bluuebunny/crossref_metadata_2025_split huggingface dataset:
Naf1 Regulates HIV-1 Latency by Suppressing Viral Promoter-Driven Gene Expression in Primary CD4
+
T Cells
Authors: Li Chuan , Wang Hai-Bo , Kuang Wen-Dong , Ren Xiao-Xin , Song Shu-Ting , Zhu Huan-Zhang , Li Qiang , Xu Li-Ran , Guo Hui-Jun , Wu Li , Wang Jian-Hua 
Published: October 2016

ABSTRACT

HIV-1 latency is characterized by reversible silencing of viral transcription driven by the long terminal repeat (LTR) promoter of HIV-1. Cellular and viral factors regulating LTR activity contribute to HIV-1 latency, and certain repressive cellular factors modulate viral transcription silencing. Nef-associated factor 1 (Naf1) is a host nucleocytoplasmic shuttling protein that regulates multiple cellular signaling pathways and HIV-1 production. We recently reported that nuclear Naf1 promoted nuclear export of unspliced HIV-1
gag
mRNA, leading to increased Gag production. Here we demonstrate new functions of Naf1 in regulating HIV-1 persistence. We found that Naf1 contributes to the maintenance of HIV-1 latency by inhibiting LTR-driven HIV-1 gene transcription in a nuclear factor kappa B-dependent manner. Interestingly, Naf1 knockdown significantly enhanced viral reactivation in both latently HIV-1-infected Jurkat T cells and primary central memory CD4
+
T cells. Furthermore, Naf1 knockdown in resting CD4
+
T cells from HIV-1-infected individuals treated with antiretroviral therapy significantly increased viral reactivation upon T-cell activation, suggesting an important role of Naf1 in modulating HIV-1 latency
in vivo
. Our findings provide new insights for a better understanding of HIV-1 latency and suggest that inhibition of Naf1 activity to activate latently HIV-1-infected cells may be a potential therapeutic strategy.

IMPORTANCE
HIV-1 latency is characterized mainly by a reversible silencing of LTR promoter-driven transcription of an integrated provirus. Cellular and viral proteins regulating LTR activity contribute to the modulation of HIV-1 latency. In this study, we found that the host protein Naf1 inhibited HIV-1 LTR-driven transcription of HIV genes and contributed to the maintenance of HIV-1 latency. Our findings provide new insights into the effects of host modulation on HIV-1 latency, which may lead to a potential therapeutic strategy for HIV persistence by targeting the Naf1 protein.
The Cellular DNA Helicase ChlR1 Regulates Chromatin and Nuclear Matrix Attachment of the Human Papillomavirus 16 E2 Protein and High-Copy-Number Viral Genome Establishment
Authors: Harris Leanne , McFarlane-Majeed Laura , Campos-León Karen , Roberts Sally , Parish Joanna L. 
Published: October 2016

ABSTRACT

In papillomavirus infections, the viral genome is established as a double-stranded DNA episome. To segregate the episomes into daughter cells during mitosis, they are tethered to cellular chromatin by the viral E2 protein. We previously demonstrated that the E2 proteins of diverse papillomavirus types, including bovine papillomavirus (BPV) and human papillomavirus 16 (HPV16), associate with the cellular DNA helicase ChlR1. This virus-host interaction is important for the tethering of BPV E2 to mitotic chromatin and the stable maintenance of BPV episomes. The role of the association between E2 and ChlR1 in the HPV16 life cycle is unresolved. Here we show that an HPV16 E2 Y131A mutant (E2
Y131A
) had significantly reduced binding to ChlR1 but retained transcriptional activation and viral origin-dependent replication functions. Subcellular fractionation of keratinocytes expressing E2
Y131A
showed a marked change in the localization of the protein. Compared to that of wild-type E2 (E2
WT
), the chromatin-bound pool of E2
Y131A
was decreased, concomitant with an increase in nuclear matrix-associated protein. Cell cycle synchronization indicated that the shift in subcellular localization of E2
Y131A
occurred in mid-S phase. A similar alteration between the subcellular pools of the E2
WT
protein occurred upon ChlR1 silencing. Notably, in an HPV16 life cycle model in primary human keratinocytes, mutant E2
Y131A
genomes were established as episomes, but at a markedly lower copy number than that of wild-type HPV16 genomes, and they were not maintained upon cell passage. Our studies indicate that ChlR1 is an important regulator of the chromatin association of E2 and of the establishment and maintenance of HPV16 episomes.

IMPORTANCE
Infections with high-risk human papillomaviruses (HPVs) are a major cause of anogenital and oropharyngeal cancers. During infection, the circular DNA genome of HPV persists within the nucleus, independently of the host cell chromatin. Persistence of infection is a risk factor for cancer development and is partly achieved by the attachment of viral DNA to cellular chromatin during cell division. The HPV E2 protein plays a critical role in this tethering by binding simultaneously to the viral genome and to chromatin during mitosis. We previously showed that the cellular DNA helicase ChlR1 is required for loading of the bovine papillomavirus E2 protein onto chromatin during DNA synthesis. Here we identify a mutation in HPV16 E2 that abrogates interaction with ChlR1, and we show that ChlR1 regulates the chromatin association of HPV16 E2 and that this virus-host interaction is essential for viral episome maintenance.
Biotic Interactions Shape the Ecological Distributions of
Staphylococcus
Species
Authors: Kastman Erik K. , Kamelamela Noelani , Norville Josh W. , Cosetta Casey M. , Dutton Rachel J. , Wolfe Benjamin E. 
Published: October 2016

ABSTRACT

Many metagenomic sequencing studies have observed the presence of closely related bacterial species or genotypes in the same microbiome. Previous attempts to explain these patterns of microdiversity have focused on the abiotic environment, but few have considered how biotic interactions could drive patterns of microbiome diversity. We dissected the patterns, processes, and mechanisms shaping the ecological distributions of three closely related
Staphylococcus
species in cheese rind biofilms. Paradoxically, the most abundant species (
S. equorum
) is the slowest colonizer and weakest competitor based on growth and competition assays in the laboratory. Through
in vitro
community reconstructions, we determined that biotic interactions with neighboring fungi help resolve this paradox. Species-specific stimulation of the poor competitor by fungi of the genus
Scopulariopsis
allows
S. equorum
to dominate communities
in vitro
as it does
in situ
. Results of comparative genomic and transcriptomic experiments indicate that iron utilization pathways, including a homolog of the
S. aureus
staphyloferrin B siderophore operon pathway, are potential molecular mechanisms underlying
Staphylococcus
-
Scopulariopsis
interactions. Our integrated approach demonstrates that fungi can structure the ecological distributions of closely related bacterial species, and the data highlight the importance of bacterium-fungus interactions in attempts to design and manipulate microbiomes.

IMPORTANCE
Decades of culture-based studies and more recent metagenomic studies have demonstrated that bacterial species in agriculture, medicine, industry, and nature are unevenly distributed across time and space. The ecological processes and molecular mechanisms that shape these distributions are not well understood because it is challenging to connect
in situ
patterns of diversity with mechanistic
in vitro
studies in the laboratory. Using tractable cheese rind biofilms and a focus on coagulase-negative staphylococcus (CNS) species, we demonstrate that fungi can mediate the ecological distributions of closely related bacterial species. One of the
Staphylococcus
species studied,
S. saprophyticus
, is a common cause of urinary tract infections. By identifying processes that control the abundance of undesirable CNS species, cheese producers will have more precise control on the safety and quality of their products. More generally,
Staphylococcus
species frequently co-occur with fungi in mammalian microbiomes, and similar bacterium-fungus interactions may structure bacterial diversity in these systems.
The Evolution of Orphan Regions in Genomes of a Fungal Pathogen of Wheat
Authors: Plissonneau Clémence , Stürchler Alessandra , Croll Daniel 
Published: October 2016

ABSTRACT

Fungal plant pathogens rapidly evolve virulence on resistant hosts through mutations in genes encoding proteins that modulate the host immune responses. The mutational spectrum likely includes chromosomal rearrangements responsible for gains or losses of entire genes. However, the mechanisms creating adaptive structural variation in fungal pathogen populations are poorly understood. We used complete genome assemblies to quantify structural variants segregating in the highly polymorphic fungal wheat pathogen
Zymoseptoria tritici
. The genetic basis of virulence in
Z. tritici
is complex, and populations harbor significant genetic variation for virulence; hence, we aimed to identify whether structural variation led to functional differences. We combined single-molecule real-time sequencing, genetic maps, and transcriptomics data to generate a fully assembled and annotated genome of the highly virulent field isolate 3D7. Comparative genomics analyses against the complete reference genome IPO323 identified large chromosomal inversions and the complete gain or loss of transposable-element clusters, explaining the extensive chromosomal-length polymorphisms found in this species. Both the 3D7 and IPO323 genomes harbored long tracts of sequences exclusive to one of the two genomes. These orphan regions contained 296 genes unique to the 3D7 genome and not previously known for this species. These orphan genes tended to be organized in clusters and showed evidence of mutational decay. Moreover, the orphan genes were enriched in genes encoding putative effectors and included a gene that is one of the most upregulated putative effector genes during wheat infection. Our study showed that this pathogen species harbored extensive chromosomal structure polymorphism that may drive the evolution of virulence.

IMPORTANCE
Pathogen outbreak populations often harbor previously unknown genes conferring virulence. Hence, a key puzzle of rapid pathogen evolution is the origin of such evolutionary novelty in genomes. Chromosomal rearrangements and structural variation in pathogen populations likely play a key role. However, identifying such polymorphism is challenging, as most genome-sequencing approaches only yield information about point mutations. We combined long-read technology and genetic maps to assemble the complete genome of a strain of a highly polymorphic fungal pathogen of wheat. Comparisons against the reference genome of the species showed substantial variation in the chromosome structure and revealed large regions unique to each assembled genome. These regions were enriched in genes encoding likely effector proteins, which are important components of pathogenicity. Our study showed that pathogen populations harbor extensive polymorphism at the chromosome level and that this polymorphism can be a source of adaptive genetic variation in pathogen evolution.
Outer Membrane Vesicle Production Facilitates LPS Remodeling and Outer Membrane Maintenance in
Salmonella
during Environmental Transitions
Authors: Bonnington Katherine E. , Kuehn Meta J. 
Published: October 2016

ABSTRACT

The ability of Gram-negative bacteria to carefully modulate outer membrane (OM) composition is essential to their survival. However, the asymmetric and heterogeneous structure of the Gram-negative OM poses unique challenges to the cell’s successful adaption to rapid environmental transitions. Although mechanisms to recycle and degrade OM phospholipid material exist, there is no known mechanism by which to remove unfavorable lipopolysaccharide (LPS) glycoforms, except slow dilution through cell growth. As all Gram-negative bacteria constitutively shed OM vesicles (OMVs), we propose that cells may utilize OMV formation as a way to selectively remove environmentally disadvantageous LPS species. We examined the native kinetics of OM composition during physiologically relevant environmental changes in
Salmonella enterica
, a well-characterized model system for activation of PhoP/Q and PmrA/B two-component systems (TCSs). In response to acidic pH, toxic metals, antimicrobial peptides, and lack of divalent cations, these TCSs modify the LPS lipid A and core, lengthen the O antigen, and upregulate specific OM proteins. An environmental change to PhoP/Q- and PmrA/B-activating conditions simultaneously induced the addition of modified species of LPS to the OM, downregulation of previously dominant species of LPS, greater OMV production, and increased OMV diameter. Comparison of the relative abundance of lipid A species present in the OM and the newly budded OMVs following two sets of rapid environmental shifts revealed the retention of lipid A species with modified phosphate moieties in the OM concomitant with the selective loss of palmitoylated species via vesiculation following exposure to moderately acidic environmental conditions.

IMPORTANCE
All Gram-negative bacteria alter the structural composition of LPS present in their OM in response to various environmental stimuli. We developed a system to track the native dynamics of lipid A change in
Salmonella enterica
serovar Typhimurium following an environmental shift to PhoP/Q- and PmrA/B-inducing conditions. We show that growth conditions influence OMV production, size, and lipid A content. We further demonstrate that the lipid A content of OMVs does not fit a stochastic model of content selection, revealing the significant retention of lipid A species containing covalent modifications that mask their 1- and 4′-phosphate moieties under host-like conditions. Furthermore, palmitoylation of the lipid A to form hepta-acylated species substantially increases the likelihood of its incorporation into OMVs. These results highlight a role for the OMV response in OM remodeling and maintenance processes in Gram-negative bacteria.
Macrophages and Iron Metabolism
Authors: Ganz Tomas 
Published: October 2016

ABSTRACT
Macrophages exert multiple important roles in iron metabolism. As scavengers, splenic and hepatic macrophages phagocytize and degrade senescent and damaged erythrocytes to recycle iron, predominantly for the production of hemoglobin in new erythrocytes. Splenic red pulp macrophages are specialized for iron recycling, with increased expression of proteins for the uptake of hemoglobin, breakdown of heme, and export of iron. Iron release from macrophages is closely regulated by the interaction of hepcidin, a peptide hormone produced by hepatocytes, with the macrophage iron exporter ferroportin. As regulators and effectors of antimicrobial host defense, macrophages employ multiple mechanisms to contain microbial infections by depriving microbes of iron. Macrophages also have an important trophic role in the bone marrow, supporting efficient erythropoiesis.
Neurological complications of sickle cell disease in Africa: protocol for a systematic review
Authors: Mengnjo Michel K , Kamtchum-Tatuene Joseph , Nicastro Nicolas , Noubiap Jean Jacques N 
Published: October 2016

IntroductionSickle cell disease (SCD) is highly prevalent in Africa. Considered as a public health problem, it is associated with high morbidity and mortality. Neurological complications of SCD can cause significant disability with important socioeconomic and psychological impact on the patients and their families, and can even lead to death if not properly managed. There are important knowledge gaps regarding the burden of neurological complications of SCD in African populations. We propose to conduct the first systematic review to summarise the epidemiological data available on neurological complications of SCD in Africa.Methods and analysisWe will search PubMed, MEDLINE, EMBASE and the African Index Medicus from 1 January 1950 to 31 May 2016 for studies of neurological complications of SCD in Africa. After study selection, full-text paper acquisition, data extraction and synthesis, we will assess all studies for quality, risk of bias and heterogeneity. Appropriate methods of meta-analysis will be used to pool prevalence estimates from studies with similar features, globally and in major subgroups. This protocol complies with the 2015 Preferred Reporting Items for Systematic reviews and Meta-Analysis protocols (PRISMA-P) guidelines.Ethics and disseminationThe proposed study will use published data. Therefore, there is no requirement for ethical approval. This review is expected to provide relevant data to help quantify the burden of neurological complications of SCD in African populations, inform policymakers and identify further research topics. The final report of the systematic review will be published in a peer-reviewed journal and presented at conferences.Review registration numberCRD42016039574.
Improving diagnosis for congenital cataract by introducing NGS genetic testing
Authors: Musleh Mohammud , Ashworth Jane , Black Graeme , Hall Georgina 
Published: October 2016

Childhood cataract (CC) has an incidence of 3.5 per 10,000 by age 15 years. Diagnosis of any underlying cause is important to ensure effective and prompt management of multisystem complications, to facilitate accurate genetic counselling and to streamline multidisciplinary care. Next generation sequencing (NGS) has been shown to be effective in providing an underlying diagnosis in 70% of patients with CC in a research setting. This project aimed to integrate NGS testing in CC within six months of presentation and increase the rate of diagnosis.A retrospective case note review was undertaken to define the baseline efficacy of current care in providing a precise diagnosis. Quality improvement methods were used to integrate and optimize NGS testing in clinical care and measure the improvements made.The percentage of children receiving an NGS result within six months increased from 26% to 71% during the project period. The mean time to NGS testing and receiving a report decreased and there was a reduction in variation over the study period. Several patients and families had a change in management or genetic counselling as a direct result of the diagnosis given by the NGS test.The current recommended investigation of patients with bilateral CC is ineffective in identifying a diagnosis. Quality Improvement methods have facilitated successful integration of NGS testing into clinical care, improving time to diagnosis and leading to development of a new care pathway.
Prospects for Future Collider Physics
Authors: Ellis John 
Published: October 2016

One item on the agenda of future colliders is certain to be the Higgs boson. What is it trying to tell us? The primary objective of any future collider must surely be to identify physics beyond the Standard Model, and supersymmetry is one of the most studied options. Is supersymmetry waiting for us and, if so, can LHC Run 2 find it? The big surprise from the initial 13 TeV LHC data has been the appearance of a possible signal for a new boson [Formula: see text] with a mass [Formula: see text] 750 GeV. What are the prospects for future colliders if the X(750) exists? One of the most intriguing possibilities in electroweak physics would be the discovery of nonperturbative phenomena. What are the prospects for observing sphalerons at the LHC or a future collider?
Testable SUSY spectra from GUTs at a 100 TeV pp collider
Authors: Antusch Stefan , Sluka Constantin 
Published: October 2016

Grand Unified Theories (GUTs) are attractive candidates for more fundamental elementary particle theories. They cannot only unify the Standard Model (SM) interactions but also different types of SM fermions, in particular quarks and leptons, in joint representations of the GUT gauge group. We discuss how comparing predictive supersymmetric GUT models with the experimental results for quark and charged lepton masses leads to constraints on the SUSY spectrum. We show an example from a recent analysis where the resulting superpartner masses where found just beyond the reach of LHC Run 1, but fully within the reach of a 100 TeV [Formula: see text] collider.
Descending propriospinal neurons mediate restoration of locomotor function following spinal cord injury
Authors: Benthall Katelyn N. , Hough Ryan A. , McClellan Andrew D. 
Published: October 2016

Following spinal cord injury (SCI) in the lamprey, there is virtually complete recovery of locomotion within a few weeks, but interestingly, axonal regeneration of reticulospinal (RS) neurons is mostly limited to short distances caudal to the injury site. To explain this situation, we hypothesize that descending propriospinal (PS) neurons relay descending drive from RS neurons to indirectly activate spinal central pattern generators (CPGs). In the present study, the contributions of PS neurons to locomotor recovery were tested in the lamprey following SCI. First, long RS neuron projections were interrupted by staggered spinal hemitransections on the right side at 10% body length (BL; normalized from the tip of the oral hood) and on the left side at 30% BL. For acute recovery conditions (≤1 wk) and before axonal regeneration, swimming muscle burst activity was relatively normal, but with some deficits in coordination. Second, lampreys received two spaced complete spinal transections, one at 10% BL and one at 30% BL, to interrupt long-axon RS neuron projections. At short recovery times (3–5 wk), RS and PS neurons will have regenerated their axons for short distances and potentially established a polysynaptic descending command pathway. At these short recovery times, swimming muscle burst activity had only minor coordination deficits. A computer model that incorporated either of the two spinal lesions could mimic many aspects of the experimental data. In conclusion, descending PS neurons are a viable mechanism for indirect activation of spinal locomotor CPGs, although there can be coordination deficits of locomotor activity. NEW & NOTEWORTHY In the lamprey following spinal lesion-mediated interruption of long axonal projections of reticulospinal (RS) neurons, sensory stimulation still elicited relatively normal locomotor muscle burst activity, but with some coordination deficits. Computer models incorporating the spinal lesions could mimic many aspects of the experimental results. Thus, after disruption of long-axon projections from RS neurons in the lamprey, descending propriospinal (PS) neurons appear to be a viable compensatory mechanism for indirect activation of spinal locomotor networks.