Exposure profiles of social-environmental neighborhood factors and psychotic-like experiences.

Importance: Recent research has demonstrated that domains of social determinants of health (SDOH) (e.g., air pollution and social context) are associated with psychosis. However, SDOHs have often been studied in isolation. Objective: To identify distinct exposure profiles, estimate their associations with persistent distressing psychotic-like experiences (PLE), and evaluate whether involvement with physical activities partially explains this association. Design Setting and Participants: This population-based study used data from the Adolescent Brain and Cognitive Development (ABCD) Study. Participants were recruited from 22 US sites between September 2016 and January 2022. Data from baseline and three follow-ups were included. Exposures: Area-level geocoded variables spanning various domains of SDOH, including socioeconomic status (SES), education, crime, built environment, social context, and crime, were clustered using a self-organizing map method to identify exposure profiles. Main Outcomes and Measures: Persistent distressing PLE was derived from the Prodromal Questionnaire-Brief Child Version across four years. Generalized linear mixed modeling tested the association between exposure profiles and persistent distressing PLE as well as physical activities (i.e., team and individual sports), adjusting for individual-level covariates including age, sex, race/ethnicity, highest level of parent education, family-relatedness, and study sites. Results: Among 8,145 participants (baseline mean [SD] age, 9.92 [0.63] years; 3,868 (47.5%) females; 5,566 (68.3%) White, 956 (11.7%) Black, 159 (2.0%) Asian, and 1,480 (18.4%) Hispanic participants), five exposure profiles were identified. Compared to the reference Profile 1 (suburban affluent areas, 2521 children, 30.9%), Profile 3 (rural areas with low walkability and high ozone; 1459 children, 17.9%; adjusted OR: 1.34, 95% CI: 1.09-1.64) and Profile 4 (urban areas with high SES deprivation, high crime, and high pollution; 715 children, 8.8%; adjusted OR: 1.40, 95% CI: 1.08-1.81), were associated with persistent distressing PLE. Team sports mediated 6.14% of the association for Profile 3. Conclusion and Relevance: This study found that neighborhoods characterized by rural areas with low walkability and urban areas with high socioeconomic deprivation, air pollutants, and crime were associated with persistent distressing PLE. Further research is needed to explore the pathways through which different environmental factors may impact the development of psychosis.

Associations Between Genetic Risk, Physical Activities, and Distressing Psychotic-like Experiences.

BACKGROUND AND HYPOTHESIS: Persistent distressing psychotic-like experiences (PLE) are associated with impaired functioning and future psychopathology. Prior research suggests that physical activities may be protective against psychopathology. However, it is unclear whether physical activities may interact with genetics in the development of psychosis. STUDY DESIGN: This study included 4679 participants of European ancestry from the Adolescent Brain Cognitive Development Study. Persistent distressing PLE was derived from the Prodromal-Questionnaire-Brief Child Version using four years of data. Generalized linear mixed models tested the association between polygenic risk score for schizophrenia (PRS-SCZ), physical activities, and PLE. The models adjusted for age, sex, parental education, income-to-needs ratio, family history of psychosis, body mass index, puberty status, principal components for PRS-SCZ, study site, and family. STUDY RESULTS: PRS-SCZ was associated with a greater risk for persistent distressing PLE (adjusted relative risk ratio (RRR) = 1.14, 95% CI [1.04, 1.24], P = .003). Physical activity was associated with less risk for persistent distressing PLE (adjusted RRR = 0.87, 95% CI [0.79, 0.96], P = .008). Moreover, physical activities moderated the association between PRS-SCZ and persistent distressing PLE (adjusted RRR = 0.89, 95% CI [0.81, 0.98], P = .015), such that the association was weaker as participants had greater participation in physical activities. CONCLUSIONS: These findings demonstrate that the interaction between genetic liability and physical activities is associated with trajectories of distressing PLE. Further research is needed to understand the mechanisms of physical activities and genetic liability for schizophrenia in the development of psychosis.

DMXL2 is required for endocytosis and recycling of synaptic vesicles in auditory hair cells.

Ribbon synapses of inner hair cells are uniquely designed for ultrafast and indefatigable neurotransmission of the sound. The molecular machinery ensuring the efficient, compensatory recycling of the synaptic vesicles, however, remains elusive. This study showed that hair cell knockout of murine Dmxl2, whose human homolog is responsible for non-syndromic sensorineural hearing loss DFNA71, resulted in auditory synaptopathy by impairing synaptic endocytosis and recycling. The mutant mice in the C57BL/6J background of either sex had mild hearing loss with severely diminished wave-I amplitude of the auditory brainstem response. Membrane capacitance measurements of the inner hair cells revealed deficiency in sustained synaptic exocytosis and endocytic membrane retrieval. Consistent with the electrophysiological findings, 3D electron microscopy reconstruction showed reduced reserve pool of synaptic vesicles and endocytic compartments, while the membrane-proximal and ribbon-associated vesicles remain intact. Our results propose an important role of DMXL2 in hair cell endocytosis and recycling of the synaptic vesicles.Significance Statement The molecular basis underlying efficient recycling of the ribbon synaptic vesicles in cochlear hair cells remains elusive. In this study, investigation of a hair cell-specific knockout mouse for Dmxl2 identifies its import roles in endocytosis and recycling of the auditory synaptic vesicles. The mutant mice display auditory synaptopathy, a common feature for noise-induced hearing loss and age-related hearing loss. The inner hair cells show deficiency in sustained synaptic exocytosis and endocytic membrane retrieval with reduced reserve pool of synaptic vesicles and endocytic compartments. Our results provide new insights into the molecular machinery ensuring ultrafast and indefatigable neurotransmission of the sound.

Aspects of Area Deprivation Index in Relation to Hippocampal Volume Among Children.

Importance: Area deprivation index (ADI) has been shown to be associated with reduced hippocampal volume (HV) among youths. The social environment may interact with the association between ADI and HV. Objective: To investigate which aspects of ADI are uniquely associated with bilateral HV and whether school and family environments have moderating interactions in associations between ADI and HV. Design, Setting, and Participants: This cross-sectional study used data from the Adolescent Brain and Cognitive Development (ABCD) study. Participants aged 9 and 10 years were recruited from 21 sites in the US between September 2016 and August 2018. Data analysis was performed between March 2023 and April 2024. Exposures: ADI aspects were derived from participant primary home addresses provided by parents or guardians. Main Outcomes and Measures: HV was automatically segmented from structural brain images ascertained from magnetic resonance imaging. Multiple generalized linear mixed modeling tested associations between 9 indices of ADI and bilateral HV, with family groups and recruitment sites as random effects. After stepwise backward selection, models were adjusted for individual-level covariates, including age, sex, race and ethnicity, parental education, household income, and estimated intracranial volume. Results: This study included 10 114 participants aged 9 and 10 years (median [IQR] age, 9.92 [9.33-10.48] years; 5294 male [52.3%]; 200 Asian [2.0%], 1411 Black [14.0%], and 6655 White [65.8%]; 1959 Hispanic [19.4%]). After stepwise backward selection and adjusting for covariates, only the percentage of neighborhood-level single-parent households was associated with right HV (adjusted ß per 1-SD increase in single-parent households, -0.03; 95% CI, -0.06 to -0.01; P = .01). School environment interacted with neighborhood-level single-parent households in its association with right HV (adjusted ß per 1-SD increase in score, 0.02; 95% CI, 0.01 to 0.03; P = .003), such that there was an inverse association only among those at a school with the mean environment score (adjusted ß per 1% increase in single-parent households, -0.03; 95% CI, -0.05 to -0.01; P = .02) and worse (-1 SD score) school environment score (adjusted ß per 1% increase in single-parent households, -0.05; 95% CI, -0.09 to -0.01; P < .001) but not among those at better (+1 SD score) school environments. Conclusions and Relevance: In this study, an increased percentage of neighborhood-level single-parent households was associated with reduced right HV among children in schools with the mean or worse but not better environment score. These findings suggest that longitudinal research concerning the association of neighborhood-level characteristics and school environments with hippocampal development may be warranted to better understand complex interactions between various social factors and child neurodevelopment and mental health outcomes.

The association between county-level mental health provider shortage areas and suicide rates in the United States during the COVID-19 pandemic.

OBJECTIVE: Prior literature has shown that mental health provider Health Professional Shortage Areas (MHPSAs) experienced a greater increase in suicide rates compared to non-shortage areas from 2010 to 2018. Although suicide rates have been on the rise, rates have slightly decreased during the COVID-19 pandemic. This study sought to characterize the differences in suicide rate trends during the pandemic by MHPSA status. METHOD: We used generalized estimating equation regression to test the associations between MHPSA status and suicide rates from 2018 to 2021. Suicide deaths were obtained from the Centers for Disease Control and Prevention's Wide-ranging Online Data for Epidemiologic Research. RESULTS: MHPSA status was associated with higher suicide rates (adjusted IRR:1.088 [95% CI, 1.024-1.156]). Furthermore, there was a significant interaction between MHPSA status and year (adjusted IRR:1.056 [95% CI, 1.022-1.091]), such that suicide rates did not significantly change among MHPSAs but slightly decreased among non-MHPSAs from 2018 to 2021. CONCLUSIONS: During the COVID-19 pandemic, there was a slight decrease in suicide rates among non-MHPSAs, while those with shortages experienced no significant changes in suicide rates. It will be important to closely monitor MHPSAs as continued at-risk regions for suicide as trendlines return to their pre-pandemic patterns.

Genome- and transcriptome-wide splicing associations with alcohol use disorder.

Genetic mechanisms of alternative mRNA splicing have been shown in the brain for a variety of neuropsychiatric traits, but not substance use disorders. Our study utilized RNA-sequencing data on alcohol use disorder (AUD) in four brain regions (n = 56; ages 40-73; 100% 'Caucasian'; PFC, NAc, BLA and CEA) and genome-wide association data on AUD (n = 435,563, ages 22-90; 100% European-American). Polygenic scores of AUD were associated with AUD-related alternative mRNA splicing in the brain. We identified 714 differentially spliced genes between AUD vs controls, which included both putative addiction genes and novel gene targets. We found 6463 splicing quantitative trait loci (sQTLs) that linked to the AUD differentially spliced genes. sQTLs were enriched in loose chromatin genomic regions and downstream gene targets. Additionally, the heritability of AUD was enriched for DNA variants in and around differentially spliced genes associated with AUD. Our study also performed splicing transcriptome-wide association studies (TWASs) of AUD and other drug use traits that unveiled specific genes for follow-up and splicing correlations across SUDs. Finally, we showed that differentially spliced genes between AUD vs control were also associated with primate models of chronic alcohol consumption in similar brain regions. Our study found substantial genetic contributions of alternative mRNA splicing in AUD.

Surgical repair of large orbital floor and medial wall fractures with destruction of the inferomedial strut: Initial experience with a combined endoscopy navigation technique.

The application of navigation and endoscope is an area of intense interest in the surgical repair of orbital fractures. This study explored the advantages of a combined endoscopy navigation technique (ENT) for repairing large orbital floor and medial wall fractures (OFMWFs) with destruction of the inferomedial strut (IMS). Fifty-two consecutive patients with large OFMWFs with the destruction of the IMS underwent ENT-assisted surgical repair from January 2013 to February 2016. Patient demographics, causes of injury, clinical features, imaging data, and follow-up information (diplopia, ocular dysmotility, enophthalmos, infraorbital hypoesthesia, and other conditions) were collected and analyzed. Orbital volumes and implant positions were also evaluated. The median follow-up duration was 21 (range, 16-29) months. At the end of the follow-up visits, orbital reconstruction was demonstrated by orbital computed tomography. Of the 30 patients with diplopia within the 30-degree visual field of gaze, 27 (90%) reached diplopia remission. Of 40 patients, 34 (85%) achieved complete elimination of ocular dysmotility. Of 47 patients with enophthalmos of >2 mm, 43 (91%) acquired good symmetry with a mean improvement of 3.00 ± 1.00 mm. Of 33 patients, 27 (82%) recovered from infraorbital hypoesthesia. The postoperative orbital volumes of the two sides showed no significant differences (p = 0.087, paired t-test). Early surgical repair showed better outcomes of diplopia, ocular motility, and enophthalmos than late repair (p = 0.001, p = 0.007, and p = 0.000, generalized estimated equations). No patient developed surgery-related complications of visual acuity compromise, strabismus, ectropion, entropion, or lacrimal canaliculus injuries. ENT-assisted surgery appears to be safe, precise, and effective for the repair of large OFMWFs with destruction of the IMS.

Cathelicidin LL37 Promotes Osteogenic Differentiation in vitro and Bone Regeneration in vivo.

Different types of biomaterials have been used to repair the defect of bony orbit. However, exposure and infections are still critical risks in clinical application. Biomaterials with characteristics of osteogenesis and antibiosis are needed for bone regeneration. In this study, we aimed to characterize the antimicrobial effects of cathelicidin-LL37 and to assess any impacts on osteogenic activity. Furthermore, we attempted to demonstrate the feasibility of LL37 as a potential strategy in the reconstruction of clinical bone defects. Human adipose-derived mesenchyme stem cells (hADSCs) were cultured with different concentrations of LL37 and the optimum concentration for osteogenesis was selected for further in vitro studies. We then evaluated the antibiotic properties of LL37 at the optimum osteogenic concentration. Finally, we estimated the efficiency of a PSeD/hADSCs/LL37 combined scaffold on reconstructing bone defects in the rat calvarial defect model. The osteogenic ability on hADSCs in vitro was shown to be dependent on the concentration of LL37 and reached a peak at 4 µg/ml. The optimum concentration of LL37 showed good antimicrobial properties against Escherichia coli and Staphylococcus anurans. The combination scaffold of PSeD/hADSCs/LL37 showed superior osteogenic properties compared to the PSeD/hADSCs, PSeD, and control groups scaffolds, indicating a strong bone reconstruction effect in the rat calvarial bone defect model. In Conclusion, LL37 was shown to promote osteogenic differentiation in vitro as well as antibacterial properties. The combination of PSeD/hADSCs/LL37 was advantageous in the rat calvarial defect reconstruction model, showing high potential in clinical bone regeneration.

Biomimetic nanofibrous hybrid hydrogel membranes with sustained growth factor release for guided bone regeneration.

Bone regeneration, a complex physiological process, remains a challenge due to the susceptibility to the environment and absence of osteogenic growth factors around the defect region. Although autologous bone grafting is regarded as the gold standard for bone defect treatment, guided bone regeneration membranes in combination with multiple functional growth factors show a striking regeneration effect. Here, a biomimetic nanofibrous hybrid hydrogel composed of bacterial cellulose membranes and alginate/CaCl2 for sustained growth factor delivery was developed. The antibacterial peptide beta-defensin 2 served as an antibacterial, osteogenic, and angiogenic growth factor and was loaded into the aforementioned hydrogel. The mechanical and physical properties of the biomimetic nanofibrous hybrid hydrogel were investigated. Then, the in vitro osteogenic and angiogenic differentiation was confirmed by alkaline phosphatase (ALP) activity, Alizarin Red S staining, qPCR, western blot analysis and tube formation assays. After implantation into a rat calvarial defect model for 12 weeks, nanofibrous hybrid hydrogel membranes could adhere to the defect surface and promote new bone and vessel regeneration.

Disruption of Hars2 in Cochlear Hair Cells Causes Progressive Mitochondrial Dysfunction and Hearing Loss in Mice.

Mutations in a number of genes encoding mitochondrial aminoacyl-tRNA synthetases lead to non-syndromic and/or syndromic sensorineural hearing loss in humans, while their cellular and physiological pathology in cochlea has rarely been investigated in vivo. In this study, we showed that histidyl-tRNA synthetase HARS2, whose deficiency is associated with Perrault syndrome 2 (PRLTS2), is robustly expressed in postnatal mouse cochlea including the outer and inner hair cells. Targeted knockout of Hars2 in mouse hair cells resulted in delayed onset (P30), rapidly progressive hearing loss similar to the PRLTS2 hearing phenotype. Significant hair cell loss was observed starting from P45 following elevated reactive oxygen species (ROS) level and activated mitochondrial apoptotic pathway. Despite of normal ribbon synapse formation, whole-cell patch clamp of the inner hair cells revealed reduced calcium influx and compromised sustained synaptic exocytosis prior to the hair cell loss at P30, consistent with the decreased supra-threshold wave I amplitudes of the auditory brainstem response. Starting from P14, increasing proportion of morphologically abnormal mitochondria was observed by transmission electron microscope, exhibiting swelling, deformation, loss of cristae and emergence of large intrinsic vacuoles that are associated with mitochondrial dysfunction. Though the mitochondrial abnormalities are more prominent in inner hair cells, it is the outer hair cells suffering more severe cell loss. Taken together, our results suggest that conditional knockout of Hars2 in mouse cochlear hair cells leads to accumulating mitochondrial dysfunction and ROS stress, triggers progressive hearing loss highlighted by hair cell synaptopathy and apoptosis, and is differentially perceived by inner and outer hair cells.

Effect of Bifunctional ß Defensin 2-Modified Scaffold on Bone Defect Reconstruction.

Bone tissue engineering has emerged as an effective alternative treatment to the problem of bone defect. To repair a bone defect, antibiosis and osteogenesis are two essential aspects of the repair process. By searching the literature and performing exploratory experiments, we found that ß defensin 2 (BD2), with bifunctional properties of antibiosis and osteogenesis, was a feasible alternative for traditional growth factors. The antimicrobial ability of BD2 against Staphylococcus aureus and Escherichia coli was studied by the spread plate and live/dead staining methods (low effective concentration of 20 ng/mL). BD2 was also demonstrated to enhance osteogenesis, with higher messenger RNA (mRNA) and protein expression of the osteogenic markers collagen I (Col1), runt-related transcription factor 2 (Runx2), osteopontin (Opn), and osteocalcin (Ocn) in vitro (1.5-2.5-fold increase compared with the control group in the most effective concentration group), which was consistent with the alkaline phosphatase (ALP) and alizarin red S (ARS) staining results. We implanted poly(sebacoyl diglyceride) (PSeD) combined with BD2 and rat bone tissue-derived mesenchymal stem cells (rBMSCs) under the back skin of rats and found that the inflammatory response was significantly lower with this combination than with the PSeD/rBMSCs scaffold without BD2 and the pure PSeD group and was similar to the control group. Importantly, when assessed in a critical-sized in vivo rat 8 m diameter calvaria defect model, a scaffold we developed combining bifunctional BD2 with porous organic polymer displayed an osteogenic effect that was 160-200% greater than the control group. The in vivo study results revealed a significant osteogenic response and antimicrobial effect and were consistent with the in vitro results. In summary, BD2 displayed a great potential of simultaneously promoting bone regeneration and preventing infection and could provide a viable alternative to traditional growth factors applied in bone defect repair.

Active DNA unwinding and transport by a membrane-adapted helicase nanopore.

Nanoscale transport through nanopores and live-cell membranes plays a vital role in both key biological processes as well as biosensing and DNA sequencing. Active translocation of DNA through these nanopores usually needs enzyme assistance. Here we present a nanopore derived from truncated helicase E1 of bovine papillomavirus (BPV) with a lumen diameter of c.a. 1.3 nm. Cryogenic electron microscopy (cryo-EM) imaging and single channel recording confirm its insertion into planar lipid bilayer (BLM). The helicase nanopore in BLM allows the passive single-stranded DNA (ssDNA) transport and retains the helicase activity in vitro. Furthermore, we incorporate this helicase nanopore into the live cell membrane of HEK293T cells, and monitor the ssDNA delivery into the cell real-time at single molecule level. This type of nanopore is expected to provide an interesting tool to study the biophysics of biomotors in vitro, with potential applications in biosensing, drug delivery and real-time single cell analysis.

Rapid Nanopore Assay for Carbapenem-Resistant Klebsiella pneumoniae.

The prevalence of carbapenem-resistant Klebsiella pneumoniae (CRKP) is rapidly increasing worldwide in recent decades and poses a challenge for today's clinical practice. Rapid detection of CRKP can avoid inappropriate antimicrobial therapy and save lives. Traditional detection methods for CRKP are extremely time-consuming; PCR and other sequencing methods are too expensive and technologically demanding, making it hard to meet the clinical demands. Nanopore assay has been used for screening biomarkers of diseases recently because of its high sensitivity, real-time detection, and low cost. In this study, we distinguished CRKP from carbapenem-sensitive K. pneumoniae (CSKP) by the detection of increasing amount of extracted 16S ribosomal RNA (16S rRNA) from bacterial culture with antibiotics imipenem, indicating the uninhibited growth of CRKP by the imipenem. Specific signals from single channel recording of 16S rRNA bound with probes by MspA nanopore allowed the ultra-sensitive and fast quantitative detection of 16S rRNA. We proved that only 4 h of CRKP culture time was needed for nanopore assay to distinguish the CRKP and CSKP. The time-cost of the assay is only about 5% of disk diffusion method while reaching the similar accuracy. This new method has the potential application in the fast screening of drug resistance in clinical microorganism samples.