Metal-organic complex coating for enhanced corrosion control and biocompatibility on biodegradable magnesium alloy for orthopaedic implants.

Magnesium alloy is currently regarded as the most favourable biodegradable metal; however, obstacles remain to be overcome in terms of managing its corrosion and ensuring its biocompatibility. In this study, a metal-organic complex comprising Ca ions incorporated in tannic acid (TA) was prepared and used to coat magnesium alloy by chemical conversion and dipping processes, followed by modification with stearic acid (SA). This metal-organic complex coating was demonstrated to be homogeneous and compact, and it significantly improved the electrochemical corrosion resistance and long-term degradation behaviour of the coated samples. Consequently, the well-controlled release of Mg and Ca ions, as well as the osteo-compatible TA and SA molecules, promoted the proliferation of osteoblast cells. This metal-organic complex coating offers a promising modifying strategy for magnesium-based orthopaedic implants.

Generation of Eroded Nanoplastics from Domestic Wastes and Their Impact on Macrophage Cell Viability and Gene Expression.

This study reports an innovative approach for producing nanoplastics (NP) from various types of domestic waste plastics without the use of chemicals. The plastic materials used included water bottles, styrofoam plates, milk bottles, centrifuge tubes, to-go food boxes, and plastic bags, comprising polyethylene terephthalate (PET), polystyrene (PS), polypropylene (PP), high-density polyethylene (HDPE), and Poly (Ethylene-co-Methacrylic Acid) (PEMA). The chemical composition of these plastics was confirmed using Raman and FTIR spectroscopy, and they were found to have irregular shapes. The resulting NP particles ranged from 50 to 400 nm in size and demonstrated relative stability when suspended in water. To assess their impact, the study investigated the effects of these NP particulates on cell viability and the expression of genes involved in inflammation and oxidative stress using a macrophage cell line. The findings revealed that all types of NP reduced cell viability in a concentration-dependent manner. Notably, PS, HDPE, and PP induced significant reductions in cell viability at lower concentrations, compared to PEMA and PET. Moreover, exposure to NP led to differential alterations in the expression of inflammatory genes in the macrophage cell line. Overall, this study presents a viable method for producing NP from waste materials that closely resemble real-world NP. Furthermore, the toxicity studies demonstrated distinct cellular responses based on the composition of the NP, shedding light on the potential environmental and health impacts of these particles.

Positive feedback regulation between glycolysis and histone lactylation drives oncogenesis in pancreatic ductal adenocarcinoma.

BACKGROUND: Metabolic reprogramming and epigenetic alterations contribute to the aggressiveness of pancreatic ductal adenocarcinoma (PDAC). Lactate-dependent histone modification is a new type of histone mark, which links glycolysis metabolite to the epigenetic process of lactylation. However, the role of histone lactylation in PDAC remains unclear. METHODS: The level of histone lactylation in PDAC was identified by western blot and immunohistochemistry, and its relationship with the overall survival was evaluated using a Kaplan-Meier survival plot. The participation of histone lactylation in the growth and progression of PDAC was confirmed through inhibition of histone lactylation by glycolysis inhibitors or lactate dehydrogenase A (LDHA) knockdown both in vitro and in vivo. The potential writers and erasers of histone lactylation in PDAC were identified by western blot and functional experiments. The potential target genes of H3K18 lactylation (H3K18la) were screened by CUT&Tag and RNA-seq analyses. The candidate target genes TTK protein kinase (TTK) and BUB1 mitotic checkpoint serine/threonine kinase B (BUB1B) were validated through ChIP-qPCR, RT-qPCR and western blot analyses. Next, the effects of these two genes in PDAC were confirmed by knockdown or overexpression. The interaction between TTK and LDHA was identified by Co-IP assay. RESULTS: Histone lactylation, especially H3K18la level was elevated in PDAC, and the high level of H3K18la was associated with poor prognosis. The suppression of glycolytic activity by different kinds of inhibitors or LDHA knockdown contributed to the anti-tumor effects of PDAC in vitro and in vivo. E1A binding protein p300 (P300) and histone deacetylase 2 were the potential writer and eraser of histone lactylation in PDAC cells, respectively. H3K18la was enriched at the promoters and activated the transcription of mitotic checkpoint regulators TTK and BUB1B. Interestingly, TTK and BUB1B could elevate the expression of P300 which in turn increased glycolysis. Moreover, TTK phosphorylated LDHA at tyrosine 239 (Y239) and activated LDHA, and subsequently upregulated lactate and H3K18la levels. CONCLUSIONS: The glycolysis-H3K18la-TTK/BUB1B positive feedback loop exacerbates dysfunction in PDAC. These findings delivered a new exploration and significant inter-relationship between lactate metabolic reprogramming and epigenetic regulation, which might pave the way toward novel lactylation treatment strategies in PDAC therapy.

An autotransferable alloy overlayer toward stable sodium metal anodes.

Sodium (Na) metal anodes receive significant attention due to their high theoretical specific energy and cost-effectiveness. However, the high reactivity of Na foil anodes and the irregular surfaces have posed challenges to the operability and reliability of Na metals in battery applications. In the absence of inert environmental protection conditions, constructing a uniform, dense, and sodiophilic Na metal anode surface is crucial for homogenizing Na deposition, but remains less-explored. Herein, we fabricated a Tin (Sn) nanoparticle-assembled film conforming to separator pores, which provided ample space for accommodating volumetric expansion during the Na alloying process. Subsequently, a seamless Na-Sn alloy overlayer was formed and transferred onto the Na foil during Na plating through a separator-assisted technique, thereby overcoming conventional operational limitations of metallic Na. As compared to traditional volumetrically expanded cracked ones, the present autotransferable, highly sodiophilic, ion-conductive, and seamless Na-Sn alloy overlayer serves as uniform nucleation sites, thereby reducing nucleation and diffusion barriers and facilitating the compact deposition of metallic Na. Consequently, the autotransferable alloy layer enables a high average Coulombic efficiency of 99.9 % at 3.0 mA cm-2 and 3.0 mAh cm-2 in the half cells as well as minimal polarization overpotentials in symmetric cells, both during prolonged cycling 1200 h. Furthermore, the assembled Na||Sn-1.0h-PP||Na3V2(PO4)3@C@CNTs full cell delivers high capacity retention of 97.5 % after 200 cycles at a high cathodic mass loading.

Emerging roles of senolytics/senomorphics in HIV-related co-morbidities.

Human immunodeficiency virus (HIV) is known to cause cellular senescence and inflammation among infected individuals. While the traditional antiretroviral therapies (ART) have allowed the once fatal infection to be managed effectively, the quality of life of HIV patients on prolonged ART use is still inferior. Most of these individuals suffer from life-threatening comorbidities like chronic obstructive pulmonary disease (COPD), pulmonary arterial hypertension (PAH), and diabetes, to name a few. Interestingly, cellular senescence is known to play a critical role in the pathophysiology of these comorbidities as well. It is therefore important to understand the role of cellular senescence in the disease progression and co-morbidity development in HIV-infected individuals. In this respect, use of senolytic/senomorphic drugs as combination therapy with ART would be beneficial for HIV patients. This review provides a critical analysis of the current literature to determine the potential and efficacy of using senolytics/senotherapeutics in managing HIV infection, latency, and associated co-morbidities in humans. The various classes of senolytics have been studied in detail to focus on their potential to combat against HIV infections and associated pathologies with advancing age.

Gut Microbiota-Tryptophan Metabolism-GLP-1 Axis Participates in ß-Cell Regeneration Induced by Dapagliflozin.

Sodium-glucose cotransporter 2 inhibitors, efficacious antidiabetic agents that have cardiovascular and renal benefits, can promote pancreatic ß-cell regeneration in type 2 diabetic mice. However, the underlying mechanism remains unclear. In this study, we aimed to use multiomics to identify the mediators involved in ß-cell regeneration induced by dapagliflozin. We showed that dapagliflozin lowered blood glucose level, upregulated plasma insulin level, and increased islet area in db/db mice. Dapagliflozin reshaped gut microbiota and modulated microbiotic and plasmatic metabolites related to tryptophan metabolism, especially l-tryptophan, in the diabetic mice. Notably, l-tryptophan upregulated the mRNA level of glucagon-like peptide 1 (GLP-1) production-related gene (Gcg and Pcsk1) expression and promoted GLP-1 secretion in cultured mouse intestinal L cells, and it increased the supernatant insulin level in primary human islets, which was eliminated by GPR142 antagonist. Transplant of fecal microbiota from dapagliflozin-treated mice, supplementation of l-tryptophan, or treatment with dapagliflozin upregulated l-tryptophan, GLP-1, and insulin or C-peptide levels and promoted ß-cell regeneration in db/db mice. Addition of exendin 9-39, a GLP-1 receptor (GLP-1R) antagonist, or pancreatic Glp1r knockout diminished these beneficial effects. In summary, treatment with dapagliflozin in type 2 diabetic mice promotes ß-cell regeneration by upregulating GLP-1 production, which is mediated via gut microbiota and tryptophan metabolism.

Evaluating the Safety and Efficacy of Sodium-Glucose Co-transporter 2 Inhibitors in Subjects with Prediabetes: A Protocol for a Randomized Controlled Trial.

INTRODUCTION: Prediabetes is a state of subclinical glycemic impairment, bridging normal glucose tolerance and diabetes. Globally, over 30% of individuals exhibit prediabetic conditions, with a significant proportion progressing to diabetes. Prediabetes augments risks of various diseases including cardiovascular and kidney disease. While interventions like lifestyle changes have shown promise in diabetes prevention, their long-term sustainability is challenging. Alternative pharmacological treatments, such as acarbose and metformin, have demonstrated efficacy in certain populations. Sodium-glucose co-transporter 2 inhibitors, a novel class of glucose-lowering agents, have shown potential benefits for heart and kidney health in patients with diabetes. This research aims to evaluate the effectiveness and safety of dapagliflozin in individuals with prediabetes, elucidating its potential role in diabetes prevention strategies. RESEARCH DESIGN AND METHODS: This prospective trial is being conducted at Peking University Third Hospital. A total of 240 participants with prediabetes will be enrolled and randomly divided into two groups: one receiving dapagliflozin (10 mg/day) with lifestyle education, and the other with lifestyle education alone over a 12-week duration (with male/female = 1:1 in each group). Anthropometric, clinical and laboratory tests, including body mass index, waist circumference, fasting blood glucose, oral glucose tolerance test, insulin, lipid profile, liver and kidney function, sperm quality, will be conducted at the onset and conclusion of the trial. For adherence monitoring, participants will receive phone follow-ups at week 4 and week 8. The primary outcome is the change in 2-h plasma glucose during an oral glucose tolerance test over the study duration. Secondary outcomes encompass changes in various health metrics, including body mass index, lipid profiles, and liver function. PLANNED OUTCOMES: The proposed study is set to refine diabetes prevention strategies on the basis of its potential benefits observed in patients with diabetes. CONCLUSIONS: This will be the first randomized controlled trial to evaluate the safety and effectiveness of sodium-glucose co-transporter 2 inhibitors compared with lifestyle education for individuals with prediabetes. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT05914857 (registered 24 July 2023).

Joint inference of clonal structure using single-cell genome and transcriptome sequencing data.

Latest advancements in the high-throughput single-cell genome (scDNA) and transcriptome (scRNA) sequencing technologies enabled cell-resolved investigation of tissue clones. However, it remains challenging to cluster and couple single cells for heterogeneous scRNA and scDNA data generated from the same specimen. In this study, we present a computational framework called CCNMF, which employs a novel Coupled-Clone Non-negative Matrix Factorization technique to jointly infer clonal structure for matched scDNA and scRNA data. CCNMF couples multi-omics single cells by linking copy number and gene expression profiles through their general concordance. It successfully resolved the underlying coexisting clones with high correlations between the clonal genome and transcriptome from the same specimen. We validated that CCNMF can achieve high accuracy and robustness using both simulated benchmarks and real-world applications, including an ovarian cancer cell lines mixture, a gastric cancer cell line, and a primary gastric cancer. In summary, CCNMF provides a powerful tool for integrating multi-omics single-cell data, enabling simultaneous resolution of genomic and transcriptomic clonal architecture. This computational framework facilitates the understanding of how cellular gene expression changes in conjunction with clonal genome alternations, shedding light on the cellular genomic difference of subclones that contributes to tumor evolution.

Prevalence and influencing factors of kinesiophobia in older patients with primary osteoporosis: A cross-sectional survey.

AIM: To explore the prevalence of kinesiophobia in older patients with primary osteoporosis and analyze its influencing factors. METHODS: A cross-sectional survey was conducted among 221 older patients with primary osteoporosis in a general hospital in Kunming, China. Data were collected through a sociodemographic-clinical questionnaire, Tampa Scale for Kinesiophobia-11 (TSK-11), Global Pain Scale (GPS), Five Facets Mindfulness Questionnaire-Short Form (FFMQ-SF), and Hospital Anxiety and Depression Scale (HADS). SPSS 27.0 software was utilized for univariate and binary logistic regression analyses. RESULTS: The findings revealed that the prevalence of kinesiophobia in this study was 57.01 %. Age, history of fractures, chronic obstructive pulmonary disease (COPD), lumbar disc herniation, chronic pain, mindfulness, anxiety, and depression were identified as significant influencing factors of kinesiophobia in the binary logistic regression analyses. CONCLUSION: Healthcare professionals should be attentive to occurrence of kinesiophobia. Timely measures should be implemented to improve pain, anxiety and depression, and employ mindfulness interventions to mitigate kinesiophobia.

A Natural Peptide from A Traditional Chinese Medicine Has the Potential to Treat Chronic Atrophic Gastritis by Activating Gastric Stem Cells.

Chronic atrophic gastritis (AG) is initiated mainly by Helicobacter pylori infection, which may progress to stomach cancer following the Correa's cascade. The current treatment regimen is H. pylori eradication, yet evidence is lacking that this treatment is effective on later stages of AG especially gastric gland atrophy. Here, using AG mouse model, patient samples, gastric organoids, and lineage tracing, this study unraveled gastric stem cell (GSC) defect as a crucial pathogenic factor in AG in mouse and human. Moreover, a natural peptide is isolated from a traditional Chinese medicine that activated GSCs to regenerate gastric epithelia in experimental AG models and revitalized the atrophic gastric organoids derived from patients. It is further shown that the peptide exerts its functions by stabilizing the EGF-EGFR complex and specifically activating the downstream ERK and Stat1 signaling. Overall, these findings advance the understanding of AG pathogenesis and open a new avenue for AG treatment.

Targeted inhibition of gut bacterial ß-glucuronidases by octyl gallate alleviates mycophenolate mofetil-induced gastrointestinal toxicity.

Mycophenolate mofetil (MMF) is a viable therapeutic option against various immune disorders as a chemotherapeutic agent. Nevertheless, its application has been undermined by the gastrotoxic metabolites (mycophenolic acid glucuronide, MPAG) produced by microbiome-associated ß-glucuronidase (ßGUS). Therefore, controlling microbiota-produced ßGUS underlines the potential strategy to improve MMF efficacy by overcoming the dosage limitation. In this study, the octyl gallate (OG) was identified with promising inhibitory activity on hydrolysis of PNPG in our high throughput screening based on a chemical collection of approximately 2000 natural products. Furthermore, OG was also found to inhibit a broad spectrum of BGUSs, including mini-Loop1, Loop 2, mini-Loop 2, and mini-Loop1,2. The further in vivo experiments demonstrated that administration of 20 mg/kg OG resulted in predominant reduction in the activity of BGUSs while displayed no impact on the overall fecal microbiome in mice. Furthermore, in the MMF-induced colitis model, the administration of OG at a dosage of 20 mg/kg effectively mitigated the gastrointestinal toxicity, and systematically reverted the colitis phenotypes. These findings indicate that the OG holds promising clinical potential for the prevention of MMF-induced gastrointestinal toxicity by inhibition of BGUSs and could be developed as a combinatorial therapy with MFF for better clinical outcomes.

Paternal genetic structure analysis of the modern Han populations based on Y-SNP and Y-STR.

The Han populations represent the largest ethnic group in China. Previous studies have primarily focused on investigating their genetic origins, migration and integration, as well as paternal genetic relationships within specific regional Han populations. However, a comprehensive analysis of the global paternal genetic structure of Han populations is lacking. In this study, we performed Y-chromosome sequencing on 362 unrelated male samples from Chinese Han individuals collected from Qinghai, Sichuan and Liaoning provinces. We then integrated relevant data from reported studies. Our final dataset comprised 1830 samples from 16 Han populations across 15 provinces in China, encompassing information on 89 Y-SNPs and 16 Y-STRs. Statistical analyses were conducted to assess Y-STR haplotype diversity (HD) and Y-SNP haplogroup frequencies. Additionally, we employed principal component analysis (PCA), phylogenetic tree and haplotype network to explore genetic differentiation within Han populations and the genetic relationships between Han populations and ethnic minorities surrounding them. Our results demonstrated that the O-M175 haplogroup represents the predominant paternal lineage in Han populations, with frequencies ranging from 60.53% (Qinghai Han) to 92.7% (Guangdong Han). Moreover, the subclades downstream of O-M175 showed distinct regional variations in their distribution patterns. The O2-M122 haplogroup was prevalent in all Han populations and demonstrated a gradual decline in frequency from north to south. Conversely, the distribution frequency of the O1b-M268 haplogroup decreased from south to north, particularly showed significant presence among Han populations in the Lingnan region. Haplogroup O1a-M119 distributed more frequently in the central Han populations. Our findings revealed that Chinese Han populations can be categorized into three subgroups: northern, central, and southern. Notably, there were significant differences among Han in Qinghai and other regions. Regarding the genetic relationships between Han populations and surrounding ethnic minorities, we observed a closer genetic affinity between different Han populations, but northern Han demonstrated a stronger relationship with the Hui ethnic group, while southern Han exhibited a closer connection with the Gelao and Li ethnic groups. In summary, this study presented a systematic analysis of haplogroup distribution, genetic substructure of Han populations and genetic relationships between Han populations and surrounding ethnic minorities based on 89 Y-SNPs and 16 Y-STRs systematically. Our research supplemented valuable insights into population genetics and forensic genetics, and provided data support for the forensic application of Y chromosome. The integration of Y-SNP haplogroups with Y-STR haplotypes offers enhanced understanding of the genetic substructure within Han populations, which holds significance for both population genetics research and forensic science applications.

Comprehensive effects of traditional Chinese medicine treatment on heart failure and changes in B-type natriuretic peptide levels: A meta-analysis.

BACKGROUND: Heart failure (HF), a common cardiovascular condition, is characterized by significant morbidity and mortality. While traditional Chinese medicine (TCM) is often used as a complementary approach in HF management, systematic evaluations of its impact on clinical outcomes, TCM syndrome scores, and B-type natriuretic peptide (BNP) levels are lacking. This study fills this gap through a comprehensive analysis of randomized controlled trials (RCTs) focusing on TCM for HF treatment. It encompasses an assessment of methodological quality, a meta-analysis, and an evaluation of evidence quality based on established standards. The results offer crucial insights into the potential advantages and constraints of TCM in HF management. AIM: To systematically analyze the effects of TCM on the clinical comprehensive outcomes, TCM syndrome scores, and BNP levels in patients with HF and evaluated the quality of evidence for these trials. METHODS: RCTs on TCM for HF treatment published since the establishment of the database were searched in four Chinese and English databases, including China National Knowledge Infrastructure, Wanfang, VIP Information Chinese Science and Technology Journal, and PubMed. Methodological quality was assessed for the included studies with the Cochrane risk-of-bias assessment tool, and the meta-analysis and publication bias assessment was performed with the RevMan5.3 software. Finally, the quality of evidence was rated according to the GRADE criteria. RESULTS: A total of 1098 RCTs were initially retrieved. After screening, 16 RCTs were finally included in our study, which were published between 2020 and 2023. These RCTs involved 1660 HF patients, including 832 in the TCM group [TCM combined with conventional Western medicine (CMW) treatment] and 828 in the CWM group (CWM treatment). The course of treatments varied from 1 wk to 3 months. TCM syndrome differentiation was analyzed in 11 of the included RCTs. In all included RCTs, outcome indicators included comprehensive clinical outcomes, TCM syndrome scores, and BNP levels. The meta-analysis results showed significant differences between the TCM and CWM groups in terms of comprehensive clinical outcomes [risk ratio = -0.54; 95% confidence interval (CI) = -0.61, -0.47; P < 0.00001], TCM syndrome scores [weighted mean difference (WMD) = -142.07; 95%CI = -147.56, -136.57; P < 0.00001], and BNP levels (WMD = -142.07; 95%CI = -147.56, -136.57; P < 0.00001). According to the GRADE criteria, RCTs where "TCM improves clinical comprehensive outcomes" were rated as low-quality evidence, and RCTs where "TCM reduces TCM syndrome scores" or "TCM decreases BNP levels" were rated as medium-quality evidence. CONCLUSION: TCM combined with CWM treatment effectively improves comprehensive clinical outcomes and diminishes TCM syndrome scores and BNP levels in HF patients. Given the low and medium quality of the included RCTs, the application of these results should be cautious.

Exploring the impact of PEGylation on pharmacokinetics: a size-dependent effect of polyethylene glycol on prostate-specific membrane antigen inhibitors.

BACKGROUND: Prostate cancer is the second most frequent cancer and the fifth leading cause of cancer-related deaths in men. Prostate-specific membrane antigen (PSMA) as a target has gained increasing attention. This research aims to investigate and understand how altering size of PEG impacts the in vitro and in vivo behavior and performance of PSMA inhibitors, with a specific focus on their pharmacokinetic characteristics and targeting properties. RESULTS: Two 68Ga-labeled PSMA-targeted radiotracers were developed, namely [68Ga]Ga-PP4-WD and [68Ga]Ga-PP8-WD, with varying sizes of polyethylene glycol (PEG). [68Ga]Ga-PP4-WD and [68Ga]Ga-PP8-WD had excellent affinity for PSMA with IC50 being 8.06 ± 0.91, 6.13 ± 0.79 nM, respectively. Both tracers enabled clear visualization of LNCaP tumors in PET images with excellent tumor-to-background contrast. They also revealed highly efficient uptake and internalization into LNCaP cells, increasing over time. The biodistribution studies demonstrated that both radioligands exhibited significant and specific uptake into LNCaP tumors. Furthermore, they were rapidly cleared through the renal pathway, as evidenced by [68Ga]Ga-PP4-WD and [68Ga]Ga-PP8-WD showing a tenfold and a fivefold less in renal uptake, respectively, compared to [68Ga]Ga-Flu-1 in 30 min. Both in vitro and in vivo experiments demonstrated that PEG size significantly impacted tumor-targeting and pharmacokinetic properties. CONCLUSIONS: These radiotracers have demonstrated their effectiveness in significantly reducing kidney uptake while maintaining the absorbed dose in tumors. Both radiotracers exhibited strong binding and internalization characteristics in vitro, displayed high specificity and affinity for PSMA in vivo.

Ultralong Cycling and Safe Lithium-Sulfur Pouch Cells for Sustainable Energy Storage.

While layered metal oxides remain the dominant cathode materials for the state-of-the-art lithium-ion batteries, conversion-type cathodes such as sulfur present unique opportunities in developing cheaper, safer, and more energy-dense next-generation battery technologies. There has been remarkable progress in advancing the laboratory scale lithium-sulfur (Li-S) coin cells to a high level of performance. However, the relevant strategies cannot be readily translated to practical cell formats such as pouch cells and even battery pack. Here these key technical challenges are addressed by molecular engineering of the Li metal for hydrophobicization, fluorination and thus favorable anode chemistry. The introduced tris(2,4-di-tert-butylphenyl) phosphite (TBP) and tetrabutylammonium fluoride (TBA+ F- ) as well as cellulose membrane by rolling enables the formation of a functional thin layer that eliminates the vulnerability of Li metal towards the already demanding environment required (1.55% relative humidity) for cell production and gives rise to LiF-rich solid electrolyte interphase (SEI) to suppress dendrite growth. As a result, Li-S pouch cells assembled at a pilot production line survive 400 full charge/discharge cycles with an average Coulombic efficiency of 99.55% and impressive rate performance of 1.5 C. A cell-level energy density of 417 Wh kg-1 and power density of 2766 W kg-1 are also delivered via multilayer Li-S pouch cell. The Li-S battery pack can even power an unmanned aerial vehicle of 3 kg for a fairly long flight time. This work represents a big step forward acceleration in Li-S battery marketization for future energy storage featuring improved safety, sustainability, higher energy density as well as reduced cost.

Comparative transcriptomics reveals common and strain-specific responses of human macrophages to infection with Mycobacterium tuberculosis and Mycobacterium bovis BCG.

Mycobacterium tuberculosis (MTB) and Mycobacterium bovis (M. bovis) are closely related pathogenic mycobacteria known to cause chronic pulmonary infections in both humans and animals. Despite sharing nearly identical genomes and virulence factors, these two bacteria display variations in host tropism, epidemiology, and clinical presentations. M. bovis Bacillus Calmette-Guérin (BCG) is an attenuated strain of M. bovis commonly utilized as a vaccine for tuberculosis (TB). Nevertheless, the molecular underpinnings of these distinctions and the intricacies of host-pathogen interactions remain areas of ongoing research. In this study, a comparative transcriptomic analysis was conducted on human leukemia macrophages (THP-1) infected with either MTB H37Rv or M. bovis BCG (Tokyo strain) to elucidate common and strain-specific responses at the transcriptional level. RNA sequencing was utilized to characterize the transcriptomes of human primary macrophages infected with MTB or BCG at 6 and 24 h post-infection. The findings indicate that both MTB and BCG induce substantial and dynamic alterations in the transcriptomes of THP-1, with a notable overlap in the quantity and extent of differentially expressed genes (DEGs). Moreover, gene ontology (GO) enrichment analysis unveiled shared pathways related to immune response, cytokine signaling, and apoptosis. The immune response of macrophages to bacterial infections at 6 h exhibited significantly greater intensity compared to that at 24 h. Furthermore, distinct gene sets displaying notable variances between MTB and BCG infections were identified. The profound impact of MTB infection on macrophage gene expression, particularly within the initial 6 h, was evident. Additionally, downregulation of pathways such as Focal adhesion, Rap1 signaling pathway, and Regulation of actin cytoskeleton was observed. The pathways associated with inflammation reactions and cell apoptosis exhibited significant differences, with BCG triggering macrophage apoptosis and MTB enhancing the survival of intracellular bacteria. Our findings reveal that MTB and BCG provoke similar yet distinct transcriptional responses in human macrophages, indicating variations in their pathogenesis and ability to adapt to host environments. These results offer novel insights into the molecular mechanisms governing host-pathogen interactions and may contribute to a deeper understanding of TB pathogenesis.

Enhancing surfactin production in Bacillus subtilis: Insights from proteomic analysis of nitrate-induced overproduction and strategies for combinatorial metabolic engineering.

Surfactin biosynthesis in Bacillus subtilis is intricately regulated by environmental conditions. In the present study, addition of nitrate, a nitrogen source, increased the production of surfactin in B. subtilis ATCC 21332, whereas its absence resulted in minimal or no surfactin production. Proteomics revealed the mechanism underlying nitrate-induced surfactin overproduction, identifying three key differential proteins (preprotein translocase subunit SecA, signal recognition particle receptor FtsY, and cell division adenosine triphosphate-binding protein FtsE) relevant to surfactin transport and regulation. Combinatorial metabolic engineering strategies (enhanced nitrate reduction, fatty acid hydroxylation, rational transporter engineering, and feeding) led to a 41.4-fold increase in surfactin production compared with the initial production in the wild-type strain. This study provides insights into the molecular mechanism of nitrate-induced surfactin overproduction and strategies to enhance the performance of surfactin-producing strains.

Antimicrobial photodynamic inactivation pH-responsive films based on gelatin/chitosan incorporated with aloe-emodin.

Using novel active food packaging has gradually become a daily necessity in terms of impeding microbial contamination. Here, an antimicrobial photodynamic inactivation (PDI) pH-responsive film is developed by incorporating aloe-emodin (AE) into a vehicle of gelatin/chitosan (GC). Besides enhancement in hydrophobicity, the well-dispersed crystals of AE in the GC matrix by hydrogen bonding can upgrade the film's mechanical strength and barrier. The matrix is capable of regulating the release of AE in response to acidic stimuli by a combination mechanism of diffusion and polymer relaxation. Being benefitted from the inherent bioactivity of AE and the PDI activity under visible light irradiation (i.e., 456 nm), the target film of GC-AE2 has excellent antibacterial effect towards Staphylococcus aureus and Escherichia coli, showing bacterial viability of 9.93 ± 1.33 % and 14.85 ± 1.16 %, respectively. Furthermore, the film can effectively thwart Botrytis cinerea infection in cherry tomatoes, demonstrating its potential in preventing the microbial spoilage of postharvest fruits.

Molecular mechanism of NAD+ and NMN binding to the Nudix homology domains of DBC1.

Deleted in breast cancer 1 (DBC1) is a human nuclear protein that modulates the activities of various proteins involved in cell survival and cancer progression. Oxidized form of nicotinamide adenine dinucleotide (NAD+) is suggested to bind to the Nudix homology domains (NHDs) of DBC1, thereby regulating DBC1-Poly (ADP-ribose) polymerase 1 (PARP1) interactions, resulting in the restoration of DNA repair. Using Nuclear Magnetic Resonance (NMR) and Isothermal Titration Calorimetry (ITC), we confirmed NAD+ and its precursor nicotinamide mononucleotide (NMN) both bind the NHD domain of DBC1 (DBC1354-396). NAD+ likely interacts with DBC1354-396 through hydrogen bonding, with a binding affinity (8.99 µM) nearly twice that of NMN (17.0 µM), and the key binding sites are primarily residues E363 and D372, in the agreement with Molecular Docking experiments. Molecular Dynamics (MD) simulation further demonstrated E363 and D372's anchoring role in the binding process. Additional mutagenesis experiments of E363 and D372 confirmed their critical involvement of ligand-protein interactions. These findings lead to a better understanding of how NAD+ and NMN regulate DBC1, thereby offering insights for the development of targeted therapies and drug research focused on DBC1-associated tumors.

A comparative study of structural variant calling in WGS from Alzheimer's disease families.

Detecting structural variants (SVs) in whole-genome sequencing poses significant challenges. We present a protocol for variant calling, merging, genotyping, sensitivity analysis, and laboratory validation for generating a high-quality SV call set in whole-genome sequencing from the Alzheimer's Disease Sequencing Project comprising 578 individuals from 111 families. Employing two complementary pipelines, Scalpel and Parliament, for SV/indel calling, we assessed sensitivity through sample replicates (N = 9) with in silico variant spike-ins. We developed a novel metric, D-score, to evaluate caller specificity for deletions. The accuracy of deletions was evaluated by Sanger sequencing. We generated a high-quality call set of 152,301 deletions of diverse sizes. Sanger sequencing validated 114 of 146 detected deletions (78.1%). Scalpel excelled in accuracy for deletions ≤100 bp, whereas Parliament was optimal for deletions >900 bp. Overall, 83.0% and 72.5% of calls by Scalpel and Parliament were validated, respectively, including all 11 deletions called by both Parliament and Scalpel between 101 and 900 bp. Our flexible protocol successfully generated a high-quality deletion call set and a truth set of Sanger sequencing-validated deletions with precise breakpoints spanning 1-17,000 bp.