TIR domains of plant immune receptors are 2',3'-cAMP/cGMP synthetases mediating cell death.

2',3'-cAMP is a positional isomer of the well-established second messenger 3',5'-cAMP, but little is known about the biology of this noncanonical cyclic nucleotide monophosphate (cNMP). Toll/interleukin-1 receptor (TIR) domains of nucleotide-binding leucine-rich repeat (NLR) immune receptors have the NADase function necessary but insufficient to activate plant immune responses. Here, we show that plant TIR proteins, besides being NADases, act as 2',3'-cAMP/cGMP synthetases by hydrolyzing RNA/DNA. Structural data show that a TIR domain adopts distinct oligomers with mutually exclusive NADase and synthetase activity. Mutations specifically disrupting the synthetase activity abrogate TIR-mediated cell death in Nicotiana benthamiana (Nb), supporting an important role for these cNMPs in TIR signaling. Furthermore, the Arabidopsis negative regulator of TIR-NLR signaling, NUDT7, displays 2',3'-cAMP/cGMP but not 3',5'-cAMP/cGMP phosphodiesterase activity and suppresses cell death activity of TIRs in Nb. Our study identifies a family of 2',3'-cAMP/cGMP synthetases and establishes a critical role for them in plant immune responses.

NLR signaling in plants: from resistosomes to second messengers.

Nucleotide binding and leucine-rich repeat-containing receptors (NLRs) have a critical role in plant immunity through direct or indirect recognition of pathogen effectors. Recent studies have demonstrated that such recognition induces formation of large protein complexes called resistosomes to mediate NLR immune signaling. Some NLR resistosomes activate Ca2+ influx by acting as Ca2+-permeable channels, whereas others function as active NADases to catalyze the production of nucleotide-derived second messengers. In this review we summarize these studies on pathogen effector-induced assembly of NLR resistosomes and resistosome-mediated production of the second messengers of Ca2+ and nucleotide derivatives. We also discuss downstream events and regulation of resistosome signaling.

FastBiCmrMLM: a fast and powerful compressed variance component mixed logistic model for big genomic case-control genome-wide association study.

Large sample datasets have been regarded as the primary basis for innovative discoveries and the solution to missing heritability in genome-wide association studies. However, their computational complexity cannot consider all comprehensive effects and all polygenic backgrounds, which reduces the effectiveness of large datasets. To address these challenges, we included all effects and polygenic backgrounds in a mixed logistic model for binary traits and compressed four variance components into two. The compressed model combined three computational algorithms to develop an innovative method, called FastBiCmrMLM, for large data analysis. These algorithms were tailored to sample size, computational speed, and reduced memory requirements. To mine additional genes, linkage disequilibrium markers were replaced by bin-based haplotypes, which are analyzed by FastBiCmrMLM, named FastBiCmrMLM-Hap. Simulation studies highlighted the superiority of FastBiCmrMLM over GMMAT, SAIGE and fastGWA-GLMM in identifying dominant, small α (allele substitution effect), and rare variants. In the UK Biobank-scale dataset, we demonstrated that FastBiCmrMLM could detect variants as small as 0.03% and with α ≈ 0. In re-analyses of seven diseases in the WTCCC datasets, 29 candidate genes, with both functional and TWAS evidence, around 36 variants identified only by the new methods, strongly validated the new methods. These methods offer a new way to decipher the genetic architecture of binary traits and address the challenges outlined above.

Multi-scale analysis of acupuncture mechanisms for motor and sensory cortex activity based on SEEG data.

Acupuncture, a traditional Chinese therapy, is gaining attention for its impact on the brain. While existing electroencephalogram and functional magnetic resonance image research has made significant contributions, this paper utilizes stereo-electroencephalography data for a comprehensive exploration of neurophysiological effects. Employing a multi-scale approach, channel-level analysis reveals notable $\delta $-band activity changes during acupuncture. At the brain region level, acupuncture modulated connectivity between the paracentral lobule and the precentral gyrus. Whole-brain analysis indicates acupuncture's influence on network organization, and enhancing $E_{glob}$ and increased interaction between the motor and sensory cortex. Brain functional reorganization is an important basis for functional recovery or compensation after central nervous system injury. The use of acupuncture to stimulate peripheral nerve trunks, muscle motor points, acupoints, etc., in clinical practice may contribute to the reorganization of brain function. This multi-scale perspective provides diverse insights into acupuncture's effects. Remarkably, this paper pioneers the introduction of stereo-electroencephalography data, advancing our understanding of acupuncture's mechanisms and potential therapeutic benefits in clinical settings.

Investigating the Inhibition of Diindolylmethane Derivatives on SARS-CoV-2 Main Protease.

The SARS-CoV-2 main protease (Mpro) is an essential enzyme that promotes viral transcription and replication. Mpro conserved nature in different variants and its nonoverlapping nature with human proteases make it an attractive target for therapeutic intervention against SARS-CoV-2. In this work, the interaction mechanism between Mpro and diindolylmethane derivatives was investigated by molecular docking, enzymatic inhibition assay, UV-vis, fluorescence spectroscopy, and circular dichroism spectroscopy. Results of IC50 values show that 1p (9.87 µM) was the strongest inhibitor for Mpro in this work, which significantly inhibited the activity of Mpro. The binding constant (4.07 × 105 Lmol-1), the quenching constant (5.41 × 105 Lmol-1), and thermodynamic parameters indicated that the quenching mode of 1p was static quenching, and the main driving forces between 1p and Mpro are hydrogen bond and van der Waals force. The influence of molecular structure on the binding is investigated. Chlorine atoms and methoxy groups are favorable for the diindolylmethane derivative inhibitors of Mpro. This work confirms the changes in the microenvironment of Mpro by 1p, and provides clues for the design of potential inhibitors.

Pluronic F127-Complexed PEGylated Poly(glutamic acid)-Cisplatin Nanomedicine for Enhanced Glioblastoma Therapy.

Glioblastoma is one of the most aggressive and treatment-resistant forms of primary brain cancer, posing significant challenges in effective therapy. This study aimed to enhance the effectiveness of glioblastoma therapy by developing a unique nanomedicine composed of Pluronic F127-complexed PEGylated poly(glutamic acid)-cisplatin (PLG-PEG/PF127-CDDP). PLG-PEG/PF127-CDDP demonstrated an optimal size of 133.97 ± 12.60 nm, facilitating efficient cell uptake by GL261 glioma cells. In vitro studies showed significant cytotoxicity against glioma cells with a half-maximal (50%) inhibitory concentration (IC50) of 12.61 µg mL-1 at 48 h and a 72.53% ± 1.89% reduction in cell invasion. Furthermore, PLG-PEG/PF127-CDDP prolonged the circulation half-life of cisplatin to 9.75 h in vivo, leading to a more than 50% reduction in tumor size on day 16 post-treatment initiation in a murine model of glioma. The treatment significantly elevated lactate levels in GL261 cells, indicating enhanced metabolic disruption. Therefore, PLG-PEG/PF127-CDDP offers a promising approach for glioblastoma therapy due to its effects on improving drug delivery efficiency, therapeutic outcomes, and safety while minimizing systemic side effects. This work underscores the potential of polymer-based nanomedicines in overcoming the challenges of treating brain tumors, paving the way for future clinical applications.

Association between sleep behaviors and stroke in Southwest China: a prospective cohort study.

BACKGROUND: Sleep can function as a potential modifiable risk factor in the control and prevention of stroke. Geography significantly influences sleep patterns. The association of sleep with stroke in population of Southwest China has not so far been investigated. METHODS: A total of 55,001 residents aged from 30 to 79 years in Southwest China were included in this study, obtaining their complete information of baseline survey and follow-up in China Kadoorie Biobank (CKB). Sleep-evaluating score was constructed on the basis of short/long sleep duration, insomnia, and snoring. The multivariate Cox proportional hazards regression was used to analyze the association between sleep behaviors and stroke. RESULTS: During 11.15 years of follow-up, 3410 stroke cases (572.78 cases/100,000 person-years) were documented. There exists no association of sleep-evaluating score with the risk of stroke in the total population. Male-predisposing association between sleep-evaluating score and risk of stroke was observed (for total stroke, HR = 1.52, 95% CI: 1.03-2.23; for hemorrhagic stroke, HR = 2.31, 95% CI: 1.22-4.34), with anisotropism in male residents with overweight and obesity (HR = 1.93, 95% CI: 1.03-3.63), and those without hypertension (HR = 1.76, 95% CI: 1.01-3.07) in the baseline survey. CONCLUSIONS: There exists the male-predisposing association between sleep-evaluating score and the risk of stroke in Southwest China. Improving sleep is required for reducing the risk of stroke.

BMAL1 involved in autophagy and injury of thoracic aortic endothelial cells of rats induced by intermittent heat stress through the AMPK/mTOR/ULK1 pathway.

Physiological activities of the body exhibit an obvious biological rhythm. At the core of the circadian rhythm, BMAL1 is the only clock gene whose deletion leads to abnormal physiological functions. However, whether intermittent heat stress influences cardiovascular function by altering the circadian rhythm of clock genes has not been reported. This study aimed to investigate whether intermittent heat stress induces autophagy and apoptosis, and the effects of BMAL1 on thoracic aortic autophagy and apoptosis. An intermittent heat stress model was established in vitro, and western blotting and immunofluorescence were used to detect the expression of autophagy, apoptosis, the AMPK/mTOR/ULK1 pathway, and BMAL1. After BMAL1 silencing, RT-qPCR was performed to detect the expression levels of autophagy and apoptosis-related genes. Our results suggest that heat stress induces autophagy and apoptosis in RTAECs. In addition, intermittent heat stress increased the phosphorylation of AMPK and ULK1, but reduced the phosphorylation of mTOR, AMPK inhibitor Compound C reversed the phosphorylation of AMPK, mTOR, and ULK1, and Beclin1 and LC3-II/LC3-I were downregulated. Furthermore, BMAL1 expression was elevated in vitro and shBMAL1 decreased autophagy and apoptosis. We revealed that intermittent heat stress induces autophagy and apoptosis, and that BMAL1 may be involved in the occurrence of autophagy and apoptosis.

Additive interactions between obesity and insulin resistance on hypertension in a Chinese rural population.

BACKGROUND: Adiposity and insulin resistance (IR) are closely associated with hypertension; however, the role of interactions between obesity phenotypes and IR in hypertension is unclear. This study aimed to evaluate the interactions of body mass index (BMI), waist circumference (WC), and body fat percentage (BF%) with IR on hypertension risk. METHODS: We analyzed data from 4888 participants (mean age 57 years, 41.2% men) in the China Northwest Natural Population Cohort, Ningxia Project. BMI, WC, and BF% were determined using bioelectrical impedance analysis devices. IR was estimated using a homeostasis model assessment index (HOMA-IR). Multivariable-adjusted logistic regression was used to evaluate the association between HOMA-IR and hypertension risk. We calculated the relative excess risk and attributable proportion with their 95% confidence intervals (CIs) to assess whether adiposity phenotypes modified the effect of HOMA-IR on hypertension risk. RESULTS: The crude prevalence of hypertension was 52.2%. The multivariable-adjusted odds ratio of HOMA-IR was 1.80 (95% CI: 1.23-2.65) for the risk of hypertension in the highest versus the lowest quartiles, but this association became marginal in models further adjusting for BMI, WC, and BF% (P for trend = 0.056). Relative excess risk and attributable proportion for interaction between high HOMA-IR and high BF% were 0.32 (0.04-0.59) and 0.33 (0.06-0.60), respectively. Additionally, high truncal and leg BF% and high HOMA-IR accounted for the hypertension risk in women, but not in men. We did not observe any significant interactions between BMI or WC and HOMA-IR on hypertension. CONCLUSION: BF% modified the association between IR and increased risk of hypertension in women with high truncal and leg BF%, but not in men.

Estimating 24-h urinary sodium excretion from casual spot urine specimen among hypertensive patients in Northwest China: the Salt Substitute and Stroke Study.

OBJECTIVE: To develop an equation that can estimate the 24-h urinary Na excretion by using casual spot urine specimen for older hypertensive participants in rural Ningxia and further to compare with the INTERSALT method, Kawasaki method and Tanaka method. DESIGN: Older hypertensive participants in rural Ningxia provided their casual spot urine samples and 24-h urine samples between January 2015 and February 2017. Sex-specific equation was developed using linear forward stepwise regression analysis. Model fit was assessed using adjusted R2. Approximately half of all participants were randomly selected to validate the equation. Mean differences, intraclass correlation coefficients and Bland-Altman plots were used to evaluate the performance of all methods. SETTING: Pingluo County and Qingtongxia County in Ningxia Hui Autonomous Region, China. PARTICIPANTS: Older hypertensive participants in rural Ningxia. RESULTS: Totally, 807 of 1120 invited participants provided qualified 24-h urine samples and spot urine samples. There was no statistical difference comparing the laboratory-based method against the new method and the INTERSALT method, while Kawasaki method had the largest bias with a mean difference of 40·81 g/d (95 % CI 39·27, 42·35 g/d). Bland-Altman plots showed similar pattern of the results. CONCLUSION: The INTERSALT method and the new equation have the potential to estimate the 24-h urinary Na excretion in this study population. However, the extrapolation of the results to other population needs to be careful. Future research is required to establish a more reliable method to estimate 24-h urinary Na excretion.

Morphologic Study of Superior Temporal Sulcus-Amygdaloid Body and Lateral Fissure-Amygdaloid Body Surgical Approach by Using Magnetic Resonance Imaging Volume Rendering.

In this research, 83 patients were measured by magnetic resonance imaging volume rendering technique. The authors acquired the curve length of the superior temporal sulcus and the lateral fissure on the cerebral hemisphere, the shortest distance from the superior temporal sulcus and the lateral fissure to the center of amygdaloid body separately, the vertical diameter, the transversal diameter, and the anteroposterior diameter of the amygdaloid body and the 2 approach angles between the median sagittal plane and the shortest segment from the superior temporal sulcus to the center of amygdaloid body and the shortest segment from lateral fissure to the center of the amygdaloid body. At the same time, we preliminarily oriented the 2 points of the superior temporal sulcus and the lateral fissure, which are closest to the center of amygdaloid body, aimed at finding out the best entrance points of surgical approach through the superior temporal sulcus and the lateral fissure to the amygdaloid body and reducing the damage to the nerve fibers or blood vessels during the operation. The results indicate that the point at the front side 1/4 of the superior temporal sulcus may be the ideal surgical approach entrance point and the point at the front side 1/3 of the lateral fissure. There is no difference between 2 cerebral hemispheres (P < 0.05).

Multistimuli-responsive supramolecular assembly of cucurbituril/cyclodextrin pairs with an azobenzene-containing bispyridinium guest.

A linear supramolecular architecture was successfully constructed by the inclusion complexation of α-cyclodextrin with azobenzene and the host-stabilized charge-transfer interaction of naphthalene and a bispyridinium guest with cucurbit[8]uril in water, which was comprehensively characterized by (1)H NMR spectroscopy, UV/Vis absorption, fluorescence, circular dichroism spectroscopy, dynamic laser scattering, and microscopic observations. Significantly, because it benefits from the photoinduced isomerization of the azophenyl group and the chemical reduction of bispyridinium moiety with noncovalent connections, the assembly/disassembly process of this supramolecular nanostructure can be efficiently modulated by external stimuli, including temperature, UV and visible-light irradiation, and chemical redox.

Targeted protein degradation: advances in drug discovery and clinical practice.

Targeted protein degradation (TPD) represents a revolutionary therapeutic strategy in disease management, providing a stark contrast to traditional therapeutic approaches like small molecule inhibitors that primarily focus on inhibiting protein function. This advanced technology capitalizes on the cell's intrinsic proteolytic systems, including the proteasome and lysosomal pathways, to selectively eliminate disease-causing proteins. TPD not only enhances the efficacy of treatments but also expands the scope of protein degradation applications. Despite its considerable potential, TPD faces challenges related to the properties of the drugs and their rational design. This review thoroughly explores the mechanisms and clinical advancements of TPD, from its initial conceptualization to practical implementation, with a particular focus on proteolysis-targeting chimeras and molecular glues. In addition, the review delves into emerging technologies and methodologies aimed at addressing these challenges and enhancing therapeutic efficacy. We also discuss the significant clinical trials and highlight the promising therapeutic outcomes associated with TPD drugs, illustrating their potential to transform the treatment landscape. Furthermore, the review considers the benefits of combining TPD with other therapies to enhance overall treatment effectiveness and overcome drug resistance. The future directions of TPD applications are also explored, presenting an optimistic perspective on further innovations. By offering a comprehensive overview of the current innovations and the challenges faced, this review assesses the transformative potential of TPD in revolutionizing drug development and disease management, setting the stage for a new era in medical therapy.

Rotenone activates the LKB1-AMPK-ULK1 signaling pathway to induce autophagy and apoptosis in rat thoracic aortic endothelial cells.

BACKGROUND: The specific mechanism by which rotenone impacts thoracic aortic autophagy and apoptosis is unknown. We aimed to investigate the regulatory effects of rotenone on autophagy and apoptosis in rat thoracic aortic endothelial cells (RTAEC) via activation of the LKB1-AMPK-ULK1 signaling pathway and to elucidate the molecular mechanisms of rotenone on autophagy and apoptosis in vascular endothelial cells. METHODS: In vivo, 60 male SD rats were randomly selected and divided into 5 groups: control (Con), DMSO, 1, 2, and 4 mg/kg groups, respectively. After 28 days of treatment, histopathological and ultrastructural changes in each group were observed using HE and transmission electron microscopy; Autophagy, apoptosis, and LKB1-AMPK-ULK1 pathway-related proteins were detected by Western blot; Apoptosis levels in the thoracic aorta were detected by TUNEL. In vitro, RTAEC were cultured and divided into control (Con), DMSO, 20, 100, 500, and 1000 nM groups. After 24 h of intervention, autophagy, apoptosis, and LKB1-AMPK-ULK1 pathway-related factors were detected by Western blot and qRT-PCR; Flow cytometry to detect apoptosis levels; Autophagy was inhibited with 3-MA and CQ to detect apoptosis levels, and changes in autophagy, apoptosis, and downstream factors were detected by the AMPK inhibitor CC intervention. RESULTS: Gavage in SD rats for 28 days, some degree of damage was observed in the thoracic aorta and heart of the rotenone group, as well as the appearance of autophagic vesicles was observed in the thoracic aorta. TUNEL analysis revealed higher apoptosis in the rotenone group's thoracic aorta; RTAEC cultured in vitro, after 24 h of rotenone intervention, showed increased ROS production and significantly decreased ATP production. The flow cytometry data suggested an increase in the number of apoptotic RTAEC. The thoracic aorta and RTAEC in the rotenone group displayed elevated levels of autophagy and apoptosis, and the LKB1-AMPK-ULK1 pathway proteins were activated and expressed at higher levels. Apoptosis and autophagy were both suppressed by the autophagy inhibitors 3-MA and CQ. The AMPK inhibitor CC reduced autophagy and apoptosis in RTAEC and suppressed the production of the AMPK downstream factors ULK1 and P-ULK1. CONCLUSIONS: Rotenone may promote autophagy in the thoracic aorta and RTAEC by activating the LKB1-AMPK-ULK1 signaling pathway, thereby inducing apoptosis.

Antifungal Activity of Difenoconazole-Loaded Microcapsules against Curvularia lunata.

Difenoconazole-loaded (CS-DIF) microcapsules were synthesized by encapsulating difenoconazole into biocompatible chitosan. The physical and chemical properties indicated that the encapsulation and chemical loading rates were 85.58% and 61.98%, respectively. The microcapsules exhibited prominent controlled-release and surface stability performance. The cumulative release rate was only 33.6% in 168 h, and the contact angle decreased by 11.73° at 120 s compared with difenoconazole. The antifungal activity of the CS-DIF microcapsules against Curvularia lunata was confirmed through observations of colony growth, in vitro and in vivo inoculation, mycelium morphology, as well as DNA and protein leakage. The antioxidant enzyme activity of superoxide dismutase, peroxidase, and catalase decreased by 65.1%, 84.9%, and 69.7%, respectively, when Curvularia lunata was treated with 200 µg/mL microcapsules, compared with the control in 24 h. The enzymatic activity of polyphenol oxidase decreased by 323.8%. The reactive oxygen species contents of hydrogen peroxide and superoxide anions increased by 204.6% and 164%, respectively. Additionally, the soluble sugar and soluble protein contents decreased by 65.5% and 69.6%, respectively. These findings provided a novel approach to control the growth of C. lunata efficiently, laying a foundation for reducing the quantity and enhancing the efficiency of chemical pesticides. The CS-DIF microcapsules exhibited a strong inhibitory effect on fungus, effectively preventing and controlling leaf spot disease and showing potential for field applications. This study might be of great significance in ensuring plant protection strategies.

Association between triglyceride glucose index and hyperuricemia: a new evidence from China and the United States.

Background: Hyperuricemia (HUA) is a glo\bal public health problem. The etiology of HUA is complex and efficient and accurate assessment metrics are still lacking when conducting large-scale epidemiologic screening. The aim of this study was to evaluate the association of the triglyceride glucose (TyG) index, TyG-body mass index (BMI), TyG-waist-to-height ratio (WHtR) with the risk of HUA. Methods: Based on data collected from the National Health and Nutrition Examination Survey (NHANES) in the United States and the China Health and Aging Longitudinal Study (CHARLS) in China, a total of 14,286 U.S. adults and 4,620 Chinese adults were included in the analysis. The study examined the levels of TyG, TyG-BMI, TyG-WHtR, and TyG-WC. Multivariate logistic regression was utilized to investigate the relationships between these variables and hyperuricemia (HUA), separately. Additionally, the study used restricted cubic splines (RCS) to explore the linear associations of TyG, TyG-BMI, TyG-WHtR, TyG-WC, and HUA, separately. Results: The NHANES results showed that TyG [Q2, 1.58(1.26, 1.98); Q3, 2.36 (1.94, 2.88); Q4, 3.21 (2.61, 3.94)], TyG-BMI [Q2, 2.14 (1.74, 2.65); Q3, 3.38 (2.74, 4.17); Q4, 6.70 (5.55, 8.02)], TyG-WHtR [Q2, 1.92 (1.56, 2.36); Q3, 3.14 (2.56, 3.85); Q4, 6.28 (5.12, 7.69)], TyG-WC [Q2, 2.32 (1.85, 2.90); Q3, 3.51 (2.84, 4.34); Q4, 7.32 (5.95, 9.02)] were identified as risk factors for hyperuricemia (HUA). Similarly, the CHARLS results, when fully adjusted for covariates, indicated that TyG [Q4, 2.36 (1.08, 5.15)], TyG-BMI [Q3, 2.60 (1.05, 6.41); Q4, 3.70 (1.64, 8.32)], TyG-WHtR (Q4, 2.84 (1.23, 6.55), TyG-WC [Q4, 2.85 (1.23, 6.5)] were also risk factors for HUA. The predictive ability of each indicator for the risk of developing HUA was stronger in women than in men. Furthermore, there was an observed nonlinear relationship between TyG, TyG-BMI, TyG-WHtR, TyG-WC, and HUA in both the NHANES and CHARLS datasets (P-nonlinearity < 0.05). Conclusion: These findings suggest that TyG, TyG-BMI, TyG-WHtR and TyG-WC are associated with an increased risk of HUA. They are potential indicators for screening HUA status in the general population in China and the United States.

Dietary inflammatory index, dietary total antioxidant capacity, and frailty among older Chinese adults.

OBJECTIVES: Frailty is an age-related syndrome associated with poor health outcomes. Studies in developed countries indicate that the dietary inflammatory index (DII) and dietary total antioxidant capacity (DTAC) are important dietary factors influencing the risk of frailty in older adults. However, few studies have explored the association between DII, DTAC, and frailty among older Chinese adults. The objective of the current study was to examine whether DII and DTAC were associated with pre-frailty or frailty among older Chinese adults. DESIGN: A cross-sectional study. SETTING: Community-based. PARTICIPANTS: We included 6414 participants aged ≥60 years. MEASUREMENTS: Dietary intake was assessed using a validated food frequency questionnaire (FFQ). The DII and energy-adjusted DII (E-DII) were calculated using food parameters. DTAC was estimated using two widely adopted antioxidant scores: DTAC based on ferric reducing antioxidant power and dietary antioxidant quality score (DAQS) obtained from vitamins (vitamins A, C, and E) and minerals (zinc and selenium) with antioxidant functions. Frailty was assessed using the frailty index (FI) calculated from 28 health-related deficits. Individuals were classified as robust (FI ≤ 0.10), pre-frailty (FI > 0.10 to <0.25), or frailty (FI ≥ 0.25). Multiple logistic regression models were used to evaluate the associations of DII and DTAC with pre-frailty and frailty. RESULTS: After adjusting for confounding factors, individuals in the highest DII quintile (Q5) were more likely to have pre-frailty (odds ratio [OR] = 1.56; 95% confidence interval [CI]: 1.25-1.93; P for trend <0.001) than those in the lowest Q1. A similar positive association was detected for E-DII and pre-frailty. A significant association was found between DII and frailty. Compared with the lowest Q1, the highest Q5 of DTAC was negatively correlated with pre-frailty (OR = 0.66; 95% CI: 0.52-0.84; P for trend <0.001) and frailty (OR = 0.71; 95% CI: 0.50-0.1.03; P for trend <0.001). The DAQS yielded results similar to pre-frailty results (OR = 0.72; 95% CI: 0.58-0.89; P < 0.001). There was no evidence suggesting an association between DAQS and frailty. CONCLUSIONS: More proinflammatory diets were linked to higher pre-frailty risk, whereas higher levels of dietary antioxidants were associated with lower pre-frailty and frailty risk among older Chinese adults.

Insights into the biodegradation of pentachlorobiphenyl by Microbacterium paraoxydans: proteomic and metabolomic studies.

Bacterial degradation mechanism for high chlorinated pentachlorobiphenyl (PentaCB) with worse biodegradability has not been fully elucidated, which could limit the full remediation of environments afflicted by the complex pollution of polychlorinated biphenyls (PCBs). In this research, a new PentaCB-degrading bacterium Microbacterium paraoxydans that has not been reported was obtained using enzymatic screening method. The characteristics of its intracellular enzymes, proteome and metabolome variation during PentaCB degradation were investigated systematically compared to non-PentaCB conditions. The findings indicate that the degradation rate of PentaCB (1 mg/L) could reach 23.9% within 4 hours and achieve complete degradation within 12 hours, with the mixture of intracellular enzymes being most effective at a pH of 6.0. During the biodegradation of PentaCB, the 12 up-regulated proteins characterized included ABC transporter PentaCB-binding protein, translocase protein TatA, and signal peptidase I (SPase I), indicating the presence of functional proteins for PentaCB degradation in both the cytoplasm and the outer surface of the cytoplasmic membrane. Furthermore, five differentially enriched metabolites were strongly associated with the aforementioned proteins, especially the up-regulated 1, 2, 4-benzenetriol which feeds into multiple degradation pathways of benzoate, chlorocyclohexane, chlorobenzene and aminobenzoate. These relevant results help to understand and speculate the complex mechanisms regarding PentaCB degradation by M. paraoxydans, which have both theoretical and practical implications for PCB bioremediation.

TIR-catalyzed nucleotide signaling molecules in plant defense.

Toll and interleukin-1 receptor (TIR) domain is a conserved immune module in prokaryotes and eukaryotes. Signaling regulated by TIR-only proteins or TIR domain-containing intracellular immune receptors is critical for plant immunity. Recent studies demonstrated that TIR domains function as enzymes encoding a variety of activities, which manifest different mechanisms for regulation of plant immunity. These enzymatic activities catalyze metabolism of NAD+, ATP and other nucleic acids, generating structurally diversified nucleotide metabolites. Signaling roles have been revealed for some TIR enzymatic products that can act as second messengers to induce plant immunity. Herein, we summarize our current knowledge about catalytic production of these nucleotide metabolites and their roles in plant immune signaling. We also highlight outstanding questions that are likely to be the focus of future investigations about TIR-produced signaling molecules.

Association of Life's Essential 8 with osteoarthritis in United States adults: mediating effects of dietary intake of live microbes.

Objective: Osteoarthritis (OA) is associated with cardiovascular disease and represents a persistent economic and physical burden on patients in the United States. This study evaluated the mediating effect of dietary live microbe intake on the association between cardiovascular health [based on Life's Essential 8 (LE8) scores] and osteoarthritis (OA) in adults. Methods: This cross-sectional study included data from the National Health and Nutrition Examination Survey, 1999-2019 (from patients aged ≥20 years). LE8 scores (0-100) were measured according to the American Heart Association definition and categorized as low (0-49), moderate (50-79), or high (80-100). OA disease status was assessed using self-reported data from patients. The relationships were evaluated using multivariate logistic and restricted cubic spline models. Mediation analysis was used to evaluate the mediating effect of dietary live microbe intake on the association between LE8 and OA risk. Results: The study included 23,213 participants aged ≥20 years. After adjusting for latent confounders, higher LE8 scores were found to be associated with a lower incidence of OA. The odds ratios (with 95% confidence intervals) for low, moderate, and high OA risk were 0.81 (0.69, 0.96) and 0.55 (0.44, 0.69), respectively; a non-linear dose-response relationship was observed (P-nonlinear = 0.012). Health behavior and health factor scores showed a similar pattern of correlation with OA risk. Low live microbe intake mediated the association between LE8, health behavior, and health factor scores with OA risk and did not appear to reduce OA risk. Conclusion: Our findings suggest that although higher LE8 scores reduce the risk of developing OA, low live microbe intake may reduce the protective effect of higher scores. It is, therefore, essential to emphasize adherence to a lifestyle that confers high LE8 scores. Individuals should also be advised to reduce the intake of foods with low live microbe content.