bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nucleic Acid Polymers Are Active against Hepatitis Delta Virus InfectionIn Vitro
Authors: Beilstein Frauke , Blanchet Matthieu , Vaillant Andrew , Sureau Camille 
Published: December 2017

ABSTRACTIn this study, anin vitroinfection model for the hepatitis delta virus (HDV) was used to evaluate the antiviral effects of phosphorothioate nucleic acid polymers (NAPs) and investigate their mechanism of action. The results show that NAPs inhibit HDV infection at concentrations less than 4 μM in cultures of differentiated human hepatoma cells. NAPs were shown to be active at viral entry but inactive postentry on HDV RNA replication. Inhibition was independent of the NAP nucleotide sequence but dependent on both size and amphipathicity of the polymer. NAP antiviral activity was effective against HDV virions bearing the main hepatitis B virus (HBV) immune escape substitutions (D144A and G145R) and was pangenomic with regard to HBV envelope proteins. Furthermore, similar to immobilized heparin, immobilized NAPs could bind HDV particles, suggesting that entry inhibition was due, at least in part, to preventing attachment of the virus to cell surface glycosaminoglycans. The results document NAPs as a novel class of antiviral compounds that can prevent HDV propagation.IMPORTANCEHDV infection causes the most severe form of viral hepatitis in humans and one of the most difficult to cure. Currently, treatments are limited to long-term administration of interferon at high doses, which provide only partial efficacy. There is thus an urgent need for innovative approaches to identify new antiviral against HDV. The significance of our study is in demonstrating that nucleic acid polymers (NAPs) are active against HDV by targeting the envelope of HDV virions. In anin vitroinfection assay, NAP activity was recorded at concentrations less than 4 μM in the absence of cell toxicity. Furthermore, the fact that NAPs could block HDV at viral entry suggests their potential to control the spread of HDV in a chronically HBV-infected liver. In addition, NAP anti-HDV activity was pangenomic with regard to HBV envelope proteins and not circumvented by HBsAg substitutions associated with HBV immune escape.
Syrian Hamster as an Animal Model for the Study of Human Influenza Virus Infection
Authors: Iwatsuki-Horimoto Kiyoko , Nakajima Noriko , Ichiko Yurie , Sakai-Tagawa Yuko , Noda Takeshi , Hasegawa Hideki , Kawaoka Yoshihiro 
Published: December 2017

ABSTRACT
Ferrets and mice are frequently used as animal models for influenza research. However, ferrets are demanding in terms of housing space and handling, whereas mice are not naturally susceptible to infection with human influenza A or B viruses. Therefore, prior adaptation of human viruses is required for their use in mice. In addition, there are no mouse-adapted variants of the recent H3N2 viruses, because these viruses do not replicate well in mice. In this study, we investigated the susceptibility of Syrian hamsters to influenza viruses with a view to using the hamster model as an alternative to the mouse model. We found that hamsters are sensitive to influenza viruses, including the recent H3N2 viruses, without adaptation. Although the hamsters did not show weight loss or clinical signs of H3N2 virus infection, we observed pathogenic effects in the respiratory tracts of the infected animals. All of the H3N2 viruses tested replicated in the respiratory organs of the hamsters, and some of them were detected in the nasal washes of infected animals. Moreover, a 2009 pandemic (pdm09) virus and a seasonal H1N1 virus, as well as one of the two H3N2 viruses, but not a type B virus, were transmissible by the airborne route in these hamsters. Hamsters thus have the potential to be a small-animal model for the study of influenza virus infection, including studies of the pathogenicity of H3N2 viruses and other strains, as well as for use in H1N1 virus transmission studies.

IMPORTANCE
We found that Syrian hamsters are susceptible to human influenza viruses, including the recent H3N2 viruses, without adaptation. We also found that a pdm09 virus and a seasonal H1N1 virus, as well as one of the H3N2 viruses, but not a type B virus tested, are transmitted by the airborne route in these hamsters. Syrian hamsters thus have the potential to be used as a small-animal model for the study of human influenza viruses.
Novel Sulfolobus Virus with an Exceptional Capsid Architecture
Authors: Wang Haina , Guo Zhenqian , Feng Hongli , Chen Yufei , Chen Xiuqiang , Li Zhimeng , Hernández-Ascencio Walter , Dai Xin , Zhang Zhenfeng , Zheng Xiaowei , Mora-López Marielos , Fu Yu , Zhang Chuanlun , Zhu Ping , Huang Li 
Published: December 2017

ABSTRACT

A novel archaeal virus, denoted
Sulfolobus ellipsoid virus 1
(SEV1), was isolated from an acidic hot spring in Costa Rica. The morphologically unique virion of SEV1 contains a protein capsid with 16 regularly spaced striations and an 11-nm-thick envelope. The capsid exhibits an unusual architecture in which the viral DNA, probably in the form of a nucleoprotein filament, wraps around the longitudinal axis of the virion in a plane to form a multilayered disk-like structure with a central hole, and 16 of these structures are stacked to generate a spool-like capsid. SEV1 harbors a linear double-stranded DNA genome of ∼23 kb, which encodes 38 predicted open reading frames (ORFs). Among the few ORFs with a putative function is a gene encoding a protein-primed DNA polymerase. Sixfold symmetrical virus-associated pyramids (VAPs) appear on the surface of the SEV1-infected cells, which are ruptured to allow the formation of a hexagonal opening and subsequent release of the progeny virus particles. Notably, the SEV1 virions acquire the lipid membrane in the cytoplasm of the host cell. The lipid composition of the viral envelope correlates with that of the cell membrane. These results suggest the use of a unique mechanism by SEV1 in membrane biogenesis.

IMPORTANCE
Investigation of archaeal viruses has greatly expanded our knowledge of the virosphere and its role in the evolution of life. Here we show that
Sulfolobus ellipsoid virus 1
(SEV1), an archaeal virus isolated from a hot spring in Costa Rica, exhibits a novel viral shape and an unusual capsid architecture. The SEV1 DNA wraps multiple times in a plane around the longitudinal axis of the virion to form a disk-like structure, and 16 of these structures are stacked to generate a spool-like capsid. The virus acquires its envelope intracellularly and exits the host cell by creating a hexagonal hole on the host cell surface. These results shed significant light on the diversity of viral morphogenesis.
HIV-1 Envelope Glycoprotein Trafficking through the Endosomal Recycling Compartment Is Required for Particle Incorporation
Authors: Kirschman Junghwa , Qi Mingli , Ding Lingmei , Hammonds Jason , Dienger-Stambaugh Krista , Wang Jaang-Jiun , Lapierre Lynne A. , Goldenring James R. , Spearman Paul 
Published: December 2017

ABSTRACTThe human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein (Env) encodes specific trafficking signals within its long cytoplasmic tail (CT) that regulate incorporation into HIV-1 particles. Rab11-family interacting protein 1C (FIP1C) and Rab14 are host trafficking factors required for Env particle incorporation, suggesting that Env undergoes sorting from the endosomal recycling compartment (ERC) to the site of particle assembly on the plasma membrane. We disrupted outward sorting from the ERC by expressing a C-terminal fragment of FIP1C (FIP1C560–649) and examined the consequences on Env trafficking and incorporation into particles. FIP1C560–649reduced cell surface levels of Env and prevented its incorporation into HIV-1 particles. Remarkably, Env was trapped in an exaggerated perinuclear ERC in a CT-dependent manner. Mutation of either the Yxxϕ endocytic motif or the YW795motif in the CT prevented Env trapping in the ERC and restored incorporation into particles. In contrast, simian immunodeficiency virus SIVmac239 Env was not retained in the ERC, while substitution of the HIV-1 CT for the SIV CT resulted in SIV Env retention in this compartment. These results provide the first direct evidence that Env traffics through the ERC and support a model whereby HIV-1 Env is specifically targeted to the ERC prior to FIP1C- and CT-dependent outward sorting to the particle assembly site on the plasma membrane.IMPORTANCEThe HIV envelope protein is an essential component of the viral particle. While many aspects of envelope protein structure and function have been established, the pathway it follows in the cell prior to reaching the site of particle assembly is not well understood. The envelope protein has a very long cytoplasmic tail that interacts with the host cell trafficking machinery. Here, we utilized a truncated form of the trafficking adaptor FIP1C protein to arrest the intracellular transport of the envelope protein, demonstrating that it becomes trapped inside the cell within the endosomal recycling compartment. Intracellular trapping resulted in a loss of envelope protein on released particles and a corresponding loss of infectivity. Mutations of specific trafficking motifs in the envelope protein tail prevented its trapping in the recycling compartment. These results establish that trafficking to the endosomal recycling compartment is an essential step in HIV envelope protein particle incorporation.
Genome Sequences Reveal Cryptic Speciation in the Human Pathogen
Histoplasma capsulatum
Authors: Sepúlveda Victoria E. , Márquez Roberto , Turissini David A. , Goldman William E. , Matute Daniel R. 
Published: December 2017

ABSTRACT

Histoplasma capsulatum
is a pathogenic fungus that causes life-threatening lung infections. About 500,000 people are exposed to
H. capsulatum
each year in the United States, and over 60% of the U.S. population has been exposed to the fungus at some point in their life. We performed genome-wide population genetics and phylogenetic analyses with 30
Histoplasma
isolates representing four recognized areas where histoplasmosis is endemic and show that the
Histoplasma
genus is composed of at least four species that are genetically isolated and rarely interbreed. Therefore, we propose a taxonomic rearrangement of the genus.

IMPORTANCE
The evolutionary processes that give rise to new pathogen lineages are critical to our understanding of how they adapt to new environments and how frequently they exchange genes with each other. The fungal pathogen
Histoplasma capsulatum
provides opportunities to precisely test hypotheses about the origin of new genetic variation. We find that
H. capsulatum
is composed of at least four different cryptic species that differ genetically and also in virulence. These results have implications for the epidemiology of histoplasmosis because not all
Histoplasma
species are equivalent in their geographic range and ability to cause disease.
Latency-Associated Expression of Human Cytomegalovirus US28 Attenuates Cell Signaling Pathways To Maintain Latent Infection
Authors: Krishna Benjamin A. , Poole Emma L. , Jackson Sarah E. , Smit Martine J. , Wills Mark R. , Sinclair John H. 
Published: December 2017

ABSTRACT

Reactivation of human cytomegalovirus (HCMV) latent infection from early myeloid lineage cells constitutes a threat to immunocompromised or immune-suppressed individuals. Consequently, understanding the control of latency and reactivation to allow targeting and killing of latently infected cells could have far-reaching clinical benefits.
US28
is one of the few viral genes that is expressed during latency and encodes a cell surface G protein-coupled receptor (GPCR), which, during lytic infection, is a constitutive cell-signaling activator. Here we now show that in monocytes, which are recognized sites of HCMV latency
in vivo
, US28 attenuates multiple cell signaling pathways, including mitogen-activated protein (MAP) kinase and NF-κB, and that this is required to establish a latent infection; viruses deleted for US28 initiate a lytic infection in infected monocytes. We also show that these monocytes then become potent targets for the HCMV-specific host immune response and that latently infected cells treated with an inverse agonist of US28 also reactivate lytic infection and similarly become immune targets. Consequently, we suggest that the use of inhibitors of US28 could be a novel immunotherapeutic strategy to reactivate the latent viral reservoir, allowing it to be targeted by preexisting HCMV-specific T cells.

IMPORTANCE
Human cytomegalovirus (HCMV) is a betaherpesvirus and a leading cause of morbidity and mortality among immunosuppressed individuals. HCMV can establish latent infection, where the viral genome is maintained in an infected cell, without production of infectious virus. A number of genes, including
US28
, are expressed by HCMV during latent infection. US28 has been shown to activate many cellular signaling pathways during lytic infection, promoting lytic gene expression and virus production. As such, the role of US28 remains unclear and seems at odds with latency. Here, we show that US28 has the opposite phenotype in cells that support latent infection—it attenuates cellular signaling, thereby maintaining latency. Inhibition of US28 with a small-molecule inhibitor causes HCMV latent infection to reactivate, allowing latently infected cells to be detected and killed by the immune system. This approach could be used to treat latent HCMV to clear it from human transplants.
Proposed Role for KaiC-Like ATPases as Major Signal Transduction Hubs in Archaea
Authors: Makarova Kira S. , Galperin Michael Y. , Koonin Eugene V. 
Published: December 2017

ABSTRACT

All organisms must adapt to ever-changing environmental conditions and accordingly have evolved diverse signal transduction systems. In bacteria, the most abundant networks are built around the two-component signal transduction systems that include histidine kinases and receiver domains. In contrast, eukaryotic signal transduction is dominated by serine/threonine/tyrosine protein kinases. Both of these systems are also found in archaea, but they are not as common and diversified as their bacterial and eukaryotic counterparts, suggesting the possibility that archaea have evolved other, still uncharacterized signal transduction networks. Here we propose a role for KaiC family ATPases, known to be key components of the circadian clock in cyanobacteria, in archaeal signal transduction. The KaiC family is notably expanded in most archaeal genomes, and although most of these ATPases remain poorly characterized, members of the KaiC family have been shown to control archaellum assembly and have been found to be a stable component of the gas vesicle system in
Halobacteria
. Computational analyses described here suggest that KaiC-like ATPases and their homologues with inactivated ATPase domains are involved in many other archaeal signal transduction pathways and comprise major hubs of complex regulatory networks. We predict numerous input and output domains that are linked to KaiC-like proteins, including putative homologues of eukaryotic DEATH domains that could function as adapters in archaeal signaling networks. We further address the relationships of the archaeal family of KaiC homologues to the bona fide KaiC of cyanobacteria and implications for the existence of a KaiC-based circadian clock apparatus in archaea.

IMPORTANCE
Little is currently known about signal transduction pathways in
Archaea
. Recent studies indicate that KaiC-like ATPases, known as key components of the circadian clock apparatus in cyanobacteria, are involved in the regulation of archaellum assembly and, likely, type IV pili and the gas vesicle system in
Archaea
. We performed comprehensive comparative genomic analyses of the KaiC family. A vast protein interaction network was revealed, with KaiC family proteins as hubs for numerous input and output components, many of which are shared with two-component signal transduction systems. Putative KaiC-based signal transduction systems are predicted to regulate the activities of membrane-associated complexes and individual proteins, such as signal recognition particle and membrane transporters, and also could be important for oxidative stress response regulation. KaiC-centered signal transduction networks are predicted to play major roles in archaeal physiology, and this work is expected to stimulate their experimental characterization.
From Cell Death to Metabolism: Holin-Antiholin Homologues with New Functions
Authors: van den Esker Marielle H. , Kovács Ákos T. , Kuipers Oscar P. 
Published: December 2017

ABSTRACT

Programmed cell death in bacteria is generally triggered by membrane proteins with functions analogous to those of bacteriophage holins: they disrupt the membrane potential, whereas antiholins antagonize this process. The holin-like class of proteins is present in all three domains of life, but their functions can be different, depending on the species. Using a series of biochemical and genetic approaches, in a recent article in
mBio
, Charbonnier et al. (mBio 8:e00976-17, 2017,
https://doi.org/10.1128/mBio.00976-17
) demonstrate that the antiholin homologue in
Bacillus subtilis
transports pyruvate and is regulated in an unconventional way by its substrate molecule. Here, we discuss the connection between cell death and metabolism in various bacteria carrying genes encoding these holin-antiholin analogues and place the recent study by Charbonnier et al. in an evolutionary context.
National survey of Ebola-related knowledge, attitudes and practices before the outbreak peak in Sierra Leone: August 2014
Authors: Jalloh Mohamed F , Sengeh Paul , Monasch Roeland , Jalloh Mohammad B , DeLuca Nickolas , Dyson Meredith , Golfa Sheku , Sakurai Yukiko , Conteh Lansana , Sesay Samuel , Brown Vance , Li Wenshu , Mermin Jonathan , Bunnell Rebecca 
Published: December 2017

BackgroundThe 2014–2015 Ebola epidemic in West Africa was the largest ever to occur. In the early phases, little was known about public knowledge, attitudes and practices (KAP) relating to Ebola virus disease (Ebola). Data were needed to develop evidence-driven strategies to address gaps in knowledge and practice.MethodsIn August 2014, we conducted interviews with 1413 randomly selected respondents from 9 out of 14 districts in Sierra Leone using multistage cluster sampling. Where suitable, Ebola-related KAP questions were adapted from other internationally validated questionnaires related to infectious diseases.ResultsAll respondents were aware of Ebola. When asked unprompted, 60% of respondents could correctly cite fever, diarrhoea and vomiting as signs/symptoms of Ebola. A majority of respondents knew that avoiding infected blood and bodily fluids (87%) and contact with an infected corpse (85%) could prevent Ebola. However, there were also widespread misconceptions such as the belief that Ebola can be prevented by washing with salt and hot water (41%). Almost everyone interviewed (95%) expressed at least one discriminatory attitude towards Ebola survivors. Unprompted, self-reported actions taken to avoid Ebola infection included handwashing with soap (66%) and avoiding physical contact with patients with suspected Ebola (40%).ConclusionThree months into the 2014 Ebola outbreak in Sierra Leone, our findings suggest there was high awareness of the disease but misconceptions and discriminatory attitudes toward survivors remained common. These findings directly informed the development of a national social mobilisation strategy and demonstrated the importance of KAP assessment early in an epidemic.
Efficacy of a bovine colostrum and egg-based intervention in acute childhood diarrhoea in Guatemala: a randomised, double-blind, placebo-controlled trial
Authors: Gaensbauer James T , Melgar Mario A , Calvimontes Diva M , Lamb Molly M , Asturias Edwin J , Contreras-Roldan Ingrid L , Dominguez Samuel R , Robinson Christine C , Berman Stephen 
Published: December 2017

BackgroundTreatments for paediatric diarrhoeal disease are limited. We assessed the impact of a bovine colostrum and egg-based treatment designed to reduce diarrhoea duration through non-specific and pathogen-directed mechanisms in children.MethodsRandomised, double-blind, placebo-controlled trial of PTM202, derived from bovine colostrum and hyperimmune hen’s egg on the duration of acute diarrhoeal disease in Guatemalan children. PTM202 contains specific immunoglobulins that target rotavirus, enterotoxigenicEscherichia coli, Shiga toxin-producingE. coliand Salmonella. Children aged 6–35 months presenting to three sites (one rural and two urban) with acute non-bloody diarrhoea were computer randomised to receive three daily doses of PTM202 or placebo. The primary outcome was the post-treatment duration of diarrhoea assessed in the per protocol population. Diarrhoeal pathogens were identified in stool by multiplex PCR (FilmArray Gastrointestinal-Panel, BioFire, Salt Lake City, Utah, USA). Key secondary outcomes included postdiarrhoeal weight gain and impact on diarrhoeal duration stratified by study site and presence of PTM202-targeted organisms in stool at enrolment. Safety was assessed in all participants.ResultsFrom 9 March 2015 to 25 January 2016, 325 children were enrolled, and 301 (154 intervention and 147 placebo) were analysed for the primary outcome. No difference in diarrhoea duration was observed between intervention and placebo in the total population, but a significant reduction was observed in the treatment group among children with at least one targeted pathogen in stool (HR=1.46, P=0.02), an effect most pronounced in urban subjects (HR 2.20, P=0.007) who had fewer stool pathogens and better nutritional status. No impact on 2-week or 4-week weight gain was noted. No adverse events attributed to PTM202 occurred.ConclusionResults demonstrate the potential to target specific pathogens occurring in children with acute non-bloody diarrhoea and shorten illness duration using a novel, safe, nutrition-based intervention. PTM202 may represent a new tool to ameliorate the effects of acute diarrhoeal disease in low/middle-income populations.Trial registration numberNCT02385773; Results.
The relevance and implications of signet-ring cell adenocarcinoma of the oesophagus
Authors: Bleaney Christopher William , Barrow Mickhaiel , Hayes Stephen , Ang Yeng 
Published: December 2017

AimTo review the current understanding of signet-ring type oesophageal adenocarcinoma including evidence for prognosis.MethodsWe conducted a literature search of nine healthcare literature databases for articles detailing the biology and clinical outcomes of signet-ring cell adenocarcinoma of the oesophagus. The impact of signet-ring cell morphology was analysed and detailed in written text and tabular format. Current understanding of the biology of signet-ring cell adenocarcinoma of the oesophagus was summarised.ResultsSignet-ring cell carcinoma was represented in 7.61% of the 18 989 cases of oesophageal carcinoma reviewed in multiple studies. The presence of signet-ring cells conferred a worse prognosis and these tumours responded differently to conventional treatments as compared with typical adenocarcinoma. Little is known about the biological features of signet-ring cell adenocarcinoma of the oesophagus. Work in gastric lesions has identified potential targets for future treatments such asCDH1andRHOAgenes. Categorisation of signet-ring cell carcinomas by the proportion of signet-ring cells within tumours differs among clinicians despite WHO criteria for classification. The current UK guidelines for histopathological reporting of oesophageal tumours do not emphasise the importance of identifying signet-ring cells.ConclusionThe presence of signet-ring cells in oesophageal adenocarcinomas leads to poorer clinical outcomes. Current understanding of signet-ring cell biology in oesophageal cancer is limited.