bluuebunny/crossref_metadata_2025 huggingface dataset:
Is Vulvovaginal Lichen Planus Associated With Squamous Cell Carcinoma?
Authors: Day Tania , Otton Geoff , Jaaback Ken , Weigner Julie , Scurry James
Published: February 2018

Objective

The aim of the study was to assess for the presence of vulvar lichen planus (LP) in association with human papillomavirus (HPV)–independent squamous cell carcinoma (SCC).

Materials and Methods

We performed a clinicohistopathologic review of consecutive vulvectomies and wide local excisions for HPV-independent vulvar or vaginal SCC from 2007 to 2017. Data collected included site of SCC, adjacent precursor lesions and dermatoses, dermatologic treatment, and outcome.

Results

There were 43 cases of primary HPV-independent vulvar SCC treated by excision, but no vaginal cancers. Eighteen women (42%) had a preoperative diagnosis of lichen sclerosus (LS); none had a diagnosis of LP. Topical corticosteroids were prescribed in 19 (44%) of 43, with 4 women placed on maintenance therapy. Tumors arose from the labia minora, labia majora, and periclitoris, but not from vestibule or perianus. On histopathological review, LS was present in 41 (95%) of 43 specimens, 1 had a nonspecific lichenoid reaction, and 1 had lichen simplex; both of the latter had subsequent biopsies showing LS. Lichen planus was not seen in association with SCC. Differentiated vulvar intraepithelial neoplasia (dVIN) was present in 38 (88%) of 43 specimens, whereas 1 had acanthosis with altered differentiation and 4 (9%) had no precursor lesion. Differentiated vulvar intraepithelial neoplasia had standard, basaloid, and hypertrophic morphology, superficially resembling erosive LP in 9 (24%) of 38 and hypertrophic LP in 6 (16%) of 38.

Conclusions

Lichen planus was not seen in association with HPV-independent vulvar SCC, whereas LS was underrecognized and inadequately treated in this group. Pathologists should be aware that dVIN may superficially resemble erosive or hypertrophic LP.
An Environmental influences on Child Health Outcomes viewpoint of data analysis centers for collaborative study designs
Authors: Jacobson Lisa P. , Lau Bryan , Catellier Diane , Parker Corette B.
Published: February 2018

Purpose of review

A highly complex collaborative study design that pools and extends existing studies, such as the Environmental influences on Child Health Outcomes (ECHO) Program, requires a Data Analysis Center (DAC) with resources and expertise to create a secure environment for housing and analyzing the shared data, harmonize and structure the shared data for different purposes, and apply appropriate and innovative designs and analytic methods. The DAC, in partnership with cohort investigators, must ensure that results from ECHO-wide cohort analyses are appropriately interpreted and reproducible.

Recent findings

Understanding the cohorts contributing to ECHO is critical for developing a collaborative environment and the methods to best analyze the data without bias. We further describe the development of the ECHO-wide cohort Metadata Catalog, the architecture of the ECHO-wide cohort data platform, and analytical approaches to facilitate early productivity.

The ECHO DAC has established a secure environment for the transfer and storage of ECHO cohort data and information, and initiated processes to promote productive collaborations. Understanding the ECHO DAC responsibilities and assets will help to overcome communication and trust challenges encountered in the initiation of this complex ECHO-wide cohort collaborative research study.
Neuropathic Pain Component in Axial Spondyloarthritis and the Influence on Disease Burden
Authors: Gok Kevser , Cengiz Gizem , Erol Kemal , Ozgocmen Salih
Published: February 2018

Objectives

Patients with nonradiographic axial spondyloarthritis (nr-axSpA) and radiographic axSpA/ankylosing spondylitis (AS) have similar burden of disease; however, the potential influence of pain characteristics including the neuropathic pain (NeP) component has not been assessed yet. The aim of this study was first to assess frequency of NeP component in patients with axSpA and second to assess the potential influence of NeP on burden of disease.

Methods

Adult patients who met the Assessment of SpondyloArthritis International Society classification criteria for axSpA were consecutively recruited. Patients were evaluated using the Douleur Neuropathique en 4 Questions interview and painDETECT questionnaire and subgrouped as patients with and without NeP.

Results

Neuropathic pain component was present in 31.4% of patients with axSpA categorized according to Douleur Neuropathique en 4 Questions (31.6% in nr-axSpA vs 31.3% in AS, P = 0.964) and in 33.5% of patients categorized according to painDETECT (35.1% in nr-axSpA vs 32.8% in AS, P = 0.762). Pain characteristics were quite similar between patients with nr-axSpA and AS. Women tented to have more frequent NeP. Patients with NeP component had significantly higher scores in visual analog scale of pain, patient and physician global, fatigue, Bath Ankylosing Spondylitis Disease Activity Index, Ankylosing Spondylitis Disease Activity Score using C-reactive protein, depression, anxiety scores, and physical functions; poorer quality of life (QoL); and similar frequency of fibromyalgia compared with patients without NeP component. In multivariable analysis, having NeP was associated with QoL measures (Ankylosing Spondylitis Quality of Life and Short-Form 36 physical component score) and visual analog scale of fatigue.

Conclusions

Nearly one third of patients with axSpA may have NeP component regardless of having nr-axSpA or AS. Neuropathic pain component may contribute worsened QoL and poorer patient-reported outcome data and should be kept in mind during patient evaluation.
Increased Prevalence of Metabolic Syndrome and Adipocytokine Levels in a Psoriatic Arthritis Cohort
Authors: Feld Joy , Nissan Sarit , Eder Lihi , Rahat Michal Amit , Elias Muna , Rimar Doron , Laor Arie , Bitterman Haim , Zisman Devy
Published: February 2018

Objective

The aims of this study were to evaluate the prevalence of metabolic syndrome (MetS) in psoriatic arthritis (PsA) patients according to the most recent definition in a Mediterranean population and to determine its association with biomarkers of inflammation and serum adipocytokine levels.

Methods

Demographic, clinical, and laboratory data were collected on 74 patients with PsA and 82 control subjects. The presence of MetS was determined according to the current “harmonization” definition. Serum adipocytokines were analyzed. Continuous variables were compared byttest and discrete variables by χ2test. Multivariate regression models compared the association between the presence of MetS and the blood levels of adipocytokines.

Results

The prevalence of MetS was higher in PsA patients compared with the control group: 54.8% versus 36.6%, respectively (P= 0.02; odds ratio, 2.33; 95% confidence interval, 1.16–4.69). The main difference between the 2 groups was waist circumference. No association was found between MetS and parameters of articular and skin disease activity or treatment. Leptin levels and leptin/adiponectin ratio were higher in PsA patients compared with control subjects: 83.4 versus 51.7 ng/mL (P= 0.001) and 6.3 × 10−3versus 4.1 × 10−3(P= 0.015), respectively. There was no significant difference in the adiponectin levels between the groups.

Conclusions

The prevalence of MetS was higher in PsA patients compared with non-PsA control subjects in this Mediterranean population. Clinicians caring for PsA patients ought to be aware of the increased risk of MetS in PsA patients, confirmed in different regions worldwide. The increased MetS seems to be linked to central obesity in these patients, and appropriate treatment recommendations are advised.
Breakthrough Reactions to Gadobenate Dimeglumine
Authors: Bhatti Zeeshaan S. , Mervak Benjamin M. , Dillman Jonathan R. , Davenport Matthew S.
Published: February 2018

Purpose

The aim of this study was to determine the severity of breakthrough reactions to gadobenate dimeglumine in patients premedicated with a 13-hour premedication regimen.

Methods

Institutional review board approval was obtained and informed consent waived for this Health Insurance Portability and Accountability Act–compliant retrospective cohort study. All acute allergic-like reactions to gadobenate dimeglumine from 11/1/2008 to 1/31/2016 were identified. Of these, 19 allergic-like reactions followed 13-hour premedication: 150 mg prednisone and 50 mg diphenhydramine (ie, “breakthrough reactions”). Reasons for premedication, risk factors, index reaction characteristics, and breakthrough reaction characteristics were catalogued. Reaction severities were assigned using American College of Radiology guidelines. Severities of breakthrough (n = 19) and nonbreakthrough reactions (n = 97) were compared with the Cochran-Armitage test for trend.

Results

Premedication was most commonly given (63% [12/19]) for a previous allergic-like reaction to gadolinium-based contrast material (GBCM); in 37% (7/19), it was given for a different risk factor. In those premedicated for a previous allergic-like reaction to GBCM of known severity (n = 9), the breakthrough reaction severity was the same as index reaction severity in 56% (5/9), less severe in 11% (1/9), and of greater severity in 33% (3/9). Two severe breakthrough reactions occurred; both were in subjects premedicated for risk factors other than a previous GBCM reaction. No subjects died. Five subjects were reexposed to GBCM a total of 9 times; no repeat breakthrough reactions occurred. Breakthrough reactions were more severe than nonbreakthrough reactions (P = 0.046), but the level of significance was borderline.

Conclusion

Premedication does not eliminate severe reactions to gadobenate dimeglumine. Breakthrough reactions to gadobenate dimeglumine can be of greater severity than index reactions.
CD44 Deficiency in Mice Protects the Heart Against Angiotensin Ii-Induced Cardiac Fibrosis
Authors: Yang Li-Wang , Qin Dong-Ze , James Erskine , McKallip Robert J. , Wang Ning-Ping , Zhang Wei-Wei , Zheng Rong-Hua , Han Qing-Hua , Zhao Zhi-Qing
Published: February 2018

This study tested the hypothesis that CD44 is involved in the development of cardiac fibrosis via angiotensin II (Ang II) AT1 receptor-stimulated TNFα/NFκB/IκB signaling pathways. Study was conducted in C57BL/6 wild type and CD44 knockout mice subjected to Ang II infusion (1,000 ng/kg/min) using osmotic minipumps up to 4 weeks or with gastric gavage administration of the AT1 receptor blocker, telmisartan at a dose of 10 mg/kg/d. Results indicated that Ang II enhances expression of the AT1 receptor, TNFα, NFκB, and CD44 as well as downregulates IκB. Further analyses revealed that Ang II increases macrophage migration, augments myofibroblast proliferation, and induces vascular/interstitial fibrosis. Relative to the Ang II group, treatment with telmisartan significantly reduced expression of the AT1 receptor and TNFα. These changes occurred in coincidence with decreased NFκB, increased IκB, and downregulated CD44 in the intracardiac vessels and intermyocardium. Furthermore, macrophage migration and myofibroblast proliferation were inhibited and fibrosis was attenuated. Knockout of CD44 did not affect Ang II-stimulated AT1 receptor and modulated TNFα/NFκB/IκB signaling, but significantly reduced macrophage/myofibroblast-mediated fibrosis as identified by less extensive collagen-rich area. These results suggest that the AT1 receptor is involved in the development of cardiac fibrosis by stimulating TNFα/NFκB/IκB-triggered CD44 signaling pathways. Knockout of CD44 blocked Ang II-induced cell migration/proliferation and cardiac fibrosis. Therefore, selective inhibition of CD44 may be considered as a potential therapeutic target for attenuating Ang II-induced deleterious cardiovascular effects.
Antibodies and the brain: anti-N-methyl-d-aspartate receptor antibody and the clinical effects in patients with systemic lupus erythematosus
Authors: Arinuma Yoshiyuki
Published: February 2018

Purpose of review

Neuropsychiatric manifestations are one of the fatal complications in patients with systemic lupus erythematosus (SLE). However, the diagnosis and monitoring of that aspect of SLE is still challenging, as there are no reliable biomarkers linked to central nervous system (CNS) damage. This review emphasizes potential candidate autoantibodies that appear to be associated with development of behavioral and psychiatric manifestations in SLE patients.

Recent findings

Developments in the pathogenesis in SLE, not surprising for this immune disorder, point to specific, autoantibody toxicity. Namely, the discovery of an antibody which reacts with DNA and with the extracellular domain of N-methyl-d-aspartate (NMDA) receptor subunit GluN2A and 2B (anti-NMDA), an important receptor on neurons that is ubiquitous in the CNS, may lead to new insights into the behavioral and psychiatric manifestations in SLE. These anti-NMDA antibodies induce neuronal apoptosis and degeneration of surviving neurons in murine models. This functional antibody is also detected in SLE patients who have behavioral and psychiatric manifestations. The presence of anti-NMDA in cerebrospinal fluid but not in serum is associated significantly with overwhelming CNS abnormalities, suggesting importance of direct access of autoantibodies to brain dysfunction.

As anti-NMDA autoantibodies are present in patients who develop psychiatric manifestations in SLE, it is possible that novel therapeutic approaches will depend on altering the activity of these autoantibodies.
Sensitivity of a Reduced EEG Montage for Seizure Detection in the Neurocritical Care Setting
Authors: Ma Brandy B. , Johnson Emily L. , Ritzl Eva K.
Published: February 2018

Introduction:

Neurocritical care units commonly implement the double-distance reduced EEG montage in postoperative neurosurgic patients who have structural barriers that hinder the placement of a standard 10-20 system array. Despite its widespread use, its sensitivity has not been adequately addressed. We evaluated the sensitivity and specificity of this montage for seizure detection.

Methods:

One hundred fifty-five full-montage continuous EEGs (cEEGs) completed in the Johns Hopkins University neurocritical care unit containing unequivocal electrographic seizures, status epilepticus, or other abnormalities were selected, comprising 73 ictal and 82 nonictal EEGs. EEGs were reformatted to the reduced montage, and 2-hour clips were reviewed independently by 2 epileptologists who documented the presence of seizures, status, or background abnormalities.

Results:

The sensitivity and specificity of the reduced montage for electrographic seizure detection was 81% and 92% with substantial interrater agreement (kappa 0.71). The sensitivity for status epilepticus was lower at 69%, but specificity remained high at 97% (kappa 0.67). Several EEGs miscategorized as nonictal were labeled as rather having rhythmic activity or periodic discharges. Evaluation of background patterns on the ictal–interictal continuum resulted in sensitivities ranging from 68% to 83%.

Conclusions:

Although the specificity of the reduced array is good, epileptologists should remain vigilant when monitoring patients using this montage, given its reduced sensitivity for epileptic activity, especially status epilepticus.
MicroRNA-132 provides neuroprotection for tauopathies via multiple signaling pathways
Authors: Fatimy Rachid El , Li Shaomin , Chen Zhicheng , Mushannen Tasnim , Gongala Sree , Wei Zhiyun , Balu Darrick T. , Rabinovsky Rosalia , Cantlon Adam , Elkhal Abdallah , Selkoe Dennis J. , Sonntag Kai C. , Walsh Dominic M. , Krichevsky Anna M.
Published: February 2018

MicroRNAs (miRNA) regulate fundamental biological processes, including neuronal plasticity, stress response, and survival. Here we describe a neuroprotective function of miR-132, the miRNA most significantly down-regulated in Alzheimer’s disease. miR-132 protects mouse and human wild-type neurons and more vulnerable Tau-mutant primary neurons against amyloid β-peptide (Aβ) and glutamate excitotoxicity. It lowers the levels of total, phosphorylated, acetylated, and cleaved forms of Tau implicated in tauopathies, promotes neurite elongation and branching, and reduces neuronal death. Similarly, miR-132 attenuates PHF Tau pathology and neurodegeneration and enhances long-term potentiation in the P301S Tau transgenic mice. The neuroprotective effects are mediated by direct regulation of the Tau modifiers acetyltransferase EP300, kinase GSK3β, RNA-binding protein Rbfox1, and proteases Calpain 2 and Caspases 3/7. These data suggest miR-132 as a master regulator of neuronal health and indicate that miR-132 supplementation could be of therapeutic benefit for the treatment of Tau-associated neurodegenerative disorders.
Citius, Fortius? Cohort, inflammation and trajectories of gait speed and grip strength in older Britons
Authors: Tampubolon Gindo , Fajarini Maria
Published: February 2018

Although the cost of long term care of physical disabilities is considerable, little is known about individual trajectories of physical function (measured by gait speed and grip strength) that preceded the process of disablement. Moreover, studies on trajectories of health function have often ignored cohort composition, precluding evidence of secular improvement. And few have explored the role of chronic inflammation on older people’s physical function trajectories. Using the English Longitudinal Study of Ageing 2004–2013 we derived trajectories of gait speed and grip strength of Britons aged ≥ 50 years and investigated the effect of inflammation. Then we drew trajectories for different cohorts to seek evidence of secular improvement. We uncovered a complex gradient of improvement in trajectories of physical function that depends on sex and maximum versus normal capacity. In conclusion, accounting for the cohort composition of older people can materially modify the future cost of long term care.
Trends in CRP, D-dimer and fibrinogen during therapy for HIV associated multidrug resistant tuberculosis
Authors: Cudahy Patrick G. T. , Warren Joshua L. , Cohen Ted , Wilson Doug
Published: February 2018

Background

HIV positive adults on treatment for multidrug-resistant tuberculosis (MDR-TB) experience high mortality. Biomarkers of HIV/MDR-TB treatment response may enable earlier treatment modifications that improve outcomes.

Methods

To determine whether trends in C-reactive protein (CRP), D-dimer and fibrinogen predict treatment outcome among those with HIV/MDR-TB co-infection we studied 20 HIV positive participants initiating therapy for MDR-TB. Serum CRP, fibrinogen, and D-dimer were measured at baseline and serially while on treatment. Results: At baseline, all biomarkers were elevated with median CRP 86.15 mg/L (IQR 29.25-149.32), D-dimer 0.85 μg/mL (IQR 0.34-1.80) and fibrinogen 4.11 g/L (IQR 3.75-6.31). CRP decreased significantly within 10 days of treatment initiation and fibrinogen within 28 days; D-dimer did not change significantly. 5 (25%) participants died. Older age (median age of 38y among survivors and 54y among deceased, p=0.008) and higher baseline fibrinogen (3.86 g/L among survivors and 6.37 g/L among deceased, p=0.02) were significantly associated with death. Higher CRP concentrations at the beginning of each measurement interval were significantly associated with a higher risk of death during that interval.

Conclusion

Trends in fibrinogen and CRP may be useful for evaluating early response to treatment among individuals with HIV/MDR-TB co-infection.
Cell type-dependent control of p53 transcription and enhancer activity by p63
Authors: Uzunbas Gizem Karsli , Ahmed Faraz , Sammons Morgan A.
Published: February 2018

Transcriptional activation by p53 provides powerful, organism-wide tumor suppression. In this work, we demonstrate that the p53-induced transcriptome varies based on cell type, reflects cell type-specific activities, and is considerably more broad than previously anticipated. This behavior is strongly influenced by p53 engagement with differentially active cell type-specific enhancers and promoters. In epithelial cell types, p53 activity is dependent on the p53 family member p63, which displays widespread enhancer binding. Notably, we demonstrate that p63 is required for epithelial enhancer identity including enhancers used by p53 during stress-dependent signaling. Loss of p63, but not p53, leads to site-specific depletion of enhancer-associated chromatin modifications, suggesting that p63 functions as an enhancer maintenance factor in epithelial cells. Additionally, a subset of epithelial-specific enhancers is dependent on the activity of p63 providing a direct link between lineage determination and enhancer structure. These data suggest a broad, cell-intrinsic mechanism for regulating the p53-dependent cellular response to stress through differential regulation ofcis-regulatory elements.
ADAR1 A-to-I RNA editing alters codon usage
Authors: Brachova Pavla , Alvarez Nehemiah S. , Hong Xiaoman , Vincent Kailey A. , Latham Keith E. , Christenson Lane K.
Published: February 2018

Background

Fully grown mammalian oocytes and eggs are transcriptionally quiescent, and therefore have a unique RNA environment in which cellular processes depend on post-transcriptional regulation. RNA editing of adenosines into inosines (A-to-I) by adenosine deaminases acting on RNA (ADARs) is a common post-transcriptional gene regulatory mechanism, yet it has not been systematically studied in oocytes.

Results

A genome-wide RNA editing analysis of transcriptionally active growing oocytes from postnatal day 12 (PND12) mice, fully grown germinal vesicle (GV) oocytes, and transcriptionally quiescent metaphase II (MII) eggs indicates an abundant amount of A-to-I editing of mRNA transcripts. Editing of mRNA was greatest in GV oocyte and MII eggs compared to the PND12 immature oocytes, this was consistent with ADAR1 levels within these cells. Compared to somatic tissues, oocytes exhibited a different pattern of RNA editing, with a high proportion of RNA edits occurring in the coding regions. These edits resulted in nucleotide substitutions that were enriched at the third nucleotide of the codon (wobble position). Codon usage can affect mRNA stability and translation efficiency.

Conclusions

RNA editing in mouse oocytes is distinct from RNA editing in somatic cells due to increased frequencies of coding sequence RNA edits. We provide evidence in support of a previously unreported phenomenon of selective ADAR1 editing of the codon wobble position. Editing of the wobble position has the potential to fine tune post-transcriptional gene regulation through altering codon usage. This important observation advances our current understanding of RNA editing in mammalian cells.
ViDGER: An R package for integrative interpretation of differential gene expression results of RNA-seq data
Authors: McDermaid Adam , Monier Brandon , Zhao Jing , Ma Qin
Published: February 2018

Differential gene expression (DGE) is one of the most common applications of RNA-sequencing (RNA-seq) data. This process allows for the elucidation of differentially expressed genes (DEGs) across two or more conditions. Interpretation of the DGE results can be non-intuitive and time consuming due to the variety of formats based on the tool of choice and the numerous pieces of information provided in these results files. Here we present an R package,ViDGER(Visualization of Differential Gene Expression Results using R), which contains nine functions that generate information-rich visualizations for the interpretation of DGE results from three widely-used tools,Cuffdiff,DESeq2, andedgeR.
SeqStruct: A New Amino Acid Similarity Matrix Based on Sequence Correlations and Structural Contacts Yields Sequence-Structure Congruence
Authors: Jia Kejue , Jernigan Robert L.
Published: February 2018

Protein sequence matching does not properly account for some well-known features of protein structures: surface residues being more variable than core residues, the high packing densities in globular proteins, and does not yield good matches of sequences of many proteins known to be close structural relatives. There are now abundant protein sequences and structures to enable major improvements to sequence matching. Here, we utilize structural frameworks to mount the observed correlated sequences to identify the most important correlated parts. The rationale is that protein structures provide the important physical framework for improving sequence matching. Combining the sequence and structure data in this way leads to a simple amino acid substitution matrix that can be readily incorporated into any sequence matching. This enables the incorporation of allosteric information into sequence matching and transforms it effectively from a 1-D to a 3-D procedure. The results from testing in over 3,000 sequence matches demonstrate a 37% gain in sequence similarity and a loss of 26% of the gaps when compared with the use of BLOSUM62. And, importantly there are major gains in the specificity of sequence matching across diverse proteins. Specifically, all known cases where protein structures match but sequences do not match well are resolved.
Endothelia extrude apoptotic cells to maintain a constant barrier
Authors: Mleynek Tara M. , Redd Michael , Chan Aubrey , Gu Yapeng , Li Dean Y , Rosenblatt Jody
Published: February 2018

The vascular system is lined with endothelial cells that, although only existing in a single monolayer, are key in the regulation of vascular barrier function. One of the major challenges these cells face is a routine exposure to environmental stressors that can induce apoptosis. Uncontrolled apoptosis in the endothelial monolayer threatens the ability of the cells to maintain their barrier function, resulting in vascular dysfunction. Therefore, we sought to identify ways in which endothelia maintain a cohesive monolayer during apoptotic events. We found that endothelial cells fated die will undergo a process of apoptotic cellular extrusion, similar to what has been described in the epithelium. We further show that endothelial extrusion uses a conserved S1P-S1PR2-RhoA signaling pathway in order to induce the formation of an actin ring that contracts closed, forcing the dying cell out of the monolayer while simultaneously filling in the gap left behind. Thus, endothelial extrusion successfully removes an apoptotic cell before it compromises the monolayer, preserving the barrier function.
Intergenerational epigenetic inheritance in reef-building corals
Authors: Liew Yi Jin , Howells Emily J. , Wang Xin , Michell Craig T. , Burt John A. , Idaghdour Youssef , Aranda Manuel
Published: February 2018

Main

The notion that intergenerational or transgenerational inheritance operates solely through genetic means is slowly being eroded: epigenetic mechanisms have been shown to induce heritable changes in gene activity in plants1,2and metazoans1,3. Inheritance of DNA methylation provides a potential pathway for environmentally induced phenotypes to contribute to evolution of species and populations1–4. However, in basal metazoans, it is unknown whether inheritance of CpG methylation patterns occurs across the genome (as in plants) or as rare exceptions (as in mammals)4. Here, we demonstrate genome-wide intergenerational transmission of CpG methylation patterns from parents to sperm and larvae in a reef-building coral. We also show variation in hypermethylated genes in corals from distinct environments, indicative of responses to variations in temperature and salinity. These findings support a role of DNA methylation in the transgenerational inheritance of traits in corals, which may extend to enhancing their capacity to adapt to climate change.
An immortalised mesenchymal stem cell line maintains mechano-responsive behaviour and can be used as a reporter of substrate stiffness
Authors: Galarza Torre Asier , Shaw Joshua E. , Wood Amber , Gilbert Hamish T. J. , Dobre Oana , Genever Paul , Brennan Keith , Richardson Stephen M. , Swift Joe
Published: February 2018

The mechanical environment can influence cell behaviour, including changes to transcriptional and proteomic regulation, morphology and, in the case of stem cells, commitment to lineage. However, current tools for characterizing substrates’ mechanical properties, such as atomic force microscopy (AFM), often do not fully recapitulate the length and time scales over which cells ‘feel’ substrates. Here, we show that an immortalised, clonal line of human mesenchymal stem cells (MSCs) maintained responsiveness to substrate mechanics observed in primary cells, and could be used as a reporter of stiffness. MSCs were cultured on soft and stiff polyacrylamide hydrogels. In both primary and immortalised MSCs, stiffer substrates promoted increased cell spreading, expression of lamin-A/C and translocation of mechano-sensitive proteins YAP1 and MKL1 to the nucleus. Stiffness was also found to regulate transcriptional markers of lineage. A GFP-YAP / RFP-H2B reporter construct was designed and virally delivered to the immortalised MSCs for in situ detection of substrate stiffness. MSCs with stable expression of the reporter showed GFP-YAP to be increasingly co-localized with nuclear RFP-H2B on stiffer substrates, enabling development of a cellular reporter of substrate stiffness. This will facilitate mechanical characterisation of new materials developed for applications in tissue engineering and regenerative medicine.
Phosphatidylethanolamine made in the inner mitochondrial membrane is essential for yeast cytochromebc1complex function
Authors: Calzada Elizabeth , McCaffery J. Michael , Claypool Steven M.
Published: February 2018

Of the four separate PE biosynthetic pathways in eukaryotes, one occurs in the mitochondrial inner membrane (IM) and is executed by phosphatidylserine decarboxylase (Psd1p). Deletion of Psd1, which is lethal in mice, compromises mitochondrial function. We hypothesize that this reflects inefficient import of non-mitochondrial PE into the IM. To test this, we re-wired PE metabolism in yeast by re-directing Psd1p to the outer mitochondrial membrane or the endomembrane system. Our biochemical and functional analyses identified the IMS as the greatest barrier for PE import and demonstrated that PE synthesis in the IM is critical for cytochromebc1complex (III) function. Importantly, mutations predicted to disrupt a conserved PE-binding site in the complex III subunit, Qcr7p, impaired complex III activity similar toPSD1deletion. Collectively, these data demonstrate that PE made in the IM by Psd1p is critical to support the intrinsic functionality of complex III and establish one likely mechanism.
Expanding the genetic toolkit of Tribolium castaneum
Authors: Rylee Johnathan C. , Siniard Dylan J. , Doucette Kaitlin , Zentner Gabriel E. , Zelhof Andrew C.
Published: February 2018

The red flour beetle, Tribolium castaneum, is an important model insect and agricultural pest.However, many standard genetic tools are lacking or underdeveloped in this system. Here, we present a set of new reagents to augment existing Tribolium genetic tools. We demonstrate a new GAL4 driver line that employs the promoter of a ribosomal protein gene to drive expression of a UAS responder in the fat body. We also present a novel dual fluorescent reporter that labels cell membranes and nuclei with different fluorophores for the analysis of cellular morphology. This approach also demonstrates the functionality of the viral T2A peptide for bicistronic gene expression in Tribolium. To facilitate classical genetic analysis, we created lines with visible genetic markers by CRISPR-mediated disruption of the yellow and ebony body color loci with a cassette carrying an attP site, enabling future φC31-mediated integration. Together,the reagents presented here will facilitate more robust genetic analysis in Tribolium and serve as a blueprint for the further development of this powerful model’s genetic toolkit.
Real-space analysis of radiation-induced specific changes with independent component analysis
Authors: Borek Dominika , Bromberg Raquel , Hattne Johan , Otwinowski Zbyszek
Published: February 2018

A method of analysis is presented that allows for the separation of specific radiation-induced changes into distinct components in real space. The method relies on independent component analysis (ICA) and can be effectively applied to electron density maps and other types of maps, provided that they can be represented as sets of numbers on a grid. Here, for glucose isomerase crystals, ICA was used in a proof-of-concept analysis to separate temperature-dependent and temperature-independent components of specific radiation-induced changes for data sets acquired from multiple crystals across multiple temperatures. ICA identified two components, with the temperature-independent component being responsible for the majority of specific radiation-induced changes at temperatures below 130 K. The patterns of specific temperature-independent radiation-induced changes suggest a contribution from the tunnelling of electron holes as a possible explanation. In the second case, where a group of 22 data sets was collected on a single thaumatin crystal, ICA was used in another type of analysis to separate specific radiation-induced effects happening on different exposure-level scales. Here, ICA identified two components of specific radiation-induced changes that likely result from radiation-induced chemical reactions progressing with different rates at different locations in the structure. In addition, ICA unexpectedly identified the radiation-damage state corresponding to reduced disulfide bridges rather than the zero-dose extrapolated state as the highest contrast structure. The application of ICA to the analysis of specific radiation-induced changes in real space and the data pre-processing for ICA that relies on singular value decomposition, which was used previously in data space to validate a two-component physical model of X-ray radiation-induced changes, are discussed in detail. This work lays a foundation for a better understanding of protein-specific radiation chemistries and provides a framework for analysing effects of specific radiation damage in crystallographic and cryo-EM experiments.
Crystal structures ofLymphocytic choriomeningitis virusendonuclease domain complexed with diketo-acid ligands
Authors: Saez-Ayala Magali , Yekwa Elsie Laban , Carcelli Mauro , Canard Bruno , Alvarez Karine , Ferron François
Published: February 2018

TheArenaviridaefamily, together with theBunyaviridaeandOrthomyxoviridaefamilies, is one of the three negative-stranded RNA viral families that encode an endonuclease in their genome. The endonuclease domain is at the N-terminus of the L protein, a multifunctional protein that includes the RNA-dependent RNA polymerase. The synthesis of mRNA in arenaviruses is a process that is primed by capped nucleotides that are `stolen' from the cellular mRNA by the endonuclease domain in cooperation with other domains of the L protein. This molecular mechanism has been demonstrated previously for the endonuclease of the prototypeLymphocytic choriomeningitis virus(LCMV). However, the mode of action of this enzyme is not fully understood as the original structure did not contain catalytic metal ions. The pivotal role played by the cap-snatching process in the life cycle of the virus and the highly conserved nature of the endonuclease domain make it a target of choice for the development of novel antiviral therapies. Here, the binding affinities of two diketo-acid (DKA) compounds (DPBA and L-742,001) for the endonuclease domain of LCMV were evaluated using biophysical methods. X-ray structures of the LCMV endonuclease domain with catalytic ions in complex with these two compounds were determined, and their efficacies were assessed in anin vitroendonuclease-activity assay. Based on these data and computational simulation, two new DKAs were synthesized. The LCMV endonuclease domain exhibits a good affinity for these DKAs, making them a good starting point for the design of arenavirus endonuclease inhibitors. In addition to providing the first example of an X-ray structure of an arenavirus endonuclease incorporating a ligand, this study provides a proof of concept that the design of optimized inhibitors against the arenavirus endonuclease is possible.
N,N-Dimethyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine monohydrate
Authors: El Hafi Mohamed , Boulhaoua Mohammed , Lahmidi Sanae , Ramli Youssef , Essassi El Mokhtar , Mague Joel T.
Published: February 2018

The asymmetric unit of the title compound, C7H9N5·H2O, consists of two formula units differing slightly in the orientation of the dimethylamino groups. In the crystal, a combination of O—H...N and N—H...O hydrogen bonds involving the water molecules of crystallization, as well as slipped π-stacking interactions between pyrazolopyrimidine units form layers parallel to thebcplane.
7-Bromo-1,4-bis(prop-2-ynyl)pyrido[2,3-b]pyrazine-2,3(1H,4H)-dione
Authors: Sikine Meriem , Kandri Rodi Youssef , Ouzidan Younes , Jasinski Jerry P. , Kaur Manpreet , Essassi El Mokhtar
Published: February 2018

In the title compound, C13H8BrN3O2, the pyrido-pyrazine fused-ring system is essentially planar (r.m.s. deviation = 0.061 Å). The prop-2-ynyl moieties are twisted away from the ring system in opposite directions. In the crystal, a single weak C—H...O interaction generates [010] chains and aromatic π–π stacking interactions between the pyridine rings are observed.
Flipped learning and formative evaluation in higher education
Authors: Otero-Saborido Fernando M. , Sánchez-Oliver Antonio J. , Grimaldi-Puyana Moisés , Álvarez-García José
Published: February 2018

Purpose

The purpose of this paper is to design and validate a continuous self-assessment tool that involves university students in reflection processes on their Flipped Learning model learning.

Design/methodology/approach

For this, 66 students (18.77±1.36) of the first year of the Degree in Physical Activity and Sports Sciences participated for nine weeks in the weekly completion of a self-assessment tool. The questionnaire followed a content validation by a group of experts and, subsequently, reliability was found from the internal consistency perspective through Cronbach’s α.

Findings

The results obtained show a reliable tool that facilitates the work by competencies in university education under the Flipped Learning model.

Originality/value

This work is the first step that responds to the almost non-existent practices of democratic evaluation in Higher Education. The design and validation of questionnaires that consider the measures adopted by the European Higher Education Area and that takes into account European Credit Transfer and Accumulation System is scarce.
The thematic landscape of literature in sustainable supply chain management (SSCM)
Authors: Roy Vivek , Schoenherr Tobias , Charan Parikshit
Published: February 2018

Purpose

The purpose of this paper is to comprehensively review the vast literature on sustainable supply chain management (SSCM), with the specific objective of a thematic exploration of the literature in order to explicate the principal facets of SSCM development.

Design/methodology/approach

This comprehensive review follows the systematic literature review approach.

Findings

The authors find SSCM to develop around five principal facets. The first facet is adoption, which accounts for the development of preparatory grounds – for facilitating the generation of a SSCM philosophy to gradually seep into the frame of traditional supply chain management (SCM). The second facet of implementation accounts for the manifestation of a SSCM-oriented transformation for producing gradual upgrades in the traditional SCM environment. The third facet of extension signifies the broadening of the scope of implementation at a more wider (supply chain) level. The fourth facet of maintenance outlines the need for ensuring the continuity of progress in the course of SSCM development. The fifth facet of outcomes focuses on the yields of SSCM’s pursuit.

Originality/value

These principal facets are built across the multiple levels and unique conceptual standpoints as propagated by 13 themes and 34 sub-themes. These themes are generated based upon 419 articles (2000-2017) from more than 40 leading journals. The authors discuss the facet-specific key implications for guiding the literature in its further advancement, and thus propose a rigorous thematic landscape of the SSCM literature with a unique approach. Overall, the outcomes of this review provide a fundamental organization of the SSCM literature – from the perspective of a journey involved in the transition from traditional to sustainable supply chains.
Is independence really an opportunity? The experience of entrepreneur-mothers
Authors: Foley Meraiah , Baird Marian , Cooper Rae , Williamson Sue
Published: February 2018

Purpose

The purpose of this paper is to explore how entrepreneur-mothers experience independence in the transition to entrepreneurship, and whether they perceive independence as an agentic, opportunity-maximisation motive or a constrained, necessity-driven response.

Design/methodology/approach

Adopting a qualitative and interpretive approach, the authors analysed interviews with 60 entrepreneur-mothers to refine conceptual understanding of independence.

Findings

The authors find that entrepreneur-mothers experience independence not as an opportunity, but as a functional necessity in managing the temporal and perceived moral demands of motherhood. The authors assert that there is a fundamental difference between wanting independence to pursue a more autonomous lifestyle, and needing independence to attend to family obligations, a difference that is not adequately captured in the existing conceptualisation of independence. Consequently, the authors propose the classification of “family-driven entrepreneurship” to capture the social and institutional factors that may disproportionately push women with caregiving responsibilities towards self-employment.

Practical implications

This paper proposes that a new category of entrepreneurial motivation be recognised to better account for the social and institutional factors affecting women’s entrepreneurship, enabling policymakers to more accurately position and support entrepreneur-mothers.

Social implications

The authors challenge the existing framing of independence as an agentic opportunity-seeking motive, and seek to incorporate family dynamics into existing entrepreneurial models.

Originality/value

This paper delivers much-needed conceptual refinement of independence as a motivator to entrepreneurship by examining the experiences of entrepreneur-mothers, and proposes a new motivational classification, that of family-driven entrepreneurship to capture the elements of agency and constraint embedded in this transition.
A sensitive flower: mechanical stimulation induces rapid flower closure in Drosera spp. (Droseraceae)
Authors: Tagawa Kazuki , Watanabe Mikio , Yahara Tetsukazu
Published: February 2018

Some plants rapidly close their leaves in response to mechanical stimulation, but no case is known in which mechanical stimulation causes rapid petal closure. In this study, we found that Drosera tokaiensis closes petals within 2–10 min after experimental stimulation of the calyx, closed flowers or scapes with a pair of tweezers. Although petal closure was induced more rapidly by touching a position closer to a flower, it was not induced by stimulating stamens and pistils. The habit of petal closure varies among species of Drosera: after experimental stimulations of the calyx or scapes, D. tokaiensis and D. spatulata often closed petals but D. rotundifolia and D. toyoakensis did not close them. The petal closure may function as defense against a specialist florivore.
VPS9 domain‐containing proteins are essential for autophagy and endocytosis in Pyricularia oryzae
Authors: Zhu Xue‐Ming , Liang Shuang , Shi Huan‐Bin , Lu Jian‐Ping , Dong Bo , Liao Qian‐Sheng , Lin Fu‐Cheng , Liu Xiao‐Hong
Published: February 2018

Pyricularia oryzae is the causal pathogen of rice blast disease. Autophagy has been shown to play important roles in P. oryzae development and plant infection. The P. oryzae endosomal system is highly dynamic and has been shown to be associated with conidiogenesis and pathogenicity as well. To date, the crosstalk between autophagy and endocytosis has not been explored in P. oryzae. Here, we identified three P. oryzae VPS9 domain‐containing proteins, PoVps9, PoMuk1 and PoVrl1. We found that PoVps9 and PoMuk1 are localized to vesicles and are each co‐localized with PoVps21, a recognized marker of early endosomes. Deletion of PoVPS9 resulted in severe defects in endocytosis and autophagosome degradation and impaired the localization of PoVps21 to endosomes. Additionally, deletion of the PoMUK1 gene in the ΔPovps9 mutant background exhibited more severe defects in development, autophagy and endocytosis compared with the ΔPovps9 mutant. Pull‐down assay showed that PoVps9 interacts with PoVps21, PoRab11 and PoRab1, which have been verified to participate in endocytosis. Furthermore, yeast two‐hybrid and co‐immunoprecipitation assays confirmed that PoVps9 directly interacts with the GDP form of PoVps21. Thus, PoVps9 is a key protein involved in autophagy and in endocytosis.
Responses to warnings about the impact of eating disorders on fertility: a qualitative study
Authors: Holmes Su
Published: February 2018

Eating disorders (EDs) have often been discussed as a risk to reproductive health. But existing research is quantitative in nature, paying no attention to issues of patient experience. In discussing data from 24 semi‐structured interviews, this article draws on sociological approaches to medical ‘risk’ and feminist approaches toEDs to explore how women with experience of anEDresponded to fertility warnings within treatment contexts. In doing so, it is suggested that responses to fertility warnings offer unique insight into the potentially damaging limitations of biomedical approaches to eating problems and their focus onEDs as individual ‘pathologies’ (rather than culturally embedded expressions of gendered embodiment). At best warnings are seen as making problematic assumptions about the aspirations of female patients, which may curtail feelings of agency and choice. At worst, they may push women further into destructive bodily and eating practices, and silence the distress that may be articulated by anED.
The career aspirations and expectations of geography doctoral students: establishing academic subjectivities within a shifting landscape
Authors: Dufty‐Jones Rae
Published: February 2018

The PhD forms a watershed period where candidates' professional identities are formed, and their career aspirations and expectations are developed. Yet little is known about Australian geography doctoral students' career aspirations and expectations. Drawing on findings from a 2016 survey of those students, the paper establishes that while a majority of students aspire to work in academia, many also feel quite pessimistic about their prospects of being able to do so. The paper argues that the uncertainty and anxiety that many Australian geography doctoral students feel about their future careers is the product of a wider cultural shift that is occurring in relation to the purpose of the research doctorate. Geographers need to critically engage with these changes and the academic subjectivities they are producing to ensure that, as a discipline, geography continues to make a positive contribution to the careers of the individuals who undertake these degrees.