Inhibiting proBDNF to mature BDNF conversion leads to ASD-like phenotypes in vivo.

Autism Spectrum Disorders (ASD) comprise a range of early age-onset neurodevelopment disorders with genetic heterogeneity. Most ASD related genes are involved in synaptic function, which is regulated by mature brain-derived neurotrophic factor (mBDNF) and its precursor proBDNF in a diametrically opposite manner: proBDNF inhibits while mBDNF potentiates synapses. Here we generated a knock-in mouse line (BDNFmet/leu) in which the conversion of proBDNF to mBDNF is attenuated. Biochemical experiments revealed residual mBDNF but excessive proBDNF in the brain. Similar to other ASD mouse models, the BDNFmet/leu mice showed reduced dendritic arborization, altered spines, and impaired synaptic transmission and plasticity in the hippocampus. They also exhibited ASD-like phenotypes, including stereotypical behaviors and deficits in social interaction. Moreover, the plasma proBDNF/mBDNF ratio was significantly increased in ASD patients compared to normal children in a case-control study. Thus, deficits in proBDNF to mBDNF conversion in the brain may contribute to ASD-like behaviors, and plasma proBDNF/mBDNF ratio may be a potential biomarker for ASD.

Endothelial POFUT1 controls injury-induced liver fibrosis by repressing fibrinogen synthesis.

BACKGROUND & AIMS: NOTCH signaling in liver sinusoidal endothelial cells (LSECs) regulates liver fibrosis, a pathological feature of chronic liver diseases. POFUT1 is an essential regulator of NOTCH signaling. Here, we investigated the role of LSEC-expressed POFUT1 in liver fibrosis. METHODS: Endothelial-specific Pofut1 knockout mice were generated and experimental liver fibrosis was induced by chronic carbon tetrachloride exposure or common bile duct ligation. Liver samples were assessed by ELISA, histology, electron microscopy, immunostaining and RNA in situ hybridization. LSECs and hepatic stellate cells (HSCs) were isolated for gene expression analysis by RNA sequencing, qPCR, and western blotting. Signaling crosstalk between LSECs and HSCs was investigated by treating HSCs with supernatant from LSEC cultures. Liver single-cell RNA sequencing datasets from patients with cirrhosis and healthy individuals were analyzed to evaluate the clinical relevance of gene expression changes observed in mouse studies. RESULTS: POFUT1 loss promoted injury-induced LSEC capillarization and HSC activation, leading to aggravated liver fibrosis. RNA sequencing analysis revealed that POFUT1 deficiency upregulated fibrinogen expression in LSECs. Consistently, fibrinogen was elevated in LSECs of patients with cirrhosis. HSCs treated with supernatant from LSECs of Pofut1 null mice showed exacerbated activation compared to those treated with supernatant from control LSECs, and this effect was attenuated by knockdown of fibrinogen or by pharmacological inhibition of fibrinogen receptor signaling, altogether suggesting that LSEC-derived fibrinogen induced the activation of HSCs. Mechanistically, POFUT1 loss augmented fibrinogen expression by enhancing NOTCH/HES1/STAT3 signaling. CONCLUSIONS: Endothelial POFUT1 prevents injury-induced liver fibrosis by repressing the expression of fibrinogen, which functions as a profibrotic paracrine signal to activate HSCs. Therapies targeting the POFUT1/fibrinogen axis offer a promising strategy for the prevention and treatment of fibrotic liver diseases. IMPACT AND IMPLICATIONS: Paracrine signals produced by liver vasculature play a major role in the development of liver fibrosis, which is a pathological hallmark of most liver diseases. Identifying those paracrine signals is clinically relevant in that they may serve as therapeutic targets. In this study, we discovered that genetic deletion of Pofut1 aggravated experimental liver fibrosis in mouse models. Moreover, fibrinogen was identified as a downstream target repressed by Pofut1 in liver endothelial cells and functioned as a novel paracrine signal that drove liver fibrosis. In addition, fibrinogen was found to be relevant to cirrhosis and may serve as a potential therapeutic target for this devastating human disease.

Maternal CHD7 gonosomal mosaicism in a fetus with CHARGE syndrome.

Parental mosaicism is important in families with de novo mutations. Herein, we report a case of fetal CHARGE syndrome (CS) with a CHD7 variant inherited from maternal CHD7 gonosomal mosaicism. The variant was detected through trio-based whole-exome sequencing and Sanger sequencing. High-depth whole-exome sequencing was performed for the identification of parental mosaicism. A novel heterozygous CHD7 nonsense mutation (c.5794G>T/ p.E1932*) was detected in the tissue from the aborted fetus. The parents were wild-type, indicating that the mutation was a de novo variant. The mutation was suspected to be the cause of the fetal CS. However, high-depth whole-exome sequencing revealed maternal gonosomal mosaicism at a variant allele frequency of 3.2%-23.3%. The variant was identified in various tissues (peripheral blood, hair follicles, buccal epithelia, and pharyngeal epithelia) from the asymptomatic mother. We confirmed maternal CHD7 gonosomal mosaicism as a genetic cause of fetal CS. Our results emphasize the importance of clinical analysis in accurately determining the parents' status in detecting the CHD7 de novo variant in fetal CS, as this analysis has vital implications for evaluating the recurrence risk for genetic counseling.

Orally biomimetic metal-phenolic nanozyme with quadruple safeguards for intestinal homeostasis to ameliorate ulcerative colitis.

BACKGROUND: Ulcerative colitis (UC) is defined by persistent inflammatory processes within the gastrointestinal tract of uncertain etiology. Current therapeutic approaches are limited in their ability to address oxidative stress, inflammation, barrier function restoration, and modulation of gut microbiota in a coordinated manner to maintain intestinal homeostasis. RESULTS: This study involves the construction of a metal-phenolic nanozyme (Cur-Fe) through a ferric ion-mediated oxidative coupling of curcumin. Cur-Fe nanozyme exhibits superoxide dismutase (SOD)-like and •OH scavenging activities, demonstrating significant anti-inflammatory and anti-oxidant properties for maintaining intracellular redox balance in vitro. Drawing inspiration from Escherichia coli Nissle 1917 (EcN), a biomimetic Cur-Fe nanozyme (CF@EM) is subsequently developed by integrating Cur-Fe into the EcN membrane (EM) to improve the in vivo targeting ability and therapeutic effectiveness of the Cur-Fe nanozyme. When orally administered, CF@EM demonstrates a strong ability to colonize the inflamed colon and restore intestinal redox balance and barrier function in DSS-induced colitis models. Importantly, CF@EM influences the gut microbiome towards a beneficial state by enhancing bacterial diversity and shifting the compositional structure toward an anti-inflammatory phenotype. Furthermore, analysis of intestinal microbial metabolites supports the notion that the therapeutic efficacy of CF@EM is closely associated with bile acid metabolism. CONCLUSION: Inspired by gut microbes, we have successfully synthesized a biomimetic Cur-Fe nanozyme with the ability to inhibit inflammation and restore intestinal homeostasis. Collectively, without appreciable systemic toxicity, this work provides an unprecedented opportunity for targeted oral nanomedicine in the treatment of ulcerative colitis.

Reliability, validity, and simplification of the Chinese version of the Global Pain Scale in patients with rheumatoid arthritis.

BACKGROUND: Persistent pain is the most reported symptom in patients with rheumatoid arthritis (RA); however, effective and brief assessment tools are lacking. We validated the Chinese version of the Global Pain Scale (C-GPS) in Chinese patients with RA and proposed a short version of the C-GPS (s-C-GPS). METHOD: The study was conducted using a face-to-face questionnaire survey with a multicenter cross-sectional design from March to December 2019. Patients aged > 18 years who met the RA diagnostic criteria were included. Based on the classical test theory (CTT) and the item response theory (IRT), we assessed the validity and reliability of the C-GPS and the adaptability of each item. An s-C-GPS was developed using IRT-based computerized adaptive testing (CAT) analytics. RESULTS: In total, 580 patients with RA (mean age, 51.04 ± 24.65 years; mean BMI, 22.36 ± 4.07 kg/m2), including 513 (88.4%) women, were included. Most participants lived in a suburb (49.3%), were employed (72.2%) and married (91.2%), reported 9-12 years of education (66.9%), and had partial medical insurance (57.8%). Approximately 88.1% smoked and 84.5% drank alcohol. Analysis of the CTT demonstrated that all items in the C-GPS were positively correlated with the total scale score, and the factor loadings of all these items were > 0.870. A significant positive relationship was found between the Visual Analog Scale (VAS) and the C-GPS. IRT analysis showed that discrimination of the C-GPS was between 2.271 and 3.312, and items 6, 8, 13, 14, and 16 provided a large amount of information. Based on the CAT and clinical practice, six items covering four dimensions were included to form the s-C-GPS, all of which had very high discrimination. The s-C-GPS positively correlated with the VAS. CONCLUSION: The C-GPS has good reliability and validity and can be used to evaluate pain in RA patients from a Chinese cultural background. The s-C-GPS, which contains six items, has good criterion validity and may be suitable for pain assessment in busy clinical practice. TRIAL REGISTRATION: This cross-sectional study was registered in the Chinese Clinical Trial Registry (ChiCTR1800020343), granted on December 25, 2018.

Effect of Microecological Regulator Combined with Enteral Nutrition on Immune and Coagulation Function in Patients with Chronic Critical Illness.

This study was to investigate the effect of microecological regulators combined with enteral nutrition on immune and coagulation function in patients with a chronic critical illness. For this purpose, 78 patients with chronic critical illness in our hospital from January 2020 to January 2022 were divided into study and control groups according to a simple random number table, with 39 cases in each group. The control group was given enteral nutrition support, and the study group was given a microecological regulator. The variables of the study were the intervention effects [albumin (ALB), prealbumin (PA), serum total protein (TP)], immune function (CD3+, CD4+, CD4+/CD8+), coagulation function [platelet count (PLT), Fibrinogen (FIB), prothrombin time (PT) and the incidence of complications. Results showed that Before the intervention, ALB (30.69 ± 3.66) G/L, PA (132.91 ± 18.04) mg/L, TP (55.65 ± 5.42) G/L in the study group and ALB (31.78 ± 4.24) TP (57.01 ± 5.13) G/L had no significant difference (P>0.05). After the intervention, the levels of ALB, PA and TP in the two groups were higher than those before the intervention. ALB (38.91 ± 3.54) G/L, PA (204.24 ± 28.80) mg/L and TP (69.75 ± 7.48) G/L in the study group were higher than those in the control group (ALB 34.83 ± 3.82) TP (62.70 ± 6.33) g/L (P<0.05). There was no significant difference between CD4+/CD8+ (1.31 ± 0.39) (P>0.05). After the intervention, the levels of CD3+, CD4+, CD4 and CD8 in the two groups were higher than those before the intervention. CD3+, CD4+ and CD4+/CD8+ were higher than that of the control group. in the study group PLT (226.57 ± 41.15) × 109/L, FIB (3.58 ± 1.09) G/L, PT (9.41 ± 0.82) s were recoeded. There was no significant difference between FIB (3.71 ± 1.13) G/L and PT (9.24 ± 0.77) s (P>0.05). After the intervention, PLT and FIB decreased and PT increased in both groups. PLT (177.15 ± 12.51) × 109/L and FIB (2.57 ± 0.39) G/L in the study group were lower than PLT (198.54 ± 10.77) × 109/L and FIB (3.04 ± 0.54) PT (15.79 ± 1.21) s was higher than PT (13.13 ± 1.33) s in the control group (P<0.05). The incidence of complications in the study group (5.13%) was lower than that in the control group (20.51%) (P<0.05). The conclusion was that the intervention effect of microecological regulators combined with enteral nutrition on patients with chronic critical illness is significant, which can improve their nutritional status and immune function, improve coagulation function, and reduce the incidence of complications.

Cascade reaction triggering and photothermal AuNPs@MIL MOFs doped intraocular lens for enhanced posterior capsular opacification prevention.

Posterior capsular opacification (PCO) is the most common complication after cataract surgery. Present strategies can't meet the clinical needs of long-term prevention. This research reports a novel intraocular lens (IOL) bulk material with high biocompatibility and synergistic therapy. Gold nanoparticles (AuNPs) doped MIL-101-NH2 metal-organic frameworks (MOFs) (AuNPs@MIL) was firstly fabricated via in situ reductions. Then the functionalized MOFs were uniformly mixed with glycidyl methacrylate (GMA) and 2-(2-ethoxyethoxy) ethyl acrylate (EA) to form the nanoparticle doped polymer (AuNPs@MIL-PGE), and which was used to fabricate IOL bulk materials. The materials' optical and mechanical properties with different mass contents of nanoparticles are investigated. Such bulk functionalized IOL material could efficiently remove residual human lens epithelial cells (HLECs) in the capsular bag in the short term, and can prevent PCO on demand in the long run by near-infrared illumination (NIR) action. In vivo and in vitro experiments demonstrate the biosafety of the material. The AuNPs@MIL-PGE exhibits excellent photothermal effects, which could inhibit cell proliferation under NIR and doesn't cause pathological effects on the surrounding tissues. Such functionalized IOL can not only avoid the side effects of the antiproliferative drugs but also realize the enhanced PCO prevention in clinical practice.

Outcomes of vertex-vertex vs. vertex-breech presentation in twin pregnancy after vaginal delivery in China.

OBJECTIVE: To compare the maternal and neonatal outcomes of twin pregnancies between vertex and nonvertex presentations of the second twin in vaginal delivery. METHODS: In this unicentric retrospective cohort study, we collected data from 213 cases of vaginal twin deliveries from January 2016 to July 2020. Participants were divided into the vertex-vertex presentation group (VV) and vertex-breech presentation group (VB). Data on maternal and neonatal outcomes were compared between groups. RESULTS: Among the 213 mothers and 426 infants (213 twin pairs), there were 140 women in the VV group and 73 women in the VB group (65.73% vs. 34.27%). Infants in the VB group had a higher incidence of admission to NICU (51.43% vs. 68.49%, p = 0.017), lower 1-min (11.43% vs. 28.77%, p < 0.001) and 5-minute Apgar scores (1.43% vs. 4.11%, p = 0.043) for the second twin. However, after the adjustment for sex of the twin, birth weight, chorionicity, and gestational age, the greater risk of admission to NICU and low 5-min Apgar score was no longer significantly different. CONCLUSION: VB twins are at no greater overall risk of a poor outcome due to breech presentation in the second twin. However, the presentation of the second fetus represents a risk factor for a low 1-min Apgar score. Obstetricians and midwives should consider appropriate interventions for second twins who present breech versus vertex.

Efficacy and safety comparison between axillary lymph node dissection with no axillary surgery in patients with sentinel node-positive breast cancer: a systematic review and meta-analysis.

BACKGROUND: This systematic review and meta-analysis aimed to study the evidence on the efficacy and safety of omitting axillary lymph node dissection (ALND) for patients with clinically node-negative but sentinel lymph node (SLN)-positive breast cancer using all the available evidence. METHODS: The Embase, Medline, and Cochrane Library databases were searched through February 25, 2023. Original trials that compared only the sentinel lymph node biopsy (SLNB) with ALND as the control group for patients with clinically node-negative but SLN-positive breast cancer were included. The primary outcomes were axillary recurrence rate, total recurrence rate, disease-free survival (DFS), and overall survival (OS). Meta-analyses were performed to compare the odds ratio (OR) in rates and the hazard ratios (HR) in time-to-event outcomes between both interventions. Based on different study designs, tools in the revised Cochrane risk of bias tool were used for randomized trials and the risk of bias in nonrandomized studies of interventions to assess the risk of bias for each included article. Funnel plots and Egger's test were used for the publication's bias assessment. RESULTS: In total, 30 reports from 26 studies were included in the systematic review (9 reports of RCTs, 21 reports of retrospective cohort studies). According to our analysis, omitting ALND in patients with clinically node-negative but SLN-positive breast cancer had a similar axillary recurrence rate (OR = 0.95, 95% confidence interval (CI): 0.76-1.20), DFS (HR = 1.02, 95% CI: 0.89-1.16), and OS (HR = 0.97, 95% CI: 0.92-1.03), but caused a significantly lower incidence of adverse events and benefited in locoregional recurrence rate (OR = 0.76, 95% CI: 0.59-0.97) compared with ALND. CONCLUSION: For patients with clinically node-negative but SLN-positive breast cancer (no matter the number of the positive SLN), this review showed that SLNB alone had a similar axillary recurrence rate, DFS, and OS, but caused a significantly lower incidence of adverse events and showed a benefit for the locoregional recurrence compared with ALND. An OS benefit was found in the Macro subset that used SLNB alone versus complete ALND. Therefore, omitting ALND is feasible in this setting. TRIAL REGISTRATION: CRD 42023397963.

Efficacy and Safety of Shortened Dual Antiplatelet Therapy in Patients Undergoing Percutaneous Coronary Intervention: A Meta-Analysis of Randomized Controlled Trials.

ABSTRACT: To update the efficacy and safety of short-term (≤3 months) dual antiplatelet therapy (DAPT) and standard (6-12 months) DAPT in patients undergoing percutaneous coronary intervention. In addition, we also explored the duration of DAPT in patients at high bleeding risk (HBR). In PubMed, Embase, and Cochrane Library, we electronically searched among all the studies from the establishment of the database to December 8, 2021, for randomized controlled trials (RCTs). Nine randomized controlled trials (45,661 patients) ultimately met the inclusion criteria. The pooled analysis revealed that, compared with standard DAPT, ≤3-month DAPT significantly reduced major adverse cardiovascular event {hazard ratio (HR) = 0.89, 95% confidence interval (CI) [0.82-0.97]}, all-cause mortality [HR = 0.88, 95% CI (0.78-0.99)], cardiovascular mortality [HR = 0.79, 95% CI (0.65-0.97)], major bleeding [HR = 0.72, 95% CI (0.56-0.93)], and any bleeding [HR = 0.57, 95% CI (0.50-0.66)], while no significant differences in the risk of myocardial infarction, stent thrombosis, and stroke. In patients with HBR, the results showed that ≤3-month DAPT significantly reduced major bleeding [HR = 0.35, 95% CI (0.14-0.88)] and any bleeding [HR = 0.53, 95% CI (0.41-0.67)] compared with standard DAPT, while the risk of other outcomes was not statistically different. In conclusion, this study showed that ≤3-month DAPT may be a valid option for most patients after percutaneous coronary intervention. Because reductions in major adverse cardiovascular event, all-cause mortality, and cardiovascular mortality were not seen in patients with HBR, this also highlights the need for specific studies in these patients about optimal duration of antiplatelet therapy.

[Preparation and evaluation of quality management samples for noninvasive prenatal screening].

OBJECTIVE: To prepare a quality control sample for non-invasive prenatal screening (NIPS) and evaluate its quality and stability. METHODS: According to the biological characteristics of cell-free fetal DNA derived from the plasma of pregnant women, the simulated samples were prepared by mixing genomic DNA fragments derived from individuals with trisomy 21, trisomy 18 and trisomy 13 and background plasma. The samples were then compared with commercially made quality control products tested on various NIPS platforms and stored at -80℃, -20℃, 4℃, 24℃ and 37℃ for various periods of time. RESULTS: The simulated samples have attained the expected results and could be detected on various platforms and stored at -80℃and -20℃ for at least 30 days. CONCLUSION: A simulated sample was successfully prepared and possessed good stability. It can be used as the quality control sample for NIPS.

Association of human papillomavirus genotype distribution and cervical cytology: a cross-sectional study.

The present study attempted to analyse human papillomavirus (HPV) genotype distribution and its association with cervical cytology results in women in western China. The present retrospective analysis was performed in 1089 female outpatients with a positive HPV test result who had undergone a cervical cytology test at the gynaecological clinic, West China Second Hospital, Sichuan University, China, between January 2014 and December 2016. Of the 1089 patients with HPV infection, multiple HPV genotypes were detected in 220 patients (20.20%). Among the 1368 HPV genotypes detected, 1145 (83.70%) were high-risk subtypes. The most common genotypes were HPV-52 (18.64%), HPV-16 (16.59%), HPV-58 (13.23%), HPV-18 (6.80%), HPV-56 (5.56%) and HPV-59 (5.56%). Cervical cytology revealed abnormal cells in 430 (39.49%) patients. The most common diagnoses were atypical squamous cells of undetermined significance (ASC-US; 236 cases, 54.88%), low-grade squamous intraepithelial lesions (LSIL; 151 cases, 35.12%), high-grade squamous intraepithelial lesions (HSIL; 63 cases, 14.65%) and atypical glandular cells (AGC; 21 cases, 4.88%). HPV-66 was significantly associated (P = 0.037) with ASC; HPV-52 and HPV-56 were significantly associated with LSIL (P = 0.009 and 0.026, respectively); HPV-16 (P < 0.001), HPV-33 (P = 0.014) and HPV-58 (P = 0.003) were significantly associated with HSIL; and HPV-16 (P = 0.005) was significantly associated with AGC. HPV-16, HPV-52 and HPV-58 are associated with different diagnoses in patients with positive cervical cytological findings.

Construction and Evaluation of a Rat Model of Postpartum Fatigue.

OBJECTIVES: The aim of the study was to construct and evaluate a rat model of postpartum fatigue. DESIGN: This is an article about animal model building. METHODS: Sprague-Dawley rats on the 1st day after delivery were randomized into control group and fatigue group. The deep sleep of rats was interfered with by forcing them to stand in water, to make the rats experience mental and physical fatigue. To maintain galactosis and lactation, rats and pups were caged for 90 min after every 3 h of separation. The control group was separated routinely without any stimulus. The model was evaluated from mental and physical fatigue on the 8th day and 15th day. The mental fatigue was evaluated by a water maze test and the rat's 5-hydroxytryptamine (5-HT) level in hippocampus, while the physical fatigue was evaluated using lactic acid level in serum and duration of weight-loaded forced swimming. RESULTS: Among the 7-day and 14-day modeling groups, compared with the control group, the success rate of water maze landing was significantly decreased, the time for water maze landing was significantly prolonged and 5-HT level in hippocampus significantly decreased in the fatigue group. With respect to physical fatigue, among the 7-day and 14-day modeling groups, the lactic acid level in serum in the fatigue group was significantly increased, and the duration of exhaustive swimming of rats was significantly shortened. LIMITATIONS: A small sample size was the main limitation of this study. CONCLUSIONS: We have successfully constructed a rat model of postpartum fatigue by forcing postpartum rats to stand in water, which was similar to a level of stress that contributes to the development of postpartum fatigue. Our model opens the door for future studies evaluating the effectiveness of pharmacological and behavioral therapies.

Phenotype-to-genotype approach reveals head-circumference-associated genes in an autism spectrum disorder cohort.

The genotype-first approach has been successfully applied and has elucidated several subtypes of autism spectrum disorder (ASD). However, it requires very large cohorts because of the extensive genetic heterogeneity. We investigate the alternate possibility of whether phenotype-specific genes can be identified from a small group of patients with specific phenotype(s). To identify novel genes associated with ASD and abnormal head circumference using a phenotype-to-genotype approach, we performed whole-exome sequencing on 67 families with ASD and abnormal head circumference. Clinically relevant pathogenic or likely pathogenic variants account for 23.9% of patients with microcephaly or macrocephaly, and 81.25% of those variants or genes are head-size associated. Significantly, recurrent pathogenic mutations were identified in two macrocephaly genes (PTEN, CHD8) in this small cohort. De novo mutations in several candidate genes (UBN2, BIRC6, SYNE1, and KCNMA1) were detected, as well as one new candidate gene (TNPO3) implicated in ASD and related neurodevelopmental disorders. We identify genotype-phenotype correlations for head-size-associated ASD genes and novel candidate genes for further investigation. Our results also suggest a phenotype-to-genotype strategy would accelerate the elucidation of genotype-phenotype relationships for ASD by using phenotype-restricted cohorts.

Genotype and phenotype correlations for SHANK3 de novo mutations in neurodevelopmental disorders.

SHANK3 has been identified as the causative gene of 22q13.3 microdeletion syndrome phenotype. De novo mutations (DNMs) of SHANK3 were subsequently identified in patients with several neurodevelopmental disorders, including autism spectrum disorders (ASDs), schizophrenia (SCZ), a Rett syndrome-like phenotype, and intellectual disability (ID). Although broad developmental phenotypes of these patients have been described in single studies, few studies have reviewed the genotype and phenotype relationships using a relatively large cohort of patients with SHANK3 DNMs. In this study, we identified a de novo splice mutation (NM_033517.1: c.2265+1G>A) that functionally impairs mRNA splicing, produces multiple splice variants, and results in the reduction of the amounts of mRNA. To analyze the genotype and phenotype correlations for SHANK3 DNMs, we reviewed 37 previously published patients with 28 SHANK3 DNMs. Our results revealed that haploinsufficiency of SHANK3 causes a broad spectrum of neurodevelopmental phenotypes with impaired social interaction, repetitive behavior, speech impairment, ID, and regression as the most common observations. Seizures, hypotonia, global development delay, dysmorphic features, and several other features also occurred recurrently. Specific phenotypes are also observed in certain genotypes. Our study provides the frequency of the heterogeneous co-occurring conditions caused by SHANK3 DNMs, which will be beneficial for diagnosis and clinical management.

Effect of pumping pressure on onset of lactation after caesarean section: A randomized controlled study.

Caesarean section is associated with weaker newborn suction pressure. This nonblinded, randomized trial explored the effect of suction pressures generating by a breast pump on mothers' onset of lactation and milk supply after caesarean section. A high pressure group (-150 mmHg), a low pressure group (-100 mmHg), and a control group (none) were generated under computer random assignment with concealed allocation in 2 tertiary hospitals. The breast pumping began within 2 hr after caesarean operation (6 times a day and 30 min per time) until onset of lactation. The primary outcomes were the timing of onset of lactation, milk supply, and mother's satisfaction in lactation, using both intention-to-treat and per-protocol analyses. The secondary endpoints were the pumping-related pain, nipple injury, and maternal fatigue. All 164 women randomized were included in analysis. The breast pumping at -150 mmHg optimally advanced the timing of the onset of lactation and increased daytime milk supply. The pumping also appeared to boost mothers' confidence in lactation. The results in the per-protocol population (n = 148) were consistent with those of intention-to-treat population (n = 164). However, the pumping aggravated maternal nipple pain and fatigue, though there was no statistical significance. The findings suggest that a higher pumping pressure within the range of normal vaginally born infant suction could promote onset of lactation and milk supply among mothers giving birth by caesarean section. The pumping could also enhance mothers' confidence in breastfeeding.

Coexistence of OSA may compensate for sleep related reduction in neural respiratory drive in patients with COPD.

BACKGROUND: The mechanisms underlying sleep-related hypoventilation in patients with coexisting COPD and obstructive sleep apnoea (OSA), an overlap syndrome, are incompletely understood. We compared neural respiratory drive expressed as diaphragm electromyogram (EMGdi) and ventilation during stage 2 sleep in patients with COPD alone and patients with overlap syndrome. METHODS: EMGdi and airflow were recorded during full polysomnography in 14 healthy subjects, 14 patients with OSA and 39 consecutive patients with COPD. The ratio of tidal volume to EMGdi was measured to indirectly assess upper airway resistance. RESULTS: Thirty-five patients with COPD, 12 healthy subjects and 14 patients with OSA completed the study. Of 35 patients with COPD, 19 had COPD alone (FEV1 38.5%±16.3%) whereas 16 had an overlap syndrome (FEV1 47.5±16.2%, AHI 20.5±14.1 events/hour). Ventilation (VE) was lower during stage 2 sleep than wakefulness in both patients with COPD alone (8.6±2.0 to 6.5±1.5 L/min, p<0.001) and those with overlap syndrome (8.3±2.0 to 6.1±1.8 L/min). Neural respiratory drive from wakefulness to sleep decreased significantly for patients with COPD alone (29.5±13.3% to 23.0±8.9% of maximal, p<0.01) but it changed little in those with overlap syndrome. The ratio of tidal volume to EMGdi was unchanged from wakefulness to sleep in patients with COPD alone and healthy subjects but was significantly reduced in patients with OSA or overlap syndrome (p<0.05). CONCLUSIONS: Stage 2 sleep-related hypoventilation in COPD alone is due to reduction of neural respiratory drive, but in overlap syndrome it is due to increased upper airway resistance.

Covalent Modification of MoS2 with Poly(N-vinylcarbazole) for Solid-State Broadband Optical Limiters.

New soluble MoS2 nanosheets covalently functionalized with poly(N-vinylcarbazole) (MoS2-PVK) were in situ synthesized for the first time. In contrast to MoS2 and MoS2 /PVK blends, both the solution of MoS2 -PVK in DMF and MoS2-PVK/poly(methyl methacrylate) (PMMA) film show superior nonlinear optical and optical limiting responses. The MoS2-PVK/PMMA film shows the largest nonlinear coefficients (ßeff) of about 917 cm GW(-1) at λ=532 nm (cf. 100.69 cm GW(-1) for MoS2/PMMA and 125.12 cm GW(-1) for MoS2/PVK/PMMA) and about 461 cm GW(-1) at λ=1064 nm (cf. -48.92 cm GW(-1) for MoS2/PMMA and 147.56 cm GW(-1) for MoS2/PVK/PMMA). A larger optical limiting effect, with thresholds of about 0.3 GW cm(-2) at λ=532 nm and about 0.5 GW cm(-2) at λ=1064 nm, was also achieved from the MoS2-PVK/PMMA film. These values are among the highest reported for MoS2-based nonlinear optical materials. These results show that covalent functionalization of MoS2 with polymers is an effective way to improve nonlinear optical responses for efficient optical limiting devices.

Betulin alleviated ethanol-induced alcoholic liver injury via SIRT1/AMPK signaling pathway.

The present study was conducted to investigate the protective effect of betulin, a triterpene from the bark of Betula platyphylla Suk, against ethanol-induced alcoholic liver injury and its possible underlying mechanisms. In vitro, human hepatic stellate cell line, LX-2 cells were treated with betulin (6.25, 12.5 and 25 µM) prior to ethanol (50mM) for 24h. Cell viability was analyzed by methyl thiazolyl tetrazolium assay, protein expressions were assessed by Western blot. In vivo, we induced alcoholic liver injury in male C57BL/6 mice, placing them on Lieber-DeCarli ethanol-containing diets for 10 days and then administering a single dose of ethanol (5 g/kg body weight) via gavage. Betulin (20 and 50mg/kg) were given by gavage every day. In vitro results showed that betulin effectively decreased LX-2 cell viability, attenuated collagen-I, α-smooth muscle actin (α-SMA) levels, activated liver kinase B-1 (LKB1) and adenosine monophosphate-activated protein kinase (AMPK) phosphorylation. Betulin suppressed the expression of sterol regulatory element-binding protein-1 (SREBP-1), and genetic deletion of AMPK blocked the effect of betulin on SREBP-1 in ethanol treated LX-2 cells. In vivo, betulin attenuated the increases in serum aminotransferase and triglyceride levels in the mice fed with chronic-binge ethanol, while significantly inhibited SREBP-1 expression and activated LKB1-AMPK phosphorylation. Additionally, betulin enhanced the sirtuin 1 (SIRT1) expression mediated by ethanol. Taken together, betulin alleviates alcoholic liver injury possibly through blocking the regulation of SREBP-1 on fatty acid synthesis and activating SIRT1-LKB1-AMPK signaling pathway.

Noninvasive prenatal testing for Wilson disease by use of circulating single-molecule amplification and resequencing technology (cSMART).

BACKGROUND: Noninvasive prenatal testing (NIPT) for monogenic diseases by use of PCR-based strategies requires precise quantification of mutant fetal alleles circulating in the maternal plasma. The study describes the development and validation of a novel assay termed circulating single-molecule amplification and resequencing technology (cSMART) for counting single allelic molecules in plasma. Here we demonstrate the suitability of cSMART for NIPT, with Wilson Disease (WD) as proof of concept. METHODS: We used Sanger and whole-exome sequencing to identify familial ATP7B (ATPase, Cu(++) transporting, ß polypeptide) gene mutations. For cSMART, single molecules were tagged with unique barcodes and circularized, and alleles were targeted and replicated by inverse PCR. The unique single allelic molecules were identified by sequencing and counted, and the percentage of mutant alleles in the original maternal plasma sample was used to determine fetal genotypes. RESULTS: Four families with WD pedigrees consented to the study. Using Sanger and whole-exome sequencing, we mapped the pathogenic ATP7B mutations in each pedigree and confirmed the proband's original diagnosis of WD. After validation of cSMART with defined plasma models mimicking fetal inheritance of paternal, maternal, or both parental mutant alleles, we retrospectively showed in second pregnancies that the fetal genotypes assigned by invasive testing and NIPT were concordant. CONCLUSIONS: We developed a reliable and accurate NIPT assay that correctly diagnosed the fetal genotypes in 4 pregnancies at risk for WD. This novel technology has potential as a universal strategy for NIPT of other monogenic disorders, since it requires only knowledge of the parental pathogenic mutations.