bluuebunny/crossref_metadata_2025_split huggingface dataset:
Optogenetic control of Wnt signaling for modeling early embryogenic patterning with human pluripotent stem cells
Authors: Repina Nicole A. , Bao Xiaoping , Zimmermann Joshua A. , Joy David A. , Kane Ravi S. , Schaffer David V. 
Published: June 2019

ABSTRACTThe processes of cell proliferation, differentiation, migration, and self-organization during early embryonic development are governed by dynamic, spatially and temporally varying morphogen signals. Analogous tissue patterns emerge spontaneously in embryonic stem cell (ESC) models for gastrulation, but mechanistic insight into this self-organization is limited by a lack of molecular methods to precisely control morphogen signal dynamics. Here we combine optogenetic stimulation and single-cell imaging approaches to study self-organization of human pluripotent stem cells. Precise control of morphogen signal dynamics, achieved through activation of canonical Wnt/β-catenin signaling over a broad high dynamic range (>500-fold) using an optoWnt optogenetic system, drove broad transcriptional changes and mesendoderm differentiation of human ESCs at high efficiency (>95% cells). Furthermore, activating Wnt signaling in subpopulations of ESCs in 2D and 3D cultures induced cell self-organization and morphogenesis reminiscent of human gastrulation, including changes in cell migration and epithelial to mesenchymal transition. Our findings thus reveal an instructive role for Wnt in directing cell patterning in this ESC model for gastrulation.
CYLD, a Mechanosensitive Deubiquitinase, Regulates TGFβ Signaling in Load-Induced Bone Formation
Authors: Nguyen Jacqueline , Massoumi Ramin , Alliston Tamara 
Published: June 2019

AbstractMany signaling pathways involved in bone homeostasis also participate in the anabolic response of bone to mechanical loading. For example, TGFβ signaling coordinates the maintenance of bone mass and bone quality through its effects on osteoblasts, osteoclasts, and osteocytes. TGFβ signaling is also essential for the mechanosensitive formation of new bone. However, the mechanosensitive mechanisms controlling TGFβ signaling in osteocytes remain to be determined, particularly those that integrate TGFβ signaling with other early responses to mechanical stimulation. Here, we used an in vivo mouse hindlimb loading model to identify mechanosensitive molecules in the TGFβ pathway, and MLOY4 cells to evaluate their interactions with the prostaglandin E2 (PGE2) pathway, which is well-known for its rapid response to mechanical stimulation and its role in bone anabolism. Although mRNA levels for several TGFβ ligands, receptors, and effectors were unchanged, the level of phosphorylated Smad3 (pSmad3) was reduced in tibial bone as early as 3 hrs after early mechanical stimulation. We found that PGE2 and its receptor, EP2, repress pSmad3 levels and transactivation of Serpine1 in osteocytes. PGE2 and EP2 control the level of pSmad3 through a proteasome-dependent mechanism that relies on the deubiquitinase CYLD. CYLD protein levels were also reduced in the tibiae within 3 hrs of mechanical loading. Using CYLD-deficient mice, we found that CYLD is required for the rapid load-mediated repression of pSmad3 and for load-induced bone formation. These data introduce CYLD as a mechanosensitive deubiquitinase that participates in the PGE2-dependent repression of TGFβ signaling in osteocytes.
Preserved global cerebral blood flow accounts for youthful processing speed in older adults
Authors: Yang Fan Nils , Xie Long , Galli Olga , Detre John A. , Wolk David A. , Rao Hengyi 
Published: June 2019

AbstractPreserved cognitive performance is one of the key contributors to successful aging. The processing speed theory and prefrontal executive theory – are competing theories regarding the general causes of cognitive aging. Here, we used a theoretically-driven framework to investigate the neural correlates of older adults with preserved processing speed. Older adults with youth-like processing speed (SuperAgers) were compared with normal aged adults (TypicalAgers) using neuroimaging methods. Global cerebral blood flow (CBF) accounted for approximately 45% of the variance in processing speed, while neither regional CBF nor other structural measures predicted additional variance. In addition, despite having significantly cortical thinning, SuperAgers still shown comparable global CBF levels with young adults. These results support the global mechanism suggested by processing speed theory and indicate that global CBF may serve as a biomarker of cognitive aging.
An integrated landscape of protein expression in human cancer
Authors: Jarnuczak Andrew F. , Najgebauer Hanna , Barzine Mitra , Kundu Deepti J. , Ghavidel Fatemeh , Perez-Riverol Yasset , Papatheodorou Irene , Brazma Alvis , Vizcaíno Juan Antonio 
Published: June 2019

ABSTRACTUsing public proteomics datasets, mostly available through the PRIDE database, we assembled a proteomics resource for 191 cancer cell lines and 246 clinical tumour samples, across 13 cancer lineages. We found that baseline protein abundance in cell lines was generally representative of tumours. However, when considering differences in protein expression between tumour subtypes, as exemplified in the breast lineage, many of these changes were no longer recapitulated in the cell line models. Integration of proteomics and transcriptomics data suggested that the level of transcriptional control in cell lines changed significantly depending on their lineage. Additionally, in agreement with previous studies, variation in mRNA levels was often a poor predictor of changes in protein abundance. To our knowledge, this work constitutes the first meta-analysis study including cancer-related proteomics datasets. We anticipate this aggregated dataset will be of significant aid to future studies requiring a reference to baseline protein expression in cancer.
The rapid divergence of the Antarctic crinoid speciesPromachocrinus kerguelensis
Authors: Chehida Yacine Ben , Eléaume Marc , Gallut Cyril , Achaz Guillaume 
Published: June 2019

AbstractClimatic oscillations in Antarctica caused a succession of expansion and reduction of the ice sheets covering the continental shelf of the Southern Ocean. For marine invertebrates, these successions are suspected to have driven allopatric speciation, endemism and the prevalence of cryptic species, leading to the so-called Antarctic ‘biodiversity pump’ hypothesis. Here we took advantage of the recent sampling effort influenced by the International Polar Year (2007-8) to test for the validity of this hypothesis for 1,797 samples of two recognized crinoid species:Promachocrinus kerguelensisandFlorometra mawsoni. Species delimitation analysis identified seven phylogroups. As previously suggested,Promachocrinus kerguelensisforms a complex of six cryptic species. Conversely, despite the morphological differences, our results show thatFlorometra mawsoniis a lineage nested withinPromachocrinus kerguelensis. It suggests thatFlorometra mawsoniandPromachocrinus kerguelensisbelong to the same complex of species. Furthermore, this study indicates that over time and space the different sectors of the Southern Ocean show a remarkable rapid turn-over in term of phylogroups composition and also of genetic variants within phylogroups. We argue that strong “apparent” genetic drift causes this rapid genetic turn-over. Finally, we dated the last common ancestor of all phylogroups at less than 1,000 years, raising doubts on the relevance of the Antarctic “biodiversity pump” for this complex of species. This work is a first step towards a better understanding of how life is diversifying in the Southern Ocean.
Respiratory viral infection alters the gut microbiota by inducing inappetence
Authors: Groves Helen T. , Higham Sophie L. , Moffatt Miriam F. , Cox Michael J. , Tregoning John S. 
Published: June 2019

AbstractThe gut microbiota has an important role in health and disease. Respiratory viral infections are extremely common but their impact on the composition and function of the gut microbiota is poorly understood. We previously observed a significant change in the gut microbiota after viral lung infection. Here we show that weight loss during Respiratory Syncytial Virus (RSV) or influenza virus infection was due to decreased food consumption, and that fasting mice independently of infection altered gut microbiota composition. While the acute phase TNF-α response drove early weight loss and inappetence during RSV infection, this was not sufficient to induce changes in the gut microbiota. However, depleting CD8+ cells increased food intake and prevented weight loss resulting in a reversal of the gut microbiota changes normally observed during RSV infection. Viral infection also led to changes in the faecal gut metabolome during RSV infection, with a significant shift in lipid metabolism. Sphingolipids, poly-unsaturated fatty acids (PUFAs) and the short-chain fatty acid (SCFA) valerate all increased in abundance in the faecal metabolome following RSV infection. Whether this, and the impact of infection-induced anorexia on the gut microbiota, are part of a protective, anti-inflammatory response during respiratory viral infections remains to be determined.
Caveolae coupling of melanocytes signaling and mechanics is required for human skin pigmentation
Authors: Domingues Lia , Hurbain Ilse , Gilles-Marsens Floriane , André Nathalie , Dewulf Melissa , Romao Maryse , de Lesegno Christine Viaris , Blouin Cédric , Guéré Christelle , Vié Katell , Raposo Graça , Lamaze Christophe , Delevoye Cédric 
Published: June 2019

SummaryTissue homeostasis requires regulation of cell-cell communication, which relies on signaling molecules and cell contacts. In skin epidermis, keratinocytes secrete specific factors transduced by melanocytes into signaling cues to promote their pigmentation and dendrite outgrowth, while melanocytes transfer melanin pigments to keratinocytes to convey skin photoprotection. How epidermal cells integrate these functions remains poorly characterized. Here, we found that caveolae polarize in melanocytes and are particularly abundant at melanocyte-keratinocyte interface. Caveolae in melanocytes are sensitive to ultra-violet radiations and miRNAs released by keratinocytes. Preventing caveolae formation in melanocytes results in increased production of intracellular cAMP and melanin pigments, but decreases cell protrusions, cell-cell contacts, pigment transfer and epidermis pigmentation. Altogether, our data establish that, in melanocytes, caveolae serve as key molecular hubs that couple signaling outputs from keratinocytes to mechanical plasticity. This process is crucial to maintain cell-cell contacts and intercellular communication, skin pigmentation and tissue homeostasis.
Severe anaemia complicating HIV in Malawi; multiple co-existing aetiologies are associated with high mortality
Authors: Huibers Minke HW , Bates Imelda , McKew Steve , Allain Theresa J , Coupland Sarah E. , Phiri Chimota , Phiri Kamija S. , van Hensbroek Michael Boele , Calis Job C 
Published: June 2019

AbstractBackgroundSevere anaemia is a major cause of morbidity and mortality in HIV-infected adults living in resource-limited countries. Comprehensive data on the aetiology is lacking and needed to improve outcomes.MethodsHIV-infected adults with severe (haemoglobin ≤70g/l) or very severe anaemia (haemoglobin ≤50 g/l) were recruited at Queen Elizabeth Central Hospital, Blantyre, Malawi. Fifteen potential causes of severe anaemia of anaemia and associations with anaemia severity and mortality were explored.Results199 patients were enrolled: 42.2% had very severe anaemia and 45.7% were on ART. Over two potential causes for anaemia were present in 94% of the patients; including iron deficiency (55.3%), underweight (BMI<20: 49.7%), TB-infection (41.2%) and unsuppressed HIV-infection (viral load >1000 copies/ml) (73.9%). EBV/CMV co-infection (16.5%) was associated with very severe anaemia (OR 2.8 95% CI 1.1-6.9). Overall mortality was high (53%; 100/199) with a median time to death of 16 days. Death was associated with folate deficiency (HR 2.2; 95% CI 1.2-3.8) and end stage renal disease (HR 3.2; 95% CI 1.6-6.2).ConclusionMortality among severely anaemic HIV-infected adults is strikingly high. Clinicians must be aware of the urgent need for a multifactorial approach, including starting or optimising HIV treatment; considering TB treatment, nutritional support and attention to potential renal impairment.
Evaluation of Osteoinductivity of Different Calcium Phosphate and PTMC-Calcium Phosphate Composite Biomaterials in a Sheep Model
Authors: van Arnhem Arden L. , Zeng Ni , van Leeuwen Anne , Kuijer Roel , Bos Ruud. R.M. , Grijpma Dirk W. 
Published: June 2019

ABSTRACTOsteoinduction refers to de novo bone formation induced by biomaterials in places where physiologically no bone tissue is formed. Biomaterials with osteoinductive capacities have been shown to fill bone defects of critical sizes with ubiquitous new bone formation. Therefore, osteoinduction has been regarded as an important characteristic for biomaterials aiming at bone regeneration. In our study, we tested osteoinductive capacities of different calcium phosphate bioceramic particles, calcium phosphate scaffolds, and porous poly(trimethylene carbonate)(PTMC)-calcium phosphate composite scaffolds in a sheep model. Biphasic calcium phosphate (BCP) particles of 45-150 μm and 150-500 μm, microporous β-tricalcium phosphate (β-TCP) particles of 45-150 μm, non-microporous β-TCP particles of 45-150 μm and 150-500 μm, and porous β-TCP scaffolds were implanted in sheep long dorsal muscle for three and nine months. Likewise, porous composite scaffolds, in which BCP particles, microporous β-TCP particles and β-TCP particles, all of 45-150 μm, had been incorporated into PTMC matrices, were implanted in sheep long dorsal muscle for three and nine months. Porous PTMC scaffolds were implanted as controls. Abundant new bone formation was induced by BCP particles of both size ranges, the β-TCP scaffold was also able to induce new bone formation at both three and nine months follow up, while no new bone formation was induced by the other biomaterials. Implantation of the abovementioned biomaterials led to uneventful degradation of the PTMC matrices and the incorporated calcium phosphate particles, and provoked no obvious tissue reaction. Future studies are needed to determine the optimal composition of composite biomaterials based on PTMC and calcium phosphate to produce osteoinductive composites.
Nitrogen-fixing Klebsiella variicola in feces from herbivorous tortoises
Authors: Montes-Grajales Diana , Jiménez Berenice , Rogel Marco A. , Alagón Alejandro , Esturau-Escofet Nuria , Esquivel Baldomero , Martínez-Romero Julio , Martínez-Romero Esperanza 
Published: June 2019

AbstractAnimals feeding on plants (herbivorous) may have nutritional deficiencies and use bacterial nitrogen fixation in guts to compensate unbalanced diets with high carbon and low nitrogen. Using the acetylene reduction assay we searched for nitrogen fixation in the feces from several herbivorous animals in captivity. We detected acetylene reduction in feces from two African spurred tortoises, Centrochelys sulcata and in feces from six Gopherus berlandieri tortoises and isolated nitrogen-fixing klebsiellas from them. Additionally, we performed a gut metagenomic study with Illumina sequencing from a healthy Mexican G. berlandieri tortoise, and the nif genes identified in the feces microbiome matched those from Klebsiella variicola. Fecal bacterial composition from tortoises was similar to that reported from other reptilian guts.
Screening and functional analysis of differentially expressed genes in an animal model ofEBV-associated lymphomas
Authors: Zhang Yang , Wang Chengkun , Liu Liangzhuan , Peng Qiu , Gan Xiaoning , Xie Lu , Tan Meiying , He Rongfang , Tang Yunlian , Wu Yimou , Gan Runliang 
Published: June 2019

AbstractEpstein-Barr virus(EBV) is an important human oncogenic virus. This paper is to explore how EBV induce malignant transformation of human lymphocytes and the related mechanism of lymphomagenesis. We have constructedhu-PBL/SCID chimeric miceand established a model of EBV-associated human-derived lymphomas. By using Agilent human whole genome microarray and a series of bioinformatic analyses, a total of 202 differentially expressed genes were screened from the EBV-induced lymphomas inhu-PBL/SCID mice, including 44 up-regulated and 158 down-regulated genes. Calculation of the rank score (RS) values of these genes in the HIPPIE protein interaction networks showed that topoisomerase II alpha (TOP2A), ubiquitin like with PHD and ring finger domains 1 (UHRF1), histone cluster 2 H2B family member E (HIST2H2BE), phosphoglycerate dehydrogenase (PHGDH), vinculin (VCL), insulin-like growth factor 1 receptor (IGF1R), Fos proto-oncogene (FOS), snail family transcriptional repressor 1 (SNAI1), PDZ binding kinase (PBK), and ring finger protein 144B (RNF144B) were the top 10 key node genes of EBV-induced lymphoma. In which, PBK, an up-regulated genes with the highest number of GO annotations, was verified by cellular function experiments and clinical lymphoma samples.Author summaryEB virus is closely associated with human lymphoma and nasopharyngeal carcinoma. Since the susceptible hosts of EBV limit to human and cottontop tammarins, there are no appropriate animal models so far to study the EBV-associated oncogenesis. In our previous experiments, the EBV-associated lymphomas were induced inhu-PBL/SCID chimera(a new humanized mouse model). However, the cellular and molecular mechanisms of malignant transformation of normal human cells and tumor formation induced by EBV remain unclear. In this study, we examined and compared the gene expression profiles of EBV-induced lymphomas and normal human lymphocytes of the same origin in SCID mice. By constructing the gene-function relationship network, we preliminarily found that TOP2A, UHRF1, HIST2H2BE, PHGDH, VCL, IGF1R, FOS, SNAI1, PBK, and RNF144B may be the key genes in EBV-induced lymphomas. These findings suggest that the induction of lymphoma by EBV is a complex process that involves multiple genes and pathways.
CAT1/SLC7A1 acts as a cellular receptor for bovine leukemia virus infection
Authors: Bai Lanlan , Sato Hirotaka , Kubo Yoshinao , Wada Satoshi , Aida Yoko 
Published: June 2019

AbstractBovine leukemia virus (BLV) is the causative agent of enzootic bovine leukosis, the most common neoplastic disease of cattle, which is closely related to human T-cell leukemia viruses. BLV has spread worldwide and causes a serious problem for the cattle industry. The cellular receptor specifically binds with viral envelope glycoprotein (Env) and this attachment mediates cell fusion to lead virus entry. BLV Env reportedly binds to cationic amino acid transporter 1 (CAT1)/SLC7A1, but whether the CAT1/SLC7A1 is an actual receptor for BLV remains unknown. Here, we showed that CAT1 functioned as an infection receptor, interacting with BLV particles. Cells expressing undetectable CAT1 levels were resistant to BLV infection but became highly susceptible upon CAT1 overexpression. CAT1 exhibited specific binding to BLV particles on the cell surface and co-localized with the Env in endomembrane compartments and membrane. Knockdown of CAT1 in permissive cells significantly reduced binding to BLV particles and BLV infection. In addition, bovine serum with neutralizing activity from a BLV-infected cattle inhibited BLV particles. Expression of CAT1 from various species demonstrated no species-specificity for BLV infection, implicating CAT1 as a functional BLV receptor responsible for its broad host range. These findings provide insights for BLV infection and for developing new strategies for treating BLV and preventing its spread.Author SummaryBovine leukemia virus (BLV), which can infect a variety of animal species and induce lymphoma in cattle, is a member of the familyRetroviridae. BLV induces huge economic losses by not only lymphoma but also subclinical forms of the disease. In addition, BLV is frequently used as an animal model of human T-cell leukemia virus (HTLV), as BLV has many similar characteristics to HTLV. Thus, understanding BLV pathogenesis contribute to resolve not only BLV-but also HTLV-induced problems. Retroviral envelope glycoprotein (Env) is specifically recognized by the cellular receptor at cell surface, which induces a conformational changes between viral and cell membrane to entry. Thus, the elucidation of cellular receptor for BLV infection is very important for virus entry. However, the BLV receptor has not been identified yet. In the current study, we found that BLV Env protein binds to cationic amino acid transporter 1 (CAT1)/SLC7A1 at cell surface, artificial expression of CAT1 in CAT1-negative cells confers the cells susceptible to BLV infection, and CAT1-silencing significantly reduces BLV infection, concluding that CAT1 is the BLV receptor. These findings will have far reaching great advantages of insights in the retrovirus study.
ENVELOPED VIRUS-LIKE PARTICLES (eVLPs) EXPRESSING MODIFIED FORMS OF ZIKA VIRUS PROTEINS E AND NS1 PROTECT MICE FROM ZIKA VIRUS INFECTION
Authors: Fluckiger Anne-Catherine , Bozic Jasminka , Diress Abebaw , Ontsouka Barthelemy , Ahmed Tanvir , Ponce Amalia , Kirchmeier Marc , Diaz-Mitoma Francisco , Conlan Wayne , Anderson David E. , Soare Catalina 
Published: June 2019

AbstractWhile Zika virus (ZIKV) infection induces mild disease in the majority of cases, it has been identified as responsible for microcephaly and severe neurological disorders in recent 2015-2016 outbreaks in South America and the Caribbean. Since then, several prophylactic vaccine strategies have been studied. Here, we describe the development of a ZIKV candidate vaccine consisting of bivalent enveloped virus-like particles (eVLPs) expressing a modified form of E and truncated NS1 (EG/NS1) proteins. In EG/NS1, the E transmembrane/cytoplasmic tail has been replaced with those domains from the VSV G protein and a β-domain of NS1 was fused in-frame to Gag from Moloney murine leukemia virus (MLV). Immunization of BALB/C mice demonstrated that bivalent EG/NS1 and monovalent EG eVLPs induced comparable levels of antibody (Ab) titers but that EG/NS1 induced much higher neutralizing activity, comparable to naturally acquired anti-ZIKV immunity. In contrast, monovalent NS1 eVLPs did not induce a significant anti-NS1 Ab response but promoted strong T cell immunity that was also elicited with EG/NS1 eVLPs. ZIKV challenge studies in C57BL/6-IFNαR−/−mice demonstrated that EG/NS1 eVLPs conferred 100% protection against clinical disease after ZIKV challenge compared to 80% protection after EG eVLP vaccination, with protection against challenge correlating with neutralizing antibody titers and overt signs of infection.Author SummaryZika virus has caused rapidly spreading epidemics with potentially severe neurological symptoms including microcephaly in new born babies. Rapid progress has been made with several candidate vaccines under clinical evaluation but no vaccine or treatment is yet available. In this context, we have produced and tested recombinant virus-like particles that incorporate one or two Zika virus proteins, E and NS1 that have been modified for optimal efficacy. Our immunogenicity studies in mice showed a synergistic effect of both proteins in the bivalent vaccine. NS1 induced a strong T cell response enhancing the neutralizing antibody production induced by the E protein. In challenge experiments, the bivalent vaccine protected 100% of mice from clinical signs of Zika virus infection. These products could be further used to explore Zika virus correlates of protection and evaluated as vaccine candidates.