scholarly journals Pathogenic Variants of Urolithiasis

2017 ◽  
Vol 8 (1) ◽  
pp. 95-105 ◽  
Author(s):  
Petr S Baketin ◽  
Rashid A Mollaev ◽  
Denis A Mazurenko ◽  
Vladislav E Grigoryev ◽  
Nariman K Gadzhiev ◽  
...  
Keyword(s):  
Clinical Practice ◽  
Kidney Stones ◽  
De Novo ◽  
Free Solution ◽  
Pathogenic Variants ◽  
Long Time ◽  
Randall’S Plaques

The essence of Urolithiasis - one of the oldest diseases known by the mankind - is still not understood completely. For a long time the comprehension of Urolithiasis was based on matrix, colloid, ionic, inhibitory and precipitation theories. In these cases it was impossible to single out separate pathogenetic patterns. Besides, in spite of the absence of in vivo proofs the fact that new concrement nucleus forming (de novo nucleation) is only possible outside of the stone-forming metastability range should be taken into consideration for metaphilactic purposes. Fortunately, certain progress in understanding Urolithiasis started with the onset of studies devoted to detailed scrutiny of stone-forming patients’ metabolic peculiarities as well as with the introduction into clinical practice of the up-to-date digital endoscopes. Based on existing publications one may classify pathogenesis of stone-forming into 4 major groups: growth of calcium-oxalic stones on Randall’s plaques in patients with hypercalciumuria; excrescences on the of Belliny’s ducts’ “gags”; microlites forming within the internal medullar layer discharging tubules’ lumen in patients with cystineuria; stones forming in free solution. There is no doubt this classification is not the final one, neither does it exclude mixed variants, however better understanding of the aforementioned pathogenic variants would facilitate a novel view at Urolithiasis and in patients with kidney stones would increase anti-relapse measures’ effectiveness.

scholarly journals Direct single-molecule measurements of phycocyanobilin photophysics in monomeric C-phycocyanin

2017 ◽  
Vol 114 (37) ◽  
pp. 9779-9784 ◽  
Author(s):  
Allison H. Squires ◽  
W. E. Moerner
Keyword(s):  
Energy Transfer ◽  
Single Molecule ◽  
Rational Design ◽  
Light Adaptation ◽  
De Novo ◽  
Photosynthetic Apparatus ◽  
Emission Spectra ◽  
Free Solution ◽  
Surface Attachment

Phycobilisomes are highly organized pigment–protein antenna complexes found in the photosynthetic apparatus of cyanobacteria and rhodophyta that harvest solar energy and transport it to the reaction center. A detailed bottom-up model of pigment organization and energy transfer in phycobilisomes is essential to understanding photosynthesis in these organisms and informing rational design of artificial light-harvesting systems. In particular, heterogeneous photophysical behaviors of these proteins, which cannot be predicted de novo, may play an essential role in rapid light adaptation and photoprotection. Furthermore, the delicate architecture of these pigment–protein scaffolds sensitizes them to external perturbations, for example, surface attachment, which can be avoided by study in free solution or in vivo. Here, we present single-molecule characterization of C-phycocyanin (C-PC), a three-pigment biliprotein that self-assembles to form the midantenna rods of cyanobacterial phycobilisomes. Using the Anti-Brownian Electrokinetic (ABEL) trap to counteract Brownian motion of single particles in real time, we directly monitor the changing photophysical states of individual C-PC monomers from Spirulina platensis in free solution by simultaneous readout of their brightness, fluorescence anisotropy, fluorescence lifetime, and emission spectra. These include single-chromophore emission states for each of the three covalently bound phycocyanobilins, providing direct measurements of the spectra and photophysics of these chemically identical molecules in their native protein environment. We further show that a simple Förster resonant energy transfer (FRET) network model accurately predicts the observed photophysical states of C-PC and suggests highly variable quenching behavior of one of the chromophores, which should inform future studies of higher-order complexes.

scholarly journals Pathogenic Variants in STXBP1 and in Genes for GABAa Receptor Subunities Cause Atypical Rett/Rett-like Phenotypes

2019 ◽  
Vol 20 (15) ◽  
pp. 3621 ◽  
Author(s):  
Francesca Cogliati ◽  
Valentina Giorgini ◽  
Maura Masciadri ◽  
Maria Teresa Bonati ◽  
Margherita Marchi ◽  
...  
Keyword(s):  
De Novo ◽  
Large Fraction ◽  
Neurodevelopmental Disorder ◽  
Gamma Aminobutyric Acid ◽  
In Vivo Models ◽  
Psychomotor Delay ◽  
Pathogenic Variants ◽  
Diagnostic Panel

Rett syndrome (RTT) is a neurodevelopmental disorder, affecting 1 in 10,000 girls. Intellectual disability, loss of speech and hand skills with stereotypies, seizures and ataxia are recurrent features. Stringent diagnostic criteria distinguish classical Rett, caused by a MECP2 pathogenic variant in 95% of cases, from atypical girls, 40–73% carrying MECP2 variants, and rarely CDKL5 and FOXG1 alterations. A large fraction of atypical and RTT-like patients remain without genetic cause. Next Generation Sequencing (NGS) targeted to multigene panels/Whole Exome Sequencing (WES) in 137 girls suspected for RTT led to the identification of a de novo variant in STXBP1 gene in four atypical RTT and two RTT-like girls. De novo pathogenic variants—one in GABRB2 and, for first time, one in GABRG2—were disclosed in classic and atypical RTT patients. Interestingly, the GABRG2 variant occurred at low rate percentage in blood and buccal swabs, reinforcing the relevance of mosaicism in neurological disorders. We confirm the role of STXBP1 in atypical RTT/RTT-like patients if early psychomotor delay and epilepsy before 2 years of age are observed, indicating its inclusion in the RTT diagnostic panel. Lastly, we report pathogenic variants in Gamma-aminobutyric acid-A (GABAa) receptors as a cause of atypical/classic RTT phenotype, in accordance with the deregulation of GABAergic pathway observed in MECP2 defective in vitro and in vivo models.

De novo SCAMP5 mutation causes a neurodevelopmental disorder with autistic features and seizures

2019 ◽  
Vol 57 (2) ◽  
pp. 138-144 ◽  
Author(s):  
Laurence Hubert ◽  
Magda Cannata Serio ◽  
Laure Villoing-Gaudé ◽  
Nathalie Boddaert ◽  
Anna Kaminska ◽  
...  
Keyword(s):  
Protein Function ◽  
De Novo ◽  
Fat Body ◽  
Neurodevelopmental Disorder ◽  
Missense Variant ◽  
Dominant Negative ◽  
Dominant Negative Effect ◽  
Functional Studies ◽  
Pathogenic Variants

BackgroundAutistic spectrum disorders (ASDs) with developmental delay and seizures are a genetically heterogeneous group of diseases caused by at least 700 different genes. Still, a number of cases remain genetically undiagnosed.ObjectiveThe objective of this study was to identify and characterise pathogenic variants in two individuals from unrelated families, both of whom presented a similar clinical phenotype that included an ASD, intellectual disability (ID) and seizures.MethodsWhole-exome sequencing was used to identify pathogenic variants in the two individuals. Functional studies performed in the Drosophila melanogaster model was used to assess the protein function in vivo.ResultsProbands shared a heterozygous de novo secretory carrier membrane protein (SCAMP5) variant (NM_001178111.1:c.538G>T) resulting in a p.Gly180Trp missense variant. SCAMP5 belongs to a family of tetraspanin membrane proteins found in secretory and endocytic compartments of neuronal synapses. In the fly SCAMP orthologue, the p.Gly302Trp genotype corresponds to human p.Gly180Trp. Western blot analysis of proteins overexpressed in the Drosophila fat body showed strongly reduced levels of the SCAMP p.Gly302Trp protein compared with the wild-type protein, indicating that the mutant either reduced expression or increased turnover of the protein. The expression of the fly homologue of the human SCAMP5 p.Gly180Trp mutation caused similar eye and neuronal phenotypes as the expression of SCAMP RNAi, suggesting a dominant-negative effect.ConclusionOur study identifies SCAMP5 deficiency as a cause for ASD and ID and underscores the importance of synaptic vesicular trafficking in neurodevelopmental disorders.

The CSF p-tau181/Aβ42 Ratio Offers a Good Accuracy “In Vivo” in the Differential Diagnosis of Alzheimer’s Dementia

2019 ◽  
Vol 16 (7) ◽  
pp. 587-595 ◽  
Author(s):  
Roberto Santangelo ◽  
Alessandro Dell'Edera ◽  
Arianna Sala ◽  
Giordano Cecchetti ◽  
Federico Masserini ◽  
...  
Keyword(s):  
Clinical Practice ◽  
Clinical Diagnosis ◽  
Fdg Pet ◽  
Amyloid Β ◽  
Cost Effective ◽  
Daily Clinical Practice ◽  
Different Types ◽  
Experimental Trials ◽  
Csf Findings

Background: The incoming disease-modifying therapies against Alzheimer’s disease (AD) require reliable diagnostic markers to correctly enroll patients all over the world. CSF AD biomarkers, namely amyloid-β 42 (Aβ42), total tau (t-tau), and tau phosphorylated at threonine 181 (p-tau181), showed good diagnostic accuracy in detecting AD pathology, but their real usefulness in daily clinical practice is still a matter of debate. Therefore, further validation in complex clinical settings, that is patients with different types of dementia, is needed to uphold their future worldwide adoption. Methods: We measured CSF AD biomarkers’ concentrations in a sample of 526 patients with a clinical diagnosis of dementia (277 with AD and 249 with Other Type of Dementia, OTD). Brain FDG-PET was also considered in a subsample of 54 patients with a mismatch between the clinical diagnosis and the CSF findings. Results: A p-tau181/Aβ42 ratio higher than 0.13 showed the best diagnostic performance in differentiating AD from OTD (86% accuracy index, 74% sensitivity, 81% specificity). In cases with a mismatch between clinical diagnosis and CSF findings, brain FDG-PET partially agreed with the p-tau181/Aβ42 ratio, thus determining an increase in CSF accuracy. Conclusions: The p-tau181/Aβ42 ratio alone might reliably detect AD pathology in heterogeneous samples of patients suffering from different types of dementia. It might constitute a simple, cost-effective and reproducible in vivo proxy of AD suitable to be adopted worldwide not only in daily clinical practice but also in future experimental trials, to avoid the enrolment of misdiagnosed AD patients.

The Application of the Cold Atmospheric Plasma-Activated Solutions in Cancer Treatment

2018 ◽  
Vol 18 (6) ◽  
pp. 769-775 ◽  
Author(s):  
Dayun Yan ◽  
Jonathan H. Sherman ◽  
Michael Keidar
Keyword(s):  
Cancer Treatment ◽  
Atmospheric Plasma ◽  
Current Status ◽  
Cold Atmospheric Plasma ◽  
Anti Cancer ◽  
Long Time ◽  
Key Topics ◽  
The Common

Background: Over the past five years, the cold atmospheric plasma-activated solutions (PAS) have shown their promissing application in cancer treatment. Similar as the common direct cold plasma treatment, PAS shows a selective anti-cancer capacity in vitro and in vivo. However, different from the direct cold atmospheric plasma (CAP) treatment, PAS can be stored for a long time and can be used without dependence on a CAP device. The research on PAS is gradually becoming a hot topic in plasma medicine. Objectives: In this review, we gave a concise but comprehensive summary on key topics about PAS including the development, current status, as well as the main conclusions about the anti-cancer mechanism achieved in past years. The approaches to make strong and stable PAS are also summarized.

scholarly journals An epilepsy-causing mutation leads to co-translational misfolding of the Kv7.2 channel

BMC Biology ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Janire Urrutia ◽  
Alejandra Aguado ◽  
Carolina Gomis-Perez ◽  
Arantza Muguruza-Montero ◽  
Oscar R. Ballesteros ◽  
...  
Keyword(s):  
Structural Instability ◽  
Binding Assays ◽  
Iq Motif ◽  
Channel Function ◽  
Human Epilepsy ◽  
Pathogenic Variants ◽  
In Silico Studies ◽  
Nascent Chain

Abstract Background The amino acid sequence of proteins generally carries all the necessary information for acquisition of native conformations, but the vectorial nature of translation can additionally determine the folding outcome. Such consideration is particularly relevant in human diseases associated to inherited mutations leading to structural instability, aggregation, and degradation. Mutations in the KCNQ2 gene associated with human epilepsy have been suggested to cause misfolding of the encoded Kv7.2 channel. Although the effect on folding of mutations in some domains has been studied, little is known of the way pathogenic variants located in the calcium responsive domain (CRD) affect folding. Here, we explore how a Kv7.2 mutation (W344R) located in helix A of the CRD and associated with hereditary epilepsy interferes with channel function. Results We report that the epilepsy W344R mutation within the IQ motif of CRD decreases channel function, but contrary to other mutations at this site, it does not impair the interaction with Calmodulin (CaM) in vitro, as monitored by multiple in vitro binding assays. We find negligible impact of the mutation on the structure of the complex by molecular dynamic computations. In silico studies revealed two orientations of the side chain, which are differentially populated by WT and W344R variants. Binding to CaM is impaired when the mutated protein is produced in cellulo but not in vitro, suggesting that this mutation impedes proper folding during translation within the cell by forcing the nascent chain to follow a folding route that leads to a non-native configuration, and thereby generating non-functional ion channels that fail to traffic to proper neuronal compartments. Conclusions Our data suggest that the key pathogenic mechanism of Kv7.2 W344R mutation involves the failure to adopt a configuration that can be recognized by CaM in vivo but not in vitro.

scholarly journals Whole-exome sequencing with targeted analysis and epilepsy after acute symptomatic neonatal seizures

2021 ◽  
Author(s):  
Adam L. Numis ◽  
Gilberto da Gente ◽  
Elliott H. Sherr ◽  
Hannah C. Glass
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
De Novo ◽  
List Type ◽  
Sequencing Analysis ◽  
Neonatal Seizures ◽  
Pathogenic Variants ◽  
Targeted Analysis ◽  
Whole Exome ◽  
Epilepsy Gene

Abstract Background The contribution of pathogenic gene variants with development of epilepsy after acute symptomatic neonatal seizures is not known. Methods Case–control study of 20 trios in children with a history of acute symptomatic neonatal seizures: 10 with and 10 without post-neonatal epilepsy. We performed whole-exome sequencing (WES) and identified pathogenic de novo, transmitted, and non-transmitted variants from established and candidate epilepsy association genes and correlated prevalence of these variants with epilepsy outcomes. We performed a sensitivity analysis with genes associated with coronary artery disease (CAD). We analyzed variants throughout the exome to evaluate for differential enrichment of functional properties using exploratory KEGG searches. Results Querying 200 established and candidate epilepsy genes, pathogenic variants were identified in 5 children with post-neonatal epilepsy yet in only 1 child without subsequent epilepsy. There was no difference in the number of trios with non-transmitted pathogenic variants in epilepsy or CAD genes. An exploratory KEGG analysis demonstrated a relative enrichment in cell death pathways in children without subsequent epilepsy. Conclusions In this pilot study, children with epilepsy after acute symptomatic neonatal seizures had a higher prevalence of coding variants with a targeted epilepsy gene sequencing analysis compared to those patients without subsequent epilepsy. Impact We performed whole-exome sequencing (WES) in 20 trios, including 10 children with epilepsy and 10 without epilepsy, both after acute symptomatic neonatal seizures. Children with post-neonatal epilepsy had a higher burden of pathogenic variants in epilepsy-associated genes compared to those without post-neonatal epilepsy. Future studies evaluating this association may lead to a better understanding of the risk of epilepsy after acute symptomatic neonatal seizures and elucidate molecular pathways that are dysregulated after brain injury and implicated in epileptogenesis.

scholarly journals Diagnostic difficulties and possibilities of NF1-like syndromes in childhood

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Eva Pinti ◽  
Krisztina Nemeth ◽  
Krisztina Staub ◽  
Anna Lengyel ◽  
Gyorgy Fekete ◽  
...  
Keyword(s):  
Diagnostic Criteria ◽  
Neurofibromatosis Type ◽  
Early Years ◽  
Diagnostic Efficiency ◽  
Clinical Criteria ◽  
Pathogenic Variants ◽  
Clinical Diagnostic ◽  
Long Time ◽  
Diagnostic Difficulties ◽  
Clinical Diagnostic Criteria

Abstract Background Neurofibromatosis type 1 (NF1), which is caused by heterozygous inactivating pathogenic variants in the NF1, has poor phenotypic expressivity in the early years of life and there are numerous conditions, including many other tumor predisposition syndromes, that can mimic its appearance. These are collectively termed NF1-like syndromes and are also connected by their genetic background. Therefore, the NF1’s clinical diagnostic efficiency in childhood could be difficult and commonly should be completed with genetic testing. Methods To estimate the number of syndromes/conditions that could mimic NF1, we compiled them through an extensive search of the scientific literature. To test the utility of NF1’s National Institutes of Health (NIH) clinical diagnostic criteria, which have been in use for a long time, we analyzed the data of a 40-member pediatric cohort with symptoms of the NF1-like syndromes’ overlapping phenotype and performed NF1 genetic test, and established the average age when diagnostic suspicion arises. To facilitate timely identification, we compiled strongly suggestive phenotypic features and anamnestic data. Results In our cohort the utility of NF1’s clinical diagnostic criteria were very limited (sensitivity: 80%, specificity: 30%). Only 53% of children with clinically diagnosed NF1 had a detectable NF1 pathogenic variation, whereas 40% of patients without fulfilled clinical criteria tested positive. The average age at first genetic counseling was 9 years, and 40% of children were referred after at least one tumor had already been diagnosed. These results highlight the need to improve NF1-like syndromes’ diagnostic efficiency in childhood. We collected the most extensive spectrum of NF1-like syndromes to help the physicians in differential diagnosis. We recommend the detailed, non-invasive clinical evaluation of patients before referring them to a clinical geneticist. Conclusions Early diagnosis of NF1-like syndromes can help to prevent severe complications by appropriate monitoring and management. We propose a potential screening, diagnostic and management strategy based on our findings and recent scientific knowledge.

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