Pharmacogenetic determinants of tenofovir diphosphate and lamivudine triphosphate concentrations in people with HIV/HBV coinfection.

The nucleos(t)ide analogs require phosphorylation to the pharmacologically active anabolites in cells. We investigated the hypothesis that single-nucleotide polymorphisms (SNPs) in genes that encode transporters and phosphodiesterase (PDE) enzymes involved in tenofovir (TFV), disoproxil fumarate (TDF), and lamivudine (3TC) disposition will be associated with concentrations of their phosphate anabolites and virologic response. Individuals with human immunodeficiency virus (HIV) and hepatitis B virus (HBV) coinfection receiving TDF/3TC-containing antiretroviral therapy were enrolled. Steady-state TFV diphosphate (TFV-DP) and 3TC triphosphate (3TC-TP) concentrations in peripheral blood mononuclear cells (PBMCs) and dried blood spot samples were quantified. The relationship between genetic variants and TFV-DP and 3TC-TP concentrations as well as with virologic response were examined using multivariable linear regression. Of the 136 participants (median age 43 years; 63% females), 6.6% had HBV non-suppression, and 7.4% had HIV non-suppression. The multidrug resistance protein 2 (encoded by ABCC2 rs2273697) SNP was associated with 3TC-TP concentrations in PBMCs. The human organic anion transporter-1 (encoded by SLC28A2) rs11854484 SNP was associated with HIV non-suppression, and when evaluated together with SNPs with marginal associations (ABCC2 rs717620 and PDE1C rs30561), participants with two or three variants compared to those with none of these variants had an adjusted odds ratio of 48.3 (confidence interval, 4.3-547.8) for HIV non-suppression. None of the SNPs were associated with HBV non-suppression. Our study identified ABCC2 SNP to be associated with 3TC-TP concentrations in PBMCs. Also, a combination of genetic variants of drug transporters and PDE was associated with HIV non-suppression.

Nomogram for predicting risk of mild renal dysfunction among general residents from rural Northeast China.

Background and objectives: Cumulative evidence confirms that mild renal dysfunction (MRD) is correlated with many cardiovascular risk factors and increases cardiovascular morbidity and mortality. The purpose of this study was to establish an effective nomogram for predicting the risk of MRD in the rural population of Northeast China. Methods: We analyzed the reports of 4944 subjects from the Northeast China Rural Cardiovascular Health Study (NCRCHS). All the participants completed the questionnaires, anthropometric measurements, and blood tests during the baseline study (2012-2013) and the follow-up study during 2015-2017 (an average of 4.6 years). The Chronic Kidney Disease Epidemiology (CKD-EPI) equation was used to calculate the estimated glomerular filtration rate (eGFR), and eGFR in the range of 60-90 mL/min/1.73m2 was defined as MRD. Results: The study revealed that a total of 889 subjects (18.0%) had MRD. Multivariate logistic analysis showed that annual income, abdominal obesity, hypertension, hyperglycemia, and frequent tea consumption were the independent risk factors (P < 0.05) for MRD. Thereafter, a nomogram with an area under the receiver operating characteristic curve (AUC) of 0.705 was constructed to accurately predict MRD. The calibration plot also showed an excellent consistency between the probability of prediction and observation. Conclusion: We constructed a nomogram based on epidemiological data, which could provide an individual prediction of MRD with good accuracy.

Effect of salt substitute and antihypertensive medications among high cardiovascular risk patients: A sub-study of Salt Substitute and Stroke Study (SSaSS).

The relationship between the differential protective effect of salt substitute between hypertensive and normotensive individuals and the use of cardiovascular medications remains unclear. This study involved 4211 individuals with a history of stroke or hypertension who participated in the Salt Substitute and Stroke Study (SSaSS) from 120 villages in Shanxi Province. The aim of this study was to investigate the differences in major adverse cardiovascular events and blood pressure changes between the salt substitute and the regular salt group in the subgroups of participants taking different antihypertensive medications. Mixed models were employed and adjusted for the cluster effect (village) and potential confounding variables. During the average follow-up period of 4.66 years, a significantly protective effect of salt substitute on reducing the risk of cardiovascular events was observed in the participants who taking antihypertensive medications (rate ratio: 0.81, 95% CI: 0.68 to 0.95. p = 0.011), whereas no significant effect in participants not taking antihypertensive medications (rate ratio: 0.91, 95% CI: 0.62 to 1.32, p = 0.612). Significant effects to lower systolic blood pressure of the salt substitutes were observed in the participants who took different antihypertensive medications. This study emphasized that the use of salt substitutes might enhance the efficacy of anti-hypertensive medications in lowering blood pressure and reducing the risk of adverse cardiovascular events.

Host-Guest Interaction Mediated Perovskite@Metal-Organic Framework Z-Scheme Heterojunction Enabled Paper-Based Photoelectrochemical Sensing.

Exploring the high-performance photoelectronic properties of perovskite quantum dots (QDs) is desirable for paper-based photoelectrochemical (PEC) sensing;however, challenges remain in improving their stability and fundamental performance. Herein, a novel Z-scheme heterostructure with host-guest interaction by the confinement of CH3NH3PbBr3 QDs within Cu3(BTC)2 metal-organic framework (MOF) crystal (MAPbBr3@Cu3(BTC)2) is successfully constructed on the paper-based PEC device for ultrasensitive detection of Ochratoxin A (OTA), with the assistance of the exciton-plasmon interaction (EPI) effect. The host-guest interaction is estabilished by encapsulating MAPbBr3 QDs as guests within Cu3(BTC)2 MOF as a host, which prevents MAPbBr3 QDs from being damaged in the polar system, offering access to long-term stability with high-performance PEC properties. Benefiting from the precise alignment of energy levels, the photogenerated charge carriers can migrate according to the Z-scheme charge-transfer pathway under the driving force of the internal electric field, achieving a high photoelectric conversion efficiency. Upon OTA recognition, the EPI effect is activated to modulate the exciton response in MAPbBr3 QDs by accelerating radiative decay, finally achieving sensitive OTA sensing with a detection limit of 0.017 pg mL-1. We believe this work renders new insight into designing host-guest Z-scheme heterojunctions in constructing the paper-based PEC sensing platforms for environmental monitoring.

Neurological outcomes for patients meeting radiographic criteria for DEFUSE 3 and SELECT2.

BACKGROUND: The DEFUSE 3 and SELECT2 thrombectomy trials included some patients with similar radiographic profiles, although the rates of good functional outcomes differed widely between the studies. OBJECTIVE: To report neurological outcomes for patients who meet CT and CT perfusion (CTP) inclusion criteria common to both DEFUSE 3 and SELECT2. METHODS: Retrospective study of thrombectomy patients, presenting between November 2016 and December 2023 to a large health system, with Alberta Stroke Program Early CT score ≥6, core infarction 50-69 mL, mismatch ratio ≥1.8, and mismatch volume ≥15 mL. The primary outcome was 90-day modified Rankin Scale score 0-2. A logistic regression analysis was performed to identify independent predictors of the primary outcome. RESULTS: 85 patients, with mean age 64.6 (16.6) years and median National Institutes of Health Stroke Scale score 18 (15-23), were included. Thirty-eight of 85 patients (44.7%) were functionally independent at 90 days. Predictors of functional independence included age (OR=0.943, 95% CI 0.908 to 0.980; P=0.003), initial glucose (OR=0.989, 95% CI 0.978 to 1.000; P=0.044), and time last known well to skin puncture (OR=0.997, 95% CI 0.994 to 1.000; P=0.028). The area under the curve for the multivariable model predicting the primary outcome was 0.82 (95% CI 0.73 to 0.92). CONCLUSION: Nearly half of patients meeting radiographic criteria common to DEFUSE 3 and SELECT2 are functionally independent at 90 days, similar to rates reported for the treated DEFUSE 3 cohort. This might be due to their moderate core volumes and large ischemic penumbra.

ZDHHC9-mediated Bip/GRP78 S-palmitoylation inhibits unfolded protein response and promotes bladder cancer progression.

Recent studies have highlighted palmitoylation, a novel protein post-translational modification, as a key player in various signaling pathways that contribute to tumorigenesis and drug resistance. Despite this, its role in bladder cancer (BCa) development remains inadequately understood. In this study, ZDHHC9 emerged as a significantly upregulated oncogene in BCa. Functionally, ZDHHC9 knockdown markedly inhibited tumor proliferation, promoted tumor cell apoptosis, and enhanced the efficacy of gemcitabine (GEM) and cisplatin (CDDP). Mechanistically, SP1 was found to transcriptionally activate ZDHHC9 expression. ZDHHC9 subsequently bound to and palmitoylated the Bip protein at cysteine 420 (Cys420), thereby inhibiting the unfolded protein response (UPR). This palmitoylation at Cys420 enhanced Bip's protein stability and preserved its localization within the endoplasmic reticulum (ER). ZDHHC9 might become a novel therapeutic target for BCa and could also contribute to combination therapy with GEM and CDDP.

TET1-Lipid Nanoparticle Encapsulating Morphine for Specific Targeting of Peripheral Nerve for Pain Alleviation.

Background: Opioids are irreplaceable analgesics owing to the lack of alternative analgesics that offer opioid-like pain relief. However, opioids have many undesirable central side effects. Restricting opioids to peripheral opioid receptors could reduce those effects while maintaining analgesia. Methods: To achieve this goal, we developed Tet1-LNP (morphine), a neural-targeting lipid nanoparticle encapsulating morphine that could specifically activate the peripheral opioid receptor in the dorsal root ganglion (DRG) and significantly reduce the side effects caused by the activation of opioid receptors in the brain. Tet1-LNP (morphine) were successfully prepared using the thin-film hydration method. In vitro, Tet1-LNP (morphine) uptake was assessed in differentiated neuron-like PC-12 cells and dorsal root ganglion (DRG) primary cells. The uptake of Tet1-LNP (morphine) in the DRGs and the brain was assessed in vivo. Von Frey filament and Hargreaves tests were used to assess the antinociception of Tet1-LNP (morphine) in the chronic constriction injury (CCI) neuropathic pain model. Morphine concentration in blood and brain were evaluated using ELISA. Results: Tet1-LNP (morphine) had an average size of 131 nm. Tet1-LNP (morphine) showed high cellular uptake and targeted DRG in vitro. CCI mice treated with Tet1-LNP (morphine) experienced prolonged analgesia for nearly 32 h compared with 3 h with free morphine (p < 0.0001). Notably, the brain morphine concentration in the Tet1-LNP (morphine) group was eight-fold lower than that in the morphine group (p < 0.0001). Conclusion: Our study presents a targeted lipid nanoparticle system for peripheral neural delivery of morphine. We anticipate Tet1-LNP (morphine) will offer a safe formulation for chronic neuropathic pain treatment, and promise further development for clinical applications.

Ginsenoside Rd reduces cell proliferation of non-small cell lung cancer cells by p53-mitochondrial apoptotic pathway.

Ginsenoside Rd is a tetracyclic triterpenoid derivative, widely existing in Panax ginseng, Panax notoginseng and other traditional Chinese medicines. Many studies have proved that ginsenoside Rd have a variety of significant biological activities on certain types of cancer. However, the mechanism of ginsenoside Rd remains unclear in lung cancer. The findings of this study reveal that GS-Rd inhibits the proliferation of NSCLC cells, induces apoptosis, and suppresses migration and invasion. The results showed Ginsenoside Rd inhibited the cell proliferation (∼99.52 %) by S phase arrest in cell cycle and promoted the apoptosis (∼54.85 %) of NSCLC cells. It also inhibited the migration and invasion of cells (p < 0.001). The expression levels of related mitochondrial apoptosis proteins (Bax/Bcl-2/Cytochrome C) and matrix metalloproteinases (MMP-2/-9) were significantly changed. The results showed that ginsenoside Rd inhibited the proliferation of tumor cells by activating p53/bax-mediated mitochondrial apoptosis and the expression of key enzymes for cell apoptosis caspase-3/cleaved-caspase-3 were significantly increased. This research contributes to a better understanding of the anti-tumor effects and molecular mechanisms of GS-Rd, paving the way for its potential development and clinical application in NSCLC therapy.

Near-infrared light-driven lab-on-paper cathodic photoelectrochemical aptasensing for di(2-ethylhexyl)phthalate based on AgInS2/Cu2O/FeOOH photocathode.

Di(2-ethylhexyl)phthalate (DEHP) is commonly released from plastics in aqueous environment, which can disrupt endocrine system and cause adverse effects on public health. There is a pressing need to highly sensitive detect DEHP. Herein, a near-infrared (NIR) light-driven lab-on-paper cathodic photoelectrochemical aptasensing platform integrated with AgInS2/Cu2O/FeOOH photocathode and "Y"-like ternary conjugated DNA nanostructure-mediated "ON-OFF" catalytic switching of hemin monomer-to-dimer was established for ultrasensitive DEHP detection. Profiting from the collaborative roles of the effective photosensitization of NIR-response AgInS2 and the fast hole extraction of FeOOH, the NIR light-activated AgInS2/Cu2O/FeOOH photocathode generated a markedly enhanced photocathodic signal. The dual hemin-labelled "Y"-like ternary conjugated DNA nanostructures made the hemin monomers separated in space and they maintained highly active to catalyze in situ generation of electron acceptors (O2). The hemin monomers were relocated in close proximity with the help of target-induced allosteric change of DNA nanostructures, which could spontaneously dimerize into catalytically inactive hemin dimers and fail to mediate electron acceptors generation, resulting in a decreased photocathodic signal. Therefore, the ultrasensitive DEHP detection was realized with a linear response range of 1 pM-500 nM and a detection limit of 0.39 pM. This work rendered a promising prototype to construct powerful paper-based photocathodic aptasensing system for sensitive and accurate screening of DEHP in aqueous environment.

Costs in Colectomy Episodes of Care: Opportunities to Prevent Emergency Operations and Decrease Costs.

INTRODUCTION: Payment structured around Episodes of Care is a method for incentivizing decreased care utilization after major procedures. We examined Major Bowel Episodes of Care (MB-EoC)-the focus among general surgery procedures-within a large health system to determine the contribution of emergency bowel surgery to higher costs of care. METHODS: Adult MB-EoC cases from July 2018 to June 2021 were reviewed for 90-d costs, examining patient age, insurance, diagnosis, cost of care, and contributors to cost. For patients aged ≥45 y who had nonelective care for colon cancer, incidence of prior screening colonoscopy was examined. RESULTS: We identified 1292 colectomy cases. Mean age was 65 y. Of these patients, 90% had Medicare/commercial insurance. Colon cancer comprised 41% of primary diagnoses. Twenty-eight percent of cases were nonelective, more likely to have Medicaid/underinsured (21% versus 7%, P < 0.001), and had higher utilization of postdischarge cost-drivers. Ninety-day EoC per case cost was 66% higher for emergent versus elective cases. Of eligible emergency cancer cases, 43% (40/93) had undergone prior colonoscopy within 10 y. For patients with colon cancer, 90-d EoC per case was 39% higher for emergent versus elective cases. CONCLUSIONS: Emergency MB-EoC cases disproportionally contribute to higher 90-d care utilization and costs. Efforts to increase screening colonoscopy in appropriate populations may have a substantial impact on MB-EoC costs.

Triglyceride-glucose index predicts all-cause mortality, but not cardiovascular mortality, in rural Northeast Chinese patients with metabolic syndrome: a community-based retrospective cohort study.

BACKGROUND: Metabolic syndrome (MetS) includes a group of metabolic irregularities, including insulin resistance (IR), atherogenic dyslipidemia, central obesity, and hypertension. Consistent evidence supports IR and ongoing low-grade inflammation as the main contributors to MetS pathogenesis. However, the association between the triglyceride-glucose (TyG) index and mortality in people with MetS remains uncertain. The objective of this study was to examine the correlation between the baseline TyG index and all-cause and cardiovascular (CV) mortality in rural Northeast Chinese individuals with MetS. METHODS: For the Northeast China Rural Cardiovascular Health Study, 3918 participants (mean age, 55 ± 10; 62.4% women) with MetS at baseline were enrolled in 2012-2013 and followed up from 2015 to 2017. The TyG index was calculated using the equation TyG index = ln [fasting TG (mg/dL) × fasting glucose (mg/dL)/2] and subdivided into tertiles [Q1(< 8.92); Q2 (8.92-9.36); Q3 (≥ 9.36)]. Multivariate Cox proportional hazards models were developed to examine the correlations between mortality and the baseline TyG index. RESULTS: During a median of 4.66 years of follow-up, 196 (5.0%) all-cause deaths and 108 (2.8%) CV disease-related deaths occurred. The incidence of all-cause mortality was significantly different among TyG index tertiles of the overall population (P = 0.045). Kaplan-Meier analysis demonstrated a significantly increased risk of all-cause mortality in rural Chinese patients with a higher TyG index (log-rank P < 0.05). After adjusting for possible confounders, Cox proportional hazard analysis revealed that the TyG index could effectively predict all-cause mortality (HR for the third vs. first tertile of TyG was 1.441 [95% confidence interval, 1.009-2.059]), but not CV mortality, in rural Chinese patients with MetS. CONCLUSIONS: The TyG index is an effective predictor of all-cause mortality in rural Chinese patients with MetS. This indicates that the TyG index may be useful for identifying rural Chinese individuals with MetS at a high risk of death.

Subclinical Hypothyroidism Predicted Adverse Cardiovascular Events in Patients with Ejection Fraction Preserved Heart Failure.

Background: Subclinical hypothyroidism (SH) increases the risk of cardiovascular events, however the influence of SH on prognosis of ejection fraction preserved heart failure (HFpEF) is not fully understood. Methods: In this prospective observational study, patients with HFpEF were divided into euthyroidism group (n = 413) and SH group (n = 79). Patients were followed up for at least 30 months to examine the association between SH and cardiovascular events in patients with HFpEF. The primary end point was composite cardiovascular events (cardiovascular death and re-hospitalization). The patients underwent flow-mediated dilation (FMD) measurement by ultrasound in order to value endothelial function. Results: The rate of composite cardiovascular events was higher in SH group than in euthyroidism group (54.49% and 26.36%, respectively; p < 0.001). The higher risk of cardiovascular events in SH group was primarily due to a higher risk of re-hospitalization compared to euthyroidism group (45.56% and 20.58%, respectively; p < 0.001). The rate of cardiovascular death was higher in SH group than in euthyroidism group (13.92% and 5.81%, respectively; p = 0.017). Cox proportional hazards regression showed that SH (hazard ratios [HR] 1.921, 95% confidence interval [CI] 1.139-3.240), level of TSH (HR 1.025, 95% CI 1.010-1.054), age (HR 1.017, 95% CI 1.002-1.034), LVEF (HR 0.975, 95% CI 0.953-0.996), atrial fibrillation (HR 1.581, 95% CI 1.083-2.307), eGFR (HR 0.987, 95% CI 0.978-0.997), and NYHA cardiac function (HR 2.342, 95% CI 1.649-3.326) were independent predictors of cardiovascular events in patients with HFpEF (all P < 0.05). Conclusion: Subclinical hypothyroidism was associated with increased cardiovascular events and death in patients with HFpEF.

Successful Treatment of Severe Case of Lipid Overload Syndrome with Pancreatitis and Pneumonia: A Case Report.

Background: Fat overload syndrome is a rare and severe adverse reaction triggered by the infusion of a single source of lipid emulsion, resulting in elevated blood triacylglycerol (TG) levels. The majority of literature reports focus on cases of fat overload syndrome in patients with mild symptoms. This case is significant because it demonstrates the diagnostic and therapeutic experience and provide valuable insights for the management for severe fat overload syndrome. Case Presentation: We present a case report of a female patient who developed fat overload syndrome following prolonged and excessive infusion of lipid emulsion after colon resection surgery. In the setting of compromised immune function and malnutrition, the patient's pulmonary infection and respiratory distress symptoms have further exacerbated. Hence, in addition to severe pancreatitis, the patient has also contracted severe pneumonia. Upon admission, tracheal intubation, plasma exchange and blood perfusion were performed. Subsequently, comprehensive treatment was provided, including anti-infection, antispasmodic, acid suppression, enzyme inhibition, as well as targeted supportive measures to stabilize electrolytes and nutritional status. After treatment, there was a progressive reduction in blood lipid levels. After assessing the relevant risks, it was deemed necessary to perform an emergency computed tomography (CT)-guided percutaneous drainage tube placement procedure targeting the necrotic area of the pancreas while the patient was still intubated. Finally, the patient was discharged from the hospital. Conclusion: The case highlights the association between fat overload syndrome and pancreatitis as well as the use of lipid emulsions and suggests the treatment strategies for severe fat overload syndrome.

Optimization of the fermentation media and growth conditions of Bacillus velezensis BHZ-29 using a Plackett-Burman design experiment combined with response surface methodology.

Introduction: Bacillus velezensis occurs extensively in the soil environment. It produces a range of antimicrobial compounds that play an important role in the field of biological control. However, during the actual application process it is often affected by factors such as the medium formulation and fermentation conditions, and therefore biocontrol measures often do not achieve their expected outcomes. Methods: In this study, the B. velezensis BHZ-29 strain was used as the research object. The carbon and nitrogen sources, and inorganic salts that affect the number of viable bacteria and antibacterial potency of B. velezensis BHZ-29, were screened by a single factor test. A Plackett-Burman design experiment was conducted to determine the significant factors affecting the number of viable bacteria and antibacterial potency, and a Box-Behnken design experiment was used to obtain the optimal growth of B. velezensis BHZ-29. The medium formula that produced the highest number of viable bacteria and most antibacterial substances was determined. The initial pH, temperature, amount of inoculant, liquid volume, shaking speed, and culture time were determined by a single factor test. The factors that had a significant influence on the number of viable bacteria of B. velezensis BHZ-29 were selected by an orthogonal test. A Box-Behnken design experiment was conducted to obtain the optimal fermentation conditions, and highest number of viable bacteria and antibacterial titer. Results: Molasses, peptone, and magnesium sulfate had significant effects on the viable count and antibacterial titer of B. velezensis BHZ-29. The viable count of B. velezensis BHZ-29 increased from 7.83 × 109 to 2.17 × 1010 CFU/mL, and the antibacterial titer increased from 111.67 to 153.13 mm/mL when the optimal media were used. The optimal fermentation conditions for B. velezensis BHZ-29 were as follows: temperature 25.57°C, pH 7.23, culture time 95.90 h, rotation speed 160 rpm, amount of inoculant 2%, and liquid volume 100 ml. After the optimization of fermentation conditions, the number of viable bacteria increased to 3.39 × 1010 CFU/mL, and the bacteriostatic titer increased to 158.85 mm/ml.The plant height and leaf number of cotton plants treated with BHZ-29 fermentation broth were higher than those of cotton inoculated with Verticillium dahliae. The number of bacteria was 1.15 × 107 CFU/g, and the number of fungi was 1.60 × 105 spores/g. The disease index of the cotton seedlings treated with the optimized fermentation broth was 2.2, and a control effect of 93.8% was achieved. B. velezensis BHZ-29 could reduce the disease index of cotton Verticillium wilt and had a controlling effect on the disease. The best effect was achieved in the treatment group with an inoculation concentration of 2 × 108 CFU/ml, the disease index was 14.50, and a control effect of 84.18% was achieved. Discussion: The fermentation process parameters of the number of viable bacteria and antibacterial titer by strain B. velezensis BHZ-29 were optimized to lay a foundation for the practical production and application of strain B. velezensis BHZ-29 in agriculture.

Flank versus prone position in percutaneous nephrolithotomy: a meta-analysis of randomized controlled studies.

The objective of this study is to assess the safety and efficacy of the flank position in percutaneous nephrolithotomy (PCNL). We searched PubMed, Embase, SCOPUS, the Cochrane database libraries, and the Chinese Biomedical Literature Database, and randomized controlled trials (RCTs) assessing PCNL in flank position are included in this meta-analysis. The related trials met the inclusion criteria were analyzed using RevMan 5.4. Seven randomized controlled trials were included, involving a total of 587 patients. We found that there was a lower decrease in hemoglobin levels in the flank position group compared to prone-position group (mean difference [MD] = - 0.15, 95% confidence interval (CI) - 0.22 to - 0.08, P < 0.00001). Moreover, our meta-analysis demonstrated no significant differences between groups regarding stone-free rate (relative risk [RR] = 1.00, 95% CI 0.93 to 1.06, P = 0.92), operative time(MD = 0.76, 95% CI - 5.31 to 6.83, P < 0.00001), hospital stay (MD = 0.03, 95% CI - 0.32 to 0.32, P < 0.00001), and complications Clavien grade I (RR = 1.01, 95% CI 0.98 to 1.05, P = 0.54), Clavien grade II (RR = 1, 95% CI 0.97 to 1.02, P = 0.78), and Clavien grade III (RR = 1, 95% CI 0.98 to 1.03, P = 0.77). The use of flank position for PCNL is associated with reduced hemoglobin change without an increase in complications. This positioning technique can be considered safe for patients with nephrolithiasis and may be particularly suitable for high-risk individuals such as those who are obese or have decreased cardiopulmonary function. However, further randomized trials are needed to confirm these findings.

Mesenchymal Stromal Cells Increase the Natural Killer Resistance of Circulating Tumor Cells via Intercellular Signaling of cGAS-STING-IFNß-HLA.

Circulating tumor cells (CTCs) shed from primary tumors must overcome the cytotoxicity of immune cells, particularly natural killer (NK) cells, to cause metastasis. The tumor microenvironment (TME) protects tumor cells from the cytotoxicity of immune cells, which is partially executed by cancer-associated mesenchymal stromal cells (MSCs). However, the mechanisms by which MSCs influence the NK resistance of CTCs remain poorly understood. This study demonstrates that MSCs enhance the NK resistance of cancer cells in a gap junction-dependent manner, thereby promoting the survival and metastatic seeding of CTCs in immunocompromised mice. Tumor cells crosstalk with MSCs through an intercellular cGAS-cGAMP-STING signaling loop, leading to increased production of interferon-ß (IFNß) by MSCs. IFNß reversely enhances the type I IFN (IFN-I) signaling in tumor cells and hence the expression of human leukocyte antigen class I (HLA-I) on the cell surface, protecting the tumor cells from NK cytotoxicity. Disruption of this loop reverses NK sensitivity in tumor cells and decreases tumor metastasis. Moreover, there are positive correlations between IFN-I signaling, HLA-I expression, and NK tolerance in human tumor samples. Thus, the NK-resistant signaling loop between tumor cells and MSCs may serve as a novel therapeutic target.

Exploring the Drought Tolerant Quantitative Trait Loci in Spring Wheat.

Drought-induced stress poses a significant challenge to wheat throughout its growth, underscoring the importance of identifying drought-stable quantitative trait loci (QTLs) for enhancing grain yield. Here, we evaluated 18 yield-related agronomic and physiological traits, along with their drought tolerance indices, in a recombinant inbred line population derived from the XC7 × XC21 cross. These evaluations were conducted under both non-stress and drought-stress conditions. Drought stress significantly reduced grain weight per spike and grain yield per plot. Genotyping the recombinant inbred line population using the wheat 90K single nucleotide polymorphism array resulted in the identification of 131 QTLs associated with the 18 traits. Drought stress also exerted negative impacts on grain formation and filling, directly leading to reductions in grain weight per spike and grain yield per plot. Among the identified QTLs, 43 were specifically associated with drought tolerance across the 18 traits, with 6 showing direct linkages to drought tolerance in wheat. These results provide valuable insights into the genetic mechanisms governing wheat growth and development, as well as the traits contributing to the drought tolerance index. Moreover, they serve as a theoretical foundation for the development of new wheat cultivars having exceptional drought tolerance and high yield potentials under both drought-prone and drought-free conditions.

Modifying humus-phosphorus-arsenic interactions in sludge composting: The strengthening of phosphorus availability and arsenic efflux detoxification mechanisms.

Arsenic (As) in sewage sludge poses a significant threat to environmental and human health, which has attracted widespread attention. This study investigated the value of adding sodium percarbonate (SP) on phosphorus (P) availability and As efflux detoxification through HS-P-As interactions. Due to the unique structure of humus (HS) and the similar chemical properties of P and As, the conditions for HS-P-As interaction are provided. This study discussed the content, morphology and microbial communities of HS, P and As by using metagenomic and correlation analysis. The results showed that the humification index in the experiment group (SPC) was 2.34 times higher than that in the control group (CK). The available phosphorus (AP) content of SPC increased from 71.09 mg/kg to 126.14 mg/kg, and SPC was 1.11 times that of CK. The relative abundance of ACR3/ArsB increased. Pst, Actinomyces and Bacillus commonly participated in P and As conversion. The correlation analysis revealed that the humification process was enhanced, the AP was strengthened, and the As was efflux detoxified after SP amendment. All in all, this study elucidated the key mechanism of HS-P-As interaction and put forward a new strategy for sewage sludge resource utilization and detoxification.

Oligosaccharides from black ginseng innovatively prepared by low-temperature steam-heating process ameliorate cognitive impairment in Alzheimer's disease mice via the Keap-1/Nrf2 pathway.

BACKGROUND: Our objective in this study was to evaluate the effectiveness of oligosaccharides extracted from black ginseng (OSBG), innovatively prepared by a low-temperature steam-heating process, in the improvement of learning and memory impairment in mice, as well as the mechanism(s). RESULTS: Eight carbohydrates involving isomaltose and maltotetraose were detected in black gensing; monosaccharide residues including mannose and rhamnose were also discovered. OSBG-treated mice showed significant amelioration in recognition and spatial memory deficits compared to the scopolamine group. OSBG could decrease acetylcholinesterase activity in a tissue-dependent fashion but not in a dose-dependent manner. Furthermore, in contrast, OSBG administration resulted in significant upregulation superoxide dismutase, glutathione, glutathione peroxidase (GPx), and Kelch-like ECH-associated protein 1, downregulation of malondialdehyde and nuclear factor erythroid 2-related factor 2 in the tissues. Finally, at the genus level, we observed that the OSBG interventions increased the relative abundance of probiotics (e.g., Barnesiella, Staphylococcus, Clostridium_XlVb) and decreased pernicious bacteria such as Eisenbergiella and Intestinimonas, compared to the Alzheimer's disease mouse model group. Herein, our results demonstrate that OSBG restores the composition of the scopolamine-induced intestinal microbiota in mice, providing homeostasis of gut microbiota and providing evidence for microbiota-regulated therapeutic potential. CONCLUSION: Our results showed for the first time a clear role for OSBG in improving scopolamine-induced memory impairment by inhibiting cholinergic dysfunction in a tissue-dependent manner. Additionally, OSBG administration relieved oxidative stress by activating the Keap-1/Nrf2 pathway and modulating the gut microbiota. Collectively, OSBG may be a promising target for neuroprotective antioxidants for improving memory and cognition in Alzheimer's disease patients. © 2024 Society of Chemical Industry.