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To evaluate the risk factors of recurrent high-grade cervical intraepithelial neoplasia grade 2 or worse (CIN2+) after loop electrosurgical excision procedure (LEEP).This retrospective study included patients with histopathologically confirmed CIN2/3 who underwent LEEP in 2015-2020. Cox regression analysis was used to evaluate the risk factors of recurrence.Recurrent CIN2+ was found in 268 patients after LEEP (268/4369, recurrence rate, 6.1%). High-risk (hr-) HPV infection (hazard ratio [HR] 12.09, 95% confidence interval [CI] 7.78-18.79), margin status (HR 6.48, 95% CI 4.75-8.84), baseline diagnosis (HR 1.45, 95% CI 1.08-1.95), smoking (HR 3.17, 95% CI 2.27-4.43), and immunosuppression (HR 1.96, 95% CI 1.33-2.91) were significant independent risk factors of recurrence. HPV16 (HR 3.61, 95% CI 2.43-5.37), HPV33 (HR 2.62, 95% CI 1.12-6.12), and HPV52 (HR 1.61, 95% CI 1.02-2.55) infection showed a higher risk of recurrence. High-risk HPV had the highest accuracy (sensitivity 88.5%; negative predictive values 98.7%) in predicting recurrence compared with liquid-based cytology test and margins.Given that positive margins present a higher risk, wide excision may be required to avoid residual lesions. More attention should be paid to the correlation between recurrence and hr-HPV genotypes. After treatment for high-grade CIN, HPV-based testing is recommended at 6 months. Timely identification of high-risk factors enables risk stratification, and enables individual management or individual follow-up and recall strategies.

Background Where the gene is expressed determines the function of the gene. Neuregulin 1 (Nrg1) encodes a tropic factor and is genetically linked with several neuropsychiatry diseases such as schizophrenia, bipolar disorder and depression. Nrg1 has broad functions ranging from regulating neurodevelopment to neurotransmission in the nervous system. However, the expression pattern of Nrg1 at the cellular and circuit levels in rodent brain is not full addressed. Methods Here we used CRISPR/Cas9 techniques to generate a knockin mouse line (Nrg1Cre/+) that expresses a P2A-Cre cassette right before the stop codon of Nrg1 gene. Since Cre recombinase and Nrg1 are expressed in the same types of cells in Nrg1Cre/+ mice, the Nrg1 expression pattern can be revealed through the Cre-reporting mice or adeno-associated virus (AAV) that express fluorescent proteins in a Cre-dependent way. Using unbiased stereology and fluorescence imaging, the cellular expression pattern of Nrg1 and axon projections of Nrg1-positive neurons were investigated. Results In the olfactory bulb (OB), Nrg1 is expressed in GABAergic interneurons including periglomerular (PG) and granule cells. In the cerebral cortex, Nrg1 is mainly expressed in the pyramidal neurons of superficial layers that mediate intercortical communications. In the striatum, Nrg1 is highly expressed in the Drd1-positive medium spiny neurons (MSNs) in the shell of nucleus accumbens (NAc) that project to substantia nigra pars reticulata (SNr). In the hippocampus, Nrg1 is mainly expressed in granule neurons in the dentate gyrus and pyramidal neurons in the subiculum. The Nrg1-expressing neurons in the subiculum project to retrosplenial granular cortex (RSG) and mammillary nucleus (MM). Nrg1 is highly expressed in the median eminence (ME) of hypothalamus and Purkinje cells in the cerebellum. Conclusions Nrg1 is broadly expressed in mouse brain, mainly in neurons, but has unique expression patterns in different brain regions.

Objectives Identification of characteristics and risk factors of new-onset dermatomyositis patients with recurrent aggravation after regular treatment. Methods In this cohort study, clinical characteristics of 142 new-onset dermatomyositis patients were analyzed. We defined three different clinical outcomes after long-term follow-up: mild, aggravation, and death. The clinical presentation of patients with recurrent aggravations was primarily analyzed and discussed in this cohort. The decision tree algorithm was used to predict the outcomes. Results In this corhort, there were 72 in the mild group, 56 in the aggravation group (39 were single aggravation and 17 were multiple aggravations), 14 in the death group. The median time point for patients to experience their first aggravation was 40 weeks after initial treatment, the median interval between multiple aggravations was 32 weeks, and for anti-MDA5 positive patients, the median interval was 16 weeks. Symptoms of aggravation were generally manifested as progression of pulmonary interstitial lesions, or extended skin rashes. Baseline CRP and CK levels were higher in the multiple aggravations or death group. Conclusions DM patients tended to aggravate after glucocorticoid was regular reduced to approximately the lowest maintenance dose. Higher baseline CRP and CK levels have a certain predictive effect on adverse outcomes in DM.

Chemokines and immunomodulatory factors involve in tumor development. Papillary thyroid carcinoma (PTC) is considered to start from dendritic cell infiltration and then produce immunomodulatory factors. In this study, CXCR4 and PD-L1 biomarkers were used to explore their prognostic role in PTC survival. Confocal microscopy detected the transfection efficiency in tumor cells. 42 PTC patients and thyroiditis patients (control) were enrolled to measure the expressions of CXCR4 and PD-L1. Multi-factor analysis analyzed the effect of combined CXCR4 and PD-L1 expression on ROC. The two groups had no differences in the baseline characteristics. CTXCR4 and PD-L1 level in PTC patients was significantly higher than control. CXCR4 was lowly expressed in thyroid cancer tissue and PD-L1 was highly expressed in serological samples. Compared with single measurement, the combined detection of CXCR4 and PD-L1 showed more ROC area. In conclusion, reduced CXCR4 and increased PD-L1 level is found in thyroid cancer and their level might be used as predictive markers for PTC to improve the curative effect.

Recent experiments have revealed multiple borophene phases of distinct lattice structures, suggesting that the unit cells of the $\nu_{1/6}$ and $\nu_{1/5}$ boron sheets, namely $\alpha$ and $\beta$ chains, serve as...

We investigated the abrupt alternation from flood to drought in southern China during summer 2019 using multiple datasets. Positive anomalies of precipitation occurred in southern China in the summer of 2019 and the daily precipitation in the Jiangnan area south of the mid and lower reaches of the Yangtze River valley showed an abrupt change from flood to drought conditions around mid-July. The highest precipitation in 39 years was recorded between 1 June and 14 July 2019. The circulation systems affecting this high precipitation included a persistent deepened East Asian trough, the southward location of the western Pacific subtropical high, an intensified East Asian subtropical jet, an anomalous low-level cyclone from southern Japan to southern China and extremely strong positive vorticity over the Jiangnan area. Completely different atmospheric circulation anomalies from 15 July to 31 August caused continuously high temperatures, below-normal precipitation and severe drought in Jiangnan. Further investigations showed that the sudden change in atmospheric circulation around mid-July started in the mid and lower troposphere and was influenced by the northward track of tropical cyclone Danas in the northwestern Pacific.

This paper investigates the economic relationship between logistics performance and export competitiveness based on the iceberg transport cost model and conducts further empirical analysis according to China’s LPI. It finds that the higher the efficiency of logistics and transport, the lower the transportation costs coefficient per unit distance; when logistics and transportation costs decrease, foreign demand for domestic goods increases, as does the export value expressed in domestic prices. Additionally, Spearman’s rank correlation method is used to analyze the relationship between logistics performance index and export level, indicating that logistics performance index has a positive rank correlation with the export level at a significant level of 1%. Moreover, a case study on China’ LPI supports the conclusion derived from the theoretical analysis, and conducive countermeasures are put forward. This research confirms the positive correlation between logistics performance and export competitiveness and proposes specific solutions to enhancing the logistics capabilities of other developing countries.

To investigate the role of moxibustion of "Feishu" (BL13)，"Tianshu" (ST25) for asthma by simultaneously treating lung and intestine (i.e., treating both lung and intestine at the same time) in asthmatic rats.A total of 48 SD rats were randomly divided into normal, model, lung treatment and joint-treatment of lung and intestine (joint-treatment) groups, with 12 rats in each. The asthma model was established by subcutaneous (bilateral back and inguinal regions) and intraperitoneal injection of mixture solution of albumin and Aluminium Hydroxide gel (on day 1Compared with the normal group, the FEF 25%, MMEF， Cdyn， FEV/FVC and PEF were significantly decreased ("Joint treatment of lung and intestine" with moxibustion is superior to "lung treatment" alone in ameliorating the lung function and mitigating airway inflammation in rats with asthma.

Protein tyrosine phosphatase 1B (PTP1B) is a member of the phosphotyrosine phosphatase family and plays an important role in the signal transduction of diabetes. Inhibition of PTP1B activity can increase insulin sensitivity and reduce blood sugar levels. Therefore, it is urgent to find compounds with novel structures that can inhibit PTP1B. This study designed imidazolidine-2,4-dione derivatives through the computer-aided drug design (CADD) strategy, and the Comp#10 showed outstanding inhibitory ability. (IC50 = 2.07 μM) and selectivity. The inhibitory mechanism at molecular level of Comp#10 on PTP1B was studied by molecular dynamics simulation. The results show that the catalytic region of PTP1B protein is more stable, which makes the catalytic sites unsuitable for exposure. Interestingly, the most obvious changes in the interaction between residues in the P-loop region (such as: His214, Cys215, and Ser216). In short, this study reported for the first time that imidazolidine-2,4-dione derivatives as novel PTP1B inhibitors had good inhibitory activity and selectivity, providing new ideas for the development of small molecule PTP1B inhibitors.

Lijin Lin,1– 4,&ast; Ze Chen,4,5,&ast; Ting Ding,1,2,&ast; Hui Liu,4,6,&ast; Feng Zhou,4,7 Xuewei Huang,3,4 Xingyuan Zhang,4,8 Weifang Liu,4,8 Bing-Hong Zhang,9 Yufeng Yuan,10 Peng Zhang,4,8 Xiao-Jing Zhang,4,8 Zhi-Gang She,3,4 Jingjing Cai,4,11 Wenping Chen,1,2 Hongliang Li2– 4,7 1Department of Endocrinology, Huanggang Central Hospital, Huanggang, People’s Republic of China; 2Huanggang Institute of Translational Medicine, Huanggang, People’s Republic of China; 3Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China; 4Institute of Model Animal of Wuhan University, Wuhan, People’s Republic of China; 5Department of Cardiology, Zhongnan Hospital of Wuhan University, Wuhan, People’s Republic of China; 6Neonatology of Gastroenterology, Tongren Hospital of Wuhan University & Wuhan Third Hospital, Wuhan, People’s Republic of China; 7Medical Science Research Center, Zhongnan Hospital of Wuhan University, Wuhan, People’s Republic of China; 8Basic Medical School of Wuhan University, Wuhan, People’s Republic of China; 9Neonatology Department, Renmin Hospital of Wuhan University, Wuhan, People’s Republic of China; 10Department of Hepatobiliary and Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, People’s Republic of China; 11Department of Cardiology, The Third Xiangya Hospital, Central South University, Changsha, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hongliang Li; Wenping Chen Email lihl@whu.edu.cn; chenwenping@hgyy.org.cnPurpose: To analyze the impact of hyperglycemia on the clinical outcome of COVID-19 in patients with newly diagnosed diabetes (NDD).Patients and Methods: We performed a retrospective study of 3114 cases of COVID-19 without pre-existing diabetes, 351 of which had NDD, in Hubei Province, China. The Cox regression model was used to calculate the risk of adverse clinical outcomes comparing the NDD vs non-NDD group before and after propensity score-matched (PSM) analysis. Patients with NDD were further divided into a sustained hyperglycemia group, a fluctuating group, and a remitted group based on their blood glucose levels during hospitalization as well as into hypoglycemic agent users and nonusers.Results: Compared to the non-NDD individuals, individuals with NDD had a significantly increased risk of all-cause mortality (adjusted HR after PSM, 2.65; 95% CI, 1.49– 4.72; P = 0.001) and secondary outcomes involving organ damage during the 28-day follow-up period. Subgroup analyses indicated that among individuals with NDD, the individuals with remitted hyperglycemia had the lowest 28-day mortality, whereas those with sustained hyperglycemia had the highest (IRR 24.27; 95% CI, 3.21– 183.36; P < 0.001). Moreover, individuals treated with hypoglycemic agents had significantly lower all-cause mortality than those not treated with hypoglycemic agents (IRR 0.08; 95% CI, 0.01– 0.56; P < 0.001).Conclusion: Our study reinforces the clinical message that NDD is strongly associated with poor outcomes in COVID-19 patients. Furthermore, resolved hyperglycemia in the later phase of the disease and the use of hypoglycemic agents were associated with improved prognosis in patients with NDD.Keywords: COVID-19, newly diagnosed diabetes, hyperglycemia, prognosis, blood glucose

Background: Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a risk predictor for cardiovascular diseases (CVD). Generally, plasma Lp-PLA2 was thought to be secreted by circulatory inflammatory cells. Lp-PLA2 mRNA expression of PBMC may also be a risk predictor. Methods: A total of 104 subjects angiographically verified ACS patients were enrolled, including 73 unstable angina pectoris (UAP) patients and 31 acute myocardial infarction (AMI) patients. Plasma lipids, Lp-PLA2 activity and Lp-PLA2 mass were measured. Lp-PLA2 mRNA expression of PBMC was relatively quantified by real-time fluorescence PCR. Results: Plasma Lp-PLA2 activity was increased in AMI patients compared to UAP patients (395.21±145.91 vs. 328.53±127.03 U/L, p=0.024). Lp-PLA2 mass of AMI patients was also higher than UAP patients (136.43±45.46 vs. 119.16±44.19 ng/mL, p=0.093), while PBMC mRNA expression was not statistically different [1.07 (0.74, 1.57) vs. 0.88(0.49, 1.99), p=0.453]. Comparing Lp-PLA2 mRNA by groups, Lp-PLA2 mRNA level was higher in male ACS patients and smoking ACS patients (p=0.008, p=0.048, respectively). Multivariate logistic regression analysis showed that Lp-PLA2 activity was an AMI risk predictor (OR=5.224, 95% CI 1.687-16.181, p=0.004), after smoking, systolic blood pressure, diabetes and hyperlipidemia were adjusted. Recurrent ACS patients were older (p=0.035), but they showed lower levels of Lp-PLA2 mass and Lp-PLA2 activity (p=0.014, p=0.045, respectively), compared to primary ACS patients. Conclusion: Smoking may be an important regulatory factor for Lp-PLA2 mRNA expression in PBMC. Among three Lp-PLA2 indexes, Lp-PLA2 activity was the best marker indicating AMI risk, while Lp-PLA2 mass maybe play better role as a predictor in avoiding ACS recurrence.

Podocyte injury contributes to glomerular injury and is implicated in the pathogenesis of diabetic nephropathy. Formyl peptide receptor (FPR) 1 is abundantly expressed in neutrophils and mediates intracellular transport of Ca 2+. Intracellular Ca 2+ regulates pathological process in renal podocyte and plays a role in diabetic nephropathy. However, the role of formyl peptide receptor 1 in podocyte injury of diabetic nephropathy has not been reported yet. Firstly, a rat model with diabetic nephropathy was established by streptozotocin injection, and a cell model was established via high glucose treatment of mouse podocytes (MPC5). Formyl peptide receptor 1 was enhanced in streptozotocin-induced rats and high glucose-treated MPC5. Secondly, streptozotocin injection promoted the glomerular injury with decreased nephrin and podocin. However, tail injection with adenovirus containing shRNA for silencing of formyl peptide receptor 1 attenuated streptozotocin-induced glomerular injury and the decrease in nephrin and podocin. Moreover, silencing of formyl peptide receptor 1 repressed cell apoptosis of podocytes in diabetic rats and high glucose-treated MPC5. Lastly, protein expression levels of p-p38, p-ERK, and p-JNK protein were up-regulated in streptozotocin-induced rats and high glucose-treated MPC5. Silencing of formyl peptide receptor 1 attenuated high glucose-induced increase in p-p38, p-ERK, and p-JNK in MPC5, and over-expression of formyl peptide receptor 1 aggravated high glucose-induced increase in p-p38, p-ERK, and p-JNK. In conclusion, inhibition of formyl peptide receptor 1 preserved glomerular function and protected against podocyte dysfunction in diabetic nephropathy.

GDC‐0334 is a novel small molecule inhibitor of transient receptor potential cation channel member A1 (TRPA1), a promising therapeutic target for many nervous system and respiratory diseases. The pharmacokinetic (PK) profile and pharmacodynamic (PD) effects of GDC‐0334 were evaluated in this first‐in‐human (FIH) study. A starting single dose of 25 mg was selected based on integrated preclinical PK, PD, and toxicology data following oral administration of GDC‐0334 in guinea pigs, rats, dogs, and monkeys. Human PK and PK‐PD of GDC‐0334 were characterized after single and multiple oral dosing using a population modeling approach. The ability of GDC‐0334 to inhibit dermal blood flow (DBF) induced by topical administration of allyl isothiocyanate (AITC) was evaluated as a target‐engagement biomarker. Quantitative models were developed iteratively to refine the parameter estimates of the dose‐concentration‐effect relationships through stepwise estimation and extrapolation. Human PK analyses revealed that bioavailability, absorption rate constant, and lag time increase when GDC‐0334 was administered with food. The inhibitory effect of GDC‐0334 on the AITC‐induced DBF biomarker exhibited a clear sigmoid‐Emax relationship with GDC‐0334 plasma concentrations in humans. This study leveraged emerging preclinical and clinical data to enable iterative refinement of GDC‐0334 mathematical models throughout the FIH study for dose selection in subsequent cohorts throughout the study. Study Highlights WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? GDC‐0334 is a novel, small molecule TRPA1 inhibitor and a pharmacokinetic‐pharmacodynamic (PK‐PD) modeling strategy could be implemented in a systematic and step‐wise manner to build and learn from emerging data for early clinical development. WHAT QUESTION DID THIS STUDY ADDRESS? Can noncompartmental and population‐based analyses be used to describe the PK and PD characteristics of GDC‐0334 in preclinical and clinical studies? WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? GDC‐0334 exposure generally increased with dose in rats, dogs, and monkeys. The starting dose (25 mg) in the clinical study was determined based on the preclinical data. GDC‐0334 exhibited linear PK in humans and the bioavailability was increased with food. The inhibitory effect of GDC‐0334 on dermal blood flow induced by the TRPA1 agonist allyl isothiocyanate in humans indicates a clear PK‐PD relationship. HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE? The models developed based on TRPA1 agonist‐induced dermal blood flow inhibition data can be used to predict PK‐PD relationships in future preclinical and clinical studies evaluating new drug entities that target TRPA1.

Background Marfan syndrome (MFS) is a rare autosomal dominant connective tissue disorder. Diagnosing MFS can be challenging as the disease's severity and clinical manifestations differ between pathogenic variants, and because a lack of published information currently exists on phenotype-genotype correlations. This report aims to underline the clinical manifestations associated with fibrillin-1 (FBN1) gene mutations by assessing MFS in 6 families from China. Methods We diagnosed 6 patients and their relatives with MFS by combining a clinical examination (based on the 2010 revised Ghent nosology criteria) with a targeted next-generation sequencing analysis. The functional analysis of the causal mutations and clinical details of the affected patients were then assessed. Results We identified 6 pathogenic mutations in FBN1, including 1 novel frameshift, 1 nonsense, and 4 missense mutations. Most uniquely, mitral valve prolapses (MVP) and ectopia lentis (EL) were found in the cysteine-related mutations. Typically, facial symptoms of MFS are observed in frameshift or nonsense mutants, not in cysteine-related ones. Furthermore, the patients with premature terminal codons had a more serious skin condition than patients with missense mutations, partly indicating the important effect FBN1 has on skin. Conclusions This study expands the mutation spectrum of MFS and highlights possible genotype-phenotype correlations, thereby improving the early diagnosis and symptomatic treatment of the disease.

Purpose: To investigate the mechanism of action of dapagliflozin on diabetic nephropathy. Methods: A rat model of diabetic nephropathy was established by injection of fructose-streptozotocin. Blood glucose and urinary protein levels were measured, while histopathological changes in kidney tissues were determined by hematoxylin & eosin staining (H & E). Serum levels of creatinine (Cr), blood urea nitrogen (BUN), malondialdehyde (MDA), superoxide dismutase (SOD), reduced glutathione (GSH), and lactate dehydrogenase (LDH) were evaluated by enzyme-linked immunosorbent assay (ELISA). Cell apoptosis and autophagy were investigated by evaluating apoptotic and autophagic protein expression by western blot. Results: Administration of fructose-streptozotocin increased the blood glucose level of the rats (p < 0.001) and induced pathological changes in the kidney tissues, including glomerulosclerosis, renal tubule dilation, and inflammatory cell infiltration of rats. However, long-term treatment with dapagliflozin attenuated the fructose-streptozotocin-induced increases in Cr, BUN, and urinary protein and reversed the fructose-streptozotocin-induced decrease in Bcl-2 expression and increases in Bax and cleaved PARP expression in diabetic rats. Dapagliflozin also reversed the increases in MDA and LDH and decreases in SOD and GSH in diabetic rats. The fructose-streptozotocin-induced increase in p62 expression and decreases in LC3 and Beclin 1 expression were reversed by dapagliflozin. It upregulated miR-30e-5p expression and downregulated phosphorylated AKT and mTOR expression in diabetic rats. MicroRNA-30e-5p targeted AKT and inhibition of miR-30e-5p attenuated the dapagliflozin-induced decrease in p-AKT and p-mTOR expression in diabetic rats. Conclusion: In fructose-streptozotocin-induced diabetic rats, dapagliflozin ameliorates kidney injury, suppresses cell apoptosis and oxidative stress, and promotes cell autophagy through upregulation of miR-30e-5p and inactivation of the AKT/mTOR pathway. Therefore, dapagliflozin is a potent therapeutic agent for the management of diabetic neuropathy.

Peiyao Li1,2 &ast;, Jialin Qi3 &ast;, Baishun Zhou,1 Ting Ding,4 Juan Long,5 Heng Xiao1 1Department of Pathology, School of Medicine, Hunan Normal University, Changsha, People’s Republic of China; 2Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, China NHC Key Laboratory of Carcinogenesis, Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 3Department of Pathology, Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 4Department of Endocrinology, Yiyang Central Hospital, Yiyang, People’s Republic of China; 5Department of Dermatology, Hunan Children’s Hospital, Changsha, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Heng Xiao, Department of Pathology, School of Medicine, Hunan Normal University, 371 Tongzipo Road, Changsha, Hunan, 410013, People’s Republic of China, Tel +86-731-88912501, Email emmaxiao1988@hotmail.comBackground: Hailey–Hailey disease (HHD) is an autosomal dominant cutaneous disorder that manifests as repeated blisters and erosions on flexural or intertriginous skin areas. The calcium-transporting ATPase type 2C member 1 gene (ATP2C1) encodes the secretory pathway Ca2+/Mn2+-ATPase 1 (SPCA1), whose deficiency is responsible for HHD. An ATP2C1 splice-site mutation (c.325-2A>G, p.Ala109_Gln120del) was previously identified in a Han Chinese family with HHD.Methods: In this study, the identified ATP2C1 splice-site mutation (c.325-2A>G, p.Ala109_Gln120del) was investigated in transfected human embryonic kidney 293 cells to analyze its pathogenic mechanism in HHD patients by using cycloheximide chase assay, CCK8 assay and in silico modeling of SPCA1 mutant.Results: Cycloheximide chase assay showed that the degradation rate of the SPCA1 mutant was not obviously faster than that of the normal SPCA1. CCK8 assay showed that cell proliferation rates in the wild-type, A109_Q120del, and empty vector control groups all decreased in the gradient Mn2+ solutions in a dose-dependent manner. The cell proliferation rate in the wild-type was lower than that in the A109_Q120del and empty vector control (both P < 0.01), indicating overexpression of normal SPCA1 may rather induce Golgi stress, and even cell death. The cell proliferation rate in the A109_Q120del was lower than that in the empty vector control (P < 0.01), indicating that overexpression of the mutated SPCA1 may decrease its detoxification capability. Three-dimensional (3D) structure model of SPCA1 built by SWISS-MODEL and PyMOL showed that absence of the 12 amino acids from p.Ala109 to p.Gln120 in the SPCA1 mutant can cause obviously shortened transmembrane 2, which may affect correct localization of SPCA1 on the Golgi.Conclusion: These results demonstrate that the ATP2C1 mutation (c.325-2A>G, p.Ala109_Gln120del) may cause impaired SPCA1 capability to detoxify Mn2+ and abnormal SPCA1 structure, which reveals a new side for the pathogenesis of HHD.Keywords: ATPase secretory pathway Ca2+ transporting 1, Hailey–Hailey disease, pathogenesis, secretory pathway Ca2+/Mn2+-ATPase 1

The nucleation and growth mechanism of electrodeposited Ni−W alloy were investigated. Cyclic voltammetry (CV) and chronoamperometry (CA) were used to examine the electrochemical behavior and nucleation mechanism of the electrodeposited Ni−W alloy. The nucleation type and kinetic parameters of the electrodeposited Ni−W alloy were obtained from the CA analysis results. SEM, AFM, and TEM were also used to investigate the nucleation and growth process of the electrodeposition of Ni−W alloy. The results demonstrate that the nucleation and initial stages of the growth phase of the Ni−W alloy undergo the formation, movement, and aggregation of atoms, single crystals, and nanoclusters. When the size of single crystal increases up to approximately 10 nm and the average size of the crystal granules is approximately 68 nm, they no longer grow. Increasing the applied potential increases the number of nuclei but does not affect the size of the final crystal granules. Therefore, the electrodeposited Ni−W alloy shows a nanocrystalline structure.

In order to better understand the heat transfer performance of shell and tube heat exchanger (STHE) with Fluoride salt as the heat transfer fluids, the steady-state heat transfer process of STHE with segmental baffles (STHE-SBs) in Fluoride-salt High Temperature Test Loop (FHTL) has been studied experimentally and numerically. Firstly, the Computational Fluid Dynamics (CFD) model was established to simulate the thermal performance of STHE-SBs. Then, thermal performance data such as temperature and heat transfer power were experimentally obtained under steady-state conditions of STHE-SBs at higher temperature (550–600°C), and to further verify the reliability of the simulation. The results show that the temperature distribution obtained by CFD is in good agreement with the experimental results, which indicates that the CFD program is reliable to describe the thermal performance of the STHE-SBs. On this basis, the effect of segmental baffles on the heat transfer enhancement of molten salt in shell side of STHE was discussed. The results show that the heat transfer enhancement effect of molten salt on the shell side of STHE-SBs is better than that of STHE without segmental baffles, and the increment of Nusselt number is about 64–73% during the low Reynolds number region. Finally, the heat transfer coefficient of molten salt in the shell side of STHE-SBs are fitted, which can be used in relatively wide ranges of Reynolds number and temperature.

Background The aim of this study was to evaluate the application of pulse contour cardiac output (PiCCO) in patients with traumatic shock. Methods Seventy-eight patients with traumatic shock were included and grouped. The control group (CG, n = 39) underwent fluid resuscitation through transthoracic echocardiography (TTE) monitoring, and the research group (RG, n = 39) received PiCCO-guided fluid resuscitation. Results The mechanical ventilation time, duration of vasoactive drug use, and duration of stay in the intensive care unit were lower in the RG compared to the CG (P < .05). At 72 h after fluid resuscitation, the mean arterial pressure and central venous pressure in the RG were higher than those in the CG (P < .05). The stroke volume variation and distensibility index of the inferior vena cava were lower at 72 h after fluid resuscitation, but the levels of extravascular lung water, global end-diastolic volume index, and intrathoracic blood volume index were higher in the RG (P < .05). The levels of endothelial 1, nitrogen monoxide, tumor necrosis factor-α, procalcitonin, C-reactive protein, and partial pressure of carbon dioxide at 72 h after fluid resuscitation in the RG were lower than those in the CG (P < .05). Conclusion PiCCO-guided liquid resuscitation may help to accurately evaluate the volumetric parameters, alleviate symptoms of ischemia and hypoxia, regulate hemodynamics and blood gas analysis, reduce inflammatory reactions, improve endothelial functions, and effectively guide the usage of vascular active drugs.

Grapevine-related microorganisms affect the health and yield of grapes, the metabolic pathways of the fermentation process, and the regional characteristics of wine. However, the diversity of epidermal microorganisms during the development of berries under the ecological viticulture model has not been described in detail. In this study, high-throughput amplicon sequencing technology was used to perform ITS and 16S sequencing of Cabernet Sauvignon epidermal microbes at different developmental stages in the Wuhai region to investigate the succession of epidermal microbes and their response to developmental stages and vineyard weather. The results showed that the diversity of fungi and bacteria decreased during development. Epidermal microorganisms recruited members according to their developmental stages, but retained the core taxa, such as the fungi genera Alternaria, Jattaea, and Jattaea and the bacteria genera Brevundimonas, Sphingomonas, Acinetobacter, and Pseudomonas. In addition, the microbial diversity was associated with specific meteorological parameters, implying that there was a connection between the environmental conditions of the vineyard and the microbial distribution pattern such as the fungus genus Filobasidium was positively correlated with relative humidity and negatively correlated with average high temperature, average low temperature, and average ground temperature; the bacterium genus Lactobacillus was positively correlated with sunlight time, and negatively correlated with relative humidity. In conclusion, this study can help vineyard managers understand the microbial consortia associated with particular diseases, and also the dynamics of infection processes in order to take preventive actions, especially at the most critical moments.

Neuregulin 1 (Nrg1) encodes a neurotrophic factor and is genetically associated with schizophrenia, bipolar disorder and major depression. NRG1 has been shown to play important roles in neurodevelopment and neurotransmission. However, the knowledge about the cellular expression pattern of Nrg1 in mouse forebrain remains controversial and inconclusive. Here we used CRISPR/Cas9 techniques to generate Nrg1Cre/+ knockin mice which express the Cre recombinase immediately before the stop codon of Nrg1 gene. By crossing the Nrg1Cre/+ mice with Ai14 reporter mice which express fluorescent protein tdTomato in a Cre-dependent manner, we generated Nrg1 reporter mice which express tdTomato in cells where Nrg1 gene is actively transcribed. Using fluorescence imaging and unbiased stereology, we revealed the cellular expression pattern of Nrg1 in mouse forebrain regions including the olfactory bulb, cerebral cortex, striatum and hippocampus. We further performed stereotaxic injection of adeno-associated virus (AAV) which express tdTomato in a Cre-dependent way into different forebrain regions of adult Nrg1Cre/+ mice, and thus explored the distribution and axon projection of Nrg1-positive cells. These results provide fundamental information needed for the study of Nrg1 function in mouse forebrain. Moreover, the Nrg1Cre/+ mice generated here may represent a useful tool to study the function of neuronal populations expressing Nrg1.

Purpose: To investigate the correlations between miR-384 expression and renal damage in lupus nephritis (LN).Methods: Lupus nephritis and normal tissues were collected during surgery. The relative miR-384 expression was evaluated by extracting RNA and performing quantitative real time PCR (qRT-PCR) assays. Expression of ten-eleven translocation (TET3) mRNA and protein were measured by qRT-PCR and western blotting, respectively. The 24-h urine protein, serum complement C3, and serum creatinine were determined using commercial enzyme-linked immunosorbent assay (ELISA) kits. TargetScan and luciferase assays were used to validate the binding site for miR-384 and its target mRNA. Relationships among miR-384, TET3, and renal damage were analyzed by Spearman rank-order correlation coefficients.Results: MiR-384 expression increased in LN tissues and was positively correlated with the activity index (AI) and chronicity index of LN, whereas miR-384 expression and serum complement C3 were negatively correlated. Positive correlations were observed between miR-384 expression and 24-h urine protein, serum creatinine, and systemic lupus erythematosus disease AI. TargetScan and luciferaseassays indicated that the TET3 3′-UTR was the direct target of miR-384. MiR-384 upregulation inhibited TET3 mRNA and protein expression, and was negatively associated with renal damage in LN.Conclusion: MiR-384 upregulation contributes to renal damage in LN by targeting the 3′-UTR of TET3 mRNA, suggesting that miR-384 is a potential biomarker and therapeutic target in LN. Keywords: MiR-384, Renal damage, Lupus nephritis, Ten-eleven translocation, TET3

Introduction Etrolizumab is a novel, dual-action anti-β7 integrin antibody studied in phase 3 trials in patients with inflammatory bowel disease. An autoinjector (AI) is being developed in parallel to complement the prefilled syringe with needle safety device (PFS-NSD) for subcutaneous (SC) administration in these trials. Here we demonstrate the comparable pharmacokinetics, tolerability, and safety of both devices. Methods This randomized, open-label, two-part study in healthy participants evaluated the comparability of etrolizumab exposure between the AI and the PFS-NSD. Part 1 (pilot) involved a small number of participants, and initial results were used to finalize the design of the larger part 2 (pivotal) study. In both parts, participants were randomly assigned to receive a single SC dose of etrolizumab 105 mg by AI or PFS-NSD. Randomization was stratified by body weight. Primary pharmacokinetic outcomes were Cmax, AUClast, and AUC0–inf. Results One hundred and eighty healthy participants (part 1, n = 30; part 2, n = 150) received a single SC dose of etrolizumab by AI or PFS-NSD. Primary pharmacokinetic results from part 1 supported modification of the part 2 study design. Results from part 2 demonstrated that etrolizumab exposure was equivalent between devices, with geometric mean ratios (GMRs) between AI and PFS-NSD of 102% (90% confidence interval [CI] 94.2–111) for Cmax, 98.0% (90% CI 89.3–107) for AUClast, and 97.6% (90% CI 88.6–107) for AUC0–inf. Median tmax and mean terminal t1/2 were also similar between devices. GMRs and 90% CIs of all primary pharmacokinetic parameters were fully contained within the predefined equivalence limits (80–125%). Conclusion This pharmacokinetic study demonstrated that single SC injections of etrolizumab 105 mg using an AI or a PFS-NSD resulted in equivalent etrolizumab exposure and similar safety and tolerability in healthy participants. Taken together, these results support the use of an AI for etrolizumab administration. Trial Registration NCT02996019.