Process-based models can be usefully employed for the assessment of field and regional-scale impact of drought on crop yields. However, in many instances, especially when they are used at the regional scale, it is necessary to identify the parameters and input variables that most influence the outputs and to assess how their influence varies when climatic and environmental conditions change. In this work, two different crop models, able to represent yield response to water, Aquacrop and SAFYE, were compared, with the aim to quantify their complexity and plasticity through Global Sensitivity Analysis (GSA), using Morris and EFAST (Extended Fourier Amplitude Sensitivity Test) techniques, for moderate to strong water limited climate scenarios. Although the rankings of the sensitivity indices was influenced by the scenarios used, the correlation among the rankings, higher for SAFYE than for Aquacrop, assessed by the top-down correlation coefficient (TDCC), revealed clear patterns. Parameters and input variables related to phenology and to water stress physiological processes were found to be the most influential for Aquacrop. For SAFYE, it was found that the water stress could be inferred indirectly from the processes regulating leaf growth, described in the original SAFY model. SAFYE has a lower complexity and plasticity than Aquacrop, making it more suitable to less data demanding regional scale applications, in case the only objective is the assessment of crop yield and no detailed information is sought on the mechanisms of the stress factors affecting its limitations.

Physical activity promotes metabolic and cardiovascular health benefits that derive in part from the transcriptional responses to exercise that occur within skeletal muscle and other organs. There is interest in discovering a pharmacologic exercise mimetic that could imbue wellness and alleviate disease burden. However, the molecular physiology by which exercise signals the transcriptional response is highly complex, making it challenging to identify a single target for pharmacological mimicry. The current studies evaluated the transcriptome responses in skeletal muscle, heart, liver, and white and brown adipose to novel small molecule activators of AMPK (pan-activators for all AMPK isoforms) compared to that of exercise. A striking level of congruence between exercise and pharmacological AMPK activation was observed across the induced transcriptome of these five tissues. However, differences in acute metabolic response between exercise and pharmacologic AMPK activation were observed, notably for acute glycogen balances and related to the energy expenditure induced by exercise but not pharmacologic AMPK activation. Nevertheless, intervention with repeated daily administration of short-acting activation of AMPK was found to mitigate hyperglycemia and hyperinsulinemia in four rodent models of metabolic disease and without the cardiac glycogen accretion noted with sustained pharmacologic AMPK activation. These findings affirm that activation of AMPK is a key node governing exercise mediated transcription and is an attractive target as an exercise mimetic.

Conversion of tropical forests into agriculture may present a serious risk to amphibian diversity if amphibians are not able to use agricultural areas as habitat. Recently, in Xishuangbanna Prefecture, Yunnan Province - a hotspot of frog diversity within China - two-thirds of the native tropical rainforests have been converted into rubber plantation agriculture. We conducted surveys and experiments to quantify habitat use for breeding and non-breeding life history activities of the native frog species in rainforest, rubber plantation and other human impacted sites. Rubber plantation sites had the lowest species richness in our non-breeding habitat surveys and no species used rubber plantation sites as breeding habitat. The absence of breeding was likely not due to intrinsic properties of the rubber plantation pools, as our experiments indicated that rubber plantation pools were suitable for tadpole growth and development. Rather, the absence of breeding in the rubber plantation was likely due to a misalignment of breeding and non-breeding habitat preferences. Analyses of our breeding surveys showed that percent canopy cover over pools was the strongest environmental variable influencing breeding site selection, with species exhibiting preferences for pools under both high and low canopy cover. Although rubber plantation pools had high canopy cover, the only species that bred in high canopy cover sites used the rainforest for both non-breeding and breeding activities, completing their entire life cycle in the rainforest. Conversely, the species that did use the rubber plantation for non-breeding habitat preferred to breed in low canopy sites, also avoiding breeding in the rubber plantation. Rubber plantations are likely an intermediate habitat type that 'slips through the cracks' of species habitat preferences and is thus avoided for breeding. In summary, unlike the rainforests they replaced, rubber plantations alone may not be able to support frog populations.

Stromal Derived Factor 1 (SDF1 or CXCL12), is a chemokine known to be critical for the migration of cells in several tissue systems including the homing of the hematopoietic stem cell (HSC) to its niche in the bone marrow. A comparative analysis of miRNA expression profiles of two stromal cell lines, distinguishable by function and by CXCL12 expression (CXCL12+ and CXCL12-), revealed that the CXCL12- cells expressed>40 fold more miR-886-3p than the CXCL12+ cells. Screening studies showed that when miR-886-3p was transfected into the CXCL12+ stromal cells, the expression of CXCL12 was down-regulated by as much as 85% when compared to appropriate controls, and results in the loss of CXCL12-directed chemotaxis. Similar reductions in CXCL12 were obtained with the transfection of miR-886-3p into primary stromal cell cultures. Additional studies showed that miR-886-3p specifically targeted the 3' untranslated region (UTR) of CXCL12 mRNA. These data suggest a role for miRNA in modulating the expression of CXCL12, a gene product with a critical role in hematopoietic regulation.

Hyperglucagonemia is implicated in the pathophysiology of hyperglycemia. Antagonism of the glucagon receptor (GCGR) thus represents a potential approach to diabetes treatment. Herein we report the characterization of GRA1, a novel small-molecule GCGR antagonist that blocks glucagon binding to the human GCGR (hGCGR) and antagonizes glucagon-induced intracellular accumulation of cAMP with nanomolar potency. GRA1 inhibited glycogenolysis dose-dependently in primary human hepatocytes and in perfused liver from hGCGR mice, a transgenic line of mouse that expresses the hGCGR instead of the murine GCGR. When administered orally to hGCGR mice and rhesus monkeys, GRA1 blocked hyperglycemic responses to exogenous glucagon. In several murine models of diabetes, acute and chronic dosing with GRA1 significantly reduced blood glucose concentrations and moderately increased plasma glucagon and glucagon-like peptide-1. Combination of GRA1 with a dipeptidyl peptidase-4 inhibitor had an additive antihyperglycemic effect in diabetic mice. Hepatic gene-expression profiling in monkeys treated with GRA1 revealed down-regulation of numerous genes involved in amino acid catabolism, an effect that was paralleled by increased amino acid levels in the circulation. In summary, GRA1 is a potent glucagon receptor antagonist with strong antihyperglycemic efficacy in preclinical models and prominent effects on hepatic gene-expression related to amino acid metabolism.