Dendritome Mapping Unveils Spatial Organization of Striatal D1/D2-Neuron Morphology.

Morphology is a cardinal feature of a neuron that mediates its functions, but profiling neuronal morphologies at scale remains a formidable challenge. Here we describe a generalizable pipeline for large-scale brainwide study of dendritic morphology of genetically-defined single neurons in the mouse brain. We generated a dataset of 3,762 3D-reconstructed and reference-atlas mapped striatal D1- and D2- medium spiny neurons (MSNs). Integrative morphometric analyses reveal distinct impacts of anatomical locations and D1/D2 genetic types on MSN morphologies. To analyze striatal regional features of MSN dendrites without prior anatomical constraints, we assigned MSNs to a lattice of cubic boxes in the reference brain atlas, and summarized morphometric representation ("eigen-morph") for each box and clustered boxes with shared morphometry. This analysis reveals 6 modules with characteristic dendritic features and spanning contiguous striatal territories, each receiving distinct corticostriatal inputs. Finally, we found aging confers robust dendritic length and branching defects in MSNs, while Huntington's disease (HD) mice exhibit selective length-related defects. Together, our study demonstrates a systems-biology approach to profile dendritic morphology of genetically-defined single-neurons; and defines novel striatal D1/D2-MSN morphological territories and aging- or HD-associated pathologies.

Long non-coding RNAs expressed in mouse pituitary development and mature hormone-producing cells.

Mammalian genomes contain thousands of genes for long non-coding RNA (lncRNAs), some of which have been shown to affect protein-coding gene expression through diverse mechanisms. The lncRNA transcripts are longer than 200 nucleotides and are often capped, spliced and polyadenylated, but not translated into protein. Nuclear lncRNAs can modify chromatin structure and transcription in trans or cis by interacting with the DNA, forming R-loops, and recruiting regulatory proteins. Not much is known about the role of lncRNA in pituitary gland differentiation and function. We mined transcriptome data from mouse pituitary glands collected at embryonic days 12.5 and 14.5 and identified over 200 different lncRNA transcripts. To develop a research resource for the study of lncRNA, we used pituitary cre transgenes to tag pituitary cell types in adult mice with fluorescent markers, and enriched for thyrotropes, gonadotropes, and somatotropes using fluorescence activated cell sorting. We determined the transcriptome of each cell population using RNA sequencing and mined the data for lncRNA. We detected hundreds of lncRNAs in adult pituitary cells, a few were located immediately nearby genes that encode pituitary hormones or lineage-specific transcription factors. The location of these lncRNAs suggests the possibility of a cis-acting regulatory role in pituitary development or function, and we observe coordinated expression of two of them with their putative target genes in transgenic mice. This research resource sets the foundation for examining the actions of lncRNAs on their putative target genes and determining whether they have roles during development and in response to physiological demand.

The Residual Activity of Fatty Acyl-CoA Reductase Underlies Thermo-Sensitive Genic Male Sterility in Rice.

Photoperiod/thermo-sensitive genic male sterility (P/TGMS) is critical for rice two-line hybrid system. Previous studies showed that slow development of pollen is a general mechanism for sterility-to-fertility conversion of TGMS in Arabidopsis. However, whether this mechanism still exists in rice is unknown. Here, we identified a novel rice TGMS line, ostms16, which exhibits abnormal pollen exine under high temperature and fertility restoration under low temperature. In mutant, a single base mutation of OsTMS16, a fatty acyl-CoA reductase (FAR), reduced its enzyme activity, leading to defective pollen wall. Under high temperature, the mOsTMS16M549I couldn't provide sufficient protection for the microspores. Under low temperature, the enzyme activity of mOsTMS16M549I is closer to that of OsTMS16, so that the imperfect exine could still protect microspore development. These results indicated whether the residual enzyme activity in mutant could meet the requirement in different temperature is a determinant factor for fertility conversion of P/TGMS lines. Additionally, we previously found that res2, the mutant of a polygalacturonase for tetrad pectin wall degradation, restored multiple TGMS lines in Arabidopsis. In this study, we proved that the osres2 in rice restored the fertility of ostms16, indicating the slow development is also suitable for the fertility restoration in rice.

Machine learning discrimination and prediction of different quality grades of sauce-flavor baijiu based on biomarker and key flavor compounds screening.

The quality grade of base Baijiu directly determines the final quality of sauce-flavor Baijiu. However, traditional methods for assessing these grades often rely on subjective experience, lacking objectivity and accuracy. This study used GC-FID, combined with quantitative descriptive analysis (QDA) and odor activity value (OAV), to identify 27 key flavor compounds, including acetic acid, propionic acid, ethyl oleate, and isoamyl alcohol etc., as crucial contributors to quality grade differences. Sixteen bacterial biomarkers, including Komagataeibacter and Acetobacter etc., and 7 fungal biomarkers, including Aspergillus and Monascus etc., were identified as key microorganisms influencing these differences. Additionally, reducing sugar content in Jiupei significantly impacted base Baijiu quality. Finally, 11 machine learning classification models and 9 prediction models were evaluated, leading to the selection of the optimal model for accurate quality grade classification and prediction. This study provides a foundation for improving the evaluation system of sauce-flavor Baijiu and ensuring consistent quality.

Deep eutectic solvent (DES) pretreatment and lignin regeneration for the development of a bamboo leaf-based bioplastic.

The excessive utilization of petroleum-based plastic products has led to a pervasive environmental and human health threat. In response, the adoption of bioplastics derived from biomass has emerged as the foremost alternative to conventional plastics, owing to their inherent biodegradability and sustainability. The present study demonstrates the preparation of a biodegradable and cost-effective lignocellulosic bioplastic by utilizing dissolving bamboo leaf powder with deep eutectic solvents (DES) and regenerating lignin in situ. The DES was synthesized through a one-step heating and stirring method using choline chloride (ChCl) and anhydrous oxalic acid. The crystallinity of the bioplastics is enhanced by DES pretreatment, thereby improving the internal structural order of the material. Moreover, lignin regeneration reduces the pore size within the bioplastics and contributes to a more compact internal structure. The prepared lignocellulosic bioplastics exhibit remarkable mechanical strength, with a tensile strength of 113 MPa. Additionally, they demonstrate good water stability, as evidenced by a contact angle of 55.52°. Moreover, these bioplastics possess an exceptional biodegradability with a degradation rate exceeding 98% after 60 days. This study presents an innovative approach for the high-value utilization of bamboo leaf resources.

Effects of steel slag mixed substrate on rooting of Hydrangea macrophylla cuttings.

To investigate the effect of steel slag used as substrate on the rooting of Hydrangea macrophylla cuttings, and to develop a new mixed substrate that can partially replace conventional cutting substrates and realize the high-efficient utilization of solid waste, we examined the physical and chemical properties of different mixed substrates containing 10% (T1), 20% (T2), 30% (T3), and 40% (T4) volume fractions of steel slag, and investigated the rooting of H. macrophylla 'Red Beauty' cuttings growing on these substrates, with conventional cutting substrates (peat and perlite) as the control (CK). The results showed that pH value, electrical conductivity, and bulk density of the mixed substrates were significantly higher than those of CK. The aeration porosity of T2 was higher than other treatments, while the total porosity and water holding porosity differed little from others. Both fresh weight and dry weight of all the four treatments were higher than those of CK, with stem diameter being higher than that of CK (except T4), plant height showing no significant difference compared to CK (except T4), and leaf chlorophyll content being significantly lower than CK. Root length ranked as T2>CK>T1>T3>T4, the root surface area and root volume both ranked as T2>T1>CK>T4>T3, the root tip ranked as T2>CK>T1>T4>T3. Both average root diameter and root activity were significantly higher than that of CK, with the highest value being observed in T2. Soluble sugar content in the leaves of T2 was the highest, followed by T4, T3, CK, and T1. The weight ranking of root growth indices was root activity > average root diameter > root volume > root surface area > root tip number > root length. Redundancy analysis indicated that pH value, electrical conductivity, aeration porosity, and water holding porosity of substrates were key factors influencing root growth and development of cuttings. Our results suggested that substrates mixed with 10% to 40% steel slag could be used for H. macrophylla cutting propagation, and 20% (T2) being the best one because it could significantly improve the survival rate, growth status, and root development of cuttings. Steel slag would be a novel substrate to partially replace conventional unrenewable substrates such as peat and perlite for flower seedling propagation, which could reduce agricultural production cost and provide a high-value utilization way of industry solid waste.

Retinol-binding protein type 1 expression predicts poor prognosis in head and neck squamous cell carcinoma.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is the sixth most prevalent malignancy worldwide, with high incidence and poor survival rates. RBP1 is highly expressed in several kinds of cancer and plays a potential prognostic factor. However, the relationship between RBP1 and HNSCC were analyzed based on The Cancer Genome Atlas (TCGA) database. MATERIALS AND METHODS: RBP1 expression and clinical information were obtained from the Cancer Genome Atlas (TCGA) database. Tumor tissue and adjacent normal tissue of 6 HNSCC patients were collected to analyze the RBP1 mRNA expression level by quantitative PCR. Cox regression analysis was used to evaluate the prognostic values of RBP1 and clinical data in HNSCC. A nomogram was also established to predict the impact of RBP1 on prognosis based on Cox multivariate results. The methylation level of RBP1 in HNSC and its prognosis were analyzed in UALACN and MethSurv. Finally, the potential biological functions of RBP1 were investigated using gene set enrichment analysis (GSEA) and single sample GSEA (ssGSEA). RESULTS: The mRNA expression levels of RBP1 were highly expressed in HNSCC tissue. The Cox analyses demonstrate that highly-expressed RBP1 is an independent prognosis marker(P < 0.05). ROC curve analysis showed that performances of RBP1 (area under the ROC curve: 0.887, sensitivity: 84.1%, specificity: 79.9%). The methylation was increased in HNSCC patients compared with normal subjects(P < 0.05) and was associated with better prognosis at sites cg06208339, cg12298268, cg12497564, cg15288618, cg20532370, cg23448348. Additionally, RBP1 expression is mildly associated with immune cell infiltration and immunological checkpoints. CONCLUSION: RBP1 is overexpressed and associated with poor patient prognosis in head and neck squamous cell carcinoma.

Printing words in alternating colors facilitates eye movements among young and older Chinese adults.

It is well known that the Chinese writing system lacks visual cues for word boundaries, such as interword spaces. However, characters must be grouped into words or phrases for understanding, and the lack of interword spaces can cause certain ambiguity. In the current study, young and older Chinese adults' eye movements were recorded during their reading of naturally unspaced sentences, where consecutive words or nonwords were printed using alternating colors. The eye movements of both the Chinese young and older adults were clearly influenced by this explicit word boundary information. Across a number of eye-movement measures, in addition to a general age-related slowdown, the results showed that both groups benefited overall from the explicit color-based word boundary and experienced interference from the nonword boundary. Moreover, the manipulations showed stronger effects among the older adults. We discuss implications for practical application.

A global view on quantitative proteomic and metabolic analysis of rat livers under different hypoxia protocols.

Hypobaric hypoxia causes altitude sickness and significantly affects human health. As of now, focusing on rats different proteomic and metabolic changes exposed to different hypoxic times at extreme altitude is blank. Our study integrated in vivo experiments with tandem mass tag (TMT)- and gas chromatography time-of-flight (GC-TOF)-based proteomic and metabolomic assessments, respectively. Male Sprague-Dawley rats were exposed to long-term constant hypoxia for 40 days or short-term constant hypoxia for three days, and their responses were compared with those of a normal control group. Post-hypoxia, serum marker assays related to lipid metabolism revealed significant increases in the levels of low-density lipoprotein (LDL), triglycerides (TG), and total cholesterol (TC) in the liver. In contrast, high-density lipoprotein (HDL) levels were upregulated in the long-term constant hypoxia cohorts and were significantly reduced in the short-term constant hypoxia cohorts. Furthermore, metabolic pathway analysis indicated that glycerolipid and glycerophospholipid metabolisms were the most significantly affected pathways in long-term hypoxia group. Subsequently, RT-qPCR analyses were performed to corroborate the key regulatory elements, including macrophage galactose-type lectin (MGL) and Fatty Acid Desaturase 2 (FADS2). The results of this study provide new information for understanding the effects of different hypobaric hypoxia exposure protocols on protein expression and metabolism in low-altitude animals.

Investigating the genetic causal relationship between breast cancer and endometrial cancer: A two-sample Mendelian randomization study.

Observational studies have consistently shown a correlation between breast cancer (BC) and endometrial cancer (EC). Despite these findings, the causal relationship between these cancers has not been clearly defined. This research employed a bidirectional two-sample Mendelian randomization to explore the genetic causality between BC and EC. Genetic instruments for BC were derived from the Breast Cancer Association Consortium genome-wide association studies summary statistics, while for EC, data were sourced from the Endometrial Cancer Association Consortium, the Epidemiology of Endometrial Cancer Consortium, and the UK Biobank. The primary analytical method was inverse-variance weighted. Additional analyses, such as MR-Egger and weighted median, were conducted to validate the robustness of our findings from multiple perspectives. The MR-Egger intercept test was conducted to examine potential pleiotropy, whereas Cochrane Q test was implemented to assess heterogeneity. A leave-one-out analysis was conducted to assess the sensitivity of the observed association. Our analysis identified a bidirectional genetic causal relationship between estrogen receptor-positive breast cancer (ER+BC) and EC. Inverse-variance weighted analysis indicated an odds ratio of 1.0686 (95% confidence interval: 1.0029-1.1386, P = .0403) from ER+BC to EC and an odds ratio of 1.0692 (95% confidence interval: 1.0183-1.1225, P = .0071) from EC to ER+BC. No significant horizontal pleiotropy was detected. This study confirms a bidirectional genetic link between ER+BC and EC, suggesting shared genetic etiologies and possibly linked pathophysiological pathways. Understanding the genetic interplay between ER+BC and EC can enhance strategies for the precise prevention and screening of these prevalent cancers, potentially leading to improved clinical outcomes and management of secondary primary malignancies.

Interannual variability and spatial diversification of global urban tree cooling effects.

While widespread urban greening is documented, how these efforts translate into changes in a city's cooling potential remains unanswered. Here, we employed multi-satellite observations to assess the spatial dynamics and temporal variations in tree cooling efficiency (TCE) over 550 cities worldwide from 2002 to 2020. Our study identified substantial interannual variability of TCE across cities, especially in developing regions like Africa, Asia, and South America. Conversely, cities in Europe and the United States, characterized by a larger share of urban trees, exhibited a markedly lower degree of year-to-year fluctuations. Despite the prevalent urban vegetation expansion, which may not considerably enhance the cooling capability, we revealed a significant association between the tree cover level and the magnitude of temporal dynamics in TCE. This study highlights that tree cover improvement may play a crucial role in contributing to the stability of tree cooling potential under a changing climate.

Correction: A comparative study of the hypolipidemic effects and mechanisms of action of Laminaria japonica- and Ascophyllum nodosum-derived fucoidans in apolipoprotein E-deficient mice.

Correction for 'A comparative study of the hypolipidemic effects and mechanisms of action of Laminaria japonica- and Ascophyllum nodosum-derived fucoidans in apolipoprotein E-deficient mice' by Tian Liu et al., Food Funct., 2024, 15, 5955-5971, https://doi.org/10.1039/D3FO05521C.

Responses of Intestinal Antioxidant Capacity, Morphology, Barrier Function, Immunity, and Microbial Diversity to Chlorogenic Acid in Late-Peak Laying Hens.

This study examined the influence of chlorogenic acid (CGA) on gut antioxidant status, morphology, barrier function, immunity, and cecal microbiota in late-peak laying hens. A total of 240 Hy-Line Brown hens, aged 43 weeks, were randomly assigned to four groups, the basal diet +0, 400, 600, and 800 mg/kg CGA, for 12 weeks. The results revealed that CGA significantly reduced ileal H2O2 and malondialdehyde levels; increased duodenal height, ileal villus height, and villus height-to-crypt depth ratio; while decreasing jejunal crypt depth. The 600 and 800 mg/kg CGA significantly upregulated the duodenal, jejunal, and ileal ZO-1 and occludin gene expression; increased IgG levels in serum and ileum; and upregulated ileal IgA gene expression. The 600 mg/kg CGA significantly upregulated CD3D and CD4 gene expression, while downregulating IL-1ß gene expression in duodenum, jejunum, and ileum. Moreover, CGA changed the gut microbiota structure. The SCFA-producing bacteria unclassified_f__Peptostreptococcaceae, unclassified_f_Oscillospiraceae, Pseudoflavonifractor, Lachnospiraceae_FCS020_group, Oscillospira, Elusimicrobium, Eubacterium_ventriosum_group, Intestinimonas, and norank_f_Coriobacteriales_Incertae_Sedis were significantly enriched in the 400, 600, and/or 800 mg/kg CGA groups. The bacteria Lactobacillus, Bacillus, and Akkermansia were significantly enriched in the 600 mg/kg CGA group. Conclusively, dietary CGA (600-800 mg/kg) improved intestinal antioxidant status, morphology, barrier and immune function, and beneficial microbiota growth in late-peak laying hens.

Role and mechanism of histone demethylase PHF8 in weightlessness osteoporosis.

Weightlessness osteoporosis, which progresses continuously and has limited protective effects, has become one of the major problems that need to be solved in manned spaceflight. Our study aims to investigate the regulatory role of PHF8 in disuse osteoporosis by observing the expression of PHF8 in bone marrow mesenchymal stem cells (BMSCs) under simulated weightlessness conditions. Therefore, we used the model of ground-based microgravity simulated by disuse osteoporosis patients and tail suspension in mice to simulate microgravity in vivo, and measured the expression of PHF8 in bone tissue. Subsequently, we used the 2D gyroscope to simulate the weightless effect on bone marrow mesenchymal stem cells. In the weightless condition, we detected the proliferation, apoptosis, osteogenesis, and osteogenic differentiation functions of BMSCs. We also detected the expression of osteogenic-related transcription factors after knocking down and overexpressing PHF8. Our results show that the weightless effect can inhibit the proliferation, osteogenesis, and osteogenic differentiation functions of BMSCs, while enhancing their apoptosis; and overexpression of PHF8 can partially alleviate the osteoporosis caused by simulated weightlessness, providing new ideas and clues for potential drug targets to prevent weightlessness and disuse osteoporosis.

Non-cytotoxic levels of resveratrol enhance the anticancer effects of cisplatin by increasing the methyltransferase activity of CARM1 in human cancer cells.

BACKGROUND: Resveratrol (RSVL) is a plant-derived polyhydroxyphenolic compound with excellent anticancer properties, alone or in combination with other chemotherapeutic drugs. However, the anticancer mechanism of RSVL is diverse and high concentrations are often required for RSVL to exert its anticancer effect, which would also adversely affect normal cells. PURPOSE: The main objective of this study is to investigate the molecular mechanism of how non-cytotoxic concentrations of RSVL enhance the anticancer effect of cisplatin involving a newly identified RSVL-binding protein. METHODS: Cell viability of cell lines from three cancer types exposed to RSVL and/or cisplatin was measured by NBB staining assay. RSVL-binding proteins were identified using RSVL-bound CNBr-activated Sepharose 4B beads coupled with LC-MS/MS, and the binding between RSVL and novel RSVL-binding protein was further confirmed with an in vitro pull-down assay. The expression of proteins was examined by immunoblot analysis, and the activity of methyltransferase was evaluated by in vitro methylation assay. The methylation level of H3R17 in the gene promoter was investigated using ChIP-qPCR. Bioinformatics analysis was conducted to identify pathway enrichment of genes, predict drug sensitivity, and analyze the survival of cancer patients. RESULTS: Low doses of RSVL might promote cancer cell growth whereas high doses of RSVL showed cytotoxic effects on normal cells. When co-treated with a lower cisplatin dose, non-cytotoxic RSVL levels showed synergistic anticancer effects. Here, coactivator-associated arginine methyltransferase 1 (CARM1) was identified as a novel RSVL-binding protein, and we showed that the upregulation of CARM1 increased the sensitivity of cancer cells to RSVL. Interestingly, we found that CARM1 was essential in the RSVL-induced sensitivity of cisplatin. Further molecular mechanistic studies revealed that RSVL could stabilize CARM1 protein, resulting in the upregulation and increased methyltransferase activity of CARM1. Additionally, we showed that the methylation levels of H3R17 in the promoter of p21, a downstream gene of CARM1 involving cell cycle arrest, were significantly increased after RSVL treatment. Finally, data from our bioinformatics analysis suggested that CARM1 could be utilized as a potential biomarker for chemotherapeutic drug sensitivity and prognosis in cancers. CONCLUSIONS: This study identified CARM1 as a RSVL-binding protein for the first time and elucidated the potential roles of CARM1 in enhancing the efficacy of cisplatin by low doses of RSVL, which could have important clinical implications.

Interfacial Interaction between Zn2+ and Surface Functional Groups Impacting Self-Assembly of ZnO on Cellulose Nanofibrils.

The mechanism underlying the interfacial interaction between ZnO and surface functional groups, which drives the self-assembly of ZnO nanoflowers on the cellulose nanofibril (CNF) surface, remains inadequately understood. Moreover, the ideal sites for the loading and growth of ZnO nanoflowers on the oxygen atoms (Os) of various surface functional groups on the CNF surface are not well-defined. This work addressed these gaps by systematically regulating the size and surface charge density of CNF templates through minor surface modifications and adjustments in processing cycles by using an ultrafine grinder. Physicochemical analyses demonstrated that the ZnO nanoflowers exhibited sizes (µm)/pieces/thickness (nm) of 0.86/16/20.1 for ZnO/TOCNFs, 0.88/17/20.4 for ZnO/ACNFs, and 0.89/16/20.5 for ZnO/ECNFs, respectively. Simulation calculations revealed that the interaction between Zn2+ ions and the Os of hydroxyl (-OH) groups exhibited the most favorable binding energy of -31.7 kcal/mol. These findings suggested that the surface charge density rather than specific surface functional groups primarily governs the loading and growth of ZnO nanoflowers on the CNF surface. The OS from -OH groups on the surface of CNF templates were optimal for both the loading and growth of ZnO nanoflowers. Overall, this study provides crucial theoretical insights into the design and optimization of the ZnO/CNF composites.

Rhabdomyolysis associated with concomitant use of colchicine and statins in the real world: identifying the likelihood of drug-drug interactions through the FDA adverse event reporting system.

Background: Currently, there remains substantial controversy in research regarding whether the concomitant use of colchicine and statins increases the occurrence of rhabdomyolysis, warranting further substantiation. Objective: This study aimed to identify the likelihood drug-drug interactions (DDIs) for the co-administration of colchicine and statins resulting in rhabdomyolysis. Methods: A disproportionality analysis was conducted by using data sourced from the US Food and Drug Administration Adverse Event Reporting System (FAERS) to detect rhabdomyolysis signals associated with the combined use of colchicine and statins. The association between (colchicine/statins/colchicine and statins) and rhabdomyolysis were evaluated using information component (IC). DDI signals were calculated based on the Ω shrinkage measure and Bayesian confidence propagation neural network (BCPNN) method. Furthermore, stratification was performed based on colchicine and individual statins agents. Results: In total, 11,119 reports of rhabdomyolysis were identified in the FAERS database, 255 (2.29%) involved both colchicine and statins. Our analysis showed potential DDI signals of rhabdomyolysis (Ω025 = 1.17) among individuals concurrent use of colchicine and statins. Moreover, further drug-specific analysis suggests DDI signals in the colchicine-atorvastatin pair (Ω025 = 1.12), and colchicine-rosuvastatin pair (Ω025 = 1.05), along with a higher proportion of rhabdomyolysis (IC025 = 5.20) and (IC025 = 4.26), respectively. Conclusion: The findings suggest that concomitant use of colchicine and statins may increase the risk of rhabdomyolysis, particularly when combined with atorvastatin or rosuvastatin. Therefore, healthcare professionals should pay special attention to life-threatening AE such as rhabdomyolysis, when co-prescribing colchicine statins.

Epigenomic biomarkers insights in PBMCs for prognostic assessment of ECMO-treated cardiogenic shock patients.

OBJECTIVE: As the global use of extracorporeal membrane oxygenation (ECMO) treatment increases, survival rates have not correspondingly improved, emphasizing the need for refined patient selection to optimize resource allocation. Currently, prognostic markers at the molecular level are limited. METHODS: Thirty-four cardiogenic shock (CS) patients were prospectively enrolled, and peripheral blood mononuclear cells (PBMCs) were collected at the initiation of ECMO (t0), two-hour post-installation (t2), and upon removal of ECMO (tr). The PBMCs were analyzed by comprehensive epigenomic assays. Using the Wilcoxon signed-rank test and least absolute shrinkage and selection operator (LASSO) regression, 485,577 DNA methylation features were analyzed and selected from the t0 and tr datasets. A random forest classifier was developed using the t0 dataset and evaluated on the t2 dataset. Two models based on DNA methylation features were constructed and assessed using receiver operating characteristic (ROC) curves and Kaplan-Meier survival analyses. RESULTS: The ten-feature and four-feature models for predicting in-hospital mortality attained area under the curve (AUC) values of 0.78 and 0.72, respectively, with LASSO alpha values of 0.2 and 0.25. In contrast, clinical evaluation systems, including ICU scoring systems and the survival after venoarterial ECMO (SAVE) score, did not achieve statistical significance. Moreover, our models showed significant associations with in-hospital survival (p < 0.05, log-rank test). CONCLUSIONS: This study identifies DNA methylation features in PBMCs as potent prognostic markers for ECMO-treated CS patients. Demonstrating significant predictive accuracy for in-hospital mortality, these markers offer a substantial advancement in patient stratification and might improve treatment outcomes.

Identification of Chemical Scaffolds That Inhibit the Mycobacterium tuberculosis Respiratory Complex Succinate Dehydrogenase.

Drug-resistant Mycobacterium tuberculosis is a significant cause of infectious disease morbidity and mortality for which new antimicrobials are urgently needed. Inhibitors of mycobacterial respiratory energy metabolism have emerged as promising next-generation antimicrobials, but a number of targets remain unexplored. Succinate dehydrogenase (SDH), a focal point in mycobacterial central carbon metabolism and respiratory energy production, is required for growth and survival in M. tuberculosis under a number of conditions, highlighting the potential of inhibitors targeting mycobacterial SDH enzymes. To advance SDH as a novel drug target in M. tuberculosis, we utilized a combination of biochemical screening and in-silico deep learning technologies to identify multiple chemical scaffolds capable of inhibiting mycobacterial SDH activity. Antimicrobial susceptibility assays show that lead inhibitors are bacteriostatic agents with activity against wild-type and drug-resistant strains of M. tuberculosis. Mode of action studies on lead compounds demonstrate that the specific inhibition of SDH activity dysregulates mycobacterial metabolism and respiration and results in the secretion of intracellular succinate. Interaction assays demonstrate that the chemical inhibition of SDH activity potentiates the activity of other bioenergetic inhibitors and prevents the emergence of resistance to a variety of drugs. Overall, this study shows that SDH inhibitors are promising next-generation antimicrobials against M. tuberculosis.

Perioperative toripalimab plus neoadjuvant chemotherapy might improve outcomes in resectable esophageal cancer: an interim analysis of a phase III randomized clinical trial.

BACKGROUND: In the era of immunotherapy, neoadjuvant immunochemotherapy (NAIC) for the treatment of locally advanced esophageal squamous cell carcinoma (ESCC) is used clinically but lacks of high-level clinical evidence. This study aimed to compare the safety and long-term efficacy of NAIC followed by minimally invasive esophagectomy (MIE) with those of neoadjuvant chemotherapy (NAC) followed by MIE. METHODS: A prospective, single-center, open-label, randomized phase III clinical trial was conducted at Henan Cancer Hospital, Zhengzhou, China. Patients were randomly assigned to receive either neoadjuvant toripalimab (240 mg) plus paclitaxel (175 mg/m2) + cisplatin (75 mg/m2) (toripalimab group) or paclitaxel + cisplatin alone (chemotherapy group) every 3 weeks for 2 cycles. After surgery, the toripalimab group received toripalimab (240 mg every 3 weeks for up to 6 months). The primary endpoint was event-free survival (EFS). The pathological complete response (pCR) and overall survival (OS) were key secondary endpoints. Adverse events (AEs) and quality of life were also assessed. RESULTS: Between May 15, 2020 and August 13, 2021, 252 ESCC patients ranging from T1N1-3M0 to T2-3N0-3M0 were enrolled for interim analysis, with 127 in the toripalimab group and 125 in the chemotherapy group. The 1-year EFS rate was 77.9% in the toripalimab group compared to 64.3% in the chemotherapy group (hazard ratio [HR] = 0.62; 95% confidence interval [CI] = 0.39 to 1.00; P = 0.05). The 1-year OS rates were 94.1% and 83.0% in the toripalimab and chemotherapy groups, respectively (HR = 0.48; 95% CI = 0.24 to 0.97; P = 0.037). The patients in the toripalimab group had a higher pCR rate (18.6% vs. 4.6%; P = 0.001). The rates of postoperative Clavien-Dindo grade IIIb or higher morbidity were 9.8% in the toripalimab group and 6.8% in the chemotherapy group, with no significant difference observed (P = 0.460). The rates of grade 3 or 4 treatment-related AEs did not differ between the two groups (12.5% versus 12.4%). CONCLUSIONS: The interim results of this ongoing trial showed that in resectable ESCC, the addition of perioperative toripalimab to NAC is safe, may improve OS and might change the standard treatment in the future.