S6K1 deficiency in tumor stroma impairs lung metastasis of melanoma in mice.

Accumulating data suggest that ribosomal protein S6 kinase 1 (S6K1), an effector in the mammalian target of rapamycin (mTOR) pathway, plays pleiotropic roles in tumor progression. However, to date, while the tumorigenic function of S6K1 in tumor cells has been well elucidated, its role in the tumor stroma remains poorly understood. We recently showed that S6K1 mediates vascular endothelial growth factor A (VEGF-A) production in macrophages, thereby supporting tumor angiogenesis and growth. As macrophage-derived VEGF-A is crucial for both tumor cell intravasation and extravasation across the vascular endothelium, our previous findings suggest that stromal S6K1 signaling is required for tumor metastatic spread. Therefore, we aimed to determine the impact of host S6K1 depletion on tumor metastasis using a murine model of pulmonary metastasis (S6k1-/- mice implanted with B16F10 melanoma). The ablation of S6K1 in the host microenvironment significantly reduced the metastasized B16F10 melanoma cells on the lung surface in both spontaneous and intravenous lung metastasis mouse models without affecting the incidence of metastasis to distant lymph nodes. In addition, stromal S6K1 loss decreased the number of tumor cells circulating in the peripheral blood of mice bearing B16F10 xenografts without affecting the vascular leakage induced by VEGF-A in vivo. These observations demonstrate that S6K1 signaling in host cells other than endothelial cells is required to modulate the host microenvironment to facilitate the metastatic spread of tumors via blood circulation, thus revealing its novel role in the tumor stroma during tumor progression.

Comparison of Enlarged Perivascular Spaces in Early-Onset and Late-Onset Alzheimer Disease-related Cognitive Impairment: A Single Clinic-based Study in South Korea.

We examined whether there were differences in the presence of centrum semiovale-enlarged perivascular spaces (CSO-ePVS) and basal ganglia-ePVS (BG-ePVS) among patients with Alzheimer disease-related cognitive impairment (ADCI) based on their age of onset. Out of a total of 239 patients with cognitive impairment, 155 with positive amyloid-PET results were included. Among these, 43 had early-onset ADCI (EOADCI) and 112 had late-onset ADCI (LOADCI). Patients with LOADCI exhibited a higher prevalence of hypertension, lacunes, white matter hyperintensities, and BG-ePVS than those with EOADCI. BG-ePVS showed a significant correlation with age at the onset and the number of lacunes, whereas CSO-ePVS did not exhibit any association. The higher prevalence of BG-ePVS in patients with LOADCI might be attributable to vascular risk factors (hypertension) and cerebral small vessel disease (CSVD). These findings support the hypothesis that BG-ePVS is associated with CSVD and vascular risk factors, whereas CSO-ePVS is associated with cerebral amyloid angiopathy.

Adaptation and validation of a Korean version of the speaking up about patient safety questionnaire (KSUPS-Q).

BACKGROUND: Speaking up by healthcare providers is an essential assertive communication strategy for ensuring patient safety and preventing incidents. However, more is needed to know about speaking up and instruments to assess it in the Korean context. Therefore, we assessed the psychometric properties of the Korean version of the Speaking Up about Patient Safety Questionnaire (KSUPS-Q) for measuring speaking up-related behavior and climate among nurses. METHODS: The translation and adaptation process followed the guidelines of the International Society for Pharmacoeconomics and Outcomes Research and the World Health Organization. Content validity was assessed by a six-member expert panel using the content validity index. In total, 314 nurses participated in an online survey to examine the psychometric properties. Internal consistencies were tested using Cronbach's alpha and McDonald's omega. Confirmatory factor analyses were conducted to examine the subscales' construct. The convergent validity of the speaking up-related climate scale was assessed by testing correlations with teamwork and safety climate domains of the Safety Attitudes Questionnaire. In addition, we investigated the convergent validity of the speaking up-related behavior scale by examining its correlation with the climate scale. RESULTS: The reliability of the 11-item behavior scale was satisfactory. Confirmatory factor analysis confirmed that a three-subscale model (perceived concerns, withholding voice, and speaking up) was appropriate (CFI = 0.98, TLI = 0.98, and SRMR = 0.05). Furthermore, the 11-item climate scale demonstrated satisfactory internal consistency. A three-subscale model (psychological safety, encouraging environment, and resignation) was confirmed (CFI = 0.98, TLI = 0.97, and SRMR = 0.05). The convergent validity of the climate scale was verified based on correlations with the teamwork (r = 0.68, p < 0.001) and safety climate (r = 0.68, p < 0.001) domains of the Safety Attitudes Questionnaire. In addition, speaking up-related behavior and climate showed a significant association, indicating that the behavior scale is conceptually valid. CONCLUSIONS: This study demonstrates that the KSUPS-Q is a valid and reliable instrument in Korea. This instrument can help nurse managers simultaneously monitor the behavior and climate of their organizations and evaluate the outcomes of interventions to enhance speaking up. Future research is needed to explore diverse factors contributing to speaking up, including clinical roles, team relationships, and supportive culture, to identify areas requiring further improvement.

Machine learning models of plasma proteomic data predict mood in chronic stroke and tie it to aberrant peripheral immune responses.

Post-stroke depression is common, long-lasting and associated with severe morbidity and death, but mechanisms are not well-understood. We used a broad proteomics panel and developed a machine learning algorithm to determine whether plasma protein data can predict mood in people with chronic stroke, and to identify proteins and pathways associated with mood. We used Olink to measure 1,196 plasma proteins in 85 participants aged 25 and older who were between 5 months and 9 years after ischemic stroke. Mood was assessed with the Stroke Impact Scale mood questionnaire (SIS3). Machine learning multivariable regression models were constructed to estimate SIS3 using proteomics data, age, and time since stroke. We also dichotomized participants into better mood (SIS3 > 63) or worse mood (SIS3 ≤ 63) and analyzed candidate proteins. Machine learning models verified that there is indeed a relationship between plasma proteomic data and mood in chronic stroke, with the most accurate prediction of mood occurring when we add age and time since stroke. At the individual protein level, no single protein or set of proteins predicts mood. But by using univariate analyses of the proteins most highly associated with mood we produced a model of chronic post-stroke depression. We utilized the fact that this list contained many proteins that are also implicated in major depression. Also, over 80% of immune proteins that correlate with mood were higher with worse mood, implicating a broadly overactive immune system in chronic post-stroke depression. Finally, we used a comprehensive literature review of major depression and acute post-stroke depression. We propose that in chronic post-stroke depression there is over-activation of the immune response that then triggers changes in serotonin activity and neuronal plasticity leading to depressed mood.

Plk2-mediated phosphorylation and translocalization of Nrf2 activates anti-inflammation through p53/Plk2/p21cip1 signaling in acute kidney injury.

The Plk2 is a cellular stress-responsive factor that is induced in response to oxidative stress. However, the roles of Plk2 in acute kidney injury (AKI) have not been clarified. We previously found that Plk2 is an interacting factor of Nrf2 in response to cellular stress, since Plk2 is upregulated in the Nrf2-dependent network. Here, we show that the levels of p53, Plk2, p21cip1, and chromatin-bound Nrf2 were all upregulated in kidney tissues of mice or NRK52E cells treated with either cisplatin or methotrexate. Upregulation of Plk2 by p53 led to an increase of Nrf2 in both soluble and chromatin fractions in cisplatin-treated NRK52E cells. Consistently, depletion of Plk2 suppressed the levels of Nrf2. Of note, Plk2 directly phosphorylated Nrf2 at Ser40, which facilitated its interaction with p21cip1 and translocation into the nuclei for the activation of anti-oxidative and anti-inflammatory factors in response to AKI. Together, these findings suggest that Plk2 may serve as an anti-oxidative and anti-inflammatory regulator through the phosphorylation and activation of Nrf2 to protect kidney cells from kidney toxicants and that Plk2 and Nrf2 therefore work cooperatively for the protection and survival of kidney cells from harmful stresses.

Factors influencing shared decision-making in long-term care facilities.

BACKGROUND: Shared decision-making, a communicative process to reach decisions based on informed preferences, evidence, and co-created goals, improves care satisfaction and patients' quality of life. However, shared decision-making has not been widely implemented in long-term care facilities, and few studies have examined how to promote the shared decision-making practice. This study aimed to identify the influencing factors of shared decision-making based on the Person-centered Practice Framework in long-term care facilities. METHODS: A total of 300 staff (nursing staff, social workers, and personal care workers) in 13 Korean long-term care facilities participated in this study. Data from 280 respondents were finally analyzed, excluding respondents with missing values. Data were collected using structured questionnaires that included items on shared decision-making, personal factors (e.g., knowledge about dementia, person-centered care education, person-centered attitude, communication behavior, and job tenure), and care environment factors (e.g., person-centered climate, staffing level, effective staff relationships, supportive supervisors, and power-sharing). Multilevel linear regression analyses were performed using Mplus Version 8.8. RESULTS: The mean shared decision-making score was 35.78 (range 8-45). Staff with experience of person-centered care education (ß = 0.198, p = 0.034), a higher person-centered attitude score (ß = 0.201, p = 0.007), and a higher communication behavior score (ß = 0.242, p < 0.001) were more likely to report a higher shared decision-making score. In addition, staff who viewed their care environment as more person-centered were more likely to report a higher shared decision-making score (ß = 0.416, p < 0.001). CONCLUSIONS: This study highlights that personal (e.g., person-centered care education, person-centered attitude, and communication behavior) and care environment (e.g., person-centered climate) factors could influence shared decision-making for long-term care residents. These findings could be foundational evidence for facilitating shared decision-making practice in long-term care settings.

Non-Directional Property of Human-Body Communication Channel for Implantable Device Application.

In this paper, we present the properties of a communication channel used for implantable devices. The human-body communication (HBC) channel was proposed for data communication in implantable devices. The impulse response was measured using a channel-mimicking model, which mimics electrical losses caused by human body tissues. Furthermore, we compared two types of channel-mimicking models to evaluate their applicability depending on the measurement environment. The resultant impulse responses of the HBC channel showed that HBC does not cause severe changes in the channel properties even when the implantable device is rotated.

Relative Effectiveness of COVID-19 Vaccination in Healthcare Workers: 3-Dose Versus 2-Dose Vaccination.

The omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is known to have high infectivity and is more likely to evade vaccine immunity. However, booster vaccination is expected to strengthen cross-reactive immunity, thereby increasing the vaccine effectiveness (VE). This study aimed to evaluate the relative VE of the 3-dose (booster) vaccination compared with the 2-dose primary series vaccination in healthcare workers during omicron variant-dominant periods. During the omicron-dominant period from February 1, 2022 to February 28, 2022, a 1:1 matched case-control study was conducted. Healthcare workers with positive SARS-CoV-2 test results were classified as positive cases, whereas those with negative results served as controls. Compared with the 2-dose primary series vaccination, booster vaccination with mRNA vaccine showed moderate VE (53.1%). However, in multivariate analysis including the time elapsed after vaccination, the significant VE disappeared, reflecting the impact of recent vaccination rather than the third dose itself.

Problematic smartphone use and functional somatic symptoms among adolescents: Mediating roles of depressive symptoms and peer relationships by gender.

This study explored the relationship between problematic smartphone use and depressive symptoms, peer relationships, and functional somatic symptoms with a representative sample of Korean male and female adolescents using serial multiple mediation models. The results identified the mediating effect of depressive symptoms and peer relationships for males in the association between problematic smartphone use and FSS. The serial mediating effect of the two mediators was also verified in the model for males. However, in the model for females, only depressive symptoms mediated the relationship between problematic smartphone use and FSS. The findings suggest that parents and professionals should assess adolescents with problematic smartphone use for the risk of FSS when depressive symptoms develop. Schools should also provide programs to build positive peer relationships to reduce FSS.

Types of social activities associated with fewer insomnia symptoms and the mediating role of loneliness in older adults.

BACKGROUND: A positive association has been known to exist between social activity engagements and fewer insomnia symptoms in later life. However, little is known about which social activities are associated with insomnia symptoms. Investigating mediating factors in this relationship may contribute to developing effective strategies for the reduction of sleep complaints in older adults. This study aimed to examine the mediating role of loneliness on the relationship between engagement in different social activities and insomnia symptoms. METHODS: We used secondary data from the 2018 Health and Retirement Study. The study sample included 3236 older adults who responded to a survey on social activity engagement, insomnia symptoms, and loneliness. After adjusting for covariates, simple mediation analyses were performed with bootstrapping to identify the mediating role. RESULTS: Among the several types of social activities, higher levels of engagement in educational courses and community arts group had a significant and direct relationship with fewer insomnia symptoms in older adults. Mediation analyses confirmed the mediating role of loneliness in the relationship between these specific social activity engagements and insomnia symptoms. CONCLUSION: These findings provide new evidence for associations among social activity, loneliness, and insomnia symptoms in older adults.

Relationships among types of activity engagement and insomnia symptoms among older adults.

BACKGROUND: An increasing awareness exists that lack of activity engagement is associated with insomnia symptoms. However, the majority of studies have focused on the association between a single type of activity engagement and insomnia symptoms. METHODS: This is a cross-sectional study using secondary data from the Health and Retirement Study examining the relationships among different types of activity engagement and insomnia symptoms among older adults. The sample for this study included 3321 older adults who responded to survey modules on activity engagement and insomnia symptoms in 2016. Activity engagement was measured using items for three types of activities (i.e., social, cognitive, and physical) validated in this study. Insomnia symptoms were measured using four items (i.e., difficulty of falling asleep, waking up during the night, waking up too early, and feeling rested). Independent t-tests were conducted to identify the differences in insomnia symptoms according to activity engagement level. Regressions were conducted to examine the associations among three types of activity engagement and insomnia symptoms after adjusting for covariates such as demographics, chronic disease, activities of daily living difficulty, cognitive function, sleep disorder, loneliness, and caregiving. RESULTS: The respondents in the high-level social, cognitive, and physical activity engagement groups were found to show fewer insomnia symptoms. Furthermore, higher social (ß = - 0.04, p = 0.040) and cognitive (ß = - 0.06, p = 0.007) activity engagements were associated with fewer insomnia symptoms even after adjusting for other types of activity engagement and all covariates. CONCLUSIONS: This study suggests that older adults with higher social and cognitive activity engagements may be likely to have fewer insomnia symptoms. Based on these results, future research is needed to develop multi-component intervention programs that can encourage older adults to engage in these activities.

Comparison of Trunk Muscle Activity Between Traditional Plank Exercise and Plank Exercise With Isometric Contraction of Ankle Muscles in Subjects With Chronic Low Back Pain.

ABSTRACT: Choi, JH, Kim, DE, and Cynn, HS. Comparison of trunk muscle activity between traditional plank exercise and plank exercise with isometric contraction of ankle muscles in subjects with chronic low back pain. J Strength Cond Res 35(9): 2407-2413, 2021-This study aimed to compare the effects of 4 different ankle conditions on the activities of rectus abdominis (RA), external oblique (EO), transversus abdominis/internal oblique (TrA/IO), and erector spinae (ES) muscles during plank exercise in subjects with chronic low back pain (CLBP). Twenty-two subjects with CLBP participated in this study. The subjects performed the traditional plank and plank with 3 different ankle muscle contraction types (isometric contraction of ankle dorsiflexor, plantarflexor, and without ankle muscle contraction). Surface electromyography was used to measure the activities of RA, EO, TrA/IO, ES, tibialis anterior, and gastrocnemius muscles. A 1-way repeated-measures analysis of variance was used to assess the statistical significance of activities of the RA, EO, TrA/IO, and ES muscles. The activities of RA, EO, and TrA/IO muscles were significantly greater in the plank with isometric contraction of ankle dorsiflexor (PlankDF) than in the other 3 plank exercises. No significant difference in the activity of ES muscles was revealed during the 4 plank exercises. The activities of all abdominal muscles during PlankDF were significantly higher than those during the traditional plank, as well as during the plank with isometric contraction of ankle plantarflexor (PlankPF) and the plank without ankle muscular contraction (Plankw/o), and more than 60% of maximal voluntary isometric contraction was observed. Thus, PlankDF could be applied not only as a rehabilitation strategy for patients with decreased core stability owing to weakness of abdominal muscles but also as fitness program for improving core strength.

A Validation Study of the Inbrain CST: a Tablet Computer-based Cognitive Screening Test for Elderly People with Cognitive Impairment.

BACKGROUND: Computerized versions of cognitive screening test could have advantages over pencil-and-paper versions by eliminating rater-dependent factors and saving the time required to score the tests and report the results. We developed a computerized cognitive screening test (Inbrain Cognitive Screening Test [Inbrain CST]) that takes about 30 minutes to administer on a touchscreen computer and is composed of neuropsychological tests already shown to be sensitive in detecting early cognitive decline in Alzheimer's disease (AD). The aims of this study were to 1) introduce normative data for Inbrain CST, 2) verify its reliability and validity, 3) assess clinical usefulness, and 4) identify neuroanatomical correlates of Inbrain CST. METHODS: The Inbrain CST runs on the Microsoft Windows 10 operating system and comprises 7 subtests that encompass 5 cognitive domains: attention, language, visuospatial, memory, and executive functions. First, we recruited 480 cognitively normal elderly people (age 50-90) from communities nationwide to establish normative data for Inbrain CST. Second, we enrolled 97 patients from our dementia clinic (26 with subjective cognitive decline [SCD], 42 with amnestic mild cognitive impairment [aMCI], and 29 with dementia due to AD) and investigated sensitivity and specificity of Inbrain CST for discriminating cognitively impaired patients from those with SCD using receiver operating characteristic (ROC) curve analyses. Third, we compared the Inbrain CST scores with those from another neuropsychological test battery to obtain concurrent validity and assessed test-retest reliability. Finally, magnetic resonance imaging (MRI)-based cortical thickness analyses were performed to provide anatomical substrates for performances on the Inbrain CST. RESULTS: First, in the normative sample, the total score on the Inbrain CST was significantly affected by age, years of education, and gender. Second, Inbrain CST scores among the three patient groups decreased in the order of SCD, aMCI, and AD dementia, and the ROC curve analysis revealed that Inbrain CST had good discriminative power for differentiating cognitively impaired patients from those with SCD. Third, the Inbrain CST subtests had high concurrent validity and test-retest reliability. Finally, in the cortical thickness analysis, each cognitive domain score and the total score of Inbrain CST showed distinct patterns of anatomical correlates that fit into the previously known brain-behavior relationship. CONCLUSION: Inbrain CST had good validity, reliability, and clinical usefulness in detecting cognitive impairment in the elderly. Furthermore, it showed neuroanatomical validity through MRI cortical thinning patterns. These results suggest that Inbrain CST is a useful cognitive screening tool with efficiency and validity to detect mild impairments in cognition in clinical settings.

SGL 121 Attenuates Nonalcoholic Fatty Liver Disease through Adjusting Lipid Metabolism Through AMPK Signaling Pathway.

A ginsenoside F2-enhanced mixture (SGL 121) increases the content of ginsenoside F2 by biotransformation. In the present study, we investigated the effect of SGL 121 on nonalcoholic fatty liver disease (NAFLD) in vitro and in vivo. High-fat, high-carbohydrate-diet (HFHC)-fed mice were administered SGL 121 for 12 weeks to assess its effect on improving NAFLD. In HepG2 cells, SGL 121 acted as an antioxidant, a hepatoprotectant, and had an anti-lipogenic effect. In NAFLD mice, SGL 121 significantly improved body fat mass; levels of hepatic triglyceride (TG), hepatic malondialdehyde (MDA), serum total cholesterol (TC), high-density lipoprotein (HDL), and low-density lipoprotein (LDL); and activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). In HepG2 cells, induced by oxidative stress, SGL 121 increased cytoprotection, inhibited reactive oxygen species (ROS) production, and increased antioxidant enzyme activity. SGL 121 activated the Nrf2/HO-1 signaling pathway and improved lipid accumulation induced by free fatty acids (FFA). Sterol regulatory element-binding protein-1 (SREBP-1) and fatty acid synthase (FAS) expression was significantly reduced in NAFLD-induced liver and HepG2 cells treated with SGL 121. Moreover, SGL 121 activated adenosine monophosphate-activated protein kinase (AMPK), which plays an important role in the regulation of lipid metabolism. The effect of SGL 121 on the improvement of NAFLD seems to be related to its antioxidant effects and activation of AMPK. In conclusion, SGL 121 can be potentially used for the treatment of NAFLD.

Neobavaisoflavone Inhibits Melanogenesis through the Regulation of Akt/GSK-3ß and MEK/ERK Pathways in B16F10 Cells and a Reconstructed Human 3D Skin Model.

Previous studies have confirmed the anti-melanogenic effect of the aerial part of Pueraria lobata, however, due to its inherent color, P. lobata has limited commercial use. In this study, an extract (GALM-DC) of the aerial part of P. lobata having improved color by the use of activated carbon was obtained. Furthermore, the active compound neobavaisoflavone (NBI) was identified from GALM-DC. The effect of NBI on melanogenesis, tyrosinase activity, α-glucosidase activity, and mechanism of action in melanocytes was investigated. Tyrosinase activity, melanin contents and the expression of melanin-related genes and proteins were determined in B16F10 cells. NBI reduced melanin synthesis and tyrosinase activity. Furthermore, NBI treatment reduced the mRNA and protein expression levels of MITF, TRP-1, and tyrosinase. NBI also works by phosphorylating and activating proteins that inhibit melanogenesis, such as GSK3ß and ERK. Specific inhibitors of Akt/GSK-3ß (LY294002) and MEK/ERK (PD98059) signaling prevented the inhibition of melanogenesis by NBI. NBI inhibited melanin production through the regulation of MEK/ERK and Akt/GSK-3ß signaling pathways in α-MSH-stimulated B16F10 cells. NBI suppresses tyrosinase activity and melanogenesis through inhibition of α-glucosidase activity. Besides, NBI significantly reduced melanogenesis in a reconstructed human 3D skin model. In conclusion, these results suggest that NBI has potential as a skin-whitening agent for hyperpigmentation.

Micropillar-based microfluidic device to regulate neurite networks of uniform-sized neurospheres.

The inability of neurons to undergo mitosis renders damage to the central or peripheral nervous system. Neural stem cell therapy could provide a path for treating the neurodegenerative diseases. However, reliable and simple tools for the developing and testing neural stem cell therapy are still required. Here, we show the development of a micropillar-based microfluidic device to trap the uniform-sized neurospheres. The neurospheres trapped within micropillar arrays were largely differentiated into neuronal cells, and their neurite networks were observed in the microfluidic device. Compared to conventional cultures on glass slides, the neurite networks generated with this method have a higher reproducibility. Furthermore, we demonstrated the effect of thapsigargin on the neurite networks in the microfluidic device, demonstrating that neural networks exposed to thapsigargin were largely diminished and disconnected from each other. Therefore, this micropillar-based microfluidic device could be a potential tool for screening of neurotoxins.

Structure-activity relationship study of thiazolyl-hydroxamate derivatives as selective histone deacetylase 6 inhibitors.

Several human diseases are associated with aberrant epigenetic pathways mediated by histone deacetylases (HDACs), especially HDAC6, a class IIb HDACs, which has emerged as an attractive target for neurodegenerative and autoimmune disease therapeutics. In a previous study, we developed the novel HDAC6-selective inhibitor 9a ((E)-N-hydroxy-4-(2-styrylthiazol-4-yl)butanamide) and showed that it has anti-sepsis activity in vivo. In this study, we conducted structure-activity relationship (SAR) studies to optimize the activity and selectivity of HDAC6, synthesizing its derivatives with various aliphatic linker sizes and cap structures. We identified 6u ((E)-N-hydroxy-3-(2-(4-fluorostyryl)thiazol-4-yl)propanamide), which has nanomolar inhibition activity and a 126-fold selectivity for HDAC6 over HDAC1. Through the docking analyses of 6u against HDAC subtypes, we revealed the importance of the optimal aliphatic linker size, as well as the electronic substituent effect and rigidity of the aryl cap group. Thus, we suggest a new rationale for the design of HDAC6-selective inhibitors.

Prevalence of intimate partner violence victimization and its association with mental disorders in the Korean general population.

This study assessed the association between experiencing physical or sexual intimate partner violence (IPV) and mental health among women in the general Korean population. A total of 3160 South Korean women aged 18 to 74 responded to the Korean version of the WHO-Composite International Diagnostic Interview (K-CIDI), version 2.1., and questions about IPV. Multiple logistic regression was used to examine the odds of developing mental disorders associated with each type of IPV. Victimization by any type of IPV was associated with significantly increased odds of experiencing any mental disorders in the lifetime (OR 4.4, 95% CI 2.4-8.0). Participants who experienced sexual IPV had the highest odds of having mental disorders (OR 14.3, 95% CI 4.1-54.8). Sexual IPV experience among participants was associated with higher odds of major depressive disorder, anxiety disorder, obsessive-compulsive disorder, post-traumatic stress disorder, generalized anxiety disorder, specific phobias, agoraphobia, and nicotine dependence. Alcohol use disorder was highly associated with experiencing physical IPV (OR 3.8, 95% CI 1.7-8.0). Among women who experienced IPV, the youngest age group, from 18 to 35 years old (2.6%, 95% CI 1.4-3.8), and the never married group (2.7%, 95% CI 1.2-4.2) experienced the highest proportion of any form of IPV. Mental disorders throughout the lifetime are highly associated with the experience of IPV among women and are most prevalent among those who experienced sexual IPV. Thus, to prevent mental disorders among female IPV victims, treatment specific to each type of IPV should be provided early.

KRIBB53 binds to OCT4 and enhances its degradation through the proteasome, causing apoptotic cell death of OCT4-positive testicular germ cell tumors.

We hypothesized that octamer-binding transcription factor 4 (OCT4) inhibition would have therapeutic benefits in testicular germ cell tumors (TGCT). To identify inhibitors of OCT4, a chemical library was screened using a luciferase reporter system under the control of an OCT4 response element. A compound named KRIBB53 was identified based on its blocking of OCT4-dependent luciferase activation. When NCCIT cells were exposed to KRIBB53, the expression levels of OCT4 target genes, such as NANOG and USP44, were inhibited with an IC50 of 13 and 15 µM, respectively. In addition, the levels of OCT4 were decreased by exposing NCCIT cells to KRIBB53, and pretreating the cells with the proteasomal inhibitor MG132 reversed the KRIBB53-induced OCT4 degradation. Biotinyl-KRIBB53 was synthesized and showed comparable activity to KRIBB53 in OCT4 downregulation. Using affinity chromatography assay, KRIBB53 was shown to associate with OCT4 in vitro. Furthermore, the drug affinity responsive target stability (DARTS) assay confirmed unmodified KRIBB53 binding to OCT4. KRIBB53 selectively inhibited proliferation of TGCT cells such as NCCIT and Tera-1 cells but not that of immortalized normal cells. Finally, the administration of KRIBB53 at 30 mg/kg reduced tumor volumes by 77% in the mice xenografted with NCCIT cells relative to their vehicle-treated counterparts. Immunoblotting assays showed that expression of OCT4 was lower in KRIBB53-treated tumor tissues than in control tissues. We provide the first report, to our knowledge, of an OCT4 inhibitor that binds to OCT4 and induces its degradation.

CRISPR/dCas9-mediated biosensor for detection of tick-borne diseases.

Rapid and highly sensitive detection of biomolecules is greatly needed for pathogen diagnosis in clinical samples, but the method needs to be significantly improved in terms of sensitivity and specificity for actual use in clinical settings. Here, we report the development of an improved molecular diagnostics tool that utilizes CRISPR/dCas9-mediated biosensor that couples a nuclease inactivated Cas9 (dCas9) and single microring resonator biosensor, enables label-free and real-time detection of pathogenic DNA and RNA. We addressed the clinical utility of this CRISPR/dCas9-mediated biosensor in tick-borne illnesses including scrub typhus (ST) and severe fever with thrombocytopenia syndrome (SFTS), whose clinical presentations are too similar to be easily differentiated. By using CRISPR/dCas9-mediated biosensor, we achieved single molecule sensitivity for the detection of ST (0.54 aM) and SFTS (0.63 aM); this detection sensitivity is 100 times more sensitive than that of RT-PCR assay. Finally, CRISPR/dCas9-mediated biosensor was able to clearly distinguish between ST and SFTS in serum samples within 20 min. We believe that CRISPR/dCas9-mediated biosensor will be useful for rapid and accurate molecular diagnostic tool that is suitable for immediate clinical applications.