scholarly journals Gene therapy with AR isoform 2 rescues spinal and bulbar muscular atrophy phenotype by modulating AR transcriptional activity

2021 ◽  
Vol 7 (34) ◽  
pp. eabi6896
Author(s):  
Wooi F. Lim ◽  
Mitra Forouhan ◽  
Thomas C. Roberts ◽  
Jesse Dabney ◽  
Ruth Ellerington ◽  
...  
Keyword(s):  
Transcriptional Activity ◽  
Muscular Atrophy ◽  
Great Promise ◽  
Adeno Associated Virus ◽  
Transcriptional Dysregulation ◽  
Vector Type ◽  
Naturally Occurring ◽  
Targeted Approach ◽  
Polyq Tract

Spinal and bulbar muscular atrophy (SBMA) is an X-linked, adult-onset neuromuscular condition caused by an abnormal polyglutamine (polyQ) tract expansion in androgen receptor (AR) protein. SBMA is a disease with high unmet clinical need. Recent studies have shown that mutant AR-altered transcriptional activity is key to disease pathogenesis. Restoring the transcriptional dysregulation without affecting other AR critical functions holds great promise for the treatment of SBMA and other AR-related conditions; however, how this targeted approach can be achieved and translated into a clinical application remains to be understood. Here, we characterized the role of AR isoform 2, a naturally occurring variant encoding a truncated AR lacking the polyQ-harboring domain, as a regulatory switch of AR genomic functions in androgen-responsive tissues. Delivery of this isoform using a recombinant adeno-associated virus vector type 9 resulted in amelioration of the disease phenotype in SBMA mice by restoring polyQ AR–dysregulated transcriptional activity.

scholarly journals Side chain to main chain hydrogen bonds stabilize a polyglutamine helix in the activation domain of a transcription factor

2018 ◽  
Author(s):  
Albert Escobedo ◽  
Busra Topal ◽  
Micha Ben Achim Kunze ◽  
Juan Aranda ◽  
Giulio Chiesa ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Hydrogen Bonds ◽  
Transcriptional Activity ◽  
Main Chain ◽  
Muscular Atrophy ◽  
Helical Structure ◽  
Structural Basis ◽  
Tract Length ◽  
Spinobulbar Muscular Atrophy ◽  
Polyq Tract

Polyglutamine (polyQ) tracts are regions of low sequence complexity of variable length found in more than one hundred human proteins. These tracts are frequent in activation domains of transcription factors and their length often correlates with transcriptional activity. In addition, in nine proteins, tract elongation beyond specific thresholds causes polyQ disorders. To study the structural basis of the association between tract length, transcriptional activity and disease, here we addressed how the conformation of the polyQ tract of the androgen receptor (AR), a transcription factor associated with the polyQ disease spinobulbar muscular atrophy (SBMA), depends on its length. We found that the tract folds into a helical structure stabilized by unconventional hydrogen bonds between glutamine side chains and main chain carbonyl groups. These bonds are bifurcate with the conventional main chain to main chain hydrogen bonds stabilizing α-helices. In addition, since tract elongation provides additional interactions, the helicity of the polyQ tract directly correlates with its length. These findings suggest a plausible rationale for the association between polyQ tract length and AR transcriptional activity and have implications for establishing the mechanistic basis of SBMA.

scholarly journals Comparison of Different Liquid Chromatography-Based Purification Strategies for Adeno-Associated Virus Vectors

Pharmaceutics ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 748
Author(s):  
Ruth Rieser ◽  
Johanna Koch ◽  
Greta Faccioli ◽  
Klaus Richter ◽  
Tim Menzen ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Liquid Chromatography ◽  
Muscular Atrophy ◽  
Scale Up ◽  
Hydrophobic Interaction Chromatography ◽  
Exchange Chromatography ◽  
Great Promise ◽  
Current Standard ◽  
Adeno Associated Virus ◽  
Purification Methods

Recombinant adeno-associated virus (rAAV) vectors have evolved as one of the most promising technologies for gene therapy due to their good safety profile, high transduction efficacy, and long-term gene expression in nondividing cells. rAAV-based gene therapy holds great promise for treating genetic disorders like inherited blindness, muscular atrophy, or bleeding disorders. There is a high demand for efficient and scalable production and purification methods for rAAVs. This is particularly true for the downstream purification methods. The current standard methods are based on multiple steps of gradient ultracentrifugation, which allow for the purification and enrichment of full rAAV particles, but the scale up of this method is challenging. Here, we explored fast, scalable, and universal liquid chromatography-based strategies for the purification of rAAVs. In contrast to the hydrophobic interaction chromatography (HIC), where a substantial amount of AAV was lost, the cation exchange chromatography (CEX) was performed robustly for multiple tested serotypes and resulted in a mixture of full and empty rAAVs with a good purity profile. For the used affinity chromatography (AC), a serotype dependence was observed. Anion exchange chromatography (AEX) worked well for the AAV8 serotype and achieved high levels of purification and a baseline separation of full and empty rAAVs. Depending on the AAV serotype, a combination of CEX and AEX or AC and AEX is recommended and holds promise for future translational projects that require highly pure and full particle-enriched rAAVs.

Fine structure and properties of defects in naturally occurring silicates and oxides

1990 ◽  
Vol 48 (4) ◽  
pp. 460-461
Author(s):  
David R. Veblen
Keyword(s):  
Chemical Reactions ◽  
High Resolution Electron Microscopy ◽  
Extended Defects ◽  
Single Chain ◽  
Naturally Occurring ◽  
Resolution Electron ◽  
Fine Structures ◽  
Image Simulations ◽  
Similar Crystal Structure

Extended defects and interfaces control many processes in rock-forming minerals, from chemical reactions to rock deformation. In many cases, it is not the average structure of a defect or interface that is most important, but rather the structure of defect terminations or offsets in an interface. One of the major thrusts of high-resolution electron microscopy in the earth sciences has been to identify the role of defect fine structures in reactions and to determine the structures of such features. This paper will review studies using HREM and image simulations to determine the structures of defects in silicate and oxide minerals and present several examples of the role of defects in mineral chemical reactions. In some cases, the geological occurrence can be used to constrain the diffusional properties of defects.The simplest reactions in minerals involve exsolution (precipitation) of one mineral from another with a similar crystal structure, and pyroxenes (single-chain silicates) provide a good example. Although conventional TEM studies have led to a basic understanding of this sort of phase separation in pyroxenes via spinodal decomposition or nucleation and growth, HREM has provided a much more detailed appreciation of the processes involved.

Towards a Stratified Targeted Approach with Biologic Treatments in Rheumatoid Arthritis: Role of Synovial Pathobiology

2015 ◽  
Vol 21 (17) ◽  
pp. 2216-2224 ◽  
Author(s):  
Elisa Astorri ◽  
Alessandra Nerviani ◽  
Michele Bombardieri ◽  
Costantino Pitzalis
Keyword(s):  
Rheumatoid Arthritis ◽  
Targeted Approach

Role of Flavonoids in Neurodegenerative Disorders with Special Emphasis on Tangeritin

2019 ◽  
Vol 18 (8) ◽  
pp. 581-597 ◽  
Author(s):  
Ambreen Fatima ◽  
Yasir Hasan Siddique
Keyword(s):  
Medicinal Plants ◽  
Mechanism Of Action ◽  
Neurodegenerative Disorders ◽  
Treatment Strategies ◽  
Dietary Supplementation ◽  
Plant Polyphenols ◽  
Promising Candidate ◽  
Naturally Occurring ◽  
The Brain

Flavonoids are naturally occurring plant polyphenols found universally in all fruits, vegetables and medicinal plants. They have emerged as a promising candidate in the formulation of treatment strategies for various neurodegenerative disorders. The use of flavonoid rich plant extracts and food in dietary supplementation have shown favourable outcomes. The present review describes the types, properties and metabolism of flavonoids. Neuroprotective role of various flavonoids and the possible mechanism of action in the brain against the neurodegeneration have been described in detail with special emphasis on the tangeritin.

Monosodium Glutamate Toxicity and the Possible Protective Role of L–Carnitine

2018 ◽  
Vol 6 (1) ◽  
pp. 45-56
Author(s):  
Lalrinzuali Sailo ◽  
◽  
Meesala Krishna Murthy ◽  
Khandayataray Pratima ◽  
Vikas Kumar Roy ◽  
...  
Keyword(s):  
Human Subjects ◽  
Monosodium Glutamate ◽  
Essential Amino Acids ◽  
Protective Role ◽  
Glutamate Toxicity ◽  
Common Salt ◽  
Genotoxic Effects ◽  
Naturally Occurring ◽  
Flavour Enhancer

Monosodium glutamate is naturally available non-essential amino acids, which found in naturally occurring foods and used as flavour enhancer worldwide. Monosodium glutamate is believed to be linked with diverse health problems. The aim of the study was toxic effects of monosodium glutamate (MSG) and the protective role of L-carnitine, light on the available literature from last 25 years about diverse toxicity studies which had been carried out on animal and human models. Google scholar, NCBI, PUBMED, EMBASE, Wangfang databases, and Web of Science databases were used to retrieve the available studies. MSG was linked with deleterious effects particularly in animals including induction of obesity, diabetes, hepatotoxic, neurotoxic and genotoxic effects showed in Literature. Few reports revealed increased hunger, food intake, and obesity in human subjects due to MSG consumption. Hepatotoxic, neurotoxic, and genotoxic effects of monosodium glutamate on humans carried out very limitedly. High consumption of monosodium glutamate may be linked with harmful health effects showed in available literatures. So, it is recommended to use common salt instead of MSG. Furthermore, intensive research is required to explore monosodium glutamate–related molecular and metabolic mechanisms. L-carnitine can protect from Hepatotoxic, neurotoxic, renal impairment and genotoxic effects functionally, biochemically and histopathologically with a corresponding reduction of oxidative stress.

How Artefacts Do Leadership: A Ventriloquial Analysis

2021 ◽  
pp. 089331892199807
Author(s):  
Jonathan Clifton ◽  
Fernando Fachin ◽  
François Cooren
Keyword(s):  
Organizational Communication ◽  
Recent Work ◽  
Distributed Leadership ◽  
Network Theory ◽  
Actor Network Theory ◽  
Fine Grained ◽  
Naturally Occurring ◽  
Human Actors

To date there has been little work that uses fine-grained interactional analyses of the in situ doing of leadership to make visible the role of non-human as well as human actants in this process. Using transcripts of naturally-occurring interaction as data, this study seeks to show how leadership is co-achieved by artefacts as an in-situ accomplishment. To do this we situate this study within recent work on distributed leadership and argue that it is not only distributed across human actors, but also across networks that include both human and non-human actors. Taking a discursive approach to leadership, we draw on Actor Network Theory and adopt a ventriloquial approach to sociomateriality as inspired by the Montreal School of organizational communication. Findings indicate that artefacts “do” leadership when a hybrid presence is made relevant to the interaction and when this presence provides authoritative grounds for influencing others to achieve the group’s goals.

scholarly journals Selenium and Dogs: A Systematic Review

Animals ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 418
Author(s):  
Viola Zentrichová ◽  
Alena Pechová ◽  
Simona Kovaříková
Keyword(s):  
Male Fertility ◽  
Clinical Signs ◽  
Complex Data ◽  
Selenium Status ◽  
Dog Food ◽  
Balanced Diet ◽  
Naturally Occurring ◽  
Correct Function ◽  
Indirect Assay

The intent of this review is to summarize the knowledge about selenium and its function in a dog’s body. For this purpose, systematic literature search was conducted. For mammals, including dogs, a balanced diet and sufficient intake of selenium are important for correct function of metabolism. As for selenium poisoning, there are no naturally occurring cases known. Nowadays, we do not encounter clinical signs of its deficiency either, but it can be subclinical. For now, the most reliable method of assessing selenium status of a dog is measuring serum or plasma levels. Levels in full blood can be measured too, but there are no reference values. The use of glutathione peroxidase as an indirect assay is questionable in canines. Commercial dog food manufactures follow recommendations for minimal and maximal selenium levels and so dogs fed commercial diets should have balanced intake of selenium. For dogs fed home-made diets, complex data are missing. However, subclinical deficiency seems to affect, for example, male fertility or recovery from parasitical diseases. Very interesting is the role of selenium in prevention and treatment of cancer.

scholarly journals Microbiomes attached to fresh perennial ryegrass are temporally resilient and adapt to changing ecological niches

Microbiome ◽  
2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Sharon A. Huws ◽  
Joan E. Edwards ◽  
Wanchang Lin ◽  
Francesco Rubino ◽  
Mark Alston ◽  
...  
Keyword(s):  
Energy Harvesting ◽  
Perennial Ryegrass ◽  
Transcriptional Activity ◽  
Ecological Niches ◽  
Ecological Interactions ◽  
Carbohydrate Degradation ◽  
Host Nutrition ◽  
Role Based ◽  
Insight Into

Abstract Background Gut microbiomes, such as the rumen, greatly influence host nutrition due to their feed energy-harvesting capacity. We investigated temporal ecological interactions facilitating energy harvesting at the fresh perennial ryegrass (PRG)-biofilm interface in the rumen using an in sacco approach and prokaryotic metatranscriptomic profiling. Results Network analysis identified two distinct sub-microbiomes primarily representing primary (≤ 4 h) and secondary (≥ 4 h) colonisation phases and the most transcriptionally active bacterial families (i.e Fibrobacteriaceae, Selemondaceae and Methanobacteriaceae) did not interact with either sub-microbiome, indicating non-cooperative behaviour. Conversely, Prevotellaceae had most transcriptional activity within the primary sub-microbiome (focussed on protein metabolism) and Lachnospiraceae within the secondary sub-microbiome (focussed on carbohydrate degradation). Putative keystone taxa, with low transcriptional activity, were identified within both sub-microbiomes, highlighting the important synergistic role of minor bacterial families; however, we hypothesise that they may be ‘cheating’ in order to capitalise on the energy-harvesting capacity of other microbes. In terms of chemical cues underlying transition from primary to secondary colonisation phases, we suggest that AI-2-based quorum sensing plays a role, based on LuxS gene expression data, coupled with changes in PRG chemistry. Conclusions In summary, we show that fresh PRG-attached prokaryotes are resilient and adapt quickly to changing niches. This study provides the first major insight into the complex temporal ecological interactions occurring at the plant-biofilm interface within the rumen. The study also provides valuable insights into potential plant breeding strategies for development of the utopian plant, allowing optimal sustainable production of ruminants.

Sign in / Sign up

Export Citation Format

Share Document