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Evaluation of left ventricular global longitudinal strain (LVGLS) has allowed better characterization than left ventricular ejection fraction (LVEF) of subtle differences in left ventricular performance. The aim of this study was to determine whether LVGLS has prognostic value in patients with severe aortic stenosis and preserved LVEF undergoing transcatheter aortic valve implantation (TAVI).Among 412 consecutive patients who underwent TAVI, 344 patients (mean age, 78.9 ± 5.0 years; 161 men) with preserved LVEF (≥50%) at baseline were analyzed. Patients with low LVEF (50%) were used as a comparison group in the survival analysis. The primary and secondary end points were all-cause death and a composite of cardiovascular death and heart failure hospitalization, respectively.The mean LVGLS and LVEF were -17.1 ± 2.7% and 63 ± 5%, respectively. Impaired LVGLS was defined as -16%, which was the first LVGLS quartile (cutoff value, -16%). The estimated actuarial 5-year survival rate was 81.7 ± 4.2% in the normal LVGLS group and 66.8 ± 7.5% in the impaired LVGLS group (P = .005). In the multivariable analysis, impaired LVGLS was an independent predictor of all-cause death (adjusted hazard ratio, 2.26; 95% CI, 1.11-4.60) and the composite outcome (adjusted hazard ratio, 3.03; 95% CI, 1.45-6.33). Moreover, the impaired LVGLS group had a poor prognosis, similar to the impaired LVEF group (50%). The addition of the absolute value of LVGLS to the clinical parameters and LVEF led to significant improvement in the prediction of all-cause mortality.In patients with severe aortic stenosis and preserved LVEF undergoing TAVI, subclinical LV dysfunction defined by impaired LVGLS is independently associated with poor clinical outcomes. LVGLS measurement provides incremental prognostic value above the established clinical and echocardiographic parameters.

The adipose tissue is a key site regulating energy metabolism. One of the contributing factors behind this is browning of white adipose tissue (WAT). However, knowledge of the intracellular determinants of the browning process remains incomplete. By generating adipocyte-specific Senp2 knockout (Senp2-aKO) mice, here we show that SENP2 negatively regulates browning by de-conjugating small ubiquitin-like modifiers from C/EBPβ. Senp2-aKO mice are resistant to diet-induced obesity due to increased energy expenditure and heat production. Senp2 knockout promotes beige adipocyte accumulation in inguinal WAT by upregulation of thermogenic gene expression. In addition, SENP2 knockdown promotes thermogenic adipocyte differentiation of precursor cells isolated from inguinal and epididymal WATs. Mechanistically, sumoylated C/EBPβ, a target of SENP2, suppresses expression of HOXC10, a browning inhibitor, by recruiting a transcriptional repressor DAXX. These findings indicate that a SENP2-C/EBPβ-HOXC10 axis operates for the control of beige adipogenesis in inguinal WAT.

This paper aims to examine the relationship between progressive teaching practice and student academic and non-academic outcomes. The teacher development and leadership(TDL) program is a Qatari teacher development program that is a part of a wider global network(called “Global Network”) that aims to expand educational opportunities through teacher development with its roots in the United States. (Names of organizations have been changed for anonymity). The training model of TDL program is based on six themes: (1) orientation to student vision, (2) ongoing reflection to improve practice, (3) setting high expectations for students, (4) ensuring content rigor and mastery in students, (5) fostering positive culture and learning environment, and (6) building positive relationships with students. We used a dataset that includes aggregate student- and teacher-level data from 136 classrooms (with2,087 students) of 41 teachers between 2015 and 2017 to understand the relationship between teacher effectiveness and student outcomes. We found that establishing a positive rapport with students, practicing ongoing reflection, and internalizing learning are associated with higher academic achievement. We also found that incorporation of student vision for teaching practice is correlated with students having more positive attitude toward learning.

Aims This study aimed to assess the impact of valvular/subvalvular calcium burden on procedural and long-term outcomes in patients undergoing transcatheter aortic valve replacement (TAVR) for severe aortic stenosis (AS). Methods and results In this prospective observational cohort study, we included patients with AS undergoing TAVR between March 2010 and December 2019. Calcium burden at baseline was quantified using multidetector computed tomography and the patients were classified into tertile groups according to the amount of calcium. Procedural outcomes [paravalvular leakage (PVL) or permanent pacemaker insertion (PPI)] and 12-month clinical outcomes (composite of death, stroke, or rehospitalization, and all-cause mortality) were assessed. A total of 676 patients (age, 79.8 ± 5.4 years) were analysed. The 30-day rates of moderate or severe PVL (P-for-trend = 0.03) and PPI (P-for-trend = 0.002) proportionally increased with the tertile levels of calcium volume. The 12-month rate of primary composite outcomes was 34.2% in low-tertile, 23.9% in middle-tertile, and 25.8% in high-tertile groups (log-rank P = 0.02). After multivariable adjustment, the risk for primary composite outcomes at 12 months was not significantly different between the tertile groups of calcium volume [reference = low-tertile; middle-tertile, hazard ratio (HR) 0.81; 95% confidence interval (CI) 0.54–1.22; P = 0.31; high-tertile, HR 0.93; 95% CI 0.56–1.57; P = 0.80]. A similar pattern was observed for all-cause mortality. Conclusion The rates of PVL and PPI proportionally increased according to the levels of valvular/subvalvular calcium volume, while the adjusted risks for composite outcomes and mortality at 12 months were not significantly different.

ObjectiveThe decision to perform percutaneous mitral commissurotomy (PMC) on asymptomatic patients requires careful weighing of the potential benefits against the risks of PMC, and we conducted a multicentre, randomised trial to compare long-term outcomes of early PMC and conventional treatment in asymptomatic, severe mitral stenosis (MS).MethodsWe randomly assigned asymptomatic patients with severe MS (defined as mitral valve area between 1.0 and 1.5 cm2) to early PMC (84 patients) or to conventional treatment (83 patients). The primary endpoint was a composite of major cardiovascular events, including PMC-related complications, cardiovascular mortality, cerebral infarction and systemic thromboembolic events. The secondary endpoints were death from any cause and mitral valve (MV) replacement during follow-up.ResultsIn the early PMC group, there were no PMC-related complications. During the median follow-up of 6.4 years, the composite primary endpoint occurred in seven patients in the early PMC group (8.3%) and in nine patients in the conventional treatment group (10.8%) (HR 0.77; 95% CI 0.29 to 2.07; p=0.61). Death from any cause occurred in four patients in the early PMC group (4.8%) and three patients in the conventional treatment group (3.6%) (HR 1.30; 95% CI 0.29 to 5.77). Ten patients (11.9%) in the early PMC group and 17 patients (20.5%) in the conventional treatment group underwent MV replacement (HR 0.59; 95% CI 0.27 to 1.29).ConclusionsCompared with conventional treatment, early PMC did not significantly reduce the incidence of cardiovascular events among asymptomatic patients with severe MS during the median follow-up of 6 years.Trial registration numberNCT01406353.

Microbe-HCI is a community whose works implicate micro-organisms in HCI. This special interest group is a venue for the first gathering of the community, offering an opportunity for networking and structured discussions. It encourages participation from both active and new researchers to microbe-HCI, with the objective of acquiring an overview of people, themes, trends, and prospective research pathways for the community.

A museum exhibit that enables direct full-body interactions with living microbes immerses human visitors into the microscopic world and could inform the design of future educational life-science technologies.

Objective To evaluate correlations between values of articulation tests and language tests for children with articulation disorder in Korea. Methods Data of outpatients with chief complaint of an articulation problem were retrospectively collected. Patients who underwent Urimal Test of Articulation and Phonation (U-TAP) with Assessment of Phonology and Articulation for Children (APAC), Preschool Receptive-Expressive Language Scale (PRES), or Receptive and Expressive Vocabulary Test (REVT) simultaneously were identified. Patients whose word-level percentages of correct consonants in U-TAP (UTAP_wC) were more than 2 standard deviations below the mean as diagnostic criteria for articulation disorder were selected. Those whose receptive language age (P_RLA), expressive language age (P_ELA), or combined language age (P_CLA) in PRES was delayed more than 24 months compared to their chronological age in months as diagnostic criteria for language disorder were excluded. Results Thirty-three children aged 3-6 years were enrolled retrospectively. PRES and U-TAP showed significant correlations for most of value relationships. PRES and APAC showed significant correlations for all value relationships except for receptive language age. All values of REVT were significantly correlated with all values from U-TAP, but not with any value from APAC. Articulation tests U-TAP and APAC showed significant correlations between percentages of correct consonants. Language tests PRES and REVT showed significant correlations for all value relationships. Conclusion This study suggests that articulation abilities and language abilities might be correlated in children with articulation disorder.

All-trans-retinoic acid (ATRA) has been well described as a positive regulator for early stage of adipocyte differentiation and lipid metabolism and also linked to an in vivo fat-lowering effect in mice. However, not all studies support this association. Our objective was to characterize the action of ATRA in mature adipocytes of mice by ablating RAR signaling through overexpression of a well-characterized dominant negative RARα mutant (RARdn) form specifically in adipocytes. Altered RAR signaling in adipocytes resulted in a significant decrease in ATRA levels in visceral and brown adipose tissues as well as liver tissue. This was linked to significant impairments in glucose clearance and elevated hepatic lipid accumulation for chow diet fed mice, indicating the development of metabolic disease, including hepatic steatosis. In addition, we found that adipose RARdn expression in mice fed a chow diet decreased thermogenesis. We conclude that altered RAR signaling and ATRA levels in adipocytes impacts glucose and lipid metabolism in mice.

Background and purpose In addition to the central nervous system-mediated action, leptin also directly induces fatty acid oxidation in skeletal muscle. Rapid induction of FAO by leptin is mediated by the AMP-activated protein kinase (AMPK) pathway, but the mechanism of prolonged FAO by leptin was previously unknown. In an earlier study, we showed that free fatty acids increase transcription of small ubiquitin-like modifier (SUMO) specific protease 2 (SENP2) in skeletal muscle, and that SENP2 stimulates expression of FAO-associated enzymes by deSUMOylating peroxisome proliferator-activated receptors, PPARδ and PPARγ. In this study, we examine whether SENP2 is involved in prolonged stimulation of FAO by leptin. Methods The Effect of leptin on expression of SENP2 and on SENP2-mediated FAO was investigated by using western blotting and real time qPCR of C2C12 myotubes, and of C2C12 myotubes in which expression of specific genes was knocked down using siRNAs. Additionally, muscle-specific SENP2 knockout mice were generated to test the involvement of SENP2 in leptin-induced FAO in vivo. Results We show that leptin treatment of C2C12 myotubes causes signal transducer and activator of transcription 3 (STAT3) to bind to the Senp2 promoter, inducing SENP2 expression. We also show that leptin increases the binding of PPARδ and PPARγ to PPRE sites in the promoters of two FAO-associated genes: long-chain acyl-CoA synthetase 1 (Acsl1) or carnitine palmitoyl transferase 1b (Cpt1b). When SENP2 is knocked down in myotubes, leptin-induced expression of FAO-associated enzymes and prolonged increase of FAO are suppressed, but rapid increase of FAO is unaffected. In addition, leptin-induced expression of FAO-associated enzymes was not observed in muscle tissue of SENP2 knockout mice. Conclusions We demonstrate that the peripheral actions of leptin on FAO are mediated by two different pathways: AMPK causes a rapid increase in FAO, and SENP2 of the STAT3 pathway causes a slow, prolonged increase in FAO.

Aortic valve (AV) replacement (AVR) is the only effective treatment for severe aortic stenosis (AS). However, survival benefits by performing AVR in asymptomatic AS patients with preserved left ventricular (LV) function remains controversial. This study included 468 patients (aged 64.2 ± 13.0 years, 232 women) with preserved LV function (≥50%) and severe AS (AV area ≤1.0 cm2, peak trans-AV velocity [Vmax] ≥4.0 m/s, or mean AV pressure gradient ≥40 mm Hg) between 2000 and 2015. AVR was performed in 221 (47.2%) patients early (within 3 months; n = 130, 27.8%) or during follow-up (n = 91, 19.4%), whereas the remainder (n = 247) received medical treatment. Time-dependent Cox regression analyses were performed to determine the impact of AVR on long-term survival outcomes. During a median follow-up of 60.9 months (quartile 1 to 3, 29.9 to 107.0 months), 72 (15.4%) patients developed AS-related symptoms and 146 (31.2%) died. On time-dependent Cox models, AVR was associated with a significant risk reduction in all-cause death (hazard ratio [HR], 0.62; 95% confidence interval [CI], 0.40 to 0.97; p = 0.036) and cardiac death (HR, 0.59; 95% CI, 0.35 to 0.995; p = 0.048) after adjusting for significant contributors to mortality. Survival benefits by performing AVR were manifested in most risk subgroups. In conclusion, AVR in asymptomatic severe AS patients with preserved LV function resulted in significant survival benefits, suggesting that early recruitment for AVR may be warranted before ventricular dysfunction or symptom development.

Deregulation of the cyclin D‐CDK4/6‐INK4‐RB pathway leading to uncontrolled cell proliferation, is frequently observed in breast cancer. Currently, three selective CDK4/6 inhibitors have been FDA approved: palbociclib, ribociclib and abemaciclib. Despite promising clinical outcomes, intrinsic or acquired resistance to CDK4/6 inhibitors has limited the success of these treatments; therefore, the development of various strategies to overcome this resistance is of great importance. We highlight the various mechanisms that are directly or indirectly responsible for resistance to CDK4/6 inhibitors, categorizing them into two broad groups; cell cycle‐specific mechanisms and cell cycle‐nonspecific mechanisms. Elucidation of the diverse mechanisms through which resistance to CDK4/6 inhibitors occurs, may aid in the design of novel therapeutic strategies to improve patient outcomes. This review summarizes the currently available knowledge regarding mechanisms of resistance to CDK4/6 inhibitors, and possible therapeutic strategies that may overcome this resistance as well.

In menopausal women, estrogen deficiency closely affects bone health. Previous studies report that MS-10, a combined extract of Cirsium japonicum and Thymus vulgaris, increases the efficiency of estrogen by activating the estrogen receptor. Here, the ability of MS-10 to enhance bone health and quality of life in women with menopausal symptoms was tested. Treatment with MS-10 induced alterations in the gene expression profile related with bone health of SaOS-2 osteoblast-like cells. MS-10 increased alkaline phosphatase (ALP) activity and osteocalcin, and reduced tartrate-resistant acid phosphatase (TRACP) activity in osteoblast-like cells. A clinical study showed that treatment with MS-10 (500 mg/day for 3 months) led to a significant decrease in ALP and osteocalcin levels. Also, women’s scores on the Menopause-Specific Quality of Life questionnaire that takes into account vasomotor, psychosocial, physical, and sexual health, improved by 18.8%. In conclusion, the herbal material MS-10 may improve menopausal symptoms, including bone health.

The possibility of preventing dental caries by taking probiotic bacterium Weissella cibaria (W. cibaria) CMU tablets to alter the pH of the dental plaque in the oral cavity was evaluated. A randomized, double-blind, placebo-controlled trial was performed on adults aged 20 years or older with 20 or more natural teeth. Ninety-two people underwent dental scaling before being randomly assigned to the experimental group (n = 49) or the control group (n = 43). Depending on the group they belonged to, W. cibaria CMU or the placebo was administered to them once daily for 8 weeks before bedtime. Twenty-four subjects were later excluded from the study because the week 8 dosing was not smoothly performed, for a final subject count of 68. The Cariview test was used to evaluate the amount of acid produced by the dental plaque to assess the risk of caries. The results showed that although there was no significant difference between the results of the two groups, the intake of the W. cibaria CMU tablets eliminated the risk of developing dental caries from acid production in the oral flora because the W. cibaria colonizes and lives in the dental plaque and the oral cavity and suppresses acids.

Severe pulmonary hypertension (PHT) is a contraindication to liver transplantation (LT); however, the prognostic implication of mild to moderate PHT in living-donor LT (LDLT) is unknown. The study cohort retrospectively included 1307 patients with liver cirrhosis who underwent LDLT. PHT was defined as a mean pulmonary artery pressure (PAP) of ≥25 mmHg, measured intraoperatively just before surgery. The primary endpoint was graft failure within 1 year after LDLT, including retransplantation or death from any cause. The secondary endpoints were in-hospital adverse events. In the overall cohort, the median Model for End-stage Liver Disease-Sodium (MELD-Na) score was 19, and 100 patients (7.7%) showed PHT. During 1-year follow-up, graft failure occurred in 94 patients (7.2%). Patients with PHT had lower 1-year graft survival (86% vs. 93.4%, P = 0.005) and survival rates (87% vs. 93.6%, P = 0.011). Mean PAP was associated with a high risk of in-hospital adverse events and 1-year graft failure. Adding the mean PAP to the clinical risk model improved the risk prediction. In conclusion, mild to moderate PHT was associated with higher risks of 1-year graft failure and in-hospital events, including mortality after LDLT in patients with liver cirrhosis. Intraoperative mean PAP can help predict the early clinical outcomes after LDLT.

Clinical advantages of sutureless rapid-deployment (RD) aortic valve replacement (AVR) for severe aortic valve stenosis (AS) have not been elucidated compared with surgical (SAVR) or transcatheter (TAVR) aortic valve replacement.This study sought to investigate comparative effectiveness and safety of RD-AVR compared with SAVR and TAVR in a prospective cohort of patients with severe AS.The primary outcome was a composite of death, stroke, or rehospitalization at 12 months. Propensity score matching was used to assemble a cohort of patients with similar baseline characteristics.Among 1,020 eligible patients, 107 (10.5%) underwent RD-AVR, 437 (42.8%) underwent SAVR, and 476 (46.7%) underwent TAVR. In the matched cohorts of RD-AVR and SAVR (n = 107), the incidence of primary composite outcome at 12 months was similar between the 2 groups (8.0% vs 10.8%, respectively; hazard ratio [HR]: 0.74; 95% confidence interval [CI]: 0.30-1.84;In this propensity-matched cohort of patients who underwent AVR for severe AS, we did not detect significant differences in the rates of the primary composite of death, stroke, or rehospitalization at 12 months when comparing RD-AVR with SAVR and TAVR. Because the study was underpowered, the results should be considered as hypothesis generating highlighting the need for further research. (ASAN Medical Center Aortic Valve Replacement Registry [ASAN-AVR]; NCT03298178).

Immediate improvement in left ventricular ejection fraction (LVEF) following transcatheter aortic valve implantation (TAVI) is common; however, data on the pattern and prognostic value of this improvement are limited. To evaluate the incidence, predictors, and clinical impact of immediate improvement in LVEF, we studied 694 consecutive patient who had underwent successful TAVI for severe aortic stenosis (AS) between March 2010 and December 2019. We defined immediate improvement of LVEF as an absolute increase of ≥5% in LVEF at post-procedure echocardiogram. The primary outcome was major adverse cardiac or cerebrovascular event (MACCE), defined as a composite of death from cardiovascular cause, myocardial infarction, stroke, or rehospitalization from cardiovascular cause. Among them, 160 patients showed immediate improvement in LVEF. The independent predictors of immediate LVEF improvement were absence of hypertension and baseline significant aortic regurgitation, and greater baseline LV mass index. Immediate improvement in LVEF was significantly associated with a lower risk of MACCE (adjusted hazard ratio, 0.48; 95% confidence interval, 0.28–0.81; p = 0.01). In conclusion, approximately one-fourth of patients with severe AS who underwent TAVI showed immediate improvement in LVEF during index hospitalization. Immediate LVEF recovery was associated with a lower risk of MACCE during follow-up.

Altogether, 81% of Korean college students experience halitosis and concomitant psychosocial problems such as depression and lowered self-esteem, as well as poor oral-health-related quality of life. Although halitosis causes many social and psychological problems among college students, there have been no reports of improvement interventions. This study aimed to identify the effects of ingesting tablets of the oral probiotic Weissella cibaria CMU (Chonnam Medical University, Gwangju, Korea) on halitosis and examine its effects on psychosocial indicators. This was a randomized, double-blind, placebo-controlled trial. The participants were randomly assigned to the experimental group or the control group. They ingested W. cibaria CMU or the placebo, depending on which group they belonged to, before going to bed daily for eight weeks. The measured indicators were subjective halitosis, subjective oral-health status, depression, self-esteem, and oral-health-related quality of life. Measurements were at baseline and eight weeks later. The participants showed statistically significant differences in subjective halitosis and oral-health-related quality of life. For college students with halitosis, intake of the oral probiotic for eight weeks could be a useful nursing intervention for reducing halitosis and improving oral-health-related quality of life.

How is Christianity discussed in textbooks as societies entered the modern era? To what extent do textbooks reflect the changes and continuities in societal worldviews and values? This chapter examines discussion of religion, science, and notions of progress in secondary school social science textbooks in the US and Canada from 1850 to 2010, using data coded from 527 textbooks. Consistent with expectations for secularizing societies, we find that discussion of religion declines over time. However, we find the extent to which Christianity is discussed and portrayed differs in the US and Canadian textbooks. Our findings suggest that discussion of Christianity in Canadian textbooks is higher than that in the US textbooks in the late nineteenth and early twentieth centuries but that discussion of religious topics decline rapidly in Canadian textbooks compared to those in the United States. Simultaneously, we observe a rise of secular morality reflecting values of progressivism in textbooks although Christian principles and values appear to be associated with notions of progress, especially in the United States. What this suggests is a shift from Christian to secular morality but with persistent links to religious values rather than values-neutral scientific emphases.

About 99 percent of cryptocurrency trades occur on organised exchanges and many investors subsequently keep their digital assets in accounts with cryptocurrency markets. This generates exposure to the risk of exchange closures. We construct a database containing eight key characteristics on 238 cryptocurrency exchanges and employ machine learning techniques to predict whether a cryptocurrency market will remain active or whether it will go out of business. Both in-sample and out-of-sample measures of forecasting performance are computed and ranked for four popular machine learning algorithms. While all four models produce satisfactory classification accuracy, our best model is a random forest classifier. It reaches accuracy of 90.4 percent on training data and 86.1 percent on test data. From the list of predictors we find that exchange lifetime, transacted volume and cyber security measures such as security audit, cold storage and bug bounty programs rank high in terms of feature importance across multiple algorithms. On the other hand, whether an exchange has previously experienced a security breach does not rank highly according to its contribution to classification accuracy.

Background Sarcopenia, known as physical frailty, is highly prevalent in older patients and is related to adverse outcomes post-cardiac surgery. However, whether sarcopenia assessment can reclassify an individual patients’ risk, which is estimated by Society of Thoracic Surgeons-predicted risk of mortality scores in patients who undergo surgical aortic valve replacement, is unclear. Methods This retrospective, single center, cohort study comprised 874 patients aged ≥65 years who underwent surgical aortic valve replacement between 2009 and 2016. Total skeletal muscle area was calculated using height-squared and was measured by preoperative computed tomography at the third lumbar vertebra inferior border using machine learning-based analysis. Sex-specific Z-scores were calculated and patients in the lowest Z-score tertile were considered to have sarcopenia. The primary endpoint was 30-day mortality, and secondary endpoints were in-hospital events, 1-year mortality, and long-term mortality. Results Thirty-day mortality, 30-day in-hospital events, and one-year mortality rates were 4.7%, 17.6%, and 8.0%, respectively. As the Z-score decreased, early adverse event odds showed a stepwise increase. Sarcopenia were independently associated with higher 30-day mortality, 30-day in-hospital events, and 1-year mortality. Reclassification analyses showed improvements in the ability to predict early adverse events after adding the Z-scores over and above the Society of Thoracic Surgeons-predicted risk of mortality scores (All, p Conclusions Sarcopenic patients had significantly higher risks of early adverse events and long-term mortality after undergoing surgical aortic valve replacement than non-sarcopenic patients. Sarcopenia determined by preoperative computed tomography can enhance the prediction of postoperative outcome risk.

This study presents a system for assessing the freshness of meat with electrical impedance spectroscopy (EIS) in the frequency range of 125 Hz to 128 kHz combined with an image classifier for non-destructive and low-cost applications. The freshness standard is established by measuring the aerobic plate count (APC), 2-thiobarbituric acid reactive substances (TBARS), and composition analysis (crude fat, crude protein, and moisture) values of the microbiological detection to represent the correlation between EIS and meat freshness. The EIS and images of meat are combined to predict the freshness with the Adaboost classification and gradient boosting regression algorithms. As a result, when the elapsed time of beef storage for 48 h is classified into three classes, the time prediction accuracy is up to 85% compared to prediction accuracy of 56.7% when only images are used without EIS information. Significantly, the relative standard deviation (RSD) of APC and TBARS value predictions with EIS and images datum achieves 0.890 and 0.678, respectively.

We investigate label-free measurement of molecular distribution by super-resolved Raman microscopy using surface plasmon (SP) localization. Localized SP was formed with plasmonic nanopost arrays (PNAs) for measurement of the molecular distribution in HeLa cells. Compared with conventional Raman microscopy on gold thin films, PNAs induce a localized near-field, which allows for the enhancement of the peak signal-to-noise ratio by as much as 4.5 dB in the Raman shifts. Super-resolved distributions of aromatic amino acids and lipids (C-C stretching and C-H2 twist mode) as targets in HeLa cells were obtained after image reconstruction. Results show almost 4-fold improvement on average in the lateral precision over conventional diffraction-limited Raman microscopy images. Combined with axial imaging in an evanescent field, the results suggest an improvement in optical resolution due to superlocalized light volume by more than an order of magnitude over that of conventional diffraction-limited Raman microscopy.

There is limited data regarding the association between sarcopenia and clinical outcomes in patients who underwent transcatheter aortic valve implantation (TAVI). From the prospective ASAN-TAVI registry, we evaluated a total of 522 patients with severe aortic stenosis who underwent TAVI between March 2010 and November 2018. Routine pre-TAVI computed tomography scan was used to calculate the skeletal muscle index (SMI), which was defined as skeletal muscle area at the L3 level divided by height squared; subject patients were classified into the gender-specific tertile groups of SMI. The patients' mean age was 79 years and 49% were men. Mean SMI values were 41.3 ± 6.7 cm2/m2 in men and 34.1 ± 6.5 cm2/m2 in women. The Kaplan-Meier estimates of all-cause mortality at 12 months were higher in the low-tertile group than in the mid- and high-tertile groups (15.5%, 7.1%, and 6.2%, respectively; p = 0.036). In multivariate analysis, low-tertile of SMI was an independent predictor of mortality (vs high-tertile of SMI, hazard ratio 2.69; 95% confidence interval, 1.18 to 6.12; p = 0.019). The all-cause mortality was substantially higher in the groups with high-surgical risk plus low SMI tertile. The risk assessment with addition of SMI on conventional STS-PROM score was significantly improved by statistical measures of model reclassification and discrimination. In patients who underwent TAVI, sarcopenia measured by SMI was significantly associated with an increased risk of 1-year mortality. The prognostic impact of SMI-measured sarcopenia was more prominent in patients with high surgical risks.

Soft tissue reconstruction of head and neck defects is a broad, challenging task. The key to a successful operation is choosing an appropriate reconstructive option based on the location, size, and characteristics of the defect. This chapter describes the main principles to consider when deciding on a primary reconstructive option for the defects created by oncologic resection. These principles include placing scars in relaxed skin tension line, minimizing donor defects, and reconstructing entire facial aesthetic subunits. This chapter also focuses on the reconstruction methods that maximize function and minimize aesthetic deformity.

Background: Recently, cyclin-dependent kinase (CDK) 4/6 inhibitors have been widely used to treat advanced hormone receptor-positive breast cancer. Despite promising clinical outcomes, almost all patients eventually acquire resistance to CDK4/6 inhibitors. Hence, understanding the mechanisms of acquired resistance to CDK4/6 inhibitors is crucial for developing alternative treatment strategies. Therefore, the present study screened genes associated with palbociclib resistance through genomics and transcriptomics in preclinical breast cancer models. Methods: Palbociclib-resistant cells, MCF7-PR and T47D-PR, were generated by exposing MCF7 and T47D cells to palbociclib. After confirming acquired resistance through in vitro assays, whole-exome sequencing (WES) and mRNA microarray were performed to compare the genomic and transcriptomic landscape between palbociclib-sensitive and resistant cells. Real time-PCR was performed to confirm differentially expressed genes.Results: Microarray analysis comparing MCF7 and MCF7-PR cells revealed 651 differentially expressed genes (DEGs) (fold change >2 or Conclusions: Palbociclib resistance was found to be associated with deregulated immune pathway in preclinical breast cancer models. Further studies are warranted to evaluate whether immune pathways may be a therapeutic target to overcome CDK4/6 inhibitor resistance.

BackgroundWell-characterized preclinical models are essential for immune-oncology research. We investigated the feasibility of our humanized mouse model for evaluating the long-term efficacy of immunotherapy and biomarkers.MethodsHumanized mice were generated by injecting human fetal cord blood-derived CD34+ hematopoietic stem cells to NOD-scid IL2rγnull (NSG) mice myeloablated with irradiation or busulfan. The humanization success was defined as a 25% or higher ratio of human CD45+ cells to mice peripheral blood mononuclear cells.ResultsBusulfan was ultimately selected as the appropriate myeloablative method because it provided a higher success rate of humanization (approximately 80%) and longer survival time (45 weeks). We proved the development of functional T cells by demonstrating the anticancer effect of the programmed cell death-1 (PD-1) inhibitor in our humanized mice but not in non-humanized NSG mice. After confirming the long-lasting humanization state (45 weeks), we further investigated the response durability of the PD-1 inhibitor and biomarkers in our humanized mice. Early increase in serum tumor necrosis factor α levels, late increase in serum interleukin 6 levels and increase in tumor-infiltrating CD8+ T lymphocytes correlated more with a durable response over 60 days than with a non-durable response.ConclusionsOur CD34+ humanized mouse model is the first in vivo platform for testing the long-term efficacy of anticancer immunotherapies and biomarkers, given that none of the preclinical models has ever been evaluated for such a long duration.

ObjectivesAlthough the incidence of patients with isolated tricuspid regurgitation (TR) is increasing, data regarding the clinical outcomes of isolated TR surgery are limited. This study sought to investigate the prognostic implications according to procedural types, and to identify preoperative predictors of clinical outcomes after isolated TR surgery.MethodsAmong consecutive 2610 patients receiving tricuspid valve (TV) procedure, we analysed 238 patients (age, 59.6 years; 143 females) who underwent stand-alone TV surgery (repair, 132; replacement, 106) for severe TR. Primary outcome was the composite of all-cause mortality and heart transplantation. Clinical outcomes between the repair and the replacement groups were compared after adjusting with the inverse probability of treatment weighting (IPTW) method.ResultsDuring follow-up (median, 4.1 years), 53 patients died and 4 received heart transplantation. Multivariable analysis revealed that age (p=0.001), haemoglobin level (p=0.003), total bilirubin (p=0.040), TR jet area (p=0.005) and right atrial (RA) pressure (p=0.022) were independent predictors of the primary outcome. After IPTW adjustment, there were no significant intergroup differences in the risk of primary outcome (HR 1.01; 95% CI 0.55 to 1.87). In the subgroup analysis, tricuspid annular diameter was identified as a significant effect modifier (p=0.012) in the comparison between repair versus replacement, showing a trend favouring replacement in patients with annular diameter >44 mm.ConclusionsThe outcomes of stand-alone severe TR surgery were independently associated with the severity of TR and RA pressure. In selected patients with severe annular dilation >44 mm, replacement may become a feasible option.

Background Weissella cibaria CMU (oraCMU) has been commercially available in the market for several years as oral care probiotics. The present study aimed to evaluate the effects of oraCMU-containing tablets on periodontal health and oral microbiota. Methods A randomised, double-blind, placebo-controlled trial was conducted in 92 adults without periodontitis (20–39 years of age). All subjects received dental scaling and root planing, and were randomly assigned to either probiotic or placebo groups. The tablets were administered once daily for 8 weeks. Periodontal clinical parameters included bleeding on probing (BOP), probing depth (PD), gingival index (GI), and plaque index (PI). In addition, microbiota in the gingival sulcus were analysed. Results BOP improved more in the probiotic group over 8 weeks. There were statistically significant differences in BOP of the maxilla buccal and lingual sites between the groups during the intervention (P Fusobacterium nucleatum at four and 8 weeks between the two groups. Besides, there were significant differences at 8 weeks in levels of Staphylococcus aureus. Conclusions We reported an improvement in BOP and microbial environment and demonstrated the antimicrobial activity of oraCMU against F. nucleatum. Thus, its supplementation may contribute to overall oral health. Trial registration Ethical issues approved by the Kangwon National University Institutional Review Board with a number of KWNUIRB-2018-05-003-005 and CRIS code Number of KCT0005078 were retrospectively registered on 06/02/2020. This study was conducted in the period of July to November 2018.

Halitosis is referred to as an unpleasant odor coming from the mouth. Recently, probiotics have been studied as an alternative prevention for halitosis. The aim of this study was to evaluate the effects of probiotic bacterium

ObjectiveTo evaluate whether the use of dipeptidyl peptidase-4 (DPP-4) inhibitors and their cardiac tissue distribution profile and anticalcification abilities are associated with risk of aortic stenosis (AS) progression.MethodsOut of the five different classes of DPP-4 inhibitors, two had relatively favourable heart to plasma concentration ratios and anticalcification ability in murine and in vitro experiments and were thus categorised as ‘favourable’. We reviewed the medical records of 212 patients (72±8 years, 111 men) with diabetes and mild-to-moderate AS who underwent echocardiographic follow-up and classified them into those who received favourable DPP-4 inhibitors (n=28, 13%), unfavourable DPP-4 inhibitors (n=69, 33%) and those who did not receive DPP-4 inhibitors (n=115, 54%).ResultsMaximal transaortic velocity (Vmax) increased from 2.9±0.3 to 3.5±0.7 m/s during follow-up (median, 3.7 years), and the changes were not different between DPP-4 users as a whole and non-users (p=0.143). However, the favourable group showed significantly lower Vmax increase than the unfavourable or non-user group (p=0.018). Severe AS progression was less frequent in the favourable group (7.1%) than in the unfavourable (29.0%; p=0.03) or the non-user (29.6%; p=0.01) group. In Cox regression analysis after adjusting for age, baseline renal function and AS severity, the favourable group showed a significantly lower risk of severe AS progression (HR 0.116, 95% CI 0.024 to 0.551, p=0.007).ConclusionsDPP-4 inhibitors with favourable pharmacokinetic and pharmacodynamic properties were associated with lower risk of AS progression. These results should be considered in the preparation of randomised clinical trials on the repositioning of DPP-4 inhibitors.

We present MicroAquarium, a new hybrid digital-biological installation that provides an immersive experience of interacting with real living cells. MicroAquarium uses a custom-built light-projection microscope equipped with an interactive input device and an immersive display to mediate the interaction between humans and microorganisms. Users' hand motions are recognized and converted into a pattern of light that is projected onto the photo-tactic microorganisms inside the microscope. The view inside the microscope is displayed on a large screen display, providing users with an immersive experience of being inside an aquarium of living cells. Our system effectively bridges the differences in size and the sensing modalities between human users and microscopic organisms and allows for unique playful and exploratory inter-species interactions.

The advancement of biotechnology enabled the development of "biotic video games", where human players manipulate real biological samples for fun and educational human-biology interactions. However, new design principles are needed to both leverage and mitigate biological properties (e.g., variability and stochasticity), and create unique play experiences that transcend traditional video games. This paper describes the implementation of Pac-Euglena, a biotic Pac-Man analog, where players guide live microscopic Euglena cells with light stimuli through a physical microfluidic maze. Through use of multi-modal stimuli, a mixed biology-digital-human reality is achieved, enabling cell interactions with virtual ghosts and collectibles. Through an iterative design process, we illustrate challenges and strategies for designing games with living organisms. A user study (n=18, conducted at a university event) showed that Pac-Euglena was fun, stimulated curiosity, and taught users about Euglena. We conclude with five general guidelines for the design and development of biotic games and HBI interfaces.

Retinol-binding protein 2 (RBP2) binds 2-monoacylglycerols affecting their intestinal levels and enteroendocrine responses., Expressed in the small intestine, retinol-binding protein 2 (RBP2) facilitates dietary retinoid absorption. Rbp2-deficient (Rbp2−/−) mice fed a chow diet exhibit by 6-7 months-of-age higher body weights, impaired glucose metabolism, and greater hepatic triglyceride levels compared to controls. These phenotypes are also observed when young Rbp2−/− mice are fed a high fat diet. Retinoids do not account for the phenotypes. Rather, RBP2 is a previously unidentified monoacylglycerol (MAG)-binding protein, interacting with the endocannabinoid 2-arachidonoylglycerol (2-AG) and other MAGs with affinities comparable to retinol. X-ray crystallographic studies show that MAGs bind in the retinol binding pocket. When challenged with an oil gavage, Rbp2−/− mice show elevated mucosal levels of 2-MAGs. This is accompanied by significantly elevated blood levels of the gut hormone GIP (glucose-dependent insulinotropic polypeptide). Thus, RBP2, in addition to facilitating dietary retinoid absorption, modulates MAG metabolism and likely signaling, playing a heretofore unknown role in systemic energy balance.

Background The role of surgical reconstruction following melanoma extirpation is well recognized. Although technical considerations depend on patient anatomy and surgeon preference, the optimal timing of reconstruction remains unclear. This study aims to evaluate clinical and oncologic outcomes in melanoma extirpation followed by immediate reconstruction. Methods We retrospectively identified patients who underwent immediate reconstruction following head and neck melanoma excision at our institution between January 2013 and December 2016. Demographic and clinical characteristics, operative variables, and outcome data were extracted. Results Overall, 197 patients (male 70.6%) underwent excision followed by immediate reconstruction. Of the 70 patients with a history of cutaneous malignancy, 46 (65.7%) had a prior melanoma and 26 (37.1%) had 2 or more types of skin cancers. Of the 202 lesions resected, 138 (68.3%) were invasive, whereas 64 (31.7%) were in situ. The most frequent anatomic location involved was the cheek (34.2%), followed by scalp (31.2%). Reconstruction technique varied, with 116 (57.4%) lesions repaired by adjacent tissue transfer, 24 (11.9%) by full-thickness skin graft, 23 (11.4%) by complex primary closure, 17 (8.4%) by split-thickness skin graft, and 22 (10.9%) by more than 1 technique. On postoperative pathologic assessment, 2 patients had positive margins and 5 experienced local recurrence (mean follow-up: 2.3 years). In an unadjusted bivariate analysis, history of melanoma (P = 0.015) was significantly associated with local recurrence. Conclusions Reconstruction at time of excision is an oncologically safe approach for the management of patients with malignant melanoma. A prior history of melanoma may be associated with local recurrence.

Background The first stage of alcoholic liver disease is hepatic steatosis. While alcohol is known to profoundly impact hepatic lipid metabolism, gaps in our knowledge remain regarding the mechanisms leading to alcohol‐induced hepatic triglyceride (TG) accumulation. As the sole enzymes catalyzing the final step in TG synthesis, diacylglycerol O‐acyltransferase (DGAT) 1 and 2 are potentially important contributors to alcoholic steatosis. Our goal was to study the effects of dietary fat content on alcohol‐induced hepatic TG accumulation, and the relative contribution of DGAT1 and DGAT2 to alcoholic steatosis. Methods These studies were carried out in wild‐type (WT) mice fed alcohol‐containing high‐fat or low‐fat formulations of Lieber‐DeCarli liquid diets, as well as follow‐up studies in Dgat1 −/− mice. Results A direct comparison of the low‐fat and high‐fat liquid diet in WT mice revealed surprisingly similar levels of alcoholic steatosis, although there were underlying differences in the pattern of hepatic lipid accumulation and expression of genes involved in hepatic lipid metabolism. Follow‐up studies in Dgat1 −/− mice revealed that these animals are protected from alcoholic steatosis when consumed as part of a high‐fat diet, but not a low‐fat diet. Conclusions Dietary macronutrient composition influences the relative contribution of DGAT1 and DGAT2 to alcoholic steatosis, such that in the context of alcohol and a high‐fat diet, DGAT1 predominates.

Chronic stress induces neuronal cell death, which can cause nervous system disorders including Parkinson's disease and Alzheimer's disease. In this study, we evaluated the neuroprotective effects of Clematis terniflora extract (CTE) against corticosterone-induced apoptosis in rat pheochromocytoma (PC12) cells, and also investigated the underlying molecular mechanisms. At concentrations of 300 and 500 μg/ml, CTE significantly decreased apoptotic cell death and mitochondrial damage induced by 200 μM corticosterone. CTE decreased the expression levels of endoplasmic reticulum (ER) stress proteins GRP78, GADD153, and mitochondrial damage-related protein BAD, suggesting that it downregulates ER stress evoked by corticosterone. Furthermore, our results suggested that these protective effects were mediated by the upregulation of p-AKT and p-ERK1/2, which are involved in cell survival signaling. Collectively, our results indicate that CTE can lessen neural damage caused by chronic stress. [BMB Reports 2018; 51(8): 400-405].

BACKGROUND AND PURPOSE Visual assessment of medial temporal-lobe atrophy (MTA) has been quick, reliable, and easy to apply in routine clinical practice. However, one of the limitations in visual assessments of MTA is the lack of widely accepted age-adjusted norms and cutoff scores for MTA for a diagnosis of Alzheimer's disease (AD). This study aimed to determine the optimal cutoff score on a T1-weighted axial MTA Visual Rating Scale (VRS) for differentiating patients with AD from cognitively normal elderly people. METHODS The 3,430 recruited subjects comprising 1,427 with no cognitive impairment (NC) and 2003 AD patients were divided into age ranges of 50-59, 60-69, 70-79, and 80-89 years. Of these, 446 participants (218 in the NC group and 228 in the AD group) were chosen by random sampling for inclusion in this study. Each decade age group included 57 individuals, with the exception of 47 subjects being included in the 80- to 89-year NC group. The scores on the T1-weighted axial MTA VRS were graded by two neurologists. The cutoff values were evaluated from the area under the receiver operating characteristic curve. RESULTS The optimal axial MTA VRS cutoff score from discriminating AD from NC increased with age: it was ≥as ≥1, ≥2, and ≥3 in subjects aged 50-59, 60-69, 70-79, and 80-89 years, respectively (all p

We investigated the beneficial effects of midazolam against vascular endothelial growth factor (VEGF)-induced vascular leakage and its molecular mechanism of action in human retinal endothelial cells (HRECs) and the retinas of diabetic mice. Midazolam inhibited VEGF-induced elevation of intracellular Ca2+, generation of reactive oxygen species (ROS), and transglutaminase activation in HRECs; these effects were reversed by the GABA, type A (GABAA) receptor antagonist flumazenil but not by the translocator protein antagonist PK11195. Midazolam also prevented VEGF-induced disassembly of adherens junctions and in vitro permeability. Intravitreal injection of midazolam prevented hyperglycemia-induced ROS generation, transglutaminase activation, and subsequent vascular leakage in the retinas of diabetic mice, and those effects were reversed by flumazenil. The roles of flumazenil were further supported by identifying GABAA receptors in mouse retinas. Thus, midazolam prevents hyperglycemia-induced vascular leakage by inhibiting VEGF-induced intracellular events in the retinas of diabetic mice.-Lee, Y.-J., Kim, M., Lee, J.-Y., Jung, S.-H., Jeon, H.-Y., Lee, S.-A., Kang, S., Han, E.-T., Park, W. S., Hong, S.-H., Kim, Y.-M., Ha, K.-S. The benzodiazepine anesthetic midazolam prevents hyperglycemia-induced microvascular leakage in the retinas of diabetic mice.

The biochemical characterization of virulence factors from entomopathogenic bacteria is important to understand entomopathogen-insect molecular interactions. Pseudomonas entomophila is a typical entomopathogenic bacterium that harbors virulence factors against several insects. However, the molecular actions of these factors against host innate immune responses are not clearly elucidated. In this study, we observed that bean bugs ( Riptortus pedestris ) that were injected with P. entomophila were highly susceptible to this bacterium. To determine how P. entomophila counteracts the host innate immunity to survive within the insect, we purified a highly enriched protein with potential host insect-killing activity from the culture supernatant of P. entomophila . Then, a 45-kDa protein was purified to homogeneity and identified as AprA which is an alkaline zinc metalloprotease of the genus Pseudomonas by liquid chromatography mass spectrometry (LC-MS). Purified AprA showed a pronounced killing effect against host insects and suppressed both host cellular and humoral innate immunity. Furthermore, to show that AprA is an important insecticidal protein of P. entomophila , we used an aprA -deficient P. entomophila mutant strain (Δ aprA ). When Δ aprA mutant cells were injected to host insects, this mutant exhibited extremely attenuated virulence. In addition, the cytotoxicity against host hemocytes and the antimicrobial peptide-degrading ability of the Δ aprA mutant were greatly decreased. These findings suggest that AprA functions as an important insecticidal protein of P. entomophila via suppression of host cellular and humoral innate immune responses.