The epithelium lining the airways of the adult human lung is composed of ciliated and secretory cells together with undifferentiated basal cells (BCs). The composition and organization of this ...epithelium is severely disrupted in many respiratory diseases. However, little is known about the mechanisms controlling airway homeostasis and repair after epithelial damage. Here, we exploit the mouse tracheobronchial epithelium, in which BCs function as resident stem cells, as a genetically tractable model of human small airways. Using a reporter allele we show that the low level of Notch signaling at steady state is greatly enhanced during repair and the generation of luminal progenitors. Loss-of-function experiments show that Notch signaling is required for the differentiation, but not self-renewal, of BCs. Moreover, sustained Notch activation in BCs promotes their luminal differentiation, primarily toward secretory lineages. We also provide evidence that this function of Notch signaling is conserved in BCs from human airways.
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► Notch signaling is active in steady-state airways and increased during repair ► Notch is required for differentiation, but not self-renewal, of airway basal cells ► Notch promotes luminal differentiation of mouse basal stem cells ► Functional evidence suggests that this mechanism is conserved in human basal cells
Conservation strategies based on charismatic flagship species, such as tigers, lions, and elephants, successfully attract funding from individuals and corporate donors. However, critics of this ...species-focused approach argue it wastes resources and often does not benefit broader biodiversity. If true, then the best way of raising conservation funds excludes the best way of spending it. Here we show that this conundrum can be resolved, and that the flagship species approach does not impede cost-effective conservation. Through a tailored prioritization approach, we identify places containing flagship species while also maximizing global biodiversity representation (based on 19,616 terrestrial and freshwater species). We then compare these results to scenarios that only maximized biodiversity representation, and demonstrate that our flagship-based approach achieves 79-89% of our objective. This provides strong evidence that prudently selected flagships can both raise funds for conservation and help target where these resources are best spent to conserve biodiversity.
Transforming growth factor beta 1 (TGFβ1) is strongly induced following brain injury and polarises microglia to an anti-inflammatory phenotype. Augmentation of TGFβ1 responses may therefore be ...beneficial in preventing inflammation in neurological disorders including stroke and neurodegenerative diseases. However, several other cell types display immunogenic potential and identifying the effect of TGFβ1 on these cells is required to more fully understand its effects on brain inflammation. Pericytes are multifunctional cells which ensheath the brain vasculature and have garnered recent attention with respect to their immunomodulatory potential. Here, we sought to investigate the inflammatory phenotype adopted by TGFβ1-stimulated human brain pericytes.
Microarray analysis was performed to examine transcriptome-wide changes in TGFβ1-stimulated pericytes, and results were validated by qRT-PCR and cytometric bead arrays. Flow cytometry, immunocytochemistry and LDH/Alamar Blue® viability assays were utilised to examine phagocytic capacity of human brain pericytes, transcription factor modulation and pericyte health.
TGFβ1 treatment of primary human brain pericytes induced the expression of several inflammatory-related genes (NOX4, COX2, IL6 and MMP2) and attenuated others (IL8, CX3CL1, MCP1 and VCAM1). A synergistic induction of IL-6 was seen with IL-1β/TGFβ1 treatment whilst TGFβ1 attenuated the IL-1β-induced expression of CX3CL1, MCP-1 and sVCAM-1. TGFβ1 was found to signal through SMAD2/3 transcription factors but did not modify nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) translocation. Furthermore, TGFβ1 attenuated the phagocytic ability of pericytes, possibly through downregulation of the scavenger receptors CD36, CD47 and CD68. Whilst TGFβ did decrease pericyte number, this was due to a reduction in proliferation, not apoptotic death or compromised cell viability.
TGFβ1 attenuated pericyte expression of key chemokines and adhesion molecules involved in CNS leukocyte trafficking and the modulation of microglial function, as well as reduced the phagocytic ability of pericytes. However, TGFβ1 also enhanced the expression of classical pro-inflammatory cytokines and enzymes which can disrupt BBB functioning, suggesting that pericytes adopt a phenotype which is neither solely pro- nor anti-inflammatory. Whilst the effects of pericyte modulation by TGFβ1 in vivo are difficult to infer, the reduction in pericyte proliferation together with the elevated IL-6, MMP-2 and NOX4 and reduced phagocytosis suggests a detrimental action of TGFβ1 on neurovasculature.
SnRK1 from Arabidopsis thaliana is an atypical AMPK Emanuelle, Shane; Hossain, Mohammed Iqbal; Moller, Isabel E. ...
Plant journal,
April 2015, 2015-Apr, 2015-04-00, 20150401, Letnik:
82, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Summary
SNF1‐related protein kinase 1 (SnRK1) is the plant orthologue of the evolutionarily‐conserved SNF1/AMPK/SnRK1 protein kinase family that contributes to cellular energy homeostasis. Functional ...as heterotrimers, family members comprise a catalytic α subunit and non‐catalytic β and γ subunits; multiple isoforms of each subunit type exist, giving rise to various isoenzymes. The Arabidopsis thaliana genome contains homologues of each subunit type, and, in addition, two atypical subunits, β3 and βγ, with unique domain architecture, that are found only amongst plants, suggesting atypical heterotrimers. The AtSnRK1 subunit structure was determined using recombinant protein expression and endogenous co‐immunoprecipitation, and six unique isoenzyme combinations were identified. Each heterotrimeric isoenzyme comprises a catalytic α subunit together with the unique βγ subunit and one of three non‐catalytic β subunits: β1, β2 or the plant‐specific β3 isoform. Thus, the AtSnRK1 heterotrimers contain the atypical βγ subunit rather than a conventional γ subunit. Mammalian AMPK heterotrimers are phosphorylated on the T–loop (pThr175/176) within both catalytic a subunits. However, AtSnRK1 is insensitive to AMP and ADP, and is resistant to T–loop dephosphorylation by protein phosphatases, a process that inactivates other SNF1/AMPK family members. In addition, we show that SnRK1 is inhibited by a heat‐labile, >30 kDa, soluble proteinaceous factor that is present in the lysate of young rosette leaves. Finally, none of the three SnRK1 carbohydrate‐binding modules, located in the β1, β2 and βγ subunits, associate with various carbohydrates, including starch, the plant analogue of glycogen to which AMPK binds in vitro. These data clearly demonstrate that AtSnRK1 is an atypical member of the SNF1/AMPK/SnRK1 family.
Significance Statement
Here we show that SnRK1, an energy‐sensing enzyme found in plants, can exist as six different isoenzymes. Compared to AMP‐activated protein kinase, the mammalian homologue, SnRK1 is not affected by phosphorylation, nucleotides or carbohydrates. This knowledge will contribute to understanding the role of SnRK1 in how plants cope with stress and maintain crop yield.
IMPORTANCE: Endovascular thrombectomy with second-generation devices is beneficial for patients with ischemic stroke due to intracranial large-vessel occlusions. Delineation of the association of ...treatment time with outcomes would help to guide implementation. OBJECTIVE: To characterize the period in which endovascular thrombectomy is associated with benefit, and the extent to which treatment delay is related to functional outcomes, mortality, and symptomatic intracranial hemorrhage. DESIGN, SETTING, AND PATIENTS: Demographic, clinical, and brain imaging data as well as functional and radiologic outcomes were pooled from randomized phase 3 trials involving stent retrievers or other second-generation devices in a peer-reviewed publication (by July 1, 2016). The identified 5 trials enrolled patients at 89 international sites. EXPOSURES: Endovascular thrombectomy plus medical therapy vs medical therapy alone; time to treatment. MAIN OUTCOMES AND MEASURES: The primary outcome was degree of disability (mRS range, 0-6; lower scores indicating less disability) at 3 months, analyzed with the common odds ratio (cOR) to detect ordinal shift in the distribution of disability over the range of the mRS; secondary outcomes included functional independence at 3 months, mortality by 3 months, and symptomatic hemorrhagic transformation. RESULTS: Among all 1287 patients (endovascular thrombectomy + medical therapy n = 634; medical therapy alone n = 653) enrolled in the 5 trials (mean age, 66.5 years SD, 13.1; women, 47.0%), time from symptom onset to randomization was 196 minutes (IQR, 142 to 267). Among the endovascular group, symptom onset to arterial puncture was 238 minutes (IQR, 180 to 302) and symptom onset to reperfusion was 286 minutes (IQR, 215 to 363). At 90 days, the mean mRS score was 2.9 (95% CI, 2.7 to 3.1) in the endovascular group and 3.6 (95% CI, 3.5 to 3.8) in the medical therapy group. The odds of better disability outcomes at 90 days (mRS scale distribution) with the endovascular group declined with longer time from symptom onset to arterial puncture: cOR at 3 hours, 2.79 (95% CI, 1.96 to 3.98), absolute risk difference (ARD) for lower disability scores, 39.2%; cOR at 6 hours, 1.98 (95% CI, 1.30 to 3.00), ARD, 30.2%; cOR at 8 hours,1.57 (95% CI, 0.86 to 2.88), ARD, 15.7%; retaining statistical significance through 7 hours and 18 minutes. Among 390 patients who achieved substantial reperfusion with endovascular thrombectomy, each 1-hour delay to reperfusion was associated with a less favorable degree of disability (cOR, 0.84 95% CI, 0.76 to 0.93; ARD, −6.7%) and less functional independence (OR, 0.81 95% CI, 0.71 to 0.92, ARD, −5.2% 95% CI, −8.3% to −2.1%), but no change in mortality (OR, 1.12 95% CI, 0.93 to 1.34; ARD, 1.5% 95% CI, −0.9% to 4.2%). CONCLUSIONS AND RELEVANCE: In this individual patient data meta-analysis of patients with large-vessel ischemic stroke, earlier treatment with endovascular thrombectomy + medical therapy compared with medical therapy alone was associated with lower degrees of disability at 3 months. Benefit became nonsignificant after 7.3 hours.
In many animals, exaggerated sex-typical male traits are preferred by females, and may be a signal of both past and current disease resistance. The proposal that the same is true in humans--i.e., ...that masculine men are immunocompetent and attractive--underpins a large literature on facial masculinity preferences. Recently, theoretical models have suggested that current condition may be a better index of mate value than past immunocompetence. This is particularly likely in populations where pathogenic fluctuation is fast relative to host life history. As life history is slow in humans, there is reason to expect that, among humans, condition-dependent traits might contribute more to attractiveness than relatively stable traits such as masculinity. To date, however, there has been little rigorous assessment of whether, in the presence of variation in other cues, masculinity predicts attractiveness or not.
The relationship between masculinity and attractiveness was assessed in two samples of male faces. Most previous research has assessed masculinity either with subjective ratings or with simple anatomical measures. Here, we used geometric morphometric techniques to assess facial masculinity, generating a morphological masculinity measure based on a discriminant function that correctly classified >96% faces as male or female. When assessed using this measure, there was no relationship between morphological masculinity and rated attractiveness. In contrast, skin colour--a fluctuating, condition-dependent cue--was a significant predictor of attractiveness.
These findings suggest that facial morphological masculinity may contribute less to men's attractiveness than previously assumed. Our results are consistent with the hypothesis that current condition is more relevant to male mate value than past disease resistance, and hence that temporally fluctuating traits (such as colour) contribute more to male attractiveness than stable cues of sexual dimorphism.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
ABSTRACT We present a comprehensive analysis of the structural properties and luminosities of the 23 dwarf spheroidal galaxies that fall within the footprint of the Pan-Andromeda Archaeological ...Survey (PAndAS). These dwarf galaxies represent the large majority of Andromeda's known satellite dwarf galaxies and cover a wide range in luminosity ( or ) and surface brightness ( mag arcsec−2). We confirm most previous measurements, but we find And XIX to be significantly larger than before ( , ) and cannot derive parameters for And XXVII as it is likely not a bound stellar system. We also significantly revise downward the luminosities of And XV and And XVI, which are now or . Finally, we provide the first detailed analysis of Cas II/And XXX, a fairly faint system ( ) of typical size ( ), located in close proximity to the two bright elliptical dwarf galaxies NGC 147 and NGC 185. Combined with the set of homogeneous distances published in an earlier contribution, our analysis dutifully tracks all relevant sources of uncertainty in the determination of the properties of the dwarf galaxies from the PAndAS photometric catalog. We further publish the posterior probability distribution functions of all the parameters we fit for in the form of MCMC chains available online; these inputs should be used in any analysis that aims to remain truthful to the data and properly account for covariance between parameters.
Phosphorylation-type (P-type) ATPases are ubiquitous primary transporters that pump cations across cell membranes through the formation and breakdown of a phosphoenzyme intermediate. Structural ...investigations suggest that the transport mechanism is defined by conformational changes in the cytoplasmic domains of the protein that are allosterically coupled to transmembrane helices so as to expose ion binding sites to alternate sides of the membrane. Here, we have used single-molecule fluorescence resonance energy transfer to directly observe conformational changes associated with the functional transitions in the Listeria monocytogenes Ca
-ATPase (LMCA1), an orthologue of eukaryotic Ca
-ATPases. We identify key intermediates with no known crystal structures and show that Ca
efflux by LMCA1 is rate-limited by phosphoenzyme formation. The transport process involves reversible steps and an irreversible step that follows release of ADP and extracellular release of Ca
.
IMPORTANCE: Individuals can be classified as being at clinical high risk (CHR) for psychosis if they meet at least one of the ultra–high-risk (UHR) inclusion criteria (brief limited intermittent ...psychotic symptoms BLIPS and/or attenuated psychotic symptoms APS and/or genetic risk and deterioration syndrome GRD) and/or basic symptoms BS. The meta-analytical risk of psychosis of these different subgroups is still unknown. OBJECTIVE: To compare the risk of psychosis in CHR individuals who met at least one of the major inclusion criteria and in individuals not at CHR for psychosis (CHR−). DATA SOURCES: Electronic databases (Web of Science, MEDLINE, Scopus) were searched until June 18, 2015, along with investigation of citations of previous publications and a manual search of the reference lists of retrieved articles. STUDY SELECTION: We included original follow-up studies of CHR individuals who reported the risk of psychosis classified according to the presence of any BLIPS, APS and GRD, APS alone, GRD alone, BS, and CHR−. DATA EXTRACTION AND SYNTHESIS: Independent extraction by multiple observers and random-effects meta-analysis of proportions. Moderators were tested with meta-regression analyses (Bonferroni corrected). Heterogeneity was assessed with the I2 index. Sensitivity analyses tested robustness of results. Publication biases were assessed with funnel plots and the Egger test. MAIN OUTCOMES AND MEASURES: The proportion of each subgroup with any psychotic disorder at 6, 12, 24, 36, and 48 or more months of follow-up. RESULTS: Thirty-three independent studies comprising up to 4227 individuals were included. The meta-analytical proportion of individuals meeting each UHR subgroup at intake was: 0.85 APS (95%CI, 0.79-0.90), 0.1 BLIPS (95%CI, 0.06-0.14), and 0.05 GRD (95%CI, 0.03-0.07). There were no significant differences in psychosis risk at any time point between the APS and GRD and the APS-alone subgroups. There was a higher risk of psychosis in the any BLIPS greater than APS greater than GRD-alone subgroups at 24, 36, and 48 or more months of follow-up. There was no evidence that the GRD subgroup has a higher risk of psychosis than the CHR− subgroup. There were too few BS or BS and UHR studies to allow robust conclusions. CONCLUSIONS AND RELEVANCE: There is meta-analytical evidence that BLIPS represents separate risk subgroup compared with the APS. The GRD subgroup is infrequent and not associated with an increased risk of psychosis. Future studies are advised to stratify their findings across these different subgroups. The CHR guidelines should be updated to reflect these differences.
Summary Background In 2015, five randomised trials showed efficacy of endovascular thrombectomy over standard medical care in patients with acute ischaemic stroke caused by occlusion of arteries of ...the proximal anterior circulation. In this meta-analysis we, the trial investigators, aimed to pool individual patient data from these trials to address remaining questions about whether the therapy is efficacious across the diverse populations included. Methods We formed the HERMES collaboration to pool patient-level data from five trials (MR CLEAN, ESCAPE, REVASCAT, SWIFT PRIME, and EXTEND IA) done between December, 2010, and December, 2014. In these trials, patients with acute ischaemic stroke caused by occlusion of the proximal anterior artery circulation were randomly assigned to receive either endovascular thrombectomy within 12 h of symptom onset or standard care (control), with a primary outcome of reduced disability on the modified Rankin Scale (mRS) at 90 days. By direct access to the study databases, we extracted individual patient data that we used to assess the primary outcome of reduced disability on mRS at 90 days in the pooled population and examine heterogeneity of this treatment effect across prespecified subgroups. To account for between-trial variance we used mixed-effects modelling with random effects for parameters of interest. We then used mixed-effects ordinal logistic regression models to calculate common odds ratios (cOR) for the primary outcome in the whole population (shift analysis) and in subgroups after adjustment for age, sex, baseline stroke severity (National Institutes of Health Stroke Scale score), site of occlusion (internal carotid artery vs M1 segment of middle cerebral artery vs M2 segment of middle cerebral artery), intravenous alteplase (yes vs no), baseline Alberta Stroke Program Early CT score, and time from stroke onset to randomisation. Findings We analysed individual data for 1287 patients (634 assigned to endovascular thrombectomy, 653 assigned to control). Endovascular thrombectomy led to significantly reduced disability at 90 days compared with control (adjusted cOR 2·49, 95% CI 1·76–3·53; p<0·0001). The number needed to treat with endovascular thrombectomy to reduce disability by at least one level on mRS for one patient was 2·6. Subgroup analysis of the primary endpoint showed no heterogeneity of treatment effect across prespecified subgroups for reduced disability (pinteraction =0·43). Effect sizes favouring endovascular thrombectomy over control were present in several strata of special interest, including in patients aged 80 years or older (cOR 3·68, 95% CI 1·95–6·92), those randomised more than 300 min after symptom onset (1·76, 1·05–2·97), and those not eligible for intravenous alteplase (2·43, 1·30–4·55). Mortality at 90 days and risk of parenchymal haematoma and symptomatic intracranial haemorrhage did not differ between populations. Interpretation Endovascular thrombectomy is of benefit to most patients with acute ischaemic stroke caused by occlusion of the proximal anterior circulation, irrespective of patient characteristics or geographical location. These findings will have global implications on structuring systems of care to provide timely treatment to patients with acute ischaemic stroke due to large vessel occlusion. Funding Medtronic.
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