Genome-wide association study implicates lipid pathway dysfunction in antipsychotic-induced weight gain: multi-ancestry validation.

Antipsychotic-induced weight gain (AIWG) is a common side effect of antipsychotic medication and may contribute to diabetes and coronary heart disease. To expand the unclear genetic mechanism underlying AIWG, we conducted a two-stage genome-wide association study in Han Chinese patients with schizophrenia. The study included a discovery cohort of 1936 patients and a validation cohort of 534 patients, with an additional 630 multi-ancestry patients from the CATIE study for external validation. We applied Mendelian randomization (MR) analysis to investigate the relationship between AIWG and antipsychotic-induced lipid changes. Our results identified two novel genome-wide significant loci associated with AIWG: rs10422861 in PEPD (P = 1.373 × 10-9) and rs3824417 in PTPRD (P = 3.348 × 10-9) in Chinese Han samples. The association of rs10422861 was validated in the European samples. Fine-mapping and functional annotation revealed that PEPD and PTPRD are potentially causal genes for AIWG, with their proteins being prospective therapeutic targets. Colocalization analysis suggested that AIWG and type 2 diabetes (T2D) shared a causal variant in PEPD. Polygenic risk scores (PRSs) for AIWG and T2D significantly predicted AIWG in multi-ancestry samples. Furthermore, MR revealed a risky causal effect of genetically predicted changes in low-density lipoprotein cholesterol (P = 7.58 × 10-4) and triglycerides (P = 2.06 × 10-3) caused by acute-phase of antipsychotic treatment on AIWG, which had not been previously reported. Our model, incorporating antipsychotic-induced lipid changes, PRSs, and clinical predictors, significantly predicted BMI percentage change after 6-month antipsychotic treatment (AUC = 0.79, R2 = 0.332). Our results highlight that the mechanism of AIWG involves lipid pathway dysfunction and may share a genetic basis with T2D through PEPD. Overall, this study provides new insights into the pathogenesis of AIWG and contributes to personalized treatment of schizophrenia.

A shaker K+ channel with a miniature engineered voltage sensor.

Voltage-gated ion channels sense transmembrane voltage changes via a paddle-shaped motif that includes the C-terminal part of the third transmembrane segment (S3b) and the N-terminal part of the fourth segment ((NT)S4) that harbors voltage-sensing arginines. Here, we find that residue triplets in S3b and (NT)S4 can be deleted individually, or even in some combinations, without compromising the channels' basic voltage-gating capability. Thus, a high degree of complementarity between these S3b and (NT)S4 regions is not required for basic voltage gating per se. Remarkably, the voltage-gated Shaker K(+) channel remains voltage gated after a 43 residue paddle sequence is replaced by a glycine triplet. Therefore, the paddle motif comprises a minimal core that suffices to confer voltage gating in the physiological voltage range, and a larger, modulatory part. Our study also shows that the hydrophobic residues between the voltage-sensing arginines help set the sensor's characteristic chemical equilibrium between activated and deactivated states.

Synaptotagmin-1 is a bidirectional Ca2+ sensor for neuronal endocytosis.

Exocytosis and endocytosis are tightly coupled. In addition to initiating exocytosis, Ca2+ plays critical roles in exocytosis­endocytosis coupling in neurons and nonneuronal cells. Both positive and negative roles of Ca2+ in endocytosis have been reported; however, Ca2+ inhibition in endocytosis remains debatable with unknown mechanisms. Here, we show that synaptotagmin-1 (Syt1), the primary Ca2+ sensor initiating exocytosis, plays bidirectional and opposite roles in exocytosis­endocytosis coupling by promoting slow, small-sized clathrin-mediated endocytosis but inhibiting fast, large-sized bulk endocytosis. Ca2+-binding ability is required for Syt1 to regulate both types of endocytic pathways, the disruption of which leads to inefficient vesicle recycling under mild stimulation and excessive membrane retrieval following intense stimulation. Ca2+-dependent membrane tubulation may explain the opposite endocytic roles of Syt1 and provides a general membrane-remodeling working model for endocytosis determination. Thus, Syt1 is a primary bidirectional Ca2+ sensor facilitating clathrin-mediated endocytosis but clamping bulk endocytosis, probably by manipulating membrane curvature to ensure both efficient and precise coupling of endocytosis to exocytosis.

Blue carbon sink capacity of mangroves determined by leaves and their associated microbiome.

Mangroves play a globally significant role in carbon capture and storage, known as blue carbon ecosystems. Yet, there are fundamental biogeochemical processes of mangrove blue carbon formation that are inadequately understood, such as the mechanisms by which mangrove afforestation regulates the microbial-driven transfer of carbon from leaf to below-ground blue carbon pool. In this study, we addressed this knowledge gap by investigating: (1) the mangrove leaf characteristics using state-of-the-art FT-ICR-MS; (2) the microbial biomass and their transformation patterns of assimilated plant-carbon; and (3) the degradation potentials of plant-derived carbon in soils of an introduced (Sonneratia apetala) and a native mangrove (Kandelia obovata). We found that biogeochemical cycling took entirely different pathways for S. apetala and K. obovata. Blue carbon accumulation and the proportion of plant-carbon for native mangroves were high, with microbes (dominated by K-strategists) allocating the assimilated-carbon to starch and sucrose metabolism. Conversely, microbes with S. apetala adopted an r-strategy and increased protein- and nucleotide-biosynthetic potentials. These divergent biogeochemical pathways were related to leaf characteristics, with S. apetala leaves characterized by lower molecular-weight, C:N ratio, and lignin content than K. obovata. Moreover, anaerobic-degradation potentials for lignin were high in old-aged soils, but the overall degradation potentials of plant carbon were age-independent, explaining that S. apetala age had no significant influences on the contribution of plant-carbon to blue carbon. We propose that for introduced mangroves, newly fallen leaves release nutrient-rich organic matter that favors growth of r-strategists, which rapidly consume carbon to fuel growth, increasing the proportion of microbial-carbon to blue carbon. In contrast, lignin-rich native mangrove leaves shape K-strategist-dominated microbial communities, which grow slowly and store assimilated-carbon in cells, ultimately promoting the contribution of plant-carbon to the remarkable accumulation of blue carbon. Our study provides new insights into the molecular mechanisms of microbial community responses during reforestation in mangrove ecosystems.

Theoretical Study on Ion Diffusion Mechanism in W-Doped K3SbS4 as Solid-State Electrolyte for K-Ion Batteries.

The development of a solid-state electrolyte (SSE) is crucial for overcoming the side reactions of metal potassium anodes and advancing the progress of K-ion batteries (KIBs). Exploring the diffusion mechanism of the K ion in SSE is important for deepening our understanding and promoting its development. In this study, we conducted static calculations and utilized deep potential molecular dynamics (DeepMD) to investigate the behavior of cubic K3SbS4. The original K3SbS4 exhibited poor ionic conductivity, but we discovered that introducing heterovalent tungsten doping created vacancies, which significantly reduced the activation energy to 0.12 eV and enhanced the ionic conductivity to 1.80 × 10-2 S/cm. The diffusion of K-ions in K3SbS4 primarily occurs through the exchange of positions with K vacancies. This research provides insights into the design of SSE with high ionic conductivity. Furthermore, it highlights the effectiveness of DeepMD as a powerful tool for studying the SSE.

Assessing the Toxicity of Benzotriazole Ultraviolet Stabilizers to Fishes: Insights into Aryl Hydrocarbon Receptor-Mediated Effects.

Benzotriazole ultraviolet stabilizers (BUVSs) are chemicals used to mitigate UV-induced damage to manufactured goods. Their presence in aquatic environments and biota raises concerns, as certain BUVSs activate the aryl hydrocarbon receptor (AhR), which is linked to adverse effects in fish. However, potencies of BUVSs as AhR agonists and species sensitivities to AhR activation are poorly understood. This study evaluated the toxicity of three BUVSs using embryotoxicity assays. Zebrafish (Danio rerio) embryos exposed to BUVSs by microinjection suffered dose-dependent increases in mortality, with LD50 values of 4772, 11 608, and 56 292 ng/g-egg for UV-P, UV-9, and UV-090, respectively. The potencies and species sensitivities to AhR2 activation by BUVSs were assessed using a luciferase reporter gene assay with COS-7 cells transfected with the AhR2 of zebrafish and eight other fishes. The rank order of potency for activation of the AhR2 from all nine species was UV-P > UV-9 > UV-090. However, AhR2s among species differed in sensitivities to activation by up to 100-fold. An approximate reversed rank order of species sensitivity was observed compared to the rank order of sensitivity to 2,3,7,8-tetrachlorodibenzo[p]dioxin, the prototypical AhR agonist. Despite this, a pre-existing quantitative adverse outcome pathway linking AhR activation to embryo lethality could predict embryotoxicities of BUVSs in zebrafish.

The effect of screw orientation on internal fixation of Letenneur type II Hoffa fractures: a biomechanics study.

BACKGROUND: To investigate the biomechanical effects of screw orientation and fracture block size on the internal fixation system for Letenneur type II Hoffa fractures. METHODS: The fracture models were randomly divided into six groups according to the fracture subtypes and the direction of nail placement, and a plumb line of the posterior condylar tangent was made across the base of the posterior femoral condyle. The fracture blocks of the three types of fracture were calculated and recorded in the sagittal position, and the biomechanical performance of the six groups was evaluated by biomechanical tests. The axial load on the fracture block at a displacement of 2 mm was set as the failure load, a gradually increasing axial load was applied to each fracture model using a customized indenter at a load of 250-750 N, and the displacements and failure loads of the six groups were recorded at different axial loads. RESULTS: Biomechanical test results showed that the larger the fracture block, the greater was the stability when nailing from front to back, and the smaller the fracture block, the greater was the strength when nailing from back to front (p < 0.001). As the fracture block became larger, the biomechanical advantage of nailing from posterior to anterior decreased.The displacement under 250 N load were 1.351 ± 0.113 mm, 1.465 ± 0.073 mm for Group IIa AP and Group IIa PA. The displacement under 500 N load were 2.596 ± 0.125 mm, 2.344 ± 0.099 mm for Group IIa AP and Group IIa PA. The displacement under 750 N load were 3.997 ± 0.164, 3.386 ± 0.125 mm for Group IIa AP and Group IIa PA. The failure loads were 384 ± 14 N, 415 ± 19 N for Group IIa AP and Group IIa PA. In the type IIa fracture group, the difference was no longer significant (p > 0.001). Therefore, there is a mechanical threshold that ranges from 38.36 to 52.33% between type IIa and type IIb fractures. CONCLUSIONS: The effect of the nailing direction on the strength of fixation has a fracture-block critical point, which is consistent overall with the trend that the larger the fracture block is, the greater the stability when nailing from anterior to posterior, and the smaller the fracture block is, the greater the strength when nailing from posterior to anterior.

Covert Communication through Robust Fragment Hiding in a Large Number of Images.

For covert communication in lossy channels, it is necessary to consider that the carrier of the hidden watermark will undergo multiple image-processing attacks. In order to ensure that secret information can be extracted without distortion from the watermarked images that have undergone attacks, in this paper, we design a novel fragmented secure communication system. The sender will fragment the secret data to be transmitted and redundantly hide it in a large number of multimodal carriers of messenger accounts on multiple social platforms. The receiver receives enough covert carriers, extracts each fragment, and concatenates the transmitted secret data. This article uses the image carrier as an example to fragment the text file intended for transmission and embeds it into a large number of images, with each fragment being redundant and embedded into multiple images. In this way, at the receiving end, only enough stego images need to be received to extract the information in each image, and then concatenate the final secret file. In order to resist various possible attacks during image transmission, we propose a strong robust image watermarking method. This method adopts a watermark layer based on DFT, which has high embedding and detection efficiency and good invisibility. Secondly, a watermark layer based on DCT is adopted, which can resist translation attacks, JPEG attacks, and other common attacks. Experiments have shown that our watermarking method is very fast; both the embedding time and the extraction time are less than 0.15 s for images not larger than 2000×2000. Our watermarking method has very good invisibility with 41dB PSNR on average. And our watermarking method is more robust than existing schemes and robust to nearly all kinds of attacks. Based on this strong robust image watermarking method, the scheme of fragmenting and hiding redundant transmission content into a large number of images is effective and practical. Our scheme can 100% restore the secret file completely under different RST or hybrid attacks, such as rotation by 1 degree and 5 degrees, scaling by 1.25 and 0.8, and cropping by 10% and 25%. Our scheme can successfully restore the secret file completely even if 30% of received images are lost. When 80% of received images are lost, our scheme can still restore 61.1% of the secret file. If all stego images can be obtained, the original text file can be completely restored.

Development and validation of age-specific risk prediction models for primary ovarian insufficiency in long-term survivors of childhood cancer: a report from the Childhood Cancer Survivor Study and St Jude Lifetime Cohort.

BACKGROUND: Female survivors of childhood cancer are at risk for primary ovarian insufficiency (POI), defined as the cessation of gonadal function before the age of 40 years. We aimed to develop and validate models to predict age-specific POI risk among long-term survivors of childhood cancer. METHODS: To develop models to predict age-specific POI risk for the ages of 21-40 years, we used data from the Childhood Cancer Survivor Study (CCSS). Female survivors aged 18 years or older at their latest follow-up, with self-reported menstrual history information and free of subsequent malignant neoplasms within 5 years of diagnosis, were included. We evaluated models that used algorithms based on statistical or machine learning to consider all predictors, including cancer treatments. Cross-validated prediction performance metrics (eg, area under the receiver operating characteristic curve [AUROC]) were compared to select the best-performing models. For external validation of the models, we used data from 5-year survivors in the St Jude Lifetime Cohort (SJLIFE) with ovarian status clinically ascertained using hormone measurements (menopause defined by follicle stimulating hormone >30 mIU/mL and oestradiol <17 pg/mL) and medical chart or questionnaire review. We also evaluated an SJLIFE-based polygenic risk score for POI among 1985 CCSS survivors with genotype data available. FINDINGS: 7891 female CCSS survivors (922 with POI) were included in the development of the POI risk prediction model, and 1349 female SJLIFE survivors (101 with POI) were included in the validation study. Median follow-up from cancer diagnosis was 23·7 years (IQR 18·3-30·0) in CCSS and 15·1 years (10·4-22·9) in SJLIFE. Between the ages of 21 and 40 years, POI prevalence increased from 7·9% (95% CI 7·3-8·5) to 18·6% (17·3-20·0) in CCSS and 7·3% (5·8-8·9) to 14·9% (11·6-19·1) in SJLIFE. Age-specific logistic regression models considering ovarian radiation dosimetry or prescribed pelvic and abdominal radiation dose, along with individual chemotherapy predictors, performed well in CCSS. In the SJLIFE validation, the prescribed radiation dose model performed well (AUROC 0·88-0·95), as did a simpler model that considered any exposures to pelvic or abdominal radiotherapy or alkylators (0·82-0·90). Addition of the polygenic risk predictor significantly improved the average positive predictive value (from 0·76 [95% CI 0·63-0·89] to 0·87 [0·80-0·94]; p=0·029) among CCSS survivors treated with ovarian radiation and chemotherapy. INTERPRETATION: POI risk prediction models using treatment information showed robust prediction performance in adult survivors of childhood cancer. FUNDING: Canadian Institutes of Health Research, US National Cancer Institute.

Upregulated TGF-ß1 contributes to hyperglycaemia in type 2 diabetes by potentiating glucagon signalling.

AIMS/HYPOTHESIS: Glucagon-stimulated hepatic gluconeogenesis contributes to endogenous glucose production during fasting. Recent studies suggest that TGF-ß is able to promote hepatic gluconeogenesis in mice. However, the physiological relevance of serum TGF-ß levels to human glucose metabolism and the mechanism by which TGF-ß enhances gluconeogenesis remain largely unknown. As enhanced gluconeogenesis is a signature feature of type 2 diabetes, elucidating the molecular mechanisms underlying TGF-ß-promoted hepatic gluconeogenesis would allow us to better understand the process of normal glucose production and the pathophysiology of this process in type 2 diabetes. This study aimed to investigate the contribution of upregulated TGF-ß1 in human type 2 diabetes and the molecular mechanism underlying the action of TGF-ß1 in glucose metabolism. METHODS: Serum levels of TGF-ß1 were measured by ELISA in 74 control participants with normal glucose tolerance and 75 participants with type 2 diabetes. Human liver tissue was collected from participants without obesity and with or without type 2 diabetes for the measurement of TGF-ß1 and glucagon signalling. To investigate the role of Smad3, a key signalling molecule downstream of the TGF-ß1 receptor, in mediating the effect of TGF-ß1 on glucagon signalling, we generated Smad3 knockout mice. Glucose levels in Smad3 knockout mice were measured during prolonged fasting and a glucagon tolerance test. Mouse primary hepatocytes were isolated from Smad3 knockout and wild-type (WT) mice to investigate the underlying molecular mechanisms. Smad3 phosphorylation was detected by western blotting, levels of cAMP were detected by ELISA and levels of protein kinase A (PKA)/cAMP response element-binding protein (CREB) phosphorylation were detected by western blotting. The dissociation of PKA subunits was measured by immunoprecipitation. RESULTS: We observed higher levels of serum TGF-ß1 in participants without obesity and with type 2 diabetes than in healthy control participants, which was positively correlated with HbA1c and fasting blood glucose levels. In addition, hyperactivation of the CREB and Smad3 signalling pathways was observed in the liver of participants with type 2 diabetes. Treating WT mouse primary hepatocytes with TGF-ß1 greatly potentiated glucagon-stimulated PKA/CREB phosphorylation and hepatic gluconeogenesis. Mechanistically, TGF-ß1 treatment induced the binding of Smad3 to the regulatory subunit of PKA (PKA-R), which prevented the association of PKA-R with the catalytic subunit of PKA (PKA-C) and led to the potentiation of glucagon-stimulated PKA signalling and gluconeogenesis. CONCLUSIONS/INTERPRETATION: The hepatic TGF-ß1/Smad3 pathway sensitises the effect of glucagon/PKA signalling on gluconeogenesis and synergistically promotes hepatic glucose production. Reducing serum levels of TGF-ß1 and/or preventing hyperactivation of TGF-ß1 signalling could be a novel approach for alleviating hyperglycaemia in type 2 diabetes.

Visualizing the Birth and Monitoring the Life of a Bimetallic Methanation Catalyst.

Well-defined bimetallic heterogeneous catalysts are not only difficult to synthesize in a controlled manner, but their elemental distributions are also notoriously challenging to define. Knowledge of these distributions is required for both the as-synthesized catalyst and its activated form under reaction conditions, where various types of reconstruction can occur. Success in this endeavor requires observation of the active catalyst via in situ analytical methods. As a step toward this goal, we present a composite material composed of bimetallic nickel-ruthenium nanoparticles supported on a protonated zeolite (Ni-Ru/HZSM-5) and probe its evolution and function as a photoactive carbon dioxide methanation catalyst using in situ X-ray absorption spectroscopy (XAS). The working Ni-Ru/HZSM-5, as a selective and durable photothermal CO2 methanation catalyst, comprises a corona of Ru nanoparticles decorating a Ni nanoparticle core. The specific Ni-Ru interactions in the bimetallic particles were confirmed by in situ XAS, which reveals significant electron transfer from Ni to Ru. The light-harvesting Ni nanoparticle core and electron-accepting Ru nanoparticle corona serve as the CO2 and H2 dissociation centers, respectively. These Ni and Ru nanoparticles also promote synergistic photothermal and hydrogen atom transfer effects. Collectively, these effects enable an associative CO2 methanation reaction pathway while hindering coking and fostering high selectivity toward methane.

Wettability Engineering of Solar Methanol Synthesis.

Engineering the wettability of surfaces with hydrophobic organics has myriad applications in heterogeneous catalysis and the large-scale chemical industry; however, the mechanisms behind may surpass the proverbial hydrophobic kinetic benefits. Herein, the well-studied In2O3 methanol synthesis photocatalyst has been used as an archetype platform for a hydrophobic treatment to enhance its performance. With this strategy, the modified samples facilitated the tuning of a wide range of methanol production rates and selectivity, which were optimized at 1436 µmol gcat-1 h-1 and 61%, respectively. Based on in situ DRIFTS and temperature-programmed desorption-mass spectrometry, the surface-decorated alkylsilane coating on In2O3 not only kinetically enhanced the methanol synthesis by repelling the produced polar molecules but also donated surface active H to facilitate the subsequent hydrogenation reaction. Such a wettability design strategy seems to have universal applicability, judged by its success with other CO2 hydrogenation catalysts, including Fe2O3, CeO2, ZrO2, and Co3O4. Based on the discovered kinetic and mechanistic benefits, the enhanced hydrogenation ability enabled by hydrophobic alkyl groups unleashes the potential of the surface organic chemistry modification strategy for other important catalytic hydrogenation reactions.

mTOR inhibition abrogates human mammary stem cells and early breast cancer progression markers.

BACKGROUND: Mammary physiology is distinguished in containing adult stem/progenitor cells that are actively amending the breast tissue throughout the reproductive lifespan of women. Despite their importance in both mammary gland development, physiological maintenance, and reproduction, the exact role of mammary stem/progenitor cells in mammary tumorigenesis has not been fully elucidated in humans or animal models. The implications of modulating adult stem/progenitor cells in women could lead to a better understanding of not only their function, but also toward possible breast cancer prevention led us to evaluate the efficacy of rapamycin in reducing mammary stem/progenitor cell activity and malignant progression markers. METHODS: We analyzed a large number of human breast tissues for their basal and luminal cell composition with flow cytometry and their stem and progenitor cell function with sphere formation assay with respect to age and menopausal status in connection with a clinical study (NCT02642094) involving a low-dose (2 mg/day) and short-term (5-7 days) treatment of the mTOR inhibitor sirolimus. The expression of biomarkers in biopsies and surgical breast samples were measured with quantitative analysis of immunohistochemistry. RESULTS: Sirolimus treatment significantly abrogated mammary stem cell activity, particularly in postmenopausal patients. It did not affect the frequency of luminal progenitors but decreased their self-renewal capacity. While sirolimus had no effect on basal cell population, it decreased luminal cell population, particularly in postmenopausal patients. It also significantly diminished prognostic biomarkers associated with breast cancer progression from ductal carcinoma in situ to invasive breast cancer including p16INK4A, COX-2, and Ki67, as well as markers of the senescence-associated secretary phenotype, thereby possibly functioning in preventing early breast cancer progression. CONCLUSION: Overall, these findings indicate a link from mTOR signaling to mammary stem and progenitor cell activity and cancer progression. Trial registration This study involves a clinical trial registered under the ClinicalTrials.gov identifier NCT02642094 registered December 30, 2015.

Phosphodiesterase and psychiatric disorders: a two-sample Mendelian randomization study.

BACKGROUND: Phosphodiesterases (PDEs) have been associated with psychiatric disorders in observational studies; however, the causality of associations remains unestablished. METHODS: Specifically, cyclic nucleotide PDEs were collected from genome-wide association studies (GWASs), including PDEs obtained by hydrolyzing both cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) (PDE1A, PDE2A, and PDE3A), specific to cGMP (PDE5A, PDE6D, and PDE9A) and cAMP (PDE4D and PDE7A). We performed a bidirectional two-sample Mendelian randomization (MR) analysis to investigate the relationship between PDEs and nine psychiatric disorders. The inverse-variance-weighted (IVW) method, MR-Egger, and weighted median were used to estimate causal effects. The Cochran's Q test, MR-Egger intercept test, MR Steiger test, leave-one-out analyses, funnel plot, and MR pleiotropy residual sum and outlier (MR-PRESSO) were used for sensitivity analyses. RESULTS: The PDEs specific to cAMP were associated with higher-odds psychiatric disorders. For example, PDE4D and schizophrenia (SCZ) (odds ratios (OR) = 1.0531, PIVW = 0.0414), as well as major depressive disorder (MDD) (OR = 1.0329, PIVW = 0.0011). Similarly, PDE7A was associated with higher odds of attention-deficit/hyperactivity disorder (ADHD) (OR = 1.0861, PIVW = 0.0038). Exploring specific PDE subtypes and increase intracellular cAMP levels can inform the development of targeted interventions. We also observed PDEs (which hydrolyzes both cAMP and cGMP) was associated with psychiatric disorders [OR of PDE1A was 1.0836 for autism spectrum disorder; OR of PDE2A was 0.8968 for Tourette syndrome (TS) and 0.9449 for SCZ; and OR of PDE3A was 0.9796 for MDD; P < 0.05]. Furthermore, psychiatric disorders also had some causal effects on PDEs [obsessive-compulsive disorder on increased PDE6D and decreased PDE2A and PDE4D; anorexia nervosa on decreased PDE9A]. The results of MR were found to be robust using multiple sensitivity analysis. CONCLUSIONS: In this study, potential causal relationships between plasma PDE proteins and psychiatric disorders were established. Exploring other PDE subtypes not included in this study could provide a more comprehensive understanding of the role of PDEs in psychiatric disorders. The development of specific medications targeting PDE subtypes may be a promising therapeutic approach for treating psychiatric disorders.

Comparison of common human respiratory pathogens among hospitalized children aged ≤ 6 years in Hainan Island, China, during spring and early summer in 2019-2021.

The coronavirus disease 2019 (COVID-19) pandemic and related public health intervention measures have been reported to have resulted in the reduction of infections caused by influenza viruses and other common respiratory viruses. However, the influence may be varied in areas that have different ecological, economic, and social conditions. This study investigated the changing epidemiology of 8 common respiratory pathogens, including Influenza A (IFVA), Influenza B (IFVB), Respiratory syncytial virus (HRSV), rhinovirus (RV), Human metapneumovirus Adenovirus, Human bocavirus, and Mycoplasma pneumoniae, among hospitalized children during spring and early summer in 2019-2021 in two hospitals in Hainan Island, China, in the COVID-19 pandemic era. The results revealed a significant reduction in the prevalence of IFVA and IFVB in 2020 and 2021 than in 2019, whereas the prevalence of HRSV increased, and it became the dominant viral pathogen in 2021. RV was one of the leading pathogens in the 3 year period, where no significant difference was observed. Phylogenetic analysis revealed close relationships among the circulating respiratory viruses. Large scale studies are needed to study the changing epidemiology of seasonal respiratory viruses to inform responses to future respiratory virus pandemics.

Mycobacterium tuberculosis protein kinase G acts as an unusual ubiquitinating enzyme to impair host immunity.

Upon Mycobacterium tuberculosis (Mtb) infection, protein kinase G (PknG), a eukaryotic-type serine-threonine protein kinase (STPK), is secreted into host macrophages to promote intracellular survival of the pathogen. However, the mechanisms underlying this PknG-host interaction remain unclear. Here, we demonstrate that PknG serves both as a ubiquitin-activating enzyme (E1) and a ubiquitin ligase (E3) to trigger the ubiquitination and degradation of tumor necrosis factor receptor-associated factor 2 (TRAF2) and TGF-ß-activated kinase 1 (TAK1), thereby inhibiting the activation of NF-κB signaling and host innate responses. PknG promotes the attachment of ubiquitin (Ub) to the ubiquitin-conjugating enzyme (E2) UbcH7 via an isopeptide bond (UbcH7 K82-Ub), rather than the usual C86-Ub thiol-ester bond. PknG induces the discharge of Ub from UbcH7 by acting as an isopeptidase, before attaching Ub to its substrates. These results demonstrate that PknG acts as an unusual ubiquitinating enzyme to remove key components of the innate immunity system, thus providing a potential target for tuberculosis treatment.

Imaginal disc growth factor is involved in melanin synthesis and energy metabolism in Bombyx mori.

The imaginal disc growth factor (IDGF), belonging to the glycoside hydrolase 18 family, plays an important role in various physiological processes in insects. However, the detail physiological function of IDGF is still unclear. In this study, transcriptome analysis was performed on the fatbody isolated from staged control and BmIDGF mutant silkworm larvae. Transcriptional profiling revealed that the absence of BmIDGF significantly affected differentially expressed genes involved in tyrosine and purine metabolism, as well as multiple energy metabolism pathways, including glycolysis, galactose, starch, and sucrose metabolism. The interruption of BmIDGF caused similar and specific gene expression changes to male and female fatbody. Furthermore, a genome-scale metabolic network integrating metabolomic and transcriptomic datasets revealed 11 pathways significantly altered at the transcriptional and metabolic levels, including amino acid, carbohydrate, uric acid metabolism pathways, insect hormone biosynthesis, and ABC transporters. In conclusion, this multiomics analysis suggests that IDGF is involved in gene-metabolism interactions, revealing its unique role in melanin synthesis and energy metabolism. This study provides new insights into the physiological function of IDGF in insects.

Analyses of human papillomavirus, Chlamydia trachomatis, Ureaplasma urealyticum, Neisseria gonorrhoeae, and co-infections in a gynecology outpatient clinic in Haikou area, China.

BACKGROUND: The purpose of this study was to study the infection rates of Chlamydia trachomatis (CT), Ureaplasma urealyticum (UU), Neisseria gonorrhoeae (NG), and co-infections with human papillomavirus (HPV) in a hospital gynecology outpatient clinic in the Haikou region in 2021. METHODS: From January to December 2021, the Women and Children Medical Center of Hainan Province collected 2389 samples of cervical exfoliated cells and vaginal swab specimens from gynecologic outpatients. The samples were then analyzed descriptively for data, and the detection rate of each pathogen was tallied. All vaginal swabs were obtained for CT, UU, and NG DNA testing, and cervical exfoliated cells for HPV genotyping. Analyses were performed on the detection rate of each group. RESULTS: In 2389 samples, the frequencies of pathogen identification among the 2389 samples were as follows: UU (58.43%); HPV (17.29%); CT (7.99%); and NG (0.38%). HPV, CT, UU, and NG were detected in 33.33%, 22.55%, 77.45%, and 2.94% of individuals between 15 and 20 years of age, respectively. The detection rates of CT, UU, and NG were substantially greater in the HPV-positive group than the the HPV-negative group (P < 0.05). CONCLUSION: Among gynecologic outpatients at a hospital in the Haikou area, the probability of mixed infections with genital tract pathogens in HPV-positive patients was higher compared to HPV-negative patients. Reproductive tract infections are becoming more prevalent in younger people, hence adolescent sexual health education needs improvement.

Therapeutic outcomes wide association scan of different antipsychotics in patients with schizophrenia: Randomized clinical trials and multi-ancestry validation.

AIM: This study identified discrepant therapeutic outcomes of antipsychotics. METHODS: A total of 5191 patients with schizophrenia were enrolled, 3030 as discovery cohort, 1395 as validation cohort, and 766 as multi-ancestry validation cohort. Therapeutic Outcomes Wide Association Scan was conducted. Types of antipsychotics (one antipsychotic vs other antipsychotics) were dependent variables, therapeutic outcomes including efficacy and safety were independent variables. RESULTS: In discovery cohort, olanzapine related to higher risk of weight gain (AIWG, OR: 2.21-2.86), liver dysfunction (OR: 1.75-2.33), sedation (OR: 1.76-2.86), increased lipid level (OR: 2.04-2.12), and lower risk of extrapyramidal syndrome (EPS, OR: 0.14-0.46); risperidone related to higher risk of hyperprolactinemia (OR: 12.45-20.53); quetiapine related to higher risk of sedation (OR = 1.73), palpitation (OR = 2.87), increased lipid level (OR = 1.69), lower risk of hyperprolactinemia (OR: 0.09-0.11), and EPS (OR: 0.15-0.44); aripiprazole related to lower risk of hyperprolactinemia (OR: 0.09-0.14), AIWG (OR = 0.44), sedation (OR: 0.33-0.47), and QTc prolongation (ß = -2.17); ziprasidone related to higher risk of increased QT interval (ß range: 3.11-3.22), nausea (OR: 3.22-3.91), lower risk of AIWG (OR: 0.27-0.46), liver dysfunction (OR: 0.41-0.38), and increased lipid level (OR: 0.41-0.55); haloperidol related to higher risk of EPS (OR: 2.64-6.29), hyperprolactinemia (OR: 5.45-9.44), and increased salivation (OR: 3.50-3.68). Perphenazine related to higher risk of EPS (OR: 1.89-2.54). Higher risk of liver dysfunction in olanzapine and lower risk of hyperprolactinemia in aripiprazole were confirmed in validation cohort, and higher risk of AIWG in olanzapine and hyperprolactinemia in risperidone were confirmed in multi-ancestry validation cohort. CONCLUSION: Future precision medicine should focus on personalized side-effects.

Robust PDF Watermarking against Print-Scan Attack.

Portable document format (PDF) files are widely used in file transmission, exchange, and circulation because of their platform independence, small size, good browsing quality, and the ability to place hyperlinks. However, their security issues are also more thorny. It is common to distribute printed PDF files to different groups and individuals after printing. However, most PDF watermarking algorithms currently cannot resist print-scan attacks, making it difficult to apply them in leak tracing of both paper and scanned versions of PDF documents. To tackle this issue, we propose an invisible digital watermarking technology based on modifying the edge pixels of text strokes to hide information in PDFs, which achieves high robustness to print-scan attacks. Moreover, it cannot be detected by human perception systems. This method focuses on the representation of text by embedding watermarks by changing the features of the text to ensure that changes in these features can be reflected in the scanned PDF after printing. We first segment each text line into two sub-blocks, then select the row of pixels with the most black pixels, and flip the edge pixels closest to this row. This method requires the participation of original PDF documents in detection. The experimental results show that all peak signal-to-noise ratio (PSNR) values of our proposed method exceed 32 dB, which indicates satisfactory invisibility. Meanwhile, this method can extract the hidden information with 100% accuracy under the JPEG compression attack, and has high robustness against noise attacks and print-scan attacks. In the case of no attacks, the watermark can be recovered without any loss. In terms of practical applications, our method can be applied in the practical leak tracing of official paper documents after distribution.