Identification of the Human Skeletal Stem Cell.

Stem cell regulation and hierarchical organization of human skeletal progenitors remain largely unexplored. Here, we report the isolation of a self-renewing and multipotent human skeletal stem cell (hSSC) that generates progenitors of bone, cartilage, and stroma, but not fat. Self-renewing and multipotent hSSCs are present in fetal and adult bones and can also be derived from BMP2-treated human adipose stroma (B-HAS) and induced pluripotent stem cells (iPSCs). Gene expression analysis of individual hSSCs reveals overall similarity between hSSCs obtained from different sources and partially explains skewed differentiation toward cartilage in fetal and iPSC-derived hSSCs. hSSCs undergo local expansion in response to acute skeletal injury. In addition, hSSC-derived stroma can maintain human hematopoietic stem cells (hHSCs) in serum-free culture conditions. Finally, we combine gene expression and epigenetic data of mouse skeletal stem cells (mSSCs) and hSSCs to identify evolutionarily conserved and divergent pathways driving SSC-mediated skeletogenesis. VIDEO ABSTRACT.

G3BP1 promotes DNA binding and activation of cGAS.

Cyclic GMP-AMP synthase (cGAS) is a key sensor responsible for cytosolic DNA detection. Here we report that GTPase-activating protein SH3 domain-binding protein 1 (G3BP1) is critical for DNA sensing and efficient activation of cGAS. G3BP1 enhanced DNA binding of cGAS by promoting the formation of large cGAS complexes. G3BP1 deficiency led to inefficient DNA binding by cGAS and inhibited cGAS-dependent interferon (IFN) production. The G3BP1 inhibitor epigallocatechin gallate (EGCG) disrupted existing G3BP1-cGAS complexes and inhibited DNA-triggered cGAS activation, thereby blocking DNA-induced IFN production both in vivo and in vitro. EGCG administration blunted self DNA-induced autoinflammatory responses in an Aicardi-Goutières syndrome (AGS) mouse model and reduced IFN-stimulated gene expression in cells from a patient with AGS. Thus, our study reveals that G3BP1 physically interacts with and primes cGAS for efficient activation. Furthermore, EGCG-mediated inhibition of G3BP1 provides a potential treatment for cGAS-related autoimmune diseases.

Identification and specification of the mouse skeletal stem cell.

How are skeletal tissues derived from skeletal stem cells? Here, we map bone, cartilage, and stromal development from a population of highly pure, postnatal skeletal stem cells (mouse skeletal stem cells, mSSCs) to their downstream progenitors of bone, cartilage, and stromal tissue. We then investigated the transcriptome of the stem/progenitor cells for unique gene-expression patterns that would indicate potential regulators of mSSC lineage commitment. We demonstrate that mSSC niche factors can be potent inducers of osteogenesis, and several specific combinations of recombinant mSSC niche factors can activate mSSC genetic programs in situ, even in nonskeletal tissues, resulting in de novo formation of cartilage or bone and bone marrow stroma. Inducing mSSC formation with soluble factors and subsequently regulating the mSSC niche to specify its differentiation toward bone, cartilage, or stromal cells could represent a paradigm shift in the therapeutic regeneration of skeletal tissues.

Heterozygous Variants in KCNJ10 Cause Paroxysmal Kinesigenic Dyskinesia Via Haploinsufficiency.

OBJECTIVE: Most paroxysmal kinesigenic dyskinesia (PKD) cases are hereditary, yet approximately 60% of patients remain genetically undiagnosed. We undertook the present study to uncover the genetic basis for undiagnosed PKD patients. METHODS: Whole-exome sequencing was performed for 106 PRRT2-negative PKD probands. The functional impact of the genetic variants was investigated in HEK293T cells and Drosophila. RESULTS: Heterozygous variants in KCNJ10 were identified in 11 individuals from 8 unrelated families, which accounted for 7.5% (8/106) of the PRRT2-negative probands. Both co-segregation of the identified variants and the significantly higher frequency of rare KCNJ10 variants in PKD cases supported impacts from the detected KCNJ10 heterozygous variants on PKD pathogenesis. Moreover, a KCNJ10 mutation-carrying father from a typical EAST/SeSAME family was identified as a PKD patient. All patients manifested dystonia attacks triggered by sudden movement with a short episodic duration. Patch-clamp recordings in HEK293T cells revealed apparent reductions in K+ currents of the patient-derived variants, indicating a loss-of-function. In Drosophila, milder hyperexcitability phenotypes were observed in heterozygous Irk2 knock-in flies compared to homozygotes, supporting haploinsufficiency as the mechanism for the detected heterozygous variants. Electrophysiological recordings showed that excitatory neurons in Irk2 haploinsufficiency flies exhibited increased excitability, and glia-specific complementation with human Kir4.1 rescued the Irk2 mutant phenotypes. INTERPRETATION: Our study established haploinsufficiency resulting from heterozygous variants in KCNJ10 can be understood as a previously unrecognized genetic cause for PKD and provided evidence of glial involvement in the pathophysiology of PKD. ANN NEUROL 2024.

Altered corticalfunctional networks in Wilson's disease: A resting-state electroencephalogram study.

The neuropsychiatric symptoms are common in Wilson's disease (WD) patients. However, it remains unclear about the associated functional brain networks. In this study, source localization-based functional connectivity analysis of close-eye resting-state electroencephalography (EEG) were implemented to assess the characteristics of functional networks in 17 WD patients with neurological involvements and 17 healthy controls (HCs). The weighted phase-lag index (wPLI) was subsequently calculated in source space across five different frequency bands and the resulting connectivity matrix was transformed into a weighted graph whose structure was measured by five graphical analysis indicators, which were finally correlated with clinical scores. Compared to HCs, WD patients revealed disconnected sub-networks in delta, theta and alpha bands. Moreover, WD patients exhibited significantly reduced global clustering coefficients and small-worldness in all five frequency bands. In WD group, the severity of neurological symptoms and structural brain abnormalities were significantly correlated with disrupted functional networks. In conclusion, our study demonstrated that functional network deficits in WD can reflect the severity of their neurological symptoms and structural brain abnormalities. Resting-state EEG may be used as a marker of brain injury in WD.

Associations of Urine and Plasma Metabolites With Kidney Failure and Death in a Chronic Kidney Disease Cohort.

RATIONALE & OBJECTIVE: Biomarkers that enable better identification of persons with chronic kidney disease (CKD) who are at higher risk for disease progression and adverse events are needed. This study sought to identify urine and plasma metabolites associated with progression of kidney disease. STUDY DESIGN: Prospective metabolome-wide association study. SETTING & PARTICIPANTS: Persons with CKD enrolled in the GCKD (German CKD) study with metabolite measurements, with external validation within the ARIC (Atherosclerosis Risk in Communities) Study. EXPOSURES: 1,513 urine and 1,416 plasma metabolites (Metabolon Inc) measured at study entry using untargeted mass spectrometry. OUTCOMES: Main end points were kidney failure (KF) and a composite kidney end point (CKE) of KF, estimated glomerular filtration rate<15mL/min/1.73m2, or a 40% decrease in estimated glomerular filtration rate. Death from any cause was a secondary end point. After a median of 6.5 years of follow-up, 500 persons had experienced KF, 1,083 had experienced the CKE, and 680 had died. ANALYTICAL APPROACH: Time-to-event analyses using multivariable proportional hazard regression models in a discovery-replication design with external validation. RESULTS: 5,088 GCKD study participants were included in analyses of urine metabolites, and 5,144 were included in analyses of plasma metabolites. Among 182 unique metabolites, 30 were significantly associated with KF, 49 with the CKE, and 163 with death. The strongest association with KF was observed for plasma hydroxyasparagine (HR, 1.95; 95% CI, 1.68-2.25). An unnamed metabolite measured in plasma and urine was significantly associated with KF, the CKE, and death. External validation of the identified associations of metabolites with KF or the CKE revealed directional consistency for 88% of observed associations. Selected associations of 18 metabolites with study outcomes have not been previously reported. LIMITATIONS: Use of observational data and semiquantitative metabolite measurements at a single time point. CONCLUSIONS: The observed associations between metabolites and KF, the CKE, or death in persons with CKD confirmed previously reported findings and also revealed several associations not previously described. These findings warrant confirmatory research in other study cohorts. PLAIN-LANGUAGE SUMMARY: Incomplete understanding of the variability of chronic kidney disease (CKD) progression motivated the search for new biomarkers that would help identify people at increased risk. We explored metabolites in plasma and urine for their association with unfavorable kidney outcomes or death in persons with CKD. Metabolomic analyses revealed 182 metabolites significantly associated with CKD progression or death. Many of these associations confirmed previously reported findings or were validated by analysis in an external study population. Our comprehensive screen of the metabolome serves as a valuable foundation for future investigations into biomarkers associated with CKD progression.

Characteristics of tandem repeat inheritance and sympathetic nerve involvement in GAA-FGF14 ataxia.

BACKGROUND: Intronic GAA repeat expansion ([GAA] ≥250) in FGF14 is associated with the late-onset neurodegenerative disorder, spinocerebellar ataxia 27B (SCA27B, GAA-FGF14 ataxia). We aim to determine the prevalence of the GAA repeat expansion in FGF14 in Chinese populations presenting late-onset cerebellar ataxia (LOCA) and evaluate the characteristics of tandem repeat inheritance, radiological features and sympathetic nerve involvement. METHODS: GAA-FGF14 repeat expansion was screened in an undiagnosed LOCA cohort (n = 664) and variations in repeat-length were analyzed in families of confirmed GAA-FGF14 ataxia patients. Brain magnetic resonance imaging (MRI) was used to evaluate the radiological feature in GAA-FGF14 ataxia patients. Clinical examinations and sympathetic skin response (SSR) recordings in GAA-FGF14 patients (n = 16) were used to quantify sympathetic nerve involvement. RESULTS: Two unrelated probands (2/664) were identified. Genetic screening for GAA-FGF14 repeat expansion was performed in 39 family members, 16 of whom were genetically diagnosed with GAA-FGF14 ataxia. Familial screening revealed expansion of GAA repeats in maternal transmissions, but contraction upon paternal transmission. Brain MRI showed slight to moderate cerebellar atrophy. SSR amplitude was lower in GAA-FGF14 patients in pre-symptomatic stage compared to healthy controls, and further decreased in the symptomatic stage. CONCLUSIONS: GAA-FGF14 ataxia was rare among Chinese LOCA cases. Parental gender appears to affect variability in GAA repeat number between generations. Reduced SSR amplitude is a prominent feature in GAA-FGF14 patients, even in the pre-symptomatic stage.

Heterozygous Seryl-tRNA Synthetase 1 Variants Cause Charcot-Marie-Tooth Disease.

OBJECTIVE: Despite the increasing number of genes associated with Charcot-Marie-Tooth (CMT) disease, many patients currently still lack appropriate genetic diagnosis for this disease. Autosomal dominant mutations in aminoacyl-tRNA synthetases (ARSs) have been implicated in CMT. Here, we describe causal missense mutations in the gene encoding seryl-tRNA synthetase 1 (SerRS) for 3 families affected with CMT. METHODS: Whole-exome sequencing was performed in 16 patients and 14 unaffected members of 3 unrelated families. The functional impact of the genetic variants identified was investigated using bioinformatic prediction tools and confirmed using cellular and biochemical assays. RESULTS: Combined linkage analysis for the 3 families revealed significant linkage (Zmax LOD = 6.9) between the genomic co-ordinates on chromosome 1: 108681600-110300504. Within the linkage region, heterozygous SerRS missense variants segregated with the clinical phenotype in the 3 families. The mutant SerRS proteins exhibited reduced aminoacylation activity and abnormal SerRS dimerization, which suggests the impairment of total protein synthesis and induction of eIF2α phosphorylation. INTERPRETATION: Our findings suggest the heterozygous SerRS variants identified represent a novel cause for autosomal dominant CMT. Mutant SerRS proteins are known to impact various molecular and cellular functions. Our findings provide significant advances on the current understanding of the molecular mechanisms associated with ARS-related CMT. ANN NEUROL 2023;93:244-256.

CoFe Alloys Dispersed on Se, N Co-Doped Graphitic Carbon as Efficient Bifunctional Catalysts for Zn-Air Batteries.

The development of a stable and efficient non-noble metal catalyst with both oxygen reduction reaction (ORR) and oxygen evolution reaction (OER) is paramount to achieving the widespread application of Zn-air batteries (ZABs) but remains a great challenge. Herein, a novel Co3 Fe7 alloy nanoparticle dispersed on Se, N co-doped graphitic carbon (denoted as CoFe/Se@CN) was prepared through a facile hydrothermal and pyrolysis process. The synthesized CoFe/Se@CN exhibits outstanding ORR and OER properties with an ultralow potential gap of 0.625 V, which is mainly attributed to the abundant porous structure, the rich structural defects formed by doping Se atoms, and the strong synergistic effects between the CoFe alloys and graphitic carbon nanosheet. Furthermore, the ZAB fabricated by CoFe/Se@CN shows a high peak power density of 160 mW cm-2 and a large specific capacity of 802 mA h g-1 with favorable cycling stability, outperforming that of Pt/C+RuO2 . Our study offers a plausible strategy to explore bifunctional carbon-based materials with efficient electrocatalytic properties for rechargeable ZABs.

Biallelic COQ4 Variants in Hereditary Spastic Paraplegia: Clinical and Molecular Characterization.

BACKGROUND: Hereditary spastic paraplegias (HSP) are neurologic disorders characterized by progressive lower-extremity spasticity. Despite the identification of several HSP-related genes, many patients lack a genetic diagnosis. OBJECTIVES: The aims were to confirm the pathogenic role of biallelic COQ4 mutations in HSP and elucidate the clinical, genetic, and functional molecular features of COQ4-associated HSP. METHODS: Whole exome sequences of 310 index patients with HSP of unknown cause from three distinct populations were analyzed to identify potential HSP causal genes. Clinical data obtained from patients harboring candidate causal mutations were examined. Functional characterization of COQ4 variants was performed using bioinformatic tools, single-cell RNA sequencing, biochemical assays in cell lines, primary fibroblasts, induced pluripotent stem cell-derived pyramidal neurons, and zebrafish. RESULTS: Compound heterozygous variants in COQ4, which cosegregated with HSP in pedigrees, were identified in 7 patients from six unrelated families. Patients from four of the six families presented with pure HSP, whereas probands of the other two families exhibited complicated HSP with epilepsy or with cerebellar ataxia. In patient-derived fibroblasts and COQ4 knockout complementation lines, stable expression of these missense variants exerted loss-of-function effects, including mitochondrial reactive oxygen species accumulation, decreased mitochondrial membrane potential, and lower ubiquinone biosynthesis. Whereas differentiated pyramidal neurons expressed high COQ4 levels, coq4 knockdown zebrafish displayed severe motor dysfunction, reflecting motor neuron dysregulation. CONCLUSIONS: Our study confirms that loss-of-function, compound heterozygous, pathogenic COQ4 variants are causal for autosomal recessive pure and complicated HSP. Moreover, reduced COQ4 levels attributable to variants correspond with decreased ubiquinone biosynthesis, impaired mitochondrial function, and higher phenotypic disease severity. © 2023 International Parkinson and Movement Disorder Society.

Protective effect of Luffa cylindrica Roemer against dexamethasone-induced muscle atrophy in primary rat skeletal muscle cells.

Glucocorticoids (GCs) are commonly used in the treatment of chronic inflammatory conditions. However, the administration of high doses and long-term use of GCs can induce muscle atrophy (MA) in patients, leading to a decline in quality of life and increased mortality. MA leads to protein degradation in skeletal muscle, resulting in a reduction of muscle mass. This process is triggered by GCs like dexamethasone (DEX), which induce the expression of E3 ubiquitin ligases, namely Atrogin-1 and muscle RING-finger protein-1 (MuRF1). In this study, we examined the anti-MA potential of Luffa cylindrica Roemer (LCR) on DEX-treated primary skeletal myotubes. Primary skeletal myotubes stimulated with LCR alone resulted in a significant upregulation of myotube development, characterized by an increase in both the number and diameter of myotubes. Contrastingly, combined treatment with LCR and DEX reduced the expression of Atrogin-1, while treatment with DEX alone induced the expression of MuRF1. Furthermore, LCR treatment successfully restored the number and diameter of myotubes that had been diminished by DEX treatment. These findings suggest that LCR holds potential for treating MA, as an accelerating effect on muscle development and anti-MA effects on primary skeletal muscle cells were observed.

Effectiveness of tofacitinib monotherapy for patients with IgG4-RD or idiopathic retroperitoneal fibrosis.

OBJECTIVES: To explore the effectiveness of tofacitinib for immunoglobulin G4-related disease (IgG4-RD) and idiopathic retroperitoneal fibrosis (IRF), and investigate the expression of JAKs in the lesion of these diseases. METHODS: Clinical data of patients with IgG4-RD or IRF who were administered with tofacitinib monotherapy were collected. IgG4-RD responder index (IgG4-RD RI) was assessed. The expression of JAK1, JAK2, JAK3, and TYK2 were analysed with immunohistochemistry staining in three salivary glands specimens of IgG4-RD and one retroperitoneal tissue of IRF. RESULTS: Two patients with IRF and two patients with IgG4-RD used tofacitinib monotherapy. Two patients with IRF achieved complete remission with diminished retroperitoneal mass and decreased CRP, as IgG4-RD RI decreased from 6 to 1 in both of them. One with IgG4-RD achieved complete remission with alleviated enlargement of pancreas and IgG4 level decreased from 13.7 g/L to 2.4 g/L, as IgG4-RD RI decreased from 12 to 1. One with IgG4-RD achieved partial response with IgG4 level decreased from 77.1g/L to 25.8g/L as IgG4-RD RI from 18 to 6. JAK1, JAK2, JAK3, and TYK2 expression were detected in biopsy tissues. The staining intensity of the JAK family on the lesion from one IRF patient was similar to those from IgG4-RD patients. CONCLUSIONS: Tofacitinib is a potentially effective treatment for IgG4-RD and IRF and it is reasonable to conduct clinical trial to validate its efficacy. The JAKs were expressed in the inflammatory lesions of IgG4-RD and IRF and they may share a common pathogenesis pathway that is independent of IgG4 production.

The impact of chelation compliance in health outcome and health related quality of life in thalassaemia patients: a systematic review.

Understanding consequences of poor chelation compliance is crucial given the enormous burden of post-transfusional iron overload complications. We systematically reviewed iron-chelation therapy (ICT) compliance, and the relationship between compliance with health outcome and health-related quality of life (HRQoL) in thalassaemia patients. Several reviewers performed systematic search strategy of literature through PubMed, Scopus, and EBSCOhost. The preferred reporting items of systematic reviews and meta-analyses (PRISMA) guidelines were followed. Of 4917 studies, 20 publications were included. The ICT compliance rate ranges from 20.93 to 75.3%. It also varied per agent, ranging from 48.84 to 85.1% for desferioxamine, 87.2-92.2% for deferiprone and 90-100% for deferasirox. Majority of studies (N = 10/11, 90.91%) demonstrated significantly negative correlation between compliance and serum ferritin, while numerous studies revealed poor ICT compliance linked with increased risk of liver disease (N = 4/7, 57.14%) and cardiac disease (N = 6/8, 75%), endocrinologic morbidity (N = 4/5, 90%), and lower HRQoL (N = 4/6, 66.67%). Inadequate compliance to ICT therapy is common. Higher compliance is correlated with lower serum ferritin, lower risk of complications, and higher HRQoL. These findings should be interpreted with caution given the few numbers of evidence.

The effect of perceived professional benefits on health professionals' job engagement: the role of psychological availability and future perceived professional benefits.

BACKGROUND: Improving the job engagement of health professionals can effectively enhance the quality of their medical services. However, few studies have investigated whether and how perceived professional benefits affect job engagement. Based on resource conservation theory, this study explored the effect of the influence of perceived professional benefits on job engagement, and also examined the mediating role of psychological availability and the moderating role of future perceived professional benefits. METHODS: A cross-sectional study was conducted in six tertiary hospitals and seven secondary hospitals in Liu Panshui, a city in western China. A total of 1,406 valid questionnaires were obtained and analysed by using correlation analysis, hierarchical regression analysis, and bootstrap tests. RESULT: The study found a significant positive association between health professionals' perceived professional benefits and their job engagement. Additionally, psychological availability was found to mediate this relationship. Future perceived professional benefits not only positively moderate this relationship between perceived professional benefits on health professionals' psychological availability but also positively moderate the mediating role of psychological availability between perceived professional benefits and job engagement. CONCLUSION: Improving health professionals' perceived professional benefits can enhance their job engagement by increasing their psychological availability. However, for health professionals with low future perceived professional benefits, this improvement may disappear. Therefore, it is important to enhance both their current and future perceived professional benefits to improve their job engagement.

Combination Analysis of PCDHGA12 and CDO1 DNA Methylation in Bronchial Washing Fluid for Lung Cancer Diagnosis.

BACKGROUND: When suspicious lesions are observed on computer-tomography (CT), invasive tests are needed to confirm lung cancer. Compared with other procedures, bronchoscopy has fewer complications. However, the sensitivity of peripheral lesion through bronchoscopy including washing cytology is low. A new test with higher sensitivity through bronchoscopy is needed. In our previous study, DNA methylation of PCDHGA12 in bronchial washing cytology has a diagnostic value for lung cancer. In this study, combination of PCDHGA12 and CDO1 methylation obtained through bronchial washing cytology was evaluated as a diagnostic tool for lung cancer. METHODS: A total of 187 patients who had suspicious lesions in CT were enrolled. PCDHGA12 methylation test, CDO1 methylation test, and cytological examination were performed using 3-plex LTE-qMSP test. RESULTS: Sixty-two patients were diagnosed with benign diseases and 125 patients were diagnosed with lung cancer. The sensitivity of PCDHGA12 was 74.4% and the specificity of PCDHGA12 was 91.9% respectively. CDO1 methylation test had a sensitivity of 57.6% and a specificity of 96.8%. The combination of both PCDHGA12 methylation test and CDO1 methylation test showed a sensitivity of 77.6% and a specificity of 90.3%. The sensitivity of lung cancer diagnosis was increased by combining both PCDHGA12 and CDO1 methylation tests. CONCLUSION: Checking DNA methylation of both PCDHGA12 and CDO1 genes using bronchial washing fluid can reduce the invasive procedure to diagnose lung cancer.

Polyhydroxylated Spirostanol Saponins from the Rhizomes of Paris dulongensis.

Three new polyhydroxylated spirostanol steroidal saponins, dulongenosides B-D (2-4), along with 14 known compounds, dulongenoside A (1), padelaoside B (5), parisyunnanoside G (6), polyphyllin D (7), ophiopogonin C' (8), formosanin C (9), dioscin (10), paris saponin VII (11), paris H (12), parisyunnanoside I (13), protodioscin (14), proprotogracillin (15), crustecdysone (16), and stigmasterol-3-O-ß-d-glucopyranoside (17), were isolated from the rhizomes of Paris dulongensis (Melanthiaceae). Their chemical structures were elucidated based on extensive analyses of NMR and MS data and acidic hydrolyses. The isolates were evaluated for their cytotoxicity to five human cancer cell lines (HL-60, SW480, MDA-MB-231, A549, and A549/Taxol) and the normal human bronchial epithelial cell line BEAS-2B by the MTS test. Compounds 7-12 and 14 showed cytotoxic activity, with IC50 values ranging from 0.20 to 4.35 µM. Proprotogracillin selectively inhibited A549 (IC50=0.58 µM) and A549/Taxol (IC50=0.74 µM) cells, with no significant cytotoxic activity against HL-60, SW480, MDA-MB-231, or BEAS-2B cells, with IC50 values greater than 40 µM.

Depth-Guided Bilateral Grid Feature Fusion Network for Dehazing.

In adverse foggy weather conditions, images captured are adversely affected by natural environmental factors, resulting in reduced image contrast and diminished visibility. Traditional image dehazing methods typically rely on prior knowledge, but their efficacy diminishes in practical, complex environments. Deep learning methods have shown promise in single-image dehazing tasks, but often struggle to fully leverage depth and edge information, leading to blurred edges and incomplete dehazing effects. To address these challenges, this paper proposes a deep-guided bilateral grid feature fusion dehazing network. This network extracts depth information through a dedicated module, derives bilateral grid features via Unet, employs depth information to guide the sampling of bilateral grid features, reconstructs features using a dedicated module, and finally estimates dehazed images through two layers of convolutional layers and residual connections with the original images. The experimental results demonstrate the effectiveness of the proposed method on public datasets, successfully removing fog while preserving image details.

Four new alkaloids from the roots of Dactylicapnos scandens.

Four new alkaloids (1 - 4), together with five known ones (5 - 9), were isolated from the bulbs of Dactylicapnos scandens. The structures were determined by analysis of their spectroscopic data and quantum-chemical calculations. All the isolates were tested for their ability to modulate neuronal Ca2+ mobilization in primary cultured neocortical neurons. Compound 8 inhibited spontaneous Ca2+ oscillations at low micromolar concentrations.

p53 genes function to restrain mobile elements.

Throughout the animal kingdom, p53 genes govern stress response networks by specifying adaptive transcriptional responses. The human member of this gene family is mutated in most cancers, but precisely how p53 functions to mediate tumor suppression is not well understood. Using Drosophila and zebrafish models, we show that p53 restricts retrotransposon activity and genetically interacts with components of the piRNA (piwi-interacting RNA) pathway. Furthermore, transposon eruptions occurring in the p53(-) germline were incited by meiotic recombination, and transcripts produced from these mobile elements accumulated in the germ plasm. In gene complementation studies, normal human p53 alleles suppressed transposons, but mutant p53 alleles from cancer patients could not. Consistent with these observations, we also found patterns of unrestrained retrotransposons in p53-driven mouse and human cancers. Furthermore, p53 status correlated with repressive chromatin marks in the 5' sequence of a synthetic LINE-1 element. Together, these observations indicate that ancestral functions of p53 operate through conserved mechanisms to contain retrotransposons. Since human p53 mutants are disabled for this activity, our findings raise the possibility that p53 mitigates oncogenic disease in part by restricting transposon mobility.

Analysis of the Psychological Factors Faced by the Final Year College Students of China During Job Interviews and While Choosing Careers.

Career choice research has attracted the attention of recruiters and young graduates. The study aims to investigate the psychological factors that influence college students' employment choices. As a result, data for the study were gathered from 250 final-year college students in China via an online questionnaire survey. The study identified the psychological barriers faced by college students during job interviews through interviews with 120 h recruiters. The SPPS tool is used for data analysis. The study identified personal interest, self-efficacy, and self- esteem; social responsibilities; confidence; professional development opportunities; and future orientation as the important psychological factors that influence the career choice of college students. The study also found that the barriers faced by the college students during the interview were anxiety, inferiority complex, cowardice, and pride. Therefore, the study suggests that the college provides job-oriented training for college students' employment choices. The college should take the initiative to provide students with career opportunities and proper training to avoid psychological barriers during interviews.