On robust estimation of the location parameter

A newly described coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is the causative agent of coronavirus disease 2019 (COVID-19), has infected over 2.3 million people, led to the death of more than 160,000 individuals and caused worldwide social and economic disruption1,2. There are no antiviral drugs with proven clinical efficacy for the treatment of COVID-19, nor are there any vaccines that prevent infection with SARS-CoV-2, and efforts to develop drugs and vaccines are hampered by the limited knowledge of the molecular details of how SARS-CoV-2 infects cells. Here we cloned, tagged and expressed 26 of the 29 SARS-CoV-2 proteins in human cells and identified the human proteins that physically associated with each of the SARS-CoV-2 proteins using affinity-purification mass spectrometry, identifying 332 high-confidence protein–protein interactions between SARS-CoV-2 and human proteins. Among these, we identify 66 druggable human proteins or host factors targeted by 69 compounds (of which, 29 drugs are approved by the US Food and Drug Administration, 12 are in clinical trials and 28 are preclinical compounds). We screened a subset of these in multiple viral assays and found two sets of pharmacological agents that displayed antiviral activity: inhibitors of mRNA translation and predicted regulators of the sigma-1 and sigma-2 receptors. Further studies of these host-factor-targeting agents, including their combination with drugs that directly target viral enzymes, could lead to a therapeutic regimen to treat COVID-19. A human–SARS-CoV-2 protein interaction map highlights cellular processes that are hijacked by the virus and that can be targeted by existing drugs, including inhibitors of mRNA translation and predicted regulators of the sigma receptors.

/pdf/a-sars-cov-2-protein-interaction-map-reveals-targets-for-5d1m2n6hc1.pdf

A SARS-CoV-2 protein interaction map reveals targets for drug repurposing.

MicroRNAs (miRNAs) are endogenous, small non-coding RNAs that function in regulation of gene expression. Compelling evidences have demonstrated that miRNA expression is dysregulated in human cancer through various mechanisms, including amplification or deletion of miRNA genes, abnormal transcriptional control of miRNAs, dysregulated epigenetic changes and defects in the miRNA biogenesis machinery. MiRNAs may function as either oncogenes or tumor suppressors under certain conditions. The dysregulated miRNAs have been shown to affect the hallmarks of cancer, including sustaining proliferative signaling, evading growth suppressors, resisting cell death, activating invasion and metastasis, and inducing angiogenesis. An increasing number of studies have identified miRNAs as potential biomarkers for human cancer diagnosis, prognosis and therapeutic targets or tools, which needs further investigation and validation. In this review, we focus on how miRNAs regulate the development of human tumors by acting as tumor suppressors or oncogenes.

/pdf/the-role-of-micrornas-in-human-cancer-2ggotut2k7.pdf

The role of MicroRNAs in human cancer

Tumours display considerable variation in the patterning and properties of angiogenic blood vessels, as well as in their responses to anti-angiogenic therapy. Angiogenic programming of neoplastic tissue is a multidimensional process regulated by cancer cells in concert with a variety of tumour-associated stromal cells and their bioactive products, which encompass cytokines and growth factors, the extracellular matrix and secreted microvesicles. In this Review, we discuss the extrinsic regulation of angiogenesis by the tumour microenvironment, highlighting potential vulnerabilities that could be targeted to improve the applicability and reach of anti-angiogenic cancer therapies.

Microenvironmental regulation of tumour angiogenesis

Oncogenic BRAF Induces Senescence and Apoptosis through Pathways Mediated by the Secreted Protein IGFBP7

Thrombosis and inflammation involve complex platelet-leukocyte interaction, the details of which are not fully elucidated. Therefore, we investigated cross talk between platelets and leukocytes in whole blood, under the following physiological conditions: at 37°C, with normal calcium concentrations, and with shear force. Platelet P-selectin and leukocyte CD11b expression were used to monitor platelet and leukocyte activation, respectively, and platelet-leukocyte aggregation (PLA) was analyzed. The leukocyte-specific agonist N-formyl-methionyl-leucyl-phenylalanine (10 26 mol/L) increased P-selectin-positive platelets from 2.560.1% to 5.160.6% (P,0.05). The increase was inhibited by either the platelet-activating factor (PAF) antagonist SR27417, the superoxide anion scavenger superoxide dismutase, the 5-lipoxygenase inhibitor Zileuton, or the 5-lipoxygenase-activating protein inhibitor MK-886, suggesting the involvement of PAF, superoxide anion, and 5-lipoxygenase products in leukocyte-induced platelet activation. The platelet-specific agonist collagen (1 mg/mL) increased leukocyte CD11b expression from 2.9460.52 to 3.8160.58 (P,0.05); this was not inhibited by the thromboxane A2 receptor antagonist ICI 192.605 or the PAF antagonist SR27417. Platelet P-selectin expression induced by N-formyl-methionyl-leucyl-phenylalanine and leukocyte CD11b expression induced by collagen could be suppressed by glycoprotein IIb/IIIa blockade or P-selectin blockade. This study documents platelet-leukocyte cross talk under conditions that mimic a physiological state and suggests that this involves multiple mediators and mechanisms. Furthermore, new evidence of integrin and selectin involvement in intracellular and intercellular signaling during platelet-leukocyte cross talk is provided. (Arterioscler Thromb Vasc Biol. 2000;20:2702- 2708.)

Platelet-Leukocyte Cross Talk in Whole Blood

In the last few years, an emerging trend in automatic speech recognition research is the study of end-to-end (E2E) systems. Connectionist Temporal Classification (CTC), Attention Encoder-Decoder (AED), and RNN Transducer (RNN-T) are the most popular three methods. Among these three methods, RNN-T has the advantages to do online streaming which is challenging to AED and it doesn't have CTC's frame-independence assumption. In this paper, we improve the RNN-T training in two aspects. First, we optimize the training algorithm of RNN-T to reduce the memory consumption so that we can have larger training minibatch for faster training speed. Second, we propose better model structures so that we obtain RNN-T models with the very good accuracy but small footprint. Trained with 30 thousand hours anonymized and transcribed Microsoft production data, the best RNN-T model with even smaller model size (216 Megabytes) achieves up-to 11.8% relative word error rate (WER) reduction from the baseline RNN-T model. This best RNN-T model is significantly better than the device hybrid model with similar size by achieving up-to 15.0% relative WER reduction, and obtains similar WERs as the server hybrid model of 5120 Megabytes in size.

Improving RNN Transducer Modeling for End-to-End Speech Recognition

Apoptosis has a vital role in maintaining tissue homeostasis, and dysregulation of the apoptotic pathway is now widely recognized as a key step in tumourigenesis Increasingly, evidence has demonstrated that microRNA (miRNA) can exert various biological functions in tumours by targeting oncogenes or tumour suppressors Nevertheless, the role of miRNA in apoptosis remains unclear Here we show that ectopical expression of miR-148a can induce apoptosis in colorectal cancer cells In addition, MYB can inhibit miR-148a by directly acting on the transcription factor binding site in miR-148a gene and miR-148a can posttranscriptionally silence Bcl-2 Subsequently, the intrinsic apoptosis pathway is activated by releasing cytochrome c, cleaving caspase 9, caspase 3 and PARP, which eventually induce cancer-cell apoptosis These findings are part of a hitherto undocumented apoptotic regulatory pathway in which a pleiotropic transcription factor controls the expression of a miRNA and the miRNA inhibits the target, leading to activation of an intrinsic mitochondrial pathway and tumour apoptosis

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MiR-148a promotes apoptosis by targeting Bcl-2 in colorectal cancer.

Distinct platelet packaging, release, and surface expression of proangiogenic and antiangiogenic factors on different platelet stimuli.

Human embryonic stem cells (hESCs) are ideal seed cells for tissue regeneration, but no research has yet been reported concerning their potential for tendon regeneration. This study investigated the strategy and efficacy of using hESCs for tendon regeneration as well as the mechanism involved. hESCs were first induced to differentiate into mesenchymal stem cells (MSCs), which had the potential to differentiate into the three mesenchymal lineages and were positive for MSC surface markers. hESC-derived MSCs (hESC-MSCs) regenerated tendon tissues in both an in vitro tissue engineering model and an in vivo ectopic tendon regeneration model, as confirmed by the expression of tendon-specific genes and structure. In in-situ rat patellar tendon repair, tendon treated with hESC-MSCs had much better structural and mechanical properties than did controls. Furthermore, hESC-MSCs remained viable at the tendon wound site for at least 4 weeks and secreted human fetal tendon-specific matrix components and differentiation factors, which then activated the endogenous regeneration process in tendon. Moreover, no teratoma was found in any samples. These findings demonstrate a safe and practical strategy of applying ESCs for tendon regeneration and may assist in future strategies to treat tendon diseases.

https://stemcellsjournals.onlinelibrary.wiley.com/doi/pdf/10.1002/stem.61

Hu Hu

Papers

Platelet-Leukocyte Cross Talk in Whole Blood

Improving RNN Transducer Modeling for End-to-End Speech Recognition

MiR-148a promotes apoptosis by targeting Bcl-2 in colorectal cancer.

Distinct platelet packaging, release, and surface expression of proangiogenic and antiangiogenic factors on different platelet stimuli.

Stepwise Differentiation of Human Embryonic Stem Cells Promotes Tendon Regeneration by Secreting Fetal Tendon Matrix and Differentiation Factors