Upregulation of ATG9b by propranolol promotes autophagic cell death of hepatic stellate cells to improve liver fibrosis.

Proranolol has long been recommended to prevent variceal bleeding in patients with cirrhosis. However, the mechanisms of propranolol in liver fibrosis have not yet been thoroughly elucidated. Autophagic cell death (ACD) of activated hepatic stellate cells (HSCs) is important in the alleviation of liver fibrosis. Our study aims to assess the mechanisms of propranolol regulating HSC ACD and liver fibrosis. ACD of HSCs was investigated using lentivirus transfection. The molecular mechanism was determined using a PCR profiler array. The role of autophagy-related protein 9b (ATG9b) in HSC ACD was detected using co-immunoprecipitation and co-localization of immunofluorescence. Changes in the signalling pathway were detected by the Phospho Explorer antibody microarray. Propranolol induces ACD and apoptosis in HSCs. ATG9b upregulation was detected in propranolol-treated HSCs. ATG9b upregulation promoted ACD of HSCs and alleviated liver fibrosis in vivo. ATG9b enhanced the P62 recruitment to ATG5-ATG12-LC3 compartments and increased the co-localization of P62 with ubiquitinated proteins. The PI3K/AKT/mTOR pathway is responsible for ATG9b-induced ACD in activated HSCs, whereas the p38/JNK pathway is involved in apoptosis. This study provides evidence for ATG9b as a new target gene and propranolol as an agent to alleviate liver fibrosis by regulating ACD of activated HSCs.

Cortical activation and brain network efficiency during dual tasks: An fNIRS study.

OBJECTIVE: Dual task (DT) is a commonly used paradigm indicative of executive functions. Brain activities during DT walking is usually measured by portable functional near infrared spectroscopy (fNIRS). Previous studies focused on cortical activation in prefrontal cortex and overlooked other brain regions such as sensorimotor cortices. This study is aimed at investigating the modulations of cortical activation and brain network efficiency in multiple brain regions from single to dual tasks with different complexities and their relationships with DT performance. METHODS: Forty-two healthy adults [12 males; mean age: 27.7 (SD=6.5) years] participated in this study. Participants performed behavioral tasks with portable fNIRS simultaneous recording. There were three parts of behavioral tasks: cognitive tasks while standing (serial subtraction of 3's and 7's), walking alone and DT (walk while subtraction, including serial subtraction of 3's and 7's). Cognitive cost, walking cost and cost sum (i.e., sum of cognitive and walking costs) were calculated for DT. Cortical activation, local and global network efficiency were calculated for each task. RESULTS: The cognitive cost was greater and the walking cost was less during DT with subtraction 3's compared with 7's (P's = 0.032 and 0.019, respectively). Cortical activation and network efficiency were differentially modulated among single and dual tasks (P's < 0.05). Prefrontal activation during DT was positively correlated with DT costs, while network efficiency was negatively correlated with DT costs (P's < 0.05). CONCLUSIONS: Our results revealed prefrontal over-activation and reduced network efficiency in individuals with poor DT performance. Our findings suggest that reduced network efficiency could be a possible mechanism contributing to poor DT performance, which is accompanied by compensatory prefrontal over-activation.

Functional near-infrared spectroscopy evidence of cognitive-motor interference in different dual tasks.

Dual tasks (DTs) combining walking with a cognitive task can cause various levels of cognitive-motor interference, depending on which brain resources are recruited in each case. However, the brain activation and functional connectivity underlying cognitive-motor interferences remain to be elucidated. Therefore, this study investigated the neural correlation during different DT conditions in 40 healthy young adults (mean age: 27.53 years, 28 women). The DTs included walking during subtraction or N-Back tasks. Cognitive-motor interference was calculated, and brain activation and functional connectivity were analysed. Portable functional near-infrared spectroscopy was utilized to monitor haemodynamics in the prefrontal cortex (PFC), motor cortex and parietal cortex during each task. Walking interference (decrease in walking speed during DT) was greater than cognitive interference (decrease in cognitive performance during DT), regardless of the type of task. Brain activation in the bilateral PFC and parietal cortex was greater for walking during subtraction than for standing subtraction. Furthermore, brain activation was higher in the bilateral motor and parietal and PFCs for walking during subtraction than for walking alone, but only increased in the PFC for walking during N-Back. Coherence between the bilateral lateral PFC and between the left lateral PFC and left motor cortex was significantly greater for walking during 2-Back than for walking. The PFC, a critical brain region for organizing cognitive and motor functions, played a crucial role in integrating information coming from multiple brain networks required for completing DTs. Therefore, the PFC could be a potential target for the modulation and improvement of cognitive-motor functions during neurorehabilitation.

CBLRR: a cauchy-based bounded constraint low-rank representation method to cluster single-cell RNA-seq data.

The rapid development of single-cel+l RNA sequencing (scRNA-seq) technology provides unprecedented opportunities for exploring biological phenomena at the single-cell level. The discovery of cell types is one of the major applications for researchers to explore the heterogeneity of cells. Some computational methods have been proposed to solve the problem of scRNA-seq data clustering. However, the unavoidable technical noise and notorious dropouts also reduce the accuracy of clustering methods. Here, we propose the cauchy-based bounded constraint low-rank representation (CBLRR), which is a low-rank representation-based method by introducing cauchy loss function (CLF) and bounded nuclear norm regulation, aiming to alleviate the above issue. Specifically, as an effective loss function, the CLF is proven to enhance the robustness of the identification of cell types. Then, we adopt the bounded constraint to ensure the entry values of single-cell data within the restricted interval. Finally, the performance of CBLRR is evaluated on 15 scRNA-seq datasets, and compared with other state-of-the-art methods. The experimental results demonstrate that CBLRR performs accurately and robustly on clustering scRNA-seq data. Furthermore, CBLRR is an effective tool to cluster cells, and provides great potential for downstream analysis of single-cell data. The source code of CBLRR is available online at https://github.com/Ginnay/CBLRR.

A Temperature-Tolerant Magnesium-Ion Battery Using Ball Cactus-like MgV2O4 as High-Performance Cathode.

Safe and high-performance secondary batteries using for all-climate conditions with different temperatures are highly required. Here, we develop a three-dimensional ball cactus-like MgV2O4 as cathode material for magnesium-ion (Mg-ion) batteries. After cycling 300 times, the capacity maintains 111.7 mAh g-1, while Coulombic efficiency stabilizes at about 100 %. Under temperatures of 45 °C and -5 °C, the capacities remain stable after 200 cycles. After three rounds of rate-performance tests, the capacity keeps quite stable. It is ascribed to the ball cactus-like morphology buffers the volumetric change during Mg2+ insertion/extraction, and provides sufficient pathways for ion diffusion, which has been verified by constant-current intermittent titration technology. It is believed that the good performance enables the Mg-ion batteries to have a all-climate capability.

Exploring causal association between circulating inflammatory cytokines and functional outcomes following ischemic stroke: A bidirectional Mendelian randomization study.

OBJECTIVES: Previous observational studies have indicated correlations between various inflammatory cytokines and functional outcomes following ischemic stroke (IS); however, the causality remains unclear. We aimed to further evaluate the causal association between 41 circulating inflammatory cytokines and functional outcomes following IS. METHODS: Two-sample bidirectional Mendelian randomization (MR) analysis was used in this study. The genetic variation of 41 circulating inflammatory cytokines were derived from genome-wide association study (GWAS) data of European ancestry (n = 8293). The corresponding genetic association of functional outcomes following IS were derived from European ancestry GWAS data (n = 6021). RESULTS: Inverse variance weighted (IVW) analysis showed that genetically predicted increased levels of regulation and activation in normal T-cell expression and secretion factor (RANTES/CCL5) and eosinophilic chemotactic factor (EOTAXIN/CCL11) were positively correlated with the increased adverse functional outcomes (modified Rankin Scale [mRS≥3] following IS (OR: 1.40, 95% CI: 1.002-1.96, p = 0.049; OR: 1.33, 95% CI: 1.15-1.54, p = 0.0001). Interleukin 18 (IL-18) level might be the downstream consequence of adverse functional outcomes following IS (ß: -0.09, p = 0.039). Other inflammatory cytokines and functional outcomes following IS did not appear to be causally related. CONCLUSIONS: This study suggests a causality between inflammation and adverse functional outcomes following IS. RANTES (CCL5) and EOTAXIN (CCL11) may be the upstream factors of adverse functional outcomes following IS, while IL-18 may be the downstream effect of adverse functional outcomes following IS. Whether these cytokines can be used to predict or improve adverse functional outcomes after IS requires further researches.

Dabigatran-related serious medication errors: an analysis using data from VigiBase.

OBJECTIVE: To analyze the serious medication errors (MEs) on dabigatran, and their related factors, in order to avoid or reduce the occurrence of adverse events. METHODS: Serious MEs related to dabigatran were extracted from the WHO global database of reported potential side effects of medicinal products (VigiBase) by using "Medication errors and other product use errors and issues" High Level Group Term (HLGT) of the international Medical Dictionary for Regulatory Activities (MedDRA). Well-documented reports, vigiGrade completeness score ≥ 0.80, or with an informative narrative were analyzed with a focus on the clinical features of the cases. The PCNE Classification for drug-related problems (DRP) was used to classify medication errors in our analysis of cases. RESULTS: Until January 26, 2020, there were 453 cases with serious MEs related to dabigatran in VigiBase, and 113 were well-documented. Among these, 69 patients (61%) were hospitalized or had prolonged hospitalization, 16 (14%) had life-threatening events, and 12 (11%) died. The MEs occurred in the prescription phase in 77 cases, in administration in 35, and at the dispensing stage in one case. The MEs in prescription were related to a drug selection error in 44 cases (24 concerning contraindications and 20 drug interactions) and to dose error in 33 cases (17 with excessive dose; eight with insufficient frequency; four had an incorrect time; in three, the dose was too low; and in one, too frequent). The MEs in administration were medical-staff-related errors in five cases (three with wrong administration route, one administration omission, and one overdose), patient-related errors in 28 (14 insufficient dose or no administration, seven improper drug storage, four wrong administration method, and three over prescribed dose), and other errors in two (without efficacy monitoring). The dispensing error of a wrong drug strength occurred in a pharmacy. The main adverse events in the 113 patients were haemorrhage in 57 cases (50%) and ischemia in 29 cases (26%). CONCLUSION: Based on the analysis of reports in VigiBase, serious MEs related to dabigatran mainly occurred during prescription and administration. Although the incidence of MEs with clinical consequences in the use of dabigatran cannot be determined, attention should be paid to selection of the appropriate dose to a right patient in the prescription, and to patient compliance and storage in drug administration. The patient harm mainly manifested itself as bleeding or ischemia including fatal outcome in rare patients.

NGEF is a potential prognostic biomarker and could serve as an indicator for immunotherapy and chemotherapy in lung adenocarcinoma.

BACKGROUND: Neuronal guanine nucleotide exchange factor (NGEF) plays a key role in several cancers; however, its role in lung adenocarcinoma (LUAD) remains unclear. The aim of this study was to evaluate the efficacy of NGEF as a prognostic biomarker and potential therapeutic target for LUAD. METHODS: NGEF expression data for multiple cancers and LUAD were downloaded from multiple databases. The high- and low-NGEF expression groups were constructed based on median NGEF expression in LUAD samples, and then performed Kaplan-Meier survival analysis. Differentially expressed genes (DEGs) from the two NGEF expression groups were screened and applied to construct a protein-protein interaction network. The primary pathways were obtained using gene set enrichment analysis. The associations between NGEF expression and clinical characteristics, immune infiltration, immune checkpoint inhibitors (ICIs), sensitivity to chemotherapy, and tumor mutation burden (TMB) were investigated using R. Levels of NGEF expression in the lung tissue was validated using single-cell RNA sequencing, quantitative polymerase chain reaction (qPCR), immunohistochemical staining, and western blot analysis. RESULTS: The expression of NGEF mRNA was upregulated in multiple cancers. mRNA and protein expression levels of NGEF were higher in patients with LUAD than in controls, as validated using qPCR and western blot. High NGEF expression was an independent prognostic factor for LUAD and was associated with advanced tumor stage, large tumor size, more lymph node metastasis, and worse overall survival (OS). A total of 182 overlapping DEGs were screened between The Cancer Genome Atlas and GSE31210, among which the top 20 hub genes were identified. NGEF expression was mainly enriched in the pathways of apoptosis, cell cycle, and DNA replication. Moreover, elevated NGEF expression were associated with a high fraction of activated memory CD4+ T cells and M0 macrophages; elevated expression levels of the ICIs: programmed cell death 1 and programmed cell death 1 ligand 1 expression; higher TMB; and better sensitivity to bortezomib, docetaxel, paclitaxel, and parthenolide, but less sensitivity to axitinib and metformin. CONCLUSION: NGEF expression is upregulated in LUAD and is significantly associated with tumor stages, OS probability, immune infiltration, immunotherapy response, and chemotherapy response. NGEF may be a potential diagnostic and prognostic biomarker and therapeutic target in LUAD.

Climate risk and renewable energy technological innovation: An institutional environment perspective.

To explore whether climate risk (CR) affects renewable energy technological innovation (RETI) and its boundary conditions, this study examines the relationship between CR and RETI as moderated by institutional environment. Based on panel data of 60 countries for the period 2000-2019, we show that CR is not conducive to RETI, and that its negative marginal impact shows an inverted U-shaped trend with the improvement of RETI. Heterogeneity analysis shows that floods and storms have the greatest negative impacts on RETI, and that innovations in solar and wind energy technologies are more vulnerable to the adverse shocks of CR. Furthermore, CR has a greater adverse effect on RETI in developing countries than in developed countries. However, the institutional environment, especially the economic institutional environment, can work to mitigate the negative effect of CR on RETI. Our findings not only enrich the research on the economic consequences of CR but also provide effective ways to mitigate the adverse impact of CR on RETI from the perspective of institutional environment.

How does climate change risk affect energy poverty? International evidence.

Based on cross-country data from 2002 to 2019, we explore the impact of climate change risk (CCR) on energy poverty (EP), and the moderating role in the CCR-EP nexus is also discussed. The empirical results suggest that CCR can exacerbate EP, especially for rural areas. Moderating effect analysis shows that financial development, technological innovation, and adaptation readiness can modify the negative impacts of CCR on EP to some extent. Moreover, the impact of CCR on EP is heterogeneous, demonstrating that CCR is more likely to exacerbate EP in countries with low economic development, low economic freedom, high carbon intensity, and the Africa region. Our findings emphasize the challenge of balancing EP alleviation with climate change response and provide the policy guidance to promote coordinated development of CCR management and energy supply security.

A fully digital workflow to design anterior guidance for an implant-supported single crown using a modified patient-specific motion technique.

Current methods for designing anterior guidance of anterior fixed prostheses are either complicated or lack accuracy. The article describes a fully digital workflow to design individualized anterior guidance of an implant-supported single crown by using a modified patient-specific motion technique. The technique aims to optimize the digital occlusal design workflow, thereby improving the occlusal fit and long-term stability of anterior fixed prostheses.

[Trueness of different digital design methods for incisal guidance of maxillary anterior implant-supported single crowns].

OBJECTIVE: To compare the trueness of incisal guidance of implant-supported single crowns designed by patient-specific motion (PSM) with that designed by average-value virtual articulator (AVA). METHODS: The study had recruited 12 participants with complete dentition and stable incisal guidance. An intraoral scanner was used to scan digital casts and record two types of patient-specific motion (data only including protrusive movement, and data including protrusive movement and lateral protrusive movement). The lingual surfaces of the maxillary incisors which guided the protrusive movement was selected and elevated to create a reference cast. A maxillary central incisor of original casts was vir-tually extracted and implanted to generate a working cast. The Dental system software program was used to design implant-supported single crowns with the anatomical coping design method. The incisal guidance was designed by different methods. The incisal guidance in control group was designed by the average-value virtual articulator. The incisal guidance in experiment groups was designed by the patient-specific motion only including protrusive movement (PSM1) and with the patient-specific motion including protrusive movement and lateral protrusive movement (PSM2). The incisal guidance of prosthesis designed by these 3 methods were compared with the original incisal guidance in Geomagic Control 2015 (3DSystem, America). The measurements included: Average of positive values, ratio of positive area and maximum value reflecting supra-occlusion; average of negative values, ratio of negative area and minimum value reflecting over-correction; and root mean square reflecting overall deviation. RESULTS: Statistical data were collected using the median (interquartile range) method. The average of positive values, ratio of positive area and average of negative values of the PSM2 group were smaller than those of the control group [8.0 (18.8) µm vs. 37.5 (47.5) µm; 0 vs. 7.2% (38.1%); -109.0 (63.8) µm vs.-66.5 (64.5) µm], and the ratio of negative area of PSM2 group was larger than those of the control group [52.9% (47.8%) vs. 17.3% (45.3%)], with significant differences (P all < 0.05). The ratio of positive area [0.1% (7.0%)] and average of negative values [-97.0 (61.5) µm] of PSM1 group, were smaller than those of the control group, and the ratio of negative area [40.7% (39.2%)] of the PSM1 group was larger than that of the control group, with significant differences (P < 0.05). The average of positive values [20.0 (42.0) µm] and ratio of positive area of PSM1 group was larger than that of the PSM2 group with significant differences (P < 0.05). CONCLUSION: To establish the incisor guidance of implant-supported single crowns, compared with the average-value virtual articulator and the patient-specific motion only including protrusive movement, the patient-specific motion including protrusive movement and lateral protrusive movement is more conducive to reducing the protrusive interference of prosthesis and improving the occlusal fit.

A digital technique for occlusal design of a posterior full crown based on physiological tooth displacement and occlusion of adjacent teeth.

This article presents a digital technique to construct a virtual occlusion in the maximal intercuspal position (MIP), considering physiological tooth displacement and reducing intermesh penetrations between occlusal surfaces, in order to design more precise and accurate occlusal contacts of a posterior full crown.

Alkyne Polymers from Stable Butatriene Homologues: Controlled Radical Polymerization of Vinylidenecyclopropanes.

Controlled polymerization of cumulenic monomers represents a promising yet underdeveloped strategy toward well-defined alkyne polymers. Here we report a stereoelectronic effect-inspired approach using simple vinylidenecyclopropanes (VDCPs) as butatriene homologues in controlled radical ring-opening polymerizations. While being thermally stable, VDCPs mimic butatrienes via conjugation of the cyclopropane ring. This leads to exclusive terminal-selective propagation that affords a highly structurally regular alkyne-based backbone, featuring complete ring-opening and no backbiting regardless of polymerization conditions.

GABA promotes interstitial fluid clearance in an AQP4-dependent manner by activating the GABAA R.

The glymphatic system is a newly discovered perivascular network where cerebrospinal fluid mixes with interstitial fluid, facilitating clearance of protein solutes and metabolic waste from the parenchyma. The process is strictly dependent on water channel aquaporin-4 (AQP4) expressed on the perivascular astrocytic end-feet. Various factors, such as noradrenaline levels related to the arousal state, influence clearance efficiency, highlighting the possibility that other neurotransmitters additionally modulate this process. To date, the specific role of γ-aminobutyric acid (GABA) in the glymphatic system remains unknown. We used C57BL/6J mice to observe the regulatory effect of GABA on glymphatic pathway by administering a cerebrospinal fluid tracer containing GABA or its GABAA receptor (GABAA R) antagonist through cisterna magna injection. Then, we employed an AQP4 knockout mouse model to explore the regulatory effects of GABA on glymphatic drainage and further study whether transcranial magnetic stimulation-continuous theta burst stimulation (cTBS) could regulate the glymphatic pathway through the GABA system. Our data showed that GABA promotes glymphatic clearance in an AQP4-dependent manner by activating the GABAA R. Furthermore, cTBS was found to modulate the glymphatic pathway by activating the GABA system. Accordingly, we propose that regulating the GABA system by cTBS could modulate glymphatic clearance and provide new insight for clinical prevention and treatment of abnormal protein deposition-related diseases.

Perioperative Renin-Angiotensin System Inhibitors Improve Major Outcomes of Heart Failure Patients Undergoing Cardiac Surgery: A Propensity-Adjusted Cohort Study.

OBJECTIVE: The aim of this study was to study the association of perioperative administration of renin angiotensin system inhibitors (RASi) and clinical outcomes of patients with heart failure (HF) undergoing cardiac surgery. SUMMARY BACKGROUND DATA: It is controversial whether the perioperative RASi should be administered in HF patients undergoing cardiac surgery. METHODS: A total of 2338 patients with HF and undergoing CABG and/or valve surgeries at multiple hospitals from 2001 to 2015 were identified from STS database. After adjustment using propensity score and instrumental variable, logistic regression was conducted to analyze the influence of preoperative continuation of RASi (PreRASi) on short-term in-hospital outcomes. Independent risk factors of 30-day mortality, major adverse cardiovascular events (MACE), and renal failure were analyzed by use of stepwise logistic regression. The effects of pre- and postoperative use of RASi (PostRASi) on long-term mortality were analyzed using survival analyses. Stepwise Cox regression was conducted to analyze the independent risk factors of 6-year mortality. The relationships of HF status and surgery type with perioperative RASi, as well as PreRASi-PostRASi, were also evaluated by subgroup analyses. RESULTS: PreRASi was associated with lower incidences of 30-day mortality [ P < 0.0001, odds ratio (OR): 0.556, 95% confidence interval (CI) 0.405-0.763], stroke ( P =0.035, OR: 0.585, 95% CI: 0.355-0.962), renal failure ( P =0.007, OR: 0.663, 95% CI: 0.493-0.894). Both PreRASi ( P =0.0137) and PostRASi ( P =0.007) reduced 6-year mortality compared with the No-RASi groups. CONCLUSIONS: Pre- and postoperative use of RASi was associated with better outcomes for the patients who have HF and undergo CABG and/or valve surgeries. Preoperative continuation and postoperative restoration are warranted in these patients.

Breast Conservation Surgery and Mastectomy Have Similar Locoregional Recurrence After Neoadjuvant Chemotherapy: Results From 1462 Patients on the Prospective, Randomized I-SPY2 Trial.

Neoadjuvant chemotherapy (NAC) increases rates of successful breast-conserving surgery (BCS) in patients with breast cancer. However, some studies suggest that BCS after NAC may confer an increased risk of locoregional recurrence (LRR). We assessed LRR rates and locoregional recurrence-free survival (LRFS) in patients enrolled on I-SPY2 (NCT01042379), a prospective NAC trial for patients with clinical stage II to III, molecularly high-risk breast cancer. Cox proportional hazards models were used to evaluate associations between surgical procedure (BCS vs mastectomy) and LRFS adjusted for age, tumor receptor subtype, clinical T category, clinical nodal status, and residual cancer burden (RCB). In 1462 patients, surgical procedure was not associated with LRR or LRFS on either univariate or multivariate analysis. The unadjusted incidence of LRR was 5.4% after BCS and 7.0% after mastectomy, at a median follow-up time of 3.5 years. The strongest predictor of LRR was RCB class, with each increasing RCB class having a significantly higher hazard ratio for LRR compared with RCB 0 on multivariate analysis. Triple-negative receptor subtype was also associated with an increased risk of LRR (hazard ratio: 2.91, 95% CI: 1.8-4.6, P < 0.0001), regardless of the type of operation. In this large multi-institutional prospective trial of patients completing NAC, we found no increased risk of LRR or differences in LRFS after BCS compared with mastectomy. Tumor receptor subtype and extent of residual disease after NAC were significantly associated with recurrence. These data demonstrate that BCS can be an excellent surgical option after NAC for appropriately selected patients.

Using whole exome sequencing to identify susceptibility genes associated with nonsyndromic cleft lip with or without cleft palate.

Cleft lip and palate is a common congenital birth defect in humans. Its incidence rate in China is as high as 1.82%, and is now a frequent deformity observed among the Chinese population; moreover, it varies across regions. Although the etiology of nonsyndromic cleft lip with or without cleft palate (NSCL/P) has been widely investigated, the results are inconsistent. The specific genes and mechanisms responsible for NSCL/P have not been fully understood. Whole exome sequencing (WES) is a new strategy for studying pathogenic genes. WES studies on NSCL/P have not been conducted in East China. Therefore, the aim of this study was to screen candidate genes of NSCL/P in East China using WES and analyze the temporal and spatial expressions of the candidate genes during embryonic palatal development. WES was performed in 30 children with NSCL/P from East China to screen candidate genes. A bioinformatics analysis was performed using commercially available software. Variants detected by WES were validated by immunohistochemistry and western blotting. After WES, 506,144 single-nucleotide variant sites were found. The results of database comparison, functional analysis, and mass spectrometry revealed that only the laminin alpha 5 (LAMA5) gene (site: rs145192286) was associated with NSCL/P. Immunohistochemistry results showed that LAMA5 expression in the medial edge epithelium changed with formation, lifting, and contact during palatogenesis. Almost no LAMA5 expression was detected in the palatal mesenchyme or after palatal fusion. Western blotting and immunohistochemistry results showed consistent trends. In conclusion, the WES results shows that the mutation at the site (rs145192286) of LAMA5 is associated with NSCL/P. The temporal and spatial expressions of LAMA5 during palatal development further demonstrate the involvement of this gene. Therefore, we speculate that LAMA5 is a new candidate pathogenic gene of NSCL/P. The identification of new pathogenic genes would help elucidate the pathogenesis of NSCL/P and provide a scientific basis for the prenatal diagnosis, prevention, and treatment of NSCL/P.

Rational engineering NiMoO4nanosheets or Mn3O4nanowires on Fe2O3microdiscs as novel hierarchical anodes for high-performance lithium-ion batteries.

Since current graphite-based lithium-ion battery anode has a low theoretical capacity, the development of high-performance lithium-ion battery is severely restricted. Here, novel hierarchical composites composing of microdisc and the secondarily grown nanosheets and nanowires are developed, taking NiMoO4nanosheets and Mn3O4nanowires growing on Fe2O3microdiscs as demonstrating examples. The growth processes of the hierarchical structures have been investigated by adjusting a series of preparation conditions. The morphologies and structures have been characterized by using scanning electron microscopy, transmission electron microscope and x-ray diffraction. Fe2O3@Mn3O4composite-based anode displays a capacity of 713 mAh g-1after 100 cycles at 0.5 A g-1with a high Coulombic efficiency. A good rate-performance is also achieved. Fe2O3@NiMoO4anode delivers 539 mAh g-1after 100 cycles at 0.5 A g-1, which is obviously higher than that of pure Fe2O3. The hierarchical structure is conducive to improve the transport of electrons and ions, and provide numerous active sites, thus significantly enhancing the electrochemical performance. Moreover, the electron transfer performance is investigated by using density functional theory calculations. It is expected the findings presented here and the rational engineering of nanosheets/nanowires on microdiscs would be applicable for developing many other high-performance energy-storage composites.

p38MAPK silencing attenuates scar proliferation after cleft palate repair surgery in rats via MRTF-A/SRF pathway.

Scarring is the primary factor of maxilla growth restriction among people who have undergone cleft palate repair surgery. p38 mitogen-activated protein kinase (p38MAPK) promotes fibrosis in a variety of organs. However, its role in post-surgery scarring on the hard palate has not been fully understood. This study is designed to investigate the role of p38MAPK in scar formation and maxilla growth of rats. We removed the mucosa on the hard palate of rats and applied the p38MAPK silencing adenovirus vector on it two weeks after surgery. Then the scarring tissue and maxilla growth were evaluated by histological and morphological examination. The effect of p38MAPK silencing on scarring-related genes in fibroblasts was also studied. We found that local injection of Ad-p38MAPK-1 in vivo effectively reduces the expression of p38MAPK and scarring-related proteins and weakens the impact of scarring on the width of the hard palate. Mechanistically, p38MAPK silencing inhibits the expression of α-smooth muscle actin (α-SMA) via mediating the production and nuclear localization of myocardin-related transcription factor A (MRTF-A) in fibroblasts. These results reveal a molecular pathway of scar formation involving p38MAPK/MRTF-A stimulation and support targeting p38MAPK as a potentially effective treatment for post-surgery scarring on the hard palate.