Identification of neprilysin as a potential target of arteannuin using computational drug repositioning

The discovery of arteannuin (qinghaosu) in the 20th Century was a major advance for medicine. Besides functioning as a malaria therapy, arteannuin is a pharmacological agent in a range of other diseases, but its mechanism of action remains obscure. In this study, the reverse docking server PharmMapper was used to identify potential targets of arteannuin. The results were checked using the chemical-protein interactome servers DRAR-CPI and DDI-CPI, and verified by AutoDock Vina. The results showed that neprilysin (also known as CD10), a common acute lymphoblastic leukaemia antigen, was the top disease-related target of arteannuin. The chemical-protein interactome and docking results agreed with those of PharmMapper, further implicating neprilysin as a potential target. Although experimental verification is required, this study provides guidance for future pharmacological investigations into novel clinical applications for arteannuin

Alternative splicing and trans-splicing events revealed by analysis of the Bombyx mori transcriptome

Alternative splicing and trans-splicing events have not been systematically studied in the silkworm Bombyx mori. Here, the silkworm transcriptome was analyzed by RNA-seq. We identified 320 novel genes, modified 1140 gene models, and found thousands of alternative splicing and 58 trans-splicing events. Studies of three SR proteins show that both their alternative splicing patterns and mRNA products are conserved from insect to human, and one isoform of Srsf6 with a retained intron is expressed sex-specifically in silkworm gonads. Trans-splicing of mod(mdg4) in silkworm was experimentally confirmed. We identified integrations from a common 5′-gene with 46 newly identified alternative 3′-exons that are located on both DNA strands over a 500-kb region. Other trans-splicing events in B. mori were predicted by bioinformatic analysis, in which 12 events were confirmed by RT-PCR, six events were further validated by chimeric SNPs, and two events were confirmed by allele-specific RT-PCR in F 1 hybrids from distinct silkworm lines of JS and L10, indicating that trans-splicing is more widespread in insects than previously thought. Analysis of the B. mori transcriptome by RNA-seq provides valuable information of regulatory alternative splicing events. The conservation of splicing events across species and newly identified trans-splicing events suggest that B. mori is a good model for future studies. Published by Cold Spring Harbor Laboratory Press. Copyrigh

Top-gated graphene field-effect-transistors formed by decomposition of SiC

Top-gated, few-layer graphene field-effect transistors (FETs) fabricated on thermally-decomposed semi-insulating 4H-SiC substrates are demonstrated. Physical vapor deposited SiO2 is used as the gate dielectric. A two-dimensional hexagonal arrangement of carbon atoms with the correct lattice vectors, observed by high-resolution scanning tunneling microscopy, confirms the formation of multiple graphene layers on top of the SiC substrates. The observation of n-type and p-type transition further verifies Dirac Fermions unique transport properties in graphene layers. The measured electron and hole mobility on these fabricated graphene FETs are as high as 5400 cm2/Vs and 4400 cm2/Vs respectively, which are much larger than the corresponding values from conventional SiC or silicon

Targeting collagen in tumor extracellular matrix as a novel targeted strategy in cancer immunotherapy

Collagen, the most abundant protein in mammal, is widely expressed in tissues and organs, as well as tumor extracellular matrix. Tumor collagen mainly accumulates in tumor stroma or beneath tumor blood vessel endothelium, and is exposed due to the fragmentary structure of tumor blood vessels. Through the blood vessels with enhanced permeability and retention (EPR) effect, collagen-binding macromolecules could easily bind to tumor collagen and accumulate within tumor, supporting tumor collagen to be a potential tumor-specific target. Recently, numerous studies have verified that targeting collagen within tumor extracellular matrix (TEM) would enhance the accumulation and retention of immunotherapy drugs at tumor, significantly improving their anti-tumor efficacy, as well as avoiding severe adverse effects. In this review, we would summarize the known collagen-binding domains (CBD) or proteins (CBP), their mechanism and application in tumor-targeting immunotherapy, and look forward to future development

Asymmetric 3D Elasticâ Plastic Strainâ Modulated Electron Energy Structure in Monolayer Graphene by Laser Shocking

Graphene has a great potential to replace silicon in prospective semiconductor industries due to its outstanding electronic and transport properties; nonetheless, its lack of energy bandgap is a substantial limitation for practical applications. To date, straining graphene to break its lattice symmetry is perhaps the most efficient approach toward realizing bandgap tunability in graphene. However, due to the weak lattice deformation induced by uniaxial or inâ plane shear strain, most strained graphene studies have yielded bandgaps <1 eV. In this work, a modulated inhomogeneous local asymmetric elasticâ plastic straining is reported that utilizes GPaâ level laser shocking at a high strain rate (dε/dt) â 106â 107 sâ 1, with excellent formability, inducing tunable bandgaps in graphene of up to 2.1 eV, as determined by scanning tunneling spectroscopy. Highâ resolution imaging and Raman spectroscopy reveal strainâ induced modifications to the atomic and electronic structure in graphene and firstâ principles simulations predict the measured bandgap openings. Laser shock modulation of semimetallic graphene to a semiconducting material with controllable bandgap has the potential to benefit the electronic and optoelectronic industries.Both the bandgap structure and the Fermi level of monolayer graphene are modulated using an easy and effective optomechanical method. Laserâ shockâ induced 3D nanoshaping enables an asymmetric elasticâ plastic straining of graphene, resulting in a wide graphene bandgap of over 2.1 eV and a wide Fermi level adjustment range of 0.6 eV.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149335/1/adma201900597.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149335/2/adma201900597-sup-0001-S1.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149335/3/adma201900597_am.pd

Transposon-induced epigenetic silencing in the X chromosome as a novel form of dmrt1 expression regulation during sex determination in the fighting fish

16 pages, 6 figures, supplementary Information https://doi.org/10.1186/s12915-021-01205-y.-- Availability of data and materials: Sequences used for RAD, RNA, and genome sequencing are achieved in the DDBJ Sequencing Read Archive (SRA) database under BioProject ID: PRJDB7253- PRJDB7255 [23, 88]Background. Fishes are the one of the most diverse groups of animals with respect to their modes of sex determination, providing unique models for uncovering the evolutionary and molecular mechanisms underlying sex determination and reversal. Here, we have investigated how sex is determined in a species of both commercial and ecological importance, the Siamese fighting fish Betta splendens. Results. We conducted association mapping on four commercial and two wild populations of B. splendens. In three of the four commercial populations, the master sex determining (MSD) locus was found to be located in a region of ~ 80 kb on LG2 which harbours five protein coding genes, including dmrt1, a gene involved in male sex determination in different animal taxa. In these fish, dmrt1 shows a male-biased gonadal expression from undifferentiated stages to adult organs and the knockout of this gene resulted in ovarian development in XY genotypes. Genome sequencing of XX and YY genotypes identified a transposon, drbx1, inserted into the fourth intron of the X-linked dmrt1 allele. Methylation assays revealed that epigenetic changes induced by drbx1 spread out to the promoter region of dmrt1. In addition, drbx1 being inserted between two closely linked cis-regulatory elements reduced their enhancer activities. Thus, epigenetic changes, induced by drbx1, contribute to the reduced expression of the X-linked dmrt1 allele, leading to female development. This represents a previously undescribed solution in animals relying on dmrt1 function for sex determination. Differentiation between the X and Y chromosomes is limited to a small region of ~ 200 kb surrounding the MSD gene. Recombination suppression spread slightly out of the SD locus. However, this mechanism was not found in the fourth commercial stock we studied, or in the two wild populations analysed, suggesting that it originated recently during domestication. Conclusions. Taken together, our data provide novel insights into the role of epigenetic regulation of dmrt1 in sex determination and turnover of SD systems and suggest that fighting fish are a suitable model to study the initial stages of sex chromosome evolutionThis study was supported by the internal funding of the Temasek Life Sciences Laboratory, SingaporeWith the institutional support of the ‘Severo Ochoa Centre of Excellence’ accreditation (CEX2019-000928-S)Peer reviewe

miR-182 Regulates Metabolic Homeostasis by Modulating Glucose Utilization in Muscle

SummaryUnderstanding the fiber-type specification and metabolic switch in skeletal muscle provides insights into energy metabolism in physiology and diseases. Here, we show that miR-182 is highly expressed in fast-twitch muscle and negatively correlates with blood glucose level. miR-182 knockout mice display muscle loss, fast-to-slow fiber-type switching, and impaired glucose metabolism. Mechanistic studies reveal that miR-182 modulates glucose utilization in muscle by targeting FoxO1 and PDK4, which control fuel selection via the pyruvate dehydrogenase complex (PDHC). Short-term high-fat diet (HFD) feeding reduces muscle miR-182 levels by tumor necrosis factor α (TNFα), which contributes to the upregulation of FoxO1/PDK4. Restoration of miR-182 expression in HFD-fed mice induces a faster muscle phenotype, decreases muscle FoxO1/PDK4 levels, and improves glucose metabolism. Together, our work establishes miR-182 as a critical regulator that confers robust and precise controls on fuel usage and glucose homeostasis. Our study suggests that a metabolic shift toward a faster and more glycolytic phenotype is beneficial for glucose control

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts