Regulation of vegfr signalling in lymphatic vascular development and disease: an update

The importance of lymphatic vessels in a myriad of human diseases is rapidly gaining recognition; lymphatic vessel dysfunction is a feature of disorders including congenital lymphatic anomalies, primary lymphoedema and obesity, while improved lymphatic vessel function increases the efficacy of immunotherapy for cancer and neurological disease and promotes cardiac repair following myocardial infarction. Understanding how the growth and function of lymphatic vessels is precisely regulated therefore stands to inform the development of novel therapeutics applicable to a wide range of human diseases. Lymphatic vascular development is initiated during embryogenesis following establishment of the major blood vessels and the onset of blood flow. Lymphatic endothelial progenitor cells arise from a combination of venous and non-venous sources to generate the initial lymphatic vascular structures in the vertebrate embryo, which are then further ramified and remodelled to elaborate an extensive lymphatic vascular network. Signalling mediated via vascular endothelial growth factor (VEGF) family members and vascular endothelial growth factor receptor (VEGFR) tyrosine kinases is crucial for development of both the blood and lymphatic vascular networks, though distinct components are utilised to different degrees in each vascular compartment. Although much is known about the regulation of VEGFA/VEGFR2 signalling in the blood vasculature, less is understood regarding the mechanisms by which VEGFC/VEGFD/VEGFR3 signalling is regulated during lymphatic vascular development. This review will focus on recent advances in our understanding of the cellular and molecular mechanisms regulating VEGFA-, VEGFC- and VEGFD-mediated signalling via VEGFRs which are important for driving the construction of lymphatic vessels during development and disease.Genevieve A. Secker and Natasha L. Harve

Pain coping tools for children and young adults with a neurodevelopmental disability: A systematic review of measurement properties

First published: 16 September 2022. OnlinePublAim: To systematically identify and evaluate the measurement properties of patient-reported outcome measures (PROMs) and observer-reported outcome measures (parent proxy report) of pain coping tools that have been used with children and young adults (aged 0–24 years) with a neurodevelopmental disability. Method: A two-stage search using MEDLINE, Embase, CINAHL, Web of Science, and PsycInfo was conducted. Search 1 in August 2021 identified pain coping tools used in neurodevelopmental disability and search 2 in September 2021 located additional studies evaluating the measurement properties of these tools. Methodological quality was assessed using the COnsensus-based Standards for the Selection of Health Measurement INstruments (COSMIN) guidelines (PROSPERO protocol registration no. CRD42021273031). Results: Sixteen studies identified seven pain coping tools, all PROMs and observer-reported outcome measures (parent proxy report) versions. The measurement properties of the seven tools were appraised in 44 studies. No tool had high-quality evidence for any measurement property or evidence for all nine measurement properties as outlined by COSMIN. Only one tool had content validity for individuals with neurodevelopmental disability: the Cerebral Palsy Quality of Life tool. Interpretation: Pain coping assessment tools with self-report and parent proxy versions are available; however, measurement invariance has not been tested in young adults with a neurodevelopmental disability. This is an area for future research.Nadine L. Smith, Meredith G. Smith, Noula Gibson, Christine Imms, Ashleigh l. Thornton, Adrienne R. Harve

Forensic Investigation of Cyberstalking Cases using Behavioural Evidence Analysis

Behavioural Evidence Analysis (BEA) is, in theory, useful in developing an understanding of the offender, the victim, the crime scene, and the dynamics of the crime. It can add meaning to the evidence obtained through digital forensic techniques and assist investigators with reconstruction of a crime. There is, however, little empirical research examining the application of BEA to actual criminal cases, particularly cyberstalking cases. This study addresses this gap by examining the utility of BEA for such cases in terms of understanding the behavioural and motivational dimensions of offending, and the way in which digital evidence can be interpreted. It reports on the forensic analysis of 20 cyberstalking cases investigated by Dubai Police in the last five years. Results showed that BEA helps to focus an investigation, enables better understanding and interpretation of victim and offender behaviour, and assists in inferring traits of the offender from available digital evidence. These benefits can help investigators to build a stronger case, reduce time wasted to mistakes, and to exclude suspects wrongly accused in cyberstalking cases

Pkd1 Regulates Lymphatic Vascular Morphogenesis during Development.

Lymphatic vessels arise during development through sprouting of precursor cells from veins, which is regulated by known signaling and transcriptional mechanisms. The ongoing elaboration of vessels to form a network is less well understood. This involves cell polarization, coordinated migration, adhesion, mixing, regression, and shape rearrangements. We identified a zebrafish mutant, lymphatic and cardiac defects 1 (lyc1), with reduced lymphatic vessel development. A mutation in polycystic kidney disease 1a was responsible for the phenotype. PKD1 is the most frequently mutated gene in autosomal dominant polycystic kidney disease (ADPKD). Initial lymphatic precursor sprouting is normal in lyc1 mutants, but ongoing migration fails. Loss of Pkd1 in mice has no effect on precursor sprouting but leads to failed morphogenesis of the subcutaneous lymphatic network. Individual lymphatic endothelial cells display defective polarity, elongation, and adherens junctions. This work identifies a highly selective and unexpected role for Pkd1 in lymphatic vessel morphogenesis during development

The luminosities of protostars in the spitzer c2d and gould belt legacy clouds

Journal ArticlePublished version available online at the Astronomical Journal, Volume 145, Number 4, Article 94; doi: doi: 10.1088/0004-6256/145/4/94Motivated by the long-standing "luminosity problem" in low-mass star formation whereby protostars are underluminous compared to theoretical expectations, we identify 230 protostars in 18 molecular clouds observed by two Spitzer Space Telescope Legacy surveys of nearby star-forming regions. We compile complete spectral energy distributions, calculate L bol for each source, and study the protostellar luminosity distribution. This distribution extends over three orders of magnitude, from 0.01 L ȯ to 69 L ȯ, and has a mean and median of 4.3 L ȯ and 1.3 L ȯ, respectively. The distributions are very similar for Class 0 and Class I sources except for an excess of low luminosity (L bol ≲ 0.5 L) Class I sources compared to Class 0. 100 out of the 230 protostars (43%) lack any available data in the far-infrared and submillimeter (70 μm <λ < 850 μm) and have L bol underestimated by factors of 2.5 on average, and up to factors of 8-10 in extreme cases. Correcting these underestimates for each source individually once additional data becomes available will likely increase both the mean and median of the sample by 35%-40%. We discuss and compare our results to several recent theoretical studies of protostellar luminosities and show that our new results do not invalidate the conclusions of any of these studies. As these studies demonstrate that there is more than one plausible accretion scenario that can match observations, future attention is clearly needed. The better statistics provided by our increased data set should aid such future work. © 2013. The American Astronomical Society. All rights reserved..National Science FoundationNational Aeronautics and Space AdministrationJet Propulsion Laboratory, California Institute of Technolog

Yap1 promotes sprouting and proliferation of lymphatic progenitors downstream of Vegfc in the zebrafish trunk

Lymphatic vascular development involves specification of lymphatic endothelial progenitors that subsequently undergo sprouting, proliferation and tissue growth to form a complex second vasculature. The Hippo pathway and effectors Yap and Taz control organ growth and regulate morphogenesis and cellular proliferation. Yap and Taz control angiogenesis but a role in lymphangiogenesis remains to be fully elucidated. Here we show that YAP displays dynamic changes in lymphatic progenitors and Yap1 is essential for lymphatic vascular development in zebrafish. Maternal and Zygotic (MZ) yap1 mutants show normal specification of lymphatic progenitors, abnormal cellular sprouting and reduced numbers of lymphatic progenitors emerging from the cardinal vein during lymphangiogenesis. Furthermore, Yap1 is indispensable for Vegfc-induced proliferation in a transgenic model of Vegfc overexpression. Paracrine Vegfc-signalling ultimately increases nuclear YAP in lymphatic progenitors to control lymphatic development. We thus identify a role for Yap in lymphangiogenesis, acting downstream of Vegfc to promote expansion of this vascular lineage.Lin Grimm, Hiroyuki Nakajima, Smrita Chaudhury, Neil I Bower, Kazuhide S Okuda, Andrew G Cox, Natasha L Harvey, Katarzyna Koltowska, Naoki Mochizuki, Benjamin M Hoga

Soil-landscape and climatic relationships in the middle Miocene of the Madrid Basin

The Miocene alluvial-lacustrine sequences of the Madrid Basin, Spain, formed in highly varied landscapes. The presence of various types of palaeosols allows assessment of the effects of local and external factors onsedimentation, pedogenesis and geomorphological development. In the northern, more arid, tectonicallyactive arca, soils were weakly developed in aggrading alluvial fans, dominated by mass flows. reflecting high sedimentation rates. In more distal parts of the fans and in playa lakes calcretes and dolocretes developed: the former were associated with Mg-poor fan sediments whitc: the latter formed on Mg-rich lake clays exposed during minar lake lowstands. The nonh-east part of the basin had a less arid climate. Alluvial fans in this area were dominated by stream Aood deposits, sourced by carbonate terrains. Floodplain and freshwater lakc deposits formed in distal areas. The high local supply of calcium carbonate may have contributed to the preferential developmenl on calcretes on the fans. Both the fan and floodplain palaeosols exhibit pedofacies relationships and more mature soils developed in settings more distant from the sediment sources. Palaeosols also developed on pond and lake margin carbonates, and led to the formation of palustrine limestones. The spatial distributions and stratigraphies of palaeosols in the Madrid Basin alluvial fans suggest that soil formation was controlled by local factors. These palaeosols differ from those seen in Quatemary fans. Which are characterized by climatically induced periods of stability and instability

Global ubiquitinome profiling identifies NEDD4 as a regulator of Profilin 1 and actin remodelling in neural crest cells

The ubiquitin ligase NEDD4 promotes neural crest cell (NCC) survival and stem-cell like properties to regulate craniofacial and peripheral nervous system development. However, how ubiquitination and NEDD4 control NCC development remains unknown. Here we combine quantitative analysis of the proteome, transcriptome and ubiquitinome to identify key developmental signalling pathways that are regulated by NEDD4. We report 276 NEDD4 targets in NCCs and show that loss of NEDD4 leads to a pronounced global reduction in specific ubiquitin lysine linkages. We further show that NEDD4 contributes to the regulation of the NCC actin cytoskeleton by controlling ubiquitination and turnover of Profilin 1 to modulate filamentous actin polymerization. Taken together, our data provide insights into how NEDD4-mediated ubiquitination coordinates key regulatory processes during NCC development.Iman Lohraseb, Peter McCarthy, Genevieve Secker, Ceilidh Marchant, Jianmin Wu, Naveid Ali, Sharad Kumar, Roger J. Daly, Natasha L. Harvey, Hiroshi Kawabe, Oded Kleifeld, Sophie Wiszniak, Quenten Schwar

Athlete experiences of disordered eating in sport

To date, research into disordered eating in sport has focused on the prevalence and the identification of putative risk factors. Findings suggest that elite female athletes participating in sports with a focus on leanness or aesthetics are at greatest risk. A paucity of research remains as to the period after onset and how existing sufferers manage their illness over time. In line with the principles of interpretative phenomenological analysis (IPA), this study 'gives voice' to four athletes who have experienced disordered eating, documenting their personal accounts and interpreting these accounts from a psychological perspective. In‐depth, semi‐structured interviews were conducted and verbatim transcripts were analysed according to the procedures of IPA. Three superordinate themes emerged from the data: the struggle to disclose, social support needs and identity challenges. Athletes' stories provided rich descriptions of their subjective disordered eating experiences. Their accounts give critical insight into the impact of eating disturbance on the lives of athletes. Future research should continue to identify athletes with existing eating problems in order to improve understanding as to how such individuals can best be helped

GATA2 deficiency syndrome: a decade of discovery

Accepted: 8 August 2021GATA2 deficiency syndrome (G2DS) is a rare autosomal dominant genetic disease predisposing to a range of symptoms of which myeloid malignancy and immunodeficiency including recurrent infections are most common. In the last decade since it was first reported, there have been over 480 individuals identified carrying a pathogenic or likely pathogenic germline GATA2 variant with symptoms of G2DS, with 240 of these confirmed to be familial and 24 de novo. For those that develop myeloid malignancy (75% of all carriers with G2DS disease symptoms), the median age of onset is 17 years (range 0-78 years) and myelodysplastic syndrome (MDS) is the first diagnosis in 75% of these cases with acute myeloid leukemia (AML) in a further 9%. All variant types appear to predispose to myeloid malignancy and immunodeficiency. Apart from lymphedema in which haploinsufficiency seems necessary, the mutational requirements of the other less common G2DS phenotypes is still unclear. These predominantly loss-of-function variants impact GATA2 expression and function in numerous ways including perturbations to DNA binding, protein structure, protein:protein interactions, and gene transcription, splicing and expression. In this review, we provide the first expert-curated ACMG/AMP classification with codes of published variants compatible for use in clinical or diagnostic settings. This article is protected by copyright. All rights reserved.Claire C. Homan, Parvathy Venugopal, Peer Arts, Nur H. Shahrin, Simone Feurstein, Lesley Rawlings, David M. Lawrence, James Andrews, Sarah L. King, Smith, Natasha L. Harvey, Anna L. Brown, Hamish S. Scott, Christopher N. Hah