Search

Sepsis affects 25 million children per year globally, leading to 2.9 million deaths and substantial disability in survivors. Extensive characterization of interactions between the host and bacteria in children is required to design novel preventive and therapeutic strategies tailored to this age group. Vγ9Vδ2 T cells are the first T cells generated in humans. These cells are defined by the expression of Vγ9Vδ2 T-cell receptors (TCRs, using the TRGV9 and TRDV2 gene segments), which react strongly against the prototypical bacterial phosphoantigen HMBPP. We investigated this reactivity by analyzing the TCR δ (TRD) repertoire in the blood of 76 children (0-16 years) with blood culture-proven bacterial sepsis caused by HMBPP-positive Escherichia coli or by HMBPP-negative Staphylococcus aureus or by HMBPP-negative Streptococcus pneumoniae. Strikingly, we found that S. aureus, and to a lesser extent E. coli but not S. pneumoniae, shaped the TRDV2 repertoire in young children (<2 years) but not in older children or adults. This dichotomy was due to the selective expansion of a fetal TRDV2 repertoire. Thus, young children possess fetal-derived Vγ9Vδ2 T cells that are highly responsive toward specific bacterial pathogens., (© 2024 The Author(s). European Journal of Immunology published by Wiley‐VCH GmbH.)

Understanding recruitment, the process by which individuals are added to a population or to a fishery, is critical for understanding population dynamics and facilitating sustainable fisheries management. Important variation in recruitment dynamics is observed among populations, wherein some populations exhibit asymptotic productivity and others exhibit overcompensation (i.e., compensatory density-dependence in recruitment). Our ability to understand this interpopulation variability in recruitment patterns is limited by a poor understanding of the underlying mechanisms, such as the complex interactions between density dependence, recruitment, and environment. Furthermore, most studies on recruitment are conducted using an observational design with long time series that are seldom replicated across populations in an experimentally controlled fashion. Without proper replication, extrapolations between populations are tenuous, and the underlying environmental trends are challenging to quantify. To address these issues, we conducted a field experiment manipulating stocking densities of juvenile brook trout Salvelinus fontinalis in three wild populations to show that these neighboring populations-which exhibit divergent patterns of density dependence due to environmental conditions-also have important differences in recruitment dynamics. Testing against four stock-recruitment models (density independent, linear, Beverton-Holt, and Ricker), populations exhibited ~twofold variation in asymptotic productivity, with no overcompensation following a Beverton-Holt model. Although environmental variables (e.g., temperature, pH, depth, substrate) correlated with population differences in recruitment, they did not improve the predictive power in individual populations. Comparing our patterns of recruitment with classic salmonid case studies revealed that despite differences in the shape and parameters of the curves (i.e., Ricker vs. Beverton-Holt), a maximum stocking density of about five YOY fish/m 2 emerged. Higher densities resulted in very marginal increases in recruitment (Beverton-Holt) or reduced recruitment due to overcompensation (Ricker)., (© 2024 The Authors. Journal of Fish Biology published by John Wiley & Sons Ltd on behalf of Fisheries Society of the British Isles.)

Aim: To evaluate the prevalence and clinical characteristics of limbal stem cell deficiency (LSCD) in the setting of a tertiary referral cornea practice at an academic center., Patient and Methods: A retrospective chart review was performed to identify all unique medical record numbers (MRNs) presenting to a single cornea specialist (JHH) at the University of Minnesota during calendar years 2019 and 2020. Records were queried and confirmed for a diagnosis of LSCD. Clinical characteristics of identified patients, including demographics, etiology of LSCD, severity of LSCD, treatment, and best corrected visual acuity (BCVA) at final follow-up, were documented., Results: In total 1436 unique MRNs were identified over the study period. There were 61 individuals (91 eyes) diagnosed with LSCD, resulting in a prevalence of 4.25% (95% CI, 3.33-5.42). Of 91 eyes, 60 eyes were bilateral (65.9%). Among all eyes, ocular surface burns were the most common etiology (18.7%) followed by iatrogenic or medicamentosa (15.4%). There were 51 eyes (56.0%) that underwent some form of transplantation. The median BCVA at final follow-up was Snellen 20/80 (range 20/20 to no light perception)., Conclusions: The prevalence of LSCD found at a cornea subspecialty tertiary referral center in our study was much higher than previously reported prevalence rates. This may reflect referral bias and potential underdiagnosis of LSCD in practices outside of subspecialty referral centers. The high prevalence rate in our study also suggests that LSCD patients are concentrated in subspecialty referral practices, with many having high morbidity disease. This constitutes a major health burden for these practices., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Goldberg, Fraser and Hou.)

Effective population size (N e ) is a particularly useful metric for conservation as it affects genetic drift, inbreeding and adaptive potential within populations. Current guidelines recommend a minimum N e of 50 and 500 to avoid short-term inbreeding and to preserve long-term adaptive potential respectively. However, the extent to which wild populations reach these thresholds globally has not been investigated, nor has the relationship between N e and human activities. Through a quantitative review, we generated a dataset with 4610 georeferenced N e estimates from 3829 populations, extracted from 723 articles. These data show that certain taxonomic groups are less likely to meet 50/500 thresholds and are disproportionately impacted by human activities; plant, mammal and amphibian populations had a <54% probability of reaching N ̂ e = 50 and a <9% probability of reaching N ̂ e = 500. Populations listed as being of conservation concern according to the IUCN Red List had a smaller median N ̂ e than unlisted populations, and this was consistent across all taxonomic groups. N ̂ e was reduced in areas with a greater Global Human Footprint, especially for amphibians, birds and mammals, however relationships varied between taxa. We also highlight several considerations for future works, including the role that gene flow and subpopulation structure plays in the estimation of N ̂ e in wild populations, and the need for finer-scale taxonomic analyses. Our findings provide guidance for more specific thresholds based on N e and help prioritise assessment of populations from taxa most at risk of failing to meet conservation thresholds., (© 2024 The Authors. Molecular Ecology published by John Wiley & Sons Ltd.)

Predicting the persistence of species under climate change is an increasingly important objective in ecological research and management. However, biotic and abiotic heterogeneity can drive asynchrony in population responses at small spatial scales, complicating species-level assessments. For widely distributed species consisting of many fragmented populations, such as brook trout (Salvelinus fontinalis), understanding the drivers of asynchrony in population dynamics can improve the predictions of range-wide climate impacts. We analyzed the demographic time series from mark-recapture surveys of 11 natural brook trout populations in eastern Canada over 13 years to examine the extent, drivers, and consequences of fine-scale population variation. The focal populations were genetically differentiated, occupied a small area (~25 km 2 ) with few human impacts, and experienced similar climate conditions. Recruitment was highly asynchronous, weakly related to climate variables and showed population-specific relationships with other demographic processes, generating diverse population dynamics. In contrast, individual growth was mostly synchronized among populations and driven by a shared positive relationship with stream temperature. Outputs from population-specific models were unrelated to four of the five hypothesized drivers (recruitment, growth, reproductive success, phylogenetic distance), but variation in groundwater inputs strongly influenced stream temperature regimes and stock-recruitment relationships. Finally, population asynchrony generated a portfolio effect that stabilized regional species abundance. Our results demonstrated that population demographics and habitat diversity at microgeographic scales can play a significant role in moderating species responses to climate change. Moreover, we suggest that the absence of human activities within study streams preserved natural habitat variation and contributed to asynchrony in brook trout abundance, while the small study area eased monitoring and increased the likelihood of detecting asynchrony. Therefore, anthropogenic habitat degradation, landscape context, and spatial scale must be considered when developing management strategies to monitor and maintain populations that are diverse, stable, and resilient to climate change., (© 2023 The Authors. Ecological Applications published by Wiley Periodicals LLC on behalf of The Ecological Society of America.)

The acute kidney injury (AKI) and dose-limiting nephrotoxicity, which occurs in 20-60% of patients following systemic administration of colistin, represents a challenge in the effective treatment of multi-drug resistant Gram-negative infections. To reduce clinical toxicity of colistin and improve targeting to infected/inflamed tissues, we previously developed dextrin-colistin conjugates, whereby colistin is designed to be released by amylase-triggered degradation of dextrin in infected and inflamed tissues, after passive targeting by the enhanced permeability and retention effect. Whilst it was evident in vitro that polymer conjugation can reduce toxicity and prolong plasma half-life, without significant reduction in antimicrobial activity of colistin, it was unclear how dextrin conjugation would alter cellular uptake and localisation of colistin in renal tubular cells in vivo . We discovered that dextrin conjugation effectively reduced colistin's toxicity towards human kidney proximal tubular epithelial cells (HK-2) in vitro , which was mirrored by significantly less cellular uptake of Oregon Green (OG)-labelled dextrin-colistin conjugate, when compared to colistin. Using live-cell confocal imaging, we revealed localisation of both, free and dextrin-bound colistin in endolysosome compartments of HK-2 and NRK-52E cells. Using a murine AKI model, we demonstrated dextrin-colistin conjugation dramatically diminishes both proximal tubular injury and renal accumulation of colistin. These findings reveal new insight into the mechanism by which dextrin conjugation can overcome colistin's renal toxicity and show the potential of polymer conjugation to improve the side effect profile of nephrotoxic drugs., Competing Interests: None to declare., (This journal is © The Royal Society of Chemistry.)

Purpose of Review: MicroRNAs (miRNAs) are emerging rapidly as a novel class of biomarkers of major organ disorders, including kidney diseases. However, current PCR-based detection methods are not amenable to development for high-throughput, cost-effective miRNA biomarker quantification., Recent Findings: MiRNA biomarkers show significant promise for diagnosis and prognosis of kidney diseases, including diabetic kidney disease, acute kidney injury, IgA nephropathy and delayed graft function following kidney transplantation. A variety of novel methods to detect miRNAs in liquid biopsies including urine, plasma and serum are being developed. As miRNAs are functional transcripts that regulate the expression of many protein coding genes, differences in miRNA profiles in disease also offer clues to underlying disease mechanisms., Summary: Recent findings highlight the potential of miRNAs as biomarkers to detect and predict progression of kidney diseases. Developing in parallel, novel methods for miRNA detection will facilitate the integration of these biomarkers into rapid routine clinical testing and existing care pathways. Validated kidney disease biomarkers also hold promise to identify novel therapeutic tools and targets., Video Abstract: http://links.lww.com/CONH/A43., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: We reported increased spleen tyrosine kinase (SYK) expression in kidney biopsies of patients with IgA nephropathy (IgAN) and that inhibition of SYK reduces inflammatory cytokines production from IgA stimulated mesangial cells., Methods: This study was a double-blind, randomized, placebo-controlled phase 2 trial of fostamatinib (an oral SYK inhibitor) in 76 patients with IgAN. Patients were randomized to receive placebo, fostamatinib at 100 mg or 150 mg twice daily for 24 weeks on top of maximum tolerated dose of renin-angiotensin system inhibitors. The primary end point was reduction of proteinuria. Secondary end points included change from baseline in estimated glomerular filtration rate (eGFR) and kidney histology., Results: Although we could not detect significant reduction in proteinuria with fostamatinib overall, in a predetermined subgroup analysis, there was a trend for dose-dependent reduction in median proteinuria (from baseline to 24 weeks by 14%, 27%, and 36% in the placebo, fostamatinib 100 mg, and 150 mg groups, respectively) in patients with baseline urinary protein-to-creatinine ratios (UPCR) more than 1000 mg/g. Kidney function (eGFR) remained stable in all groups. Fostamatinib was well-tolerated. Side effects included diarrhea, hypertension, and increased liver enzymes. Thirty-nine patients underwent repeat biopsy showing reductions in SYK staining associated with therapy at low dose (-1.5 vs. 1.7 SYK+ cells/glomerulus in the placebo group, P  < 0.05)., Conclusions: There was a trend toward reduction in proteinuria with fostamatinib in a predefined analysis of high risk patients with IgAN despite maximal care, as defined by baseline UPCR greater than 1000 mg/g. Further study may be warranted., (© 2023 International Society of Nephrology. Published by Elsevier Inc.)

The broad scale distribution of population-specific genetic diversity (GD P ) across taxa remains understudied relative to species diversity gradients, despite its relevance for systematic conservation planning. We used nuclear DNA data collected from 3678 vertebrate populations across the Americas to assess the role of environmental and spatial variables in structuring the distribution of GD P , a key component of adaptive potential in the face of environmental change. We specifically assessed non-linear trends for a metric of GD P, expected heterozygosity (H E ), and found more evidence for spatial hotspots and cold spots in H E rather than a strict pattern with latitude. We also detected inconsistent relationships between H E and environmental variables, where only 11 of 30 environmental comparisons among taxa groups were statistically significant at the .05 level, and the shape of significant trends differed substantially across vertebrate groups. Only one of six taxonomic groups, freshwater fishes, consistently showed significant relationships between H E and most (four of five) environmental variables. The remaining groups had statistically significant relationships for either two (amphibians, reptiles), one (birds, mammals), or no variables (anadromous fishes). Our study highlights gaps in the theoretical foundation upon which macrogenetic predictions have been made thus far in the literature, as well as the nuances for assessing broad patterns in GD P among vertebrate groups. Overall, our results suggest a disconnect between patterns of species and genetic diversity, and underscores that large-scale factors affecting genetic diversity may not be the same factors as those shaping taxonomic diversity. Thus, careful spatial and taxonomic-specific considerations are needed for applying macrogenetics to conservation planning., (© 2023 The Authors. Molecular Ecology published by John Wiley & Sons Ltd.)

Salmonids are of immense socio-economic importance in much of the world, but are threatened by climate change. This has generated a substantial literature documenting the effects of climate variation on salmonid productivity in freshwater ecosystems, but there has been no global quantitative synthesis across studies. We conducted a systematic review and meta-analysis to gain quantitative insight into key factors shaping the effects of climate on salmonid productivity, ultimately collecting 1321 correlations from 156 studies, representing 23 species across 24 countries. Fisher's Z was used as the standardized effect size, and a series of weighted mixed-effects models were compared to identify covariates that best explained variation in effects. Patterns in climate effects were complex and were driven by spatial (latitude, elevation), temporal (time-period, age-class), and biological (range, habitat type, anadromy) variation within and among study populations. These trends were often consistent with predictions based on salmonid thermal tolerances. Namely, warming and decreased precipitation tended to reduce productivity when high temperatures challenged upper thermal limits, while opposite patterns were common when cold temperatures limited productivity. Overall, variable climate impacts on salmonids suggest that future declines in some locations may be counterbalanced by gains in others. In particular, we suggest that future warming should (1) increase salmonid productivity at high latitudes and elevations (especially >60° and >1500 m), (2) reduce productivity in populations experiencing hotter and dryer growing season conditions, (3) favor non-native over native salmonids, and (4) impact lentic populations less negatively than lotic ones. These patterns should help conservation and management organizations identify populations most vulnerable to climate change, which can then be prioritized for protective measures. Our framework enables broad inferences about future productivity that can inform decision-making under climate change for salmonids and other taxa, but more widespread, standardized, and hypothesis-driven research is needed to expand current knowledge., (© 2022 The Authors. Global Change Biology published by John Wiley & Sons Ltd.)

Sustainable management of exploited populations benefits from integrating demographic and genetic considerations into assessments, as both play a role in determining harvest yields and population persistence. This is especially important in populations subject to size-selective harvest, because size selective harvesting has the potential to result in significant demographic, life-history, and genetic changes. We investigated harvest-induced changes in the effective number of breeders ( N ^ b ) for introduced brook trout populations ( Salvelinus fontinalis ) in alpine lakes from western Canada. Three populations were subject to 3 years of size-selective harvesting, while three control populations experienced no harvest. The N ^ c decreased consistently across all harvested populations (on average 60.8%) but fluctuated in control populations. There were no consistent changes in N ^ b between control or harvest populations, but one harvest population experienced a decrease in N ^ b of 63.2%. The N ^ b / N ^ c ratio increased consistently across harvest lakes; however we found no evidence of genetic compensation (where variance in reproductive success decreases at lower abundance) based on changes in family evenness ( FE ^ ) and the number of full-sibling families ( N ^ fam ). We found no relationship between FE ^ and N ^ c or between N ^ fam / N ^ c and FE ^ . We posit that change in N ^ b was buffered by constraints on breeding habitat prior to harvest, such that the same number of breeding sites were occupied before and after harvest. These results suggest that effective size in harvested populations may be resilient to considerable changes in N c in the short-term, but it is still important to monitor exploited populations to assess the risk of inbreeding and ensure their long-term survival., Competing Interests: The authors declare no conflict of interest., (© 2022 The Authors. Evolutionary Applications published by John Wiley & Sons Ltd.)

The global prevalence of diabetes mellitus was estimated to be 463 million people in 2019 and is predicted to rise to 700 million by 2045. The associated financial and societal costs of this burgeoning epidemic demand an understanding of the pathology of this disease, and its complications, that will inform treatment to enable improved patient outcomes. Nearly two decades after the sequencing of the human genome, the significance of noncoding RNA expression is still being assessed. The family of functional noncoding RNAs known as microRNAs regulates the expression of most genes encoded by the human genome. Altered microRNA expression profiles have been observed both in diabetes and in diabetic complications. These transcripts therefore have significant potential and novelty as targets for therapy, therapeutic agents and biomarkers., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: TB and DF are inventors for patent WO/2017/129977 Chronic Kidney Disease Diagnostic. LD is the recipient of PhD studentship co-funding from Regulus Therapeutics and GSK., (Copyright © 2021. Published by Elsevier B.V.)

Understanding the drivers of successful species invasions is important for conserving native biodiversity and for mitigating the economic impacts of introduced species. However, whole-genome resolution investigations of the underlying contributions of neutral and adaptive genetic variation in successful introductions are rare. Increased propagule pressure should result in greater neutral genetic variation, while environmental differences should elicit selective pressures on introduced populations, leading to adaptive differentiation. We investigated neutral and adaptive variation among nine introduced brook trout ( Salvelinus fontinalis ) populations using whole-genome pooled sequencing. The populations inhabit isolated alpine lakes in western Canada and descend from a common source, with an average of ~19 (range of 7-41) generations since introduction. We found some evidence of bottlenecks without recovery, no strong evidence of purifying selection, and little support that varying propagule pressure or differences in local environments shaped observed neutral genetic variation differences. Putative adaptive loci analysis revealed nonconvergent patterns of adaptive differentiation among lakes with minimal putatively adaptive loci (0.001%-0.15%) that did not correspond with tested environmental variables. Our results suggest that (i) introduction success is not always strongly influenced by genetic load; (ii) observed differentiation among introduced populations can be idiosyncratic, population-specific, or stochastic; and (iii) conservatively, in some introduced species, colonization barriers may be overcome by support through one aspect of propagule pressure or benign environmental conditions., Competing Interests: We declare no conflicts of interest., (© 2022 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd.)

Local support is critical to the success and longevity of fishery management initiatives. Previous research suggests that how resource users perceive ecological changes, explain them, and cope with them, influences local support. The objectives of this study were two-fold. First, we collated local fishers' knowledge to characterize the long-term socio-ecological dynamics of the small-scale fishery of Sainte-Marie Island, in Madagascar. Second, we empirically assessed the individual- and site-level factors influencing support for fishery restrictions. Our results indicate that fishers observed a decline in fish abundance and catch sizes, especially in nearshore areas; many also perceived a reduction in fish sizes and the local disappearance of species. To maintain their catches, most fishers adapted by fishing harder and further offshore. Accordingly, fishers identified increased fishing effort (number of fishers and gear evolution) as the main cause of fishery changes. Collectively, our results highlight that the transition from a subsistence to commercial fishery, and resulting changes in the relationship between people and the fisheries, was an underlying driver of fishery changes. Additionally, we found that gender, membership to local associations, coping mechanisms, and perceptions of ecological health, were all interlinked and significantly associated with conservation-oriented attitudes. Conservation-oriented attitudes, however, were not associated with fishers' willingness to decrease fishing. In the short-term, area-based restrictions could contribute to building support for conservation. In the long-term, addressing the underlying causes of the decline will necessitate collaborations among the various groups involved to progressively build livelihood flexibility. Collectively, our study provides additional insights on the individual- and site-level factors influencing support for fishery restrictions. It also highlights the importance of dialoguing with fishers to ensure that fishery management plans are adapted to the local context., Competing Interests: The authors have declared that no competing interests exist.

Abstract: Brachytherapy programs within radiation therapy departments are subject to stringent radiation safety requirements in order to ensure the safety of the staff and patients. Training programs often include brachytherapy-specific radiation safety training modules that address the specific risks associated with radioactive sources, emergency procedures, and regulatory requirements specific to the use of radioisotopes. Unlike other uses of radioactive materials, brachytherapy uses sealed sources and therefore under routine operations does not encounter radioactive contaminants. This article presents an unusual clinical situation in which an 125I brachytherapy seed was damaged during routine clinical workflow, resulting in radioactive contamination within the clinical environment. Decisions made at the time of the incident resulted in contamination that spread beyond the initial location. The incident highlighted a shortcoming of the radiation safety program in preparing staff for the possibility of having to deal with unsealed radioactivity. Brachytherapy programs would be strengthened by including training specific to radioactive contamination in their emergency training to equip staff to respond to unexpected damage to the sealed sources., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Health Physics Society.)

Acute kidney injury (AKI) is a global clinical problem characterised by a sudden decline in renal function and mortality as high as 60%. Current AKI biomarkers have limited ability to classify disease progression and identify underlying pathological mechanisms. Here we hypothesised that alterations in urinary microRNA profiles could predict AKI recovery/nonrecovery after 90 days, and that injury-specific changes would signify microRNA mediators of AKI pathology. Comparison of urinary microRNA profiles from AKI patients with controls detected significant injury-specific increases in miR-21, miR-126 and miR-141 (p < 0.05) and decreases in miR-192 (p < 0.001) and miR-204 (p < 0.05). Expression of miR-141 increased in renal proximal tubular epithelial cells (PTECs) under oxidative stress in vitro and unilateral ischaemic reperfusion injury in vivo. Forced miR-141 expression in the presence of H 2 O 2 increased PTEC death and decreased cell viability. Of nine messenger RNA targets with two or more miR-141 3'-untranslated region binding sites, we confirmed protein tyrosine phosphatase receptor type G (PTPRG) as a direct miR-141 target in PTECs. PTPRG-specific siRNA knockdown under oxidative stress increased PTEC death and decreased cell viability. In conclusion, we detected significant alterations in five urinary microRNAs following AKI, and identified proximal tubular cell PTPRG as a putative novel therapeutic target., (© 2021. The Author(s).)

Organism abundance is a critical parameter in ecology, but its estimation is often challenging. Approaches utilizing eDNA to indirectly estimate abundance have recently generated substantial interest. However, preliminary correlations observed between eDNA concentration and abundance in nature are typically moderate in strength with significant unexplained variation. Here, we apply a novel approach to integrate allometric scaling coefficients into models of eDNA concentration and organism abundance. We hypothesize that eDNA particle production scales nonlinearly with mass, with scaling coefficients < 1. Wild populations often exhibit substantial variation in individual body size distributions; we therefore predict that the distribution of mass across individuals within a population will influence population-level eDNA production rates. To test our hypothesis, we collected standardized body size distribution and mark-recapture abundance data using whole-lake experiments involving nine populations of brook trout. We correlated eDNA concentration with three metrics of abundance: density (individuals/ha), biomass (kg/ha) and allometrically scaled mass (ASM) (∑(individual mass 0.73 )/ha). Density and biomass were both significantly positively correlated with eDNA concentration (adj. r 2  = 0.59 and 0.63, respectively), but ASM exhibited improved model fit (adj. r 2  = 0.78). We also demonstrate how estimates of ASM derived from eDNA samples in "unknown" systems can be converted to biomass or density estimates with additional size-structure data. Future experiments should empirically validate allometric scaling coefficients for eDNA production, particularly where substantial intraspecific size distribution variation exists. Incorporating allometric scaling may improve predictive models to the extent that eDNA concentration may become a reliable indicator of abundance in nature., (© 2020 John Wiley & Sons Ltd.)

This paper describes a straightforward electrochemical method for rapid and robust urinary microRNA (miRNA) quantification using disposable biosensors that can discriminate between urine from diabetic kidney disease (DKD) patients and control subjects. Aberrant miRNA expression has been observed in several major human disorders, and we have identified a urinary miRNA signature for DKD. MiRNAs therefore have considerable promise as disease biomarkers, and techniques to quantify these transcripts from clinical samples have significant clinical and commercial potential. Current RT-qPCR-based methods require technical expertise, and more straightforward methods such as electrochemical detection offer attractive alternatives. We describe a method to detect urinary miRNAs using diazo sulfonamide-modified screen printed carbon electrode-based biosensors that is amenable to parallel analysis. These sensors showed a linear response to buffered miR-21, with a 17 fM limit of detection, and successfully discriminated between urine samples ( n = 6) from DKD patients and unaffected control subjects ( n = 6) by differential miR-192 detection. Our technique for quantitative miRNA detection in liquid biopsies has potential for development as a platform for non-invasive high-throughput screening and/or to complement existing diagnostic procedures in disorders such as DKD., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Ischemic preconditioning (IPC) is effective in limiting subsequent ischemic acute kidney injury in experimental models. MicroRNAs are an important class of post-transcriptional regulator and show promise as biomarkers of kidney injury. We evaluated the time- and dose-dependence of benefit from IPC in a rat model of functional (bilateral) ischemia-reperfusion injury (IRI). We found optimal protection from subsequent injury following short, repetitive sequences of preconditioning insult. We subsequently used hybridization array and microRNA sequencing to characterize microRNA signatures of protective IPC and of IRI. These approaches identified a profile of microRNA changes consequent on IRI, that were limited by prior IPC. To localize these signals within the kidney, we used laser capture microdissection and RT-qPCR to measure microRNA abundance in nephron segments, pinpointing microRNA changes principally to glomeruli and proximal tubules. Our data describe a unique microRNA signature for IRI in the rat kidney. Pulsatile IPC reduces kidney damage following IRI and diminishes this microRNA signal. We have also identified candidate microRNAs that may act as biomarkers of injury and therapeutic targets in this context.

Road networks and human density are major factors contributing to habitat fragmentation and loss, isolation of wildlife populations, and reduced genetic diversity. Terrestrial mammals are particularly sensitive to road networks and encroachment by human populations. However, there are limited assessments of the impacts of road networks and human density on population-specific nuclear genetic diversity, and it remains unclear how these impacts are modulated by life-history traits. Using generalized linear mixed models and microsatellite data from 1444 North American terrestrial mammal populations, we show that taxa with large home range sizes, dense populations, and large body sizes had reduced nuclear genetic diversity with increasing road impacts and human density, but the overall influence of life-history traits was generally weak. Instead, we observed a high degree of genus-specific variation in genetic responses to road impacts and human density. Human density negatively affected allelic diversity or heterozygosity more than road networks (13 vs. 5-7 of 25 assessed genera, respectively); increased road networks and human density also positively affected allelic diversity and heterozygosity in 15 and 6-9 genera, respectively. Large-bodied, human-averse species were generally more negatively impacted than small, urban-adapted species. Genus-specific responses to habitat fragmentation by ongoing road development and human encroachment likely depend on the specific capability to (i) navigate roads as either barriers or movement corridors, and (ii) exploit resource-rich urban environments. The nonuniform genetic response to roads and human density highlights the need to implement efforts to mitigate the risk of vehicular collisions, while also facilitating gene flow between populations of particularly vulnerable taxa., Competing Interests: The authors have no conflicts of interest to declare., (© 2021 The Authors. Evolutionary Applications published by John Wiley & Sons Ltd.)

Background: Low pass sequencing has been proposed as a cost-effective alternative to genotyping arrays to identify genetic variants that influence multifactorial traits in humans. For common diseases this typically has required both large sample sizes and comprehensive variant discovery. Genotyping arrays are also routinely used to perform pharmacogenetic (PGx) experiments where sample sizes are likely to be significantly smaller, but clinically relevant effect sizes likely to be larger., Results: To assess how low pass sequencing would compare to array based genotyping for PGx we compared a low-pass assay (in which 1x coverage or less of a target genome is sequenced) along with software for genotype imputation to standard approaches. We sequenced 79 individuals to 1x genome coverage and genotyped the same samples on the Affymetrix Axiom Biobank Precision Medicine Research Array (PMRA). We then down-sampled the sequencing data to 0.8x, 0.6x, and 0.4x coverage, and performed imputation. Both the genotype data and the sequencing data were further used to impute human leukocyte antigen (HLA) genotypes for all samples. We compared the sequencing data and the genotyping array data in terms of four metrics: overall concordance, concordance at single nucleotide polymorphisms in pharmacogenetics-related genes, concordance in imputed HLA genotypes, and imputation r 2 . Overall concordance between the two assays ranged from 98.2% (for 0.4x coverage sequencing) to 99.2% (for 1x coverage sequencing), with qualitatively similar numbers for the subsets of variants most important in pharmacogenetics. At common single nucleotide polymorphisms (SNPs), the mean imputation r 2 from the genotyping array was 0.90, which was comparable to the imputation r 2 from 0.4x coverage sequencing, while the mean imputation r 2 from 1x sequencing data was 0.96., Conclusions: These results indicate that low-pass sequencing to a depth above 0.4x coverage attains higher power for association studies when compared to the PMRA and should be considered as a competitive alternative to genotyping arrays for trait mapping in pharmacogenetics.

Phenotypic reaction norms are often shaped and constrained by selection and are important for allowing organisms to respond to environmental change. However, selection cannot constrain reaction norms for environmental conditions that populations have not experienced. Consequently, cryptic neutral genetic variation for the reaction norm can accumulate such that a release of phenotypic variation occurs upon exposure to novel14 conditions. Most genomic diversity behaves as if functionally neutral. Therefore, genome-wide diversity metrics may correlate with levels of cryptic genetic variation and, as a result, exhibit a positive relationship with a release of phenotypic variation in novel environments. To test this hypothesis, we conducted translocations of juvenile brook trout (Salvelinus fontinalis) from 12 populations to novel uninhabited ponds that represented a gradient of environmental conditions. We assessed reaction norms for morphological traits (body size and four morphometric relative warps) across pond environmental gradients and evaluated the effect of genome-wide heterozygosity on phenotypic variability. All traits displayed plastic reaction norms. Overall, we found some evidence that a release of phenotypic variation consistent with cryptic genetic variation can occur in novel environmental conditions. However, the extent to which this release correlated with average genome-wide diversity was limited to only one of five traits examined. Our results suggest a limited link between genomic diversity26 and the accumulation of cryptic genetic variation in reaction norms. Similarly, reaction norms were constrained for many of the morphological traits examined. Past conditions may have constrained reaction norms in the putatively novel environments despite significant deviations from contemporary source population habitat. Additionally, as a generalist colonizing species brook trout may exhibit plastic phenotypes across a wide range of environmental conditions., (© 2020 European Society For Evolutionary Biology. Journal of Evolutionary Biology © 2020 European Society For Evolutionary Biology.)

Investigating whether changes within fish populations may result from harvesting requires a comprehensive approach, especially in more data-sparse northern regions. Our study took a three-pronged approach to investigate walleye population change by combining Indigenous knowledge (IK), phenotypic traits, and genomics. We thank Larson et al. (2020) for their critiques of our study; certainly, there are aspects of their critique that are warranted and merit further investigation. However, we argue that their critique is over-stated and misleading, primarily given that (a) one of three prongs of our research, IK, was dismissed in their assessment of our study's conclusions; (b) our Bayesian size-at-age modeling should help to mitigate sample size issues; (c) their re-analysis of our size-at-age data does not actually refute our results; (d) genomic changes that we observed are nascent; (e) the data file that Larson et al. (2020) used for their genomic re-analysis was not correct; and (f) criteria that Larson et al. (2020) use for their genomic re-analysis were not properly justified., Competing Interests: The authors declare no conflicts of interest., (© 2020 The Authors. Evolutionary Applications published by John Wiley & Sons Ltd.)

Chronic kidney disease (CKD) is a health problem reaching epidemic proportions. There is no cure for CKD, and patients may progress to end-stage renal disease (ESRD). Peritoneal dialysis (PD) is a current replacement therapy option for ESRD patients until renal transplantation can be achieved. One important problem in long-term PD patients is peritoneal membrane failure. The mechanisms involved in peritoneal damage include activation of the inflammatory and immune responses, associated with submesothelial immune infiltrates, angiogenesis, loss of the mesothelial layer due to cell death and mesothelial to mesenchymal transition, and collagen accumulation in the submesothelial compact zone. These processes lead to fibrosis and loss of peritoneal membrane function. Peritoneal inflammation and membrane failure are strongly associated with additional problems in PD patients, mainly with a very high risk of cardiovascular disease. Among the inflammatory mediators involved in peritoneal damage, cytokine IL-17A has recently been proposed as a potential therapeutic target for chronic inflammatory diseases, including CKD. Although IL-17A is the hallmark cytokine of Th17 immune cells, many other cells can also produce or secrete IL-17A. In the peritoneum of PD patients, IL-17A-secreting cells comprise Th17 cells, γδ T cells, mast cells, and neutrophils. Experimental studies demonstrated that IL-17A blockade ameliorated peritoneal damage caused by exposure to PD fluids. This article provides a comprehensive review of recent advances on the role of IL-17A in peritoneal membrane injury during PD and other PD-associated complications.

Neutrophil infiltration is a hallmark of peritoneal inflammation, but mechanisms regulating neutrophil recruitment in patients with peritoneal dialysis (PD)-related peritonitis are not fully defined. We examined 104 samples of PD effluent collected during acute peritonitis for correspondence between a broad range of soluble parameters and neutrophil counts. We observed an association between peritoneal IL-17 and neutrophil levels. This relationship was evident in effluent samples with low but not high IFN-γ levels, suggesting a differential effect of IFN-γ concentration on neutrophil infiltration. Surprisingly, there was no association of neutrophil numbers with the level of CXCL1, a key IL-17-induced neutrophil chemoattractant. We investigated therefore the production of CXCL1 by human peritoneal mesothelial cells (HPMCs) under in vitro conditions mimicking clinical peritonitis. Stimulation of HPMCs with IL-17 increased CXCL1 production through induction of transcription factor SP1 and activation of the SP1-binding region of the CXCL1 promoter. These effects were amplified by TNFα. In contrast, IFN-γ dose-dependently suppressed IL-17-induced SP1 activation and CXCL1 production through a transcriptional mechanism involving STAT1. The SP1-mediated induction of CXCL1 was also observed in HPMCs exposed to PD effluent collected during peritonitis and containing IL-17 and TNFα, but not IFN-γ. Supplementation of the effluent with IFN-γ led to a dose-dependent activation of STAT1 and a resultant inhibition of SP1-induced CXCL1 expression. Transmesothelial migration of neutrophils in vitro increased upon stimulation of HPMCs with IL-17 and was reduced by IFN-γ. In addition, HPMCs were capable of binding CXCL1 at their apical cell surface. These observations indicate that changes in relative peritoneal concentrations of IL-17 and IFN-γ can differently engage SP1-STAT1, impacting on mesothelial cell transcription of CXCL1, whose release and binding to HPMC surface may determine optimal neutrophil recruitment and retention during peritonitis. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland., (© 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.)

The extent and rate of harvest-induced genetic changes in natural populations may impact population productivity, recovery, and persistence. While there is substantial evidence for phenotypic changes in harvested fishes, knowledge of genetic change in the wild remains limited, as phenotypic and genetic data are seldom considered in tandem, and the number of generations needed for genetic changes to occur is not well understood. We quantified changes in size-at-age, sex-specific changes in body size, and genomic metrics in three harvested walleye ( Sander vitreus ) populations and a fourth reference population with low harvest levels over a 15-year period in Mistassini Lake, Quebec. We also collected Indigenous knowledge (IK) surrounding concerns about these populations over time. Using ~9,000 SNPs, genomic metrics included changes in population structure, neutral genomic diversity, effective population size, and signatures of selection. Indigenous knowledge revealed overall reductions in body size and number of fish caught. Smaller body size, a small reduction in size-at-age, nascent changes to population structure (population differentiation within one river and homogenization between two others), and signatures of selection between historical and contemporary samples reflected coupled phenotypic and genomic change in the three harvested populations in both sexes, while no change occurred in the reference population. Sex-specific analyses revealed differences in both body size and genomic metrics but were inconclusive about whether one sex was disproportionately affected. Although alternative explanations cannot be ruled out, our collective results are consistent with the hypothesis that genetic changes associated with harvesting may arise within 1-2.5 generations in long-lived wild fishes. This study thus demonstrates the need to investigate concerns about harvest-induced evolution quickly once they have been raised., Competing Interests: The authors declare no competing interests., (© 2020 The Authors. Evolutionary Applications published by John Wiley & Sons Ltd.)

Important variation in the shape and strength of density-dependent growth and mortality is observed across animal populations. Understanding this population variation is critical for predicting density-dependent relationships in natural populations, but comparisons amongst studies are challenging as studies differ in methodologies and in local environmental conditions. Consequently, it is unclear whether: (a) the shape and strength of density-dependent growth and mortality are population-specific; (b) the potential trade-off between density-dependent growth and mortality differs amongst populations; and (c) environmental characteristics can be related to population differences in density-dependent relationships. To elucidate these uncertainties, we manipulated the density (0.3-7 fish/ m 2 ) of young-of-the-year brook trout (Salvelinus fontinalis) simultaneously in three neighbouring populations in a field experiment in Newfoundland, Canada. Within each population, our experiment included both spatial (three sites per stream) and temporal (three consecutive summers) replication. We detected temporally consistent population variation in the shape of density-dependent growth (negative linear and negative logarithmic), but not for mortality (positive logarithmic). The strength of density-dependent growth across populations was reduced in sections with a high percentage of boulder substrate, whereas density-dependent mortality increased with increasing flow, water temperature and more acidic pH. Neighbouring populations exhibited different mortality-growth trade-offs: the ratio of mortality-to-growth increased linearly with increasing density at different rates across populations (up to 4-fold differences), but also increased with increasing temperature. Our results are some of the first to demonstrate temporally consistent, population-specific density-dependent relationships and trade-offs at small spatial scales that match the magnitude of interspecific variation observed across the globe. Furthermore, key environmental characteristics explain some of these differences in predictable ways. Such population differences merit further attention in models of density dependence and in science-based management of animal populations., (© 2019 The Authors. Journal of Animal Ecology © 2019 British Ecological Society.)

Little empirical work in nature has quantified how wild populations with varying effective population sizes and genetic diversity perform when exposed to a gradient of ecologically important environmental conditions. To achieve this, juvenile brook trout from 12 isolated populations or closed metapopulations that differ substantially in population size and genetic diversity were transplanted to previously fishless ponds spanning a wide gradient of ecologically important variables. We evaluated the effect of genome-wide variation, effective population size ( N e ), pond habitat, and initial body size on two fitness correlates (survival and growth). Genetic variables had no effect on either fitness correlate, which was determined primarily by habitat (pond temperature, depth, and pH) and initial body size. These results suggest that some vertebrate populations with low genomic diversity, low N e , and long-term isolation can represent important sources of variation and are capable of maintaining fitness in, and ultimately persisting and adapting to, changing environments. Our results also reinforce the paramount importance of improving available habitat and slowing habitat degradation for species conservation.

Evolutionary biologists have long trained their sights on adaptation, focusing on the power of natural selection to produce relative fitness advantages while often ignoring changes in absolute fitness. Ecologists generally have taken a different tack, focusing on changes in abundance and ranges that reflect absolute fitness while often ignoring relative fitness. Uniting these perspectives, we articulate various causes of relative and absolute maladaptation and review numerous examples of their occurrence. This review indicates that maladaptation is reasonably common from both perspectives, yet often in contrasting ways. That is, maladaptation can appear strong from a relative fitness perspective, yet populations can be growing in abundance. Conversely, resident individuals can appear locally adapted (relative to nonresident individuals) yet be declining in abundance. Understanding and interpreting these disconnects between relative and absolute maladaptation, as well as the cases of agreement, is increasingly critical in the face of accelerating human-mediated environmental change. We therefore present a framework for studying maladaptation, focusing in particular on the relationship between absolute and relative fitness, thereby drawing together evolutionary and ecological perspectives. The unification of these ecological and evolutionary perspectives has the potential to bring together previously disjunct research areas while addressing key conceptual issues and specific practical problems.

Evolutionary biologists tend to approach the study of the natural world within a framework of adaptation, inspired perhaps by the power of natural selection to produce fitness advantages that drive population persistence and biological diversity. In contrast, evolution has rarely been studied through the lens of adaptation's complement, maladaptation. This contrast is surprising because maladaptation is a prevalent feature of evolution: population trait values are rarely distributed optimally; local populations often have lower fitness than imported ones; populations decline; and local and global extinctions are common. Yet we lack a general framework for understanding maladaptation; for instance in terms of distribution, severity, and dynamics. Similar uncertainties apply to the causes of maladaptation. We suggest that incorporating maladaptation-based perspectives into evolutionary biology would facilitate better understanding of the natural world. Approaches within a maladaptation framework might be especially profitable in applied evolution contexts - where reductions in fitness are common. Toward advancing a more balanced study of evolution, here we present a conceptual framework describing causes of maladaptation. As the introductory article for a Special Feature on maladaptation, we also summarize the studies in this Issue, highlighting the causes of maladaptation in each study. We hope that our framework and the papers in this Special Issue will help catalyze the study of maladaptation in applied evolution, supporting greater understanding of evolutionary dynamics in our rapidly changing world., Competing Interests: None declared.

Infection remains a major cause of morbidity, mortality and technique failure in patients with end stage kidney failure who receive peritoneal dialysis (PD). Recent research suggests that the early inflammatory response at the site of infection carries diagnostically relevant information, suggesting that organ and pathogen-specific "immune fingerprints" may guide targeted treatment decisions and allow patient stratification and risk prediction at the point of care. Here, we recorded microRNA profiles in the PD effluent of patients presenting with symptoms of acute peritonitis and show that elevated peritoneal miR-223 and reduced miR-31 levels were useful predictors of bacterial infection. Cell culture experiments indicated that miR-223 was predominantly produced by infiltrating immune cells (neutrophils, monocytes), while miR-31 was mainly derived from the local tissue (mesothelial cells, fibroblasts). miR-223 was found to be functionally stabilised in PD effluent from peritonitis patients, with a proportion likely to be incorporated into neutrophil-derived exosomes. Our study demonstrates that microRNAs are useful biomarkers of bacterial infection in PD-related peritonitis and have the potential to contribute to disease-specific immune fingerprints. Exosome-encapsulated microRNAs may have a functional role in intercellular communication between immune cells responding to the infection and the local tissue, to help clear the infection, resolve the inflammation and restore homeostasis.

Infectious peritonitis is a common complication in patients undergoing chronic peritoneal dialysis (PD), limiting the duration of PD as a modality for renal replacement therapy and increasing patient morbidity and mortality. Antimicrobial peptides (AMPs) serve critical roles in mucosal defense, but their expression and activity during peritonitis are poorly understood. We hypothesized that AMPs belonging to the Ribonuclease (RNase) A Superfamily are present in peritoneal fluid and increase during peritonitis in patients undergoing chronic PD. In the absence of peritonitis, we detected RNase 3, RNase 6, and RNase 7 in cell-free supernatants and viable cells obtained from peritoneal fluid of chronic PD patients. The cellular sources of these RNases were eosinophils (RNase 3), macrophages (RNase 6), and mesothelial cells (RNase 7). During peritonitis, RNase 3 increased 55-fold and RNase 7 levels increased 3-fold on average, whereas RNase 6 levels were unchanged. The areas under the receiver-operating characteristic curves for RNase 3 and RNase 7 were 0.99 (95% confidence interval (CI): 0.96-1.0) and 0.79 (95% CI: 0.64-0.93), respectively, indicating their potential as biomarkers of peritonitis. Discrete omental reservoirs of these RNases were evident in patients with end stage kidney disease prior to PD initiation, and omental RNase 3 reactive cells increased in patients undergoing PD with a history of peritonitis. We propose that constitutive and inducible pools of antimicrobial RNases form a network to shield the peritoneal cavity from microbial invasion in patients undergoing chronic PD.

Evolutionary approaches are gaining popularity in conservation science, with diverse strategies applied in efforts to support adaptive population outcomes. Yet conservation strategies differ in the type of adaptive outcomes they promote as conservation goals. For instance, strategies based on genetic or demographic rescue implicitly target adaptive population states whereas strategies utilizing transgenerational plasticity or evolutionary rescue implicitly target adaptive processes . These two goals are somewhat polar: adaptive state strategies optimize current population fitness, which should reduce phenotypic and/or genetic variance, reducing adaptability in changing or uncertain environments; adaptive process strategies increase genetic variance, causing maladaptation in the short term, but increase adaptability over the long term. Maladaptation refers to suboptimal population fitness, adaptation refers to optimal population fitness, and (mal)adaptation refers to the continuum of fitness variation from maladaptation to adaptation. Here, we present a conceptual classification for conservation that implicitly considers (mal)adaptation in the short-term and long-term outcomes of conservation strategies. We describe cases of how (mal)adaptation is implicated in traditional conservation strategies, as well as strategies that have potential as a conservation tool but are relatively underutilized. We use a meta-analysis of a small number of available studies to evaluate whether the different conservation strategies employed are better suited toward increasing population fitness across multiple generations. We found weakly increasing adaptation over time for transgenerational plasticity, genetic rescue, and evolutionary rescue. Demographic rescue was generally maladaptive, both immediately after conservation intervention and after several generations. Interspecific hybridization was adaptive only in the F 1 generation, but then rapidly leads to maladaptation. Management decisions that are made to support the process of adaptation must adequately account for (mal)adaptation as a potential outcome and even as a tool to bolster adaptive capacity to changing conditions., Competing Interests: None declared.

Population genetic data from nuclear DNA has yet to be synthesized to allow broad scale comparisons of intraspecific diversity versus species diversity. The MacroPopGen database collates and geo-references vertebrate population genetic data across the Americas from 1,308 nuclear microsatellite DNA studies, 897 species, and 9,090 genetically distinct populations where genetic differentiation (F ST ) was measured. Caribbean populations were particularly distinguished from North, Central, and South American populations, in having higher differentiation (F ST  = 0.12 vs. 0.07-0.09) and lower mean numbers of alleles (MNA = 4.11 vs. 4.84-5.54). While mammalian populations had lower MNA (4.86) than anadromous fish, reptiles, amphibians, freshwater fish, and birds (5.34-7.81), mean heterozygosity was largely similar across groups (0.57-0.63). Mean F ST was consistently lowest in anadromous fishes (0.06) and birds (0.05) relative to all other groups (0.09-0.11). Significant differences in Family/Genera variance among continental regions or taxonomic groups were also observed. MacroPopGen can be used in many future applications including latitudinal analyses, spatial analyses (e.g. central-margin), taxonomic comparisons, regional assessments of anthropogenic impacts on biodiversity, and conservation of wild populations.

Predicting immediate and subsequent graft function is important in clinical decision-making around kidney transplantation, but is difficult using available approaches. Here we have evaluated urinary microRNAs as biomarkers in this context. Profiling of 377 microRNAs in the first urine passed post-transplantation identified 6 microRNAs, confirmed to be upregulated by RT-qPCR in an expanded cohort (miR-9, -10a, -21, -29a, -221, and -429, n = 33, P < 0.05 for each). Receiver operating characteristic analysis showed Area Under the Curve 0.94 for this panel. To establish whether this early signal was sustained, miR-21 was measured daily for 5 days post-transplant, and was consistently elevated in those developing Delayed Graft Function (n = 165 samples from 33 patients, p < 0.05). The biomarker panel was then evaluated in an independent cohort, sampled at varying times in the first week post-transplantation in a separate transplant center. When considered individually, all miRs in the panel showed a trend to increase or a significant increase in those developing delayed Graft Function (miR-9: P = 0.068, mIR-10a: P = 0.397, miR-21: P = 0.003, miR-29a: P = 0.019, miR-221: P = 0.1, and miR-429: P = 0.013, n = 47) with Area Under the Curve 0.75 for the panel. In conclusion, combined measurement of six microRNAs had predictive value for delayed graft function following kidney transplantation.

The kidneys play key roles in the maintenance of homeostasis, including fluid balance, blood filtration, erythropoiesis and hormone production. Disease-driven perturbation of renal function therefore has profound pathological effects, and chronic kidney disease is a leading cause of morbidity and mortality worldwide. Successive annual increases in global chronic kidney disease patient numbers in part reflect upward trends for predisposing factors, including diabetes, obesity, hypertension, cardiovascular disease and population age. Each kidney typically possesses more than one million functional units called nephrons, and each nephron is divided into several discrete domains with distinct cellular and functional characteristics. A number of recent analyses have suggested that signaling between these nephron regions may be mediated by microRNAs. For this to be the case, several conditions must be fulfilled: (i) microRNAs must be released by upstream cells into the ultrafiltrate; (ii) these microRNAs must be packaged protectively to reach downstream cells intact; (iii) these packaged microRNAs must be taken up by downstream recipient cells without functional inhibition. This review will examine the evidence for each of these hypotheses and discuss the possibility that this signaling process might mediate pathological effects.

Rosacea is a common, chronic skin disease of variable severity with limited treatment options. The cause of rosacea is unknown, but it is believed to be due to a combination of hereditary and environmental factors. Little is known about the genetics of the disease. We performed a genome-wide association study (GWAS) of rosacea symptom severity with data from 73 265 research participants of European ancestry from the 23andMe customer base. Seven loci had variants associated with rosacea at the genome-wide significance level (P < 5 × 10-8). Further analyses highlighted likely gene regions or effector genes including IRF4 (P = 1.5 × 10-17), a human leukocyte antigen (HLA) region flanked by PSMB9 and HLA-DMB (P = 2.2 × 10-15), HERC2-OCA2 (P = 4.2 × 10-12), SLC45A2 (P = 1.7 × 10-10), IL13 (P = 2.8 × 10-9), a region flanked by NRXN3 and DIO2 (P = 4.1 × 10-9), and a region flanked by OVOL1and SNX32 (P = 1.2 × 10-8). All associations with rosacea were novel except for the HLA locus. Two of these loci (HERC-OCA2 and SLC45A2) and another precedented variant (rs1805007 in melanocortin 1 receptor) with an association P value just below the significance threshold (P = 1.3 × 10-7) have been previously associated with skin phenotypes and pigmentation, two of these loci are linked to immuno-inflammation phenotypes (IL13 and PSMB9-HLA-DMA) and one has been associated with both categories (IRF4). Genes within three loci (PSMB9-HLA-DMA, HERC-OCA2 and NRX3-DIO2) were differentially expressed in a previously published clinical rosacea transcriptomics study that compared lesional to non-lesional samples. The identified loci provide specificity of inflammatory mechanisms in rosacea, and identify potential pathways for therapeutic intervention., (© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Effective remediation of heavy metal pollution in aquatic systems is desired in many regions, but it requires integrative assessments of sediments, water, and biota that can serve as robust biomonitors. We assessed the effects of a 5-year metal contamination remediation along the Xiangjiang River, China, by comparing concentrations of trace metals in water and surface sediments between 2010-2011 and 2016. We also explored the trace metal biomonitoring potential of a freshwater gastropod (Bellamya aeruginosa). Metal concentrations in water (means and ranges) dropped over time to within permissible limits of drinking water guidelines set by China, USEPA, and WHO in 2016. Although sediment means and ranges of Cd, Pb, Zn, and Mn also diminished with remediation, those for Cr and Cu slightly increased, and all six metals retained concentrations higher than standards set by China. All metals in sediments could also be associated with anthropogenic inputs using a hierarchical clustering analysis, and they generate high potential ecological risks based on several indices, especially for Cd and As. The bio-sediment accumulation factors of all measured trace metals in gastropod soft tissues and shells were lower than 1.0, except for Ca. Trace metal contents in gastropods were positively correlated with those in water and surface sediments for As (soft tissues) and Cr (shells). Collectively, our results do not yet highlight strong beneficial effects of 5-year remediation and clearly illustrate the heavy metal pollution remaining in Xiangjiang River sediment. Additional physical, chemical, and biological measurements should be implemented to improve sediment quality. We further conclude that gastropod soft tissues and shells can be suitable biomonitors of spatial differences in some heavy metals found within river sediments (e.g., As, Cr).