Adrenoleukodystrophy (ALD) is an X-linked peroxisomal disorder with an incidence of 1 in 14-17,000 male births, caused by pathogenic variants within the ABCD1 gene. By adulthood, approximately 40% of ...the patients develop cerebral ALD, a severe, neuroinflammatory condition that is generally progressive and fatal without intervention.
Historically, only allogeneic hematopoietic stem cell transplantation (HSCT) has been shown to halt progression of cerebral ALD, with superior outcomes obtained when HSCT is performed early in the disease process. More recently, a lentiviral-based gene therapy approach has been investigated as therapy for cerebral ALD as an alternative to allogeneic transplantation. A focused literature review was performed using the terms 'hematopoietic stem cell transplantation,' 'gene therapy' and 'adrenoleukodystrophy' to include relevant literature, especially comparing the experience with gene therapy and HSCT outcomes. We review the history and experience with HSCT in cerebral ALD and its limitations, as well as the information currently available in association with the gene therapy trials for cerebral ALD.
The data regarding this lentiviral-based gene therapy approach and its relative risks and benefits is still being evaluated. This information is explored in the context of the experience with allogeneic HSCT for cerebral ALD.
Expansion of tandem repeat sequences is responsible for more than 20 human diseases. Several cis elements and trans factors involved in repeat instability (expansion and contraction) have been ...identified. However no comprehensive model explaining large intergenerational or somatic changes of the length of the repeating sequences exists. Several lines of evidence, accumulated from different model studies, indicate that transcription through repeat sequences is an important factor promoting their instability. The persistent interaction between transcription template DNA and nascent RNA (RNA•DNA hybrids, R loops) was shown to stimulate genomic instability. Recently, we demonstrated that cotranscriptional RNA•DNA hybrids are preferentially formed at GC-rich trinucleotide and tetranucleotide repeat sequences in vitro as well as in human genomic DNA. Additionally, we showed that cotranscriptional formation of RNA•DNA hybrids at CTG•CAG and GAA•TTC repeats stimulate instability of these sequences in both E. coli and human cells. Our results suggest that persistent RNA•DNA hybrids may also be responsible for other downstream effects of expanded trinucleotide repeats, including gene silencing. Considering the extent of transcription through the human genome as well as the abundance of GC-rich and/or non-canonical DNA structure forming tandem repeats, RNA•DNA hybrids may represent a common mutagenic conformation. Hence, R loops are potentially attractive therapeutic target in diseases associated with genomic instability.
New insights into repeat instability McIvor, Elizabeth I.; Polak, Urszula; Napierala, Marek
RNA biology,
20/9/1/, Letnik:
7, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Expansion of tandem repeat sequences is responsible for more than 20 human diseases. Several cis elements and trans factors involved in repeat instability (expansion and contraction) have been ...identified. However no comprehensive model explaining large intergenerational or somatic changes of the length of the repeating sequences exists. Several lines of evidence, accumulated from different model studies, indicate that transcription through repeat sequences is an important factor promoting their instability. The persistent interaction between transcription template DNA and nascent RNA (RNA*DNA hybrids, R loops) was shown to stimulate genomic instability. Recently, we demonstrated that cotranscriptional RNA*DNA hybrids are preferentially formed at GC-rich trinucleotide and tetranucleotide repeat sequences in vitro as well as in human genomic DNA. Additionally, we showed that cotranscriptional formation of RNA*DNA hybrids at CTG*CAG and GAA*TTC repeats stimulate instability of these sequences in both E. coli and human cells. Our results suggest that persistent RNA*DNA hybrids may also be responsible for other downstream effects of expanded trinucleotide repeats, including gene silencing. Considering the extent of transcription through the human genome as well as the abundance of GC-rich and/or non-canonical DNA structure forming tandem repeats, RNA*DNA hybrids may represent a common mutagenic conformation. Hence, R loops are potentially attractive therapeutic target in diseases associated with genomic instability.
Salt marshes can play a vital role in mitigating the effects of global environmental change by dissipating incident storm wave energy and, through accretion, tracking increasing water depths ...consequent upon sea level rise. Atmospheric CO2 concentrations and nutrient availability are two key variables that can affect the biological processes that contribute to marsh surface elevation gain. We measured the effects of CO2 concentrations and nutrient availability on surface elevation change in intact mixed‐species blocks of UK salt marsh using six open‐top chambers receiving CO2‐enriched (800 ppm) or ambient (400 ppm) air. We found more rapid surface elevation gain in elevated CO2 conditions: an average increase of 3.4 mm over the growing season relative to ambient CO2. Boosted regression analysis to determine the relative influence of different parameters on elevation change identified that a 10% reduction in microbial activity in elevated CO2‐grown blocks had a positive influence on elevation. The biomass of Puccinellia maritima also had a positive influence on elevation, while other salt marsh species (e.g. Suaeda maritima) had no influence or a negative impact on elevation. Reduced rates of water use by the vegetation in the high CO2 treatment could be contributing to elevation gain, either directly through reduced soil shrinkage or indirectly by decreasing microbial respiration rates due to lower redox levels in the soil. Eutrophication did not influence elevation change in either CO2 treatment despite doubling aboveground biomass. The role of belowground processes (transpiration, root growth and decomposition) in the vertical adjustment of European salt marshes, which are primarily minerogenic in composition, could increase as atmospheric CO2 concentrations rise and should be considered in future wetland models for the region. Elevated CO2 conditions could enhance resilience in vulnerable systems such as those with low mineral sediment supply or where migration upwards within the tidal frame is constrained.
Histone H2B monoubiquitination (H2Bub1) is centrally involved in gene regulation. The deubiquitination module (DUBm) of the SAGA complex is a major regulator of global H2Bub1 levels, and components ...of this DUBm are linked to both neurodegenerative diseases and cancer. Unexpectedly, we find that ablation of USP22, the enzymatic center of the DUBm, leads to a reduction, rather than an increase, in global H2bub1 levels. In contrast, depletion of non-enzymatic components, ATXN7L3 or ENY2, results in increased H2Bub1. These observations led us to discover two H2Bub1 DUBs, USP27X and USP51, which function independently of SAGA and compete with USP22 for ATXN7L3 and ENY2 for activity. Like USP22, USP51 and USP27X are required for normal cell proliferation, and their depletion suppresses tumor growth. Our results reveal that ATXN7L3 and ENY2 orchestrate activities of multiple deubiquitinating enzymes and that imbalances in these activities likely potentiate human diseases including cancer.
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•USP22 competes with USP27X and USP51 for activation by ATXN7L3 and ENY2•USP27X and USP51 function independently of SAGA•ATXN7L3 and ENY2 availability is tightly regulated in cells•USP51 and USP27x ablation impairs cell proliferation and tumor progression
Atanassov et al. identify two deubiquitinating enzymes (DUBs) that act on the histone H2B, independent of the SAGA complex. They demonstrate that two adaptor proteins, ATXN7L3 and ENY2, orchestrate the functions of multiple DUBs and that imbalances in these activities likely potentiate different pathologies.
We sought to determine whether mannequin-based simulation can reliably characterize how board-certified anesthesiologists manage simulated medical emergencies. Our primary focus was to identify gaps ...in performance and to establish psychometric properties of the assessment methods.
A total of 263 consenting board-certified anesthesiologists participating in existing simulation-based maintenance of certification courses at one of eight simulation centers were video recorded performing simulated emergency scenarios. Each participated in two 20-min, standardized, high-fidelity simulated medical crisis scenarios, once each as primary anesthesiologist and first responder. Via a Delphi technique, an independent panel of expert anesthesiologists identified critical performance elements for each scenario. Trained, blinded anesthesiologists rated video recordings using standardized rating tools. Measures included the percentage of critical performance elements observed and holistic (one to nine ordinal scale) ratings of participant's technical and nontechnical performance. Raters also judged whether the performance was at a level expected of a board-certified anesthesiologist.
Rater reliability for most measures was good. In 284 simulated emergencies, participants were rated as successfully completing 81% (interquartile range, 75 to 90%) of the critical performance elements. The median rating of both technical and nontechnical holistic performance was five, distributed across the nine-point scale. Approximately one-quarter of participants received low holistic ratings (i.e., three or less). Higher-rated performances were associated with younger age but not with previous simulation experience or other individual characteristics. Calling for help was associated with better individual and team performance.
Standardized simulation-based assessment identified performance gaps informing opportunities for improvement. If a substantial proportion of experienced anesthesiologists struggle with managing medical emergencies, continuing medical education activities should be reevaluated.
The management of bonefishes Albula spp. has been hindered by unresolved species distributions and a general lack of life‐history information. This study provides the first genetic species ...identifications of Albula spp. from the northern Indian Ocean. The roundjaw bonefish Albula glossodonta was documented in the Red Sea, and the smallscale bonefish A. oligolepis was identified in the Gulf of Aden with no evidence supporting sympatry. Estimates of genetic differentiation indicate three closely related lineages of A. glossodonta in the Red Sea, Indian Ocean and Pacific Ocean (Red Sea‐Pacific Ocean, Fst = 0.295; Red Sea‐Seychelles, Fst = 0.193; Pacific Ocean‐Seychelles, Fst = 0.141). In addition, the authors provide the first life‐history information of Albula spp. in the Indian Ocean. Age‐based growth models of A. glossodonta from the Red Sea demonstrated statistically significant differences compared to previously published data from the Pacific Ocean. Spawning activity during winter months was derived from gonado‐somatic index values of A. glossodonta from the Red Sea and corresponded with spawning seasonality previously documented for the species in the Pacific Ocean. The results of this study aid in refining biogeographical uncertainties of Albula spp. and illustrate the importance of collecting regional growth information for subsequent management of A. glossodonta.
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