4EGI-1 targets breast cancer stem cells by selective inhibition of translation that persists in CSC maintenance, proliferation and metastasis

Cancer death is a leading cause of global mortality. An estimated 14.1 million new cancer cases and 8.2 million cancer deaths occurred worldwide in 2012 alone. Cancer stem cells (CSCs) within tumors are essential for tumor metastasis and reoccurrence, the key factors of cancer lethality. Here we report that 4EGI-1, an inhibitor of the interaction between translation initiation factors eIF4E1 and eIF4G1 effectively inhibits breast CSCs through selectively reducing translation persistent in breast CSCs. Translation initiation factor eIF4E1 is significantly enhanced in breast CSCs in comparison to non-CSC breast cancer cells. 4EGI-1 presents increased cytotoxicity to breast CSCs compared to non-CSC breast cancer cells. 4EGI-1 promotes breast CSC differentiation and represses breast CSC induced tube-like structure formation of human umbilical vein endothelial cells (HUVECs). 4EGI-1 isomers suppress breast CSC tumorangiogenesis and tumor growth in vivo. In addition, 4EGI-1 decreases proliferation in and induces apoptosis into breast CSC tumor cells. Furthermore, 4EGI-1 selectively inhibits translation of mRNAs encoding NANOG, OCT4, CXCR4, c-MYC and VEGF in breast CSC tumors. Our study demonstrated that 4EGI-1 targets breast CSCs through selective inhibition of translation critical for breast CSCs, suggesting that selective translation initiation interference might be an avenue targeting CSCs within tumors

The Implementation of China's Mental Health Law-Defined Risk Criteria for Involuntary Admission: A National Cross-Sectional Study of Involuntarily Hospitalized Patients

Objective: Involuntary admission is one of the most controversial issues in psychiatry in China. This study aimed to examine the implementation of the new risk criteria for involuntary admission, as defined by the new Mental Health Law (MHL), in major psychiatric hospitals; and to explore factors associated with the implementation.Method: We selected 32 psychiatric hospitals in 29 provincial capital cities in mainland China. We included all involuntarily admitted psychiatric inpatients who were discharged from December 25 to 27, 2017. Patients' demographic and clinical data and reasons for admission were retrieved. Hospitals' information was also collected. Multilevel logistic regression was applied to explore factors associated with the implementation.Results: We collected valid data from 814 inpatients. Rates of risk criteria implementation ranged from 7.9 to 88.5% in these hospitals. Only 369 inpatients (45.3%) met the MHL-defined risk criteria. Overall, between 62.2 and 78.5% of the variance in risk criteria implementation was at the patient level, and between 21.5 and 37.8% of the variance was at the hospital level. Patients with higher Global Assessment of Functioning (GAF) scores at admission were less likely to meet the risk criteria (OR 1.02, 95% CI 1.01–1.03). No statistically significant association was found between risk criteria implementation and other patient level or hospital level factors.Conclusion: Our findings show the implementation rate of the MHL's risk criteria overall was low, with only 45.3% of involuntary admissions meeting the MHL-defined criteria. This suggests that some patients' civil rights might have been violated

Psychiatry Residents in China: Socio-Demographic Characteristics, Career Satisfaction, and Related Factors

Objective: To study the socio-demographic characteristics, the working environment, and the level of career satisfaction among psychiatry residents in China.Method: This was a part of a large-scale, nation-wide online survey of hospitals, healthcare professionals, and patients. Data, including socio-demographics, work hours, income, job satisfaction, and intention to quit were collected anonymously. Respondents also completed the Minnesota Satisfaction Questionnaire (MSQ).Results: One thousand sixty residents nested in 32 psychiatric hospitals in 29 provinces in China completed the survey. Respondents were predominantly female (69.0%), worked an average of 47.8 ± 11.6 h per week, and 28.97% had experienced medical disputes in the previous year. The top three reported reasons for dissatisfaction were low pay (50.1%), contentious doctor-patient relationships (17.6%), and high workload (10.8%). An intention to quit their current job was reported by 18.7% of residents. The overall mean MSQ score was 73.8 ± 13.8, with significant differences across post-graduate training years and regions. A multilevel regression analysis found that a higher MSQ score was significantly associated with fewer years in residency, shorter work hours, higher monthly pay, having medical liability insurance, and feeling satisfied with the level of doctor-nurse cooperation, their hospitals' medical disputes prevention/management, and the healthcare workers' social environment.Conclusion: Psychiatry residents in China are predominantly female and well-educated. They are only moderately satisfied with their career. Poor salaries, contentious doctor-patient relationships and high workload are among their top complaints and may explain why a considerable proportion are intending to leave their current residency. More support from the government regarding residents' salaries, workload and working environment may help improve their job satisfaction and retention, ensuring that China will have a pool of well-trained and engaged psychiatrists for the future

eIF1A augments Ago2-mediated Dicer-independent miRNA biogenesis and RNA interference

MicroRNA (miRNA) biogenesis and miRNA-guided RNA interference (RNAi) are essential for gene expression in eukaryotes. Here we report that translation initiation factor eIF1A directly interacts with Ago2 and promotes Ago2 activities in RNAi and miR-451 biogenesis. Biochemical and NMR analyses demonstrate that eIF1A binds to the MID-domain of Ago2 and this interaction does not impair translation initiation. Alanine mutation of the Ago2-facing Lys56 in eIF1A impairs RNAi activities in human cells and zebrafish. The eIF1A-Ago2 assembly facilitates Dicer-independent biogenesis of miR-451, which mediates erythrocyte maturation. Human eIF1A (heIF1A), but not heIF1A(K56A), rescues the erythrocyte maturation delay in eif1axb knockdown zebrafish. Consistently, miR-451 partly compensates erythrocyte maturation defects in zebrafish with eif1axb knockdown and eIF1A(K56A) expression, supporting a role of eIF1A in miRNA-451 biogenesis in this model. Our results suggest that eIF1A is a novel component of the Ago2-centered RNA induced silencing complexes (RISCs) and augments Ago2-dependent RNAi and miRNA biogenesis

The C-terminal domain of eukaryotic initiation factor 5 promotes start codon recognition by its dynamic interplay with eIF1 and eIF2 beta

Recognition of the proper start codon on mRNAs is essential for protein synthesis, which requires scanning and involves eukaryotic initiation factors (eIFs) eIF1, eIF1A, eIF2, and eIF5. The carboxyl terminal domain (CTD) of eIF5 stimulates 43S preinitiation complex (PIC) assembly; however, its precise role in scanning and start codon selection has remained unknown. Using nuclear magnetic resonance (NMR) spectroscopy, we identified the binding sites of eIF1 and eIF2β on eIF5-CTD and found that they partially overlapped. Mutating select eIF5 residues in the common interface specifically disrupts interaction with both factors. Genetic and biochemical evidence indicates that these eIF5-CTD mutations impair start codon recognition and impede eIF1 release from the PIC by abrogating eIF5-CTD binding to eIF2β. This study provides mechanistic insight into the role of eIF5-CTD's dynamic interplay with eIF1 and eIF2β in switching PICs from an open to a closed state at start codons.publishedVersio

Alcohol misuse, health-related behaviors, and burnout among clinical therapists in China during the early Covid-19 pandemic: A Nationwide survey

ObjectivesThis study aimed to assess the extent of alcohol use and misuse among clinical therapists working in psychiatric hospitals in China during the early COVID-19 Pandemic, and to identify associated factors.MethodsAn anonymous nationwide survey was conducted in 41 tertiary psychiatric hospitals. We collected demographic data as well as alcohol use using the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) and burnout using the Maslach Burnout Inventory Human Services Survey.ResultsIn total, 396 clinical therapists completed the survey, representing 89.0% of all potential participants we targeted. The mean age of participants was 33.8 years old, and more than three-quarters (77.5%) were female. Nearly two-fifths (39.1%) self-reported as current alcohol users. The overall prevalence of alcohol misuse was 6.6%. Nearly one-fifth (19.9%) reported symptoms of burnout with high emotional exhaustion in 46 (11.6%), and high depersonalization in 61 (15.4%). Multiple logistic regression showed alcohol use was associated with male gender (OR = 4.392; 95% CI =2.443–7.894), single marital status (OR = 1.652; 95% CI =0.970–2.814), smoking habit (OR = 3.847; 95%CI =1.160–12.758) and regular exercise (OR = 2.719; 95%CI =1.490–4.963). Alcohol misuse was associated with male gender (OR = 3.367; 95% CI =1.174–9.655), a lower education level (OR = 3.788; 95%CI =1.009–14.224), smoking habit (OR = 4.626; 95%CI =1.277–16.754) and high burnout (depersonalization, OR = 4.848; 95%CI =1.433–16.406).ConclusionDuring the COVID-19 pandemic, clinical therapists’ alcohol consumption did not increase significantly. Male gender, cigarette smoking, and burnout are associated with an increased risk of alcohol misuse among clinical therapists. Targeted intervention is needed when developing strategies to reduce alcohol misuse and improve clinical therapists’ wellness and mental health

Prevalence and associated factors of depression, anxiety and stress among clinical therapists in China in the context of early COVID-19 pandemic

ObjectivesTo study the socio-demographic characteristics and the prevalence of depression, anxiety, and stress among clinical therapists in China during the early Coronavirus disease 2019 (COVID-19) pandemic and to identify associated factors.MethodThis cross-sectional study was part of a multicenter, nationally representative survey conducted through WeChat from January 2021 to March 2021. Data, including socio-demographics, health-related behaviors, and information on whether they participated in the frontline work of treating COVID-19, were collected anonymously. Respondents also completed the Depression Anxiety Stress Scales-21 (DASS-21).ResultsIn total, 396 clinical therapists in the selected hospitals completed the questionnaires, with a response rate of 89.0%. Respondents were predominantly female (77.3%). About 6.6% of the participants were current tobacco users, and 20.7% had participated in the frontline work of treating COVID-19. Overall, 22.0%, 17.9%, and 8.8% of participants were classified as having clinically meaningful depression, anxiety, and stress, respectively, based on DASS-21 scores. Multiple logistic regression in Model 1 and Model 2 showed that depression, anxiety, and stress were associated with regular physical activity and frequent insomnia (all, p < 0.05). In anxiety model 2, the associated factors for anxiety during the pandemic were identified as education (master’s degree or more, OR=0.520; 95% CI=0.283-0.955), marital status (single, OR=2.064; 95% CI=1.022-4.168), tobacco use (OR=4.265; 95% CI=1.352-13.454), regular physical activity (OR=0.357; 95% CI=0.192-0.663), frequent insomnia (OR=6.298; 95% CI =2.522-15.729), and participation in the frontline work of treating COVID-19 (OR=3.179; 95% CI=1.697-5.954). The COVID-19 epidemic did not significantly increase the depression and stress levels among clinical therapists, but it did significantly increase anxiety levels.ConclusionDuring the COVID-19 pandemic, depression, anxiety and stress were relatively common among clinical therapists in China. Regular physical activity and good sleep were important protective factors against emotional problems. Therefore, encouraging regular physical activity and actively addressing clinical therapists’ sleep problems is beneficial to improving the ability to cope with negative emotions. The COVID-19 epidemic significantly increased anxiety, and awareness and interventions should be recommended to reduce anxiety among clinical therapists during the COVID-19 pandemic

The Roles of Transmembrane Domain Helix-III during Rhodopsin Photoactivation

Background: Rhodopsin, the prototypic member of G protein-coupled receptors (GPCRs), undergoes isomerization of 11- cis-retinal to all-trans-retinal upon photoactivation. Although the basic mechanism by which rhodopsin is activated is well understood, the roles of whole transmembrane (TM) helix-III during rhodopsin photoactivation in detail are not completely clear. Principal Findings: We herein use single-cysteine mutagenesis technique to investigate conformational changes in TM helices of rhodopsin upon photoactivation. Specifically, we study changes in accessibility and reactivity of cysteine residues introduced into the TM helix-III of rhodopsin. Twenty-eight single-cysteine mutants of rhodopsin (P107C-R135C) were prepared after substitution of all natural cysteine residues (C140/C167/C185/C222/C264/C316) by alanine. The cysteine mutants were expressed in COS-1 cells and rhodopsin was purified after regeneration with 11-cis-retinal. Cysteine accessibility in these mutants was monitored by reaction with 4, 49-dithiodipyridine (4-PDS) in the dark and after illumination. Most of the mutants except for T108C, G109C, E113C, I133C, and R135C showed no reaction in the dark. Wide variation in reactivity was observed among cysteines at different positions in the sequence 108–135 after photoactivation. In particular, cysteines at position 115, 119, 121, 129, 131, 132, and 135, facing 11-cis-retinal, reacted with 4-PDS faster than neighboring amino acids. The different reaction rates of mutants with 4-PDS after photoactivation suggest that the amino acids in different positions in helix-III are exposed to aqueous environment to varying degrees. Significance: Accessibility data indicate that an aqueous/hydrophobic boundary in helix-III is near G109 and I133. The lack of reactivity in the dark and the accessibility of cysteine after photoactivation indicate an increase of water/4-PDS accessibility for certain cysteine-mutants at Helix-III during formation of Meta II. We conclude that photoactivation resulted in water-accessible at the chromophore-facing residues of Helix-III.National Institutes of Health (U.S.) (grant GM28289)National Eye Institute (Grant Grant EY11716)National Science Foundation (U.S.) (grant EIA-0225609

Molecular epidemiological characteristics of Mycobacterium leprae in highly endemic areas of China during the COVID-19 epidemic

ObjectivesThe present study analyzed the impact of the COVID-19 pandemic on the prevalence and incidence of new leprosy cases, as well as the diversity, distribution, and temporal transmission of Mycobacterium leprae strains at the county level in leprae-endemic provinces in Southwest China.MethodsA total of 219 new leprosy cases during two periods, 2018–2019 and 2020–2021, were compared. We genetically characterized 83 clinical isolates of M. leprae in Guizhou using variable number tandem repeats (VNTRs) and single nucleotide polymorphisms (SNPs). The obtained genetic profiles and cluster consequences of M. leprae were compared between the two periods.ResultsThere was an 18.97% decrease in the number of counties and districts reporting cases. Considering the initial months (January–March) of virus emergence, the number of new cases in 2021 increased by 167% compared to 2020. The number of patients with a delay of >12 months before COVID-19 (63.56%) was significantly higher than that during COVID-19 (48.51%). Eighty-one clinical isolates (97.60%) were positive for all 17 VNTR types, whereas two (2.40%) clinical isolates were positive for 16 VNTR types. The (GTA)9, (TA)18, (TTC)21 and (TA)10 loci showed higher polymorphism than the other loci. The VNTR profile of these clinical isolates generated five clusters, among which the counties where the patients were located were adjacent or relatively close to each other. SNP typing revealed that all clinical isolates possessed the single SNP3K.ConclusionCOVID-19 may have a negative/imbalanced impact on the prevention and control measures of leprosy, which could be a considerable fact for official health departments. Isolates formed clusters among counties in Guizhou, indicating that the transmission chain remained during the epidemic and was less influenced by COVID-19 preventative policies

Influence of natural factors and land use change on changes in the main lake area in China over the past 30 years

Being one of the main elements of water resources, lakes perform an indispensable part in social production as well as in life. During recent decades, the area of the lake has significantly altered due to global climate variability and growing intensity of the anthropogenic activities. The shrinkage and expansion of lakes have seriously affected both its ecological function and the sustainable development of the regional economy. With this study, we obtain the areas of 38 lakes in China by using the Landsat serial of remote-sensing satellite images in the period 1989–2019 in combination with NDWI water body index and Otsu adaptive thresholding method according to Google Earth Engine (GEE) to explore the trends of lake area changes and related drivers. The outcomes revealed that (1) the overall lake area in the Yunnan-Guizhou Plateau Lake Region (YGP_LR) showed a decreasing trend during the period from 1989 to 2019; the total area of the two lakes(Selin Co and Yangzhuoyong Co) in the Qinghai-Tibet Plateau (QTP_LR) shows an expanding trend; the area of Wulungu Lake in the Mong-Xin Plateau Lake Region (MXP_LR) and Xingkai Lake in the Northeast Plain and Mountain Lake Region (NPM_LR) on a tendency to expand; the area of lakes in the Eastern Plain Lake Region (EP_LR) fluctuated greatly, and the overall area shows a decreasing trend. (2) The increase of temperature promoted the expansion of lake area fed by glacier melt. The increase of rainfall is conducive to the expansion of lake area. The lake area of YGP_LR and EP_LR is closely related to the conversion of other land use types. (3) The lake area of the QTP_LR (Selin Co, Yangzhuoyong Co) varies are mainly affected by climatic factors. Lake area changes in the YGP_LR, Northeast Plain and Mountainous Lake Region (Xingkai Lake), MXP_LR (Wulungu Lake), and EP_LR are influenced by a combination of both climatic changes and the activities of humans. Impact factors of area change in the NPM_LR (Xingkai Lake) need to be further explored