Genetic Dissection of Cardiac Remodeling in an Isoproterenol-Induced Heart Failure Mouse Model.

We aimed to understand the genetic control of cardiac remodeling using an isoproterenol-induced heart failure model in mice, which allowed control of confounding factors in an experimental setting. We characterized the changes in cardiac structure and function in response to chronic isoproterenol infusion using echocardiography in a panel of 104 inbred mouse strains. We showed that cardiac structure and function, whether under normal or stress conditions, has a strong genetic component, with heritability estimates of left ventricular mass between 61% and 81%. Association analyses of cardiac remodeling traits, corrected for population structure, body size and heart rate, revealed 17 genome-wide significant loci, including several loci containing previously implicated genes. Cardiac tissue gene expression profiling, expression quantitative trait loci, expression-phenotype correlation, and coding sequence variation analyses were performed to prioritize candidate genes and to generate hypotheses for downstream mechanistic studies. Using this approach, we have validated a novel gene, Myh14, as a negative regulator of ISO-induced left ventricular mass hypertrophy in an in vivo mouse model and demonstrated the up-regulation of immediate early gene Myc, fetal gene Nppb, and fibrosis gene Lgals3 in ISO-treated Myh14 deficient hearts compared to controls

GPER-induced signaling is essential for the survival of breast cancer stem cells.

G protein-coupled estrogen receptor-1 (GPER), a member of the G protein-coupled receptor (GPCR) superfamily, mediates estrogen-induced proliferation of normal and malignant breast epithelial cells. However, its role in breast cancer stem cells (BCSCs) remains unclear. Here we showed greater expression of GPER in BCSCs than non-BCSCs of three patient-derived xenografts of ER- /PR+ breast cancers. GPER silencing reduced stemness features of BCSCs as reflected by reduced mammosphere forming capacity in vitro, and tumor growth in vivo with decreased BCSC populations. Comparative phosphoproteomics revealed greater GPER-mediated PKA/BAD signaling in BCSCs. Activation of GPER by its ligands, including tamoxifen (TMX), induced phosphorylation of PKA and BAD-Ser118 to sustain BCSC characteristics. Transfection with a dominant-negative mutant BAD (Ser118Ala) led to reduced cell survival. Taken together, GPER and its downstream signaling play a key role in maintaining the stemness of BCSCs, suggesting that GPER is a potential therapeutic target for eradicating BCSCs

High-fidelity Rydberg control-Z gates with time-optimal pulses

High-fidelity control-$Z$ ($C_Z$) gates are essential and mandatory to build a large-scale quantum computer. In neutral atoms, the strong dipole-dipole interactions between their Rydberg states make them one of the pioneering platforms to implement $C_Z$ gates. Here we numerically investigate the time-optimal pulses to generate a high-fidelity Rydberg $C_{Z}$ gate in a three-level ladder-type atomic system. By tuning the temporal shapes of Gaussian or segmented pulses, the populations on the intermediate excited states are shown to be suppressed within the symmetric gate operation protocol, which leads to a $C_{Z}$ gate with a high Bell fidelity up to $0.9998$. These optimized pulses are robust to thermal fluctuations and the excitation field variations. Our results promise a high-fidelity and fast gate operation under amenable and controllable experimental parameters, which goes beyond the adiabatic operation regime under a finite Blockade strength.Comment: 6 figure

The spontaneous emergence of ordered phases in crumpled sheets

X-ray tomography is performed to acquire 3D images of crumpled aluminum foils. We develop an algorithm to trace out the labyrinthian paths in the three perpendicular cross sections of the data matrices. The tangent-tangent correlation function along each path is found to decay exponentially with an effective persistence length that shortens as the crumpled ball becomes more compact. In the mean time, we observed ordered domains near the crust, similar to the lamellae phase mixed by the amorphous portion in lyotropic liquid crystals. The size and density of these domains grow with further compaction, and their orientation favors either perpendicular or parallel to the radial direction. Ordering is also identified near the core with an arbitrary orientation, exemplary of the spontaneous symmetry breaking

Effects of Selfâ Assembled Monolayer Modification of Nickel Oxide Nanoparticles Layer on the Performance and Application of Inverted Perovskite Solar Cells

Entirely lowâ temperature solutionâ processed (â ¤100â °C) planar pâ iâ n perovskite solar cells (PSCs) offer great potential for commercialization of rollâ toâ roll fabricated photovoltaic devices. However, the stable inorganic holeâ transporting layer (HTL) in PSCs is usually processed at high temperature (200â 500â °C), which is far beyond the tolerant temperature (â ¤150â °C) of rollâ toâ roll fabrication. In this context, inorganic NiOx nanoparticles (NPs) are an excellent candidate to serve as the HTL in PSCs, owing to their excellent solution processability at room temperature. However, the lowâ temperature processing condition is usually accompanied with defect formation, which deteriorates the film quality and device efficiency to a large extent. To suppress this setback, we used a series of benzoic acid selfassembled monolayers (SAMs) to passivate the surface defects of the NiOx NPs and found that 4â bromobenzoic acid could effectively play the role of the surface passivation. This SAM layer reduces the trapâ assisted recombination, minimizes the energy offset between the NiOx NPs and perovskite, and changes the HTL surface wettability, thus enhancing the perovskite crystallization, resulting in more stable PSCs with enhanced power conversion efficiency (PCE) of 18.4â %, exceeding the control device PCE (15.5â %). Also, we incorporated the aboveâ mentioned SAMs into flexible PSCs (Fâ PSCs) and achieved one of the highest PCE of 16.2â % on a polyethylene terephthalate (PET) substrate with a remarkable powerâ perâ weight of 26.9â Wâ gâ 1. This facile interfacial engineering method offers great potential for the largeâ scale manufacturing and commercialization of PSCs.Engineered layers: Lowâ temperature solutionâ processed NiOx nanoparticle film is usually accompanied with defect formation. Here, we find that 4â bromobenzoic acid can form a selfâ assembled monolayer (SAM) on the NiOx film and effectively tune the interfacial properties, resulting in high perovskite solar cells (PSCs) efficiency. Also, we incorporate the aboveâ mentioned SAM into flexible PSCsPeer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138886/1/cssc201701262_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/138886/2/cssc201701262.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/138886/3/cssc201701262-sup-0001-misc_information.pd

Clustering Heart Rate Dynamics Is Associated with β-Adrenergic Receptor Polymorphisms: Analysis by Information-Based Similarity Index

Background: Genetic polymorphisms in the gene encoding the β-adrenergic receptors (β -AR) have a pivotal role in the functions of the autonomic nervous system. Using heart rate variability (HRV) as an indicator of autonomic function, we present a bottom-up genotype–phenotype analysis to investigate the association between β -AR gene polymorphisms and heart rate dynamics. Methods: A total of 221 healthy Han Chinese adults (59 males and 162 females, aged 33.6610.8 years, range 19 to 63 years) were recruited and genotyped for three common β-AR polymorphisms: β$_1$-AR Ser49Gly, β$_2$-AR Arg16Gly and β$_2$-AR Gln27Glu. Each subject underwent two hours of electrocardiogram monitoring at rest. We applied an information-based similarity (IBS) index to measure the pairwise dissimilarity of heart rate dynamics among study subjects. Results: With the aid of agglomerative hierarchical cluster analysis, we categorized subjects into major clusters, which were found to have significantly different distributions of β$_2$-AR Arg16Gly genotype. Furthermore, the non-randomness index, a nonlinear HRV measure derived from the IBS method, was significantly lower in Arg16 homozygotes than in Gly16 carriers. The non-randomness index was negatively correlated with parasympathetic-related HRV variables and positively correlated with those HRV indices reflecting a sympathovagal shift toward sympathetic activity. Conclusions: We demonstrate a bottom-up categorization approach combining the IBS method and hierarchical cluster analysis to detect subgroups of subjects with HRV phenotypes associated with β-AR polymorphisms. Our results provide evidence that β$_2$-AR polymorphisms are significantly associated with the acceleration/deceleration pattern of heart rate oscillation, reflecting the underlying mode of autonomic nervous system control

Association of epilepsy, anti-epileptic drugs (AEDs), and type 2 diabetes mellitus (T2DM): a population-based cohort retrospective study, impact of AEDs on T2DM-related molecular pathway, and via peroxisome proliferator-activated receptor γ transactivation

IntroductionA potential association between epilepsy and subsequent type 2 diabetes mellitus (T2DM) has emerged in recent studies. However, the association between epilepsy, anti-epileptic drugs (AEDs), and the risk of T2DM development remains controversial. We aimed to conduct a nationwide, population-based, retrospective, cohort study to evaluate this relationship.MethodsWe extracted data from the Taiwan Longitudinal Generation Tracking Database of patients with new-onset epilepsy and compared it with that of a comparison cohort of patients without epilepsy. A Cox proportional hazards regression model was used to analyze the difference in the risk of developing T2DM between the two cohorts. Next-generation RNA sequencing was used to characterize T2DM-related molecularchanges induced by AEDs and the T2DM-associated pathways they alter. The potential of AEDs to induce peroxisome proliferator-activated receptor γ (PPARγ) transactivation was also evaluated.ResultsAfter adjusting for comorbidities and confounding factors, the case group (N = 14,089) had a higher risk for T2DM than the control group (N = 14,089) [adjusted hazards ratio (aHR), 1.27]. Patients with epilepsy not treated with AEDs exhibited a significantly higher risk of T2DM (aHR, 1.70) than non-epileptic controls. In those treated with AEDs, the risk of developing T2DM was significantly lower than in those not treated (all aHR ≤ 0.60). However, an increase in the defined daily dose of phenytoin (PHE), but not of valproate (VPA), increased the risk of T2DM development (aHR, 2.28). Functional enrichment analysis of differentially expressed genes showed that compared to PHE, VPA induced multiple beneficial genes associated with glucose homeostasis. Among AEDs, VPA induced the specific transactivation of PPARγ.DiscussionOur study shows epilepsy increases the risk of T2DM development, however, some AEDs such as VPA might yield a protective effect against it. Thus, screening blood glucose levels in patients with epilepsy is required to explore the specific role and impact of AEDs in the development of T2DM. Future in depth research on the possibility to repurpose VPA for the treatment of T2DM, will offer valuable insight regarding the relationship between epilepsy and T2DM