bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genotype Considerations for Virus-Like Particle-Based Bivalent Norovirus Vaccine Composition
Authors: Malm Maria , Tamminen Kirsi , Lappalainen Suvi , Uusi-Kerttula Hanni , Vesikari Timo , Blazevic Vesna 
Published: April 2015

ABSTRACT
Norovirus (NoV) genogroup I (GI) and GII are responsible for most human infections with NoV. Because of the high genetic variability of NoV, natural infection does not induce sufficient protective immunity to different genotypes or to variants of the same genotype and there is little or no cross-protection against different genogroups. NoV-derived virus-like particles (VLPs) are promising vaccine candidates that induce high levels of NoV-specific humoral and cellular immune responses. It is believed that a bivalent NoV vaccine consisting of a representative VLP from GI and GII is a minimum requirement for an effective vaccine. Here, we compared the abilities of monovalent immunizations with NoV GI.1-2001, GI.3-2002, GII.4-1999, and GII.4-2010 New Orleans VLPs to induce NoV type-specific and cross-reactive immune responses and protective blocking antibody responses in BALB/c mice. All of the VLPs induced comparable levels of type-specific serum IgG antibodies, as well as blocking antibodies to the VLPs used for immunization. However, the abilities of different VLP genotypes to induce cross-reactive IgG and cross-blocking antibodies varied remarkably. Our results confirm previous findings of a lack of cross-protective immune responses between GI and GII NoVs. These data support the rationale for including NoV GI.3 and GII.4-1999 VLPs in the bivalent vaccine formulation, which could be sufficient to induce protective immune responses across NoV genotypes in the two common genogroups in humans.
Molecular Basis of Resistance to Selected Antimicrobial Agents in the Emerging Zoonotic Pathogen Streptococcus suis
Authors: Gurung Mamata , Tamang Migma Dorji , Moon Dong Chan , Kim Su-Ran , Jeong Jin-Ha , Jang Geum-Chan , Jung Suk-Chan , Park Yong-Ho , Lim Suk-Kyung 
Published: April 2015

ABSTRACT

Characterization of 227
Streptococcus suis
strains isolated from pigs during 2010 to 2013 showed high levels of resistance to clindamycin (95.6%), tilmicosin (94.7%), tylosin (93.8%), oxytetracycline (89.4%), chlortetracycline (86.8%), tiamulin (72.7%), neomycin (70.0%), enrofloxacin (56.4%), penicillin (56.4%), ceftiofur (55.9%), and gentamicin (55.1%). Resistance to tetracyclines, macrolides, aminoglycosides, and fluoroquinolone was attributed to the
tet
gene,
erm
(B),
erm
(C),
mph
(C), and
mef
(A) and/or
mef
(E) genes,
aph(3′)-IIIa
and
aac(6′)-Ie-aph(2″)-Ia
genes, and single point mutations in the quinolone resistance-determining region of ParC and GyrA, respectively.
Comparative Profile of Heme Acquisition Genes in Disease-Causing and Colonizing Nontypeable Haemophilus influenzae and Haemophilus haemolyticus
Authors: Hariadi Nurul I. , Zhang Lixin , Patel Mayuri , Sandstedt Sara A. , Davis Gregg S. , Marrs Carl F. , Gilsdorf Janet R. 
Published: April 2015

ABSTRACT

Nontypeable
Haemophilus influenzae
(NTHI) are Gram-negative bacteria that colonize the human pharynx and can cause respiratory tract infections, such as acute otitis media (AOM). Since NTHI require iron from their hosts for aerobic growth, the heme acquisition genes may play a significant role in avoiding host nutritional immunity and determining virulence. Therefore, we employed a hybridization-based technique to compare the prevalence of five heme acquisition genes (
hxuA
,
hxuB
,
hxuC
,
hemR
, and
hup
) between 514 middle ear strains from children with AOM and 235 throat strains from healthy children. We also investigated their prevalences in 148
Haemophilus haemolyticus
strains, a closely related species that colonizes the human pharynx and is considered to be nonpathogenic. Four out of five genes (
hxuA
,
hxuB
,
hxuC
, and
hemR
) were significantly more prevalent in the middle ear strains (96%, 100%, 100%, and 97%, respectively) than in throat strains (80%, 92%, 93%, and 85%, respectively) of NTHI, suggesting that strains possessing these genes have a virulence advantage over those lacking them. All five genes were dramatically more prevalent in NTHI strains than in
H. haemolyticus
, with 91% versus 9%
hxuA
, 98% versus 11%
hxuB
, 98% versus 11%
hxuC
, 93% versus 20%
hemR
, and 97% versus 34%
hup
, supporting their potential role in virulence and highlighting their possibility to serve as biomarkers to distinguish
H. influenzae
from
H. haemolyticus
. In summary, this study demonstrates that heme acquisition genes are more prevalent in disease-causing NTHI strains isolated from the middle ear than in colonizing NTHI strains and
H. haemolyticus
isolated from the pharynx.
High-Level Pan-Azole-Resistant Aspergillosis
Authors: van Ingen Jakko , van der Lee Henrich A. L. , Rijs Antonius J. M. M. , Snelders Eveline , Melchers Willem J. G. , Verweij Paul E. 
Published: April 2015

ABSTRACT

High-level pan-azole-resistant
Aspergillus fumigatus
was recovered from four patients with chronic lung disease. In one patient, the development of progressive resistance followed long-term azole therapy and switching between antifungal azoles. The high-level pan-azole-resistant phenotypes were not associated with a specific
cyp51A
gene mutation. New strategies that avoid the development of progressive azole resistance are needed.
Impact of the MRN Complex on Adeno-Associated Virus Integration and Replication during Coinfection with Herpes Simplex Virus 1
Authors: Millet Rachel , Jolinon Nelly , Nguyen Xuan-Nhi , Berger Gregory , Cimarelli Andrea , Greco Anna , Bertrand Pascale , Odenthal Margarete , Büning Hildegard , Salvetti Anna 
Published: April 2015

ABSTRACT
Adeno-associated virus (AAV) is a helper-dependent parvovirus that requires coinfection with adenovirus (AdV) or herpes simplex virus 1 (HSV-1) to replicate. In the absence of the helper virus, AAV can persist in an episomal or integrated form. Previous studies have analyzed the DNA damage response (DDR) induced upon AAV replication to understand how it controls AAV replication. In particular, it was shown that the Mre11-Rad50-Nbs1 (MRN) complex, a major player of the DDR induced by double-stranded DNA breaks and stalled replication forks, could negatively regulate AdV and AAV replication during coinfection. In contrast, MRN favors HSV-1 replication and is recruited to AAV replication compartments that are induced in the presence of HSV-1. In this study, we examined the role of MRN during AAV replication induced by HSV-1. Our results indicated that knockdown of MRN significantly reduced AAV DNA replication after coinfection with wild-type (wt) HSV-1 or HSV-1 with the polymerase deleted. This effect was specific to wt AAV, since it did not occur with recombinant AAV vectors. Positive regulation of AAV replication by MRN was dependent on its DNA tethering activity but did not require its nuclease activities. Importantly, knockdown of MRN also negatively regulated AAV integration within the human AAVS1 site, both in the presence and in the absence of HSV-1. Altogether, this work identifies a new function of MRN during integration of the AAV genome and demonstrates that this DNA repair complex positively regulates AAV replication in the presence of HSV-1.

IMPORTANCE
Viral DNA genomes trigger a DNA damage response (DDR), which can be either detrimental or beneficial for virus replication. Adeno-associated virus (AAV) is a defective parvovirus that requires the help of an unrelated virus such as adenovirus (AdV) or herpes simplex virus 1 (HSV-1) for productive replication. Previous studies have demonstrated that the cellular Mre11-Rad50-Nbs1 (MRN) complex, a sensor and regulator of the DDR, negatively regulates AAV replication during coinfection with AdV, which counteracts this effect by inactivating the complex. Here, we demonstrate that MRN positively regulates AAV replication during coinfection with HSV-1. Importantly, our study also indicates that MRN also favors integration of AAV genomes within the human AAVS1 site. Altogether, this work indicates that MRN differentially regulates AAV replication depending on the helper virus which is present and identifies a new function of this DNA repair complex during AAV integration.
Plasmacytoid Dendritic Cell Infection and Sensing Capacity during Pathogenic and Nonpathogenic Simian Immunodeficiency Virus Infection
Authors: Jochems Simon P. , Jacquelin Beatrice , Chauveau Lise , Huot Nicolas , Petitjean Gaël , Lepelley Alice , Liovat Anne-Sophie , Ploquin Mickaël J. , Cartwright Emily K. , Bosinger Steven E. , Silvestri Guido , Barré-Sinoussi Françoise , Lebon Pierre , Schwartz Olivier , Müller-Trutwin Michaela C. 
Published: April 2015

ABSTRACT

Human immunodeficiency virus (HIV) in humans and simian immunodeficiency virus (SIV) in macaques (MAC) lead to chronic inflammation and AIDS. Natural hosts, such as African green monkeys (AGM) and sooty mangabeys (SM), are protected against SIV-induced chronic inflammation and AIDS. Here, we report that AGM plasmacytoid dendritic cells (pDC) express extremely low levels of CD4, unlike MAC and human pDC. Despite this, AGM pDC efficiently sensed SIVagm, but not heterologous HIV/SIV isolates, indicating a virus-host adaptation. Moreover, both AGM and SM pDC were found to be, in contrast to MAC pDC, predominantly negative for CCR5. Despite such limited CD4 and CCR5 expression, lymphoid tissue pDC were infected to a degree similar to that seen with CD4
+
T cells in both MAC and AGM. Altogether, our finding of efficient pDC infection by SIV
in vivo
identifies pDC as a potential viral reservoir in lymphoid tissues. We discovered low expression of CD4 on AGM pDC, which did not preclude efficient sensing of host-adapted viruses. Therefore, pDC infection and efficient sensing are not prerequisites for chronic inflammation. The high level of pDC infection by SIVagm suggests that if CCR5 paucity on immune cells is important for nonpathogenesis of natural hosts, it is possibly not due to its role as a coreceptor.

IMPORTANCE
The ability of certain key immune cell subsets to resist infection might contribute to the asymptomatic nature of simian immunodeficiency virus (SIV) infection in its natural hosts, such as African green monkeys (AGM) and sooty mangabeys (SM). This relative resistance to infection has been correlated with reduced expression of CD4 and/or CCR5. We show that plasmacytoid dendritic cells (pDC) of natural hosts display reduced CD4 and/or CCR5 expression, unlike macaque pDC. Surprisingly, this did not protect AGM pDC, as infection levels were similar to those found in MAC pDC. Furthermore, we show that AGM pDC did not consistently produce type I interferon (IFN-I) upon heterologous SIVmac/HIV type 1 (HIV-1) encounter, while they sensed autologous SIVagm isolates. Pseudotyping SIVmac/HIV-1 overcame this deficiency, suggesting that reduced uptake of heterologous viral strains underlays this lack of sensing. The distinct IFN-I responses depending on host species and HIV/SIV isolates reveal the host/virus species specificity of pDC sensing.
Particle-to-PFU Ratio of Ebola Virus Influences Disease Course and Survival in Cynomolgus Macaques
Authors: Alfson Kendra J. , Avena Laura E. , Beadles Michael W. , Staples Hilary , Nunneley Jerritt W. , Ticer Anysha , Dick Edward J. , Owston Michael A. , Reed Christopher , Patterson Jean L. , Carrion Ricardo , Griffiths Anthony 
Published: April 2015

ABSTRACT

This study addresses the role of Ebola virus (EBOV) specific infectivity in virulence. Filoviruses are highly lethal, enveloped, single-stranded negative-sense RNA viruses that can cause hemorrhagic fever. No approved vaccines or therapies exist for filovirus infections, and infectious virus must be handled in maximum containment. Efficacy testing of countermeasures, in addition to investigations of pathogenicity and immune response, often requires a well-characterized animal model. For EBOV, an obstacle in performing accurate disease modeling is a poor understanding of what constitutes an infectious dose in animal models. One well-recognized consequence of viral passage in cell culture is a change in specific infectivity, often measured as a particle-to-PFU ratio. Here, we report that serial passages of EBOV in cell culture resulted in a decrease in particle-to-PFU ratio. Notably, this correlated with decreased potency in a lethal cynomolgus macaque (
Macaca fascicularis
) model of infection; animals were infected with the same viral dose as determined by plaque assay, but animals that received more virus particles exhibited increased disease. This suggests that some particles are unable to form a plaque in a cell culture assay but are able to result in lethal disease
in vivo
. These results have a significant impact on how future studies are designed to model EBOV disease and test countermeasures.

IMPORTANCE
Ebola virus (EBOV) can cause severe hemorrhagic disease with a high case-fatality rate, and there are no approved vaccines or therapies. Specific infectivity can be considered the total number of viral particles per PFU, and its impact on disease is poorly understood. In stocks of most mammalian viruses, there are particles that are unable to complete an infectious cycle or unable to cause cell pathology in cultured cells. We asked if these particles cause disease in nonhuman primates by infecting monkeys with equal infectious doses of genetically identical stocks possessing either high or low specific infectivities. Interestingly, some particles that did not yield plaques in cell culture assays were able to result in lethal disease
in vivo
. Furthermore, the number of PFU needed to induce lethal disease in animals was very low. Our results have a significant impact on how future studies are designed to model EBOV disease and test countermeasures.
Nonneutralizing Antibodies Induced by the HIV-1 gp41 NHR Domain Gain Neutralizing Activity in the Presence of the HIV Fusion Inhibitor Enfuvirtide: a Potential Therapeutic Vaccine Strategy
Authors: Wang Qian , Bi Wenwen , Zhu Xiaojie , Li Haoyang , Qi Qianqian , Yu Fei , Lu Lu , Jiang Shibo 
Published: April 2015

ABSTRACT
A key barrier against developing preventive and therapeutic human immunodeficiency virus (HIV) vaccines is the inability of viral envelope glycoproteins to elicit broad and potent neutralizing antibodies. However, in the presence of fusion inhibitor enfuvirtide, we show that the nonneutralizing antibodies induced by the HIV type 1 (HIV-1) gp41 N-terminal heptad repeat (NHR) domain (N63) exhibit potent and broad neutralizing activity against laboratory-adapted HIV-1 strains, including the drug-resistant variants, and primary HIV-1 isolates with different subtypes, suggesting the potential of developing gp41-targeted HIV therapeutic vaccines.
Move Over, Bacteria! Viruses Make Their Mark as Mutualistic Microbial Symbionts
Authors: Roossinck Marilyn J. 
Published: April 2015

ABSTRACT
Viruses are being redefined as more than just pathogens. They are also critical symbiotic partners in the health of their hosts. In some cases, viruses have fused with their hosts in symbiogenetic relationships. Mutualistic interactions are found in plant, insect, and mammalian viruses, as well as with eukaryotic and prokaryotic microbes, and some interactions involve multiple players of the holobiont. With increased virus discovery, more mutualistic interactions are being described and more will undoubtedly be discovered.
A cluster randomised trial of cloth masks compared with medical masks in healthcare workers
Authors: MacIntyre C Raina , Seale Holly , Dung Tham Chi , Hien Nguyen Tran , Nga Phan Thi , Chughtai Abrar Ahmad , Rahman Bayzidur , Dwyer Dominic E , Wang Quanyi 
Published: April 2015

Editor's NoteThe authors of this article, published in 2015, have written a response to their work in light of the COVID-19 pandemic. We urge our readers to consider the response when reading the article.https://bmjopen.bmj.com/content/5/4/e006577.responses#covid-19-shortages-of-masks-and-the-use-of-cloth-masks-as-a-last-resortObjectiveThe aim of this study was to compare the efficacy of cloth masks to medical masks in hospital healthcare workers (HCWs). The null hypothesis is that there is no difference between medical masks and cloth masks.Setting14 secondary-level/tertiary-level hospitals in Hanoi, Vietnam.Participants1607 hospital HCWs aged ≥18 years working full-time in selected high-risk wards.InterventionHospital wards were randomised to: medical masks, cloth masks or a control group (usual practice, which included mask wearing). Participants used the mask on every shift for 4 consecutive weeks.Main outcome measureClinical respiratory illness (CRI), influenza-like illness (ILI) and laboratory-confirmed respiratory virus infection.ResultsThe rates of all infection outcomes were highest in the cloth mask arm, with the rate of ILI statistically significantly higher in the cloth mask arm (relative risk (RR)=13.00, 95% CI 1.69 to 100.07) compared with the medical mask arm. Cloth masks also had significantly higher rates of ILI compared with the control arm. An analysis by mask use showed ILI (RR=6.64, 95% CI 1.45 to 28.65) and laboratory-confirmed virus (RR=1.72, 95% CI 1.01 to 2.94) were significantly higher in the cloth masks group compared with the medical masks group. Penetration of cloth masks by particles was almost 97% and medical masks 44%.ConclusionsThis study is the first RCT of cloth masks, and the results caution against the use of cloth masks. This is an important finding to inform occupational health and safety. Moisture retention, reuse of cloth masks and poor filtration may result in increased risk of infection. Further research is needed to inform the widespread use of cloth masks globally. However, as a precautionary measure, cloth masks should not be recommended for HCWs, particularly in high-risk situations, and guidelines need to be updated.Trial registration numberAustralian New Zealand Clinical Trials Registry: ACTRN12610000887077.
Paediatric reference interval and biological variation trends of thyrotropin (TSH) and free thyroxine (T4) in an Asian population
Authors: Loh Tze Ping , Sethi Sunil Kumar , Metz Michael Patrick 
Published: April 2015

AimsTo describe the reference intervals and biological variation data for thyrotropin (TSH) and free thyroxine (FT4) in a mixed Asian population using an indirect sampling approach and to compare them with published reports.MethodsTSH and FT4 of children measured once or twice over a 7-year period (2008–2014) at primary-care and tertiary-care settings were extracted from the laboratory information system. After excluding outliers, age-related reference intervals were derived using the Lambda-Mu-Sigma (LMS) approach, while age-partitioned biological variation data were obtained according to recommendations by Fraser and Harris.ResultsBoth TSH and FT4 were very high at birth and declined with age. Similarly within-individual and between-individual biological variations were higher for both TSH and FT4 at birth and also declined with age. Our data were broadly similar to previous studies. Significant heterogeneity in study population and methods prohibited direct numerical comparison between this and previously published studies.ConclusionsThis study fills two important gaps in our knowledge of paediatric thyroid function by reporting the centile trends (and reference values) in a mixed Asian population, as well as providing age-partitioned biological variation data. The variation in published reference intervals highlights the difficulty in harmonising paediatric thyroid reference intervals or recommending universal clinical cut-offs.
Behaviourally designed treatments that increase willingness to treatment from families with children suffering from autism spectrum disorder
Authors: Bogliacino Francesco , Parra Forero Israel Andrés 
Published: April 2015

BackgroundAutism spectrum disorder is a lifelong disability that is not well known by the general population and tends to be associated with social stigma; also, because it involves children, it may get highly emotionally charged. These stylised facts engender a number of possible heuristics and biases at the moment of deciding on following a treatment or looking for a diagnosis, which should be considered in the presentation of information. Using insights from Behavioural Economics, three treatments are designed to present the information regarding possible therapies.MethodsBetween-subjects design with one level of variation. Interviews were performed with a convenience sample of 154 households from the metropolitan area of Bogotá (Colombia). The treatments include: use of default option, use of professional interviewer to illustrate the therapy and emotionally charged presentation.ResultsKruskal-Wallis test of the intention to be treated rejects the null hypothesis (χ2=22.14, p=0.00). The cognitive processing of the information is not a determinant, supporting the claim that genuine framing effects shape the choice. The strongest effect of the treatment with a professional suggests a key role for asymmetry of the information, which is confirmed indirectly through the postexperiment questionnaire.ConclusionsBad healthcare decisions are not necessarily driven by lack of information. Asymmetric information (eg, delegating the decision to a professional) improves choices, especially when social stigma is involved. Cognitive processing of information seems to be less relevant than the framing effect.
Immune Mechanisms Are Major Players in Cancer
Authors: Hellstrom Karl Erik , Hellstrom Ingegerd 
Published: April 2015

Abstract
Vaccination with sipuleucel-T produced IgG antibodies to secondary prostatic carcinoma antigens and prolonged survival in some patients, and assaying for antibodies may provide prognostic information and identify new vaccine targets. Additional approaches to improve T-cell responses are needed to improve the clinical efficacy. Clin Cancer Res; 21(16); 3581–3. ©2015 AACR.
See related article by GuhaThakurta et al., p. 3619
Aspirin and P2Y12 Inhibitors in platelet-mediated activation of neutrophils and monocytes
Authors: Schrottmaier Waltraud , Kral Julia , Badrnya Sigrun , Assinger Alice 
Published: April 2015

SummaryPlatelets are key players in haemostasis and represent a pivotal link between inflammation, immunity and atherogenesis. Depending on the (patho)physiological environment platelets modulate various leukocyte functions via release of inflammatory mediators and direct cell-cell interactions. Elevated levels of circulating platelet-leukocyte aggregates are found in patients suffering from several thrombotic or inflammatory conditions. Platelet-monocyte and platelet-neutrophil interaction can trigger pro- and anti-inflammatory responses and modulate effector functions of all leukocyte subpopulations. These platelet-mediated immune responses have implications for the progression of cardiovascular diseases and also play a crucial role during infections, cancer, transplantations and other inflammatory diseases of several organs. Antiplatelet therapy including the COX inhibitor aspirin and/or ADP receptor P2Y12 inhibitors such as clopidogrel, prasugrel and ticagrelor are the therapy of choice for various cardiovascular complications. Both aspirin and P2Y12 inhibitors attenuate platelet-leukocyte interactions, thereby also modulating immune responses. This may have beneficial effects in some pathological conditions, while it might be detrimental in others. This review aims to summarise the current knowledge on platelet-leukocyte interactions and the impact of aspirin and P2Y12 inhibition on platelet-mediated immune responses and to give an overview on the effects of antiplatelet therapy on platelet-leukocyte interplay in various diseases.