bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Highly Conserved gp120 Inner Domain Residue Modulates Env Conformation and Trimer Stability
Authors: Ding Shilei , Tolbert William D. , Prévost Jérémie , Pacheco Beatriz , Coutu Mathieu , Debbeche Olfa , Xiang Shi-Hua , Pazgier Marzena , Finzi Andrés 
Published: July 2016

ABSTRACT

Previous studies have shown that highly conserved residues in the inner domain of gp120 are required for HIV-1 envelope glycoprotein (Env) transitions to the CD4-bound conformation (A. Finzi, S. H. Xiang, B. Pacheco, L. Wang, J. Haight, et al., Mol Cell
37:
656–667, 2010,
http://dx.doi.org/10.1016/j.molcel.2010.02.012
; A. Desormeaux, M. Coutu, H. Medjahed, B. Pacheco, A. Herschhorn, et al., J Virol
87:
2549–2562, 2013,
http://dx.doi.org/10.1128/JVI.03104-12
). Moreover, W69, a highly conserved residue located at the interface between layer 1 and layer 2 of the inner domain, was recently shown to be important for efficient Env recognition by CD4-induced (CD4i) antibodies capable of potent antibody-dependent cellular cytotoxicity (W. D. Tolbert, N. Gohain, M. Veillette, J. P. Chapleau, C. Orlandi, et al., 2016, Structure
24:
697–709,
http://dx.doi.org/10.1016/j.str.2016.03.005
; S. Ding, M. Veillette, M. Coutu, J. Prevost, L. Scharf, et al., 2016, J Virol
90:
2127–2134,
http://dx.doi.org/10.1128/JVI.02779-15
). We evaluated the contribution of the hydrophobicity of W69 to conformational changes of Env by replacing it with a series of residues with aliphatic or aromatic side chains of decreasing chain length. We have found that the hydrophobicity of residue 69 is important for Env processing, CD4 binding, and its transition to the CD4-bound conformation. The most deleterious effect was observed when W69 was replaced with alanine or glycine residues. However, the functions lost due to W69 mutations could be progressively restored with amino acids of increasing aliphatic chain length and fully recovered with residues bearing an aromatic ring. Interestingly, poor CD4 binding of W69A could be fully restored by introducing a compensatory mutation within layer 2 (S115W). Structural studies of HIV-1 gp120 core
e
W69A/S115W mutant bound to the CD4 peptide mimetic M48U1 and Fab of anti-cluster A antibody N60-i3 revealed no perturbations to the overall structure of the double mutant compared to the wild-type protein but identified higher mobility within the interface between layer 1 and layer 2, the bridging sheet region, and the CD4 binding site.

IMPORTANCE
HIV-1 Env transitions to the CD4-bound conformation are required for viral entry. Previous studies identified a highly conserved residue of the inner domain, W69, as being involved in these conformational transitions (A. Finzi, S. H. Xiang, B. Pacheco, L. Wang, J. Haight, et al., Mol Cell 37:656–667, 2010,
http://dx.doi.org/10.1016/j.molcel.2010.02.012
). Here, we show that W69, located at the interface between gp120 and gp41 in the PGT151-bound trimer, plays a critical role in the interprotomer signaling induced by CD4 binding. This new information might be useful in immunogen design.
Specificity, Size, and Frequency of Spaces That Characterize the Mechanism of Bulk Transepithelial Transport of Prions in the Nasal Cavities of Hamsters and Mice
Authors: Kincaid A. E. , Ayers J. I. , Bartz J. C. 
Published: July 2016

ABSTRACT
Inhalation of infected brain homogenate results in transepithelial transport of prions across the nasal mucosa of hamsters, some of which occurs rapidly in relatively large amounts between cells (A. E. Kincaid, K. F. Hudson, M. W. Richey, and J. C. Bartz, J. Virol 86:12731–12740, 2012, doi:http://dx.doi.org/10.1128/JVI.01930-12). Bulk transepithelial transport in the nasal cavity has not been studied to date. In the present study, we characterized the frequency, size, and specificity of the intercellular spaces that mediate the bulk transport of inhaled prions between cells of mice or hamsters following extranasal inoculation with mock-infected brain homogenate, different strains of prion-infected brain homogenate, or brain homogenate mixed with India ink. Infected or mock-infected inoculum was identified within lymphatic vessels of the lamina propria and in spaces of >5 μm between a small number of cells of the nasal mucosa in >90% of animals from 5 to 60 min after inhalation. The width of the spaces between cells, the amount of the inoculum within the lumen of lymphatic vessels, and the timing of the transport indicate that this type of transport was taking place through preexisting spaces in the nasal cavity that were orders of magnitude wider than what is normally reported for paracellular transport. The indiscriminate rapid bulk transport of brain homogenate in the nasal cavity results in immediate entry into nasal cavity lymphatics following inhalation. This novel mechanism may underlie the recent report of the early detection of prions in blood following inhalation and has implications for horizontal prion transmission.

IMPORTANCE
The results of these studies demonstrate that the nasal mucosa of mice and hamsters is not an absolute anatomical barrier to inhaled prion-infected or uninfected brain homogenate. Relatively large amounts of infected and uninfected brain homogenate rapidly cross the nasal mucosa and enter the lumen of lymphatic vessels following inhalation. These bulk transepithelial transport events were relatively rare but present in >90% of animals 5 to 60 min following inhalation. This novel mechanism of bulk transepithelial transport was seen in experimental and control hamsters and mice, indicating that it was not species specific or in response to prion exposure. The indiscriminate bulk intercellular transport of inhaled pathogens across the nasal mucosa followed by entry into the lymphatic system may be a mechanism that underlies the entry and spread of other toxins and pathogens in olfactory system-driven animals.
Unusual Features of Sodium Taurocholate Cotransporting Polypeptide as a Hepatitis B Virus Receptor
Authors: Li Jisu , Zong Li , Sureau Camille , Barker Luke , Wands Jack R. , Tong Shuping 
Published: July 2016

ABSTRACT
Cell culture (cc)-derived hepatitis B virus (HBV) can infect differentiated HepaRG cells, but efficient infection requires addition of polyethylene glycol (PEG) during inoculation. Identification of sodium taurocholate cotransporting polypeptide (NTCP) as an HBV receptor enabled ccHBV infection of NTCP reconstituted HepG2 cells, although very little hepatitis B surface antigen (HBsAg) is produced. We found infection by patient serum-derived HBV (sHBV), which required purification of viral particles through ultracentrifugation or PEG precipitation, was PEG independent and much more efficient in HepaRG cells than in HepG2/NTCP cells. In contrast to hepatitis B e antigen (HBeAg), HBsAg was not a reliable marker of productive sHBV infection at early time points. A low HBsAg/HBeAg ratio by ccHBV-infected HepG2/NTCP cells was attributable to dimethyl sulfoxide (DMSO) in culture medium, NTCP overexpression, and HBV genotype D. HepG2/NTCP cells released more viral antigens than HepG2 cells after HBV genome delivery by adeno-associated virus, and stable expression of NTCP in a ccHBV producing cell line increased viral mRNAs, proteins, replicative DNA, and covalently closed circular DNA. NTCP protein expression in HepG2/NTCP cells, despite being driven by the cytomegalovirus promoter, was markedly increased by DMSO treatment. This at least partly explains ability of DMSO to promote ccHBV infection in such cell lines. In conclusion, NTCP appeared inefficient to mediate infection by serum-derived HBV. It could promote HBV RNA transcription while inhibiting HBsAg secretion. Efficient PEG-independent sHBV infection of HepaRG cells permits comparative studies of diverse clinical HBV isolates and will help identify additional factors on virion surface promoting attachment to hepatocytes.

IMPORTANCE
Currently
in vitro
infection with hepatitis B virus (HBV) depends on cell culture-derived HBV inoculated in the presence of polyethylene glycol. We found patient serum-derived HBV could efficiently infect differentiated HepaRG cells independent of polyethylene glycol, which represents a more physiological infection system. Serum-derived HBV has poor infectivity in HepG2 cells reconstituted with sodium taurocholate cotransporting polypeptide (NTCP), the currently accepted HBV receptor. Moreover, HepG2/NTCP cells secreted very little hepatitis B surface antigen after infection with cell culture-derived HBV, which was attributed to NTCP overexpression, genotype D virus, and dimethyl sulfoxide added to culture medium. NTCP could promote HBV RNA transcription, protein expression, and DNA replication in HepG2 cells stably transfected with HBV DNA, while dimethyl sulfoxide could increase NTCP protein level despite transcriptional control by a cytomegalovirus promoter. Therefore, this study revealed several unusual features of NTCP as an HBV receptor and established conditions for efficient serum virus infection
in vitro
.
Infection of Common Marmosets with GB Virus B Chimeric Virus Encoding the Major Nonstructural Proteins NS2 to NS4A of Hepatitis C Virus
Authors: Zhu Shaomei , Li Tingting , Liu Bochao , Xu Yuxia , Sun Yachun , Wang Yilin , Wang Yuanzhan , Shuai Lifang , Chen Zixuan , Allain Jean-Pierre , Li Chengyao 
Published: July 2016

ABSTRACT
A lack of immunocompetent-small-primate models has been an obstacle for developing hepatitis C virus (HCV) vaccines and affordable antiviral drugs. In this study, HCV/GB virus B (GBV-B) chimeric virus carrying the major nonstructural proteins NS2 to NS4A (HCV NS2 to -4A chimera) was produced and used to infect common marmosets, since HCV NS2 to NS4A proteins are critical proteases and major antigens. Seven marmosets were inoculated intrahepatically with HCV NS2 to -4A chimera RNA for primary infection or intravenously injected with chimera-containing serum for passage infection. Three animals used as controls were injected with phosphate-buffered saline (PBS) or GBV-B, respectively. Six of seven HCV NS2 to -4A chimera-infected marmosets exhibited consistent viremia and one showed transient viremia during the course of follow-up detection. All six infected animals with persistent circulating viremia presented characteristics typical of viral hepatitis, including viral RNA and proteins in hepatocytes and histopathological changes in liver tissue. Viremia was consistently detected for 5 to 54 weeks of follow-up. FK506 immunosuppression facilitated the establishment of persistent chimera infection in marmosets. An animal with chimera infection spontaneously cleared the virus in blood 7 weeks following the first inoculation, but viral-RNA persistence, low-level viral protein, and mild necroinflammation remained in liver tissue. The specific antibody and T-cell response to HCV NS3 in this viremia-resolved marmoset was boosted by rechallenging, but no viremia was detected during 57 weeks of follow-up. The chimera-infected marmosets described can be used as a suitable small-primate animal model for studying novel antiviral drugs and T-cell-based vaccines against HCV infection.

IMPORTANCE
HCV infection causes approximately 70% of chronic hepatitis and is frequently associated with primary liver cancer globally. Chimpanzees have been used as a reliable primate model for HCV infection, but ethical considerations have restricted their utility in biomedical research. GB virus B (GBV-B) is a flavivirus related to HCV. It can infect common marmosets, a New World small primate, and induces viral hepatitis similar to HCV infection in humans. To minimize differences between GBV-B and HCV, we generated HCV NS2 to -4A/GBV-B chimeric viruses and established a chimera-infected marmoset model. HCV NS2 to -4A chimera-infected marmosets provide a small-animal model for evaluating novel antiviral drugs targeting HCV NS3-NS4A protease and T-cell-based HCV vaccines.
Why is Africa rifting?
Authors: Kendall J.-Michael , Lithgow-Bertelloni Carolina 
Published: July 2016

Abstract

Continental rifting has a fundamental role in the tectonic behaviour of the Earth, shaping the surface we live on. Although there is not yet a consensus about the dominant mechanism for rifting, there is a general agreement that the stresses required to rift the continental lithosphere are not readily available. Here we use a global finite element model of the lithosphere to calculate the stresses acting on Africa. We consider the stresses induced by mantle flow, crustal structure and topography in two types of models: one in which flow is exclusively driven by the subducting slabs and one in which it is derived from a shear wave tomographic model. The latter predicts much larger stresses and a more realistic dynamic topography. It is therefore clear that the mantle structure beneath Africa plays a key part in providing the radial and horizontal tractions, dynamic topography and gravitational potential energy necessary for rifting. Nevertheless, the total available stress (
c.
100 MPa) is much less than that needed to break thick, cold continental lithosphere. Instead, we appeal to a model of magma-assisted rifting along pre-existing weaknesses, where the strain is localized in a narrow axial region and the strength of the plate is reduced significantly. Mounting geological and geophysical observations support such a model.
Risk of Lung Cancer Associated with COPD Phenotype Based on Quantitative Image Analysis
Authors: Schwartz Ann G. , Lusk Christine M. , Wenzlaff Angela S. , Watza Donovan , Pandolfi Stephanie , Mantha Laura , Cote Michele L. , Soubani Ayman O. , Walworth Garrett , Wozniak Antoinette , Neslund-Dudas Christine , Ardisana Amy A. , Flynn Michael J. , Song Thomas , Spizarny David L. , Kvale Paul A. , Chapman Robert A. , Gadgeel Shirish M. 
Published: July 2016

Abstract
Background: Chronic obstructive pulmonary disease (COPD) is a risk factor for lung cancer. This study evaluates alternative measures of COPD based on spirometry and quantitative image analysis to better define a phenotype that predicts lung cancer risk.
Methods: A total of 341 lung cancer cases and 752 volunteer controls, ages 21 to 89 years, participated in a structured interview, standardized CT scan, and spirometry. Logistic regression, adjusted for age, race, gender, pack-years, and inspiratory and expiratory total lung volume, was used to estimate the odds of lung cancer associated with FEV1/FVC, percent voxels less than −950 Hounsfield units on the inspiratory scan (HUI) and percent voxels less than −856 HU on expiratory scan (HUE).
Results: The odds of lung cancer were increased 1.4- to 3.1-fold among those with COPD compared with those without, regardless of assessment method; however, in multivariable modeling, only percent voxels &lt;−856 HUE as a continuous measure of air trapping [OR = 1.04; 95% confidence interval (CI), 1.03–1.06] and FEV1/FVC &lt; 0.70 (OR = 1.71; 95% CI, 1.21–2.41) were independent predictors of lung cancer risk. Nearly 10% of lung cancer cases were negative on all objective measures of COPD.
Conclusion: Measures of air trapping using quantitative imaging, in addition to FEV1/FVC, can identify individuals at high risk of lung cancer and should be considered as supplementary measures at the time of screening for lung cancer.
Impact: Quantitative measures of air trapping based on imaging provide additional information for the identification of high-risk groups who might benefit the most from lung cancer screening. Cancer Epidemiol Biomarkers Prev; 25(9); 1341–7. ©2016 AACR.
A Nomogram Derived by Combination of Demographic and Biomarker Data Improves the Noninvasive Evaluation of Patients at Risk for Bladder Cancer
Authors: Huang Sijia , Kou Lei , Furuya Hideki , Yu Changhong , Goodison Steve , Kattan Michael W. , Garmire Lana , Rosser Charles J. 
Published: July 2016

Abstract
Background: Improvements in the noninvasive clinical evaluation of patients at risk for bladder cancer would be of benefit both to individuals and to health care systems. We investigated the potential utility of a hybrid nomogram that combined key demographic features with the results of a multiplex urinary biomarker assay in hopes of identifying patients at risk of harboring bladder cancer.
Methods: Logistic regression analysis was used to model the probability of bladder cancer burden in a cohort of 686 subjects (394 with bladder cancer) using key demographic features alone, biomarker data alone, and the combination of demographic features and key biomarker data. We examined discrimination, calibration, and decision curve analysis techniques to evaluate prediction model performance.
Results: Area under the receiver operating characteristic curve (AUC) analyses revealed that demographic features alone predicted tumor burden with an accuracy of 0.806 [95% confidence interval (CI), 0.76–0.85], while biomarker data had an accuracy of 0.835 (95% CI, 0.80–0.87). The addition of molecular data into the nomogram improved the predictive performance to 0.891 (95% CI, 0.86–0.92). Decision curve analyses showed that the hybrid nomogram performed better than demographic or biomarker data alone.
Conclusion: A nomogram construction strategy that combines key demographic features with biomarker data may facilitate the accurate, noninvasive evaluation of patients at risk of harboring bladder cancer. Further research is needed to evaluate the bladder cancer risk nomogram for potential clinical utility.
Impact: The application of such a nomogram may better inform the decision to perform invasive diagnostic procedures. Cancer Epidemiol Biomarkers Prev; 25(9); 1361–6. ©2016 AACR.
ADAMTS5 promotes murine adipogenesis and visceral adipose tissue expansion
Authors: Bauters Dries , Scroyen Ilse , Deprez-Poulain Rebecca , Lijnen H. Roger 
Published: July 2016

SummaryEnhanced expression of the aggrecanase ADAMTS5 (A Disintegrin And Metalloproteinase with Thrombospondin type 1 motifs; member 5) has been observed in adipose tissue (AT) of obese rodents. Here, we have investigated the role of ADAMTS5 in adipogenesis, AT expansion and associated angiogenesis. In vitro differentiation of precursor cells into mature adipocytes was studied using murine embryonic fibroblasts (MEF) derived from wild-type (Adamts5 +/+) and ADAMTS5 deficient (Adamts5 -/-) mice, or 3T3-F442A preadipocytes with stable gene silencing of Adamts5. De novo adipogenesis was monitored by injection of 3T3-F442A cells with or without Adamts5 knockdown in Nude mice. Furthermore, Adamts5+/+ and Adamts5/- mice were kept on a high-fat diet (HFD) to monitor AT development. Adamts5-/- MEF, as well as 3T3-F442A preadipocytes with Adamts5 knockdown, showed significantly reduced differentiation as compared to control cells. In mice, de novo formed fat pads arising from 3T3-F442A cells with Adamts5 knockdown were significantly smaller as compared to controls. After 15 or 25 weeks on HFD, total body weight and subcutaneous AT weight were similar for Adamts5++/+ and Adamts5-/- mice, but visceral/gonadal fat mass was significantly lower for Adamts5-/-mice. These data were confirmed by magnetic resonance imaging. In addition, the blood vessel density in adipose tissue was higher for Adamts5-/- mice kept on HFD. In conclusion, our data support the concept that ADAMTS5 promotes adipogenesis in vitro and in vivo, as well as development of visceral AT and associated angiogenesis in mice kept on HFD.
Poza sceną, czyli jawne i niejawne w "Dybuku" Szymona An-skiego
Authors: Lipska Małgorzata 
Published: July 2016

Offstage: The revealed and the concealed in An-sky’s The DybbukThe Israeli theatre scholar Shimon Levy describes the works of Samuel Beckett using the category of “offstage,” i.e. what is “backstage” or “behind the scenes.” This notion is also suitable to describe the plot of An-sky’s play The Dybbuk. The plot, which follows the wanderings of the soul of a prematurely deceased lover, is based on a continuous interplay between the explicit and the implicit, the revealed and the concealed, the present and the absent. Applying the category of “offstage” as an analytical tool allows for speaking about the supernatural forces which are depicted in the play, while replacing religious nomenclature with a glossary of terms from the field of theatre. Poza sceną, czyli jawne i niejawne w Dybuku Szymona An-skiegoIzraelski teatrolog Shimon Levy opisuje twórczość Samuela Becketta, posługując się kategorią „offstage”, czyli tego, co znajduje się poza sceną, za kulisami. Kategoria ta doskonale nadaje się także do opisu fabuły Dybuka Szymona An-skiego. Akcja dramatu o wędrówce duszy przedwcześnie zmarłego kochanka opiera się na ciągłej grze jawnego z niejawnym, odkrytego z zakrytym, obecnego z nieobecnym. Zastosowanie kategorii „offstage” jako narzędzia analitycznego pozwala mówić o ukazanych w dramacie siłach nadprzyrodzonych przy zastąpieniu nomenklatury religijnej zestawem pojęć ze sfery teatru.
„(A) nasze dusze smutne mają pyski.leżą na dywanie. wyją. nie dają żyć” (J. Mansztajn, O duszy) – leksem dusza w najnowszej poezji polskiej
Authors: Stempel-Gancarczyk Karina 
Published: July 2016

“(Y)et the faces of our souls are sad. lying on the carpet. howling. tormenting us.” (J. Mansztajn, O duszy) – the lexeme dusza (soul) in contemporary Polish poetryThe article concerns the occurrences of the lexeme soul in contemporary Polish poetry. Due to the extensive amount of material available for analysis, it concentrates on volumes that were awarded or nominated in the selected Polish poetry contests in 2010–2015 (Wisława Szymborska Award, “Nike” Literary Award, “Silesius” Wrocław Poetry Award, Kościelscy Award, “Orfeusz” K. I. Gałczyński Poetry Award, “Gdynia” Literary Prize and “Złoty Środek Poezji” Award). The article presents the contexts of occurrence of the lexeme dusza (soul), as well as the related lexemes duch (spirit) and duszyczka (small soul – animula), it characterizes the term in relation to its both religious and non-religious aspects, and shows what functions it serves in poetic texts. „(A) nasze dusze smutne mają pyski. leżą na dywanie. wyją. nie dają żyć” (J. Mansztajn, O duszy) – leksem dusza w najnowszej poezji polskiejArtykuł dotyczy wystąpień leksemu dusza w najnowszej poezji polskiej. Z uwagi na zakres materiału dostępnego do analizy rozważania skupiają się na tomach nagrodzonych lub nominowanych do nagród w wybranych ogólnopolskich konkursach poetyckich w latach 2010–2015 (Nagroda im. Wisławy Szymborskiej, Nagroda Literacka „Nike”, Wrocławska Nagroda Poetycka „Silesius”, Nagroda Fundacji im. Kościelskich, Nagroda Poetycka im. K. I. Gałczyńskiego „Orfeusz”, Nagroda Literacka „Gdynia” oraz Nagroda „Złoty Środek Poezji”). W artykule przedstawione są konteksty pojawiania się leksemu dusza oraz leksemów pokrewnych: duch i duszyczka, charakterystyka tego pojęcia z uwzględnieniem aspektów religijnych i niereligijnych, a także funkcje, jakie zyskuje ono w tekstach poetyckich.