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com/xmuyulab/DreamDIA-XMBD for high coverage and accuracy DIA data analysis.Development of cortical tissue during infancy is critical for the emergence of typical brain functions in cortex. However, how cortical microstructure develops during infancy remains unknown. We measured the longitudinal development of cortex from birth to six months of age using multimodal quantitative imaging of cortical microstructure. Here we show that infants' cortex undergoes profound microstructural tissue growth during the first six months of human life. Comparison of postnatal to prenatal transcriptomic gene expression data demonstrates that myelination and synaptic processes are dominant contributors to this postnatal microstructural tissue growth. Using visual cortex as a model system, we find hierarchical microstructural growth higher-level visual areas have less mature tissue at birth than earlier visual areas but grow at faster rates. This overturns the prominent view that visual areas that are most mature at birth develop fastest. Together, in vivo, longitudinal, and quantitative measurements, which we validated with ex vivo transcriptomic data, shed light on the rate, sequence, and biological mechanisms of developing cortical systems during early infancy. Importantly, our findings propose a hypothesis that cortical myelination is a key factor in cortical development during early infancy, which has important implications for diagnosis of neurodevelopmental disorders and delays in infants.The adoptive transfer of regulatory T-cells (Tregs) is a promising therapeutic approach in transplantation and autoimmunity. However, because large cell numbers are needed to achieve a therapeutic effect, in vitro expansion is required. By comparing their function, phenotype and transcriptomic profile against ex vivo Tregs, we demonstrate that expanded human Tregs switch their metabolism to aerobic glycolysis and show enhanced suppressive function through hypoxia-inducible factor 1-alpha (HIF1A) driven acquisition of CD73 expression. In conjunction with CD39, CD73 expression enables expanded Tregs to convert ATP to immunosuppressive adenosine. We conclude that for maximum therapeutic benefit, Treg expansion protocols should be optimised for CD39/CD73 co-expression.Uni-modal, not bi-modal, of abnormal grain growth has been observed in (111) oriented and nano-twinned Cu films. Because of the highly anisotropic microstructure, our kinetic analysis and calculation showed that it is the mobility which dominates the uni-modal growth, in which the lateral growth rate can be two orders of magnitude higher than the vertical growth rate. As a consequence, the abnormal grain growth has been converted from bi-modal to uni-modal.Recent work has found that an individual's beliefs and personal characteristics can impact perceptions of and responses to the COVID-19 pandemic. Certain individuals-such as those who are politically conservative or who endorse conspiracy theories-are less likely to engage in preventative behaviors like social distancing. The current research aims to address whether these individual differences not only affect people's reactions to the pandemic, but also their actual likelihood of contracting COVID-19. In the early months of the pandemic, U.S. participants responded to a variety of individual difference measures as well as questions specific to the pandemic itself. Four months later, 2120 of these participants responded with whether they had contracted COVID-19. Nearly all of our included individual difference measures significantly predicted whether a person reported testing positive for the virus in this four-month period. Additional analyses revealed that all of these relationships were primarily mediated by whether participants held accurate knowledge about COVID-19. These findings offer useful insights for developing more effective interventions aimed at slowing the spread of both COVID-19 and future diseases. Moreover, some findings offer critical tests of the validity of such theoretical frameworks as those concerning conspiratorial ideation and disgust sensitivity within a real-world context.Phosphatidylinositol-4,5-bisphosphate (PIP2) is a signaling lipid which regulates voltage-gated Kv7/KCNQ potassium channels. Altered PIP2 sensitivity of neuronal Kv7.2 channel is involved in KCNQ2 epileptic encephalopathy. However, the molecular action of PIP2 on Kv7.2 gating remains largely elusive. Here, we use molecular dynamics simulations and electrophysiology to characterize PIP2 binding sites in a human Kv7.2 channel. In the closed state, PIP2 localizes to the periphery of the voltage-sensing domain (VSD). In the open state, PIP2 binds to 4 distinct interfaces formed by the cytoplasmic ends of the VSD, the gate, intracellular helices A and B and their linkers. PIP2 binding induces bilayer-interacting conformation of helices A and B and the correlated motion of the VSD and the pore domain, whereas charge-neutralizing mutations block this coupling and reduce PIP2 sensitivity of Kv7.2 channels by disrupting PIP2 binding. These findings reveal the allosteric role of PIP2 in Kv7.2 channel activation.Refined understanding of the association of retinal microstructure with current and future (post-treatment) function in chronic central serous chorioretinopathy (cCSC) may help to identify patients that would benefit most from treatment. In this post-hoc analysis of data from the prospective, randomized PLACE trial (NCT01797861), we aimed to determine the accuracy of AI-based inference of retinal function from retinal morphology in cCSC. Longitudinal spectral-domain optical coherence tomography (SD-OCT) data from 57 eyes of 57 patients from baseline, week 6-8 and month 7-8 post-treatment were segmented using deep-learning software. Fundus-controlled perimetry data were aligned to the SD-OCT data to extract layer thickness and reflectivity values for each test point. Point-wise retinal sensitivity could be inferred with a (leave-one-out) cross-validated mean absolute error (MAE) [95% CI] of 2.93 dB [2.40-3.46] (scenario 1) using random forest regression. With addition of patient-specific baseline data (scenario 2), retinal sensitivity at remaining follow-up visits was estimated even more accurately with a MAE of 1.07 dB [1.06-1.08]. In scenario 3, month 7-8 post-treatment retinal sensitivity was predicted from baseline SD-OCT data with a MAE of 3.38 dB [2.82-3.94]. Our study shows that localized retinal sensitivity can be inferred from retinal structure in cCSC using machine-learning. Especially, prediction of month 7-8 post-treatment sensitivity with consideration of the treatment as explanatory variable constitutes an important step toward personalized treatment decisions in cCSC.Fluorescein and indocyanine green angiography have been the traditional ways to image the vasculature of the iris in the last few decades. Because of the invasive nature of these procedures, they are performed in rare situations, and thus, our understanding about iris vasculature is very limited. Optical coherence tomography angiography (OCTA) is a noninvasive imaging method that enables the detailed visualization of the retinal and choroidal vascular networks. More recently, it has been also used for the examination of the iris vasculature in healthy and disease eyes. However, there is a lack of uniformity in the image acquisition protocols and interpretations in both healthy and pathological conditions. Artifacts of iris OCTA include shadowing, motion, segmentations errors, mirror effects. OCTA devices have an eye-tracking system designed for the posterior segment and the applications of these systems on the anterior segment can determine motion lines, vessel duplication, and vessel discontinuity. OCTA of the iris should always be performed under ambient room lighting to create miosis and reduce iris vasculature changes during the examination. In the near future, eye-tracking systems specifically designed for the iris vessels could permit the follow-up function, and the development of new OCTA metrics could reveal interesting applications of this new imaging technique.MYC is a prolific proto-oncogene driving the malignant behaviors of numerous common cancers, yet potent and selective cell-permeable inhibitors of MYC remain elusive. In order to ultimately realize the goal of therapeutic MYC inhibition in cancer, we have initiated discovery chemistry efforts aimed at inhibiting MYC translation. Here we describe a series of conformationally stabilized synthetic antisense oligonucleotides designed to target MYC mRNA (MYCASOs). To support bioactivity, we designed and synthesized this focused library of MYCASOs incorporating locked nucleic acid (LNA) bases at the 5'- and 3'-ends, a phosphorothioate backbone, and internal DNA bases. Treatment of MYC-expressing cancer cells with MYCASOs leads to a potent decrease in MYC mRNA and protein levels. CP-690550 research buy Cleaved MYC mRNA in MYCASO-treated cells is detected with a sensitive 5' Rapid Amplification of cDNA Ends (RACE) assay. MYCASO treatment of cancer cell lines leads to significant inhibition of cellular proliferation while specifically perturbing MYC-driven gene expression signatures. In a MYC-induced model of hepatocellular carcinoma, MYCASO treatment decreases MYC protein levels within tumors, decreases tumor burden, and improves overall survival. MYCASOs represent a new chemical tool for in vitro and in vivo modulation of MYC activity, and promising therapeutic agents for MYC-addicted tumors.Aberrant glucose metabolism and elevated O-linked β-N-acetylglucosamine modification (O-GlcNAcylation) are hallmarks of hepatocellular carcinoma (HCC). Loss of phosphoenolpyruvate carboxykinase 1 (PCK1), the major rate-limiting enzyme of hepatic gluconeogenesis, increases hexosamine biosynthetic pathway (HBP)-mediated protein O-GlcNAcylation in hepatoma cell and promotes cell growth and proliferation. However, whether PCK1 deficiency and hyper O-GlcNAcylation can induce HCC metastasis is largely unknown. Here, gain- and loss-of-function studies demonstrate that PCK1 suppresses HCC metastasis in vitro and in vivo. Specifically, lysine acetyltransferase 5 (KAT5), belonging to the MYST family of histone acetyltransferases (HAT), is highly modified by O-GlcNAcylation in PCK1 knockout hepatoma cells. link2 Mechanistically, PCK1 depletion suppressed KAT5 ubiquitination by increasing its O-GlcNAcylation, thereby stabilizing KAT5. KAT5 O-GlcNAcylation epigenetically activates TWIST1 expression via histone H4 acetylation, and enhances MMP9 and MMP14 expression via c-Myc acetylation, thus promoting epithelial-mesenchymal transition (EMT) in HCC. link3 In addition, targeting HBP-mediated O-GlcNAcylation of KAT5 inhibits lung metastasis of HCC in hepatospecific Pck1-deletion mice. Collectively, our findings demonstrate that PCK1 depletion increases O-GlcNAcylation of KAT5, epigenetically induces TWIST1 expression and promotes HCC metastasis, and link metabolic enzyme, post-translational modification (PTM) with epigenetic regulation.Previous work has demonstrated that action video game training produces enhancements in a wide range of cognitive abilities. Here we evaluate a possible mechanism by which such breadth of enhancement could be attained that action game training enhances learning rates in new tasks (i.e., "learning to learn"). In an initial controlled intervention study, we show that individuals who were trained on action video games subsequently exhibited faster learning in the two cognitive domains that we tested, perception and working memory, as compared to individuals who trained on non-action games. We further confirmed the causal effect of action video game play on learning ability in a pre-registered follow-up study that included a larger number of participants, blinding, and measurements of participant expectations. Together, this work highlights enhanced learning speed for novel tasks as a mechanism through which action video game interventions may broadly improve task performance in the cognitive domain.
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