bluuebunny/crossref_metadata_2025 huggingface dataset:
One hundred years after the 1918 pandemic: new concepts for preparing for influenza pandemics
Authors: Pavia Andrew
Published: May 2019

Purpose of review

In the 100 years since the influenza pandemic of 1918–1919, the most deadly event in human history, we have made substantial progress yet we remain vulnerable to influenza pandemics This article provides a brief overview of important advances in preparing for an influenza pandemic, viewed largely from the perspective of the healthcare system.

Recent findings

We have gained insights into influenza pathogenicity, the animal reservoir and have improved global surveillance for new strains and tools for assessing the pandemic risk posed by novel strains. Public health has refined plans for severity assessment, distribution of countermeasures and nonpharmaceutical approaches. Modest improvements in vaccine technology include cell culture-based vaccines, adjuvanted vaccine and recombinant technology. Conventional infection control tools will be critical in healthcare settings. New evidence suggests that influenza virus may be present in aerosols; the contribution of airborne transmission and role of N95 respirators remains unknown. Baloxavir and pimodivir are new antivirals that may improve treatment, especially for severely ill patients. Optimal use and the risk of resistance require further study.

Despite the progress in pandemic preparedness, gaps remain including important scientific questions, adequate resources and most importantly, the ability to rapidly deliver highly effective vaccines.
Training Cesarean Section
Authors: Zetner Diana B. , Petersen Iben , Konge Lars , Thinggaard Ebbe
Published: May 2019

Summary Statement

This study is a scoping review that reviews the existing literature on educational strategies in training of cesarean section. A systematic search was carried out in relevant databases, identifying 28 studies for inclusion. Thematic analysis revealed the following training strategies: simulation-based training (team training, in situ training, technical training), simulators (low-fidelity simulators, high-fidelity simulators), clinical training, e-learning or videos, classroom-based learning (lectures, small groups), and assessment (assessment programs/interventions, assessment of learners). Simulation-based training provides a unique milieu for training in a safe and controlled environment. Simulation-based team training is widely accepted and used in obstetrics and improves nontechnical skills, which are important in emergency cesarean section. High-fidelity simulators are advanced and realistic, but because of the expense, low-fidelity simulators may provide a reasonable method for training surgical skills. The literature in training and assessment of surgical skills in relation to cesarean section is sparse, and more studies are warranted.
Acute imaging for evidence-based treatment of ischemic stroke
Authors: Thomalla Götz , Gerloff Christian
Published: May 2019

Purpose of review

Until recently, intravenous thrombolysis and mechanical thrombectomy for acute stroke treatment relied on reported information on the known time of symptom onset and was limited to treatment within a narrow time window. New trials have provided evidence for imaging-based effective reperfusion treatment in an extended time window and unknown-onset stroke. This review summarizes evidence from recent clinical trials and suggests a simple algorithm for the choice of imaging modalities to guide evidence-based reperfusion treatment of acute stroke.

Recent findings

Two trials have provided evidence for benefit of mechanical thombectomy in patients with stroke from large vessel occlusion up to 24 h after symptom onset or with unknown symptom onset who have a small infarct core but large perfusion lesion or severe clinical deficit (DAWN, DEFUSE-3). An MRI-based trial has demonstrated the benefit of intravenous thrombolysis with alteplase in patients with unknown onset stroke who present with MRI findings of DWI-FLAIR mismatch (WAKE-UP). Another trial demonstrated benefit of intravenous alteplase in an extended or unknown time-window in patients with penumbral pattern on MRI or CT perfusion (EXTEND).

In stroke patients with unknown symptom onset or known symptom onset up to 24 h, advanced imaging with MRI or with CT perfusion can guide effective acute reperfusion treatment with mechanical thrombectomy and intravenous alteplase.
Solitary ecology as a phenomenon extending beyond insular systems: exaptive evolution inAnolislizards
Authors: Velasco Julián A. , Poe Steven , González-Salazar Constantino , Flores-Villela Oscar
Published: May 2019

The mechanisms driving phenotypic evolution have been of interest to biologists since Darwin. Ecological release—wherein adaptive evolution occurs following relaxation of constraining selective pressures—and environmental filtering—wherein exaptive traits allow colonization of a new area—have been studied in several insular cases.Anolislizards, which may exist in solitude or sympatry with multiple congeners, are an excellent system for evaluating whether ecological release and environmental filtering are associated with phenotypic shifts across phylogenetic and geographical scales. Insular solitaryAnolisexhibit phenotypic differentiation in body size and sexual size dimorphism—SSD—through exaptive and adaptive evolution, respectively. But, the generality of these effects has not yet been addressed. Here, we analyse the evolution of body size and SSD relative to sympatry in mainlandAnolis. We found that mainland species co-occurring with few congeners exhibit uniform body size and greater SSD relative to other random mainland assemblages, consistent with the insular solitary pattern. The locations of evolutionary shifts for both traits do not coincide with evolutionary transitions to decreased levels of sympatry. These results are consistent with exaptive environmental filtering but not adaptive ecological release. Future studies should be conducted at local scales to evaluate the role of these factors in the evolution of solitary existence in mainland and island species.
Telomere shortening as a mechanism of long-term cost of infectious diseases in natural animal populations
Authors: Giraudeau Mathieu , Heidinger Britt , Bonneaud Camille , Sepp Tuul
Published: May 2019

Pathogens are potent selective forces that can reduce the fitness of their hosts. While studies of the short-term energetic costs of infections are accumulating, the long-term costs have only just started to be investigated. Such delayed costs may, at least in part, be mediated by telomere erosion. This hypothesis is supported by experimental investigations conducted on laboratory animals which show that infection accelerates telomere erosion in immune cells. However, the generalizability of such findings to natural animal populations and to humans remains debatable. First, laboratory animals typically display long telomeres relative to their wild counterparts. Second, unlike humans and most wild animals, laboratory small-bodied mammals are capable of telomerase-based telomere maintenance throughout life. Third, the effect of infections on telomere shortening and ageing has only been studied using single pathogen infections, yet hosts are often simultaneously confronted with a range of pathogens in the wild. Thus, the cost of an infection in terms of telomere-shortening-related ageing in natural animal populations is likely to be strongly underestimated. Here, we discuss how investigations into the links between infection, immune response and tissue ageing are now required to improve our understanding of the long-term impact of disease.
Modelling and measuring intracellular competition for finite resources during gene expression
Authors: Sabi Renana , Tuller Tamir
Published: May 2019

Dissecting the competition between genes for shared expressional resources is of fundamental importance for understanding the interplay between cellular components. Owing to the relationship between gene expression and cellular fitness, genomes are shaped by evolution to improve resource allocation. Whereas experimental approaches to investigate intracellular competition require technical resources and human expertise, computational models and
in silico
simulations allow vast numbers of experiments to be carried out and controlled easily, and with significantly reduced costs. Thus, modelling competition has a pivotal role in understanding the effects of competition on the biophysics of the cell. In this article, we review various computational models proposed to describe the different types of competition during gene expression. We also present relevant synthetic biology experiments and their biotechnological implications, and discuss the open questions in the field.
Three-dimensional extent of flow stagnation in transcatheter heart valves
Authors: Raghav Vrishank , Clifford Chris , Midha Prem , Okafor Ikechukwu , Thurow Brian , Yoganathan Ajit
Published: May 2019

The recent unexpected discovery of thrombosis in transcatheter heart valves (THVs) has led to increased concerns of long-term valve durability. Based on the clinical evidence combined with Virchow's triad, the primary hypothesis is that low-velocity blood flow around the valve could be a primary cause for thrombosis. However, due to limited optical access in such unsteady three-dimensional biomedical flows, measurements are challenging. In this study, for the first time, we employ a novel single camera volumetric velocimetry technique to investigate unsteady three-dimensional cardiovascular flows. Validation of the novel volumetric velocimetry technique with standard planar particle image velocimetry (PIV) technique demonstrated the feasibility of adopting this new technique to investigate biomedical flows. This technique was used to quantify the three-dimensional velocity field in the vicinity of a validated, custom developed, transparent THV in a bench-top pulsatile flow loop. Large volumetric regions of flow stagnation were observed in the neo-sinus throughout the cardiac cycle, with stagnation defined as a velocity magnitude lower than 0.05 m s
−1
. The volumetric scalar viscous shear stress quantified via the three-dimensional shear stress tensor was within the range of low shear-inducing thrombosis observed in the literature. Such high-fidelity volumetric quantitative data and novel imaging techniques used to obtain it will enable fundamental investigation of heart valve thrombosis in addition to providing a reliable and robust database for validation of computational tools.
Eyes on the size: accuracy of visual length estimates of white sharks,
Carcharodon carcharias
Authors: May Cameron , Meyer Lauren , Whitmarsh Sasha , Huveneers Charlie
Published: May 2019

Visual estimates have been used extensively to determine the length of large organisms that are logistically challenging to measure. However, there has been little effort to quantify the accuracy or validity of this technique despite inaccurate size estimates leading to incorrect population assessments and misinformed management strategies. Here, we compared visually estimated total length measurements of white sharks,
Carcharodon carcharias
, during cage-diving operations with measurements obtained from stereo-video cameras and assessed the accuracy of those estimates in relation to suspected biases (shark size, and observer experience and gender) using generalized linear mixed-models and linear regressions. Observer experience on board cage-diving vessels had the greatest effect on the accuracy of visual length estimates, with
scientists
being more accurate (mean accuracy ± standard error: 23.0 ± 16.5 cm) than
crew
(39.9 ± 33.8 cm) and
passengers
(49.4 ± 38.5 cm). Observer gender and shark size had no impact on the overall accuracy of visual length estimates, but
passengers
overestimated sharks less than 3 m and underestimated sharks greater than 3 m. Our findings show that experience measuring animals is the most substantial driver of accurate visual length estimates regardless of the amount of exposure to the species being measured.
Scientists
were most accurate, even though
crew
observe white sharks more frequently. Our results show that visual length estimates are not impacted by shark size and are a valid measurement tool for many aspects of
C. carcharias
research, provided they come from people who have previously been involved in measuring animals, i.e.
scientists
.
Na
+
K
+
ATPase isoform switching in zebrafish during transition to dilute freshwater habitats
Authors: Esbaugh Andrew J. , Brix Kevin V. , Grosell Martin
Published: May 2019

Na
+
K
+
ATPase (NKA) is crucial to branchial ion transport as it uses the energy from ATP to move Na
+
against its electrochemical gradient. When fish encounter extremely dilute environments the energy available from ATP hydrolysis may not be sufficient to overcome thermodynamic constraints on ion transport. Yet many fish species—including zebrafish—are capable of surviving in dilute environments. Despite much study, the physiological mechanisms by which this occurs remain poorly understood. Here, we demonstrate that zebrafish acclimated to less than 10 µM Na
+
water exhibit upregulation of a specific NKA
α
subunit (
zatp1a1a.5
) that, unlike most NKA heterotrimers, would result in transfer of only a single Na
+
and K
+
per ATP hydrolysis reaction. Thermodynamic models demonstrate that this change is sufficient to reduce the activation energy of NKA, allowing it to overcome the adverse electrochemical gradient imposed by dilute freshwater. Importantly, upregulation of
zatp1a1a.5
also coincides with the recovery of whole body Na
+
post-transfer, which occurs within 24 h. While these structural modifications are crucial for allowing zebrafish to survive in ion-poor environments, phylogenetic and structural analysis of available α subunits from a range of teleosts suggests this adaptation is not widely distributed.
One model to rule them all? Modelling approaches across OneHealth for human, animal and plant epidemics
Authors: Kleczkowski Adam , Hoyle Andy , McMenemy Paul
Published: May 2019

One hundred years after the 1918 influenza outbreak, are we ready for the next pandemic? This paper addresses the need to identify and develop collaborative, interdisciplinary and cross-sectoral approaches to modelling of infectious diseases including the fields of not only human and veterinary medicine, but also plant epidemiology. Firstly, the paper explains the concepts on which the most common epidemiological modelling approaches are based, namely the division of a host population into susceptible, infected and removed (SIR) classes and the proportionality of the infection rate to the size of the susceptible and infected populations. It then demonstrates how these simple concepts have been developed into a vast and successful modelling framework that has been used in predicting and controlling disease outbreaks for over 100 years. Secondly, it considers the compartmental models based on the SIR paradigm within the broader concept of a ‘disease tetrahedron’ (comprising host, pathogen, environment and man) and uses it to review the similarities and differences among the fields comprising the ‘OneHealth’ approach. Finally, the paper advocates interactions between all fields and explores the future challenges facing modellers.

This article is part of the theme issue ‘Modelling infectious disease outbreaks in humans, animals and plants: approaches and important themes’. This issue is linked with the subsequent theme issue ‘Modelling infectious disease outbreaks in humans, animals and plants: epidemic forecasting and control’.
Host density dependence and environmental factors affecting laurel wilt invasion
Authors: Choudhury Robin A. , Er Hong L. , Hughes Marc , Smith Jason A. , Pruett Grechen E. , Konkol Joshua , Ploetz Randy C. , Marois James J. , Garrett Karen A. , van Bruggen Ariena H.C.
Published: May 2019

Host size, density and distribution, in addition to climate, can affect the likelihood a pathogen will invade and saturate landscapes. Laurel wilt, caused by the vector-borne forest pathogenRaffaelea lauricola, has devastated populations of native Lauraceae in the Southeastern US, and continues to spread. We surveyed 87 plots in six coastal islands in South Carolina, Georgia and North Florida, and one inland site (Archbold Biological Station) in South Florida for laurel wilt-affected and non-affected individual plants belonging to the genusPersea. The coastal island sites were surveyed once in 2008 or 2009, and the inland site was surveyed eight times from 2011 to 2013. Disease incidence per plot ranged from 0% to 96%, with mean disease incidence 45% across all sites. Disease incidence was positively correlated with trunk diameter and density of hosts with trunk diameter > 5 cm, but negatively with the degree of clustering, which was highest for small trees. A recursive partitioning model indicated that higher disease incidence was associated with moderate temperatures, wider trunk diameter, lower relative humidity, and lower wind speeds. Disease progress over time at Archbold followed a Gompertz curve, plateauing at 3% in two years. The dispersal kernel for disease incidence from a focus followed a negative exponential distribution. The number of plots with diseased trees at Archbold was similar for redbay (P. borbonia) and swampbay (P. palustris), but was lower for silkbay (P. humilis). Understanding how host density, size, and diversity interact with environmental effects will help guide future risk prediction efforts.
Ultrastructural heterogeneity of human layer 4 excitatory synaptic boutons in the adult temporal lobe neocortex
Authors: Yakoubi Rachida , Rollenhagen Astrid , von Lehe Marec , Miller Dorothea , Walkenfort Bernd , Hasenberg Mike , Sätzler Kurt , Lübke Joachim HR
Published: May 2019

Synapses are fundamental building blocks that control and modulate the ‘behavior’ of brain networks. How their structural composition, most notably their quantitative morphology underlies their computational properties remains rather unclear, particularly in humans. Here, excitatory synaptic boutons (SBs) in layer 4 (L4) of the temporal lobe neocortex (TLN) were quantitatively investigated.

Biopsies from epilepsy surgery were used for fine-scale and tomographic electron microscopy to generate 3D-reconstructions of SBs. Particularly, the size of active zones (AZs) and of the three functionally defined pools of synaptic vesicles (SVs) were quantified.

SBs were comparably small (∼2.50 μm2), with a single AZ (∼0.13 µm2) and preferentially established on spines. SBs had a total pool of ∼1800SVs with strikingly large readily releasable (∼ 20), recycling (∼ 80) and resting pools (∼850).

Thus, human L4 SBs may act as ‘amplifiers’ of signals from the sensory periphery and integrate, synchronize and modulate intra- and extra-cortical synaptic activity.
β-bursts reveal the trial-to-trial dynamics of movement initiation and cancellation
Authors: Wessel Jan R.
Published: May 2019

The neurophysiological basis of motor processes and their control is of tremendous interest to basic researchers and clinicians alike. Notably, both movement initiation and cancellation are accompanied by prominent field potential changes in the β-frequency band (15-29Hz). In trial-averages, movement initiation is indexed by β-band desynchronization over sensorimotor sites, while movement cancellation is signified by β-power increases over (pre)frontal areas. However, averaging misrepresents the true nature of the β-signal. As recent work has highlighted, raw β-band activity is characterized by short-lasting, burst-like events, rather than by steady modulations. To investigate how such β-bursts relate to movement initiation and cancellation in humans, we investigated scalp-recorded β-band activity in 234 healthy subjects performing the Stop-signal task. Four observations were made: First, both movement initiation and cancellation were indexed by systematic, localized changes in β-bursting. While β-bursting at bilateral sensorimotor sites steadily declined during movement initiation, β-bursting increased at fronto-central sites when Stop-signals instructed movement cancellation. Second, the amount of fronto-central β-bursting clearly distinguished successful from unsuccessful movement cancellation. Third, the emergence of fronto-central β-bursting coincided with the latency of the movement cancellation process, indexed by Stop-signal reaction time. Fourth, individual fronto-central β-bursts during movement cancellation were followed by a low-latency re-instantiation of bilateral sensorimotor β-bursting. These findings suggest that β-bursting is a fundamental signature of the motor system, reflecting a steady inhibition of motor cortex that is suppressed during movement initiation, and can be rapidly re-instantiated by frontal areas when movements have to be rapidly cancelled.

Significance Statement

Movement-related β-frequency (15-29Hz) changes are among the most prominent features of neural recordings across species, scales, and methods. However, standard averaging-based methods obscure the true dynamics of β-band activity, which is dominated by short-lived, burst-like events. Here, we demonstrate that both movement-initiation and cancellation in humans are characterized by unique trial-to-trial patterns of β-bursting. Movement initiation is characterized by steady reductions of β-bursting over bilateral sensorimotor sites. In contrast, during rapid movement cancellation, β–bursts first emerge over fronto-central sites typically associated with motor control, after which sensorimotor β–bursting re-initiates. These findings suggest a fundamentally novel, non-invasive measure of the neural interaction underlying movement-initiation and –cancellation, opening new avenues for the study of motor control in health and disease.
Allelic polymorphism shapes community function in evolving Pseudomonas aeruginosa populations
Authors: Azimi Sheyda , Roberts Aled E. L. , Peng Shengyun , Weitz Joshua S. , McNally Alan , Brown Samuel P. , Diggle Stephen P.
Published: May 2019

Pseudomonas aeruginosa is an opportunistic pathogen that chronically infects the lungs of individuals with cystic fibrosis (CF) by forming antibiotic resistant biofilms. Emergence of phenotypically diverse isolates within CF P. aeruginosa populations has previously been reported, however, the impact of heterogeneity on social behaviors and community function is poorly understood. Here we describe how this heterogeneity impacts on behavioral traits by evolving the strain PAO1 in biofilms grown in a synthetic sputum medium for 50 days. We measured social trait production and antibiotic tolerance and used a metagenomic approach to analyze and assess genomic changes over the duration of the evolution experiment. We found that (i) evolutionary trajectories were reproducible in independently evolving populations; (ii) over 60% of genomic diversity occurred within the first 10 days of selection. We then focused on quorum sensing (QS), a well-studied P. aeruginosa trait that is commonly mutated in strains isolated from CF lungs. We found that at the population level (i) evolution in sputum medium selected for decreased production of QS and QS-dependent traits; (ii) there was a significant correlation between lasR mutant frequency, the loss of protease and the 3O-C12-HSL signal, and an increase in resistance to clinically relevant β-lactam antibiotics, despite no previous antibiotic exposure. Overall, our findings provide insights into the effect of allelic polymorphism on community functions in diverse P. aeruginosa populations. Further, we demonstrate that P. aeruginosa population and evolutionary dynamics can impact on traits important for virulence and can lead to increased tolerance to β-lactam antibiotics.
Ferroptosis is programmed by the coordinated regulation of glutathione and iron metabolism by BACH1
Authors: Nishizawa Hironari , Matsumoto Mitsuyo , Shindo Tomohiko , Saigusa Daisuke , Kato Hiroki , Suzuki Katsushi , Sato Masaki , Ishii Yusho , Shimokawa Hiroaki , Igarashi Kazuhiko
Published: May 2019

Ferroptosis is an iron-dependent programmed cell death resulting from alterations of metabolic processes. However, its regulation and physiological significance remain to be elucidated. By analyzing transcriptional responses of murine embryonic fibroblasts exposed to the ferroptosis-inducer erastin, we found that a set of genes related to oxidative stress protection was induced upon ferroptosis. We further showed that the transcription factor BACH1 promoted ferroptosis by repressing the expression of a subset of erastin-inducible genes involved in the synthesis of glutathione or metabolism of intracellular labile iron, including Gclm, Gclc, Slc7a11, Hmox1, Fth1, Ftl1, and Slc40a1. Compared with wild-type mice, Bach1-/- mice showed resistance to myocardial infarction, the seriousness of which was palliated by the iron-chelator deferasirox, which suppressed ferroptosis. Our findings suggest that ferroptosis is programmed at the transcriptional level to induce genes combating labile-iron-induced oxidative stress and executed upon disruption of the balance between the transcriptional induction of protective genes and accumulation of iron-mediated damage. BACH1 is suggested to control the threshold of ferroptosis and to be a therapeutic target for palliating myocardial infarction.
Rapid and sensitive quantitation of glucose and glucose phosphates derived from storage carbohydrates using gas chromatography mass spectrometry
Authors: Young Lyndsay E.A. , Brizzee Corey O. , Macedo Jessica K. A. , Gentry Matthew S. , Sun Ramon C.
Published: May 2019

Glycogen is the primary storage carbohydrate in mammals and it is synthesized in most tissues. Glycogen contains covalently attached phosphate groups on hydroxyls of glucose units. The addition of phosphate modulates branching pattern, granular size, and crystallinity of a glycogen molecule, which all impact its accessibility to glycogen interacting enzymes during catabolism. As glycogen architecture modulates its role in metabolism, it is essential to accurately evaluate and quantify phosphate content in glycogen. Simultaneous quantitation of glucose and its phosphate esters is challenging and requires an assay with high sensitivity and a robust dynamic range. Currently, this method is lacking in the field. Herein, we describe a highly-sensitive method for the detection of both glycogen-derived glucose and glucose-phosphate esters utilizing gas-chromatography coupled mass spectrometry. Using this method, we observed higher glycogen levels in the liver compared to skeletal muscle, but skeletal muscle contained much more phosphate esters. These results confirm previous findings and establish the validity of the method. Importantly, this method can detect femtomole levels of glucose and glucose phosphate esters within an extremely robust dynamic range with excellent accuracy and reproducibility. The method can also be easily adapted for the quantification of glucose from plant starch, amylopectin or other biopolymers as well as covalently attached phosphate within them.
Directional stepping model for yeast dynein: Longitudinal- and side- step distributions
Authors: Fayer Itay , Granek Rony
Published: May 2019

We deduce the directional step distribution of yeast dynein motor protein on the microtubule surface by combing intrinsic features of the dynein and microtubule. These include the probability distribution of the separation vector between the two microtubule binding domains (MTBDs), the angular probability distribution of a single MTBD translation, the existence of a microtubule seam defect, microtubule binding sites, and theoretical extension that accounts for a load force on the motor. Our predictions are in excellent accord with the measured longitudinal step size distributions at various load forces. Moreover, we predict the side-step distribution and its dependence on longitudinal load forces, which shows a few surprising features. First, the distribution is broad. Second, in the absence of load, we find a small right-hand bias. Third, the side-step bias is susceptible to the longitudinal load force; it vanishes at a load equal to the motor stalling force and changes to a left-hand bias above that value. Fourth, our results are sensitive to the ability of the motor to explore the seam several times during its walk. While available measurements of side-way distribution are limited, our findings are amenable to experimental check and, moreover, suggest a diversity of results depending on whether the microtubule seam is viable to motor sampling.

Significance Statement

The function of microtubule (MT) associated protein motors, kinesin and dynein, is essential for a myriad of intracellular processes. Different measurements on yeast cytoplasmic-dynein stepping characteristics appear to be unrelated to each other. We provide a unified physical-statistical model that combines these seemingly independent features with a theoretical expression that accounts for the exertion of a longitudinal load force, to yield the longitudinal step distribution at various load forces. The latter is in excellent accord with the measured distributions. Moreover, we deduce the side-step distribution, which surprisingly is susceptible to longitudinal load forces and comprises a right or left bias. This side-way bias is consistent with observations of helical motion of a nanoparticle carried by a number of motors.
PUMILIO, but not RBMX, binding is required for regulation of genomic stability by noncoding RNA NORAD
Authors: Elguindy Mahmoud M. , Kopp Florian , Goodarzi Mohammad , Rehfeld Frederick , Thomas Anu , Chang Tsung-Cheng , Mendell Joshua T.
Published: May 2019

NORAD is a highly-conserved and abundant long noncoding RNA (lncRNA) that is required for maintenance of genomic stability in mammals. Although initial characterization of NORAD established it as a negative regulator of PUMILIO (PUM) proteins in the cytoplasm, a nuclear role for NORAD in genome maintenance through an interaction with the RNA binding protein RBMX has also been reported. Here we addressed the relative contributions of NORAD:PUM and NORAD:RBMX interactions to the regulation of genomic stability by this lncRNA. Extensive RNA FISH and fractionation experiments established that NORAD localizes predominantly to the cytoplasm with or without DNA damage. Moreover, genetic rescue experiments demonstrated that PUM binding is required for maintenance of genomic stability by NORAD whereas binding of RBMX is dispensable for this function. These data therefore establish an essential role for the NORAD:PUM interaction in genome maintenance and provide a foundation for further mechanistic dissection of this pathway.
Epigenomic profiling discovers trans-lineage SOX2 partnerships driving tumor heterogeneity in lung squamous cell carcinoma
Authors: Sato Takashi , Yoo Seungyeul , Kong Ranran , Fridrikh Maya , Sinha Abhilasha , Chandramani-Shivalingappa Prashanth , Patel Ayushi , Nagano Osamu , Masuko Takashi , Beasley Mary Beth , Powell Charles A. , Zhu Jun , Watanabe Hideo
Published: May 2019

Molecular characterization of lung squamous cell carcinoma (LUSC), a major subtype of lung cancer, has not sufficiently improved its non-stratified treatment strategies over decades. Accumulating evidence suggests that lineage-specific transcriptional regulators control differentiation states during cancer evolution, and underlie their distinct biological behaviors. In this study, by investigating the super-enhancer landscape of LUSC, we identified a previously undescribed ‘neural’ subtype defined by Sox2 and a neural lineage factor Brn2, as well as the classical LUSC subtype defined by Sox2 and its classical squamous partner p63. Robust protein-protein interaction and genomic co-occupancy of Sox2 and Brn2, in place for p63 in the classical LUSC, indicated their transcriptional cooperation imparting this unique lineage state in the ‘neural’ LUSC. Forced expression of p63 downregulated Brn2 in the ‘neural’ LUSC cells and invoked the classical LUSC lineage with more squamous/epithelial features, which were accompanied by increased activities of ErbB/Akt and MAPK-ERK pathways suggesting differential dependency. Collectively, our data demonstrate heterogeneous cell lineage states of LUSC featured by Sox2 cooperation with Brn2 or p63, for which distinct therapeutic approaches may be warranted.
Cataract-associated deamidations on the surface of γS-crystallin increase protein unfolding and flexibility at distant regions
Authors: Forsythe Heather M. , Vetter Calvin , Jara Kayla Ann , Reardon Patrick N. , David Larry L. , Barbar Elisar J. , Lampi Kirsten J.
Published: May 2019

Deamidation is a major age-related modification in the human lens that is highly prevalent in crystallins isolated from cataractous lenses. However, the mechanism by which deamidation causes proteins to become insoluble is not known, because of only subtle structural changes observed in vitro. We have identified Asn14 and Asn76 of γS-crystallin as highly deamidated in insoluble proteins. These sites are on the surface of the N-terminal domain and were mimicked by replacing the Asn with Asp residues. We used heteronuclear NMR spectroscopy to measure their amide hydrogen exchange and 15N relaxation dynamics to identify regions with significantly increased dynamics compared to wildtype-γS. Changes in dynamics were localized to the C-terminal domain, particularly to helix and surface loops distant from the mutation sites. Thus, a potential mechanism for γS deamidation-induced insolubilization in cataractous lenses is altered dynamics due to local regions of unfolding and increased flexibility.
Nup93 and CTCF co-modulate spatiotemporal dynamics and function of the HOXA gene cluster during differentiation
Authors: Labade Ajay S. , Salvi Adwait , Karmodiya Krishanpal , Sengupta Kundan
Published: May 2019

Nucleoporins regulate nuclear transport. In addition, nucleoporins also modulate chromatin organization and gene expression. Here we investigated the role of nucleoporin Nup93, in regulating HOXA gene expression during differentiation. ChIP-Seq analysis revealed that Nup93 associates with genes involved in development and differentiation. Furthermore, Nup93 occupancy significantly overlaps with CTCF. Interestingly, Nup93 and CTCF show antagonistic roles in regulating 3’ and 5’ end HOXA genes in undifferentiated cells. The HOXA gene locus untethered from the nuclear periphery upon Nup93 but not CTCF depletion, consistent with its upregulation. Remarkably, occupancy of Nup93 and CTCF on HOXA gene locus progressively declined during differentiation but was restored in differentiated cells, consistent with the rerepression and re-localization of the HOXA gene locus with the nuclear periphery upon differentiation. In summary, Nup93 is a key modulator of the spatiotemporal dynamics and function of the HOXA gene locus during differentiation.
Mastitis risk effect on the economic consequences of paratuberculosis control in dairy cattle: A stochastic modeling study
Authors: Chiu L. J. Verteramo , Tauer L. W. , Gröhn Y.T. , Smith R. L.
Published: May 2019

The benefits and efficacy of control programs for herds infected with Mycobacterium avium subsp. paratuberculosis (MAP) have been investigated under various contexts. However, most previous research investigated paratuberculosis control programs in isolation, without modeling the potential association with other dairy diseases. This paper evaluated the benefits of MAP control programs when the herd is also affected by mastitis, a common disease causing the largest losses in dairy production. The effect of typically suggested MAP controls were estimated under the assumption that MAP infection increased the rate of clinical mastitis. We evaluated one hundred twenty three control strategies comprising various combinations of testing, culling, and hygiene, and found that the association of paratuberculosis with mastitis alters the ranking of specific MAP control programs, but only slightly alters the cost-effectiveness of particular MAP control components, as measured by the distribution of net present value of a representative U.S. dairy operation. In particular, although testing and culling for MAP resulted in a reduction in MAP incidence, that control led to lower net present value (NPV) per cow. When testing was used, ELISA was more cost-effective than alternative testing regimes, especially if mastitis was explicitly modeled as more likely in MAP-infected animals, but ELISA testing was only significantly associated with higher NPV if mastitis was not included in the model at all. Additional hygiene was associated with a lower NPV per cow, although it lowered MAP prevalence. Overall, the addition of an increased risk of mastitis in MAP-infected animals did not change model recommendations as much as failing to consider mastitis at all.
Intrinsically disordered proteins and structured proteins with intrinsically disordered regions have different functional roles in the cell
Authors: Deiana Antonio , Forcelloni Sergio , Porrello Alessandro , Giansanti Andrea
Published: May 2019

Many studies about classification and the functional annotation of intrinsically disordered proteins (IDPs) are based on either the occurrence of long disordered regions or the fraction of disordered residues in the sequence. Taking into account both criteria we separate the human proteome, taken as a case study, into three variants of proteins: i) ordered proteins (ORDPs), ii) structured proteins with intrinsically disordered regions (IDPRs), and iii) intrinsically disordered proteins (IDPs). The focus of this work is on the different functional roles of IDPs and IDPRs, which up until now have been generally considered as a whole. Previous studies assigned a large set of functional roles to the general category of IDPs. We show here that IDPs and IDPRs have non-overlapping functional spectra, play different roles in human diseases, and deserve to be treated as distinct categories of proteins. IDPs enrich only a few classes, functions, and processes: nucleic acid binding proteins, chromatin binding proteins, transcription factors, and developmental processes. In contrast, IDPRs are spread over several functional protein classes and GO annotations which they partly share with ORDPs. As regards to diseases, we observe that IDPs enrich only cancer-related proteins, at variance with previous results reporting that IDPs are widespread also in cardiovascular and neurodegenerative pathologies. Overall, the operational separation of IDPRs from IDPs is relevant towards correct estimates of the occurrence of intrinsically disordered proteins in genome-wide studies and in the understanding of the functional spectra associated to different flavors of protein disorder.
Room-temperature photo-induced martensitic transformation in a protein crystal
Authors: Dajnowicz Steven , Langan Patricia S. , Weiss Kevin L. , Ivanov Ilia N. , Kovalevsky Andrey
Published: May 2019

Martensitic transformations are the first-order crystal-to-crystal phase transitions that occur mostly in materials such as steel, alloys and ceramics, thus having many technological applications. These phase transitions are rarely observed in molecular crystals and have not been detected in protein crystals. Reversibly switchable fluorescent proteins are widely used in biotechnology, including super-resolution molecular imaging, and hold promise as candidate biomaterials for future high-tech applications. Here, we report on a reversibly switchable fluorescent protein, Tetdron, whose crystals undergo a photo-induced martensitic transformation at room temperature. Room-temperature X-ray crystallography demonstrates that at equilibrium Tetdron chromophores are all in the trans configuration, with an ∼1:1 mixture of their protonated and deprotonated forms. Irradiation of a Tetdron crystal with 400 nm light induces a martensitic transformation, which results in Tetdron tetramerization at room temperature revealed by X-ray photocrystallography. Crystal and solution spectroscopic measurements provide evidence that the photo-induced martensitic phase transition is coupled with the chromophore deprotonation, but no trans–cis isomerization is detected in the structure of an irradiated crystal. It is hypothesized that protein dynamics assists in the light-induced proton transfer from the chromophore to the bulk solvent and in the ensuing martensitic phase transition. The unique properties of Tetdron may be useful in developing novel biomaterials for optogenetics, data storage and nanotechnology.
Cocrystals in the Cambridge Structural Database: a network approach
Authors: Devogelaer Jan-Joris , Meekes Hugo , Vlieg Elias , de Gelder René
Published: May 2019

To obtain a better understanding of which coformers to combine for the successful formation of a cocrystal, techniques from data mining and network science are used to analyze the data contained in the Cambridge Structural Database (CSD). A network of coformers is constructed based on cocrystal entries present in the CSD and its properties are analyzed. From this network, clusters of coformers with a similar tendency to form cocrystals are extracted. The popularity of the coformers in the CSD is unevenly distributed: a small group of coformers is responsible for most of the cocrystals, hence resulting in an inherently biased data set. The coformers in the network are found to behave primarily in a bipartite manner, demonstrating the importance of combining complementary coformers for successful cocrystallization. Based on our analysis, it is demonstrated that the CSD coformer network is a promising source of information for knowledge-based cocrystal prediction.
Simulation of diffuse scattering in DL-norleucine
Authors: Welberry Thomas Richard , Görbitz Carl Henrik
Published: May 2019

The diffraction patterns of DL-norleucine (SR-2-aminohexanoic acid, DL-Nle) crystals may show obvious diffuse scattering, usually described as `streaking', between the Bragg peaks. This phenomenon is obviously related to the non-ideal behaviour of the crystal. The normal interpretation is disorder in the stacking of weakly interacting 2D layers, known also for a number of other racemates of amino acids with linear hydrophobic side chains, as well as 1:1 complexes between different L- and D-enantiomers (quasi-racemates). Presented here is the first attempt to extract the information hidden in the diffuse scattering for this group of compounds by applying Monte Carlo simulations to the site distributions of two polymorphs in a block of 48 × 48 × 48 unit cells (four sites in each unit cell, 442 368 in total). The results demonstrate that it is indeed possible to model the diffuse scattering and relate it to processes expected to take place during phase transitions, characterized by slipping of molecular bilayers (or parts of them) relative to their neighbours. The understanding of the (intermediate) mixed phases in terms of domain size and defect density is consequently brought to a new level.
Corporate governance and corporate internet reporting in sub-Saharan Africa:the case of Kenya and Tanzania
Authors: Waweru Nelson , Mangena Musa , Riro George
Published: May 2019

Purpose

This paper aims to investigate corporate internet reporting (CIR) by Kenyan and Tanzanian listed companies and whether the level of CIR is related to corporate governance structures.

Design/methodology/approach

The authors collect data over a four-year period from companies listed on the Nairobi Securities Exchange and the Dar es Salaam Securities Exchange. Panel data models (random effects) are used for the analysis.

Findings

The results indicate that the level of CIR in both countries is high, but the highest in Kenya. The authors find that CIR increases with foreign ownership, audit committee independence and financial expertise but decreases with domestic ownership concentration. They also show that the effects of ownership concentration are moderated by country-specific factors. Overall, the results demonstrate that effective governance structures may lead to higher levels CIR in sub-Saharan Africans.

Originality/value

This study extends, as well as contributes to the existing literature by the examining the corporate governance-disclosure nexus relating to CIR in sub-Saharan Africa. These findings have policy implications for African countries looking to attract foreign investment.
Corporate governance in Ghana
Authors: Amartey Larry Amartei , Yu Mei , Chukwu-lobelu Osita
Published: May 2019

Purpose

This study aims to examine the mechanisms that were being used to enhance board accountability of Ghanaian listed banks, and how board accountability can be improved.

Design/methodology/approach

The 2011 and 2016 annual reports of listed banks on the Ghana Stock Exchange were examined, and a survey questionnaire was sent to board members of nine banks.

Findings

The results show that the directors of Ghanaian listed banks prioritise a shareholder approach to accountability, with a shift towards stakeholders. Audit committees, external audits and internal audits were the main mechanisms used by these banks to enhance board accountability. Some of these mechanisms were not used effectively by a number of these banks.

Practical implications

Board accountability can be improved by appointing very competent people to the board, the national adoption of a mandatory code of corporate governance, regular rotation of external auditors and requiring non-executive directors to stand for re-election more frequently. Our research identifies weaknesses of accountability mechanisms and offers timely recommendations for banks and regulators to build stronger corporate governance systems.

Originality/value

This study obtained valuable opinions of the boards of directors, provides insights on boards of Ghanaian listed banks and contributes to the literature of corporate governance and accountability in Africa.