bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chronic Ovine Studies Demonstrate Low Thromboembolic Risk in the Penn State Infant Ventricular Assist Device
Authors: Lukic Branka , Clark J. Brian , Izer Jenelle M. , Cooper Timothy K. , Finicle Heidi A. , Cysyk Johua , Doxtater Bradly , Yeager Eric , Reibson John , Newswanger Raymond K. , Leibich Patrick , Bletcher Kirby , Weiss William J. 
Published: January 2019

Mechanical circulatory support for children under 6 years of age remains a challenge. This article describes the preclinical status and the results of recent animal testing with the Penn State Infant Left Ventricular Assist Device (VAD). The objectives have been to 1) demonstrate acceptably low thromboembolic risk to support Food and Drug Administration approval, 2) challenge the device by using minimal to no anticoagulation in order to identify any design or manufacturing weaknesses, and 3) improve our understanding of device thrombogenicity in the ovine animal model, using multicomponent measurements of the coagulation system and renal ischemia quantification, in order to better correlate animal results with human results.
The Infant VAD was implanted as a left VAD (LVAD) in 18–29 kg lambs. Twelve LVAD and five surgical sham animals were electively terminated after approximately 30 or 60 days. Anticoagulation was by unfractionated heparin targeting thromboelastography R times of 2x normal (n = 6) or 1x normal (n = 6) resulting in negligible heparin activity as measured by anti-Xa assay (<0.1 IU/ml). Platelet inhibitors were not used.
There were no clinically evident strokes or evidence of end organ dysfunction in any of the 12 electively terminated LVAD studies. The degree of renal ischemic lesions in device animals was not significantly different than that found in five surgical sham studies, demonstrating minimal device thromboembolism.
In summary, these results in a challenging animal test protocol support the conclusion that the Penn State Infant VAD has a low thromboembolic risk and may allow lower levels of anticoagulation.
Chest computed tomography imaging utility for radiographically occult rib fractures in elderly fall-injured patients
Authors: Singleton Jennifer M. , Bilello Leslie A. , Canham Louisa S. , Levenson Robin B. , Lopez Gregory J. , Tadiri Sarah P. , Shapiro Nathan I. , Rosen Carlo L. 
Published: January 2019

BACKGROUND
Previous studies demonstrate an association between rib fractures and morbidity and mortality in trauma. This relationship in low-mechanism injuries, such as ground-level fall, is less clearly defined. Furthermore, computed tomography (CT) has increased sensitivity for rib fractures compared with chest x-ray (CXR); its utility in elderly fall patients is unknown. We sought to determine whether CT-diagnosed rib fractures in elderly fall patients with a normal CXR were associated with increased in-hospital resource utilization or mortality.

METHODS
Retrospective analysis of emergency department patients presenting over a 3-year period. Inclusion criteria: age, 65 years or older; chief complaint, including mechanical fall; and both CXR and CT obtained. We quantified rib fractures on CXR and CT and reported operating characteristics for both. Outcomes of interest included hospital admission/length of stay (LOS), intensive care unit (ICU) admission/LOS, endotracheal intubation, tube thoracostomy, locoregional anesthesia, pneumonia, in-hospital mortality.

RESULTS
We identified 330 patients, mean age was 84 years (±SD, 9.4 years); 269 (82%) of 330 were admitted. There were 96 (29%) patients with CT-diagnosed rib fracture, 56 (17%) by CT only. Compared with CT, CXR had a sensitivity of 40% (95% confidence interval, 30–50%) and specificity of 99% (95% confidence interval, 97–100%) for rib fracture. A median of two additional radiographically occult rib fractures were identified on CT. Despite an increased hospital admission rate (91% vs. 78%) p = 0.02, there was no difference between patients with and without radiographically occult (CT+ CXR−) rib fracture(s) for: median LOS (4; interquartile range (IQR) 2–7 vs 4, IQR 2–8); p = 0.92), ICU admission (28% vs. 27%) p = 0.62, median ICU LOS (2, IQR 1–8 vs 3, IQR 1–5) p = 0.54, or in-hospital mortality (10.3% vs. 7.3%) p = 0.45.

CONCLUSION
Among elderly fall patients, CT-identified rib fractures were associated with increased hospital admissions. However, there was no difference in procedural interventions, ICU admission, hospital/ICU LOS or mortality for patients with and without radiographically occult fractures.

LEVEL OF EVIDENCE
Diagnostic, level III.
Sexual selection, phenotypic plasticity and female reproductive output
Authors: Fox Rebecca J. , Fromhage Lutz , Jennions Michael D. 
Published: January 2019

In a rapidly changing environment, does sexual selection on males elevate a population's reproductive output? If so, does phenotypic plasticity enhance or diminish any such effect? We outline two routes by which sexual selection can influence the reproductive output of a population: a genetic correlation between male sexual competitiveness and female lifetime reproductive success; and direct effects of males on females' breeding success. We then discuss how phenotypic plasticity of sexually selected male traits and/or female responses (e.g. plasticity in mate choice), as the environment changes, might influence how sexual selection affects a population's reproductive output. Two key points emerge. First, condition-dependent expression of male sexual traits makes it likely that sexual selection increases female fitnessifreproductively successful males disproportionately transfer genes that are under natural selection in both sexes, such as genes for foraging efficiency. Condition-dependence is a form of phenotypic plasticity if some of the variation in net resource acquisition and assimilation is attributable to the environment rather than solely genetic in origin. Second, the optimal allocation of resources into different condition-dependent traits depends on their marginal fitness gains. As male condition improves, this can therefore increase or, though rarely highlighted, actually decrease the expression of sexually selected traits. It is therefore crucial to understand how condition determines male allocation of resources to different sexually selected traits that vary in their immediate effects on female reproductive output (e.g. ornaments versus coercive behaviour). In addition, changes in the distribution of condition among males as the environment shifts could reduce phenotypic variance in certain male traits, thereby reducing the strength of sexual selection imposed by females. Studies of adaptive evolution under rapid environmental change should consider the possibility that phenotypic plasticity of sexually selected male traits, even if it elevates male fitness, could have a negative effect on female reproductive output, thereby increasing the risk of population extinction.This article is part of the theme issue ‘The role of plasticity in phenotypic adaptation to rapid environmental change’.
Sparse evidence for selection on phenotypic plasticity in response to temperature
Authors: Arnold Pieter A. , Nicotra Adrienne B. , Kruuk Loeske E. B. 
Published: January 2019

Phenotypic plasticity is frequently assumed to be an adaptive mechanism by which organisms cope with rapid changes in their environment, such as shifts in temperature regimes owing to climate change. However, despite this adaptive assumption, the nature of selection on plasticity within populations is still poorly documented. Here, we performed a systematic review and meta-analysis of estimates of selection on thermal plasticity. Although there is a large literature on thermal plasticity, we found very few studies that estimated coefficients of selection on measures of plasticity. Those that did do not provide strong support for selection on plasticity, with the majority of estimates of directional selection on plasticity being weak and non-significant, and no evidence for selection on plasticity overall. Although further estimates are clearly needed before general conclusions can be drawn, at present there is not clear empirical support for any assumption that plasticity in response to temperature is under selection. We present a multivariate mixed model approach for robust estimation of selection on plasticity and demonstrate how it can be implemented. Finally, we highlight the need to consider the environments, traits and conditions under which plasticity is (or is not) likely to be under selection, if we are to understand phenotypic responses to rapid environmental change.This article is part of the theme issue ‘The role of plasticity in phenotypic adaptation to rapid environmental change’.
Effects of variations in adaptation potential on invasion speeds and species ranges
Authors: Méndez-Vera José , Raoul Gaël , Massol François , Loeuille Nicolas 
Published: January 2019

AbstractConfronted with global changes and their potential impacts on biodiversity, an important question is to understand the ecological and evolutionary determinants of species geographical distributions. In order to understand how adaptation in heterogeneous environments constrains such distributions, we analyze how the potential of adaptation along an environmental cline affects the geographical distribution and propagation dynamics (invasion or extinction) of a single species. We re-analyse a model initially proposed by Kirkpatrick and Barton using propagation speed to assess whether species distribution is spatially limited or not.We found that for big adaptation potentials, the species invades space following Fisher’s model, whereas for small adaptation potentials the propagation depends on the evolutionary challenge to overcome. We have explicit approximations for the propagation speeds in both cases. We discuss the utility of these propagation speeds as an eco-evolutionary index based on empirical studies.
Centering based on active diffusion in mouse oocytes is non-specific
Authors: Colin Alexandra , Razin Nitzan , Almonacid Maria , Ahmed Wylie , Betz Timo , Terret Marie-Emilie , Gov Nir S , Voituriez Raphaël , Gueroui Zoher , Verlhac Marie-Hélène 
Published: January 2019

AbstractThe mechanism for nucleus centering in mouse oocytes results from a gradient of actin-positive vesicles. By microinjecting oil droplets and fluorescent beads, we analyze the consequences of the gradient of activity on transport of exogenous tracer particles of different sizes. We also use optical tweezers to probe rheological properties of the cytoplasm. We find that the gradient activity induces a general centering force, akin to an effective pressure gradient, leading to centering of oil droplets with velocities comparable to nuclear ones. High temporal resolution measurements reveal that passive particles, larger than 1µm, experience the activity gradient by a biased diffusion towards the cell center. Unexpectedly, this general and size dependent mechanism is maintained in Meiosis I but contrasted by a further process that specifically off-centers the spindle. These antagonizing processes depend on myosin activity, thus we reconcile how the same molecular actors can have two opposite functions (centering versus off-centering).
Dual airway and alveolar contributions to adult lung homeostasis and carcinogenesis
Authors: Spella Magda , Lilis Ioannis , Pepe Mario A. , Chen Yuanyuan , Armaka Maria , Lamort Anne-Sophie , Zazara Dimitra E. , Roumelioti Fani , Vreka Malamati , Kanellakis Nikolaos I. , Wagner Darcy E. , Giannou Anastasios D. , Armenis Vasileios , Arendt Kristina A.M. , Klotz Laura V. , Toumpanakis Dimitrios , Karavana Vassiliki , Zakynthinos Spyros G. , Giopanou Ioanna , Marazioti Antonia , Aidinis Vassilis , Sotillo Rocio , Stathopoulos Georgios T. 
Published: January 2019

ABSTRACTLung adenocarcinoma (LUAD) and chronic lung diseases caused by smoking and environmental noxious agents are the deadliest diseases worldwide, sharing a partially charted pathobiology of dysfunctional alveolar repair. Here we sought to identify the respiratory epithelial dynamics and molecular signatures participating in adult lung maintenance and chemical carcinogenesis. We employed novel mouse models of respiratory epithelial marking and ablation, a battery of pulmonary toxins and carcinogens, experimental protocols of carcinogen-induced LUAD, tobacco carcinogen-induced LUAD cell lines, and human transcriptomic data and identified a prominent involvement of airway molecular programs in alveolar maintenance and carcinogen-induced LUAD. The airway-specific transcriptomic signature was redistributed to the alveoli after toxic and carcinogenic insults and resulted in marked contributions of airway-labeled cells to injury-recovered alveoli and LUAD. Airway cells maintained Kras mutations and therefore possibly contributed to lung cancer initiation, while LUAD were spatially linked to neighboring airways. Transcriptomic profiling of carcinogen-induced murine and human LUAD revealed enrichment in airway signatures, while ablation of airway cells distorted alveolar structure and function and protected mice from LUAD development. Collectively, these results indicate that airway cells and/or transcriptomic signatures are essential for alveolar maintenance and LUAD development.
Potential hydrodynamic cytoplasmic transfer between mammalian cells: Cell-projection pumping
Authors: Zoellner Hans , Paknejad Navid , Cornwell James , Chami Belal , Romin Yevgeniy , Boyko Vitaly , Fujisawa Sho , Kelly Elizabeth , Lynch Garry W. , Rogers Glynn , Manova Katia , Moore Malcolm A.S. 
Published: January 2019

ABSTRACTWe earlier reported cytoplasmic fluorescence exchange between cultured human fibroblasts (Fib) and malignant cells (MC). Others report similar transfer via either tunneling nanotubes (TNT) or shed membrane vesicles and this changes the phenotype of recipient cells. Our current time-lapse microscopy showed most exchange was from Fib into MC, with less in the reverse direction. Although TNT were seen, we were surprised transfer was not via TNT, but was instead via fine and often branching cell projections that defied direct visual resolution because of their size and rapid movement. Their structure was revealed nonetheless, by their organellar cargo and the grooves they formed indenting MC, while this was consistent with holotomography. Discrete, rapid and highly localized transfer events, evidenced against a role for shed vesicles. Transfer coincided with rapid retraction of the cell-projections, suggesting a hydrodynamic mechanism. Increased hydrodynamic pressure in retracting cell-projections normally returns cytoplasm to the cell body. We hypothesize ‘cell-projection pumping’ (CPP), where cytoplasm in retracting cell-projections partially equilibrates into adjacent recipient cells via micro-fusions that form temporary inter-cellular cytoplasmic continuities. We tested plausibility for CPP by combined mathematical modelling, comparison of predictions from the model with experimental results, and then computer simulations based on experimental data. The mathematical model predicted preferential CPP into cells with lower cell stiffness, expected from equilibration of pressure towards least resistance. Predictions from the model were satisfied when Fib were co-cultured with MC, and fluorescence exchange related with cell stiffness by atomic force microscopy. When transfer into 5000 simulated recipient MC or Fib was studied in computer simulations, inputting experimental cell stiffness and donor cell fluorescence values generated transfers to simulated recipient cells similar to those seen by experiment. We propose CPP as a potentially novel mechanism in mammalian inter-cellular cytoplasmic transfer and communication.SIGNIFICANCETime-lapse observations of co-cultured cells led us to hypothesize what we believe to be a novel hydrodynamic mechanism transferring cytoplasm between cells. Similar transfer by other mechanisms markedly affects cell behavior. Combined mathematical modelling, satisfaction of predictions from the mathematical model in cell culture experiments, and separate computer simulations that generate outcomes similar to experimental observations, support our hypothesized mechanism.
Applying CRISPR-based genetic screens to identify drivers of tumor-cell sensitivity towards NK-cell attack
Authors: Klein Klara , Wang Tim , Lander Eric S. , Altfeld Marcus , Garcia-Beltran Wilfredo F. 
Published: January 2019

ABSTRACTNatural killer (NK) cells distinguish cancer cells from healthy cells using an array of germline-encoded receptors that interact with ligands expressed on target cells. A balance of inhibitory and activating signals transduced by these receptors regulate NK cell function to provide anti-tumor immunity while maintaining self-tolerance. However, knowledge of the spectrum of factors regulating NK-cell-mediated cytotoxicity, including the contribution of specific ligands and regulatory mechanisms for their expression on tumor cells, remains incomplete. Here, we apply a genome-wide loss-of-function screen in tumor cells using CRISPR/Cas9 technology to identify the factors that promote NK-cell cytotoxicity towards tumor cells. We established the drivers of tumor-cell sensitivity towards NK-cell attack (TuSeNKA) screening approach using the chronic myeloid leukemia (CML) cell line, K562. Interestingly, we identified B7H6, the ligand for the activating NK cell receptor NKp30, as the single factor whose loss resulted in increased resistance of K562 cells towards NK cells. Our study shows that combination of CRISPR-based genetic screens with NK-cell cytotoxicity assays is a valuable tool for identifying functionally relevant NK cell-tumor cell interactions, paving the way for further investigations that unravel the complexity of signals that promote NK-cell recognition of transformed cells and develop therapies that target these modes of tumor-cell killing.
Bone marrow stromal cells from a GDF5 origin produce zonal tendon-to-bone attachments following anterior cruciate ligament reconstruction
Authors: Hagiwara Yusuke , Dyrna Felix , Kuntz Andrew F , Adams Douglas J , Dyment Nathaniel A 
Published: January 2019

ABSTRACTFollowing anterior cruciate ligament (ACL) injury, the ligament is often reconstructed with a tendon graft passed through bone marrow tunnels. This procedure results in a staged repair response where cell death occurs in the tendon graft, the graft is repopulated by host cells outside the graft, and tendon-to-bone attachments form at the graft/bone interface. While this healing process is well appreciated, the biological mechanisms that regulate it including the cellular origin of the repair response is poorly understood. Embryonic progenitor cells expressing growth and differentiation factor 5 (GDF5) give rise to several mesenchymal tissues in the joint and epiphyses. Therefore, we hypothesized that cells from a GDF5 origin, even in the adult tissue, would give rise to cells that contribute to the stages of repair following ACL reconstruction. ACLs were reconstructed in Gdf5Cre;R26R-tdTomato lineage tracing mice to monitor the contribution of Gdf5Cre;tdTom+ cells to graft revitalization and examine the extent to which these cells are capable of creating mineralized attachments within the bone tunnels. Anterior-posterior drawer tests were used to establish the stability of the knee following the procedure and demonstrated 58% restoration in anterior-posterior stability. Following reconstruction, Gdf5Cre;tdTom+ cells within the bone marrow expanded by 135-fold compared to intact controls in response to the injury. These cells migrated to the tendon graft interface, repopulated regions of the graft, and initiated tendon-to-bone attachments. These cells continued to organize and mature the attachments yielding a zonal insertion site at 4 weeks with collagen fibers spanning across unmineralized and mineralized fibrocartilage and anchored to adjacent bone. The zonal attachment possessed organized tidemarks with concentrated alkaline phosphatase activity similar to normal tendon or ligament entheses. This study established that mesenchymal cells from a GDF5 origin contribute to the creation of zonal tendon-to-bone attachments within bone tunnels following ACL reconstruction. Future studies will target this cell population to modulate the repair response in order to better understand key biological mechanisms that regulate tendon-to-bone repair.
Summary statistic analyses do not correct confounding bias
Authors: Holmes John B. , Speed Doug , Balding David J. 
Published: January 2019

AbstractLD SCore regression (LDSC) has become a popular approach to estimate confounding bias, heritability and genetic correlation using only genome wide association study (GWAS) test statistics. SumHer is a newly-introduced alternative with similar aims. We show using theory and simulations that both approaches fail to adequately account for confounding bias, even when the assumed heritability model is correct. Consequently, these methods may estimate heritability poorly if there was inadequate adjustment for confounding in the original GWAS analysis. We also show that choice of summary statistic for use in LDSC or SumHer can have a large impact on resulting inferences. Further, covariate adjustments in the original GWAS can alter the target of heritability estimation, which can be problematic when LDSC or SumHer is applied to test statistics from a meta-analysis of GWAS with different covariate adjustments.
Automated identification of Cell Types in Single Cell RNA Sequencing
Authors: Ma Feiyang , Pellegrini Matteo 
Published: January 2019

AbstractCell type identification is one of the major goals in single cell RNA sequencing (scRNA-seq). Current methods for assigning cell types typically involve the use of unsupervised clustering, the identification of signature genes in each cluster, followed by a manual lookup of these genes in the literature and databases to assign cell types. However, there are several limitations associated with these approaches, such as unwanted sources of variation that influence clustering and a lack of canonical markers for certain cell types. Here, we present ACTINN (Automated Cell Type Identification using Neural Networks), which employs a neural network with 3 hidden layers, trains on datasets with predefined cell types, and predicts cell types for other datasets based on the trained parameters. We trained the neural network on a mouse cell type atlas (Tabula Muris Atlas) and a human immune cell dataset, and used it to predict cell types for mouse leukocytes, human PBMCs and human T cell sub types. The results showed that our neural network is fast and accurate, and should therefore be a useful tool to complement existing scRNA-seq pipelines.Author SummarySingle cell RNA sequencing (scRNA-seq) provides high resolution profiling of the transcriptomes of individual cells, which inevitably results in high volumes of data that require complex data processing pipelines. Usually, one of the first steps in the analysis of scRNA-seq is to assign individual cells to known cell types. To accomplish this, traditional methods first group the cells into different clusters, then find marker genes, and finally use these to manually assign cell types for each cluster. Thus these methods require prior knowledge of cell type canonical markers, and some level of subjectivity to make the cell type assignments. As a result, the process is often laborious and requires domain specific expertise, which is a barrier for inexperienced users. By contrast, our neural network ACTINN automatically learns the features for each predefined cell type and uses these features to predict cell types for individual cells. This approach is computationally efficient and requires no domain expertise of the tissues being studied. We believe ACTINN allows users to rapidly identify cell types in their datasets, thus rendering the analysis of their scRNA-seq datasets more efficient.