Identification of Hsp20 gene family in Malus domestica and functional characterization of Hsp20 class I gene MdHsp18.2b.

Heat shock protein 20 (Hsp20) is a small molecule heat shock protein that plays an important role in plant growth, development, and stress resistance. Little is known about the function of Hsp20 family genes in apple (Malus domestica). Here, we performed a genome-wide analysis of the apple Hsp20 gene family, and a total of 49 Hsp20s genes were identified from the apple genome. Phylogenetic analysis revealed that the 49 genes were divided into 11 subfamilies, and MdHsp18.2b, a member located in the CI branch, was selected as a representative member for functional characterization. Treatment with NaCl and Botryosphaeria dothidea (B. dothidea), the causal agent of apple ring rot disease, significantly induced MdHsp18.2b transcription level. Further analysis revealed that overexpressing MdHsp18.2b reduced the resistance to salt stress but enhanced the resistance to B. dothidea infection in apple calli. Moreover, MdHsp18.2b positively regulated anthocyanin accumulation in apple calli. Physiology assays revealed that MdHsp18.2b promoted H2O2 production, even in the absence of stress factors, which might contribute to its functions in response to NaCl and B. dothidea infection. Hsps usually function as homo- or heterooligomers, and we found that MdHsp18.2b could form a heterodimer with MdHsp17.9a and MdHsp17.5, two members from the same branch with MdHsp18.2b in the phylogenetic tree. Therefore, we identified 49 Hsp20s genes from the apple genome and found that MdHsp18.2b was involved in regulating plant resistance to salt stress and B. dothidea infection, as well as in regulating anthocyanin accumulation in apple calli.

Effects of micro-nano plastics on the environmental biogeochemical cycle of nitrogen: A comprehensive review.

Micro-nano plastics (MNPs; size <5 mm), ubiquitous and emerging pollutants, accumulated in the natural environment through various sources, and are likely to interact with nutrients, thereby influencing their biogeochemical cycle. Increasing scientific evidences reveal that MNPs can affect nitrogen (N) cycle processes by affecting biotopes and organisms in the environmental matrix and MNPs biofilms, thus plays a crucial role in nitrous oxide (N2O) and ammonia (NH3) emission. Yet, the mechanism and key processes behind this have not been systematically reviewed in natural environments. In this review, we systematically summarize the effects of MNPs on N transformation in terrestrial, aquatic, and atmospheric ecosystems. The effects of MNPs properties on N content, composition, and function of the microbial community, enzyme activity, gene abundance and plant N uptake in different environmental conditions has been briefly discussed. The review highlights the significant potential of MNPs to alter the properties of the environmental matrix, microbes and plant or animal physiology, resulting in changes in N uptake and metabolic efficiency in plants, thereby inhibiting organic nitrogen (ON) formation and reducing N bioavailability, or altering NH3 emissions from animal sources. The faster the decomposition of plastics, the more intense the perturbation of MNPs to organisms in the natural ecosystem. Findings of this provide a more comprehensive analysis and research directions to the environmentalists, policy makers, water resources planners & managers, biologists, and biotechnologists to do integrate approaches to reach the practical engineering solutions which will further diminish the long-term ecological and climatic risks.

A magnetic beads-based ligand fishing method for rapid discovery of monoterpene indoles as monoamine oxidase A inhibitors from Hunteria zeylanica.

In this study, a novel magnetic bead-based ligand fishing method was developed for rapid discovery of monoterpene indoles as monoamine oxidase A inhibitors from natural products. In order to improve the screening efficiency, two different magnetic beads, i.e. amine and carboxyl terminated magnetic beads, were comprehensively compared in terms of their ability to immobilize monoamine oxidase A (MAOA), biocatalytic activity and specific adsorption rates for affinity ligands. Carboxyl terminated magnetic beads performed better for MAOA immobilization and demonstrated superior performance in ligand fishing. The MAOA immobilized magnetic beads were applied to screen novel monoamine oxidase inhibitors in an alkaloid-rich plant, Hunteria zeylanica. Twelve MAOA affinity ligands were screened out, and ten of them were identified as monoterpene indole alkaloids by HPLC-Obitrap-MS/MS. Among them, six ligands, namely geissoschizol, vobasinol, yohimbol, dihydrocorynanthenol, eburnamine and (+)-isoeburnamine which exhibited inhibitory activity against MAOA with low IC50 values. To further explore their inhibitory mechanism, enzyme kinetic analysis and molecular docking studies were conducted.

Overcoming the challenges encountered in CAR-T therapy: latest updates from the 2023 ASH annual conference.

Chimeric antigen receptor (CAR) -T cell therapy has entered the breakthrough era, characterized by a blend of therapeutic opportunities and challenges. With the integration of genome-editing technology, CAR-T cells will be empowered to become super warriors in eradicating tumor cells and attacking various tumors, including T-cell malignancies and acute myeloid leukemia. Notably, the optimization of CAR-T cells, including efficacy, safety, and manufacturing speed, coupled with other therapeutic strategies such as radiotherapy, hematopoietic stem cell transplantation, small-molecule inhibitors, and bispecific antibodies, could revolutionize the therapeutic landscape of tumors. Consequently, next-generation cellular immunotherapy, including universal CAR-NK cells and synergistic combination approaches, are anticipated to significantly impact cancer treatment in the coming decade. Nevertheless, the failure rates of CAR-T therapy continue to be significant. The challenge lies in determining the optimal combination strategy and identifying reliable and robust biomarkers to effectively select the patients who will derive the greatest benefit from CAR-T therapy. Herein, we highlight recent innovations in CAR-T products, combination strategies and predictive biomarkers of response presented at the 2023 ASH Annual Meeting.

The association between O2-pulse slope ratio and functional severity of coronary stenosis: A combined cardiopulmonary exercise testing and quantitative flow ratio study.

Background: The role of cardiopulmonary exercise testing (CPET) parameters in evaluating the functional severity of coronary disease remains unclear. The aim of this study was to quantify the O2-pulse morphology and investigate its relevance in predicting the functional severity of coronary stenosis, using Murray law-based quantitative flow ratio (µQFR) as the reference. Methods: CPET and µQFR were analyzed in 138 patients with stable coronary artery disease (CAD). The O2-pulse morphology was quantified through calculating the O2-pulse slope ratio. The presence of O2-pulse plateau was defined according to the best cutoff value of O2-pulse slope ratio for predicting µQFR ≤ 0.8. Results: The optimal cutoff value of O2-pulse slope ratio for predicting µQFR ≤ 0.8 was 0.4, with area under the curve (AUC) of 0.632 (95 % CI: 0.505-0.759, p = 0.032). The total discordance rate between O2-pulse slope ratio and µQFR was 27.5 %, with 13 patients (9.4 %) being classified as mismatch (O2-pulse slope ratio > 0.4 and µQFR ≤ 0.8) and 25 patients being classified as reverse-mismatch (O2-pulse slope ratio ≤ 0.4 and µQFR > 0.8). Angiography-derived microvascular resistance was independently associated with mismatch (OR 0.07; 95 % CI: 0.01-0.38, p = 0.002) and reverse-mismatch (OR 9.76; 95 % CI: 1.47-64.82, p = 0.018). Conclusion: Our findings demonstrate the potential of the CPET-derived O2-pulse slope ratio for assessing myocardial ischemia in stable CAD patients.

Unraveling the nexus: Microplastics, antibiotics, and ARGs interactions, threats and control in aquaculture - A review.

In recent years, aquaculture has expanded rapidly to address food scarcity and provides high-quality aquatic products. However, this growth has led to the release of significant effluents, containing emerging contaminants like antibiotics, microplastics (MPs), and antibiotic resistance genes (ARGs). This study investigated the occurrence and interactions of these pollutants in aquaculture environment. Combined pollutants, such as MPs and coexisting adsorbents, were widespread and could include antibiotics, heavy metals, resistance genes, and pathogens. Elevated levels of chemical pollutants on MPs could lead to the emergence of resistance genes under selective pressure, facilitated by bacterial communities and horizontal gene transfer (HGT). MPs acted as vectors, transferring pollutants into the food web. Various technologies, including membrane technology, coagulation, and advanced oxidation, have been trialed for pollutants removal, each with its benefits and drawbacks. Future research should focus on ecologically friendly treatment technologies for emerging contaminants in aquaculture wastewater. This review provided insights into understanding and addressing newly developing toxins, aiming to develop integrated systems for effective aquaculture wastewater treatment.

The critical role of residues Phe120 and Val161 of (2 R,3 R)­2,3­butanediol dehydrogenase from Neisseria gonorrhoeae as probed by molecular docking and site-directed mutagenesis.

NAD+-dependent (2 R,3 R)­2,3­butanediol dehydrogenase (BDH) from Neisseria gonorrhoeae (NgBDH) is a representative member of the medium-chain dehydrogenase/reductase (MDR) superfamily. To date, little information is available on the substrate binding sites and catalytic residues of BDHs from this superfamily. In this work, according to molecular docking studies, we found that conserved residues Phe120 and Val161 form strong hydrophobic interactions with both (2 R,3 R)­2,3­butanediol (RR-BD) and meso-2,3­butanediol (meso-BD) and that mutations of these residues to alanine or threonine impair substrate binding. To further evaluate the roles of these two residues, Phe120 and Val161 were mutated to alanine or threonine. Kinetic analysis revealed that, relative to those of wild type, the apparent KM values of the Phe120Ala mutant for RR-BD and meso-BD increased 36- and 369-fold, respectively; the catalytic efficiencies of this mutant with RR-BD and meso-BD decreased approximately 586- and 3528-fold, respectively; and the apparent KM values of the Val161Ala mutant for RR-BD and meso-BD increased 4- and 37-fold, respectively, the catalytic efficiencies of this mutant with RR-BD and meso-BD decreased approximately 3- and 28-fold, respectively. Additionally, the Val161Thr mutant slightly decreased catalytic efficiencies (twofold with RR-BD; 7.3-fold with meso-BD) due to an increase in KM (sixfold for RR-BD; 24-fold for meso-BD) and a slight increase (2.8-fold with RR-BD; 3.3-fold with meso-BD) in kcat. These findings validate the critical roles of Phe120 and Val161 of NgBDH in substrate binding and catalysis. Overall, the current study provides a better understanding of the substrate binding and catalysis of BDHs within the MDR superfamily.

g-C3N4@TiO2 photoanodes for high-efficiency QDSSCs: improved electron transfer and photochemical stability.

In QDSSCs, a photoanode is an important part of connecting the external circuit, providing support for the transmission of photogenerated carriers to the external circuit, and also providing an attachment site for QDs. In this study, we prepared a g-C3N4@TiO2 composite for the photoanode by a two-step process. The results show that the use of g-C3N4@TiO2 greatly increases the specific surface area of the material, effectively inhibits the "electron-hole" recombination, and optimizes the stability and catalytic performance of the photoanode. Among them, the cell equipped with the g-C3N4@TiO2 photoanode has improved performance: Jsc = 26.5 mA cm-2, PCE = 8.2%, Voc = 0.62 eV, and FF = 0.50. Based on the research in this paper, it can be seen that the g-C3N4@TiO2 composite applied to the photoanode can effectively improve the cell performance and provide a feasible idea for optimizing QDSSCs.

High Expression of ZFP42 Improves Early Development of Pig Embryos Produced by Handmade Cloning.

Handmade Cloning (HMC) is a pivotal technique for cloning pig embryos. Despite its significance, the low efficiency of this method hampers its widespread application. Although numerous factors and signaling pathways influencing embryo development have been studied, the mechanisms underlying low developmental capacity and insufficient reprogramming of cloned embryos remain elusive. In the present study, we sought to elucidate key regulatory factors involved in the development of pig HMC embryos by comparing and analyzing the gene expression profiles of HMC embryos with those of naturally fertilized (NF) embryos at the 4-cell, 8-cell, and 16-cell stages. The results showed that ZFP42 expression is markedly higher in NF embryos than in cloned counterparts. Subsequent experiments involving the injection of ZFP42 messenger RNA (mRNA) into HMC embryos showed that ZFP42 could enhance the blastocyst formation rate, upregulate pluripotent genes and metabolic pathways. This highlights the potential of ZFP42 as a critical factor in improving the development of pig HMC embryos.

High-throughput discovery of highly selective reversible hMAO-B inhibitors based on at-line nanofractionation.

Human monoamine oxidase B (hMAO-B) has emerged as a pivotal therapeutic target for Parkinson's disease. Due to adverse effects and shortage of commercial drugs, there is a need for novel, highly selective, and reversible hMAO-B inhibitors with good blood-brain barrier permeability. In this study, a high-throughput at-line nanofractionation screening platform was established with extracts from Chuanxiong Rhizoma, which resulted in the discovery of 75 active compounds, including phenolic acids, volatile oils, and phthalides, two of which were highly selective novel natural phthalide hMAO-B inhibitors that were potent, selective, reversible and had good blood‒brain permeability. Molecular docking and molecular dynamics simulations elucidated the inhibition mechanism. Sedanolide (IC50 = 103 nmol/L; SI = 645) and neocnidilide (IC50 = 131 nmol/L; SI = 207) demonstrated their excellent potential as hMAO-B inhibitors. They offset the limitations of deactivating enzymes associated with irreversible hMAO-B inhibitors such as rasagiline. In SH-SY5Y cell assays, sedanolide (EC50 = 0.962 µmol/L) and neocnidilide (EC50 = 1.161 µmol/L) exhibited significant neuroprotective effects, comparable to the positive drugs rasagiline (EC50 = 0.896 µmol/L) and safinamide (EC50 = 1.079 µmol/L). These findings underscore the potential of sedanolide as a novel natural hMAO-B inhibitor that warrants further development as a promising drug candidate.

Increased miR-6132 promotes deep vein thrombosis formation by downregulating FOXP3 expression.

Background: Deep vein thrombosis (DVT) is associated with aberrant gene expression that is a common peripheral vascular disease. Here, we aimed to elucidate that the epigenetic modification of forkhead box protein 3 (FOXP3) at the post-transcriptional level, which might be the key trigger leading to the down-regulation of FOXP3 expression in DVT. Methods: In order to explore the relationship between microRNAs (miRNAs) and FOXP3, mRNA and microRNA microarray analysis were performed. Dual luciferase reporter assay was used to verify the upstream miRNAs of FOXP3. Quantitative real-time polymerase chain reaction, flow cytometry and Western blot were used to detect the relative expression of miR-6132 and FOXP3. Additionally, DVT models were established to investigate the role of miR-6132 by Murine Doppler Ultrasound and Hematoxylin-Eosin staining. Results: Microarray and flow cytometry results showed that the FOXP3 expression was decreased while miR-6132 level was increased substantially in DVT, and there was significant negative correlation between miR-6132 and FOXP3. Moreover, we discovered that overexpressed miR-6132 reduced FOXP3 expression and aggravated DVT formation, while miR-6132 knockdown increased FOXP3 expression and alleviated DVT formation. Dual luciferase reporter assay validated the direct binding of miR-6132 to FOXP3. Conclusion: Collectively, our data elucidate a new avenue through which up-regulated miR-6132 contributes to the formation and progression of DVT by inhibiting FOXP3 expression.

Early molecular events of autosomal-dominant Alzheimer's disease in marmosets with PSEN1 mutations.

INTRODUCTION: Fundamental questions remain about the key mechanisms that initiate Alzheimer's disease (AD) and the factors that promote its progression. Here we report the successful generation of the first genetically engineered marmosets that carry knock-in (KI) point mutations in the presenilin 1 (PSEN1) gene that can be studied from birth throughout lifespan. METHODS: CRISPR/Cas9 was used to generate marmosets with C410Y or A426P point mutations in PSEN1. Founders and their germline offspring are comprehensively studied longitudinally using non-invasive measures including behavior, biomarkers, neuroimaging, and multiomics signatures. RESULTS: Prior to adulthood, increases in plasma amyloid beta were observed in PSEN1 mutation carriers relative to non-carriers. Analysis of brain revealed alterations in several enzyme-substrate interactions within the gamma secretase complex prior to adulthood. DISCUSSION: Marmosets carrying KI point mutations in PSEN1 provide the opportunity to study the earliest primate-specific mechanisms that contribute to the molecular and cellular root causes of AD onset and progression. HIGHLIGHTS: We report the successful generation of genetically engineered marmosets harboring knock-in point mutations in the PSEN1 gene. PSEN1 marmosets and their germline offspring recapitulate the early emergence of AD-related biomarkers. Studies as early in life as possible in PSEN1 marmosets will enable the identification of primate-specific mechanisms that drive disease progression.

Environmental magnesium ion affects global gene expression, motility, biofilm formation and virulence of Vibrio parahaemolyticus.

Vibrio parahaemolyticus is widely distributed in marine ecosystems. Magnesium ion (Mg2+) is the second most abundant metal cation in seawater, and plays important roles in the growth and gene expression of V. parahaemolyticus, but lacks the detailed mechanisms. In this study, the RNA sequencing data demonstrated that a total of 1494 genes was significantly regulated by Mg2+. The majority of the genes associated with lateral flagella, exopolysaccharide, type III secretion system 2, type VI secretion system (T6SS) 1, T6SS2, and thermostable direct hemolysin were downregulated. A total of 18 genes that may be involved in c-di-GMP metabolism and more than 80 genes encoding putative regulators were also significantly and differentially expressed in response to Mg2+, indicating that the adaptation process to Mg2+ stress may be strictly regulated by complex regulatory networks. In addition, Mg2+ promoted the proliferative speed, swimming motility and cell adhesion of V. parahaemolyticus, but inhibited the swarming motility, biofilm formation, and c-di-GMP production. However, Mg2+ had no effect on the production of capsular polysaccharide and cytoxicity against HeLa cells. Therefore, Mg2+ had a comprehensive impact on the physiology and gene expression of V. parahaemolyticus.

Analysis of the Correlation Between Dynamic Characteristics and Symptoms of Gastroesophageal Reflux Disease.

OBJECTIVE: To investigate the esophageal motility characteristics of gastroesophageal reflux disease (GERD) and their relationship with symptoms. PATIENTS AND METHODS: We examined 101 patients diagnosed with GERD by endoscopy and divided them into 3 groups as follows: nonerosive reflux disease (NERD), reflux esophagitis, and Barrett esophagus. Esophageal high-resolution manometry and the GERD Questionnaire were used to investigate the characteristics of esophageal dynamics and symptoms. In addition, the reflux symptom index was completed and the patients were divided into 7 groups according to symptoms. We then determined the correlation between dynamic esophageal characteristics and clinical symptoms. RESULTS: Upper (UES) and lower (LES) esophageal sphincter pressures and the 4-second integrated relaxation pressure in the RE group were lower than those in the NERD group. The 4-second integrated relaxation pressure in the Barrett esophagus group was also lower than that in the NERD group. In the analysis of extraesophageal symptoms, high-resolution manometry showed significant differences in UES pressures among all groups. Further subgroup analysis showed that compared with the group without extraesophageal symptoms, the UES pressure of the groups with pharyngeal foreign body sensation, throat clearing, and multiple extraesophageal symptoms was lower. CONCLUSIONS: As GERD severity increases, motor dysfunction of the LES and esophageal body gradually worsens, and the LES plays an important role in GERD development. Decreased UES pressure plays an important role in the occurrence of extraesophageal symptoms, which is more noticeable in patients with pharyngeal foreign body sensation and throat clearing.

The Inhibition of Fibrosis and Inflammation in Obstructive Kidney Injury via the miR-122-5p/SOX2 Axis Using USC-Exos.

Background: Fibrosis and inflammation due to ureteropelvic junction obstruction substantially contributes to poor renal function. Urine-derived stem-cell-derived exosomes (USC-Exos) have therapeutic effects through paracrine. Methods: In vitro, the effects of USC-Exos on the biological functions of HK-2 and human umbilical vein endothelial cells were tested. Cell inflammation and fibrosis were induced by transforming growth factor-ß1 and interleukin-1ß, and their anti-inflammatory and antifibrotic effects were observed after exogenous addition of USC-Exos. Through high-throughput sequencing of microRNA in USC-Exos, the pathways and key microRNAs were selected. Then, the antifibrotic and anti-inflammatory effects of exosomal miR-122-5p and target genes were verified. The role of the miR-122-5p/SOX2 axis in anti-inflammatory and antifibrotic effects was verified. In vivo, a rabbit model of partial unilateral ureteral obstruction (PUUO) was established. Magnetic resonance imaging recorded the volume of the renal pelvis after modeling, and renal tissue was pathologically analyzed. Results: We examined the role of USC-Exos and their miR-122-5p content in obstructive kidney injury. These Exos exhibit antifibrotic and anti-inflammatory activities. SOX2 is the hub gene in PUUO and negatively related to renal function. We confirmed the binding relationship between miR-122-5p and SOX2. The anti-inflammatory and antifibrotic effects of miR-122-5p were inhibited, indicating that miR-122-5p has anti-inflammatory and antifibrotic effects by inhibiting SOX2 expression. In vivo, the PUUO group showed typical obstructive kidney injury after modeling. After USC-Exo treatment, the shape of the renal pelvis shown a remarkable improvement, and inflammation and fibrosis decreased. Conclusions: We confirmed that miR-122-5p from USC-Exos targeting SOX2 is a new molecular target for postoperative recovery treatment of obstructive kidney injury.

Integrated analysis of purine metabolism assists in predicting prognosis and treatment decisions for patients with lung adenocarcinoma.

The incidence of lung cancer, especially lung adenocarcinoma (LUAD), has recently increased. Targeted therapy and immunotherapy combined with conventional treatment have shown surprising benefits in enhancing the LUAD patient's prognosis. For the purpose of guiding treatment planning and the prognosis of LUAD, more research is required. The particular aim of this work was to establish a purine metabolism scoring (PMS) model for the purpose of individually forecasting treatment outcomes and overall survival for patients who have LUAD. Clinical and whole genome data were obtained from the TCGA-LUAD cohort via "UCSC". The 25 driver purine metabolism-related prognostic genes were determined founded on univariate Cox regression. Then PMS was developed through stepwise LASSO Cox regression. Survival analysis indicated that patients who have PMS experienced worse outcomes. We validated the PGM2 effect on lung adenocarcinoma malignancy in in vitro experiments. Univariate as well as multivariate Cox regression suggested that PMS was an independent prognostic indicator for LUAD patients, which was confirmed in subgroup analysis. Functional assay demonstrated that immune response as well as cytotoxicity pathways have a connection with lower PMS, and patients who have low PMS possess an active immune microenvironment. Moreover, the LUAD patients who have low PMS showed greater sensitivity to immunotherapy, targeted therapy, as well as chemotherapy. Knockdown of PGM2 was discovered to decrease the proliferation, invasion, as well as migration of lung adenocarcinoma cells in an in vitro assay. Pertaining to this particular research, we created a PMS model and conducted a thorough analysis of purine metabolism in LUAD in order to determine prognosis and offer recommendations for treatment. This finding offered a fresh concept for the clinical management of LUAD and novel therapy protocols.

A tempo-spatial controllable microfluidic shear-stress generator for in-vitro mimicking of the thrombus.

Pathological conditions linked to shear stress have been identified in hematological diseases, cardiovascular diseases, and cancer. These conditions often exhibit significantly elevated shear stress levels, surpassing 1000 dyn/cm2 in severely stenotic arteries. Heightened shear stress can induce mechanical harm to endothelial cells, potentially leading to bleeding and fatal consequences. However, current technology still grapples with limitations, including inadequate flexibility in simulating bodily shear stress environments, limited range of shear stress generation, and spatial and temporal adaptability. Consequently, a comprehensive understanding of the mechanisms underlying the impact of shear stress on physiological and pathological conditions, like thrombosis, remains inadequate. To address these limitations, this study presents a microfluidic-based shear stress generation chip as a proposed solution. The chip achieves a substantial 929-fold variation in shear stress solely by adjusting the degree of constriction in branch channels after PDMS fabrication. Experiments demonstrated that a rapid increase in shear stress up to 1000 dyn/cm2 significantly detached 88.2% cells from the substrate. Long-term exposure (24 h) to shear stress levels below 8.3 dyn/cm2 did not significantly impact cell growth. Furthermore, cells exposed to shear stress levels equal to or greater than 8.3 dyn/cm2 exhibited significant alterations in aspect ratio and orientation, following a normal distribution. This microfluidic chip provides a reliable tool for investigating cellular responses to the wide-ranging shear stress existing in both physiological and pathological flow conditions.

Prevalence and correlates of mental health problems among different occupations of medical workers during COVID-19 outbreak in China.

Background: Health workers involved in the fight to prevent the COVID-19 outbreak were exposed to hazards. Detailed information on mental health problems in different medical occupations is crucial. To examined the prevalence of mental health issues in three medical occupations as well as the relationships between mental health problems and correlates in each occupation. Methods: This study utilizing the Questionnaire Star program was conducted among medical workers working at medical institutions in China from February 17 to 24, 2020. The Self-Reporting Questionnaire (SRQ-20), the Zung Self-rating Anxiety Scale (SAS), and the Zung Self-rating Depression Scale (SDS) were used to assess mental health problems. Results: The prevalence of any mental health problems in the three occupations was 43.6, 34.6, and 32.9% for nurses, paramedical workers (PMWs), and doctors, respectively. Three occupations shared some correlates, such as being overworked, not having enough time to rest, support from colleagues, and previous mental health status. There were specific factors for each occupation. For doctors, age, educational level, living status, support from family, and previous physical status were related factors in mental health problems. Working in a designated hospital for treating COVID-19, having COVID-19 event exposures, and receiving support from family were associated with the mental health problems of the nurses. PMWs' mental health problems was linked to educational level and care from supervisors or heads of department. Conclusion: Different medical occupations have distinct impacts on mental health issues. Policy makers and mental health professionals working to prepare for potential disease outbreaks should be aware of multiple factors in different occupations.

The subcommissural organ regulates brain development via secreted peptides.

The subcommissural organ (SCO) is a gland located at the entrance of the aqueduct of Sylvius in the brain. It exists in species as distantly related as amphioxus and humans, but its function is largely unknown. To explore its function, we compared transcriptomes of SCO and non-SCO brain regions and found three genes, Sspo, Car3, and Spdef, that are highly expressed in the SCO. Mouse strains expressing Cre recombinase from endogenous promoter/enhancer elements of these genes were used to genetically ablate SCO cells during embryonic development, resulting in severe hydrocephalus and defects in neuronal migration and development of neuronal axons and dendrites. Unbiased peptidomic analysis revealed enrichment of three SCO-derived peptides, namely thymosin beta 4, thymosin beta 10, and NP24, and their reintroduction into SCO-ablated brain ventricles substantially rescued developmental defects. Together, these data identify a critical role for the SCO in brain development.

Pharmacogenomic profiling of intra-tumor heterogeneity using a large organoid biobank of liver cancer.

Inter- and intra-tumor heterogeneity is a major hurdle in primary liver cancer (PLC) precision therapy. Here, we establish a PLC biobank, consisting of 399 tumor organoids derived from 144 patients, which recapitulates histopathology and genomic landscape of parental tumors, and is reliable for drug sensitivity screening, as evidenced by both in vivo models and patient response. Integrative analysis dissects PLC heterogeneity, regarding genomic/transcriptomic characteristics and sensitivity to seven clinically relevant drugs, as well as clinical associations. Pharmacogenomic analysis identifies and validates multi-gene expression signatures predicting drug response for better patient stratification. Furthermore, we reveal c-Jun as a major mediator of lenvatinib resistance through JNK and ß-catenin signaling. A compound (PKUF-01) comprising moieties of lenvatinib and veratramine (c-Jun inhibitor) is synthesized and screened, exhibiting a marked synergistic effect. Together, our study characterizes the landscape of PLC heterogeneity, develops predictive biomarker panels, and identifies a lenvatinib-resistant mechanism for combination therapy.