A Gelatin/Alginate Double Network Hydrogel Nerve Guidance Conduit Fabricated by a Chemical-Free Gamma Radiation for Peripheral Nerve Regeneration.

Nerve guidance conduits (NGCs) are widely developed using various materials for the functional repair of injured or diseased peripheral nerves. Especially, hydrogels are considered highly suitable for the fabrication of NGCs due to their beneficial tissue-mimicking characteristics (e.g., high water content, softness, and porosity). However, the practical applications of hydrogel-based NGCs are hindered due to their poor mechanical properties and complicated fabrication processes. To bridge this gap, a novel double-network (DN) hydrogel using alginate and gelatin by a two-step crosslinking process involving chemical-free gamma irradiation and ionic crosslinking, is developed. DN hydrogels (1% alginate and 15% gelatin), crosslinked with 30 kGy gamma irradiation and barium ions, exhibit substantially improved mechanical properties, including tensile strength, elastic modulus, and fracture stain, compared to single network (SN) gelatin hydrogels. Additionally, the DN hydrogel NGC exhibits excellent kink resistance, mechanical stability to successive compression, suture retention, and enzymatic degradability. In vivo studies with a sciatic defect rat model indicate substantially improved nerve function recovery with the DN hydrogel NGC compared to SN gelatin and commercial silicone NGCs, as confirm footprint analysis, electromyography, and muscle weight measurement. Histological examination reveals that, in the DN NGC group, the expression of Schwann cell and neuronal markers, myelin sheath, and exon diameter are superior to the other controls. Furthermore, the DN NGC group demonstrates increased muscle fiber formation and reduced fibrotic scarring. These findings suggest that the mechanically robust, degradable, and biocompatible DN hydrogel NGC can serve as a novel platform for peripheral nerve regeneration and other biomedical applications, such as implantable tissue constructs.

Improvement effect of gemigliptin on salivary gland dysfunction in exogenous methylglyoxal-injected rats.

The symptom of hyposalivation associated with hypofunction of the salivary glands is a common feature of diabetes. Inadequate saliva production can cause tissue damage in the mouth, making it susceptible to infections and leading to oral health diseases. Previous studies have highlighted the harmful effects of methylglyoxal (MGO) and MGO-derived advanced glycation end products (AGEs) in diabetes. In this study, we investigated the protective effects of gemigliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, against MGO-induced salivary gland dysfunction. MGO treatment of immortalized human salivary gland acinar cells induced apoptosis via reactive oxygen species (ROS)-mediated pathways, but this effect was mitigated by gemigliptin. In vivo experiments involved the simultaneous administration of MGO (17.25 mg/kg) with aminoguanidine (100 mg/kg) and gemigliptin (10 and 100 mg/kg) daily to rats for two weeks. Gemigliptin increased the saliva volume and amylase levels in MGO-injected rats. Gemigliptin reduced the DPP-4 activity in both the salivary glands and serum of MGO-injected rats. Furthermore, gemigliptin exerted anti-glycation effects by reducing the accumulation of AGEs in the saliva, salivary glands, and serum and suppressing the expression of the receptor for AGEs. These actions protected the salivary gland cells from ROS-mediated apoptosis. Overall, gemigliptin protected the salivary gland cells from ROS-mediated cell death, reduced the accumulation of amylase and mucins in the salivary glands, and enhanced the salivary function by upregulating aquaporin 5 expression, and it exerted protective effects against MGO-induced salivary gland dysfunction by enhancing the anti-glycation, antioxidant, and salivary secretion activities. Our findings suggest gemigliptin as a potential therapeutic for patients with salivary gland dysfunction caused by the complications of diabetes.

KSCBi005-A-10(hiPSC-HIF1αKO), a HIF1α knockout human induced pluripotent stem cell line, for demonstrating the role of cellular response to hypoxia.

Under hypoxia, hypoxia-inducible factor (HIF)-1 regulates hypoxia-inducible genes, such as vascular endothelial growth factor (VEGF) and its receptors VEGFR1 and VEGFR2. It is an oxygen-dependent transcriptional activator that plays a crucial role in tumor angiogenesis and mammalian embryo development. It is a heterodimeric protein comprising a constitutively expressed HIF-1ß subunit and the highly regulated HIF-1α subunits. Using CRISPR-Cas9 genome editing, we generated biallelic HIF-1α mutants in human induced pluripotent stem cells (hiPSCs). The HIF-1α homozygous-knockout hiPSCs retained their normal morphology, gene expression, and in vivo differentiation potential.

Association of Plasma n-3 Polyunsaturated Fatty Acid Levels and the Prevalence of Frailty in Older Adults: A Cross-Sectional Analysis of UK Biobank.

BACKGROUND: Circulating levels of n-3 polyunsaturated fatty acids (PUFAs) have been associated with frailty among Koreans (a population with a high intake of fish), but whether this association exists in Western populations with low fish intake is unknown. The present study examined the hypothesis that the prevalence of frailty was inversely associated with plasma levels of n-3 PUFAs, with the intake of oily fish, and with fish oil supplementation in older adults in the United Kingdom. METHODS: UK Biobank including 79 330 adults aged ≥65 years with dietary data, and 18 802 participants with plasma fatty acid data were used. Frailty was defined using the Cardiovascular Health Study index, plasma levels of n-3 PUFAs were measured by nuclear magnetic resonance, and intake of oily fish and/or fish oil supplements was collected via food frequency questionnaire. RESULTS: Frailty prevalence was inversely associated with n-3 PUFA levels [odds ratios (OR) per SD: 0.86, 95% confidence interval (CI) 0.79-0.94; p < .001], with oily fish intake (never vs ≥2 servings per week; OR 0.59, 95% CI 0.52-0.68, p < .001), and with the use of fish oil supplements (OR 0.72; 95% CI 0.66-0.78; p < .001) after adjusting for confounding factors. All 3 exposures were also associated with each frailty criterion, particularly low physical activity and walking pace. CONCLUSIONS: Inverse associations between plasma n-3 PUFA levels and measures of frailty suggest that higher intakes of oily fish or the use of fish oil supplements may help prevent frailty in older adults in the United Kingdom.

Epstein-Barr virus gp42 antibodies reveal sites of vulnerability for receptor binding and fusion to B cells.

Epstein-Barr virus (EBV) causes infectious mononucleosis and is associated with B cell lymphomas. EBV glycoprotein 42 (gp42) binds HLA class II and activates membrane fusion with B cells. We isolated gp42-specific monoclonal antibodies (mAbs), A10 and 4C12, which use distinct mechanisms to neutralize virus infection. mAb A10 was more potent than the only known neutralizing gp42 mAb, F-2-1, in neutralizing EBV infection and blocking binding to HLA class II. mAb 4C12 was similar to mAb A10 in inhibiting glycoprotein-mediated B cell fusion but did not block receptor binding, and it was less effective in neutralizing infection. Crystallographic structures of gH/gL/gp42/A10 and gp42/4C12 complexes revealed two distinct sites of vulnerability on gp42 for receptor binding and B cell fusion. Passive transfer of mAb A10 into humanized mice conferred nearly 100% protection from viremia and EBV lymphomas after EBV challenge. These findings identify vulnerable sites on EBV that may facilitate therapeutics and vaccines.

Exercise affects high-fat diet-stimulated breast cancer metastasis through irisin secretion by altering cancer stem cell properties.

Background: Regular physical activities reduce the growth of breast cancer, but research on the effects of steady exercise on metastasis and its mechanisms is limited. In this study, the effects of steady exercise on breast cancer metastasis and its possible mechanism were demonstrated. Methods: Experimental metastasis was induced after 8 weeks of steady exercise using a mouse model. Furthermore, one of the myokines, irisin, was studied to elucidate the effects of metastasis-regulating protein expression, and colony and sphere formation, which are cancer stem cell properties. Results: Low- and moderate-intensity exercise significantly reduced the number and volume of metastasized tumors. Among myokines, only irisin was significantly increased by steady exercise but decreased by a high-fat diet. In vitro studies, irisin significantly decreased the number of colonies and sphere formation. Irisin also inhibited cell migration and invasion and suppressed the malignancy of breast cancer cells by reducing the expression of vimentin, MMP-2, MMP-9, and HIF-1 and by increasing the expression of TIMP-1 and TIMP-2. Conclusion: Steady exercise modulates myokine secretions and among them, irisin suppresses breast cancer metastasis by decreasing self-renewal properties and invasion regulating protein expressions. Thus, regular exercise may be beneficial in the prevention of breast tumor metastasis.

Coinfection of Influenza A and B and Human OC43 Coronavirus in Normal Human Bronchial Epithelial Cells.

BACKGROUND: Influenza viruses and seasonal coronaviruses are pathogens transmitted via an airborne route that can cause respiratory diseases in humans that have similar symptoms such as fever, cough, and pneumonia. These two viruses can infect similar human tissues, such as the respiratory tract and nasal, bronchial, and alveolar epithelial cells. Influenza virus and seasonal coronavirus coinfections are poorly understood. METHODS: Here, we coinfected normal human bronchial epithelial (NHBE) cells with influenza A/California/04/09 (IAV) or B/Victoria/504/2000 (IBV) strains and the seasonal human beta-coronavirus OC43 and evaluated viral replication capacities. We also examined changes in the expression of various cytokines/chemokines by qPCR and Luminex assay. RESULTS: We observed that the replication of IAV and IBV was not affected by coinfection with OC43. However, coinfection reduced OC43 titers (~3-fold) compared with infection with OC43 alone. Select cytokine/chemokine expression was increased in coinfected cells compared with all single infections with greater differences seen between coinfected cells and cells infected with OC43 alone compared with IAV- or IBV-infected cells. In addition, IL-8 and IL-1RA showed the highest expression among a panel of 22 cytokines by Luminex. CONCLUSIONS: As the rate of influenza and seasonal coronavirus coinfection continue to increase, our findings may help set guidelines for the treatments of the individuals coinfected with both viruses.

Corticostriatal activity related to performance during continuous de novo motor learning.

Corticostriatal regions play a pivotal role in visuomotor learning. However, less research has been done on how fMRI activity in their subregions is related to task performance, which is provided as visual feedback during motor learning. To address this, we conducted an fMRI experiment in which participants acquired a complex de novo motor skill using continuous or binary visual feedback related to performance. We found a highly selective response related to performance in the entire striatum in both conditions and a relatively higher response in the caudate nucleus for the binary feedback condition. However, the ventromedial prefrontal cortex (vmPFC) response was significant only for the continuous feedback condition. Furthermore, we also found functional distinction of the striatal subregions in random versus goal-directed motor control. These findings underscore the substantial effects of the visual feedback indicating performance on distinct corticostriatal responses, thereby elucidating its significance in reinforcement-based motor learning.

COP1 controls light-dependent chromatin remodeling.

Light is a crucial environmental factor that impacts various aspects of plant development. Phytochromes, as light sensors, regulate myriads of downstream genes to mediate developmental reprogramming in response to changes in environmental conditions. CONSTITUTIVELY PHOTOMORPHOGENIC 1 (COP1) is an E3 ligase for a number of substrates in light signaling, acting as a central repressor of photomorphogenesis. The interplay between phytochrome B (phyB) and COP1 forms an antagonistic regulatory module that triggers extensive gene expression reprogramming when exposed to light. Here, we uncover a role of COP1 in light-dependent chromatin remodeling through the regulation of VIL1 (VIN3-LIKE 1)/VERNALIZATION 5, a Polycomb protein. VIL1 directly interacts with phyB and regulates photomorphogenesis through the formation of repressive chromatin loops at downstream growth-promoting genes in response to light. Furthermore, we reveal that COP1 governs light-dependent formation of chromatin loop and limiting a repressive histone modification to fine-tune expressions of growth-promoting genes during photomorphogenesis through VIL1.

Effect of YC-1102 on the Improvement of Obesity in High-Fat Diet-Induced Obese Mice.

Obesity is one of the major risk factors for metabolic diseases worldwide. This study examined the effects of YC-1102, an extract derived from the roots of Rosa multiflora, on 3T3-L1 preadipocytes and high-fat diet (HFD)-induced obese mice. In vivo experiments involved the oral administration of YC-1102 (100, 150, and 200 mg/kg body weight) daily to mice for eight weeks. YC-1102 was found to downregulate the expressions of PPARγ and C/EBPα during adipogenesis, inhibiting adipocyte differentiation and upregulating the expression of PGC-1α for energy metabolism to enhance mitochondrial biogenesis and fatty acid oxidation. It has been shown that daily administration of YC-1102 to mice receiving a HFD prevented an increase in body weight and the accumulation of body fat. YC-1102 administration also reduced TG, TC, and LDL cholesterol levels, as well as glucose and leptin levels, and increased adiponectin levels, thus effectively inhibiting the metabolism of lipids. YC-1102-treated mice showed significant reductions in the mRNA expression of PPARγ and C/EBPα. The levels of PGC-1α involved in energy metabolism increased significantly in the YC-1102-treated mice when compared to the HFD-treated mice. According to the findings of this study, YC-1102 has a dual mechanism that reduces transcription factors that promote the differentiation of adipocytes and increases transcription factors that promote energy consumption.

A mouse model of Zhu-Tokita-Takenouchi-Kim syndrome reveals indispensable SON functions in organ development and hematopoiesis.

Rare diseases are underrepresented in biomedical research, leading to insufficient awareness. Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome is a rare disease caused by genetic alterations that result in heterozygous loss of function of SON. While patients with ZTTK syndrome live with numerous symptoms, the lack of model organisms hampers our understanding of SON and this complex syndrome. Here, we developed Son haploinsufficiency (Son+/-) mice as a model of ZTTK syndrome and identified the indispensable roles of Son in organ development and hematopoiesis. Son+/- mice recapitulated clinical symptoms of ZTTK syndrome, including growth retardation, cognitive impairment, skeletal abnormalities, and kidney agenesis. Furthermore, we identified hematopoietic abnormalities in Son+/- mice, including leukopenia and immunoglobulin deficiency, similar to those observed in human patients. Surface marker analyses and single-cell transcriptome profiling of hematopoietic stem and progenitor cells revealed that Son haploinsufficiency shifted cell fate more toward the myeloid lineage but compromised lymphoid lineage development by reducing genes required for lymphoid and B cell lineage specification. Additionally, Son haploinsufficiency caused inappropriate activation of erythroid genes and impaired erythropoiesis. These findings highlight the importance of the full gene expression of Son in multiple organs. Our model serves as an invaluable research tool for this rare disease and related disorders associated with SON dysfunction.

Biomarkers of the relationship of particulate matter exposure with the progression of chronic respiratory diseases.

A high level of particulate matter (PM) in air is correlated with the onset and development of chronic respiratory diseases. We conducted a systematic literature review, searching the MEDLINE, EMBASE, and Cochrane databases for studies of biomarkers of the effect of PM exposure on chronic respiratory diseases and the progression thereof. Thirty-eight articles on biomarkers of the progression of chronic respiratory diseases after exposure to PM were identified, four of which were eligible for review. Serum, sputum, urine, and exhaled breath condensate biomarkers of the effect of PM exposure on chronic obstructive pulmonary disease (COPD) and asthma had a variety of underlying mechanisms. We summarized the functions of biomarkers linked to COPD and asthma and their biological plausibility. We identified few biomarkers of PM exposure-related progression of chronic respiratory diseases. The included studies were restricted to those on biomarkers of the relationship of PM exposure with the progression of chronic respiratory diseases. The predictive power of biomarkers of the effect of PM exposure on chronic respiratory diseases varies according to the functions of the biomarkers.

Epigenetic repression of CHCHD2 enhances survival from single cell dissociation through attenuated Rho A kinase activity.

During in vitro culture, human pluripotent stem cells (hPSCs) often acquire survival advantages characterized by decreased susceptibility to mitochondrial cell death, known as "culture adaptation." This adaptation is associated with genetic and epigenetic abnormalities, including TP53 mutations, copy number variations, trisomy, and methylation changes. Understanding the molecular mechanisms underlying this acquired survival advantage is crucial for safe hPSC-based cell therapies. Through transcriptome and methylome analysis, we discovered that the epigenetic repression of CHCHD2, a mitochondrial protein, is a common occurrence during in vitro culture using enzymatic dissociation. We confirmed this finding through genetic perturbation and reconstitution experiments in normal human embryonic stem cells (hESCs). Loss of CHCHD2 expression conferred resistance to single cell dissociation-induced cell death, a common stress encountered during in vitro culture. Importantly, we found that the downregulation of CHCHD2 significantly attenuates the activity of Rho-associated protein kinase (ROCK), which is responsible for inducing single cell death in hESCs. This suggests that hESCs may survive routine enzyme-based cell dissociation by downregulating CHCHD2 and thereby attenuating ROCK activity. These findings provide insights into the mechanisms by which hPSCs acquire survival advantages and adapt to in vitro culture conditions.

Efficacy of Allogeneic and Xenogeneic Exosomes for the Treatment of Canine Atopic Dermatitis: A Pilot Study.

Canine atopic dermatitis (CAD) is a genetically predisposed inflammatory pruritic skin disease. The available treatments for CAD have several adverse effects and vary in efficacy, indicating the need for the development of improved treatments. In this study, we aimed to elucidate the therapeutic effects of allogeneic and xenogeneic exosomes on CAD. Six laboratory beagle dogs with CAD were randomly assigned to three treatment groups: control, canine exosome (cExos), or human exosome (hExos) groups. Dogs in the cExos and hExos groups were intravenously administered 1.5 mL of cExos (5 × 1010) and hExos (7.5 × 1011) solutions, respectively, while those in the control group were administered 1.5 mL of normal saline three times per week for 4 weeks. Skin lesion score and transepidermal water loss decreased in cExos and hExos groups compared with those in the control group. The exosome treatments decreased the serum levels of inflammatory cytokines (interferon-γ, interleukin-2, interleukin-4, interleukin-12, interleukin-13, and interleukin-31) but increased those of anti-inflammatory cytokines (interleukin-10 and transforming growth factor-ß), indicating the immunomodulatory effect of exosomes. Skin microbiome analysis revealed that the exosome treatments alleviated skin bacterial dysbiosis. These results suggest that allogeneic and xenogeneic exosome therapy may alleviate CAD in dogs.

Cross-cultural adaptation of the Korean Synkinesis Assessment Questionnaire: A validation study.

Objective: The Synkinesis Assessment Questionnaire (SAQ) is a reliable tool to assess synkinesis symptoms; however, it is yet to be validated in Korea. Thus, this study aimed to translate and validate the Korean SAQ. Methods: This validation study was set in a clinic in Seoul, Korea, that provides general integrative medicine services. A total of 100 participants with facial palsy were enrolled. Participants completed the SAQ, House-Brackmann grade (HB grade), Sunnybrook Facial Grading System (SB), and Facial Disability Index (FDI). The forward-backward translation method was followed. Of the 100 participants, 31 underwent a second assessment for test-retest reliability. Internal consistency and test-retest reliability were evaluated using Cronbach's alpha coefficient. The construct validity of the Korean version of the SAQ was tested using Spearman's rank correlation coefficient. Results: The internal consistency score for the SAQ was 0.789, and the test-retest reliability score was 0.787. According to Spearman's rank correlation coefficient, the SAQ correlations to the synkinesis subdomain of SB score, total SB score, HB grade, and physical function domain in the FDI score were 0.366 (p < .001), -0.386 (p < .001), 0.315 (p = .001), and -0.269 (p = .007), respectively. All values were statistically significant. Conclusions: The Korean SAQ is a valid and reliable tool used to evaluate synkinesis in patients with facial palsy. Level of Evidence: Level 3.

Rapid Suppression of Quantum Many-Body Magnetic Exciton in Doped van der Waals Antiferromagnet (Ni,Cd)PS3.

The unique discovery of the magnetic exciton in van der Waals antiferromagnet NiPS3 arises between two quantum many-body states of a Zhang-Rice singlet excited state and a Zhang-Rice triplet ground state. Simultaneously, the spectral width of photoluminescence originating from this exciton is exceedingly narrow as 0.4 meV. These extraordinary properties, including the extreme coherence of the magnetic exciton in NiPS3, beg many questions. We studied doping effects using Ni1-xCdxPS3 using two experimental techniques and theoretical studies. Our experimental results show that the magnetic exciton is drastically suppressed upon a few % Cd doping. All this happens while the width of the exciton only gradually increases and the antiferromagnetic ground state is robust. These results highlight the lattice uniformity's hidden importance as a prerequisite for coherent magnetic exciton. Finally, an exciting scenario emerges: the broken charge transfer forbids the otherwise uniform formation of the coherent magnetic exciton in (Ni,Cd)PS3.

Applying Sequential Pattern Mining to Investigate the Temporal Relationships between Commonly Occurring Internal Medicine Diseases and Intervals for the Risk of Concurrent Disease in Canine Patients.

Sequential pattern mining (SPM) is a data mining technique used for identifying common association rules in multiple sequential datasets and patterns in ordered events. In this study, we aimed to identify the relationships between commonly occurring internal medicine diseases in canine patients. We obtained medical records of dogs referred to the Konkuk University Veterinary Medicine Teaching Hospital. The data used for SPM included comorbidities and intervals between the diagnoses of internal medicine diseases. Additionally, we estimated the 3-year risk of developing an additional disease after the initial diagnosis of a commonly occurring veterinary internal medicine disease using logistic regression. We identified 547 canine patients diagnosed with ≥ 1 internal medicine disease. The SPM-based analysis assessed comorbidities and intervals for each of the five most common internal medical diseases, including hyperadrenocorticism, myxomatous mitral valve disease, canine atopic dermatitis, chronic kidney disease, and chronic pancreatitis. The highest values of the association rule were 3.01%, 6.02%, 3.9%, 4.1%, and 4.84%, and the shortest intervals were 1.64, 13.14, 5.37, 17.02, and 1.7 days, respectively. This study proposes that SPM is an effective technique for identifying common associations and temporal relationships between internal medicine diseases, and can be used to assess the probability of additional admission due to the development of the subsequent disease that may be diagnosed in canine patients. The results of this study will help veterinarians suggest appropriate preventive measures or other medical treatments for canine patients with medical conditions that have not yet been diagnosed, but are likely to develop in the short term.

Invasive FoxM1 phosphorylated by PLK1 induces the polarization of tumor-associated macrophages to promote immune escape and metastasis, amplified by IFITM1.

BACKGROUND: Understanding the mechanism behind immune cell plasticity in cancer metastasis is crucial for identifying key regulators. Previously we found that mitotic factors regulate epithelial-mesenchymal transition, but how these factors convert to metastatic players in the tumor microenvironment (TME) is not fully understood. METHODS: The clinical importance of mitotic factors was analyzed by heatmap analysis, a KM plot, and immunohistochemistry in lung adenocarcinoma (LUAD) patients. Immunoprecipitation, LC-MS/MS, kinase assay, and site-directed mutagenesis were performed for the interaction and phosphorylation. A tail-vein injection mouse model, Transwell-based 3D culture, microarray analysis, coculture with monocytes, and chromatin immunoprecipitation assays were used to elucidate the function of phosphorylated FoxM1 in metastasis of TME. RESULTS: The phosphorylated FoxM1 at Ser25 by PLK1 acquires the reprogramming ability to stimulate the invasive traits in cancer and influence immune cell plasticity. This invasive form of p-FoxM1 upregulates the expression of IL1A/1B, VEGFA, and IL6 by direct activation, recruiting monocytes and promoting the polarization of M2d-like tumor-associated macrophages (TAMs). Upregulation of PD-L1 in LUAD having phosphomimetic FoxM1 facilitates immune evasion. In invasive LUAD with phosphomimetic FoxM1, IFITM1 is the most highly expressed through the activation of the STING-TBK1-IRF3 signaling, which enhances FoxM1-mediated signaling. Clinically, higher expression of FOXM1, PLK1, and IFITM1 is inversely correlated with the survival rate of advanced LUAD patients, providing a promising therapeutic strategy for the treatment of LUAD. CONCLUSION: FoxM1-based therapy would be a potential therapeutic strategy for LUAD to reduce TAM polarization, immune escape, and metastasis, since FoxM1 functions as a genetic reprogramming factor reinforcing LUAD malignancy in the TME.