The host inflammatory response contributes to disease severity in Crimean-Congo hemorrhagic fever virus infected mice

Crimean-Congo hemorrhagic fever virus (CCHFV) is an important human pathogen. In cell culture, CCHFV is sensed by the cytoplasmic RNA sensor retinoic acid-inducible gene I (RIG-I) molecule and its adaptor molecule mitochondrial antiviral signaling (MAVS) protein. MAVS initiates both type I interferon (IFN-I) and proinflammatory responses. Here, we studied the role MAVS plays in CCHFV infection in mice in both the presence and absence of IFN-I activity. MAVS-deficient mice were not susceptible to CCHFV infection when IFN-I signaling was active and showed no signs of disease. When IFN-I signaling was blocked by antibody, MAVS-deficient mice lost significant weight, but were uniformly protected from lethal disease, whereas all control mice succumbed to infection. Cytokine activity in the infected MAVS-deficient mice was markedly blunted. Subsequent investigation revealed that CCHFV infected mice lacking TNF-α receptor signaling (TNFA-R-deficient), but not IL-6 or IL-1 activity, had more limited liver injury and were largely protected from lethal outcomes. Treatment of mice with an anti-TNF-α neutralizing antibody also conferred partial protection in a post-virus exposure setting. Additionally, we found that a disease causing, but non-lethal strain of CCHFV produced more blunted inflammatory cytokine responses compared to a lethal strain in mice. Our work reveals that MAVS activation and cytokine production both contribute to CCHFV pathogenesis, potentially identifying new therapeutic targets to treat this disease.     

Searching for sustainability: are assessments of wildlife harvests behind the times?

The unsustainable harvest of wildlife is a major threat to global biodiversity and to the millions of people who depend on wildlife for food and income. Past research has called attention to the fact that commonly used methods to evaluate the sustainability of wildlife hunting perform poorly, yet these methods remain in popular use today. Here, we conduct a systematic review of empirical sustainability assessments to quantify the use of sustainability indicators in the scientific literature and highlight associations between analytical methods and their outcomes. We find that indicator type, continent of study, species body mass, taxonomic group and socio‐economic status of study site are important predictors of the probability of reported sustainability. The most common measures of sustainability include population growth models, the Robinson & Redford (1991) model and population trends through time. Indicators relying on population‐specific biological data are most often used in North America and Europe, while cruder estimates are more often used in Africa, Latin America and Oceania. Our results highlight both the uncertainty and lack of uniformity in sustainability science. Given our urgent need to conserve both wildlife and the food security of rural peoples around the world, improvements in sustainability indicators are of utmost importance.     

A unique FGF23 with the ability to activate FGFR signaling through both αKlotho and βKlotho

Three fibroblast growth factor (FGF) molecules, FGF19, FGF21, and FGF23, form a unique subfamily that functions as endocrine hormones. FGF19 and FGF21 can regulate glucose, lipid, and energy metabolism, while FGF23 regulates phosphate homeostasis. The FGF receptors and co-receptors for these three FGF molecules have been identified, and domains important for receptor interaction and specificity determination are beginning to be elucidated. However, a number of questions remain unanswered, such as the identification of fibroblast growth factor receptor responsible for glucose regulation. Here, we have generated a variant of FGF23: FGF23-21c, where the C-terminal domain of FGF23 was replaced with the corresponding regions from FGF21. FGF23-21c showed a number of interesting and unexpected properties in vitro. In contrast to wild-type FGF23, FGF23-21c gained the ability to activate FGFR1c and FGFR2c in the presence of βKlotho and was able to stimulate glucose uptake into adipocytes in vitro and lower glucose levels in ob/ob diabetic mice model to similar extent as FGF21 in vivo. These results suggest that βKlotho/FGFR1c or FGFR2c receptor complexes are sufficient for glucose regulation. Interestingly, without the FGF23 C-terminal domain, FGF23-21c was still able to activate fibroblast growth factor receptors in the presence of αKlotho. This suggests not only that sequences outside of the C-terminal region may also contribute to the interaction with co-receptors but also that FGF23-21c may be able to regulate both glucose and phosphate metabolisms. This raises an interesting concept of designing an FGF molecule that may be able to address multiple diseases simultaneously. Further understanding of FGF/receptor interactions may allow the development of exciting opportunities for novel therapeutic discovery.     

The cyanobacterial circadian system: a clock apart

Several new molecular components of the circadian clocks of animals, fungi, and bacteria have been unveiled in the past two years. Enough parts are now identified to indicate that there is more than one way to build a biological clock, although there are parallels in the cycling molecular events among disparate groups of organisms.     

Shrubline but not treeline advance matches climate velocity in montane ecosystems of south‐central Alaska

Tall shrubs and trees are advancing into many tundra and wetland ecosystems but at a rate that often falls short of that predicted due to climate change. For forest, tall shrub, and tundra ecosystems in two pristine mountain ranges of Alaska, we apply a Bayesian, error‐propagated calculation of expected elevational rise (climate velocity), observed rise (biotic velocity), and their difference (biotic inertia). We show a sensitive dependence of climate velocity on lapse rate and derive biotic velocity as a rigid elevational shift. Ecosystem presence identified from recent and historic orthophotos ~50 years apart was regressed on elevation. Biotic velocity was estimated as the difference between critical point elevations of recent and historic logistic fits divided by time between imagery. For both mountain ranges, the 95% highest posterior density of climate velocity enclosed the posterior distributions of all biotic velocities. In the Kenai Mountains, mean tall shrub and climate velocities were both 2.8 m y^?1. In the better sampled Chugach Mountains, mean tundra retreat was 1.2 m y^?1 and climate velocity 1.3 m y^?1. In each mountain range, the posterior mode of tall woody vegetation velocity (the complement of tundra) matched climate velocity better than either forest or tall shrub alone, suggesting competitive compensation can be important. Forest velocity was consistently low at 0.1–1.1 m y^?1, indicating treeline is advancing slowly. We hypothesize that the high biotic inertia of forest ecosystems in south‐central Alaska may be due to competition with tall shrubs and/or more complex climate controls on the elevational limits of trees than tall shrubs. Among tall shrubs, those that disperse farthest had lowest inertia. Finally, the rapid upward advance of woody vegetation may be contributing to regional declines in Dall's sheep (Ovis dalli), a poorly dispersing alpine specialist herbivore with substantial biotic inertia due to dispersal reluctance.     

An inside job for siRNAs

Among the three main categories of small silencing RNAs in insects and mammals-siRNAs, miRNAs, and piRNAs-siRNAs were thought to arise primarily from exogenous sources, whereas miRNAs and piRNAs arise from endogenous loci. Recent work in flies and mice reveals several classes of endogenous siRNAs (endo-siRNAs) that contribute to functions previously reserved for miRNAs and piRNAs, including gene regulation and transposon suppression.     

Nitrogen catabolite repression of the L-asparaginase of Bacillus licheniformis.

We report the presence of a single L-asparagine aminohydrolase activity (EC 3.5.1.1) in extracts of Bacillus licheniformis A5. The synthesis of the enzyme was apparently under nitrogen catabolite repression control.     

A sequence-specific DNA-binding factor (VF1) from Anabaena sp. strain PCC 7120 vegetative cells binds to three adjacent sites in the xisA upstream region.

A DNA-binding factor (VF1) partially purified from Anabaena sp. strain PCC 7120 vegetative cell extracts by heparin-Sepharose chromatography was found to have affinity for the xisA upstream region. The xisA gene is required for excision of an 11-kilobase element from the nifD gene during heterocyst differentiation. Previous studies of the xisA upstream sequences demonstrated that deletion of this region is required for the expression of xisA from heterologous promoters in vegetative cells. Mobility shift assays with a labeled 250-base-pair fragment containing the binding sites revealed three distinct DNA-protein complexes. Competition experiments showed that VF1 also bound to the upstream sequences of the rbcL and glnA genes, but the rbcL and glnA fragments showed only single complexes in mobility shift assays. The upstream region of the nifH gene formed a weak complex with VF1. DNase footprinting and deletion analysis of the xisA binding site mapped the binding to a 66-base-pair region containing three repeats of the consensus recognition sequence ACATT.