An association between differential expression and genetic divergence in the Patagonian olive mouse (Abrothrix olivacea).

Recent molecular studies have found striking differences between desert-adapted species and model mammals regarding water conservation. In particular, aquaporin 4, a classical gene involved in water regulation of model species, is absent or not expressed in the kidneys of desert-adapted species. To further understand the molecular response to water availability, we studied the Patagonian olive mouse Abrothrix olivacea, a species with an unusually broad ecological tolerance that exhibits a great urine concentration capability. The species is able to occupy both the arid Patagonian steppe and the Valdivian and Magellanic forests. We sampled 95 olive mouse specimens from four localities (two in the steppe and two in the forests) and analysed both phenotypic variables and transcriptomic data to investigate the response of this species to the contrasting environmental conditions. The relative size of the kidney and the ratio of urine to plasma concentrations were, as expected, negatively correlated with annual rainfall. Expression analyses uncovered nearly 3,000 genes that were differentially expressed between steppe and forest samples and indicated that this species resorts to the "classical" gene pathways for water regulation. Differential expression across biomes also involves genes that involved in immune and detoxification functions. Overall, genes that were differentially expressed showed a slight tendency to be more divergent and to display an excess of intermediate allele frequencies, relative to the remaining loci. Our results indicate that both differential expression in pathways involved in water conservation and geographical allelic variation are important in the occupation of contrasting habitats by the Patagonian olive mouse.

Characterization of the kidney transcriptome of the South American olive mouse Abrothrix olivacea.

BACKGROUND: The olive mouse Abrothrix olivacea is a cricetid rodent of the subfamily Sigmodontinae that inhabits a wide range of contrasting environments in southern South America, from aridlands to temperate rainforests. Along its distribution, it presents different geographic forms that make the olive mouse a good focal case for the study of geographical variation in response to environmental variation. We chose to characterize the kidney transcriptome because this organ has been shown to be associated with multiple physiological processes, including water reabsorption. RESULTS: Transcriptomes of thirteen kidneys from individuals from Argentina and Chile were sequenced using Illumina technology in order to obtain a kidney reference transcriptome. After combining the reads produced for each sample, we explored three assembly strategies to obtain the best reconstruction of transcripts, TrinityNorm and DigiNorm, which include its own normalization algorithms for redundant reads removal, and Multireads, which simply consist on the assembly of the joined reads. We found that Multireads strategy produces a less fragmented assembly than normalization algorithms but recovers fewer number of genes. In general, about 15000 genes were annotated, of which almost half had at least one coding sequence reconstructed at 99% of its length. We also built a list of highly expressed genes, of which several are involved in water conservation under laboratory conditions using mouse models. CONCLUSION: Based on our assembly results, Trinity's in silico normalization is the best algorithm in terms of cost-benefit returns; however, our results also indicate that normalization should be avoided if complete or nearly complete coding sequences of genes are desired. Given that this work is the first to characterize the transcriptome of any member of Sigmodontinae, a subfamily of cricetid rodents with about 400 living species, it will provide valuable resources for future ecological and evolutionary genomic analyses.

Electronic Health Record-Integrated Clinical Decision Support for Clinicians Serving Populations Facing Health Care Disparities: Literature Review.

OBJECTIVES: To review current studies about designing and implementing clinician-facing clinical decision support (CDS) integrated or interoperable with an electronic health record (EHR) to improve health care for populations facing disparities. METHODS: We searched PubMed to identify studies published between January 1, 2011 and October 22, 2021 about clinician-facing CDS integrated or interoperable with an EHR. We screened abstracts and titles and extracted study data from articles using a protocol developed by team consensus. Extracted data included patient population characteristics, clinical specialty, setting, EHR, clinical problem, CDS type, reported user-centered design, implementation strategies, and outcomes. RESULTS: There were 28 studies (36 articles) included. Most studies were performed at safety net institutions (14 studies) or Indian Health Service sites (6 studies). CDS tools were implemented in primary care outpatient settings in 24 studies (86%) for screening or treatment. CDS included point-of-care alerts (93%), order facilitators (46%), workflow support (39%), relevant information display (36%), expert systems (11%), and medication dosing support (7%). Successful outcomes were reported in 19 of 26 studies that reported outcomes (73%). User-centered design was reported during CDS planning (39%), development (32%), and implementation phase (25%). Most frequent implementation strategies were education (89%) and consensus facilitation (50%). CONCLUSIONS: CDS tools may improve health equity and outcomes for patients who face disparities. The present review underscores the need for high-quality analyses of CDS-associated health outcomes, reporting of user-centered design and implementation strategies used in low-resource settings, and methods to disseminate CDS created to improve health equity.

Genetic Diversity and Demographic History of the Shaggy Soft-Haired Mouse Abrothrix hirta (Cricetidae; Abrotrichini).

Genetic information on species can inform decision making regarding conservation of biodiversity since the response of organisms to changing environments depend, in part, on their genetic makeup. Territories of central-southern Chile and Argentina have undergone a varying degree of impact during the Quaternary, where the response of local fauna and flora was rather species-specific. Here, we focus on the sigmodontine rodent Abrothrix hirta, distributed from 35° S in Chile and Argentina to northern Tierra del Fuego. Based on 119,226 transcriptome-derived SNP loci from 46 individuals of A. hirta, we described the geographic distribution of the genetic diversity of this species using a maximum likelihood tree, principal component and admixture analyses. We also addressed the demographic history of the main intraspecific lineages of A. hirta using GADMA. We found that A. hirta exhibited four allopatric intraspecific lineages. Three main genetic groups were identified by a Principal Component Analysis and by Ancestry analysis. The demographic history of A. hirta was characterized by recent population stability for populations at the northernmost part of the range, while southern populations experienced a recent population expansion.

Genetic variation of the Chilean endemic long-haired mouse Abrothrix longipilis (Rodentia, Supramyomorpha, Cricetidae) in a geographical and environmental context.

Quaternary climate and associated vegetational changes affected the fauna of the Chilean Mediterranean ecosystem. Here we studied the genetic variation of the long-haired mouse, Abrothrix longipilis, a sigmodontine rodent endemic to this area. Within an environmentally explicit context, we examined the geographic distribution of the genetic diversity and demographic history of the species based on sequences of the mitochondrial Cytochrome-b gene of 50 individuals from 13 localities and a large panel of single nucleotide polymorphisms of 17 individuals from 6 localities. The gene genealogy of A. longipilis revealed three intraspecific lineages that are allopatric and latitudinally segregated (northern, central, and southern lineages) with an estimated crown age for the whole species clade of 552.3 kyr B.P. A principal component analysis based on 336,596 SNP loci is in line with the information given by the the mitochondrial gene genealogy. Along its complete distributional range, A. longipilis showed patterns of isolation by distance and also isolation by environment. The general pattern of historical demography showed stability for most intraspecific lineages of A. longipilis. Northern and central lineages showed signals of historical demographic stability, while the southern lineage showed contrasting signals. In agreement with this, the niche models performed showed that in the northern range of A. longipilis, areas of high suitability for this species increased towards the present time; areas of central range would have remained relatively stable, while southern areas would have experienced more change through time. In summary, our study shows three distinct allopatric lineages of A. longipilis, each showing slightly different demographic history.

Local persistence of Mann's soft-haired mouse Abrothrix manni (Rodentia, Sigmodontinae) during Quaternary glaciations in southern Chile.

Quaternary climatic oscillations have impacted Patagonian sigmodontine fauna, leaving traceable genetic footprints. In southern Chile, changes in the landscape included transitions to different vegetation formations as well as the extension of ice sheets. In this study, we focus on the Valdivian forest endemic and recently described sigmodontine species Abrothrix manni. We aim to assess the genetic structure of this species, testing for the existence of intraspecific lineages, and inferring the recent demographic history of the species. Analyses were based on the first 801 bp of the mitochondrial gene Cytocrhome-b from 49 individuals of A. manni collected at 10 localities that covers most part of its geographic distribution. Genealogical analyses recovered two main intraspecific lineages that are geographically segregated and present an intermediate site of secondary contact. Historical demography shows signal of recent population decrease. Based on these results, we proposed that current genetic diversity of A. manni differentiated in at least two distinct refugial areas in southern Chile. This scenario, in addition to be unique among those uncovered for the so far studied Valdivian forest rodents, is noteworthy because of the reduced geographic scale inhabited by the species.

Etiology and treatment of adrenoleukodystrophy: new insights from Drosophila.

Adrenoleukodystrophy (ALD) is a fatal progressive neurodegenerative disorder affecting brain white matter. The most common form of ALD is X-linked (X-ALD) and results from mutation of the ABCD1-encoded very-long-chain fatty acid (VLCFA) transporter. X-ALD is clinically heterogeneous, with the cerebral form being the most severe. Diagnosed in boys usually between the ages of 4 and 8 years, cerebral X-ALD symptoms progress rapidly (in as little as 2 years) through declines in cognition, learning and behavior, to paralysis and ultimately to a vegetative state and death. Currently, there are no good treatments for X-ALD. Here, we exploit the Drosophila bubblegum (bgm) double bubble (dbb) model of neurometabolic disease to expand diagnostic power and therapeutic potential for ALD. We show that loss of the Drosophila long-/very-long-chain acyl-CoA synthetase genes bgm and/or dbb is indistinguishable from loss of the Drosophila ABC transporter gene ABCD Shared loss-of-function phenotypes for synthetase and transporter mutants point to a lipid metabolic pathway association with ALD-like neurodegenerative disease in Drosophila; a pathway association that has yet to be established in humans. We also show that manipulation of environment increases the severity of neurodegeneration in bgm and dbb mutant flies, adding even further to a suite of new candidate ALD disease-causing genes and pathways in humans. Finally, we show that it is a lack of lipid metabolic pathway product and not (as commonly thought) an accumulation of pathway precursor that is causative of neurometabolic disease: addition of medium-chain fatty acids to the diet of bgm or dbb mutant flies prevents the onset of neurodegeneration. Taken together, our data provide new foundations both for diagnosing ALD and for designing effective, mechanism-based treatment protocols.This article has an associated First Person interview with the first author of the paper.

Characterization of the kidney transcriptome of the long-haired mouse Abrothrix hirta (Rodentia, Sigmodontinae) and comparison with that of the olive mouse A. olivacea.

To understand how small mammals cope with the challenge of water homeostasis is a matter of interest for ecologists and evolutionary biologists. Here we take a step towards the understanding of the transcriptomic functional response of kidney using as a model the long-haired mouse (Abrothrix hirta) a species that distributes across Patagonian steppes and Austral temperate rainforests in Argentina and Chile. Specifically, we i) characterize the renal transcriptome of A. hirta, and ii) compare it with that-already available-of the co-generic and co-distributed A. olivacea. Renal mRNA transcripts from 16 specimens of A. hirta from natural populations were analyzed. Over 500 million Illumina paired-end reads were assembled de novo under two approaches, an individual assembly for each specimen, and a single in-silico normalized joint assembly including all reads from all specimens. The total number of annotated genes was similar with both strategies: an average of 14,956 in individual assemblies and 14,410 in the joint assembly. Overall, 15,463 distinct genes express in the kidney of A. hirta. Transcriptomes of A. hirta and A. olivacea were similar in terms of gene abundance and composition: 95.6% of the genes of A. hirta were also found in A. olivacea making their functional profiles also similar. However, differences in the transcriptome of these two species were observed in the set of highly expressed genes, in terms of private genes for each species and the functional profiles of highly expressed genes. As part of the novel transcriptome characterization, we provide distinct gene lists with their functional annotation that would constitute the basis for further research on these or any other species of the subfamily Sigmodontinae, which includes about 400 living species distributed from Tierra del Fuego to southern United States.

Up-regulation of L-selectin and E-selectin in hypersensitivity pneumonitis.

BACKGROUND: Selectins are adhesion molecules that contribute to leukocyte recruitment into the tissue after an injury. Hypersensitivity pneumonitis (HP) is a lymphocytic alveolitis, and we hypothesized that the overexpression of selectins could play a role in this process. PATIENTS AND MEASUREMENTS: We studied 16 patients with HP and 7 healthy control subjects (HCs). Sera and BAL selectins and tumor necrosis factor-alpha were determined by enzyme-linked immunosorbent assay, and cellular lung localization was determined by immunohistochemistry. Additionally, BAL L-selectin, and L-selectin-bearing T-lymphocytes analyzed by flow cytometry were evaluated in HP patients and in exposed but asymptomatic subjects (EAS). SETTING: Tertiary referral center and immunohistochemistry laboratory. RESULTS: Raised levels of E-selectin (mean [+/- SD], 178.9 +/- 30.5 vs 59.4 +/- 4.7 ng/mL, respectively; p < 0.001) and P-selectin (mean, 232.6 +/- 29.9 vs 67.6 +/- 14.2 ng/mL, respectively; p < 0.001) were detected in HP patient sera compared to control subjects, while L-selectin levels showed no differences between groups. Conversely, HP patients displayed a significant increase in levels of L-selectin found in BAL fluid compared with both HCs and EAS (11.0 +/- 1.7 vs 6.9 +/- 0.43 and 3.1 +/- 0.5 ng/mL, respectively; p < 0.05). The levels of E-selectin found in BAL fluid were similar in patients from both groups, and P-selectin was not detected. Percentage of CD3+CD62 L+ lymphocytes was lower in HP patients compared with EAS (2.33 +/- 0.8 vs 4.31 +/- 2.4, respectively; p = 0.05). By immunohistochemistry, L-selectin was detected in interstitial macrophages and polymorphonuclear cells, and E-selectin was detected in endothelial cells. CONCLUSION: These findings demonstrate that L-selectin and E-selectin are up-regulated during the development of HP, suggesting that they may contribute to the increased traffic of lung inflammatory cells.