Prevalence and spectrum of Nkx2.5 mutations associated with idiopathic atrial fibrillation

OBJECTIVE: The aim of this study was to evaluate the prevalence and spectrum of Nkx2.5 mutations associated with idiopathic atrial fibrillation (AF). METHODS: A cohort of 136 unrelated patients with idiopathic atrial fibrillation and 200 unrelated, ethnically matched healthy controls were enrolled. The coding exons and splice junctions of the Nkx2.5 gene were sequenced in 136 atrial fibrillation patients, and the available relatives of mutation carriers and 200 controls were subsequently genotyped for the identified mutations. The functional characteristics of the mutated Nkx2.5 gene were analyzed using a dual-luciferase reporter assay system. RESULTS: Two novel heterozygous Nkx2.5 mutations (p.N19D and p.F186S) were identified in 2 of the 136 unrelated atrial fibrillation cases, with a mutational prevalence of approximately 1.47%. These missense mutations co-segregated with atrial fibrillation in the families and were absent in the 400 control chromosomes. Notably, 2 mutation carriers also had congenital atrial septal defects and atrioventricular block. Multiple alignments of the Nkx2.5 protein sequences across various species revealed that the altered amino acids were completely conserved evolutionarily. Functional analysis demonstrated that the mutant Nkx2.5 proteins were associated with significantly reduced transcriptional activity compared to their wild-type counterpart. CONCLUSION: These findings associate the Nkx2.5 loss-of-function mutation with atrial fibrillation and atrioventricular block and provide novel insights into the molecular mechanism involved in the pathogenesis of atrial fibrillation. These results also have potential implications for early prophylaxis and allele-specific therapy of this common arrhythmia

PITX2C loss-of-function mutations responsible for idiopathic atrial fibrillation

OBJECTIVE: This study aimed to identify novel PITX2c mutations responsible for idiopathic atrial fibrillation. METHODS: A cohort of 210 unrelated patients with idiopathic atrial fibrillation and 200 unrelated, ethnically matched healthy individuals used as controls were recruited. The whole coding exons and splice junctions of the PITX2c gene, which encodes a paired-like homeobox transcription factor required for normal cardiovascular morphogenesis, were sequenced in 210 patients and 200 control subjects. The causative potentials of the identified mutations were automatically predicted by MutationTaster and PolyPhen-2. The functional characteristics of the PITX2c mutations were explored using a dual-luciferase reporter assay system. RESULTS: Two novel heterozygous PITX2c mutations (p.Q105L and p.R122C) were identified in 2 of the 210 unrelated patients with idiopathic atrial fibrillation. These missense mutations were absent in the 400 control chromosomes and were both predicted to be pathogenic. Multiple alignments of PITX2c protein sequences across various species showed that the altered amino acids were highly evolutionarily conserved. A functional analysis demonstrated that the mutant PITX2c proteins were both associated with significantly reduced transcriptional activity compared with their wild-type counterparts. CONCLUSION: The findings of this study associate PITX2c loss-of-function mutations with atrial fibrillation, supporting the hypothesis that dysfunctional PITX2c confers enhanced susceptibility to atrial fibrillation and suggesting potential implications for early prophylaxis and allele-specific therapy for this common arrhythmia

Case report: Anterior mediastinal mass in a patient with pleural effusion and dyspnea

BackgroundCompound lymphoma is an uncommon type of lymphoid malignancy, and those consisting of concurrent B- and T-cell tumors are relatively rare.Case SummaryA 41-year-old man was presented with a 1-month history of progressively worsening cough, chest tightness, and dyspnea after exercise, which could be relieved following rest. Contrast-enhanced computed tomography scan demonstrated a 7.4 × 4.9 cm2 heterogeneous mass in the anterior mediastinum, where a large area of cystic liquid existed, and multiple enlarged lymph nodes in the mediastinum. Since the biopsy failed to yield an exact diagnosis and there was no sign of metastasis, the tumor was surgically resectioned. Surgical findings included obscure boundaries and consistent tumor stiffness with pericardial and pleural invasion. Further pathological examination combined with immunophenotype and gene rearrangement test found the mass composite of angioimmunoblastic T-cell lymphoma (AITL) and B-cell lymphoma. The patient recovered well after R0 resection and received chemotherapy with four cycles of CHOP combined with chidamide 2 weeks after surgery. The patient has had a complete response for over 60 months.ConclusionIn conclusion, we reported a composite lymphoma of AITL combined with B-cell lymphomas. Our experience provides the first successful attempt to treat this rare disease with combined surgery and chemotherapy

Identification of Magnetic Interactions and High-field Quantum Spin Liquid in α\alpha-RuCl3_3

The frustrated magnet $\alpha$-RuCl$_3$ constitutes a fascinating quantum material platform that harbors the intriguing Kitaev physics. However, a consensus on its intricate spin interactions and field-induced quantum phases has not been reached yet. Here we exploit multiple state-of-the-art many-body methods and determine the microscopic spin model that quantitatively explains major observations in $\alpha$-RuCl$_3$, including the zigzag order, double-peak specific heat, magnetic anisotropy, and the characteristic M-star dynamical spin structure, etc. According to our model simulations, the in-plane field drives the system into the polarized phase at about 7 T and a thermal fractionalization occurs at finite temperature, reconciling observations in different experiments. Under out-of-plane fields, the zigzag order is suppressed at 35 T, above which, and below a polarization field of 100 T level, there emerges a field-induced quantum spin liquid. The fractional entropy and algebraic low-temperature specific heat unveil the nature of a gapless spin liquid, which can be explored in high-field measurements on $\alpha$-RuCl$_3$.Comment: To appear in Nature Communications (12 pages, 6 figures, and 5 Supplementary Notes

Genome sequences reveal global dispersal routes and suggest convergent genetic adaptations in seahorse evolution

Seahorses have a circum-global distribution in tropical to temperate coastal waters. Yet, seahorses show many adaptations for a sedentary, cryptic lifestyle: they require specific habitats, such as seagrass, kelp or coral reefs, lack pelvic and caudal fins, and give birth to directly developed offspring without pronounced pelagic larval stage, rendering long-range dispersal by conventional means inefficient. Here we investigate seahorses’ worldwide dispersal and biogeographic patterns based on a de novo genome assembly of Hippocampus erectus as well as 358 re-sequenced genomes from 21 species. Seahorses evolved in the late Oligocene and subsequent circum-global colonization routes are identified and linked to changing dynamics in ocean currents and paleo-temporal seaway openings. Furthermore, the genetic basis of the recurring “bony spines” adaptive phenotype is linked to independent substitutions in a key developmental gene. Analyses thus suggest that rafting via ocean currents compensates for poor dispersal and rapid adaptation facilitates colonizing new habitats.Fil: Chunyan, Li. Southern Marine Science and Engineering Guangdong Laboratory; China. Pilot National Laboratory for Marine Science and Technology; China. Chinese Academy of Sciences; República de ChinaFil: Olave, Melisa. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto Argentino de Investigaciones de las Zonas Áridas. Provincia de Mendoza. Instituto Argentino de Investigaciones de las Zonas Áridas. Universidad Nacional de Cuyo. Instituto Argentino de Investigaciones de las Zonas Áridas; Argentina. University of Konstanz; AlemaniaFil: Hou, Yali. Chinese Academy of Sciences; República de ChinaFil: Geng, Qi. Chinese Academy of Sciences; República de China. Southern Marine Science and Engineering Guangdong Laboratory; ChinaFil: Schneider, Ralf. University Of Konstanz; Alemania. Helmholtz Centre for Ocean Research Kie; AlemaniaFil: Zeixa, Gao. Huazhong Agricultural University; ChinaFil: Xiaolong, Tu. Allwegene Technologies ; ChinaFil: Xin, Wang. Chinese Academy of Sciences; República de ChinaFil: Furong, Qi. China National Center for Bioinformation; China. University of Chinese Academy of Sciences; ChinaFil: Nater, Alexander. University of Konstanz; AlemaniaFil: Kautt, Andreas F.. University of Konstanz; Alemania. Harvard University; Estados UnidosFil: Wan, Shiming. Chinese Academy of Sciences; República de ChinaFil: Yanhong, Zhang. Chinese Academy of Sciences; República de ChinaFil: Yali, Liu. Chinese Academy of Sciences; República de ChinaFil: Huixian, Zhang. Chinese Academy of Sciences; República de ChinaFil: Bo, Zhang. Chinese Academy of Sciences; República de ChinaFil: Hao, Zhang. Chinese Academy of Sciences; República de ChinaFil: Meng, Qu ,. Chinese Academy of Sciences; República de ChinaFil: Shuaishuai, Liu. Chinese Academy of Sciences; República de ChinaFil: Zeyu, Chen. Chinese Academy of Sciences; República de China. University of Chinese Academy of Sciences; ChinaFil: Zhong, Jia. Chinese Academy of Sciences; República de ChinaFil: Zhang, He. BGI-Shenzhen; ChinaFil: Meng, Lingfeng. BGI-Shenzhen; ChinaFil: Wang, Kai. Ludong University; ChinaFil: Yin, Jianping. Chinese Academy of Sciences; República de ChinaFil: Huang, Liangmin. Chinese Academy of Sciences; República de China. University of Chinese Academy of Sciences; ChinaFil: Venkatesh, Byrappa. Institute of Molecular and Cell Biology; SingapurFil: Meyer, Axel. University of Konstanz; AlemaniaFil: Lu, Xuemei. Chinese Academy of Sciences; República de ChinaFil: Lin, Qiang. Chinese Academy of Sciences; República de China. Southern Marine Science and Engineering Guangdong Laboratory; China. Pilot National Laboratory for Marine Science and Technology; China. University of Chinese Academy of Sciences; Chin

Safety profile of 0.0015% tafluprost eye drops in China: a post-marketing observational study

AIM: To investigate the treatment pattern and safety of tafluprost for glaucoma and ocular hypertension (OH) in clinical practice in China. METHODS: This post-marketing observational study included patients who received tafluprost to lower intraocular pressure (IOP) within 30d between September 2017 and March 2020 in 20 hospitals in China. Adverse drug reactions (ADRs) during tafluprost treatment and within 30d after the treatment were collected. RESULTS: A total of 2544 patients were included in this study, of them 58.5% (1488/2544) had primary open angle glaucoma (POAG), 21.9% (556/2544) had OH and 19.7% (500/2544) used tafluprost for other reasons. Of 359 ADRs occurred in 10.1% (258/2544) patients, and no serious adverse event occurred. The most common ADR was conjunctival hyperemia (128 ADRs in 124 patients, 4.9%). Totally 1670 participants (65.6%) combined tafluprost with carbonic anhydrase inhibitors (CAIs; 37.1%, 620/1670), sympathomimetics (33.5%, 559/1670), β-blockers (33.2%, 555/1670), other prostaglandin analogs (PGAs; 15.6%, 260/1670) and other eye drops (15.1%, 253/1670). The highest incidence of conjunctival hyperemia was noted in patients who received tafluprost in combination with other PGAs (23 ADRs in 23 patients, 8.8%, 23/260) and the lowest was in combination with CAIs (16 ADRs in 16 patients, 2.6%, 16/620). Tafluprost was applied in primary angle-closure glaucoma (41.6%, 208/500), after glaucoma surgery (17.8%, 89/500) and after non-glaucoma surgery (15.8%, 79/500). CONCLUSION: Tafluprost is safe for POAG and OH, and tolerable when combined with other eye drops and under various clinical circumstances

Real-time Monitoring for the Next Core-Collapse Supernova in JUNO

Core-collapse supernova (CCSN) is one of the most energetic astrophysical events in the Universe. The early and prompt detection of neutrinos before (pre-SN) and during the SN burst is a unique opportunity to realize the multi-messenger observation of the CCSN events. In this work, we describe the monitoring concept and present the sensitivity of the system to the pre-SN and SN neutrinos at the Jiangmen Underground Neutrino Observatory (JUNO), which is a 20 kton liquid scintillator detector under construction in South China. The real-time monitoring system is designed with both the prompt monitors on the electronic board and online monitors at the data acquisition stage, in order to ensure both the alert speed and alert coverage of progenitor stars. By assuming a false alert rate of 1 per year, this monitoring system can be sensitive to the pre-SN neutrinos up to the distance of about 1.6 (0.9) kpc and SN neutrinos up to about 370 (360) kpc for a progenitor mass of 30$M_{\odot}$ for the case of normal (inverted) mass ordering. The pointing ability of the CCSN is evaluated by using the accumulated event anisotropy of the inverse beta decay interactions from pre-SN or SN neutrinos, which, along with the early alert, can play important roles for the followup multi-messenger observations of the next Galactic or nearby extragalactic CCSN.Comment: 24 pages, 9 figure

Robust estimation of bacterial cell count from optical density

Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals <1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data

Search for anomalous couplings in boosted WW/WZ -> l nu q(q)over-bar production in proton-proton collisions at root s=8TeV

Peer reviewe

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure < 100 mmHg (n = 1127), estimated glomerular filtration rate < 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation