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Background: Women with congenital long QT syndrome (LQTS) experience increased cardiac event risk after the onset of adolescence, perhaps stemming from the known modulating effects of sex hormones on the cardiac potassium channels. Objective: We hypothesized that the effect of sex hormones on cardiac ion channel function may modify electrocardiographic (ECG) parameters associated with the propensity for ventricular tachyarrhythmias during the menstrual cycle in women with LQTS. Methods: We prospectively enrolled 65 women with congenital LQTS (type 1 LQTS [LQT1], n = 24 [36.9%]; type 2 LQTS [LQT2], n = 20 [30.8%]) and unaffected female relatives (n = 21 [32.3%]). Patients underwent three 7-day ECG recordings during their menstrual cycles. Simultaneous saliva testing of sex hormone levels was conducted on the first day of each 7-day ECG recording cycle. Results: The mean age was 35 ± 8 years, without a significant difference among the groups. In women with LQT2, linear mixed effects models showed significant inverse correlations of the corrected QT interval with progesterone levels (P < .001) and with the progesterone to estradiol ratio (P < .001). Inverse relationships of the R-R interval with estradiol levels (P = .003) and of the T-wave duration with testosterone levels (P = .014) were also observed in women with LQT2. In contrast, no significant associations were observed between ECG parameters and sex hormone levels in women with LQT1 or unaffected relatives. Conclusion: This is the first study to prospectively assess correlations between repolarization dynamics and sex hormone levels during the menstrual cycle in women with congenital LQTS. Our findings show genotype-specific unique corrected QT dynamics during the menstrual cycle that may affect the propensity for ventricular tachyarrhythmia in women with LQTS, particularly women with LQT2.

Variability and prolongation of ventricular repolarization - measured by changes in QT interval and QT variability are independently associated with ventricular arrhythmias, sudden death, and mortality but such studies did not examine the role of sleep-disordered breathing. We aimed to determine whether sleep-disordered breathing moderated the association between measures of ventricular repolarization and overall mortality.Eight hundred participants were randomly selected from each of the following four groups in the Sleep Heart Health Study: mild, moderate, severe or no sleep disordered breathing (n = 200 each). Overnight electrocardiograms were analyzed for QTc duration and QT variability (standard deviation of QT intervals, normalized QT interval variance and the short-term interval beat-to-beat QT variability). Cox proportional hazards penalized regression modeling was used to identify predictors of mortality.Eight hundred of 5600 participants were randomly selected. The participants (68 ± 10 years; 56.8% male) were followed for an average of 8.2 years during which time 222 (28.4%) died. QTc, SDQT, and QTVN were associated with the presence of SDB (p = 0.002, p = 0.014, and p = 0.024, respectively). After adjusting for covariates, the presence of sleep-disordered breathing did not moderate the association between QTc length, QT variability and mortality (p 0.05).Sleep-disordered breathing was associated with some measures of ventricular repolarization. However, sleep-disordered breathing was not an effect modifier for the relationship between QTc and QT variability and mortality.

Introduction Heart failure and sleep disordered breathing are prevalent in the United States and often co-exist; diagnostic strategy and management for sleep disordered breathing may change based on the presence, absence and type of heart failure. The goal of this study was to evaluate how many additional patients would be identified with either heart failure with reduced (HFrEF) or preserved (HFpEF) ejection fraction through existing echocardiogram results when this diagnosis is not explicitly stated in the medical records for patients evaluated at a single academic sleep center. Methods A retrospective chart review was performed for all patients undergoing for a sleep study and/or a PAP device from February 2012 through September 2019 at the University of Arizona. Sleep disordered breathing was identified through either polysomnography (PSG) or home sleep apnea testing (HSAT). Patients were identified with heart failure with reduced ejection fraction if an echocardiogram (TTE) listed ejection fraction Results 2,817 patients were evaluated (age 57 (±16 years), 53% male and 77% Caucasian). Ninety-nine patients (3.51%) were noted to have HFrEF based on past medical history and an additional 38 patients were identified through TTE. One hundred and fifteen patients (4.08%) were noted to have HFpEF based on past medical history and an additional 265 patients were identified through TTE. Among these, a majority had OSA (77% HFrEF and 83% HFpEF), followed by combined OSA and CSA (7% HFrEF and 5% HFpEF), and primary CSA (5% HFrEF and 3% HFpEF). Of the patients identified after having reviewed TTE results, 6 (16%) with HFrEF and 42 (16%) with HFpEF developed treatment emergent central sleep apnea. Conclusion Existing echocardiography data in the electronic medical record can identify additional patients with HFrEF and HFpEF which may impact clinical diagnosis and management of sleep disordered breathing. Support (if any) AASM Foundation (203-JF-18), NIH (HL126140, 2L30HL154400-023), University of Arizona (5299903; 5833261; 4258021)

Introduction Obstructive sleep apnea (OSA) is associated with prolonged ventricular repolarization at baseline that further increases during sleep when an apnea/hypopnea event occurs. Aggressive treatment of OSA with positive airway pressure therapy (PAP) may further prolong ventricular repolarization during apnea/hypopnea events particularly in patients with heart failure (HF). The goal of this study was to evaluate how ventricular repolarization changes during apnea/hypopnea events in patients with heart failure with reduced (HFrEF) and preserved (HFpEF) ejection fraction and in those patients without HF. Methods Thirty patients with OSA in each of the following groups were randomly selected from a dataset of 2,817 patients: HFrEF, HFpEF and no HF failure. Overnight polysomographies (PSG) for these patients were reviewed and beat-to beat measurements during apnea/hypopnea events were obtained at baseline (without PAP) and on the highest PAP setting attempted. Fridericia’s heart rate corrections were used to calculate QTc. QT variability was measured as the standard deviation of QT intervals (SDQT). Results The electrocardiogram was analyzable for n=11 with HFrEF (age 71± 17 years , 91% male) , n=28 with HFpEF (age 71± 12 years , 43% male) and n=30 without HF (age 57± 12 years , 50% male). In those with HFrEF, the mean (SD) QTc increased from 442(12)ms to 452(13)ms and SDQT increased from 9(2) to 13 (2) from baseline to the highest level of PAP attempted. In those with HFpEF, the mean (SD) QTc decreased from 448 (8) to 436 (8) ms and SDQT increased from 10 (1) to 11 (1) from baseline to the highest level of PAP attempted. In those without HF, the mean (SD) QTc increased from 429(37) to 439(56) and SDQT was stable from 8(6) to 8(8) from baseline (no PAP) to the highest level of PAP attempted. There were significant differences noted between the groups in changes in QTc (p=0.002) and SDQT (p=0.048) on PAP when compared to baseline. Conclusion Patients with HFrEF had increases in both QTc and SDQT with PAP at high pressures placing them at greater risk for ventricular arrhythmias. Support (if any) AASM Foundation (203-JF-18), NIH (HL126140, 2L30HL154400-023), University of Arizona (5299903; 5833261; 4258021)

A capacitively coupled noise circulating voltage-controlled oscillator (VCO) is proposed. Through capacitive coupling from the LC tank to the gates of the active devices, a simple inductor-based resonator can realize the same noise circulating effect as the conventional transformer-based topology, leading to a more compact chip area, as well as larger tuning range. The proposed VCO is fabricated with a 28-nm CMOS process using only thick-oxide devices. The core chip area is 0.09 mm2. The measured oscillation frequency ranges from 6.17 to 10.45 GHz, and the phase noise at 1-MHz offset is from −121.6 to −115 dBc/Hz, with a power dissipation from 32 to 41 mW under a 1.8-V supply voltage across the frequency tuning range. The achieved figure-of-merit with tuning range (FoM $_{T}$ ) is from 193.1 to 196.4 dBc/Hz.

In this paper, a novel sandwich immunosensor based on a toluidine blue (Tb) loaded metal organic framework (Cu(II)-HKUST-1/Tb) as the signal element and a nitrogen-doped 3D carbon nanostructure as the electrode substrate was constructed for the detection of C-reactive protein (CRP). Tb as an electrochemically active agent usually forms a polymer by aggregation in the solvent, causing a poor electrochemical response. Therefore, in order to overcome this obstacle, Cu(II)-HKUST-1 with a porous nanostructure and large specific surface area as a carrier could adsorb a large number of Tb molecules on its surface to improve its electrochemical performance. In addition, the high electron transfer efficiency of the N-doped bamboo-like carbon nanotubes (CoFe/N-GCT) improves the sensitivity of the biosensor. Differential pulse voltammetry (DPV) was used to detect the current signal of Tb at −0.2 V. The current response increased with the increase in concentration of CRP, ranging from 0.5 to 200 ng mL−1. The detection limit is 166.7 pg mL−1 (S/N = 3). Moreover, the proposed biosensor can be applied in real serum sample detection. It has potential applications in the field of biomedicine assays.

In this paper, using molybdenum disulfide doped with gold nanoclusters (Au NCs@MoS2) as the substrate, an aflatoxin aptamer sensor was constructed utilizing iron porphyrin organic porous material modified with streptavidin and loaded with gold nano-bipyramids (SA-Au NBPs@ porous aromatic framework (PAF)-40-Fe) as a label. The catalyzed reduction current of hydrogen peroxide (H2O2) by Au NBPs@PAF-40-Fe was detected which is proportional to the concentration of aflatoxin B1. Thereby, quantitative detection of aflatoxin B1 (AFB1) is achieved. Under the optimal conditions, the linear range of the sensor is 0.05 ~ 85 ng/mL with detection limit of 0.017 ng/mL and the linear correlation coefficient (R2) of 0.9825. The average recovery is 99.28 %. This aflatoxin aptamer sensor has good selectivity and provides a highly sensitive method for the detection of aflatoxin.

Ochratoxin is teratogenic, carcinogenic and immunotoxic to humans. It contains ochratoxin in many foods, so the detection of ochratoxin in food is particularly important. In this paper, gold nanoparticles (Au NPs)@g-C3N4 composite was synthesized by loading Au NPs on carbon nitride material, and it was immobilized on the surface of glassy carbon electrode by chitosan (Chit) as the substrate of electrochemical aptasensors. An ochratomycin A electrochemical aptasensor was constructed by hybridizing DNA1 and ochratoxin A (OTA) aptamers. The resulting hybrid strands were immobilized on the substrate of glassy carbon electrode. Electrochemical alternating current impedance (EIS) was used to detect the impedance value of the aptasensor when incubating different concentrations of OTA. The impedance value is inversely ratio to the concentration of OTA, achieving quantitative detection of OTA. The aptasensor can detect OTA with a linear range of 0.5–100 ng/mL, the linear correlation coefficient is 0.9506, and the detection limit is 0.167 ng/mL. This aptasensor provides a novel and efficient method for detecting OTA.

This paper reports a new readout integrated circuit designed for hybridization with P-on-N detector such as InSb, HgCdTe and InGaAs, and it can support a wide range of system through flexibility and versatile functions. This ROIC is fabricated using CSMC 0.18um double poly, six metal process that utilized high-speed CMOS transistors. The device can work at temperatures of 80K with 5.5V supply voltage. It still has a build-in temperature sensor to detect the temperature of the chip. The pixel cell occupies an area of 25×25µm2 with an input charge-handling of 18Me- carriers. After testing at 80K, the output swing was larger than 3V; the power consumption of chip was about 180mW; the output noise was about 400uV and its dynamic range was about 78dB.

Ochratoxin is teratogenic, carcinogenic and immunotoxic to humans. It contains ochratoxin in many foods, so the detection of ochratoxin in food is particularly important. In this paper, gold nanoparticles (Au NPs)@g-C₃N₄ composite was synthesized by loading Au NPs on carbon nitride material, and it was immobilized on the surface of glassy carbon electrode by chitosan (Chit) as the substrate of electrochemical aptasensors. An ochratomycin A electrochemical aptasensor was constructed by hybridizing DNA1 and ochratoxin A (OTA) aptamers. The resulting hybrid strands were immobilized on the substrate of glassy carbon electrode. Electrochemical alternating current impedance (EIS) was used to detect the impedance value of the aptasensor when incubating different concentrations of OTA. The impedance value is inversely ratio to the concentration of OTA, achieving quantitative detection of OTA. The aptasensor can detect OTA with a linear range of 0.5-100 ng/mL, the linear correlation coefficient is 0.9506, and the detection limit is 0.167 ng/mL. This aptasensor provides a novel and efficient method for detecting OTA.

Background Risk stratification in non‐ischemic myocardial disease poses a challenge. While cardiovascular magnetic resonance (CMR) is a comprehensive tool, the electrocardiogram (ECG) provides quick impactful clinical information. Studying the relationships between CMR and ECG can provide much‐needed risk stratification. We evaluated the electrocardiographic signature of myocardial fibrosis defined as presence of late gadolinium enhancement (LGE) or extracellular volume fraction (ECV) ≥29%. Methods We evaluated 240 consecutive patients (51% female, 47.1 ± 16.6 years) referred for a clinical CMR who underwent 12‐lead ECGs within 90 days. ECG parameters studied to determine association with myocardial fibrosis included heart rate, QRS amplitude/duration, T‐wave amplitude, corrected QT and QT peak, and Tpeak‐Tend. Abnormal T‐wave was defined as low T‐wave amplitude ≤200 µV or a negative T wave, both in leads II and V5. Results Of the 147 (61.3%) patients with myocardial fibrosis, 67 (28.2%) had ECV ≥ 29%, and 132 (54.6%) had non‐ischemic LGE. An abnormal T‐wave was more prevalent in patients with versus without myocardial fibrosis (66% versus 42%, p

Introduction Evidence suggests that patients with obstructive sleep apnea (OSA) are at risk for QTc prolongation which, is a known risk factor for arrhythmias, sudden cardiac death and all cause mortality. QTc risk scores have been implemented widely to help physicians identify patients at risk for mortality however, these risk scores have not been routinely implemented in patients undergoing sleep studies or those diagnosed with OSA. The goal of this study was to evaluate the distribution of pro-QTc risk scores for patients with and without OSA diagnosed at our facility and its relationship to mortality. Methods Medical records of all patients undergoing a sleep study at our sleep center from 2/2012 through 8/2020 were analyzed. Patients were identified with or without OSA based on polysomnography or Type III home sleep study. The pro-QTc risk score was calculated with 1 point assigned for: female sex, QT-prolonging diagnoses and conditions, QT-prolonging electrolyte abnormalities, and QT-prolonging medications defined as medications with known and possible risk of torsades de Pointes based on the CredibleMeds website. Mortality was determined if a death date was noted in the electronic medical record. Results A total of 2,834 patient records (54% male, age 58 ± 16 years, n=106 dead) were evaluated. A total of 2,265 patients (age 58 ±15, 54% male, 89 dead) were identified as having OSA and 428 patients (age 54 ± 18, 41% male, 17 dead) did not have OSA. The remaining patients (n=141) had either central sleep apnea or a combination of both obstructive and central sleep apnea. A higher pro-QTc score was associated with greater mortality regardless of presence of OSA (HR 1.3, p Conclusion Increased pro-QTc scores were associated with greater mortality in all patients undergoing sleep studies. OSA status did not affect this association. Support (If Any) American Academy of Sleep Medicine Foundation (203-JF-18), National Institutes of Health (HL126140, 2L30HL154400-023), University of Arizona Health Sciences Career Development Award (5299903), and University of Arizona Faculty Seed Grant (5833261)

Introduction Positive airway pressure (PAP) therapy is the mainstay treatment for obstructive sleep apnea (OSA). Continuous PAP (CPAP) therapy has been shown to decrease QTc length in electrocardiograms in patients with OSA in small studies. The impact of higher pressures of CPAP and Bilevel PAP (BPAP) on ventricular repolarization—QTc length and QT variability in OSA is unknown. The goal of this pilot study is to explore this relationship. Methods 10 consecutive patients who underwent polysomnography during which they had a diagnostic, CPAP titration, and BPAP titration portion were included for analysis. Bazett’s heart rate correction was used to calculate QTc. QT variability was measured as short-term interval QT variability (STVQT) and normalized QT interval variance (QTVN). All variables were analyzed for the entire duration of the diagnostic period, on the highest CPAP pressure and highest BPAP pressure delivered. Results The patients were 49 ± 15 years of age and 60% women. Median CPAP pressure was 14.5 cm H2O (mean 13.5 ± 5 cm H2O). For BPAP, the median inspiratory PAP was 21.5 cm H2O (mean 20.5 ± 5 cm H2O) and EPAP median was 16 cm H2O (mean 15.9 ± 4 cm H2O). Mean QTc for the diagnostic portion, highest CPAP pressure and highest BPAP pressure were 430 ± 17 ms, 445 ± 15 ms and 441 ± 21 ms, respectively (p=0.141). Mean QTVN for the diagnostic portion, highest CPAP pressure and highest BPAP pressure settings were 0.0011 ± 0.0008 dimensionless units (du), 0.0012± 0.0008 du and 0.002 ± 0.0012 du, respectively (p=0.127). STVQT for the diagnostic portion, highest CPAP pressure and highest BPAP pressure settings were 6.62 ± 4.13 ms, 9.12 ± 4.7271 ms and 12.62 ± 4.99 ms, respectively (P=0.041). Post-hoc pairwise comparisons between BPAP and diagnostic portions of the study were significant for STVQT (P=0.034). Conclusion Short-term QT variability, STVQT, was significantly increased on BPAP when compared to the diagnostic portion of the study. Support (If Any) American Academy of Sleep Medicine Foundation (203-JF-18), National Institutes of Health (HL126140, 2L30HL154400-023) University of Arizona Health Sciences Career Development Award (5299903), and University of Arizona Faculty Seed Grant (5833261)

Objective Long QT-Syndrome (LQTS) patients are at risk of arrhythmias and seizures. We investigated whether autonomic and cardiac repolarization measures differed based on LQTS genotypes, and in LQTS patients with vs. without arrhythmias and seizures. Methods We used 24-h ECGs from LQTS1 (n = 87), LQTS2 (n = 50), and LQTS genotype negative patients (LQTS(−), n = 16). Patients were stratified by LQTS genotype, and arrhythmias/seizures. Heart rate variability (HRV) and QT variability index (QTVI) measures were compared between groups during specific physiological states (minimum, middle, & maximum sympathovagal balance, LF/HF). Results were further tested using logistic regression for each ECG measure, and all HRV measures in a single multivariate model. Results Across multiple physiological states, total autonomic (SDNN) and vagal (RMSSD, pNN50) function were lower and repolarization dynamics (QTVI) were elevated in LQTS(+), LQTS1, and LQTS2, compared to LQTS(−). Many measures remained significant in the regression models. Multivariate modeling demonstrated that SDNN, RMSSD, and pNN50 were independent markers of LQTS(+) vs. LQTS(−), and SDNN and pNN50 were markers for LQTS1 vs. LQTS(−). During sympathovagal balance (middle LF/HF), RMSSD and pNN50 distinguished LQTS1 vs. LQTS2. LQTS1 patients with arrhythmias had lower total (SDNN) and vagal (RMSSD and pNN50) autonomic function, and SDNN remained significant in the models. In contrast, ECG measures did not differ in LQTS2 patients with vs. without arrhythmias, and LQTS1 and LQTS2 with vs. without seizures. Conclusion Autonomic (HRV) and cardiac repolarization (QTVI) ECG measures differ based on LQTS genotype and history of arrhythmias in LQTS1. SDNN, RMSSD, and pNN50 were each independent markers for LQTS genotype.

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Microthlaspi erraticum is widely distributed in temperate Eurasia, but restricted to Ca2+-rich habitats, predominantly on white Jurassic limestone, which is made up by calcium carbonate, with little other minerals. Thus, naturally occurring Microthlaspi erraticum individuals are confronted with a high concentration of Ca2+ ions while Mg2+ ion concentration is relatively low. As there is a competitive uptake between these two ions, adaptation to the soil condition can be expected. In this study, it was the aim to explore the genomic consequences of this adaptation by sequencing and analysing the genome of Microthlaspi erraticum. Its genome size is comparable with other diploid Brassicaceae, while more genes were predicted. Two Mg2+ transporters known to be expressed in roots were duplicated and one showed a significant degree of positive selection. It is speculated that this evolved due to the pressure to take up Mg2+ ions efficiently in the presence of an overwhelming amount of Ca2+ ions. Future studies on plants specialized on similar soils and affinity tests of the transporters are needed to provide unequivocal evidence for this hypothesis. If verified, the transporters found in this study might be useful for breeding Brassicaceae crops for higher yield on Ca2+-rich and Mg2+ -poor soils.

The convergence between wearable and medical device technologies is a natural progression. Miniaturization has allowed the design of small, compact monitoring systems that can record physiological signals over longer periods of time. Thus, the potential for these devices to expand the understanding of disease progression and patients' clinical status is very high. The accuracy of these devices, however, is dependent upon the computer algorithms utilized in the analysis of the large volume of physiological data monitored and/or recorded by the devices. Automated interpretation of the data by these new technologies, therefore, necessitates closer examination by regulatory organizations. The current requirements for the validation of novel Ambulatory ECG (A-ECG) annotation algorithms are based on the AAMI/ANSI-EC57 and IEC60601-2-47 Standard. These standards are being updated, but they rely on a very limited set of digitized ECG recordings from a couple of ECG databases built in the first half of the 70's. These reference signals are obsolete. We are developing a validation tool for computerized methods designed to detect and monitor cardiac activities based on body-surface ECGs. We will rely on a set of existing digital high-resolution 12‑lead A-ECG recordings acquired in cardiac patients and healthy individuals. These ECG signals include a large and unique set of electrocardiographic events. This tool is being qualified by the Center for Devices and Radiological Health of the United States Food and Drug Administration (FDA) as a Medical Device Development Tool (MDDT). This document provides insights into the design of the M.A.D.A.E. database, its functionalities, and its ultimate role in enabling the next generations of automatic interpretation of ECG signals.

Background Cardiac Resynchronization Therapy (CRT) is widely used for treating selected heart failure patients, but patients with myocardial scar respond worse to treatment. The Selvester QRS scoring system estimates myocardial scar burden using 12-lead ECG. This study's objective was to investigate the scores correlation to mortality in a CRT population. Methods and results Data on consecutive CRT patients was collected. 401 patients with LBBB and available ECG data were included in the study. QuAReSS software was used to perform Selvester scoring. Mean Selvester score was 6.4, corresponding to 19% scar burden. The endpoint was death or heart transplant; outcome was analyzed using Cox proportional hazards models. A Selvester score > 8 was significantly associated with higher risk of the combined endpoint (HR 1.59, p = .014, CI 1.09–2.3). Conclusion Higher Selvester scores correlate to mortality in CRT patients with strict LBBB and might be of value in prognosticating survival.

Introduction Sleep disordered breathing (SDB) is associated with increased mortality. Obstructive apneas/hypopneas have been associated with an increase in both QTc duration and QT variability. These markers of ventricular repolarization are associated with arrhythmias and death. It is unknown whether SDB-related QTc changes are responsible for the relationship between QTc/QT variability and cardiovascular death (CVD). Methods From the Sleep Heart Health Study, we randomly selected 200 subjects in each of four groups based on overall apnea/hypopnea index: those with no SDB and those in either, mild, moderate or severe SDB at baseline, matched for gender, age and BMI. Respiratory-related channels and electrocardiograms (ECG) from each polysomnography were analyzed. QTc was calculated using Bazett’s heart rate correction. The following measures of QT variability were obtained: i) standard deviation of QT intervals (SDQT) at 1- and 5-minute intervals and ii) short-term interval QT variability (STVQT) at 5-minute intervals. Cox proportional hazards regression models were used to evaluate potential predictors of CVD. Results Twenty-nine subjects were excluded either due to missing data or low quality ECG. The 771 subjects included were 68±10 years of age, half were female. During follow-up, 220 subjects (28.5%) died of CVD among whom, 67 (30.5%) had comorbid severe SDB, 45 (20.5%) had no SDB, and the remaining CVD deaths had mild (47, 21.4%) and moderate 61 (27.7%) SDB. The CVD patients were more likely to be older(p Conclusion SDB was not a factor in the relationship between QTc prolongation/QT variability and CVD. Support (if any) American Academy of Sleep Medicine Foundation (203-JF-18), National Institutes of Health (HL126140), University of Arizona Health Sciences Career and Development Award (5299903)

Genome editing enabled unprecedented new opportunities for targeted genomic engineering of a wide variety of organisms ranging from microbes, plants, animals and even human embryos. The serial establishing and rapid applications of genome editing tools significantly accelerated Bombyx mori (B. mori) research during the past years. However, the only CRISPR system in B. mori was the commonly used SpCas9, which only recognize target sites containing NGG PAM sequence. In the present study, we first improve the efficiency of our previous established SpCas9 system by 3.5 folds. The improved high efficiency was also observed at several loci in both BmNs cells and B. mori embryos. Then to expand the target sites, we showed that two newly discovered CRISPR system, SaCas9 and AsCpf1, could also induce highly efficient site-specific genome editing in BmNs cells, and constructed an integrated CRISPR system. Genome-wide analysis of targetable sites was further conducted and showed that the integrated system cover 69,144,399 sites in B. mori genome, and one site could be found in every 6.5 bp. The efficiency and resolution of this CRISPR platform will probably accelerate both fundamental researches and applicable studies in B. mori, and perhaps other insects.

Along withPlasmopara destructor, Peronosopora belbahriihas arguably been the economically most important newly emerging downy mildew pathogen of the past two decades. Originating from Africa, it has started devastating basil production throughout the world, most likely due to the distribution of infested seed material. Here we present the genome of this pathogen and results from comparisons of its genomic features to other oomycetes. The assembly of the nuclear genome was ca. 35.4 Mbp in length, with an N50 scaffold length of ca. 248 kbp and an L50 scaffold count of 46. The circular mitochondrial genome consisted of ca. 40.1 kbp. From the repeat-masked genome 9049 protein-coding genes were predicted, out of which 335 were predicted to have extracellular functions, representing the smallest secretome so far found in peronosporalean oomycetes. About 16 % of the genome consists of repetitive sequences, and based on simple sequence repeat regions, we provide a set of microsatellites that could be used for population genetic studies ofPe. belbahrii. Peronospora belbahriihas undergone a high degree of convergent evolution, reflecting its obligate biotrophic lifestyle. Features of its secretome, signalling networks, and promoters are presented, and some patterns are hypothesised to reflect the high degree of host specificity inPeronosporaspecies. In addition, we suggest the presence of additional virulence factors apart from classical effector classes that are promising candidates for future functional studies.

Item does not contain fulltext INTRODUCTION: We evaluated the association between a novel electrocardiographic (ECG) marker of late, rightward electrocardiographic forces (termed the lead one ratio [LOR]), and left ventricular ejection fraction (LVEF), myocardial scar, and clinical outcomes in patients with left bundle branch block (LBBB). METHODS AND RESULTS: LOR was calculated in patients with LBBB from a derivation cohort (n = 240) and receiver operator characteristic curves identified optimal threshold values for predicting myocardial scar and LVEF less than 35%. An independent validation cohort of patients with LBBB (n = 196) was used to test the association of LOR with the myocardial scar, LVEF, and the likelihood of death, heart transplant or left ventricular assist device (LVAD) implantation. The optimal thresholds in the derivation cohort were LOR less than 13.7 for identification of scar (sensitivity 55%, specificity 80%), and LOR less than 12.1 for LVEF less than 35% (sensitivity 49%, specificity 80%). In the validation cohort, LOR less than 13.7 was not associated with scar size or presence (P > 0.05 for both). LOR less than 12.1 was associated with lower LVEF (30 [20-40] versus 40 [25-55]%; P = 0.002) and predicted LVEF less than 35% in univariable (odds ratio [OR], 2.2 [1.2-4.1]; P = 0.01) and multivariable analysis (OR, 2.2 [1.2-4.3]; P = 0.02). LOR less than 12.1 was associated with scar presence when patients with nonischemic cardiomyopathy were excluded (OR = 7.2 [1.5-33.2]; P = 0.002). LOR less than 12.1 had an adjusted hazard ratio of 1.53 ([1.05-2.21]; P = 0.03) for death, transplant or LVAD implantation. CONCLUSIONS: In conclusion, ECG LOR less than 12.1 predicts reduced-LV systolic function and poorer prognosis in patients with LBBB.

Quaternary climatic oscillations had strong effects on Palearctic biodiversity. Although Transcaucasia is hypothesised to be a centre of diversity for many taxa, relatively few studies have investigated its potential role as such, or as a Pleistocene refugium. Using AFLP and sequence data (ITS, matK, trnL-F) from samples collected across the entire range of Microthlaspi perfoliatum, from the Iberian peninsula to Kazakhstan, and including the Mediterranean Basin and Central Europe, in this study it is examined how the interplay of Pleistocene climatic oscillations and historical demography may have shaped the current genetic structure of the species. The results of this study provide evidence that M. perfoliatum survived Pleistocene glaciation in five major refugia, Iberia, southwestern France, Italy, the Balkans and Anatolia/Transcaucasia and a sixth, unknown refugium in the disjunct distribution area in Central Asia. Our analyses support an ancient colonisation of M. perfoliatum towards the western and central Palearctic, perhaps, during the early Pleistocene or late Pliocene, likely starting from Transcaucasia. However, postglacial recolonisation of western and Central Europe has taken place from two distinct refugia, namely southwestern France/northern Italy, and Anatolia/Southern Balkans, respectively. The Iberian populations apparently did not contribute to postglacial recolonisation of Europe, perhaps because the Pyrenees acted as a significant barrier to dispersal. It is also conceivable that a rapidly expanding population from southwestern France and the southeastern part of the range effectively blocked the establishment of latecomers. The present study thus reveals a complex pattern of colonisation of Europe from Transcaucasia, with an interplay of climate and physical geography as main factors shaping the present-day genetic structure of M. perfoliatum. © 2019 Elsevier GmbH

Introduction The apneas and hypopneas that characterize sleep-disordered breathing (SDB) are associated with QTc prolongation and increased QT variability. There have been mixed results as to whether QTc and QT variability increase with increasing SDB severity. This study assesses whether QTc prolongation and QT variability are likely to increase with increasing severity of SDB in a large multi-center cohort. Methods 200 subjects with no SDB and approximately 600 with three levels of SDB (mild, moderate, severe) were randomly selected from the Sleep Heart Health study and matched by age, gender and BMI. SDB was defined as an apnea/hypopnea index ≥5. Respiratory and electrocardiograms (ECG) signals from polysomnography studies were analyzed. Bazett’s heart rate correction was used to calculate QTc. QT variability was measured as standard deviation of QT intervals (SDQT) and short-term interval QT variability (STVQT), at 5-minute intervals. Subjects were excluded if there were missing data or low-quality ECG. Results Seven hundred and seventy-one subjects (age 68±10 years, 51% female, 92% Caucasian) were included. One hundred and sixty-five subjects had no SDB, 235 mild, 195 moderate and 176 had severe SDB. The mean (SD) QTc was 422(29), 411(26), 419 (34) and 418 (36) ms for the no SDB, mild, moderate, and severe SDB groups, respectively (p=0.017). The mean (SD) STVQT was 7 (9), 11 (16), 8 (9) and 9 (11) for the no SDB, mild, moderate severe SDB groups, respectively (p= Conclusion QTc duration and QT variability were not increased with SDB severity. Support (if any) American Academy of Sleep Medicine Foundation (203-JF-18), National Institutes of Health (HL126140), University of Arizona Health Sciences Career Development Award (5299903), and University of Arizona Faculty Seed Grant (5833261)

Microthlaspi is a predominantly Eurasian genus which also occurs in the northernmost parts of Africa (Maghreb). The most widespread species of the genus is M. perfoliatum , which can be found from Sweden to Algeria and from Portugal to China. The other species are thought to have much more confined distribution ranges, often covering only a few hundred kilometres. This is also believed for the diploid M. erraticum , which was recently re-appraised as a taxon independent from the tetra- to hexaploid M. perfoliatum . Previously, M. erraticum was believed to be present only in Central Europe, from the East of France to Slovenia. In order to gain a deeper understanding of the ecology, evolution and migration history of Microthlaspi it was the focus of the current study to investigate, if M. erraticum is present in habitats outside Central Europe, but with microclimates similar to Central Europe. It is demonstrated that M. erraticum is much more widespread than previously thought, while other lineages apart from M. perfoliatum s.str. and M. erraticum seem to have restricted distribution ranges. The latter species was observed from the Alps and their foreland, the Balkans, the mountainous areas around the Black Sea, Southern Siberia, as well as the Altai and Tien Shan mountains. This demonstrates a widespread occurrence of this easily-overlooked species.

A novel gradual charge appointment concept is proposed to provide a clear physical insight of RESURF effects in bulk silicon lateral power devices. Due to the expandable substrate depletion region in silicon power device, the Linearly Graded Approximation is unable to fully describe the 2-D coupling effects between vertical and lateral junction. In this paper, by defining a charge appointment line, the lateral abrupt junction behaves as an effective gradual junction, thus resulting in the wider depletion layer, lower field peak and higher breakdown voltage. Based on the hypothesis, a simple 1-D model is proposed to quantify the breakdown voltage of the bulk silicon RESURF device and formulize the surface electric field. To our knowledge, the proposed model is the first 1-D model for bulk silicon RESURF device which can accurately describe the surface field profiles under various applied voltages and structure parameters. Furthermore, we provide a new RESURF criterion to explore the sensitivity of the breakdown voltage to structure parameters. Fair agreements among the analytical, numerical and experimental results verify the availability of the proposed concept and model.

The genus Thlaspi has been variously subdivided since its description by Linnaeus in 1753, but due to similarities in fruit shape several segregates have still not gained broad recognition, despite the fact that they are not directly related to Thlaspi. This applies especially to segregates now considered to belong to the tribe Coluteocarpeae, which includes several well-studied taxa, e.g., Noccaea caerulescens (syn. Thlaspi caerulescens), and the widespread Microthlaspi perfoliatum (syn. Thlaspi perfoliatum). The taxonomy of this tribe is still debated, as a series of detailed monographs on Coluteocarpeae was not published in English and a lack of phylogenetic resolution within this tribe was found in previous studies. The current study presents detailed phylogenetic investigations and a critical review of morphological features, with focus on taxa previously placed in Microthlaspi. Based on one nuclear (ITS) and two chloroplast (matK, trnL-F) loci, four strongly supported major groups were recovered among the Coluteocarpeae genera included, corresponding to Ihsanalshehbazia gen. nov., Friedrichkarlmeyeria gen. nov., Microthlaspi s.str., and Noccaea s.l. In addition, two new species of Microthlaspi, M. sylvarum-cedri sp. nov. and M. mediterraneo-orientale sp. nov., were discovered, which are well supported by both morphological and molecular data. Furthermore, M. erraticum comb. nov. (diploid) and M. perfoliatum s.str. (polyploid) were shown to be distinct species, phylogenetically widely separate, but with some overlap in several morphological characters. Detailed descriptions, notes on taxonomy, geographical distribution, and line drawings for the new species and each species previously included in Microthlaspi are provided. In addition, the current taxonomic state of the tribe Coluteocarpeae is briefly discussed and it is concluded that while several annual taxa are clearly distinct from Noccaea, many perennial taxa, after thorough phylogenetic and morphological investigations, may have to be merged with this genus.

Root endophytic fungi are found in a great variety of plants and ecosystems, but the ecological drivers of their biogeographic distribution are poorly understood. Here, we investigate the occurrence of root endophytes in the non-mycorrhizal plant genus Microthlaspi, and the effect of environmental factors and geographic distance in structuring their communities at a continental scale. We sampled 52 plant populations across the northern Mediterranean and central Europe and used a cultivation approach to study their endophytic communities. Cultivation of roots yielded 2601 isolates, which were grouped into 296 operational taxonomic units (OTUs) by internal transcribed spacer sequencing of 1998 representative colonies. Climatic and spatial factors were the best descriptors of the structure of endophytic communities, outweighing soil characteristics, host genotype and geographical distance. OTU richness was negatively affected by precipitation, and the composition of communities followed latitudinal gradients of precipitation and temperature. Only six widespread OTUs belonging to the orders Pleosporales, Hypocreales and Helotiales represented about 50% of all isolates. Assessments of their individual distribution revealed particular ecological preferences or a cosmopolitan occurrence. Our findings support a strong influence of the local environment in determining root endophytic communities, and show a different niche occupancy by individual endophytes.

Introduction Patients with untreated obstructive sleep apnea (OSA) have a 2-3—fold increased risk of cardiovascular mortality (CVD) compared with individuals without OSA. QTc prolongation and increased QT variability among OSA patients may contribute to this association. Methods Patients with OSA from the Sleep Heart Health study were identified based on polysomnography criteria and their continuous electrocardiograms (ECG) analyzed for QTc duration and QT variability. Both Fridericia’s and Bazett’s heart rate corrections were used to calculate QTc. QT variability was measured as standard deviation of QT intervals (SDQT) and normalized QT interval variance (QTVN) at 1- and 5-minute intervals and short-term interval beat-to-beat QT variability (STVQT) was measured at 5-minute intervals. Lasso with elastic-net regularization was used as the variable/covariate selection method. Cox proportional hazards regression models were used to determine predictors of CVD. Results Data from 365 patients with OSA were screened. Ninety-seven patients were excluded from analysis due to low quality ECG data (n=50) or extremely high (> ln (10)) variability in QT/QTc and/or QT variability (n=12). Fifty two percent of the sample was male with mean age 65 years (±10). Fifty-six of these patients died of CVD. The mean (SD) QTc in the group that died was 411 (30) ms and 416 (34) ms compared to 406 (24) ms and 411 (25) ms using Fridericia (Cox LR p-value 0.055) and Bazett (p=0.090), respectively. Gender, age, race, diabetes, SDQT and STVQT were significant predictors for CVD. We fit models with the covariates and SDQT (at both 1 and 5 min) and STVQT as three models and demonstrate that both SDQT and STVQT are significantly associated with CVD death (p-values of 0.0048, 0.0089, and 0.0113, respectively) and all models had high area under the curve (0.8095, 0.8085, and 0.8125, respectively). Conclusion In patients with OSA, QT variability was associated with CVD. Support American Academy of Sleep Medicine Foundation

This paper presents a digitally controlled ring oscillator (DCRO) which has a high frequency resolution. The proposed oscillator includes three tuning stages and regulates its frequency by using MOS capacitors in the output of each delay cell. The DCRO implemented in a 130 nm CMOS process operates at the center frequency of 2.4 GHz under a supply of 1.2 V. The phase noise of the presented DCRO at 1 MHz offset frequency is −106.3 dBc/Hz and the power consumption is 0.58 mW. The figure of merit obtained for the DCRO is −176.3 dBc/Hz.

A two-step time-to-digital converter (TDC) that achieves linear, high-speed time quantization, high-resolution under a 0.6-V supply is proposed in this paper. In order to work in low-voltage supply, dynamic threshold technology is used. The TDC mainly consists of two vernier delay-line TDCs and an array of SR-latch-based time amplifiers to achieve high resolution. This TDC is designed in a 65-nm CMOS technology. Simulation results of this TDC show that the minimum time resolution is 2.5ps while only consuming 0.5mW. The differential nonlinearity (DNL) of this proposed TDC is 0.9LSB and the integral nonlinearity (INL) is 2.3LSB.

This paper presents a pipeline time-to-digital converter (TDC) using a programmable time amplifier (TA). The TA adds time intervals that contain quantization errors in different stages of the first conversion step to achieve time amplification. Therefore, the TA has advantages of programmability, good linearity and wide input range. The TDC is designed in a 65nm CMOS technology. A time resolution up to 5ps at 230MHz is achieved. The total power consumption is 3mW under a 1V supply.

INTRODUCTION Adverse electrical remodeling (AER), represented here as the sum absolute QRST integral (SAI QRST), has previously been shown to be directly associated with the risk for ventricular arrhythmia (VA). Cardiac resynchronization therapy (CRT) is known to reduce the risk for VA through various mechanisms, including reverse remodeling, and we aimed to evaluate the association between baseline AER and the risk for VA in CRT recipients. METHODS AND RESULTS The study population comprised 961 CRT-D implanted patients from the MADIT CRT study. The relationship between SAI QRST, VA risk, and VA risk/death was evaluated as a continuous and as a categorical variable-tertiles (T1 ≤ 0.527, T2 0.528-0.766, T3 > 0.766). In a multivariable model, AER was inversely associated with the risk of VA. Each unit increase in SAI QRST was associated with 64% (P = 0.007) and 54% (P = 0.003) decrease in the risk of VA and VA/death, respectively. Patients with high SAI QRST (T3) and medium SAI QRST (T2) had 52% (P

Item does not contain fulltext AIMS: We aimed to improve the electrocardiographic 2009 left bundle branch block (LBBB) Selvester QRS score (2009 LBSS) for scar assessment. METHODS: We retrospectively identified 325 LBBB patients with available ECG and cardiovascular magnetic resonance imaging (CMR) with late gadolinium enhancement from four centers (142 [44%] with CMR scar). Forty-four semi-automatically measured ECG variables pre-selected based on the 2009 LBSS yielded one multivariable model for scar detection and another for scar quantification. RESULTS: The 2009 LBSS achieved an area under the curve (AUC) of 0.60 (95% confidence interval 0.54-0.66) for scar detection, and R(2)=0.04, p

A novel silicon-on-insulator (SOI) lateral power device with step width drift region (SW) is proposed in this paper. The drift region of the new device is divided into several regions with different width increasing from source to drain. New additional electric field peaks are formed at the steps, which modulate the electric field and enhance the breakdown voltage. Meanwhile, the drift doping concentration is increased and thus reduces the specific on-resistance. Compared with the conventional device, a 35% increase in the breakdown voltage and a 21% decrease in the specific on-resistance are obtained in the proposed device.

Background Estimation of the infarct size from body-surface ECGs in post-myocardial infarction patients has become possible using the Selvester scoring method. Automation of this scoring has been proposed in order to speed-up the measurement of the score and improving the inter-observer variability in computing a score that requires strong expertise in electrocardiography. In this work, we evaluated the quality of the QuAReSS software for delivering correct Selvester scoring in a set of standard 12-lead ECGs. Method Standard 12-lead ECGs were recorded in 105 post-MI patients prescribed implantation of an implantable cardiodefibrillator (ICD). Amongst the 105 patients with standard clinical left bundle branch block (LBBB) patterns, 67 had a LBBB pattern meeting the strict criteria. The QuAReSS software was applied to these 67 tracings by two independent groups of cardiologists (from a clinical group and an ECG core laboratory) to measure the Selvester score semi-automatically. Using various level of agreement metrics, we compared the scores between groups and when automatically measured by the software. Results The average of the absolute difference in Selvester scores measured by the two independent groups was 1.4 ± 1.5 score points, whereas the difference between automatic method and the two manual adjudications were 1.2 ± 1.2 and 1.3 ± 1.2 points. Eighty-two percent score agreement was observed between the two independent measurements when the difference of score was within two point ranges, while 90% and 84% score agreements were reached using the automatic method compared to the two manual adjudications. Conclusion The study confirms that the QuAReSS software provides valid measurements of the Selvester score in patients with strict LBBB with minimal correction from cardiologists.

Ceraceosorus bombacis is an early-diverging lineage of smut fungi and a pathogen of cotton trees (Bombax ceiba). To study the evolutionary genomics of smut fungi in comparison with other fungal and oomycete pathogens, the genome of C. bombacis was sequenced and comparative genomic analyses were performed. The genome of 26.09 Mb encodes for 8,024 proteins, of which 576 are putative-secreted effector proteins (PSEPs). Orthology analysis revealed 30 ortholog PSEPs among six Ustilaginomycotina genomes, the largest groups of which are lytic enzymes, such as aspartic peptidase and glycoside hydrolase. Positive selection analyses revealed the highest percentage of positively selected PSEPs in C. bombacis compared with other Ustilaginomycotina genomes. Metabolic pathway analyses revealed the absence of genes encoding for nitrite and nitrate reductase in the genome of the human skin pathogen Malassezia globosa, but these enzymes are present in the sequenced plant pathogens in smut fungi. Interestingly, these genes are also absent in cultivable oomycete animal pathogens, while nitrate reductase has been lost in cultivable oomycete plant pathogens. Similar patterns were also observed for obligate biotrophic and hemi-biotrophic fungal and oomycete pathogens. Furthermore, it was found that both fungal and oomycete animal pathogen genomes are lacking cutinases and pectinesterases. Overall, these findings highlight the parallel evolution of certain genomic traits, revealing potential common evolutionary trajectories among fungal and oomycete pathogens, shaping the pathogen genomes according to their lifestyle.

The range-wide genetic diversity of Microthlaspi erraticum (Brassicaceae), a Eurasian calcareous annual plant, was investigated with respect to its migration and post-glacial re-colonisation of Central Europe. Both AFLP and sequence data (ITS, matK, trnL-F) were used to analyse 85 populations of the species sampled across its range, including Europe and Anatolia as well as the disjunct populations in Central Asia. A substantial portion of the explainable genetic variation was found to be correlated with climatic heterogeneity. A low level of within-population genetic diversity throughout the range, and a clear genetic differentiation among populations is consistent with the mainly selfing nature and fragmented distribution of the species. The highest within-population genetic diversity was found in Central Europe. However, the number of rare and private fragments was substantially higher in southern Europe and Anatolia, the inferred ancestral range of M. erraticum, whereas populations found in Kazakhstan originated from Anatolia, following a profound population bottleneck. The diversity patterns found in Central Europe and migration models support postglacial re-colonisation from two regions; the south-western Alps and the Balkans. Hence, our results provide molecular evidence for a suture zone in Central Europe, where advancing genotypes from different refugia meet and mix. © 2017 Elsevier GmbH

Stacked bonding is one of the most promising approaches to realize three-dimensional integration. In this paper, an analytical model is proposed for the low frequency and high frequency capacitance-voltage characteristics of the symmetric stacked bonding structure. The model is verified by the agreements between the analytical results and numerical simulation results using MEDICI, a two-dimensional semiconductor device simulator. Then, the influence of the doping concentration, oxide thickness and flat-band voltage on the capacitance-voltage characteristics under various bias conditions is researched. This work carries on an approach for the non-destructive characterization of the symmetric stacked bonding structure in three-dimensional integration.