Establishment and validation of a gene mutation-based risk model for predicting prognosis and therapy response in acute myeloid leukemia.

Background: Acute myeloid leukemia (AML) is a malignant clonal proliferative disease of hematopoietic system. Despite tremendous progress in uncovering the AML genome, only a small number of mutations have been incorporated into risk stratification and used as therapeutic targets. In this research, we performed to construct a predictive prognosis risk model for AML patients according to gene mutations. Methods: Next-generation sequencing (NGS) technology was utilized to detect gene mutation from 118 patients. mRNA expression profiles and related clinical information were mined from TCGA and GEO databases. Consensus cluster analysis was applied to obtain molecular subtypes, and differences in clinicopathological features, prognosis, and immune microenvironment of different clusters were systematically compared. According to the differentially expressed genes (DEGs) between clusters, univariate and LASSO regression analysis were applied to identify gene signatures to build a prognostic risk model. Patients were classified into high-risk (HR) and low-risk (LR) groups according to the median risk score (RS). Differences in prognosis, immune profile, and therapeutic sensitivity between two groups were analyzed. The independent predictive value of RS was assessed and a nomogram was developed. Results: NGS detected 24 mutated genes, with higher mutation frequencies in CBL (63 %) and SETBP1 (49 %). Two clusters exhibited different immune microenvironments and survival probability (p = 0.0056) were identified. A total of 444 DEGs were screened in two clusters, and a mutation-associated risk model was constructed, including MPO, HGF, SH2B3, SETBP1, HLA-DRB1, LGALS1, and KDM5B. Patients in LR had a superior survival time compared to HR. Predictive performance of this model was confirmed and the developed nomogram further improved the applicability of the risk model with the AUCs for predicting 1-, 3-, 5-year survival rate were 0.829, 0.81 and 0.811, respectively. HR cases were more sensitive to erlotinib, CI-1040, and AZD6244. Conclusion: These findings supplemented the understanding of gene mutations in AML, and constructed models had good application prospect to provide effective information for predicting prognosis and treatment response of AML.

Prenatal arsenic metabolite exposure is associated with increased newborn mitochondrial DNA copy number: evidence from a birth cohort study.

While mitochondria are susceptible to environmental detriments, little is known about potential associations between arsenic metabolites and mitochondria DNA copy number (mtDNAcn). We attempted to examine whether maternal urinary arsenic metabolite levels in different trimesters were related to neonatal cord blood mtDNAcn. We included 819 mother-newborn pairs embedded in an in-progress birth cohort survey performed from April 2014 to October 2016 in Wuhan, China. We determined maternal urinary arsenic species concentrations in different trimesters. We determined cord blood mtDNAcn using quantitative real-time polymerase chain reaction. In covariate-adjusted models, each one-unit increment of dimethylated arsenic (DMA) and total arsenic (TAs) in the third trimester was related to 8.43% (95% CI 1.13%, 16.26%) and 12.15% (95% CI 4.35%, 20.53%) increases in mtDNAcn, respectively. The dose-response trend with statistical significance was observed across tertiles of DMA and TAs in the third trimester with mtDNAcn (DMA percent changes (%Δ) = 25.60 (95% CI 6.73, 47.82), for the highest vs the lowest tertile (P = 0.02); TAs %Δ = 40.31 (95% CI 19.25, 65.10), for the highest vs the lowest tertile (P = 0.0002)). These findings may prove the relationships between prenatal arsenic species levels and neonatal mitochondrial dysfunction.

Forensic features and phylogenetic structure survey of four populations from southwest China via the autosomal insertion/deletion markers.

Insertion/Deletion (InDel) polymorphisms, characterized by their smaller amplicons, reduced mutation rates, and compatibility with the prevalent capillary electrophoresis (CE) platforms in forensic laboratories, significantly contribute to the advancement and application of genetic analysis. Guizhou province in China serves as an important region for investigating the genetic structure, ethnic group origins, and human evolution. However, DNA data and the sampling of present-day populations are lacking, especially about the InDel markers. Here, we reported data on 47 autosomal InDels from 592 individuals from four populations in Guizhou (Han, Dong, Yi, and Chuanqing). Genotyping was performed with the AGCU InDel 50 kit to evaluate their utility for forensic purposes and to explore the population genetic structure. Our findings showed no significant deviations from Hardy-Weinberg and linkage equilibriums. The combined power of discrimination (CPD) and the combined power of exclusion (CPE) for each population demonstrated that the kit could be applied to forensic individual identification and was an effective supplement for parentage testing. Genetic structure analyses, including principal component analysis, multidimensional scaling, genetic distance calculation, STRUCTURE, and phylogenetic analysis, highlighted that the genetic proximity of the studied populations correlates with linguistic, geographical, and cultural factors. The observed genetic variances within four research populations were less pronounced than those discerned between populations across different regions. Notably, the Guizhou Han, Dong, and Chuanqing populations showed closer genetic affiliations with linguistically similar groups than the Guizhou Yi. These results underscore the potential of InDel markers in forensic science and provide insights into the genetic landscape and human evolution in multi-ethnic regions like Guizhou. Key points: InDel markers show promise for forensic individual identification and parentage testing via the AGCU InDel 50 kit.Genetic analysis of Guizhou populations reveals correlations with linguistic, geographical, and cultural factors.Guizhou Han, Dong, and Chuanqing populations showed closer genetic affiliations with linguistically similar groups than the Guizhou Yi.

Genetic association of serum lipids and lipid-modifying targets with endometriosis: Trans-ethnic Mendelian-randomization and mediation analysis.

BACKGROUND: Prior observational research identified dyslipidemia as a risk factor for endometriosis (EMS) but the causal relationship remains unestablished due to inherent study limitations. METHODS: Genome-wide association study data for high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and total cholesterol (TC) from European (EUR) and East Asian (EAS) ancestries were sourced from the Global Lipids Genetics Consortium. Multi-ancestry EMS data came from various datasets. Univariable Mendelian randomization (MR) examined causal links between serum lipids and EMS. Multivariable and mediation MR explored the influence of seven confounding factors and mediators. Drug-target MR investigates the association between lipid-lowering target genes identified in positive results and EMS. The primary method was inverse-variance weighted (IVW), with replication datasets and meta-analyses reinforcing causal associations. Sensitivity analyses included false discovery rate (FDR) correction, causal analysis using summary effect estimates (CAUSE), and colocalization analysis. RESULTS: IVW analysis in EUR ancestry showed a significant causal association between TG and increased EMS risk (OR = 1.112, 95% CI 1.033-1.198, P = 5.03×10-3, PFDR = 0.03), supported by replication and meta-analyses. CAUSE analysis confirmed unbiased results (P < 0.05). Multivariable and mediation MR revealed that systolic blood pressure (Mediation effect: 7.52%, P = 0.02) and total testosterone (Mediation effect: 10.79%, P = 0.01) partly mediated this relationship. No causal links were found between other lipid traits and EMS (P > 0.05 & PFDR > 0.05). In EAS ancestry, no causal relationships with EMS were detected (P > 0.05 & PFDR > 0.05). Drug-target MR indicated suggestive evidence for the influence of ANGPTL3 on EMS mediated through TG (OR = 0.798, 95% CI 0.670-0.951, P = 0.01, PFDR = 0.04, PP.H4 = 0.85%). CONCLUSIONS: This MR study in EUR ancestry indicated an increased EMS risk with higher serum TG levels.

Risk factors for invasive pulmonary aspergillosis in patients with severe fever with thrombocytopenia syndrome: A multicenter retrospective study.

Invasive pulmonary aspergillosis (IPA) is a life-threatening complication in patients with severe fever with thrombocytopenia syndrome (SFTS), yet SFTS-associated IPA (SAPA)'s risk factors remain undefined. A multicenter retrospective cohort study across Hubei and Anhui provinces (May 2013-September 2022) utilized least absolute shrinkage and selection operator (LASSO) regression for variable selection. Multivariable logistic regression identified independent predictors of SAPA, Cox regression highlighted mortality-related risk factors. Of the 1775 screened SFTS patients, 1650 were included, with 169 developing IPA, leading to a 42-day mortality rate of 26.6% among SAPA patients. Multivariable logistic regression revealed SAPA risk factors including advanced age, petechia, hemoptysis, tremor, low albumin levels, elongated activated partial thromboplastin time (APTT), intensive care unit (ICU) admission, glucocorticoid usage, intravenous immunoglobulin (IVIG) and prolonged hospital stays. Cox regression identified predictors of 42-day mortality, including ecchymosis at venipuncture sites, absence of ICU admission, elongated prothrombin time (PT), vasopressor and glucocorticoid use, non-antifungals. Nomograms constructed on these predictors registered concordance indexes of 0.855 (95% CI: 0.826-0.884) and 0.778 (95% CI: 0.702-0.854) for SAPA onset and 42-day mortality, respectively. Lower survival rates for SAPA patients treated with glucocorticoids (p < 0.001) and improved 14-day survival with antifungal therapy (p = 0.036). Improving IPA management in SFTS-endemic areas is crucial, with effective predictive tool.

Preparing a novel baicalin-loaded microemulsion-based gel for transdermal delivery and testing its anti-gout effect.

We previously demonstrated that baicalin had efficacy against gouty arthritis (GA) by oral administration. In this paper, a novel baicalin-loaded microemulsion-based gel (B-MEG) was prepared and assessed for the transdermal delivery of baicalin against GA. The preparation method and transdermal capability of B-MEG was screened and optimized using the central composite design, Franz diffusion cell experiments, and the split-split plot design. Skin irritation tests were performed in guinea pigs. The anti-gout effects were evaluated using mice. The optimized B-MEG comprised of 50 % pH 7.4 phosphate buffered saline, 4.48 % ethyl oleate, 31.64 % tween 80, 13.88 % glycerin, 2 % borneol, 0.5 % clove oil and 0.5 % xanthan gum, with a baicalin content of (10.42 ± 0.08) mg/g and particle size of (15.71 ± 0.41) nm. After 12 h, the cumulative amount of baicalin permeated from B-MEG was (672.14 ± 44.11) µg·cm-2. No significant skin irritation was observed following B-MEG application. Compared to the model group, B-MEG groups significantly decreased the rate of auricular swelling (P < 0.01) and number of twists observed in mice (P < 0.01); and also reduced the rate of paw swelling (P < 0.01) and inflammatory cell infiltration in a mouse model of GA. In conclusion, B-MEG represents a promising transdermal carrier for baicalin delivery and can be used as a potential therapy for GA.

Succession changes of microbial community for inferring the time since deposition of saliva.

Saliva is a common biological examination material at crime scenes and has high application value in forensic case investigations. It can reflect the suspect's time of crime at the scene and provide evidence of the suspect's criminal facts. Even though many researchers have proposed their experimental protocols for estimating the time since deposition (TsD) of saliva, there is still a relative lack of research on the use of microorganisms to estimate TsD. In the current study, the succession change of microbial community in saliva with different TsD values was explored to discern the microbial markers related to TsD of saliva. We gathered saliva samples from six unrelated healthy Han individuals living in Guizhou, China and exposed these samples to indoor conditions at six time points (0, 1, 3, 7, 15, and 28 days). Temporal changes of microbial compositions in these samples were investigated by 16S rRNA sequencing (V3-V4 regions). By assessing temporal variation patterns of microbial abundance at the genus level, four bacteria (Brucella, Prevotella, Pseudomonas, and Fusobacterium) were observed to show good time dependence in these samples. In addition, the hierarchical clustering and principal co-ordinates analysis results revealed that these saliva samples could be classified into t-short (≤7 days) and t-long (>7 days) groups. In the end, the random forest model was developed to predict the TsD of these samples. For the model, the root mean square error, R2, and mean absolute error between predicted and actual TsD values were 1.5213, 0.9851, and 1.1969, respectively. To sum up, we identified TsD-related microbial markers in saliva samples, which could be viewed as valuable markers for inferring the TsD of saliva.

[Annual review of clinical research on extracorporeal life support in 2023].

The clinical research in the field of extracorporeal life support (ECLS) in 2023 has focused on the efficacy of veno-arterial extracorporeal membrane oxygenation (ECMO) in patients with infarct-related cardiogenic shock. Additionally, the research also explored the efficacy of prone positioning during veno-venous ECMO, transfusion strategies, and the impact of obesity on outcomes. Awake veno-venous ECMO has shown novel therapeutic potential, but its optimal practice methods and management strategies remain to be determined. In in-hospital cardiac arrest patients, extracorporeal cardiopulmonary resuscitation has demonstrated higher survival rates and better neurological recovery compared to conventional cardiopulmonary resuscitation. The effectiveness of extracorporeal carbon dioxide removal varies among patients with different types of respiratory failure. Future research should focus on optimizing the application strategies and process management of ECLS technologies, investigating personalized therapy, and studying how to improve long-term rehabilitation and quality of life for survivors.

Spatiotemporal transformable nano-assembly for on-demand drug delivery to enhance anti-tumor immunotherapy.

Induction of tumor cell senescence has become a promising strategy for anti-tumor immunotherapy, but fibrotic matrix severely blocks senescence inducers penetration and immune cells infiltration. Herein, we designed a cancer-associated fibroblasts (CAFs) triggered structure-transformable nano-assembly (HSD-P@V), which can directionally deliver valsartan (Val, CAFs regulator) and doxorubicin (DOX, senescence inducer) to the specific targets. In detail, DOX is conjugated with hyaluronic acid (HA) via diselenide bonds (Se-Se) to form HSD micelles, while CAFs-sensitive peptide is grafted onto the HSD to form a hydrophilic polymer, which is coated on Val nanocrystals (VNs) surface for improving the stability and achieving responsive release. Once arriving at tumor microenvironment and touching CAFs, HSD-P@V disintegrates into VNs and HSD micelles due to sensitive peptide detachment. VNs can degrade the extracellular matrix, leading to the enhanced penetration of HSD. HSD targets tumor cells, releases DOX to induce senescence, and recruits effector immune cells. Furthermore, senescent cells are cleared by the recruited immune cells to finish the integrated anti-tumor therapy. In vitro and in vivo results show that the nano-assembly remarkably inhibits tumor growth as well as lung metastasis, and extends tumor-bearing mice survival. This work provides a promising paradigm of programmed delivering multi-site nanomedicine for cancer immunotherapy.

Extracorporeal membrane oxygenation in adult patients with sepsis and septic shock: Why, how, when, and for whom.

Sepsis and septic shock remain the leading causes of death in intensive care units. Some patients with sepsis fail to respond to routine treatment and rapidly progress to refractory respiratory and circulatory failure, necessitating extracorporeal membrane oxygenation (ECMO). However, the role of ECMO in adult patients with sepsis has not been fully established. According to existing studies, ECMO may be a viable salvage therapy in carefully selected adult patients with sepsis. The choice of venovenous, venoarterial, or hybrid ECMO modes is primarily determined by the patient's oxygenation and hemodynamics (distributive shock with preserved cardiac output, septic cardiomyopathy (left, right, or biventricular heart failure), or right ventricular failure caused by acute respiratory distress syndrome). Veno-venous ECMO can be used in patients with sepsis and severe acute respiratory distress syndrome when conventional mechanical ventilation fails, and early application of veno-arterial ECMO in patients with sepsis-induced refractory cardiogenic shock may be critical in improving their chances of survival. When ECMO is indicated, the choice of an appropriate mode and determination of the optimal timing of initiation and weaning are critical, particularly in an experienced ECMO center. Furthermore, some special issues, such as ECMO flow, anticoagulation, and antibiotic therapy, should be noted during the management of ECMO support.

Ultrasensitive Optical Detection and Elimination of Residual Microtumors with a Postoperative Implantable Hydrogel Sensor for Preventing Cancer Recurrence.

In vivo optical imaging of trace biomarkers in residual microtumors holds significant promise for cancer prognosis but poses a formidable challenge. Here, a novel hydrogel sensor is designed for ultrasensitive and specific imaging of the elusive biomarker. This hydrogel sensor seamlessly integrates a molecular beacon nanoprobe with fibroblasts, offering both high tissue retention capability and an impressive signal-to-noise ratio for imaging. Signal amplification is accomplished through exonuclease I-mediated biomarker recycling. The resulting hydrogel sensor sensitively detects the biomarker carcinoembryonic antigen with a detection limit of 1.8 pg mL-1 in test tubes. Moreover, it successfully identifies residual cancer nodules with a median diameter of less than 2 mm in mice bearing partially removed primary triple-negative breast carcinomas (4T1). Notably, this hydrogel sensor is proven effective for the sensitive diagnosis of invasive tumors in post-surgical mice with infiltrating 4T1 cells, leveraging the role of fibroblasts in locally enriching tumor cells. Furthermore, the residual microtumor is rapidly photothermal ablation by polydopamine-based nanoprobe under the guidance of visualization, achieving ≈100% suppression of tumor recurrence and lung metastasis. This work offers a promising alternative strategy for visually detecting residual microtumors, potentially enhancing the prognosis of cancer patients following surgical interventions.

Analysis of maternal genetic structure of mitochondrial DNA control region from Tai-Kadai-speaking Buyei population in southwestern China.

BACKGROUND: Even though the Buyei are a recognised ethnic group in southwestern China, there hasn't been much work done on forensic population genetics, notably using mitochondrial DNA. The sequences and haplogroups of mitochondrial DNA control regions of the Buyei peoples were studied to provide support for the establishment of a reference database for forensic DNA analysis in East Asia. METHODS AND RESULTS: The mitochondrial DNA control region sequences of 200 Buyei individuals in Guizhou were investigated. The haplotype frequencies and haplogroup distribution of the Buyei nationality in Guizhou were calculated. At the same time, the paired Fst values of the study population and other populations around the world were computed, to explore their genetic polymorphism and population relationship. A total of 179 haplotypes were detected in the Buyei population, with frequencies of 0.005-0.015. All haplotypes were assigned to 89 different haplogroups. The haplotype diversity and random matching probability were 0.999283 and 0.0063, respectively. The paired Fst genetic distances and correlation p-values among the 54 populations revealed that the Guizhou Buyei was most closely related to the Henan Han and the Guizhou Miao, and closer to the Hazara population in Pakistan and the Chiang Mai population. CONCLUSIONS: The study of mitochondrial DNA based on the maternal genetic structure of the Buyei nationality in Guizhou will benefit the establishment of an East Asian forensic DNA reference database and provide a reference for anthropological research in the future.

Associations of intrauterine exposure to manganese with fetal and early-childhood growth: a prospective prenatal cohort study.

Prenatal manganese (Mn) exposure may be related to poor birth outcomes; however, there are few relevant epidemiological reports on the effects of intrauterine Mn levels on intrauterine fetal and early childhood growth. From 2013 to 2016, 2082 pairs of mothers and infants were recruited in Wuhan, China, who provided an entire set of urine samples during their first, second, and third trimesters. Fetal head circumference (HC), abdominal circumference (AC), femoral length (FL), and estimated fetal weight (EFW) were obtained by ultrasound at the 16, 24, and 31 weeks of pregnancy. When the children were born, 6 months old, 12 months old, and 24 months old, their weight, height, weight-for-height, and BMI were measured. We used generalized linear models, generalized estimated equations, and restricted cubic spline curves (RCS) to investigate the linear and nonlinear relationships between antenatal Mn levels and fetal and early childhood growth. In all fetuses, Mn exposure during the 1st and 2nd gestation was associated with decreased fetal AC, FL, and EFW at 24 weeks (e.g., for each doubling of urinary Mn concentrations during the 1st and 2nd gestation, the SD score of EFW at 24 weeks decreased by - 4.16% (95% CI, - 6.22%, - 2.10%) and - 3.78% (95% CI, - 5.86%, - 1.70%)). Mn concentrations in the highest tertile group of the 1st and 2nd gestation were related to decreased fetus growth parameters compared to the lowest tertile group. For each doubling of the average Mn concentrations during pregnancy, the z-scores of weight, weight-for-height, and BMI at 12 months decreased, with percentage changes of - 2.93% (95% CI, - 5.08%, - 0.79%), - 3.25% (95% CI, - 5.56%, - 0.94%), and - 3.09% (95% CI, - 5.44%, - 0.73%). In the RCS model, we found a reverse U-shaped association between 1st trimester Mn concentration and fetal FL at 16 weeks and HC at 31 weeks in male fetuses and a non-linear association between mean Mn concentration during pregnancy and girls' weight-for-height and BMI at 6 months. Intrauterine exposure to Mn may be related to restricted growth in the fetus and early childhood, especially in fetuses at 24 weeks of gestation and children at 12 months of age. Also, meaningful curvilinear relationships were found in the sex stratification.

Effect of Thyroid-Stimulating Hormone Suppression Therapy on Cardiac Structure and Function in Patients With Differentiated Thyroid Cancer After Thyroidectomy: A Systematic Review and Meta-Analysis.

OBJECTIVE: We aimed to evaluate the effects of thyroid-stimulating hormone (TSH) suppression therapy on cardiac structure and function in patients with differentiated thyroid cancer (DTC) following thyroidectomy. METHODS: Two investigators independently searched the PubMed, Embase, Cochrane Library, and Web of Science databases for relevant studies published from inception to January 6, 2023, without any restrictions on language. Standard mean differences and 95% confidence intervals were calculated using fixed or random effects models. Thirteen clinical outcomes were analyzed, mainly evaluating cardiac morphology, systolic function, and diastolic function. RESULTS: Thirteen studies were included in the quantitative analysis. Compared to healthy controls, left ventricular mass index, left ventricular posterior wall thickness, interventricular septal thickness, and isovolumic relaxation time values increased; the ratio of E-wave velocity to A-wave velocity and E-wave velocity values decreased. The left ventricular ejection fraction and cardiac output did not change in patients with DTC who underwent long-term TSH suppression therapy. Interventricular septal thickness values were significantly correlated with the duration of TSH suppression therapy. CONCLUSION: Long-term TSH suppression therapy leads to cardiac hypertrophy and impaired cardiac diastolic function in patients with DTC. These changes may be related to the duration of TSH suppression therapy. Large prospective studies with long follow-up periods are needed to validate these findings.

Associations of maternal urinary rare earth elements individually and in mixtures with neonatal size at birth.

Prenatal rare earth elements (REEs) exposure is linked to unfavorable health consequences. Epidemiologic research on repeated measurements of REEs during gestation correlated with fetal growth is exiguous. Until now, few studies have characterized exposure characteristics of REEs in pregnant women. We aimed to ascertain the characteristics and predictors of REEs exposure over three trimesters among pregnant women and examine the possible effects of prenatal REEs exposure on size at birth. Urinary REEs concentrations exhibited considerable within-subject variation with intraclass correlation coefficients ranging from 0.16 to 0.58. Maternal age, household income, gestational weight gain, passive smoking during pregnancy, parity, and neonatal gender were associated with maternal urinary REEs concentrations. Elevated maternal urinary holmium and thulium concentrations in the 3rd trimester were significantly related to reductions in birth weight. Weighted quantile sum (WQS) regression model identified that urinary REEs mixture in the 3rd trimester were negatively related to birth weight (WQSREEs ß = -26.22; 95% confidence interval [CI]: -47.62, -4.82), with holmium (40%) and thulium (24%) receiving the highest weights. Male infants received the most weight (>50%) related to decreased birth weight. This study revealed a significant association between individual and mixture REE exposure in late pregnancy with a reduction in birth weight.

Assessment of nonylphenol exposure based on global urinary concentration data and its risk analysis.

Nonylphenol (NP) has been recognized as a priority hazardous substance because of its estrogenic activity and ubiquity in the environment. Therefore, it is important to understand the daily intake of NP in humans and evaluate the potential health risks of NP. The median or average estimated daily intake (EDI) of NP was estimated based on urinary NP or alkyl-chain-oxidized NP metabolites concentration data from published epidemiological studies. In brief, we acquired 34 peer-reviewed publications, which contained 14235 samples from twelve countries or regions. The global average estimated daily intake of NP was 1.003 µg/(kg bw·day), which was lower than the tolerable daily intake recommended by the Danish Veterinary and Food Authority [5 µg/(kg bw·day)]. Korea had the highest exposure level [3.471 µg/(kg bw·day)] among different countries or regions. Compared with the adult [0.743 µg/(kg bw·day)] and pregnant women [0.806 µg/(kg bw·day)] groups, the children group had the highest estimated daily intake of NP at 2.368 µg/(kg bw·day). Besides, the global NP risk hazard quotient was 0.201, and the risk hazard quotients of all countries or regions were less than 1. However, the global HQ value of the 95th quantile population was 2.299, which was much higher than 1, the potential health risk cannot be ignored and needs to be confirmed by more research. To our knowledge, this is the first study to assess the overall NP exposure levels based on published biomonitoring data, and has important implications for assessing the potential effects of NP exposure on human health. In addition, OH-NP is a robust and sensitive novel biomarker for NP, there are fewer studies on the application of this biomarker, and more studies are needed in the future for quantitative exposure and risk assessment of NP.

Comparative Transcriptome Analysis of Galeruca daurica Reveals Cold Tolerance Mechanisms.

Galeruca daurica (Joannis) is a pest species with serious outbreaks in the Inner Mongolian grasslands in recent years, and its larvae and eggs are extremely cold-tolerant. To gain a deeper understanding of the molecular mechanism of its cold-tolerant stress response, we performed de novo transcriptome assembly of G. daurica via RNA-Seq and compared the differentially expressed genes (DEGs) of first- and second-instar larvae grown and developed indoors and outdoors, respectively. The results show that cold tolerance in G. daurica is associated with changes in gene expression mainly involved in the glycolysis/gluconeogenesis pathway, the fatty acid biosynthesis pathway and the production of heat shock proteins (HSPs). Compared with the control group (indoor), the genes associated with gluconeogenesis, fatty acid biosynthesis and HSP production were up-regulated in the larvae grown and developed outdoors. While the changes in these genes were related to the physiological metabolism and growth of insects, it was hypothesized that the proteins encoded by these genes play an important role in cold tolerance in insects. In addition, we also investigated the expression of genes related to the metabolic pathway of HSPs, and the results show that the HSP-related genes were significantly up-regulated in the larvae of G. daurica grown and developed outdoors compared with the indoor control group. Finally, we chose to induce significant expression differences in the Hsp70 gene (Hsp70A1, Hsp70-2 and Hsp70-3) via RNAi to further illustrate the role of heat stress proteins in cold tolerance on G. daurica larvae. The results show that separate and mixed injections of dsHSP70A1, dsHsp70-2 and dsHsp70-3 significantly reduced expression levels of the target genes in G. daurica larvae. The super-cooling point (SCP) and the body fluid freezing point (FP) of the test larvae were determined after RNAi using the thermocouple method, and it was found that silencing the Hsp70 genes significantly increased the SCP and FP of G. daurica larvae, which validated the role of heat shock proteins in the cold resistance of G. daurica larvae. Our findings provide an important theoretical basis for further excavating the key genes and proteins in response to extremely cold environments and analyzing the molecular mechanism of cold adaptation in insects in harsh environments.

Long-Term Safety and Efficacy of Initial and Repeat Treatment Courses With Zuranolone in Adult Patients With Major Depressive Disorder: Interim Results From the Open-Label, Phase 3 SHORELINE Study.

Objective: Zuranolone is a positive allosteric modulator of both synaptic and extrasynaptic γ-aminobutyric acid (GABA) type A receptors and a neuroactive steroid approved in the United States as an oral, once-daily, 14-day treatment course for adults with postpartum depression and under investigation for adults with major depressive disorder (MDD). Interim results from the open-label, longitudinal, phase 3 SHORELINE Study (NCT03864614) that evaluated the long-term safety and efficacy of zuranolone in adults with MDD are reported.Methods: This interim report includes patients who were enrolled and had the opportunity to be on study for up to 1 year between February 2019 and September 2021. Adults aged 18-75 years with MDD diagnosed per DSM-5 criteria and a 17-item Hamilton Rating Scale for Depression (HAMD-17) total score ≥ 20 received an initial 30-mg or 50-mg 14-day zuranolone course. HAMD-17 responders (≥ 50% reduction from baseline) at Day (D)15 of the initial treatment period were allowed to continue in the study beyond D28 and were followed up for ≤ 1 year, during which repeat treatment courses were permitted. The primary endpoint was safety and tolerability of the initial and repeat treatment courses through 1 year. Secondary endpoints included change from baseline (CFB) in HAMD-17 total score and need for repeat treatment course(s).Results: As of September 2021, among patients in the 30-mg (n = 725) and 50-mg (n = 199) Cohorts who received a zuranolone dose, 493 (68.0%) and 137 (68.8%), respectively, reported a treatment-emergent adverse event (TEAE); most patients who experienced TEAEs reported mild/moderate events (30-mg Cohort, 90.9% [448/493]; 50-mg Cohort, 85.4% [117/137]). Mean (standard deviation) CFB HAMD-17 total score at D15 of the initial treatment period was -15.2 (7.1) and -16.0 (6.0) for the 30-mg and 50-mg Cohorts, respectively; similar improvements were observed after repeat treatment courses. The proportion of patients who received only 1 treatment course during their time on study was 42.9% (210/489) in the 30-mg Cohort and 54.8% (80/146) in the 50-mg Cohort; 57.1% (279/489) and 45.2% (66/146) patients, respectively, received 2-5 total treatment courses. The majority of patients who initially responded to zuranolone received ≤ 2 total treatment courses (30-mg Cohort, 68.5% [335/489]; 50-mg Cohort, 79.5% [116/146]).Conclusions: Of patients who experienced TEAEs, most reported mild or moderately severe events, and responders to zuranolone experienced improvements in depressive symptoms with initial and repeat treatment courses.Trial Registration: ClinicalTrials.gov identifier: NCT03864614.

Insertion/deletion polymorphism for genetic background and forensic performance exploration of the Sui group from Guizhou.

Insertion/deletion polymorphisms (InDels) as ideal genetic markers for forensic genetics are appreciated by scholars both nationally and internationally because they integrated the favorable features of single nucleotide polymorphisms (SNPs) and short tandem repeats (STRs). Nevertheless, with the limited identification efficiency of InDels, the multiplex amplification systems of InDels might just be applied as the supplementary methods in paternity testing with respect to commonly used STRs. In the current research, we successfully genotyped 105 unrelated individuals from the Guizhou Sui population based on a six-color fluorescence multiplex panel that could simultaneously detect 64 genetic markers (59 autosomal InDels, two autosomal miniSTRs and three Y chromosomal genetic markers). In addition, frequency distributions and forensic statistical parameters of these loci in the Sui group were assessed using the STRAF software. Phylogenetic relationships among the Sui group and other reference populations were dissected by two methods (principal component analysis and phylogenetic trees) based on 59 InDels. The combined discrimination power and probability of exclusion values of 61 autosomal genetic markers in the Sui group were nearly equal to 1-1.90063 × 10-27 and 0.999998272, respectively. Furthermore, we observed that the Sui group from Guizhou had closer genetic affinities with East Asian populations with respect to other continental populations. In summary, we stated that the multiplex amplification system might be utilized as a prospective independent tool for human individual identification and parentage testing in the Sui group residing in Guizhou.

Altered cord blood mitochondrial DNA content and prenatal exposure to arsenic metabolites in low-arsenic areas.

While mitochondria are susceptible to environmental detriments, little is known about potential associations between arsenic metabolites and mitochondria DNA copy number (mtDNAcn). We attempted to examine whether arsenic metabolism in different trimesters was related to cord blood mtDNAcn alteration. We included 819 mother-newborn pairs embedded in an in-progress birth cohort survey performed from April 2014 to October 2016 in Wuhan, China. We determined maternal urinary arsenic species concentrations in different trimesters using HPLC-ICPMS. We decided on cord blood mtDNAcn using quantitative real-time polymerase chain reaction. In covariate-adjusted models, each two-fold increment of dimethylated arsenic (DMA) and total arsenic (TAs) in the 3rd trimester were related to 8.43% (95% CI: 1.13%, 16.26%) and 12.15% (95% CI:4.35%, 20.53%) increases in mtDNAcn, respectively. The dose-response trend with statistical significance was observed across tertiles of DMA and TAs in the 3rd trimester with mtDNAcn. These findings may prove the relationships between arsenic species and mitochondrial dysfunction.