MST1 Negatively Regulates TNFα-Induced NF-κB Signaling through Modulating LUBAC Activity.

The nuclear factor (NF)-κB pathway plays a central role in inflammatory and immune responses, with aberrant activation of NF-κB signaling being implicated in various human disorders. Here, we show that mammalian ste20-like kinase 1 (MST1) is a previously unrecognized component of the tumor necrosis factor α (TNFα) receptor 1 signaling complex (TNF-RSC) and attenuates TNFα-induced NF-κB signaling. Genetic ablation of MST1 in mouse embryonic fibroblasts and bone marrow-derived macrophages potentiated the TNFα-induced increase in IκB kinase (IKK) activity, as well as the expression of NF-κB target genes. TNFα induced the recruitment of MST1 to TNF-RSC and its interaction with HOIP, the catalytic component of the E3 ligase linear ubiquitin assembly complex (LUBAC). Furthermore, MST1 activated in response to TNFα stimulation mediates the phosphorylation of HOIP and thereby inhibited LUBAC-dependent linear ubiquitination of NEMO/IKKγ. Together, our findings suggest that MST1 negatively regulates TNFα-induced NF-κB signaling by targeting LUBAC.

Amyotrophic lateral sclerosis-related mutant superoxide dismutase 1 aggregates inhibit 14-3-3-mediated cell survival by sequestration into the JUNQ compartment.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by motor neuron loss in the spinal cord and brain. Mutations in the superoxide dismutase 1 (SOD1) gene have been linked to familial ALS. To elucidate the role of SOD1 mutations in ALS, we investigated 14-3-3, a crucial regulator of cell death that was identified in patients with familial ALS. In a transgenic mouse model (SOD1-G93A) of ALS, 14-3-3 co-localized with mutant SOD1 aggregates and was more insoluble in the spinal cords of mutant SOD1 transgenic mice than in those of wild-type mice. Immunofluorescence and co-immunoprecipitation experiments showed that the 14-3-3ɛ and θ isoforms interact with mutant SOD1 aggregates in the juxtanuclear quality control compartment of N2a neuroblastoma cells. Fluorescence loss in photobleaching experiments revealed that movement of the isoforms of 14-3-3 was markedly reduced in SOD1 aggregates. Bax translocation into and cytochrome c release from the mitochondria were promoted by the sequestration of 14-3-3 into mutant SOD1 aggregates, increasing cell death. Mutant SOD1 aggregates were dissolved by the Hsp104 chaperone, which increased the interaction of 14-3-3 with Bax, reducing cell death. Our study demonstrates that mutant SOD1 inhibits 14-3-3-mediated cell survival. This information may contribute to the identification of a novel therapeutic target for ALS.

Elevated Serum Vitamin B12 Levels as a Prognostic Factor for Survival Time in Metastatic Cancer Patients: A Retrospective Study.

BACKGROUND: Serum vitamin B12 levels have been proposed as one of the survival prediction factors, although no survival analysis in metastatic cancer patients has been conducted yet. This study examined whether serum vitamin B12 levels could be a prognostic factor in metastatic cancer patients. METHODS: Data from a retrospective chart review were used to perform Kaplan-Meier and multivariate analyses of the Cox proportional hazards. Subgroup analysis was performed on patients without a liver lesion (hepatocellular carcinoma or liver metastasis). RESULTS: A total of 523 patients were included. The median survival time was 1.8 months (mo) in the high B12 group (>911 pg/mL) and 5.1 mo in the normal B12 group (211-911 pg/mL) (p < 0.001). In patients without a liver lesion, the median survival times were 2.1 and 6.1 mo in the high and normal B12 groups, respectively (p < 0.001). Multivariate analysis revealed that serum vitamin B12 level was an independent prognostic factor for overall survival (hazard ratio [HR]: 1.62; 95% confidence interval [CI]: 1.34-1.96, p < 0.001). CONCLUSION: Serum vitamin B12 level can be used to predict survival time in metastatic cancer patients. Further large-scale cohort studies are required to confirm these findings.

Factors influencing post-traumatic stress disorder among police officers in South Korea.

Objectives: This study aims to identify critical incident trauma (CIT), social support, resilience, and post-traumatic stress disorder (PTSD) in Korean police officers and to determine factors related to PTSD to obtain basic data for developing a PTSD intervention. Methods: A mixed-methods approach was adopted by administering structured questionnaires to Korean police officers and conducting semi-structured interviews with seven Korean police stakeholders. The structured questionnaires elicited information on CIT, social support, resilience, and PTSD. Data from 189 participants were analyzed using independent t-tests, Pearson's correlation coefficients, and multiple linear regression analysis. The interview data, which elicited information on difficulties and coping strategies after CIT, police organizational culture, current status of counseling programs, and suggestions for PTSD interventions, were analyzed using an inductive thematic analysis. Results: Factors that are significantly related to PTSD (28.7% of variance) are very healthy subjective health status (B = -0.44, p = 0.013), CIT (B = 0.18, p ≤ 0.001), social support (B = -0.38, p ≤ 0.001), and resilience (B = -0.18, p = 0.044). The stakeholders revealed the following PTSD-related factors: the difficulties and limitations of overcoming traumatic experiences, coping strategies, police counseling program status, and opinions on PTSD-related programs. Conclusion: Perceived health status, CIT, social support, and resilience had a strong relationship with PTSD. Therefore, the success of PTSD interventions for Korean police officers should be considered.

Comparison of Effects of Mothers' and Mozart's Lullabies on Physiological Responses, Feeding Volume, and Body Weight of Premature Infants in NICU.

Objectives: The purpose of this study was to compare the effects of mothers' and Mozart's lullabies on physiological parameters, feeding volume, and body weight of premature infants in a neonatal intensive care unit (NICU). Methods: This study used a non-equivalent control group, non-synchronized design as a quasi-experimental study. Two intervention groups (recorded mother's lullaby and Mozart's lullaby) and a control group were formed from a total of 65 premature infants: a mother's lullaby group of 22 infants, a Mozart's lullaby group of 22 infants, and a control group of 21 infants not provided with any lullabies. Their physiological parameters included heart rate, blood pressure, respiratory rate, and O2 saturation. The infants' feeding volume and body weight were measured as indicators related to the growth of premature infants. The mother's and Mozart's lullabies were played on a speaker in an incubator for 15 min for 7 consecutive days per group. Results: There were significant differences in the mean difference before and after intervention in neonatal heart rate (χ2 = 45.03, P < 0.001), systolic pressure (F = 43.29, P < 0.001), diastolic pressure (χ2 = 33.01, P < 0.001), respiratory rate (F = 76.06, P < 0.001), and O2 saturation (χ2 = 40.82, P < 0.001) between the three groups. The mean differences of both mother's and Mozart's lullaby groups were significantly higher than those of the routine care group in all physiological parameters, and those of the mother's lullaby group was significantly higher when compared with the Mozart's lullaby group. In repeated-measures ANOVA, there was a significant interaction between time and group in feeding volume (F = 2.46, P = 0.041). However, body weight did not significantly differ in an interaction between time and group (F = 1.75, P = 0.151). Conclusion: This study showed beneficial effects of mother's lullaby and Mozart's lullaby on physiological parameters. Especially, the mother's lullaby was found to significantly improve all physiological parameters and feeding volume of premature infants in the NICU compared to Mozart's lullaby group. Therefore, we recommend the regular integration of the mother's lullaby into supportive care of premature infants in the NICU, as this intervention highlights the need for mothers to participate in their care. Trial Registration: ClinicalTrials.gov, identifier: KCT0004842 (https://cris.nih.go.kr).

Genome editing-mediated knock-in of therapeutic genes ameliorates the disease phenotype in a model of hemophilia.

Recently, clinical trials of adeno-associated virus-mediated replacement therapy have suggested long-term therapeutic effects for several genetic diseases of the liver, including hemophilia. However, there remain concerns regarding decreased therapeutic effects when the liver is regenerated or when physiological proliferation occurs. Although genome editing using the clustered regularly interspaced short palindromic repeats/Cas9 system provides an opportunity to solve this problem, low knock-in efficiency may limit its application for therapeutically relevant expression. Here, we identified a novel gene, APOC3, in which a strong promoter facilitated the expression of knocked-in genes in hepatocytes. We also investigated the effects of APOC3 editing using a small Cas9 protein derived from Campylobacter jejuni (CjCas9) in a hemophilic model. We demonstrated that adeno-associated virus-mediated delivery of CjCas9 and donor led to moderate levels of human factor 9 expression in APOC3-humanized mice. Moreover, knock-in-driven expression induced substantial recovery of clotting function in mice with hemophilia B. There was no evidence of off-target editing in vitro or in vivo. Collectively, our findings demonstrated therapeutically relevant expression using a precise and efficient APOC3-editing platform, providing insights into the development of further long-term therapeutics for diverse monogenic liver diseases.

In vivo delivery of CRISPR-Cas9 using lipid nanoparticles enables antithrombin gene editing for sustainable hemophilia A and B therapy.

Hemophilia is a hereditary disease that remains incurable. Although innovative treatments such as gene therapy or bispecific antibody therapy have been introduced, substantial unmet needs still exist with respect to achieving long-lasting therapeutic effects and treatment options for inhibitor patients. Antithrombin (AT), an endogenous negative regulator of thrombin generation, is a potent genome editing target for sustainable treatment of patients with hemophilia A and B. In this study, we developed and optimized lipid nanoparticles (LNPs) to deliver Cas9 mRNA along with single guide RNA that targeted AT in the mouse liver. The LNP-mediated CRISPR-Cas9 delivery resulted in the inhibition of AT that led to improvement in thrombin generation. Bleeding-associated phenotypes were recovered in both hemophilia A and B mice. No active off-targets, liver-induced toxicity, and substantial anti-Cas9 immune responses were detected, indicating that the LNP-mediated CRISPR-Cas9 delivery was a safe and efficient approach for hemophilia therapy.

Effects of nurses' shiftwork characteristics and aspects of private life on work-life conflict.

BACKGROUND: As nurses work highly irregular hours, the characteristics of shiftwork and aspects of their private lives are important factors that may contribute significantly to work-life conflict. PURPOSE: This study examined the effects of nurses' shiftwork characteristics and aspects of their private lives on work-life conflict. METHODS: The participants included 271 registered nurses working three-shift rotations in five types of units at four hospitals in South Korea. We distributed structured questionnaires regarding shiftwork characteristics, private life, and work-life conflict. Data were analyzed using multiple linear regression analysis. RESULTS: The significant factors relating to work-life conflict included control over shift start and finish times (ß = -0.16, p = .019), frequency of swapping shifts with colleagues (ß = 0.15, p = .025) among shiftwork characteristics, and leisure constraints (ß = 0.39, p = < .001) in aspects of private life. CONCLUSION: Plan and policies for improving nursing environments should focus on improving nurses' control over shiftwork and decreasing leisure constraints.

Quality of life of Korean and Korean American older adults: a comparison.

This study compared the quality of life (QOL) between Korean and Korean American older adults. The participants included 306 older adults (155 Korean, 151 Korean American) age 65 and older who met eligibility criteria and agreed to participate in the study. No significant difference was found in QOL between Korean and Korean American older adults. Differences in the subcategories of QOL between the two groups in cluded higher scores for the Korean older adults in physical functioning, social functioning, and body pain. Scores for the subcategories of role limitations due to physical problems and vitality were higher for the Korean American older adults. Multiple regression analysis revealed that the powerful predictors of QOL for both groups were self-esteem and activities of daily living (ADLs)/instrumental ADLs (IADLs). It is recommended that nursing interventions to increase self-esteem and performance of ADLs/IADLs be developed to enhance QOL among older adults.

Factors influencing nutritional practices among mothers in Dakar, Senegal.

BACKGROUND: Maternal undernutrition is a leading cause of maternal mortality. Furthermore, health statuses and habits of mothers influence health statuses of newborns as well as healthy habits and mortality of children. The Senegal government is aware of the severity of these issues and has devised a national policy goal of reducing maternal, infant, and adolescent mortality rates by the end of 2018. This study aimed to identify nutritional knowledge, attitudes, and practices of lactating women in Senegal, and determine factors related to nutritional practices to obtain basic data for developing a maternal and child nutrition project. METHOD: This study used a mixed-method approach, collecting data via structured questionnaires administered to lactating women in Senegal and semistructured interviews with seven stake-holders. Questions for stuctured questionnaires were about nutritional knowledge, attitudes, and practices. For the quantitative analysis of the structured questionnaires, data from 171 participants analyzed using independent t-tests, Pearson's correlation coefficients, and multiple linear regression analysis. Interview data were analyzed using an inductive thematic analysis approach. The questions for the interviews concerned maternal and child nutritional status, causes of undernutrition, and restrictions. RESULTS: Factors significantly related to healthy nutritional practices(explaining 27.1% of variance) included having a household (B = 1.03, p = .015) and a mother (B = 0.96, p = .017) with an above primary school education, and being in the 5th quintile of income level (B = 1.24, p = .014). The interviews with seven stakeholders revealed obstructive factors of nutritional management were insufficient nutritional programs within health centers, incomplete national policy on nutrition, lack of general interest in undernutrition-related topics, inadequate economic environment, and the absence of partnerships to produce sustainable solutions. CONCLUSION: Education and income levels, rather than knowledge and attitudes, had a strong relationship with healthy nutritional practices. Therefore, economic factors and educational background must be considered to succeed in Senegalese nutrition projects.

Efficacy and Safety of the Traditional Herbal Medicine, Gamiguibi-tang, in Patients With Cancer-Related Sleep Disturbance: A Prospective, Randomized, Wait-List-Controlled, Pilot Study.

BACKGROUND: Sleep disturbance is the second most bothersome symptom in patients with cancer, and it can significantly impair their quality of life. The aim of this study was to investigate the efficacy and safety of the traditional herbal medicine Gamiguibi-tang (GGBT) in patients with cancer-related sleep disturbance. METHODS: We conducted a prospective, randomized, wait-list-controlled, open-label pilot clinical trial on cancer-related sleep disturbance. Patients with cancer experiencing poor sleep quality with a Pittsburgh Sleep Quality Index of at least 6 were randomly assigned to the GGBT and wait-list groups to receive GGBT and conventional care, respectively, for 2 weeks. The primary endpoint was the Insomnia Severity Index (ISI) score. Fatigue, depression, and cognitive impairment were assessed as the secondary endpoints by using the Brief Fatigue Inventory (BFI), Beck Depression Inventory (BDI), and Montreal Cognitive Assessment (MoCA). RESULTS: Thirty participants who met the eligibility criteria were enrolled. Sleep disturbance assessed using the ISI improved significantly more in the GGBT group than in the wait-list group (-5.5 ± 4.4 vs 0.1 ± 1.1, P < .001). Fatigue level determined using the BFI also improved significantly more in the GGBT group than in the wait-list group (-0.8 ± 0.8 vs 0.0 ± 0.3, P = .002). The BDI and MoCA scores showed no significant changes. Adverse events were reported in two patients in the GGBT group and consisted of mild dyspepsia and mild edema. CONCLUSION: GGBT may be a potential treatment option for cancer-related sleep disturbance. Further research is needed to investigate the efficacy and safety of GGBT.

The effects of meridian exercise on anxiety, depression, and self-esteem of female college students in Korea.

This study examined the effects of meridian exercise on anxiety, depression, and self-esteem of female college students in Korea. The effects of meridian exercise on anxiety, depression, and self-esteem were statistically significant (t = -7.982, P= .000; t= -8.814, P = .000; t = 9.649, P = .000) between the experimental and control group.