Distribution and function of HCN channels in the apical dendritic tuft of neocortical pyramidal neurons

The apical tuft is the most remote area of the dendritic tree of neocortical pyramidal neurons. Despite its distal location, the apical dendritic tuft of layer 5 pyramidal neurons receives substantial excitatory synaptic drive and actively processes corticocortical input during behavior. The properties of the voltage-activated ion channels that regulate synaptic integration in tuft dendrites have, however, not been thoroughly investigated. Here, we use electrophysiological and optical approaches to examine the subcellular distribution and function of hyperpolarization-activated cyclic nucleotide-gated nonselective cation (HCN) channels in rat layer 5B pyramidal neurons. Outside-out patch recordings demonstrated that the amplitude and properties of ensembleHCNchannel activity were uniform in patches excised from distal apical dendritic trunk and tuft sites. Simultaneous apical dendritic tuft and trunk whole-cell current-clamp recordings revealed that the pharmacological blockade of HCN channels decreased voltage compartmentalization and enhanced the generation and spread of apical dendritic tuft and trunk regenerative activity. Furthermore, multisite two-photon glutamate uncaging demonstrated that HCN channels control the amplitude and duration of synaptically evoked regenerative activity in the distal apical dendritic tuft. In contrast, at proximal apical dendritic trunk and somatic recording sites, the blockade of HCN channels decreased excitability. Dynamicclamp experiments revealed that these compartment-specific actions of HCN channels were heavily influenced by the local and distributed impact of the high density of HCN channels in the distal apical dendritic arbor. The properties and subcellular distribution pattern of HCN channels are therefore tuned to regulate the interaction between integration compartments in layer 5B pyramidal neurons

Type Iax SNe as a few-parameter family

We present direct spectroscopic modeling of five Type Iax supernovae (SNe) with the one dimensional Monte Carlo radiative transfer code TARDIS. The abundance tomography technique is used to map the chemical structure and physical properties of the SN atmosphere. Through via fitting of multiple spectral epochs with self-consistent ejecta models, we can then constrain the location of some elements within the ejecta. The synthetic spectra of the best-fit models are able to reproduce the flux continuum and the main absorption features in the whole sample. We find that the mass fractions of IGEs and IMEs show a decreasing trend toward the outer regions of the atmospheres using density profiles similar to those of deflagration models in the literature. Oxygen is the only element, which could be dominant at higher velocities. The stratified abundance structure contradicts the well-mixed chemical profiles predicted by pure deflagration models. Based on the derived densities and abundances, a template model atmosphere is created for the SN Iax class and compared to the observed spectra. Free parameters are the scaling of the density profile, the velocity shift of the abundance template, and the peak luminosity. The results of this test support the idea that all SNe Iax can be described by a similar internal structure, which argues for a common origin of this class of explosions.Comment: 21 pages, 7 tables, 16 figures, accepted by MNRA

Lensed type Ia supernovae in light of SN Zwicky and iPTF16geu

Strong gravitationally lensed supernovae (glSNe) are a powerful probe to obtain a measure of the expansion rate of the Universe, but they are also extremely rare. To date, only two glSNe with multiple images strongly lensed by galaxies have been found, but their short time delays make them unsuitable for cosmography. We simulate a realistic catalogue of lensed supernovae and study the characteristics of the population of detectable systems for different surveys. Our simulations show that the properties of glSNe in shallow surveys (such as the Zwicky Transient Facility; ZTF) are determined by the need for large magnifications, which favours systems of four images with short time delays and low image separations. This picture is consistent with the properties of iPTF16geu and SN~Zwicky, but is not representative of the population found in deeper surveys, which are limited by the volume of the Universe that is strongly lensed. In our simulations of the Legacy Survey of Space and Time (LSST), glSNe show longer time delays and greater angular separations. Of these systems in LSST, 35\% will allow for time-delay measurements with a precision of 10\% or better. In the 10 years of the survey LSST should be able to find $\approx$ 180 systems, of which 60 will be suited for cosmography enabling a $\approx 1.5 \%$ precision $H_0$ measurement with LSST glSNe.Comment: 11 pages, 9 figures. Submitte

Variceal Hemorrhage and Adverse Liver Outcomes in Patients With Cystic Fibrosis Cirrhosis

OBJECTIVES: Cirrhosis occurs in 5% to 10% of cystic fibrosis (CF) patients, often accompanied by portal hypertension. We analyzed 3 adverse liver outcomes, variceal bleeding (VB), liver transplant (LT), and liver-related death (LD), and risk factors for these in CF Foundation Patient Registry subjects with reported cirrhosis. METHODS: We determined 10-year incidence rates for VB, LT, LD, and all-cause mortality (ACM), and examined risk factors using competing risk models and Cox-proportional hazard regression. RESULTS: From 2003 to 2012, 943 participants (41% females, mean age 18.1 years) had newly reported cirrhosis; 24.7% required insulin, 85% had previous pseudomonas. Seventy-three subjects had reported VB: 38 with first VB and new cirrhosis reported simultaneously and 35 with VB after cirrhosis report. Ten-year cumulative VB, LT, and LD rates were 6.6% (95% confidence interval [CI]: 4.0, 9.1%), 9.9% (95% CI: 6.6%, 13.2%), and 6.9% (95% CI: 4.0%, 9.8%), respectively, with an ACM of 39.2% (95% CI: 30.8, 36.6%). ACM was not increased in subjects with VB compared to those without (hazard ratio [HR] 1.10, 95% CI: 0.59, 2.08). CF-related diabetes (HR: 3.141, 95% CI:1.56, 6.34) and VB (HR: 4.837, 95% CI: 2.33, 10.0) were associated with higher LT risk, whereas only worse lung function was associated with increased LD in multivariate analysis. Death rate among subjects with VB was 24% with LT and 20.4% with native liver. CONCLUSIONS: VB is an uncommon complication of CF cirrhosis and can herald the diagnosis, but does not affect ACM. Adverse liver outcomes and ACM are frequent by 10 years after cirrhosis report

A new method for quantifying anisotropic martensitic transformation strains accumulated during constrained cooling

Martensitic phase transformations during welding can play a major role in determining the final residual stresses and they can be anisotropic if the transformation occurs under stress. Traditionally, the Satoh test has been used to quantify the response, but it suffers from the fact that the temperature is not uniform along the specimen length, making it difficult to interpret the data. This shortcoming is overcome in our new experimental method using digital image correlation (DIC) to quantify the temperature dependent evolution of the transformation strain locally both parallel and perpendicular to an applied load, in this case for a high-strength low alloy (HSLA) steel and a tough, low transformation temperature weld consumable designed to mitigate tensile weld residual stresses. The method is able to separate the volumetric component of the transformation strain from the deviatoric transformation plasticity component. The volumetric component is shown to be independent of applied load, while the deviatoric component varies approximately linearly with applied load. For the HSLA steel studied here the method also reveals that the transformation start temperature rises under both tensile and compressive loading, confirming previous work. From a weld modelling viewpoint our method provides sufficient information to include the stress dependency of the anisotropic transformation strain in numerical finite element models of the weld process

Discovery of Two Distant Type Ia Supernovae in the Hubble Deep Field North with the Advanced Camera for Surveys

We present observations of the first two supernovae discovered with the recently installed Advanced Camera for Surveys (ACS) on the Hubble Space Telescope. The supernovae were found in Wide Field Camera images of the Hubble Deep Field North taken with the F775W, F850LP, and G800L optical elements as part of the ACS guaranteed time observation program. Spectra extracted from the ACS G800L grism exposures confirm that the objects are Type Ia supernovae (SNe Ia) at redshifts z=0.47 and z=0.95. Follow-up HST observations have been conducted with ACS in F775W and F850LP and with NICMOS in the near-infrared F110W bandpass, yielding a total of 9 flux measurements in the 3 bandpasses over a period of 50 days in the observed frame. We discuss many of the important issues in doing accurate photometry with the ACS. We analyze the multi-band light curves using two different fitting methods to calibrate the supernovae luminosities and place them on the SNe Ia Hubble diagram. The resulting distances are consistent with the redshift-distance relation of the accelerating universe model, although evolving intergalactic grey dust remains as a less likely possibility. The relative ease with which these SNe Ia were found, confirmed, and monitored demonstrates the potential ACS holds for revolutionizing the field of high-redshift SNe Ia, and therefore of testing the accelerating universe cosmology and constraining the "epoch of deceleration".Comment: 11 pages, 8 embedded figures. Accepted for publication in Ap

Early-time spectroscopic modelling of the transitional Type Ia Supernova 2021rhu with TARDIS

An open question in SN Ia research is where the boundary lies between 'normal' Type Ia supernovae (SNe Ia) that are used in cosmological measurements and those that sit off the Phillips relation. We present the spectroscopic modelling of one such '86G-like' transitional SN Ia, SN 2021rhu, that has recently been employed as a local Hubble Constant calibrator using a tip of the red-giant branch measurement. We detail its modelling from -12 d until maximum brightness using the radiative-transfer spectral-synthesis code tardis. We base our modelling on literature delayed-detonation and deflagration models of Chandrasekhar mass white dwarfs, as well as the double-detonation models of sub-Chandrasekhar mass white dwarfs. We present a new method for 'projecting' abundance profiles to different density profiles for ease of computation. Due to the small velocity extent and low outer densities of the W7 profile, we find it inadequate to reproduce the evolution of SN 2021rhu as it fails to match the high-velocity calcium components. The host extinction of SN 2021rhu is uncertain but we use modelling with and without an extinction correction to set lower and upper limits on the abundances of individual species. Comparing these limits to literature models we conclude that the spectral evolution of SN 2021rhu is also incompatible with double-detonation scenarios, lying more in line with those resulting from the delayed detonation mechanism (although there are some discrepancies, in particular a larger titanium abundance in SN 2021rhu compared to the literature). This suggests that SN 2021rhu is likely a lower luminosity, and hence lower temperature, version of a normal SN Ia.Comment: 25 pages, 22 figures, accepted for publication in MNRA

A risk prediction model for the assessment and triage of women with hypertensive disorders of pregnancy in low-resourced settings: the miniPIERS (Pre-eclampsia Integrated Estimate of RiSk) multi-country prospective cohort study.

BACKGROUND: Pre-eclampsia/eclampsia are leading causes of maternal mortality and morbidity, particularly in low- and middle- income countries (LMICs). We developed the miniPIERS risk prediction model to provide a simple, evidence-based tool to identify pregnant women in LMICs at increased risk of death or major hypertensive-related complications. METHODS AND FINDINGS: From 1 July 2008 to 31 March 2012, in five LMICs, data were collected prospectively on 2,081 women with any hypertensive disorder of pregnancy admitted to a participating centre. Candidate predictors collected within 24 hours of admission were entered into a step-wise backward elimination logistic regression model to predict a composite adverse maternal outcome within 48 hours of admission. Model internal validation was accomplished by bootstrapping and external validation was completed using data from 1,300 women in the Pre-eclampsia Integrated Estimate of RiSk (fullPIERS) dataset. Predictive performance was assessed for calibration, discrimination, and stratification capacity. The final miniPIERS model included: parity (nulliparous versus multiparous); gestational age on admission; headache/visual disturbances; chest pain/dyspnoea; vaginal bleeding with abdominal pain; systolic blood pressure; and dipstick proteinuria. The miniPIERS model was well-calibrated and had an area under the receiver operating characteristic curve (AUC ROC) of 0.768 (95% CI 0.735-0.801) with an average optimism of 0.037. External validation AUC ROC was 0.713 (95% CI 0.658-0.768). A predicted probability ≥25% to define a positive test classified women with 85.5% accuracy. Limitations of this study include the composite outcome and the broad inclusion criteria of any hypertensive disorder of pregnancy. This broad approach was used to optimize model generalizability. CONCLUSIONS: The miniPIERS model shows reasonable ability to identify women at increased risk of adverse maternal outcomes associated with the hypertensive disorders of pregnancy. It could be used in LMICs to identify women who would benefit most from interventions such as magnesium sulphate, antihypertensives, or transportation to a higher level of care

Identification of PKD1L1 Gene Variants in Children with the Biliary Atresia Splenic Malformation Syndrome

Biliary atresia (BA) is the most common cause of end‐stage liver disease in children and the primary indication for pediatric liver transplantation, yet underlying etiologies remain unknown. Approximately 10% of infants affected by BA exhibit various laterality defects (heterotaxy) including splenic abnormalities and complex cardiac malformations — a distinctive subgroup commonly referred to as the biliary atresia splenic malformation (BASM) syndrome. We hypothesized that genetic factors linking laterality features with the etiopathogenesis of BA in BASM patients could be identified through whole exome sequencing (WES) of an affected cohort. DNA specimens from 67 BASM subjects, including 58 patient‐parent trios, from the NIDDK‐supported Childhood Liver Disease Research Network (ChiLDReN) underwent WES. Candidate gene variants derived from a pre‐specified set of 2,016 genes associated with ciliary dysgenesis and/or dysfunction or cholestasis were prioritized according to pathogenicity, population frequency, and mode of inheritance. Five BASM subjects harbored rare and potentially deleterious bi‐allelic variants in polycystin 1‐like 1, PKD1L1, a gene associated with ciliary calcium signaling and embryonic laterality determination in fish, mice and humans. Heterozygous PKD1L1 variants were found in 3 additional subjects. Immunohistochemical analysis of liver from the one BASM subject available revealed decreased PKD1L1 expression in bile duct epithelium when compared to normal livers and livers affected by other non‐cholestatic diseases. Conclusion WES identified bi‐allelic and heterozygous PKD1L1 variants of interest in 8 BASM subjects from the ChiLDReN dataset. The dual roles for PKD1L1 in laterality determination and ciliary function suggest that PKD1L1 is a new, biologically plausible, cholangiocyte‐expressed candidate gene for the BASM syndrome

Music, computing and health: A roadmap for the current and future roles of music technology for health care and well-being.

Health and self-regulatio