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1.
medRxiv ; 2024 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-38978643

RESUMO

Frontotemporal lobar degeneration with neuronal inclusions of the TAR DNA-binding protein 43 (FTLD-TDP) is a fatal neurodegenerative disorder with only a limited number of risk loci identified. We report our comprehensive genome-wide association study as part of the International FTLD-TDP Whole-Genome Sequencing Consortium, including 985 cases and 3,153 controls, and meta-analysis with the Dementia-seq cohort, compiled from 26 institutions/brain banks in the United States, Europe and Australia. We confirm UNC13A as the strongest overall FTLD-TDP risk factor and identify TNIP1 as a novel FTLD-TDP risk factor. In subgroup analyses, we further identify for the first time genome-wide significant loci specific to each of the three main FTLD-TDP pathological subtypes (A, B and C), as well as enrichment of risk loci in distinct tissues, brain regions, and neuronal subtypes, suggesting distinct disease aetiologies in each of the subtypes. Rare variant analysis confirmed TBK1 and identified VIPR1 , RBPJL , and L3MBTL1 as novel subtype specific FTLD-TDP risk genes, further highlighting the role of innate and adaptive immunity and notch signalling pathway in FTLD-TDP, with potential diagnostic and novel therapeutic implications.

2.
Nat Commun ; 15(1): 4251, 2024 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-38762487

RESUMO

Sea level rise (SLR) affects coastal flood regimes and poses serious challenges to flood risk management, particularly on ungauged coasts. To address the challenge of monitoring SLR at local scales, we propose a high tide flood (HTF) thresholding system that leverages machine learning (ML) techniques to estimate SLR and HTF thresholds at a relatively fine spatial resolution (10 km) along the United States' coastlines. The proposed system, complementing conventional linear- and point-based estimations of HTF thresholds and SLR rates, can estimate these values at ungauged stretches of the coast. Trained and validated against National Oceanic and Atmospheric Administration (NOAA) gauge data, our system demonstrates promising skills with an average Kling-Gupta Efficiency (KGE) of 0.77. The results can raise community awareness about SLR impacts by documenting the chronic signal of HTF and providing useful information for adaptation planning. The findings encourage further application of ML in achieving spatially distributed thresholds.

3.
AJNR Am J Neuroradiol ; 45(7): 850-854, 2024 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-38724198

RESUMO

Epstein-Barr virus, a herpesvirus, has been associated with a variety of cancers, including Burkitt, Hodgkin, and non-Hodgkin lymphomas; posttransplant lymphoproliferative disorders; gastric carcinoma; and nasopharyngeal carcinoma, in both immunocompetent and immunocompromised individuals. Previous studies have established a connection between Epstein-Barr virus and the development of smooth-muscle tumors. Smooth-muscle tumors of the brain are very rare and are often misdiagnosed as meningiomas on imaging. To our knowledge, advanced imaging findings such as MR perfusion of smooth-muscle tumors of the brain have never been reported. We describe the radiologic and pathologic features of the Epstein-Barr virus-associated smooth-muscle tumors of the brain in a person with newly diagnosed advanced HIV.


Assuntos
Neoplasias Encefálicas , Infecções por Vírus Epstein-Barr , Tumor de Músculo Liso , Humanos , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/diagnóstico por imagem , Tumor de Músculo Liso/virologia , Tumor de Músculo Liso/diagnóstico por imagem , Tumor de Músculo Liso/patologia , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/virologia , Masculino , Imageamento por Ressonância Magnética/métodos , Infecções por HIV/complicações , Infecções por HIV/diagnóstico por imagem , Adulto
4.
J Neurol ; 271(7): 4540-4550, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38717612

RESUMO

OBJECTIVES: To investigate whether a history of traumatic brain injury (TBI) is associated with greater long-term grey-matter loss in patients with mild cognitive impairment (MCI). METHODS: 85 patients with MCI were identified, including 26 with a previous history of traumatic brain injury (MCI[TBI-]) and 59 without (MCI[TBI+]). Cortical thickness was evaluated by segmenting T1-weighted MRI scans acquired longitudinally over a 2-year period. Bayesian multilevel modelling was used to evaluate group differences in baseline cortical thickness and longitudinal change, as well as group differences in neuropsychological measures of executive function. RESULTS: At baseline, the MCI[TBI+] group had less grey matter within right entorhinal, left medial orbitofrontal and inferior temporal cortex areas bilaterally. Longitudinally, the MCI[TBI+] group also exhibited greater longitudinal declines in left rostral middle frontal, the left caudal middle frontal and left lateral orbitofrontal areas sover the span of 2 years (median = 1-2%, 90%HDI [-0.01%: -0.001%], probability of direction (PD) = 90-99%). The MCI[TBI+] group also displayed greater longitudinal declines in Trail-Making-Test (TMT)-derived ratio (median: 0.737%, 90%HDI: [0.229%: 1.31%], PD = 98.8%) and differences scores (median: 20.6%, 90%HDI: [-5.17%: 43.2%], PD = 91.7%). CONCLUSIONS: Our findings support the notion that patients with MCI and a history of TBI are at risk of accelerated neurodegeneration, displaying greatest evidence for cortical atrophy within the left middle frontal and lateral orbitofrontal frontal cortex. Importantly, these results suggest that long-term TBI-mediated atrophy is more pronounced in areas vulnerable to TBI-related mechanical injury, highlighting their potential relevance for diagnostic forms of intervention in TBI.


Assuntos
Lesões Encefálicas Traumáticas , Disfunção Cognitiva , Substância Cinzenta , Imageamento por Ressonância Magnética , Humanos , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/patologia , Disfunção Cognitiva/diagnóstico por imagem , Masculino , Feminino , Lesões Encefálicas Traumáticas/diagnóstico por imagem , Lesões Encefálicas Traumáticas/patologia , Lesões Encefálicas Traumáticas/complicações , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/patologia , Idoso , Pessoa de Meia-Idade , Estudos Longitudinais , Testes Neuropsicológicos , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/patologia , Teorema de Bayes
7.
Cells Dev ; : 203924, 2024 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-38692409

RESUMO

While understanding the genetic underpinnings of osteogenesis has far-reaching implications for skeletal diseases and evolution, a comprehensive characterization of the osteoblastic regulatory landscape in non-mammalian vertebrates is still lacking. Here, we compared the ATAC-Seq profile of Xenopus tropicalis (Xt) osteoblasts to a variety of non mineralizing control tissues, and identified osteoblast-specific nucleosome free regions (NFRs) at 527 promoters and 6747 distal regions. Sequence analyses, Gene Ontology, RNA-Seq and ChIP-Seq against four key histone marks confirmed that the distal regions correspond to bona fide osteogenic transcriptional enhancers exhibiting a shared regulatory logic with mammals. We report 425 regulatory regions conserved with human and globally associated to skeletogenic genes. Of these, 35 regions have been shown to impact human skeletal phenotypes by GWAS, including one trps1 enhancer and the runx2 promoter, two genes which are respectively involved in trichorhinophalangeal syndrome type I and cleidocranial dysplasia. Intriguingly, 60 osteoblastic NFRs also align to the genome of the elephant shark, a species lacking osteoblasts and bone tissue. To tackle this paradox, we chose to focus on dlx5 because its conserved promoter, known to integrate regulatory inputs during mammalian osteogenesis, harbours an osteoblast-specific NFR in both frog and human. Hence, we show that dlx5 is expressed in Xt and elephant shark odontoblasts, supporting a common cellular and genetic origin of bone and dentine. Taken together, our work (i) unravels the Xt osteogenic regulatory landscape, (ii) illustrates how cross-species comparisons harvest data relevant to human biology and (iii) reveals that a set of genes including bnc2, dlx5, ebf3, mir199a, nfia, runx2 and zfhx4 drove the development of a primitive form of mineralized skeletal tissue deep in the vertebrate lineage.

8.
Neuroradiology ; 66(6): 947-953, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38625616

RESUMO

PURPOSE: Basal duct-like recess (DR) sign serves as a specific marker of papillary craniopharyngiomas (PCPs) of the strictly third-ventricular (3 V) topography. Origins of this sign are poorly understood with limited validation in external cohorts. METHODS: In this retrospective study, MRIs of pathologically proven PCPs were reviewed and evaluated for tumor topography, DR sign prevalence, and morphological subtypes. RESULTS: Twenty-three cases with 24 MRIs satisfied our inclusion criteria. Median age was 44.5 years with a predominant male distribution (M/F ratio 4.7:1). Overall, strictly 3 V was the commonest tumor topography (8/24, 33.3%), and tumors were most commonly solid-cystic (10/24, 41.7%). The prevalence of DR sign was 21.7% (5/23 cases), all with strictly 3 V topography and with a predominantly solid consistency. The sensitivity, specificity and positive and negative predictive value of the DR sign for strict 3 V topography was 62.5%, 100%, 100% and 84.2% respectively. New pertinent findings associated with the DR sign were observed in our cohort. This included development of the cleft-like variant of DR sign after a 9-year follow-up initially absent at baseline imaging. Additionally, cystic dilatation of the basal tumor cleft at the pituitary stalk-tumor junction and presence of a vascular structure overlapping the DR sign were noted. Relevant mechanisms, hypotheses, and implications were explored. CONCLUSION: We confirm the DR sign as a highly specific marker of the strictly 3 V topography in PCPs. While embryological and molecular factors remain pertinent in understanding origins of the DR sign, non-embryological mechanisms may play a role in development of the cleft-like variant.


Assuntos
Craniofaringioma , Imageamento por Ressonância Magnética , Neoplasias Hipofisárias , Sensibilidade e Especificidade , Humanos , Masculino , Craniofaringioma/diagnóstico por imagem , Feminino , Neoplasias Hipofisárias/diagnóstico por imagem , Adulto , Pessoa de Meia-Idade , Estudos Retrospectivos , Imageamento por Ressonância Magnética/métodos , Idoso , Prevalência , Adolescente , Terceiro Ventrículo/diagnóstico por imagem , Terceiro Ventrículo/patologia
9.
Cogn Behav Neurol ; 37(1): 3-12, 2024 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-38498721

RESUMO

We present a review of the definition, classification, and epidemiology of primary progressive aphasia (PPA); an update of the taxonomy of the clinical syndrome of PPA; and recent advances in the neuroanatomy, pathology, and genetics of PPA, as well as the search for biomarkers and treatment. PPA studies that have contributed to concepts of language organization and disease propagation in neurodegeneration are also reviewed. In addition, the issues of heterogeneity versus the relationships of the clinical phenotypes and their relationship to biological, pathological, and genetic advances are discussed, as is PPA's relationship to other conditions such as frontotemporal dementia, corticobasal degeneration, progressive supranuclear palsy, Pick disease, and amyotrophic lateral sclerosis. Arguments are presented in favor of considering these conditions as one entity versus many.


Assuntos
Afasia Primária Progressiva , Demência Frontotemporal , Paralisia Supranuclear Progressiva , Humanos , Demência Frontotemporal/diagnóstico , Demência Frontotemporal/genética , Paralisia Supranuclear Progressiva/genética , Paralisia Supranuclear Progressiva/patologia , Síndrome
10.
Int J Geriatr Psychiatry ; 39(3): e6074, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38491809

RESUMO

OBJECTIVES: Neuropsychiatric symptoms (NPS) increase risk of developing dementia and are linked to various neurodegenerative conditions, including mild cognitive impairment (MCI due to Alzheimer's disease [AD]), cerebrovascular disease (CVD), and Parkinson's disease (PD). We explored the structural neural correlates of NPS cross-sectionally and longitudinally across various neurodegenerative diagnoses. METHODS: The study included individuals with MCI due to AD, (n = 74), CVD (n = 143), and PD (n = 137) at baseline, and at 2-years follow-up (MCI due to AD, n = 37, CVD n = 103, and PD n = 84). We assessed the severity of NPS using the Neuropsychiatric Inventory Questionnaire. For brain structure we included cortical thickness and subcortical volume of predefined regions of interest associated with corticolimbic and frontal-executive circuits. RESULTS: Cross-sectional analysis revealed significant negative correlations between appetite with both circuits in the MCI and CVD groups, while apathy was associated with these circuits in both the MCI and PD groups. Longitudinally, changes in apathy scores in the MCI group were negatively linked to the changes of the frontal-executive circuit. In the CVD group, changes in agitation and nighttime behavior were negatively associated with the corticolimbic and frontal-executive circuits, respectively. In the PD group, changes in disinhibition and apathy were positively associated with the corticolimbic and frontal-executive circuits, respectively. CONCLUSIONS: The observed correlations suggest that underlying pathological changes in the brain may contribute to alterations in neural activity associated with MBI. Notably, the difference between cross-sectional and longitudinal results indicates the necessity of conducting longitudinal studies for reproducible findings and drawing robust inferences.


Assuntos
Doença de Alzheimer , Transtornos Cerebrovasculares , Disfunção Cognitiva , Doença de Parkinson , Humanos , Estudos Transversais , Doença de Parkinson/psicologia , Estudos Longitudinais , Disfunção Cognitiva/psicologia , Doença de Alzheimer/psicologia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Transtornos Cerebrovasculares/complicações , Testes Neuropsicológicos
11.
Neurooncol Adv ; 6(1): vdae001, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38312227

RESUMO

Background: Patients with glioblastoma (GBM) have a median overall survival (OS) of approximately 16 months. However, approximately 5% of patients survive >5 years. This study examines the differences in methylation profiles between long-term survivors (>5 years, LTS) and short-term survivors (<1 year, STS) with isocitrate dehydrogenase (IDH)-wild-type GBMs. Methods: In a multicenter retrospective analysis, we identified 25 LTS with a histologically confirmed GBM. They were age- and sex-matched to an STS. The methylation profiles of all 50 samples were analyzed with EPIC 850k, classified according to the DKFZ methylation classifier, and the methylation profiles of LTS versus STS were compared. Results: After methylation profiling, 16/25 LTS and 23/25 STS were confirmed to be IDH-wild-type GBMs, all with +7/-10 signature. LTS had significantly increased O6-methylguanine methyltransferase (MGMT) promoter methylation and higher prevalence of FGFR3-TACC3 fusion (P = .03). STS were more likely to exhibit CDKN2A/B loss (P = .01) and higher frequency of NF1 (P = .02) mutation. There were no significant CpGs identified between LTS versus STS at an adjusted P-value of .05. Unadjusted analyses identified key pathways involved in both LTS and STS. The most common pathways were the Hippo signaling pathway and the Wnt pathway in LTS, and GPCR ligand binding and cell-cell signaling in STS. Conclusions: A small group of patients with IDH-wild-type GBM survive more than 5 years. While there are few differences in the global methylation profiles of LTS compared to STS, our study highlights potential pathways involved in GBMs with a good or poor prognosis.

12.
Neuroradiology ; 66(4): 521-530, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38347151

RESUMO

PURPOSE: T2-FLAIR mismatch serves as a highly specific but insensitive marker for IDH-mutant (IDHm) astrocytoma with potential limitations in real-world application. We aimed to assess the utility of a broader definition of T2-FLAIR discordance across a cohort of adult-type diffuse lower-grade gliomas (LrGG) to see if specific patterns emerge and additionally examine factors determining deviation from the classic T2-FLAIR mismatch sign. METHODS: Preoperative MRIs of non-enhancing adult-type diffuse LrGGs were reviewed. Relevant demographic, molecular, and MRI data were compared across tumor subgroups. RESULTS: Eighty cases satisfied the inclusion criteria. Highest discordance prevalence and > 50% T2-FLAIR discordance volume were noted with IDHm astrocytomas (P < 0.001), while < 25% discordance volume was associated with oligodendrogliomas (P = 0.03) and IDH-wildtype (IDHw) LrGG (P = 0.004). "T2-FLAIR matched pattern" was associated with IDHw LrGG (P < 0.001) and small or minimal areas of discordance with oligodendrogliomas (P = 0.03). Sensitivity and specificity of classic mismatch sign for IDHm astrocytoma were 25.7% and 100%, respectively (P = 0.06). Retained ATRX expression and/or non-canonical IDH mutation (n = 10) emerged as a significant factor associated with absence of classic T2-FLAIR mismatch sign in IDHm astrocytomas (100%, P = 0.02) and instead had minimal discordance or matched pattern (40%, P = 0.04). CONCLUSION: T2-FLAIR discordance patterns in adult-type diffuse LrGGs exist on a diverging but distinct spectrum of classic mismatch to T2-FLAIR matched patterns. Specific molecular markers may play a role in deviations from classic mismatch sign.


Assuntos
Astrocitoma , Neoplasias Encefálicas , Glioma , Oligodendroglioma , Adulto , Humanos , Neoplasias Encefálicas/patologia , Estudos Retrospectivos , Isocitrato Desidrogenase/genética , Glioma/patologia , Imageamento por Ressonância Magnética , Astrocitoma/genética , Mutação
13.
Anal Chem ; 96(3): 1019-1028, 2024 01 23.
Artigo em Inglês | MEDLINE | ID: mdl-38190738

RESUMO

Picosecond infrared laser mass spectrometry (PIRL-MS) is shown, through a retrospective patient tissue study, to differentiate medulloblastoma cancers from pilocytic astrocytoma and two molecular subtypes of ependymoma (PF-EPN-A, ST-EPN-RELA) using laser-extracted lipids profiled with PIRL-MS in 10 s of sampling and analysis time. The average sensitivity and specificity values for this classification, taking genomic profiling data as standard, were 96.41 and 99.54%, and this classification used many molecular features resolvable in 10 s PIRL-MS spectra. Data analysis and liquid chromatography coupled with tandem high-resolution mass spectrometry (LC-MS/MS) further allowed us to reduce the molecular feature list to only 18 metabolic lipid markers most strongly involved in this classification. The identified 'metabolite array' was comprised of a variety of phosphatidic and fatty acids, ceramides, and phosphatidylcholine/ethanolamine and could mediate the above-mentioned classification with average sensitivity and specificity values of 94.39 and 98.78%, respectively, at a 95% confidence in prediction probability threshold. Therefore, a rapid and accurate pathology classification of select pediatric brain cancer types from 10 s PIRL-MS analysis using known metabolic biomarkers can now be available to the neurosurgeon. Based on retrospective mining of 'survival' versus 'extent-of-resection' data, we further identified pediatric cancer types that may benefit from actionable 10 s PIRL-MS pathology feedback. In such cases, aggressiveness of the surgical resection can be optimized in a manner that is expected to benefit the patient's overall or progression-free survival. PIRL-MS is a promising tool to drive such personalized decision-making in the operating theater.


Assuntos
Neoplasias Encefálicas , Neoplasias Cerebelares , Humanos , Criança , Cromatografia Líquida , Lipidômica , Estudos Retrospectivos , Raios Infravermelhos , Espectrometria de Massas em Tandem , Lasers , Neoplasias Encefálicas/diagnóstico
14.
J Clin Rheumatol ; 30(2): 52-57, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38206921

RESUMO

BACKGROUND/OBJECTIVE: The 2019 American College of Rheumatology/European League Against Rheumatism Classification Criteria (2019 AECC) for IgG4-related disease (IgG4-RD) is considered a significant advancement in the study of this condition. Most studies evaluating their performance have focused on White and Asian patients, leaving a knowledge gap regarding Latin American populations. Therefore, this study aimed to assess the performance of the 2019 AECC for IgG4-RD in a cohort of Latin American patients. METHODS: A multicenter medical records review study was conducted, involving centers from Argentina, Chile, Mexico, Peru, and Uruguay. Data on IgG4-RD patients and mimicker conditions were collected through a standardized online form. The criterion standard for diagnosing IgG4-RD was based on the fulfillment of the Comprehensive Diagnostic Criteria for IgG4-RD and/or the Consensus Statement on Pathology. The 2019 AECC was retrospectively applied. RESULTS: We included 300 patients, with 180 (60%) having IgG4-RD and 120 (40%) having mimicker conditions. The 2019 AECC had a sensitivity of 66.7% and a specificity of 100%. Sensitivity increased to 73.3% when disease-specific autoantibody items were removed, without affecting specificity. The true-positive cases had more involved organs, a higher availability of biopsy results, and were more likely to belong to the Mikulicz/systemic and proliferative phenotypes. CONCLUSIONS: The use of the 2019 AECC for IgG4-RD in a Latin American population confirms its high specificity in excluding those without the disease. The presence of concomitant autoimmune diseases and clinically nonsignificant disease-specific autoantibodies excludes a significant number of patients from fulfilling the criteria.


Assuntos
Doença Relacionada a Imunoglobulina G4 , Doenças Reumáticas , Reumatologia , Humanos , Estados Unidos , Doença Relacionada a Imunoglobulina G4/diagnóstico , Estudos Retrospectivos , América Latina , Doenças Reumáticas/diagnóstico , Autoanticorpos
15.
Nat Rev Genet ; 25(4): 237-254, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38291236

RESUMO

To contend with the diversity and ubiquity of bacteriophages and other mobile genetic elements, bacteria have developed an arsenal of immune defence mechanisms. Bacterial defences include CRISPR-Cas, restriction-modification and a growing list of mechanistically diverse systems, which constitute the bacterial 'immune system'. As a response, bacteriophages and mobile genetic elements have evolved direct and indirect mechanisms to circumvent or block bacterial defence pathways and ensure successful infection. Recent advances in methodological and computational approaches, as well as the increasing availability of genome sequences, have boosted the discovery of direct inhibitors of bacterial defence systems. In this Review, we discuss methods for the discovery of direct inhibitors, their diverse mechanisms of action and perspectives on their emerging applications in biotechnology and beyond.


Assuntos
Bacteriófagos , Sistemas CRISPR-Cas , Bactérias/genética , Bacteriófagos/genética
17.
Neurobiol Aging ; 134: 43-56, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37992544

RESUMO

We explored mechanisms involved in the age-dependent degeneration of human substantia nigra (SN) dopamine (DA) neurons. Owing to its important metabolic functions in post-mitotic neurons, we investigated the developmental and age-associated changes in the purine biosynthetic enzyme inosine monophosphate dehydrogenase (IMPDH). Tissue microarrays prepared from post-mortem samples of SN from 85 neurologically intact participants humans spanning the age spectrum were immunostained for IMPDH combined with other proteins. SN DA neurons contained two types of IMPDH structures: cytoplasmic IMPDH filaments and intranuclear IMPDH inclusions. The former were not age-restricted and may represent functional units involved in sustaining purine nucleotide supply in these highly metabolically active cells. The latter showed age-associated changes, including crystallization, features reminiscent of pathological inclusion bodies, and spatial associations with Marinesco bodies; structures previously associated with SN neuron dysfunction and death. We postulate dichotomous roles for these two subcellularly distinct IMPDH structures and propose a nucleus-based model for a novel mechanism of SN senescence that is independent of previously known neurodegeneration-associated proteins.


Assuntos
Inosina Monofosfato , Corpos de Inclusão Intranuclear , Humanos , Inosina Monofosfato/metabolismo , Substância Negra/metabolismo , Envelhecimento , Neurônios Dopaminérgicos/metabolismo , Oxirredutases/metabolismo
19.
Nature ; 623(7987): 601-607, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37853129

RESUMO

Many bacteria use CRISPR-Cas systems to combat mobile genetic elements, such as bacteriophages and plasmids1. In turn, these invasive elements have evolved anti-CRISPR proteins to block host immunity2,3. Here we unveil a distinct type of CRISPR-Cas Inhibition strategy that is based on small non-coding RNA anti-CRISPRs (Racrs). Racrs mimic the repeats found in CRISPR arrays and are encoded in viral genomes as solitary repeat units4. We show that a prophage-encoded Racr strongly inhibits the type I-F CRISPR-Cas system by interacting specifically with Cas6f and Cas7f, resulting in the formation of an aberrant Cas subcomplex. We identified Racr candidates for almost all CRISPR-Cas types encoded by a diverse range of viruses and plasmids, often in the genetic context of other anti-CRISPR genes5. Functional testing of nine candidates spanning the two CRISPR-Cas classes confirmed their strong immune inhibitory function. Our results demonstrate that molecular mimicry of CRISPR repeats is a widespread anti-CRISPR strategy, which opens the door to potential biotechnological applications6.


Assuntos
Bactérias , Bacteriófagos , Sistemas CRISPR-Cas , Mimetismo Molecular , RNA Viral , Bactérias/genética , Bactérias/imunologia , Bactérias/virologia , Bacteriófagos/genética , Bacteriófagos/imunologia , Biotecnologia/métodos , Biotecnologia/tendências , Proteínas Associadas a CRISPR/metabolismo , Sistemas CRISPR-Cas/genética , Sistemas CRISPR-Cas/imunologia , Plasmídeos/genética , Prófagos/genética , Prófagos/imunologia , RNA Viral/genética
20.
Artigo em Inglês | MEDLINE | ID: mdl-37698643

RESUMO

PURPOSE: In modern societies, motorcycle accidents have become a great problem for health systems worldwide. In Spain, the size and the power of the engine of 2-wheel vehicles determine the type of driving license and the age at which these vehicles can be used (mopeds and motorcycles, which at the same time can have a small or large engine capacity). The objective of the present study was to analyze and characterize low- and high-power motorcycle accidents in Spain, between 2014 and 2020, both included and compared these categories with each other. METHODS: Retrospective, descriptive, and observational study of motorcycle and moped accidents in Spain between 2014 and 2020, both included. RESULTS: The mortality of motorcycle accident riders in Spain is associated with males aged between 30 and 40 years old, with a high-power motorcycle, and an A or A1 driver's license, who is 6.7 times more likely to die in crossings and highways than a moped, while wearing a helmet, and if not, this increases to 4.89 times. During the COVID-19 pandemic, an increase in death at 24 h after a high-power motorcycle accident was observed, as compared with a large reduction in the total medical assistance provided in 2019-2020. CONCLUSIONS: High-power motorcycles had higher scores in mortality and morbity rates than low-power ones, with a significant increase in mortality during the pandemic, even though number of accidents and medical assistance provided were drastically reduced.

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