bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterization of the Pore Structure of Porous Media Using non‐Newtonian Fluids
Authors: Hauswirth Scott C. , Abou Najm Majdi R. , Miller Cass T.
Published: August 2019

We demonstrate a simple, cheap method for pore size characterization of porous media that generates a distribution of pore radii for improved flow and transport modeling. The new method for pore structure characterization utilizes recent theoretical developments in non‐Newtonian fluids. Numerical evaluations and validations with synthetic porous media showed potential for obtaining a distribution of effective pore radii and their contribution to total flow only by complementing water with non‐Newtonian fluids in saturated infiltration experiments. To demonstrate this ability on real sands, a series of one‐dimensional column experiments was conducted with varying porous medium packings, including Accusands and a polydisperse sand/glass bead mixture. For each packing, distilled water and varying concentrations of guar and xanthan gum were injected over a range of flow rates and pressure gradients. The model‐generated pore radii were compared with pore radius distributions measured by X‐ray microcomputed tomography (μCT), with results demonstrating good agreement between the model and μCT data. Simulations of saturated water flow and drainage curves using model‐generated pore radii compared favorably to experimental data, with errors typically between 2% and 10% for single‐phase flow and approaching the error of the μCT measured radius distributions for the drainage curves.
IFN-β is a macrophage-derived effector cytokine facilitating the resolution of bacterial inflammation
Authors: Kumaran Satyanarayanan Senthil , El Kebir Driss , Soboh Soaad , Butenko Sergei , Sekheri Meriem , Saadi Janan , Peled Neta , Assi Simaan , Othman Amira , Schif-Zuck Sagie , Feuermann Yonatan , Barkan Dalit , Sher Noa , Filep János G. , Ariel Amiram
Published: August 2019

The uptake of apoptotic polymorphonuclear cells (PMN) by macrophages is critical for timely resolution of inflammation. High-burden uptake of apoptotic cells is associated with loss of phagocytosis in resolution phase macrophages. Here, using a transcriptomic analysis of macrophage subsets, we show that non-phagocytic resolution phase macrophages express a distinct IFN-β-related gene signature in mice. We also report elevated levels of IFN-β in peritoneal and broncho-alveolar exudates in mice during the resolution of peritonitis and pneumonia, respectively. Elimination of endogenous IFN-β impairs, whereas treatment with exogenous IFN-β enhances, bacterial clearance, PMN apoptosis, efferocytosis and macrophage reprogramming. STAT3 signalling in response to IFN-β promotes apoptosis of human PMNs. Finally, uptake of apoptotic cells promotes loss of phagocytic capacity in macrophages alongside decreased surface expression of efferocytic receptors in vivo. Collectively, these results identify IFN-β produced by resolution phase macrophages as an effector cytokine in resolving bacterial inflammation.
An oxalate cathode for lithium ion batteries with combined cationic and polyanionic redox
Authors: Yao Wenjiao , Armstrong A. Robert , Zhou Xiaolong , Sougrati Moulay-Tahar , Kidkhunthod Pinit , Tunmee Sarayut , Sun Chenghua , Sattayaporn Suchinda , Lightfoot Philip , Ji Bifa , Jiang Chunlei , Wu Nanzhong , Tang Yongbing , Cheng Hui-Ming
Published: August 2019

The growing demand for advanced lithium-ion batteries calls for the continued development of high-performance positive electrode materials. Polyoxyanion compounds are receiving considerable interest as alternative cathodes to conventional oxides due to their advantages in cost, safety and environmental friendliness. However, polyanionic cathodes reported so far rely heavily upon transition-metal redox reactions for lithium transfer. Here we show a polyanionic insertion material, Li2Fe(C2O4)2, in which in addition to iron redox activity, the oxalate group itself also shows redox behavior enabling reversible charge/discharge and high capacity without gas evolution. The current study gives oxalate a role as a family of cathode materials and suggests a direction for the identification and design of electrode materials with polyanionic frameworks.
Hydrogen peroxide release by bacteria suppresses inflammasome-dependent innate immunity
Authors: Erttmann Saskia F. , Gekara Nelson O.
Published: August 2019

Hydrogen peroxide (H2O2) has a major function in host-microbial interactions. Although most studies have focused on the endogenous H2O2produced by immune cells to kill microbes, bacteria can also produce H2O2. How microbial H2O2influences the dynamics of host-microbial interactions is unclear. Here we show that H2O2released byStreptococcus pneumoniaeinhibits inflammasomes, key components of the innate immune system, contributing to the pathogen colonization of the host. We also show that the oral commensal H2O2-producing bacteriaStreptococcus oraliscan block inflammasome activation. This study uncovers an unexpected role of H2O2in immune suppression and demonstrates how, through this mechanism, bacteria might restrain the immune system to co-exist with the host.
Cryoprotectant enables structural control of porous scaffolds for exploration of cellular mechano-responsiveness in 3D
Authors: Jiang Shumeng , Lyu Cheng , Zhao Peng , Li Wenjing , Kong Wenyu , Huang Chenyu , Genin Guy M. , Du Yanan
Published: August 2019

Despite the wide applications, systematic mechanobiological investigation of 3D porous scaffolds has yet to be performed due to the lack of methodologies for decoupling the complex interplay between structural and mechanical properties. Here, we discover the regulatory effect of cryoprotectants on ice crystal growth and use this property to realize separate control of the scaffold pore size and stiffness. Fibroblasts and macrophages are sensitive to both structural and mechanical properties of the gelatin scaffolds, particularly to pore sizes. Interestingly, macrophages within smaller and softer pores exhibit pro-inflammatory phenotype, whereas anti-inflammatory phenotype is induced by larger and stiffer pores. The structure-regulated cellular mechano-responsiveness is attributed to the physical confinement caused by pores or osmotic pressure. Finally, in vivo stimulation of endogenous fibroblasts and macrophages by implanted scaffolds produce mechano-responses similar to the corresponding cells in vitro, indicating that the physical properties of scaffolds can be leveraged to modulate tissue regeneration.
Functional genetic variants can mediate their regulatory effects through alteration of transcription factor binding
Authors: Johnston Andrew D. , Simões-Pires Claudia A. , Thompson Taylor V. , Suzuki Masako , Greally John M.
Published: August 2019

Functional variants in the genome are usually identified by their association with local gene expression, DNA methylation or chromatin states. DNA sequence motif analysis and chromatin immunoprecipitation studies have provided indirect support for the hypothesis that functional variants alter transcription factor binding to exert their effects. In this study, we provide direct evidence that functional variants can alter transcription factor binding. We identify a multifunctional variant within theTBC1D4gene encoding a canonical NFκB binding site, and edited it using CRISPR-Cas9 to remove this site. We show that this editing reducesTBC1D4expression, local chromatin accessibility and binding of the p65 component of NFκB. We then used CRISPR without genomic editing to guide p65 back to the edited locus, demonstrating that this re-targeting, occurring ~182 kb from the gene promoter, is enough to restore the function of the locus, supporting the central role of transcription factors mediating the effects of functional variants.
Galectin-3 is required for the microglia-mediated brain inflammation in a model of Huntington’s disease
Authors: Siew Jian Jing , Chen Hui-Mei , Chen Huan-Yuan , Chen Hung-Lin , Chen Chiung-Mei , Soong Bing-Wen , Wu Yih-Ru , Chang Ching-Pang , Chan Yi-Chen , Lin Chun-Hung , Liu Fu-Tong , Chern Yijuang
Published: August 2019

Huntington’s disease (HD) is a neurodegenerative disorder that manifests with movement dysfunction. The expression of mutant Huntingtin (mHTT) disrupts the functions of brain cells. Galectin-3 (Gal3) is a lectin that has not been extensively explored in brain diseases. Herein, we showed that the plasma Gal3 levels of HD patients and mice correlated with disease severity. Moreover, brain Gal3 levels were higher in patients and mice with HD than those in controls. The up-regulation of Gal3 in HD mice occurred before motor impairment, and its level remained high in microglia throughout disease progression. The cell-autonomous up-regulated Gal3 formed puncta in damaged lysosomes and contributed to inflammation through NFκB- and NLRP3 inflammasome-dependent pathways. Knockdown of Gal3 suppressed inflammation, reduced mHTT aggregation, restored neuronal DARPP32 levels, ameliorated motor dysfunction, and increased survival in HD mice. Thus, suppression of Gal3 ameliorates microglia-mediated pathogenesis, which suggests that Gal3 is a novel druggable target for HD.
Degron-tagged reporters probe membrane topology and enable the specific labelling of membrane-wrapped structures
Authors: Beer Katharina B. , Fazeli Gholamreza , Judasova Kristyna , Irmisch Linda , Causemann Jona , Mansfeld Jörg , Wehman Ann M.
Published: August 2019

Visualization of specific organelles in tissues over background fluorescence can be challenging, especially when reporters localize to multiple structures. Instead of trying to identify proteins enriched in specific membrane-wrapped structures, we use a selective degradation approach to remove reporters from the cytoplasm or nucleus of C. elegans embryos and mammalian cells. We demonstrate specific labelling of organelles using degron-tagged reporters, including extracellular vesicles, as well as individual neighbouring membranes. These degron-tagged reporters facilitate long-term tracking of released cell debris and cell corpses, even during uptake and phagolysosomal degradation. We further show that degron protection assays can probe the topology of the nuclear envelope and plasma membrane during cell division, giving insight into protein and organelle dynamics. As endogenous and heterologous degrons are used in bacteria, yeast, plants, and animals, degron approaches can enable the specific labelling and tracking of proteins, vesicles, organelles, cell fragments, and cells in many model systems.
LncRNA GLCC1 promotes colorectal carcinogenesis and glucose metabolism by stabilizing c-Myc
Authors: Tang Jiayin , Yan Tingting , Bao Yujie , Shen Chaoqin , Yu Chenyang , Zhu Xiaoqiang , Tian Xianglong , Guo Fangfang , Liang Qian , Liu Qiang , Zhong Ming , Chen Jinxian , Ge Zhizheng , Li Xiaobo , Chen Xiaoyu , Cui Yun , Chen Yingxuan , Zou Weiping , Chen Haoyan , Hong Jie , Fang Jing-Yuan
Published: August 2019

Long non-coding RNAs (lncRNAs) contribute to colorectal cancer (CRC). However, the role of lncRNAs in CRC metabolism, especially glucose metabolism remains largely unknown. In this study, we identify a lncRNA, GLCC1, which is significantly upregulated under glucose starvation in CRC cells, supporting cell survival and proliferation by enhancing glycolysis. Mechanistically, GLCC1 stabilizes c-Myc transcriptional factor from ubiquitination by direct interaction with HSP90 chaperon and further specifies the transcriptional modification pattern on c-Myc target genes, such asLDHA, consequently reprogram glycolytic metabolism for CRC proliferation. Clinically, GLCC1 is associated with tumorigenesis, tumor size and predicts poor prognosis. Thus, GLCC1 is mechanistically, functionally, and clinically oncogenic in colorectal cancer. Targeting GLCC1 and its pathway may be meaningful for treating patients with colorectal cancer.
Evolution of fast root gravitropism in seed plants
Authors: Zhang Yuzhou , Xiao Guanghui , Wang Xiaojuan , Zhang Xixi , Friml Jiří
Published: August 2019

An important adaptation during colonization of land by plants is gravitropic growth of roots, which enabled roots to reach water and nutrients, and firmly anchor plants in the ground. Here we provide insights into the evolution of an efficient root gravitropic mechanism in the seed plants. Architectural innovation, with gravity perception constrained in the root tips along with a shootward transport route for the phytohormone auxin, appeared only upon the emergence of seed plants. Interspecies complementation and protein domain swapping revealed functional innovations within the PIN family of auxin transporters leading to the evolution of gravitropism-specific PINs. The unique apical/shootward subcellular localization of PIN proteins is the major evolutionary innovation that connected the anatomically separated sites of gravity perception and growth response via the mobile auxin signal. We conclude that the crucial anatomical and functional components emerged hand-in-hand to facilitate the evolution of fast gravitropic response, which is one of the major adaptations of seed plants to dry land.
Global ecological predictors of the soil priming effect
Authors: Bastida Felipe , García Carlos , Fierer Noah , Eldridge David J. , Bowker Matthew A. , Abades Sebastián , Alfaro Fernando D. , Asefaw Berhe Asmeret , Cutler Nick A. , Gallardo Antonio , García-Velázquez Laura , Hart Stephen C. , Hayes Patrick E. , Hernández Teresa , Hseu Zeng-Yei , Jehmlich Nico , Kirchmair Martin , Lambers Hans , Neuhauser Sigrid , Peña-Ramírez Víctor M. , Pérez Cecilia A. , Reed Sasha C. , Santos Fernanda , Siebe Christina , Sullivan Benjamin W. , Trivedi Pankaj , Vera Alfonso , Williams Mark A. , Luis Moreno José , Delgado-Baquerizo Manuel
Published: August 2019

Identifying the global drivers of soil priming is essential to understanding C cycling in terrestrial ecosystems. We conducted a survey of soils across 86 globally-distributed locations, spanning a wide range of climates, biotic communities, and soil conditions, and evaluated the apparent soil priming effect using13C-glucose labeling. Here we show that the magnitude of the positive apparent priming effect (increase in CO2release through accelerated microbial biomass turnover) was negatively associated with SOC content and microbial respiration rates. Our statistical modeling suggests that apparent priming effects tend to be negative in more mesic sites associated with higher SOC contents. In contrast, a single-input of labile C causes positive apparent priming effects in more arid locations with low SOC contents. Our results provide solid evidence that SOC content plays a critical role in regulating apparent priming effects, with important implications for the improvement of C cycling models under global change scenarios.
InSe as a case between 3D and 2D layered crystals for excitons
Authors: Shubina T. V. , Desrat W. , Moret M. , Tiberj A. , Briot O. , Davydov V. Yu. , Platonov A. V. , Semina M. A. , Gil B.
Published: August 2019

InSe is a promising material in many aspects where the role of excitons is decisive. Here we report the sequential appearance in its luminescence of the exciton, the biexciton, and the P-band of the exciton-exciton scattering while the excitation power increases. The strict energy and momentum conservation rules of the P-band are used to reexamine the exciton binding energy. The new value ≥20 meV is markedly higher than the currently accepted one (14 meV), being however well consistent with the robustness of the excitons up to room temperature. A peak controlled by the Sommerfeld factor is found near the bandgap (~1.36 eV). Our findings supported by theoretical calculations taking into account the anisotropic material parameters question the pure three-dimensional character of the exciton in InSe, assumed up to now. The refined character and parameters of the exciton are of paramount importance for the successful application of InSe in nanophotonics.
Wearable multifunctional printed graphene sensors
Authors: Kaidarova Altynay , Khan Mohammed Asadullah , Marengo Marco , Swanepoel Liam , Przybysz Alexander , Muller Cobus , Fahlman Andreas , Buttner Ulrich , Geraldi Nathan R. , Wilson Rory P. , Duarte Carlos M. , Kosel Jurgen
Published: August 2019

The outstanding properties of graphene have initiated myriads of research and development; yet, its economic impact is hampered by the difficulties encountered in production and practical application. Recently discovered laser-induced graphene is generated by a simple printing process on flexible and lightweight polyimide films. Exploiting the electrical features and mechanical pliability of LIG on polyimide, we developed wearable resistive bending sensors that pave the way for many cost-effective measurement systems. The versatile sensors we describe can be utilized in a wide range of configurations, including measurement of force, deflection, and curvature. The deflection induced by different forces and speeds is effectively sensed through a resistance measurement, exploiting the piezoresistance of the printed graphene electrodes. The LIG sensors possess an outstanding range for strain measurements reaching >10% A double-sided electrode concept was developed by printing the same electrodes on both sides of the film and employing difference measurements. This provided a large bidirectional bending response combined with temperature compensation. Versatility in geometry and a simple fabrication process enable the detection of a wide range of flow speeds, forces, and deflections. The sensor response can be easily tuned by geometrical parameters of the bending sensors and the LIG electrodes. As a wearable device, LIG bending sensors were used for tracking body movements. For underwater operation, PDMS-coated LIG bending sensors were integrated with ultra-low power aquatic tags and utilized in underwater animal speed monitoring applications, and a recording of the surface current velocity on a coral reef in the Red Sea.
Rescue-like Behaviour in Mice is Mediated by Their Interest in the Restraint Tool
Authors: Ueno Hiroshi , Suemitsu Shunsuke , Murakami Shinji , Kitamura Naoya , Wani Kenta , Takahashi Yu , Matsumoto Yosuke , Okamoto Motoi , Ishihara Takeshi
Published: August 2019

Acting without the expectation of compensation is called prosocial behaviour. Since prosocial behaviour requires high cognitive and social abilities, it has been thought to be only shown by primates. Although prosocial behaviour has been recently reported in rats, there are still questions regarding this finding. We demonstrated rescue-like behaviour in mice in a previous report. In this study, we investigated the motives underlying rescue-like behaviour for constrained cage-mates among mice. We prepared either a tube containing a ball of yarn or an opaque tube and assessed whether mice displayed the same rescue-like behaviour shown in the case of tube-restrained cage-mates. Mice did not open the lid of the tube containing the ball of yarn but opened the opaque tube lid. Mice showed a high interest in the tube in which the cage-mate had been restrained and prioritized staying in this tube rather than rescuing additional cage-mates. Oxytocin, which increases empathy, had no effect on the lid-opening behaviour. Thus, the rescue-like behaviour of mice is not based on empathy but is related to social interest in the cage-mate and the tube itself. These results suggest that rodent lid-opening behaviour may not conclusively prove the presence of prosocial behaviour.
Mechanism of CuO nano-particles on stimulating production of actinorhodin in Streptomyces coelicolor by transcriptional analysis
Authors: Liu Xiaomei , Tang Jingchun , Wang Lan , Liu Rutao
Published: August 2019

In this research, antibiotic-producing bacteria, Streptomyces coelicolor (S. coelicolor) M145, was exposed to copper oxide (CuO) particles to investigate the effects of nano-particles (NPs) on antibiotic production. Results showed that a higher yield of antibiotics was obtained with smaller particle sizes of CuO NPs. When exposed to 10 mg/L of 40 nm CuO NPs, the maximum amount of actinorhodin (ACT) obtained was 2.6 mg/L after 144 h, which was 2.0-fold greater than that of control. However, the process was inhibited when the concentration of CuO NPs was increased to higher than 20 mg/L. Transcriptome analysis showed that all the genes involved in the ACT cluster were significantly up-regulated after exposure to 10 mg/L NPs, which could be the direct cause of the increase of ACT production. Additionally, some genes related to the generation of acetyl-coA were up-regulated. In this way, CuO NPs led to an increase of secondary metabolites. The mechanism related to these changes indicated that nano-particle‒induced ROS and Cu2+ played synergetic roles in promoting ACT biosynthesis. This is a first report suggesting that CuO NPs had a significant effect on antibiotic production, which will be helpful in understanding the mechanism of antibiotic production in nature.
Random peptide mixtures entrapped within a copper-cuprite matrix: new antimicrobial agent against methicillin-resistant Staphylococcus aureus
Authors: Bauer Tal Stern , Menagen Barak , Avnir David , Hayouka Zvi
Published: August 2019

The emergence of global antibiotic resistance necessitates the urgent need to develop new and effective antimicrobial agents. Combination of two antimicrobial agents can potentially improve antimicrobial potency and mitigate the development of resistance. Therefore, we have utilized metal molecular doping methodology whereby antimicrobial random peptides mixture (RPMs) are entrapped in a bactericidal copper metal matrix. The copper/RPM composite exhibits greater antimicrobial activity toward methicillin-resistant Staphylococcus aureus (MRSA) than either copper or RPMs alone. Our findings indicate that this bactericidal antimicrobial biomaterial could be utilized to efficiently eradicate antibiotic-resistant pathogenic bacteria for health, agricultural and environmental applications.
Modeling and Cost Benefit Analysis to Guide Deployment of POC Diagnostics for Non-typhoidal Salmonella Infections with Antimicrobial Resistance
Authors: Manore Carrie , Graham Todd , Carr Alexa , Feryn Alicia , Jakhar Shailja , Mukundan Harshini , Highlander Hannah Callender
Published: August 2019

Invasive non-typhoidal Salmonella (NTS) is among the leading causes of blood stream infections in sub-Saharan Africa and other developing regions, especially among pediatric populations. Invasive NTS can be difficult to treat and have high case-fatality rates, in part due to emergence of strains resistant to broad-spectrum antibiotics. Furthermore, improper treatment contributes to increased antibiotic resistance and death. Point of care (POC) diagnostic tests that rapidly identify invasive NTS infection, and differentiate between resistant and non-resistant strains, may greatly improve patient outcomes and decrease resistance at the community level. Here we present for the first time a model for NTS dynamics in high risk populations that can analyze the potential advantages and disadvantages of four strategies involving POC diagnostic deployment, and the resulting impact on antimicrobial treatment for patients. Our analysis strongly supports the use of POC diagnostics coupled with targeted antibiotic use for patients upon arrival in the clinic for optimal patient and public health outcomes. We show that even the use of imperfect POC diagnostics can significantly reduce total costs and number of deaths, provided that the diagnostic gives results quickly enough that patients are likely to return or stay to receive targeted treatment.
FePO4 nanoparticles produced by an industrially scalable continuous-flow method are an available form of P and Fe for cucumber and maize plants
Authors: Sega Davide , Ciuffreda Giuseppe , Mariotto Gino , Baldan Barbara , Zamboni Anita , Varanini Zeno
Published: August 2019

Nanomaterials are widely used in medical and pharmaceutical fields, but their application in plant nutrition is at its infancy. Phosphorous (P) and iron (Fe) are essential mineral nutrients limiting in a wide range of conditions the yield of crops. Phosphate and Fe fertilizers to-date on the market display low efficiency (P fertilizers) and low persistence in soil (Fe fertilizers) and negatively affect the environment. In the tentative to overcome these problems, we developed a continuous industrially scalable method to produce FePO4NPs based on the rapid mixing of salt solutions in a mixing chamber. The process, that included the addition of citrate as capping agent allowed to obtain a stable suspension of NPs over the time. The NPs were tested for their effectiveness as P and Fe sources on two hydroponically grown crop species (cucumber and maize) comparing their effects to those exerted by non-nanometric FePO4(bulk FePO4). The results showed that FePO4NPs improved the availability of P and Fe, if compared to the non-nano counterpart, as demonstrated by leaf SPAD indexes, fresh biomasses and P and Fe contents in tissues. The results open a new avenue in the application of nanosized material in the field of plant nutrition and fertilization.
The population structure of Clostridium tetani deduced from its pan-genome
Authors: Chapeton-Montes Diana , Plourde Lucile , Bouchier Christiane , Ma Laurence , Diancourt Laure , Criscuolo Alexis , Popoff Michel Robert , Brüggemann Holger
Published: August 2019

Clostridium tetani produces a potent neurotoxin, the tetanus neurotoxin (TeNT) that is responsible for the worldwide neurological disease tetanus, but which can be efficiently prevented by vaccination with tetanus toxoid. Until now only one type of TeNT has been characterized and very little information exists about the heterogeneity among C. tetani strains. We report here the genome sequences of 26 C. tetani strains, isolated between 1949 and 2017 and obtained from different locations. Genome analyses revealed that the C. tetani population is distributed in two phylogenetic clades, a major and a minor one, with no evidence for clade separation based on geographical origin or time of isolation. The chromosome of C. tetani is highly conserved; in contrast, the TeNT-encoding plasmid shows substantial heterogeneity. TeNT itself is highly conserved among all strains; the most relevant difference is an insertion of four amino acids in the C-terminal receptor-binding domain in four strains that might impact on receptor-binding properties. Other putative virulence factors, including tetanolysin and collagenase, are encoded in all genomes. This study highlights the population structure of C. tetani and suggests that tetanus-causing strains did not undergo extensive evolutionary diversification, as judged from the high conservation of its main virulence factors.
In silico design and optimization of selective membranolytic anticancer peptides
Authors: Gabernet Gisela , Gautschi Damian , Müller Alex T. , Neuhaus Claudia S. , Armbrecht Lucas , Dittrich Petra S. , Hiss Jan A. , Schneider Gisbert
Published: August 2019

Membranolytic anticancer peptides represent a potential strategy in the fight against cancer. However, our understanding of the underlying structure-activity relationships and the mechanisms driving their cell selectivity is still limited. We developed a computational approach as a step towards the rational design of potent and selective anticancer peptides. This machine learning model distinguishes between peptides with and without anticancer activity. This classifier was experimentally validated by synthesizing and testing a selection of 12 computationally generated peptides. In total, 83% of these predictions were correct. We then utilized an evolutionary molecular design algorithm to improve the peptide selectivity for cancer cells. This simulated molecular evolution process led to a five-fold selectivity increase with regard to human dermal microvascular endothelial cells and more than ten-fold improvement towards human erythrocytes. The results of the present study advocate for the applicability of machine learning models and evolutionary algorithms to design and optimize novel synthetic anticancer peptides with reduced hemolytic liability and increased cell-type selectivity.
Spatio-temporal secondary instabilities near the Turing-Hopf bifurcation
Authors: Ledesma-Durán Aldo , Aragón José L.
Published: August 2019

In this work, we provide a framework to understand and quantify the spatiotemporal structures near the codimension-two Turing-Hopf point, resulting from secondary instabilities of Mixed Mode solutions of the Turing-Hopf amplitude equations. These instabilities are responsible for solutions such as (1) patterns which change their effective wavenumber while they oscillate as well as (2) phase instability combined with a spatial pattern. The quantification of these instabilities is based on the solution of the fourth order polynomial for the dispersion relation, which is solved using perturbation techniques. With the proposed methodology, we were able to identify and numerically corroborate that these two kinds of solutions are generalizations of the well known Eckhaus and Benjamin-Feir-Newell instabilities, respectively. Numerical simulations of the coupled system of real and complex Ginzburg-Landau equations are presented in space-time maps, showing quantitative and qualitative agreement with the predicted stability of the solutions. The relation with spatiotemporal intermittency and chaos is also illustrated.
Molecular integration of the anti-tropomyosin compound ATM-3507 into the coiled coil overlap region of the cancer-associated Tpm3.1
Authors: Janco Miro , Rynkiewicz Michael J. , Li Liang , Hook Jeff , Eiffe Eleanor , Ghosh Anita , Böcking Till , Lehman William J. , Hardeman Edna C. , Gunning Peter W.
Published: August 2019

Tropomyosins (Tpm) determine the functional capacity of actin filaments in an isoform-specific manner. The primary isoform in cancer cells is Tpm3.1 and compounds that target Tpm3.1 show promising results as anti-cancer agents both in vivo and in vitro. We have determined the molecular mechanism of interaction of the lead compound ATM-3507 with Tpm3.1-containing actin filaments. When present during co-polymerization of Tpm3.1 with actin, 3H-ATM-3507 is incorporated into the filaments and saturates at approximately one molecule per Tpm3.1 dimer and with an apparent binding affinity of approximately 2 µM. In contrast, 3H-ATM-3507 is poorly incorporated into preformed Tpm3.1/actin co-polymers. CD spectroscopy and thermal melts using Tpm3.1 peptides containing the C-terminus, the N-terminus, and a combination of the two forming the overlap junction at the interface of adjacent Tpm3.1 dimers, show that ATM-3507 shifts the melting temperature of the C-terminus and the overlap junction, but not the N-terminus. Molecular dynamic simulation (MDS) analysis predicts that ATM-3507 integrates into the 4-helix coiled coil overlap junction and in doing so, likely changes the lateral movement of Tpm3.1 across the actin surface resulting in an alteration of filament interactions with actin binding proteins and myosin motors, consistent with the cellular impact of ATM-3507.
A Novel Cell-Penetrating Antibody Fragment Inhibits the DNA Repair Protein RAD51
Authors: Pastushok Landon , Fu Yongpeng , Lin Leo , Luo Yu , DeCoteau John F. , Lee Ken , Geyer C. Ronald
Published: August 2019

DNA damaging chemotherapies are successful in cancer therapy, however, the damage can be reversed by DNA repair mechanisms that may be up-regulated in cancer cells. We hypothesized that inhibiting RAD51, a protein involved in homologous recombination DNA repair, would block DNA repair and restore the effectiveness of DNA damaging chemotherapy. We used phage-display to generate a novel synthetic antibody fragment that bound human RAD51 with high affinity (KD = 8.1 nM) and inhibited RAD51 ssDNA bindingin vitro. As RAD51 is an intracellular target, we created a corresponding intrabody fragment that caused a strong growth inhibitory phenotype on human cells in culture. We then used a novel cell-penetrating peptide “iPTD” fusion to generate a therapeutically relevant antibody fragment that effectively entered living cells and enhanced the cell-killing effect of a DNA alkylating agent. The iPTD may be similarly useful as a cell-penetrating peptide for other antibody fragments and open the door to numerous intracellular targets previously off-limits in living cells.
Confined System Analysis of a Predator-Prey Minimalistic Model
Authors: Mohapatra Siddhant , Mahapatra Pallab Sinha
Published: August 2019

In nature exists a properly defined food chain- an order of hunting and getting hunted. One such hunter-hunted pair is considered in this context and coordinated escape manoeuvres in response to predation is studied in case of a rarely examined confined system. Both the predator agent and prey agents are considered to be self-propelled particles moving in a viscous fluid. The state of motility when alive and passivity on death has been accounted for. A novel individual-based combination of Vicsek model and Boids flocking model is used for defining the self-propelling action and inter-agent interactions. The regimes observed at differing levels of co-ordination segregated by quantification of global order parameter are found to be in agreement with the extant literature. This study strives to understand the penalty on the collective motion due to the restraints employed by the rigid walls of the confinement and the predator’s hunting tactics. The success of any escape manoeuvre is dependent on the rate of information transfer and the strength of the agitation at the source of the manoeuvre. The rate of information transfer is studied as a function of co-ordination and the size of the influence zone and the source strength is studied as a function of escape acceleration activated on the agitated prey. The role of these factors in affecting survival rate of prey is given due coverage.
Neural indices of listening effort in noisy environments
Authors: Dimitrijevic Andrew , Smith Michael L. , Kadis Darren S. , Moore David R.
Published: August 2019

Listening in a noisy environment is challenging for individuals with normal hearing and can be a significant burden for those with hearing impairment. The extent to which this burden is alleviated by a hearing device is a major, unresolved issue for rehabilitation. Here, we found adult users of cochlear implants (CIs) self-reported listening effort during a speech-in-noise task that was positively related to alpha oscillatory activity in the left inferior frontal cortex, canonical Broca’s area, and inversely related to speech envelope coherence in the 2–5 Hz range originating in the superior-temporal plane encompassing auditory cortex. Left frontal cortex coherence in the 2–5 Hz range also predicted speech-in-noise identification. These data demonstrate that neural oscillations predict both speech perception ability in noise and listening effort.
A portable epigenetic switch for bistable gene expression in bacteria
Authors: Olivenza David R. , Nicoloff Hervé , Sánchez-Romero María Antonia , Cota Ignacio , Andersson Dan I. , Casadesús Josep
Published: August 2019

We describe a portable epigenetic switch based on opvAB, a Salmonella enterica operon that undergoes bistable expression under DNA methylation control. A DNA fragment containing the opvAB promoter and the opvAB upstream regulatory region confers bistability to heterologous genes, yielding OFF and ON subpopulations. Bistable expression under opvAB control is reproducible in Escherichia coli, showing that the opvAB switch can be functional in a heterologous host. Subpopulations of different sizes can be produced at will using engineered opvAB variants. Controlled formation of antibiotic-resistant and antibiotic-susceptible subpopulations may allow use of the opvAB switch in the study of bacterial heteroresistance to antibiotics.
Cells´ Flow and Immune Cell Priming under alternating g-forces in Parabolic Flight
Authors: Moser D. , Sun S. J. , Li N. , Biere K. , Hoerl M. , Matzel S. , Feuerecker M. , Buchheim J.-I. , Strewe C. , Thiel C. S. , Gao Y. X. , Wang C. Z. , Ullrich O. , Long M. , Choukèr A.
Published: August 2019

Gravitational stress in general and microgravity (µg) in particular are regarded as major stress factors responsible for immune system dysfunction in space. To assess the effects of alternating µg and hypergravity (hyper-g) on immune cells, the attachment of peripheral blood mononuclear cells (PBMCs) to adhesion molecules under flow conditions and the antigen-induced immune activation in whole blood were investigated in parabolic flight (PF). In contrast to hyper-g (1.8 g) and control conditions (1 g), flow and rolling speed of PBMCs were moderately accelerated during µg-periods which were accompanied by a clear reduction in rolling rate. Whole blood analyses revealed a “primed” state of monocytes after PF with potentiated antigen-induced pro-inflammatory cytokine responses. At the same time, concentrations of anti-inflammatory cytokines were increased and monocytes displayed a surface molecule pattern that indicated immunosuppression. The results suggest an immunologic counterbalance to avoid disproportionate immune responses. Understanding the interrelation of immune system impairing and enhancing effects under different gravitational conditions may support the design of countermeasures to mitigate immune deficiencies in space.
Episodic curiosity for avoiding asteroids: Per-trial information gain for choice outcomes drive information seeking
Authors: Holm Linus , Wadenholt Gustaf , Schrater Paul
Published: August 2019

Humans often appear to desire information for its own sake, but it is presently unclear what drives this desire. The important role that resolving uncertainty plays in stimulating information seeking has suggested a tight coupling between the intrinsic motivation to gather information and performance gains, construed as a drive for long-term learning. Using an asteroid-avoidance game that allows us to study learning and information seeking at an experimental time-scale, we show that the incentive for information-seeking can be separated from a long-term learning outcome, with information-seeking best predicted by per-trial outcome uncertainty. Specifically, participants were more willing to take time penalties to receive feedback on trials with increasing uncertainty in the outcome of their choices. We found strong group and individual level support for a linear relationship between feedback request rate and information gain as determined by per-trial outcome uncertainty. This information better reflects filling in the gaps of the episodic record of choice outcomes than long-term skill acquisition or assessment. Our results suggest that this easy to compute quantity can drive information-seeking, potentially allowing simple organisms to intelligently gather information for a diverse episodic record of the environment without having to anticipate the impact on future performance.
Electron energy increase in a laser wakefield accelerator using up-ramp plasma density profiles
Authors: Aniculaesei Constantin , Pathak Vishwa Bandhu , Kim Hyung Taek , Oh Kyung Hwan , Yoo Byung Ju , Brunetti Enrico , Jang Yong Ha , Hojbota Calin Ioan , Shin Jung Hun , Jeon Jong Ho , Cho Seongha , Cho Myung Hoon , Sung Jae Hee , Lee Seong Ku , Hegelich Björn Manuel , Nam Chang Hee
Published: August 2019

The phase velocity of the wakefield of a laser wakefield accelerator can, theoretically, be manipulated by shaping the longitudinal plasma density profile, thus controlling the parameters of the generated electron beam. We present an experimental method where using a series of shaped longitudinal plasma density profiles we increased the mean electron peak energy more than 50%, from 175 ± 1 MeV to 262 ± 10 MeV and the maximum peak energy from 182 MeV to 363 MeV. The divergence follows closely the change of mean energy and decreases from 58.9 ± 0.45 mrad to 12.6 ± 1.2 mrad along the horizontal axis and from 35 ± 0.3 mrad to 8.3 ± 0.69 mrad along the vertical axis. Particle-in-cell simulations show that a ramp in a plasma density profile can affect the evolution of the wakefield, thus qualitatively confirming the experimental results. The presented method can increase the electron energy for a fixed laser power and at the same time offer an energy tunable source of electrons.
Comparison of respiratory pathogen yields from Nasopharyngeal/Oropharyngeal swabs and sputum specimens collected from hospitalized adults in rural Western Kenya
Authors: Nyawanda Bryan O. , Njuguna Henry N. , Onyango Clayton O. , Makokha Caroline , Lidechi Shirley , Fields Barry , Winchell Jonas M. , Katieno Jim S. , Nyaundi Jeremiah , Ade Fredrick , Emukule Gideon O. , Mott Joshua A. , Otieno Nancy , Widdowson Marc-Alain , Chaves Sandra S.
Published: August 2019

Molecular diagnostic methods are becoming increasingly available for assessment of acute lower respiratory illnesses (ALRI). However, nasopharyngeal/oropharyngeal (NP/OP) swabs may not accurately reflect etiologic agents from the lower respiratory tract where sputum specimens are considered as a more representative sample. The pathogen yields from NP/OP against sputum specimens have not been extensively explored, especially in tropical countries. We compared pathogen yields from NP/OP swabs and sputum specimens from patients ≥18 years hospitalized with ALRI in rural Western Kenya. Specimens were tested for 30 pathogens using TaqMan Array Cards (TAC) and results compared using McNemar’s test. The agreement for pathogen detection between NP/OP and sputum specimens ranged between 85–100%. More viruses were detected from NP/OP specimens whereas Klebsiella pneumoniae and Mycobacterium tuberculosis were more common in sputum specimens. There was no clear advantage in using sputum over NP/OP specimens to detect pathogens of ALRI in adults using TAC in the context of this tropical setting.
Evolution of the rodent Trim5 cluster is marked by divergent paralogous expansions and independent acquisitions of TrimCyp fusions
Authors: Boso Guney , Shaffer Esther , Liu Qingping , Cavanna Kathryn , Buckler-White Alicia , Kozak Christine A.
Published: August 2019

Evolution of cellular innate immune genes in response to viral threats represents a rich area of study for understanding complex events that shape mammalian genomes. One of these genes, TRIM5, is a retroviral restriction factor that mediates a post-entry block to infection. Previous studies on the genomic cluster that contains TRIM5 identified different patterns of gene amplification and the independent birth of CypA gene fusions in various primate species. However, the evolution of Trim5 in the largest order of mammals, Rodentia, remains poorly characterized. Here, we present an expansive phylogenetic and genomic analysis of the Trim5 cluster in rodents. Our findings reveal substantial evolutionary changes including gene amplifications, rearrangements, loss and fusion. We describe the first independent evolution of TrimCyp fusion genes in rodents. We show that the TrimCyp gene found in some Peromyscus species was acquired about 2 million years ago. When ectopically expressed, the P. maniculatus TRIMCyp shows anti-retroviral activity that is reversed by cyclosporine, but it does not activate Nf-κB or AP-1 promoters, unlike the primate TRIMCyps. These results describe a complex pattern of differential gene amplification in the Trim5 cluster of rodents and identify the first functional TrimCyp fusion gene outside of primates and tree shrews.
Talaromyces variabilis interferes with Pythium aphanidermatum growth and suppresses Pythium-induced damping-off of cucumbers and tomatoes
Authors: Halo Boshra A. , Al-Yahyai Rashid A. , Maharachchikumbura Sajeewa S. N. , Al-Sadi Abdullah M.
Published: August 2019

Pythium-induced damping-off disease is a major disease limiting cucumber and tomato production in different parts of the world. The current study investigated the efficiency of Talaromyces variabilis and its bioactive metabolites in suppressing Pythium-induced damping-off of cucumbers and tomatoes. T. variabilis inhibited the in vitro growth of P. aphanidermatum in solid and liquid media. In addition, abnormalities in P. aphanidermatum hyphae were observed as a result of T. variabilis. Extracts from T. variabilis induced cellular leakage and suppressed oospore production of P. aphanidermatum. Biochemical analyses of T. variabilis metabolites showed that T. variabilis produces glucanase, cellulase and siderophores, suggesting the contribution of these metabolites in the inhibition of P. aphandermatum growth and in hyphal abnormalities. Treating cucumber seeds with spore and mycelial suspension of T. variabilis isolates led to a significant improvement in the seedling survival of P. aphanidermatum-inoculated seedlings from 18 to 52% (improvement by 34%) for isolate 48 P and from 30–66% (improvement by 36%) for isolate 28 R. Similarly, treating tomato seeds with spore and mycelial suspension of T. variabilis isolates led to a significant improvement in the seedling survival of P. aphanidermatum-inoculated seedlings from 7 to 36% (improvement by 29%) for isolate 28 R and from 20 to 64% (improvement by 44%) for isolate 48 P. Differences in the percent improvement in seedling survival between experiments may be related to difference in the efficacy of the two different isolates or their interaction with the hosts and pathogen. The use of T. variabilis in the biocontrol of Pythium-induced diseases may offer alternatives to the currently used chemical control.
Short-term CFTR inhibition reduces islet area in C57BL/6 mice
Authors: Khan Dawood , Kelsey Ryan , Maheshwari Rashmi R. , Stone Virginia M. , Hasib Annie , Manderson Koivula Fiona N. , Watson Aoife , Harkin Stephen , Irwin Nigel , Shaw James A. , McClenaghan Neville H. , Venglovecz Viktória , Ébert Attila , Flodström-Tullberg Malin , White Michael G. , Kelly Catriona
Published: August 2019

Cystic fibrosis-related diabetes (CFRD) worsens CF lung disease leading to early mortality. Loss of beta cell area, even without overt diabetes or pancreatitis is consistently observed. We investigated whether short-term CFTR inhibition was sufficient to impact islet morphology and function in otherwise healthy mice. CFTR was inhibited in C57BL/6 mice via 8-day intraperitoneal injection of CFTRinh172. Animals had a 7-day washout period before measures of hormone concentration or islet function were performed. Short-term CFTR inhibition increased blood glucose concentrations over the course of the study. However, glucose tolerance remained normal without insulin resistance. CFTR inhibition caused marked reductions in islet size and in beta cell and non-beta cell area within the islet, which resulted from loss of islet cell size rather than islet cell number. Significant reductions in plasma insulin concentrations and pancreatic insulin content were also observed in CFTR-inhibited animals. Temporary CFTR inhibition had little long-term impact on glucose-stimulated, or GLP-1 potentiated insulin secretion. CFTR inhibition has a rapid impact on islet area and insulin concentrations. However, islet cell number is maintained and insulin secretion is unaffected suggesting that early administration of therapies aimed at sustaining beta cell mass may be useful in slowing the onset of CFRD.