Exercise interventions for adults and children with cerebral palsy (Protocol)

This is the protocol for a review and there is no abstract. The objectives are as follows: - The primary aim of this systematic review is to evaluate the effect of exercise interventions on activity, participation, and health-related quality of life (HRQoL) in adults and children with CP. - The secondary aim is to evaluate the effect of exercise interventions on body functions and body structures.Jennifer M Ryan is receiving funding from Action Medical Research and the Chartered Society of Physiotherapy Charitable Trust to evaluate the feasibility, acceptability, and efficacy of resistance training in adolescents with cerebral palsy

Inositol phosphatase SHIP1 is a primary target of miR-155

MicroRNA-155 (miR-155) has emerged as a critical regulator of immune cell development, function, and disease. However, the mechanistic basis for its impact on the hematopoietic system remains largely unresolved. Because miRNAs function by repressing specific mRNAs through direct 3′UTR interactions, we have searched for targets of miR-155 implicated in the regulation of hematopoiesis. In the present study, we identify Src homology-2 domain-containing inositol 5-phosphatase 1 (SHIP1) as a direct target of miR-155, and, using gain and loss of function approaches, show that miR-155 represses SHIP1 through direct 3′UTR interactions that have been highly conserved throughout evolution. Repression of endogenous SHIP1 by miR-155 occurred following sustained over-expression of miR-155 in hematopoietic cells both in vitro and in vivo, and resulted in increased activation of the kinase Akt during the cellular response to LPS. Furthermore, SHIP1 was also repressed by physiologically regulated miR-155, which was observed in LPS-treated WT versus miR-155−/− primary macrophages. In mice, specific knockdown of SHIP1 in the hematopoietic system following retroviral delivery of a miR-155-formatted siRNA against SHIP1 resulted in a myeloproliferative disorder, with striking similarities to that observed in miR-155-expressing mice. Our study unveils a molecular link between miR-155 and SHIP1 and provides evidence that repression of SHIP1 is an important component of miR-155 biology

Socializing, networking and development: a report from the second ‘Young Microbiologists Symposium on Microbe Signalling, Organization and Pathogenesis’

In mid-June, the second Young Microbiologists Symposium took place under the broad title of ‘Microbe signalling, organization and pathogenesis’ on the picturesque campus of University College Cork, Ireland. The symposium attracted 150 microbiologists from 15 different countries. The key feature of this meeting was that it was specifically aimed at providing a platform for junior scientists to present their work to a broad audience. The meeting was principally supported by Science Foundation Ireland with further backing from the Society for General Microbiology, the American Society for Microbiology and the European Molecular Biology Organization. Sessions focused on microbial gene expression, biogenesis, pathogenicity and host interaction. In this MicroMeeting report, we highlight some of the most significant advances and exciting developments reported during various talks and poster presentations given by the young and talented microbiologists

Galaxy Formation In The Reionization Epoch As Hinted By Wide Field Camera 3 Observations Of The Hubble Ultra Deep Field

We present a large sample of candidate galaxies at z~7--10, selected in the HUDF using the new observations made by the HST/WFC3. Our sample is composed of 20 z-dropouts, 15 Y-dropouts, and 20 J-dropouts. The surface densities of the z-dropouts are close to what predicted by earlier studies, however, those of the Y- and J-dropouts are quite unexpected. While no Y- or J-dropouts have been found at AB < 28.0 mag, their surface densities seem to increase sharply at fainter levels. While some of these candidates seem to be close to foreground galaxies and thus could possibly be gravitationally lensed, the overall surface densities after excluding such cases are still much higher than what would be expected if the luminosity function does not evolve from z~7 to 10. Motivated by such steep increases, we tentatively propose a set of Schechter function parameters to describe the LFs at z~8 and 10. As compared to their counterpart at z~7, here L* decreases by ~ 6.5x and Phi* increases by 17--90x. Although such parameters are not yet demanded by the existing observations, they are allowed and seem to agree with the data better than other alternatives. If these LFs are still valid beyond our current detection limit, this would imply a sudden emergence of a large number of low-luminosity galaxies when looking back in time to z~10, which, while seemingly exotic, would naturally fit in the picture of the cosmic hydrogen reionization. These early galaxies could easily account for the ionizing photon budget required by the reionization, and they would imply that the global star formation rate density might start from a very high value at z~10, rapidly reach the minimum at z~7, and start to rise again towards z~6. In this scenario, the majority of the stellar mass that the universe assembled through the reionization epoch seems still undetected by current observations at z~6. [Abridged]Comment: accepted for publication in Research in Astronomy and Astrophysic

Mechanisms of Excitation and Remodeling of the Cardiac Action Potential in Two Model Systems.

Differences in cardiac ionic currents underlie action potential duration (APD) heterogeneity and alterations of any current may be arrhythmogenic. Biophysical analysis of ionic currents is crucial in understanding electrophysiological mechanisms of regional electrical heterogeneity and underlying factors that promote arrhythmogenicity. The first project presented in this dissertation characterized, for the first time, the electrophysiology of the Purkinje system of the murine heart. Current-clamp analysis of Purkinje cells (PCs) demonstrated pacemaker activity and a prolonged plateau phase compared to ventricular myocytes (VMs). We investigated, using voltage-clamp, the major ionic currents underlying the action potential and automaticity in PCs and VMs. We observed hyperpolarization activated currents, which contribute to automaticity in PCs, but not VMs. PCs demonstrated differences in transient outward potassium currents, sodium current and T-type calcium current, which was not present in VMs. A computational model of the mouse PC was developed and simulations determined that unlike VMs, in PCs the presence of T-type calcium current was capable of prolonging APD. The second project of this dissertation investigated the remodeling of action potentials in atrial cells by free fatty acids (FAs), which has not been investigated in large mammals. This project used an ovine model to serve as a better surrogate of human cardiac structure, electrophysiology and metabolism. Current-clamp analysis of ovine left atrial (LA) myocytes exposed to each of the major FAs showed that only stearic acid (SA) altered LA APD at all values measured. Voltage-clamp recordings showed a ~60% and ~30% reduction of ICaL and ITO in SA-treated cells. Integration of the experimental data into a computational model of the human atrial action potential showed reduction of ICaL was sufficient to remodel LA APD. Reduction in ICaL in SA-treated cells was accompanied by disruption of transverse (t)-tubules, a membrane compartment in which calcium channels are predominantly located into microdomains, thus providing a novel mechanism of cellular remodeling by fatty acids. These two studies provide insight into ionic remodeling and importance of calcium currents in heterogeneity and alterations of the cardiac action potential.PHDMolecular and Integrative PhysiologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/107266/1/oconnelr_1.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/107266/2/oconnelr_2.pd

Sirolimus Enhances Cyclosporine A-Induced Cytotoxicity in Human Renal Glomerular Mesangial Cells

End Stage Renal Disease (ESRD) is an ever increasing problem worldwide. However the mechanisms underlying disease progression are not fully elucidated. This work addressed nephrotoxicity induced by the immunosuppressive agents' cyclosporine A (CsA) and sirolimus (SRL). Nephrotoxicity is the major limiting factor in long term use of CsA. SRL causes less nephrotoxicity than CsA. Therefore investigations into the differential effects of these agents may identify potential mechanisms of nephrotoxicity and means to prevent ESRD induced by therapeutic drugs. Using ELISA, Western blotting, quantitative PCR and a reporter gene assay we detailed the differential effects of CsA and SRL in human renal mesangial cells. CsA treatment increased profibrotic TGF-β1 secretion in human mesangial cells whereas SRL did not, indicating a role for TGF-β in CsA toxicity. However we observed a synergistic nephrotoxic effect when CsA and SRL were co-administered. These synergistic alterations may have been due to an increase in CTGF which was not evident when the immunosuppressive drugs were used alone. The CsA/SRL combination therapy significantly enhanced Smad signalling and altered the extracellular matrix regulator matrix metalloproteinase 9 (MMP-9). Inhibition of the ERK 1/2 pathway, attenuated these CsA/SRL induced alterations indicating a potentially significant role for this pathway

Association Between Drive-Through Mobile Vaccination Clinics and Neighborhood-Level Factors

ABSTRACT: Background: In Fall 2020, at the height of the COVID-19 pandemic, the importance of avoiding a simultaneous influenza and COVID-19 “twindemic” led to the implementation of socially distanced, drive-through mobile vaccination clinics. Mobile clinics have been valuable in providing primary and preventative care to underserved populations and expanding healthcare access to individuals marginalized by geographic, social, and structural barriers. Although there are ~2,000 mobile clinics throughout the United States and 120 mobile clinics providing services in California, few studies to date have evaluated neighborhood-level factors to determine whether social drivers of health (SDOH) influence the use of mobile drive-through clinics versus static clinics for immunizations. Methods: We conducted a retrospective cohort study of a total of 25,246 patients, 3,151 of whom received immunizations in 3 mobile clinics and 22,095 of whom received immunizations in 3 static clinics in Orange County from 8/1/2020 to 12/31/2020. Data were collected from patient charts on demographic characteristics. Age was stratified 0-21 years, 22-64 years, and 65 years and older. SDOH was measured using state-ranked Area Deprivation Index (ADI), a composite measure of 17 variables across income, education, employment, and housing domains by neighborhood/block group. ADI ranking was categorized into quintiles with higher ADI indices corresponding to greater levels of disadvantage. Chi-squared analysis was paired with logistic regression to examine potential associations. Significance was set at p &lt; 0.05. Statistical analysis was conducted using SPSS (version 28) The study was approved by our institution’s IRB. Results: A similar percentage of patients who identified as White attended the mobile and static clinics (60.3% and 66.8%, respectively), while a lesser percentage of patients who were &lt;60 years of age (60.3% vs 74.4%); identified as Hispanic (19.4% vs 58.8%); spoke Spanish (5.6% vs 33.7%); and were on public insurance (36.7% vs 74.9%) attended the mobile (vs static) clinics. Less likely to obtain vaccines through mobile clinics were those who identified as Black (OR 0.51; 95% CI 0.35, 0.75) relative to Caucasian patients, had public insurance (0.25; 0.23, 0.28) versus commercial insurance, and whose primary language was Spanish (0.29; 0.24, 0.35). Those greater than 65 years of age (7.04; 5.94, 8.34) compared to those under 21 years, and those identified as non-Hispanic (1.67; 1.44, 1.90) versus Hispanic were more likely to obtain their vaccines through the mobile clinic. Additionally, those who lived in the most disadvantaged neighborhoods were the least likely to obtain vaccines at the mobile clinic (0.67; 0.48, 0.93). Conclusions: The study demonstrates that patients who lived in more disadvantaged neighborhoods were less likely to seek vaccinations at mobile clinics. Additional work is needed to identify why the mobile influenza clinics were highly skewed towards those who lived in more advantaged areas

Coordination of tolerogenic immune responses by the commensal microbiota

All mammals are born ignorant to the existence of micro-organisms. Soon after birth, however, every mammal begins a lifelong association with a multitude of microbes that lay residence on the skin, mouth, vaginal mucosa and gastrointestinal (GI) tract. Approximately 500–1000 different species of microbes have highly evolved to occupy these bodily niches, with the highest density and diversity occurring within the intestine [1]. These organisms play a vital role in mammalian nutrient breakdown and provide resistance to colonization by pathogenic micro-organisms. More recently, however, studies have demonstrated that the microbiota can have a profound and long-lasting effect on the development of our immune system both inside and outside the intestine [2]. While our immune system has evolved to recognize and eradicate foreign entities, it tolerates the symbiotic micro-organisms of the intestine. How and why this tolerance occurs has remained unclear. Here we present evidence that the commensal microbes of the intestine actively induce tolerant responses from the host that coordinate healthy immune responses. Potentially, disruption of this dialogue between the host and microbe can lead to the development of autoimmune diseases such as inflammatory bowel disease (IBD), rheumatoid arthritis (RA), or Type I diabetes (TID). As a wealth of publications have focused on the impact of the microbiota on intestinal immune responses and IBD, this chapter will focus on the extra-intestinal impacts of the microbiota from development to disease and integrate the known mechanisms by which the microbiota is able to actively communicate with its host to promote health

Sustained expression of microRNA-155 in hematopoietic stem cells causes a myeloproliferative disorder

Mammalian microRNAs are emerging as key regulators of the development and function of the immune system. Here, we report a strong but transient induction of miR-155 in mouse bone marrow after injection of bacterial lipopolysaccharide (LPS) correlated with granulocyte/monocyte (GM) expansion. Demonstrating the sufficiency of miR-155 to drive GM expansion, enforced expression in mouse bone marrow cells caused GM proliferation in a manner reminiscent of LPS treatment. However, the miR-155–induced GM populations displayed pathological features characteristic of myeloid neoplasia. Of possible relevance to human disease, miR-155 was found to be overexpressed in the bone marrow of patients with certain subtypes of acute myeloid leukemia (AML). Furthermore, miR-155 repressed a subset of genes implicated in hematopoietic development and disease. These data implicate miR-155 as a contributor to physiological GM expansion during inflammation and to certain pathological features associated with AML, emphasizing the importance of proper miR-155 regulation in developing myeloid cells during times of inflammatory stress

Consensus mutagenesis reveals that non-helical regions influence thermal stability of horseradish peroxidase

The enzyme horseradish peroxidase has many uses in biotechnology but a stabilized derivative would have even wider applicability. To enhance thermal stability, we applied consensus mutagenesis (used successfully with other proteins) to recombinant horseradish peroxidase and generated five single-site mutants. Unexpectedly, these mutations had greater effects on steady-state kinetics than on thermal stability. Only two mutants (T102A, T110V) marginally exceeded the wild type's thermal stability (4% and 10% gain in half-life at 50 °C respectively); the others (Q106R, Q107D, I180F) were less stable than wild type. Stability of a five-fold combination mutant matched that of Q106R, the least-stable single mutant. These results were perplexing: the Class III plant peroxidases display wide differences in thermal stability, yet the consensus mutations failed to reflect these natural variations. We examined the sequence content of Class III peroxidases to determine if there are identifiable molecular reasons for the stability differences observed. Bioinformatic analysis validated our choice of sites and mutations and generated an archetypal peroxidase sequence for comparison with extant sequences. It seems that both genetic variation and differences in protein stability are confined to non-helical regions due to the presence of a highly conserved alpha-helical structural scaffold in these enzymes