Nickela‐electrooxidative C−H alkoxylations with challenging secondary alcohols were accomplished in a fully dehydrogenative fashion, thereby avoiding stoichiometric chemical oxidants, with H2 as the ...only stoichiometric byproduct. The nickela‐electrocatalyzed oxygenation proved viable with various (hetero)arenes, including naturally occurring secondary alcohols, without racemization. Detailed mechanistic investigation, including DFT calculations and cyclovoltammetric studies of a well‐defined C−H activated nickel(III) intermediate, suggest an oxidation‐induced reductive elimination at nickel(III).
II, III, or IV: Challenging secondary C−H alkoxygenations were accomplished with a versatile nickel electrocatalyst. Mechanistic investigation through isolation experiments, cyclovoltammetry, and density functional theory (DFT) calculations provided support for a process involving oxidation‐induced reductive elimination. MQ=6‐methylquinoline.
Single-cell RNA sequencing can reveal the transcriptional state of cells, yet provides little insight into the upstream regulatory landscape associated with open or accessible chromatin regions. ...Joint profiling of accessible chromatin and RNA within the same cells would permit direct matching of transcriptional regulation to its outputs. Here, we describe droplet-based single-nucleus chromatin accessibility and mRNA expression sequencing (SNARE-seq), a method that can link a cell's transcriptome with its accessible chromatin for sequencing at scale. Specifically, accessible sites are captured by Tn5 transposase in permeabilized nuclei to permit, within many droplets in parallel, DNA barcode tagging together with the mRNA molecules from the same cells. To demonstrate the utility of SNARE-seq, we generated joint profiles of 5,081 and 10,309 cells from neonatal and adult mouse cerebral cortices, respectively. We reconstructed the transcriptome and epigenetic landscapes of major and rare cell types, uncovered lineage-specific accessible sites, especially for low-abundance cells, and connected the dynamics of promoter accessibility with transcription level during neurogenesis.
A fundamental task in various disciplines of science, including biology, is to find underlying causal relations and make use of them. Causal relations can be seen if interventions are properly ...applied; however, in many cases they are difficult or even impossible to conduct. It is then necessary to discover causal relations by analyzing statistical properties of purely observational data, which is known as causal discovery or causal structure search. This paper aims to give a introduction to and a brief review of the computational methods for causal discovery that were developed in the past three decades, including constraint-based and score-based methods and those based on functional causal models, supplemented by some illustrations and applications.
An early diagnosis of hepatocellular carcinoma (HCC) followed by effective treatment is currently critical for improving the prognosis and reducing the associated economic burden. Alpha-fetoprotein ...(AFP) is the most widely used biomarker for HCC diagnosis. Based on elevated serum AFP levels as well as typical imaging features, AFP-positive HCC (APHC) can be easily diagnosed, but AFP-negative HCC (ANHC) is not easily detected due to lack of ideal biomarkers and thus mainly reliance on imaging. Imaging for the diagnosis of ANHC is probably insufficient in sensitivity and/or specificity because most ANHC tumors are small and early-stage HCC, and it is involved in sophisticated techniques and high costs. Moreover, ANHC accounts for nearly half of HCC and exhibits a better prognosis compared with APHC. Therefore, the diagnosis of ANHC in clinical practice has been a critical issue for the early treatment and prognosis improvement of HCC. In recent years, tremendous efforts have been made to discover new biomarkers complementary to AFP for HCC diagnosis. In this review, we systematically review and discuss the recent advances of blood biomarkers for HCC diagnosis, including DNA biomarkers, RNA biomarkers, protein biomarkers, and conventional laboratory metrics, focusing on their diagnostic evaluation alone and in combination, in particular on their diagnostic performance for ANHC.
To ensure a successful infection, herpesviruses have developed elegant strategies to counterbalance the host anti-viral responses. Sterile alpha motif and HD domain 1 (SAMHD1) was recently identified ...as an intrinsic restriction factor for a variety of viruses. Aside from HIV-2 and the related simian immunodeficiency virus (SIV) Vpx proteins, the direct viral countermeasures against SAMHD1 restriction remain unknown. Using Epstein-Barr virus (EBV) as a primary model, we discover that SAMHD1-mediated anti-viral restriction is antagonized by EBV BGLF4, a member of the conserved viral protein kinases encoded by all herpesviruses. Mechanistically, we find that BGLF4 phosphorylates SAMHD1 and thereby inhibits its deoxynucleotide triphosphate triphosphohydrolase (dNTPase) activity. We further demonstrate that the targeting of SAMHD1 for phosphorylation is a common feature shared by beta- and gamma-herpesviruses. Together, our findings uncover an immune evasion mechanism whereby herpesviruses exploit the phosphorylation of SAMHD1 to thwart host defenses.
Ruthenium(II)‐catalyzed meta‐selective C−H (di)fluoromethylation was accomplished by phosphine and carboxylate cooperation. The remote C−H functionalization was characterized by ample substrate ...scope, thereby setting the stage for meta‐(di)fluoromethylation through facile C−H cleavage.
2 for meta: meta‐C−H mono‐ and difluoromethylation reactions with ample scope and excellent levels of remote selectivity were accessed with a ruthenium(II) catalyst bearing cooperative electron‐deficient triarylphosphine and carboxylate ligands.
Breakthroughs in the development of high-throughput technologies for profiling transcriptomes at the single-cell level have helped biologists to understand the heterogeneity of cell populations, ...disease states and developmental lineages. However, these single-cell RNA sequencing (scRNA-seq) technologies generate an extraordinary amount of data, which creates analysis and interpretation challenges. Additionally, scRNA-seq datasets often contain technical sources of noise owing to incomplete RNA capture, PCR amplification biases and/or batch effects specific to the patient or sample. If not addressed, this technical noise can bias the analysis and interpretation of the data. In response to these challenges, a suite of computational tools has been developed to process, analyse and visualize scRNA-seq datasets. Although the specific steps of any given scRNA-seq analysis might differ depending on the biological questions being asked, a core workflow is used in most analyses. Typically, raw sequencing reads are processed into a gene expression matrix that is then normalized and scaled to remove technical noise. Next, cells are grouped according to similarities in their patterns of gene expression, which can be summarized in two or three dimensions for visualization on a scatterplot. These data can then be further analysed to provide an in-depth view of the cell types or developmental trajectories in the sample of interest.
A
bstract
We explore the thermodynamics and the underlying kinetics of the van der Waals type phase transition of Reissner-Nordström anti-de Sitter (RNAdS) black holes based on the free energy ...landscape. We show that the thermodynamic stabilities of the three branches of the RNAdS black holes are determined by the underlying free energy landscape topography. We suggest that the large (small) RNAdS black hole can have the probability to switch to the small (large) black hole due to the thermal fluctuation. Such a state switching process under the thermal fluctuation is taken as a stochastic process and the associated kinetics can be described by the probabilistic Fokker-Planck equation. We obtained the time dependent solutions for the probabilistic evolution by numerically solving Fokker-Planck equation with the reflecting boundary conditions. We also investigated the first passage process which describes how fast a system undergoes a stochastic process for the first time. The distributions of the first passage time switching from small (large) to large (small) black hole and the corresponding mean first passage time as well as its fluctuations at different temperatures are studied in detail. We conclude that the mean first passage time and its fluctuations are related to the free energy landscape topography through barrier heights and temperatures.
PDF
