scholarly journals Codon-optimized TDP-43-mediated neurodegeneration in a Drosophila model for ALS/FTLD

2019 ◽  
Author(s):  
Tanzeen Yusuff ◽  
Shreyasi Chatterjee ◽  
Ya-Chu Chang ◽  
Tzu-Kang Sang ◽  
George R. Jackson
Keyword(s):  
The Novel ◽  
Genetic Screens ◽  
Gain Of Function ◽  
Function Mechanism ◽  
Promoter Fusion ◽  
Drosophila Model ◽  
Weight Protein ◽  
Photoreceptor Neurons ◽  
And Function

ABSTRACTTransactive response DNA binding protein-43 (TDP-43) is known to mediate neurodegeneration associated with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). The exact mechanism by which TDP-43 exerts toxicity in the brains of affected patients remains unclear. In a novel Drosophila melanogaster model, we report gain-of-function phenotypes due to misexpression of insect codon-optimized version of human wild-type TDP-43 (CO-TDP-43) using both the binary GAL4/UAS system and direct promoter fusion constructs. The CO-TDP-43 model showed robust tissue specific phenotypes in the adult eye, wing, and bristles in the notum. Compared to non-codon optimized transgenic flies, the CO-TDP-43 flies produced increased amount of high molecular weight protein, exhibited pathogenic phenotypes, and showed cytoplasmic aggregation with both nuclear and cytoplasmic expression of TDP-43. Further characterization of the adult retina showed a disruption in the morphology and function of the photoreceptor neurons with the presence of acidic vacuoles that are characteristic of autophagy. Based on our observations, we propose that TDP-43 has the propensity to form toxic protein aggregates via a gain-of-function mechanism, and such toxic overload leads to activation of protein degradation pathways such as autophagy. The novel codon optimized TDP-43 model is an excellent resource that could be used in genetic screens to identify and better understand the exact disease mechanism of TDP-43 proteinopathies and find potential therapeutic targets.

scholarly journals Roles of the novel coiled-coil protein Rng10 in septum formation during fission yeast cytokinesis

2016 ◽  
Vol 27 (16) ◽  
pp. 2528-2541 ◽  
Author(s):  
Yajun Liu ◽  
I-Ju Lee ◽  
Mingzhai Sun ◽  
Casey A. Lower ◽  
Kurt W. Runge ◽  
...  
Keyword(s):  
Fission Yeast ◽  
Rho Gtpases ◽  
Cellular Localization ◽  
Affinity Purification ◽  
Coiled Coil ◽  
The Novel ◽  
Septum Formation ◽  
Division Site ◽  
And Function

Rho GAPs are important regulators of Rho GTPases, which are involved in various steps of cytokinesis and other processes. However, regulation of Rho-GAP cellular localization and function is not fully understood. Here we report the characterization of a novel coiled-coil protein Rng10 and its relationship with the Rho-GAP Rga7 in fission yeast. Both rng10Δ and rga7Δ result in defective septum and cell lysis during cytokinesis. Rng10 and Rga7 colocalize on the plasma membrane at the cell tips during interphase and at the division site during cell division. Rng10 physically interacts with Rga7 in affinity purification and coimmunoprecipitation. Of interest, Rga7 localization is nearly abolished without Rng10. Moreover, Rng10 and Rga7 work together to regulate the accumulation and dynamics of glucan synthases for successful septum formation in cytokinesis. Our results show that cellular localization and function of the Rho-GAP Rga7 are regulated by a novel protein, Rng10, during cytokinesis in fission yeast.

scholarly journals A Drosophila model of neuronal ceroid lipofuscinosis CLN4 reveals a hypermorphic gain of function mechanism

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Elliot Imler ◽  
Jin Sang Pyon ◽  
Selina Kindelay ◽  
Meaghan Torvund ◽  
Yong-quan Zhang ◽  
...  
Keyword(s):  
Membrane Trafficking ◽  
Neuronal Ceroid Lipofuscinosis ◽  
Gene Dosage ◽  
Neuronal Ceroid Lipofuscinoses ◽  
Dependent Manner ◽  
Membrane Structures ◽  
Gain Of Function ◽  
Function Mechanism ◽  
Ubiquitinated Proteins ◽  
Drosophila Model

The autosomal dominant neuronal ceroid lipofuscinoses (NCL) CLN4 is caused by mutations in the synaptic vesicle (SV) protein CSPα. We developed animal models of CLN4 by expressing CLN4 mutant human CSPα (hCSPα) in Drosophila neurons. Similar to patients, CLN4 mutations induced excessive oligomerization of hCSPα and premature lethality in a dose-dependent manner. Instead of being localized to SVs, most CLN4 mutant hCSPα accumulated abnormally, and co-localized with ubiquitinated proteins and the prelysosomal markers HRS and LAMP1. Ultrastructural examination revealed frequent abnormal membrane structures in axons and neuronal somata. The lethality, oligomerization and prelysosomal accumulation induced by CLN4 mutations was attenuated by reducing endogenous wild type (WT) dCSP levels and enhanced by increasing WT levels. Furthermore, reducing the gene dosage of Hsc70 also attenuated CLN4 phenotypes. Taken together, we suggest that CLN4 alleles resemble dominant hypermorphic gain of function mutations that drive excessive oligomerization and impair membrane trafficking.

scholarly journals Multimodality diagnosis of cardiac involvement in COVID-19 patients

2021 ◽  
Vol 31 (1) ◽  
pp. 17-26
Author(s):  
Anca Balinisteanu ◽  
Hayat Memis ◽  
Gratiela Postulache-Cosmulescu ◽  
Diana Mihalcea ◽  
Sorina Mihaila ◽  
...  
Keyword(s):  
Myocardial Injury ◽  
Wide Spectrum ◽  
Multiorgan Failure ◽  
Cardiovascular Complications ◽  
Cardiac Biomarkers ◽  
The Novel ◽  
Correct Treatment ◽  
And Function

The Coronavirus disease 2019 (COVID-19) pandemic, caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV2), exhibits a wide spectrum of manifestations, from asymptomatic presentations to acute respiratory failure, myocardial injury, arterial or venous thrombosis, multiorgan failure, and death. Although COVID-19 mainly disrupts the respiratory syndrome, it has been shown to have detrimental impact on cardiac morphology and function, resulting in a broad range of cardiovascular complications and poor outcome, increasing morbidity and mortality of these patients. This review will summarize the knowledge on characterization of myocardial injury in COVID 19, by using cardiac biomarkers, electrocardiographic, and cardiac multi-modality imaging findings for an early and accurate diagnosis, proper management, correct treatment, and follow-up of COVID-19 patients.

scholarly journals Beyond classic editing: innovative CRISPR approaches for functional studies of long non-coding RNA

2019 ◽  
Vol 4 (1) ◽  
Author(s):  
Dahlia A Awwad
Keyword(s):  
Genetic Manipulation ◽  
Functional Characterization ◽  
The Novel ◽  
Functional Studies ◽  
Non Coding Rna ◽  
Rna Targeting ◽  
Potential Applications ◽  
And Function ◽  
Long Non Coding Rna

Abstract Long non-coding RNAs (lncRNAs) makeup a considerable part of the non-coding human genome and had been well-established as crucial players in an array of biological processes. In spite of their abundance and versatile roles, their functional characteristics remain largely undiscovered mainly due to the lack of suitable genetic manipulation tools. The emerging CRISPR/Cas9 technology has been widely adapted in several studies that aim to screen and identify novel lncRNAs as well as interrogate the functional properties of specific lncRNAs. However, the complexity of lncRNAs genes and the regulatory mechanisms that govern their transcription, as well as their unique functionality pose several limitations the utilization of classic CRISPR methods in lncRNAs functional studies. Here, we overview the unique characteristics of lncRNAs transcription and function and the suitability of the CRISPR toolbox for applications in functional characterization of lncRNAs. We discuss some of the novel variations to the classic CRISPR/Cas9 system that have been tailored and applied previously to study several aspects of lncRNAs functionality. Finally, we share perspectives on the potential applications of various CRISPR systems, including RNA-targeting, in the direct editing and manipulation of lncRNAs.

scholarly journals Micro/Nanoscale Tribological and Mechanical Investigation of the Articular Surfaces of Katydid Leg Joints: Potential for the Novel Bioinspired Lubrication Systems

MRS Advances ◽  
2017 ◽  
Vol 2 (19-20) ◽  
pp. 1117-1123 ◽  
Author(s):  
Jun Kyun Oh ◽  
Cengiz Yegin ◽  
Mustafa Akbulut
Keyword(s):  
Hierarchical Structures ◽  
Surface Characteristics ◽  
The Novel ◽  
Periodic Patterns ◽  
Real Area Of Contact ◽  
Dry Conditions ◽  
Mechanical Investigation ◽  
Micromechanical Systems ◽  
And Function

ABSTRACTInsects are recognized with their ability to efficiently move, operate, and function, and hence are inspiration for the design of micromechanical systems. This work deals with the structural, mechanical, and frictional characterization of the leg joint articulations of the katydid (Orthoptera: Tettigoniidae). For the katydids, the tibia joints were found to show a nanosmooth texture while the femur joint had a micro/nanotextured surface characteristics. The nanotexture was a two-tone periodic patterns with the hierarchical structures involving cylindrical ridges that are covered with nanoscale lamellar patterns perpendicular to the long axis and valleys between ridges that are decorated with the hillock patterns. The tibia and femur contact regions showed the reduced elastic modulus (Er) values ranging from 0.88 ± 0.01 GPa to 3.90 ± 0.11 GPa. The friction coefficient (μ) value of 0.053 ± 0.001 was recorded for the sliding contact of the tibia joint against the femur joint in air under dry conditions. The low friction values are attributed to the reduced real area of contact between the joint pair due to the coupling of the nanosmooth surfaces against the hierarchically nanotextured surfaces.

A new Drosophila homeobox gene, bsh, is expressed in a subset of brain cells during embryogenesis

Development ◽  
1993 ◽  
Vol 117 (2) ◽  
pp. 793-806 ◽  
Author(s):  
B. Jones ◽  
W. McGinnis
Keyword(s):  
Homeobox Genes ◽  
Homeobox Gene ◽  
Brain Morphology ◽  
Genetic Screens ◽  
Internal Structures ◽  
Drosophila Brain ◽  
And Function ◽  
The Brain

Homeobox genes have been shown to control the determination of positional, tissue and cellular identity during the development of the fruitfly Drosophila melanogaster. Because genes involved in the determination of internal structures derived from neural, mesodermal and endodermal tissues may have been overlooked in conventional genetic screens, we undertook the identification of new homeobox genes expressed in these internal tissues. Here we describe the characterization of one of these new Drosophila homeobox genes, called brain-specific-homeobox (bsh). In embryos, bsh is expressed exclusively in the brain. bsh protein accumulates in approximately 30 cells in each brain hemisphere. One of these bsh expressing cells is closely associated with the terminus of the larval visual nerve (Bolwig's nerve). While deletions of chromosomal interval containing the bsh gene show no dramatic changes in embryonic brain morphology, the expression pattern of the bsh gene suggests that it may play a highly specialized role in the determination and function of cell type in the Drosophila brain.

Functional characterization of human brown adipose tissue metabolism

2020 ◽  
Vol 477 (7) ◽  
pp. 1261-1286 ◽  
Author(s):  
Marie Anne Richard ◽  
Hannah Pallubinsky ◽  
Denis P. Blondin
Keyword(s):  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Functional Characterization ◽  
Human Infants ◽  
Positron Emission ◽  
Brown Adipose ◽  
Treatment Of Obesity ◽  
And Function

Brown adipose tissue (BAT) has long been described according to its histological features as a multilocular, lipid-containing tissue, light brown in color, that is also responsive to the cold and found especially in hibernating mammals and human infants. Its presence in both hibernators and human infants, combined with its function as a heat-generating organ, raised many questions about its role in humans. Early characterizations of the tissue in humans focused on its progressive atrophy with age and its apparent importance for cold-exposed workers. However, the use of positron emission tomography (PET) with the glucose tracer [18F]fluorodeoxyglucose ([18F]FDG) made it possible to begin characterizing the possible function of BAT in adult humans, and whether it could play a role in the prevention or treatment of obesity and type 2 diabetes (T2D). This review focuses on the in vivo functional characterization of human BAT, the methodological approaches applied to examine these features and addresses critical gaps that remain in moving the field forward. Specifically, we describe the anatomical and biomolecular features of human BAT, the modalities and applications of non-invasive tools such as PET and magnetic resonance imaging coupled with spectroscopy (MRI/MRS) to study BAT morphology and function in vivo, and finally describe the functional characteristics of human BAT that have only been possible through the development and application of such tools.

Parasite defense mechanisms in bees: behavior, immunity, antimicrobials, and symbionts

2019 ◽  
Vol 4 (1) ◽  
pp. 59-76 ◽  
Author(s):  
Alison E. Fowler ◽  
Rebecca E. Irwin ◽  
Lynn S. Adler
Keyword(s):  
Defense Mechanisms ◽  
Poor Quality ◽  
Future Research ◽  
Immune Priming ◽  
Social Bees ◽  
Bee Health ◽  
Landscape Scales ◽  
And Function ◽  
Solitary Species

Parasites are linked to the decline of some bee populations; thus, understanding defense mechanisms has important implications for bee health. Recent advances have improved our understanding of factors mediating bee health ranging from molecular to landscape scales, but often as disparate literatures. Here, we bring together these fields and summarize our current understanding of bee defense mechanisms including immunity, immunization, and transgenerational immune priming in social and solitary species. Additionally, the characterization of microbial diversity and function in some bee taxa has shed light on the importance of microbes for bee health, but we lack information that links microbial communities to parasite infection in most bee species. Studies are beginning to identify how bee defense mechanisms are affected by stressors such as poor-quality diets and pesticides, but further research on this topic is needed. We discuss how integrating research on host traits, microbial partners, and nutrition, as well as improving our knowledge base on wild and semi-social bees, will help inform future research, conservation efforts, and management.

Gaunilo Parodies Anselm

2014 ◽  
Vol 17 (1) ◽  
pp. 45-71
Author(s):  
Geo Siegwart
Keyword(s):  
Detailed Comparison ◽  
The Third ◽  
Common Structure ◽  
Logical Reconstruction ◽  
Points Of View ◽  
And Function

The main objective is an interpretation of the island parody, in particular a logical reconstruction of the parodying argument that stays close to the text. The parodied reasoning is identified as the proof in the second chapter of the Proslogion, more specifically, this proof as it is represented by Gaunilo in the first chapter of his Liber pro insipiente. The second task is a detailed comparison between parodied and parodying argument as well as an account of their common structure. The third objective is a tentative characterization of the nature and function of parodies of arguments. It seems that parodying does not add new pertinent points of view to the usual criticism of an argument.

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