bluuebunny/crossref_metadata_2025_split huggingface dataset:
RETRACTED ARTICLE: Nucleic acid sensing activates the innate cytosolic surveillance pathway and promotes parasite survival in visceral leishmaniasis
Authors: Das Sushmita , Kumar Ashish , Mandal Abhishek , Abhishek Kumar , Verma Sudha , Kumar Ajay , Das Pradeep 
Published: July 2019

AbstractMicrobial pattern recognition critically contributes to innate response, both at extracellular and intracellular cytosolic surveillance pathway (CSP) interface. However, the role of pattern recognition by host innate receptors in CSP is poorly understood in Leishmania donovani infection. Here, we have demonstrated that cytosolic targeting of L.donovani DNA (Ld-DNA) inhibits macrophage responsiveness to IFNɣ, through decreased MHC-II expression and lowered pSTAT1 (Y701) levels, involving host three-prime repair exonuclease-1 (TREX-1). The Ld-DNA potently induced type-1 IFNs, i.e. significant over-production of IFNβ through activation of the IRF pathway. Interestingly, knockdown of TRIF or MyD88 expression in macrophages had no effect on cytosolic Ld-DNA transfection-mediated IFN-β production, indicating involvement of a TLR independent pathway. Contrastingly, Ld-DNA failed to induce IFNβ in both TBK-1 and IRF3KO knockout macrophages. Although IFNβ was not induced by Ld-DNA in STING- knockout macrophages, STING alone was not enough for the induction. Evidently, besides STING, Ld-DNA recognition for induction of IFNβ critically required cytosolic cyclic GMP-AMP synthase (cGAS). Furthermore, the cGAS dependent targeting of Ld-DNA induced IFNβ over-production that contributed to antimony resistance in L.donovani infection. We provide the first evidence that enhanced cytosolic sensing of Ld-DNA in infection by antimony resistant (SBR-LD), but not antimony sensitive L.donovani strains (SBS-LD), was critically regulated by host MDRs, multi drug resistant associated protein 1 (MRP 1) and permeability glycoprotein (P-gp) in macrophages. Collectively, our results disclose Ld-DNA as a vital pathogen associated molecular pattern (PAMP) driving host Type-I IFN responses and antimony resistance. The findings may help in future development of policies for novel anti-leishmanial therapeutics.
BODIPY-cholesterol can be reliably used to monitor cholesterol efflux from capacitating mammalian spermatozoa
Authors: Bernecic N. C. , Zhang M. , Gadella B. M. , Brouwers J. F. H. M. , Jansen J. W. A. , Arkesteijn G. J. A. , de Graaf S. P. , Leahy T. 
Published: July 2019

AbstractCapacitation is the final maturation step spermatozoa undergo prior to fertilisation. The efflux of cholesterol from the sperm membrane to the extracellular environment is a crucial step during capacitation but current methods to quantify this process are suboptimal. In this study, we validate the use of a BODIPY-cholesterol assay to quantify cholesterol efflux from spermatozoa during in vitro capacitation, using the boar as a model species. The novel flow cytometric BODIPY-cholesterol assay was validated with endogenous cholesterol loss as measured by mass spectrometry and compared to filipin labelling. Following exposure to a range of conditions, the BODIPY-cholesterol assay was able to detect and quantify cholesterol efflux akin to that measured with mass spectrometry. The ability to counterstain for viability is a unique feature of this assay that allowed us to highlight the importance of isolating viable cells only for a reliable measure of cholesterol efflux. Finally, the BODIPY-cholesterol assay proved to be the superior method to quantify cholesterol efflux relative to filipin labelling, though filipin remains useful for assessing cholesterol redistribution. Taken together, the BODIPY-cholesterol assay is a simple, inexpensive and reliable flow cytometric method for the measurement of cholesterol efflux from spermatozoa during in vitro capacitation.
A reliable Epstein-Barr Virus classification based on phylogenomic and population analyses
Authors: Zanella Louise , Riquelme Ismael , Buchegger Kurt , Abanto Michel , Ili Carmen , Brebi Priscilla 
Published: July 2019

AbstractThe Epstein-Barr virus (EBV) infects more than 90% of the human population, playing a key role in the origin and progression of malignant and non-malignant diseases. Many attempts have been made to classify EBV according to clinical or epidemiological information; however, these classifications show frequent incongruences. For instance, they use a small subset of genes for sorting strains but fail to consider the enormous genomic variability and abundant recombinant regions present in the EBV genome. These could lead to diversity overestimation, alter the tree topology and misinterpret viral types when classified, therefore, a reliable EBV phylogenetic classification is needed to minimize recombination signals. Recombination events occur 2.5-times more often than mutation events, suggesting that recombination has a much stronger impact than mutation in EBV genomic diversity, detected within common ancestral node positions. The Hierarchical Bayesian Analysis of Population Structure (hierBAPS) resulted in the differentiation of 12 EBV populations showed seven monophyletic and five paraphyletic. The populations identified were related to geographic location, of which three populations (EBV-p1/Asia/GC, EBV-p2/Asia II/Tumors and EBV-p4/China/NPC) were related to tumor development. Therefore, we proposed a new consistent and non-simplistic EBV classification, beneficial in minimizing the recombination signal in the phylogeny reconstruction, investigating geography relationship and even infer associations to human diseases. These EBV classifications could also be useful in developing diagnostic applications or defining which strains need epidemiological surveillance.
mTOR Signaling Upregulates CDC6 via Suppressing miR-3178 and Promotes the Loading of DNA Replication Helicase
Authors: Wu Xianjin , Li Shenghua , Hu Xing , Xiang Xiaoliang , Halloran Megan , Yang Linlin , Williams Terence M. , Houghton Peter J. , Shen Changxian , He Zhengfu 
Published: July 2019

AbstractmTOR signaling pathway is deregulated in most cancers and uncontrolled cell cycle progression is a hallmark of cancer cell. However, the precise molecular mechanisms of the regulation of DNA replication and chromatin metabolism by mTOR signaling are largely unknown. We herein report that mTOR signaling promotes the loading of MCM2-7 helicase onto chromatin and upregulates DNA replication licensing factor CDC6. Pharmacological inhibition of mTOR kinase resulted in CHK1 checkpoint activation and decreased MCM2-7 replication helicase and PCNA associated with chromatins. Further pharmacological and genetic studies demonstrated CDC6 is positively controlled by mTORC1-S6K1 and mTORC2 signaling. miRNA screening revealed mTOR signaling suppresses miR-3178 thereby upregulating CDC6. Analysis of TCGA data found that CDC6 is overexpressed in most cancers and associates with the poor survival of cancer patients. Our findings suggest that mTOR signaling may control DNA replication origin licensing and replisome stability thereby cell cycle progression through CDC6 regulation.
The adeno-associated virus rh10 vector is an effective gene transfer system for chronic spinal cord injury
Authors: Hoshino Yutaka , Nishide Kenji , Nagoshi Narihito , Shibata Shinsuke , Moritoki Nobuko , Kojima Kota , Tsuji Osahiko , Matsumoto Morio , Kohyama Jun , Nakamura Masaya , Okano Hideyuki 
Published: July 2019

AbstractTreatment options for chronic spinal cord injury (SCI) remain limited due to unfavourable changes in the microenvironment. Gene therapy can overcome these barriers through continuous delivery of therapeutic gene products to the target tissue. In particular, adeno-associated virus (AAV) vectors are potential candidates for use in chronic SCI, considering their safety and stable gene expression in vivo. Given that different AAV serotypes display different cellular tropisms, it is extremely important to select an optimal serotype for establishing a gene transfer system during the chronic phase of SCI. Therefore, we generated multiple AAV serotypes expressing ffLuc-cp156, a fusion protein of firefly luciferase and Venus, a variant of yellow fluorescent protein with fast and efficient maturation, as a reporter, and we performed intraparenchymal injection in a chronic SCI mouse model. Among the various serotypes tested, AAVrh10 displayed the highest photon count on bioluminescence imaging. Immunohistological analysis revealed that AAVrh10 showed favourable tropism for neurons, astrocytes, and oligodendrocytes. Additionally, with AAVrh10, the area expressing Venus was larger in the injury epicentre and extended to the surrounding tissue. Furthermore, the fluorescence intensity was significantly higher with AAVrh10 than with the other vectors. These results indicate that AAVrh10 may be an appropriate serotype for gene delivery to the chronically injured spinal cord. This promising tool may be applied for research and development related to the treatment of chronic SCI.
Differentiation of single lymphoma primary cells and normal B-cells based on their adhesion to mesenchymal stromal cells in optical tweezers
Authors: Duś-Szachniewicz Kamila , Drobczyński Sławomir , Woźniak Marta , Zduniak Krzysztof , Ostasiewicz Katarzyna , Ziółkowski Piotr , Korzeniewska Aleksandra K. , Agrawal Anil K. , Kołodziej Paweł , Walaszek Kinga , Bystydzieński Zbigniew , Rymkiewicz Grzegorz 
Published: July 2019

AbstractWe have adapted a non-invasive method based on optical tweezers technology to differentiate between the normal B-cells and the B-cell non-Hodgkin lymphoma (B-NHL) cells derived from clinical samples. Our approach bases on the nascent adhesion between an individual B-cell and a mesenchymal stromal cell. In this study, a single B-cell was trapped and optically seeded on a mesenchymal stromal cell and kept in a direct contact with it until a stable connection between the cells was formed in time scale. This approach allowed us to avoid the introduction of any exogenous beads or chemicals into the experimental setup which would have affected the cell-to-cell adhesion. Here, we have provided new evidence that aberrant adhesive properties found in transformed B-cells are related to malignant neoplasia. We have demonstrated that the mean time required for establishing adhesive interactions between an individual normal B-cell and a mesenchymal stromal cell was 26.7 ± 16.6 s, while for lymphoma cell it was 208.8 ± 102.3 s, p < 0.001. The contact time for adhesion to occur ranged from 5 to 90 s and from 60 to 480 s for normal B-cells and lymphoma cells, respectively. This method for optically controlled cell-to-cell adhesion in time scale is beneficial to the successful differentiation of pathological cells from normal B-cells within the fine needle aspiration biopsy of a clinical sample. Additionally, variations in time-dependent adhesion among subtypes of B-NHL, established here by the optical trapping, confirm earlier results pertaining to cell heterogeneity.
Onset of schizophrenia diagnoses in a large clinical cohort
Authors: Lopez-Castroman Jorge , Leiva-Murillo José Miguel , Cegla-Schvartzman Fanny , Blasco-Fontecilla Hilario , Garcia-Nieto Rebeca , Artes-Rodriguez Antonio , Morant-Ginestar Consuelo , Courtet Philippe , Blanco Carlos , Aroca Fuensanta , Baca-García Enrique 
Published: July 2019

AbstractWe aimed to describe the diagnostic patterns preceding and following the onset of schizophrenia diagnoses in outpatient clinics. A large clinical sample of 26,163 patients with a diagnosis of schizophrenia in at least one outpatient visit was investigated. We applied a Continuous Time Hidden Markov Model to describe the probability of transition from other diagnoses to schizophrenia considering time proximity. Although the most frequent diagnoses before schizophrenia were anxiety and mood disorders, direct transitions to schizophrenia usually came from psychotic-spectrum disorders. The initial diagnosis of schizophrenia was not likely to change for two of every three patients if it was confirmed some months after its onset. When not confirmed, the most frequent alternative diagnoses were personality, affective or non-schizophrenia psychotic disorders. Misdiagnosis or comorbidity with affective, anxiety and personality disorders are frequent before and after the diagnosis of schizophrenia. Our findings give partial support to a dimensional view of schizophrenia and emphasize the need for longitudinal assessment.
Differences in placental capillary shear stress in fetal growth restriction may affect endothelial cell function and vascular network formation
Authors: Tun Win M. , Yap Choon Hwai , Saw Shier Nee , James Joanna L. , Clark Alys R. 
Published: July 2019

AbstractFetal growth restriction (FGR) affects 5–10% of pregnancies, leading to clinically significant fetal morbidity and mortality. FGR placentae frequently exhibit poor vascular branching, but the mechanisms driving this are poorly understood. We hypothesize that vascular structural malformation at the organ level alters microvascular shear stress, impairing angiogenesis. A computational model of placental vasculature predicted elevated placental micro-vascular shear stress in FGR placentae (0.2 Pa in severe FGR vs 0.05 Pa in normal placentae). Endothelial cells cultured under predicted FGR shear stresses migrated significantly slower and with greater persistence than in shear stresses predicted in normal placentae. These cell behaviors suggest a dominance of vessel elongation over branching. Taken together, these results suggest (1) poor vascular development increases vessel shear stress, (2) increased shear stress induces cell behaviors that impair capillary branching angiogenesis, and (3) impaired branching angiogenesis continues to drive elevated shear stress, jeopardizing further vascular formation. Inadequate vascular branching early in gestation could kick off this cyclic loop and continue to negatively impact placental angiogenesis throughout gestation.
A universal approach for drainage basins
Authors: Oliveira Erneson A. , Pires Rilder S. , Oliveira Rubens S. , Furtado Vasco , Herrmann Hans J. , Andrade José S. 
Published: July 2019

AbstractDrainage basins are essential to Geohydrology and Biodiversity. Defining those regions in a simple, robust and efficient way is a constant challenge in Earth Science. Here, we introduce a model to delineate multiple drainage basins through an extension of the Invasion Percolation-Based Algorithm (IPBA). In order to prove the potential of our approach, we apply it to real and artificial datasets. We observe that the perimeter and area distributions of basins and anti-basins display long tails extending over several orders of magnitude and following approximately power-law behaviors. Moreover, the exponents of these power laws depend on spatial correlations and are invariant under the landscape orientation, not only for terrestrial, but lunar and martian landscapes. The terrestrial and martian results are statistically identical, which suggests that a hypothetical martian river would present similarity to the terrestrial rivers. Finally, we propose a theoretical value for the Hack’s exponent based on the fractal dimension of watersheds, γ = D/2. We measure γ = 0.54 ± 0.01 for Earth, which is close to our estimation of γ ≈ 0.55. Our study suggests that Hack’s law can have its origin purely in the maximum and minimum lines of the landscapes.
Super-resolution modularity analysis shows polyhedral caveolin-1 oligomers combine to form scaffolds and caveolae
Authors: Khater Ismail M. , Liu Qian , Chou Keng C. , Hamarneh Ghassan , Nabi Ivan Robert 
Published: July 2019

AbstractCaveolin-1 (Cav1), the coat protein for caveolae, also forms non-caveolar Cav1 scaffolds. Single molecule Cav1 super-resolution microscopy analysis previously identified caveolae and three distinct scaffold domains: smaller S1A and S2B scaffolds and larger hemispherical S2 scaffolds. Application here of network modularity analysis of SMLM data for endogenous Cav1 labeling in HeLa cells shows that small scaffolds combine to form larger scaffolds and caveolae. We find modules within Cav1 blobs by maximizing the intra-connectivity between Cav1 molecules within a module and minimizing the inter-connectivity between Cav1 molecules across modules, which is achieved via spectral decomposition of the localizations adjacency matrix. Features of modules are then matched with intact blobs to find the similarity between the module-blob pairs of group centers. Our results show that smaller S1A and S1B scaffolds are made up of small polygons, that S1B scaffolds correspond to S1A scaffold dimers and that caveolae and hemispherical S2 scaffolds are complex, modular structures formed from S1B and S1A scaffolds, respectively. Polyhedral interactions of Cav1 oligomers, therefore, leads progressively to the formation of larger and more complex scaffold domains and the biogenesis of caveolae.
Inhibition of activin-like kinase 4/5 attenuates cancer cachexia associated muscle wasting
Authors: Levolger S. , Wiemer E. A. C. , van Vugt J. L. A. , Huisman S. A. , van Vledder M. G. , van Damme-van Engel S. , Ambagtsheer G. , IJzermans J. N. M. , de Bruin R. W. F. 
Published: July 2019

AbstractCancer mediated activation of the ActRIIB-ALK4/5 heterodimer by myostatin is strongly associated with muscle wasting. We investigated in vitro and in vivo the efficacy of ALK4/5 receptor blockers SB431542 and GW788388 in preventing muscle wasting, and explored synergy with IGF-I analogue LONG R3 (LR3) IGF-I. In vitro, C2C12 skeletal muscle cells were treated with vehicle, SB431542, GW788388 and LR3 IGF-I. A C26-CD2F1 cachexia model was used to induce cachexia in vivo. Mice were allocated as non-tumour bearing (NTB) or C26 tumour-bearing (C26 TB) vehicle control, treated with SB431542, LR3 IGF-I, SB431542 and LR3 IGF-I, or GW788388 (intraperitoneally or orally). In vitro, differentiation index and mean nuclei count increased using SB431542, GW788388, LR3 IGF-I. In vivo, GW788388 was superior to SB431542 in limiting loss of bodyweight, grip-strength and gastrocnemius weight. and downregulated Atrogin-1 expression comparable to NTB mice. LR3 IGF-I treatment limited loss of muscle mass, but at the expense of accelerated tumour growth. In conclusion, treatment with GW788388 prevented cancer cachexia, and downregulated associated ubiquitin ligase Atrogin-1.
Physiological condition of nestling great tits (Parus major) declines with the date of brood initiation: a long term study of first clutches
Authors: Kaliński Adam , Bańbura Mirosława , Glądalski Michał , Markowski Marcin , Skwarska Joanna , Wawrzyniak Jarosław , Zieliński Piotr , Bańbura Jerzy 
Published: July 2019

AbstractIn seasonal environments, a temporal decline in breeding performance (e.g. clutch size, nestling condition, and fledging success) of altricial bird species is a well-known phenomenon. In this study, we present the effect of laying phenology on the physiological condition of nestling great tits (Parus major)in 14 consecutive breeding seasons. We used blood haemoglobin and baseline glucose concentrations as indicators of nestling physiological condition. Nestling blood haemoglobin reflects food base quality and availability during the breeding period. Blood glucose concentration can be used as a supplementary reverse index of condition, since it is negatively related to environmental quality. It might be indicative of the stress caused by unfavourable extrinsic factors, though, due to potential confounding factors such as adverse weather conditions, low food quality, or feeding interruptions, glucose levels should be used in this ecological context with caution. Great tit nestlings from earlier broods were characterised by higher mean haemoglobin concentrations, indicating a seasonal decline in food quality and availability. The blood glucose concentration displayed an opposite pattern, with nestlings from earlier broods being characterised by lower mean concentrations than those from later broods. However, very little of the variation in blood glucose concentration can be explained by the variation in laying date, which suggests that blood glucose concentration is of little importance in the context of breeding phenology. Our results show that the physiological condition of nestlings of this species decreases as the breeding season progresses, most probably due to environmental factors.
The mammalian CTLH complex is an E3 ubiquitin ligase that targets its subunit muskelin for degradation
Authors: Maitland Matthew E. R. , Onea Gabriel , Chiasson Christopher A. , Wang Xu , Ma Jun , Moor Sarah E. , Barber Kathryn R. , Lajoie Gilles A. , Shaw Gary S. , Schild-Poulter Caroline 
Published: July 2019

AbstractThe multi-subunit C-terminal to LisH (CTLH) complex is the mammalian homologue of the yeast Gid E3 ubiquitin ligase complex. In this study, we investigated the human CTLH complex and characterized its E3 ligase activity. We confirm that the complex immunoprecipitated from human cells comprises RanBPM, ARMC8 α/β, muskelin, WDR26, GID4 and the RING domain proteins RMND5A and MAEA. We find that loss of expression of individual subunits compromises the stability of other complex members and that MAEA and RMND5A protein levels are interdependent. Using in vitro ubiquitination assays, we demonstrate that the CTLH complex has E3 ligase activity which is dependent on RMND5A and MAEA. We report that the complex can pair with UBE2D1, UBE2D2 and UBE2D3 E2 enzymes and that recombinant RMND5A mediates K48 and K63 poly-ubiquitin chains. Finally, we show a proteasome-dependent increase in the protein levels of CTLH complex member muskelin in RMND5A KO cells. Furthermore, muskelin ubiquitination is dependent on RMND5A, suggesting that it may be a target of the complex. Overall, we further the characterization of the CTLH complex as an E3 ubiquitin ligase complex in human cells and reveal a potential autoregulation mechanism.
Marine and non-marine strata preserving Ediacaran microfossils
Authors: Lehn Ilana , Horodyski Rodrigo Scalise , Paim Paulo Sérgio Gomes 
Published: July 2019

AbstractWe report the first occurrence of microfossils in Ediacaran strata of the Camaquã Basin. The assemblage includes simple (Leiosphaeridiasp. predominantly) and ornamented acritarchs associated with microbial mats. They are related to the Ediacaran Complex Acanthomorph Palynoflora (ECAP) and Late Ediacaran Leiosphere Palynoflora (LELP) due to the similar morphology and time interval assigned to those assemblages, though the observed specimens are a lot simpler and less diversified. However, different from the usual occurrences, this case study reports Neoproterozoic cosmopolitan communities living in marine (basal unit) and lacustrine (middle units) settings. Fossils within non-marine strata in the Precambrian record are rare. Therefore, this first finding of microfossils in the Camaquã Basin constitutes a new piece of the puzzle related to the history of the Panafrican-Brasiliano basins and shed some light on possible settings where the Ediacaran eukaryotes have evolved.