107 research outputs found
FAN1 controls mismatch repair complex assembly via MLH1 retention to stabilize CAG repeat expansion in Huntington's disease
CAG repeat expansion in the HTT gene drives Huntingtonâs disease (HD) pathogenesis and is modulated by
DNA damage repair pathways. In this context, the interaction between FAN1, a DNA-structure-specific
nuclease, and MLH1, member of the DNA mismatch repair pathway (MMR), is not defined. Here, we identify
a highly conserved SPYF motif at the N terminus of FAN1 that binds to MLH1. Our data support a model where
FAN1 has two distinct functions to stabilize CAG repeats. On one hand, it binds MLH1 to restrict its recruitment by MSH3, thus inhibiting the assembly of a functional MMR complex that would otherwise promote CAG
repeat expansion. On the other hand, it promotes accurate repair via its nuclease activity. These data highlight a potential avenue for HD therapeutics in attenuating somatic expansion
Arthritis, osteomyelitis, septicemia and meningitis caused by Klebsiella in a low-birth-weight newborn: a case report
Sustained high prevalence of sexually transmitted infections among female sex workers in Cambodia: high turnover seriously challenges the 100% condom use programme
Population Pharmacokinetics of Sifalimumab, an Investigational Anti-Interferon-α Monoclonal Antibody, in Systemic Lupus Erythematosus
Surgery versus Watchful Waiting in Patients with Craniofacial Fibrous Dysplasia â a Meta-Analysis
Fibrous dysplasia (FD) is a benign bone tumor which most commonly involves the craniofacial skeleton. The most devastating consequence of craniofacial FD (CFD) is loss of vision due to optic nerve compression (ONC). Radiological evidence of ONC is common, however the management of this condition is not well established. Our objective was to compare the long-term outcome of patients with optic nerve compression (ONC) due to craniofacial fibrous dysplasia (CFD) who either underwent surgery or were managed expectantly.We performed a meta-analysis of 27 studies along with analysis of the records of a cohort of patients enrolled in National Institutes of Health (NIH) protocol 98-D-0145, entitled Screening and Natural History of Fibrous Dysplasia, with a diagnosis of CFD. The study group consisted of 241 patients; 122 were enrolled in the NIH study and 119 were extracted from cases published in the literature. The median follow-up period was 54 months (range, 6-228 months). A total of 368 optic nerves were investigated. All clinically impaired optic nerves (nâ=â86, 23.3%) underwent therapeutic decompression. Of the 282 clinically intact nerves, 41 (15%) were surgically decompressed and 241 (85%) were followed expectantly. Improvement in visual function was reported in fifty-eight (67.4%) of the clinically impaired nerves after surgery. In the intact nerves group, long-term stable vision was achieved in 31/45 (75.6%) of the operated nerves, compared to 229/241 (95.1%) of the non-operated ones (pâ=â0.0003). Surgery in asymptomatic patients was associated with visual deterioration (RR 4.89; 95% CI 2.26-10.59).Most patients with CFD will remain asymptomatic during long-term follow-up. Expectant management is recommended in asymptomatic patients even in the presence of radiological evidence of ONC
Transcriptional correlates of the pathological phenotype in a Huntingtonâs disease mouse model
Huntington disease (HD) is a fatal neurodegenerative disorder without a cure that is caused by an
aberrant expansion of CAG repeats in exon 1 of the huntingtin (HTT) gene. Although a negative
correlation between the number of CAG repeats and the age of disease onset is established, additional
factors may contribute to the high heterogeneity of the complex manifestation of symptoms
among patients. This variability is also observed in mouse models, even under controlled genetic
and environmental conditions. To better understand this phenomenon, we analysed the R6/1 strain
in search of potential correlates between pathological motor/cognitive phenotypical traits and
transcriptional alterations. HD-related genes (e.g., Penk, Plk5, Itpka), despite being downregulated
across the examined brain areas (the prefrontal cortex, striatum, hippocampus and cerebellum),
exhibited tissue-specific correlations with particular phenotypical traits that were attributable to
the contribution of the brain region to that trait (e.g., striatum and rotarod performance, cerebellum
and feet clasping). Focusing on the striatum, we determined that the transcriptional dysregulation
associated with HD was partially exacerbated in mice that showed poor overall phenotypical scores,
especially in genes with relevant roles in striatal functioning (e.g., Pde10a, Drd1, Drd2, Ppp1r1b).
However, we also observed transcripts associated with relatively better outcomes, such as Nfya
(CCAAT-binding transcription factor NF-Y subunit A) plus others related to neuronal development,
apoptosis and differentiation. In this study, we demonstrated that altered brain transcription can be
related to the manifestation of HD-like symptoms in mouse models and that this can be extrapolated to
the highly heterogeneous population of HD patients
Recent improvements in the development of A2B adenosine receptor agonists
Adenosine is known to exert most of its physiological functions by acting as local modulator at four receptor subtypes named A1, A2A, A2B and A3 (ARs). Principally as a result of the difficulty in identifying potent and selective agonists, the A2B AR is the least extensively characterised of the adenosine receptors family. Despite these limitations, growing understanding of the physiological meaning of this target indicates promising therapeutic perspectives for specific ligands. As A2B AR signalling seems to be associated with pre/postconditioning cardioprotective and anti-inflammatory mechanisms, selective agonists may represent a new therapeutic group for patients suffering from coronary artery disease. Herein we present an overview of the recent advancements in identifying potent and selective A2B AR agonists reported in scientific and patent literature. These compounds can be classified into adenosine-like and nonadenosine ligands. Nucleoside-based agonists are the result of modifying adenosine by substitution at the N6-, C2-positions of the purine heterocycle and/or at the 5âČ-position of the ribose moiety or combinations of these substitutions. Compounds 1-deoxy-1-{6-[NâČ-(furan-2-carbonyl)-hydrazino]-9H-purin-9-yl}-N-ethyl-ÎČ-D-ribofuranuronamide (19, hA1Kiâ=â1050 nM, hA2AKiâ=â1550 nM, hA2B EC50â=â82 nM, hA3Kiâ>â5 ΌM) and its 2-chloro analogue 23 (hA1Kiâ=â3500 nM, hA2AKiâ=â4950 nM, hA2B EC50â=â210 nM, hA3Kiâ>â5 ΌM) were confirmed to be potent and selective full agonists in a cyclic adenosine monophosphate (cAMP) functional assay in Chinese hamster ovary (CHO) cells expressing hA2B AR. Nonribose ligands are represented by conveniently substituted dicarbonitrilepyridines, among which 2-[6-amino-3,5-dicyano-4-[4-(cyclopropylmethoxy)phenyl]pyridin-2-ylsulfanyl]acetamide (BAY-60â6583, hA1, hA2A, hA3 EC50â>â10 ΌM; hA2B EC50â=â3 nM) is currently under preclinical-phase investigation for treating coronary artery disorders and atherosclerosis
Evolution of the TOR Pathway
The TOR kinase is a major regulator of growth in eukaryotes. Many components of the TOR pathway are implicated in cancer and metabolic diseases in humans. Analysis of the evolution of TOR and its pathway may provide fundamental insight into the evolution of growth regulation in eukaryotes and provide a practical framework on which experimental evidence can be compared between species. Here we performed phylogenetic analyses on the components of the TOR pathway and determined their point of invention. We find that the two TOR complexes and a large part of the TOR pathway originated before the Last Eukaryotic Common Ancestor and form a core to which new inputs have been added during animal evolution. In addition, we provide insight into how duplications and sub-functionalization of the S6K, RSK, SGK and PKB kinases shaped the complexity of the TOR pathway. In yeast we identify novel AGC kinases that are orthologous to the S6 kinase. These results demonstrate how a vital signaling pathway can be both highly conserved and flexible in eukaryotes
RD-Connect: An Integrated Platform Connecting Databases, Registries, Biobanks and Clinical Bioinformatics for Rare Disease Research
International Consensus Statement on Rhinology and Allergy: Rhinosinusitis
Background: The 5 years since the publication of the first International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICARâRS) has witnessed foundational progress in our understanding and treatment of rhinologic disease. These advances are reflected within the more than 40 new topics covered within the ICARâRSâ2021 as well as updates to the original 140 topics. This executive summary consolidates the evidenceâbased findings of the document. Methods: ICARâRS presents over 180 topics in the forms of evidenceâbased reviews with recommendations (EBRRs), evidenceâbased reviews, and literature reviews. The highest grade structured recommendations of the EBRR sections are summarized in this executive summary. Results: ICARâRSâ2021 covers 22 topics regarding the medical management of RS, which are grade A/B and are presented in the executive summary. Additionally, 4 topics regarding the surgical management of RS are grade A/B and are presented in the executive summary. Finally, a comprehensive evidenceâbased management algorithm is provided. Conclusion: This ICARâRSâ2021 executive summary provides a compilation of the evidenceâbased recommendations for medical and surgical treatment of the most common forms of RS
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