bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of endotoxins in gelatine hydrogels on chondrogenic differentiation and inflammatory cytokine secretionin vitro
Authors: Groen Wilhelmina M.G.A.C. , Utomo Lizette , Castilho Miguel , Gawlitta Debby , Malda Jos , van Weeren Paul René , Levato Riccardo , Korthagen Nicoline M. 
Published: July 2020

AbstractGelatine methacryloyl (GelMA) hydrogels are widely used in studies aiming at cartilage regeneration. However, the endotoxin content of commercially available GelMAs and gelatines used in these studies is often overlooked, even though endotoxins may influence several cellular functions. Moreover, regulations for clinical use of biomaterials dictate a stringent endotoxin limit.We determined the endotoxin level of five different GelMAs and evaluated the effect on the chondrogenic differentiation of equine mesenchymal stromal cells (MSCs). Cartilage-like matrix production was evaluated by biochemical assays and immunohistochemistry. Furthermore, equine peripheral blood mononuclear cells (PBMCs) were cultured on the hydrogels for 24 hours, followed by the assessment of tumour necrosis factor (TNF)-α and C-C motif chemokine ligand (CCL)2 as inflammatory markers.The GelMAs were found to have widely varying endotoxin content (two with >1000 EU/ml and three with <10 EU/ml), however, this was not a critical factor determiningin vitrocartilage-like matrix production of embedded MSCs. PBMCs did produce significantly higher TNF-α and CCL2 in response to the GelMA with the highest endotoxin level compared to the other GelMAs.Although limited effects on chondrogenic differentiation were found in this study, caution with the use of commercial hydrogels is warranted in the translation fromin vitrotoin vivostudies because of regulatory constraints and potential inflammatory effects of the content of these hydrogels.
Density-dependent private benefit leads to bacterial mutualism
Authors: Jimenez Paul , Scheuring István 
Published: July 2020

Microorganisms produce materials leaked from the cell which are beneficial for themselves and their neighbors. We modeled the situation when cells can produce different costly secretions which increase the carrying capacity of the population. Strains that lose the function of producing one or more secretions avoid the cost of production and can exhaust the producers. However, secreting substances provides a private benefit for the producers in a density-dependent way. We developed a model to examine the outcome of the selection among different type of producer strains from the non-producer strain to the partial producers, to the full producer one. We were particularly interested in circumstances under which selection maintains partners that produce complementary secreted materials thus forming an interdependent mutualistic interaction.We show that interdependent mutualism is selected under broad range of conditions if private benefit decreases with density. Selection frequently causes the coexistence of more and less generalist cooperative strains, thus cooperation and exploitation co-occur. Interdependent mutual-ism is evolved under more specific circumstances if private benefit increases with density and these general observations are valid in a well-mixed and in a structured deme model. We show that the applied population structure supports cooperation in general, which, depending on the level of private benefit and intensity of mixing helps either the specialist or the generalist cooperators.
Brain age prediction in schizophrenia: does the choice of machine learning algorithm matter?
Authors: Lee Won Hee , Antoniades Mathilde , Schnack Hugo G , Kahn Rene S. , Frangou Sophia 
Published: July 2020

AbstractBackgroundSchizophrenia has been associated with lifelong deviations in the normative trajectories of brain structure. These deviations can be captured using the brain-predicted age difference (brainPAD), which is the difference between the biological age of an individual’s brain, as inferred from neuroimaging data, and their chronological age. Various machine learning algorithms are currently used for this purpose but their comparative performance has yet to be systematically evaluated.MethodsSix linear regression algorithms, ordinary least squares (OLS) regression, ridge regression, least absolute shrinkage and selection operator (Lasso) regression, elastic-net regression, linear support vector regression (SVR), and relevance vector regression (RVR), were applied to brain structural data acquired on the same 3T scanner using identical sequences from patients with schizophrenia (n=90) and healthy individuals (n=200). The performance of each algorithm was quantified by the mean absolute error (MAE) and the correlation (R) between predicted brain-age and chronological age. The inter-algorithm similarity in predicted brain-age, brain regional regression weights and brainPAD were compared using correlation analyses and hierarchical clustering.ResultsIn patients with schizophrenia, ridge regression, Lasso regression, elastic-net regression, and RVR performed very similarly and showed a high degree of correlation in predicted brain-age (R>0.94) and brain regional regression weights (R>0.66). By contrast, OLS regression, which was the only algorithm without a penalty term, performed markedly worse and showed a lower similarity with the other algorithms. The mean brainPAD was higher in patients than in healthy individuals but varied by algorithm from 3.8 to 5.2 years although all analyses were performed on the same dataset.ConclusionsLinear machine learning algorithms, with the exception of OLS regression, have comparable performance for age prediction on the basis of a combination of cortical and subcortical structural measures. However, algorithm choice introduced variation in brainPAD estimation, and therefore represents an important source of inter-study variability.
Genomic analyses of glycine decarboxylase neurogenic mutations, yield a large scale prediction model for prenatal disease
Authors: Farris Joseph D. , Alam Md. Suhail , MysoreRajashekara Arpitha , Haldar Kasturi 
Published: July 2020

AbstractGlycine decarboxylase (GLDC) is a mitochondrial protein, hundreds of mutations in which cause a neurometabolic disorder Non-ketotic Hyperglycinemia (NKH), associated with elevation of plasma glycine. But why a mutation induces severe or attenuated neurological disease is poorly understood. We combined a human multiparametric mutation scale that separates severe from attenuated clinical, neurological disease, with newin silicotools to assess 238 of 255 NKH mutations in murine GLDC. We unified novel murine and human genome level-analyses across a linear scale of neurological severity, within vivoevidence from mice engineered with a top-ranking attenuated mutation and another mutation >10 times more pathogenic and integrated the data in a model of pre- and post-natal disease outcomes, relevant for over a hundred major and minor neurogenic mutations. Our findings suggest that highly severe neurogenic mutations predict fatal, prenatal disease that can be remedied by metabolic supplementation of dams, in absence of amelioration of persistent and age-dependent elevation of plasma glycine.
Relationship Between Neuroendocrine and Immune Gene Expression in Small Cell Lung Cancer
Authors: Cai Ling , Liu Hongyu , Huang Fang , Fujimoto Junya , Girard Luc , Chen Jun , Li Yongwen , Zhang Yuan , Deb Dhruba , Stastny Victor , Kuo Christin S. , Jia Gaoxiang , Yang Chendong , Zou Wei , Alomar Adeeb , Huffman Kenneth , Papari-Zareei Mahboubeh , Yang Lin , Drapkin Benjamin , Akbay Esra , Shames David S. , Wistuba Ignacio I. , Wang Tao , Xiao Guanghua , DeBerardinis Ralph J. , Minna John D. , Xie Yang , Gazdar Adi F. 
Published: July 2020

ABSTRACTSmall cell lung cancer (SCLC) is classified as a high-grade neuroendocrine (NE) tumor, but a subset of SCLC has been termed “variant” due to the loss of NE characteristics. In this study, we computed NE scores for patient-derived SCLC cell lines and xenografts, as well as human tumors. We aligned NE properties with transcription factor-defined molecular subtypes. Then we investigated the different immune phenotypes associated with high and low NE scores. We found repression of immune response genes as a shared feature between classic SCLC and pulmonary neuroendocrine cells of the healthy lung. With loss of NE fate, variant SCLC tumors regain cell-autonomous immune gene expression and exhibit higher tumor-immune interactions. Pan-cancer analysis revealed this NE lineage-specific immune phenotype in other cancers. Additionally, we observed MHC I re-expression in SCLC upon development of chemoresistance. These findings provide a new framework to guide design of treatment regimens in SCLC.
Elucidation of tumor-stromal heterogeneity and the ligand-receptor interactome by single cell transcriptomics in real-world pancreatic cancer biopsies
Authors: Lee Jaewon J. , Bernard Vincent , Semaan Alexander , Monberg Maria E. , Huang Jonathan , Stephens Bret M. , Lin Daniel , Weston Brian R. , Bhutani Manoop S. , Haymaker Cara L. , Bernatchez Chantale , Taniguchi Cullen M. , Maitra Anirban , Guerrero Paola A. 
Published: July 2020

AbstractPrecision medicine approaches in pancreatic ductal adenocarcinoma (PDAC) are imperative for improving disease outcomes. However, the long-term fidelity of recently deployedex vivopreclinical platforms, such as patient-derived organoids (PDOs) remains unknown. Through single-cell RNA sequencing (scRNA-seq), we identify substantial transcriptomic evolution of PDOs propagated from the parental tumor, which may alter predicted drug sensitivity. In contrast, scRNA-seq is readily applicable to limited biopsies from human primary and metastatic PDAC and identifies most cancers as being an admixture of previously described epithelial transcriptomic subtypes. Integrative analyses of our data provide an in-depth characterization of the heterogeneity within the tumor microenvironment, including cancer-associated fibroblast (CAF) subclasses, and predicts for a multitude of ligand-receptor interactions, revealing potential targets for immunotherapy approaches. While PDOs continue to enable prospective therapeutic prediction, our analysis also demonstrates the complementarity of using orthogonalde novobiopsies from PDAC patients paired with scRNA-seq to inform clinical decision-making.Statement of SignificanceThe application of single-cell RNA sequencing to diagnostic pancreatic cancer biopsies provides in-depth transcriptomic characterization of the tumor epithelium and microenvironment, while minimizing potential artifacts introduced by an interveningex vivopassaging step. Thus, this approach can complement the use of patient-derived organoids in implementing precision oncology.
Effects of osteogenic ambulatory mechanical stimulation on early stages of BMP-2 mediated bone repair
Authors: Klosterhoff Brett S. , Vantucci Casey E. , Kaiser Jarred , Ong Keat Ghee , Wood Levi B. , Weiss Jeffrey A. , Guldberg Robert E. , Willett Nick J. 
Published: July 2020

AbstractMechanical loading of bone defects through rehabilitation is a promising therapeutic approach to stimulate repair and reduce the risk of non-union; however, little is known about how therapeutic mechanical stimuli modulate early stages of repair before mineralized bone formation. In a previous study, we established an osteogenic mechanical loading protocol using early ambulatory rehabilitation and a compliant, load-sharing fixator in a rat model of BMP-2 mediated bone defect repair. The objective of this study was to investigate the early effects of osteogenic loading on cytokine expression, tissue composition, and angiogenesis during the first 3 weeks of repair in this model. Using a wireless implantable strain sensor for local measurements of mechanical boundary conditions, finite element simulations showed that osteogenic mechanical loading increased mean compressive strain in defect soft tissue during rehabilitative ambulation at 1 week (load-sharing: −1.54 ± 0.17% vs. load-shielded: −0.76 ± 0.06%), and that strain was amplified in remaining soft tissue regions at 3 weeks as mineralization progressed (load-sharing: −1.89 ± 0.35% vs. load-shielded: −1.38 ± 0.35%). Multivariate analysis of multiplex cytokine arrays revealed that loading significantly altered cytokine expression profiles in the defect tissue at 2 weeks compared to load-shielded defects. Specifically, loading reduced VEGF and increased CXCL5 (LIX) levels. Subsequently, vascular volume in loaded defects was reduced relative to load-shielded defects but similar to intact bone at 3 weeks. Endochondral bone repair was also observed histologically in loaded defects only at 3 weeks. Together, these results demonstrate that moderate ambulatory strains previously shown to stimulate functional bone regeneration significantly alter early angiogenic and cytokine signaling and may promote endochondral ossification in large segmental bone defects.Authors’ ContributionsB.S.K., N.J.W., and R.E.G. designed the research and performed surgeries; B.S.K., C.E.V., and J.K. performed experiments; B.S.K., C.E.V., J.K., and L.B.W., analyzed data; B.S.K., C.E.V., N.J.W., and R.E.G. wrote the manuscript; All authors interpreted data, critically edited, and have read and approved the final manuscript.
The genetic architecture and evolution of life history divergence among perennials in theMimulus guttatusspecies complex
Authors: Coughlan Jenn M. , Brown Maya Wilson , Willis J.H. 
Published: July 2020

AbstractEcological divergence is a main source of trait divergence between closely related species. Despite its importance in generating phenotypic diversity, the genetic architecture of most ecologically relevant traits is poorly understood. Differences in elevation can impose substantial selection for phenotypic divergence of both complex, correlated suites of traits (such as life history), as well as novel adaptations. Here, we use theMimulus guttatusspecies complex to assess if divergence in elevation is accompanied by trait divergence in a group of closely related perennial species, and determine the genetic architecture of this divergence. We find that divergence in elevation is associated with differences in multivariate quantitative life history traits, as well as a unique trait; the production of rhizomes, which may play an important role in overwintering survival. However, the extent of phenotypic divergence among species depended on ontogeny, suggesting that species also diverged in investment strategies across development. Lastly, we show that the genetic architecture of life history divergence between two species is simple, involving few mid to large effect Quantitative Trait Loci (QTLs), and that the genetic architecture of the ability to produce rhizomes changes through development, which has potential implications for hybrid fitness in the wild.
A White Noise Approach to Evolutionary Ecology
Authors: Week Bob , Nuismer Scott L. , Harmon Luke J. , Krone Stephen M. 
Published: July 2020

AbstractAlthough the evolutionary response to random genetic drift is classically modelled as a sampling process for populations with fixed abundance, the abundances of populations in the wild fluctuate over time. Furthermore, since wild populations exhibit demographic stochasticity, it is reasonable to consider the evolutionary response to demographic stochasticity and its relation to random genetic drift. Here we close this gap in the context of quantitative genetics by deriving the dynamics of the distribution of a quantitative character and the abundance of a biological population from a stochastic partial differential equation driven by space-time white noise. In the process we develop a useful set of heuristics to operationalize the powerful, but abstract theory of white noise and measure-valued stochastic processes. This approach allows us to compute the full implications of demographic stochasticity on phenotypic distributions and abundances of populations. We demonstrate the utility of our approach by deriving a quantitative genetic model of diffuse coevolution mediated by exploitative competition for a continuum of resources. In addition to trait and abundance distributions, this model predicts interaction networks defined by rates of interactions, competition coefficients, or selection gradients. Analyzing the relationship between selection gradients and competition coefficients reveals independence between linear selection gradients and competition coefficients. In contrast, absolute values of linear selection gradients and quadratic selection gradients tend to be positively correlated with competition coefficients. That is, competing species that strongly affect each other’s abundance tend to also impose selection on one another, but the directionality is not predicted. This approach contributes to the development of a synthetic theory of evolutionary ecology by formalizing first principle derivations of stochastic models that underlie rigorous investigations of the relationship between feedbacks of biological processes and the patterns of diversity they produce.
Characterization of the gut DNA and RNA viromes in a cohort of Chinese residents and visiting Pakistanis
Authors: Yan Qiulong , Wang Yu , Chen Xiuli , Jin Hao , Wang Guangyang , Guan Kuiqing , Zhang Yue , Zhang Pan , Ayaz Taj , Liang Yanshan , Wang Junyi , Cui Guangyi , Sun Yuanyuan , Xiao Manchun , Zhang Aiqin , Li Peng , Liu Xueyang , Ma Yufang , Li Shenghui , Ma Tonghui 
Published: July 2020

AbstractBackgroundTrillions of viruses inhabit the gastrointestinal tract. Some of them have been well-studied on their roles in infection and human health, but the majority remain unsurveyed. It has been established that the composition of the gut virome is highly variable based on the changes of diet, physical state, and environmental factors. However, the effect of host genetic factors, e.g. ethnic origin, on the gut virome is rarely investigated.Methods and ResultsHere, we characterized and compared the gut virome in a cohort of local Chinese residents and visiting Pakistani individuals, each group containing 24 healthy adults and 6 children. Using metagenomic shotgun sequencing and assembly of fecal samples, a huge number of viral operational taxonomic units (vOTUs) were identified for profiling the DNA and RNA viromes. National background contributed a primary variation to individuals’ gut virome. Compared with the Chinese adults, the Pakistan adults showed higher macrodiversity and different compositional and functional structures in their DNA virome and lower diversity and altered composition in their RNA virome. The virome variations of Pakistan children were inherited from the that of the adults but also tended to share similar characteristics with the Chinese cohort. We also analyzed and compared the bacterial microbiome between two cohorts and further revealed numerous connections between virus and bacterial host. Statistically, the gut DNA and RNA viromes were covariant to some extent (p<0.001), and they both influenced the holistic bacterial composition and vice versa.ConclusionsThis study provides an overview of gut viral community in Chinese and visiting Pakistanis and proposes a considerable role of ethnic origin in shaping the virome.
Zinc Sulfide-Based Hybrid Exosome-Coated Nanoplatform for Targeted Treatment of Glioblastoma in an Orthotopic Mouse Glioblastoma Model
Authors: Mo Jingxin , Li Meiying , Tang Edith K.Y. , Li Shaoyuan , Zhao Wei , Gooding J. Justin 
Published: July 2020

AbstractCore-hybrid shell hydroxychloroquine (HCQ) loaded zinc sulfide (ZnS) nanoparticles were synthesized, characterized and evaluated for the treatment of glioblastoma cellsin vitroandin vivo. These particles, denoted as HCQ@ZnS@exo@iRGD, consist of hollow ZnS nanoparticles loading with the autophagic inhibitor of hydroxychloroquine and covered by a hybrid shell containing exosomes (exo) and phosphatidylserine derived pH- and redox-responsive pegylated iRGD peptide, a gliomablastoma-homing and penetrating peptide. The hybrid exosomes enable HCQ@ZnS with good permeability across the blood-brain barrier and targeting ability to glioblastoma cells in orthotopic mouse glioblastoma model. ZnS acts as a photosensitizer for reactive oxygen species (ROS) production to inflict damage to organelles within glioblastoma cells. Hydroxychloroquine inhibits autophagic flux, which can subsequently lead to the accumulation of impaired organelles caused by the ROS. As a result, substantial selective damage to glioblastoma cells was realized owing to the hybrid exosomes guiding the anti-tumour effects of hydroxychloroquine and ZnS under light irradiation. The results provide evidence for the utility of HCQ@ZnS@exo@iRGD as a therapeutic strategy for glioblastoma.
Vision affects gait speed but not patterns of muscle activation during inclined walking – a virtual reality study
Authors: Benady Amit , Zadik Sean , Ben-Gal Oran , Cano-Porras Desiderio , Wenkert Atalia , Gilaie-Dotan Sharon , Plotnik Meir 
Published: July 2020

AbstractWhile walking, our locomotion is affected by and adapts to the environment based on vision-based and body-based (vestibular and proprioception) cues, all contributing to an “Internal Model of Gravity”. During surface inclination transitions, we modulate gait to counteract gravitational forces by braking during downhill walking to avoid uncontrolled acceleration or by exerting effort to avoid deceleration while walking uphill. In this study, we investigated the role of vision in gait modulation during surface inclination transitions by using an immersive large-scale Virtual Reality (VR) system equipped with a self-paced treadmill and projected visual scenes that allowed us to modulate physical-visual inclinations congruence parametrically. Gait speed and leg muscle electromyography (EMG) were measured in 12 healthy young adults. In addition, the magnitude of subjective visual misperception of verticality was measured by the rod and frame test. During virtual (non-veridical) inclination transitions, vision modulated gait speed after transitions by (i) slowing down to counteract the excepted gravitational ‘boost’ in virtual downhill inclinations and by (ii) speeding up to counteract the expected gravity resistance in virtual uphill inclinations. These gait speed modulations were reflected in muscle activation intensity changes and associated with subjective visual verticality misperception. However, temporal patterns of muscle activation, which are significantly affected by real gravitational inclination transitions, were not affected by virtual (visual) inclination transitions. Our results delineate the contribution of vision to functional locomotion on uneven surfaces and may lead to enhanced rehabilitation strategies for neurological disorders affecting movement.Significance statementA crucial component of successful locomotion is maintaining balance and speed while walking on uneven surfaces. In order to reach successful locomotion, an individual must utilize multisensory integration of visual, gravitational, and proprioception cues. The contribution of vision to this process is still unclear, thus we used a fully immersive virtual reality treadmill setup allowing us to manipulate visual (virtual) and gravitational (real) surface inclinations independently during locomotion of healthy adults. While vision modulated gait speed for a short period after inclination transitions and this was predictive of individual’s visual dependency, muscle activation patterns were only affected by gravitational surface inclinations, not by vision. Understanding the vision’s contribution to successful locomotion may lead to improved rehabilitation for movement disorders.