bluuebunny/crossref_metadata_2025_split huggingface dataset:
Latent Membrane Protein 1 (LMP1) and LMP2A Collaborate To Promote Epstein-Barr Virus-Induced B Cell Lymphomas in a Cord Blood-Humanized Mouse Model but Are Not Essential
Authors: Ma Shi-Dong , Tsai Ming-Han , Romero-Masters James C. , Ranheim Erik A. , Huebner Shane M. , Bristol Jillian A. , Delecluse Henri-Jacques , Kenney Shannon C. 
Published: January 2017

ABSTRACT

Epstein-Barr virus (EBV) infection is associated with B cell lymphomas in humans. The ability of EBV to convert human B cells into long-lived lymphoblastoid cell lines (LCLs)
in vitro
requires the collaborative effects of EBNA2 (which hijacks Notch signaling), latent membrane protein 1 (LMP1) (which mimics CD40 signaling), and EBV-encoded nuclear antigen 3A (EBNA3A) and EBNA3C (which inhibit oncogene-induced senescence and apoptosis). However, we recently showed that an LMP1-deleted EBV mutant induces B cell lymphomas in a newly developed cord blood-humanized mouse model that allows EBV-infected B cells to interact with CD4 T cells (the major source of CD40 ligand). Here we examined whether the EBV LMP2A protein, which mimics constitutively active B cell receptor signaling, is required for EBV-induced lymphomas in this model. We find that the deletion of LMP2A delays the onset of EBV-induced lymphomas but does not affect the tumor phenotype or the number of tumors. The simultaneous deletion of both LMP1 and LMP2A results in fewer tumors and a further delay in tumor onset. Nevertheless, the LMP1/LMP2A double mutant induces lymphomas in approximately half of the infected animals. These results indicate that neither LMP1 nor LMP2A is absolutely essential for the ability of EBV to induce B cell lymphomas in the cord blood-humanized mouse model, although the simultaneous loss of both LMP1 and LMP2A decreases the proportion of animals developing tumors and increases the time to tumor onset. Thus, the expression of either LMP1 or LMP2A may be sufficient to promote early-onset EBV-induced tumors in this model.

IMPORTANCE
EBV causes human lymphomas, but few models are available for dissecting how EBV causes lymphomas
in vivo
in the context of a host immune response. We recently used a newly developed cord blood-humanized mouse model to show that EBV can cooperate with human CD4 T cells to cause B cell lymphomas even when a major viral transforming protein, LMP1, is deleted. Here we examined whether the EBV protein LMP2A, which mimics B cell receptor signaling, is required for EBV-induced lymphomas in this model. We find that the deletion of LMP2A alone has little effect on the ability of EBV to cause lymphomas but delays tumor onset. The deletion of both LMP1 and LMP2A results in a smaller number of lymphomas in infected animals, with an even more delayed time to tumor onset. These results suggest that LMP1 and LMP2A collaborate to promote early-onset lymphomas in this model, but neither protein is absolutely essential.
Characterization of Hepatitis C Virus (HCV) Envelope Diversification from Acute to Chronic Infection within a Sexually Transmitted HCV Cluster by Using Single-Molecule, Real-Time Sequencing
Authors: Ho Cynthia K. Y. , Raghwani Jayna , Koekkoek Sylvie , Liang Richard H. , Van der Meer Jan T. M. , Van Der Valk Marc , De Jong Menno , Pybus Oliver G. , Schinkel Janke , Molenkamp Richard 
Published: January 2017

ABSTRACT

In contrast to other available next-generation sequencing platforms, PacBio single-molecule, real-time (SMRT) sequencing has the advantage of generating long reads albeit with a relatively higher error rate in unprocessed data. Using this platform, we longitudinally sampled and sequenced the hepatitis C virus (HCV) envelope genome region (1,680 nucleotides [nt]) from individuals belonging to a cluster of sexually transmitted cases. All five subjects were coinfected with HIV-1 and a closely related strain of HCV genotype 4d. In total, 50 samples were analyzed by using SMRT sequencing. By using 7 passes of circular consensus sequencing, the error rate was reduced to 0.37%, and the median number of sequences was 612 per sample. A further reduction of insertions was achieved by alignment against a sample-specific reference sequence. However,
in vitro
recombination during PCR amplification could not be excluded. Phylogenetic analysis supported close relationships among HCV sequences from the four male subjects and subsequent transmission from one subject to his female partner. Transmission was characterized by a strong genetic bottleneck. Viral genetic diversity was low during acute infection and increased upon progression to chronicity but subsequently fluctuated during chronic infection, caused by the alternate detection of distinct coexisting lineages. SMRT sequencing combines long reads with sufficient depth for many phylogenetic analyses and can therefore provide insights into within-host HCV evolutionary dynamics without the need for haplotype reconstruction using statistical algorithms.

IMPORTANCE
Next-generation sequencing has revolutionized the study of genetically variable RNA virus populations, but for phylogenetic and evolutionary analyses, longer sequences than those generated by most available platforms, while minimizing the intrinsic error rate, are desired. Here, we demonstrate for the first time that PacBio SMRT sequencing technology can be used to generate full-length HCV envelope sequences at the single-molecule level, providing a data set with large sequencing depth for the characterization of intrahost viral dynamics. The selection of consensus reads derived from at least 7 full circular consensus sequencing rounds significantly reduced the intrinsic high error rate of this method. We used this method to genetically characterize a unique transmission cluster of sexually transmitted HCV infections, providing insight into the distinct evolutionary pathways in each patient over time and identifying the transmission-associated genetic bottleneck as well as fluctuations in viral genetic diversity over time, accompanied by dynamic shifts in viral subpopulations.
RNA Interference in Fungi: Retention and Loss
Authors: Nicolás Francisco E. , Garre Victoriano 
Published: January 2017

ABSTRACT

RNA interference (RNAi) is a mechanism conserved in eukaryotes, including fungi, that represses gene expression by means of small noncoding RNAs (sRNAs) of about 20 to 30 nucleotides. Its discovery is one of the most important scientific breakthroughs of the past 20 years, and it has revolutionized our perception of the functioning of the cell. Initially described and characterized in
Neurospora crassa
, the RNAi is widespread in fungi, suggesting that it plays important functions in the fungal kingdom. Several RNAi-related mechanisms for maintenance of genome integrity, particularly protection against exogenous nucleic acids such as mobile elements, have been described in several fungi, suggesting that this is the main function of RNAi in the fungal kingdom. However, an increasing number of fungal sRNAs with regulatory functions generated by specific RNAi pathways have been identified. Several mechanistic aspects of the biogenesis of these sRNAs are known, but their function in fungal development and physiology is scarce, except for remarkable examples such as
Mucor circinelloides
, in which specific sRNAs clearly regulate responses to environmental and endogenous signals. Despite the retention of RNAi in most species, some fungal groups and species lack an active RNAi mechanism, suggesting that its loss may provide some selective advantage. This article summarizes the current understanding of RNAi functions in the fungal kingdom.
Lichenized Fungi and the Evolution of Symbiotic Organization
Authors: Grube Martin , Wedin Mats 
Published: January 2017

ABSTRACT
Lichen symbioses comprise a fascinating relationship between algae and fungi. The lichen symbiotic lifestyle evolved early in the evolution of ascomycetes and is also known from a few basidiomycetes. The ascomycete lineages have diversified in the lichenized stage to give rise to a tremendous variety of morphologies. Their thalli are often internally complex and stratified for optimized integration of algal and fungal metabolisms. Thalli are frequently colonized by specific nonlichenized fungi and occasionally also by other lichens. Microscopy has revealed various ways these fungi interact with their hosts. Besides the morphologically recognizable diversity of the lichen mycobionts and lichenicolous (lichen-inhabiting) fungi, many other microorganisms including other fungi and bacterial communities are now detected in lichens by culture-dependent and culture-independent approaches. The application of multi-omics approaches, refined microscopic techniques, and physiological studies has added to our knowledge of lichens, not only about the taxa involved in the lichen interactions, but also about their functions.
Evolution of Cell-Autonomous Effector Mechanisms in Macrophages versus Non-Immune Cells
Authors: Gaudet Ryan G. , Bradfield Clinton J. , MacMicking John D. 
Published: January 2017

ABSTRACTSpecialized adaptations for killing microbes are synonymous with phagocytic cells including macrophages, monocytes, inflammatory neutrophils, and eosinophils. Recent genome sequencing of extant species, however, reveals that analogous antimicrobial machineries exist in certain non-immune cells and also within species that ostensibly lack a well-defined immune system. Here we probe the evolutionary record for clues about the ancient and diverse phylogenetic origins of macrophage killing mechanisms and how some of their properties are shared with cells outside the traditional bounds of immunity in higher vertebrates such as mammals.
Clinical Testing of Tuberculosis Vaccine Candidates
Authors: Hatherill Mark , Tait Dereck , McShane Helen 
Published: January 2017

ABSTRACT
It is almost 100 years since the development of bacille Calmette-Guérin (BCG), the only licensed vaccine against tuberculosis (TB). While BCG does confer consistent protection against disseminated disease, there is an urgent need for a more effective vaccine against pulmonary disease. There are several indications for such an improved vaccine, including prevention of infection, prevention of disease, and a therapeutic vaccine to prevent recurrent disease. The two main approaches to TB vaccine development are developing an improved whole mycobacterial priming agent to replace BCG and/or developing a subunit booster vaccine to be administered after a BCG or BCG replacement priming vaccination. In this article we review the status of the current candidate vaccines being evaluated in clinical trials. The critical challenges to successful TB vaccine development are the uncertain predictive value of the preclinical animal models and the lack of a validated immune correlate of protection. While it is relatively simple to evaluate safety and immunogenicity in phase 1/2 studies, the evaluation of efficacy requires complex studies with large numbers of subjects and long periods of follow-up. This article reviews the potential role for human Experimental Medicine studies, in parallel with product development, to help improve the predictive value of the early-stage trials.
Invasion of Host Cells and Tissues by Uropathogenic Bacteria
Authors: Lewis Adam J. , Richards Amanda C. , Mulvey Matthew A. 
Published: January 2017

ABSTRACT

Within the mammalian urinary tract uropathogenic bacteria face many challenges, including the shearing flow of urine, numerous antibacterial molecules, the bactericidal effects of phagocytes, and a scarcity of nutrients. These problems may be circumvented in part by the ability of uropathogenic
Escherichia coli
and several other uropathogens to invade the epithelial cells that line the urinary tract. By entering host cells, uropathogens can gain access to additional nutrients and protection from both host defenses and antibiotic treatments. Translocation through host cells can facilitate bacterial dissemination within the urinary tract, while the establishment of stable intracellular bacterial populations may create reservoirs for relapsing and chronic urinary tract infections. Here we review the mechanisms and consequences of host cell invasion by uropathogenic bacteria, with consideration of the defenses that are brought to bear against facultative intracellular pathogens within the urinary tract. The relevance of host cell invasion to the pathogenesis of urinary tract infections in human patients is also assessed, along with some of the emerging treatment options that build upon our growing understanding of the infectious life cycle of uropathogenic
E. coli
and other uropathogens.
The Case for Adopting the “Species Complex” Nomenclature for the Etiologic Agents of Cryptococcosis
Authors: Kwon-Chung Kyung J. , Bennett John E. , Wickes Brian L. , Meyer Wieland , Cuomo Christina A. , Wollenburg Kurt R. , Bicanic Tihana A. , Castañeda Elizabeth , Chang Yun C. , Chen Jianghan , Cogliati Massimo , Dromer Françoise , Ellis David , Filler Scott G. , Fisher Matthew C. , Harrison Thomas S. , Holland Steven M. , Kohno Shigeru , Kronstad James W. , Lazera Marcia , Levitz Stuart M. , Lionakis Michail S. , May Robin C. , Ngamskulrongroj Popchai , Pappas Peter G. , Perfect John R. , Rickerts Volker , Sorrell Tania C. , Walsh Thomas J. , Williamson Peter R. , Xu Jianping , Zelazny Adrian M. , Casadevall Arturo 
Published: January 2017

ABSTRACT

Cryptococcosis is a potentially lethal disease of humans/animals caused by
Cryptococcus neoformans
and
Cryptococcus gattii
. Distinction between the two species is based on phenotypic and genotypic characteristics. Recently, it was proposed that
C. neoformans
be divided into two species and
C. gattii
into five species based on a phylogenetic analysis of 115 isolates. While this proposal adds to the knowledge about the genetic diversity and population structure of cryptococcosis agents, the published genotypes of 2,606 strains have already revealed more genetic diversity than is encompassed by seven species. Naming every clade as a separate species at this juncture will lead to continuing nomenclatural instability. In the absence of biological differences between clades and no consensus about how DNA sequence alone can delineate a species, we recommend using “
Cryptococcus neoformans
species complex” and “
C. gattii
species complex” as a practical intermediate step, rather than creating more species. This strategy recognizes genetic diversity without creating confusion.
The Mw 8.3 Illapel earthquake (Chile): Preseismic and postseismic activity associated with hydrated slab structures
Authors: Poli Piero , Maksymowicz Andrei , Ruiz Sergio 
Published: January 2017

Abstract
The accumulated stress in subduction zones is discharged with earthquake and aseismic activity; the latter is hosted in rheological complex regions, characterized by high pore fluid pressure, and is often accompanied by repeated earthquakes and earthquake swarms. The spatiotemporal analysis of seismic activity can reveal the presence of aseismic transients associated with large earthquakes. Here we study 20 years of seismicity prior to and after the Mw 8.3 earthquake that occurred in A.D. 2015 in central Chile. We identified several earthquake swarms before the main shock and repeating aftershocks at the border of the main slip area. Spatial clustering of the seismic activity shares similar orientation with the main fracture zones observed on the outer rise of the subducting Nazca plate. Our findings suggest that the fracture zones enclosing the rupture are playing a major role in accommodating the pre and post–main shock stress evolution. We further recognize how fracture regions have acted as barriers to the propagation of large earthquakes in the region.
Bacterial sulfur disproportionation constrains timing of Neoproterozoic oxygenation
Authors: Kunzmann Marcus , Bui Thi Hao , Crockford Peter W. , Halverson Galen P. , Scott Clint , Lyons Timothy W. , Wing Boswell A. 
Published: January 2017

Abstract
Various geochemical records suggest that atmospheric O2 increased in the Ediacaran (635–541 Ma), broadly coincident with the emergence and diversification of large animals and increasing marine ecosystem complexity. Furthermore, geochemical proxies indicate that seawater sulfate levels rose at this time too, which has been hypothesized to reflect increased sulfide oxidation in marine sediments caused by sediment mixing of the newly evolved macrofauna. However, the exact timing of oxygenation is not yet understood, and there are claims for significant oxygenation prior to the Ediacaran. Furthermore, recent evidence suggests that physical mixing of sediments did not become important until the late Silurian. Here we report a multiple sulfur isotope record from a ca. 835–630 Ma succession from Svalbard, further supported by data from Proterozoic strata in Canada, Australia, Russia, and the United States, in order to investigate the timing of oxygenation. We present isotopic evidence for onset of globally significant bacterial sulfur disproportionation and reoxidative sulfur cycling following the 635 Ma Marinoan glaciation. Widespread sulfide oxidation helps to explain the observed first-order increase in seawater sulfate concentration from the earliest Ediacaran to the Precambrian-Cambrian boundary by reducing the amount of sulfur buried as pyrite. Expansion of reoxidative sulfur cycling to a global scale also indicates increasing environmental O2 levels. Thus, our data suggest that increasing atmospheric O2 levels may have played a role in the emergence of the Ediacaran macrofauna and increasing marine ecosystem complexity.
Flexible and responsive growth strategy of the Ediacaran skeletal Cloudina from the Nama Group, Namibia
Authors: Wood Rachel , Curtis Andrew , Penny Amelia , Zhuravlev Andrey Yu. , Curtis-Walcott Shona , Iipinge Secilie , Bowyer Frederick 
Published: January 2017

Abstract
The Ediacaran skeletal tubular putative metazoan Cloudina occurs globally in carbonate settings, which both provided lithified substrates and minimized the cost of skeletonization. Habitat and substrate preferences and the relationship of Cloudina to other metazoans have not been fully documented, so we know little as to its ecological demands or community dynamics. In situ Cloudina from the Nama Group, Namibia (ca. 550–541 Ma), formed mutually attached reefs composed of successive assemblages in shallow, high-energy environments, and also communities attached to either stromatolites in storm-influenced deep inner-ramp settings or thin microbial mats in lower-energy habitats. Each assemblage shows statistically distinct tube diameter cohorts, but in sum, Cloudina shows an exponential frequency distribution of diameter size. In reefs, we document a periodicity of size variation, where mean, minimum, and maximum tube diameters vary together and show a systematic increase toward the top of each assemblage. We conclude that most Nama Group Cloudina represent one ecologically generalist taxon with highly variable size, that size was environmentally mediated, and that Cloudina could respond rapidly to periodic environmental changes. While Nama Group skeletal metazoans coexisted with soft-bodied biota, there was no apparent ecological interaction, as they were segregated into lithified carbonate and non-lithified clastic microbial mat communities, respectively. We infer that ecological flexibility allowed Cloudina to form varied communities that colonized diverse carbonate substrates under low levels of interspecific substrate competition. This is in notable contrast to the earliest Cambrian skeletal epibenthos that formed biodiverse reef communities with specialist niche occupancy.
Taking the health aid debate to the subnational level: the impact and allocation of foreign health aid in Malawi
Authors: Marty Robert , Dolan Carrie B , Leu Matthias , Runfola Daniel 
Published: January 2017

ObjectiveCross-national studies provide inconclusive results as to the effectiveness of foreign health aid. We highlight a novel application of using subnational data to evaluate aid impacts, using Malawi as a case study.DesignWe employ two rounds of nationally representative household surveys (2004/2005 and 2010/2011) and geo-referenced foreign aid data. We examine the determinants of Malawi's traditional authorities receiving aid according to health, environmental risk, socioeconomic and political factors. We use two approaches to estimate the impact of aid on reducing malaria prevalence and increasing healthcare quality: difference-in-difference models, which include traditional authority and month-of-interview fixed effects and control for individual and household level time-varying factors, and entropy balancing, where models balance on health-related and socioeconomic baseline characteristics. General health aid and four specific health aid sectors are examined.ResultsTraditional authorities with greater proportions of individuals living in urban areas, more health facilities and greater proportions of those in major ethnic groups were more likely to receive aid. Difference-in-difference models show health infrastructure and parasitic disease control aid reduced malaria prevalence by 1.20 (95% CI −0.36 to 2.76) and 2.20 (95% CI 0.43 to 3.96) percentage points, respectively, and increased the likelihood of individuals reporting healthcare as more than adequate by 12.1 (95% CI 1.51 to 22.68) and 14.0 (95% CI 0.11 to 28.11) percentage points. Entropy balancing shows similar results.ConclusionsAid was targeted to areas with greater existing health infrastructure rather than areas most in need, but still effectively reduced malaria prevalence and enhanced self-reported healthcare quality.
Incidence of surgical site infection following caesarean section: a systematic review and meta-analysis protocol
Authors: Saeed Khalid B M , Greene Richard A , Corcoran Paul , O'Neill Sinéad M 
Published: January 2017

IntroductionCaesarean section (CS) rates have increased globally during the past three decades. Surgical site infection (SSI) following CS is a common cause of morbidity with reported rates of 3–15%. SSI represents a substantial burden to the health system including increased length of hospitalisation and costs of postdischarge care. The definition of SSI varies with the postoperative follow-up period among different health systems, resulting in differences in the reporting of SSI incidence. We propose to conduct the first systematic review and meta-analysis to determine the pooled estimate for the overall incidence of SSI following CS.Methods and analysisWe will perform a comprehensive search to identify all potentially relevant published studies on the incidence of SSI following CS reported from 1992 in the English language. Electronic databases including PubMed, CINAHL, EMBASE and Scopus will be searched using a detailed search strategy. Following study selection, full-text paper retrieval, data extraction and synthesis, we will appraise study quality and risk of bias and assess heterogeneity. Incidence data will be combined where feasible in a meta-analysis using Stata software and fixed-effects or random-effects models as appropriate. This systematic review will be reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.Ethics and disseminationEthical approval is not required as this review will use published data. The review will evaluate the overall incidence of SSI following CS and will provide the first quantitative estimate of the magnitude of SSI. It will serve as a benchmark for future studies, identify research gaps and remaining challenges, and emphasise the need for appropriate prevention and control measures for SSI post-CS. A manuscript reporting the results of the systematic review and meta-analysis will be submitted to a peer-reviewed journal and presented at scientific conferences.Trial registration numberCRD42015024426.