WGA-M001, a Mixture of Total Extracts of Tagetes erecta and Ocimum basilicum, Synergistically Alleviates Cartilage Destruction by Inhibiting ERK and NF-κB Signaling.

Tagetes erecta and Ocimum basilicum are medicinal plants that exhibit anti-inflammatory effects against various diseases. However, their individual and combined effects on osteoarthritis (OA) are unknown. Herein, we aimed to demonstrate the effects of T. erecta, O. basilicum, and their mixture, WGA-M001, on OA pathogenesis. The administration of total extracts of T. erecta and O. basilicum reduced cartilage degradation and inflammation without causing cytotoxicity. Although WGA-M001 contained lower concentrations of the individual extracts, it strongly inhibited the expression of pathogenic factors. In vivo OA studies also supported that WGA-M001 had protective effects against cartilage destruction at lower doses than those of T. erecta and O. basilicum. Moreover, its effects were stronger than those observed using Boswellia and Perna canaliculus. WGA-M001 effectively inhibited the interleukin (IL)-1ß-induced nuclear factor kappa-light-chain-enhancer of the activated B cell (NF-κB) pathway and ERK phosphorylation. Furthermore, RNA-sequence analysis also showed that WGA-M001 decreased the expression of genes related to the IL-1ß-induced NF-κB and ERK signaling pathways. Therefore, WGA-M001 is more effective than the single total extracts of T. erecta and O. basilicum in attenuating OA progression by regulating ERK and NF-κB signaling. Our results open new possibilities for WGA-M001 as a potential therapeutic agent for OA treatment.

Low-density lipoprotein cholesterol reduction and target achievement after switching from statin monotherapy to statin/ezetimibe combination therapy: Real-world evidence.

WHAT IS KNOWN AND OBJECTIVES: This study investigated the additional low-density lipoprotein cholesterol (LDL-C) reductions and target (LDL-C < 100 mg/dL) achievement rates in patients after switching from statin monotherapy to statin/ezetimibe combination therapy, in clinical practice. METHODS: This retrospective study used data recovered from the electronic medical record systems of two tertiary care medical centres for patients treated between 2015 and 2017. Patients prescribed statin/ezetimibe combination therapy after switching from statin monotherapy were enrolled. The observed LDL-C reductions and the percentage of patients achieving LDL-C levels of <100 mg/dL, after 3 months of treatment, were assessed relative to baseline values. RESULTS AND DISCUSSION: A total of 4252 patients with prescriptions for statin/ezetimibe combination therapy were enrolled. Changing from statin monotherapy to the combination therapy resulted in additional LDL-C level reductions of 31.0-41.0% (all intensity groups, P < .01). Similarly, 88.3-91.1% of the enrolled patients successfully achieved LDL-C levels of <100 mg/dL (all intensity groups, P < .01). A subgroup analysis of patients with baseline LDL-C levels ≥ 100 mg/dL showed that switching from moderate- or high-intensity statin monotherapy to a rosuvastatin/ezetimibe combination showed greater LDL-C reductions than did switching to an atorvastatin/ezetimibe combination, within the same statin intensity groups. WHAT IS NEW AND CONCLUSION: The present study provides real-world evidence of the LDL-C reduction benefits associated with statin/ezetimibe combinations in the clinical practice setting. The results also demonstrate that if statin monotherapy does not effectively help patients reach their target LDL-C goals, changing to a statin/ezetimibe combination prescription may show enhanced LDL-C-lowering effects and improve the likelihood of achieving LDL-C targets, in real practice.

Discontinuation rate and reason for discontinuation after sodium-glucose cotransporter 2 inhibitor prescription in real clinical practice.

WHAT IS KNOWN AND OBJECTIVES: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are novel antidiabetic agents that have advantages of weight loss and prevention of cardiovascular diseases. However, SGLT2i have various side effects. To understand their effectiveness, we analysed patients who had discontinued the use of dapagliflozin, an SGLT2i, 3 months after the initial prescription. We evaluated the discontinuation rate of dapagliflozin and the incidence rate of its side effects. METHODS: Patients who were initially prescribed dapagliflozin for blood sugar control from December 2014 to December 2016 were analysed. Data of patients in whom dapagliflozin administration was discontinued 90 days after initial prescription were collected separately, and the reasons were evaluated by a direct chart review. RESULTS AND DISCUSSION: A total of 8.96% (149/1663) patients discontinued dapagliflozin or switched medications within 3 months. Dapagliflozin was discontinued in 24.8% (37/149) of cases due to unexpected causes such as increased blood sugar and weight gain. The patients who discontinued dapagliflozin use due to side effects comprised 49.7% (74/149). Two major side effects were genital tract infection in women (P < .001 compared with men) and urinary tract infection, which increased with age (P = .030). Malpractice of medical personnel, insurance problems or causes of termination not related to dapagliflozin use comprised 14.1% (21/149). WHAT IS NEW AND CONCLUSION: The incidence of side effects with dapagliflozin was not as high as expected. Physicians should consider instructions prior to prescribing dapagliflozin so that its discontinuation would decrease considerably.

Gapless Kitaev Spin Liquid to Classical String Gas through Tensor Networks.

We provide a framework for understanding the gapless Kitaev spin liquid (KSL) in the language of the tensor network (TN). Without introducing a Majorana fermion, most of the features of the KSL, including the symmetries, gauge structure, criticality, and vortex freeness, are explained in a compact TN representation. Our construction reveals a hidden string gas structure of the KSL. With only two variational parameters to adjust, we obtain an accurate KSL Ansatz with the bond dimension D=8 in a compact form, where the energy is about 0.007% higher than the exact one.

DW2008S and its major constituents from Justicia procumbens exert anti-asthmatic effect via multitargeting activity.

Our previous study revealed that the ethanolic extract of Justicia procumbens ameliorates ovalbumin-induced airway inflammation and airway hyper-responsiveness in a mouse model of asthma. However, the mechanism of action of the extract remains unknown. In this study, we prepared DW2008S, an optimized and standardized powder extracted from J. procumbens using anhydrous ethanol, and investigated its anti-asthmatic effect and mechanism of action. Our results showed that DW2008S contains two major ingredients, justicidin A (JA) and justicidin B (JB), which selectively inhibit T helper 2 (Th2) cell responses in concanavalin A-activated spleen cells and polarized Th2 cells. Blockade of T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domains (TIGIT) using a neutralizing antibody also selectively inhibited Th2 cell responses. Furthermore, DW2008S regulated TIGIT expression in the mice and cultured cells. Additionally, DW2008S and JA antagonized human adenosine receptor A3 (A3 AR), which mediates mast cell-dependent inflammation and bronchoconstriction. DW2008S and JB inhibited human phosphodiesterase 4 (PDE4), which is known to cause bronchoconstriction; however, the required concentrations were higher than those needed to affect TIGIT . These findings suggest that DW2008S can potentially ameliorate Th2-driven airway inflammation and bronchoconstriction through negative regulation of TIGIT and blockade of A3 AR and PDE4 activities.

Spin Thermal Hall Conductivity of a Kagome Antiferromagnet.

A clear thermal Hall signal (κ_{xy}) was observed in the spin-liquid phase of the S=1/2 kagome antiferromagnet Ca kapellasite [CaCu_{3}(OH)_{6}Cl_{2}·0.6H_{2}O]. We found that κ_{xy} is well reproduced, both qualitatively and quantitatively, using the Schwinger-boson mean-field theory with the Dzyaloshinskii-Moriya interaction of D/J∼0.1. In particular, κ_{xy} values of Ca kapellasite and those of another kagome antiferromagnet, volborthite, converge to one single curve in simulations modeled using Schwinger bosons, indicating a common temperature dependence of κ_{xy} for the spins of a kagome antiferromagnet.

The differences in the incidence of diabetes mellitus and prediabetes according to the type of HMG-CoA reductase inhibitors prescribed in Korean patients.

BACKGROUND: Very few studies conducted in Korea have investigated the relationship between statins and the incidence of diabetes. Therefore, we analyzed the progression from normal blood glucose to prediabetes and then to diabetes mellitus (DM) according to the type, intensity, and dose of statin prescribed. METHODS: Data of patients who were first prescribed statins between 2009 and 2011 were extracted from electronic medical records. Patients with normal blood glucose or prediabetes were observed for 4 years after initiation of statin therapy. RESULTS: A total of 2890 patients were included in our study and analyzed on the basis of the first statin they were prescribed. The incidence rate of DM in patients with prediabetes was 1.72 times that of patients with normal glucose levels (odds ratio = 1.72, 95% confidence interval = 1.41-2.10, P < .001). Regarding progression from normal blood glucose to prediabetes, the incidence rate of prediabetes was significantly lower in patients prescribed pitavastatin (odds ratio = 0.62, 95% confidence interval = 0.40-0.96, P = .031) compared to that in patients prescribed atorvastatin. Regarding the progression from normal blood glucose or prediabetes to DM, there were no significant differences among all statins. CONCLUSIONS: Lower DM incidence in patients prescribed pitavastatin appears to be primarily because of the lower rate of progression from normal blood glucose to prediabetes. These findings indicate that avoiding statins because of DM risk is unjustified and that clinicians should prescribe statins from the appropriate potency group.

Justicia procumbens Extract (DW2008) Selectively Suppresses Th2 Cytokines in Splenocytes and Ameliorates Ovalbumin-Induced Airway Inflammation in a Mouse Model of Asthma.

DW2008 is an anhydrous ethanol extract of Justicia procumbens produced by Dong-Wha Pharmaceutical, Inc., Co. as a candidate anti-asthmatic drug. In this study, DW2008 selectively reduced T helper 2 (Th2) cytokines in mouse splenocytes and ameliorated ovalbumin-induced airway inflammation by downregulating pulmonary infiltration of differential inflammatory cells and Th2 cytokines more than a decoction or ethanol extract of J. procumbens did in a mouse asthma model. DW2008 also significantly inhibited airway hyperresponsiveness and reduced the thickness of the airway epithelium. HPLC analysis showed that the major peaks (justicidin A and B) of DW2008 were higher than those of the other extracts. Justicidin A and B significantly suppressed Th2 cytokine levels in mouse spleen cells and exhibited a protective effect in ovalbumin-induced airway inflammation. Our findings indicate that DW2008 effectively inhibits allergic airway inflammatory reactions and airway hyperresponsiveness in a mouse model of asthma, suggesting its potential as an anti-asthmatic agent.

The ethanol extract of Aquilariae Lignum ameliorates hippocampal oxidative stress in a repeated restraint stress mouse model.

BACKGROUND: Chronic stress contributes to the development of brain disorders, such as neurodegenerative and psychiatric diseases. Oxidative damage is well known as a causative factor for pathogenic process in brain tissues. The aim of this study is to evaluate the neuroprotective effect of a 30% ethanol extract of Aquilariae Lignum (ALE) in repeated stress-induced hippocampal oxidative injury. METHODS: Fifty BALB/c male mice (12 weeks old) were randomly divided into five groups (n = 10). For 11 consecutive days, each group was orally administered with distilled water, ALE (20 or 80 mg/kg) or N-acetylcysteine (NAC; 100 mg/kg), and then all mice (except unstressed group) were subjected to restraint stress for 6 h. On the final day, brain tissues and sera were isolated, and stress hormones and hippocampal oxidative alterations were examined. We also treated lipopolysaccharide (LPS, 1 µg/mL)-stimulated BV2 microglial cells with ALE (1 and 5 µg/mL) or NAC (10 µM) to investigate the pharmacological mechanism. RESULTS: Restraint stress considerably increased the serum levels of corticosterone and adrenaline and the hippocampal levels of reactive oxygen species (ROS), nitric oxide (NO), and malondialdehyde (MDA). ALE administration significantly attenuated the above abnormalities. ALE also significantly normalized the stress-induced activation of astrocytes and microglial cells in the hippocampus as well as the elevation of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1ß). The in vitro assay outcome supplemented ALE could dramatically block NF-κB activation in microglia. The anti-oxidative stress effects of ALE were supported by the results of antioxidant components, 4-hydroxynonenal (4-HNE), NADPH oxidase 2 (NOX2), inducible nitric oxide synthase (iNOS) and NFE2L2 (Nrf2) in the hippocampal tissues. CONCLUSIONS: We firstly demonstrated the neuroprotective potentials of A. Lignum against hippocampal oxidative injury in repeated restraint stress. The corresponding mechanisms might involve modulations in the release of ROS, pro-inflammatory cytokines and stress hormones.

DW1029M, a novel botanical drug candidate, inhibits advanced glycation end-product formation, rat lens aldose reductase activity, and TGF-ß1 signaling.

DW1029M is a botanical extract consisting of Morus bark and Puerariae radix, produced by Dong-Wha Pharmaceutical, for nephroprotective drug development; it has been in phase II clinical trials in Korea. In our mechanistic investigations, we found that DW1029M inhibits advanced glycation end products (AGEs), rat lens aldose reductase (RLAR), and transforming growth factor (TGF)-ß1 signaling, all of which are implicated in diabetic complications such as diabetic nephropathy and diabetic retinopathy. DW1029M inhibits AGE formation via Fe(2+) chelation. The extract contains 13 active constituents that inhibit AGE formation, 8 active constituents that inhibit RLAR activity, and 1 inhibitor of TGF-ß1 signaling. Our results suggest DW1029M protects against diabetic nephropathy via blockade of AGE formation, RLAR activity, and TGF-ß1 signaling.

Small-diameter vascular graft composing of core-shell structured micro-nanofibers loaded with heparin and VEGF for endothelialization and prevention of neointimal hyperplasia.

Despite the significant progress made in recent years, clinical issues with small-diameter vascular grafts related to low mechanical strength, thrombosis, intimal hyperplasia, and insufficient endothelialization remain unresolved. This study aims to design and fabricate a core-shell fibrous small-diameter vascular graft by co-axial electrospinning process, which will mechanically and biologically meet the benchmarks for blood vessel replacement. The presented graft (PGHV) comprised polycaprolactone/gelatin (shell) loaded with heparin-VEGF and polycaprolactone (core). This study hypothesized that the shell structure of the fibers would allow rapid degradation to release heparin-VEGF, and the core would provide mechanical strength for long-term application. Physico-mechanical evaluation, in vitro biocompatibility, and hemocompatibility assays were performed to ensure safe in vivo applications. After 25 days, the PGHV group released 79.47 ± 1.54% of heparin and 86.25 ± 1.19% of VEGF, and degradation of the shell was observed but the core remained pristine. Both the control (PG) and PGHV groups demonstrated robust mechanical properties. The PGHV group showed excellent biocompatibility and hemocompatibility compared to the PG group. After four months of rat aorta implantation, PGHV exhibited smooth muscle cell regeneration and complete endothelialization with a patency rate of 100%. The novel core-shell structured graft could be pivotal in vascular tissue regeneration application.

Poly(l-lactide)/polycaprolactone based multifunctional coating to deliver paclitaxel/VEGF and control the degradation rate of magnesium alloy stent.

Despite significant advancements made in cardiovascular stents, restenosis, thrombosis, biocompatibility, and clinical complications remain a matter of concern. Herein, we report a biodegradable Mg alloy stent with a dual effect of the drug (Paclitaxel) and growth factor (VEGF) release. To mitigate the fast degradation of Mg alloy, inorganic and organic coatings were formed on the alloy surface. The optimized hierarchal sequence of the coating was the first layer consisting of magnesium fluoride, followed by poly(l-lactide) and hydroxyapatite coating, and finally sealed by a polycaprolactone layer (MgC). PLLA and HAp were used to increase the adhesion strength and biocompatibility of the coating. Paclitaxel and VEGF were loaded in the final PCL layer (Mg-C/PTX-VEGF). As compared to bare Mg alloy (28 % weight loss), our MgC system showed (3.1 % weight loss) successful decrease in the degradation rate. Further, the in vitro biocompatibility illustrated the highly biocompatible nature of our drug and growth factor-loaded system. The in vivo results displayed that the drug loading decreased the inflammation and neointimal hyperplasia as indicated by the α-SMA and CD-68 antibody staining. The growth factor helped in the endothelialization which was established by the FLKI and ICAM antibody staining of the tissue.

Prognostic significance of programmed cell death-ligand 1 expression on immune cells and epithelial-mesenchymal transition expression in patients with hepatocellular carcinoma.

Purpose: Immune checkpoint inhibitors (ICIs) have been shown significant oncological improvements in several cancers. However, ICIs are still in their infancy in hepatocellular carcinoma (HCC). Programmed cell death-ligand 1 (PD-L1), tumor-infiltrating lymphocytes (TILs), and epithelial-mesenchymal transition (EMT) have been known as prognostic factors in HCC. Therefore, we have focused on identifying the molecular mechanisms between each marker to evaluate a predictive role. Methods: Formalin-fixed paraffin-embedded samples were obtained from 166 patients with HCC who underwent surgery. The expression of PD-L1 and TILs and EMT marker were evaluated by immunohistochemical analysis. Results: The multivariate analysis showed that TIL expression (hazard ratio [HR], 0.483; 95% confidence interval [CI], 0.269-0.866; P = 0.015) were independent prognostic factors for overall survival. The prognostic factors for disease-free survival were EMT marker expression (HR, 1.565; 95% CI, 1.019-2.403; P = 0.005). Patients with high expression of TILs had significantly better survival compared to patients with low expression (P = 0.023). Patients who were TIL+/EMT- showed a significantly better prognosis than those who were TIL-/EMT+ (P = 0.049). Conclusion: This study demonstrates that PD-L1 expression of TILs is closely associated with EMT marker expression in HCC. Clinical investigations using anti-PD-1/PD-L1 inhibitors in patients with EMT-associated PD-L1 upregulation are warranted.

New disordered anyon phase of doped graphene zigzag nanoribbon.

We investigate interacting disordered zigzag nanoribbons at low doping, using the Hubbard model to treat electron interactions within the density matrix renormalization group and Hartree-Fock method. Extra electrons that are inserted into an interacting disordered zigzag nanoribbon divide into anyons. Furthermore, the fractional charges form a new disordered anyon phase with a highly distorted edge spin density wave, containing numerous localized magnetic moments residing on the zigzag edges, thereby displaying spin-charge separation and a strong non-local correlation between the opposite zigzag edges. We make the following new predictions, which can be experimentally tested: (1) In the low doping case and weak disorder regime, the soft gap in the tunneling density of states is replaced by a sharp peak at the midgap energy with two accompanying peaks. The [Formula: see text] fractional charges that reside on the boundary of the zigzag edges are responsible for these peaks. (2) We find that the midgap peak disappears as the doping concentration increases. The presence of [Formula: see text] fractional charges will be strongly supported by the detection of these peaks. Doped zigzag ribbons may also exhibit unusual transport, magnetic, and inter-edge tunneling properties.

Physico-mechanical and biological evaluation of heparin/VEGF-loaded electrospun polycaprolactone/decellularized rat aorta extracellular matrix for small-diameter vascular grafts.

Although the continuous development of small-diameter vascular grafts (SDVGs) (D < 5 mm) continues, most vascular grafts are made from synthetic polymers, which lead to serious complications from arteriosclerosis, thrombosis, and vascular ischemia. Here, to address these shortcomings, we combine synthetic polymers with natural decellularized small-diameter vessels and loaded with growth factor. We fabricated vascular grafts by electrospinning polycaprolactone (PCL) to decellularized rat aorta matrix (ECM) followed by heparin and vascular endothelial growth factor (VEGF) loading. In- vitro studies showed that PCL/ECM/VEGF vascular grafts, showed excellent hemocompatibility and biocompatibility properties. The vascular grafts implanted into the rat aorta revealed that the PCL/ECM/VEGF grafts promotes endothelial cells and smooth-muscle cells infiltration with a rate of FLK-1, ICAM1, and a-SMA distribution higher than that of the PCL and PCL/ECM vascular grafts at 2 weeks and 4 weeks after implantation. The PCL/ECM/VEGF vascular graft should be considered for potential small-diameter vascular grafts in clinical fields.

Blood glucose levels and bodyweight change after dapagliflozin administration.

AIMS/INTRODUCTION: Increased blood glucose or increased weight is often observed in patients who are prescribed sodium-glucose cotransporter 2 inhibitors (SGLT2i). The aim of this study was to determine in advance which patients, among those prescribed a SGLT2i, would be likely to have improved or worsened blood glucose levels and gain or loss of weight through the use of real-world data-based prescriptions. MATERIALS AND METHODS: After 3 months of dapagliflozin prescription, patients were divided into four groups: H(+)W(+) for improved glucose and weight loss; H(+)W(-) for improved blood glucose and weight gain; H(-)W(+) for worsened glucose and weight loss; and H(-)W(-) for worsened glucose and weight gain. RESULTS: The proportion of patients in the H(+)W(+) group was 53.5% (325/608 patients), H(+)W(-) was 19.7% (120/608), H(-)W(+) was 26.8% (114/608) and H(-)W(-) was 8.1% (49/608). The odds of proceeding to H(+)W(-) compared with H(+)W(+), which served as the reference, were 144% in baseline hemoglobin A1c (HbA1c) 7.0-8.0%, 233% in baseline HbA1c 8.0-9.0% and 359% in baseline HbA1c ≥ 9.0% (odds ratio 3.59, P < 0.05) compared with the reference. The odds of proceeding to H(-)W(+) were 29, 13 and 8%, respectively (all P < 0.05), and to H(-)W(-) were 17, 15 and 8%, respectively (all P < 0.05), compared with the reference. The results were expected to vary individually, because changes in blood glucose and bodyweight are more affected by diet and exercise than by drugs. CONCLUSIONS: When first prescribing dapagliflozin, a physician should be aware of the weight gain rather than glucose change if the baseline HbA1c is high, and might concentrate on weight-related lifestyle training, such as diet and exercise.

Onset of Hyperkalemia following the Administration of Angiotensin-Converting Enzyme Inhibitor or Angiotensin II Receptor Blocker.

INTRODUCTION: In spite of the established importance of detecting angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker- (ARB-) induced hyperkalemia, there have not been many studies on the time of its occurrence. METHODS: We retrospectively analyzed electronic medical records to determine the onset time and incidence rate of hyperkalemia (serum potassium > 5.5 mEq/L or 6.0 mEq/L) among hospitalized patients newly started on a 15-day ACEI or ARB therapy. RESULTS: Among 3101 hospitalized patients, hyperkalemia incidence was 0.5%-0.9% and 0.8%-2.1% in the ACEI and ARB groups, respectively. However, it was not significantly different among different ARB types. Hyperkalemia's onset was distributed throughout 15 days, without any trend. Hyperkalemia incidence was 7.3 and 35.1 times higher at 5.5 mEq/L (hazard ratio (HR) = 7.31, 95%confidence interval (CI) = 4.19-12.76, p < 0.001) and 6.0 mEq/L (HR = 35.11, 95%CI = 8.25-149.52, p < 0.001), respectively, than the baseline creatinine level. Hyperkalemia incidence in patients with chronic renal failure was 5.7 and 9.2 times higher at 5.5 mEq/L (HR = 5.72, 95%CI = 3.24-10.12, p < 0.001) and 6.0 mEq/L (HR = 9.16, 95%CI = 4.02-20.88, p < 0.001), respectively. CONCLUSIONS: It is unlikely that it is necessary to monitor hyperkalemia immediately after administration of ACEI or ARB. However, when prescribed for patients with abnormal kidney function, clinicians should always consider the possibility of developing hyperkalemia.

Factors associated with severity, incidence or persistence of internet gaming disorder in children and adolescents: a 2-year longitudinal study.

AIM: This study examined factors associated with severity, incidence and/or persistence of internet gaming disorder (IGD) in children and adolescents. DESIGN, SETTING, PARTICIPANTS: Prospective cohort study with 2-year follow-up study in South Korea. A total of 2319 3rd-, 4th- and 7th-graders enrolled into the internet user cohort for unbiased recognition of gaming disorder in early adolescence [intramural Continuing Umbrella of Research Experiences (iCURE)] and analyzed for the current study. MEASUREMENTS: Severity of the IGD features was assessed by the Internet Game Use-Elicited Symptom Screen (IGUESS), a self-reported questionnaire based on the DSM-5 IGD criteria. Participants with IGUESS scores ≥ 10 were considered to be at high risk for IGD (HIGD). Time spent playing on-line games, game types, depressive symptoms, trait anxiety, attention deficit hyperactivity disorder (ADHD) symptoms, social support, openness of communication with parents, attachment to parents and potential confounders were assessed by self-report. FINDINGS: A total of 175 (7.5%) students were classified as HIGD cases upon initial assessment. The independent risk factors of incidence of HIGD included playing on-line games for ≥ 240 minutes/day, playing multi-player games, depressive symptoms and ADHD symptoms [adjusted rate ratios (aRRs) = 2.03, 1.63, 2.04, 2.53, respectively; all P < 0.05]. Factors related to changing IGD severity scores were playing on-line games for 60-239 minutes/day, playing single-player on-line games, higher attachment and social support [adjusted incidence rate ratio (aIRRs) = 1.38, 1.22, 0.86, 0.87, respectively; all P < 0.05]. Independent predictors of persistence of HIGD were playing on-line games for ≥ 240 minutes/day and ADHD symptoms (aRRs = 2.63, 2.14, respectively; all P < 0.05). CONCLUSIONS: Among adolescents in South Korea, the existence of ADHD symptoms and spending more than 4 hours per day playing on-line games were associated with the occurrence or persistence of high risk for internet gaming disorder.

LGI1 governs neuritin-mediated resilience to chronic stress.

Depression is accompanied by neuronal atrophy and decreased neuroplasticity. Leucine-rich glioma-inactivated protein 1 (LGI1), a metastasis suppressor, plays an important role in the development of CNS synapses. We found that LGI1 expression was reduced in the hippocampi of mice that underwent chronic unpredictable stress (CUS), and could be rescued by the antidepressant, fluoxetine. Recombinant soluble neuritin, an endogenous protein previously implicated in antidepressant-like behaviors, elevated hippocampal LGI1 expression in a manner dependent on histone deacetylase 5 (HDAC5) phosphorylation. Accordingly, Nrn1 flox/flox ;Pomc-cre (Nrn1 cOE) mice, which conditionally overexpress neuritin, displayed increases in hippocampal LGI1 level under CUS and exhibited resilience to CUS that were blocked by hippocampal depletion of LGI1. Interestingly, neuritin-mediated LGI1 expression was inhibited by HNMPA-(AM)3, an insulin receptor inhibitor, as was neuritin-mediated HDAC5 phosphorylation. We thus establish hippocampal LGI1 as an effector of neurite outgrowth and stress resilience, and suggest that HDAC5-LGI1 plays a critical role in ameliorating pathological depression.

Magnetic field induced quantum phases in a tensor network study of Kitaev magnets.

Recent discovery of the half quantized thermal Hall conductivity in [Formula: see text]-RuCl[Formula: see text], a candidate material for the Kitaev spin liquid, suggests the presence of a highly entangled quantum state in external magnetic fields. This field induced phase appears between the low field zig-zag magnetic order and the high field polarized state. Motivated by this experiment, we study possible field induced quantum phases in theoretical models of the Kitaev magnets, using the two dimensional tensor network approach or infinite tensor product states. We find various quantum ground states in addition to the chiral Kitaev spin liquid occupying a small area in the phase diagram. They form a band of emergent quantum phases in an intermediate window of external magnetic fields, somewhat reminiscent of the experiment. We discuss the implications of these results in view of the experiment and previous theoretical studies.