We investigate the climate feedback parameter α (W m−2 K−1) during the historical period (since 1871) in experiments using the HadGEM2 and HadCM3 atmosphere general circulation models (AGCMs) with ...constant preindustrial atmospheric composition and time‐dependent observational sea surface temperature (SST) and sea ice boundary conditions. In both AGCMs, for the historical period as a whole, the effective climate sensitivity is ∼2 K (α≃1.7 W m−2 K−1), and α shows substantial decadal variation caused by the patterns of SST change. Both models agree with the AGCMs of the latest Coupled Model Intercomparison Project in showing a considerably smaller effective climate sensitivity of ∼1.5 K (α = 2.3 ± 0.7 W m−2 K−1), given the time‐dependent changes in sea surface conditions observed during 1979–2008, than the corresponding coupled atmosphere‐ocean general circulation models (AOGCMs) give under constant quadrupled CO2 concentration. These findings help to relieve the apparent contradiction between the larger values of effective climate sensitivity diagnosed from AOGCMs and the smaller values inferred from historical climate change.
Key Points
We have carried out AGCM experiments with observed time‐dependent historical sea surface conditions
The effective climate sensitivity in these experiments is 2 K with substantial decadal variation
For 1979–2008 in our and other AGCMs, it is 1.5 K, considerably less than for 4 × CO2 in AOGCMs
Multicellular animals match costly activities, such as growth and reproduction, to the environment through nutrient-sensing pathways. The insulin/IGF signaling (IIS) pathway plays key roles in ...growth, metabolism, stress resistance, reproduction, and longevity in diverse organisms including mammals. Invertebrate genomes often contain multiple genes encoding insulin-like ligands, including seven Drosophila insulin-like peptides (DILPs). We investigated the evolution, diversification, redundancy, and functions of the DILPs, combining evolutionary analysis, based on the completed genome sequences of 12 Drosophila species, and functional analysis, based on newly-generated knock-out mutations for all 7 dilp genes in D. melanogaster. Diversification of the 7 DILPs preceded diversification of Drosophila species, with stable gene diversification and family membership, suggesting stabilising selection for gene function. Gene knock-outs demonstrated both synergy and compensation of expression between different DILPs, notably with DILP3 required for normal expression of DILPs 2 and 5 in brain neurosecretory cells and expression of DILP6 in the fat body compensating for loss of brain DILPs. Loss of DILP2 increased lifespan and loss of DILP6 reduced growth, while loss of DILP7 did not affect fertility, contrary to its proposed role as a Drosophila relaxin. Importantly, loss of DILPs produced in the brain greatly extended lifespan but only in the presence of the endosymbiontic bacterium Wolbachia, demonstrating a specific interaction between IIS and Wolbachia in lifespan regulation. Furthermore, loss of brain DILPs blocked the responses of lifespan and fecundity to dietary restriction (DR) and the DR response of these mutants suggests that IIS extends lifespan through mechanisms that both overlap with those of DR and through additional mechanisms that are independent of those at work in DR. Evolutionary conservation has thus been accompanied by synergy, redundancy, and functional differentiation between DILPs, and these features may themselves be of evolutionary advantage.
Mammalian hibernation presents a unique opportunity to study naturally occurring neuroprotection. Hibernating ground squirrels undergo rapid and extreme physiological changes in body temperature, ...oxygen consumption, and heart rate without suffering neurological damage from ischemia and reperfusion injury. Different brain regions show markedly different activity during the torpor/arousal cycle: the cerebral cortex shows activity only during the periodic returns to normothermia, while the hypothalamus is active over the entire temperature range. Therefore, region-specific neuroprotective strategies must exist to permit this compartmentalized spectrum of activity. In this study, we use the Illumina HiSeq platform to compare the transcriptomes of these two brain regions at four collection points across the hibernation season: April Active, October Active, Torpor, and IBA. In the cerebral cortex, 1,085 genes were found to be differentially expressed across collection points, while 1,063 genes were differentially expressed in the hypothalamus. Comparison of these transcripts indicates that the cerebral cortex and hypothalamus implement very different strategies during hibernation, showing less than 20% of these differentially expressed genes in common. The cerebral cortex transcriptome shows evidence of remodeling and plasticity during hibernation, including transcripts for the presynaptic cytomatrix proteins bassoon and piccolo, and extracellular matrix components, including laminins and collagens. Conversely, the hypothalamic transcriptome displays upregulation of transcripts involved in damage response signaling and protein turnover during hibernation, including the DNA damage repair gene RAD50 and ubiquitin E3 ligases UBR1 and UBR5. Additionally, the hypothalamus transcriptome also provides evidence of potential mechanisms underlying the hibernation phenotype, including feeding and satiety signaling, seasonal timing mechanisms, and fuel utilization. This study provides insight into potential neuroprotective strategies and hibernation control mechanisms, and also specifically shows that the hibernator brain exhibits both seasonal and regional differences in mRNA expression.
In the Coupled Model Intercomparison Project Phase 5 (CMIP5), the model-mean increase in global mean surface air temperature T under the lpctC02 scenario (atmospheric CO2 increasing at 1% yr-1) ...during the second doubling of CO2 is 40% larger than the transient climate response (TCR), i.e. the increase in T during the first doubling. We identify four possible contributory effects. First, the surface climate system loses heat less readily into the ocean beneath as the latter warms. The model spread in the thermal coupling between the upper and deep ocean largely explains the model spread in ocean heat uptake efficiency. Second, CO2 radiative forcing may rise more rapidly than logarithmically with CO2 concentration. Third, the climate feedback parameter may decline as the CO2 concentration rises. With CMIP5 data, we cannot distinguish the second and third possibilities. Fourth, the climate feedback parameter declines as time passes or T rises; in 1pctCO2, this effect is less important than the others. We find that T projected for the end of the twenty-first century correlates more highly with T at the time of quadrupled CO2 in 1pctCO2 than with the TCR, and we suggest that the TCR may be underestimated from observed climate change.
Secretion systems require high-fidelity mechanisms to discriminate substrates among the vast cytoplasmic pool of proteins. Factors mediating substrate recognition by the type VI secretion system ...(T6SS) of Gram-negative bacteria, a widespread pathway that translocates effector proteins into target bacterial cells, have not been defined. We report that haemolysin coregulated protein (Hcp), a ring-shaped hexamer secreted by all characterized T6SSs, binds specifically to cognate effector molecules. Electron microscopy analysis of an Hcp-effector complex from Pseudomonas aeruginosa revealed the effector bound to the inner surface of Hcp. Further studies demonstrated that interaction with the Hcp pore is a general requirement for secretion of diverse effectors encompassing several enzymatic classes. Though previous models depict Hcp as a static conduit, our data indicate it is a chaperone and receptor of substrates. These unique functions of a secreted protein highlight fundamental differences between the export mechanism of T6 and other characterized secretory pathways.
•Hcp is a chaperone required for the intracellular accumulation of Tse2•Export of type VI secretion effectors requires direct interaction with the pore of Hcp•Cognate Hcp-effector interactions can define substrate specificity of the T6SS•Substrate recognition and energization of secretion are uncoupled in the T6SS
Brown adipose tissue (BAT) is a unique thermogenic tissue in mammals that rapidly produces heat via nonshivering thermogenesis. Small mammalian hibernators have evolved the greatest capacity for BAT ...because they use it to rewarm from hypothermic torpor numerous times throughout the hibernation season. Although hibernator BAT physiology has been investigated for decades, recent efforts have been directed toward understanding the molecular underpinnings of BAT regulation and function using a variety of methods, from mitochondrial functional assays to 'omics' approaches. As a result, the inner-workings of hibernator BAT are now being illuminated. In this Review, we discuss recent research progress that has identified players and pathways involved in brown adipocyte differentiation and maturation, as well as those involved in metabolic regulation. The unique phenotype of hibernation, and its reliance on BAT to generate heat to arouse mammals from torpor, has uncovered new molecular mechanisms and potential strategies for biomedical applications.
Genetic mutations account for many devastating early onset immune deficiencies. In contrast, less severe and later onset immune diseases, including in patients with no prior family history, remain ...poorly understood. Whole exome sequencing in two cohorts of such patients identified a novel heterozygous de novo
missense mutation (c.607G>A) in two separate kindreds in whom probands presented with immune dysregulation, combined T and B cell deficiency, inflammation, and epithelial defects.
encodes IKK2, which activates NF-κB signaling. IKK2
results in enhanced NF-κB signaling, as well as T and B cell functional defects. IKK2
is a highly conserved residue, and to prove causation, we generated an accurate mouse model by introducing the precise orthologous codon change in
using CRISPR/Cas9. Mice and humans carrying this missense mutation exhibit remarkably similar cellular and biochemical phenotypes. Accurate mouse models engineered by CRISPR/Cas9 can help characterize novel syndromes arising from de novo germline mutations and yield insight into pathogenesis.
Drug repurposing and human parasitic protozoan diseases Andrews, Katherine T.; Fisher, Gillian; Skinner-Adams, Tina S.
International journal for parasitology -- drugs and drug resistance,
08/2014, Letnik:
4, Številka:
2
Journal Article
Recenzirano
Odprti dostop
•Anti-protozoan drug discovery is challenging, time consuming and expensive.•Drug repurposing has historically played a role in anti-protozoan drug discovery.•Drug repurposing can result in ...significant time and cost savings.•Here we review drug repurposing for major human protozoan diseases.
Parasitic diseases have an enormous health, social and economic impact and are a particular problem in tropical regions of the world. Diseases caused by protozoa and helminths, such as malaria and schistosomiasis, are the cause of most parasite related morbidity and mortality, with an estimated 1.1million combined deaths annually. The global burden of these diseases is exacerbated by the lack of licensed vaccines, making safe and effective drugs vital to their prevention and treatment. Unfortunately, where drugs are available, their usefulness is being increasingly threatened by parasite drug resistance. The need for new drugs drives antiparasitic drug discovery research globally and requires a range of innovative strategies to ensure a sustainable pipeline of lead compounds. In this review we discuss one of these approaches, drug repurposing or repositioning, with a focus on major human parasitic protozoan diseases such as malaria, trypanosomiasis, toxoplasmosis, cryptosporidiosis and leishmaniasis.
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