DNA methylation is a defining feature of mammalian cellular identity and is essential for normal development. Most cell types, except germ cells and pre-implantation embryos, display relatively ...stable DNA methylation patterns, with 70-80% of all CpGs being methylated. Despite recent advances, we still have a limited understanding of when, where and how many CpGs participate in genomic regulation. Here we report the in-depth analysis of 42 whole-genome bisulphite sequencing data sets across 30 diverse human cell and tissue types. We observe dynamic regulation for only 21.8% of autosomal CpGs within a normal developmental context, most of which are distal to transcription start sites. These dynamic CpGs co-localize with gene regulatory elements, particularly enhancers and transcription-factor-binding sites, which allow identification of key lineage-specific regulators. In addition, differentially methylated regions (DMRs) often contain single nucleotide polymorphisms associated with cell-type-related diseases as determined by genome-wide association studies. The results also highlight the general inefficiency of whole-genome bisulphite sequencing, as 70-80% of the sequencing reads across these data sets provided little or no relevant information about CpG methylation. To demonstrate further the utility of our DMR set, we use it to classify unknown samples and identify representative signature regions that recapitulate major DNA methylation dynamics. In summary, although in theory every CpG can change its methylation state, our results suggest that only a fraction does so as part of coordinated regulatory programs. Therefore, our selected DMRs can serve as a starting point to guide new, more effective reduced representation approaches to capture the most informative fraction of CpGs, as well as further pinpoint putative regulatory elements.
This book aims to present meshfree methods in a friendly and straightforward manner, so that beginners can very easily understand, comprehend, program, implement, apply and extend these methods. It ...provides first the fundamentals of numerical analysis that are particularly important to meshfree methods. Typical meshfree methods, such as EFG, RPIM, MLPG, LRPIM, MWS and collocation methods are then introduced systematically detailing the formulation, numerical implementation and programming. Many well-tested computer source codes developed by the authors are attached with useful descriptions. The application of the codes can be readily performed using the examples with input and output files given in table form. These codes consist of most of the basic meshfree techniques, and can be easily extended to other variations of more complex procedures of meshfree methods. Readers can easily practice with the codes provided to effective learn and comprehend the basics of meshfree methods.
The key nuclear export protein CRM1/XPO1 may represent a promising novel therapeutic target in human multiple myeloma (MM). Here we showed that chromosome region maintenance 1 (CRM1) is highly ...expressed in patients with MM, plasma cell leukemia cells and increased in patient cells resistant to bortezomib treatment. CRM1 expression also correlates with increased lytic bone and shorter survival. Importantly, CRM1 knockdown inhibits MM cell viability. Novel, oral, irreversible selective inhibitors of nuclear export (SINEs) targeting CRM1 (KPT-185, KPT-330) induce cytotoxicity against MM cells (ED50<200 nM), alone and cocultured with bone marrow stromal cells (BMSCs) or osteoclasts (OC). SINEs trigger nuclear accumulation of multiple CRM1 cargo tumor suppressor proteins followed by growth arrest and apoptosis in MM cells. They further block c-myc, Mcl-1, and nuclear factor κB (NF-κB) activity. SINEs induce proteasome-dependent CRM1 protein degradation; concurrently, they upregulate CRM1, p53-targeted, apoptosis-related, anti-inflammatory and stress-related gene transcripts in MM cells. In SCID mice with diffuse human MM bone lesions, SINEs show strong anti-MM activity, inhibit MM-induced bone lysis and prolong survival. Moreover, SINEs directly impair osteoclastogenesis and bone resorption via blockade of RANKL-induced NF-κB and NFATc1, with minimal impact on osteoblasts and BMSCs. These results support clinical development of SINE CRM1 antagonists to improve patient outcome in MM.
► Mechanical properties of graphene are investigated via MD simulations. ► Effects of different layer numbers, temperatures and isotopes are considered. ► Temperature exerts negative effect on the ...mechanical properties. ► Layer number and isotopes pose marginal influence on the mechanical properties.
Herein the mechanical properties of graphene, including Young’s modulus, fracture stress and fracture strain have been investigated by molecular dynamics simulations. The simulation results show that the mechanical properties of graphene are sensitive to the temperature changes but insensitive to the layer numbers in the multilayer graphene. Increasing temperature exerts adverse and significant effects on the mechanical properties of graphene. However, the adverse effect produced by the increasing layer number is marginal. On the other hand, isotope substitutions in graphene play a negligible role in modifying the mechanical properties of graphene.
Background
This phase 3 trial is the first to evaluate the efficacy and safety of treatment with the systemic TNF‐α inhibitor, adalimumab, for Chinese patients with moderate‐to‐severe plaque ...psoriasis.
Methods
In the 12‐week, double‐blind, placebo‐controlled Period A, patients were randomized 4 : 1 to receive adalimumab 40 mg every‐other‐week (following a single 80 mg dose), or placebo every‐other‐week. In the subsequent 12‐week, open‐label, Period B, all patients received adalimumab 40 mg every‐other‐week starting at week 13, following a single, blinded dose at week 12 of adalimumab 80 mg or matching placebo (for patients receiving placebo or adalimumab in Period A respectively). In Period A, efficacy was analysed for all randomized patients and safety for all patients receiving ≥1 dose of the study drug.
Results
For the 425 patients in this study (87 placebo; 338 adalimumab), a higher percentage randomized to adalimumab achieved the primary endpoint of ≥75% improvement from baseline in PASI score (PASI 75) at week 12: placebo 11.5% (10/87); adalimumab 77.8% (263/338; P < 0.001). Physician's Global Assessment of clear to minimal was achieved at week 12 by 14.9% placebo (13/87) and 80.5% adalimumab (272/338; P < 0.001). For patients who received adalimumab at any time during the study (All‐adalimumab Population), treatment‐emergent adverse events (AEs) were reported by 63.4%; the most common was upper respiratory infection (16.1%). Serious AEs were reported by 3.5% of the All‐adalimumab Population, and serious infectious AEs by 1.2%, which include lung infection, pneumonia and tuberculosis 2 (0.5%) patients each. There was one death (chronic heart failure).
Conclusion
In these Chinese patients with moderate‐to‐severe psoriasis, a significantly greater percentage treated with adalimumab compared with placebo achieved efficacy endpoints at week 12 and efficacy was sustained to week 24. Safety results were consistent with the known adalimumab safety profile; no new safety signals were identified in the 24 weeks of treatment.
Contrary to the formation of complicated polycrystals induced by general crystallization, a modulated superlatticelike nanostructure, which grows layer by layer from the surface to the interior of a ...Pd_{40}Ni_{10}Cu_{30}P_{20} metallic glass, is observed via isothermal annealing below the glass transition temperature. The generation of the modulated nanostructure can be solely controlled by the annealing temperature, and it can be understood based on the fast dynamic and liquidlike behavior of the glass surface. The observations have implications for understanding the glassy surface dynamics and pave a way for the controllable fabrication of a unique and sophisticated nanostructure on a glass surface to realize the properties' modification.
The antibody response magnitude and kinetics may impact clinical severity, serological diagnosis and long-term protection of COVID-19, which may play a role in why children experience lower ...morbidity. We therefore tested samples from 122 children in Hong Kong with symptomatic (n = 78) and asymptomatic (n = 44) SARS-CoV-2 infections up to 200 days post infection, relative to 71 infected adults (symptomatic n = 61, and asymptomatic n = 10), and negative controls (n = 48). We assessed serum IgG antibodies to a 14-wide antigen panel of structural and accessory proteins by Luciferase Immuno-Precipitation System (LIPS) assay and circulating cytokines. Infected children have lower levels of Spike, Membrane, ORF3a, ORF7a, ORF7b antibodies, comparable ORF8 and elevated E-specific antibodies than adults. Combination of two unique antibody targets, ORF3d and ORF8, can accurately discriminate SARS-CoV-2 infection in children. Principal component analysis reveals distinct pediatric serological signatures, and the highest contribution to variance from adults are antibody responses to non-structural proteins ORF3d, NSP1, ORF3a and ORF8. From a diverse panel of cytokines that can modulate immune priming and relative inflammation, IL-8, MCP-1 and IL-6 correlate with the magnitude of pediatric antibody specificity and severity. Antibodies to SARS-CoV-2 internal proteins may become an important sero surveillance tool of infection with the roll-out of vaccines in the pediatric population.
A better understanding of plant cell micromechanics would enhance the current opinion on "how things are happening" inside a plant cell, enabling more detailed insights into plant physiology as well ...as processing plant biomaterials. However, with the contemporary laboratory equipment, the experimental investigation of cell micromechanics has been a challenging task due to diminutive spatial and time scales involved. In this investigation, a three-dimensional (3-D) coupled Smoothed Particle Hydrodynamics (SPH) and Coarse-Grained (CG) computational approach has been employed to model micromechanics of single plant cells going through drying or dehydration. This meshfree-based computational model has conclusively demonstrated that it can effectively simulate the behaviour of stress and strain in a plant cell being compressed at different levels of dryness: ranging from a fresh state to an extremely dried state. In addition, different biological and physical circumstances have been approximated through the proposed novel computational framework in the form of different turgor pressures, strain rates, mechanical properties and cell sizes. The proposed computational framework has potential not only to study the micromechanical characteristics of plant cellular structure during drying, but also other equivalent, biological structures and processes with relevant modifications. There are no underlying difficulties in adopting the model to replicate other types of cells and more sophisticated micromechanical phenomena of the cells under different external loading conditions.
Post-transcriptional modification of RNA is an important determinant of RNA quality control, translational efficiency, RNA-protein interactions and stress response. This is illustrated by the ...observation of toxicant-specific changes in the spectrum of tRNA modifications in a stress-response mechanism involving selective translation of codon-biased mRNA for crucial proteins. To facilitate systems-level studies of RNA modifications, we developed a liquid chromatography-mass spectrometry (LC-MS) technique for the quantitative analysis of modified ribonucleosides in tRNA. The protocol includes tRNA purification by HPLC, enzymatic hydrolysis, reversed-phase HPLC resolution of the ribonucleosides, and identification and quantification of individual ribonucleosides by LC-MS via dynamic multiple reaction monitoring (DMRM). In this approach, the relative proportions of modified ribonucleosides are quantified in several micrograms of tRNA in a 15-min LC-MS run. This protocol can be modified to analyze other types of RNA by modifying the steps for RNA purification as appropriate. By comparison, traditional methods for detecting modified ribonucleosides are labor- and time-intensive, they require larger RNA quantities, they are modification-specific or require radioactive labeling.
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