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Dopamine dysregulation is centrally linked to major psychosis. Here, the authors characterise the hypomethylation of an enhancer within the insulin-like growth factor 2 gene in neurons of patients with major psychosis and provide evidence that this enhancer targets the tyrosine hydroxylase gene, responsible for dopamine synthesis. more...

Abstract Background Maintenance of physiological circadian rhythm plays a crucial role in human health. Numerous studies have shown that disruption of circadian rhythm may increase risk for malignant, psychiatric, metabolic, and other diseases. Results Extending our recent findings of oscillating cytosine modifications (osc-modCs) in mice, in this study, we show that osc-modCs are also prevalent in human neutrophils. Osc-modCs may play a role in gene regulation, can explain parts of intra- and inter-individual epigenetic variation, and are signatures of aging. Finally, we show that osc-modCs are linked to three complex diseases and provide a new interpretation of cross-sectional epigenome-wide association studies. Conclusions Our findings suggest that loss of balance between cytosine methylation and demethylation during the circadian cycle can be a potential mechanism for complex disease. Additional experiments, however, are required to investigate the possible involvement of confounding effects, such as hidden cellular heterogeneity. Circadian rhythmicity, one of the key adaptations of life forms on Earth, may contribute to frailty later in life. more...

While epigenetic factors have been implicated in the circadian rhythm, the detection of circadian cytosine modifications has remained elusive. Here the authors identify a large number of epigenetically variable cytosines that show circadian oscillations in their modification status in mice. more...

Hybrid distribution transformer (HDT) has powerful control ability, which is significant for the intelligentisation of the distribution network. A kind of HDT is presented here, the grid current control system of which is emphatic researched. Based on the mathematical model of ideal HDTs, a grid current control system is designed with quasi proportional-resonant controller (QPR). Using the characteristics that infinite gain and large bandwidth at the resonant frequency of QPR controller, the grid current system achieve the effects of unit power factor and sinusoidal symmetrical waveform. Tracking control with no static error of grid current was achieved in MATLAB. Compared with the traditional PI control, QPR controller can modulate AC signals in the static coordinate system, rather than rotary coordinate system. So the QPR controller has advantages of lower steady-state error, stronger anti-interference ability, and simpler calculation. Simulation results show that it has good dynamic and steady performance. more...

Abstract Background The objective of this study was to evaluate the effects of dietary fatty acids (FA) saturation and lysophospholipids supplementation on growth, meat quality, oxidative stability, FA profiles, and lipid metabolism of finishing beef bulls. Thirty-two Angus bulls (initial body weight: 623 ± 22.6 kg; 21 ± 0.5 months of age) were used. The experiment was a completely randomized block design with a 2 × 2 factorial arrangement of treatments: 2 diets with FA of different degree of unsaturation [high saturated FA diet (HSFA) vs. high unsaturated FA diet (HUFA)] combined with (0.075%, dry matter basis) and without lysophospholipids supplementation. The bulls were fed a high-concentrate diet (forage to concentrate, 15:85) for 104 d including a 14-d adaptation period and a 90-d data and sample collection period. Results No interactions were observed between dietary FA and lysophospholipids supplementation for growth and meat quality parameters. A greater dietary ratio of unsaturated FA (UFA) to saturated FA (SFA) from 1:2 to 1:1 led to lower DM intake and backfat thickness, but did not affect growth performance and other carcass traits. Compared with HSFA, bulls fed HUFA had greater shear force in Longissimus thoracis (LT) muscle, but had lower intramuscular fat (IMF) content and SOD content in LT muscle. Compared with HUFA, feeding the HSFA diet up-regulated expression of ACC, FAS, PPARγ, and SCD1, but down-regulated expression of CPT1B. Compared with feeding HSFA, the HUFA diet led to greater concentrations of c9-C18:1 and other monounsaturated FA in LT muscle. Feeding HUFA also led to lower plasma concentrations of cholesterol, but there were no interactions between FA and lysophospholipids detected. Feeding lysophospholipids improved growth and feed conversion ratio and altered meat quality by increasing muscle pH24h, redness values (24 h), IMF content, and concentrations of C18:3, C20:5 and total polyunsaturated fatty acids. Furthermore, lysophospholipids supplementation led to lower malondialdehyde content and up-regulated the expression of ACC, FAS, and LPL in LT muscle. Conclusions Results indicated that supplementing a high-concentrate diet with lysophospholipids to beef bulls can enhance growth rate, feed efficiency, meat quality, and beneficial FA. Increasing the dietary ratio of UFA to SFA reduced DM intake and backfat thickness without compromising growth, suggesting potential improvements in feed efficiency. more...

Abstract P2‐type layered Ni–Mn‐based oxides are vital cathode materials for sodium‐ion batteries (SIBs) due to their high discharge capacity and working voltage. However, they suffer from the detrimental P2 → O2 phase transition induced by the O2−−O2− electrostatic repulsion upon high‐voltage charge, which leads to rapid capacity fade. Herein, we construct a P2‐type Ni–Mn‐based layered oxide cathode with a core‐shell structure (labeled as NM–Mg–CS). The P2‐Na0.67[Ni0.25Mn0.75]O2 (NM) core is enclosed by the robust P2‐Na0.67[Ni0.21Mn0.71Mg0.08]O2 (NM–Mg) shell. The NM–Mg–CS exhibits the phase‐transition‐free character with mitigated volume change because the confinement effect of shell is conductive to inhibit the irreversible phase transition of the core material. As a result, it drives a high capacity retention of 81% after 1000 cycles at 5 C with an initial capacity of 78 mA h/g. And the full cell with the NM–Mg–CS cathode and hard carbon anode delivers stable capacities over 250 cycles. The successful construction of the core‐shell structure in P2‐type layered oxides sheds light on the development of high‐capacity and long‐life cathode materials for SIBs. more...

The technique of epigenomic profiling is employed to study the various DNA-methylation changes in the frontal cortex and germline that are associated with major psychosis. These changes are found to be extremely significant for the etiology of schizophrenia and other bipolar disorders. more...

Abstract Endometriosis is linked to increased infertility and pregnancy complications due to defective endometrial decidualization. We hypothesized that identification of altered signaling pathways during decidualization could identify the underlying cause of infertility and pregnancy complications. Our study reveals that transforming growth factor β (TGFβ) pathways are impaired in the endometrium of individuals with endometriosis, leading to defective decidualization. Through detailed transcriptomic analyses, we discovered abnormalities in TGFβ signaling pathways and key regulators, such as SMAD4, in the endometrium of affected individuals. We also observed compromised activity of bone morphogenetic proteins (BMP), a subset of the TGFβ family, that control endometrial receptivity. Using 3-dimensional models of endometrial stromal and epithelial assembloids, we showed that exogenous BMP2 improved decidual marker expression in individuals with endometriosis. Our findings reveal dysfunction of BMP/SMAD signaling in the endometrium of individuals with endometriosis, explaining decidualization defects and subsequent pregnancy complications in these individuals. more...

Abstract Background Clostridium butyricum (CB) is a probiotic that can regulate intestinal microbial composition and improve meat quality. Rumen protected fat (RPF) has been shown to increase the dietary energy density and provide essential fatty acids. However, it is still unknown whether dietary supplementation with CB and RPF exerts beneficial effects on growth performance and nutritional value of goat meat. This study aimed to investigate the effects of dietary CB and RPF supplementation on growth performance, meat quality, oxidative stability, and meat nutritional value of finishing goats. Thirty-two goats (initial body weight, 20.5 ± 0.82 kg) were used in a completely randomized block design with a 2 RPF supplementation (0 vs. 30 g/d) × 2 CB supplementation (0 vs. 1.0 g/d) factorial treatment arrangement. The experiment included a 14-d adaptation and 70-d data and sample collection period. The goats were fed a diet consisted of 400 g/kg peanut seedling and 600 g/kg corn-based concentrate (dry matter basis). Result Interaction between CB and RPF was rarely observed on the variables measured, except that shear force was reduced (P more...

Demonstration that SMAD2/3 regulate regeneration and differentiation of the endometrium in a manner important for suppression of endometrial carcinogenesis.

The nutritional value of goat milk is determined by the composition of its fatty acids, with particular importance placed on the role of unsaturated fatty acids in promoting human health. CircRNAs have been known to affect fatty acid metabolism through different pathways. In this study, high-throughput sequencing was employed to construct expression profiles of mammary tissue harvested during the dry period and peak lactation stages of dairy goats. Differentially expressed circRNAs and mRNAs were screened, revealing significantly higher expression levels of circRNA-08436 and ELOVL6 during the peak lactation period compared with the dry period. Thus, circRNA-08436 and ELOVL6 were chosen for subsequent studies. The findings demonstrated that circRNA-08436 not only promotes the synthesis of triglyceride (TAG) and cholesterol in goat mammary epithelial cells (GMECs), but also increases the concentrations of saturated fatty acids in the cells. Through the utilization of software prediction, the dual luciferase reporter system, and qRT-PCR, it was observed that circRNA-08436 binds to miR-195, with its overexpression reducing the expression levels of miR-195 and inhibiting TAG synthesis. In addition, circRNA-08436 upregulated the expression levels of the miR-195 target gene ELOVL6. The data also revealed that YTHDC1 facilitated the transport of circRNA-08436 from the nucleus to the cytoplasm, while YTHDC2 in the cytoplasm functioned as a “reader” to identify and degrade circRNA-08436. Taken together, these findings contribute to a better understanding of the molecular regulation of fatty acid metabolism in the mammary glands of dairy goats, thus offering a sound theoretical basis for the production of high-quality goat milk. more...

Abstract Background Lung cancer is the leading cause of cancer death, partially owing to its extensive heterogeneity. The analysis of intertumor heterogeneity has been limited by an inability to concurrently obtain tissue from synchronous metastases unaltered by multiple prior lines of therapy. Methods In order to study the relationship between genomic, epigenomic and T cell repertoire heterogeneity in a rare autopsy case from a 32-year-old female never-smoker with left lung primary late-stage lung adenocarcinoma (LUAD), we did whole-exome sequencing (WES), DNA methylation and T cell receptor (TCR) sequencing to characterize the immunogenomic landscape of one primary and 19 synchronous metastatic tumors. Results We observed heterogeneous mutation, methylation, and T cell patterns across distinct metastases. Only TP53 mutation was detected in all tumors suggesting an early event while other cancer gene mutations were later events which may have followed subclonal diversification. A set of prevalent T cell clonotypes were completely excluded from left-side thoracic tumors indicating distinct T cell repertoire profiles between left-side and non left-side thoracic tumors. Though a limited number of predicted neoantigens were shared, these were associated with homology of the T cell repertoire across metastases. Lastly, ratio of methylated neoantigen coding mutations was negatively associated with T-cell density, richness and clonality, suggesting neoantigen methylation may partially drive immunosuppression. Conclusions Our study demonstrates heterogeneous genomic and T cell profiles across synchronous metastases and how restriction of unique T cell clonotypes within an individual may differentially shape the genomic and epigenomic landscapes of synchronous lung metastases. more...

The family of Abelson interactor (Abi) proteins is a component of WAVE regulatory complex (WRC) and a downstream target of Abelson (Abl) tyrosine kinase. The fact that Abi proteins also interact with diverse membrane proteins and intracellular signaling molecules places these proteins at a central position in the network that controls cytoskeletal functions and cancer cell metastasis. Here, we identified a motif in Abi proteins that conforms to consensus sequences found in a cohort of receptor and non-receptor tyrosine kinases that bind to Cbl-tyrosine kinase binding domain. The phosphorylation of tyrosine 213 in this motif is essential for Abi degradation. Double knockout of c-Cbl and Cbl B in Bcr-Abl-transformed leukemic cells abolishes Abi1, Abi2, and WAVE2 degradation. Moreover, knockout of Abi1 reduces Src family kinase Lyn activation in Bcr-Abl-positive leukemic cells and promotes EGF-induced EGF receptor downregulation in breast cancer cells. Importantly, Abi1 depletion impeded breast cancer cell invasion in vitro and metastasis in mouse xenografts. Together, these studies uncover a novel mechanism by which the WRC and receptor/non-receptor tyrosine kinases are regulated and identify Abi1 as a potential therapeutic target for metastatic breast cancer. more...

The aim of this study was to investigate the gas production (GP), dry matter disappearance (DMD), fermentation parameters, and rumen microbiota in response to Clostridium butyricum (CB) supplementation in batch culture using a high forage substrate. The doses of CB were supplemented at 0 (Control), 0.5 × 106, 1 × 106, and 2 × 106 CFU/bottle, respectively, at either media pH 6.0 or pH 6.6. The 16S rRNA gene sequencing was used to detect the microbiota of fermentation culture in control and 1 × 106 CFU/bottle after 24 h of incubation. The results showed that the GP (p more...

An experiment was conducted to investigate the influences of supplemental lysophospholipids (LPL) on the growth performance, nutrient digestibility, and fecal bacterial profile, and short-chain fatty acids (SCFAs) of beef cattle. Thirty-six Angus beef cattle [565 ± 10.25 kg body weight (BW)] were grouped by BW and age, and randomly allocated to 1 of 3 treatment groups: (1) control (CON, basal diet); (2) LLPL [CON supplemented with 0.5 g/kg LPL, dry matter (DM) basis]; and (3) HLPL (CON supplemented with 0.75 g/kg, DM basis). The Angus cattle were fed a total mixed ration that consisted of 25% roughage and 75% concentrate (dry matter [DM] basis). The results reveal that LPL inclusion linearly increased the average daily gain (P = 0.02) and the feed efficiency (ADG/feed intake, P = 0.02), while quadratically increasing the final weight (P = 0.02) of the beef cattle. Compared with CON, the total tract digestibilities of DM (P < 0.01), ether extract (P = 0.04) and crude protein (P < 0.01) were increased with LPL supplementation. At the phylum-level, the relative abundance of Firmicutes (P = 0.05) and ratio of Firmicutes: Bacteroidetes (P = 0.04) were linearly increased, while the relative abundances of Bacteroidetes (P = 0.04) and Proteobacteria (P < 0.01) were linearly decreased with increasing LPL inclusion. At the genus-level, the relative abundances of Clostridium (P < 0.01) and Roseburia (P < 0.01) were quadratically increased, and the relative abundances of Ruminococcus was linearly increased (P < 0.01) with LPL supplementation. Additionally, increasing the dose of LPL in diets linearly increased the molar proportion of butyrate (P < 0.01) and total SCFAs (P = 0.01) concentrations. A conclusion was drawn that, as a promising feed additive, LPL promoted growth performance and nutrient digestibility, which may be associated with the change of fecal microbiome and SCFAs. more...

Circadian rhythmicity governs a remarkable array of fundamental biological functions and is mediated by cyclical transcriptomic and proteomic activities. Epigenetic factors are also involved in this circadian machinery; however, despite extensive efforts, detection and characterization of circadian cytosine modifications at the nucleotide level have remained elusive. In this study, we report that a large proportion of epigenetically variable cytosines show a circadian pattern in their modification status in mice. Importantly, the cytosines with circadian epigenetic oscillations significantly overlap with the cytosines exhibiting age-related changes in their modification status. Our findings suggest that evolutionary advantageous processes such as circadian rhythmicity can also contribute to an organism’s deterioration. [ABSTRACT FROM AUTHOR] more...

Abstract Background Abl interactor 1 (Abi1) is a downstream target of Abl tyrosine kinases and a component of the WAVE regulatory complex (WRC) that plays an important role in regulating actin cytoskeleton remodeling and membrane receptor signaling. While studies using short hairpin RNA (shRNA) have suggested that Abi1 plays a critical role in Bcr-Abl-induced leukemogenesis, the mechanism involved is not clear. Methods In this study, we knocked out Abi1 expression in p185Bcr-Abl-transformed hematopoietic cells using CRISPR/Cas9-mediated gene editing technology. The effects of Abi1 deficiency on actin cytoskeleton remodeling, the Bcr-Abl signaling, IL-3 independent growth, and SDF-induced chemotaxis in these cells were examined by various in vitro assays. The leukemogenic activity of these cells was evaluated by a syngeneic mouse transplantation model. Results We show here that Abi1 deficiency reduced the IL3-independent growth and SDF-1α-mediated chemotaxis in p185Bcr-Abl-transformed hematopoietic cells and inhibited Bcr-Abl-induced abnormal actin remodeling. Depletion of Abi1 also impaired the Bcr-Abl signaling to the ERK and PI3 kinase/Akt pathways. Remarkably, the p185Bcr-Abl-transformed cells with Abi1 deficiency lost their ability to develop leukemia in syngeneic mice. Even though these cells developed drug tolerance in vitro after prolonged selection with imatinib as their parental cells, the imatinib-tolerant cells remain incapable of leukemogenesis in vivo. Conclusions Together, this study highlights an essential role of Abi1 in Bcr-Abl-induced leukemogenesis and provides a model system for dissecting the Abi1 signaling in Bcr-Abl-positive leukemia. more...

Clostridium butyricum (C. butyricum) can survive at low pH, and it has been widely used as an alternative to antibiotics for the improvement of feed efficiency and animal health in monogastrics. A recent study suggested that the improved ruminal fermentation with supplementing C. butyricum is may be associated with increasing the abundance of rumen microbiota in Holstein heifers, as ruminal pH plays a key role in rumen microbiota and the probiotics are often active in a dose-dependent manner. The objective of this study was to determine the effects of increasing the doses of C. butyricum on gas production (GP) kinetics, dry matter disappearance (DMD), fermentation characteristics, and rumen microbiota using a high grain substrate in batch culture varying with media pH levels. The doses of C. butyricum were supplemented at 0 (control), 0.5 × 106, 1 × 106, and 2 × 106 CFU/bottle, respectively, at either media pH 6.0 or pH 6.6. The fermentation microbiota at 0 and 1 × 106 CFU/bottle were determined using the 16S rRNA high throughput sequencing technology. Overall, the GP, DMD, total volatile fatty acid (VFA) concentration, and the ratio of acetate:propionate were higher (P more...

Background Adoptive cell transfer (ACT) of tumor-infiltrating lymphocytes (TIL) yielded clinical benefit in patients with checkpoint blockade immunotherapy-refractory non-small cell lung cancer (NSCLC) prompting a renewed interest in TIL-ACT. This preclinical study explores the feasibility of producing a NSCLC TIL product with sufficient numbers and enhanced attributes using an improved culture method.Methods TIL from resected NSCLC tumors were initially cultured using (1) the traditional method using interleukin (IL)-2 alone in 24-well plates (TIL 1.0) or (2) IL-2 in combination with agonistic antibodies against CD3 and 4-1BB (Urelumab) in a G-Rex flask (TIL 3.0). TIL subsequently underwent a rapid expansion protocol (REP) with anti-CD3. Before and after the REP, expanded TIL were phenotyped and the complementarity-determining region 3 β variable region of the T-cell receptor (TCR) was sequenced to assess the T-cell repertoire.Results TIL 3.0 robustly expanded NSCLC TIL while enriching for CD8+ TIL in a shorter manufacturing time when compared with the traditional TIL 1.0 method, achieving a higher success rate and producing 5.3-fold more TIL per successful expansion. The higher proliferative capacity and CD8 content of TIL 3.0 was also observed after the REP. Both steps of expansion did not terminally differentiate/exhaust the TIL but a lesser differentiated population was observed after the first step. TIL initially expanded with the 3.0 method exhibited higher breadth of clonotypes than TIL 1.0 corresponding to a higher repertoire homology with the original tumor, including a higher proportion of the top 10 most prevalent clones from the tumor. TIL 3.0 also retained a higher proportion of putative tumor-specific TCR when compared with TIL 1.0. Numerical expansion of TIL in a REP was found to perturb the clonal hierarchy and lessen the proportion of putative tumor-specific TIL from the TIL 3.0 process.Conclusions We report the feasibility of robustly expanding a T-cell repertoire recapitulating the clonal hierarchy of the T cells in the NSCLC tumor, including a large number of putative tumor-specific TIL clones, using the TIL 3.0 methodology. If scaled up and employed as a sole expansion platform, the robustness and speed of TIL 3.0 may facilitate the testing of TIL-ACT approaches in NSCLC. more...

Toll-like receptor 4 (TLR4) is a critical pattern recognition receptor that plays a critical role in the host innate immune system’s recognition of Gram-negative bacteria. Since it is the lipopolysaccharide (LPS) receptor, it links the activated inflammatory response with autophagy and oxidative stress. Autophagy, or type II programmed cell death, was reported to have defensive functions in response to the production of inflammatory cytokines and oxidative stress. To explore the relationship between autophagy, inflammation, and oxidative stress, a TLR4-enriched transgenic (Tg) animal model (sheep) was generated. Autophagy activity in the Tg blood monocytes was significantly higher than in the wild-type animal under LPS stress, and it returned to normal after transfection of TLR4 siRNA. Pretreatment with 3-methyladenine (3-MA) inhibited autophagy and enhanced oxidative stress and the production of TNF-α. The LPS-induced reactive oxygen species (ROS) level was markedly increased in the Tg group at an early stage before quickly returning to normal values. In addition, suppressing ROS production by N-acetyl-L-cysteine down-regulated the number of intracellular autophagosomes and the expression of Beclin-1, ATG5, and cytokines IL-1β, IL-6, and TNF-α. Further mechanistic investigation suggested that the TLR4-associated p38 mitogen-activated protein kinase (MAPK) signaling pathway was involved in autophagy and oxidative stress. P38 MAPK promotes intracellular autophagy, ROS production, and inflammatory response. Moreover, TLR4 over-expression suppressed oxidative stress and the production of inflammatory cytokines and increased autophagy activity in vivo. Taken together, our results showed that LPS induced autophagy, which was related to TLR4-mediated ROS production through the p38 MAPK signaling pathway. In addition, our study also provided a novel transgenic animal model to analyze the effects of TLR4 on autophagy, oxidative stress, and inflammatory responses. more...

Experiments were conducted to evaluate the effects of an aflatoxin B1 (AFB1)-contaminated diet treated with ammonia on the diet detoxification and growth performance, nutrient digestibility, nitrogen utilization, and blood metabolites in sheep. Twenty-four female mutton sheep with an initial body weight of 50 ± 2.5 kg were randomly assigned to one of three groups: (1) control diet (C); (2) aflatoxin diet (T; control diet supplemented with 75 μg of AFB1/kg of dry matter); and (3) ammoniated diet (AT; ammoniated aflatoxin diet). The results showed decreases (p < 0.05) in average daily feed intake, nutrient digestibility of dry matter, crude protein and ether extract, and retained nitrogen, and an increase (p < 0.05) in urine nitrogen excretion in sheep fed diet T compared with those fed the other diets. In comparison to C and AT, feeding T decreased (p < 0.05) the concentrations of total protein, immunoglobulin A, immunoglobulin G, immunoglobulin M, superoxide dismutase, and total antioxidants and increased (p < 0.05) the concentrations of alanine amino transferase, malondialdehyde, and interleukin-6. In summary, ammonia treatment has the potential to decrease the concentration of AFB1 and alleviate the adverse effects of AFB1. more...

The complete genome sequence of cultivated rice (Oryza sativa) provides an unprecedented opportunity to understand the biology of this model cereal. An essential and necessary step in this effort is the determination of the coding information and expression patterns of each sequenced chromosome. Here, we report an analysis of the transcriptional activity of rice chromosome 4 using a tiling path microarray based on PCR-generated genomic DNA fragments. Six representative rice organ types were examined using this microarray to catalog the transcribed regions of rice chromosome 4 and to reveal organ- and developmental stage-specific transcription patterns. This analysis provided expression support for 82% of the gene models in the chromosome. Transcriptional activities in 1643 nonannotated regions were also detected. Comparison with cytologically defined chromatin features indicated that in juvenile-stage rice the euchromatic region is more actively transcribed than is the transposon-rich heterochromatic portion of the chromosome. Interestingly, increased transcription of transposon-related gene models in certain heterochromatic regions was observed in mature-stage rice organs and in suspension-cultured cells. These results suggest a close correlation between transcriptional activity and chromosome organization and the developmental regulation of transcription activity at the chromosome level. [ABSTRACT FROM AUTHOR] more...