scholarly journals Genetic and functional insights into CDA-I prevalence and pathogenesis

2020 ◽  
pp. jmedgenet-2020-106880 ◽  
Author(s):  
Aude-Anais Olijnik ◽  
Noémi B A Roy ◽  
Caroline Scott ◽  
Joseph A Marsh ◽  
Jill Brown ◽  
...  
Keyword(s):  
Novel Mutation ◽  
Cell Types ◽  
Subcellular Localisation ◽  
Type I ◽  
Specific Nature ◽  
Pathogenic Variants ◽  
Cellular Pathways ◽  
Biallelic Mutations ◽  
Mutation Distribution ◽  
Insight Into

BackgroundCongenital dyserythropoietic anaemia type I (CDA-I) is a hereditary anaemia caused by biallelic mutations in the widely expressed genes CDAN1 and C15orf41. Little is understood about either protein and it is unclear in which cellular pathways they participate.MethodsGenetic analysis of a cohort of patients with CDA-I identifies novel pathogenic variants in both known causative genes. We analyse the mutation distribution and the predicted structural positioning of amino acids affected in Codanin-1, the protein encoded by CDAN1. Using western blotting, immunoprecipitation and immunofluorescence, we determine the effect of particular mutations on both proteins and interrogate protein interaction, stability and subcellular localisation.ResultsWe identify six novel CDAN1 mutations and one novel mutation in C15orf41 and uncover evidence of further genetic heterogeneity in CDA-I. Additionally, population genetics suggests that CDA-I is more common than currently predicted. Mutations are enriched in six clusters in Codanin-1 and tend to affect buried residues. Many missense and in-frame mutations do not destabilise the entire protein. Rather C15orf41 relies on Codanin-1 for stability and both proteins, which are enriched in the nucleolus, interact to form an obligate complex in cells.ConclusionStability and interaction data suggest that C15orf41 may be the key determinant of CDA-I and offer insight into the mechanism underlying this disease. Both proteins share a common pathway likely to be present in a wide variety of cell types; however, nucleolar enrichment may provide a clue as to the erythroid specific nature of CDA-I. The surprisingly high predicted incidence of CDA-I suggests that better ascertainment would lead to improved patient care.

scholarly journals Modeling In-Match Sports Dynamics Using the Evolving Probability Method

2021 ◽  
Vol 11 (10) ◽  
pp. 4429
Author(s):  
Ana Šarčević ◽  
Damir Pintar ◽  
Mihaela Vranić ◽  
Ante Gojsalić
Keyword(s):  
Monte Carlo Simulation ◽  
Statistical Models ◽  
Empirical Bayes ◽  
Hybrid Approach ◽  
Real Life ◽  
Bayes Estimation ◽  
Probability Method ◽  
Specific Nature ◽  
Sport Event ◽  
Insight Into

The prediction of sport event results has always drawn attention from a vast variety of different groups of people, such as club managers, coaches, betting companies, and the general population. The specific nature of each sport has an important role in the adaption of various predictive techniques founded on different mathematical and statistical models. In this paper, a common approach of modeling sports with a strongly defined structure and a rigid scoring system that relies on an assumption of independent and identical point distributions is challenged. It is demonstrated that such models can be improved by introducing dynamics into the match models in the form of sport momentums. Formal mathematical models for implementing these momentums based on conditional probability and empirical Bayes estimation are proposed, which are ultimately combined through a unifying hybrid approach based on the Monte Carlo simulation. Finally, the method is applied to real-life volleyball data demonstrating noticeable improvements over the previous approaches when it comes to predicting match outcomes. The method can be implemented into an expert system to obtain insight into the performance of players at different stages of the match or to study field scenarios that may arise under different circumstances.

scholarly journals Classical Xanthinuria in Nine Israeli Families and Two Isolated Cases from Germany: Molecular, Biochemical and Population Genetics Aspects

Biomedicines ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 788
Author(s):  
Hava Peretz ◽  
Ayala Lagziel ◽  
Florian Bittner ◽  
Mustafa Kabha ◽  
Meirav Shtauber-Naamati ◽  
...  
Keyword(s):  
Autosomal Recessive ◽  
Heterologous Protein ◽  
Heterologous Protein Expression ◽  
Type I ◽  
Type Ii ◽  
Amino Acid Residues ◽  
Cysteine Desulfurase ◽  
Cofactor Binding ◽  
Pathogenic Variants ◽  
Expression Studies

Classical xanthinuria is a rare autosomal recessive metabolic disorder caused by variants in the XDH (type I) or MOCOS (type II) genes. Thirteen Israeli kindred (five Jewish and eight Arab) and two isolated cases from Germany were studied between the years 1997 and 2013. Four and a branch of a fifth of these families were previously described. Here, we reported the demographic, clinical, molecular and biochemical characterizations of the remaining cases. Seven out of 20 affected individuals (35%) presented with xanthinuria-related symptoms of varied severity. Among the 10 distinct variants identified, six were novel: c.449G>T (p.(Cys150Phe)), c.1434G>A (p.(Trp478*)), c.1871C>G (p.(Ser624*)) and c.913del (p.(Leu305fs*1)) in the XDH gene and c.1046C>T (p.(Thr349Ileu)) and c.1771C>T (p.(Pro591Ser)) in the MOCOS gene. Heterologous protein expression studies revealed that the p.Cys150Phe variant within the Fe/S-I cluster-binding site impairs XDH biogenesis, the p.Thr349Ileu variant in the NifS-like domain of MOCOS affects protein stability and cysteine desulfurase activity, while the p.Pro591Ser and a previously described p.Arg776Cys variant in the C-terminal domain affect Molybdenum cofactor binding. Based on the results of haplotype analyses and historical genealogy findings, the potential dispersion of the identified variants is discussed. As far as we are aware, this is the largest cohort of xanthinuria cases described so far, substantially expanding the repertoire of pathogenic variants, characterizing structurally and functionally essential amino acid residues in the XDH and MOCOS proteins and addressing the population genetic aspects of classical xanthinuria.

Rhabdomyolysis, Acute Kidney Injury, and a Novel Frameshift Mutation in a Child with Glutaric Acidemia Type I

Nephron ◽  
2021 ◽  
pp. 1-6
Author(s):  
Linlin Huang ◽  
Ting Shi ◽  
Ying Li ◽  
Xiaozhong Li
Keyword(s):  
Acute Kidney Injury ◽  
Case Report ◽  
Frameshift Mutation ◽  
Novel Mutation ◽  
Kidney Injury ◽  
Febrile Illness ◽  
Type I ◽  
Continuous Venovenous Hemodiafiltration ◽  
Glutaric Acidemia Type I ◽  
Acute Decompensation

This is a case report of a girl with glutaric acidemia type I (GA-I) who experienced rhabdomyolysis and acute kidney injury (AKI). Her first acute metabolic crisis occurred at the age of 5 months, which mainly manifested as irritable crying, poor appetite, and hyperlactatemia. Mutation analysis showed 2 pathogenic mutations in the glutaryl-CoA dehydrogenase (GCDH) gene, which were c.383G>A (p.R128Q) and c.873delC (p.N291Kfs*41), the latter of which is a novel frameshift mutation of GA-I. She had a febrile illness at the age of 12 months, followed by AKI and severe rhabdomyolysis. Four days of continuous venovenous hemodiafiltration (CVVHDF) helped to overcome this acute decompensation. This case report describes a novel mutation in the GCDH gene, that is, c.873delC (p.N291Kfs*41). Also, it highlights the fact that patients with GA-I have a high risk of rhabdomyolysis and AKI, which may be induced by febrile diseases and hyperosmotic dehydration; CVVHDF can help to overcome this acute decompensation.

scholarly journals Multi-omic profiling of lung and liver tumor microenvironments of metastatic pancreatic cancer reveals site-specific immune regulatory pathways

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Won Jin Ho ◽  
Rossin Erbe ◽  
Ludmila Danilova ◽  
Zaw Phyo ◽  
Emma Bigelow ◽  
...  
Keyword(s):  
Mouse Model ◽  
Primary Tumors ◽  
Regulatory Pathways ◽  
Tumor Microenvironments ◽  
Clinical Responses ◽  
Cellular Pathways ◽  
Autopsy Specimens ◽  
Rapid Autopsy ◽  
Insight Into ◽  
Systemic Therapies

Abstract Background The majority of pancreatic ductal adenocarcinomas (PDAC) are diagnosed at the metastatic stage, and standard therapies have limited activity with a dismal 5-year survival rate of only 8%. The liver and lung are the most common sites of PDAC metastasis, and each have been differentially associated with prognoses and responses to systemic therapies. A deeper understanding of the molecular and cellular landscape within the tumor microenvironment (TME) metastasis at these different sites is critical to informing future therapeutic strategies against metastatic PDAC. Results By leveraging combined mass cytometry, immunohistochemistry, and RNA sequencing, we identify key regulatory pathways that distinguish the liver and lung TMEs in a preclinical mouse model of metastatic PDAC. We demonstrate that the lung TME generally exhibits higher levels of immune infiltration, immune activation, and pro-immune signaling pathways, whereas multiple immune-suppressive pathways are emphasized in the liver TME. We then perform further validation of these preclinical findings in paired human lung and liver metastatic samples using immunohistochemistry from PDAC rapid autopsy specimens. Finally, in silico validation with transfer learning between our mouse model and TCGA datasets further demonstrates that many of the site-associated features are detectable even in the context of different primary tumors. Conclusions Determining the distinctive immune-suppressive features in multiple liver and lung TME datasets provides further insight into the tissue specificity of molecular and cellular pathways, suggesting a potential mechanism underlying the discordant clinical responses that are often observed in metastatic diseases.

Poly-L-Lysine Induces Fibrosis on Alginate Microcapsules via the Induction of Cytokines

2001 ◽  
Vol 10 (3) ◽  
pp. 263-275 ◽  
Author(s):  
Berit L. Strand ◽  
Liv Ryan ◽  
Peter In't Veld ◽  
Bård Kulseng ◽  
Anne Mari Rokstad ◽  
...  
Keyword(s):  
Lipid A ◽  
Kinase Inhibitor ◽  
Inflammatory Responses ◽  
Type I Diabetes ◽  
Annexin V ◽  
Cell Types ◽  
P38 Map Kinase ◽  
Common Element ◽  
Type I ◽  
Inflammatory Reactions

Alginate – poly-l-lysine (PLL) microcapsules can be used for transplantation of insulin-producing cells for treatment of type I diabetes. In this work we wanted to study the inflammatory reactions against implanted microcapsules due to PLL. We have seen that by reducing the PLL layer, less overgrowth of the capsule is obtained. By incubating different cell types with PLL and afterwards measuring cell viability with MTT, we found massive cell death at concentrations of PLL higher than 10 μg/ml. Staining with annexin V and propidium iodide showed that PLL induced necrosis but not apoptosis. The proinflammatory cytokine, tumor necrosis factor (TNF), was detected in supernatants from monocytes stimulated with PLL. The TNF response was partly inhibited with antibodies against CD14, which is a well-known receptor for lipopolysaccharide (LPS). Bactericidal permeability increasing protein (BPI) and a lipid A analogue (B-975), which both inhibit LPS, did not inhibit PLL from stimulating monocytes to TNF production. This indicates that PLL and LPS bind to different sites on monocytes, but because they both are inhibited by a p38 MAP kinase inhibitor, they seem to have a common element in the signal transducing pathway. These results suggest that PLL may provoke inflammatory responses either directly or indirectly through its necrosis-inducing abilities. By combining soluble PLL and alginate both the toxic and TNF-inducing effects of PLL were reduced. The implications of these data are to use alginate microcapsules with low amounts of PLL for transplantation purposes.

Pathogenic variants in nucleoporin TPR (translocated promoter region, nuclear basket protein) cause severe intellectual disability in humans

2021 ◽  
Author(s):  
Nicole J Van Bergen ◽  
Katrina M Bell ◽  
Kirsty Carey ◽  
Russell Gear ◽  
Sean Massey ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Neurological Disorders ◽  
Promoter Region ◽  
Nuclear Pore ◽  
Valuable Insight ◽  
Amino Acid Deletion ◽  
Pathogenic Variants ◽  
Severe Intellectual Disability ◽  
Functional Analyses ◽  
Insight Into

Abstract The nuclear pore complex (NPC) is a multi-protein complex that regulates the trafficking of macromolecules between the nucleus and cytoplasm. Genetic variants in components of the NPC have been shown to cause a range of neurological disorders, including intellectual disability and microcephaly. Translocated promoter region, nuclear basket protein (TPR) is a critical scaffolding element of the nuclear facing interior of the NPC. Here we present two siblings with biallelic variants in TPR who present with a phenotype of microcephaly, ataxia and severe intellectual disability. The variants result in a premature truncation variant, and a splice variant leading to a 12-amino acid deletion respectively. Functional analyses in patient fibroblasts demonstrate significantly reduced TPR levels, and decreased TPR-containing NPC density. A compensatory increase in total NPC levels was observed, and decreased global RNA intensity in the nucleus. The discovery of variants that partly disable TPR function provide valuable insight into this essential protein in human disease, and our findings suggest that TPR variants are the cause of the siblings’ neurological disorder.

An Overview of the Latest Applications of Platelet-Derived Microparticles and Nanoparticles in Medical Technology 2010-2020

2021 ◽  
Vol 21 ◽  
Author(s):  
Tahereh Zadeh Mehrizi
Keyword(s):  
Drug Delivery ◽  
Cell Types ◽  
Current Status ◽  
Target Cells ◽  
Interesting Point ◽  
Large Size ◽  
Review Study ◽  
Cellular Pathways ◽  
Different Cell Types

: Today, Platelets and platelet-derived nanoparticles and microparticles have found many applications in nanomedical technology. The results of our review study show that no article has been published in this field to review the current status of applications of these platelet derivatives so far. Therefore, in present study, our goal is to compare the applications of platelet derivatives and review their latest status between 2010 and 2020 to present the latest findings to researchers. A very interesting point about the role of platelet derivatives is the presence of molecules on their surface which makes them capable of hiding from the immune system, reaching different target cells, and specifically attaching to different cell types. According to the results of this study, most of their applications include drug delivery, diagnosis of various diseases, and tissue engineering. However, their application in drug delivery is limited due to heterogeneity, large size, and the possibility of interference with cellular pathways in microparticles derived from other cells. On the other hand, platelet nanoparticles are more controllable and have been widely used for drug delivery in treatment of cancer, atherosclerosis, thrombosis, infectious diseases, repair of damaged tissue, and photothermal therapy. The results of this study show that platelet nanoparticles are more controllable than platelet microparticles and have a higher potential for use in medicine.

Cellular pathways of the conducted electrical response in arterioles of hamster cheek pouch in vitro

1995 ◽  
Vol 269 (6) ◽  
pp. H2031-H2038 ◽  
Author(s):  
J. Xia ◽  
T. L. Little ◽  
B. R. Duling
Keyword(s):  
Electrical Response ◽  
Electrical Current ◽  
Cell Types ◽  
Cheek Pouch ◽  
Resting Membrane Potential ◽  
Hamster Cheek Pouch ◽  
Cellular Pathways ◽  
Current Flows ◽  
Electrical Responses

We have previously shown that conducted vasomotor responses follow patterns that are consistent with a passive spread of electrical current along the length of the arterioles [(Xia and Duling, Am. J. Physiol. 269 (Heart Circ. Physiol. 38): H2022-H2030, 1995]. In this study, we define the cells through which the current flows. Isolated arterioles of hamster cheek pouch were used. The mean resting membrane potential (RMP) for randomly sampled arteriolar cells was -67 mV. When cell types were identified by dye injection, the RMPs were -68 and -67 mV for smooth muscle (SM) and endothelium (EC), respectively. Pulses of KCl induced transient, monophasic depolarizations at the site of stimulation (local), which were conducted decrementally along the length of the arteriole over several millimeters. During electrical conduction, three patterns of responses could be observed, but identical patterns of the conducted electrical responses were always observed in SM and EC. Phenylephrine stimulation also caused transient local and conducted depolarizations in both SM and EC. As with KCl stimuli, shapes of conducted electrical responses were identical in records made in both cell types. The results suggest that SM and EC are electrically coupled both homocellularly and heterocellularly.

scholarly journals Differential Requirement for TANK-binding Kinase-1 in Type I Interferon Responses to Toll-like Receptor Activation and Viral Infection

2004 ◽  
Vol 199 (12) ◽  
pp. 1651-1658 ◽  
Author(s):  
Andrea K. Perry ◽  
Edward K. Chow ◽  
Julia B. Goodnough ◽  
Wen-Chen Yeh ◽  
Genhong Cheng
Keyword(s):  
Viral Infection ◽  
Nuclear Translocation ◽  
Sendai Virus ◽  
Cell Types ◽  
Receptor Activation ◽  
Northern Blotting ◽  
Type I ◽  
Toll Like Receptor ◽  
Embryonic Fibroblasts ◽  
Iκb Kinase

TANK-binding kinase-1 (TBK1) and the inducible IκB kinase (IKK-i) have been shown recently to activate interferon (IFN) regulatory factor-3 (IRF3), the primary transcription factor regulating induction of type I IFNs. Here, we have compared the role and specificity of TBK1 in the type I IFN response to lipopolysaccharide (LPS), polyI:C, and viral challenge by examining IRF3 nuclear translocation, signal transducer and activator of transcription 1 phosphorylation, and induction of IFN-regulated genes. The LPS and polyI:C-induced IFN responses were abolished and delayed, respectively, in macrophages from mice with a targeted disruption of the TBK1 gene. When challenged with Sendai virus, the IFN response was normal in TBK1−/− macrophages, but defective in TBK1−/− embryonic fibroblasts. Although both TBK1 and IKK-i are expressed in macrophages, only TBK1 but not IKK-i was detected in embryonic fibroblasts by Northern blotting analysis. Furthermore, the IFN response in TBK1−/− embryonic fibroblasts can be restored by reconstitution with wild-type IKK-i but not a mutant IKK-i lacking kinase activity. Thus, our studies suggest that TBK1 plays an important role in the Toll-like receptor–mediated IFN response and is redundant with IKK-i in the response of certain cell types to viral infection.

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