Reduced thymic output, cell cycle abnormalities, and increased apoptosis of T lymphocytes in patients with cartilage-hair hypoplasia

Producción CientíficaBackground: Cartilage-hair hypoplasia (CHH) is characterized by metaphyseal dysplasia, bone marrow failure, increased risk of malignancies, and a variable degree of immunodeficiency. CHH is caused by mutations in the RNA component of the mitochondrial RNA processing (RMRP) endoribonuclease gene, which is involved in ribosomal assembly, telomere function, and cell cycle control. Objectives: We aimed to define thymic output and characterize immune function in a cohort of patients with molecularly defined CHH with and without associated clinical immunodeficiency. Methods: We studied the distribution of B and T lymphocytes (including recent thymic emigrants), in vitro lymphocyte proliferation, cell cycle, and apoptosis in 18 patients with CHH compared with controls. Results: Patients with CHH have a markedly reduced number of recent thymic emigrants, and their peripheral T cells show defects in cell cycle control and display increased apoptosis, resulting in poor proliferation on activation. Conclusion: These data confirm that RMRP mutations result in significant defects of cell-mediated immunity and provide a link between the cellular phenotype and the immunodeficiency in CH

Dominion cartoon satire as trench culture narratives: complaints, endurance and stoicism

Although Dominion soldiers’ Great War field publications are relatively well known, the way troops created cartoon multi-panel formats in some of them has been neglected as a record of satirical social observation. Visual narrative humour provides a ‘bottom-up’ perspective for journalistic observations that in many cases capture the spirit of the army in terms of stoicism, buoyed by a culture of internal complaints. Troop concerns expressed in the early comic strips of Australians, Canadians, New Zealanders and British were similar. They shared a collective editorial purpose of morale boosting among the ranks through the use of everyday narratives that elevated the anti-heroism of the citizen soldier, portrayed as a transnational everyman in the service of empire. The regenerative value of disparagement humour provided a redefinition of courage as the very act of endurance on the Western Front

The Derivation of Bearing Characteristics by Means of Transient Excitation Applied Directly to a Rotating Shaft

graph are the square roots of the appropriate diagonal elements from the error covariance matrix P. These elements provide a first-order approximation to the estimated variance in the states and hence ± Vi^, is an approximate measure of the standard deviation of state estimate x ,•. Increasing the running speed (and hence the excitation frequency) has little effect upon the accuracy of estimation, as shown by the results in A key assumption in producing the above results is that the values of (e/c) and <p are known exactly. Where the unbalance is introduced artificially this is a reasonable assumption, however where natural unbalance is exploited its effective magnitude and angular position would be harder to assess. Consequently a further set of tests was performed involving deliberately-induced errors in the assumed values of (e/c) and Typical results (for a running speed of 3000 rev/min) are shown in Discussion This note has discussed an approach to the identification of linearized journal bearing dynamics under normal operating conditions. Given that an effective technique is already available for estimating the four oil-film stiffness terms, a method must now be developed for extracting reliable estimates of the four damping terms, preferably without the need to conduct further experiments. We have suggested that this can be achieved by reformulating the problem so that an existing algorithm can be applied to estimate the damping terms from noisy measurements of the displacement responses to synchronous excitation. These responses are acquired automatically in any identification experiment and hence the approach could be applied retrospectively to refine estimates of the damping terms. The feasibility of the approach has been tested under controlled conditions by generating data from a linearized model of a simple rotor-bearing system and demonstrating that the governing equations can be reconstructed. In practice the effectiveness of such an approach will depend upon the robustness of the algorithm when processing actual operating data and the accuracy with which the unbalance parameters can be assessed. The effects of modeling errors (introduced by the linearization process) and other disturbances not considered in this note (for example, surface roughness of the shaft and bearings) will obviously be reflected in the eventual results. It is hoped that the results presented here will encourage experimental work to quantify such effects. 2 Holmes, R., "The Vibration of a Rigid Shaft on Short Journal Bearings," J. Mech. Eng. Set., Vol. 2, 1960, pp. 337-341. 3 Allaire, P. E., Nicholas, J. C, and Gunter, E. J., "Finite-Element Analysis of Fluid-Film Bearings," University of Virginia Report ME-543-120-75, Charlottesville, Va. 4 Stanway, R., Burrows, C. R., and Holmes, R., "Discrete-Time Modelling of a Squeeze-Film Bearing," J. Mech. Eng. Sci., Vol. 21, 1979, pp. 419-427. 5 Morton, P. G., "The Derivation of Bearing Characteristics by Means of Transient Excitation Applied Directly to a Rotating Shaft," G. E. C. Journal of Science and Technology, Vol. 42, 1975, pp. 37-47. 6 Burrows, C. R., and Stanway, R., "Identification of Journal Bearing Characteristics," ASME JOURNAL OF DYNAMIC SYSTEMS, MEASUREMENT AND CONTROL, Vol. 99, 1977, pp. 167-173. 7 Detchmendy, D. M., and Sridhar, R., "Sequential Estimation of States and Parameters in Noisy Non-Linear Dynamical Systems," ASME Journal of Basic Engineering, Vol. 88, 1966, pp. 362-368. 8 Woodcock, J. S., and Holmes, R., "The Determination and Application of the Dynamic Properties of a Turbo-Rotor Bearing Oil-Film," Proc. I. Mech. £., Vol. 184, 1969Vol. 184, -1970. Control of Systems Subject to Introduction Although the study of linear systems receives disproportionate attention in the literature, the fact remains that nonlinear equations are necessary to adequately describe many important control processes. Linear feedback theory may still find an application even in this instance. If the nonlinear system operates near a known nominal condition, a nominal state trajectory and a nominal actuating signal can be determined. Under appropriate conditions, the deviations from the nominal path can be described by a linear model. Linear synthesis algorithms can then be applied to this perturbation model, and a regulator which causes the system to track its nominal trajectory can be deduced thereby. To be more specific about these ideas, consider the problem of synthesizing a feedwater flow rate regulator for control of a solar receiver. Certain aspects of this problem were addressed in [1] an

Glucocorticoid receptor haploinsufficiency causes hypertension and attenuates hypothalamic-pituitary-adrenal axis and blood pressure adaptions to high-fat diet

Glucocorticoid hormones are critical to respond and adapt to stress. Genetic variations in the glucocorticoid receptor (GR) gene alter hypothalamic-pituitary-adrenal (HPA) axis activity and associate with hypertension and susceptibility to metabolic disease. Here we test the hypothesis that reduced GR density alters blood pressure and glucose and lipid homeostasis and limits adaption to obesogenic diet. Heterozygous GR βgeo/+ mice were generated from embryonic stem (ES) cells with a gene trap integration of a β-galactosidase-neomycin phosphotransferase (βgeo) cassette into the GR gene creating a transcriptionally inactive GR fusion protein. Although GRβgeo/+ mice have 50% less functional GR, they have normal lipid and glucose homeostasis due to compensatory HPA axis activation but are hypertensive due to activation of the renin-angiotensin- aldosterone system (RAAS). When challenged with a high-fat diet, weight gain, adiposity, and glucose intolerance were similarly increased in control and GRβgeo/+ mice, suggesting preserved control of intermediary metabolism and energy balance. However, whereas a high-fat diet caused HPA activation and increased blood pressure in control mice, these adaptions were attenuated or abolished in GRβgeo/+ mice. Thus, reduced GR density balanced by HPA activation leaves glucocorticoid functions unaffected but mineralocorticoid functions increased, causing hypertension. Importantly, reduced GR limits HPA and blood pressure adaptions to obesogenic diet

Ernst Freund as Precursor of the Rational Study of Corporate Law

Gindis, David, Ernst Freund as Precursor of the Rational Study of Corporate Law (October 27, 2017). Journal of Institutional Economics, Forthcoming. Available at SSRN: https://ssrn.com/abstract=2905547, doi: https://dx.doi.org/10.2139/ssrn.2905547The rise of large business corporations in the late 19th century compelled many American observers to admit that the nature of the corporation had yet to be understood. Published in this context, Ernst Freund's little-known The Legal Nature of Corporations (1897) was an original attempt to come to terms with a new legal and economic reality. But it can also be described, to paraphrase Oliver Wendell Holmes, as the earliest example of the rational study of corporate law. The paper shows that Freund had the intuitions of an institutional economist, and engaged in what today would be called comparative institutional analysis. Remarkably, his argument that the corporate form secures property against insider defection and against outsiders anticipated recent work on entity shielding and capital lock-in, and can be read as an early contribution to what today would be called the theory of the firm.Peer reviewe

Student engagement and perceptions of blended-learning of a clinical module in a veterinary degree program.

Blended learning has received much interest in higher education as a way to increase learning efficiency and effectiveness. By combining face-to-face teaching with technology-enhanced learning through online resources, students can manage their own learning. Blended methods are of particular interest in professional degree programs such as veterinary medicine in which students need the flexibility to undertake intra- and extramural activities to develop the range of competencies required to achieve professional qualification. Yet how veterinary students engage with blended learning activities and whether they perceive the approach as beneficial is unclear. We evaluated blended learning through review of student feedback on a 4-week clinical module in a veterinary degree program. The module combined face-to-face sessions with online resources. Feedback was collected by means of a structured online questionnaire at the end of the module and log data collected as part of a routine teaching audit. The features of blended learning that support and detract from students’ learning experience were explored using quantitative and qualitative methods. Students perceived a benefit from aspects of face-to-face teaching and technology-enhanced learning resources. Face-to-face teaching was appreciated for practical activities, whereas online resources were considered effective for facilitating module organization and allowing flexible access to learning materials. The blended approach was particularly appreciated for clinical skills in which students valued a combination of visual resources and practical activities. Although we identified several limitations with online resources that need to be addressed when constructing blended courses, blended learning shows potential to enhance student-led learning in clinical courses

Genotype- phenotype correlation and molecular heterogeneity in pyruvate kinase deficiency

Pyruvate kinase (PK) deficiency is a rare recessive congenital hemolytic anemia caused by mutations in the PKLR gene. This study reports the molecular features of 257 patients enrolled in the PKD Natural History Study. Of the 127 different pathogenic variants detected, 84 were missense and 43 non- missense, including 20 stop- gain, 11 affecting splicing, five large deletions, four in- frame indels, and three promoter variants. Within the 177 unrelated patients, 35 were homozygous and 142 compound heterozygous (77 for two missense, 48 for one missense and one non- missense, and 17 for two non- missense variants); the two most frequent mutations were p.R510Q in 23% and p.R486W in 9% of mutated alleles. Fifty- five (21%) patients were found to have at least one previously unreported variant with 45 newly described mutations. Patients with two non- missense mutations had lower hemoglobin levels, higher numbers of lifetime transfusions, and higher rates of complications including iron overload, extramedullary hematopoiesis, and pulmonary hypertension. Rare severe complications, including lower extremity ulcerations and hepatic failure, were seen more frequently in patients with non- missense mutations or with missense mutations characterized by severe protein instability. The PKLR genotype did not correlate with the frequency of complications in utero or in the newborn period. With ICCs ranging from 0.4 to 0.61, about the same degree of clinical similarity exists within siblings as it does between siblings, in terms of hemoglobin, total bilirubin, splenectomy status, and cholecystectomy status. Pregnancy outcomes were similar across genotypes in PK deficient women. This report confirms the wide genetic heterogeneity of PK deficiency.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154955/1/ajh25753.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154955/2/ajh25753_am.pd

Genetic Mapping and Exome Sequencing Identify Variants Associated with Five Novel Diseases

The Clinic for Special Children (CSC) has integrated biochemical and molecular methods into a rural pediatric practice serving Old Order Amish and Mennonite (Plain) children. Among the Plain people, we have used single nucleotide polymorphism (SNP) microarrays to genetically map recessive disorders to large autozygous haplotype blocks (mean = 4.4 Mb) that contain many genes (mean = 79). For some, uninformative mapping or large gene lists preclude disease-gene identification by Sanger sequencing. Seven such conditions were selected for exome sequencing at the Broad Institute; all had been previously mapped at the CSC using low density SNP microarrays coupled with autozygosity and linkage analyses. Using between 1 and 5 patient samples per disorder, we identified sequence variants in the known disease-causing genes SLC6A3 and FLVCR1, and present evidence to strongly support the pathogenicity of variants identified in TUBGCP6, BRAT1, SNIP1, CRADD, and HARS. Our results reveal the power of coupling new genotyping technologies to population-specific genetic knowledge and robust clinical data

Search for squarks and gluinos in events with isolated leptons, jets and missing transverse momentum at s√=8 TeV with the ATLAS detector

The results of a search for supersymmetry in final states containing at least one isolated lepton (electron or muon), jets and large missing transverse momentum with the ATLAS detector at the Large Hadron Collider are reported. The search is based on proton-proton collision data at a centre-of-mass energy s√=8 TeV collected in 2012, corresponding to an integrated luminosity of 20 fb−1. No significant excess above the Standard Model expectation is observed. Limits are set on supersymmetric particle masses for various supersymmetric models. Depending on the model, the search excludes gluino masses up to 1.32 TeV and squark masses up to 840 GeV. Limits are also set on the parameters of a minimal universal extra dimension model, excluding a compactification radius of 1/R c = 950 GeV for a cut-off scale times radius (ΛR c) of approximately 30

Evidence for the Higgs-boson Yukawa coupling to tau leptons with the ATLAS detector

Results of a search for H → τ τ decays are presented, based on the full set of proton-proton collision data recorded by the ATLAS experiment at the LHC during 2011 and 2012. The data correspond to integrated luminosities of 4.5 fb−1 and 20.3 fb−1 at centre-of-mass energies of √s = 7 TeV and √s = 8 TeV respectively. All combinations of leptonic (τ → `νν¯ with ` = e, µ) and hadronic (τ → hadrons ν) tau decays are considered. An excess of events over the expected background from other Standard Model processes is found with an observed (expected) significance of 4.5 (3.4) standard deviations. This excess provides evidence for the direct coupling of the recently discovered Higgs boson to fermions. The measured signal strength, normalised to the Standard Model expectation, of µ = 1.43 +0.43 −0.37 is consistent with the predicted Yukawa coupling strength in the Standard Model