bluuebunny/crossref_metadata_2025_split huggingface dataset:
Polymorphic Nature of Human T-Cell Leukemia Virus Type 1 Particle Cores as Revealed through Characterization of a Chronically Infected Cell Line
Authors: Meissner Morgan E. , Mendonça Luiza M. , Zhang Wei , Mansky Louis M. 
Published: June 2017

ABSTRACT

Human T-cell leukemia virus type 1 (HTLV-1) is the etiological agent of adult T-cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-1 cell-to-cell transmission is dependent on the release of infectious virus particles into the virological synapse. The HTLV-1 particle structure is still poorly understood, and previous studies analyzed viruses produced by transformed lymphocytic cell lines chronically infected with HTLV-1, particularly the MT-2 cell line, which harbors truncated proviruses and expresses aberrant forms of the Gag protein. In this study, we demonstrate that the chronically infected SP cell line harbors a relatively low number of proviruses, making it a more promising experimental system for the study of the HTLV-1 particle structure. We first identified the genomic sites of integration and characterized the genetic structure of the
gag
region in each provirus. We also determined that despite encoding a truncated Gag protein, only the full-length Gag protein was incorporated into virus particles. Cryo-transmission electron microscopy analyses of the purified virus particles revealed three classes of particles based upon capsid core morphology: complete cores, incomplete cores, and particles without distinct electron densities that would correlate with the capsid region of a core structure. Observed cores were generally polygonal, and virus particles were on average 115 nm in diameter. These data corroborate particle morphologies previously observed for MT-2 cells and provide evidence that the known poor infectivity of HTLV-1 particles may correlate with HTLV-1 particle populations containing few virus particles possessing a complete capsid core structure.

IMPORTANCE
Studies of retroviral particle core morphology have demonstrated a correlation between capsid core stability and the relative infectivity of the virus. In this study, we used cryo-transmission electron microscopy to demonstrate that HTLV-1 particles produced from a distinct chronically infected cell line are polymorphic in nature, with many particles lacking organized electron densities that would correlate with a complete core structure. These findings have important implications for infectious HTLV-1 spread, particularly in the context of cell-to-cell transmission, a critical step in HTLV-1 transmission and pathogenesis.
In VitroReplication of Chelonid Herpesvirus 5 in Organotypic Skin Cultures from Hawaiian Green Turtles (Chelonia mydas)
Authors: Work Thierry M. , Dagenais Julie , Weatherby Tina M. , Balazs George H. , Ackermann Mathias 
Published: June 2017

ABSTRACTFibropapillomatosis (FP) is a tumor disease of marine turtles associated with chelonid herpesvirus 5 (ChHV5), which has historically been refractory to growth in tissue culture. Here we show, for the first time,de novoformation of ChHV5-positive intranuclear inclusions in cultured green turtle cells, which is indicative of active lytic replication of the virus. The minimal requirements to achieve lytic replication in cultured cells included (i) eitherin vitrocultures of ChHV5-positive tumor biopsy specimens (plugs) or organotypic cultures (rafts) consisting of ChHV5-positive turtle fibroblasts in collagen rafts seeded with turtle keratinocytes and (ii) keratinocyte maturation induced by raising raft or biopsy cultures to the air-liquid interface. Virus growth was confirmed by detailed electron microscopic studies that revealed intranuclear sun-shaped capsid factories, tubules, various stages of capsid formation, nuclear export by budding into the perinuclear space, tegument formation, and envelopment to completede novovirus production. Membrane synthesis was also observed as a sign of active viral replication. Interestingly, cytoplasmic particles became associated with keratin filaments, a feature not seen in conventional monolayer cell cultures, in which most studies of herpesvirus replication have been performed. Our findings draw a rich and realistic picture of ChHV5 replication in cells derived from its natural host and may be crucial not only to better understand ChHV5 circulation but also to eventually complete Koch's postulates for FP. Moreover, the principles described here may serve as a model for culture of other viruses that are resistant to replication in conventional cell culture.IMPORTANCEA major challenge in virology is the study of viruses that cannot be grown in the laboratory. One example is chelonid herpesvirus 5 (ChHV5), which is associated with fibropapillomatosis, a globally distributed, debilitating, and fatal tumor disease of endangered marine turtles. Pathological examination shows that ChHV5 is shed in skin. Here we show that ChHV5 will growin vitroif we replicate the complex three-dimensional structure of turtle skin. Moreover, lytic virus growth requires a close interplay between fibroblasts and keratinocytes. Finally, the morphogenesis of herpesviral growth in three-dimensional cultures reveals a far richer, and likely more realistic, array of capsid morphologies than that encountered in traditional monolayer cell cultures. Our findings have applications to other viruses, including those of humans.
Follicular Regulatory T Cells Are Highly Permissive to R5-Tropic HIV-1
Authors: Miller Shannon M. , Miles Brodie , Guo Kejun , Folkvord Joy , Meditz Amie L. , McCarter Martin D. , Levy David N. , MaWhinney Samantha , Santiago Mario L. , Connick Elizabeth 
Published: June 2017

ABSTRACTFollicular regulatory T (TFR) cells are a subset of CD4+T cells in secondary lymphoid follicles. TFR cells were previously included in the follicular helper T (TFH) cell subset, which consists of cells that are highly permissive to HIV-1. The permissivity of TFR cells to HIV-1 is unknown. We find that TFR cells are more permissive than TFH cells to R5-tropic HIV-1ex vivo. TFR cells expressed more CCR5 and CD4 and supported higher frequencies of viral fusion. Differences in Ki67 expression correlated with HIV-1 replication. Inhibiting cellular proliferation reduced Ki67 expression and HIV-1 replication. Lymph node cells from untreated HIV-infected individuals revealed that TFR cells harbored the highest concentrations of HIV-1 RNA and highest levels of Ki67 expression. These data demonstrate that TFR cells are highly permissive to R5-tropic HIV-1 bothex vivoandin vivo. This is likely related to elevated CCR5 levels combined with a heightened proliferative state and suggests that TFR cells contribute to persistent R5-tropic HIV-1 replicationin vivo.IMPORTANCEIn chronic, untreated HIV-1 infection, viral replication is concentrated in secondary lymphoid follicles. Within secondary lymphoid follicles, follicular helper T (TFH) cells have previously been shown to be highly permissive to HIV-1. Recently, another subset of T cells in secondary lymphoid follicles was described, follicular regulatory T (TFR) cells. These cells share some phenotypic characteristics with TFH cells, and studies that showed that TFH cells are highly permissive to HIV-1 included TFR cells in their definition of TFH cells. The permissivity of TFR cells to HIV-1 has not previously been described. Here, we show that TFR cells are highly permissive to HIV-1 bothex vivoandin vivo. The expression of Ki67, a marker of proliferative capacity, is predictive of expression of viral proteins, and downregulating Ki67 leads to concurrent decreases in expression of viral proteins. Our study provides new insight into HIV-1 replication and a potential new cell type to target for future treatment.
Conserved Vδ1 Binding Geometry in a Setting of Locus-Disparate pHLA Recognition by δ/αβ T Cell Receptors (TCRs): Insight into Recognition of HIV Peptides by TCRs
Authors: Shi Yi , Kawana-Tachikawa Ai , Gao Feng , Qi Jianxun , Liu Chuansheng , Gao Jia , Cheng Hao , Ueno Takamasa , Iwamoto Aikichi , Gao George F. 
Published: June 2017

ABSTRACTGiven the limited set of T cell receptor (TCR) V genes that are used to create TCRs that are reactive to different ligands, such as major histocompatibility complex (MHC) class I, MHC class II, and MHC-like proteins (for example, MIC molecules and CD1 molecules), the Vδ1 segment can be rearranged with Dδ-Jδ-Cδ or Jα-Cα segments to form classical γδTCRs or uncommon αβTCRs using a Vδ1 segment (δ/αβTCR). Here we have determined two complex structures of the δ/αβTCRs (S19-2 and TU55) bound to different locus-disparate MHC class I molecules with HIV peptides (HLA-A*2402-Nef138-10 and HLA-B*3501-Pol448-9). The overall binding modes resemble those of classical αβTCRs but display a strong tilt binding geometry of the Vδ1 domain toward the HLA α1 helix, due to a conserved extensive interaction between the CDR1δ loop and the N-terminal region of the α1 helix (mainly in position 62). The aromatic amino acids of the CDR1δ loop exploit different conformations (“aromatic ladder” or “aromatic hairpin”) to accommodate distinct MHC helical scaffolds. This tolerance helps to explain how a particular TCR V region can similarly dock onto multiple MHC molecules and thus may potentially explain the nature of TCR cross-reactivity. In addition, the length of the CDR3δ loop could affect the extent of tilt binding of the Vδ1 domain, and adaptively, the pairing Vβ domains adjust their mass centers to generate differential MHC contacts, hence probably ensuring TCR specificity for a certain peptide-MHC class I (pMHC-I). Our data have provided further structural insights into the TCR recognition of classical pMHC-I molecules, unifying cross-reactivity and specificity.IMPORTANCEThe specificity of αβ T cell recognition is determined by the CDR loops of the αβTCR, and the general mode of binding of αβTCRs to pMHC has been established over the last decade. Due to the intrinsic genomic structure of the TCR α/δ chain locus, some Vδ segments can rearrange with the Cα segment, forming a hybrid VδCαVβCβ TCR, the δ/αβTCR. However, the basis for the molecular recognition of such TCRs of their ligands is elusive. Here an αβTCR using the Vδ1 segment, S19-2, was isolated from an HIV-infected patient in an HLA-A*24:02-restricted manner. We then solved the crystal structures of the S19-2 TCR and another δ/αβTCR, TU55, bound to their respective ligands, revealing a conserved Vδ1 binding feature. Further binding kinetics analysis revealed that the S19-2 and TU55 TCRs bind pHLA very tightly and in a long-lasting manner. Our results illustrate the mode of binding of a TCR using the Vδ1 segment to its ligand, virus-derived pHLA.
Allosteric HIV-1 Integrase Inhibitors Lead to Premature Degradation of the Viral RNA Genome and Integrase in Target Cells
Authors: Madison Michaela K. , Lawson Dana Q. , Elliott Jennifer , Ozantürk Ayşe Naz , Koneru Pratibha C. , Townsend Dana , Errando Manel , Kvaratskhelia Mamuka , Kutluay Sebla B. 
Published: June 2017

ABSTRACT
Recent evidence indicates that inhibition of HIV-1 integrase (IN) binding to the viral RNA genome by allosteric integrase inhibitors (ALLINIs) or through mutations within IN yields aberrant particles in which the viral ribonucleoprotein complexes (vRNPs) are eccentrically localized outside the capsid lattice. These particles are noninfectious and are blocked at an early reverse transcription stage in target cells. However, the basis of this reverse transcription defect is unknown. Here, we show that the viral RNA genome and IN from ALLINI-treated virions are prematurely degraded in target cells, whereas reverse transcriptase remains active and stably associated with the capsid lattice. The aberrantly shaped cores in ALLINI-treated particles can efficiently saturate and be degraded by a restricting TRIM5 protein, indicating that they are still composed of capsid proteins arranged in a hexagonal lattice. Notably, the fates of viral core components follow a similar pattern in cells infected with eccentric particles generated by mutations within IN that inhibit its binding to the viral RNA genome. We propose that IN-RNA interactions allow packaging of both the viral RNA genome and IN within the protective capsid lattice to ensure subsequent reverse transcription and productive infection in target cells. Conversely, disruption of these interactions by ALLINIs or mutations in IN leads to premature degradation of both the viral RNA genome and IN, as well as the spatial separation of reverse transcriptase from the viral genome during early steps of infection.

IMPORTANCE
Recent evidence indicates that HIV-1 integrase (IN) plays a key role during particle maturation by binding to the viral RNA genome. Inhibition of IN-RNA interactions yields aberrant particles with the viral ribonucleoprotein complexes (vRNPs) eccentrically localized outside the conical capsid lattice. Although these particles contain all of the components necessary for reverse transcription, they are blocked at an early reverse transcription stage in target cells. To explain the basis of this defect, we tracked the fates of multiple viral components in infected cells. Here, we show that the viral RNA genome and IN in eccentric particles are prematurely degraded, whereas reverse transcriptase remains active and stably associated within the capsid lattice. We propose that IN-RNA interactions ensure the packaging of both vRNPs and IN within the protective capsid cores to facilitate subsequent reverse transcription and productive infection in target cells.
Prenatal markers and longitudinal follow-up in simple and complex gastroschisis
Authors: Hijkoop Annelieke , IJsselstijn Hanneke , Wijnen René M H , Tibboel Dick , Rosmalen Joost van , Cohen-Overbeek Titia E 
Published: June 2017

ObjectiveWe aimed to identify gestational-age corrected prenatal ultrasound markers of complex gastroschisis, and to compare physical growth and neurodevelopment between children with simple and complex gastroschisis.DesignWe included prenatally diagnosed gastroschisis patients from 2000 to 2012 who joined our longitudinal follow-up programme. Associations between complex gastroschisis and prenatal ultrasound markers collected at 30 weeks’ gestation and prior to delivery were tested using logistic regression. Physical growth (SD scores (SDS)), mental and psychomotor developmental index (MDI, PDI; Bayley Scales of Infant Development) were recorded at 12 and 24 months. Data were analysed using general linear models and compared with population norms.ResultsData of 61 children were analysed (82% of eligible cases). Extra-abdominal bowel dilatation at 30 weeks’ gestation was significantly associated with complex gastroschisis (OR (95% CI): 5.00 (1.09 to 22.98)), with a high negative (88%) but low positive (40%) predictive value. The mean (95% CI) height SDS at 12 months (−0.46 (–0.82 to –0.11)), and weight SDS at 12 and 24 months (−0.45 (–0.85 to –0.05), and −0.44 (−0.87 to –0.01), respectively) fell significantly below 0 SDS. MDI and PDI were significantly below 100 at 24 months; 93 (88 to 99) and 83 (78 to 87), respectively). Children with complex gastroschisis had a significantly lower PDI (76 (68 to 84)) than those with simple gastroschisis (94 (90 to 97), p<0.001).ConclusionsPrenatal ultrasound markers could not reliably distinguish between simple and complex gastroschisis. Children with complex gastroschisis may be at increased risk for delayed psychomotor development; they should be monitored more closely, and offered timely intervention.
Ibuprofen exposure in early neonatal life does not affect renal function in young adolescence
Authors: Raaijmakers Anke , Zhang Zhen-Yu , Levtchenko Elena , Simons Sinno HP , Cauwenberghs Nicholas , Heuvel Lambertus P van den , Jacobs Lotte , Staessen Jan A , Allegaert Karel 
Published: June 2017

IntroductionIbuprofen exposure results in acute transient renal dysfunction in preterm neonates, but we are unaware of data on long-term renal safety.MethodsIn a previously studied cohort of extreme low birth weight (ELBW, <1000 g) cases, the PREMATurity as predictor of children’s Cardiovascular-renal Health study generated data on renal function (renal length, estimated glomerular filtration rate based on cystatin C (eGFRcysC) at the age of 11 years. This data set in 93 ELBW cases may also generate data on long-term drug safety on ibuprofen. In this post hoc analysis, we linked markers of renal function in young adolescence in ELBW cases with their perinatal (prenatal maternal, setting at birth, treatment modalities including drug prescription during neonatal stay, neonatal creatinine values, postdischarge growth) characteristics, including but not limited to ibuprofen exposure during neonatal stay.ResultsIbuprofen exposure was not associated with significant differences in renal length or eGFRcysC. Moreover, we were unable to identify any other risk factor (perinatal characteristics, postnatal creatinine trends, postdischarge growth) on renal outcome in this cohort.ConclusionsNeonatal exposure to ibuprofen did not affect renal function. Larger studies are needed to explore the confounders of variability in renal function in former ELBW cases. This matters since ELBW relates to risk for hypertension, cardiovascular events and renal disease in later life and identification of risk factors holds the promise of secondary prevention.Trial registration numberNCT02147457.
Tension enterothorax and hepatothorax due to a diaphragmatic hernia: successful emergency repair of a life-threatening condition
Authors: Martinou Eirini , Gatenby Piers 
Published: June 2017

A 70-year-old female patient presented with acute severe respiratory distress at a district general hospital. Medical history included type 2 diabetes, recurrent pulmonary embolisms and pre-existing diaphragmatic hernia containing part of the liver. Despite initial treatment with steroid inhalers, her clinical picture rapidly deteriorated requiring emergency intubation and positive pressure ventilation. Imaging investigations revealed tension enterothorax and hepatothorax with tracheal deviation. The patient was transferred and underwent an emergency laparotomy at the Regional Oesophagogastric Unit. A large diaphragmatic hernia (central tendon defect) which contained the duodenum, porta hepatis, right lobe of liver, gallbladder and right colon was reduced and successfully repaired. Her postoperative course was uneventful with no signs of recurrence at 2 months follow-up.This case describes an extremely rare and life-threatening condition of tension enterothorax and hepatothorax, which should be considered in the differential diagnosis of acute respiratory distress with tracheal deviation.
Does leisure time physical activity protect against low back pain? Systematic review and meta-analysis of 36 prospective cohort studies
Authors: Shiri Rahman , Falah-Hassani Kobra 
Published: June 2017

BackgroundThere are plausible mechanisms whereby leisure time physical activity may protect against low back pain (LBP) but there have been no quality systematic reviews and meta-analyses of the subject.ObjectiveThis review aims to assess the effect of leisure time physical activity on non-specific LBP.MethodsLiterature searches were conducted in PubMed, Embase, Web of Science, Scopus and Google Scholar databases from their inception through July 2016. Methodological quality of included studies was evaluated. A random-effects meta-analysis was performed, and heterogeneity and publication bias were assessed.ResultsThirty-six prospective cohort studies (n=158 475 participants) qualified for meta-analyses. Participation in sport or other leisure physical activity reduced the risk of frequent or chronic LBP, but not LBP for>1 day in the past month or past 6–12 months. Risk of frequent/chronic LBP was 11% lower (adjusted risk ratio (RR)=0.89, CI 0.82 to 0.97, I2=31%, n=48 520) in moderately/highly active individuals, 14% lower (RR=0.86, CI 0.79 to 0.94, I2=0%, n=33 032) in moderately active individuals and 16% lower (RR=0.84, CI 0.75 to 0.93, I2=0%, n=33 032) in highly active individuals in comparison with individuals without regular physical activity. For LBP in the past 1–12 months, adjusted RR was 0.98 (CI 0.93 to 1.03, I2=50%, n=32 654) for moderate/high level of activity, 0.94 (CI 0.84 to 1.05, I2=3%, n=8549) for moderate level of activity and 1.06 (CI 0.89 to 1.25, I2=53%, n=8554) for high level of activity.ConclusionsLeisure time physical activity may reduce the risk of chronic LBP by 11%–16%. The finding, however, should be interpreted cautiously due to limitations of the original studies. If this effect size is proven in future research, the public health implications would be substantial.
Acute kidney injury associated with endurance events—is it a cause for concern? A systematic review
Authors: Hodgson LE , Walter E , Venn RM , Galloway R , Pitsiladis Y , Sardat F , Forni LG 
Published: June 2017

IntroductionA growing body of evidence suggests even small rises in serum creatinine (SCr) are of considerable clinical relevance. Given that participants in endurance events are exposed to potential (repeated) renal insults, a systematic review was undertaken to collate current evidence for acute kidney injury (AKI), complicating such events.MethodsA systematic review of studies and case reports meeting inclusion criteria on Medline and EMBASE (inception to October 2015). Included: studies with markers of renal function before and after endurance or ultraendurance events; case reports of severe AKI. Two reviewers assessed risk of bias using the Newcastle-Ottawa scale.ResultsEleven case report publications (n=27 individuals) of severe AKI, were retrieved, with risk factors including systemic illness or nephrotoxic medications usually identified. From 30 studies of endurance and ultraendurance events, mean rise in SCr was 29 (±12.3) µmol/L after marathon or ultramarathon (17 studies, n=568 participants) events. Where follow-up tests were conducted, SCr returned to baseline within 48 hours. Rises in biomarkers suggest potential parenchymal insult, rather than simply muscle breakdown. However, evidence of long-term deleterious effects is lacking.ConclusionsRaised levels of SCr are reported immediately after endurance events. It is not clear whether this is either clinically significant, or if repeated participation predisposes to long-term sequelae. The aetiology of severe exercise-associated AKI is usually multifactorial, with risk factors generally identified in the rare cases reported. On-site biochemistry, urine analysis and biomarkers of AKI may help identify collapsed runners who are at significant short-term risk and allow suitable follow-up.