bluuebunny/crossref_metadata_2025 huggingface dataset:
Polynomial Parametrization for SL2 over Quadratic Number Rings
Authors: Larsen Michael , Nguyen Dong Quan Ngoc
Published: February 2019

If $R$ is the ring of integers of a number field, then there exists a polynomial parametrization of the set $\operatorname{SL}_2(R)$, that is, an element $A\in{\textrm{SL}}_2(\mathbb{Z}[x_1,\ldots ,x_n])$ such that every element of $\operatorname{SL}_2(R)$ is obtained by specializing $A$ via some homomorphism $\mathbb{Z}[x_1,\ldots ,x_n]\to R$.
Decision-Making in Revolutionary States: Beyond the Whims of Charismatic Leaders
Authors: Rouhi Mahsa , Snow Jonathan L
Published: February 2019

Understanding how foreign policy decisions are made in revolutionary states has proven to be a difficult puzzle for scholars and practitioners alike. While political scientists have made great strides in developing standard decision-making frameworks, those have generally been based on the experiences and conditions of Western states and rely on stable government structures for their explanatory power. Revolutionary states by their very nature lack this stability, since the conditions of revolution commonly result in major reorganizations or wholesale removal of preexisting government structures. In this article, we begin to build a new framework for understanding decision-making in revolutionary states and employ case studies of Iran, Russia, Sudan, and Afghanistan to show that the process in these states involves input and considerations from various actors and therefore cannot be understood by simply looking at the desires of the charismatic leaders that are so often the focus of outside analysts.
The Current State of Personality Disorders Through the Lens of PDTRT
Authors: Lejuez Carl W. , Matusiewicz Alexis , Bounoua Nadia , Soldinger James
Published: February 2019

This chapter examines recent trends in personality disorder research as they appear in one of the top personality disorder journals—Personality Disorders: Theory, Research, and Treatment (PDTRT). The chapter provides an overview of the history of PDTRT, as well as describes the types of submissions and manuscripts published in the journal over the last 5 years. It also reports on research trends over that time period, noting increasing interest in the alternative model for personality disorders, the surfeit of research in borderline personality disorder and psychopathy, the increasing use of dimensional versus categorical approaches, the use of nonclinical samples, and the extension of personality disorder traits to younger populations.
The Interpersonal Situation
Authors: Hopwood Christopher J. , Pincus Aaron L. , Wright Aidan G. C.
Published: February 2019

Interpersonal theory assumes that the most important expressions of personality and psychopathology occur in interpersonal situations between a self and an other, and that personality pathology is best understood in terms of patterned affective, behavioral, and self dysregulations as well as perceptual distortions in these interpersonal situations. This chapter presents an evidence-based model of interpersonal situations that is structured by dimensions relevant to the self (agency and communion), interpersonal behavior (dominance and warmth), and affect (valence and arousal). This dimensions in this structure can be assessed as relatively stable traits or as dynamic processes. The ability of the interpersonal situation model to provide a useful heuristic model for testable clinical hypotheses is illustrated through a case study of David.
Somatization and Coping in Ethnic Minority Recruits
Authors: Nakkas Can , Annen Hubert , Brand Serge
Published: February 2019

Introduction

Military service can have beneficial social effects on minorities. However, minority groups are also often at greater risk of somatizing psychological distress and coping maladaptively. In military training this would result in lower mental health of minorities and contribute to higher drop-out rates. We thus examined if recruits with different ethnocultural backgrounds report different somatization levels and coping styles.

Materials and Methods

Seven hundred and forty male recruits of the Swiss Armed Forces aged 18–26 took part in a cross-sectional study during basic training. Participants filled out self-rating questionnaires covering sociodemographics, somatization (SCL-90-R), coping styles (INCOPE-2), and social support (F-SozU). The recruits’ ethnic self-identification was used to compare three groups: native Swiss (89%); Turkish or Balkan minority (5%); heterogeneous ethnic minority (6%). Group differences in somatization scores were tested with a Kruskal–Wallis test; group differences in coping styles were tested with a multivariate ANCOVA, controlling for the level of social support experienced.

Results

Recruits from the heterogeneous ethnic minority group reported significantly greater levels of somatization than their native Swiss comrades. Coping styles did not differ between the three ethnic groups, but higher levels of social support were associated with better coping.

Conclusion

Military doctors ought to place importance on the differential diagnosis of medically unexplained physical symptoms in ethnic minority recruits. This would contribute to minimize the risk of misdiagnosis. Military mental health professionals who counsel recruits reporting somatic symptoms are advised to be sensitized to an ethnic minority status. Physical complaints could mask affective problems or be part of an adjustment disorder symptomatology.
Young Adult Tobacco and E-cigarette Use Transitions: Examining Stability Using Multistate Modeling
Authors: Niaura Raymond , Rich Ilan , Johnson Amanda L , Villanti Andrea C , Romberg Alexa R , Hair Elizabeth C , Vallone Donna M , Abrams David B
Published: February 2019

Introduction

The objective of this study was to describe tobacco and nicotine product use state transition probabilities among youth and young adults over time.

Methods

A national sample of young adult tobacco product users and nonusers between the ages of 18 and 34 years at baseline was surveyed at 6-month intervals for 3 years. Use and nonuse states were defined as mutually exclusive categories based on self-reported, past 30-day use of the various products. Never use, noncurrent use, and current use of combustible, noncombustible tobacco, and electronic cigarette (e-cigarette) products was assessed at each interval. A multistate model was fit to estimate transition probabilities between states and length of stay within each state.

Results

After 6 months, same-state transition probabilities were high for all use states (0.76–0.96), except for dual product use (0.48). After 3 years, transition probabilities were smaller and tended to converge toward combustible product use for baseline e-cigarette (0.42), combustible (0.51), and dual product users (0.52). Age was inversely associated with transition risk from never or noncurrent use to use of combustible or e-cigarette products.

Conclusions

Never and noncurrent users, followed by combustible product users, were most likely to remain in those states throughout the 3-year observation interval. Users of any tobacco or e-cigarette product at baseline were most likely to transition to combustible product use or noncurrent use by the final follow-up.

Implications

This study describes the probability of transitioning between various states of tobacco product use, including never and no current use, over a span of 3 years in a sample of young adults. This type of longitudinal description, which includes all tobacco product use states, is lacking in most studies that tend to focus on one or only a few products. The results suggest that it is important to assess outcomes over a sufficiently long period to capture true variability in patterns of product use.
Assessment of Parent-Child Interaction Is Important With Infants in Rehabilitation and Can Use High-Tech or Low-Tech Methods
Authors: Dusing Stacey C , Marcinowski Emily C , Rocha Nelci A C F , Tripathi Tanya , Brown Shaaron E
Published: February 2019

Parents are their infant's first teachers and play a very important role in early development. Early intervention strives to enhance infant participation in the family, and regulations require the engagement of families in assessment and intervention. Infants born preterm or with motor impairments demonstrate altered social engagements that can influence parent-child interaction and the efficacy of therapy services. However, in research focused on the efficacy of interventions or in clinical practice, therapists rarely assess or report on the quality of parent-infant interaction. Understanding these interactions can help determine what perceptual motor opportunities parents provide that can enhance learning. This Perspective article will: (1) present evidence on the need for early assessment and ongoing measurement of parent-infant interaction; (2) describe an example of each of 3 methods for assessment of parent-child interaction—low-tech, low-resource (Dyadic Mutuality Code), low-tech, high-resource (Parent Children Early Relational Assessment), and high-tech, high-resource (customized behavioral coding); (3) compare 3 approaches theoretically highlighting the strengths and weaknesses of each assessment; and (4) reflect on the challenges and value of adding these measures to future research on the efficacy of interventions and clinical practice.
Medicare Outpatient Physical Therapy Expenditures Vary by Diagnosis and Functional Mobility
Authors: Pardasaney Poonam K , Pope Gregory C , Amico Peter , Deutsch Anne , Kline Tracy , Dever Jill , Silver Benjamin , Scheffler Scott , Meadow Ann , West Pamela
Published: February 2019

Background

Clinical characteristics driving variations in Medicare outpatient physical therapy expenditures are inadequately understood.

Objective

The objectives of this study were to examine variations in annual outpatient physical therapy expenditures of Medicare fee-for-service beneficiaries by primary diagnosis and baseline functional mobility, and to assess whether case mix groups based on primary diagnosis and functional mobility scores would be useful for expenditure differentiation.

Design

This was an observational, longitudinal study.

Methods

Volunteer providers in community settings participated in data collection with Continuity Assessment Record and Evaluation—Community (CARE-C) assessments for Medicare fee-for-service beneficiaries. Annual outpatient physical therapy expenditures were calculated using allowed charges on Medicare claims; primary diagnosis and baseline functional mobility were obtained from CARE-C assessments. Whether annual expenditures varied significantly across primary diagnosis groups and within diagnosis groups by functional mobility was examined.

Results

Data for 4210 patients (mean [SD] age = 72.9 [9.9] years; 64.6% women) from 127 providers were included. Mean expenditures differed significantly across 12 primary diagnosis groups created from CARE-C clinician-reported diagnoses (F = 12.73; df = 11). Twenty-five pairwise differences in 66 pairwise diagnosis group comparisons were statistically significant. Within 8 diagnosis groups, expenditures were significantly higher for low-mobility subgroups than for high-mobility subgroups; borderline significance was achieved for 1 diagnosis group.

Limitations

The small convenience sample limited the statistical power and the generalizability of the results.

Conclusions

Significant variations in physical therapy expenditures based on primary diagnosis and baseline functional mobility support the use of these variables in predicting outpatient physical therapy expenditures. Although Medicare's annual therapy spending cap was repealed effective January 2018, the data from this study provide an initial foundation to inform any future policy efforts, such as targeted medical review, risk-adjusted therapy payments, or case mix groups as potential payment alternatives. Additional research with larger samples is needed to further develop and test case mix groups and improve generalizability to the national population. Refined case mix groups could also help providers prognosticate physical therapy expenditures based on patient profiles.
“In Today's Market, Your Food Chooses You”: News Media Constructions of Responsibility for Health through Home Cooking
Authors: Oleschuk Merin
Published: February 2019

This article examines North American national news media’s 2015–16 presentation of family meals. Analyzing 326 articles, I identify the ubiquity of a narrative of deterioration, or the presumption that families are replacing meals made from whole, unprocessed ingredients consumed communally around a table, with processed and pre-prepared foods eaten alone or “on the go”. In analyzing the construction of responsibility for this deterioration, I find that the sample predominately frames the production of healthy family meals as constrained by a food environment saturated with inexpensive, highly processed food, and dictated by the competing demands of paid work and inflated normative standards. Yet, when differentiating frames that define the social problem from those that offer solutions, I find that individualization prevails in the frames that target solutions. One important exception is media reporting on low-income families, which are framed as facing exceptional structural constraint. Analyzing these frames, I argue that neoliberal ideology that over-emphasizes individual agency and minimizes structural constraint operates in more subtle ways than previous literature suggests—showing some awareness of the difficulty of people’s lives, but prescribing solutions that leave individuals responsible for the outcomes. These findings offer implications for understanding dominant cultural values surrounding health and the family meal, as well as the allocation of responsibility for social problems within neoliberalism more broadly.
A primer in genomics for social and behavioral investigators
Authors: Turbitt Erin , Biesecker Barbara B
Published: February 2019

Genomics is being increasingly utilized in medical research and health care. Countless opportunities exist for social and behavioral scientists to answer novel and important research questions. Evidence that will be produced from such enquiries can help ensure appropriate use of genomic information and realize the potential of genomics to improve patient care and medical outcomes. Here, we provide an accessible overview of different types of genetic and genomic tests and the resulting information produced. There are important nuances that distinguish genetic from genomic tests and different information that each yield. We outline key examples where social and behavioral scientists have made an impact in this field, and opportunities for future research. The intention of this primer is to introduce or clarify genomics concepts to social and behavioral scientists, summarize prior research and outline future research directions. The time is ripe for social and behavioral scientists to engage in genomics and make important contributions to improve clinical and community translation of genomic discoveries.
How the extracellular matrix shapes neural development
Authors: Long Katherine R. , Huttner Wieland B.
Published: February 2019

During development, both cells and tissues must acquire the correct shape to allow their proper function. This is especially relevant in the nervous system, where the shape of individual cell processes, such as the axons and dendrites, and the shape of entire tissues, such as the folding of the neocortex, are highly specialized. While many aspects of neural development have been uncovered, there are still several open questions concerning the mechanisms governing cell and tissue shape. In this review, we discuss the role of the extracellular matrix (ECM) in these processes. In particular, we consider how the ECM regulates cell shape, proliferation, differentiation and migration, and more recent work highlighting a key role of ECM in the morphogenesis of neural tissues.
Hyaluronic acid-functionalized gelatin hydrogels reveal extracellular matrix signals temper the efficacy of erlotinib against patient-derived glioblastoma specimens
Authors: Pedron Sara , Wolter Gabrielle L. , Chen Jee-Wei E. , Laken Sarah E. , Sarkaria Jann N. , Harley Brendan A. C.
Published: February 2019

Therapeutic options to treat primary glioblastoma (GBM) tumors are scarce. GBM tumors with epidermal growth factor receptor (EGFR) mutations, in particular a constitutively active EGFRvIII mutant, have extremely poor clinical outcomes. GBM tumors with concurrent EGFR amplification and active phosphatase and tensin homolog (PTEN) are sensitive to the tyrosine kinase inhibitor erlotinib, but the effect is not durable. A persistent challenge to improved treatment is the poorly understood role of cellular, metabolic, and biophysical signals from the GBM tumor microenvironment on therapeutic efficacy and acquired resistance. The intractable nature of studying GBM cell in vivo motivates tissue engineering approaches to replicate aspects of the complex GBM tumor microenvironment. Here, we profile the effect of erlotinib on two patient-derived GBM specimens: EGFR+ GBM12 and EGFRvIII GBM6. We use a three-dimensional gelatin hydrogel to present brain-mimetic hyaluronic acid (HA) and evaluate the coordinated influence of extracellular matrix signals and EGFR mutation status on GBM cell migration, survival and proliferation, as well as signaling pathway activation in response to cyclic erlotinib exposure. Comparable to results observed in vivo for xenograft tumors, erlotinib exposure is not cytotoxic for GBM6 EGFRvIII specimens. We also identify a role of extracellular HA (via CD44) in altering the effect of erlotinib in GBM EGFR+ cells by modifying STAT3 phosphorylation status. Taken together, we report an in vitro tissue engineered platform to monitor signaling associated with poor response to targeted inhibitors in GBM.
Unification of optimal targeting methods in Transcranial Electrical Stimulation
Authors: Fernandez-Corazza Mariano , Turovets Sergei , Muravchik Carlos
Published: February 2019

One of the major questions in high-density transcranial electrical stimulation (TES) is: given a region of interest (ROI), and given electric current limits for safety, how much current should be delivered by each electrode for optimal targeting? Several solutions, apparently unrelated, have been independently proposed depending on how “optimality” is defined and on how this optimization problem is stated mathematically. Among them, there are closed-formula solutions such as ones provided by the least squares (LS) or weighted LS (WLS) methods, that attempt to fit a desired stimulation pattern at ROI and non-ROI, or reciprocity-based solutions, that maximize the directional dose at ROI under safety constraints. A more complete optimization problem can be stated as follows: maximize directional dose at ROI, limit dose at non-ROI, and constrain total injected current and current per electrode (safety constraints). To consider all these constraints (or some of them) altogether, numerical convex or linear optimization solvers are required. We theoretically demonstrate in this work that LS, WLS and reciprocity-based closed-form solutions are particular solutions to the complete optimization problem stated above, and we validate these findings with simulations on an atlas head model. Moreover, the LS and reciprocity solutions are the two opposite cases emerging under variation of one parameter of the optimization problem, the dose limit at non-ROI. LS solutions belong to one extreme case, when the non-ROI dose limit is strictly imposed, and reciprocity-based solutions belong to the opposite side, i.e., when this limit is loose. As we couple together most optimization approaches published so far, these findings will allow a better understanding of the nature of the TES optimization problem and help in the development of advanced and more effective targeting strategies.
Predicting potential current distribution of Lycorma delicatula (Hemiptera: Fulgoridae) using MaxEnt model in South Korea
Authors: Namgung Hyeban , Kim Min-Jung , Baek Sunghoon , Lee Joon-Ho , Kim Hyojoong
Published: February 2019

Lycorma delicatula (Hemiptera: Fulgoridae) is invasive insect in Korea which causes plant damages by sucking and sooty molds. Lycorma delicatula was first detected in South Korea in 2004, where its introduction and spreading possibly were affected by human activity-related factors. Here, we used MaxEnt to describe current distribution of L. delicatula in Korea and tried to find out the impact of human influences for distribution. We used 143 sites of occurrence data, 19 bioclimatic variables, duration of temperature below −11°C, average daily minimum temperature in January, cumulative thermal unit variable, the distribution of grape orchard variable and human footprint to create models. These models were estimated by two sets of 24 candidates with feature combinations and regularization multipliers. In addition, these two sets were created as models with and without footprint for how human influence affect to distribution. Model selection for optimal model was performed by selecting a model with a lowest sum of each rank in small sample-size corrected Akaike’s information criterion and difference between training and test AUC. Model of LQ10 parameter combinations was selected as optimal models for both model sets. Consequently, both of distribution maps from these models showed similar patterns of presence probability for L. delicatula. Both models expected that low altitude regions were relatively more suitable than mountain areas in Korea. Footprint might be limited for the distribution and L. delicatula might already occupy most of available habitats. Human-related factors might contribute to spread of L. delicatula to uninfected areas.
Subcellular localization of drug distribution by super-resolution ion beam imaging
Authors: Rovira-Clave Xavier , Jiang Sizun , Bai Yunhao , Barlow Graham , Bhate Salil , Coskun Ahmet F. , Han Guojun , Zhu Bokai , Ho Chin-Min Kimmy , Hitzman Chuck , Chen Shih-Yu , Bava Felice-Alessio , Nolan Garry P.
Published: February 2019

Technologies that visualize multiple biomolecules at the nanometer scale in cells will enable deeper understanding of biological processes that proceed at the molecular scale. Current fluorescence-based methods for microscopy are constrained by a combination of spatial resolution limitations, limited parameters per experiment, and detector systems for the wide variety of biomolecules found in cells. We present here super-resolution ion beam imaging (srIBI), a secondary ion mass spectrometry approach capable of high-parameter imaging in 3D of targeted biological entities and exogenously added small molecules. Uniquely, the atomic constituents of the biomolecules themselves can often be used in our system as the “tag”. We visualized the subcellular localization of the chemotherapy drug cisplatin simultaneously with localization of five other nuclear structures, with further carbon elemental mapping and secondary electron visualization, down to ∼30 nm lateral resolution. Cisplatin was preferentially enriched in nuclear speckles and excluded from closed-chromatin regions, indicative of a role for cisplatin in active regions of chromatin. These data highlight how multiplexed super-resolution techniques, such as srIBI, will enable studies of biomolecule distributions in biologically relevant subcellular microenvironments.

One Sentence Summary

Three-dimensional multiplexed mass spectrometry-based imaging revealed the subcellular localization of proteins and small molecules at super-resolution.
Perinatal Programming of Mucosal Stromal Cell Identity by the Lymphotoxin Pathway Regulates Mucosal Immune Responses in the Adult
Authors: Li Conglei , Lam Evelyn , Perez-Shibayama Christian , Lee Dennis , Ward Lesley A. , Nguyen Albert , Ahmed Musaddeque , Korneev Kirill V. , Rojas Olga , Sun Tian , He Housheng Hansen , Martin Alberto , Ludewig Burkhard , Gommerman Jennifer L.
Published: February 2019

Redundant mechanisms support IgA responses to intestinal antigens. These include multiple priming sites (mesenteric lymph nodes (MLN), Peyer’s patches and isolated lymphoid follicles) and various cytokines that promote class switch to IgA, even in the absence of T cells. In spite of these back-up mechanisms, vaccination against enteric pathogens such as Rotavirus has limited success in some populations. Genetic and environmental signals experienced during early life are known to influence mucosal immunity, yet the mechanisms for how these exposures operate remain unclear. Here we used Rotavirus infection to follow antigen-specific IgA responses through time and in different gut compartments. Using genetic and pharmacological approaches, we tested the role of a pathway known to support IgA responses (Lymphotoxin – LT) at different developmental stages. We found that LT-beta receptor (LTβR) signallingin uteroprograms intestinal IgA responses in adulthood by affecting antibody class switch recombination to IgA and subsequent generation of IgA antibody-secreting cells within an intact MLN. In addition,in uteroLTβR signalling dictates the phenotype and function of MLN stromal cells in order to support IgA responses in the adult. Collectively, our studies uncover new mechanistic insights into howin uteroLTβR signalling impacts mucosal immune responses during adulthood.

One Sentence Summary

Early life LTβR signalling is critical for programming the mesenteric lymph node stromal cell environment, impacting both antibody isotype switching to IgA and the differentiation of IgA+antibody secreting cells.

Graphic Abstract
Synthetic gene circuits enable systems-level biosensor discovery at the host-microbe interface
Authors: Naydich Alexander D , Nangle Shannon N , Bues Johannes J , Trivedi Disha , Nissar Nabeel , Inniss Mara C , Neiderhuber Matthew J , Way Jeffrey C , Silver Pamela A , Riglar David T
Published: February 2019

The composition and function of the gut microbiota are strongly associated with human health, and dysbiosis is linked to an array of diseases, ranging from obesity and diabetes to infection and inflammation. Engineering synthetic circuits into gut bacteria to sense, record and respond toin vivosignals is a promising new approach for the diagnosis, treatment and prevention of disease. Here, we repurpose a synthetic bacterial memory circuit to rapidly screen for and discover newin vivo-responsive biosensors in commensal gutEscherichia coli. We develop a pipeline for rapid systems-level library construction and screening, using next-generation sequencing and computational analysis, which demonstrates remarkably robust identification of responsive biosensors from pooled libraries. By testing both genome-wide and curated libraries of potential biosensor triggers—each consisting of a promoter and ribosome binding site (RBS)—and using RBS variation to augment the range of trigger sensitivity, we identify and validate triggers that selectively activate our synthetic memory circuit during transit through the gut. We further identify biosensors with increased response in the inflamed gut through comparative screening of our libraries in healthy mice and those with intestinal inflammation. Our results demonstrate the power of systems-level screening for the identification of novel biosensors in the gut and provide a platform for disease-specific screening using synthetic circuits, capable of contributing to both the understanding and clinical management of intestinal illness.

IMPORTANCE

The gut is a largely obscure and inaccessible environment. The use of live, engineered probiotics to detect and respond to disease signalsin vivorepresents a new frontier in the management of gut diseases. Engineered probiotics have also shown promise as a novel mechanism for drug delivery. However, the design and construction of effective strains that respond to thein vivoenvironment is hindered by our limited understanding of bacterial behavior in the gut. Our work expands the pool of potential biosensors for the healthy and diseased gut, providing insight into host-microbe interactions and enabling future development of increasingly complex synthetic circuits. This method also provides a framework for rapid prototyping of engineered systems and for application across bacterial strains and disease models.
singleCellHaystack: Finding surprising genes in 2-dimensional representations of single cell transcriptome data
Authors: Vandenbon Alexis , Diez Diego
Published: February 2019

Single-cell sequencing data is often visualized in 2-dimensional plots, including t-SNE plots. However, it is not straightforward to extract biological knowledge, such as differentially expressed genes, from these plots. Here we introduce singleCellHaystack, a methodology that addresses this problem. singleCellHaystack uses Kullback-Leibler Divergence to find genes that are expressed in subsets of cells that are non-randomly positioned on a 2D plot. We illustrate the usage of singleCellHaystack through applications on several single-cell datasets. singleCellHaystack is implemented as an R package, and includes additional functions for clustering and visualization of genes with interesting expression patterns.

Availability and implementation

https://github.com/alexisvdb/singleCellHaystack

Contact

alexisvdb@infront.kyoto-u.ac.jp
Comparative proteomics of osmotic signal transduction mutants inBotrytis cinereaexplain loss of pathogenicity phenotypes and highlight interaction with cAMP and Ca2+signalling pathways
Authors: Kilani Jaafar , Davanture Marlène , Zivy Michel , Fillinger Sabine
Published: February 2019

Signal transduction (ST) is essential for rapid adaptive responses to changing environmental conditions through rapid post-translational modifications of signalling proteins and downstream effectors that regulate the activity of target proteins and/or the expression of downstream genes.

We have performed a comparative proteomics study of ST mutants in the phytopathogenic fungusBotrytis cinereaduring axenic growth under non-stressed conditions to decipher the roles of two kinases of the hyper-osmolarity pathway inB. cinereaphysiology. We studied the mutants of the sensor histidine kinase Bos1 and of the MAP kinase Sak1.

Multiplex shotgun proteomics detected 628 differential proteins between mutants and wild-type, 280 common to both mutants, indicating independent and shared regulatory functions for both kinases. Gene ontology analysis showed significant changes in proteins related to plant infection (secondary metabolism enzymes, lytic enzymes, proteins linked to osmotic, oxidative and cell wall stress) that may explain the virulence defects of both mutants. Intracellular accumulation of secreted proteins in theΔbos1histidine-kinase mutant suggests a potential secretion defect. The proteome data also highlight a new link between Sak1 MAPK, cAMP and Ca2+ signalling.

This study reveals the potential of proteomic analyses of signal transduction mutants to decipher their biological functions.
Mechanisms Underlying the Enhanced Biomass and Abiotic Stress Tolerance Phenotypes of an Arabidopsis MIOX Over-expresser
Authors: Nepal Nirman , Yactayo-Chang Jessica P. , Medina-Jiménez Karina , Acosta-Gamboa Lucia M. , González-Romero María Elena , Arteaga-Vázquez Mario A. , Lorence Argelia
Published: February 2019

Myo-inositol oxygenase (MIOX) is the first enzyme in the inositol route to ascorbate (L-ascorbic acid, AsA, vitamin C). We have previously shown that Arabidopsis plants constitutively expressing MIOX have elevated foliar AsA content and displayed enhanced growth rate, biomass accumulation, and increased tolerance to multiple abiotic stresses. In this work, we used a combination of transcriptomics, chromatography, microscopy, and physiological measurements to gain a deeper understanding of the underlying mechanisms mediating the phenotype of the AtMIOX4 line. Transcritpomic analysis revealed increased expression of genes involved in auxin synthesis, hydrolysis, transport, and metabolism, which are supported by elevated auxin levels both in vitro and in vivo, and confirmed by assays demonstrating their effect on epidermal cell elongation in the AtMIOX4 over-expresser plants. Additionally, we detected up-regulation of transcripts involved in photosynthesis that was validated by increased efficiency of the photosystem II and proton motive force. We also found increased expression of amylase leading to higher intracellular glucose levels. Multiple gene families conferring plants tolerance to cold, water limitation, and heat stresses were found to be elevated in the AtMIOX4 line. Interestingly, the high AsA plants also displayed up-regulation of transcripts and hormones involved in defense including jasmonates, defensin, glucosinolates, and transcription factors that are known to be important for biotic stress tolerance. These results overall indicate that elevated levels of auxin and glucose, and enhanced photosynthetic efficiency in combination with up-regulation of abiotic stresses response genes underly the higher growth rate and abiotic stresses tolerance phenotype of the AtMIOX4 over-expressers.
Transcriptome analysis reveals that fertilization with cryopreserved sperm downregulates genes relevant for early embryo development in the horse
Authors: Ortiz-Rodriguez JM , Ortega Ferrusola C , Gil MC , Martín Cano FE , Gaitskell-Phillips G , Rodríguez-Martínez H , Hinrichs K , Álvarez-Barrientos A , Román A , Peña FJ
Published: February 2019

Artificial insemination with cryopreserved sperm is a major assisted reproductive technology in many species. In horses, as in humans, insemination with cryopreserved sperm is associated with lower pregnancy rates than those for fresh sperm, however, direct effects of sperm cryopreservation on the development of resulting embryos are largely unexplored. The aim of this study was to investigate differences in gene expression between embryos resulting from fertilization with fresh or cryopreserved sperm. Embryos were obtained at 8, 10 or 12 days after ovulation from mares inseminated post-ovulation on successive cycles with either fresh sperm or frozen-thawed sperm from the same stallion, providing matched embryo pairs at each day. RNA was isolated from two matched pairs (4 embryos) for each day, and cDNA libraries were built and sequenced. Significant differences in transcripts per kilobase million (TPM) were determined using (i) genes for which the expression difference between treatments was higher than 99% of that in the random case (P < 0.01), and (ii) genes for which the fold change was ≥ 2, to avoid expression bias in selection of the candidate genes. Molecular pathways were explored using the DAVID webserver, followed by network analyses using STRING, with a threshold of 0.700 for positive interactions. The transcriptional profile of embryos obtained with frozen-thawed sperm differed significantly from that for embryos derived from fresh sperm on all days, showing significant down-regulation of genes involved in biological pathways related to oxidative phosphorylation, DNA binding, DNA replication, and immune response. Many genes with reduced expression were orthologs of genes known to be embryonic lethal in mice. This study, for the first time, provides evidence of altered transcription in embryos resulting from fertilization with cryopreserved spermatozoa in any species. As sperm cryopreservation is commonly used in many species, including human, the effect of this intervention on expression of developmentally important genes in resulting embryos warrants attention.
The Nanodiffraction beamline ID01/ESRF: a microscope for imaging strain and structure
Authors: Leake Steven J. , Chahine Gilbert A. , Djazouli Hamid , Zhou Tao , Richter Carsten , Hilhorst Jan , Petit Lucien , Richard Marie-Ingrid , Morawe Christian , Barrett Raymond , Zhang Lin , Homs-Regojo Roberto A. , Favre-Nicolin Vincent , Boesecke Peter , Schülli Tobias U.
Published: February 2019

The ID01 beamline has been built to combine Bragg diffraction with imaging techniques to produce a strain and mosaicity microscope for materials in their native or operando state. A scanning probe with nano-focused beams, objective-lens-based full-field microscopy and coherent diffraction imaging provide a suite of tools which deliver micrometre to few nanometre spatial resolution combined with 10−5 strain and 10−3 tilt sensitivity. A detailed description of the beamline from source to sample is provided and serves as a reference for the user community. The anticipated impact of the impending upgrade to the ESRF – Extremely Brilliant Source is also discussed.
A versatile liquid-jet setup for the European XFEL
Authors: Schulz J. , Bielecki J. , Doak R. B. , Dörner K. , Graceffa R. , Shoeman R. L. , Sikorski M. , Thute P. , Westphal D. , Mancuso A. P.
Published: February 2019

The SPB/SFX instrument of the European XFEL provides unique possibilities for high-throughput serial femtosecond crystallography. This publication presents the liquid-jet sample delivery setup of this instrument. The setup is compatible with state-of-the-art gas dynamic virtual nozzle systems as well as high-viscosity extruders and provides space and flexibility for other liquid injection devices and future upgrades. The liquid jets are confined in a differentially pumped catcher assembly and can be replaced within a couple of minutes through a load-lock. A two-microscope imaging system allows visual control of the jets from two perspectives.
(Z)-1-Benzoyl-5-benzylidene-2-hydroxy-4-oxo-4,5-dihydro-1H-pyrrole-3-carbonitrile
Authors: Onami Yuika , Siddaraju Budanur P. , Anilkumar Haleyur G. , Yathirajan Hemmige S. , Haraguchi Tomoyuki , Akitsu Takashiro
Published: February 2019

The title compound, C19H12N2O3, obtained as an intermediate in the synthesis of a pyrrole derivative, is composed of a five-membered heterocycle with substituted groups via double or triple bonds as well as single bonds, without an asymmetric carbon atom. An intramolecular O—H...O link occurs. In the crystal, O—H...N hydrogen bonds link the molecules.
5,8,13,13-Tetrachloro-13H-dibenzo[a,i]fluorene cyclohexane hemisolvate
Authors: Detert Heiner , Schollmeyer Dieter
Published: February 2019

In the crystal structure of the solvated pentacyclic title compound, C21H10Cl4·0.5C6H12, the pentacyclic chloroaromatic rings are arranged in parallel layers, with the chlorine atoms protruding from these planes. Channels orthogonal to these layers are filled with disordered cyclohexane molecules.
Exposure and susceptibility drive reinfection with gastrointestinal parasites in a social primate
Authors: Müller‐Klein Nadine , Heistermann Michael , Strube Christina , Franz Mathias , Schülke Oliver , Ostner Julia
Published: February 2019

Increased risk of infectious disease transmission has been proposed as one major cost of group living. While factors corresponding to transmission via exposure to infectious stages and susceptibility to contracting infections upon contact are relatively well understood, both aspects are rarely investigated simultaneously.

Here, we assessed the influence of exposure and susceptibility measures on strongyle nematode reinfection after experimental deworming of Barbary macaques (Macaca sylvanus) (n = 57). We investigated impacts of behaviour (social bonds, grooming and ground use) and physiology (faecal glucocorticoids, urinary C‐Peptides, urinary neopterin, gastrointestinal [GI] helminth coinfection) on the likelihood of reinfection, using patch occupancy modelling and information theoretic model selection to determine the best models predicting reinfection patterns.

Coinfection was the most consistent risk factor, spending time on presumably contaminated soil, interacting with many partners and forming strong same‐sex bonds also tended to increase infection risk. In contrast, strong social bonds with opposite‐sex partners had a consistently protective effect.

Our results indicate that coinfections could serve as an integrative measure of individual disease susceptibility. Furthermore, we show that social contact contributes to both exposure and susceptibility to environmentally transmitted parasites, with the outcome depending on specific interaction patterns.

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Non‐invasive analysis of tumor mutation profiles and druggable mutations by sequencing of cell free DNA of Chinese metastatic breast cancer patients
Authors: Li Shunying , Wang Baoxiao , Li Yuquan , Lai Hongna , Liu Yujie , Jin Liang
Published: February 2019

Background

Metastatic breast cancer (MBC) remains an incurable disease worldwide. Tumor gene mutations have evolved and led to drug resistance in the treatment course of MBC. However, data on the mutation profiles and druggable genomic alterations of MBC remain limited, particularly among Chinese patients. Our study aimed to depict the mutation profiles and identify druggable mutations in circulating tumor DNA (ctDNA) in Chinese MBC patients.

Methods

Targeted deep sequencing of a 1021‐gene panel was performed on 17 blood samples and 5 available tissue samples from 17 Chinese MBC patients.

Results

We identified 60 somatic mutations in 17 blood samples (sensitivity 100%). Somatic mutations were identified in the blood samples of all patients, and 41.18% (7/17) of patients harbored at least one druggable mutation. A high ctDNA level in plasma is associated with shorter progression‐free survival.

Conclusion

Targeted deep sequencing of cell free DNA is a highly sensitive, noninvasive method to depict tumor mutation profiles, identify druggable mutations in MBC, and predict patient outcome. Our study shed light on the utility of ctDNA as noninvasive “liquid biopsy” in the management of MBC.
Systems biology identifies preserved integrity but impaired metabolism of mitochondria due to a glycolytic defect in Alzheimer's disease neurons
Authors: Theurey Pierre , Connolly Niamh M. C. , Fortunati Ilaria , Basso Emy , Lauwen Susette , Ferrante Camilla , Moreira Pinho Catarina , Joselin Alvin , Gioran Anna , Bano Daniele , Park David S. , Ankarcrona Maria , Pizzo Paola , Prehn Jochen H. M.
Published: February 2019

Mitochondrial dysfunction is implicated in most neurodegenerative diseases, including Alzheimer's disease (AD). We here combined experimental and computational approaches to investigate mitochondrial health and bioenergetic function in neurons from a double transgenic animal model of AD (PS2APP/B6.152H). Experiments in primary cortical neurons demonstrated that AD neurons had reduced mitochondrial respiratory capacity. Interestingly, the computational model predicted that this mitochondrial bioenergetic phenotype could not be explained by any defect in the mitochondrial respiratory chain (RC), but could be closely resembled by a simulated impairment in the mitochondrial NADH flux. Further computational analysis predicted that such an impairment would reduce levels of mitochondrial NADH, both in the resting state and following pharmacological manipulation of the RC. To validate these predictions, we utilized fluorescence lifetime imaging microscopy (FLIM) and autofluorescence imaging and confirmed that transgenic AD neurons had reduced mitochondrial NAD(P)H levels at rest, and impaired power of mitochondrial NAD(P)H production. Of note, FLIM measurements also highlighted reduced cytosolic NAD(P)H in these cells, and extracellular acidification experiments showed an impaired glycolytic flux. The impaired glycolytic flux was identified to be responsible for the observed mitochondrial hypometabolism, since bypassing glycolysis with pyruvate restored mitochondrial health. This study highlights the benefits of a systems biology approach when investigating complex, nonintuitive molecular processes such as mitochondrial bioenergetics, and indicates that primary cortical neurons from a transgenic AD model have reduced glycolytic flux, leading to reduced cytosolic and mitochondrial NAD(P)H and reduced mitochondrial respiratory capacity.
Copy number variation and variant discovery in Bullmastiff dogs
Authors: Mortlock S.‐A. , Williamson P. , Khatkar M. S.
Published: February 2019

Identification of genomic variants within dogs is important for understanding genetic factors contributing to breed diversity and phenotypic traits. This study aimed to identify sources of variation in the Bullmastiff using high‐density signal intensity and whole‐genome sequence data. Close to 3000 copy number variants (CNVs) were identified in Bullmastiff dogs using Canine HD BeadChip data. When CNVs were collated, 82 CNV regions (CNVRs) were detected, 50% in transcribed regions encompassing 432 genes. Fifty of the CNVRs detected have not been reported in other breeds and represent potential breed‐specific variants. A proportion of the CNVR variants with predicted modifying effects on gene pathways may contribute to breed traits. Approximately 5 million putative variants per dog, inclusive of single nucleotide polymorphisms (SNPs), multi‐nucleotide polymorphisms (MNPs) and insertion and deletions (INDELs), were identified from DNA sequence data on a small number of animals. Identification of genetic variants in the Bullmastiff highlights sources of variation in the breed and molecular markers that will assist in future trait and disease investigations in dogs.
Multicentre clinical simulation evaluation of the ISO 80369‐6 neuraxial non‐Luer connector
Authors: Cook T. M. , Wilkes A. , Bickford Smith P. , Dorn L. , Stacey M. , Kinsella S. M. , Sharpe P. , Phillips P.
Published: February 2019

To avoid potentially fatal wrong‐route neuraxial drug errors, international standard ISO 80369‐6 specifying a non‐Luer neuraxial connector design was published in 2016. We describe usability studies used in development of the design. Thirty‐eight doctors and 17 nurses performed simulated procedures on manikins, using devices fitted with Luer connectors or draft ISO 80369‐6 ‘non‐Luer’ connectors. The procedures included spinal anaesthesia; intrathecal chemotherapy; lumbar puncture, cerebrospinal fluid collection and pressure measurement; epidural catheter placement with bolus injection and critical care use. Participants attempted cross connection between neuraxial connectors and a range of other medical device connectors, including those from the ISO 80369 small‐bore connector series. Video recording analysis was used for all assessments. Participants subjectively assessed performance of the draft non‐Luer connector, including suitability for routine clinical use. Participants performed 198 procedures. The connector achieved easy, leak‐free connections. The willingness of participants to use the non‐Luer connectors were: spinal anaesthesia 100%; intrathecal chemotherapy 88%; lumbar puncture, cerebrospinal fluid collection and pressure measurement 93%; epidural catheter placement with bolus injection 78%; critical care use 100%. Concerns raised were generally device related, rather than connector related. Most cross‐connection attempts failed, even using above clinical forces and, when successful, were judged of low clinical risk potential; the exception was a malaligned connection between the non‐Luer slip and female Luer connectors. This led to revision of the dimensional tolerances of the non‐Luer connector to reduce this risk, before publication of the final specification in 2016. We conclude that the ISO 80369‐6 neuraxial non‐Luer connector is suitable for clinical use.