The health crisis due to coronavirus disease 2019 (COVID-19) has shocked the world, with more than 1 million infections and casualties. COVID-19 can present from mild illness to multi-organ ...involvement, but especially acute respiratory distress syndrome. Cardiac injury and arrhythmias, including atrial fibrillation (AF), are not uncommon in COVID-19. COVID-19 is highly contagious, and therapy against the virus remains premature and largely unknown, which makes the management of AF patients during the pandemic particularly challenging. We describe a possible pathophysiological link between COVID-19 and AF, and therapeutic considerations for AF patients during this pandemic.
Mesenchymal stem cells (MSCs) are promising tools for the treatment of diseases such as infarcted myocardia and strokes because of their ability to promote endogenous angiogenesis and neurogenesis ...via a variety of secreted factors. MSCs found in the Wharton's jelly of the human umbilical cord are easily obtained and are capable of transplantation without rejection. We isolated MSCs from Wharton's jelly and bone marrow (WJ-MSCs and BM-MSCs, respectively) and compared their secretomes. It was found that WJ-MSCs expressed more genes, especially secreted factors, involved in angiogenesis and neurogenesis. Functional validation showed that WJ-MSCs induced better neural differentiation and neural cell migration via a paracrine mechanism. Moreover, WJ-MSCs afforded better neuroprotection efficacy because they preferentially enhanced neuronal growth and reduced cell apoptotic death of primary cortical cells in an oxygen-glucose deprivation (OGD) culture model that mimics the acute ischemic stroke situation in humans. In terms of angiogenesis, WJ-MSCs induced better microvasculature formation and cell migration on co-cultured endothelial cells. Our results suggest that WJ-MSC, because of a unique secretome, is a better MSC source to promote in vivo neurorestoration and endothelium repair. This study provides a basis for the development of cell-based therapy and carrying out of follow-up mechanistic studies related to MSC biology.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
ST3Gal1 is a key sialyltransferase which adds α2,3‐linked sialic acid to substrates and generates core 1 O‐glycan structure. Upregulation of ST3Gal1 has been associated with worse prognosis of breast ...cancer patients. However, the protein substrates of ST3Gal1 implicated in tumor progression remain elusive. In our study, we demonstrated that ST3GAL1‐silencing significantly reduced tumor growth along with a notable decrease in vascularity of MCF7 xenograft tumors. We identified vasorin (VASN) which was shown to bind TGF‐β1, as a potential candidate that links ST3Gal1 to angiogenesis. LC‐MS/MS analysis of VASN secreted from MCF7, revealed that more than 80% of its O‐glycans are sialyl‐3T and disialyl‐T. ST3GAL1‐silencing or desialylation of VASN by neuraminidase enhanced its binding to TGF‐β1 by 2‐ to 3‐fold and thereby dampening TGF‐β1 signaling and angiogenesis, as indicated by impaired tube formation of HUVECs, suppressed angiogenesis gene expression and reduced activation of Smad2 and Smad3 in HUVEC cells. Examination of 114 fresh primary breast cancer and their adjacent normal tissues showed that the expression levels of ST3Gal1 and TGFB1 were high in tumor part and the expression of two genes was positively correlated. Kaplan Meier survival analysis showed a significantly shorter relapse‐free survival for those with lower expression VASN, notably, the combination of low VASN with high ST3GAL1 yielded even higher risk of recurrence (p = 0.025, HR = 2.967, 95% CI = 1.14–7.67). Since TGF‐β1 is known to transcriptionally activate ST3Gal1, our findings illustrated a feedback regulatory loop in which TGF‐β1 upregulates ST3Gal1 to circumvent the negative impact of VASN.
What's new?
The addition of sialic acid to glycoproteins is dysregulated in many cancers, and enhanced expression of one key enzyme, the sialyltransferase ST3Gal1, is associated with poor prognosis. Here, the authors identified the membrane protein vasorin as a new ST3Gal1 substrate and connect it with TGF‐β1‐induced signaling and angiogenesis in breast cancer. As silencing of ST3Gal1 dampened TGF‐β1 signaling and suppressed angiogenesis, development of ST3Gal1 inhibitors might be clinically useful to improve the prognosis of breast cancer patients.
Background Height is an important anthropometric measurement and is associated with many health-related outcomes. Genome-wide association studies (GWASs) have identified hundreds of genetic loci ...associated with height, mainly in individuals of European ancestry. Methods We performed genome-wide association analyses and replicated previously reported GWAS-determined single nucleotide polymorphisms (SNPs) in the Taiwanese Han population (Taiwan Biobank; n = 67,452). A genetic instrument composed of 251 SNPs was selected from our GWAS, based on height and replication results as the best-fit polygenic risk score (PRS), in accordance with the clumping and p-value threshold method. We also examined the association between genetically determined height (PRS.sub.251) and measured height (phenotype). We performed observational (phenotype) and genetic PRS.sub.251 association analyses of height and health-related outcomes. Results GWAS identified 6843 SNPs in 89 genomic regions with genome-wide significance, including 18 novel loci. These were the most strongly associated genetic loci (EFEMP1, DIS3L2, ZBTB38, LCORL, HMGA1, CS, and GDF5) previously reported to play a role in height. There was a positive association between PRS.sub.251 and measured height (p < 0.001). Of the 14 traits and 49 diseases analyzed, we observed significant associations of measured and genetically determined height with only eight traits (p < 0.05/14 + 49). Height was positively associated with body weight, waist circumference, and hip circumference but negatively associated with body mass index, waist-hip ratio, body fat, total cholesterol, and low-density lipoprotein cholesterol (p < 0.05/14 + 49). Conclusions This study contributes to the understanding of the genetic features of height and health-related outcomes in individuals of Han Chinese ancestry in Taiwan. Keywords: Height, Genome-wide association studies, Genetic single nucleotide polymorphisms, Polygenic risk score, Health-related outcomes
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
MicroRNAs (miRNAs) are small noncoding RNAs that play fundamental roles in diverse biological and pathological processes by targeting the expression of specific genes. Here, we identified 38 ...methylation‐associated miRNAs, the expression of which could be epigenetically restored by cotreatment with 5‐aza‐2′‐deoxycytidine and trichostatin A. Among these 38 miRNAs, we further analyzed miR‐34b, miR‐127‐3p, miR‐129‐3p and miR‐409 because CpG islands are predicted adjacent to them. The methylation‐silenced expression of these miRNAs could be reactivated in gastric cancer cells by treatment with demethylating drugs in a time‐dependent manner. Analysis of the methylation status of these miRNAs showed that the upstream CpG‐rich regions of mir‐34b and mir‐129‐2 are frequently methylated in gastric cancer tissues compared to adjacent normal tissues, and their methylation status correlated inversely with their expression patterns. The expression of miR‐34b and miR‐129‐3p was downregulated by DNA hypermethylation in primary gastric cancers, and the low expression was associated with poor clinicopathological features. In summary, our study shows that tumor‐specific methylation silences miR‐34b and miR‐129 in gastric cancer cells.
Compared to male pups, perinatal female rats rely heavily on neuronal glutamine (Gln) transport for sustaining glutamatergic synaptic release in neurons of the ventrolateral ventral media nucleus of ...the hypothalamus (vlVMH). VMH mainly regulates female sexual behavior and increases glutamate release of perinatal hypothalamic neurons, permanently enhances dendrite spine numbers and is associated with brain and behavioral defeminization. We hypothesized that perinatal interruption of neuronal Gln transport may alter the glutamatergic synaptic transmission during adulthood. Perinatal rats of both sexes received an intracerebroventricular injection of a neuronal Gln uptake blocker, alpha‐(methylamino) isobutyric acid (MeAIB, 5 mM), and were raised until adulthood. Whole‐cell voltage‐clamp recordings of miniature excitatory postsynaptic currents (mEPSCs) and evoked EPSCs (eEPSCs) of vlVMH neurons in adult rats with the perinatal pretreatment were conducted and neuron morphology was subjected to post hoc examination. Perinatal MeAIB treatment sex‐differentially increased mEPSC frequency in males, but decreased mEPSC amplitude and synaptic Glu release in females. The pretreatment sex‐differentially decreased eEPSC amplitude in males but increased AMPA/NMDA current ratio in females, and changed the morphology of vlVMH neurons of adult rats to that of the opposite sex. Most alterations in the glutamatergic synaptic transmission resembled the changes occurring during MeAIB acute exposure in perinatal rats of both sexes. We conclude that perinatal blockade of neuronal Gln transport mediates changes via different presynaptic and postsynaptic mechanisms to induce sex‐differential alterations of the glutamatergic synaptic transmission and organization of vlVMH neurons in adult rats. These changes may be permanent and associated with brain and behavior feminization and/or defeminization in rats.
A schematic representation of sex‐differential alterations of glutamatergic synaptic transmission of neurons in the ventral lateral ventromedial nucleus of the hypothalamus (vlVMH) of male and female adult rats at ages between postnatal day (PN) 60 and PN103. The animals were centrally injected with a neuronal glutamine (Gln) uptake blocker, MeAIB, on PN 5 or 6. Note the sex differences in the presynaptic and postsynaptic mechanisms and neuronal morphology mediated by perinatal MeAIB administration. Most of the changes may be permanent.
Abstract
We herein report a method for the synthesis of 1,4‐dicarbonyl compounds using light‐activated electron donor‐acceptor (EDA) complexes. This multi‐component reaction involves the ...photoactivation of EDA complexes formed by carboxylic acid derivatives, triphenylphosphine, and sodium iodide, resulting in single‐electron reduction. The subsequent decarboxylation fragmentation leads to the formation of nucleophilic alkyl free radicals, which can undergo sequential radical coupling reactions with electron‐deficient and electron‐rich olefins. This method has been successfully applied to various aliphatic carboxylic acid derivatives, including tertiary, secondary, and primary ones, as well as multiple types of electron‐deficient olefins and enol silyl ethers. The entire process is conducted under mild conditions, indicating its potential for the synthesis of valuable synthetic compounds.
Interpolating video frames involving large motions remains an elusive challenge. In case that frames involve small and fast-moving objects, conventional feed-forward neural network-based approaches ...that estimate optical flow and synthesize in-between frames sequentially often result in loss of motion features and thus blurred boundaries. To address the problem, we propose a novel Recurrent Motion-Enhanced Interpolation Network (ReMEI-Net) by assigning attention to the motion features of small objects from both the intra-scale and inter-scale perspectives. Specifically, we add recurrent feedback blocks in the existing multi-scale autoencoder pipeline, aiming to iteratively enhance the motion information of small objects across different scales. Second, to further refine the motion features of the highly moving objects, we propose a Multi-Directional ConvLSTM (MD-ConvLSTM) block to capture the global spatial contextual information of motion from multiple directions. In this way, the coarse-scale features can be utilized to correct and enhance the fine-scale features through the feedback mechanism. Extensive experiments on various datasets demonstrate the superiority of our proposed method over state-of-the-art approaches in terms of clear locations and complete shape.
Understanding foggy image sequence in driving scene is critical for autonomous driving, but it remains a challenging task due to the difficulty in collecting and annotating real-world images of ...adverse weather. Recently, self-training strategy has been considered as a powerful solution for unsupervised domain adaptation, which iteratively adapts the model from the source domain to the target domain by generating target pseudo labels and re-training the model. However, the selection of confident pseudo labels inevitably suffers from the conflict between sparsity and accuracy, both of which will lead to suboptimal models. To tackle this problem, we exploit the characteristics of the foggy image sequence of driving scenes to densify the confident pseudo labels. Specifically, based on the two discoveries of local spatial similarity and adjacent temporal correspondence of the sequential image data, we propose a novel Target-Domain driven pseudo label Diffusion (TDo-Dif) scheme. It employs superpixels and optical flows to identify the spatial similarity and temporal correspondence, respectively, and then diffuses the confident but sparse pseudo labels within a superpixel or a temporal corresponding pair linked by the flow. Moreover, to ensure the feature similarity of the diffused pixels, we introduce local spatial similarity loss and temporal contrastive loss in the model re-training stage. Experimental results show that our TDo-Dif scheme helps the adaptive model achieve 51.92% and 53.84% mean intersection-over-union (mIoU) on two publicly available natural foggy datasets (Foggy Zurich and Foggy Driving), which exceeds the state-of-the-art unsupervised domain adaptive semantic segmentation methods. The proposed method can also be applied to non-sequential images in the target domain by considering only spatial similarity.
Completing a corrupted image by filling in correct structures and reasonable textures for a complex scene remains an elusive challenge. In case that a missing hole involves diverse semantic ...information, conventional two-stage approaches based on structural information often lead to unreliable structural prediction and ambiguous visual texture generation. To address the problem, we propose a SEmantic GUidance and Estimation Network (SeGuE-Net) that iteratively evaluates the uncertainty of inpainted visual contents based on pixel-wise semantic inference and optimize structural priors and inpainted contents alternatively. Specifically, SeGuE-Net utilizes semantic segmentation maps as guidance in each iteration of image inpainting, under which location-dependent inferences are re-estimated, and, accordingly, poorly-inferred regions are refined in subsequent iterations. Extensive experiments on real-world images demonstrate the superiority of our proposed method over state-of-the-art approaches in terms of clear boundaries and photo-realistic textures.
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