bluuebunny/crossref_metadata_2025 huggingface dataset:
Congenital Myasthenic Syndrome: Spectrum of Mutations in an Indian Cohort
Authors: Selvam Pavalan , Arunachal Gautham , Danda Sumita , Chapla Aaron , Sivadasan Ajith , Alexander Mathew , Thomas Maya Mary , Thomas Nihal J.
Published: August 2018

Objectives:

To investigate the mutational spectrum and genotype–phenotype correlation in Indian patients with congenital myasthenic syndrome (CMS), using next-generation sequencing of 5 genes.

Methods:

CHRNE, COLQ, DOK7, RAPSN, and GFPT1 were sequenced in 25 affected patients.

Results:

We found clinically significant variants in 18 patients, of which variants in CHRNE were the most common, and 9 were novel. A common pathogenic COLQ variant was also detected in 4 patients with isolated limb-girdle congenital myasthenia.

Conclusions:

Targeted screening of 5 genes is an effective alternate test for CMS, and an affordable one even in a developing country such as India. In addition, we recommend that patients with isolated limb-girdle congenital myasthenia be screened initially for the common COLQ pathogenic variant. This study throws the first light on the genetic landscape of CMSs in India.
Evaluation of Anterior and Posterior Corneal Irregularity After Descemet Membrane Endothelial Keratoplasty
Authors: Oyakawa Itaru , Hayashi Takahiko , Kobashigawa Yuji , Matsuzawa Akiko , Takahashi Hidenori , Kato Naoko
Published: August 2018

Purpose:

To investigate the changes in anterior and posterior corneal irregularity after Descemet membrane endothelial keratoplasty (DMEK).

Methods:

This retrospective study included 27 eyes of 23 patients who underwent DMEK and 27 eyes of age-matched healthy controls. Corneal irregularity indexes, surface regularity of height (SR_H), and higher-order aberrations were evaluated in 4- and 6-mm diameters of the cornea, preoperatively and postoperatively, using anterior segment optical coherence tomography.

Results:

The best spectacle-corrected visual acuity (logarithm of the minimum angle of resolution) improved from 1.01 ± 0.54 preoperatively to 0.08 ± 0.11 at 6 months postoperatively. Anterior SR_H was significantly lower at 6 months postoperatively [from 1.86 ± 0.73 to 1.20 ± 0.34 (P < 0.01) (4-mm) and from 2.29 ± 0.62 to 1.64 ± 0.42 (P < 0.01) (6-mm)]. Posterior SR_H showed a significant decrease from 6.87 ± 4.19 to 2.18 ± 0.51 (4-mm) and from 5.21 ± 2.60 to 2.44 ± 0.38 (6-mm) at 6 months postoperatively (P < 0.001). The SR_H was positively correlated with best spectacle-corrected visual acuity (anterior 4 mm: R = 0.524; anterior 6 mm: R = 0.477; posterior 4 mm: R = 0.655; posterior 6 mm: R = 0.655, P < 0.001) and with higher-order aberrations for 4-mm and 6-mm diameters (R = 0.511 and R = 0.325, P < 0.001, respectively).

Conclusions:

The SR_H reflects corneal irregularity and is correlated with the visual outcome after DMEK, which may be very helpful to corneal surgeons as an index indicating the severity before DMEK, and the quality of visual function after DMEK.
Generic Quality of Life in Persons With Hearing Loss: A Review of the Recent Literature: RETRACTED
Authors: Brodie Arjuna , Ray Jaydip
Published: August 2018

Background:

It is unknown whether persons with hearing loss (HL) have reduced generic quality of life (QoL) and to what extent a hearing aid (HA) might improve QoL. The main aim of the study was to review studies about the relationship between HL and QoL. A supporting aim was to study the association between distress and HL.

Methods:

Literature databases (CINAHL, Pub Med, and Web of Science) were searched for relevant articles published from January 2000 to March 17, 2016. A primary search was performed regarding the relationship between HL, HA, and QoL (search one) followed by a supporting search about the relationship between distress/mood/anxiety and HL (search two). After removing duplications and screening the titles of the articles, the abstracts of the remaining articles were read and those that met the inclusion criteria were included.

Results:

The two searches yielded a total of 4,188 journal articles. Twenty journal articles were included in the present review: 13 from search one, and 7 from search two. The literature shows distressed persons tend to have a lowered generic QoL. Some studies suggest an improved generic QoL following the use of HA. Other studies suggest that HA use is one of several possible factors that contribute to improved generic QoL.

Conclusion:

Most of the studies suggest that HL is associated with reduced generic QoL. Using HA seems to improve general QoL. Further research is needed to explore the relationship between HL and generic QoL, in addition to the importance of influencing variables on this relationship.
Identification of Grossing Criteria for Intraoperative Evaluation by Frozen Section of Lung Cancer Resection Margins
Authors: Gagné Andréanne , Racine Étienne , Orain Michèle , Meziou Salma , Simard Serge , Couture Christian , Pagé Sylvain , Trahan Sylvain , Ugalde Paula , Lacasse Yves , Joubert David , Joubert Philippe
Published: August 2018

Because of a lack of official guidelines, systematic use of intraoperative frozen section for the evaluation of surgical margins in lung oncology constitutes standard practice in many pathology departments. This costly and time-consuming procedure seems unjustified as reported rates of positive margins remain low. We aimed to evaluate clinicopathologic criteria associated with positive margins and establish evidence-based recommendations regarding the use of frozen sections. This retrospective cohort included 1903 consecutive patients with a lung resection for malignant neoplasm between 2006 and 2015. Clinicopathologic data were retrieved from medical files. Univariate and multivariate analyses were used to identify variables associated with a positive margin. Receiver operating characteristic curves and a probability table of positive margins based on tumor-margin distance were created. Our results were confirmed in a validation cohort of 27 patients with positive margins. The rate of positive margins was 3.8%. A positive margin status changed the surgical management in 48.6% of patients. A short macroscopic tumor-margin distance was associated with a higher risk of positive bronchovascular and parenchymal margins in univariate and multivariate analyses. Selecting a 2.0 cm tumor-margin distance cut-off for performing a frozen section would result in a 55.3% reduction of intraoperative evaluations, with a risk of missing a positive margin of 0.61%. Overall, we showed that systematic use of frozen section for intraoperative evaluation of surgical margins is unnecessary. A better selection of patients with a higher risk of a positive margin can be achieved with tumor-margin distance as a simple gross evaluation parameter.
Surfactant Protein D Dampens Lung Injury by Suppressing NLRP3 Inflammasome Activation and NF-κB Signaling in Acute Pancreatitis
Authors: Yu Jia , Ni Lan , Zhang Xiaoyi , Zhang Jing , Abdel-Razek Osama , Wang Guirong
Published: August 2018

Severe acute pancreatitis (SAP) often causes acute lung injury (ALI) by systemic inflammatory response. Surfactant protein D (SP-D) plays critical roles in host defense and inflammation regulation. NLRP3 inflammasomes and NF-κB signaling are key regulators in innate immunity and inflammation. We hypothesized that SP-D attenuates ALI by suppressing NLRP3 inflammasome and NF-κB activation.

Methods:

Wild-type C57BL/6 (WT), SP-D knockout (KO), and humanized transgenic SP-D (hTG) mice were used in this study. SAP was induced by administration of one-dose lipopolysaccharide (10 mg/kg) and 6 hourly intraperitoneal injections of cerulein (Cn) (100 μg/kg). Animals were killed 6 and 24 h after first Cn treatment. Histopathologic changes in pancreas and lung were assessed by light and electron microscopes. Serum amylase, IL-1β, IL-6, and MCP-1 levels were determined by kit/ELISA. NLRP3 inflammasome, NF-κB, and MPO activations were analyzed by western blotting and immunofluorescence.

Results:

KO mice showed more severe pancreatic and lung injury than WT mice in SAP. hTG mice exhibited similar degree in lung injury as WT mice. Mitochondrial and rough endoplasmic reticulum damages, autophagosome formation were observed in the alveolar type II and acinar cells of SAP mice. SAP KO mice had increased bronchoalveolar lavage fluid inflammatory cells, higher levels of serum IL-1β, IL-6, and MCP-1 than SAP WT and hTG mice. Levels of NLRP3 inflammasome (NLRP3, ASC, and Caspase-1) and NF-κB activation in SAP KO mice were higher than SAP WT and hTG mice.

Conclusion:

SP-D exerts protective effects against ALI via suppressing NLRP3 inflammasome and NF-κB activation in experimental SAP.
Whole blood mitigates the acute coagulopathy of trauma and avoids the coagulopathy of crystalloid resuscitation
Authors: Sheppard Forest R. , Schaub Leasha J. , Cap COL Andrew P. , Macko Antoni R. , Moore Hunter B. , Moore Ernest E. , Glaser CDR Jacob J.
Published: August 2018

INTRODUCTION

The contributions of type and timing of fluid resuscitation to coagulopathy in trauma remain controversial. As part of a multifunctional resuscitation fluid research effort, we sought to further characterize the coagulation responses to resuscitation, specifically as compared to whole blood. We hypothesized that early whole blood administration mitigates the acute coagulopathy of trauma by avoiding the coagulopathy of CR resuscitation.

METHODS

Anesthetized rhesus macaques underwent polytraumatic, hemorrhagic shock, then a crossover study design resuscitation (n = 6 each) with either whole blood first (WB-1st) followed by crystalloid (CR); or CR-1st followed by WB. Resuscitation strategies were the following: WB-1st received 50% shed blood in 30minutes, followed by twice the shed blood volume (SBV) of CR over 30minutes and one times the SBV CR over 60minutes, where CR-1st received twice the SBV of CR over 30minutes, followed by 50% of shed blood in 30minutes, and one times the SBV CR over 60minutes. Blood samples were collected at baseline, end-of-shock, end-of-first and end-of-second resuscitation stages, and end-of-resuscitation for assessment (thromboelastometry, platelet aggregation, and plasmatic coagulation factors). Statistical analyses were conducted using two-way analysis of variance ANOVA with Bonferroni correction and t-tests; significance was at p < 0.05.

RESULTS

Survival, blood loss, hemodynamics, and shock duration were equivalent between the groups. Compared to baseline, parameters measured at first and second resuscitation stage time points directly following CR infusion revealed abnormalities in thromboelastometry (clot formation time, α angle, and maximum clot firmness), platelet aggregation response (to collagen, arachidonic acid, and adenosine diphosphate), and plasmatic coagulation (prothrombin time, anti-thrombin 3, and fibrinogen), while whole blood infusion resulted in stabilization or correction of these parameters following its administration.

CONCLUSIONS

These data suggest that in the setting of trauma and hemorrhagic shock, the coagulation alterations begin before intervention/resuscitation; however, these are significantly aggravated by CR resuscitation and could perhaps be best termed acute coagulopathy of resuscitation.

Study type: Translational animal model
The hallmarks of living systems: towards creating artificial cells
Authors: Yewdall N. Amy , Mason Alexander F. , van Hest Jan C. M.
Published: August 2018

Despite the astonishing diversity and complexity of living systems, they all share five common hallmarks: compartmentalization, growth and division, information processing, energy transduction and adaptability. In this review, we give not only examples of how cells satisfy these requirements for life and the ways in which it is possible to emulate these characteristics in engineered platforms, but also the gaps that remain to be bridged. The bottom-up synthesis of life-like systems continues to be driven forward by the advent of new technologies, by the discovery of biological phenomena through their transplantation to experimentally simpler constructs and by providing insights into one of the oldest questions posed by mankind, the origin of life on Earth.
Human ubiquitin-like proteins as central coordinators in autophagy
Authors: Mohan Jagan , Wollert Thomas
Published: August 2018

Autophagy is one of the most versatile recycling systems of eukaryotic cells. It degrades diverse cytoplasmic components such as organelles, protein aggregates, ribosomes and multi-enzyme complexes. Not surprisingly, any failure of autophagy or reduced activity of the pathway contributes to the onset of various pathologies, including neurodegeneration, cancer and metabolic disorders such as diabetes or immune diseases. Furthermore, autophagy contributes to the innate immune response and combats bacterial or viral pathogens. The hallmark of macroautophagy is the formation of a membrane sack that sequesters cytoplasmic cargo and delivers it to lysosomes for degradation. More than 40 autophagy-related (ATG) proteins have so far been identified. A unique protein-conjugation system represents one of the core components of this highly elaborate machinery. It conjugates six homologous ATG8 family proteins to the autophagic membrane. In this review, we summarize the current knowledge regarding the various functions of ATG8 proteins in autophagy and briefly discuss how physical approaches andin vitroreconstitution contributed in deciphering their function.
Liquid–liquid phase separation in artificial cells
Authors: Crowe Charles D. , Keating Christine D.
Published: August 2018

Liquid–liquid phase separation (LLPS) in biology is a recently appreciated means of intracellular compartmentalization. Because the mechanisms driving phase separations are grounded in physical interactions, they can be recreated within less complex systems consisting of only a few simple components, to serve as artificial microcompartments. Within these simple systems, the effect of compartmentalization and microenvironments upon biological reactions and processes can be studied. This review will explore several approaches to incorporating LLPS as artificial cytoplasms and in artificial cells, including both segregative and associative phase separation.
The artificial cell: biology-inspired compartmentalization of chemical function
Authors: Beales Paul A. , Ciani Barbara , Mann Stephen
Published: August 2018

The concept of compartmentalization in artificial cell research was the focus of a Royal Society Theo Murphy meeting at the Kavli Royal Society Centre, Chichelely Hall in Buckinghamshire, UK, 26–27 February 2018.
Shear flow over flexible three-dimensional patches in a surface
Authors: Smith F. T.
Published: August 2018

Slowly varying shear flow is considered over one or more flexible three-dimensional patches in a surface inside a boundary layer. At certain shear values, resonances emerge in which the effects on flow and patch shape are enlarged by an order of magnitude. Fast evolution then occurs: this leads to fully nonlinear unsteady interaction, after some delay, combining with finite-time break-ups to form a distinct path into transition.

This article is part of the theme issue ‘Modelling of sea-ice phenomena’.
Extreme copy number variation at a tRNA ligase affecting phenology and fitness in yellow monkeyflowers
Authors: Nelson Thom , Monnahan Patrick , McIntosh Mariah , Finseth Findley R. , Anderson Kayli , MacArthur-Waltz Evan , Kelly John K. , Fishman Lila
Published: August 2018

Copy number variation (CNV) is a major part of the genetic diversity segregating within populations, but remains poorly understood relative to single nucleotide variation. Here, we report on a tRNA ligase gene (Migut.N02091; RLG1a) exhibiting unprecedented, and fitness-relevant, CNV within an annual population of the yellow monkeyflowerMimulus guttatus. RLG1a variation was associated with multiple traits in pooled population sequencing (PoolSeq) scans of phenotypic and phenological cohorts. Resequencing of inbred lines revealed intermediate frequency three-copy variants of RLG1a (trip+;5/35 = 14%), andtrip+lines exhibited elevated RLG1a expression under multiple conditions.trip+carriers, in addition to being over-represented in late-flowering and large-flowered PoolSeq populations, flowered later under stressful conditions in a greenhouse experiment (P < 0.05). In wild population samples, we discovered an additional rare RLG1a variant (high+)that carries 250-300 copies of RLG1a totaling ∼5.7Mb (20-40% of a chromosome). In the progeny of ahigh+carrier, Mendelian segregation of diagnostic alleles and qPCR-based copy counts indicate thathigh+is a single tandem array unlinked from the single copy RLG1a locus. In the wild,high+carriers had highest fitness in two particularly dry and/or hot years (2015 and 2017; both p < 0.01), while single copy individuals were twice as fecund as either CNV type in a lush year (2016: p < 0.005). Our results demonstrate fluctuating selection on CNVs affecting phenological traits in a wild population, suggest that plant tRNA ligases mediate stress-responsive life-history traits, and introduce a novel system for investigating the molecular mechanisms of gene amplification.
Regularization Improves the Robustness of Learned Sequence-to-Expression Models
Authors: Lunt Bryan , Sinha Saurabh
Published: August 2018

Understanding of the gene regulatory activity of enhancers is a major problem in regulatory biology. The nascent field of sequence-to-expression modelling seeks to create quantitative models of gene expression based on regulatory DNA (cis) and cellular environmental (trans) contexts. All quantitative models are defined partially by numerical parameters, and it is common to fit these parameters to data provided by existing experimental results. However, the relative paucity of experimental data appropriate for this task, and lacunae in our knowledge of all components of the systems, results in problems often being under-specified, which in turn may lead to a situation where wildly different model parameterizations perform similarly well on training data. It may also lead to models being fit to the idiosyncrasies of the training data, without representing the more general process (overfitting).

In other contexts where parameter-fitting is performed, it is common to apply regularization to reduce overfitting. We systematically evaluated the efficacy of three types of regularization in improving the generalizability of trained sequence-to-expression models. The evaluation was performed in two types of cross-validation experiments: one training on D. melanogaster data and predicting on orthologous enhancers from related species, and the other cross-validating between four D. melanogaster neurogenic ectoderm enhancers, which are thought to be under control of the same transcription factors. We show that training with a combination of noise-injection, L1, and L2 regularization can drastically reduce overfitting and improve the generalizability of learned sequence-to-expression models. These results suggest that it may be possible to mitigate the tendency of sequence-to-expression models to overfit available data, thus improving predictive power and potentially resulting in models that provide better insight into underlying biological processes.
Suppression of p16 induces mTORC1-mediated nucleotide metabolic reprogramming
Authors: Buj Raquel , Chen Chi-Wei , Dahl Erika S. , Leon Kelly E. , Kuskovsky Ross , Maglakelidze Natella , Navaratnarajah Maithili , Zhang Gao , Doan Mary T. , Jiang Helen , Zaleski Michael , Kutzler Lydia , Lacko Holly , Lu Yiling , Mills Gordan B. , Gowda Raghavendra , Robertson Gavin P. , Warrick Joshua I. , Herlyn Meenhard , Imamura Yuka , Kimball Scot R. , DeGraff David J. , Snyder Nathaniel W. , Aird Katherine M.
Published: August 2018

Reprogrammed metabolism and cell cycle dysregulation are two cancer hallmarks. p16 is a cell cycle inhibitor and tumor suppressor that is upregulated during oncogene-induced senescence (OIS). Loss of p16 allows for uninhibited cell cycle progression, bypass of OIS, and tumorigenesis. Whether p16 loss affects pro-tumorigenic metabolism is unclear. We report that suppression of p16 plays a central role in reprogramming metabolism by increasing nucleotide synthesis. This occurred via activation of mTORC1 signaling, which directly mediated increased translation of the mRNA encoding ribose-5-phosphate isomerase A (RPIA), a pentose phosphate pathway enzyme. p16 loss correlated with activation of the mTORC1-RPIA axis in multiple cancer types. Suppression of RPIA inhibited proliferation only in p16-low cells by inducing senescence bothin vitroandin vivo. These data reveal the molecular basis whereby p16 loss modulates pro-tumorigenic metabolism through mTORC1-mediated upregulation of nucleotide synthesis and reveals a metabolic vulnerability of p16-null cancer cells.

Highlights

mTORC1 is activated by p16 knockdown to increase nucleotide synthesis and bypass senescence

mTORC1 directly increases translation RPIA to increase ribose-5-phosphate

Activation of mTORC1 pathway downstream of p16 suppression is independent of RB

RPIA suppression induces senescence only in cells and tumors with low p16
De novogenesis of retinal ganglion cells by targeted expression of KLF4in vivo
Authors: Rocha-Martins Maurício , Toledo Beatriz C. de , Santos-França Pedro L. , Oliveira-Valença Viviane M. , Vieira-Vieira Carlos H. , Matos-Rodrigues Gabriel E. , Linden Rafael , Norden Caren , Martins Rodrigo A. P. , Silveira Mariana S.
Published: August 2018

Retinal ganglion cell (RGC) degeneration is a hallmark of glaucoma, the most prevalent cause of irreversible blindness. Thus, innovative therapeutic strategies are needed to protect and replace these projection neurons. It has been shown that endogenous glial cells of the retina, Müller cells, can be directly reprogrammed into late-born retinal interneurons. However, since RGCs are the first neurons born during development, the replacement of damaged RGCs requires the reprograming to an early neurogenic state. Here, we demonstrate that the pluripotency regulator Klf4 is sufficient to reprogram the potency of lineage-restricted retinal progenitor cells (RPCs) to generate RGCsin vivo. Transcriptome analysis disclosed that the overexpression of Klf4 induces crucial regulators of RGC competence and specification, including Atoh7 and Eya2. In contrast, loss-of-function studies in mice and zebrafish demonstrated that Klf4 is not essential for generation or differentiation of RGCs during retinogenesis. Nevertheless, induced RGCs (iRGCs) generated upon Klf4 overexpression migrate to the proper layer and project axons aligned with endogenous fascicles that reach the optic nerve head. Notably, iRGCs survive for up to 30 days afterin vivoreprogramming. Finally, we demonstrate that Klf4 converts Müller cells into neurons that express markers of RGCs. Altogether, we identified Klf4 as a promising tool to reprogram retinal cells and regenerate RGCs in the mature retina.

Significance Statement

Cell fate determination is a key process for development, regeneration and for the design of therapeutic strategies that involve cellular reprogramming. This work shows that the manipulation of a single pluripotency regulator (Klf4) is sufficient to reprogram restricted progenitor cellsin vivo. These reprogrammed progenitors reacquire the potency to generate retinal ganglion cells. Ganglion cell degeneration is the leading cause of irreversible blindness; therefore, manipulation of ganglion cell competence is of relevance for human health. Our findings point to Klf4 as a promising tool to develop therapeutic strategies for the replacement of damaged ganglion cells.
Environmental DNA for the enumeration and management of Pacific salmon
Authors: Levi Taal , Allen Jennifer M. , Bell Donovan , Joyce John , Russell Joshua R. , Tallmon David A. , Vulstek Scott C. , Yang Chunyan , Yu Douglas W.
Published: August 2018

Pacific salmon are a keystone resource in Alaska, generating annual revenues of well over ∼US$500 million/yr. Due to their anadromous life history, adult spawners distribute amongst thousands of streams, posing a huge management challenge. Currently, spawners are enumerated at just a few streams because of reliance on human counters and, rarely, sonar. The ability to detect organisms by shed tissue (environmental DNA, eDNA) promises a more efficient counting method. However, although eDNA correlates generally with local fish abundances, we do not know if eDNA can accurately enumerate salmon. Here we show that daily, and near-daily, flow-corrected eDNA rate closely tracks daily numbers of returning sockeye and coho spawners and outmigrating sockeye smolts. eDNA thus promises accurate and efficient enumeration, but to deliver the most robust numbers will need higher-resolution stream-flow data, at-least-daily sampling, and a focus on species with simple life histories, since shedding rate varies amongst jacks, juveniles, and adults.
Ab initio derivation of the FRET equations resolves old puzzles and suggests measurement strategies
Authors: Raicu V.
Published: August 2018

Quantitative FRET-based imaging methods rely on the determination of an apparent FRET efficiency (Eapp) as well as donor and acceptor concentrations, in order to uncover the identity and relative abundance of the oligomeric (or quaternary) structures of associating macromolecules. Theoretical work has provided “upwards” relationships between the experimentally determined Eapp distributions and the quaternary structure models that underlie them. By contrast, the body of work that predicates the “downwards” dependence of Eapp on directly measurable quantities (i.e., fluorescence emission of donors and acceptors) relies largely on plausibility arguments, one of which is the seemingly obvious assumption that the fraction of fluorescent molecules in the ground state pretty nearly equals the total concentration of molecules. In this work, we use the kinetic models of fluorescence in the presence and absence of FRET to rigorously derive useful relationships between Eapp and measurable fluorescence signals. Analysis of these relationships reveals a few anticipated surprises and some unexpected explanations for known experimental FRET puzzles, and it provides theoretical foundations for optimizing measurement strategies.
A non-dimensional, two-parameter mechanical model reveals alterations in nuclear mechanics upon Hepatitis C Virus infection
Authors: Balakrishnan Sreenath , Suma M S , Sharma Geetika , Raju Shilpa R , Reddy Uma , Das Saumitra , Ananthasuresh G. K.
Published: August 2018

Morphology of the nucleus is an important regulator of gene-expression. Nuclear morphology is in turn a function of the forces acting on it and the mechanical properties of the nuclear envelope. Here, we present a two-parameter, non-dimensional mechanical model of the nucleus that reveals a relationship among nuclear shape parameters such as projected area, surface area and volume. Our model fits the morphology of individual nuclei and predicts the ratio between forces and modulus in each nucleus. We analyzed the changes in nuclear morphology of liver cells due to Hepatitis C Virus (HCV) infection using this model. The model predicted a decrease in the elastic modulus of the nuclear envelope and an increase in the pre-tension in cortical actin as the causes for the change in nuclear morphology. These predictions were validated biomechanically by showing that liver cells expressing HCV proteins possessed enhanced cellular stiffness and reduced nuclear stiffness. Concomitantly, cells expressing HCV proteins showed down-regulation of lamin-A,C and up-regulation of actin, corroborating the predictions of the model. Our modelling assumptions are broadly applicable to adherent, monolayer cell cultures making the model amenable to investigate changes in nuclear mechanics due to other stimuli by merely measuring nuclear morphology. Towards this, we present two techniques, graphical and numerical, to use our model for predicting physical changes in the nucleus.
A Note on Stochastic Modeling of Biological Systems: Automatic Generation of an Optimized Gillepsie Algorithm
Authors: Vanhaelen Quentin
Published: August 2018

Signaling pathways and gene regulatory networks (GRNs) play a central role in the signal trans-duction and regulation of biochemical processes occurring within the cellular environment. Under-standing their mechanisms and dynamics is of major interest in various areas of life sciences and biological sciences. For example controlling stem cell fate decision requires a comprehension of the dynamical behavior of the networks involved in stem cell differentiation and pluripotency mainte-nance. In addition to analytical mathematical methods which are applicable for small or medium sized systems, there are many computational approaches to model and analyze the behavior of larger systems. However, from a dynamical point of view, modeling a combination of signaling pathways and GRNs present several challenges. Indeed, in addition to being of large dimensionality, these systems have specific dynamical features. Among the most commonly encountered is that the signal transduction controlled by the signaling pathways occurs at a different time scale than the transcription and translation processes. Also, stochasticity is known to strongly impact the regulation of gene expression. In this paper, we describe a simple implementation of an optimized version of the Gille-spie algorithm for simulating relatively large biological networks which include delayed reactions. The implementation presented herein comes with a script for automatically generating the different data structures and source files of the algorithm using standardized input files.

Code availability

The Fortran90 implementation of the code and the R script described here as well as the tutorial with practical instructions are stored on the following github repository qvhaelen/ typhon
Conformational ensemble of the human TRPV3 ion channel
Authors: Zubcevic Lejla , Herzik Mark A. , Wu Mengyu , Borschel William F. , Hirschi Marscha , Song Albert , Lander Gabriel C. , Lee Seok-Yong
Published: August 2018

Transient receptor potential vanilloid channel 3 (TRPV3), a member of the thermosensitive TRP (thermoTRPV) channels, is activated by warm temperatures and serves as a key regulator of normal skin physiology through the release of pro-inflammatory messengers. Mutations in trpv3 have been identified as the cause of the congenital skin disorder, Olmsted syndrome. Unlike other members of the thermoTRPV channel family, TRPV3 sensitizes upon repeated simulation, yet a lack of structural information about the channel precludes a molecular-level understanding of TRPV3 sensitization and gating. Here, we present the cryo-electron microscopy structures of apo and sensitized human TRPV3, as well as several structures of TRPV3 in the presence of the common thermoTRPV agonist 2-aminoethoxydiphenyl borate (2-APB). Our results show α-to-π-helix transitions in the S6 during sensitization, and suggest a critical role for the S4-S5 linker π-helix during ligand gating.
DNA-dependent protein kinase promotes DNA end processing by MRN and CtIP
Authors: Deshpande Rajashree A. , Myler Logan R. , Soniat Michael M. , Makharashvili Nodar , Lee Linda , Lees-Miller Susan P. , Finkelstein Ilya J. , Paull Tanya T.
Published: August 2018

The repair of DNA double-strand breaks occurs through non-homologous end joining or homologous recombination in vertebrate cells - a choice that is thought to be decided by a competition between DNA-dependent protein kinase (DNA-PK) and the Mre11/Rad50/Nbs1 (MRN) complex but is not well understood. Using ensemble biochemistry and single-molecule approaches, here we show that the MRN complex is dependent on DNA-PK and phosphorylated CtIP to perform efficient processing and resection of DNA ends in physiological conditions, thus eliminating the competition model. Endonucleolytic removal of DNA-PK-bound DNA ends is also observed at double-strand break sites in human cells. The involvement of DNA-PK in MRN-mediated end processing promotes an efficient and sequential transition from non-homologous end joining to homologous recombination by facilitating DNA-PK removal.

One Sentence Summary

DNA-dependent protein kinase, an enzyme critical for non-homologous repair of DNA double-strand breaks, also stimulates end processing for homologous recombination.
Inhibition of HtrA2 alleviated colitis by preventing necroptosis of intestinal epithelial cells
Authors: Zhang Chong , He Andong , Liu Shuai , He Qiaoling , Luo Yiqin , Chen Yujiao , He Zhilan , Tao Ailin , Yan Jie
Published: August 2018

Necroptosis of intestinal epithelial cells has been indicated to play an important role in the pathogenesis of inflammatory bowel disease (IBD). The identification of dysregulated proteins that can regulate necroptosis in dextran sulfate sodium (DSS)-induced colitis is the key to the rational design of therapeutic strategies for colitis. Through Tandem Mass Tag (TMT)-based quantitative proteomics, HtrA2 was found to be downregulated in the colon of DSS-treated mice. UCF-101, a specific serine protease inhibitor of HtrA2, significantly alleviated DSS-induced colitis as indicated by prevention of body weight loss and decreased mortality. UCF-101 decreased DSS-induced colonic inflammation, prevented intestinal barrier function loss and inhibited necroptosis of intestinal epithelial cells. In vitro, UCF-101 or silencing of HtrA2 decreased necroptosis of HT-29 and L929 cells. UCF-101 decreased phosphorylation of RIPK1 and subsequent phosphorylation of RIPK3 and MLKL during necroptosis. HtrA2 directly interacted with RIPK1 and promoted its degradation during a specific time phase of necroptosis. Our findings highlight the importance of HtrA2 in regulating colitis by modulation of necroptosis and suggest HtrA2 as an attractive target for anti-colitis treatment.
The nature and intensity of mechanical stimulation drive different dynamics of MRTF-A nuclear redistribution after actin remodeling in myoblasts
Authors: Montel Lorraine , Sotiropoulos Athanassia , Hénon Sylvie
Published: August 2018

Serum response factor and its cofactor myocardin-related transcription factor (MRTF) are key elements of muscle-mass adaptation to workload. The transcription of target genes is activated when MRTF is present in the nucleus. The localization of MRTF is controlled by its binding to G-actin. Thus, the pathway can be mechanically activated through the mechanosensitivity of the actin cytoskeleton. The pathway has been widely investigated from a biochemical point of view, but its mechanical activation and the timescales involved are poorly understood. Here, we applied local and global mechanical cues to myoblasts through two custom-built set-ups, magnetic tweezers and stretchable substrates. Both induced nuclear accumulation of MRTF-A. However, the dynamics of the response varied with the nature and level of mechanical stimulation and correlated with the polymerization of different actin sub-structures. Local repeated force induced local actin polymerization and nuclear accumulation of MRTF-A by 30 minutes, whereas a global static strain induced both rapid (minutes) transient nuclear accumulation, associated with the polymerization of an actin cap above the nucleus, and long-term (hours) accumulation, with a global increase in polymerized actin. Conversely, high strain induced actin depolymerization at intermediate times, associated with cytoplasmic MRTF accumulation.
The freeze-dried extracts of Salvia coccinea Juss. Ex Murray attenuate myocardial ischemia reperfusion injury in a global ischemia Rat model
Authors: Nyaga Nelly Murugi , Mwangi Peter Waweru , Bukachi Frederick
Published: August 2018

Background

Ischemia reperfusion injury is the leading cause of myocardial cell death in Ischemic Heart Disease. Thus intensive research efforts are geared at discovering pharmacological approaches that prevent it. Over twenty species from the genus Salvia are widely applied in traditional Chinese medicine in the management of heart diseases with Salvia miltiorrhiza (Danshen) being a canonical example. Our study aimed to investigate the cardio-protective effects of the freeze-dried extracts of salvia coccinea against ischemia reperfusion injury in a rodent in-vitro model of global ischemia.

Methods

Forty two (42) Sprague Dawley rats were randomly assigned into five groups: positive control (Glucosamine 1000mg/kg), negative control group (Krebs Henseleit buffer), low dose test (50 mg/100ml), medium dose test (100 mg/100ml), and high dose test (200 mg/100ml).

The cardio-protective effects of the different treatments were evaluated in a global ischemia model using isolated rat hearts mounted on a Langendorff system.

Naloxone 2.2 μmol/L (μ opioid receptor blocker), and theophylline 1000 μmol/L (non-specific adenosine receptor blocker) were co-administered with 50 mg of S.coccinea in the mechanism of action experiments.

The following indices of cardiac function were recorded pre- and post-ischemia: left ventricular developed pressure (LVDP), heart rate, and maximum rate of contraction and relaxation. All data were expressed as Mean ± Standard Error of Mean and analyzed using one-way ANOVA and Tukey post-hoc tests. Significance was set at p < 0.05.

Results

The freeze-dried extracts of S. coccinea had significant effects on post-ischemic contractile function recovery in the early [51.4 ± 9.7% (low dose test) vs. 14.9 ± 3.3% (medium dose test) vs. 12.7 ± 2.6% (high dose test) vs. 13.7 ± 5.7% (negative control): p<0.05] and late [38.6 ± 8.9% (low dose test) vs. 22.0± 7.1% (medium dose test) vs. 14.6 ± 5.8 (high dose test) vs. 12.5 ± 4.2% (negative control): p< 0.05]. Reperfusion phases with the highest LVDP recovery were observed at the 50 mg dosage level.

The freeze-dried extracts of S. coccinea had significant negative chronotropic effects on heart rate [234.0 ± 2.4 beats/min to 90.0 ± 7.0 beats/min, 50 mg vs. 102.0 ± 13.9 beats/min to 135.0 ± 25.9 beats/min, control P<0.05].

The cardioprotective effects of S. coccinea displayed an inverted U-shaped dose-response curve with low dose stimulation and high dose inhibition.

Naloxone completely abolished the LVDP recovery afforded by the freeze-dried extracts of S. coccinea at the 50 mg dosage level while adenosine only partly abolished the LVDP recovery (9.5 ± 3.2% (naloxone) vs. 15.5 ± 5.8% (adenosine): P>0.05).

Conclusion

The freeze-dried extracts of S. coccinea possessed significant cardioprotective effects which appear to be mediated by activation of the opioidergic pathway in the heart.
Mitogen activated protein kinases function as a cohort during a plant defense response
Authors: McNeece Brant T. , Sharma Keshav , Lawrence Gary W. , Lawrence Kathy S. , Klink Vincent P.
Published: August 2018

Mitogen activated protein kinases (MAPKs) play important signal transduction roles. However, little is known regarding whether MAPKs influence the gene expression of other family members and the relationship that expression has to a biological process. Transcriptomic studies have identified MAPK gene expression occurring within root cells undergoing a defense response to a pathogenic event in the allotetraploidGlycine max. Furthermore, functional analyses are presented for its 32 MAPKs revealing 9 of the 32 MAPKs have a defense role, including homologs ofArabidopsis thalianaMAPK (MPK) MPK2, MPK3, MPK4, MPK5, MPK6, MPK13, MPK16 and MPK20. Defense signal transduction processes occurring through pathogen activated molecular pattern (PAMP) triggered immunity (PTI) and effector triggered immunity (ETI) have been determined in relation to these MAPKs. PTI has been analyzed by examiningBOTRYTIS INDUCED KINASE1(BIK1),ENHANCED DISEASE SUSCEPTIBILITY1(EDS1) andLESION SIMULATING DISEASE1(LSD1). ETI has been analyzed by examining the role of the bacterial effector protein harpin and the downstream cell membrane receptorNON-RACE SPECIFIC DISEASE RESISTANCE1(NDR1). Experiments have identified 5 different types of gene expression relating to MAPK expression. The MAPKs are shown to influence PTI and ETI gene expression and a panel of proven defense genes including an ABC-G type transporter, 20S membrane fusion particle components, glycoside biosynthesis, carbon metabolism, hemicellulose modification, transcription andPATHOGENESIS RELATED 1(PR1). The experiments show MAPKs broadly influence the expression of other defense MAPKs, including the co-regulation of parologous MAPKs and reveal its relationship to proven defense genes.
Organizational policies and diversity management in Saudi Arabia
Authors: Abaker Mohamed-Osman Shereif Mahdi , Al-Titi Omar Ahmad Khalid , Al-Nasr Natheer Shawqi
Published: August 2018

Purpose

The purpose of this paper is to report empirical research conducted in Saudi Arabia on the impacts of organizational policies and practices on the diversity management of the Saudi private sector. To this end, the Saudization policy and views of key respondents have been tested and discussed.

Design/methodology/approach

Primary data were collected through questionnaire surveys from the largest 11 private sector organizations listed on the Saudi Stock Market in the financial/banking, oil and gas, petrochemical, private higher education and private health service sectors. Statistical tools such as means and standard deviations and one-samplet-tests were used for analysis.

Findings

The findings suggest that Saudization, retention, pay with benefits and health insurance policies significantly affect the diversity management in the Saudi private sector. Therefore, there is a need to develop organizational policies that support the existence of foreign employees for private businesses in Saudi Arabia. Considering differences as strengths that can be utilized to enhance performance, a diverse workforce might better be able to serve diverse markets.

Research limitations/implications

Collecting data from a closed environment such as Saudi Arabia is constrained by access difficulties, as well as inadequate literature on relevant diversity issues. However, the convenience sampling method and snowballing approach adopted in this study generated reliable data. As a result, this study has implications for both the multinational corporations operating in Saudi Arabia and Saudi owned companies operating in the West and intending to adopt and implement diversity management initiatives for branches in different countries. As such, further research on the gulf countries’ diversity management issues would be critical.

Originality/value

The current study is a first survey-based research endeavor on the topic of diversity management in the Saudi context. The findings contribute to the limited knowledge base on middle eastern countries, thus presenting new empirical evidence on the organizational policies and practices of Saudization, retention, pay and benefits and health insurance policies. The study of the Saudi case, thus adds value to the existing knowledge on diversity management.
On modeling mechanisms and applicable ranges of grey incidence analysis models
Authors: Dong Wenjie , Liu Sifeng , Fang Zhigeng
Published: August 2018

Purpose

The purpose of this paper is to study the modelling mechanisms of several grey incidence analysis models with great influence, including Deng’s grey incidence model, absolute degree of grey incidence model, slope degree of incidence model, similitude degree of incidence model and closeness degree of incidence model; then analyse the problems to be solved in grey incidence analysis models; and clarify the applicable ranges of commonly used grey incidence models.

Design/methodology/approach

The paper comes to conclusions by means of comparable analysis. The authors compare several commonly used grey incidence analysis models, including Deng’s grey incidence model, absolute degree of grey incidence model, slope degree of incidence model, similitude degree of incidence model and closeness degree of incidence model and give several examples to clarify the reasons why quantitative analysis results of different models are not exactly the same.

Findings

As the intension of each kind of incidence model is clear and the extension is relatively obscure, grey incidence orders calculated by different incidence models are often different. When making actual decisions, incompatible results may appear. According to different characteristics of extraction, grey incidence analysis models can be divided into three types: incidence model based on closeness perspective, incidence model based on similarity perspective and incidence model based on comprehensive perspective.

Practical implications

The conclusions obtained in this paper can help people avoid some defects in the process of actual selection and choose the better incidence analysis model.

Originality/value

The conclusions can be used as a reference and basis for the selection of grey incidence analysis models, it can help to overcome the defects and shortcomings of models caused by themselves and screen out more excellent analytical models.
The practice of professional skills and civic engagement through service learning
Authors: Cheng Shuhui Sophy
Published: August 2018

Purpose

The purpose of this paper is to explore the community service learning initiative among Taiwanese communication students by examining the link between the value of work-based learning and learning outcomes from the applied classroom projects.

Design/methodology/approach

This study involves the applied classroom projects. Data are captured in both quantitative (i.e. survey) and qualitative methods (i.e. reflective papers). The survey is designed to measure general attitudes and perceptions of service learning students. The reflective papers focus on the participants’ expectations of the service learning outcome.

Findings

The findings suggest that work-based and service learning projects are beneficial for the students, faculty, university and community partners. As an extension of experiential learning, students acquire a deeper understanding of the course material, gain practical expertise in the real world, develop interpersonal communication skills and engage in civic responsibility.

Practical implications

This study supports the notion that service learning engagements help students develop problem-solving skills. It is suggested that since the content of traditional learning in the discipline of communication has changed extensively over the past decades (i.e. from traditional media to new digital media), service learning can be a complimentary tool to not only broaden students’ learning, but to also expand their professional horizons and opportunities.

Originality/value

The current study expands existing theory and advances our understanding of service learning in the discipline of communication in a Taiwanese context. With practical roots embedded in Western educational initiatives linking service learning to higher education, this paper reveals that service learning does work across cultures as well.