Systematic transcriptome analysis associated with physiological and chronological aging in Caenorhabditis elegans.

Aging is associated with changes in a variety of biological processes at the transcriptomic level, including gene expression. Two types of aging occur during a lifetime: chronological and physiological aging. However, dissecting the difference between chronological and physiological ages at the transcriptomic level has been a challenge because of its complexity. We analyzed the transcriptomic features associated with physiological and chronological aging using Caenorhabditis elegans as a model. Many structural and functional transcript elements, such as noncoding RNAs and intron-derived transcripts, were up-regulated with chronological aging. In contrast, mRNAs with many biological functions, including RNA processing, were down-regulated with physiological aging. We also identified an age-dependent increase in the usage of distal 3' splice sites in mRNA transcripts as a biomarker of physiological aging. Our study provides crucial information for dissecting chronological and physiological aging at the transcriptomic level.

Comparing Rates of Undiagnosed Hypertension and Diabetes in Patients With and Without Substance Use Disorders.

BACKGROUND: Individuals with substance use disorders (SUDs) have increased risk for developing chronic conditions, though few studies assess rates of diagnosis of these conditions among patients with SUDs. OBJECTIVE: To compare rates of undiagnosed hypertension and diabetes among patients with and without an SUD. DESIGN: Cross-sectional analysis using electronic health record (EHR) data from 58 primary care clinics at a large, urban, healthcare system in New York. PARTICIPANTS: Patients who had at least two primary care visits from 2019-2022 were included in our patient sample. Patients without an ICD-10 hypertension diagnosis or prescribed hypertension medications and with at least two blood pressure (BP) readings ≥ 140/90 mm were labeled 'undiagnosed hypertension,' and patients without a diabetes diagnosis or prescribed diabetes medications and with A1C/hemoglobin ≥ 6.5% were labeled 'undiagnosed diabetes.' MAIN MEASURES: We calculated the mean number of patients with and without an ICD-10 SUD diagnosis who were diagnosed and undiagnosed for each condition. We used multivariate logistic regression to assess the association between being undiagnosed for each condition, and having an SUD diagnosis, patient demographic characteristics, clinical characteristics (body mass index, Elixhauser comorbidity count, diagnosed HIV and psychosis), the percentage of visits without a BP screening, and the total number of visits during the time period. KEY RESULTS: The percentage of patients with undiagnosed hypertension (2.74%) and diabetes (22.98%) was higher amongst patients with SUD than patients without SUD. In multivariate models, controlling for other factors, patients with SUD had significantly higher odds of having undiagnosed hypertension (OR: 1.81; 95% CI: 1.48, 2.20) and undiagnosed diabetes (OR: 1.93; 1.72, 2.16). Being younger, female, and having an HIV diagnosis was also associated with significantly higher odds for being undiagnosed. CONCLUSIONS: We found significant disparities in rates of undiagnosed chronic diseases among patients with SUDs, compared with patients without SUDs.

Metabolomic profiles of ovariectomized mice and their associations with body composition and frailty-related parameters in postmenopausal women.

BACKGROUND: Menopause, a dramatical estrogen-deficient condition, is considered the most significant milestone in women's health. PURPOSE: To investigate the metabolite changes attributed to estrogen deficiency using random forest (RF)-based machine learning (ML) modeling strategy in ovariectomized (OVX) mice as well as determine the clinical relevance of selected metabolites in older women. METHODS AND RESULTS: Untargeted and targeted metabolomic analyses revealed that metabolites related to TCA cycle, sphingolipids, phospholipids, fatty acids, and amino acids, were significantly changed in the plasma and/or muscle of OVX mice. Subsequent ML classifiers based on RF algorithm selected alpha-ketoglutarate (AKG), arginine, carnosine, ceramide C24, phosphatidylcholine (PC) aa C36:6, and PC ae C42:3 in plasma as well as PC aa 34:1, PC aa C34:3, PC aa C36:5, PC aa C32:1, PC aa C36:2, and sphingosine in muscle as top featured metabolites that differentiate the OVX mice from the sham-operated group. When circulating levels of AKG, arginine, and carnosine, which showed the most significant changes in OVX mice blood, were measured in postmenopausal women, higher plasma AKG levels were associated with lower bone mass, weak grip strength, poor physical performance, and increased frailty risk. CONCLUSIONS: Metabolomics- and ML-based methods identified the key metabolites of blood and muscle that were significantly changed after ovariectomy in mice, and the clinical implication of several metabolites was investigated by looking at their correlation with body composition and frailty-related parameters in postmenopausal women. These findings provide crucial context for understanding the diverse physiological alterations caused by estrogen deficiency in women.

The transcription factor OsNAC5 regulates cadmium accumulation in rice.

Cadmium (Cd) is a hazardous heavy metal that threatens human health through the consumption of contaminated rice. To mitigate Cd accumulation in rice grains, it is crucial to reduce Cd uptake. Nevertheless, the transcriptional mechanisms governing Cd uptake in rice remain largely unknown. This research identifies the transcription factor OsNAC5 in Oryza sativa as a positive regulator of the Cd transporter gene OsNRAMP1, thereby influencing Cd uptake. OsNAC5 is predominantly expressed in the roots, resides in the nucleus, and is upregulated by Cd-induced hydrogen peroxide (H2O2). Knocking out OsNAC5 results in lower Cd concentrations in both shoots and roots and heightens sensitivity to Cd. The expression of OsNRAMP1, enhanced by Cd stress, is dependent on OsNAC5. OsNAC5 binds to "CATGTG" motifs in the OsNRAMP1 promoter, activating its expression. The loss of OsNAC5 function leads to reduced Cd accumulation in rice grains. Our findings provide insights into the transcriptional regulation of Cd stress response in rice and propose biotechnological strategies to lower Cd uptake in crops.

Trends in the availability of comprehensive services within outpatient substance use treatment facilities from 2018 to 2022.

Background: Little is known regarding the extent to which substance use disorder (SUD) treatment facilities adopt comprehensive services to meet patients' medical and social needs.Objective: To examine trends in the availability of comprehensive services within outpatient SUD treatment facilities from 2018 to 2022.Methods: We used data from the Mental Health and Addiction Treatment Tracking Repository, a national database of SUD treatment facilities (n = 13,793). We examined the availability of four domains of comprehensive services and four types of SUD treatment services from 2018 to 2022. We conducted bivariate and multivariate logistic regression predicting the availability of a comprehensive service model (defined as having at least one service from each service domain), controlling for organizational and community characteristics.Results: Comprehensive services were increasingly offered from 2018 to 2022. In unadjusted and adjusted models, facilities which were externally accredited (OR: 1.50; 95%CI: 1.30-1.74), accepted Medicaid (OR: 1.51; 95%CI: 1.30-1.74), performed community outreach (OR: 2.05; 95%CI: 1.80-2.33), provided naloxone and overdose education (OR: 3.50; 95%CI: 3.06-3.99), had a robust SUD treatment infrastructure (OR: 2.33; 95%CI; 2.08-2.62), and were located in a county with a lower percentage of White residents (OR: 0.99; 95%CI: 0.99-0.99), a higher percentage of residents in poverty (OR: 1.02; 95%CI: 1.00-1.03), and the Northeast compared with the South (OR: 1.21; 95%CI: 1.01-1.45), had significantly higher odds of adopting a comprehensive service model.Conclusion: Findings highlight the importance of factors reflecting experience with organizational change efforts and enhanced external support. Policymakers working to enhance the uptake of comprehensive services should focus on obtaining the financial and technical support necessary to develop these models.

Examining the Relationship Between Local Governmental Expenditures on the Social Determinants of Health and County-Level Overdose Deaths, 2017-2020.

CONTEXT: Prior studies have examined the social determinants of health (SDOH) characteristics of counties with elevated rates of overdose deaths. However, this research often ignores variation in upstream governmental investment in these SDOH categories. OBJECTIVE: To examine the association of local governmental investments in SDOH with drug overdose mortality at the county level, controlling for demographic and socioeconomic characteristics. DESIGN: Longitudinal analysis from 2017 to 2020. SETTING: United States counties. PARTICIPANTS: 3126 counties. MAIN OUTCOME AND MEASURES: The primary study outcome was county overdose death rates per 100 000 population taken from the Centers for Disease Control and Prevention. The main predictor of interest was the per capita average of local governmental expenditures in public health, social service, and education drawn from the U.S. Census of Governments, categorized into quartiles. Covariates included county-level socioeconomic and demographic characteristics as well as county-level SUD services from the AHRQ SDOH Database. RESULTS: In longitudinal multivariate linear regression models with state and year fixed effects, counties in the highest 3 quartiles of SDOH spending had significantly lower rates of overdose deaths compared with counties in the lowest quartile of SDOH spending; in particular, counties in quartile 2 had an average of 9.09 fewer overdose deaths per 100 000 population (95% CI: -12.58, -5.60), counties in quartile 3 had an average of 13.18 fewer deaths per 100 000 population (95% CI: -17.56; -8.80), and counties in quartile 4 had an average of 13.92 deaths per 100 000 population (95% CI: -19.16, -8.68). CONCLUSIONS: Our findings demonstrate that higher levels of local governmental investments in SDOH were associated with significantly lower rates of overdose death in U.S. counties after controlling for socioeconomic and demographic characteristics. Going forward, research should focus on determining causality in this relationship, the mechanisms through which this relationship occurs, as well as assess the impact of local public health expenditures allocated toward SUD prevention and treatment specifically on substance use outcomes at the local level.

GSDMD-Mediated Cardiomyocyte Pyroptosis Promotes Myocardial I/R Injury.

[Figure: see text].

An observational, sequential analysis of the relationship between local economic distress and inequities in health outcomes, clinical care, health behaviors, and social determinants of health.

BACKGROUND: Socioeconomic status has long been associated with population health and health outcomes. While ameliorating social determinants of health may improve health, identifying and targeting areas where feasible interventions are most needed would help improve health equity. We sought to identify inequities in health and social determinants of health (SDOH) associated with local economic distress at the county-level. METHODS: For 3,131 counties in the 50 US states and Washington, DC (wherein approximately 325,711,203 people lived in 2019), we conducted a retrospective analysis of county-level data collected from County Health Rankings in two periods (centering around 2015 and 2019). We used ANOVA to compare thirty-three measures across five health and SDOH domains (Health Outcomes, Clinical Care, Health Behaviors, Physical Environment, and Social and Economic Factors) that were available in both periods, changes in measures between periods, and ratios of measures for the least to most prosperous counties across county-level prosperity quintiles, based on the Economic Innovation Group's 2015-2019 Distressed Community Index Scores. RESULTS: With seven exceptions, in both periods, we found a worsening of values with each progression from more to less prosperous counties, with least prosperous counties having the worst values (ANOVA p < 0.001 for all measures). Between 2015 and 2019, all except six measures progressively worsened when comparing higher to lower prosperity quintiles, and gaps between the least and most prosperous counties generally widened. CONCLUSIONS: In the late 2010s, the least prosperous US counties overwhelmingly had worse values in measures of Health Outcomes, Clinical Care, Health Behaviors, the Physical Environment, and Social and Economic Factors than more prosperous counties. Between 2015 and 2019, for most measures, inequities between the least and most prosperous counties widened. Our findings suggest that local economic prosperity may serve as a proxy for health and SDOH status of the community. Policymakers and leaders in public and private sectors might use long-term, targeted economic stimuli in low prosperity counties to generate local, community health benefits for vulnerable populations. Doing so could sustainably improve health; not doing so will continue to generate poor health outcomes and ever-widening economic disparities.

A novel conservative system with hidden flows evolved from the simplest memristive circuit.

Over the past few decades, the research of dissipative chaotic systems has yielded many achievements in both theory and application. However, attractors in dissipative systems are easily reconstructed by the attacker, which leads to information security problems. Compared with dissipative systems, conservative ones can effectively avoid these reconstructing attacks due to the absence of attractors. Therefore, conservative systems have advantages in chaos-based applications. Currently, there are still relatively few studies on conservative systems. For this purpose, based on the simplest memristor circuit in this paper, a non-Hamiltonian 3D conservative system without equilibria is proposed. The phase volume conservatism is analyzed by calculating the divergence of the system. Furthermore, a Kolmogorov-type transformation suggests that the Hamiltonian energy is not conservative. The most prominent property in the conservative system is that it exhibits quasi-periodic 3D tori with heterogeneous coexisting and different amplitude rescaling trajectories triggered by initial values. In addition, the results of Spectral Entropy analysis and NIST test show that the system can produce pseudo-random numbers with high randomness. To the best of our knowledge, there is no 3D conservative system with such complex dynamics, especially in a memristive conservative system. Finally, the analog circuit of the system is designed and implemented to test its feasibility as well.

Rapid Transition to Telehealth and the Digital Divide: Implications for Primary Care Access and Equity in a Post-COVID Era.

Policy Points Telehealth has many potential advantages during an infectious disease outbreak such as the COVID-19 pandemic, and the COVID-19 pandemic has accelerated the shift to telehealth as a prominent care delivery mode. Not all health care providers and patients are equally ready to take part in the telehealth revolution, which raises concerns for health equity during and after the COVID-19 pandemic. Without proactive efforts to address both patient- and provider-related digital barriers associated with socioeconomic status, the wide-scale implementation of telehealth amid COVID-19 may reinforce disparities in health access in already marginalized and underserved communities. To ensure greater telehealth equity, policy changes should address barriers faced overwhelmingly by marginalized patient populations and those who serve them. CONTEXT: The COVID-19 pandemic has catalyzed fundamental shifts across the US health care delivery system, including a rapid transition to telehealth. Telehealth has many potential advantages, including maintaining critical access to care while keeping both patients and providers safe from unnecessary exposure to the coronavirus. However, not all health care providers and patients are equally ready to take part in this digital revolution, which raises concerns for health equity during and after the COVID-19 pandemic. METHODS: The study analyzed data about small primary care practices' telehealth use and barriers to telehealth use collected from rapid-response surveys administered by the New York City Department of Health and Mental Hygiene's Bureau of Equitable Health Systems and New York University from mid-April through mid-June 2020 as part of the city's efforts to understand how primary care practices were responding to the COVID-19 pandemic following New York State's stay-at-home order on March 22. We focused on small primary care practices because they represent 40% of primary care providers and are disproportionately located in low-income, minority or immigrant areas that were more severely impacted by COVID-19. To examine whether telehealth use and barriers differed based on the socioeconomic characteristics of the communities served by these practices, we used the Centers for Disease Control and Prevention Social Vulnerability Index (SVI) to stratify respondents as being in high-SVI or low-SVI areas. We then characterized respondents' telehealth use and barriers to adoption by using means and proportions with 95% confidence intervals. In addition to a primary analysis using pooled data across the five waves of the survey, we performed sensitivity analyses using data from respondents who only took one survey, first wave only, and the last two waves only. FINDINGS: While all providers rapidly shifted to telehealth, there were differences based on community characteristics in both the primary mode of telehealth used and the types of barriers experienced by providers. Providers in high-SVI areas were almost twice as likely as providers in low-SVI areas to use telephones as their primary telehealth modality (41.7% vs 23.8%; P <.001). The opposite was true for video, which was used as the primary telehealth modality by 18.7% of providers in high-SVI areas and 33.7% of providers in low-SVI areas (P <0.001). Providers in high-SVI areas also faced more patient-related barriers and fewer provider-related barriers than those in low-SVI areas. CONCLUSIONS: Between April and June 2020, telehealth became a prominent mode of primary care delivery in New York City. However, the transition to telehealth did not unfold in the same manner across communities. To ensure greater telehealth equity, policy changes should address barriers faced overwhelmingly by marginalized patient populations and those who serve them.

Clinicopathologic and MRI features of combined hepatocellular-cholangiocarcinoma in patients with or without cirrhosis.

BACKGROUND AND AIMS: Differences in combined hepatocellular-cholangiocarcinomas (cHCC-CCAs) arising in high-risk patients with or without liver cirrhosis have not been elucidated. This study aimed to compare the clinicopathologic and imaging characteristics of cHCC-CCAs in patients with or without cirrhosis and to determine the prognostic factors for recurrence-free survival (RFS) after curative resections of single cHCC-CCAs. METHODS: This retrospective study included 113 patients with surgically resected single cHCC-CCAs who underwent preoperative magnetic resonance imaging from January 2008 to December 2019 at two tertiary referral centres. Clinical, pathologic and imaging features of tumours were compared in high-risk patients with or without cirrhosis. Imaging features were assessed using the Liver Imaging Reporting and Data System (LI-RADS) version 2018. RFS and associated factors were evaluated using Cox proportional hazards regression analysis, Kaplan-Meier analysis and log-rank test. RESULTS: cHCC-CCAs arising from cirrhotic livers had a smaller mean tumour size (2.9 cm vs. 4.5 cm; P < .001) and were more frequently categorized as LR-5 or 4 (41.2% vs. 20.0%; P = .024) than those arising from non-cirrhotic livers. In multivariable analysis, a tumour size of > 3 cm (hazard ratio [HR], 2.081; 95% confidence interval [CI], 1.180-3.668; P = .011) and the LR-M category (HR, 2.302; 95% CI, 1.198-4.424; P = .012) were independent predictors associated with worse RFS. CONCLUSIONS: The tumour size and distribution of LI-RADS categories of cHCC-CCAs differed in high-risk patients with or without cirrhosis. And LR-M category was a worse prognosis predictor after curative resections than LR-5 or 4 category.

SH3YL1 protein as a novel biomarker for diabetic nephropathy in type 2 diabetes mellitus.

BACKGROUND AND AIMS: Oxidative stress contributes to development of diabetic nephropathy. We implicated SH3YL1 in oxidative stress-induced inflammation and examined whether SH3YL1 could be used as a new biomarker of diabetic nephropathy. METHODS AND RESULTS: In this study, we investigated the relationship between plasma level of SH3YL1 and diabetic nephropathy in patients with type 2 diabetes. In addition, we examined the physiological role of SH3YL1 in db/db mice and cultured podocytes. Plasma SH3YL1 concentration was significantly higher in patients with diabetes than in controls, even in normoalbuminuric patients, and was markedly increased in the macroalbuminuria group. Plasma SH3YL1 level was positively correlated with systolic blood pressure, HOMA-IR, postprandial blood glucose, plasma level of retinol binding protein 4 (RBP 4), and urinary albumin excretion (UAE) and was inversely correlated with BMI. Regression analysis showed that plasma level of RBP 4, UAE, and BMI were the only independent determinants of plasma SH3YL1 concentration. In db/db mice, plasma and renal SH3YL1 levels were significantly increased in mice with diabetes compared with control mice. In cultured podocytes, high glucose and angiotensin II stimuli markedly increased SH3YL1 synthesis. CONCLUSION: These findings suggest that plasma level of SH3YL1 offers a promising new biomarker for diabetic nephropathy.

Neutrophil-derived advanced glycation end products-Nε-(carboxymethyl) lysine promotes RIP3-mediated myocardial necroptosis via RAGE and exacerbates myocardial ischemia/reperfusion injury.

Nε-(carboxymethyl) lysine (CML), the major member of advanced glycation end products, was widely studied in diabetic complications and aging-associated diseases. However, the impact of CML on myocardial ischemia/reperfusion injury (MI/RI) was rarely reported. In the present study, CML was increased in both patients with acute myocardial infarction (53.4 ± 7.8 vs. 28.1 ± 4.4 ng; P = 0.017), and mice underwent MI/RI (16.4 ± 1.4 vs. 10.8 ± 0.9 ng; P = 0.006). Depletion of neutrophils reduced CML (17.8 ± 1.0 vs. 9.9 ± 0.3 ng; P < 0.001), indicating neutrophils were the major cells contributing to CML formation during MI/RI. CML treatment exacerbated MI/RI by elevating myocardial injury marker (274.3 ± 18.0 vs. 477.2 ± 34.3 pg; P < 0.001), enlarging myocardial infarct size (32.9 ± 3.6 vs. 45.2 ± 3.8%; P = 0.03), increasing myocardial fibrosis (17.5 ± 1.6 vs. 29.7 ± 2.2%; P < 0.001) and impairing cardiac function (59.4 ± 2.4% vs. 46.0 ± 1.3%; P = 0.001). Further study revealed that CML increased the phosphorylation of receptor interacting protein (RIP) 3, an important initiator of necroptosis, and its downstream proteins. Receptor for advanced glycation end product (RAGE) deficiency effectively blocked RIP3 phosphorylation induced by CML and rescued CML-mediated MI/RI, indicating CML promoted RIP3-mediated necroptosis through RAGE. In addition, glyoxalase-1 overexpression could effectively attenuate MI/RI by reducing CML formation, providing a potential therapeutic target for MI/RI.-Yang, J., Zhang, F., Shi, H., Gao, Y., Dong, Z., Ma, L., Sun, X., Li, X., Chang, S., Wang, Z., Qu, Y., Li, H., Hu, K., Sun, A., Ge, J. Neutrophil-derived advanced glycation end products-Nε-(carboxymethyl) lysine promotes RIP3-mediated myocardial necroptosis via RAGE and exacerbates myocardial ischemia/reperfusion injury.

Robotic single-site surgery in benign gynecologic diseases: Experiences and learning curve based on 626 robotic cases at a single institute.

AIM: The purpose of this study was to report on 626 cases of successful robotic single-site (RSS) surgeries to address various types of gynecologic disease and to evaluate the outcomes and learning curve inherent to RSS surgery in the gynecology field. METHODS: A total of 626 cases of RSS surgeries were performed by 3 gynecologic surgeons at Ewha Womans University Medical Center, Robot Surgery Center from November 2014 to January 2018 were collected retrospectively. All of the patients' charts were reviewed, and the clinical characteristics and surgical variables were analyzed. RESULTS: Among the total of 626 cases, there were 220 cases of RSS myomectomy (RSSM), 182 cases of RSS hysterectomy (RSSH), 195 of RSS adnexectomy, 24 of RSS sacrocolpopexy (RSS SCP) and 5 were classified as other RSS surgeries. The patient's mean age was 38.98 ± 10.07 years. There was 3.99 ± 2.15 min of mean docking time and 117.78 ± 51.18 min of mean operating time. The surgical variables were analyzed annually. The total operating time was seen to decrease significantly according to each period. The docking time declined significantly and gradually after 1 year. We also analyzed each of the surgical types by time. The operating time of RSSH, RSSM, RSS adnexectomy and RSS SCP fell over time. The tendency found was for operating time to decline sharply following the first 10 cases. When we analyzed the data at annual intervals, the operating time was most significantly less and stable following the first year. There were a few intraoperative or perioperative complications in 16 cases (2.6%). CONCLUSION: Robotic single-site surgery is a feasible and safe procedure for treating various kinds of gynecologic diseases. The learning curve was approximately 10 cases of RSS surgery in gynecologic disease, having a greater amount of experience at performing RSS surgery was revealed to be key to achieving better surgical outcomes.

SECONDARY WALL ASSOCIATED MYB1 is a positive regulator of secondary cell wall thickening in Brachypodium distachyon and is not found in the Brassicaceae.

Grass biomass is comprised chiefly of secondary walls that surround fiber and xylem cells. A regulatory network of interacting transcription factors in part regulates cell wall thickening. We identified Brachypodium distachyon SECONDARY WALL ASSOCIATED MYB1 (SWAM1) as a potential regulator of secondary cell wall biosynthesis based on gene expression, phylogeny, and transgenic plant phenotypes. SWAM1 interacts with cellulose and lignin gene promoters with preferential binding to AC-rich sequence motifs commonly found in the promoters of cell wall-related genes. SWAM1 overexpression (SWAM-OE) lines had greater above-ground biomass with only a slight change in flowering time while SWAM1 dominant repressor (SWAM1-DR) plants were severely dwarfed with a striking reduction in lignin of sclerenchyma fibers and stem epidermal cell length. Cellulose, hemicellulose, and lignin genes were significantly down-regulated in SWAM1-DR plants and up-regulated in SWAM1-OE plants. There was no reduction in bioconversion yield in SWAM1-OE lines; however, it was significantly increased for SWAM1-DR samples. Phylogenetic and syntenic analyses strongly suggest that the SWAM1 clade was present in the last common ancestor between eudicots and grasses, but is not in the Brassicaceae. Collectively, these data suggest that SWAM1 is a transcriptional activator of secondary cell wall thickening and biomass accumulation in B. distachyon.

Myelin degeneration induced by mutant superoxide dismutase 1 accumulation promotes amyotrophic lateral sclerosis.

Myelin is a specialized membrane that wraps around nerve fibers and is essential for normal axonal conduction in neurons. In the central nervous system, oligodendrocytes are responsible for myelin formation. Recent studies have reported pathological abnormalities in oligodendrocytes in human patients with amyotrophic lateral sclerosis (ALS) and a mouse model of ALS expressing the G93A mutation of the human superoxide dismutase 1 (mtSOD1). However, it is unclear whether oligodendrocyte pathology in ALS represents the primary dysfunction induced by mtSOD1 and how mtSOD1 contributes to oligodendrocyte degeneration and ALS pathogenesis. We analyzed GAL4-VP16-UAS transgenic zebrafish selectively expressing mtSOD1 in mature oligodendrocytes. We observed that mtSOD1 directly induced oligodendrocyte degeneration by disrupting the myelin sheath and downregulating monocarboxylate transporter 1 (MCT1), thereby causing spinal motor neuron degeneration. Pathological changes observed in this transgenic zebrafish were similar to the pathology observed in the SOD1G93A mouse model of ALS, which is characterized by expression of mtSOD1 in all cells. In addition, oligodendrocyte dysfunction induced by mtSOD1 was associated with anxiety-related behavioral abnormalities, learning impairments, and motor defects in the early symptomatic stage. We also found that treatment with potassium channel inhibitors rescued behavioral abnormalities without rescuing MCT1 expression, suggesting that myelin disruption induces behavioral abnormalities independently of MCT1. These results indicate that mtSOD1-induced dysfunction of mature oligodendrocytes is sufficient to induce motor neuron degeneration, thus informing future therapeutic strategies targeted at oligodendrocytes in ALS.

ESRP1-Induced CD44 v3 Is Important for Controlling Pluripotency in Human Pluripotent Stem Cells.

The importance of alternative splicing (AS) events in pluripotency regulation has been highlighted by the determination of different roles and contributions of different splice isoforms of pluripotency-related genes and by the identification of distinct pluripotency-related splicing factors. In particular, epithelial splicing regulatory protein 1 (ESRP1) has been characterized as an essential splicing factor required for the regulation of human pluripotency and differentiation. Nevertheless, a detailed molecular characterization of ESRP1 (mRNA splice variants 1-6) in human pluripotency is lacking. In this study, we determined that ESRP1 splice variants are differentially expressed in undifferentiated and differentiated human pluripotent stem cells (PSCs). Undifferentiated human PSCs predominantly expressed the ESRP1 v1, v4, and v5, and their expression was downregulated upon differentiation. Ectopic expression of ESRP1 v1, v4, or v5 enhanced the pluripotent reprogramming of human fibroblasts and restored the ESRP1 knockdown-mediated reduction of reprogramming efficiency. Notably, undifferentiated human PSCs expressed the cell surface protein CD44 variant 3 (CD44 v3), and isoform switching from CD44 v3 to CD44 variant 6 (CD44 v6) occurred upon differentiation. Importantly, the human PSC-specific ESRP1 variants influenced CD44 v3 expression. CD44 knockdown or inhibition of binding of CD44 with its major ligand, hyaluronan, significantly induced the loss of human PSC pluripotency and the reduction of reprogramming efficiency. Our results demonstrate that the effect of ESRP1 and CD44 on human PSC pluripotency is isoform-dependent and that ESRP1-induced CD44 v3 is functionally associated with human PSC pluripotency control. Stem Cells 2018;36:1525-1534.

Gender-Related Differences in Clinical Characteristics and Outcomes of Premature Coronary Artery Disease: Insight from the FOCUS Registry.

INTRODUCTION: Although coronary artery disease (CAD) presentations and clinical outcomes differ by sex, little is known about premature CAD (PCAD). The present analysis aimed to evaluate the gender-related differences of PCAD in an Asian population from the FOCUS registry. METHODS: A total of 1397 Asian young patients with angiographically confirmed CAD undergoing drug-eluting stent implantation were included in this analysis and divided into two groups according to the genders. Patients were followed up for three years and clinical outcomes were compared between groups. RESULTS: Young women were older and more likely to have hypertension and diabetes than men (all p<0.001). In contrast, males with PCAD had higher BMI and higher prevalence of current smoking as well as previous vessel revascularizations (all p<0.05). Men were more likely to be manifested as total occlusive lesions (p<0.001). Regardless of the clinical characteristics, the cumulative incidences of adverse events such as major adverse cardiovascular event (MACE), cardiovascular death, and all-cause death were not significantly different at one- or three-year follow-up (all p>0.05). CONCLUSION: Despite remarkable differences in clinical characteristics between Asian males and females with PCAD, the two groups did not differ significantly in clinical outcomes.

An Atypical Late Embryogenesis Abundant Protein OsLEA5 Plays a Positive Role in ABA-Induced Antioxidant Defense in Oryza sativa L.

OsLEA5 acts as a co-regulator of a transcriptional fact ZFP36 to enhance the expression and the activity of ascorbate peroxidase OsAPX1 to regulate seed germination in rice, but it it unknown whether OsLEA5 is also crucial in plant seedlings under stress conditions. To determine this, we generated OsLEA5 overexpression and knockdown rice plants. We found that overexpression of OsLEA5 in rice plants enhanced the tolerance to drought and salt stress; in contrast, an RNA interference (RNAi) mutant of OsLEA5 rice plants was more sensitive to drought and salinity. Further investigation found that various stimuli and ABA could induce OsLEA5 expression, and OsLEA5 acted downstream of ZFP36 to be involved in ABA-induced generation of hydrogen peroxide (H2O2), and the regulation of the expression and the activities of antioxidant defense enzymes in plants leaves, and OsLEA5 contributed to stabilize ZFP36. Additionally, OsLEA5 participates in the accumulation of ABA by up-regulating ABA biosynthesis genes and down-regulating ABA metabolism genes. Moreover, we found that two homologs of OsLEA5 (5C700, short for Os05g0526700; and 5C300, short for Os05g0584300) which were induced by ABA also interacted with ZFP36 separately; interestingly, the nuclear-located 5C700 could also act as a co-activator of ZFP36 to modulate OsAPX1, while 5C300 which was down-regulated by ABA induction acted as an ABA-induced inhibitor of ZFP36 to regulate OsAPX1. Hence, our conclusion is that OsLEA5 participates in the ABA-mediated antioxidant defense to function in drought and salt stress response in rice, and the 5C subgroup of LEAs contribute by acting as co-regulators of the transcription factor ZFP36.