Transcriptome-wide transmission disequilibrium analysis identifies novel risk genes for autism spectrum disorder.

Recent advances in consortium-scale genome-wide association studies (GWAS) have highlighted the involvement of common genetic variants in autism spectrum disorder (ASD), but our understanding of their etiologic roles, especially the interplay with rare variants, is incomplete. In this work, we introduce an analytical framework to quantify the transmission disequilibrium of genetically regulated gene expression from parents to offspring. We applied this framework to conduct a transcriptome-wide association study (TWAS) on 7,805 ASD proband-parent trios, and replicated our findings using 35,740 independent samples. We identified 31 associations at the transcriptome-wide significance level. In particular, we identified POU3F2 (p = 2.1E-7), a transcription factor mainly expressed in developmental brain. Gene targets regulated by POU3F2 showed a 2.7-fold enrichment for known ASD genes (p = 2.0E-5) and a 2.7-fold enrichment for loss-of-function de novo mutations in ASD probands (p = 7.1E-5). These results provide a novel connection between rare and common variants, whereby ASD genes affected by very rare mutations are regulated by an unlinked transcription factor affected by common genetic variations.

[Clinical and gene mutation features of cystic fibrosis: an analysis of 8 cases]. / 8ä¾‹å›Šæ€§çº¤ç»´åŒ–æ‚£å„¿ä¸´åºŠåŠåŸºå› çªå˜åˆ†æž.

OBJECTIVES: To study the clinical features and gene mutation sites of children with cystic fibrosis (CF), in order to improve the understanding of CF to reduce misdiagnosis and missed diagnosis. METHODS: A retrospective analysis was performed on the medical records of 8 children with CF who were diagnosed in Hebei Children's Hospital from 2018 to 2021. RESULTS: Among the 8 children with CF, there were 5 boys and 3 girls, with an age of 3-48 months (median 8 months) at diagnosis, and the age of onset ranged from 0 to 24 months (median 2.5 months). Clinical manifestations included recurrent respiratory infection in 7 children, sinusitis in 3 children, bronchiectasis in 4 children, diarrhea in 8 children, fatty diarrhea in 3 children, suspected pancreatic insufficiency in 6 children, pancreatic cystic fibrosis in 1 child, malnutrition in 5 children, and pseudo-Bartter syndrome in 4 children. The most common respiratory pathogens were Pseudomonas aeruginosa (4 children). A total of 16 mutation sites were identified by high-throughput sequencing, multiplex ligation-dependent probe amplification, and Sanger sequencing, including 5 frameshift mutations, 4 nonsense mutations, 4 missense mutations, 2 exon deletions, and 1 splice mutation. CFTR mutations were found in all 8 children. p.G970D was the most common mutation (3 children), and F508del mutation was observed in one child. Four novel mutations were noted: deletion exon15, c.3796_3797dupGA(p.I1267Kfs*12), c.2328dupA(p.V777Sfs*2), and c.2950G>A(p.D984N). CONCLUSIONS: p.G970D is the most common mutation type in children with CF. CF should be considered for children who have recurrent respiratory infection or test positive for Pseudomonas aeruginosa, with or without digestive manifestations or pseudo-Bartter syndrome.

Nanobodies targeting the interaction interface of programmed death receptor 1 (PD-1)/PD-1 ligand 1 (PD-1/PD-L1).

Targeting the interaction interface is an effective strategy to obtain programmed death receptor 1 (PD-1)/PD-1 ligand 1 (PD-L1) nanobody blockers. To validate this strategy, the interaction interface between PD-1 and the PD-L1 extracellular domain were analyzed using Cn3D 4.1. The peptide PD-1125-136 located at the interface of PD-1 was selected as the antigen to screen nanobodies from a humanized nanobody phage display library. Six different nanobodies were screened, with molecular weights of 12 ∼ 13 kDa, excluding a single basic protein. The nanobody with the longest CDR3 region, termed PD-1-Nb-B20, was selected for further analysis. For mass production, the C-terminal His6-tagged nanobody coding sequence was optimized and cloned into pET-21b for over-expression under the T7 promoter in Escherichia coli BL21 (DE3). PD-1-Nb-B20 was expressed and pancreatic adenocarcinoma cells BxPC-3 over-expressing PD-L1 were selected for nanobody competitive inhibition assays. The purified nanobodies significantly inhibited PD-1 binding to the surface of target cells, indicating their ability to block the PD-1/PD-L1 interaction.

Effect of physical interactions on structure of lysozyme in presence of three kinds of polysaccharides.

In this work the influences of κ-carrageenan (CRG), konjac glucomannan (KGM) and inulin on lysozyme (Ly)'s structure, activity, and their complex phase behavior were investigated through spectroscopy and activity measurement in heated and unheated conditions. It was found that the impact on the structure and activity of Ly was determined by the interactions with polysaccharides. After heat treatment, KGM and CRG improved the stability of complex systems. However, inulin did not have significant impact. Heating process promoted to change the structure of Ly, and the intervention retard following the sequence of CRG > KGM > inulin. The worthwhile work indicated protein's structure and activity could be regulated by the interaction with polysaccharide, which might provide theoretical basis for food preservation and processing in different temperature treatments. Besides, the bidirectional effects of polysaccharide on protein would be beneficial to rational selection of functional properties of polysaccharide/protein systems.

[Efficacy of early treatment via fiber bronchoscope in children with Mycoplasma pneumoniae pneumonia complicated by airway mucus obstruction].

OBJECTIVE: To study the efficacy of early treatment via fiber bronchoscope in children with Mycoplasma pneumoniae pneumonia (MPP) complicated by airway mucus obstruction. METHODS: According to the time from admission to the treatment via fiber bronchoscope, the children with MPP who were found to have airway mucus obstruction under a fiber bronchoscope were randomly divided into early intervention group (≤3 days; n=40) and late intervention group (>3 days; n=56). The two groups were compared in terms of clinical data and imaging recovery.The children were followed for 1-3 months. RESULTS: Of the 96 children, 38 were found to have the formation of plastic bronchial tree, among whom 10 were in the early intervention group and 28 were in the late intervention group (P=0.01). Compared with the late intervention group, the early intervention group had a shorter duration of fever, length of hospital stay, and time to the recovery of white blood cell count and C-reactive protein (P<0.05), as well as a higher atelectasis resolution rate (P<0.05). Compared with the late intervention group, the early intervention group had a higher percentage of children with a ≥ 60% absorbed area of pulmonary consolidation at discharge. After 3 months of follow-up, the early intervention group had a higher percentage of children with a ≥ 90% absorbed area of pulmonary consolidation than the late intervention group (80% vs 55%; P=0.01), and the early intervention group had a lower incidence rate of atelectasis than the late intervention group (P<0.05). CONCLUSIONS: Early treatment via fiber bronchoscope can shorten the course of the disease and reduce complications and sequelae in MPP children with airway mucus obstruction.

Functional outcome in acute stroke patients with oropharyngeal Dysphagia after swallowing therapy.

Dysphagia after stroke is associated with mortality and increased pulmonary complications. Swallowing therapies may decrease pulmonary complications and improve patients' quality of life after stroke. This study used clinical swallowing assessments and videofluoroscopy (VFS) to assess the functional recovery of acute stroke patients with dysphagia after different swallowing therapies. We enrolled 29 acute stroke patients with dysphagia and randomly divided them into 3 therapy groups: traditional swallowing (TS), oropharyngeal neuromuscular electrical stimulation (NMES), and combined NMES/TS. All patients were assessed using the clinical functional oral intake scale (FOIS), 8-point penetration-aspiration scale (PAS), and functional dysphagia scale (FDS) of VFS before and after treatment. There were no differences in the clinical parameters and swallowing results of the FOIS and VFS before swallowing treatment among the 3 groups (P > .05). TS therapy and combined therapy both had significant swallowing improvement after therapy according to the FOIS and 8-point PAS (P < .05). When comparing the results of the VFS among the 3 groups, we found significant improvements in patients eating cookies and thick liquid after combined NMES/TS therapy (P < .05). In acute stroke patients with dysphagia, combined NMES/TS therapy is the most effective swallowing therapy in taking solid diets and thick liquids.

Inactivation of Heterosigma akashiwo under UV/peroxydisulfate advanced disinfection system in marine waters.

Heterosigma akashiwo (H. akashiwo) is recognized as a harmful algal bloom (HABs) species with a global distribution, capable of posing significant threats to marine ecosystems, particularly when spread through ship ballast water. This investigation focused on elucidating the inactivation kinetics and underlying mechanism of H. akashiwo through a combined ultraviolet irradiation and peroxydisulfate (UV/PDS) process. The results demonstrated a strong synergistic effect within the UV/PDS system, resulting in an inactivation of 0.78-ln and 2.67-ln within 40 min of UV and UV/PDS processes. The principal agents accountable for inactivation were identified as sulfate radicals (•SO4-) and hydroxyl radical (•OH), which exhibited a synergistic effect in the UV/PDS process. Furthermore, the study observed a negatively impact of seawater pH and salinity on the efficiency of inactivation. UV/PDS caused oxidative stress on algal cells, initially involving the participation of antioxidant enzymes in counteracting cellular damage, but this protective mechanism diminished as the reaction duration extended. The UV/PDS treatment not only inflicted damage upon H. akashiwo's photosynthetic system but also caused the extracellular release of DNA and algal organic matter (AOM) due to damaged cell membranes. Transcriptome analysis provided a molecular biology perspective on the cellular inactivation process. Upregulation of genes linked to photosynthesis and oxidative phosphorylation suggested a potential elevation in energy metabolism. In contrast, genes associated with cellular and metabolic processes, including glycolysis and the tricarboxylic acid cycle (TCA cycle), exhibited downregulation. Moreover, this treatment exerted an inhibitory influence on RNA polymerase and protein synthesis, resulting in the reduced expression of genetic information.

mTORC1-Induced Bone Marrow-Derived Mesenchymal Stem Cell Exhaustion Contributes to the Bone Abnormalities in Klotho-Deficient Mice of Premature Aging.

Stem cell exhaustion is a hallmark of aging. Klotho-deficient mice (kl/kl mice) is a murine model that mimics human aging with significant bone abnormalities. The aim of this study is using kl/kl mice to investigate the functional change of bone marrow-derived mesenchymal stem cells (BMSCs) and explore the underlying mechanism. We found that klotho deficiency leads to bone abnormalities. In addition, kl/kl BMSCs manifested hyperactive proliferation but functionally declined both in vivo and in vitro. Mammalian target of rapamycin complex 1 (mTORC1) activity was higher in freshly isolated kl/kl BMSCs, and autophagy in kl/kl BMSCs was significantly decreased, possibly through mTORC1 activation. Conditional medium containing soluble Klotho protein (sKL) rescued hyperproliferation of kl/kl BMSCs by inhibiting mTORC1 activity and restoring autophagy. Finally, intraperitoneal injection of mTORC1 inhibitor rapamycin restored BMSC quiescence, ameliorated bone phenotype, and increased life span of kl/kl mice in vivo. This research highlights a therapeutic strategy to maintain the homeostasis of adult stem cell pool for healthy bone aging.

Analysis of Risk Factors of Bronchiolitis Obliterans in Children with Mycoplasma pneumoniae Bronchiolitis.

OBJECTIVE: To investigate the related risk factors for bronchiolitis obliterans (BO) in children with mycoplasma pneumonia (MP) bronchiolitis. METHOD: The clinical data of 227 children with MP bronchiolitis who were admitted to the II Department of Respiratory of Children's Hospital of Hebei Province from January 2018 to June 2020 were retrospectively analyzed. According to the sequelae of BO, they were divided into 32 cases in the BO group and 195 cases in the non-BO group. The univariate analysis was performed on the clinical and laboratory parameters of the two groups, and the multifactor logistic regression was performed further to determine the independent risk factors for the occurrence of BO in MP bronchiolitis, and then, the cut-off value with the maximum diagnostic value of indicators was found through the ROC curve analysis. RESULTS: The results of univariate and multivariate logistic regression analysis showed that the independent risk factors for the occurrence of BO in MP bronchioles were longer duration of moist rales (OR = 1.203, P = 0.003), higher levels of serum lactate dehydrogenase (LDH) (OR = 1.005, P = 0.036), hypoxemia (OR = 7.442, P = 0.035), and pleural effusion (OR = 4.437, P = 0.004). The area under the ROC curve was 78.2%, 72.0%, 68.2%, and 71.0%, respectively (P < 0.001). The cut-off value of duration of moist rales and levels of serum LDH are 7.5 d and 330 U/L, respectively. CONCLUSION: Children with MP bronchiolitis with high serum LDH level (≥330 U/L), combined with hypoxemia, pleural effusion, and lung wet rale duration (≥7.5 d), may be more prone to BO, in which lung wet rale duration prediction value is the largest. Among them, duration of pulmonary moist rales has the highest predictive value.

Kinetics and mechanisms of flumequine degradation by sulfate radical based AOP in different water samples containing inorganic anions.

Many studies have reported that hydroxyl radical (HO˙) driven advanced oxidation processes (AOPs) could degrade fluoroquinolones (FQs) antibiotics effectively. Compared with HO˙, sulfate radical (SO4˙-) shows a similar oxidation capacity but a longer half-life. SO4˙- could cause chain reactions and resulted in the generation of halogen radicals and carbonate radicals from the main anions in sea water including Cl-, Br- and HCO3 -. However, few studies were focused on the degradation of FQs in marine aquaculture water and seawater, as well as the bioaccumulation of transformation products. As a typical member of FQs, flumequine (FLU) was degraded by UV/peroxodisulfate (PDS) AOPs in synthetic fresh water, marine aquaculture water and seawater. The reaction rate constants in the three water samples were 0.0348 min-1, 0.0179 min-1 and 0.0098 min-1, respectively. The reason was attributed to the inhibition of the anions as they could consume SO4˙- and initiate the quenching reaction of free radicals. When the pH value increased from 5 to 9, the reaction rate decreased from 0.0197 min-1 to 0.0066 min-1. The energy difference between HOMO and LUMO of FLU was calculated to be 8.07 eV indicating that FLU was a stable compound. The atoms on quinolone ring of FLU with high negative charge would be more vulnerable to attack by free radicals through electrophilic reactions. Two possible degradation pathways of FLU were inferred according to the degradation products. Preliminary bioaccumulation analysis of transformation products by the EPI suite software proved that the values of log K ow and log BCF of the final product P100 were less than those of FLU and the intermediates.

Inactivation of E. coli and Streptococcus agalactiae by UV/persulfate during marine aquaculture disinfection.

Sulfate radical (•SO4-)-based advanced oxidation processes have attracted a great deal of attention for use in water disinfection because of their strong oxidation ability toward electron-rich moieties on microorganism molecules. However, a few studies have focused on the effects of •SO4- on pathogenic microorganism inactivation in marine aquaculture water containing various inorganic anions. We employed the gram-negative bacteria E. coli and gram-positive bacteria S. agalactiae as representatives to evaluate the application of UV/persulfate (S2O82-, PDS), to the disinfection of marine aquaculture water in a comprehensive manner. Total inactivation of 4.13ˍlog of E. coli cells and 4.74ˍlog of S. agalactiae cells was reached within 120 s in the UV/PDS system. The inactivation of pathogenic bacteria in marine aquaculture water increased with the increasing PDS concentration and UV intensity. An acidic pH was beneficial for UV/PDS inactivation. Halogen-free radicals showed a strong influence on the inactivation. Anions in seawater, including Cl-, Br-, and HCO3- inhibited the disinfection. The inactivation rates of pathogenic bacteria followed the order seawater < marine aquaculture water < freshwater. Pathogenic bacteria could also be effectively inactivated in actual marine aquaculture water and reservoir water. The analysis of the inactivation mechanisms showed that S2O82- was activated by UV to produce •SO4-, which damaged the cell membranes. In addition, antioxidant enzymes, including SOD and CAT, were induced. The genomic DNA was also damaged. Inorganic disinfection byproducts such as chlorate and bromate were not formed during the disinfection of marine aquaculture water, which indicated that UV/PDS was a safe and efficient disinfection method.

Analysis of Clinical Manifestations, Imaging Features, and Gene Mutation Characteristics of 6 Children with Cystic Fibrosis in China.

OBJECTIVE: To explore the clinical manifestations, imaging features, and gene mutation characteristics of 6 children with cystic fibrosis (CF) so as to improve the understanding and diagnosis awareness of CF in children and reduce the missed diagnosis and misdiagnosis. METHODS: The clinical manifestations, imaging, and gene mutation data of six children with CF were collected and retrospectively analyzed. RESULTS: Among the 6 cases of CF, there were 4 males and 2 females. Among the 6 children with CF, 5 cases presented with recurrent respiratory tract infection. Etiology suggested 3 cases of Pseudomonas aeruginosa and 2 cases of Staphylococcus aureus. 3 cases had pancreatic exocrine dysfunction, manifested as diarrhea and aliphatic diarrhea, of which 1 case had high lipase in blood examination, and pancreatic ultrasound showed rough and enhanced pancreatic echo, considering pancreatic cystic fibrosis. 2 cases of CF combined with pseudo-Bartter syndrome (PBS); 1 case involved only the biliary tract and started with cholestasis without other systemic involvement. In 2 cases of sweat test, sweat chloride ions were all >60 mmol/L. 3 cases underwent fiberoptic bronchoscopy, and a large number of sticky secretions were visible under the bronchoscopy. CT of the chest revealed thickening of the bronchial wall (3 cases), bronchiectasis (1 case), atelectasis (1 case), and thin bronchial lumen (2 cases). 1 patient was found to have small airway lesions and mosaic perfusion during follow-up. All 6 children with CF underwent genetic testing. A total of 12 CF transmembrane conductance regulator (CFTR) gene mutations were found, of which 4 mutations were not reported in the literature. CONCLUSION: CF is a disease caused by CFTR mutation. The incidence of this disease in China is low, and the clinical manifestations have great differences. The main symptoms are respiratory symptoms. Some children have gastrointestinal symptoms and/or PBS, and some children only show a single systemic lesion.

SUPERGNOVA: local genetic correlation analysis reveals heterogeneous etiologic sharing of complex traits.

Local genetic correlation quantifies the genetic similarity of complex traits in specific genomic regions. However, accurate estimation of local genetic correlation remains challenging, due to linkage disequilibrium in local genomic regions and sample overlap across studies. We introduce SUPERGNOVA, a statistical framework to estimate local genetic correlations using summary statistics from genome-wide association studies. We demonstrate that SUPERGNOVA outperforms existing methods through simulations and analyses of 30 complex traits. In particular, we show that the positive yet paradoxical genetic correlation between autism spectrum disorder and cognitive performance could be explained by two etiologically distinct genetic signatures with bidirectional local genetic correlations.

Interfacial and emulsion stabilized behavior of lysozyme/xanthan gum nanoparticles.

Interfacial adsorption kinetics and stabilizing emulsion behavior of lysozyme/xanthan gum nanoparticles (Ly/XG NPs) by variation of particle size and energy input. The interfacial rheology indicated that interfacial adsorption behavior of Ly/XG NPs displayed in a particle size manner. Increasing the particle size of Ly/XG NPs hindered its initial diffusion onto the interface. Smaller size was helpful for its fast diffusion to the interface. KP (rate constant of penetration) and KR (rate constant of penetration) of Ly/XG NPs were both affected by particle size. The KP for adsorbed Ly/XG NPs increased as the particle sizes increased. KR was considerably higher than KP, indicating the structural rearrangement of adsorbed Ly/XG NPs played an important part in interfacial film formation. The morphology of Pickering emulsion indicated its drop sizes were determined by the oil/aqueous volume fraction and prepared style. The higher energy input the size become smaller. Based on interfacial adsorption kinetics and microstructure of Pickering emulsions, the stabilization behavior was related to particle-particle associations and conformational changes of Ly/XG NPs. This work confirmed Ly/XG NPs could form Pickering emulsion by selecting different particle size and emulsification process, and offer promising prospects in stabilizing emulsion with the demands of surfactant-free.

Catalytic and anti-bacterial properties of biosynthesized silver nanoparticles using native inulin.

Silver nanoparticles (Ag NPs) were green synthesized using native inulin as the reducing and capping agent with varied incubation temperatures, incubation times and Ag+ concentrations. The biosynthesized Ag NPs were characterized using UV-visible spectroscopy, Field Emission Transmission Electron Microscopy (FE-TEM) and X-ray powder diffraction. The UV visible spectra of the Ag NPs revealed a characteristic surface plasmon resonance peak at 420 nm. FE-TEM showed that the biosynthesized Ag NPs were spherically shaped and monodispersed nanoparticles. The sizes were 18.5 ± 0.9 nm and 20.0 ± 1.2 nm for the Ag NPs synthesized at 80 °C and 100 °C for 2 h using 0.1% inulin and 2 mM Ag+. Their PDIs were 0.180 ± 0.05 and 0.282 ± 0.13, respectively. Improving the incubation temperature, incubation time and silver nitrate concentration promoted Ag NP synthesis. The prepared Ag NPs were effective in the catalytic reduction of 4-NP and in inhibiting the growth of bacteria. The inhibition zone could reach 10.21 ± 2.12 mm and 9.92 ± 0.50 mm for Escherichia coli and Staphylococcus aureus. The kinetic rate constant (k app) could reach 0.0113 s-1, and the maximum inhibitory zones were 10.21 ± 2.12 mm and 9.92 ± 0.50 mm, respectively, for the two microorganisms. This biosynthesis illustrates that native inulin could be a potential candidate in the green fabrication of Ag NPs, and this is promising in catalytic and bacteriostatic fields.