bluuebunny/crossref_metadata_2025 huggingface dataset:
Prevalence and Characteristics of Tracheal Lesions Observed in Tracheostomized Patients
Authors: Planells Fernando , Villalba Dario , Viviana Feld , Leiva Valeria , Scrigna Mariana , Distéfano Eduardo , Collins Jessica , Rocco Ana , Matesa Amelia , Áreas Laura , Golfarini Nicolas , Gil-Rossetti Gregorio , Pini María P. , Hannun Marcos , Boni Sabrina , Grimaldi Sabrina , Pedace Paula , Díaz-Ballvé Pablo , Andreu Mauro , Buñirigo Pablo , Noval Diego
Published: July 2018

Background:

Our objective was to describe the prevalence and characteristics of tracheal lesions observed in flexile bronchoscopies of tracheostomized patients, and to determine those factors associated with severe injuries.

Methods:

This is an analytical, observational, and transversal study. The flexible bronchoscopies of tracheostomized patients from our database were reviewed to assess their lesions. The tracheal lesions were classified according to their severity; lesions obstructing above 50% of the lumen were interpreted as severe and those obstructing <50% as mild. The lesions were also classified according to location as glottic, subglottic, at the level of the tracheal ostomy, tracheal, and bronchial. The types of lesions found were granuloma, stenosis, and excessive central airway collapse. Possible predictors of severe lesions were assessed.

Results:

A total of 414 patients were included in the study, the mean age being 65 years (±16.2 y). Of all the bronchoscopies assessed, 202 (49%) showed mild lesions, and 91 (22%) were severe. We found granulomas in 230 patients (55%), and 32 (26%) were severe. Of the 27 patients with stenosis (7%), 17 (63%) were severe. Excessive central airway collapse was seen in 120 patients (31.8%), and 65 (54%) were severe. There were statistically significant differences related to age in the group that developed severe lesions (mean age, 73 y; Q1 to Q3, 58 to 81) compared with the group free of lesions (mean age, 69 y; Q1 to Q3, 55.7 to 75; P = 0.001) and also in the duration requiring an artificial airway (mean, 84.5 d; Q1 to Q3, 49 to 135.5) compared with the group free of lesions (mean of 59.5 d; Q1 to Q3, 42 to 98; P = 0.035).

Conclusion:

There was a high prevalence of tracheal lesions, mainly subglottic granulomas. Age and the duration for which the patient required an artificial airway were related to the presence of severe lesions.
18F-FDOPA Uptake Reflects the Efficacy of Dopamine Agonists Treatment in Pituitary Prolactinoma
Authors: Heimburger Céline , Bund Caroline , Addeo Pietro , Goichot Bernard , Imperiale Alessio
Published: July 2018

We report the results of 18F-FDOPA PET/CT in an asymptomatic MEN-1 patient with secreting pituitary prolactinoma investigated before and during dopamine agonists treatment. PET/CT showed intense and focal 18F-FDOPA uptake in the right part of anterior pituitary corresponding to a microadenoma on MRI imaging. Six months after the beginning of cabergoline, prolactin secretion normalized, pituitary 18F-FDOPA uptake completely regressed, and tumor size reduced on follow-up PET/CT and MRI, respectively.
Sexual Dichromatism Drives Diversification Within a Major Radiation of African Amphibians
Authors: Portik Daniel M. , Bell Rayna C. , Blackburn David C. , Bauer Aaron M. , Barratt Christopher D. , Branch William R. , Burger Marius , Channing Alan , Colston Timothy J. , Conradie Werner , Dehling J. Maximillian , Drewes Robert C. , Ernst Raffael , Greenbaum Eli , Gvoždík Václav , Harvey James , Hillers Annika , Hirschfeld Mareike , Jongsma Gregory F.M. , Kielgast Jos , Kouete Marcel T. , Lawson Lucinda P. , Leaché Adam D. , Loader Simon P. , Lötters Stefan , Meijden Arie van der , Menegon Michele , Müller Susanne , Nagy Zoltán T. , Ofori-Boateng Caleb , Ohler Annemarie , Papenfuss Theodore J. , Rößler Daniela , Sinsch Ulrich , Rödel Mark-Oliver , Veith Michael , Vindum Jens , Zassi-Boulou Ange-Ghislain , McGuire Jimmy A.
Published: July 2018

Theory predicts that sexually dimorphic traits under strong sexual selection, particularly those involved with intersexual signaling, can accelerate speciation and produce bursts of diversification. Sexual dichromatism (sexual dimorphism in color) is widely used as a proxy for sexual selection and is associated with rapid diversification in several animal groups, yet studies using phylogenetic comparative methods to explicitly test for an association between sexual dichromatism and diversification have produced conflicting results. Sexual dichromatism is rare in frogs, but it is both striking and prevalent in African reed frogs, a major component of the diverse frog radiation termed Afrobatrachia. In contrast to most other vertebrates, reed frogs display female-biased dichromatism in which females undergo color transformation, often resulting in more ornate coloration in females than in males. We produce a robust phylogeny of Afrobrachia to investigate the evolutionary origins of sexual dichromatism in this radiation and examine whether the presence of dichromatism is associated with increased rates of net diversification. We find that sexual dichromatism evolved once within hyperoliids and was followed by numerous independent reversals to monochromatism. We detect significant diversification rate heterogeneity in Afrobatrachia and find that sexually dichromatic lineages have double the average net diversification rate of monochromatic lineages. By conducting trait simulations on our empirical phylogeny, we demonstrate our inference of trait-dependent diversification is robust. Although sexual dichromatism in hyperoliid frogs is linked to their rapid diversification and supports macroevolutionary predictions of speciation by sexual selection, the function of dichromatism in reed frogs remains unclear. We propose that reed frogs are a compelling system for studying the roles of natural and sexual selection on the evolution of sexual dichromatism across both micro- and macroevolutionary timescales.
Long-range memory of growth and cycle progression correlates cell cycles in lineage trees
Authors: Kuchen Erika E , Becker Nils , Claudino Nina , Höfer Thomas
Published: July 2018

Mammalian cell proliferation is controlled by mitogens. However, how proliferation is coordinated with cell growth is poorly understood. Here we show that statistical properties of cell lineage trees – the cell-cycle length correlations within and across generations – reveal how cell growth controls proliferation. Analyzing extended lineage trees with latent-variable models, we find that two antagonistic heritable variables account for the observed cycle-length correlations. Using molecular perturbations of mTOR and MYC we identify these variables as cell size and regulatory license to divide, which are coupled through a minimum-size checkpoint. The checkpoint is relevant only for fast cell cycles, explaining why growth control of mammalian cell proliferation has remained elusive. Thus, correlated fluctuations of the cell cycle encode its regulation.
TCRex: detection of enriched T cell epitope specificity in full T cell receptor sequence repertoires
Authors: Gielis Sofie , Moris Pieter , Bittremieux Wout , De Neuter Nicolas , Ogunjimi Benson , Laukens Kris , Meysman Pieter
Published: July 2018

High-throughput T cell receptor (TCR) sequencing allows the characterization of an individual’s TCR repertoire and directly query their immune state. However, it remains a non-trivial task to couple these sequenced TCRs to their antigenic targets. In this paper, we present a novel strategy to annotate full TCR sequence repertoires. The strategy is based on a machine learning algorithm to learn the TCR patterns common to the recognition of a specific epitope. These results are then combined with a statistical analysis to evaluate the occurrence of specific epitope-reactive TCR sequences per epitope in repertoire data. In this manner, we can directly study the capacity of full TCR repertoires to target specific epitopes of the relevant vaccines or pathogens. We demonstrate the usability of this approach on three independent datasets related to vaccine monitoring and infectious disease diagnostics by independently identifying the epitopes that are targeted by the TCR repertoire. The developed method is freely available as a web tool for academic use at tcrex.biodatamining.be.
Spectral fingerprints or spectral tilt? Evidence for distinct oscillatory signatures of memory formation
Authors: Fellner Marie-Christin , Gollwitzer Stephanie , Rampp Stefan , Kreiselmeyr Gernot , Bush Daniel , Diehl Beate , Axmacher Nikolai , Hamer Hajo , Hanslmayr Simon
Published: July 2018

Decreases in low frequency power (2-30 Hz) alongside high frequency power increases (>40 Hz) have been demonstrated to predict successful memory formation. Parsimoniously this change in the frequency spectrum can be explained by one factor, a change in the tilt of the power spectrum (from steep to flat) indicating engaged brain regions. A competing view is that the change in the power spectrum contains several distinct brain oscillatory fingerprints, each serving different computations. Here, we contrast these two theories in a parallel MEG-intracranial EEG study where healthy participants and epilepsy patients, respectively, studied either familiar verbal material, or unfamiliar faces. We investigated whether modulations in specific frequency bands can be dissociated in time, space and by experimental manipulation. Both, MEG and iEEG data, show that decreases in alpha/beta power specifically predicted the encoding of words, but not faces, whereas increases in gamma power and decreases in theta power predicted memory formation irrespective of material. Critically, these different oscillatory signatures of memory encoding were evident in different brain regions. Moreover, high frequency gamma power increases occurred significantly earlier compared to low frequency theta power decreases. These results speak against a “spectral tilt” and demonstrate that brain oscillations in different frequency bands serve different functions for memory encoding.
Natural variation inC. elegansarsenic toxicity is explained by differences in branched chain amino acid metabolism
Authors: Zdraljevic Stefan , Fox Bennett W. , Strand Christine , Panda Oishika , Tenjo Francisco J. , Brady Shannon C. , Crombie Tim A. , Doench John G. , Schroeder Frank C. , Andersen Erik C.
Published: July 2018

We find that variation in thedbt-1gene underlies natural differences inCaenorhabditis elegansresponses to the toxin arsenic. This gene encodes the E2 subunit of the branched-chain α-keto acid dehydrogenase (BCKDH) complex, a core component of branched-chain amino acid (BCAA) metabolism. We causally linked a non-synonymous variant in the conserved lipoyl domain of DBT-1 to differential arsenic responses. Using targeted metabolomics and chemical supplementation, we demonstrate that differences in responses to arsenic are caused by variation in iso-branched chain fatty acids. Additionally, we show that levels of branched chain fatty acids in human cells are perturbed by arsenic treatment. This finding has broad implications for arsenic toxicity and for arsenic-focused chemotherapeutics across human populations. Our study implicates the BCKDH complex and BCAA metabolism in arsenic responses, demonstrating the power ofC. elegansnatural genetic diversity to identify novel mechanisms by which environmental toxins affect organismal physiology.
Non-parametric analysis of thermal proteome profiles reveals novel drug-binding proteins
Authors: Childs Dorothee , Bach Karsten , Franken Holger , Anders Simon , Kurzawa Nils , Bantscheff Marcus , Savitski Mikhail , Huber Wolfgang
Published: July 2018

Detecting the targets of drugs and other molecules in intact cellular contexts is a major objective in drug discovery and in biology more broadly. Thermal proteome profiling (TPP) pursues this aim at proteome-wide scale by inferring target engagement from its effects on temperature-dependent protein denaturation. However, a key challenge of TPP is the statistical analysis of the measured melting curves with controlled false discovery rates at high proteome coverage and detection power. We present non-parametric analysis of response curves (NPARC), a statistical method for TPP based on functional data analysis and nonlinear regression. We evaluate NPARC on five independent TPP datasets and observe that it is able to detect subtle changes in any region of the melting curves, reliably detects the known targets, and outperforms a melting point-centric, single-parameter fitting approach in terms of specificity and sensitivity. NPARC can be combined with established analysis of variance (ANOVA) statistics and enables flexible, factorial experimental designs and replication levels. To facilitate access to a wide range of users, a freely available software implementation of NPARC is provided.
Formulation, Evaluation and Antibacterial Efficiency of water-based herbal Hand Sanitizer Gel
Authors: Acharya Shri Balakrishna , Ghosh Saradindu , Yadav Giriraj , Sharma Kavita , Ghosh Sirsendu , Joshi Sushil
Published: July 2018

Hands are the primary mode of transmission of microbes and infections. Hand-washing is critical in food production, food service and also important in healthcare setting, homes and day care preparations. The present research was aimed to evaluate the antibacterial efficacy of various herbal oils such as Cinnamon oil, Eucalyptus oil, menthol oil and lavender oil and found that cinnamon oil showed better antibacterial activity. Also the research was carried out to formulate and evaluate the poly herbal Hand wash gel containing Azadirachta indica, Ocimum sanctum and Citrus limon extracts. The anti-microbial activity of the formulated herbal hand wash gel was tested against Escherichia coli, Staphylococcus aureus and Salmonella by spread plate techniques and the results obtained were compared with commercial antibacterial standards. Also the efficiency was checked by using the hand wash gel on volunteers. The results from the present work suggest and support the incorporation and utilization of herbs in the formulations to give better effect.
The landscape of coadaptation in Vibrio parahaemolyticus
Authors: Cui Yujun , Yang Chao , Qiu Hongling , Wang Hui , Yang Ruifu , Falush Daniel
Published: July 2018

Investigating fitness interactions in natural populations remains a considerable challenge. We take advantage of the unique population structure of Vibrio parahaemolyticus, a bacterial pathogen of humans and shrimp, to perform a genome-wide screen for coadapted genetic elements. We identified 90 interaction groups involving 1,560 coding genes. 82 of these interaction groups are between accessory genes, many of which have functions related to carbohydrate transport and metabolism. Only 8 interaction groups involve both core and accessory genomes. The largest includes 1,540 SNPs in 82 genes and 338 accessory genome elements, many involved in lateral flagella and cell wall biogenesis. The interactions have a complex hierarchical structure encoding at least four distinct ecological strategies. Preliminary experiments imply that the strategies influence biofilm formation and bacterial growth rate in vitro. One strategy involves a divergent profile in multiple genome regions, implying that strains have irreversibly specialized, while the others involve fewer genes and are more plastic. Our results imply that most genetic alliances are ephemeral but that increasingly complex strategies can evolve and eventually cause speciation.
Web-based design and analysis tools for CRISPR base editing
Authors: Hwang Gue-Ho , Park Jeongbin , Lim Kayeong , Kim Sunghyun , Yu Jihyeon , Kim Sang-Tae , Eils Roland , Kim Jin-Soo , Bae Sangsu
Published: July 2018

Background

As a result of its simplicity and high efficiency, the CRISPR-Cas system has been widely used as a genome editing tool. Recently, CRISPR base editors, which consist of deactivated Cas9 (dCas9) or Cas9 nickase (nCas9) linked with a cytidine or a guanine deaminase, have been developed. Base editing tools will be very useful for gene correction because they can produce highly specific DNA substitutions without the introduction of any donor DNA, but dedicated web-based tools to facilitate the use of such tools have not yet been developed.

Results

We present two web tools for base editors, named BE-Designer and BE-Analyzer. BE-Designer provides all possible base editor target sequences in a given input DNA sequence with useful information including potential off-target sites. BE-Analyzer, a tool for assessing base editing outcomes from next generation sequencing (NGS) data, provides information about mutations in a table and interactive graphs. Furthermore, because the tool runs client-side, large amounts of targeted deep sequencing data (>100MB) do not need to be uploaded to a server, substantially reducing running time and increasing data security. BE-Designer and BE-Analyzer can be freely accessed at http://www.rgenome.net/bedesigner/ and http://www.rgenome.net/be-analyzer/respectively

Conclusion

We develop two useful web tools to design target sequence (BE-Designer) and to analyze NGS data from experimental results (BE-Analyzer) for CRISPR base editors.
Components of Executive Function Predict Regional Prefrontal Volumes
Authors: Mace Ryan A. , Waters Abigail B. , Sawyer Kayle S. , Turrisi Taylor , Gansler David A.
Published: July 2018

Objective

Designed to measure a diversity of executive functioning (EF) through classical neuropsychological tests, the Delis-Kaplan Executive Function Scale (D-KEFS) allows for the investigation of the neural architecture of EF. We examined how the D-KEFS Tower, Verbal Fluency, Design Fluency, Color–Word Interference, and Trail Making Test tasks related to regional frontal lobe volumes, quantifying how components of EF were represented in disparate neural networks.

Method

Adults from the Nathan Kline Institute – Rockland Sample (NKI-RS), an open-access community study of brain development, with complete MRI (3T scanner) and D-KEFS data were selected for analysis (N = 478; ages 20-85). In a mixed-effects model predicting volume, D-KEFS task, D-KEFS score, region of interest (ROI; 13 frontal, 1 occipital control), were entered as fixed effects with intercepts for participants as random effects.

Results

“Unitary” EF (average of D-KEFS scores) was positively associated with superior frontal, rostral middle frontal, and lateral orbitofrontal volumes; a negative association was observed with frontal pole volume (| z-score slope | range = 0.040 to 0.051). “Diverse” EF skills (individual D-KEFS task scores) were differentially associated with two or three ROIs, respectively, but to a stronger extent (| z-score slope | range = 0.053 to 0.103).

Conclusions

The neural correlates found for the D-KEFS support the prefrontal modularity of EF at both the unitary (aspects of EF ability common to all tasks) and task (diverse EF skills) levels. The separation of task-general variance in neurocognition from task-specific variance can further evaluate neuropsychological tests as indices of brain integrity.

Public Significance Statements

Our results support the relationship between larger lateral prefrontal cortex and greater executive function.

A composite of executive function performance, which was broadly associated with the prefrontal cortex, may be ideal for assessing diffuse frontal lobe damage (e.g., hypoxia).

Individual executive functions, which were more narrowly but strongly related to specific prefrontal regions, could be better for assessing the effects of localized brain injuries (e.g., tumor).
ROSeq: Modeling expression ranks for noise-tolerant differential expression analysis of scRNA-Seq data
Authors: Gupta Krishan , Lalit Manan , Biswas Aditya , Maulik Ujjwal , Bandyopadhyay Sanghamitra , Ahuja Gaurav , Ghosh Abhik , Sengupta Debarka
Published: July 2018

1

Systematic delineation of complex biological systems is an ever-challenging and resource-intensive process. Single cell transcriptomics allows us to study cell-to-cell variability in complex tissues at an unprecedented resolution. Accurate modeling of gene expression plays a critical role in the statistical determination of tissue-specific gene expression patterns. In the past few years, considerable efforts have been made to identify appropriate parametric models for single cell expression data. The zero-inflated version of Poisson/Negative Binomial and Log-Normal distributions have emerged as the most popular alternatives due to their ability to accommodate high dropout rates, as commonly observed in single cell data. While the majority of the parametric approaches directly model expression estimates, we explore the potential of modeling expression-ranks, as robust surrogates for transcript abundance. Here we examined the performance of the Discrete Generalized Beta Distribution (DGBD) on real data and devised a Wald-type test for comparing gene expression across two phenotypically divergent groups of single cells. We performed a comprehensive assessment of the proposed method, to understand its advantages as compared to some of the existing best practice approaches. Besides striking a reasonable balance between Type 1 and Type 2 errors, we concluded that ROSeq, the proposed differential expression test is exceptionally robust to expression noise and scales rapidly with increasing sample size. For wider dissemination and adoption of the method, we created an R package called ROSeq, and made it available on the Bioconductor platform.
Tissue-specific actions of Pax6 on proliferation-differentiation balance in the developing forebrain are Foxg1-dependent
Authors: Quintana-Urzainqui Idoia , Kozić Zrinko , Mitra Soham , Tian Tian , Manuel Martine , Mason John O. , Price David J.
Published: July 2018

Differences in the growth and maturation of diverse forebrain tissues depends on region-specific transcriptional regulation. Individual transcription factors act simultaneously in multiple regions that develop very differently, raising questions about the extent to which their actions vary regionally. We found that the transcription factor Pax6 affects the transcriptomes and the balance between proliferation and differentiation in opposite directions in murine diencephalon versus cortex. We tested several possible mechanisms to explain Pax6’s tissue-specific actions and found that the presence of the transcription factor Foxg1 in cortex but not diencephalon was most influential. We found that Foxg1 is responsible for many of the differences in cell cycle gene expression between diencephalon and cortex. In cortex lacking Foxg1, Pax6’s action on the balance of proliferation versus differentiation became diencephalon-like. Our findings reveal a mechanism for generating regional forebrain diversity in which the actions of one transcription factor completely reverse the actions of another.
High-dimensional geometry of population responses in visual cortex
Authors: Stringer Carsen , Pachitariu Marius , Steinmetz Nicholas , Carandini Matteo , Harris Kenneth D.
Published: July 2018

A neuronal population encodes information most efficiently when its activity is uncorrelated and high-dimensional, and most robustly when its activity is correlated and lower-dimensional. Here, we analyzed the correlation structure of natural image coding, in large visual cortical populations recorded from awake mice. Evoked population activity was high dimensional, with correlations obeying an unexpected power-law: the nth principal component variance scaled as 1/n. This was not inherited from the 1/f spectrum of natural images, because it persisted after stimulus whitening. We proved mathematically that the variance spectrum must decay at least this fast if a population code is smooth, i.e. if small changes in input cannot dominate population activity. The theory also predicts larger power-law exponents for lower-dimensional stimulus ensembles, which we validated experimentally. These results suggest that coding smoothness represents a fundamental constraint governing correlations in neural population codes.
Domestic gardens as favorable pollinator habitats in impervious landscapes
Authors: Levé Marine , Baudry Emmanuelle , Bessa-Gomes Carmen
Published: July 2018

Urban expansion is correlated to negative biodiversity trends. The amount of impervious surfaces in urban areas is a determinant of pollinator species assemblages. While the increase in urbanization and impervious surfaces negatively impacts pollinators, cities also encompass urban green spaces, which have a significant capacity to support biodiversity. Among them, domestic gardens that represent a non-negligible fraction of green spaces have been shown to benefit pollinators. Domestic gardens may form habitat clusters in residential areas, although their value at a landscape scale is still unknown. Here, we investigate the combined effects of impervious surfaces and domestic garden areas on pollinator richness. Due to the difficulty of accessing privately owned domestic gardens, we chose to use citizen science data from a well-established French citizen science program known as SPIPOLL. Using regression tree analysis on buffers located from 50m to 1000m around the data points, we show the importance of pollinators being in close proximity to domestic gardens as locally favorable habitats that are embedded within a landscape, in which impervious surfaces represent unfavorable areas. We highlight the inter-connection between local and landscape scales, the potential for patches of domestic gardens in residential areas, and the need to consider the potential of gardeners’ coordinated management decisions within a landscape context.

Highlights

Citizen science provided access to domestic gardens, understudied urban green spaces

Impervious surfaces limit pollinators presence at landscape level

Sufficient critical amount of gardens increased pollinator diversity at local scale

Critical amount of gardens’ knowledge may favor coordinated decisions by gardeners

Pollinators may benefit from patches of domestic gardens in an urban matrix
Regression of solid breast tumours in mice by Newcastle disease virus is associated with production of apoptosis related-cytokines
Authors: Ahmad Umar , Raihan Juraimi , Yong Yoke Keong , Eshak Zolkapli , Othman Fauziah , Ideris Aini
Published: July 2018

Background

Different strains of Newcastle disease virus (NDV) worldwide proved to have tumouricidal activity in several types of cancer cells. However, the possible anti-cancer activity of Malaysian NDV AF2240 strain and its mechanism of action remains unknown. The ability of cytokine-related apoptosis-inducing NDV AF2240 to treat breast cancer was investigated in the current study.

Methods

A total of 90 mice were used and divided into 15 groups, each group comprising of 6 mice. Tumour, body weight and mortality of the mice were determined throughout the experiment, to observe the effect of NDV and NDV+Tamoxifen treatments on the mice. In addition, the toxic effect of the treatments was determined through liver function test. In order to elucidate the involvement of cytokine production induced by NDV, a total of six cytokines, i.e. IL-6, IFN-γ, MCP-1, IL-10, IL12p70 and TNF-α were measured using cytometric bead array assay (plasma) and enzyme-linked immunosorbent spot (isolated splenocytes).

Results

The results demonstrated that 4T1 breast cancer cells in allotransplanted mice treated with AF2240 showed a noticeable inhibition in tumour growth and induce apoptotic-related cytokines.

Conclusion

NDV AF2240 suppression of breast tumour growth is associated with induction of apoptotic-related cytokines.
Co-occurring alterations in the RAS-MAPK pathway limit response to MET inhibitor treatment inMETexon 14 skipping mutation positive lung cancer
Authors: Rotow Julia K. , Gui Philippe , Wu Wei , Raymond Victoria M. , Lanman Richard B. , Kaye Frederic J. , Peled Nir , de la Cruz Ferran Fece , Nadres Brandon , Corcoran Ryan B. , Yeh Iwei , Bastian Boris C. , Starostik Petr , Newsom Kimberly , Olivas Victor R , Wolff Alexander M. , Fraser James S. , Collisson Eric A. , McCoach Caroline E. , Camidge D. Ross , Pacheco Jose , Bazhenova Lyudmila , Li Tianhong , Bivona Trever G. , Blakely Collin M.
Published: July 2018

PURPOSE

While patients with advanced-stage non-small cell lung cancers (NSCLCs) harboringMETexon 14 skipping mutations (METex14) often benefit from MET tyrosine kinase inhibitor (TKI) treatment, clinical benefit is limited by primary and acquired drug resistance. The molecular basis for this resistance remains incompletely understood.

METHODS

Targeted sequencing analysis was performed on cell-free circulating tumor DNA obtained from 289 patients with advanced-stageMETex14-mutated NSCLC.

RESULTS

Prominent co-occurring RAS-MAPK pathway gene alterations (e.g. inKRAS, NF1) were detected in NSCLCs withMETex14 skipping alterations as compared toEGFR-mutated NSCLCs. There was an association between decreased MET TKI treatment response and RAS-MAPK pathway co-occurring alterations. In a preclinical model expressing a canonicalMETex14 mutation, KRAS overexpression or NF1 downregulation hyperactivated MAPK signaling to promote MET TKI resistance. This resistance was overcome by co-treatment with crizotinib and the MEK inhibitor trametinib.

CONCLUSION

Our study provides a genomic landscape of co-occurring alterations in advanced-stageMETex14-mutated NSCLC and suggests a potential combination therapy strategy targeting MAPK pathway signaling to enhance clinical outcomes.
Social and nutritional factors shape larval aggregation, foraging, and body mass in a polyphagous fly
Authors: Morimoto Juliano , Nguyen Binh , Tabrizi Shabnam Tarahi , Ponton Fleur , Taylor Phillip W.
Published: July 2018

The majority of insect species have a clearly defined larval stage during development. Larval nutrition is crucial for individuals’ growth and development, and larval foraging success often depends on both resource availability and competition for those resources. To date, however, little is known about how these factors interact to shape larval development and behaviour. Here we manipulated the density of larvae of the polyphagous fruit fly pest Bactrocera tryoni (‘Queensland fruit fly’), and the diet concentration of patches in a foraging arena to address this gap. Using advanced statistical methods of machine learning and linear regression models, we showed that high larval density results in increased larval aggregation across all diets except in extreme diet dilutions. Larval aggregation was positively associated with larval body mass across all diet concentrations except in extreme diet dilutions where this relationship was reversed. Larvae in low-density arenas also tended to aggregate while those in high-density arenas tended to disperse, an effect that was observed for all diet concentrations. Furthermore, larvae in high-density arenas displayed significant avoidance of low concentration diets – a behaviour that was not observed amongst larvae in low-density arenas. Thus, aggregation can help, rather than hinder, larval growth in high-density environments, and larvae may be better able to explore available nutrition when at high-density than when at low density.
Assessment of Auditable Pharmaceutical Transactions at Public Hospitals in Gamo Gofa, Southern Ethiopia, a Comparative cross-sectional study, July 2017
Authors: Mensa Mende , Ayele Akililu , Wogayehu Biruk
Published: July 2018

Background

Availability of essential medicines is necessary to maintain health of the community. In Ethiopia, availability of medicines was low (65%), with high expiry rate (8.24%), low patient knowledge on correct dosage (50.5%) and satisfaction on pharmacy services (74.5%). To avert these problems, the government had endorsed legislation on a system called “Auditable Pharmaceutical Transactions and Services (APTS)”. However, the outcomes and challenges in implementation of this system were not assessed.

Objective

To assess the implementation status of APTS and its challenges at public hospitals in Gamo Gofa Zone Southern Ethiopia, April 2017.

Methods

Facility based Cross sectional study was conducted in two APTS implementing hospitals in Gamo Gofa zone. Semi structured Self-administered questionnaire was distributed to all pharmacy staffs in selected hospitals. APTS reports of 12 months (with different characteristics) were reviewed. Four hundred patients were interviewed by data collectors about patient knowledge and satisfaction using WHO questionnaire. The data were entered and analyzed using Statistical package for social science students/SPSS version 20. T-test and linear regression was used to evaluate significant differences between two hospitals with level of significance pre-set at p-value ≤0.05.

Results

All dispensing units in primary hospital had six (75%) out of the eight essential equipment for dispensing practice. it was found that respondents in general hospital stated higher scores in general setting of outpatient pharmacy (4.58 Versus 4.25; P <0.001), but lower scores for availability and cost of medicines (4.24 vs 4.43; P<0.05) when compared with those in primary level hospital. There was no significant difference in instruction of medicine provided by dispenser (2.58 vs 2.59; P>0.05), dispenser client interaction (3.09 vs 4.08; P>0.05) and total satisfaction score (2.09 vs 2.02; P>0.05).

Conclusion and recommendations

In our study Quality of Auditable Pharmaceutical Transactions and Service was low, especially regarding patient knowledge about medicines, unaffordability of medicines, less availability of prescribed drugs, poor transparency of pharmaceutical transactions, insufficient counseling practice and limited facilities for dispensing such as, key medicines, formularies and standard guidelines. We therefore recommend the following measures responsible bodies to improve these gaps y taking administrative actions and providing continued education and training for dispensers.
Microbiota composition and evenness predict survival rate of oysters confronted to Pacific Oyster Mortality Syndrome
Authors: Clerissi Camille , de Lorgeril Julien , Petton Bruno , Lucasson Aude , Escoubas Jean-Michel , Gueguen Yannick , Dégremont Lionel , Mitta Guillaume , Toulza Eve
Published: July 2018

Pacific Oyster Mortality Syndrome (POMS) affects Crassostrea gigas oysters worldwide and caused important economic losses. Disease dynamics was recently deciphered and revealed a multiple and progressive infection caused by the Ostreid herpesvirus OsHV-1 µVar, triggering an immunosuppression followed by microbiota destabilization and bacteraemia by opportunistic bacterial pathogens. However, it remains unknown if microbiota might participate to oyster protection to POMS, and if microbiota characteristics might be predictive of oyster mortalities. To tackle this issue, we transferred full-sib progenies of resistant and susceptible oyster families from hatchery to the field during a period in favour of POMS. After five days of transplantation, oysters from each family were either sampled for individual microbiota analyses using 16S rRNA gene-metabarcoding or transferred into facilities to record their survival using controlled condition. As expected, all oysters from susceptible families died, and all oysters from the resistant family survived. Quantification of OsHV-1 and bacteria showed that five days of transplantation was long enough to contaminate oysters by POMS, but not for entering the pathogenesis process. Thus, it was possible to compare microbiota characteristics between resistant and susceptible oyster families at the early steps of infection. Strikingly, we found that microbiota evenness and abundances of Cyanobacteria (Subsection III, family I), Mycoplasmataceae, Rhodobacteraceae, and Rhodospirillaceae were significantly different between resistant and susceptible oyster families. We concluded that these microbiota characteristics might predict oyster mortalities.
Sex differences in hippocampal cytokine networks after systemic immune challenge
Authors: Finnell Julie E. , Speirs Ian C. , Tronson Natalie C.
Published: July 2018

Increased production of cytokines in the in the brain during illness or injury modulates physiological processes, behavior, and cognitive function. It is likely that the pattern of cytokines, rather than the activation of any individual cytokine, determines the functional outcome of neuroimmune signaling. Cytokine networks may thus be particularly useful for understanding sex differences in immune and neuroimmune activation and outcomes. In this project, we aimed to determine the activation and resolution of hippocampal cytokine networks in both male and female mice. We measured 32 cytokines in the hippocampus and periphery of male and female mice at rest, 2, 6, 24, 48, and 168 hours after an acute systemic injection of lipopolysaccharide (LPS; 250μg/kg). We hypothesized that males and females would exhibit both differences in individual cytokine levels and differences in network dynamics of hippocampal cytokines. Cytokines with sex-specific activation by LPS included male-specific elevations of IFNɣ, CSF1, CSF2, and IL-10; and female-specific activation of the IL-2 family and IL-4. We also observed differences in time course, where females showed more rapid elevations, and faster resolution of cytokine activity compared with males. Network analysis using ARACNE and Cytoscape demonstrated markedly different hippocampal cytokine networks across sex even at baseline, and sex differences in cytokine network activation states in response to LPS. Analysis of global shifts in cytokine concentrations further identified a period of cytokine and chemokine downregulation at 48 hours that was more pronounced in females compared with males. Together, these findings demonstrate that sex differences in neuroimmune responses include both differences in intensity of the cytokine response, and importantly differences in cytokine networks activated. Such sex differences in cytokine networks in the brain are likely critical for short and long-term functional outcomes associated with neuroimmune activation.
CRISPR-induced deletion with SaCas9 restores dystrophin expression in dystrophic models in vitro and in vivo
Authors: Duchêne Benjamin L. , Cherif Khadija , Iyombe-Engembe Jean-Paul , Guyon Antoine , Rousseau Joel , Ouellet Dominique L. , Barbeau Xavier , Lague Patrick , Tremblay Jacques P.
Published: July 2018

Duchenne Muscular Dystrophy (DMD), a severe hereditary disease, affecting 1 boy out of 3500, mainly results from the deletion of one or more exons leading to a reading frame shift of the DMD gene that abrogates dystrophin protein synthesis. We used the Cas9 of Staphylococcus aureus (SaCas9) to edit the human DMD gene. Pairs of sgRNAs were meticulously chosen to induce a genomic deletion to not only restore the reading frame but also produced a dystrophin protein with normally phased spectrin-like repeats. The formation of a dystrophin protein with spectrin-like repeats normally phased is not usually obtained by skipping or by deletion of complete exons. This can however be obtained in rare instances where the exon/intron borders of the beginning and the end of the complete deletion (patient deletion plus CRISPR-induced deletion are at similar positions in the spectrin-like repeat. We used pairs of sgRNAs, targeting exons 47 and 58 and a normal reading frame was restored in 67 to 86% of the resulting hybrid exons in myoblasts derived from muscle biopsies of 4 DMD patients with different exon deletions. The restoration of the DMD reading frame and restoration of the dystrophin expression was also obtained in vivo in the heart of the del52hDMD/mđx. Our results provide a proof-of-principle that SaCas9 could be used to edit the human DMD gene and could be considered for the further development of a therapy for DMD.
Analysis of stacking disorder in ice I using pair distribution functions
Authors: Playford Helen Y. , Whale Thomas F. , Murray Benjamin J. , Tucker Matt G. , Salzmann Christoph G.
Published: July 2018

Stacking-disordered materials display crystalline order in two dimensions but are disordered along the direction in which layered structural motifs are stacked. Countless examples of stacking disorder exist, ranging from close-packed metals, ice I and diamond to open-framework materials and small-molecule pharmaceuticals. In general, the presence of stacking disorder can have profound consequences for the physical and chemical properties of a material. Traditional analyses of powder diffraction data are often complicated by the presence of memory effects in the stacking sequences. Here it is shown that experimental pair distribution functions of stacking-disordered ice I can be used to determine local information on the fractions of cubic and hexagonal stacking. Ice is a particularly challenging material in this respect, since both the stacking disorder and the orientational disorder of the water molecules need to be described. Memory effects are found to contribute very little to the pair distribution functions, and consequently, the analysis of pair distribution functions is the method of choice for characterizing stacking-disordered samples with complicated and high-order memory effects. In the context of this work, the limitations of current structure-reconstruction approaches are also discussed.
Measurement of independent piezoelectric moduli of Ca3NbGa3Si2O14, La3Ga5.5Ta0.5O14 and La3Ga5SiO14 single crystals
Authors: Irzhak D. , Roshchupkin D.
Published: July 2018

Results of measurements of independent piezoelectric moduli d
11 and d
14 in Ca3NbGa3Si2O14, La3Ga5.5Ta0.5O14 and La3Ga5SiO14, promising single crystals of the calcium gallogermanate structural type, are presented. The moduli were measured with a triple-axis X-ray diffractometer under an external electric field which causes changes in the interplanar distances due to the reverse piezoelectric effect. The results of the X-ray diffractometry measurements agree fairly well (within less than 10%) with the results obtained by different methods.
Why are reactions of 2- and 8-thioquinoline derivatives with iodine different?
Authors: Rudakov Boris V. , Stash Adam I. , Makarov Gennady I. , Matveychuk Yury V. , Zherebtsov Dmitry A. , Bartashevich Ekaterina V.
Published: July 2018

The crystal structures of 1,2-dihydro-1,1′-bi[thiazolo[3,2-a]quinoline]-10a,10a′-diium diiodide hemihydrate, C22H16N2S2
2+·2I−·0.5H2O, and 1,2-dihydro-1,1′-bi[thiazolo[3,2-a]quinoline]-10a,10a′-diium iodide triiodide, C22H16N2S2
2+·I−·I3
−, obtained during the reaction of 1,4-bis(quinolin-2-ylsulfanyl)but-2-yne (2TQB) with iodine, have been determined at 120 K. The crystalline products contain the dication as a result of the reaction proceeding along the iodocyclization pathway. This is fundamentally different from the previously observed reaction of 1,4-bis(quinolin-8-ylsulfanyl)but-2-yne (8TQB) with iodine under similar conditions. A comparative analysis of the possible conformational states indicates differences in the relative stabilities and free rotation for the 2- and 8-thioquinoline derivatives which lead to a disparity in the convergence of the potential reaction centres for 2TQB and 8TQB.
Structure of a Talaromyces pinophilus GH62 arabinofuranosidase in complex with AraDNJ at 1.25 Å resolution
Authors: Moroz Olga V. , Sobala Lukasz F. , Blagova Elena , Coyle Travis , Peng Wei , Mørkeberg Krogh Kristian B. R. , Stubbs Keith A. , Wilson Keith S. , Davies Gideon J.
Published: July 2018

The enzymatic hydrolysis of complex plant biomass is a major societal goal of the 21st century in order to deliver renewable energy from nonpetroleum and nonfood sources. One of the major problems in many industrial processes, including the production of second-generation biofuels from lignocellulose, is the presence of `hemicelluloses' such as xylans which block access to the cellulosic biomass. Xylans, with a polymeric β-1,4-xylose backbone, are frequently decorated with acetyl, glucuronyl and arabinofuranosyl `side-chain' substituents, all of which need to be removed for complete degradation of the xylan. As such, there is interest in side-chain-cleaving enzymes and their action on polymeric substrates. Here, the 1.25 Å resolution structure of the Talaromyces pinophilus arabinofuranosidase in complex with the inhibitor AraDNJ, which binds with a K
d of 24 ± 0.4 µM, is reported. Positively charged iminosugars are generally considered to be potent inhibitors of retaining glycosidases by virtue of their ability to interact with both acid/base and nucleophilic carboxylates. Here, AraDNJ shows good inhibition of an inverting enzyme, allowing further insight into the structural basis for arabinoxylan recognition and degradation.
A perspective on structural and mechanistic aspects of proteinO-fucosylation
Authors: Lira-Navarrete Erandi , Hurtado-Guerrero Ramon
Published: July 2018

ProteinO-fucosylation is an important post-translational modification (PTM) found in cysteine-rich repeats in proteins. ProteinO-fucosyltransferases 1 and 2 (PoFUT1 and PoFUT2) are the enzymes responsible for this PTM and selectively glycosylate specific residues in epidermal growth factor-like (EGF) repeats and thrombospondin type I repeats (TSRs), respectively. Within the past six years, crystal structures of both enzymes have been reported, revealing important information on how they recognize protein substrates and achieve catalysis. Here, the structural information available today is summarized and how PoFUT1 and PoFUT2 employ different catalytic mechanisms is discussed.
Crystal structure of highly glycosylated human leukocyte elastase in complex with an S2′ site binding inhibitor
Authors: Hochscherf Jennifer , Pietsch Markus , Tieu William , Kuan Kevin , Abell Andrew D. , Gütschow Michael , Niefind Karsten
Published: July 2018

Glycosylated human leukocyte elastase (HLE) was crystallized and structurally analysed in complex with a 1,3-thiazolidine-2,4-dione derivative that had been identified as an HLE inhibitor in preliminary studies. In contrast to previously described HLE structures with small-molecule inhibitors, in this structure the inhibitor does not bind to the S1 and S2 substrate-recognition sites; rather, this is the first HLE structure with a synthetic inhibitor in which the S2′ site is blocked that normally binds the second side chain at the C-terminal side of the scissile peptide bond in a substrate protein. The inhibitor also induces the formation of crystalline HLE dimers that block access to the active sites and that are also predicted to be stable in solution. Neither such HLE dimers nor the corresponding crystal packing have been observed in previous HLE crystal structures. This novel crystalline environment contributes to the observation that comparatively large parts of the N-glycan chains of HLE are defined by electron density. The final HLE structure contains the largest structurally defined carbohydrate trees among currently available HLE structures.
Crystal structure and Hirshfeld surface analysis of (E)-3-[(2,3-dichlorobenzylidene)amino]-5-phenylthiazolidin-2-iminium bromide
Authors: Akkurt Mehmet , Duruskari Gulnara Sh. , Toze Flavien A. A. , Khalilov Ali N. , Huseynova Afat T.
Published: July 2018

In the cation of the title salt, C16H14Cl2N3S+·Br−, the central thiazolidine ring adopts an envelope conformation. The phenyl ring is disordered over two sites with a refined occupancy ratio of 0.541 (9):0.459 (9). In the crystal, C—H...Br and N—H...Br hydrogen bonds link the components into a three-dimensional network with the cations and anions stacked along theb-axis direction. Weak C—H...π interactions, which only involve the minor disorder component of the ring, also contribute to the molecular packing. In addition, there are also inversion-related Cl...Cl halogen bonds and C—Cl...π (ring) contacts. A Hirshfeld surface analysis was conducted to verify the contributions of the different intermolecular interactions.