Target product profiles for protecting against outdoor malaria transmission.

BACKGROUND\ud \ud Long-lasting insecticidal nets (LLINs) and indoor residual sprays (IRS) have decimated malaria transmission by killing indoor-feeding mosquitoes. However, complete elimination of malaria transmission with these proven methods is confounded by vectors that evade pesticide contact by feeding outdoors.\ud \ud METHODS\ud \ud For any assumed level of indoor coverage and personal protective efficacy with insecticidal products, process-explicit malaria transmission models suggest that insecticides that repel mosquitoes will achieve less impact upon transmission than those that kill them outright. Here such models are extended to explore how outdoor use of products containing either contact toxins or spatial repellents might augment or attenuate impact of high indoor coverage of LLINs relying primarily upon contact toxicity.\ud \ud RESULTS\ud \ud LLIN impact could be dramatically enhanced by high coverage with spatial repellents conferring near-complete personal protection, but only if combined indoor use of both measures can be avoided where vectors persist that prefer feeding indoors upon humans. While very high levels of coverage and efficacy will be required for spatial repellents to substantially augment the impact of LLINs or IRS, these ambitious targets may well be at least as practically achievable as the lower requirements for equivalent impact using contact insecticides.\ud \ud CONCLUSIONS\ud \ud Vapour-phase repellents may be more acceptable, practical and effective than contact insecticides for preventing outdoor malaria transmission because they need not be applied to skin or clothing and may protect multiple occupants of spaces outside of treatable structures such as nets or houses

Very Late Antigen-4 (α<inf>4</inf>β<inf>1</inf> Integrin) Targeted PET Imaging of Multiple Myeloma

Biomedical imaging techniques such as skeletal survey and 18F-fluorodeoxyglucose (FDG)/Positron Emission Tomography (PET) are frequently used to diagnose and stage multiple myeloma (MM) patients. However, skeletal survey has limited sensitivity as it can detect osteolytic lesions only after 30-50% cortical bone destruction, and FDG is a marker of cell metabolism that has limited sensitivity for intramedullary lesions in MM. Targeted, and non-invasive novel probes are needed to sensitively and selectively image the unique molecular signatures and cellular processes associated with MM. Very late antigen-4 (VLA-4; also called α4β1 integrin) is over-expressed on MM cells, and is one of the key mediators of myeloma cell adhesion to the bone marrow (BM) that promotes MM cell trafficking and drug resistance. Here we describe a proof-of-principle, novel molecular imaging strategy for MM tumors using a VLA-4 targeted PET radiopharmaceutical, 64Cu-CB-TE1A1P-LLP2A. Cell uptake studies in a VLA-4-positive murine MM cell line, 5TGM1, demonstrated receptor specific uptake (P<0.0001, block vs. non-block). Tissue biodistribution at 2 h of 64Cu-CB-TE1A1P-LLP2A in 5TGM1 tumor bearing syngeneic KaLwRij mice demonstrated high radiotracer uptake in the tumor (12±4.5%ID/g), and in the VLA-4 rich organs, spleen (8.8±1.0%ID/g) and marrow (11.6±2.0%ID/g). Small animal PET/CT imaging with 64Cu-CB-TE1A1P-LLP2A demonstrated high uptake in the 5TGM1 tumors (SUV 6.6±1.1). There was a 3-fold reduction in the in vivo tumor uptake in the presence of blocking agent (2.3±0.4). Additionally, 64Cu-CB-TE1A1P-LLP2A demonstrated high binding to the human MM cell line RPMI-8226 that was significantly reduced in the presence of the cold targeting agent. These results provide pre-clinical evidence that VLA-4-targeted imaging using 64Cu-CB-TE1A1P-LLP2A is a novel approach to imaging MM tumors. © 2013 Soodgupta et al

A Complete Pathway Model for Lipid A Biosynthesis in Escherichia coli.

Lipid A is a highly conserved component of lipopolysaccharide (LPS), itself a major component of the outer membrane of Gram-negative bacteria. Lipid A is essential to cells and elicits a strong immune response from humans and other animals. We developed a quantitative model of the nine enzyme-catalyzed steps of Escherichia coli lipid A biosynthesis, drawing parameters from the experimental literature. This model accounts for biosynthesis regulation, which occurs through regulated degradation of the LpxC and WaaA (also called KdtA) enzymes. The LpxC degradation signal appears to arise from the lipid A disaccharide concentration, which we deduced from prior results, model results, and new LpxK overexpression results. The model agrees reasonably well with many experimental findings, including the lipid A production rate, the behaviors of mutants with defective LpxA enzymes, correlations between LpxC half-lives and cell generation times, and the effects of LpxK overexpression on LpxC concentrations. Its predictions also differ from some experimental results, which suggest modifications to the current understanding of the lipid A pathway, such as the possibility that LpxD can replace LpxA and that there may be metabolic channeling between LpxH and LpxB. The model shows that WaaA regulation may serve to regulate the lipid A production rate when the 3-deoxy-D-manno-oct-2-ulosonic acid (KDO) concentration is low and/or to control the number of KDO residues that get attached to lipid A. Computation of flux control coefficients showed that LpxC is the rate-limiting enzyme if pathway regulation is ignored, but that LpxK is the rate-limiting enzyme if pathway regulation is present, as it is in real cells. Control also shifts to other enzymes if the pathway substrate concentrations are not in excess. Based on these results, we suggest that LpxK may be a much better drug target than LpxC, which has been pursued most often

The comparative osmoregulatory ability of two water beetle genera whose species span the fresh-hypersaline gradient in inland waters (Coleoptera: Dytiscidae, Hydrophilidae).

A better knowledge of the physiological basis of salinity tolerance is essential to understanding the ecology and evolutionary history of organisms that have colonized inland saline waters. Coleoptera are amongst the most diverse macroinvertebrates in inland waters, including saline habitats; however, the osmoregulatory strategies they employ to deal with osmotic stress remain unexplored. Survival and haemolymph osmotic concentration at different salinities were examined in adults of eight aquatic beetle species which inhabit different parts of the fresh-hypersaline gradient. Studied species belong to two unrelated genera which have invaded saline waters independently from freshwater ancestors; Nebrioporus (Dytiscidae) and Enochrus (Hydrophilidae). Their osmoregulatory strategy (osmoconformity or osmoregulation) was identified and osmotic capacity (the osmotic gradient between the animal's haemolymph and the external medium) was compared between species pairs co-habiting similar salinities in nature. We show that osmoregulatory capacity, rather than osmoconformity, has evolved independently in these different lineages. All species hyperegulated their haemolymph osmotic concentration in diluted waters; those living in fresh or low-salinity waters were unable to hyporegulate and survive in hyperosmotic media (> 340 mosmol kg(-1)). In contrast, the species which inhabit the hypo-hypersaline habitats were effective hyporegulators, maintaining their haemolymph osmolality within narrow limits (ca. 300 mosmol kg(-1)) across a wide range of external concentrations. The hypersaline species N. ceresyi and E. jesusarribasi tolerated conductivities up to 140 and 180 mS cm(-1), respectively, and maintained osmotic gradients over 3500 mosmol kg(-1), comparable to those of the most effective insect osmoregulators known to date. Syntopic species of both genera showed similar osmotic capacities and in general, osmotic responses correlated well with upper salinity levels occupied by individual species in nature. Therefore, osmoregulatory capacity may mediate habitat segregation amongst congeners across the salinity gradient

The genomic landscape of cutaneous SCC reveals drivers and a novel azathioprine associated mutational signature

Cutaneous squamous cell carcinoma (cSCC) has a high tumour mutational burden (50 mutations per megabase DNA pair). Here, we combine whole-exome analyses from 40 primary cSCC tumours, comprising 20 well-differentiated and 20 moderately/poorly differentiated tumours, with accompanying clinical data from a longitudinal study of immunosuppressed and immunocompetent patients and integrate this analysis with independent gene expression studies. We identify commonly mutated genes, copy number changes and altered pathways and processes. Comparisons with tumour differentiation status suggest events which may drive disease progression. Mutational signature analysis reveals the presence of a novel signature (signature 32), whose incidence correlates with chronic exposure to the immunosuppressive drug azathioprine. Characterisation of a panel of 15 cSCC tumour-derived cell lines reveals that they accurately reflect the mutational signatures and genomic alterations of primary tumours and provide a valuable resource for the validation of tumour drivers and therapeutic targets

The individual environment, not the family is the most important influence on preferences for common non-alcoholic beverages in adolescence

Beverage preferences are an important driver of consumption, and strong liking for beverages high in energy (e.g. sugar-sweetened beverages [SSBs]) and dislike for beverages low in energy (e.g. non-nutritive sweetened beverages [NNSBs]) are potentially modifiable risk factors contributing to variation in intake. Twin studies have established that both genes and environment play important roles in shaping food preferences; but the aetiology of variation in non-alcoholic beverage preferences is unknown. 2865 adolescent twins (18–19-years old) from the Twins Early Development Study were used to quantify genetic and environmental influence on variation in liking for seven non-alcoholic beverages: SSBs; NNSBs; fruit cordials, orange juice, milk, coffee, and tea. Maximum Likelihood Structural Equation Modelling established that beverage preferences have a moderate to low genetic basis; from 18% (95% CI: 10%, 25%) for orange juice to 42% (36%, 43%) for fruit cordials. Aspects of the environment that are not shared by twin pairs explained all remaining variance in drink preferences. The sizeable unique environmental influence on beverage preferences highlights the potential for environmental modification. Policies and guidelines to change preferences for unhealthy beverages may therefore be best directed at the wider environment

Behind the confession: Relating false confession, interrogative compliance, personality traits, and psychopathy

The present study further supports the established notion that personality traits contribute to the phenomenon of false confessions and compliance in an interrogative setting. Furthermore, the study provides an investigation into the more recent interest in the potential effect of psychopathic traits in this context. A sample of university students (N = 607) completed questionnaires measuring psychopathic traits, interrogative compliance, and the big five personality factors. Of these, only 4.9% (n=30) claimed to have falsely confessed to an academic or criminal offense, with no participant taking the blame for both types of offense. Across measures the big five personality traits were the strongest predictors of compliance. The five personality traits accounted for 17.9 % of the total variance in compliance, with neuroticism being the strongest predictor, followed by openness and agreeableness. Psychopathy accounted for 3.3% of variance, with the lifestyle facet being the only significant predictor. After controlling for the big five personality factors, psychopathy only accounted for a small percentage of interrogative compliance, indicating that interrogators should take into account a person’s personality traits during the interrogation.N/

Synergistic effects of various Her inhibitors in combination with IGF-1R, C-MET and Src targeting agents in breast cancer cell lines

Introduction: Overexpression of the receptor tyrosine kinase HER2 has been reported in around 25% of human breast cancers, usually indicating a poor prognosis. As a result, HER2 has become a popular target for therapy. However, despite recent advances in HER2 targeted therapy, many patients still experience primary and secondary resistance to such treatments. It is therefore important to understand the underlying mechanism of resistance and to develop more effective therapeutic interventions for breast cancer. Methods: The sensitivity of a panel of seven breast cancer cell lines to treatment with various types HER-family inhibitors alone, or in combination with a selection of other tyrosine kinase inhibitors (TKIs) or chemotherapeutic agents was determined using the Sulforhodamine B colorimetric assay. Receptor expression, cell-cycle distribution, cell signalling and cell migration were determined using flow cytometry, Western blot and Incucyte Zoom Live-Cell Analysis System respectively. Results: Overall, breast cancer cells were more sensitive to treatment with the irreversible pan-HER family inhibitors, particularly afatinib and neratinib, than treatment with the first-generation reversible inhibitors. Of three HER-2 overexpressing cell lines in this panel, SKBr3 and BT474 were highly sensitive to treatment with HER-family inhibitors (IC50s as low as 3 nM), while MDA-MB-453 was relatively resistant (lowest IC50 = 0.11 μM). When the HER-family inhibitors were combined with other agents such as NVP-AEW541 (an IGF-1R inhibitor), dasatinib (a Src inhibitor) or crizotinib (a c-Met/ALK inhibitor), such combination produced synergistic effects in some of the cell lines examined. Interestingly, co-targeting of Src and HER-family members in MDA-MB-453 cells led to synergistic growth inhibition, suggesting the importance of Src in mediating resistance to HER2-targeting agents. Finally, treatment with the irreversible HER family blockers and dasatinib were also most effective at inhibiting the migration of breast cancer cells. Conclusion: We concluded that the irreversible inhibitors of HER-family members are generally more effective at inhibiting growth, downstream signalling and migration compared with reversible inhibitors, and that combining HER-family inhibitors with other TKIs such as dasatinib may have therapeutic advantages in certain breast cancer subtypes and warrants further investigation

Remote Measurement of the Elastic Parameters by Ultrasound- Stimulated Vibro-Acoustic Spectrography

Estimation of the Young’s modulus of metals based on the resonance frequency of a given structure has been reported previously. In some of these methods, an electromagnetic or piezoelectric actuator has been used to induce resonance in the structure [1]. The resulting response could be measured by different means, for example by a piezoelectric device. In most cases either the excitation and/or detection require some form of contact with the structure. In many applications such a contact is not desirable, either because of its loading effect or limitation in accessing the object, especially when the object under test is too small for such measurements