scholarly journals An internal promoter underlies the difference in disease severity between N- and C-terminal truncation mutations of Titin in zebrafish

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Jun Zou ◽  
Diana Tran ◽  
Mai Baalbaki ◽  
Ling Fung Tang ◽  
Annie Poon ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Disease Severity ◽  
Protein Product ◽  
Dominant Negative ◽  
Precise Position ◽  
Internal Promoter ◽  
Sarcomeric Protein ◽  
Skeletal Myopathy ◽  
The Difference ◽  
Shed Light

Truncating mutations in the giant sarcomeric protein Titin result in dilated cardiomyopathy and skeletal myopathy. The most severely affected dilated cardiomyopathy patients harbor Titin truncations in the C-terminal two-thirds of the protein, suggesting that mutation position might influence disease mechanism. Using CRISPR/Cas9 technology, we generated six zebrafish lines with Titin truncations in the N-terminal and C-terminal regions. Although all exons were constitutive, C-terminal mutations caused severe myopathy whereas N-terminal mutations demonstrated mild phenotypes. Surprisingly, neither mutation type acted as a dominant negative. Instead, we found a conserved internal promoter at the precise position where divergence in disease severity occurs, with the resulting protein product partially rescuing N-terminal truncations. In addition to its clinical implications, our work may shed light on a long-standing mystery regarding the architecture of the sarcomere.

scholarly journals Variety resistance of winter barley to powdery mildew in the field in 1976−2005

2008 ◽  
Vol 43 (No. 3) ◽  
pp. 87-96 ◽  
Author(s):  
A. Dreiseitl
Keyword(s):  
Powdery Mildew ◽  
Disease Severity ◽  
Powdery Mildew Resistance ◽  
Specific Resistance ◽  
Winter Barley ◽  
Mildew Resistance ◽  
Average Resistance ◽  
The Difference ◽  
The Given ◽  
Resistance Of Varieties

The results of evaluation of powdery mildew resistance in winter barley varieties in 285 Czech Official Trials conducted at 20 locations were analysed. Over the period, the number of varieties tested per year increased from four to seven in 1976−1985 to 53−61 in 2002−2005. To assess the resistance of varieties, only trials with sufficient disease severity were used. In 1976−2000, six varieties (1.7% of the varieties tested in the given years) ranked among resistant (average resistance of a variety in a year > 7.5) including NR-468 possessing the gene <i>Mla13</i>, KM-2099 with <i>mlo</i> and Marinka with the genes <i>Mla7</i>, <i>MlaMu2</i>. In 2001−2005, already 33 varieties (16.9%) ranked among resistant, of which Traminer possessing the genes <i>Ml(St)</i> and <i>Ml(IM9 </i> dominated. The proportion of susceptible varieties (average resistance ≤ 5.5) did not change in the two mentioned periods. Two-rowed varieties began to be tested as late as in 1990 (the first variety was Danilo), however, no difference was found in the resistance of two- and six-rowed varieties. Using an example of two pairs of varieties (Dura-Miraj and Marinka-Tiffany) with identical genes for specific resistance but with different resistance in the field, the efficiency of non-specific resistance is discussed. The resistance of domestic and foreign varieties was similar in 1994−2000; however, in 2001−2005 the difference was 0.75 point to disadvantage of domestic ones.

scholarly journals SETBP1 accumulation induces P53 inhibition and genotoxic stress in neural progenitors underlying neurodegeneration in Schinzel-Giedion syndrome

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Federica Banfi ◽  
Alicia Rubio ◽  
Mattia Zaghi ◽  
Luca Massimino ◽  
Giulia Fagnocchi ◽  
...  
Keyword(s):  
Dna Damage ◽  
Neuronal Death ◽  
Neuronal Loss ◽  
Genotoxic Stress ◽  
Protein Product ◽  
Neural Progenitors ◽  
Cell Identity ◽  
Neurodegenerative Process ◽  
Parp 1 ◽  
Shed Light

AbstractThe investigation of genetic forms of juvenile neurodegeneration could shed light on the causative mechanisms of neuronal loss. Schinzel-Giedion syndrome (SGS) is a fatal developmental syndrome caused by mutations in the SETBP1 gene, inducing the accumulation of its protein product. SGS features multi-organ involvement with severe intellectual and physical deficits due, at least in part, to early neurodegeneration. Here we introduce a human SGS model that displays disease-relevant phenotypes. We show that SGS neural progenitors exhibit aberrant proliferation, deregulation of oncogenes and suppressors, unresolved DNA damage, and resistance to apoptosis. Mechanistically, we demonstrate that high SETBP1 levels inhibit P53 function through the stabilization of SET, which in turn hinders P53 acetylation. We find that the inheritance of unresolved DNA damage in SGS neurons triggers the neurodegenerative process that can be alleviated either by PARP-1 inhibition or by NAD + supplementation. These results implicate that neuronal death in SGS originates from developmental alterations mainly in safeguarding cell identity and homeostasis.

scholarly journals Three-Dimensional Left Ventricular Torsion in Patients With Dilated Cardiomyopathy　― A Marker of Disease Severity ―

2017 ◽  
Vol 81 (4) ◽  
pp. 529-536 ◽  
Author(s):  
Krunoslav Michael Sveric ◽  
Stefan Ulbrich ◽  
Mohamed Rady ◽  
Tobias Ruf ◽  
Heda Kvakan ◽  
...  
Keyword(s):  
Dilated Cardiomyopathy ◽  
Disease Severity ◽  
Three Dimensional ◽  
Left Ventricular ◽  
Left Ventricular Torsion ◽  
Ventricular Torsion

scholarly journals A case of atypical systemic primary carnitine deficiency in Saudi Arabia

2018 ◽  
Vol 10 (2) ◽  
Author(s):  
Abdulrahman Alghamdi ◽  
Hani Almalki ◽  
Aiman Shawli ◽  
Rahaf Waggass ◽  
Fahad Hakami
Keyword(s):  
Dilated Cardiomyopathy ◽  
Autosomal Recessive ◽  
Acid Metabolism ◽  
Age Of Onset ◽  
Carnitine Deficiency ◽  
Proximal Muscle ◽  
Skeletal Myopathy ◽  
Primary Carnitine Deficiency ◽  
Elevated Transaminases ◽  
Work Up

Systemic primary carnitine deficiency (SPCD) is an autosomal recessive inborn error of fatty acid metabolism caused by a defect in the transporter responsible for moving carnitine across plasma membrane. The clinical features of SPCD vary widely based on the age of onset and organs involved. During infancy, patients might show episodes of hypoketotic hypoglycemia, hepatomegaly, elevated transaminases, and hyperammonemia. Skeletal myopathy, elevated creatine kinase, and cardiomyopathy are the main manifestations in children with SPCD, while in adults, the disorder is usually manifested as cardiomyopathy, arrhythmias, or fatigability. Here, we report a 5-year-old boy with SPCD that presented as dilated cardiomyopathy with atypical features, such as anemia, respiratory distress, and proximal muscle weakness. This report supports considering carnitine deficiency treatment in the work-up of unexplained pediatric dilated cardiomyopathy.

scholarly journals Getting Vaccinated Helps: Prospective Study Reveals Lower CT Severity Scores amongst COVID Vaccine Recipients

2022 ◽  
Author(s):  
Priscilla C. Joshi ◽  
Vandana Jahanvi ◽  
Mangal S. Mahajan ◽  
Nivedita C. Ghule Patil ◽  
Priyankkumar G. Moradiya ◽  
...  
Keyword(s):  
Disease Severity ◽  
Age Groups ◽  
P Value ◽  
Disease Prognosis ◽  
Important Message ◽  
Severity Scores ◽  
Reduce Infection Rate ◽  
The Mean ◽  
The Difference ◽  
The Government

Abstract Context Computerized tomography (CT) is an invaluable imaging investigation for evaluating COVID-19 disease. CT detects early changes of COVID-19 pneumonia and predicts the disease prognosis based on a semiquantitative 25-point CT severity score (CT-SS). India launched its vaccination drive in January 2021 with two different vaccines being approved by the government. These vaccines are believed to prevent the disease itself, in majority of the cases and at least decrease disease severity, in the rest. Aim This study aims to evaluate the CT-SS in vaccinated and non-vaccinated subjects who have been diagnosed with COVID-pneumonia or are COVID suspects. Subjects and Methods A total of 3,235 patients with typical COVID-19 related imaging findings on HRCT thorax were included in the study. These subjects were divided into three age categories, 18–44, 45–59 and ≥60 years. The CT severity scores were allotted by experienced radiologists. Medians of the scores in different age groups were compared amongst vaccinated and non-vaccinated individuals using the Kruskal–Wallis H test. A p-value < 0.05 was considered significant. All results were shown with 95% confidence interval. Results The difference in the medians amongst the vaccinated and non-vaccinated groups was significant, p-values being < 0.001 in all age categories. Conclusion The mean CT-SS was less in vaccinated subjects and the difference in median CT-SS amongst vaccinated and non-vaccinated individuals was statistically significant, thus sending an important message that it is mandatory for the population at large to get vaccinated to reduce infection rate/disease severity.

scholarly journals Fragment answers and double negation in strict negative concord languages

2016 ◽  
Vol 26 ◽  
pp. 584 ◽  
Author(s):  
Anamaria Fălăuș ◽  
Andreea Nicolae
Keyword(s):  
Negative Concord ◽  
Double Negation ◽  
Polarity Item ◽  
Polarity Sensitivity ◽  
Fragment Answers ◽  
Explanatory Account ◽  
The Difference ◽  
Two Parameters ◽  
Polarity Sensitive ◽  
Shed Light

This paper revisits the phenomenon of negative concord (NC) as an instance of polarity sensitivity. We shed light on a new set of data regarding n-words as fragment answers to negative questions and show that we find unexpected double negation (DN) readings for fragment n-words in view of their behavior in non-elliptical constructions. To account for this pattern, we offer an updated version of the hypothesis that n-words are strong NPIs, making use of an alternative and exhaustification approach. We argue that the difference between n-words and other NPIs should be seen as the result of two parameters: (i) whether reconstruction of the polarity item is allowed, and (ii) whether the polarity item has the ability to license a covert negation operator. The result is an explanatory account of NC and DN readings in both non-elliptical and elliptical environments, which allows for an easier integration of n-words in the broader typology of polarity sensitive items. 

Sign in / Sign up

Export Citation Format

Share Document