Highly efficient blue InGaN nanoscale light-emitting diodes.

Indium gallium nitride (InGaN)-based micro-LEDs (µLEDs) are suitable for meeting ever-increasing demands for high-performance displays owing to their high efficiency, brightness and stability1-5. However, µLEDs have a large problem in that the external quantum efficiency (EQE) decreases with the size reduction6-9. Here we demonstrate a blue InGaN/GaN multiple quantum well (MQW) nanorod-LED (nLED) with high EQE. To overcome the size-dependent EQE reduction problem8,9, we studied the interaction between the GaN surface and the sidewall passivation layer through various analyses. Minimizing the point defects created during the passivation process is crucial to manufacturing high-performance nLEDs. Notably, the sol-gel method is advantageous for the passivation because SiO2 nanoparticles are adsorbed on the GaN surface, thereby minimizing its atomic interactions. The fabricated nLEDs showed an EQE of 20.2 ± 0.6%, the highest EQE value ever reported for the LED in the nanoscale. This work opens the way for manufacturing self-emissive nLED displays that can become an enabling technology for next-generation displays.

CX3CR1+ macrophages interact with hepatic stellate cells to promote hepatocellular carcinoma through CD8+ T cell suppression.

BACKGROUND AND AIMS: Hepatic stellate cells (HSCs) contribute to hepatocellular carcinoma (HCC) progression by regulating multiple factors. However, the entire immunoregulatory functions of HSCs are still obscure. Here, we aim to investigate whether HSCs impose CX3CR1+ macrophages to pro-tumorigenic properties in the peritumoral area. APPROACH AND RESULTS: In single cell RNA-sequencing analysis of HCC patients, a subpopulation of macrophages specifically expressed Arg1 and Cx3cr1 in the peritumoral area, and were highly enriched with retinol metabolism-related genes. Flow cytometry analysis showed significantly increased frequencies of CD14+CD11b+HLA-DR‒ macrophages with CX3CR1 in the HCC adjacent region where α-SMA-expressing activated HSCs (aHSCs) showed co-localized expression of CX3CL1. Accordingly, in tumor-bearing mice, Cx3cl1 mRNA expression was notably increased in aHSCs within the adjacent HCC, where infiltration of CX3CR1+Ly6C+ macrophages was mostly observed with decreased CD8+ T cells. In adoptive transfer and in vitro co-culture of myeloid cells, we demonstrated that CX3CR1+Ly6C+ macrophages migrated and highly expressed arginase-1 by interacting with retinoid-enriched aHSCs in the adjacent HCC. Direct treatment of retinoids or co-culturing with retinol-storing mouse aHSCs or human LX-2 cells significantly increased arginase-1 expression in CX3CR1+Ly6C+ macrophages and human blood CD14+ cells, leading to the suppression of CD8+ T cell proliferation. Moreover, genetic deficiency of CX3CR1 in myeloid cells or pharmacological inhibition of retinol metabolism remarkably attenuated HCC development. CONCLUSION: We showed that CX3CR1+Ly6C+ macrophages migrate and interact with aHSCs in the peritumoral region where retinoids induce arginase-1 expression in CX3CR1+Ly6C+ macrophages, subsequently depriving CD8+ T cells of arginine and promoting HCC.

The Impact of the COVID-19 Pandemic on the Mental Health of First-Year Undergraduate Students Studying at a Major Canadian University: A Successive Cohort Study.

OBJECTIVE: To examine the impact of the COVID-19 pandemic on first year undergraduate student mental health. METHODS: As part of the Queen's University U-Flourish Student Well-Being and Academic Success study, three successive cohorts of students entering undergraduate studies in 2018 (pre-pandemic), 2019 (transitional), and 2020 (during pandemic) completed electronic surveys at entry and completion of first year. Validated self-report measures were used to assess mental health status including symptom levels of anxiety, depression, and insomnia, self-harm and frequency of substance use. Propensity matching and multivariable log-binomial regression were used in comparisons of mental health indicators across the cohorts. RESULTS: Clinically significant symptoms of depression, anxiety, insomnia, and self-harm were reported more frequently in the 2020-2021 cohort, coincident with remote learning and pandemic restrictions. In female students, screen positive rates for anxiety and depression, and suicidal ideation increased from about one-third to just under one-half in association with the pandemic (χ2, p < .01), while increases in mental health concerns were less pronounced among males. Among females, increases in clinically significant symptoms over first year appeared greatest during the pandemic year, while striking decreases in alcohol consumption in both females and males were reported in that same year. Studying under pandemic conditions had a negative impact on student well-being, social relationships and school connectedness, quality of learning experience, leisure activities, and optimism about future prospects. CONCLUSIONS: Mental health concerns including anxiety, depression and sleep problems increased in first year students during the pandemic, especially among females, while alcohol use declined. These findings highlight the negative mental health impact associated with studying under pandemic restrictions involving remote learning and social distancing.

Childhood Adversity and Mental Health Outcomes Among University Students: A Longitudinal Study.

BACKGROUND: Mental health concerns are common among university students and maybe elevated among those with specific risk exposures. The study examined the association between childhood adversities and mental health outcomes among undergraduate university students and assessed whether psychosocial and behavioral factors mediate those associations. METHODS: The Queen's University Student Well-Being and Academic Success Survey identified two large cohorts of first-year undergraduate students entering university in Fall 2018 and 2019 (n = 5,943). At baseline, students reported sociodemographic information, family-related mental health history, childhood physical abuse, sexual abuse, peer bullying, and parental separation or divorce. Baseline and follow-up surveys in Spring 2019, Fall 2019, and Spring 2020 included validated measures of anxiety (7-item Generalized Anxiety Disorder) and depressive symptoms (9-item Patient Health Questionnaire ), non-suicidal self-harm, and suicidality, along with psychological processes and lifestyle variables. Repeated measures logistic regression using Generalized Estimating Equations was used to characterize the associations between childhood adversities and mental health outcomes and examine potential mediation. RESULTS: Adjusting for age, gender, ethnicity, familial mental illness, and parental education, any childhood abuse (odds ratio: 2.89; 95% confidence interval, 2.58 to 3.23) and parental separation or divorce (odds ratio: 1.29; 95% confidence interval, 1.12 to 1.50) were significantly associated with a composite indicator of mental health outcomes (either 9-item Patient Health Questionnaire score ≥10 or 7-item Generalized Anxiety Disorderscore ≥10 or suicidality or self-harm). The association with childhood abuse weakened when adjusted for perceived stress, self-esteem, and insomnia (odds ratio: 2.05; 95% confidence interval, 1.80 to 2.34), and that with parental divorce weakened when adjusted for self-esteem (odds ratio: 1.17; 95% confidence interval, 1.00 to 1.36). CONCLUSION: Childhood abuse and parental separation or divorce were associated with mental health concerns among university students. Childhood adversities may impact later mental health through an association with stress sensitivity, self-esteem, and sleep problems. The findings suggest that prevention and early intervention focusing on improving sleep, self-esteem, and coping with stress while considering the individual risk profile of help-seeking students may help support student mental health.

Cutaneous Layer and SMAS Suspension (CaSS) Lift as a Minimally Invasive Lateral Midface Lift.

BACKGROUND: In our prior study, the authors determined that pulling on the superficial adipose layer is more effective in lifting the skin than pulling on the superficial musculoaponeurotic system (SMAS). Applying this concept of using the superficial adipose layer to transmit the lifting force to the skin, this study examined improvements in patients who underwent lateral midface lifting using our minimally invasive multilayer lifting technique and measured the duration of those improvements. METHODS: Along the hairline in front of the sideburns, a W-shaped zigzag incision of 3 to 8 mm in width and 3 to 4 cm in length was made. On the temporal scalp, 3 to 4 cm away from the first incision, a second incision was made more lateral/posterior to the first incision, and an elliptical excision of 3 to 5 mm in width and 3 to 4 cm in length was made. From the medial cut margin of the anterior first incision, the superficial temporal fascia/SMAS (the deep layer), and the superficial adipose layer (the superficial layer) were purchased with 3-0 polyester sutures, tunneled under the soft tissue, and fixed to the deep temporal fascia of the second posterior temporal incision. Prior to the excised temporal scalp closure, the dermis in the medial cut margin of the second incision was pulled to the rear as much as possible and fixed to the deep temporal fascia. RESULTS: The effects of surgery were monitored for 6 to 42 months after surgery. The nasolabial folds were improved. Skin elasticity also showed significant improvements, which lasted throughout the follow-up period (up to 42 mo). CONCLUSIONS: Unlike traditional wide dissection SMAS facelift, our method requires minimal incisions and does not require skin undermining. Therefore, the operating time is shorter, and postoperative swelling is minimized. In our technique, the superficial adipose layer, the superficial temporal fascia/SMAS, and the dermis were pulled individually to lift all layers of the lateral midface soft tissues. This results in a significant and long-lasting lateral midface rejuvenation.

The correlation of gagging threshold with intra-oral tactile and psychometric profiles in healthy subjects: A pilot study.

Excessive gag reflex could be problematic for adequate dental care. Although various factors may increase the susceptibility to gagging, its contributing factors have not been fully determined. This study aimed to determine whether gag reflex was associated with tactile sensitivity and psychological characteristics. Fifteen volunteers of healthy males and females each were recruited for this study. After completing a questionnaire describing the self-perceived gag reflex activity, a disposable saliva ejector was inserted along the palate into the mouth until gagging was evoked. The ratio of the insertion depth to the palatal length was used as an index for the gagging threshold. The two-point discrimination (TPD) and Semmes-Weinstein monofilament (SWM) tests were performed to assess the tactile sensitivity of the palatal regions (hard palate, anterior and posterior soft palate). The Symptom Checklist-90-Revised was used to investigate the relationship between the gagging threshold and the psychological status. Our findings showed that the gagging threshold had a significant positive correlation with the TPD and SWM thresholds on the hard palate. The psychological profiles of psychoticism and hostility score were also significantly correlated with the gagging threshold. However, there were no significant differences in the tactile and gagging thresholds, as well as the psychological profiles, between males and females. Our results suggested that the tactile sensitivity of the anterior palate is a determining factor for the gagging threshold and implied that the initial response of the oral entry site to stimulation may lead to the development of gag reflex.

A case report of a tongue ulcer presented as the first sign of occult tuberculosis.

BACKGROUND: Tuberculosis (TB) is a serious infectious disease with considerable fatality, typically affecting the pulmonary system and, rarely, other body organs including the oral cavity. Due to the rarity of oral TB, it is frequently overlooked in differential diagnosis of oral lesions. Despite a declining trend in TB incidence in recent years, it is still a major public health problem with high contagiousness, thereby requiring the early diagnosis and prompt treatment. CASE PRESENTATION: A 57-year-old male patient presented with chief complaint of painful ulcer on tip of his tongue. He reported that the ulcer developed without any remarkable event such as mechanical trauma, vesicle formation or systemic illness. His past medical history revealed the TB over 40 years ago, which had reportedly healed after pharmacological treatments. As the ulceration persisted after topical steroid application and careful education about avoiding possible mechanical stimuli, biopsy was performed and histological finding showed typical findings of oral tuberculosis including intense granulomatous inflammatory features with small red rods of mycobacterial organisms as well as epithelioid cells and Langhans giant cells. After suitable antituberculosis treatments, oral tuberculosis ulcer was almost completely healed. We present a case of oral TB affecting tip of the tongue in a patient with a history of pulmonary TB and emphasize the understanding of intraoral manifestations for early diagnosis and prompt treatment of TB. CONCLUSIONS: The present case represented the importance of understanding oral tuberculosis manifestations for dental clinicians who might be frequently the first health care professionals to encounter various oral lesions.

Cellular toxicity driven by high-dose vitamin C on normal and cancer stem cells.

As a powerful antioxidant, vitamin C protects cells from oxidative damage by inhibiting production of free radicals. However, high levels of vitamin C shows cytotoxicity especially on cancerous cells through generating excessive ROS and blocking the energy homeostasis. Although the double-sided character of vitamin C has been extensively studied in many cell types, there is little research on the consequence of vitamin C treatment in stem cells. Here, we identified that high-dose vitamin C shows cellular toxicity on proliferating NSPCs. We also demonstrated that undifferentiated NSPCs are more sensitive to vitamin C-driven DNA damage than differentiated cells, due to higher expression of Glut genes. Finally, we showed that high-dose vitamin C selectively induces DNA damage on cancer stem cells rather than differentiated tumor cells, raising a possibility that vitamin C may be used to target cancer stem cells.

Loss of toll-like receptor 3 aggravates hepatic inflammation but ameliorates steatosis in mice.

The importance of toll-like receptor (TLR) 4 in the pathogenesis of steatohepatitis has been well documented; however, little is known about the role of TLR3. In this study, we determined whether the depletion of TLR3 modulated hepatic injury in mice and further aimed to provide mechanistic insights into the TLR3-mediated modulation of diet-induced hepatic inflammation and fat accumulation. Hepatic steatosis and inflammatory response were induced by feeding wild-type (WT) or TLR3 knockout mice a high-fat diet for 8 weeks. Primary liver resident cells, including hepatocytes, Kupffer cells, and hepatic stellate cells (HSCs), were treated with palmitic acid. TLR3 knockout mice fed a high-fat diet showed severe hepatic inflammation accompanied by nuclear factor-κB and IRF3 activation, which is mainly induced by the activation of Kupffer cells. Decreased TLR4 expression was restored in hepatic mononuclear cells and Kupffer cells in TLR3 knockout mice compared to that in the WT. Moreover, hepatic steatosis was decreased in TLR3 knockout mice. Hepatocytes from TLR3 knockout mice exhibited reduced expression of cannabinoid receptors. HSCs from TLR3 knockout mice showed decreased expression of the enzymes involved in endocannabinoid synthesis. In conclusion, this study suggests that the selective modulation of TLR3 could be a novel therapeutic target for the treatment of hepatic inflammation and steatosis.

Kv3.1 and Kv3.4, Are Involved in Cancer Cell Migration and Invasion.

Voltage-gated potassium (Kv) channels, including Kv3.1 and Kv3.4, are known as oxygen sensors, and their function in hypoxia has been well investigated. However, the relationship between Kv channels and tumor hypoxia has yet to be investigated. This study demonstrates that Kv3.1 and Kv3.4 are tumor hypoxia-related Kv channels involved in cancer cell migration and invasion. Kv3.1 and Kv3.4 protein expression in A549 and MDA-MB-231 cells increased in a cell density-dependent manner, and the pattern was similar to the expression patterns of hypoxia-inducible factor-1α (HIF-1α) and reactive oxygen species (ROS) according to cell density, whereas Kv3.3 protein expression did not change in A549 cells with an increase in cell density. The Kv3.1 and Kv3.4 blocker blood depressing substance (BDS) did not affect cell proliferation; instead, BDS inhibited cell migration and invasion. We found that BDS inhibited intracellular pH regulation and extracellular signal-regulated kinase (ERK) activation in A549 cells cultured at a high density, potentially resulting in BDS-induced inhibition of cell migration and invasion. Our data suggest that Kv3.1 and Kv3.4 might be new therapeutic targets for cancer metastasis.

Levator Aponeurosis and Muller Muscle Plication Reinforced With Levator Sheath Advancement for Blepharoptosis Correction.

The authors innovated the levator aponeurosis and Muller muscle plication reinforced with levator sheath advancement (AMPSA) for blepharoptosis correction. The orbital septum was opened 1 mm above its fusion with the levator aponeurosis. The preaponeurotic fat was retracted and the thickened part of the levator sheath was identified. Two plication sutures were made: medial suture at the medial border of the pupil and lateral between the lateral border of the pupil and the lateral limbus. A needle with 6-0 nylon thread first bit the tarsal plate approximately 1 mm below its upper border, then bit the levator aponeurosis and the Muller muscle together at 3 to 6 mm above the upper border of the tarsal plate. The needle bit 1 to 3 mm of the thickened part of the levator sheath and the suture was tied. A total of 116 eyes were operated on using levator aponeurosis and Muller muscle plication (AMP), and 79 eyes using AMPSA. The mean follow-up period was 11.4 months. In the AMP group, the postoperative marginal reflex distance-1 (MRD-1) (3.8 ±â€Š0.2 mm) was significantly greater than the preoperative MRD-1 (2.7 ±â€Š0.3 mm) (P < 0.001). In the AMPSA group, the postoperative MRD-1 (3.5 ±â€Š0.3 mm) was also significantly greater than the preoperative MRD-1 (1.7 ±â€Š0.4 mm) (P < 0.001). The improvement in MRD-1 was greater in the AMPSA group (1.7 ±â€Š0.4 mm) than in the AMP group (1.1 ±â€Š0.3 mm) (P < 0.001). The difference in the MRD-1 outcome between AMPSA and AMP (0.6 mm) was obtained by advancing the thickened part of the levator sheath. AMPSA may be an effective procedure for correcting blepharoptosis.

The presence of altered craniocervical posture and mobility in smartphone-addicted teenagers with temporomandibular disorders.

[Purpose] Smartphones are widely used by teenagers and adults for various purposes. As teenagers use smartphones more actively than adults, they are more prone to be addicted to smartphones. Furthermore, excessive usage of smartphones can lead to various psychosocial and physical symptoms. [Subjects and Methods] One hundred teenage subjects were recruited and divided into normal and addiction groups, based on the criteria of the smartphone addiction scale-short version questionnaire. Craniocervical posture and mobility were examined by lateral cephalometric analysis and a cervical range of motion instrument. [Results] Cephalometric analysis showed no significant difference in the craniocervical angles of the resting positions of the two groups. However, measurement using an inclinometer revealed a significantly flexed cervical posture while using smartphones and decreased cervical range of motion in the smartphone-addicted teenagers. The clinical profile of temporomandibular disorders revealed that muscular problems were more frequently presented in the smartphone-addicted teenagers. [Conclusion] These findings suggest that smartphone addiction has a negative influence on craniocervical posture and mobility. Further, it can be postulated that smartphone addiction among teenagers may have contributed to the occurrence of myogenous temporomandibular disorders. In conclusion, smartphone-addicted teenagers may be more frequently subjected to muscular disturbance in the craniocervical area, which probably affects the pathologic process of temporomandibular disorders in teenagers.

Alcohol dehydrogenase III exacerbates liver fibrosis by enhancing stellate cell activation and suppressing natural killer cells in mice.

UNLABELLED: The important roles of retinols and their metabolites have recently been emphasized in the interactions between hepatic stellate cells (HSCs) and natural killer (NK) cells. Nevertheless, the expression and role of retinol metabolizing enzyme in both cell types have yet to be clarified. Thus, we investigated the expression of retinol metabolizing enzyme and its role in liver fibrosis. Among several retinol metabolizing enzymes, only alcohol dehydrogenase (ADH) 3 expression was detected in isolated HSCs and NK cells, whereas hepatocytes express all of them. In vitro treatment with 4-methylpyrazole (4-MP), a broad ADH inhibitor, or depletion of the ADH3 gene down-regulated collagen and transforming growth factor-ß1 (TGF-ß1) gene expression, but did not affect α-smooth muscle actin gene expression in cultured HSCs. Additionally, in vitro, treatments with retinol suppressed NK cell activities, whereas inhibition of ADH3 enhanced interferon-γ (IFN-γ) production and cytotoxicity of NK cells against HSCs. In vivo, genetic depletion of the ADH3 gene ameliorated bile duct ligation- and carbon tetrachloride-induced liver fibrosis, in which a higher number of apoptotic HSCs and an enhanced activation of NK cells were detected. Freshly isolated HSCs from ADH3-deficient mice showed reduced expression of collagen and TGF-ß1, but enhanced expression of IFN-γ was detected in NK cells from these mice compared with those of control mice. Using reciprocal bone marrow transplantation of wild-type and ADH3-deficient mice, we demonstrated that ADH3 deficiency in both HSCs and NK cells contributed to the suppressed liver fibrosis. CONCLUSION: ADH3 plays important roles in promoting liver fibrosis by enhancing HSC activation and inhibiting NK cell activity, and could be used as a potential therapeutic target for the treatment of liver fibrosis.

Effect of Low-Level Laser Therapy on Human Adipose-Derived Stem Cells: In Vitro and In Vivo Studies.

BACKGROUND: Low-level laser therapy (LLLT) continues to receive much attention in many clinical fields. Also, LLLT has been used to enhance the proliferation of various cell lines, including stem cells. This study investigated the effect of LLLT on human adipose-derived stem cells (ADSCs) through in vitro and in vivo studies. METHODS: Low-level laser irradiation of cultured ADSCs was performed using a 830 nm Ga-Al-As (gallium-aluminum-arsenide) laser. Then, proliferation of ADSCs was quantified by a cell counting kit-8. In the in vivo study, irradiated ADSCs or non-irradiated ADSCs were transplanted, and then, low-level laser irradiation of each rat was performed as per the protocol. Cell viability was quantified by immunofluorescent staining using the human mitochondria antibody. RESULTS: In the in vitro study, the laser-irradiated groups showed an increase in absorbance compared to the control group. Also, in the in vivo study, there was a significant increase in the number of human ADSCs in the laser-irradiated groups compared to the control group (p < 0.001). CONCLUSIONS: Our study showed that LLLT could enhance the proliferation and viability of ADSCs. The ADSCs enhanced by LLLT could be applied in various clinical fields. With the use of LLLT, the proliferation and viability of various cells can be enhanced, besides ADSCs. NO LEVEL ASSIGNED: This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors http://www.springer.com/00266 .

Diagnostic Performance Using a Combination of MRI Findings for Evaluating Cognitive Decline.

Purpose: We investigated potentially promising imaging findings and their combinations in the evaluation of cognitive decline. Materials and Methods: This retrospective study included 138 patients with subjective cognitive impairments, who underwent brain MRI. We classified the same group of patients into Alzheimer's disease (AD) and non-AD groups, based on the neuropsychiatric evaluation. We analyzed imaging findings, including white matter hyperintensity (WMH) and cerebral microbleeds (CMBs), using the Kruskal-Wallis test for group comparison, and receiver operating characteristic (ROC) curve analysis for assessing the diagnostic performance of imaging findings. Results: CMBs in the lobar or deep locations demonstrated higher prevalence in the patients with AD compared to those in the non-AD group. The presence of lobar CMBs combined with periventricular WMH (area under the ROC curve [AUC] = 0.702 [95% confidence interval: 0.599-0.806], p < 0.001) showed the highest performance in differentiation of AD from non-AD group. Conclusion: Combinations of imaging findings can serve as useful additive diagnostic tools in the assessment of cognitive decline.

Modulation of synaptic transmission through O-GlcNAcylation.

O-GlcNAcylation is a posttranslational modification where N-acetylglucosamine (O-GlcNAc) is attached and detached from a serine/threonine position by two enzymes: O-GlcNAc transferase and O-GlcNAcase. In addition to roles in diabetes and cancer, recent pharmacological and genetic studies have revealed that O-GlcNAcylation is involved in neuronal function, specifically synaptic transmission. Global alteration of the O-GlcNAc level does not affect basal synaptic transmission while the effect on synaptic plasticity is unclear. Although synaptic proteins that are O-GlcNAcylated are gradually being discovered, the mechanism of how O-GlcNAcylated synaptic protein modulate synaptic transmission has only been reported on CREB, synapsin, and GluA2 subunit of AMPAR. Future research enabling the manipulation of O-GlcNAcylation in individual synaptic proteins should reveal hidden aspects of O-GlcNAcylated synaptic proteins as modulators of synaptic transmission.

Acceptability and utility of digital well-being and mental health support for university students: A pilot study.

AIM: To assess the acceptability and explore the utility of a novel digital platform designed as a student-facing well-being and mental health support. METHODS: An adapted version of i-spero® was piloted as a student-facing well-being support and as part of routine university-based mental health care. In both pathways, student participants completed baseline demographics and brief validated measures of well-being and mental health. Weekly measures of anxiety (GAD-7) and depression (PHQ-9) and a Week 8 Experience Survey were also scheduled. Integrated mixed methods analysis was used to assess acceptability and explore the utility of these platforms. RESULTS: Students in the well-being (n = 120) and care pathways (n = 121) were mostly female and between 19 and 22 years of age. Baseline screen positive rates for anxiety and depression were high in both the well-being (68%) and care pathways (80%). There was a substantial drop in adherence over Week 1 (50% well-being; 40% care) followed by minor attrition up to Week 8. Anxiety and depressive symptom levels improved from baseline in students who dropped out after Week 1 (p ≤ .06). The student experience was that i-spero® improved their emotional self-awareness, understanding of progress in care, and knowledge about when to seek help. Most students agreed (>75%) that i-spero® should form part of regular university student wellness support. CONCLUSIONS: Digital well-being and mental health support seems acceptable to university students; however, engagement and persistence are areas for further development. Such digital tools could make a positive contribution to an evidence-based stepped approach to student well-being and mental health support.

Activation of toll-like receptor 3 attenuates alcoholic liver injury by stimulating Kupffer cells and stellate cells to produce interleukin-10 in mice.

BACKGROUND & AIMS: The important function of toll-like receptor (TLR) 4 in Kupffer cells and hepatic stellate cells (HSCs) has been well documented in alcoholic liver injury. However, little is known about the role of TLR3. Thus, we tested whether TLR3 activation in HSCs and Kupffer cells could attenuate alcoholic liver injury in vivo, and investigated its possible mechanism in vitro. METHODS: Alcoholic liver injury was achieved by feeding wild type (WT), TLR3 knockout (TLR3(-/-)) and interleukin (IL)-10(-/-) mice with high-fat diet plus binge ethanol drinking for 2 weeks. To activate TLR3, polyinosinic-polycytidylic acid (poly I:C) was injected into mice. For in vitro studies, HSCs and Kupffer cells were isolated and treated with poly I:C. RESULTS: In WT mice, poly I:C treatment reduced alcoholic liver injury and fat accumulation by suppressing nuclear factor-κB activation and sterol response element-binding protein 1c expression in the liver. In addition, freshly isolated HSCs and Kupffer cells from poly I:C-treated mice showed enhanced expression of IL-10 compared to controls. Infiltrated macrophage numbers and the expression of tumor necrosis factor-α, monocyte chemoattractant protein-1 and IL-6 on these cells were decreased after poly I:C treatment. In vitro, poly I:C treatment enhanced the expression of IL-10 via a TLR3-dependent mechanism in HSCs and Kupffer cells. Finally, the protective effects of poly I:C on alcoholic liver injury were diminished in TLR3(-/-) and IL-10(-/-) mice. CONCLUSIONS: TLR3 activation ameliorates alcoholic liver injury via the stimulation of IL-10 production in HSCs and Kupffer cells. TLR3 could be a novel therapeutic target for the treatment of alcoholic liver injury.

CD11b(+) Gr1(+) bone marrow cells ameliorate liver fibrosis by producing interleukin-10 in mice.

UNLABELLED: Clinical trials and animal models suggest that infusion of bone marrow cells (BMCs) is effective therapy for liver fibrosis, but the underlying mechanisms are obscure, especially those associated with early effects of BMCs. Here, we analyzed the early impact of BMC infusion and identified the subsets of BMCs showing antifibrotic effects in mice with carbon tetrachloride-induced liver fibrosis. An interaction between BMCs and activated hepatic stellate cells (HSCs) was investigated using an in vitro coculturing system. Within 24 hours, infused BMCs were in close contact with activated HSCs, which was associated with reduced liver fibrosis, enhanced hepatic expression of interleukin (IL)-10, and expanded regulatory T cells but decreased macrophage infiltration in the liver at 24 hours after BMC infusion. In contrast, IL-10-deficient (IL-10(-/-) ) BMCs failed to reproduce these effects in fibrotic livers. Intriguingly, in isolated cells, CD11b(+) Gr1(high) F4/80(-) and CD11b(+) Gr1(+) F4/80(+) BMCs expressed more IL-10 after coculturing with activated HSCs, leading to suppressed expression of collagen and α-smooth muscle actin in HSCs. Moreover, these effects were either enhanced or abrogated, respectively, when BMCs were cocultured with IL-6(-/-) and retinaldehyde dehydrogenase 1(-/-) HSCs. Similar to murine data, human BMCs expressed more IL-10 after coculturing with human HSC lines (LX-2 or hTERT), and serum IL-10 levels were significantly elevated in patients with liver cirrhosis after autologous BMC infusion. CONCLUSION: Activated HSCs increase IL-10 expression in BMCs (CD11b(+) Gr1(high) F4/80(-) and CD11b(+) Gr1(+) F4/80(+) cells), which in turn ameliorates liver fibrosis. Our findings could enhance the design of BMC therapy for liver fibrosis.

The Hippo-Salvador pathway restrains hepatic oval cell proliferation, liver size, and liver tumorigenesis.

Loss of Hippo signaling in Drosophila leads to tissue overgrowth as a result of increased cell proliferation and decreased cell death. YAP (a homolog of Drosophila Yorkie and target of the Hippo pathway) was recently implicated in control of organ size, epithelial tissue development, and tumorigenesis in mammals. However, the role of the mammalian Hippo pathway in such regulation has remained unclear. We now show that mice with liver-specific ablation of WW45 (a homolog of Drosophila Salvador and adaptor for the Hippo kinase) manifest increased liver size and expansion of hepatic progenitor cells (oval cells) and eventually develop hepatomas. Moreover, ablation of WW45 increased the abundance of YAP and induced its localization to the nucleus in oval cells, likely accounting for their increased proliferative capacity, but not in hepatocytes. Liver tumors that developed in mice heterozygous for WW45 deletion or with liver-specific WW45 ablation showed a mixed pathology combining characteristics of hepatocellular carcinoma and cholangiocarcinoma and seemed to originate from oval cells. Together, our results suggest that the mammalian Hippo-Salvador pathway restricts the proliferation of hepatic oval cells and thereby controls liver size and prevents the development of oval cell-derived tumors.