Analysis of risk factors for early death in patients with acute promyelocytic leukaemia treated with arsenic trioxide.

To date, no specific studies have evaluated early death (ED) in patients with acute promyelocytic leukaemia (APL) homogeneously treated with arsenic trioxide induction therapy and investigated according to the white blood cell (WBC) count at onset. Such patients were retrospectively analysed in this study, including 314 patients with a WBC count ≤ 10 × 109/L (standard-risk (SR) group) and 144 with a WBC count > 10 × 109/L (high-risk (HR) group). The baseline clinical characteristics and risk factors for ED were compared between the two groups. The incidence of fibrinogen < 1.0 g/L and elevated serum uric acid, aspartate aminotransferase and creatinine levels were higher in the HR group than in the SR group (P = 0.001; P < 0.001; P < 0.001; P = 0.044, respectively). The ED rate was significantly higher in the HR group than in the SR group (29.17% vs. 10.83%, P < 0.001). The main cause of ED was bleeding, followed by infection and differentiation syndrome (DS) in the HR group, while it was bleeding, followed by DS and infection in the SR group. Male sex, age > 50 years old, and fibrinogen < 1.0 g/L were independent risk factors for ED in the SR group. Increased serum creatinine levels, decreased albumin levels, and fibrinogen < 1.0 g/L were independent risk factors for ED in the HR group. Overall, the incidence of ED was higher in the HR group, and the baseline clinical characteristics, causes, times, and predictors of ED in the HR group differed from those in the SR group.

Immune-related genes of the larval Holotrichia parallela in response to entomopathogenic nematodes Heterorhabditis beicherriana LF.

BACKGROUND: Entomopathogenic nematodes (EPNs) emerge as compatible alternatives to conventional insecticides in controlling Holotrichia parallela larvae (Coleoptera: Scarabaeidae). However, the immune responses of H. parallela against EPNs infection remain unclear. RESULTS: In present research, RNA-Seq was firstly performed. A total of 89,427 and 85,741 unigenes were achieved from the midgut of H. parallela larvae treated with Heterorhabditis beicherriana LF for 24 and 72 h, respectively; 2545 and 3156 unigenes were differentially regulated, respectively. Among those differentially expressed genes (DEGs), 74 were identified potentially related to the immune response. Notably, some immune-related genes, such as peptidoglycan recognition protein SC1 (PGRP-SC1), pro-phenoloxidase activating enzyme-I (PPAE-I) and glutathione s-transferase (GST), were induced at both treatment points. Bioinformatics analysis showed that PGRP-SC1, PPAE-I and GST were all involved in anti-parasitic immune process. Quantitative real-time PCR (qRT-PCR) results showed that the three immune-related genes were expressed in all developmental stages; PGRP-SC1 and PPAE-I had higher expressions in midgut and fat body, respectively, while GST exhibited high expression in both of them. Moreover, in vivo silencing of them resulted in increased susceptibility of H. parallela larvae to H. beicherriana LF. CONCLUSION: These results suggest that H. parallela PGRP-SC1, PPAE-I and GST are involved in the immune responses to resist H. beicherriana LF infection. This study provides the first comprehensive transcriptome resource of H. parallela exposure to nematode challenge that will help to support further comparative studies on host-EPN interactions.

Depression and anxiety in relation to cancer incidence and mortality: a systematic review and meta-analysis of cohort studies.

The link between depression and anxiety status and cancer outcomes has been well-documented but remains unclear. We comprehensively quantified the association between depression and anxiety defined by symptom scales or clinical diagnosis and the risk of cancer incidence, cancer-specific mortality, and all-cause mortality in cancer patients. Pooled estimates of the relative risks (RRs) for cancer incidence and mortality were performed in a meta-analysis by random effects or fixed effects models as appropriate. Associations were tested in subgroups stratified by different study and participant characteristics. Fifty-one eligible cohort studies involving 2,611,907 participants with a mean follow-up period of 10.3 years were identified. Overall, depression and anxiety were associated with a significantly increased risk of cancer incidence (adjusted RR: 1.13, 95% CI: 1.06-1.19), cancer-specific mortality (1.21, 1.16-1.26), and all-cause mortality in cancer patients (1.24, 1.13-1.35). The estimated absolute risk increases (ARIs) associated with depression and anxiety were 34.3 events/100,000 person years (15.8-50.2) for cancer incidence and 28.2 events/100,000 person years (21.5-34.9) for cancer-specific mortality. Subgroup analyses demonstrated that clinically diagnosed depression and anxiety were related to higher cancer incidence, poorer cancer survival, and higher cancer-specific mortality. Psychological distress (symptoms of depression and anxiety) was related to higher cancer-specific mortality and poorer cancer survival but not to increased cancer incidence. Site-specific analyses indicated that overall, depression and anxiety were associated with an increased incidence risks for cancers of the lung, oral cavity, prostate and skin, a higher cancer-specific mortality risk for cancers of the lung, bladder, breast, colorectum, hematopoietic system, kidney and prostate, and an increased all-cause mortality risk in lung cancer patients. These analyses suggest that depression and anxiety may have an etiologic role and prognostic impact on cancer, although there is potential reverse causality; Furthermore, there was substantial heterogeneity among the included studies, and the results should be interpreted with caution. Early detection and effective intervention of depression and anxiety in cancer patients and the general population have public health and clinical importance.

Effects of medication-assisted treatment on mortality among opioids users: a systematic review and meta-analysis.

Opioid use disorder (OUD) is associated with a high risk of premature death. Medication-assisted treatment (MAT) is the primary treatment for opioid dependence. We comprehensively assessed the effects of different MAT-related characteristics on mortality among those with OUD by a systematic review and meta-analysis. The all-cause and overdose crude mortality rates (CMRs) and relative risks (RRs) by treatment status, different type, period, and dose of medication, and retention time were pooled using random effects, subgroup analysis, and meta-regression. Thirty cohort studies involving 370,611 participants (1,378,815 person-years) were eligible in the meta-analysis. From 21 studies, the pooled all-cause CMRs were 0.92 per 100 person-years (95% CI: 0.79-1.04) while receiving MAT, 1.69 (1.47-1.91) after cessation, and 4.89 (3.54-6.23) for untreated period. Based on 16 studies, the pooled overdose CMRs were 0.24 (0.20-0.28) while receiving MAT, 0.68 (0.55-0.80) after cessation of MAT, and 2.43 (1.72-3.15) for untreated period. Compared with patients receiving MAT, untreated participants had higher risk of all-cause mortality (RR 2.56 [95% CI: 1.72-3.80]) and overdose mortality (8.10 [4.48-14.66]), and discharged participants had higher risk of all-cause death (2.33 [2.02-2.67]) and overdose death (3.09 [2.37-4.01]). The all-cause CMRs during and after opioid substitution treatment with methadone or buprenorphine were 0.93 (0.76-1.10) and 1.79 (1.47-2.10), and corresponding estimate for antagonist naltrexone treatment were 0.26 (0-0.59) and 1.97 (0-5.18), respectively. Retention in MAT of over 1-year was associated with a lower mortality rate than that with retention ≤1 year (1.62, 1.31-1.93 vs. 5.31, -0.09-10.71). Improved coverage and adherence to MAT and post-treatment follow-up are crucial to reduce the mortality. Long-acting naltrexone showed positive advantage on prevention of premature death among persons with OUD.

Greater Peripouch Fat Area on CT Image Is Associated with Chronic Pouchitis and Pouch Failure in Inflammatory Bowel Diseases Patients.

BACKGROUND: The causes of chronic antibiotic refractory pouchitis (CARP) and pouch failure in inflammatory bowel disease (IBD) patients remain unknown. Our previous small study showed peripouch fat area measured by MRI was associated with pouchitis. AIMS: To explore the relationship between peripouch fat area on CT imaging and pouch outcomes. METHODS: This is a historical cohort study. Demographic, clinical, and radiographic data of IBD patients with abdominal CT scans after pouch surgery between 2002 and 2017 were collected. Peripouch fat areas and mesenteric peripouch fat areas were measured on CT images at the middle pouch level. RESULTS: A total of 435 IBD patients were included. Patients with higher peripouch fat areas had a higher prevalence of CARP. Univariate analyses demonstrated that long duration of the pouch, high weight or body mass index, the presence of primary sclerosing cholangitis or other autoimmune disorders, and greater peripouch fat area or mesenteric peripouch fat area were risk factors for CARP. Multivariable analyses demonstrated that the presence of primary sclerosing cholangitis or autoimmuned disorders, and greater peripouch fat area (odds ratio [OR] 1.031; 95% confidence interval [CI] 1.016-1.047, P < 0.001) or mesenteric peripouch fat area were independent risk factors for CARP. Of the 435 patients, 139 (32.0%) had two or more CT scans. Multivariable Cox proportional hazard analyses showed that "peripouch fat area increase ≥ 15%" (OR 3.808, 95%CI 1.703-8.517, P = 0.001) was an independent predictor of pouch failure. CONCLUSIONS: A great peripouch fat area measured on CT image is associated with a higher prevalence of CARP, and the accumulation of peripouch fat is a risk factor for pouch failure. The assessment of peripouch fat may be used to monitor the disease course of the ileal pouch.

An overview of osteocalcin progress.

An increasing amount of data indicate that osteocalcin is an endocrine hormone which regulates energy metabolism, male fertility and brain development. However, the detailed functions and mechanism of osteocalcin are not well understood and conflicting results have been obtained from researchers worldwide. In the present review, we summarize the progress of osteocalcin studies over the past 40 years, focusing on the structure of carboxylated and undercarboxylated osteocalcin, new functions and putative receptors, the role of osteocalcin in bone remodeling, specific expression and regulation in osteoblasts, and new indices for clinical studies. The complexity of osteocalcin in completely, uncompletely and non-carboxylated forms may account for the discrepancies in its tertiary structure and clinical results. Moreover, the extensive expression of osteocalcin and its putative receptor GPRC6A imply that there are new physiological functions and mechanisms of action of osteocalcin to be explored. New discoveries related to osteocalcin function will assist its potential clinical application and physiological theory, but comprehensive investigations are required.

Effects of 60-day head-down bed rest on osteocalcin, glycolipid metabolism and their association with or without resistance training.

INTRODUCTION: Bone loss and subclinical diabeteslike are developed during long-term spaceflight. Recently, it was demonstrated that bone was able to regulate energy metabolism and testosterone synthesis via osteocalcin. The aim of this study was to determine whether serum osteocalcin level is associated with glycolipid metabolism or testosterone under the influence of microgravity with or without resistive vibration exercise (RVE). METHODS: A total of 14 healthy adult male volunteers (25-40 years) were randomly assigned to two groups (n = 7 each): control (CON) group and RVE group. Radioimmunoassay kits and ELISA kits were used for measurement of serum indices. RESULTS: During 60-day bed rest, serum osteocalcin of both groups increased at day 4 during bed rest. Serum OPG started decreasing and reached its lowest value at day 30 during bed rest. In control group, serum insulin increased at day 4 during bed rest. IGF-I did not change significantly during the entire period of bed rest. The serum glucose decline 10% and 14% in CON and RVE groups at day 4 during bed rest. Relatively, the same results as glucose were found in serum HDL and LDL for both groups. Leptin rose and became highest at day 60 during bed rest in both groups. The level of serum testosterone was declined in control group at day 4 during bed rest. Cortisol kept stable in both group during bed rest. By spearman correlation analysis, serum osteocalcin was significantly associated with serum insulin (P < 0·05), LDL (P < 0·01) and Leptin (P < 0·01). CONCLUSION: Our findings suggested that the mutual regulation may exist between skeletal and energy metabolism under simulated microgravity.

Comprehensive analysis of cuproptosis-related genes on bladder cancer prognosis, tumor microenvironment invasion, and drug sensitivity.

Cuproptosis, a newly discovered form of programmed cell death, plays a vital role in the occurrence and development of tumors. However, the role of cuproptosis in the bladder cancer tumor microenvironment remains unclear. In this study, we developed a method for predicting the prognostic outcomes and guiding the treatment selection for patients with bladder cancer. We obtained 1001 samples and survival data points from The Cancer Genome Atlas database and Gene Expression Omnibus database. Using cuproptosis-related genes (CRGs) identified in previous studies, we analyzed CRG transcriptional changes and identified two molecular subtypes, namely high- and low-risk patients. The prognostic features of eight genes (PDGFRB, COMP, GREM1, FRRS1, SDHD, RARRES2, CRTAC1, and HMGCS2) were determined. The CRG molecular typing and risk scores were correlated with clinicopathological features, prognosis, tumor microenvironment cell infiltration characteristics, immune checkpoint activation, mutation burden, and chemotherapy drug sensitivity. Additionally, we constructed an accurate nomogram to improve the clinical applicability of the CRG_score. qRT-PCR was used to detect the expression levels of eight genes in bladder cancer tissues, and the results were consistent with the predicted results. These findings may help us to understand the role of cuproptosis in cancer and provide new directions for the design of personalized treatment and prediction of survival outcomes in patients with bladder cancer.

Single-cell analyses EMP1 as a marker of the ratio of M1/M2 macrophages is associated with EMT, immune infiltration, and prognosis in bladder cancer.

Background: Bladder cancer is among the most lethal urinary system cancers across the globe. Macrophage 1 and Macrophage 2 play an essential role in the pathogenesis of tumors. Nevertheless, prior studies failed to investigate the implication of the two cells, working in combination, in the development, growth, progression and metastasis of bladder cancer. Methods: We computed the M1/M2 ratio of the samples retrieved from The Cancer Genome Atlas (TCGA) by using the Cibersortx algorithm and calculated the ratio in 32 patients in our series by employing flow cytometry. SurvivalRandomForest was utilized to reduce the dimension of the list of the M1/M2-related genes, with an aim to obtain the most survival-predictive gene (EMP1) encoding epithelial membrane protein 1 (EMP1). The EMP1 was biologically characterized by using Gene Set Enrichment Analysis (GSEA), Gene Set Variation Analysis (GSVA), and Gene Ontology (GO). The single-cell transcriptome (sc-RNA) analysis was then applied to further look into the function of EMP1. Finally, Cellchat was employed to examine the interaction between macrophages and epithelium cells. Results: The results showed that higher M1/M2 ratio was found to be associated with a more favorable prognosis of bladder cancer. EMP1 was identified to be the key gene indicative of M1/M2 ratio and higher EMP1 expression was associated with poor prognosis. Further analyses showed that EMP1 might promote tumor invasion and metastasis via epithelial-mesenchymal transition (EMT) and focal adhesion (FA). Moreover, the expression level of EMP1 could serve as an indicator of immunotherapy efficacy. The scRNA-seq data indicated that EMP1 in cancer cells was strongly associated with tumor proliferation. Finally, the Cellchat results exhibited that EMP1 might promote the interaction between macrophages and cancer cells through the fibronectin 1-syndecan 1 (FN1-SDC1) pathway. Conclusion: Our study identified EMP1, an M1/M2-related gene, the expression of which may act as a prognostic indicator for the proliferation, metastasis, and response to immunotherapy. EMP1 might be involved in the regulation on M1/M2 ratio.

Characterization of a novel LTA/LPS-binding antimicrobial and anti-inflammatory temporin peptide from the skin of Fejervary limnocharis (Anura: Ranidae).

Septic shock caused by Gram-positive bacteria continues to be a major cause of morbidity and mortality in intensive care units globally. Most Temporins are excellent growth inhibitors of gram-positive bacteria and candidates for developing antimicrobial treatments due to their biological action and small molecular weight. In this study, a novel Temporin peptide from the skin of Fejervarya limnocharis frog, named as Temporin-FL, was characterized. Temporin-FL was found to adopt typical α-helical conformation in SDS solution and to exhibit selective antibacterial activity against Gram-positive bacteria through a membrane destruction mechanism. Accordingly, Temporin-FL showed protective effects against Staphylococcus aureus-induced sepsis in mice. Finally, Temporin-FL was demonstrated to exert anti-inflammatory effects by neutralizing the action of LPS/LTA and by inhibiting MAPK pathway activation. Therefore, Temporin-FL represents a novel candidate for moleculartherapy of Gram-positive bacterial sepsis.

Peptide TK-HR from the Skin of Chinese Folk Medicine Frog Hoplobatrachus Rugulosus Accelerates Wound Healing via the Activation of the Neurokinin-1 Receptor.

Wound healing is a complex process and remains a considerable challenge in clinical trials due to the lack of ideal therapeutic drugs. Here, a new peptide TK-HR identified from the skin of the frog Hoplobatrachus rugulosus was tested for its ability to heal cutaneous wounds in mice. Topical application of TK-HR at doses of 50-200 µg/mL significantly accelerated wound closure without causing any adverse effects in the animals. In vitro and in vivo investigations proved the regulatory role of the peptide on neutrophils, macrophages, keratinocytes, and vein endothelial cells involved in the inflammatory, proliferative, and remodeling phases of wound healing. Notably, TK-HR activated the MAPK and TGF-ß-Smad signaling pathways by acting on NK1R in RAW264.7 cells and mice. The current work has identified that TK-HR is a potent wound healing regulator that can be applied for the treatment of wounds, including diabetic foot ulcers and infected wounds, in the future.

Novel Amphibian Bowman-Birk-Like Inhibitor with Antioxidant and Anticoagulant Effects Ameliorates Pancreatitis Symptoms in Mice.

Acute pancreatitis (AP) is a serious inflammatory disorder and still lacks effective therapy globally. In this study, a novel Ranacyclin peptide, Ranacin, was identified from the skin of Pelophylax nigromaculatus frog. Ranacin adopted a compact ß-hairpin conformation with a disulfide bond (Cys5-Cys15). Ranacin was also demonstrated effectively to inhibit trypsin and have anticoagulant and antioxidant activities in vitro. Furthermore, the severity of pancreatitis was significantly alleviated in l-Arg-induced AP mice after treatment with Ranacin. In addition, structure-activity studies of Ranacin analogues confirmed that the sequences outside the trypsin inhibitory loop (TIL), especially at the C-terminal side, might be closely associated with the efficacy of its trypsin inhibitory activity. In conclusion, our data suggest that Ranacin can improve pancreatic injury in mice with severe AP through its multi-activity. Therefore, Ranacin is considered a potential drug candidate in AP therapy.

Positive association between triglyceride glucose index and central systolic blood pressure among hypertensive adults.

BACKGROUND: While studies have suggested the association between triglyceride-glucose (TyG) index, a reliable surrogate for insulin resistance and hypertension data are limited to the correlation of TyG and central blood pressure. This study aims to test the hypothesis that a higher TyG index is associated with elevated central systolic blood pressure (cSBP). METHODS: A total of 9249 Chinese hypertensive adults from the H-type Hypertension and Stroke Prevention and Control Project were analyzed in this study. cSBP was measured noninvasively using an A-Pulse CASPro device. TyG index was calculated as ln [fasting triglycerides (mg/dL) × fasting glucose (mg/dL)/2]. Smoothing curve and multivariate linear regression models [beta coefficient (ß) with 95% CI] were applied to analyze the association between TyG index and cSBP. Subgroup analyses were conducted to explore potential modifications to such a correlation. RESULTS: The overall mean TyG index is 8.8 ± 0.7, and the total mean cSBP is 131.3 ± 12.8 mmHg. TyG index was observed to be independently and positively associated with cSBP among the total population (ß = 0.92, 95% CI: 0.53-1.31, P < 0.001), and participants who do not use antihypertensive drugs (ß = 1.03, 95% CI: 0.46-1.60, P < 0.001), which is in accordance with the result of the smoothing curve. The association between TyG index and cSBP appears robust in all tested subgroups. CONCLUSIONS: TyG index is positively and independently associated with cSBP among hypertensive adults. Our study result suggests that TyG index might serve as an effective marker for vascular function.

The Strong Anti-Tumor Effect of Smp24 in Lung Adenocarcinoma A549 Cells Depends on Its Induction of Mitochondrial Dysfunctions and ROS Accumulation.

Non-small cell lung cancer (NSCLC) is the leading cause of death in lung cancer due to its aggressiveness and rapid migration. The potent antitumor effect of Smp24, an antimicrobial peptide derived from Egyptian scorpion Scorpio maurus palmatus via damaging the membrane and cytoskeleton have been reported earlier. However, its effects on mitochondrial functions and ROS accumulation in human lung cancer cells remain unknown. In the current study, we discovered that Smp24 can interact with the cell membrane and be internalized into A549 cells via endocytosis, followed by targeting mitochondria and affect mitochondrial function, which significantly causes ROS overproduction, altering mitochondrial membrane potential and the expression of cell cycle distribution-related proteins, mitochondrial apoptotic pathway, MAPK, as well as PI3K/Akt/mTOR/FAK signaling pathways. In summary, the antitumor effect of Smp24 against A549 cells is related to the induction of apoptosis, autophagy plus cell cycle arrest via mitochondrial dysfunction, and ROS accumulation. Accordingly, our findings shed light on the anticancer mechanism of Smp24, which may contribute to its further development as a potential agent in the treatment of lung cancer cells.

Irisin Regulating Skeletal Response to Endurance Exercise in Ovariectomized Mice by Promoting Akt/ß-Catenin Pathway.

Purpose: Thought irisin is recognized as a pivotal modulator for bone formation, its role in regulating skeletal response to exercise training remains unknown. Therefore, we aimed to determine the change of irisin in response to 8-week exercise training and its role in regulating the effects of exercise on bone loss in ovariectomized (Ovx) mice. Methods: Forty 3-month old female C57BL/6 mic were randomly allocated into four groups: (1) Sham-operated (Sham); (2) ovariectomized; (3) Ovx plus 8-week downhill running exercise (Ex); (4) Ovx plus exercise and received twice weekly injection of cyclo RGDyk protein (a putative anti-irisin receptor agents) (ExRg). Results: Ex group showed enhanced cortical and trabecular volumetric bone mineral density (vBMD) (p < 0.05), improved bone microarchitecture, and increased intensity of alkaline phosphatase positive (ALP+) cells compared with Ovx group. However, cyclo RGDyk administration weakened the exercise-related improvement of vBMD, BV/TV, and ALP intensity in bone. Serum estradiol, irisin, and bone alkaline phosphatase were higher, whereas circulating tartrate-resistant acid phosphatase was lower in Ex group compared with Ovx group (p < 0.05). Exercise promoted mRNA expression of fibronectin type III domain-containing protein 5 (FNDC5), Akt and ß-catenin, and enhanced protein levels of FNDC5, the ratio of phosphorylated Akt (p-Akt) to Akt, and ß-catenin (p < 0.05). When irisin pathways were blocked with cyclo RGDyk, increment of Akt, p-Akt/Akt, and ß-catenin in Ex mice were attenuated. Conclusion: It is suggested that irisin plays a potential role in regulating skeletal response to exercise partly through its interaction with Akt/ß-catenin pathways.

Anticholinergic drugs and the risk of dementia: A systematic review and meta-analysis.

Dementia is one of the greatest global challenges for public health; however, the relationship between anticholinergic drugs and dementia remains unclear. The aim of the present study was to perform a systematic review and meta-analysis of the predictive roles of anticholinergic drugs in dementia risk. After pooling fourteen longitudinal and case-control studies with a total of 1,564,181 subjects, anticholinergic drug use was associated with an increased risk of all-cause dementia and Alzheimer's disease. Both low and high anticholinergic drug burdens were associated with dementia. Moreover, there was a dose-dependent relationship between anticholinergic drugs and risk of dementia. With respect to the categories of anticholinergic drugs, antiparkinson, urological drugs, and antidepressants increased the risk for dementia; however, cardiovascular and gastrointestinal drugs played potentially protective roles. These findings underscore the importance of anticholinergic drugs as a potential modifiable risk factor for dementia and provide treatment priorities to optimize dementia prevention.

Undercarboxylated osteocalcin inhibits the early differentiation of osteoclast mediated by Gprc6a.

Osteocalcin (OCN) was the most abundant noncollagen protein and considered as an endocrine factor. However, the functions of Undercarboxylated osteocalcin (ucOCN) on osteoclast and bone resorption are not well understood. In the present study, preosteoclast RAW264.7 cells and bone marrow mononuclear cells (BMMs) were treated with ucOCN purified from prokaryotic bacteria. Our results showed that ucOCN attenuated the proliferation of RAW264.7 cells with a concentration dependant manner by MTS assay. Scrape wounding assay revealed the decreased motility of RAW264.7 cells after ucOCN treatment. RT-qPCR results manifested the inhibitory effects of ucOCN on the expression of osteoclastic marker genes in RAW264.7 cells during inducing differentiation of RANKL. It was also observed that ucOCN inhibited the formation of multinucleated cells from RAW264.7 cells and BMMs detected by TRAP staining. The number and area of bone resorb pits were also decreased after treatment with ucOCN during their osteoclast induction by toluidine blue staining. The formation and integrity of the osteoclast actin ring were impaired by ucOCN by immunofluorescent staining. Time dependant treatment of ucOCN during osteoclastic induction demonstrated the inhibitory effects mainly occurred at the early stage of osteoclastogenesis. Signaling analysis of luciferase activity of the CRE or SRE reporter and ERK1/2 phosphorylation showed the selective inhibitor or siRNA of Gprc6a (a presumptive ucOCN receptor) could attenuate the promotion of ucOCN on CRE-luciferase activity. Taken together, we provided the first evidence that ucOCN had negative effects on the early differentiation and bone resorption of osteoclasts via Gprc6a.

Sleep disturbances during pregnancy and adverse maternal and fetal outcomes: A systematic review and meta-analysis.

Sleep disturbances are highly prevalent in pregnancy and are frequently overlooked as a potential cause of significant morbidity. The association between sleep disturbances and pregnancy outcomes remains largely controversial and needs to be clarified to guide management. To evaluate the association between sleep disturbances and maternal complications and adverse fetal outcomes, we performed a systematic search of PubMed, Embase and Web of Science for English-language articles published from inception to March 6, 2020, including observational studies of pregnant women with and without sleep disturbances assessing the risk of obstetric complications in the antenatal, intrapartum or postnatal period, and neonatal complications. Data extraction was completed independently by two reviewers. We utilized the Newcastle-Ottawa Scales to assess the methodological quality of included studies and random-effect models to pool the associations. A total of 120 studies with 58,123,250 pregnant women were included. Sleep disturbances were assessed, including poor sleep quality, extreme sleep duration, insomnia symptoms, restless legs syndrome, subjective sleep-disordered breathing and diagnosed obstructive sleep apnea. Significant associations were found between sleep disturbances in pregnancy and a variety of maternal complications and adverse fetal outcomes. Overall sleep disturbances were significantly associated with pre-eclampsia (odds ratio = 2.80, 95% confidence interval: 2.38-3.30), gestational hypertension (1.74, 1.54-1.97), gestational diabetes mellitus (1.59, 1.45-1.76), cesarean section (1.47, 1.31-1.64), preterm birth (1.38, 1.26-1.51), large for gestational age (1.40, 1.11-1.77), and stillbirth (1.25, 1.08-1.45), but not small for gestational age (1.03, 0.92-1.16), or low birth weight (1.27, 0.98-1.64). Sleep disturbances were related to higher morbidities in pregnant women who are 30 y or older and overweight before pregnancy. The findings indicate that sleep disturbances, which are easily ignored and treatable for both pregnant women and clinical services, deserve more attention from health care providers during prenatal counseling and health care services.

Association of Longitudinal Patterns of Habitual Sleep Duration With Risk of Cardiovascular Events and All-Cause Mortality.

Importance: Single self-reported measures of sleep duration are associated with adverse health outcomes; however, long-term patterns of self-reported sleep duration and their association with cardiovascular events (CVEs) and all-cause mortality remain unknown. Objective: To determine whether trajectories of long-term vs single-measure sleep duration are associated with subsequent risk of CVEs and all-cause mortality. Design, Setting, and Participants: The Kailuan study is a prospective, population-based cohort study that began in 2006. The present cohort included 52 599 Chinese adults without atrial fibrillation, myocardial infarction, stroke, or cancer to 2010. Trajectories in sleep duration from January 1, 2006, to December 31, 2010, were identified to investigate the association with risk of CVEs and all-cause mortality from January 1, 2010, to December 31, 2017. Data analysis was conducted from July 1 to October 31, 2019. Exposures: Habitual self-reported nocturnal sleep durations were collected in 2006, 2008, and 2010. Trajectories in sleep duration for 4 years were identified by latent mixture modeling. Main Outcomes and Measures: All-cause mortality and first incident CVEs (atrial fibrillation, myocardial infarction, and stroke) from 2010 to 2017 were confirmed by medical records. Based on the baseline sleep duration and patterns over time, 4 trajectories were categorized (normal stable, normal decreasing, low increasing, and low stable). Results: Of the 52 599 adults included in the study (mean [SD] age at baseline, 52.5 [11.8] years), 40 087 (76.2%) were male and 12 512 (23.8%) were female. Four distinct 4-year sleep duration trajectory patterns were identified: normal stable (range, 7.4 to 7.5 hours [n = 40 262]), normal decreasing (mean decrease from 7.0 to 5.5 hours [n = 8074]), low increasing (mean increase from 4.9 to 6.9 hours [n = 3384]), and low stable (range, 4.2 to 4.9 hours [n = 879]). During a mean (SD) follow-up of 6.7 (1.1) years, 2361 individuals died and 2406 had a CVE. Compared with the normal-stable pattern and adjusting for potential confounders, a low-increasing pattern was associated with increased risk of first CVEs (hazard ratio [HR], 1.22; 95% CI, 1.04-1.43), a normal-decreasing pattern was associated with increased risk of all-cause mortality (HR, 1.34; 95% CI, 1.15-1.57), and the low-stable pattern was associated with the highest risk of CVEs (HR, 1.47; 95% CI, 1.05-2.05) and death (HR, 1.50; 95% CI, 1.07-2.10). Conclusions and Relevance: In this study, sleep duration trajectories with lower or unstable patterns were significantly associated with increased risk of subsequent first CVEs and all-cause mortality. Longitudinal sleep duration patterns may assist in more precise identification of different at-risk groups for possible intervention. People reporting consistently sleeping less than 5 hours per night should be regarded as a population at higher risk for CVE and mortality.

Molecular Characterization and Key Binding Sites of Sex Pheromone-Binding Proteins from the Meadow Moth, Loxostege sticticalis.

The meadow moth, Loxostege sticticalis, is a typical agricultural pest that uses sex pheromones to mediate mating behavior; however, the mechanism underlying the selectivity of its pheromone-binding proteins (PBPs) remains unknown. In this study, LstiPBP1 and LstiPBP3 were cloned, expressed, and purified, and the fluorescence binding assay showed that LstiPBP1 binds to the major sex pheromone component, E-11-tetradecenol (E11-14:OH), with high affinity; moreover, E11-14:OH could evoke a significant antennal electrophysiological response and attract L. sticticalis males. After LstiPBP1 was silenced, both the antennal response and attractiveness of E11-14:OH decreased significantly. Molecular docking predicted that a hydrogen bonding site, Leu37, played key role in the binding of LstiPBP1 to E11-14:OH. After Leu37 was mutated, the E11-14:OH-binding affinity decreased drastically. These results suggest that LstiPBP1 participates in E11-14:OH recognition and could be used as a target gene to disturb the mating behavior of L. sticticalis and develop new odorants for pest control.