Characterization of heterozygous and homozygous mouse models with the most common hypertrophic cardiomyopathy mutation MYBPC3 c.2373InsG in the Netherlands.

Hypertrophic cardiomyopathy (HCM) is frequently caused by mutations in the cardiac myosin binding protein-C (cMyBP-C) encoding gene MYBPC3. In the Netherlands, approximately 25% of patients carry the MYBPC3 c.2373InsG founder mutation. Most patients are heterozygous (MYBPC3 +/InsG) and have highly variable phenotypic expression, whereas homozygous (MYBPC3 InsG/InsG) patients have severe HCM at a young age. To improve understanding of disease progression and genotype-phenotype relationship based on the hallmarks of human HCM, we characterized mice with CRISPR/Cas9-induced heterozygous and homozygous mutations. At 18-28 weeks of age, we assessed the cardiac phenotype of Mybpc3 +/InsG and Mybpc3 InsG/InsG mice with echocardiography, and performed histological analyses. Cytoskeletal proteins and cardiomyocyte contractility of 3-4 week old and 18-28 week old Mybpc3 c.2373InsG mice were compared to wild-type (WT) mice. Expectedly, knock-in of Mybpc3 c.2373InsG resulted in the absence of cMyBP-C and our 18-28 week old homozygous Mybpc3 c.2373InsG model developed cardiac hypertrophy and severe left ventricular systolic and diastolic dysfunction, whereas HCM was not evident in Mybpc3 +/InsG mice. Mybpc3 InsG/InsG cardiomyocytes also presented with slowed contraction-relaxation kinetics, to a greater extent in 18-28 week old mice, partially due to increased levels of detyrosinated tubulin and desmin, and reduced cardiac troponin I (cTnI) phosphorylation. Impaired cardiomyocyte contraction-relaxation kinetics were successfully normalized in 18-28 week old Mybpc3 InsG/InsG cardiomyocytes by combining detyrosination inhibitor parthenolide and β-adrenergic receptor agonist isoproterenol. Both the 3-4 week old and 18-28 week old Mybpc3 InsG/InsG models recapitulate HCM, with a severe phenotype present in the 18-28 week old model

Detection of interstellar CH_3

Observations with the Short Wavelength Spectrometer (SWS) onboard the {\it Infrared Space Observatory} (ISO) have led to the first detection of the methyl radical ${\rm CH_3}$ in the interstellar medium. The $\nu_2$ $Q-$branch at 16.5 $\mu$m and the $R$(0) line at 16.0 $\mu$m have been unambiguously detected toward the Galactic center SgrA$^*$. The analysis of the measured bands gives a column density of (8.0$\pm$2.4)$\times10^{14}$ cm$^{-2}$ and an excitation temperature of $(17\pm 2)$ K. Gaseous ${\rm CO}$ at a similarly low excitation temperature and ${\rm C_2H_2}$ are detected for the same line of sight. Using constraints on the ${\rm H_2}$ column density obtained from ${\rm C^{18}O}$ and visual extinction, the inferred ${\rm CH_3}$ abundance is $(1.3{{+2.2}\atop{-0.7}}) \times 10^{-8}$. The chemically related ${\rm CH_4}$ molecule is not detected, but the pure rotational lines of ${\rm CH}$ are seen with the Long Wavelength Spectrometer (LWS). The absolute abundances and the ${\rm CH_3/CH_4}$ and ${\rm CH_3/CH}$ ratios are inconsistent with published pure gas-phase models of dense clouds. The data require a mix of diffuse and translucent clouds with different densities and extinctions, and/or the development of translucent models in which gas-grain chemistry, freeze-out and reactions of ${\rm H}$ with polycyclic aromatic hydrocarbons and solid aliphatic material are included.Comment: 2 figures. ApJL, Accepte

Optical Star-Formation Rate Indicators

Using integrated optical spectrophotometry for 412 star-forming galaxies at z~0, and fiber-aperture spectrophotometry for 120,846 SDSS galaxies at z~0.1, we investigate the H-alpha, H-beta, [O II] 3727, and [O III] 5007 nebular emission lines and the U-band luminosity as quantitative star-formation rate (SFR) indicators. We demonstrate that the extinction-corrected H-alpha luminosity is a reliable SFR tracer even in highly obscured star-forming galaxies. We find that variations in dust reddening dominate the systematic uncertainty in SFRs derived from the observed H-beta, [O II], and U-band luminosities, producing a factor of ~1.7, ~2.5, and ~2.1 scatter in the mean transformations, respectively. We show that [O II] depends weakly on variations in oxygen abundance over a wide range in metallicity, 12+log(O/H)=8.15-8.7 dex (Z/Z_sun=0.28-1.0), and that in this metallicity interval galaxies occupy a narrow range in ionization parameter (-3.8<log U<-2.9 dex). We show that the scatter in [O III] 5007 as a SFR indicator is a factor of 3-4 due to its sensitivity to metal abundance and ionization. We develop empirical SFR calibrations for H-beta and [O II] parameterized in terms of the B-band luminosity, which remove the systematic effects of reddening and metallicity, and reduce the SFR scatter to +/-40% and +/-90%, respectively, although individual galaxies may deviate substantially from the median relations. Finally, we compare the z~0 relations between blue luminosity and reddening, ionization, and [O II]/H-alpha ratio against measurements at z~1 and find broad agreement. (Abridged.)Comment: ApJ, accepted; no changes from previously posted version; emulateapj style; 41 pages, 23 figures, 2 table

STAT2 signaling restricts viral dissemination but drives severe pneumonia in SARS-CoV-2 infected hamsters

Emergence of SARS-CoV-2 causing COVID-19 has resulted in hundreds of thousands of deaths. In search for key targets of effective therapeutics, robust animal models mimicking COVID-19 in humans are urgently needed. Here, we show that Syrian hamsters, in contrast to mice, are highly permissive to SARS-CoV-2 and develop bronchopneumonia and strong inflammatory responses in the lungs with neutrophil infiltration and edema, further confirmed as consolidations visualized by micro-CT alike in clinical practice. Moreover, we identify an exuberant innate immune response as key player in pathogenesis, in which STAT2 signaling plays a dual role, driving severe lung injury on the one hand, yet restricting systemic virus dissemination on the other. Our results reveal the importance of STAT2-dependent interferon responses in the pathogenesis and virus control during SARS-CoV-2 infection and may help rationalizing new strategies for the treatment of COVID-19 patients. SARS-CoV-2 infection can result in severe lung inflammation and pathology, but host response remains incompletely understood. Here the authors show in Syrian hamsters that STAT2 signaling restricts systemic virus dissemination but also drives severe lung injury, playing a dual role in SARS-CoV-2 infection

Demographic, clinical and antibody characteristics of patients with digital ulcers in systemic sclerosis: data from the DUO Registry

OBJECTIVES: The Digital Ulcers Outcome (DUO) Registry was designed to describe the clinical and antibody characteristics, disease course and outcomes of patients with digital ulcers associated with systemic sclerosis (SSc). METHODS: The DUO Registry is a European, prospective, multicentre, observational, registry of SSc patients with ongoing digital ulcer disease, irrespective of treatment regimen. Data collected included demographics, SSc duration, SSc subset, internal organ manifestations, autoantibodies, previous and ongoing interventions and complications related to digital ulcers. RESULTS: Up to 19 November 2010 a total of 2439 patients had enrolled into the registry. Most were classified as either limited cutaneous SSc (lcSSc; 52.2%) or diffuse cutaneous SSc (dcSSc; 36.9%). Digital ulcers developed earlier in patients with dcSSc compared with lcSSc. Almost all patients (95.7%) tested positive for antinuclear antibodies, 45.2% for anti-scleroderma-70 and 43.6% for anticentromere antibodies (ACA). The first digital ulcer in the anti-scleroderma-70-positive patient cohort occurred approximately 5 years earlier than the ACA-positive patient group. CONCLUSIONS: This study provides data from a large cohort of SSc patients with a history of digital ulcers. The early occurrence and high frequency of digital ulcer complications are especially seen in patients with dcSSc and/or anti-scleroderma-70 antibodies

<i>Euclid </i>: Improving the efficiency of weak lensing shear bias calibration : Pixel noise cancellation and the response method on trial

To obtain an accurate cosmological inference from upcoming weak lensing surveys such as the one conducted by Euclid , the shear measurement requires calibration using galaxy image simulations. As it typically requires millions of simulated galaxy images and consequently a substantial computational effort, seeking methods to speed the calibration up is valuable. We study the efficiency of different noise cancellation methods that aim at reducing the simulation volume required to reach a given precision in the shear measurement. The more efficient a method is, the faster we can estimate the relevant biases up to a required precision level. Explicitly, we compared fit methods with different noise cancellations and a method based on responses. We used GalSim to simulate galaxies both on a grid and at random positions in larger scenes. Placing the galaxies at random positions requires their detection, which we performed with SExtractor . On the grid, we neglected the detection step and, therefore, the potential detection bias arising from it. The shear of the simulated images was measured with the fast moment-based method KSB, for which we note deviations from purely linear shear measurement biases. For the estimation of uncertainties, we used bootstrapping as an empirical method. We extended the response-based approach to work on a wider range of shears and provide accurate estimates of selection biases. We find that each method we studied on top of shape noise cancellation can further increase the efficiency of calibration simulations. The improvement depends on the considered shear amplitude range and the type of simulations (grid-based or random positions). The response method on a grid for small shears provides the biggest improvement. Here the runtime for the estimation of multiplicative biases can be lowered by a factor of 145 compared to the benchmark simulations without any cancellation. In the more realistic case of randomly positioned galaxies, we still find an improvement factor of 70 for small shears using the response method. Alternatively, the runtime can be lowered by a factor of 7 already using pixel noise cancellation on top of shape noise cancellation. Furthermore, we demonstrate that the efficiency of shape noise cancellation can be enhanced in the presence of blending if entire scenes are rotated instead of individual galaxies

Seizure occurrence and the circadian rhythm of cortisol : A systematic review

Purpose: Stress is the seizure precipitant most often reported by patients with epilepsy or their caregivers. The relation between stress and seizures is presumably mediated by stress hormones such as cortisol, affecting neuronal excitability. Endogenous cortisol is released in a circadian pattern. To gain insight into the relation between the circadian rhythm of cortisol and seizure occurrence, we systematically reviewed studies on the diurnal distribution of epileptic seizures in children and adults and linked the results to the circadian rhythm of cortisol. Methods: A structured literature search was conducted to identify relevant articles, combining the terms 'epilepsy' and 'circadian seizure distribution', plus synonyms. Articles were screened using predefined selection criteria. Data on 24-hour seizure occurrence were extracted, combined, and related to a standard circadian rhythm of cortisol. Results: Fifteen relevant articles were identified of which twelve could be used for data aggregation. Overall, seizure occurrence showed a sharp rise in the early morning, followed by a gradual decline, similar to cortisol rhythmicity. The occurrence of generalized seizures and focal seizures originating from the parietal lobe in particular followed the circadian rhythm of cortisol. Conclusions: The diurnal occurrence of epileptic seizures shows similarities to the circadian rhythm of cortisol. These results support the hypothesis that circadian fluctuations in stress hormone level influence the occurrence of epileptic seizures

Seizure occurrence and the circadian rhythm of cortisol : A systematic review

Purpose: Stress is the seizure precipitant most often reported by patients with epilepsy or their caregivers. The relation between stress and seizures is presumably mediated by stress hormones such as cortisol, affecting neuronal excitability. Endogenous cortisol is released in a circadian pattern. To gain insight into the relation between the circadian rhythm of cortisol and seizure occurrence, we systematically reviewed studies on the diurnal distribution of epileptic seizures in children and adults and linked the results to the circadian rhythm of cortisol. Methods: A structured literature search was conducted to identify relevant articles, combining the terms 'epilepsy' and 'circadian seizure distribution', plus synonyms. Articles were screened using predefined selection criteria. Data on 24-hour seizure occurrence were extracted, combined, and related to a standard circadian rhythm of cortisol. Results: Fifteen relevant articles were identified of which twelve could be used for data aggregation. Overall, seizure occurrence showed a sharp rise in the early morning, followed by a gradual decline, similar to cortisol rhythmicity. The occurrence of generalized seizures and focal seizures originating from the parietal lobe in particular followed the circadian rhythm of cortisol. Conclusions: The diurnal occurrence of epileptic seizures shows similarities to the circadian rhythm of cortisol. These results support the hypothesis that circadian fluctuations in stress hormone level influence the occurrence of epileptic seizures

Ototopical drops containing a novel antibacterial synthetic peptide: Safety and efficacy in adults with chronic suppurative otitis media.

OBJECTIVE:Chronic suppurative otitis media (CSOM) is a chronic infectious disease with worldwide prevalence that causes hearing loss and decreased quality of life. As current (antibiotic) treatments often unsuccessful and antibiotic resistance is emerging, alternative agents and/or strategies are urgently needed. We considered the synthetic antimicrobial and anti-biofilm peptide P60.4Ac to be an interesting candidate because it also displays anti-inflammatory activities including lipopolysaccharide-neutralizing activity. The aim of the present study was to investigate the safety and efficacy of ototopical drops containing P60.4Ac in adults with CSOM without cholesteatoma. METHODS:We conducted a range-finding study in 16 subjects followed by a randomized, double blinded, placebo-controlled, multicentre phase IIa study in 34 subjects. P60.4Ac-containing ototopical drops or placebo drops were applied twice a day for 2 weeks and adverse events (AEs) and medication use were recorded. Laboratory tests, swabs from the middle ear and throat for bacterial cultures, and audiometry were performed at intervals up to 10 weeks after therapy. Response to treatment was assessed by blinded symptom scoring on otoscopy. RESULTS:Application of P60.4Ac-containing ototopical drops (0.25-2.0 mg of peptide/ml) in the ear canal of patients suffering from CSOM was found to be safe and well-tolerated. The optimal dose (0.5 mg of peptide/ml) was selected for the subsequent phase IIa study. Safety evaluation revealed only a few AEs that were unlikely related to study treatment and all, except one, were of mild to moderate intensity. In addition to this excellent safety profile, P60.4Ac ototopical drops resulted in a treatment success in 47% of cases versus 6% in the placebo group. CONCLUSION:The efficacy/safety balance assessed in the present study provides a compelling justification for continued clinical development of P60.4Ac in therapy-resistant CSOM