bluuebunny/crossref_metadata_2025 huggingface dataset:
The role of serologic testing for Zika virus infection
Authors: Tran Anthony , Theel Elitza S.
Published: December 2017

Direct detection of Zika virus (ZIKV) nucleic acid with nucleic acid tests is definitive laboratory evidence of infection. Initial studies suggest that the ZIKV viremic period is limited, leading the Centers for Disease Control and Prevention to recommend that nucleic acid tests be utilized only up to 14 days postsymptom onset in serum and urine. The host immune response to flaviviruses, including to ZIKV, primarily targets the viral envelope (E) protein, which has three main domains (ED I–III). Recent studies suggest that neutralizing antibodies against the EDIII domain are relatively specific and potentially able to discriminate between ZIKV and dengue virus, which share 29% amino acid homology at that region. Comparatively, neutralizing antibodies to EDI and EDII, with amino acid homologies of 35 and 51% between these two viruses, respectively, are highly cross-reactive and likely responsible for the nonspecific reactions observed in the respective serologic assays.

The current article describes the humoral immune response to ZIKV, reviews serologic assays for detection of antibodies to ZIKV, discusses performance characteristics of commercially available tests, and summarizes the strengths and limitations of currently available serologic methods. Assays examined in the review include the Centers for Disease Control and Prevention Zika IgM antibody capture ELISA, InBios ZIKV Detect IgM Capture ELISA, DiaSorin, LIAISON XL Zika Capture IgM Assay, Euroimmun anti-ZIKV IgM ELISA, and plaque reduction neutralization tests. Despite the availability of multiple diagnostic tests, there remains a need for modified and novel testing strategies, including the potential use of multiple enzyme immunoassays either in parallel or sequentially and IgG in addition to IgM determination.
Management of Intussusception in the Pediatric Emergency Department
Authors: Vo Andrea , Levin Terry L. , Taragin Benjamin , Khine Hnin
Published: December 2017

Background

The standard treatment for intussusception is air reduction enema (ARE) with inpatient observation for 24 to 48 hours to monitor for recurrence. More recent but limited observations suggest that patients who have undergone successful ARE can safely be discharged after 4 to 6 hours of observation. Our primary objective was to identify risk factors associated with early recurrence. Our secondary objectives included validating risk criteria from prior studies and identifying risk factors for ARE failures.

Design/Methods

A retrospective cohort study of children discharged from a large urban quaternary hospital with a final diagnosis of intussusception (International Classification of Diseases, Ninth Revision, code 560.0) or who underwent ARE from 2005 to 2015 was identified. Demographic data, radiology images, and clinical course were recorded. Repeat visits, cases with incomplete medical records, and those with incorrect diagnoses were excluded.

Results

A total of 250 cases were identified. Two hundred cases were included for analysis. Fifty were excluded. Of the 163 who had successful reduction with ARE, 22 patients (13.5%) recurred, and 12 (7.3%) recurred within 48 hours. Fever (odds ratio, 4.25; P = 0.04; 95% confidence interval, 1.04–17.3) and female sex (odds ratio, 7.94; P = 0.01; 95% confidence interval, 1.82–34.6) were independently associated with early recurrence. No radiologic features were associated with early recurrence.

Conclusions

Early recurrence after successful ARE was low, although more frequent in girls and in those with fever over 100.4°F. We therefore advocate for prospective studies to validate these risk criteria to identify patients who are at low risk for early recurrence and may qualify for early discharge from the emergency department.
Comparison Between Effectiveness of Ultrasound-Guided Corticosteroid Injection Above Versus Below the Median Nerve in Mild to Moderate Carpal Tunnel Syndrome
Authors: Babaei-Ghazani Arash , Nikbakht Nadere , Forogh Bijan , Raissi Gholam Reza , Ahadi Tannaz , Ebadi Safoora , Roomizadeh Peyman , Fadavi Hamid Reza , Raeissadat Seyed Ahmad , Eftekharsadat Bina
Published: December 2017

Objective

In this study, the clinical effectiveness of ultrasound-guided corticosteroid injection “above” versus “below” the median nerve for treatment of patients with mild to moderate carpal tunnel syndrome was compared.

Design

This prospective randomized double-blind clinical trial included 44 patients with mild to moderate carpal tunnel syndrome. The subjects were randomly assigned to two groups to receive ultrasound-guided injection of 40 mg of triamcinolone either “above” or “below” the involved median nerve. Outcome measures were the Boston Carpal Tunnel Questionnaire, visual analog scale, electrophysiological tests, and ultrasonographic measurement of the median nerve cross-sectional area at baseline, 6, and 12 wks after the injection.

Results

All outcome measures improved significantly in both groups at 6 wks after intervention, and these improvements were persevered up to 12 wks of follow-up (all P values <0.05). However, there was no significant difference in measured outcomes between the two groups. No adverse effects were observed.

Conclusions

Both above and under median nerve ultrasound-guided steroid injection techniques were effective in reducing the symptoms, improving the function, and improving electrodiagnostic and sonographic findings of carpal tunnel syndrome. However, the amount of improvement in the outcomes did not differ between groups, implying that none of technique has the superiority over another.
The Impact of Osteoarthritis on the Functioning and Health Status of a Low-Income Population
Authors: Esquivel-Valerio Jorge A. , Orzua-de la Fuente Wendy Marisol , Vázquez-Fuentes Brenda R. , Garza-Elizondo Mario Alberto , Negrete-López Roberto , Treviño-Montes Daniel O. , Martínez-Villarreal Rebeca Thelma , Rodríguez-Amado Jaqueline , Peláez-Ballestas Ingris , Loyola-Sánchez Adalberto
Published: December 2017

Objective

The aim of this study was to measure the impact of osteoarthritis on the functioning and health status of individuals living in a low-income urban community in Mexico.

Methods

We conducted a cross-sectional, community-based study from December 2014 to November 2015, using the Community Oriented Program for Control of Rheumatic Diseases methodology to identify cases of musculoskeletal disease in a sample of adults older than 18 years in Pueblo Nuevo, Apodaca, Mexico. Two rheumatologists confirmed all cases of osteoarthritis (OA) using predefined criteria. Functioning was evaluated through (a) self-report of difficulty doing personal care, work, and leisure activities; (b) the modified Stanford Health Assessment Questionnaire–Disability Index; and (c) the Timed Up and Go test. Health status was evaluated using the EuroQoL 5 Dimensions. Statistical analyses were performed using χ2 tests and logistic regression models.

Results

Four hundred thirty-nine individuals with a mean age of 45.2 years were included, and 83 cases of OA were confirmed. The presence of OA was not significantly associated with having difficulties to do personal care, work, or leisure activities, but it was significantly associated with a higher Health Assessment Questionnaire–Disability Index score, longer time to complete the Timed Up and Go, and lower health status.

Conclusions

Osteoarthritis is associated with having higher disability and worse health status in the community studied. A disability paradox was detected as some individuals perceived disability for doing standard activities but did not present disability performing their real-life activities. This underlies the importance of addressing the mental dimension during the management of this population.
Incidence of Antidrug Antibodies in Rheumatoid Arthritis Patients From Argentina Treated With Adalimumab, Etanercept, or Infliximab in a Real-World Setting
Authors: Maid Pablo J. , Xavier Ricardo , Real Rosa M. , Pedersen Ron , Shen Qi , Marshall Lisa , Solano Gaston , Borlenghi Cecilia Elena , Hidalgo Rodolfo Pardo
Published: December 2017

Background

Biologic agents may induce immune responses that could impact drug action.

Objectives

The aims of this study were to assess antidrug antibodies (ADAs) in patients with rheumatoid arthritis (RA) from Argentina treated with etanercept, adalimumab, or infliximab at a single visit and correlate it with efficacy outcomes.

Methods

In this subset analysis of a noninterventional, multinational, cross-sectional study (NCT01981473), adult patients with RA treated continuously for 6 to 24 months with etanercept, adalimumab, or infliximab were evaluated for ADAs and trough drug concentrations of 2 days or less prior to the next scheduled dose. Efficacy measurements included Disease Activity Score based on a 28-joint count–erythrocyte sedimentation rate, low disease activity, and Health Assessment Questionnaire—Disability Index. Targeted medical history of injection site/infusion reactions, serum sickness, and thromboembolic events were reported.

Results

Baseline demographics, disease characteristics, and duration of treatment of the 119 patients (etanercept: n = 54, adalimumab: n = 52, infliximab: n = 13) were similar across all groups. No etanercept-treated patient tested positive for ADAs compared with 19 (36.5%) of 52 patients and 4 (30.8%) of 13 patients treated with adalimumab and infliximab, respectively. In adalimumab- and infliximab-treated patients, ADA presence correlated negatively with trough drug levels. A greater proportion of ADA-negative patients achieved Health Assessment Questionnaire—Disability Index of 0.5 or less and had better composite efficacy measures compared with ADA-positive patients. The rate of targeted medical events reported was low.

Conclusions

In this subset analysis, RA patients from Argentina treated with adalimumab or infliximab, but not etanercept, tested positive for ADAs. Antidrug antibody–negative patients showed a tendency toward better clinical outcomes compared with ADA-positive patients.
Cross-sectional Areas of the Thoracic Aorta in Children and Adolescents With Repaired Tetralogy of Fallot Obtained by Cardiac Magnetic Resonance Angiography
Authors: Gräfe Daniel , Gutberlet Matthias , Mende Meinhard , Dähnert Ingo , Lücke Christian , Kostelka Martin , Nitzsche Stefan , Hoffmann Janine , Grothoff Matthias
Published: December 2017

Purpose:

Dilatation of the thoracic aorta is a well-known finding in corrected Tetralogy of Fallot. Complications are rare but can be life-threatening. Standard 1-dimensional (1D) measurements have several limitations. We sought to establish contrast-enhanced magnetic resonance angiography cross-sectional areas of the aorta that could serve as reference values and to identify parameters that are associated with aortic dilatation.

Materials and Methods:

We enrolled 101 children and adolescents. The aortic areas were measured at the level of the aortic sinus (AS), the sinotubular junction (STJ), the ascending aorta (AA), the brachiocephalic trunk (TBC), and the descending aorta (DA). Sex-specific aortic dimensions were presented as percentile curves as well as regression equations. Furthermore volumetric and functional parameters as well as clinical data were analyzed to identify parameters that are associated with aortic dilatation.

Results:

Aortic areas (mm2) for female subjects were 139+366×body surface area (BSA) for the AS, 134+255×BSA for the STJ, 113+239×BSA for the AA, 88+185×BSA proximal to the TBC, and 2.9+88×BSA for the DA. Aortic areas (mm2) for male subjects were 162+403×BSA for the AS, 171+258×BSA for the STJ, 151+233×BSA for the AA, 73+206×BSA proximal to the TBC, and 21+80×BSA for the DA. The postoperative interval and age at examination were parameters associated with aortic size.

Conclusions:

We provide aortic areas in children and adolescents after correction of Tetralogy of Fallot measured by contrast-enhanced magnetic resonance angiography. Our 2D data may better depict the geometry of enlarged aortae than standard 1D diameters and serve as reference values for evaluating aortic disease in these patients.
Pelvic Organ Prolapse Repair Using the Uphold Vaginal Support System: 5-Year Follow-Up
Authors: Rahkola-Soisalo Päivi , Mikkola Tomi S. , Altman Daniel , Falconer Christian
Published: December 2017

Objective

This study aimed to assess the long-term (5 years) outcomes of the Uphold Vaginal Support System for symptomatic vaginal apical prolapse with or without anterior colporraphy.

Methods

In total, 164 (81.2%) of 202 women operated on in 24 centers were reached for follow-up. Outcomes were assessed by using the Pelvic Organ Prolapse Quantification, the Pelvic Floor Distress Inventory 20, and the Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire questionnaires. Pain on pelvic area was evaluated using a visual analog scale. Adverse events and secondary procedures were recorded.

Results

An optimal outcome at the apical compartment (Pelvic Organ Prolapse Quantification stage <2) was achieved in 83.3% of patients (94% at 1 year). Quality of life improved in 78.8% of the women, with a significant decrease of bother in all domains (pelvic organ prolapse, rectoanal, urinary) compared with that preoperatively. Overall sexual satisfaction improved after 1 year, but the number of sexually active women was low. In total, 19.7% of patients had undergone repeat pelvic surgery during follow-up, most common of these were midurethral sling (38.4%), followed by prolapse-related operations. Mesh removal due to pain was performed in 3 women. Number of women with any pain decreased overall from 1 to 5 years, but 3 women had persistent severe pain despite treatment efforts (visual analog scale ≥7).

Conclusions

Apical objective and subjective outcomes were sustained after 5 years in women operated on for apical compartment prolapse by the Uphold Vaginal Support System.
System drift and speciation
Authors: Schiffman Josh S , Ralph Peter L
Published: December 2017

Even if a species’ phenotype does not change over evolutionary time, the underlying mechanism may change, as distinct molecular pathways can realize identical phenotypes. Here we use linear system theory to explore the consequences of this idea, describing how a gene network underlying a conserved phenotype evolves, as the genetic drift of small changes to these molecular pathways cause a population to explore the set of mechanisms with identical phenotypes. To do this, we model an organism’s internal state as a linear system of differential equations for which the environment provides input and the phenotype is the output, in which context there exists an exact characterization of the set of all mechanisms that give the same input–output relationship. This characterization implies that selectively neutral directions in genotype space should be common and that the evolutionary exploration of these distinct but equivalent mechanisms can lead to the reproductive incompatibility of independently evolving populations. This evolutionary exploration, or system drift, is expected to proceed at a rate proportional to the amount of intrapopulation genetic variation divided by the effective population size (Ne). At biologically reasonable parameter values this could lead to substantial interpopulation incompatibility, and thus speciation, on a time scale of Ne generations. This model also naturally predicts Haldane’s rule, thus providing a concrete explanation of why heterogametic hybrids tend to be disrupted more often than homogametes during the early stages of speciation.
Robust parallel decision-making in neural circuits with nonlinear inhibition
Authors: Kriener Birgit , Chaudhuri Rishidev , Fiete Ila R.
Published: December 2017

Identifying the maximal element (max,argmax) in a set is a core computational element in inference, decision making, optimization, action selection, consensus, and foraging. Running sequentially through a list of N fluctuating items takes N log(N) time to accurately find the max, prohibitively slow for large N. The power of computation in the brain is ascribed in part to its parallelism, yet it is theoretically unclear whether leaky and noisy neurons can perform a distributed computation that cuts the required time of a serial computation by a factor of N, a benchmark for parallel computation. We show that conventional winner-take-all neural networks fail the parallelism benchmark and in the presence of noise altogether fail to produce a winner when N is large. We introduce the nWTA network, in which neurons are equipped with a second nonlinearity that prevents weakly active neurons from contributing inhibition. Without parameter fine-tuning or re-scaling as the number of options N varies, the nWTA network converges N times faster than the serial strategy at equal accuracy, saturating the parallelism benchmark. The nWTA network self-adjusts integration time with task difficulty to maintain fixed accuracy without parameter change. Finally, the circuit generically exhibits Hick's law for decision speed. Our work establishes that distributed computation that saturates the parallelism benchmark is possible in networks of noisy, finite-memory neurons.
VlbZIP30 of grapevine functions in drought tolerance via the abscisic acid core signaling pathway
Authors: Tu Mingxing , Wang Xianhang , Zhu Yanxun , Wang Dejun , Zhang Xuechuan , Cui Ye , Li Yajuan , Gao Min , Li Zhi , Wang Xiping
Published: December 2017

Drought stress limits the growth and development of grapevines, thereby reducing productivity, but the mechanisms by which grapevines respond to drought stress remain largely uncharacterized. Here, we characterized a group A bZIP gene from ‘Kyoho’ grapevine, VlbZIP30, which was shown to be induced by abscisic acid (ABA) and dehydration stress. Overexpression of VlbZIP30 in transgenic Arabidopsis enhanced dehydration tolerance during seed germination, and in the seedling and adult stages. Transcriptome analysis revealed that a major proportion of ABA- and/or drought-responsive genes are transcriptionally regulated by VlbZIP30 during ABA or mannitol treatment at the cotyledon greening stage. We identified an A. thaliana G-box motif (CACGTG) and a potential grapevine G-box motif (MCACGTGK) in the promoters of the 39 selected A. thaliana genes up-regulated in the transgenic plants and in the 35 grapevine homologs, respectively. Subsequently, using two grapevine-related databases, we found that 74% and 84% (a total of 27 genes) of the detected grapevine genes were significantly up-regulated by ABA and drought stress, respectively, suggesting that these 27 genes involve in ABA or dehydration stress and may be regulated by VlbZIP30 in grapevine. We propose that VlbZIP30 functions as a positive regulator of drought-responsive signaling in the ABA core signaling pathway.

Highlight

VlbZIP30 positively regulate plant drought tolerance through regulated the expression of 27 grapevine candidate genes via G-box cis-element (MCACGTGK) in ABA signaling pathway.
Rarefaction, alpha diversity, and statistics
Authors: Willis Amy
Published: December 2017

Understanding the drivers of microbial diversity is a fundamental question in microbial ecology. Extensive literature discusses different methods for describing microbial diversity and documenting its effects on ecosystem function. However, it is widely believed that diversity depends on the number of reads that are sequenced. I discuss a statistical perspective on diversity, framing the diversity of an environment as an unknown parameter, and discussing the bias and variance of plug-in and rarefied estimates. I argue that by failing to account for both bias and variance, we invalidate analysis of alpha diversity. I describe the state of the statistical literature for addressing these problems, and suggest that measurement error modeling can address issues with variance, but bias corrections need to be utilized as well. I encourage microbial ecologists to avoid motivating their investigations with alpha diversity analyses that do not use valid statistical methodology.
Two conceptions of evolutionary games: reductive vs effective
Authors: Kaznatcheev Artem
Published: December 2017

Evolutionary game theory (EGT) was born from economic game theory through a series of analogies. Given this heuristic genealogy, a number of central objects of the theory (like strategies, players, and games) have not been carefully defined or interpreted. A specific interpretation of these terms becomes important as EGT sees more applications to understanding experiments in microscopic systems typical of oncology and microbiology. In this essay, I provide two interpretations of the central objects of games theory: one that leads to reductive games and the other to effective games. These interpretation are based on the difference between views of fitness as a property of individuals versus fitness as a summary statistic of (sub)populations. Reductive games are typical of theoretical work like agent-based models. But effective games usually correspond more closely to experimental work. However, confusing reductive games for effective games or vice-versa can lead to divergent results, especially in spatially structured populations. As such, I propose that we treat this distinction carefully in future work at the interface of EGT and experiment.
Molecular map of GNAO1-related disease phenotypes and reactions to therapy
Authors: Mihalek Ivana , Waugh Jeff L. , Park Meredith , Kayani Saima , Poduri Annapurna , Bodamer Olaf
Published: December 2017

The GNAO1 gene codes for the most commonly expressed Gαprotein in the central nervous system. Pathogenic GNAO1 variants result in early-onset neurological phenotypes, sometimes with distinct epilepsy or movement disorder, and sometimes with both mani-festations in the same patient. The existing extensive knowledge about G-protein coupled receptor (GPCR) signaling provides the input needed to describe quantitatively how mutations modify the GPCR signal. This in turn allows rational interpretation of distinct phenotypes arising from mutations in GNAO1. In this work we outline a model that enables understanding of clinical phenotypes at a molecular level. The mutations affecting the catalytic pocket of GNAO1, we show, result in the improper withdrawal of the signal, and give rise to epileptic phenotypes (EPs). The converse is not true - some pure EPs are caused by mutations with no obvious impact on catalysis. Mutations close to the interface with GNAO1’s downstream effector block the signal propagation in that direction, and manifest as a movement disorder phenotype without epilepsy. Quantifying the reported reaction to therapy highlights the tendency of the latter group to be unresponsive to the therapies currently in use. We argue, however, that the majority of clinically described mutations can impact several aspects of GNAO1 function at once, resulting in the continuum of phenotypes observed in patients. The reasoning based on GNAO1 signaling model provides a precision medicine paradigm to aid clinicians in selecting effective categories of medication, and in addition, can suggest pragmatic targets for future therapies.
Differential medial temporal lobe and default-mode network functional connectivity and morphometric changes in Alzheimer’s Disease
Authors: Grajski Kamil A. , Bressler Steven L. ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: December 2017

We report group level differential detection of medial temporal lobe resting-state functional connectivity disruption and morphometric changes in the transition from cognitively normal to early mild cognitive impairment in an age-, education- and gender-matched 105 subjects Alzheimer’s Disease Neuroimaging Initiative dataset. In mild Alzheimer’s Disease, but not early mild cognitive impairment, characteristic brain atrophy was detected in FreeSurfer estimates of cortical thickness and subcortical and hippocampal subfield volumes. By contrast, functional connectivity analysis detected earlier significant changes. In early mild cognitive impairment these changes involved medial temporal lobe regions of transentorhinal, perirhinal and entorhinal cortices (associated with the earliest stages of neurofibrillary changes in Alzheimer’s Disease), hippocampus, parahippocampal gyrus and temporal pole, and cortical regions comprising or co-activated with the default-mode network, including rostral and medial prefrontal cortex, anterior cingulate cortex, precuneus and inferior temporal cortex. Key findings include: a) focal and bilaterally symmetric spatial organization of affected medial temporal lobe regions; b) mutual hyperconnectivity bilaterally involving ventral medial temporal lobe structures (temporal pole, uncus); and c) dorsal medial temporal lobe hypoconnectivity with anterior and posterior midline default-mode network nodes. These findings position medial temporal lobe resting state functional connectivity as a candidate biomarker of an Alzheimer’s Disease pathophysiological cascade, potentially in advance of clinical biomarkers, and coincident with biomarkers of the earliest stages of Alzheimer’s neuropathology. Our results indicate that medial temporal lobe resting-state functional connectivity should be further investigated as a potential biomarker in the diagnosis of Alzheimer’s Disease.

Highlights

Functional connectivity change seen before structural change in Alzheimer’s Disease

Medial temporal lobes mutually hyper-connect in mild cognitive impairment

Medial temporal lobe and default mode network decouple in mild cognitive impairment

Loci of functional change in hippocampi are focal with bilaterally symmetric features

Nonmonotonic functional connectivity changes in Alzheimer’s Disease progression
Pivotal roles of PCNA loading and unloading on heterochromatin function
Authors: Janke Ryan , King Grant , Kupiec Martin , Rine Jasper
Published: December 2017

InSaccharomyces cerevisiae, heterochromatin structures required for transcriptional silencing of theHMLandHMRloci are duplicated in coordination with passing DNA replication forks. Despite major reorganization of chromatin structure, the heterochromatic, transcriptionally-silent states ofHMLandHMRare successfully maintained throughout S-phase. Mutations of specific components of the replisome diminish the capacity to maintain silencing ofHMLandHMRthrough replication. Similarly, mutations in histone chaperones involved in replication-coupled nucleosome assembly reduce gene silencing. Bridging these observations, we determined that the PCNA unloading activity of Elg1 was important for coordinating DNA replication forks with the process of replication-coupled nucleosome assembly to maintain silencing ofHMLandHMRthrough S-phase. Collectively these data identified a mechanism by which chromatin reassembly is coordinated with DNA replication to maintain silencing through S-phase.

SIGNIFICANCE STATEMENT

DNA replication poses a unique logistical challenge for the cell in that structural features of chromatin and their regulatory functions must be carefully coordinated with passage of replication machinery so faithful duplication of both the genome and its chromatin structures may be achieved. Nucleosome assembly is fundamental to reestablishment of chromatin in the wake of DNA replication, and here a mechanism by which nucleosome assembly is coordinated with DNA replication to maintain silenced chromatin is described.
“TRIF is a key inflammatory mediator of acute sickness behavior and cancer cachexia”
Authors: Burfeind Kevin G. , Zhu Xinxia , Levasseur Peter R. , Michaelis Katherine A. , Norgard Mason A. , Marks Daniel L.
Published: December 2017

Hypothalamic inflammation is a key component of acute sickness behavior and cachexia, yet mechanisms of inflammatory signaling in the central nervous system remain unclear. We assessed the role of TRIF signaling in acute inflammation (lipopolysaccharide (LPS) challenge) and in a chronic inflammatory state (cancer cachexia). TRIFKO mice resisted anorexia and weight loss after peripheral (intraperitoneal, IP) or central (intracerebroventricular, ICV) LPS challenge and in a model of pancreatic cancer cachexia. Compared to WT mice, TRIFKO mice showed attenuated upregulation of Il6, Ccl2, Ccl5, Cxcl1, Cxcl2, and Cxcl10 in the hypothalamus after IP LPS treatment, as well as attenuated microglial activation and neutrophil infiltration into the brain after ICV LPS treatment. Our results show that TRIF is an important inflammatory signaling mediator of sickness behavior and cachexia and presents a novel therapeutic target for these conditions.
Cell-wall synthesis and ribosome maturation are co-regulated by an RNA switch in Mycobacterium tuberculosis
Authors: Schwenk Stefan , Moores Alexandra , Nobeli Irene , McHugh Timothy D. , Arnvig Kristine B.
Published: December 2017

The success of Mycobacterium tuberculosis as a pathogen relies on the ability to switch between active growth and non-replicating persistence, associated with latent TB infection. Resuscitation promoting factors (Rpfs) are essential for the transition of M. tuberculosis to dormancy and for emergence from the non-replicating persistent state. But these enzymes are double-edged swords, as their ability to degrade the cell wall, is potentially lethal to the bacterium itself. Hence, Rpf expression is tightly regulated. We have identified a novel regulatory element in the 5’ untranslated region (UTR) of rpfB. We demonstrate that this element is a transcriptionally regulated RNA switch/riboswitch candidate, which is restricted to pathogenic mycobacteria, suggesting a role in virulence. Moreover, we have used translation start site mapping to re-annotate the RpfB start codon and identified and validated a ribosome binding site that is likely to be targeted by an RpfB antisense RNA. Finally, we show that rpfB is co-transcribed with downstream genes, ksgA and ispE. ksgA encodes a universally conserved methyl transferase involved in ribosome maturation and ispE encodes an essential ATP-dependent kinase involved in cell wall synthesis. This arrangement implies co-regulation of resuscitation, cell wall synthesis and ribosome maturation via the RNA switch. We propose that deregulation of this switch, associated with cell wall synthesis and ribosome function, presents a new target for anti-tuberculosis drug development.

Importance

This work describes the identification and characterisation of a novel regulatory RNA element/attenuator that controls cell wall synthesis and ribosome function in Mycobacterium tuberculosis, the causative agent of human tuberculosis (TB). By switching between two different conformations, this RNA switch can either enable or inhibit transcription of a tri-cistronic mRNA that encodes a cell-wall remodelling enzyme crucial for activation of latent TB, an RNA methytransferase that is important for ribosome function and a protein kinase essential for early steps in cell wall synthesis. This RNA switch is only present in a subset of pathogenic mycobacteria, and by regulating the expression of three genes associated with classical antimicrobial targets we believe that it offers a novel important target for future anti-tuberculosis drugs.
An attenuated CRISPR-Cas system in Enterococcus faecalis permits DNA acquisition
Authors: Hullahalli Karthik , Rodrigues Marinelle , Nguyen Uyen Thy , Palmer Kelli
Published: December 2017

Antibiotic resistant bacteria are critical public health concerns. Among the prime causative factors for the spread of antibiotic resistance is horizontal gene transfer (HGT). A useful model organism for investigating the relationship between HGT and antibiotic resistance is the opportunistic pathogen Enterococcus faecalis, since the species possesses highly conjugative plasmids that readily disseminate antibiotic resistance genes and virulence factors in nature. Unlike many commensal E. faecalis strains, the genomes of multidrug-resistant (MDR) E. faecalis clinical isolates are enriched for mobile genetic elements (MGEs) and lack CRISPR-Cas genome defense systems. CRISPR-Cas systems cleave foreign DNA in a programmable, sequence-specific manner and are disadvantageous for MGE-derived genome expansion. An unexplored facet of CRISPR biology in E. faecalis is that MGEs that are targeted by native CRISPR-Cas systems can be transiently maintained. Here, we investigate the basis for this “CRISPR tolerance.” We observe that E. faecalis can maintain self-targeting constructs that direct Cas9 to cleave the chromosome, but at a fitness cost. Interestingly, DNA repair genes were not up-regulated during self-targeting, but integrated prophages were strongly induced. We determined that low cas9 expression contributes to this transient non-lethality and use this knowledge to develop a robust CRISPR-assisted genome editing scheme. Our results suggest that E. faecalis has maximized the potential for DNA acquisition by attenuating its CRISPR machinery, thereby facilitating acquisition of potentially beneficial MGEs that may otherwise be restricted by genome defense.

Importance

CRISPR-Cas has provided a powerful toolkit to manipulate bacteria, resulting in improved genetic manipulations and novel antimicrobials. These powerful applications rely on the premise that CRISPR-Cas chromosome targeting, which leads to double-stranded DNA breaks, is lethal. In this study, we show that chromosomal CRISPR targeting in Enterococcus faecalis is transiently non-lethal. We uncover novel phenotypes associated with this “CRISPR tolerance” and, after determining its genetic basis, develop a genome editing platform in E. faecalis with negligible off-target effects. Our findings reveal a novel strategy exploited by a bacterial pathogen to cope with CRISPR-induced conflicts to more readily accept DNA, and our robust CRISPR editing platform will help simplify genetic modifications in this organism.
DNA mismatch repair preferentially protects genes from mutation
Authors: Belfield Eric J. , Ding Zhong Jie , Jamieson Fiona J.C. , Visscher Anne M. , Zheng Shao Jian , Mithani Aziz , Harberd Nicholas P.
Published: December 2017

Mutation is the source of genetic variation and fuels biological evolution. Many mutations first arise as DNA replication errors. These errors subsequently evade correction by cellular DNA repair, for example, by the well-known DNA mismatch repair (MMR) mechanism. Here, we determine the genome-wide effects of MMR on mutation. We first identify almost 9000 mutations accumulated over five generations in eight MMR-deficient mutation accumulation (MA) lines of the model plant species, Arabidopsis thaliana. We then show that MMR deficiency greatly increases the frequency of both smaller-scale insertions and deletions (indels) and of single-nucleotide variant (SNV) mutations. Most indels involve A or T nucleotides and occur preferentially in homopolymeric (poly A or poly T) genomic stretches. In addition, we find that the likelihood of occurrence of indels in homopolymeric stretches is strongly related to stretch length, and that this relationship causes ultrahigh localized mutation rates in specific homopolymeric stretch regions. For SNVs, we show that MMR deficiency both increases their frequency and changes their molecular mutational spectrum, causing further enhancement of the GC to AT bias characteristic of organisms with normal MMR function. Our final genome-wide analyses show that MMR deficiency disproportionately increases the numbers of SNVs in genes, rather than in nongenic regions of the genome. This latter observation indicates that MMR preferentially protects genes from mutation and has important consequences for understanding the evolution of genomes during both natural selection and human tumor growth.
Deep experimental profiling of microRNA diversity, deployment, and evolution across the Drosophila genus
Authors: Mohammed Jaaved , Flynt Alex S. , Panzarino Alexandra M. , Mondal Md Mosharrof Hossain , DeCruz Matthew , Siepel Adam , Lai Eric C.
Published: December 2017

To assess miRNA evolution across the Drosophila genus, we analyzed several billion small RNA reads across 12 fruit fly species. These data permit comprehensive curation of species- and clade-specific variation in miRNA identity, abundance, and processing. Among well-conserved miRNAs, we observed unexpected cases of clade-specific variation in 5′ end precision, occasional antisense loci, and putatively noncanonical loci. We also used strict criteria to identify a large set (649) of novel, evolutionarily restricted miRNAs. Within the bulk collection of species-restricted miRNAs, two notable subpopulations are splicing-derived mirtrons and testes-restricted, recently evolved, clustered (TRC) canonical miRNAs. We quantified miRNA birth and death using our annotation and a phylogenetic model for estimating rates of miRNA turnover. We observed striking differences in birth and death rates across miRNA classes defined by biogenesis pathway, genomic clustering, and tissue restriction, and even identified flux heterogeneity among Drosophila clades. In particular, distinct molecular rationales underlie the distinct evolutionary behavior of different miRNA classes. Mirtrons are associated with high rates of 3′ untemplated addition, a mechanism that impedes their biogenesis, whereas TRC miRNAs appear to evolve under positive selection. Altogether, these data reveal miRNA diversity among Drosophila species and principles underlying their emergence and evolution.
Integrated analysis of motif activity and gene expression changes of transcription factors
Authors: Madsen Jesper Grud Skat , Rauch Alexander , Van Hauwaert Elvira Laila , Schmidt Søren Fisker , Winnefeld Marc , Mandrup Susanne
Published: December 2017

The ability to predict transcription factors based on sequence information in regulatory elements is a key step in systems-level investigation of transcriptional regulation. Here, we have developed a novel tool, IMAGE, for precise prediction of causal transcription factors based on transcriptome profiling and genome-wide maps of enhancer activity. High precision is obtained by combining a near-complete database of position weight matrices (PWMs), generated by compiling public databases and systematic prediction of PWMs for uncharacterized transcription factors, with a state-of-the-art method for PWM scoring and a novel machine learning strategy, based on both enhancers and promoters, to predict the contribution of motifs to transcriptional activity. We applied IMAGE to published data obtained during 3T3-L1 adipocyte differentiation and showed that IMAGE predicts causal transcriptional regulators of this process with higher confidence than existing methods. Furthermore, we generated genome-wide maps of enhancer activity and transcripts during human mesenchymal stem cell commitment and adipocyte differentiation and used IMAGE to identify positive and negative transcriptional regulators of this process. Collectively, our results demonstrate that IMAGE is a powerful and precise method for prediction of regulators of gene expression.
A soft X-ray free-electron laser beamline at SACLA: the light source, photon beamline and experimental station
Authors: Owada Shigeki , Togawa Kazuaki , Inagaki Takahiro , Hara Toru , Tanaka Takashi , Joti Yasumasa , Koyama Takahisa , Nakajima Kyo , Ohashi Haruhiko , Senba Yasunori , Togashi Tadashi , Tono Kensuke , Yamaga Mitsuhiro , Yumoto Hirokatsu , Yabashi Makina , Tanaka Hitoshi , Ishikawa Tetsuya
Published: December 2017

The design and performance of a soft X-ray free-electron laser (FEL) beamline of the SPring-8 Compact free-electron LAser (SACLA) are described. The SPring-8 Compact SASE Source test accelerator, a prototype machine of SACLA, was relocated to the SACLA undulator hall for dedicated use for the soft X-ray FEL beamline. Since the accelerator is operated independently of the SACLA main linac that drives the two hard X-ray beamlines, it is possible to produce both soft and hard X-ray FEL simultaneously. The FEL pulse energy reached 110 µJ at a wavelength of 12.4 nm (i.e. photon energy of 100 eV) with an electron beam energy of 780 MeV.
The co-movement and causality between housing and stock markets in the time and frequency domains considering inflation
Authors: Fan Jiaojiao , Li Xin , Shi Qinghua , Su Chi-Wei
Published: December 2017

Purpose

The purpose of this paper is to examine the causal relationship between Chinese housing and stock markets. The authors discuss the three transmission mechanisms between the two markets: wealth effect, modern portfolio theory and credit-price effect. Moreover, the authors focus on the effects of inflation on the relationship between the two markets.

Design/methodology/approach

This paper uses wavelet analysis to test the housing and stock markets relationship both in the frequency domain and time domain.

Findings

The empirical results indicate that housing prices have a positive effect on stock prices, and these have the same effect on housing prices. Moreover, this positive effect means that stock prices have a wealth effect on housing prices and these have a credit-price effect on stock prices.

Research limitations/implications

These results provide information to financial institutions and individual investors in China to assist them in constructing investment portfolios within these two asset markets.

Originality/value

The authors first use wavelet analysis to analyze Chinese housing and stock markets and to provide information both on the frequency domain and time domain. Moreover, the authors take the inflation factor as a control variable in the causal relationship between the housing and stock markets.
The distinctive challenges and opportunities for creating leadership within social enterprises
Authors: Jackson Brad , Nicoll Matthew , Roy Michael J.
Published: December 2017

Purpose

The purpose of this study is to present a systematic assessment of the distinctive challenges and opportunities associated with creating leadership within the realm of social enterprise. A modified and expanded form of Grint’s leadership lenses heuristic framework (i.e. person, position, process, performance, purpose and place) is used to examine and highlight what is particular about creating leadership in social enterprises by virtue of their distinctive missions, strategic contexts, legal forms and organisational structures and cultures. Based on this initial exploration, five research priorities are identified to better understand and then develop leadership practice in the social enterprise realm.

Design/methodology/approach

An enhanced heuristic framework for systematically examining leadership within the social enterprise research literature has been applied, drawing on the leadership practice literature. The application is illustrated through six instrumental case studies.

Findings

While there are a number of similarities between leading in the social enterprise realm and leading within the private, public and not-for-profit sectors, the levels of complexity, ambiguity and the lack of an established theoretical and practical knowledge base makes creating leadership in the social enterprise sector that much more challenging. On the positive side of the ledger, the fact that the purpose is at the core of social enterprise means that it is relatively easier to use the purpose to create a basis for common meaningful action, compared to leadership within the private and public sectors. Related to this, given the strongly local or “glocal” nature of social enterprise, a ready opportunity exists for leaders to draw upon a place as a strategic resource in mobilising followers and other stakeholders. The novel, uncertain and pioneering nature of a social enterprise is also arguably more tolerant and accommodating of a leadership mindset that focuses on posing questions regarding “wicked” problems compared to public, private for-profit and, indeed, traditional not-for-profit sector organisations.

Originality/value

As far as we can ascertain, this is the first systematic attempt to examine the distinctive challenges and opportunities associated with creating leadership within the social enterprise realm. The application of the heuristic framework leads to the identification of five key inter-related lines of empirical research into leadership practices within social enterprises.
Renegotiations of Target CEOs' Personal Benefits During Mergers and Acquisitions
Authors: Patrick Paige H.
Published: December 2017

Many view large payments following mergers or acquisitions as excessive and evidence of rent extraction. Using additional disclosures required by the SEC since 2006, I hand‐collect details of preexisting change in control (CIC) provisions in employment agreements and CIC benefits granted to target CEOs during mergers. I find that CIC benefits are renegotiated in approximately 50 percent of my sample. I then investigate whether renegotiation of CIC benefits tends to be opportunistic, or, instead, evidence of efficient contracting. The overall evidence is more consistent with efficient contracting. This contrasts prior research that focuses solely on certain components of CIC benefits, such as employment in merged firms or merger bonuses. I find that changes in CIC benefits are positively associated with the CEO's horizon, as would be predicted by efficient contracting, but only limited evidence that changes in CIC benefits are positively associated with proxies for CEO power, as would be predicted by rent extraction. Acquiring firm shareholders interpret increases in target CEOs' CIC benefits as evidence of rent extraction, although I find that the merged firm's post‐merger performance is positively associated with changes in CIC benefits. This result is more consistent with acquiring firms providing target CEOs increased CIC benefits to complete mergers and realize synergies than with value‐reducing rent extraction.
FOREWORD
Authors: ARENA VALENTINA , GÓRÁIN FIACHRA MAC
Published: December 2017

For we were wandering around and lost like visitors in our own city, and it was as if your books led us home, so that we could finally recognize who and where we were. You revealed the age of our homeland, the chronology of our history, you revealed the laws of the rites and the laws of the priests, you revealed our civic and military institutions, you revealed the topography of our districts and places, you revealed the names, kinds, functions, and origins of all things divine and human. Indeed you have shed a flood of light on our poets and in fact on the whole of Latin language and literature. (Cic. Acad. 1.9: editors' translation)
VARRO IN VIRGILIAN COMMENTARIES: TRANSMISSION IN FRAGMENTS
Authors: VALLAT DANIEL
Published: December 2017

This paper analyses the transmission of Varro in late antique Virgil commentaries. Various problems are identified and discussed: the reliability of authors' names and titles of works in citations and testimonies; different forms of quotation; complications entailed by manuscript transmission; the delimitation of the fragments; the indirect transmission of Varro already in antiquity; the status and function of Varro in a Virgil commentary. Finally I suggest that Varro had a special if implicit status in fourth-century ideological debates, in the tacit rivalry of grammarians with Christian polemicists.