PCAF-Mediated Histone Acetylation Promotes Replication Fork Degradation by MRE11 and EXO1 in BRCA-Deficient Cells.

Stabilization of stalled replication forks is a prominent mechanism of PARP (Poly(ADP-ribose) Polymerase) inhibitor (PARPi) resistance in BRCA-deficient tumors. Epigenetic mechanisms of replication fork stability are emerging but remain poorly understood. Here, we report the histone acetyltransferase PCAF (p300/CBP-associated) as a fork-associated protein that promotes fork degradation in BRCA-deficient cells by acetylating H4K8 at stalled replication forks, which recruits MRE11 and EXO1. A H4K8ac binding domain within MRE11/EXO1 is required for their recruitment to stalled forks. Low PCAF levels, which we identify in a subset of BRCA2-deficient tumors, stabilize stalled forks, resulting in PARPi resistance in BRCA-deficient cells. Furthermore, PCAF activity is tightly regulated by ATR (ataxia telangiectasia and Rad3-related), which phosphorylates PCAF on serine 264 (S264) to limit its association and activity at stalled forks. Our results reveal PCAF and histone acetylation as critical regulators of fork stability and PARPi responses in BRCA-deficient cells, which provides key insights into targeting BRCA-deficient tumors and identifying epigenetic modulators of chemotherapeutic responses.

Advances in an In Vitro Tuberculosis Infection Model Using Human Lung Organoids for Host-Directed Therapies.

The emergence of drug-resistant Mycobacterium tuberculosis (M.tb) has led to the development of novel anti-tuberculosis (anti-TB) drugs. Common methods for testing the efficacy of new drugs, including two-dimensional cell culture models or animal models, have several limitations. Therefore, an appropriate model representative of the human organism is required. Here, we developed an M.tb infection model using human lung organoids (hLOs) and demonstrated that M.tb H37Rv can infect lung epithelial cells and human macrophages (hMφs) in hLOs. This novel M.tb infection model can be cultured long-term and split several times while maintaining a similar number of M.tb H37Rv inside the hLOs. Anti-TB drugs reduced the intracellular survival of M.tb in hLOs. Notably, M.tb growth in hLOs was effectively suppressed at each passage by rifampicin and bedaquiline. Furthermore, a reduction in inflammatory cytokine production and intracellular survival of M.tb were observed upon knockdown of MFN2 and HERPUD1 (host-directed therapeutic targets for TB) in our M.tb H37Rv-infected hLO model. Thus, the incorporation of hMφs and M.tb into hLOs provides a powerful strategy for generating an M.tb infection model. This model can effectively reflect host-pathogen interactions and be utilized to test the efficacy of anti-TB drugs and host-directed therapies.

Seven Tesla Evidence for Columnar and Rostral-Caudal Organization of the Human Periaqueductal Gray Response in the Absence of Threat: A Working Memory Study.

The periaqueductal gray (PAG) is a small midbrain structure that surrounds the cerebral aqueduct, regulates brain-body communication, and is often studied for its role in "fight-or-flight" and "freezing" responses to threat. We used ultra-high-field 7 T fMRI to resolve the PAG in humans and distinguish it from the cerebral aqueduct, examining its in vivo function during a working memory task (N = 87). Both mild and moderate cognitive demands elicited spatially similar patterns of whole-brain blood oxygenation level-dependent (BOLD) response, and moderate cognitive demand elicited widespread BOLD increases above baseline in the brainstem. Notably, these brainstem increases were not significantly greater than those in the mild demand condition, suggesting that a subthreshold brainstem BOLD increase occurred for mild cognitive demand as well. Subject-specific masks were group aligned to examine PAG response. In PAG, both mild and moderate demands elicited a well-defined response in ventrolateral PAG, a region thought to be functionally related to anticipated painful threat in humans and nonhuman animals-yet, the present task posed only the most minimal (if any) "threat," with the cognitive tasks used being approximately as challenging as remembering a phone number. These findings suggest that the PAG may play a more general role in visceromotor regulation, even in the absence of threat.

Genome- and transcriptome-wide association studies of 386,000 Asian and European-ancestry women provide new insights into breast cancer genetics.

By combining data from 160,500 individuals with breast cancer and 226,196 controls of Asian and European ancestry, we conducted genome- and transcriptome-wide association studies of breast cancer. We identified 222 genetic risk loci and 137 genes that were associated with breast cancer risk at a p < 5.0 × 10-8 and a Bonferroni-corrected p < 4.6 × 10-6, respectively. Of them, 32 loci and 15 genes showed a significantly different association between ER-positive and ER-negative breast cancer after Bonferroni correction. Significant ancestral differences in risk variant allele frequencies and their association strengths with breast cancer risk were identified. Of the significant associations identified in this study, 17 loci and 14 genes are located 1Mb away from any of the previously reported breast cancer risk variants. Pathways analyses including 221 putative risk genes identified multiple signaling pathways that may play a significant role in the development of breast cancer. Our study provides a comprehensive understanding of and new biological insights into the genetics of this common malignancy.

Estimation of intrafamilial DNA contamination in family trio genome sequencing using deviation from Mendelian inheritance.

With the increasing number of sequencing projects involving families, quality control tools optimized for family genome sequencing are needed. However, accurately quantifying contamination in a DNA mixture is particularly difficult when genetically related family members are the sources. We developed TrioMix, a maximum likelihood estimation (MLE) framework based on Mendel's law of inheritance, to quantify DNA mixture between family members in genome sequencing data of parent-offspring trios. TrioMix can accurately deconvolute any intrafamilial DNA contamination, including parent-offspring, sibling-sibling, parent-parent, and even multiple familial sources. In addition, TrioMix can be applied to detect genomic abnormalities that deviate from Mendelian inheritance patterns, such as uniparental disomy (UPD) and chimerism. A genome-wide depth and variant allele frequency plot generated by TrioMix facilitates tracing the origin of Mendelian inheritance deviations. We showed that TrioMix could accurately deconvolute genomes in both simulated and real data sets.

Advancing Electrically Conductive Metal-Organic Frameworks for Photocatalytic Energy Conversion.

ConspectusPhotocatalytic energy conversion is a pivotal process for harnessing solar energy to produce chemicals and presents a sustainable alternative to fossil fuels. Key strategies to enhance photocatalytic efficiency include facilitating mass transport and reactant adsorption, improving light absorption, and promoting electron and hole separation to suppress electron-hole recombination. This Account delves into the potential advantages of electrically conductive metal-organic frameworks (EC-MOFs) in photocatalytic energy conversion and examines how manipulating electronic structures and controlling morphology and defects affect their unique properties, potentially impacting photocatalytic efficiency and selectivity. Moreover, with a proof-of-concept study of photocatalytic hydrogen peroxide production by manipulating the EC-MOF's electronic structure, we highlight the potential of the strategies outlined in this Account.EC-MOFs not only possess porosity and surface areas like conventional MOFs, but exhibit electronic conductivity through d-p conjugation between ligands and metal nodes, enabling effective charge transport. Their narrow band gaps also allow for visible light absorption, making them promising candidates for efficient photocatalysts. In EC-MOFs, the modular design of metal nodes and ligands allows fine-tuning of both the electronic structure and physical properties, including controlling the particle morphology, which is essential for optimizing band positions and improving charge transport to achieve efficient and selective photocatalytic energy conversion.Despite their potential as photocatalysts, modulating the electronic structure or controlling the morphology of EC-MOFs is nontrivial, as their fast growth kinetics make them prone to defect formation, impacting mass and charge transport. To fully leverage the photocatalytic potential of EC-MOFs, we discuss our group's efforts to manipulate their electronic structures and develop effective synthetic strategies for morphology control and defect healing. For tuning electronic structures, diversifying the combinations of metals and linkers available for EC-MOF synthesis has been explored. Next, we suggest that synthesizing ligand-based solid solutions will enable continuous tuning of the band positions, demonstrating the potential to distinguish between photocatalytic reactions with similar redox potentials. Lastly, we present incorporating a donor-acceptor system in an EC-MOF to spatially separate photogenerated carriers, which could suppress electron-hole recombination. As a synthetic strategy for morphology control, we demonstrated that electrosynthesis can modify particle morphology, enhancing electrochemical surface area, which will be beneficial for reactant adsorption. Finally, we suggest a defect healing strategy that will enhance charge transport by reducing charge traps on defects, potentially improving the photocatalytic efficiency.Our vision in this Account is to introduce EC-MOFs as an efficient platform for photocatalytic energy conversion. Although EC-MOFs are a new class of semiconductor materials and have not been extensively studied for photocatalytic energy conversion, their inherent light absorption and electron transport properties indicate significant photocatalytic potential. We envision that employing modular molecular design to control electronic structures and applying effective synthetic strategies to customize morphology and defect repair can promote charge separation, electron transfer to potential reactants, and mass transport to realize high selectivity and efficiency in EC-MOF-based photocatalysts. This effort not only lays the foundation for the rational design and synthesis of EC-MOFs, but has the potential to advance their use in photocatalytic energy conversion.

Maximizing the Potential of Electrically Conductive MOFs.

ConspectusElectrically conductive metal-organic frameworks (EC-MOFs) have emerged as a compelling class of materials, drawing increasing attention due to their unique properties facilitating charge transport within porous structures. The synergy between electrical conductivity and porosity has opened a wide range of applications, including electrocatalysis, energy storage, chemiresistive sensing, and electronic devices that have been underexplored for their insulating counterparts. Despite these promising prospects, a prevalent challenge arises from the predominant adoption of two-dimensional (2D) structures by most EC-MOFs. These 2D frameworks often show modest surface areas and short interlayer distances, hindering molecular accessibility, which deviates from the inherent characteristics of conventional MOFs. Furthermore, the quest for efficient charge transport imposes design constraints, leading to a restricted selection of functional building blocks. Additionally, there is a lack of established functionalization methods within EC-MOFs, limiting their functional diversity. Thus, these challenges have impeded EC-MOFs from reaching their full potential.In this Account, we summarize and discuss our group's efforts aimed at enhancing molecular accessibility and deploying the functional diversity of EC-MOFs. Our focus on enhancing molecular accessibility involves several strategies. First, we employed macrocyclic ligands with intrinsic pockets as the building blocks for EC-MOFs. The integrated intrinsic pockets in the frameworks supplement surface areas and additional pores to enhance molecular accessibility. The resulting macrocyclic ligand-based EC-MOFs exhibit exceptionally high surface areas and confer advantages in electrochemical performances. Second, our efforts extend to addressing the structural limitations, frequently associated with EC-MOFs' 2D structures. Through the pillar insertion strategy, we transformed a 2D EC-MOF platform into a three-dimensional (3D) structure, thereby achieving higher porosity and enhanced molecular accessibility. In pursuing functional diversity, we have delved into molecular-level tuning of EC-MOF building blocks. We demonstrated that electron-rich alkyne-based pockets in the macrocyclic ligands can host transition metals and alkali ions, enabling ion selectivity and showcasing diverse use of EC-MOFs. We utilized a postsynthetic approach to further functionalize metal nodes on the molecular level within an EC-MOF framework, introducing a proton-conducting pathway while preserving its electrical conductivity.We aspire for this Account to provide practical insights and strategies to surmount structural and functional diversity limitations in the realm of EC-MOFs. By integrating enhanced molecular accessibility and diverse functionality, our endeavor to propel the utility of these materials will inspire further rational development for future EC-MOFs and unlock their full potential.

Epigenetic MRI: Noninvasive imaging of DNA methylation in the brain.

Both neuronal and genetic mechanisms regulate brain function. While there are excellent methods to study neuronal activity in vivo, there are no nondestructive methods to measure global gene expression in living brains. Here, we present a method, epigenetic MRI (eMRI), that overcomes this limitation via direct imaging of DNA methylation, a major gene-expression regulator. eMRI exploits the methionine metabolic pathways for DNA methylation to label genomic DNA through 13C-enriched diets. A 13C magnetic resonance spectroscopic imaging method then maps the spatial distribution of labeled DNA. We validated eMRI using pigs, whose brains have stronger similarity to humans in volume and anatomy than rodents, and confirmed efficient 13C-labeling of brain DNA. We also discovered strong regional differences in global DNA methylation. Just as functional MRI measurements of regional neuronal activity have had a transformational effect on neuroscience, we expect that the eMRI signal, both as a measure of regional epigenetic activity and as a possible surrogate for regional gene expression, will enable many new investigations of human brain function, behavior, and disease.

KDS2010, a reversible MAO-B inhibitor, extends the lifetime of neural probes by preventing glial scar formation.

Implantable neural probes have been extensively utilized in the fields of neurocircuitry, systems neuroscience, and brain-computer interface. However, the long-term functionality of these devices is hampered by the formation of glial scar and astrogliosis at the surface of electrodes. In this study, we administered KDS2010, a recently developed reversible MAO-B inhibitor, to mice through ad libitum drinking in order to prevent glial scar formation and astrogliosis. The administration of KDS2010 allowed long-term recordings of neural signals with implantable devices, which remained stable over a period of 6 months and even restored diminished neural signals after probe implantation. KDS2010 effectively prevented the formation of glial scar, which consists of reactive astrocytes and activated microglia around the implant. Furthermore, it restored neural activity by disinhibiting astrocytic MAO-B dependent tonic GABA inhibition induced by astrogliosis. We suggest that the use of KDS2010 is a promising approach to prevent glial scar formation around the implant, thereby enabling long-term functionality of neural devices.

Photocatalytic Hydrogen Peroxide Production through Functionalized Semiconductive Metal-Organic Frameworks.

Hydrogen peroxide (H2O2) holds significance as a vital chemical with the potential to serve as an energy carrier. Compared with the conventional anthraquinone process, photocatalytic H2O2 production has emerged as an appealing alternative because of its energy efficiency and environmental sustainability. However, the existing photocatalysts suffer from low catalytic efficiency, limited tunability of optical properties, and reliance on sacrificial agents due to high energy loss caused by inefficient charge separation. Therefore, developing catalysts with tunable optical properties and efficient charge separation is desirable. In this work, we introduce postsynthetic functionalization into an electrically conductive metal-organic framework, namely, DPT-MOF. Leveraging DPT (3,6-di(4-pyridyl)-1,2,4,5-tetrazine) as a pillar ligand, we exploited click-type chemistry to manipulate band position and charge separation efficiency, allowing for photocatalytic nonsacrificial H2O2 production. Notably, the fluorine-functionalized MOF exhibited the highest H2O2 production rate of 1676 µmol g-1 h-1 under visible light in O2-saturated water among our other samples. This high production rate is attributed to the tuned electronic structure and prolonged charge lifetime facilitated by the fluorine groups. This work highlights the effectiveness of postsynthetic methodology in tuning optical properties, opening a promising avenue for advancing the field of semiconductive MOF-based photocatalysis.

Differential patterns of reproductive and lifestyle risk factors for breast cancer according to birth cohorts among women in China, Japan and Korea.

BACKGROUND: The birth cohort effect has been suggested to influence the rate of breast cancer incidence and the trends of associated reproductive and lifestyle factors. We conducted a cohort study to determine whether a differential pattern of associations exists between certain factors and breast cancer risk based on birth cohorts. METHODS: This was a cohort study using pooled data from 12 cohort studies. We analysed associations between reproductive (menarche age, menopause age, parity and age at first delivery) and lifestyle (smoking and alcohol consumption) factors and breast cancer risk. We obtained hazard ratios (HRs) with 95% confidence intervals (CIs) using the Cox proportional hazard regression analysis on the 1920s, 1930s, 1940s and 1950s birth cohorts. RESULTS: Parity was found to lower the risk of breast cancer in the older but not in the younger birth cohort, whereas lifestyle factors showed associations with breast cancer risk only among the participants born in the 1950s. In the younger birth cohort group, the effect size was lower for parous women compared to the other cohort groups (HR [95% CI] 0.86 [0.66-1.13] compared to 0.60 [0.49-0.73], 0.46 [0.38-0.56] and 0.62 [0.51-0.77]). Meanwhile, a higher effect size was found for smoking (1.45 [1.14-1.84] compared to 1.25 [0.99-1.58], 1.06 [0.85-1.32] and 0.86 [0.69-1.08]) and alcohol consumption (1.22 [1.01-1.48] compared to 1.10 [0.90-1.33], 1.15 [0.96-1.38], and 1.07 [0.91-1.26]). CONCLUSION: We observed different associations of parity, smoking and alcohol consumption with breast cancer risk across various birth cohorts.

Association of female reproductive and hormonal factors with gallbladder cancer risk in Asia: A pooled analysis of the Asia Cohort Consortium.

The female predominance of gallbladder cancer (GBC) has led to a hypothesis regarding the hormone-related aetiology of GBC. We aimed to investigate the association between female reproductive factors and GBC risk, considering birth cohorts of Asian women. We conducted a pooled analysis of 331,323 women from 12 cohorts across 4 countries (China, Japan, Korea, and Singapore) in the Asia Cohort Consortium. Cox proportional hazard models were used to estimate the hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) to assess the association between reproductive factors (age at menarche, parity, age at first delivery, breastfeeding, and age at menopause) and GBC risk. We observed that a later age at menarche was associated with an increased risk of GBC (HR 1.4, 95% CI 1.16-1.70 for 17 years and older vs. 13-14 years), especially among the cohort born in 1940 and later (HR 2.5, 95% CI 1.50-4.35). Among the cohort born before 1940, women with a later age at first delivery showed an increased risk of GBC (HR 1.56, 95% CI 1.08-2.24 for 31 years of age and older vs. 20 years of age and younger). Other reproductive factors did not show a clear association with GBC risk. Later ages at menarche and at first delivery were associated with a higher risk of GBC, and these associations varied by birth cohort.

Association between reproductive factors with lung cancer incidence and mortality: A pooled analysis of over 308,000 females in the Asia cohort consortium.

Previous studies have investigated the association between reproductive factors and lung cancer risk; however, findings have been inconsistent. In order to assess this association among Asian women, a total of 308,949 female participants from 11 prospective cohorts and four Asian countries (Japan, Korea, China, and Singapore) were included. Cox proportional hazards regression models were used to estimate the hazard ratios (HR) and 95% confidence intervals (CIs). A total of 3,119 primary lung cancer cases and 2247 lung cancer deaths were identified with a mean follow-up of 16.4 years. Parous women had a lower risk of lung cancer incidence and mortality as compared with nulliparous women, with HRs of 0.82 (95% CI = 0.70-0.96) and 0.78 (95% CI = 0.65-0.94). The protective association of parity and lung cancer incidence was greater among ever-smokers (HR = 0.66, 95% CI = 0.49-0.87) than in never-smokers (HR = 0.90, 95% CI = 0.74-1.09) (P-interaction = 0.029). Compared with age at first delivery ≤20 years, older age at first delivery (21-25, ≥26 years) was associated with a lower risk of lung cancer incidence and mortality. Women who ever used hormone replacements had a higher likelihood of developing non-small cell lung cancer (HR = 1.31, 95% CI = 1.02-1.68), compared to those who never used hormone replacements. Future studies are needed to assess the underlying mechanisms, the relationships within these female reproductive factors, and the potential changes in smoking habits over time.

Dual Immunoglobulin Domain-Containing Cell Adhesion Molecule Increases Early in Renal Tubular Cell Injury and Plays Anti-Inflammatory Role.

Dual immunoglobulin domain-containing cell adhesion molecule (DICAM) is a type I transmembrane protein that presents in various cells including renal tubular cells. This study evaluated the expression and protective role of DICAM in renal tubular cell injury. HK-2 cells were incubated and treated with lipopolysaccharide (LPS, 30 µg/mL) or hydrogen peroxide (H2O2, 100 µM) for 24 h. To investigate the effect of the gene silencing of DICAM, small interfering RNA of DICAM was used. Additionally, to explain its role in cellular response to injury, DICAM was overexpressed using an adenoviral vector. DICAM protein expression levels significantly increased following treatment with LPS or H2O2 in HK-2 cells. In response to oxidative stress, DICAM showed an earlier increase (2-4 h following treatment) than neutrophil gelatinase-associated lipocalin (NGAL) (24 h following treatment). DICAM gene silencing increased the protein expression of inflammation-related markers, including IL-1ß, TNF-α, NOX4, integrin ß1, and integrin ß3, in H2O2-induced HK-2 cell injury. Likewise, in the LPS-induced HK-2 cell injury, DICAM knockdown led to a decrease in occludin levels and an increase in integrin ß3, IL-1ß, and IL-6 levels. Furthermore, DICAM overexpression followed by LPS-induced HK-2 cell injury resulted in an increase in occludin levels and a decrease in integrin ß1, integrin ß3, TNF-α, IL-1ß, and IL-6 levels, suggesting an alleviating effect on inflammatory responses. DICAM was elevated in the early stage of regular tubular cell injury and may protect against renal tubular injury through its anti-inflammatory properties. DICAM has a potential as an early diagnostic marker and therapeutic target for renal cell injury.

Functional annotation of the 2q35 breast cancer risk locus implicates a structural variant in influencing activity of a long-range enhancer element.

A combination of genetic and functional approaches has identified three independent breast cancer risk loci at 2q35. A recent fine-scale mapping analysis to refine these associations resulted in 1 (signal 1), 5 (signal 2), and 42 (signal 3) credible causal variants at these loci. We used publicly available in silico DNase I and ChIP-seq data with in vitro reporter gene and CRISPR assays to annotate signals 2 and 3. We identified putative regulatory elements that enhanced cell-type-specific transcription from the IGFBP5 promoter at both signals (30- to 40-fold increased expression by the putative regulatory element at signal 2, 2- to 3-fold by the putative regulatory element at signal 3). We further identified one of the five credible causal variants at signal 2, a 1.4 kb deletion (esv3594306), as the likely causal variant; the deletion allele of this variant was associated with an average additional increase in IGFBP5 expression of 1.3-fold (MCF-7) and 2.2-fold (T-47D). We propose a model in which the deletion allele of esv3594306 juxtaposes two transcription factor binding regions (annotated by estrogen receptor alpha ChIP-seq peaks) to generate a single extended regulatory element. This regulatory element increases cell-type-specific expression of the tumor suppressor gene IGFBP5 and, thereby, reduces risk of estrogen receptor-positive breast cancer (odds ratio = 0.77, 95% CI 0.74-0.81, p = 3.1 × 10-31).

Elucidating the Mechanism of Radiation Therapy on Mesenchymal Cell Fate in Preventing Heterotopic Ossification.

Radiation therapy is a clinically proven, localized preventive measure for heterotopic ossification (HO). Despite its efficacy, there is a lack of standardization of radiation prescription dosing and fractionation, and the mechanism of the impact of radiation in HO prevention remains unknown. Here, using an established mouse model of traumatic HO induced by burn and tenotomy, we demonstrate that 7Gy in one fraction delivered to the injury site within 72 hours postoperatively significantly decreases HO formation and improves hindlimb range of motion. In-depth single-cell transcriptomic analyses, in combination with immunofluorescent staining, demonstrate decreased cellular numbers as well as aberrant endochondral differentiation and downregulation of associated upstream signaling pathways in irradiated mesenchymal progenitor cells. Our study provides the framework for future mechanistic and clinically relevant studies exploring radiation efficacy in preventing HO formation.

Visceral Adipose Tissue Reduction Measured by Deep Neural Network Architecture Improved Reflux Esophagitis Endoscopic Grade.

INTRODUCTION: Visceral obesity is a risk factor for reflux esophagitis (RE). We investigated the risk of RE according to visceral adipose tissue (VAT) measured by deep neural network architecture using computed tomography (CT) and evaluated the longitudinal association between abdominal adipose tissue changes and the disease course of RE. METHODS: Individuals receiving health checkups who underwent esophagogastroduodenoscopy (EGD) and abdominal CT at Seoul National University Healthcare System Gangnam Center between 2015 and 2016 were included. Visceral and subcutaneous adipose tissue areas and volumes were measured using a deep neural network architecture and CT. The association between the abdominal adipose tissue area and volume and the risk of RE was evaluated. Participants who underwent follow-up EGD and abdominal CT were selected; the effects of changes in abdominal adipose tissue area and volume on RE endoscopic grade were investigated using Cox proportional hazards regression. RESULTS: We enrolled 6,570 patients who underwent EGD and abdominal CT on the same day. RE was associated with male sex, hypertension, diabetes, excessive alcohol intake, current smoking status, and levels of physical activity. The VAT area and volume increased the risk of RE dose-dependently. A decreasing VAT volume was significantly associated with improvement in RE endoscopic grade (hazard ratio: 3.22, 95% confidence interval: 1.82-5.71). Changes in subcutaneous adipose tissue volume and the disease course of RE were not significantly correlated. DISCUSSION: Visceral obesity is strongly associated with RE. VAT volume reduction was prospectively associated with improvement in RE endoscopic grade dose-dependently. Visceral obesity is a potential target for RE treatment.

The impact of early cryoballoon ablation on clinical outcome in patients with atrial fibrillation: From the Korean cryoballoon ablation registry.

INTRODUCTION: Influence of early atrial fibrillation (AF) ablation, particularly cryoballoon ablation (CBA), on clinical outcome during long-term follow-up has not been clarified. The objective was to determine whether an early CBA (diagnosis-to-ablation of ≤6 months) strategy could affect freedom from AF recurrence after index CBA. METHODS: The study included 2605 patients from Korean CBA registry data with follow-up >12 months after de novo CBA. The primary outcome was recurrence of atrial tachyarrhythmias (ATs) of ≥30-s after a 3-month blanking period. RESULTS: Compared to patients in early CBA group, patients in late CBA group had higher prevalence of diabetes, congestive heart failure, and chronic kidney disease, and higher mean CHA2 DS2 -VAS score. During mean follow-up of >21 months, ATs recurrence was detected in 839 (32.2%) patients. The early CBA group showed a significantly lower 2-year recurrence rate of ATs than the late CBA group (26.1% vs. 31.7%, p = 0.043). In subgroup analysis, the early CBA group showed significantly higher 1-year and 2-year freedom from ATs recurrence than the late CBA group only in paroxysmal atrial fibrillation (PAF) patients in overall and propensity score matched cohorts. Multivariate analysis showed that early CBA was an independent factor for preventing ATs recurrence in PAF (hazard ratio: 0.637; 95% confidence intervals: 0.412-0.984). CONCLUSION: Early CBA strategy, resulting in significantly lower ATs recurrence during 2-year follow-up after index CBA, might be considered as an initial rhythm control therapy in patients with paroxysmal AF.

Ex vivo kidney machine perfusion: meta-analysis of randomized clinical trials.

BACKGROUND: Machine perfusion is an organ preservation strategy used to improve function over simple storage in a cold environment. This article presents an updated systematic review and meta-analysis of machine perfusion in deceased donor kidneys. METHODS: RCTs from November 2018 to July 2023 comparing machine perfusion versus static cold storage in kidney transplantation were evaluated for systematic review. The primary outcome in meta-analysis was delayed graft function. RESULTS: A total 19 studies were included, and 16 comparing hypothermic machine perfusion with static cold storage were analysed. The risk of delayed graft function was lower with hypothermic machine perfusion (risk ratio (RR) 0.77, 95% c.i. 0.69 to 0.86), even in kidneys after circulatory death (RR 0.78, 0.68 to 0.90) or brain death (RR 0.73, 0.63 to 0.84). Full hypothermic machine perfusion decreased the risk of delayed graft function (RR 0.69, 0.60 to 0.79), whereas partial hypothermic machine perfusion did not (RR 0.92, 0.69 to 1.22). Normothermic machine perfusion or short-term oxygenated hypothermic machine perfusion preservation after static cold storage was equivalent to static cold storage in terms of delayed graft function and 1-year graft survival. CONCLUSION: Hypothermic machine perfusion reduces delayed graft function risks and normothermic approaches show promise.

Metal Cocatalyst Engineering in Metal-Semiconductor Hybrid Photocatalysts Achieves a Fivefold Enhancement of Hydrogen Evolution.

This study explores the optimal morphology of photochemical hydrogen evolution catalysts in a one-dimensional system. Systematic engineering of metal tips on precisely defined CdSe@CdS dot-in-rods is conducted to exert control over morphology, composition, and both factors. The outcome yields an optimized configuration, a Au-Pt core-shell structure with a rough Pt surface (Au@r-Pt), which exhibits a remarkable fivefold increase in quantum efficiency, reaching 86% at 455 nm and superior hydrogen evolution rates under visible and AM1.5G irradiation conditions with prolonged stability. Kinetic investigations using photoelectrochemical and time-resolved measurements demonstrate a greater extent and extended lifetime of the charge-separated state on the tips as well as rapid water reduction kinetics on high-energy surfaces. This approach sheds light on the critical role of cocatalysts in hybrid photocatalytic systems for achieving high performance.