bluuebunny/crossref_metadata_2025 huggingface dataset:
From CFTR biology toward combinatorial pharmacotherapy: expanded classification of cystic fibrosis mutations
Authors: Veit Gudio , Avramescu Radu G. , Chiang Annette N. , Houck Scott A. , Cai Zhiwei , Peters Kathryn W. , Hong Jeong S. , Pollard Harvey B. , Guggino William B. , Balch William E. , Skach William R. , Cutting Garry R. , Frizzell Raymond A. , Sheppard David N. , Cyr Douglas M. , Sorscher Eric J. , Brodsky Jeffrey L. , Lukacs Gergely L.
Published: January 2016

More than 2000 mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) have been described that confer a range of molecular cell biological and functional phenotypes. Most of these mutations lead to compromised anion conductance at the apical plasma membrane of secretory epithelia and cause cystic fibrosis (CF) with variable disease severity. Based on the molecular phenotypic complexity of CFTR mutants and their susceptibility to pharmacotherapy, it has been recognized that mutations may impose combinatorial defects in CFTR channel biology. This notion led to the conclusion that the combination of pharmacotherapies addressing single defects (e.g., transcription, translation, folding, and/or gating) may show improved clinical benefit over available low-efficacy monotherapies. Indeed, recent phase 3 clinical trials combining ivacaftor (a gating potentiator) and lumacaftor (a folding corrector) have proven efficacious in CF patients harboring the most common mutation (deletion of residue F508, ΔF508, or Phe508del). This drug combination was recently approved by the U.S. Food and Drug Administration for patients homozygous for ΔF508. Emerging studies of the structural, cell biological, and functional defects caused by rare mutations provide a new framework that reveals a mixture of deficiencies in different CFTR alleles. Establishment of a set of combinatorial categories of the previously defined basic defects in CF alleles will aid the design of even more efficacious therapeutic interventions for CF patients.
Economic valuation of Baltic marine ecosystem services: blind spots and limited consistency
Authors: Sagebiel Julian , Schwartz Carmen , Rhozyel Mounaim , Rajmis Sandra , Hirschfeld Jesko
Published: January 2016

Economic valuation of marine ecosystem services in the Baltic Sea region has gained importance, as policy-makers are recognizing their decline and focusing on achieving good environmental status there in terms of, for example, reduced eutrophication. Parallel with this development, several initiatives have been launched, leading to a large number of economic valuation studies. However, current research indicates that neither a common approach to classifying ecosystem services nor a widely accepted methodological framework for assessing their economic value exist yet. This paper seeks to shed light on the current state of the economic valuation of ecosystem services provided by the Baltic Sea through reviewing all currently available empirical studies on the topic. The results indicate that only a few ecosystem services, including recreation and reduction of eutrophication, have been extensively monetarily valued, and still lack cross-study methodological consistency, while many other marine ecosystem services have rarely or never been valued with economic methods. The paper concludes that existing economic valuation studies provide only limited practical guidance for policy-makers intending to improve the environmental status of the Baltic Sea. There is a need for more widely shared agreement on the systematic nature of marine and coastal ecosystem services and especially on a coherent methodological framework for assessing their economic value.
The migration of fin whales into the southern Chukchi Sea as monitored with passive acoustics
Authors: Tsujii Koki , Otsuki Mayuko , Akamatsu Tomonari , Matsuo Ikuo , Amakasu Kazuo , Kitamura Minoru , Kikuchi Takashi , Miyashita Kazushi , Mitani Yoko
Published: January 2016

Fin whales (Balaenoptera physalus) undergo seasonal migration in the Arctic Sea. Because their migration and distribution is likely affected by changes in global climate, we aimed to examine the migration timing of fin whales, and the relationship with prey availability within the oceanographic environment of the Arctic Sea, using passive and active acoustic monitoring methods. Automatic Underwater Sound Monitoring Systems were deployed in the southern Chukchi Sea from July 2012 to 2014 to determine the acoustic presence of fin whales. Furthermore, water temperature and salinity were recorded by a fixed data logger. An Acoustic Zooplankton Fish Profiler was additionally deployed to estimate prey abundance through backscattering strength. Sea ice concentrations were obtained by remote sensing data. Fin whale calls were automatically detected using a custom-made software, and the per cent of half-hours containing calls were counted. Fin whale calls were detected from 4 August to 20 October 2012 (78 d) and 25 July to 1 November 2013 (100 d). The extended period of acoustic presence of fin whales during 2013 when compared with 2012 is likely related to a longer ice-free period during 2013. Furthermore, generalized linear model analyses showed that half-hour periods containing calls increased with a rise in water temperature and zooplankton abundance during the initial call presence period, while they decreased with a decrease in water temperature and salinity during the end of the call presence period. Our results suggest that the rise in water temperature and zooplankton abundance affect the timing of migration of fin whales in a way that is consistent with the expansion of their suitable habitats and the extension of their presence in the Arctic Sea.
A Single-Incision Fasciotomy for Compartment Syndrome of the Lower Leg
Authors: Ebraheim Nabil A. , Siddiqui Saaid , Raberding Craig
Published: January 2016

Lower leg fasciotomy may be performed with a single lateral incision with or without fibulectomy, or by a double incision technique, with most surgeons preferring the later. The aim of this article is to describe a variation of an existing single-incision technique that will allow for the release of all four compartments with 1 incision. Our approach uses a paratibial route to release the deep posterior compartment (DPC) rather than a transfibular or parafibular route that has already been discussed in the literature. We approach the DPC from the anterior compartment, whereas the parafibular approach uses the posterior aspect of the fibula to reach the DPC. This affords a faster fasciotomy with a smaller flap, avoids potential damage to neurovascular bundle and among other advantages, makes its especially pragmatic for bedside fasciotomy, without the risk of injury to the peroneal nerves, which is common with dissection at the posterior aspect of the fibula.
Computer Hexapod–Assisted Orthopaedic Surgery for the Correction of Tibial Deformities
Authors: Hughes Andrew , Parry Michael , Heidari Nima , Jackson Mark , Atkins Roger , Monsell Fergal
Published: January 2016

We describe the intraoperative use of the Taylor Spatial Frame to correct complex multiplanar deformities of the tibia before definitive internal stabilization using minimally invasive techniques. Thirteen consecutive procedures were performed in 12 patients. All deformities of the tibia were assessed with standardized radiographs allowing estimation of the center of rotation of angulation (CORA) or multiple CORA for multiplanar deformities. The cause of the deformity included both posttraumatic and metabolic conditions. A wide range of deformities was deemed appropriate for correction with this technique. All underwent acute intraoperative correction through single or multiple osteotomies mediated by the Taylor Spatial Frame before definitive internal stabilization using a locked intramedullary nail. Deformity correction and restoration of the tibial mechanical axis was achieved in all cases. There were no cases of nonunion. There was only one superficial infection necessitating removal of implants following union of the osteotomies. Two patients developed a common peroneal nerve palsy, 1 had full recovery at 18 months and 1 had partial recovery. Another patient developed a tibial artery pseudoaneurysm treated successfully with a percutaneous stent. This series demonstrates the use of the Taylor Spatial Frame for acute intraoperative correction of complex tibial deformities and definitive internal stabilization.
Is the Digital Divide for Orthopaedic Trauma Patients a Myth? Prospective Cohort Study on Use of a Custom Internet Site
Authors: Matuszewski Paul E. , Costales Timothy , Zerhusen Timothy , Coale Max , Mehta Samir , Pollak Andrew N. , O'Toole Robert V.
Published: January 2016

Objectives:

Some have proposed that a so-calleddigital divideexists for orthopaedic trauma patients and that the clinical usefulness of the Internet for these patients is limited. No studies to date have confirmed this or whether patients would use a provided web resource. The hypotheses of this study were (1) a larger than expected percentage of trauma patients have access to the Internet and (2) if given access to a custom site, patients will use it.

Design:

Prospective cohort.

Setting:

Level 1 regional trauma center.

Patients:

Patients who were 18 years or older with acute operative fractures participated in this study. Enrollment was initiated either before discharge or at initial outpatient follow-up.

Intervention:

We conducted a survey of demographics, Internet usage, device type, eHealth Literacy, and intent to use the web site. Participants received a keychain containing the web address and a unique access code to our custom orthopaedic trauma web site.

Main Outcome Measurements:

Percentage of patients with Internet access and percentage of patients who visited the web site.

Results:

One hundred twelve patients were enrolled. Ninety-three percent (104/112) reported having Internet access (P< 0.0001). Only increasing age predicted lack of access (P< 0.015; odds ratio, 0.95). Most (95%, 106/112) planned to visit our site; however, only 11% (P< 0.001) accessed it.

Conclusions:

The digital divide is a myth in orthopaedic trauma. Despite widespread access and enthusiasm for our web site, few patients visited. This cautions against the allocation of resources for patient-specific web sites for orthopaedic trauma until a rationale for use can be better delineated.

Level of Evidence:

Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.
Clinical Trial of Thermal Pulsation (LipiFlow) in Meibomian Gland Dysfunction With Preteatment Meibography
Authors: Zhao Yang , Veerappan Anuradha , Yeo Sharon , Rooney David M. , Acharya Rajendra U. , Tan Jen Hong , Tong Louis ,   Collaborative Research Initiative for Meibomian gland dysfunction (CORIM)
Published: January 2016

Objectives:

Thermal pulsation (LipiFlow) has been advocated for meibomian gland dysfunction (MGD) treatment and was found useful. We aimed to evaluate the efficacy and safety of thermal pulsation in Asian patients with different grades of meibomian gland loss.

Methods:

A hospital-based interventional study comparing thermal pulsation to warm compresses for MGD treatment. Fifty patients were recruited from the dry eye clinic of a Singapore tertiary eye hospital. The ocular surface and symptom were evaluated before treatment, and one and three months after treatment. Twenty-five patients underwent thermal pulsation (single session), whereas 25 patients underwent warm compresses (twice daily) for 3 months. Meibomian gland loss was graded using infrared meibography, whereas function was graded using the number of glands with liquid secretion.

Results:

The mean age (SD) of participants was 56.4 (11.4) years in the warm compress group and 55.6 (12.7) years in the thermal pulsation group. Seventy-six percent of the participants were female. Irritation symptom significantly improved over 3 months in both groups (P<0.01), whereas tear breakup time (TBUT) was modestly improved at 1 month in only the thermal pulsation group (P=0.048), without significant difference between both groups over the 3 months (P=0.88). There was also no significant difference in irritation symptom, TBUT, Schirmer test, and gland secretion variables between patients with different grades of gland loss or function at follow-ups.

Conclusions:

A single session of thermal pulsation was similar in its efficacy and safety profile to 3 months of twice daily warm compresses in Asians. Treatment efficacy was not affected by pretreatment gland loss.
Agreement Between Autorefraction and Subjective Refraction in Keraring-Implanted Keratoconic Eyes
Authors: Al-Tuwairqi Waleed S. , Ogbuehi Kelechi C. , Razzouk Haya , Alanazi Mana A. , Osuagwu Uchechukwu L.
Published: January 2016

Objectives:

To assess the agreement between subjective refraction and autorefraction and to explore the relationship between the magnitude of higher order aberration, and visual acuity and refraction, before and after keraring implantation.

Methods:

This prospective, randomized, interventional study enrolled 27 subjects (mean age 28.1±6.5 years) with keratoconus. Noncycloplegic refraction was performed subjectively by one clinician and with an autorefractor by another clinician, before and 6 months after surgery. The limit of agreement (LoA) between methods was assessed, and the relationships between the corrected distance visual acuity, logMAR on the one hand and refraction measurements and higher-order aberrations on the other, were examined.

Results:

The agreement in mean spherical equivalent refraction (MSER) between methods was good postoperatively but poor preoperatively. The autorefractor gave a more myopic refraction than subjective refraction preoperatively (−3.28±3.06 D; LoA −9.27 to +2.71 D, P<0.0001) and postoperatively (−0.63±1.64 D; LoA −3.85 to +2.58 D, P=0.055), and returned higher negative cylinders preoperatively (−1.10±1.17 D; LoA −3.40 to +1.19 D, P<0.0001) and postoperatively (−1.08±1.27 D; LoA −3.60 to +1.41 D, P<0.0001) in keratoconic eyes. The difference in MSER between methods was significantly related to the refractive error at both visits (P<0.05) and to the magnitude of higher-order aberrations in keratoconic eyes preoperatively (P<0.05). The logMAR visual acuity achieved subjectively worsened as the magnitude of higher-order aberrations increased preoperatively (P<0.001).

Conclusions:

The autorefractor returns values that are significantly more myopic in MSER and higher negative cylinders than subjective refraction, preoperatively, but the MSER was similar between devices postoperatively. The autorefactor seems a valid starting point for subjective refraction in keratoconic eyes treated with keraring, but the cylinder should be corrected by about +1 D. The instruments agree more in less myopic than high myopic eyes.
Vitamin D Intake in Very Low Birth Weight Infants in Neonatal Intensive Care Unit
Authors: Munshi Upender K. , Graziano Pauline D. , Meunier Kara , Ludke Jennifer , Rios Angel
Published: January 2016

It is unknown how often preterm infants in neonatal intensive care units achieve the American Academy of Pediatrics‐recommended daily intake of 400 international units of Vitamin D. We studied 378 preterm infants with birth weight 1500 g or less admitted to our neonatal intensive care unit, 151 infants before and 227 infants after daily vitamin D‐intake monitoring was introduced. Infants were stratified into 2 groups: extremely low birth weight (<1000 g) and Very low birth weight (1000–1500 g). Monitoring of daily intake coincided with significant improvement in vitamin D intake in both extremely low birth weight and very low birth weight groups.
Improving Selection Criteria for ALK Inhibitor Therapy in Non–Small Cell Lung Cancer
Authors: Jiang Long , Yang Haihong , He Ping , Liang Wenhua , Zhang Jianrong , Li Jingpei , Liu Yang , He Jianxing
Published: January 2016

Lung cancer is often diagnosed by molecular markers for prediction and treatment. To date, the golden standard for detection of anaplastic lymphoma kinase (ALK) rearrangements is fluorescence in situ hybridization (FISH). We performed a pooled-data analysis on the diagnostic operating characteristics of immunohistochemistry (IHC) assay on non–small cell lung cancer (NSCLC). We searched Embase, Pubmed, and Springer databases. The results of IHC were evaluated using a modified H-score. We used a 2-level bivariate meta-analysis following a random effect model to summarize sensitivity and specificity and fit hierarchical summary receiver-operating characteristic curves. We also performed sensitivity analysis using different antibodies to investigate potential heterogeneity. Twelve studies consisting of a total of 3754 NSCLC specimens were analyzed. When we defined 1+/2+/3+, 2+/3+, and 3+ as ALK positive, we found the sensitivities to be 99% (95% confidence interval [CI], 97%-100%), 86% (95% CI, 73%-93%), and 56% (95% CI, 36%-74%) and the specificities to be 98% (95% CI, 95%-99%), 99% (95% CI, 99%-100%), and 100% (95% CI, 100%-100%), respectively. We demonstrated that when defining 3+ as positive and 0 as negative the sensitivity was 99% and specificity was 100%. In our sensitivity analysis, we found the sensitivity of D5F3 and 5A4 antibodies to be much higher than that of ALK1. We concluded that IHC scores 0 and 3+ were nearly 100% concordant with FISH-negative and FISH-positive status, respectively. However, IHC scores 1+ and 2+ might require further confirmatory testing by FISH assay. IHC assay using D5F3 and 5A4 antibodies reliably detected NSCLC with ALK rearrangement and may be useful as a screening method to identify these tumors.
Endocervicosis of the Uterine Cervix
Authors: Mobarki Mousa , Karpathiou Georgia , Forest Fabien , Corsini Thomas , Peoc’h Michel
Published: January 2016

Endocervicosis is considered a form of Mülleriosis affecting mainly the bladder and is comprised of endocervical-type glands and cysts. It has been rarely described in the uterine cervix where the extensive involvement of cervical and paracervical tissue poses the suspicion of malignancy, mostly minimal-deviation adenocarcinoma. We describe a case of cervical endocervicosis causing long-term symptoms leading to hysterectomy. We provide evidence that this pathology is associated with cesarean section similar with isthmocele. Its differential diagnosis is discussed.
A neurocomputational model of human frontopolar cortex function
Authors: HYAFIL Alexandre , KOECHLIN Etienne
Published: January 2016

The frontopolar cortex (FPC), the most anterior part of the lateral prefrontal cortex corresponding to Brodmann area 10, is involved in human high-order cognition, including reasoning, problem-solving and multitasking. Its specific contribution to prefrontal executive function, however, remains unclear. A neurocomputational model suggests that the FPC implements a basic process referred to as cognitive branching that maintains a task in a pending state during the execution of another, and enables to revert back to it upon completion of the ongoing one. However, the FPC is engaged in other cognitive functions including prospective memory, relational reasoning, episodic memory retrieval and attentional set-shifting, which are not directly linked to the notion of cognitive branching. Here we used a neurocomputional branching model to simulate the involvement of the FPC in these various cognitive functions. Simulation results indicate that the model accounts for the variety of FPC activations observed in these various experimental paradigms. Thus, the present study provides theoretical evidence suggesting that all these behavioral paradigms implicitly involve branching processes, and supports the idea that cognitive branching is the core function of the human frontopolar cortex.
Physiological reason for ceasing growth of unfertilized eggs produced by unmated queens in the subterranean termiteReticulitermes chinensis
Authors: Li Ganghua , Liu Long , Sun Pengdong , Wu Yao , Lei Chaoliang , Chen Xiongwen , Huang Qiuying
Published: January 2016

InReticulitermes chinensis,a close relative ofR. speratuswith asexual queen succession, unfertilized eggs can be produced but are not incubated. To explain this phenomenon, we analysed the physiological differences between unfertilized eggs/unmated queens and fertilized eggs/mated queens. Fertilized eggs consumed significantly larger quantities of five amino acids (Cys, Met, Ile, Leu and Tyr), Ca, protein and cholesterol during incubation. The higher levels of four trace elements (Na, K, Zn and Fe) in fertilized eggs and their lower levels in mated queens indicated that mated queens might transfer these trace elements to fertilized eggs to complete incubation. The higher levels of Mn, triglycerides and serotonin in mated queens and higher levels of Mn and glucose in fertilized eggs suggested that these substances are very important for normal ovarian and embryonic growth. The different expression of three reproductive genes(vtgl, rabilandJHE1)suggested that they might be involved in the regulation of ovarian and embryonic growth. Overall, changes in these physiological indices may substantially affect ovarian and embryonic growth and prohibit the incubation of unfertilized eggs inR. chinensis.
A Quantitative Analysis of Localized Robustness of MYCN in Neuroblastoma
Authors: Sandhu Romeil , Tannenbaum Sarah , Diolaiti Daniel , Ambesi-Impiombato Alberto , Kung Andrew , Tannenbaum Allen
Published: January 2016

The amplification of the gene MYCN (V-myc mye-locytomatosis viral-valeted oncogene, neuroblastoma derived) has been a well-documented indicator for poor prognosis in neuroblastoma, a childhood cancer. Unfortunately, there has been limited success in understanding MYCN functionality in the landscape of neuroblastoma and more importantly given that MYCN has been deemed "undruggable," the need to potentially illuminate key opportunities that indirectly target MYCN is of great interest. To this end, this work employs an emerging quantitative technique from network science, namely network curvature, to quantify the biological robustness of MYCN and its surrounding neighborhood. In particular, when amplified in Stage IV cancer, MYCN exhibits higher curvature (more robust) than those samples with under expressed MYCN levels. When examining the surrounding neighborhood, the above argument still holds for network curvature, but is lost when only analyzing differential expression - a common technique amongst oncologists and computational/molecular biologists. This finding points to the problem (and possible solution) of drug targeting in the context ofcomplexity and indirect cell signaling affects that have often been obfuscated through traditional techniques.
The basis of sharp spike onset in standard biophysical models
Authors: Telenczuk Maria , Fontaine Bertrand , Brette Romain
Published: January 2016

In most vertebrate neurons, spikes initiate in the axonal initial segment (AIS). When recorded in the soma, they have a surprisingly sharp onset, as if sodium (Na) channels opened abruptly. The main view stipulates that spikes initiate in a conventional manner at the distal end of the AIS, then progressively sharpen as they backpropagate to the soma. We examined the biophysical models used to substantiate this view, and we found that orthodromic spikes do no initiate through a local axonal current loop that propagates along the axon, but through a global current loop encompassing the AIS and soma, which forms an electrical dipole. Therefore, the phenomenon is not adequately modeled as the backpropagation of an electrical wave along the axon, since the wavelength would be as large as the entire system. Instead, in these models, we found that spike initiation rather follows the critical resistive coupling model proposed recently, where the Na current entering the AIS is matched by the axial resistive current flowing to the soma. Besides demonstrating it by examining the balance of currents at spike initiation, we show that the observed increase in spike sharpness along the axon is artifactual and disappears when an appropriate measure of rapidness is used; instead, somatic onset rapidness can be predicted from spike shape at initiation site. Finally, we reproduce the phenomenon in a two-compartment model, showing that it does not rely on propagation. In these models, the sharp onset of somatic spikes is therefore not an artifact of observing spikes at the incorrect location, but rather the signature that spikes are initiated through a global soma-AIS current loop forming an electrical dipole.

Author summary

In most vertebrate neurons, spikes are initiated in the axonal initial segment, next to the soma. When recorded at the soma, action potentials appear to suddenly rise as if all sodium channels opened at once. This has been previously attributed to the backpropagation of spikes from the initial segment to the soma. Here we demonstrate with biophysical models that backpropagation does not contribute to the sharpness of spike onset. Instead, we show that the phenomenon is due to the resistive coupling between the large somatodendritic compartment and the small axonal compartment, a geometrical discontinuity that leads to an abrupt variation in voltage.
Identification of positive selection in genes is greatly improved by using experimentally informed site-specific models
Authors: Bloom Jesse D.
Published: January 2016

Sites of positive selection are identified by comparing observed evolutionary patterns to those expected under a null model for evolution in the absence of such selection. For protein-coding genes, the most common null model is that nonsynonymous and synonymous mutations fix at equal rates; this unrealistic model has limited power to detect many interesting forms of selection. I describe a new approach that uses a null model based on high-throughput lab measurements of a gene's site-specific amino-acid preferences. This null model makes it possible to identify diversifying selection for amino-acid change and differential selection for mutations to amino acids that are unexpected given the measurements made in the lab. I show that this approach identifies sites of adaptive substitutions in four genes (lactamase, Gal4, influenza nucleoprotein, and influenza hemagglutinin) far better than a comparable method that simply compares the rates of nonsynonymous and synonymous substitutions. As rapid increases in biological data enable increasingly nuanced descriptions of the constraints on individual sites, approaches like the one here can improve our ability to identify many interesting forms of selection.
Statistics of Cellular Evolution in Leukemia: Allelic Variations in Patient Trajectories Based on Immune Repertoire Sequencing
Authors: Gao Hong , Wang Chunlin , Seok Junhee , Feldman Marcus W. , Xiao Wenzhong
Published: January 2016

The evolution of a cancer system consisting of cancer clones and normal cells is a complex dynamic process with multiple interacting factors including clonal expansion, somatic mutation, and sequential selection. As a typical example, in patients with chronic lymphocytic leukemia (CLL), a monoclonal population of transformed B cells expands to dominate the B cell population in the peripheral blood and bone marrow. This expansion of transformed B cells suggests that they might evolve through processes distinct from those of normal B cells. Recent advances in next generation sequencing enable the high-throughput identification and tracking of individual B cell clones through sequencing of the V-D-J junction segments of the immunoglobulin heavy chain (IGH). Here we developed a statistical approach to modeling cellular evolution of the immune repertoire. Adapting the infinitely many alleles model from population genetics, we studied abnormalities occurring in the immune repertoire of patients as substantial deviations from the null model. The Ewens sampling test (EST) distinguished the immune repertoires of CLL patients with imminent relapse from healthy controls and patients in sustained remission. Extensive simulations based on sequencing data showed that EST is sensitive in detecting cancer-related derangements of the IGH repertoire. In addition, we suggest two potentially useful parameters: the rate at which donor’s B cell clones enter the circulation and the average time to regenerate a transplanted immune repertoire, both of which help to distinguish relapsing CLL patients from those in sustained remission and provide additional information about the dynamics of immune reconstitution in the latter patients. We anticipate that our models and statistics will be useful in diagnosis and prognosis of leukemia, and may be adapted for application to other diseases related to adaptive immunity.
Multi-scale computational study of the mechanical regulation of cell mitotic rounding in epithelia
Authors: Nematbakhsh Ali , Sun Wenzhao , Brodskiy Pavel A. , Amiri Aboutaleb , Narciso Cody , Xu Zhiliang , Zartman Jeremiah J. , Alber Mark S
Published: January 2016

Mitotic rounding during cell division is critical for preventing daughter cells from inheriting an abnormal number of chromosomes, a condition that occurs frequently in cancer cells. Cells must significantly expand their apical area and transition from a polygonal to circular apical shape to achieve robust mitotic rounding in epithelial tissues, which is where most cancers initiate. However, how cells mechanically regulate robust mitotic rounding within packed tissues is unknown. Here, we analyze mitotic rounding using a newly developed multi-scale subcellular element computational model that is calibrated using experimental data. Novel biologically relevant features of the model include separate representations of the sub-cellular components including the apical membrane and cytoplasm of the cell at the tissue scale level as well as detailed description of cell properties during mitotic rounding. Regression analysis of predictive model simulation results reveals the relative contributions of osmotic pressure, cell-cell adhesion and cortical stiffness to mitotic rounding. Mitotic area expansion is largely driven by regulation of cytoplasmic pressure. Surprisingly, mitotic shape roundness within physiological ranges is most sensitive to variation in cell-cell adhesivity and stiffness. An understanding of how perturbed mechanical properties impact mitotic rounding has important potential implications on, amongst others, how tumors progressively become more genetically unstable due to increased chromosomal aneuploidy and more aggressive.

Author Summary

Mitotic rounding (MR) during cell division which is critical for the robust segregation of chromosomes into daughter cells, plays important roles in tissue growth and morphogenesis, and is frequently perturbed in cancerous cells. Mechanisms of MR have been investigated in individual cultured cells, but mechanisms regulating MR in tissues are still poorly understood. We developed and calibrated an advanced subcellular element-based computational model called Epi-Scale that enables quantitative testing of hypothesized mechanisms governing epithelial cell behavior within the developing tissue microenvironment. Regression analysis of predictive model simulation results reveals the relative contributions of osmotic pressure, cell-cell adhesion and cortical stiffness to mitotic rounding and establishes a novel mechanism for ensuring robustness in mitotic rounding within densely packed epithelia.
Pressure-induced polymorphism in nanostructured SnSe
Authors: Michielon de Souza Sergio , Ordozgoith da Frota Hidembergue , Trichês Daniela Menegon , Ghosh Angsula , Chaudhuri Puspitapallab , Silva dos Santos Gusmao Marta , de Figueiredo Pereira Aercio Filipe Franklim , Couto Siqueira Mariana , Daum Machado Kleber , Cardoso de Lima Joao
Published: January 2016

The pressure-induced phase transitions in nanostructured SnSe were investigated using angle-dispersive X-ray diffraction in a synchrotron source along with first-principles density functional theory (DFT) calculations. The variation of the cell parameters along with enthalpy calculations for pressures up to 18 GPa have been considered. Both the experimental and the theoretical approaches demonstrate a phase transition at around 4 GPa. Below 8.2 GPa the X-ray diffraction patterns were fitted using the Rietveld method with space groupPnma(No. 62). The lattice parameters and atomic positions for the above-mentioned symmetry were used in DFT calculations of thermodynamic parameters. The enthalpy calculations with the computationally optimized structure and the proposedPnmastructure of SnSe were compatible. The variations of the cell volume for the high-pressure phases are described by a third-order Birch–Murnaghan equation of state.
A visible-light-excited fluorescence method for imaging protein crystals without added dyes
Authors: Lukk Tiit , Gillilan Richard E. , Szebenyi Doletha M. E. , Zipfel Warren R.
Published: January 2016

Fluorescence microscopy methods have seen an increase in popularity in recent years for detecting protein crystals in screening trays. The fluorescence-based crystal detection methods have thus far relied on intrinsic UV-inducible tryptophan fluorescence, nonlinear optics or fluorescence in the visible light range dependent on crystals soaked with fluorescent dyes. In this paper data are presented on a novel visible-light-inducible autofluorescence arising from protein crystals as a result of general stabilization of conjugated double-bond systems and increased charge delocalization due to crystal packing. The visible-light-inducible autofluorescence serves as a complementary method to bright-field microscopy in beamline applications where accurate crystal centering about the rotation axis is essential. Owing to temperature-dependent chromophore stabilization, protein crystals exhibit tenfold higher fluorescence intensity at cryogenic temperatures, making the method ideal for experiments where crystals are cooled to 100 K with a cryostream. In addition to the non-damaging excitation wavelength and low laser power required for imaging, the method can also serve a useful role for differentiating protein crystals from salt crystals in screening trays.
X-ray asterism and the structure of cracks from indentations in silicon
Authors: Tanner B. K. , Garagorri J. , Gorostegui-Colinas E. , Elizalde M. R. , Allen D. , McNally P. J. , Wittge J. , Ehlers C. , Danilewsky A. N.
Published: January 2016

The asterism observed in white radiation X-ray diffraction images (topographs) of extended cracks in silicon is investigated and found to be associated with material that is close to breakout and surrounded by extensive cracking. It is a measure of the mechanical damage occurring when the fracture planes do not follow the low-index cleavage planes associated with the crystal structure. It is not related to a propensity for some cracked wafers to shatter during subsequent high-temperature processing. There is no correlation between crack morphology and alignment of an indenter with respect to the orientation of a silicon wafer, the cracks being generated from the apices of the indenter and having threefold symmetry for Berkovich indents and fourfold symmetry for Vickers indents. X-ray diffraction imaging (XRDI) of indents does not reveal this underlying symmetry and the images exhibit a very substantial degree of variation in their extent. This arises because the XRDI contrast is sensitive to the long-range strain field around the indent and breakout reduces the extent of this long-range strain field. Breakout is also detected in the loss of symmetry in the short-range strain field imaged by scanning micro-Raman spectroscopy. Weak fourfold symmetric features at the extremes of the images, and lying along 〈110〉 directions, are discussed in the context of slip generated below the room-temperature indents. Scanning electron microscopy imaging of the region around an indent during focused ion beam milling has permitted the three-dimensional reconstruction of the crack morphology. The surface-breaking Palmqvist cracks are found to be directly connected to the median subsurface cracks, and the presence of extensive lateral cracks is a prerequisite for material breakout at indenter loads above 200 mN. The overall crack shape agrees with that predicted from simulation.
Cryogenic coherent X-ray diffraction imaging of biological samples at SACLA: a correlative approach with cryo-electron and light microscopy
Authors: Takayama Yuki , Yonekura Koji
Published: January 2016

Coherent X-ray diffraction imaging at cryogenic temperature (cryo-CXDI) allows the analysis of internal structures of unstained, non-crystalline, whole biological samples in micrometre to sub-micrometre dimensions. Targets include cells and cell organelles. This approach involves preparing frozen-hydrated samples under controlled humidity, transferring the samples to a cryo-stage inside a vacuum chamber of a diffractometer, and then exposing the samples to coherent X-rays. Since 2012, cryo-coherent diffraction imaging (CDI) experiments have been carried out with the X-ray free-electron laser (XFEL) at the SPring-8 Ångstrom Compact free-electron LAser (SACLA) facility in Japan. Complementary use of cryo-electron microscopy and/or light microscopy is highly beneficial for both pre-checking samples and studying the integrity or nature of the sample. This article reports the authors' experience in cryo-XFEL-CDI of biological cells and organelles at SACLA, and describes an attempt towards reliable and higher-resolution reconstructions, including signal enhancement with strong scatterers and Patterson-search phasing.
Bragg–von Laue diffraction generalized to twisted X-rays
Authors: Jüstel Dominik , Friesecke Gero , James Richard D.
Published: January 2016

A pervasive limitation of nearly all practical X-ray methods for the determination of the atomic scale structure of matter is the need to crystallize the molecule, compound or alloy in a sufficiently large (∼10 × 10 × 10 µm) periodic array. In this paper an X-ray method applicable to structure determination of some important noncrystalline structures is proposed. It is designed according to a strict mathematical analog of von Laue's method, but replacing the translation group by another symmetry group, and simultaneously replacing plane waves by different exact closed-form solutions of Maxwell's equations. Details are presented for helical structures like carbon nanotubes or filamentous viruses. In computer simulations the accuracy of the determination of structure is shown to be comparable to the periodic case.
Three-dimensional structures of two heavily N-glycosylatedAspergillussp. family GH3 β-D-glucosidases
Authors: Agirre Jon , Ariza Antonio , Offen Wendy A. , Turkenburg Johan P. , Roberts Shirley M. , McNicholas Stuart , Harris Paul V. , McBrayer Brett , Dohnalek Jan , Cowtan Kevin D. , Davies Gideon J. , Wilson Keith S.
Published: January 2016

The industrial conversion of cellulosic plant biomass into useful products such as biofuels is a major societal goal. These technologies harness diverse plant degrading enzymes, classical exo- and endo-acting cellulases and, increasingly, cellulose-active lytic polysaccharide monooxygenases, to deconstruct the recalcitrant β-D-linked polysaccharide. A major drawback with this process is that the exo-acting cellobiohydrolases suffer from severe inhibition from their cellobiose product. β-D-Glucosidases are therefore important for liberating glucose from cellobiose and thereby relieving limiting product inhibition. Here, the three-dimensional structures of two industrially important family GH3 β-D-glucosidases fromAspergillus fumigatusandA. oryzae, solved by molecular replacement and refined at 1.95 Å resolution, are reported. Both enzymes, which share 78% sequence identity, display a three-domain structure with the catalytic domain at the interface, as originally shown for barley β-D-glucan exohydrolase, the first three-dimensional structure solved from glycoside hydrolase family GH3. Both enzymes show extensive N-glycosylation, with only a few external sites being truncated to a single GlcNAc molecule. Those glycans N-linked to the core of the structure are identified purely as high-mannose trees, and establish multiple hydrogen bonds between their sugar components and adjacent protein side chains. The extensive glycans pose special problems for crystallographic refinement, and new techniques and protocols were developed especially for this work. These protocols ensured that all of the D-pyranosides in the glycosylation trees were modelled in the preferred minimum-energy4C1chair conformation and should be of general application to refinements of other crystal structures containing O- or N-glycosylation. TheAspergillusGH3 structures, in light of other recent three-dimensional structures, provide insight into fungal β-D-glucosidases and provide a platform on which to inform and inspire new generations of variant enzymes for industrial application.
(6-Bromo-2-oxo-2H-chromen-4-yl)methyl diethylcarbamodithioate
Authors: Vinduvahini M. , Anitha B. R. , Kumar K. Mahesh , Kotresh O. , Devarajegowda H. C.
Published: January 2016

In the title compound, C15H16BrNO2S2, the 2H-chromene ring system is nearly planar, with a maximum deviation of 0.0182 (22) Å. In the crystal, π–π interactions between pyran and benzene rings of chromene [shortest centroid–centroid distance = 3.7588 (14) Å] occur.
(η4-Bicyclo[2.2.1]hepta-2,5-diene)bis(η2-3,5-di-tert-butyl-1,2,4-diazaphospholido)ruthenium
Authors: Ren Lili , Zheng Wenjun
Published: January 2016

In the title compound, [Ru(C10H18N2P)2(C7H8)], the two 1,2,4-diazaphospholide (dp) ligands are coordinated to the RuIIion in an almost perfect η2-geometry, with Ru—N bond lengths in the range 2.071 (3)–2.135 (3) Å. The N—Ru—N angles within each η2-1,2,4-diazaphospholide ligand are similar, with values of 37.10 (11) and 37.44 (11)°, and hence the coodination geometry around the RuIIion is highly distorted from the expected octahedral geometry. One of thetert-butyl groups was refined as disordered over two sets of sites, with a ratio of occupancies of 0.719 (6):0.281 (6).
Gathering Data for Archival, Field, Survey, and Experimental Accounting Research
Authors: BLOOMFIELD ROBERT , NELSON MARK W. , SOLTES EUGENE
Published: January 2016

In the published proceedings of the first Journal of Accounting Research Conference, Vatter [1966] lamented that “Gathering direct and original facts is a tedious and difficult task, and it is not surprising that such work is avoided.” For the fiftieth JAR Conference, we introduce a framework to help researchers understand the complementary value of seven empirical methods that gather data in different ways: prestructured archives, unstructured (“hand‐collected”) archives, field studies, field experiments, surveys, laboratory studies, and laboratory experiments. The framework spells out five goals of an empirical literature and defines the seven methods according to researchers’ choices with respect to five data gathering tasks. We use the framework and examples of successful research studies in the financial reporting literature to clarify how data gathering choices affect a study's ability to achieve its goals, and conclude by showing how the complementary nature of different methods allows researchers to build a literature more effectively than they could with less diverse approaches to gathering data.
Product Market Competition and Corporate Real Estate Investment under Demand Uncertainty
Authors: Ambrose Brent W. , Diop Moussa , Yoshida Jiro
Published: January 2016

This article theoretically and empirically analyzes the interactions among corporate real estate investment, product market competition and firm risk. In our model, firms own strategic real estate or lease generic real estate. Our model predicts that strategic real estate ownership is positively correlated with industry concentration and negatively related to demand uncertainty. Also, firm risk is higher for firms with more strategic real estate operating in a more concentrated market. This prediction arises because smaller investments induce greater market competition, which effectively eliminates the right tail of the firm's profit distribution. We provide strong empirical support for our predictions. In particular, firm value is more volatile in less competitive markets for a given level of demand uncertainty.
The mediating role of leader–member exchange: a study of job satisfaction and turnover intentions in temporary work
Authors: Flickinger Miriam , Allscher Marcel , Fiedler Marina
Published: January 2016

This paper focuses on turnover intentions in temporary work. Specifically, we analyse whether job satisfaction and leader–member exchange (LMX) play the same role as antecedents of turnover intentions for both temporary and permanent employees. Results from a total‐effects moderation model based on a survey of 593 individuals placed by a temporary work agency suggest that temporary work lessens the impact that high job satisfaction has in terms of reducing turnover intentions. Furthermore, while for permanent employees, high‐quality LMX relationships play a central role in the link between job satisfaction and turnover intentions; for temporary employees, job satisfaction is less important in the formation of high‐quality LMX relationships. Therefore, we contribute to knowledge on turnover intentions in temporary work by showing that within this context, turnover intentions cannot be directly remedied by high job satisfaction and that temporary work inhibits LMX's reinforcing role in the relationship between job satisfaction and turnover intentions.
The consequences of dual and unilateral commitment to the organisation and union
Authors: Redman Tom , Snape Ed
Published: January 2016

This article examines the pattern and consequences of commitment to organisation and union amongst union members in a UK National Health Service Trust. Those who perceived the industrial relations climate as positive were more likely to be dually committed to both organisation and union. As anticipated, union commitment predicted union citizenship behaviours and intent to quit the union. However, organisational commitment predicted intent to quit the organisation but not organisational citizenship behaviour, which was predicted by union commitment. Findings suggest that those with a unilateral commitment to the union are more likely than the dually committed to engage in citizenship behaviours aimed at helping fellow members and colleagues, perhaps because they feel unconstrained by any strong loyalty to the organisation.
Reducing perceptions of overqualification and its impact on job satisfaction: the dual roles of interpersonal relationships at work
Authors: Alfes Kerstin , Shantz Amanda , van Baalen Sabine
Published: January 2016

A sizeable portion of the working population perceives that they are overqualified for their jobs. This is problematic, given that research consistently shows that such beliefs translate into lower levels of job satisfaction. Hence, it behoves human resource management (HRM) scholars to identify factors that influence perceptions of overqualification and also moderators that may reduce the negative effect of perceived overqualification on job satisfaction. In this study, we present a moderated path model that posits that the quality of the relationships that employees hold with their leader and with their team is not only antecedents of perceived overqualification but it is also hypothesised to weaken the negative relationship between perceived overqualification and job satisfaction. Survey data that were gathered from two organisations in the Netherlands (n = 183) supported the model. Implications for theory and practice in HRM are discussed. © 2015 John Wiley & Sons Ltd