Pharmacokinetics, safety, and efficacy of Fuqi Guben Gao in the treatment of kidney-yang deficiency syndrome: a randomized, double-blind phase I trial.

Introduction: Fuqi Guben Gao (FQGBG) is a botanical drug formulation composed of FuZi (FZ; Aconitum carmichaelii Debeaux [Ranunculaceae; Aconiti radix cocta]), Wolfberry (Lycium barbarum L. [Solanaceae; Lycii fructus]), and Cinnamon (Neolitsea cassia (L.) Kosterm. [Lauraceae; Cinnamomi cortex]). It has been used to clinically treat nocturia caused by kidney-yang deficiency syndrome (KYDS) for over 30 years and warms kidney yang. However, the pharmacological mechanism and the safety of FQGBG in humans require further exploration and evaluation. Methods: We investigated the efficacy of FQGBG in reducing urination and improving immune organ damage in two kinds of KYDS model rats (hydrocortisone-induced model and natural aging model), and evaluated the safety of different oral FQGBG doses through pharmacokinetic (PK) parameters, metabonomics, and occurrence of adverse reactions in healthy Chinese participants in a randomized, double-blind, placebo-controlled, single ascending dose clinical trial. Forty-two participants were allocated to six cohorts with FQGBG doses of 12.5, 25, 50, 75, 100, and 125 g. The PKs of FQGBG in plasma were determined using a fully validated LC-MS/MS method. Results: FQGBG significantly and rapidly improved the symptoms of increased urination in both two KYDS model rats and significantly resisted the adrenal atrophy in hydrocortisone-induced KYDS model rats. No apparent increase in adverse events was observed with dose escalation. Major adverse drug reactions included toothache, thirst, heat sensation, gum pain, diarrhea, abdominal distension, T-wave changes, and elevated creatinine levels. The PK results showed a higher exposure level of benzoylhypaconine (BHA) than benzoylmesaconine (BMA) and a shorter half-life of BMA than BHA. Toxic diester alkaloids, aconitine, mesaconitine, and hypaconitine were below the lower quantitative limit. Drug-induced metabolite markers primarily included lysophosphatidylcholines, fatty acids, phenylalanine, and arginine metabolites; no safety-related metabolite changes were observed. Conclusion: Under the investigated dosing regimen, FQGBG was safe. The efficacy mechanism of FQGBG in treating nocturia caused by KYDS may be related to the improvement of the hypothalamus-pituitary-adrenal axis function and increased energy metabolism. Clinical Trial Registration: https://www.chictr.org.cn/showproj.html?proj=26934, identifier ChiCTR1800015840.

Influence of Natural Risks and Non-Agricultural Income on Agricultural Trusteeship Decisions in Northeast China.

As the main service mode and management mode of socialized service, agricultural production trusteeship services (APTS) are an important way to realize the tight link between farmers and modern agricultural development, which is highly important for ensuring national food security. By constructing a utility model of farmers, this paper deduces the decision-making mechanism of farmers' APTS from the dual mechanism of natural risk and non-agricultural employment income (NAEI) and uses the survey data of 956 farmers in the three northeastern provinces to verify the empirical results by using multivariate logit (Mlogit) and propensity score matching (PSM) methods. The research shows that natural risk hinders farmers' choice of the APTS; NAEI has a positive impact on APST, and an increase in NAEI weakens the negative effect of natural risk on the choice of the APTS, and has an enhanced moderating effect. In addition, the scale heterogeneity analysis revealed that the impacts of natural risk and NAEI on farmers of different scales are significantly different. The NAEI adjustment effect has the greatest impact on small-scale farmers, followed by medium-scale farmers. In view of this, the government should stabilize the nonagricultural employment market and improve the nonagricultural employment opportunities of farmers. APTS organizations should transfer natural risks and improve the agricultural insurance system. According to the differences of different scales of farmers, different promotion policies are formulated, and the expansion of management and deepening services is proposed to further promote the development of APTS and consolidate the foundation of food security in China.

Transcriptomic insights into the shift of trophic strategies in mixotrophic dinoflagellate Lepidodinium in the warming ocean.

The shift between photoautotrophic and phagotrophic strategies in mixoplankton significantly impacts the planktonic food webs and biogeochemical cycling. Considering the projected global warming, studying how temperature impacts this shift is crucial. Here, we combined the transcriptome of in-lab cultures (mixotrophic dinoflagellate Lepidodinium sp.) and the metatranscriptome dataset of the global ocean to investigate the mechanisms underlying the shift of trophic strategies and its relationship with increasing temperatures. Our results showed that phagocytosis-related pathways, including focal adhesion, regulation of actin cytoskeleton, and oxidative phosphorylation, were significantly stimulated in Lepidodinium sp. when cryptophyte prey were added. We further compared the expression profiles of photosynthesis and phagocytosis genes in Lepidodinium sp. in the global sunlit ocean. Our results indicated that Lepidodinium sp. became more phagotrophic with increasing temperatures when the ambient chlorophyll concentration was >0.3 mg.m-3 (~20.58% of the ocean surface) but became more photoautotrophic with increasing temperatures when the chlorophyll concentration was between 0.2 and 0.3 mg.m-3 (~11.47% of the ocean surface). Overall, we emphasized the crucial role of phagocytosis in phago-mixotrophy and suggested that the expression profile of phagocytosis genes can be a molecular marker to target the phagotrophic activity of mixoplankton in situ.

Enhanced flexibility of high-yield bamboo pulp fibers via cellulase immobilization within guar gum/polyacrylamide/polydopamine interpenetrating network hydrogels.

Softness is a crucial criterion in assessing the comfort and usability of tissue paper. Flexible fibers contribute to the softness of the tissue paper by allowing the sheets to conform to the contours of the skin without feeling rough or abrasive. This study focuses on developing innovative CGG/APAM/PDA hydrogels with interpenetrating networks consisting of cationic guar gum, anionic polyacrylamide, and polydopamine for cellulase immobilization, aimed at improving bamboo fiber flexibility. Cellulase biomolecules are efficiently immobilized on CGG/APAM/PDA hydrogels through the Schiff base reaction. Immobilized cellulases have a wider pH applicability than free cellulases, good storage stability, and can maintain high relative activity at relatively high temperatures. The treatment of bamboo fibers with immobilized cellulase results in a significant increase in flexibility, reaching 6.90 × 1014 N·m2, which is 7.18 times higher than that of untreated fibers. The immobilization of cellulases using CGG/APAM/PDA hydrogels as carriers results in a substantial enhancement of storage stability, pH applicability, and inter-fiber bonding strength, as well as the capacity to sustain high relative enzymatic activity at elevated temperatures. The immobilization of cellulase within CGG/APAM/PDA interpenetrating network hydrogels presents a viable strategy for enhancing bamboo fiber flexibility, thereby expanding the accessibility of tissue products.

Ag-thiolate interactions to enable an ultrasensitive and stretchable MXene strain sensor with high temporospatial resolution.

High-sensitivity strain sensing elements with a wide strain range, fast response, high stability, and small sensing areas are desirable for constructing strain sensor arrays with high temporospatial resolution. However, current strain sensors rely on crack-based conductive materials having an inherent tradeoff between their sensing area and performance. Here, we present a molecular-level crack modulation strategy in which we use layer-by-layer assembly to introduce strong, dynamic, and reversible coordination bonds in an MXene and silver nanowire-matrixed conductive film. We use this approach to fabricate a crack-based stretchable strain sensor with a very small sensing area (0.25 mm2). It also exhibits an ultrawide working strain range (0.001-37%), high sensitivity (gauge factor ~500 at 0.001% and >150,000 at 35%), fast response time, low hysteresis, and excellent long-term stability. Based on this high-performance sensing element and facile assembly process, a stretchable strain sensor array with a device density of 100 sensors per cm2 is realized. We demonstrate the practical use of the high-density strain sensor array as a multichannel pulse sensing system for monitoring pulses in terms of their spatiotemporal resolution.

NCF4 attenuates colorectal cancer progression by modulating inflammasome activation and immune surveillance.

The spatiotemporal regulation of inflammasome activation remains unclear. To examine the mechanism underlying the assembly and regulation of the inflammasome response, here we perform an immunoprecipitation-mass spectrometry analysis of apoptosis-associated speck-like protein containing a CARD (ASC) and identify NCF4/1/2 as ASC-binding proteins. Reduced NCF4 expression is associated with colorectal cancer development and decreased five-year survival rate in patients with colorectal cancer. NCF4 cooperates with NCF1 and NCF2 to promote NLRP3 and AIM2 inflammasome activation. Mechanistically, NCF4 phosphorylation and puncta distribution switches from the NADPH complex to the perinuclear region, mediating ASC oligomerization, speck formation and inflammasome activation. NCF4 functions as a sensor of ROS levels, to establish a balance between ROS production and inflammasome activation. NCF4 deficiency causes severe colorectal cancer in mice, increases transit-amplifying and precancerous cells, reduces the frequency and activation of CD8+ T and NK cells, and impairs the inflammasome-IL-18-IFN-γ axis during the early phase of colorectal tumorigenesis. Our study implicates NCF4 in determining the spatial positioning of inflammasome assembly and contributing to inflammasome-mediated anti-tumor responses.

Dynamic response and deformation failure microscopic characteristics of cyclic impact-cemented tailing backfill.

Frequent blasting disruptions can lead to cumulative damage within the cemented tailing backfill (CTB), increasing the risks associated with mining operations and reducing the recovery rate of the pillar. To address this issue, the Split Hopkinson Pressure Bar (SHPB) was utilized to conduct cyclic impact tests on CTB containing various cement tailing ratios (CTR) at different curing ages. The tests analyzed the stress-strain curve law, dynamic compressive strength (DCS), dynamic strength increase factor (DIF), absorption energy, and deformation failure characteristics of CTB under different impact velocities. Additionally, nuclear magnetic resonance (NMR) and scanning electron microscopy (SEM) were employed to investigate the internal pore structural properties of CTB. The research findings indicate that (1) Average strain rate exhibits a linear relationship with the DCS and impact velocity. A lower number of impacts occurred at higher impact velocities and shorter curing age. The number of impacts was drastically reduced when the impact velocity surpassed 3 m/s. As the CTR increased, the number of impacts also increased. When the number of impacts increased, the elastic modulus, dynamic impact strength, and peak strain initially increased before ultimately decreasing. (2) Under the cyclic impact load, the shear failure and axial splitting failure were the main failure modes of CTB. Increasing the CTR may be a more effective strategy for reducing the degree of CTB fragmentation compared to prolonging the curing age. When the impact velocity is lower than 3 m/s, CTB can withstand multiple impacts and maintain high levels of integrity. When the DIF of the first shock is below 1.5, the CTB demonstrates a capability to withstand more than four shocks. If the DIF exceeds 2, the CTB can only endure a single shock. (3) NMR and SEM observations revealed that CTB itself contains more pores. A dense network structure will grow inside CTB as the curing age and CTR are increased, reducing the porosity. The pore size observed in the samples also support that increasing CTR may be a more effective strategy. Our findings contribute to a better understanding of the kinetic response of CTB in deep mines under frequent blasting disruption and offer a valuable reference point for future research in this area.

CWF19L2 is Essential for Male Fertility and Spermatogenesis by Regulating Alternative Splicing.

The progression of spermatogenesis along specific developmental trajectories depends on the coordinated regulation of pre-mRNA alternative splicing (AS) at the post-transcriptional level. However, the fundamental mechanism of AS in spermatogenesis remains to be investigated. Here, it is demonstrated that CWF19L2 plays a pivotal role in spermatogenesis and male fertility. In germline conditional Cwf19l2 knockout mice exhibiting male sterility, impaired spermatogenesis characterized by increased apoptosis and decreased differentiated spermatogonia and spermatocytes is observed. That CWF19L2 interacted with several spliceosome proteins to participate in the proper assembly and stability of the spliceosome is discovered. By integrating RNA-seq and LACE-seq data, it is further confirmed CWF19L2 directly bound and regulated the splicing of genes related to spermatogenesis (Znhit1, Btrc, and Fbxw7) and RNA splicing (Rbfox1, Celf1, and Rbm10). Additionally, CWF19L2 can indirectly amplify its effect on splicing regulation through modulating RBFOX1. Collectively, this research establishes that CWF19L2 orchestrates a splicing factor network to ensure accurate pre-mRNA splicing during the early steps of spermatogenesis.

Nitrification inhibitor chlorate and nitrogen substrates differentially affect comammox Nitrospira in a grassland soil.

Introduction: Through the combined use of two nitrification inhibitors, Dicyandiamide (DCD) and chlorate with nitrogen amendment, this study aimed to investigate the contribution of comammox Nitrospira clade B, ammonia oxidizing bacteria (AOB) and archaea (AOA) to nitrification in a high fertility grassland soil, in a 90-day incubation study. Methods: The soil was treated with nitrogen (N) at three levels: 0 mg-N kg-1 soil, 50 mg-N kg-1 soil, and 700 mg-N kg-1 soil, with or without the two nitrification inhibitors. The abundance of comammox Nitrospira, AOA, AOB, and nitrite oxidising bacteria (NOB) was measured using qPCR. The comammox Nitrospira community structure was assessed using Illumina sequencing. Results and Discussion: The results showed that the application of chlorate inhibited the oxidation of both NH4+ and NO2- in all three nitrogen treatments. The application of chlorate significantly reduced the abundance of comammox Nitrospira amoA and nxrB genes across the 90-day experimental period. Chlorate also had a significant effect on the beta diversity (Bray-Curtis dissimilarity) of the comammox Nitrospira clade B community. Whilst AOB grew in response to the N substrate additions and were inhibited by both inhibitors, AOA showed litle or no response to either the N substrate or inhibitor treatments. In contrast, comammox Nitrospira clade B were inhibited by the high ammonium concentrations released from the urine substrates. These results demonstrate the differential and niche responses of the three ammonia oxidising communities to N substrate additions and nitrification inhibitor treatments. Further research is needed to investigate the specificity of the two inhibitors on the different ammonia oxidising communities.

The clinical significance of mitochondrial calcium uniporter in gastric cancer patients and its preliminary exploration of the impact on mitochondrial function and metabolism.

Objective: The objective of this study is to elucidate the influence of MCU on the clinical pathological features of GC patients, to investigate the function and mechanism of the mitochondrial calcium uptake transporter MCU in the initiation and progression of GC, and to explore its impact on the metabolic pathways and biosynthesis of mitochondria. The ultimate goal is to identify novel targets and strategies for the clinical management of GC patients. Methods: Tumor and adjacent tissue specimens were obtained from 205 patients with gastric cancer, and immunohistochemical tests were performed to assess the expression of MCU and its correlation with clinical pathological characteristics and prognosis. Data from TCGA, GTEx and GEO databases were retrieved for gastric cancer patients, and bioinformatics analysis was utilized to investigate the association between MCU expression and clinical pathological features. Furthermore, we conducted an in-depth analysis of the role of MCU in GC patients. We investigated the correlation between MCU expression in GC and its impact on mitochondrial function, metabolism, biosynthesis, and immune cells. Additionally, we studied the proteins or molecules that interact with MCU. Results: Our research revealed high expression of MCU in the GC tissues. This high expression was associated with poorer T and N staging, and indicated a worse disease-free survival period. MCU expression was positively correlated with mitochondrial function, mitochondrial metabolism, nucleotide, amino acid, and fatty acid synthesis metabolism, and negatively correlated with nicotinate and nicotinamide metabolism. Furthermore, the MCU also regulates the function of the mitochondrial oxidative respiratory chain. The MCU influences the immune cells of GC patients and regulates ROS generation, cell proliferation, apoptosis, and resistance to platinum-based drugs in gastric cancer cells. Conclusion: High expression of MCU in GC indicates poorer clinical outcomes. The expression of the MCU are affected through impacts the function of mitochondria, energy metabolism, and cellular biosynthesis in gastric cancer cells, thereby influencing the growth and metastasis of gastric cancer cells. Therefore, the mitochondrial changes regulated by MCU could be a new focus for research and treatment of GC.

Risk factors for cerebral edema following aneurysm clipping in patients with aneurysmal subarachnoid hemorrhage.

OBJECTIVES: To investigate the factors that contribute to the development of cerebral edema after aneurysm clipping in individuals with aneurysmal subarachnoid hemorrhage (aSAH). METHODS: A total of 232 patients with aSAH caused by rupture and treated with aneurysm clipping were included in the retrospective analysis of clinical data. Postoperatively, the participants were categorized into two groups based on the presence or absence of cerebral edema: a complication group (n=33) and a non-complication group (n=199).A comparison was made between the overall data of the 2 groups. RESULTS: In the complication group, there were higher proportions of patients experiencing recurrent bleeding, aneurysm in the posterior circulation, Fisher grade III-IV, World Federation of Neurosurgical Societies (WFNS) grade II, Hunt-Hess grade III-IV, concomitant hypertension, duration from onset to operation ≥12 h, and concomitant hematoma compared to the non-complication group (p<0.05). Cerebral edema after aneurysm clipping was associated with several risk factors including repeated bleeding, aneurysm in the back of the brain, Fisher grade III-IV, WFNS grade II, Hunt-Hess grade III-IV, simultaneous high blood pressure and hematoma, and a duration of at least 12 hours from the start of symptoms to the surgical procedure (p<0.05). CONCLUSION: In patients with aSAH, the risk of cerebral edema after aneurysm clipping is increased by recurrent bleeding, aneurysm in the posterior circulation, Fisher grade III-IV, WFNS grade II, Hunt-Hess grade III-IV, concomitant hypertension and hematoma, and duration of ≥12 h from onset to operation.

Soluble ST2 for predicting heart failure, atrial fibrillation and death in patients with coronary heart disease with or without renal insufficiency.

Background: This study aimed to investigate the relationship between baseline soluble suppression of tumorigenesis-2 (sST2) concentration and the outcomes of heart failure (HF), atrial fibrillation (AF) or death in patients with coronary heart disease (CHD) with or without renal insufficiency (RI). Methods: Between March 2011 and December 2015, 3454 patients with CHD from the Chinese PLA General Hospital were enrolled in this cohort study. The patients were followed up until October 2021. AF, HF, and death events were recorded. Associations between baseline sST2 concentrations and clinical outcomes were assessed using Kaplan-Meier (K-M) curves, and Cox regression and generalised additive models. Subgroup analysis were carried out between RI and non-RI groups. Results: Among the patients with CHD (61.5 ± 11.8 years; 78.6 % men), 415 (12.02 %) had RI. During a median follow-up of 8.37 years, HF and AF were reported in 216 (6.25 %) and 174 (5.04 %) patients, respectively, and 297 (8.60 %) died. The K-M curves indicated that patients in the higher quartiles of sST2 concentrations were correlated with a poor survival rate of HF, AF, or death (all Ps < 0.001). Generalised additive model (GAM) demonstrated a nonlinear positive association between sST2 concentration and the risk of HF, AF, and death in CHD patients. The cut-off value of sST2 for predicting HF, AF and death were 32.1, 25.4 and 28.6 ng/mL, respectively. CHD patients with sST2 higher than the cut-off value had higher risks of HF (HR: 3.02, 95%CI: 2.24-4.05), AF (HR: 2.86; 95%CI: 2.10-3.90), and death (HR:2.11, 95%CI: 1.67-2.67). Furthermore, in patients with RI (12.02 %, n = 415), the prognostic value of sST2 over the cut-off value for HF and death remained unchanged (HR: 3.21 and 2.35; P < 0.05). In patients with CHD with or without RI, sST2 improved the area under the curve (AUC) of traditional risk models for predicting clinical endpoint events. Conclusions: The biomarker sST2 may be useful for predicting HF, AF, and death in patients with CHD. The predicted value was not affected by renal function.

Wogonin mitigates acetaminophen-induced liver injury in mice through inhibition of the PI3K/AKT signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Scutellaria baicalensis Georgi (SBG), a widely used traditional Chinese medicine, exhibits anti-inflammatory and antioxidant properties. Wogonin is one of the primary bioactive components of SBG. Acetaminophen (APAP)-induced liver injury (AILI) represents a prevalent form of drug-induced liver damage and is primarily driven by inflammatory responses and oxidative stress. AIM OF STUDY: To investigate the therapeutic effects of Wogonin on AILI and the underlying mechanisms. MATERIALS AND METHODS: C57BL/6 J mice were pre-treated with Wogonin (1, 2.5, and 5 mg/kg bodyweight) for 3 days, followed by treatment with APAP (300 mg/kg bodyweight). The serum and liver tissue samples were collected at 24 h post-APAP treatment. Bone marrow-derived macrophages and RAW264.7 cells were cultured and pre-treated with Wogonin (5, 10, and 20 µM) for 30 min, followed by stimulation with lipopolysaccharide (LPS; 100 ng/mL) for 3 h. To examine the role of the PI3K/AKT signaling pathway in the therapeutic effect of Wogonin on AILI, mice and cells were treated with LY294002 (a PI3K inhibitor) and MK2206 (an AKT inhibitor). RESULTS: Wogonin pre-treatment dose-dependently alleviated AILI in mice. Additionally, Wogonin suppressed oxidative stress and inflammatory responses. Liver transcriptome analysis indicated that Wogonin primarily regulates immune function and cytokines in AILI. Wogonin suppressed inflammatory responses of macrophages by inhibiting the PI3K/AKT signaling pathway. Consistently, Wogonin exerted therapeutic effects on AILI in mice through the PI3K/AKT signaling pathway. CONCLUSIONS: Wogonin alleviated AILI and APAP-induced hepatotoxicity in mice through the PI3K/AKT signaling pathway.

Oral bacteria relative abundance in faeces increases due to gut microbiota depletion and is linked with patient outcomes.

The detection of oral bacteria in faecal samples has been associated with inflammation and intestinal diseases. The increased relative abundance of oral bacteria in faeces has two competing explanations: either oral bacteria invade the gut ecosystem and expand (the 'expansion' hypothesis), or oral bacteria transit through the gut and their relative increase marks the depletion of other gut bacteria (the 'marker' hypothesis). Here we collected oral and faecal samples from mouse models of gut dysbiosis (antibiotic treatment and DSS-induced colitis) and used 16S ribosomal RNA sequencing to determine the abundance dynamics of oral bacteria. We found that the relative, but not absolute, abundance of oral bacteria increases, reflecting the 'marker' hypothesis. Faecal microbiome datasets from diverse patient cohorts, including healthy individuals and patients with allogeneic haematopoietic cell transplantation or inflammatory bowel disease, consistently support the 'marker' hypothesis and explain associations between oral bacterial abundance and patient outcomes consistent with depleted gut microbiota. By distinguishing between the two hypotheses, our study guides the interpretation of microbiome compositional data and could potentially identify cases where therapies are needed to rebuild the resident microbiome rather than protect against invading oral bacteria.

Fenobam modulates distinct electrophysiological mechanisms for regulating excessive gamma oscillations in the striatum of dyskinetic rats.

Gamma oscillations have been frequently observed in levodopa-induced dyskinesia (LID), manifest as broadband (60-120 Hz) and narrowband (80-110 Hz) gamma activity in cortico-striatal projection. We investigated the electrophysiological mechanisms and correlation of gamma oscillations with dyskinesia severity, while assessing the administration of fenobam, a selective metabotropic glutamate receptor 5 (mGluR5) antagonist, in regulating dyskinesia-associated gamma activity. We conducted simultaneous electrophysiological recordings in Striatum (Str) and primary motor cortex (M1), together with Abnormal Involuntary Movement Scale scoring (AIMs). Phase-amplitude coupling (PAC), power, coherence, and Granger causality analyses were conducted for electrophysiological data. The findings demonstrated increased beta oscillations with directionality from M1 to Str in parkinsonian state. During on-state dyskinesia, elevated broadband gamma activity was modulated by the phase of theta activity in Str, while M1 â†’ Str gamma causality mediated narrowband gamma oscillations in Str. Striatal gamma power (both periodic and aperiodic power), periodic power, peak frequency, and PAC at 80 min (corresponding to the peak dyskinesia) after repeated levodopa injections across recording days (day 30, 33, 36, 39, and 42) increased progressively, correlating with total AIMs. Additionally, a time-dependent parabolic trend of PAC, peak frequency and gamma power was observed after levodopa injection on day 42 from 20 to 120 min, which also correlated with corresponding AIMs. Fenobam effectively alleviates dyskinesia, suppresses enhanced gamma oscillations in the M1-Str directionality, and reduces PAC in Str. The temporal characteristics of gamma oscillations provide parameters for classifying LID severity. Antagonizing striatal mGluR5, a promising therapeutic target for dyskinesia, exerts its effects by modulating gamma activity.

ß-hydroxybutyrate restrains colitis-associated tumorigenesis by inhibiting HIF-1α-mediated angiogenesis.

Decreased levels of ß-hydroxybutyrate (BHB), a lipid metabolic intermediate known to slow the progression of colorectal cancer (CRC), have been observed in the colon mucosa of patients with inflammatory bowel diseases (IBD). In particular, patients with recurrent IBD present an increased risk of developing colitis-associated colorectal cancer (CAC). The role and molecular mechanism of BHB in the inflammatory and carcinogenic process of CAC remains unclear. Here, the anti-tumor effect of BHB was investigated in the Azoxymethane (AOM)/Dextran Sulfate Sodium (DSS)-induced CAC model and tumor organoids derivatives. The underlying mechanisms were studied using transcriptome and non-target metabolomic assay and further validated in colon tumor cell lineage CT26 in vitro. The tumor tissues and the nearby non-malignant tissues from colon cancer patients were collected to measure the expression levels of ketogenic enzymes. The exogenous BHB supplement lightened tumor burden and angiogenesis in the CAC model. Notably, transcriptome analysis revealed that BHB effectively decreased the expression of VEGFA in the CAC tumor mucosa. In vitro, BHB directly reduced VEGFA expression in hypoxic-treated CT26 cells by targeting transcriptional factor HIF-1α. Conversely, the deletion of HIF-1α largely reversed the inhibitory effect of BHB on CAC tumorigenesis. Additionally, decreased expression of ketogenesis-related enzymes in tumor tissues were associated with poor survival outcomes in patients with colon cancer. In summary, BHB carries out anti-angiogenic activity in CAC by regulating HIF-1α/VEGFA signaling. These findings emphasize the role of BHB in CAC and may provide novel perspectives for the prevention and treatment of colonic tumors.

Association between triglyceride glucose-body mass index and long-term adverse outcomes of heart failure patients with coronary heart disease.

BACKGROUND: The triglyceride glucose-body mass index (TyG-BMI) is recognized as a reliable surrogate for evaluating insulin resistance and an effective predictor of cardiovascular disease. However, the link between TyG-BMI index and adverse outcomes in heart failure (HF) patients remains unclear. This study examines the correlation of the TyG-BMI index with long-term adverse outcomes in HF patients with coronary heart disease (CHD). METHODS: This single-center, prospective cohort study included 823 HF patients with CHD. The TyG-BMI index was calculated as follows: ln [fasting triglyceride (mg/dL) × fasting blood glucose (mg/dL)/2] × BMI. To explore the association between the TyG-BMI index and the occurrences of all-cause mortality and HF rehospitalization, we utilized multivariate Cox regression models and restricted cubic splines with threshold analysis. RESULTS: Over a follow-up period of 9.4 years, 425 patients died, and 484 were rehospitalized due to HF. Threshold analysis revealed a significant reverse "J"-shaped relationship between the TyG-BMI index and all-cause mortality, indicating a decreased risk of all-cause mortality with higher TyG-BMI index values below 240.0 (adjusted model: HR 0.90, 95% CI 0.86-0.93; Log-likelihood ratio p = 0.003). A distinct "U"-shaped nonlinear relationship was observed with HF rehospitalization, with the inflection point at 228.56 (adjusted model: below: HR 0.95, 95% CI 0.91-0.98; above: HR 1.08, 95% CI 1.03-1.13; Log-likelihood ratio p < 0.001). CONCLUSIONS: This study reveals a nonlinear association between the TyG-BMI index and both all-cause mortality and HF rehospitalization in HF patients with CHD, positioning the TyG-BMI index as a significant prognostic marker in this population.

The deubiquitinase cofactor UAF1 interacts with USP1 and plays an essential role in spermiogenesis.

Spermiogenesis defines the final phase of male germ cell differentiation. While multiple deubiquitinating enzymes have been linked to spermiogenesis, the impacts of deubiquitination on spermiogenesis remain poorly characterized. Here, we investigated the function of UAF1 in mouse spermiogenesis. We selectively deleted Uaf1 in premeiotic germ cells using the Stra8-Cre knock-in mouse strain (Uaf1 sKO), and found that Uaf1 is essential for spermiogenesis and male fertility. Further, UAF1 interacts and colocalizes with USP1 in the testes. Conditional knockout of Uaf1 in testes results in disturbed protein levels and localization of USP1, suggesting that UAF1 regulates spermiogenesis through the function of the deubiquitinating enzyme USP1. Using tandem mass tag-based proteomics, we identified that conditional knockout of Uaf1 in the testes results in reduced levels of proteins that are essential for spermiogenesis. Thus, we conclude that the UAF1/USP1 deubiquitinase complex is essential for normal spermiogenesis by regulating the levels of spermiogenesis-related proteins.

Agricultural management practices in China enhance nitrogen sustainability and benefit human health.

The potential of enhanced agricultural management practices to drive sustainability is rarely quantified at grassroots level. Here we analyse nitrogen use and loss in Chinese cropland, drawing from data collected in 2,238,550 sites in two national agricultural pollution source censuses from 2007 to 2017. We find an upswing of 10% in crop yields and an 8% reduction in nitrogen pollution during this period, owing to the promotion and adoption of various management practices (including the combination of organic and chemical fertilizers, straw recycling and deep placement of fertilizer). These practices have collectively contributed to an 18% increase in nitrogen use efficiency in the country. By fully embracing them, we project that annual cropland pollution could be further reduced by up to 1.4 Mt of nitrogen without compromising crop yields. Environmental and human health benefits are projected to consistently outweigh implementation costs in the future, with total benefits reaching US$15 billion.