Digoxin Suppresses Pyruvate Kinase M2-Promoted HIF-1α Transactivation in Steatohepatitis

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Quantifying the importance of geographic replication and representativeness when estimating demographic rates,using a coastal species as a case study

Demographic rates are rarely estimated over an entire species range, limiting empirical tests of ecological patterns and theories, and raising questions about the representativeness of studies that use data from a small part of a range. The uncertainty that results from using demographic rates from just a few sites is especially pervasive in population projections, which are critical for a wide range of questions in ecology and conservation. We developed a simple simulation to quantify how this lack of geographic representativeness can affect inferences about the global mean and variance of growth rates, which has implications for the robust design of a wide range of population studies. Using a coastal songbird, saltmarsh sparrow Ammodramus caudacutus, as a case study, we first estimated survival, fecundity, and population growth rates at 21 sites distributed across much of their breeding range. We then subsampled this large, representative dataset according to five sampling scenarios in order to simulate a variety of geographic biases in study design. We found spatial variation in demographic rates, but no large systematic patterns. Estimating the global mean and variance of growth rates using subsets of the data suggested that at least 10–15 sites were required for reasonably unbiased estimates, highlighting how relying on demographic data from just a few sites can lead to biased results when extrapolating across a species range. Sampling at the full 21 sites, however, offered diminishing returns, raising the possibility that for some species accepting some geographical bias in sampling can still allow for robust range‐wide inferences. The subsampling approach presented here, while conceptually simple, could be used with both new and existing data to encourage efficiency in the design of long‐term or large‐scale ecological studies.     

Role of CD25+ dendritic cells in the generation of Th17 autoreactive T cells in autoimmune experimental uveitis

In the current study, we showed that in vivo administration of an anti-CD25 Ab (PC61) decreased the Th17 response in C57BL/6 mice immunized with the uveitogenic peptide interphotoreceptor retinoid-binding protein, while enhancing the autoreactive Th1 response. The depressed Th17 response was closely associated with decreased numbers of a splenic dendritic cell (DC) subset expressing CD11c(+)CD3(-)CD25(+) and decreased expansion of γδ T cells. We demonstrated that ablation of the CD25(+) DC subset accounted for the decreased activation and the expansion of γδ T cells, leading to decreased activation of IL-17(+) interphotoreceptor retinoid-binding protein-specific T cells. Our results show that an enhanced Th17 response in an autoimmune disease is associated with the appearance of a DC subset expressing CD25 and that treatment of mice with anti-CD25 Ab causes functional alterations in a number of immune cell types, namely DCs and γδ T cells, in addition to CD25(+)αβTCR(+) regulatory T cells.     

Using a bistable animal opsin for switchable and scalable optogenetic inhibition of neurons

There is no consensus on the best inhibitory optogenetic tool. Since Gi/o signalling is a native mechanism of neuronal inhibition, we asked whether Lamprey Parapinopsin (“Lamplight”), a Gi/o‐coupled bistable animal opsin, could be used for optogenetic silencing. We show that short (405 nm) and long (525 nm) wavelength pulses repeatedly switch Lamplight between stable signalling active and inactive states, respectively, and that combining these wavelengths can be used to achieve intermediate levels of activity. These properties can be applied to produce switchable neuronal hyperpolarisation and suppression of spontaneous spike firing in the mouse hypothalamic suprachiasmatic nucleus. Expressing Lamplight in (predominantly) ON bipolar cells can photosensitise retinas following advanced photoreceptor degeneration, with 405 and 525 nm stimuli producing responses of opposite sign in the output neurons of the retina. We conclude that bistable animal opsins can co‐opt endogenous signalling mechanisms to allow optogenetic inhibition that is scalable, sustained and reversible.     

Using genetic variants to evaluate the causal effect of cholesterol lowering on head and neck cancer risk: A Mendelian randomization study

Head and neck squamous cell carcinoma (HNSCC), which includes cancers of the oral cavity and oropharynx, is a cause of substantial global morbidity and mortality. Strategies to reduce disease burden include discovery of novel therapies and repurposing of existing drugs. Statins are commonly prescribed for lowering circulating cholesterol by inhibiting HMG-CoA reductase (HMGCR). Results from some observational studies suggest that statin use may reduce HNSCC risk. We appraised the relationship of genetically-proxied cholesterol-lowering drug targets and other circulating lipid traits with oral (OC) and oropharyngeal (OPC) cancer risk using two-sample Mendelian randomization (MR). For the primary analysis, germline genetic variants in HMGCR, NPC1L1, CETP, PCSK9 and LDLR were used to proxy the effect of low-density lipoprotein cholesterol (LDL-C) lowering therapies. In secondary analyses, variants were used to proxy circulating levels of other lipid traits in a genome-wide association study (GWAS) meta-analysis of 188,578 individuals. Both primary and secondary analyses aimed to estimate the downstream causal effect of cholesterol lowering therapies on OC and OPC risk. The second sample for MR was taken from a GWAS of 6,034 OC and OPC cases and 6,585 controls (GAME-ON). Analyses were replicated in UK Biobank, using 839 OC and OPC cases and 372,016 controls and the results of the GAME-ON and UK Biobank analyses combined in a fixed-effects meta-analysis. We found limited evidence of a causal effect of genetically-proxied LDL-C lowering using HMGCR, NPC1L1, CETP or other circulating lipid traits on either OC or OPC risk. Genetically-proxied PCSK9 inhibition equivalent to a 1 mmol/L (38.7 mg/dL) reduction in LDL-C was associated with an increased risk of OC and OPC combined (OR 1.8 95%CI 1.2, 2.8, p = 9.31 x10^-05), with good concordance between GAME-ON and UK Biobank (I² = 22%). Effects for PCSK9 appeared stronger in relation to OPC (OR 2.6 95%CI 1.4, 4.9) than OC (OR 1.4 95%CI 0.8, 2.4). LDLR variants, resulting in genetically-proxied reduction in LDL-C equivalent to a 1 mmol/L (38.7 mg/dL), reduced the risk of OC and OPC combined (OR 0.7, 95%CI 0.5, 1.0, p = 0.006). A series of pleiotropy-robust and outlier detection methods showed that pleiotropy did not bias our findings. We found limited evidence for a role of cholesterol-lowering in OC and OPC risk, suggesting previous observational results may have been confounded. There was some evidence that genetically-proxied inhibition of PCSK9 increased risk, while lipid-lowering variants in LDLR, reduced risk of combined OC and OPC. This result suggests that the mechanisms of action of PCSK9 on OC and OPC risk may be independent of its cholesterol lowering effects; however, this was not supported uniformly across all sensitivity analyses and further replication of this finding is required.     

Reaching out in anticipation: bacterial membrane extensions represent a permanent investment in polysaccharide sensing and utilization

Outer membrane extensions are common in many marine bacteria. However, the function of these surface enlargements or extracellular compartments is poorly understood. Using a combined approach of microscopy and subproteome analyses, we therefore examined Pseudoalteromonas distincta ANT/505, an Antarctic polysaccharide degrading gamma-proteobacterium. P. distincta produced outer membrane vesicles (MV) and vesicle chains (VC) on polysaccharide and non-polysaccharide carbon sources during the exponential and stationary growth phase. Surface structures of carbohydrate-grown cells were equipped with increased levels of highly substrate-specific proteins. At the same time, proteins encoded in all other polysaccharide degradation-related genomic regions were also detected in MV and VC samples under all growth conditions, indicating a basal expression. In addition, two alkaline phosphatases were highly abundant under non-limiting phosphate conditions. Surface structures may thus allow rapid sensing and fast responses in nutritionally deprived environments. It may also facilitate efficient carbohydrate processing and reduce loss of substrates and enzymes by diffusion as important adaptions to the aquatic ecosystem.     

Understanding ‘it depends’ in ecology: a guide to hypothesising,visualising and interpreting statistical interactions

Ecologists routinely use statistical models to detect and explain interactions among ecological drivers, with a goal to evaluate whether an effect of interest changes in sign or magnitude in different contexts. Two fundamental properties of interactions are often overlooked during the process of hypothesising, visualising and interpreting interactions between drivers: the measurement scale – whether a response is analysed on an additive or multiplicative scale, such as a ratio or logarithmic scale; and the symmetry – whether dependencies are considered in both directions. Overlooking these properties can lead to one or more of three inferential errors: misinterpretation of (i) the detection and magnitude (Type-D error), and (ii) the sign of effect modification (Type-S error); and (iii) misidentification of the underlying processes (Type-A error). We illustrate each of these errors with a broad range of ecological questions applied to empirical and simulated data sets. We demonstrate how meta-analysis, a widely used approach that seeks explicitly to characterise context dependence, is especially prone to all three errors. Based on these insights, we propose guidelines to improve hypothesis generation, testing, visualisation and interpretation of interactions in ecology.