Single-Cell Transcriptomic Atlas of Primate Ovarian Aging.

Molecular mechanisms of ovarian aging and female age-related fertility decline remain unclear. We surveyed the single-cell transcriptomic landscape of ovaries from young and aged non-human primates (NHPs) and identified seven ovarian cell types with distinct gene-expression signatures, including oocyte and six types of ovarian somatic cells. In-depth dissection of gene-expression dynamics of oocytes revealed four subtypes at sequential and stepwise developmental stages. Further analysis of cell-type-specific aging-associated transcriptional changes uncovered the disturbance of antioxidant signaling specific to early-stage oocytes and granulosa cells, indicative of oxidative damage as a crucial factor in ovarian functional decline with age. Additionally, inactivated antioxidative pathways, increased reactive oxygen species, and apoptosis were observed in granulosa cells from aged women. This study provides a comprehensive understanding of the cell-type-specific mechanisms underlying primate ovarian aging at single-cell resolution, revealing new diagnostic biomarkers and potential therapeutic targets for age-related human ovarian disorders.

Dose-response associations of triglyceride to high-density lipoprotein cholesterol ratio and triglyceride-glucose index with arterial stiffness risk.

BACKGROUND: The triglyceride to high-density lipoprotein cholesterol (TG/HDL-C) ratio and triglyceride-glucose (TyG) index are novel indexes for insulin resistance (IR). We aimed to evaluate associations of TG/HDL-C and TyG with arterial stiffness risk. METHODS: We enrolled 1979 participants from the Rural Chinese Cohort Study, examining arterial stiffness by brachial-ankle pulse wave velocity (baPWV). Logistic and linear regression models were employed to calculate effect estimates. For meta-analysis, we searched relevant articles from PubMed, Embase and Web of Science up to August 26, 2023. The fixed-effects or random-effects models were used to calculate the pooled estimates. We evaluated dose-response associations using restricted cubic splines. RESULTS: For cross-sectional studies, the adjusted ORs (95%CIs) for arterial stiffness were 1.12 (1.01-1.23) and 1.78 (1.38-2.30) for per 1 unit increment in TG/HDL-C and TyG. In the meta-analysis, the pooled ORs (95% CIs) were 1.26 (1.14-1.39) and 1.57 (1.36-1.82) for per 1 unit increment of TG/HDL-C and TyG. Additionally, both TG/HDL-C and TyG were positively related to PWV, with ß of 0.09 (95% CI 0.04-0.14) and 0.57 (95% CI 0.35-0.78) m/s. We also found linear associations of TG/HDL-C and TyG with arterial stiffness risk. CONCLUSIONS: High TG/HDL-C and TyG were related to increased arterial stiffness risk, indicating TG/HDL-C and TyG may be convincing predictors of arterial stiffness.

EZH2 inhibition induces senescence via ERK1/2 signaling pathway in multiple myeloma.

Epigenetic modifications play an important role in cellular senescence, and enhancer of zeste homolog 2 (EZH2) is a key methyltransferase involved in epigenetic remodeling in multiple myeloma (MM) cells. We have previously demonstrated that GSK126, a specific EZH2 inhibitor, exhibits anti-MM therapeutic efficacy and safety in vivo and in vitro; however, its specific mechanism remains unclear. This study shows that GSK126 induces cellular senescence in MM, which is characterized by the accumulation of senescence-associated heterochromatin foci (SAHF) and p21, and increased senescence-associated ß galactosidase activity. Furthermore, EZH2 is inhibited in ribonucleotide reductase regulatory subunit M2 (RRM2) overexpression OCI-MY5 and RPMI-8226 cells. RRM2 overexpression inhibits the methyltransferase function of EZH2 and promotes its degradation through the ubiquitin-proteasome pathway, thereby inducing cellular senescence. In this senescence model, Lamin B1, a key component of the nuclear envelope and a marker of senescence, does not decrease but instead undergoes aberrant accumulation. Meanwhile, phosphorylation of extracellular signal-regulated protein kinase (ERK1/2) is significantly increased. The inhibition of ERK1/2 phosphorylation in turn partially restores Lamin B1 level and alleviates senescence. These findings suggest that EZH2 inhibition increases Lamin B1 level and induces senescence by promoting ERK1/2 phosphorylation. These data indicate that EZH2 plays an important role in MM cellular senescence and provide insights into the relationships among Lamin B1, p-ERK1/2, and cellular senescence.

Obesity and risk of depressive disorder in children and adolescents: A meta-analysis of observational studies.

PURPOSE: This meta-analysis evaluated the relationship between overweight/obesity and depressive disorders in children and adolescents. METHODS: We examined the databases of PubMed, Embase and Web of Science for pertinent observational studies released up until 20 February 2022. The pooled relative risks (RRs) and 95% confidence intervals (CIs) of obesity and overweight with depressive disorder were calculated by means of random-effects models. The Newcastle-Ottawa Quality Assessment Scale and Agency for Healthcare Research and Quality scale were adopted to evaluate the study quality. RESULTS: Finally, for this meta-analysis, we evaluated 22 observational publications covering 175 135 participants (5 cohort study articles, 1 case-control study article and 16 cross-sectional study articles). A significant positive association was found between obesity and the risk of depression (RR 1.32, 95% CI 1.09-1.60, I2 = 79.90%, Pheterogeneity < 0.001) and in the association between obesity and depressive symptoms (RR 1.16, 95% CI: 1.00-1.35, I2 = 25.0%, Pheterogeneity = 0.247). On sensitivity analysis, the pooled RRs remained robust. Subgroup analysis indicated that obese children and teenagers in western countries were more prone to depression. CONCLUSION: Evidence from this meta-analysis, based on observational studies, supported the idea that obese children and adolescents are more likely to experience depression and depressive symptoms.

Withdrawal of MTX in rheumatoid arthritis patients on bDMARD/tsDMARD plus methotrexate at target: a systematic review and meta-analysis.

OBJECTIVES: To evaluate the effect of MTX withdrawal on disease activity and remission rate in patients at target after treatment with biologic DMARDs (bDMARDs)/targeted synthetic DMARDs (tsDMARDs) plus MTX. MATERIAL AND METHODS: We searched the PubMed, EMBASE and Cochrane Central Register of Controlled Trials (CENTRAL) databases for all randomized controlled trials (RCTs) on MTX withdrawal in patients with RA at target after combination therapy from inception to 7 March 2022 in order to extract data, including: the change from withdrawal in DAS28 at the endpoint; proportion of low disease activity (LDA) assessed by DAS28, Simplified Disease Activity Index (SDAI) or Clinical Disease Activity Index (CDAI); proportion of remission assessed by DAS28, SDAI CDAI or ACR/EULAR Boolean remission. The Cochrane Q test and I2 test were used to assess heterogeneity, and random-effects models were used for data synthesis. This study is registered with PROSPERO (CRD42022303891). RESULTS: Six articles were included for qualitative and quantitative analysis, all of which were noninferior RCTs involving 1430 patients (734 in the withdrawal group and 696 in the continuation group). Compared with continuing combination therapy, tapering off or discontinuing MTX increased DAS28 by 0.20 (95% CI 0.09, 0.32, I2 = 0%) and decreased the percentage of patients with LDA assessed by DAS28 to <3.2 [risk ratio (RR) 0.88 (0.80, 0.97), I2 = 0%]. However, MTX withdrawal did not decrease remission rates assessed by DAS28, SDAI, CDAI or ACR/EULAR Boolean remission [RR 0.90 (0.81, 1.01), 0.93 (0.77, 1.11), 0.90 (0.74, 1.11), 0.95 (0.70, 1.29), respectively]. CONCLUSIONS: Withdrawing MTX slightly increases the RA disease activity in patients treated at target with bDMARDs/tsDMARDs plus MTX and has limited effects for patients with deep remission.

Long-Term Exposure to Traffic Noise and Risk of Incident Cardiovascular Diseases: a Systematic Review and Dose-Response Meta-Analysis.

While noise pollution from transportation has become an important public health problem, the relationships between different sources of traffic noise and cardiovascular diseases (CVDs) remain inconclusive. A comprehensive meta-analysis was therefore conducted to quantitatively assess the effects of long-term exposure to road traffic, railway, and aircraft noise on CVDs and relevant subtypes. We systematically retrieved PubMed, Embase, and Web of Science for articles published before April 4, 2022. Summary relative risks (RRs) and 95% confidence intervals (CIs) were estimated by the fixed- or random-effects models. In total, 23 articles were included in our meta-analysis. The risk of CVDs increased by 2% (RR 1.020, 95% CI 1.006-1.035) and 1.6% (RR 1.016, 95% CI 1.000-1.032) for every 10 dB increment of road traffic and aircraft noise. For CVD subtypes, the risk increased by 3.4% (1.034, 1.026-1.043) for stroke and 5% (1.050, 1.006-1.096) for heart failure with each 10 dB increment of road traffic noise; the risk of atrial fibrillation increased by 1.1% (1.011, 1.002-1.021) with each 10 dB increment of railway noise; and the risk increased by 1% (1.010, 1.003-1.017) for myocardial infarction, 2.7% (1.027, 1.004-1.050) for atrial fibrillation, and 2.3% (1.023, 1.016-1.030) for heart failure with each 10 dB increment in aircraft noise. Further, effects from road traffic, railway, and aircraft noise all followed positive linear trends with CVDs. Long-term exposure to traffic noise is positively related to the incidence risk of cardiovascular events, especially road traffic noise which significantly increases the risk of CVDs, stroke, and heart failure.

Independent and interactive effect of sedentary time and physical activity on risk of all-cause mortality: A prospective cohort study.

OBJECTIVES: Sedentary behavior (SB) and physical inactivity have been associated with an increased risk of all-cause mortality. Evidence in China is scarce, and it is unclear whether physical activity (PA) attenuates or even eliminates the harmful effects of prolonged SB in the Chinese population. METHODS: We conducted a prospective cohort study of 17 084 Chinese adults. PA and sitting time (ST) were assessed using the IPAQ. Cox proportional hazards models were used to estimate the risk of PA and ST with all-cause mortality. Interaction plots were used to visualize the interaction effects. RESULTS: During a median follow-up of 6.01 years, a total of 1106 deaths occurred. PA level was inversely associated with the incidence of all-cause mortality, while ST showed a detrimental association (all ptrend < 0.05). In the stratified analysis, ST was associated with all-cause mortality in the low PA, while the association was attenuated in the moderate PA group: the HRs (95% CI) comparing ST of 4-8, 8-11, and ≥11 to <4 h/day were 1.15 (0.73-1.81), 1.55 (0.92-2.59), and 2.70 (1.52-4.80), respectively. In the high PA group, no significant association was found across all ST levels. In the joint analysis, compared with the high PA and ST <4 h/day, the harmful effect was found only in the combined low PA and moderate PA groups with ST ≥11 h/day (HR:2.71, 95% CI:1.69-4.35). In addition, a significant interaction association was found. CONCLUSION: Our study, based on a prospective cohort, suggests that the detrimental effect of ST on all-cause mortality is attenuated or eliminated by high PA levels in the Chinese population.

A novel alkaloid compound, DCZ0358, exerts significant antitumor activity in bortezomib-resistant multiple myeloma cells through inhibition of JAK2/STAT3 pathway.

Multiple myeloma (MM), the second most common haematological malignancy, is currently incurable because patients often develop multiple drug resistance and experience subsequent relapse of the disease. This study aims to identify a potential therapeutic agent that can counter bortezomib (BTZ) resistance in MM. DCZ0358, a novel alkaloid compound, is found to exert potent cytotoxic effects against BTZ-resistant MM cells in vivo and in vitro. The anti-myeloma activity of DCZ0358 is associated with inhibition of cell proliferation, promotion of cell apoptosis via caspase-mediated apoptotic pathways, and induction of G0/G1 phase arrest via downregulation of cyclin D1, CDK4, and CDK6. Further investigation of the molecular mechanism shows that DCZ0358 suppresses the JAK2/STAT3 signaling pathway. In conclusion, DCZ0358 can successfully counter BTZ resistance in MM cells. This study provides evidence that warrants future preclinical assessments of DCZ0358 as a therapeutic agent against BTZ resistance in MM.

Spatial confinement of receptor activity by tyrosine phosphatase during directional cell migration.

Directional cell migration involves signaling cascades that stimulate actin assembly at the leading edge, and additional pathways must inhibit actin polymerization at the rear. During neuroblast migration in Caenorhabditis elegans, the transmembrane protein MIG-13/Lrp12 acts through the Arp2/3 nucleation-promoting factors WAVE and WASP to guide the anterior migration. Here we show that a tyrosine kinase, SRC-1, directly phosphorylates MIG-13 and promotes its activity on actin assembly at the leading edge. In GFP knockin animals, SRC-1 and MIG-13 distribute along the entire plasma membrane of migrating cells. We reveal that a receptor-like tyrosine phosphatase, PTP-3, maintains the F-actin polarity during neuroblast migration. Recombinant PTP-3 dephosphorylates SRC-1-dependent MIG-13 phosphorylation in vitro. Importantly, the endogenous PTP-3 accumulates at the rear of the migrating neuroblast, and its extracellular domain is essential for directional cell migration. We provide evidence that the asymmetrically localized tyrosine phosphatase PTP-3 spatially restricts MIG-13/Lrp12 receptor activity in migrating cells.

Correlation of heavy metals' exposure with the prevalence of coronary heart disease among US adults: findings of the US NHANES from 2003 to 2018.

We sought to explore the association between heavy metal exposure and coronary heart disease (CHD) based on data from the US National Health and Nutrition Examination Survey (NHANES, 2003-2018). In the analyses, participants were all aged > 20 and had participated in heavy metal sub-tests with valid CHD status. The Mann-Kendall test was employed to assess the trends in heavy metals' exposure and the trends in CHD prevalence over 16 years. Spearman's rank correlation coefficient and a logistics regression (LR) model were used to estimate the association between heavy metals and CHD prevalence. 42,749 participants were included in our analyses, 1802 of whom had a CHD diagnosis. Total arsenic, dimethylarsonic acid, monomethylarsonic acid, barium, cadmium, lead, and antimony in urine, and cadmium, lead, and total mercury in blood all showed a substantial decreasing exposure level tendency over the 16 years (all Pfor trend < 0.05). CHD prevalence varied from 3.53 to 5.23% between 2003 and 2018. The correlation between 15 heavy metals and CHD ranges from - 0.238 to 0.910. There was also a significant positive correlation between total arsenic, monomethylarsonic acid, and thallium in urine and CHD by data release cycles (all P < 0.05). The cesium in urine showed a negative correlation with CHD (P < 0.05). We found that exposure trends of total arsenic, dimethylarsonic acid, monomethylarsonic acid, barium, cadmium, lead, and antimony in urine and blood decreased. CHD prevalence fluctuated, however. Moreover, total arsenic, monomethylarsonic acid, and thallium in urine all showed positive relationships with CHD, while cesium in urine showed a negative relationship with CHD.

[Quality evaluation of Cnidii Fructus in commodity grade based on theory of "quality evaluation through morphological identification"].

From the perspective of market classification of Cnidii Fructus, this paper revealed the scientific connotation of evaluating the quality grade of Cnidii Fructus by its appearance traits. Thirty batches of Cnidii Fructus in different grades were selected as the research objects. The canonical correlation analysis and principal component analysis(PCA) were used to explore the measurement values of 15 appearance traits and intrinsic content indexes. The results of correlation analysis showed that except the aspect ratio, the 5 appearance trait indexes(length, width, 1 000-grain weight, broken grain weight proportion, and chroma) and 9 internal content indexes(the content of moisture, total ash, acid insoluble ash, osthole, imperatorin, 5-methoxy psoralen, isopimpinellin, xanthotoxin, and xanthotol) showed significant correlation to varying degrees. In addition, there was a significant positive correlation between the first typical variable U_1 composed of appearance traits and the first typical variable V_1 composed of internal content indexes(CR_1=0.963, P<0.01). The results of PCA showed that the classification results of appearance traits for 30 batches of Cnidii Fructus were consistent with the actual information of the samples. Under the same analysis conditions, 30 batches of Cnidii Fructus were reclassified by 9 groups of internal content indexes, and the analysis results were consistent. From the classification standard of the appearance traits of the system study, the statistical results of 6 appearance traits of Cnidii Fructus showed a correlation with grades. There was a good correlation between the appearance and the internal content of Cnidii Fructus, and the appearance quality effectively predicted the level of the internal content. There is a certain scientific basis for the quality classification of Cnidii Fructus by main appearance traits. Appearance classification can replace quality grading to realize the "quality evaluation through morphological identification" of Cnidii Fructus.

Total dietary flavonoid intake and risk of cardiometabolic diseases: A dose-response meta-analysis of prospective cohort studies.

Several epidemiological studies have suggested that flavonoid intake is associated with a decreased risk of cardiometabolic disease. However, the results remained inconsistent and there is no dose-response meta-analysis for specific outcomes. We conducted a meta-analysis to synthesize the knowledge about their associations and to explore their dose-response relationships. We comprehensively searched the PubMed, Embase, and Web of Science databases for prospective cohort studies published up to December 1, 2021. Summary relative risks (RR) and 95% confidence intervals (CI) were pooled for the association between flavonoid intake and cardiometabolic disease. Evaluations of linear or nonlinear dose-response were presented by restricted cubic splines. We identified 47 articles, including 1,346 676 participants and 127,507 cases in this meta-analysis. The summary of RR per 500 mg/d increase in flavonoid intake was 0.93 (95% CI 0.88-0.98) for cardiovascular disease, 0.89 (95% CI 0.84-0.94) for diabetes, and 0.97 (95% CI 0.94-0.99) for hypertension, respectively. We also found a linearity dose-response association between total flavonoid intake and cardiovascular disease (p nonlinearity = 0.541), and diabetes (p nonlinearity = 0.077). Our finding based on quantitative data suggested that a higher level of flavonoid intake is beneficial for the prevention of cardiometabolic diseases.

Metabolic Score for Visceral Fat: a novel predictor for the risk of type 2 diabetes mellitus.

To investigate the association between the Metabolic Score for Visceral Fat (METS-VF) and risk of type 2 diabetes mellitus (T2DM) and compare the predictive value of the METS-VF for T2DM incidence with other obesity indices in Chinese people. A total of 12 237 non-T2DM participants aged over 18 years from the Rural Chinese Cohort Study of 2007-2008 were included at baseline and followed up during 2013-2014. The cox proportional hazards regression was used to calculate hazard ratios (HR) and 95 % CI for the association between baseline METS-VF and T2DM risk. Restricted cubic splines were used to model the association between METS-VF and T2DM risk. Area under the receiver operating characteristic curve (AUC) analysis was used to evaluate the ability of METS-VF to predict T2DM incidence. During a median follow-up of 6·01 (95 % CI 5·09, 6·06) years, 837 cases developed T2DM. After adjusting for potential confounding factors, the adjusted HR for the highest v. lowest METS-VF quartile was 5·97 (95 % CI 4·28, 8·32), with a per 1-sd increase in METS-VF positively associated with T2DM risk. Positive associations were also found in the sensitivity and subgroup analyses, respectively. A significant nonlinear dose-response association was observed between METS-VF and T2DM risk for all participants (Pnonlinearity = 0·0347). Finally, the AUC value of METS-VF for predicting T2DM was largest among six indices. The METS-VF may be a reliable and applicable predictor of T2DM incidence in Chinese people regardless of sex, age or BMI.

ZKSCAN3 counteracts cellular senescence by stabilizing heterochromatin.

Zinc finger protein with KRAB and SCAN domains 3 (ZKSCAN3) has long been known as a master transcriptional repressor of autophagy. Here, we identify a novel role for ZKSCAN3 in alleviating senescence that is independent of its autophagy-related activity. Downregulation of ZKSCAN3 is observed in aged human mesenchymal stem cells (hMSCs) and depletion of ZKSCAN3 accelerates senescence of these cells. Mechanistically, ZKSCAN3 maintains heterochromatin stability via interaction with heterochromatin-associated proteins and nuclear lamina proteins. Further study shows that ZKSCAN3 deficiency results in the detachment of genomic lamina-associated domains (LADs) from the nuclear lamina, loss of heterochromatin, a more accessible chromatin status and consequently, aberrant transcription of repetitive sequences. Overexpression of ZKSCAN3 not only rescues premature senescence phenotypes in ZKSCAN3-deficient hMSCs but also rejuvenates physiologically and pathologically senescent hMSCs. Together, these data reveal for the first time that ZKSCAN3 functions as an epigenetic modulator to maintain heterochromatin organization and thereby attenuate cellular senescence. Our findings establish a new functional link among ZKSCAN3, epigenetic regulation, and stem cell aging.

CabHLH79 Acts Upstream of CaNAC035 to Regulate Cold Stress in Pepper.

Cold stress is one of the main restricting factors affecting plant growth and agricultural production. Complex cold signaling pathways induce the expression of hundreds of cold-sensitive genes. The NAC transcription factor CaNAC035 has previously been reported to significantly influence the response of pepper to cold stress. Here, using Yeast one-hybrid (Y1H) library screened to search for other relevant molecular factors, we identified that CabHLH79 directly binds to the CaNAC035 promoter. Different basic helix-loop-helix (bHLH) transcription factors (TFs) in plants significantly respond to multiple plant stresses, but the mechanism of bHLHs in the cold tolerance of pepper is still unclear. This study investigated the functional characterization of CabHLH79 in the regulation of cold resistance in pepper. Down-regulation of CabHLH79 in pepper by virus-induced gene silencing (VIGS) increased its sensitivity to low temperature, whereas overexpression of CabHLH79 in pepper or Arabidopsis enhanced cold resistance. Compared with control plants, VIGS mediated of CabHLH79 had lower enzyme activity and related gene expression levels, accompanied by higher reactive oxygen species (ROS) accumulation, relative electrolyte leakage (REL), and malondialdehyde accumulation (MDA) contents. Transient overexpression of CabHLH79 pepper positively regulated cold stress response genes and ROS genes, which reduced REL and MDA contents. Similarly, ectopic expression of CabHLH79 in Arabidopsis showed less ROS accumulation, and higher enzymes activities and expression levels. These results indicated that CabHLH79 enhanced cold tolerance by enhancing the expression of ROS-related and other cold stress tolerance-related genes. Taken together, our results showed a multifaceted module of bHLH79-NAC035 in the cold stress of pepper.

Expression, purification and characterization of the second DUSP domain of deubiquitinase USP20/VDU2.

Deubiquitinase USP20/VDU2 (VHL-interacting Deubiquitinating Enzyme 2) has been proved to play vital roles in multiple cellular processes by controlling the life-span of substrate proteins including hypoxia-inducible factor HIF1α, ß2-adrenergic receptor, and type 2 iodothyronine deiodinase etc. USP20 contains four distinct structural domains, which include the N-terminal zinc-finger ubiquitin binding domain (ZnF-UBP), the catalytic domain (USP domain), and two tandem DUSP domains (DUSP1 and DUSP2). Here in this study, we report the setting up of the production approach for USP20 DUSP2, and the NMR characterization of the produced target protein. With the assistance of GB1 tag and glycerol, both the solubility and stability of USP20 DUSP2 are significantly enhanced. And by using the optimized protein production procedure, monomeric and stable 15N, 13C-labeled USP20 DUSP2 sample for NMR data acquisition was obtained. The secondary structural elements of USP20 DUSP2 were then revealed by the analysis of recorded NMR spectra, and USP20 DUSP2 forms an AB3 fold in solution. The production protocol and NMR characterization results reported in this manuscript could be utilized in the extended structural and functional studies of USP20 DUSP2.

High Familial Recurrence of Congenital Heart Defects in Laterality Defects Patients: An Evaluation of 184 Families.

As a rare disease with genetic pathogenesis, observational study about familial CHD recurrence risk on CHD patients with laterality defects is lacking. This study aimed to investigate familial recurrence among families of patients with CHD and laterality defects, and compare them with CHD patients without laterality defects. A total of 184 patients with CHD and laterality defects treated in Cardiovascular Center, Children's Hospital of Fudan University were observed from 2008 to 2019. A detailed family history was documented by trained staff using questionnaires, and information about the subtypes of CHD and laterality defects was also collected. In addition, positive family history information, including all three degrees relatives and all affected family members, was reconfirmed by trained medical staff through face-to-face interviews, telephone interviews, and letter return visits. Of the 184 included patients, 30 had at least one family member (from among three linear generations and distant relatives) with CHD. The familial recurrence rate of CHD in our cohort was 16.3% (30/184), which was higher than the 3.3% (67/2024) of patients with CHD without laterality defects. This result shows that the recurrence rate among the first-, second-, and third-degree relatives was 11.7% (11/94), 1.5% (3/204), and 3.1% (6/91) and that the recurrence rate among siblings (21.4%, 9/42) was higher than that among parents (3.8%, 2/52). The familial recurrence risk of CHD among patients with CHD and laterality defects is high, which is consistent with the previous study that reported a high familial recurrence of heterotaxy of 10%. First-degree relatives have a higher recurrence rate than second- and third-degree relatives, especially siblings. These findings have important significance for prenatal screening, intervention, and genetic counseling in the Chinese population, but may not be generalizable to other populations that may have different rates of familial and sporadic cases.

CaDHN3, a Pepper (Capsicum annuum L.) Dehydrin Gene Enhances the Tolerance against Salt and Drought Stresses by Reducing ROS Accumulation.

Dehydrins (DHNs) play an important role in abiotic stress tolerance in a large number of plants, but very little is known about the function of DHNs in pepper plants. Here, we isolated a Y1SK2-type DHN gene "CaDHN3" from pepper. To authenticate the function of CaDHN3 in salt and drought stresses, it was overexpressed in Arabidopsis and silenced in pepper through virus-induced gene silencing (VIGS). Sub-cellular localization showed that CaDHN3 was located in the nucleus and cell membrane. It was found that CaDHN3-overexpressed (OE) in Arabidopsis plants showed salt and drought tolerance phenotypic characteristics, i.e., increased the initial rooting length and germination rate, enhanced chlorophyll content, lowered the relative electrolyte leakage (REL) and malondialdehyde (MDA) content than the wild-type (WT) plants. Moreover, a substantial increase in the activities of antioxidant enzymes; including the superoxide dismutase (SOD), peroxidase (POD), catalase (CAT), ascorbate peroxidase (APX), and lower hydrogen peroxide (H2O2) contents and higher O2•- contents in the transgenic Arabidopsis plants. Silencing of CaDHN3 in pepper decreased the salt- and drought-stress tolerance, through a higher REL and MDA content, and there was more accumulation of reactive oxygen species (ROS) in the CaDHN3-silenced pepper plants than the control plants. Based on the yeast two-hybrid (Y2H) screening and Bimolecular Fluorescence Complementation (BiFC) results, we found that CaDHN3 interacts with CaHIRD11 protein in the plasma membrane. Correspondingly, the expressions of four osmotic-related genes were significantly up-regulated in the CaDHN3-overexpressed lines. In brief, our results manifested that CaDHN3 may play an important role in regulating the relative osmotic stress responses in plants through the ROS signaling pathway. The results of this study will provide a basis for further analyses of the function of DHN genes in pepper.

Aha1 Exhibits Distinctive Dynamics Behavior and Chaperone-Like Activity.

Aha1 is the only co-chaperone known to strongly stimulate the ATPase activity of Hsp90. Meanwhile, besides the well-studied co-chaperone function, human Aha1 has also been demonstrated to exhibit chaperoning activity against stress-denatured proteins. To provide structural insights for a better understanding of Aha1's co-chaperone and chaperone-like activities, nuclear magnetic resonance (NMR) techniques were used to reveal the unique structure and internal dynamics features of full-length human Aha1. We then found that, in solution, both the two domains of Aha1 presented distinctive thermal stabilities and dynamics behaviors defined by their primary sequences and three-dimensional structures. The low thermal stability (melting temperature of Aha128-162: 54.45 °C) and the internal dynamics featured with slow motions on the µs-ms time scale were detected for Aha1's N-terminal domain (Aha1N). The aforementioned experimental results suggest that Aha1N is in an energy-unfavorable state, which would therefore thermostatically favor the interaction of Aha1N with its partner proteins such as Hsp90's middle domain. Differently from Aha1N, Aha1C (Aha1's C-terminal domain) exhibited enhanced thermal stability (melting temperature of Aha1204-335: 72.41 °C) and the internal dynamics featured with intermediate motions on the ps-ns time scale. Aha1C's thermal and structural stabilities make it competent for the stabilization of the exposed hydrophobic groove of dimerized Hsp90's N-terminal domain. Of note, according to the NMR data and the thermal shift results, although the very N-terminal region (M1-W27) and the C-terminal relaxin-like factor (RLF) motif showed no tight contacts with the remaining parts of human Aha1, they were identified to play important roles in the recognition of intrinsically disordered pathological α-synuclein.

Unwrap Them First: Operando Potential- induced Activation Is Required when Using PVP-Capped Ag Nanocubes as Catalysts of CO2 Electroreduction.

Metallic nanoparticles of different shape can be used as efficient electrocatalysts for many technologically and environmentally relevant processes, like the electroreduction of CO2. Intense research is thus targeted at finding the morphology of nanosized features that best suits catalytic needs. In order to control the shape and size distribution of the designed nanoobjects, and to prevent their aggregation, synthesis routes often rely on the use of organic capping agents (surfactants). It is known, however, that these agents tend to remain adsorbed on the surface of the synthesized nanoparticles and may significantly impair their catalytic performance, both in terms of overall yield and of product selectivity. It thus became a standard procedure to apply certain methods (e.g. involving UV-ozone or plasma treatments) for the removal of capping agents from the surface of nanoparticles, before they are used as catalysts. Proper design of the operating procedure of the electrocatalysis process may, however, render such cleaning steps unnecessary. In this paper we use poly-vinylpyrrolidone (PVP) capped Ag nanocubes to demonstrate a mere electrochemical, operando activation method. The proposed method is based on an observed hysteresis of the catalytic yield of CO (the desired product of CO2 electroreduction) as a function of the applied potential. When as-synthesized nanocubes were directly used for CO2 electroreduction, the CO yield was rather low at moderate overpotentials. However, following a potential excursion to more negative potentials, most of the (blocking) PVP was irreversibly removed from the catalyst surface, allowing a significantly higher catalytic yield even under less harsh operating conditions. The described hysteresis of the product distribution is shown to be of transient nature, and following operando activation by a single 'break-in' cycle, a truly efficient catalyst was obtained that retained its stability during long hours of operation.