NASP gene contributes to autism by epigenetic dysregulation of neural and immune pathways.

BACKGROUND: Epigenetics makes substantial contribution to the aetiology of autism spectrum disorder (ASD) and may harbour a unique opportunity to prevent the development of ASD. We aimed to identify novel epigenetic genes involved in ASD aetiology. METHODS: Trio-based whole exome sequencing was conducted on ASD families. Genome editing technique was used to knock out the candidate causal gene in a relevant cell line. ATAC-seq, ChIP-seq and RNA-seq were performed to investigate the functional impact of knockout (KO) or mutation in the candidate gene. RESULTS: We identified a novel candidate gene NASP (nuclear autoantigenic sperm protein) for epigenetic dysregulation in ASD in a Chinese nuclear family including one proband with autism and comorbid atopic disease. The de novo likely gene disruptive variant tNASP(Q289X) subjects the expression of tNASP to nonsense-mediated decay. tNASP KO increases chromatin accessibility, promotes the active promoter state of genes enriched in synaptic signalling and leads to upregulated expression of genes in the neural signalling and immune signalling pathways. Compared with wild-type tNASP, tNASP(Q289X) enhances chromatin accessibility of the genes with enriched expression in the brain. RNA-seq revealed that genes involved in neural and immune signalling are affected by the tNASP mutation, consistent with the phenotypic impact and molecular effects of nasp-1 mutations in Caenorhabditis elegans. Two additional patients with ASD were found carrying deletion or deleterious mutation in the NASP gene. CONCLUSION: We identified novel epigenetic mechanisms mediated by tNASP which may contribute to the pathogenesis of ASD and its immune comorbidity.

Target genes regulated by CLEC16A intronic region associated with common variable immunodeficiency.

BACKGROUND: CLEC16A intron 19 has been identified as a candidate locus for common variable immunodeficiency (CVID). OBJECTIVES: This study sought to elucidate the molecular mechanism by which variants at the CLEC16A intronic locus may contribute to the pathogenesis of CVID. METHODS: The investigators performed fine-mapping of the CLEC16A locus in a CVID cohort, then deleted the candidate functional SNP in T-cell lines by the CRISPR-Cas9 technique and conducted RNA-sequencing to identify target gene(s). The interactions between the CLEC16A locus and its target genes were identified using circular chromosome conformation capture. The transcription factor complexes mediating the chromatin interactions were determined by proteomic approach. The molecular pathways regulated by the CLEC16A locus were examined by RNA-sequencing and reverse phase protein array. RESULTS: This study showed that the CLEC16A locus is an enhancer regulating expression of multiple target genes including a distant gene ATF7IP2 through chromatin interactions. Distinct transcription factor complexes mediate the chromatin interactions in an allele-specific manner. Disruption of the CLEC16A locus affects the AKT signaling pathway, as well as the molecular response of CD4+ T cells to immune stimulation. CONCLUSIONS: Through multiomics and targeted experimental approaches, this study elucidated the underlying target genes and signaling pathways involved in the genetic association of CLEC16A with CVID, and highlighted plausible molecular targets for developing novel therapeutics.

Revealing Novel Genomic Insights and Therapeutic Targets for Juvenile Idiopathic Arthritis through Omics.

BACKGROUND: The genetic architecture of juvenile idiopathic arthritis (JIA) remains only partially comprehended. There is a clear imperative for continued endeavors to uncover insights into the underlying causes of JIA. METHODS: This study encompassed a comprehensive spectrum of endeavors, including conducting a JIA GWAS meta-analysis that incorporated data from 4,550 JIA cases and 18 446 controls. We employed in silico and genome-editing approaches to prioritize target genes. To investigate pleiotropic effects, we conducted phenome-wide association studies. Cell-type enrichment analyses were performed by integrating bulk and single-cell sequencing data. Finally, we delved into potential druggable targets for JIA. RESULTS: Fourteen genome-wide significant non-HLA loci were identified including four novel loci, each exhibiting pleiotropic associations with other autoimmune diseases or musculoskeletal traits. We uncovered strong genetic correlation between JIA and bone mineral density (BMD) traits at 52 genomic regions, including three GWAS loci for JIA. Candidate genes with immune functions were captured by in silico analyses at each novel locus, with additional findings identified through our experimental approach. Cell-type enrichment analysis revealed 21 specific immune cell types crucial for affected organs in JIA, indicating their potential contribution to the disease. Finally, 24 known or candidate druggable target genes were prioritized. CONCLUSIONS: Our identification of four novel JIA associated genes, CD247, RHOH, COLEC10 and IRF8, broadens novel potential drug repositioning opportunities. We established a new genetic link between COLEC10, TNFRSF11B and JIA/BMD. Additionally, the identification of RHOH underscores its role in positive thymocyte selection, thereby illuminating a critical facet of JIA's underlying biological mechanisms.

White matter integrity of right frontostriatal circuit predicts internet addiction severity among internet gamers.

Excessive use of the internet, which is a typical scenario of self-control failure, could lead to potential consequences such as anxiety, depression, and diminished academic performance. However, the underlying neuropsychological mechanisms remain poorly understood. This study aims to investigate the structural basis of self-control and internet addiction. In a cohort of 96 internet gamers, we examined the relationships among grey matter volume and white matter integrity within the frontostriatal circuits and internet addiction severity, as well as self-control measures. The results showed a significant and negative correlation between dACC grey matter volume and internet addiction severity (p < 0.001), but not with self-control. Subsequent tractography from the dACC to the bilateral ventral striatum (VS) was conducted. The fractional anisotropy (FA) and radial diffusivity of dACC-right VS pathway was negatively (p = 0.011) and positively (p = 0.020) correlated with internet addiction severity, respectively, and the FA was also positively correlated with self-control (p = 0.036). These associations were not observed for the dACC-left VS pathway. Further mediation analysis demonstrated a significant complete mediation effect of self-control on the relationship between FA of the dACC-right VS pathway and internet addiction severity. Our findings suggest that the dACC-right VS pathway is a critical neural substrate for both internet addiction and self-control. Deficits in this pathway may lead to impaired self-regulation over internet usage, exacerbating the severity of internet addiction.

Knockdown the moyamoya disease susceptibility gene, RNF213, upregulates the expression of basic fibroblast growth factor and matrix metalloproteinase-9 in bone marrow derived mesenchymal stem cells.

Moyamoya disease (MMD) is a chronic, progressive cerebrovascular occlusive disease. Ring finger protein 213 (RNF213) is a susceptibility gene of MMD. Previous studies have shown that the expression levels of angiogenic factors increase in MMD patients, but the relationship between the susceptibility gene RNF213 and these angiogenic mediators is still unclear. The aim of the present study was to investigate the pathogenesis of MMD by examining the effect of RNF213 gene knockdown on the expression of matrix metalloproteinase-9 (MMP-9) and basic fibroblast growth factor (bFGF) in rat bone marrow-derived mesenchymal stem cells (rBMSCs). Firstly, 40 patients with MMD and 40 age-matched normal individuals (as the control group) were enrolled in the present study to detect the levels of MMP-9 and bFGF in serum by ELISA. Secondly, Sprague-Dawley male rat BMSCs were isolated and cultured using the whole bone marrow adhesion method, and subsequent phenotypic analysis was performed by flow cytometry. Alizarin red and oil red O staining methods were used to identify osteogenic and adipogenic differentiation, respectively. Finally, third generation rBMSCs were transfected with lentivirus recombinant plasmid to knockout expression of the RNF213 gene. After successful transfection was confirmed by reverse transcription-quantitative PCR and fluorescence imaging, the expression levels of bFGF and MMP-9 mRNA in rBMSCs and the levels of bFGF and MMP-9 protein in the supernatant of the culture medium were detected on the 7th and 14th days after transfection. There was no significant difference in the relative expression level of bFGF among the three groups on the 7th day. For the relative expression level of MMP-9, there were significant differences on the 7th day and 14th day. In addition, there was no statistically significant difference in the expression of bFGF in the supernatant of the RNF213 shRNA group culture medium, while there was a significant difference in the expression level of MMP-9. The knockdown of the RNF213 gene affects the expression of bFGF and MMP-9. However, further studies are needed to determine how they participate in the pathogenesis of MMD. The findings of the present study provide a theoretical basis for clarifying the pathogenesis and clinical treatment of MMD.

Mental Health and Quality of Life in Chronic Kidney Disease Patients with Mild-to-Moderate Depression: A Retrospective Cohort Study of Mindfulness-Based Stress Reduction Therapy.

BACKGROUND: Chronic kidney disease (CKD) patients may experience pessimism, and even despair, due to long-term nature of the condition, which increases the risk of depression. Mindfulness-based stress reduction (MBSR) can relieve depression. This retrospective cohort study aimed to investigate the effects of MBSR on mental health and quality of life in CKD patients with mild-to-moderate depression, so as to provide guidance for clinical nursing programs. METHODS: The clinical data of 100 CKD patients with mild-to-moderate depression who were treated in Jiading District Central Hospital Affiliated Shanghai University of Medicine & Health Sciences from January 2021 to March 2023 were retrospectively analyzed. Based on nursing method received, the patients were divided into the conventional group (conventional management) and the MBSR group (MBSR therapy was implemented in addition to conventional management). After matching, there were 35 cases in each group. The scores for the self-rating depression scale (SDS), Connor-Davidson Resilience Scale (CD-RISC), Five-factor Mindfulness Questionnaire (FFMQ), Pittsburgh Sleep Quality Index (PSQI), and 36-item Short Form Health Survey (SF-36) were compared between the two groups. RESULTS: After management, the SDS and PSQI scores of the MBSR group were lower than those of the conventional group, and the CD-RISC, FFMQ and SF-36 scores were higher than those of the conventional group (p < 0.05). CONCLUSION: MBSR can improve the mental health, sleep quality, and quality of life of CKD patients with mild-to-moderate depression, and improve psychological resilience and mindfulness.

Application value of CT radiomic nomogram in predicting T790M mutation of lung adenocarcinoma.

BACKGROUND: The purpose of this study was to develop a radiomic nomogram to predict T790M mutation of lung adenocarcinoma base on non-enhanced CT lung images. METHODS: This retrospective study reviewed demographic data and lung CT images of 215 lung adenocarcinoma patients with T790M gene test results. 215 patients (including 52 positive) were divided into a training set (n = 150, 36 positive) and an independent test set (n = 65, 16 positive). Multivariate logistic regression was used to select demographic data and CT semantic features to build clinical model. We extracted quantitative features from the volume of interest (VOI) of the lesion, and developed the radiomic model with different feature selection algorithms and classifiers. The models were trained by a 5-fold cross validation strategy on the training set and assessed on the test set. ROC was used to estimate the performance of the clinical model, radiomic model, and merged nomogram. RESULTS: Three demographic features (gender, smoking, emphysema) and ten radiomic features (Kruskal-Wallis as selection algorithm, LASSO Logistic Regression as classifier) were determined to build the models. The AUC of the clinical model, radiomic model, and nomogram in the test set were 0.742(95%CI, 0.619-0.843), 0.810(95%CI, 0.696-0.907), 0.841(95%CI, 0.743-0.938), respectively. The predictive efficacy of the nomogram was better than the clinical model (p = 0.042). The nomogram predicted T790M mutation with cutoff value was 0.69 and the score was above 130. CONCLUSION: The nomogram developed in this study is a non-invasive, convenient, and economical method for predicting T790M mutation of lung adenocarcinoma, which has a good prospect for clinical application.

Clinical value of O-RADS combined with serum CA125 and HE4 for the diagnosis of ovarian tumours.

BACKGROUND: Ovarian tumors (OTs) are common gynecological tumors in women. It is very important to correctly distinguish benign and malignant OTs. PURPOSE: To assess the diagnostic performance of the American College of Radiology (ACR) Ovarian-Adnexal Reporting and Data System (O-RADS) and evaluate the clinical value of O-RADS combined with serum carbohydrate antigen 125 (CA125) and human epididymis protein 4 (HE4) in differentiating benign from malignant OTs. MATERIAL AND METHODS: A retrospective analysis was performed on 431 cases including pathology and clinical data. The receiver operating characteristic (ROC) curve was drawn, and sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were calculated. RESULTS: In premenopausal women, O-RADS and O-RADS combined with serum CA125 and HE4 showed sensitivity at 92.2% and 94.8%, specificity at 91.8% and 93.4%, and accuracy at 91.9% and 93.8%, respectively. In postmenopausal women, the sensitivity of O-RADS, O-RADS combined with serum CA125 and HE4 was 94.8% and 95.8%, specificity was 83.9% and 93.6%, and accuracy was 90.5% and 95.6%, respectively. The sensitivity, specificity, and accuracy of O-RADS combined with CA125 and HE4 in premenopausal and postmenopausal women were higher than that of O-RADS (P<0.05). CONCLUSION: O-RADS has high diagnostic performance in OTs. When O-RADS is combined with CA125 and HE4 in the diagnosis of OTs, the sensitivity and specificity are improved, which is helpful to improve the diagnostic efficiency of OTs and has high clinical application value.

Orai3 mediates Orai channel remodelling to activate fibroblast in pulmonary fibrosis.

Orai family are a calcium channel of cell membrane extracellular Ca2+ influx which participates in tissue fibrosis. But the roles of Orai3 have less attention on the mechanism of regulating lung fibrosis. In this study, we found that Orai3 expression was increased significantly in BLM-induced lung fibrosis. The knockdown of Orai3 decreased TGF-ß1-induced fibroblast proliferation, ECM production, activation of NFAT1 and Calpain/ERK signal pathway and glycolysis levels. Orai3 interacting with Orai1 was increased in BLM-induced lung fibrosis and TGF-ß1-induced fibroblast, while the Stim1 interacting with Orai1 and SOCE activity was suppressed, leading in a high and stable extracellular Ca2+ influx. Furthermore, the over-expression of Orai3 did not enhance Orai3 interacting with Orai1 under TGF-ß1 free fibroblast. And then, the deeper mechanism of TGF-ß1-induced increased SEPTIN4 promoted Orai3 interacting with Orai1. Our results indicated that Orai3 could be one of the therapy targets for PF in which remodels Orai channel, suppresses SOCE activity and activated fibroblast to alleviate fibrosis progress.

Poly ADP-ribose polymerase-1 promotes seed-setting rate by facilitating gametophyte development and meiosis in rice (Oryza sativa L.).

Poly(ADP-ribose) polymerases (PARPs), which transfer either monomer or polymer of ADP-ribose from nicotinamide adenine dinucleotide (NAD+ ) onto target proteins, are required for multiple processes in DNA damage repair, cell cycle, development, and abiotic stress in animals and plants. Here, the uncharacterized rice (Oryza sativa) OsPARP1, which has been predicted to have two alternative OsPARP1 mRNA splicing variants, OsPARP1.1 and OsPARP1.2, was investigated. However, bimolecular fluorescence complementation showed that only OsPARP1.1 interacted with OsPARP3 paralog, suggesting that OsPARP1.1 is a functional protein in rice. OsPARP1 was preferentially expressed in the stamen primordial and pollen grain of mature stamen during flower development. The osparp1 mutant and CRISPR plants were delayed in germination, indicating that defective DNA repair machinery impairs early seed germination. The mutant displayed a normal phenotype during vegetative growth but had a lower seed-setting rate than wild-type plants under normal conditions. Chromosome bridges and DNA fragmentations were detected in male meiocytes at anaphase I to prophase II. After meiosis II, malformed tetrads or tetrads with micronuclei were formed. Meanwhile, the abnormality was also found in embryo sac development. Collectively, these results suggest that OsPARP1 plays an important role in mediating response to DNA damage and gametophyte development, crucial for rice yield in the natural environment.

A Highly Selective Hg2+ Fluorescent Chemosensor Based On Photochromic Diarylethene With Quinoline Unit.

A novel diarylethene-based fluorescent chemosensor containing a quinoline unit (1o) had been designed and synthesized. 1o showed good photochromic ability and fluorescence switching properties by alternating UV/vis light irradiation. The chemosensor showed high "Turn-off" fluorescent selectivity for Hg2+ by competitive tests of the fluorescence reaction in the presence other ions in acetonitrile solution. The stoichiometry between the compound 1o and Hg2+ was 1:1 by Job's plot curve and HRMS analysis. In addition, the LOD for Hg2+ was calculated as 60 nM. The fluorescence emission can be back to the "Turn-on" state by adding EDTA. Based on these facts, a molecular logic gate that including four input signals (UV/vis and Hg2+/EDTA) and one output signal (fluorescent intensity at 491 nm) was designed.

USMRI Features and Clinical Data-Based Model for Predicting the Degree of Placenta Accreta Spectrum Disorders and Developing Prediction Models.

Aim: This study aimed to investigate the ability of ultrasound/magnetic resonance imaging (MRI) signature and clinical data-based model for preoperatively predicting the degree of placenta accreta spectrum disorders and develop combined prediction models. Methods: The clinicopathological characteristics, prenatal ultrasound images, and MRI features of 132 pregnant women with placenta accreta spectrum disorders at Xiangyang No. 1 People's Hospital were retrospectively reviewed from January 2016 to December 2020. In the training set of 99 patients, the ultrasound/MRI features model, clinical characteristics model, and combined model were developed by multivariate logistic regression analysis to predict the degree of placenta accreta spectrum disorders. The prediction performance of different models was compared using the Delong test. The developed models were validated by assessing their prediction performance in a test set of 33 patients. Results: The multivariate logistic regression analysis identified history of abortion, history of endometrial injury, and blurred boundary between the placenta and the myometrium/between the uterine serosa and the bladder to construct a combined model for predicting the degree of placenta accreta spectrum disorders (area under the curve (AUC) = 0.931; 95% confidence interval (CI): 0.882-0.980). The AUC of the clinical characteristics model and ultrasound/MRI features model was 0.858 (95% CI 0.794-0.921) and 0.709 (95% CI 0.624-0.798), respectively. The AUC of the combined model was significantly higher than that of the ultrasound/MRI features model (P < 0.001) or clinical characteristics model (P < 0.0015) in the training set. In the test set, the combined model also showed higher prediction performance. Conclusions: Ultrasound/MRI-based signature is a powerful predictor for the degree of placenta accreta spectrum disorders in an early stage. A combined model (constructed with history of abortion, history of endometrial injury, and blurred boundary between the placenta and the myometrium/between the uterine serosa and the bladder) can improve the accuracy for predicting the degree of placenta accreta spectrum disorders in an early stage.

Clinical and Imaging Data-Based Model for Predicting Reversible Posterior Leukoencephalopathy Syndrome (RPLS) in Pregnant Women With Severe Preeclampsia or Eclampsia and Analysis of Perinatal Outcomes.

Objective: This study aimed to investigate the risk factors of reversible posterior leukoencephalopathy syndrome (RPLS) in pregnant women with severe preeclampsia or eclampsia (SPE/E) based on a predicting model and to analyze the perinatal outcomes. Methods: From January 2015 to March 2020, 78 pregnant women data diagnosed with severe preeclampsia or eclampsia with cranial magnetic resonance imaging (MRI) and transcranial Doppler (TCD) screening in Xiangyang No. 1 People's Hospital and Jiangsu Province Hospital of Chinese Medicine were analyzed retrospectively. They were divided into the RPLS group (n = 33) and non-RPLS group (n = 45) based on the MRI results. The general clinical data (blood pressure, BMI, symptoms, and so forth), laboratory examination, TCD results, and perinatal outcomes in the two groups were compared. The risk factors of severe preeclampsia or eclampsia complicated with RPLS were analyzed by multivariate logistic regression. The prediction model and decision curve (DCA) were established according to the clinical-imaging data. Results: The univariate analysis showed that poor placental perfusion, hypertension emergency, use of two or more oral antihypertensive drugs, headache, white blood cell (WBC) count, platelet (PLT) count, lactate dehydrogenase (LDH), alanine aminotransferase (ALT), uric acid (UA), serum albumin (ALB), average flow velocity, and resistance index of the posterior cerebral and basilar arteries were significantly different in the RPLS group compared with the non-RPLS group (all P < 0.05). The multivariate logistic regression analysis showed that hypertensive emergency, headache, WBC, PLT, ALT, and average flow velocity of the basilar artery (BAAFV) were the risk factors in the RPLS group. The aforementioned clinical-imaging data modeling (general data model, laboratory examination model, TCD model, and combined model) showed that the combined model predicted RPLS better. DCA also confirmed that the net benefit of the combined model was higher. In addition, the incidence of postpartum hemorrhage, stillbirth, and preterm infants was higher in the RPLS group than in the non-RPLS group (all P < 0.05). Conclusions: More postpartum complications were detected in pregnant women with severe preeclampsia or eclampsia complicated with RPLS. Hypertensive emergency, headache, WBC, PLT, ALT, and BAAFV were the important risk factors for RPLS. The combined model had a better effect in predicting RPLS.

Clinical outcomes observation in stage IIB-IIIB cervical cancer treated by adjuvant surgery following concurrent chemoradiotherapy.

BACKGROUND: To explore the feasibility of adjuvant surgery following concurrent chemoradiation therapy (CCRT) in stage IIB-IIIB (according to FIGO staging of 2009) cervical cancer and analyze risk factors of recurrence after surgery. METHODS: Forty-nine patients diagnosed with stage IIB-IIIB cervical cancer were reviewed retrospectively. We investigated the risk factors of recurrence after surgery using Chi-squared Test and further analyzed multiple factors affecting postoperative recurrence using the multi-factor logistic regression. Furthermore, the correlation of surgery outcomes (including operation time, bleeding, and hospitalization date and surgery complications) with the time which carried out between CCRT and completion surgery was analyzed. RESULTS: Tumor histology and residual tumor in the cervix were significantly associated with postoperative recurrence (P = 0.014 and P = 0.040, respectively). Logistic regression analysis demonstrated that the independent risk factors of postoperative recurrence were age and residual tumor in the cervix (P = 0.017 and P = 0.030, respectively). Complications (operation time, bleeding, hospitalization date) were compared between patients with an interval with radiotherapy less than 6 weeks and patients with an interval longer than 6 weeks. There were statistical differences in the amount of bleeding and postoperative complications between the two groups (P = 0.019 and P = 0.044, respectively). CONCLUSION: CCRT combined with surgery for stage IIB-IIIB cervical cancer was feasible, reduced the rate of postoperative recurrence and surgery complications were tolerated.

A Novel Diarylethene-rhodamine Unit Based Chemosensor for Fluorimetric and Colorimetric Detection of Hg2.

A novel fluorimetric and colorimetric chemosensor (1O) was synthesized with diarylethene-rhodamine unit and characterized by ESI-MS, 1H NMR, and 13C NMR. The chemosensor can selectively recognize extremely low concentrations of Hg2+ over a variety of metal ions with remarkable colorimetric and fluorescent responses. The colorimetric and fluorescent changes were ascribed the reaction between 1O and Hg2+ destructed the rhodamine hydrazide into open-ring form which was proved by mass spectrometry and nuclear magnetic titration analyses. The detection limits of the UV absorption and fluorescence methods for Hg2+ were found to be 0.708 µM and 24.6 nM, respectively. Moreover, the chemosensor exhibited excellent photochromism and outstanding fatigue resistance property under alternating UV and visible light irradiation. The application potential of the chemosensor was demonstrated with the qualitative detection of Hg2+ in real water samples.

A novel two-dimensional beryllium diphosphide (BeP2) with superconductivity: the first-principles exploration.

In this study, three stable two-dimensional beryllium diphosphide (2D-BeP2) structures with the wrinkle and planar monolayers, namely MoS2-like 6[combining macron]m-BeP2 phase (1H-BeP2), pentagonal 4[combining macron]2m-BeP2 (Penta-BeP2) and planar mm2-BeP2 (Planar-BeP2), have been successfully predicted through the first-principles calculation combined with a global structure search method. The structural stabilities, mechanical properties, electron properties and superconductivities are also systematically investigated. Results indicated that the 2D MoS2-like 1H-BeP2 showed higher stability than the Penta- and Planar-BeP2 structures. The 1H-BeP2 structure possessed an intrinsic metallic characteristics with the bands crossing the Fermi level. Notably, the Penta-BeP2 is a typical semiconductor, and the planar-BeP2 is semi-metal with Dirac corn. Based on the calculation results of the electron properties, phonon properties and electron-phonon coupling (EPC), the layer 1H-BeP2 sheet is a phonon-mediated superconductor with a critical temperature (Tc) of about 1.32 K.

Template-Free Self-Assembly of Two-Dimensional Polymers into Nano/Microstructured Materials.

In the past few decades, enormous efforts have been made to synthesize covalent polymer nano/microstructured materials with specific morphologies, due to the relationship between their structures and functions. Up to now, the formation of most of these structures often requires either templates or preorganization in order to construct a specific structure before, and then the subsequent removal of previous templates to form a desired structure, on account of the lack of "self-error-correcting" properties of reversible interactions in polymers. The above processes are time-consuming and tedious. A template-free, self-assembled strategy as a "bottom-up" route to fabricate well-defined nano/microstructures remains a challenge. Herein, we introduce the recent progress in template-free, self-assembled nano/microstructures formed by covalent two-dimensional (2D) polymers, such as polymer capsules, polymer films, polymer tubes and polymer rings.

Lactobacillus plantarum FRT10 alleviated high-fat diet-induced obesity in mice through regulating the PPARα signal pathway and gut microbiota.

Previous studies showed that probiotics supplementation contributed to alleviate obesity. This work was to assess the efficacy of Lactobacillus plantarum FRT10 from sour dough in alleviating obesity in mice fed with a high-fat diet (HFD), and the underlying mechanisms focusing on modulation of the gut microbiota profile. Kunming mice were fed with a regular diet (CT), a high-fat diet (HFD), and two HFDs containing low and high doses of L. plantarum FRT10 for 8 weeks. The physiological and biochemical modulations in liver were analyzed. Cecal contents were analyzed by high-throughput 16S ribosomal RNA sequencing. FRT10 supplementation significantly reduced body weight gain, fat weight, and liver triacylglycerols (TGs) and alanine aminotransferase (ALT) concentrations (P < 0.05). FRT10 significantly ameliorated the HFD-induced gut dysbiosis, as evidenced by increased abundance of microbes, including Butyricicoccus, Butyricimonas, Intestinimonas, Odoribacter, and Alistipes, and decreased abundance of Desulfovibrionaceae, Roseburia, and Lachnoclostridium. Lactobacillus, Bifidobacterium, and Akkermansia were markedly increased after FRT10 intervention. In addition, real-time quantitative PCR revealed that FRT10 upregulated the mRNA expression levels of peroxisome proliferator-activated receptor-α (PPARα) and carnitine palmitoyltransferase-1α (CPT1α), and downregulated the mRNA expression levels of sterol regulatory element-binding protein 1 (SREBP-1) and TG-synthesizing enzyme diacylglycerol acyltransferase 1 (DGAT1) in liver. These findings suggested that FRT10 had anti-obesity effects in obese mice partly related to the activation of PPARα/CPT1α pathway. FRT10 can be considered a single probiotic agent for preventing HFD-induced obesity in humans and animals.

Computational Design and Study of Artificial Selenoenzyme with Controllable Activity Based on an Allosteric Protein Scaffold.

The establishment of new enzymatic function in an existing scaffold is a great challenge for protein engineers. In previous work, a highly efficient artificial selenoenzyme with controllable activity was constructed, based on a Ca2+ -responsive recoverin (Rn) protein. In this study, a design strategy combining docking, molecular dynamics, and MM-PBSA is presented, to predict the catalytically active site of glutathione peroxidase (GPx) on the allosteric domain of Rn. The energy contributions of the binding hot spot residues are evaluated further by energy decomposition analysis to determine the detailed substrate recognition mechanism of Rn, which provides clear guidance for artificial enzyme design for improved substrate binding (Michaelis-Menten constant, Km ).

ISL1 loss-of-function mutation contributes to congenital heart defects.

Congenital heart defect (CHD) is the most common form of birth deformity and is responsible for substantial morbidity and mortality in humans. Increasing evidence has convincingly demonstrated that genetic defects play a pivotal role in the pathogenesis of CHD. However, CHD is a genetically heterogeneous disorder and the genetic basis underpinning CHD in the vast majority of cases remains elusive. This study was sought to identify the pathogenic mutation in the ISL1 gene contributing to CHD. A cohort of 210 unrelated patients with CHD and a total of 256 unrelated healthy individuals used as controls were registered. The coding exons and splicing boundaries of ISL1 were sequenced in all study subjects. The functional effect of an identified ISL1 mutation was evaluated using a dual-luciferase reporter assay system. A novel heterozygous ISL1 mutation, c.409G > T or p.E137X, was identified in an index patient with congenital patent ductus arteriosus and ventricular septal defect. Analysis of the proband's pedigree revealed that the mutation co-segregated with CHD, which was transmitted in the family in an autosomal dominant pattern with complete penetrance. The nonsense mutation was absent in 512 control chromosomes. Functional analysis unveiled that the mutant ISL1 protein failed to transactivate the promoter of MEF2C, alone or in synergy with TBX20. This study firstly implicates ISL1 loss-of-function mutation with CHD in humans, which provides novel insight into the molecular mechanism of CHD, implying potential implications for genetic counseling and individually tailored treatment of CHD patients.