Effects of guanidino acetic acid and betaine supplementation on growth, dietary nutrient digestion and intestinal creatine metabolism in sheep.

BACKGROUND: The intestine of young ruminants is in the developmental stage and has weaker resistance to the changes of external environment. Improving intestinal health is vital to promoting growth of young ruminants. This study investigated effects of guanidino acetic acid (GAA) and rumen-protected betaine (RPB) supplementation on growth, dietary nutrient digestion and GAA metabolism in the small intestine of sheep. METHODS: Eighteen healthy Kazakh rams (27.46 ± 0.10 kg of body weight and 3-month old) were categorized into control, test group I and test group II, which were fed a basal diet, 1500 mg/kg GAA and 1500 mg/kg GAA + 600 mg/kg RPB, respectively. RESULTS: Compared with control group, test group II had increased (p < 0.05) average daily gain, plasma creatine level, ether extract (EE) and phosphorus digestibility on day 30. On day 60, the EE apparent digestibility, jugular venous plasma GAA, GAA content in the duodenal mucosa and GAA content in the jejunal and ileal mucosa of test group II were higher (p < 0.05) than other groups. Transcriptome analysis revealed that the differentially expressed genes (DEGs) involved in the duodenal pathways of oxidative phosphorylation and non-alcoholic fatty liver disease were significantly altered in test group II versus test group I (p < 0.05). Moreover, in the jejunum, the MAPK signalling pathway, complement and coagulation cascade and B-cell receptor signalling pathway were significantly enriched, with ATPase, solute carrier transporter protein, DHFR, SI, GCK, ACACA and FASN being the significantly DEGs (p < 0.05). CONCLUSION: Dietary supplementation of RPB on top of GAA in sheep diets may promote sheep growth and development by improving the body's energy, amino acid, glucose and lipid metabolism capacity.

Multispecies synbiotics alleviate dextran sulfate sodium (DSS)-induced colitis: Effects on clinical scores, intestinal pathology, and plasma biomarkers in male and female mice.

BACKGROUND: Inflammatory bowel disease (IBD) is characterized by recurrent inflammation of the gastrointestinal tract and has been linked to an imbalance in gut bacteria. Synbiotics, which combine probiotics and prebiotics, are emerging as potential IBD treatments. AIM: To examine the effects of four synbiotic formulations on intestinal inflammation and peripheral biomarkers in a rodent IBD model of both sexes. METHODS: Colitis was induced in male and female C57BL/6 mice using 1% dextran sulfate sodium (DSS). Concurrently, a non-exposed control group was maintained. Starting on day 4 post-induction, DSS-exposed mice received one of four synbiotic preparations (Synbio1-4 composed of lactic acid bacteria, Bifidobacterium and dietary fibres), an anti-inflammatory drug used to treat IBD (mesalazine), or placebo (water) until day 14. Clinical symptoms and body weight were monitored daily. Blood samples (taken on days -3, 4, and 14, relative to DSS introduction), were used to analyze plasma biomarkers. At the end of the study, intestinal tissues underwent histological and morphological evaluation. RESULTS: Compared to placebo, the Synbio1-, 2- and 3-treated groups had improved clinical scores by day 14. Synbio1 was the only preparation that led to clinical improvements to scores comparable to those of controls. The Synbio1-and 3-treated groups also demonstrated histological improvements in the colon. Plasma biomarker analyses revealed significant Synbio1-induced changes in plasma IL17A, VEGFD, and TNFRSF11B levels that correlated with improved clinical or histological scores. Sex-stratified analyses revealed that most therapeutic-like effects were more pronounced in females. CONCLUSION: Our findings underscore the potential therapeutic benefits of specific synbiotics for IBD management. However, further research is needed to validate these outcomes in human subjects.

Oleanolic acid improved intestinal immune function by activating and potentiating bile acids receptor signaling in E. coli-challenged piglets.

BACKGROUND: Infection with pathogenic bacteria during nonantibiotic breeding is one of the main causes of animal intestinal diseases. Oleanolic acid (OA) is a pentacyclic triterpene that is ubiquitous in plants. Our previous work demonstrated the protective effect of OA on intestinal health, but the underlying molecular mechanisms remain unclear. This study investigated whether dietary supplementation with OA can prevent diarrhea and intestinal immune dysregulation caused by enterotoxigenic Escherichia coli (ETEC) in piglets. The key molecular role of bile acid receptor signaling in this process has also been explored. RESULTS: Our results demonstrated that OA supplementation alleviated the disturbance of bile acid metabolism in ETEC-infected piglets (P < 0.05). OA supplementation stabilized the composition of the bile acid pool in piglets by regulating the enterohepatic circulation of bile acids and significantly increased the contents of UDCA and CDCA in the ileum and cecum (P < 0.05). This may also explain why OA can maintain the stability of the intestinal microbiota structure in ETEC-challenged piglets. In addition, as a natural ligand of bile acid receptors, OA can reduce the severity of intestinal inflammation and enhance the strength of intestinal epithelial cell antimicrobial programs through the bile acid receptors TGR5 and FXR (P < 0.05). Specifically, OA inhibited NF-κB-mediated intestinal inflammation by directly activating TGR5 and its downstream cAMP-PKA-CREB signaling pathway (P < 0.05). Furthermore, OA enhanced CDCA-mediated MEK-ERK signaling in intestinal epithelial cells by upregulating the expression of FXR (P < 0.05), thereby upregulating the expression of endogenous defense molecules in intestinal epithelial cells. CONCLUSIONS: In conclusion, our findings suggest that OA-mediated regulation of bile acid metabolism plays an important role in the innate immune response, which provides a new diet-based intervention for intestinal diseases caused by pathogenic bacterial infections in piglets.

Multi-branch myocardial infarction detection and localization framework based on multi-instance learning and domain knowledge.

Objective. Myocardial infarction (MI) is a serious cardiovascular disease that can cause irreversible damage to the heart, making early identification and treatment crucial. However, automatic MI detection and localization from an electrocardiogram (ECG) remain challenging. In this study, we propose two models, MFB-SENET and MFB-DMIL, for MI detection and localization, respectively.Approach. The MFB-SENET model is designed to detect MI, while the MFB-DMIL model is designed to localize MI. The MI localization model employs a specialized attention mechanism to integrate multi-instance learning with domain knowledge. This approach incorporates handcrafted features and introduces a new loss function called lead-loss, to improve MI localization. Grad-CAM is employed to visualize the decision-making process.Main Results.The proposed method was evaluated on the PTB and PTB-XL databases. Under the inter-patient scheme, the accuracy of MI detection and localization on the PTB database reached 93.88% and 67.17%, respectively. The accuracy of MI detection and localization on the PTB-XL database were 94.89% and 85.83%, respectively.Significance. Our method achieved comparable or better performance than other state-of-the-art algorithms. The proposed method combined deep learning and medical domain knowledge, demonstrates effectiveness and reliability, holding promise as an efficient MI diagnostic tool to assist physicians in formulating accurate diagnoses.

A lightweight deep learning approach for detecting electrocardiographic lead misplacement.

Objective. Electrocardiographic (ECG) lead misplacement can result in distorted waveforms and amplitudes, significantly impacting accurate interpretation. Although lead misplacement is a relatively low-probability event, with an incidence ranging from 0.4% to 4%, the large number of ECG records in clinical practice necessitates the development of an effective detection method. This paper aimed to address this gap by presenting a novel lead misplacement detection method based on deep learning models.Approach. We developed two novel lightweight deep learning model for limb and chest lead misplacement detection, respectively. For limb lead misplacement detection, two limb leads and V6 were used as inputs, while for chest lead misplacement detection, six chest leads were used as inputs. Our models were trained and validated using the Chapman database, with an 8:2 train-validation split, and evaluated on the PTB-XL, PTB, and LUDB databases. Additionally, we examined the model interpretability on the LUDB databases. Limb lead misplacement simulations were performed using mathematical transformations, while chest lead misplacement scenarios were simulated by interchanging pairs of leads. The detection performance was assessed using metrics such as accuracy, precision, sensitivity, specificity, and Macro F1-score.Main results. Our experiments simulated three scenarios of limb lead misplacement and nine scenarios of chest lead misplacement. The proposed two models achieved Macro F1-scores ranging from 93.42% to 99.61% on two heterogeneous test sets, demonstrating their effectiveness in accurately detecting lead misplacement across various arrhythmias.Significance. The significance of this study lies in providing a reliable open-source algorithm for lead misplacement detection in ECG recordings. The source code is available athttps://github.com/wjcai/ECG_lead_check.

An All-Protein Multisensory Highly Bionic Skin.

To achieve a highly realistic robot, closely mimicking human skin in terms of materials and functionality is essential. This paper presents an all-protein silk fibroin bionic skin (SFBS) that emulates both fast-adapting (FA) and slow-adapting (SA) receptors. The mechanically different silk film and hydrogel, which exhibited skin-like properties, such as stretchability (>140%), elasticity, low modulus (<10 kPa), biocompatibility, and degradability, were prepared through mesoscopic reconstruction engineering to mimic the epidermis and dermis. Our SFBS, incorporating SA and FA sensors, demonstrated a highly sensitive (1.083 kPa-1) static pressure sensing performance (in vitro and in vivo), showed the ability to sense high-frequency vibrations (50-400 Hz), could discriminate materials and sliding, and could even identify the fine morphological differences between objects. As proof of concept, an SFBS-integrated rehabilitation glove was synthesized, which could help stroke patients regain sensory feedback. In conclusion, this work provides a practical approach for developing skin equivalents, prostheses, and smart robots.

Effects of Lifestyle Interventions on Health and Life Quality of Colorectal Cancer Survivors: A Systematic Review and Meta-analysis.

BACKGROUND: The results of previous studies on the effects of lifestyle interventions on the quality of life (QoL) in colorectal cancer (CRC) survivors remain controversial, and there have been several new publications in this area in recent years. OBJECTIVES: To assess whether lifestyle interventions can lead to favorable health outcomes and improved QoL in CRC survivors, we performed a meta-analysis. METHODS: PubMed, EMBASE, Web of Science, and Cochrane Library were systematically searched to obtain relevant literature published from January 1, 1990, to November 1, 2021. The required data were extracted and summarized to compare the physical activity levels, QoL, mental health assessment, and anthropometric data between lifestyle interventions and routine nursing. RESULTS: Twelve studies were included. Compared with the control group, lifestyle interventions could significantly increase the physical activity time (weighted mean difference [WMD], 9.84; 95% confidence interval [CI], 1.20-18.48; P = .026), metabolic equivalent task levels (WMD, 10.40; 95% CI, 5.30-15.49; P < .001), and Functional Assessment of Cancer Therapy Scale-Colorectal scores (WMD, 3.12; 95% CI, 0.24-5.99; P = .034). However, lifestyle interventions were not noticeably able to improve the fatigue, depression levels, anxiety levels, waist circumference, or body mass index in CRC survivors. CONCLUSION: Lifestyle interventions could generate an increase in physical activity time, metabolic equivalent task levels, and QoL in CRC survivors. IMPLICATIONS FOR PRACTICE: Lifestyle interventions in the future that include physical activity, diet, or comprehensive programs are needed to increase physical activity levels and improve QoL in CRC survivors.

Deciphering Oligodendrocyte Lineages in the Human Fetal Central Nervous System Using Single-Cell RNA Sequencing.

Oligodendrocytes form myelin sheaths and wrap axons of neurons to facilitate various crucial neurological functions. Oligodendrocyte progenitor cells (OPCs) persist in the embryonic, postnatal, and adult central nervous system (CNS). OPCs and mature oligodendrocytes are involved in a variety of biological processes such as memory, learning, and diseases. How oligodendrocytes are specified in different regions in the CNS, in particular in humans, remains obscure. We here explored oligodendrocyte development in three CNS regions, subpallium, brainstem, and spinal cord, in human fetuses from gestational week 8 (GW8) to GW12 using single-cell RNA sequencing. We detected multiple lineages of OPCs and illustrated distinct developmental trajectories of oligodendrocyte differentiation in three CNS regions. We also identified major genes, particularly transcription factors, which maintain status of OPC proliferation and promote generation of mature oligodendrocytes. Moreover, we discovered new marker genes that might be crucial for oligodendrocyte specification in humans, and detected common and distinct genes expressed in oligodendrocyte lineages in three CNS regions. Our study has demonstrated molecular heterogeneity of oligodendrocyte lineages in different CNS regions and provided references for further investigation of roles of important genes in oligodendrocyte development in humans.

PRL2 Phosphatase Promotes Oncogenic KIT Signaling in Leukemia Cells through Modulating CBL Phosphorylation.

Receptor tyrosine kinase KIT is frequently activated in acute myeloid leukemia (AML). While high PRL2 (PTP4A2) expression is correlated with activation of SCF/KIT signaling in AML, the underlying mechanisms are not fully understood. We discovered that inhibition of PRL2 significantly reduces the burden of oncogenic KIT-driven leukemia and extends leukemic mice survival. PRL2 enhances oncogenic KIT signaling in leukemia cells, promoting their proliferation and survival. We found that PRL2 dephosphorylates CBL at tyrosine 371 and inhibits its activity toward KIT, leading to decreased KIT ubiquitination and enhanced AKT and ERK signaling in leukemia cells. IMPLICATIONS: Our studies uncover a novel mechanism that fine-tunes oncogenic KIT signaling in leukemia cells and will likely identify PRL2 as a novel therapeutic target in AML with KIT mutations.

Gut microbial dysbiosis is associated with metabolism and immune factors in liver fibrosis mice.

Gut microbial dysbiosis has always served as a potential factor in the occurrence and development of liver fibrosis. Liver and gut microflora can regulate each other through the gut-liver axis. In this study, the 16S rRNA and RNA-seq were chosen to sequence gut microbiota alteration and liver differentially expressed genes (DEGs) in carbon tetrachloride (CCl4) included-liver fibrosis mice, and analyze the correlations between gut microbiota constituents and DEGs. Results indicated that, CCl4 significantly increased the abundance of Desulfobactera in the phylum level, destroyed gut microbiota balance in the genus levels, especially Enterorhabdus and Desulfovibrio. Through analysis, 1416 genes were found differentially expressed in mice liver tissue in the CCl4 Group, compared with the Control Group; and the DEGs were mainly involved in the lipid metabolic process and immune system process. The correlation analysis revealed that the relative abundance of microbiota phylum (Desulfobactera) and genus (Enterorhabdus and Desulfovibrio) was negatively correlated with the metabolism related genes, while positively correlated with immune-related genes and the genes enriched in PI3K-Akt signaling pathway. To sum up, CCl4 can partially regulate gene expression in metabolism, immune response and the PI3K/Akt pathway, and further maintain the stability of the gut environment in liver fibrosis mice.

SEResUTer: a deep learning approach for accurate ECG signal delineation and atrial fibrillation detection.

Objective.Accurate detection of electrocardiogram (ECG) waveforms is crucial for computer-aided diagnosis of cardiac abnormalities. This study introduces SEResUTer, an enhanced deep learning model designed for ECG delineation and atrial fibrillation (AF) detection.Approach. Built upon a U-Net architecture, SEResUTer incorporates ResNet modules and Transformer encoders to replace convolution blocks, resulting in improved optimization and encoding capabilities. A novel masking strategy is proposed to handle incomplete expert annotations. The model is trained on the QT database (QTDB) and evaluated on the Lobachevsky University Electrocardiography Database (LUDB) to assess its generalization performance. Additionally, the model's scope is extended to AF detection using the the China Physiological Signal Challenge 2021 (CPSC2021) and the China Physiological Signal Challenge 2018 (CPSC2018) datasets.Main results.The proposed model surpasses existing traditional and deep learning approaches in ECG waveform delineation on the QTDB. It achieves remarkable average F1 scores of 99.14%, 98.48%, and 98.46% for P wave, QRS wave, and T wave delineation, respectively. Moreover, the model demonstrates exceptional generalization ability on the LUDB, achieving average SE, positive prediction rate, and F1 scores of 99.05%, 94.59%, and 94.62%, respectively. By analyzing RR interval differences and the existence of P waves, our method achieves AF identification with 99.20% accuracy on the CPSC2021 test set and demonstrates strong generalization on CPSC2018 dataset.Significance.The proposed approach enables highly accurate ECG waveform delineation and AF detection, facilitating automated analysis of large-scale ECG recordings and improving the diagnosis of cardiac abnormalities.

New Evolutionary Insights into RpoA: A Novel Quorum Sensing Reprograming Factor in Pseudomonas aeruginosa.

Quorum-sensing (QS) coordinates the expression of virulence factors in Pseudomonas aeruginosa, an opportunistic pathogen known for causing severe infections in immunocompromised patients. QS has a master regulator, the lasR gene, but in clinical settings, P. aeruginosa isolates have been found that are QS-active but LasR-null. In this study, we developed an experimental evolutionary approach to identify additional QS-reprogramming determinants. We began the study with a LasR-null mutant with an extra copy of mexT, a transcriptional regulator gene that is known to be able to reprogram QS in laboratory LasR-null strains. In this strain, spontaneous single mexT mutations are expected to have no or little phenotypic consequences. Using this novel method, which we have named "targeted gene duplication followed by mutant screening", we identified QS-active revertants with mutations in genes other than mexT. One QS-active revertant had a point mutation in rpoA, a gene encoding the α-subunit of RNA polymerase. QS activation in this mutant was found to be associated with the downregulated expression of mexEF-oprN efflux pump genes. Our study therefore uncovers a new functional role for RpoA in regulating QS activity. Our results indicate that a RpoA-dependent regulatory circuit controlling the expression of the mexEF-oprN operon is critical for QS-reprogramming. In conclusion, our study reports on the identification of non-MexT proteins associated with QS-reprogramming in a laboratory strain, shedding light on possible QS activation mechanisms in clinical P. aeruginosa isolates.

Nomogram for prognosis of elderly patients with cervical cancer who receive combined radiotherapy.

This retrospective study identified prognostic factors to help guide the clinical treatment of elderly patients (≥ 65 years) with cervical cancer who had undergone radiotherapy. A personalized model to predict 3- and 5-years survival was developed. A review was conducted of 367 elderly women with cervical cancer (staged II-III) who had undergone radiotherapy in our hospital between January 2012 and December 2016. The Cox proportional hazards regression model was used for survival analysis that considered age, hemoglobin, squamous cell carcinoma antigen, pathologic type, stage, pelvic lymph node metastasis status, and others. A nomogram was constructed to predict the survival rates. The median follow-up time was 71 months (4-118 months). The 3- (5-) years overall, progression-free, local recurrence-free, and distant metastasis-free survival rates were, respectively, 91.0% (84.4%), 92.3% (85.9%), 99.18% (99.01%), and 99.18% (97.82%). The following were significant independent prognostic factors for overall survival: tumor size, pre-treatment hemoglobin, chemotherapy, and pelvic lymph node metastasis. The C-index of the line chart was 0.699 (95% CI 0.652-0.746). The areas under the receiver operating characteristic curves for 3- and 5-years survival were 0.751 and 0.724. The nomogram was in good concordance with the actual survival rates. The independent prognostic factors for overall survival in elderly patients with cervical cancer after radiotherapy were: tumor size, pre-treatment hemoglobin, chemotherapy, and pelvic lymph node metastasis. The novel prognostic nomogram based on these factors showed good concordance with the actual survival rates and can be used to guide personalized clinical treatment.

Novel antibiotic susceptibility of an RNA polymerase α-subunit mutant in Pseudomonas aeruginosa.

BACKGROUND: RNA polymerase (RNAP) is highly conserved and essential for prokaryotic housekeeping activities, making it an important target for the development of new antibiotics. The rpoB gene, encoding a ß-subunit of bacterial RNAP, has a well-known association with rifampicin resistance. However, the roles of other RNAP component genes such as rpoA, encoding an α-subunit of RNAP, in antibiotic resistance remain unexplored. OBJECTIVES: To characterize the antibiotic resistance-related role of RpoA. METHODS: We measured the expression of the MexEF-OprN efflux pump in an RpoA mutant using a transcriptional reporter. The MICs of various antibiotics for this RpoA mutant were determined. RESULTS: We uncover a novel role of antibiotic susceptibility for an RpoA mutant in Pseudomonas aeruginosa. We found that a single amino acid substitution in RpoA resulted in reduced activity of the MexEF-OprN efflux pump, which is responsible for the exportation of various antibiotics, including ciprofloxacin, chloramphenicol, ofloxacin and norfloxacin. This attenuated efflux pump activity, caused by the RpoA mutation, conferred the bacteria further susceptibility to antibiotics regulated by MexEF-OprN. Our work further revealed that certain clinical P. aeruginosa isolates also contained the same RpoA mutation, providing clinical relevance to our findings. Our results elucidate why this new antibiotic-susceptible function of RpoA mutants would have remained undetected in conventional screens for mutants involving antibiotic resistance. CONCLUSIONS: The discovery of antibiotic susceptibility in an RpoA mutant implicates a new therapeutic approach for treating clinical isolates of P. aeruginosa with RpoA mutations, using specific antibiotics regulated by MexEF-OprN. More generally, our work suggests that RpoA could serve as a promising candidate target for anti-pathogen therapeutic purposes.

Hydrogen sulfide functions as a micro-modulator bound at the copper active site of Cu/Zn-SOD to regulate the catalytic activity of the enzyme.

The present study examines whether there is a mechanism beyond the current concept of post-translational modifications to regulate the function of a protein. A small gas molecule, hydrogen sulfide (H2S), was found to bind at active-site copper of Cu/Zn-SOD using a series of methods including radiolabeled binding assay, X-ray absorption near-edge structure (XANES), and crystallography. Such an H2S binding enhanced the electrostatic forces to guide the negatively charged substrate superoxide radicals to the catalytic copper ion, changed the geometry and energy of the frontier molecular orbitals of the active site, and subsequently facilitated the transfer of an electron from the superoxide radical to the catalytic copper ion and the breakage of the copper-His61 bridge. The physiological relevance of such an H2S effect was also examined in both in vitro and in vivo models where the cardioprotective effects of H2S were dependent on Cu/Zn-SOD.

Wood cellulose microfibrils have a 24-chain core-shell nanostructure in seed plants.

Wood cellulose microfibril (CMF) is the most abundant organic substance on Earth but its nanostructure remains poorly understood. There are controversies regarding the glucan chain number (N) of CMFs during initial synthesis and whether they become fused afterward. Here, we combined small-angle X-ray scattering, solid-state nuclear magnetic resonance and X-ray diffraction analyses to resolve CMF nanostructures in native wood. We developed small-angle X-ray scattering measurement methods for the cross-section aspect ratio and area of the crystalline-ordered CMF core, which has a higher scattering length density than the semidisordered shell zone. The 1:1 aspect ratio suggested that CMFs remain mostly segregated, not fused. The area measurement reflected the chain number in the core zone (Ncore). To measure the ratio of ordered cellulose over total cellulose (Roc) by solid-state nuclear magnetic resonance, we developed a method termed global iterative fitting of T1ρ-edited decay (GIFTED), in addition to the conventional proton spin relaxation editing method. Using the formula N = Ncore/Roc, most wood CMFs were found to contain 24 glucan chains, conserved between gymnosperm and angiosperm trees. The average CMF has a crystalline-ordered core of ~2.2 nm diameter and a semidisordered shell of ~0.5 nm thickness. In naturally and artificially aged wood, we observed only CMF aggregation (contact without crystalline continuity) but not fusion (forming a conjoined crystalline unit). This further argued against the existence of partially fused CMFs in new wood, overturning the recently proposed 18-chain fusion hypothesis. Our findings are important for advancing wood structural knowledge and more efficient use of wood resources in sustainable bio-economies.

Pharmacological treatment of neuropsychiatric symptoms of dementia: a network meta-analysis.

BACKGROUND: Pharmacological treatments are very common to be used for alleviating neuropsychiatric symptoms (NPS) in dementia. However, decision on drug selection is still a matter of controversy. AIMS: To summarise the comparative efficacy and acceptability of currently available monotherapy drug regimens for reducing NPS in dementia. METHOD: We searched PubMed, MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials between inception and 26 December 2022 without language restrictions; and reference lists scanned from selected studies and systematic reviews. Double-blind randomised controlled trials were identified from electronic databases for reporting NPS outcomes in people with dementia. Primary outcomes were efficacy and acceptability. Confidence in the evidence was assessed using Confidence in Network Meta-Analysis (CINeMA). RESULTS: We included 59 trials (15,781 participants; mean age, 76.6 years) and 15 different drugs in quantitative syntheses. Risperidone (standardised mean difference [SMD] -0.20, 95% credible interval [CrI] -0.40 to -0.10) and galantamine (-0.20, -0.39 to -0.02) were more effective than placebo in short-term treatment (median duration: 12 weeks). Galantamine (odds ratio [OR] 1.95, 95% CrI 1.38-2.94) and rivastigmine (1.87, 1.24-2.99) were associated with more dropouts than placebo, and some active drugs. Most of the results were rated as low or very low according to CINeMA. CONCLUSIONS: Despite the scarcity of high-quality evidence, risperidone is probably the best pharmacological option to consider for alleviating NPS in people with dementia in short-term treatment when considering the risk-benefit profile of drugs.

Targeting PHB1 to inhibit castration-resistant prostate cancer progression in vitro and in vivo.

BACKGROUND: Castration-resistant prostate cancer (CRPC) is currently the main challenge for prostate cancer (PCa) treatment, and there is an urgent need to find novel therapeutic targets and drugs. Prohibitin (PHB1) is a multifunctional chaperone/scaffold protein that is upregulated in various cancers and plays a pro-cancer role. FL3 is a synthetic flavagline drug that inhibits cancer cell proliferation by targeting PHB1. However, the biological functions of PHB1 in CRPC and the effect of FL3 on CRPC cells remain to be explored. METHODS: Several public datasets were used to analyze the association between the expression level of PHB1 and PCa progression as well as outcome in PCa patients. The expression of PHB1 in human PCa specimens and PCa cell lines was examined by immunohistochemistry (IHC), qRT-PCR, and Western blot. The biological roles of PHB1 in castration resistance and underlying mechanisms were investigated by gain/loss-of-function analyses. Next, in vitro and in vivo experiments were conducted to investigate the anti-cancer effects of FL3 on CRPC cells as well as the underlying mechanisms. RESULTS: PHB1 expression was significantly upregulated in CRPC and was associated with poor prognosis. PHB1 promoted castration resistance of PCa cells under androgen deprivation condition. PHB1 is an androgen receptor (AR) suppressive gene, and androgen deprivation promoted the PHB1 expression and its nucleus-cytoplasmic translocation. FL3, alone or combined with the second-generation anti-androgen Enzalutamide (ENZ), suppressed CRPC cells especially ENZ-sensitive CRPC cells both in vitro and in vivo. Mechanically, we demonstrated that FL3 promoted trafficking of PHB1 from plasma membrane and mitochondria to nucleus, which in turn inhibited AR signaling as well as MAPK signaling, yet promoted apoptosis in CRPC cells. CONCLUSION: Our data indicated that PHB1 is aberrantly upregulated in CRPC and is involved in castration resistance, as well as providing a novel rational approach for treating ENZ-sensitive CRPC.

Integrative epigenome profiling of 47XXY provides insights into whole genomic DNA hypermethylation and active chromatin accessibility.

Klinefelter syndrome (KS, 47XXY) is a disorder characterized by sex chromosomal aneuploidy, which may lead to changes in epigenetic regulations of gene expression. To define epigenetic architectures in 47XXY, we annotated DNA methylation in euploid males (46XY) and females (46XX), and 47XXY individuals using whole genome bisulfite sequencing (WGBS) and integrated chromatin accessbilty, and detected abnormal hypermethylation in 47XXY. Furthermore, we detected altered chromatin accessibility in 47XXY, in particular in chromosome X, using Assay for Transposase-Accessible Chromatin sequencing (ATAC-seq) in cultured amniotic cells. Our results construct the whole genome-wide DNA methylation map in 47XXY, and provide new insights into the early epigenomic dysregulation resulting from an extra chromosome X in 47XXY.

Improved probe detection sensitivity by flexible tandem biotin labeling.

We develop a biotin-based tandem labeling approach to improve detection sensitivity of DNA probe. Through DNA polymerase-mediated overhand filling, the 3'end of DNA probe was tandemly labeled with biotin molecules. The intensity of biotin signals could be flexibly manipulated by controlling the introduced length of poly(A) in the 5' overhang.