An epigenome-wide association study of waist circumference in Chinese monozygotic twins.

OBJECTIVES: Central obesity poses significant health risks because it increases susceptibility to multiple chronic diseases. Epigenetic features such as DNA methylation may be associated with specific obesity traits, which could help us understand how genetic and environmental factors interact to influence the development of obesity. This study aims to identify DNA methylation sites associated with the waist circumference (WC) in Northern Han Chinese population, and to elucidate potential causal relationships. METHODS: A total of 59 pairs of WC discordant monozygotic twins (ΔWC >0) were selected from the Qingdao Twin Registry in China. Generalized estimated equation model was employed to estimate the methylation levels of CpG sites on WC. Causal relationships between methylation and WC were assessed through the examination of family confounding factors using FAmiliaL CONfounding (ICE FALCON). Additionally, the findings of the epigenome-wide analysis were corroborated in the validation stage. RESULTS: We identified 26 CpG sites with differential methylation reached false discovery rate (FDR) < 0.05 and 22 differentially methylated regions (slk-corrected p < 0.05) strongly linked to WC. These findings provided annotations for 26 genes, with notable emphasis on MMP17, ITGA11, COL23A1, TFPI, A2ML1-AS1, MRGPRE, C2orf82, and NINJ2. ICE FALCON analysis indicated the DNA methylation of ITGA11 and TFPI had a causal effect on WC and vice versa (p < 0.05). Subsequent validation analysis successfully replicated 10 (p < 0.05) out of the 26 identified sites. CONCLUSIONS: Our research has ascertained an association between specific epigenetic variations and WC in the Northern Han Chinese population. These DNA methylation features can offer fresh insights into the epigenetic regulation of obesity and WC as well as hints to plausible biological mechanisms.

The co-dispersal strategy of Endocarpon (Verrucariaceae) shapes an unusual lichen population structure.

The reproduction and dispersal strategies of lichens play a major role in shaping their population structure and photobiont diversity. Sexual reproduction, which is common, leads to high lichen genetic diversity and low photobiont selectivity. However, the lichen genus Endocarpon adopts a special co-dispersal model in which algal cells from the photobiont and ascospores from the mycobiont are released together into the environment. To explore the dispersal strategy impact on population structures, a total of 62 Endocarpon individuals and 12 related Verrucariaceae genera individuals, representing co-dispersal strategy and conventional independent dispersal mode were studied. Phylogenetic analysis revealed that Endocarpon, with a large-scale geographical distribution, showed an extremely high specificity of symbiotic associations with their photobiont. Furthermore, three types of group I intron at 1769 site have been found in most Endocarpon mycobionts, which showed a high variety of group I intron in the same insertion site even in the same species collected from one location. This study suggested that the ascospore-alga co-dispersal mode of Endocarpon resulted in this unusual mycobiont-photobiont relationship; also provided an evidence for the horizontal transfer of group I intron that may suggest the origin of the complexity and diversity of lichen symbiotic associations.

Expression of signal recognition particle 14 in hepatocellular carcinoma and its relationship with disease progression and patient survival. / 信号识别颗粒14è°ƒæŽ§è‚ç»†èƒžç™Œè¿›ç¨‹å¹¶å½±å“æ‚£è€ é¢„åŽ.

OBJECTIVES: To investigate the expression of signal recognition particle 14 (SRP14) in hepatocellular carcinoma (HCC) and its clinical significance. METHODS: The data of SRP14 expression in HCC were obtained from bioinformatics study, and from investigation with quantitative reverse transcription polymerase chain reaction (qRT-PCR), immunohistochemical staining and Western blotting in clinical samples. The Kaplan-Meier analysis was used to determine the associations between SRP14 mRNA expression and the overall survival, progression-free survival, and disease-specific survival of HCC patients. The effect of SRP14 on the proliferation and migration of HCC cells were determined by EdU staining, MTS, Transwell and wound-healing assays. The potential mechanism for SRP14 regulating HCC was explored through Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analysis as well as qRT-PCR. RESULTS: According to the data from GSE14520, TNMplot database and clinical samples, compared with paired tumor-adjacent tissues, non-paired tumor-adjacent tissues and normal tissues, the mRNA expression of SPR14 in HCC tissues was upregulated (all P<0.05). In clinical samples, compared with paired tumor-adjacent tissues, the protein expression of SPR14 in HCC tissues was increased (P<0.05). The increased mRNA expression of SRP14 was associated with good overall survival, progression-free survival, and disease-specific survival in HCC patients. SRP14 inhibited the proliferation and migration of HCC cells in vitro. According to the KEGG and GO enrichment analysis, in non-specific HCC, the genes co-expressed with SRP14 may predominantly regulate protein synthesis, processing, and transport, while in nonalcoholic fatty liver disease related HCC, the genes co-expressed with SRP14 could control multiple signaling pathways such as MAPK, cAMP, PI3K-Akt, and Wnt. Mechanistically, SRP14 up-regulated the mRNA expression of tumor suppressor gene GPRC5A inHCC cells (P<0.05). CONCLUSIONS: SRP14 may regulate HCC progression and influence patient prognosis.

Genome-wide DNA methylation analysis of body composition in Chinese monozygotic twins.

BACKGROUND: Little is currently known about epigenetic alterations associated with body composition in obesity. Thus, we aimed to explore epigenetic relationships between genome-wide DNA methylation levels and three common traits of body composition as measured by body fat percentage (BF%), fat mass (FM) and lean body mass (LBM) among Chinese monozygotic twins. METHODS: Generalized estimated equation model was used to regress the methylation level of CpG sites on body composition. Inference about Causation Through Examination Of Familial Confounding was used to explore the evidence of a causal relationship. Gene expression analysis was further performed to validate the results of differentially methylated genes. RESULTS: We identified 32, 22 and 28 differentially methylated CpG sites (p < 10-5 ) as well as 20, 17 and eight differentially methylated regions (slk-corrected p < 0.05) significantly associated with BF%, FM and LBM which were annotated to 65 genes, showing partially overlapping. Causal inference demonstrated bidirectional causality between DNA methylation and body composition (p < 0.05). Gene expression analysis revealed significant correlations between expression levels of five differentially methylated genes and body composition (p < 0.05). CONCLUSIONS: These DNA methylation signatures will contribute to increased knowledge about the epigenetic basis of body composition and provide new strategies for early prevention and treatment of obesity and its related diseases.

Cellular immunotherapy combined with platinum-based chemotherapy prolongs survival for non-small cell lung cancer patients.

Platinum-based chemotherapy is the primary treatment option for advanced non-small cell lung cancer (NSCLC) patients without a driver gene mutation, but its efficacy is still modest. Through a potential synergistic effect, autologous cellular immunotherapy (CIT) composed of cytokine-induced killer (CIK), natural killer (NK), and T cells might enhance it. NK cells exhibited in vitro cytotoxicity toward lung cancer cells (A549 cells) following platinum therapy. Using flow cytometry, the expression of MICA, MICB, DR4, DR5, CD112, and CD155 on lung cancer cells was assessed. In this retrospective cohort study, there were included 102 previously untreated stage IIIB/IV NSCLC patients ineligible for tyrosine kinase inhibitor (TKI) target therapy who received either chemotherapy alone (n=75) or combination therapy (n=27). The cytotoxicity of NK cells for A549 cells was increased obviously and a time-dependent enhancement of this effect was also observed. After platinum therapy, the levels of MICA, MICB, DR4, DR5, CD112, and CD155 on the surface of A549 cells were increased. In the combination group, the median PFS was 8.3 months, compared to 5.5 months in the control group (p=0.042); the median overall survival was 18.00 months, compared to 13.67 months in the combined group (p=0.003). The combination group had no obvious immune-related adverse effects. The combination of NK cells with platinum showed synergistic anticancer effects. Combining the two strategies increased survival with minor adverse effects. Incorporating CIT into conventional chemotherapy regimens may improve NSCLC treatment. However, additional evidence will require multicenter randomized controlled trials.

Effects of Bempedoic Acid in Acute Myocardial Infarction in Rats: No Cardioprotection and No Hidden Cardiotoxicity.

Lipid-lowering drugs have been shown to have cardioprotective effects but may have hidden cardiotoxic properties. Therefore, here we aimed to investigate if chronic treatment with the novel lipid-lowering drug bempedoic acid (BA) exerts hidden cardiotoxic and/or cardioprotective effects in a rat model of acute myocardial infarction (AMI). Wistar rats were orally treated with BA or its vehicle for 28 days, anesthetized and randomized to three different groups (vehicle + ischemia/reperfusion (I/R), BA + I/R, and positive control vehicle + ischemic preconditioning (IPC)) and subjected to cardiac 30 min ischemia and 120 min reperfusion. IPC was performed by 3 × 5 min I/R cycles before ischemia. Myocardial function, area at risk, infarct size and arrhythmias were analyzed. Chronic BA pretreatment did not influence cardiac function or infarct size as compared to the vehicle group, while the positive control IPC significantly reduced the infarct size. The incidence of reperfusion-induced arrhythmias was significantly reduced by BA and IPC. This is the first demonstration that BA treatment does not show cardioprotective effect although moderately reduces the incidence of reperfusion-induced arrhythmias. Furthermore, BA does not show hidden cardiotoxic effect in rats with AMI, showing its safety in the ischemic/reperfused heart.

Hsp16.3 of mycobacterium tuberculosis in exosomes as a biomarker of tuberculosis.

Exosomes are selectively packaged cell-derived vesicles that contain a rich cargo of nucleic acids and proteins. The small heat shock protein, Hsp16.3, is an important capsule protein produced by Mycobacterium tuberculosis (MTB). Exploring the distribution of Hsp16.3 in exosomes is valuable to tuberculosis biomarker development. Our results showed that Hsp16.3 protein overexpressed in cells can be efficiently packaged into exosomes. U937 cells infected with MTB secreted abnormally excessive amounts of Hsp16.3 protein in exosomes. Finally, a substantial number of Hsp16.3 proteins were detected in blood exosomes of tuberculosis patients. The research provides a potential exosome-based tuberculosis biomarker for MTB diagnosis.

Advances in novel molecular typing and precise treatment strategies for small cell lung cancer.

Small cell lung cancer (SCLC) is a high-grade neuroendocrine (NE) cancer characterized by high circulating tumor-cell burden and early extensive metastasis. Considering the complexity of SCLC genes and the immune microenvironment, their unique molecular heterogeneity profiles have been continuously explored. The understanding of SCLC subtypes has recently changed from traditional "classical" and "variant" types to "NE" and "non-NE" phenotypes and to the subtypes defined by major transcriptional regulators, which indicates the gradual revelation of high intratumoral heterogeneity and plasticity characteristics of SCLCs. Advances in genomics as well as the development of single-cell sequencing analysis and new preclinical models have helped investigators gain many new insights into SCLCs and the development of targeted therapy and immunotherapy strategies. This article provides an overview of changes in molecular typing, tumor heterogeneity, and plasticity and that of advances in the precise treatment of different subtypes of SCLC.

In Vitro and In Vivo Efficacies of the EGFR/MEK/ERK Signaling Inhibitors in the Treatment of Alveolar Echinococcosis.

Alveolar echinococcosis (AE), caused by the larval stage of the cestode Echinococcus multilocularis, is a lethal disease in humans. Novel therapeutic options are urgently needed since the current chemotherapy displays limited efficiency in AE treatment. In this study, we assessed the in vitro and in vivo effects of the epidermal growth factor receptor (EGFR)/MEK/extracellular signal-regulated kinase (ERK) signaling inhibitors, including BIBW2992, CI-1033, and U0126, on E. multilocularis Our data showed that BIBW2992, CI-1033, and U0126 all displayed in vitro effects on the viability of the E. multilocularis metacestode. These inhibitors also showed protoscolicidal activities and caused severe ultrastructural alterations in the parasite. Moreover, BIBW2992 and CI-1033 exhibited potent proapoptotic effects on E. multilocularis metacestodes. Strikingly, a large portion of the apoptotic cells were found to be the germinative cells. In vivo studies showed that BIBW2992 and U0126 significantly reduced parasite burden, and the parasite obtained from BIBW2992-treated mice displayed impaired structural integrity of the germinal layer. In conclusion, these findings demonstrate the potential of EGFR-mediated signaling as a target for the development of novel anti-AE agents. The EGFR inhibitor BIBW2992 represents a promising drug candidate and/or a lead compound for anti-AE chemotherapy.

Adoptive transfer of natural killer cells in combination with chemotherapy improves outcomes of patients with locally advanced colon carcinoma.

BACKGROUND: Despite the availability of multiple treatment strategies, patients with advanced colon carcinoma (CC) have poor prognoses. The aim of this study was to evaluate the efficacy and safety of natural killer (NK) cell therapy in combination with chemotherapy in patients with locally advanced CC. METHODS: We assessed the cytotoxicity of NK cells to CC cells (CCs) and CC stem cells (CSCs) pre-treated with 5-fluorouracil or oxaliplatin in vitro. Then, an open-label cohort study was conducted with locally advanced CC patients who had received radical resection. Patients received either NK cell therapy combined with chemotherapy (NK cell group, 27 patients) or pure chemotherapy (control group, 33 patients). Progression-free survival (PFS), overall survival (OS) and adverse effects were investigated. RESULTS: Chemotherapy sensitized CCs and CSCs to NK cell cytotoxicity through regulation of NK cell-activating/inhibitory receptor ligands. Poorly differentiated CCs were more susceptible to NK cells than well-differentiated ones. In the cohort study, the 5-year PFS and OS rates in the NK cell group were significantly higher than those in the control group (51.1% versus 35%, P= 0.044; 72.5% versus 51.6%, P= 0.037, respectively). Among patients with poorly differentiated carcinomas and low expression of human leukocyte antigen (HLA)-1, the median PFS in the NK cell group versus the control group was 23.5 versus 12.1 months (P= 0.0475) and 33.1 versus 18.5 months (P= 0.045), respectively. No significant adverse reactions were reported. CONCLUSION: NK cell therapy in combination with chemotherapy in locally advanced CC prevented recurrence and prolonged survival with acceptable adverse effects, especially for poorly differentiated carcinomas.

Low-dose radiation may be a novel approach to enhance the effectiveness of cancer therapeutics.

It has been generally accepted that both natural and man-made sources of ionizing radiation contribute to human exposure and consequently pose a possible risk to human health. However, accumulating evidence has shown that the biological effects of low-dose radiation (LDR) are different from those of high-dose radiation. LDR can stimulate proliferation of normal cells and activate their defense systems, while these biological effects are not observed in some cancer cell types. Although there is still no concordance on this matter, the fact that LDR has the potential to enhance the effects of cancer therapeutics and reduce the toxic side effects of anti-cancer therapy has garnered significant interest. Here, we provide an overview of the current knowledge regarding the experimental data detailing the different responses of normal and cancer tissues to LDR, the underlying mechanisms, and its significance in clinical application.

Cellular immunotherapy as maintenance therapy prolongs the survival of the patients with small cell lung cancer.

BACKGROUND: Small cell lung cancer (SCLC) relapses rapidly after the initial response to chemotherapy and shows drug-resistance. This study was to investigate the efficacy and safety of cellular immunotherapy (CIT) with autologous natural killer (NK), γδT, and cytokine-induced killer (CIK) cells as maintenance therapy for SCLC patients. METHODS: A pilot prospective cohort study was conducted with SCLC patients who had responded to initial chemotherapy. Patients elected to receive either CIT as maintenance therapy (study group), or to be followed-up without further treatment (control group). Progression-free survival (PFS), overall survival (OS), and adverse effects were investigated. RESULTS: We recruited 58 patients (29 in each group). The patient characteristics of the 2 groups were well balanced. PFS was not significantly different between the groups, but OS was significantly longer in the study group than the control (20 vs. 11.5 months, P = 0.005; hazard ratio [HR], 0.434, 95 % confidence interval [CI], 0.236-0.797, P = 0.007). Among patients with limited-stage disease, there was no difference in PFS between the groups, but OS was longer in the study group compared to the control (26.5 vs. 11.8 months, P = 0.033; HR, 0.405, 95 % CI, 0.169-0.972, P = 0.043). Among patients with extensive-stage disease, both PFS and OS were longer in the study group than the control (5 vs. 2.7 months, P = 0.037; HR, 0.403, 95 % CI, 0.162-1.003, P = 0.051, and 14.5 vs. 9 months, P = 0.038; HR, 0.403, 95 % CI, 0.165-0.987, P = 0.047, respectively). No significant adverse reactions occurred in patients undergoing CIT. CONCLUSIONS: CIT maintenance therapy in SCLC prolonged survival with only minimal side effects. Integrating CIT into current treatment may be a novel strategy for SCLC therapy, although further multi-center randomized studies are needed.

Combined cellular immunotherapy and chemotherapy improves clinical outcome in patients with gastric carcinoma.

BACKGROUND AIMS: Despite the availability of multiple treatment strategies, patients with gastric carcinoma (GC) have a dismal prognosis. The aim of this study was to evaluate the efficacy and safety of cellular immunotherapy (CIT) with the use of autologous natural killer cells, γδT cells and cytokine-induced killer cells in combination with chemotherapy in patients with GC. METHODS: In this open-label pilot cohort study, patients were treated with the combination therapy (chemo/CIT group) or chemotherapy alone (control group). Progression-free survival (PFS), overall survival (OS), quality of life (QOL) and adverse events were investigated. RESULTS: Fifty-eight patients were analyzed, 30 in the chemo/CIT group and 28 in the control group. The median PFS of the chemo/CIT group was significantly longer compared with the control group (P = 0.021). In subgroup analysis, in patients with stage III GC, node-positive metastasis or poorly differentiated carcinoma, the 2-year PFS rate in chemo/CIT versus control groups was 62.5% versus 26.7% (P = 0.022), 50% versus 27.3% (P = 0.016) and 56.3% versus 28.6% (P = 0.005), respectively. The median OS in either group has not yet been reached, and there was no significant difference in OS between the groups. The QOL was improved in the patients treated with chemo/CIT compared with the control group. CIT was well tolerated and not related to any significant adverse events. CONCLUSIONS: A combination of CIT and chemotherapy for patients with GC was safe, improved QOL, and might prevent recurrence, especially in GC patients with advanced stage, poorly differentiated carcinoma or lymph node metastasis.

The exopolysaccharides produced by Leuconostoc mesenteroides XR1 and its effect on silk drawing phenomenon of yoghurt.

Yoghurt fermented by Leuconostoc mesenteroides XR1 from Kefir grains was found to produce a unique silk drawing phenomenon. This property was found to be associated with the exopolysaccharides (EPS), X-EPS, produced by strain XR1. In order to better understand the mechanism that produced this phenomenon, the X-EPS was extracted, purified and characterized. The molecular weight and monosaccharide composition were determined by size exclusion chromatography coupled with multi-angle laser light scattering (SEC-MALLS) and ion chromatography (IC) analysis, respectively. The results showed that its molecular weight was 4.183 × 106 g/mol and its monosaccharide composition was glucose, and glucuronic acid, with the contents of 567.6148 and 0.2096 µg/mg, respectively. FT-IR and NMR analyses showed that X-EPS was an α-pyranose polysaccharide and was composed of 92.22 % α-(1 â†’ 6) linked d-glucopyranose units and 7.77 % α-(1 â†’ 3) branching. Furthermore, it showed a chain-like microstructure with branches in atomic force microscopy (AFM) and scanning electron microscopy (SEM) experiments. These results suggested that the unique structure of X-EPS, gave the yoghurt a strong viscosity and cohesiveness, which resulted in the silk drawing phenomenon. This work suggested that X-EPS holds the potential for food and industrial applications.

A Hierarchical Mechanotransduction System: From Macro to Micro.

Mechanotransduction is a strictly regulated process whereby mechanical stimuli, including mechanical forces and properties, are sensed and translated into biochemical signals. Increasing data demonstrate that mechanotransduction is crucial for regulating macroscopic and microscopic dynamics and functionalities. However, the actions and mechanisms of mechanotransduction across multiple hierarchies, from molecules, subcellular structures, cells, tissues/organs, to the whole-body level, have not been yet comprehensively documented. Herein, the biological roles and operational mechanisms of mechanotransduction from macro to micro are revisited, with a focus on the orchestrations across diverse hierarchies. The implications, applications, and challenges of mechanotransduction in human diseases are also summarized and discussed. Together, this knowledge from a hierarchical perspective has the potential to refresh insights into mechanotransduction regulation and disease pathogenesis and therapy, and ultimately revolutionize the prevention, diagnosis, and treatment of human diseases.

The predictive value of GLIM criteria on clinical outcomes and responses to nutritional support in patients with neurocritical illnesses.

Neurocritically ill patients frequently exhibit coma, gastroparesis, and intense catabolism, leading to an increased risk of malnutrition. The Global Leadership Initiative on Malnutrition (GLIM) criteria for the diagnosis of malnutrition was created to achieve a consistent malnutrition diagnosis across diverse populations. This study aimed to validate the concurrent and predictive validity of GLIM criteria in patients with neurocritical illnesses. A total of 135 participants were followed from admission to the neurocritical unit (NCU) until discharge. Comparing GLIM criteria to the Subjective Global Assessment (SGA), sensitivity was 0.95 and specificity was 0.69. Predictive validity of GLIM criteria was assessed using a composite adverse clinical outcome, comprising mortality and various major complications. Adjusted hazard ratios for moderate and severe malnutrition were 2.86 (95% CI 1.45-5.67) and 3.88 (95% CI 1.51-9.94), respectively. Changes in indicators of nutritional status, including skeletal muscle mass and abdominal fat mass, within 7 days of admission were obtained for 61 participants to validate the predictive capability of the GLIM criteria for the patients' response of standardized nutritional support. The GLIM criteria have a statistically significant predictive validity on changes in rectus femoris muscle thickness and midarm muscle circumference. In conclusion, the GLIM criteria demonstrate high sensitivity for diagnosing malnutrition in neurocritically ill patients and exhibit good predictive validity.

Exopolysaccharide from Leuconostoc mesenteroides XR1: Yield optimization, partial characterization and properties.

The production conditions of exopolysaccharide (EPS) from Leuconostoc mesenteroides XR1 were optimized by response surface methodology (RSM). Maximum EPS yield was 56.59 ± 0.51 g/L under fermentation conditions with 2.6 g/L ammonium citrate, initial pH 6.5 and temperature 23 °C, which was 6.21-fold greater than the EPS yield before optimization. Characterization of the chain conformation using Congo red test and circular dichroism (CD) showed that EPS exhibited a random coil structure in aqueous solution. The CD results revealed that the EPS concentration altered its hydrogen-bond interactions and chirality, but did not change its chain conformation. The average polydispersity index (PDI) of the EPS solution was only 27.16 %, indicating that it was uniformly distributed in the aqueous solution with high stability. The degradation temperature of EPS was 253.11 °C, indicating high thermal stability. EPS possessed the ability to scavenge activities of free radicals and was protective against oxidative stress-induced plasmid DNA damage. In addition, stable hydrogels could be formed at EPS concentrations above 5 % (w/v). These results collectively showed that EPS can be used commercially as an antioxidant and drug delivery carrier.

Are immune checkpoint inhibitors ineffective in treating patients with head and neck squamous cell carcinoma aged 75 years or Older? A Meta-Analysis.

OBJECTIVES: The efficacy of immune checkpoint inhibitors (ICIs) is unclear in patients aged ≥ 75 years with head and neck squamous cell carcinoma (HNSCC). We conducted a systematic review and meta-analysis of randomized trials that compared ICIs with standard-of-care (SOC) therapy for recurrent/metastatic HNSCC. MATERIALS AND METHODS: PubMed, EMBASE, Web of Science, and ClinicalTrials.gov were searched for eligible trials. We evaluated the overall survival (OS) benefit of ICIs versus SOC according to patient age (<75 versus ≥ 75 years). The OS benefit was evaluated and compared between the age subgroups using hazard ratios (HRs). Data were pooled using a random-effects model. RESULTS: Five phase 3 trials involving 3437 patients were included. In patients aged ≥ 75 years (n = 207), ICIs did not improve OS compared to SOC (HR = 1.30, 95 % confidence interval [CI]: 0.93-1.81, P = 0.127). However, an improvement in OS was observed in patients aged < 75 years (n = 3230, HR = 0.90, 95 % CI: 0.83-0.99, P = 0.025). There is a significant difference in OS benefit between patients aged < 75 and ≥ 75 years (ratio of HR = 0.69, 95 % CI: 0.49-0.98, P = 0.036). Subgroup, meta-regression, and sensitivity analyses supported the reliability of the results. CONCLUSIONS: Given the small sample size, our findings showing no improvement in OS suggest a lack of evidence to support the use of ICIs in patients with recurrent/metastatic HNSCC aged ≥ 75 years. Therefore, prospective studies are needed to clarify their efficacy among this age group.

Association between social isolation and depression: Evidence from longitudinal and Mendelian randomization analyses.

BACKGROUND: Increasing evidence shows that social isolation and depression are likely to interact with each other, yet the direction and causality of the association are not clear. This study aims to examine the possible reciprocity in the relationship between social isolation and depression. METHODS: This study fitted a cross-lagged panel model (CLPM) by using data from the English Longitudinal Study of Aging (ELSA, 2014-2019, n = 6787) to examine the temporal relationship between social isolation and depressive symptoms in older adults. We then conducted two-sample bidirectional Mendelian randomization (MR) analyses by using independent genetic variants associated with multiple social isolation phenotypes (n = 448,858-487,647) and with depression (n = 215,644-2,113,907) as genetic instruments from genome-wide association studies to assess the causality between social isolation and onset of depression. RESULTS: The CLPM in the ELSA cohort showed a significant and positive lagged effect of social isolation on depressive symptoms (ß = 0.037, P < .001). The reverse cross-lagged path from depressive symptoms to social isolation was also statistically significant (ß = 0.039, P < .001). In two-sample bidirectional MR, the genetically predicted loneliness and social isolation combined phenotype (LNL-ISO) was positively associated with occurrence of depression (OR = 1.88, 95 % CI: 1.41-2.50, P < .001), vice versa (OR = 1.16, 95 % CI:1.13-1.20, P < .001). LIMITATIONS: The self-report nature of the assessments and missing data are study limitations. CONCLUSIONS: These findings suggest a bidirectional relationship between social isolation and depression. It is important to develop interventions that highlight the reciprocal consequences of improving either mental health or social connection in older adults.

ROS are required for the germinative cell proliferation and metacestode larval growth of Echinococcus multilocularis.

The potentially lethal zoonotic disease alveolar echinococcosis (AE) is caused by the metacestode larval stages of the tapeworm Echinococcus multilocularis. Metacestode growth and proliferation occurs within the inner organs of mammalian hosts, which is associated with complex molecular parasite-host interactions. The host has developed various ways to resist a parasitic infection, and the production of reactive oxygen species (ROS) is one of the most important strategies. Here, we found that scavenging of ROS reduced metacestode larval growth and germinative cell proliferation in in vivo models. Furthermore, using in vitro-cultured metacestode vesicles, we found that increased ROS levels enhanced metacestode growth and germinative cell proliferation, which was achieved by positively activating the ROS-EmERK-EmHIF1α axis. These results indicate that, beside its capacity to damage the parasite, ROS also play critical roles in metacestode growth and germinative cell proliferation. This study suggests that the effects of ROS on parasite may be bidirectional during AE infection, reflecting the parasite's adaptation to the oxidative stress microenvironment.