CTC1‐STN1 coordinates G‐ and C‐strand synthesis to regulate telomere length

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/145241/1/acel12783.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/145241/2/acel12783_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/145241/3/acel12783-sup-0001-FigS1-S4.pd

Study on the migration law of aggregate sediment in the water inrush channel of coal rock mass

Grouting after pouring aggregate can effectively control water inrush from coal and rock mass. The study on the deposition and migration law of aggregate in the water inrush channel from coal and rock mass is an important prerequisite to determine the aggregate particle size, aggregate grouting volume and the spacing of aggregate grouting holes. However, there are few theoretical and experimental studies in this area at present, and the actual construction mainly depends on experience, which is blind. In view of this, based on the slurry pipeline transportation theory and sediment movement mechanics, combined with Newton’s second law, the whole movement process of aggregate from the pouring hole to the water inrush channel is divided into three movement stages: free fall, similar horizontal throwing and sliding, and their stress analysis is carried out respectively. A sedimentation, migration and diffusion model from single aggregate to aggregate particle group is established, and the sedimentation and migration rules characterizing the aggregate particle group in the horizontal direction are obtained; A model test platform for visualization of aggregate deposition and movement in water inrush channel of coal and rock mass is designed by ourselves. With the help of this platform, aggregate deposition and movement model tests are carried out under the influence of various factors such as different hydrodynamic velocity, aggregate particle size, pouring height, et al, to analyze the deposition and movement rules of aggregates in water inrush channel, and to obtain the total length of aggregate deposition and movement area under different test schemes. The experimental results show that the actual migration process of aggregate is consistent with the assumption of three movement stages in theory, and the average error between the experimental value and the theoretical calculation value of the sediment migration distance of aggregate is 7.34%; On the premise that the injection height is controlled to be consistent with the dynamic water conditions, the theoretical formula is more applicable to coarse aggregate (particle size > 5 mm) than to fine aggregate (particle size ≤ 5 mm); When solving the problem of water inrush from coal and rock mass in engineering, if the aggregate particle size is greater than 5 mm, the migration distance of aggregate particle group in the horizontal direction can be calculated by using the theoretical formula in this paper, so as to determine the spacing of aggregate grouting holes and reduce the blindness in the actual construction process

SLX4 Assembles a Telomere Maintenance Toolkit by Bridging Multiple Endonucleases with Telomeres

SummarySLX4 interacts with several endonucleases to resolve structural barriers in DNA metabolism. SLX4 also interacts with telomeric protein TRF2 in human cells. The molecular mechanism of these interactions at telomeres remains unknown. Here, we report the crystal structure of the TRF2-binding motif of SLX4 (SLX4TBM) in complex with the TRFH domain of TRF2 (TRF2TRFH) and map the interactions of SLX4 with endonucleases SLX1, XPF, and MUS81. TRF2 recognizes a unique HxLxP motif on SLX4 via the peptide-binding site in its TRFH domain. Telomeric localization of SLX4 and associated nucleases depend on the SLX4-endonuclease and SLX4-TRF2 interactions and the protein levels of SLX4 and TRF2. SLX4 assembles an endonuclease toolkit that negatively regulates telomere length via SLX1-catalyzed nucleolytic resolution of telomere DNA structures. We propose that the SLX4-TRF2 complex serves as a double-layer scaffold bridging multiple endonucleases with telomeres for recombination-based telomere maintenance

miRNA Regulatory Circuits in ES Cells Differentiation: A Chemical Kinetics Modeling Approach

MicroRNAs (miRNAs) play an important role in gene regulation for Embryonic Stem cells (ES cells), where they either down-regulate target mRNA genes by degradation or repress protein expression of these mRNA genes by inhibiting translation. Well known tables TargetScan and miRanda may predict quite long lists of potential miRNAs inhibitors for each mRNA gene, and one of our goals was to strongly narrow down the list of mRNA targets potentially repressed by a known large list of 400 miRNAs. Our paper focuses on algorithmic analysis of ES cells microarray data to reliably detect repressive interactions between miRNAs and mRNAs. We model, by chemical kinetics equations, the interaction architectures implementing the two basic silencing processes of miRNAs, namely “direct degradation” or “translation inhibition” of targeted mRNAs. For each pair (M,G) of potentially interacting miRMA gene M and mRNA gene G, we parameterize our associated kinetic equations by optimizing their fit with microarray data. When this fit is high enough, we validate the pair (M,G) as a highly probable repressive interaction. This approach leads to the computation of a highly selective and drastically reduced list of repressive pairs (M,G) involved in ES cells differentiation

Direct and indirect effects of climatic variations on the interannual variability in net ecosystem exchange across terrestrial ecosystems

Climatic variables not only directly affect the interannual variability (IAV) in net ecosystem exchange of CO2 (NEE) but also indirectly drive it by changing the physiological parameters. Identifying these direct and indirect paths can reveal the underlying mechanisms of carbon (C) dynamics. In this study, we applied a path analysis using flux data from 65 sites to quantify the direct and indirect climatic effects on IAV in NEE and to evaluate the potential relationships among the climatic variables and physiological parameters that represent physiology and phenology of ecosystems. We found that the maximum photosynthetic rate was the most important factor for the IAV in gross primary productivity (GPP), which was mainly induced by the variation in vapour pressure deficit. For ecosystem respiration (RE), the most important drivers were GPP and the reference respiratory rate. The biome type regulated the direct and indirect paths, with distinctive differences between forests and non-forests, evergreen needleleaf forests and deciduous broadleaf forests, and between grasslands and croplands. Different paths were also found among wet, moist and dry ecosystems. However, the climatic variables can only partly explain the IAV in physiological parameters, suggesting that the latter may also result from other biotic and disturbance factors. In addition, the climatic variables related to NEE were not necessarily the same as those related to GPP and RE, indicating the emerging difficulty encountered when studying the IAV in NEE. Overall, our results highlight the contribution of certain physiological parameters to the IAV in C fluxes and the importance of biome type and multi-year water conditions, which should receive more attention in future experimental and modelling research

Novel MicroRNA Candidates and miRNA-mRNA Pairs in Embryonic Stem (ES) Cells

MicroRNAS (miRNAS: a class of short non-coding RNAs) are emerging as important agents of post transcriptional gene regulation and integral components of gene networks. MiRNAs have been strongly linked to stem cells, which have a remarkable dual role in development. They can either continuously replenish themselves (self-renewal), or differentiate into cells that execute a limited number of specific actions (pluripotence).In order to identify novel miRNAs from narrow windows of development we carried out an in silico search for micro-conserved elements (MCE) in adult tissue progenitor transcript sequences. A plethora of previously unknown miRNA candidates were revealed including 545 small RNAs that are enriched in embryonic stem (ES) cells over adult cells. Approximately 20% of these novel candidates are down-regulated in ES (Dicer(-/-)) ES cells that are impaired in miRNA maturation. The ES-enriched miRNA candidates exhibit distinct and opposite expression trends from mmu-mirs (an abundant class in adult tissues) during retinoic acid (RA)-induced ES cell differentiation. Significant perturbation of trends is found in both miRNAs and novel candidates in ES (GCNF(-/-)) cells, which display loss of repression of pluripotence genes upon differentiation.Combining expression profile information with miRNA target prediction, we identified miRNA-mRNA pairs that correlate with ES cell pluripotence and differentiation. Perturbation of these pairs in the ES (GCNF(-/-)) mutant suggests a role for miRNAs in the core regulatory networks underlying ES cell self-renewal, pluripotence and differentiation

A multicentre single arm phase 2 trial of neoadjuvant pyrotinib and letrozole plus dalpiciclib for triple-positive breast cancer.

peer reviewedCurrent therapies for HER2-positive breast cancer have limited efficacy in patients with triple-positive breast cancer (TPBC). We conduct a multi-center single-arm phase 2 trial to test the efficacy and safety of an oral neoadjuvant therapy with pyrotinib, letrozole and dalpiciclib (a CDK4/6 inhibitor) in patients with treatment-naïve, stage II-III TPBC with a Karnofsky score of ≥70 (NCT04486911). The primary endpoint is the proportion of patients with pathological complete response (pCR) in the breast and axilla. The secondary endpoints include residual cancer burden (RCB)-0 or RCB-I, objective response rate (ORR), breast pCR (bpCR), safety and changes in molecular targets (Ki67) from baseline to surgery. Following 5 cycles of 4-week treatment, the results meet the primary endpoint with a pCR rate of 30.4% (24 of 79; 95% confidence interval (CI), 21.3-41.3). RCB-0/I is 55.7% (95% CI, 44.7-66.1). ORR is 87.4%, (95% CI, 78.1-93.2) and bpCR is 35.4% (95% CI, 25.8-46.5). The mean Ki67 expression reduces from 40.4% at baseline to 17.9% (P < 0.001) at time of surgery. The most frequent grade 3 or 4 adverse events are neutropenia, leukopenia, and diarrhoea. There is no serious adverse event- or treatment-related death. This fully oral, chemotherapy-free, triplet combined therapy has the potential to be an alternative neoadjuvant regimen for patients with TPBC