11 research outputs found
Structural characterization of the protein tyrosine phosphatase Shp2 in solution
No full textIntracellular signalling cascades are mediated by a plethora of receptors, enzymes, adaptors and small molecules. The Protein Tyrosine Phosphatase (PTP) Shp2 is a highly conserved enzyme involved in a myriad of cellular processes including growth, differentiation and apoptosis. Shp2 is multi-domain protein composed of two SH2 domains in tandem, a PTP catalytic domain and a C-terminal tail containing multiple phosphorylation sites and a proline-rich region. The majority of biophysical research has utilised X-ray crystallography to study interactions and effects of mutations at the structural level. To gain a further understanding of Shp2 ligand binding and perturbations caused by disease relevant mutations, a structural investigation was performed with Nuclear Magnetic Resonance (NMR) spectroscopy and Small-angle X-ray Scattering (SAXS) in solution. The NMR signals from the backbone of both SH2 domains were assigned and residue-level interactions and differential SH2 domain specificities with peptides from the novel receptor G6b-B were delineated. In addition, the E76K point mutation that causes Noonan Syndrome and leukaemia was found to have increased conformational dynamics, the first experimental evidence of this phenomenon at the structural level
Challenges and Considerations for Delivering Bioinformatics Training in LMICs: Perspectives From Pan-African and Latin American Bioinformatics Networks
Get PDF© 2021 Ras, Carvajal-López, Gopalasingam, Matimba, Chauke, Mulder, Guerfali, Del Angel, Reyes, Oliveira, De Las Rivas and Cristancho.In general, institutions and research groups based in Low to Middle Income Countries (LMICs) battle a number of challenges ranging from a shortage of infrastructure, lack of training facilities, and poor internet, to a lack of local expertise (Karikari et al., 2015; Tastan Bishop et al., 2015; Shaffer et al., 2019). A shortage of local experts, particularly within more specialised topics, still remains a key obstacle in developing bioinformatics research capacity within LMICs (Tastan Bishop et al., 2015; Mulder et al., 2018).The authors who contributed to this manuscript are funded in whole, or in part, by the Wellcome Trust (WT108749/Z/15/Z), (WT108749/Z/15/A), H3ABioNet NIH grant U24HG006941, H3ABioNet NIH grant U24HG006942,
CABANA—Capacity building for bioinformatics in Latin America’ (CABANA), funded by UKRI-BBSRC on behalf of the Global Challenges Research Fund (BB/P027849/1), CSIC/ USAL and EMBL-EBI
Structure and dynamics of the insulin receptor: implications for receptor activation and drug discovery
No full textComparing modes of delivery of a combination of ion channel inhibitors for limiting secondary degeneration following partial optic nerve transection
Get PDF© 2019, The Author(s).
Injury to the central nervous system is exacerbated by secondary degeneration. Previous research has shown that a combination of orally and locally administered ion channel inhibitors following partial optic nerve injury protects the myelin sheath and preserves function in the ventral optic nerve, vulnerable to secondary degeneration. However, local administration is often not clinically appropriate. This study aimed to compare the efficacy of systemic and local delivery of the ion channel inhibitor combination of lomerizine, brilliant blue G (BBG) and YM872, which inhibits voltage-gated calcium channels, P2X7 receptors and Ca2+ permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors respectively. Following a partial optic nerve transection, adult female PVG rats were treated with BBG and YM872 delivered via osmotic mini pump directly to the injury site, or via intraperitoneal injection, both alongside oral administration of lomerizine. Myelin structure was preserved with both delivery modes of the ion channel inhibitor combination. However, there was no effect of treatment on inflammation, either peripherally or at the injury site, or on the density of oligodendroglial cells. Taken together, the data indicate that even at lower concentrations, the combinatorial treatment may be preserving myelin structure, and that systemic and local delivery are comparable at improving outcomes following neurotrauma
Ten simple rules for organizing a bioinformatics training course in low- and middle-income countries.
Get PDF© 2021 Moore et al.Bioinformatics training is required at every stage of a scientist’s research career. Continual bioinformatics training allows exposure to an ever-changing and growing repertoire of techniques and databases, and so biologists, computational scientists, and healthcare practitioners are all seeking learning opportunities in the use of computational resources and tools designed for data storage, retrieval, and analysis. There are abundant opportunities for accessing bioinformatics training for scientists in high-income countries (HICs), with well-equipped facilities and participants and trainers requiring minimal travel and financial costs alongside a range of general advice for developing short bioinformatics training courses [1–3]. However, regionally targeted bioinformatics training in low- and middle-income countries (LMICs) often requires more extensive local and external support, organization, and travel. Due to the limited expertise in bioinformatics in LMICs in general, most bioinformatics training requires a fair amount of collaboration with experts beyond the local community, country, or region. A common model of training, used as the basis of this article, includes a local host collaborating with local, regional, and international experts gathering to train local or regional participants. Recently, there has been a growth of capacity strengthening initiatives in LMICs, such as the Pan African Bioinformatics Network for Human Heredity and Health in Africa (H3ABioNet) Initiative [4–6], the Capacity Building for Bioinformatics in Latin America (CABANA) Project [7], the Asia Pacific BioInformatics Network (APBioNet) [8], and the Wellcome Connecting Science Courses and Conferences program [9]. One of the important strands of these initiatives is a drive to organize and deliver valuable bioinformatics training, but organizing and delivering short bioinformatics training workshops in an LMIC present a unique set of challenges. This paper attempts to build upon the sage advice for organizing bioinformatics workshops with specific guidance for organizing and delivering them in LMICs. It describes the processes to follow in organizing courses taking into consideration the low-resource setting. We should also note that LMICs are not a monolithic group and that setting, context, temporality, and specific location matters. LMICs are a complex regional grouping [10] and should be treated as such; however, we will present some common lessons that we hope will help organizers and trainers of bioinformatics training events in LMICs to navigate the often different, challenging, and rewarding experience.The authors who contributed to this manuscript are funded as follows: BM receives salary support from Wellcome Trust grants [WT108749/Z/15/Z, WT108749/Z/15/A], PC, VR, NM, AG’s salaries are funded in whole, or in part, by the NIH Common Fund H3ABioNet grant [U24HG006941], MC, SLFV, AR, PG, PCL’s salaries were partly funded by the UKRI-BBSRC ‘Capacity building for bioinformatics in Latin America’ (CABANA) grant, on behalf of the Global Challenges Research Fund [BB/P027849/1], JDLR is funded by ISCiii AES [ref. PI18/00591] at the CSIC/USAL (Spain) and by CYTED, RIABIO (Red Iberoamericana 521RT0118), AM’s salary is funded by [WT206194/Z/17/Z], GO is funded by the CABANA grant and SM is funded by the EMBL-EBI
Summary of the 10 simple rules for organizing a bioinformatics training event in an LMIC.
No full textFAIR, Findable, Accessible, Interoperable, and Reusable; LMIC, low- and middle-income country.</p
Venue checklist: special characteristics that a venue must fulfill to have a fruitful workshop.
No full textVenue checklist: special characteristics that a venue must fulfill to have a fruitful workshop.</p
Potential challenges experienced when delivering training in LMICs and their respective solutions.
No full textPotential challenges experienced when delivering training in LMICs and their respective solutions.</p
Uncoupling ITIM receptor G6b-B from tyrosine phosphatases Shp1 and Shp2 disrupts murine platelet homeostasis.
Get PDFThe immunoreceptor tyrosine-based inhibitory motif (ITIM)-containing receptor G6b-B has emerged as a key regulator of platelet homeostasis. However, it remains unclear how it mediates its effects. Tyrosine phosphorylation of ITIM and immunoreceptor tyrosine-based switch motif (ITSM) within the cytoplasmic tail of G6b-B provides a docking site for Src homology 2 domain-containing protein-tyrosine phosphatases Shp1 and Shp2, which are also critical regulators of platelet production and function. In this study, we investigate the physiological consequences of uncoupling G6b-B from Shp1 and Shp2. To address this, we generated a transgenic mouse model expressing a mutant form of G6b-B in which tyrosine residues 212 and 238 within ITIM and ITSM were mutated to phenylalanine. Mice homozygous for the mutation (G6b-B diY/F) were macrothrombocytopenic, as a result of the reduction in platelet production, and had large clusters of megakaryocytes and myelofibrosis at sites of hematopoiesis, similar to those observed in G6b-deficient mice and patients. Platelets from G6b-B diY/F mice were hyporesponsive to collagen, as a result of the significant reduction in the expression of the immunoreceptor tyrosine-based activation motif (ITAM)-containing collagen receptor complex GPVI-FcR γ-chain, as well as thrombin, which could be partially rescued by costimulating the platelets with adenosine diphosphate. In contrast, platelets from G6b-B diY/F, G6b KO, and megakaryocyte-specific Shp2 KO mice were hyperresponsive to antibody-mediated cross-linking of the hemi-ITAM-containing podoplanin receptor CLEC-2, suggesting that G6b-B inhibits CLEC-2-mediated platelet activation through Shp2. Findings from this study demonstrate that G6b-B must engage with Shp1 and Shp2 to mediate its regulatory effects on platelet homeostasis
