bluuebunny/crossref_metadata_2025_split huggingface dataset:
Deficiencies in Cellular Processes Modulated by the Retinoblastoma Protein Do Not Account for Reduced Human Cytomegalovirus Replication in Its Absence
Authors: VanDeusen Halena R. , Kalejta Robert F. 
Published: September 2015

ABSTRACT
Despite encoding multiple viral proteins that modulate the retinoblastoma (Rb) protein in a manner classically defined as inactivation, human cytomegalovirus (HCMV) requires the presence of the Rb protein to replicate efficiently. In uninfected cells, Rb controls numerous pathways that the virus also commandeers during infection. These include cell cycle progression, senescence, mitochondrial biogenesis, apoptosis, and glutaminolysis. We investigated whether a potential inability of HCMV to regulate these Rb-controlled pathways in the absence of the Rb protein was the reason for reduced viral productive replication in Rb knockdown cells. We found that HCMV was equally able to modulate these pathways in the parental Rb-expressing and Rb-depleted cells. Our results suggest that Rb may be required to enhance a specific viral process during HCMV productive replication.

IMPORTANCE
The retinoblastoma (Rb) tumor suppressor is well established as a repressor of E2F-dependent transcription. Rb hyperphosphorylation, degradation, and binding by viral oncoproteins are also codified. Recent reports indicate Rb can be monophosphorylated, repress the transcription of antiviral genes in association with adenovirus E1A, modulate cellular responses to polycomb-mediated epigenetic methylations in human papillomavirus type 16 E7 expressing cells, and increase the efficiency of human cytomegalovirus (HCMV) productive replication. Since Rb function also now extends to regulation of mitochondrial function (apoptosis, metabolism), it is clear that our current understanding of this protein is insufficient to explain its roles in virus-infected cells and tumors. Work here reinforces this concept, showing the known roles of Rb are insufficient to explain its positive impact on HCMV replication. Therefore, HCMV, along with other viral systems, provide valuable tools to probe functions of Rb that might be modulated with therapeutics for cancers with viral or nonviral etiologies.
Structural and Thermodynamic Basis of Epitope Binding by Neutralizing and Nonneutralizing Forms of the Anti-HIV-1 Antibody 4E10
Authors: Rujas Edurne , Gulzar Naveed , Morante Koldo , Tsumoto Kouhei , Scott Jamie K. , Nieva José L. , Caaveiro Jose M. M. 
Published: September 2015

ABSTRACT

The 4E10 antibody recognizes the membrane-proximal external region (MPER) of the HIV-1 Env glycoprotein gp41 transmembrane subunit, exhibiting one of the broadest neutralizing activities known to date. The neutralizing activity of 4E10 requires solvent-exposed hydrophobic residues at the apex of the complementarity-determining region (CDR) H3 loop, but the molecular basis for this requirement has not been clarified. Here, we report the cocrystal structures and the energetic parameters of binding of a peptide bearing the 4E10-epitope sequence (4E10ep) to nonneutralizing versions of the 4E10 Fab. Nonneutralizing Fabs were obtained by shortening and decreasing the hydrophobicity of the CDR-H3 loop (termed ΔLoop) or by substituting the two tryptophan residues of the CDR-H3 apex with Asp residues (termed WDWD), which also decreases hydrophobicity but preserves the length of the loop. The analysis was complemented by the first crystal structure of the 4E10 Fab in its ligand-free state. Collectively, the data ruled out major conformational changes of CDR-H3 at any stage during the binding process (equilibrium or transition state). Although these mutations did not impact the affinity of wild-type Fab for the 4E10ep in solution, the two nonneutralizing versions of 4E10 were deficient in binding to MPER inserted in the plasma membrane (mimicking the environment faced by the antibody
in vivo
). The conclusions of our structure-function analysis strengthen the idea that to exert effective neutralization, the hydrophobic apex of the solvent-exposed CDR-H3 loop must recognize an antigenic structure more complex than just the linear α-helical epitope and likely constrained by the viral membrane lipids.

IMPORTANCE
The broadly neutralizing anti-HIV-1 4E10 antibody blocks infection caused by nearly all viral strains and isolates examined thus far. However, 4E10 (or 4E10-like) antibodies are rarely found in HIV-1-infected individuals or elicited through vaccination. Impediments to the design of successful 4E10 immunogens are partly attributed to an incomplete understanding of the structural and binding characteristics of this class of antibodies. Since the broadly neutralizing activity of 4E10 is abrogated by mutations of the tip of the CDR-H3, we investigated their impact on binding of the MPER-epitope at the atomic and energetic levels. We conclude that the difference between neutralizing and nonneutralizing antibodies of 4E10 is neither structural nor energetic but is related to the capacity to recognize the HIV-1 gp41 epitope inserted in biological membranes. Our findings strengthen the idea that to elicit similar neutralizing antibodies, the suitable MPER vaccine must be “delivered” in a membrane environment.
A Novel Tricyclic Polyketide, Vanitaracin A, Specifically Inhibits the Entry of Hepatitis B and D Viruses by Targeting Sodium Taurocholate Cotransporting Polypeptide
Authors: Kaneko Manabu , Watashi Koichi , Kamisuki Shinji , Matsunaga Hiroki , Iwamoto Masashi , Kawai Fumihiro , Ohashi Hirofumi , Tsukuda Senko , Shimura Satomi , Suzuki Ryosuke , Aizaki Hideki , Sugiyama Masaya , Park Sam-Yong , Ito Takayoshi , Ohtani Naoko , Sugawara Fumio , Tanaka Yasuhito , Mizokami Masashi , Sureau Camille , Wakita Takaji 
Published: September 2015

ABSTRACT

Anti-hepatitis B virus (HBV) drugs are currently limited to nucleos(t)ide analogs (NAs) and interferons. A challenge of drug development is the identification of small molecules that suppress HBV infection from new chemical sources. Here, from a fungus-derived secondary metabolite library, we identify a structurally novel tricyclic polyketide, named vanitaracin A, which specifically inhibits HBV infection. Vanitaracin A inhibited the viral entry process with a submicromolar 50% inhibitory concentration (IC
50
) (IC
50
= 0.61 ± 0.23 μM), without evident cytotoxicity (50% cytotoxic concentration of >256 μM; selectivity index value of >419) in primary human hepatocytes. Vanitaracin A did not affect the HBV replication process. This compound was found to directly interact with the HBV entry receptor sodium taurocholate cotransporting polypeptide (NTCP) and impaired its bile acid transport activity. Consistent with this NTCP targeting, antiviral activity of vanitaracin A was observed with hepatitis D virus (HDV) but not hepatitis C virus. Importantly, vanitaracin A inhibited infection by all HBV genotypes tested (genotypes A to D) and clinically relevant NA-resistant HBV isolate. Thus, we identified a fungal metabolite, vanitaracin A, which was a potent, well-tolerated, and broadly active inhibitor of HBV and HDV entry. This compound, or its related analogs, could be part of an antiviral strategy for preventing reinfection with HBV, including clinically relevant nucleos(t)ide analog-resistant virus.

IMPORTANCE
For achieving better treatment and prevention of hepatitis B virus (HBV) infection, anti-HBV agents targeting a new molecule are in great demand. Although sodium taurocholate cotransporting polypeptide (NTCP) has recently been reported to be an essential host factor for HBV entry, there is a limited number of reports that identify new compounds targeting NTCP and inhibiting HBV entry. Here, from an uncharacterized chemical library, we isolated a structurally new compound, named vanitaracin A, which inhibited the process of entry of HBV and hepatitis D virus (HDV). This compound was suggested to directly interact with NTCP and inhibit its transporter activity. Importantly, vanitaracin A inhibited the entry of all HBV genotypes examined and of a clinically relevant nucleos(t)ide analog-resistant HBV isolate.
Resolving the Origin of Rabbit Hemorrhagic Disease Virus: Insights from an Investigation of the Viral Stocks Released in Australia
Authors: Eden John-Sebastian , Read Andrew J. , Duckworth Janine A. , Strive Tanja , Holmes Edward C. 
Published: September 2015

ABSTRACT
To resolve the evolutionary history of rabbit hemorrhagic disease virus (RHDV), we performed a genomic analysis of the viral stocks imported and released as a biocontrol measure in Australia, as well as a global phylogenetic analysis. Importantly, conflicts were identified between the sequences determined here and those previously published that may have affected evolutionary rate estimates. By removing likely erroneous sequences, we show that RHDV emerged only shortly before its initial description in China.
Mimivirus Fibrils Are Important for Viral Attachment to the Microbial World by a Diverse Glycoside Interaction Repertoire
Authors: Rodrigues Rodrigo Araújo Lima , dos Santos Silva Ludmila Karen , Dornas Fábio Pio , de Oliveira Danilo Bretas , Magalhães Thais Furtado Ferreira , Santos Daniel Assis , Costa Adriana Oliveira , de Macêdo Farias Luiz , Magalhães Paula Prazeres , Bonjardim Cláudio Antônio , Kroon Erna Geessien , La Scola Bernard , Cortines Juliana Reis , Abrahão Jônatas Santos 
Published: September 2015

ABSTRACT

Acanthamoeba polyphaga mimivirus
(APMV) is a giant virus from the
Mimiviridae
family. It has many unusual features, such as a pseudoicosahedral capsid that presents a starfish shape in one of its vertices, through which the ∼1.2-Mb double-stranded DNA is released. It also has a dense glycoprotein fibril layer covering the capsid that has not yet been functionally characterized. Here, we verified that although these structures are not essential for viral replication, they are truly necessary for viral adhesion to amoebae, its natural host. In the absence of fibrils, APMV had a significantly lower level of attachment to the
Acanthamoeba castellanii
surface. This adhesion is mediated by glycans, specifically, mannose and
N
-acetylglucosamine (a monomer of chitin and peptidoglycan), both of which are largely distributed in nature as structural components of several organisms. Indeed, APMV was able to attach to different organisms, such as Gram-positive bacteria, fungi, and arthropods, but not to Gram-negative bacteria. This prompted us to predict that (i) arthropods, mainly insects, might act as mimivirus dispersers and (ii) by attaching to other microorganisms, APMV could be ingested by amoebae, leading to the successful production of viral progeny. To date, this mechanism has never been described in the virosphere.

IMPORTANCE
APMV is a giant virus that is both genetically and structurally complex. Its size is similar to that of small bacteria, and it replicates inside amoebae. The viral capsid is covered by a dense glycoprotein fibril layer, but its function has remained unknown, until now. We found that the fibrils are not essential for mimivirus replication but that they are truly necessary for viral adhesion to the cell surface. This interaction is mediated by glycans, mainly
N
-acetylglucosamine. We also verified that APMV is able to attach to bacteria, fungi, and arthropods. This indicates that insects might act as mimivirus dispersers and that adhesion to other microorganisms could facilitate viral ingestion by amoebae, a mechanism never before described in the virosphere.
Monoclonal Antibodies Directed toward the Hepatitis C Virus Glycoprotein E2 Detect Antigenic Differences Modulated by the N-Terminal Hypervariable Region 1 (HVR1), HVR2, and Intergenotypic Variable Region
Authors: Alhammad Yousef , Gu Jun , Boo Irene , Harrison David , McCaffrey Kathleen , Vietheer Patricia T. , Edwards Stirling , Quinn Charles , Coulibaly Fásseli , Poumbourios Pantelis , Drummer Heidi E. 
Published: September 2015

ABSTRACT

Hepatitis C virus (HCV) envelope glycoproteins E1 and E2 form a heterodimer and mediate receptor interactions and viral fusion. Both E1 and E2 are targets of the neutralizing antibody (NAb) response and are candidates for the production of vaccines that generate humoral immunity. Previous studies demonstrated that N-terminal hypervariable region 1 (HVR1) can modulate the neutralization potential of monoclonal antibodies (MAbs), but no information is available on the influence of HVR2 or the intergenotypic variable region (igVR) on antigenicity. In this study, we examined how the variable regions influence the antigenicity of the receptor binding domain of E2 spanning HCV polyprotein residues 384 to 661 (E2
661
) using a panel of MAbs raised against E2
661
and E2
661
lacking HVR1, HVR2, and the igVR (Δ123) and well-characterized MAbs isolated from infected humans. We show for a subset of both neutralizing and nonneutralizing MAbs that all three variable regions decrease the ability of MAbs to bind E2
661
and reduce the ability of MAbs to inhibit E2-CD81 interactions. In addition, we describe a new MAb directed toward the region spanning residues 411 to 428 of E2 (MAb24) that demonstrates broad neutralization against all 7 genotypes of HCV. The ability of MAb24 to inhibit E2-CD81 interactions is strongly influenced by the three variable regions. Our data suggest that HVR1, HVR2, and the igVR modulate exposure of epitopes on the core domain of E2 and their ability to prevent E2-CD81 interactions. These studies suggest that the function of HVR2 and the igVR is to modulate antibody recognition of glycoprotein E2 and may contribute to immune evasion.

IMPORTANCE
This study reveals conformational and antigenic differences between the Δ123 and intact E2
661
glycoproteins and provides new structural and functional data about the three variable regions and their role in occluding neutralizing and nonneutralizing epitopes on the E2 core domain. The variable regions may therefore function to reduce the ability of HCV to elicit NAbs directed toward the conserved core domain. Future studies aimed at generating a three-dimensional structure for intact E2 containing HVR1, and the adjoining NAb epitope at residues 412 to 428, together with HVR2, will reveal how the variable regions modulate antigenic structure.
Corresponding waist circumference and body mass index values based on 10-year absolute type 2 diabetes risk in an Australian Aboriginal community
Authors: Adegbija Odewumi , Hoy Wendy E , Wang Zhiqiang 
Published: September 2015

ObjectiveThere is a lack of waist circumference (WC) thresholds to identify Aboriginal individuals at high risk of type 2 diabetes. We generated gender-specific WC values with equivalent 10-year absolute risk of type 2 diabetes as body mass index (BMI) points in an Australian Aboriginal community to contribute to guidelines needed for establishing WC cut-off points for Aboriginals.Research design and methodsA cohort of 803 adult participants free from type 2 diabetes in an Aboriginal community was followed up for up to 20 years. We derived WC values with absolute risks equivalent for the development of type 2 diabetes as BMI values (20–35 kg/m2) using the Weibull accelerated failure-time model.ResultsAfter a mean follow-up of 15.7 years, 110 participants developed type 2 diabetes. Absolute risk of type 2 diabetes increased as WC increased, ranging from 3.52% (WC=77.5 cm) to 14.14% (WC=119.9 cm) in males, and 5.04% (WC=79.5 cm) to 24.25% (WC=113.7 cm) in females. In males, WC values with same absolute risks of type 2 diabetes as BMI values were 77.5 cm for BMI=20 kg/m2, 91.5 cm for BMI=25 kg/m2(overweight threshold), 105.7 cm for BMI=30 kg/m2(obesity threshold) and 119.9 cm for BMI=35 kg/m2. In females, WC values were 79.5 cm for BMI=20 kg/m2, 90.9 cm for BMI=25 kg/m2, 102.3 cm for BMI=30 kg/m2and 113.7 cm for BMI=35 kg/m2. Interaction between WC and gender was not statistically significant (p=0.53).ConclusionsThe absolute risk of type 2 diabetes increased with higher WC measured at baseline screening. Males were not significantly different from females in the association between WC and type 2 diabetes. Our findings are useful contributions for future establishment of WC cut-off points for identifying high-risk individuals in Aboriginal people.
Factors influencing obesogenic dietary intake in young children (0–6 years): systematic review of qualitative evidence
Authors: Mazarello Paes Veena , Ong Ken K , Lakshman Rajalakshmi 
Published: September 2015

BackgroundObesogenic dietary intake is prevalent in young children and is associated with obesity and other adverse health outcomes in childhood and later in life.ObjectiveTo describe the barriers to and facilitators of obesogenic dietary intake in early childhood, in order to inform interventions and public health policies to prevent obesity.DesignSystematic review of qualitative literature on factors influencing obesogenic diets in children aged 0–6 years.Data sourcesMEDLINE, EMBASE, CINAHL, PsycINFO, Web of Knowledge, British Nursing Index, ASSIA and Sociological Abstracts.Review methodsQualitative studies meeting the inclusion criteria were synthesised. Data were analysed by creating a thematic framework, underpinned by the socioecological model, which included familiarisation of data across the studies, indexing, charting, mapping and interpretation.Results20 studies from the USA (10), Europe (6) and Australia (4) included the views of 1067 participants (901 parents/caregivers, 37 children, 87 teachers, 15 dieticians and 27 nursery staff). Study designs included focus groups (n=16), individual interviews (n=6) and ethnography (n=1) with some studies using more than one design. Despite wide differences in the study context and focus, several consistent themes emerged. Parental factors increasing young children's obesogenic diets were: negative parent/family/peer modelling, lack of knowledge, time constraints, using food as reward, affordability and concerns about child's health. Child preferences also increased intake. Environmental factors increasing intake include: availability, advertising, societal, cultural and preschool/childcare influences.ConclusionsFuture intervention strategies should aim to promote modelling of positive behaviours, create home and preschool environments that promote healthy diets, and simultaneously target factors at the family and preschool/childcare levels.Trial registration numberThis review is one of a series of systematic reviews on the determinants of obesogenic behaviours in young children, registered with the International Prospective Register for Systematic Reviews (PROSPERO), CRD42012002881.
Older people, the natural environment and common mental disorders: cross-sectional results from the Cognitive Function and Ageing Study
Authors: Wu Yu-Tzu , Prina A Matthew , Jones Andy , Matthews Fiona E , Brayne Carol ,   MRC CFAS
Published: September 2015

ObjectivesTo explore the hypothesis that higher exposure to natural environments in local areas is associated with a lower odds of depression and anxiety in later life.DesignA cross-sectional study based on the year-10 interview of the Medical Research Council Cognitive Function and Ageing Study (CFAS), a population-based study of ageing in the UK. Postcodes of the CFAS participants were mapped onto small geographic units, lower-layer super output areas (LSOAs) and linked to environmental data from government databases. The natural environment was characterised as the percentage of green space and private gardens in each LSOA based on the UK Generalised Land Use 2001 Dataset.Participants2424 people aged 74 and over in the CFAS year-10 follow-up interview (2001) from 4 English centres (Cambridgeshire, Nottingham, Newcastle and Oxford).Main outcome measuresDepression and anxiety; clinical and subthreshold cases were identified using the Geriatric Mental State Examination (GMS) package and its associated diagnostic algorithm: the Automated Geriatric Examination for Computer Assisted Taxonomy.ResultsCompared with the lowest quartile, living in the highest quartile of neighbourhood natural environment provision was associated with a reduced odds of subthreshold depression (OR 0.66, 95% CI 0.46 to 0.95), anxiety symptoms (OR 0.62, 95% CI 0.46 to 0.83) and their co-occurrence (OR 0.55, 95% CI 0.35 to 0.84) after adjusting for individual-level factors. Controlling for area deprivation attenuated the strength of associations for subthreshold depression by 20% but not for anxiety symptoms or for co-occurrence of the conditions.ConclusionsA high exposure to natural environments (green space and gardens) in communities was associated with fewer mental disorders among older people. Increasing provision of green environments in local areas could be a potential population-level intervention to improve mental health among older people.
A time series analysis of alcohol-related presentations to emergency departments in Queensland following the increase in alcopops tax
Authors: Kisely Steve , Lawrence David 
Published: September 2015

BackgroundRaising duty on alcohol across the board can reduce morbidity, mortality and other adverse consequences of alcohol use. However, effectiveness is less certain for measures that target specific types of alcohol beverage in isolation. One example from Australia was the increase in tax on alcopops favoured by young people to curb risky drinking in this demographic.MethodsWe measured alcohol-related health harms in 15–29-year-olds presenting to emergency departments (EDs) in Queensland following the tax increase. These presentations were compared with following ED controls: (1) 15–29-year-olds with asthma or appendicitis; and (2) 30–49-year-olds presenting with alcohol-related harms. We analysed data over a 5-year period (April 2005–April 2010) using a time series analysis. This covered 3 years before, and 2 years after, the tax increase. We investigated both mental and behavioural consequences (F10 codes), and intentional/unintentional injuries (S and T codes).ResultsWe fitted an ARIMA (autoregressive integrated moving average) model to test for a change following the increased ‘alcopops’ tax in April 2008. There was no significant decrease in alcohol-related ED presentations in 15–29-year-olds compared to any of the controls. We found similar results for males and females, narrow and broad definitions of alcohol-related harms, under-19s and ED presentations at night-time and weekends.ConclusionsThe increase in tax on ‘alcopops’ did not result in any reduction in alcohol-related harms in this population. Targeting particular alcoholic drinks may therefore not be as effective as more comprehensive policies such as minimum unit pricing for alcohol.
The experimental study of Cr6+ contaminated water remediation by zero-valent nano-Fe
Authors: Sun X. N. , Liu A. P. , Chen Q. F. , Wang X. 
Published: September 2015

In recent years, researchers have developed a number of new types of zero-valent nano-Fe remediation materials applied in the remediation of contaminated soil and water, which has attracted wide attentions. This paper selected soil leaching wastewater severely contaminated by chromium as target of the study and chose zero-valent nano-Fe, [Formula: see text] and [Formula: see text] for comparison experiments to study the effects on removing [Formula: see text] under experimental conditions of different pH values, dosages and reaction times. As is shown in the experiments, zero-valent nano-Fe has the highest removal rates for [Formula: see text], while the reaction of [Formula: see text] is the slowest under the same conditions. However, both removal rates are prone to be stable after 10 min. Dosages do not make a distinct difference and the pH value has the least effect on the repair of zero-valent nano-Fe.