Elf1 promotes Rad26's interaction with lesion-arrested Pol II for transcription-coupled repair.

Transcription-coupled nucleotide excision repair (TC-NER) is a highly conserved DNA repair pathway that removes bulky lesions in the transcribed genome. Cockayne syndrome B protein (CSB), or its yeast ortholog Rad26, has been known for decades to play important roles in the lesion-recognition steps of TC-NER. Another conserved protein ELOF1, or its yeast ortholog Elf1, was recently identified as a core transcription-coupled repair factor. How Rad26 distinguishes between RNA polymerase II (Pol II) stalled at a DNA lesion or other obstacles and what role Elf1 plays in this process remains unknown. Here, we present cryo-EM structures of Pol II-Rad26 complexes stalled at different obstacles that show that Rad26 uses a common mechanism to recognize a stalled Pol II, with additional interactions when Pol II is arrested at a lesion. A cryo-EM structure of lesion-arrested Pol II-Rad26 bound to Elf1 revealed that Elf1 induces further interactions between Rad26 and a lesion-arrested Pol II. Biochemical and genetic data support the importance of the interplay between Elf1 and Rad26 in TC-NER initiation. Together, our results provide important mechanistic insights into how two conserved transcription-coupled repair factors, Rad26/CSB and Elf1/ELOF1, work together at the initial lesion recognition steps of transcription-coupled repair.

Deletions of singular U1 snRNA gene significantly interfere with transcription and 3'-end mRNA formation.

Small nuclear RNAs (snRNAs) are structural and functional cores of the spliceosome. In metazoan genomes, each snRNA has multiple copies/variants, up to hundreds in mammals. However, the expressions and functions of each copy/variant in one organism have not been systematically studied. Focus on U1 snRNA genes, we investigated all five copies in Drosophila melanogaster using two series of constructed strains. Analyses of transgenic flies that each have a U1 promoter-driven gfp revealed that U1:21D is the major and ubiquitously expressed copy, and the other four copies have specificities in developmental stages and tissues. Mutant strains that each have a precisely deleted copy of U1-gene exhibited various extents of defects in fly morphology or mobility, especially deletion of U1:82Eb. Interestingly, splicing was changed at limited levels in the deletion strains, while large amounts of differentially-expressed genes and alternative polyadenylation events were identified, showing preferences in the down-regulation of genes with 1-2 introns and selection of proximal sites for 3'-end polyadenylation. In vitro assays suggested that Drosophila U1 variants pulled down fewer SmD2 proteins compared to the canonical U1. This study demonstrates that all five U1-genes in Drosophila have physiological functions in development and play regulatory roles in transcription and 3'-end formation.

Genomic loci influence patterns of structural covariance in the human brain.

Normal and pathologic neurobiological processes influence brain morphology in coordinated ways that give rise to patterns of structural covariance (PSC) across brain regions and individuals during brain aging and diseases. The genetic underpinnings of these patterns remain largely unknown. We apply a stochastic multivariate factorization method to a diverse population of 50,699 individuals (12 studies and 130 sites) and derive data-driven, multi-scale PSCs of regional brain size. PSCs were significantly correlated with 915 genomic loci in the discovery set, 617 of which are newly identified, and 72% were independently replicated. Key pathways influencing PSCs involve reelin signaling, apoptosis, neurogenesis, and appendage development, while pathways of breast cancer indicate potential interplays between brain metastasis and PSCs associated with neurodegeneration and dementia. Using support vector machines, multi-scale PSCs effectively derive imaging signatures of several brain diseases. Our results elucidate genetic and biological underpinnings that influence structural covariance patterns in the human brain.

Study of impacts of two types of cellular aging on the yeast bud morphogenesis.

Understanding the mechanisms of the cellular aging processes is crucial for attempting to extend organismal lifespan and for studying age-related degenerative diseases. Yeast cells divide through budding, providing a classical biological model for studying cellular aging. With their powerful genetics, relatively short cell cycle, and well-established signaling pathways also found in animals, yeast cells offer valuable insights into the aging process. Recent experiments suggested the existence of two aging modes in yeast characterized by nucleolar and mitochondrial declines, respectively. By analyzing experimental data, this study shows that cells evolving into those two aging modes behave differently when they are young. While buds grow linearly in both modes, cells that consistently generate spherical buds throughout their lifespan demonstrate greater efficacy in controlling bud size and growth rate at young ages. A three-dimensional multiscale chemical-mechanical model was developed and used to suggest and test hypothesized impacts of aging on bud morphogenesis. Experimentally calibrated model simulations showed that during the early stage of budding, tubular bud shape in one aging mode could be generated by locally inserting new materials at the bud tip, a process guided by the polarized Cdc42 signal. Furthermore, the aspect ratio of the tubular bud could be stabilized during the late stage as observed in experiments in this work. The model simulation results suggest that the localization of new cell surface material insertion, regulated by chemical signal polarization, could be weakened due to cellular aging in yeast and other cell types, leading to the change and stabilization of the bud aspect ratio.

miR-148b-5p regulates hypercalciuria and calcium-containing nephrolithiasis.

Calcium-containing stones represent the most common form of kidney calculi, frequently linked to idiopathic hypercalciuria, though their precise pathogenesis remains elusive. This research aimed to elucidate the molecular mechanisms involved by employing urinary exosomal microRNAs as proxies for renal tissue analysis. Elevated miR-148b-5p levels were observed in exosomes derived from patients with kidney stones. Systemic administration of miR-148b-5p in rat models resulted in heightened urinary calcium excretion, whereas its inhibition reduced stone formation. RNA immunoprecipitation combined with deep sequencing identified miR-148b-5p as a suppressor of calcitonin receptor (Calcr) expression, thereby promoting urinary calcium excretion and stone formation. Mice deficient in Calcr in distal epithelial cells demonstrated elevated urinary calcium excretion and renal calcification. Mechanistically, miR-148b-5p regulated Calcr through the circRNA-83536/miR-24-3p signaling pathway. Human kidney tissue samples corroborated these results. In summary, miR-148b-5p regulates the formation of calcium-containing kidney stones via the circRNA-83536/miR-24-3p/Calcr axis, presenting a potential target for novel therapeutic interventions to prevent calcium nephrolithiasis.

Enhancing Surface Strain of Intermetallic Fuel Cell Catalysts by Composition-Induced Phase Transition.

The lattice parameter of platinum-based intermetallic compounds (IMCs), which correlates with the intrinsic activity of the oxygen reduction reaction (ORR), can be modulated by crystal phase engineering. However, the controlled preparation of IMCs with unconventional crystal structures remains highly challenging. Here, we demonstrate the synthesis of carbon-supported PtCu-based IMC catalysts with an unconventional L10 structure by a composition-regulated strategy. Experiment and machine learning reveal that the thermodynamically favorable structure changes from L11 to L10 when slight Cu atoms are substituted with Co. Benefiting from crystal-phase-induced strain enhancement, the prepared L10-type PtCu0.8Co0.2 catalyst exhibits much-enhanced mass and specific activities of 1.82 A mgPt-1 and 3.27 mA cmPt-2, which are 1.91 and 1.73 times higher than those of the L11-type PtCu catalyst, respectively. Our work highlights the important role of crystal phase in determining the surface strain of IMCs, and opens a promising avenue for the rational preparation of IMCs with different crystal phases by doping.

Oxygen Reduction Kinetics of Fe-N-C Single Atom Catalysts Boosted by Pyridinic N Vacancy for Temperature-Adaptive Zn-Air Batteries.

The design of temperature-adaptive Zn-air batteries (ZABs) with long life spans and high energy efficiencies is challenging owing to sluggish oxygen reduction reaction (ORR) kinetics and an unstable Zn/electrolyte interface. Herein, a quasi-solid-state ZAB is designed by combining atomically dispersed Fe-N-C catalysts containing pyridinic N vacancies (FeNC-VN) with a polarized organo-hydrogel electrolyte. First-principles calculation predicts that adjacent VN sites effectively enhance the covalency of Fe-Nx moieties and moderately weaken *OH binding energies, significantly boosting the ORR kinetics and stability. In situ Raman spectra reveal the dynamic evolution of *O2- and *OOH on the FeNC-VN cathode in the aqueous ZAB, proving that the 4e- associative mechanism is dominant. Moreover, the ethylene glycol-modulated organo-hydrogel electrolyte forms a zincophilic protective layer on the Zn anode surface and tailors the [Zn(H2O)6]2+ solvation sheath, effectively guiding epitaxial deposition of Zn2+ on the Zn (002) plane and suppressing side reactions. The assembled quasi-solid-state ZAB demonstrates a long life span of over 1076 h at 2 mA cm-2 at -20 °C, outperforming most reported ZABs.

Artificial intelligence alphafold model for molecular biology and drug discovery: a machine-learning-driven informatics investigation.

AlphaFold model has reshaped biological research. However, vast unstructured data in the entire AlphaFold field requires further analysis to fully understand the current research landscape and guide future exploration. Thus, this scientometric analysis aimed to identify critical research clusters, track emerging trends, and highlight underexplored areas in this field by utilizing machine-learning-driven informatics methods. Quantitative statistical analysis reveals that the AlphaFold field is enjoying an astonishing development trend (Annual Growth Rate = 180.13%) and global collaboration (International Co-authorship = 33.33%). Unsupervised clustering algorithm, time series tracking, and global impact assessment point out that Cluster 3 (Artificial Intelligence-Powered Advancements in AlphaFold for Structural Biology) has the greatest influence (Average Citation = 48.36 ± 184.98). Additionally, regression curve and hotspot burst analysis highlight "structure prediction" (s = 12.40, R2 = 0.9480, p = 0.0051), "artificial intelligence" (s = 5.00, R2 = 0.8096, p = 0.0375), "drug discovery" (s = 1.90, R2 = 0.7987, p = 0.0409), and "molecular dynamics" (s = 2.40, R2 = 0.8000, p = 0.0405) as core hotspots driving the research frontier. More importantly, the Walktrap algorithm further reveals that "structure prediction, artificial intelligence, molecular dynamics" (Relevance Percentage[RP] = 100%, Development Percentage[DP] = 25.0%), "sars-cov-2, covid-19, vaccine design" (RP = 97.8%, DP = 37.5%), and "homology modeling, virtual screening, membrane protein" (RP = 89.9%, DP = 26.1%) are closely intertwined with the AlphaFold model but remain underexplored, which implies a broad exploration space. In conclusion, through the machine-learning-driven informatics methods, this scientometric analysis offers an objective and comprehensive overview of global AlphaFold research, identifying critical research clusters and hotspots while prospectively pointing out underexplored critical areas.

Association of Proton Pump Inhibitor Use With Incident Dementia and Cognitive Decline in Older Adults: A Prospective Cohort Study.

BACKGROUND & AIMS: Prior studies have suggested that proton pump inhibitor (PPI) use is associated with increased risk of dementia; however, these have been limited by incomplete assessment of medication use and failure to account for confounders. Furthermore, prior studies have relied on claims-based diagnoses for dementia, which can lead to misclassification. We investigated the associations of PPI and histamine-2 receptor antagonist (H2RA) use with dementia and cognitive decline. METHODS: We conducted a post hoc analysis of ASPirin in Reducing Events in the Elderly (ASPREE), a randomized trial of aspirin in the United States and Australia, including 18,934 community-based adults ≥65 years of all races/ethnicities. Baseline and recent PPI and H2RA use were determined according to review of medications during annual in-person study visits. Incident dementia was defined according to Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition, criteria. Secondary endpoints include cognitive impairment, no dementia (CIND) and changes in cognition. Associations of medication use with dementia and CIND outcomes were examined using Cox proportional hazards models. Changes in cognitive test scores were examined using linear mixed-effects models. RESULTS: Baseline PPI use vs nonuse was not associated with incident dementia (multivariable hazard ratio, 0.88; 95% confidence interval, 0.72-1.08), CIND (multivariable hazard ratio, 1.00; 95% confidence interval, 0.92-1.09), or with changes in overall cognitive test scores over time (multivariable B, -0.002; standard error, 0.01; P = .85). Similarly, no associations were observed between H2RA use and all cognitive endpoints. CONCLUSIONS: In adults ≥65 years of age, PPI and H2RA use were not associated with incident dementia, CIND, or decline in cognition over time. These data provide reassurance about the safety of long-term use of PPIs among older adults.

Predicting Invasiveness of Lung Adenocarcinoma at Chest CT with Deep Learning Ternary Classification Models.

Background Preoperative discrimination of preinvasive, minimally invasive, and invasive adenocarcinoma at CT informs clinical management decisions but may be challenging for classifying pure ground-glass nodules (pGGNs). Deep learning (DL) may improve ternary classification. Purpose To determine whether a strategy that includes an adjudication approach can enhance the performance of DL ternary classification models in predicting the invasiveness of adenocarcinoma at chest CT and maintain performance in classifying pGGNs. Materials and Methods In this retrospective study, six ternary models for classifying preinvasive, minimally invasive, and invasive adenocarcinoma were developed using a multicenter data set of lung nodules. The DL-based models were progressively modified through framework optimization, joint learning, and an adjudication strategy (simulating a multireader approach to resolving discordant nodule classifications), integrating two binary classification models with a ternary classification model to resolve discordant classifications sequentially. The six ternary models were then tested on an external data set of pGGNs imaged between December 2019 and January 2021. Diagnostic performance including accuracy, specificity, and sensitivity was assessed. The χ2 test was used to compare model performance in different subgroups stratified by clinical confounders. Results A total of 4929 nodules from 4483 patients (mean age, 50.1 years ± 9.5 [SD]; 2806 female) were divided into training (n = 3384), validation (n = 579), and internal (n = 966) test sets. A total of 361 pGGNs from 281 patients (mean age, 55.2 years ± 11.1 [SD]; 186 female) formed the external test set. The proposed strategy improved DL model performance in external testing (P < .001). For classifying minimally invasive adenocarcinoma, the accuracy was 85% and 79%, sensitivity was 75% and 63%, and specificity was 89% and 85% for the model with adjudication (model 6) and the model without (model 3), respectively. Model 6 showed a relatively narrow range (maximum minus minimum) across diagnostic indexes (accuracy, 1.7%; sensitivity, 7.3%; specificity, 0.9%) compared with the other models (accuracy, 0.6%-10.8%; sensitivity, 14%-39.1%; specificity, 5.5%-17.9%). Conclusion Combining framework optimization, joint learning, and an adjudication approach improved DL classification of adenocarcinoma invasiveness at chest CT. Published under a CC BY 4.0 license. Supplemental material is available for this article. See also the editorial by Sohn and Fields in this issue.

Short- and long-term impact of aspirin cessation in older adults: a target trial emulation.

BACKGROUND: The net benefit of aspirin cessation in older adults remains uncertain. This study aimed to use observational data to emulate a randomized trial of aspirin cessation versus continuation in older adults without cardiovascular disease (CVD). METHODS: Post hoc analysis using a target trial emulation framework applied to the immediate post-trial period (2017-2021) of a study of low-dose aspirin initiation in adults aged ≥ 70 years (ASPREE; NCT01038583). Participants from Australia and the USA were included if they were free of CVD at the start of the post-trial intervention period (time zero, T0) and had been taking open-label or randomized aspirin immediately before T0. The two groups in the target trial were as follows: aspirin cessation (participants who were taking randomized aspirin immediately before T0; assumed to have stopped at T0 as instructed) versus aspirin continuation (participants on open-label aspirin at T0 regardless of their randomized treatment; assumed to have continued at T0). The outcomes after T0 were incident CVD, major adverse cardiovascular events (MACE), all-cause mortality, and major bleeding during 3, 6, and 12 months (short-term) and 48 months (long-term) follow-up. Hazard ratios (HRs) comparing aspirin cessation to continuation were estimated from propensity-score (PS) adjusted Cox proportional-hazards regression models. RESULTS: We included 6103 CVD-free participants (cessation: 5427, continuation: 676). Over both short- and long-term follow-up, aspirin cessation versus continuation was not associated with elevated risk of CVD, MACE, and all-cause mortality (HRs, at 3 and 48 months respectively, were 1.23 and 0.73 for CVD, 1.11 and 0.84 for MACE, and 0.23 and 0.79 for all-cause mortality, p > 0.05), but cessation had a reduced risk of incident major bleeding events (HRs at 3 and 48 months, 0.16 and 0.63, p < 0.05). Similar findings were seen for all outcomes at 6 and 12 months, except for a lowered risk of all-cause mortality in the cessation group at 12 months. CONCLUSIONS: Our findings suggest that deprescribing prophylactic aspirin might be safe in healthy older adults with no known CVD.

Ionic Bonding Without Directionality Facilitates Efficient Interfacial Bridging for Perovskite Solar Cells.

Interface passivation through Lewis acid-base coordinate chemistry in perovskite solar cells (PSCs) is a universal strategy to reduce interface defects and hinder ion migration. However, the formation of coordinate covalent bonding demands strict directional alignment of coordinating atoms. Undoubtedly, this limits the selected range of the interface passivation molecules, because a successful molecular bridge between charge transport layer and perovskite bottom interface needs a well-placed molecular orientation. In this study, it is discovered that potassium ions can migrate to the hollow sites of multiple iodine ions from perovskite to form K-Ix ionic bonding, and the ionic bonds without directionality can support molecular backbone rotation to facilitate polar sites (carboxyl groups) chelating Pb at the bottom perovskite interface, finally forming a closed-loop bonding structure. The synergy of coordinate and ionic bonding significantly reduces interface defects, changes electric field distribution, and immobilizes iodine at the perovskite bottom interface, resulting in eliminating the hysteresis effect and enhancing the performance of PSCs. As a result, the corresponding devices achieve a high efficiency exceeding 24.5% (0.09 cm2), and a mini-module with 21% efficiency (12.4 cm2). These findings provide guidelines for designing molecular bridging strategies at the buried interface of PSCs.

Mast cell stabilizer, an anti-allergic drug, reduces ventricular arrhythmia risk via modulation of neuroimmune interaction.

Mast cells (MCs) are important intermediates between the nervous and immune systems. The cardiac autonomic nervous system (CANS) crucially modulates cardiac electrophysiology and arrhythmogenesis, but whether and how MC-CANS neuroimmune interaction influences arrhythmia remain unclear. Our clinical data showed a close relationship between serum levels of MC markers and CANS activity, and then we use mast cell stabilizers (MCSs) to alter this MC-CANS communication. MCSs, which are well-known anti-allergic agents, could reduce the risk of ventricular arrhythmia (VA) after myocardial infarction (MI). RNA-sequencing (RNA-seq) analysis to investigate the underlying mechanism by which MCSs could affect the left stellate ganglion (LSG), a key therapeutic target for modulating CANS, showed that the IL-6 and γ-aminobutyric acid (GABA)-ergic system may be involved in this process. Our findings demonstrated that MCSs reduce VA risk along with revealing the potential underlying antiarrhythmic mechanisms.

Association of stress hyperglycemia ratio with left ventricular function and microvascular obstruction in patients with ST-segment elevation myocardial infarction: a 3.0 T cardiac magnetic resonance study.

BACKGROUND: Stress hyperglycemia, which is associated with poor prognosis in patients with acute myocardial infarction (AMI), can be determined using the stress hyperglycemia ratio (SHR). Impaired left ventricular function and microvascular obstruction (MVO) diagnosed using cardiac magnetic resonance (CMR) have also been proven to be linked to poor prognosis in patients with AMI and aid in risk stratification. However, there have been no studies on the correlation between fasting SHR and left ventricular function and MVO in patients with acute ST-segment elevation myocardial infarction (ASTEMI). Therefore, this study aimed to investigate the additive effect of fasting SHR on left ventricular function and global deformation in patients with ASTEMI and to explore the association between fasting SHR and MVO. METHODS: Consecutive patients who underwent CMR at index admission (3-7 days) after primary percutaneous coronary intervention (PPCI) were enrolled in this study. Basic clinical, biochemical, and CMR data were obtained and compared among all patients grouped by fasting SHR tertiles: SHR1: SHR < 0.85; SHR2: 0.85 ≤ SHR < 1.01; and SHR3: SHR ≥ 1.01. Spearman's rho (r) was used to assess the relationship between fasting SHR and left ventricular function, myocardial strain, and the extent of MVO. Multivariable linear regression analysis was performed to evaluate the determinants of left ventricular function and myocardial strain impairment in all patients with AMI. Univariable and multivariable regression analyses were performed to investigate the correlation between fasting SHR and the presence and extent of MVO in patients with AMI and those with AMI and diabetes mellitus (DM). RESULTS: A total of 357 patients with ASTEMI were enrolled in this study. Left ventricular ejection fraction (LVEF) and left ventricular global function index (LVGFI) were significantly lower in SHR2 and SHR3 than in SHR1. Compared with SHR1 and SHR2 groups, left ventricular strain was lower in SHR3, as evidenced by global radial (GRS), global circumferential (GCS), and global longitudinal (GLS) strains. Fasting SHR were negatively correlated with LVEF, LVGFI, and GRS (r = - 0.252; r = - 0.261; and r = - 0.245; all P<0.001) and positively correlated with GCS (r = 0.221) and GLS (r = 0.249; all P <0.001). Multivariable linear regression analysis showed that fasting SHR was an independent determinant of impaired LVEF, LVGFI, GRS, and GLS. Furthermore, multivariable regression analysis after adjusting for covariates signified that fasting SHR was associated with the presence and extent of MVO in patients with AMI and those with AMI and DM. CONCLUSION: Fasting SHR in patients with ASTEMI successfully treated using PPCI is independently associated with impaired cardiac function and MVO. In patients with AMI and DM, fasting SHR is an independent determinant of the presence and extent of MVO.

Prognostic Value of Left Ventricular Longitudinal Function and Myocardial Fibrosis in Patients With Ischemic and Non-Ischemic Dilated Cardiomyopathy Concomitant With Type 2 Diabetes Mellitus: A 3.0 T Cardiac MR Study.

BACKGROUND: Poorly controlled type 2 diabetes mellitus (T2DM) is known to result in left ventricular (LV) dysfunction, myocardial fibrosis, and ischemic/nonischemic dilated cardiomyopathy (ICM/NIDCM). However, less is known about the prognostic value of T2DM on LV longitudinal function and late gadolinium enhancement (LGE) assessed with cardiac MRI in ICM/NIDCM patients. PURPOSE: To measure LV longitudinal function and myocardial scar in ICM/NIDCM patients with T2DM and to determine their prognostic values. STUDY TYPE: Retrospective cohort. POPULATION: Two hundred thirty-five ICM/NIDCM patients (158 with T2DM and 77 without T2DM). FIELD STRENGTH/SEQUENCE: 3T; steady-state free precession cine; phase-sensitive inversion recovery segmented gradient echo LGE sequences. ASSESSMENT: Global peak longitudinal systolic strain rate (GLPSSR) was evaluated to LV longitudinal function with feature tracking. The predictive value of GLPSSR was determined with ROC curve. Glycated hemoglobin (HbA1c) was measured. The primary adverse cardiovascular endpoint was follow up every 3 months. STATISTICAL TESTS: Mann-Whitney U test or student's t-test; Intra and inter-observer variabilities; Kaplan-Meier method; Cox proportional hazards analysis (threshold = 5%). RESULTS: ICM/NIDCM patients with T2DM exhibited significantly lower absolute value of GLPSSR (0.39 ± 0.14 vs. 0.49 ± 0.18) and higher proportion of LGE positive (+) despite similar LV ejection fraction, compared to without T2DM. LV GLPSSR was able to predict primary endpoint (AUC 0.73) and optimal cutoff point was 0.4. ICM/NIDCM patients with T2DM (GLPSSR < 0.4) had more markedly impaired survival. Importantly, this group (GLPSSR < 0.4, HbA1c ≥ 7.8%, or LGE (+)) exhibited the worst survival. In multivariate analysis, GLPSSR, HbA1c, and LGE (+) significantly predicted primary adverse cardiovascular endpoint in overall ICM/NIDCM and ICM/NIDCM patients with T2DM. CONCLUSIONS: T2DM has an additive deleterious effect on LV longitudinal function and myocardial fibrosis in ICM/NIDCM patients. Combining GLPSSR, HbA1c, and LGE could be promising markers in predicting outcomes in ICM/NIDCM patients with T2DM. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: 5.

Histone methyltransferase MLL4 protects against pressure overload-induced heart failure via a THBS4-mediated protection in ER stress.

Pressure overload-induced pathological cardiac hypertrophy eventually leads to heart failure (HF). Unfortunately, lack of effective targeted therapies for HF remains a challenge in clinical management. Mixed-lineage leukemia 4 (MLL4) is a member of the SET family of histone methyltransferase enzymes, which possesses histone H3 lysine 4 (H3K4)-specific methyltransferase activity. However, whether and how MLL4 regulates cardiac function is not reported in adult HF. Here we report that MLL4 is required for endoplasmic reticulum (ER) stress homeostasis of cardiomyocytes and protective against pressure overload-induced cardiac hypertrophy and HF. We observed that MLL4 is increased in the heart tissue of HF mouse model and HF patients. The cardiomyocyte-specific deletion of Mll4 (Mll4-cKO) in mice leads to aggravated ER stress and cardiac dysfunction following pressure overloading. MLL4 knockdown neonatal rat cardiomyocytes (NRCMs) also display accelerated decompensated ER stress and hypertrophy induced by phenylephrine (PE). The combined analysis of Cleavage Under Targets and Tagmentation sequencing (CUT&Tag-seq) and RNA sequencing (RNA-seq) data reveals that, silencing of Mll4 alters the chromatin landscape for H3K4me1 modification and gene expression patterns in NRCMs. Interestingly, the deficiency of MLL4 results in a marked reduction of H3K4me1 and H3K27ac occupations on Thrombospondin-4 (Thbs4) gene loci, as well as Thbs4 gene expression. Mechanistically, MLL4 acts as a transcriptional activator of Thbs4 through mono-methylation of H3K4 and further regulates THBS4-dependent ER stress response, ultimately plays a role in HF. Our study indicates that pharmacologically targeting MLL4 and ER stress might be a valid therapeutic approach to protect against cardiac hypertrophy and HF.

Angiotensin Receptor Blockers and Cognition: a Scoping Review.

PURPOSE OF REVIEW: To provide an overview of the association between angiotensin II receptor blocker (ARB) use and cognitive outcomes. RECENT FINDINGS: ARBs have previously shown greater neuroprotection compared to other anti-hypertensive classes. The benefits are primarily attributed to the ARB's effect on modulating the renin-angiotensin system via inhibiting the Ang II/AT1R pathway and activating the Ang II/AT2R, Ang IV/AT4R, and Ang-(1-7)/MasR pathways. These interactions are associated with pleiotropic neurocognitive benefits, including reduced ß-amyloid accumulation and abnormal hyperphosphorylation of tau, ameliorated brain hypo-fusion, reduced neuroinflammation and synaptic dysfunction, better neurotoxin clearing, and blood-brain barrier function restoration. While ACEis also inhibit AT1R, they simultaneously lower Ang II and block the Ang II/AT2R and Ang IV/AT4R pathways that counterbalance the potential benefits. ARBs may be considered an adjunctive approach for neuroprotection. This preliminary evidence, coupled with their underlying mechanistic pathways, emphasizes the need for future long-term randomized trials to yield more definitive results.

Functionalized MBenes as promising anode materials for high-performance alkali-ion batteries: a first-principles study.

The discovery of novel electrode materials based on two-dimensional (2D) structures is critical for alkali metal-ion batteries. Herein, we performed first-principles computations to investigate functionalized MXenes, Mo2BT2(T = O, S), which are also regarded as B-based MXenes, or named as MBenes, as potential anode materials for Li-ion batteries and beyond. The pristine and T-terminated Mo2BT2(T = O, S) monolayers reveal metallic character with higher electronic conductivity and are thermodynamically stable with an intrinsic dipole moment. Both Mo2BO2and Mo2BS2monolayers exhibit high theoretical Li/Na/K storage capacity and low ion diffusion barriers. These findings suggest that functionalized Mo2BT2(T = O, S) monolayers are promising for designing viable anode materials for high-performance alkali-ion batteries.

Deciphering the Roles of Extracellular Polymeric Substances (EPS) in Shaping Disinfection Kinetics through Permanent Removal via Genetic Disruption.

Extracellular polymeric substances (EPS) ubiquitously encapsulate microbes and play crucial roles in various environmental processes. However, understanding their complex interactions with dynamic bacterial behaviors, especially during the disinfection process, remains very limited. In this work, we investigated the impact of EPS on bacterial disinfection kinetics by developing a permanent EPS removal strategy. We genetically disrupted the synthesis of exopolysaccharides, the structural components of EPS, in Pseudomonas aeruginosa, a well-known EPS-producing opportunistic pathogen found in diverse environments, creating an EPS-deficient strain. This method ensured a lasting absence of EPS while maintaining bacterial integrity and viability, allowing for real-time in situ investigations of the roles of EPS in disinfection. Our findings indicate that removing EPS from bacteria substantially lowered their susceptibility threshold to disinfectants such as ozone, chloramine B, and free chlorine. This removal also substantially accelerated disinfection kinetics, shortened the resistance time, and increased disinfection efficiency, thereby enhancing the overall bactericidal effect. The absence of EPS was found to enhance bacterial motility and increase bacterial cell vulnerability to disinfectants, resulting in greater membrane damage and intensified reactive oxygen species (ROS) production upon exposure to disinfectants. These insights highlight the central role of EPS in bacterial defenses and offer promising implications for developing more effective disinfection strategies.

Deciphering Multidrug-Resistant Plasmids in Disinfection Residual Bacteria from a Wastewater Treatment Plant.

Current disinfection processes pose an emerging environmental risk due to the ineffective removal of antibiotic-resistant bacteria, especially disinfection residual bacteria (DRB) carrying multidrug-resistant plasmids (MRPs). However, the characteristics of DRB-carried MRPs are poorly understood. In this study, qPCR analysis reveals that the total absolute abundance of four plasmids in postdisinfection effluent decreases by 1.15 log units, while their relative abundance increases by 0.11 copies/cell compared to investigated wastewater treatment plant (WWTP) influent. We obtain three distinctive DRB-carried MRPs (pWWTP-01-03) from postdisinfection effluent, each carrying 9-11 antibiotic-resistant genes (ARGs). pWWTP-01 contains all 11 ARGs within an ∼25 Kbp chimeric genomic island showing strong patterns of recombination with MRPs from foodborne outbreaks and hospitals. Antibiotic-, disinfectant-, and heavy-metal-resistant genes on the same plasmid underscore the potential roles of disinfectants and heavy metals in the coselection of ARGs. Additionally, pWWTP-02 harbors an adhesin-type virulence operon, implying risks of both antibiotic resistance and pathogenicity upon entering environments. Furthermore, some MRPs from DRB are capable of transferring and could confer selective advantages to recipients under environmentally relevant antibiotic pressure. Overall, this study advances our understanding of DRB-carried MRPs and highlights the imminent need to monitor and control wastewater MRPs for environmental security.