Atrial Fibrosis, Ischaemic Stroke and Atrial Fibrillation

Atrial fibrosis is an important component of the arrhythmic substrate in AF. Evidence suggests that atrial fibrosis also plays a role in increasing the risk of stroke in patients with the arrhythmia. Patients with embolic stroke of undetermined source (ESUS), who are suspected to have AF but are rarely shown to have it, frequently demonstrate evidence of atrial fibrosis; measured using late-gadolinium enhancement MRI, this manifests as atrial remodelling encompassing structural, functional and electrical properties. In this review, the authors discuss the available evidence linking atrial disease, including fibrosis, with the risk of ischaemic stroke in AF, as well as in the ESUS population, in whom it has been linked to recurrent stroke and new-onset AF. They also discuss the implications of this association on future research that may elucidate the mechanism of stroke and stroke prevention strategies in the AF and ESUS populations

Visit-to-Visit Blood Pressure Variability and Sleep Architecture

Visit‐to‐visit blood pressure (BP) variability (BPV) is an independent risk factor of cardiovascular disease (CVD). Sleep architecture characterizes the distribution of different stages of sleep and may be important in CVD development. We examined the association between visit‐to‐visit BPV and sleep architecture using in‐lab polysomnographic data from 3,565 patients referred to an academic sleep center. BPV was calculated using the intra‐individual coefficient of variation of BP measures collected 12 months before the sleep study. We conducted multiple linear regression analyses to assess the association of systolic and diastolic BPV with sleep architecture—rapid eye movement (REM) and non‐rapid eye movement (NREM) sleep duration. Our results show that systolic BPV was inversely associated with REM sleep duration (p = .058). When patients were divided into tertile groups based on their BPV, those in the third tertile (highest variability) spent 2.7 fewer minutes in REM sleep than those in the first tertile (lowest variability, p = .032), after adjusting for covariates. We did not find an association of systolic BPV with other measures of sleep architecture. Diastolic BPV was not associated with sleep architecture either. In summary, our study showed that greater systolic BPV was associated with lower REM sleep duration. Future investigation is warranted to clarify the directionality, mechanism, and therapeutic implications

Obstructive sleep apnea and electrocardiographic P-wave morphology.

INTRODUCTION: Obstructive sleep apnea (OSA) is a highly prevalent sleep disorder with important cardiovascular implications. Left atrial abnormality can be identified by electrocardiographic P-wave morphology and is considered an important risk for atrial fibrillation (AF) and stroke, both of which have been associated with OSA. We hypothesized that severity of OSA would be associated with more abnormal electrocardiographic P-wave morphology as indicated by P-wave terminal force in V METHODS: Patients who underwent clinically indicated polysomnography and had 12-lead ECG were identified through medical record review. Logistic regression was used to determine the associations between the measures of OSA severity (apnea hypopnea index [AHI] and mean nocturnal oxygen [O RESULTS: A total of 261 patients (mean age: 57 years old, male: 52%) were included in the study. Multivariate analysis showed that AHI was associated with abnormal PTFV CONCLUSION: In a sleep clinic cohort, there was significant association between OSA severity and ECG-defined left atrial abnormality

Brd4 binds to active enhancers to control cell identity gene induction in adipogenesis and myogenesis

The epigenomic reader Brd4 is an important drug target for cancers. However, its role in cell differentiation and animal development remains largely unclear. Using two conditional knockout mouse strains and derived cells, we demonstrate that Brd4 controls cell identity gene induction and is essential for adipogenesis and myogenesis. Brd4 co-localizes with lineage-determining transcription factors (LDTFs) on active enhancers during differentiation. LDTFs coordinate with H3K4 mono-methyltransferases MLL3/MLL4 (KMT2C/KMT2D) and H3K27 acetyltransferases CBP/p300 to recruit Brd4 to enhancers activated during differentiation. Brd4 deletion prevents the enrichment of Mediator and RNA polymerase II transcription machinery, but not that of LDTFs, MLL3/MLL4-mediated H3K4me1, and CBP/p300-mediated H3K27ac, on enhancers. Consequently, Brd4 deletion prevents enhancer RNA production, cell identity gene induction and cell differentiation. Interestingly, Brd4 is dispensable for maintaining cell identity genes in differentiated cells. These findings identify Brd4 as an enhancer epigenomic reader that links active enhancers with cell identity gene induction in differentiation

Molecular-scale substrate anisotropy and crowding drive long-range nematic order of cell monolayers

The ability of cells to reorganize in response to external stimuli is important in areas ranging from morphogenesis to tissue engineering. Elongated cells can co-align due to steric effects, forming states with local order. We show that molecular-scale substrate anisotropy can direct cell organization, resulting in the emergence of nematic order on tissue scales. To quantitatively examine the disorder-order transition, we developed a high-throughput imaging platform to analyze velocity and orientational correlations for several thousand cells over days. The establishment of global, seemingly long-ranged order is facilitated by enhanced cell division along the substrate's nematic axis, and associated extensile stresses that restructure the cells' actomyosin networks. Our work, which connects to a class of systems known as active dry nematics, provides a new understanding of the dynamics of cellular remodeling and organization in weakly interacting cell collectives. This enables data-driven discovery of cell-cell interactions and points to strategies for tissue engineering.Comment: 29 pages, 7 figure

Identification of a novel locus C2 controlling canary yellow flesh color in watermelons

The flesh color of watermelon is an important trait that is determined by carotenoid composition and affects consumers’ fruit desirability. Although a complete dominant control by C locus (Cllcyb) for canary yellow flesh (CY) over red flesh has been reported, red and CY colors frequently appear as a mixed pattern in the same flesh (incomplete canary yellow, ICY) in F1 and inbred lines carrying dominant C alleles. Therefore, we examined the genetic control of the mixed color pattern in ICY using whole-genome resequencing of three ICY (ICY group) and three CY inbred lines (CY group), as well as genetic linkage mapping of an F2 population. The segregation pattern in 135 F2 plants indicated that CY is controlled by a single locus (named C2) dominant over ICY. The whole-genome resequencing of ICY and CY inbred lines revealed an ICY/CY-specific region of approximately 27.60–27.88 Mb on Chr. 2 that was polymorphic between the ICY and CY groups. Our genetic map, using nine cleaved amplified polymorphic sequence markers developed based on the single-nucleotide polymorphisms from the ICY/CY-specific region, confirmed that C2 is located on Chr. 2 and cosegregated with the marker (M7) derived from a non-synonymous single-nucleotide polymorphism of the pentatricopeptide repeat (PPR) gene (ClPPR, Cla97C02G039880). Additionally, 27 watermelon inbred lines of ICY, CY, and red flesh were evaluated using previously reported Cllcyb (C locus)-based markers and our C2 locus-linked ClPPR-based marker (M7). As a result, dominant alleles at the C2 locus were required to produce CY, in addition to dominant alleles at the C locus, while a recessive homozygous genotype at the C locus gave the red flesh irrespective of the genotype at the C2 locus. Using a ClPPR-based cleaved amplified polymorphic sequence developed in this study and Cllcyb-based markers, watermelon cultivars with CY, ICY, and red flesh could be successfully discerned, implying that the combined use of these markers will be efficient for marker-assisted selection of flesh color in watermelon breeding

Characterization of fiber-optic light delivery and light-induced temperature changes in a rodent brain for precise optogenetic neuromodulation

Understanding light intensity and temperature increase is of considerable importance in designing or performing in vivo optogenetic experiments. Our study describes the optimal light power at target depth in the rodent brain that would maximize activation of light-gated ion channels while minimizing temperature increase. Monte Carlo (MC) simulations of light delivery were used to provide a guideline for suitable light power at a target depth. In addition, MC simulations with the Pennes bio-heat model using data obtained from measurements with a temperature-measuring cannula having 12.3 mV/°C of thermoelectric sensitivity enabled us to predict tissue heating of 0.116 °C/mW on average at target depth of 563 μm and specifically, a maximum mean plateau temperature increase of 0.25 °C/mW at 100 μm depth for 473 nm light. Our study will help to improve the design and performance of optogenetic experiments while avoiding potential over-and underillumination. © 2016 Optical Society of America.1

c-Jun N-terminal kinase activation has a prognostic implication and is negatively associated with FOXO1 activation in gastric cancer

BACKGROUND: Since the biological function of c-Jun N-terminal kinase (JNK) in gastric cancer remains unclear, we investigated the clinical significance of JNK activation and its association with FOXO1 activation. METHODS: Immunohistochemical tissue array analysis of 483 human gastric cancer specimens was performed, and the results of the immunostaining were quantified. The correlation between JNK activation (nuclear staining for pJNK) and clinicopathological features, the proliferation index, prognosis or FOXO1 inactivation (cytoplasmic staining for pFOXO1) was analyzed. The SNU-638 gastric cancer cell line was used for in vitro analysis. RESULTS: Nuclear staining of pJNK was found in 38 % of the gastric carcinomas and was higher in the early stages of pTNM (P < 0.001). pJNK staining negatively correlated with lymphatic invasion (P = 0.034) and positively correlated with intestinal type by Lauren’s classification (P = 0.037), Ki-67-labeling index (P < 0.001), cyclin D1 (P = 0.045), cyclin E (P < 0.001) and pFOXO1 (P < 0.001). JNK activation correlated with a longer patients survival (P =0.008) and patients with a JNK-active and FOXO1-inactive tumor had a higher survival rate than the remainder of the population (P = 0.004). In vitro analysis showed that JNK inhibition by SP600125 in SNU-638 cells decreased cyclin D1 protein expression and increased FOXO1 activation. Further, JNK inhibition markedly suppressed colony formation, which was partially restored by FOXO1 shRNA expression. CONCLUSIONS: Our results indicate that JNK activation may serve as a valuable prognostic factor in gastric cancer, and that it is implicated in gastric tumorigenesis, at least in part, through FOXO1 inhibition

Bio-inspired Design and Additive Manufacturing of Resilient Composites Materials: From Mussel Adhesion to 3D-printed Polymer Foams

Natural materials have long inspired the design and fabrication of advanced materials. Characterized by intricate structures featuring hierarchical porosity, spatial heterogeneities, and architectural gradients, these materials offer unique combinations of stiffness, strength, and toughness at low density. Inspired by nature, this thesis explores the development of advanced materials through two distinct avenues.In the initial investigation, the adhesive capabilities of marine mussels are examined on various geometry-controlled surfaces. Through mechanical tests, the adhesion strength of mussel structures is assessed, revealing consistent detachment forces . This suggests their robustness to different substrate geometries. Subsequent scanning electron microscopy (SEM) analysis reveals substrate-dependent damages within microstructures, indicating that mussels are capable of changing damage mechanisms to maintain characteristic pull-off force, suggesting their adaptability to geometric conditions. Building upon the insights gained from natural materials, subsequent work focuses on the development of advanced materials using additive manufacturing (AM) techniques. Specifically, digital light processing (DLP) of photocurable resins combined with thermally expandable microspheres is employed to create polymer composite foams that are lightweight yet stiff. A two-step material processing approach enables precise control over porosity with tunable mechanical properties of the materials. Through mechanical analysis under compression, we elucidate how foaming alters the mechanics of the composite material, including changes in modulus, Poisson’s ratio, energy dissipation, and fatigue performance. In the final chapter, we investigate thermally induced transformations in the properties of the polymer foams. We observe that 3D-printed objects undergo extra-curing upon heating above the expansion temperature of the microspheres, indicating that the materials bear latent transformation capabilities. Through comprehensive thermal analysis and mechanical characterization, we identify exothermic reactions at elevated temperatures, along with shifts in the glass transition temperature. This confirms that the processed material still contains unreacted residual monomers, which can lead to on-demand thermal polymerization. An understanding of thermal polymerization kinetics is established, enabling the further tailoring of mechanical properties of the foams post-cure. This work provides insights into the processing-structure-property relationships of additively manufactured composite foams, offering feasible pathways for the design of materials with practical applications across various engineering fields