Activity-Based Therapy in a Community Setting for Independence, Mobility, and Sitting Balance for People With Spinal Cord Injuries.

Introduction: Activity-based therapy (ABT) aims to activate the neuromuscular system below the level of the spinal cord lesion and promote recovery of motor tasks through spinal reorganisation, motor learning and changes to muscles and sensory system. We investigated the effects of a multimodal ABT program on mobility, independence and sitting balance in individuals with spinal cord injury (SCI). Methods: Retrospective clinical data from 91 adults who independently enrolled in four community-based ABT centres in Australia were analysed. The multimodal ABT program was delivered for 3 to 12 months, one to four times per week. Assessments were undertaken every 3 months and included the Modified Rivermead Mobility Index (MRMI), Spinal Cord Independence Measure (SCIM) and seated reach distance (SRD). A linear mixed model analysis was used to determine time-based and other predictors of change. Results: There was a significant improvement after 12 months for all outcome measures, with a mean change score of 4 points in the SCIM (95% confidence interval [CI]: 2.7-5.3, d = 0.19), 2 points in the MRMI (95% CI: 1-2.3, d = 0.19) and 0.2 in the SRD (95% CI: 0.1-2.2, d = 0.52). Greater improvements occurred in the first 3 months of intervention. There were no interaction effects between time and the neurological level of injury, American Spinal Injury Association Impairment Scale classification, or duration post-injury for most outcomes. Conclusions: A community-based ABT exercise program for people with SCI can lead to small improvements in mobility, independence and balance in sitting, with greater improvements occurring early during intervention

Investigating the Responses of Human Epithelial Cells to Predatory Bacteria

One beguiling alternative to antibiotics for treating multi-drug resistant infections are Bdellovibrio-and-like-organisms (BALOs), predatory bacteria known to attack human pathogens. Consequently, in this study, the responses from four cell lines (three human and one mouse) were characterized during an exposure to different predatory bacteria, Bdellovibrio bacteriovorus HD100, Bacteriovorus BY1 and Bacteriovorax stolpii EB1. TNF-alpha levels were induced in Raw 264.7 mouse macrophage cultures with each predator, but paled in comparison to those obtained with E. coli. This was true even though the latter strain was added at an 11.1-fold lower concentration (p < 0.01). Likewise, E. coli led to a significant (54%) loss in the Raw 264.7 murine macrophage viability while the predatory strains had no impact. Tests with various epithelial cells, including NuLi-1 airway, Caco2, HT29 and T84 colorectal cells, gave similar results, with E. coli inducing IL-8 production. The viabilities of the NuLi-1 and Caco-2 cells were slightly reduced (8%) when exposed to the predators, while T84 viability remained steady. In no cases did the predatory bacteria induce actin rearrangement. These results clearly demonstrate the gentle natures of predatory bacteria and their impacts on human cells.ope

The Drosophila neural lineages: a model system to study brain development and circuitry

In Drosophila, neurons of the central nervous system are grouped into units called lineages. Each lineage contains cells derived from a single neuroblast. Due to its clonal nature, the Drosophila brain is a valuable model system to study neuron development and circuit formation. To better understand the mechanisms underlying brain development, genetic manipulation tools can be utilized within lineages to visualize, knock down, or over-express proteins. Here, we will introduce the formation and development of lineages, discuss how one can utilize this model system, offer a comprehensive list of known lineages and their respective markers, and then briefly review studies that have utilized Drosophila neural lineages with a look at how this model system can benefit future endeavors

β-defensin 1 expression in HCV infected liver/liver cancer: an important role in protecting HCV progression and liver cancer development

Abstract β-defensin family plays a role in host defense against viral infection, however its role in HCV infection is still unknown. In this study, we demonstrated that β-defensin 1 was significantly reduced in HCV-infected liver specimens. Treatment with interferon and ribavirin upregulated β-defensin-1, but not other β-defensin tested, with the extent and duration of upregulation associated with treatment response. We investigated β-defensin family expression in liver cancer in publicly available datasets and found that among all the β-defensins tested, only β-defensin 1 was significantly downregulated, suggesting β-defensin 1 plays a crucial role in liver cancer development. Further analysis identified E-cadherin as the top positive correlated gene, while hepatocyte growth factor-regulated tyrosine kinase substrate as the top negative correlated gene. Expression of two proteoglycans were also positively correlated with that of β-defensin 1. We have also identified small molecules as potential therapeutic agents to reverse β-defensin 1-associated gene signature. Furthermore, the downregulation of β-defensin 1 and E-cadherin, and upregulation of hepatocyte growth factor-regulated tyrosine kinase substrate, were further confirmed in liver cancer and adjacent normal tissue collected from in-house Chinese liver cancer patients. Together, our results suggest β-defensin 1 plays an important role in protecting HCV progression and liver cancer development

Characterisation of the opposing effects of G6PD deficiency on cerebral malaria and severe malarial anaemia.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is believed to confer protection against Plasmodium falciparum malaria, but the precise nature of the protective effecthas proved difficult to define as G6PD deficiency has multiple allelic variants with different effects in males and females, and it has heterogeneous effects on the clinical outcome of P. falciparum infection. Here we report an analysis of multiple allelic forms of G6PD deficiency in a large multi-centre case-control study of severe malaria, using the WHO classification of G6PD mutations to estimate each individual's level of enzyme activity from their genotype. Aggregated across all genotypes, we find that increasing levels of G6PD deficiency are associated with decreasing risk of cerebral malaria, but with increased risk of severe malarial anaemia. Models of balancing selection based on these findings indicate that an evolutionary trade-off between different clinical outcomes of P. falciparum infection could have been a major cause of the high levels of G6PD polymorphism seen in human populations

Small molecules, big targets: drug discovery faces the protein-protein interaction challenge.

Protein-protein interactions (PPIs) are of pivotal importance in the regulation of biological systems and are consequently implicated in the development of disease states. Recent work has begun to show that, with the right tools, certain classes of PPI can yield to the efforts of medicinal chemists to develop inhibitors, and the first PPI inhibitors have reached clinical development. In this Review, we describe the research leading to these breakthroughs and highlight the existence of groups of structurally related PPIs within the PPI target class. For each of these groups, we use examples of successful discovery efforts to illustrate the research strategies that have proved most useful.JS, DES and ARB thank the Wellcome Trust for funding.This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/nrd.2016.2

Asymmetric and symmetric stem-cell divisions in development and cancer

Much has been made of the idea that asymmetric cell division is a defining characteristic of stem cells that enables them to simultaneously perpetuate themselves (self-renew) and generate differentiated progeny. Yet many stem cells can divide symmetrically, particularly when they are expanding in number during development or after injury. Thus, asymmetric division is not necessary for stem-cell identity but rather is a tool that stem cells can use to maintain appropriate numbers of progeny. The facultative use of symmetric or asymmetric divisions by stem cells may be a key adaptation that is crucial for adult regenerative capacity.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/62868/1/nature04956.pd

A Novel Function of DELTA-NOTCH Signalling Mediates the Transition from Proliferation to Neurogenesis in Neural Progenitor Cells

A complete account of the whole developmental process of neurogenesis involves understanding a number of complex underlying molecular processes. Among them, those that govern the crucial transition from proliferative (self-replicating) to neurogenic neural progenitor (NP) cells remain largely unknown. Due to its sequential rostro-caudal gradients of proliferation and neurogenesis, the prospective spinal cord of the chick embryo is a good experimental system to study this issue. We report that the NOTCH ligand DELTA-1 is expressed in scattered cycling NP cells in the prospective chick spinal cord preceding the onset of neurogenesis. These Delta-1-expressing progenitors are placed in between the proliferating caudal neural plate (stem zone) and the rostral neurogenic zone (NZ) where neurons are born. Thus, these Delta-1-expressing progenitors define a proliferation to neurogenesis transition zone (PNTZ). Gain and loss of function experiments carried by electroporation demonstrate that the expression of Delta-1 in individual progenitors of the PNTZ is necessary and sufficient to induce neuronal generation. The activation of NOTCH signalling by DELTA-1 in the adjacent progenitors inhibits neurogenesis and is required to maintain proliferation. However, rather than inducing cell cycle exit and neuronal differentiation by a typical lateral inhibition mechanism as in the NZ, DELTA-1/NOTCH signalling functions in a distinct manner in the PNTZ. Thus, the inhibition of NOTCH signalling arrests proliferation but it is not sufficient to elicit neuronal differentiation. Moreover, after the expression of Delta-1 PNTZ NP continue cycling and induce the expression of Tis21, a gene that is upregulated in neurogenic progenitors, before generating neurons. Together, these experiments unravel a novel function of DELTA–NOTCH signalling that regulates the transition from proliferation to neurogenesis in NP cells. We hypothesize that this novel function is evolutionary conserved