bluuebunny/crossref_metadata_2025 huggingface dataset:
Origins and effects of mix on magnetized liner inertial fusion target performance
Authors: Knapp P. F. , Gomez M. R. , Hansen S. B. , Glinsky M. E. , Jennings C. A. , Slutz S. A. , Harding E. C. , Hahn K. D. , Weis M. R. , Evans M. , Martin M. R. , Harvey-Thompson A. J. , Geissel M. , Smith I. C. , Ruiz D. E. , Peterson K. J. , Jones B. M. , Schwarz J. , Rochau G. A. , Sinars D. B. , McBride R. D. , Gourdain P.-A.
Published: January 2019

In magneto-inertial-fusion experiments, energy losses such as a radiation need to be well controlled in order to maximize the compressional work done on the fuel and achieve thermonuclear conditions. One possible cause for high radiation losses is high-Z material mixing from the target components into the fuel. In this work, we analyze the effects of mix on target performance in Magnetized Liner Inertial Fusion (MagLIF) experiments at Sandia National Laboratories. Our results show that mix is likely produced from a variety of sources, approximately half of which originates during the laser heating phase and the remainder near stagnation, likely from the liner deceleration. By changing the “cushion” component of MagLIF targets from Al to Be, we achieved a 10× increase in neutron yield, a 60% increase in ion temperature, and an ∼50% increase in fuel energy at stagnation.
Unification of field emission and space charge limited emission with collisions
Authors: Darr Adam M. , Loveless Amanda M. , Garner Allen L.
Published: January 2019

Electron emission plays a vital role in device design for systems with pressures ranging from vacuum to atmospheric pressure. Nonuniform pressure in vacuum devices and gap sizes below microscale for electronics near atmospheric pressure necessitate further theoretical characterization of the transition between electron emission phenomena. This letter incorporates collisions into analytical equations describing the transition from the Fowler-Nordheim (FN) equation for field emission to space-charge limited emission (SCLE). We recover the Child-Langmuir (CL) law for vacuum, SCLE at high mobility μ, and the Mott-Gurney (MG) law for collisional SCLE at low μ. The exact solutions follow asymptotic solutions for FN at low voltage V, before transitioning to MG at higher V, and, ultimately, to CL independent of μ. We also define a never before seen “triple-point,” where the asymptotic solutions of all three electron emission regimes converge. Fixing V, μ, or gap distance D uniquely specifies the other two parameters to achieve this triple point, which defines a regime where the electron emission mechanism is very sensitive to experimental conditions. The implications on device design are discussed.
doFORC tool for calculating first-order reversal curve diagrams of noisy scattered data
Authors: Cimpoesu Dorin , Dumitru Ioan , Stancu Alexandru
Published: January 2019

The first-order reversal curve (FORC) diagram method is one of the most successful characterization techniques used to characterize complex hysteretic phenomena not only in magnetism but also in other areas of science like in ferroelectricity, geology, archeology, in spin-transition materials, etc. Because the definition of the FORC diagram involves a second-order derivative, the main problem in their numerical calculation is that the derivative of a function for which only discrete noise-contaminated data values are available magnifies the noise that is inevitably present in measurements. In this paper, we present the doFORC tool for calculating FORC diagrams of noise scattered data. It can provide both a smooth approximation of the measured magnetization and all its partial derivatives. Even if doFORC is mainly dedicated to FORC diagrams’ computation, it can process a general set of arbitrarily distributed two-dimensional points. doFORC is a free, portable application working on various operating systems, with an easy to use graphical interface, with four regression methods implemented to obtain a smooth approximation of the data which may then be differentiated to obtain approximations for derivatives. In order to perform the diagnostics and goodness of fit, doFORC computes residuals to characterize the difference between the observed and predicted values, generalized cross-validation to measure the predictive performance, two information criteria to quantify the information that is lost by using an approximate model, and three degrees of freedom to compare different amounts of smoothing being performed by different smoothing methods. Based on these, doFORC can perform automatic smoothing parameter selection.
Alpha heating enhancement in MagLIF targets: A simple analytic model
Authors: Paradela J. , García-Rubio F. , Sanz J.
Published: January 2019

In this article, a dynamic ignition criterion for magnetized cylindrical implosions is derived. The analysis of the hot spot dynamics after stagnation performed by Christopherson et al. [Phys. Plasmas 25, 012703 (2018)] for spherical implosions is extended to cylindrical geometry with the addition of an external magnetic field. The hot spot dynamics have been consistently solved with a kinetic model for the alpha particle motion. The magnetic field confines the alpha particles and enhances their energy deposition inside the fuel. The ignition criterion is based on the identification of ignited solutions, where pressure exhibits a singularity in finite time and neutron yield diverges. It is formulated in terms of a normalized Lawson parameter and the magnetization of the alpha particles at stagnation. The beneficial effect of magnetizing the fuel to increase the neutron yield is asserted by the analysis.
Experimental investigation of the electron impact excitation behavior in pulse-modulated radio frequency Ar/O2 inductively coupled plasma
Authors: Xue Chan , Gao Fei , Wen De-Qi , Wang You-Nian
Published: January 2019

In inductively coupled plasmas (ICPs), mode transition between capacitive coupling (E mode) and inductive coupling (H mode) is a key issue. Using an intensified charge-coupled device camera, the mode transition-related behaviors of the electron impact excitation of Ar(2p1) are investigated under different discharge conditions in pulse-modulated radio-frequency (rf) Ar/O2 ICPs. The initiation time of the E-H mode transition at the initial stage of a pulse period is examined under nanosecond time-resolution for the first time. It is found that the initiation time increases with increasing the applied power (300-600 W), while it decreases with raising the duty cycle (50%-80%) or gas pressure (20-80 mTorr). Besides, we also examined the spatial-temporal electron impact excitation rate over the whole pulse period (microsecond time-resolution), especially in the H mode when the discharge is operated at the steady state. We found that as the O2 content/pressure increases, the electron impact excitation axially concentrates closer to the quartz window, and the bimodal structure becomes more prominent in the H mode. However, the excitation gets farther away from the window at higher power. In addition, the maximum value of the excitation rate appears earlier at the initial stage of a pulse period at higher pressure/O2 content.
Operando monitoring of charging-induced defect formation in battery electrodes by positrons
Authors: Klinser G. , Kren H. , Koller S. , Würschum R.
Published: January 2019

The defect specific technique of positron–electron annihilation is utilized in an appropriate electrochemical cell for operando monitoring of vacancy-type defect formation which occurs in battery electrodes upon charging, using the cathode material LiNi1/3Mn1/3Co1/3O2 as a case study. The variation of the positron lifetime with charging-induced Li ion extraction indicates the formation of divacancies and vacancy agglomerates in a progressive amount as well as a reordering of vacancy agglomerates to one-dimensional vacancy chains at the end of charging. A remarkable correlation of the charging-induced variation of the positron lifetime with that of Li ion diffusion data in the literature has been found.
Evaluating a research capacity strengthening program for Aboriginal community-controlled health organisations
Authors: Stajic Janet , Harfield Stephen , Brown Alex , Dawson Anna , Davy Carol , Aromataris Edoardo , Braunack-Mayer Annette
Published: January 2019

A Masterclass Program was developed to strengthen the research capacity of staff within Aboriginal Community-Controlled Health Organisations (ACCHOs) and featured three Masterclasses delivered across Australia, including Understanding Research, Undertaking Research and Research Evaluation. A mixed-method process and impact evaluation of the Masterclass Program was undertaken. The process evaluation examined the reach of the Program and the impact evaluation comprised an online survey (n=45) and semi-structured interviews (n=21) with Masterclass participants. During 2014–17, 27 Masterclasses were delivered to 260 people, including predominantly ACCHO personnel but also Indigenous doctors and research institute staff who work closely with the ACCHO sector. Most survey respondents felt the Masterclasses improved their understanding of research and their willingness to participate in and undertake research. The qualitative analysis confirmed this and suggested that Masterclasses were implemented in a supportive learning environment which led to increased research capacity (increased research awareness, changed perceptions, increased understanding, critical thinking and new confidence) and ultimately enhanced research engagement (willingness to participate, motivating others, empowered critique of research partners and proposals, interest in further research training). Barriers to research engagement and areas for improvement of the Masterclass Program before, during and after Masterclasses were also identified.
Marsupial chromosomics: bridging the gap between genomes and chromosomes
Authors: Deakin Janine E. , Potter Sally
Published: January 2019

Marsupials have unique features that make them particularly interesting to study, and sequencing of marsupial genomes is helping to understand their evolution. A decade ago, it was a huge feat to sequence the first marsupial genome. Now, the advances in sequencing technology have made the sequencing of many more marsupial genomes possible. However, the DNA sequence is only one component of the structures it is packaged into: chromosomes. Knowing the arrangement of the DNA sequence on each chromosome is essential for a genome assembly to be used to its full potential. The importance of combining sequence information with cytogenetics has previously been demonstrated for rapidly evolving regions of the genome, such as the sex chromosomes, as well as for reconstructing the ancestral marsupial karyotype and understanding the chromosome rearrangements involved in the Tasmanian devil facial tumour disease. Despite the recent advances in sequencing technology assisting in genome assembly, physical anchoring of the sequence to chromosomes is required to achieve a chromosome-level assembly. Once chromosome-level assemblies are achieved for more marsupials, we will be able to investigate changes in the packaging and interactions between chromosomes to gain an understanding of the role genome architecture has played during marsupial evolution.
Decision making over condom use during menses to avert sexually transmissible infections
Authors: Crosby Richard A. , Graham Cynthia A. , Sanders Stephanie A. , Yarber William L. , Wheeler Marija V. , Milhausen Robin R. , Vitzthum Virginia J.
Published: January 2019

Background
The aim of this study was to test the hypothesis that receptive partners in penile–vaginal intercourse (PVI) who exercise independent decision making over condom use during menses do so to avert sexually transmissible infection (STI) transmission or acquisition. Methods: Data were collected through a partnership with Clue, the industry-leading female health app. A brief web-based questionnaire was developed, translated into 10 languages, and made accessible via a URL link sent to Clue users and posted on social media. Inclusion criteria were: age ≥14 years, not being currently pregnant and engaging in PVI and condom use during menses in the past 3 months. The analytical subsample comprised 12889 respondents residing in 146 countries. Results: Twenty per cent indicated independent decision making about condom use during menses. Independent decision making was associated with lower odds of reporting that condoms were used for contraception (adjusted odds ratio (aOR) 0.65; 99% confidence interval (CI) 0.57–0.73) and higher odds that they were used for the prevention of STIs (aOR 1.44; 99% CI 1.28–1.61). A third significant finding pertained to always using condoms during menses; this was less likely among those indicating independent (female only) decision making (aOR 0.69; 99% CI 0.62–0.78). Non-significant associations with another two outcomes were found: protecting the partner against menstrual blood and protecting themselves against semen. Conclusions: Findings from people in 146 countries strongly support the hypothesis that those exercising independent decision making over condom use during menses do so to avert STI transmission or acquisition. That only one-fifth of this global sample reported this type of independent decision making suggests that empowerment-oriented (structural-level) interventions may be advantageous for individuals who are the receptive partner in PVI that occurs during menses.
Gender influences in agricultural production: the dynamic role of the female farmer.
Authors: Lange K. , Tewari Rachna , Zivkovic S. , McCallister D.
Published: January 2019

Women have played an integral role in agricultural production for centuries. This article reviews multiple perspectives on women's involvement in US agricultural production, including economics, rural sociology, geography, gender ethnography and similarly related fields. We focus on studies surrounding women's roles in US agriculture over time, recent trends of US female farm operators and farm sector gender influences of women.
TPX2 joins 53BP1 to maintain DNA repair and fork stability
Authors: Cantor Sharon
Published: January 2019

In this issue, Byrum et al. (2019. J. Cell Biol. https://doi.org/10.1083/jcb.201803003) surprisingly identify an interaction between 53BP1 and the mitotic regulators TPX2 and Aurora A that lead them to novel mechanistic insights about DNA double-stranded break repair regulation and a new fork protection pathway during replication stress.
A simple convolutional neural network for prediction of enhancer–promoter interactions with DNA sequence data
Authors: Zhuang Zhong , Shen Xiaotong , Pan Wei
Published: January 2019

Motivation

Enhancer–promoter interactions (EPIs) in the genome play an important role in transcriptional regulation. EPIs can be useful in boosting statistical power and enhancing mechanistic interpretation for disease- or trait-associated genetic variants in genome-wide association studies. Instead of expensive and time-consuming biological experiments, computational prediction of EPIs with DNA sequence and other genomic data is a fast and viable alternative. In particular, deep learning and other machine learning methods have been demonstrated with promising performance.

Results

First, using a published human cell line dataset, we demonstrate that a simple convolutional neural network (CNN) performs as well as, if no better than, a more complicated and state-of-the-art architecture, a hybrid of a CNN and a recurrent neural network. More importantly, in spite of the well-known cell line-specific EPIs (and corresponding gene expression), in contrast to the standard practice of training and predicting for each cell line separately, we propose two transfer learning approaches to training a model using all cell lines to various extents, leading to substantially improved predictive performance.

Availability and implementation

Computer code is available at https://github.com/zzUMN/Combine-CNN-Enhancer-and-Promoters.

Supplementary information

Supplementary data are available at Bioinformatics online.
Mapping Alterations of the Functional Structure of the Cerebral Cortex in Obsessive–Compulsive Disorder
Authors: Pujol Jesus , Blanco-Hinojo Laura , Maciá Dídac , Alonso Pino , Harrison Ben J , Martínez-Vilavella Gerard , Deus Joan , Menchón José M , Cardoner Narcís , Soriano-Mas Carles
Published: January 2019

We mapped alterations of the functional structure of the cerebral cortex using a novel imaging approach in a sample of 160 obsessive–compulsive disorder (OCD) patients. Whole-brain functional connectivity maps were generated using multidistance measures of intracortical neural activity coupling defined within isodistant local areas. OCD patients demonstrated neural activity desynchronization within the orbitofrontal cortex and in primary somatosensory, auditory, visual, gustatory, and olfactory areas. Symptom severity was significantly associated with the degree of functional structure alteration in OCD-relevant brain regions. By means of a novel imaging perspective, we once again identified brain alterations in the orbitofrontal cortex, involving areas purportedly implicated in the pathophysiology of OCD. However, our results also indicated that weaker intracortical activity coupling is also present in each primary sensory area. On the basis of previous neurophysiological studies, such cortical activity desynchronization may best be interpreted as reflecting deficient inhibitory neuron activity and altered sensory filtering.
Misuse of Discharge Antimicrobial Prescription in the Emergency Department: An Observational Study at a Tertiary Care Center
Authors: Tagashira Yasuaki , Yamane Naofumi , Miyahara Satoshi , Orihara Azusa , Uehara Yuki , Hiramatsu Keiichi , Honda Hitoshi
Published: January 2019

We conducted a restrospective cohort study of patients discharged from the emergency department at a tertiary care center with an antimicrobial prescription. More than half of the prescribed antimicrobials were misused and frequently inappropriate for various infectious diseases. In this study, we analyzed the physician-related and environment-related factors predicting misuse.
Real Exchange Rates and Currency Risk Premiums
Authors: Balduzzi Pierluigi , Chiang I-Hsuan Ethan
Published: January 2019

Standard finite horizon tests uncover only weak evidence of the predictive power of the real exchange rate for excess currency returns. On the other hand, in long-horizon tests, the real exchange rate strongly and negatively predicts future excess currency returns. Conversely, we can attribute most of the variability in real exchange rates to changes in currency risk premiums. The “habit” and “long-run risks” models replicate the predictive power of the real exchange rate for excess currency returns, but substantially overstate the fraction of the volatility of the real exchange rate due to risk premiums.

Received December 14, 2017; Editorial decision October 14, 2018 by Editor: Raman Uppal. Authors have furnished an Internet Appendix, which is available on the Oxford University Press Web site next to the link to the final published paper online.
A narrative review of the use of agent-based modeling in health behavior and behavior intervention
Authors: Yang Yong
Published: January 2019

The application of ABMs have provided insights on health behavior intervention, but their potential has been not fully explored due to our limited knowledge of behaviors at the individual level.
Building a botanical foundation for perennial agriculture: Global inventory of wild, perennial herbaceous Fabaceae species
Authors: Ciotir Claudia , Applequist Wendy , Crews Timothy E. , Cristea Neculai , DeHaan Lee R. , Frawley Emma , Herron Sterling , Magill Robert , Miller James , Roskov Yury , Schlautman Brandon , Solomon James , Townesmith Andrew , Van Tassel David , Zarucchi James , Miller Allison J.
Published: January 2019

Concerns about soil health and stability are focusing attention on crops that deliver both agricultural products and ecological services. Deep rooted, perennial plants that build soil organic matter, support diverse below-ground microbial communities, and produce edible seeds are key components underpinning ecological intensification; however few perennial, herbaceous crops have been domesticated for food.

To facilitate development of edible, perennial, herbaceous crops, including perennial grains, we constructed an online resource of wild, perennial, herbaceous species – the Perennial Agriculture Project Global Inventory (PAPGI; http://www.tropicos.org/Project/PAPGI). The first component of this project focuses on wild, perennial, herbaceous Fabaceae species. We extracted taxonomic names and descriptors from the International Legume Database and Information Service. Names were added to PAPGI, a special project within the botanical database TROPICOS, where they link to specimen records and ethnobotanical and toxicological data. PAPGI includes 6,644 perennial, herbaceous Fabaceae species. We built a searchable database of more than 60 agriculturally important traits. Here we highlight food and forage uses for 314 legume species, and toxicological data for 278 species.

The novel contribution of PAPGI is its focus on wild, perennial herbaceous species that generally have not entered the domestication process but that hold promise for development as perennial food crops. By extracting botanical information relevant for agriculture we provide a dynamic resource for breeders and plant scientists working to advance ecological intensification of agriculture, and for conservation managers working to preserve wild species of potential agricultural importance.

Societal Impact Statement

Agroecosystems are constantly evolving to meet the needs of a growing population in a sustainable manner. Perennial, herbaceous crops deliver both agricultural products and ecological services. Until recently, edible, perennial, herbaceous crops, including perennial grains, were absent from agriculture. Perennial, herbaceous crops can be developed through wide hybridization between annual crops and perennial relatives or by de novo domestication of wild species. The diversity of wild, perennial, herbaceous legume species documented by the PAPGI increases resources available to breeders of perennial, herbaceous legumes, and raises awareness about previously untapped wild plant diversity in future crop development.
Colistin heteroresistance in Enterobacter cloacae is mediated by PmrAB-independent 4-amino-4-deoxy-L-arabinose addition to lipid A
Authors: Kang Katie N. , Klein Dustin R. , Kazi Misha I. , Guérin François , Cattoir Vincent , Brodbelt Jennifer S. , Boll Joseph M.
Published: January 2019

The Enterobacter cloacae complex (ECC) consists of closely-related, but genetically distinct bacteria commonly associated with the human microbiota. ECC have been increasingly isolated from healthcare-associated infections, demonstrating that these Enterobacteriaceae are emerging nosocomial pathogens. ECC strains can rapidly acquire multidrug resistance to conventional antibiotics. Cationic antimicrobial peptides (CAMPs) have served as therapeutic alternatives because they target the highly conserved lipid A component of the Gram-negative outer membrane to lyse the bacterial cell. Many Gram-negative Enterobacteriaceae fortify their outer membrane with cationic amine-containing moieties to protect from CAMP-inflicted lysis. The PmrAB two-component system (TCS) transcriptionally activates 4-amino-4-deoxy-L-arabinose (L-Ara4N) biosynthesis to result in amine moiety addition to lipid A in many Enterobacteriaceae such as E. coli and Salmonella. In contrast, PmrAB in E. cloacae is dispensable for CAMP resistance. Instead, fitness against CAMPs presents as heteroresistance, or a subpopulation of cells that exhibit clinically significant increases in resistance levels compared to the majority population. We demonstrate that E. cloacae lipid A is modified with L-Ara4N to induce CAMP heteroresistance and that the regulatory mechanism is independent of the PmrABEcl TCS. We show that the response regulator, PhoPEcl, directly binds to the arnBEcl promoter to induce expression of L-Ara4N biosynthesis and PmrAB-independent addition to the lipid A disaccharolipid. Therefore, we have identified a mechanism of ECC colistin heteroresistance that directly involves the PhoPQ system.

Importance

Members of the Enterobacter cloacae complex (ECC) are Gram-negative nosocomial pathogens that have emerged within healthcare facilities around the world. ECC infections are associated with immunocompromised patients and infections are often life threatening. The cationic antimicrobial peptide, colistin (polymyxin E), is a last-line treatment option to combat Gram-negative multidrug resistant infections. However, many ECC intrinsically encode a colistin heteroresistance mechanism. Our analysis to characterize colistin heteroresistance in E. cloacae revealed that 4-amino-4-deoxy-L-arabinose is conjugated to the lipid A disaccharolipid to protect from colistin-mediated lysis. Additionally, this mechanism is directly regulated by the PhoPQEcl two-component system. Elucidation of outer membrane antimicrobial resistance modifications and their regulatory pathways in E. cloacae isolates will advance our understanding of CAMP heteroresistance.
Control of Staphylococcus aureus quorum sensing by a membrane-embedded peptidase
Authors: Cosgriff Chance J. , White Chelsea R. , Ping Teoh Wei , Grayczyk James P. , Alonzo Francis
Published: January 2019

Gram-positive bacteria process and release small peptides or “pheromones” that act as signals for the induction of adaptive traits including those involved in pathogenesis. One class of small signaling pheromones is the cyclic auto-inducing peptides (AIPs), which regulate expression of genes that orchestrate virulence and persistence in a range of microbes including Staphylococci, Listeria, Clostridia, and Enterococci. In a genetic screen for Staphylococcus aureus secreted virulence factors, we identified a S. aureus mutant containing an insertion in gene SAUSA300_1984 (mroQ), which encodes a putative membrane-embedded metalloprotease. A ΔmroQ mutant exhibits impaired induction of TLR2-dependent inflammatory responses from macrophages, but elicits greater production of the inflammatory cytokine IL-1β and is attenuated in a murine skin and soft tissue infection model. The ΔmroQ mutant phenocopies a S. aureus mutant containing a deletion of the accessory gene regulatory system (Agr), wherein both strains have significantly reduced production of secreted toxins and virulence factors, but increased surface Protein A abundance. The Agr system controls virulence factor gene expression in S. aureus through sensing accumulation of AIP via the histidine kinase AgrC and response regulator AgrA. We provide evidence to suggest that MroQ acts within the Agr pathway to facilitate optimal processing or export of AIP for signal amplification through AgrC/A and induction of virulence factor gene expression. Mutation of MroQ active site residues significantly reduces AIP signaling and attenuates virulence. Altogether, this work identifies a new component of the Agr quorum sensing circuit that is critical for the production of S. aureus virulence factors.
Low-dose IFN-γ induces tumor cell stemness in tumor microenvironment of non-small cell lung cancer
Authors: Song Mengjia , Ping Yu , Zhang Kai , Yang Li , Li Feng , Cheng Shaoyan , Yue Dongli , Maimela Nomathamsanqa Resegofetse , Qu Jiao , Liu Shasha , Sun Ting , Li Zihai , Xia Jianchuan , Zhang Bin , Wang Liping , Zhang Yi
Published: January 2019

Interferon-γ (IFN-γ) is conventionally recognized as an inflammatory cytokine that play a central role in antitumor immunity. Clinically, although has been used clinically to treat a variety of malignancies, low-level IFN-γ in the tumor microenvironment (TME) increases the risk of tumor metastasis during immunotherapy. Accumulating evidence has suggested that IFN-γ can induce cancer progression. The mechanisms underlying the controversial role of IFN-γ regulating tumor development remain unclear. Herein, we firstly revealed a dose-dependent effect of IFN-γ in inducing tumor stemness to accelerate cancer progression in patients with a variety of cancer types. Mechanically, low-level IFN-γ endowed cancer stem-like properties via the intercellular adhesion molecule-1 (ICAM1)-PI3K-Akt-Notch1 axis, whereas high-level IFN-γ activated the JAK1-STAT1-caspase pathway to induce apoptosis in non-small cell lung cancer (NSCLC). Inhibition of ICAM1 abrogated the stem-like properties of NSCLC cells induced by the low dose of IFN-γ bothin vitroandin vivo. Our study first defines the role of low-level IFN-γ in conferring tumor stemness and clearly elucidate the distinct signaling pathways activated by IFN-γ in a dose-dependent manner, providing new insights into cancer treatment, particularly patients with low-level IFN-γ expression in the TME.
Hsc70 Ameliorates the Vesicle Recycling Defects Caused by Excess α-Synuclein at Synapses
Authors: Banks Susan M. L. , Medeiros Audrey T. , McQuillan Molly , Busch David J. , Ibarraran-Viniegra Ana Sofia , Roy Subhojit , Sousa Rui , Lafer Eileen M. , Morgan Jennifer R.
Published: January 2019

α-Synuclein overexpression and aggregation are linked to Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and several other neurodegenerative disorders. In addition to effects in the cell body, α-synuclein accumulation occurs at presynapses where the protein is normally localized. While it is generally agreed that excess α-synuclein impairs synaptic vesicle trafficking, the underlying mechanisms are unknown. We show here that acute introduction of excess human α-synuclein at a classic vertebrate synapse, the lamprey reticulospinal synapse, selectively impaired the uncoating of clathrin-coated vesicles (CCVs) during synaptic vesicle recycling, leading to a severe depletion of synaptic vesicles. Furthermore, human α-synuclein and lamprey γ-synuclein both interact in vitro with Hsc70, the chaperone protein that uncoats CCVs at synapses. After introducing excess α-synuclein to lamprey axons, Hsc70 availability was reduced at the synapses, suggesting Hsc70 sequestration as a possible mechanism underlying the synaptic vesicle trafficking defects. In support of this hypothesis, increasing the levels of exogenous Hsc70 together with α-synuclein ameliorated the CCV uncoating and vesicle recycling defects. These experiments identify a reduction in Hsc70 availability at synapses, and consequently its function, as the mechanism by which α-synuclein induces synaptic vesicle recycling defects. To our knowledge, this is the first report of a viable chaperone-based strategy for reversing the toxic impacts of excess α-synuclein at synapses, which may be of value for ameliorating synaptic defects in PD and other synuclein-linked diseases.

SIGNIFICANCE STATEMENT

Synaptic defects caused by α-synuclein overexpression are linked to cognitive deficits in PD and other diseases. However, the mechanisms by which excess α-synuclein impairs synaptic vesicle trafficking are unknown. Data presented here demonstrate that acute introduction of excess α-synuclein at a classical vertebrate synapse selectively inhibits CCV uncoating, leading to impaired vesicle recycling. Furthermore, increasing α-synuclein reduced synaptic levels of Hsc70, the clathrin uncoating ATPase. Subsequently increasing Hsc70 restored CCV uncoating and improved vesicle recycling. This study identifies a novel molecular mechanism underlying the α-synuclein-induced synaptic defects and presents one viable strategy for reversing them.
Lactate and glycerol-3-phosphate metabolism cooperatively regulate growth and redox balance during Drosophila melanogaster larval development
Authors: Li Hongde , Buddika Kasun , Sterrett Maria C. , Julick Cole R. , Pletcher Rose C. , Gosney Chelsea J. , Burton Anna K. , Karty Jonathan A. , Montooth Kristi L. , Sokol Nicholas S. , Tennessen Jason M.
Published: January 2019

The dramatic growth that occurs during Drosophila larval development requires rapid conversion of nutrients into biomass. Many larval tissues respond to these biosynthetic demands by increasing carbohydrate metabolism and lactate dehydrogenase (dLDH) activity. The resulting metabolic program is ideally suited to synthesize macromolecules and mimics the manner by which cancer cells rely on aerobic glycolysis. To explore the potential role of Drosophila dLDH in promoting biosynthesis, we examined how dLdh mutations influence larval development. Our studies unexpectantly found that dLdh mutants grow at a normal rate, indicating that dLDH is dispensable for larval biomass production. However, subsequent metabolomic analyses suggested that dLdh mutants compensate for the inability to produce lactate by generating excess glycerol-3-phosphate (G3P), the production of which also influences larval redox balance. Consistent with this possibility, larvae lacking both dLDH and G3P dehydrogenase (GPDH1) exhibit developmental delays, synthetic lethality, and aberrant carbohydrate metabolism. Considering that human cells also generate G3P upon Lactate Dehydrogenase A (LDHA) inhibition, our findings hint at a conserved mechanism in which the coordinate regulation of lactate and G3P synthesis imparts metabolic robustness upon growing animal tissues.
Seasonal and directional dispersal behavior in an ongoing dove invasion
Authors: Slager David L.
Published: January 2019

The dispersal behavior that underlies range expansions can be difficult to study. Eurasian Collared-Doves have staged independent northwestward invasions across both Europe and North America, reaching carrying capacity in Europe but continuing to increase exponentially in the Americas, where their dispersal behavior remains enigmatic. I used citizen science observations to investigate Eurasian Collared-Dove dispersal behavior along the North American Pacific coast, a natural barrier to land-bird dispersal. Using coastal and pelagic observations, I assessed the seasonality and directionality of dispersal and its prevalence across years. Dispersal flights peaked in spring, like in Europe, and were north-biased, consistent with northwestward initial colonization. A non-significant trend of increasing dispersal across years may reflect evolution of dispersal via spatial sorting and selection. These results inform management of this invasive dove, raise new questions about evolutionary mechanisms behind the invasion, and exemplify using citizen science to study dispersal behavior, a longstanding challenge in ecology.
A Domain-general Cognitive Core defined in Multimodally Parcellated Human Cortex
Authors: Assem Moataz , Glasser Matthew F. , Van Essen David C. , Duncan John
Published: January 2019

Numerous brain imaging studies identified a domain-general or “multiple-demand” (MD) activation pattern accompanying many tasks and may play a core role in cognitive control. Though this finding is well established, the limited spatial localization provided by traditional imaging methods precluded a consensus regarding the precise anatomy, functional differentiation and connectivity of the MD system. To address these limitations, we used data from 449 subjects from the Human Connectome Project, with cortex of each individual parcellated using neurobiologically grounded multi-modal MRI features. The conjunction of three cognitive contrasts reveals a core of 10 widely distributed MD parcels per hemisphere that are most strongly activated and functionally interconnected, surrounded by a penumbra of 17 additional areas. Outside cerebral cortex, MD activation is most prominent in the caudate and cerebellum. Comparison with canonical resting state networks shows MD regions concentrated in the fronto-parietal network but also engaging three other networks. MD activations show modest relative task preferences accompanying strong co-recruitment. With distributed anatomical organization, mosaic functional preferences, and strong interconnectivity, we suggest MD regions are well positioned to integrate and assemble the diverse components of cognitive operations. Our precise delineation of MD regions provides a basis for refined analyses of their functions.
Glycolysis upregulation is neuroprotective as a compensatory mechanism in ALS
Authors: Manzo Ernesto , Lorenzini Ileana , Barrameda Dianne , O’Conner Abigail G. , Barrows Jordan M. , Starr Alexander , Kovalik Tina , Rabichow Benjamin E. , Lehmkuhl Erik M. , Shreiner Dakotah D. , Joardar Archi , Liévens Jean-Charles , Bowser Robert , Sattler Rita , Zarnescu Daniela C.
Published: January 2019

Amyotrophic Lateral Sclerosis (ALS), is a fatal neurodegenerative disorder, with TDP-43 inclusions as a major pathological hallmark. Using a Drosophila model of TDP-43 proteinopathy we found significant alterations in glucose metabolism including increased pyruvate, suggesting that modulating glycolysis may be neuroprotective. Indeed, a high sugar diet improves locomotor and lifespan defects caused by TDP-43 proteinopathy in motor neurons or glia, but not muscle, suggesting that metabolic dysregulation occurs in the nervous system. Overexpressing human glucose transporter GLUT-3 in motor neurons mitigates TDP-43 dependent defects in synaptic vesicle recycling and improves locomotion. Furthermore, PFK mRNA, a key indicator of glycolysis, is upregulated in flies and patient derived iPSC motor neurons with TDP-43 pathology. Surprisingly, PFK overexpression rescues TDP-43 induced locomotor deficits. These findings from multiple ALS models show that mechanistically, glycolysis is upregulated in degenerating motor neurons as a compensatory mechanism and suggest that increased glucose availability is protective.
CIC-DUX4 expression drives the development of small round cell sarcoma in transgenic zebrafish: a new model revealing a role for ETV4 in CIC-mediated sarcomagenesis
Authors: Watson Sarah , Kendall Genevieve C. , Rakheja Dinesh , McFaul Matthew E. , Draper Bruce W. , Tirode Franck , Delattre Olivier , Amatruda James F
Published: January 2019

CIC-DUX4 sarcoma is a rare subtype of sarcoma characterized by a devastating prognosis and resistance to conventional therapeutic strategies. So far, only few models of the disease have been reported, and its biological mechanisms remain to be elucidated. We established mosaic transgenic zebrafish expressing the human CIC-DUX4 fusion under the control of the β-actin promoter. CIC-DUX4 transgenic fish rapidly developed aggressive soft tissue tumors with a high penetrance. RNAseq profiling revealed that fish tumors shared major common targets with human tumors and cell lines, including the overexpression of the Pea3 transcription factors, etv4 and etv5. Tumor development was strongly impaired in etv4-deficient zebrafish, implicating Etv4 as a critical effector of CIC-DUX4-mediated oncogenesis. Altogether, we report here the first in vivo model of CIC-DUX4 sarcoma in zebrafish, which will represent a major tool for future preclinical research.
Economic Burden of Hypoglycaemia among Type II Diabetes Mellitus Patients in Malaysia
Authors: Aljunid Syed Mohamed , Aung Yin New , Ismail Aniza , Abdul Rashid Siti Athirah Zafirah , Nur Amrizal M , Cheah Julius , Matzen Priya
Published: January 2019

Objective

The main aim of this study is to identify the direct cost and economic burden of hypoglycaemia among patients with Type II diabetes mellitus in Malaysia.

Methods

The incurred cost for hypoglycaemia among patients admitted to University Kebangsaan Malaysia Medical Centre (UKMMC) was explored from a cross sectional study. 20-79 year patients discharged between Jan 2010 to Sept 2015 and having an ICD-10 code of hypoglycaemia as a primary diagnosis in the casemix database were included in the study. Costing analysis from the perspective of health providers was completed using step-down approach. Data related to hospital cost were collected using hospital-costing template, based on three levels of cost centres. The costing data from UKMMC was used to estimate the national burden of hypoglycaemia among type II diabetics for the whole country.

Results

Of 244 diabetes patients admitted primarily for hypoglycaemia to UKMMC, 52% were female and 88% were over 50 years old. The cost increased with severity. Managing a hypoglycaemic case requires 5 days (median) of inpatient stay with a range of 2-26 days; and costs RM 9,083 (USD 2,323). 30% of the cost came from the ward services cost (final cost centre), 16% of the cost came from ICU services and 15% from pharmacy services(secondarylevel cost centres). Based on the prevalence of hypoglycaemia-related admissions of 3.2%, the total cost of care for hypoglycaemia among adult diabetes in Malaysia is estimated to be RM 117.4 (USD 30.0) million, which is translated as 0.5% of Ministry of Health budget.

Conclusion

Hypoglycaemia imposes substantial economic impact even without the direct and indirect cost incurred by patients and other cost of complications. Proper diabetic care and health education is needed in diabetic management to reduce episodes of hypoglycaemia.
Transposon insertional mutagenesis in Saccharomyces uvarum reveals trans-acting effects influencing species-dependent essential genes
Authors: Sanchez Monica R. , Payen Celia , Cheong Frances , Hovde Blake T. , Bissonnette Sarah , Arkin Adam P. , Skerker Jeffrey M. , Brem Rachel B. , Caudy Amy A. , Dunham Maitreya J.
Published: January 2019

To understand how complex genetic networks perform and regulate diverse cellular processes, the function of each individual component must be defined. Comprehensive phenotypic studies of mutant alleles have been successful in model organisms in determining what processes depend on the normal function of a gene. These results are often ported to newly sequenced genomes by using sequence homology. However, sequence similarity does not always mean identical function or phenotype, suggesting that new methods are required to functionally annotate newly sequenced species. We have implemented comparative analysis by high-throughput experimental testing of gene dispensability in Saccharomyces uvarum, a sister species of Saccharomyces cerevisiae. We created haploid and heterozygous diploid Tn7 insertional mutagenesis libraries in S. uvarum to identify species-dependent essential genes, with the goal of detecting genes with divergent functions and/or different genetic interactions. Comprehensive gene dispensability comparisons with S. cerevisiae predicted diverged dispensability at 12% of conserved orthologs, and validation experiments confirmed 22 differentially essential genes. Despite their differences in essentiality, these genes were capable of cross-species complementation, demonstrating that trans-acting factors that are background-dependent contribute to differential gene essentiality. This study shows that direct experimental testing of gene disruption phenotypes across species can inform comparative genomic analyses and improve gene annotations. Our method can be widely applied in microorganisms to further our understanding of genome evolution.
Crystal structure of 7′-(4-chlorophenyl)-2′′-(4-methoxyphenyl)-7′,7a',7′′,8′′-tetrahydro-1′H,3′H,5′′H-dispiro[indoline-3,5′-pyrrolo[1,2-c]thiazole-6′,6′′-quinoline]-2,5′′-dione and an unknown solvent
Authors: Vishnupriya R. , Venkateshan M. , Suresh J. , Sumesh R. V. , Kumar R. Ranjith , Lakshman P. L. Nilantha
Published: January 2019

The asymmetric unit of the title compound, C34H28ClN3O3S, contains two independent molecules (A and B). They differ essentially in the orientation of the 4-methoxyphenyl ring with respect to the pyridine ring of the quinoline moiety; this dihedral angle is 37.01 (18)° in molecule A but only 7.06 (17)° in molecule B. In both molecules, the cyclohexanone ring of the isoquinoline unit has a half-chair conformation. In the pyrrolothiazole ring system, the pyrrolo ring in molecule A has a twisted conformation on the N—C fused bond and an envelope conformation in molecule B with the N atom as the flap. The thiazole rings of both molecules have twisted conformations on the N—C fused bond. In the crystal, the A molecules are linked by pairs of N—H...O hydrogen bonds, forming inversion dimers with an R
2
2(8) ring motif. These dimers are linked to the B molecules by an N—H...N hydrogen bond and a series of C—H...O hydrogen bonds, forming layers lying parallel to the (101) plane. The layers are linked by C—H...π interactions and offset π–π interactions [intercentroid distance = 3.427 (1) Å], forming a supramolecular framework. The contribution to the scattering from a region of highly disordered solvent molecules was removed with the SQUEEZE routine in PLATON [Spek (2015). Acta Cryst. C71, 9–18]. The solvent formula mass and unit-cell characteristics were not taken into account during refinement.
Three closely related 1-[(1,3-benzodioxol-5-yl)methyl]-4-(halobenzoyl)piperazines: similar molecular structures but different intermolecular interactions
Authors: Mahesha Ninganayaka , Sagar Belakavadi K. , Yathirajan Hemmige S. , Furuya Tetsundo , Haraguchi Tomoyuki , Akitsu Takashiro , Glidewell Christopher
Published: January 2019

In each of the compounds 1-[(1,3-benzodioxol-5-yl)methyl]-4-(3-fluorobenzoyl)piperazine, C19H19FN2O3 (I), 1-[(1,3-benzodioxol-5-yl)methyl]-4-(2,6-difluorobenzoyl)piperazine, C19H18F2N2O3 (II), and 1-[(1,3-benzodioxol-5-yl)methyl]-4-(2,4-dichlorobenzoyl)piperazine, C19H19Cl2N2O3 (III), the piperazine rings adopt a chair conformation with the (1,3-benzodioxol-5-yl)methyl substituent occupying an equatorial site: the five-membered rings are all slightly folded across the O...O line leading to envelope conformations. The dihedral angle between the planar amidic fragment and the haloaryl ring is 62.97 (5)° in (I) but 77.72 (12)° and 75.50 (5)° in (II) and (III), respectively. Despite their similarity in constitution and conformation, the supramolecular interactions in (I)–(III) differ: in (I), a combination of C—H...O and C—H...π(arene) hydrogen bonds links the molecules into a three-dimensional framework structure, but there are no hydrogen bonds of any sort in either (II) or (III), although the structure of (III) contains a short Cl...Cl contact between inversion-related pairs of molecules.
25,27-(3,6,9-Trioxaundecane-1,11-dioxy)-26,28-{3-[4-(tricyanoethylene)phenyl]-3-azapentane-1,5-dioxy}calix[4]arene dichloromethane monosolvate
Authors: Lee Jae Myoung , Kim Sung Baek , Sim Wonbo , Lee Jai Young
Published: January 2019

The title compound, C51H48N2O7, was synthesized by the reaction of 25,27-(3,6,9-trioxaundecane-1,11-dioxy)-26,28-(3-phenyl)-3-azapentane-1,5-dioxy)calix[4]arene with tetracyanoethylene in dry DMF. The compound has a 1,3-alternate conformation with an oxo-crown-5 unit and an aza-crown-3 unit with a nitrogen atom connecting tricyanoethylenephenyl group as a chromophore. Pairs of benzene rings of the calixarene are facing one another. Three of the four oxygen atoms connected to a benzene have endo-conformations while the other is exo. The oxo-crown-5 system has a t–g–g–t conformation. The dichloromethane solvent molecule is linked to the main molecule by a C—H...Cl hydrogen bond. In the crystal, C—H...O, C—H...Cl hydrogen bonds and C—H...π(ring) interactions are observed.