Spatial co‐localisation of extreme weather events: a clear and present danger

Extreme weather events have become a dominant feature of the narrative surrounding changes in global climate with large impacts on ecosystem stability, functioning and resilience; however, understanding of their risk of co‐occurrence at the regional scale is lacking. Based on the UK Met Office’s long‐term temperature and rainfall records, we present the first evidence demonstrating significant increases in the magnitude, direction of change and spatial co‐localisation of extreme weather events since 1961. Combining this new understanding with land‐use data sets allowed us to assess the likely consequences on future agricultural production and conservation priority areas. All land‐uses are impacted by the increasing risk of at least one extreme event and conservation areas were identified as the hotspots of risk for the co‐occurrence of multiple event types. Our findings provide a basis to regionally guide land‐use optimisation, land management practices and regulatory actions preserving ecosystem services against multiple climate threats.     

Spatial variation of microtubule depolymerization in large asters

Microtubule plus-end depolymerization rate is a potentially important target of physiological regulation, but it has been challenging to measure, so its role in spatial organization is poorly understood. Here we apply a method for tracking plus ends based on time difference imaging to measure depolymerization rates in large interphase asters growing in Xenopus egg extract. We observed strong spatial regulation of depolymerization rates, which were higher in the aster interior compared with the periphery, and much less regulation of polymerization or catastrophe rates. We interpret these data in terms of a limiting component model, where aster growth results in lower levels of soluble tubulin and microtubule-associated proteins (MAPs) in the interior cytosol compared with that at the periphery. The steady-state polymer fraction of tubulin was ∼30%, so tubulin is not strongly depleted in the aster interior. We propose that the limiting component for microtubule assembly is a MAP that inhibits depolymerization, and that egg asters are tuned to low microtubule density.     

Determinants and long‐term costs of early reproduction in males of a long‐lived polygynous mammal

In long‐lived polygynous species, male reproductive success is often monopolized by a few mature dominant individuals. Young males are generally too small to be dominant and may employ alternative tactics; however, little is known about the determinants of reproductive success for young males. Understanding the causes and consequences of variability in early reproductive success may be crucial to assess the strength of sexual selection and possible long‐term trade‐offs among life‐history traits. Selective pressures driven by fluctuating environmental conditions may depend on age class. We evaluated the determinants of reproduction in male bighorn sheep (Ovis canadensis) aged 2–4 years using 30 years of individual‐level data. These young males cannot defend estrous ewes and use alternative mating tactics. We also investigated how the age of first detected reproduction was correlated to lifetime reproductive success and longevity. We found that reproductive success of males aged 3 years was positively correlated to body mass, to the proportion of males aged 2–4 years in the competitor pool, and to the number of females available per adult male. These results suggest that reproductive success depends on both competitive ability and population age–sex structure. None of these variables, however, had significant effects on the reproductive success of males aged 2 or 4 years. Known reproduction before the age of five increased lifetime reproductive success but decreased longevity, suggesting a long‐term survival cost of early reproduction. Our analyses reveal that both individual‐level phenotypic and population‐level demographic variables influence reproductive success by young males and provide a rare assessment of fitness trade‐offs in wild polygynous males.     

Monitoring Monoclonal Antibody Delivery in Oncology: The Example of Bevacizumab

Developing therapeutic monoclonal antibodies paves the way for new strategies in oncology using targeted therapy which should improve specificity. However, due to a lack of biomarkers, a personalized therapy scheme cannot always be applied with monoclonal antibodies. As a consequence, the efficacy or side effects associated with this type of treatment often appear to be sporadic. Bevacizumab is a therapeutic monoclonal antibody targeting Vascular Endothelial Growth Factor (VEGF). It is used to limit tumor vascularization. No prognosis or response biomarker is associated with this antibody, we therefore assessed whether the administration protocol could be a possible cause of heterogeneous responses (or variable efficacy). To do this, we developed a bevacizumab assay with a broad sensitivity range to measure blood bevacizumab concentrations. We then analyzed bevacizumab concentrations in 17 patients throughout the first quarter of treatment. In line with previously published data, average blood concentrations were 88+/−27 mg/L following the first dose administered, and 213+/−105 mg/L after the last (6^th) dose administered. However, the individual values were scattered, with a mean 4-fold difference between the lowest and the highest concentration for each dose administered. We demonstrated that the bevacizumab administration schedule results in a high inter-individual variability in terms of blood concentrations. Comparison of assay data with clinical data indicates that blood concentrations above the median are associated with side effects, whereas values below the median favor inefficacy. In conclusion, bevacizumab-based therapy could benefit from a personalized administration schedule including follow-up and adjustment of circulating bevacizumab concentrations.     

Improved Detection of Rare HIV-1 Variants using 454 Pyrosequencing

454 pyrosequencing, a massively parallel sequencing (MPS) technology, is often used to study HIV genetic variation. However, the substantial mismatch error rate of the PCR required to prepare HIV-containing samples for pyrosequencing has limited the detection of rare variants within viral populations to those present above ~1%. To improve detection of rare variants, we varied PCR enzymes and conditions to identify those that combined high sensitivity with a low error rate. Substitution errors were found to vary up to 3-fold between the different enzymes tested. The sensitivity of each enzyme, which impacts the number of templates amplified for pyrosequencing, was shown to vary, although not consistently across genes and different samples. We also describe an amplicon-based method to improve the consistency of read coverage over stretches of the HIV-1 genome. Twenty-two primers were designed to amplify 11 overlapping amplicons in the HIV-1 clade B gag-pol and env gp120 coding regions to encompass 4.7 kb of the viral genome per sample at sensitivities as low as 0.01-0.2%.     

Relating Recombination,Density of States,and Device Performance in an Efficient Polymer:Fullerene Organic Solar Cell Blend

We explore the interrelation between density of states, recombination kinetics, and device performance in efficient poly[4,8‐bis‐(2‐ethylhexyloxy)‐benzo[1,2‐b:4,5‐b']dithiophene‐2,6‐diyl‐alt‐4‐(2‐ethylhexyloxy‐1‐one)thieno[3,4‐b]thiophene‐2,6‐diyl]:[6,6]‐phenyl‐C₇₁‐butyric acid methyl ester (PBDTTT‐C:PC₇₁BM) bulk‐heterojunction organic solar cells. We modulate the active‐layer density of states by varying the polymer:fullerene composition over a small range around the ratio that leads to the maximum solar cell efficiency (50–67 wt% PC₇₁BM). Using transient and steady‐state techniques, we find that nongeminate recombination limits the device efficiency and, moreover, that increasing the PC₇₁BM content simultaneously increases the carrier lifetime and drift mobility in contrast to the behavior expected for Langevin recombination. Changes in electronic properties with fullerene content are accompanied by a significant change in the magnitude or energetic separation of the density of localized states. Our comprehensive approach to understanding device performance represents significant progress in understanding what limits these high‐efficiency polymer:fullerene systems.     

TGF-β-Elicited Induction of Tissue Inhibitor of Metalloproteinases (TIMP)-3 Expression in Fibroblasts Involves Complex Interplay between Smad3, p38α, and ERK1/2

Transforming growth factor-β (TGF-β) promotes extracellular matrix deposition by down-regulating the expression of matrix degrading proteinases and upregulating their inhibitors. Tissue inhibitor of metalloproteinases (TIMP)-3 is an ECM-associated specific inhibitor of matrix degrading metalloproteinases. Here, we have characterized the signaling pathways mediating TGF-β-induced expression of TIMP-3. Basal and TGF-β-induced TIMP-3 mRNA expression was abolished in Smad4-deficient mouse embryonic fibroblasts and restoring Smad4 expression rescued the response. Inhibition of Smad signaling by expression of Smad7 and dominant negative Smad3 completely abolished TGF-β-elicited expression of TIMP-3 in human fibroblasts, whereas overexpression of Smad3 enhanced it. Inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) activation with PD98059 and p38 mitogen-activated protein kinase activity by SB203580 resulted in suppression of TGF-β-induced TIMP-3 expression, indicating that ERK1/2 and p38 MAPK mediate the effect of TGF-β on TIMP-3 expression. Specific activation of p38α and ERK1/2 by constitutively active mutants of MKK3b or MEK1, respectively, and simultaneous co-expression of Smad3 resulted in induction of TIMP-3 expression in the absence of TGF-β indicating that Smad3 co-operates with p38 and ERK1/2 in the induction of TIMP-3 expression. These results demonstrate the complex interplay between Smad3, p38α, and ERK1/2 signaling in the regulation of TIMP-3 gene expression in fibroblasts, which may play a role in inflammation, tissue repair, and fibrosis.     

Microsatellite primer development in elasmobranchs using next generation sequencing of enriched libraries

Molecular Biology Reports - Microsatellites are useful in studies of population genetics, sibship, and parentage. Here, we screened for microsatellites from multiple elasmobranch genomic libraries...