stroke-induced functional impairment of both WT and
conditional knock-out mice. More importantly, inhibiting other isoforms of HDACs had no effect. Thus, the intervention by precisely targeting HDAC2 in this window phase is a novel strategy for the functional recovery of stroke survivors.
Narrow time window phase impedes current therapies for stroke patients. Understanding the key mechanisms underlying secondary injury may open a new window for pharmacological interventions to promote recovery from stroke. Our study indicates that ischemia-induced histone deacetylase 2 upregulation from 5 to 7 d after stroke mediates the secondary functional loss by reducing survival and neuroplasticity of peri-infarct neurons as well as augmenting neuroinflammation. Thus, precisely targeting histone deacetylase 2 in the window phase provides a novel therapeutic strategy for stroke recovery.
In this work, a fluorescent probe,
TPABF-HS
, was developed for detecting hydrogen sulfide (H
2
S) using a human serum albumin (HSA)-binding-based approach for amplifying the fluorescence signal and ...extending the linear correlation range. Compared to the most recent probes for H
2
S, the most interesting feature of the detection system developed herein was the especially wide linear range (0-1000 μM (0-100 eq.)), which covered the physiological and pathological levels of H
2
S.
TPABF-HS
could be used in applications high sensitivity and selectivity with an LOD value of 0.42 μM. Further, site-competition experiments and molecular docking simulation experiments indicated that signal amplification was realized by the binding of the
TPABF
fluorophore to the naproxen-binding site of HSA. Moreover, the extension of the measurement span could allow for applications in living cells and
Caenorhabditis elegans
for imaging both exogenous and endogenous H
2
S. This work brings new information to the strategy of signal processing by exploiting fluorescent probes.
TPABF-HS
, accompanied by an HSA-binding-based approach for amplifying the fluorescence signal, has achieved a wide linear range of 0-1000 μM.
Glioma stem cells (GSCs) are responsible for glioma recurrence and drug resistance, yet the mechanisms underlying their maintenance remains unclear. This study aimed to identify enhancer-controlled ...genes involved in GSCs maintenance and elucidate the mechanisms underlying their regulation.
We analyzed RNA-seq data and H3K27ac ChIP-seq data from GSE119776 to identify differentially expressed genes and enhancers, respectively. Gene Ontology analysis was performed for functional enrichment. Transcription factors were predicted using the Toolkit for Cistrome Data Browser. Prognostic analysis and gene expression correlation was conducted using the Chinese Glioma Genome Atlas (CGGA) data. Two GSC cell lines, GSC-A172 and GSC-U138MG, were isolated from A172 and U138MG cell lines. qRT-PCR was used to detect gene transcription levels. ChIP-qPCR was used to detect H3K27ac of enhancers, and binding of E2F4 to target gene enhancers. Western blot was used to analyze protein levels of p-ATR and γH2AX. Sphere formation, limiting dilution and cell growth assays were used to analyze GSCs growth and self-renewal.
We found that upregulated genes in GSCs were associated with ataxia-telangiectasia-mutated-and-Rad3-related kinase (ATR) pathway activation, and that seven enhancer-controlled genes related to ATR pathway activation (LIN9, MCM8, CEP72, POLA1, DBF4, NDE1, and CDKN2C) were identified. Expression of these genes corresponded to poor prognosis in glioma patients. E2F4 was identified as a transcription factor that regulates enhancer-controlled genes related to the ATR pathway activation, with MCM8 having the highest hazard ratio among genes positively correlated with E2F4 expression. E2F4 bound to MCM8 enhancers to promote its transcription. Overexpression of MCM8 partially restored the inhibition of GSCs self-renewal, cell growth, and the ATR pathway activation caused by E2F4 knockdown.
Our study demonstrated that E2F4-mediated enhancer activation of MCM8 promotes the ATR pathway activation and GSCs characteristics. These findings offer promising targets for the development of new therapies for gliomas.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Informing people of health threats is crucial as they may lack situation awareness (SA) of risky situations when they do not have personal experiences or lessons learned from dangerous encounters. In ...this work, we explored the potential of using a VR data story to raise people’s SA of health risks. We first invited seven participants and conducted participatory design studies to capture the design considerations. Then, we implemented the VR data story with five design features referring to the design considerations. Using a between-subjects study (N=62), we evaluated the effects of the data story on raising SA and investigated the role of each design feature. Our results show that the data story can promote SA by enhancing people’s connection to risky situations. Design features such as immersive visualizations, multiple perspectives, and embodied interactions contribute to this connection. Drawing on qualitative and quantitative findings, we discuss the implications of designing data stories in VR for promoting public health.
•This paper conducts a design study with users to explore the design considerations of creating the immersive experience of a data story in VR.•This paper designs an interactive VR data story prototype that aims to raise people’s situation awareness (SA) of public health threats.•This paper examines the effectiveness of the VR data story in improving people’s SA and finds that three features of the story contribute to the improvement of SA.•This paper provides detailed design implications for designing VR data stories for the promotion of public health communication and user engagement.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPUK, ZAGLJ, ZRSKP
Background
Stroke is a leading cause of long‐term disability worldwide. However, current therapies that promote functional recovery from stroke are limited to physical rehabilitation. No ...pharmacological therapy is available. Thus, understanding the role of histone deacetylase 2 (HDAC2) in the pathophysiological process of stroke‐induced functional loss may provide a novel strategy for stroke recovery.
Methods and Results
Focal stroke was induced by photothrombosis. LV‐HDAC2‐shRNA‐GFP, LV‐GFP, Ad‐HDAC2‐Flag, or Ad‐inactive‐HDAC2‐Flag was microinjected into the peri‐infarct area immediately after stroke. HDAC inhibitors were microinjected into the peri‐infarct area 4 to 10 days after stroke. Grid‐walking task and cylinder task were conducted to assess motor function. Golgi‐Cox staining, chromatin immunoprecipitation, and electrophysiology were used to reveal the mechanisms underlying stroke recovery. Knockdown or knockout of HDAC2 promoted stroke recovery, whereas overexpression of HDAC2 worsened stroke‐induced functional impairment. More importantly, trichostatin A, a pan‐HDAC inhibitor, promoted functional recovery from stroke in WT mice when used in the delayed phase, but it was ineffective in Hdac2 conditional knockout (Hdac2 CKO) mice. Treatment with suberoylanilide hydroxamic acid, a selective HDAC1 and HDAC2 inhibitor, in the delayed phase of stroke produced sustained functional recovery in mice via epigenetically enhancing neuroplasticity of surviving neurons in the peri‐infarct zone.
Conclusions
Our novel findings provide evidence that HDAC2 is a crucial target for functional recovery from stroke. As there are clinically available HDAC inhibitors, our findings could be directly translated into clinical research of stroke.
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