Type I interferon inhibits varicella-zoster virus replication by interfering with the dynamic interaction between mediator and IE62 within replication compartments

BACKGROUND: Varicella-zoster virus (VZV) is the causative agent of varicella and zoster. The immediate-early protein, IE62 is the predominant VZ virion tegument protein, transactivating the expression of all kinetic classes of VZV genes. IE62 is localized to punctae that form DNA replication compartments in the nuclei of VZV infected cells. The morphological changes and the increase in the size of replication compartments that express IE62 are correlated with production of VZ virions. Mammalian Mediator serves as a coactivator of IE62 and functions by bridging DNA-binding transcription factors¸ RNA polymerase II (RNAP II) and their target DNAs for VZV replication. While VZV is highly sensitive to type I interferons (IFNs), how IFN-α inhibits early events during VZV replication is poorly understood. RESULTS: In this study, we performed in situ analysis to investigate the effects of IFN-α on the dynamic interactions of IE62 with the Mediator MED25 subunit and the RNAP II negative regulator cycle-dependent kinase 8 (CDK8) in VZV infected cells by confocal immunofluorescence. We found that in addition to dose-dependent inhibition of the yields of infectious virus by IFN treatment, IFN-α prominently impeded the development of large IE62(+) nuclear compartments and significantly decreased transcription of VZV genes. Both the expression level and stable recruitment of MED25 to IE62(+) replication compartments were inhibited by IFN-α. While IFN-α treatment upregulated CDK8 expression, redistribution and recruitment of CDK8 to IE62(+) replication compartments in infected cells was not affected by VZV. CONCLUSION: IFN-α exerts multiple inhibitory activities against virus infections. In this study, we provide visionary demonstration that continuous translocation of MED25 into VZV replication compartments ensures production of virions. IFN-α greatly impedes the formation of a stable complex between IE62 and the Mediator complex thereby suppresses VZV gene transcription. Our demonstration that IFN-α-induced antiviral effect against VZV infection is through inhibiting the reorganization of nuclear components uncovers a novel function of IFN-α. Targeting the interaction between IE62 and MED25 may offer a novel approach to the development of antiviral agents against VZV infection

Adhesive L1CAM-Robo Signaling Aligns Growth Cone F-Actin Dynamics to Promote Axon-Dendrite Fasciculation in C. elegans

Neurite fasciculation through contact-dependent signaling is important for the wiring and function of the neuronal circuits. Here, we describe a type of axon-dendrite fasciculation in C. elegans, where proximal dendrites of the nociceptor PVD adhere to the axon of the ALA interneuron. This axon-dendrite fasciculation is mediated by a previously uncharacterized adhesive signaling by the ALA membrane signal SAX-7/L1CAM and the PVD receptor SAX-3/Robo but independent of Slit. L1CAM physically interacts with Robo and instructs dendrite adhesion in a Robo-dependent manner. Fasciculation mediated by L1CAM-Robo signaling aligns F-actin dynamics in the dendrite growth cone and facilitates dynamic growth cone behaviors for efficient dendrite guidance. Disruption of PVD dendrite fasciculation impairs nociceptive mechanosensation and rhythmicity in body curvature, suggesting that dendrite fasciculation governs the functions of mechanosensory circuits. Our work elucidates the molecular mechanisms by which adhesive axon-dendrite signaling shapes the construction and function of sensory neuronal circuits

All-trans retinoic acid ameliorates glycemic control in diabetic mice via modulating pancreatic islet production of vascular endothelial growth factor-A.

Patients with type 1 diabetes mellitus are associated with impairment in vitamin A metabolism. This study evaluated whether treatment with retinoic acid, the biologically active metabolite of vitamin A, can ameliorate diabetes. All-trans retinoic acid (atRA) was used to treat streptozotocin (STZ)-induced diabetic mice which revealed atRA administration ameliorated blood glucose levels of diabetic mice. This hyperglycemic amelioration was accompanied by an increase in the amount of β cells co-expressed Pdx1 and insulin and by restoration of the vascular laminin expression. The atRA-induced production of vascular endothelial growth factor-A from the pancreatic islets was possibly the key factor that mediated the restoration of islet vascularity and recovery of β-cell mass. Furthermore, the combination of islet transplantation and atRA administration significantly rescued hyperglycemia in diabetic mice. These findings suggest that vitamin A derivatives can potentially be used as a supplementary treatment to improve diabetes management and glycemic control

Comorbid Mental Disorders in Anxiety Disorders: Genetic Aspects of Bipolar Disorders and of Ethnicity

Anxiety disorder (AD) is commonly comorbid with other mental illness. It could be a state or trait, controversially. Evidence for an association between alcoholism and anxiety has emerged from clinical studies of patients with alcoholism, and those of patients with anxiety disorders. Alcohol dependence (or abuse) as well as bipolar disorder (BP) is usually comorbid with anxiety disorder and/or depressive disorder, which often coexist and are difficult to distinguish from one another. However, in Han Chinese population, the comorbidity rate either with alcoholism or bipolar disorder was not reported as much high as reported in Caucasians, this finding of comorbidity between anxiety/depressive disorders and alcohol dependence (or abuse) or/and bipolar disorders, possibly at the genetic level, makes the differentiation of their categorical diagnoses in the association study vitally important

KL-Divergence Guided Temperature Sampling

Temperature sampling is a conventional approach to diversify large language model predictions. As temperature increases, the prediction becomes diverse but also vulnerable to hallucinations -- generating tokens that are sensible but not factual. One common approach to mitigate hallucinations is to provide source/grounding documents and the model is trained to produce predictions that bind to and are attributable to the provided source. It appears that there is a trade-off between diversity and attribution. To mitigate any such trade-off, we propose to relax the constraint of having a fixed temperature over decoding steps, and a mechanism to guide the dynamic temperature according to its relevance to the source through KL-divergence. Our experiments justifies the trade-off, and shows that our sampling algorithm outperforms the conventional top-k and top-p algorithms in conversational question-answering and summarization tasks

Look, the World is Watching How We Treat Migrants! The Making of the Anti-Trafficking Legislation during the Ma Administration

Employing the spiral model, this research analyses how anti-human trafficking legislation was promulgated during the Ma Ying-jeou (Ma Yingjiu) presidency. This research found that the gov- ernment of Taiwan was just as accountable for the violation of mi- grants’ human rights as the exploitive placement agencies and abusive employers. This research argues that, given its reliance on the United States for political and security support, Taiwan has made great ef- forts to improve its human rights records and meet US standards for protecting human rights. The reform was a result of multilevel inputs, including US pressure and collaboration between transnational and domestic advocacy groups. A major contribution of this research is to challenge the belief that human rights protection is intrinsic to dem- ocracy. In the same light, this research also cautions against Taiwan’s subscription to US norms since the reform was achieved at the cost of stereotyping trafficking victimhood, legitimising state surveillance, and further marginalising sex workers

Adhesive L1CAM-Robo Signaling Aligns Growth Cone F-Actin Dynamics to Promote Axon-Dendrite Fasciculation in C. elegans

Neurite fasciculation through contact-dependent signaling is important for the wiring and function of the neuronal circuits. Here, we describe a type of axon-dendrite fasciculation in C. elegans, where proximal dendrites of the nociceptor PVD adhere to the axon of the ALA interneuron. This axon-dendrite fasciculation is mediated by a previously uncharacterized adhesive signaling by the ALA membrane signal SAX-7/L1CAM and the PVD receptor SAX-3/Robo but independent of Slit. L1CAM physically interacts with Robo and instructs dendrite adhesion in a Robo-dependent manner. Fasciculation mediated by L1CAM-Robo signaling aligns F-actin dynamics in the dendrite growth cone and facilitates dynamic growth cone behaviors for efficient dendrite guidance. Disruption of PVD dendrite fasciculation impairs nociceptive mechanosensation and rhythmicity in body curvature, suggesting that dendrite fasciculation governs the functions of mechanosensory circuits. Our work elucidates the molecular mechanisms by which adhesive axon-dendrite signaling shapes the construction and function of sensory neuronal circuits

Observational connection of non-thermal X-ray emission from pulsars with their timing properties and thermal emission

The origin and radiation mechanisms of high energy emissions from pulsars have remained mysterious since their discovery. Here we report, based on a sample of 68 pulsars, observational connection of non-thermal X-ray emissions from pulsars with their timing properties and thermal emissions, which may provide some constraints on theoretical modeling. Besides strong correlations with the spin-down power $\dot{E}$ and the magnetic field strength at the light cylinder $B_{\rm lc}$, the non-thermal X-ray luminosity in 0.5 - 8 keV, $L_{\rm p}$, represented by the power-law component in the spectral model, is found to be strongly correlated with the highest possible electric field strength in the polar gap, $E_{\rm pc}$, of the pulsar. The spectral power index $\Gamma_{\rm p}$ of that power-law component is also found, for the first time in the literature, to strongly correlate with $\dot{E}$, $B_{\rm lc}$ and $E_{\rm pc}$, thanks to the large sample. In addition, we found that $L_{\rm p}$ can be well described by $L_{\rm p}\propto T^{5.96\pm 0.64}R^{2.24\pm 0.18}$, where $T$ and $R$ are the surface temperature and the emitting-region radius of the surface thermal emission, represented by the black-body component in the spectral model. $\Gamma_{\rm p}$, on the other hand, can be well described only when timing variables are included, and the relation is $\Gamma_{\rm p} = \log(T^{-5.8\pm 1.93}R^{-2.29\pm 0.85}P^{-1.19\pm 0.88}\dot{P}^{0.94\pm 0.44})$ plus a constant. These relations strongly suggest the existence of connections between surface thermal emission and electron-positron pair production in pulsar magnetospheres.Comment: 13 pages, 11 figures, accepted by MNRA

Transformed extracellular vesicles with high angiogenic ability as therapeutics of distal ischemic tissues

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