bluuebunny/crossref_metadata_2025_split huggingface dataset:
Partial coherence and frustration in self-organizing spherical grids
Authors: Stella Federico , Urdapilleta Eugenio , Treves Alessandro 
Published: February 2019

ABSTRACTNearby grid cells have been observed to express a remarkable degree of long-range order, which is often idealized as extending potentially to infinity. Yet their strict periodic firing and ensemble coherence are theoretically possible only in flat environments, much unlike the burrows which rodents usually live in. Are the symmetrical, coherent grid maps inferred in the lab relevant to chart their way in their natural habitat?We consider spheres as simple models of curved environments and, waiting for the appropriate experiments to be performed, we use our adaptation model to predict what grid maps would emerge in a network with the same recurrent connections, which on the plane produce coherence among the units. We find that on the sphere such connections distort the maps that single grid units would express on their own, and aggregate them into clusters. When remapping to a different spherical environment, units in each cluster maintain only partial coherence, similar to what is observed in disordered materials, such as spin glasses.
Positive feedback loop of regulating ERK phosphorylation in mESCs mediated by Etv5-Tet2-Fgfr2 axis
Authors: Fan Chen , Zhu Kui , Liu Yuan , Zhang Mengyao , Cao Hongxia , Li Na , Wang Yan , Hua Jinlian , Wang Huayan , Zhang Shiqiang 
Published: February 2019

ABSTRACTDynamic equilibrium of extracellular signal-regulated kinase (ERK) activity is regulated elaborately by multiple feedback loops to ensure the normal self-renewal of mouse embryonic stem cells (mESCs). Previous studies on mESCs have demonstrated that the negative feedback loops are engaged to prevent the overactivated ERK phosphorylation (pERK). It is not clear whether there is any positive feedback loop involved to maintain a minimum of pERK in mESCs. Here, we found that blocking fibroblast growth factor (FGF)-ERK pathway by chemical PD0325901 downregulated the transcription of E26 transformation-specific (ETS) family transcription factor Etv5 in mESCs. In turn, knockout (KO) of Etv5 by CRISPR/Cas9 decreased pERK. Moreover, Etv5 KO enhanced the DNA methylation at promoter of fibroblast growth factor receptor 2 (Fgfr2) by downregulating DNA hydroxylase Tet2, which further decreased the expression of Fgfr2 in mESCs. Collectively, a positive feedback loop of regulating pERK was revealed in mESCs, which was mediated by Etv5-Tet2-Fgfr2 axis. Our findings provide a new paradigm for pERK regulation in mESCs and will be useful to understand the cell fate determination during early embryo development.
Controllability of molecular pathways
Authors: Wuchty Stefan 
Published: February 2019

ABSTRACTInputs to molecular pathways that are the backbone of cellular activity drive the cell to certain outcomes and phenotypes. Here, we investigated proteins that topologically controlled different human pathways represented as independent molecular interaction networks, suggesting that a minority of proteins control a high number of pathways and vice versa. Transcending different topological levels, proteins that controlled a large number of pathways also controlled a network of interactions when all pathways were combined. Furthermore, control proteins that were robust when interactions were rewired or inverted also increasingly controlled an increasing number of pathways. As for functional characteristics, such control proteins were enriched with regulatory and signaling genes, disease genes and drug targets. Focusing on evolutionary characteristics, proteins that controlled different pathways had a penchant to be evolutionarily conserved as equal counterparts in other organisms, indicating the fundamental role that control analysis of pathways plays for our understanding of regulation, disease and evolution.
Head motion predictability explains activity-dependent suppression of vestibular balance control
Authors: Dietrich H , Heidger F , Schniepp R , MacNeilage PR , Glasauer S , Wuehr M 
Published: February 2019

AbstractVestibular balance control is dynamically weighted during locomotion. This might result from a selective suppression of vestibular inputs in favor of a feed-forward balance regulation based on locomotor efference copies. The feasibility of such a feed-forward mechanism should however critically depend on the predictability of head movements (PHM) during locomotion. To test this, we studied in healthy subjects the differential impact of a stochastic vestibular stimulation (SVS) on body sway (center-of-pressure, COP) during standing and walking at different speeds using time-frequency analyses and compared it to activity-dependent changes in PHM. SVS-COP coupling decreased from standing to walking and further dropped with faster locomotion. Correspondingly, PHM increased with faster locomotion. Furthermore, SVS-COP coupling depended on the gait-cycle-phase with peaks corresponding to periods of least PHM. These findings support the assumption that during stereotyped human self-motion, locomotor efference copies selectively replace vestibular cues, similar to what was previously observed in animal models.
Calcium alginate entrapped Eupatorium adenophorum Sprengel stems powder for Chromium(VI) biosorption in aqueous medium
Authors: Aryal Mahendra 
Published: February 2019

ABSTRACTA novel biosorbent, Eupatorium adenophorum Sprengel was used for biosorption of chromium (VI) from aqueous solutions. Optimum pH, biomass concentration and contact time were estimated at 2.0, 1.0 g/L and 60 min respectively. Data obtained from batch studies confirmed well to the Langmuir model. It was found that the overall biosorption process was best described by pseudo second-order kinetics. The results demonstrated that intraparticle diffusion is not the sole rate-controlling step for the whole sorption process. In binary mixtures, biosorption efficiency of Cr(VI) was not significantly affected by the presence of ions up to 50 mg/L. Thermodynamic study showed that Cr(VI) biosorption on Eupatorium adenophorum-alginate beads was spontaneous, exothermic and physisorption in nature. Cr(VI) ions were recovered effectively from Eupatorium adenophorum-alginate beads using 0.5 M HNO3 solution.
LRRC33 is a novel binding and regulating protein of TGF-β1 function in human acute myeloid leukemia cells
Authors: Ma Wenjiang , Qin Yan , Chapuy Bjoern , Lu Chafen 
Published: February 2019

AbstractTransforming growth factor – β1 (TGF-β1) is a versatile cytokine. It has context-dependent pro- and anti-cell proliferation functions. Activation of latent TGF-β1 requires release of the growth factor from pro-complexes and is regulated through TGF-β binding proteins. Two types of TGF-β binding partners, latent TGF-β-binding proteins (LTBPs) and leucine-rich-repeat-containing protein 32 (LRRC32), have been identified and their expression are cell specific. TGF-β1 also plays important roles in acute myeloid leukemia (AML) cells. However, the expression of LTBPs and LRRC32 are lacking in myeloid lineage cells and the binding protein of TGF-β1 in these cells are unknown. Here we show that a novel leucine-rich-repeat-containing protein family member, LRRC33, with high mRNA level in AML cells, to be the binding and regulating protein of TGF-β1 in AML cells. Using two representative cell lines MV4-11 and AML193, we demonstrate that the protein expression of LRRC33 and TGF-β1 are correlated. LRRC33 co-localizes and forms complex with latent TGF-β1 protein on the cell surface and intracellularly in these cells. Similar as in other cell types, the activation of TGF-β1 in MV4-11 and AML193 cells are also integrin dependent. We anticipate our study to be a starting point of more comprehensive research on LRRC33 as novel TGF-β regulating protein and potential non-genomic based drug target for AML and other myeloid malignancy.
Build a better mouse task – can an open-source rodent joystick enhance reaching behavior outcomes through improved monitoring of real-time spatiotemporal kinematics?
Authors: Belsey Parley , Nicholas Mark A. , Yttri Eric A 
Published: February 2019

SUMMARYFor decades, advanced behavioral tasks have only been used in human and non-human primates. However, with improved analytical and genetic techniques, there has been a growing drive to implement complex reaching, decision-making, and reaction time tasks – not in primates – but in rodents. Here, we assess the hypothesis that a mouse can learn a cued reaction time task. Moreover, we tested multiple training regimens and found that introducing elements of the reaction time task serially hindered, rather than helped task acquisition. Additionally, we include a step-by-step manual for inexpensive implementation and use of a rodent joystick for behavioral analysis. Task and analysis code for the evaluated behaviors are included such that they may be replicated and tested further. With these, we also include code for a probabilistic reward ‘two-arm bandit’ task. These various tasks, and the method to construct and implement them, will enable greatly improved study of the neural correlates of behavior in the powerful mouse model organism. In summary, we have tested and demonstrated that mice can learn sophisticated tasks with A joystick, and that targeted task design provides a significant advantage. These results of this study stand to inform the implementation of other sophisticated tasks using the mouse model.
Oncogenic Mutations in Histologically Normal Endometrium: The New Normal?
Authors: Lac Vivian , Nazeran Tayyebeh M. , Tessier-Cloutier Basile , Aguirre-Hernandez Rosalia , Albert Arianne , Lum Amy , Khattra Jaswinder , Praetorius Teresa , Mason Madeline , Chiu Derek , Köbel Martin , Yong Paul J. , Gilks Blake C. , Anglesio Michael S. , Huntsman David G. 
Published: February 2019

AbstractThe presence of somatic driver mutations in endometriosis has previously been believed to represent early events in transformation, however our group and others have described such mutations in roughly one-third of cases of deep infiltrating or iatrogenic endometriosis. These forms of endometriosis rarely progress to malignancy. Recent studies have also shown somatic driver mutations in normal skin, blood, peritoneal washings, and esophageal epithelium. Such findings prompt speculation on whether such mutations exist in the eutopic endometrium – the likely tissue of origin of endometriosis. In the current study we investigated the presence of somatic driver mutations in histologically normal endometrium from women lacking evidence of gynecologic malignancy or endometrial hyperplasia. Twenty-five women who underwent hysterectomies and 85 women who underwent endometrial biopsies were included in this study. Formalin-fixed, paraffin-embedded tissue specimens were analyzed by means of targeted sequencing followed by orthogonal validation with droplet digital PCR. PTEN and ARID1A immunohistochemistry (IHC) was also performed as surrogates for inactivating mutations in the respective genes. Overall, we observed somatic driver-like events in over 50% of histologically normal endometrial samples analyzed, which included hotspot mutations in KRAS, PIK3CA, and FGFR2 as well as PTEN-loss by IHC. Analysis of anterior and posterior samplings collected from women who underwent hysterectomies is consistent with the presence of somatic driver mutations within clonal pockets spread throughout the uterus. The prevalence of such oncogenic mutations also increased with age (OR: 1.05 (95% CI: 1.00 – 1.10), p = 0.035). These findings have implications on our understanding of aging and so-called “normal tissues”, thereby necessitating caution in the utilization of mutation-based early detection tools for endometrial or other cancers.
A Signaling Network based Computational Model to Uncover Loop as the Novel Molecular Mechanisms for Medulloblastoma
Authors: Xu Jielin , Li Fuhai 
Published: February 2019

AbstractMedulloblastoma (MB) is the most common malignant brain tumor in children. Despite aggressive therapy, about one-third of patients with MB still die, and survivors suffer severe long-term side effects due to the treatments. The poor post-treatment outcomes are tightly linked to unpredictable drug resistance. Therefore, before developing robust single drug or drug combination recommendation algorithms, uncovering the underlying protein-protein interaction (PPI) network patterns that accurately explain and predict drug resistances for MB subtypes is essential and important. In this study, we hypothesize that the loop sub-structure within the PPI network can explain and predict drug resistance. Both static and dynamic models are built to evaluate this hypothesis for three MB subtypes. Specifically, a static model is created to first validate that many reported therapeutic targets are located topologically on highly deregulated loop sub-structure and then to characterize the loop for tumors without treatment. Next, with the after-treatment time-series genomics data, a dynamic hidden Markov model (HMM) with newly designed initialization scheme estimates the successful and unsuccessful occurrence probabilities for each given PPI and then re-delineates the loop for post-treatment tumors. Finally, the comparison of loop structures pre- and post-treatment distinguishes effective and ineffective treatment options, demonstrating that the loop sub-structure is capable of interpreting the mechanism of drug resistance. In summary, effective treatments show much stronger inhibition of cell cycle and DNA replication proteins when compared to ineffective treatments after considering the cross talk of multiple pathways (the loop).
Nonparametric expression analysis using inferential replicate counts
Authors: Zhu Anqi , Srivastava Avi , Ibrahim Joseph G. , Patro Rob , Love Michael I. 
Published: February 2019

AbstractA primary challenge in the analysis of RNA-seq data is to identify differentially expressed genes or transcripts while controlling for technical biases present in the observations. Ideally, a statistical testing procedure should incorporate information about the inherent uncertainty of the abundance estimates, whether at the gene or transcript level, that arise from quantification of abundance. Most popular methods for RNA-seq differential expression analysis fit a parametric model to the counts or scaled counts for each gene or transcript, and a subset of methods can incorporate information about the uncertainty of the counts. Previous work has shown that nonparametric models for RNA-seq differential expression may in some cases have better control of the false discovery rate, and adapt well to new data types without requiring reformulation of a parametric model. Existing nonparametric models do not take into account the inferential uncertainty of the observations, leading to an inflated false discovery rate, in particular at the transcript level. Here we propose a nonparametric model for differential expression analysis using inferential replicate counts, extending the existing SAMseq method to account for inferential uncertainty, batch effects, and sample pairing. We compare our method, “SAMseq With Inferential Samples Helps”, or Swish, with popular differential expression analysis methods. Swish has improved control of the false discovery rate, in particular for transcripts with high inferential uncertainty. We apply Swish to a singlecell RNA-seq dataset, assessing sensitivity to recover DE genes between sub-populations of cells, and compare its performance to the Wilcoxon rank sum test.
Comparative analyses of phenotypic sequences using phylogenetic trees
Authors: Caetano Daniel S. , Beaulieu Jeremy M. 
Published: February 2019

AbstractPhenotypic sequences are a type of multivariate trait organized structurally, such as teeth distributed along the dental arch, or temporally, such as the stages of an ontogenetic series. However, unlike other multivariate traits, the elements of a phenotypic sequence are arranged along a vector, which allows for distinct evolutionary patterns between neighboring and distant positions. In fact, sequence traits share many characteristics with molecular sequences. We implement an approach to estimate rates of trait evolution that explicitly incorporates the sequence organization of traits. We apply models to study the temporal pattern evolution of cricket calling songs. We test whether songs show autocorrelation of rates (i.e., neighboring positions along a phenotypic sequence have correlated rates of evolution), or if they are best described by rate variation independent of sequence position. Our results show that models perform well when used with sequence phenotypes even under small sample sizes. We also show that silent regions of the songs evolve faster than chirp regions, which suggests that macroevolutionary changes are faster when associated with axes of variation less constrained by multiple sources of selection. Our approach is flexible and can be applied to any multivariate trait with units organized in a sequence-like structure.
Highly Efficient Repair of the ΔF508 Mutation in Airway Stem Cells of Cystic Fibrosis Patients with Functional Rescue of the Differentiated Epithelia
Authors: Vaidyanathan Sriram , Salahudeen Ameen A. , Sellers Zachary M. , Bravo Dawn T. , Choi Shannon S. , Batish Arpit , Le Wei , La O Sean De , Kaushik Milan P. , Galper Noah , Lee Ciaran M. , Bao Gang , Chang Eugene H. , Wine Jeffrey J. , Milla Carlos E. , Desai Tushar J. , Nayak Jayakar V. , Kuo Calvin J. , Porteus Matthew H. 
Published: February 2019

AbstractCystic fibrosis (CF) is a monogenic autosomal recessive disorder caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Cl- channel. CF results in multiorgan dysfunction and ultimately mortality from respiratory sequelae. Although pharmacologic approaches have demonstrated efficacy in reducing symptoms and respiratory decline, a curative treatment modality remains elusive. Gene therapy, a promising curative strategy, has been limited due to poor correction efficiencies both in vitro and in vivo. Here, we use Cas9 and adeno-associated virus 6 (AAV6) to correct the ΔF508 mutation (found in ∼70% of CF alleles and ∼90% of CF patients in North America) in upper airway basal stem cells (UABCs) obtained from CF and non-CF patients undergoing functional endoscopic sinus surgery (FESS). In UABCs from homozygous (ΔF508/ΔF508) and compound heterozygous (ΔF508/Other) CF patients, we achieved 28 ± 5 % and 42 ± 15% correction, respectively. In homozygous human bronchial epithelial cells (HBECs), we achieved 41± 4 % correction. Upon differentiation in air-liquid interface (ALI), cultures of corrected CF cells displayed partial restoration of CFTRinh-172 sensitive Cl- currents relative to non-CF controls: 31± 5 % in UABCs and 51 ± 3 % in HBECs (both from subjects homozygous for ΔF508 CFTR). Finally, gene edited cells embedded successfully and retained expression of cytokeratin 5 (KRT5), a basal cell marker, on a FDA-approved porcine small intestinal submucosal (pSIS) membrane previously shown to improve re-mucosalization after FESS. In summary, we present an efficient, feeder-free, selection-free and clinically compatible approach to generate cell-based therapies for CF from autologous airway stem cells. This approach represents a first step towards developing patient-specific autologous airway stem cell transplant as a curative treatment for CF.
Suppression of GABAergic transmission in the spinal dorsal horn induces pain-related behavior in a chicken model of spina bifida
Authors: Khan Md. Sakirul I , Nabeka Hiroaki , Islam Farzana , Shimokawa Tetsuya , Saito Shouichiro , Tachibana Tetsuya , Matsuda Seiji 
Published: February 2019

AbstractSpina bifida aperta (SBA), one of the most common congenital malformations, causes various neurological disorders. Pain is a common complaint of patients with SBA. However, little is known about the neuropathology of SBA-related pain. Because loss of γ-aminobutyric acid (GABA)ergic neurons in the spinal cord dorsal horn is associated with pain, we hypothesized the existence of cross-talk between SBA-related pain and alterations in GABAergic transmission in the spinal cord. Therefore, we investigated the kinetics of GABAergic transmission in the spinal cord dorsal horn in a chicken model of SBA. Neonatal chicks with SBA exhibited various pain-like behaviors, such as an increased number of vocalizations with elevated intensity (loudness) and frequency (pitch), reduced mobility, difficulty with locomotion, and escape reactions. Furthermore, the chicks with SBA did not respond to standard toe-pinching, indicating disruption of the spinal cord sensorimotor networks. These behavioral observations were concomitant with loss of GABAergic transmission in the spinal cord dorsal horn. We also found apoptosis of GABAergic neurons in the superficial dorsal horn in the early neonatal period, although cellular abnormalization and propagation of neurodegenerative signals were evident at middle to advanced gestational stages. In conclusion, ablation of GABAergic neurons induced alterations in spinal cord neuronal networks, providing novel insights into the pathophysiology of SBA-related pain-like complications.
Do combinations of clinical parameters related to caries activity status predict progression more accurately than individual parameters?
Authors: Floriano I , Matos R , Mattos-Silveira J , Rocha ES , Ekstrand KR , Mendes FM , Braga MM 
Published: February 2019

AbstractFew studies have addressed the predictive power of the clinical parameters used in assessing caries lesion activity. This study assessed the predictive validity of evaluating clinical parameters that are related to caries lesion activity status, individually and combined, in a long-term analysis. The occlusal surfaces of primary molars (1361 surfaces) were examined in 205 children according to the following clinical features: potential for plaque stagnation, colour, luster, cavitation, texture, and clinical depth. Cavities with frankly exposed dentine were excluded from this sample. After 1 year, 148 children (828 surfaces) were re-evaluated using the International Caries Detection and Assessment System to assess caries lesion progression. Progression was set as an outcome to verify the predictive power of the initially assessed clinical parameters. Different combinations of two or more parameters were also tested to check for any association with caries progression. Multilevel Poisson regression analyses were performed and the relative risk for each parameter/combination tested was calculated by considering a confidence interval of 95%. Forty percent of the reassessed surfaces presented caries progression after 1 year. Despite their surface integrity, dentine caries lesions were approximately 10-fold more likely and enamel lesions were approximately three-fold more likely to progress than sound surfaces. Similarly, cavitated lesions showed the highest risk of progression compared to sound/non-cavitated lesions. When only non-cavitated surfaces were considered, roughness proved to be a risk factor for caries progression. In conclusion, the lesions presenting clinical involvement of the dentine and even those cavitations clinically involving only the enamel had a higher risk of progression compared to sound or non-cavitated surfaces. For these lesions, the evaluation of other conjoint parameters seems unnecessary. Nevertheless, surface roughness can be a useful feature in predicting the risk of non-cavitated caries lesion progression.