Miracle-dz/UniFAR-FTUs huggingface dataset:
RLA8—A New and Highly Effective Quadruple PPAR-α/γ/δ and GPR40 Agonist to Reverse Nonalcoholic Steatohepatitis and Fibrosis

Nonalcoholic fatty liver disease (NAFLD) is a very common chronic hepatic disease, with nonalcoholic steatohepatitis (NASH) as a major and severe subcategory that can lead to cirrhosis and hepatocellular carcinoma, and thereby to a high mortality rate. Currently, there has been no approved drug to treat NAFLD or NASH. The current study has presented RLA8, a novel and balanced quadruple agonist for hepatic lipid metabolism and inflammation-related peroxisome proliferator-activated receptors (PPARs)-α/γ/δ and G protein–coupled receptor 40 (GPR40), as a NASH drug candidate. The efficacy of RLA8 to treat NASH was evaluated in vivo using two mouse models induced by methionine/choline-deficient diet or by high-fat diet, respectively. RLA8 was shown to improve serum alanine aminotransferase and high-density lipoprotein cholesterol levels, reduce hepatic free fatty acid and triglyceride levels, and alleviate insulin resistance. Cytokine and lipoperoxide analysis revealed that RLA8 could reduce oxidative stress and inflammation. Histochemical and morphologic examination of mouse livers showed that RLA8 could improve pathologic changes such as steatosis, ballooning, collagen fiber, and inflammation. Polymerase chain reaction and Western blot analyses proved that RLA8 could result in PPARs and GPR40 activation, accompanied by upregulation of the 5′AMP-activated protein kinase-acetyl-CoA carboxylase pathway and inhibition of the expression of lipogenic genes and proteins, which provided more insights into its action mechanisms. In summary, RLA8 has significantly better efficacy to improve NASH-induced liver damage such as steatosis, inflammation, and fibrosis, and, consequently, it represents a new and highly promising NASH drug candidate that is worthy of further investigation and development.
Endophilin‐A regulates presynaptic Ca2+ influx and synaptic vesicle recycling in auditory hair cells

Ribbon synapses of cochlear inner hair cells (IHCs) operate with high rates of neurotransmission; yet, the molecular regulation of synaptic vesicle (SV) recycling at these synapses remains poorly understood. Here, we studied the role of endophilins‐A1‐3, endocytic adaptors with curvature‐sensing and curvature‐generating properties, in mouse IHCs. Single‐cell RT–PCR indicated the expression of endophilins‐A1‐3 in IHCs, and immunoblotting confirmed the presence of endophilin‐A1 and endophilin‐A2 in the cochlea. Patch‐clamp recordings from endophilin‐A‐deficient IHCs revealed a reduction of Ca2+ influx and exocytosis, which we attribute to a decreased abundance of presynaptic Ca2+ channels and impaired SV replenishment. Slow endocytic membrane retrieval, thought to reflect clathrin‐mediated endocytosis, was impaired. Otoferlin, essential for IHC exocytosis, co‐immunoprecipitated with purified endophilin‐A1 protein, suggestive of a molecular interaction that might aid exocytosis–endocytosis coupling. Electron microscopy revealed lower SV numbers, but an increased occurrence of coated structures and endosome‐like vacuoles at IHC active zones. In summary, endophilins regulate Ca2+ influx and promote SV recycling in IHCs, likely via coupling exocytosis to endocytosis, and contributing to membrane retrieval and SV reformation.
Detecting the somatic mutations spectrum of Chinese lung cancer by analyzing the whole mitochondrial DNA genomes

Abstract To detect the somatic mutations and character its spectrum in Chinese lung cancer patients. In this study, we sequenced the whole mitochondrial DNA (mtDNA) genomes for 10 lung cancer patients including the primary cancerous, matched paracancerous normal and distant normal tissues. By analyzing the 30 whole mtDNA genomes, eight somatic mutations were identified from five patients investigated, which were confirmed with the cloning and sequencing of the somatic mutations. Five of the somatic mutations were detected among control region and the rests were found at the coding region. Heterogeneity was the main character of the somatic mutations in Chinese lung cancer patients. Further potential disease-related screening showed that, except the C deletion at position 309 showed AD-weakly associated, most of them were not disease-related. Although the role of aforementioned somatic mutations was unknown, however, considering the relative higher frequency of somatic mutations among the whole mtDNA genomes, it hints that detecting the somatic mutation(s) from the whole mtDNA genomes can serve as a useful tool for the Chinese lung cancer diagnostic to some extent.
Ribonucleotide reductase M2 promotes RNA replication of hepatitis C virus by protecting NS5B protein from hPLIC1-dependent proteasomal degradation

Hepatitis C virus (HCV) establishes a chronic infection that can lead to cirrhosis and hepatocellular carcinoma. The HCV life cycle is closely associated with host factors that promote or restrict viral replication, the characterization of which could help to identify potential therapeutic targets. To this end, here we performed a genome-wide microarray analysis and identified ribonucleotide reductase M2 (RRM2) as a cellular factor essential for HCV replication. We found that RRM2 is up-regulated in response to HCV infection in quiescent hepatocytes from humanized chimeric mouse livers. To elucidate the molecular basis of RRM2 expression in HCV-infected cells, we used HCV-infected hepatocytes from chimeric mice and hepatoma cells infected with the HCV strain JFH1. Both models exhibited increased RRM2 mRNA and protein expression levels. Moreover, siRNA-mediated silencing of RRM2 suppressed HCV replication and infection. Of note, RRM2 and RNA polymerase nonstructural protein 5B (NS5B) partially co-localized in cells and co-immunoprecipitated, suggesting that they might interact. RRM2 knockdown reduced NS5B expression, which depended on the protein degradation pathway, as NS5B RNA levels did not decrease and NS5B protein stability correlated with RRM2 protein levels. We also found that RRM2 silencing decreased levels of hPLIC1 (human homolog 1 of protein linking integrin-associated protein and cytoskeleton), a ubiquitin-like protein that interacts with NS5B and promotes its degradation. This finding suggests that there is a dynamic interplay between RRM2 and the NS5B–hPLIC1 complex that has an important function in HCV replication. Together, these results identify a role of host RRM2 in viral RNA replication.
Alzheimer's Disease Normative Cerebrospinal Fluid Biomarkers Validated in PET Amyloid-β Characterized Subjects from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study.

BACKGROUND The cerebrospinal fluid (CSF) amyloid-β (Aβ)(1-42), total-tau (T-tau), and phosphorylated-tau (P-tau181P) profile has been established as a valuable biomarker for Alzheimer's disease (AD). OBJECTIVE The current study aimed to determine CSF biomarker cut-points using positron emission tomography (PET) Aβ imaging screened subjects from the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging, as well as correlate CSF analyte cut-points across a range of PET Aβ amyloid ligands. METHODS Aβ pathology was determined by PET imaging, utilizing ¹¹C-Pittsburgh Compound B, ¹⁸F-flutemetamol, or ¹⁸F-florbetapir, in 157 AIBL participants who also underwent CSF collection. Using an INNOTEST assay, cut-points were established (Aβ(1-42) >544 ng/L, T-tau <407 ng/L, and P-tau181P <78 ng/L) employing a rank based method to define a "positive" CSF in the sub-cohort of amyloid-PET negative healthy participants (n = 97), and compared with the presence of PET demonstrated AD pathology. RESULTS CSF Aβ(1-42) was the strongest individual biomarker, detecting cognitively impaired PET positive mild cognitive impairment (MCI)/AD with 85% sensitivity and 91% specificity. The ratio of P-tau181P or T-tau to Aβ(1-42) provided greater accuracy, predicting MCI/AD with Aβ pathology with ≥92% sensitivity and specificity. Cross-validated accuracy, using all three biomarkers or the ratio of P-tau or T-tau to Aβ(1-42) to predict MCI/AD, reached ≥92% sensitivity and specificity. CONCLUSIONS CSF Aβ(1-42) levels and analyte combination ratios demonstrated very high correlation with PET Aβ imaging. Our study offers additional support for CSF biomarkers in the early and accurate detection of AD pathology, including enrichment of patient cohorts for treatment trials even at the pre-symptomatic stage.
A multicenter randomized controlled trial on the efficacy of intradiscal methylene blue injection for chronic discogenic low back pain: the IMBI study

Abstract A study published in PAIN in 2010 showed remarkable effects of intradiscal methylene blue (MB) injections compared with placebo on pain intensity in patients with chronic discogenic low back pain (CD-LBP). Both groups received lidocaine hydrochloride injections for pain associated with the procedure. We replicated the design of the previously published study and performed a multicenter, double-blind, randomized, placebo-controlled trial to assess whether the extraordinary effects of MB on pain intensity could be confirmed. The primary outcomes were treatment success defined as at least 30% reduction in pain intensity and the Patients' Global Impression of Change 6 months after the intervention. We included 84 patients with CD-LBP of which 14 (35%) in the MB plus lidocaine group showed treatment success compared with 11 (26.8%) in the control group who received placebo plus lidocaine (P = 0.426). Twenty-seven percent of all participants treated with MB stated that their overall health improved much or very much (Patients' Global Impression of Change), vs 25.6% in the placebo group (P = 0.958). We were unable to confirm that intradiscal MB injections are better capable of significantly reducing pain in patients with CD-LBP 6 months after treatment compared with placebo. We observed that over one-quarter of patients receiving only lidocaine injections reported treatment success, which is in contrast with the previously published study. Our results do not support the recommendation of using intradiscal MB injections for patients with CD-LBP.
Micro-CT analysis of chronic apical periodontitis induced by several specific pathogens.

AIM To conduct three-dimensional micro-CT analysis of bone destruction, periapical sclerotic changes and inflammatory root resorption (IRR) to compare the differences between Enterococcus faecalis (Ef)- and Porphyromonas gingivalis (Pg)-induced chronic apical periodontitis (CAP). METHODOLOGY Mono-species bacteria-induced CAP was established in the first and second molars of the right maxilla and mandible of male Sprague-Dawley rats. Fifteen animals were divided into three groups with five rats in each group: control group, Ef-CAP group and Pg-CAP group. The maxilla and mandible were harvested and then scanned by micro-CT. Alveolar bone destruction was evaluated by measuring the volume of alveolar bone resorption, bone volume fraction (BV/TV), trabecular thickness (Tb. Th), trabecular number (Tb. N) and trabecular spacing (Tb. Sp). The results were analysed using one-way analysis of variance and Fisher's least significant difference methods (LSD). The sclerotic changes in the periapical bone were graded and the IRR indexes were scored. The data were analysed using the chi-square test. RESULTS The alveolar bone resorption volume of the Pg-CAP group was significantly larger than that of the Ef-CAP group (P < 0.01). In the maxilla, both Pg-CAP and Ef-CAP groups had a significant decrease in BV/TV and increase in Tb. Sp (P < 0.01) with the more significant changes of trabecular bone in the Pg-CAP group. A significant reduction of Tb. N was only found in the Pg-CAP group (P < 0.05). There was no significant change in Tb. Th in either group (P > 0.05). In the mandible, except for an increase in Tb. Sp in the Pg-CAP group (P < 0.05), there was no significant change in BV/TV, Tb. Th or Tb. N (P > 0.05). No obvious sclerotic change was observed. IRR was detected in significantly more root surfaces in the Pg-CAP group (240 surfaces, 60%) than those in the Ef-CAP group (178 surfaces, 44.5%) (P < 0.001). The IRR extension was also significantly more advanced in the Pg-CAP group (P < 0.05). CONCLUSIONS Pg-CAP caused more substantial alveolar bone destruction and IRR than Ef-CAP. The maxilla was more susceptible to CAP in terms of microstructural changes of trabecular bone than the mandible. Tb. Sp was the most sensitive index for evaluating the residual alveolar bone of CAP.
Unique epithelial expression of S100A calcium binding protein A7A in the endometrium at conceptus implantation in pigs

Objective S100A7A, a member of the S100 protein family, is involved in various biological processes, including innate immunity, antimicrobial function, and epithelial tumorigenesis. However, the expression and function of S100A7A in the endometrium during the estrous cycle and pregnancy are not well understood in pigs. Therefore, this study determined the expression and regulation of S100A7A at the maternal-conceptus interface in pigs. Methods We obtained endometrial tissues from pigs throughout the estrous cycle and pregnancy, conceptus tissues during early pregnancy, and chorioallantoic tissues during mid- to late pregnancy and analyzed the expression of S100A7A in these tissues. We also determined the effects of steroid hormones, estradiol-17β (E2) and progesterone, and interleukin-1β (IL1B) on S100A7A expression in endometrial tissues. Results We found that S100A7A was expressed in the endometrium during the estrous cycle and pregnancy in a pregnancy status- and stage-dependent manner and was localized to endometrial luminal epithelial (LE) and superficial glandular epithelial cells with strong intensity in LE cells on day 12 of pregnancy. Early stage conceptuses and chorioallantoic tissues from day 30 to term pregnancy also expressed S100A7A. The expression of S100A7A was increased by E2 and IL1B in endometrial tissues. Conclusion S100A7A was expressed at the maternal-conceptus interface at the initiation of implantation in response to conceptus-derived estrogen and IL1B and could be a unique endometrial epithelial marker for conceptus implantation in pigs. These findings provide an important insight into the understanding of conceptus-endometrial interactions for the successful establishment of pregnancy in pigs.
Proteoliposome‐based model for screening inhibitors targeting histidine kinase AgrC

AgrC, as an integral membrane receptor protein with histidine kinase activity, is an important component of the agr quorum‐sensing system of Staphylococcus aureus. AgrC acts as a sensor for the recognition of environmental signals and transduction of the signals into the cytoplasm. Therefore, AgrC is considered to be a compelling target for the development of novel quorum‐sensing inhibitors. Here, we constructed a proteoliposome‐based model for screening inhibitors targeting AgrC by incorporating AgrC into liposomes. We demonstrated that the dissolution state of the liposome was a critical factor in the reconstruction of the AgrC proteoliposome, in which AgrC maintained similar orientation and function as those in natural biological membranes. Two monomers, namely, rhein and aloeemodin, were successfully screened out as inhibitors targeting AgrC by the proteoliposome‐based model from 14 traditional Chinese medicine monomers. The inhibitory effects of these compounds on the growth of suspended bacteria was dose dependent, and subinhibitory concentrations of these compounds significantly reduced the expression of three virulence factors (hla, clfA, and clpP), that are regulated by the agr system. The results preliminarily indicated that rhein and aloeemodin can inhibit the agr signaling pathway and also indirectly confirmed the feasibility and effectiveness of the AgrC proteoliposome as a drug screening model.
Handrail support produces a higher rate pressure product in apparently healthy non-treadmill users during maximal exercise testing

Objective: Exercise treadmill testing (ETT) is a well-established procedure for the diagnosis, prognosis and functional assessment of patients with suspected cardiovascular disease. The use of handrail support during ETT is often discouraged as this has been demonstrated to overestimate functional capacity. It is unknown if this increase in functional capacity translates to an increase in cardiac workload. The aim of this study was to investigate if the use of handrail support during maximal ETT produces an increase in cardiac workload when compared to no handrail support. Approach: Fifty-two consenting volunteers performed two maximal ETTs, one with handrail support and the other without, approximately one week apart. Participants were identified as either experienced treadmill users (treadmill use ⩾ once per fortnight) (n = 24) or inexperienced users (n = 28). Cardiac workload was quantified using rate pressure product (RPP) (systolic blood pressure (SBP) × heart rate (HR)) Main results: The average age of participants was 38.4 ± 11.4 years (44% male). Overall exercise duration was significantly prolonged by 44.4% with handrail support (with support 15:01 ± 2:54 min; without support 10:24 ± 2:09 min). Overall HR, SBP and maximum RPP were not significantly different between conditions. For the 28 inexperienced treadmill users maximum RPP was significantly higher during handrail support (7.5% increase) (with support 34 417 ± 4906; without support 31 821 ± 4565). Significance: Handrail support overestimates functional capacity, however produces greater maximal RPP in inexperienced treadmill users. If accurate aerobic data is required during ETT, or subjects performing ETT are experienced treadmill users, handrail support should be discouraged. Non-treadmill users or subjects fearful of falling may benefit from handrail support, particularly when maximal cardiac workload is desired.
Effect of bamboo grass (Tiliacora triandra, Diels) pellet supplementation on rumen fermentation characteristics and methane production in Thai native beef cattle

Objective The objective of this study was to investigate the effect of bamboo grass (Tiliacora triandra, Diels) pellet (Bamboo-Cass) supplementation on feed intake, nutrient digestibility, rumen microbial population and methane production in Thai native beef cattle. Methods Four Thai native beef cattle bulls (190±2 kg) were randomly allotted to four respective dietary treatments in a 4×4 Latin square design. Treatments were the varying levels of Bamboo-Cass supplementation at 0, 50, 100, and 150 g/head/d, respectively. Rice straw was fed ad libitum and the concentrate offered at 0.5% of body weight. Results Under this experiment, the findings revealed that acetate and butyrate production were decreased (p<0.05), propionate increased (p<0.05), whilst ruminal NH3-N concentration was decreased (p<0.05) by supplementation of Bamboo-Cass at 150 g/head/d. Moreover, rice straw intake, and microbial population were linearly increased (p<0.05), while methane production was decreased (p<0.05). Conclusion The results from the present study indicate that supplementation of Bamboo-Cass at 150 g/head/d significantly enhanced feed intake, decreased protozoa and increased bacterial population, rumen fermentation efficiency while decreased methane production. Therefore, Bamboo-Cass as a supplement is promising as a rumen enhancer in beef cattle fed on rice straw.
Mediodorsal thalamus regulates sensory and mapping uncertainties in flexible decision making

The mediodorsal (MD) thalamus is a critical partner for the prefrontal cortex (PFC) in cognitive flexibility. Accumulating evidence has shown that the MD regulates task uncertainty in decision making. However, the mechanism of this cognitive process remains unclear. Here we used a reverse-engineering approach and trained biologically-constrained computational models to delineate these mechanisms. We found that the inclusion of an MD-like feedforward module increased robustness to sensory noise, enhanced working memory and enabled rapid context switching in the recurrent PFC network performing two versions of context-dependent decision-making tasks with sensory and mapping uncertainties. Incorporating genetically identified thalamocortical pathways and interneuron cell types replicated neurophysiological findings of neuronal tuning and uncovered attractor-like population dynamics. Our model revealed key computational mechanisms of context-invariant MD in regulating cueing uncertainty and context switching. It also made experimentally testable predictions linking cognitive deficits with disrupted thalamocortical connectivity, prefrontal excitation-inhibition imbalance and dysfunctional inhibitory cell types.
Antibiotic resistance genes in sewages from hospitals and the urban setting in a Peruvian city in the highlands

Background The establishment of metagenomics seems a suitable approach to assess the abundance and diversity of antibiotic resistance genes (ARG) Methods Metagenomics study in a Peruvian city from the highlands, where samples were derived from sewage waters from two hospitals and the urban setting. DNA extraction was performed in 250 mL and then 16S rRNA gene amplification and shotgun sequencing were carried out. The bioinformatics pipeline was performed following recommendations for metagenomics analysis. Alpha diversity was evaluated with the Shannon and Simpson’s indices; whereas beta diversity was evaluated through the Bray-Curtis index, and using the principal coordinate analysis (PCoA) to explore and visualize the differences. Results We found a high abundance of bacteria related to resistance to beta-lactams, macrolides, aminoglycosides, fluoroquinolones, and tetracyclines. The urban sample did not differ significantly from the wastewater ARG presence from the hospitals in Huanuco. Conclusion Metagenomics analysis through sewage strategies seems to help to monitor the AMR to establish local public health policies, especially in cities or countries with limited resources to establish large projects conceiving the One Health approach.
The RhoGAP SPV-1 regulates calcium signaling to control the contractility of the Caenorhabditis elegans spermatheca during embryo transits

Contractility of the nonmuscle and smooth muscle cells that comprise biological tubing is regulated by the Rho-ROCK (Rho-associated protein kinase) and calcium signaling pathways. Although many molecular details about these signaling pathways are known, less is known about how they are coordinated spatiotemporally in biological tubes. The spermatheca of the Caenorhabditis elegans reproductive system enables study of the signaling pathways regulating actomyosin contractility in live adult animals. The RhoGAP (GTPase-activating protein toward Rho family small GTPases) SPV-1 was previously identified as a negative regulator of RHO-1/Rho and spermathecal contractility. Here, we uncover a role for SPV-1 as a key regulator of calcium signaling. spv-1 mutants expressing the calcium indicator GCaMP in the spermatheca exhibit premature calcium release, elevated calcium levels, and disrupted spatial regulation of calcium signaling during spermathecal contraction. Although RHO-1 is required for spermathecal contractility, RHO-1 does not play a significant role in regulating calcium. In contrast, activation of CDC-42 recapitulates many aspects of spv-1 mutant calcium signaling. Depletion of cdc-42 by RNA interference does not suppress the premature or elevated calcium signal seen in spv-1 mutants, suggesting other targets remain to be identified. Our results suggest that SPV-1 works through both the Rho-ROCK and calcium signaling pathways to coordinate cellular contractility.