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1.
Nat Commun ; 11(1): 492, 2020 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-31980615

RESUMO

White lupin (Lupinus albus L.) is an annual crop cultivated for its protein-rich seeds. It is adapted to poor soils due to the production of cluster roots, which are made of dozens of determinate lateral roots that drastically improve soil exploration and nutrient acquisition (mostly phosphate). Using long-read sequencing technologies, we provide a high-quality genome sequence of a cultivated accession of white lupin (2n = 50, 451 Mb), as well as de novo assemblies of a landrace and a wild relative. We describe a modern accession displaying increased soil exploration capacity through early establishment of lateral and cluster roots. We also show how seed quality may have been impacted by domestication in term of protein profiles and alkaloid content. The availability of a high-quality genome assembly together with companion genomic and transcriptomic resources will enable the development of modern breeding strategies to increase and stabilize white lupin yield.

2.
Cell ; 179(1): 147-164.e20, 2019 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-31539493

RESUMO

Long-distance RNA transport enables local protein synthesis at metabolically-active sites distant from the nucleus. This process ensures an appropriate spatial organization of proteins, vital to polarized cells such as neurons. Here, we present a mechanism for RNA transport in which RNA granules "hitchhike" on moving lysosomes. In vitro biophysical modeling, live-cell microscopy, and unbiased proximity labeling proteomics reveal that annexin A11 (ANXA11), an RNA granule-associated phosphoinositide-binding protein, acts as a molecular tether between RNA granules and lysosomes. ANXA11 possesses an N-terminal low complexity domain, facilitating its phase separation into membraneless RNA granules, and a C-terminal membrane binding domain, enabling interactions with lysosomes. RNA granule transport requires ANXA11, and amyotrophic lateral sclerosis (ALS)-associated mutations in ANXA11 impair RNA granule transport by disrupting their interactions with lysosomes. Thus, ANXA11 mediates neuronal RNA transport by tethering RNA granules to actively-transported lysosomes, performing a critical cellular function that is disrupted in ALS.

3.
BMC Genet ; 20(1): 68, 2019 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-31412771

RESUMO

BACKGROUND: Yellow lupin (Lupinus luteus L.) is a promising grain legume for productive and sustainable crop rotations. It has the advantages of high tolerance to soil acidity and excellent seed quality, but its current yield potential is poor, especially in low rainfall environments. Key adaptation traits such as phenology and enhanced stress tolerance are often complex and controlled by several genes. Genomic-enabled technologies may help to improve our basic understanding of these traits and to provide selective markers in breeding. However, in yellow lupin there are very limited genomic resources to support research and no published information is available on the genetic control of adaptation traits. RESULTS: We aimed to address these deficiencies by developing the first linkage map for yellow lupin and conducting quantitative trait locus (QTL) analysis of yield under well-watered (WW) and water-deficit (WT) conditions. Two next-generation sequencing marker approaches - genotyping-by-sequencing (GBS) and Diversity Array Technology (DArT) sequencing - were employed to genotype a recombinant inbred line (RIL) population developed from a bi-parental cross between wild and domesticated parents. A total of 2,458 filtered single nucleotide polymorphism (SNP) and presence / absence variation (PAV) markers were used to develop a genetic map comprising 40 linkage groups, the first reported for this species. A number of significant QTLs controlling total biomass and 100-seed weight under two water (WW and WD) regimes were found on linkage groups YL-03, YL-09 and YL-26 that together explained 9 and 28% of total phenotypic variability. QTLs associated with length of the reproductive phase and time to flower were found on YL-01, YL-21, YL-35 and YL-40 that together explained a total of 12 and 44% of total phenotypic variation. CONCLUSION: These genomic resources and the QTL information offer significant potential for use in marker-assisted selection in yellow lupin.

4.
Genetics ; 213(1): 267-279, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31292211

RESUMO

Sleep is evolutionarily conserved, thus studying simple invertebrates such as Caenorhabditis elegans can provide mechanistic insight into sleep with single cell resolution. A conserved pathway regulating sleep across phylogeny involves cyclic adenosine monophosphate (cAMP), a ubiquitous second messenger that functions in neurons by activating protein kinase A. C. elegans sleep in response to cellular stress caused by environmental insults [stress-induced sleep (SIS)], a model for studying sleep during sickness. SIS is controlled by simple neural circuitry, thus allowing for cellular dissection of cAMP signaling during sleep. We employed a red-light activated adenylyl cyclase, IlaC22, to identify cells involved in SIS regulation. We found that pan-neuronal activation of IlaC22 disrupts SIS through mechanisms independent of the cAMP response element binding protein. Activating IlaC22 in the single DVA interneuron, the paired RIF interneurons, and in the CEPsh glia identified these cells as wake-promoting. Using a cAMP biosensor, epac1-camps, we found that cAMP is decreased in the RIF and DVA interneurons by neuropeptidergic signaling from the ALA neuron. Ectopic overexpression of sleep-promoting neuropeptides coded by flp-13 and flp-24, released from the ALA, reduced cAMP in the DVA and RIFs, respectively. Overexpression of the wake-promoting neuropeptides coded by pdf-1 increased cAMP levels in the RIFs. Using a combination of optogenetic manipulation and in vivo imaging of cAMP we have identified wake-promoting neurons downstream of the neuropeptidergic output of the ALA. Our data suggest that sleep- and wake-promoting neuropeptides signal to reduce and heighten cAMP levels during sleep, respectively.

5.
Clin Pharmacol Ther ; 106(5): 1028-1036, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31066027

RESUMO

Carbamazepine (CBZ) causes life-threating T-cell-mediated hypersensitivity reactions, including serious cutaneous adverse reactions (SCARs) and drug-induced liver injury (CBZ-DILI). In order to evaluate shared or phenotype-specific genetic predisposing factors for CBZ hypersensitivity reactions, we performed a meta-analysis of two genomewide association studies (GWAS) on a total of 43 well-phenotyped Northern and Southern European CBZ-SCAR cases and 10,701 population controls and a GWAS on 12 CBZ-DILI cases and 8,438 ethnically matched population controls. HLA-A*31:01 was identified as the strongest genetic predisposing factor for both CBZ-SCAR (odds ratio (OR) = 8.0; 95% CI 4.10-15.80; P = 1.2 × 10-9 ) and CBZ-DILI (OR = 7.3; 95% CI 2.47-23.67; P = 0.0004) in European populations. The association with HLA-A*31:01 in patients with SCAR was mainly driven by hypersensitivity syndrome (OR = 12.9; P = 2.1 × 10-9 ) rather than by Stevens-Johnson syndrome/toxic epidermal necrolysis cases, which showed an association with HLA-B*57:01. We also identified a novel risk locus mapping to ALK only for CBZ-SCAR cases, which needs replication in additional cohorts and functional evaluation.

6.
BMC Genomics ; 20(1): 385, 2019 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-31101009

RESUMO

BACKGROUND: Narrow-leafed lupin is an emerging crop of significance in agriculture, livestock feed and human health food. However, its susceptibility to various diseases is a major obstacle towards increased adoption. Sclerotinia sclerotiorum and Botrytis cinerea - both necrotrophs with broad host-ranges - are reported among the top 10 lupin pathogens. Whole-genome sequencing and comparative genomics are useful tools to discover genes responsible for interactions between pathogens and their hosts. RESULTS: Genomes were assembled for one isolate of B. cinerea and two isolates of S. sclerotiorum, which were isolated from either narrow-leafed or pearl lupin species. Comparative genomics analysis between lupin-derived isolates and others isolated from alternate hosts was used to predict between 94 to 98 effector gene candidates from among their respective non-conserved gene contents. CONCLUSIONS: Detection of minor differences between relatively recently-diverged isolates, originating from distinct regions and with hosts, may highlight novel or recent gene mutations and losses resulting from host adaptation in broad host-range fungal pathogens.


Assuntos
Adaptação Fisiológica , Ascomicetos/genética , Botrytis/genética , Proteínas Fúngicas/genética , Genoma Fúngico , Lupinus/microbiologia , Doenças das Plantas/microbiologia , Ascomicetos/patogenicidade , Botrytis/patogenicidade , Especificidade de Hospedeiro , Virulência , Sequenciamento Completo do Genoma
7.
Cogn Behav Neurol ; 32(1): 46-53, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30896577

RESUMO

Four patients with primary progressive aphasia displayed a greater deficit in understanding words they heard than words they read, and a further deficiency in naming objects orally rather than in writing. All four had frontotemporal lobar degeneration-transactive response DNA binding protein Type A neuropathology, three determined postmortem and one surmised on the basis of granulin gene (GRN) mutation. These features of language impairment are not characteristic of any currently recognized primary progressive aphasia variant. They can be operationalized as manifestations of dysfunction centered on a putative auditory word-form area located in the superior temporal gyrus of the left hemisphere. The small size of our sample makes the conclusions related to underlying pathology and auditory word-form area dysfunction tentative. Nonetheless, a deeper assessment of such patients may clarify the nature of pathways that link modality-specific word-form information to the associations that mediate their recognition as concepts. From a practical point of view, the identification of these features in patients with primary progressive aphasia should help in the design of therapeutic interventions where written communication modalities are promoted to circumvent some of the oral communication deficits.


Assuntos
Afasia Primária Progressiva/fisiopatologia , Percepção de Forma/fisiologia , Degeneração Lobar Frontotemporal/patologia , Percepção da Fala/fisiologia , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Lobo Temporal/patologia
9.
BMC Bioinformatics ; 20(1): 69, 2019 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-30736745

RESUMO

BACKGROUND: Determining which target to pursue is a challenging and error-prone first step in developing a therapeutic treatment for a disease, where missteps are potentially very costly given the long-time frames and high expenses of drug development. With current informatics technology and machine learning algorithms, it is now possible to computationally discover therapeutic hypotheses by predicting clinically promising drug targets based on the evidence associating drug targets with disease indications. We have collected this evidence from Open Targets and additional databases that covers 17 sources of evidence for target-indication association and represented the data as a tensor of 21,437 × 2211 × 17. RESULTS: As a proof-of-concept, we identified examples of successes and failures of target-indication pairs in clinical trials across 875 targets and 574 disease indications to build a gold-standard data set of 6140 known clinical outcomes. We designed and executed three benchmarking strategies to examine the performance of multiple machine learning models: Logistic Regression, LASSO, Random Forest, Tensor Factorization and Gradient Boosting Machine. With 10-fold cross-validation, tensor factorization achieved AUROC = 0.82 ± 0.02 and AUPRC = 0.71 ± 0.03. Across multiple validation schemes, this was comparable or better than other methods. CONCLUSION: In this work, we benchmarked a machine learning technique called tensor factorization for the problem of predicting clinical outcomes of therapeutic hypotheses. Results have shown that this method can achieve equal or better prediction performance compared with a variety of baseline models. We demonstrate one application of the method to predict outcomes of trials on novel indications of approved drug targets. This work can be expanded to targets and indications that have never been clinically tested and proposing novel target-indication hypotheses. Our proposed biologically-motivated cross-validation schemes provide insight into the robustness of the prediction performance. This has significant implications for all future methods that try to address this seminal problem in drug discovery.


Assuntos
Algoritmos , Descoberta de Drogas , Modelos Teóricos , Teorema de Bayes , Benchmarking , Ensaios Clínicos como Assunto , Sistemas de Liberação de Medicamentos/métodos , Humanos , Modelos Logísticos
10.
Gastroenterology ; 156(6): 1707-1716.e2, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30664875

RESUMO

BACKGROUND & AIMS: We performed genetic analyses of a multiethnic cohort of patients with idiosyncratic drug-induced liver injury (DILI) to identify variants associated with susceptibility. METHODS: We performed a genome-wide association study of 2048 individuals with DILI (cases) and 12,429 individuals without (controls). Our analysis included subjects of European (1806 cases and 10,397 controls), African American (133 cases and 1,314 controls), and Hispanic (109 cases and 718 controls) ancestry. We analyzed DNA from 113 Icelandic cases and 239,304 controls to validate our findings. RESULTS: We associated idiosyncratic DILI with rs2476601, a nonsynonymous polymorphism that encodes a substitution of tryptophan with arginine in the protein tyrosine phosphatase, nonreceptor type 22 gene (PTPN22) (odds ratio [OR] 1.44; 95% confidence interval [CI] 1.28-1.62; P = 1.2 × 10-9 and replicated the finding in the validation set (OR 1.48; 95% CI 1.09-1.99; P = .01). The minor allele frequency showed the same effect size (OR > 1) among ethnic groups. The strongest association was with amoxicillin and clavulanate-associated DILI in persons of European ancestry (OR 1.62; 95% CI 1.32-1.98; P = 4.0 × 10-6; allele frequency = 13.3%), but the polymorphism was associated with DILI of other causes (OR 1.37; 95% CI 1.21-1.56; P = 1.5 × 10-6; allele frequency = 11.5%). Among amoxicillin- and clavulanate-associated cases of European ancestry, rs2476601 doubled the risk for DILI among those with the HLA risk alleles A*02:01 and DRB1*15:01. CONCLUSIONS: In a genome-wide association study, we identified rs2476601 in PTPN22 as a non-HLA variant that associates with risk of liver injury caused by multiple drugs and validated our finding in a separate cohort. This variant has been associated with increased risk of autoimmune diseases, providing support for the concept that alterations in immune regulation contribute to idiosyncratic DILI.


Assuntos
Afro-Americanos/genética , Doença Hepática Induzida por Substâncias e Drogas/genética , Grupo com Ancestrais do Continente Europeu/genética , Hispano-Americanos/genética , Proteína Tirosina Fosfatase não Receptora Tipo 22/genética , Adulto , Amoxicilina/efeitos adversos , Antibacterianos/efeitos adversos , Estudos de Casos e Controles , Ácido Clavulânico/efeitos adversos , Feminino , Frequência do Gene , Estudo de Associação Genômica Ampla , Antígeno HLA-A2/genética , Cadeias HLA-DRB1/genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Polimorfismo de Nucleotídeo Único , Fatores de Risco
11.
Clin Pharmacol Ther ; 106(1): 245-253, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30661239

RESUMO

Some patients prescribed flucloxacillin (~ 0.01%) develop drug-induced liver injury (DILI). HLA-B*57:01 is an established genetic risk factor for flucloxacillin DILI. To consolidate this finding, identify additional genetic factors, and assess relevance of risk factors for flucloxacillin DILI in relation to DILI due to other penicillins, we performed a genomewide association study involving 197 flucloxacillin DILI cases and 6,835 controls. We imputed single-nucleotide polymorphism and human leukocyte antigen (HLA) genotypes. HLA-B*57:01 was the major risk factor (allelic odds ratio (OR) = 36.62; P = 2.67 × 10-97 ). HLA-B*57:03 also showed an association (OR = 79.21; P = 1.2 × 10-6 ). Within the HLA-B protein sequence, imputation showed valine97 , common to HLA-B*57:01 and HLA-B*57:03, had the largest effect (OR = 38.1; P = 9.7 × 10-97 ). We found no HLA-B*57 association with DILI due to other isoxazolyl penicillins (n = 6) or amoxicillin (n = 15) and no significant non-HLA signals for any penicillin-related DILI.

12.
Neurology ; 92(3): e224-e233, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30578374

RESUMO

OBJECTIVE: To explore atrophy-deficit correlations of word comprehension and repetition in temporoparietal cortices encompassing the Wernicke area, based on patients with primary progressive aphasia (PPA). METHODS: Cortical thickness in regions within and outside the classical Wernicke area, measured by FreeSurfer, was correlated with repetition and single word comprehension scores in 73 right-handed patients at mild to moderate stages of PPA. RESULTS: Atrophy in the Wernicke area was correlated with repetition (r = 0.42, p = 0.001) but not single word comprehension (r = -0.072, p = 0.553). Correlations with word comprehension were confined to more anterior parts of the temporal lobe, especially its anterior third (r = 0.60, p < 0.001). A single case with postmortem autopsy illustrated preservation of word comprehension but not repetition 6 months prior to death despite nearly 50% loss of cortical volume and severe neurofibrillary degeneration in core components of the Wernicke area. CONCLUSIONS: Temporoparietal cortices containing the Wernicke area are critical for language repetition. Contrary to the formulations of classic aphasiology, their role in word and sentence comprehension is ancillary rather than critical. Thus, the Wernicke area is not sufficient to sustain word comprehension if the anterior temporal lobe is damaged. Traditional models of the role of the Wernicke area in comprehension are based almost entirely on patients with cerebrovascular lesions. Such lesions also cause deep white matter destruction and acute network diaschisis, whereas progressive neurodegenerative diseases associated with PPA do not. Conceptualizations of the Wernicke area that appear to conflict, therefore, can be reconciled by considering the hodologic and physiologic differences of the underlying lesions.


Assuntos
Afasia Primária Progressiva/patologia , Afasia Primária Progressiva/fisiopatologia , Compreensão/fisiologia , Lobo Temporal/patologia , Vocabulário , Área de Wernicke/patologia , Idoso , Afasia Primária Progressiva/diagnóstico por imagem , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Testes de Linguagem , Estudos Longitudinais , Imagem por Ressonância Magnética , Masculino
13.
Plant Cell Environ ; 42(1): 174-187, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29677403

RESUMO

Narrow-leafed lupin (Lupinus angustifolius L.) cultivation was transformed by 2 dominant vernalization-insensitive, early flowering time loci known as Ku and Julius (Jul), which allowed expansion into shorter season environments. However, reliance on these loci has limited genetic and phenotypic diversity for environmental adaptation in cultivated lupin. We recently predicted that a 1,423-bp deletion in the cis-regulatory region of LanFTc1, a FLOWERING LOCUS T (FT) homologue, derepressed expression of LanFTc1 and was the underlying cause of the Ku phenotype. Here, we surveyed diverse germplasm for LanFTc1 cis-regulatory variation and identified 2 further deletions of 1,208 and 5,162 bp in the 5' regulatory region, which overlap the 1,423-bp deletion. Additionally, we confirmed that no other polymorphisms were perfectly associated with vernalization responsiveness. Phenotyping and gene expression analyses revealed that Jul accessions possessed the 5,162-bp deletion and that the Jul and Ku deletions were equally capable of removing vernalization requirement and up-regulating gene expression. The 1,208-bp deletion was associated with intermediate phenology, vernalization responsiveness, and gene expression and therefore may be useful for expanding agronomic adaptation of lupin. This insertion/deletion series may also help resolve how the vernalization response is mediated at the molecular level in legumes.

14.
Plant Cell Environ ; 42(1): 6-19, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29603775

RESUMO

Our agricultural system and hence food security is threatened by combination of events, such as increasing population, the impacts of climate change, and the need to a more sustainable development. Evolutionary adaptation may help some species to overcome environmental changes through new selection pressures driven by climate change. However, success of evolutionary adaptation is dependent on various factors, one of which is the extent of genetic variation available within species. Genomic approaches provide an exceptional opportunity to identify genetic variation that can be employed in crop improvement programs. In this review, we illustrate some of the routinely used genomics-based methods as well as recent breakthroughs, which facilitate assessment of genetic variation and discovery of adaptive genes in legumes. Although additional information is needed, the current utility of selection tools indicate a robust ability to utilize existing variation among legumes to address the challenges of climate uncertainty.

15.
mSphere ; 3(5)2018 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-30355664

RESUMO

Genome-wide association studies (GWAS) can identify genetic variants responsible for naturally occurring and quantitative phenotypic variation. Association studies therefore provide a powerful complement to approaches that rely on de novo mutations for characterizing gene function. Although bacteria should be amenable to GWAS, few GWAS have been conducted on bacteria, and the extent to which nonindependence among genomic variants (e.g., linkage disequilibrium [LD]) and the genetic architecture of phenotypic traits will affect GWAS performance is unclear. We apply association analyses to identify candidate genes underlying variation in 20 biochemical, growth, and symbiotic phenotypes among 153 strains of Ensifer meliloti For 11 traits, we find genotype-phenotype associations that are stronger than expected by chance, with the candidates in relatively small linkage groups, indicating that LD does not preclude resolving association candidates to relatively small genomic regions. The significant candidates show an enrichment for nucleotide polymorphisms (SNPs) over gene presence-absence variation (PAV), and for five traits, candidates are enriched in large linkage groups, a possible signature of epistasis. Many of the variants most strongly associated with symbiosis phenotypes were in genes previously identified as being involved in nitrogen fixation or nodulation. For other traits, apparently strong associations were not stronger than the range of associations detected in permuted data. In sum, our data show that GWAS in bacteria may be a powerful tool for characterizing genetic architecture and identifying genes responsible for phenotypic variation. However, careful evaluation of candidates is necessary to avoid false signals of association.IMPORTANCE Genome-wide association analyses are a powerful approach for identifying gene function. These analyses are becoming commonplace in studies of humans, domesticated animals, and crop plants but have rarely been conducted in bacteria. We applied association analyses to 20 traits measured in Ensifer meliloti, an agriculturally and ecologically important bacterium because it fixes nitrogen when in symbiosis with leguminous plants. We identified candidate alleles and gene presence-absence variants underlying variation in symbiosis traits, antibiotic resistance, and use of various carbon sources; some of these candidates are in genes previously known to affect these traits whereas others were in genes that have not been well characterized. Our results point to the potential power of association analyses in bacteria, but also to the need to carefully evaluate the potential for false associations.


Assuntos
Estudos de Associação Genética , Estudo de Associação Genômica Ampla/métodos , Sinorhizobium meliloti/genética
16.
Theor Appl Genet ; 131(12): 2543-2554, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30225643

RESUMO

KEY MESSAGE: This study revealed that the western Mediterranean provided the founder population for domesticated narrow-leafed lupin and that genetic diversity decreased significantly during narrow-leafed lupin domestication. The evolutionary history of plants during domestication profoundly shaped the genome structure and genetic diversity of today's crops. Advances in next-generation sequencing technologies allow unprecedented opportunities to understand genome evolution in minor crops, which constitute the majority of plant domestications. A diverse set of 231 wild and domesticated narrow-leafed lupin (Lupinus angustifolius L.) accessions were subjected to genotyping-by-sequencing using diversity arrays technology. Phylogenetic, genome-wide divergence and linkage disequilibrium analyses were applied to identify the founder population of domesticated narrow-leafed lupin and the genome-wide effect of domestication on its genome. We found wild western Mediterranean population as the founder of domesticated narrow-leafed lupin. Domestication was associated with an almost threefold reduction in genome diversity in domesticated accessions compared to their wild relatives. Selective sweep analysis identified no significant footprints of selection around domestication loci. A genome-wide association study identified single nucleotide polymorphism markers associated with pod dehiscence. This new understanding of the genomic consequences of narrow-leafed lupin domestication along with molecular marker tools developed here will assist plant breeders more effectively access wild genetic diversity for crop improvement.


Assuntos
Evolução Biológica , Variação Genética , Genética Populacional , Genoma de Planta , Lupinus/genética , Produtos Agrícolas/genética , Domesticação , Desequilíbrio de Ligação , Região do Mediterrâneo , Fenótipo , Filogenia , Polimorfismo de Nucleotídeo Único , Seleção Genética
17.
Can J Cardiol ; 34(7): 850-862, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29960614

RESUMO

Worldwide, more than 230 million adults have major noncardiac surgery each year. Although surgery can improve quality and duration of life, it can also precipitate major complications. Moreover, a substantial proportion of deaths occur after discharge. Current systems for monitoring patients postoperatively, on surgical wards and after transition to home, are inadequate. On the surgical ward, vital signs evaluation usually occurs only every 4-8 hours. Reduced in-hospital ward monitoring, followed by no vital signs monitoring at home, leads to thousands of cases of undetected/delayed detection of hemodynamic compromise. In this article we review work to date on postoperative remote automated monitoring on surgical wards and strategy for advancing this field. Key considerations for overcoming current barriers to implementing remote automated monitoring in Canada are also presented.


Assuntos
Monitorização Fisiológica/métodos , Cuidados Pós-Operatórios/métodos , Procedimentos Cirúrgicos Operatórios , Telemedicina/métodos , Sinais Vitais/fisiologia , Humanos
18.
Microb Genom ; 4(5)2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29671722

RESUMO

Ensifer meliloti (formerly Rhizobium meliloti and Sinorhizobium meliloti) is a model bacterium for understanding legume-rhizobial symbioses. The tripartite genome of E. meliloti consists of a chromosome, pSymA and pSymB, and in some instances strain-specific accessory plasmids. The majority of previous sequencing studies have relied on the use of assemblies generated from short read sequencing, which leads to gaps and assembly errors. Here we used PacBio-based, long-read assemblies and were able to assemble, de novo, complete circular replicons. In this study, we sequenced, de novo-assembled and analysed 10 E. meliloti strains. Sequence comparisons were also done with data from six previously published genomes. We identified genome differences between the replicons, including mol% G+C and gene content, nucleotide repeats, and transposon-associated loci. Additionally, genomic rearrangements both within and between replicons were identified, providing insight into evolutionary processes at the structural level. There were few cases of inter-replicon gene transfer of core genes between the main replicons. Accessory plasmids were more similar to pSymA than to either pSymB or the chromosome, with respect to gene content, transposon content and G+C content. In our population, the accessory plasmids appeared to share an open genome with pSymA, which contains many nodulation- and nitrogen fixation-related genes. This may explain previous observations that horizontal gene transfer has a greater effect on the content of pSymA than pSymB, or the chromosome, and why some rhizobia show unstable nodulation phenotypes on legume hosts.


Assuntos
Elementos de DNA Transponíveis/genética , Loci Gênicos , Genoma Bacteriano , Replicon , Sinorhizobium meliloti/genética , Animais , Proteínas de Bactérias/genética , Composição de Bases , Cromossomos Bacterianos , Evolução Molecular , Fabaceae/microbiologia , Transferência Genética Horizontal , Genômica , Fixação de Nitrogênio/genética , Nodulação/genética , Plasmídeos , Rhizobium/genética , Rhizobium/metabolismo , Análise de Sequência de DNA , Sinorhizobium meliloti/metabolismo
19.
J Biol Chem ; 293(23): 9078-9089, 2018 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-29695503

RESUMO

Genetically targeting biological systems to control cellular processes with light is the concept of optogenetics. Despite impressive developments in this field, underlying molecular mechanisms of signal transduction of the employed photoreceptor modules are frequently not sufficiently understood to rationally design new optogenetic tools. Here, we investigate the requirements for functional coupling of red light-sensing phytochromes with non-natural enzymatic effectors by creating a series of constructs featuring the Deinococcus radiodurans bacteriophytochrome linked to a Synechocystis guanylate/adenylate cyclase. Incorporating characteristic structural elements important for cyclase regulation in our designs, we identified several red light-regulated fusions with promising properties. We provide details of one light-activated construct with low dark-state activity and high dynamic range that outperforms previous optogenetic tools in vitro and expands our in vivo toolkit, as demonstrated by manipulation of Caenorhabditis elegans locomotor activity. The full-length crystal structure of this phytochrome-linked cyclase revealed molecular details of photoreceptor-effector coupling, highlighting the importance of the regulatory cyclase element. Analysis of conformational dynamics by hydrogen-deuterium exchange in different functional states enriched our understanding of phytochrome signaling and signal integration by effectors. We found that light-induced conformational changes in the phytochrome destabilize the coiled-coil sensor-effector linker, which releases the cyclase regulatory element from an inhibited conformation, increasing cyclase activity of this artificial system. Future designs of optogenetic functionalities may benefit from our work, indicating that rational considerations for the effector improve the rate of success of initial designs to obtain optogenetic tools with superior properties.


Assuntos
Adenilil Ciclases/genética , Deinococcus/genética , Guanilato Ciclase/genética , Optogenética/métodos , Fitocromo/genética , Synechocystis/enzimologia , Adenilil Ciclases/química , Sequência de Aminoácidos , Animais , Caenorhabditis elegans , Cristalografia por Raios X , Deinococcus/química , Guanilato Ciclase/química , Luz , Simulação de Dinâmica Molecular , Fitocromo/química , Conformação Proteica , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/genética , Synechocystis/genética
20.
Am J Community Psychol ; 61(3-4): 285-295, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29512822

RESUMO

This study explores the relationship between mental health and place at microgeographic units of analysis. We examine self-reported symptomology for depression and PTSD for 2,724 survey respondents interviewed in three types of randomly selected street segments: violent crime hot spots, cool spots, and cold spots. We find that the mean symptomology score is 61% higher for depression in violent crime hot spots than cold spots, and 85% higher for PTSD. Overall, we estimate that 14.8% of residents of violent crime hot spots meet thresholds for moderate depression or a diagnosis of PTSD. This can be compared to only 6.5% of residents at the cold spots. Using PSM and weighted negative binomial regression approaches we show that observable selection factors are not responsible for the relationships identified. Examining geographic influences, we find an important area effect of violent crime for both mental health measures, and an additional impact of the specific street of residence for PTSD.


Assuntos
Crime/psicologia , Depressão/epidemiologia , Depressão/etiologia , Saúde Mental , Transtornos de Estresse Pós-Traumáticos/epidemiologia , Transtornos de Estresse Pós-Traumáticos/etiologia , Baltimore/epidemiologia , Feminino , Humanos , Masculino , Inquéritos e Questionários , Violência
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