Large-scale whole-exome sequencing of neuropsychiatric diseases and traits in 350,770 adults.

While numerous genomic loci have been identified for neuropsychiatric conditions, the contribution of protein-coding variants has yet to be determined. Here we conducted a large-scale whole-exome-sequencing study to interrogate the impact of protein-coding variants on 46 neuropsychiatric diseases and 23 traits in 350,770 adults from the UK Biobank. Twenty new genes were associated with neuropsychiatric diseases through coding variants, among which 16 genes had impacts on the longitudinal risks of diseases. Thirty new genes were associated with neuropsychiatric traits, with SYNGAP1 showing pleiotropic effects across cognitive function domains. Pairwise estimation of genetic correlations at the coding-variant level highlighted shared genetic associations among pairs of neurodegenerative diseases and mental disorders. Lastly, a comprehensive multi-omics analysis suggested that alterations in brain structures, blood proteins and inflammation potentially contribute to the gene-phenotype linkages. Overall, our findings characterized a compendium of protein-coding variants for future research on the biology and therapeutics of neuropsychiatric phenotypes.

The proteomic landscape of fall armyworm oral secretion reveals its role in plant adaptation.

BACKGROUND: The fall armyworm (FAW, Spodoptera frugiperda (J.E. Smith)) is a polyphagous agricultural pest with rapidly evolving adaptations to host plants. We found the oral secretion (OS) of FAW from different plants influences plant defense response differentially, suggesting its role in adapting to host plants. However, the protein expression profile of FAW OS respond to different plants is largely unknown. RESULTS: Here, from the mass spectrometry assay, we identified a total of 256 proteins in the OS of FAW fed on cotton (Gossypium hirsutum L.), tobacco (Nicotiana benthamiana Domin), maize (Zea mays L.) and artificial diet. The FAW OS primarily comprise of 60 proteases, 32 esterases and 92 non-enzymatic proteins. It displays high plasticity across different diets. We found that more than half of the esterases are lipases which have been reported as insect elicitors to enhance plant defense response. The lipase accumulation in cotton-fed larvae was the highest, followed by maize-fed larvae. In the presence of lipase inhibitors, the enhanced induction on defense genes in wounded leaves by OS was attenuated. However, the putative effectors were most highly accumulated in the OS from FAW larvae fed on maize compared to those fed on other diets. We identified that one of them (VRLP4) reduces the OS-mediated induction on defense genes in wounded leaves. CONCLUSION: Together, our investigation presents the proteomic landscape of the OS of FAW influenced by different diets and reveals diet-mediated plasticity of OS is involved in FAW adaptation to host plants. © 2024 Society of Chemical Industry.

Prolonged oral intake of green tea polyphenols attenuates delirium-like behaviors in mice induced by anesthesia/surgery.

Postoperative delirium (POD) is a severe postoperative complication characterized by delirium-like symptoms. So far, no effective preventable strategy for POD prevention has been identified. Reports show that the consumption of green tea polyphenols (GTP) is associated with better cognitive function by modulating the composition of gut microbiota. Whether GTP also play a role in alleviating POD through gut microbiota is unknown. Herein, we studied the effect of prolonged (eight weeks) GTP intake on postoperative delirium in C57BL/6 mice with laparotomies under isoflurane anesthesia (anesthesia/surgery). We subsequently investigated anesthesia/surgery caused behavioral changes and increased the expression of malondialdehyde (MAD), an oxidative stress marker, and the activities of superoxide dismutase (SOD), an antioxidant marker, in the mice at 6 h after anesthesia/surgery. However, GTP administration reversed these changes and alleviated anesthesia/surgery-induced decrease in the abundance of gut bacterial genera, Roseburia. Further, fecal microbiota transplant demonstrated that compared with mice in the control group, treatment of C57BL/6 mice with feces from GTP-treated mice had a slight effect on the behavioral changes of mice. These data suggest that daily consumption of GTP could protect against anesthesia/surgery-induced behavioral changes, which is closely associated with gut microbiota modification by GTP.

Virtual formalin-fixed and paraffin-embedded staining of fresh brain tissue via stimulated Raman CycleGAN model.

Intraoperative histology is essential for surgical guidance and decision-making. However, frozen-sectioned hematoxylin and eosin (H&E) staining suffers from degraded accuracy, whereas the gold-standard formalin-fixed and paraffin-embedded (FFPE) H&E is too lengthy for intraoperative use. Stimulated Raman scattering (SRS) microscopy has shown rapid histology of brain tissue with lipid/protein contrast but is challenging to yield images identical to nucleic acid-/protein-based FFPE stains interpretable to pathologists. Here, we report the development of a semi-supervised stimulated Raman CycleGAN model to convert fresh-tissue SRS images to H&E stains using unpaired training data. Within 3 minutes, stimulated Raman virtual histology (SRVH) results that matched perfectly with true H&E could be generated. A blind validation indicated that board-certified neuropathologists are able to differentiate histologic subtypes of human glioma on SRVH but hardly on conventional SRS images. SRVH may provide intraoperative diagnosis superior to frozen H&E in both speed and accuracy, extendable to other types of solid tumors.

Harnessing innate immune pathways for therapeutic advancement in cancer.

The innate immune pathway is receiving increasing attention in cancer therapy. This pathway is ubiquitous across various cell types, not only in innate immune cells but also in adaptive immune cells, tumor cells, and stromal cells. Agonists targeting the innate immune pathway have shown profound changes in the tumor microenvironment (TME) and improved tumor prognosis in preclinical studies. However, to date, the clinical success of drugs targeting the innate immune pathway remains limited. Interestingly, recent studies have shown that activation of the innate immune pathway can paradoxically promote tumor progression. The uncertainty surrounding the therapeutic effectiveness of targeted drugs for the innate immune pathway is a critical issue that needs immediate investigation. In this review, we observe that the role of the innate immune pathway demonstrates heterogeneity, linked to the tumor development stage, pathway status, and specific cell types. We propose that within the TME, the innate immune pathway exhibits multidimensional diversity. This diversity is fundamentally rooted in cellular heterogeneity and is manifested as a variety of signaling networks. The pro-tumor effect of innate immune pathway activation essentially reflects the suppression of classical pathways and the activation of potential pro-tumor alternative pathways. Refining our understanding of the tumor's innate immune pathway network and employing appropriate targeting strategies can enhance our ability to harness the anti-tumor potential of the innate immune pathway and ultimately bridge the gap from preclinical to clinical application.

The potential of DEirlncRNAs: A novel approach to predict glioblastoma prognosis.

Background: Despite tremendous evolution in therapies, the prognosis of glioblastoma (GBM) remains grim, which calls for innovative approaches to optimize chemotherapy efficacy and predict risk. Methods: The transcriptome and clinical data of GBM were acquired from the Cancer Genome Atlas (TCGA), followed by the identification of differentially expressed immune-related long noncoding RNAs (DEirlncRNAs) with Pearson correlation and limma packet analyses. Survival-related DEirlncRNA pairs were screened with univariate Cox proportional hazard regression. Prognostic markers were obtained, and risk scores were calculated with Lasso regression and multivariate Cox risk regression analyses. The association of the prognostic risk model with immune cell infiltration was evaluated by comprehensively analyzing tumor-infiltrating immune cells with TIMER, XCELL, CIBERSORT, QUANTISEQ, and EPIC. Differences in half-maximal inhibitory concentration (IC50) values between the high- and low-risk groups were assessed with the Wilcoxon signed-rank test. Results: A total of 276 DEirlncRNAs were identified, followed by the visualization of their expression patterns. Two prognosis-related DEirlncRNA pairs were screened, with high accuracy and reliability. The constructed prognostic risk model effectively distinguished between high- and low-risk patients, and significant differences were observed in survival outcomes between the high- and low-risk groups. Furthermore, risk scores were associated with tumor-infiltrating immune cells and DEirlncRNA expression. Additionally, the risk model had a correlation with the effectiveness of commonly used chemotherapeutic agents, providing clues into potential treatment responses. Conclusions: In our study, a novel signature was constructed with paired DEirlncRNAs (regardless of their expression), which holds significant clinical predictive value and is a potential breakthrough for personalized management of GBM.

Enhanced brain distribution of Ginsenoside F1 via intranasal administration in combination with absorption enhancers.

Ginsenoside F1 (GF1) is a potential drug candidate for the treatment of Alzheimer's disease. Nevertheless, its low oral bioavailability and poor solubility limit clinical application. By utilizing either a direct or indirect approach, intranasal administration is a non-invasive drug delivery method that can deliver drugs to the brain rapidly. But large molecule drug delivered to the brain through intranasal administration may be insufficient to reach required concentration for therapeutic effect. In this study, using GF1 as a model drug, the feasibility of intranasal administration in combination with absorption enhancers to increase brain distribution of GF1 was explored. First of all, the appropriate absorption enhancers were screened by in situ nasal perfusion study. GF1-HP-ß-CD inclusion complex was prepared and characterized. Thereafter, in vivo absorption of GF1 after intranasal or intravenous administration of its inclusion complex with/without absorption enhancers was investigated, and safety of the formulations was evaluated. The results showed that 2% Solutol HS 15 was a superior absorption enhancer. HP-ß-CD inclusion complex improved GF1 solubility by 150 fold. Following intranasal delivery, the absolute bioavailability of inclusion complex was 46%, with drug brain targeting index (DTI) 247% and nose-to-brain direct transport percentage (DTP) 58%. Upon further addition of 2% Solutol HS 15, the absolute bioavailability was increased to 75%, with DTI 315% and DTP 66%. Both nasal cilia movement and biochemical substances (total protein and lactate dehydrogenase) leaching studies demonstrated 2% Solutol HS 15 was safe to the nasal mucosa. In conclusion, intranasal administration combining with safe absorption enhancers is an effective strategy to enhance drug distribution in the brain, showing promise for treating disorders related to the central nervous system.

Switching of brain networks across different cerebral perfusion states: insights from EEG dynamic microstate analyses.

The alteration of neural interactions across different cerebral perfusion states remains unclear. This study aimed to fulfill this gap by examining the longitudinal brain dynamic information interactions before and after cerebral reperfusion. Electroencephalogram in eyes-closed state at baseline and postoperative 7-d and 3-month follow-ups (moyamoya disease: 20, health controls: 23) were recorded. Dynamic network analyses were focused on the features and networks of electroencephalogram microstates across different microstates and perfusion states. Considering the microstate features, the parameters were disturbed of microstate B, C, and D but preserved of microstate A. The transition probabilities of microstates A-B and B-D were increased to play a complementary role across different perfusion states. Moreover, the microstate variability was decreased, but was significantly improved after cerebral reperfusion. Regarding microstate networks, the functional connectivity strengths were declined, mainly within frontal, parietal, and occipital lobes and between parietal and occipital lobes in different perfusion states, but were ameliorated after cerebral reperfusion. This study elucidates how dynamic interaction patterns of brain neurons change after cerebral reperfusion, which allows for the observation of brain network transitions across various perfusion states in a live clinical setting through direct intervention.

Educational attainment, income, and attention deficit hyperactivity disorder: A mediation analysis based on two-step Mendelian randomization.

Previous studies have reported the relationship between educational attainment and attention deficit hyperactivity disorder (ADHD). However, the mechanism of this relationship remains unknown. It is well known that educational attainment correlates with income. Therefore, based on summary data from a genome-wide association study we used two-step Mendelian randomization (MR) to explore the role of income between education and ADHD. The inverse variance weighted (IVW) method was used in our analysis. The IVW results suggested that educational attainment and income were protective factors against ADHD. Educational attainment affects ADHD through income [ADHD: Beta = -0.68, 95% confidence interval (CI) = -0.87, -0.49; female: Beta = -0.87, 95% CI = -1.28, -0.47; male: Beta = -1.01, 95% CI = -1.34, -0.68; childhood: Beta = -0.52, 95% CI = -0.74, -0.30; late-diagnosed: Beta = -0.78, 95% CI = -1.11, -0.47; persistent: Beta = -0.82, 95% CI = -1.33, -0.31]. Income also affected ADHD through educational attainment [female: Beta = -1.08, 95% CI = -1.35, -0.83; male: Beta = -1.16, 95% CI = -1.57, -0.77; persistent: Beta = -1.48, 95% CI = -2.09, -0.94]. In the final analysis, data with heterogeneity were analyzed using IVW random effects results. The mechanism is that income will mediate the relationship between educational attainment and ADHD.

Modeling the precise interaction of glioblastoma with human brain region-specific organoids.

Glioblastoma is a highly aggressive malignant tumor of the central nervous system, but the interaction between glioblastoma and different types of neurons remains unclear. Here, we established a co-culture model in vitro using 3D printed molds with microchannels, in which glioblastoma organoids (GB), dorsal forebrain organoids (DO, mainly composed of excitatory neurons), and ventral forebrain organoids (VO, mainly composed of inhibitory neurons) were assembled. Our results indicate that DO has a greater impact on altered gene expression profiles of GB, resulting in increased invasive potential. GB cells preferentially invaded DO along axons, whereas this phenomenon was not observed in VO. Furthermore, GB cells selectively inhibited neurite outgrowth in DOs and reduced the expression of the vesicular GABA transporter (VGAT), leading to neuronal hyperexcitability. By revealing how glioblastoma interacts with brain cells, our study provides a more comprehensive understanding of this disease.

Cell Membrane Perforation: Patterns, Mechanisms and Functions.

Cell membrane is crucial for the cellular activities, and any disruption to it may affect the cells. It is demonstrated that cell membrane perforation is associated with some biological processes like programmed cell death (PCD) and infection of pathogens. Specific developments make it a promising technique to perforate the cell membrane controllably and precisely. The pores on the cell membrane provide direct pathways for the entry and exit of substances, and can also cause cell death, which means reasonable utilization of cell membrane perforation is able to assist intracellular delivery, eliminate diseased or cancerous cells, and bring about other benefits. This review classifies the patterns of cell membrane perforation based on the mechanisms into 1) physical patterns, 2) biological patterns, and 3) chemical patterns, introduces the characterization methods and then summarizes the functions according to the characteristics of reversible and irreversible pores, with the aim of providing a comprehensive summary of the knowledge related to cell membrane perforation and enlightening broad applications in biomedical science.

Zwitterion mediated anti-protein adsorption on polypropylene mesh to reduce inflammation for efficient hernia repair.

The effectiveness of polypropylene (PP) mesh is often compromised by severe inflammation. Engineering anti-inflammatory coatings has significant implications for PP mesh to repair unwanted hernias. Here, we presented a facile strategy to develop an anti-fouling coating consisting of zwitterionic poly(carboxybetaine methacrylate) (PCBMA), which could prohibit protein adsorption to endow PP mesh with anti-inflammatory efficacy. The incorporation of PCBMA coating had little impact on the raw features of PP mesh. While the modified mesh PCBMA-PP possessed noticeable hydrophilicity increase and surface charge reduction. The excellent lubricity and surface stability enabled PCBMA-PP to exhibit superior anti-fouling capacity, thus efficiently inhibiting the adsorption of proteins. In vivo experiments showed that incorporating the PCBMA layer could provide PP meshes with outstanding anti-inflammatory effects and tissue compatibility for repairing hernias.

The causal impact of maternal smoking around birth on offspring ADHD: A two-sample Mendelian randomization study.

BACKGROUND: The previous literature highlights a relationship between maternal smoking around birth (MSAB) and offspring attention-deficit/hyperactivity disorder (ADHD). These studies have focused on the causal effects of MSAB on offspring ADHD. METHOD: A Mendelian randomization analysis was conducted using summary statistics. Data on MSAB were obtained from a recent study including 391,992 participants. ADHD data were obtained from six sources for 246,888 participants. The present study used five methods to examine the causal impact from outcomes on exposures. The inverse variance weighted (IVW) was the main method of analysis, while the other four methods were supplementary methods. RESULT: The IVW revealed that MSAB was a risk factor for offspring ADHD (OR: 2.54; 95 % confidence interval [CI]: 1.61-4.00, p = 6.04 × 10-5). Concerning ADHD in both sexes, MSAB was associated with females (OR = 3.96, 95 % CI: 1.99-7.90, p = 8.98 × 10-5) and males (OR = 3.74, 95 % CI: 1.74-5.72, p = 1.48 × 10-4). In different diagnosis periods for ADHD, MSAB increased the risk of childhood (OR = 3.63, 95 % CI: 2.25-5.87, p = 1.31 × 10-7), late-diagnosed (OR = 2.99, 95 % CI: 1.74-5.14, p = 7.33 × 10-5), and persistent (OR = 4.77, 95 % CI: 1.88-12.14, p = 1.03 × 10-3) ADHD. The final analysis did not reveal heterogeneity. CONCLUSIONS: A causal impact of MSAB on offspring ADHD was observed. These findings highlight the need for careful consideration of prenatal exposure (MSAB) during the assessment of offspring ADHD. Additionally, it can provide targeted guidance for prenatal interventions. Future studies should analyze the effects of different doses of maternal smoking on ADHD.

Effect of high-field iMRI guided resection in cerebral glioma surgery: A randomized clinical trial.

BACKGROUND: Extent of resection (EOR) in glioma contributes to longer survival. The purpose of NCT01479686 was to prove whether intraoperative magnetic resonance imaging (iMRI) increases EOR in glioma surgery and benefit survival. METHODS: Patients were randomized (1:1) to receive the iMRI (n = 161) or the conventional neuronavigation (n = 160). The primary endpoint was gross total resection (GTR); secondary outcomes reported were progression-free survival (PFS), overall survival (OS), and safety. RESULTS: 188 high-grade gliomas (HGGs) and 133 low-grade gliomas (LGGs) were enrolled. GTR was 83.85% in the iMRI group vs. 50.00% in the control group (P < 0.0001). In 321 patients, the median PFS (mPFS) was 65.12 months in the iMRI group and 61.01 months in the control group (P = 0.0202). For HGGs, mPFS was improved in the iMRI group (19.32 vs. 13.34 months, P = 0.0015), and a trend of superior OS compared with control was observed (29.73 vs. 25.33 months, P = 0.1233). In the predefined eloquent area HGG subgroup, mPFS, and mOS were 20.47 months and 33.58 months in the iMRI vs. 12.21 months and 21.16 months in the control group (P = 0.0098; P = 0.0375, respectively). From the exploratory analyses of HGGs, residual tumor volume (TV) < 1.0 cm3 decreased the risk of survival (mPFS: 18.99 vs. 9.43 months, P = 0.0055; mOS: 29.77 vs. 18.10 months, P = 0.0042). LGGs with preoperative (pre-OP) TV > 43.1 cm3 and postoperative (post-OP) TV > 4.6 cm3 showed worse OS (P= 0.0117) CONCLUSIONS: It showed that iMRI significantly increased EOR and indicated survival benefits for HGGs, particularly eloquent HGGs. Residual TV in either HGGs or LGGs is a prognostic factor for survival.

Microneedle Patch Delivery of PLCG1-siRNA Efficient Enhanced Temozolomide Therapy for Glioblastoma.

The blood-brain barrier (BBB) and drug resistance present challenges for chemotherapy of glioblastoma (GBM). A microneedle (MN) patch with excellent biocompatibility and biodegradability was designed to bypass the BBB and release temozolomide (TMZ) and PLCG1-siRNA directly into the tumor site for synergistic treatment of GBM. The codelivery of TMZ and PLCG1-siRNA enhanced DNA damage and apoptosis. The potential mechanism behind this enhancement is to knockdown of PLCG1 expression, which positively regulates the expression of signal transducer and activator of transcription 3 genes, thereby preventing DNA repair and enhancing the sensitivity of GBM to TMZ. The MN patch enables long-term sustainable drug release through in situ implantation and increases local drug concentrations in diseased areas, significantly extending mouse survival time compared to other drug treatment groups. MN drug delivery provides a platform for the combination treatment of GBM and other central nervous system diseases.

Organophosphorus-Catalyzed Direct Dehydroxylative Thioetherification of Alcohols with Hypervalent Organosulfur Compounds.

A metal-free and thiol-free organophosphorus-catalyzed method for forming thioethers was disclosed, driven by PIII/PV═O redox cycling. In this work, one-step dehydroxylative thioetherification of alcohols was fulfilled with various hypervalent organosulfur compounds. This established strategy features an excellent functional group tolerance and broad substrate scope, especially inactivated alcohols. The scale-up reaction and further transformation of the product were also successful. Additionally, this method offers a protecting-group-free and step-efficient approach for synthesizing peroxisome proliferator-activated receptor agonists which exhibited promising potential for treating osteoporosis in mammals.

The Temporoparietal Fascia Flap Transposition Technique for Ventral Skull Base Reconstruction: Anatomic Analysis and Surgical Application.

BACKGROUND AND OBJECTIVES: The temporoparietal fascia (TPF) flap is an alternative for revision endoscopic skull base reconstruction in the absence of the nasoseptal flap, and we aimed to investigate the anatomy and surgical application of TPF flap transposition in endoscopic endonasal surgery. METHODS: Six lightly embalmed postmortem human heads and 30 computed tomography angiography imaging scans were used to analyze the anatomic features of the TPF flap transposition technique. Three cases selected from a 512 endoscopic endonasal cases database were presented for the clinical application of the TPF flap. RESULTS: The TPF flap, composed by the deepest 3 scalp layers (galea aponeurotica, loose areolar connective tissue, and pericranium), can be harvested and then transposed through the infratemporal-maxillary-pterygoid tunnel to the ventral skull base. The superficial temporal artery as its feeding artery, gives frontal and parietal branches with similar diameter (1.5 ± 0.3 mm) at its bifurcation. The typical bifurcation was present in 50 sides (83.3%), with single (frontal) branch in 5 sides (8.3%), single (parietal) branch in 2 sides (3.3%), and multiple branches (>2) in 3 sides (5%). The transposed TPF flap was divided into 3 parts according to its anatomic location: (1) infratemporal part with an area of 19.5 ± 2.5 cm2, (2) maxillary part with an area of 23.7 ± 2.8 cm2, and (3) skull base part with an area of 44.2 ± 4 cm2. Compared with the nasoseptal flap, nasal floor flap, inferior turbinate flap, and extended septal flap, the coverage area of the skull base part of the TPF flap was significantly larger than any of them (P < .0001). CONCLUSION: The TPF flap technique is an effective alternative for endoscopic endonasal skull base reconstruction. The TPF flap could successfully cover large skull base defects through the infratemporal-maxillary-pterygoid tunnel.

Rare Pediatric Cerebellar High-Grade Gliomas Mimic Medulloblastomas Histologically and Transcriptomically and Show p53 Mutations.

Pediatric high-grade gliomas (HGG) of the cerebellum are rare, and only a few cases have been documented in detail in the literature. A major differential diagnosis for poorly differentiated tumors in the cerebellum in children is medulloblastoma. In this study, we described the histological and molecular features of a series of five pediatric high-grade gliomas of the cerebellum. They actually showed histological and immunohistochemical features that overlapped with those of medulloblastomas and achieved high scores in NanoString-based medulloblastoma diagnostic assay. Methylation profiling demonstrated these tumors were heterogeneous epigenetically, clustering to GBM_MID, DMG_K27, and GBM_RTKIII methylation classes. MYCN amplification was present in one case, and PDGFRA amplification in another two cases. Interestingly, target sequencing showed that all tumors carried TP53 mutations. Our results highlight that pediatric high-grade gliomas of the cerebellum can mimic medulloblastomas at histological and transcriptomic levels. Our report adds to the rare number of cases in the literature of cerebellar HGGs in children. We recommend the use of both methylation array and TP53 screening in the differential diagnoses of poorly differentiated embryonal-like tumors of the cerebellum.

Knockout of TGF-ß receptor II by CRISPR/Cas9 delays mesenchymal transition of Lens epithelium and posterior capsule opacification.

Posterior capsule opacification (PCO) is the most common postoperative complication of cataract surgery. Transforming growth factor-ß (TGF-ß) is related to epithelial-mesenchymal transition (EMT) of lens epithelial cells (LECs) that is proven to induce PCO formation in clinical and experimental studies. In this study, CRISPR sequences targeting exon of TGF-ßRII were knocked out with lentiviral transfection in LECs. Rabbits' PCO model was established and recombinant adeno-associated virus (AAV) for transferring the gRNA of TGF ßRII were intravitreally injected. SgRNA inhibited TGF-ßRII expression and human LECs proliferation. In TGF-ßRII knockout group, LECs motility and migration were suppressed, N-cadherin and vimentin expressions were significantly decreased, whereas E-cadherin was increased. The animal model showed that TGF-ßRII knockout in vivo was effective in suppressing PCO. The current study suggested that the CRISPR/Cas9 endonuclease system could suppress TGF-ßRII secretion, which participates in the EMT procedure of LECs in vitro and PCO in vivo. These findings might provide a new gene-editing approach and insight into a novel therapeutic strategy for PCO.