Effect of Probiotics in Stress-Associated Constipation Model in Zebrafish (Danio rerio) Larvae.

The pathophysiology of functional bowel disorders is complex, involving disruptions in gut motility, visceral hypersensitivity, gut-brain-microbiota interactions, and psychosocial factors. Light pollution, as an environmental stressor, has been associated with disruptions in circadian rhythms and the aggravation of stress-related conditions. In this study, we investigated the effects of environmental stress, particularly continuous light exposure, on intestinal motility and inflammation using zebrafish larvae as a model system. We also evaluated the efficacy of probiotics, specifically Bifidobacterium longum (B. longum), at alleviating stress-induced constipation. Our results showed that continuous light exposure in zebrafish larvae increased the cortisol levels and reduced the intestinal motility, establishing a stress-induced-constipation model. We observed increased inflammatory markers and decreased intestinal neural activity in response to stress. Furthermore, the expressions of aquaporins and vasoactive intestinal peptide, crucial for regulating water transport and intestinal motility, were altered in the light-induced constipation model. Administration of probiotics, specifically B. longum, ameliorated the stress-induced constipation by reducing the cortisol levels, modulating the intestinal inflammation, and restoring the intestinal motility and neural activity. These findings highlight the potential of probiotics to modulate the gut-brain axis and alleviate stress-induced constipation. Therefore, this study provides a valuable understanding of the complex interplay among environmental stressors, gut function, and potential therapeutic strategies.

Therapeutic base editing and prime editing of COL7A1 mutations in recessive dystrophic epidermolysis bullosa.

Recessive dystrophic epidermolysis bullosa (RDEB) is a severe skin fragility disorder caused by loss-of-function mutations in the COL7A1 gene, which encodes type VII collagen (C7), a protein that functions in skin adherence. From 36 Korean RDEB patients, we identified a total of 69 pathogenic mutations (40 variants without recurrence), including point mutations (72.5%) and insertion/deletion mutations (27.5%). For fibroblasts from two patients (Pat1 and Pat2), we applied adenine base editors (ABEs) to correct the pathogenic mutation of COL7A1 or to bypass a premature stop codon in Pat1-derived primary fibroblasts. To expand the targeting scope, we also utilized prime editors (PEs) to correct the COL7A1 mutations in Pat1- and Pat2-derived fibroblasts. Ultimately, we found that transfer of edited patient-derived skin equivalents (i.e., RDEB keratinocytes and PE-corrected RDEB fibroblasts from the RDEB patient) into the skin of immunodeficient mice led to C7 deposition and anchoring fibril formation within the dermal-epidermal junction, suggesting that base editing and prime editing could be feasible strategies for ex vivo gene editing to treat RDEB.

Identification of gaze pattern and blind spots by upper gastrointestinal endoscopy using an eye-tracking technique.

BACKGROUND: The lesion detection rate of esophagogastroduodenoscopy (EGD) varies depending on the degree of experience of the endoscopist and anatomical blind spots. This study aimed to identify gaze patterns and blind spots by analyzing the endoscopist's gaze during real-time EGD. METHODS: Five endoscopists were enrolled in this study. The endoscopist's eye gaze tracked by an eye tracker was selected from the esophagogastric junction to the second portion of the duodenum without the esophagus during insertion and withdrawal, and then matched with photos. Gaze patterns were visualized as a gaze plot, blind spot detection as a heatmap, observation time (OT), fixation duration (FD), and FD-to-OT ratio. RESULTS: The mean OT and FD were 11.10 ± 11.14 min and 8.37 ± 9.95 min, respectively, and the FD-to-OT ratio was 72.5%. A total of 34.3% of the time was spent observing the antrum. When observing the body of the stomach, it took longer to observe the high body in the retroflexion view and the low-to-mid body in the forward view. CONCLUSIONS: It is necessary to minimize gaze distraction and observe the posterior wall in the retroflexion view. Our results suggest that eye-tracking techniques may be useful for future endoscopic training and education.

Long-term natural history after endoscopic resection for gastric dysplasia.

BACKGROUND AND STUDY AIMS: Natural history after endoscopic resection (ER) for gastric dysplasia is still unclear. The aim of this study was to evaluate the long-term clinical outcomes and risk factors after ER for gastric dysplasia between control and cases with synchronous or metachronous gastric neoplasm. METHODS: A total of 1090 patients who had undergone ER for gastric dysplasia and been followed up for at least one year from December 2002 to December 2013 were finally analyzed. Risk factors affecting the development of synchronous or metachronous neoplasm (SMN) and long-term clinical outcomes after ER for gastric dysplasia were evaluated. RESULTS: Synchronous and metachronous neoplasms had developed in 126 (11.6%) and 133 patients (12.2%) during the mean follow-up duration of 63.6 months, respectively. Five-year and 10-year risk of metachronous neoplasm were 9.8% and 27.2%, respectively. Median duration to the development of metachronous neoplasm was 103.1 months. While age (P < 0.001) and mucosal atrophy (P = 0.09) of index cases were associated with the development of synchronous neoplasm, age (P = 0.017), incomplete resection (P = 0.025), and intestinal metaplasia (P = 0.017) of background mucosa of index cases were significantly related to the development of metachronous neoplasm in multivariate analysis. Cumulative incidence of SMN was not significantly different among H. pylori negative, eradicated, and persistent group. CONCLUSIONS: Age, incomplete ER, and background intestinal metaplasia of index gastric dysplasia were significantly associated with metachronous recurrence. Endoscopic surveillance for metachronous recurrence after ER for gastric dysplasia is mandatory for longer than 10 years.

Phospho switch triggers Brd4 chromatin binding and activator recruitment for gene-specific targeting.

Bromodomain-containing protein 4 (Brd4) is an epigenetic reader and transcriptional regulator recently identified as a cancer therapeutic target for acute myeloid leukemia, multiple myeloma, and Burkitt's lymphoma. Although chromatin targeting is a crucial function of Brd4, there is little understanding of how bromodomains that bind acetylated histones are regulated, nor how the gene-specific activity of Brd4 is determined. Via interaction screen and domain mapping, we identified p53 as a functional partner of Brd4. Interestingly, Brd4 association with p53 is modulated by casein kinase II (CK2)-mediated phosphorylation of a conserved acidic region in Brd4 that selectively contacts either a juxtaposed bromodomain or an adjacent basic region to dictate the ability of Brd4 binding to chromatin and also the recruitment of p53 to regulated promoters. The unmasking of bromodomains and activator recruitment, concurrently triggered by the CK2 phospho switch, provide an intriguing mechanism for gene-specific targeting by a universal epigenetic reader.

The G protein-coupled taste receptor T1R1/T1R3 regulates mTORC1 and autophagy.

Cells continually assess their energy and nutrient state to maintain growth and survival and engage necessary homeostatic mechanisms. Cell-autonomous responses to the fed state require the surveillance of the availability of amino acids and other nutrients. The mammalian target of rapamycin complex 1 (mTORC1) integrates information on nutrient and amino acid availability to support protein synthesis and cell growth. We identify the G protein-coupled receptor (GPCR) T1R1/T1R3 as a direct sensor of the fed state and amino acid availability. Knocking down this receptor, which is found in most tissues, reduces the ability of amino acids to signal to mTORC1. Interfering with this receptor alters localization of mTORC1, downregulates expression of pathway inhibitors, upregulates key amino acid transporters, blocks translation initiation, and induces autophagy. These findings reveal a mechanism for communicating amino acid availability through a GPCR to mTORC1 in mammals.

Multistep regulation of autophagy by WNK1.

The with-no-lysine (K) (WNK) kinases are an atypical family of protein kinases that regulate ion transport across cell membranes. Mutations that result in their overexpression cause hypertension-related disorders in humans. Of the four mammalian WNKs, only WNK1 is expressed throughout the body. We report that WNK1 inhibits autophagy, an intracellular degradation pathway implicated in several human diseases. Using small-interfering RNA-mediated WNK1 knockdown, we show autophagosome formation and autophagic flux are accelerated. In cells with reduced WNK1, basal and starvation-induced autophagy is increased. We also show that depletion of WNK1 stimulates focal class III phosphatidylinositol 3-kinase complex (PI3KC3) activity, which is required to induce autophagy. Depletion of WNK1 increases the expression of the PI3KC3 upstream regulator unc-51-like kinase 1 (ULK1), its phosphorylation, and activation of the kinase upstream of ULK1, the AMP-activated protein kinase. In addition, we show that the N-terminal region of WNK1 binds to the UV radiation resistance-associated gene (UVRAG) in vitro and WNK1 partially colocalizes with UVRAG, a component of a PI3KC3 complex. This colocalization decreases upon starvation of cells. Depletion of the SPS/STE20-related proline-alanine-rich kinase, a WNK1-activated enzyme, also induces autophagy in nutrient-replete or -starved conditions, but depletion of the related kinase and WNK1 substrate, oxidative stress responsive 1, does not. These results indicate that WNK1 inhibits autophagy by multiple mechanisms.

Recovery Mechanism of Degraded Black Phosphorus Field-Effect Transistors by 1,2-Ethanedithiol Chemistry and Extended Device Stability.

Black phosphorus (BP) has drawn enormous attention for both intriguing material characteristics and electronic and optoelectronic applications. In spite of excellent advantages for semiconductor device applications, the performance of BP devices is hampered by the formation of phosphorus oxide on the BP surface under ambient conditions. It is thus necessary to resolve the oxygen-induced degradation on the surface of BP to recover the characteristics and stability of the devices. To solve this problem, it is demonstrated that a 1,2-ethanedithiol (EDT) treatment is a simple and effective way to remove the bubbles formed on the BP surface. The device characteristics of the degraded BP field-effect transistor (FET) are completely recovered to the level of the pristine cases by the EDT treatment. The underlying principle of bubble elimination on the BP surface by the EDT treatment is systematically analyzed by density functional theory calculation, atomic force microscopy, and X-ray photoelectron spectroscopy analysis. In addition, the performance of the hexagonal boron nitride-protected BP FET is completely retained without changing device characteristics even when exposed to 30 d or more in air. The EDT-induced recovering effect will allow a new route for the optimization of electronic and optoelectronic devices based on BP.

Effect of weight loss on circulating fatty acid profiles in overweight subjects with high visceral fat area: a 12-week randomized controlled trial.

BACKGROUND: Significant associations between visceral fat and alterations in plasma fatty acids have been identified in overweight individuals. However, there are scant data regarding the relationships of the visceral fat area (VFA) with the plasma fatty acid profiles and desaturase activities following weight loss. We investigated the effect of weight loss with mild calorie restriction on the circulating fatty acid profiles and desaturase activities in nondiabetic overweight subjects with high VFA. METHODS: Eighty overweight subjects with high VFA (L4 VFA ≥100 cm2) were randomized into the 12-week mild-calorie-restriction (300 kcal/day) or control groups. RESULTS: Comparison of the percent of body weight changes between groups revealed that the weight-loss group had greater reductions in body weight. The VFA decreased by 17.7 cm2 from baseline in the weight-loss group (P < 0.001). At follow-up, the weight-loss group showed greater reductions in serum triglycerides, insulin, and HOMA-IR than the control group. Significantly greater reductions in total saturated fatty acids, palmitic acid, stearic acid, total monounsaturated fatty acids, palmitoleic acid, oleic acid, eicosadienoic acid, and dihomo-γ-linolenic acid levels were detected in the weight-loss group compared with the control group after adjusting for baseline values. Following weight loss, C16 Δ9-desaturase activity was significantly decreased and Δ5-desaturase activity was significantly increased, and the changes were greater in the weight-loss group than in the control group. CONCLUSIONS: The results suggest that mild weight loss improves abdominal obesity, overall fatty acid profiles, and desaturase activities; therefore, mild calorie restriction has potential health benefits related to obesity-related diseases in overweight subjects with high VFA. TRIAL REGISTRATION: NCT02992639. Retrospectively registered 11 December 2016.

Effects of Working Couple's Retirement Sequence on Satisfaction in Patriarchal Culture Country: Probing on Gender Difference.

We examined the effects of the differences in the retirement sequence (i.e., who retires first between spouses) on satisfaction in Korea of patriarchal culture. Our empirical study demonstrates that households where men retired first had a much lower satisfaction than households where women retired first. In addition, men were found to show lower satisfaction than wives in both households where women retire first and the households where men retire first. Retirement sequence affecting their satisfaction at the point when only one of the spouses is retired continues to affect their satisfaction after both of them are retired. This means that the difference in the couple's retirement sequence has an ongoing effect on their later happiness. The analysis of the effect of a couple's retirement sequence on the satisfaction in their old life may be useful for improving an individual and couples' quality of life in countries with similar cultures.

Effect of altered carrying angle on the medial-to-lateral activation ratio in the biceps brachii and triceps brachii.

[Purpose] The purpose of this research was to examine differences in muscle activity between the resting forearm position (RFP) and the straight forearm position (SFP) during upper arm strengthening exercises. [Participants and Methods] In total, 35 healthy college students were randomly sampled (18 males and 17 females). Surface electromyography data were collected from the medial and lateral sides of the biceps and triceps brachii muscles. [Results] The medial muscles showed greater activity during SFP versus RFP, but no difference in overall activation was found between the two positions. [Conclusion] Carrying angle less affected to biceps and triceps brachii muscles activation during upper arm strengthening exercises.

Development of a ssDNA aptamer for detection of residual benzylpenicillin.

Antibiotics are useful for improving the living conditions of livestock. However, residual antibiotics induce several human diseases such as food-borne illness and infection of carbapenem-resistant Enterobacteriaceae (CRE). In this study, the identification of a benzylpenicillin-specific aptamer was selected by rGO-SELEX (reduced Graphene Oxide-Systematic Evolution of Ligands by EXponential enrichment). A random ssDNA library was incubated with rGO for adsorption and eluted with benzylpenicillin. As a result of the selection process, a DNA aptamer was found that specifically bound to benzylpenicillin with high binding affinity, Kd = 383.4 nM, and had a low limit of detection (LOD) of 9.2 nM. The characterization of the aptamer was performed through the fluorescence recovery signal from rGO surface. In addition, detection of benzylpenicillin was performed in pretreated milk samples, and its detection accuracy was shown to be 100± 10%. This represented that BBA1 was used for fluorescence aptasensor system in real sample. Furthermore, this benzylpenicillin binding aptamer showed high specificity against other antibiotics except for ampicillin. With these advantageous characteristics, we expect that this aptamer could be applied to an on-site detection system for residual benzylpenicillin.

Association between increased visceral fat area and alterations in plasma fatty acid profile in overweight subjects: a cross-sectional study.

BACKGROUND: Visceral fat accumulation in overweight status has been resulted in changes of fatty acid profiles. The fatty acids profiles can be altered by fatty acid desaturase; the activity of which is highly associated with obesity and other metabolic diseases. We hypothesized that fatty acid composition, desaturase activity, and accumulation of visceral fat are interrelated. Thus, the aim of this study was to investigate the association between increased visceral fat area and alterations in plasma fatty acid profile in overweight subjects with different amounts of visceral fat. METHODS: Healthy overweight subjects (25.0 kg/m2 ≤ BMI < 30 kg/m2, n=232) were classified into lower (T1), middle (T2), and upper tertiles (T3) according to L4 visceral fat area (T1: <71.8 cm2, T2: 71.8 cm2-99.6 cm2, T3: >99.6 cm2). RESULTS: The T3 group showed higher amounts of cis-10-heptadecenoic acid and activity of C16 Δ9-desaturase and C18 Δ9-desaturase and lower activity of Δ5-desaturase than the T1 group. Additionally, the T3 group showed higher amounts of saturated fatty acids, myristic acid, palmitic acid, stearic acid, monounsaturated fatty acids, palmitoleic acid, oleic acid, n-6 polyunsaturated fatty acids, linoleic acid, dihomo-γ-linolenic acid, arachidonic acid, n-3 PUFAs, and docosapentaenoic acid than the T1 and T2 groups. CONCLUSIONS: This study indicates that greater than a certain area (>99.6 cm2) of visceral fat is needed to observe altered levels of individual fatty acid species and desaturase activities. The results suggest that increased activity of C16 Δ9-desaturase and C18 Δ9-desaturase in parallel with decreased Δ5-desaturase activity may be a causative factor in disturbed fatty acid metabolism.

The impact of city epidemics on rural labor market: The Korean Middle East Respiratory Syndrome case.

This study compared the changes in employment in urban areas in Korea, where a large number of people were quarantined by the Middle East Respiratory Syndrome epidemic, to those in rural areas, where only a small number of people were quarantined using the difference-in-difference approach. The results indicate that the urban labor market experienced a direct effect in terms of a reduction in employment of the group vulnerable to the epidemic while the rural labor market experienced an indirect effect on its economy through a reduction in employment resulting from a decline in consumption and leisure activities. If one looks into the employment in the accommodation and leisure industry, which sustained the most severe blow, dropped to its lowest level right after the Middle East Respiratory Syndrome outbreak. The rural leisure and accommodation industries are highly likely to be dependent on consumption and spending from urban areas. The results suggest that the rural labor market was influenced by the spillover/external effects caused by behavioral changes among people in urban areas due to fear of infection. Thus, this empirical analysis can be used to customize policy to support regions that can be negatively impacted by spillovers due to epidemic in order to respond against economic stresses.

The impact of epidemics on labor market: identifying victims of the Middle East Respiratory Syndrome in the Korean labor market.

BACKGROUND: The vulnerability approach suggests that disasters such as epidemics have different effects according not only to physical vulnerability but also to economic class (status). This paper examines the effect of the Middle East Respiratory Syndrome epidemic on the labor market to investigate whether vulnerable groups become more vulnerable due to an interaction between the socio-economic structure and physical risk. METHODS: This paper examines the effect of the Middle East Respiratory Syndrome epidemic on the labor market by considering unemployment status, job status, working hours, reason for unemployment and underemployment status. In particular, the study investigates whether the U-shaped curve becomes a J-shaped curve due to the interaction between medical vulnerability and labor market vulnerability after an outbreak, assuming that the relative vulnerability in the labor market by age shows a U curve with peaks for the young group and middle aged and old aged groups using the Economically Active Population Survey. We use the difference in difference approach and also conduct a falsification check and robustness check. RESULTS: The results suggest that older workers faced a higher possibility of unemployment after the Middle East Respiratory Syndrome outbreak. In particular, they experienced higher involuntary unemployment and underemployment status as well as decreased working hours. It was confirmed that the relative vulnerability of the labor market for older workers was higher than for the other age groups after the epidemic outbreak due to the double whammy of vulnerability in the medical and labor market. The vulnerability in the young group partially increased compared to the 30s and 40s age groups due to their relative vulnerability in the labor market despite being healthy. We find that assuming the relative vulnerability in the existing labor market shows a U shape with age increase, the U-shaped curve became J-shaped after the outbreak. CONCLUSIONS: Disasters like epidemics can occur unexpectedly and affect certain groups more than other. Therefore, medical protection should be enhanced for groups vulnerable to disease and economic measures are also required for the protection of their livelihoods in the labor market to prevent unemployment stemming from inequality.

Negative Pressure Wound Therapy on Closed Surgical Wounds With Dead Space: Animal Study Using a Swine Model.

BACKGROUND: Closed incisional wound surgery frequently leaves dead space under the repaired skin, which results in delayed healing. The purpose of this study was to evaluate the effect of negative pressure wound therapy (NPWT) on incisional wounds with dead space after primary closure by evaluating the fluid volume through the suction drain, blood flow of the skin, tensile strength, and histology of the wounds. METHODS: Bilateral 25-cm-long incisional wounds with dead space were created on the back of 6 pigs by partially removing the back muscle and then suturing the skin with nylon sutures. NPWT (experimental group) or gauze dressing (control group) was applied over the closed incision for 7 days. Analysis of the wound included monitoring the amount of closed suction drain, blood perfusion unit, tensile strength of the repaired skin, and histology of the incision site. RESULTS: The drainage amount was significantly reduced in the experimental group (49.8 mL) compared to the control group (86.2 mL) (P = 0.046). Skin perfusion was increased in the experimental group with statistical significance compared to the control group (P = 0.0175). Collagen staining was increased in the experimental group. The tensile strength of the incision site was significantly higher in the experimental group (24.6 N at 7 days, 61.67 N at 21 days) compared to the control group (18.26 N at 7 days, 50.05 N at 21 days) (P = 0.02). CONCLUSION: This study explains some of the mechanism for using NPWT in closed incision wounds with dead space. It demonstrates that NPWT significantly reduces drainage amount, increases skin perfusion, increases tensile strength, and has the tendency to promote collagen synthesis for closed wound with dead space indicating enhanced healing.

A Comparative Study on Retirement Process in Korea, Germany, and the United States: Identifying Determinants of Retirement Process.

This study classifies the retirement process and empirically identifies the individual and institutional characteristics determining the retirement process of the aged in South Korea, Germany, and the United States. Using data from the Cross-National Equivalent File, we use a multinomial logistic regression with individual factors, public pension, and an interaction term between an occupation and an education level. We found that in Germany, the elderly with a higher education level were more likely to continue work after retirement with a relatively well-developed social support system, while in Korea, the elderly, with a lower education level in almost all occupation sectors, tended to work off and on after retirement. In the United States, the public pension and the interaction terms have no statistically significant impact on work after retirement. In both Germany and Korea, receiving a higher pension decreased the probability of working after retirement, but the influence of a pension in Korea was much greater than that of Germany. In South Korea, the elderly workers, with lower education levels, tended to work off and on repeatedly because there is no proper security in both the labor market and pension system.

Raster-stereographic evaluation of the effects of biomechanical foot orthoses in patients with scoliosis.

[Purpose] Little is known about the effects of biomechanical foot orthoses in scoliosis, as determined by raster stereography. The objective of this study was to investigate the effect of individually manufactured biomechanical foot orthoses on scoliosis angle, trunk imbalance, and pelvic obliquity by comparing them with general insoles by using DIERS formetric 4 dimensional in patients with scoliosis. [Subjects and Methods] Twenty-six patients with scoliosis were recruited at Yeungnam University Hospital and allocated equally to one of two groups, the biomechanical foot orthoses group or the control group. Parameters, such as, trunk rotation, imbalance, and scoliosis angle, were obtained using a DIERS formetric 4D. [Results] Scoliosis angle, pelvic obliquity, and trunk imbalance were significantly different between the two groups and improved in the biomechanical foot orthoses group with time, but no significant improvement in any parameter was observed in the control group. [Conclusion] Biomechanical foot orthoses could be effective in patients with scoliosis, and DIERS formetric 4D provides a useful method for evaluating scoliosis parameters.

Enhanced osteoinductivity of recombinant human bone morphogenetic protein-2 in combination with epidermal growth factor in a rabbit tibial defect model.

This study aims to explore the effect of recombinant human bone morphogenetic protein-2 (rhBMP-2) on bone formation when treated with epidermal growth factor (EGF) using human mesenchymal stem cells (hMSCs) and a rabbit tibial defect model. The rhBMP-2 (250 ng/ml)+EGF (10 ng/ml) group showed higher alkaline phosphatase (ALP) activity, ALP expression, increased calcium amount than rhBMP-2 group. In micro-CT and histology results of animal experiments, the rhBMP-2+EGF group showed more amount of bone bridging compared to the rhBMP-2 group. Among the 8-week groups, the rhBMP-2+EGF group showed significantly higher percent bone volume and trabecular number compared to the rhBMP-2 group. The combined treatment with EGF and rhBMP-2 induced significantly higher bone formation compared to that of rhBMP-2 only in both hMSCs and a rabbit tibial defect model. Therefore, EGF is expected to facilitate bone formation effect of rhBMP-2 when both factors are treated in combination.

Protein kinase WNK3 regulates the neuronal splicing factor Fox-1.

We report an action of the protein kinase WNK3 on the neuronal mRNA splicing factor Fox-1. Fox-1 splices mRNAs encoding proteins important in synaptic transmission and membrane excitation. WNK3, implicated in the control of neuronal excitability through actions on ion transport, binds Fox-1 and inhibits its splicing activity in a kinase activity-dependent manner. Phosphorylation of Fox-1 by WNK3 does not change its RNA binding capacity; instead, WNK3 increases the cytoplasmic localization of Fox-1, thereby suppressing Fox-1-dependent splicing. These findings demonstrate a role of WNK3 in RNA processing. Considering the implication of WNK3 and Fox-1 in disorders of neuronal development such as autism, WNK3 may offer a target for treatment of Fox-1-induced disease.