bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gene therapy conversion of striatal astrocytes into GABAergic neurons in mouse models of Huntington’s disease
Authors: Wu Zheng , Parry Matthew , Hou Xiao-Yi , Liu Min-Hui , Wang Hui , Cain Rachel , Pei Zi-Fei , Chen Yu-Chen , Guo Zi-Yuan , Abhijeet Sambangi , Chen Gong 
Published: February 2020

AbstractHuntington’s disease (HD) is caused by Huntingtin (Htt) gene mutation resulting in the loss of striatal GABAergic neurons and motor functional deficits. We report here an in vivo cell conversion technology to reprogram striatal astrocytes into GABAergic neurons in both R6/2 and YAC128 HD mouse models through AAV-mediated ectopic expression of NeuroD1 and Dlx2 transcription factors. We found that the astrocyte-to-neuron (AtN) conversion rate reached 80% in the striatum and >50% of the converted neurons were DARPP32+ medium spiny neurons. The striatal astrocyte-converted neurons showed action potentials and synaptic events, and projected their axons to the targeted globus pallidus and substantia nigra in a time-dependent manner. Behavioral analyses found that NeuroD1 and Dlx2-treated R6/2 mice showed a significant extension of life span and improvement of motor functions. This study demonstrates that in vivo AtN conversion may be a disease-modifying gene therapy to treat HD and other neurodegenerative disorders.
Mass cytometry reveals cellular fingerprint associated with IgE+ peanut tolerance and allergy in early life
Authors: Neeland Melanie R. , Andorf Sandra , Manohar Monali , Dunham Diane , Lyu Shu-Chen , Dang Thanh D. , Peters Rachel L. , Perrett Kirsten P. , Tang Mimi L. K. , Saffery Richard , Koplin Jennifer J. , Nadeau Kari C. 
Published: February 2020

AbstractIgE-mediated peanut allergic is common, often serious, and usually lifelong. Not all individuals who produce peanut-specific IgE will react upon consumption of peanut and can eat the food without adverse reactions, known as sensitized tolerance. Here, we employ high-dimensional mass cytometry to define the circulating immune cell signatures associated with sensitized tolerance and clinical allergy to peanut in the first year of life. Key features of clinical peanut allergic are increased frequency of activated B cells (CD19hiHLADRhi), overproduction of TNFα and increased frequency of peanut-specific memory CD4 T cells. Infants with sensitized tolerance display reduced frequency but hyper-responsive naive CD4 T cells and an increased frequency of plasmacytoid dendritic cells. This work demonstrates the utility and power of high-dimensional mass cytometry analysis to interrogate the cellular interactions that are associated with allergic sensitization and clinical food allergy in the first year of life.
Cerebellum-enriched protein INPP5A contributes to selective neuropathology in mouse model of spinocerebellar ataxias type 17
Authors: Liu Qiong , Huang Shanshan , Yin Peng , Yang Su , Zhang Jennifer , Jing Liang , Cheng Siying , Tang Beisha , Li Xiao-Jiang , Pan Yongcheng , Li Shihua 
Published: February 2020

AbstractSpinocerebellar ataxias 17 (SCA17) is caused by polyglutamine (polyQ) expansion in the TATA box-binding protein (TBP). The selective neurodegeneration in the cerebellum in SCA17 raises the question of why ubiquitously expressed polyQ proteins can cause neurodegeneration in distinct brain regions in different polyQ diseases. By expressing mutant TBP in different brain regions in adult wild-type mice via stereotaxic injection of adeno-associated virus, we found that adult cerebellar neurons are particularly vulnerable to mutant TBP. In SCA17 knock-in mice, mutant TBP inhibits SP1-mediated gene transcription to down-regulate INPP5A, a protein that is highly abundant in the cerebellum. CRISPR/Cas9-mediated deletion of Inpp5a in the cerebellum of wild-type mice leads to Purkinje cell degeneration, and Inpp5a overexpression decreases inositol 1,4,5-trisphosphate (IP3) levels and ameliorates Purkinje cell degeneration in SCA17 knock-in mice. Our findings demonstrate the important contribution of a tissue-specific protein to the polyQ protein-mediated selective neuropathology.
A comparative genomics methodology reveals a widespread family of membrane-disrupting T6SS effectors
Authors: Fridman Chaya M. , Keppel Kinga , Gerlic Motti , Bosis Eran , Salomon Dor 
Published: February 2020

AbstractGram-negative bacteria deliver effectors via the type VI secretion system (T6SS) to outcompete their rivals. Each bacterial strain carries a different arsenal of effectors; the identities of many remain unknown. Here, we present an approach to identify T6SS effectors encoded in bacterial genomes of interest, without prior knowledge of the effectors’ domain content or genetic neighborhood. Our pipeline comprises a comparative genomics analysis followed by screening using a surrogate T6SS+ strain. Using this approach, we identify an antibacterial effector belonging to the T6SS1 of Vibrio parahaemolyticus, representing a widespread family of T6SS effectors sharing a C-terminal domain that we name Tme (Type VI membrane-disrupting effector). Tme effectors function in the periplasm where they intoxicate bacteria by disrupting membrane integrity. We believe our approach can be scaled up to identify additional T6SS effectors in various bacterial genera.
A toxin-antidote CRISPR gene drive system for regional population modification
Authors: Champer Jackson , Lee Esther , Yang Emily , Liu Chen , Clark Andrew G. , Messer Philipp W. 
Published: February 2020

AbstractEngineered gene drives based on a homing mechanism could rapidly spread genetic alterations through a population. However, such drives face a major obstacle in the form of resistance against the drive. In addition, they are expected to be highly invasive. Here, we introduce the Toxin-Antidote Recessive Embryo (TARE) drive. It functions by disrupting a target gene, forming recessive lethal alleles, while rescuing drive-carrying individuals with a recoded version of the target. Modeling shows that such drives will have threshold-dependent invasion dynamics, spreading only when introduced above a fitness-dependent frequency. We demonstrate a TARE drive in Drosophila with 88-95% transmission by female heterozygotes. This drive was able to spread through a large cage population in just six generations following introduction at 24% frequency without any apparent evolution of resistance. Our results suggest that TARE drives constitute promising candidates for the development of effective, flexible, and regionally confinable drives for population modification.
A multi-omics dataset of heat-shock response in the yeast RNA binding protein Mip6
Authors: Nuño-Cabanes Carme , Ugidos Manuel , Tarazona Sonia , Martín-Expósito Manuel , Ferrer Alberto , Rodríguez-Navarro Susana , Conesa Ana 
Published: February 2020

AbstractGene expression is a biological process regulated at different molecular levels, including chromatin accessibility, transcription, and RNA maturation and transport. In addition, these regulatory mechanisms have strong links with cellular metabolism. Here we present a multi-omics dataset that captures different aspects of this multi-layered process in yeast. We obtained RNA-seq, metabolomics, and H4K12ac ChIP-seq data for wild-type and mip6Δ strains during a heat-shock time course. Mip6 is an RNA-binding protein that contributes to RNA export during environmental stress and is informative of the contribution of post-transcriptional regulation to control cellular adaptations to environmental changes. The experiment was performed in quadruplicate, and the different omics measurements were obtained from the same biological samples, which facilitates the integration and analysis of data using covariance-based methods. We validate our dataset by showing that ChIP-seq, RNA-seq and metabolomics signals recapitulate existing knowledge about the response of ribosomal genes and the contribution of trehalose metabolism to heat stress. Raw data, processed data and preprocessing scripts are made available.
A multi-scale model for determining the effects of pathophysiology and metabolic disorders on tumor growth
Authors: Nikmaneshi Mohammad Reza , Firoozabadi Bahar , Mozafari Aliasghar , Munn Lance L. 
Published: February 2020

AbstractThe search for efficient chemotherapy drugs and other anti-cancer treatments would benefit from a deeper understanding of the tumor microenvironment (TME) and its role in tumor progression. Because in vivo experimental methods are unable to isolate or control individual factors of the TME and in vitro models often do not include all the contributing factors, some questions are best addressed with systems biology mathematical models. In this work, we present a new fully-coupled, agent-based, multi-scale mathematical model of tumor growth, angiogenesis and metabolism that includes important aspects of the TME spanning subcellular-, cellular- and tissue-level scales. The mathematical model is computationally implemented for a three-dimensional TME, and a double hybrid continuous-discrete (DHCD) method is applied to solve the governing equations. The model recapitulates the distinct morphological and metabolic stages of a solid tumor, starting with an avascular tumor and progressing through angiogenesis and vascularized tumor growth. To examine the robustness of the model, we simulated normal and abnormal blood conditions, including hyperglycemia/hypoglycemia, hyperoxemia/hypoxemia, and hypercarbia/hypocarbia – conditions common in cancer patients. The results demonstrate that tumor progression is accelerated by hyperoxemia, hyperglycemia and hypercarbia but inhibited by hypoxemia and hypoglycemia; hypocarbia had no appreciable effect. Because of the importance of interstitial fluid flow in tumor physiology, we also examined the effects of hypo- or hypertension, and the impact of decreased hydraulic conductivity common in desmoplastic tumors. The simulations show that chemotherapy-increased blood pressure, or reduction of interstitial hydraulic conductivity increase tumor growth rate and contribute to tumor malignancy.
Perceptual mechanisms of social affiliation in zebrafish
Authors: Nunes Ana Rita , Carreira Leonor , Anbalagan Savani , Blechman Janna , Levkowitz Gil , Oliveira Rui F. 
Published: February 2020

AbstractSocial living animals need to recognize the presence of conspecifics in the environment in order to engage in adaptive social interactions. Social cues can be detected through different sensory modalities, including vision. Two main visual features can convey information about the presence of conspecifics: body form and biological motion (BM). Given the role that oxytocin plays in social behavior regulation across vertebrates, particularly in the salience and reward values of social stimuli, we hypothesized that it may also be involved in the modulation of perceptual mechanisms for conspecific detection. Here, using videoplaybacks, we assessed the role of conspecific form and BM in zebrafish social affiliation, and how oxytocin regulates the perception of these cues. We demonstrated that while each visual cue is important for social attraction, BM promotes a higher fish engagement than the static conspecific form alone. Moreover, using a mutant line for one of the two oxytocin receptors, we show that oxytocin signaling is involved in the regulation of BM detection but not conspecific form recognition. In summary, our results indicate that, apart from oxytocin role in the regulation of social behaviors through its effect on higher-order cognitive mechanisms, it may regulate social behavior by modulating very basic perceptual mechanisms underlying the detection of socially-relevant cues.
Initial interaction of citrate-coated iron oxide nanoparticles with the glycocalyx of THP-1 monocytes assessed by real-time magnetic particle spectroscopy and electron microscopy
Authors: Poller Wolfram C. , Löwa Norbert , Schleicher Moritz , Münster-Wandowski Agnieszka , Taupitz Matthias , Stangl Verena , Ludwig Antje , Wiekhorst Frank 
Published: February 2020

AbstractInteraction with biological material can alter physicochemical parameters of magnetic nanoparticles and might thereby change their magnetic behavior with potentially important implications for various nanoparticle applications. Little is known about changes of the magnetic behavior that occur during the initial phase of cell binding and uptake. We investigate the magnetic behavior of very small superparamagnetic iron-oxide nanoparticles (VSOP) during initial contact with THP-1 monocytes. We combine real-time magnetic particle spectroscopy (MPS), a fast and sensitive method for specific detection of magnetic nanoparticles in biological specimen with high-pressure-freezing/freeze-substitution transmission electron microscopy (HPF/FS-TEM), enabling us to generate snapshots of the interaction of VSOP with the cellular glycocalyx. MPS reveals significant changes of the dynamic magnetic behavior within seconds after VSOP injection into monocyte suspensions that correlate with the formation of nanoparticle clusters in the glycocalyx. The combination of real-time MPS and HPF/FS-TEM provides an ideal platform to analyze magnetic behaviors of nanoparticles upon interaction with cells and tissues.
Identifying relationships between imaging phenotypes and lung cancer-related mutation status: EGFR and KRAS
Authors: Pinheiro Gil , Pereira Tania , Dias Catarina , Freitas Cláudia , Hespanhol Venceslau , Costa José Luis , Cunha António , Oliveira Hélder P. 
Published: February 2020

AbstractEGFR and KRAS are the most frequently mutated genes in lung cancer, being active research topics in targeted therapy. The biopsy is the traditional method to genetically characterise a tumour. However, it is a risky procedure, painful for the patient, and, occasionally, the tumour might be inaccessible. This work aims to study and debate the nature of the relationships between imaging phenotypes and lung cancer-related mutation status. Until now, the literature has failed to point to new research directions, mainly consisting of results-oriented works in a field where there is still not enough available data to train clinically viable models. We intend to open a discussion about critical points and to present new possibilities for future radiogenomics studies. We conducted high-dimensional data visualisation and developed classifiers, which allowed us to analyse the results for EGFR and KRAS biological markers according to different combinations of input features. We show that EGFR mutation status might be correlated to CT scans imaging phenotypes; however, the same does not seem to hold for KRAS mutation status. Also, the experiments suggest that the best way to approach this problem is by combining nodule-related features with features from other lung structures.
Segmental Bioelectrical Impedance Spectroscopy to Monitor Fluid Status in Heart Failure
Authors: Zink Matthias Daniel , König Fabienne , Weyer Sören , Willmes Klaus , Leonhardt Steffen , Marx Nikolaus , Napp Andreas 
Published: February 2020

AbstractBioelectrical impedance spectroscopy (BIS) measures body composition, including fluid status. Acute decompensated heart failure (ADHF) is associated with fluid overload in different body compartments. This investigation aimed to evaluate the feasibility of measuring and monitoring fluid accumulation in patients with ADHF using BIS. The extracellular impedance as a surrogate marker for fluid accumulation was measured in 67 participants (25 healthy reference volunteers and 42 patients admitted with ADHF) using BIS in the “transthoracic”, “foot-to-foot”, “whole-body” and “hand-to-hand” segments. At baseline, BIS showed significantly lower extracellular resistance values for the “whole-body” (P < 0.001), “foot-to-foot” (P = 0.03), “hand-to-hand” (P < 0.001) and “transthoracic” (P = 0.014) segments in patients with ADHF than the reference cohort, revealing a specific pattern for peripheral, central and general fluid accumulation. The “foot-to-foot” (AUC = 0.8, P < 0.001) and “hand-to-hand” (AUC = 0.74, P = 0.04) segments indicated compartments of fluid accumulation with good prediction. During cardiac recompensation, BIS values changed significantly and were in line with routine parameters for monitoring ADHF. Mean bodyweight change per day correlated moderately to good with BIS values in the “whole-body” (r = −0.4), “foot-to-foot” (r = −0.8) and “transthoracic” (r = −0.4) segments. Based on our analysis, we conclude that measuring and monitoring fluid accumulation in ADHF using segmental BIS is feasible and correlates with clinical parameters during recompensation.
Synthesis, characterization, and crystallization behaviors of poly(D-lactic acid)-based triblock copolymer
Authors: Wu Yifan , Li Lingtong , Chen Shaopeng , Qin Jun , Chen Xiaolang , Zhou Dengfeng , Wu Hong 
Published: February 2020

AbstractPoly(D-lactic acid) (PDLA) with different polyethylene glycol (PEG) segment synthesized PDLA-PEG-PDLA triblock copolymer through the ring-opening reaction ofD-LA and PEG will be used as a toughening modifier. The microstructure, crystal structures and crystallization behaviors of this triblock copolymer were investigated by Fourier transform infrared (FTIR) spectroscopy, nuclear magnetic resonance (NMR) spectroscopy, X-ray diffraction (XRD), differential scanning calorimetry (DSC) and polarized optical microscopy (POM). The triblock copolymer is synthesized from the appearance of CH2stretching vibration peak at 2910 cm−1and C-O stretching vibration peak at 1200 cm−1from PEG in FTIR spectra. Moreover, the chemical shift that is about 3.6 ppm in1H NMR and 68.8ppm in13C NMR proves this matter. The results of XRD and DSC reveal that PDLA and PEG are crystallized separately, and are not fully compatible, and microphase separation has occurred in this triblock copolymer. PEG can induce the triblock copolymer to accelerate the rate of crystallization, allowing it to crystallize more completely in the same amount of time. When the molecular weight of PEG is 6000 or the ratio ofD-LA/PEG is 1/1, the crystallizability of PDLA-PEG-PDLA triblock copolymer is the best.
Subcellular proteomics combined with bioenergetic phenotyping reveals protein biomarkers of respiratory insufficiency in the setting of proofreading-deficient mitochondrial polymerase
Authors: McLaughlin Kelsey L. , Kew Kimberly A. , McClung Joseph M. , Fisher-Wellman Kelsey H. 
Published: February 2020

AbstractThe mitochondrial mutator mouse is a well-established model of premature aging. In addition to accelerated aging, these mice develop hypertrophic cardiomyopathy at ~13 months of age, presumably due to overt mitochondrial dysfunction. Despite evidence of bioenergetic disruption within heart mitochondria, there is little information about the underlying changes to the mitochondrial proteome that either directly underly or predict respiratory insufficiency in mutator mice. Herein, nLC-MS/MS was used to interrogate the mitochondria-enriched proteome of heart and skeletal muscle of aged mutator mice. The mitochondrial proteome from heart tissue was then correlated with respiratory conductance data to identify protein biomarkers of respiratory insufficiency. The majority of downregulated proteins in mutator mitochondria were subunits of respiratory complexes I and IV, including both nuclear and mitochondrial-encoded proteins. Interestingly, the mitochondrial-encoded complex V subunits, were unchanged or upregulated in mutator mitochondria, suggesting a robustness to mtDNA mutation. Finally, the proteins most strongly correlated with respiratory conductance were PPM1K, NDUFB11, and C15orf61. These results suggest that mitochondrial mutator mice undergo a specific loss of mitochondrial complexes I and IV that limit their respiratory function independent of an upregulation of complex V. Additionally, the role of PPM1K in responding to mitochondrial stress warrants further exploration.
Early and Quantitative Assessment of Myocardial Deformation in Essential Hypertension Patients by Using Cardiovascular Magnetic Resonance Feature Tracking
Authors: Liu Huina , Wang Jiajia , Pan Yukun , Ge Yinghui , Guo Zhiping , Zhao Shihua 
Published: February 2020

AbstractThe aims of the study were to identify subclinical global systolic function abnormalities and evaluate influencing factors associated with left ventricular (LV) strain parameters in hypertensive subjects using cardiovascular magnetic resonance imaging feature tracking (CMR-FT). The study enrolled 57 patients with essential hypertension (mean age: 43.04 ± 10.90 years; 35 males) and 26 healthy volunteers (mean age: 38.69 ± 10.44 years; 11 males) who underwent clinical evaluation and CMR examination. Compared with controls, hypertensive patients had significantly impaired myocardial strain values while ejection fraction (EF) did not differ. After multivariate regression analyses adjustment for confounders, the global radial strains (GRS) was independently associated with the mean arterial pressure (MAP) and left ventricular mass index (LVMI) (β = −0.219, p = 0.009 and β = −0.224, p = 0.015, respectively; Adjusted R2 = 0.4); the global circumferential strains (GCS) was also independently associated with the MAP and LVMI (β = 0.084, p = 0.002 and β = 0.073, p = 0.01, respectively; Adjusted R2 = 0.439); the global longitudinal strains (GLS) was independently associated with the Age and MAP (β = 0.065, p = 0.021 and β = 0.077, p = 0.009, respectively; Adjusted R2 = 0.289). Myocardial strain can early detect the myocardial damage and may be an appropriate target for preventive strategies before abnormalities of EF.
The effect of sediment grain properties and porewater flow on microbial abundance and respiration in permeable sediments
Authors: Ahmerkamp Soeren , Marchant Hannah K , Peng Chao , Probandt David , Littmann Sten , Kuypers Marcel M. M. , Holtappels Moritz 
Published: February 2020

AbstractSandy sediments cover 50–60% of the continental shelves and are highly efficient bioreactors in which organic carbon is remineralized and inorganic nitrogen is reduced to N2. As such they seem to play an important role, buffering the open ocean from anthropogenic nitrogen inputs and likely remineralizing the vast amounts of organic matter formed in the highly productive surface waters. To date however, little is known about the interrelation between porewater transport, grain properties and microbial colonization and the consequences for remineralization rates in sandy sediments. To constrain the effect of theses factors on remineralization in silicate sands, we incubated North Sea sediments in flow-through reactors after separating into five different grain size fractions. Bulk sediment and sediment grain properties were measured along with microbial colonization and cell abundances, oxygen consumption and denitrification rates. Volumetric oxygen consumption ranged from 14 to 77 µmol O2 l−1 h−1 while nitrogen-loss via denitrification was between 3.7 and 8.4 µmol N l−1 h−1. Oxygen consumption and denitrification rates were linearly correlated to the microbial cell abundances, which ranged from 2.9 to 5.4·108 cells cm−3. We found, that cell abundance and consumption rates in sandy sediments are influenced (i) by the surface area available for microbial colonization and (ii) by the exposure of these surfaces to the solute-supplying porewater flow. While protective structures such as cracks and depressions promote microbial colonization, the oxygen demand is only met by good ventilation of these structures, which is supported by a high sphericity of the grains. Based on our results, spherical sand grains with small depressions, i.e. golf ball like structures, provide the optimal supporting mineral structure for microorganisms on continental shelves.