scholarly journals The thrombospondin module 1 domain of the matricellular protein CCN3 shows an atypical disulfide pattern and incomplete CWR layers

2020 ◽  
Vol 76 (2) ◽  
pp. 124-134
Author(s):  
Emma-Ruoqi Xu ◽  
Aleix Lafita ◽  
Alex Bateman ◽  
Marko Hyvönen
Keyword(s):  
Bone Development ◽  
Cell Signalling ◽  
Matricellular Protein ◽  
Ccn Proteins ◽  
Charged Cluster ◽  
Extracellular Matrix Components ◽  
Wide Range ◽  
Sequence Profiles ◽  
Thrombospondin Type 1 Repeats

The members of the CCN (Cyr61/CTGF/Nov) family are a group of matricellular regulatory proteins that are essential to a wide range of functional pathways in cell signalling. Through interacting with extracellular matrix components and growth factors via one of their four domains, the CCN proteins are involved in critical biological processes such as angiogenesis, cell proliferation, bone development, fibrogenesis and tumorigenesis. Here, the crystal structure of the thrombospondin module 1 (TSP1) domain of CCN3 (previously known as Nov) is presented, which shares a similar three-stranded fold with the thrombospondin type 1 repeats of thrombospondin-1 and spondin-1, but with variations in the disulfide connectivity. Moreover, the CCN3 TSP1 domain lacks the typical π-stacked ladder of charged and aromatic residues on one side of the domain that is seen in other TSP1 domains. Using conservation analysis among orthologous domains, it is shown that a charged cluster in the centre of the domain is the most conserved site and this cluster is predicted to be a potential functional epitope for heparan sulfate binding. This variant TSP1 domain has also been used to revise the sequence determinants of TSP1 domains and to derive improved Pfam sequence profiles for the identification of novel TSP1 domains in more than 10 000 proteins across diverse phyla.

scholarly journals Thrombospondin module 1 domain (TSP1) of the matricellular protein CCN3 shows an atypical disulfide pattern and incomplete CWR layers

2019 ◽  
Author(s):  
Emma-Ruoqi Xu ◽  
Aleix Lafita ◽  
Alex Bateman ◽  
Marko Hyvönen
Keyword(s):  
Bone Development ◽  
Heparan Sulphate ◽  
Cell Signalling ◽  
Matricellular Protein ◽  
Ccn Proteins ◽  
Ccn Family ◽  
X Ray Crystallography ◽  
Extracellular Matrix Components ◽  
Wide Range ◽  
Definition Of

AbstractMembers of the CCN (Cyr61/CTGF/Nov) family are a group of matricellular regulatory proteins, essential to a wide range of functional pathways in cell signalling. Through interacting with extracellular matrix components and growth factors via one of its four domains, the CCN proteins are involved in critical biological processes such as angiogenesis, cell proliferation, bone development, fibrogenesis, and tumorigenesis. We present here the crystal structure of the thrombospondin module 1 (TSP1) domain of CCN3 (previously known as Nov), which shares a similar three-stranded fold with the thrombospondin type 1 repeats of thrombospondin-1 and Spondin-1, but with variations in the disulfide connectivity. Moreover, the CCN3 TSP1 lacks the typical pi-stacked ladder of charged and aromatic residues on one side of the domain, as seen in other TSP1 domains. Using conservation analysis among orthologous domains, we show that a charged cluster in the centre of the domain is the most conserved site and predict it to be a potential functional epitope for heparan sulphate binding. This variant TSP1 domain has also been used to revise the sequence determinants of TSP1 domains and derive improved Pfam sequence profiles for identification of novel TSP1 domains in more than 10,000 proteins across diverse phyla.SynopsisThe first structure of a thrombospondin module 1 domain (TSP1) from a CCN family matricellular protein has been determined by X-ray crystallography. The structure shows a typical three-stranded fold, but with an incomplete pi-stacked structure that is usually found in these domains. The structure reveals highest conservation in the positively charged central segment, which we predict to be a binding site for heparan sulphates. The atypical features of this domain have been used to revise the definition of the TSP1 domains and identify a number of new domains in sequence databases.

AGN1 vs AGN2 dichotomy as seen from the point of view of ionized outflows

2019 ◽  
Vol 15 (S356) ◽  
pp. 96-96
Author(s):  
Eleonora Sani
Keyword(s):  
Accretion Rate ◽  
Point Of View ◽  
Emission Lines ◽  
Black Hole Mass ◽  
X Ray ◽  
Bolometric Luminosity ◽  
Wide Range ◽  
Strong Contrast

AbstractI present a detailed study of ionized outflows in a large sample of 650 hard X-ray detected AGN. Taking advantage of the legacy value of the BAT AGN Spectroscopic Survey (BASS, DR1), we are able to reveal the faintest wings of the [OIII] emission lines associated with outflows. The sample allows us to derive the incidence of outflows covering a wide range of AGN bolometric luminosity and test how the outflow parameters are related with various AGN power tracers, such as black hole mass, Eddington ratio, luminosity. I’ll show how ionized outflows are more frequently found in type 1.9 and type 1 AGN (50% and 40%) with respect to the low fraction in type 2 AGN (20%). Within such a framework, I’ll demonstrate how type 2 AGN outflows are almost evenly balanced between blue- and red-shifted winds. This, in strong contrast with type 1 and type 1.9 AGN outflows which are almost exclusively blue-shifted. Finally, I’ll prove how the outflow occurrence is driven by the accretion rate, whereas the dependence of outflow properties with respect to the other AGN power tracers happens to be quite mild.

scholarly journals A global perspective on the issue of access to insulin

Diabetologia ◽  
2021 ◽  
Author(s):  
David Beran ◽  
Maria Lazo-Porras ◽  
Camille M. Mba ◽  
Jean Claude Mbanya
Keyword(s):  
Type 1 Diabetes ◽  
Diabetes Management ◽  
Multinational Companies ◽  
Global Perspective ◽  
Patient Access ◽  
Middle Income ◽  
Middle Income Countries ◽  
Wide Range ◽  
Pricing And Reimbursement

AbstractThe discovery of insulin in 1921 changed the prognosis for people with type 1 diabetes. A century later, availability and affordability of insulin remain a challenge in many parts of the globe. Using the WHO’s framework on understanding the life cycle of medicines, this review details the global and national challenges that affect patients’ abilities to access and afford insulin. Current research and development in diabetes has seen some innovations, but none of these have truly been game-changing. Currently, three multinational companies control over 95% of global insulin supply. The inclusion of insulin on the WHO’s Prequalification Programme is an opportunity to facilitate entry of new companies into the market. Many governments lack policies on the selection, procurement, supply, pricing and reimbursement of insulin. Moreover, mark-ups in the supply chain also affect the final price to the consumer. Whilst expenses related to diabetes are mostly covered by insurance in high-income countries, many patients from low- and middle-income countries have to pay out of their own pockets. The organisation of diabetes management within the healthcare system also affects patient access to insulin. The challenges affecting access to insulin are complex and require a wide range of solutions. Given that 2021 marks the centenary of the discovery of insulin, there is need for global advocacy to ensure that the benefits of insulin and innovations in diabetes care reach all individuals living with diabetes. Graphical abstract

Congenital ADAMTS-13 deficiency presenting as life-threatening thrombosis during pregnancy

2021 ◽  
Vol 14 (8) ◽  
pp. e239901
Author(s):  
Faheema Hasan ◽  
Anshul Gupta ◽  
Dinesh Chandra ◽  
Soniya Nityanand
Keyword(s):  
Late Presentation ◽  
Fresh Frozen Plasma ◽  
Artery Thrombosis ◽  
Fresh Frozen ◽  
Life Threatening ◽  
A Disintegrin And Metalloproteinase ◽  
Thrombospondin Type 1 Repeats ◽  
Frozen Plasma ◽  
Plasma Infusions

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disease characterised by thrombocytopenia, microangiopathic haemolytic anaemia and microvascular thrombosis. Congenital TTP accounting for less than 5% of all TTP cases can have a late presentation in adulthood mostly triggered by predisposing factors such as infection, pregnancy and inflammation. We present a case of a 23-year-old woman who presented to us in the postpartum period with mesenteric artery thrombosis with infarcts and later was diagnosed as a case of TTP based on congenital a disintegrin and metalloproteinase with thrombospondin type 1 repeats 13 (ADAMTS-13) deficiency detected on ADAMTS-13 levels and gene sequencing. She was successfully managed initially with therapeutic plasma exchanges and is now on prophylactic fortnightly fresh frozen plasma infusions at 15 mL/kg body weight and continues to be in remission.

scholarly journals Characterization of Monoclonal Antibodies against Bovine herpesvirus type 1 selected by Phage Display Technology

2017 ◽  
Vol 38 (6) ◽  
pp. 3915
Author(s):  
Greice Japolla ◽  
Ana Flávia Batista Penido ◽  
Greyciele Rodrigues Almeida ◽  
Luiz Artur Mendes Bataus ◽  
Jair Pereira Cunha Junior ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Phage Display ◽  
Bovine Herpesvirus ◽  
Single Chain ◽  
Phage Display Technology ◽  
Herpesvirus Type ◽  
Wide Range ◽  
Display Technology ◽  
Bovine Herpesvirus Type 1

The specificity of monoclonal antibodies (mAbs) to desired targets makes these molecules suitable for therapeutic and diagnostic uses against a wide range of pathogens. Phage display antibody libraries offer one method by which mAbs can be selected for, without the use of conventional hybridoma technology. In this work, phage display technology was used to construct, select and characterize a combinatorial single chain fragment variable (scFv) antibody library against bovine herpesvirus type 1 (BoHV-1) from the immune repertoire of chickens immunized with the virus. In silico analysis of the hypervariable domains of the antibody heavy chains revealed a high frequency of scFv fragments with low variability, suggesting that selection had probably been carried out and favored by a few im-munogenic viral antigens. The reactivity of the scFv fragments selected against BoHV-1 was demon-strated by Phage-ELISA. A significant increase in antibody reactivity to the target was observed after six rounds of library selection, showing its potential use as a molecule for BoHV-1 diagnosis. The strategy described here opens up a field for the use of phage display as a tool for selection of mono-clonal antibodies that could be used for theranostic applications against infectious and parasitic dis-eases of veterinary interest.

scholarly journals Extracellular Matrix Components in the Pathogenesis of Type 1 Diabetes

2014 ◽  
Vol 14 (12) ◽  
Author(s):  
Marika Bogdani ◽  
Eva Korpos ◽  
Charmaine J. Simeonovic ◽  
Christopher R. Parish ◽  
Lydia Sorokin ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Type 1 Diabetes ◽  
Extracellular Matrix Components ◽  
Matrix Components

scholarly journals The 3-O-sulfation of heparan sulfate modulates protein binding and lyase degradation

2021 ◽  
Vol 118 (3) ◽  
pp. e2012935118
Author(s):  
Pradeep Chopra ◽  
Apoorva Joshi ◽  
Jiandong Wu ◽  
Weigang Lu ◽  
Tejabhiram Yadavalli ◽  
...  
Keyword(s):  
Heparan Sulfate ◽  
Binding Proteins ◽  
Factor Xa ◽  
Tissue Expression ◽  
Cell Entry ◽  
Synthetic Approach ◽  
Array Technology ◽  
Wide Range ◽  
Simplex Virus

Humans express seven heparan sulfate (HS) 3-O-sulfotransferases that differ in substrate specificity and tissue expression. Although genetic studies have indicated that 3-O-sulfated HS modulates many biological processes, ligand requirements for proteins engaging with HS modified by 3-O-sulfate (3-OS) have been difficult to determine. In particular, the context in which the 3-OS group needs to be presented for binding is largely unknown. We describe herein a modular synthetic approach that can provide structurally diverse HS oligosaccharides with and without 3-OS. The methodology was employed to prepare 27 hexasaccharides that were printed as a glycan microarray to examine ligand requirements of a wide range of HS-binding proteins. The binding selectivity of antithrombin-III (AT-III) compared well with anti-Factor Xa activity supporting robustness of the array technology. Many of the other examined HS-binding proteins required an IdoA2S-GlcNS3S6S sequon for binding but exhibited variable dependence for the 2-OS and 6-OS moieties, and a GlcA or IdoA2S residue neighboring the central GlcNS3S. The HS oligosaccharides were also examined as inhibitors of cell entry by herpes simplex virus type 1, which, surprisingly, showed a lack of dependence of 3-OS, indicating that, instead of glycoprotein D (gD), they competitively bind to gB and gC. The compounds were also used to examine substrate specificities of heparin lyases, which are enzymes used for depolymerization of HS/heparin for sequence determination and production of therapeutic heparins. It was found that cleavage by lyase II is influenced by 3-OS, while digestion by lyase I is only affected by 2-OS. Lyase III exhibited sensitivity to both 3-OS and 2-OS.

scholarly journals THE EFFECT OF CHRONIC HYPERGLYCEMIA ON THE STATE OF MUSCULOSKELETAL SYSTEM (LITERATURE REVIEW)

2021 ◽  
Vol 21 (1) ◽  
pp. 184-187
Author(s):  
A.O. Ponyrko
Keyword(s):  
Diabetes Mellitus ◽  
Type 1 Diabetes ◽  
Bone Tissue ◽  
Musculoskeletal System ◽  
Metabolic Disorder ◽  
Skeletal System ◽  
Complex Disorders ◽  
Chronic Hyperglycemia ◽  
Wide Range

Diabetes mellitus is a metabolic disorder that today has become a threatening problem for human health. Its prevalence has been constantly increasing throughout the world over the past decades. Diabetes mellitus is regarded as an incurable metabolic disorder characterized by hyperglycemia, which is caused by defects in insulin secretion. This disease annually affects almost 3% of the total population of the planet. Chronic hyperglycemia causes dysfunction of various organs of the body, such as the eyes, kidneys, heart, blood vessels, and nerves. The most common complications of diabetes include lesions of the vessels of the eye, kidneys, lower limbs and nervous system. A high level of glucose in the blood causes the development of a wide range of pathological disorders, which affect bones as well. Recent studies have shown that diseases of the skeletal system are often observed in diabetes mellitus. Speaking about the effect of hyperglycemia on bones, the development of osteopenia and osteoporosis should be noted. In this regard, an important area of research is to study changes in the bone tissue in patients with type 1 diabetes mellitus and the mechanisms that lead to disruption of bone structure and metabolism. The article highlights the pathophysiological mechanisms of hyperglycemia action in type 1 diabetes that explains complex disorders of the organs of the musculoskeletal system. The detrimental effect of hyperglycemia results in marked degenerative changes in bone cells. The pathogenic effect of hyperglycemia on bone tissue is manifested in a decrease in bone mineral density that is due to the lack of insulin and, as a consequence, significant metabolic disorders, a decrease in bone mass, inhibition of bone tissue formation, a significant decrease in the trace element composition of bone. The combination of these factors creates the appropriate pathomorphological basis for the development of diabetic osteopathy. The article highlights the mechanism of action of hyperglycemia on skeletal system in order to stimulate to a more detailed investigation of diabetes mellitus in experimental animals.

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