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Nephronophthisis (NPH) is an autosomal recessive tubulointerstitial nephropathy belonging to the ciliopathy disorders and known as the most common cause of hereditary end-stage renal disease in children. Yet, no curative treatment is available. The major gene, NPHP1, encodes a protein playing key functions at the primary cilium and cellular junctions. Using a medium-throughput drug-screen in NPHP1 knockdown cells, we identified 51 Food and Drug Administration-approved compounds by their ability to alleviate the cellular phenotypes associated with the loss of NPHP1; 11 compounds were further selected for their physicochemical properties. Among those compounds, prostaglandin E1 (PGE1) rescued ciliogenesis defects in immortalized patient NPHP1 urine-derived renal tubular cells, and improved ciliary and kidney phenotypes in our NPH zebrafish and Nphp1 knockout mouse models. Furthermore, Taprenepag, a nonprostanoid prostaglandin E2 receptor agonist, alleviated the severe retinopathy observed in Nphp1−/− mice. Finally, comparative transcriptomics allowed identification of key signaling pathways downstream PGE1, including cell cycle progression, extracellular matrix, adhesion, or actin cytoskeleton organization. In conclusion, using in vitro and in vivo models, we showed that prostaglandin E2 receptor agonists can ameliorate several of the pleotropic phenotypes caused by the absence of NPHP1; this opens their potential as a first therapeutic option for juvenile NPH-associated ciliopathies.
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Ciliopatias , Doenças Renais Policísticas , Animais , Cílios/metabolismo , Ciliopatias/tratamento farmacológico , Ciliopatias/genética , Ciliopatias/metabolismo , Feminino , Humanos , Doenças Renais Císticas/congênito , Masculino , Camundongos , Doenças Renais Policísticas/metabolismo , Prostaglandinas/metabolismo , Receptores de Prostaglandina E/metabolismo , Peixe-ZebraRESUMO
Nephronophthisis is an autosomal recessive tubulointerstitial nephropathy, belonging to the ciliopathy disorders, characterized by fibrosis and/or cysts. It is the most common genetic cause of kidney failure in children and young adults. Clinically and genetically heterogeneous, it is caused by variants in ciliary genes, resulting in either an isolated kidney disease or syndromic forms in association with other manifestations of ciliopathy disorders. No curative treatment is currently available. Over the past 2 decades, advances in understanding disease mechanisms have identified several dysregulated signaling pathways, some shared with other cystic kidney diseases. Notably, molecules previously developed to target these pathways have shown promising beneficial effects in orthologous mouse models. In addition to these knowledge-based repurposing approaches, unbiased "in cellulo" phenotypic screens of "repurposing" libraries identified small molecules able to rescue the ciliogenesis defects observed in nephronophthisis conditions. Those compounds appeared to act on relevant pathways and, when tested, showed beneficial nephronophthisis-associated kidney and/or extrarenal defects in mice. In this review, we have summarized those studies that highlight the drug repurposing strategies in the context of a rare disorders, such as nephronophthisis-related ciliopathies, with broad genetic heterogeneity and systemic manifestations but with shared disease mechanisms.
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Ciliopatias , Doenças Renais Císticas , Doenças Renais Policísticas , Insuficiência Renal , Animais , Camundongos , Rim/patologia , Doenças Renais Policísticas/genética , Doenças Renais Císticas/tratamento farmacológico , Doenças Renais Císticas/genética , Ciliopatias/tratamento farmacológico , Ciliopatias/genética , Insuficiência Renal/complicações , Fibrose , Cílios/patologiaRESUMO
Genomic plasticity mediated by transposable elements can have a dramatic impact on genome integrity. To minimize its genotoxic effects, it is tightly regulated either by intrinsic mechanisms (linked to the element itself) or by host-mediated mechanisms. Using mass spectrometry, we show here for the first time that MOS1, the transposase driving the mobility of the mariner Mos1 element, is phosphorylated. We also show that the transposition activity of MOS1 is downregulated by protein kinase AMP cyclic-dependent phosphorylation at S170, which renders the transposase unable to promote Mos1 transposition. One step in the transposition cycle, the assembly of the paired-end complex, is specifically inhibited. At the cellular level, we provide evidence that phosphorylation at S170 prevents the active transport of the transposase into the nucleus. Our data suggest that protein kinase AMP cyclic-dependent phosphorylation may play a double role in the early stages of genome invasion by mariner elements.
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Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Proteínas de Ligação a DNA/metabolismo , Transposases/metabolismo , Animais , Linhagem Celular , Proteínas de Ligação a DNA/química , Espectrometria de Massas , Fosforilação , Serina/metabolismo , Spodoptera , Transposases/químicaRESUMO
Correct positioning of neurotransmitter-gated receptors at postsynapses is essential for synaptic transmission. At Caenorhabditis elegans neuromuscular junctions, clustering of levamisole-sensitive acetylcholine receptors (L-AChRs) requires the muscle-secreted scaffolding protein LEV-9, a multidomain factor containing complement control protein (CCP) modules. Here we show that LEV-9 needs to be cleaved at its C terminus to exert its function. LEV-9 cleavage is not required for trafficking nor secretion but directly controls scaffolding activity. The cleavage site is evolutionarily conserved, and post-translational cleavage ensures the structural and functional decoupling between different isoforms encoded by the lev-9 gene. Data mining indicates that most human CCP-containing factors are likely cleaved C-terminally from CCP tandems, suggesting that not only domain architectures but also cleavage location can be conserved in distant architecturally related proteins.
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Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/metabolismo , Processamento de Proteína Pós-Traducional/fisiologia , Proteólise , Receptores Colinérgicos/metabolismo , Animais , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Linhagem Celular , Humanos , Junção Neuromuscular/genética , Junção Neuromuscular/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Transporte Proteico/fisiologia , Receptores Colinérgicos/genéticaRESUMO
Genome sequence comparisons have highlighted many novel gene families that are conserved across animal phyla but whose biological function is unknown. Here, we functionally characterize a member of one such family, the macoilins. Macoilins are characterized by several highly conserved predicted transmembrane domains towards the N-terminus and by coiled-coil regions C-terminally. They are found throughout Eumetazoa but not in other organisms. Mutants for the single Caenorhabditis elegans macoilin, maco-1, exhibit a constellation of behavioral phenotypes, including defects in aggregation, O2 responses, and swimming. MACO-1 protein is expressed broadly and specifically in the nervous system and localizes to the rough endoplasmic reticulum; it is excluded from dendrites and axons. Apart from subtle synapse defects, nervous system development appears wild-type in maco-1 mutants. However, maco-1 animals are resistant to the cholinesterase inhibitor aldicarb and sensitive to levamisole, suggesting pre-synaptic defects. Using in vivo imaging, we show that macoilin is required to evoke Ca²(+) transients, at least in some neurons: in maco-1 mutants the O2-sensing neuron PQR is unable to generate a Ca²(+) response to a rise in O2. By genetically disrupting neurotransmission, we show that pre-synaptic input is not necessary for PQR to respond to O2, indicating that the response is mediated by cell-intrinsic sensory transduction and amplification. Disrupting the sodium leak channels NCA-1/NCA-2, or the N-,P/Q,R-type voltage-gated Ca²(+) channels, also fails to disrupt Ca²(+) responses in the PQR cell body to O2 stimuli. By contrast, mutations in egl-19, which encodes the only Caenorhabditis elegans L-type voltage-gated Ca²(+) channel α1 subunit, recapitulate the Ca²(+) response defect we see in maco-1 mutants, although we do not see defects in localization of EGL-19. Together, our data suggest that macoilin acts in the ER to regulate assembly or traffic of ion channels or ion channel regulators.
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Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Retículo Endoplasmático/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Neurônios/metabolismo , Aldicarb/farmacologia , Sequência de Aminoácidos , Animais , Antinematódeos/farmacologia , Axônios/metabolismo , Comportamento Animal/fisiologia , Caenorhabditis elegans/classificação , Caenorhabditis elegans/efeitos dos fármacos , Proteínas de Caenorhabditis elegans/química , Cálcio/metabolismo , Canais Iônicos/metabolismo , Levamisol/farmacologia , Proteínas de Membrana/química , Dados de Sequência Molecular , Mutação/genética , Neurônios/citologia , Filogenia , Alinhamento de Sequência , Sinapses/metabolismoRESUMO
BACKGROUND: The heterogeneous nature and determinants of stroke among different Hispanic groups was examined by comparing hospitalized Hispanic stroke patients in Miami, where the Hispanic population is largely of Caribbean origin, to a Mestizo population in Mexico City. METHODS: Consecutive Hispanic patients who were admitted with stroke or transient ischemic attack (TIA) and included in the prospective stroke registries of 2 tertiary care teaching hospitals were studied. Demographic factors, stroke subtypes, vascular risk factors, stroke severity, and outcomes were compared. Vascular risk factor definitions were standardized. RESULTS: A total of 928 patients (520 Mexicans and 408 Miami Hispanics) were analyzed. Mexicans were younger, with a greater proportion of women. More cerebral venous thromboses (CVTs) were admitted in Mexico, while TIA and stroke mimics were more commonly admitted in Miami; cardioembolic strokes were more commonly ascertained in Miami, and more cryptogenic strokes in Mexico. Stroke severity was similar for intracerebral hemorrhages, but more severe ischemic strokes and CVTs were included in the Mexican registry. Outcome at 1 and 3 months was similar in both registries after adjusting for age and baseline stroke severity. After adjusting for age and sex, hypertension, dyslipidemia, and atrial fibrillation were more frequent, and diabetes mellitus was less frequent, among Miami Hispanics compared to Mexicans. CONCLUSIONS: We found significant differences in the frequency of hypertension, diabetes, dyslipidemia, and atrial fibrillation in Miami Hispanics and Mexican stroke patients, highlighting the heterogeneity of the Hispanic ethnic group. Future studies are needed to clarify the relative contribution of genetic and environmental disparities amongst Mexican and Caribbean Hispanic stroke patients.
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Disparidades nos Níveis de Saúde , Hispânico ou Latino , Ataque Isquêmico Transitório/etnologia , Grupos Minoritários , Acidente Vascular Cerebral/etnologia , Saúde da População Urbana/etnologia , Idoso , Idoso de 80 Anos ou mais , Fibrilação Atrial/etnologia , Distribuição de Qui-Quadrado , Diabetes Mellitus/etnologia , Dislipidemias/etnologia , Feminino , Florida/epidemiologia , Cardiopatias/etnologia , Hospitalização , Hospitais de Ensino , Humanos , Hipertensão/etnologia , Embolia Intracraniana/etnologia , Trombose Intracraniana/etnologia , Ataque Isquêmico Transitório/diagnóstico , Modelos Logísticos , Masculino , México/epidemiologia , Pessoa de Meia-Idade , Análise Multivariada , Razão de Chances , Prevalência , Prognóstico , Sistema de Registros , Fatores de Risco , Índice de Gravidade de Doença , Acidente Vascular Cerebral/diagnóstico , Centros de Atenção Terciária , Fatores de Tempo , Trombose Venosa/etnologiaRESUMO
Pharmacological adaptation is a common phenomenon observed during prolonged drug exposure and often leads to drug resistance. Understanding the cellular events involved in adaptation could provide new strategies to circumvent this resistance issue. We used the nematode Caenorhabditis elegans to analyze the adaptation to levamisole, an ionotropic acetylcholine receptor agonist, used for decades to treat nematode parasitic infections. Genetic screens in C. elegans identified "adapting mutants" that initially paralyze upon exposure to levamisole as the wild type (WT), but recover locomotion after a few hours whereas WT remain paralyzed. Here, we show that levamisole induces a sustained increase in cytosolic calcium concentration in the muscle cells of adapting mutants, lasting several hours and preceding a decrease in levamisole-sensitive acetylcholine receptors (L-AChR) at the muscle plasma membrane. This decrease correlated with a drop in calcium concentration, a relaxation of the animal's body and a resumption of locomotion. The decrease in calcium and L-AChR content depends on calcineurin activation in muscle cells. We also showed that levamisole adaptation triggers homeostatic mechanisms in muscle cells including mitochondria remodeling, lysosomal tubulation and an increase in autophagic activity. Levamisole adaptation thus provides a new experimental paradigm for studying how cells cope with calcium stress.
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Caenorhabditis elegans , Calcineurina , Animais , Cálcio , Levamisol/farmacologia , Células Musculares , Receptores ColinérgicosRESUMO
Autosomal recessive whole gene deletions of nephrocystin-1 (NPHP1) result in abnormal structure and function of the primary cilia. These deletions can result in a tubulointerstitial kidney disease known as nephronophthisis and retinal (Senior-Løken syndrome) and neurological (Joubert syndrome) diseases. Nephronophthisis is a common cause of end-stage kidney disease (ESKD) in children and up to 1% of adult onset ESKD. Single nucleotide variants (SNVs) and small insertions and deletions (Indels) have been less well characterised. We used a gene pathogenicity scoring system (GenePy) and a genotype-to-phenotype approach on individuals recruited to the UK Genomics England (GEL) 100,000 Genomes Project (100kGP) (n = 78,050). This approach identified all participants with NPHP1-related diseases reported by NHS Genomics Medical Centres and an additional eight participants. Extreme NPHP1 gene scores, often underpinned by clear recessive inheritance, were observed in patients from diverse recruitment categories, including cancer, suggesting the possibility of a more widespread disease than previously appreciated. In total, ten participants had homozygous CNV deletions with eight homozygous or compound heterozygous with SNVs. Our data also reveals strong in-silico evidence that approximately 44% of NPHP1 related disease may be due to SNVs with AlphaFold structural modelling evidence for a significant impact on protein structure. This study suggests historical under-reporting of SNVS in NPHP1 related diseases compared with CNVs.
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Doenças Renais Císticas , Falência Renal Crônica , Humanos , Proteínas de Membrana/genética , Proteínas do Citoesqueleto/genética , Doenças Renais Císticas/genética , Falência Renal Crônica/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Homozigoto , Fenótipo , Nucleotídeos , Reino UnidoRESUMO
A timely diagnosis is a key challenge for many rare diseases. As an expanding group of rare and severe monogenic disorders with a broad spectrum of clinical manifestations, ciliopathies, notably renal ciliopathies, suffer from important underdiagnosis issues. Our objective is to develop an approach for screening large-scale clinical data warehouses and detecting patients with similar clinical manifestations to those from diagnosed ciliopathy patients. We expect that the top-ranked similar patients will benefit from genetic testing for an early diagnosis. The dependence and relatedness between phenotypes were taken into account in our similarity model through medical concept embedding. The relevance of each phenotype to each patient was also considered by adjusted aggregation of phenotype similarity into patient similarity. A ranking model based on the best-subtype-average similarity was proposed to address the phenotypic overlapping and heterogeneity of ciliopathies. Our results showed that using less than one-tenth of learning sources, our language and center specific embedding provided comparable or better performances than other existing medical concept embeddings. Combined with the best-subtype-average ranking model, our patient-patient similarity-based screening approach was demonstrated effective in two large scale unbalanced datasets containing approximately 10,000 and 60,000 controls with kidney manifestations in the clinical data warehouse (about 2 and 0.4% of prevalence, respectively). Our approach will offer the opportunity to identify candidate patients who could go through genetic testing for ciliopathy. Earlier diagnosis, before irreversible end-stage kidney disease, will enable these patients to benefit from appropriate follow-up and novel treatments that could alleviate kidney dysfunction.
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The roles of quantum correlations, entanglement, discord, and dissonance needed for performing unambiguous quantum state discrimination assisted by an auxiliary system are studied. In general, this procedure for conclusive recognition between two nonorthogonal states relies on the availability of entanglement and discord. However, we find that there exist special cases for which the procedure can be successfully achieved without entanglement. In particular, we show that the optimal case for discriminating between two nonorthogonal states prepared with equal a priori probabilities does not require entanglement but quantum dissonance only.
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Background Reports on sex differences in stroke outcome and risk factors are scarce in Latin America. Our objective was to analyze clinical and prognostic differences according to sex among participants in the LASE (Latin American Stroke Registry). Methods and Results Nineteen centers across Central and South America compiled data on demographics, vascular risk factors, clinical stroke description, ancillary tests, and functional outcomes at short-term follow-up of patients included from January 2012 to January 2017. For the present study, all these variables were analyzed according to sex at hospital discharge. We included 4788 patients with a median in-hospital stay of 8 days (interquartile range, 5-8); 2677 were male (median age, 66 years) and 2111 female (median age, 60 years). Ischemic stroke occurred in 4293: 3686 as cerebral infarction (77%) and 607 as transient ischemic attack cases (12.7%); 495 patients (10.3%) corresponded to intracerebral hemorrhage. Poor functional outcome (modified Rankin scale, 3-6) was present in 1662 (34.7%) patients and 38.2% of women (P<0.001). Mortality was present in 6.8% of the registry, with 7.8% in women compared with 6.0% in men (P=0.01). Death and poor functional outcome for all-type stroke showed a higher risk in female patients (hazard ratio, 1.3, P=0.03; and hazard ratio, 1.1, P=0.001, respectively). Conclusions A worse functional outcome and higher mortality rates occurred in women compared with men in the LASE, confirming sex differences issues at short-term follow-up.
Assuntos
Disparidades nos Níveis de Saúde , Disparidades em Assistência à Saúde , Acidente Vascular Cerebral/terapia , Idoso , Idoso de 80 Anos ou mais , América Central/epidemiologia , Feminino , Estado Funcional , Humanos , Masculino , Pessoa de Meia-Idade , Recuperação de Função Fisiológica , Sistema de Registros , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores Sexuais , América do Sul/epidemiologia , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/mortalidade , Fatores de Tempo , Resultado do TratamentoRESUMO
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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Mining the antibody repertoire of plasma cells and plasmablasts could enable the discovery of useful antibodies for therapeutic or research purposes1. We present a method for high-throughput, single-cell screening of IgG-secreting primary cells to characterize antibody binding to soluble and membrane-bound antigens. CelliGO is a droplet microfluidics system that combines high-throughput screening for IgG activity, using fluorescence-based in-droplet single-cell bioassays2, with sequencing of paired antibody V genes, using in-droplet single-cell barcoded reverse transcription. We analyzed IgG repertoire diversity, clonal expansion and somatic hypermutation in cells from mice immunized with a vaccine target, a multifunctional enzyme or a membrane-bound cancer target. Immunization with these antigens yielded 100-1,000 IgG sequences per mouse. We generated 77 recombinant antibodies from the identified sequences and found that 93% recognized the soluble antigen and 14% the membrane antigen. The platform also allowed recovery of ~450-900 IgG sequences from ~2,200 IgG-secreting activated human memory B cells, activated ex vivo, demonstrating its versatility.
Assuntos
Anticorpos/genética , Sequenciamento de Nucleotídeos em Larga Escala , Técnicas Analíticas Microfluídicas/instrumentação , Análise de Célula Única , Animais , Antígenos/imunologia , Linfócitos B/imunologia , Vacinas Anticâncer/imunologia , DNA/análise , DNA/genética , Sequenciamento de Nucleotídeos em Larga Escala/instrumentação , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Imunoglobulina G/genética , Camundongos , Análise de Célula Única/instrumentação , Análise de Célula Única/métodosRESUMO
Studies of the dynamics of the antibody-mediated immune response have been hampered by the absence of quantitative, high-throughput systems to analyze individual antibody-secreting cells. Here we describe a simple microfluidic system, DropMap, in which single cells are compartmentalized in tens of thousands of 40-pL droplets and analyzed in two-dimensional droplet arrays using a fluorescence relocation-based immunoassay. Using DropMap, we characterized antibody-secreting cells in mice immunized with tetanus toxoid (TT) over a 7-week protocol, simultaneously analyzing the secretion rate and affinity of IgG from over 0.5 million individual cells enriched from spleen and bone marrow. Immunization resulted in dramatic increases in the range of both single-cell secretion rates and affinities, which spanned at maximum 3 and 4 logs, respectively. We observed differences over time in dynamics of secretion rate and affinity within and between anatomical compartments. This system will not only enable immune monitoring and optimization of immunization and vaccination protocols but also potentiate antibody screening.
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Imunoglobulina G/metabolismo , Monitorização Imunológica/métodos , Análise de Célula Única/métodos , Animais , Células CHO , Calibragem , Cricetinae , Cricetulus , Imunização , Camundongos Endogâmicos C57BL , Fenótipo , Fatores de TempoRESUMO
Enzymes that efficiently hydrolyze highly toxic organophosphorus nerve agents could potentially be used as medical countermeasures. As sufficiently active enzymes are currently unknown, we synthesized twelve fluorogenic analogues of organophosphorus nerve agents with the 3-chloro-7-oxy-4-methylcoumarin leaving group as probes for high-throughput enzyme screening. This set included analogues of the pesticides paraoxon, parathion, and dimefox, and the nerve agents DFP, tabun, sarin, cyclosarin, soman, VX, and Russian-VX. Data from inhibition of acetylcholinesterase, in vivo toxicity tests of a representative analogue (cyclosarin), and kinetic studies with phosphotriesterase (PTE) from Pseudomonas diminuta, and a mammalian serum paraoxonase (PON1), confirmed that the analogues mimic the parent nerve agents effectively. They are suitable tools for high-throughput screens for the directed evolution of efficient nerve agent organophosphatases.
Assuntos
Acetilcolinesterase/efeitos dos fármacos , Substâncias para a Guerra Química/química , Inibidores da Colinesterase/química , Corantes Fluorescentes/química , Compostos Organofosforados/química , Compostos Organotiofosforados/toxicidade , Hidrolases de Triester Fosfórico/química , Animais , Arildialquilfosfatase/química , Substâncias para a Guerra Química/toxicidade , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/toxicidade , Cumarínicos/química , Avaliação Pré-Clínica de Medicamentos/métodos , Cobaias , Hidrólise , Cinética , Masculino , Estrutura Molecular , Compostos Organofosforados/síntese química , Compostos Organofosforados/toxicidade , Compostos Organotiofosforados/química , Praguicidas/química , Relação Estrutura-AtividadeRESUMO
Upon fertilization, the highly specialised sperm and oocyte genomes are remodelled to confer totipotency. The mechanisms of the dramatic reprogramming events that occur have remained unknown, and presumed roles of histone modifying enzymes are just starting to be elucidated. Here, we explore the function of the oocyte-inherited pool of a histone H3K4 and K9 demethylase, LSD1/KDM1A during early mouse development. KDM1A deficiency results in developmental arrest by the two-cell stage, accompanied by dramatic and stepwise alterations in H3K9 and H3K4 methylation patterns. At the transcriptional level, the switch of the maternal-to-zygotic transition fails to be induced properly and LINE-1 retrotransposons are not properly silenced. We propose that KDM1A plays critical roles in establishing the correct epigenetic landscape of the zygote upon fertilization, in preserving genome integrity and in initiating new patterns of genome expression that drive early mouse development.
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Cromatina/metabolismo , Desenvolvimento Embrionário , Regulação da Expressão Gênica no Desenvolvimento , Histona Desmetilases/metabolismo , Transcrição Gênica , Zigoto/enzimologia , Zigoto/fisiologia , Animais , Epigênese Genética , Camundongos , Oócitos/enzimologia , Oócitos/fisiologiaRESUMO
The crystal structures of the two title piperidine derivatives show different conformations for the six-membered heterocycle. The N-substituted 4-piperidinone 1-[(1R)-2-hy-droxy-1-phenyl-eth-yl]piperidin-4-one, C13H17NO2, (I), has a chair conformation, while the piperidine substituted in position 2 with a thio-carbonyl group, 8-[(1S)-1-phenyl-eth-yl]-1,4-dioxa-8-aza-spiro-[4.5]decane-7-thione, C15H19NO2S, (II), features a half-chair conformation. Comparison of the two structures, and data retrieved from the literature, suggests that the conformational flexibility is mainly related to the hybridization state of the C atom α to the piperidinic N atom: a Csp (3) atom favours the chair conformer, while a Csp (2) atom distorts the ring towards a half-chair conformer. In the crystal structure of (I), weak C-Hâ¯O hydrogen bonds link the mol-ecules into supra-molecular chains propagating along the b-axis direction. In the crystal of (II), the mol-ecules are linked by weak C-Hâ¯S contacts into supra-molecular chains propagating along the b-axis direction.
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RESUMEN PROPÓSITO: En marzo 11 del 2020 la Organización Mundial de la Salud declara la pandemia por Covid-19. El clínico se va enfrentar a pacientes con ataque cerebrovascular (ACV) y sospecha o presencia de la infección. Miembros participantes del comité vascular de la Asociación Colombiana de Neurología basados en la experticia y la literatura amplían las primeras recomendaciones en el manejo de los pacientes con ACV isquémico agudo durante la actual pandemia. MÉTODOS: Mediante reuniones virtuales y por consenso de los participantes se escogieron tres ejes de trabajo: Tamización para Covid-19, Medidas de bioseguridad y Aspectos relevantes del ACV isquémico en época de pandemia por Covid-19. Se desarrollaron los ejes por grupos de trabajo mediante la modalidad de pregunta-respuesta pretendiendo generar en cada una de ellas recomendaciones sobre el tema. La versión final del documento conto con la revisión y el aval de todos los participantes. RESULTADOS: El documento cuenta con tres secciones correspondientes a los ejes de trabajo. En el primer eje se responden 3 preguntas y se dan recomendaciones sobre la tamización de la infección por Covid-19 en ACV agudo. En el segundo se responden 8 preguntas y se dan recomendaciones sobre las medidas de bioseguridad en la atención de pacientes con ACV durante la pandemia. En el tercero se tratan 13 aspectos relevantes del ACV durante la pandemia, según criterio de los participantes, y se dan recomendaciones pertinentes. CONCLUSIÓN: Las recomendaciones son basadas en la literatura y consenso de los participantes para el cuidado de pacientes con ACV isquémico agudo con sospecha o infección por Covid-19. No pretenden reemplazar las guías o protocolos establecidos sino ampliar las primeras recomendaciones del comité y apoyar al clínico en la atención de pacientes con ACV isquémico durante la pandemia.
SUMMARY PURPOSE: The World Health Organization declared the COVID-19 pandemic on March 11th 2020. Clinicians will face patients with stroke and confirmed or suspected infection. Members of the Stroke Committee of the Colombian Neurological Association based on their expertise and literature review extend on the first recommendations on acute ischemic stroke management during the pandemic. METHODS: Through virtual meetings and by consensus of participants three topics were selected: COVID-19 screening, biosafety measures and relevant aspects of acute ischemic stroke care during the pandemic. A question and answer format was used to develop recommendations for each topic. RESULTS: The manuscript is divided into three sections. The first includes three questions and recommendations on screening for COVID-19 in stroke patients. The second includes 8 questions and recommendations on biosafety measures on stroke patients during the pandemic. The last section includes 13 relevant stroke topics during COVID-19 pandemic, as deemed by the authors, and their recommendations. CONCLUSIONS: Recommendations on stroke care and COVID-19 are based on literature review and expert consensus. The aim of the manuscript is to extend on the first recommendations forwarded by the Committee, not to replace current guidelines, and to support the clinician caring for stroke patients during the pandemic.
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Mobilidade UrbanaRESUMO
Chiral, non-racemic hexahydro-oxazolo[3,2-a]pyridin-5-ones are strategic starting materials for the asymmetric synthesis of alkaloids, via the stereoselective C-C bond formation at the position a to the nitrogen atom. The stereoselectivity of this key step is mainly driven by the geometry of the fused rings of the oxazolopyridine moiety. In this work, the synthesis and X-ray structure of trans(3R,2aS)-(-)-3-phenyl-hexahydro-oxazolo[3,2-a]pyridin-5-one is reported.