bluuebunny/crossref_metadata_2025 huggingface dataset:
Whole genome sequencing reveals the emergence of aPseudomonas aeruginosashared strain sub-lineage among patients treated within a single cystic fibrosis centre
Authors: Wee Bryan A. , Tai Anna S. , Sherrard Laura J. , Ben Zakour Nouri L. , Hanks Kirt R. , Kidd Timothy J. , Ramsay Kay A. , Lamont Iain , Whiley David M. , Bell Scott C. , Beatson Scott A.
Published: March 2018

Background

Chronic lung infections byPseudomonas aeruginosaare a significant cause of morbidity and mortality in people with cystic fibrosis (CF). SharedP. aeruginosastrains, that can be transmitted between patients, are of concern and in Australia the AUST-02 shared strain is predominant in individuals attending CF centres in Queensland and Western Australia. M3L7 is a multidrug resistant sub-type of AUST-02 that was recently identified in a Queensland CF centre and was shown to be associated with poorer clinical outcomes. The main aim of this study was to resolve the relationship of the emergent M3L7 sub-type within the AUST-02 group of strains using whole genome sequencing.

Results

A whole-genome core phylogeny of 63 isolates indicated that M3L7 is a monophyletic sub-lineage within the context of the broader AUST-02 group. Relatively short branch lengths connected all of the M3L7 isolates. A phylogeny based on nucleotide polymorphisms present across the genome showed that the chronological estimation of the most recent common ancestor was around 2001 (± 3 years). SNP differences between sequential M3L7 isolates collected 3-4 years apart from five patients suggested both continuous infection of the same strain and cross-infection of some M3L7 variants between patients. The majority of polymorphisms that were characteristic of M3L7 (i.e. acquired after divergence from all other AUST-02 isolates sequenced) were found to produce non-synonymous mutations in virulence and antibiotic resistance genes.

Conclusions

M3L7 has recently diverged from a common ancestor indicating descent from a single carrier at a CF treatment centre in Australia. Both adaptation to the lung and transmission of M3L7 between adults attending this centre may have contributed to its rapid dissemination. The study emphasises the importance of clinical management in controlling the emergence of shared strains in CF.
Mathematical modeling and simulations for large-strain J-shaped diagrams of soft biological tissues
Authors: Mitsuhashi K. , Ghosh S. , Koibuchi H.
Published: March 2018

Herein, we study stress-strain diagrams of soft biological tissues such as animal skin, muscles and arteries by Finsler geometry (FG) modeling. The stress-strain diagram of these biological materials is always J-shaped and is composed of toe, heel, linear and failure regions. In the toe region, the stress is zero, and the length of this zero-stress region becomes very large (≃ 150%) in, for example, certain arteries. In this paper, we study long-toe diagrams using two-dimensional (2D) and 3D FG modeling techniques and Monte Carlo (MC) simulations. We find that except for the failure region, large-strain J-shaped diagrams are successfully reproduced by the FG models. This implies that the complex J-shaped curves originate from the interaction between the directional and positional degrees of freedom of polymeric molecules, as implemented in the FG model.
Weakly-bound Dimers that Underlie the Crystal Nucleation Precursors in Lysozyme Solutions
Authors: Byington M.C. , Safari M.S. , Lubchenko V. , McCabe J.W. , Angel L.A. , Hawke D.H. , Bark S.J. , Conrad J.C. , Vekilov P.G.
Published: March 2018

Protein crystallization is central to understanding of molecular structure in biology, a vital part of processes in the pharmaceutical industry, and a crucial component of numerous disease pathologies. Crystallization starts with nucleation and how nucleation proceeds determines the crystallization rate and essential properties of the resulting crystal population. Recent results with several proteins indicate that crystals nucleate within preformed mesoscopic protein-rich clusters. The origin of the mesoscopic clusters is poorly understood. In the case of lysozyme, a common model of protein biophysics, earlier findings suggest that clusters exist owing to the dynamics of formation and decay of weakly-bound transient dimers. Here we present evidence of a weakly bound lysozyme dimer in solutions of this protein. We employ two electrospray mass spectrometry techniques, a combined ion mobility separation mass spectrometry and a high-resolution implementation. To enhance the weak but statistically-significant dimer signal we develop a method based on the residuals between the maxima of the isotope peaks in Fourier space and their Gaussian envelope. We demonstrate that these procedures sensitively detect the presence of a non-covalently bound dimer and distinguish its signal from other polypeptides, noise, and sampling artefacts. These findings contribute essential elements of the crystal nucleation mechanism of lysozyme and other proteins and suggest pathways to control nucleation and crystallization by enhancing or suppressing weak oligomerization.
A fluorescence correlation spectrometer for measurements in cuvettes
Authors: Sahoo B , Sil TB , Karmakar B , Garai K
Published: March 2018

We have developed a fluorescence correlation spectroscopy (FCS) setup for performing single molecule measurements on samples inside regular cuvettes. We built this by using an Extra Long Working Distance (ELWD), 0.7 NA, air objective with working distance > 1.8 mm. We have achieved counts per molecule > 44 kHz, diffusion time < 64 μs for rhodamine B in aqueous buffer and a confocal volume < 2 fl. The cuvette-FCS can be used for measurements over a wide range of temperature that is beyond the range permitted in the microscope-based FCS. Finally, we demonstrate that cuvette-FCS can be coupled to automatic titrators to study urea dependent unfolding of proteins with unprecedented accuracy. The ease of use and compatibility with various accessories will enable applications of cuvette-FCS in the experiments that are regularly performed in fluorimeters but are generally avoided in microscope-based FCS.
A theoretical high-density nanoscopy study leads to the design of UNLOC, an unsupervised algorithm
Authors: Mailfert Sébastien , Touvier Jérôme , Benyoussef Lamia , Fabre Roxane , Rabaoui Asma , Blache Marie-Claire , Hamon Yannick , Brustlein Sophie , Monneret Serge , Marguet Didier , Bertaux Nicolas
Published: March 2018

Among the superresolution microscopy techniques, the ones based on serially imaging sparse fluorescent particles enable the reconstruction of high-resolution images by localizing single molecules. Although challenging, single-molecule localization microscopy (SMLM) methods aim at listing the position of individual molecules leading a proper quantification of the stoichiometry and spatial organization of molecular actors. However, reaching the precision requested to localize accurately single molecules is mainly constrained by the signal-to-noise ratio (SNR) but also the density (Dframe), i.e., the number of fluorescent particles per μm2per frame. Of central interest, we establish here a comprehensive theoretical study relying on both SNR andDframeto delineate the achievable limits for accurate SMLM observations. We demonstrate that, for low-density hypothesis (i.e. one-Gaussian fitting hypothesis), any fluorescent particle biases the localization of a particle of interest when they are distant by less than ≈ 600 nm. Unexpectedly, we also report that even dim fluorescent particles should be taken into account to ascertain unbiased localization of any surrounding particles. Therefore, increasedDframequickly deteriorates the localization precision, the image reconstruction and more generally the quantification accuracy. The first outcome is a standardized density-SNR space diagram to determine the achievable SMLM resolution expected with experimental data. Additionally, this study leads to the identification of the essential requirements for implementing UNLOC (UNsupervised particle LOCalization), an unsupervised and fast computing algorithm approaching the Cramér-Rao bound for particles at high-density per frame and without any prior on their intensity. UNLOC is available as an ImageJ plugin.
Developmental origin and morphogenesis of the diaphragm, an essential mammalian muscle
Authors: Sefton Elizabeth M , Gallardo Mirialys , Kardon Gabrielle
Published: March 2018

The diaphragm is a mammalian skeletal muscle essential for respiration and for separating the thoracic and abdominal cavities. Development of the diaphragm requires the coordinated development of muscle, muscle connective tissue, tendon, nerves, and vasculature that derive from different embryonic sources. However, defects in diaphragm development are common and the cause of an often deadly birth defect, Congenital Diaphragmatic Hernia (CDH). Here we comprehensively describe the normal developmental origin and complex spatial-temporal relationship between the different developing tissues to form a functional diaphragm using a developmental series of mouse embryos genetically and immunofluorescently labeled and analyzed in whole mount. We find that the earliest developmental events are the emigration of muscle progenitors from cervical somites followed by the projection of phrenic nerve axons from the cervical neural tube. Muscle progenitors and phrenic nerve target the pleuroperitoneal folds (PPFs), transient pyramidal-shaped structures that form between the thoracic and abdominal cavities. Subsequently, the PPFs expand across the surface of the liver to give rise to the muscle connective tissue and central tendon, and the leading edge of their expansion precedes muscle morphogenesis, formation of the vascular network, and outgrowth and branching of the phrenic nerve. Thus development and morphogenesis of the PPFs is critical for diaphragm formation. In addition, our data indicate that the earliest events in diaphragm development are critical for the etiology of CDH and instrumental to the evolution of the diaphragm. CDH initiates prior to E12.5 in mouse and suggests that defects in the early PPF formation or their ability to recruit muscle are an important source of CDH. Also, the recruitment of muscle progenitors from cervical somites to the nascent PPFs is uniquely mammalian and a key developmental innovation essential for the evolution of the muscularized diaphragm.

Highlights

Diaphragm development begins with emigration of muscle progenitors from cervical somites.

Phrenic nerve axons follow muscle path towards nascent pleuroperitoneal folds (PPFs).

PPFs are the target of muscle migration and phrenic nerve axon projection

PPF expansion precedes and likely directs muscle, nerve, and vasculature development.

Early defects in PPFs and muscle recruitment are likely a source of CDH.
A network for computing value homeostasis in the human medial prefrontal cortex
Authors: Juechems Keno , Balaguer Jan , Castañón Santiago Herce , Ruz María , O’Reilly Jill X. , Summerfield Christopher
Published: March 2018

Humans and other animals make decisions in order to satisfy their goals. However, it remains unknown how neural circuits compute which of multiple possible goals should be pursued (e.g. when balancing hunger and thirst) and combine these signals with estimates of available reward alternatives. Here, humans undergoing functional magnetic resonance imaging (fMRI) accumulated two distinct assets over a sequence of trials. Financial outcomes depended on the minimum cumulate of either asset, creating a need to maintain “value homeostasis” by redressing any imbalance among the assets. BOLD signals in the dorsal anterior cingulate cortex (dACC) tracked the level of homeostatic imbalance among goals, whereas the ventromedial prefrontal cortex (vmPFC) signalled the level of homeostatic redress incurred by a choice, rather than the overall amount received. These results suggest that a network of medial frontal brain regions compute a value signal that maintains homeostatic balance among internal goals.
Dimensionality Reduction on Spatio-Temporal Maximum Entropy Models of Spiking Networks
Authors: Herzog Rubén , Escobar María-José , Cofre Rodrigo , Palacios Adrián G. , Cessac Bruno
Published: March 2018

Maximum entropy models (MEM) have been widely used in the last 10 years to characterize the statistics of networks of spiking neurons. A major drawback of this approach is that the number of parameters used in the statistical model increases very fast with the network size, hindering its interpretation and fast computation. Here, we present a novel framework of dimensionality reduction for generalized MEM handling spatio-temporal correlations. This formalism is based on information geometry where a MEM is a point on a large-dimensional manifold. We exploit the geometrical properties of this manifold in order to find a projection on a lower dimensional space that best captures the high-order statistics. This allows us to define a quantitative criterion that we call the “degree of compressibility” of the neuronal code. A powerful aspect of this method is that it does not require fitting the model. Indeed, the matrix defining the metric of the manifold is computed directly via the data without parameters fitting. The method is first validated using synthetic data generated by a known statistics. We then analyze a MEM having more parameters than the underlying data statistics and show that our method detects the extra dimensions. We then test it on experimental retinal data. We record retinal ganglion cells (RGC) spiking data using multi-electrode arrays (MEA) under different visual stimuli: spontaneous activity, white noise stimulus, and natural scene. Using our method, we report a dimensionality reduction up to 50% for retinal data. As we show, this is quite a huge reduction compared to a randomly generated spike train, suggesting that the neuronal code, in these experiments, is highly compressible. This additionally shows that the dimensionality reduction depends on the stimuli statistics, supporting the idea that sensory networks adapt to stimuli statistics by modifying the level of redundancy.

Author Summary

Maximum entropy models (MEM) have been widely used to characterize the statistics of networks of spiking neurons. However, as the network size increases, the number of model parameters increases rapidly, hindering its interpretation and fast computation. Here, we propose a method to evaluate the dimensionality reduction of MEM, based on the geometrical properties of the manifold best capturing the network high-order statistics. Our method is validated with synthetic data using independent or correlated neural responses. Importantly, we show that dimensionality reduction depends on the stimuli statistics, supporting the idea that sensory networks adapt to stimuli statistics modifying the level of redundancy.
Cellular cooperation shapes tumor growth: a statistical mechanics mathematical model
Authors: West Jeffrey , Newton Paul K.
Published: March 2018

A tumor is made up of a heterogeneous collection of cell types all competing on a fitness landscape mediated by micro-environmental conditions that dictate their interactions. Despite the fact that much is known about cell signaling and cellular cooperation, the specifics of how the cell-to-cell coupling and the range over which this coupling acts affect the macroscopic tumor growth laws that govern total volume, mass, and carrying capacity remain poorly understood. We develop a statistical mechanics approach that focuses on the total number of possible states each cell can occupy, and show how different assumptions on correlations of these states gives rise to the many different macroscopic tumor growth laws used in the literature. Although it is widely understood that molecular and cellular heterogeneity within a tumor is a driver of growth, here we emphasize that focusing on the functional coupling of these states at the cellular level is what determines macroscopic growth characteristics.

Significance statement

A mathematical model relating tumor heterogeneity at the cellular level to tumor growth at the macroscopic level is described based on a statistical mechanics framework. The model takes into account the number of accessible states available to each cell as well as their long-range coupling (population cooperation) to other cells. We show that the degree to which cell populations cooperate determine the number of independent cell states, which in turn dictates the macroscopic (volumetric) growth law. It follows that targeting cell-to-cell interactions could be a way of mitigating and controlling tumor growth.
Behavioral phenotyping of an improved mouse model of Phelan-McDermid Syndrome with a complete deletion of the Shank3 gene
Authors: Drapeau Elodie , Riad Mohammed , Kajiwara Yuji , Buxbaum Joseph D.
Published: March 2018

Phelan-McDermid Syndrome (PMS) is a rare genetic disorder in which one copy of the SHANK3 gene is missing or mutated, leading to a global developmental delay, intellectual disability, and autism. Multiple intragenic promoters and alternatively spliced exons are responsible for the formation of numerous isoforms. Many genetically-modified mouse models of PMS have been generated but most disrupt only some of the isoforms. In contrast, the vast majority of known SHANK3 mutations found in patients involve deletions that disrupt all isoforms. Here, we report the production and thorough behavioral characterization of a new mouse model in which all Shank3 isoforms are disrupted. Our mice are more severely affected than previously published models. While the deficits were typically more pronounced in homozygotes, an intermediate phenotype was observed for heterozygotes in many paradigms. As in other Shank3 mouse models, stereotypies, including increased grooming, were observed. Additionally, both sensory and motor deficits were detected in neonatal and adult mice. While social behaviors were not strongly impacted, Shank3-deficient mice displayed a strong escape behavior and avoidance of inanimate objects indicating increased novelty-induced anxiety. Similarly, increased freezing was observed during fear conditioning training and amygdala-dependent cued retrieval. Finally, deficits were observed in both initial training and reversal in the Barnes maze and in contextual fear memory that are memory tasks involving hippocampal-prefrontal circuits. This new mouse model of PMS, engineered to most closely represent human mutations, recapitulates core symptoms of PMS providing improvements for both construct and face validity, compared to previous models.

Significant statement

Phelan-McDermid syndrome, caused by happloinsufficiency of Shank3, is a severe and complex neurodevelopmental disorder. This study investigates the behavioral consequences of a disruption of all Shank3 isoforms in neonatal and adult mice using a detailed battery of tests tailored to investigate core symptoms and usual comorbidities of PMS. We found that our new model is more severely affected than previously published mouse models with only partial deletions of Shank3 and more closely recapitulates symptoms of PMS thus providing improvements for both construct and face validity. Our results highlight the significance of using a mouse model with a complete deletion of Shank3 for studying mechanisms underlying autism spectrum disorder and PMS, carrying preclinical studies and testing test novel therapeutic approaches.
Fasting prevents hypoxia-induced defects of proteostasis inC. elegans
Authors: Iranon Nicole N , Jochim Bailey E , Miller Dana L
Published: March 2018

Low oxygen conditions (hypoxia) can impair essential physiological processes and cause cellular damage and death. We have shown that specific hypoxic conditions disrupt protein homeostasis inC. elegans, leading to protein aggregation and proteotoxicity. Here, we show that nutritional cues regulate this effect of hypoxia on proteostasis. Animals fasted prior to hypoxic exposure develop dramatically fewer protein aggregates compared to their fed counterparts, indicating that the effect of hypoxia is abrogated. Fasting is effective at protecting against hypoxia-induced proteostasis defects in multiple developmental stages, tissues, and in different models of misfolded or aggregation prone proteins. Our data also demonstrate that the effect of fasting is induced and reversed quite rapidly, suggesting that the nutritional environment experienced at the onset of hypoxia dictates at least some aspects of the physiological response to hypoxia. We further demonstrate that the insulin/IGF-like signaling pathway plays a role in mediating the protective effects of fasting in hypoxia. Animals with mutations indaf-2, theC. elegansinsulin-like receptor, display wild-type levels of hypoxia-induced protein aggregation upon exposure to hypoxia when fed, but are not protected by fasting. However, we found that DAF-2 acts independently of the FOXO transcription factor, DAF-16, to mediate the protective effects of fasting. These results suggest a non-canonical role for the insulin/IGF-like signaling pathway in coordinating the effects of hypoxia and nutritional state on proteostasis.

Author Summary

When blood flow to various parts of the body becomes restricted, those tissues suffer from a lack of oxygen, a condition called hypoxia. Hypoxia can cause cellular damage and death, such as is observed as a result of stroke and cardiovascular disease. We have found that in the model organismC. elegans(a roundworm) specific concentrations of hypoxia cause aggregation of polyglutamine proteins – the same kind of proteins that are found in an aggregated state in the neurodegenerative disorder Huntington’s disease. Here, we show that that worms can be protected from hypoxia-induced protein aggregation if they are fasted (removed from their food source) prior to experiencing hypoxia. Furthermore, we show that the insulin receptor is required for this protection. The insulin receptor is responsible for detecting insulin, a hormone that is released after feeding. Worms with a nonfunctional version of the insulin receptor displayed hypoxia-induced protein aggregation despite being fasted before the hypoxic exposure. Our results highlight a new role for the insulin signaling pathway in coordinating the effects of both hypoxia and nutritional state on protein aggregation.
The expression tractability of a biological trait
Authors: Liu Li , Wang Jianguo , Yang Jianrong , He Xionglei
Published: March 2018

Understanding how gene expression is translated to phenotype is central to modern molecular biology, but the success is contingent on the intrinsic tractability of the specific traits under examination. However, an a priori estimate of trait tractability from the perspective of gene expression is unavailable. Motivated by the concept of entropy in a thermodynamic system, we here propose such an estimate (ST) by gauging the number (N) of different expression states that underlie the same trait abnormality, with large ST corresponding to large N. By analyzing over 200 yeast morphological traits we show that ST is constrained by natural selection, which builds co-regulated gene modules to minimize the total number of possible expression states. We further show that ST is a good measure of the titer of recurrent patterns of an expression-trait relationship, predicting the extent to which the trait could be deterministically understood with gene expression data.
An expression atlas of chemosensory ionotropic glutamate receptors identifies a molecular basis of carbonation detection
Authors: Sánchez-Alcañiz Juan Antonio , Silbering Ana Florencia , Croset Vincent , Zappia Giovanna , Sivasubramaniam Anantha Krishna , Abuin Liliane , Sahai Saumya Yashmohini , Auer Thomas O. , Cruchet Steeve , Neagu-Maier G. Larisa , Sprecher Simon G. , Yapici Nilay , Benton Richard
Published: March 2018

Taste perception is thought to involve the encoding of appetitive and aversive chemical cues in food through a limited number of sensory pathways. Through expression analysis of the complete repertoire ofDrosophilaIonotropic Receptors (IRs), a sensory subfamily of ionotropic glutamate receptors, we reveal that the majority of IRs is expressed in diverse peripheral neuron populations across gustatory organs in both larvae and adults, implying numerous roles in taste-evoked behaviours. We characteriseIr56d, which labels two anatomically-distinct classes of neurons in the proboscis: one represents a subset of sugar- and fatty acid-sensing neurons, while the other responds to carbonated solutions and fatty acids. Mutational analysis shows that IR56d, together with the broadly-expressed co-receptors IR25a and IR76b, is essential for physiological activation by carbonation and fatty acids, but not sucrose. We further demonstrate that carbonation is behaviourally attractive to flies (in an IR56d-dependent manner), but in a distinct way to other appetitive stimuli. Our work provides a valuable toolkit for investigating the taste functions of IRs, defines a molecular basis of carbonation sensing, and illustrates how the gustatory system uses combinatorial expression of sensory receptors in distinct neuron types to coordinate behaviour.
Bub1 is not required for the checkpoint response to unattached kinetochores in diploid human cells
Authors: Currie Cerys E. , Mora-Santos Mar , Smith Chris , McAinsh Andrew D. , Millar Jonathan B.A.
Published: March 2018

Error-free chromosome segregation during mitosis depends on a functional spindle assembly checkpoint (SAC). The SAC is a multi-component signaling system that is recruited to incorrectly attached kinetochores to catalyze the formation of a soluble inhibitor, known as the mitotic checkpoint complex (MCC), which binds and inhibits the anaphase promoting complex [1]. We have previously proposed that two separable pathways, composed of KNL1-Bub3-Bub1 (KBB) and Rod-Zwilch-Zw10 (RZZ), recruit Mad1-Mad2 complexes to human kinetochores to activate the SAC [2]. We refer to this as the dual pathway model. Although Bub1 is absolutely required for MCC formation in yeast (which lack RZZ), there is conflicting evidence as to whether this is also the case in human cells based on siRNA studies [2–5]. Here we report, using genome editing, that Bub1 is not strictly required for the SAC response to unattached kinetochores in human diploid hTERT-RPE1 cells, consistent with the dual pathway model.
Alzheimer’s environmental and genetic risk scores are differentially associated with ‘g’ and δ
Authors: Andrews Shea J. , McFall G. Peggy , Dixon Roger A. , Cherbuin Nicolas , Eramudugolla Ranmalee , Anstey Kaarin J
Published: March 2018

Introduction

We investigated the association of the Australian National University Alzheimer’s Disease Risk Index (ANU-ADRI) and an AD genetic risk score (GRS) with cognitive performance.

Methods

The ANU-ADRI (composed of 11 risk factors for AD) and GRS (composed of 25 AD risk loci) were computed in 1,061 community-dwelling older adults. Participants were assessed on 11 cognitive tests and activities of daily living. Structural equation modelling was used to evaluate the association of the ANU-ADRI and GRS with: 1) general cognitive ability (g) 2) dementia related variance in cognitive performance (δ) and 3) verbal ability, episodic memory, executive function and processing speed.

Results

A worse ANU-ADRI score was associated with poorer performance in ‘g’, δ, and each cognitive domain. A worse GRS was associated with poorer performance in δ and episodic memory.

Discussion

The ANU-ADRI was broadly associated with worse cognitive performance, validating its further use in early dementia risk assessment.

Highlights

An environmental/lifestyle dementia risk index is broadly associated with cognitive performance

An Alzheimer’s genetic risk score is associated with dementia severity and episodic memory

The environmental risk index is more strongly associated with dementia severity than genetic risk

Research in Context

Systematic Review

The authors reviewed the literature using online databases (e.g. PubMed). Previous research has highlighted the need for dementia risk assessment tools to be evaluated on outcomes prior to dementia onset, such as cognitive performance. The relevant citations have been appropriately cited.

Interpretation

The Australian National University Alzheimer’s Disease Risk Index (ANU-ADRI) was more broadly associated with cognitive performance than Alzheimer’s genetic risk. For the ANU-ADRI, stronger effects were observed for dementia-related variance in cognitive task performance that for variance in general cognitive function. This suggests that ANU-ADRI is more specifically associated with dementia-related processes and further validates its use in early risk assessment for dementia.

Future Directions

Accordingly, future studies should seek to evaluate the association of the ANU-ADRI and genetic risk with AD biomarkers and longitudinal cognitive performance to evaluate differential trajectories in ‘g’ and δ.
Anti-CRISPR phages cooperate to overcome CRISPR-Cas immunity
Authors: Landsberger Mariann , Gandon Sylvain , Meaden Sean , Chabas Hélène , Buckling Angus , Westra Edze R. , Houte Stineke van
Published: March 2018

Some phages encode anti-CRISPR (acr) genes, which antagonize bacterial CRISPR-Cas immune systems by binding components of its machinery, but it is less clear how deployment of these acr genes impacts phage replication and epidemiology. Here we demonstrate that bacteria with CRISPR-Cas resistance are still partially immune to Acr-encoding phage. As a consequence, Acr-phages often need to cooperate in order to overcome CRISPR resistance, with a first phage taking down the host CRISPR-Cas immune system to allow a second Acr- phage to successfully replicate. This cooperation leads to epidemiological tipping points in which the initial density of Acr-phage tips the balance from phage extinction to a phage epidemic. Furthermore, both higher levels of CRISPR-Cas immunity and weaker Acr activities shift the tipping points towards higher phage densities. Collectively these data help to understand how interactions between phage-encoded immune suppressors and the CRISPR systems they target shape bacteria-phage population dynamics.

Highlights

Bacteria with CRISPR immunity remain partially resistant to Acr-phage

Sequentially infecting Acr phages cooperate to overcome CRISPR resistance

Acr-phage epidemiology depends on the initial phage density

CRISPR resistant bacteria can drive Acr phages extinct

eTOC blurb

Some phages encode Acr proteins that block bacterial CRISPR-Cas immune systems. Although CRISPR-Cas can clear the first infection, this Acr-phage still suppresses the host immune system, which can be exploited by other Acr-phages. This is critical for Acr-phage amplification, but this “cooperation” only works beyond a critical Acr-phage density threshold.
Improvement of the memory function of a mutual repression network in a stochastic environment by negative autoregulation
Authors: Hasan A B M Shamim Ul , Kurata Hiroyuki , Pechmann Sebastian
Published: March 2018

Background

Cellular memory is a ubiquitous function of biological systems. By generating a sustained response to a transient inductive stimulus, often due to bistability, memory is central to the robust control of many important biological processes. However, our understanding of the origins of cellular memory remains incomplete. Stochastic fluctuations that are inherent to most biological systems have been shown to hamper memory function. Yet, how stochasticity changes the behavior of genetic circuits is generally not clear from a deterministic analysis of the network alone. Here, we apply deterministic rate equations, stochastic simulations, and theoretical analyses of Fokker-Planck equations to investigate how intrinsic noise affects the memory function in a mutual repression network.

Results

We find that the addition of negative autoregulation improves the persistence of memory in a small gene regulatory network by reducing stochastic fluctuations. Our theoretical analyses reveal that this improved memory function stems from an increased stability of the steady states of the system. Moreover, we show how the tuning of critical network parameters can further enhance memory.

Conclusions

Our work illuminates the power of stochastic and theoretical approaches to understanding biological circuits, and the importance of considering stochasticity to designing synthetic circuits with memory function.
Presurgical language fMRI: Current technical practices in epilepsy surgical planning
Authors: Benjamin Christopher F. A. , Dhingra Isha , Li Alexa X , Blumenfeld Hal , Alkawadri Rafeed , Bickel Stephan , Helmstaedter Christoph , Meletti Stefano , Bronen Richard A. , Warfield Simon K. , Peters Jurriaan M. , Reutens David , Połczyńska Monika M. , Hirsch Lawrence J. , Spencer Dennis D.
Published: March 2018

Little is known about how language functional MRI (fMRI) is executed in clinical practice in spite of its widespread use. Here we comprehensively documented its execution in surgical planning in epilepsy. A questionnaire focusing on cognitive design, imaging acquisition, analysis and interpretation and practical considerations was developed. Individuals responsible for collecting, analyzing, and interpreting clinical language fMRI data at 63 epilepsy surgical programs responded. The central finding was of marked heterogeneity in all aspects of fMRI. Most programs use multiple tasks, with a fifth routinely using 2, 3, 4 or 5 tasks with a modal run duration of five minutes. Variants of over fifteen protocols are in routine use with forms of noun-verb generation, verbal fluency, and semantic decision-making used most often. Nearly all aspects of data acquisition and analysis vary markedly. Neither of the two best-validated protocols were used by more than 10% of respondents. Preprocessing steps are broadly consistent across sites, language-related blood flow is most often identified using general linear modeling (76% of respondents), and statistical thresholding typically varies by patient (79%). The software SPM is most often used. fMRI programs inconsistently include input from experts with all required skills (imaging, cognitive assessment, MR physics, statistical analysis, brain-behavior relationships). These data highlight marked gaps between the evidence supporting fMRI and its clinical application. Teams performing language fMRI may benefit from evaluating practice with reference to the best-validated protocols to date and ensuring individuals trained in all aspects of fMRI are involved to optimize patient care.
Bacteriophage cooperation suppresses CRISPR-Cas3 and Cas9 immunity
Authors: Borges Adair L. , Zhang Jenny Y. , Rollins MaryClare F. , Osuna Beatriz A. , Wiedenheft Blake , Bondy-Denomy Joseph
Published: March 2018

>Bacteria utilize CRISPR-Cas adaptive immune systems for protection from bacteriophages (phages), and some phages produce anti-CRISPR (Acr) proteins that inhibit immune function. Despite thorough mechanistic and structural information for some Acr proteins, how they are deployed and utilized by a phage during infection is unknown. Here, we show that Acr production does not guarantee phage replication, but instead, infections fail when phage population numbers fall below a critical threshold. Failing infections can be rescued by related phages that act as Acr donors, demonstrating that infections succeed if a sufficient Acr dose is contributed to a single cell by multiple phage genomes. The production of Acr proteins by phage genomes that fail to replicate leave the cell immunosuppressed, which predisposes the cell for successful infection by other phages in the population. This “cooperative” phage mechanism for CRISPR-Cas inhibition demonstrates inter-virus cooperation that may also manifest in other host-parasite interactions.
Posterior and Mid-Fusiform Contribute to Distinct Stages of Facial Expression Processing
Authors: Li Yuanning , Richardson R. Mark , Ghuman Avniel Singh
Published: March 2018

Though the fusiform is well-established as a key node in the face perception network, its role in facial expression processing remains unclear, due to competing models and discrepant findings. To help resolve this debate, we recorded from 17 subjects with intracranial electrodes implanted in face sensitive patches of the fusiform. Multivariate classification analysis showed that facial expression information is represented in fusiform activity, in the same regions that represent identity, though with a smaller effect size. Examination of the spatiotemporal dynamics revealed a functional distinction between posterior and mid-fusiform expression coding, with posterior fusiform showing an early peak of facial expression sensitivity at around 180 ms after subjects viewed a face and mid-fusiform showing a later and extended peak between 230 – 460 ms. These results support the hypothesis that the fusiform plays a role in facial expression perception and highlight a qualitative functional distinction between processing in posterior and mid-fusiform, with each contributing to temporally segregated stages of expression perception.
Structural studies of crystalline forms of triamterene with carboxylic acid, GRAS and API molecules
Authors: Rehman Abida , Delori Amit , Hughes David S. , Jones William
Published: March 2018

Pharmaceutical salt solvates (dimethyl sulfoxide, DMSO) of the drug triamterene with the coformers acetic, succinic, adipic, pimelic, azelaic and nicotinic acid and ibuprofen are prepared by liquid-assisted grinding and solvent-evaporative crystallization. The modified ΔpK
a rule as proposed by Cruz-Cabeza [(2012). CrystEngComm, 14, 6362–6365] is in close agreement with the results of this study. All adducts were characterized by X-ray diffraction and thermal analytical techniques, including single-crystal X-ray diffraction, powder X-ray diffraction, differential scanning calorimetry and thermal gravimetric analysis. Hydrogen-bonded motifs combined to form a variety of extended tapes and sheets. Analysis of the crystal structures showed that all adducts existed as salt solvates and contained the aminopyridinium–carboxylate heterodimer, except for the solvate containing triamterene, ibuprofen and DMSO, as a result of the presence of a strong and stable hemitriamterenium duplex. A search of the Cambridge Structural Database (CSD 5.36, Version 1.18) to determine the frequency of occurrence of the putative supramolecular synthons found in this study showed good agreement with previous work.
Crystal structure of (2-{[(8-aminonaphthalen-1-yl)imino]methyl}-4,6-di-tert-butylphenolato-κ3
N,N′,O)bromidonickel(II)
Authors: O'Brien Patrick , Zeller Matthias , Lee Wei-Tsung
Published: March 2018

The title compound, [NiBr(C25H29N2O)], contains an NiII atom with a slightly distorted square-planar coordination environment defined by one O and two N atoms from the 2-{[(8-aminonaphthalen-1-yl)imino]methyl}-4,6-di-tert-butylphenolate ligand and a bromide anion. The Ni—O and Ni—N bond lengths are slightly longer than those observed in the phenyl backbone counterpart, which can be attributed to the larger steric hindrance of the naphthyl group in the structure of the title compound. The molecule as a whole is substantially distorted, with both the planar naphthalene-1,8-diamine and imino–methyl–phenolate substitutents rotated against the NiN2OBr plane by 38.92 (7) and 37.22 (8)°, respectively, giving the molecule a twisted appearance. N—H...Br hydrogen bonds and N—H...C(π) contacts connect the molecules into dimers, and additional C—H...Br contacts, C—H...π interactions, and an offset stacking interaction between naphthyl units interconnect these dimers into a three-dimensional network.
Crystal structures and antioxidant capacity of (E)-5-benzyloxy-2-{[(4-chlorophenyl)imino]methyl}phenol and (E)-5-benzyloxy-2-({[2-(1H-indol-3-yl)ethyl]iminiumyl}methyl)phenolate
Authors: Ghichi Nadir , Bensouici Chawki , Benboudiaf Ali , DJebli Yacine , Merazig Hocine
Published: March 2018

The title Schiff base compounds, C20H16ClNO2(I) and C24H22N2O2(II), were synthesizedviathe condensation reaction of 2-amino-4-chlorophenol for (I), and 2-(2,3-dihydro-1H-indol-3-yl)ethan-1-amine for (II), with 4-benzyloxy-2-hydroxybenzaldehyde. In both compounds, the configuration about the C=N imine bond isE. Neither molecule is planar. In (I), the central benzene ring makes dihedral angles of 49.91 (12) and 53.52 (11)° with the outer phenyl and chlorophenyl rings, respectively. In (II), the central benzene ring makes dihedral angles of 89.59 (9) and 72.27 (7)°, respectively, with the outer phenyl ring and the mean plane of the indole ring system (r.m.s. deviation = 0.011 Å). In both compounds there is an intramolecular hydrogen bond forming anS(6) ring motif; an O—H...O hydrogen bond in (I), but a charge-assisted N+—H...O−hydrogen bond in (II). In the crystal of (I), molecules are linked by C—H...π interactions, forming slabs parallel to plane (001). In the crystal of (II), molecules are linked by pairs of N—H...O hydrogen bonds, forming inversion dimers. The dimers are linked by C—H...O hydrogen bonds, C—H...π interactions and a weak N—H...π interaction, forming columns propagating along thea-axis direction. The antioxidant capacity of the synthesized compounds was determined by cupric reducing antioxidant capacity (CUPRAC) for compound (I) and by 2,2-picrylhydrazyl hydrate (DPPH) for compound (II).
Crystal structures of two new 3-(2-chloroethyl)-r(2),c(6)-diarylpiperidin-4-ones
Authors: Rajkumar K. , Sivakumar S. , Arulraj R. , Kaur Manpreet , Jasinski Jerry P. , Manimekalai A. , Thiruvalluvar A.
Published: March 2018

The syntheses and crystal structures of 3-(2-chloroethyl)-r-2,c-6-diphenylpiperidin-4-one, C19H20ClNO, (I), and 3-(2-chloroethyl)-r-2,c-6-bis(4-fluorophenyl)piperidin-4-one, C19H18ClF2NO, (II), are described. The piperidone ring adopts a chair conformation in (I), whereas a slightly distorted chair conformation is formed in (II). The dihedral angle between the mean plane of the phenyl rings is 59.1 (1)° in (I) and 76.1 (1)° in (II). The crystal packing features weak intermolecular N—H...O hydrogen bonds in each structure.
Synthesis, crystal structure and catalytic activity in reductive amination of dichlorido(η6-p-cymene)(2′-dicyclohexylphosphanyl-2,6-dimethoxybiphenyl-κP)ruthenium(II)
Authors: Makarova Maria , Tsygankov Alexey A. , Chusova Olga , Linko Ivan V. , Dorovatovskii Pavel V. , Zubavichus Yan V.
Published: March 2018

The title compound, [RuCl2(C10H14)(C26H35O2P)] (I), crystallizes in the monoclinic space groupP21/cwith two crystallographically independent molecules (AandB) in the asymmetric unit. The geometries of both molecules are very similar and distinguished only by the twist angles of the two benzene rings in the phosphine substituents [89.54 (14) and 78.36 (14)° for moleculesAandB, respectively]. The Ru atoms have classical pseudo-tetrahedral piano-stool coordination environments. The conformation of each molecule is stabilized by intramolecular C—H...O and C—H...Cl hydrogen bonds and C—H...π interactions. The two molecules are linked by a C—H...Cl hydrogen bond. In the crystal, the molecules are further linked by C—H... π interactions, forming –A–B–A–B– chains propagating along thea-axis direction. ComplexIis an active catalyst for reductive amination reaction. The catalytic activity of this complex can be explained by the lability of thep-cymene ligand, which can be replaced by two-electron ligands such as CO or amine.
Crystal structure of calcium perchlorate anhydrate, Ca(ClO4)2, from laboratory powder X-ray diffraction data
Authors: Lee Dongmin , Bu Hyeri , Kim Dohwan , Hyoung Jooeun , Hong Seung-Tae
Published: March 2018

The crystal structure of calcium perchlorate anhydrate was determined from laboratory X-ray powder diffraction data. The title compound was obtained by heating hydrated calcium perchlorate [Ca(ClO4)2·xH2O] at 623 K in air for 12 h. It crystallizes in the orthorhombic space group Pbca and is isotypic with Ca(AlD4)2. The asymmetric unit contains one Ca, two Cl and eight O sites, all on general sites (Wyckoff position 8c). The crystal structure consists of isolated ClO4
− tetrahedra and Ca2+ cations. The Ca2+ cation is coordinated by eight O atoms of eight symmetry-related ClO4
− tetrahedra within a distorted square-antiprismatic environment.
Conflict coping strategy evolution of top management team members in China’s family enterprises
Authors: Wu Mengyun , Zhang Linrong , Imran Muhammad , Lu Jie , Hu Xinting
Published: March 2018

Purpose

Conflicts among top management team (TMT) members have a significant impact on sustainable development of family enterprises in China. The complex attributes of different kinds of conflicts in a TMT have dual effects on firm performance and its stability. Thus, avoiding conflicts in a TMT through a systematic conflict management strategy is very important. This paper aims to therefore investigate how to maximize the performance and income level of the TMT in family enterprises through managing conflict systematically, while adopting the best conflict coping strategies.

Design/methodology/approach

In this study, the authors apply conflict coping strategies as a useful tool of conflict management and propose five kinds of dynamic conflict coping strategies among TMT members. Repeated game and multi-agent simulation by computer experiment are used to dynamically simulate the rules and evolution of individual conflict coping strategy choices.

Findings

It is found that with the passage of time, different conflict coping strategies have different effects on earnings of individuals and teams at different conflict levels. It is also revealed that conflict coping strategies affect not only the earnings of individuals and teams but also their distribution; it also reflects the conflict level in TMT of a family enterprise but in reverse.

Originality/value

This study contributes to the existing literature on conflict management in relevance to the choice and revolution of conflict coping strategies in a Chinese business culture context. It focuses on strengthening the unity and cooperation of TMT members. Controlling the conflict level of TMT members at a reasonable level, investigating the primary cause of conflict and identifying its nature lead to better performance of the TMT and the sustainable development of Chinese family enterprises. Based on these outcomes, different conflict coping strategies can be appropriately used to solve TMT conflicts.
Determinants of bank profitability before, during, and after the financial crisis
Authors: Adelopo Ismail , Lloydking Robert , Tauringana Venancio
Published: March 2018

Purpose

The purpose of this paper is to report the results of an investigation into the relationship between bank-specific, macroeconomic factors and bank profitability before (1999-2006), during (2007-2009), and after (2010-2013) the financial crisis.

Design/methodology/approach

Using the Economic Community of West African States’ bank panel data from 1999 to 2013, the paper used fixed effect models. The panel model includes bank-specific determinants (size, cost management, and liquidity), industry level, and macroeconomic variables.

Findings

Panel data analyses results show that there is a significant relationship between bank-specific determinants (size, cost management, and liquidity) and bank profitability (ROA) before, during, and after the financial crisis. However, the relationships between other bank-specific (capital strength, credit risk, and market power), macroeconomic (gross domestic product and inflation) determinants are sensitive to both periods of analysis (before, during, and after financial crisis) and bank profitability measure used (ROA or NIM).

Originality/value

Overall, these results suggest that the financial crisis did not affect the relationships between some bank-specific determinants and bank profitability.