RESUMO
The cellular prion protein PrPC is necessary for prion replication, and its reduction greatly increases life expectancy in animal models of prion infection. Hence the factors controlling the levels of PrPC may represent therapeutic targets against human prion diseases. Here we performed an arrayed whole-transcriptome RNA interference screen to identify modulators of PrPC expression. We cultured human U251-MG glioblastoma cells in the presence of 64'752 unique siRNAs targeting 21'584 annotated human genes, and measured PrPC using a one-pot fluorescence-resonance energy transfer immunoassay in 51'128 individual microplate wells. This screen yielded 743 candidate regulators of PrPC. When downregulated, 563 of these candidates reduced and 180 enhanced PrPC expression. Recursive candidate attrition through multiple secondary screens yielded 54 novel regulators of PrPC, 9 of which were confirmed by CRISPR interference as robust regulators of PrPC biosynthesis and degradation. The phenotypes of 6 of the 9 candidates were inverted in response to transcriptional activation using CRISPRa. The RNA-binding post-transcriptional repressor Pumilio-1 was identified as a potent limiter of PrPC expression through the degradation of PRNP mRNA. Because of its hypothesis-free design, this comprehensive genetic-perturbation screen delivers an unbiased landscape of the genes regulating PrPC levels in cells, most of which were unanticipated, and some of which may be amenable to pharmacological targeting in the context of antiprion therapies.
Assuntos
Regulação da Expressão Gênica/fisiologia , Proteínas PrPC/biossíntese , Proteínas de Ligação a RNA/metabolismo , Linhagem Celular , Estudo de Associação Genômica Ampla , Humanos , Interferência de RNARESUMO
Avian influenza A(H5N8) virus has caused major epizootics in Europe since 2016. We conducted virologic analysis of aerosol and dust collected on poultry farms in France during 2020-2021. Our results suggest dust contributes to viral dispersal, even early in an outbreak, and could be a valuable surveillance tool.
Assuntos
Vírus da Influenza A Subtipo H5N8 , Influenza Aviária , Influenza Humana , Doenças das Aves Domésticas , Animais , Animais Selvagens , Aves , Surtos de Doenças/veterinária , Poeira , Fazendas , França/epidemiologia , Humanos , Vírus da Influenza A Subtipo H5N8/genética , Influenza Aviária/epidemiologia , Influenza Humana/epidemiologia , Filogenia , Aves Domésticas , Doenças das Aves Domésticas/epidemiologiaRESUMO
Infections by A/H5 and A/H7 avian influenza viruses (AIVs) can cause acute disease and are therefore notifiable in poultry and wild birds. During winter 2015-2016, several cases of infection caused by highly pathogenic (HP) AIVs belonging to the A/H5N1, A/H5N2, and A/H5N9 subtypes were detected in southwestern France. Throughout winter 2016-2017, several cases of infections caused mainly by A/H5N8 HP AIV (A/goose/GD/1/1996, clade 2.3.4.4) were detected across Europe. On both occasions, the viruses were widely detected on palmiped farms in France. This study was designed to evaluate the persistence of A/H5 HP AIV in slurry from various duck productions. This was achieved (i) in the laboratory setting by artificially spiking four AIV-free slurry samples with known amounts of A/H5N9 HP AIV and monitoring virus infectivity, with or without lime treatment to achieve pH 10 or pH 12, and (ii) by sampling slurry tanks on five naturally A/H5N8 HP-contaminated farms. Experimental results in artificially spiked slurry suggested virus survival for 4 weeks in slurry from Muscovy or Pekin duck breeders and for 2 weeks in slurry from ducks for foie gras production during the assisted-feeding period, without lime treatment. Persistence of infectious A/H5N9 HP AIV in all slurry samples after lime treatment at pH 10 or pH 12 was less than 1 week. The A/H5N8 HP AIV persisted in naturally contaminated untreated slurry for 7 weeks. The results obtained provide experimental support for the 60-day storage period without treatment or the 7-day interval after lime treatment defined in French regulations for slurry sanitization.IMPORTANCE From November 2015 to July 2017, two successive episodes of H5 highly pathogenic avian influenza viruses (HP AIVs) infections occurred on poultry farms in France, mostly in domestic ducks raised for foie gras production in southwestern France. During the two epizootics, epidemiological investigations were carried out on infected farms and control and biosafety measures were implemented in association with surveillance in order to stop the spread of the viruses. Effluents are known to be an important factor in environmental dissemination of viruses, and suitable effluent management is needed to help prevent the spread of epizootics to other farms or pathogen persistence at the farm level. The present study was therefore designed to assess how long infectious A/H5 HP AIVs can persist in naturally or experimentally contaminated fecal slurry samples from ducks, with or without sanitization by lime treatment.
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Compostos de Cálcio/farmacologia , Controle de Doenças Transmissíveis/métodos , Patos , Vírus da Influenza A Subtipo H5N8/isolamento & purificação , Influenza Aviária/prevenção & controle , Óxidos/farmacologia , Doenças das Aves Domésticas/prevenção & controle , Águas Residuárias/virologia , Criação de Animais Domésticos , Animais , França , Resíduos Industriais , Influenza Aviária/virologia , Doenças das Aves Domésticas/virologiaRESUMO
The ability of calcium peroxide (CaO2) to degrade hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) in contaminated soil slurries using CaO2-based modified Fenton oxidation was investigated. Results showed that increasing the CaO2 dose increased degradation rates of RDX and pH. RDX concentrations decreased to below detection after 18 h with 2 M and 2.5 M CaO2, after 30 h with 1.5 M CaO2, after 54 h with 1 M CaO2, but 0.1 M CaO2 achieved no significant RDX removal. Increasing the soil organic matter content decreased the rate and extent of RDX degradation. RDX degradation products 4-nitro-2,4-diazabutanal (NDAB) and methylenedinitramine (MEDINA) were quantified, and the greater accumulation of NDAB than MEDINA suggests denitration of RDX was the most likely initial degradation step. Isotopic ratios for nitrogen and oxygen associated with RDX oxidation are also consistent with either nitrification of NH4+ from soil or precipitation. Existing technologies merely only extract energetics from soils for treatment ex situ, whereas the approach introduced herein destroys RDX in situ with a one-step application.
Assuntos
Esgotos , Triazinas , Biodegradação Ambiental , Peróxidos , Solo , Triazinas/análiseRESUMO
To reveal the molecular mechanisms involved in cardiac lineage determination and differentiation, we quantified the proteome of human embryonic stem cells (hESCs), cardiac progenitor cells (CPCs), and cardiomyocytes during a time course of directed differentiation by label-free quantitative proteomics. This approach correctly identified known stage-specific markers of cardiomyocyte differentiation, including SRY-box2 (SOX2), GATA binding protein 4 (GATA4), and myosin heavy chain 6 (MYH6). This led us to determine whether our proteomic screen could reveal previously unidentified mediators of heart development. We identified Disabled 2 (DAB2) as one of the most dynamically expressed proteins in hESCs, CPCs, and cardiomyocytes. We used clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) mutagenesis in zebrafish to assess whether DAB2 plays a functional role during cardiomyocyte differentiation. We found that deletion of Dab2 in zebrafish embryos led to a significant reduction in cardiomyocyte number and increased endogenous WNT/ß-catenin signaling. Furthermore, the Dab2-deficient defects in cardiomyocyte number could be suppressed by overexpression of dickkopf 1 (DKK1), an inhibitor of WNT/ß-catenin signaling. Thus, inhibition of WNT/ß-catenin signaling by DAB2 is essential for establishing the correct number of cardiomyocytes in the developing heart. Our work demonstrates that quantifying the proteome of human stem cells can identify previously unknown developmental regulators.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Coração/embriologia , Proteômica , Proteínas Supressoras de Tumor/fisiologia , Via de Sinalização Wnt/fisiologia , beta Catenina/fisiologia , Animais , Proteínas Reguladoras de Apoptose , Diferenciação Celular , Células Cultivadas , Células-Tronco Embrionárias/citologia , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Miócitos Cardíacos/citologia , Peixe-Zebra/embriologiaRESUMO
INTRODUCTION: Pharyngeal airway space (PAS) assessment has been used in the past for a better understanding of orthodontic and surgical outcomes; however, this analysis could be unreliable. Our objective was to evaluate possible changes in the PAS reading in the same patient from their consecutive cone-beam computed tomography (CBCT) scans. METHODS: We evaluated a total of 27 patients' CBCT scans obtained at 2 time points with the use of a standardized acquisition protocol. The mean age at T0 was 31 years (range 17-62 years) and the follow-up records (T1) were taken after 4-6 months. Dolphin Imaging software was used to measure the volumes of the nasopharynx, oropharynx, and hypopharynx. We also evaluated the craniocervical position with the use of a lateral cephalogram. RESULTS: The variables exhibited high intraclass correlation coefficients (ICCs) when measuring the same CBCT scan twice (T0 and T0). However, The ICC between the measurements performed on the first and second CBCT scans (T0 and T1) showed that the only variable with high reproducibility between the 2 scans was cranial base, with an ICC >0.97. Average differences of 682.1 mm3, 2255.3 mm3, and 517.4 mm3 were found for the nasopharynx, oropharynx, and hypopharynx, respectively. Regarding the cephalometric angles, average differences between T0 and T1 scans were 0.6°, 2.7°, and 0.4° for OPT.CVT, OPT.SN, and cranial base, respectively. CONCLUSIONS: Different CBCT exams with equal scanning and patient positioning protocols can result in different 3D PAS readings. A more careful interpretation of CBCT volumetric data to achieve adequate conclusions of the clinical outcomes is necessary.
Assuntos
Tomografia Computadorizada de Feixe Cônico/métodos , Tomografia Computadorizada de Feixe Cônico/normas , Posicionamento do Paciente/métodos , Posicionamento do Paciente/normas , Faringe/anatomia & histologia , Faringe/diagnóstico por imagem , Adolescente , Adulto , Cefalometria/métodos , Feminino , Seguimentos , Humanos , Hipofaringe/anatomia & histologia , Hipofaringe/diagnóstico por imagem , Processamento de Imagem Assistida por Computador/métodos , Imageamento Tridimensional/métodos , Masculino , Pessoa de Meia-Idade , Nasofaringe/anatomia & histologia , Nasofaringe/diagnóstico por imagem , Variações Dependentes do Observador , Orofaringe/anatomia & histologia , Orofaringe/diagnóstico por imagem , Procedimentos Cirúrgicos Ortognáticos , Valores de Referência , Reprodutibilidade dos Testes , Software , Adulto JovemRESUMO
New genomic sequence data were acquired for the Acipenser iridovirus-European (AcIV-E), a virus whose complete genome and classification still remain to be elucidated. Here, we obtained the first full-length Major capsid protein (MCP) gene sequence for AcIV-E, as well as two additional open reading frames (ORFs) adjacent to the MCP gene. BLAST searches of the first ORF (α) resulted in no match to any gene or protein in the public databases. The other ORF (ß) was identified as a subunit of a replication factor C (RFC), known to function as a clamp loader in eukaryotes, archae and some viruses. The presence of similar RFC genes was confirmed in two distinct, yet related, viruses, the white sturgeon iridovirus and a European variant of Namao virus. The existence of an RFC gene in AcIV-E suggests a genome size larger than that of other classifiable members of the family Iridoviridae along with a mode of replication involving an interaction between a clamp loader and a proliferating nuclear cell antigen. Sequencing and comparison of the full-length RFC gene from various sturgeon samples infected with AcIV-E revealed two distinct clusters of sequences within one particular sample in which the coexistence of two lineages had previously been predicted based on analysis of the partial MCP gene sequence. These genetic data provide further evidence of the circulation of at least two concurrent AcIV-E lineages, sometimes co-infecting cultured European sturgeon.
Assuntos
Infecções por Vírus de DNA/veterinária , Doenças dos Peixes/virologia , Iridovirus/enzimologia , Proteína de Replicação C/metabolismo , Proteínas Virais/metabolismo , Animais , Proteínas do Capsídeo/genética , Proteínas do Capsídeo/metabolismo , Replicação do DNA , Infecções por Vírus de DNA/virologia , Peixes , Iridovirus/classificação , Iridovirus/genética , Iridovirus/isolamento & purificação , Fases de Leitura Aberta , Filogenia , Proteína de Replicação C/genética , Proteínas Virais/genéticaRESUMO
INTRODUCTION: In this study, we quantitatively assessed 3-dimensional condylar displacement during counterclockwise maxillomandibular advancement surgery (CMMA) with or without articular disc repositioning, focusing on surgical stability in the follow-up period. METHODS: The 79 patients treated with CMMA had cone-beam computed tomography scans taken before surgery, immediately after surgery, and, on average, 15 months postsurgery. We divided the 142 condyles into 3 groups: group 1 (n = 105), condyles of patients diagnosed with symptomatic presurgical temporomandibular joint articular disc displacement who had articular disc repositioning concomitantly with CMMA; group 2 (n = 23), condyles of patients with clinical verification of presurgical articular disc displacement who had only CMMA; and group 3 (n = 14), condyles of patients with healthy temporomandibular joints who had CMMA. Presurgical and postsurgical 3-dimensional models were superimposed using voxel-based registration on the cranial base. Three-dimensional cephalometrics and shape correspondence were applied to assess surgical and postsurgical displacement changes. RESULTS: Immediately after surgery, the condyles moved mostly backward and medially and experienced lateral yaw, medial roll, and upward pitch in the 3 groups. Condyles in group 1 showed downward displacement, whereas the condyles moved upward in groups 2 and 3 (P ≤0.001). Although condylar displacement changes occurred in the 3 groups, the overall surgical procedure appeared to be fairly stable, particularly for groups 1 and 3. Group 2 had the greatest amount of relapse (P ≤0.05). CONCLUSIONS: CMMA has been shown to be a stable procedure for patients with healthy temporomandibular joints and for those who had simultaneous articular disc repositioning surgery.
Assuntos
Tomografia Computadorizada de Feixe Cônico , Imageamento Tridimensional , Luxações Articulares/diagnóstico por imagem , Avanço Mandibular/métodos , Côndilo Mandibular/diagnóstico por imagem , Maxila/cirurgia , Complicações Pós-Operatórias/diagnóstico por imagem , Disco da Articulação Temporomandibular/diagnóstico por imagem , Adolescente , Adulto , Feminino , Humanos , Luxações Articulares/cirurgia , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/cirurgia , Estudos Retrospectivos , Disco da Articulação Temporomandibular/cirurgia , Adulto JovemRESUMO
Pre-pregnancy maladaptive eating behaviors have predicted inadequate or excess gestational weight gain and poor dietary intake during pregnancy, but little is known about effects of pre-pregnancy adaptive eating behaviors on pregnancy outcomes. The purpose of this study was to produce a valid and reliable measure of adaptive pre-pregnancy eating behaviors for pregnant women using the Intuitive Eating Scale. Data were collected from 266 pregnant women, aged 18 and older who were attending a private prenatal clinic at Texas Children's Hospital Pavilion for Women in Houston, TX using self-administered questionnaires. Confirmatory factor analysis was performed to validate the factor structure of the Intuitive Easting Scale (IES). Concurrent validity was determined using correlations between the three subscale scores [unconditional permission to eat (UPE), eating for physical not emotional reasons (EPR), and relying on hunger/satiety cues (RIH)], perinatal depression status (Edinburgh Postnatal Depression Scale), and pre-pregnancy body mass index (BMI) calculated from self-reported height and weight. After discarding 6 items, the second order model did not fit the data, however, the first order model with three latent factors had reasonable fit (RMSEA = 0.097, CFI = 0.961, TLI = 0.951 and WRMR = 1.21). The internal consistency of the scale was confirmed by Cronbach's alphas (UPE = 0.781, EPR = 0.878 and RIH = 0.786). All subscale scores were inversely related to perinatal depression status. EPR and RIH subscale scores were inversely related to pre-pregnancy BMI, supporting the measure's validity. Among pregnant women, the revised 15 item pre-pregnancy IES (IES-PreP) should be used to evaluate pre-pregnancy adaptive eating behaviors.
Assuntos
Dieta , Ingestão de Alimentos , Comportamento Alimentar , Intuição , Modelos Biológicos , Gestantes , Adulto , Índice de Massa Corporal , Peso Corporal , Sinais (Psicologia) , Depressão/complicações , Emoções , Análise Fatorial , Feminino , Humanos , Fome , Gravidez , Complicações na Gravidez , Gestantes/psicologia , Psicometria , Reprodutibilidade dos Testes , Resposta de Saciedade , Inquéritos e Questionários , Texas , Aumento de PesoRESUMO
Several new highly pathogenic (HP) H5 avian influenza virus (AIV) have been detected in poultry farms from south-western France since November 2015, among which an HP H5N1. The zoonotic potential and origin of these AIVs immediately became matters of concern. One virus of each subtype H5N1 (150169a), H5N2 (150233) and H5N9 (150236) was characterised. All proved highly pathogenic for poultry as demonstrated molecularly by the presence of a polybasic cleavage site in their HA protein - with a sequence (HQRRKR/GLF) previously unknown among avian H5 HPAI viruses - or experimentally by the in vivo demonstration of an intravenous pathogenicity index of 2.9 for the H5N1 HP isolate. Phylogenetic analyses based on the full genomes obtained by NGS confirmed that the eight viral segments of the three isolates were all part of avian Eurasian phylogenetic lineage but differed from the Gs/Gd/1/96-like lineage. The study of the genetic characteristics at specific amino acid positions relevant for modulating the adaptation to and the virulence for mammals showed that presently, these viruses possess most molecular features characteristic of AIV and lack some major characteristics required for efficient respiratory transmission to or between humans. The three isolates are therefore predicted to have no significant pandemic potential.
Assuntos
Virus da Influenza A Subtipo H5N1/genética , Virus da Influenza A Subtipo H5N1/patogenicidade , Vírus da Influenza A Subtipo H5N2/genética , Vírus da Influenza A Subtipo H5N2/patogenicidade , Influenza Aviária/virologia , Animais , Aves , Galinhas , Surtos de Doenças , Patos , França/epidemiologia , Genes Virais/genética , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Humanos , Virus da Influenza A Subtipo H5N1/classificação , Virus da Influenza A Subtipo H5N1/isolamento & purificação , Vírus da Influenza A Subtipo H5N2/classificação , Vírus da Influenza A Subtipo H5N2/isolamento & purificação , Influenza Aviária/epidemiologia , Dados de Sequência Molecular , Filogenia , Reação em Cadeia da Polimerase , Aves Domésticas/virologia , Doenças das Aves Domésticas/virologia , RNA Viral/genética , Análise de Sequência de DNARESUMO
An anterior open bite is a challenge to orthodontic treatment; it has a multifactorial etiology and a wide range of intervention options. Temporomandibular joint (TMJ) disorders are a risk factor for the development of malocclusions such as the anterior open bite, especially in patients who have TMJ osteoarthritis with disc displacement. Articular disc repositioning surgery is an available option for treating this pathology, and it contributes to maintaining the condyles in a more stable position. The aim of this article was to report the case of a 20-year-old woman diagnosed with anterior open bite and TMJ osteoarthritis with bilateral disc displacement. The patient received both orthodontic treatment and TMJ disc repositioning surgery. Cone-beam computed tomography was used to create 3-dimensional models of the condyles with regional superposition, and assessment of bone remodeling was performed at different time intervals. Complete orthodontic and surgical treatment time was approximately 12 months. The results provided a stable correction of the patient's anterior open bite with a 2-year follow-up and favorable bone remodeling of the condyles due to functional improvement of the TMJ.
Assuntos
Mordida Aberta/complicações , Mordida Aberta/terapia , Ortodontia Corretiva , Osteoartrite/complicações , Osteoartrite/cirurgia , Disco da Articulação Temporomandibular/cirurgia , Transtornos da Articulação Temporomandibular/complicações , Transtornos da Articulação Temporomandibular/cirurgia , Feminino , Humanos , Adulto JovemRESUMO
Yersinia ruckeri is a pathogen that has an impact on aquaculture worldwide. The disease caused by this bacterial species, yersiniosis or redmouth disease, generates substantial economic losses due to the associated mortality and veterinary costs. For predicting outbreaks and improving control strategies, it is important to characterize the population structure of the bacteria. The phenotypic and genetic homogeneities described previously indicate a clonal population structure as observed in other fish bacteria. In this study, the pulsed-field gel electrophoresis (PFGE) and multi locus sequence typing (MLST) methods were used to describe a population of isolates from outbreaks on French fish farms. For the PFGE analysis, two enzymes (NotI and AscI) were used separately and together. Results from combining the enzymes showed the great homogeneity of the outbreak population with a similarity > 80.0% but a high variability within the cluster (cut-off value = 80.0%) with a total of 43 pulsotypes described and an index of diversity = 0.93. The dominant pulsotypes described with NotI (PtN4 and PtN7) have already been described in other European countries (Finland, Germany, Denmark, Spain and Italy). The MLST approach showed two dominant sequence types (ST31 and ST36), an epidemic structure of the French Y. ruckeri population and a preferentially clonal evolution for rainbow trout isolates. Our results point to multiple types of selection pressure on the Y. ruckeri population attributable to geographical origin, ecological niche specialization and movements of farmed fish.
Assuntos
Doenças dos Peixes/genética , Variação Genética , Oncorhynchus mykiss , Yersiniose/veterinária , Yersinia ruckeri/genética , Animais , Aquicultura , Eletroforese em Gel de Campo Pulsado/veterinária , Doenças dos Peixes/microbiologia , França , Tipagem de Sequências Multilocus/veterinária , Yersiniose/genética , Yersiniose/microbiologiaRESUMO
Yersinia ruckeri is the causative agent of yersiniosis, a disease reported in a number of fish species, especially rainbow trout. This study was undertaken to describe the phenotypes of Y. ruckeri on French rainbow trout farms. More than 100 isolates, collected during recent outbreaks on trout farms, were characterized by phenotypic tests, namely using biochemical tests of the API 20E system, serotyping, biotyping (tests for motility and lipase activity) and by describing the pattern of susceptibility to several antibiotics. The isolates showed a low phenotypic diversity with a prevalent serotype (O1) and API 20E profile 5 1(3)07 100. As in other European countries, Biotype 2 (BT2), which lacks both motility and secreted lipase activity, was found to be present in France. The emergence of 'French' BT2 was different than that observed for other European countries (Finland, Spain, Denmark and the UK). The antibiotic pattern was uniform for all isolates, regardless of the geographical area studied. The results indicate that no resistance has yet emerged, and the efficacy of the antibiotic generally used against yersiniosis in France, trimethoprim/sulfamethoxasol, is not compromised (minimum inhibitory concentrations [MIC] of between 0.016 and 0.128 µg ml-1). Enrofloxacin and doxycycline, not used as a first-line treatment in fish diseases, have reasonably good efficacies (with MICs ≤0.128 and 0.256, respectively).
Assuntos
Antibacterianos/farmacologia , Farmacorresistência Bacteriana , Doenças dos Peixes/microbiologia , Yersiniose/veterinária , Yersinia ruckeri/classificação , Yersinia ruckeri/isolamento & purificação , Animais , Doenças dos Peixes/epidemiologia , Peixes , França/epidemiologia , Sorotipagem , Yersiniose/epidemiologia , Yersiniose/microbiologiaRESUMO
BACKGROUND: Total hip arthroplasty (THA) is a common procedure for end stage osteoarthritis. The learning curve for THA is complex and challenging. One of the most difficult skills to master is acetabular reaming. We wish to identify if experience in arthroplasty leads to preservation of more bone stock. AIM: To investigate if increasing surgeon experience will predict an ever decreasing acetabular cup size. METHODS: A retrospective case series of four attending orthopaedic surgeons was completed. All uncemented elective total hip arthroplasties since appointment were selected for inclusion. The size of acetabular cup used was noted and logistic regression was used to identify if a trend to smaller cups existed. RESULTS: A total of 1614 subjects were included with a mean age of 64 years. Overall cups were on average 0.18mm smaller per year (95% confidence interval -0.25 to -0.11, P < 0.001). Individual surgeon trends showed cup sizes to decrease 0.27 mm/year for surgeon A, 0.02 mm/year for surgeon B, 0.15 mm/year for surgeon C and 0.29 mm/year for surgeon D. Three of the four surgeons had a more pronounced trend to smaller cups for male subjects than their female counterparts. CONCLUSION: We found increasing surgeon experience to be associated with an ever-decreasing acetabular cup size. Smaller acetabular cup size may act as a surrogate marker of surgical proficiency by virtue of decreased acetabular reaming.
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Recent studies using electron microscopy, protein crystallography, classic biochemistry and novel live-cell imaging have provided numerous insights into the endocytic pathway, describing a dynamic system in which compartment morphology, molecular identity and the mechanics of cargo sorting are intimately connected. Current evidence supports a model of maturation in which the lipids, cargo proteins and Rab population at the endosome determine its competence to perform the functions of late endosomes, including the sorting of cargoes into lumenal vesicles and fusion with lysosomes.
Assuntos
Endossomos/fisiologia , Animais , Proteínas de Transporte/metabolismo , Endossomos/ultraestrutura , Humanos , Lisossomos/fisiologia , Modelos Biológicos , Vesículas Transportadoras/fisiologiaRESUMO
INTRODUCTION: Resident physicians are uniquely at high financial risk given their long training programs, lack of financial education, and documented poor financial literacy. Budgeting for retirement savings is an important metric for financial literacy. METHODS: Semi-structured interviews were conducted with residents from two distinct surgery programs to assess their current financial status and their knowledge of and attitudes toward retirement savings strategies. Qualitative analysis was performed and the themes identified were examined in the context of previously reported quantitative survey data. RESULTS: As previously reported, 105 residents at Site 1 completed a comprehensive financial survey 56% of respondents reported having no retirement savings. On additional analysis, only 26% residents surveyed reported optimal savings habits defined as contributing $5000/year to a retirement account starting their first year of training. 23 residents from both sites and representing all post-graduate-year (PGY) levels then participated in the focused, semi-structured interviews. Site 2 residents were less likely to be female (P = .02) and carried a significantly larger debt burden (p < .01) but were otherwise comparable to residents from Site 1. On qualitative analysis three consistent themes emerged: (1) Resident understanding of strategies for retirement savings is poor; (2) Lack of knowledge is the primary barrier; (3) Surgical residents desire financial education. CONCLUSIONS: Surgery residents have a large debt burden, minimal retirement savings and an overall lack of understanding of savings strategies. Well-designed, early, and accessible educational interventions may improve the "financial vital signs" of surgical trainees and establish habits for long-term financial success.
Assuntos
Internato e Residência , Alfabetização , Humanos , Feminino , Masculino , Renda , Escolaridade , Inquéritos e QuestionáriosRESUMO
OBJECTIVES: Patients with hypertrophic cardiomyopathy often have concomitant pulmonary hypertension, which has a negative prognostic effect in patients undergoing myectomy. Our objective was to investigate the effect of myectomy on pulmonary artery pressure obtained via Swan-Ganz catheter and characterize how changes in pulmonary artery systolic pressure may indicate outcomes in these patients. METHODS: We performed a single-center retrospective analysis of 271 patients with recordings of intraoperative pulmonary artery pressures during surgical myectomy. We analyzed primary composite outcomes as 30-day or in-hospital major cardiopulmonary adverse events. RESULTS: There was a 5.17% adverse event rate. Patients with adverse events were older, were more likely to be female, had chronic obstructive pulmonary disease, and had longer cardiopulmonary bypass times. Some 35.7% of those with adverse events had moderate to severe pulmonary hypertension (pulmonary artery systolic pressure ≥50 mm Hg) on postbypass stress test, compared with 4.3% of those without adverse events (P < .001). Further, 21.4% of patients with adverse events had pulmonary artery systolic pressure 50 mm Hg or greater at the end of surgery, compared with 1.9% of patients without adverse events (P < .001). The pulmonary artery systolic pressure decrease after surgery in those without adverse events was on average 5 mm Hg more than in those with adverse events. CONCLUSIONS: Postoperative pulmonary hypertension was associated with a higher rate of adverse cardiopulmonary events. This may influence the decision to use Swan-Ganz catheters in patients undergoing septal myectomy in monitoring pulmonary artery pressures to better risk stratify and manage these patients postoperatively.
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The Madagascar's periwinkle is the model plant for studies of plant specialized metabolism and monoterpenoid indole alkaloids (MIAs), and an important source for the anticancer medicine vinblastine. The elucidation of entire 28-step biosynthesis of vinblastine allowed further investigations for the formation of other remarkably complex bioactive MIAs. In this study, we describe the discovery and characterization of vindolinine synthase, a Fe(II)/α-ketoglutarate-dependent (Fe/2OG) dioxygenase, that diverts assembly of tabersonine to vinblastine toward the formation of three alternatively cyclized MIAs: 19S-vindolinine, 19R-vindolinine, and venalstonine. Vindolinine synthase catalyzes a highly unusual, redox-neutral reaction to form a radical from dehydrosecodine, which is further cyclized by hydrolase 2 to form the three MIA isomers. We further show the biosynthesis of vindolinine epimers from tabersonine using hydrolase 2 catalyzed reverse cycloaddition. While the occurrence of vindolinines is rare in nature, the more widely found venalstonine derivatives are likely formed from similar redox-neutral reactions by homologous Fe/2OG dioxygenases.
Assuntos
Catharanthus , Alcaloides de Triptamina e Secologanina , Dioxigenase FTO Dependente de alfa-Cetoglutarato/metabolismo , Catharanthus/metabolismo , Compostos Ferrosos/metabolismo , Regulação da Expressão Gênica de Plantas , Hidrolases/metabolismo , Oxirredução , Proteínas de Plantas/genética , Alcaloides de Triptamina e Secologanina/metabolismo , Vimblastina/análogos & derivados , Vimblastina/metabolismoRESUMO
BACKGROUND: The transition from primary to secondary school is particularly difficult for autistic children, a transition underpinned by an increase in prospective memory (PM) demands. AIMS: To better understand PM in autistic children of the relevant age range and its underlying processes, the current study investigated the impact of cue salience (distinctiveness) on PM in autistic and non-autistic children and adolescents. The study was unique in manipulating the visual and auditory salience of PM cues. Salient cues are assumed to put lower demands on executive control resources as compared to cues that blend in with the ongoing activity. METHODS AND PROCEDURES: The children completed a computer-based categorisation task in which an event-based PM task was embedded. The salience of PM cues was manipulated (low, high visual and high auditory salience). OUTCOMES AND RESULTS: Results revealed that both groups benefitted from an increase in visual and auditory salience, but only autistic participants were faster to respond to auditory cues. CONCLUSIONS AND IMPLICATIONS: Increased cue salience improved PM performance for all children. Positive effects of auditory cues were especially evident in autistic children.
Assuntos
Transtorno Autístico , Memória Episódica , Adolescente , Criança , Cognição , Sinais (Psicologia) , Função Executiva , HumanosRESUMO
Glaesserella australis, a newly described bacterial species, has been isolated from pig lungs that displayed lesions very similar to those caused by Actinobacillus pleuropneumoniae, prompting the need for a validated diagnostic tool. In this work, we have altered a multiplex PCR used for the identification of cultures of G. australis, A. pleuropneumoniae and Pasteurella multocida to be more sensitive and then evaluated the use of the altered diagnostic tool on cultures and directly on tissues. The altered multiplex PCR was validated using 47 related species, both type/reference strains and field isolates. The sensitivity was assessed by serial dilutions and used a mixture of target bacteria in different concentrations. Further, 166 lung samples from 54 farms from four Australian States were used to validate the ability of the multiplex PCR to detect bacteria in lung swabs. The multiplex PCR was specific for the three target species. The assay could detect a minimum of 40 colony forming units (CFU) of G. australis, 786 CFU of A. pleuropneumoniae and 238 CFU of P. multocida. The multiplex PCR yielded more positives than coventional bacteriological examination. From a total of 166 lung samples, 51.9%, 51.9% and 5.6% of farms were PCR positive for P. multocida, A. pleuropneumoniae and G. australis, respectively. The results suggested that the new multiplex PCR was specific, sensitive and out performed traditional culture. The prevalence of G. australis was not very high, but it was the dominant pathogen in infected pigs.