The Novel Tetra-Specific Drug C-192, Conjugated Using UniStac, Alleviates Non-Alcoholic Steatohepatitis in an MCD Diet-Induced Mouse Model.

Non-alcoholic steatohepatitis (NASH) is a complex disease resulting from chronic liver injury associated with obesity, type 2 diabetes, and inflammation. Recently, the importance of developing multi-target drugs as a strategy to address complex diseases such as NASH has been growing; however, their manufacturing processes remain time- and cost-intensive and inefficient. To overcome these limitations, we developed UniStac, a novel enzyme-mediated conjugation platform for multi-specific drug development. UniStac demonstrated high conjugation yields, optimal thermal stabilities, and robust biological activities. We designed a tetra-specific compound, C-192, targeting glucagon-like peptide 1 (GLP-1), glucagon (GCG), fibroblast growth factor 21 (FGF21), and interleukin-1 receptor antagonist (IL-1RA) simultaneously for the treatment of NASH using UniStac. The biological activity and treatment efficacy of C-192 were confirmed both in vitro and in vivo using a methionine-choline-deficient (MCD) diet-induced mouse model. C-192 exhibited profound therapeutic efficacies compared to conventional drugs, including liraglutide and dulaglutide. C-192 significantly improved alanine transaminase levels, triglyceride accumulation, and the non-alcoholic fatty liver disease activity score. In this study, we demonstrated the feasibility of UniStac in creating multi-specific drugs and confirmed the therapeutic potential of C-192, a drug that integrates multiple mechanisms into a single molecule for the treatment of NASH.

Behavioral changes of sows with changes in flattening rate.

In this study, considering the difficulties for all farms to convert farm styles to animal welfare-based housing, an experiment was performed to observe the changes in the behavior and welfare of sows when the slat floor was changed to a collective breeding ground. Twenty-eight sows used in this study were between the second and fifth parities to minimize the influence of parity. Using a flats floor cover, the flattening rates were treated as 0%, 20%, 30%, 40%, and 50%. Data collection was the behavior of sows visually observed using a camera (e.g., standing, lying, fighting and excessive biting behaviors, and abnormal behaviors) and the animal welfare level measured through field visits. Lying behavior was found to be higher (p < 0.01) as the flattening rate increased, and sows lying on the slatted cover also increased as the flattening rate increased (p < 0.01). Fighting behavior wasincreased when the flattening rate was increased to 20%, and chewing behavior was increased (p < 0.05) as the flattening rate increased. The animal welfare level of sows, 'good feeding', it was found that all treatment groups for body condition score and water were good at 100 (p < 0.05). 'Good housing' was the maximum value (100) in each treatment group. As the percentage of floor increased, the minimum good housing was increased from 78 in 0% flattening rate to 96 in 50% flattening rate. The maximum (100) 'good health' was achieved in the 0% and 20% flattening rates, and it was 98, 98, and 99 in the 30%, 50%, and 40% flattening rate, respectively. 'Appropriate behavior' score was significantly lower than that of other paremeters, but when the flattening ratio was 0% and 20%, the maximum and minimum values were 10. At 40% and 50%, the maximum values were 39 and 49, respectively, and the minimum values were analyzed as 19 for both 40% and 50%. These results will be used as basic data about sow welfare for farmers to successfully transition to group housing and flat floors.

The stability of graphene and boron nitride for III-nitride epitaxy and post-growth exfoliation.

A challenging approach, but one providing a key solution to material growth, remote epitaxy (RE)-a novel concept related to van der Waals epitaxy (vdWE)-requires the stability of a two-dimensional (2-D) material. However, when graphene, a representative 2-D material, is present on substrates that have a nitrogen atom, graphene loss occurs. Although this phenomenon has remained a hurdle for over a decade, restricting the advantages of applying graphene in the growth of III-nitride materials, few previous studies have been conducted. Here, we report the stability of graphene on substrates containing oxygen or nitrogen atoms. Graphene has been observed on highly decomposed Al2O3; however, graphene loss occurred on decomposed AlN at temperatures over 1300 °C. To overcome graphene loss, we investigated 2-D hexagonal boron nitride (h-BN) as an alternative. Unlike graphene on AlN, it was confirmed that h-BN on AlN was intact after the same high-temperature process. Moreover, the overgrown AlN layers on both h-BN/AlN and h-BN/Al2O3 could be successfully exfoliated, which indicates that 2-D h-BN survived after AlN growth and underlines its availability for the vdWE/RE of III-nitrides with further mechanical transfer. By enhancing the stability of the 2-D material on the substrate, our study provides insights into the realization of a novel epitaxy concept.

Korean Guidelines for the Pharmacological Treatment of Social Anxiety Disorder: Initial Treatment Strategies.

OBJECTIVE: The aim of the present study was to provide clinical consensus and evidence regarding initial treatment strategies for the pharmacological treatment of social anxiety disorder (SAD) in Korea. METHODS: We prepared a questionnaire to derive a consensus from clinicians regarding their preference for the pharmacological treatment of SAD in Korea. Data regarding medication regimens and psychotropic drugs used during initial treatment, the doses used, and the pharmacological treatment duration were obtained. Responses were obtained from 66 SAD experts, and their opinions were classified into three categories (first-line, second-line, third-line) using a chi-square analysis. RESULTS: Clinicians agreed upon first-line regimens for SAD involving monotherapy with selective serotonin reuptake inhibitors (SSRIs) or the serotonin-norepinephrine reuptake inhibitor (SNRI) venlafaxine, or combined therapy using antidepressants with betablockers or benzodiazepines on a standing or as-needed basis. First-line psychotropic drug choices for initial treatment included the following: escitalopram, paroxetine, sertraline, venlafaxine, and propranolol. The medication dosage used by domestic clinicians was found to be comparable with foreign guidelines. Domestic clinicians tended to make treatment decisions in a shorter amount of time and preferred a similar duration of maintenance treatment for SAD when compared with foreign clinicians. CONCLUSION: This study may provide significant information for developing SAD pharmacotherapy guidelines in Korea, especially in the early stage of treatment.

Fabrication of a vertically-stacked passive-matrix micro-LED array structure for a dual color display.

We report a color tunable display consisting of two passive-matrix micro-LED array chips. The device has combined vertically stacked blue and green passive-matrix LED array chips sandwiched by a transparent bonding material. We demonstrate that vertically stacked blue and green micro-pixels are independently controllable with operation of four color modes. Moreover, the color of each pixel is tunable in the entire wavelength from the blue to green region (450 nm - 540 nm) by applying pulse-width-modulation bias voltage. This study is meaningful in that a dual color micro-LED array with a vertically stacked subpixel structure is realized.

Effectiveness of Duloxetine Monotherapy Compared to Combination Therapy with Other Antidepressants in Patients with Major Depressive Disorder: A Short-Term, Retrospective Study.

OBJECTIVE: The purpose of this study was to compare duloxetine monotherapy to combination therapy with other antidepressants in patients with major depressive disorder in a clinical, real world setting. METHODS: An eight-week, retrospective, multi-center study of outpatients with major depressive disorder was undertaken. After screening 415 patients, enrolled in this study from July 2009 to June 2014 were 82 patients from among three centers who had been taking duloxetine with or without other antidepressant and not administered with atypical antipsychotics. We compared the mean changes of the Clinical Global Impression-Severity Scale (CGI-S) as a primary measure and the discontinuation rate as a secondary measure between the duloxetine monotherapy group (n=36, 43.9%) and the combination therapy with other antidepressants group (n=46, 56.1%) at baseline, one, two, four and eight weeks. RESULTS: There were no significant differences across the demographic characteristics between two groups. There was, however, a statistically greater improvement on the CGI-S at weeks 2, 4 and 8 in the combination group compared with the monotherapy group. There were no significant differences in discontinuation rate and adverse events between two groups. No serious adverse events were reported in both groups during the study period. CONCLUSION: This result suggests that the duloxetine combination therapy with other antidepressants could improve effectiveness and have comparable tolerability with the monotherapy in the treatment of outpatients with major depressive disorders in a naturalistic setting. Adequately powered, well-controlled clinical trials are strongly warranted to confirm our findings due to methodological shortcomings.

Serotonin Transporter and COMT Polymorphisms as Independent Predictors of Health-related Quality of Life in Patients with Panic Disorder.

There is growing evidence of poor health-related quality of life (HRQOL) in patients with panic disorder (PD). However, little is known about the factors affecting HRQOL in patients with PD. The authors examined whether 5-HTTLPR tri-allelic approach and Cathechol-O-methyltransferase (COMT) Val(158)Met polymorphism can predict HRQOL in patients with PD controlling for sociodemographic factors and disorder-related symptom levels. The sample consisted of 179 patients with PD consecutively recruited from an outpatient clinic and age- and gender ratio-matched 110 healthy controls. The SF-36 was used to assess multiple domains of HRQOL. Hierarchical multiple regression analysis was performed to determine the independent effect of the 5-HTTLPR and COMT Val(158)Met on the SF-36 in panic patients. Patients with PD showed lowered HRQOL in all sub-domains of the SF-36 compared to healthy controls. The 5-HTTLPR independently and additively accounted for 2.2% of variation (6.7% of inherited variance) of perceived general health and the COMT Val(158)Met independently and additively accounted for 1.5% of variation (5.0% of inherited variance) of role limitation due to emotional problems in patient group. The present study suggests that specific genetic polymorphisms are associated with certain domains of HRQOL and provides a new insight on exploring the factors that predict HRQOL in patients with PD.

Color tunable monolithic InGaN/GaN LED having a multi-junction structure.

In this study, we have fabricated a blue-green color-tunable monolithic InGaN/GaN LED having a multi-junction structure with three terminals. The device has an n-p-n structure consisting of a green and a blue active region, i.e., an n-GaN / blue-MQW / p-GaN / green-MQW / n-GaN / Al2O3 structure with three terminals for independently controlling the two active regions. To realize this LED structure, a typical LED consisting of layers of n-GaN, blue MQW, and p-GaN is regrown on a conventional green LED by using a metal organic chemical vapor deposition (MOCVD) method. We explain detailed mechanisms of three operation modes which are the green, blue, and cyan mode. Moreover, we discuss optical properties of the device.

Differential discriminative-stimulus effects of cigarette smoke condensate and nicotine in nicotine-discriminating rats.

Although it is widely accepted that nicotine plays a key role in tobacco dependence, nicotine alone cannot account for all of the pharmacological effects associated with cigarette smoke found in preclinical models. Thus, the present study aimed to determine the differential effects of the interoceptive cues of nicotine alone versus those of cigarette smoke condensate (CSC) in nicotine-trained rats. First, the rats were trained to discriminate nicotine (0.4mg/kg, subcutaneous [s.c.]) from saline in a two-lever drug discrimination paradigm. Then, to clarify the different neuropharmacological mechanisms underlying the discriminative-stimulus effects in the nicotine and CSC in nicotine-trained rats, either the α4ß2 nicotinic acetylcholine receptor (nAChR) antagonist dihydro-ß-erythroidine (DHßE; 0.3-1.0mg/kg, s.c.) or the α7 nAChR antagonist methyllycaconitine citrate (MLA; 5-10mg/kg, intraperitoneal [i.p.]) was administered prior to the injection of either nicotine or CSC. Separate set of experiments was performed to compare the duration of action of the discriminative-stimulus effects of CSC and nicotine. CSC exhibited a dose-dependent nicotine generalization, and interestingly, 1.0mg/kg of DHßE antagonized the discriminative effects of nicotine (0.4mg/kg) but not CSC (0.4mg/kg nicotine content). However, pretreatment with MLA had no effect. In the time-course study, CSC had a relatively longer half-life in terms of the discriminative-stimulus effects compared with nicotine alone. Taken together, the present findings indicate that CSC has a distinct influence on interoceptive effects relative to nicotine alone and that these differential effects might be mediated, at least in part, by the α4ß2, but not the α7, nAChR.

The mGluR5 antagonist MPEP suppresses the expression and reinstatement, but not the acquisition, of the ethanol-conditioned place preference in mice.

The glutamatergic system may play a vital role in regulating neurobehavioral effects of various drugs of abuse. In the present study, we evaluated the effects of 2-methyl-6-(phenylethynyl)-pyridine (MPEP), a selective antagonist of the type 5 metabotropic glutamate receptor (mGluR5) on the acquisition, expression and reinstatement of ethanol conditioned place preference (CPP). In the ethanol acquisition study, mice were conditioned with saline or ethanol (20% v/v, 2g/kg) on alternating days for 8 consecutive days and were given MPEP 10 min before ethanol conditioning. In another experiment, animals were conditioned with 2g/kg ethanol and MPEP was administered 10 min prior to the post-conditioning test. In a reinstatement study, following the extinction phase, animals were pretreated with MPEP 10 min prior to a priming injection of 1.0 g/kg ethanol. The mGluR5 antagonist MPEP significantly reduced the expression and the reinstatement in dose-dependent manner, but not acquisition of ethanol-induced CPP. These results indicate that mGluR5 may be involved in the expression and reinstatement of conditioned rewarding effects of ethanol, but not the acquisition of ethanol, which provide an evidence that mGluR5 blockade might make dissociable contributions during the training (acquisition phase), the performance of behavior (expression phase) and reinstatement.

Outcomes of acute kidney injury patients with and without cancer.

Incidence of AKI in hospitalized patients with cancer is increasing, but there have been few studies on AKI in patients with cancer. We conducted a retrospective cohort study in a South Korean tertiary care hospital. A total of 2211 consecutive patients (without cancer 61.5%; with cancer 38.5%) were included over a 140-month period. Predictors of all-cause death were examined using the Kaplan-Meier method and the Cox proportional hazards model. The main contributing factors of AKI were sepsis (31.1%) and ischemia (52.7%). AKI was multifactorial in 78% of patients with cancer and in 71% of patients without cancer. Hospital mortality rates were higher in patients with cancer (42.8%) than in patients without cancer (22.5%) (p = 0.014). In multivariate analyses, diabetes mellitus (DM) and cancer diagnosis were associated with hospital mortality. Cancer diagnosis was independently associated with mortality [odds ratio = 3.010 (95% confidence interval, 2.340-3.873), p = 0.001]. Kaplan-Meier analysis revealed that subjects with DM and cancer (n = 146) had lower survival rates than subjects with DM and without cancer (n = 687) (log rank test, p = 0.001). The presence of DM and cancer was independently associated with mortality in AKI patients both with and without cancer. Studies are warranted to determine whether proactive measures may limit AKI and improve outcomes.

Effects of neurofeedback on adult patients with psychiatric disorders in a naturalistic setting.

Few well-controlled studies have considered neurofeedback treatment in adult psychiatric patients. In this regard, the present study investigates the characteristics and effects of neurofeedback on adult psychiatric patients in a naturalistic setting. A total of 77 adult patients with psychiatric disorders participated in this study. Demographic data and neurofeedback states were retrospectively analyzed, and the effects of neurofeedback were evaluated using clinical global impression (CGI) and subjective self-rating scales. Depressive disorders were the most common psychiatric disorders (19; 24.7 %), followed by anxiety disorders (18; 23.4 %). A total of 69 patients (89.6 %) took medicine, and the average frequency of neurofeedback was 17.39 ± 16.64. Neurofeedback was applied to a total of 39 patients (50.6 %) more than 10 times, and 48 patients (62.3 %) received both ß/SMR and α/θ training. The discontinuation rate was 33.8 % (26 patients). There was significant difference between pretreatment and posttreatment CGI scores (<.001), and the self-rating scale also showed significant differences in depressive symptoms, anxiety, and inattention (<.001). This is a naturalistic study in a clinical setting, and has several limitations, including the absence of a control group and a heterogenous sample. Despite these limitations, the study demonstrates the potential of neurofeedback as an effective complimentary treatment for adult patients with psychiatric disorders.

Panic disorder and health-related quality of life: the predictive roles of anxiety sensitivity and trait anxiety.

Panic disorder (PD) is a very common anxiety disorder and is often a chronic disabling condition. However, little is known about the factors that predict health-related quality of life (HRQOL) other than sociodemographic factors and illness-related symptomatology that explain HRQOL in only small to modest degrees. This study explored whether anxiety-related individual traits including anxiety sensitivity and trait anxiety can predict independently HRQOL in panic patients. Patients with panic disorder with or without agoraphobia (N=230) who met the diagnostic criteria in the Structured Clinical Interview for DSM-IV were recruited. Stepwise regression analysis was performed to determine the factors that predict HRQOL in panic disorder. HRQOL was assessed by the 36-item Short-Form Health Survey (SF-36). Anxiety sensitivity was an independent predictor of bodily pain and social functioning whereas trait anxiety independently predicted all of the eight domains of the SF-36. Our data suggests that the assessment of symptomatology as well as individual anxiety-related trait should be included in the evaluation of HRQOL in panic patients.

Graphene interlayer for current spreading enhancement by engineering of barrier height in GaN-based light-emitting diodes.

Pristine graphene and a graphene interlayer inserted between indium tin oxide (ITO) and p-GaN have been analyzed and compared with ITO, which is a typical current spreading layer in lateral GaN LEDs. Beyond a certain current injection, the pristine graphene current spreading layer (CSL) malfunctioned due to Joule heat that originated from the high sheet resistance and low work function of the CSL. However, by combining the graphene and the ITO to improve the sheet resistance, it was found to be possible to solve the malfunctioning phenomenon. Moreover, the light output power of an LED with a graphene interlayer was stronger than that of an LED using ITO or graphene CSL. We were able to identify that the improvement originated from the enhanced current spreading by inspecting the contact and conducting the simulation.

Factors associated with treatment outcomes in mindfulness-based cognitive therapy for panic disorder.

PURPOSE: Although the effectiveness of Mindfulness-Based Cognitive Therapy (MBCT) for panic disorder (PD) has been studied previously, data on the predictors of treatment outcomes in MBCT for PD are scarce. MATERIALS AND METHODS: Eighty patients with PD were screened to analyze treatment outcomes such as MBCT completion, treatment response, and remission after undergoing MBCT for PD. Sociodemographic characteristics, comorbid personality disorders, and baseline medication doses were examined. The study administered the Panic Disorder Severity Scale, Hamilton Anxiety Rating Scale, Hamilton Depression Rating Scale and Anxiety Sensitivity Inventory-Revised to patients at baseline and at eight weeks. RESULTS: Sixty-five participants were enrolled in the present study. Comorbid personality disorder was significantly associated with MBCT non-completion. We found that anxiety sensitivity (AS) improvement after an eight week MBCT program was a statistically significant factor associated with treatment response. Using logistic regression analysis, AS improvement after MBCT showed significant association with PD remission after MBCT. CONCLUSION: Comorbid personality disorders of participants could be a potential predictor of MBCT non-completion. Furthermore, AS improvement after MBCT may predict treatment response and remission after MBCT for PD. However, better designed studies with a larger number of patients are needed to confirm our findings.

Size-controlled InGaN/GaN nanorod array fabrication and optical characterization.

We demonstrate a cost-effective top-down approach for fabricating InGaN/GaN nanorod arrays using a wet treatment process in a KOH solution. The average diameter of the as-etched nanorods was effectively reduced from 420 nm to 180 nm. The spatial strain distribution was then investigated by measuring the high-resolution cathodoluminescence directly on top of the nanorods. The smaller nanorods showed a higher internal quantum efficiency and lower potential fluctuation, which can subsequently be exploited for high-efficiency photonic devices.

Two cases of hypersexuality probably associated with aripiprazole.

Sexual dysfunction is a common side effect in patients treated with antipsychotics but significant differences exist across different compounds. We report hypersexuality symptoms in two female patients with schizophrenia who were receiving treatment with aripiprazole. The patients experienced more frequent sexual desire and greater sexual preoccupation after taking aripiprazole. We discuss the potential neuro-chemical mechanisms for this and argue that aripiprazole's unique pharmacological profile, partial agonism with high affinity at dopamine D2-receptor, may have contributed to the development of these symptoms.

Serotonergic genes (5-HTT and HTR1A) and separation life events: gene-by-environment interaction for panic disorder.

BACKGROUND: The polymorphisms of serotonergic genes (5-HTTLPR and HTR1A rs6295) and separation life events have been studied to find an association with panic disorder, respectively. However, there are no studies that have yet evaluated the interaction effect between serotonergic genes and separation life events for panic disorder. METHODS: For this study, 194 panic disorder patients and 172 healthy controls were included for genotyping and environmental factor analysis. Separation life events were assessed using the Stressful Life Events Scale and clinical interviews. To evaluate the potential endophenotypes of panic disorder, the Anxiety Sensitivity Index-revised (ASI-R), harm avoidance in the Temperament and Character Inventory (HA), and neuroticism in the Eysenck Personality Questionnaire (neuroticism) scales were administered. RESULTS: For 5-HTTLPR and HTR1A rs6295, there was no significant main effect of each genotype on panic disorder alone. However, the number of separation life events and their interaction with 5-HTTLPR showed a statistically significant effect on panic disorder. In addition, the interaction between 5-HTTLPR and the number of separation life events significantly affected the HA for potential endophenotypes. CONCLUSION: This study could suggest the effect of the interaction between 5-HTTLPR and separation life events on panic disorder and its potential endophenotype.

Comparison of panic disorder with and without comorbid major depression by using brain structural magnetic resonance imaging.

BACKGROUND: Strong lifetime and current comorbidity occur between panic disorder and depression. However, no study has examined the influence of comorbid depression on brain structural characteristics in panic disorder patients. We aimed to compare gray matter (GM) volume and white matter (WM) connectivity in panic disorder patients with and without depression. METHODS: Twenty-one panic disorder patients without comorbid major depression (PD-D) and seventeen panic disorder patients with major depression (PD+D) were investigated. The Panic Disorder Severity Scale (PDSS) and Beck Depression Inventory (BDI) were assessed for all subjects. Voxel Based Morphometry 5 toolbox and Tract-Based Spatial Statistics were used. RESULTS: Compared to the PD-D group, GM volumes of patients with PD+D were significantly increased in a cluster located across the left cingulate gyrus, right medial frontal gyrus, and left paracentral lobule. Clinical symptom severity such as PDSS and BDI scores showed positive correlation with GM volumes in the PD+D group. Of the highlighted regions, the left posterior cingulate gyrus demonstrated both a GM volume difference between the groups and a positive correlation of GM volume with symptom severity in the PD+D group. Fractional anisotropy values were significantly higher across almost all the WM tracts in the PD+D group compared to the PD-D group. CONCLUSION: Alteration of GM volume and WM connectivity was associated with comorbid depression in panic disorder patients in this study. These findings suggest that distinct structural characteristics may be related to comorbid depression occurring in the context of panic disorder.