Innate immune activation by macrophages is an essential part of host defence against infection. Cytosolic recognition of microbial DNA in macrophages leads to induction of interferons and cytokines ...through activation of cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING). Other host factors, including interferon-gamma inducible factor 16 (IFI16), have been proposed to contribute to immune activation by DNA. However, their relation to the cGAS-STING pathway is not clear. Here, we show that IFI16 functions in the cGAS-STING pathway on two distinct levels. Depletion of IFI16 in macrophages impairs cGAMP production on DNA stimulation, whereas overexpression of IFI16 amplifies the function of cGAS. Furthermore, IFI16 is vital for the downstream signalling stimulated by cGAMP, facilitating recruitment and activation of TANK-binding kinase 1 in STING complex. Collectively, our results suggest that IFI16 is essential for efficient sensing and signalling upon DNA challenge in macrophages to promote interferons and antiviral responses.
Large comparative studies in animal ecology, physiology and evolution often use animals reared in the laboratory for many generations; however, the relevance of these studies hinges on the assumption ...that laboratory populations are still representative for their wild living conspecifics. In this study, we investigate whether laboratory‐maintained and freshly collected animal populations are fundamentally different and whether data from laboratory‐maintained animals are valid to use in large comparative investigations of ecological and physiological patterns. Here, we obtained nine species of Drosophila with paired populations of laboratory‐maintained and freshly collected flies. These species, representing a range of ecotypes, were assayed for four stress‐tolerance, two body‐size traits and six life‐history traits. For all of these traits, we observed small differences in species‐specific comparisons between field and laboratory populations; however, these differences were unsystematic and laboratory maintenance did not eclipse fundamental species characteristics. To investigate whether laboratory maintenance influence the general patterns in comparative studies, we correlated stress tolerance and life‐history traits with environmental traits for the laboratory‐maintained and freshly collected populations. Based on this analysis, we found that the comparative physiological and ecological trait correlations are similar irrespective of provenience. This finding is important for comparative biology in general because it validates comparative meta‐analyses based on laboratory‐maintained populations.
The adaptability of organisms to novel environmental conditions depends on the amount of genetic variance present in the population as well as on the ability of individuals to adjust their phenotype ...through phenotypic plasticity. Here, we investigated the phenotypic plasticity induced by a single generation's exposure to three different temperature regimes with respect to several life‐history and stress‐resistance traits in a natural population of Drosophila simulans. We studied a constant as well as a predictably and an unpredictably fluctuating temperature regime. We found high levels of phenotypic plasticity among all temperature regimes, suggesting a strong influence of both temperature fluctuations and their predictability. Increased heat tolerance was observed for flies developed in both types of fluctuating thermal environments compared with flies developed in a constant environment. We suggest that this was due to beneficial hardening when developing in either fluctuating temperature environment. To our surprise, flies that developed in constant and predictably changing environments were similar to each other in most traits when compared to flies from the unpredictably fluctuating environment. The unpredictably changing thermal environment imposed the most stressful condition, resulting in the lowest performance for stress‐related traits, even though the absolute temperature changes never exceeded that of the predictably fluctuating environment. The overall decreased stress resistance of flies in the unpredictably fluctuating environment may be the consequence of maladaptive phenotypic plasticity in this setting, indicating that the adaptive value of plasticity depends on the predictability of the environment.
The selective past of populations is presumed to affect the levels of phenotypic plasticity. Experimental evolution at constant temperatures is generally expected to lead to a decreased level of ...plasticity due to presumed costs associated with phenotypic plasticity when not needed. In this study, we investigated the effect of experimental evolution in constant, predictable and unpredictable daily fluctuating temperature regimes on the levels of phenotype plasticity in several life history and stress resistance traits in Drosophila simulans. Contrary to the expectation, evolution in the different regimes did not affect the levels of plasticity in any of the traits investigated even though the populations from the different thermal regimes had evolved different stress resistance and fitness trait means. Although costs associated with phenotypic plasticity are known, our results suggest that the maintenance of phenotypic plasticity might come at low and negligible costs, and thus, the potential of phenotypic plasticity to evolve in populations exposed to different environmental conditions might be limited.
A short exposure to a mild cold stress is sufficient to increase cold tolerance in many insects. This phenomenon, termed rapid cold hardening (RCH) expands the thermal interval that can be exploited ...by the insect. To investigate the possible role of altered metabolite levels during RCH, the present study used untargeted
1H NMR metabolomic profiling to examine the metabolomic response in
Drosophila melanogaster during the 72
h following RCH and cold shock treatment. These findings are discussed in relation to the costs and benefits of RCH that are measured in terms of survival and reproductive output.
Cold shock caused a persistent disturbance of the metabolite profile that correlated well with a delayed onset of cold shock mortality. The disruption of metabolite homeostasis was smaller following RCH, where control levels were fully recovered after 72
h. RCH improved both survival and reproductive output after a subsequent cold shock but the RCH treatment alone was associated with costs in terms of reduced survival and reproductive output. The most pronounced changes following the RCH treatment were elevated levels of glucose and trehalose. Although, it is difficult to discern if a change in a specific metabolite is linked to physiological processes of adaptive, neutral or detrimental nature we observed that the onset and magnitude of the increased sugar levels correlated tightly with the improved chill tolerance following RCH. These findings suggest a putative role of cryoprotectants during RCH which are discussed in the light of the existing literature on the mechanistic background of RCH.
Theory predicts that geographic variation in traits and genes associated with climatic adaptation may be initially driven by the correlated evolution of thermal preference and thermal sensitivity. ...This assumes that an organism’s preferred body temperature corresponds with the thermal optimum in which performance is maximized; hence, shifts in thermal preferences affect the subsequent evolution of thermal‐related traits. Drosophila subobscura evolved worldwide latitudinal clines in several traits including chromosome inversion frequencies, with some polymorphic inversions being apparently associated with thermal preference and thermal tolerance. Here we show that flies carrying the warm‐climate chromosome arrangement O3+4 have higher basal protein levels of Hsp70 than their cold‐climate Ost counterparts, but this difference disappears after heat hardening. O3+4 carriers are also more heat tolerant, although it is difficult to conclude from our results that this is causally linked to their higher basal levels of Hsp70. The observed patterns are consistent with the thermal co‐adaptation hypothesis and suggest that the interplay between behaviour and physiology underlies latitudinal and seasonal shifts in inversion frequencies.
Vitamin D levels have been linked to certain pain states, including migraine. This study investigated whether vitamin D supplementation would be beneficial for adult patients with migraine ...(ClinicalTrials.gov Identifier: NCT01695460).
A randomized, double-blinded, placebo-controlled parallel trial was conducted in migraine patients (36 women and 12 men, 18-65 years of age). A 4-week baseline period was conducted before randomization to 24 weeks of treatment. Participants were assigned to receive D3-Vitamin (n = 24, 18 women and 6 men, 100 μg/day D3-Vitamin) or placebo (n = 24, 18 women and 6 men). Migraine attacks and related symptoms were assessed by self-reported diaries. The response rate (i.e. experiencing a 50% or greater reduction in migraine frequency from baseline to week 24), change in migraine severity, and number of migraine days were recorded. Changes in migraine-related symptoms, HIT-6
scores, and pain sensitivity tests (pressure pain threshold and temporal summation) were also evaluated. Serum levels of both 25 (OH)D and 1,25 (OH)
D were assessed from baseline to week 24.
The number of headache days changed from 6.14 ± 3.60 in the treatment group and 5.72 ± 4.52 in the placebo group at baseline to 3.28 ± 3.24 and 4.93 ± 3.24 by the end of the trial, respectively. Migraine patients on D3-Vitamin demonstrated a significant decrease (p < .001) in migraine frequency from baseline to week 24 compared with placebo. However, migraine severity, pressure pain thresholds, or temporal summation did not show a significant change. 25(OH)D levels increased significantly for the D3-Vitamin group during the first 12 weeks of treatment. There was no significant change in 1,25(OH)
D. No side-effects were reported or noted.
D3-Vitamin was superior to placebo in reducing migraine days in migraine patients. Larger studies are required to confirm that vitamin D
might be one of the prophylactic options for adult patients with migraine.
Here, we report a detailed analysis of changes in gene expression in Drosophila melanogaster selected for ecologically relevant environmental stress resistance traits. We analysed females from seven ...replicated selection regimes and one control regime using whole genome gene expression arrays. When compared with gene expression profiles of control lines, we were able to detect consistent selection responses at the transcript level in each specific selection regime and also found a group of differentially expressed genes that were changed among all selected lines. Replicated selection lines showed similar changes in gene expression (compared with controls) and thus showed that 10 generations of artificial selection give a clear signal with respect to the resulting gene expression profile. The changes in gene expression in lines selected for increased longevity, desiccation and starvation resistance, respectively, showed high similarities. Cold resistance-selected lines showed little differentiation from controls. Different methods of heat selection (heat survival, heat knock down and constant 30 °C) showed little similarity verifying that different mechanisms are involved in high temperature adaptation. For most individual selection regimes, and in the comparison of all selected lines and controls, the gene expression changes were exclusively in one direction, although the different selection regimes varied in the direction of response. The responses to selection restricted to individual selection regimes can be interpreted as stress specific, whereas the response shared among all selected lines can be considered as a general stress response. Here, we identified genes belonging to both types of responses to selection for stress resistance.
To determine factors associated with outcomes following pelvic exenteration for advanced nonrectal pelvic malignancy.
The PelvEx Collaborative provides large volume data from specialist centers to ...ascertain factors associated with improved outcomes.
Consecutive patients who underwent pelvic exenteration for nonrectal pelvic malignancy between 2006 and 2017 were identified from 22 tertiary centers. Patient demographics, neoadjuvant therapy, histopathological assessment, length of stay, 30-day major complication/mortality rate were recorded.The primary endpoints were factors associated with survival. The secondary endpoints included the difference in margin rates across the cohorts, impact of neoadjuvant treatment on survival, associated morbidity, and mortality.
One thousand two hundred ninety-three patients were identified. 40.4% (n = 523) had gynecological malignancies (endometrial, ovarian, cervical, and vaginal), 35.7% (n = 462) urological (bladder), 18.1% (n = 234) anal, and 5.7% had sarcoma (n = 74).The median age across the cohort was 63 years (range, 23-85). The median 30-day mortality rate was 1.7%, with the highest rates occurring following exenteration for recurrent sarcoma or locally advanced cervical cancer (3.3% each). The median length of hospital stay was 17.5 days. 34.5% of patients experienced a major complication, with highest rate occurring in those having salvage surgery for anal cancer.Multivariable analysis showed R0 resection was the main factor associated with long-term survival. The 3-year overall-survival rate for R0 resection was 48% for endometrial malignancy, 40.6% for ovarian, 49.4% for cervical, 43.8% for vaginal, 59% for bladder, 48.3% for anal, and 48.1% for sarcoma.
Pelvic exenteration remains an important treatment in selected patients with advanced or recurrent nonrectal pelvic malignancy. The range in 3-year overall survival following R0 resection (40%-59%) reflects the diversity of tumor types.
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