Towards building data analytics benchmarks for IoT intrusion detection

Cluster Computing - Data analytics projects span all types of domains and applications. Researchers publish results using certain datasets and classification models. They present results with a...     

Novel homozygous mutations in the WNT10B gene underlying autosomal recessive split hand/foot malformation in three consanguineous families

Split-hand/split-foot malformation (SHFM), representing variable degree of median clefts of hands and feet, is a genetically heterogeneous group of limb malformations with seven loci mapped on different human chromosomes. However, only 3 genes (TP63, WNT10B, DLX5) for the seven loci have been identified.     

Pathogenic ACVR1R206H activation by Activin A‐induced receptor clustering and autophosphorylation

Fibrodysplasia ossificans progressiva (FOP) and diffuse intrinsic pontine glioma (DIPG) are debilitating diseases that share causal mutations in ACVR1, a TGF‐β family type I receptor. ACVR1^R206H is a frequent mutation in both diseases. Pathogenic signaling via the SMAD1/5 pathway is mediated by Activin A, but how the mutation triggers aberrant signaling is not known. We show that ACVR1 is essential for Activin A‐mediated SMAD1/5 phosphorylation and is activated by two distinct mechanisms. Wild‐type ACVR1 is activated by the Activin type I receptors, ACVR1B/C. In contrast, ACVR1^R206H activation does not require upstream kinases, but is predominantly activated via Activin A‐dependent receptor clustering, which induces its auto‐activation. We use optogenetics and live‐imaging approaches to demonstrate Activin A‐induced receptor clustering and show it requires the type II receptors ACVR2A/B. Our data provide molecular mechanistic insight into the pathogenesis of FOP and DIPG by linking the causal activating genetic mutation to disrupted signaling.     

Structure of MMACHC reveals an arginine-rich pocket and a domain-swapped dimer for its B12 processing function

Defects in the MMACHC gene represent the most common disorder of cobalamin (Cbl) metabolism, affecting synthesis of the enzyme cofactors adenosyl-Cbl and methyl-Cbl. The encoded MMACHC protein binds intracellular Cbl derivatives with different upper axial ligands and exhibits flavin mononucleotide (FMN)-dependent decyanase activity toward cyano-Cbl as well as glutathione (GSH)-dependent dealkylase activity toward alkyl-Cbls. We determined the structure of human MMACHC·adenosyl-Cbl complex, revealing a tailor-made nitroreductase scaffold which binds adenosyl-Cbl in a "base-off, five-coordinate" configuration for catalysis. We further identified an arginine-rich pocket close to the Cbl binding site responsible for GSH binding and dealkylation activity. Mutation of these highly conserved arginines, including a replication of the prevalent MMACHC missense mutation, Arg161Gln, disrupts GSH binding and dealkylation. We further showed that two Cbl-binding monomers dimerize to mediate the reciprocal exchange of a conserved "PNRRP" loop from both subunits, serving as a protein cap for the upper axial ligand in trans and required for proper dealkylation activity. Our dimeric structure is supported by solution studies, where dimerization is triggered upon binding its substrate adenosyl-Cbl or cofactor FMN. Together our data provide a structural framework to understanding catalytic function and disease mechanism for this multifunctional enzyme.     

Tissue engineering applications and stem cell approaches to the skin, nerves and blood vessels

Tissue engineering applies the principles of life sciences and engineering to the development of biological substitutes to restore, maintain or improve tissue function. Developments in this multidisciplinary field have yielded advances in the reconstruction of skin, peripheral nerves and blood vessels. In this review we highlight the fundamental principles and challenges of engineering products which can mimic both the structure and function of these tissues in their healthy state. We discuss the recent progress in the field with its implications for revolutionising healthcare in the future.     

Studies on the protective effect of dietary fish oil on gentamicin-induced nephrotoxicity and oxidative damage in rat kidney

Gentamicin (GM)-induced nephrotoxicity limits its long-term clinical use. Several agents/strategies were attempted to prevent GM nephrotoxicity but were not found suitable for clinical practice. Dietary fish oil (FO) retard the progression of certain types of cancers, cardiovascular and renal disorders. We aimed to evaluate protective effect of FO on GM-induced renal proximal tubular damage. The rats were pre-fed experimental diets for 10 days and then received GM (80 mg/kg body weight/day) treatment for 10 days while still on diet. Serum/urine parameters, enzymes of carbohydrate metabolism, brush border membrane (BBM), oxidative stress and phosphate transport in rat kidney were analyzed. GM nephrotoxicity was recorded by increased serum creatinine and blood urea nitrogen. GM increased the activities of lactate and glucose-6-phosphate dehydrogenases whereas decreased malate, isocitrate dehydrogenases; glucose-6 and fructose-1,6-bisphosphatases; superoxide dismutase, catalase, glutathione peroxidase and BBM enzymes. In contrast, FO alone increased enzyme activities of carbohydrate metabolism, BBM and oxidative stress. FO feeding to GM treated rats markedly enhanced resistance to GM elicited deleterious effects and prevented GM-induced decrease in 32Pi uptake across BBM. Dietary FO supplementation ameliorated GM-induced specific metabolic alterations and oxidative damage due to its intrinsic biochemical/antioxidant properties.     

The Role of Rac1 in the Growth Cone Dynamics and Force Generation of DRG Neurons

We used optical tweezers, video imaging, immunocytochemistry and a variety of inhibitors to analyze the role of Rac1 in the motility and force generation of lamellipodia and filopodia from developing growth cones of isolated Dorsal Root Ganglia neurons. When the activity of Rac1 was inhibited by the drug EHop-016, the period of lamellipodia protrusion/retraction cycles increased and the lamellipodia retrograde flow rate decreased; moreover, the axial force exerted by lamellipodia was reduced dramatically. Inhibition of Arp2/3 by a moderate amount of the drug CK-548 caused a transient retraction of lamellipodia followed by a complete recovery of their usual motility. This recovery was abolished by the concomitant inhibition of Rac1. The filopodia length increased upon inhibition of both Rac1 and Arp2/3, but the speed of filopodia protrusion increased when Rac1 was inhibited and decreased instead when Arp2/3 was inhibited. These results suggest that Rac1 acts as a switch that activates upon inhibition of Arp2/3. Rac1 also controls the filopodia dynamics necessary to explore the environment.     

A Subset of Cerebrospinal Fluid Proteins from a Multi-Analyte Panel Associated with Brain Atrophy,Disease Classification and Prediction in Alzheimer’s Disease

In this exploratory neuroimaging-proteomic study, we aimed to identify CSF proteins associated with AD and test their prognostic ability for disease classification and MCI to AD conversion prediction. Our study sample consisted of 295 subjects with CSF multi-analyte panel data and MRI at baseline downloaded from ADNI. Firstly, we tested the statistical effects of CSF proteins (n = 83) to measures of brain atrophy, CSF biomarkers, ApoE genotype and cognitive decline. We found that several proteins (primarily CgA and FABP) were related to either brain atrophy or CSF biomarkers. In relation to ApoE genotype, a unique biochemical profile characterised by low CSF levels of Apo E was evident in ε4 carriers compared to ε3 carriers. In an exploratory analysis, 3/83 proteins (SGOT, MCP-1, IL6r) were also found to be mildly associated with cognitive decline in MCI subjects over a 4-year period. Future studies are warranted to establish the validity of these proteins as prognostic factors for cognitive decline. For disease classification, a subset of proteins (n = 24) combined with MRI measurements and CSF biomarkers achieved an accuracy of 95.1% (Sensitivity 87.7%; Specificity 94.3%; AUC 0.95) and accurately detected 94.1% of MCI subjects progressing to AD at 12 months. The subset of proteins included FABP, CgA, MMP-2, and PPP as strong predictors in the model. Our findings suggest that the marker of panel of proteins identified here may be important candidates for improving the earlier detection of AD. Further targeted proteomic and longitudinal studies would be required to validate these findings with more generalisability.     

Antagonism of rat beta-cell voltage-dependent K+ currents by exendin 4 requires dual activation of the cAMP/protein kinase A and phosphatidylinositol 3-kinase signaling pathways

Antagonism of voltage-dependent K+ (Kv) currents in pancreatic beta-cells may contribute to the ability of glucagon-like peptide-1 (GLP-1) to stimulate insulin secretion. The mechanism and signaling pathway regulating these currents in rat beta-cells were investigated using the GLP-1 receptor agonist exendin 4. Inhibition of Kv currents resulted from a 20-mV leftward shift in the voltage dependence of steady-state inactivation. Blocking cAMP or protein kinase A (PKA) signaling (Rp-cAMP and H-89, respectively) prevented the inhibition of currents by exendin 4. However, direct activation of this pathway alone by intracellular dialysis of cAMP or the PKA catalytic subunit (cPKA) could not inhibit currents, implicating a role for alternative signaling pathways. A number of phosphorylation sites associated with phosphatidylinositol 3 (PI3)-kinase activation were up-regulated in GLP-1-treated MIN6 insulinoma cells, and the PI3 kinase inhibitor wortmannin could prevent antagonism of beta-cell currents by exendin 4. Antagonists of Src family kinases (PP1) and the epidermal growth factor (EGF) receptor (AG1478) also prevented current inhibition by exendin 4, demonstrating a role for Src kinase-mediated trans-activation of the EGF tyrosine kinase receptor. Accordingly, the EGF receptor agonist betacellulin could replicate the effects of exendin 4 in the presence of elevated intracellular cAMP. Downstream, the PKCzeta pseudosubstrate inhibitor could prevent current inhibition by exendin 4. Therefore, antagonism of beta-cell Kv currents by GLP-1 receptor activation requires both cAMP/PKA and PI3 kinase/PKCzeta signaling via trans-activation of the EGF receptor. This represents a novel dual pathway for the control of Kv currents by G protein-coupled receptors.     

Expression of VHIII-associated cross-reactive idiotype on human B lymphocytes. Association with staphylococcal protein A binding and Staphylococcus aureus Cowan I stimulation.

It has been demonstrated that staphylococcal protein A (SPA) has an "alternative" binding site with specificity for human Ig H chain V region of the VHIII subgroup. Because the major mitogenic component of Staphylococcus aureus Cowan I (SAC) is SPA, it is possible that SAC stimulates a subpopulation of B cells expressing Ig of the VHIII H chain subgroup. In the present study, we have investigated further the relationship between SPA binding and the expression of VHI- or VHIII-associated cross-reactive idiotype (CRI) on the surface of tonsillar B lymphocytes enriched for the expression or nonexpression of the CRI, and we examined the Ig secreted by cell lines established from these populations of B cells by EBV transformation. The VHIII CRI (D12)-enriched population yielded 21 cell lines, with 67% of them secreting SPA-reactive Ig; in contrast, only 6% (1 of 16) of VHI CRI-expressing lines secreted SPA-reactive Ig. The CRI-negative B cell population yielded 54 cell lines, of which 20% secreted SPA-reactive Ig, as might be anticipated because a majority of VHIII Ig+ B cells will be CRI-. SAC stimulation of CRI+ and CRI- populations showed preferential stimulation of the D12 population. These data support the proposal that SAC stimulation of human B cells is mediated through binding of SPA by its alternative binding site to IgV regions of the VHIII subgroup.