Development of reverse genetics system for Guanarito virus: substitution of E1497K in the L protein of Guanarito virus S-26764 strain changes plaque phenotype and growth kinetics.

Guanarito virus (GTOV) is the causative agent of Venezuelan hemorrhagic fever. GTOV belongs to the genus Mammarenavirus, family Arenaviridae and has been classified as a Category A bioterrorism agent by the United States Centers for Disease Control and Prevention. Despite being a high-priority agent, vaccines and drugs against Venezuelan hemorrhagic fever are not available. GTOV S-26764, isolated from a non-fatal human case, produces an unclear cytopathic effect (CPE) in Vero cells, posing a significant obstacle to research and countermeasure development efforts. Vero cell-adapted GTOV S-26764 generated in this study produced clear CPE and demonstrated rapid growth and high yield in Vero cells compared to the original GTOV S-26764. We developed a reverse genetics system for GTOV to study amino acid changes acquired through Vero cell adaptation and leading to virus phenotype changes. The results demonstrated that E1497K in the L protein was responsible for the production of clear plaques as well as enhanced viral RNA replication and transcription efficiency. Vero cell-adapted GTOV S-26764, capable of generating CPE, will allow researchers to easily perform neutralization assays and anti-drug screening against GTOV. Moreover, the developed reverse genetics system will accelerate vaccine and antiviral drug development.IMPORTANCEGuanarito virus (GTOV) is a rodent-borne virus. GTOV causes fever, prostration, headache, arthralgia, cough, sore throat, nausea, vomiting, diarrhea, epistaxis, bleeding gums, menorrhagia, and melena in humans. The lethality rate is 23.1% or higher. Vero cell-adapted GTOV S-26764 shows a clear cytopathic effect (CPE), whereas the parental virus shows unclear CPE in Vero cells. We generated a reverse genetics system to rescue recombinant GTOVs and found that E1497K in the L protein was responsible for the formation of clear plaques as well as enhanced viral RNA replication and transcription efficiency. This reverse genetic system will accelerate vaccine and antiviral drug developments, and the findings of this study contribute to the understanding of the function of GTOV L as an RNA polymerase.

CD4 T-cell depletion prevents Lassa fever associated hearing loss in the mouse model.

Lassa virus (LASV) is the causative agent of Lassa fever (LF), which presents as a lethal hemorrhagic disease in severe cases. LASV-induced hearing loss in survivors is a huge socioeconomic burden, however, the mechanism(s) leading to hearing loss is unknown. In this study, we evaluate in a mouse LF model the auditory function using auditory brainstem response (ABR) and distortion product otoacoustic emissions (DPOAE) to determine the mechanisms underlying LASV-induced hearing loss. In the process, we pioneered measures of ABR and DPOAE tests in rodents in biosafety level 4 (BSL-4) facilities. Our T cell depletion studies demonstrated that CD4 T-cells play an important role in LASV-induced hearing loss, while CD8 T-cells are critical for the pathogenicity in the acute phase of LASV infection. Results presented in this study may help to develop future countermeasures against acute disease and LASV-induced hearing loss.

Digit Ratio (2D:4D; Right-Left 2D:4D) and Multiple Phenotypes for Same-Sex Attraction: The BBC Internet Study Revisited.

Same-sex attraction may be linked to low prenatal androgen (in men) and high prenatal androgen (in women). Digit ratio (2D:4D) is thought to be a negative correlate of prenatal androgen and right-left 2D:4D (Dr-l) to reflect lateralized differences in sensitivity to prenatal androgen. Lower 2D:4D has been reported for lesbians compared to heterosexuals, but links to high 2D:4D in gay men are less clear. The largest study thus far (the BBC Internet study) found no significant difference between the 2D:4D of lesbians and heterosexual women but a higher 2D:4D in gay men compared to heterosexual men. Here we consider the possibility that low and high prenatal androgen is associated with same-sex attraction in men (n = 108,779) and women (n = 87,742), resulting in more than two phenotypes. We examined the associations between 2D:4D, Dr-l, and same-sex attraction scores in the BBC Internet study. In contrast to the earlier report, which considered sexual orientation in categories, there were positive linear associations in men (right and left 2D:4D, but not Dr-l) and negative linear associations in women (right 2D:4D and Dr-l, but not left 2D:4D). There were no curvilinear relationships for right and left 2D:4D. However, Dr-l showed a U-shaped association with same-sex attraction in men. Thus, (1) high prenatal androgen may be implicated in female homosexuality, while both low and high prenatal androgen may be implicated in male homosexuality, and (2) large side differences in sensitivity to androgen may be associated with elevated same-sex attraction in men.

The associations between digit ratio (2D:4D and right - left 2D:4D), maximal oxygen consumption and ventilatory thresholds in professional male football players.

INTRODUCTION: Digit ratio (2D:4D: the relative length of the 2nd and 4th digit) is thought to be a negative correlate of prenatal testosterone. The 2D:4D is related to oxygen metabolism, but the precise nature of this relationship is unclear. The purpose of the present study was to consider associations between digit ratios (right 2D:4D, left 2D:4D, right-left 2D:4D [Dr-l]) and VO2max and ventilatory thresholds (VT1 and VT2). METHODS: One hundred and thirty-three Caucasian (n = 133) professional football players competing in Cyprus participated in the study. Players underwent anthropometric measurements, and digit lengths were measured from hand scans. They also completed an incremental cardiopulmonary test to exhaustion on a treadmill. RESULTS: There were negative correlations between digit ratios and VO2max (right 2D:4D, r = -.65; left 2D:4D r = -.37, both p < .0001; Dr-l r = -.30, p = .0005). There were no relationships between digit ratios and VT1. For VT2, there were negative relationships with digit ratios (right 2D:4D, r = -.43, p < .0001; left 2D:4D, r = -.21 and Dr-l, r = -.21, both p = .02). Digit ratios are negatively related to VO2max with large (right 2D:4D) and medium (left 2D:4D, Dr-l) effect sizes. For VT2, there were also negative correlations, which were medium (right 2D:4D) and small (left 2D:4D, Dr-l). CONCLUSION: Our findings may help clarify the relationships between digit ratios and high-intensity actions for extended periods, which are dependent on efficient oxygen metabolism.

Machupo Virus with Mutations in the Transmembrane Domain and Glycosylation Sites of the Glycoprotein Is Attenuated and Immunogenic in Animal Models of Bolivian Hemorrhagic Fever.

Several highly pathogenic mammarenaviruses cause severe hemorrhagic and neurologic disease in humans for which vaccines and antivirals are limited or unavailable. New World (NW) mammarenavirus Machupo virus (MACV) infection causes Bolivian hemorrhagic fever in humans. We previously reported that the disruption of specific N-linked glycan sites on the glycoprotein (GPC) partially attenuates MACV in an interferon alpha/beta and gamma (IFN-α/ß and -γ) receptor knockout (R-/-) mouse model. However, some capability to induce neurological pathology still remained. The highly pathogenic Junin virus (JUNV) is another NW arenavirus closely related to MACV. An F427I substitution in the GPC transmembrane domain (TMD) rendered JUNV attenuated in a lethal mouse model after intracranial inoculation. In this study, we rationally designed and rescued a MACV containing mutations at two glycosylation sites and the corresponding F438I substitution in the GPC TMD. The MACV mutant is fully attenuated in IFN-α/ß and -γ R-/- mice and outbred guinea pigs. Furthermore, inoculation with this mutant MACV completely protected guinea pigs from wild-type MACV lethal challenge. Last, we found the GPC TMD F438I substitution greatly impaired MACV growth in neuronal cell lines of mouse and human origins. Our results highlight the critical roles of the glycans and the TMD on the GPC in arenavirus virulence, which provide insight into the rational design of potential vaccine candidates for highly pathogenic arenaviruses. IMPORTANCE For arenaviruses, the only vaccine available is the live attenuated Candid#1 vaccine, a JUNV vaccine approved in Argentina. We and others have found that the glycans on GPC and the F427 residue in the GPC TMD are important for virulence of JUNV. Nevertheless, mutating either of them is not sufficient for full and stable attenuation of JUNV. Using reverse genetics, we disrupted specific glycosylation sites on MACV GPC and also introduced the corresponding F438I substitution in the GPC TMD. This MACV mutant is fully attenuated in two animal models and protects animals from lethal infection. Thus, our studies highlight the feasibility of rational attenuation of highly pathogenic arenaviruses for vaccine development. Another important finding from this study is that the F438I substitution in GPC TMD could substantially affect MACV replication in neurons. Future studies are warranted to elucidate the underlying mechanism and the implication of this mutation in arenavirus neural tropism.

Glycoprotein N-linked glycans play a critical role in arenavirus pathogenicity.

Several arenaviruses cause hemorrhagic fevers in humans with high case fatality rates. A vaccine named Candid#1 is available only against Junin virus (JUNV) in Argentina. Specific N-linked glycans on the arenavirus surface glycoprotein (GP) mask important epitopes and help the virus evade antibody responses. However the role of GPC glycans in arenavirus pathogenicity is largely unclear. In a lethal animal model of hemorrhagic fever-causing Machupo virus (MACV) infection, we found that a chimeric MACV with the ectodomain of GPC from Candid#1 vaccine was partially attenuated. Interestingly, mutations resulting in acquisition of N-linked glycans at GPC N83 and N166 frequently occurred in late stages of the infection. These glycosylation sites are conserved in the GPC of wild-type MACV, indicating that this is a phenotypic reversion for the chimeric MACV to gain those glycans crucial for infection in vivo. Further studies indicated that the GPC mutant viruses with additional glycans became more resistant to neutralizing antibodies and more virulent in animals. On the other hand, disruption of these glycosylation sites on wild-type MACV GPC rendered the virus substantially attenuated in vivo and also more susceptible to antibody neutralization, while loss of these glycans did not affect virus growth in cultured cells. We also found that MACV lacking specific GPC glycans elicited higher levels of neutralizing antibodies against wild-type MACV. Our findings revealed the critical role of specific glycans on GPC in arenavirus pathogenicity and have important implications for rational design of vaccines against this group of hemorrhagic fever-causing viruses.

Superior Capsule Reconstruction With Fascia Lata Allograft Has Initial Stiffness and Ultimate Load Comparable to the Native Shoulder Superior Capsule: A Cadaveric Biomechanical Study.

PURPOSE: The purpose of this study was to compare the biomechanical characteristics of a fascia lata superior capsule reconstruction (FL-SCR) to the native superior capsule. METHODS: The native superior capsule of 8 cadaveric shoulders was tested with cyclic loading from 10 to 50 N for 30 cycles in 20° of glenohumeral abduction followed by load to failure at 60 mm/min. Following native superior capsule testing, FL-SCR was performed, which was tested as described for the native capsule. Paired t test was used for statistical analyses with P < .05 for significance. RESULTS: The stiffness for cycle 1 to 50 N was significantly higher for the native superior capsule compared to the FL-SCR (P = .001). By cycle 30, the stiffness between the two was not statistically different (P = .734). During load to failure, the initial stiffness to 2 mm for the FL-SCR and the native superior capsule was not statistically different (P = .262). The linear stiffness and yield load of the native superior capsule were significantly greater than that of the FL-SCR (94.5 vs 28.0 N/mm, P = .013; 386.9 vs 123.8 N, P = .029). There was no significant difference in ultimate load between the native superior capsule and the FL-SCR (444.9 vs 369.0 N, P = .413). CONCLUSIONS: FL-SCR has initial stiffness and ultimate load similar to the native superior capsule. CLINICAL RELEVANCE: The biomechanical properties of FL allograft make it an appealing option as a graft choice for superior capsule reconstruction.

Implementation of a Urinary Tract Infection Management Pathway to Evaluate Emergency Department Length of Stay in a Pediatric Emergency Department.

STUDY OBJECTIVE: Point-of-care urine testing is an alternative to urine microscopy in children. However, it remains unclear if utilizing point-of-care urine testing without urine microscopy decreases length of stay in the emergency department (ED). We implemented a point-of-care-driven urinary tract infection management pathway to evaluate effects on length of stay. METHODS: This was an uncontrolled before and after study examining a point-of-care urinalysis pathway in a children's ED. We obtained preliminary data by prospectively evaluating urine microscopy. We then implemented a pathway in which point-of-care urine testing determined treatment and disposition. Outcomes included time from urinalysis order to discharge order, length of stay, and rate of delayed treatment. RESULTS: A total of 118 patients were enrolled before pathway initiation, and 97 patients were enrolled after. Demographics and infection rates were similar between the 2 groups. When urine microscopy was compared to point-of-care urine testing, there were significant reductions in time from urinalysis order to discharge order (median difference of 30 minutes; 95% confidence interval 19 to 42 minutes) and length of stay (median difference of 36 minutes; 95% confidence interval 19 to 55 minutes). There was no treatment delayed because of institution of the point-of-care pathway. CONCLUSION: Using point-of-care urine testing as an alternative to urine microscopy significantly reduced pediatric ED length of stay and time from urinalysis order to discharge order.

The Antiviral Effects of 2-Deoxy-D-glucose (2-DG), a Dual D-Glucose and D-Mannose Mimetic, against SARS-CoV-2 and Other Highly Pathogenic Viruses.

Viral infection almost invariably causes metabolic changes in the infected cell and several types of host cells that respond to the infection. Among metabolic changes, the most prominent is the upregulated glycolysis process as the main pathway of glucose utilization. Glycolysis activation is a common mechanism of cell adaptation to several viral infections, including noroviruses, rhinoviruses, influenza virus, Zika virus, cytomegalovirus, coronaviruses and others. Such metabolic changes provide potential targets for therapeutic approaches that could reduce the impact of infection. Glycolysis inhibitors, especially 2-deoxy-D-glucose (2-DG), have been intensively studied as antiviral agents. However, 2-DG's poor pharmacokinetic properties limit its wide clinical application. Herein, we discuss the potential of 2-DG and its novel analogs as potent promising antiviral drugs with special emphasis on targeted intracellular processes.

The Glycoprotein of the Live-Attenuated Junin Virus Vaccine Strain Induces Endoplasmic Reticulum Stress and Forms Aggregates prior to Degradation in the Lysosome.

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.

Biogeographic origins of southern African Silene (Caryophyllaceae).

Silene (Caryophyllaceae) is distributed predominantly in the northern Hemisphere, where it is most diverse around the Mediterranean Basin. The genus is also well represented in North Africa, extending into tropical, sub-Saharan and southern Africa. Eight native species are recognized in southern Africa, taxonomically placed in two sections: Elisanthe and Silene s.l. Although the taxonomy of the southern African taxa has recently been revised, their phylogenetic relationships and biogeographic history remain unclear. This study aims to infer the phylogenetic position and geographic origins of the southern African taxa. We generated DNA sequences of nuclear and plastid loci from several individuals belonging to all eight species of Silene recognized from southern Africa, and combined our DNA sequences with existing data representing species from major clades (i.e. sections) based on the recently revised Silene infrageneric taxonomy. We used a Bayesian coalescent species tree continuous diffusion approach to co-estimate the species tree and the ancestral areas of representative members of the genus. Our results show that the perennial southern African members of section Elisanthe form a strongly-supported clade with the Eurasian annual S. noctiflora and the Central Asian perennial S. turkestanica. The rest of the perennial species form a strongly-supported clade together with the annual S. aethiopica, which is nested in a larger Mediterranean clade comprising mostly annual species classified in section Silene s.l. Estimates of ancestral areas indicate a late Pleistocene dispersal to southern Africa from central and East Africa for the sub-Saharan members of section Silene s.l. The Elisanthe clade is inferred to have colonized southern Africa through long-distance dispersal from Eurasia during the late Pleistocene. Our findings support the hypothesis of a relatively recent colonization into southern Africa resulting from two independent dispersal events during the Pleistocene.

Daily physical activity and alcohol use among young adults.

Evidence suggests that physical activity and alcohol use are positively related among young adults. Two studies have examined daily relations, and results have shown conflicting findings. We examined relations between physical activity and alcohol use at both within- and between-individual levels and investigated moderators of the relation at both levels. 269 college students wore accelerometers to collect physical activity data over a 2-week period. At the end of each day, they indicated whether or not they drank alcohol. Multilevel logistic regression indicated neither within- nor between-subject relations were statistically significant. Positive affect, negative affect, and drinking motives moderated these relations at the between-subject level. Contrary to previous research, we did not observe a relation between physical activity and alcohol use at the daily level. Unique features of the current study suggest next steps for future research examining the perplexing PA-alcohol relation in this population.

Focal Rosai-Dorfman disease coexisting with lymphoma in the same anatomic site: a localized histiocytic proliferation associated with MAPK/ERK pathway activation.

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.

Prevalence of a Histologic Change of Ocular Adnexal Lymphoma in Patients With a History of Lymphoma.

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.

Sexual dimorphism in the ontogeny of second (2D) and fourth (4D) digit lengths, and digit ratio (2D:4D).

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.

Relationships between the second to fourth digit ratio (2D:4D) and game-related statistics in semi-professional female basketball players.

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.

Relationships between the digit ratio (2D:4D) and game-related statistics in professional and semi-professional male basketball players.

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.

Relationships between digit ratio (2D:4D) and basketball performance in Australian men.

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.

The glycoprotein precursor gene of Junin virus determines the virulence of the Romero strain and the attenuation of the Candid #1 strain in a representative animal model of Argentine hemorrhagic fever.

UNLABELLED: The New World arenavirus Junin virus (JUNV) is the causative agent of Argentine hemorrhagic fever (AHF), a potentially deadly disease endemic to central regions of Argentina. The live-attenuated Candid #1 (Can) strain of JUNV is currently used to vaccinate the human population at risk. However, the mechanism of attenuation of this strain is still largely unknown. Therefore, the identification and functional characterization of viral genetic determinants dictating JUNV virulence or attenuation would significantly improve the understanding of the mechanisms underlying AHF and facilitate the development of novel, more effective, and safer vaccines. Here, we utilized a reverse genetics approach to generate recombinant JUNV (rJUNV) strains encoding different gene combinations of the pathogenic Romero (Rom) and attenuated Can strains of JUNV. All strains of rJUNV exhibited in vitro growth kinetics similar to those of their parental counterparts. Analysis of virulence of the rJUNV in a guinea pig model of lethal infection that closely reproduces the features of AHF identified the envelope glycoproteins (GPs) as the major determinants of pathogenesis and attenuation of JUNV. Accordingly, rJUNV strains expressing the full-length GPs of Rom and Can exhibited virulent and attenuated phenotypes, respectively, in guinea pigs. Mutation F427I in the transmembrane region of JUNV envelope glycoprotein GP2 has been shown to attenuate the neurovirulence of JUNV in suckling mice. We document that in the guinea pig model of AHF, mutation F427I in GP2 is also highly attenuating but insufficient to prevent virus dissemination and development of mild clinical and pathological symptoms, indicating that complete attenuation of JUNV requires additional mutations present in Can glycoprotein precursor (GPC). IMPORTANCE: Development of antiviral strategies against viral hemorrhagic fevers, including AHF, is one of the top priorities within the Implementation Plan of the U.S. Department of Health and Human Services Public Health Emergency Medical Countermeasures Enterprise. Live-attenuated Candid #1 strain, derived from the 44th mouse brain passage of the prototype XJ strain of JUNV, has been demonstrated to be safe, immunogenic, and highly protective and is currently licensed for human use in Argentina. However, the bases for the attenuated phenotype of Candid #1 have not been established. Therefore, the identification and functional characterization of viral genetic factors implicated in JUNV pathogenesis and attenuation would significantly improve the understanding of the molecular mechanisms underlying AHF and facilitate the development of novel antiviral strategies.

Prognostic value of miR-155 in individuals with monoclonal B-cell lymphocytosis and patients with B chronic lymphocytic leukemia.

Noncoding RNAs play a pivotal role in the pathogenesis of chronic lymphocytic leukemia (CLL). We hypothesized that microRNAs (miRs) are involved in the transition from monoclonal B-cell lymphocytosis (MBL) to CLL and tested miR-15a/16-1 cluster, miR-21, and miR-155 expression in purified B cells of normal individuals, individuals with MBL, and patients with CLL. When we analyzed 224 samples from 2 independent training and validation cohorts, we found that miR-155 was overexpressed in B cells from individuals with MBL, and even more so in B cells from patients with CLL, when compared with B cells from normal individuals. Furthermore, we were able to identify miR-155 in circulating microvesicles from both individuals with MBL and patients with CLL. Next, to examine the prognostic role of miR-155, we measured its expression level in plasma samples collected before treatment initiation in 228 patients with CLL. We found significantly higher miR-155 expression levels in patients who failed to achieve a complete response compared with those who experienced complete response. Our findings support the use of cellular and plasma levels of miR-155 as biomarkers for the risk of progression in individuals with MBL, as well as to identify patients with CLL who may not respond well to therapy.