Carbon monoxide-releasing molecule-3 ameliorates traumatic brain injury-induced cardiac dysfunctions via inhibition of pyroptosis and apoptosis.

Traumatic brain injury (TBI) frequently results in cardiac dysfunction and impacts the quality of survivors' life. It has been reported that carbon monoxide-releasing molecule-3 (CORM-3) administration immediately after hemorrhagic shock and resuscitation (HSR) ameliorated the HSR­induced cardiac dysfunctions. The purpose of this study was to determine whether the application of CORM-3 on TBI exerted therapeutic effects against TBI-induced cardiac dysfunctions. Rats were randomly divided into four groups (n = 12) including Sham, TBI, TBI/CORM-3 and TBI/inactive CORM-3 (iCORM-3) groups. TBI was established by a weight-drop model. The rats in the TBI/CORM-3 group and TBI/iCORM-3 group were intravenously injected with CORM-3 and iCORM-3 (4 mg/kg) following TBI, respectively. The time of death in the rats that did not survive within 24 h was recorded. 24 h post-trauma, the cardiac function, pathological change, serum troponin T and creatine kinase-MB (CK-MB) levels, pyroptosis, apoptosis and expressions of TUNEL staining, Gasdermin D (GSDMD), IL-1ß, IL-18, ratio Bax/Bcl-2 were assessed by echocardiography, hematoxylin-eosin staining, chemiluminescence, immunofluorescence, and western blot assays, respectively. TBI-treated rats exhibited dramatically decreased ejection fraction and aggravated myocardial injury, increased mortality rate, elevated levels of serum troponin T and CK-MB, promoted cardiac pyroptosis and apoptosis, and upregulated expressions of cleaved caspase-3, GSDMD N-terminal fragments, IL-1ß, IL-18, and ratio of Bax/Bcl-2, whereas CORM-3 partially reversed these changes. CORM-3 ameliorated TBI-induced cardiac injury and dysfunction. This mechanism may be responsible for the inhibition of pyroptosis and apoptosis in cardiomyocyte.

Association of chronic kidney disease with cognitive impairment risk in middle-aged and older adults: the first longitudinal evidence from CHARLS.

Previous studies have yielded inconsistent results regarding the association between chronic kidney disease (CKD) and the risk of cognitive impairment (CI). This study aimed to investigate the longitudinal association of CKD with CI risk in the Chinese middle-aged and older population. A total of 16,515 CI-free participants 45 years of age or older including 15,595 without CKD and 920 with CKD were followed from 2011 until 2018 (median [interquartile range]: 7 [5.5-7]) to detect incident CI. Over the follow-up, 648 participants developed CI. Data were analyzed using multi-adjusted Cox proportional hazard regression and Laplace regression. The incidence rate (IR) of CI was significantly higher in individuals with CKD at 11.46 per 1,000 person-years (95% confidence interval [CI], 8.90 to 14.76) than in those without CKD at 6.38 per 1,000 person-years (95% CI, 5.89 to 6.92). Compared to those without CKD, the hazard ratios of those with CKD was 1.56 (95% CI, 1.19 to 2.04) for CI. Participants with CKD in the middle-aged group (45-54 years) exhibited a heightened risk of CI in age-stratified analyses. CKD accelerated the onset of CI by 1.24 years (10th percentile difference [PD]; 95% CI, -2.03 to -0.43, p < 0.01). The findings from this study revealed a significantly increased risk of CI in individuals with CKD, especially in middle-aged population, where the risk appeared to be more pronounced. This observation underscores the importance of early detection and intervention strategies to alleviate the potential cognitive decline associated with CKD.

Synergistic effect of concurrent high molecular risk mutations and lower JAK2 mutant variant allele frequencies on prognosis in patients with myelofibrosis-insights from a multicenter study.

In addition to high-molecular risk (HMR) mutations (ASXL1, EZH2, SRSF2, IDH, and U2AF1Q157), lower JAK2V617F variant allele frequencies (VAF) have been demonstrated to be associated with poor prognosis of myelofibrosis (MF) patients. Nevertheless, the relationship between JAK2V617F VAF and HMR mutations remains inconclusive. To address this, we analyzed the mutation status of 54 myeloid neoplasm-relevant genes using targeted next-generation sequencing in 124 MF patients. Three cohorts from multiple international centers were analyzed for external validation. Among JAK2-mutated patients, the presence of HMR mutations drove poor prognosis in patients with lower JAK2V617F VAF but not in those with higher JAK2V617F VAF. Survival analyses showed consistent results across validation cohorts. In multivariable analysis, concurrent HMR and a lower JAK2V617F VAF was identified as an independent adverse prognostic factor for survival, irrespective of age, MIPSS70, MIPSS70 + v2, and GIPSS risk groups. Mutation co-occurrence tests revealed no shared mutational pattern over different cohorts, excluding potential confounding effect from other concurrent mutations. Importantly, the integration of HMR/JAK2V617F VAF (≤50%) status significantly enhanced existing prognostic models, as evidenced by higher c-indexes and time-dependent ROC analyses. Single-cell studies with sequential follow-ups are warranted to decipher the clonal evolution of MF and how it relates to JAK2V617F VAF dynamics.

Phosphorus modifies the association between body mass index and uric acid: Results from NHANES 2007-2018.

INTRODUCTION: Studies in recent years have shown that high uric acid causes harm to the human body, which has become a serious public health problem. Elevated serum uric acid has been shown to be associated with obesity, but the relationship between BMI and uric acid (UA) remains controversial. Although the association between BMI and UA has been well studied, the effect of phosphorus levels in vivo on this association remains unclear. This study aimed to determine the relationship between BMI and serum uric acid and the effect of phosphorus on the relationship between the two. RESEARCH DESIGN AND METHODS: The present study analyzed data from the National Health and Nutrition Examination Survey (NHANES) continuous 2007-2018 cycle. We included 10786 participants aged 20 years and over. Multivariable linear regression was performed to assess the association between BMI and serum uric acid. phosphorus was stratified into low phosphorus (<3.3 mg/dl), middle phosphorus (3.3-3.9 mg/dl) and high phosphorus (>3.9 mg/dl). Correction of the effect of phosphorus was assessed by testing the interaction between BMI and UA in multivariate linear regression. RESULTS: In this cross-sectional study, we found that BMI was positively associated with UA in the female population but not significantly in the male population or in the total population. In multiple regression analysis, UA was 0.51 higher in the highest female BMI group than in the lowest group (p = 0.0001). The relationship between BMI and UA differed significantly by gender under the influence of phosphorus, with men and women in Model II having a greater elevation of UA in men than in women within most groups. (BMI >30, phosphorus >3.9 mg/dl, ß:0.83 95% CI: 0.43, 1.23 vs ß: 0.79 95% CI: 0.30, 1.29). In addition, phosphorus significantly altered the positive association between BMI and UA in most models. CONCLUSION: Our results indicate significant associations between BMI and uric acid in women, with higher BMI values likely to be associated with a higher risk of hyperuricemia, suggesting that uric acid levels in obese people should be closely monitored in clinical practice. Phosphorus and BMI have an interactive effect in elevating UA and should be noted as indicators of phosphorus in clinical practice.

A covalent creatine kinase inhibitor ablates glioblastoma migration and sensitizes tumors to oxidative stress.

Glioblastoma is a Grade 4 primary brain tumor defined by therapy resistance, diffuse infiltration, and near-uniform lethality. The underlying mechanisms are unknown, and no treatment has been curative. Using a recently developed creatine kinase inhibitor (CKi), we explored the role of this inhibitor on GBM biology in vitro. While CKi minimally impacted GBM cell proliferation and viability, it significantly affected migration. In established GBM cell lines and patient-derived xenografts, CKi ablated both the migration and invasion of GBM cells. CKi also hindered radiation-induced migration. RNA-seq revealed a decrease in invasion-related genes, with an unexpected increase in glutathione metabolism and ferroptosis protection genes post-CKi treatment. The effects of CKi could be reversed by the addition of cell-permeable glutathione. Carbon-13 metabolite tracing indicated heightened glutathione biosynthesis post-CKi treatment. Combinatorial CKi blockade and glutathione inhibition or ferroptosis activation abrogated cell survival. Our data demonstrated that CKi perturbs promigratory and anti-ferroptotic roles in GBM, identifying the creatine kinase axis as a druggable target for GBM treatment.

Polygala fallax Hemsl. ameliorated high glucose-induced podocyte injury by modulating mitochondrial mPTP opening through the SIRT1/PGC-1α pathway.

This study aimed to investigate the effects and molecular mechanism of PF on high glucose (HG)-induced podocyte injury. Results found that PF increased proliferation activity, decreased apoptosis, LDH, and caspase-3 levels, and increased nephrin and podocin expression in HG-induced cells. Similarly, PF improved HG-induced mitochondrial damage, decreased Ca2+ and ROS content, alleviated oxidative stress, inhibited mPTP opening, increased mitochondrial membrane potential, and decreased the expressions of Drp1, Bak, Bax, and Cytc in cytoplasm, increased the expressions of SIRT1, PGC-1α, HSP70, HK2, and Cytc in mitochondria of podocytes. The use of mPTP agonist/blocker and SIRT1 inhibitor confirmed that PF alleviates HG-induced podocyte injury by regulating mitochondrial mPTP opening through SIRT1/PGC-1α. In addition, PF affected HK2-VDAC1 protein binding to regulate mPTP opening via the SIRT1/PGC-1α pathway. In conclusion, PF-regulated HK2-VDAC1 protein binding affected mitochondrial mPTP opening and improved HG-induced podocyte injury through the SIRT1/PGC-1α pathway.

Regional differences in the Association of Healthy Aging with the incidence of falls: an analysis based on the China Health and Retirement Longitudinal Study from 2011 to 2020.

Background: Falls frequently occur among the older adult population. In this study, we examined the variations in fall incidence across different regions over time, focusing on the disparities between urban and rural areas among older adult Chinese individuals, Healthy aging is comprised of five dimensions: (1) absence of chronic diseases, (2) good physical functioning, (3) normal cognitive function, (4) active social participation, and (5) absence of depression. Additionally, we explored the relationship between healthy aging and the occurrence of falls in middle-aged and older adults. Falls are defined as events that occurred within the past two years. Results: Among 9,918 participants, 33.8% lived in urban areas and 23.0% achieved healthy aging. In contrast, 66.2% resided in rural areas with 16.5% achieving healthy aging. In 2011, rural residents had a higher fall incidence rate (17% in rural vs. 13.5% in urban); by 2020, the fall rate remained higher in rural areas (19.5% in rural vs. 17.3% in urban). Unhealthy aging (HR = 1.08, 95%CI: 1.00-1.16) were risk factors for falls. Subgroup analysis revealed that in rural areas, unhealthy aging increased the risk of falls. In urban areas, the increased risk of falls associated with unhealthy aging was not significant (Rural HR = 1.11, 95%CI:1.01-1.22; Urban HR = 1.05, 95%CI: 0.93-1.18). Conclusion: Healthy aging may be more strongly associated with a lower risk of falls in rural areas, while this association might be less pronounced in urban areas due to different environmental and social factors. This highlights the need for environment-specific fall prevention strategies and targeted measures for the older adult.

The significance of risk stratification through nomogram-based assessment in determining postmastectomy radiotherapy for patients diagnosed with pT1 - 2N1M0 breast cancer.

OBJECTIVE: To explore the high-risk factors affecting the prognosis of pT1 - 2N1M0 patients after mastectomy, establish a nomogram prediction model, and screen the radiotherapy benefit population. METHOD: The clinical data of 936 patients with pT1 - 2N1M0 who underwent mastectomy in the fourth hospital of Hebei Medical University from 2010 to 2016 were retrospectively analyzed. There were 583 patients received postmastectomy radiotherapy(PMRT), and 325 patients without PMRT. Group imbalances were mitigated using the propensity score matching (PSM) method, and the log-rank test was employed to compare overall survival (OS) and disease-free survival (DFS) between the cohorts. The efficacy of PMRT across various risk groups was evaluated using a nomogram model. RESULT: The median follow-up period was 98 months, Patients who received PMRT demonstrated significantly improved 5-year and 8-year OS and DFS compared to those who did not (P < 0.001). Multivariate analysis revealed that age, primary tumor site, positive lymph node, stage, and Ki-67 level independently influenced OS, while age, primary tumor site, and stage independently affected DFS. PMRT drastically enhanced OS in the high-risk group (P = 0.001), but did not confer benefits in the low-risk and intermediate risk groups (P = 0.057, P = 0.099). PMRT led to a significant improvement in disease-free survival (DFS) among patients in the intermediate and high-risk groups (P = 0.036, P = 0.001), whereas the low-risk group did not experience a significant benefit (P = 0.475). CONCLUSION: Age ≤ 40 years, tumor located in the inner quadrant or central area, T2 stage, 2-3 lymph nodes metastasis, and Ki67 > 30% were the high-risk factors affecting the prognosis of this cohort of patients. In OS nomogram, patients with a risk score of 149 or higher who received PMRT exhibited improved OS. Similarly, in DFS nomogram, patients with a risk score of 123 or higher who received PMRT demonstrated enhanced DFS.

Effect of Industrial Byproduct Gypsum on the Mechanical Properties and Stabilization of Hazardous Elements of Cementitious Materials: A Review.

Industrial byproduct gypsum (BPG) is a secondary product that is mainly composed of calcium sulfate discharged during industrial production. BPG primarily consists of desulfurized gypsum, phosphogypsum, and titanium gypsum, which account for 88% of the total BPG in China. The large-scale utilization of these three types of solid waste is crucial for the safe disposal of BPG. BPG contains various impurities and harmful elements, limiting its applications. The continuous accumulation of BPG poses a serious threat to the safety of the environment. Based on a literature review (2021-2023), it was found that 52% of BPG is used in the preparation of cementitious materials, and the addition of BPG results in an average improvement of 7-30% in the mechanical properties of cementitious materials. Moreover, BPG has a positive impact on the immobilization of hazardous elements in raw materials. Therefore, the utilization of BPG in cementitious materials is beneficial for its large-scale disposal. This study primarily reviews the effects and mechanisms of BPG on the mechanical properties of cementitious materials and the solidification of hazardous elements. Most importantly, the review reveals that BPG positively influences the hydration activity of silica-alumina-based solid waste (such as steel slag and blast furnace slag) and alkaline solid waste (such as carbide slag and red mud). This improves the proportion of solid waste in cement and reduces production costs and carbon emissions. Finally, this article summarizes and proposes the application of BPG in cementitious materials. The application of BPG + silica-alumina solid waste + alkaline solid-waste-based cementitious materials is expected to realize a new type of green ecological chain for the joint utilization of multiple industrial solid wastes and to promote the low-carbon sustainable development of industrial clusters.

One-Pot Stereoselective Synthesis of the Naphthofurano-Iminosugars via a [3 + 2] Cycloaddition Reaction.

This study presents the synthesis of novel naphthofurano-iminosugars (4) using 2,3-O-isopropylidene D-ribose tosylate (1a), anilines (2), and 1,4-benzoquinone (3a) as starting materials through key iminium ion/enamine intermediates via [3 + 2] cyclization reactions at room temperature. The reaction has unique regioselectivity and stereoselectivity with moderate to excellent yields. The adaptability of this method has been demonstrated using various substituted anilines, on which both electron-donating and electron-withdrawing groups were well employed in the reactions. Notably, the treatment of the fused multicyclic iminosugar 4 with TFA efficiently leads to an interesting unexpected pyridinium salt (8), possible via four sequential steps: deprotection of the 2,3-O-isopropylidene group, furan ring opening, dehydration condensation of the OH groups, and elimination of water.

PNLDC1 catalysis and postnatal germline function are required for piRNA trimming, LINE1 silencing, and spermatogenesis in mice.

PIWI-interacting RNAs (piRNAs) play critical and conserved roles in transposon silencing and gene regulation in the animal germline. Three distinct piRNA populations are present during mouse spermatogenesis: fetal piRNAs in fetal/perinatal testes, pre-pachytene and pachytene piRNAs in postnatal testes. PNLDC1 is required for piRNA 3' end maturation in multiple species. However, whether PNLDC1 is the bona fide piRNA trimmer and the physiological role of 3' trimming of different piRNA populations in spermatogenesis in mammals remain unclear. Here, by inactivating Pnldc1 exonuclease activity in vitro and in mice, we reveal that the PNLDC1 trimmer activity is essential for spermatogenesis and male fertility. PNLDC1 catalytic activity is required for both fetal and postnatal piRNA 3' end trimming. Despite this, postnatal piRNA trimming but not fetal piRNA trimming is critical for LINE1 transposon silencing. Furthermore, conditional inactivation of Pnldc1 in postnatal germ cells causes LINE1 transposon de-repression and spermatogenic arrest in mice, indicating that germline-specific postnatal piRNA trimming is essential for transposon silencing and germ cell development. Our findings highlight the germ cell-intrinsic role of PNLDC1 and piRNA trimming in mammals to safeguard the germline genome and promote fertility.

Optical MRI imaging based on computer vision for extracting and analyzing morphological features of renal tumors.

Computer vision technology is more and more widely used in the market. Target detection and feature extraction are two important auxiliary means of this technique, which are helpful to analyze target motion data. However, in the field of biology, there are some data limitations in the analysis of targets such as bacteria and tumors, which need to be further explored. Optical MRI imaging technology based on computer vision provides a new way to extract and analyze morphological features of renal tumors. In this paper, an optical MRI imaging method based on computer vision is designed and developed for the extraction and analysis of morphological features of kidney tumors. By using optical MRI imaging technology based on computer vision, the morphological characteristics of kidney tumors were extracted by analyzing the optical characteristics and MRI images of kidney tumors, and a simulation model was established to simulate the morphological characteristics of different types of kidney tumors, and feature extraction and analysis were carried out by computer algorithm. Through the analysis of the simulation model, the morphological characteristics of renal tumors were extracted and analyzed, which provided a new and non-invasive method for clinical diagnosis and treatment of renal tumors.

The neurotrophic factor artemin and its receptor GFRα3 mediate migraine-like pain via the ion channel TRPM8.

Background: Migraine has a strong genetic foundation, including both monogenic and polygenic types. The former are rare, with most migraine considered polygenic, supported by genome-wide association studies (GWAS) identifying numerous genetic variants associated with migraine risk. Surprisingly, some of the most common mutations are associated with TRPM8, a non-selective cation channel that is the primary sensor of cold temperatures in primary afferent neurons of the somatosensory system. However, it is unlikely that the temperature sensitivity of TRPM8 underlies its role in migraine pathogenesis. To define the basis of the channel's involvement, we reasoned that cellular processes that increase cold sensitivity in the skin, such as the neurotrophic factor artemin, via its receptor GFRα3, also mediate TRPM8-associated migraine-like pain in the meninges. Methods: To investigate the role of artemin and GFRα3 in preclinical rodent migraine models, we infused nitroglycerin acutely and chronically, and measured changes in periorbital and hind paw mechanical sensitivity in male and female mice lacking GFRα3, after neutralization of free artemin with specific monoclonal antibodies, or by systemic treatment with a TRPM8-specific antagonist. Further, in wildtypes and mice lacking either GFRα3 or TRPM8, we tested the effects of supradural infusions of a mix of inflammatory mediators, artemin, and a TRPM8-specific agonist on migraine-related pain in mice. Results: We find that mechanical allodynia induced by systemic nitroglycerin, or supradural infusion of inflammatory mediators, involves GFRα3. In addition, neutralization of circulating artemin reduces the nitroglycerin phenotype, demonstrating the importance of this neurotrophic pathway. Further, we show TRPM8 expression in the meninges and that direct supradural infusion of either a TRPM8-specific agonist or artemin itself produces mechanical allodynia, the latter dependent on TRPM8 and ameliorated by concurrent treatment with sumatriptan. Conclusions: These results indicate that neuroinflammatory events in the meninges can produce migraine-like pain in mice via artemin and GFRα3, likely acting upstream of TRPM8, providing a novel pathway that may contribute to migraine pathogenesis.

Phylogeny and evolution of hemipteran insects based on expanded genomic and transcriptomic data.

BACKGROUND: Hemiptera is the fifth species-rich order of insects and the most species-rich order of hemimetabolous insects, including numerous insect species that are of agricultural or medical significance. Despite much effort and recent advance in inferring the Hemiptera phylogeny, some high-level relationships among superfamilies remain controversial. RESULTS: We sequenced the genomes of 64 hemipteran species from 15 superfamilies and the transcriptomes of two additional scale insect species, integrating them with existing genomic and transcriptomic data to conduct a comprehensive phylogenetic analysis of Hemiptera. Our datasets comprise an average of 1625 nuclear loci of 315 species across 27 superfamilies of Hemiptera. Our analyses supported Cicadoidea and Cercopoidea as sister groups, with Membracoidea typically positioned as the sister to Cicadoidea + Cercopoidea. In most analyses, Aleyrodoidea was recovered as the sister group of all other Sternorrhyncha. A sister-group relationship was supported between Coccoidea and Aphidoidea + Phylloxeroidea. These relationships were further supported by four-cluster likelihood mapping analyses across diverse datasets. Our ancestral state reconstruction indicates phytophagy as the primary feeding strategy for Hemiptera as a whole. However, predation likely represents an ancestral state for Heteroptera, with several phytophagous lineages having evolved from predatory ancestors. Certain lineages, like Lygaeoidea, have undergone a reversal transition from phytophagy to predation. Our divergence time estimation placed the diversification of hemipterans to be between 60 and 150 million years ago. CONCLUSIONS: By expanding phylogenomic taxon sampling, we clarified the superfamily relationships within the infraorder Cicadomorpha. Our phylogenetic analyses supported the sister-group relationship between the superfamilies Cicadoidea and Cercopoidea, and the superfamily Membracoidea as the sister to Cicadoidea + Cercopoidea. Our divergence time estimation supported the close association of hemipteran diversification with the evolutionary success and adaptive radiation of angiosperms during the Cretaceous period.

The role of glutathione peroxidase 4 in neuronal ferroptosis and its therapeutic potential in ischemic and hemorrhagic stroke.

Ferroptosis is a type of cell death that depends on iron and is driven by lipid peroxidation, playing a crucial role in neuronal death during stroke. A central element in this process is the inactivation of glutathione peroxidase 4 (GPx4), an antioxidant enzyme that helps maintain redox balance by reducing lipid hydroperoxides. This review examines the critical function of GPx4 in controlling neuronal ferroptosis following ischemic and hemorrhagic stroke. We explore the mechanisms through which GPx4 becomes inactivated in various stroke subtypes. In strokes, excess glutamate depletes glutathione (GSH) and products of hemoglobin breakdown overwhelm GPx4. Studies using genetic models with GPx4 deficiency underscore its vital role in maintaining neuronal survival and function. We also consider new therapeutic approaches to enhance GPx4 activity, including novel small molecule activators, adjustments in GSH metabolism, and selenium supplementation. Additionally, we outline the potential benefits of combining these GPx4-focused strategies with other anti-ferroptotic methods like iron chelation and lipoxygenase inhibition for enhanced neuroprotection. Furthermore, we highlight the significance of understanding the timing of GPx4 inactivation during stroke progression to design effective therapeutic interventions.

Seminal Vesicle-Derived Exosomes for the Regulation of Sperm Activity.

The seminal vesicle contributes to a large extent of the semen volume and composition. Removal of seminal vesicle or lack of seminal vesicle proteins leads to decreased fertility. Seminal plasma proteome revealed that seminal fluid contained a wide diversity of proteins. Many of them are known to modulate sperm capacitation and serve as capacitation inhibitors or decapacitation factors. Despite identifying secretory vesicles from the male reproductive tract, such as epididymosomes or prostasomes, isolation, identification, and characterization of seminal vesicle-derived exosomes are still unknown. This chapter aims to review the current understanding of the function of seminal vesicles on sperm physiology and male reproduction and provide ultracentrifugation-based isolation protocols for the isolation of seminal vesicle exosomes. Moreover, via proteomic analysis and functional categorization, a total of 726 proteins IDs were identified in the purified seminal vesicle exosomes fraction. Preliminary data showed seminal vesicle-derived exosomes inhibited sperm capacitation; however, more studies will be needed to reveal other functional involvements of seminal vesicle-derived exosomes on the sperm physiology and, more importantly, how these exosomes interact with sperm membrane to achieve their biological effects.

Sequential use of capsular typing and whole-genome sequencing-based analysis for transmission of carbapenem-resistant Acinetobacter baumannii in a tertiary medical center.

BACKGROUND: During the COVID-19 pandemic, there has been an increasing trend in healthcare-associated infections (HAIs) caused by carbapenem-resistant Acinetobacter baumannii (CRAB), posting a global public health concern. The heightened sensitivity of whole-genome sequencing (WGS) renders it an optimal and potent tool for monitoring outbreaks and tracing the transmission routes of nosocomial pathogens. METHOD: We collected CRAB isolates from March 1, 2023, to April 6, 2023 in Chang Gung Memorial Hospital Lin Kou branch, a tertiary medical center in northern Taiwan. Any two or more isolates with the same identifiable capsular K-locus (KL) types were selected, and analyzed via WGS to identify putative transmission clusters, combined with epidemiologic and retrospective analysis on medical records to confirm risk factors and hidden transmission chains. RESULT: A total of 48 non-redundant CRAB isolates were collected, belonging to ST2 of Pasteur MLST scheme and identifiable KL types of KL2, KL3, KL9, KL10, KL22, KL52. Excluding the KL types that was only found in 1 case, KL2 (n = 9, 22.5 %), KL3 (n = 24, 60 %), KL9 (n = 3, 7.5 %), and KL10 (n = 4, 10 %) were selected for further WGS analysis. Four distinct transmission clusters comprised of 2, 3, 10, and 23 cases were identified on a basis of phylogenetic status. 12 probable transmission chains were revealed, and 2 hidden transmission routes can be speculated. CONCLUSION: This study referred to some hidden transmission chains that may be missed from traditional surveillance measures. Despite its low prevalence and high cost currently, implementing WGS could be a efficient, prompt, and unequivocal option for future MDRO infection control.

Directed differentiation of human embryonic stem cells into conjunctival epithelial cells.

Severe conjunctival damage can lead to extensive ocular cicatrisation, fornix shortening, and even ocular surface failure, resulting in significant vision impairment. Conjunctival reconstruction is the primary therapeutic strategy for these clinical conjunctival diseases. However, there have been limited studies on induced differentiation of conjunctival epithelial cells derived from stem cells. In this study, we established a chemical defined differentiation protocol from human embryonic stem cells (hESCs) into conjunctival epithelial cells. hES cell line H1 was used for differentiation, and RT-qPCR, immunofluorescence staining, Periodic-acid-Schiff staining (PAS), and transcriptome analysis were employed to identify the differentiated cells. Here, to imitate the development of the vertebrate conjunctiva, hESCs were induced using a three-step process involving first chetomin was used to induce ocular surface ectoderm, then nicotinamide was used to induce ocular surface epithelial progenitor cells, and finally epidermal growth factor, keratinocyte growth factor and other factors were used to differentiate mature conjunctival epithelial cells. hESC-derived conjunctival epithelial cells expressed mature conjunctival epithelial lineage markers (including PAX6, P63, K13). The presence of goblet cells was confirmed by positive PAS. Transcriptome analysis revealed that hESC-derived conjunctival epithelial cells possessed a more naïve phenotype, and exhibited greater proliferation capacity compared to mature human conjunctival epithelial cells, suggesting their potential as alternative seed cells for conjunctival reconstruction.

Aqueous Extracts of Ocimum gratissimum Sensitize Hepatocellular Carcinoma Cells to Cisplatin through BRCA1 Inhibition.

Ocimum gratissimum (O. gratissimum), a medicinal herb with antifungal and antiviral activities, has been found to prevent liver injury and liver fibrosis and induce apoptosis in hepatocellular carcinoma (HCC) cells. In this study, we evaluated the effect of aqueous extracts of O. gratissimum (OGE) on improving the efficacy of chemotherapeutic drugs in HCC cells. Proteomic identification and functional assays were used to uncover the critical molecules responsible for OGE-induced sensitization mechanisms. The antitumor activity of OGE in combination with a chemotherapeutic drug was evaluated in a mouse orthotopic tumor model, and serum biochemical tests were further utilized to validate liver function. OGE sensitized HCC cells to the chemotherapeutic drug cisplatin. Proteomic analysis and Western blotting validation revealed the sensitization effect of OGE, likely achieved through the inhibition of breast cancer type 1 susceptibility protein (BRCA1). Mechanically, OGE treatment resulted in BRCA1 protein instability and increased proteasomal degradation, thereby synergistically increasing cisplatin-induced DNA damage. Moreover, OGE effectively inhibited cell migration and invasion, modulated epithelial-to-mesenchymal transition (EMT), and impaired stemness properties in HCC cells. The combinatorial use of OGE enhanced the efficacy of cisplatin and potentially restored liver function in a mouse orthotopic tumor model. Our findings may provide an alternate approach to improving chemotherapy efficacy in HCC.

Using biothesiometer, Neuropathy Symptom Score, and Neuropathy Disability Score for the early detection of peripheral neuropathy: A cross-sectional study.

Patients with peripheral neuropathy could have damaged peripheral nerves, which leads to sensory and motor dysfunction. Diabetes, infections, and trauma are the major causes of peripheral neuropathy. Vibratory perception threshold (VPT) tools are commonly used to detect peripheral neuropathy. This study aims to determine the assessment of peripheral neuropathy through the different diagnostic tools in the community in Malaysia. A total number of 1283 participants were recruited from the seven retail pharmacies located in Selangor, Malaysia. The peripheral neuropathy test was conducted based on VPT tools on both feet using the digital biothesiometer. Following that, Neurological Symptom Score (NSS) and Neurological Disability Score (NDS) were taken from the participants to assess the neurological symptoms. Participants had an average age of 40.6 ± 12.9 years and were mostly of Chinese ethnicity (54.1%). The findings show that increasing age was associated with more severe peripheral neuropathy across the various assessment tools, but gender differences were found with the biothesiometer test and ethnicity has severity in the biothesiometer and disability scores. The sensitivity and specificity of the biothesiometer test were 0.63 and 0.84, respectively. The combined tool NSS and NDS had high specificity and a high positive predictive value, suggesting that it could be a reliable indicator of peripheral neuropathy when both scores are elevated. The findings show that the biothesiometer test, NSS, and NDS are considered screening VPT tools for diagnosing peripheral neuropathy. However, further evaluation and diagnostic testing are necessary in cases of a positive test result.