Optimizing the energy level alignment for achieving record-breaking efficiency in hot exciton deep red OLEDs.

To effectively compete with the quenching process in long-wavelength regions like deep red (DR) and near-infrared (NIR), rapid radiative decay is urgently needed to address the challenges posed by the "energy gap law". Herein, we confirmed that it is crucial for hot exciton emitters to attain a narrow energy gap (ΔES1-T2) between the lowest singlet excited (S1) state and second triplet excited (T2) state, while ensuring that T2 slightly exceeds S1 in the energy level. Two proofs-of-concept of hot exciton DR emitters, namely αT-IPD and ßT-IPD, were successfully designed and synthesized by coupling electron-acceptors N,N-diphenylnaphthalen-2-amine (αTPA) and N,N-diphenylnaphthalen-1-amine (ßTPA) with an electron-withdrawing unit 5-(4-(tert-butyl) phenyl)-5H-pyrazino[2,3-b]indole-2,3-dicarbonitrile (IPD). Both emitters exhibited a narrow ΔES1-T2, with T2 being slightly higher than S1. Additionally, both emitters showed significantly large ΔET2-T1. Moreover, due to their aggregation-induced emission characteristics, J-aggregated packing modes, moderate strength intermolecular CN⋯H-C and C-H⋯π interactions, and unique, comparatively large center-to-center distances among trimers in the crystalline state, both αT-IPD and ßT-IPD emitters exhibited remarkable photoluminescence quantum yields of 68.5% and 73.5%, respectively, in non-doped films. Remarkably, the corresponding non-doped DR-OLED based on ßT-IPD achieved a maximum external quantum efficiency of 15.5% at an emission peak wavelength of 667 nm, representing the highest reported value for hot exciton DR-OLEDs.

Pulmonary delivery of icariin-phospholipid complex prolongs lung retention and improves therapeutic efficacy in mice with acute lung injury/ARDS.

Icariin has been shown the promising therapeutic potential to treat inflammatory airway diseases, yet its poor lung distribution and retention restrict the clinical applications. To this end, this work aimed to prepare an icariin-phospholipid complex (IPC) formulation for sustained nebulization delivery that enabled excellent inhalability, improved lung exposure and prolonged duration of action. Icariin was found to react with soybean phospholipid to form supramolecular IPC, which was able to self-assemble into nanoparticle suspension. The suspension was stable during steam sterilization and nebulization processes, and its aerosols generated by a commercial nebulizer exhibited excellent aerodynamic properties and delivery efficiency. In vitro studies showed that the formation of complex sustained drug release, enhanced lung affinity and slowed lung clearance. The drug distribution in lung epithelial lining fluid (ELF) also demonstrated in vivo sustained release after intratracheal administration to mice. In addition, compared to free icariin, IPC improved the drug exposure to lung tissues and immune cells in the ELF by 4.61-fold and 39.5-fold, respectively. This resulted in improved and prolonged local anti-inflammatory effects up to 24 h in mice with lipopolysaccharide (LPS)-induced acute lung injury. Moreover, IPC improved survival rate of mice with acute respiratory distress syndrome (ARDS). Overall, the present phospholipid complex represented a promising formulation of icariin for the treatment of acute lung injury/ARDS by nebulization delivery.

Acquisition of different transcriptional shear mRNA and biological function of porcine interleukin 18 binding protein in PRRSV infection.

Interleukin-18 binding protein (IL-18BP), a natural regulator molecule of the pro-inflammatory cytokine interleukin-18 (IL-18), plays an important role in regulating the expression of the cellular immunity factor interferon-γ (IFN-γ). In a previous RNA-seq analysis of porcine alveolar macrophages (PAM) infected with the TIM and TJ strains of porcine reproductive and respiratory syndrome virus (PRRSV), we unexpectedly found that the mRNA expression of porcine interleukin 18-binding protein (pIL-18BP) in PAM cells infected with the TJM strain was significantly higher than that infected with the TJ strain. Studies have shown that human interleukin-18 binding protein (hIL-18bp) plays an important role in regulating cellular immunity in the course of the disease. However, there is a research gap on pIL-18BP. At the same time, PRRSV infection in pigs triggers weak cellular immune response problems. To explore the expression and the role of pIL-18BP in the cellular immune response induced by PRRSV, we strived to acquire the pIL-18BP gene from PAM or peripheral blood mononuclear cell (PBMC) with RT-PCR and sequencing. Furthermore, pIL-18BP and pIL-18 were both expressed prokaryotically and eukaryotically. The colocalization and interaction based on recombinant pIL-18BP and pIL-18 on cells were confirmed in vitro. Finally, the expression of pIL-18BP, pIL-18, and pIFN-γ was explored in pigs with different PRRSV infection states to interpret the biological function of pIL-18BP in vivo. The results showed there were five shear mutants of pIL-18BP. The mutant with the longest coding region was selected for subsequent functional validation. First, it was demonstrated that TJM-induced pIL-18BP mRNA expression was higher than that of TJ. A direct interaction between pIL-18BP and pIL-18 was confirmed through fluorescence colocalization, bimolecular fluorescent complimentary (BIFC), and co-immunoprecipitation (CO-IP). pIL-18BP also can regulate pIFN-γ mRNA expression. Finally, the expression of pIL-18BP, pIL-18, and pIFN-γ was explored in different PRRSV infection states. Surprisingly, both mRNA and protein expression of pIL-18 were suppressed. These findings fill the gap in understanding the roles played by pIL-18BP in PRRSV infection and provide a foundation for further research.IMPORTANCEPRRSV-infected pigs elicit a weak cellular immune response and the mechanisms of cellular immune regulation induced by PRRSV have not yet been fully elucidated. In this study, we investigated the role of pIL-18BP in PRRSV-induced immune response referring to the regulation of human IL-18BP to human interferon-gamma (hIFN-γ). This is expected to be used as a method to enhance the cellular immune response induced by the PRRSV vaccine. Here, we mined five transcripts of the pIL-18BP gene and demonstrated that it interacts with pIL-18 and regulates pIFN-γ mRNA expression. Surprisingly, we also found that both mRNA and protein expression of pIL-18 were suppressed under different PRRSV strains of infection status. These results have led to a renewed understanding of the roles of pIL-18BP and pIL-18 in cellular immunity induced by PRRSV infection, which has important implications for the prevention and control of PRRS.

Genetic regulation of human brain proteome reveals proteins implicated in psychiatric disorders.

Psychiatric disorders are highly heritable yet polygenic, potentially involving hundreds of risk genes. Genome-wide association studies have identified hundreds of genomic susceptibility loci with susceptibility to psychiatric disorders; however, the contribution of these loci to the underlying psychopathology and etiology remains elusive. Here we generated deep human brain proteomics data by quantifying 11,608 proteins across 268 subjects using 11-plex tandem mass tag coupled with two-dimensional liquid chromatography-tandem mass spectrometry. Our analysis revealed 788 cis-acting protein quantitative trait loci associated with the expression of 883 proteins at a genome-wide false discovery rate <5%. In contrast to expression at the transcript level and complex diseases that are found to be mainly influenced by noncoding variants, we found protein expression level tends to be regulated by non-synonymous variants. We also provided evidence of 76 shared regulatory signals between gene expression and protein abundance. Mediation analysis revealed that for most (88%) of the colocalized genes, the expression levels of their corresponding proteins are regulated by cis-pQTLs via gene transcription. Using summary data-based Mendelian randomization analysis, we identified 4 proteins and 19 genes that are causally associated with schizophrenia. We further integrated multiple omics data with network analysis to prioritize candidate genes for schizophrenia risk loci. Collectively, our findings underscore the potential of proteome-wide linkage analysis in gaining mechanistic insights into the pathogenesis of psychiatric disorders.

Depressive symptoms are not associated with clinically important levels of digital home blood pressure in the electronic Framingham Heart Study.

Background: Depressive symptoms are common and share many biopsychosocial mechanisms with hypertension. Association studies between depressive symptoms and blood pressure (BP) have been inconsistent. Home BP monitoring may provide insight. Objective: To investigate the association between depressive symptoms and digital home BP. Methods: Electronic Framingham Heart Study (eFHS) participants were invited to obtain a smartphone app and digital BP cuff at research exam 3 (2016-2019). Participants with ≥3 weeks of home BP measurements within 1 year were included. Depressive symptoms were measured using the Center for Epidemiological Studies Depression Scale (CES-D). Multivariable linear mixed models were used to test the associations of continuous CES-D score and dichotomous depressive symptoms (CES-D ≥16) (independent) with home BP (dependent), adjusting for age, sex, cohort, number of weeks since baseline, lifestyle factors, diabetes, and cardiovascular disease. Results: Among 883 participants (mean age 54 years, 59% women, 91% White), the median CES-D score was 4. Depressive symptom prevalence was 7.6%. Mean systolic and diastolic BP at exam 3 were 119 and 76 mm Hg; hypertension prevalence was 48%. A 1 SD higher CES-D score was associated with 0.9 (95% CI: 0.18-1.56, P = .01) and 0.6 (95% CI: 0.06-1.07, P = .03) mm Hg higher home systolic BP and diastolic BP, respectively. Dichotomous depressive symptoms were not significantly associated with home BP (P > .2). Conclusion: Depressive symptoms were not associated with clinically substantive levels of home BP. The association between depression and cardiovascular disease risk factors warrants more data, which may be supported by mobile health measures.

Exome sequencing in four families with neurodevelopmental disorders: genotype-phenotype correlation and identification of novel disease-causing variants in VPS13B and RELN.

Neurodevelopmental disorders (NDDs) are a clinically and genetically heterogeneous group of early-onset pediatric disorders that affect the structure and/or function of the central or peripheral nervous system. Achieving a precise molecular diagnosis for NDDs may be challenging due to the diverse genetic underpinnings and clinical variability. In the current study, we investigated the underlying genetic cause(s) of NDDs in four unrelated Pakistani families. Using exome sequencing (ES) as a diagnostic approach, we identified disease-causing variants in established NDD-associated genes in all families, including one hitherto unreported variant in RELN and three recurrent variants in VPS13B, DEGS1, and SPG11. Overall, our study highlights the potential of ES as a tool for clinical diagnosis.

s-TBN: A New Neural Decoding Model to Identify Stimulus Categories From Brain Activity Patterns.

Neural decoding is still a challenging and a hot topic in neurocomputing science. Recently, many studies have shown that brain network patterns containing rich spatiotemporal structural information represent the brain's activation information under external stimuli. In the traditional method, brain network features are directly obtained using the standard machine learning method and provide to a classifier, subsequently decoding external stimuli. However, this method cannot effectively extract the multidimensional structural information hidden in the brain network. Furthermore, studies on tensors have show that the tensor decomposition model can fully mine unique spatiotemporal structural characteristics of a spatiotemporal structure in data with a multidimensional structure. This research proposed a stimulus-constrained Tensor Brain Network (s-TBN) model that involves the tensor decomposition and stimulus category-constraint information. The model was verified on real neuroimaging data obtained via magnetoencephalograph and functional mangetic resonance imaging). Experimental results show that the s-TBN model achieve accuracy matrices of greater than 11.06% and 18.46% on the accuracy matrix compared with other methods on two modal datasets. These results prove the superiority of extracting discriminative characteristics using the STN model, especially for decoding object stimuli with semantic information.

Preoperative Ultrasound for the Prediction of Postinduction Hypotension: A Systematic Review and Meta-Analysis.

Postinduction hypotension (PIH) is closely associated with postoperative adverse outcomes. Preoperative hypovolemia is a key risk factor, and many parameters are available from ultrasound to detect hypovolemia, but the accuracy of PIH from ultrasound remains unclear. This systematic review and meta-analysis aimed to evaluate the commonly used measurements from ultrasound to predict PIH. We searched the PubMed, Cochrane Library, Embase, CNKI, and Web of Science databases from their inception to December 2023. Thirty-six studies were included for quantitative analysis. The pooled sensitivities for the inferior vena cava collapsibility index (IVC-CI), maximum inferior vena cava diameter (DIVCmax), minimum inferior vena cava diameter (DIVCmin), and carotid artery corrected flow time (FTc) were 0.73 (95% CI = 0.65, 0.79), 0.66 (95% CI = 0.54, 0.77), 0.74 (95% CI = 0.60, 0.85), and 0.81 (95% CI = 0.72, 0.88). The pooled specificities for the IVC-CI, DIVCmax, DIVCmin, and carotid artery FTc were 0.82 (95% CI = 0.75, 0.87), 0.75 (95% CI = 0.66, 0.82), 0.76 (95% CI = 0.65, 0.84), and 0.87 (95% CI = 0.77, 0.93). The AUC for the IVC-CI, DIVCmax, DIVCmin, and carotid artery FTc were 0.84 (95% CI = 0.81, 0.87), 0.77 (95% CI = 0.73, 0.81), 0.82 (95% CI = 0.78, 0.85), and 0.91 (95% CI = 0.88, 0.93). Our study demonstrated that ultrasound indices are reliable predictors for PIH. The carotid artery FTc is probably the optimal ultrasound measurement for identifying patients who will develop PIH in our study.

Rice Origin Tracing Technology Based on Fluorescence Spectroscopy and Stoichiometry.

The origin of agricultural products is crucial to their quality and safety. This study explored the differences in chemical composition and structure of rice from different origins using fluorescence detection technology. These differences are mainly affected by climate, environment, geology and other factors. By identifying the fluorescence characteristic absorption peaks of the same rice seed varieties from different origins, and comparing them with known or standard samples, this study aims to authenticate rice, protect brands, and achieve traceability. The study selected the same variety of rice seed planted in different regions of Jilin Province in the same year as samples. Fluorescence spectroscopy was used to collect spectral data, which was preprocessed by normalization, smoothing, and wavelet transformation to remove noise, scattering, and burrs. The processed spectral data was used as input for the long short-term memory (LSTM) model. The study focused on the processing and analysis of rice spectra based on NZ-WT-processed data. To simplify the model, uninformative variable elimination (UVE) and successive projections algorithm (SPA) were used to screen the best wavelengths. These wavelengths were used as input for the support vector machine (SVM) prediction model to achieve efficient and accurate predictions. Within the fluorescence spectral range of 475-525 nm and 665-690 nm, absorption peaks of nicotinamide adenine dinucleotide (NADPH), riboflavin (B2), starch, and protein were observed. The origin tracing prediction model established using SVM exhibited stable performance with a classification accuracy of up to 99.5%.The experiment demonstrated that fluorescence spectroscopy technology has high discrimination accuracy in tracing the origin of rice, providing a new method for rapid identification of rice origin.

A DNA demethylase reduces seed size by decreasing the DNA methylation of AT-rich transposable elements in soybean.

Understanding how to increase soybean yield is crucial for global food security. The genetic and epigenetic factors influencing seed size, a major crop yield determinant, are not fully understood. We explore the role of DNA demethylase GmDMEa in soybean seed size. Our research indicates that GmDMEa negatively correlates with soybean seed size. Using CRISPR-Cas9, we edited GmDMEa in the Dongnong soybean cultivar, known for small seeds. Modified plants had larger seeds and greater yields without altering plant architecture or seed nutrition. GmDMEa preferentially demethylates AT-rich transposable elements, thus activating genes and transcription factors associated with the abscisic acid pathway, which typically decreases seed size. Chromosomal substitution lines confirm that these modifications are inheritable, suggesting a stable epigenetic method to boost seed size in future breeding. Our findings provide insights into epigenetic seed size control and suggest a strategy for improving crop yields through the epigenetic regulation of crucial genes. This work implies that targeted epigenetic modification has practical agricultural applications, potentially enhancing food production without compromising crop quality.

Epigenetic Age Mediates the Association of Life's Essential 8 With Cardiovascular Disease and Mortality.

BACKGROUND: Life's Essential 8 (LE8) is an enhanced metric for cardiovascular health. The interrelations among LE8, biomarkers of aging, and disease risks are unclear. METHODS AND RESULTS: LE8 score was calculated for 5682 Framingham Heart Study participants. We implemented 4 DNA methylation-based epigenetic age biomarkers, with older epigenetic age hypothesized to represent faster biological aging, and examined whether these biomarkers mediated the associations between the LE8 score and cardiovascular disease (CVD), CVD-specific mortality, and all-cause mortality. We found that a 1 SD increase in the LE8 score was associated with a 35% (95% CI, 27-41; P=1.8E-15) lower risk of incident CVD, a 36% (95% CI, 24-47; P=7E-7) lower risk of CVD-specific mortality, and a 29% (95% CI, 22-35; P=7E-15) lower risk of all-cause mortality. These associations were partly mediated by epigenetic age biomarkers, particularly the GrimAge and the DunedinPACE scores. The potential mediation effects by epigenetic age biomarkers tended to be more profound in participants with higher genetic risk for older epigenetic age, compared with those with lower genetic risk. For example, in participants with higher GrimAge polygenic scores (greater than median), the mean proportion of mediation was 39%, 39%, and 78% for the association of the LE8 score with incident CVD, CVD-specific mortality, and all-cause mortality, respectively. No significant mediation was observed in participants with lower GrimAge polygenic score. CONCLUSIONS: DNA methylation-based epigenetic age scores mediate the associations between the LE8 score and incident CVD, CVD-specific mortality, and all-cause mortality, particularly in individuals with higher genetic predisposition for older epigenetic age.

Transcriptomic sex differences in postmortem brain samples from patients with psychiatric disorders.

Many psychiatric disorders exhibit sex differences, but the underlying mechanisms remain poorly understood. We analyzed transcriptomics data from 2160 postmortem adult prefrontal cortex brain samples from the PsychENCODE consortium in a sex-stratified study design. We compared transcriptomics data of postmortem brain samples from patients with schizophrenia (SCZ), bipolar disorder (BD), and autism spectrum disorder (ASD) with transcriptomics data of postmortem control brains from individuals without a known history of psychiatric disease. We found that brain samples from females with SCZ, BD, and ASD showed a higher burden of transcriptomic dysfunction than did brain samples from males with these disorders. This observation was supported by the larger number of differentially expressed genes (DEGs) and a greater magnitude of gene expression changes observed in female versus male brain specimens. In addition, female patient brain samples showed greater overall connectivity dysfunction, defined by a higher proportion of gene coexpression modules with connectivity changes and higher connectivity burden, indicating a greater degree of gene coexpression variability. We identified several gene coexpression modules enriched in sex-biased DEGs and identified genes from a genome-wide association study that were involved in immune and synaptic functions across different brain cell types. We found a number of genes as hubs within these modules, including those encoding SCN2A, FGF14, and C3. Our results suggest that in the context of psychiatric diseases, males and females exhibit different degrees of transcriptomic dysfunction and implicate immune and synaptic-related pathways in these sex differences.

Inhalable spray-dried porous microparticles containing dehydroandrographolide succinate phospholipid complex capable of improving and prolonging pulmonary anti-inflammatory efficacy in mice.

Due to the unique physiological barriers within the lungs, there are considerable challenges in developing drug delivery systems enabling prolonged drug exposure to respiratory epithelial cells. Here, we report a PulmoSphere-based dry powder technology that incorporates a drug-phospholipid complex to promote intracellular retention of dehydroandrographolide succinate (DAS) in respiratory epithelial cells following pulmonary delivery. The DAS-phospholipid complex has the ability to self-assemble into nanoparticles. After spray-drying to produce PulmoSphere microparticles loaded with the drug-phospholipid complex, the rehydrated microparticles discharge the phospholipid complex without altering its physicochemical properties. The microparticles containing the DAS-phospholipid complex exhibit remarkable aerodynamic properties with a fine particle fraction of ∼ 60% and a mass median aerodynamic diameter of ∼ 2.3 µm. These properties facilitate deposition in the alveolar region. In vitro cell culture and lung tissue explants experiments reveal that the drug-phospholipid complex prolongs intracellular residence time and lung tissue retention due to the slow intracellular disassociation of drug from the complex. Once deposited in the lungs, the DAS-phospholipid complex loaded microparticles increase and extend drug exposure to the lung tissues and the immune cells compared to the free DAS counterpart. The improved drug exposure to airway epithelial cells, but not immune cells, is related to a prolonged duration of pulmonary anti-inflammation at decreased doses in a mouse model of acute lung injury induced by lipopolysaccharide. Overall, the phospholipid complex loaded microparticles present a promising approach for improved treatment of respiratory diseases, e.g. pneumonia and acute respiratory distress syndrome.

Peripheral blood stem cell harvesting in young children weighing less than 15 kg.

Autologous peripheral blood stem cell (PBSC) transplantation is crucial in pediatric cancer treatment, and tandem transplantation is beneficial in certain malignancies. Collecting PBSCs in small children with low body weight is challenging. We retrospectively analyzed data of pediatric cancer patients weighing <15 kg who underwent autologous PBSC harvesting in our hospital. Collections were performed in the pediatric intensive care unit over 2 or 3 consecutive days, to harvest sufficient stem cells (goal ≥2 × 106 CD34+ cells/kg per apheresate). From April 2006 to August 2021, we performed 129 collections after 50 mobilizations in 40 patients, with a median age of 1.9 (range, 0.6-5.6) years and a body weight of 11.0 (range, 6.6-14.7) kg. The median CD34+ cells in each apheresate were 4.2 (range, 0.01-40.13) × 106/kg. 78% and 56% of mobilizations achieved sufficient cell dose for single or tandem transplantation, respectively, without additional aliquoting. The preapheresis hematopoietic progenitor cell (HPC) count was highly correlated with the CD34+ cell yield in the apheresate (r = 0.555, P < 0.001). Granulocyte colony-stimulating factor alone was not effective for mobilization in children ≥2 years of age, even without radiation exposure. By combining the preapheresis HPC count ≥20/µL and the 3 significant host factors, including age <2 years, no radiation exposure and use of chemotherapy, the prediction rate of goal achievement was increased (area under the curve 0.787).

Evolution Characterization and Pathogenicity of an NADC34-like PRRSV Isolated from Inner Mongolia, China.

Porcine reproductive and respiratory syndrome virus (PRRSV) is a pathogen that causes severe abortions in sows and high piglet mortality, resulting in huge economic losses to the pig industry worldwide. The emerging and novel PRRSV isolates are clinically and biologically important, as there are likely recombination and pathogenic differences among PRRSV genomes. Furthermore, the NADC34-like strain has become a major epidemic strain in some parts of China, but the characterization and pathogenicity of the latest strain in Inner Mongolia have not been reported in detail. In this study, an NADC34-like strain (CHNMGKL1-2304) from Tongliao City, Inner Mongolia was successfully isolated and characterized, and confirmed the pathogenicity in pigs. The phylogenetic tree showed that this strain belonged to sublineage 1.5 and had high homology with the strain JS2021NADC34. There is no recombination between CHNMGKL1-2304 and any other domestic strains. Animal experiments show that the CHNMGKL1-2304 strain is moderately virulent to piglets, which show persistent fever, weight loss and high morbidity but no mortality. The presence of PRRSV nucleic acids was detected in both blood, tissues, nasal and fecal swabs. In addition, obvious pathological changes and positive signals were observed in lung, lymph node, liver and spleen tissues when subjected to hematoxylin-eosin (HE) staining and immunohistochemistry (IHC). This report can provide a basis for epidemiological investigations and subsequent studies of PRRSV.

Association analysis between an epigenetic risk score and blood pressure.

Background: Epigenome-wide association studies have revealed multiple DNA methylation sites (CpGs) associated with alcohol consumption, an important lifestyle risk factor for cardiovascular diseases. Results: We generated an alcohol consumption epigenetic risk score (ERS) based on previously reported 144 alcohol-associated CpGs and examined the association of the ERS with systolic blood pressure (SBP), diastolic blood pressure (DBP), and hypertension (HTN) in 3,898 Framingham Heart Study (FHS) participants. We found an association of alcohol intake with the ERS in the meta-analysis with 0.09 units higher ERS per drink consumed per day (p < 0.0001). Cross-sectional analyses in FHS revealed that a one-unit increment of the ERS was associated with 1.93 mm Hg higher SBP (p = 4.64E-07), 0.68 mm Hg higher DBP (p = 0.006), and an odds ratio of 1.78 for HTN (p < 2E-16). Meta-analysis of the cross-sectional association of the ERS with BP traits in eight independent external cohorts (n = 11,544) showed similar relationships with blood pressure levels, i.e., a one-unit increase in ERS was associated with 0.74 (p = 0.002) and 0.50 (p = 0.0006) mm Hg higher SBP and DBP, but could not confirm the association with hypertension. Longitudinal analyses in FHS (n = 3,260) and five independent external cohorts (n = 4,021) showed that the baseline ERS was not associated with a change in blood pressure over time or with incident HTN. Conclusions: Our findings provide proof-of-concept that utilizing an ERS is a useful approach to capture the recent health consequences of lifestyle behaviors such as alcohol consumption.

Evaluating performance and applications of sample-wise cell deconvolution methods on human brain transcriptomic data.

Sample-wise deconvolution methods estimate cell-type proportions and gene expressions in bulk tissue samples, yet their performance and biological applications remain unexplored, particularly in human brain transcriptomic data. Here, nine deconvolution methods were evaluated with sample-matched data from bulk tissue RNA sequencing (RNA-seq), single-cell/nuclei (sc/sn) RNA-seq, and immunohistochemistry. A total of 1,130,767 nuclei per cells from 149 adult postmortem brains and 72 organoid samples were used. The results showed the best performance of dtangle for estimating cell proportions and bMIND for estimating sample-wise cell-type gene expressions. For eight brain cell types, 25,273 cell-type eQTLs were identified with deconvoluted expressions (decon-eQTLs). The results showed that decon-eQTLs explained more schizophrenia GWAS heritability than bulk tissue or single-cell eQTLs did alone. Differential gene expressions associated with Alzheimer's disease, schizophrenia, and brain development were also examined using the deconvoluted data. Our findings, which were replicated in bulk tissue and single-cell data, provided insights into the biological applications of deconvoluted data in multiple brain disorders.

The c-Fos/AP-1 inhibitor inhibits sulfur mustard-induced chondrogenesis impairment in zebrafish larvae.

Sulfur mustard (SM, dichlorodiethyl sulfide) is a potent erosive chemical poison that can cause pulmonary lung, skin and eye disease complications in humans. Currently, there is no designated remedy for SM, and its operation's toxicological process remains unidentified. This work employed zebrafish as a model organism to investigate the toxic manifestations and mechanisms of exposure to SM, aiming to offer novel insights for preventing and treating this condition. The results showed that SM caused a decrease in the survival rate of the zebrafish larvae (LC50 = 2.47 mg/L), a reduction in the hatching rate, an increase in the pericardial area, and small head syndrome. However, T-5224 (a selective inhibitor of c-Fos/activator protein) attenuated the reduction in mortality (LC50 = 2.79 mg/L), the reduction in hatching rate, and the worsening of morphological changes. We discovered that SM causes cartilage developmental disorders in zebrafish larvae. The reverse transcription-quantitative polymerase chain reaction found that SM increased the expression of inflammation-related genes (IL-1ß, IL-6, and TNF-α) and significantly increased cartilage development-related gene expression (fosab, mmp9, and atf3). However, the expression of sox9a, sox9b, and Col2a1a was reduced. The protein level detection also found an increase in c-fos protein expression and a significant decrease in COL2A1 expression. However, T-5224,also and mitigated the changes in gene expression, and protein levels caused by SM exposure. The results of this study indicate that SM-induced cartilage development disorders are closely related to the c-Fos/AP-1 pathway in zebrafish.

Developmental isoform diversity in the human neocortex informs neuropsychiatric risk mechanisms.

RNA splicing is highly prevalent in the brain and has strong links to neuropsychiatric disorders; yet, the role of cell type-specific splicing and transcript-isoform diversity during human brain development has not been systematically investigated. In this work, we leveraged single-molecule long-read sequencing to deeply profile the full-length transcriptome of the germinal zone and cortical plate regions of the developing human neocortex at tissue and single-cell resolution. We identified 214,516 distinct isoforms, of which 72.6% were novel (not previously annotated in Gencode version 33), and uncovered a substantial contribution of transcript-isoform diversity-regulated by RNA binding proteins-in defining cellular identity in the developing neocortex. We leveraged this comprehensive isoform-centric gene annotation to reprioritize thousands of rare de novo risk variants and elucidate genetic risk mechanisms for neuropsychiatric disorders.