Correlation between aquaporin-4 and brain edema in an animal model of astrocytic oxygen-glucose deprivation and reintroduction

BACKGROUND：Previous studies have demonstrated that aquaporin-4 （AQP4） plays a key role in the formation and resolution of brain edema.However,the molecular mechanisms and role of AQP4 in hypoxia-ischemia-induced brain edema remain poorly understood.OBJECTIVE：To establish a newborn animal model of astrocytic oxygen-glucose deprivation and reintroduction,to observe the correlation between AQP4 and cellular volume,and to investigate the role of AQP4 in the development of brain edema following oxygen deprivation and reintroduction.DESIGN,TIME AND SETTING：A comparative experiment was performed at the Experimental Center of West China Second University Hospital between October 2007 and April 2009.MATERIALS：Astrocytes were derived from the neocortex of Sprague Dawley rats aged 3 days.METHODS：Astrocytes were incubated in glucose/serum-free Dulbecco＇s modified Eagle＇s medium,followed by 1% oxygen for 6 hours.Finally,oxygen-glucose deprivation and reintroduction models were successfully established.MAIN OUTCOME MEASURES：Real-time polymerase chain reaction and Western blot analysis were used to measure expression of AQP4 mRNA and protein in cultured rat astrocytes following oxygen-glucose deprivation and reintroduction.Astrocytic cellular volume,as determined by [3H]-3-O-methyl-D-glucose,was used to represent the extent of astrocytic swelling.RESULTS：During oxygen-glucose deprivation,AQP4 mRNA and protein expression gradually decreased in astrocytes,whereas cellular volume increased in a time-dependent manner （P〈 0.01）.Following oxygen-glucose reintroduction,AQP4 mRNAand protein expression was upregulated,peaked at day 7,and then gradually decreased,but still higher than normal levels （P 〈 0.05）.However,cellular volume gradually decreased （P 〈 0.01）,and then reached normal levels at day 7.CONCLUSION：AQP4 expression highly correlated with cellular volume changes,suggesting that AQP4 played an important role in modulating brain water transport in an astrocytic oxygen-glucose deprivation and reintroduction model.

A genetic variant study of bortezomib-induced peripheral neuropathy in Chinese multiple myeloma patients

Background:Bortezomib results in peripheral neuropathy(PN)in approximately 50%of patients,during multiple myeloma(MM)treatment,a complication known as Bortezomib-induced peripheral neuropathy(BIPN).The drug response varies among individuals.Genetic factor may play an important role in BIPN.Methods:A nextgeneration sequencing(NGS)panel containing 1659 targets from 233 genes was used to identify risk variants for developing BIPN in 204 MM patients who received bortezomib therapy.mRNA expression of MTHFR and ALDH1A1 in 62 peripheral blood samples was detected by real-time quantitative PCR(RT-qPCR).Serum homocysteine(Hcy)levels were detected in 40 samples by chemiluminescent microparticle immunoassay(CMIA).Results:Compared with the non-BIPN group(n=89),a total of 8 significantly associated single nucleotide polymorphisms(SNPs)were identified in the BIPN group(n=115):MTHFR(rs1801131,rs1801133,rs17421511),EPHX1(rs1051740),MME(rs2016848),ALDH1A1(rs6151031),HTR7(rs1935349)and CYP2A6(rs8192720).The mRNA expression level of MTHFR in newly diagnosed patients with peripheral neuritis after treatment(NP group)was lower than that of newly diagnosed patients without peripheral neuritis after treatment(NnP group)(1.70±0.77 vs.2.81±0.97,p=0.009).Serum Hcy levels were significantly higher in BIPN group than in non-BIPN group(11.66±1.79μmol/L vs.8.52±3.29μmol/L,p=0.016)and healthy controls(11.66±1.79μmol/L vs.8.55±2.13μmol/L,p≤0.001).Conclusion:CYP2A6,EPHX1,MTHFR,ALDH1A1,HTR7,MME and BIPN are linked in Chinese MM patients.BIPN is more likely to occur in patients with lower MTHFR mRNA expression,which might result in higher serum Hcy levels.

Analyzing the potential mechanism of Buyang Huanwu decoction for the treatment of salt-sensitive hypertension based on network pharmacology and in vivo experiments

Background:Buyang Huanwu decoction(BHD)is a traditional Chinese medicine herbal formula used for treating hypertension,particularly in the later stages of hypertension when it is associated with intracerebral hemorrhage.This study aims to investigate the treatment mechanism of BHD to provide a basis for its clinical application in hypertension treatment.Methods:Network pharmacology analysis and cell culture experiments were performed to explore the potential proteins and mechanisms of action of BHD against hypertension.Bioactive compounds related to BHD were screened,and relevant targets associated with hypertension and BHD were retrieved.Molecular docking technology was used to identify the effective signaling pathway based on the Kyoto Encyclopedia of Genes and Genomes and protein-protein interaction network cores.Lastly,the effects and mechanisms of BHD on salt-sensitive hypertensive endothelial cells were investigated.Results:Ninety-three potential therapeutic targets for BHD and salt-sensitive hypertension were found to be closely associated with the PI3K/Akt/eNOS signaling pathway and oxidative stress.Cell experiments further indicated the pivotal role of endothelial cells in hypertension,and validation analysis showed that BHD significantly preserved cell morphology,suppressed oxidative stress reactions,activated the PI3K/Akt/eNOS signaling pathways,preserved normal endothelial cell function,and reduced cell apoptosis.Conclusion:BHD effectively activates the PI3K/Akt/VEGF signaling pathway,attenuates oxidative stress-induced injury in endothelial cells exposed to high salt levels,and mitigates apoptosis,supporting the use of traditional Chinese medicine BHD in the treatment of salt-sensitive hypertension.

Short Pulse Width and High Peak Power 457 nm Deep Blue Laser with V-Type Cavity

An intracavity frequency doubling acousto-optically Q-switched Neodymium-doped Yttrium Orthvanadate (Nd:YVO4) 457 nm blue laser by employing a three-mirror folded cavity was demonstrated. With the incident pump power of 40.4 W, the maximum average output power of 439 mW 457 nm laser, and the minimum pulse duration of 86.14 ns and the maximum peak power of 510 W were achieved at 10 kHz. The M2 factors are 1.23 and 1.61 in X and Y directions, respectively. The power stability in two hours is better than 2%.

Structure Design of Disposable Ocean Temperature Depth Sensing Probe Based on F-P Cavity and FBG

The basic principle of sensing is the combination of F-P cavity interference and fiber grating reflection. A hybrid structure sensor probe has been designed based on the combination of an F-P cavity of liquid-filled thermometer structure, and a fiber grating with an elastic diaphragm, herein F-P cavity is used for temperature sensing, and the fiber grating is used for pressure sensing. By adopting the dual optical path structure, the dual-parameter detection of temperature and depth is realized, which solves the problem of low accuracy caused by the cross response of temperature and pressure of a single sensor device and the calculation of the depth information of the ocean with empirical formulas. Compared with traditional sensors, the sensitivity is effectively improved. Theoretical analysis shows that the sensitivity of the F-P cavity with a thermometer structure filled with kerosene reaches 1.334 nm/?C, and the depth sensitivity of the fiber grating is 284.6 pm/Mpa within the ocean depth range of 0 - 400 m.

长蛇灸治疗脾肾阳虚型功能性腹泻的临床研究

【目的】观察长蛇灸疗法对脾肾阳虚型功能性腹泻患者的临床疗效及对肠道菌群的影响。【方法】将60例脾肾阳虚型功能性腹泻患者随机分为观察组和对照组,每组各30例。观察组给予长蛇灸治疗,每周1次,连续治疗4周。对照组给予四神丸合附子理中丸治疗,每次各9 g,每日2次,7 d为1个疗程,共治疗4个疗程。评价2组临床疗效,比较2组患者治疗前后各项中医症状积分及症状总积分的变化情况,以及观察组患者肠道菌群物种丰度、Alpha多样性指数、优势菌群、菌群分布及治疗前后群落差异等指标。【结果】(1)观察组总有效率为73.33%,对照组为56.67%。观察组疗效优于对照组(P<0.05)。(2)治疗后,2组患者的各项临床症状积分均明显改善,但差异无统计学意义(P>0.05);治疗后,2组患者症状总积分明显改善(P<0.05),且观察组优于对照组(P<0.05)。2组患者治疗前后症状总积分差值比较,观察组优于对照组(P<0.05)。(3)治疗前后能够检测到的比例在1%以上的肠道菌群共有5个门,即拟杆菌门、厚壁菌门、变形菌门、放线菌门、梭杆菌门。其中长蛇灸疗法治疗后梭杆菌门的相对丰度明显高于治疗前(P<0.05),其他菌门相对丰度值治疗前后比较,差异无统计学意义(P>0.05)。(4)治疗后观察组毛螺菌属、嗜血杆菌属、萨特氏菌属相对丰度值明显低于治疗前,而梭杆菌属相对丰度值明显高于治疗前(P<0.05)。(5)观察组属分类水平物种丰度聚类热图结果显示:普雷沃氏菌属、拟杆菌属、栖粪杆菌属在各样本中丰度较高;患者治疗前后样本肠道菌群的优势菌群存在明显区别。(6)观察组患者治疗后Observed species指数较治疗前下降(P<0.05),治疗前后Chao1指数、Shannon指数、Simpson指数和PD whole tree指数变化无统计学意义(P>0.05)。(7)Beta多样性检测显示,治疗前5个样本分布比较集中;治疗后3个样本较集中、2个样本分布离散,可能是由于个体差异的存在,治疗对不同个体的肠道菌群结构的作用也存在一定差异。(8)观察组治疗后毛螺菌科梭菌属较治疗前显著升高,梭菌科梭菌属、毛螺菌属以及厚壁菌门梭菌目菌属均较治疗前显著下降。(9)2组患者中仅有1例患者在长蛇灸治疗后出现了少量局部的水泡,其余患者均无不良反应发生。【结论】长蛇灸疗法治疗脾肾阳虚型功能性腹泻具有良好的临床疗效,其疗效可能是通过改善肠道菌群结构来实现的。

Comparison of intravitreal bevacizumab with intravitreal triamcinolone acetonide for treatment of cystoid macular edema secondary to retinal vein occlusion : a Meta-analysis

AIMTo compare the effects of intravitreal injection of bevacizumab (IVB) with intravitreal triamcinolone acetonide (IVTA) on the treatment of cystoid macular edema (CME) secondary to retinal vein occlusion (RVO).METHODSA literature search was conducted using PubMed, the Cochrane Central Register of Controlled Trials, Web of Science and the Chinese Biomedical Database. The comparison was divided into two groups, group 1 conducted comparison in branch RVO (BRVO) or central RVO (CRVO), group 2 conducted comparison in ischemic-RVO or nonischemic-RVO. Pooled mean differences (MDs) for changes in visual acuity (VA), central macular thickness (CMT) and intraocular pressure (IOP) were calculated in groups at 4, 12 and 24wk after treatment respectively.RESULTSEight studies comparing the efficacy of IVB with IVTA were included in the Meta-analysis. In group 1, in BRVO, significant difference was shown on the comparison of CMT at 24wk (MD, -45.66; 95% CI, -76.03 to -15.28; P=0.003), IVB was effective on BRVO for at least 24wk; no significant differences were found in the comparison of VA at each time points (P&#x0003e;0.05 respectively). In CRVO, no significant differences were found in the comparison of VA or CMT between IVB and IVTA at each time points (P&#x0003e;0.05, respectively). In group 2, in ischemic-RVO, significant differences were shown in the comparison of VA (MD, -0.28; 95% CI, -0.42 to -0.14; P&#x0003c;0.0001) and CMT (MD, -86.50; 95% CI, -151.18 to -22.43; P=0.008) at 24wk; In nonischemic-RVO, no significant differences were demonstrated in the comparison of VA or CMT between IVB and IVTA at each time points (P&#x0003e;0.05, respectively). The occurrence of high IOP was much lower in IVB group.CONCLUSIONThis Meta-analysis suggested that IVB was effective in decreasing CMT in BRVO for at least 24wk, IVB is more effective on improving VA and reducing CMT in ischemic-RVO. IVB is more promising on RVO than IVTA.

Anemia in patients with Takayasu arteritis: prevalence, clinical features, and treatment

Background Anemia is a common comorbidity of patients with Takayasu arteritis(TA). This study evaluated the prevalence, clinical characteristics, and treatment in Chinese TA patients with anemia. Methods This retrospective study included 533 consecutive patients hospitalized for TA from January 2009 to April 2018. Anemia was diagnosed on the basis of hemoglobin level, according to World Health Organization criteria. Results A total of 194 patients(36.4%) were diagnosed with anemia. Most had mild anemia(177, 91.2%). Female patients were predominant(92.8% of anemic patients). Normocytic anemia(62.9%) was the most common pattern. Anemic patients were more likely than non-anemic patients to have dizziness(29.4% vs. 21.2%), low body mass index(22.0 ± 3.6 vs. 22.9 ± 3.4 kg/m2), and active disease stage(64.9% vs. 50.1%);pulmonary involvement(12.4% vs. 26.8%), pulmonary hypertension(12.9% vs. 20.1%) and pulmonary hypertensive-target drugs(2.8% vs. 11.6%) were less common among anemic than non-anemic patients(all P < 0.05). Larger left ventricular end-diastolic diameter and lower left ventricular ejection fraction were observed in anemic patients. Over a median follow-up of four months, the increase of hemoglobin in anemic patients was associated with the use of iron supplementation. Conclusions Anemia is a very common concurrent condition in TA, especially in young, female patients. Patients with anemia are more likely to be in the active disease stage. Iron supplementation helps increase hemoglobin.

Change of retinal nerve fiber layer thickness in patients with nonarteritic inflammatory anterior ischemic optic neuropathy

In this study, 16 patients （19 eyes） with nonarteritic anterior ischemic optic neuropathy in the acute stage （within 4 weeks） and resolving stage （after 12 weeks） were diagnosed by a series of complete ophthalmic examinations, including fundus examination, optical coherence tomography and fluorescein fundus angiography, and visual field defects were measured with standard automated perimetry. The contralateral uninvolved eyes were used as controls. The retinal nerve fiber layer thickness was determined by optical coherence tomography which showed that the mean retinal nerve fiber layer thickness and the retinal nerve fiber layer thickness from temporal, superior, nasal and inferior quadrants were significantly higher for all measurements in the acute stage than the corresponding normal values. In comparison, the retinal nerve fiber layer thickness from each optic disc quadrant was found to be significantly lower when measured at the resolving stages, than in the control group. Statistical analysis on the correlation between optic disc nerve fiber layer thickness and visual defects demonstrated a positive correlation in the acute stage and a negative correlation in the resolving stage. Our experimental findings indicate that optical coherence tomography is a useful diagnostic method for nonarteritic anterior ischemic optic neuropathy and can be used to evaluate the effect of treatment.

Vascular endothelial growth factor: an attractive target in the treatment of hypoxic/ischemic brain injury

Cerebral hypoxia or ischemia results in cell death and cerebral edema, as well as other cellular reactions such as angiogenesis and the reestablishment of functional microvasculature to promote recovery from brain injury. Vascular endothelial growth factor is expressed in the central nervous system after hypoxic/ischemic brain injury, and is involved in the process of brain repair via the regulation of angiogenesis, neurogenesis, neurite outgrowth, and cerebral edema, which all require vascular endothelial growth factor signaling. In this review, we focus on the role of the vascular endothelial growth factor signaling pathway in the response to hypoxic/ischemic brain injury, and discuss potential therapeutic interventions.

Influence of hypoxia-inducible factor 1-alpha on neuronal apoptosis in a rat model of hypoxia-or hypoxia-ischemia-induced brain injury

BACKGROUND： In addition to neuroprotective genes, the targeted genes of hypoxia-inducible factor 1α （HIF-1α） include pro-apoptotic genes. However, the influence of HIF-1α on neuronal apoptosis in hypoxia-ischemia remains poorly understood. OBJECTIVE： To investigate the relationship between HIF-1α expression and neuronal apoptosis in hypoxia or hypoxia-ischemia brain injury and to determine the role of HIF-1α in regulating neuronal apoptosis. DESIGN, TIME AND SETTING： A randomized, controlled animal experiment was performed at the Laboratory of Children Neurology of Sichuan University between May 2006 and May 2007. MATERIALS： In situ cell death detected kit was provided by Roche, USA; rabbit anti-mouse HIF-1α polyclonal antibody was purchased from Santa Cruz Biotechnologies, USA; rabbit anti-mouse cleaved caspase-3 polyclonal antibody was purchased from Chemicon, USA. METHODS： A total of 36 Sprague Dawley rats aged 10 days were randomly assigned to 3 groups： sham-surgery, hypoxia, and hypoxia-ischemia, with 12 rats per group. The rats were treated at 3 time points： 4, 8, and 24 hours, with 4 rats per time point. In the hypoxia-ischemia group, the right common carotid artery was exposed and permanently ligated through a midline cervical incision. A 2.5-hour exposure to hypoxia （8% O2/92% N2） was used to induce hypoxia-ischemia injury. In the hypoxia group, rats were exposed to hypoxia without ligation of the common carotid artery. In the sham-surgery group, the common carotid artery was exposed without ligation or hypoxia. MAIN OUTCOME MEASURES： Histopathological changes, HIF-1α and activated caspase-3 protein expression, integrated optical density of positive cells, and apoptosis-positive cells. RESULTS： Hematoxylin and eosin staining showed that neuronal degeneration and edema was most prominent at 24 hours after hypoxia-ischemia. HIF-1α protein expression was significantly upregulated at 4 hours, peaked at 8 hours, and decreased at 24 hours after hypoxia or hypoxia-ischemia. HIF-1α protein expression was significant greater in the hypoxia and hypoxia-ischemia groups compared with the sham-surgery group （P 〈 0.01）. Activated caspase-3 protein expression began to increase at 4 and 8 hours following hypoxia or hypoxia-ischemia and was significantly upregulated at 24 hours. Activated caspase-3 protein expression remained at low levels in the sham controls compared with the hypoxia and hypoxia-ischemia groups （P〈 0.01）. TUNEL staining showed that the number of apoptotic cells significantly increased at 24 hours after hypoxia or hypoxia-ischemia. In addition, HIF-1α protein expression was greater in the hypoxia group compared with the hypoxia-ischemia group at the same time point （P 〈 0.05）. However, activated caspase-3 expression and the number of TUNEL-positive cells were less in the hypoxia group compared with the hypoxia-ischemia group at the same time point （P〈 0.05）. CONCLUSION： HIF-1α played a neuroprotective role following hypoxia-ischemia brain injury.

High power semiconductor laser array with single-mode emission

The semiconductor laser array with single-mode emission is presented in this paper.The 6-μm-wide ridge waveguides(RWGs)are fabricated to select the lateral mode.Thus the fundamental mode of laser array can be obtained by the RWGs.And the maximum output power of single-mode emission can reach 36 W at an injection current of 43 A,after that,a kink will appear.The slow axis(SA)far-field divergence angle of the unit is 13.65.The beam quality factor M;of the units determined by the second-order moment(SOM)method,is 1.2.This single-mode emission laser array can be used for laser processing.

Subconjunctival injections of triamcinolone acetonide to treat uveitic macular edema

AIM:To evaluate the efficacy and safety of subconjunctival triamcinolone acetonide(TA)injections for treating uveitic macular edema(UME).METHODS:This retrospective case series study included patients with UME who received subconjunctival TA injections with a minimum follow-up period of 6 mo.The main outcome measure was central macular thickness(CMT).The secondary outcome measures included best-corrected visual acuity(BCVA),recurrence rate and intraocular pressure(IOP).RESULTS:In total,65 patients(80 eyes),mainly including idiopathic uveitis in 33 patients(50.77%)and VogtKoyanagi-Harada(VKH)syndrome in 19 patients(29.23%),were enrolled in this study.The mean CMT decreased from 457.6±173.0μm at baseline to 325.9±176.8,302.7±148.2,332.2±177.3 and 270.6±121.6μm at 1-,2-,3-and 6-months postinjection,respectively(all P<0.001).BCVA increased from log MAR 0.5±0.3 at baseline to log MAR 0.4±0.3,0.4±0.3,0.4±0.4 and 0.4±0.3 at the 1-,2-,3-and 6-months postinjection visits,respectively(all P<0.001).Twenty-one(21/80,26.25%)eyes underwent relapse of UME within 6 mo.A total of 20/80(25%)eyes exhibited elevated IOPs,of which 13 eyes were controlled with topical IOP-lowering agents and 7 eyes underwent surgical removal of subconjunctival TA deposit.CONCLUSION:Subconjunctival TA injections appear to be safe and effective for UME.

Clinical characteristics and management of coexistent cardiomyopathy in patients with bicuspid aortic valve

BACKGROUND Bicuspid aortic valve(BAV)is the most common congenital heart disease.However,the prevalence,clinical characteristics,and current management of BAV associated with inherited cardiomyopathy,including hypertrophic cardiomy-opathy(HCM),dilated cardiomyopathy(DCM),and left ventricular noncompaction(LVNC)have not been well described.METHODS Consecutive patients diagnosed with BAV at a large tertiary cardiovascular referral center between 2009 and 2018 were retrospectively assessed for HCM,DCM,and LVNC based on clinical and echocardiographic criteria.Patients with coexist-ent conditions were investigated further.RESULTS Of 3533 patients with BAV screened,57(1.6%)had concomitant cardiomyopathy.BAV was combined with HCM in 30 of these patients,with DCM in 19,and with LVNC in eight.Forty-six patients(80.7%)were male,and the mean age at first dia-gnosis was 47 years for BAV with HCM,49 years for BAV with DCM,and 35 years for BAV with LVNC.Heart failure and aortic valve dysfunction were common in these patients,and the prevalence of coexisting aortopathy was 43.3%,26.3%and 25.0%,re-spectively,for BAV with HCM,DCM and LVNC.During the index hospitalization,24 of the 57 patients(42.1%)underwent sur-gery,16(28%)underwent aortic valve and/or aortic surgery,and 16 of the 30 patients with HCM had a Morrow procedure.There were no deaths or other major adverse cardiovascular events.CONCLUSIONS The prevalence of inherited cardiomyopathy was higher in our patients with BAV than in the general popula-tion.Aortopathy and heart failure were common,with almost half of patients requiring surgery at diagnosis.

Implication of a novel truncating mutation in titin as a cause of autosomal dominant left ventricular noncompaction

BACKGROUND Mutation in the titin gene(TTN)in left ventricular noncompaction(LVNC)has been reported with a highly heterogeneous prevalence,and the molecular mechanisms underlying the pathogenesis of TTN gene mutation are uncharacteri-zed.In the present study,we identified a novel TTN mutation in a pedigree with LVNC and investigated the potential pathogenic mechanism by functional studies.METHODS The whole-genome sequencing with linkage analysis was performed in a 3-generation family affected by autoso-mal dominant LVNC cardiomyopathy.The clustered regularly interspaced short palindromic repeats associated protein 9(CRISPR/Cas9)technology was used to establish novel truncating mutation in TTN in a rat cardiomyoblast H9C2 cell line in vitro,in which functional studies were carried out and characterized in comparison to its wild-type counterpart.RESULTS A novel truncating mutation TTN p.R2021X was identified as the only plausible disease-causing variant that segreg-ated with disease among the five surviving affected individuals,with an interrogation of the entire genome excluding other po-tential causes.Quantitative reverse transcription-polymerase chain reaction and cellular immunofluorescence supported a haplo-insufficient disease mechanism in titin truncation mutation cardiomyocytes.Further functional studies suggested mitochondrial abnormities in the presence of mutation,including decreased oxygen consumption rate,reduced adenosine triphosphate produc-tion,impaired activity of electron translation chain,and abnormal mitochondrial structure on electron microscopy.Impaired aut-ophagy under electron microscopy accompanied with activation of the Akt-mTORC1 signaling pathway was observed in TTN p.R2021X truncation mutation cardiomyocytes.CONCLUSIONS The TTN p.R2021X mutation has a function in the cause of a highly penetrant familial LVNC.These findings expand the spectrum of titin’s roles in cardiomyopathies and provide novel insight into the molecular basis of titin-truncating variants-associated LVNC.

A novel missense mutation in obscurin gene in a Chinese consanguineous family with left ventricular noncompaction

BACKGROUND Left ventricular noncompaction(LVNC) is an increasingly recognised cardiomyopathy of which a significant percentage are genetic in origin. The purpose of the present study was to identify potential pathogenic mutation leading to disease in a Chinese LVNC family.METHODS A 3-generation family affected by LVNC was recruited. Clinical assessments were performed on available family members, with clinical examination, ECG, echocardiography and cardiac MRI. The proband(Ⅰ-2), the proband’s daughter(Ⅱ-1, affected) and mother(Ⅲ-1, unaffected) were selected for WGS. Sanger sequencing were performed in all of the 4 surviving family members.RESULTS Combined whole genome sequencing with linkage analysis identified a novel missense mutation in the giant protein obscurin(OBSCN NM_001098623, c.C19063T), as the only plausible disease-causing variant that segregates with disease among the four surviving individuals, with interrogation of the entire genome excluding other potential causes. This c.C19063T missense mutation resulted in p.R6355W in the encoded OBSCN protein. It affected a highly conserved residue in the C terminus of the obscurin-B-like isoform between the PH and STKc domains, which was predicted to affect the function of the protein by different bioinformatics tools.CONCLUSIONS Here we present clinical and genetic evidence implicating the novel R6355W missense mutation in obscurin as the cause of familial LVNC. This expands the spectrum of obscurin’s roles in cardiomyopathies. It furthermore highlights that rare obscurin missense variants, currently often ignored or left uninterpreted, should be considered to be relevant for cardiomyopathies and can be identified by the approach presented here. This study also provided new insights into the molecular basis of OBSCN mutation positive LVNC.

Effect of the yaw angle on turbulent flow structures around the submarine model

The objective of this paper is to investigate the turbulent flow structures around the submarine model and evaluate the effect of the yaw angle on the turbulent flow characteristics.The large eddy simulation based on the boundary data immersion method is used to investigate.The computational domain consists of 1.2×10^(8)uniformly distributed Cartesian orthogonal grid nodes to capture the basic flow characteristics around the model.The pressure coefficient,friction coefficient and wake velocity distribution are in good agreement with the experimental data.Three different types of vortex structures were mainly captured around the model,including horseshoe vortex,sail tip vortex and crossflow separation vortex.With the increase of the yaw angle,the asymmetry of the horseshoe vortex and the tip vortex gradually increases,and the vortex strength of the vortex leg on the windward of the horseshoe vortex and the vortex strength of the tip vortex also increase gradually.For the crossflow separation vortex,the flow separation zone gradually expands and migrates downstream with the increase of the yaw angle.

A new cell death program regulated by toll-like receptor 9 through p38 mitogen-activated protein kinase signaling pathway in a neonatal rat model with sepsis associated encephalopathy

Background:Sepsis,a serious condition with high mortality,usually causes sepsis associated encephalopathy(SAE)that involves neuronal cell death.However,the cell death programs involved and their underlying mechanisms are not clear.This study aimed to explore the regulatory mechanisms of different cell death programs in SAE.Methods:A neonatal rat model of SAE was established by cecal ligation and perforation.Survival rate and vital signs(mean arterial pressure and heart rate)were monitored,nerve reflexes were evaluated,and cortical pathological changes were observed by hematoxylin and eosin staining.The expression of pyroptosis,apoptosis,and necroptosis(PANoptosis)-related proteins,mitogen-activated protein kinase(MAPK),and its upstream regulator toll-like receptor 9(TLR9)were detected.The expression of TLR9 in neurons was observed by immunofluorescence staining.The ultrastructure of neurons was observed by transmission electron microscope.Results:First,PANoptosis was found in cortical nerve cells of the SAE rats.Meanwhile,the subunits of MAPKs,p38 MAPK,Jun N-terminal kinase,and extracellular signal-regulated kinase(ERK)were activated.After pharmacologically inhibiting each of the subunits,only p38 MAPK was found to be associated with PANoptosis.Furthermore,blocking the p38 MAPK signaling pathway activated necroptosis but inhibited apoptosis and pyroptosis.When necroptosis was pharmacologically inhibited,apoptosis and pyroptosis were reactivated.Finally,we found that the expression of TLR9,a regulator of MAPKs,was significantly increased in this model.After down-regulation of TLR9,p38 MAPK,and ERK signaling pathways were inhibited,which led to the inhibition of PANoptosis.Further analysis found that down-regulation of TLR9 improved the survival rate and reduced the pathological changes in SAE rats.Conclusions:Our study showed that the programs comprising PANoptosis are activated simultaneously in SAE rats.TLR9 activated PANoptosis through the p38 MAPK signaling pathway.TLR9 may work as a potential target for SAE treatment.

Intensive phototherapy vs.exchange transfusion for the treatment of neonatal hyperbilirubinemia:a multicenter retrospective cohort study

Background:Intensive phototherapy(IPT)and exchange transfusion(ET)are the main treatments for extreme hyperbilirubinemia.However,there is no reliable evidence on determining the thresholds for these treatments.This multicenter study compared the effectiveness and complications of IPT and ET in the treatment of extreme hyperbilirubinemia.Methods:This retrospective cohort study was conducted in seven centers from January 2015 to January 2018.Patients with extreme hyperbilirubinemia that met the criteria of ET were included.Patients were divided into three subgroups(low-,medium-,and high-risk)according to gestational week and risk factors.Propensity score matching(PSM)was performed to balance the data before treatment.Study outcomes included the development of bilirubin encephalopathy,duration of hospitalization,expenses,and complications.Mortality,auditory complications,seizures,enamel dysplasia,ocular motility disorders,athetosis,motor,and language development were evaluated during follow-up at age of 3 years.Results:A total of 1164 patients were included in this study.After PSM,296 patients in the IPT only group and 296 patients in the IPT plus ET group were further divided into the low-,medium-,and high-risk subgroups with 188,364,and 40 matched patients,respectively.No significant differences were found between the IPT only and IPT plus ET groups in terms of morbidity,complications,and sequelae.Hospitalization duration and expenses were lower in the low-and medium-risk subgroups in the IPT only group.Conclusions:In this study,our results suggest that IPT is a safe and effective treatment for extreme hyperbilirubinemia.The indication of ET for patients with hyperbilirubinemia could be stricter.However,it is necessary to have a contingency plan for emergency ET as soon as IPT is commenced especially for infants with risk factors.If IPT can be guaranteed and proved to be therapeutic,ET should be avoided as much as possible.

Assessing the ecological vulnerability of protected areas by using Big Earth Data

The ecological vulnerability of global protected areas(PAs)is linked to the 2030 United Nations Sustainable Development Goals.We developed a novel degree of ecological vulnerability(DEV)index based on Big Earth Data to assess the ecological vulnerability of PAs.This is a transparent,repeatable,large-scale and rapid assessment method.We applied the method to case studies of International Union for Conservation of Nature(IUCN)PAs in the basins of the Aral Sea,the Caspian Sea,the Black Sea and the Lake Baikal.Between 2001 and 2015,the spatial pattern of ecological vulnerability in the study area was relatively stable.The Caspian Sea basin and protected landscape/seascape(category V)showed high ecological vulnerability,while the Black Sea basin and wilderness areas(category Ib)showed low ecological vulnerability.Big Earth Data shows great vitality in PAs ecological vulnerability assessment.Strengthening international cooperation is an important means to break the bottleneck of ecological environment and resource endowment in these important international basins.