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1.
Mol Cell ; 66(4): 558-567.e4, 2017 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-28525745

RESUMO

Ribosome frameshifting during translation of bacterial dnaX can proceed via different routes, generating a variety of distinct polypeptides. Using kinetic experiments, we show that -1 frameshifting predominantly occurs during translocation of two tRNAs bound to the slippery sequence codons. This pathway depends on a stem-loop mRNA structure downstream of the slippery sequence and operates when aminoacyl-tRNAs are abundant. However, when aminoacyl-tRNAs are in short supply, the ribosome switches to an alternative frameshifting pathway that is independent of a stem-loop. Ribosome stalling at a vacant 0-frame A-site codon results in slippage of the P-site peptidyl-tRNA, allowing for -1-frame decoding. When the -1-frame aminoacyl-tRNA is lacking, the ribosomes switch into -2 frame. Quantitative mass spectrometry shows that the -2-frame product is synthesized in vivo. We suggest that switching between frameshifting routes may enrich gene expression at conditions of aminoacyl-tRNA limitation.


Assuntos
Proteínas de Bactérias/biossíntese , DNA Polimerase III/biossíntese , Escherichia coli/enzimologia , Mudança da Fase de Leitura do Gene Ribossômico , RNA Bacteriano/metabolismo , RNA Mensageiro/metabolismo , Aminoacil-RNA de Transferência/metabolismo , Proteínas de Bactérias/genética , DNA Polimerase III/genética , Escherichia coli/genética , Regulação Bacteriana da Expressão Gênica , Regulação Enzimológica da Expressão Gênica , Cinética , Mutação , Conformação de Ácido Nucleico , RNA Bacteriano/química , RNA Bacteriano/genética , RNA Mensageiro/química , RNA Mensageiro/genética , Aminoacil-RNA de Transferência/química , Aminoacil-RNA de Transferência/genética , Espectrometria de Massas por Ionização por Electrospray , Relação Estrutura-Atividade , Espectrometria de Massas em Tandem
2.
Fungal Genet Biol ; 169: 103827, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37640199

RESUMO

Vegetative incompatibility is a fungal allorecognition system characterised by the inability of genetically distinct conspecific fungal strains to form a viable heterokaryon and is controlled by multiple polymorphic loci termed vic (vegetative incompatibility) or het (heterokaryon incompatibility). We have genetically identified and characterised the first vic locus in the economically important, plant-pathogenic, necrotrophic fungus Botrytis cinerea. A bulked segregant approach coupled with whole genome Illumina sequencing of near-isogenic lines of B. cinerea was used to map a vic locus to a 60-kb region of the genome. Within that locus, we identified two adjacent, highly polymorphic open reading frames, Bcvic1 and Bcvic2, which encode predicted proteins that contain domain architectures implicated in vegetative incompatibility in other filamentous fungi. Bcvic1 encodes a predicted protein containing a putative serine esterase domain, a NACHT family of NTPases domain, and several Ankyrin repeats. Bcvic2 encodes a putative syntaxin protein containing a SNARE domain; such proteins typically function in vesicular transport. Deletion of Bcvic1 and Bcvic2 individually had no effect on vegetative incompatibility. However, deletion of the region containing both Bcvic1 and Bcvic2 resulted in mutant lines that were severely restricted in growth and showed loss of vegetative incompatibility. Complementation of these mutants by ectopic expression restored the growth and vegetative incompatibility phenotype, indicating that Bcvic1 and Bcvic2 are controlling vegetative incompatibility at this vic locus.


Assuntos
Proteínas Fúngicas , Genes Fúngicos , Sequência de Aminoácidos , Genes Fúngicos/genética , Proteínas Fúngicas/genética , Botrytis/genética
3.
J Appl Clin Med Phys ; 23(12): e13798, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36453139

RESUMO

A hybrid quality control (QC) program was developed that integrates automated and conventional Linac QC, realizing the benefits of both automated and conventional QC, increasing efficiency and maintaining independent measurement methods. Failure mode and effects analysis (FMEA) was then applied in order to validate the program prior to clinical implementation. The hybrid QC program consists of automated QC with machine performance check and DailyQA3 array on the TrueBeam Linac, and Delta4 volumetric modulated arc therapy (VMAT) standard plan measurements, alongside conventional monthly QC at a reduced frequency. The FMEA followed the method outlined in TG-100. Process maps were created for each treatment type at our center: VMAT, stereotactic body radiotherapy (SBRT), conformal, and palliative. Possible failure modes were established by evaluating each stage in the process map. The FMEA followed semiquantitative methods, using data from our QC records from eight Linacs over 3 years for the occurrence estimates, and simulation of failure modes in the treatment planning system, with scoring surveys for severity and detectability. The risk priority number (RPN) was calculated from the product of the occurrence, severity, and detectability scores and then normalized to the maximum and ranked to determine the most critical failure modes. The highest normalized RPN values (100, 90) were found to be for MLC position dynamic for both VMAT and SBRT treatments. The next highest score was 35 for beam position for SBRT, and the majority of scores were less than 20. Overall, these RPN scores for the hybrid Linac QC program indicated that it would be acceptable, but the high RPN score associated with the dynamic MLC failure mode indicates that it would be valuable to perform more rigorous testing of the MLC. The FMEA proved to be a useful tool in validating hybrid QC.


Assuntos
Análise do Modo e do Efeito de Falhas na Assistência à Saúde , Radiocirurgia , Radioterapia de Intensidade Modulada , Humanos , Radiocirurgia/métodos , Controle de Qualidade , Fatores de Risco , Simulação por Computador , Planejamento da Radioterapia Assistida por Computador/métodos , Dosagem Radioterapêutica
4.
Nucleic Acids Res ; 47(6): 2932-2945, 2019 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-30649420

RESUMO

Assessment of the fidelity of gene expression is crucial to understand cell homeostasis. Here we present a highly sensitive method for the systematic Quantification of Rare Amino acid Substitutions (QRAS) using absolute quantification by targeted mass spectrometry after chromatographic enrichment of peptides with missense amino acid substitutions. By analyzing incorporation of near- and non-cognate amino acids in a model protein EF-Tu, we show that most of missense errors are too rare to detect by conventional methods, such as DDA, and are estimated to be between <10-7-10-5 by QRAS. We also observe error hotspots of up to 10-3 for some types of mismatches, including the G-U mismatch. The error frequency depends on the expression level of EF-Tu and, surprisingly, the amino acid position in the protein. QRAS is not restricted to any particular miscoding event, organism, strain or model protein and is a reliable tool to analyze very rare proteogenomic events.


Assuntos
Proteínas de Escherichia coli/genética , Expressão Gênica/genética , Mutação de Sentido Incorreto/genética , Fator Tu de Elongação de Peptídeos/genética , Aminoácidos , Escherichia coli/genética , Homeostase/genética
5.
J Appl Clin Med Phys ; 21(8): 224-235, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32790139

RESUMO

Machine Performance Check (MPC) is an automated Quality Control (QC) tool that is integrated into the TrueBeam and Halcyon linear accelerators (Linacs), utilizing the imaging systems to verify the Linac beam and geometry. This work compares the concordance of daily MPC results with conventional QC tests over a 3-year period for eight Linacs in order to assess the sensitivity of MPC in detecting faults. The MPC output measurements were compared with the monthly ionization chamber measurements for 6 and 10 MV photon beams and 6, 9, 12, 16, and 18 MeV electron beams. All 6 MV Beam and Geometry (6MVBG) MPC test failures were analyzed to determine the failure rate and the number of true and false negative results, using the conventional QC record as the reference. The concordance between conventional QC test failures and MPC test failures was investigated. The mean agreement across 1933 MPC output and monthly comparison chamber measurements for all beam energies was 0.2%, with 97.8% within 1.5%, and a maximum difference of 2.9%. Of the 5000-6000 MPC individual test parameter results for the 6MVBG test, the highest failure rate was BeamOutputChange (0.5%), then BeamCenterShift (0.3%), and was ≤ 0.1% for the remaining parameters. There were 50 true negative and 27 false negative out of tolerance MPC results, with false negatives resolved by repeating MPC or by independent measurement. The analysis of conventional QC failures demonstrated that MPC detected all failures, except occasions when MPC reported output within tolerance, a result of the MPC-chamber response variation. The variation in MPC output versus chamber measurement indicates MPC is appropriate for daily output constancy but not for the measurement of absolute output. The comparison of the 6MVBG results and conventional records provides evidence that MPC is a sensitive method of performing beam and mechanical checks in a clinical setting.


Assuntos
Aceleradores de Partículas , Radiometria , Humanos , Imagens de Fantasmas , Controle de Qualidade
6.
J Gen Virol ; 99(5): 615-616, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29589826

RESUMO

The Hypoviridae, comprising one genus, Hypovirus, is a family of capsidless viruses with positive-sense, ssRNA genomes of 9.1-12.7 kb that possess either a single large ORF or two ORFs. The ORFs appear to be translated from genomic RNA by non-canonical mechanisms, i.e. internal ribosome entry site-mediated and stop/restart translation. Hypoviruses have been detected in ascomycetous or basidiomycetous filamentous fungi, and are considered to be replicated in host Golgi-derived, lipid vesicles that contain their dsRNA as a replicative form. Some hypoviruses induce hypovirulence to host fungi, while others do not. This is a summary of the current ICTV report on the taxonomy of the Hypoviridae, which is available at www.ictv.global/report/hypoviridae.


Assuntos
Vírus de RNA/classificação , Vírus de RNA/genética , Fungos/virologia , Genoma Viral , Fases de Leitura Aberta , Filogenia , RNA de Cadeia Dupla/genética , RNA Viral/genética
8.
Arch Virol ; 162(2): 591-595, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27812834

RESUMO

We present the first complete genome of vanilla mosaic virus (VanMV). The VanMV genomic structure is consistent with that of a potyvirus, containing a single open reading frame (ORF) encoding a polyprotein of 3139 amino acids. Motif analyses indicate the polyprotein can be cleaved into the expected ten individual proteins; other recognised potyvirus motifs are also present. As expected, the VanMV genome shows high sequence similarity to the published Dasheen mosaic virus (DsMV) genome sequences; comparisons with DsMV continue to support VanMV as a vanilla infecting strain of DsMV. Phylogenetic analyses indicate that VanMV and DsMV share a common ancestor, with VanMV having the closest relationship with DsMV strains from the South Pacific.


Assuntos
Genoma Viral , Filogenia , Potyvirus/genética , RNA Viral/genética , Vanilla/virologia , Sequência de Aminoácidos , Mapeamento Cromossômico , Fases de Leitura Aberta , Doenças das Plantas/virologia , Polinésia , Potyvirus/classificação , Potyvirus/isolamento & purificação , Análise de Sequência de DNA
9.
Arch Virol ; 162(8): 2493-2504, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28389807

RESUMO

In 2017, the order Mononegavirales was expanded by the inclusion of a total of 69 novel species. Five new rhabdovirus genera and one new nyamivirus genus were established to harbor 41 of these species, whereas the remaining new species were assigned to already established genera. Furthermore, non-Latinized binomial species names replaced all paramyxovirus and pneumovirus species names, thereby accomplishing application of binomial species names throughout the entire order. This article presents the updated taxonomy of the order Mononegavirales as now accepted by the International Committee on Taxonomy of Viruses (ICTV).


Assuntos
Genoma Viral , Mononegavirais/classificação , Ordem dos Genes , Mononegavirais/genética , Filogenia , Especificidade da Espécie
10.
Virol J ; 13: 29, 2016 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-26891841

RESUMO

BACKGROUND: The genus Tobamovirus (Virgaviridae) comprises 33 accepted species with the recent addition of eight new viruses and is divided in to three subgroups based on the origin of assembly of the virion and host range. Within the subgroup 1 tobamoviruses the orchid-associated tobamovirus was hypothesized to be a chimeric derivative of recombinations between genome fragments from subgroup 3 and 1. Recombination events involving RdRp, movement and coat protein genes are recorded within subgroup 1 and 2. However natural recombinations have not previously been reported between subgroup 3 tobamoviruses. FINDINGS: The organization and phylogenetic analyses of the complete genome and the different ORFs placed the new isolate within the Ribgrass mosaic virus clade of subgroup 3 tobamoviruses. Recombination detection analyses indicated that the isolate was a chimeric genome with fragments of high similarity to Ribgrass mosaic virus (RMV) strains NZ-439 (HQ667978) and Actinidia-AC (GQ401365.1) infecting herbaceous Plantago sp. and woody Actinidia spp., respectively. The recombinant differed across the whole genome by 3-8 % from other published RMV genomes. CONCLUSION: In this investigation we report an intra-specific recombination between RMV strains NZ-439 (HQ667978) and Actinidia-AC (GQ401365.1), in the replicase component between viral-methyltransferase and viral-helicase regions, resulting in a novel RMV strain FSHS (JQ319720.1) that represents the first described natural recombinant within the RMV cluster of subgroup 3 tobamoviruses.


Assuntos
Genoma Viral , Recombinação Genética , Tobamovirus/classificação , Tobamovirus/genética , Fases de Leitura Aberta , Filogenia
11.
Arch Virol ; 161(5): 1371-5, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26906692

RESUMO

In this study of three grapevine leafroll-associated virus 3 (GLRaV-3) genetic variants in two grapevine rootstock hosts, GLRaV-3 detection was shown to be affected by the virus distribution, titre, and the genetic variant. Group VI and NZ2 GLRaV-3 variants had reduced detectability compared with the group I variant. Differences in the genomic and subgenomic RNA (sgRNA) expression levels, and differences in the level of expression between the genetic variants were also observed. The observed differences in virus titre and sgRNA expression levels suggest differences in plant-virus interactions by the various GLRaV-3 genetic variants.


Assuntos
Closteroviridae/genética , Doenças das Plantas/virologia , Raízes de Plantas/virologia , Vitis/virologia , Variação Genética/genética , Brotos de Planta/virologia , Reação em Cadeia da Polimerase em Tempo Real
12.
Arch Virol ; 161(3): 745-8, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26687584

RESUMO

We report the first genome sequence of a Colocasia bobone disease-associated virus (CBDaV) derived from bobone-affected taro [Colocasia esculenta L. Schott] from Solomon Islands. The negative-strand RNA genome is 12,193 nt long, with six major open reading frames (ORFs) with the arrangement 3'-N-P-P3-M-G-L-5'. Typical of all rhabdoviruses, the 3' leader and 5' trailer sequences show complementarity to each other. Phylogenetic analysis indicated that CBDaV is a member of the genus Cytorhabdovirus, supporting previous reports of virus particles within the cytoplasm of bobone-infected taro cells. The availability of the CBDaV genome sequence now makes it possible to assess the role of this virus in bobone, and possibly alomae disease of taro and confirm that this sequence is that of Colocasia bobone disease virus (CBDV).


Assuntos
Colocasia/virologia , Genoma Viral , Doenças das Plantas/virologia , RNA Viral/genética , Rhabdoviridae/genética , Rhabdoviridae/isolamento & purificação , Análise de Sequência de DNA , Análise por Conglomerados , Ordem dos Genes , Melanesia , Dados de Sequência Molecular , Fases de Leitura Aberta , Filogenia , Rhabdoviridae/classificação , Homologia de Sequência
13.
Gut ; 63(2): 250-61, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23426895

RESUMO

OBJECTIVE: To determine whether variation in gastroscopy rates in English general practice populations is associated with inequality in oesophagogastric (OG) cancer outcome. DESIGN: Retrospective observational study of the Hospital Episode Statistics (HES) dataset for England (2006-2008) linked to death registration. METHODS: were validated using independent local and national data. General practices with new cases of OG cancer were included. Practices were grouped into tertiles according to standardised elective gastroscopy rate per capita (low, medium or high). Outcome measures for cancer cases were: emergency admission during diagnostic pathway, major surgical resection and mortality at 1 year. Covariates were: age group, gender, comorbidity, general practice average deprivation and patient deprivation. RESULTS: 22 488 incident cases of OG cancer from 6513 general practices were identified. Patients registered with the low tertile group of practices had the lowest rate of major surgery, highest rate of emergency admission and highest mortality. The inequality was widest for the most socioeconomically deprived cases. After adjustment for covariates in logistic regression, the gastroscopy rate (low, medium or high) at the patient's general practice was an independent predictor of emergency admission, major surgery and mortality. CONCLUSIONS: There is wide variation in the rate of gastroscopy among general practice populations in England. On average, OG cancer patients belonging to practices with the lowest rates of gastroscopy are at greater risk of poor outcome. These findings suggest that initiatives or current guidelines aimed at limiting the use of gastroscopy may adversely affect cancer outcomes.


Assuntos
Neoplasias Esofágicas/diagnóstico , Gastroscopia/estatística & dados numéricos , Hospitalização/estatística & dados numéricos , Neoplasias Gástricas/diagnóstico , Adulto , Idoso , Emergências , Neoplasias Esofágicas/mortalidade , Neoplasias Esofágicas/cirurgia , Feminino , Medicina Geral , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Estudos Retrospectivos , Neoplasias Gástricas/mortalidade , Neoplasias Gástricas/cirurgia , Taxa de Sobrevida
14.
RNA ; 18(9): 1656-65, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22847815

RESUMO

The 2,2,7-trimethylguanosine caps of eukaryal snRNAs and snoRNA are formed by the enzyme Tgs1, which catalyzes sequential guanine-N2 methylations of m(7)G caps. Atypically, in the divergent unicellular eukaryote Trichomonas vaginalis, spliceosomal snRNAs lack a guanosine cap and the recombinant T. vaginalis trimethylguanosine synthase (TvTgs) produces only m(2,7)G in vitro. Here, we show by direct metabolic labeling that endogenous T. vaginalis RNAs contain m(7)G, m(2,7)G, and m(2,2,7)G caps. Immunodepletion of TvTgs from cell extracts and TvTgs add-back experiments demonstrate that TvTgs produces m(2,7)G and m(2,2,7)G caps. Expression of TvTgs in yeast tgs1Δ cells leads to the formation of m(2,7)G and m(2,2,7)G caps and complementation of the lethality of a tgs1Δ mud2Δ strain. Whereas TvTgs is present in the nucleus and cytosol of T. vaginalis cells, TMG-containing RNAs are localized primarily in the nucleolus. Molecular cloning of anti-TMG affinity-purified T. vaginalis RNAs identified 16 box H/ACA snoRNAs, which are implicated in guiding RNA pseudouridylation. The ensemble of new T. vaginalis H/ACA snoRNAs allowed us to predict and partially validate an extensive map of pseudouridines in T. vaginalis rRNA.


Assuntos
Metiltransferases/metabolismo , RNA Nucleolar Pequeno/metabolismo , Trichomonas vaginalis/enzimologia , Sequência de Bases , Transporte Biológico , Guanosina/análogos & derivados , Guanosina/metabolismo , Metilação , Dados de Sequência Molecular , Conformação de Ácido Nucleico , Capuzes de RNA/metabolismo , RNA Nucleolar Pequeno/química , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Alinhamento de Sequência , Especificidade por Substrato , Trichomonas vaginalis/genética
15.
Arch Virol ; 159(11): 3157-60, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25034670

RESUMO

Seven putative mitoviral genomes, representing four species from three Sclerotinia sclerotiorum isolates, were fully sequenced. The genome lengths ranged from 2438 to 2815 nucleotides. The RNA-dependent RNA polymerase (RdRp) of one genome shared high amino acid (aa) sequence identity (98.5 %) with the previously described Sclerotinia sclerotiorum mitovirus 2 (SsMV2/NZ1) and was provisionally assigned the name SsMV2/14563. The RdRps of three of the genomes with closest aa sequence identity of 78.8-79.3 % to Sclerotinia sclerotiorum mitovirus 1 (SsMV1/KL1) were provisionally considered to represent a new species, and the corresponding virus was named Sclerotinia sclerotiorum mitovirus 5 (SsMV5/11691, SsMV5/14563 and SsMV5/Lu471). The remaining two novel genomes, for which the viruses were provisionally named Sclerotinia sclerotiorum mitovirus 6 (SsMV6/14563 and SsMV6/Lu471) and Sclerotinia sclerotiorum mitovirus 7 (SsMV7/Lu471), showed closest aa sequence identities to Sclerotinia sclerotiorum mitovirus 3 (SsMV3/NZ1; 57.5-57.8 %) and Cryphonectria cubensis mitovirus 1a (CcMV1a; 32 %), respectively. The RdRp proteins of all seven genomes contained the conserved aa sequence motifs (I-IV) previously reported for mitoviruses, and their 5' and 3' untranslated regions (UTRs) have the potential to fold into stem-loop secondary structures.


Assuntos
Ascomicetos/virologia , Doenças das Plantas/microbiologia , Vírus de RNA/genética , Vírus de RNA/isolamento & purificação , Dados de Sequência Molecular , Fases de Leitura Aberta , Filogenia , Vírus de RNA/classificação , Vírus de RNA/enzimologia , RNA Polimerase Dependente de RNA/química , RNA Polimerase Dependente de RNA/genética , Homologia de Sequência de Aminoácidos , Proteínas Virais/química , Proteínas Virais/genética
16.
Arch Virol ; 159(6): 1321-7, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24327093

RESUMO

New Zealand isolates of the entomopathogenic fungus Beauveria were examined for the presence of dsRNAs and virus-like particles. Seven out of nine isolates contained one or more high-molecular-weight dsRNAs and all seven contained isometric virus particles ranging in size from 30 to 50 nm. B. bassiana isolate ICMP#6887 contained a single dsRNA band of ~6 kb and isometric virus-like particles of ~50 nm in diameter. Sequencing revealed that the virus from ICMP#6887 had a genome of 5,327 nt with two overlapping ORFs coding for a putative coat protein (CP) and an RNA-dependent RNA-polymerase (RdRp). The sequence showed a highest CP identity of 58.3 % to Tolypocladium cylindrosporum virus 1 (TcV1) and a highest RdRp identity of 48.8 % to Sphaeropsis sapinea RNA virus 1 (SsRV1). Since both TcV1 and SsRV1 belong to the genus Victorivirus, the new virus from B. bassiana ICMP#6887 was tentatively assigned the name Beauveria bassiana victorivirus 1 (BbVV1-6887).


Assuntos
Beauveria/virologia , Genoma Viral , RNA Viral/genética , Análise de Sequência de DNA , Totiviridae/classificação , Totiviridae/genética , Animais , Análise por Conglomerados , Nova Zelândia , Fases de Leitura Aberta , Filogenia , Homologia de Sequência de Aminoácidos , Totiviridae/isolamento & purificação , Proteínas Virais/genética
17.
Brain Behav ; 14(7): e3611, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38956818

RESUMO

PURPOSE: Mild cognitive impairment (MCI) can be the prodromal phase of Alzheimer's disease (AD) where appropriate intervention might prevent or delay conversion to AD. Given this, there has been increasing interest in using magnetic resonance imaging (MRI) and neuropsychological testing to predict conversion from MCI to AD. Recent evidence suggests that the choroid plexus (ChP), neural substrates implicated in brain clearance, undergo volumetric changes in MCI and AD. Whether the ChP is involved in memory changes observed in MCI and can be used to predict conversion from MCI to AD has not been explored. METHOD: The current study used data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database to investigate whether later progression from MCI to AD (progressive MCI [pMCI], n = 115) or stable MCI (sMCI, n = 338) was associated with memory scores using the Rey Auditory Verbal Learning Test (RAVLT) and ChP volumes as calculated from MRI. Classification analyses identifying pMCI or sMCI group membership were performed to compare the predictive ability of the RAVLT and ChP volumes. FINDING: The results indicated a significant difference between pMCI and sMCI groups for right ChP volume, with the pMCI group showing significantly larger right ChP volume (p = .01, 95% confidence interval [-.116, -.015]). A significant linear relationship between the RAVLT scores and right ChP volume was found across all participants, but not for the two groups separately. Classification analyses showed that a combination of left ChP volume and auditory verbal learning scores resulted in the most accurate classification performance, with group membership accurately predicted for 72% of the testing data. CONCLUSION: These results suggest that volumetric ChP changes appear to occur before the onset of AD and might provide value in predicting conversion from MCI to AD.


Assuntos
Doença de Alzheimer , Plexo Corióideo , Disfunção Cognitiva , Progressão da Doença , Imageamento por Ressonância Magnética , Aprendizagem Verbal , Humanos , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/fisiopatologia , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/fisiopatologia , Disfunção Cognitiva/diagnóstico , Masculino , Feminino , Idoso , Aprendizagem Verbal/fisiologia , Plexo Corióideo/diagnóstico por imagem , Plexo Corióideo/patologia , Idoso de 80 Anos ou mais , Testes Neuropsicológicos
18.
J Nucl Med Technol ; 2024 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-38901967

RESUMO

We devised and clinically validated a schema of rapid personalized predictive dosimetry for 177Lu-PSMA-I&T in metastatic castration-resistant prostate cancer. It supersedes traditional empiric prescription by providing clinically meaningful predicted absorbed doses for first-strike optimization. Methods: Prostate-specific membrane antigen PET was conceptualized as a simulation study that captures the complex dosimetric interplay between tumor, marrow, and kidneys at a single time point. Radiation principles of fractionation, heterogeneity, normal-organ constraints (marrow, kidney), absorbed dose, and dose rate were introduced. We created a predictive calculator in the form of a free, open-source, and user-friendly spreadsheet that can be completed within minutes. Our schema achieves speed and accuracy by sampling tissue radioconcentrations (kBq/cm3) to be analyzed in conjunction with clinical input from the user that reflect dosimetric preconditions. The marrow-absorbed dose constraint was 0.217 Gy (dose rate, ≤0.0147 Gy/h) per fraction with an interfraction interval of at least 6 wk. Results: Our first 10 patients were analyzed. The first-strike mean tumor-absorbed dose threshold for any prostate-specific antigen (PSA) response was more than 10 Gy (dose rate, >0.1 Gy/h). The metastasis with the lowest first-strike tumor-absorbed dose correlated the best with the percentage decrease of PSA; its threshold to achieve hypothetical zero PSA was 20 Gy or more. Each patient's PSA doubling time can be used to personalize their unique absorbed dose-response threshold. The predicted mean first-strike prescription constrained by marrow-absorbed dose rate per fraction was 11.0 ± 4.0 GBq. Highly favorable conditions (tumor sink effect) were dosimetrically expressed as the combination of tumor-to-normal-organ ratios of more than 150 for marrow and more than 4 for kidney. Our schema obviates the traditional role of the SUV as a predictive parameter. Conclusion: Our rapid schema is feasible to implement in any busy real-world theranostics unit and exceeds today's best practice standards. Our dosimetric thresholds and predictive parameters can radiobiologically rationalize each patient's first-strike prescription down to a single becquerel. Favorable tumor-to-normal-organ ratios can be prospectively exploited by predictive dosimetry to optimize the first-strike prescription. The scientific framework of our schema may be applied to other systemic radionuclide therapies.

19.
Clin Nucl Med ; 2024 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-39093035

RESUMO

ABSTRACT: A patient with widespread intensely prostate-specific membrane antigen-expressing, BRCA gene mutation-positive bone metastases at the time of prostate cancer diagnosis had progressed on multiple lines of standard therapy. He received 177Lu-prostate-specific membrane antigen 8.5 GBq augmented by a short course of olaparib radiosensitization and achieved 90% decrease in serum PSA level after a single treatment. His tumor response was much better than expected by predictive dosimetry. However, his marrow radiotoxicity was worse than anticipated and required hospitalization. This suggests radiosensitizing agents to be a double-edged sword that must be carefully considered and balanced during activity prescription.

20.
Sci Adv ; 10(15): eadj0954, 2024 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-38608027

RESUMO

Occupied between ~10,300 and 9300 years ago, the Pre-Pottery Neolithic site of Asikli Höyük in Central Anatolia went through early phases of sheep domestication. Analysis of 629 mitochondrial genomes from this and numerous sites in Anatolia, southwest Asia, Europe, and Africa produced a phylogenetic tree with excessive coalescences (nodes) around the Neolithic, a potential signature of a domestication bottleneck. This is consistent with archeological evidence of sheep management at Asikli Höyük which transitioned from residential stabling to open pasturing over a millennium of site occupation. However, unexpectedly, we detected high genetic diversity throughout Asikli Höyük's occupation rather than a bottleneck. Instead, we detected a tenfold demographic bottleneck later in the Neolithic, which caused the fixation of mitochondrial haplogroup B in southwestern Anatolia. The mitochondrial genetic makeup that emerged was carried from the core region of early Neolithic sheep management into Europe and dominates the matrilineal diversity of both its ancient and the billion-strong modern sheep populations.


Assuntos
Genoma Mitocondrial , Animais , Ovinos/genética , Filogenia , Carneiro Doméstico/genética , Turquia , África
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