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Abstract Background To profile genomic and epigenomic of a naïve Chinese non-small cell lung cancer (NSCLC) cohort and investigate the association between tumor mutation burden (TMB) and DNA methylation (DNAm) to explore potential alternative/complimentary biomarkers for NSCLC immunotherapies. Methods A total of 89 tumor tissues with matched normal tissues from Chinese NSCLC patients were collected and subjected to whole exome sequencing (WES). From comparison, each patient was evaluated for the TMB value and divided into high, medium and low TMB based on TMB tertile distribution and then relatively high and low TMB samples were selected and subjected to DNAm profiling. Results Patients in the low (n = 30), medium (n = 29), and high (n = 30) TMB tertiles had 1.1–2.5, 2.5–4.1, and 4.2–13.9 mutations/Mb, respectively. A statistical directly association between differential methylation probes (DMPs) and TMB level was observed in our cohort (r = 0.63, P value =0.0003) and this was confirmed by using TCGA NSCLC dataset (r = 0.43, P value =0.006). Relatively high TMB group (n = 16, 7.5–13.9 mutations/Mb) harbors more differential DMPs while less in relatively low TMB group (n = 13, 1.1–2.4 mutations/Mb). Eight hundred fifty-eight differential methylation regions (DMRs) were found in relatively high TMB group. In addition, 437 genes show DNAm aberrance status in high TMB patient group and 99 have been reported as its association with lung cancer. Conclusion To our knowledge, this is the first report for direct link between the methylome alterations and TMB in NSCLCs. High TMB NSCLCs had more DNAm aberrance and copy number variations (CNVs). In addition, the TMB distribution of Chinese NSCLCs population is lower than that of TCGA.

During late gestation and lactation, oxidative stress in sows can affect their health and reproductive performance. Supplemental amino acid contributes to the antioxidant capacity of pigs. This study was conducted to evaluate the effects of different combinations of Gln, Leu and γ-GABA (amino acid mixtures, AAMs) during late gestation and lactation on the performance of the sows and their offspring. Fifty large white × landrace sows were randomly assigned to 5 groups (n = 10), including a control group and four AAMs groups (AAMs1, Gln + Leu; AAMs2 (Gln + GABA; AAMs3, Leu + GABA; AAMs4, Gln + Leu + GABA). AAMs supplementation improved the antioxidant capacity of sows, including significantly enhanced total antioxidant capacity in AAMs2, 3 and 4 groups and reduced malonaldehyde concentration in AAMs1, 3 and 4 groups. Additionally, all AAMs significantly increased lactoprotein, total solid and IgA levels of colostrum in sows during lactation. Average body weight of piglets on day 21 after birth in all AAMs groups were significantly increased. Furthermore, the significantly increased total antioxidant capacity was observed in the piglets of every AAMs group. In conclusion, supplementing AAMs during late gestation and lactation improved the antioxidant capacity of sows and colostrum composition, thereby enhancing antioxidant status and the growth performance of piglets. This study provides the possibility of maternal amino acid mixtures to improve the productivity of the swine industry.

The estimation of the Individual Treatment Effect (ITE) on survival time is an important research topic in clinics-based causal inference. Various representation learning methods have been proposed to deal with its three key problems, i.e., reducing selection bias, handling censored survival data, and avoiding balancing non-confounders. However, none of them consider all three problems in a single method. In this study, by combining the Counterfactual Survival Analysis (CSA) model and Dragonnet from the literature, we first propose a CSA–Dragonnet to deal with the three problems simultaneously. Moreover, we found that conclusions from traditional Randomized Controlled Trials (RCTs) or Retrospective Cohort Studies (RCSs) can offer valuable bound information to the counterfactual learning of ITE, which has never been used by existing ITE estimation methods. Hence, we further propose a CSA–Dragonnet with Embedded Prior Knowledge (CDNEPK) by formulating a unified expression of the prior knowledge given by RCTs or RCSs, inserting counterfactual prediction nets into CSA–Dragonnet and defining loss items based on the bounds for the ITE extracted from prior knowledge. Semi-synthetic data experiments showed that CDNEPK has superior performance. Real-world experiments indicated that CDNEPK can offer meaningful treatment advice.

This study aimed to investigate the maternal effects of the combination (GC) of galactooligosaccharides (GOS) and casein glycomacropeptides (CGMP) on their offspring. Twenty-two multiparous sows were divided into CON group (basal diet) and GC group (basal diet plus GC, 10 g/d with a ratio of 2: 1). Our results indicated that GC supplementation elevated the litter’s characteristics, faecal Prevotella, Fusobacterium and unclassified_f__Prevotellaceae of sows. Maternal GC supplementation also enriched norank_f__Ruminococcaceae, Christensenellaceae_R-7_group, Ruminococcaceae_UCG-005 and Ruminococcaceae_UCG-010, elevated their piglets’ body weight on day 21 and enhanced intestinal barrier functions by upregulating mRNA transcript levels of tight junctions and mucins. Positive correlations of the enriched microbes and intestinal barrier parameters were found by the spearman correlation analysis. Collectively, maternal GC intervention modulated the neonatal microbiota colonization, which potentially promoted the gut development and growth performance of the piglets. Our findings will provide an insight for future application of GC in maternal-foetal nutrition.

Nerve conduits enhance nerve regeneration in the repair of long-distance peripheral nerve defects. To help optimize the effectiveness of nerve conduits for nerve repair, we developed a multi-step electrospinning process for constructing nerve guide conduits with aligned nanofibers. The alignment of the nerve guide conduits was characterized by scanning electron microscopy and fast Fourier transform. The mechanical performance of the nerve guide conduits was assessed by testing for tensile strength and compression resistance. The biological performance of the aligned fibers was examined using Schwann cells, PC12 cells and dorsal root ganglia in vitro. Immunohistochemistry was performed for the Schwann cell marker S100 and for the neurofilament protein NF200 in PC12 cells and dorsal root ganglia. In the in vivo experiment, a 1.5-cm defect model of the right sciatic nerve in adult female Sprague-Dawley rats was produced and bridged with an aligned nerve guide conduit. Hematoxylin-eosin staining and immunohistochemistry were used to observe the expression of ATF3 and cleaved caspase-3 in the regenerating matrix. The recovery of motor function was evaluated using the static sciatic nerve index. The number of myelinated fibers, axon diameter, fiber diameter, and myelin thickness in the distal nerve were observed by electron microscopy. Gastrocnemius muscle mass ratio was also determined. The analyses revealed that aligned nanofiber nerve guide conduits have good mechanical properties and can induce Schwann cells, PC12 cells and dorsal root ganglia to aggregate along the length of the nanofibers, and promote the growth of longer axons in the latter two (neuronal) cell types. The aligned fiber nerve conduits increased the expression of ATF3 and cleaved caspase-3 at the middle of the regenerative matrix and at the distal nerve segment, improved sciatic nerve function, increased muscle mass of the gastrocnemius muscle, and enhanced recovery of distal nerve ultrastructure. Collectively, the results show that highly aligned nanofibers improve the performance of the nerve conduit bridge, and enhance its effectiveness in repairing peripheral nerve defects.

Autophagy is an intracellular trafficking and degradation system for recycling of damaged organelles, mis-folded proteins and cytoplasmic constituents. Autophagy can be divided into non-selective autophagy and selective autophagy according to the cargo specification. Key to the process is the timely formation of the autophagosome, a double-membrane structure which is responsible for the delivery of damaged organelles and proteins to lysosomes or vacuoles for their turnover. Autophagosomes are formed by the closure of cup-shaped phagophore which depends on the proper communication with membrane contributors. The endoplasmic reticulum (ER) is a major membrane source for autophagosome biogenesis whereby the ER connects with phagophore through membrane contact sites (MCSs). MCSs are closely apposed domains between organelle membranes where lipids and signals are exchanged. Lipid transfer proteins (LTPs) are a large family of proteins including Oxysterol-binding protein related proteins (ORP) which can be found at MCSs and mediate lipid transfer in mammals and yeast. In addition, interaction between autophagosomes and other organelles can also be detected in selective autophagy for selection and degradation of various damaged organelles. Selective autophagy is mediated by the binding of a receptor or an adaptor between a cargo and an autophagosome. Here we summarize what we know about the MCS between autophagosomes and other organelles in eukaryotes. We then discuss progress in our understanding about ORPs at MCSs in plants and the underlying mechanisms of selective autophagy in plants with a focus on receptors/adaptors that are involved in the interaction of the autophagosome with other cytoplasmic constituents, including the Neighbor of BRCA1 gene 1 (NBR1), ATG8-interacting protein 1 (ATI1), Regulatory Particle Non-ATPase 10 (RPN10), and Dominant Suppressor of KAR2 (DSK2).

Abstract The Upper Ordovician–Lower Silurian mudstones (including the Wufeng, Guanyinqiao and Longmaxi Formations) in the Sichuan Basin are some of the most important shale gas plays in China. In order to enhance our understanding of the process of formation of organic carbon up to 10%, optical, microscopy and geochemical methods have been used to investigate the petrographic and geochemical characteristics of the formation. Firstly, three mudstone lithofacies were identified based on a wide variety of mudstone laminations. These are: (a) indistinctly laminated mudstone; (b) parallel-laminated mudstone; and (c) nonparallel-laminated mudstone. Then, combining with the evidence from depocenter migration, Th/U ratios and total organic carbon, the abundant organo-minerallic fabrics suggest that organic carbon was preferentially deposited and preserved in anoxic, low energy and stagnant water conditions during deposition of the Wufeng and Longmaxi Formations. On the contrary, the Guanyinqiao Formation with poor organic carbon was deposited in oxic and high-energy water conditions.

Background/Purpose: Although antiviral therapy reduces development of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C (CHC), HCC often develops in patients with non-sustained virologic response (non-SVR). We aimed to evaluate risk factors for HCC in HCV patients with non-SVR. Methods: From March 2002 to December 2013, 800 patients with CHC who had received combined pegylated interferon (peg-IFN)/ribavirin (RBV) therapy without achieving SVR were enrolled. Main outcome measure was HCC development. Variables were cirrhosis, platelet count, α-fetoprotein (AFP) levels, aspartate aminotransferase (AST) to platelet ratio index (APRI), and IL28B polymorphism (CT + TT). Results: One-hundred of 800 non-SVR patients developed HCC within a median 53.5-months follow-up. Cumulative incidence of HCC for all patients was 1.4%, 5.6% and 12.3%, respectively, at 1st, 3rd and 5th years of follow-up. In univariate analysis, patients who developed HCC tended to have LC (p

The coal measure of Middle Jurassic Walloon Subgroup is the main reservoir of coalbed methane (CBM) reservoirs in the Surat Basin, Australia, and it is a set of typical low-rank, high-yield coal measure. To figure out the CBM accumulation conditions and enrichment models of this coal measure, its distribution characteristics, source rock characteristics, reservoir characteristics and preservation conditions were investigated based on mud logging, experimental and testing data. Then, based on the analysis results of gas origin and gas bearing property of this coal measure, 3 CBM development areas in northeastern Surat Basin were analyzed and compared in terms of its gas enrichment model, and favorable conditions for CBM accumulation and enrichment of Walloon coal measure (WCM) was summarized. It is indicated that tectonic movements, groundwater conditions and macerals provide favorable conditions for gas generation of Walloon coal. The roof, floor and interbed of this coal measure are lithologically tight, presenting a good sealing capacity. Besides, the Walloon CBM reservoir is a mixed origin gas reservoir with the secondary biogenic methane as the dominant component formed in a monocline structure jointly sealed by hydrodynamic force and lithology. CBM enrichment is controlled by 3 factors, i.e., local structure, methane generating capacity of coal bed and underground hydrodynamic force, and it can be divided into 3 models, i.e., anticline model, syncline model and slope model, among which, the CBM enrichment degree of the former two models is higher. Finally, different from other CBM reservoirs, the Walloon CBM reservoir satisfies four favorable conditions in CBM accumulation and enrichment, including dual-carbon source, efficient methane generation, moderate hydrodynamic force and double sealing. Keywords: Australia, Surat Basin, Jurassic, Walloon coal measure, CBM, CBM accumulation condition, CBM enrichment model

Abstract Background Peripheral nerve injury (PNI) is a worldwide issue associated with severe social and economic burden. Autologous nerve grafting, the gold standard treatment for peripheral nerve defects, still has a number of technical limitations. Tissue engineering technology is a novel therapeutic strategy, and mesenchymal stromal cells (MSCs) are promising seed cells for nerve tissue engineering. However, the efficiency of traditional methods for inducing the differentiation of MSCs to Schwann cell-like cells (SCLCs) remains unsatisfactory. Methods Here, we propose an intermittent induction method with alternate use of complete and incomplete induction medium to induce differentiation of adipose-derived stem cells (ASCs) to SCLCs. The time dependence of traditional induction methods and the efficiency of the intermittent induction method and traditional induction methods were evaluated and compared using immunocytochemistry, quantitative reverse transcription polymerase chain reaction (qRT-PCR), enzyme-linked immunosorbent assay (ELISA), and co-culture with the dorsal root ganglion (DRG) in vitro. Cell transplantation was used to compare the effects of the traditional induction method and the intermittent induction method in repairing sciatic nerve defects in vivo. Results The results of the present study indicated that the intermittent induction method is more efficient than traditional methods for inducing ASCs to differentiate into SCLCs. In addition, SCLCs induced by this method were closer to mature myelinating Schwann cells and were capable of secreting neurotrophins and promoting DRG axon regeneration in vitro. Furthermore, SCLCs induced by the intermittent induction method could repair sciatic nerve defects in rats by cell transplantation in vivo more effectively than those produced by traditional methods. Conclusion Intermittent induction represents a novel strategy for obtaining seed cells for use in nerve tissue engineering.