Search

α-Klotho is a type 1 transmembrane protein that exhibits aging suppression function. The large amino-terminal extracellular domain of α-klotho is shed as soluble klotho (sKlotho) and functions as a circulating cardioprotective hormone. Diacylglycerol (DAG)-activated calcium-permeable TRPC6 channel plays a critical role in stress-induced cardiac remodeling. DAG activates TRPC6 by acting directly on the channel to increase its activity and by stimulation of channel exocytosis. sKlotho protects the heart by inhibiting DAG stimulation of TRPC6 exocytosis. How DAG stimulates TRPC6 exocytosis and thereby inhibition by sKlotho are unknown. Using a compound that directly activates TRPC6 without affecting channel exocytosis, we validate that sKlotho selectively blocks DAG stimulation of channel exocytosis. We further show that DAG stimulates exocytosis of TRPC6-containing vesicles pre-docked to the plasma membrane. Mnuc13 family proteins play important roles in the proper assembly of SNARE proteins and priming the vesicle competent for fusion. We show that DAG stimulates TRPC6 exocytosis by targeting to the C1 domain of Munc13-2. The results provide fresh insights into the molecular mechanism by which DAG regulates vesicle fusion and how sKlotho protects the heart against injury.

The klotho gene encodes a type I single-pass transmembrane protein that contains a large extracellular domain, a membrane spanning segment, and a short intracellular domain. Klotho protein exists in several forms including the full-length membrane form (mKl) and a soluble circulating form [soluble klotho (sKl)]. mKl complexes with fibroblast growth factor receptors to form coreceptors for FGF23, which allows it to participate in FGF23-mediated signal transduction and regulation of phosphate and calcium homeostasis. sKl is present in the blood, urine, and cerebrospinal fluid where it performs a multitude of functions including regulation of ion channels/transporters and growth factor signaling. How sKl exerts these pleiotropic functions is poorly understood. One hurdle in understanding sKl’s mechanism of action as a “hormone” has been the inability to identify a receptor that mediates its effects. In the body, the kidneys are a major source of sKl and sKl levels decline during renal disease. sKl deficiency in chronic kidney disease makes the heart susceptible to stress-induced injury. Here, we summarize the current knowledge of mKl’s mechanism of action, the mechanistic basis of sKl’s protective, FGF23-independent effects on the heart, and provide new insights into the mechanism of action of sKl focusing on recent findings that sKl binds sialogangliosides in membrane lipid rafts to regulate growth factor signaling.

Background This study investigated the real-world efficacy and safety of insulin degludec/insulin aspart (IDegAsp) in Korean adults with type 2 diabetes mellitus (T2DM), whose insulin treatment was switched to IDegAsp. Methods This was a multicenter, retrospective, observational study comprising two 26-week treatment periods, before and after switching to IDegAsp, respectively. Korean adults with uncontrolled T2DM treated with basal or premix insulin (±oral antidiabetic drugs) were enrolled. The primary objective was to compare the degree of glycosylated hemoglobin (HbA1c) change in each 26-week observation period. The analyses included changes in HbA1c, fasting plasma glucose (FPG), body weight, proportion of participants achieving HbA1c

In the case of nuclear power plants near end of their design life, a reassessment of the performance of safety-related equipment may be necessary to determine whether to shut down or extend the operation of the power plant. Therefore, it is necessary to evaluate the level of performance decline due to degradation. Electrical cabinets, including MCC and switchgear, are representative safety-related equipment. Several studies have assessed the degradation and seismic performance of nuclear power plant equipment. Most of those researches are limited to individual components due to the size of safety-related equipment and test equipment. However, only a few studies assessed the degradation performance of electrical cabinets. The equipment of various nuclear power plants is anchored to concrete foundations, and crack in concrete foundations is one of the most representative of degradation that could be visually confirmed. However, it is difficult to find a study for analysis through testing the effect of cracks in concrete foundations on the response of electrical cabinet internal equipment fixed by anchors. In this study, using a simple cabinet model considering cast-in-place anchor in uncracked and cracked concretes, a tri-axial shaking table tests were performed and the seismic behavior were observed.

Abstract Neuroinflammation contributes to the pathophysiology of various mental illnesses including schizophrenia. We investigated peripheral inflammatory cytokines as a biomarker for predicting symptomatic remission in patients with first-episode schizophrenia. The study included 224 patients aged 15–60 years who fulfilled the criteria for schizophrenia spectrum disorder with a treatment duration ≤6 months. Serum levels of tumor necrosis factor (TNF) -α, interferon-γ, interleukin (IL)-1α, IL-1β, IL-6, IL-8, IL-10, and IL-12 were measured. Psychotic symptoms, depressive symptoms, and general functioning were assessed using the Positive and Negative Syndrome Scale, Beck Depression Inventory (BDI), Calgary Depression Scale for Schizophrenia, and Personal and Social Performance scale, respectively. Duration of untreated psychosis (DUP) was also recorded. We investigated the factors associated with remission for each sex in logistic regression analysis. In total, 174 patients achieved remission at the 6-month follow-up (females, 83.5%; males, 70.9%). Remission was associated with older age and lower BDI scores in male patients and with lower TNF-α levels and shorter DUP in female patients. Our findings suggest that peripheral inflammatory cytokines may impede early symptomatic remission in female patients with schizophrenia. In addition, depressive symptoms in males and long DUP in females may be poor prognostic factors for early remission in patients with first-episode psychosis.

ObjectivesThis study aimed to investigate the predictors of both early- and delayed-onset PTSD over a 2-year period following physical injuries.MethodsPatients were recruited from a trauma center at a university hospital in South Korea (June 2015 ~ January 2021). At baseline, 1142 patients underwent comprehensive assessments including socio-demographic, pre-trauma, trauma-related, and peri-trauma evaluations. Diagnoses of acute stress disorder (ASD) and subthreshold ASD were also determined using the Clinician-administered PTSD Scale (CAPS). Follow-up assessments at three months included diagnoses of PTSD and subthreshold PTSD using CAPS, and stressful life events (SLEs), with additional evaluations at 6, 12, and 24 months. The analyzed sample comprised 1014 patients followed up at least once after the baseline and 3-month evaluations. PTSD diagnoses were categorized into early-onset (within the first six months after trauma) and delayed-onset (more than six months after trauma). Logistic regression models identified predictors for each group.ResultsEarly-onset and delayed-onset PTSD were diagnosed in 79 and 35 patients, respectively. Early-onset PTSD was predicted by previous psychiatric disorders, previous traumatic events, ASD and subthreshold ASD diagnoses, and higher anxiety levels. In contrast, delayed-onset PTSD was linked to higher education, higher injury severity, and subthreshold PTSD and SLEs at 3-month follow-up.ConclusionDistinct predictors were found for early-onset and delayed-onset PTSD. The findings underscore the heterogeneous factors influencing the temporal development of PTSD post-trauma, and may provide valuable guidance for more targeted interventions and improved patient outcomes.

Osteoporosis after bariatric surgery is an increasing health concern as the rate of bariatric surgery has risen. In animal studies mimicking bariatric procedures, bone disease, together with decreased serum levels of Ca2+, Mg2+ and the gastric hormone Ghrelin were described. Ghrelin regulates metabolism by binding to and activating the growth hormone secretagogue receptor (GHSR) which is also expressed in the kidney. As calcium and magnesium are key components of bone, we tested the hypothesis that Ghrelin-deficiency contributes to osteoporosis via reduced upregulation of the renal calcium channel TRPV5 and the heteromeric magnesium channel TRPM6/7. We expressed GHSR with TRPV5 or TRPM6/7 channel in HEK293 cells and treated them with purified Ghrelin. Whole-cell current density was analyzed by patch-clamp recording. Nephron-specific gene expression was performed by tubular microdissection followed by qPCR in wild-type (WT) mice, and immunofluorescent imaging of GHSR-eGFP mice. Tubular magnesium homeostasis was analyzed in GHSR-null and WT mice at baseline and after caloric restriction. After Ghrelin exposure, whole-cell current density did not change for TRPV5 but increased for TRPM6/7 in a dose-dependent fashion. Applying the Ghrelin-mimetic (D-Trp7, Ala8,D-Phe10)-α-MSH (6–11) amide without and with the GHSR antagonist (D-Lys3)-GHRP6, we confirmed the stimulatory role of Ghrelin towards TRPM6/7. As GHSR initiates downstream signaling via protein kinase A (PKA), we found that the PKA inhibitor H89 abrogated TRPM6/7 stimulation by Ghrelin. Similarly, transfected Gαs, but not the Gαs mutant Q227L, nor Gαi2, Gαq, or Gα13 upregulated TRPM6/7 current density. In microdissected TALs and DCTs similar levels of GHSR mRNA were detected. In contrast, TRPM6 mRNA was expressed in the DCT and also detected in the TAL at 25% expression compared to DCT. Immunofluorescent studies using reporter GHSR-eGFP mice showed a strong eGFP signal in the TAL but surprisingly displayed no eGFP signal in the DCT. In 3-, 6-, and 9-month-old GHSR-null and WT mice, baseline serum magnesium was not significantly different, but 24-h urinary magnesium excretion was elevated in 9-month-old GHSR-null mice. In calorically restricted GHSR-null mice, we detected excess urinary magnesium excretion and reduced serum magnesium levels compared to WT mice. The kidneys from calorically restricted WT mice showed upregulated gene expression of magnesiotropic genes Hnf1b, Cldn-16, Cldn-19, Fxyd-2b, and Parvalbumin compared to GHSR-null mice. Our in vitro studies show that Ghrelin stimulates TRPM6/7 via GHSR and Gαs-PKA signaling. The murine studies are consistent with Ghrelin-GHSR signaling inducing reduced urinary magnesium excretion, particularly in calorically restricted mice when Ghrelin levels are elevated. This effect may be mediated by Ghrelin-upregulation of TRPM6 in the TAL and/or upregulation of other magnesiotropic genes. We postulate that rising Ghrelin levels with hunger contribute to increased renal Mg2+ reabsorption to compensate for lack of enteral Mg2+ uptake.

Abstract Virtual reality (VR) technology can be a supporting tool to enhance mindfulness. Recently, many research using VR-based mindfulness (VBM) has been carried out in various psychiatric disorders but not in psychosis. We investigated safety and effects of virtual reality-based mindfulness (VBM) in patients with psychosis as a pilot study. Sixty-four patients were randomly assigned to VBM or to VR control. For VBM, education and meditation videos were provided. For VR control, 3-dimensional natural scenes were shown. Both programs consisted of 8 weekly sessions, each lasting about 30 min. Pre- and post-assessments were performed using the experiences questionnaire (EQ), psychotic symptom rating scales-delusion (PSYRATS-D), PSYRATS-auditory hallucinations (AH), motivation and pleasure scale-self rating (MAP-SR) and etc. The safety questionnaire was also surveyed after 1st and 8th session. Physiological measures such as skin conductance level (SCL), heart rate (HR) and RR interval, were collected during the VR interventions. Limited individuals participated in the safety questionnaire and physiological measures. All the results were presented in mean and standard deviation. We did not observe significant results in group x time interaction and main effects of group and time in the decentering and clinical scales. However, within group comparison showed that patients randomized to VBM showed increased decentering (p = 0.029) and decreased amount (p = 0.032) and duration of preoccupation (p = 0.016) in the PSYRATS-D. For the feelings and motivations about close caring relationships of the MAP-SR, we observed a significant group x time interaction (p = 0.027). The frequency of VR sickness was high but its severity was mild. There were significant differences only in HR over time in the VBM group (p = 0.01). These results suggest that VBM was not more effective in reducing decentering and psychiatric symptoms than VR control but its adversity was modest.

Periventricular heterotopia (PH) is a developmental malformation in the brain. Because the clinical symptoms are heterogeneous, few studies have investigated the psychiatric symptoms associated with PH. We describe the case of a 17-year-old male with bipolar disorder (BD), who had been treated for attention deficit-hyperactivity disorder (ADHD) and developmental delay in childhood. He had experienced depression for 1 year and was admitted to the emergency room following a suicide attempt. He was admitted to the psychiatric ward for further evaluation and treatment for elated mood, decreased need for sleep, increased sexuality, and delusion. The patient was diagnosed with BP-I disorder and PH via brain magnetic resonance imaging. After combined treatment with valproic acid and aripiprazole, his manic symptoms stabilized. To our knowledge, this is the first report of an adolescent PH case with a history of early onset BD and ADHD in childhood.

ObjectiveTo investigate the anti-cancer efficacy of ENB101-LNP, an ionizable lipid nanoparticles (LNPs) encapsulating siRNA against E6/E7 of HPV 16, in combination therapy with cisplatin in cervical cancer in vitro and in vivo.MethodsCaSki cells were treated with ENB101-LNP, cisplatin, or combination. Cell viability assessed the cytotoxicity of the treatment. HPV16 E6/E7 gene knockdown was verified with RT-PCR both in vitro and in vivo. HLA class I and PD-L1 were checked by flow cytometry. A xenograft model was made using CaSki cells in BALB/c nude mice. To evaluate anticancer efficacy, mice were grouped. ENB101-LNP was given three times weekly for 3 weeks intravenously, and cisplatin was given once weekly intraperitoneally. Tumor growth was monitored. On day 25, mice were euthanized; tumors were collected, weighed, and imaged. Tumor samples were analyzed through histopathology, immunostaining, and western blot.ResultsENB101-LNP and cisplatin synergistically inhibit CaSki cell growth. The combination reduces HPV 16 E6/E7 mRNA and boosts p21 mRNA, p53, p21, and HLA class I proteins. In mice, the treatment significantly blocked tumor growth and promoted apoptosis. Tumor inhibition rates were 29.7% (1 mpk ENB101-LNP), 29.6% (3 mpk), 34.0% (cisplatin), 47.0% (1 mpk ENB101-LNP-cisplatin), and 68.8% (3 mpk ENB101-LNP-cisplatin). RT-PCR confirmed up to 80% knockdown of HPV16 E6/E7 in the ENB101-LNP groups. Immunohistochemistry revealed increased p53, p21, and HLA-A expression with ENB101-LNP treatments, alone or combined.ConclusionThe combination of ENB101-LNP, which inhibits E6/E7 of HPV 16, with cisplatin, demonstrated significant anticancer activity in the xenograft mouse model of cervical cancer.

This study aimed to confirm the characteristics of auditory function alterations in tinnitus patients with concomitant decreased sound tolerance (ST) and provide insights for developing tailored therapeutic approaches. A retrospective analysis was conducted on patient records from a tertiary university hospital's tinnitus clinic between March 2020 and June 2023. Demographic attributes and audiological profiles were reviewed. Patients were categorized into Group 1 if loudness discomfort level test outcomes were 77 dB or below, measured using an average of frequencies from 250 Hz to 8 kHz. The remaining patients were allocated to Group 2. Among the 434 tinnitus patients, 115 (26.5%) demonstrated decreased ST and were classified as Group 1. This group exhibited higher DPOAE amplitudes (p < 0.001), shortened latency, and decreased threshold of ABR wave V bilaterally (p < 0.05). No significant disparities were observed in gender, age, tinnitus handicap inventory, visual analog scale, and pure-tone audiometry results except subjective hyperacusis. Binary logistic regression analysis utilizing the forward conditional method revealed that the difference between groups was independently linked to DPOAE response at 7,277 Hz on the left side [B = 0.093, p < 0.001, EXP(B) = 1.07, 95% CI = 1.044–1.153]. Increased DPOAE amplitude and shorter and decreased ABR wave V in tinnitus patients with decreased ST might suggest a possible association with lesions in or around the superior olivary complex or higher central auditory pathway, potentially linked to the inhibition of medial olivocochlear efferents.

IntroductionSuicide is a major concern for patients with recent-onset schizophrenia. We hypothesized that preserved cognitive function might be associated with a higher level of suicidality in patients with schizophrenia. We investigated the associations between cognitive function and suicidal ideation (SI) in young patients recently diagnosed with a psychotic disorder.MethodsThis study analyzed data from a naturalistic clinical cohort study that comprised 402 patients with schizophrenia spectrum disorder. Patients with a treatment duration of ≤5 years and an age range of 15–39 years were enrolled. Participants were categorized into two groups based on SI as assessed by the Columbia Suicidal Severity Rating Scale. We collected demographic and clinical data and administered psychiatric, neurocognitive, and social cognitive measures.ResultsAmong participants, 52% reported experiencing SI. Patients with SI were significantly younger and had a longer duration of untreated psychosis (DUP) than those without it. The Positive and Negative Syndrome Scale-general psychopathology score was significantly higher in the SI group. Scores on the Calgary Depression Scale for Schizophrenia, Perceived Stress Scale, Beck Depression Inventory (BDI), and Beck Hopelessness Scale were significantly higher among patients with SI, while scores on the Subjective Well-being Under Neuroleptics-Short Form and Brief Resilience Scale were significantly lower compared to those without it. Patients with SI demonstrated significantly higher scores on the verbal and visual learning test, false belief task, picture stories task, and Controlled Oral Word Association Test. They also completed the Trail Making Test (TMT) parts A and B in significantly less time than those without it. After adjusting for age, DUP, and scores on the BDI, group differences in scores on the verbal and visual learning tests, TMT (parts A and B), and the false belief task, and the picture story task remained significant.DiscussionOur results suggest that along with traditional risk factors, better cognitive function may also be a major risk factor for suicidality in patients with schizophrenia. Providing psychological support and cognitive interventions is essential for young patients with recent-onset schizophrenia spectrum disorders, particularly those with high levels of depression, hopelessness, perceived stress, low resilience, and good cognitive function.