Real-time continuous glucose monitoring-guided glucose management in inpatients with diabetes receiving short-term continuous subcutaneous insulin infusion: a randomized clinical trial.

Background: The use of real-time continuous glucose monitoring (rtCGM) technology remains largely investigational in the hospital setting. The current study aimed to evaluate the effectiveness of rtCGM in inpatients with diabetes who were treated with short-term continuous subcutaneous insulin infusion (CSII). Methods: In this randomized, parallel controlled trial conducted on the endocrinology wards in a tertiary hospital located in Shanghai, adults with type 1 and type 2 diabetes who required short-term CSII during hospitalization were randomly assigned (1:1) to receive either rtCGM-based glucose monitoring and management program or point-of-care (POC) standard of care (8 times/day) with blinded CGM. Primary outcome measure was the difference in the percentage of time within the target glucose range of 3.9-10 mmol/L (TIR, %). This study was registered at www.chictr.org.cn (ChiCTR2300068933). Findings: Among the 475 randomized participants (237 in the rtCGM group and 238 in the POC group), the mean age of was 60 ± 13 years, and the mean baseline glycated hemoglobin level was 9.4 ± 1.8%. The CGM-recorded mean TIR was 71.1 ± 15.8% in the rtCGM group and 62.9 ± 18.9% in the POC group, with a mean difference of 8.2% (95% confidence interval [CI]: 5.1-11.4%, P < 0.001). The mean time above range >10 mmol/L was significantly lower in the rtCGM group than in the POC group (28.3 ± 15.8% vs. 36.6 ± 19.0%, P < 0.001), whereas there was no significant between-group difference in the time below range <3.9 mmol/L (P = 0.11). Moreover, the time to reach target glucose was significantly shorter in the rtCGM group than in the POC group (2.0 [1.0-4.0] days vs. 4.0 [2.0-5.0] days, P < 0.001). There were no serious adverse events in both groups. Interpretation: In patients with diabetes who received short-term CSII during hospitalization, the rtCGM program resulted in better glucose control than the POC standard of care, without increasing the risk of hypoglycemia. Funding: The Program of Shanghai Academic Research Leader (22XD1402300), Shanghai Oriental Talent Program (Youth Project) (No. NA), the Shanghai "Rising Stars of Medical Talent" Youth Development Program-Outstanding Youth Medical Talents (SHWSRS(2021)_099), and the Shanghai Research Center for Endocrine and Metabolic Diseases (2022ZZ01002).

Mechanism of Autocatalytic Reduction of CO2 over MgCO3 to High Value-Added Chemicals: A DFT & AIMD Study.

Calcination of MgCO3 is an important industrial reaction, but it causes significant and unfavorable CO2 production. Calcination in a reducing green hydrogen atmosphere can substantially reduce CO2 release and produce high value-added products such as CO or hydrocarbons, but the mechanism is still unclear. Here, the in situ transformation process of MgCO3 interacting with hydrogen and the specific formation mechanism of the high value-added products are thoroughly investigated based on reaction thermodynamic, ab initio molecular dynamics (AIMD) simulations, and density functional theory (DFT) calculations. The reaction thermodynamic parameters of MgCO3 coupled with hydrogen to produce CO or methane are calculated, revealing that increasing and decreasing the thermal reductive decomposition temperature favors the production of CO and methane, respectively. Kinetically, the energy barriers of each possible production pathway for the dominant products CO and methane are further calculated in conjunction with the AIMD simulation results of the transformation process. The results suggest that CO is produced via the MgO catalytic-carboxyl pathway (CO2*→ COOH*trans→ COOH*cis→ CO*→ CO), which is autocatalyzed by MgO derived from the thermal reductive decomposition of MgCO3. For the mechanism of methane formation, it prefers to be produced by the stepwise interaction of carbonates in the MgCO3 laminates with hydrogen adsorbed on their surfaces (direct conversion pathway: sur-O-CO → sur-O-HCO → sur-O-HCOH → sur-O-HC → sur-O-CH2 → sur-O-CH3 → sur-O + CH4*).

Electrochemical detection of FTO with N3-kethoxal labeling and MazF cleavage.

N6-Methyladenosine (m6A) is a prevalent modification in eukaryotic mRNAs and is linked to various human cancers. The fat mass and obesity-associated protein (FTO), a key m6A demethylase, is crucial in m6A regulation, affecting many biological processes and diseases. Detecting FTO is vital for clinical and research applications. Our study leverages the specific cleavage properties of the MazF endoribonuclease to design an electrochemical method with signal amplification guided by streptavidin-horseradish peroxidase (SA-HRP), intended for FTO detection. Initially, the compound N3-kethoxal is employed for its reversible tagging ability, selectively attaching to guanine (G) bases. Subsequently, dibenzocyclooctyne polyethylene glycol biotin (DBCO-PEG4-Biotin), is introduced through a reaction with N3-kethoxal. HRP is then employed to catalyze the redox system to enhance the current response further. A promising linear correlation between the peak current and the FTO concentration was observed within the range of 7.90 × 10-8 to 3.50 × 10-7 M, with a detection limit of 5.80 × 10-8 M. Moreover, this method assessed the FTO inhibitor FB23's inhibitory effect, revealing a final IC50 value of 54.73 nM. This result aligns with the IC50 value of 60 nM obtained through alternative methods and is very close to the values reported in the literature. The study provides reference value for research into obesity, diabetes, cancer, and other FTO-related diseases, as well as for the screening of potential therapeutic drugs.

OsWNK9 regulates cadmium concentration in brown rice by restraining cadmium transport from straw to brown rice.

Selecting and breeding rice cultivars that enable strong cadmium (Cd) accumulation in rice straw but low accumulation in brown rice is a promising way to achieve Cd phytoremediation as well as to ensure the food safety of rice. Herein, we isolated a gene OsWNK9 from the quantitative trait locus associated with reducing Cd translocation from rice straw to brown rice and decreasing the Cd concentration in brown rice (BRCdC). Continuous strong expression of OsWNK9 was observed in nodes and internode and was induced after Cd supply. OsWNK9 was localized in the rice cell nucleus and participated in the regulation of Cd transport in yeast. Two independent oswnk9 rice mutants were generated via CRISPR/Cas9 gene-editing and showed significantly higher BRCdC than that of the wild type (WT). The BRCdC of knockout oswnk9 mutants was 0.227 mg kg-1and 0.238 mg kg-1, increased by 14 % and 19 % compared with that of the WT due to the lower Cd allocation in the basal stem, internode, and node III, which was unrelated to Cd uptake. Interestingly, OsWNK9 could promote iron (Fe) accumulation in rice under Cd-contaminated conditions, suggesting that OsWNK9 is an ideal gene for Cd phytoremediation and Fe biofortification in rice to support safe food production.

Comparative genomics of Tn6411 transposons carrying the blaIMP-1 gene in Pseudomonas aeruginosa.

We aimed to determine the molecular characteristics of carbapenem-resistant Pseudomonas aeruginosa strains 18081308 and 18083286, which were isolated from the urine and the sputum of two Chinese patients, respectively. Additionally, we conducted a comparative analysis between Tn6411 carrying blaIMP-1 in strain 18083286 and transposons from the same family available in GenBank. Bacterial genome sequencing was carried out on strains 18081308 and 18083286 to obtain their whole genome sequence. Average nucleotide identity (ANI) was used for their precise species identification. Serotyping and multilocus sequence typing were performed. Furthermore, the acquired drug resistance genes of these strains were identified. The carbapenem-resistant P. aeruginosa strains isolated in the present study were of sequence type ST865 and serotype O6. They all carried the same resistance genes (aacC2, tmrB, and blaIMP-1). Tn6411, a Tn7-like transposon carrying blaIMP-1, was found in strain 18083286 by single molecule real time (SMRT) sequencing. We also identified the presence of this transposon sequence in other chromosomes of P. aeruginosa and plasmids carried by Acinetobacter spp. in GenBank, indicating the necessity for heightening attention to the potential transferability of this transposon.

A disposable electrochemical magnetic immunosensor for the rapid and sensitive detection of 5-formylcytosine and 5-carboxylcytosine in DNA.

5-formylcytosine (5 fC) and 5-carboxylcytosine (5caC) serve as key intermediates in DNA demethylation process with significant implications for gene regulation and disease progression. In this study, we introduce a novel electrochemical sensing platform specifically designed for the sensitive and selective detection of 5 fC and 5caC in DNA. Protein A-modified magnetic beads (ProtA-MBs) coupled with specific antibodies facilitate the immunorecognition and enrichment of these modified bases. Signal amplification is achieved through several chemical reactions involving the interaction between N3-kethonaxl and guanine, copper-free click chemistry for the attachment of dibenzocyclooctyne (DBCO)-Biotin, and the subsequent recognition by streptavidin-conjugated horseradish peroxidase (SA-HRP). The assay's readout is performed on a disposable laser-induced graphene (LIG) electrode, modified with the bead-antibody-DNA complex in a magnetic field, and analyzed using differential pulse voltammetry in a system employing hydroquinone (HQ) as the redox mediator and H2O2 as the substrate. This immunosensor displayed excellent sensitivity, with detection limits of 14.8 fM for 5 fC across a 0.1-1000 pM linear range and 87.4 fM for 5caC across a 0.5-5000 pM linear range, and maintained high selectivity even in the presence of interferences from other DNA modifications. Successful application in quantifying 5 fC and 5caC in genomic DNA from cell extracts, with recovery rates between 97.7% to 102.9%, underscores its potential for clinical diagnostics. N3-kethoxal was used for the first time in an electrochemical sensor. This work not only broadens the toolkit for detecting DNA modifications but also provides a fresh impetus for the development of point-of-care testing (POCT) technologies.

Reprogrammed IDO-Induced Immunosuppressive Microenvironment Synergizes with Immunogenic Magnetothermodynamics for Improved Cancer Therapy.

Indoleamine 2,3-dioxygenase (IDO), highly expressed in hepatocellular carcinoma (HCC), plays a pivotal role in creating an immune-suppressive tumor microenvironment. Inhibiting IDO activity has emerged as a promising immunotherapeutic strategy; however, the delivery of IDO inhibitors to the tumor site is constrained, limiting their therapeutic efficacy. In this study, we developed a magnetic vortex nanodelivery system for the targeted delivery of the IDO inhibitor NLG919, integrated with magnetic hyperthermia therapy to reverse the immune-suppressive microenvironment of liver cancer and inhibit tumor growth. This system comprises thermoresponsive polyethylenimine-coated ferrimagnetic vortex-domain iron oxide nanorings (PI-FVIOs) loaded with NLG919 (NLG919/PI-FVIOs). Under thermal effects, NLG919 can be precisely released from the delivery system, counteracting IDO-mediated immune suppression and synergizing with NLG919/PI-FVIOs-mediated magnetothermodynamic (MTD) therapy-induced immunogenic cell death (ICD), resulting in effective HCC suppression. In vivo studies demonstrate that this combination therapy significantly inhibits tumor growth and metastasis by enhancing the accumulation of cytotoxic T lymphocytes and suppressing regulatory T cells within the tumor. Overall, our findings reveal that NLG919/PI-FVIOs can induce a potent antitumor immune response by disrupting the IDO pathway and activating the ICD, offering a promising therapeutic avenue for HCC treatment.

Shootin1 Regulates Retinal Ganglion Cell Neurite Development: Insights From an RGC Direct Somatic Cell Reprogramming Model.

Purpose: Retinal ganglion cells (RGCs) connect the retina to the brain. Proper development of the axons and dendrites of RGCs is the basis for these cells to function as projection neurons to deliver visual information to the brain. The purpose of this study was to investigate the function of Shtn1 (which encodes shootin1) in RGC neurite development. Methods: Immunofluorescence (IF) was used to characterize the expression pattern of marker genes. An in vitro direct somatic cell reprogramming system was used to generate RGC-like neurons (iRGCs), which was subsequently used to study the function of Shtn1. Short-hairpin RNAs (shRNAs) were used to knock down Shtn1, and the coding sequence (CDS) of Shtn1 was used to overexpress the gene. Lentiviruses were used to deliver shRNAs or CDSs into iRGCs. The patch clamp technique was used to measure the electrophysiological properties of the iRGCs. RNA sequencing (RNA-seq) was used to examine transcriptome expression. Results: Using IF, we demonstrated that shootin1 is distinctively expressed in RGCs during the period in which RGCs actively develop and adjust the connections of their neurites with upstream and downstream neurons. Using the iRGC system, we demonstrated that Shtn1 promotes the growth and complexity of neurites and thus the electrophysiological maturation, of iRGCs. RNA-seq analyses showed that Shtn1 may also regulate gene expression and neurogenesis in iRGCs. Conclusions: Shtn1 promotes RGC neurite development. These findings improve our understanding of the molecular machinery governing RGC neurite development and may help to optimize future RGC regeneration methods.

Intracellular magnetic hyperthermia reverses sorafenib resistance in hepatocellular carcinoma through its action on signaling pathways.

Sorafenib, a first-line drug for advanced hepatocellular carcinoma (HCC), unfortunately encounters resistance in most patients, leading to disease progression. Traditional approaches to counteract this resistance, particularly those targeting the RAF-MEK-ERK pathway, often face clinical feasibility limitations. Magnetic hyperthermia (MH), unlike conventional thermal therapies, emerges as a promising alternative. It uniquely combines magnetothermal effects with an increase in reactive oxygen species (ROS). This study found the potential of intracellular MH enhanced the efficacy of sorafenib, increased cellular sensitivity to sorafenib, and reversed sorafenib resistance by inhibiting the RAF-MEK-ERK pathway in an ROS-dependent manner in a sorafenib-resistant HCC cell. Further, in a sorafenib-resistant HCC mouse model, MH significantly sensitized tumors to sorafenib therapy, resulting in inhibited tumor growth and improved survival rates. This presents a promising strategy to overcome sorafenib resistance in HCC, potentially enhancing therapeutic outcomes for patients with this challenging condition.

Nanomaterials in modulating tumor-associated macrophages and enhancing immunotherapy.

Tumor-associated macrophages (TAMs) are predominantly present in the tumor microenvironment (TME) and play a crucial role in shaping the efficacy of tumor immunotherapy. These TAMs primarily exhibit a tumor-promoting M2-like phenotype, which is associated with the suppression of immune responses and facilitation of tumor progression. Interestingly, recent research has highlighted the potential of repolarizing TAMs from an M2 to a pro-inflammatory M1 status-a shift that has shown promise in impeding tumor growth and enhancing immune responsiveness. This concept is particularly intriguing as it offers a new dimension to cancer therapy by targeting the tumor microenvironment, which is a significant departure from traditional approaches that focus solely on tumor cells. However, the clinical application of TAM-modulating agents is often challenged by issues such as insufficient tumor accumulation and off-target effects, limiting their effectiveness and safety. In this regard, nanomaterials have emerged as a novel solution. They serve a dual role: as delivery vehicles that can enhance the accumulation of therapeutic agents in the tumor site and as TAM-modulators. This dual functionality of nanomaterials is a significant advancement as it addresses the key limitations of current TAM-modulating strategies and opens up new avenues for more efficient and targeted therapies. This review provides a comprehensive overview of the latest mechanisms and strategies involving nanomaterials in modulating macrophage polarization within the TME. It delves into the intricate interactions between nanomaterials and macrophages, elucidating how these interactions can be exploited to drive macrophage polarization towards a phenotype that is more conducive to anti-tumor immunity. Additionally, the review explores the burgeoning field of TAM-associated nanomedicines in combination with tumor immunotherapy. This combination approach is particularly promising as it leverages the strengths of both nanomedicine and immunotherapy, potentially leading to synergistic effects in combating cancer.

Associations between organophosphate esters and bone mineral density in adults in the United States: 2011-2018 NHANES.

BACKGROUND: Organophosphate esters (OPEs) are used extensively as flame retardants and plasticizers. Laboratory studies have shown that OPEs exhibit osteotoxicity by inhibiting osteoblast differentiation; however, little is known about how OPEs exposure is associated with bone health in humans. OBJECTIVES: We conducted a cross-sectional study to investigate the association between OPEs exposure and bone mineral density (BMD) in adults in the United States using data from the 2011-2018 National Health and Nutrition Examination Survey (NHANES). METHODS: Multivariate linear regression models were used to assess the association between concentrations of individual OPE metabolites and BMDs. We also used the Bayesian kernel machine regression (BKMR) and quantile g-computation (qgcomp) models to estimate joint associations between OPE mixture exposure and BMDs. All the analyses were stratified according to gender. RESULTS: A total of 3546 participants (median age, 40 years [IQR, 30-50 years]; 50.11% male) were included in this study. Five urinary OPE metabolites with a detection rate of > 50% were analyzed. After adjusting for the potential confounders, OPE metabolite concentrations were associated with decreased total-body BMD and lumbar spine BMD in males, although some associations only reached significance for bis(1-chloro-2-propyl) phosphate (BCPP), dibutyl phosphate (DBUP), and bis(2-chloroethyl) phosphate (BCEP) (ß = -0.013, 95% CI: -0.026, -0.001 for BCPP and total-body BMD; ß = -0.022, 95% CI: -0.043, -0.0001 for DBUP and lumbar spine BMD; ß=-0.018, 95% CI: -0.034, -0.002 for BCEP and lumbar spine BMD). OPE mixture exposure was also inversely associated with BMD in males, as demonstrated in the BMKR and qgcomp models. CONCLUSIONS: This study provides preliminary evidence that urinary OPE metabolite concentrations are inversely associated with BMD. The results also suggested that males were more vulnerable than females. However, further studies are required to confirm these findings.

Molecular mechanism of dissolvable metal nanoparticles-enhanced CO2 fixation by algae: Metal-chlorophyll synthesis.

Algae-driven photosynthetic CO2 fixation is a promising strategy to mitigate global climate changes and energy crises. Yet, the presence of metal nanoparticles (NPs), particularly dissolvable NPs, in aquatic ecosystems introduces new complexities due to their tendency to release metal ions that may perturb metabolic processes related to algal CO2 fixation. This study selected six representative metal NPs (Fe3O4, ZnO, CuO, NiO, MgO, and Ag) to investigate their impacts on CO2 fixation by algae (Chlorella vulgaris). We discovered an intriguing phenomenon that bivalent metal ions released from the metal NPs, especially from ZnO NPs, substituted Mg2+ within the porphyrin ring. This interaction led to 81.8% and 76.1% increases in Zinc-chlorophyll and Magnesium-chlorophyll contents within algal cells at 0.01 mM ZnO NPs, respectively. Integrating metabolomics and transcriptomics analyses revealed that ZnO NPs mainly promoted the photosynthesis-antenna protein pathway, porphyrin and chlorophyll metabolism, and carbon fixation pathway, thereby mitigating the adverse effects of Zn2+ substitution in light harvesting and energy transfer for CO2 fixation. Ultimately, the genes encoding Rubisco large subunit (rbcL) responsible for CO2 fixation were upregulated to 2.60-fold, resulting in a 76.3% increase in carbon fixation capacity. Similar upregulations of rbcL expression (1.13-fold) and carbon fixation capacity (76.1%) were observed in algal cells even at 0.001 mM ZnO NPs, accompanied by valuable lipid accumulation. This study offers novel insights into the molecular mechanism underlying NPs on CO2 fixation by algae and potentially introduces strategies for global carbon sequestration.

Exercise-induced improvement of glycemic fluctuation and its relationship with fat and muscle distribution in type 2 diabetes.

AIMS: Management of blood glucose fluctuation is essential for diabetes. Exercise is a key therapeutic strategy for diabetes patients, although little is known about determinants of glycemic response to exercise training. We aimed to investigate the effect of combined aerobic and resistance exercise training on blood glucose fluctuation in type 2 diabetes patients and explore the predictors of exercise-induced glycemic response. MATERIALS AND METHODS: Fifty sedentary diabetes patients were randomly assigned to control or exercise group. Participants in the control group maintained sedentary lifestyle for 2 weeks, and those in the exercise group specifically performed combined exercise training for 1 week. All participants received dietary guidance based on a recommended diet chart. Glycemic fluctuation was measured by flash continuous glucose monitoring. Baseline fat and muscle distribution were accurately quantified through magnetic resonance imaging (MRI). RESULTS: Combined exercise training decreased SD of sensor glucose (SDSG, exercise-pre vs exercise-post, mean 1.35 vs 1.10 mmol/L, p = .006) and coefficient of variation (CV, mean 20.25 vs 17.20%, p = .027). No significant change was observed in the control group. Stepwise multiple linear regression showed that baseline MRI-quantified fat and muscle distribution, including visceral fat area (ß = -0.761, p = .001) and mid-thigh muscle area (ß = 0.450, p = .027), were significantly independent predictors of SDSG change in the exercise group, as well as CV change. CONCLUSIONS: Combined exercise training improved blood glucose fluctuation in diabetes patients. Baseline fat and muscle distribution were significant factors that influence glycemic response to exercise, providing new insights into personalized exercise intervention for diabetes.

The lack of PPARα exacerbated the progression of non-alcoholic steatohepatitis in mice with spleen deficiency syndrome by triggering an inflammatory response.

Background: In addition to abnormal liver inflammation, the main symptoms of non-alcoholic steatohepatitis (NASH) are often accompanied by gastrointestinal digestive dysfunction, consistent with the concept of spleen deficiency (SD) in traditional Chinese medicine. As an important metabolic sensor, whether peroxisome proliferator-activated receptor alpha (PPARα) participates in regulating the occurrence and development of NASH with SD (NASH-SD) remains to be explored. Methods: Clinical liver samples were collected for RNA-seq analysis. C57BL/6J mice induced by folium sennae (SE) were used as an SD model. qPCR analysis was conducted to evaluate the inflammation and metabolic levels of mice. PPARα knockout mice (PPARαko) were subjected to SE and methionine-choline-deficient (MCD) diet to establish the NASH-SD model. The phenotype of NASH and the inflammatory indicators were measured using histopathologic analysis and qPCR as well. Results: The abnormal expression of PPARα signaling, coupled with metabolism and inflammation, was found in the results of RNA-seq analysis from clinical samples. SD mice showed a more severe inflammatory response in the liver evidenced by the increases in macrophage biomarkers, inflammatory factors, and fibrotic indicators in the liver. qPCR results also showed differences in PPARα between SD mice and control mice. In PPARαko mice, further evidence was found that the lack of PPARα exacerbated the inflammatory response phenotype as well as the lipid metabolism disorder in NASH-SD mice. Conclusion: The abnormal NR signaling accelerated the vicious cycle between lipotoxicity and inflammatory response in NAFLD with SD. Our results provide new evidence for nuclear receptors as potential therapeutic targets for NAFLD with spleen deficiency.

Enhancing Gastrodin Production in Yarrowia lipolytica by Metabolic Engineering.

Gastrodin, 4-hydroxybenzyl alcohol-4-O-ß-D-glucopyranoside, has been widely used in the treatment of neurogenic and cardiovascular diseases. Currently, gastrodin biosynthesis is being achieved in model microorganisms. However, the production levels are insufficient for industrial applications. In this study, we successfully engineered a Yarrowia lipolytica strain to overproduce gastrodin through metabolic engineering. Initially, the engineered strain expressing the heterologous gastrodin biosynthetic pathway, which comprises chorismate lyase, carboxylic acid reductase, phosphopantetheinyl transferase, endogenous alcohol dehydrogenases, and a UDP-glucosyltransferase, produced 1.05 g/L gastrodin from glucose in a shaking flask. Then, the production was further enhanced to 6.68 g/L with a productivity of 2.23 g/L/day by overexpressing the key node DAHP synthases of the shikimate pathway and alleviating the native tryptophan and phenylalanine biosynthetic pathways. Finally, the best strain, Gd07, produced 13.22 g/L gastrodin in a 5 L fermenter. This represents the highest reported production of gastrodin in an engineered microorganism to date, marking the first successful de novo production of gastrodin using Y. lipolytica.

Organoids as preclinical models of human disease: progress and applications.

In the field of biomedical research, organoids represent a remarkable advancement that has the potential to revolutionize our approach to studying human diseases even before clinical trials. Organoids are essentially miniature 3D models of specific organs or tissues, enabling scientists to investigate the causes of diseases, test new drugs, and explore personalized medicine within a controlled laboratory setting. Over the past decade, organoid technology has made substantial progress, allowing researchers to create highly detailed environments that closely mimic the human body. These organoids can be generated from various sources, including pluripotent stem cells, specialized tissue cells, and tumor tissue cells. This versatility enables scientists to replicate a wide range of diseases affecting different organ systems, effectively creating disease replicas in a laboratory dish. This exciting capability has provided us with unprecedented insights into the progression of diseases and how we can develop improved treatments. In this paper, we will provide an overview of the progress made in utilizing organoids as preclinical models, aiding our understanding and providing a more effective approach to addressing various human diseases.

Associations between type 1 diabetes and pulmonary tuberculosis: a bidirectional mendelian randomization study.

BACKGROUND: Type 1 diabetes mellitus (T1DM) has been associated with higher pulmonary tuberculosis (PTB) risk in observational studies. However, the causal relationship between them remains unclear. This study aimed to assess the causal effect between T1DM and PTB using bidirectional Mendelian randomization (MR) analysis. METHODS: Single nucleotide polymorphisms (SNPs) of T1DM and PTB were extracted from the public genetic variation summary database. In addition, GWAS data were collected to explore the causal relationship between PTB and relevant clinical traits of T1DM, including glycemic traits, lipids, and obesity. The inverse variance weighting method (IVW), weighted median method, and MR‒Egger regression were used to evaluate the causal relationship. To ensure the stability of the results, sensitivity analyses assess the robustness of the results by estimating heterogeneity and pleiotropy. RESULTS: IVW showed that T1DM increased the risk of PTB (OR = 1.07, 95% CI: 1.03-1.12, P < 0.001), which was similar to the results of MR‒Egger and weighted median analyses. Moreover, we found that high-density lipoprotein cholesterol (HDL-C; OR = 1.28, 95% CI: 1.03-1.59, P = 0.026) was associated with PTB. There was no evidence of an effect of glycemic traits, remaining lipid markers, or obesity on the risk of PTB. In the reverse MR analysis, no causal relationships were detected for PTB on T1DM and its relevant clinical traits. CONCLUSION: This study supported that T1DM and HDL-C were risk factors for PTB. This implies the effective role of treating T1DM and managing HDL-C in reducing the risk of PTB, which provides an essential basis for the prevention and comanagement of concurrent T1DM and PTB in clinical practice.

Hydrochloric Acid-Induced Acute Lung Injury Models: Dynamic Change and Quantitative Analysis of Modified Lung Ultrasound Scoring System and High-Resolution Computed Tomography.

OBJECTIVE: Acute lung injury (ALI) has become a research hotspot due to its significant public health impact. To explore the value of the use of modified lung ultrasound (MLUS) scoring system for evaluating ALI using a rabbit model of ALI induced by hydrochloric acid (HCl) and investigate its correlation with high-resolution computed tomography (HRCT) and histopathological scores. METHODS: Twenty New Zealand laboratory rabbits were randomly assigned to control group (N = 5) and 3 experimental groups (N = 5 each). The control group received instillation of physiological saline, while the 3 experimental groups received 2 mL/kg of different doses of HCl instillation (mild group: pH 1.5, moderate group: pH 1.2, and severe group: pH 1.0) through the trachea under ultrasound guidance. Pulmonary ultrasound (using Mindray Reason9 linear array probes with frequency of 6-15 mHz) and HRCT examinations were performed before modeling (0H) and at 1H, 2H, 4H, 8H, 12H after modeling. The experimental rabbits were sacrificed at 12H for examination of gross lung morphology and hematoxylin-eosin-stained histopathological sections. The correlation of MLUS scores with HRCT/histopathological scores was assessed. RESULTS: All rabbits in the experimental groups showed oxygenation index PaO2/FiO2<300. Successful establishment of ALI model was proven by autopsy (successful modeling rate: 100%). The pathological damage increased with increase in HCl dosage. MLUS scores showed a positive correlation with HRCT scores/pathological severity. There was a strong positive correlation between MLUS scores and histopathological scores (r = 0.963, p < 0.05) as well as between HRCT scores and histopathological scores (r = 0.932, p < 0.05). CONCLUSION: Transtracheal injection of different dosages of HCl under ultrasound guidance induced different degrees of ALI. The MLUS scoring system can be used for semiquantitative evaluation of ALI, and is suitable as a screening tool.

Pogostone attenuated high-fat diet-induced nonalcoholic fatty liver disease in mice through inhibition of NLRP3 inflammasome signaling.

Inhibition of inflammasome activation is a potential therapeutic strategy for treating nonalcoholic fatty liver disease (NAFLD). Pogostone (PO), an active ingredient in Pogostemon cablin, exhibits various pharmacological properties, including anti-inflammation. However, there are no reports of the hepatoprotective effects of PO in NAFLD induced by a high-fat diet (HFD). Molecular biology methods and molecular docking analysis were used to determine the therapeutic effects and mechanisms of PO in NAFLD in vitro and in vivo. Results showed that in vitro, PO reduced lipid deposition, accelerated fatty acid oxidation (FAO), and inhibited the inflammatory response by elevating mRNA expression of FAO genes and decreasing mRNA expression of proinflammatory genes such as NLRP3. In vivo, PO significantly reduced body weight and liver fat deposition and lowered the generation of inflammatory factors, thereby ameliorating liver fibrosis and liver injury. The hepatoprotective effect of PO against HFD was largely impaired in NLRP3-/- mice. Molecular docking experiments demonstrated a strong interaction between PO and NLRP3. In conclusion, PO decreased fat deposition and the inflammatory response by inhibiting NLRP3 expression, resulting in the alleviation of NAFLD. Our study suggests that PO may be a promising treatment for NAFLD.

First Report of Colletotrichum fructicola Causing Leaf Spot on Smilax glabra Roxb in China.

Smilax glabra Roxb is a medicinal plant distributed in 17 countries and used in the production of food and tea (Wu et al. 2022). In May 2021, a leaf spot disease was observed on ~60% of S. glabra plants in a field (∼0.4 ha) in Qinzhou City, Guangxi Province. Initially, small, circular, brown spots appeared on the leaf surfaces, which then gradually expanded into large, sunken, dark brown necrotic areas. As disease progressed, lesions merged into large spots, eventually leading to defoliation. To determine the causal agent, six symptomatic plants were collected from the field. Small pieces (∼5 mm2) were cut from the infected leaves (n = 12), sterilized for two min in 1% NaOCl, and rinsed three times in sterile water. Then, the leaf tissues were placed on potato dextrose agar (PDA) with chloramphenicol (0.1 g/liter) and incubated for 3 days at 28°C (12-h photoperiod). Pure cultures were obtained by transferring hyphal tips from recently germinated spores or colony edges onto PDA. Among the 17 isolates, 15 exhibited similar morphologies. Two single-spore isolates (TFL45.1 and TFL46.2) were subjected to further morphological and molecular characterization. Colonies on PDA were grayish green with a white outer ring and cottony surface, and pale blackish green on the reverse side. Conidia were hyaline, aseptate, straight, and cylindrical, with rounded ends, and 11.4 to 16.5 µm × 4.1 to 6.1 µm (average 13.9 × 4.8 µm, n = 100). Appressoria were brown to dark brown, with a smooth edge and different shapes such as ovoid, elliptical or irregular, and 6.8 to 8.9 µm × 5.9 to 7.8 µm (average 7.7 × 6.6 µm, n = 25). For molecular identification, eight target gene sequences, internal transcribed spacer (ITS), glyceraldehydes-3-phosphate dehydrogenase (GAPHD), calmodulin (CAL), partial actin (ACT), chitin synthase (CHS-1), glutamine synthetase (GS), manganese superoxide dismutase (SOD2), and ß-tubulin (TUB) were selected for PCR amplification (Weir et al. 2012). The resulting sequences were deposited in GenBank (OR399160-61 and OR432537-50). BLASTn analysis of the obtained sequences showed 99-100% identity with those of the ex-type strain C. fructicola ICMP:18581 (JX010165, JX010033, FJ917508, FJ907426, JX009866, JX010095, JX010327, JX010405) (Weir et al. 2012). In addition, a phylogenetic analysis confirmed the isolates as C. fructicola. Therefore, based on morphological and molecular characteristics (Park et al. 2018; Weir et al. 2012), the isolates were identified as C. fructicola. To verify pathogenicity, three healthy leaves on each of six two-year-old S. glabra plants were inoculated with ∼5 mm2 mycelial discs or aliquots of 10 µl suspension (106 conidia/ml) of the strain TFL46.2, and six control plants were inoculated with sterile PDA discs or sterile water. All plants were enclosed in plastic bags and incubated in a greenhouse at 25°C (12-h photoperiod). Six days post-inoculation, leaf spot symptoms appeared on the inoculated leaves. No symptoms were detected in the controls. Experiments were replicated three times with similar results. To fulfill Koch's postulates, C. fructicola was consistently re-isolated from symptomatic tissue and confirmed by morphology and sequencing of the eight genes, whereas no fungus was isolated from the control plants. To our knowledge, this is the first report of C. fructicola causing leaf spot disease on S. glabra. Further studies will be needed to develop strategies against this disease based on the identification of this pathogen.