Multimodal neuroimaging exploration of the mechanisms of sleep quality deterioration after SARS-CoV-2 Omicron infection.

BACKGROUND: To evaluate the neurological alterations induced by Omicron infection, to compare brain changes in chronic insomnia with those in exacerbated chronic insomnia in Omicron patients, and to examine individuals without insomnia alongside those with new-onset insomnia. METHODS: In this study, a total of 135 participants were recruited between January 11 and May 4, 2023, including 26 patients with chronic insomnia without exacerbation, 24 patients with chronic insomnia with exacerbation, 40 patients with no sleep disorder, and 30 patients with new-onset insomnia after infection with Omicron (a total of 120 participants with different sleep statuses after infection), as well as 15 healthy controls who were never infected with Omicron. Neuropsychiatric data, clinical symptoms, and multimodal magnetic resonance imaging data were collected. The gray matter thickness and T1, T2, proton density, and perivascular space values were analyzed. Associations between changes in multimodal magnetic resonance imaging findings and neuropsychiatric data were evaluated with correlation analyses. RESULTS: Compared with healthy controls, gray matter thickness changes were similar in the patients who have and do not have a history of chronic insomnia groups after infection, including an increase in cortical thickness near the parietal lobe and a reduction in cortical thickness in the frontal, occipital, and medial brain regions. Analyses showed a reduced gray matter thickness in patients with chronic insomnia compared with those with an aggravation of chronic insomnia post-Omicron infection, and a reduction was found in the right medial orbitofrontal region (mean [SD], 2.38 [0.17] vs. 2.67 [0.29] mm; P < 0.001). In the subgroups of Omicron patients experiencing sleep deterioration, patients with a history of chronic insomnia whose insomnia symptoms worsened after infection displayed heightened medial orbitofrontal cortical thickness and increased proton density values in various brain regions. Conversely, patients with good sleep quality who experienced a new onset of insomnia after infection exhibited reduced cortical thickness in pericalcarine regions and decreased proton density values. In new-onset insomnia patients post-Omicron infection, the thickness in the right pericalcarine was negatively correlated with the Self-rating Anxiety Scale (r = - 0.538, P = 0.002, PFDR = 0.004) and Self-rating Depression Scale (r = - 0.406, P = 0.026, PFDR = 0.026) scores. CONCLUSIONS: These findings help us understand the pathophysiological mechanisms involved when Omicron invades the nervous system and induces various forms of insomnia after infection. In the future, we will continue to pay attention to the dynamic changes in the brain related to insomnia caused by Omicron infection.

A protein-protein interaction map reveals that the Coxiella burnetii effector CirB inhibits host proteasome activity.

Coxiella burnetii is the etiological agent of the zoonotic disease Q fever, which is featured by its ability to replicate in acid vacuoles resembling the lysosomal network. One key virulence determinant of C. burnetii is the Dot/Icm system that transfers more than 150 effector proteins into host cells. These effectors function to construct the lysosome-like compartment permissive for bacterial replication, but the functions of most of these effectors remain elusive. In this study, we used an affinity tag purification mass spectrometry (AP-MS) approach to generate a C. burnetii-human protein-protein interaction (PPI) map involving 53 C. burnetii effectors and 3480 host proteins. This PPI map revealed that the C. burnetii effector CBU0425 (designated CirB) interacts with most subunits of the 20S core proteasome. We found that ectopically expressed CirB inhibits hydrolytic activity of the proteasome. In addition, overexpression of CirB in C. burnetii caused dramatic inhibition of proteasome activity in host cells, while knocking down CirB expression alleviated such inhibitory effects. Moreover, we showed that a region of CirB that spans residues 91-120 binds to the proteasome subunit PSMB5 (beta 5). Finally, PSMB5 knockdown promotes C. burnetii virulence, highlighting the importance of proteasome activity modulation during the course of C. burnetii infection.

Common and distinct functional brain network abnormalities in adolescent, early-middle adult, and late adult major depressive disorders.

BACKGROUND: The age-related heterogeneity in major depressive disorder (MDD) has received significant attention. However, the neural mechanisms underlying such heterogeneity still need further investigation. This study aimed to explore the common and distinct functional brain abnormalities across different age groups of MDD patients from a large-sample, multicenter analysis. METHODS: The analyzed sample consisted of a total of 1238 individuals including 617 MDD patients (108 adolescents, 12-17 years old; 411 early-middle adults, 18-54 years old; and 98 late adults, > = 55 years old) and 621 demographically matched healthy controls (60 adolescents, 449 early-middle adults, and 112 late adults). MDD-related abnormalities in brain functional connectivity (FC) patterns were investigated in each age group separately and using the whole pooled sample, respectively. RESULTS: We found shared FC reductions among the sensorimotor, visual, and auditory networks across all three age groups of MDD patients. Furthermore, adolescent patients uniquely exhibited increased sensorimotor-subcortical FC; early-middle adult patients uniquely exhibited decreased visual-subcortical FC; and late adult patients uniquely exhibited wide FC reductions within the subcortical, default-mode, cingulo-opercular, and attention networks. Analysis of covariance models using the whole pooled sample further revealed: (1) significant main effects of age group on FCs within most brain networks, suggesting that they are decreased with aging; and (2) a significant age group × MDD diagnosis interaction on FC within the default-mode network, which may be reflective of an accelerated aging-related decline in default-mode FCs. CONCLUSIONS: To summarize, these findings may deepen our understanding of the age-related biological and clinical heterogeneity in MDD.

Evaluating test-retest reliability and sex-/age-related effects on temporal clustering coefficient of dynamic functional brain networks.

The multilayer dynamic network model has been proposed as an effective method to understand the brain function. In particular, derived from the definition of clustering coefficient in static networks, the temporal clustering coefficient provides a direct measure of the topological stability of dynamic brain networks and shows potential in predicting altered brain functions. However, test-retest reliability and demographic-related effects on this measure remain to be evaluated. Using a data set from the Human Connectome Project (157 male and 180 female healthy adults; 22-37 years old), the present study investigated: (1) the test-retest reliability of temporal clustering coefficient across four repeated resting-state functional magnetic resonance imaging scans as measured by intraclass correlation coefficient (ICC); and (2) sex- and age-related effects on temporal clustering coefficient. The results showed that (1) the temporal clustering coefficient had overall moderate test-retest reliability (ICC > 0.40 over a wide range of densities) at both global and subnetwork levels, (2) female subjects showed significantly higher temporal clustering coefficient than males at both global and subnetwork levels, particularly within the default-mode and subcortical regions, and (3) temporal clustering coefficient of the subcortical subnetwork was positively correlated with age in young adults. The results of sex effects were robustly replicated in an independent REST-meta-MDD data set, while the results of age effects were not. Our findings suggest that the temporal clustering coefficient is a relatively reliable and reproducible approach for identifying individual differences in brain function, and provide evidence for demographically related effects on the human brain dynamic connectomes.

Sequenced treatment alternatives to relieve adolescent depression (STAR-AD): a multicentre open-label randomized controlled trial protocol.

BACKGROUND: Adolescent major depressive disorder (MDD) is a prevalent mental health problem with low treatment success rates. Whether fluoxetine or fluoxetine combined with cognitive-behavioural therapy (CBT) is the more effective initial treatment for adolescent MDD remains controversial, and few studies have investigated whether treatment switching or augmentation is preferred when the initial treatment is not working well. METHODS: We developed a multicentre open-label Sequential Multiple Assignment Randomized Trial (SMART) design, consisting of two phases lasting 8 weeks each. In phase 1 (at baseline), patients will be recruited and grouped in fluoxetine group or fluoxetine combined with CBT group by patient self-selection. In phase 2 (after 8 weeks of treatment), the nonresponders will be randomly assigned to six groups, in which participants will switch to sertraline, vortioxetine, or duloxetine or added aripiprazole, olanzapine, or lithium carbonate to fluoxetine. After the full 16 weeks of treatment, we will assess the long-term sustainability of the treatment effects by evaluating participants during their subsequent naturalistic treatment. The primary outcome will be the response rate, determined by the Children's Depression Rating Scale-Revised (CDRS-R). Secondary outcomes include the change in scores on the Beck Depression Inventory (BDI), the Screen for Child Anxiety-Related Emotional Disorders (SCARED) and the Safe Assessment. DISCUSSION: The results from this study will aid clinicians in making informed treatment selection decisions for adolescents with MDD. TRIAL REGISTRATION: This protocol was registered at ClinicalTrials.gov with Identifier: NCT05814640.

Profiles of depressive symptoms and influential factors among people living with HIV in China.

BACKGROUND: Depressive symptoms are highly prevalent among people living with HIV (PLWH). We leveraged Latent Profile Analysis (LPA) to identify profiles of depressive symptoms among PLWHs. We also investigated differences in psychological factors of interest, demographic characteristics, and HIV-related factors across patients' profiles. METHODS: A cross-sectional study was conducted at one hospital and two designated prison facilities in Hunan province, China. A total sample of 533 PLWHs (320 recruited from the hospital, 213 recruited from prisons) completed the survey. Depressive symptoms were assessed using the 9-item Patient Health Questionnaire (PHQ-9). Family function, resilience, childhood trauma, demographic characteristics, and HIV-related factors were also evaluated. We conducted LPA and multinomial logistic regression analyses to: 1) identify distinct profiles for depressive symptoms; 2) identify demographic characteristics, and HIV-related, and psychological factors predicting PLWHs' likelihood to express a specific profile. RESULTS: We identified three distinct profiles of depressive symptoms among PLWHs: severe symptoms (11.8%), moderate symptoms (40.5%), and low/no symptoms (47.7%). Moderate/ severe family dysfunction, low resilience, experiencing emotional abuse and neglect were more likely to fall in the "severe symptoms" rather than the "low/no symptoms" profile. In addition, severe family dysfunction, low resilience, and experiencing emotional neglect indicated a higher likelihood of being classified in the "moderate symptoms" profile, compared to the "low/no symptoms" profile. CONCLUSION: Identifying profiles of depressive symptoms among PLWHs using the PHQ-9 items allows for understanding of the distinct paths of development of depressive symptoms and for developing tailored prevention and intervention programs for PLWHs.

Prostaglandin F2α Regulates Adipogenesis by Modulating Extracellular Signal-Regulated Kinase Signaling in Graves' Ophthalmopathy.

Prostaglandin F2α (PGF2α), the first-line anti-glaucoma medication, can cause the deepening of the upper eyelid sulcus due to orbital lipoatrophy. However, the pathogenesis of Graves' ophthalmopathy (GO) involves the excessive adipogenesis of the orbital tissues. The present study aimed to determine the therapeutic effects and underlying mechanisms of PGF2α on adipocyte differentiation. In this study primary cultures of orbital fibroblasts (OFs) from six patients with GO were established. Immunohistochemistry, immunofluorescence, and Western blotting (WB) were used to evaluated the expression of the F-prostanoid receptor (FPR) in the orbital adipose tissues and the OFs of GO patients. The OFs were induced to differentiate into adipocytes and treated with different incubation times and concentrations of PGF2α. The results of Oil red O staining showed that the number and size of the lipid droplets decreased with increasing concentrations of PGF2α and the reverse transcription-polymerase chain reaction (RT-PCR) and WB of the peroxisome proliferator-activated receptor γ (PPARγ) and fatty-acid-binding protein 4 (FABP4), both adipogenic markers, were significantly downregulated via PGF2α treatment. Additionally, we found the adipogenesis induction of OFs promoted ERK phosphorylation, whereas PGF2α further induced ERK phosphorylation. We used Ebopiprant (FPR antagonist) to interfere with PGF2α binding to the FPR and U0126, an Extracellular Signal-Regulated Kinase (ERK) inhibitor, to inhibit ERK phosphorylation. The results of Oil red O staining and expression of adipogenic markers showed that blocking the receptor binding or decreasing the phosphorylation state of the ERK both alleviate the inhibitory effect of PGF2a on the OFs adipogenesis. Overall, PGF2α mediated the inhibitory effect of the OFs adipogenesis through the hyperactivation of ERK phosphorylation via coupling with the FPR. Our study provides a further theoretical reference for the potential application of PGF2α in patients with GO.

Recent Advances in N-O Bond Cleavage of Oximes and Hydroxylamines to Construct N-Heterocycle.

Oximes and hydroxylamines are a very important class of skeletons that not only widely exist in natural products and drug molecules, but also a class of synthon, which have been widely used in industrial production. Due to weak N-O σ bonds of oximes and hydroxylamines, they can be easily transformed into other functional groups by N-O bond cleavage. Therefore, the synthesis of N-heterocycle by using oximes and hydroxylamines as nitrogen sources has attracted wide attention. Recent advances for the synthesis of N-heterocycle through transition-metal-catalyzed and radical-mediated cyclization classified by the type of nitrogen sources and rings are summarized. In this paper, the recent advances in the N-O bond cleavage of oximes and hydroxylamines are reviewed. We hope that this review provides a new perspective on this field, and also provides a reference to develop environmentally friendly and sustainable methods.

Coxiella burnetii Plasmid Effector B Promotes LC3-II Accumulation and Contributes To Bacterial Virulence in a SCID Mouse Model.

Coxiella burnetii, the causative agent of zoonotic Q fever, is characterized by replicating inside the lysosome-derived Coxiella-containing vacuole (CCV) in host cells. Some effector proteins secreted by C. burnetii have been reported to be involved in the manipulation of autophagy to facilitate the development of CCVs and bacterial replication. Here, we found that the Coxiella plasmid effector B (CpeB) localizes on vacuole membrane targeted by LC3 and LAMP1 and promotes LC3-II accumulation. Meanwhile, the C. burnetii strain lacking the QpH1 plasmid induced less LC3-II accumulation, which was accompanied by smaller CCVs and lower bacterial loads in THP-1 cells. Expression of CpeB in the strain lacking QpH1 led to restoration in LC3-II accumulation but had no effect on the smaller CCV phenotype. In the severe combined immune deficiency (SCID) mouse model, infections with the strain expressing CpeB led to significantly higher bacterial burdens in the spleen and liver than its parent strain devoid of QpH1. We also found that CpeB targets Rab11a to promote LC3-II accumulation. Intratracheally inoculated C. burnetii resulted in lower bacterial burdens and milder lung lesions in Rab11a conditional knockout (Rab11a-/- CKO) mice. Collectively, these results suggest that CpeB promotes C. burnetii virulence by inducing LC3-II accumulation via a pathway involving Rab11a.

Intermolecular 1,2-Difunctionalization of Alkenes Enabled by Fluoroamide-Directed Remote Benzyl C(sp3)-H Functionalization.

A copper-catalyzed remote benzylic C-H functionalization strategy enabling 1,2-difunctionalization of alkenes with 2-methylbenzeneamides and nucleophiles, including alcohols, indoles, pyrroles, and the intrinsic amino groups, is reported, which is characterized by its redox-neutral conditions, exquisite site-selectivity, broad substrate scope, and wide utilizations of late-stage modifying bioactive molecules. This reaction proceeds through nitrogen-centered radical generation, hydrogen atom transfer, benzylic radical addition across the alkenes, single-electron oxidation, and carbocation electrophilic course cascades. While using external nucleophiles manipulates three-component alkene alkylalkoxylation and alkyl-heteroarylation with 2-methylbenzeneamides to access dialkyl ethers, 3-alkylindoles, and 3-alkylpyrroles, omitting the external nucleophiles results in two-component alkylamidation ([5+2] annulation) of alkenes with 2-methylbenzeneamides to benzo-[f][1,2]thiazepine 1,1-dioxides.

Novel genotypes of Coxiella burnetii circulating in rats in Yunnan Province, China.

BACKGROUND: Coxiella burnetii (Cb) is the causative agent of the zoonotic disease Q fever which is distributed worldwide. Molecular typing of Cb strains is essential to find out the infectious source and prevent Q fever outbreaks, but there has been a lack of typing data for Cb strains in China. The aim of this study was to investigate the genotypes of Cb strains in wild rats in Yunnan Province, China. RESULTS: Eighty-six wild rats (Rattus flavipectus) were collected in Yunnan Province and 8 of the 86 liver samples from the wild rats were positive in Cb-specific quantitative PCR (qPCR). The Cb strains from the 8 rats were then typed into 3 genotypes using 10-spacer multispacer sequence typing (MST), and 2 of the 3 genotypes were recognized as novel ones. Moreover, the Cb strains in the wild rats were all identified as genotype 1 using 6-loci multilocus variable number of tandem repeat analysis (MLVA). CONCLUSIONS: This is the first report of genotypic diversity of Cb strains from wild rats in China. Further studies are needed to explore the presence of more genotypes and to associate the genotypes circulating in the wildlife-livestock interaction with those causing human disease to further expand on the epidemiological aspects of the pathogen.

Factors influencing medication adherence among patients with severe mental disorders from the perspective of mental health professionals.

BACKGROUND: Medication adherence is a common issue influenced by various factors among patients with severe mental disorders worldwide. However, most literature to date has been primarily quantitative and has focused on medication adherence issue from the perspective of patients or their caregivers. Moreover, research focused on medication adherence issue in China is scarce. Present study aims to explore the influential factors of medication adherence among patients with severe mental disorders form the perspective of mental health professionals in Hunan Province, China. METHODS: A qualitative study was performed in Hunan Province, China with 31 mental health professionals recruited from October to November 2017. And semi-structured interviews or focus group interviews were conducted along with audio recordings of all interviews. Interview transcripts were then coded and analyzed in Nvivo software with standard qualitative approaches. RESULTS: Three major themes influencing medication adherence among patients with severe mental disorders were identified as: (1) attitudes towards mental disorder/treatment; (2) inadequate aftercare; (3) resource shortages. CONCLUSIONS: This qualitative study identified the factors influencing medication adherence among patients with severe mental disorders in China. As a locally driven research study, it provides practical advice on medication adherence promotion for mental health workers and suggests culturally tailored models that improve the management of patients with severe mental disorders in order to reduce economic burden on individual and societal level.

Mental health characteristics and their associations with childhood trauma among subgroups of people living with HIV in China.

BACKGROUND: People living with HIV (PLWH) carry a high risk for mental health problems, which has been extensively reported in the literature. However, an understanding of mental health characteristics in different subgroups of PLWH is still limited. In the present study, we conducted a cross-sectional survey to explore mental health characteristics and their associations with childhood trauma in two major subgroups of PLWH in China. METHODS: A total of 533 PLWH (213 prisoners in the prison system, and 320 outpatients) were assessed using the 8-item Positive Subscale of the Community Assessment of Psychic Experiences (CAPE-P8), Generalized Anxiety Disorder scale (GAD-7), Patient Health Questionnaire (PHQ-9), and Childhood Trauma Questionnaire (CTQ). RESULTS: From the total sample, 22.0% PLWH frequently experienced psychotic-like experiences (PLEs), 21.8% had clinically significant anxiety syndrome, 34.0% had clinically significant depressive syndrome, and 63.6% experienced at least one type of traumatic exposure during their childhood, with physical neglect being the most common. Compared to outpatients with HIV, prisoners living with HIV reported more severe mental health problems and a higher frequency of childhood trauma, with childhood trauma in turn predicting higher risk for mental health problems. Similarly, among outpatients living with HIV, both childhood emotional and sexual abuse had predictive effects on all the three mental health problems. CONCLUSIONS: The study suggests that PLWH have higher risk of anxiety, depression and PLEs, and childhood trauma could serve as predicting factors for such risks. In addition, childhood trauma may play distinct roles in predicting the risk for the mental health problems, depending on different subgroup of PLWH.

Mediating role of impaired wisdom in the relation between childhood trauma and psychotic-like experiences in Chinese college students: a nationwide cross-sectional study.

BACKGROUND: The association between childhood trauma (CT) and psychotic-like experiences (PLEs) is well-established. Many previous studies have recognized wisdom as a protective factor for mental health, but its role in the relation between CT and PLEs remains unknown. We aimed to investigate the mediating effect of wisdom in the above association among Chinese college students. METHODS: We conducted a nationwide survey covering 9 colleges across China and recruited a total of 5873 students using online questionnaires between September 14 and October 18, 2021. Convenience sampling was adopted. We employed the San Diego Wisdom Scale (SD-WISE), the Childhood Trauma Questionnaire (CTQ-28), and the 15-item Positive Subscale of the Community Assessment of Psychic Experiences (CAPE-15) to measure the wisdom, CT and PLEs, respectively. Descriptive, correlation, and mediation analysis were utilized. RESULTS: The positive correlation between CT and PLEs was well-replicated among college students (Pearson's r = 0.30, p < 0.001). Wisdom was negatively associated with CT (Pearson's r = - 0.46, p < 0.001) and frequency of PLEs (Pearson's r = - 0.25, p < 0.001). Total wisdom scores partially mediated the relationship between cumulative childhood trauma, neglect, abuse and PLEs, separately. The mediated model respectively explained 21.9%, 42.54% and 18.27% of the effect of CT on PLEs. Our model further suggested that childhood trauma could be related to PLEs through decreasing the following wisdom components: decisiveness, emotional regulation and prosocial behavior. CONCLUSION: For the first time, our results suggested that impaired wisdom played a role in the translation from childhood adversity to subclinical psychotic symptoms, implicating wisdom as a possible target for early intervention for psychosis among young individuals. Longitudinal work is warranted to verify the clinical implications.

Acoustic Sensor-Based Soundscape Analysis and Acoustic Assessment of Bird Species Richness in Shennongjia National Park, China.

Passive acoustic sensor-based soundscape analysis has become an increasingly important ecological method for evaluation of ecosystem conditions using acoustic indices. Understanding the soundscape composition and correlations between acoustic indices and species richness of birds, the most important sound source in the ecosystem, are of great importance for measuring biodiversity and the level of anthropogenic disturbance. In this study, based on yearlong sound data obtained from five acoustic sensors deployed in Dalongtan, Shennongjia National Park, we analyzed the soundscape composition by comparing the distributions of the soundscape power in different frequency ranges, and examined the correlations between acoustic indices and bird species richness by means of the Spearman rank correlation coefficient method. The diurnal dynamic characteristics of acoustic indices in different seasons were also described. Results showed that the majority of sounds were in the frequency of 2-8 kHz, in which over 50% sounds were in 2-6 kHz, commonly considered the bioacoustic frequency range. The Acoustics Complexity Index, Bioacoustic Index, and Normalized Difference Soundscape Index were significantly correlated with bird species richness, suggesting that these indices can be used for evaluation of bird species richness; Apparent diurnal dynamic patterns of bird acoustic activities were observed in spring, summer, and autumn; however, the intensity and duration of bird acoustic activities in summer is larger/longer than in spring and autumn.

TRIM32 Drives Pathogenesis in Streptococcal Toxic Shock-Like Syndrome and Streptococcus suis Meningitis by Regulating Innate Immune Responses.

Streptococcus suis is an emerging zoonotic agent that causes streptococcal toxic shock-like syndrome (STSLS) and meningitis in humans, with high mortality and morbidity. The pathogenesis of both STSLS and central nervous system (CNS) infections caused by S. suis is not well understood. TRIM32, a member of the tripartite motif (TRIM) protein family, has been reported to regulate host inflammatory responses. In this study, we showed that TRIM32 deficiency significantly reduced the level of bacteremia and the production of proinflammatory cytokines following severe S. suis infection, protecting infected mice from STSLS. The influence of TRIM32 gene deletion on a range of processes known to be involved in S. suis meningitis was also examined. Both levels of bacterial loads and indications of brain hemorrhage were reduced in infected Trim32-/- mice compared with infected wild-type (WT) controls. We also found that TRIM32 deficiency increased the permeability of the blood-brain barrier (BBB) and the recruitment of inflammatory monocytes during the early course of S. suis infection, potentially limiting the development of S. suis meningitis. Our results suggest that TRIM32 sensitizes S. suis-induced infection via innate immune response regulation.

Senescence-associated genes and non-coding RNAs function in pancreatic cancer progression.

Pancreatic cancer is a major cause of mortality with a poor diagnosis and prognosis that most often occurs in elderly patients. Few studies, however, focus on the interplay of age and pancreatic cancer at the transcriptional level. Here we evaluated the possible roles of age-dependent, differentially expressed genes (DEGs) in pancreatic cancer. These DEGs were used to construct a correlation network and clustered in six gene modules, among which two modules were highly correlated with patients' survival time. Integrating different datasets, including ATAC-Seq and ChIP-Seq, we performed multi-parallel analyses and identified eight age-dependent protein coding genes and two non-coding RNAs as potential candidates. These candidates, together with KLF5, a potent functional transcription factor in pancreatic cancer, are likely to be key elements linking cellular senescence and pancreatic cancer, providing insights on the balance between them, as well as on diagnosis and subsequent prognosis of pancreatic cancer.

In situ molecular characterization of endoneurial microvessels that form the blood-nerve barrier in normal human adult peripheral nerves.

The blood-nerve barrier (BNB) formed by tight junction-forming endoneurial microvessels located in the innermost compartment of peripheral nerves, and the perineurium serve to maintain the internal microenvironment required for normal signal transduction. The specific molecular components that define the normal adult human BNB are not fully known. Guided by data derived from the adult human BNB transcriptome, we evaluated the in situ expression of 25 junctional complex, transporter, cell membrane, and cytoskeletal proteins in four histologically normal adult sural nerves by indirect fluorescent immunohistochemistry to determine proteins specifically expressed by restrictive endoneurial microvascular endothelium. Using Ulex Europaeus Agglutinin-1 expression to detect endothelial cells, we ascertained that the selected proteins were uniformly expressed in ≥90% of endoneurial microvessels. P-glycoprotein (also known as adenosine triphosphate-binding cassette subfamily B member 1) and solute carrier family 1 member 1 demonstrated restricted expression by endoneurial endothelium only, with classic tight junction protein claudin-5 also expressed on fenestrated epineurial macrovessels, and vascular-specific adherens junction protein cadherin-5 also expressed by the perineurium. The expression profiles of the selected proteins provide significant insight into the molecular composition of normal adult peripheral nerves. Further work is required to elucidate the human adult BNB molecular signature in order to better understand its development and devise strategies to restore function in peripheral neuropathies.

The Psychiatry Major: A Curricular Innovation to Improve Undergraduate Psychiatry Education in China.

OBJECTIVE: In China, a psychiatry major curriculum (PMC) has been implemented in select medical schools to improve the quality of undergraduate psychiatry education (UPE). Our aim was to describe this PMC and compare it with UPE in the standard Chinese clinical medicine curriculum (CMC). We also benchmarked PMC to UPE programs in the Hong Kong Special Administrative Region of China and the United States of America (USA) to determine how well it met standards of well-established programs and to highlight areas for improvement. METHODS: Based on archival information, relevant literature, and communication with key informants, we described PMC and CMC in a Chinese school with both curriculums. We then compared PMC to UPE curriculums in Hong Kong and the USA. RESULTS: PMC provides substantially more comprehensive exposure to psychiatry than CMC, with more preclinical experiences and psychiatry clerkship course hours, greater diversity of clinical sites, and exploration of subspecialties. PMC employs a variety of teaching methods and offers mentoring for students. PMC has similar UPE preclinical content and course hours as programs in Hong Kong and the USA. PMC also provides more clinical exposure than programs in Hong Kong or the USA, although there is less variety in clinical settings. CONCLUSION: We recommend implementation of concrete measures to improve UPE in Chinese medical schools, using the PMC curriculum as a model that has been successfully implemented in China. We also recommend improvements to PMC based on comparisons with existing programs outside Mainland China.

KLF4 expression enhances the efficacy of chemotherapy drugs in ovarian cancer cells.

KLF4 is a transcriptional factor that can function either as a tumor suppressor or oncogene in cancer based on its cellular context. We recently demonstrated that KLF4 was a tumor suppressor in ovarian cancer cells by inhibiting the epithelial to mesenchymal transition. Here we report that KLF4 expression was downregulated in ovarian cancer tissue compared to normal ovarian tissue, and low KLF4 expression correlated with high risk ovarian carcinoma and poor patient survival. Enforced KLF4 expression by lentiviral transduction sensitized ovarian cancer cells to the effects of the chemotherapy drugs, paclitaxel and cisplatin. Treatment of ovarian cancer cells with APTO-253, a small molecule inducer of KLF4, enhanced the efficacy of both chemotherapy drugs. KLF4 expression mediated by lentiviral vector or induced by APTO-253 resulted in G1 phase arrest in ovarian cancer cells. Our results demonstrate that for the first time that inducing KLF4 expression with APTO-253 is a novel therapeutic strategy for treating ovarian cancer.