p38 MAPK-mediated regulation of Xbp1s is crucial for glucose homeostasis

Here we show that p38 mitogen-activated protein kinase (p38 MAPK) phosphorylates the spliced form of X-box binding protein 1 (Xbp1s) on its Thr48 and Ser61 residues and greatly enhances its nuclear migration in mice, whereas mutation of either residue to alanine substantially reduces its nuclear translocation and activity. We also show that p38 MAPK activity is markedly reduced in the livers of obese mice compared with lean mice. Further, we show that activation of p38 MAPK by expression of constitutively active MAP kinase kinase 6 (MKK6Glu) greatly enhances nuclear translocation of Xbp1s, reduces endoplasmic reticulum stress and establishes euglycemia in severely obese and diabetic mice. Hence, our results define a crucial role for phosphorylation on Thr48 and Ser61 of Xbp1s in the maintenance of glucose homeostasis in obesity, and they suggest that p38 MAPK activation in the livers of obese mice could lead to a new therapeutic approach to the treatment of type 2 diabetes.     

EGFR and EphA2 are host factors for hepatitis C virus entry and possible targets for antiviral therapy

Hepatitis C virus (HCV) is a major cause of liver disease, but therapeutic options are limited and there are no prevention strategies. Viral entry is the first step of infection and requires the cooperative interaction of several host cell factors. Using a functional RNAi kinase screen, we identified epidermal growth factor receptor and ephrin receptor A2 as host cofactors for HCV entry. Blocking receptor kinase activity by approved inhibitors broadly impaired infection by all major HCV genotypes and viral escape variants in cell culture and in a human liver chimeric mouse model in vivo. The identified receptor tyrosine kinases (RTKs) mediate HCV entry by regulating CD81-claudin-1 co-receptor associations and viral glycoprotein-dependent membrane fusion. These results identify RTKs as previously unknown HCV entry cofactors and show that tyrosine kinase inhibitors have substantial antiviral activity. Inhibition of RTK function may constitute a new approach for prevention and treatment of HCV infection.     

A genomic map enriched for markers linked to Avr1 in Cronartium quercuum f.sp. fusiforme

A novel approach is presented to map avirulence gene Avr1 in the basidiomycete Cronartium quercuum f.sp. fusiforme, the causal agent of fusiform rust disease in pines. DNA markers tightly linked to resistance gene Fr1 in loblolly pine tree 10-5 were used to classify 10-5 seedling progeny as either resistant or susceptible. A single dikaryotic isolate (P2) heterozygous at the corresponding Avr1 gene was developed by crossing Fr1 avirulent isolate SC20-21 with Fr1 virulent isolate NC2-40. Bulk basidiospore inoculum derived from isolate P2 was used to challenge the pine progeny. The ability to unambiguously marker classify 10-5 progeny as resistant (selecting for virulence) or susceptible (non-selecting) permitted the genetic mapping of the corresponding Avr1 gene by bulked segregant analysis. Using this approach, 14 genetic markers significantly linked to Avr1 were identified and placed within the context of a genome-wide linkage map produced for isolate P2 using samples from susceptible seedlings.     

A complex of Pdi1p and the mannosidase Htm1p initiates clearance of unfolded glycoproteins from the endoplasmic reticulum

Endoplasmic reticulum (ER)-resident mannosidases generate asparagine-linked oligosaccharide signals that trigger ER-associated protein degradation (ERAD) of unfolded glycoproteins. In this study, we provide in vitro evidence that a complex of the yeast protein disulfide isomerase Pdi1p and the mannosidase Htm1p processes Man(8)GlcNAc(2) carbohydrates bound to unfolded proteins, yielding Man(7)GlcNAc(2). This glycan serves as a signal for HRD ligase-mediated glycoprotein disposal. We identified a point mutation in PDI1 that prevents complex formation of the oxidoreductase with Htm1p, diminishes mannosidase activity, and delays degradation of unfolded glycoproteins in vivo. Our results show that Pdi1p is engaged in both recognition and glycan signal processing of ERAD substrates and suggest that protein folding and breakdown are not separated but interconnected processes. We propose a stochastic model for how a given glycoprotein is partitioned into folding or degradation pathways and how the flux through these pathways is adjusted to stress conditions.     

Early response of the platypus to climate warming

Combining a climatic envelope modelling technique with more than two centuries (1800–2009) of distribution records has revealed the effects of a changing climate on the egg‐laying monotreme, the platypus, Ornithorhynchus anatinus. We show that the main factor associated with platypus occurrence switched from aquatic habitat availability (estimated by rainfall) to thermal tolerances (estimated by annual maximum temperature) in the 1960s. This correlates directly with the change in the annual maximum temperature anomaly from cooler to warmer conditions in southeastern Australia. Modelling of platypus habitat under emission scenarios (A1B, A2, B1 and B2) revealed large decreases (>30%) in thermally suitable habitat by 2070. This reduction, compounded by increasing demands for water for agriculture and potable use, suggests that there is real cause for concern over the future status of this species, and highlights the need for restoration of thermal refugia within the platypus’ modelled range.     

Crossmodal session rating of perceived exertion response at low and moderate intensities

Session rating of perceived exertion (SRPE) permits global effort estimations after an exercise bout and has shown promise for evaluating training load. However, factors mediating SRPE are not well understood. The purpose of this study was to compare SRPE between cycling and treadmill exercise at low and moderate intensities. In a counterbalanced order, male subjects (n = 7) completed a VO2max trial on a cycle ergometer and a motor-driven treadmill. Then, participants completed trials at 50 and 75% mode-specific VO2max on a cycle ergometer (BK75, BK50) and a treadmill (TM75, TM50) to achieve ～ 400-kcal energy expenditure per trial. Acute RPE (i.e., during exercise) at 5 minutes, midway, and test termination were recorded with SRPE (20-minutes postexercise) expressed as overall (SRPEO), legs (SRPEL), and breathing also recorded were heart rate (HR) and change in rectal temperature (ΔTrec). Significance was accepted at p ≤ 0.05. Repeated-measures analysis of variance revealed significantly greater SRPE for higher intensities within each mode. Crossmodal comparisons also show a higher SRPE at moderate (75% VO2max) intensities [SRPEO] = BK75: 7.6 ± 1.0, TM75: 6.9 ± 1.3) vs. lower (50% VO2max) intensities (BK50: 4.6 ± 1.4, TM50: 4.6 ± 1.1). Within modes, SRPE corresponded well with ΔTrec and HR. Acute RPE was linked with intensity and drifted upward across time. Results indicated that overall and differentiated SRPEs are magnified with exercise intensity with the corresponding disruption in internal environment potentially mediating subjective responses. From a practical application standpoint, SRPE provides a subjective assessment for immediate evaluation of daily training. Results indicate that, when using SRPE to monitor training, consideration should be given to responses across differing exercise modes.     

Biology and systematics of the New World Phyllocnistis Zeller leafminers of the avocado genus Persea (Lepidoptera, Gracillariidae)

Four New World species of Phyllocnistis Zeller are described from serpentine mines in Persea (Family Lauraceae). Phyllocnistis hyperpersea,new species, mines the upper leaf surfaces of avocado, Persea americana Mill., and red bay, Persea borbonia (L.) Spreng. and ranges over much of the southeastern United States into Central America. Phyllocnistis subpersea,new species, mines the underside and occasionally upper sides of new leaves of Persea borbonia in southeastern United States. Phyllocnistis longipalpa, new species, known only from southern Florida also mines the undersides of new leaves of Persea borbonia. Phyllocnistis perseafolia,new species, mines both leaf surfaces and possibly fruits of Persea americana in Colombia, South America. As in all known species of Phyllocnistis, the early instars are subepidermal sapfeeders in young (not fully hardened) foliage, and the final instar is an extremely specialized, nonfeeding larval form, whose primary function is to spin the silken cocoon, at the mine terminus, prior to pupation. Early stages are illustrated and described for three of the species. The unusual morphology of the pupae, particularly the frontal process of the head, is shown to be one of the most useful morphological sources of diagnostic characters for species identification of Phyllocnistis. COI barcode sequence distances are provided for the four proposed species and a fifth, undescribed species from Costa Rica.     

Imaging and characterisation of the surface of live cells

Determining the organisation of key molecules on the surface of live cells in two dimensions and how this changes during biological processes, such as signaling, is a major challenge in cell biology and requires methods with nanoscale resolution. Recent advances in fluorescence imaging both at the diffraction limit tracking single molecules and exploiting super resolution imaging have now reached a stage where they can provide fundamentally new insights. Complementary developments in scanning ion conductance microscopy also allow the cell surface to be imaged with nanoscale resolution. The challenge now is to combine the information obtained using these different methods and on different cells to obtain a coherent view of the cell surface. In the future this needs to be driven by interdisciplinary research between physical scientists and biologists.