Household-specific physical activity levels and energy intakes according to the presence of metabolic syndrome in Korean young adults: Korean National Health and nutrition examination survey 2016-2018.

BACKGROUND: Participation in exercise, and dietary and nutritional intakes have an impact on the risk and prevalence of metabolic syndrome (MetS), but these effects may differ according to whether a person lives alone or in a multi-person household. We analyzed differences in physical activity (PA) levels and energy intake according to household-type and MetS presence among young adults, to investigate the relationships among these factors. METHODS: Data of 3974 young adults (aged > 19 years and < 40 years) were obtained from the Korean National Health and Nutrition Examination Survey (2016-2018). We analyzed PA levels (occupational and recreational PA, and transport) and energy intake (total, carbohydrate, protein, and fat). RESULTS: Logistic regression data showed that low PA levels and higher energy intake were associated with MetS incidence and its components in young adults, after adjusting for body mass index, smoking, household-type, and sex. Overall, there was no significant difference in PA level between the MetS and non-MetS group. The total energy intake was higher in the MetS than in the non-MetS group (p <  0.05). These results were similar to those found in multi-person households. In single-person households, the MetS group had significantly lower PA levels (p <  0.01) and total energy intake (p <  0.05) than the non-MetS group. CONCLUSIONS: We found significant association among low PA levels, high energy intake, and MetS components in young Korean adults, but with patterns differing according to household type. Energy intake was higher in young adults with than those without MetS, who lived in multi-person households, while young adults with MetS who lived alone had lower PA levels and lower energy intake than those without MetS. These findings highlight the need for different approaches of implementing PA and nutrition strategies according to the type of household in order to prevent MetS.

ATR checkpoint kinase and CRL1ßTRCP collaborate to degrade ASF1a and thus repress genes overlapping with clusters of stalled replication forks.

Many agents used for chemotherapy, such as doxorubicin, interfere with DNA replication, but the effect of this interference on transcription is largely unknown. Here we show that doxorubicin induces the firing of dense clusters of neoreplication origins that lead to clusters of stalled replication forks in gene-rich parts of the genome, particularly on expressed genes. Genes that overlap with these clusters of stalled forks are actively dechromatinized, unwound, and repressed by an ATR-dependent checkpoint pathway. The ATR checkpoint pathway causes a histone chaperone normally associated with the replication fork, ASF1a, to degrade through a CRL1(ßTRCP)-dependent ubiquitination/proteasome pathway, leading to the localized dechromatinization and gene repression. Therefore, a globally active checkpoint pathway interacts with local clusters of stalled forks to specifically repress genes in the vicinity of the stalled forks, providing a new mechanism of action of chemotherapy drugs like doxorubicin. Finally, ASF1a-depleted cancer cells are more sensitive to doxorubicin, suggesting that the 7%-10% of prostate adenocarcinomas and adenoid cystic carcinomas reported to have homozygous deletion or significant underexpression of ASF1a should be tested for high sensitivity to doxorubicin.

Network-Based Approaches for Disease-Gene Association Prediction Using Protein-Protein Interaction Networks.

Genome-wide association studies (GWAS) can be used to infer genome intervals that are involved in genetic diseases. However, investigating a large number of putative mutations for GWAS is resource- and time-intensive. Network-based computational approaches are being used for efficient disease-gene association prediction. Network-based methods are based on the underlying assumption that the genes causing the same diseases are located close to each other in a molecular network, such as a protein-protein interaction (PPI) network. In this survey, we provide an overview of network-based disease-gene association prediction methods based on three categories: graph-theoretic algorithms, machine learning algorithms, and an integration of these two. We experimented with six selected methods to compare their prediction performance using a heterogeneous network constructed by combining a genome-wide weighted PPI network, an ontology-based disease network, and disease-gene associations. The experiment was conducted in two different settings according to the presence and absence of known disease-associated genes. The results revealed that HerGePred, an integrative method, outperformed in the presence of known disease-associated genes, whereas PRINCE, which adopted a network propagation algorithm, was the most competitive in the absence of known disease-associated genes. Overall, the results demonstrated that the integrative methods performed better than the methods using graph-theory only, and the methods using a heterogeneous network performed better than those using a homogeneous PPI network only.

ATP synthase inhibitory factor 1 (IF1), a novel myokine, regulates glucose metabolism by AMPK and Akt dual pathways.

ATPase inhibitory factor 1 (IF1) is an ATP synthase-interacting protein that suppresses the hydrolysis activity of ATP synthase. In this study, we observed that the expression of IF1 was up-regulated in response to electrical pulse stimulation of skeletal muscle cells and in exercized mice and healthy men. IF1 stimulates glucose uptake via AMPK in skeletal muscle cells and primary cultured myoblasts. Reactive oxygen species and Rac family small GTPase 1 (Rac1) function in the upstream and downstream of AMPK, respectively, in IF1-mediated glucose uptake. In diabetic animal models, the administration of recombinant IF1 improved glucose tolerance and down-regulated blood glucose level. In addition, IF1 inhibits ATP hydrolysis by ß-F1-ATPase in plasma membrane, thereby increasing extracellular ATP and activating the protein kinase B (Akt) pathway, ultimately leading to glucose uptake. Thus, we suggest that IF1 is a novel myokine and propose a mechanism by which AMPK and Akt contribute independently to IF1-mediated improvement of glucose tolerance impairment. These results demonstrate the importance of IF1 as a potential antidiabetic agent.-Lee, H. J., Moon, J., Chung, I., Chung, J. H., Park, C., Lee, J. O., Han, J. A., Kang, M. J., Yoo, E. H., Kwak, S.-Y., Jo, G., Park, W., Park, J., Kim, K. M., Lim, S., Ngoei, K. R. W., Ling, N. X. Y., Oakhill, J. S., Galic, S., Murray-Segal, L., Kemp, B. E., Mantzoros, C. S., Krauss, R. M., Shin, M.-J., Kim, H. S. ATP synthase inhibitory factor 1 (IF1), a novel myokine, regulates glucose metabolism by AMPK and Akt dual pathways.

WQ-3810 inhibits DNA gyrase activity in ofloxacin-resistant Mycobacterium leprae.

BACKGROUND: Mycobacterium leprae causes leprosy and ofloxacin is used to control this bacterium. However, specific amino acid substitutions in DNA gyrases of M. leprae interferes with the effect of ofloxacin. METHODOLOGY/PRINCIPAL FINDINGS: Here we tested the inhibitory effect of WQ-3810 on DNA gyrases in M. leprae, using recombinant gyrases. We theorized that WQ-3810 and DNA gyrases interacted, which was tested in silico. Compared with control drugs like ofloxacin, WQ-3810 showed a better inhibitory effect on ofloxacin-resistant DNA gyrases. The in-silico study showed that, unlike control drugs, a specific linkage between a R1 group in WQ-3810 and aspartic acid at position 464 in the subunit B of DNA gyrases existed, which would enhance the inhibitory effect of WQ-3810. This linkage was confirmed in a further experiment, using recombinant DNA gyrases with amino acid substitutions in subunits B instead. CONCLUSIONS/SIGNIFICANCE: The inhibitory effect of WQ-3810 was likely enhanced by the specific linkage between a R1 group residue in its structure and DNA gyrases. Using interactions like the one found in the present work may help design new fluoroquinolones that contribute to halt the emergence of antibiotic-resistant pathogens.

A Rapid Colorimetric Sensor for Soluble Interleukin-2 Receptor α, Based on Aptamer-Adsorbed AuNP.

The soluble interleukin-2 receptor α (sIL-2Rα) is a broad indicator of clinical disease activity in various inflammatory diseases. Here we have developed, for the first time, a rapid, washing-free colorimetric aptasensor based on a sIL-2Rα aptamer (Kd =1.33 nm). The aptasensor was fabricated with Au nanoparticles (AuNPs) adsorbing sIL-2Rα aptamers. On addition of sIL-2Rα, the aptamers become desorbed from the AuNPs, and this in turn weakens the absorption corresponding to AuNP-catalyzed oxidation of ortho-phenylenediamine (oPD) with H2 O2 . The aptasensor was characterized by TEM imaging, ζ potential measurements, dynamic light scattering (DLS) analysis, and UV/Vis spectrometry, followed by further optimization. The fabricated sensor exhibited great analytical performance, with a linear range of 1 to 100 nm and a detection limit of 1 nm both in buffer and in spiked human serum within 25 min. Other proteins, such as bovine serum albumin (BSA), IL-17Rα, IL-5Rα, IL-13Rα2 , and CD166, showed negligible effects on the aptasensor. Thanks to the great advantages of the aptamers and AuNPs, this aptasensor provides a rapid, simple, and inexpensive process that might offer insights into various diagnostic applications of sIL-2Rα.

CRL4(Cdt2) regulates cell proliferation and histone gene expression by targeting PR-Set7/Set8 for degradation.

PR-Set7/Set8 is a cell-cycle-regulated enzyme that monomethylates lysine 20 of histone H4 (H4K20). Set8 and monomethylated H4K20 are virtually undetectable during G1 and S phases of the cell cycle but increase in late S and in G2. We identify CRL4(Cdt2) as the principal E3 ubiquitin ligase responsible for Set8 proteolytic degradation in the S phase of the cell cycle, which requires Set8-PCNA interaction. Inactivation of the CRL4-Cdt2-PCNA-Set8 degradation axis results in (1) DNA damage and the induction of tumor suppressor p53 and p53-transactivated proapoptotic genes, (2) delayed progression through G2 phase of the cell cycle due to activation of the G2/M checkpoint, (3) specific repression of histone gene transcription and depletion of the histone proteins, and (4) repression of E2F1-dependent gene transcription. These results demonstrate a central role of CRL4(Cdt2)-dependent cell-cycle regulation of Set8 for the maintenance of a stable epigenetic state essential for cell viability.

Flow Cytometry-Based Quantification of Cellular Au Nanoparticles.

There has been a great deal of research regarding the cellular association of nanoparticles (NPs), although there are only a few methods available yet for the quantitative measurements of cellular NPs. In this study, we propose a simple and quantitative method to estimate the cellular uptake of Au NPs into cervical cancer cells (HeLa) based on their side scattering (SSC) intensities measured by flow cytometry (FCM). We have compared SSC intensities of HeLa cells exposed to eight different types of Au NPs (40-100 nm size, with positive or negative surface charge) with the amount of cellular Au NPs measured by inductively coupled plasma mass spectrometry (ICPMS). On the basis of these comparisons, we have found linear correlations between the cellular Au NPs and the SSC intensities and used them to estimate the amount of Au NPs associated with HeLa cells. Once the correlations were found for specific cell lines and types of nanoparticles, this approach is useful for simple and quantitative estimation of the cellular Au NPs, without performing labor-intensive and complicated sample preparation procedures required for the ICPMS approach.

Allogeneic Blood Transfusion Is a Significant Risk Factor for Surgical-Site Infection Following Total Hip and Knee Arthroplasty: A Meta-Analysis.

BACKGROUND: Blood loss occurs significantly more frequently during total hip and knee arthroplasty than among any other type of orthopedic operation, which can sometimes lead to requiring a blood transfusion. Although allogeneic blood transfusion has been identified as a risk factor for postoperative surgical-site infection following arthroplasty, results are inconclusive. The purpose of this study was to conduct a systematic meta-analysis to investigate whether having an allogeneic blood transfusion significantly increases the risk for surgical-site infection, particularly after total hip and knee arthroplasty. METHODS: We performed a systematic review and meta-analysis using random-effect models. Using an electronic database search, we selected 6 studies that included data on 21,770 patients and among these studies compared the postoperative infection rate between an allogeneic blood-transfusion exposure group and a nonexposure group. We calculated the pooled odds ratios and 95% confidence intervals for the groups. RESULTS: The prevalences of surgical-site infections in our pooled analyses were 2.88% and 1.74% for the transfusion and nontransfusion groups, respectively. The allogeneic blood transfusion group had a significantly higher frequency of surgical-site infections based on pooled analysis using a random-effect model (pooled odds ratio = 1.71, 95% confidence interval: 1.23-2.40, P = .002). CONCLUSION: Allogeneic blood transfusion is a significant risk factor for increasing the surgical-site infection rate after total hip and knee arthroplasty.

Accuracy of Estimating Step Counts and Intensity Using Accelerometers in Older People With or Without Assistive Devices.

The purpose of this study was to examine the accuracy of uni- and triaxial accelerometers in monitoring step counts and gait intensity in older people who did or did not use an assistive device. Forty-nine healthy and frail older adults wore uniaxial (Lifecorder, Suzuken Co. Ltd.) and triaxial accelerometers (Activity Monitor, Matsushita Electronic Works, Ltd., and Active Style Pro, Omron Healthcare Co., Ltd.) during three trials at different gait speeds. All accelerometers gave relatively accurate step counts for healthy older participants compared with direct observation; however, the error was greater for frail older people with assistive devices. Gait intensity detection error was unaffected by gait speed. Among frail older people with assistive devices, the gait intensity error was smaller than for step count error. To accurately assess the steps walked or the gait intensity among frail older people using assistive devices, more study is needed on these groups of participants.

IFT46 plays an essential role in cilia development.

Cilia are microtubule-based structures that project into the extracellular space. Ciliary defects are associated with several human diseases, including polycystic kidney disease, primary ciliary dyskinesia, left-right axis patterning, hydrocephalus and retinal degeneration. However, the genetic and cellular biological control of ciliogenesis remains poorly understood. The IFT46 is one of the highly conserved intraflagellar transport complex B proteins. In zebrafish, ift46 is expressed in various ciliated tissues such as Kupffer׳s vesicle, pronephric ducts, ears and spinal cord. We show that ift46 is localized to the basal body. Knockdown of ift46 gene results in multiple phenotypes associated with various ciliopathies including kidney cysts, pericardial edema and ventral axis curvature. In ift46 morphants, cilia in kidney and spinal canal are shortened and abnormal. Similar ciliary defects are observed in otic vesicles, lateral line hair cells, olfactory pits, but not in Kupffer׳s vesicle. To explore the functions of Ift46 during mouse development, we have generated Ift46 knock-out mice. The Ift46 mutants have developmental defects in brain, neural tube and heart. In particular Ift46(-/-) homozygotes displays randomization of the embryo heart looping, which is a hallmark of defective left-right (L/R) axis patterning. Taken together, our results demonstrated that IFT46 has an essential role in vertebrate ciliary development.

Oral proteasome inhibitor with strong preclinical efficacy in myeloma models.

BACKGROUND: The proteasome is a validated anti-cancer target and various small-molecule inhibitors are currently in clinical development or on the market. However, adverse events and resistance associated with those proteasome inhibitors indicate the need for a new generation of drugs. Therefore, we focused on developing an oral proteasome inhibitor with improved efficacy and safety profiles. METHOD: The in vitro inhibition of the 20S proteasome catalytic activities was determined in human multiple myeloma (MM) cellular lysates with fluorogenic peptide substrates specific for each catalytic subunit. Cell cytotoxicity was assessed with the ATP bioluminescence assay using human cell samples from tumor cell lines, MM patients or normal healthy donors. In mice bearing human MM xenografts, a single dose of LC53-0110 was administered orally, and concentration-time profiles of LC53-0110 and the 20S proteasome catalytic activities in plasma, blood, and tumor were determined. The efficacy of repeat-dose compound with regard to tumor growth inhibition in vivo was also evaluated in the same MM xenograft models. RESULTS: LC53-0110 is far more specific for the chymotrypsin-like proteolytic (ß5) site of the 20S proteasome as compared to bortezomib, carfilzomib, or ixazomib. LC53-0110 treatment showed accumulation of ubiquitinated proteins, inhibited cell viability with a low nM range potency in various tumor cell lines, and showed potent activity on CD138(+) cells isolated from MM patients who are resistant/refractory to current FDA-approved drug treatment. When a single dose was administered orally to tumor-bearing mice, LC53-0110 showed both greater maximum and sustained tumor proteasome inhibition as compared with ixazomib in MM xenograft models. The robust pharmacodynamic responses in tumor correlated with tumor growth regression. In addition, LC53-0151, an analog of LC53-0110, in combination with pomalidomide, a third-generation immunomodulatory drug, showed synergistic inhibition of tumor growth both in vitro and in the xenograft mouse model. CONCLUSIONS: In view of the in vitro, in vivo, and ex vivo profiles, further investigation of additional LC compounds in preclinical studies is warranted for the nomination of a clinical development candidate.

Effects of Pilates Exercise on Salivary Secretory Immunoglobulin A Levels in Older Women.

We examined the effects of a Pilates exercise program on the mucosal immune function in older women. The study population comprised 12 older women who were divided into a Pilates group (PG, n = 6) and a control group (CG, n = 6). Saliva samples were obtained from both groups before and after the experimental period for salivary secretory immunoglobulin A level measurement. In addition, acute high-intensity exercises were performed before and after the three-month Pilates exercise program. After three months, salivary flow was significantly higher in the PG than in the CG. After the acute high-intensity exercises were performed following the three-month Pilates exercise program, the salivary flow rate was significantly higher at all time points. The S-IgA secretion rate significantly increased 30 min after acute high-intensity exercise performed following the three-month Pilates exercise program. This study suggests that regular participation in a moderate-intensity Pilates exercise program can increase salivary flow rate and S-IgA secretion in older women.

MicroRNA-23a has minimal effect on endurance exercise-induced adaptation of mouse skeletal muscle.

Skeletal muscles contain several subtypes of myofibers that differ in contractile and metabolic properties. Transcriptional control of fiber-type specification and adaptation has been intensively investigated over the past several decades. Recently, microRNA (miRNA)-mediated posttranscriptional gene regulation has attracted increasing attention. MiR-23a targets key molecules regulating contractile and metabolic properties of skeletal muscle, such as myosin heavy-chains and peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PGC-1α). In the present study, we analyzed the skeletal muscle phenotype of miR-23a transgenic (miR-23a Tg) mice to explore whether forced expression of miR-23a affects markers of mitochondrial content, muscle fiber composition, and muscle adaptations induced by 4 weeks of voluntary wheel running. When compared with wild-type mice, protein markers of mitochondrial content, including PGC-1α, and cytochrome c oxidase complex IV (COX IV), were significantly decreased in the slow soleus muscle, but not the fast plantaris muscle of miR-23a Tg mice. There was a decrease in type IId/x fibers only in the soleus muscle of the Tg mice. Following 4 weeks of voluntary wheel running, there was no difference in the endurance exercise capacity as well as in several muscle adaptive responses including an increase in muscle mass, capillary density, or the protein content of myosin heavy-chain IIa, PGC-1α, COX IV, and cytochrome c. These results show that miR-23a targets PGC-1α and regulates basal metabolic properties of slow but not fast twitch muscles. Elevated levels of miR-23a did not impact on whole body endurance capacity or exercise-induced muscle adaptations in the fast plantaris muscle.

Deltoid muscle injury scratched by an osteophyte on the greater tuberosity of the humeral head: an unusual cause of shoulder pain.

Few reports to date have discussed acute deltoid muscle injury, including partial or complete deltoid muscle detachment from its origin. The present report describes a different pathomechanism and clinical manifestations of deltoid muscle injury. A 52-year-old man experienced acute severe pain in the right shoulder as a result of abrupt elevation of the arm. The deltoid muscle had apparently been scratched by an osteophyte on the greater tuberosity. After arthroscopic excision of the osteophyte, the symptoms resolved completely.

Postural stability in patients with anterior cruciate ligament tears with and without medial meniscus tears.

PURPOSE: To compare postural stability in patients with isolated anterior cruciate ligament (ACL) tears and ACL tears with associated meniscal tears. METHODS: Quadriceps and hamstring muscle strength and their ratio, as well as the relationships of these parameters with postural stability, were compared in 23 patients with isolated ACL tears and 27 with combined ACL and medial meniscus tears. Postural stability was determined from the anterior-posterior, medial-lateral, and overall stability indices using the Biodex Stability System. RESULTS: On both the involved and uninvolved sides, there were no differences in mean stability indices, including anterior-posterior, medial-lateral, and overall stability indices, in patients with isolated and combined ACL tears. In patients with isolated ACL tears, both overall (2.3 ± 1.2 vs. 1.8 ± 1.4, p = 0.033) and medial-lateral (1.2 ± 0.6 vs. 1.0 ± 0.5, p = 0.031) stability indices were significantly higher on the involved compared to the uninvolved side. These differences, however, were not observed in the combined ACL tear group. CONCLUSION: No significant differences in postural instability on the affected and unaffected sides were observed in patients with isolated ACL tears and those with combined ACL and medial meniscus tears. These findings indicate that there is no need to reduce the goal of restoring proprioception in patients with combined compared with isolated ACL tears. LEVEL OF EVIDENCE: III.

The relationship of body composition to daily physical activity in free-living Japanese adult men.

The objective of the present study was to investigate whether a previously reported apparent negative relationship between fat mass and daily physical activity in Japanese adult women would also be observed in Japanese adult men. The subjects were grouped into quartiles of BMI and body fat percentage (%BF). The number of steps walked each day and the duration of light- to vigorous-intensity physical activity were assessed by an accelerometer over the same period of time as for the doubly labelled water experiment. The results showed that BMI negatively correlated with the number of steps and time spent in moderate-intensity physical activity, whereas %BF showed a negative relationship with physical activity-related energy expenditure (PAEE)/body weight (BW) and physical activity level. The analysis of data using %BF quartiles revealed that PAEE/BW decreased from the second quartile in which the BMI was < 25 kg/m2. These observations are similar to those reported in our previous study in Japanese adult women. These cross-sectional studies cannot prove causality, and that obesity causes physical inactivity may be the case. However, the results of the present study provide information regarding which physical activity variables should be used in longitudinal studies.

Synovial osteochondromatosis in the subacromial bursa mimicking calcific tendinitis: sonographic diagnosis.

Synovial osteochondromatosis is an idiopathic benign metaplasia of the synovial membrane rarely found in an extra-articular bursa. We describe the case of a 55-year-old woman with synovial osteochondromatosis in the subacromial bursa mimicking calcific tendinitis. Plain radiographs showed a radiopaque mass over the middle facet of the greater tuberosity, suggesting calcific tendinitis. Sonography, however, showed a loose body in the subacromial bursa, and no evidence of calcification inside the rotator cuff.

Computational drug repositioning with attention walking.

Drug repositioning aims to identify new therapeutic indications for approved medications. Recently, the importance of computational drug repositioning has been highlighted because it can reduce the costs, development time, and risks compared to traditional drug discovery. Most approaches in this area use networks for systematic analysis. Inferring drug-disease associations is then defined as a link prediction problem in a heterogeneous network composed of drugs and diseases. In this article, we present a novel method of computational drug repositioning, named drug repositioning with attention walking (DRAW). DRAW proceeds as follows: first, a subgraph enclosing the target link for prediction is extracted. Second, a graph convolutional network captures the structural features of the labeled nodes in the subgraph. Third, the transition probabilities are computed using attention mechanisms and converted into random walk profiles. Finally, a multi-layer perceptron takes random walk profiles and predicts whether a target link exists. As an experiment, we constructed two heterogeneous networks with drug-drug similarities based on chemical structures and anatomical therapeutic chemical classification (ATC) codes. Using 10-fold cross-validation, DRAW achieved an area under the receiver operating characteristic (ROC) curve of 0.903 and outperformed state-of-the-art methods. Moreover, we demonstrated the results of case studies for selected drugs and diseases to further confirm the capability of DRAW to predict drug-disease associations.

Effects of water-table changes following rainfall events on arsenic fate and transport in groundwater-surface water mixing zones.

This study investigated the effects of groundwater-surface water (GW-SW) interactions on the fate and transport of arsenic (As) following rainfall events and subsequent water-table changes in GW-SW mixing zones, comprising the riparian and hyporheic zones, near an abandoned gold mine. During the dry and wet periods, stream conditions changed from flow-through to gaining, respectively. Water-table changes caused by rainfall events controlled flow paths between riparian zones and the stream, affecting spatiotemporal variation in the redox and pH conditions of the aquatic environment. Subsequently, the fate and transport of As in GW-SW mixing zones was responsive to variations in redox and pH conditions. Through the oxidative dissolution of As-bearing sulfide minerals and the reductive dissolution of iron (Fe) oxides with adsorbed As, As was released into the groundwater in the riparian zones and transported to the stream and streambed along the baseflow discharge. However, As was also immobilized in the sediment through adsorption onto Fe-oxides and coprecipitation with calcium (Ca) and zinc (Zn), suggesting that the sediment acts as a sink-and-source of As in aquatic environments. Therefore, water-table changes and GW-SW interactions could play an important role in the fate and transport of As in aquatic environments, specifically groundwater-riparian-streambed-stream systems. The findings of this study will provide scientific insights into the mechanisms of As in aquatic environments, aiding in improved decision-making to ensure safe and sustainable water management in response to future climate change.