bluuebunny/crossref_metadata_2025 huggingface dataset:
Deletion of a Csf1r enhancer selectively impacts CSF1R expression and development of tissue macrophage populations
Authors: Rojo Rocío , Raper Anna , Ozdemir Derya D. , Lefevre Lucas , Grabert Kathleen , Wollscheid-Lengeling Evi , Bradford Barry , Caruso Melanie , Gazova Iveta , Sánchez Alejandra , Lisowski Zofia M. , Alves Joana , Molina-Gonzalez Irene , Davtyan Hayk , Lodge Rebecca J. , Glover James D. , Wallace Robert , Munro David A. D. , David Eyal , Amit Ido , Miron Véronique E. , Priller Josef , Jenkins Stephen J. , Hardingham Giles E. , Blurton-Jones Mathew , Mabbott Neil A. , Summers Kim M. , Hohenstein Peter , Hume David A. , Pridans Clare
Published: July 2019

The proliferation, differentiation and survival of mononuclear phagocytes depend on signals from the receptor for macrophage colony-stimulating factor, CSF1R. The mammalian Csf1r locus contains a highly conserved super-enhancer, the fms-intronic regulatory element (FIRE). Here we show that genomic deletion of FIRE in mice selectively impacts CSF1R expression and tissue macrophage development in specific tissues. Deletion of FIRE ablates macrophage development from murine embryonic stem cells. Csf1rΔFIRE/ΔFIRE mice lack macrophages in the embryo, brain microglia and resident macrophages in the skin, kidney, heart and peritoneum. The homeostasis of other macrophage populations and monocytes is unaffected, but monocytes and their progenitors in bone marrow lack surface CSF1R. Finally, Csf1rΔFIRE/ΔFIRE mice are healthy and fertile without the growth, neurological or developmental abnormalities reported in Csf1r−/− rodents. Csf1rΔFIRE/ΔFIRE mice thus provide a model to explore the homeostatic, physiological and immunological functions of tissue-specific macrophage populations in adult animals.
Molecular mechanism of setron-mediated inhibition of full-length 5-HT3A receptor
Authors: Basak Sandip , Gicheru Yvonne , Kapoor Abhijeet , Mayer Megan L. , Filizola Marta , Chakrapani Sudha
Published: July 2019

Serotonin receptor (5-HT3AR) is the most common therapeutic target to manage the nausea and vomiting during cancer therapies and in the treatment of irritable bowel syndrome. Setrons, a class of competitive antagonists, cause functional inhibition of 5-HT3AR in the gastrointestinal tract and brainstem, acting as effective anti-emetic agents. Despite their prevalent use, the molecular mechanisms underlying setron binding and inhibition of 5-HT3AR are not fully understood. Here, we present the structure of granisetron-bound full-length 5-HT3AR solved by single-particle cryo-electron microscopy to 2.92 Å resolution. The reconstruction reveals the orientation of granisetron in the orthosteric site with unambiguous density for interacting sidechains. Molecular dynamics simulations and electrophysiology confirm the granisetron binding orientation and the residues central for ligand recognition. Comparison of granisetron-bound 5-HT3AR with the apo and serotonin-bound structures, reveals key insights into the mechanism underlying 5-HT3AR inhibition.
Launching of hyperbolic phonon-polaritons in h-BN slabs by resonant metal plasmonic antennas
Authors: Pons-Valencia P. , Alfaro-Mozaz F. J. , Wiecha M. M. , Biolek V. , Dolado I. , Vélez S. , Li P. , Alonso-González P. , Casanova F. , Hueso L. E. , Martín-Moreno L. , Hillenbrand R. , Nikitin A. Y.
Published: July 2019

Launching and manipulation of polaritons in van der Waals materials offers novel opportunities for field-enhanced molecular spectroscopy and photodetection, among other applications. Particularly, the highly confined hyperbolic phonon polaritons (HPhPs) in h-BN slabs attract growing interest for their capability of guiding light at the nanoscale. An efficient coupling between free space photons and HPhPs is, however, hampered by their large momentum mismatch. Here, we show —by far-field infrared spectroscopy, infrared nanoimaging and numerical simulations— that resonant metallic antennas can efficiently launch HPhPs in thin h-BN slabs. Despite the strong hybridization of HPhPs in the h-BN slab and Fabry-Pérot plasmonic resonances in the metal antenna, the efficiency of launching propagating HPhPs in h-BN by resonant antennas exceeds significantly that of the non-resonant ones. Our results provide fundamental insights into the launching of HPhPs in thin polar slabs by resonant plasmonic antennas, which will be crucial for phonon-polariton based nanophotonic devices.
Subtype-specific secretomic characterization of pulmonary neuroendocrine tumor cells
Authors: Wang Xu-Dong , Hu Rongkuan , Ding Qing , Savage Trisha K. , Huffman Kenneth E. , Williams Noelle , Cobb Melanie H. , Minna John D. , Johnson Jane E. , Yu Yonghao
Published: July 2019

Pulmonary neuroendocrine (NE) cancer, including small cell lung cancer (SCLC), is a particularly aggressive malignancy. The lineage-specific transcription factors Achaete-scute homolog 1 (ASCL1), NEUROD1 and POU2F3 have been reported to identify the different subtypes of pulmonary NE cancers. Using a large-scale mass spectrometric approach, here we perform quantitative secretome analysis in 13 cell lines that signify the different NE lung cancer subtypes. We quantify 1,626 proteins and identify IGFBP5 as a secreted marker for ASCL1High SCLC. ASCL1 binds to the E-box elements in IGFBP5 and directly regulates its transcription. Knockdown of ASCL1 decreases IGFBP5 expression, which, in turn, leads to hyperactivation of IGF-1R signaling. Pharmacological co-targeting of ASCL1 and IGF-1R results in markedly synergistic effects in ASCL1High SCLC in vitro and in mouse models. We expect that this secretome resource will provide the foundation for future mechanistic and biomarker discovery studies, helping to delineate the molecular underpinnings of pulmonary NE tumors.
Cytomembrane nanovaccines show therapeutic effects by mimicking tumor cells and antigen presenting cells
Authors: Liu Wen-Long , Zou Mei-Zhen , Liu Tao , Zeng Jin-Yue , Li Xue , Yu Wu-Yang , Li Chu-Xin , Ye Jing-Jie , Song Wen , Feng Jun , Zhang Xian-Zheng
Published: July 2019

Most cancer vaccines are unsuccessful in eliciting clinically relevant effects. Without using exogenous antigens and adoptive cells, we show a concept of utilizing biologically reprogrammed cytomembranes of the fused cells (FCs) derived from dendritic cells (DCs) and cancer cells as tumor vaccines. The fusion of immunologically interrelated two types of cells results in strong expression of the whole tumor antigen complexes and the immunological co-stimulatory molecules on cytomembranes (FMs), allowing the nanoparticle-supported FM (NP@FM) to function like antigen presenting cells (APCs) for T cell immunoactivation. Moreover, tumor-antigen bearing NP@FM can be bio-recognized by DCs to induce DC-mediated T cell immunoactivation. The combination of these two immunoactivation pathways offers powerful antitumor immunoresponse. Through mimicking both APCs and cancer cells, this cytomembrane vaccine strategy can develop various vaccines toward multiple tumor types and provide chances for accommodating diverse functions originating from the supporters.
A novel rapamycin analog is highly selective for mTORC1 in vivo
Authors: Schreiber Katherine H. , Arriola Apelo Sebastian I. , Yu Deyang , Brinkman Jacqueline A. , Velarde Michael C. , Syed Faizan A. , Liao Chen-Yu , Baar Emma L. , Carbajal Kathryn A. , Sherman Dawn S. , Ortiz Denise , Brunauer Regina , Yang Shany E. , Tzannis Stelios T. , Kennedy Brian K. , Lamming Dudley W.
Published: July 2019

Rapamycin, an inhibitor of mechanistic Target Of Rapamycin Complex 1 (mTORC1), extends lifespan and shows strong potential for the treatment of age-related diseases. However, rapamycin exerts metabolic and immunological side effects mediated by off-target inhibition of a second mTOR-containing complex, mTOR complex 2. Here, we report the identification of DL001, a FKBP12-dependent rapamycin analog 40x more selective for mTORC1 than rapamycin. DL001 inhibits mTORC1 in cell culture lines and in vivo in C57BL/6J mice, in which DL001 inhibits mTORC1 signaling without impairing glucose homeostasis and with substantially reduced or no side effects on lipid metabolism and the immune system. In cells, DL001 efficiently represses elevated mTORC1 activity and restores normal gene expression to cells lacking a functional tuberous sclerosis complex. Our results demonstrate that highly selective pharmacological inhibition of mTORC1 can be achieved in vivo, and that selective inhibition of mTORC1 significantly reduces the side effects associated with conventional rapalogs.
Estimating dispensable content in the human interactome
Authors: Ghadie Mohamed , Xia Yu
Published: July 2019

Protein-protein interaction (PPI) networks (interactome networks) have successfully advanced our knowledge of molecular function, disease and evolution. While much progress has been made in quantifying errors and biases in experimental PPI datasets, it remains unknown what fraction of the error-free PPIs in the cell are completely dispensable, i.e., effectively neutral upon disruption. Here, we estimate dispensable content in the human interactome by calculating the fractions of PPIs disrupted by neutral and non-neutral mutations. Starting with the human reference interactome determined by experiments, we construct a human structural interactome by building homology-based three-dimensional structural models for PPIs. Next, we map common mutations from healthy individuals as well as Mendelian disease-causing mutations onto the human structural interactome, and perform structure-based calculations of how these mutations perturb the interactome. Using our predicted as well as experimentally-determined interactome perturbation patterns by common and disease mutations, we estimate that <~20% of the human interactome is completely dispensable.
Effects of changing population or density on urban carbon dioxide emissions
Authors: Ribeiro Haroldo V. , Rybski Diego , Kropp Jürgen P.
Published: July 2019

The question of whether urbanization contributes to increasing carbon dioxide emissions has been mainly investigated via scaling relationships with population or population density. However, these approaches overlook the correlations between population and area, and ignore possible interactions between these quantities. Here, we propose a generalized framework that simultaneously considers the effects of population and area along with possible interactions between these urban metrics. Our results significantly improve the description of emissions and reveal the coupled role between population and density on emissions. These models show that variations in emissions associated with proportionate changes in population or density may not only depend on the magnitude of these changes but also on the initial values of these quantities. For US areas, the larger the city, the higher is the impact of changing its population or density on its emissions; but population changes always have a greater effect on emissions than population density.
Global evidence of positive biodiversity effects on spatial ecosystem stability in natural grasslands
Authors: Wang Yongfan , Cadotte Marc W. , Chen Yuxin , Fraser Lauchlan H. , Zhang Yuhua , Huang Fengmin , Luo Shan , Shi Nayun , Loreau Michel
Published: July 2019

The effect of biodiversity on primary productivity has been a hot topic in ecology for over 20 years. Biodiversity–productivity relationships in natural ecosystems are highly variable, although positive relationships are most common. Understanding the conditions under which different relationships emerge is still a major challenge. Here, by analyzing HerbDivNet data, a global survey of natural grasslands, we show that biodiversity stabilizes rather than increases plant productivity in natural grasslands at the global scale. Our results suggest that the effect of species richness on productivity shifts from strongly positive in low-productivity communities to strongly negative in high-productivity communities. Thus, plant richness maintains community productivity at intermediate levels. As a result, it stabilizes plant productivity against environmental heterogeneity across space. Unifying biodiversity–productivity and biodiversity–spatial stability relationships at the global scale provides a new perspective on the functioning of natural ecosystems.
TurboID-based proximity labeling reveals that UBR7 is a regulator of N NLR immune receptor-mediated immunity
Authors: Zhang Yongliang , Song Gaoyuan , Lal Neeraj K. , Nagalakshmi Ugrappa , Li Yuanyuan , Zheng Wenjie , Huang Pin-jui , Branon Tess C. , Ting Alice Y. , Walley Justin W. , Dinesh-Kumar Savithramma P.
Published: July 2019

Nucleotide-binding leucine-rich repeat (NLR) immune receptors play a critical role in defence against pathogens in plants and animals. However, we know very little about NLR-interacting proteins and the mechanisms that regulate NLR levels. Here, we used proximity labeling (PL) to identify the proteome proximal to N, which is an NLR that confers resistance to Tobacco mosaic virus (TMV). Evaluation of different PL methods indicated that TurboID-based PL provides more efficient levels of biotinylation than BioID and BioID2 in plants. TurboID-based PL of N followed by quantitative proteomic analysis and genetic screening revealed multiple regulators of N-mediated immunity. Interestingly, a putative E3 ubiquitin ligase, UBR7, directly interacts with the TIR domain of N. UBR7 downregulation leads to an increased amount of N protein and enhanced TMV resistance. TMV-p50 effector disrupts the N-UBR7 interaction and relieves negative regulation of N. These findings demonstrate the utility of TurboID-based PL in plants and the N-interacting proteins we identified enhance our understanding of the mechanisms underlying NLR regulation.
Trade-off in membrane distillation with monolithic omniphobic membranes
Authors: Wang Wei , Du Xuewei , Vahabi Hamed , Zhao Song , Yin Yiming , Kota Arun K. , Tong Tiezheng
Published: July 2019

Omniphobic membranes are attractive for membrane distillation (MD) because of their superior wetting resistance. However, a design framework for MD membrane remains incomplete, due to the complexity of omniphobic membrane fabrication and the lack of fundamental relationship between wetting resistance and water vapor permeability. Here we present a particle-free approach that enables rapid fabrication of monolithic omniphobic membranes for MD desalination. Our monolithic omniphobic membranes display excellent wetting resistance and water purification performance in MD desalination of hypersaline feedwater containing surfactants. We identify that a trade-off exists between wetting resistance and water vapor permeability of our monolithic MD membranes. Utilizing membranes with tunable wetting resistance and permeability, we elucidate the underlying mechanism of such trade-off. We envision that our fabrication method as well as the mechanistic insight into the wetting resistance-vapor permeability trade-off will pave the way for smart design of MD membranes in diverse water purification applications.
NQO1 targeting prodrug triggers innate sensing to overcome checkpoint blockade resistance
Authors: Li Xiaoguang , Liu Zhida , Zhang Anli , Han Chuanhui , Shen Aijun , Jiang Lingxiang , Boothman David A. , Qiao Jian , Wang Yang , Huang Xiumei , Fu Yang-Xin
Published: July 2019

Lack of proper innate sensing inside tumor microenvironment (TME) limits T cell-targeted immunotherapy. NAD(P)H:quinone oxidoreductase 1 (NQO1) is highly enriched in multiple tumor types and has emerged as a promising target for direct tumor-killing. Here, we demonstrate that NQO1-targeting prodrug β-lapachone triggers tumor-selective innate sensing leading to T cell-dependent tumor control. β-Lapachone is catalyzed and bioactivated by NQO1 to generate ROS in NQO1high tumor cells triggering oxidative stress and release of the damage signals for innate sensing. β-Lapachone-induced high mobility group box 1 (HMGB1) release activates the host TLR4/MyD88/type I interferon pathway and Batf3 dendritic cell-dependent cross-priming to bridge innate and adaptive immune responses against the tumor. Furthermore, targeting NQO1 is very potent to trigger innate sensing for T cell re-activation to overcome checkpoint blockade resistance in well-established tumors. Our study reveals that targeting NQO1 potently triggers innate sensing within TME that synergizes with immunotherapy to overcome adaptive resistance.
Epitope targeting with self-assembled peptide vaccines
Authors: Zeigler David F. , Gage Emily , Roque Richard , Clegg Christopher H.
Published: July 2019

Nanoparticle-based delivery systems are being used to simplify and accelerate new vaccine development. Previously, we described the solid-phase synthesis of a 61-amino acid conjugate vaccine carrier comprising a α-helical domain followed by two universal T cell epitopes. Circular dichroism, analytical centrifugation, and dynamic light scattering indicate that this carrier forms coiled-coil nanoparticles. Here we expand the potential of this carrier by appending B cell epitopes to its amino acid sequence, thereby eliminating the need for traditional conjugation reactions. Peptides containing Tau or amyloid-β epitopes at either terminus assemble into ~20 nm particles and induce antibody responses in outbred mice. Vaccine function was verified in three experiments. The first targeted gonadotropin-releasing hormone, a 10-amino acid neuropeptide that regulates sexual development. Induction of peak antibody titers in male mice stimulated a dramatic loss in fertility and marked testis degeneration. The second experiment generated antibodies to an epitope on the murine IgE heavy chain analogous to human IgE sequence recognized by omalizumab, the first monoclonal antibody approved for the treatment of allergic asthma. Like omalizumab, the anti-IgE antibodies in immunized mice reduced the concentrations of circulating free IgE and prevented IgE-induced anaphylaxis. Finally, a peptide containing the highly conserved Helix A epitope within the influenza hemagglutinin stem domain induced antibodies that successfully protected mice against a lethal H1N1 challenge. These results establish the utility of a new vaccine platform for eliciting prophylactic and therapeutic antibodies to linear and helical B cell epitopes.
Ex vivo metabolite profiling of paediatric central nervous system tumours reveals prognostic markers
Authors: Bennett Christopher D. , Gill Simrandip K. , Kohe Sarah E. , Wilson Martin P. , Davies Nigel P. , Arvanitis Theodoros N. , Tennant Daniel A. , Peet Andrew C.
Published: July 2019

Brain tumours are the most common cause of cancer death in children. Molecular studies have greatly improved our understanding of these tumours but tumour metabolism is underexplored. Metabolites measured in vivo have been reported as prognostic biomarkers of these tumours but analysis of surgically resected tumour tissue allows a more extensive set of metabolites to be measured aiding biomarker discovery and providing validation of in vivo findings. In this study, metabolites were quantified across a range of paediatric brain tumours using 1H-High-Resolution Magic Angle Spinning nuclear magnetic resonance spectroscopy (HR-MAS) and their prognostic potential investigated. HR-MAS was performed on pre-treatment frozen tumour tissue from a single centre. Univariate and multivariate Cox regression was used to examine the ability of metabolites to predict survival. The models were cross validated using C-indices and further validated by splitting the cohort into two. Higher concentrations of glutamine were predictive of a longer overall survival, whilst higher concentrations of lipids were predictive of a shorter overall survival. These metabolites were predictive independent of diagnosis, as demonstrated in multivariate Cox regression models. Whilst accurate quantification of metabolites such as glutamine in vivo is challenging, metabolites show promise as prognostic markers due to development of optimised detection methods and increasing use of 3 T clinical scanners.
Large-scale Discovery of Substrates of the Human Kinome
Authors: Sugiyama Naoyuki , Imamura Haruna , Ishihama Yasushi
Published: July 2019

Kinase networks are important for cellular signal transduction. Despite tremendous efforts to uncover these signaling pathways, huge numbers of uncharacterized phosphosites still remain in the human proteome. Because of the transient nature of kinase-substrate interactions in vivo, it is almost impossible to identify direct substrates. Here, we present a strategy for the rapid, accurate and high-throughput discovery of in vitro kinase substrates using quantitative proteomics. Using 385 purified kinases (354 wild-type protein kinases, 21 mutants and 10 lipid kinases), we identified a total of 175,574 potential direct kinase substrates. In addition, we identified novel kinase groups, such as one group containing 30 threonine-directed kinases and another containing 15 serine/threonine/tyrosine kinases. Surprisingly, we observed that the diversity of substrates for tyrosine kinases was much higher than that for serine-threonine kinases.
Adiabatic Quantum-Flux-Parametron: Towards Building Extremely Energy-Efficient Circuits and Systems
Authors: Chen Olivia , Cai Ruizhe , Wang Yanzhi , Ke Fei , Yamae Taiki , Saito Ro , Takeuchi Naoki , Yoshikawa Nobuyuki
Published: July 2019

Adiabatic Quantum-Flux-Parametron (AQFP) logic is an adiabatic superconductor logic family that has been proposed as a future technology towards building extremely energy-efficient computing systems. In AQFP logic, dynamic energy dissipation can be drastically reduced due to the adiabatic switching operations using AC excitation currents, which serve as both clock signals and power supplies. As a result, AQFP could overcome the power/energy dissipation limitation in conventional superconductor logic families such as rapid-single-flux-quantum (RSFQ). Simulation and experimental results show that AQFP logic can achieve an energy-delay-product (EDP) near quantum limit using practical circuit parameters and available fabrication processes. To shed some light on the design automation and guidelines of AQFP circuits, in this paper we present an automatic synthesis framework for AQFP and perform synthesis on 18 circuits, including 11 ISCAS-85 circuit benchmarks, 6 deep-learning accelerator components, and a 32-bit RISC-V ALU, based on our developed standard cell library of AQFP technology. Synthesis results demonstrate the significant advantage of AQFP technology. We forecast 9,313×, 25,242× and 48,466× energy-per-operation advantage, compared to the synthesis results of TSMC (Taiwan Semiconductor Manufacturing Company) 12 nm fin field-effect transistor (FinFET), 28 nm and 40 nm complementary metal-oxide-semiconductor (CMOS) technology nodes, respectively.
Large-scale viral genome analysis identifies novel clinical associations between hepatitis B virus and chronically infected patients
Authors: Podlaha Ondrej , Gane Edward , Brunetto Maurizia , Fung Scott , Chuang Wan-Long , Pan Calvin Q. , Jiang Zhaoshi , Liu Yang , Bhardwaj Neeru , Mukherjee Prasenjit , Flaherty John , Gaggar Anuj , Subramanian Mani , Izumi Namiki , Shalimar  , Lim Young-Suk , Marcellin Patrick , Buti Maria , Chan Henry L. Y. , Agarwal Kosh
Published: July 2019

Despite the high global prevalence of chronic hepatitis B (CHB) infection, datasets covering the whole hepatitis B viral genome from large patient cohorts are lacking, greatly limiting our understanding of the viral genetic factors involved in this deadly disease. We performed deep sequencing of viral samples from patients chronically infected with HBV to investigate the association between viral genome variation and patients’ clinical characteristics. We discovered novel viral variants strongly associated with viral load and HBeAg status. Patients with viral variants C1817T and A1838G had viral loads nearly three orders of magnitude lower than patients without those variants. These patients consequently experienced earlier viral suppression while on treatment. Furthermore, we identified novel variants that either independently or in combination with precore mutation G1896A were associated with the transition from HBeAg positive to the negative phase of infection. These observations are consistent with the hypothesis that mutation of the HBeAg open reading frame is an important factor driving CHB patient’s HBeAg status. This analysis provides a detailed picture of HBV genetic variation in the largest patient cohort to date and highlights the diversity of plausible molecular mechanisms through which viral variation affects clinical phenotype.
Crystallized but not soluble uric acid elicits pro-inflammatory response in short-term whole blood cultures from healthy men
Authors: Brovold Henrik , Lund Trine , Svistounov Dmitri , Solbu Marit D. , Jenssen Trond G. , Ytrehus Kirsti , Zykova Svetlana N.
Published: July 2019

Several epidemiological studies have pointed at serum uric acid (SUA) as an independent risk factor for mortality, diabetes, hypertension, cardiovascular and kidney disease; however, no clear pathogenic pathway is established. Uric acid (UA) crystals show pro-inflammatory properties and can thus create or contribute to the state of chronic low-grade inflammation, a widely accepted pathogenic mechanism in several of the above-mentioned pathologies. On the other hand, soluble uric acid possesses antioxidant properties that might attenuate inflammatory responses. We aimed to explore the net effects of experimentally rising SUA in human whole blood cultures on several mediators of inflammation. Production of TNF-α, IL-1ß, IL-1RA, MCP-1 and IL-8 was assessed upon addition of 200 µM UA, 500 µM UA or monosodium urate (MSU) crystals in the presence or absence of 5 ng/ml lipopolysaccharide (LPS). RT-qPCR and multiplex bead based immunoassay were used to measure mRNA expression and cytokine release at 2 and 4 h of culture, respectively. 14C labeled UA was used to assess intracellular uptake of UA. We show that crystallized, but not soluble, UA induces production of pro-inflammatory mediators in human whole blood. Soluble UA is internalized in blood cells but does not potentiate or reduce LPS-induced release of cytokines.
Excitation spectra in fluids: How to analyze them properly
Authors: Kryuchkov Nikita P. , Mistryukova Lukiya A. , Brazhkin Vadim V. , Yurchenko Stanislav O.
Published: July 2019

Although the understanding of excitation spectra in fluids is of great importance, it is still unclear how different methods of spectral analysis agree with each other and which of them is suitable in a wide range of parameters. Here, we show that the problem can be solved using a two-oscillator model to analyze total velocity current spectra, while other considered methods, including analysis of the spectral maxima and single mode analysis, yield rough results and become unsuitable at high temperatures and wavenumbers. To prove this, we perform molecular dynamics (MD) simulations and calculate excitation spectra in Lennard-Jones and inverse-power-law fluids at different temperatures, both in 3D and 2D cases. Then, we analyze relations between thermodynamic and dynamic features of fluids at (Frenkel) crossover from a liquid- to gas-like state and find that they agree with each other in the 3D case and strongly disagree in 2D systems due to enhanced anharmonicity effects. The results provide a significant advance in methods for detail analysis of collective fluid dynamics spanning fields from soft condensed matter to strongly coupled plasmas.
The Role of Conformational Dynamics in Abacavir-Induced Hypersensitivity Syndrome
Authors: Fodor James , Riley Blake T. , Kass Itamar , Buckle Ashley M. , Borg Natalie A.
Published: July 2019

Abacavir is an antiretroviral drug used to reduce human immunodeficiency virus (HIV) replication and decrease the risk of developing acquired immune deficiency syndrome (AIDS). However, its therapeutic value is diminished by the fact that it is associated with drug hypersensitivity reactions in up to 8% of treated patients. This hypersensitivity is strongly associated with patients carrying human leukocyte antigen (HLA)-B*57:01, but not patients carrying closely related alleles. Abacavir’s specificity to HLA-B*57:01 is attributed to its binding site within the peptide-binding cleft and subsequent influence of the repertoire of peptides that can bind HLA-B*57:01. To further our understanding of abacavir-induced hypersensitivity we used molecular dynamics (MD) to analyze the dynamics of three different peptides bound to HLA-B*57:01 in the presence and absence of abacavir or abacavir analogues. We found that abacavir and associated peptides bind to HLA-B*57:01 in a highly diverse range of conformations that are not apparent from static crystallographic snapshots, but observed no difference in either the conformations, nor degree of flexibility when compared to abacavir-unbound systems. Our results support hypersensitivity models in which abacavir-binding alters the conformational ensemble of neopeptides, so as to favour exposed peptide surfaces that are no longer recognized as self by circulating CD8+ T cells, and are conducive to TCR binding. Our findings highlight the need to also consider the role of dynamics in understanding drug-induced hypersensitivities at the molecular and mechanistic level. This additional insight can help inform the chemical modification of abacavir to prevent hypersensitivity reactions in HLA-B*57:01+ HIV patients whilst retaining potent antiretroviral activity.
The anti-aflatoxigenic mechanism of cinnamaldehyde in Aspergillus flavus
Authors: Wang Ping , Ma Longxue , Jin Jing , Zheng Mumin , Pan Lin , Zhao Yueju , Sun Xiulan , Liu Yang , Xing Fuguo
Published: July 2019

Aflatoxin B1 (AFB1), the predominant and most carcinogenic naturally polyketide, is mainly produced by Aspergillus flavus and Aspergillus parasiticus. Cinnamaldehyde has been reported for inhibiting the growth and aflatoxin biosynthesis in A. flavus. But its molecular mechanism of action still remains largely ambiguous. Here, the anti-aflatoxigenic mechanism of cinnamaldehyde in A. flavus was investigated via a comparative transcriptomic analysis. The results indicated that twenty five of thirty genes in aflatoxin cluster showed down-regulation by cinnamaldehyde although the cluster regulators aflR and aflS were slightly up-regulated. This may be due to the up-regulation of the oxidative stress-related genes srrA, msnA and atfB being caused by the significant down-regulation of the diffusible factor FluG. Cinnamaldehyde also inhibited aflatoxin formation by perturbing GPCRs and oxylipins normal function, cell wall biosynthesis and redox equilibrium. In addition, accumulation of NADPH due to up-regulation of pentose phosphate pathway drove acetyl-CoA to lipids synthesis rather than polyketides. Both GO and KEGG analysis suggested that pyruvate and phenylalanine metabolism, post-transcriptional modification and key enzymes biosynthesis might be involved in the suppression of AFB1 production by cinnamaldehyde. This study served to decipher the anti-aflatoxigenic properties of cinnamaldehyde in A. flavus and provided powerful evidence for its use in practice.
Categorical processing of fast temporal sequences in the guinea pig auditory brainstem
Authors: Burghard Alice , Voigt Mathias Benjamin , Kral Andrej , Hubka Peter
Published: July 2019

Discrimination of temporal sequences is crucial for auditory object recognition, phoneme categorization and speech understanding. The present study shows that auditory brainstem responses (ABR) to pairs of noise bursts separated by a short gap can be classified into two distinct groups based on the ratio of gap duration to initial noise burst duration in guinea pigs. If this ratio was smaller than 0.5, the ABR to the trailing noise burst was strongly suppressed. On the other hand, if the initial noise burst duration was short compared to the gap duration (a ratio greater than 0.5), a release from suppression and/or enhancement of the trailing ABR was observed. Consequently, initial noise bursts of shorter duration caused a faster transition between response classes than initial noise bursts of longer duration. We propose that the described findings represent a neural correlate of subcortical categorical preprocessing of temporal sequences in the auditory system.
Essential genes shape cancer genomes through linear limitation of homozygous deletions
Authors: Pertesi Maroulio , Ekdahl Ludvig , Palm Angelica , Johnsson Ellinor , Järvstråt Linnea , Wihlborg Anna-Karin , Nilsson Björn
Published: July 2019

The landscape of somatic acquired deletions in cancer cells is shaped by positive and negative selection. Recurrent deletions typically target tumor suppressor, leading to positive selection. Simultaneously, loss of a nearby essential gene can lead to negative selection, and introduce latent vulnerabilities specific to cancer cells. Here we show that, under basic assumptions on positive and negative selection, deletion limitation gives rise to a statistical pattern where the frequency of homozygous deletions decreases approximately linearly between the deletion target gene and the nearest essential genes. Using DNA copy number data from 9,744 human cancer specimens, we demonstrate that linear deletion limitation exists and exposes deletion-limiting genes for seven known deletion targets (CDKN2A, RB1, PTEN, MAP2K4, NF1, SMAD4, and LINC00290). Downstream analysis of pooled CRISPR/Cas9 data provide further evidence of essentiality. Our results provide further insight into how the deletion landscape is shaped and identify potentially targetable vulnerabilities.
Positive functional synergy of structurally integrated artificial protein dimers assembled by Click chemistry
Authors: Worthy Harley L. , Auhim Husam Sabah , Jamieson W. David , Pope Jacob R. , Wall Aaron , Batchelor Robert , Johnson Rachel L. , Watkins Daniel W. , Rizkallah Pierre , Castell Oliver K. , Jones D. Dafydd
Published: July 2019

Construction of artificial higher order protein complexes allows sampling of structural architectures and functional features not accessible by classical monomeric proteins. Here, we combine in silico modelling with expanded genetic code facilitated strain promoted azide-alkyne cycloaddition to construct artificial complexes that are structurally integrated protein dimers and demonstrate functional synergy. Using fluorescent proteins sfGFP and Venus as models, homodimers and heterodimers are constructed that switched ON once assembled and display enhanced spectral properties. Symmetrical crosslinks are found to be important for functional enhancement. The determined molecular structure of one artificial dimer shows that a new long-range polar network comprised mostly of organised water molecules links the two chromophores leading to activation and functional enhancement. Single molecule analysis reveals the dimer is more resistant to photobleaching spending longer times in the ON state. Thus, genetically encoded bioorthogonal chemistry can be used to generate truly integrated artificial protein complexes that enhance function.
A high-voltage concept with sodium-ion conducting β-alumina for magnesium-sodium dual-ion batteries
Authors: Kravchyk Kostiantyn V. , Walter Marc , Kovalenko Maksym V.
Published: July 2019

Rechargeable magnesium-sodium dual-ion batteries that use dendrite-free magnesium metal as an anode, magnesium-sodium dual-ion electrolyte and sodium-ion cathode are appealing as safe, low-cost systems for large-scale stationary electricity storage. Although substantial advances have been made on magnesium-sodium dual-ion batteries with various sodium-ion cathodes, further development of such batteries is inherently limited by the low electrochemical oxidative stability of known dual-ion electrolytes (2–2.6 V vs. Mg2+/Mg). Here, we examine a magnesium-sodium dual-ion concept, which allows for higher operating voltages of magnesium-sodium dual-ion batteries by using oxidatively stable sodium-ion electrolytes along with a sodium-ion conducting β-alumina membrane on the cathode side. The proposed concept is assessed using a high-voltage Na1.5VPO4.8F0.7 cathode demonstrating a high average discharge voltage of 3.0 V, a cathodic capacity of 110 mAh g−1 and an energy efficiency of 90%.
Optical analogue of the dynamical Casimir effect in a dispersion-oscillating fibre
Authors: Vezzoli Stefano , Mussot Arnaud , Westerberg Niclas , Kudlinski Alexandre , Dinparasti Saleh Hatef , Prain Angus , Biancalana Fabio , Lantz Eric , Faccio Daniele
Published: July 2019

The dynamical Casimir effect is the generation of pairs of real particles or photons from the vacuum as a result of a non-adiabatic change of a system parameter or boundary condition. As opposed to standard parametric amplification where the modulation occurs both in space and in time, this fundamental process requires a pure modulation in time, which makes its detection particularly challenging at optical frequencies. In this paper we experimentally demonstrate a realization of the analogue dynamical Casimir effect in the near-infrared optical regime in a dispersion-oscillating photonic crystal fibre. The experiments are based on the equivalence of the spatial modulation of the fibre core diameter to a pure temporal modulation when this is considered in the co-moving frame of the travelling pump pulse. We provide evidence of optical dynamical Casimir effect by measuring quantum correlations between the spectrally resolved photon pairs and prove their non-classical nature with photon anti-bunching.
Confinement and substrate topography control cell migration in a 3D computational model
Authors: Winkler Benjamin , Aranson Igor S. , Ziebert Falko
Published: July 2019

Cell movement in vivo is typically characterized by strong confinement and heterogeneous, three-dimensional environments. Such external constraints on cell motility are known to play important roles in many vital processes e.g. during development, differentiation, and the immune response, as well as in pathologies like cancer metastasis. Here we develop a physics-driven three-dimensional computational modeling framework that describes lamellipodium-based motion of cells in arbitrarily shaped and topographically structured surroundings. We use it to investigate the primary in vitro model scenarios currently studied experimentally: motion in vertical confinement, confinement in microchannels, as well as motion on fibers and on imposed modulations of surface topography. We find that confinement, substrate curvature and topography modulate the cell’s speed, shape and actin organization and can induce changes in the direction of motion along axes defined by the constraints. Our model serves as a benchmark to systematically explore lamellipodium-based motility and its interaction with the environment.
A naphthalimide-based novel “Turn-On” fluorescence approach for the determination of uric acid and monitoring of xanthine oxidase activity
Authors: Sidhu Jagpreet Singh , Sharma Shilpa , Singh Ashutosh , Garg Neha , Kaur Navneet , Singh Narinder
Published: July 2019

Fluorescence emission of the receptor enhanced upon its binding with uric acid due to the cancellation of the PET phenomenon.
Biomimetic proteoglycan nanoparticles for growth factor immobilization and delivery
Authors: Zandi Nooshin , Mostafavi Ebrahim , Shokrgozar Mohammad Ali , Tamjid Elnaz , Webster Thomas J. , Annabi Nasim , Simchi Abdolreza
Published: July 2019

Growth factor delivery is often challenging due to their short half-life, low stability, and rapid deactivation. Here, we engineered novel biomimetic proteoglycan nanocarriers for the immobilization and controlled release of growth factors.
A highly durable carbon-nanofiber-supported Pt–C core–shell cathode catalyst for ultra-low Pt loading proton exchange membrane fuel cells: facile carbon encapsulation
Authors: Karuppannan Mohanraju , Kim Youngkwang , Gok Sujin , Lee Eunjik , Hwang Jee Youn , Jang Ji-Hoon , Cho Yong-Hun , Lim Taeho , Sung Yung-Eun , Kwon Oh Joong
Published: July 2019

Ultra-stable Pt cathode catalysts in ultra-low Pt loading proton exchange membrane fuel cells were synthesized by facile carbon encapsulation.
Emerging investigator series: characterization of silver and silver nanoparticle interactions with zinc finger peptides
Authors: Park Grace , Amaris Zoe N. , Eiken Madeline K. , Baumgartner Karl V. , Johnston Kathryn A. , Williams Mari A. , Marckwordt Jasmine G. , Millstone Jill E. , Splan Kathryn E. , Wheeler Korin E.
Published: July 2019

Zn finger peptides catalyze dissolution and agglomeration of silver nanomaterials. In turn, the nanomaterials disrupt native structure and metalation of the peptide. Disruption of Zn finger function constitutes a potential toxicity mechanism.
Facile synthesis of carbon nanobranches towards cobalt ion sensing and high-performance micro-supercapacitors
Authors: Chen Qiao-Ling , Wu Xingjiang , Cheng Hengyang , Li Qing , Chen Su
Published: July 2019

A facile strategy is developed for fabrication of carbon nanobranches (CNBs) via in situ pyrolysis of starch.
X-ray micro-computed tomography as a non-destructive tool for imaging the uptake of metal nanoparticles by graphene-based 3D carbon structures
Authors: Smith Christopher T. G. , Mills Christopher A. , Pani Silvia , Rhodes Rhys , Bailey Josh J. , Cooper Samuel J. , Pathan Tanveerkhan S. , Stolojan Vlad , Brett Daniel J. L. , Shearing Paul R. , Silva S. Ravi P.
Published: July 2019

Showcasing X-ray micro-computerized tomography as a method to image metal nanoparticle dispersion throughout sponge-like graphene matrices suitable for environmental remediation.
Atmospheric nanoparticles affect vascular function using a 3D human vascularized organotypic chip
Authors: Li Yan , Wu Yang , Liu Yan , Deng Qi-Hong , Mak Michael , Yang Xu
Published: July 2019

Inhaled atmospheric nanoparticles (ANPs) affect vessel function.
Stabilizing the B-site oxidation state in ABO3 perovskite nanoparticles
Authors: Ofoegbuna Tochukwu , Darapaneni Pragathi , Sahu Smriti , Plaisance Craig , Dorman James A.
Published: July 2019

Crystallization of Sr1−xNbO3−δ nanoparticles using the low-pressure wet-chemical method.
Cyclic voltammetry growth and characterization of Sn–Ag alloys of different nanomorphologies and compositions for efficient hydrogen evolution in alkaline solutions
Authors: Shaban Mohamed , Kholidy Islam , Ahmed Ghada M. , Negem Mosaad , Abd El-Salam Hanafy M.
Published: July 2019

Electrodeposition of silver, tin and their alloys from different aqueous electrolytes suffer from various environmental issues and deposits are affected by H2 evolution and metal oxide formation.
Stability of the interface of an isotropic active fluid
Authors: Soni Harsh , Luo Wan , Pelcovits Robert A. , Powers Thomas R.
Published: July 2019

We study the linear stability of an isotropic active fluid in three different geometries: a film of active fluid on a rigid substrate, a cylindrical thread of fluid, and a spherical fluid droplet.
Inclusion crystals as vapochromic chemosensors: fabrication of a mini-sensor array for discrimination of small aromatic molecules based on side-chain engineering of naphthalenediimide derivatives
Authors: Ono Toshikazu , Tsukiyama Yoshifumi , Hatanaka Sou , Sakatsume Yuma , Ogoshi Tomoki , Hisaeda Yoshio
Published: July 2019

A mini-sensor array based on side-chain engineering of NDI derivatives achieved unique vapochromic/vapofluorochromic behaviors for aromatic vapors.
Influenza A matrix protein M1 induces lipid membrane deformation via protein multimerization
Authors: Dahmani Ismail , Ludwig Kai , Chiantia Salvatore
Published: July 2019

The matrix protein M1 of the Influenza A virus (IAV) is supposed to mediate viral assembly and budding at the plasma membrane (PM) of infected cells. In order for a new viral particle to form, the PM lipid bilayer has to bend into a vesicle toward the extracellular side. Studies in cellular models have proposed that different viral proteins might be responsible for inducing membrane curvature in this context (including M1), but a clear consensus has not been reached. In the present study, we use a combination of fluorescence microscopy, cryogenic transmission electron microscopy (cryo-TEM), cryo-electron tomography (cryo-ET) and scanning fluorescence correlation spectroscopy (sFCS) to investigate M1-induced membrane deformation in biophysical models of the PM. Our results indicate that M1 is indeed able to cause membrane curvature in lipid bilayers containing negatively charged lipids, in the absence of other viral components. Furthermore, we prove that protein binding is not sufficient to induce membrane restructuring. Rather, it appears that stable M1–M1 interactions and multimer formation are required in order to alter the bilayer three-dimensional structure, through the formation of a protein scaffold. Finally, our results suggest that, in a physiological context, M1-induced membrane deformation might be modulated by the initial bilayer curvature and the lateral organization of membrane components (i.e. the presence of lipid domains).
Formation and photochemistry of covalently bonded large functional PAH clusters
Authors: Zhen Junfeng , Yang Yuanyuan , Zhang Weiwei , Zhu Qingfeng
Published: July 2019

Polycyclic aromatic hydrocarbon (PAH) molecules belong to a large and diverse chemical family in the interstellar medium (ISM). We study the formation and photochemistry of covalently bonded large functional PAH clusters, dicoronylene (DC, C48H20)/9-vinylanthracene (C16H12) and dicoronylene/9-methylanthracene (C15H12) cluster cations, in the gas phase, and we offer an approach to the evolution of different types of large (covalently bonded) PAH clusters in the ISM. The experiments, which we combined with a quadrupole ion trap and time-of-flight mass spectrometry, show that large functional PAH cluster cations can form by gas-phase condensation through molecular-ion reactions. One group of functional PAH cluster cations contain the vinyl group (−CHCH2), that is, from C16H12DDC+ (e.g., C16H12C48H19+, m/z = 799) to (C16H12)2DDC+ (e.g., (C16H12)2C48H18+, m/z = 1002). The other group of functional PAH cluster cations contain the methyl group (−CH3), that is, from C15H12DDC+ (e.g., C15H12C48H19+, m/z = 787) to (C15H12)2DDC+ (e.g., (C15H12)2C48H18+, m/z = 990). With laser irradiation, the DC/9-vinylanthracene and DC/9-methylanthracene cluster cations show a very complicated dissociation process (e.g., dehydrogenation, −CH3 or −CHCH2 unit losses). We investigate the structure of newly formed PAH cluster cations, the bond energy, and the photodissociation energy for these reaction pathways with quantumchemical calculations. The obtained results provide a general molecular growth route toward large PAH cluster cations (e.g., functional PAH clusters) in a bottom-up formation process and the insight of the functional group (e.g., vinyl, −C2H3 and methyl, −CH3) effect on their evolutionary behavior. In addition, the studies of DC/9-vinylanthracene and DC/9-methylanthracene clusters (94–123 atoms, ∼2 nm in size) also provide a possible way of interpreting the formation processes of nanometer-sized grains in the ISM, especially when functional PAHs are included.
Venous Access for Cardiovascular Procedures
Authors: Nemani Lalita , Vikas Medep
Published: July 2019

Venous access is an integral and essential part of cardiovascular interventions for both diagnostic and therapeutic procedures, and it can be lifesaving in cardiac emergencies. Peripheral venous access though simple can sometimes be not achieved for multitude of reasons; hence, knowledge of central venous access is important and is an integral part of cardiac interventional training.