Subaortic Stenosis: What Lies Beneath.
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ABSTRACT:
SUBMITTER: Russell DJ
PROVIDER: S-EPMC6098166 | biostudies-other | 2018 Aug
REPOSITORIES: biostudies-other
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Project description:BackgroundEvolution leaves an imprint in species through genetic change. At the molecular level, evolutionary changes can be explored by studying ratios of nucleotide substitutions. The interplay among molecular evolution, derived phenotypes, and ecological ranges can provide insights into adaptive radiations. Caecilians (order Gymnophiona), probably the least known of the major lineages of vertebrates, are limbless tropical amphibians, with adults of most species burrowing in soils (fossoriality). This enigmatic order of amphibians are very distinct phenotypically from other extant amphibians and likely from the ancestor of Lissamphibia, but little to nothing is known about the molecular changes underpinning their radiation. We hypothesised that colonization of various depths of tropical soils and of freshwater habitats presented new ecological opportunities to caecilians.ResultsA total of 8540 candidate groups of orthologous genes from transcriptomic data of five species of caecilian amphibians and the genome of the frog Xenopus tropicalis were analysed in order to investigate the genetic machinery behind caecilian diversification. We found a total of 168 protein-coding genes with signatures of positive selection at different evolutionary times during the radiation of caecilians. The majority of these genes were related to functional elements of the cell membrane and extracellular matrix with expression in several different tissues. The first colonization of the tropical soils was connected to the largest number of protein-coding genes under positive selection in our analysis. From the results of our study, we highlighted molecular changes in genes involved in perception, reduction-oxidation processes, and aging that likely were involved in the adaptation to different soil strata.ConclusionsThe genes inferred to have been under positive selection provide valuable insights into caecilian evolution, potentially underpin adaptations of caecilians to their extreme environments, and contribute to a better understanding of fossorial adaptations and molecular evolution in vertebrates.
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Project description:Across the Bilateria, FGF/FGFR signaling is critical for normal development, and in both Drosophila and vertebrates, docking proteins are required to connect activated FGFRs with downstream pathways. While vertebrates use Frs2 to dock FGFR to the RAS/MAPK or PI3K pathways, the unrelated protein, downstream of FGFR (Dof/stumps/heartbroken), fulfills the corresponding function in Drosophila. To better understand the evolution of the signaling pathway downstream of FGFR, the available sequence databases were screened to identify Frs2, Dof, and other key pathway components in phyla that diverged early in animal evolution. While Frs2 homologues were detected only in members of the Bilateria, canonical Dof sequences (containing Dof, ankyrin, and SH2/SH3 domains) were present in cnidarians as well as bilaterians (but not in other animals or holozoans), correlating with the appearance of FGFR. Although these data suggested that Dof coupling might be ancestral, gene expression analysis in the cnidarian Hydra revealed that Dof is not upregulated in the zone of strong FGFRa and FGFRb expression at the bud base, where FGFR signaling controls detachment. In contrast, transcripts encoding other, known elements of FGFR signaling in Bilateria, namely the FGFR adaptors Grb2 and Crkl, which are acting downstream of Dof (and Frs2), as well as the guanyl nucleotide exchange factor Sos, and the tyrosine phosphatase Csw/Shp2, were strongly upregulated at the bud base. Our expression analysis, thus, identified transcriptional upregulation of known elements of FGFR signaling at the Hydra bud base indicating a highly conserved toolkit. Lack of transcriptional Dof upregulation raises the interesting question, whether Hydra FGFR signaling requires either of the docking proteins known from Bilateria.
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Project description:Fungi are phylogenetically diverse organisms found in nearly every environment as key contributors to the processes of nutrient cycling and decomposition. To date, most fungal diversity has been documented from terrestrial habitats leaving aquatic habitats underexplored. In particular, comparatively little is known about fungi inhabiting freshwater lakes, particularly the benthic zone, which may serve as an untapped resource for fungal biodiversity. Advances in technology allowing for direct sequencing of DNA from environmental samples provide a new opportunity to investigate freshwater benthic fungi. In this study, we employed both culture-dependent and culture-independent methods to evaluate the diversity of fungi in one of the largest freshwater systems on Earth, the North American Laurentian Great Lakes. This study presents the first comprehensive survey of fungi from sediment from Lake Michigan and Lake Superior, resulting in 465 fungal taxa with only 7% of sequence overlap between these two methods. Additionally, culture-independent analyses of the ITS1 and ITS2 regions revealed 49% and 72%, respectively, of the OTUs did not match a described fungal taxonomic group below kingdom Fungi. The low level of sequence overlap between methods and high percentage of fungal taxa that can only be classified at the kingdom level suggests an immense amount of fungal diversity remains to be studied in these aquatic fungal communities.
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Project description:Discrete subaortic stenosis (DSS) is a congenital heart disease that results in the formation of a fibro-membranous tissue, causing an increased pressure gradient in the left ventricular outflow tract (LVOT). While surgical resection of the membrane has shown some success in eliminating the obstruction, it poses significant risks associated with anesthesia, sternotomy, and heart bypass, and it remains associated with a high rate of recurrence. Although a genetic etiology had been initially proposed, the association between DSS and left ventricle (LV) geometrical abnormalities has provided more support to a hemodynamic etiology by which congenital or post-surgical LVOT geometric derangements could generate abnormal shear forces on the septal wall, triggering in turn a fibrotic response. Validating this hypothetical etiology and understanding the mechanobiological processes by which altered shear forces induce fibrosis in the LVOT are major knowledge gaps. This perspective paper describes the current state of knowledge of DSS, articulates the research needs to yield mechanistic insights into a significant pathologic process that is poorly understood, and proposes several strategies aimed at elucidating the potential mechanobiological synergies responsible for DSS pathogenesis. The proposed roadmap has the potential to improve DSS management by identifying early targets for prevention of the fibrotic lesion, and may also prove beneficial in other fibrotic cardiovascular diseases associated with altered flow.
| S-EPMC6166095 | biostudies-other
Project description:BackgroundCommunity engagement is key to developing local and context-specific strategies for the prevention and control of COVID-19. However, expedited research design and approval in the early days of the pandemic may have limited the opportunities for community members to influence pandemic-related research. In this study, we sought to understand how a Community Engagement Group (CEG) could impact a large longitudinal COVID-19 research project (Optimise), when involved solely in the interpretation and knowledge translation phases of the research.MethodsSeven community members were recruited for the CEG, representing a diverse range of groups. Each month, Optimise data of topical importance were compiled into a draft report. The CEG discussed the draft report at their monthly meeting and members' contributions were incorporated into the final report for distribution to policy-makers. In this study, a document analysis was undertaken of ten consecutive reports produced between February and November 2021. Each report was compared pre- and post- the inclusion of CEG contributions, which were then analysed using thematic analysis.ResultsCommunity engagement in the interpretation and knowledge translation phases of Optimise had positive impacts on reports for policy-makers, including grounding the empirical findings in broader community perspectives, identifying policy issues affecting different groups and contributing unique insights beyond the empirical findings. Overall, the CEG contributions demonstrated the complexity of lived experience lying beneath the empirical data.ConclusionCommunity engagement in the translation of the Optimise findings resulted in research reports to policy-makers that were reflective of a broader range of community perspectives, and that provided potential solutions to emerging policy issues related to COVID-19. This study adds to the evidence base about the impact of community engagement in the later interpretation and knowledge translation phases of research, particularly in the context of reporting to policy-makers during a public health emergency.
| S-EPMC11270602 | biostudies-literature
Project description:PurposeDiscrete subaortic stenosis (DSS) is an obstructive cardiac disease caused by a membranous lesion in the left ventricular (LV) outflow tract (LVOT). Although its etiology is unknown, the higher prevalence of DSS in LVOT anatomies featuring a steep aortoseptal angle (AoSA) suggests a potential role for hemodynamics. Therefore, the objective of this study was to quantify the impact of AoSA steepening on the LV three-dimensional (3D) hemodynamic stress environment.MethodsA 3D LV model reconstructed from cardiac cine-magnetic resonance imaging was connected to four LVOT geometrical variations spanning the clinical AoSA range (115°-160°). LV hemodynamic stresses were characterized in terms of cycle-averaged pressure, temporal shear magnitude (TSM), and oscillatory shear index. The wall shear stress (WSS) topological skeleton was further analyzed by computing the scaled divergence of the WSS vector field.ResultsAoSA steepening caused an increasingly perturbed subaortic flow marked by LVOT flow skewness and complex 3D secondary flow patterns. These disturbances generated WSS overloads (>45% increase in TSM vs. 160° model) on the inferior LVOT wall, and increased WSS contraction (>66% decrease in WSS divergence vs. 160° model) in regions prone to DSS membrane formation.ConclusionsAoSA steepening generated substantial hemodynamic stress abnormalities in LVOT regions prone to DSS formation. Further studies are needed to assess the possible impact of such mechanical abnormalities on the tissue and cellular responses.
| S-EPMC10570849 | biostudies-literature
Project description:Discrete subaortic stenosis (DSS) is an obstruction of the left ventricular outflow tract (LVOT) due to the formation of a fibromuscular membrane upstream of the aortic valve. DSS is a major risk factor for aortic regurgitation (AR), which often persists after surgical resection of the membrane. While the etiology of DSS and secondary AR is largely unknown, the frequent association between DSS and aortoseptal angle (AoSA) abnormalities has supported the emergence of a mechanobiological pathway by which hemodynamic stress alterations on the septal wall could trigger a biological cascade leading to fibrosis and membrane formation. The resulting LVOT flow disturbances could activate the valve endothelium and contribute to AR. In an effort to assess this hypothetical mechano-etiology, this study aimed at isolating computationally the effects of AoSA abnormalities on septal wall shear stress (WSS), and the impact of DSS on LVOT hemodynamics. Two-dimensional computational fluid dynamics models featuring a normal AoSA (N-LV), a steep AoSA (S-LV), and a steep AoSA with a DSS lesion (DSS-LV) were designed to compute the flow in patient-specific left ventricles (LVs). Boundary conditions consisted of transient velocity profiles at the mitral inlet and LVOT outlet, and patient-specific LV wall motion. The deformation of the DSS lesion was computed using a two-way fluid-structure interaction modeling strategy. Turbulence was accounted for via implementation of the k-ω turbulence model. While the N-LV and S-LV models generated similar LVOT flow characteristics, the DSS-LV model resulted in an asymmetric LVOT jet-like structure, subaortic stenotic conditions (up to 2.4-fold increase in peak velocity, 45% reduction in effective jet diameter vs. N-LV/S-LV), increased vorticity (2.8-fold increase) and turbulence (5- and 3-order-of-magnitude increase in turbulent kinetic energy and Reynolds shear stress, respectively). The steep AoSA subjected the septal wall to a 23% and 69% overload in temporal shear magnitude and gradient, respectively, without any substantial change in oscillatory shear index. This study reveals the existence of WSS overloads on septal wall regions prone to DSS lesion formation in steep LVOTs, and the development of highly turbulent, stenotic and asymmetric flow in DSS LVOTs, which support a possible mechano etiology for DSS and secondary AR.
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Project description:BackgroundPlanning population care in a specific health care setting requires deep knowledge of the clinical characteristics of the target care recipients, which tend to be country specific. Our area virtually lacks any descriptive, far-reaching publications about institutionalized older people (IOP). We aimed to investigate the demographic and clinical characteristics of institutionalized older people (IOP) ≥65 years old and compare them with those of the rest of the population of the same age.MethodsRetrospective analysis (total cohort approach) of clinical and resource-use characteristics of IOP and non-IOP older than 65 years in Catalonia (North-East Spain). Variables analysed included age and sex, diagnoses, morbidity burden-using Adjusted Morbidity Groups (GMA, Grupos de Morbilidad Ajustada)-, mortality, use of resources, and medications taken. All data were obtained from the administrative database of the local healthcare system.ResultsThis study included 93,038, 78,458, 68,545 and 67,456 IOP from 2011, 2013, 2015 and 2017, respectively. In this interval, an increase in median age (83 vs. 87 years), in women (68.64% vs. 72.11%) and in annual mortality (11.74% vs. 20.46%) was observed. Compared with non-IOP (p < 0.001 in all comparisons), IOP showed a higher annual mortality (20.46% vs. 3.13%), a larger number of chronic diseases (specially dementia: 46.47% vs. 4.58%), higher multimorbidity (15.2% vs. 4.2% with GMA of maximum complexity), and annual admissions to acute care (47.6% vs. 27.7%) and skilled nursing facilities (27.8% vs. 7.4%), mean length of hospital stay (10.0 vs. 7.2 days) and mean of medications taken (11.7 vs. 8.0).ConclusionsThere is a growing gap between the clinical and demographic characteristics of age-matched IOP and non-IOP, which overlaps with a higher mortality rate of IOP. The profile of resources utilization of IOP compared with non-IOP strongly suggests a deficiency of preventive actions and stresses the need to rethink the care model for IOP from a social and health care perspective.
| S-EPMC7265641 | biostudies-literature
Project description:Eutherian mammals and saurischian dinosaurs both evolved lineages of huge terrestrial herbivores. Although significantly more saurischian dinosaurs were giants than eutherians, the long bones of both taxa scale similarly and suggest that locomotion was dynamically similar. However, articular cartilage is thin in eutherian mammals but thick in saurischian dinosaurs, differences that could have contributed to, or limited, how frequently gigantism evolved. Therefore, we tested the hypothesis that sub-articular bone, which supports the articular cartilage, changes shape in different ways between terrestrial mammals and dinosaurs with increasing size. Our sample consisted of giant mammal and reptile taxa (i.e., elephants, rhinos, sauropods) plus erect and non-erect outgroups with thin and thick articular cartilage. Our results show that eutherian mammal sub-articular shape becomes narrow with well-defined surface features as size increases. In contrast, this region in saurischian dinosaurs expands and remains gently convex with increasing size. Similar trends were observed in non-erect outgroup taxa (monotremes, alligators), showing that the trends we report are posture-independent. These differences support our hypothesis that sub-articular shape scales differently between eutherian mammals and saurischian dinosaurs. Our results show that articular cartilage thickness and sub-articular shape are correlated. In mammals, joints become ever more congruent and thinner with increasing size, whereas archosaur joints remained both congruent and thick, especially in sauropods. We suggest that gigantism occurs less frequently in mammals, in part, because joints composed of thin articular cartilage can only become so congruent before stress cannot be effectively alleviated. In contrast, frequent gigantism in saurischian dinosaurs may be explained, in part, by joints with thick articular cartilage that can deform across large areas with increasing load.
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