C-Reactive Protein: The Most Familiar Stranger.

C-reactive protein (CRP) is a highly conserved pentraxin with pattern recognition receptor-like activities. However, despite being used widely as a clinical marker of inflammation, the in vivo functions of CRP and its roles in health and disease remain largely unestablished. This is, to certain extent, due to the drastically different expression patterns of CRP in mice and rats, raising concerns about whether the functions of CRP are essential and conserved across species and how these model animals should be manipulated to examine the in vivo actions of human CRP. In this review, we discuss recent advances highlighting the essential and conserved functions of CRP across species, and propose that appropriately designed animal models can be used to understand the origin-, conformation-, and localization-dependent actions of human CRP in vivo. The improved model design will contribute to establishing the pathophysiological roles of CRP and facilitate the development of novel CRP-targeting strategies.

Dual-Network Collaborative Matrix Factorization for predicting small molecule-miRNA associations.

MicroRNAs (miRNAs) play crucial roles in multiple biological processes and human diseases and can be considered as therapeutic targets of small molecules (SMs). Because biological experiments used to verify SM-miRNA associations are time-consuming and expensive, it is urgent to propose new computational models to predict new SM-miRNA associations. Here, we proposed a novel method called Dual-network Collaborative Matrix Factorization (DCMF) for predicting the potential SM-miRNA associations. Firstly, we utilized the Weighted K Nearest Known Neighbors (WKNKN) method to preprocess SM-miRNA association matrix. Then, we constructed matrix factorization model to obtain two feature matrices containing latent features of SM and miRNA, respectively. Finally, the predicted SM-miRNA association score matrix was obtained by calculating the inner product of two feature matrices. The main innovations of this method were that the use of WKNKN method can preprocess the missing values of association matrix and the introduction of dual network can integrate more diverse similarity information into DCMF. For evaluating the validity of DCMF, we implemented four different cross validations (CVs) based on two distinct datasets and two different case studies. Finally, based on dataset 1 (dataset 2), DCMF achieved Area Under receiver operating characteristic Curves (AUC) of 0.9868 (0.8770), 0.9833 (0.8836), 0.8377 (0.7591) and 0.9836 ± 0.0030 (0.8632 ± 0.0042) in global Leave-One-Out Cross Validation (LOOCV), miRNA-fixed local LOOCV, SM-fixed local LOOCV and 5-fold CV, respectively. For case studies, plenty of predicted associations have been confirmed by published experimental literature. Therefore, DCMF is an effective tool to predict potential SM-miRNA associations.

miR-194 Up-Regulates Cholesterol 7 Alpha-Hydroxylase Expression via ß-Catenin Signaling and Aggravates Cholestatic Liver Diseases.

miR-194 is abundantly expressed in hepatocytes, and its depletion increases hepatic resistance to acetaminophen-induced acute injuries. In this study, the biological role of miR-194 in cholestatic liver injury was investigated by using miR-194/miR-192 cluster liver-specific knockout (LKO) mice, in which no liver injuries or metabolic disorders were predisposed. Bile duct ligation (BDL) and 1-naphthyl isothiocyanate (ANIT) were applied to LKO and matched control wild-type (WT) mice to induce hepatic cholestasis. Periportal liver damage, mortality rate, and liver injury biomarkers in LKO mice were significantly less than in WT mice after BDL and ANIT injection. Intrahepatic bile acid level was significantly lower in the LKO liver within 48 hours of BDL- and ANIT-induced cholestasis compared with WT. Western blot analysis showed that ß-catenin (CTNNB1) signaling and genes involved in cellular proliferation were activated in BDL- and ANIT-treated mice. The expression levels of cholesterol 7 alpha-hydroxylase (CYP7A1), pivotal in bile synthesis, and its upstream regulator hepatocyte nuclear factor 4α were reduced in primary LKO hepatocytes and liver tissues compared with WT. The knockdown of miR-194 using miRNA inhibitors reduced CYP7A1 expression in WT hepatocytes. In contrast, the knockdown of CTNNB1 and overexpression of miR-194, but not miR-192, in LKO hepatocytes and AML12 cells increased CYP7A1 expression. In conclusion, the results suggest that the loss of miR-194 ameliorates cholestatic liver injury and may suppress CYP7A1 expression via activation of CTNNB1 signaling.

Tale of Two Polymorphs: Investigating the Structural Differences and Dynamic Relationship between Nirmatrelvir Solid Forms (Paxlovid).

Two anhydrous polymorphs of the novel antiviral medicine nirmatrelvir were discovered during the development of Paxlovid, Pfizer's oral Covid-19 treatment. A comprehensive experimental and computational approach was necessary to distinguish the two closely related polymorphs, herein identified as Forms 1 and 4. This approach paired experimental methods, including powder X-ray diffraction and single-crystal X-ray diffraction, solid-state experimental methods, thermal analysis, solid-state nuclear magnetic resonance and Raman spectroscopy with computational investigations comprising crystal structure prediction, Gibbs free energy calculations, and molecular dynamics simulations of the polymorphic transition. Forms 1 and 4 were ultimately determined to be enantiotropically related polymorphs with Form 1 being the stable form above the transition temperature of ∼17 °C and designated as the nominated form for drug development. The work described in this paper shows the importance of using highly specialized orthogonal approaches to elucidate the subtle differences in structure and properties of similar solid-state forms. This synergistic approach allowed for unprecedented speed in bringing Paxlovid to patients in record time amidst the pandemic.

Highly Emissive and Robust Cd-Based MOF with an Unprecedented Topology for Tetracycline Sensing.

Herein, an unprecedented cadmium-based metal-organic framework (JNU-106) fabricated by utilizing pyrazole-functionalized tetraphenylethylene ligands (Py-TPE) and rod-shaped secondary building units is reported, possessing a new (3,3,3,6,6,8)-connected topological network. Thanks to the ingeniously designed intramolecular charge transfer behavior, which originates from the congruent coplanarity between Py and TPE, JNU-106 exhibits intense green luminescence with a quantum yield increased by 1.5 times. The phenomenon of remarkable fluorescence quenching of JNU-106 reveals that it possesses extremely high anti-interference performance, superior sensitivity, and dedicated selectivity toward tetracycline antibiotics (TCAs) in aqueous solutions, which are comparable to those of the state-of-the-art porous sensing compounds. Taking the theoretical calculations and experimental results into account, the luminescence quenching is mainly attributed to the internal filtration effect and the static quenching effect. Considering the portable and rapid performance of JNU-106-based testing strips for sensing TCAs, the fabricated JNU-106 provides an alternative for ecological monitoring and environmental governance.

CyanoStrainChip: A Novel DNA Microarray Tool for High-Throughput Detection of Environmental Cyanobacteria at the Strain Level.

Detecting cyanobacteria in environments is an important concern due to their crucial roles in ecosystems, and they can form blooms with the potential to harm humans and nonhuman entities. However, the most widely used methods for high-throughput detection of environmental cyanobacteria, such as 16S rRNA sequencing, typically provide above-species-level resolution, thereby disregarding intraspecific variation. To address this, we developed a novel DNA microarray tool, termed the CyanoStrainChip, that enables strain-level comprehensive profiling of environmental cyanobacteria. The CyanoStrainChip was designed to target 1277 strains; nearly all major groups of cyanobacteria are included by implementing 43,666 genome-wide, strain-specific probes. It demonstrated strong specificity by in vitro mock community experiments. The high correlation (Pearson's R > 0.97) between probe fluorescence intensities and the corresponding DNA amounts (ranging from 1-100 ng) indicated excellent quantitative capability. Consistent cyanobacterial profiles of field samples were observed by both the CyanoStrainChip and next-generation sequencing methods. Furthermore, CyanoStrainChip analysis of surface water samples in Lake Chaohu uncovered a high intraspecific variation of abundance change within the genus Microcystis between different severity levels of cyanobacterial blooms, highlighting two toxic Microcystis strains that are of critical concern for Lake Chaohu harmful blooms suppression. Overall, these results suggest a potential for CyanoStrainChip as a valuable tool for cyanobacterial ecological research and harmful bloom monitoring to supplement existing techniques.

The coexistence of high piezoelectricity and superior optical absorption in Janus Bi2X2Y (X = Te, Se; Y = Te, Se, S) monolayers.

Bismuth chalcogenide and its derivatives have been attracting attention in various fields as semiconductors or topological insulators. Inspired by the high piezoelectric properties of Janus Bi2TeSeS monolayer and the excellent optical absorption properties of the Bi2X3 (X = Te, Se, S) monolayers, we theoretically predicted four new-type two-dimensional (2D) monolayers Janus Bi2X2Y (X = Te, Se; Y = Te, Se, S) using the first principles combined with density functional theory (DFT). The thermal, dynamic, and mechanical stabilities of Janus Bi2X2Y monolayers were confirmed based on ab initio molecular dynamics (AIMD) simulations, phonon dispersion, and elastic constants calculations. Their elastic properties, band structures, piezoelectric, and optical properties were systematically investigated. It was found that Janus Bi2X2Y monolayers have a typical Mexican hat-shaped valence band edge structure and, therefore, have a ring-shaped flat band edge, which results in their indirect band gaps. The results show that Janus Bi2X2Y monolayers are semiconductors with moderate band gaps (0.62-0.98 eV at the HSE + SOC level). After considering the electron-phonon renormalization (EPR), the band gaps are reduced by less than 5% at 0 K under the zero-point renormalization (ZPR) and further reduced by approximately 10% at 300 K. Besides, Janus Bi2X2Y monolayers also exhibit excellent optical absorption properties in the blue-UV light region, with the peak values at the order of 8 × 105 cm-1. Particularly, the Janus Bi2Te2S monolayer was found to exhibit a piezoelectric strain coefficient d11 of up to 20.30 pm V-1, which is higher than that of most of the 2D materials. Our results indicate that Janus Bi2X2Y monolayers could be promising candidates in solar cells, optical absorption, and optoelectronic devices; especially, a Janus Bi2Te2S monolayer can also be an excellent piezoelectric material with great prospects in the fields of mechanical and electrical energy conversion.

Risks of Glaucoma among Individuals with Psoriasis: A Population-based Cohort Study.

BACKGROUND: Psoriasis is a chronic systemic disorder with ocular involvement. OBJECTIVES: The aim of the present study is to evaluate the risk of glaucoma among psoriatic patients. METHODS: Subjects of this cohort study were selected based on Chang Gung Research Database from January 1, 2003, to December 31, 2012. Follow-up ended on December 31, 2017. The participants of the control group were matched with the psoriatic group by gender, age, and index date at a 4:1 ratio. The hazard ratios of glaucoma were estimated using Cox regression analysis. We also evaluated the relationship between the risk of glaucoma and systemic therapies as well as phototherapy and topical corticosteroid in patients with psoriasis. RESULTS: A total of 6,682 patients with psoriasis and 26,728 matched controls were enrolled. The study population is composed of mainly Males accounting for 64.2% of the study population. The psoriatic group had higher incidence rates than the control group for glaucoma (adjusted hazard ratio 1.405 [95% confidence interval, 1.051-1.879]). Psoriatic patients receiving psoralen and ultraviolet-A (PUVA) therapy for more than 200 sessions had an increased risk of glaucoma. CONCLUSIONS: Psoriatic patients had an increased risk of glaucoma. Long-term PUVA therapy raised the risk of glaucoma in psoriatic populations.

Phosphorylation Modification, Structural Characterization, Antioxidant and DNA Protection Capacities of Polysaccharides from Asarum Sieboldii Miq.

Polysaccharide from Asarum sieboldii Miq (ASP) was extracted and five phosphorylation polysaccharides with different degree of substitution were obtained, namely ASPP1, ASPP2, ASPP3, ASPP4, and ASPP5 (ASPPs). The physical and chemical structure and biological activities were studied. The results suggested that the carbohydrate and protein content were reduced while uronic acid was increased after phosphorylation modification. The molecular weight of ASPPs was significantly lower than that of ASP. ASPPs were acidic heteropolysaccharides mainly composed of galacturonic acid, galactose, glucose, fructose, and arabinose. The UV-vis spectrum indicated that the polysaccharides did not contain nucleic acid or protein after modification. The Fourier transform infrared spectrum demonstrated that ASPPs contained characteristic absorption peaks of P=O and P-O-C near 1270 and 980 cm-1 . ASPPs presented a triple helix conformation, but it was not presented in ASP. The scanning electron microscopy analysis showed that the surface topography and particle structure of ASP were different after modification. Compared with ASP, ASPPs enhanced the activity to scavenge DPPH and ABTS free radicals and possessed more protective ability to DNA oxidation caused by OH⋅, GS⋅, and AAPH free radicals. These results suggest that chemical modification is beneficial for the exploitation and utilization of natural polysaccharides.

Lipopolysaccharide-Induced Lysosomal Cell Death Through Reactive Oxygen Species in Rat Liver Cell Clone 9.

In sepsis, bacterial components, particularly lipopolysaccharide (LPS), trigger organ injuries such as liver dysfunction. Although sepsis induces hepatocyte damage, the mechanisms underlying sepsis-related hepatic failure remain unclear. In this study, we demonstrated that the LPS-treated rat hepatocyte cell line Clone 9 not only induced reactive oxygen species (ROS) generation and apoptosis but also increased the expression of the autophagy marker proteins LC3-II and p62, and decreased the expression of intact Lamp2A, a lysosomal membrane protein. Additionally, LPS increased lysosomal membrane permeability and galectin-3 puncta formation, and promoted lysosomal alkalization in Clone 9 cells. Pharmacological inhibition of caspase-8 and cathepsin D (CTSD) suppressed the activation of caspase-3 and rescued the viability of LPS-treated Clone 9 cells. Furthermore, LPS induced CTSD release associated with lysosomal leakage and contributed to caspase-8 activation. Pretreatment with the antioxidant N-acetylcysteine (NAC) not only diminished ROS generation and increased the cell survival rate, but also decreased the expression of activated caspase-8 and caspase-3 and increased the protein level of Lamp2A in LPS-treated Clone 9 cells. These results demonstrate that LPS-induced ROS causes lysosomal membrane permeabilization and lysosomal cell death, which may play a crucial role in hepatic failure in sepsis. Our results may facilitate the development of new strategies for sepsis management.

Association of lipid levels with motor and cognitive function and decline in Parkinson's disease.

BACKGROUND: Most studies have focused on comparing blood lipid biomarkers between Parkinson's disease (PD) and normal controls (NC). However, further research is necessary to explore the impact of blood lipid levels on motor and cognitive function, as well as the progression of motor dysfunction and cognitive decline over time. Thus, the aim of this study is to investigate the relationship between blood lipid biomarkers and these indicators in individuals with PD. METHODS: The cohort study enrolled 157 PD patients and 146 NC from the Tianjin Huanhu Hospital from September 2017 to September 2019. Serum lipid fractions were detected in fasting serum samples. PD patients were followed up at 2 ± 0.6 years for clinical assessment. RESULTS: PD patients exhibited lower serum triglyceride (TG) levels as compared to NC (P = 0.008). PD male patients exhibited lower serum lipoprotein cholesterol(LDL-C) and total cholesterol (TC) levels than female patients (LDL-C: P = 0.034; TC: P = 0.019). Serum TG levels correlated significantly with Unified PD Rating Scale III, Hoehn and Yahr stage and Montreal Cognitive Assessment scores in PD patients. Additionally, serum TG levels were associated with follow-up motor function decline and cognitive decline in adjusted regression models in PD patients. CONCLUSIONS: To summarise, the study findings suggest that decreased serum TG levels are significantly associated with greater motor dysfunction, cognitive dysfunction and the greater deterioration of the two indicators.

High contrast ratio electrophoretic displays based on high structural stability and high transmittance microcup.

In the age of Internet of Things, electrophoretic electronic paper (E-paper) holds a unique position in the display area due to its energy-saving, environmental friendliness, excellent readability in strong ambient light, and eye protection. Compared with E-papers of microcapsules, microcups have several advantages including higher mechanical strength, lower production costs, and better feasibility to show multiple colors with high contrast, thereby making it a significant research interest. However, there is currently no systematic study on the structural mechanics and display performances of microcups. Herein, we simulate the structural stability of microcups with various shapes and sizes during nanoimprint process, and also calculated the aperture ratio of these microcups. We fabricated devices with different geometrical morphologies to verify the microcups for achieving a balance between high contrast, high transmittance and high structural stability. This study provides a new method for designing and manufacturing the E-papers of microcups in using nanoimprint roll-to-roll (R2R) production.

Spatiotemporal roles of AMPK in PARP-1- and autophagy-dependent retinal pigment epithelial cell death caused by UVA.

BACKGROUND: Although stimulating autophagy caused by UV has been widely demonstrated in skin cells to exert cell protection, it remains unknown the cellular events in UVA-treated retinal pigment epithelial (RPE) cells. METHODS: Human ARPE-19 cells were used to measure cell viability, mitochondrial reactive oxygen species (ROS), mitochondrial membrane potential (MMP), mitochondrial mass and lysosomal mass by flow cytometry. Mitochondrial oxygen consumption rate (OCR) was recorded using Seahorse XF flux analyzer. Confocal microscopic images were performed to indicate the mitochondrial dynamics, LC3 level, and AMPK translocation after UVA irradiation. RESULTS: We confirmed mitochondrial ROS production and DNA damage are two major features caused by UVA. We found the cell death is prevented by autophagy inhibitor 3-methyladenine and gene silencing of ATG5, and UVA induces ROS-dependent LC3II expression, LC3 punctate and TFEB expression, suggesting the autophagic death in the UVA-stressed RPE cells. Although PARP-1 inhibitor olaparib increases DNA damage, ROS production, and cell death, it also blocks AMPK activation caused by UVA. Interestingly we found a dramatic nuclear export of AMPK upon UVA irradiation which is blocked by N-acetylcysteine and olaparib. In addition, UVA exposure gradually decreases lysosomal mass and inhibits cathepsin B activity at late phase due to lysosomal dysfunction. Nevertheless, cathepsin B inhibitor, CA-074Me, reverses the death extent, suggesting the contribution of cathepsin B in the death pathway. When examining the role of EGFR in cellular events caused by UVA, we found that UVA can rapidly transactivate EGFR, and treatment with EGFR TKIs (gefitinib and afatinib) enhances the cell death accompanied by the increased LC3II formation, ROS production, loss of MMP and mass of mitochondria and lysosomes. Although AMPK activation by ROS-PARP-1 mediates autophagic cell death, we surprisingly found that pretreatment of cells with AMPK activators (A769662 and metformin) reverses cell death. Concomitantly, both agents block UVA-induced mitochondrial ROS production, autophagic flux, and mitochondrial fission without changing the inhibition of cathepsin B. CONCLUSION: UVA exposure rapidly induces ROS-PARP-1-AMPK-autophagic flux and late lysosomal dysfunction. Pre-inducing AMPK activation can prevent cellular events caused by UVA and provide a new protective strategy in photo-oxidative stress and photo-retinopathy.

Impact on carbamazepine usage and cutaneous adverse reactions before and after the reimbursement of HLA-B*1502 genotyping in Taiwan, 2000-2017: A nationwide longitudinal study.

OBJECTIVE: The HLA-B*1502 allele is strongly associated with carbamazepine (CBZ)-induced Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) in the Han Chinese population. This study investigated the impact of HLA-B*1502 screening on CBZ utilization and rates of severe cutaneous allergic reactions (SCARs) and SJS/TEN over time in Taiwan, where screening for HLA-B*1502 genotyping before prescribing CBZ was reimbursed in June 2010. METHODS: Using the Taiwan National Health Insurance Research Database, we analyzed 13 277 457 episodes of seeking treatment for epilepsy or neuralgia between 2000 and 2017. Episodes were categorized into quarters based on treatment time. Propensity score-based stabilized weighting (PSSW) ensured well-balanced covariates. The difference in 3-month SCAR and SJS/TEN rates between phase 2 (2011-2017) and phase 1 (2000-2009) was examined using a one-sample Z-test. Pearson correlation coefficients assessed the association between screening rate, the number of CBZ users and nonusers, and SCAR and SJS/TEN rates after HLA-B*1502 genotyping. RESULTS: CBZ prescriptions reduced from 7% (2000-2003) to 6% (2004-2010) and 4% (2011-2017). The screening rates of CBZ nonusers and CBZ users increased from 0%, .5% in 2011 to .8%, 16% in 2017, respectively. After PSSW, the mean 3-month SCAR incidence rates (per 10 000 episodes) significantly decreased from phase 1 to phase 2 for CBZ users (6.91 vs. 3.09, p < .0001) and nonusers (1.96 vs. 1.65, p < .0001). SJS/TEN incidence rates (per 10 000 episodes) significantly decreased from phase 1 to phase 2 for CBZ users (2.94 vs. 1.93, p < .0001) but not for nonusers (.71 vs. .74, p = .1492). In phase 2, SCAR incidence rates were significantly and negatively correlated with the screening rate for both CBZ users (r = -.38, p = .0342) and nonusers (r = -.80, p < .001). No significant correlation was found between SJS/TEN incidence rates and screening rates. SIGNIFICANCE: Recognizing HLA-B*1502 allele and avoiding CBZ therapy in HLA-B*1502-positive patients is critical for preventing CBZ-induced severe adverse events.

Effects of High-Definition Transcranial Direct Current Stimulation Targeting the Anterior Cingulate Cortex on the Pain Thresholds: A Randomized Controlled Trial.

BACKGROUND: The majority of existing clinical studies used active transcranial direct current stimulation (tDCS) over superficial areas of the pain neuromatrix to regulate pain, with conflicting results. Few studies have investigated the effect of tDCS on pain thresholds by focusing on targets in deep parts of the pain neuromatrix. METHODS: This study applied a single session of high-definition tDCS (HD-tDCS) targeting the anterior cingulate cortex (ACC) and used a parallel and sham-controlled design to compare the antinociceptive effects in healthy individuals by assessing changes in pain thresholds. Sixty-six female individuals (mean age, 20.5 ± 2.4 years) were randomly allocated into the anodal, cathodal, or sham HD-tDCS groups. The primary outcome of the study was pain thresholds (pressure pain threshold, heat pain threshold, and cold pain threshold), which were evaluated before and after stimulation through the use of quantitative sensory tests. RESULTS: Only cathodal HD-tDCS targeting the ACC significantly increased heat pain threshold (P < 0.05) and pressure pain threshold (P < 0.01) in healthy individuals compared with sham stimulation. Neither anodal nor cathodal HD-tDCS showed significant analgesic effects on cold pain threshold. Furthermore, no statistically significant difference was found in pain thresholds between anodal and sham HD-tDCS (P > 0.38). Independent of HD-tDCS protocols, the positive and negative affective schedule scores were decreased immediately after stimulation compared with baseline. CONCLUSIONS: The present study has found that cathodal HD-tDCS targeting the ACC provided a strong antinociceptive effect (increase in pain threshold), demonstrating a positive biological effect of HD-tDCS.

Soluble TREM2 in body fluid in Alzheimer's disease and Parkinson's disease.

BACKGROUND: Previous studies showed conflicting results regarding soluble triggering receptor expressed on myeloid cells 2 (sTREM2) level alteration in body fluid in Alzheimer's disease (AD) and Parkinson's disease (PD). METHODS: We applied the STATA 12.0 software to compute standard mean difference (SMD) and 95% confidence interval (CI). RESULTS: The study showed elevated sTREM2 level in cerebrospinal fluid (CSF) in AD, mild cognitive impairment (MCI), and preclinical AD (pre-AD) patients, compared to healthy controls (HCs) with random effects models (AD: SMD 0.28, 95% CI 0.12 to 0.44, I2 = 77.6%, p < 0.001; MCI: SMD 0.29, 95% CI 0.09 to 0.48, I2 = 89.7%, p < 0.001; pre-AD: SMD 0.24, 95% CI 0.00 to 0.48, I2 = 80.8%, p < 0.001). The study showed no significant difference in sTREM2 level in plasma between AD patients and HCs with a random effects model (SMD 0.06, 95% CI - 0.16 to 0.28, I2 = 65.6%, p = 0.008). The study showed no significant difference in sTREM2 level in CSF or plasma between PD patients and HCs with random effects models (CSF: SMD 0.33, 95% CI - 0.02 to 0.67, I2 = 85.6%, p < 0.001; plasma: SMD 0.37, 95% CI - 0.17 to 0.92, I2 = 77.8%, p = 0.011). CONCLUSIONS: In conclusion, the study highlighted the CSF sTREM2 as a promising biomarker in the different clinical stages of AD. More studies were essential to explore the CSF and plasmatic concentrations of sTREM2 alteration in PD.

Pulse Wave Analysis Predicts Invasive Hemodynamics in Pre-Capillary Pulmonary Hypertension.

Background: We tested the hypothesis that non-invasive pulse wave analysis (PWA)-derived systemic circulation variables can predict invasive hemodynamics of pulmonary circulation and the indicator of right heart function, N-terminal pro-brain natriuretic peptide (NT-proBNP), in patients with precapillary pulmonary hypertension (PH). Methods: This prospective study enrolled patients with group 1 and 4 PH who had complete PWA, NT-proBNP, and hemodynamics data. Risk assessment-based "hemodynamic score (HS)" and principal component analysis-based PWA variable grouping were determined/performed. Models of hierarchical multiple linear regression (HMLR) and receiver operating characteristic (ROC) curves were used to determine the relationships of PWA variables with HS and NT-proBNP and to predict the latter parameters. Results: Fifty-three PWAs were included. PWA variables were classified into 4 eigenvalue principal components (representing 90% configuration). Univariate analysis showed that left ventricular ejection time (LVET) was significantly negatively associated with HS and NT-proBNP levels. HMLR analysis showed that LVET was still significantly, negatively, and independently associated with HS (B = -0.006 [-0.010~-0.001]) and NT-proBNP (B = -13.47 [-21.20~-5.73]). ROC curve analysis showed that LVET > 306.9 msec and > 313.2 msec predicted the low-risk group of HS (AUC: 0.802; p = 0.001; sensitivity: 100%; and specificity: 59%) and low-to-intermediate risk levels of NT-proBNP (AUC: 0.831; p < 0.001; sensitivity: 100%; and specificity: 59%). Conclusions: The non-invasive PWA parameter, LVET, is an independent predictor of invasive right heart HS and NT-proBNP levels; it may serve as a novel biomarker of right ventricular function in patients with pre-capillary PH.

2023 Taiwan Society of Cardiology (TSOC) and Taiwan College of Rheumatology (TCR) Joint Consensus on Connective Tissue Disease-Associated Pulmonary Arterial Hypertension.

Background: Pulmonary arterial hypertension (PAH), defined as the presence of a mean pulmonary artery pressure > 20 mmHg, pulmonary artery wedge pressure ≤ 15 mmHg, and pulmonary vascular resistance (PVR) > 2 Wood units based on expert consensus, is characterized by a progressive and sustained increase in PVR, which may lead to right heart failure and death. PAH is a well-known complication of connective tissue diseases (CTDs), such as systemic sclerosis, systemic lupus erythematosus, Sjogren's syndrome, and other autoimmune conditions. In the past few years, tremendous progress in the understanding of PAH pathogenesis has been made, with various novel diagnostic and screening methods for the early detection of PAH proposed worldwide. Objectives: This study aimed to obtain a comprehensive understanding and provide recommendations for the management of CTD-PAH in Taiwan, focusing on its clinical importance, prognosis, risk stratification, diagnostic and screening algorithm, and pharmacological treatment. Methods: The members of the Taiwan Society of Cardiology (TSOC) and Taiwan College of Rheumatology (TCR) reviewed the related literature thoroughly and integrated clinical trial evidence and real-world clinical experience for the development of this consensus. Conclusions: Early detection by regularly screening at-risk patients with incorporations of relevant autoantibodies and biomarkers may lead to better outcomes of CTD-PAH. This consensus proposed specific screening flowcharts for different types of CTDs, the risk assessment tools applicable to the clinical scenario in Taiwan, and a recommendation of medications in the management of CTD-PAH.

Bromodomains regulate dynamic targeting of the PBAF chromatin-remodeling complex to chromatin hubs.

Chromatin remodelers actively target arrays of acetylated nucleosomes at select enhancers and promoters to facilitate or shut down the repeated recruitment of RNA polymerase II during transcriptional bursting. It is poorly understood how chromatin remodelers such as PBAF dynamically target different chromatin states inside a live cell. Our live-cell single-molecule fluorescence microscopy study reveals chromatin hubs throughout the nucleus where PBAF rapidly cycles on and off the genome. Deletion of PBAF's bromodomains impairs targeting and stable engagement of chromatin in hubs. Dual color imaging reveals that PBAF targets both euchromatic and heterochromatic hubs with distinct genome-binding kinetic profiles that mimic chromatin stability. Removal of PBAF's bromodomains stabilizes H3.3 binding within chromatin, indicating that bromodomains may play a direct role in remodeling of the nucleosome. Our data suggests that PBAF's dynamic bromodomain-mediated engagement of a nucleosome may reflect the chromatin-remodeling potential of differentially bound chromatin states.

Atomically Dispersed Cu in Zeolitic Imidazolate Framework Nanoflake Array for Dendrite-Free Zn Metal Anode.

Aqueous Zn metal batteries (AZMBs) have been considered as a promising alternative to the existing Li-ion batteries. Nevertheless, the large-scale application of the AZMBs is restricted by the dendrite formation and side reactions within the Zn metal anodes (ZMAs) during cycling. Herein, an atomically dispersed Cu in leaf-like Zn-coordinated zeolitic imidazolate framework (ZIF-L) nanoflakes on Ti mesh (CuZIF-L@TM) as ZMA host is developed. The 3D conductive network formed by the interconnected ZIF-L nanoflakes can reduce the local current density and homogenize the electric field distribution. Moreover, experimental data and theoretical calculations reveal the Cu single atoms within the ZIF-L can serve as the zincophilic sites to facilitate the Zn deposition. As expected, the CuZIF-L@TM host enables a homogeneous Zn deposition on the surface without dendrites. The resultant CuZIF-L@TM/Zn electrode shows stable Zn plating/stripping over 1100 h at 1 mA cm-2 with a low voltage hysteresis of about 50 mV. As a proof of concept, a full cell based on the designed CuZIF-L@TM/Zn anode shows a stable cycling performance over 1000 cycles.