bluuebunny/crossref_metadata_2025 huggingface dataset:
Pain and quality of life in youth with inflammatory bowel disease: the role of parent and youth perspectives on family functioning
Authors: Caes Line , Chambers Christine T. , Otley Anthony , Stinson Jennifer
Published: March 2019

Introduction:

Daily pain experiences are a common feature of pediatric inflammatory bowel disease (IBD), which can negatively influence their health-related quality of life (HRQOL). A holistic, family systems approach is needed to further our understanding of daily pain experiences in youth with IBD and their influence on youth's HRQOL.

Objectives:

The study's objectives were to (1) provide a detailed description of daily pain experiences in youth with IBD, (2) investigate the relative contribution of family functioning and pain in explaining youth's HRQOL, and (3) explore differences in parental and youth perspectives.

Methods:

Sixty youth with IBD (8–17 years) and a parent completed questionnaires to assess family functioning, HRQOL, and pain experiences within the past week. A subsample of 16 youth completed an online diary (7 days) about their pain experiences.

Results:

When including any pain experiences, higher youth-reported family satisfaction and lower pain intensity were related to better HRQOL, whereas higher parent-reported family cohesion and satisfaction indirectly related to youth HRQOL through lower pain intensity. When only accounting for abdominal pain, pain intensity related negatively with HRQOL, and only parent-reported cohesion showed an indirect relation with HRQOL through pain intensity. Diary data revealed large heterogeneity: abdominal pain, described as cramping, sharp, and/or stinging was most frequent, but other pain symptoms (eg, back pain and headache) often co-occurred.

Conclusion:

The findings provide a rich picture of the daily pain experiences of youth with IBD and underscore the importance of a family systems approach to understand how family functioning and pain symptoms influence HRQOL.
When Global ART Budgets Cannot Cover All Patients, Who Should Be Eligible?
Authors: Zhang Yi , Bärnighausen Till , Eyal Nir
Published: March 2019

Background:

Widely expected cuts to budgets for global HIV/AIDS response force hard prioritization choices.

Setting:

We examine policies for antiretroviral therapy (ART) eligibility through the lens of the most relevant ethical approaches.

Methods:

We compare earlier ART eligibility to later ART eligibility in terms of saving the most lives, life-years, and quality-adjusted life-years, special consideration for the sickest, special consideration for those who stand to benefit the most, special consideration for recipients' own health needs, and special consideration to avoid denying ART permanently.

Results:

We argue that, in most low- and middle-income countries with generalized HIV/AIDS epidemic, ethically, ART for sicker patients should come before ART eligibility for healthier ones immediately on diagnosis (namely, before “universal test and treat”). In particular, reserving all ART for sicker patients would usually save more life-years, prioritize the sickest, and display other properties that some central ethical approaches find important, and that concern none—so ethically, it is “cross-theoretically dominant,” as we put it.

Conclusions:

In most circumstances of depressed financing in low- and middle-income countries with generalized HIV/AIDS epidemic, reserving all ART for sicker patients is more ethical than the current international standard.
Maxillofacial Injuries Due to Traffic Accidents
Authors: Roccia Fabio , Sotong Jacqueline , Savoini Matteo , Ramieri Guglielmo , Zavattero Emanuele
Published: March 2019

Purpose:

The purpose of this retrospective study was to analyze the epidemiology, patterns, and management of maxillofacial due to road traffic accidents over a 17-year period.

Methods:

Between January 2001 and December 2017, 2924 patients with maxillofacial fractures were admitted to the Division of Maxillofacial Surgery, Turin, Italy.

The following data were analyzed: age, gender, data of the trauma, alcohol and drug abuse, mechanism of injury, fracture site, facial injury severity scale, associated injuries, type of treatment, and length of hospital stay.

Results:

Of the 605 patients included in the study, 419 were male and 186 were female (ratio, 2.2:1). The most common mechanism of injury was car accidents (62.6%).

More than half of the patients had fractures of the middle third of the maxillofacial skeleton.

Associated injuries were detected in 172 (45.5%) patients. In total 5.3% of patients did not undergo surgery. The average hospital stay was 7.3 days.

Conclusions:

This study shows an important reduction in maxillofacial fractures following road traffic accidents since the turn of the new millennium. At least in north-western Italy, road safety policies implemented in the last 30 years seem to have affected the behavior of motorists and motorcyclists.
Review of the Pathways Involved in the Osteogenic Differentiation of Adipose-Derived Stem Cells
Authors: Asserson Derek B. , Orbay Hakan , Sahar David E.
Published: March 2019

Grafts and prosthetic materials used for the repair of bone defects are often accompanied by comorbidity and rejection. Therefore, there is an immense need for novel approaches to combating the issues surrounding such defects. Because of their accessibility, substantial proportion, and osteogenic differentiation potential, adipose-derived stem cells (ASCs) make for an ideal source of bone tissue in regenerative medicine. However, efficient induction of ASCs toward an osteoblastic lineage in vivo is met with challenges, and many signaling pathways must come together to secure osteoblastogenesis. Among them are bone morphogenic protein, wingless-related integration site protein, Notch, Hedgehog, fibroblast growth factor, vascular endothelial growth factor, and extracellular regulated-signal kinase. The goal of this literature review is to conglomerate the present research on these pathways to formulate a better understanding of how ASCs are most effectively transformed into bone in the context of tissue engineering.
Targeting the mTORC2 signaling complex in B cell malignancies
Authors: Liao Wei , Jordaan Gwen , Benavides-Serrato Angelica , Holmes Brent , Gera Joseph , Sharma Sanjai
Published: March 2019

Hyperactive PI3 kinase-Akt (PI3K-Akt) signaling has an important role in cell growth and resistance to apoptosis in B cell malignancies. Inhibition of this pathway by blocking PI3K activity, and or inhibiting mTORC1/2 signaling complexes is an active area of research in B cell leukemia/lymphoma such as chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL). With a tissue-scan array, the expression of Rictor is a component of the mTORC2 complex was determined by quantitative PCR in a number of B cell malignancies. Rictor was found to be over-expressed in CLL and MCL cells as compared to normal B cells with no over-expression in Hodgkins and non-Hodgkins lymphomas. Inactivation of Rictor was performed by shRNA in two Mantle cell lines and these stable Rictor knockdown cell lines demonstrated a slower growth of cells as compared to scrambled shRNA control. In addition, there was a decrease of mTORC2 signaling and B cell receptor (BCR) cross-linking mediated Akt (Ser473) and NDRG1 (Thr 346) phosphorylation. To specifically disrupt the mTORC2 signaling complex and target Rictor overexpression, previously identified inhibitors that block Rictor and MTOR interaction in a yeast two-hybrid system were analyzed. Treatment of primary CLL specimens with these inhibitors followed by immunoprecipitation experiments confirmed the disruption of the mTORC2 complex. These inhibitors also induced apoptosis in CLL specimens and were more effective than rapamycin, an MTOR inhibitor and pp242, an mTORC1 and 2 inhibitors, at equimolar concentrations. Treatment of CLL specimens with the lead inhibitor, compound#6, resulted in inhibition of p-Akt, p-GSK 3 beta, p-PKC alpha, p-Foxo1, and p-Foxo3, with minimal effect on the phosphorylation of an mTORC1 target gene, S6 kinase. In comparison with Idelalisib (CAL-101), a clinically approved PI3Kinase p110 delta inhibitor in CLL, comp#6 is more effective in inducing apoptosis in primary CLL specimens at equimolar concentrations (mean 51.2, SD 21.7 as compared to mean 26.9, SD 17.2). The data support the effectiveness of these novel inhibitors that specifically disrupt the mTORC2 complex in primary CLL specimens.
Polychromatic solar energy conversion in pigment-protein chimeras that unite the two kingdoms of (bacterio)chlorophyll-based photosynthesis
Authors: Liu Juntai , Friebe Vincent M. , Frese Raoul N. , Jones Michael R.
Published: March 2019

Natural photosynthesis can be divided between the chlorophyll-containing plants, algae and cyanobacteria that make up the oxygenic phototrophs and a diversity of bacteriochlorophyll-containing bacteria that make up the anoxygenic phototrophs. Photosynthetic light harvesting and reaction centre proteins from both groups of organisms have been exploited in a wide range of biohybrid devices for solar energy conversion, solar fuel synthesis and a variety of sensing technologies, but the energy harvesting abilities of these devices are limited by each protein’s individual palette of (bacterio)chlorophyll, carotenoid and bilin pigments. In this work we demonstrate a range of genetically-encoded, self-assembling photosystems in which recombinant plant light harvesting complexes are covalently locked with reaction centres from a purple photosynthetic bacterium, producing macromolecular chimeras that display mechanisms of polychromatic solar energy harvesting and conversion not present in natural systems. Our findings illustrate the power of a synthetic biology approach in which bottom-up construction of a novel photosystem using naturally disparate but mechanistically complementary components is achieved in a predictable fashion through the genetic encoding of adaptable, plug-and-play covalent interfaces.

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Quantifying Molecular Bias in DNA Data Storage
Authors: Chen Yuan-Jyue , Takahashi Christopher N. , Organick Lee , Stewart Kendall , Ang Siena Dumas , Weiss Patrick , Peck Bill , Seelig Georg , Ceze Luis , Strauss Karin
Published: March 2019

DNA has recently emerged as an attractive medium for future digital data storage because of its extremely high information density and potential longevity. Recent work has shown promising results in developing proof-of-principle prototype systems. However, very uneven (biased) sequencing coverage distributions have been reported, which indicates inefficiencies in the storage process and points to optimization opportunities. These deviations from the average coverage in oligonucleotide copy distribution result in sequence drop-out and make error-free data retrieval from DNA more challenging. The uneven copy distribution was believed to stem from the underlying molecular processes, but the interplay between these molecular processes and the copy number distribution has been poorly understood until now. In this paper, we use millions of unique sequences from a DNA-based digital data archival system to study the oligonucleotide copy unevenness problem and show that two important sources of bias are the synthesis process and the Polymerase Chain Reaction (PCR) process. By mapping the sequencing coverage of a large complex oligonucleotide pool back to its spatial distribution on the synthesis chip, we find that significant bias comes from array-based oligonucleotide synthesis. We also find that PCR stochasticity is another main driver of oligonucleotide copy variation. Based on these findings, we develop a statistical model for each molecular process as well as the overall process and compare the predicted bias with our experimental data. We further use our model to explore the trade-offs between synthesis bias, storage physical density and sequencing redundancy, providing insights for engineering efficient, robust DNA data storage systems.
Enduring and sex-specific changes in hippocampal gene expression after a subchronic immune challenge
Authors: Tchessalova Daria , Tronson Natalie C.
Published: March 2019

Major illnesses, including heart attack and sepsis, can cause cognitive impairments, depression, and progressive memory decline that persist long after recovery from the original illness. In rodent models of sepsis or subchronic immune challenge, memory deficits also persist for weeks or months, even in the absence of ongoing neuroimmune activation. This raises the question of what mechanisms in the brain mediate such persistent changes in neural function. Here, we used RNA-sequencing as a large-scale, unbiased approach to identify changes in hippocampal gene expression long after a subchronic immune challenge previously established to cause persistent memory impairments in both males and females. We observed enduring dysregulation of gene expression three months after the end of a subchronic immune challenge, Surprisingly, we also found striking sex differences in both the magnitude of changes and the specific genes and pathways altered, where males showed persistent changes in both immune- and plasticity-related genes three months after immune challenge, whereas females showed few such changes. In contrast, females showed striking differential gene expression in response to a subsequent immune challenge. Thus, immune activation has enduring and sex-specific consequences for hippocampal gene expression and the transcriptional response to subsequent stimuli. Together with findings of long-lasting memory impairments after immune challenge, these data suggest that illnesses can cause enduring vulnerability to, cognitive decline, affective disorders, and memory impairments via dysregulation of transcriptional processes in the brain.
Neural circuits mediating visual stabilization during active motion in zebrafish
Authors: Sun Sha , Zuo Zhentao , Ma Michelle Manxiu , Qian Chencan , Chen Lin , Zhou Wu , Drasbek Kim Ryun , Zuxiang Liu
Published: March 2019

Visual stabilization is an inevitable requirement for animals during active motion interaction with the environment. Visual motion cues of the surroundings or induced by self-generated behaviors are perceived then trigger proper motor responses mediated by neural representations conceptualized as the internal model: one part of it predicts the consequences of sensory dynamics as a forward model, another part generates proper motor control as a reverse model. However, the neural circuits between the two models remain mostly unknown. Here, we demonstrate that an internal component, the efference copy, coordinated the two models in a push-pull manner by generating extra reset saccades during active motion processing in larval zebrafish. Calcium imaging indicated that the saccade preparation circuit is enhanced while the velocity integration circuit is inhibited during the interaction, balancing the internal representations from both directions. This is the first model of efference copy on visual stabilization beyond the sensorimotor stage.
Analysis of miRNA inhibitors Efficacy using Capillary Electrophoresis with Laser-Induced Fluorescence
Authors: Chae Dong-Kyu , Ban Eunmi
Published: March 2019

In the recent years, microRNAs (miRNAs) have been discovered to play a very important role in biological processes such as development, differentiation, and apoptosis. The miRNA expression levels in cells are associated with diverse diseases including cancers. MiRNA inhibitors have been widely employed for studying the functions and targets of miRNAs by transfecting the inhibitors into cells. The concentrations of miRNA inhibitors used for such studies can vary depending on the types of miRNAs being tested, the cell lines under study, and the analysis methods. Therefore, in order to obtain accurate results, appropriate amounts of miRNA inhibitors have to be used in the experiments. Apart from amounts, the evaluation of inhibitors may also have to be conducted for functional studies.

Here we developed capillary electrophoresis with laser-induced fluorescence (CE-LIF) method for evaluating miRNA inhibitor and for optimizing miRNA inhibitor concentrations, in the A549 lung cancer cell line. The target miRNAs, miRNA-23a and miRNA-24 are biomarker candidates in lung cancer cell lines. Our results showed that miRNA-23a and miRNA-24 were effectively inhibited upon transfection with 20 nM miRNA inhibitors using CE-LIF method. Furthermore, these results demonstrated the potential of CE for fast, specific, sensitive and specific analyses for the evaluation and determination of the optimal concentration of miRNA inhibitors for functional studies.

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Chromatin activity at GWAS loci identifies T cell states driving complex immune diseases
Authors: Soskic Blagoje , Cano-Gamez Eddie , Smyth Deborah J. , Rowan Wendy C. , Nakic Nikolina , Esparza-Gordillo Jorge , Bossini-Castillo Lara , Tough David F. , Larminie Christopher G. C. , Bronson Paola G. , Wille David , Trynka Gosia
Published: March 2019

Complex immune disease variants are enriched in active chromatin regions of T cells and macrophages. However, whether these variants function in specific cell states or stages of cell activation is unknown. We stimulated T cells and macrophages in the presence of thirteen different cytokine cocktails linked to immune diseases and profiled active enhancers and promoters together with regions of open chromatin. We observed that T cell activation induced major chromatin remodelling, while additional exposure to cytokines fine-tuned the magnitude of these changes. Therefore, we developed a new statistical method that accounts for subtle changes in chromatin landscape to identify SNP enrichment across cell states. Our results point towards the role of immune disease variants in early rather than late activation of memory CD4+ T cells, and with limited differences across polarizing cytokines. Furthermore, we demonstrate that inflammatory bowel disease variants are enriched in chromatin regions active in Th1 cells, while asthma variants overlap regions active in Th2 cells. We also show that Alzheimer’s disease variants are enriched in different macrophage cell states. Our results represent the first in-depth analysis of immune disease variants across a comprehensive panel of activation states of T cells and macrophages.
Shared neural underpinnings of multisensory integration and trial-by-trial perceptual recalibration
Authors: Park Hame , Kayser Christoph
Published: March 2019

Multisensory stimuli create behavioral flexibility, e.g. by allowing us to derive a weighted combination of the information received by different senses. They also allow perception to adapt to discrepancies in the sensory world, e.g. by biasing the judgement of unisensory cues based on preceding multisensory evidence. While both facets of multisensory perception are central for behavior, it remains unknown whether they arise from a common neural substrate. In fact, very little is known about the neural mechanisms underlying multisensory perceptual recalibration. To reveal these, we measured whole-brain activity using MEG while human participants performed an audio-visual ventriloquist paradigm designed to reveal multisensory integration within a trial, and the (trial-by-trial) recalibration of subsequent unisensory judgements. Using single trial classification and behavioral modelling, we localized the encoding of sensory information within and between trials, and determined the behavioral relevance of candidate neural representations. While we found neural signatures of perceptual integration within temporal and parietal regions, of these, only medial superior parietal activity retained multisensory information between trials and combined this with current evidence to mediate perceptual recalibration. These results suggest a common neural substrate of sensory integration and trial-by-trial perceptual recalibration, and expose the medial superior parietal cortex as a flexible hub that links present and previous evidence within and between senses to guide behavior.
Single-cell RNA-sequencing of Herpes simplex virus 1-infected cells identifies NRF2 activation as an antiviral program
Authors: Wyler Emanuel , Franke Vedran , Menegatti Jennifer , Christine Kocks , Boltengagen Anastasiya , Praktiknjo Samantha , Walch-Rückheim Barbara , Rajewsky Nikolaus , Grässer Friedrich , Akalin Altuna , Markus Landthaler
Published: March 2019

Herpesvirus infection initiates a range of perturbations in the host cell, which remain poorly understood at the level of individual cells. Here, we quantified the transcrips of single human primary fibroblasts during the first hours of lytic infection with HSV-1. By applying a generalizable analysis scheme, we defined a precise temporal order of early viral gene expression and found unexpected bifurcations and bottlenecks. We identified individual host cell genes and pathways relevant in early infection by combining three different computational approaches: gene and pathway overdispersion analysis, prediction of cell-state transition probabilities as well as future cell states. One transcriptional program, which was turned on in infected cells and correlated with increased resistance to infection, implicated the transcription factor NRF2. Consequently, Bardoxolone methyl, a known NRF2 agonist, impaired virus production, suggesting that NRF2 activation restricts the progression of viral infection. Our study provides novel insights into early stages of HSV-1 infection and serves as a general blueprint for the investigation of heterogenous cell states in virus infection.
A high-density genetic map and molecular sex-typing assay for gerbils
Authors: Brekke Thomas D. , Supriya Sushmita , Denver Megan , Thom Angharad , Steele Katherine A. , Mulley John F.
Published: March 2019

We constructed a high-density genetic map in Mongolian gerbils (Meriones unguiculatus). We genotyped 137 F2 individuals with a genotype-by-sequencing (GBS) approach at over 10,000 loci and built the genetic map using a two-step approach. First, we chose the highest-quality set of 485 markers to construct a high-quality framework map of 1,239cM with 22 linkage groups as expected from the published karyotype. Second, we added an additional 5,449 markers onto the map based on their genotype similarity with the original markers. We used the final marker set to assemble 1,140 genomic scaffolds (containing ∼20% of annotated genes) into a chromosome-level framework. We used both genetic linkage and relative sequencing coverage in males and females to identify X- and Y-chromosome scaffolds and from these we designed a robust and internally-controlled PCR assay to determine sex. This assay will facilitate early stage sex-typing of embryonic and young gerbils which is not possible using current visual methods.
Impacts of climate change on high priority fruit fly species in Australia
Authors: Sultana Sabira , Baumgartner John B. , Dominiak Bernard C. , Royer Jane E. , Beaumont Linda J.
Published: March 2019

Tephritid fruit flies are among the most destructive horticultural pests and pose risks to Australia’s multi-billion-dollar horticulture industry. Currently, there are 11 pest fruit fly species of economic concern present in various regions of Australia. Of these, nine are native to this continent (Bactrocera aquilonis, B. bryoniae, B. halfordiae, B. jarvisi, B. kraussi, B. musae, B. neohumeralis, B. tryoniandZeugodacus cucumis), whileB. frauenfeldiandCeratitis capitataare introduced. To varying degrees these species are costly to Australia’s horticulture through in-farm management, monitoring to demonstrate pest freedom, quarantine and trade restrictions, and crop losses. Here, we used a common species distribution modelling approach, Maxent, to assess habitat suitability for these 11 species under current and future climate scenarios. These projections indicate that the Wet Tropics is likely to be vulnerable to all 11 species. The east coast of Australia will likely remain vulnerable to multiple species until at least 2070. Both the Cape York Peninsula and Northern Territory are also likely to be vulnerable, however, extrapolation to novel climates in these areas decrease confidence in model projections. The climate suitability of current major horticulture regions in north-western Australia, the Northern Territory, southern-central regions of New South Wales and southern Victoria to these pests is projected to increase as climate changes. Our study highlights areas at risk of pest range expansion in the future, to guide Australia’s horticulture industry in developing effective monitoring and management strategies.
Simulation of calcium signaling in fine astrocytic processes: effect of spatial properties on spontaneous activity
Authors: Audrey Denizot , Misa Arizono , Valentin Nägerl U. , Hédi Soula , Hugues Berry
Published: March 2019

Astrocytes, a glial cell type of the central nervous system, have emerged as detectors and regulators of neuronal information processing. Astrocyte excitability resides in transient variations of free cytosolic calcium concentration over a range of temporal and spatial scales, from sub-microdomains to waves propagating throughout the cell. Despite extensive experimental approaches, it is not clear how these signals are transmitted to and integrated within an astrocyte. The localization of the main molecular actors and the geometry of the system, including calcium channels IP3R spatial organization, are deemed essential. However, as most calcium signals occur in astrocytic ramifications that are too fine to be resolved by conventional light microscopy, most of those spatial data are unknown and computational modeling remains the only methodology to study this issue. Here, we propose an IP3R-mediated calcium signaling model for dynamics in such small sub-cellular volumes. To account for the expected stochasticity and low copy numbers, our model is both spatially explicit and particle-based. Extensive simulations show that spontaneous calcium signals arise in the model via the interplay between excitability and stochasticity. The model reproduces the main forms of calcium signals and indicates that their frequency crucially depends on the spatial organization of the IP3R channels. Importantly, we show that two processes expressing exactly the same calcium channels can display different types of calcium signals depending on channels spatial organization. Our model with realistic process volume and calcium concentrations successfully reproduces spontaneous calcium signals that we measured in calcium micro-domains with confocal microscopy. To our knowledge, this model is the first model suited to investigate calcium dynamics in fine astrocytic processes and to propose plausible mechanisms responsible for their variability.
Analysis of factor V in zebrafish demonstrates minimal levels needed for hemostasis and risk stratifies human variants
Authors: Weyand Angela C. , Grzegorski Steve. J. , Rost Megan. S. , Lavik Kari. I. , Ferguson Allison C. , Menegatti Marzia , Richter Catherine E. , Asselta Rosanna , Duga Stefano , Peyvandi Flora , Shavit Jordan A.
Published: March 2019

In humans, coagulation factor V (F5) deficiency is a rare, clinically heterogeneous bleeding disorder, suggesting that genetic modifiers may contribute to disease expressivity. Complete loss of mouse F5 results in early lethality. Zebrafish possess many distinct advantages including high fecundity, optical clarity, external development, and homology with the mammalian hemostatic system, features that make it ideal for genetic studies. Our aim was to study the role of F5 in zebrafish through targeted mutagenesis, and apply the model to the study of humanF5variants. CRISPR-mediated genome editing of the zebrafishf5locus was performed, generating mutants homozygous for a 49 base pair deletion in exon 4. Thrombus formation secondary to vascular endothelial injury was absent inf5-/-mutant embryos and larvae. Despite this severe hemostatic defect, homozygous mutants survived before succumbing to severe hemorrhage in adulthood. HumanF5variants of uncertain significance from patients with F5 deficiency were evaluated, and the causative mutations identified and stratified by their ability to restore thrombus formation in larvae. Analysis of these novel mutations demonstrates variable residual F5 function, with minimal activity being required to restore hemostasis. Thisin vivoevaluation may be beneficial for patients whose factor activity levels lack correlation with bleeding symptomatology. Furthermore, homozygous mutant embryos tolerate what is a severe and lethal defect in mammals, suggesting the possibility of species-specific factors enabling survival, and allowing further study not possible in the mouse. Identification of these factors or other genetic modifiers could lead to novel therapeutic modalities.

Key Points

F5 mutant fish embryos tolerate symptoms lethal in mammals but succumb to bleeding in adulthood

Analysis of human variants demonstrate that all have some residual function and that minimal F5 activity is required to restore hemostasis
The cellular response towards lanthanum is substrate specific and reveals a novel route for glycerol metabolism inPseudomonas putidaKT2440
Authors: Wehrmann Matthias , Toussaint Maxime , Pfannstiel Jens , Billard Patrick , Klebensberger Janosch
Published: March 2019

Ever since the discovery of the first rare earth element (REE)-dependent enzyme, the physiological role of lanthanides has become an emerging field of research due to the potential environmental implications and biotechnological opportunities. InPseudomonas putidaKT2440, the two pyrroloquinoline quinone-dependent alcohol dehydrogenases (PQQ-ADHs) PedE and PedH are inversely produced in response to La3+-availability. This REE-switch is orchestrated by a complex regulatory network including the PedR2/PedS2 two-component system and is important for efficient growth on several alcoholic volatiles. AsP. putidais exposed to a broad variety of organic compounds in its natural soil habitat, the cellular responses towards La3+during growth on various carbon and energy sources were investigated with a differential proteomic approach. Apart from the Ca2+-dependent enzyme PedE, the differential abundance of most other identified proteins was conditional and revealed a substrate specificity. Concomitant with the proteomic changes, La3+had a beneficial effect on lag-phases while causing reduced growth rates and lower optical densities in stationary phase during growth on glycerol. When these growth phenotypes were evaluated with mutant strains, a novel metabolic route for glycerol utilization was identified that seems to be functional in parallel with the main degradation pathway encoded by theglpFKRDoperon. The newly discovered route is initiated by PedE and/or PedH, which most likely convert glycerol to glyceraldehyde. In the presence of lanthanum, glyceraldehyde seems to be further oxidized to glycerate, which, upon phosphorylation to glycerate-2-phosphate by the glycerate kinase GarK, is finally channelled into the central metabolism.

Importance

The biological role of rare earth elements has long been underestimated and research has mainly focused on methanotrophic bacteria. We have recently demonstrated thatP. putida,a plant growth promoting bacterium that thrives in the rhizosphere of various feed crops, possesses a REE-dependent alcohol dehydrogenase (PedH), but knowledge about lanthanide-dependent effects on physiological traits in non-methylotrophic bacteria is still scarce. This study demonstrates that the cellular response ofP. putidaKT2440 towards La3+is mostly substrate specific and that during growth on glycerol, La3+has a severe effect on several growth parameters. We provide compelling evidence that the observed physiological changes are linked to the catalytic activity of PedH and thereby identify a novel route for glycerol metabolism in this biotechnological relevant organism. Overall, these findings demonstrate that lanthanides can alter important physiological traits of non-methylotrophic bacteria, which might consequently influence their competitiveness during colonization of various environmental niches.
Characterizing the epigenetic landscape of cellular populations from bulk and single-cell ATAC-seq information
Authors: Gabitto Mariano I. , Rasmussen Anders , Wapinski Orly , Allaway Kathryn , Carriero Nicholas , Fishell Gordon J. , Bonneau Richard
Published: March 2019

Given its ability to map chromatin accessibility with single base pair resolution, ATAC-seq has become a leading technology to probe the epigenomic landscape of single and aggregated cells. Understanding ATAC-seq data presents distinct analysis challenges, compared to RNA-seq technologies, because of the relative sparseness of the data produced and the interaction of complex noise with multiple chromatin structure scales. Methods commonly used to analyze chromatin accessibility datasets are adapted from algorithms designed to process different experimental technologies, disregarding the statistical and biological differences intrinsic to the ATAC-seq technology. Here, we present a Bayesian statistical approach, termed ChromA, to analyze ATAC-seq data. ChromA annotates the cellular epigenetic landscape by integrating information from replicates, producing a consensus de-noised annotation of chromatin accessibility. Our method can analyze single cell ATAC-seq data, improving cell type identification and correcting many of the biases generated by the sparse sampling inherent in single cell technologies. We validate ChromA on several biological systems, including mouse and human immune cells and find it effective at recovering accessible chromatin, establishing ChromA as a top preforming general platform for mapping the chromatin landscape in different cellular populations from diverse experimental designs.
Loss of tau and Fyn reduces compensatory effects of MAP2 for tau and reveals a Fyn-independent effect of tau on glutamate-induced Ca2+response
Authors: Liu Guanghao , Thangavel Ramasamy , Rysted Jacob , Kim Yohan , Francis Meghan B , Adams Eric , Lin Zhihong , Taugher Rebecca J , Wemmie John A , Usachev Yuriy M , Lee Gloria
Published: March 2019

Microtubule-associated protein tau associates with Src family tyrosine kinase Fyn. A tau-Fyn double knockout (DKO) mouse was generated to investigate the role of the complex. DKO mice resembled Fyn KO in cognitive tasks and resembled tau KO mice in motor tasks and protection from pentylenetetrazole-induced seizures. In Ca2+response, Fyn KO was decreased relative to WT and DKO had a greater reduction relative to Fyn KO, suggesting that tau may have a Fyn-independent role. Since tau KO resembled WT in its Ca2+response, we investigated whether MAP2 served to compensate for tau, since its level was increased in tau KO but decreased in DKO mice. We found that like tau, MAP2 increased Fyn activity. Moreover, tau KO neurons had increased density of dendritic MAP2-Fyn complexes relative to WT neurons. Therefore, we hypothesize that in the tau KO, the absence of tau would be compensated by MAP2, especially in the dendrites, where tau-Fyn complexes are of critical importance. In the DKO, decreased levels of MAP2 made compensation more difficult, thus revealing the effect of tau in the Ca2+response.

Summary Statement

The downstream effect of the interaction between microtubule-associated protein tau and Src family non-receptor tyrosine kinase Fyn was investigated with a tau/Fyn double KO mouse. We demonstrate that tau has a Fyn-independent role in glutamate-induced calcium response and that MAP2 can compensate for tau in interacting with Fyn in dendrites.
Unexpected higher resilience to distraction during visual working memory in schizophrenia
Authors: Zhao Yijie , Ran Xuemei , Zhang Li , Zhang Ruyuan , Ku Yixuan
Published: March 2019

Visual working memory (VWM) and distractibility are two core executive functions in human cognition. It has been suggested that schizophrenia (SZ) patients exhibit worse VWM performance and lower resilience to distraction compared with healthy control (HC) subjects. Previous studies, however, have largely investigated these two functions separately. It still remains unclear what are the mechanisms of the deficits, especially the interactions between the two cognitive domains. Here we modify the standard delay-estimation task in VWM and explicitly add distractors in the task so as to examine the two domains simultaneously. We find that SZ indeed exhibit worse performance compared with HC in almost all VWM load and distraction levels, a result consistent with most prior experimental findings. But adding distractors does not selectively impose larger impacts on SZ performance. Furthermore, unlike most previous studies that only focused on behavioral performance, we use the variable precision model to disentangle the distraction effect on different computational components of VWM (resources and resources allocation variability etc.). Surprisingly, adding distractors significantly elevates resources allocation variability—a parameter describing the heterogeneity of resource allocation across different targets—in HC but not in SZ. This counterintuitive result suggests that the internal VWM process in SZ is less interfered by the distractors. However, this unexpected higher resilience to distraction might be associated with less flexible cognitive control mechanisms. In sum, our work demonstrates that multiple cognitive functions might jointly contribute to dysfunctions in SZ and their interactions might manifest differently from merely summing their independent effects.
ARBoR: An Identity and Security Solution for Clinical Reporting
Authors: Venner Eric , Murugan Mullai , Hale Walker , Jones Jordan , Lu Shan , Yi Victoria , Gibbs Richard A.
Published: March 2019

Motivation

Clinical genome sequencing laboratories return reports containing clinical testing results, signed by an Board Certified clinical geneticist, to the ordering physician. This report is often a pdf, but can also be a physical paper copy or a structured data file. The reports are frequently modified and re-issued, due to changes in variant interpretation or clinical attributes. To precisely track report authenticity we developed ARBoR, an application for tracking the lineage of versioned clinical reports even when they are distributed as pdf or paper copies. ARBoR employs a modified blockchain approach and instead of relying on a computationally intensive consensus mechanism for determining authenticity, we allow supervised and digitally signed writes to an encrypted ledger, which is then exactly replicated to many clients.

Results

ARBoR was implemented for clinical reporting in the HGSC-CL Clinical Laboratory, initially as part of the NIH’s Electronic Medical Record and Genomics (eMERGE) project. To date we have issued 15,205 versioned clinical reports tracked by ARBoR. This system has provided us with a simple and tamper-proof mechanism for tracking clinical reports with a complicated update history.
Arabidopsis phytochelatin synthase 1, but not phytochelatin synthesis, functions in extracellular defense against multiple fungal pathogens
Authors: Hematy Kian , Lim Melisa , Cherk Candice , Bednarek Paweł , Piślewska-Bednarek Mariola , Sanchez-Rodriguez Clara , Stein Monica , Fuchs Rene , Klapprodt Christine , Lipka Volker , Molina Antonio , Grill Erwin , Schulze-Lefert Paul , Somerville Shauna
Published: March 2019

Phytochelatin synthase (PCS) is a key component of heavy metal detoxification in plants. PCS catalyzes both the synthesis of the peptide phytochelatin from glutathione as well as the degradation of glutathione conjugates via peptidase activity. Here, we describe a hitherto uncharacterized role for PCS in disease resistance against plant pathogenic fungi. The pen4 mutant, which is allelic to cadmium insensitive 1 (cad1/pcs1) mutants, was recovered from a screen for Arabidopsis mutants with reduced resistance to the non-adapted barley fungal pathogen, Blumeria graminis f. sp. hordei. PCS1, which is found in the cytoplasm of cells of healthy plants, translocates upon pathogen attack and colocalizes with the PEN2 myrosinase on the surface of immobilized mitochondria. pcs1 and pen2 mutant plants exhibit a similar metabolic defect in the accumulation of pathogen-inducible indole glucosinolate-derived compounds, suggesting that PEN2 and PCS1 act in the same metabolic pathway. The function of PCS1 in this pathway is independent of phytochelatin synthesis and deglycination of glutathione conjugates, as catalytic-site mutants of PCS1 are still functional in indole glucosinolate metabolism. In uncovering a previously unknown function for PCS1, we reveal this enzyme to be a moonlighting protein important for plant responses to both biotic and abiotic stresses.
Kinematics associated with treadmill walking in Rett Syndrome
Authors: Layne Charles S. , Young David R. , Lee Beom-Chan , Glaze Daniel G. , Schwabe Aloysia , Suter Bernhard
Published: March 2019

Individuals with Rett syndrome suffer from severely impaired cognitive and motor performance. Current movement-related therapeutic programs often include traditional physical therapy activities and assisted treadmill walking routines for those patients who are ambulatory. However, there are no quantitative reports of kinematic gait parameters obtained during treadmill walking. Here we report the results of an investigation of 17 females diagnosed with typical Rett who walked on a treadmill as speed gradually increased. The objective included characterizing lower limb kinematics, including knee and hip joint range of motions, velocities, limb asymmetries, and the variance associated with these measures. Joint kinematics were obtained using a 12 camera motion capture system and associated processing and analysis software. Stride times progressively decreased as treadmill speeds increased although the range of speeds our participant could walk was quite slow: range 0.2 m/s – 0.5 m/s. There were significant main effects of speed on sagittal knee and hip range of motions and hip velocity. There were large joint asymmetries and variance values relative to both healthy walkers and others patient populations although variance values decreased as walking speed increased. There were significant correlations between joint range of motions and stride times and joint velocities and stride times. The results indicate that Rett patients can adapt their kinematic gait patterns in response to increasing treadmill speed but their ability to do so lies within a narrow range of speeds. We suggest that treadmill training for ambulatory individuals with Rett may further promote improved walking kinematics as well as overall health benefits.
Impact of an intra-abdominal cooling device during open kidney transplantation in pigs
Authors: Longchamp Alban , Meier Raphael P. H. , Colucci Nicola , Balaphas Alexandre , Orci Lorenzo , Nastasi Antonio , Longchamp Grégoire , Moll Solange , Klauser Antoine , Pascual Manuel , Lazeyras François , Corpataux Jean-Marc , Bühler Leo
Published: March 2019

Background

Kidney transplantation using deceased donors still suffers from high post-operative dysfunction rate. During implantation into the recipient, the kidney rewarms. This second warm ischemia time, which is not monitored, is harmful especially if prolonged. We recently developed an intra-abdominal cooling device that efficiently prevents kidney rewarming during robotic transplantation, and prevent ischemia-reperfusion injuries. Here, we tested the benefits of this cooling device during open kidney transplantation in pigs.

Materials

Kidneys were procured from large pigs by open bilateral nephrectomy. Following procurement, kidneys were flushed with 4°C Institut Georges Lopez-1 preservation solution, and placed on ice for 128.5 ± 23.2 min. The cooling device was used to continuously cool down the kidney during the vascular anastomosis time.

Methods

Animals underwent double sequential autologous open renal transplantation with (n = 7) and without (n = 6) intra-abdominal cooling. Renal cortex temperature and urine output were monitored. The severity of the ischemia reperfusion lesions was analyzed by histology (modified Goujon score).

Results

Mean anastomosis time was similar between groups (43.9 ± 13 min). At reperfusion, the renal cortex temperature was lower in the group with cooling (4.3 ± 1.1°C vs 26.5 ± 5.5°C p <0.001). The cooled kidneys tended to be protected from injury, including some histopathological ischemia–reperfusion lesions. With the device, kidneys had a better immediate post-operative urine output (p=0.05).

Conclusions

Our results indicate that the intra-abdominal cooling device significantly reduces second warm ischemic time during transplantation, is technically safe, and does not prolong anastomotic time.
Personal bankruptcy prediction using decision tree model
Authors: Syed Nor Sharifah Heryati , Ismail Shafinar , Yap Bee Wah
Published: March 2019

Purpose

Personal bankruptcy is on the rise in Malaysia. The Insolvency Department of Malaysia reported that personal bankruptcy has increased since 2007, and the total accumulated personal bankruptcy cases stood at 131,282 in 2014. This is indeed an alarming issue because the increasing number of personal bankruptcy cases will have a negative impact on the Malaysian economy, as well as on the society. From the aspect of individual’s personal economy, bankruptcy minimizes their chances of securing a job. Apart from that, their account will be frozen, lost control on their assets and properties and not allowed to start any business nor be a part of any company’s management. Bankrupts also will be denied from any loan application, restricted from travelling overseas and cannot act as a guarantor. This paper aims to investigate this problem by developing the personal bankruptcy prediction model using the decision tree technique.

Design/methodology/approach

In this paper, bankrupt is defined as terminated members who failed to settle their loans. The sample comprised of 24,546 cases with 17 per cent settled cases and 83 per cent terminated cases. The data included a dependent variable, i.e. bankruptcy status (Y = 1(bankrupt), Y = 0 (non-bankrupt)) and 12 predictors. SAS Enterprise Miner 14.1 software was used to develop the decision tree model.

Findings

Upon completion, this study succeeds to come out with the profiles of bankrupts, reliable personal bankruptcy scoring model and significant variables of personal bankruptcy.

Practical implications

This decision tree model is possible for patent and income generation. Financial institutions are able to use this model for potential borrowers to predict their tendency toward personal bankruptcy.

Social implications

Create awareness to society on significant variables of personal bankruptcy so that they can avoid being a bankrupt.

Originality/value

This decision tree model is able to facilitate and assist financial institutions in evaluating and assessing their potential borrower. It helps to identify potential defaulting borrowers. It also can assist financial institutions in implementing the right strategies to avoid defaulting borrowers.
Perfect partial reconstructions for multiple simultaneous sources
Authors: Wittsten Jens , Andersson Fredrik , Robertsson Johan , Amundsen Lasse
Published: March 2019

A major focus of research in the seismic industry of the past two decades has been the acquisition and subsequent separation of seismic data using multiple sources fired simultaneously. The recently introduced method of signal apparition provides a new take on the problem by replacing the random time‐shifts usually employed to encode the different sources by fully deterministic periodic time‐shifts. In this paper, we give a mathematical proof showing that the signal apparition method results in optimally large regions in the frequency–wavenumber space where exact separation of sources is achieved. These regions are diamond shaped and we prove that using any other method of source encoding results in strictly smaller regions of exact separation. The results are valid for arbitrary number of sources. Numerical examples for different number of sources (three, respectively, four sources) demonstrate the exact recovery of these diamond‐shaped regions. The implementation of the theoretical proofs in the field is illustrated by the results of a conducted field test.