LKB1 Destabilizes Microtubules in Myoblasts and Contributes to Myoblast Differentiation

Background: Skeletal muscle myoblast differentiation and fusion into multinucleate myotubes is associated with dramatic cytoskeletal changes. We find that microtubules in differentiated myotubes are highly stabilized, but premature microtubule stabilization blocks differentiation. Factors responsible for microtubule destabilization in myoblasts have not been identified. Findings: We find that a transient decrease in microtubule stabilization early during myoblast differentiation precedes the ultimate microtubule stabilization seen in differentiated myotubes. We report a role for the serine-threonine kinase LKB1 in both microtubule destabilization and myoblast differentiation. LKB1 overexpression reduced microtubule elongation in a Nocodazole washout assay, and LKB1 RNAi increased it, showing LKB1 destabilizes microtubule assembly in myoblasts. LKB1 levels and activity increased during myoblast differentiation, along with activation of the known LKB1 substrates AMPactivated protein kinase (AMPK) and microtubule affinity regulating kinases (MARKs). LKB1 overexpression accelerated differentiation, whereas RNAi impaired it. Conclusions: Reduced microtubule stability precedes myoblast differentiation and the associated ultimate microtubule stabilization seen in myotubes. LKB1 plays a positive role in microtubule destabilization in myoblasts and in myoblast differentiation. This work suggests a model by which LKB1-induced microtubule destabilization facilitates the cytoskeleta

Compensatory Paracrine Mechanisms That Define The Urothelial Response to Injury in Partial Bladder Outlet Obstruction

Diseases and conditions affecting the lower urinary tract are a leading cause of dysfunctional sexual health, incontinence, infection, and kidney failure. The growth, differentiation, and repair of the bladder's epithelial lining are regulated, in part, by fibroblast growth factor (FGF)-7 and -10 via a paracrine cascade originating in the mesenchyme (lamina propria) and targeting the receptor for FGF-7 and -10 within the transitional epithelium (urothelium). The FGF-7 gene is located at the 15q15-q21.1 locus on chromosome 15 and four exons generate a 3.852-kb mRNA. Five duplicated FGF-7 gene sequences that localized to chromosome 9 were predicted not to generate functional protein products, thus validating the use of FGF-7-null mice as an experimental model. Recombinant FGF-7 and -10 induced proliferation of human urothelial cells in vitro and transitional epithelium of wild-type and FGF-7-null mice in vivo.To determine the extent that induction of urothelial cell proliferation during the bladder response to injury is dependent on FGF-7, an animal model of partial bladder outlet obstruction was developed. Unbiased stereology was used to measure the percentage of proliferating urothelial cells between obstructed groups of wild-type and FGF-7-null mice. The stereological analysis indicated that a statistical significant difference did not exist between the two groups, suggesting that FGF-7 is not essential for urothelial cell proliferation in response to partial outlet obstruction. In contrast, a significant increase in FGF-10 expression was observed in the obstructed FGF-7-null group, indicating that the compensatory pathway that functions in this model results in urothelial repair

Phosphorylation of Nicastrin by SGK1 Leads to Its Degradation through Lysosomal and Proteasomal Pathways

The gamma-secretase complex is involved in the intramembranous proteolysis of a variety of substrates, including the amyloid precursor protein and the Notch receptor. Nicastrin (NCT) is an essential component of the gamma-secretase complex and functions as a receptor for gamma-secretase substrates. In this study, we determined that serum- and glucocorticoid-induced protein kinase 1 (SGK1) markedly reduced the protein stability of NCT. The SGK1 kinase activity was decisive for NCT degradation and endogenous SGK1 inhibited gamma-secretase activity. SGK1 downregulates NCT protein levels via proteasomal and lysosomal pathways. Furthermore, SGK1 directly bound to and phosphorylated NCT on Ser437, thereby promoting protein degradation. Collectively, our findings indicate that SGK1 is a gamma-secretase regulator presumably effective through phosphorylation and degradation of NCT

Improving heart failure care and guideline-directed medical therapy through proactive remote patient monitoring-home telehealth and pharmacy integration.

To address ambulatory care sensitive hospitalisations in heart failure (HF), we implemented a quality improvement initiative to reduce admissions and improve guideline-directed medical therapy (GDMT) prescription, through proactive integration of remote patient monitoring-home telehealth (RPM-HT) and pharmacist consultations. Each enrolled patient (n=38) was assigned an RPM-HT registered nurse (RN), cardiology licensed independent provider (provider), and, if referred, a clinical pharmacy specialist (pharmacist). The RN called patients weekly and for changes detected by RPM-HT, while the pharmacist worked to optimise GDMT. The RN and pharmacist communicated clinical status changes to the provider for expedited management. Process measures were the percentage of outbound RN weekly calls missed per enrolled patient; the weekly percentage of provider interventions missed; and the number of initiative-driven diuretic changes. Outcome measures included eligible GDMT medications prescribed, optimisation of those medications, and the pre-post difference in emergency department (ED) visits/hospitalisations. After a 4-week run-in period, RN weekly calls missed per enrolled patient decreased from a mean of 21.4% (weeks 5-15) to 10.2% (weeks 16-23). Weekly missed provider interventions decreased from a mean of 15.1% (weeks 1-15) to 3.4% (weeks 16-23), with special cause variation detected. The initiative resulted in 43 diuretic changes in 21 patients. Among 34 active patients, 65 ED visits (0.16 per person-month) occurred in 12 months pre intervention compared with 8 ED visits (0.04 per person-month) for 6 intervention months (p<0.001). Among 16 patients referred to pharmacist, the per cent of eligible GDMT medications prescribed increased by 17.1% (p<0.001); the number of patients receiving all eligible medications increased from 3 to 11 (p=0.008). Similarly, the per cent optimisation of GDMT doses increased by 25.3% (p<0.001), with the number of patients maximally optimised on GDMT increasing from 1 to 6 (p=0.06). We concluded that a cardiology, RPM-HT RN and pharmacist team improved prescription of GDMT and may have reduced HF admissions

Beginning with the Seventies

"Looking at the relationship between art, archives and activism, the Beginning with the Seventies publication begins with the 1970s, an era when social movements – feminism, environmentalism, LGBTQ2SIA+ rights, Indigenous rights, access to health services and housing – began to coalesce into models of self-organization that overlapped with the production of art and culture." -- Publisher's website

Possible basis for the emergence of H1N1 viruses with pandemic potential from avian hosts

Influenza A viruses of the H1N1 subtype have emerged from the avian influenza gene pool in aquatic birds and caused human pandemics at least twice during the past century. Despite this fact, surprisingly little is known about the H1N1 gene pool in the aquatic bird reservoir. A preliminary study showed that an H1N1 virus from a shorebird of the Charadriiformes order was transmitted between animals through the airborne route of infection, whereas an H1N1 virus from a bird of the Anseriformes order was not. Here we show that two of the three H1N1 viruses isolated from Charadriiformes species in 2009 were transmitted between animals through the airborne route of infection, and five H1N1 isolates from Anseriformes species were not. The one H1N1 virus from a Charadriiformes species that failed to transmit through the airborne route was a reassortant possessing multiple internal gene segments from Anseriformes species. The molecular differences between the airborne-transmissible and non-airborne-transmissible H1N1 viruses were multigenic, involving the selection of virus with human-like receptor-binding specificity (α2-6 sialic acid) and multiple differences in the polymerase complex, mainly in the PB2, PB1-F2, and nonstructural genes

MP00-75 The 2000-2001 Nebraska Poultry Report

The Nebraska Poultry Report is produced every two years by the Animal Science Department\u27s poultry faculty with contributions from others in the University of Nebraska who work with avian species. The purpose of the report is to make our activities known to the poultry industries in Nebraska. The majority of articles are based on on-going research but are written in a relaxed style for ease of reading