An 84-year-old woman with type B WPW with Ebstein anomaly was admitted with heart failure. She had rapid wide QRS tachcardia due to accessory pathway conduction associated with atrial fibrillation (AF). Since transesophageal echocardiography before catheter ablation showed a left atrial thrombus, ablation was performed using a 3D mapping system under AF. After marking the functional tricuspid anulus with intracardiac echocardiography, three dimensional intracardiac electrogram visualization (ripple map) during AF enabled clear identification of location of the accessory pathway. After ablation, there was no complication of cerebral infarction and heart failure improved.

Background: Nerve growth factor (NGF) and growth associated protein 43 (GAP43) are dramatically increased in damaged tissue after myocardial infarction (MI) and proposed to retrogradely transport to left stellate ganglion (LSG). In this study, we determine whether local ablation of cardiac sympathetic nerves is able to block the neurothrophin transportation. Methods and results: Forty rabbits were randomly assigned into the sham-operated, MI and MI-ablation groups. Three days after operation, the levels of NGF and GAP43 were determined in each group. In MI group, the protein of NGF and GAP43 were both elevated in infarcted border zone (IBZ) and LSG. The elevation of GAP43 protein was correlated with the increase of its mRNA levels in both areas. However, the elevation of NGF mRNA was displayed only in IBZ, not in LSG, suggesting that the increase of NGF protein in LSG was possibly due to its retrograde transportation from IBZ. Furthermore, local ablation of sympathetic nerves leading to no increase of NGF protein in LSG post MI. Correspondingly, GAP43 protein and mRNA were not increased in LSG, and slightly elevated in IBZ, suggesting the upregulation of GAP43 in IBZ is subjected to the influence of promoting signal from LSG. Four weeks later, immunohistochemistry showed MI caused pronounced GAP43 and tyrosine hydroxylase positive nerves in cardiac tissue, especially in IBZ, which could be precluded by ablation. Conclusion: The local ablation of cardiac sympathetic nerves blocks neurotrophin transportation from damaged tissue to LSG post MI, and inhibits nerve sprouting, sympathetic hyperinnervation and cardiac remodeling.

Introduction Little is known regarding the pathogenesis of essential hypertension despite the great amount of research data in this field, yet an association of hypertension with inflammation has been shown, like in other chronic diseases. We aimed to investigate the relationship between the inflammatory response indicator and mean neutrophil volume (MNV) in patients newly diagnosed with hypertension. Materials and Methods Medical records of patients newly diagnosed with hypertension (HT) were retrospectively reviewed. Healthy patients with normal ambulatory blood pressure records were also included as a control group. Newly diagnosed hypertensive patients were further divided into two groups according to their immersion status. Results Two hundred twenty-two patients were included in the current study. While 104 patients had HT, 118 subjects were normotensive. MNV was significantly higher in hypertensive group when than normotensive group (140,3 (135,1-145,5) vs. 144,1 (136,1-152,1), p=0.001). In the hypertensive group, 51 patients had dipper hypertension and 53 patients had non-dipper hypertension. MNV was significantly higher in non-dipper hypertension group (145,7 (138,1-153,46) vs. 142,3 (134,3-150,3), p=0.022). Multivariate regression analysis revealed MNV [95% confidence interval (CI): 1,006-1,122, p = .032] and PWV [95% confidence interval (CI): 1,203-2,655, p = .004] were independently associated with the non- dipping status in newly diagnosed hypertensive patients. Conclusion A significant increase in MNV is present among patients with hypertension when compared to the normotensive patients. In addition, increased MNV measurements were associated with non-dipper HT.

Abstract: Aim/Objective: To present the epidemiological and clinical effects of skiing training and use of protective equipment on skiing, sledding and snowboarding injuries. Material and method: This study was conducted prospectively in the emergency department of a tertiary hospital. The patients were evaluated in two groups according to both their skiing experience and use of protective equipment. The characteristics of the patients, such as age, gender, injury area, and injury type were statistically evaluated according to the groups. Results: A total of 191 patients, 68 (35.6%) female and 123 (64.4%) male, were evaluated. There was a significant difference between the skiing type of the patients with and without skiing experience (p=0.000). When the patients were evaluated according to the presence of protective equipment, 25 (59.5%) patients who had no experience did not wear protective equipment, and this rate was statistically significant compared to the experienced group (p=0.000). Concerning the diagnoses of the patients according to injury areas, joint dislocation and soft tissue trauma were mostly detected in the upper extremities, bone fractures in the lower extremities, and organ injury in the thorax. Conclusion: Shoulder and wrist traumas were the most common injuries among the patients with skiing experience while tibial fractures were mostly seen in those without such experience. Tibia fractures were mostly observed in the patients using protective equipment, and skin incisions in those that did not use protective equipment. Therefore, in winter sports injuries, patients’ skiing experience and protective equipment use should be questioned and more attention should be paid to the above-mentioned injuries.

Objective This study aims to investigate the factors affecting development of acute kidney injury (AKI) due to severe hypothyroidism. Methods This single-centre, retrospective observational study involved patients with primary hypothyroidism and thyroid stimulating hormone (TSH) levels of more than 50 mIU/L at their review in the endocrinology outpatient clinic, between January 2015 and April 2021. Patients whose medical history and laboratory data were complete were included in the study. Demographic and laboratory data of patients with AKI (case group) and without (control group) were compared. Factors affecting the development of AKI were examined by logistic regression analysis. Results A total of 100 patients, 20 (11 male (M), 9 female (F)) in the AKI (case) group and 80 (23 M, 57 F) patients in control group, were included in our study. The median age of the case group (56 years, interquartile range (IQR) 44.3–68.5) was significantly higher than the control group (49 years, IQR 32.3–60; p = 0.027), and the ratio of males to females was significantly higher in the case group (p = 0.001). Multivariate logistic regression analyses showed that hypothyroidism diagnosed after the age of 60 years (odds ratio (OR) 59.674, 95% confidence intervals (CI) 5.955–598.031; p = 0.001), free triiodothyronine (FT3) < 1.3 pg/mL (OR 17.151, 95% CI 2.491–118.089; p = 0.004) and creatine kinase (CK) > 1000 U/L (OR 1.522, 95% CI 1.602–82.848; p = 0.015) were predictors for the development of AKI due to severe hypothyroidism. Conclusion We recommend close follow-up and monitoring of patients with AKI caused by severe hypothyroidism if aged > 60 years, CK > 1000 U/L or FT3 < 1.3 pg/mL.

Background: MiRNAs have been recently implicated in the pathogenesis underlying ischemia-reperfusion (IR) injury. We investigated the miRNAs expression profiles in the early stages after lung transplantation (LT) and studied the involvement of Toll-like receptor(TLR) signaling pathway in lung IR injury following LT. Methods: We established the left LT model in mice, The mice were injected with a miRNA-122 specific inhibitor, following which pathological changes in the lung tissue were studied using different lung injury indicators. In addition, we performed deep sequencing in transplanted lung tissues to indentify differentially expressed (DE) miRNAs and their target genes. Results: A total of 12DE miRNAs were selected and 2,476 target genes were identified; The gene ontology (GO) enrichment analysis predicted 6,063 terms and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis predicted 1,554 biological pathways. Compared with the control group, inhibiting the expression of miRNA-122 significantly reduced the lung injury and lung W / D ratio (p<0.05). In addition, the activity of myeloperoxidase (MPO) and expression of tumor necrosis factor (TNF)-α and TLR2/4 decreased (p<0.05); whereas the expression of interleukin-10(IL-10) expression levels increased (p<0,05). Furthermore, the inhibition of miRNA-122 suppressed the IR injury-induced activation of the TLR signaling pathway. Conclusions: Our findings showed the differential expression of several miRNAs in the early inflammatory response following LT. Of these, miRNA-122 promoted the IR injury following LT, whereas its inhibition prevented IR injury in a TLR-dependent manner.

Mixed convective flow of transfer of heat and mass of Jeffrey fluid on peristaltic flow alongwith Newtonian fluid in a vertical channel is studied. Mathematical modelling, by using regular perturbation method the coupled nonlineargoverning equations are solved analytically. The effects of the various parameters and inclination angle on the velocity, temperature and concentration are discussed through the graphical representations and results are discussed. The consequences of Jeffrey fluid parameters λ have been noted.

Machine learning (ML) algorithms have gained more and more successful applications in the field of energy prediction. However, current conventional application process of ML algorithms lacks screening of dominant factors and model validation, resulting in weakening the predictive ability of the model. In this work, systematic and robust predictive models are provided to address this issue. Based on 147 sets of data, various methods were used to predict. The results show that in the process of learning curve analysis, the eight models can get satisfactory results, but there are three models with overfitting or underfitting. Besides, through analyze the model by the single-factor control variables method, two additional defective models were found. Therefore, current conventional ML modeling methods are not reliable. This paper addresses the main reasons for the poor performance of some predictive models built by ML and provides guidelines on how to build robust predictive models.

It is still a huge challenge to find nonnoble-metal oxygen reduction reaction (ORR) catalysts that can replace Pt. Here, we report a heterostructure Ni(OH)2/ZrO2 catalyst made in one step using a simple alcohol thermal method that has the same onset potential (0.84 V) and overpotential (390 mV) as 20% Pt/C, abundant active sites, low Tafel slope (57 mV dec–1), good stability and excellent methanol tolerance. Moreover, we found that ZrO2 has a great influence on Ni(OH)2 through its abundant oxygen vacancies and inhibits the oxidation of Ni2+. However, the nature of its excellent catalytic performance is still unclear, so we analyzed it using a density functional theory (DFT) calculation. In particular, we studied the heterostructure Ni(OH)2/ZrO2 due to the abnormal synergistic effect of charge transfer and heterostructure interface and stabilized O radicals using ZrO2, which promoted the spontaneous progress of the Ni(OH)2/ZrO2 ORR, thereby improving the catalytic performance.

Objective: High prevalence rates of gestational diabetes mellitus (GDM) is a public health concern worldwide. The mechanism that leads to glucose tolerance beyond normal physiological levels to pathogenic conditions remains incompletely understood, and it is speculated that the maternal microbiome may play an important role. The objective of this study is to analyze the gut microbiota composition in each trimester of weight-matched women with and without GDM and examined possible bacterial genera associations. Design: A cohort study. Setting: This study was conducted in an outpatient clinic at the Federal University of São Paulo. Population: 56 women with GDM and 59 without during their first/second or third trimester of gestation. Methods: They were submitted to a standardized questionnaire, dietary recalls, clinical examination, biological samples collection and molecular profile of the fecal microbiota. Results: There was no difference in the alpha diversity and in the overall microbiota structure. A higher abundance of Bacteroides in GDM group was found. A positive correlation between Christensenellaceae and Intestinobacter abundances with 1-hour post-challenge plasma glucose and a negative correlation between Enterococcus and 2-hour plasma glucose level were observed. Bifidobacterium and Peptococcus abundances were increased in the third gestational trimester for both groups. Conclusion: The gut microbiota composition wasn’t dependent on the presence of GDM during the whole gestation. However, some genera abundances showed associations with glucose metabolism. Our findings may motivate deepening the knowledge about physiological and pathophysiological changes in the microbiota throughout pregnancy, which could have further implications for diseases prevention.

The elucidation of adaptive evolution mechanisms in the early stage of speciation is important for understanding the origin and evolution of species. Aquilegia viridiflora is in the early stage of speciation, has a wide distribution range, and shows obvious phenotypic variation among its different populations. In this study, to analyze the adaptive evolution mechanism of phenotypic differences in the early stages of speciation, we analyzed the phenotypes, genomes, and transcriptomes of different populations of A. viridiflora. Our results indicated that A. viridiflora originated in northwestern China, and the uplift of the northeastern Qinghai--Tibet Plateau in the late Miocene may have caused its differentiation. Aqcoe5G459400 was a key gene in the early stage of A. viridiflora speciation. Its expression was reduced in environments with large temperature differences between day and night, causing A. viridiflora to develop larger flowers and enhancing its attractiveness to pollinators. Our research revealed the genetic basis of the adaptive evolution of the phenotype in the early stage of speciation and provides new evidence of the pattern of speciation via adaptative radiation in columbine.

Objectives: Diabetic Mellitus is a global epidemic, exerting a substantial burden on health care services. This high prevalence of diabetes leads to an increase in diabetic complications, and diabetic retinopathy is a leading cause of blindness and vision disability. Individual studies on the prevalence of diabetic retinopathy in EMR showed the high prevalence of diabetic retinopathy in EMR. Therefore, we conducted a systematic review and meta-analysis of relevant studies to estimate diabetic retinopathy in EMR. Method: We searched for the relevant keywords in the title and abstract of Medline/PubMed, Scopus, Embase, and Web of knowledge, as well as Google Scholar and manual search to identify the published target studies from Jan 1st, 2000 to December 13, 2019. The two-step screening was carried out by two independent researchers and relevant data were extracted. Estimation of summary proportions, subgroup analysis, meta-regressions, and publication bias assessment was performed. Results: Amongst 4,139 identified citations, 109 articles were entered into a meta-analysis, involving 280,566 patients. We found that the prevalence of diabetic retinopathy was 30.67% (95% CI= 26.94%, 34.53%). Low HDI countries and very high HDI countries had the highest 63.55% (95% CI= 52.37%, 74.04%) and the lowest 22.59 (95% CI= 20.53, 24.71%) diabetic retinopathy prevalence. The meta-regression analysis showed that HDI had a significant negative moderating effect (p <0.0001), publication year had not a significant modulator effect (p = 0.6679), and the mean duration of diagnosed diabetes had a significant positive moderating effect (p <0.0001) on the prevalence of retinopathy in diabetes. Conclusions: We estimated a high prevalence of diabetic retinopathy in EMR. Our results implicate the importance of diabetes screening, on-time and periodic examinations for retinopathy, diabetes care, and risk factor controls.

Objective- To determine the prevalence of peripartum depression (PPD) and anxiety during the COVID-19 pandemic, any differences between COVID-infected and non-infected mothers and its risk factors. Study design- Cross-sectional study. Setting- Tertiary care maternity hospital Population- Pregnant and postpartum women Methods- Questionnaire based direct interview. EPDS (Edinburgh postnatal depression scale) score, COVID-19 anxiety scale (CAS) was used. Outcome measures- Possible PPD (EPDS13), Probable PPD (EPDS14), Peripartum anxiety (EPDS anxiety sub score4), COVID-19 related anxiety and risk factors of PPD. Results- Out of 842 eligible subjects, 142 were confirmed COVID-19 positive and 670 patients were without the infection. The mean age was 25±3.9 years and 571 (67.8%) subjects were postpartum. Among the subjects, 383 (45.5%) had possible depression, 317 (37.6%) had probable depression. Peripartum anxiety was observed among 763(90.6%) subjects and the median CAS score was 15(8-28). While there was no significant difference in the prevalence of PPD, peripartum anxiety was higher among COVID non-infected subjects (91.6% vs 86.6%, p=0.04). The CAS score was higher among COVID-19 infected compared to the non-infected [17(10-28) vs 15(8-25), p=0.00]. In multivariate analysis, history of psychiatric illness [OR- 4.2(95% CI- 1.82-9.93), p=0.001], domestic violence [OR-2.4(95% CI-1.16-5.10), p=0.019] and past obstetric complications [OR-1.5(95%CI-1.01-2.27), p=0.042] were significant risk factors for PPD. Conclusion- High prevalence of PPD was observed during COVID-19 pandemic without any significant difference between COVID-19 infected and non-infected subjects. COVID-19 infected patients had higher COVID related anxiety. Funding- None taken Keywords- peripartum depression; EPDS; COVID-19 anxiety scale.

We study a phase-field model, which describes the transformations for the austenite-martensite and the multiple twinning in Martensite. The model consists of two nonlinear parabolic equations of second order. We first show the existence of local solutions to an initial-boundary value problem by utilizing the Banach fixed-point theorem. Then we verify the solutions is global. Finally we investigate the regularity and uniqueness of the solution.

Stevia rebaudiana is a sweet herbaceous perennial plant, which is frequently used in the preparation of plant-based sweeteners. The demand for such sweeteners continues to increase due to purposeful nutrition and modern-day metabolic syndromes. More than 20 types of steviol glycosides provide a sweet taste, which are more than 300 times sweeter than sucrose. They are formed of two main components, namely stevioside and rebaudioside A. Only a handful of studies have dealt with Stevia rebaudiana leaf extracts, the conversion of pure stevioside into the preferred rebaudioside A is more common. The aim of this study was to enrich the rebaudioside A content of Stevia rebaudiana leaf extract using enzymatic bioconversion by applying fermented cyclodextrin glycosyltransferase from Bacillus licheniformis DSM13. Two differently processed plant materials, namely dried and lyophilized Stevia rebaudiana plants, were extracted and compared. Following the bioconversion, the rebaudioside A content was on average doubled. The maximum increase was fivefold with a 70-80% conversion of the stevioside.

Background: Clinical pharmacists play a significant role in clinical practice, but their work in the clinical pathway (CP) of acute exacerbations of chronic obstructive pulmonary disease (AECOPD) remains undefined. Objective: To study the role of clinical pharmacists in the CP of AECOPD. Methods: This prospective study included patients who met the discharge criteria during hospitalization at the department of respiratory medicine of the Second Affiliated Hospital of Fujian Medical University from March to December 2017 (no pharmacists involved) and from March 2018 to January 2019 (pharmacists involved). The Adverse Drug Reaction (ADR) reporting rate, antimicrobial use intensity, the per capita cost of pharmaceutical services, and the benefit-cost ratio (B/C) were analyzed. Results: Eighty participants were enrolled during the traditional period and 85 during the clinical pharmacist period. The average hospital stays (9.2±0.4 vs. 10.7±0.6 days, P=0.032), the total cost of treatment (14,058±826 vs. 18,765±1434yuan, P=0.004), the total cost of drugs (5717±449 vs. 8002±755yuan, P=0.004), and cost of antimicrobial drugs (3639±379 vs. 5636±641yuan, P=0.007) were all lower in the clinical pharmacist group than in the traditional group. The B/C was 10.38 and 5.05 in the intervention and traditional groups, respectively. The clinical pharmacists’ participation was independently associated with the total hospitalization expenses (β=-0.201, 95% confidence interval: -0.390-0.055, P=0.010). Conclusion: The participation of the clinical pharmacist in the implementation of an AECOPD CP significantly reduces patients’ hospitalization days, healthcare expenses, and antibiotic use and improves the B/C of AECOPD management. The clinical pharmacists’ participation was independently associated with the total hospitalization expenses.

Rationale, aims and objectives: Chronic hepatitis B virus (HBV) infection and alcoholism are the leading cirrhotic etiologies. Cirrhosis cases caused by different etiologies have different clinical features, which leads to different clinical outcomes. This study aimed to investigate the differences in complications between HBV- and alcohol-related cirrhosis. Methods: Medical records of hospitalized patients with HBV- or alcohol-related cirrhosis treated from January 2014 to January 2021 were retrospectively reviewed. The unadjusted rate and adjusted risk of cirrhotic complications between the two groups were assessed. Results: The rates of hepatocellular carcinoma (HCC) and hypersplenism were notably higher in HBV-related cirrhosis (HCC: 39.55% vs 1.45%, P < 0.001; hypersplenism: 45.84% vs 28.99%, P = 0.009), whereas the rates of hepatic encephalopathy (HE) and acute-on-chronic liver failure (ACLF) were higher in alcohol-related cirrhosis (HE: 15.94% vs 4.49%, P = 0.001; ALCF: 7.25% vs 2.28%, P = 0.040). After adjusting for potential confounders, HBV-related cirrhotic patients still had higher risks of HCC (odds ratio [OR] = 34.06, 95% confidence interval [CI]: 4.61–251.77, P = 0.001) and hypersplenism (OR = 2.29, 95% CI: 1.18–4.42, P = 0.014), while alcohol-related cirrhotic patients still had higher risks of HE (OR= 0.22, 95% CI: 0.06–0.73, P = 0.013) and ACLF (OR = 0.30, 95% CI: 0.14–0.73, P = 0.020). Conclusion: HBV-related cirrhotic patients had increased risks of HCC and hypersplenism, while alcohol-related cirrhotic patients more readily developed HE and ACLF.

Objective: Adult-onset Still’s disease (AOSD) is a multisystem autoinflammatory disorder characterized by a high spiking fever, arthralgia or arthritis, skin rash, leukocytosis, and hyperferritinemia. The relapse rate is high, from 40% to 50%. Our objective was to retrospectively analyze the risk of relapse for AOSD. Methods: Retrospective data of patients diagnosed with AOSD in our institute during 2013-2018 were analyzed. The diagnoses were based on the Yamaguchi criteria for AOSD. All long-term follow-up data were collected from medical records and phone calls. Results: In total, 56 patients with AOSD were included in this study. The mean age of the patients was 39.2 ± 14.2 years, and 37 patients (66.1%) were female. Twenty-three patients (41.1%) had experienced at least one relapse of AOSD. The factors associated with relapse were increased levels of lactic dehydrogenase (LDH) (OR = 1.003, P = 0.044) and creatine kinase-myocardial band (CK-MB) (OR = 1.111, P = 0.032). Conclusion: AOSD patients with elevated serum levels of LDH and CK-MB were more likely to have relapses, these prognostic factors may be helpful for the clinical management of AOSD patients.

Here we report a case of a previously unoperated 35-year-old male TOF patient. He was admitted due to dyspnea, initial physical examination demonstrated cyanosis and heart murmurs. Echocardiography suggested secundum atrial septal defect, perimembranous ventricular septal defect and mild-severe aortic regurgitation. Computed tomography angiography indicated aortic root dilation and suspicious right coronary artery aneurysm. Concurrent repair of TOF and VSARR was performed successfully and the patient had a satisfactory recovery.

This paper deals with a class of nonsmooth interval-valued optimization problems (NIVOPs) whose objective and constraints are interval-valued functions (IVFs). For this, we propose a new concept of symmetric invexity (S-invexity) for IVFs based on gH-symmetrically derivative, and deduce a sufficient optimality condition for non-dominated solutions. Furthermore, we establish appropriate duality theorems for Wolfe and Mond-Weir type duals. Examples are also presented to illustrate corresponding results.

BACKGROUND AND PURPOSE: There are clear sex differences in the pathophysiology of aortic valve (AV) calcification in aortic stenosis (AS) patients. However, the molecular and cellular mechanisms underlying such sex differences have not been elucidated yet. Aldosterone (Aldo) promotes proteoglycan synthesis in valve interstitial cells (VICs) from mitral valves via the mineralocorticoid receptor (MR). We investigated the influence of sex in the role of Aldo/MR pathway in AV calcification in AS patients. EXPERIMENTAL APPROACH AND KEY RESULTS: MR was expressed by primary aortic VICs and in AVs from AS patients. MR expression was positively correlated with VICs activation markers in AVs from both sexes. However, MR expression was positively associated with molecules involved in AV calcification only AV from in men. Aldo enhanced VICs activation markers in cells from men and women. Interestingly, Aldo increased the expression of calcification markers only in VICs isolated from men. MR antagonism blocked (spironolactone) all the above effects. Cytokine arrays showed intercellular adhesion molecule (ICAM)-1 and osteopontin to be specifically increased by Aldo in male VICs. In AVs from men, MR expression positively associated with both ICAM-1 and osteopontin. CONCLUSION AND IMPLICATIONS: These findings demonstrate that the Aldo/MR pathway could play a role in early stages of AS by promoting VICs activation and ulterior calcification. Importantly, Aldo/MR pathway is involved in early AV calcification only in men. Accordingly, MR antagonism emerges as a new sex-specific pharmacological treatment to prevent AV calcification in men.

BACKGROUND AND PURPOSE: Neuromyelitis optica spectrum disorders (NMOSD) is an autoantibody-mediated, B cell-driven disease. Inebilizumab is a humanized, affinity-optimized, afucosylated IgG1 kappa monoclonal antibody that binds to the B cell specific surface antigen CD19, resulting in rapid, profound, and sustained depletion of circulating peripheral B cells in NMOSD subjects (pivotal study). The objective of this study was to conduct population modeling of B cell response following inebilizumab treatment in adult subjects with NMOSD, and to assess the impact of drug exposure to outcome. EXPERIMENTAL APPROACH: A hematopoietic transit model was developed to describe the joint effects of reducing influx from pro-B cells and accelerating CD20+ B cell depletion in the blood by inebilizumab. Furthermore, the relationships between inebilizumab pharmacokinetic (PK) exposure and the primary efficacy endpoint and key secondary efficacy endpoints were evaluated. KEY RESULTS: At the 300 mg dose, there was no apparent relationship between efficacy (reduction in disease attack risk, risk of worsening from baseline in Expanded Disability Status Scale, cumulative total active MRI lesions, and the number of NMOSD-related in-patient hospitalizations) and PK exposure. Subjects with low, medium, and high PK exposure had a similar hazard ratio of NMOSD attack vs Placebo group. CONCLUSION AND IMPLICATIONS: The pharmacodynamic modeling confirmed effective depletion of B cells is achieved with a 300 mg intravenous dose of inebilizumab administered on Day 1 and Day 15 and every 6 months thereafter. The PK variability between patients had no apparent effect on clinical efficacy.

Background and Purpose: Mitochondrial fission-fusion dynamics and bioenergy dysfunctions are participated in cerebral ischemia/reperfusion (I/R) injury. Our study aims to investigate the role of Mul1-dependent Mfn2 ubiquitination and its mediated mitochondrial dysfunctions and explain the molecular mechanism of ginsenoside compound K (CK) targeting Mul1 against cerebral I/R injury. Experimental Approach: We used a combination of in vitro and in vivo models, including oxygen and glucose deprivation/reperfusion-induced PC12 cell model and middle cerebral artery occlusion/reperfusion-induced rat model, to mimic I/R injury. The potential mechanisms and pharmacological effects of ginsenoside CK on mitochondrial dynamics and bioenergy were evaluated by Mul1 knockdown and pharmacological antagonism study using a series of experiments. Key Results: I/R injury stimuli upregulated the binding of Mul1 with Mfn2 to regulate Mfn2 ubiquitination and degradation, which resulted in increased mitochondrial fission, bioenergy dysfunction, neuronal apoptosis, and neurological impairment. Knockdown of Mul1 exerted beneficial effect on cerebral I/R-induced neuronal death by abolishing mitochondrial fission, mitophagy, and bioenergy dysfunction. More importantly, ginsenoside CK mainly inhibited Mul1 expression to reduce Mfn2 ubiquitination and mitochondrial translocation of DRP1, thereby inhibiting mitochondrial fission, mitophagy and mitochondrial apoptosis against cerebral I/R injury in both in vitro and in vivo models. Conclusions and Implications: These data for the first time explain molecular basis of the Mul-dependent mitochondrial dysfunctions during I/R damages and provide the evidence that ginsenoside CK may be a promising therapeutic agent against cerebral I/R injury by targeting Mul1/Mfn2-mediated mitochondrial dynamics and bioenergy.

Background and Purpose: Mu opioid receptors (MORs) are expressed in the dorsal striatum, a brain region that mediates goal-directed (via the dorsomedial striatum), and habitual (via the dorsolateral striatum, DLS) behaviors. Our previous work indicates that glutamate transmission is depressed when MORs are activated in the dorsal striatum, inducing MOR-mediated long-term synaptic depression (MOR-LTD) or short-term depression (MOR-STD), depending on the input. In the DLS, MOR-LTD is produced by MORs on anterior insular cortex (AIC) inputs and MOR-STD occurs at thalamic inputs, suggesting input-specific MOR plasticity mechanisms. Experimental Approach: We evaluated the mechanisms of induction of MOR-LTD and MOR-STD in the DLS using pharmacology and optogenetics combined with patch clamp electrophysiology. To evaluate glutamatergic synapses, we used C57BL/6J (all glutamatergic inputs or targeted probing of AIC-DLS inputs), Emx1-Ai32 (cortical inputs), VGluT2-Ai32 (thalamic inputs) and HCN1-flox (AIC-DLS HCN1 deletion) mice. Key Results: We found that cAMP/PKA signaling and protein synthesis are necessary for MOR-LTD expression, similar to previous studies of endocannabinoid-mediated LTD (eCB-LTD) in DLS. However, MOR-LTD does not require mTOR signaling as eCB-LTD does. MOR-STD does not utilize these same mechanisms. We characterized a novel role of presynaptic HCN1 channels in MOR-LTD induction as HCN1 channels expressed in AIC are necessary for MOR-LTD expression in the DLS. Conclusion and Implications: These results show a novel mechanism in which MOR activation needs HCN1 to induce MOR-LTD, suggesting a new target for pharmacological modulation of synaptic plasticity, providing new opportunities to develop novel drugs to treat alcohol and opioid use disorders.