Ventilatory insufficiency remains the leading cause of death and late stage morbidity in Duchenne muscular dystrophy (DMD). To address critical gaps in our knowledge of the pathobiology of ...respiratory functional decline, we used an integrative approach to study respiratory mechanics in a translational model of DMD. In studies of individual dogs with the Golden Retriever muscular dystrophy (GRMD) mutation, we found evidence of rapidly progressive loss of ventilatory capacity in association with dramatic morphometric remodeling of the diaphragm. Within the first year of life, the mechanics of breathing at rest, and especially during pharmacological stimulation of respiratory control pathways in the carotid bodies, shift such that the primary role of the diaphragm becomes the passive elastic storage of energy transferred from abdominal wall muscles, thereby permitting the expiratory musculature to share in the generation of inspiratory pressure and flow. In the diaphragm, this physiological shift is associated with the loss of sarcomeres in series (∼ 60%) and an increase in muscle stiffness (∼ 900%) compared with those of the nondystrophic diaphragm, as studied during perfusion ex vivo. In addition to providing much needed endpoint measures for assessing the efficacy of therapeutics, we expect these findings to be a starting point for a more precise understanding of respiratory failure in DMD.
Autosomal recessive limb-girdle muscular dystrophy type 2G (LGMD2G) is an adult-onset myopathy characterized by distal lower limb weakness, calf hypertrophy and progressive decline in ambulation. The ...disease is caused by mutations in Tcap, a z-disc protein of skeletal muscle, although the precise mechanisms resulting in clinical symptoms are unknown. To provide a model for preclinical trials and for mechanistic studies, we generated knockout (KO) mice carrying a null mutation in the Tcap gene. Here we present the first report of a Tcap KO mouse model for LGMD2G and the results of an investigation into the effects of Tcap deficiency on skeletal muscle function in 4- and 12-month-old mice. Muscle histology of Tcap-null mice revealed abnormal myofiber size variation with central nucleation, similar to findings in the muscles of LGMD2G patients. An analysis of a Tcap binding protein, myostatin, showed that deletion of Tcap was accompanied by increased protein levels of myostatin. Our Tcap-null mice exhibited a decline in the ability to maintain balance on a rotating rod, relative to wild-type controls. No differences were detected in force or fatigue assays of isolated extensor digitorum longus (EDL) and soleus (SOL) muscles. Finally, a mechanical investigation of EDL and SOL indicated an increase in muscle stiffness in KO animals. We are the first to establish a viable KO mouse model of Tcap deficiency and our model mice demonstrate a dystrophic phenotype comparable to humans with LGMD2G.
Genomes of the Hymenoptera Branstetter, Michael G; Childers, Anna K; Cox-Foster, Diana ...
Current opinion in insect science,
02/2018, Letnik:
25
Journal Article
Recenzirano
Odprti dostop
Display omitted
•Hyper-diverse Hymenoptera order includes parasitic and social insects.•Economically impactful for biological control and pollination.•Though second most sequenced order, still only ...15% of families represented.•High quality genome assemblies are proposed for 150 Hymenopteran species.•With additional comparative genomes and transcriptomes to increase data breadth.
Hymenoptera is the second-most sequenced arthropod order, with 52 publically archived genomes (71 with ants, reviewed elsewhere), however these genomes do not capture the breadth of this very diverse order (Figure 1, Table 1). These sequenced genomes represent only 15 of the 97 extant families. Although at least 55 other genomes are in progress in an additional 11 families (see Table 2), stinging wasps represent 35 (67%) of the available and 42 (76%) of the in progress genomes. A more comprehensive catalog of hymenopteran genomes is needed for research into the evolutionary processes underlying the expansive diversity in terms of ecology, behavior, and physiological traits within this group. Additional sequencing is needed to generate an assembly for even 0.05% of the estimated 1 million hymenopteran species, and we recommend premier level assemblies for at least 0.1% of the >150,000 named species dispersed across the order. Given the haplodiploid sex determination in Hymenoptera, haploid male sequencing will help minimize genome assembly issues to enable higher quality genome assemblies.
Abstract
Helicoverpa zea (Lepidoptera: Noctuidae) is an insect pest of major cultivated crops in North and South America. The species has adapted to different host plants and developed resistance to ...several insecticidal agents, including Bacillus thuringiensis (Bt) insecticidal proteins in transgenic cotton and maize. Helicoverpa zea populations persist year-round in tropical and subtropical regions, but seasonal migrations into temperate zones increase the geographic range of associated crop damage. To better understand the genetic basis of these physiological and ecological characteristics, we generated a high-quality chromosome-level assembly for a single H. zea male from Bt-resistant strain, HzStark_Cry1AcR. Hi-C data were used to scaffold an initial 375.2 Mb contig assembly into 30 autosomes and the Z sex chromosome (scaffold N50 = 12.8 Mb and L50 = 14). The scaffolded assembly was error-corrected with a novel pipeline, polishCLR. The mitochondrial genome was assembled through an improved pipeline and annotated. Assessment of this genome assembly indicated 98.8% of the Lepidopteran Benchmark Universal Single-Copy Ortholog set were complete (98.5% as complete single copy). Repetitive elements comprised approximately 29.5% of the assembly with the plurality (11.2%) classified as retroelements. This chromosome-scale reference assembly for H. zea, ilHelZeax1.1, will facilitate future research to evaluate and enhance sustainable crop production practices.
Recent evidence suggests that simple peptides can access diverse amphiphilic phases, and that these structures underlie the robust and widely distributed assemblies implicated in nearly 40 protein ...misfolding diseases. Here we exploit a minimal nucleating core of the Aβ peptide of Alzheimer’s disease to map its morphologically accessible phases that include stable intermolecular molten particles, fibers, twisted and helical ribbons, and nanotubes. Analyses with both fluorescence lifetime imaging microscopy (FLIM) and transmission electron microscopy provide evidence for liquid–liquid phase separations, similar to the coexisting dilute and dense protein-rich liquid phases so critical for the liquid–solid transition in protein crystallization. We show that the observed particles are critical for transitions to the more ordered cross-β peptide phases, which are prevalent in all amyloid assemblies, and identify specific conditions that arrest assembly at the phase boundaries. We have identified a size dependence of the particles in order to transition to the para-crystalline phase and a width of the cross-β assemblies that defines the transition between twisted fibers and helically coiled ribbons. These experimental results reveal an interconnected network of increasing molecularly ordered cross-β transitions, greatly extending the initial computational models for cross-β assemblies.
Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder in which the loss of dystrophin causes progressive degeneration of skeletal and cardiac muscle. Potential therapies that carry ...substantial risk, such as gene- and cell-based approaches, must first be tested in animal models, notably the mdx mouse and several dystrophin-deficient breeds of dogs, including golden retriever muscular dystrophy (GRMD). Affected dogs have a more severe phenotype, in keeping with that of DMD, so may better predict disease pathogenesis and treatment efficacy. Various phenotypic tests have been developed to characterize disease progression in the GRMD model. These biomarkers range from measures of strength and joint contractures to magnetic resonance imaging. Some of these tests are routinely used in clinical veterinary practice, while others require specialized equipment and expertise. By comparing serial measurements from treated and untreated groups, one can document improvement or delayed progression of disease. Potential treatments for DMD may be broadly categorized as molecular, cellular, or pharmacologic. The GRMD model has increasingly been used to assess efficacy of a range of these therapies. A number of these studies have provided largely general proof-of-concept for the treatment under study. Others have demonstrated efficacy using the biomarkers discussed. Importantly, just as symptoms in DMD vary among patients, GRMD dogs display remarkable phenotypic variation. Though confounding statistical analysis in preclinical trials, this variation offers insight regarding the role that modifier genes play in disease pathogenesis. By correlating functional and mRNA profiling results, gene targets for therapy development can be identified.
Background
The Learning Assistant (LA) model with its subsequent support and training has evidenced significant gains for undergraduate STEM learning and persistence, especially in high-stakes ...courses like Calculus. Yet, when a swift and unexpected transition occurs from face-to-face to online, remote learning of the LA environment, it is unknown how LAs are able to maintain their motivation (competence, autonomy, and relatedness), adapt to these new challenges, and sustain their student-centered efforts. This study used Self-Determination Theory (SDT) to model theoretical aspects of LAs’ motivations (persistence and performance) both before and after changes were made in delivery of a Calculus II course at Texas Tech University due to COVID-19 interruptions.
Results
Analysis of weekly written reflections, a focus group session, and a post-course questionnaire of 13 Calculus II LAs throughout Spring semester of 2020 showed that LAs’ reports of competence proportionally decreased when they transitioned online, which was followed by a moderate proportional increase in reports of autonomy (actions they took to adapt to distance instruction) and a dramatic proportional increase in reports of relatedness (to build structures for maintaining communication and building community with undergraduate students).
Conclusions
Relatedness emerged as the most salient factor from SDT to maintain LA self-determination due to the COVID-19 facilitated interruption to course delivery in a high-stakes undergraduate STEM course. Given that online learning continues during the pandemic and is likely to continue after, this research provides an understanding to how LAs responded to this event and the mounting importance of relatedness when LAs are working with undergraduate STEM learners. Programmatic recommendations are given for enhancing LA preparation including selecting LAs for autonomy and relatedness factors (in addition to competence), modeling mentoring for remote learners, and coaching in best practices for online instruction.
Measuring the energy distribution (spectrum) of nonthermal radiation is a valuable diagnostic for Z-pinch plasmas. However, the spatial origin and transport of these X-rays are challenging to study ...in Z-pinches due to broad charge state distributions and spatial gradients of nonthermal emitters. Knowledge of this information can refine our understanding of plasma radiation, enhance the microphysics of multiphysics simulations, and constrain future Z-pinch experiments and diagnostics. In this work, nonthermal iron K<inline-formula> <tex-math notation="LaTeX">\alpha</tex-math> </inline-formula> X-rays are modeled in a Magnetized Liner Inertial Fusion (MagLIF) plasma produced on Sandia National Laboratories' Z-machine using a novel Monte Carlo radiation transport code. The code employs an ancillary screened-hydrogenic atomic data package to self-consistently calculate transport of thermal photons from a fusion core into a beryllium liner shell with 114 ppm iron impurities. Iron fluorescence production in the liner shell is analyzed with spatial statistics, providing novel insight into the origin of nonthermal radiation over a broad region of the plasma shell. Spatial analysis indicates an average radius of fluorescence production that is less than the radial midpoint of the liner plasma, suggesting enhanced photoabsorption near the boundary between the fusion core and liner plasma. Results include an approximated average iron ionization, average bulk thermal electron temperature, and iron K-shell fluorescence yield. A radial temperature profile from deposition of transport photons as well as an emergent transmission spectrum with escaped iron K<inline-formula> <tex-math notation="LaTeX">\alpha</tex-math> </inline-formula> and K<inline-formula> <tex-math notation="LaTeX">\beta</tex-math> </inline-formula> intensities are constructed. Spectroscopic utility of the code is validated against experimental MagLIF data, showing good agreement among spectroscopic features.
The increasing accuracy of large-bore (11- or 8-gauge) vacuum-assisted core needle biopsies (VACNB) has challenged the commonly-accepted practice that surgery is needed for definitive diagnosis when ...atypical ductal hyperplasia (ADH) is found on VACNB. This study seeks to demonstrate the impact of increased VACNB caliber on the pathologic upgrade rate of ADH.
Patients diagnosed with isolated ADH by VACNB who subsequently underwent surgical excision at our tertiary medical center were retrospectively studied. Demographics, needle gauge, number of needle passes, and pathology results were analyzed.
From June 1996 to June 2016, approximately 3740 VACNBs were performed. 139 patients were diagnosed with isolated ADH on VACNB and underwent surgical excision. 30 patients (22%) were upgraded to ductal carcinoma in-situ or invasive cancer; 17 upgrades (21%) from 11-gauge CNB vs. 13 upgrades (23%) from 8-gauge CNB (p = 0.67).
Increasing core needle biopsy size from 11 g to 8 g does not decrease the rate of pathologic upstaging at the time of surgical excision. Surgical excision of ADH is still required for complete diagnosis.
•Research Highlights:•Evolving technology has led to controversy in the management of atypical ductal hyperplasia.•Increased core biopsy size from 11 to 8 g does not lower the pathologic upgrade rate of ADH.•Surgical excision of ADH is still required for complete tissue diagnosis.
The isomeric content of a 34Cl beam produced in the intermediate-energy projectile fragmentation of a 150 MeV/u 36Ar beam on a 3 mm-thick Be target was studied. β-delayed γ-ray spectroscopy was used ...to measure the population of 34Cl fragments in the ground vs. isomeric states at zero degrees relative to the incoming primary beam for four different momentum settings of the fragment separator near the predicted central velocity of these fragments, as well as, at two non-zero-degree settings for one momentum setting. Of the settings explored, which excluded rigidities within 0.5% of the value predicted to maximize total 34Cl yield due to unreacted primary beam, the maximum rate for the production of 34mCl was found at a rigidity setting 0.75% below the predicted peak 34Cl yield. The maximum population of the isomeric state relative to the ground state was observed at a rigidity 1.25% below the predicted maximum 34Cl yield. Studies such as this are important in generating the understanding needed for producing isomer-enriched rare-isotope beams.
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