Iron metabolism and biomarkers in idiopathic pulmonary arterial hypertension

Idiopathic pulmonary arterial hypertension (IPAH) is a progressive disease characterised by increased vascular resistance and remodelling of the pulmonary vasculature. This causes strain on the right ventricle, leading eventually to failure and death. Iron status is thought to influence pulmonary vascular tone, particularly in hypoxia, and may be important in IPAH. Proteomic studies of lung tissues from IPAH patients versus control lobectomy samples revealed downregulated levels of the haemoglobin- and haem-scavenging proteins haptoglobin (Hp) and haemopexin. Plasma levels of Hp were also reduced in IPAH and related to the Hp genotype. Consistently low Hp levels were associated with dysregulated iron homeostasis in IPAH patients. Iron deficiency, as defined by raised plasma soluble transferrin receptor (sTfR) levels, was prevalent in IPAH patients and related to increased levels of the master iron regulator hepcidin. Iron deficiency was also associated with poor exercise capacity, disease progression and mortality. Circulating sTfR levels were compared against other iron-related and established prognostic biomarkers in IPAH, including N-terminal brain natriuretic peptide (NT-proBNP), red cell distribution width (RDW), growth differentiation factor-15 and interleukin-6. All predicted survival and related to disease severity in IPAH, but RDW and NT-proBNP provided the most information when clinical and haemodynamic indices were considered. Dysfunctional bone morphogenetic protein (BMP) receptor type II (BMPR2) signalling contributes to idiopathic as well as heritable PAH. Downregulation of BMPR2, but not the other type II BMP receptors ActRIIA and ActRIIB, led to increased hepcidin expression and secretion in response to BMP-6 stimulation in hepatocellular carcinoma HepG2 cells. Hepcidin expression was also enhanced in rat lung tissue following 1 or 2 weeks exposure to hypoxia. In conclusion, dysregulation of iron homeostasis is common in IPAH and appears to be important clinically. Increased hepcidin levels may contribute to this phenomenon and reflect the dysfunctional BMPR2 signalling associated with the disease

A chemical probe based on the PreQ1 metabolite enables transcriptome-wide mapping of binding sites

The role of metabolite-responsive riboswitches in regulating gene expression in bacteria is well known and makes them useful systems for the study of RNA-small molecule interactions. Here, we study the PreQ1 riboswitch system, assessing sixteen diverse PreQ1-derived probes for their ability to selectively modify the class-I PreQ1 riboswitch aptamer covalently. For the most active probe (11), a diazirine-based photocrosslinking analog of PreQ1, X-ray crystallography and gel-based competition assays demonstrated the mode of binding of the ligand to the aptamer, and functional assays demonstrated that the probe retains activity against the full riboswitch. Transcriptome-wide mapping using Chem-CLIP revealed a highly selective interaction between the bacterial aptamer and the probe. In addition, a small number of RNA targets in endogenous human transcripts were found to bind specifically to 11, providing evidence for candidate PreQ1 aptamers in human RNA. This work demonstrates a stark influence of linker chemistry and structure on the ability of molecules to crosslink RNA, reveals that the PreQ1 aptamer/ligand pair are broadly useful for chemical biology applications, and provides insights into how PreQ1, which is similar in structure to guanine, interacts with human RNAs

Variation in the helminth community structure in spiny mice (Acomys dimidiatus) from four montane wadis in the St Katherine region of the Sinai Peninsula in Egypt

We compared helminth communities in spiny mice (Acomys dimidiatus) from 4 wadis in the arid montane region of the southern Sinai in Egypt, in a 4-week period in late summer. Total helminth species richness was 14 (8 nematodes, 5 cestodes and 1 acanthocephalan) with 94% of mice carrying at least 1 species and an overall mean species richness of 1.85. The most prevalent parasites were Protospirura muricola (47.8%) and Dentostomella kuntzi (46.3%). One larval cestode, Joyeuxiella rossicum, represents a new host record. The helminth community was dominated by intestinal nematodes (88.7%) of which 58.2% were arthropod-transmitted heteroxenic species. At the component community level, 70% of the worms were recovered from mice in just two wadis (Gharaba and Tlah) and 48.6% of intestinal nematodes were from Wadi Gharaba. Although only 7 species of helminths were recorded from Wadi Gharaba, this site gave the highest Berger-Parker dominance index because P. muricola. P. muricola was also dominant in Wadi El Arbaein whilst Syphacia minuta was the dominant species in Wadis Gebal and Tlah. At the infracommunity level, mean species richness and Brillouin’s index of diversity were highest in Wadi Tlah and lowest in Wadi Gebal, and the former was age dependent. Whilst mice from different wadis differed in the nematodes that were most common, those from Wadi Gharaba carried the highest mean number of worms/mouse. The abundance of P. muricola in particular varied markedly between sites: Wadi Gharaba was distinct as the site showing the highest mean worm burden whereas mice from Wadi Gebal were uninfected. None of the directly transmitted oxyuroid nematodes showed significant variation in abundance between wadis, or host sex or age classes. Overall, the single extrinsic factor in the study, site of capture, was more important than the intrinsic factors in explaining variation in helminth communities in the region. We conclude that in the high mountains of southern Sinai, each wadi is distinct in terms of its rodent parasites, and hence we expect spatially different coevolutionary pressures on their hosts, with resultant variation in life-histories

Measurements from the University of Colorado RAAVEN Uncrewed Aircraft System during ATOMIC

Between 24&nbsp;January and 15&nbsp;February 2020, small uncrewed aircraft systems (sUASs) were deployed to Morgan Lewis (Barbados) as part of the Atlantic Tradewind Ocean&ndash;Atmosphere Mesoscale Interaction Campaign (ATOMIC), a sister project to the ElUcidating the RolE of Cloud-Circulation Coupling in ClimAte (EUREC4A) project. The observations from ATOMIC and EUREC4A were aimed at improving our understanding of trade-wind cumulus clouds and the environmental regimes supporting them and involved the deployment of a wide variety of observational assets, including aircraft, ships, surface-based systems, and profilers. The current paper describes ATOMIC observations obtained using the University of Colorado Boulder RAAVEN (Robust Autonomous Aerial Vehicle&nbsp;&ndash; Endurant Nimble) sUAS. This platform collected nearly 80&thinsp;h of data throughout the lowest kilometer of the atmosphere, sampling the near-shore environment upwind from Barbados. Data from these platforms are publicly available through the National Oceanic and Atmospheric Administration's National Center for Environmental Intelligence (NCEI) archive. The primary DOI for the quality-controlled dataset described in this paper is https://doi.org/10.25921/jhnd-8e58 (de Boer et al., 2021). &nbsp;</p

Biomechanical and Neuromuscular Performance Requirements of Horizontal Deceleration: A Review with Implications for Random Intermittent Multi-Directional Sports

Rapid horizontal accelerations and decelerations are crucial events enabling the changes of velocity and direction integral to sports involving random intermittent multi-directional movements. However, relative to horizontal acceleration, there have been considerably fewer scientific investigations into the biomechanical and neuromuscular demands of horizontal deceleration and the qualities underpinning horizontal deceleration performance. Accordingly, the aims of this review article are to: (1) conduct an evidence-based review of the biomechanical demands of horizontal deceleration and (2) identify biomechanical and neuromuscular performance determinants of horizontal deceleration, with the aim of outlining relevant performance implications for random intermittent multi-directional sports. We highlight that horizontal decelerations have a unique ground reaction force profile, characterised by high-impact peak forces and loading rates. The highest magnitude of these forces occurs during the early stance phase (< 50 ms) and is shown to be up to 2.7 times greater than those seen during the first steps of a maximal horizontal acceleration. As such, inability for either limb to tolerate these forces may result in a diminished ability to brake, subsequently reducing deceleration capacity, and increasing vulnerability to excessive forces that could heighten injury risk and severity of muscle damage. Two factors are highlighted as especially important for enhancing horizontal deceleration ability: (1) braking force control and (2) braking force attenuation. Whilst various eccentric strength qualities have been reported to be important for achieving these purposes, the potential importance of concentric, isometric and reactive strength, in addition to an enhanced technical ability to apply braking force is also highlighted. Last, the review provides recommended research directions to enhance future understanding of horizontal deceleration ability

SOX17 Enhancer Variants Disrupt Transcription Factor Binding And Enhancer Inactivity Drives Pulmonary Hypertension

BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare disease characterized by remodeling of the pulmonary arteries, increased vascular resistance, and right-sided heart failure. Genome-wide association studies of idiopathic/heritable PAH established novel genetic risk variants, including conserved enhancers upstream of transcription factor (TF) SOX17 containing 2 independent signals. SOX17 is an important TF in embryonic development and in the homeostasis of pulmonary artery endothelial cells (hPAEC) in the adult. Rare pathogenic mutations in SOX17 cause heritable PAH. We hypothesized that PAH risk alleles in an enhancer region impair TF-binding upstream of SOX17, which in turn reduces SOX17 expression and contributes to disturbed endothelial cell function and PAH development. METHODS: CRISPR manipulation and siRNA were used to modulate SOX17 expression. Electromobility shift assays were used to confirm in silico–predicted TF differential binding to the SOX17 variants. Functional assays in hPAECs were used to establish the biological consequences of SOX17 loss. In silico analysis with the connectivity map was used to predict compounds that rescue disturbed SOX17 signaling. Mice with deletion of the SOX17 signal 1 enhancer region (SOX17-4593/enhKO) were phenotyped in response to chronic hypoxia and SU5416/hypoxia. RESULTS: CRISPR inhibition of SOX17-signal 2 and deletion of SOX17signal 1 specifically decreased SOX17 expression. Electromobility shift assays demonstrated differential binding of hPAEC nuclear proteins to the risk and nonrisk alleles from both SOX17 signals. Candidate TFs HOXA5 and ROR-α were identified through in silico analysis and antibody electromobility shift assays. Analysis of the hPAEC transcriptomes revealed alteration of PAH-relevant pathways on SOX17 silencing, including extracellular matrix regulation. SOX17 silencing in hPAECs resulted in increased apoptosis, proliferation, and disturbance of barrier function. With the use of the connectivity map, compounds were identified that reversed the SOX17-dysfunction transcriptomic signatures in hPAECs. SOX17 enhancer knockout in mice reduced lung SOX17 expression, resulting in more severe pulmonary vascular leak and hypoxia or SU5416/hypoxia-induced pulmonary hypertension. CONCLUSIONS: Common PAH risk variants upstream of the SOX17 promoter reduce endothelial SOX17 expression, at least in part, through differential binding of HOXA5 and ROR-α. Reduced SOX17 expression results in disturbed hPAEC function and PAH. Existing drug compounds can reverse the disturbed SOX17 pulmonary endothelial transcriptomic signature