Geographic variation in thermal sensitivity of early life traits in a widespread reptile

Taxa with large geographic distributions generally encompass diverse macroclimatic conditions, potentially requiring local adaptation and/or phenotypic plasticity to match their phenotypes to differing environments. These eco‐evolutionary processes are of particular interest in organisms with traits that are directly affected by temperature, such as embryonic development in oviparous ectotherms. Here we examine the spatial distribution of fitness‐related early life phenotypes across the range of a widespread vertebrate, the painted turtle (Chrysemys picta). We quantified embryonic and hatchling traits from seven locations (in Idaho, Minnesota, Oregon, Illinois, Nebraska, Kansas, and New Mexico) after incubating eggs under constant conditions across a series of environmentally relevant temperatures. Thermal reaction norms for incubation duration and hatchling mass varied among locations under this common‐garden experiment, indicating genetic differentiation or pre‐ovulatory maternal effects. However, latitude, a commonly used proxy for geographic variation, was not a strong predictor of these geographic differences. Our findings suggest that this macroclimatic proxy may be an unreliable surrogate for microclimatic conditions experienced locally in nests. Instead, complex interactions between abiotic and biotic factors likely drive among‐population phenotypic variation in this system. Understanding spatial variation in key life‐history traits provides an important perspective on adaptation to contemporary and future climatic conditions

Macrocerebellum: Neuroimaging and Clinical Features of a Newly Recognized Condition

Other than hamartomatous enlargement of the cerebellum as in Lhermitte-Duclos syndrome, diffuse enlargement of the cerebellum is not clearly described. We report four patients (ages 9 months to 2 years) with diffusely enlarged cerebelli as identified by measurement of the cerebellum and comparison to age appropriate normal values. The cerebellar measurements were determined in absolute numbers and expressed as ratios of cerebellum to whole brain and supratentorial brain. The clinical features of these four children (3 boys, 1 girl) consistently include global developmental delay, tone abnormalities, preserved reflexes, delayed or abnormal maturation of the visual system (oculomotor apraxia), and deficient or delayed myelination of cerebral white matter. The etiology of the macrocerebellum is unknown but we propose that the cerebellum is responding to the elaboration of growth factors intended to augment the slow development of cerebral structures. Regardless of the etiology, the finding of a macrocerebellum appears to allow the clinician to predict the clinical features of the patient and probably represents a marker for disturbed cerebral development. (J Child Neurol 1997;12:365-368).Yeshttps://us.sagepub.com/en-us/nam/manuscript-submission-guideline

Co-administration With the Pharmacological Chaperone AT1001 Increases Recombinant Human α-Galactosidase A Tissue Uptake and Improves Substrate Reduction in Fabry Mice

Fabry disease is an X-linked lysosomal storage disorder (LSD) caused by mutations in the gene (GLA) that encodes the lysosomal hydrolase α-galactosidase A (α-Gal A), and is characterized by pathological accumulation of the substrate, globotriaosylceramide (GL-3). Regular infusion of recombinant human α-Gal A (rhα-Gal A), termed enzyme replacement therapy (ERT), is the primary treatment for Fabry disease. However, rhα-Gal A has low physical stability, a short circulating half-life, and variable uptake into different disease-relevant tissues. We hypothesized that coadministration of the orally available, small molecule pharmacological chaperone AT1001 (GR181413A, 1-deoxygalactonojirimycin, migalastat hydrochloride) may improve the pharmacological properties of rhα-Gal A via binding and stabilization. AT1001 prevented rhα-Gal A denaturation and activity loss in vitro at neutral pH and 37 °C. Coincubation of Fabry fibroblasts with rhα-Gal A and AT1001 resulted in up to fourfold higher cellular α-Gal A and ~30% greater GL-3 reduction compared to rhα-Gal A alone. Furthermore, coadministration of AT1001 to rats increased the circulating half-life of rhα-Gal A by >2.5-fold, and in GLA knockout mice resulted in up to fivefold higher α-Gal A levels and fourfold greater GL-3 reduction than rhα-Gal A alone. Collectively, these data highlight the potentially beneficial effects of AT1001 on rhα-Gal A, thus warranting clinical investigation

X-Shooting ULLYSES: Massive stars at low metallicity: I. Project description

Observations of individual massive stars, super-luminous supernovae, gamma-ray bursts, and gravitational wave events involving spectacular black hole mergers indicate that the low-metallicity Universe is fundamentally different from our own Galaxy. Many transient phenomena will remain enigmatic until we achieve a firm understanding of the physics and evolution of massive stars at low metallicity (Z). The Hubble Space Telescope has devoted 500 orbits to observing ∼250 massive stars at low Z in the ultraviolet (UV) with the COS and STIS spectrographs under the ULLYSES programme. The complementary X-Shooting ULLYSES (XShootU) project provides an enhanced legacy value with high-quality optical and near-infrared spectra obtained with the wide-wavelength coverage X-shooter spectrograph at ESOa's Very Large Telescope. We present an overview of the XShootU project, showing that combining ULLYSES UV and XShootU optical spectra is critical for the uniform determination of stellar parameters such as effective temperature, surface gravity, luminosity, and abundances, as well as wind properties such as mass-loss rates as a function of Z. As uncertainties in stellar and wind parameters percolate into many adjacent areas of astrophysics, the data and modelling of the XShootU project is expected to be a game changer for our physical understanding of massive stars at low Z. To be able to confidently interpret James Webb Space Telescope spectra of the first stellar generations, the individual spectra of low-Z stars need to be understood, which is exactly where XShootU can deliver

Suitability of external controls for drug evaluation in Duchenne muscular dystrophy

OBJECTIVE: To evaluate the suitability of real-world data (RWD) and natural history data (NHD) for use as external controls in drug evaluations for ambulatory Duchenne muscular dystrophy (DMD). METHODS: The consistency of changes in the 6-minute walk distance (Δ6MWD) was assessed across multiple clinical trial placebo arms and sources of NHD/RWD. Six placebo arms reporting 48-week Δ6MWD were identified via literature review and represented 4 sets of inclusion/exclusion criteria (n = 383 patients in total). Five sources of RWD/NHD were contributed by Universitaire Ziekenhuizen Leuven, DMD Italian Group, The Cooperative International Neuromuscular Research Group, ImagingDMD, and the PRO-DMD-01 study (n = 430 patients, in total). Mean Δ6MWD was compared between each placebo arm and RWD/NHD source after subjecting the latter to the inclusion/exclusion criteria of the trial for baseline age, ambulatory function, and steroid use. Baseline covariate adjustment was investigated in a subset of patients with available data. RESULTS: Analyses included ∼1,200 patient-years of follow-up. Differences in mean Δ6MWD between trial placebo arms and RWD/NHD cohorts ranged from -19.4 m (i.e., better outcomes in RWD/NHD) to 19.5 m (i.e., worse outcomes in RWD/NHD) and were not statistically significant before or after covariate adjustment. CONCLUSIONS: We found that Δ6MWD was consistent between placebo arms and RWD/NHD subjected to equivalent inclusion/exclusion criteria. No evidence for systematic bias was detected. These findings are encouraging for the use of RWD/NHD to augment, or possibly replace, placebo controls in DMD trials. Multi-institution collaboration through the Collaborative Trajectory Analysis Project rendered this study feasible