Hypidone Hydrochloride (YL-0919) Produces a Fast-Onset Reversal of the Behavioral and Synaptic Deficits Caused by Chronic Stress Exposure

Our previous study showed that hypidone hydrochloride (YL-0919), a partial serotonin 1A (5-HT1A) receptor agonist and 5-HT reuptake inhibitor, exerts a significant antidepressant effect in various animal models. The aim of the present study was to further investigate the underlying mechanisms and whether it could act as a fast-onset antidepressant. In the current study, depressive-like behavior was induced in rats by a chronic unpredictable stress (CUS) model and assessed with the Sucrose Preference Test (SPT). Treatment with YL-0919 (2.5 mg/kg, i.g.), but not with fluoxetine (Flx; 10 mg/kg, i.g.), caused a fast improvement in the SPT scores. In CUS-exposed rats, YL-0919 treatment for 5 days decreased the immobility time in a forced swimming test (FST), and a 10-day treatment decreased the latency to feed in a Novelty-Suppressed Feeding Test (NSFT). In addition to the behavioral tests, the effects of YL-0919 on synaptic protein expression were also evaluated. Western blotting showed that YL-0919 significantly enhanced the expression levels of synaptic proteins such as synapsin I, postsynaptic density protein 95 (PSD95), phosphorylated mammalian targeting of rapamycin (pmTOR) and brain-derived neurotrophic factor (BDNF) in the hippocampus. To determine how the mTOR signaling is involved in the fast-onset antidepressant-like effects of YL-0919, the mTOR-specific inhibitor rapamycin was administered intracerebroventricularly (i.c.v.) together with the YL-0919 treatment. The observed changes in behavioral tests and protein expression could be reversed by rapamycin treatment. This suggests that the fast-onset antidepressant effects of YL-0919 were partially caused by changes in synaptogenesis mediated by activation of mTOR pathways. Our data suggest that YL-0919 may be a powerful/effective antidepressant with fast-onset

Excess Deaths of Gastrointestinal, Liver, and Pancreatic Diseases During the COVID-19 Pandemic in the United States

Objectives: To evaluate excess deaths of gastrointestinal, liver, and pancreatic diseases in the United States during the COVID-19 pandemic.Methods: We retrieved weekly death counts from National Vital Statistics System and fitted them with a quasi-Poisson regression model. Cause-specific excess deaths were calculated by the difference between observed and expected deaths with adjustment for temporal trend and seasonality. Demographic disparities and temporal-spatial patterns were evaluated for different diseases.Results: From March 2020 to September 2022, the increased mortality (measured by excess risks) for Clostridium difficile colitis, gastrointestinal hemorrhage, and acute pancreatitis were 35.9%; 24.8%; and 20.6% higher than the expected. For alcoholic liver disease, fibrosis/cirrhosis, and hepatic failure, the excess risks were 1.4–2.8 times higher among younger inhabitants than older inhabitants. The excess deaths of selected diseases were persistently observed across multiple epidemic waves with fluctuating trends for gastrointestinal hemorrhage and fibrosis/cirrhosis and an increasing trend for C. difficile colitis.Conclusion: The persistently observed excess deaths of digestive diseases highlights the importance for healthcare authorities to develop sustainable strategies in response to the long-term circulating of SARS-CoV-2 in the community

Genome Sequence and Transcriptome Analysis of the Radioresistant Bacterium Deinococcus gobiensis: Insights into the Extreme Environmental Adaptations

The desert is an excellent model for studying evolution under extreme environments. We present here the complete genome and ultraviolet (UV) radiation-induced transcriptome of Deinococcus gobiensis I-0, which was isolated from the cold Gobi desert and shows higher tolerance to gamma radiation and UV light than all other known microorganisms. Nearly half of the genes in the genome encode proteins of unknown function, suggesting that the extreme resistance phenotype may be attributed to unknown genes and pathways. D. gobiensis also contains a surprisingly large number of horizontally acquired genes and predicted mobile elements of different classes, which is indicative of adaptation to extreme environments through genomic plasticity. High-resolution RNA-Seq transcriptome analyses indicated that 30 regulatory proteins, including several well-known regulators and uncharacterized protein kinases, and 13 noncoding RNAs were induced immediately after UV irradiation. Particularly interesting is the UV irradiation induction of the phrB and recB genes involved in photoreactivation and recombinational repair, respectively. These proteins likely include key players in the immediate global transcriptional response to UV irradiation. Our results help to explain the exceptional ability of D. gobiensis to withstand environmental extremes of the Gobi desert, and highlight the metabolic features of this organism that have biotechnological potential

Determinants and clinical outcomes of stroke following revascularization among patients with reduced ejection fraction

Abstract Objective Stoke after revascularization including both percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) is an uncommon but devastating complication. Patients with reduced ejection fraction (EF) had an increased risk of stroke after revascularization. However, little is known about the determinants and outcomes of stroke among patients with reduced EF following revascularization. Materials and Methods A cohort study of patients with preoperative reduced EF (≤40%) who received revascularization by either PCI or CABG between January 1, 2005 and December 31, 2014 was performed. Multivariate logistic regression was used to identify independent correlates of stroke. Logistic regression models were applied to evaluate the association of stroke with clinical outcomes. Results A total of 1937 patients were enrolled in this study. Of these, 111 (5.7%) patients suffered from stroke during the median 3.5‐year follow‐up. Older age (odds ratio [OR], 1.03; 95% CI, 1.01–1.05; p = .009), history of hypertension (OR, 1.79; 95% CI, 1.18–2.73; p = .007), and history of stroke (OR, 2.00; 95% CI, 1.19–3.36; p = .008) were found to be independent predictors for stroke. Patients with and without stroke had similar risk of all‐cause death (OR, 0.91; 95% CI, 0.59–1.41; p = .670). However, stroke was associated with higher odds ratio of heart failure (HF) hospitalization (OR, 2.77; 95% CI, 1.74–4.40; p < .001) and composite end point (OR, 1.61; 95% CI, 1.07–2.42; p = .021). Conclusions Further research appears warranted to minimize the complication of stroke and improve long‐term outcomes among patients with reduced EF who underwent such high risk revascularization procedural

Effects of intraoperative esketamine addition on gastrointestinal function after benign gynaecological laparoscopic surgery: a double-blind, randomized controlled study

Abstract Background Gastrointestinal hypokinesis can occur transiently after benign gynecologic surgery. Opioids cause the side effect of postoperative gastrointestinal hypokinesis, but an opioid-sparing anaesthetic protocol based on esketamine reduces intraoperative opioid consumption. Therefore, this study hypothesised that an opioid-sparing anaesthetic protocol based on esketamine would shorten the gastrointestinal function recovery time after benign gynaecological laparoscopic surgery. Methods This was a prospective randomized controlled double-blind study conducted in a single centre. All patients scheduled for elective benign laparoscopic gynaecological surgery at Xing’an Meng People’s Hospital, Inner Mongolia Autonomous Region, from November 2021 to April 2022 were consecutively enrolled and randomly divided into the opioid-sparing anaesthesia group (Group OS) and the conventional anaesthesia group (Group C). Postoperative first exhaust time, feeding time and postoperative nausea and/or vomiting (PONV) were analyzed in both groups. Results A total of 71 patients were enrolled in this study, including 35 in Group OS and 36 in Group C. The general condition, operative time, type of surgery, intraoperative bleeding, intraoperative fluid volume and intraoperative urine volume were not statistically different between the two groups. Compared with Group C, significantly shorter first postoperative flatus time (11 [8, 14] h vs. 14 [11, 18], p = 0.003) and anaesthesia resuscitation time (7 [6, 9] h vs. 9 [7, 11] h, p = 0.013)were observed in the OS group. The incidence of PONV in Group OS was significantly lower compared with Group C (11.4% vs. 41.7%, p = 0.007). Conclusion The esketamine-based opioid-sparing anaesthetic protocol can shorten the postoperative first flatus time after benign laparoscopic surgery in gynaecology, and reduce the incidence of PONV. In addition, the application of esketamine may reduce the postoperative opioid dose requirement of patients. Trial registration : This study was registered with the China Clinical Trials Registry (registration number: ChiCTR2100052528, 30/10/2021)

The complete mitochondrial genome of a Chinese endemic species, Paraprenanthes diversifolia (Vaniot) N. Kilian (Cichorieae; Asteraceae)

The first complete mitochondrial genome (mt) of Paraprenanthes diversifolia (Vaniot) N. Kilian (Cichorieae; Asteraceae) was sequenced and successfully assembled in this study. The full length of the mt genome is 360,751 bp, containing 73 genes (33 protein-coding genes, 29 tRNA genes, 6 rRNA genes, and 5 protein-coding genes containing internal stop codons). There are two pairs of long (over 1000 bp) repeat regions in the mt genome of P. diversifolia. The phylogenetic analysis indicated that P. diversifolia has a close relationship with other Lactucinae species

EF24 Suppresses Invasion and Migration of Hepatocellular Carcinoma Cells In Vitro via Inhibiting the Phosphorylation of Src

Diphenyl difluoroketone (EF24), a curcumin analog, is a promising anticancer compound that exerts its effects by inhibiting cell proliferation and inducing apoptosis. However, the efficacy of EF24 against cancer metastasis, particularly in hepatocellular carcinoma (HCC), remains elusive. In this study, the effect of EF24 on HCCLM-3 and HepG2 cell migration and invasion was detected by wound healing and transwell assay, respectively. The results revealed that EF24 suppressed the migration and invasion of both HCCLM-3 and HepG2 cells. Furthermore, EF24 treatment decreased the formation of filopodia on the cell surface and inhibited the phosphorylation of Src in both cell lines, which may help contribute towards understanding the mechanism underlying the suppressive effect of EF24 on HCC migration and invasion. Additionally, the expression of total- and phosphorylated-Src in primary HCC tissues and their paired lymph node metastatic tissues was detected, and phosphorylated-Src was found to be associated with HCC lymph node metastasis. The results of this study suggest that Src is a novel and promising therapeutic target in HCC and provide evidence to support the hypothesis that EF24 may be a useful therapeutic agent for the treatment of HCC

Active and separate secretion of fiber and penton base during the early phase of Ad2 or Ad5 infection

Fiber and penton base overproduced in adenovirus (Ad) infected cells can be secreted prior to progeny release and thereby regulate progeny spread. We aimed to investigate the mechanisms of fiber and penton base secretion in Ad2- or Ad5-infected A549 cells. Our flow cytometry analyses detected abundant surface fiber molecules, but little penton base molecules at 12 h post infection. Immunogold staining combined with transmission electron microscopic analyses revealed separate, non-co-localized release of fiber and penton base in the proximity of the plasma membrane. Depolymerization of microtubule and actin cytoskeletons, and inhibition of Rock kinase and myosin II activity together demonstrated cytoskeletal network-dependent fiber secretion. Inhibition of intracellular calcium [Ca2+]i signaling caused diminished fiber secretion, which was associated with diminished progeny production. Thus, fiber and penton base are actively and separately secreted during the early stages of Ad2 or Ad5 infection, their secretion may play important role in Ad life cycle