Atrial fibrillation and electrophysiology in transgenic mice with cardiac-restricted overexpression of FKBP12

Cardiomyocyte-restricted overexpression of FK506-binding protein 12 transgenic (αMyHC-FKBP12) mice develop spontaneous atrial fibrillation (AF). The aim of the present study is to explore the mechanisms underlying the occurrence of AF in αMyHC-FKBP12 mice. Spontaneous AF was documented by telemetry in vivo and Langendorff-perfused hearts of αMyHC-FKBP12 and littermate control mice in vitro. Atrial conduction velocity was evaluated by optical mapping. The patch-clamp technique was applied to determine the potentially altered electrophysiology in atrial myocytes. Channel protein expression levels were evaluated by Western blot analyses. Spontaneous AF was recorded in four of seven αMyHC-FKBP12 mice but in none of eight nontransgenic (NTG) controls. Atrial conduction velocity was significantly reduced in αMyHC-FKBP12 hearts compared with NTG hearts. Interestingly, the mean action potential duration at 50% but not 90% was significantly prolonged in αMyHC-FKBP12 atrial myocytes compared with their NTG counterparts. Consistent with decreased conduction velocity, average peak Na+ current ( INa) density was dramatically reduced and the INa inactivation curve was shifted by approximately +7 mV in αMyHC-FKBP12 atrial myocytes, whereas the activation and recovery curves were unaltered. The Nav1.5 expression level was significantly reduced in αMyHC-FKBP12 atria. Furthermore, we found increases in atrial Cav1.2 protein levels and peak L-type Ca2+ current density and increased levels of fibrosis in αMyHC-FKBP12 atria. In summary, cardiomyocyte-restricted overexpression of FKBP12 reduces the atrial Nav1.5 expression level and mean peak INa, which is associated with increased peak L-type Ca2+ current and interstitial fibrosis in atria. The combined electrophysiological and structural changes facilitated the development of local conduction block and altered action potential duration and spontaneous AF. NEW & NOTEWORTHY This study addresses a long-standing riddle regarding the role of FK506-binding protein 12 in cardiac physiology. The work provides further evidence that FK506-binding protein 12 is a critical component for regulating voltage-gated sodium current and in so doing has an important role in arrhythmogenic physiology, such as atrial fibrillation

ELM of ELM-WD: An extremely low mass hot donor star discovered in LAMOST survey

The Extremely Low Mass White Dwarfs (ELM WDs) and pre-ELM WDs are helium core white dwarfs with mass $<\sim 0.3M_{\odot}$. They are formed in close binaries and have lost over half of their initial masses via Common Envelope (CE) ejection or stable Roche Lobe Over Flow (RLOF). Both evolution simulations and observations show that a lower mass limit for ELM WDs exists at $\approx0.14M_{\odot}$. Here we report the discovery of an extremely low mass ELM WD, ID70904216 in LAMOST survey, that may be lower than the ELM WD mass limit. Based on LAMOST and P200 spectroscopic observations, ID70904216 shows orbital period $P_{orb} =$ 0.219658 days and radial velocity semi-amplitude $K1=317.33km/s$, which gives the mass function of 0.73$M_{\odot}$, indicating the companion is a compact star. The low resolution spectra shows a F type star with $T_{\rm eff} \sim 7361K$ without emission features. The temperature is consistent with that derived from SED fitting($7440K$) and multi-color light curve solution($7400K$). The optical light curves, in ZTF g, r and i bands and Catalina V band, show ellipsoidal variability with amplitudes $\approx30\%$, suggesting that the visible companion is heavily tidal distorted. Combining with the distance from Gaia survey, the WD code modeling estimates that the mass of the visible star is $M1=0.08^{+0.06}_{-0.03}M_{\odot}$, and the mass of the invisible star is $M2=0.94^{+0.45}_{-0.10}M_{\odot}$. The radius of the visible donor is $R=0.29\pm0.01R_{\odot}$. The inclination angle is constrained between 60$^{\circ}$ and 90$^{\circ}$. The observations indicate the system is a pre-ELM WD + WD/NS binary system with an extremely low mass hot donor below the $0.14M_{\odot}$ theoretical limit.Comment: 16 pages, 10 figure

Protection against SHIV-KB9 Infection by Combining rDNA and rFPV Vaccines Based on HIV Multiepitope and p24 Protein in Chinese Rhesus Macaques

Developing an effective vaccine against HIV infection remains an urgent goal. We used a DNA prime/fowlpox virus boost regimen to immunize Chinese rhesus macaques. The animals were challenged intramuscularly with pathogenic molecularly cloned SHIV-KB9. Immunogenicity and protective efficacy of vaccines were investigated by measuring IFN-γ levels, monitoring HIV-specific binding antibodies, examining viral load, and analyzing CD4/CD8 ratio. Results show that, upon challenge, the vaccine group can induce a strong immune response in the body, represented by increased expression of IFN-γ, slow and steady elevated antibody production, reduced peak value of acute viral load, and increase in the average CD4/CD8 ratio. The current research suggests that rapid reaction speed, appropriate response strength, and long-lasting immune response time may be key protection factors for AIDS vaccine. The present study contributes significantly to AIDS vaccine and preclinical research

Orbital parameters for an ELM white dwarf with a white dwarf companion: LAMOST J033847.06+413424.2

Double white dwarf systems are of great astrophysical importance in the field of gravitational wave and Type Ia supernova. While the binary fraction of CO core white dwarf is about a few percents, the extremely low mass white dwarfs are all thought to be within binary systems. In this work, we report the orbital solution of a double degenerate system: J033847.06+413424.24, an extremely low mass He core white dwarf orbiting a CO core white dwarf. With LAMOST and P200, time domain spectroscopic observations have been made and spectral atmosphere parameters are estimated to be $T_{\rm eff}\sim22500$ K and log $g\sim5.6$ dex. Combining Gaia parallax, 3D extinction, and evolution tracks, we estimate a radius of $\sim0.12$ $R_{\odot}$ and a mass of $\sim0.22$ $M_{\odot}$. With the 37 single exposure spectra, the radial velocities are measured and the orbital parameters are estimated to be $P=0.1253132(1)$ days, $K1=289\pm4$ km/s and $V_{sys}=-41\pm3$ km/s. The radial velocity based system ephemeris is also provided. The light curves from several photometric surveys show no orbital modulation. The orbital solution suggests that the invisible companion has a minimum mass of about 0.60 $M_{\odot}$ and is $\sim0.79$ $M_{\odot}$ for an inclination of $60.0^{\circ}$, indicating most probably a CO core white dwarf. The system is expected to merge in about 1 Gyr. With present period and distance ($\sim596$ pc) it can not irradiate strong enough gravitational wave for LISA. More double degenerate systems are expected to be discovered and parameterized as the LAMOST survey goes on.Comment: 12 pages, 11 figure

Precision Higgs physics at the CEPC

The discovery of the Higgs boson with its mass around 125 GeV by the ATLAS and CMS Collaborations marked the beginning of a new era in high energy physics. The Higgs boson will be the subject of extensive studies of the ongoing LHC program. At the same time, lepton collider based Higgs factories have been proposed as a possible next step beyond the LHC, with its main goal to precisely measure the properties of the Higgs boson and probe potential new physics associated with the Higgs boson. The Circular Electron Positron Collider~(CEPC) is one of such proposed Higgs factories. The CEPC is an $e^+e^-$ circular collider proposed by and to be hosted in China. Located in a tunnel of approximately 100~km in circumference, it will operate at a center-of-mass energy of 240~GeV as the Higgs factory. In this paper, we present the first estimates on the precision of the Higgs boson property measurements achievable at the CEPC and discuss implications of these measurements.Comment: 46 pages, 37 figure

Cardiovascular Safety Evaluation of Febuxostat and Allopurinol: Findings from the FDA Adverse Event Reporting System

Background: Febuxostat and allopurinol are the most commonly used uric acid-lowering medications, and their safety is of great concern, especially the cardiovascular adverse reactions associated with febuxostat. We propose to study the cardiovascular toxicity of febuxostat and allopurinol using the FDA Adverse Event Reporting System (FAERS) database. Methods: A total of 64 quarters of FAERS data were downloaded from 2004 to 2019. Febuxostat- and allopurinol-related cardiovascular adverse events were extracted after data cleaning. Signal detection was conducted by reporting odds ratio (ROR) and proportional reporting ratio (PRR). Results: There were 2939 and 25,219 reports of febuxostat- and allopurinol-related cardiovascular adverse events (CVAEs), respectively. The most frequent CVAEs with febuxostat and allopurinol were edema peripheral (14.38%) and peripheral swelling (8.76%), respectively. In elderly gout patients, febuxostat is associated with an increased risk of heart failure, ischemic heart disease, hypertension, and cardiomyopathy. Febuxostat in combination with acetic acid derivatives nonsteroidal anti-inflammatory drug (NSAIDS) also increases the risk of cardiovascular adverse events. Conclusions: Compared with allopurinol, febuxostat may increase cardiovascular toxicity in patients with gout

lncRNA MIR503HG Targets miR-191-5p/PLCD1 Axis and Negatively Modulates Apoptosis, Extracellular Matrix Disruption, and Inflammation in Abdominal Aortic Aneurysm

As the most prevalent subtype of aortic aneurysm, abdominal aortic aneurysm (AAA) features the apoptosis, extracellular matrix (ECM) disruption, and inflammation response of vascular smooth muscle cells (VSMCs). Noncoding RNAs (ncRNAs) are crucial factors in AAA progression, while the investigations have not been fully explained. miR-191-5p upregulation is found in aortic aneurysm. However, its role in AAA has not been addressed. This research purposed to excavate the possible and associated molecular axis of miR-191-5p in AAA. In our study, miR-191-5p level was detected to be high in the tissues from AAA patients in comparison with the control group. After miR-191-5p expression was enhanced, cell viability was repressed, cell apoptosis was boosted, and ECM disruption and the inflammation response were fortified. Furthermore, the relationship among MIR503HG, miR-191-5p, and phospholipase C delta 1 (PLCD1) in VSMCs was disclosed via mechanism assays. Decreased MIR503HG lacked the inhibition on miR-191-5p targeting PLCD1, resulting in downregulation of PLCD1, which facilitated the progression of AAA. Thus, targeting MIR503HG/miR-191-5p/PLCD1 pathway will provide an additional method for the cure of AAA patients

Toward High-Performance Poly(l‑lactide) Fibers via Tailoring Crystallization with the Aid of Fibrillar Nucleating Agent

As a sustainable alternative to conventional petrochemical-based polymers, biobased and biodegradable poly­(l-lactide) (PLLA) exhibits tremendous application potential in the textile industry due to its attractive elastic recovery, moisture regain, and flammability. However, the commercial adoption of PLLA textile fibers still faces some hurdles mainly associated with their poor heat resistance (i.e., high thermal shrinkage or low dimensional stability) because the low crystallization rate makes PLLA difficult to crystallize during melt spinning. Herein, we report a simple but robust strategy to address this hurdle via simultaneously manipulating crystallinity and lamellae orientation with the aid of a highly active nucleating agent (NA) that can be completely dissolved in PLLA melt and reorganize into fine fibrils upon cooling. By taking full advantage of strong elongational flow field involved in the melt spinning, the NA fibrils with high nucleation efficiency on PLLA crystallization tend to align along the flow direction and subsequently serve as nucleation templates to induce the growth of kebab-like PLLA lamellae perpendicular to their long axis, finally forming large amounts of highly orientated crystal structure in melt-spun PLLA fibers. In this way, the crystallization manipulation imparts the PLLA fibers with an impressive combination of superior mechanical strength and heat resistance. Compared with neat PLLA fiber, a prominent increase of 78% in tensile strength and a substantial decline of 1069% in boiling water shrinkage are achieved in the fiber nucleated with 0.3 wt % NA. This work could open up an avenue toward the design and development of high-performance PLLA fibers by using fibrillar nucleating agent as a nucleation template to tailor effectively crystallization in the melt spinning process