Opticin: a potent anti-angiogenic/antiproliferative agent for breast cancer therapy

No abstract available

The Glasgow-Maastricht foot model, evaluation of a 26 segment kinematic model of the foot

BACKGROUND: Accurately measuring of intrinsic foot kinematics using skin mounted markers is difficult, limited in part by the physical dimensions of the foot. Existing kinematic foot models solve this problem by combining multiple bones into idealized rigid segments. This study presents a novel foot model that allows the motion of the 26 bones to be individually estimated via a combination of partial joint constraints and coupling the motion of separate joints using kinematic rhythms. METHODS: Segmented CT data from one healthy subject was used to create a template Glasgow-Maastricht foot model (GM-model). Following this, the template was scaled to produce subject-specific models for five additional healthy participants using a surface scan of the foot and ankle. Forty-three skin mounted markers, mainly positioned around the foot and ankle, were used to capture the stance phase of the right foot of the six healthy participants during walking. The GM-model was then applied to calculate the intrinsic foot kinematics. RESULTS: Distinct motion patterns where found for all joints. The variability in outcome depended on the location of the joint, with reasonable results for sagittal plane motions and poor results for transverse plane motions. CONCLUSIONS: The results of the GM-model were comparable with existing literature, including bone pin studies, with respect to the range of motion, motion pattern and timing of the motion in the studied joints. This novel model is the most complete kinematic model to date. Further evaluation of the model is warranted

Direct correction of haemoglobin E β-thalassaemia using base editors

Haemoglobin E (HbE) β-thalassaemia causes approximately 50% of all severe thalassaemia worldwide; equating to around 30,000 births per year. HbE β-thalassaemia is due to a point mutation in codon 26 of the human HBB gene on one allele (GAG; glutamatic acid → AAG; lysine, E26K), and any mutation causing severe β-thalassaemia on the other. When inherited together in compound heterozygosity these mutations can cause a severe thalassaemic phenotype. However, if only one allele is mutated individuals are carriers for the respective mutation and have an asymptomatic phenotype (β-thalassaemia trait). Here we describe a base editing strategy which corrects the HbE mutation either to wildtype (WT) or a normal variant haemoglobin (E26G) known as Hb Aubenas and thereby recreates the asymptomatic trait phenotype. We have achieved editing efficiencies in excess of 90% in primary human CD34 + cells. We demonstrate editing of long-term repopulating haematopoietic stem cells (LT-HSCs) using serial xenotransplantation in NSG mice. We have profiled the off-target effects using a combination of circularization for in vitro reporting of cleavage effects by sequencing (CIRCLE-seq) and deep targeted capture and have developed machine-learning based methods to predict functional effects of candidate off-target mutations

On improvement in ejection fraction with iron chelation in thalassemia major and the risk of future heart failure

<p>Abstract</p> <p>Background</p> <p>Trials of iron chelator regimens have increased the treatment options for cardiac siderosis in beta-thalassemia major (TM) patients. Treatment effects with improved left ventricular (LV) ejection fraction (EF) have been observed in patients without overt heart failure, but it is unclear whether these changes are clinically meaningful.</p> <p>Methods</p> <p>This retrospective study of a UK database of TM patients modelled the change in EF between serial scans measured by cardiovascular magnetic resonance (CMR) to the relative risk (RR) of future development of heart failure over 1 year. Patients were divided into 2 strata by baseline LVEF of 56-62% (below normal for TM) and 63-70% (lower half of the normal range for TM).</p> <p>Results</p> <p>A total of 315 patients with 754 CMR scans were analyzed. A 1% absolute increase in EF from baseline was associated with a statistically significant reduction in the risk of future development of heart failure for both the lower EF stratum (EF 56-62%, RR 0.818, p < 0.001) and the higher EF stratum (EF 63-70%, RR 0.893 p = 0.001).</p> <p>Conclusion</p> <p>These data show that during treatment with iron chelators for cardiac siderosis, small increases in LVEF in TM patients are associated with a significantly reduced risk of the development of heart failure. Thus the iron chelator induced improvements in LVEF of 2.6% to 3.1% that have been observed in randomized controlled trials, are associated with risk reductions of 25.5% to 46.4% for the development of heart failure over 12 months, which is clinically meaningful. In cardiac iron overload, heart mitochondrial dysfunction and its relief by iron chelation may underlie the changes in LV function.</p

Within-Host Dynamics of Multi-Species Infections: Facilitation, Competition and Virulence

Host individuals are often infected with more than one parasite species (parasites defined broadly, to include viruses and bacteria). Yet, research in infection biology is dominated by studies on single-parasite infections. A focus on single-parasite infections is justified if the interactions among parasites are additive, however increasing evidence points to non-additive interactions being the norm. Here we review this evidence and theoretically explore the implications of non-additive interactions between co-infecting parasites. We use classic Lotka-Volterra two-species competition equations to investigate the within-host dynamical consequences of various mixes of competition and facilitation between a pair of co-infecting species. We then consider the implications of these dynamics for the virulence (damage to host) of co-infections and consequent evolution of parasite strategies of exploitation. We find that whereas one-way facilitation poses some increased virulence risk, reciprocal facilitation presents a qualitatively distinct destabilization of within-host dynamics and the greatest risk of severe disease

Fine-Scale Variation in Vector Host Use and Force of Infection Drive Localized Patterns of West Nile Virus Transmission

The influence of host diversity on multi-host pathogen transmission and persistence can be confounded by the large number of species and biological interactions that can characterize many transmission systems. For vector-borne pathogens, the composition of host communities has been hypothesized to affect transmission; however, the specific characteristics of host communities that affect transmission remain largely unknown. We tested the hypothesis that vector host use and force of infection (i.e., the summed number of infectious mosquitoes resulting from feeding upon each vertebrate host within a community of hosts), and not simply host diversity or richness, determine local infection rates of West Nile virus (WNV) in mosquito vectors. In suburban Chicago, Illinois, USA, we estimated community force of infection for West Nile virus using data on Culex pipiens mosquito host selection and WNV vertebrate reservoir competence for each host species in multiple residential and semi-natural study sites. We found host community force of infection interacted with avian diversity to influence WNV infection in Culex mosquitoes across the study area. Two avian species, the American robin (Turdus migratorius) and the house sparrow (Passer domesticus), produced 95.8% of the infectious Cx. pipiens mosquitoes and showed a significant positive association with WNV infection in Culex spp. mosquitoes. Therefore, indices of community structure, such as species diversity or richness, may not be reliable indicators of transmission risk at fine spatial scales in vector-borne disease systems. Rather, robust assessment of local transmission risk should incorporate heterogeneity in vector host feeding and variation in vertebrate reservoir competence at the spatial scale of vector-host interaction

Nucleo-cytoplasmic transport of proteins and RNA in plants

Merkle T. Nucleo-cytoplasmic transport of proteins and RNA in plants. Plant Cell Reports. 2011;30(2):153-176.Transport of macromolecules between the nucleus and the cytoplasm is an essential necessity in eukaryotic cells, since the nuclear envelope separates transcription from translation. In the past few years, an increasing number of components of the plant nuclear transport machinery have been characterised. This progress, although far from being completed, confirmed that the general characteristics of nuclear transport are conserved between plants and other organisms. However, plant-specific components were also identified. Interestingly, several mutants in genes encoding components of the plant nuclear transport machinery were investigated, revealing differential sensitivity of plant-specific pathways to impaired nuclear transport. These findings attracted attention towards plant-specific cargoes that are transported over the nuclear envelope, unravelling connections between nuclear transport and components of signalling and developmental pathways. The current state of research in plants is summarised in comparison to yeast and vertebrate systems, and special emphasis is given to plant nuclear transport mutants