bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular dynamics simulation of the thermal pulse explosion of metal nanowire
Authors: Lv Fangwei , Qi Hui , Liu Pingan , Liu Junpeng
Published: July 2018

Molecular dynamics simulation of the thermal pulse explosion of metal nanowire, which modeled the slow mode electric explosion of metal wire, was carried out. The potential calculated in the framework of the embedded atom method (EAM). The expansion of wire core and the explosion products in the simulated system were investigated. Simulation results confirm that the collapse of material tensile stress triggers the cavitation and subsequent explosion; due to size effect, the thermal pulse explosion is not preferential atoms evaporation, but clustered together into clusters synchronously; small clusters and free atoms formed in the nanowire explosion account for a certain proportion of the total mass which cannot be ignored in nanoscale objects. It is shown that this method can simulate the slow mode electric explosion of metal wires (EEW) effectively.
Micropipette-powered droplet based microfluidics
Authors: Langer Krzysztof , Bremond Nicolas , Boitard Laurent , Baudry Jean , Bibette Jérôme
Published: July 2018

Droplet-based microfluidics, using water-in-oil emulsion droplets as micro-reactors, is becoming a widespread method for performing assays and especially in the cell biology field. Making a simple and highly portable system for creating emulsion droplets would help to continue the popularization of such a technique. Also, the ability to emulsify all the samples would strengthen this compartimenlization technique to handle samples with limited volume. Here, we propose a strategy of droplet formation that combines a classical flow-focusing microfluidic chip, which could be commercially available, with a standard laboratory adjustable micropipette. The micropipette is used as a negative pressure generator for controlling liquid flows. In that way, emulsification does neither require any electrical power supply nor a cumbersome device and functions with small liquid volumes. Droplet formation can be easily and safely performed in places with limited space, opening a wide range of applications especially in biological laboratory environments with higher level of safety regulations, i.e., BSL-3/4. Fortunately, the present methodology that involves small fluid volumes, and thus possible time dependent flow conditions, allows to minimize dead volume while keeping drops' size homogeneous. A physical characterization of droplet production and a model that describes the emulsion features, in terms of drop size and size distribution, are proposed for rationalizing the performances of the micropipette-powered emulsification process.
Pseudomagnetic field modulation of stopping power for a charged particle moving above graphene
Authors: Zhang Ya , Jiang Wei
Published: July 2018

We use a linearized two-component hydrodynamic model to study the wake potential and stopping power of electrons in a strained graphene sheet with a charged particle moving above it. The self-consistent numerical solution indicates the existence of surface plasmons due to a strain-induced pseudomagnetic field and Coulomb interactions. The wake potential is induced under this interaction, and the stopping power is calculated in terms of the wake potential. The influence on the wake potential, stopping function, and stopping power of the pseudomagnetic field, intrusive particle velocity and distance, and wave number and frequency are shown and discussed. The results indicate that the stopping power obviously differs for different materials in both cases with and without magnetic modulation. Moreover, the pseudomagnetic field modulation is significant in graphene. This feature is not captured for a free-electron gas on a semiconductor heterostructure. Our hydrodynamic results quantitatively agree with those obtained by a local-frequency-dependent dielectric method.
A novel laboratory-based hard X-ray photoelectron spectroscopy system
Authors: Regoutz Anna , Mascheck Manfred , Wiell Tomas , Eriksson Susanna K. , Liljenberg Cristopher , Tetzner Kornelius , Williamson Benjamin A. D. , Scanlon David O. , Palmgren Paul
Published: July 2018

Hard X-ray photoelectron spectroscopy (HAXPES) has seen continuous development since the first experiments in the 1970s. HAXPES systems are predominantly located at synchrotron sources due to low photoionization cross sections necessitating high X-ray intensities, which limits the technique’s availability to a wide range of users and potential applications. Here, a new laboratory-based instrument capable of delivering monochromated X-rays with an energy of 9.25 keV and a microfocused 30 × 45 μm2 X-ray spot is introduced. The system gives an excellent energy resolution of below 500 meV coupled with good X-ray intensity. It allows stable measurements under grazing incidence conditions to maximise signal intensities. This article outlines the instrument behavior, showcases applications including bulk and multilayer measurements, and describes the overall performance of the spectrometer. This system presents an alternative to synchrotron-based experimental end stations and will help expand the number and range of HAXPES experiments performed in the future.
Contemporary group alternatives for genetic evaluation of milk yield in small populations of dairy cattle
Authors: Pereira R. J. , Schenkel F. S. , Ventura R. V. , Ayres D. R. , El Faro L. , Machado C. H. C. , Albuquerque L. G.
Published: July 2018

In the present study, different random regression models, focussed on the nature of the effect of the contemporary group, fixed or random, were compared for genetic evaluation of test-day milk yield in dairy Gir breed, whose herds are characterised by relatively reduced numbers of cows. Cows were assigned to the same contemporary group if they were tested in the same herd, year and month. In one of the evaluated models, the contemporary group was investigated as a fixed effect and a clustering procedure was adopted to group herd-year subclasses in order to, at the end of the process, all contemporary groups contained at least three cows. The models were compared by the quality of fit, the accuracy of the predicted breeding values and their estimates of genetic parameters. The clustering procedure did not significantly improve the accuracy of predicted breeding values. Moreover, the fit to the data for this model was negatively affected. Therefore, this strategy should not be further implemented. The model including the herd-calving period effect and contemporary group treated as random effect showed similar characteristics to its equivalent, where the contemporary group was modelled as a fixed effect. However, the fit to the data for this model was slightly worse. Thus, the results suggest a random regression model including the herd-calving period effect and the fixed effect of contemporary group for the genetic evaluations of production traits in dairy Gir cattle. These findings could be extended to small dairy cattle populations whose herds are small-sized.
Competitive 1,3-Dipolar Cycloaddition Reactions of an Azomethine Ylide with Aromatic and Carbonyl Groups of Nitro-Substituted Isatoic Anhydrides
Authors: D'Souza Asha M. , Rivinoja Daniel J. , Mulder Roger J. , White Jonathan M. , Meyer Adam G. , Hyland Christopher J. T. , Ryan John H.
Published: July 2018

A study of the reactivity of a non-stabilised azomethine ylide, derived from N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine, with nitro-substituted isatoic anhydrides was undertaken. N-Methyl-4-nitroisatoic anhydride underwent a 1,3-dipolar cycloaddition reaction exclusively at the isatoic anhydride C1-carbonyl group, followed by decarboxylative rearrangement to yield a benzo-1,3-diazepin-5-one derivative. In contrast, N-methyl-5-nitroisatoic anhydride underwent competing cycloaddition processes to the isatoic anhydride C1-carbonyl group and to the nitro-substituted aromatic ring. The dearomative addition reaction resulted in the formation of novel tetracyclic products.
Relative phytotoxicity of parthenium weed (Parthenium hysterophorus L.) residues on the seedling growth of a range of Australian native and introduced species
Authors: Shi Boyang , Adkins Steve
Published: July 2018

The invasive herbaceous species Parthenium hysterophorus L. (Asteraceae), commonly known as parthenium weed has rapidly become a significant weed in more than 30 countries. Parthenium weed litter taken from the introduced biotypes was relatively more phytotoxic than that taken from biotypes coming from the native range when tested on lettuce and this may indicate one reason for invasion success. However, no significant difference was observed in phytotoxicity to lettuce seedling growth when two Australian biotypes of parthenium weed were compared, one invasive and one non-invasive, indicating that invasiveness was not associated with litter phytotoxicity in all cases. Residue from the invasive parthenium weed biotype had a greater phytotoxic effect upon Australian native pasture grass species relative to the introduced pasture grass species with buffel grass (Cenchrus ciliaris L.) and bull Mitchell grass (Astreble sequarrosa C.E.Hubb) showing the greatest tolerance to parthenium weed phytochemicals. When compared with residue taken from plants that has a range of phytotoxic capacity, parthenium weed residue was considered to be only moderately phytotoxic suggesting that the phytotoxicity of its residue may not be the main reason for the plants invasive trait.
Forest stream biota carbon : nitrogen ratios are unaffected by nutrient subsidies from breeding Westland petrels (Procellaria westlandica)
Authors: Gamlen-Greene Roseanna , Harding Jon S. , Hawke David J. , Horton Travis W.
Published: July 2018

Stable isotope studies have repeatedly shown marine nutrient incorporation from seabirds, anadromous fish and tidal wrack into terrestrial and freshwater ecosystems. However, little is known about the physiological consequences of marine-derived nutrient subsidies. Protein content and lipid storage are important physiologically, and the C:N ratio is a widely used proxy that reflects changes in these quantities. In this study we tested the response of C:N ratios in stream biota to the presence of marine-derived nutrients from Westland petrels, a forest breeding seabird. Samples of different stream invertebrate functional feeding groups, predatory freshwater fish, coarse particulate organic matter and riparian soil and vegetation came from four reference streams and four streams with a wide range of seabird densities. Samples were analysed for percentage C, percentage N and δ15N using isotope ratio mass spectrometry. The data were tested against petrel colony size, stream size and distance from colony to sampling site. Despite increased δ15N accompanying petrel presence (as reported previously), Westland petrels had no effect on stream biota C:N ratios, regardless of colony presence or absence or colony size. Despite the nutrients provided by petrels, we conclude that petrel N replaced rather than enhanced non-marine N in these stream ecosystems.
α-Synuclein oligomers induce early axonal dysfunction in human iPSC-based models of synucleinopathies
Authors: Prots Iryna , Grosch Janina , Brazdis Razvan-Marius , Simmnacher Katrin , Veber Vanesa , Havlicek Steven , Hannappel Christian , Krach Florian , Krumbiegel Mandy , Schütz Oliver , Reis André , Wrasidlo Wolfgang , Galasko Douglas R. , Groemer Teja W. , Masliah Eliezer , Schlötzer-Schrehardt Ursula , Xiang Wei , Winkler Jürgen , Winner Beate
Published: July 2018

Significance

α-Synuclein (α-Syn) aggregation underlies neurodegeneration in synucleinopathies. However, the nature of α-Syn aggregates and their toxic mechanisms in human pathology remains elusive. Here, we delineate a role of α-Syn oligomeric aggregates for axonal integrity in human neuronal models of synucleinopathies. α-Syn oligomers disrupt anterograde axonal transport of mitochondria by causing subcellular changes in transport-regulating proteins and energy deficits. An increase of α-Syn oligomers in human neurons finally results in synaptic degeneration. Together, our data provide mechanistic insights of α-Syn oligomeric toxicity in human neurons. Taking into account that α-Syn oligomers and axonal dysfunction are characteristic for early neurodegeneration in synucleinopathies, our data might deliver targets for therapeutic interference with early disease pathology.
Role of sodium channel subtype in action potential generation by neocortical pyramidal neurons
Authors: Katz Efrat , Stoler Ohad , Scheller Anja , Khrapunsky Yana , Goebbels Sandra , Kirchhoff Frank , Gutnick Michael J. , Wolf Fred , Fleidervish Ilya A.
Published: July 2018

Significance

Under most conditions cortical pyramidal neurons are strongly biased to initiate action potentials in the distal part of the axon initial segment (AIS) rather than in the dendrites, where the excitatory postsynaptic potential amplitude is largest. This feature is widely attributed to the axonal presence of the low-threshold Na
+
channel subtype Na
v
1.6. Here, using electrical and high-speed Na
+
imaging recordings from Na
v
1.6 null pyramidal neurons, we demonstrate that the presence of this subunit is neither critical for positioning the spike initiation site within the AIS nor for the spike backpropagation to the dendrites. We also find that one of the most important features of axonal Na
+
channel kinetics, the lower activation threshold, is not entirely dependent on the Na
+
channel subtype.
Oscillatory inertial focusing in infinite microchannels
Authors: Mutlu Baris R. , Edd Jon F. , Toner Mehmet
Published: July 2018

Significance

Inertial microfluidics is a widely used technology which enables label-free manipulation of particles in microchannels. However, this technology has been limited to bioparticles larger than RBCs, due to the strong correlation between the inertial lift forces and the particle size. This paper presents a method to extend the capabilities of inertial microfluidics to smaller bioparticles, of which a plethora of clinically relevant types exist in the human body. Therefore, this method can be integrated with microfluidic devices for inertial manipulation of bioparticles that have defied all prior attempts, enabling a variety of applications in clinical diagnosis including cytometry of micron-scale bioparticles, isolation and characterization of pathogens and extracellular microvesicles, or phenotyping of cancer or stem cells at physiological shear stresses.
Do alien free-ranging birds affect human health? A global summary of known zoonoses.
Authors: Mori E. , Meini S. , Strubbe D. , Ancillotto L. , Sposimo P. , Menchetti M.
Published: July 2018

Non-native birds are prominent among alien taxa, with at least 415 species established outside their natural distribution ranges. Impacts of introduced birds on human health have received little attention up to now, despite previous works suggesting that disease transmission is a major impact exerted by introduced bird species. Our synthesis reveals that at least 42 species of introduced birds may represent a hazard to human well-being. Among those, most are Psittaciformes, Columbiformes and Anseriformes, species that frequently occur in urban areas, partly because of their popularity as pets and ornamental species. The main zoonoses potentially brought by these birds include psittacosis, cryptococcosis, listeriosis and salmonellosis, transmitted by direct contact or via arthropod vectors (fleas, lice, ticks and mites). Many Galliformes introduced for hunting purposes can lead to salmonellosis and other gastroenteric diseases in humans. Non-native birds can threaten human health through bird-strikes around airports and through noise pollution by species sharing colonial roosts. While we found that alien birds can theoretically transmit several diseases to humans, empirical case studies of disease outbreaks linked to alien birds are rare or non-existent. The synergistic impacts of ongoing species introductions and global climate change may increase the risk of health hazards in the future. Therefore, sanitary monitoring of traded birds, mainly of the most synanthropic and game species released for human consumption would be prudent. Strict attention should be paid to alien bird populations already established within urban areas, to verify their role in affecting human health and well-being.
Solidification behaviour and microstructure of welding transition zone using low-transformation-temperature welding consumables
Authors: Di Xinjie , Geng Dudu , Wu Shipin , Wang Dongpo , Zhang Zhi , Li Chengning
Published: July 2018

The solidification behaviour and microstructure of welding transition zone between low-transformation-temperature deposited metals and high-strength low-alloy steels were investigated. It was found that the steep composition gradient provided driving forces for the diffusion of carbon from base metal to weld metal, leading to the hardened and softened regions near fusion boundary. In weld metal near fusion boundary, there were retained δ-ferrites when the base metal dilution rate below 35% and Creq/Nieq value larger than 2.62. Compared with martensite, the mixed microstructures of martensite + δ-ferrite obtained less strain localisation, dislocation density and more percentages of large misorientation, which were more liable to resist microcrack initiation and propagation during deformation.
Equations of heat generation during friction stir welding for tapered polygonal tools
Authors: Al Bhadle Basim M. A. , Al Azzawi Rafat A. A. , Thornton R. , Beamish K. , Shi S. , Dong H. B.
Published: July 2018

Owing to the complex nature of heat generation in friction stir welding, equations are required to understand the effect of process parameters and tool geometry on heat generation. In this study, simplified equations for straight tool profiles have been extended to treat tapered tool profiles for triangular, square, pentagonal and hexagonal geometries. New equations have been implemented to model heat generation in a finite element software package for welding aluminium alloy. The calculated thermal profiles agree better with experimental data than those calculated using the simplified equations. It was also demonstrated that the amount of heat generation increases with increasing number of flats on the tapered tool profile, with a hexagonal tapered tool profile generating the highest temperature.
Morphologies of co-depositing W layer formed during He plasma irradiation
Authors: Kajita Shin , Kawaguchi Shota , Yoshida Naoaki , Ohno Noriyasu , Tanaka Hirohiko
Published: July 2018

Tungsten (W) samples were exposed to helium (He) plasmas with precipitation of W particles. It was shown that visible large-scale fiberform nanostructures (LFNs) were formed on the surface. The height of the LFN increased exponentially with the irradiation time in the initial phase of the growth. The growth rate was totally different from that of the conventional W nanostructure (fuzz) growth by He plasma irradiation, where the thickness increased in proportion to the square root of time. The LFNs growth had a directionality in a millimeter global scale; the direction was always  ∼45–60 degree rotated in clockwise direction from the magnetic field. The plasma flow measured spectroscopically near the sample was found to significantly increase when inserting a negatively biased sample, and the growth direction of the LFN was consistent with the direction of the plasma flow. Moreover, highly porous fiberform nanostructures or cauliflower-like structures comprised the deposition layer even when the He incident ion energy was lower than the threshold energy of fuzz growth (20–30 eV).
Longitudinal Assessment of Aesthetic Plastic Surgery Training in the United States: The Effect of Increased ACGME Case Log Minimum Requirements
Authors: Kraft Casey T , Harake Mazen S , Janis Jeffrey E
Published: July 2018

Background

In 2014, the Accreditation Council for Graduate Medical Education (ACGME) increased the minimum required aesthetic surgery cases for graduation from plastic surgery residency from 50 to 150. To date, there has been no research into how this has impacted resident aesthetic surgery training focusing on the resident perception.

Objectives

We sought to evaluate resident perception and satisfaction with their aesthetic surgery training before and after the ACGME case log requirement increase to assess its impact on training and comfort level.

Methods

A survey was administered to all graduating senior residents attending the Senior Residents Conference of the ASPS Annual Meeting in 2014 and 2017. The survey evaluated senior resident aesthetic surgery experience and their confidence and satisfaction with their training.

Results

The response rate was 70% in 2014 and 45% in 2017. There was an increase in the number of programs with resident-run cosmetic clinics (14% increase) and designated aesthetic rotations (33% increase) during that time. Resident-run cosmetic clinics were consistently considered the most valuable form of aesthetic training for residents. There also was a substantial increase in the percentage of residents feeling prepared to incorporate aesthetic surgery into their practice after graduation, increasing from 36% to 59% in 2017. The majority of responding residents felt that the ACGME case log requirement increase in 2014 was beneficial for their aesthetic surgery training (68%).

Conclusions

The recent ACGME case log requirement increase for aesthetic surgery training has had a positive effect on resident comfort with aesthetic procedures and their ability to incorporate them into future practice.
If you build it, they may not come: modifiable barriers to patient portal use among pre- and post-kidney transplant patients
Authors: Lockwood Mark B , Dunn-Lopez Karen , Pauls Heather , Burke Larisa , Shah Sachin D , Saunders Milda A
Published: July 2018

Background

Patient access to health information using electronic patient portals is increasingly common. Portal use has the potential to improve patients’ engagement with their health and is particularly important for patients with chronic illness; however, patients’ abilities, attitudes, and use of portals are poorly understood.

Methods

A single-center, cross-sectional survey was conducted of 240 consecutive pre- and post-kidney transplant patients of all levels of technological proficiency who presented to an urban transplant center in the United States. The investigator-developed Patient Information and Technology Assessment-Patient Portal was used to assess patients’ attitudes towards the use of patient portals.

Results

Most patients surveyed did not use the patient portal (n = 176, 73%). Patients were more likely to use the patient portal if they were White, highly educated, in the post-transplant period, more comfortable with technology, and reported being a frequent internet user (P < .05). The most common reasons for not using the patient portal included: (1) preference for traditional communication, (2) not being aware of the portal, (3) low technological proficiency, and (4) poor interoperability between the portal at the transplant center and the patient’s primary care center.

Conclusions

We identified several modifiable barriers to patient portal use. Some barriers can be addressed by patient education and training on portal use, and federal initiatives are underway to improve interoperability; however, a preference for traditional communications represents the most prominent barrier. Additional strategies are needed to improve portal adoption by encouraging acceptance of technologies as a way of clinical communication.
Incidence, prevalence, mortality and chronic renal damage of anti-neutrophil cytoplasmic antibody-associated glomerulonephritis in a 20-year population-based cohort
Authors: Berti Alvise , Cornec-Le Gall Emilie , Cornec Divi , Casal Moura Marta , Matteson Eric L , Crowson Cynthia S , Ravindran Aishwarya , Sethi Sanjeev , Fervenza Fernando C , Specks Ulrich
Published: July 2018

Background

True population-based clinical and outcomes data are lacking for anti-neutrophil cytoplasmic autoantibody (ANCA)-associated glomerulonephritis (AAGN). Therefore we aimed to estimate the incidence, prevalence and mortality of AAGN, as well as the relationship between the grade of chronic renal damage at presentation and renal and non-renal outcomes.

Methods

Patients with AAGN were identified among a population-based incident cohort of 57 Olmsted County residents diagnosed with ANCA-associated vasculitis (AAV) in 1996–2015. Incidence rates were age and sex adjusted to the 2010 US white population. Age- and sex-adjusted prevalence was calculated for 1 January 2015. Survival rates were compared with expected rates in the Minnesota population. Chronic renal damage was assessed by chronicity score (CS) on biopsies performed at diagnosis.

Results

Thirty-four (60%) patients had AAGN. Of these, 65% had microscopic polyangiitis (MPA) and 74% were myeloperoxidase (MPO)-ANCA positive. The annual incidence of AAGN was 2.0/100 000 population [95% confidence interval (CI) 1.3–2.7] and the overall prevalence was 35/100 000 (95% CI 24–47). Mortality for AAGN was increased (P < 0.001), whereas mortality for AAV without glomerulonephritis did not differ from the general population. Minimal to mild CS predicted recovery of renal function at 1 year; clinical diagnosis (granulomatosis with polyangiitis versus MPA) and ANCA specificity (proteinase 3 versus MPO) did not. This observation was replicated in an independent cohort of 38 newly diagnosed AAGN patients seen at our centre over the 1999–2014 period.

Conclusions

The annual incidence and prevalence of AAGN in Minnesota are 2.0/100 000 and 35/100 000, respectively. Mortality is worse compared with AAV patients without glomerulonephritis. More advanced renal damage at diagnosis predicts less renal recovery.
Endothelial sphingosine-1-phosphate receptor 1 deficiency exacerbates brain injury and blood brain barrier dysfunction upon subarachnoid hemorrhage in mice
Authors: Ito Akira , Uchida Hiroki , Kim Gab Seok , Faraco Giuseppe , Proia Richard , Niizuma Kuniyasu , Tominaga Teiji , Anrather Josef , Iadecola Costantino , Kluk Michael J , Sanchez Teresa
Published: July 2018

Blood brain barrier (BBB) dysfunction upon ischemia and hypoxia has been implicated in the exacerbation of neuronal injury in stroke. Despite the therapeutic potential of the cerebrovascular endothelium, the limited understanding of the endothelial signaling pathways governing BBB function restricts progress towards developing novel therapeutic approaches specifically targeting the endothelium. Sphingosine-1-phosphate (S1P) is a potent modulator of endothelial function via its receptors (S1PR). Recent human and mouse studies indicate that vasoprotective endothelial S1P signaling via S1PR1 may be impaired in cardiovascular and inflammatory diseases. Herein, we investigated the expression of S1PR1 in the mouse and human cerebrovascular endothelium and the role of endothelial-specific S1PR1 signaling in brain injury in a mouse model of aneurysmal subarachnoid hemorrhage (SAH), the most devastating type of stroke. We found that S1PR1 is the most abundant S1PR transcript in the mouse brain and in mouse and human brain endothelial cells (20-100 mRNA copies per cell). S1PR1 transcripts were significantly enriched (~6 fold) in mouse cortical microvessels compared to total brain. Using the S1PR1-eGFP knock in mouse, we found that S1PR1-eGFP is abundantly expressed in the cerebrovascular endothelium in the mouse brain. A similar pattern of expression was observed in human brain samples. Endothelial specific deletion of S1PR1 in adult mice (S1pr1flox/floxxCdh5-CreERT2, referred to asS1pr1iECKO), resulted in exacerbation of brain edema, neuronal injury and worsened neurological outcomes upon SAH compared toS1pr1flox/floxlittermates. No differences in the subarachnoid blood, hemostasis or cerebral blood flow changes during and after SAH were found between groups. Mechanistically,S1pr1iECKOexhibited aggravated BBB dysfunction and increased phosphorylation of myosin light chain (MLC) in isolated cortical microvessels, a downstream effector of the Rho-ROCK pathway implicated in endothelial inflammation and barrier dysfunction. Taken together, our data indicate that S1PR1 is an endogenous protective signaling pathway in the endothelium, critical to maintain BBB function and to mitigate neuronal injury in pathological conditions. Thus, the therapeutic and diagnostic potential of the endothelial sphingosine-1-phosphate pathway in stroke deserves further study.
An integrative systems biology and experimental approach identifies convergence of epithelial plasticity, metabolism, and autophagy to promote chemoresistance
Authors: Xu Shengnan , Ware Kathryn E. , Ding Yuantong , Kim So Young , Sheth Maya , Rao Sneha , Chan Wesley , Armstrong Andrew J. , Eward William C. , Jolly Mohit K. , Somarelli Jason A.
Published: July 2018

The evolution of therapeutic resistance is a major cause of death for patients with solid tumors. The development of therapy resistance is shaped by the ecological dynamics within the tumor microenvironment and the selective pressure induced by the host immune system. These ecological and selective forces often lead to evolutionary convergence on one or more pathways or hallmarks that drive progression. These hallmarks are, in turn, intimately linked to each other through gene expression networks. Thus, a deeper understanding of the evolutionary convergences that occur at the gene expression level could reveal vulnerabilities that could be targeted to treat therapy-resistant cancer. To this end, we used a combination of phylogenetic clustering, systems biology analyses, and wet-bench molecular experimentation to identify convergences in gene expression data onto common signaling pathways. We applied these methods to derive new insights about the networks at play during TGF-β-mediated epithelial-mesenchymal transition in a lung cancer model system. Phylogenetics analyses of gene expression data from TGF-β treated cells revealed evolutionary convergence of cells toward amine-metabolic pathways and autophagy during TGF-β treatment. Using high-throughput drug screens, we found that knockdown of the autophagy regulatory, ATG16L1, re-sensitized lung cancer cells to cancer therapies following TGF-β-induced resistance, implicating autophagy as a TGF-β-mediated chemoresistance mechanism. Analysis of publicly-available clinical data sets validated the adverse prognostic importance of ATG16L expression in multiple cancer types including kidney, lung, and colon cancer patients. These analyses reveal the usefulness of combining evolutionary and systems biology methods with experimental validation to illuminate new therapeutic vulnerabilities.
Intentional gestures predict complex sociality in wild chimpanzee
Authors: Roberts Anna Ilona , Roberts Sam George Bradley
Published: July 2018

A key challenge for primates is coordinating behavior with conspecifics in large, complex social groups. Gestures play a key role in this process and chimpanzees show considerable flexibility communicating through single gestures, sequences of gestures interspersed with periods of response waiting (persistence) and rapid sequences where gestures are made in quick succession, too rapid for the response waiting to have occurred. Previous studies examined behavioral reactions to single gestures and sequences, but whether this complexity is associated with more complex sociality at the level of the dyad partner and the group as a whole is not well understood. We used social network analysis to examine how the production of single gestures and sequences of gestures was related to the duration of time spent in proximity and individual differences in proximity in wild East African chimpanzees (Pan troglodytes schweinfurthii). Pairs of chimpanzees that spent a longer duration of time in proximity had higher rates of persistence, but not a higher rate of single gesture or rapid sequences. Central individuals in the social network received higher rates of persistence, but not rapid sequence or single gesture. Intentional gestural communication plays an important role in regulating social interactions in complex primate societies.
CTCF sites display cell cycle dependent dynamics in factor binding and nucleosome positioning
Authors: Oomen Marlies E. , Hansen Anders S. , Liu Yu , Darzacq Xavier , Dekker Job
Published: July 2018

CTCF plays a key role in formation of topologically associating domains (TADs) and loops in interphase. During mitosis TADs are absent, but how TAD formation is dynamically controlled during the cell cycle is not known. Several contradicting observations have been made regarding CTCF binding to mitotic chromatin using both genomics and microscopy-based techniques. Here we have used 4 different assays to address this debate. First, using 5C we confirmed that TADs and CTCF loops are readily detected in interphase, but absent during prometaphase. Second, ATAC-seq analysis showed that CTCF sites display greatly reduced accessibility and lose the CTCF footprint in prometaphase, suggesting loss of CTCF binding and rearrangement of the nucleosomal array around the binding motif. In contrast, transcription start sites remain accessible in prometaphase, although adjacent nucleosomes can also become repositioned and occupy at least a subset of start sites during mitosis. Third, loss of site-specific CTCF binding was directly demonstrated using CUT&RUN. Histone modifications and histone variants are maintained in mitosis, suggesting a role in bookmarking of active CTCF sites. Finally, live-cell imaging, fluorescence recovery after photobleaching and single molecule tracking showed that almost all CTCF chromatin binding is lost in prometaphase. Combined, our results demonstrate loss of CTCF binding to CTCF sites during prometaphase and rearrangement of the chromatin landscape around CTCF motifs. This contributes to loss of TADs and CTCF loops during mitosis, and reveals that CTCF sites, a key architectural cis-element of the genome, display cell cycle stage-dependent dynamics in factor binding and nucleosome positioning.
Analysis of Local Variability and Allostery in Macromolecular Assemblies using Cryo-EM and Focused Classification
Authors: Zhang Cheng , Cantara William , Jeon Youngmin , Musier-Forsyth Karin , Grigorieff Nikolaus , Lyumkis Dmitry
Published: July 2018

Single-particle electron cryo-microscopy and computational image classification can be used to analyze structural variability in macromolecules and their assemblies. In some cases, a particle may contain different regions that each display a range of distinct conformations. We have developed strategies, implemented within the Frealign andcisTEM image processing packages, to focus classify on specific regions of a particle and detect potential covariance. The strategies are based on masking the region of interest using either a 2-D mask applied to reference projections and particle images, or a 3-D mask applied to the 3-D volume. We show that focused classification approaches can be used to study structural allostery, a concept that is likely to gain more importance as datasets grow in size, allowing the distinction of more structural states and smaller differences between states. Finally, we apply the approaches to an experimental dataset containing the HIV-1 Transactivation Response (TAR) element RNA fused into the large bacterial ribosomal subunit, to deconvolve structural mobility within localized regions of interest.

Highlights

Description of different image classification strategies in single-particle cryo-EM

Quantitative evaluation of two classification methods using simulated data

Application of the two classification methods to an experimental dataset
Expression estimation and eQTL mapping for HLA genes with a personalized pipeline
Authors: Aguiar Vitor R.C. , Cesar Jonatas E. , Delaneau Olivier , Dermitzakis Emmanouil T. , Meyer Diogo
Published: July 2018

The HLA (Human Leukocyte Antigens) genes are well-documented targets of balancing selection, and variation at these loci is associated with many disease phenotypes. Variation in expression levels also influences disease susceptibility and resistance, but little information exists about the regulation and population-level patterns of expression due to the difficulty in mapping short reads to these highly polymorphic loci, and in accounting for the existence of several paralogues. We developed a computational pipeline to accurately estimate expression for HLA genes based on RNA-seq, improving both locus-level and allele-level estimates. First, reads are aligned to all known HLA sequences in order to infer HLA genotypes, then quantification of expression is carried out using a personalized index. We use simulations to show that expression estimates are not biased due to divergence from the reference genome. We applied our pipeline to GEUVADIS dataset, and compared the quantifications to those obtained with reference transcriptome, and found that a substantial portion of the variation captured by the HLA-personalized index in not captured by the standard index (23%). We describe the impact of the HLA-personalized approach on downstream analyses for seven HLA loci (HLA-A, HLA-B, HLA-C, HLA-DPB1, HLA-DQA1, HLA-DQB1, HLA-DRB1). Although the influence of the HLA-personalized approach is modest for eQTL mapping, the p-values and the causality of the eQTLs obtained are better than when the reference transcriptome is used. Finally, we integrate information on HLA-allele level expression with the eQTL findings to show that the HLA allele is an important layer of variation to understand HLA regulation.
Comprehensive analysis of potential immunotherapy genomic biomarkers in 1,000 Chinese patients with cancer
Authors: Jiao Shunchang , Zang Yuansheng , Dai Chun , Xu Xiaoman , Cai Xin , Wang Guan , Wei Jinwang , Wu Angela , Sun Wending , Xu Qiang
Published: July 2018

Background

Tumor mutation burden (TMB), DNA mismatch repair deficiency (dMMR), microsatellite instability (MSI), and PD-L1 amplification (PD-L1 AMP) may predict the efficacy of PD-1/PD-L1 blockade. In this study, we aimed to characterize the distributions of these biomarkers in over 1,000 Chinese patients with cancer.

Methods

TMB, MSI, dMMR, and PD-L1 AMP were determined based on whole-exome sequencing of tumor/blood samples from > 1,000 Chinese patients with cancer.

Results

Incidence rates among 953 Chinese patients with cancer showing high TMB (TMB-H), high MSI (MSI-H), dMMR and PD-L1 AMP were 35%, 4%, 0.53% and 3.79%, respectively. We found higher rates of TMB-H among hepatocellular carcinoma, breast cancer, and esophageal cancer patients than was reported for The Cancer Genome Atlas data. Lung cancer patients withEGFRmutations had significantly lower TMB values than those with wild-typeEGFR, and increased TMB was significantly associated with dMMR in colorectal cancer (CRC). The frequency of tumors with MSI-H was highest in CRC (14%) and gastric cancer (4%). PD-L1 AMP occurred most frequently in lung squamous cell carcinoma (14.3%) and HER2-positive breast cancer (8.8%). Most MSI-H and dMMR cases exhibited TMB-H, but the overlap among the other biomarkers was low.

Conclusion

While MSI and dMMR are associated with higher mutational loads, correlations between TMB-H and other biomarkers, between MSI-H and dMMR, and between PD-L1 AMP and other biomarkers were low, indicating different underlying causes of the four biomarkers. Thus, it is recommended that all four biomarkers be assessed for certain cancers before administration of PD-1/PD-L1 blockade treatment.
P2X antagonists inhibit HIV-1 productive infection and inflammatory cytokines IL-10 and IL-1β in a human tonsil explant model
Authors: Soare Alexandra Y. , Durham Natasha D. , Gopal Ramya , Tweel Benjamin , Hoffman Kevin W. , Brown Julia A. , O’Brien Megan , Bhardwaj Nina , Lim Jean K. , Chen Benjamin K. , Swartz Talia H.
Published: July 2018

HIV-1 causes a persistent infection of the immune system that is associated with chronic comorbidities. The mechanisms that underlie this inflammation are poorly understood. Emerging literature has implicated pro-inflammatory purinergic receptors and downstream signaling mediators in HIV-1 infection. This study probed whether inhibitors of purinergic receptors would reduce HIV-1 infection and HIV-1 stimulated inflammation. A human ex vivo human tonsil histo-culture infection model was developed to support HIV-1 productive infection and stimulated inflammatory cytokine interleukin-1 beta (IL-1β) and immunosuppressive cytokine, interleukin-10 (IL-10). This study tests whether inhibitors of purinergic receptors would reduce HIV-1 infection and HIV-1 stimulated inflammation. The purinergic P2X1 receptor antagonist, NF449, the purinergic P2X7 receptor antagonists, A438079, and azidothymidine (AZT) were tested in HIV-1 infected human tonsil explants to compare inhibition of HIV-1 infection and HIV-stimulated inflammatory cytokine production. All drugs limited HIV-1 productive infection but P2X-selective antagonists (NF449, and A438079) significantly lowered HIV-stimulated IL-10 and IL-1β. We further observed that P2X1- and P2X7-selective antagonists can act differentially as inhibitors of both HIV-1 infection and HIV-1-stimulated inflammation. Our findings highlight the differential effects of HIV-1 on inflammation in peripheral blood as compared to lymphoid tissue. For the first time, we demonstrate that P2X-selective antagonists act differentially as inhibitors of both HIV-1 infection and HIV-1-stimulated inflammation. Drugs that block these pathways can have independent inhibitory activities against HIV-1 infection and HIV-induced inflammation.

Importance

Patients who are chronically infected with HIV-1 experience sequelae related to chronic inflammation. The mechanisms of this inflammation have not been elucidated. Here we describe a class of drugs that target the P2X pro-inflammatory signaling receptors in a human tonsil explant model. This model highlights differences in HIV-1 stimulation of lymphoid tissue inflammation and peripheral blood. These drugs serve to both block HIV-1 infection and production of IL-10 and IL-1β in lymphoid tissue suggesting a novel approach to HIV-1 therapeutics in which both HIV-1 replication and inflammatory signaling are simultaneously targeted.
Bloodstream Infection with Extended-spectrum Beta-lactamase–producingEscherichia coli: the role of virulence genes
Authors: Hung Wan-Ting , Cheng Ming-Fang , Tseng Fan-Chen , Chen Yao-Shen , Lee Susan Shin-Jung , Chang Tsung-Hsien , Lin Hsi-Hsun , Hung Chih-Hsin , Wang Jiun-Ling
Published: July 2018

Background

Various bacterial putative virulence factors are involved in the pathogenesis of bacterial infection. However, the effect of comorbidities or infection syndrome in the association of virulence factors and mortality remains inconclusive.

Method

This study addressed whether specific sequence type (ST) and virulence factors of extended-spectrum beta-lactamase–producingEscherichia coli(ESBL-EC) are associated with different outcomes in patients with bloodstream infection.121 adults from southern Taiwan with ESBL-producingE. colibloodstream infections were enrolled during a 6-year period. Demographic data, including infection syndromes, underlying disease and outcomes, were collected. The virulence factors in isolates were analyzed by PCR and multilocus sequence typing.

Result

Positivity for the virulence genes iha,hlyD,sat,iut,fyu,malX,ompT,uspandtraTwas associated with ST131 positivity (P<0.05). Some ESBL-EC virulence genes associated with urinary tract infection (UTI) were revealed. Positivity for ST405 and the virulence genesiroNandisswas significantly associated with increased 30-day mortality (death within 30 days) on univariate analysis (P<0.05). Independent risk factors of 30-day mortality in bacteremic patients with UTI included underlying chronic liver disease and malignancy. ST131 was borderline associated with 30-day mortality. Independent risk factors associated with 30-day mortality among bacteremic patients without UTI included comorbidities andiroNpositivity.

Conclusion

In bacteremic patients with UTI, and the ST131 clone was borderline associated with mortality. Positivity for the virulence geneiroNmay be linked to mortality in bacteremic patients without UTI.
How Mg2+stimulates DNA repair in prokaryotic (6-4) photolyases
Authors: Ma Hongju , Holub Daniel , Gillet Natacha , Kaeser Gero , Thoulass Katharina , Elstner Marcus , Krauß Norbert , Lamparter Tilman
Published: July 2018

Prokaryotic (6-4) photolyases branch at the base of the evolution of cryptochromes and photolyases. In theAgrobacterium(6-4) photolyase PhrB, the repair of DNA with UV-induced (6-4) pyrimidin dimers is stimulated by Mg2+. We show that Mg2+is required for efficient lesion binding and for charge stabilization after electron transfer from the FADH-chromophore to the DNA lesion. Two highly conserved Asp residues close to the DNA binding site are essential for the Mg2+effect. Simulations showed that two Mg2+bind to the region around these residues. DNA repair by eukaryotic (6-4) photolyases is not increased by Mg2+. Here, the structurally overlapping region contains no Asp but positively charged Lys or Arg. During evolution, charge stabilization and DNA binding by Mg2+was therefore replaced by a positive amino acid. We argue that this transition has evolved in a freshwater environment. Prokaryotic (6-4) photolyases usually contain an FeS cluster. DNA repair of a cyanobacterial member of this group which is missing the FeS cluster was also found to be stimulated by Mg2+.
Multipurpose virtual reality environment for biomedical and health applications
Authors: Torner Jordi , Skouras Stavros , Molinuevo José L. , Gispert Juan D. , Alpiste Francisco
Published: July 2018

Virtual reality is a trending, widely accessible, contemporary technology of increasing utility to biomedical and health applications. However, most implementations of VR environments are tailored to specific applications. We describe the complete development of a novel, open-source virtual reality environment that is suitable for multipurpose biomedical and healthcare applications. The developed environment simulates an immersive (first-person perspective) run in the countryside, in a virtual landscape with various salient features. The utility of the developed VR environment has been validated via two test usage cases: an application in the context of motor rehabilitation following injury of the lower limbs and an application in the context of real-time functional magnetic resonance imaging neurofeedback, to regulate brain function in specific regions of interest. The resulting test applications suggest that the implemented approach is robust, versatile and efficient. Both applications are publicly available via a GitHub repository, in support of the Open Science initiative. We anticipate our contribution to catalyze further progress and replicability with regards to the usage of virtual reality in biomedical and health applications.

Index Terms— Motor rehabilitation, neurofeedback, virtual reality.