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1.
Orphanet J Rare Dis ; 15(1): 315, 2020 11 09.
Artigo em Inglês | MEDLINE | ID: mdl-33168042

RESUMO

BACKGROUND: Many people living and working with rare diseases describe consistent difficulties accessing appropriate information and support. In this study an evaluation of the awareness of rare diseases, alongside related information and educational resources available for patients, their families and healthcare professionals, was conducted in 2018-2019 using an online survey and semi-structured interviews with rare disease collaborative groups (charities, voluntary and community groups) active across Northern Ireland (NI). METHODS: This study had 2 stages. Stage 1 was an online survey and stage 2 involved semi-structured interviews both with rare disease collaborative groups in Northern Ireland. The surveys and interviews were used to locate existing resources as well as identify gaps where the development of further resources would be appropriate. RESULTS: Ninety-nine rare disease collaborative groups engaged with the survey with 31 providing detailed answers. Resources such as information, communication, 'registries', online services, training and improvements to support services were queried. Excellent communication is an important factor in delivering good rare disease support. Training for health professionals was also highlighted as an essential element of improving support for those with a rare disease to ensure they approach people with these unique and challenging diseases in an appropriate way. Carers were mentioned several times throughout the study; it is often felt they are overlooked in rare disease research and more support should be in place for them. Current care/support for those with a rare disease was highlighted as inadequate. Nine semi-structured interviews were conducted with rare disease collaborative groups. Reoccurring themes included a need for more effective information and communication, training for health professionals, online presence, support for carers, and involvement in research. CONCLUSIONS: All rare disease collaborative groups agreed that current services for people living and working with a rare disease are not adequate. An important finding to consider in future research within the rare disease field is the inclusion of carers perceptions and experiences in studies. This research provides insight into the support available for rare diseases across Northern Ireland, highlights unmet needs, and suggests approaches to improve rare disease support.


Assuntos
Cuidadores , Doenças Raras , Pessoal de Saúde , Humanos , Irlanda do Norte , Inquéritos e Questionários
2.
Nucleic Acids Res ; 45(20): 11891-11907, 2017 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-28981840

RESUMO

RNase III enzymes cleave double stranded (ds)RNA. This is an essential step for regulating the processing of mRNA, rRNA, snoRNA and other small RNAs, including siRNA and miRNA. Arabidopsis thaliana encodes nine RNase III: four DICER-LIKE (DCL) and five RNASE THREE LIKE (RTL). To better understand the molecular functions of RNase III in plants we developed a biochemical assay using RTL1 as a model. We show that RTL1 does not degrade dsRNA randomly, but recognizes specific duplex sequences to direct accurate cleavage. Furthermore, we demonstrate that RNase III and dsRNA binding domains (dsRBD) are both required for dsRNA cleavage. Interestingly, the four DCL and the three RTL that carry dsRBD share a conserved cysteine (C230 in Arabidopsis RTL1) in their dsRBD. C230 is essential for RTL1 and DCL1 activities and is subjected to post-transcriptional modification. Indeed, under oxidizing conditions, glutathionylation of C230 inhibits RTL1 cleavage activity in a reversible manner involving glutaredoxins. We conclude that the redox state of the dsRBD ensures a fine-tune regulation of dsRNA processing by plant RNase III.


Assuntos
Proteínas de Arabidopsis/metabolismo , Cisteína/metabolismo , RNA de Cadeia Dupla/metabolismo , RNA de Plantas/metabolismo , Proteínas Repressoras/metabolismo , Regiões 3' não Traduzidas/genética , Sequência de Aminoácidos , Arabidopsis/genética , Arabidopsis/metabolismo , Proteínas de Arabidopsis/química , Proteínas de Arabidopsis/genética , Sequência de Bases , Cisteína/genética , Glutationa/metabolismo , Modelos Moleculares , Conformação de Ácido Nucleico , Oxirredução , Domínios Proteicos , Clivagem do RNA , RNA de Cadeia Dupla/química , RNA de Cadeia Dupla/genética , RNA de Plantas/química , RNA de Plantas/genética , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Motivos de Ligação ao RNA/genética , Proteínas Repressoras/química , Proteínas Repressoras/genética , Ribonuclease III/genética , Ribonuclease III/metabolismo , Homologia de Sequência do Ácido Nucleico
3.
Plant Cell ; 28(2): 406-25, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26764378

RESUMO

RNaseIII enzymes catalyze the cleavage of double-stranded RNA (dsRNA) and have diverse functions in RNA maturation. Arabidopsis thaliana RNASE THREE LIKE2 (RTL2), which carries one RNaseIII and two dsRNA binding (DRB) domains, is a unique Arabidopsis RNaseIII enzyme resembling the budding yeast small interfering RNA (siRNA)-producing Dcr1 enzyme. Here, we show that RTL2 modulates the production of a subset of small RNAs and that this activity depends on both its RNaseIII and DRB domains. However, the mode of action of RTL2 differs from that of Dcr1. Whereas Dcr1 directly cleaves dsRNAs into 23-nucleotide siRNAs, RTL2 likely cleaves dsRNAs into longer molecules, which are subsequently processed into small RNAs by the DICER-LIKE enzymes. Depending on the dsRNA considered, RTL2-mediated maturation either improves (RTL2-dependent loci) or reduces (RTL2-sensitive loci) the production of small RNAs. Because the vast majority of RTL2-regulated loci correspond to transposons and intergenic regions producing 24-nucleotide siRNAs that guide DNA methylation, RTL2 depletion modifies DNA methylation in these regions. Nevertheless, 13% of RTL2-regulated loci correspond to protein-coding genes. We show that changes in 24-nucleotide siRNA levels also affect DNA methylation levels at such loci and inversely correlate with mRNA steady state levels, thus implicating RTL2 in the regulation of protein-coding gene expression.


Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/genética , Regulação da Expressão Gênica de Plantas , RNA Interferente Pequeno/genética , Ribonuclease III/metabolismo , Arabidopsis/fisiologia , Proteínas de Arabidopsis/genética , Metilação de DNA , Inativação Gênica , Genes Reporter , Loci Gênicos/genética , Raízes de Plantas/genética , Raízes de Plantas/fisiologia , RNA de Cadeia Dupla/genética , RNA Mensageiro/genética , RNA de Plantas/genética , RNA Interferente Pequeno/metabolismo , Ribonuclease III/genética
4.
PLoS Biol ; 13(12): e1002326, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26696443

RESUMO

Small RNAs play essential regulatory roles in genome stability, development, and responses to biotic and abiotic stresses in most eukaryotes. In plants, the RNaseIII enzyme DICER-LIKE1 (DCL1) produces miRNAs, whereas DCL2, DCL3, and DCL4 produce various size classes of siRNAs. Plants also encode RNASE THREE-LIKE (RTL) enzymes that lack DCL-specific domains and whose function is largely unknown. We found that virus infection induces RTL1 expression, suggesting that this enzyme could play a role in plant-virus interaction. To first investigate the biochemical activity of RTL1 independent of virus infection, small RNAs were sequenced from transgenic plants constitutively expressing RTL1. These plants lacked almost all DCL2-, DCL3-, and DCL4-dependent small RNAs, indicating that RTL1 is a general suppressor of plant siRNA pathways. In vivo and in vitro assays revealed that RTL1 prevents siRNA production by cleaving dsRNA prior to DCL2-, DCL3-, and DCL4-processing. The substrate of RTL1 cleavage is likely long-perfect (or near-perfect) dsRNA, consistent with the RTL1-insensitivity of miRNAs, which derive from DCL1-processing of short-imperfect dsRNA. Virus infection induces RTL1 mRNA accumulation, but viral proteins that suppress RNA silencing inhibit RTL1 activity, suggesting that RTL1 has evolved as an inducible antiviral defense that could target dsRNA intermediates of viral replication, but that a broad range of viruses counteract RTL1 using the same protein toolbox used to inhibit antiviral RNA silencing. Together, these results reveal yet another level of complexity in the evolutionary battle between viruses and plant defenses.


Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/virologia , Regulação da Expressão Gênica de Plantas , Interações Hospedeiro-Patógeno , Vírus de RNA/fisiologia , RNA de Plantas/antagonistas & inibidores , RNA Interferente Pequeno/antagonistas & inibidores , Proteínas Repressoras/metabolismo , Substituição de Aminoácidos , Arabidopsis/enzimologia , Arabidopsis/genética , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Carmovirus/fisiologia , Biologia Computacional/métodos , Cucumovirus/fisiologia , Isoenzimas/genética , Isoenzimas/metabolismo , Mutagênese Sítio-Dirigida , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Plantas Geneticamente Modificadas/enzimologia , Plantas Geneticamente Modificadas/genética , Plantas Geneticamente Modificadas/metabolismo , Plantas Geneticamente Modificadas/virologia , Mutação Puntual , RNA Mensageiro/metabolismo , RNA de Plantas/metabolismo , RNA Interferente Pequeno/metabolismo , Proteínas Recombinantes de Fusão/metabolismo , Proteínas Repressoras/genética , Tobamovirus/fisiologia , Tymovirus/fisiologia
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