Corrigendum: Identification of ACKR4 as an immune checkpoint in pulmonary arterial hypertension.

[This corrects the article DOI: 10.3389/fimmu.2023.1153573.].

Identification of ACKR4 as an immune checkpoint in pulmonary arterial hypertension.

Objective: Inflammation is recognized as a contributor in the development of pulmonary arterial hypertension (PAH), and the recruitment and functional capacity of immune cells are well-orchestrated by chemokines and their receptors. This study is aimed at identification of critical chemokines in the progression of PAH via transcriptomic analysis. Methods: Differentially expressed genes (DEGs) from lungs of PAH patients were achieved compared to controls based on Gene Expression Omnibus (GEO) database. Gene set enrichment analysis (GSEA) was applied for functional annotation and pathway enrichement. The abundance of immune cells was estimated by the xCell algorithm. Weighted correlation network analysis (WGCNA) was used to construct a gene expression network, based on which a diagnostic model was generated to determine its accuracy to distinguish PAH from control subjects. Target genes were then validated in lung of hypoxia-induce pulmonary hypertension (PH) mouse model. Results: ACKR4 (atypical chemokine receptor 4) was downregulated in PAH lung tissues in multiple datasets. PAH relevant biological functions and pathways were enriched in patients with low-ACKR4 level according to GSEA enrichment analysis. Immuno-infiltration analysis revealed a negative correlation of activated dendritic cells, Th1 and macrophage infiltration with ACKR4 expression. Three gene modules were associated with PAH via WGCNA analysis, and a model for PAH diagnosis was generated using CXCL12, COL18A1 and TSHZ2, all of which correlated with ACKR4. The ACKR4 expression was also downregulated in lung tissues of our experimental PH mice compared to that of controls. Conclusions: The reduction of ACKR4 in lung tissues of human PAH based on transcriptomic data is consistent with the alteration observed in our rodent PH. The correlation with immune cell infiltration and functional annotation indicated that ACKR4 might serve as a protective immune checkpoint for PAH.

Gender-specific impacts of thigh skinfold thickness and grip strength for predicting osteoporosis in type 2 diabetes.

BACKGROUND: Diabetes with co-existing bone fragility or osteoporosis is common in elderly patients, whereas is frequently underestimated. METHODS: We conducted dual-energy x-ray absorptiometry (DXA) with 7-site skinfold (SF) and dominant hand grip strength measurements among patients with type 2 diabetes (T2DM) to assess their gender-specific associations. A total of 103 patients with T2DM (60 females and 43 males), aged between 50 and 80 years (median 68.0 years) were enrolled and 45 non-DM females were also included to compare with T2DM females. RESULTS: Our results revealed osteoporosis was negatively correlated with grip strength in both genders, negatively correlated with lean mass solely in males and negatively correlated with fat mass (particular the gynoid fat mass and thigh SF thickness) in females. Via performing multivariable stepwise logistic regression, we identified grip strength in both genders and thigh SF thickness in females as predictors for osteoporosis. Receiver operating characteristic curve analysis further disclosed 20.5 mm female thigh skinfold thickness, 18.1 kg female grip strength and 29.0 kg male grip strength as reasonable cutoff levels for predicting osteoporosis in the Taiwanese patients with T2DM. CONCLUSIONS: Patients with T2DM presented gender-specific associations between osteoporosis, body composition and grip strength. Grip strength and thigh SF thickness might serve as predictors for detection of osteoporosis in patients with T2DM.

Using Arterial Pulse and Laser Doppler Analyses to Discriminate between the Cardiovascular Effects of Different Running Levels.

BACKGROUND AND AIMS: Running can induce advantageous cardiovascular effects such as improved arterial stiffness and blood-supply perfusion. However, the differences between the vascular and blood-flow perfusion conditions under different levels of endurance-running performance remains unclear. The present study aimed to assess the vascular and blood-flow perfusion conditions among 3 groups (44 male volunteers) according to the time taken to run 3 km: Level 1, Level 2, and Level 3. METHODS: The radial blood pressure waveform (BPW), finger photoplethygraphy (PPG), and skin-surface laser-Doppler flowmetry (LDF) signals of the subjects were measured. Frequency-domain analysis was applied to BPW and PPG signals; time- and frequency-domain analyses were applied to LDF signals. RESULTS: Pulse waveform and LDF indices differed significantly among the three groups. These could be used to evaluate the advantageous cardiovascular effects provided by long-term endurance-running training, such as vessel relaxation (pulse waveform indices), improvement in blood supply perfusion (LDF indices), and changes in cardiovascular regulation activities (pulse and LDF variability indices). Using the relative changes in pulse-effect indices, we achieved almost perfect discrimination between Level 3 and Level 2 (AUC = 0.878). Furthermore, the present pulse waveform analysis could also be used to discriminate between the Level-1 and Level-2 groups. CONCLUSIONS: The present findings contribute to the development of a noninvasive, easy-to-use, and objective evaluation technique for the cardiovascular benefits of prolonged endurance-running training.

Prevalence of Ideal Cardiovascular Health Metrics among Young Asian Adults over 5 Years of Follow-Up.

BACKGROUND: Ideal cardiovascular health (CVH) metrics play an important role in preventing cardiovascular disease (CVD). However, there is a lack of cohort studies on CVH metrics among young Asian adults. The aims of this study were to describe early changes in CVH among young Asian adults and to investigate the association between CVH metrics and sociodemographic variables. METHODS: A total of 10,000 young adults (aged 21-30 years) were recruited between 2000 and 2016. There were two CVH measurements taken from these participants over the study period. One measurement was taken at the beginning, and the other was taken five years later. Subgroup analysis of the changes in CVH metrics was divided by education level and marital status. RESULTS: The mean age of the participants was 26.8 years. The initial prevalence of ideal CVH metrics was 52.3% and 86.8% and decreased to 43.8% and 81.2% after five years for males and females, respectively. In the subgroup analysis, males with less than a university education had a smaller ideal CVH metric decrease (6.2%) than males with more than a university education (8.9%), while females with more than a university education had a smaller ideal CVH metric decrease (5.4%) than females with less than a university education (7.3%). Married males had a smaller ideal CVH metric decrease (6.1%) than single males (9.1%), while single females had a smaller ideal CVH metric decrease (5.3%) than married females (6.2%). CONCLUSIONS: The prevalence of ideal CVH metrics among young adults gradually decreased as age increased. Higher educational attainment and unmarried status were associated with a greater prevalence of ideal CVH metrics regardless of sex, but early CVH changes differed by sex, education level, and marital status. The prevalence of CVH changes found early among young adults can be used to monitor CVH changes quickly. Effective health promotion programs are needed to maintain CVH metrics among young adults.

Discrimination between possible sarcopenia and metabolic syndrome using the arterial pulse spectrum and machine-learning analysis.

Sarcopenia is defined as decreased skeletal muscle mass and function, and is an important cause of frailty in the elderly, also being associated with vascular lesions and poor microcirculation. The present study aimed to combine noninvasive pulse measurements, frequency-domain analysis, and machine learning (ML) analysis (1) to determine the effects on the pulse waveform induced by sarcopenia and (2) to develop discriminating models for patients with possible sarcopenia. Radial blood pressure waveform (BPW) signals were measured noninvasively for 1 min in 133 subjects who visited Tri-Service General Hospital for geriatric health checkups. They were assigned to a robust group and a possible-sarcopenia group that combined dynapenia, presarcopenia, and sarcopenia. Two classification methods were used: ML analysis and a self-developed scoring system that used 40 harmonic pulse indices as features: amplitude proportions and their coefficients of variation, and phase angles and their standard deviations. Significant differences were found in several spectral indices of the BPW between possible-sarcopenia and robust subjects. Threefold cross-validation results indicated excellent discrimination performance, with AUC equaling 0.77 when using LDA and 0.83 when using our scoring system. The present noninvasive and easy-to-use measurement and analysis method for detecting sarcopenia-induced changes in the arterial pulse transmission condition could aid the discrimination of possible sarcopenia.

Comparison of Mitochondrial Adenosine Triphosphate-Sensitive Potassium Channel High- vs Low-Affinity Sulfonylureas and Cardiovascular Outcomes in Patients With Type 2 Diabetes Treated With Metformin.

Importance: Sulfonylureas are frequently used as add-on to metformin in type 2 diabetes (T2D), and individual sulfonylurea agents carry different risks of cardiovascular disease. Sulfonylureas' different affinities to cardiac mitochondrial adenosine triphosphate-sensitive potassium (mitoKATP) channels have been speculated to account for the intraclass difference in cardiovascular risk from in vitro and ex vivo studies; however, this hypothesis has not been assessed in a general population with diabetes receiving sulfonylureas added to metformin. Objective: To compare the risk of myocardial infarction (MI), ischemic stroke, or cardiovascular death in patients with T2D treated with mitoKATP channel high-affinity sulfonylureas and low-affinity sulfonylureas as add-on to metformin. Design, Setting, and Participants: This is a new-user, active-comparator, and propensity score-matched cohort study with analysis of the Taiwanese Diabetes Mellitus Health Database from 2006, to 2017. Data analysis was performed from August 2020 to July 2021. Exposures: Cardiac mitoKATP channel high-affinity (glyburide and glipizide) and low-affinity (gliclazide and glimepiride) sulfonylureas combined with metformin. Main Outcomes and Measures: Primary outcome was major adverse cardiovascular events (MACEs), a composite of cardiovascular death or hospitalization for either MI or ischemic stroke. Secondary outcomes included individual MACE components, heart failure, arrhythmia, all-cause mortality, and severe hypoglycemia. Cox proportional hazards models were used to estimate adjusted hazard ratios (aHRs). Results: Each sulfonylurea group comprised 53 714 patients (mean [SD] age, 54.7 [12.1] years; 31 962 men [59.5%]). MitoKATP channel high-affinity sulfonylureas vs low-affinity sulfonylureas when combined with metformin were associated with an increased risk of MACE (aHR, 1.18; 95% CI, 1.03-1.34), MI (aHR, 1.34; 95% CI, 1.04-1.73), all-cause mortality (aHR, 1.27; 95% CI, 1.03-1.57), and severe hypoglycemia (aHR, 1.82; 95% CI, 1.58-2.10), but not with increased risks of ischemic stroke, cardiovascular death, arrhythmia, and heart failure. The duration analyses revealed the highest MACE risk during 1 to 90 days after initiation of mitoKATP channel high-affinity sulfonylureas (aHR, 6.06; 95% CI, 4.86-7.55). Conclusions and Relevance: Use of mitoKATP channel high-affinity sulfonylureas vs low-affinity sulfonylureas was associated with an increased MACE risk in patients with T2D concomitantly receiving metformin, suggesting that high-affinity blockage of the mitoKATP channels could account for sulfonylurea-associated MACEs.

Machine-Learning Classification of Pulse Waveform Quality.

Pulse measurements made using wearable devices can aid the monitoring of human physiological condition. Accurate estimation of waveforms is often difficult for nonexperts; motion artifacts may occur during tonometry measurements when the skin-sensor contact pressure is insufficient. An alternative approach is to extract only high-quality pulses for use in index calculations. The present study aimed to determine the effectiveness of using machine-learning analysis in discriminating between high-quality and low-quality pulse waveforms induced by applying different contact pressures. Radial blood pressure waveform (BPW) signals were measured noninvasively in healthy young subjects using a strain-gauge transducer. One-minute-long trains of pulse data were measured when applying the appropriate contact pressure (67.80 ± 1.55 mmHg) and a higher contact pressure (151.80 ± 3.19 mmHg). Eight machine-learning algorithms were employed to evaluate the following 40 harmonic pulse indices: amplitude proportions and their coefficients of variation and phase angles and their standard deviations. Significant differences were noted in BPW indices between applying appropriate and higher skin-surface contact pressures. The present appropriate contact pressure could not only provide a suitable holding force for the wearable device but also helped to maintain the physiological stability of the underlying tissues. Machine-learning analysis provides an effective method for distinguishing between the high-quality and low-quality pulses with excellent discrimination performance (leave-one-subject-out test: random-forest AUC = 0.96). This approach will aid the development of an automatic screening method for waveform quality and thereby improve the noninvasive acquisition reliability. Other possible interfering factors in practical applications can also be systematically studied using a similar procedure.

Relationship between Ideal Cardiovascular Health and Incident Proteinuria: A 5 Year Retrospective Cohort Study.

The objective of this study was to examine whether a higher number of ideal cardiovascular health (CVH) metrics are beneficial for lowering the risk of proteinuria. This is a retrospective cohort study with an average follow-up of 5 years. Participants between 21 and 75 years old and without a history of cardiovascular disease and proteinuria were enrolled. CVH metrics, including smoking, diet, physical activity, blood pressure, body mass index (BMI), cholesterol, and fasting glucose, were assessed by questionnaires, physical examination, and blood analysis. Proteinuria was assessed by dipstick measurement. During the follow-up period, 169,366 participants were enrolled, and 1481 subjects developed proteinuria. A higher number of ideal CVH metrics was related to a lower risk of proteinuria after adjustment. Among the components of CVH metrics, ideal blood pressure (HR = 0.33, 95% CI = 0.25-0.43), fasting glucose (HR = 0.17, 95% CI = 0.12-0.22), and BMI (HR = 0.20, 95% CI = 0.15-0.27) had beneficial effects on proteinuria. Despite no significant benefit of diet score, the corresponding lower sodium intake showed a lower risk of proteinuria (HR = 0.58, 95% CI = 0.43-0.79). Incident proteinuria was inversely related to the number of ideal CVH metrics. CVH metrics may be a predictor of proteinuria, and achieving a higher number of ideal scores should be recommended as a proteinuria prevention strategy.

Characteristics of sarcopenia subjects in arterial pulse spectrum analysis.

Aims: Sarcopenia is significantly associated with the number of cardiovascular and metabolic diseases, however, the underlying pathophysiological processes are largely unknown. This study performed harmonic index of finger photoplethysmography (PPG) waveforms with the aims of distinguishing different arterial pulse waveform signals between sarcopenia, presarcopenia, dynapenia, and healthy subjects. Methods: Sixty-eight subjects were enrolled and obtained 1-min PPG signals, then were assigned to four age-matched groups: control, dynapenia, presarcopenia, and sarcopenia which definition according to Asian Working Group for Sarcopenia (AWGS): 2019 Consensus Update on Sarcopenia Diagnosis and Treatment. Harmonics 1-10 of the PPG waveform were obtained and calculated each of the amplitude proportions (C n ), standard deviations (SD n ), coefficients of variations (CV n ), and vascular elasticity index (VEI) for to evaluating the blood-pressure harmonic variability. Results: The prevalence of sarcopenia in women gender (8 out of 9, 88.9%, p = 0.046) and osteoporosis in dynapenia (7 out of 16, 43.8%, p = 0.005) were significant higher. Among the four groups, compared with control, dynapenia, and presarcopenia, sarcopenia had largest SD n -values for harmonics 1, 2, 3, and 5 (ratio 1, 2, 3, 5 = 0.354, 0.209, 0.137, 0.074); whereas sarcopenia had largest coefficients of variations (CV n ) values for harmonics 1, 2, 3 and 10 (ratio 1, 2, 3, 10 = 0.263, 0.310, 0.402, 0.791). Besides, the Δ odds ratio of ratio 3, 4,and 6 tertile values were significantly increased in sarcopenia and possible sarcopenia group compared with control group. Subjects with sarcopenia had significantly higher VEI in mean, SD, and CV of the PPG waveform (mean = 2.332, SD = 1.479, CV = 0.634, p = 0.007) among the groups and the results of binary logistic regression analysis in the tertiles met statistical significance between the sarcopenia and non-sarcopenia groups whether adjusted or unadjusted (adjusted odds ratio 6.956, p = 0.030, unadjusted odds ratio 3.937, p = 0.039). Conclusions: The elasticity of vessels among sarcopenia groups in lower-frequency components of harmonic ratio in which we defined as VEI showed a significantly highest VEI mean, SD, and CV in sarcopenia indicates the poorer elasticity of the arteries. The present findings showed finger PPG waveform measurements may be useful for early detection of vascular diseases with patients with sarcopenia in a non-invasive and easy-to-perform technique which may expand the clinical applicability in the future.

Comparison Analysis Based on Complete Chloroplast Genomes and Insights into Plastid Phylogenomic of Four Iris Species.

Iris species, commonly known as rainbow flowers because of their attractive flowers, are extensively grown in landscape gardens. A few species, including Belamcanda chinensis, the synonym of I. domestica and I. tectorum, are known for their medicinal properties. However, research on the genomes and evolutionary relationships of Iris species is scarce. In the current study, the complete chloroplast (CP) genomes of I. tectorum, I. dichotoma, I. japonica, and I. domestica were sequenced and compared for their identification and relationship. The CP genomes of the four Iris species were circular quadripartite with similar lengths, GC contents, and codon usages. A total of 113 specific genes were annotated, including the ycf1 pseudogene in all species and rps19 in I. japonica alone. All the species had mononucleotide (A/T) simple sequence repeats (SSRs) and long forward and palindromic repeats in their genomes. A comparison of the CP genomes based on mVISTA and nucleotide diversity (Pi) identified three highly variable regions (ndhF-rpl32, rps15-ycf1, and rpl16). Phylogenetic analysis based on the complete CP genomes concluded that I. tectorum is a sister of I. japonica, and the subgenus Pardanthopsis with several I. domestica clustered into one branch is a sister of I. dichotoma. These findings confirm the feasibility of superbarcodes (complete CP genomes) for Iris species authentication and could serve as a resource for further research on Iris phylogeny.

Phylogenetic position and morphological polymorphism of the chafer, Clinterocera nigra (Coleoptera: Scarabaeidae: Cetoniinae) from Taiwan.

Three mitochondrial genomes of the cetoniine beetle, Clinterocera nigra (Kano, 1931) were assembled via next-generation sequencing. The newly sequenced mitogenomes all have 37 genes, showing standard gene order and annotation as the other insects. To examine their phylogenetic positions and relationships between their elytral color (red-spot and melanistic forms) and sequence variation, a total of 118 public mitogenomes of Scarabaeidae were used to infer a maximum-likelihood (ML) tree. Our results show that the melanistic form is grouped within red-spot ones, revealing a population level variation on the elytra color. Our work also provides the first mitogenomic reference of myrmecophilous chafers.

Arthrospira Enhances Seroclearance in Patients with Chronic Hepatitis B Receiving Nucleos(t)ide Analogue through Modulation of TNF-α/IFN-γ Profile.

Chronic hepatitis B (CHB) virus infection, causing immune dysfunction and chronic hepatitis, is one of the leading risk factors for hepatocellular cancer. We investigated how Arthrospira affected hepatitis B surface antigen (HBsAg) reduction in CHB patients under continued nucleos(t)ide analogues (NA). Sixty CHB patients who had been receiving NA for at least one year with undetectable HBV DNA were randomized into three groups: control and oral Arthrospira at 3 or 6 g daily add-on therapy groups. Patients were followed up for 6 months. Oral Arthrospira-diet mice were established to investigate the possible immunological mechanism of Arthrospira against HBV. Within 6 months, mean quantitative HBsAg (qHBsAg) decreased in the oral Arthrospira add-on therapy group. Interestingly, interferon gamma (IFN-γ) increased but TNF-α, interleukin 6 (IL-6), hepatic fibrosis, and steatosis decreased in the add-on groups. In mice, Arthrospira enhanced both innate and adaptive immune system, especially natural killer (NK) cell cytotoxicity, B cell activation, and the interleukin 2 (IL-2), IFN-γ immune response. Arthrospira may modulate IL-2- and TNF-α/IFN-γ-mediated B and T cell activation to reduce HBsAg. Also, Arthrospira has the potential to restore immune tolerance and enhance HBsAg seroclearance in CHB patients through promoting T, B, and NK cell activation.

Proteinuria as a Nascent Predictor of Frailty Among People With Metabolic Syndrome: A Retrospective Observational Study.

Frailty is a commonly occurring geriatric condition that increases the risk of adverse health outcomes. The factors and predictors behind frailty are not yet well understood. A better understanding of these factors can enable prevention of frailty in elderly patients. The objective of this study was to determine the association between proteinuria and frailty in US individuals with metabolic syndrome (MetS). Data from the National Health and Nutrition Examination Survey III (NHANES III, 1988-1994) conducted by the National Center for Health Statistics of the Centers for Disease Control and Prevention. This is a cross-sectional study, and proteinuria and frailty were measured only once at enrollment. The study included 2,272 participants with MetS aged 40-90 years from the NHANES III. The participants underwent assessments to evaluate frailty and frailty components (low body weight, weakness, exhaustion, low physical activity, and slow walking). Proteinuria was represented as albumin-to-creatinine ratio (ACR) (mg/g) and divided into tertiles: T1-normal range (ACR <30 mg/g), T2-microalbuminuria (ACR 30-299 mg/g), and T3-macroalbuminuria (ACR ≥ 300 mg/g). We applied multiple logistic regression to determine the odds ratios (ORs) of frailty for T2 vs. T1 and T3 vs. T1 in both sexes. In the adjusted analysis for male participants, the ORs of frailty for T2 and T3 vs. T1 were 3.106 (95% confidence interval [CI] = 1.078-8.948, P = 0.036) and 14.428 (95% CI = 4.231-49.193, P < 0.001), respectively. For female participants, the ORs of frailty for T2 and T3 vs. T1 were 1.811 (95% CI = 1.071-3.063, P = 0.027) and 2.926 (95% CI = 1.202-7.124, P = 0.018), respectively. The positive association between T2 and T3 vs. T1, and frailty were statistically significant. The trends of higher likelihood of every frailty component were also statistically significant across increasing tertiles of proteinuria after multiple levels of adjustment for covariates (P < 0.05). Increased proteinuria levels were positively associated with frailty and each frailty component. Proteinuria might be a useful maker for frailty in individuals with MetS.

Association Between Ideal Cardiovascular Health and Vegetarian Dietary Patterns Among Community-Dwelling Individuals.

Background: Vegetarians have been shown to have better metabolic profiles than non-vegetarians, and vegetarianism has potential beneficial effects on cardiovascular disease. However, there is a lack of studies on vegetarians that examine both metabolic profiles and lifestyle habits, such as physical activity, smoking habits, and dietary patterns, which are equally important in the context of cardiovascular disease. We explored whether a vegetarian diet is associated with both metabolic traits and lifestyle habits by assessing cardiovascular health (CVH) metrics. Methods: This was a cross-sectional study conducted in a Taiwanese population. Data collected between 2000 and 2016 were extracted from the MJ Health database. Participants aged 40 years and older without cardiovascular disease were included. CVH metrics included smoking habits, blood pressure, total cholesterol, serum glucose, body mass index, physical activity, and healthy diet score. Vegetarian participants were full-time vegetarians who did not consume meat or fish. All the data were assessed from self-report questionnaires, physical examinations, and blood analyses following standard protocol. Multiple logistic regression analysis was used to evaluate the association between vegetarianism and CVH metrics. Results: Of 46,287 eligible participants, 1,896 (4.1%) were vegetarian. Overall, vegetarians had better CVH metrics (OR = 2.09, 95% CI = 1.84-2.37) but lower healthy diet scores (OR = 0.41, 95% CI = 0.33-0.51) after adjustment. No difference in physical activity (OR = 0.86, 95% CI = 0.73-1.02) was identified between vegetarians and non-vegetarians. Additionally, vegetarians had higher whole grain intake (OR = 2.76, 95% CI = 2.28-3.35) and lower sugar-sweetened beverage consumption (OR = 1.36, 95% CI = 1.18-1.58). Conclusions: Our results suggested that vegetarians had better overall ideal CVH metrics but lower ideal healthy diet scores than non-vegetarians, which was likely due to the lack of fish consumption in this population group. When assessing CVH metrics and healthy diet scores for vegetarians, metrics and scores chosen should be suitable for use with vegetarian populations.

Aberrant overexpression of HOTAIR inhibits abdominal adipogenesis through remodelling of genome-wide DNA methylation and transcription.

OBJECTIVE: Abdominal adiposity is strongly associated with diabetic and cardiovascular comorbidities. The long noncoding RNA HOTAIR (HOX Transcript Antisense Intergenic RNA) is an important epigenetic regulator with fat depot-specific expression. Its functional roles and epigenetic regulation in abdominal adipogenesis remain uncertain. METHODS: We collected different fat depots from healthy, severely obese, and uraemic subjects to measure fat-depot specific gene expression and quantify regional adiposity via dual-energy X-ray absorptiometry (DXA). HOTAIR was overexpressed to evaluate its functional roles. Reduced representation bisulfite sequencing (RRBS), RNA-sequencing, real-time qPCR and RNA/chromatin immunoprecipitation were performed to analyse HOTAIR-mediated epigenetic regulation. RESULTS: A negative correlation between adipose tissue HOTAIR expression (arm or abdominal subcutaneous fat depots) and regional adiposity under the status of severe obesity or uraemia was observed. HOTAIR overexpression using human immortalized abdominal preadipocytes further revealed its anti-adipogenic effects. Integrative analysis of genome-wide DNA methylation by reduced representation bisulfite sequencing (RRBS) and gene expression was performed. Overall, the differentially methylated genes were functionally enriched for nervous system development, suggesting that HOTAIR may be epigenetically associated with cell lineage commitment. We specifically found that HOTAIR-mediated genes showed strong changes in both DNA methylation and gene expression during abdominal adipogenesis. We observed that two HOTAIR-repressed genes, SLITRK4 and PITPNC1, present an obesity-driven fat-depot specific expression pattern that is positively correlated with the central body fat distribution. CONCLUSIONS: Our study indicated that HOTAIR is a key regulator of abdominal adipogenesis via intricate DNA methylation and is likely to be associated with the transcriptional regulation of genes involved in nervous system development and lipid metabolism, such as SLITRK4 and PITPNC1.

Out of Asia: Intercontinental dispersals after the Eocene-Oligocene transition shaped the zoogeography of Limenitidinae butterflies (Lepidoptera: Nymphalidae).

Most members of the nymphalid subfamily Limenitidinae are distributed in tropical regions of Africa, Asia, and the Americas. Previous studies have inferred their higher-level phylogeny and found that Southeast Asia seems to be the center of origin, with numerous dispersal events to other continents. However, the complete biogeographic history of Limenitidinae butterflies is still largely unknown. We sampled 181 taxa from 164 species and used a metagenomic method to obtain 40 genes (mitogenomes and three nuclear ribosomal loci) for inferring the historical biogeography of the group. We find that Limenitidinae originated in eastern Asia during the early Eocene (ca. 52 Ma) and started to diversify and disperse into Africa before the end of Eocene. Intercontinental exchanges between Africa and eastern Asia continued in the early Miocene: Asian Adoliadini and Asian endemic taxa Bhagadatta had African origins in the Oligocene, whereas African Neptini dispersed in the opposite direction from Asia in the early Miocene. In addition, ancestors of the tribes Limenitidini and Adoliadini dispersed into the Neotropics and Australasia multiple times during the early-to-middle Miocene. Eastern Asia is the center of origin of the tribe Limenitidini, with several taxa disjunctly distributed in eastern Asia and the Americas. Our work provides a robust phylogenetic hypothesis of relationships in the tribe Limenitidini and suggests that the alala-species group of Adelpha should be placed in the genus Limenitis. Renamed taxa comb. nov. based on our findings are listed in the text.

Relationship between ideal cardiovascular health metrics and hearing loss: A 10-year retrospective cohort study.

OBJECTIVE: The role of ideal cardiovascular health (CVH) metrics in developing hearing loss remains uncertain. Thus, our objective was to analyse the connection between hearing loss and ideal CVH metrics in a 10-year retrospective cohort. STUDY DESIGN: Retrospective cohort study. SETTING: A health management centre in Taiwan. PARTICIPANTS: Participants who underwent the first annual health check-up between 2000 and 2006 and with a follow-up check-up more than ten years later. MAIN OUTCOME MEASURES: Hearing thresholds were measured at 500 Hz, 1000 Hz, 2000 Hz and 4000 Hz. Individuals with a best ear pure-tone audiometry four-frequency average of >25 dB HL were defined as having hearing loss. The ideal CVH metrics were classified into 7 categories based on the American Heart Association's definition. The associations of hearing loss with the sum of the ideal CVH metrics and each ideal CVH metric were examined by multiple logistic regression analysis. RESULTS: The present study consisted of 6974 participants. The 10-year follow-up showed that the odds ratio (OR) of hearing loss was .74 for participants with 5-7 ideal CVH metrics (95% CI, .59-.93, p = .01) compared with those with 0-2 ideal CVH metrics. Among the CVH metrics, participants with an ideal smoking status might have reduced odds of developing hearing loss; the OR was .72 (95% CI, .58-.89, p = .003). CONCLUSIONS: Participants with an increased number of ideal CVH metrics and better performance on the smoking metric had a significantly protective effect regarding hearing loss development.

The Polymorphism at PLCB4 Promoter (rs6086746) Changes the Binding Affinity of RUNX2 and Affects Osteoporosis Susceptibility: An Analysis of Bioinformatics-Based Case-Control Study and Functional Validation.

Purpose: Genome-wide association studies have identified numerous genetic variants that are associated with osteoporosis risk; however, most of them are present in the non-coding regions of the genome and the functional mechanisms are unknown. In this study, we aimed to investigate the potential variation in runt domain transcription factor 2 (RUNX2), which is an osteoblast-specific transcription factor that normally stimulates bone formation and osteoblast differentiation, regarding variants within RUNX2 binding sites and risk of osteoporosis in postmenopausal osteoporosis (PMOP). Methods: We performed bioinformatics-based prediction by combining whole genome sequencing and chromatin immunoprecipitation sequencing to screen functional SNPs in the RUNX2 binding site using data from the database of Taiwan Biobank; Case-control studies with 651 postmenopausal women comprising 107 osteoporosis patients, 290 osteopenia patients, and 254 controls at Tri-Service General Hospital between 2015 and 2019 were included. The subjects were examined for bone mass density and classified into normal and those with osteopenia or osteoporosis by T-scoring with dual-energy X-ray absorptiometry. Furthermore, mRNA expression and luciferase reporter assay were used to provide additional evidence regarding the associations identified in the association analyses. Chi-square tests and logistic regression were mainly used for statistical assessment. Results: Through candidate gene approaches, 3 SNPs in the RUNX2 binding site were selected. A novel SNP rs6086746 in the PLCB4 promoter was identified to be associated with osteoporosis in Chinese populations. Patients with AA allele had higher risk of osteoporosis than those with GG+AG (adjusted OR = 6.89; 95% confidence intervals: 2.23-21.31, p = 0.001). Moreover, the AA genotype exhibited lower bone mass density (p < 0.05). Regarding mRNA expression, there were large differences in the correlation between PLCB4 and different RUNX2 alleles (Cohen's q = 0.91). Functionally, the rs6086746 A allele reduces the RUNX2 binding affinity, thus enhancing the suppression of PLCB4 expression (p < 0.05). Conclusions: Our results provide further evidence to support the important role of the SNP rs6086746 in the etiology of osteopenia/osteoporosis, thereby enhancing the current understanding of the susceptibility to osteoporosis. We further studied the mechanism underlying osteoporosis regulation by PLCB4.

Favorable self­rated health is associated with ideal cardiovascular health: a cohort study.

INTRODUCTION: Both self­rated health (SRH) and the cardiovascular health (CVH) metrics of the American Heart Association have been reported as predictors of cardiovascular events. However, a longitudinal study of the relationships between these metrics has not been conducted before. OBJECTIVES: We investigated the association between SRH and CVH metrics in a longitudinal study involving an Asian population. PATIENTS AND METHODS: Eligible participants were enrolled between 2009 and 2014. Multivariable logistic regression models were used to examine the association between SRH and overall ideal CVH metrics as well as each ideal CVH metric at baseline and during follow­up. Additionally, we classified participants into 3 groups according to the change in SRH after 3 years of follow­up and analyzed the changes in ideal CVH metrics in these groups. RESULTS: Our study group consisted of 15 608 participants. After a mean follow­up of 2.69 years, participants who classified their health as "Poor" or "Very Poor" had reduced odds ratios (ORs) for ideal CVH metrics, with ORs of 0.68 (95% CI, 0.54-0.85; P = 0.001) and 0.59 (95% CI, 0.37-0.96; P = 0.03) for "Poor" and "Very Poor" SRH, respectively. In contrast, the odds for increased ideal CVH metrics rose as SRH improved (OR, 1.20; 95% CI, 1.07-1.36; P = 0.002). CONCLUSIONS: Changes in SRH ratings might accurately reflect changes in CVH metrics. Our longitudinal study demonstrated that SRH was significantly associated with the number of ideal CVH metrics. Our findings provide epidemiological evidence for future public health strategies targeting cardiovascular disease.