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1.
J Virol ; 94(8)2020 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-31996435

RESUMO

Argentine hemorrhagic fever is a potentially lethal disease that is caused by Junin virus (JUNV). There are currently around 5 million individuals at risk of infection within regions of endemicity in Argentina. The live attenuated vaccine strain Candid #1 (Can) is approved for use in regions of endemicity and has substantially decreased the number of annual Argentine hemorrhagic fever (AHF) cases. The glycoprotein (GPC) gene is primarily responsible for attenuation of the Can strain, and we have shown that the absence of an N-linked glycosylation motif in the subunit G1 of the glycoprotein complex of Can, which is otherwise present in the wild-type pathogenic JUNV, causes GPC retention in the endoplasmic reticulum (ER). Here, we show that Can GPC aggregates in the ER of infected cells, forming incorrect cross-chain disulfide bonds, which results in impaired GPC processing into G1 and G2. The GPC fails to cleave into its G1 and G2 subunits and is targeted for degradation within lysosomes. Cells infected with the wild-type Romero (Rom) strain do not produce aggregates that are observed in Can infection, and the stress on the ER remains minimal. While the mutation of the N-linked glycosylation motif (T168A) is primarily responsible for the formation of aggregates, other mutations within G1 that occurred earlier in the passage history of the Can strain also contribute to aggregation of the GPC within the ER.IMPORTANCE The development of vaccines and therapeutics to combat viral hemorrhagic fevers remains a top priority within the Implementation Plan of the U.S. Department of Health and Human Services Public Health Emergency Medical Countermeasures Enterprise. The Can strain, derived from the pathogenic XJ strain of JUNV, has been demonstrated to be both safe and protective against AHF. While the vaccine strain is approved for use in regions of endemicity within Argentina, the mechanisms of Can attenuation have not been elucidated. A better understanding of the viral genetic determinants of attenuation will improve our understanding of the mechanisms contributing to disease pathogenesis and provide critical information for the rational design of live attenuated vaccine candidates for other viral hemorrhagic fevers.

2.
Vaccine ; 37(45): 6824-6831, 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31561999

RESUMO

Lassa virus (LASV), the causative agent of Lassa fever (LF), was first identified in 1969. Since then, outbreaks in the endemic countries of Nigeria, Liberia, and Sierra Leone occur on an annual basis resulting in a case-fatality rate of 15-70% in hospitalized patients. There is currently no licensed vaccine and there are limited animal models to test vaccine efficacy. An estimated 37.7 million people are at risk of contracting LASV; therefore, there is an urgent need for the development of a safe, effective vaccine against LASV infection. The LF endemic countries are also inflicted with HIV, Ebola, and malaria infections. The safety in immunocompromised populations must be considered in LASV vaccine development. The novel adenovirus vector-based platform, Ad5 (E1-,E2b-) has been used in clinical trial protocols for treatment of immunocompromised individuals, has been shown to exhibit high stability, low safety risk in humans, and induces a strong cell-mediated and pro-inflammatory immune response even in the presence of pre-existing adenovirus immunity. To this nature, our lab has developed an Ad5 (E1-,E2b-) vector-based vaccine expressing the LASV-NP or LASV-GPC. We found that guinea pigs vaccinated with two doses of Ad5 (E1-,E2b-) LASV-NP and Ad5 (E1-,E2b-) LASV-GPC were protected against lethal LASV challenge. The Ad5 (E1-,E2b-) LASV-NP and LASV-GPC vaccine represents a potential vaccine candidate against LF.

3.
mSphere ; 4(5)2019 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-31554720

RESUMO

Lassa virus (LASV), a member of the family Arenaviridae, is the causative agent of Lassa fever. Lassa virus is endemic in West African countries, such as Nigeria, Guinea, Liberia, and Sierra Leone, and causes outbreaks annually. Lassa fever onset begins with "flu-like" symptoms and may develop into lethal hemorrhagic disease in severe cases. Although Lassa virus is one of the most alarming pathogens from a public health perspective, there are few licensed vaccines or therapeutics against Lassa fever. The fact that animal models are limited and the fact that mostly laboratory-derived viruses are used for studies limit the successful development of countermeasures. In this study, we demonstrated that the LASV isolate LF2384-NS-DIA-1 (LF2384), which was directly isolated from a serum sample from a fatal human Lassa fever case in the 2012 Sierra Leone outbreak, causes uniformly lethal infection in outbred Hartley guinea pigs without virus-host adaptation. This is the first report of a clinically isolated strain of LASV causing lethal infection in outbred guinea pigs. This novel guinea pig model of Lassa fever may contribute to Lassa fever research and the development of vaccines and therapeutics.IMPORTANCE Lassa virus, the causative agent of Lassa fever, is a zoonotic pathogen causing annual outbreaks in West African countries. Human patients can develop lethal hemorrhagic fever in severe cases. Although Lassa virus is one of the most alarming pathogens from a public health perspective, there are few available countermeasures, such as antiviral drugs or vaccines. Moreover, the fact that animal models are not readily accessible and the fact that mostly laboratory viruses, which have been passaged many times after isolation, are used for studies further limits the successful development of countermeasures. In this study, we demonstrate that a human isolate of Lassa virus causes lethal infection uniformly in Hartley guinea pigs. This novel animal model of Lassa fever may contribute to Lassa fever research and the development of vaccines and therapeutics.


Assuntos
Modelos Animais de Doenças , Febre Lassa/mortalidade , Febre Lassa/veterinária , Vírus Lassa/patogenicidade , Animais , Anticorpos Antivirais/sangue , Antígenos Virais/imunologia , Cobaias , Humanos , Vírus Lassa/isolamento & purificação , Dose Letal Mediana , Carga Viral
4.
Ophthalmic Plast Reconstr Surg ; 35(3): 243-246, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30124609

RESUMO

PURPOSE: The authors examined the prevalence of a histologic change of ocular adnexal lymphoma (OAL) grade in patients with a history of lymphoma in nonocular sites. METHODS: In this retrospective study, the authors reviewed the clinical and pathological data of 209 patients with OAL treated by the senior author during 2000 to 2017. RESULTS: Of 209 patients with OAL, 65 (31%) had a history of lymphoma. In 54 of the 65 patients (83%), the original lymphoma and OAL were of the same histologic type. In 8 of the 65 patients (12.3%), the OAL was more indolent than the original lymphoma: 6 patients with a history of diffuse large B-cell lymphoma, one of mantle cell lymphoma, and one of grade 3 follicular lymphoma had biopsy-proven extranodal marginal-zone lymphoma in the orbital area. Two additional patients (3%) with a history of chronic lymphocytic leukemia developed OAL: diffuse large B-cell lymphoma in one patient and extranodal marginal-zone lymphoma in the other. One patient (1.5%) with a history of a low-grade follicular lymphoma relapsed as a different low-grade histology of extranodal marginal-zone lymphoma. Lower-grade OAL than the original lymphoma was more common than higher-grade OAL than the original lymphoma (p = 0.048). CONCLUSIONS: In this cohort of 209 patients with OAL, the authors found that nearly one third had a history of lymphoma, 17% of whom had a different histologic type of lymphoma in the orbit, more commonly a more indolent type. This underscores the importance of biopsy of OAL even in patients with a known history of lymphoma to determine the histologic subtype of orbital lymphoma and to help guide appropriate treatment.


Assuntos
Linfoma de Zona Marginal Tipo Células B/diagnóstico , Linfoma/epidemiologia , Estadiamento de Neoplasias , Neoplasias Orbitárias/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Feminino , Seguimentos , Humanos , Linfoma/diagnóstico , Masculino , Pessoa de Meia-Idade , Neoplasias Orbitárias/diagnóstico , Prevalência , Estudos Retrospectivos , Estados Unidos/epidemiologia
5.
Mod Pathol ; 32(1): 16-26, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30323237

RESUMO

Rosai-Dorfman disease is a rare histiocytic disorder shown to have gene mutations that activate the MAPK/ERK pathway in at least one-third of cases. Most patients with Rosai-Dorfman disease present with bulky lymphadenopathy or extranodal disease, but rarely Rosai-Dorfman disease is detected concomitantly with lymphoma in the same biopsy specimen. The underlying molecular mechanisms of focal Rosai-Dorfman disease occurring in the setting of lymphoma have not been investigated. We report 12 cases of Rosai-Dorfman disease and lymphoma involving the same anatomic site. There were five men and seven women (age, 23 to 77 years) who underwent lymph node (n = 11) or skin (n = 1) biopsy; the lymphomas included nodular lymphocyte predominant Hodgkin lymphoma (n = 6), classical Hodgkin lymphoma (n = 4), small lymphocytic lymphoma (n = 1) and extranodal marginal zone lymphoma (n = 1). The foci of Rosai-Dorfman disease in all cases had S100 protein-positive histiocytes undergoing emperipolesis. No patients had Rosai-Dorfman disease at other anatomic sites at initial diagnosis and at last follow-up (median, 40 months). We performed immunohistochemical analysis to assess activity of the MAPK/ERK pathway in the Rosai-Dorfman disease foci. We also micro-dissected disease foci and analyzed 146 genes using next-generation sequencing in four cases with adequate DNA; the panel included genes previously reported to be mutated in Rosai-Dorfman disease. All cases were negative for gene mutations. Nevertheless, all cases were positive for cyclin D1 and most cases showed p-ERK expression indicating that the MAPK/ERK pathway is active in the histiocytes of focal Rosai-Dorfman disease. We conclude that focal Rosai-Dorfman disease coexisting with lymphoma is a clinically benign and localized histiocytic proliferation. These data also indicate that the MAPK/ERK pathway is active in focal Rosai-Dorfman disease although we did not identify activating mutations. These findings suggest that the pathogenesis of focal Rosai-Dorfman disease is different from that of usual cases of Rosai-Dorfman disease.


Assuntos
Histiocitose Sinusal/complicações , Linfoma/complicações , Sistema de Sinalização das MAP Quinases/fisiologia , Adulto , Idoso , Feminino , Histiocitose Sinusal/enzimologia , Humanos , Linfoma/enzimologia , Masculino , Pessoa de Meia-Idade , Adulto Jovem
6.
Early Hum Dev ; 127: 28-32, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30223207

RESUMO

BACKGROUND: Digit ratio (2D:4D), has been the subject of many studies. However, the best method of measuring digit length, either directly (d2D:4D) or indirectly (i2D:4D), is controversial. In many reports i2D:4D has been found to show a directional effect such that d2D:4D > i2D:4D. The exception is three studies from one group of researchers in Austria. Thus, it is unclear whether this effect is nation- or lab-specific. AIMS: To examine evidence for effects of direct versus indirect measurements of mean 2D:4D in Austrians. STUDY DESIGN: We compared 2D:4D based on direct and indirect measurements of digit lengths of Austrians. SUBJECTS: There were 80 participants, 21 adults and 59 children. OUTCOME MEASURES: 2D:4D of right and left hands, measured directly (from the palm) and indirectly (from hand scans). RESULTS: Repeatability was high for both d2D:4D and i2D:4D, with the latter slightly higher than the former. d2D:4D and i2D:4D correlated strongly and the sex difference in 2D:4D (males < females) was greater for i2D:4D. With regard to directional differences, we found d2D:4D > i2D:4D for both right (d = -0.53) and left hands (d = -0.80). CONCLUSION: There was no evidence of an "Austrian" effect on direct versus indirect measurements of 2D:4D, i.e. mean d2D:4D was greater than i2D:4D. We discuss our findings in the light of issues regarding "clarity of report" from earlier Austrian studies.


Assuntos
Dedos , Caracteres Sexuais , Adulto , Antropometria , Áustria , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
7.
Am J Hum Biol ; 30(6): e23182, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30251289

RESUMO

OBJECTIVES: The primary aim of this study was to examine relationships between digit ratio (2D:4D) and game-related statistics in professional and semi-professional male basketball players. The secondary aim was to quantify differences in mean 2D:4Ds between starting and reserve players. METHODS: Using a cross-sectional design, 93 male basketball players from the professional Australian National Basketball League and the semi-professional South Australian Premier League were measured in-season for height, mass, and 2D:4D, with game-related statistics collected end-season. Linear relationships between right and left 2D:4Ds and game-related statistics were quantified using nonparametric partial correlations, and differences in mean 2D:4Ds between starting and reserve players were quantified using analysis of covariance (ANCOVA). All partial correlations and ANCOVAs were adjusted for playing experience, body size, and competitive standard. RESULTS: 2D:4D was a weak to moderate negative correlate of points scored and assists-to-turnovers ratio, indicating that males with lower 2D:4Ds were generally better offensively as they recorded more points and assists relative to turnovers. The difference in mean 2D:4D between starting and reserve players was negligible. CONCLUSIONS: 2D:4D was favorably correlated with open-skill sports performance, as evidenced by the better offensive statistics of male basketball players with lower 2D:4Ds. These results probably reflect the organizational benefits of prenatal testosterone and indicate that 2D:4D may be a useful complement to traditional physical, physiological, skill, and behavioral predictors of basketball success.


Assuntos
Desempenho Atlético/estatística & dados numéricos , Basquetebol/estatística & dados numéricos , Dedos/anatomia & histologia , Adulto , Estudos Transversais , Humanos , Masculino , Austrália do Sul , Adulto Jovem
8.
Am J Hum Biol ; 30(4): e23138, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-30133905

RESUMO

OBJECTIVE: Sex differences are often reported in digit lengths and digit ratio (2D:4D). However, the ontogeny of these sex differences and their interrelationships are less well known. METHODS: We considered sex differences in the lengths of the 2nd (2D) and 4th (4D) digit and 2D:4D in children aged 2 to 18 years (Sample I, n = 680) and adults aged 18 to 30 years (Sample II, n = 89,246). Digit length was determined by direct experimenter-measurement (Sample I) and direct self-measurement (Sample II). The data were tested with two-factor ANOVA's (sex and year-group). RESULTS: In both samples, there were significant main effects of sex and year-group, and a significant interaction effect on digit length. Digit length was positively related to age in both samples. Boys had longer digits than girls but only after 13 years. Men had longer digits than women and the dimorphism increased from 18 to 30 years. There were significant sex differences in 2D:4D (males < females), but no significant effect of age and no interaction effect of age and sex on 2D:4D in children or adults. CONCLUSIONS: Between 2 and 30 years, the lengths and the sexual dimorphisms of 2D and 4D are dependent on age. In contrast, 2D:4D is not age-dependent. We discuss our findings in the context of the ontogeny of digits and in the light of recent claims on the presence of static allometry in 2D and 4D lengths.


Assuntos
Dedos/anatomia & histologia , Caracteres Sexuais , Criança , Pré-Escolar , Feminino , Dedos/crescimento & desenvolvimento , Humanos , Masculino
9.
Nat Commun ; 9(1): 1884, 2018 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-29760382

RESUMO

While five arenaviruses cause human hemorrhagic fevers in the Western Hemisphere, only Junin virus (JUNV) has a vaccine. The GP1 subunit of their envelope glycoprotein binds transferrin receptor 1 (TfR1) using a surface that substantially varies in sequence among the viruses. As such, receptor-mimicking antibodies described to date are type-specific and lack the usual breadth associated with this mode of neutralization. Here we isolate, from the blood of a recipient of the live attenuated JUNV vaccine, two antibodies that cross-neutralize Machupo virus with varying efficiency. Structures of GP1-Fab complexes explain the basis for efficient cross-neutralization, which involves avoiding receptor mimicry and targeting a conserved epitope within the receptor-binding site (RBS). The viral RBS, despite its extensive sequence diversity, is therefore a target for cross-reactive antibodies with activity against New World arenaviruses of public health concern.


Assuntos
Anticorpos Neutralizantes/química , Anticorpos Antivirais/química , Arenavirus do Novo Mundo/imunologia , Febre Hemorrágica Americana/prevenção & controle , Fragmentos Fab das Imunoglobulinas/química , Vírus Junin/imunologia , Proteínas do Envelope Viral/química , Sequência de Aminoácidos , Anticorpos Neutralizantes/isolamento & purificação , Anticorpos Antivirais/isolamento & purificação , Antígenos CD/química , Antígenos CD/genética , Antígenos CD/imunologia , Antígenos Virais/química , Antígenos Virais/genética , Antígenos Virais/imunologia , Arenavirus do Novo Mundo/genética , Sítios de Ligação de Anticorpos , Reações Cruzadas , Epitopos/química , Epitopos/genética , Epitopos/imunologia , Células HEK293 , Febre Hemorrágica Americana/imunologia , Febre Hemorrágica Americana/virologia , Humanos , Soros Imunes/química , Fragmentos Fab das Imunoglobulinas/isolamento & purificação , Vírus Junin/genética , Modelos Moleculares , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Estrutura Terciária de Proteína , Subunidades Proteicas/química , Subunidades Proteicas/genética , Subunidades Proteicas/imunologia , Receptores da Transferrina/química , Receptores da Transferrina/genética , Receptores da Transferrina/imunologia , Receptores Virais/química , Receptores Virais/genética , Receptores Virais/imunologia , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Proteínas do Envelope Viral/genética , Proteínas do Envelope Viral/imunologia , Vacinas Virais/administração & dosagem
10.
Antiviral Res ; 149: 34-40, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29126899

RESUMO

Zika virus (ZIKV), a member of the Flaviviridae family, has recently been linked to abnormal pregnancies, fetal death, microcephaly, and Guillain-Barré syndrome in humans. Merimepodib (MMPD, VX-497), a potent inhibitor of inosine-5'-monophosphate dehydrogenase (IMPDH), has shown antiviral activity against HCV and a variety of DNA and RNA viruses in vitro. In this report, we expand the antiviral spectrum of MMPD, and demonstrate that MMPD inhibits ZIKV RNA replication with an EC50 of 0.6 µM. Furthermore, MMPD reduces the virus production of ZIKV as well as several other important emerging viral pathogens such as Ebola, Lassa, Chikungunya, and Junin viruses. The inhibition can be reversed by addition of exogenous guanosine to culture media, consistent with the mechanism of action of MMPD as an IMPDH inhibitor. We also provide evidence that MMPD can be used in combination with other antivirals such as ribavirin and T-705 (favipiravir) to enhance suppression of virus production.


Assuntos
Antivirais/farmacologia , Carbamatos/farmacologia , IMP Desidrogenase/antagonistas & inibidores , Compostos de Fenilureia/farmacologia , Replicação Viral/efeitos dos fármacos , Zika virus/efeitos dos fármacos , Animais , Linhagem Celular , Ebolavirus/efeitos dos fármacos , Humanos , RNA Viral/biossíntese , Células Vero , Infecção por Zika virus/metabolismo , Infecção por Zika virus/virologia
11.
Am J Hum Biol ; 30(1)2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29024156

RESUMO

OBJECTIVE: Digit ratio (2D:4D) is a negative correlate of sports performance, although this relationship may be weak in open-skill sports such as basketball. The primary aim was to quantify relationships between 2D:4D and game-related statistics in semi-professional female basketball players. The secondary aim was to quantify the differences in mean 2D:4Ds between players based on their position in the starting lineup. METHODS: Using a cross-sectional design, 64 female basketball players who competed in the South Australian Premier League were measured in-season for height, mass, and 2D:4D, with game-related statistics collected end-season. Partial correlations (adjusted for age and body mass index) were used to quantify relationships between right and left 2D:4Ds and game-related statistics. Unpaired t-tests were used to quantify differences in mean 2D:4Ds between starting and reserve players. RESULTS: 2D:4D was a substantial negative correlate of blocks, rebounds, and field-goal percentage; meaning, females with lower 2D:4Ds were generally better defensively as they recorded more blocks and rebounds, and were more efficient scorers, irrespective of their age and body size. Mean 2D:4D differed by position in the starting lineup, as females with lower 2D:4Ds were more likely to be in the starting lineup. CONCLUSIONS: This study found evidence that 2D:4D was a correlate of performance in an open-skill sport. Female players with lower digit ratios tended to perform better in several aspects of basketball, especially defensively, and were more likely to be starters, suggesting they are the best players on the team in their positions. These results probably reflect the organizational benefits of prenatal testosterone.


Assuntos
Desempenho Atlético/fisiologia , Basquetebol/fisiologia , Dedos/anatomia & histologia , Adulto , Estudos Transversais , Feminino , Humanos , Austrália do Sul , Adulto Jovem
13.
Hum Pathol ; 68: 136-146, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28873356

RESUMO

Follicular lymphoma (FL) with features reminiscent of hyaline-vascular Castleman disease (CD) is an unusual morphologic variant that may create diagnostic difficulties. To our knowledge, only 5 cases of this variant have been reported. We describe the clinicopathologic features of 6 cases including 2 men and 4 women with a median age of 63 years (range, 41-77). Morphologically, all lymph node biopsy specimens showed at least a focal area of conventional FL; 4 cases showed neoplastic follicles with hyalinized blood vessels penetrating into germinal centers (lollipop-like lesions); 4 cases had interfollicular areas with increased vascular stroma; 2 cases showed small neoplastic follicles with prominent, onionskin-like mantle zones; and 1 case showed 2 or more germinal centers within follicles (twinning). The small neoplastic follicles were more cellular than lymphocyte-depleted follicles of true hyaline-vascular CD, and the interface between germinal centers and mantle zones was ill defined. No cases showed dysplastic follicular dendritic cells. Immunohistochemistry for BCL-2 was positive in all 6 cases. Flow cytometry immunophenotypic analysis showed a monotypic B-cell population in 2 of 3 cases assessed. Conventional cytogenetic or fluorescence in situ hybridization studies performed in 3 cases showed t(14;18)(q32;q21) or IGH-BCL2, supporting the diagnosis of FL. The cases presented here add clinicopathologic data to the few cases of FL with hyaline-vascular CD-like features reported previously in the literature. Distinguishing this variant of FL from hyaline-vascular CD is important given the differences in treatment and prognosis of patients with each disease.


Assuntos
Biomarcadores Tumorais/metabolismo , Hiperplasia do Linfonodo Gigante/patologia , Hialina/metabolismo , Linfonodos/patologia , Linfoma Folicular/patologia , Adulto , Idoso , Biomarcadores Tumorais/genética , Biópsia , Hiperplasia do Linfonodo Gigante/genética , Hiperplasia do Linfonodo Gigante/metabolismo , Diagnóstico Diferencial , Feminino , Citometria de Fluxo , Centro Germinativo/química , Centro Germinativo/patologia , Humanos , Imuno-Histoquímica , Imunofenotipagem/métodos , Hibridização in Situ Fluorescente , Linfonodos/química , Linfoma Folicular/química , Linfoma Folicular/genética , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes
15.
Am J Hum Biol ; 29(3)2017 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-28504855

RESUMO

OBJECTIVE: To investigate relationships between the digit ratio (2D:4D) and competitive basketball performance in Australian men. METHODS: Using an observational cross-sectional design a total of 221 Australian basketball players who competed in the Olympic Games, International Basketball Federation World Championships/Cup, Australian National Basketball League, Central Australian Basketball League or socially had their 2D:4Ds measured. Analysis of variance was used to assess differences in mean 2D:4Ds between men playing at different competitive standards, with relationships between 2D:4Ds and basketball game-related statistics assessed using Pearson's product moment correlations in men playing at a single competitive standard. RESULTS: There were significant differences between competitive standards for the left 2D:4D following Bonferroni correction, but not for the right 2D:4D, with basketballers who achieved higher competitive standards tending to have lower left 2D:4Ds. No important correlations between 2D:4D and basketball game-related statistics were found, with correlations typically negligible. CONCLUSIONS: This study indicated that the 2D:4D can discriminate between basketballers competing at different standards, but not between basketballers within a single competitive standard using objective game-related statistics.


Assuntos
Desempenho Atlético , Basquetebol , Dedos/anatomia & histologia , Adulto , Antropometria , Austrália , Estudos Transversais , Humanos , Masculino , Adulto Jovem
16.
EBioMedicine ; 20: 182-192, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28465156

RESUMO

Prevalence of Kaposi sarcoma-associated herpesvirus (KSHV/HHV-8) varies greatly in different populations. We hypothesized that the actual prevalence of KSHV/HHV8 infection in humans is underestimated by the currently available serological tests. We analyzed four independent patient cohorts with post-surgical or post-chemotherapy sepsis, chronic lymphocytic leukemia and post-surgical patients with abdominal surgical interventions. Levels of specific KSHV-encoded miRNAs were measured by reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and KSHV/HHV-8 IgG were measured by immunoassay. We also measured specific miRNAs from Epstein Barr Virus (EBV), a virus closely related to KSHV/HHV-8, and determined the EBV serological status by ELISA for Epstein-Barr nuclear antigen 1 (EBNA-1) IgG. Finally, we identified the viral miRNAs by in situ hybridization (ISH) in bone marrow cells. In training/validation settings using independent multi-institutional cohorts of 300 plasma samples, we identified in 78.50% of the samples detectable expression of at least one of the three tested KSHV-miRNAs by RT-qPCR, while only 27.57% of samples were found to be seropositive for KSHV/HHV-8 IgG (P<0.001). The prevalence of KSHV infection based on miRNAs qPCR is significantly higher than the prevalence determined by seropositivity, and this is more obvious for immuno-depressed patients. Plasma viral miRNAs quantification proved that EBV infection is ubiquitous. Measurement of viral miRNAs by qPCR has the potential to become the "gold" standard method to detect certain viral infections in clinical practice.


Assuntos
MicroRNAs , RNA Viral , Carga Viral , Viroses/sangue , Viroses/virologia , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Estudos de Coortes , Ensaio de Imunoadsorção Enzimática , Herpesvirus Humano 8/genética , Herpesvirus Humano 8/imunologia , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Hibridização In Situ , Contagem de Leucócitos , Contagem de Linfócitos , Prevalência , Reação em Cadeia da Polimerase em Tempo Real , Reprodutibilidade dos Testes , Viroses/diagnóstico , Viroses/epidemiologia
18.
Artigo em Inglês | MEDLINE | ID: mdl-28220142

RESUMO

Junin virus (JUNV), a highly pathogenic New World arenavirus, is the causative agent of Argentine hemorrhagic fever (AHF). The live-attenuated Candid #1 (Can) strain currently serves as a vaccine for at-risk populations. We have previously shown that the Can glycoprotein (GPC) gene is the primary gene responsible for attenuation in a guinea pig model of AHF. However, the mechanisms through which the GPC contributes to the attenuation of the Can strain remain unknown. A more complete understanding of the mechanisms underlying the attenuation and immunogenicity of the Can strain will potentially allow for the rational design of additional safe and novel vaccines. Here, we provide a detailed comparison of both RNA and protein expression profiles between both inter- and intra-segment chimeric JUNV recombinant clones expressing combinations of genes from the Can strain and the pathogenic Romero (Rom) strain. The recombinant viruses that express Can GPC, which were shown to be attenuated in guinea pigs, displayed different RNA levels and GPC processing patterns as determined by Northern and Western blot analyses, respectively. Analysis of recombinant viruses containing amino acid substitutions selected at different mouse brain passages during the generation of Can revealed that altered Can GPC processing was primarily due to the T168A substitution within G1, which eliminates an N-linked glycosylation motif. Incorporation of the T168A substitution in the Rom GPC resulted in a Can-like processing pattern of Rom GPC. In addition, JUNV GPCs containing T168A substitution were retained within the endoplasmic reticulum (ER) and displayed significantly lower cell surface expression than wild-type Rom GPC. Interestingly, the reversion A168T in Can GPC significantly increased GPC expression at the cell surface. Our results demonstrate that recombinant JUNV (rJUNV) expressing Can GPC display markedly different protein expression and elevated genomic RNA expression when compared to viruses expressing Rom GPC. Additionally, our findings indicate that the N-linked glycosylation motif at amino acid positions 166-168 is important for trafficking of JUNV GPC to the cell surface, and the elimination of this motif interferes with the GPC release from the ER.


Assuntos
Motivos de Aminoácidos , Arenavirus do Novo Mundo/imunologia , Glicoproteínas/genética , Glicoproteínas/metabolismo , Febre Hemorrágica Americana , Vacinas Virais , Animais , Arenavirus do Novo Mundo/genética , Linhagem Celular , Células Cultivadas , Cricetinae , Retículo Endoplasmático/metabolismo , Estresse do Retículo Endoplasmático , Expressão Gênica , Regulação Viral da Expressão Gênica , Glicoproteínas/química , Glicoproteínas/imunologia , Glicosilação , Febre Hemorrágica Americana/imunologia , Febre Hemorrágica Americana/metabolismo , Febre Hemorrágica Americana/prevenção & controle , Febre Hemorrágica Americana/virologia , Humanos , Processamento de Proteína Pós-Traducional , Transporte Proteico , Transcrição Genética , Vacinas Virais/genética , Vacinas Virais/imunologia , Virulência
20.
Early Hum Dev ; 104: 23-26, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27960112

RESUMO

BACKGROUND: Digit ratio (2D:4D) is a sexually dimorphic trait and its determination in utero is influenced by testosterone. The solstitial-melatonin-testosterone hypothesis posits that melatonin inhibits the production of foetal testosterone and melatonin levels are at their lowest in months when light levels are high. AIMS: We test the relationship between 2D:4D, month-of-birth and light levels. STUDY DESIGN: We recruited participants whose year of birth was spread across the 20th Century. SUBJECTS: 323 Polish men and women. OUTCOME MEASURES: Finger lengths, month-of-birth, mean daylight hours per month in and around Poznan, Poland. RESULTS: Our sample was born between 1907 and 1997. In comparison to late-Spring births, late-Autumn births had low right-left 2D:4D (high prenatal testosterone). Regarding light levels, there were significant relationships between low right 2D:4D and right-left 2D:4D (high prenatal testosterone) and long days at the end of the 1st trimester. These relationships were strongest for participants born in the first half of the 20th Century. CONCLUSIONS: Participants born in the late-Autumn and who experienced long days in the 2nd and 3rd prenatal months had low 2D:4D. The effects were strongest for early 20th Century births where photoperiods would be less disrupted by artificial light.


Assuntos
Declaração de Nascimento , Dedos/anatomia & histologia , Melatonina/metabolismo , Estações do Ano , Testosterona/metabolismo , Adulto , Fenômenos Astronômicos , Feminino , Dedos/crescimento & desenvolvimento , Humanos , Masculino , Fotoperíodo
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