A proposal for new diagnostic criteria for ALS Shefner, Jeremy M.; Al-Chalabi, Ammar; Baker, Mark R. ...
Clinical neurophysiology,
August 2020, 2020-08-00, 20200801, Letnik:
131, Številka:
8
Journal Article
Currently, no disease-modifying therapies for osteoarthritis (OA) exist, and attempts to identify novel cellular targets have been challenging. Risk factors for OA include advanced age, obesity, and ...metabolic syndrome. This creates an attractive opportunity to repurpose existing drugs that are used to treat comorbidities commonly encountered in patients with OA, if those drugs possess OA disease modifying properties.
This narrative review incorporates findings from knee or hand OA randomized clinical trials, post-hoc clinical trial analyses, prospective cohort studies, and observational data.
Drugs used for the treatment of rheumatoid arthritis (methotrexate; TNFa, IL-1, and IL-6 pathway inhibitors; hydroxychloroquine), atopic/allergic disease (anti-histamines), osteoporosis (bisphosphonates and vitamin D), type 2 diabetes (metformin and GLP-1 agonists), and cardiovascular disease (atorvastatin, fish oil, and beta blockers) were reviewed for their potential benefit in OA. This review outlines the successful attributes of repurposed drugs, the challenges in repurposing drugs, and strategies for future clinical trials to support OA drug repurposing. Potential drug candidates for OA may be identified through the use of existing datasets and via collaborations with researchers in other fields to include OA endpoints in future clinical trials.
Given the association of OA with several commonly treated comorbidities, drug repurposing is an appealing approach that could provide a favorable benefit-to-risk ratio for chronic OA treatment.
Committing to ecological restoration Suding, Katharine; Higgs, Eric; Palmer, Margaret ...
Science (American Association for the Advancement of Science),
05/2015, Letnik:
348, Številka:
6235
Journal Article
Recenzirano
Odprti dostop
At the September 2014 United Nations Climate Summit, governments rallied around an international agreement-the New York Declaration on Forests-that underscored restoration of degraded ecosystems as ...an auspicious solution to climate change. Ethiopia committed to restore more than one-sixth of its land. Uganda, the Democratic Republic of Congo, Guatemala, and Colombia pledged to restore huge areas within their borders. In total, parties committed to restore a staggering 350 million hectares by 2030.
Algorithms for Olfactory Search across Species Baker, Keeley L; Dickinson, Michael; Findley, Teresa M ...
The Journal of neuroscience,
2018-Oct-31, 2018-10-31, 20181031, Letnik:
38, Številka:
44
Journal Article
Recenzirano
Odprti dostop
Localizing the sources of stimuli is essential. Most organisms cannot eat, mate, or escape without knowing where the relevant stimuli originate. For many, if not most, animals, olfaction plays an ...essential role in search. While microorganismal chemotaxis is relatively well understood, in larger animals the algorithms and mechanisms of olfactory search remain mysterious. In this symposium, we will present recent advances in our understanding of olfactory search in flies and rodents. Despite their different sizes and behaviors, both species must solve similar problems, including meeting the challenges of turbulent airflow, sampling the environment to optimize olfactory information, and incorporating odor information into broader navigational systems.
Increasing evidence suggests that defective RNA processing contributes to the development of amyotrophic lateral sclerosis (ALS). This may be especially true for ALS caused by a repeat expansion in ...C9orf72 (c9ALS), in which the accumulation of RNA foci and dipeptide-repeat proteins are expected to modify RNA metabolism. We report extensive alternative splicing (AS) and alternative polyadenylation (APA) defects in the cerebellum of c9ALS subjects (8,224 AS and 1,437 APA), including changes in ALS-associated genes (for example, ATXN2 and FUS), and in subjects with sporadic ALS (sALS; 2,229 AS and 716 APA). Furthermore, heterogeneous nuclear ribonucleoprotein H (hnRNPH) and other RNA-binding proteins are predicted to be potential regulators of cassette exon AS events in both c9ALS and sALS. Co-expression and gene-association network analyses of gene expression and AS data revealed divergent pathways associated with c9ALS and sALS.
Individuals carrying (GGGGCC) expanded repeats in the
C9orf72
gene represent a significant portion of patients suffering from amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). ...Elucidating how these expanded repeats cause “c9FTD/ALS” has since become an important goal of the field. Toward this end, we sought to investigate whether epigenetic changes are responsible for the decrease in
C9orf72
expression levels observed in c9FTD/ALS patients. We obtained brain tissue from ten c9FTD/ALS individuals, nine FTD/ALS cases without a
C9orf72
repeat expansion, and nine disease control participants, and generated fibroblastoid cell lines from seven
C9orf72
expanded repeat carriers and seven participants carrying normal alleles. Chromatin immunoprecipitation using antibodies for histone H3 and H4 trimethylated at lysines 9 (H3K9), 27 (H3K27), 79 (H3K79), and 20 (H4K20) revealed that these trimethylated residues bind strongly to
C9orf72
expanded repeats in brain tissue, but not to non-pathogenic repeats. Our finding that
C9orf72
mRNA levels are reduced in the frontal cortices and cerebella of c9FTD/ALS patients is consistent with trimethylation of these histone residues, an event known to repress gene expression. Moreover, treating repeat carrier-derived fibroblasts with 5-aza-2-deoxycytidine, a DNA and histone demethylating agent, not only decreased
C9orf72
binding to trimethylated histone residues, but also increased
C9orf72
mRNA expression. Our results provide compelling evidence that trimethylation of lysine residues within histones H3 and H4 is a novel mechanism involved in reducing
C9orf72
mRNA expression in expanded repeat carriers. Of importance, we show that mutant
C9orf72
binding to trimethylated H3K9 and H3K27 is detectable in blood of c9FTD/ALS patients. Confirming these exciting results using blood from a larger cohort of patients may establish this novel epigenetic event as a biomarker for c9FTD/ALS.
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