Search

Background and Hypothesis Viral infections are increasingly recognized in the etiology of psychiatric disorders based on epidemiological and serological studies. Few studies have analyzed viruses directly within the brain and no comprehensive investigation of viral infection within diseased brains has been completed. This study aims to determine whether viral infection in brain tissues is a risk factor for 3 major psychiatric disorders, including schizophrenia, bipolar disorder, and autism spectrum disorder. Study Design This study directly evaluated the presence of viral DNA or RNA in 1569 brains of patients and controls using whole-genome sequencing and RNA sequencing data with 4 independent cohorts. The PathSeq tool was used to identify known human viruses in the genome and transcriptome of patients and controls. Study Results A variety of DNA and RNA viruses related to the central nervous system were detected in the brains of patients with major psychiatric disorders, including viruses belonging to Herpesviridae, Polyomaviridae, Retroviridae, Flaviviridae, Parvoviridae, and Adenoviridae. However, no consistent significant differences were found between patients and controls in terms of types and amount of virus detected at both DNA and RNA levels. Conclusions The findings of this study do not suggest an association between viral infection in postmortem brains and major psychiatric disorders.

An active noise control (ANC) system generates an anti-noise wave to reduce the noise level at a control point, where the error microphone is conventionally placed. Virtual sensing techniques are developed for situations when the error microphone cannot be permanently placed at the control point. The remote microphone (RM) method is one of the most straightforward virtual sensing methods. Previous studies have demonstrated that the performance of the RM method is influenced by the causality between the physical and virtual error microphones, which can be resolved by introducing a delayed version of the virtual error signal. So far, the RM method has mainly been examined with the filtered reference least mean squares (FxLMS) algorithm. This paper applies the RM method in the filtered error least mean squares (FeLMS) algorithm. The FeLMS algorithm introduces an adjoint filter to reduce the computational complexity of the ANC system. The delay incurred by the adjoint filter is just right to implement the delayed virtual error signal of the RM method.

Passivation of organic iodides without annealing induces the formation of iodine interstitial (Ii) defects. The cations of organic iodides with appropriate structures can suppress Ii migration, leading to a device efficiency of 24.20% and enhanced operational stability.

Rabies is a viral disease that is nearly 100% fatal once clinical signs and symptoms develop. Post-exposure prophylaxis can efficiently prevent rabies, and antibody (Ab) induction by vaccination or passive immunization of human rabies immunoglobulin (HRIG) or monoclonal antibodies (mAbs) play an integral role in prevention against rabies. In addition to their capacity to neutralize viruses, antibodies exert their antiviral effects by antibody-dependent cellular cytotoxicity (ADCC), which plays an important role in antiviral immunity and clearance of viral infections. For antibodies against rabies virus (RABV), evaluation of ADCC activity was neglected. Here, we developed a robust cell-based reporter gene assay (RGA) for the determination of the ADCC activity of anti-RABV antibodies using CVS-N2c-293 cells, which stably express the glycoprotein (G) of RABV strain CVS-N2c as target cells, and Jurkat cells, which stably express FcγRⅢa and nuclear factor of activated T cells (NFAT) reporter gene as effector cells (Jurkat/NFAT-luc/FcγRⅢa cells). The experimental parameters were carefully optimized, and the established ADCC assay was systematically validated according to the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Q2 guideline. We also evaluated the ADCC activity of anti-RABV antibodies, including mAbs, HRIG, and vaccine induced antisera, and found that all test antibodies exhibited ADCC activity with varied strengths. The established RGA provides a novel method for evaluating the ADCC of anti-RABV antibodies.

Although distinctive neural and physiological states are suggested to underlie the six basic emotions, basic emotions are often indistinguishable from functional magnetic resonance imaging (fMRI) voxelwise activation (VA) patterns. Here, we hypothesize that functional connectivity (FC) patterns across brain regions may contain emotion-representation information beyond VA patterns. We collected whole-brain fMRI data while human participants viewed pictures of faces expressing one of the six basic emotions (i.e., anger, disgust, fear, happiness, sadness, and surprise) or showing neutral expressions. We obtained FC patterns for each emotion across brain regions over the whole brain and applied multivariate pattern decoding to decode emotions in the FC pattern representation space. Our results showed that the whole-brain FC patterns successfully classified not only the six basic emotions from neutral expressions but also each basic emotion from other emotions. An emotion-representation network for each basic emotion that spanned beyond the classical brain regions for emotion processing was identified. Finally, we demonstrated that within the same brain regions, FC-based decoding consistently performed better than VA-based decoding. Taken together, our findings revealed that FC patterns contained emotional information and advocated for paying further attention to the contribution of FCs to emotion processing.

Background: The availability of whole-genome sequencing data in large studies has enabled the assessment of coding and noncoding variants across the allele frequency spectrum for their associations with blood pressure. Methods: We conducted a multiancestry whole-genome sequencing analysis of blood pressure among 51 456 Trans-Omics for Precision Medicine and Centers for Common Disease Genomics program participants (stage-1). Stage-2 analyses leveraged array data from UK Biobank (N=383 145), Million Veteran Program (N=318 891), and Reasons for Geographic and Racial Differences in Stroke (N=10 643) participants, along with whole-exome sequencing data from UK Biobank (N=199 631) participants. Results: Two blood pressure signals achieved genome-wide significance in meta-analyses of stage-1 and stage-2 single variant findings ( P -8 ). Among them, a rare intergenic variant at novel locus, LOC100506274 , was associated with lower systolic blood pressure in stage-1 (beta [SE]=−32.6 [6.0]; P =4.99×10 -8 ) but not stage-2 analysis ( P =0.11). Furthermore, a novel common variant at the known INSR locus was suggestively associated with diastolic blood pressure in stage-1 (beta [SE]=−0.36 [0.07]; P =4.18×10 -7 ) and attained genome-wide significance in stage-2 (beta [SE]=−0.29 [0.03]; P =7.28×10 -23 ). Nineteen additional signals suggestively associated with blood pressure in meta-analysis of single and aggregate rare variant findings ( P -6 and P -4 , respectively). Discussion: We report one promising but unconfirmed rare variant for blood pressure and, more importantly, contribute insights for future blood pressure sequencing studies. Our findings suggest promise of aggregate analyses to complement single variant analysis strategies and the need for larger, diverse samples, and family studies to enable robust rare variant identification.

Hereditary neurological disorders (HNDs) are a clinically and genetically heterogeneous group of disorders. These disorders arise from the impaired function of the central or peripheral nervous system due to aberrant electrical impulses. More than 600 various neurological disorders, exhibiting a wide spectrum of overlapping clinical presentations depending on the organ(s) involved, have been documented. Owing to this clinical heterogeneity, diagnosing these disorders has been a challenge for both clinicians and geneticists and a large number of patients are either misdiagnosed or remain entirely undiagnosed. Contribution of genetics to neurological disorders has been recognized since long; however, the complete picture of the underlying molecular bases are under-explored. The aim of this study was to accurately diagnose 11 unrelated Pakistani families with various HNDs deploying NGS as a first step approach. Using exome sequencing and gene panel sequencing, we successfully identified disease-causing genomic variants these families. We report four novel variants, one each in, ECEL1, NALCN, TBR1 and PIGP in four of the pedigrees. In the rest of the seven families, we found five previously reported pathogenic variants in POGZ, FA2H, PLA2G6 and CYP27A1. Of these, three families segregate a homozygous 18 bp in-frame deletion of FA2H, indicating a likely founder mutation segregating in Pakistani population. Genotyping for this mutation can help low-cost population wide screening in the corresponding regions of the country. Our findings not only expand the existing repertoire of mutational spectrum underlying neurological disorders but will also help in genetic testing of individuals with HNDs in other populations.

Overcoming thermal quenching is an essential issue in the practical application of luminescent materials. Herein, we found that negative thermal expansion (NTE) can achieve the thermal enhancement of luminescence in molecular materials based on three metal-organic frameworks CuX-bpy (X = Cl, Br, I; bpy = 4,4'-bipyridine). All complexes exhibit NTE on the

Matched energy level alignment and minimal non-radiative recombination at the buried perovskite/charge transport material interface are essential for efficient electron transfer and highly-efficient perovskite solar cells (PSCs). Herein, we develop a facile and feasible method by inserting Cesium(I) Bis(trifluoromethanesulfonyl)imide (CsTFSI) interlayer to fabricate high performance PSCs with negligible hysteresis. With CsTFSI modification, tin oxide displays less trap density, improved electrical conductivity and better energy level alignment with perovskite, leading to a considerable increase in power conversion efficiency (PCE). Consequently, the champion target device presents a PCE of 22.05%, much higher than that of the control device (19.93%). Our work provides an effective and simple strategy for the modification of perovskite buried interface to obtain highly efficient PSCs.

Hypertension is the leading cause of overall mortality in low- and middle-income countries. In Brazil, there is paucity of data on the determinants of incident hypertension and related risk factors. We aimed to determine the incidence of hypertension in a sample from the Brazilian population and investigate possible relationships with body adiposity indexes. We assessed risk factors associated with cardiovascular disease, including adiposity body indexes and biochemical analysis, in a sample from the Baependi Heart Study before and after a 10-year follow-up. Hypertension was defined by the presence of systolic blood pressure (SBP) ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg or the use of antihypertensive drugs. From an initial sample of 1693 participants, 498 (56% women; mean age 38 ± 13 years) were eligible to be included. The overall hypertension incidence was 24.3% (22.3% in men and 25.6% in women). Persons who developed hypertension had higher prevalence of obesity, higher levels for blood pressure, higher frequency of dyslipidemia, and higher body adiposity indexes at baseline. The best prediction model for incident hypertension includes age, sex, HDL-c, SBP, and Body Mass Index (BMI) [AUC = 0.823, OR = 1.58 (95% CI 1.23-2.04)]. BMI was superior in its predictive capacity when compared to Body Adiposity Index (BAI), Body Roundness Index (BRI), and Visceral Adiposity Index (VAI). Incident hypertension in a sample from the Brazilian population was 24.3% after 10-year follow-up and BMI, albeit the simpler index to be calculated, is the best anthropometric index to predict incident hypertension.

Metabolic syndrome (MetS) is significantly correlated with urolithiasis. However, few studies have evaluated the severity of urolithiasis. This study aimed to investigate the relationship of MetS with severe urolithiasis disease (SUD). The data of 910 patients with urolithiasis in the Department of Urology, Second Hospital of Tianjin Medical University from June 2020 to May 2021 were retrospectively collected. The patients were divided into two groups according to the severity of urolithiasis, and the relationships of MetS and its components with SUD were evaluated. The results showed 605 SUD and 272 Mets patients. Multiple regression analysis showed that middle age, male gender, and MetS increased the risk of SUD, whereas serum magnesium decreased it (P 0.05). Further analysis revealed that the odds ratio (OR) of SUD increased with MetS grade (0-4) (1.029-2.117). Grade 4 patients had a 2.1-fold higher risk of SUD than grade 0 patients (OR 2.117; 95% CI 1.053-4.256; P = 0.035); hypertension and dyslipidemia were most strongly associated with SUD among the four MetS features (P 0.05). Additionally, calcium oxalate was the most predominant stone component (78.7%) in the SUD(+) group, which also had stones with higher uric acid and lower calcium oxalate dihydrate levels than those of the SUD(-) group (P 0.05). Our study concluded that SUD is more common in middle-aged men, MetS is an independent risk factor for SUD. The more severe the MetS, the higher the risk of SUD, in which hypertension and dyslipidemia play major roles.

In order to explore the research on library book information resource management, the author proposes a method based on artificial intelligence and sensors. Using an improved SVM algorithm, in order to realize the personalized data mining of the library, the support vector machine algorithm has supervised, scalable, and nonlinear high-efficiency characteristics in the use process, able to achieve nonlinear multicore data clustering effect, thereby improving the learning ability of data mining. The experimental results show the following: BP neural network was used to adaptively train the processed data samples, users give certain positive feedback during use, the sensor system is based on the result of feedback, continuous self-learning was carried out, sample data were updated and optimized, and a closed virtuous circle has been realized. In the classification experiment of Sogou Chinese text corpus data set, the classification effect of several classification models in the “sports” category is significantly higher than that of other categories; it shows that the text classification characteristics of the “sports” category are more significant. Among them, KNN ( K -Nearest Neighbor) has a classification accuracy of 99.7% in the “sports” category; this shows that some classification algorithms, in a specific category, can achieve its best classification performance. Prove the method based on artificial intelligence; it can better realize library book information resource management.

Psychological stress can increase the risk of a wide range of negative health outcomes. Studies have been completed to determine if DNA methylation changes occur in the human brain because of stress and are associated with long-term effects and disease, but results have been inconsistent. Human candidate gene studies (150) and epigenome-wide association studies (67) were systematically evaluated to assess how DNA methylation is impacted by stress during the prenatal period, early childhood and adulthood. The association between DNA methylation of NR3C1 exon 1F and child maltreatment and early life adversity was well demonstrated, but other genes did not exhibit a clear association. The reproducibility of individual CpG sites in epigenome-wide association studies was also poor. However, biological pathways, including stress response, brain development and immunity, have been consistently identified across different stressors throughout the life span. Future studies would benefit from the increased sample size, longitudinal design, standardized methodology, optimal quality control, and improved statistical procedures.

Von Hippel-Lindau (VHL) genes are intimately involved in renal cell carcinoma (RCC), including clear cell RCC (ccRCC) pathogenesis. However, the contribution of pathogenic VHL mutations to ccRCC remains poorly understood. We report a xanthoderm with non-obstructive azoospermia (NOA)-associated cystic ccRCC, and the missense VHL mutation (c.262T > C, p.Try88Arg). In a 34-year-old patient, a urologic physical examination identified hard epididymis, and imaging tests revealed deferens-associated NOA, as well as multi-organ hydatid cysts, including bilateral epididymal cysts, bilateral testicular cysts, bilateral renal cysts, and pancreatic cysts. Five years later, ccRCC was developed based on clinical and radiologic evidence. Two different prediction models of protein structure and multiple sequence alignment across species were applied to assess the pathological effects of the VHL mutation. The reliability of the assessment in silico was determined by both the cellular location and protein levels of the mutant products, using IF and Western blot, respectively. Our study shows that the missense VHL mutation (c.262T > C, p.Try88Arg) plays a deleterious role in pVHL functions, as predicted by multiple sequence alignment across species. While a structural analysis identified no significant structural alterations in pVHL, the detrimental effects of this mutation were determined by exogenous expression, evidenced by a markedly different spatial distribution and reduced expression of mutant pVHL. This is the first report of the VHL gene mutation (c.475T > C, p.Try88Arg) in a xanthoderm.

By the popularization of Internet, and mobile terminals, there are more and more activities that are helpful for rehabilitation training. Among them, software products represented by sports pedometers have attracted much attention. Based on mastering one’s own physical condition, one can carry out effective social activities, such as brisk walking, running, etc., to improve people’s communication, thereby enriching people’s leisure activities, and thus achieving the purpose of rehabilitation. Therefore, this paper proposes the design, and implementation of basic course teaching system for sports rehabilitation based on the Android platform. This paper mainly analyzed the health system of Android platform. Researchers have thoroughly researched Motor Imagery (MI) rehabilitation training, and their algorithm has been analyzed. An experiment on its efficacy was also conducted in the experimental part, along with a system modeling exercise. The final experimental results showed that the success rate of motor imagery direction control in G1 group was 59.88%, 58.89%, and 59.22%, and the G2 group was 64.22%, 63.33%, and 64.11%. The results showed that G2 using feedback information had a significantly higher success rate of action imagery than G1 that did not provide the feedback information under different test modes. Therefore, feedback information in motor fantasy training can improve motor fantasy effect.

Rheumatoid arthritis (RA) is a risk factor for atherosclerotic cardiovascular diseases (CVD). Given the critical roles of the immune system and inflammatory signals in the pathogenesis of CVD, we hypothesized that interrogation of CVD-related proteins using integrative genomics might provide new insights into the pathophysiology of RA. We utilized two-sample Mendelian randomization (MR) for causal inference between circulating protein levels and RA by incorporating genetic variants, followed by colocalization to characterize the causal associations. Genetic variants from three sources were obtained: those associated with 71 CVD-related proteins measured in nearly 7000 Framingham Heart Study participants, a published genome-wide association study (GWAS) of RA (19 234 cases, 61 565 controls), and GWAS of rheumatoid factor (RF) levels from the UK Biobank (n = 30 565). We identified the soluble receptor for advanced glycation end products (sRAGE), a critical inflammatory pathway protein, as putatively causal and protective for both RA (odds ratio per 1-standard deviation increment in inverse-rank normalized sRAGE level = 0.364; 95% confidence interval 0.342–0.385; P = 6.40 × 10–241) and RF levels (β [change in RF level per sRAGE increment] = − 1.318; SE = 0.434; P = 0.002). Using an integrative genomic approach, we highlight the AGER/RAGE axis as a putatively causal and promising therapeutic target for RA.

Purpose To evaluate the Metabolic syndrome(MetS) in patients with unilateral and bilateral staghorn calculus(SC) and compare the impact on the outcome of percutaneous nephrolithotomy(PCNL).Methods The patients who underwent PCNL for the treatment of SC were retrospectively reviewed between 2019–2022. SC were divided into unilateral and bilateral. The variables of the patients were calculated to evaluate the MetS difference between unilateral and bilateral SC and the impact on the outcome of PCNL.Results 1778 patients were received PCNL between 2019 and 2022, After screening computed tomography, A total of 379 patients with staghorn calculus, patients without follow-up and incomplete data were excluded, finaly 310 patients with SC were included. 84 with bilateral SC and 226 with unilateral. More higher body mass index, complete staghorn and metabolic syndrome were found in the patients with bilateral SC. Higher body mass index, hypertension, diabetes mellitus, hyperlipidemia, MetS were 62.58%, 44.84%, 21.94%, 60.65% and 27.42% in patients. 85 patients with MetS(+) resulted in higher rate of overall complication(Number(N)(%), 29(38.10) VS 54(23.89), p = 0.013) and comparable stone free rate with 225 MetS(-). Multivariable analysis confirmed that hyperlipidemia(p = 0.044, odds ratio[OR] = 1.991, 95% confidence interval[CI] 1.020–3.888) and MetS ( p = 0.005, OR = 2.427, 95%CI 1.316–4.477) were independent risk factors for overall complication.Conclusions MetS are strongly correlated with the formation of bilateral SC and is the core predictor in assessing overall complication for PCNL.

Identifying genes whose expression is associated with schizophrenia (SCZ) risk by transcriptome-wide association studies (TWAS) facilitates downstream experimental studies. Here, we integrated multiple published datasets of TWAS (including FUSION, PrediXcan, summary-data-based Mendelian randomization (SMR), joint-tissue imputation approach with Mendelian randomization (MR-JTI)), gene coexpression, and differential gene expression analysis to prioritize SCZ candidate genes for functional study. Convergent evidence prioritized Propionyl-CoA Carboxylase Subunit Beta (PCCB), a nuclear-encoded mitochondrial gene, as an SCZ risk gene. However, the PCCB’s contribution to SCZ risk has not been investigated before. Using dual luciferase reporter assay, we identified that SCZ-associated SNP rs35874192, an eQTL SNP for PCCB, showed differential allelic effects on transcriptional activities. PCCB knockdown in human forebrain organoids (hFOs) followed by RNA-seq revealed dysregulation of genes enriched with multiple neuronal functions including gamma-aminobutyric acid (GABA)-ergic synapse, as well as genes dysregulated in postmortem brains of SCZ patients or in cerebral organoids derived from SCZ patients. The metabolomic and mitochondrial function analyses confirmed the deceased GABA levels resulted from reduced tricarboxylic acid cycle in PCCB knockdown hFOs. Multielectrode array recording analysis showed that PCCB knockdown in hFOs resulted into SCZ-related phenotypes including hyper-neuroactivities and decreased synchronization of neural network. In summary, this study utilized hFOs-based multi-omics data and revealed that PCCB downregulation may contribute to SCZ risk through regulating GABAergic system, highlighting the mitochondrial function in SCZ.

Human brain development is under tight molecular genetic control and the recent advent of single-cell genomics has revolutionized our ability to elucidate the diverse underlying cell-types and states. Although RNA splicing is highly prevalent in the brain and has strong links to neuropsychiatric disorders, previous work has not systematically investigated the role of cell-type-specific splicing or transcript-isoform diversity during human brain development. Here, we leverage single molecule long-read sequencing to deeply profile the full-length transcriptome of the germinal zone (GZ) and cortical plate (CP) regions of the developing human neocortex at tissue and single-cell resolution. We identify 214,516 unique isoforms, corresponding to 22,391 genes. Remarkably, we find that 72.6% of these are novel and together with >7,000 novel-spliced exons expands the proteome by 92,422 proteoforms. We uncover myriad novel isoform switches during cortical neurogenesis, implicating previously-uncharacterized RNA-binding protein-mediated and other regulatory mechanisms in cellular identity and disease. Early-stage excitatory neurons exhibit the greatest isoform diversity and isoform-based single-cell clustering identifies previously uncharacterized cell states. Leveraging this resource, we re-prioritize thousands of rarede novorisk variants associated with neurodevelopmental disorders (NDDs) and reveal that risk genes are strongly associated with the number of unique isoforms observed per gene. Altogether, this work uncovers a substantial contribution of transcript-isoform diversity in cellular identity in the developing neocortex, elucidates novel genetic risk mechanisms for neurodevelopmental and neuropsychiatric disorders, and provides a comprehensive isoform-centric gene annotation for the developing human brain.One-Sentence SummaryA novel cell-specific atlas of gene isoform expression reshapes our understanding of brain development and disease.

Purpose To compare the outcomes of standard-percutaneous nephrolithotomy combined ultrasonic lithotripsy system(s-PCNL+ULS) and mini-percutaneous nephrolithotomy combined high-power holmium laser(m-PCNL+hHL) for the treatment of staghorn calculus. Methods The data of patients who underwent PCNL for the treatment of staghorn calculus were retrospectively reviewed between 2019 and 2022 from the second hospital of Tianjin medical university. The nephrostomy tracts were dilatated to 24 F in standard PCNL and 16-18 F in mini PCNL, standard PCNL combined ultrasonic lithotripsy system and mini PCNL combined high-power holmium laser. The preoperative, intraoperative, and postoperative variables of the patients were calculated to evaluate the efficacy and reliability of the two groups. Results 1778 patients were received PCNL between 2019 and 2022, After screening computed tomography, finaly 310 patients with staghorn calculus were included. 98 underwent s-PCNL+ULS and 212 underwent m-PCNL+hHL. The total operative time (min) ,haemoglobin deficit (ΔHGB (g/L)) ,the postoperative hospitalization days for s-PCNL+ULS and m-PCNL+hHL groups were 76.07±26.68 vs 103.93±24.84(P＜0.001), 9.30±9.26 VS 7.73±7.50(P=0.017); 7.32±5.14 VS 4.71±2.42(P＜0.001). The incidence complications for s-PCNL+ULS and m-PCNL+hHL groups were 28.57% vs 16.04%(P = 0.064), s-PCNL+ULS group had more severity complications (9.18% vs 2.83%, P = 0.022) . The firist and second stone-free rates of PCNL were 56.12% VS 57.08%(P=0.902) and 92.86% VS 86.32%(P=0.126) for the m-PCNL+hHL and s-PCNL+ULS groups. Conclusion The efficacy of m-PCNL+hHL was comparable to s-PCNL+ULS in the treatment of staghorn calculus. The advantages of m-PCNL+hHL included the lower haemoglobin deficit, shorter hospital stay and lesser severity complications.

Male infertility is common and complex, presenting a wide range of heterogeneous phenotypes. Although about 50% of cases are estimated to have a genetic component, the underlying cause often remains undetermined. Here, from whole-exome sequencing on samples from 168 infertile men with asthenoteratozoospermia due to severe sperm flagellum, we identified homozygousZMYND12variants in four unrelated patients. In sperm cells from these individuals, immunofluorescence revealed altered localization of DNAH1, DNALI1, WDR66 and TTC29. Axonemal localization of ZMYND12 ortholog TbTAX-1 was confirmed using theTrypanosoma bruceimodel. RNAi knock-down of TbTAX-1 dramatically affected flagellar motility, with a phenotype similar to ZMYND12-variant-bearing human sperm. Co-immunoprecipitation and ultrastructure expansion microscopy inT. bruceirevealed TbTAX-1 to form a complex with TTC29. Comparative proteomics with samples fromTrypanosomaandTtc29KO mice identified a third member of this complex: DNAH1. The data presented revealed that ZMYND12 is part of the same axonemal complex as TTC29 and DNAH1, which is critical for flagellum function and assembly in humans, and Trypanosoma. ZMYND12 is thus a new asthenoteratozoospermia-associated gene, bi-allelic variants of which cause severe flagellum malformations and primary male infertility.

Background To quantitatively investigate corneal changes and the correlation between corneal densitometry (CD) and endothelial parameters after phacovitrectomy. Methods Thirty-eight eyes with idiopathic full-thickness macular holes (iFTMHs) and cataracts underwent phacovitrectomy. Examinations were conducted at baseline and Day 1, Day 7, Month 1, and Month 3 postoperatively. CD and central corneal thickness (CCT) were measured using Pentacam. Corneal endothelial cell density (ECD), coefficient of variation (CV), and hexagonality (HEX) were measured using specular microscopy. Results ECD and HEX significantly decreased after surgery and the change in HEX occurred prior to CV. CCT increased immediately after surgery and recovered 3 months postoperatively. CD values increased significantly 1 day after surgery and then gradually decreased. For CD in the 0–2 mm zone, it took 1 month to recover in the central and posterior layers and 3 months in the anterior and total layers. For CD in the 2–6 mm zone, the central layer recovered at Day 7, the anterior and total layers recovered at 1 month, and the posterior layer did not recover until 3 months postoperatively. The CD within all layers in the 0–2 mm zone was positively correlated with CCT. Posterior CD in the 0–2 mm zone was negatively correlated with ECD and HEX. Conclusions CD is not only correlated with CCT, ECD, and HEX but also reflects the state of the whole cornea and each layer. CD can be an objective, rapid, and noninvasive tool that reflects corneal health and undetectable edema and monitors the process of lesion repair. Trial registration This study was registered with the Chinese Clinical Trial Registry (31/10/2021, ChiCTR2100052554).

Recurrent proximal 16p11.2 deletion (16p11.2del) is a risk factor for diverse neurodevelopmental disorders with incomplete penetrance and variable expressivity. Although investigation with human induced pluripotent stem cell models has confirmed disruption of neuronal development in 16p11.2del neuronal cells, which genes are responsible for abnormal cellular phenotypes and what determines the penetrance of neurodevelopmental abnormalities are unknown. We performed haplotype phasing of the 16p11.2 region in a 16p11.2del neurodevelopmental disorders cohort and generated human induced pluripotent stem cells for two 16p11.2del families with distinct residual haplotypes and variable neurodevelopmental disorder phenotypes. Using transcriptomic profiles and cellular phenotypes of the human induced pluripotent stem cell-differentiated cortex neuronal cells, we revealed MAPK3 to be a contributor to dysfunction in multiple pathways related to early neuronal development, with altered soma and electrophysiological properties in mature neuronal cells. Notably, MAPK3 expression in 16p11.2del neuronal cells varied on the basis of a 132 kb 58 single nucleotide polymorphism (SNP) residual haplotype, with the version composed entirely of minor alleles associated with reduced MAPK3 expression. Ten SNPs on the residual haplotype were mapped to enhancers of MAPK3. We functionally validated six of these SNPs by luciferase assay, implicating them in the residual haplotype-specific differences in MAPK3 expression via cis-regulation. Finally, the analysis of three different cohorts of 16p11.2del subjects showed that this minor residual haplotype is associated with neurodevelopmental disorder phenotypes in 16p11.2del carriers. TOC summary Liu et al. provide a molecular explanation for the variable penetrance of the neurodevelopmental disorder phenotype in 16p11.2 deletion syndrome, by characterizing residual haplotype-specific transcriptomic profiles and neuronal phenotypes.

BackgroundAs a common type of asthenoteratozoospermia, multiple morphological abnormalities of the sperm flagella (MMAF) can cause male infertility. Previous studies have revealed genetic factors as a major cause of MMAF. The known MMAF-associated genes are involved in the mitochondrial sheath, outer dense fibre or axoneme of the sperm flagella. These findings indicate the genetic heterogeneity of MMAF.Methods and resultsHere, we conducted genetic analyses using whole-exome sequencing in a cohort of 150 Han Chinese men with asthenoteratozoospermia. Homozygous deleterious variants ofAKAP3(A-kinase anchoring protein 3) were identified in two MMAF-affected men from unrelated families. OneAKAP3variant was a frameshift (c.2286_2287del, p.His762Glnfs*22) and the other variant was a missense mutation (c.44G>A, p.Cys15Tyr), which was predicted to be damaging by multiple bioinformatics tools. Further western blotting and immunofluorescence assays revealed the absence of AKAP3 in the spermatozoa from the man harbouring the homozygous frameshift variant, whereas the expression of AKAP3 was markedly reduced in the spermatozoa of the man with theAKAP3missense variant p.Cys15Tyr. Notably, the clinical outcomes after intracytoplasmic sperm injection (ICSI) were divergent between these two cases, suggesting a possibility of AKAP3 dosage-dependent prognosis of ICSI treatment.ConclusionsOur study revealedAKAP3as a novel gene involved in human asthenoteratozoospermia.

Purpose Breast cancer is increasing around the globe, including Asia. We aimed to examine the survival and risk of contralateral breast cancer (CBC) in Asian breast cancer patients with BRCA mutations. MethodsA total of 128 breast cancer patients with germline BRCA mutations and 4,754 control breast cancer patients were enrolled. Data on clinical pathologic characteristics, survival and CBC were collected from the medical record. The rates of survival and CBC were estimated by Kaplan-Meier method. Results The mean age of onset in BRCA mutation carriers was significantly younger than control patients (BRCA vs. Non-BRCA: 43.9 vs. 53.2 years-old). BRCA mutation carriers had a higher proportion of triple-negative breast cancer (TNBC) (52%) than control patients (12%, pBRCA mutation patients than in control cases (hazard ratio (HR) = 3.95, 95% CI 2.71-5.75); when stratified by genotype, the HRs (95%CI) were 4.84 (3.00-7.82) for BRCA1 and 3.13 (1.78-5.49) for BRCA2 carriers, respectively. Moreover, BRCA1 mutation patients with triple-negative breast cancer (TNBC) as their first breast cancer had the highest risk of CBC (HR = 5.55, 95% CI 3.29-9.34). However, we did not observe any differences in relapse-free survival and overall survival between mutation carriers and control patients. ConclusionOur study suggest that BRCA patients had a significantly higher risk of developing CBC, particularly for BRCA1 mutation carriers with TNBC as the first breast cancer.

Fluorescent hydrazone-linked COFs and their aerogel composites applied in acid vapor sensing and Fe3+ sensing.

Mathematical ability is moderately heritable, and it is a complex trait which can be evaluated in several different categories. A few genetic studies have been published on general mathematical ability. However, no genetic study focused on specific mathematical ability categories. In this study, we separately performed genome-wide association studies (GWASs) on 11 mathematical ability categories in 1 146 students from Chinese elementary schools. We identified 7 genome-wide significant single nucleotide polymorphisms (SNPs) with strong linkage disequilibrium (LD) among each other (all r2>0.8) associated with mathematical reasoning ability (top SNP: rs34034296,p=2.01×10−8, nearest gene: CUB and Sushi multiple domains 3, CSMD3). We replicated one SNP (rs133885) from 585 SNPs previously reported to be associated with general mathematical ability associated with division ability in our data (p=1.053×10−5). In the gene- and gene-set enrichment analysis by MAGMA, we found three significant enrichments of associations with three mathematical ability categories for three genes. We also observed four significant enrichments of associations with four mathematical ability categories for three gene sets. Our results suggest new candidate genetic loci for the genetics of mathematical ability.