Association of preoperative and recurrent serum carcinoembryonic antigen and outcome of colorectal cancer patients with metastatic relapse.

Background: Seldom have the associations of preoperative CEA (p-CEA) and recurrent CEA (r-CEA) levels as well as changes in p-CEA and r-CEA with survival in patients with stage I-III colorectal cancer (CRC) who have experienced metastatic relapse, been thoroughly examined. Methods: 241 consecutive patients with stage I-III CRC who experienced metastatic relapse at Fudan University Shanghai Cancer Center (FUSCC) between January 2008 and January 2016 were investigated. The influence of p-CEA, r-CEA and CEA alteration on the overall survival (OS) and relapse-to-death survival (RDS) was evaluated. The restricted cubic spline regression model was employed to explore the optimal cut-off value of CEA. Results: All 241 patients were categorized into four groups built on their CEA alteration patterns as follows: A, patients presenting elevated p-CEA levels but normal r-CEA levels (P-N); B, patients displaying normal levels of both p-CEA and r-CEA (N-N); C, patients exhibiting elevated levels of both p-CEA and r-CEA (P-P); D, patients with normal p-CEA levels but elevated r-CEA levels (N-P). The correlation between p-CEA and OS (P = 0.3266) and RDS (P = 0.2263) was insignificant. However, r-CEA exhibited a significant association with both OS (P = 0.0005) and RDS (P = 0.0002). Group A demonstrated the longest OS and RDS, whereas group D exhibited the poorest OS and RDS outcomes. For both OS and RDS, the CEA alteration groups served as an independent prognostic indicator. The optimal cut-off threshold for CEA was determined to be 5.1 ng/ml via the restricted cubic spline regression model. Conclusion: r-CEA has a stronger correlation with OS and RDS in individuals with stage I-III CRC who have experienced metastatic relapse.The change between p-CEA and r-CEA could further indicate post-relapse survival, thereby facilitating the assessment of mortality risk stratification in stage I-III CRC patients experiencing metastatic relapse.

Comparative analysis of codon usage patterns in the chloroplast genomes of nine forage legumes.

Leguminosae is one of the three largest families of angiosperms after Compositae and Orchidaceae. It is widely distributed and grows in a variety of environments, including plains, mountains, deserts, forests, grasslands, and even waters where almost all legumes can be found. It is one of the most important sources of starch, protein and oil in the food of mankind and also an important source of high-quality forage material for animals, which has important economic significance. In our study, the codon usage patterns and variation sources of the chloroplast genome of nine important forage legumes were systematically analyzed. Meanwhile, we also constructed a phylogenetic tree based on the whole chloroplast genomes and protein coding sequences of these nine forage legumes. Our results showed that the chloroplast genomes of nine forage legumes end with A/T bases, and seven identical high-frequency (HF) codons were detected among the nine forage legumes. ENC-GC3s mapping, PR2 analysis, and neutral analysis showed that the codon bias of nine forage legumes was influenced by many factors, among which natural selection was the main influencing factor. The codon usage frequency showed that the Nicotiana tabacum and Saccharomyces cerevisiae can be considered as receptors for the exogenous expression of chloroplast genes of these nine forage legumes. The phylogenetic relationships of the chloroplast genomes and protein coding genes were highly similar, and the nine forage legumes were divided into three major clades. Among the clades Melilotus officinalis was more closely related to Medicago sativa, and Galega officinalis was more closely related to Galega orientalis. This study provides a scientific basis for the molecular markers research, species identification and phylogenetic studies of forage legumes. Supplementary Information: The online version contains supplementary material available at 10.1007/s12298-024-01421-0.

Social isolation and the risk of Parkinson disease in the UK biobank study.

Parkinson disease (PD) has become one of the most rapidly growing causes of disability among the older population and social isolation is a major concern in the PD community. However, the relationship between social isolation and future risk of PD remains unclear. This study included 192,340 participants aged 60 or older who were free of dementia and PD at baseline from the UK Biobank study. Social isolation was measured using a composite score derived from three questions on number in household, frequency of friend/family visits, and leisure/social activities. Incident PD cases were identified through electronic health records. Multivariable-adjusted Cox regression models were used to compute the hazard ratio (HR) and 95% confidence interval (CI). Among the 192,340 participants (mean [standard deviation] age, 64.2 [2.9] years; 103,253 [53.7%] women), 89,075 (46.3%) participants were in the least isolated group and 26,161 (13.6%) were in the most isolated group. Over a median follow-up of 12.5 years, 2048 incident PD cases were documented. Compared to the least isolated group, the multivariable-adjusted HRs (95% CIs) for PD were 1.00 (0.91-1.10) for the moderately isolated group and 1.19 (1.05-1.36) for the most isolated group (P-trend = 0.04). The observed association was independent of the genetic susceptibility to PD and consistent in subgroup analyses. Social isolation was associated with a higher risk of PD regardless of genetic risk. Our findings highlighted the importance of developing screening and intervention strategies for social isolation among older adults to reduce the risk of PD.

Transcriptomic Analysis of Alternative Splicing Events during Different Fruit Ripening Stages of Coffea arabica L.

To date, genomic and transcriptomic data on Coffea arabica L. in public databases are very limited, and there has been no comprehensive integrated investigation conducted on alternative splicing (AS). Previously, we have constructed and sequenced eighteen RNA-seq libraries of C. arabica at different ripening stages of fruit development. From this dataset, a total of 3824, 2445, 2564, 2990, and 3162 DSGs were identified in a comparison of different fruit ripening stages. The largest proportion of DSGs, approximately 65%, were of the skipped exon (SE) type. Biologically, 9 and 29 differentially expressed DSGs in the spliceosome pathway and carbon metabolism pathway, respectively, were identified. These DSGs exhibited significant variations, primarily in S1 vs. S2 and S5 vs. S6, and they involve many aspects of organ development, hormone transduction, and the synthesis of flavor components. Through the examination of research findings regarding the biological functions and biochemical pathways associated with DSGs and DEGs, it was observed that six DSGs significantly enriched in ABC transporters, namely, LOC113712394, LOC113726618, LOC113739972, LOC113725240, LOC113730214, and LOC113707447, were continually down-regulated at the fruit ripening stage. In contrast, a total of four genes, which were LOC113732777, LOC113727880, LOC113690566, and LOC113711936, including those enriched in the cysteine and methionine metabolism, were continually up-regulated. Collectively, our findings may contribute to the exploration of alternative splicing mechanisms for focused investigations of potential genes associated with the ripening of fruits in C. arabica.

Stress response membrane protein gene OsSMP2 negatively regulates rice tolerance to drought.

In our gene chip analysis, OsSMP2 gene expression was induced under various abiotic stresses, prompting an investigation into its role in drought resistance and ABA signaling. Subsequent experiments, including qRT-PCR and GUS activity detection, affirmed the OsSMP2 gene's predominant induction by drought stress. Subcellular localization experiments indicated the OsSMP2 protein primarily localizes to the cell membrane system. Overexpressing OsSMP2 increased sensitivity to exogenous ABA, reducing drought resistance and leading to reactive oxygen species accumulation under drought stress. Conversely, in simulated drought experiments, OsSMP2-silenced transgenic plants showed significantly longer root lengths compared to the wild-type Nipponbare. These results suggest that OsSMP2 overexpression negatively affects rice drought resistance, offering valuable insights into molecular mechanisms and proposing OsSMP2 as a potential target for enhancing crop resilience to drought stress.

Association of Cancer History with Lifetime Risk of Dementia and Alzheimer's Disease.

Background: The literature presents conflicting results regarding the potential protective effect of prevalent cancer on the development of dementia and Alzheimer's disease (AD). Objective: Association between cancer and subsequent risk of dementia and/or AD was reported previously, but survival bias has been of concern. Here, we aimed to calculate the lifetime risk of dementia and AD and evaluate the association of cancer history with these two conditions. Methods: In this retrospective analysis, we included 292,654 participants aged 60+ y during the follow-up and free of dementia at baseline, within the UK Biobank cohort. Lifetime risks of dementia and AD were estimated in individuals with and without cancer history, and different durations of cancer exposure and cancer types. Results: During a median of 12.5 follow-up years, 5,044 new dementia and 2,141 AD cases were reported. Lifetime risks of dementia and AD were lower in cancer survivors compared to those without cancer, and this effect was more pronounced in participants with cancer history exposure≥5 years. Similar relationship was observed in individual cancer types, except for breast cancer. Conclusions: Results suggested an inverse association between cancer history and lifetime risk of dementia and AD, which may be modified by different cancer types and cancer exposure time.

Association between gardening and multiple sleep complaints: A nationwide study of 62,098 adults.

BACKGROUND: Physical activity was suggested to be related to sleep health, while the gardening-sleep association among the community population remained unrevealed. Therefore, this study aimed to explore whether gardening was associated with sleep complaints. METHODS: A total of 62,098 adults from the 2017 Behavioral Risk Factor Surveillance System (BRFSS) were included in this study and further categorized as non-exercisers, gardeners, and other exercisers, based on their self-reported exercise status. Sleep complaints including short/prolonged sleep duration, probable insomnia, daytime sleepiness, and sleep apnea were surveyed via a questionnaire. Primary outcome was multiple sleep complaints (coexistence of ≥2 sleep complaints) and secondary outcomes referred to individual sleep complaints. The adjusted odds ratios (ORs) and 95 % confidence intervals (CIs) were estimated to assess the associations between gardening or tertiles of gardening duration and the outcomes using multivariable logistic regression models. RESULTS: The sample included 16,707 non-exercisers, 4243 gardeners, and 41,148 other exercisers. Relative to non-exercisers, gardeners (OR 0.58, 95%CI 0.49-0.67) and other exercisers (OR 0.67, 95%CI 0.61-0.72) had a lower likelihood of experiencing multiple sleep complaints. The adjusted OR comparing the highest gardening duration tertile to non-exercise was 0.45 (95%CI 0.33-0.63) for multiple sleep complaints (P for trend <0.001). Similar patterns persisted in several individual sleep complaints, such as short sleep duration, probable insomnia, daytime sleepiness, and sleep apnea. LIMITATIONS: Cross-sectional study design and use of self-reported variables. CONCLUSIONS: This nationwide study observed an inverse association of gardening with multiple sleep complaints and several individual sleep complaints, in a dose-response manner.

Exploratory Study of the Phase IV Immunization Schedule of Quadrivalent Influenza Split-Virion Vaccine in Children Aged 3-8 Years.

This study explored the optimum immunization schedule for the quadrivalent influenza split-virion vaccine containing influenza A strains (H1N1 and H3N2) and B lineage strains (Yamagata and Victoria) in children aged 3-8 years. The 652 participants enrolled were divided into two groups based on a history of influenza immunization (IH group) or no history of influenza immunization (NH group). The groups were administered a two-dose immunization schedule on days 0 and 30. In the NH group, on day 30 after the first dose, the positive rates of influenza hemagglutination-inhibition antibodies of strains H1N1, H3N2, BV, and BY were 85.85%, 71.70%, 65.27% and 60.45%, respectively. The positive rates of BV and BY failed to meet the absolute criteria for evaluating the immunogenicity of influenza vaccine in the population aged 3-60 years (for each strain antibody). On day 30 after the second dose, HI antibodies to strains H1N1, H3N2, BV, and BY met the immunogenicity acceptable criteria. In the IH group, on day 30 after the first dose, HI antibodies to strains H1N1, H3N2, BV, and BY met the acceptable criteria for immunogenicity. The incidence rates of adverse reactions (vaccine-related adverse events) from the first dose up until 30 days after the second dose were 20.80% in the IH group and 19.50% in the NH group. Only two Grade 3 adverse reactions (fever: temperature ≥ 39.5 °C, swelling: area ≥ 50% of the injection site area) occurred in the IH group, and no Grade 3 adverse reactions occurred in the NH group. No serious adverse reactions occurred in either group. We conclude that for the NH group, two doses of quadrivalent influenza vaccine should be administered, and for the IH group, a one-dose regimen is acceptable.

Prevalence of intestinal trichomonads in captive non-human primates in China.

Trichomonads are protozoan symbionts with the capacity to infect vertebrates including humans and non-human primates (NHPs), sometimes with pathogenic effects. However, their diversity and prevalence in NHPs in China are poorly understood. A total of 533 fecal samples were collected from captive NHPs in Yunnan Province, China, of which 461 samples from Macaca fascicularis and 72 from Macaca mulatta. Trichomonadidae species were identified using PCR amplification of the ITS-1/5.8S/ITS-2 sequences. The overall prevalence of trichomonads in NHPs was determined to be 11.4% (61/533), with gender, diarrhea, and region identified as potential risk factors for the infections. Sequence alignment and phylogenetic analysis identified three species of trichomonads, i.e., Trichomitopsis minor (n = 45), Pentatrichomonas hominis (n = 11), and Tetratrichomonas sp. (n = 5). To the best of our knowledge, this is the first study to report Trichomitopsis minor infection in NHPs in China. Of note, Pentatrichomonas hominis is generally recognized as a parasitic organism affecting humans. Collectively, our results suggest that NHPs are potential sources of zoonotic trichomonad infections, highlighting the importance of surveillance and control measures to protect human and animal populations.

Title: Prévalence des Trichomonadidae intestinaux chez les primates non humains captifs en Chine. Abstract: Les Trichomonadidae sont des symbiotes protozoaires capables d'infecter les vertébrés, notamment les humains et les primates non humains (PNH), parfois avec des effets pathogènes. Cependant, leur diversité et leur prévalence chez les PNH en Chine sont mal comprises. Au total, 533 échantillons fécaux ont été collectés sur des PNH captifs dans la province du Yunnan, en Chine, dont 461 échantillons de Macaca fascicularis et 72 de Macaca mulatta. Les espèces de Trichomonadidae ont été identifiées par amplification PCR des séquences ITS-1/5.8S/ITS-2. La prévalence globale des Trichomonadidae dans les PNH a été déterminée à 11,4 % (61 / 533) et le sexe, la diarrhée et la région ont été identifiés comme facteurs de risque potentiels d'infection. L'alignement des séquences et l'analyse phylogénétique ont identifié trois espèces de Trichomonadidae, à savoir Trichomitopsis minor (n = 45), Pentatrichomonas hominis (n = 11) et Tetratrichomonas sp. (n = 5). À notre connaissance, il s'agit de la première étude à signaler une infection par Trichomitopsis minor chez les PNH en Chine. Il convient de noter que Pentatrichomonas hominis est généralement reconnu comme un organisme parasitaire affectant les humains. Collectivement, nos résultats suggèrent que les PNH sont des sources potentielles d'infections zoonotiques à Trichomonadidae, soulignant l'importance des mesures de surveillance et de contrôle pour protéger les populations humaines et animales.

PLA2G4A and ACHE modulate lipid profiles via glycerophospholipid metabolism in platinum-resistant gastric cancer.

BACKGROUND: Bioactive lipids involved in the progression of various diseases. Nevertheless, there is still a lack of biomarkers and relative regulatory targets. The lipidomic analysis of the samples from platinum-resistant in gastric cancer patients is expected to help us further improve our understanding of it. METHODS: We employed LC-MS based untargeted lipidomic analysis to search for potential candidate biomarkers for platinum resistance in GC patients. Partial least squares discriminant analysis (PLS-DA) and variable importance in projection (VIP) analysis were used to identify differential lipids. The possible molecular mechanisms and targets were obtained by metabolite set enrichment analysis and potential gene network screened. Finally, verified them by immunohistochemical of a tissue microarray. RESULTS: There were 71 differential lipid metabolites identified in GC samples between the chemotherapy-sensitivity group and the chemotherapy resistance group. According to Foldchange (FC) value, VIP value, P values (FC > 2, VIP > 1.5, p < 0.05), a total of 15 potential biomarkers were obtained, including MGDG(43:11)-H, Cer(d18:1/24:0) + HCOO, PI(18:0/18:1)-H, PE(16:1/18:1)-H, PE(36:2) + H, PE(34:2p)-H, Cer(d18:1 + hO/24:0) + HCOO, Cer(d18:1/23:0) + HCOO, PC(34:2e) + H, SM(d34:0) + H, LPC(18:2) + HCOO, PI(18:1/22:5)-H, PG(18:1/18:1)-H, Cer(d18:1/24:0) + H and PC(35:2) + H. Furthermore, we obtained five potential key targets (PLA2G4A, PLA2G3, DGKA, ACHE, and CHKA), and a metabolite-reaction-enzyme-gene interaction network was built to reveal the biological process of how they could disorder the endogenous lipid profile of platinum resistance in GC patients through the glycerophospholipid metabolism pathway. Finally, we further identified PLA2G4A and ACHE as core targets of the process by correlation analysis and tissue microarray immunohistochemical verification. CONCLUSION: PLA2G4A and ACHE regulated endogenous lipid profile in the platinum resistance in GC patients through the glycerophospholipid metabolism pathway. The screening of lipid biomarkers will facilitate earlier precision medicine interventions for chemotherapy-resistant gastric cancer. The development of therapies targeting PLA2G4A and ACHE could enhance platinum chemotherapy effectiveness.

Trends in Calcium Intake among the US Population: Results from the NHANES (1999-2018).

Inadequate calcium intake is common in the US. Trends in calcium intake among the US population have been less studied, especially in more recent years. We used data from the National Health and Nutrition Examination Survey (NHANES) 1999-2000 to 2017-2018 to study trends in calcium derived from diet and dietary supplements among the US population aged 2 years, stratified by sex, age group, race, and ethnicity. Among the 80,880 participants included in our study, a substantial portion consistently lacked sufficient calcium intake, even when considering calcium from supplements. Concerning trends were observed over the more recent ten years (2009-2018), with decreased dietary calcium intake and no significant improvement in the prevalence of dietary calcium intake < Estimated Average Requirement (EAR) or the prevalence of taking calcium-containing dietary supplements among them. Decreasing trends in dietary calcium intake were more concerning among men, children, and non-Hispanic Whites. Attention should be given to subgroups with higher calcium intake requirements (e.g., 9-18 years and 60+ years), and subgroups with low levels of dietary calcium and a low prevalence of obtaining calcium from dietary supplements (e.g., the non-Hispanic Black subgroup). Concerning trends of calcium intake were observed among the US population from 2009 to 2018. Tailored guidance on dietary choices and dietary supplement use is required to change consumers' behaviors.

Personalized circulating tumor DNA monitoring improves recurrence surveillance and management after curative resection of colorectal liver metastases: A prospective cohort study.

BACKGROUND: Approximately 60% of patients with CRLM experience relapse within 2 years after radical resection, previous studies have proven that repeat local treatment (LT) could prolong survival, however, it is difficult to seize the window for LT due to the lack of a high-sensitive surveillance method. In this study, we aim to examine the value of longitudinal circulating tumor DNA (ctDNA) in guiding adjuvant chemotherapy (ACT), optimizing clinical surveillance strategy, and thereby improving CRLM outcomes. MATERIALS AND METHODS: We conducted a prospective clinical trial using a personalized, tumor-informed ctDNA assay to monitor 60 CRLM patients undergoing resection with curative intent. Formalin-fixed paraffin-embedded (FFPE) tumor samples were collected after surgery. Blood samples were collected before surgery, 30 days after surgery (post-OP), and every third month until relapse or up to 2 years. RESULTS: A total of 394 plasma samples from 60 eligible patients were analyzed, with a median follow-up time of 31.3 months. Landmark analyses revealed that detectable ctDNA at post-OP (HR, 4.8), post-ACT (HR, 6.0), and end-of-treatment (EOT) (HR, 5.6) were associated with higher recurrence risk (P < 0.001). Post-OP ctDNA positivity served as the only independent prognostic marker in the multivariant analysis (HR, 5.1; P < 0.001). Longitudinal ctDNA analysis identified relapsed patients at both sensitivity and specificity of 100%. Most (75%) patients were found with radiological relapse within 6 months after the first detectable ctDNA with a median lead time of 3.5 months. In relapsed patients, 73.2% had oligometastatic disease and 61% were liver-restricted, of which 72.0% received repeat LTs, and 60.0% achieved a secondary no evidence of disease (NED) status. CONCLUSIONS: Longitudinal ctDNA monitoring assists in early prediction of relapse, and thereby improves survival of CRLM patients by increased secondary resection rate and secondary NED rate.

D-A Conjugated Polymer/CdS S-Scheme Heterojunction with Enhanced Interfacial Charge Transfer for Efficient Photocatalytic Hydrogen Generation.

Owing to the improved charge separation and maximized redox capability of the system, Step-scheme (S-scheme) heterojunctions have garnered significant research attention for efficient photocatalysis of H2 evolution. In this work, an innovative linear donor-acceptor (D-A) conjugated polymer fluorene-alt-(benzo-thiophene-dione) (PFBTD) is coupled with the CdS nanosheets, forming the organic-inorganic S-scheme heterojunction. The CdS/PFBTD (CP) composite exhibits an impressed hydrogen production rate of 7.62 mmol g-1  h-1 without any co-catalysts, which is ≈14 times higher than pristine CdS. It is revealed that the outstanding photocatalytic performance is attributed to the formation of rapid electron transfer channels through the interfacial Cd─O bonding as evidenced by the density functional theory (DFT) calculations and in situ X-ray photoelectron spectroscopy (XPS) analysis. The charge transfer mechanism involved in S-scheme heterojunctions is further investigated through the photo-irradiated Kelvin probe force microscopy (KPFM) analysis. This work provides a new point of view on the mechanism of interfacial charge transfer and points out the direction of designing superior organic-inorganic S-scheme heterojunction photocatalysts.

Plasma metabolomic profile in orthostatic intolerance children with high levels of plasma homocysteine.

BACKGROUND: Orthostatic intolerance, which includes vasovagal syncope and postural orthostatic tachycardia syndrome, is common in children and adolescents. Elevated plasma homocysteine levels might participate in the pathogenesis of orthostatic intolerance. This study was designed to analyze the plasma metabolomic profile in orthostatic intolerance children with high levels of plasma homocysteine. METHODS: Plasma samples from 34 orthostatic intolerance children with a plasma homocysteine concentration > 9 µmol/L and 10 healthy children were subjected to ultra-high-pressure liquid chromatography and quadrupole-time-of-flight mass spectrometry analysis. RESULTS: A total of 875 metabolites were identified, 105 of which were significantly differential metabolites. Choline, 1-stearoyl-2-linoleoyl-sn-glycero-3-phosphocholine, 1-(1Z-octadecenyl)-2-(4Z,7Z,10Z,13Z,16Z,19Z-docosahexaenoyl)-sn-glycero-3-phosphocholine, histidine, isocitric acid, and DL-glutamic acid and its downstream metabolites were upregulated, whereas 1-palmitoyl-sn-glycero-3-phosphocholine, 1-stearoyl-sn-glycerol 3-phosphocholine, sphingomyelin (d18:1/18:0), betaine aldehyde, hydroxyproline, and gamma-aminobutyric acid were downregulated in the orthostatic intolerance group compared with the control group. All these metabolites were related to choline and glutamate. Heatmap analysis demonstrated a common metabolic pattern of higher choline, 1-stearoyl-2-linoleoyl-sn-glycero-3-phosphocholine, and DL-glutamic acid, and lower sphingomyelin (d18:1/18:0), 1-stearoyl-sn-glycerol 3-phosphocholine, and 1-palmitoyl-sn-glycero-3-phosphocholine in patients with certain notable metabolic changes (the special group) than in the other patients (the common group). The maximum upright heart rate, the change in heart rate from the supine to the upright position, and the rate of change in heart rate from the supine to the upright position of vasovagal syncope patients were significantly higher in the special group than in the common group (P < 0.05). Choline, 1-stearoyl-2-linoleoyl-sn-glycero-3-phosphocholine, and DL-glutamic acid were positively correlated with the rate of change in heart rate from the supine to the upright position in vasovagal syncope patients (P < 0.05). CONCLUSIONS: The levels of choline-related metabolites and glutamate-related metabolites changed significantly in orthostatic intolerance children with high levels of plasma homocysteine, and these changes were associated with the severity of illness. These results provided new light on the pathogenesis of orthostatic intolerance.

Nobiletin targets SREBP1/ACLY to induce autophagy-dependent cell death of gastric cancer cells through PI3K/Akt/mTOR signaling pathway.

BACKGROUND: Autophagy could sense metabolic conditions and safeguard cells against nutrient deprivation, ultimately supporting the survival of cancer cells. Nobiletin (NOB) is a kind of bioactive component of the traditional Chinese medicine Citri Reticulatae Pericarpium and has been proven to induce GC cell death by reducing de novo fatty acid synthesis in our previous study. Nevertheless, the precise mechanisms by which NOB induces cell death in GC cells still need further elucidation. OBJECTIVES: To examine the mechanism by which NOB inhibits gastric cancer progression through the regulation of autophagy under the condition of lipid metabolism inhibition. METHODS/ STUDY DESIGN: Proliferation was detected by the CCK-8 assay. RNA sequencing (RNA-seq) was used to examine signaling pathway changes. Electron microscopy and mRFP-GFP-LC3 lentiviral transfection were performed to observe autophagy in vitro. Western blot, plasmid transfection, immunofluorescence staining, and CUT & Tag-qPCR techniques were utilized to explore the mechanisms by which NOB affects GC cells. Molecular docking and molecular dynamics simulations were conducted to predict the binding mode of NOB and SREBP1. CETSA was adopted to verify the predicted of binding model. A patient-derived xenograft (PDX) model was employed to verify the therapeutic efficacy of NOB in vivo. RESULTS: We conducted functional studies and discovered that NOB inhibited the protective effect of autophagy via the PI3K/Akt/mTOR axis in GC cells. Based on previous research, we found that the overexpression of ACLY abrogated the NOB-induced autophagy-dependent cell death. In silico analysis predicted the formation of a stable complex between NOB and SREBP1. In vitro assays confirmed that NOB treatment increased the thermal stability of SREBP1 at the same temperature conditions. Moreover, CUT&TAG-qPCR analysis revealed that NOB could inhibit SREBP1 binding to the ACLY promoter. In the PDX model, NOB suppressed tumor growth, causing SREBP1 nuclear translocation inhibition, PI3K/Akt/mTOR inactivation, and autophagy-dependent cell death. CONCLUSION: NOB demonstrated the ability to directly bind to SREBP1, inhibiting its nuclear translocation and binding to the ACLY promoter, thereby inducing autophagy-dependent cell death via PI3K/Akt/mTOR pathway.

Study protocol of short-course radiotherapy combined with CAPOX and PD-1 inhibitor for locally advanced colon cancer: a randomised, prospective, multicentre, phase II trial (TORCH-C).

INTRODUCTION: The preliminary result of the TORCH trial has shown a promising complete response (CR) for managing locally advanced rectal cancer with neoadjuvant short-course radiotherapy (SCRT) combined with chemotherapy and PD-1 inhibitor. For locally advanced colon cancer (LACC) with bulky nodal disease and/or clinically T4, neoadjuvant chemotherapy followed by colectomy with en bloc removal of regional lymph nodes is the suggested treatment. However, the CR rate is less than 5%. TORCH-C will aim to investigate neoadjuvant SCRT combined with chemotherapy and PD-1 inhibitor in LACC. METHODS AND ANALYSIS: TORCH-C is a randomised, prospective, multicentre, double-arm, open, phase II trial of SCRT combined with chemotherapy and immunotherapy in LACC with microsatellite stable (MSS) patients and cT4 or bulky nodes. Eligible patients will be identified by the multidisciplinary team. 120 patients will be randomised 1:1 to the intervention or control arm. The patients in the control arm will receive four cycles of capecitabine plus oxaliplatin (CAPOX). The patients in the intervention arm will receive SCRT, followed by four cycles of CAPOX and PD-1 inhibitor (serplulimab). Both arms will receive curative surgery, followed by four cycles of CAPOX. The primary endpoint is pathological complete regression.TORCH-C (TORCH-colon) trial aims to investigate whether the combination of immunotherapy and chemoradiotherapy improves the treatment effect in LACC with MSS. TORCH-C will establish the TORCH platform, a key part of our long-term strategy to develop neoadjuvant treatment for colorectal cancer. ETHICS AND DISSEMINATION: This study was approved by the Ethics Committee of Fudan University Shanghai Cancer Center (approval number: 2211265-12). TRIAL REGISTRATION NUMBER: NCT05732493.

Computational framework for the generation of one-dimensional vascular models accounting for uncertainty in networks extracted from medical images.

One-dimensional (1D) cardiovascular models offer a non-invasive method to answer medical questions, including predictions of wave-reflection, shear stress, functional flow reserve, vascular resistance, and compliance. This model type can predict patient-specific outcomes by solving 1D fluid dynamics equations in geometric networks extracted from medical images. However, the inherent uncertainty in in-vivo imaging introduces variability in network size and vessel dimensions, affecting hemodynamic predictions. Understanding the influence of variation in image-derived properties is essential to assess the fidelity of model predictions. Numerous programs exist to render three-dimensional surfaces and construct vessel centerlines. Still, there is no exact way to generate vascular trees from the centerlines while accounting for uncertainty in data. This study introduces an innovative framework employing statistical change point analysis to generate labeled trees that encode vessel dimensions and their associated uncertainty from medical images. To test this framework, we explore the impact of uncertainty in 1D hemodynamic predictions in a systemic and pulmonary arterial network. Simulations explore hemodynamic variations resulting from changes in vessel dimensions and segmentation; the latter is achieved by analyzing multiple segmentations of the same images. Results demonstrate the importance of accurately defining vessel radii and lengths when generating high-fidelity patient-specific hemodynamics models.

Nature of ultrafast dynamics in the lowest-lying singlet excited state of [Ru(bpy)3]2.

This work presents mechanisms to rationalize the nature of ultrafast photochemical and photophysical processes on the first singlet metal-ligand charge transfer state (1MLCT1) of the [Ru(bpy)3]2+ complex. The 1MLCT1 state is the lowest-lying singlet excited state and the most important intermediate in the early evolution of photoexcited [Ru(bpy)3]2+*. The results obtained from simple but interpretable theoretical models show that the 1MLCT1 state can be very quickly formed via both direct photo-excitation and internal conversions and then can efficiently relax to its equilibrium geometry in ca. 5 fs. The interligand electron transfer (ILET) on the potential energy surface of the 1MLCT1 state is also extremely fast, with a rate constant of ca. 1.38 × 1013 s-1. The ultrafast ILET implies that the excited electron can dynamically delocalize over the three bpy ligands, despite the fact that the excited electron may be localized on either one of the three ligands at the equilibrium geometries of the three symmetric equivalent minima. Since rapid ILET essentially suggests delocalization, the long-standing controversy in inorganic photophysics-whether the excited electron is localized or delocalized-may therefore be calmed down to some extent.

ToxMPNN: A deep learning model for small molecule toxicity prediction.

Machine learning (ML) has shown a great promise in predicting toxicity of small molecules. However, the availability of data for such predictions is often limited. Because of the unsatisfactory performance of models trained on a single toxicity endpoint, we collected toxic small molecules with multiple toxicity endpoints from previous study. The dataset comprises 27 toxic endpoints categorized into seven toxicity classes, namely, carcinogenicity and mutagenicity, acute oral toxicity, respiratory toxicity, irritation and corrosion, cardiotoxicity, CYP450, and endocrine disruption. In addition, a binary classification Common-Toxicity task was added based on the aforementioned dataset. To improve the performance of the models, we added marketed drugs as negative samples. This study presents a toxicity predictive model, ToxMPNN, based on the message passing neural network (MPNN) architecture, aiming to predict the toxicity of small molecules. The results demonstrate that ToxMPNN outperforms other models in capturing toxic features within the molecular structure, resulting in more precise predictions with the ROC_AUC testing score of 0.886 for the Toxicity_drug dataset. Furthermore, it was observed that adding marketed drugs as negative samples not only improves the predictive performance of the binary classification Common-Toxicity task but also enhances the stability of the model prediction. It shows that the graph-based deep learning (DL) algorithms in this study can be used as a trustworthy and effective tool to assess small molecule toxicity in the development of new drugs.

The relationship between nighttime exercise and problematic smartphone use before sleep and associated health issues: a cross-sectional study.

OBJECTIVE: Physical exercise has the potential to mitigate addictive behaviors and relevant health issues. However, the nighttime exercise has not been studied regarding this research topic. This study aims to explore the association between nocturnal physical exercise and problematic smartphone use before sleep, as well as related health issues. METHODS: To explore the association between nighttime physical exercise and problematic smartphone use before sleep as well as related health issues, we conducted a cross-sectional survey among 1,334 college students. Their daily exercise behaviors (including timeframe, rationale, frequency, and duration), smartphone use before sleep, sleep quality, smartphone addiction, anxiety, and depression were measured by questionnaires. The associations were assessed using generalized linear models. RESULTS: Our findings indicate that nearly 70% of participants chose to perform exercise at nighttime. Among these individuals who exercised at nighttime, the frequency and duration of nighttime exercise were significantly associated with decreased probabilities of smartphone use before sleep. Additionally, the frequency and duration of nighttime exercise were associated with lower levels of smartphone addiction and anxiety disorders. CONCLUSION: Nighttime Exercise behaviors can effectively reduce sleep delays caused by problematic smartphone use before bedtime. These findings contribute to understanding the potential effects of nighttime exercise on problematic smartphone use and relevant health issues. Future research should employ more precise methodologies to examine these associations.