bluuebunny/crossref_metadata_2025 huggingface dataset:
The behavioral phenotype of early life adversity: a 3-level meta-analysis of preclinical studies
Authors: Bonapersona V , Kentrop J , Van Lissa CJ , van der Veen R , Joëls M , Sarabdjitsingh RA
Published: January 2019

1

Background

Altered cognitive performance has been suggested as an intermediate phenotype mediating the effects of early life adversity (ELA) on later-life development of mental disorders, e.g. depression. Whereas most human studies are limited to correlational conclusions, rodent studies can prospectively investigate how ELA alters cognitive performance in a number of domains. Despite the vast volume of reports, no consensus has yet been reached on thei)behavioral domains being affected by ELA andii)the extent of these effects.

Methods

To test how ELA (here: aberrant maternal care) affects specific behavioral domains, we used a 3-level mixed-effect meta-analysis, a flexible model that accounts for the dependency of observations. We thoroughly explored heterogeneity with MetaForest, a machine-learning data-driven analysis never applied before in preclinical literature. We validated the robustness of our findings with substantial sensitivity analyses and bias assessments.

Results

Our results, based on >400 independent experiments, yielded >700 comparisons, involving ~8600 animals. Especially in males, ELA promotes memory formation during stressful learning but impairs non-stressful learning. Furthermore, ELA increases anxiety and decreases social behavior. The ELA phenotype was strongest wheni)combined with other negative experiences (“hits”);ii)in rats;iii)in ELA models of ~10days duration.

Conclusion

Prospective and well-controlled animal studies demonstrate that ELA durably and differentially impacts distinct behavioral domains. All data is now easily accessible with MaBapp (https://osf.io/ra947/), which allows researchers to run tailor-made meta-analyses on the topic, thereby revealing the optimal choice of experimental protocols and study power.
Genes lost during the transition from land to water in cetaceans highlight genomic changes involved in aquatic adaptations
Authors: Huelsmann Matthias , Hecker Nikolai , Springer Mark S. , Gatesy John , Sharma Virag , Hiller Michael
Published: January 2019

The transition from land to water in whales and dolphins (cetaceans) was accompanied by remarkable anatomical, physiological and behavioral adaptations. To better understand the genomic changes that occurred during this transition, we systematically screened for protein-coding genes that were inactivated in the ancestral cetacean lineage. We discovered genes whose loss is likely beneficial for cetaceans by reducing the risk of thrombus formation during diving (F12,KLKB1), improving the fidelity of oxidative DNA damage repair (POLM), and protecting from oxidative stress-induced lung inflammation (MAP3K19). Additional gene losses may reflect other diving-related adaptations, such as enhanced vasoconstriction during the diving response (mediated bySLC6A18) and altered pulmonary surfactant composition (SEC14L3), while loss ofSLC4A9relates to a reduced need for saliva in aquatic environments. Finally, the complete loss of melatonin synthesis and receptor genes (AANAT,ASMT,MTNR1A/B) may have been a precondition for the evolution of unihemispheric sleep. Our findings suggest that some genes lost in the ancestral cetacean lineage may have been involved in adapting to a fully-aquatic lifestyle.
Identification of the Calmodulin-dependent NAD+kinase sustaining the elicitor-induced oxidative burst in plants
Authors: Dell’ Aglio Elisa , Giustini Cécile , Kraut Alexandra , Couté Yohann , Mazars Christian , Matringe Michel , Finazzi Giovanni , Curien Gilles
Published: January 2019

NADP(H) is an essential cofactor ofmultiple metabolic processes in all living organisms. While NADP+ production in plants has long been known to involve a Calmodulin (CaM)/Ca2+-dependent NAD+kinase, the nature of the enzyme catalyzing this activity has remained enigmatic, as well as its role in plant physiology. Here, we identify an Arabidopsis P-loop ATPase (Atlg04280) with a bacterial type II zeta toxin domain, that catalyzes NADP+production upon binding of CaM/Ca2+to a domain located in its N-terminal region. The encoded protein (NADKc-1) is associated with the mitochondria and amplifies the elicitor-induced oxidative burst in Arabidopsis leaves representing the missing link between calcium signalling and metabolism in the response to pathogen elicitor. By analysis of various plants and algae, we show that NADKc is well conserved in the plant lineage and present in basal plants. Our data allows proposing that the CaM-dependent NAD kinase activity is only found in photosynthetic species carrying NADKc-1 related proteins, which would represent the only proteins harboring CaM-dependent NAD kinase activity in plants and algae.
Phosgene Inhalation Causes Hemolysis and Acute Lung Injury
Authors: Aggarwal Saurabh , Jilling Tamas , Doran Stephen , Ahmad Israr , Eagen Jeannette E. , Gu Stephen , Gillespie Mark , Albert Carolyn J. , Ford David , Oh Joo-Yeun , Patel Rakesh P. , Matalon Sadis
Published: January 2019

Phosgene (Carbonyl Chloride, COCl2) remains an important chemical intermediate in many industrial processes such as combustion of chlorinated hydrocarbons and synthesis of solvents (degreasers, cleaners). It is a sweet smelling gas, and therefore does not prompt escape by the victim upon exposure. Supplemental oxygen and ventilation are the only available management strategies. This study was aimed to delineate the pathogenesis and identify novel biomarkers of acute lung injury post exposure to COCl2gas. Adult male and female C57BL/6 mice (20-25 g), exposed to COCl2gas (10 or 20ppm) for 10 minutes in environmental chambers, had a dose dependent reduction in PaO2and an increase in PaCO2, 1 day post exposure. However, mortality increased only in mice exposed to 20ppm of COCl2for 10 minutes. Correspondingly, these mice (20ppm) also had severe acute lung injury as indicated by an increase in lung wet to dry weight ratio, extravasation of plasma proteins and neutrophils into the bronchoalveolar lavage fluid, and an increase in total lung resistance. The increase in acute lung injury parameters in COCl2(20ppm, 10min) exposed mice correlated with simultaneous increase in oxidation of red blood cells (RBC) membrane, RBC fragility, and plasma levels of cell-free heme. In addition, these mice had decreased plasmalogen (plasmenylethanolamine) and elevated levels of their breakdown product, polyunsaturated lysophosphatidylethanolamine, in the circulation suggesting damage to cellular plasma membranes. This study highlights the importance of free heme in the pathogenesis of COCl2 lung injury and identifies plasma membrane breakdown product as potential biomarkers of COCl2toxicity.
Computational modeling reveals frequency modulation of calcium-cAMP/PKA pathway in dendritic spines
Authors: Ohadi D. , Schmitt D. L. , Calabrese B. , Halpain S. , Zhang J. , Rangamani P.
Published: January 2019

Dendritic spines are the primary excitatory postsynaptic sites that act as subcompartments of signaling. Ca2+is often the first and most rapid signal in spines. Downstream of calcium, the cAMP/PKA pathway plays a critical role in the regulation of spine formation, morphological modifications, and ultimately, learning and memory. While the dynamics of calcium are reasonably well-studied, calcium-induced cAMP/PKA dynamics, particularly with respect to frequency modulation, are not fully explored. In this study, we present a well-mixed model for the dynamics of calcium-induced cAMP/PKA dynamics in dendritic spines. The model is constrained using experimental observations in the literature. Further, we measured the calcium oscillation frequency in dendritic spines of cultured hippocampal CA1 neurons and used these dynamics as model inputs. Our model predicts that the various steps in this pathway act as frequency modulators for calcium and the high frequency of calcium input is filtered by AC1 and PDEs in this pathway such that cAMP/PKA only responds to lower frequencies. This prediction has important implications for noise filtering and long-timescale signal transduction in dendritic spines. A companion manuscript presents a three-dimensional spatial model for the same pathway.

Statement of Significance

cAMP/PKA activity triggered by calcium is an essential biochemical pathway for synaptic plasticity, regulating spine structure, and long-term potentiation. In the current study, we predicted that for a given calcium input, AC1, and PDE1 kinetics reflect both the high and the low frequencies with different amplitudes and cAMP/PKA acts as a leaky integrator of calcium because of frequency attenuation by the intermediary steps. These findings have implications for cAMP/PKA signaling in dendritic spines in particular and neuronal signal transduction in general.
Chromosome dynamics in bacteria: triggering replication at opposite location and segregation in opposite direction
Authors: Meléndez Ady B. , Menikpurage Inoka P. , Mera Paola E.
Published: January 2019

The accurate onset of chromosome replication and segregation are fundamental for the survival of the cell. In bacteria, regulation of chromosome replication lies primarily at the initiation step. The bacterial replication initiator DnaA recognizes the origin of replication (ori) and opens this double stranded site allowing for the assembly of the DNA replication machinery. Following the onset of replication initiation, the partitioning protein ParA triggers the onset of chromosome segregation by direct interactions with ParB-bound to the centromere. The subcellular organization oforiand centromere are maintained after the completion of each cell cycle. It remains unclear what triggers the onset of these key chromosome regulators DnaA and ParA. One potential scenario is that the microenvironment of where the onset of replication and segregation take place hosts the regulators that trigger the activity of DnaA and ParA. In order to address this, we analyzed whether the activity of DnaA and ParA are restricted to only one site within the cell. In non-dividing cells of the alpha proteobacteriumCaulobacter crescentus,oriand centromere are found near the stalked pole. To test DnaA’s ability to initiate replication away from the stalked pole, we engineered a strain where movement oforiwas induced in the absence of chromosome replication. Our data show that DnaA can initiate replication of the chromosome independently of the subcellular localization ofori. Furthermore, we discovered that the partitioning protein ParA was functional and could segregate the replicated centromere in the opposite direction from the new pole toward the stalked pole. We showed that the organization of the ParA gradient can be completely reconstructed in the opposite orientation by rearranging the location of the centromere. Our data reveal the high flexibility of the machineries that trigger the onset of chromosome replication and segregation in bacteria. Our work also provides insights into the coordination between replication and segregation with the cellular organization of specific chromosomal loci.
Cerebellar disruption impairs working memory during evidence accumulation
Authors: Deverett Ben , Kislin Mikhail , Tank David W. , Wang Samuel S.-H.
Published: January 2019

To select actions based on sensory evidence, animals must create and manipulate representations of stimulus information in memory. We found that during accumulation of somatosensory evidence, optogenetic manipulation of cerebellar Purkinje cells reduced the accuracy of subsequent memory-guided decisions and caused mice to downweight prior information. Behavioral deficits were consistent with the addition of noise and leak to the evidence accumulation process, suggesting the cerebellum can influence the maintenance of working memory contents.
A multimodal approach to identify clinically relevant parameters to monitor disease progression in a preclinical model of neuropediatric disease
Authors: Johnson Tyler B. , Brudvig Jon J. , Lehtimäki Kimmo K. , Cain Jacob T. , White Katherine A. , Bragge Timo , Rytkönen Jussi , Huhtala Tuulia , Timm Derek , Vihma Maria , Puoliväli Jukka T. , Nurmi Antti , Weimer Jill M.
Published: January 2019

While research has accelerated the development of new treatments for pediatric neurodegenerative disorders, the ability to demonstrate the long-term efficacy of these therapies has been hindered by the lack of convincing, noninvasive methods for tracking disease progression both in animal models and in human clinical trials. Here, we unveil a new translational platform for tracking disease progression in an animal model of a pediatric neurodegenerative disorder, CLN6-Batten disease. Instead of looking at a handful of parameters or a single “needle in a haystack”, we embrace the idea that disease progression, in mice and patients alike, is a diverse phenomenon best characterized by a combination of relevant biomarkers. Thus, we employed a multi-modal quantitative approach where 144 parameters were longitudinally monitored to allow for individual variability. We use a range of noninvasive neuroimaging modalities and kinematic gait analysis, all methods that parallel those commonly used in the clinic, followed by a powerful statistical platform to identify key progressive anatomical and metabolic changes that correlate strongly with the progression of pathological and behavioral deficits. This innovative, highly sensitive platform can be used as a powerful tool for preclinical studies on neurodegenerative diseases, and provides proof-of-principle for use as a potentially translatable tool for clinicians in the future.

One Sentence Summary

Principal component analysis identifies a set of clinically relevant parameters able to measure progression of Batten disease in a mouse model.
Age-dependent characterization of the carotid and cerebral artery morphologies in a transgenic mouse model of sickle cell anemia using ultrasound and microcomputed tomography
Authors: Rivera Christian P. , Li Li , Cai Shuangyi , Pei Nui , McAlear George E. , Bollavaram Keval , Aryio Oluwasanmi V. , Omojola Victor O. , Song Hannah , Tan Wenchang , Huo Yunlong , Platt Manu O.
Published: January 2019

Children with sickle cell anemia have elevated stroke risks as well as other arterial complications, but morphological changes to large arteries are not well defined, and the focus has been on the microcirculation where deoxygenation promotes sickling of red blood cells. The goal of this study was to define morphological changes in carotid and cerebral arteries in the Townes transgenic sickle cell mouse model, and to specifically determine anatomical measurement differences in mice homozygous for β-globin S mutation (SS) compared to heterozygous (AS) littermate controls. We used a combination of live imaging with ultrasound and microcomputed tomography (micro-CT) imaging of corrosion casted vessels to quantify arterial dimensions and changes in mice 4, 12, and 24 weeks of age with or without sickle cell anemia. 12 week SS mice had significantly larger common carotid artery diameters than AS mice, and significantly larger diameters in the extracranial and intracranial portions of the internal carotid artery (ICA), determined by ultrasound and micro-CT, respectively. There were also side specific differences between the left and right vessels. There was significant narrowing along ICA length in 12-and 24-week SS mice, decreasing by as much as 70%, such that there was no difference in size between the anterior and middle cerebral arteries, where the ICA terminates, by genotype. Significant narrowing along the length was also measured in the anterior cerebral arteries of 12-and 24-week SS mice, but not AS. Collectively, these findings indicate that sickle cell anemia causes increased arterial dimensions in 12-and 24-week aged mice. We also provide these measurements for the common carotid, internal carotid, anterior cerebral, and middle cerebral arteries for left and right sides, for AS and SS genotypes as a reference for other investigators using in silico modeling of arterial complications caused by aging with sickle cell anemia.
Superadditive and subadditive dynamics are not inherent to the types of interacting threat
Authors: Haller-Bull V , Bode M
Published: January 2019

Species and ecosystems usually face more than one threat. The damage caused by these multiple threats can accumulate nonlinearly: either subadditively, when the joint damage of combined threats is less than the damages of both threats individually added together, or superadditively, when the joint damage is greater than the two individual damages added together. These additivity dynamics are commonly attributed to the nature of the threatening processes, but conflicting empirical observations challenge this assumption. Here, we use a theoretical model to demonstrate that the additivity of threats can change with different magnitudes of threat impacts (effect of a threat on the population parameter, like growth rate). We use a harvested single-species population model to integrate the effects of multiple threats on equilibrium abundance. Our results reveal that threats do not always display consistent additive behavior, even in simple systems. Instead, their additivity depends on the magnitudes of the impacts of two threats, and the population parameter that is impacted by each threat. In our model specifically, when multiple threats have a low impact on the growth rate of a population, they display superadditive dynamics. In contrast, threats that impact the species’ carrying capacity are always additive or subadditive. These dynamics can be understood by reference to the curvature of the relationship between a given population parameter (e.g., growth) and equilibrium population size. Our results suggest that management actions can achieve amplified benefits if they target low-amplitude threats that affect the growth rate, since these will be in a superadditive phase. More generally, our results suggest that cumulative impact theory should focus more than previously on the magnitude of the impact on the population parameter, and should be cautious about attributing additive dynamics to particular threat combinations.
Image-derived Models of Cell Organization Changes During Differentiation of PC12 Cells
Authors: Ruan Xiongtao , Johnson Gregory R. , Bierschenk Iris , Nitschke Roland , Boerries Melanie , Busch Hauke , Murphy Robert F.
Published: January 2019

Cellular differentiation is a complex process requiring the coordination of many cellular components. PC12 cells are a popular model system to study changes driving and accompanying neuronal differentiation. While significant attention has been paid to changes in transcriptional regulation and protein signaling, much less is known about the changes in cell organization that accompany PC12 differentiation. Fluorescence microscopy can provide extensive information about this, although photobleaching and phototoxicity frequently limit the ability to continuously observe changes in single cells over the many days that differentiation occurs. Here we describe a generative model of differentiation-associated changes in cell and nuclear shape and their relationship to mitochondrial distribution constructed from images of different cells at discrete time points. We show that our spherical harmonic-based model can accurately represent cell and nuclear shapes by measuring reconstruction errors. We then learn a regression model that relates cell and nuclear shape and mitochondrial distribution and observe that the predictive accuracy generally increases during differentiation. Most importantly, we propose a method, based on cell matching and linear interpolation in the shape space, to model the dynamics of cell differentiation using only static images. Without any prior knowledge, the method produces a realistic shape evolution process.

Author Summary

Cellular differentiation is an important process that is challenging to study due to the number of organizational changes it includes and the different time scales over which it occurs. Fluorescent microscopy is widely used to study cell dynamics and differentiation, but photobleaching and phototoxicity often make it infeasible to continuously observe a single cell undergoing differentiation for several days. In this work, we described a method to model aspects of the dynamics of PC12 cell differentiation without continuous imaging. We constructed accurate representations of cell and nuclear shapes and quantified the relationships between shapes and mitochondrial distributions. We used these to construct a generative model and combined it with a matching process to infer likely sequences of the changes in single cells undergoing differentiation.
Organization in complex brain networks: energy distributions and phase shift
Authors: Sharma Saurabh Kumar , Singh Soibam Shyamchand , Haobijam Dineshchandra , Malik Md. Zubbair , Brojen Singh R.K.
Published: January 2019

The Hamiltonian function of a network, derived from the intrinsic distributions of nodes and edges, magnified by resolution parameter has information on the distribution of energy in the network. In brain networks, the Hamiltonian function follows hierarchical features reflecting a power-law behavior which can be a signature of self-organization. Further, the transition of three distinct phases driven by resolution parameter is observed which could correspond to various important brain states. This resolution parameter could thus reflect a key parameter that controls and balances the energy distribution in the brain network.
Improved polygenic prediction by Bayesian multiple regression on summary statistics
Authors: Lloyd-Jones Luke R. , Zeng Jian , Sidorenko Julia , Yengo Loïc , Moser Gerhard , Kemper Kathryn E. , Wang Huanwei , Zheng Zhili , Magi Reedik , Esko Tonu , Metspalu Andres , Wray Naomi R. , Goddard Michael E. , Yang Jian , Visscher Peter M.
Published: January 2019

The capacity to accurately predict an individual’s phenotype from their DNA sequence is one of the great promises of genomics and precision medicine. Recently, Bayesian methods for generating polygenic predictors have been successfully applied in human genomics but require the individual level data, which are often limited in their access due to privacy or logistical concerns, and are computationally very intensive. This has motivated methodological frameworks that utilise publicly available genome-wide association studies (GWAS) summary data, which now for some traits include results from greater than a million individuals. In this study, we extend the established summary statistics methodological framework to include a class of point-normal mixture prior Bayesian regression models, which have been shown to generate optimal genetic predictions and can perform heritability estimation, variant mapping and estimate the distribution of the genetic effects. In a wide range of simulations and cross-validation using 10 real quantitative traits and 1.1 million variants on 350,000 individuals from the UK Biobank (UKB), we establish that our summary based method, SBayesR, performs similarly to methods that use the individual level data and outperforms other state-of-the-art summary statistics methods in terms of prediction accuracy and heritability estimation at a fraction of the computational resources. We generate polygenic predictors for body mass index and height in two independent data sets and show that by exploiting summary statistics on 1.1 million variants from the largest GWAS meta-analysis (n ≈ 700, 000) that the SBayesR prediction R2 improved on average across traits by 6.8% relative to that estimated from an individual-level data BayesR analysis of data from the UKB (n ≈ 450, 000). Compared with commonly used state-of-the-art summary-based methods, SBayesR improved the prediction R2 by 4.1% relative to LDpred and by 28.7% relative to clumping and p-value thresholding. SBayesR gave comparable prediction accuracy to the recent RSS method, which has a similar model, but at a computational time that is two orders of magnitude smaller. The methodology is implemented in a very efficient and user-friendly software tool titled GCTB.
Differential Effector Response of Amnion- and Adipose-Derived Mesenchymal Stem Cells to Inflammation; Implications for Intradiscal Therapy
Authors: Borem Ryan , Madeline Allison , Bowman Mackenzie , Gill Sanjitpal , Tokish John , Mercuri Jeremy
Published: January 2019

Intervertebral disc degeneration (IVDD) is a progressive condition marked by inflammation and tissue destruction. The effector functions of mesenchymal stem cells (MSCs) make them an attractive therapy for patients with IVDD. While several sources of MSCs exist, the optimal choice for use in the inflamed IVD remains a significant question. Adipose (AD)- and amnion (AM)-derived MSCs have several advantages compared to other sources, however, no study has directly compared the impact of IVDD inflammation on their effector functions. Human MSCs were cultured in media with or without supplementation of interleukin-1β and tumor necrosis factor-α at concentrations produced by IVDD cells. MSC proliferation and production of pro- and anti-inflammatory cytokines were quantified following 24- and 48-hours of culture. Additionally, the osteogenic and chondrogenic potential of AD- and AM-MSCs was characterized via histology and biochemical analysis following 28 days of culture. In inflammatory culture, AM-MSCs produced significantly more anti-inflammatory IL-10 (p=0.004) and larger chondrogenic pellets (p=0.04) with greater percent area staining positively for glycosaminoglycan (p<0.001) compared to AD-MSCs. Conversely, AD-MSCs proliferated more resulting in higher cell numbers (p=0.048) and produced higher concentrations of pro-inflammatory cytokines PGE2 (p=0.030) and IL-1β (p=0.010) compared to AM-MSCs. Additionally, AD-MSCs produced more mineralized matrix (p<0.001) compared to AM-MSCs. These findings begin to inform researchers and clinicians as to which MSC source may be optimal for different IVD therapies including those that may promote regeneration or fusion. Further study is warranted evaluating these cells in systems which recapitulate the nutrient- and oxygen-deprived environment of the degenerate IVD.
A DNA-based voltmeter for organelles
Authors: Saminathan Anand , Devany John , Pillai Kavya S. , Veetil Aneesh T. , Schwake Michael , Krishnan Yamuna
Published: January 2019

The role of membrane potential in most intracellular organelles remains unexplored because of the lack of suitable probes. We describe a DNA-based fluorescent reporter that quantitates membrane potential and can be targeted to specific organelles in live cells. It is equipped with a voltage sensitive fluorophore, a reference fluorophore for ratiometric quantification, and acts as an endocytic tracer. We could thereby measure the membrane potential of different intracellular organelles in living cells, which has not been possible previously. Our understanding of how membrane potential regulates organelle biology is poised to expand through the use of these new sensors.

One Sentence Summary

Using a DNA-based voltmeter we can non-invasively measure the membrane potential of specific organelles in live cells.
The Efficacy of the Antimicrobial Peptide Melittin and the Enzyme DNase I Against E. coli Biofilms
Authors: Phillips Abigail
Published: January 2019

Biofilms are aggregations of bacteria that often cause nosocomial infections and are tolerant to antibiotic treatments due to a variety of factors, including the physical barrier of their matrix. One field of treatment that has been explored is the use of antimicrobial peptides, like melittin. Melittin has been demonstrated to have antimicrobial effects on bacteria in both a biofilm and a planktonic state. Its required concentration to affect biofilms, however, is too high to be applicable in clinical settings. One potential way to increase efficacy is to use a compound like DNase I that degrades the matrix and thereby increases the penetration of melittin into the biofilm. I investigated whether DNase I would enhance the efficacy of melittin in relatively low concentrations that could be clinically viable. Melittin and DNase I were applied to E. coli biofilms in 24-well plates, both individually and in combination; biofilm density was measured at two time-points afterwards, using a crystal violet staining assay. The results showed DNase I was the most effective treatment. Surprisingly, none of the melittin treatments were statistically significant. A second experiment investigated variation among 11 bioreplicates and found that there was approximately 5-fold variation in response to treatment with DNase I. Given these promising results, further study on DNase I should be conducted.

Importance

This work is important as it is crucial to have as many viable treatment options as possible for biofilm infections. Biofilm infections are common and many of our standard antibiotic options are simply not effective against them. According to the NIH, 65% of microbial infections and 80% of chronic infections are associated with biofilms, costing the United States millions of dollars each year (Jamal et al., 2018). Every avenue that could potentially further efforts to increase the efficacy and practicality of treatment options should be explored. Antimicrobial peptides are one of the most promising fields for biofilm treatment, and this study further investigates the potential for treatment that they hold.
Inhibition of MreB and ftsZ proteins to minimize E. coli biofilms formation
Authors: Charles Emile
Published: January 2019

In the United States, more than two million individuals become infected by antibiotic-resistant bacteria, resulting in over 23,000 deaths annually. Bacterial biofilms, one of the major causes of this resistance, form a complex extracellular matrix that physically block antibiotic treatment. Within planktonic bacteria, two proteins, MreB and ftsZ, play a key role in bacterial cell growth and development. MreB regulates this development through maintaining the rod-like shape of gram-negative bacteria, while ftsZ regulates the timing and location of cell division. The present study compared the effects of two protein-inhibitors on biofilm formation of E. coli; the inhibitors, A22 Hydrochloride and PC190723, inhibit MreB (cell shape) and ftsZ (cell division), respectively. Efficacy was measured with a crystal violet staining assay. Four experiments were designed testing 1) the minimum inhibitory concentration of the inhibitors, 2) the synergistic effect of the inhibitors, 3) the microscopic effects of the inhibitors, and 4) the effect of the inhibitors on antibiotic susceptibility. A mid-level dosage of A22 significantly decreased biofilm density while there was no response to PC190732. The effect of A22 was verified microscopically, observing the change from bacilli cells to coccoid ones via the inhibition of MreB. In the second experiment, with conjunct inhibition, no interaction was found. Lastly, A22 was as effective as Amoxicillin in disrupting biofilms. The inhibition of MreB was found to have a key role in biofilm development. A model is proposed for biofilm density based on cell shape as affected by MreB.

Importance

Each year, more than 2 million Americans acquire antibiotic-resistant infection and 23,000 of them die (CDC, 2013). In a study done by Barsoumian et. al (2015), there was a 16% mortality rate pertaining to biofilm-related infections while non-biofilm infection caused a 5% mortality rate. These casualties aren’t limited to the United States. Abroad, antibiotic resistance is a huge issue: 25,000 deaths estimated in the EU; 38,000 deaths in Thailand; and 58,000 deaths in India, among infants alone (CDC, 2012). It is these statistics that inform us that antibiotic resistance must be addressed.
Human and mouse iPSC-derived astrocyte subtypes reveal vulnerability in Vanishing White Matter
Authors: Leferink Prisca S. , Dooves Stephanie , Hillen Anne E.J. , Watanabe Kyoko , Jacobs Gerbren , Gasparotto Lisa , Cornelissen-Steijger Paulien , van der Knaap Marjo S. , Heine Vivi M.
Published: January 2019

Astrocytes gained attention as important players in neurological disease, including a number of leukodystrophies. Several studies explored the generation of induced pluripotent stem cell-derived astrocytes for drug screening and regenerative studies. Developing robust models of patient induced pluripotent stem cells is challenged by high variability due to diverse genetic backgrounds and long-term culture procedures. While human models are of special interest, mouse-based models have the advantage that for them these issues are less pronounced. Here we present astrocyte differentiation protocols for both human and mouse induced pluripotent stem cells to specifically induce grey and white matter astrocytes. Both subtypes expressed astrocyte-associated markers, had typical astrocyte morphologies, and gave a reactive response to stress. Importantly, the grey and white matter-like astrocytes differed in size, complexity of processes, and expression profile, conform primary grey and white matter astrocytes. The newly presented mouse and human stem cell-based models for the leukodystrophy Vanishing White Matter replicated earlier findings, such as increased proliferation, decreased OPC maturation and modulation by hyaluronidase. We studied intrinsic astrocyte subtype vulnerability in Vanishing White Matter in both human and mouse cells. Oligodendrocyte maturation was specifically inhibited in cultures with Vanishing White Matter white matter-like astrocytes. By performing RNA sequencing, we found more differentially regulated genes in the white than in the grey matter-like astrocytes. Human and mouse astrocytes showed the same affected pathways, although human white matter-like astrocytes presented human-specific disease mechanisms involved in Vanishing White Matter. Using both human and mouse induced pluripotent stem cells, our study presents protocols to generate white and grey matter-like astrocytes, and shows astrocyte subtype-specific defects in Vanishing White Matter. While mouse induced pluripotent stem cell-based cultures may be less suitable to mimic human astrocyte subtype- or patient-specific changes, they might more robustly represent disease mutation-related cellular phenotypes as the cells are derived from inbred mice and the protocols are faster. The presented models give new tools to generate astrocyte subtypes forin vitrodisease modeling andin vivoregenerative applications.
To what extent gene connectivity within co-expression network matters for phenotype prediction?
Authors: Chateigner Aurélien , Lesage-Descauses Marie-Claude , Rogier Odile , Jorge Véronique , Leplé Jean-Charles , Brunaud Véronique , Roux Christine Paysant-Le , Soubigou-Taconnat Ludivine , Martin-Magniette Marie-Laure , Sanchez Leopoldo , Segura Vincent
Published: January 2019

Recent literature on the differential role of genes within networks distinguishes core from peripheral genes. If previous works have shown contrasting features between them, whether such categorization matters for phenotype prediction remains to be studied. We sequenced RNA in a Populus nigra collection and built co-expression networks to define core and peripheral genes. We found that cores were more differentiated between populations than peripherals while being less variable, suggesting that they have been constrained through potentially divergent selection. We also showed that while cores were overrepresented in a subset of genes deemed important for trait prediction, they did not systematically predict better than peripherals or even random genes. Our work is the first attempt to assess the importance of co-expression network connectivity in phenotype prediction. While highly connected core genes appear to be important, they do not bear enough information to systematically predict better quantitative traits than other gene sets.
Understanding the variation in wood densities of trees and its implications for carbon assessments
Authors: Teegalapalli Karthik , Pandey Chandan Kumar , Osuri Anand M , Ratnam Jayashree , Sankaran Mahesh
Published: January 2019

Wood density is a key functional trait used to estimate aboveground biomass (AGB) and carbon stocks. A common practice in forest AGB and carbon estimation is to substitute genus averages (across species with known wood densities) in cases where wood densities of particular species are unknown. However, the extent to which genus-level averages are reflective of species wood densities across tree genera is uncertain, and understanding this is critical for estimating the accuracy of carbon stock estimates. Using primary field data from India and secondary data from a published global dataset, we quantified the extent to which wood density varied among individuals within species (intraspecific variation) at the regional scale and among species within genera (interspecific variation) at regional to global scales. We used a published global database with wood density data for 7743 species belonging to 1741 genera. Linear models were used to compare the species values with the genera averages and the individual values with the species averages, respectively. To estimate the error associated with using genus-level averages for carbon stocks estimation, we compared genus values averaged at the global, old world and continental scales with species values from actually measured data. We also ran a simulation using vegetation data from a published database to calculate the estimation errors in a 1 hectare plot level when genera-averaged wood densities are used. Intraspecific variation was significantly lower than interspecific variation. Continental level genera averages led to estimates closer to the species values for the 10 genera for which most data on species was available. This was also evident from a comparison of genera averages at these three spatial scales with species values from our data. Species within certain ‘hypervarying’ genera showed relatively high levels of variation, irrespective of the spatial scale of the dataset used. The error in estimation of AGB when genera-averaged values were used for species wood densities was 0.35, 0.71 and 2.43% when 0, 10 and 25% of the girth of the trees in the simulated plot were from hypervariable genera. Our findings indicate that species values provide the most accurate estimates for individuals. Genus average wood density values at the continental scale provided more reliable estimates than those at larger spatial scales. The aboveground biomass estimation error when species wood densities were approximated to the genera-average values was 1.4 to 3.7 tonnes per ha when 10% and 25%, respectively, of the girth of trees was from species from hypervariable genera. Our findings indicate that regional or continental scale genera averages provide more reliable estimates than global data and we propose a method to identify hypervariable genera, for which species values rather than genera averages can provide better estimates of carbon stocks.
Gene duplication and genetic innovation in cereal genomes
Authors: Guo Hui , Jiao Yuannian , Tan Xu , Wang Xiyin , Huang Xianzhong , Jin Huizhe , Paterson Andrew H.
Published: January 2019

Organisms continuously require genetic variation to adapt to fluctuating environments, yet major evolutionary events are episodic, making the relationship between genome evolution and organismal adaptation of considerable interest. Here, by genome-wide comparison of sorghum, maize, and rice SNPs, we investigated reservoirs of genetic variations with high precision. For sorghum and rice, which have not experienced whole-genome duplication in 96 million years or more, tandem duplicates accumulate relatively more SNPs than paralogous genes retained from genome duplication. However, maize, which experienced lineage-specific genome duplication and has a relatively larger supply of paralogous duplicates, shows SNP enrichment in paralogous genes. The proportion of genes showing signatures of recent positive selection is higher in small-scale (tandem and transposed) than genome-scale duplicates in sorghum, but the opposite is true in maize. A large proportion of recent duplications in rice are species-specific; however, most recent duplications in sorghum are derived from ancestral gene families. A new retrotransposon family was also a source of many recent sorghum duplications, illustrating a role in providing variation for genetic innovations. This study shows that diverse evolutionary mechanisms provide the raw genetic material for adaptation in taxa with divergent histories of genome evolution.
Do patients really perceive better quality of service in private hospitals than public hospitals in India?
Authors: Swain Swapnarag
Published: January 2019

Purpose

The purpose of this paper is to compare perceived service quality of public/government and private medical college hospitals.

Design/methodology/approach

This study adopts a descriptive, cross-sectional and research design. The research sample includes 340 in patients from six medical college hospitals located in the state of Odisha, India. Primary data are collected through a structured closed ended questionnaire containing 66 items on 1–7 point Likert scale. Statistical tools like factor analysis and ANOVA are performed with the help of SPSS-17 software to analyze the collected data.

Findings

This study identifies 13 dimensions of perceived hospital service quality. The comparative study indicates better performance of public/government hospitals across the technical dimensions of perceived service quality, whereas private hospitals report better performance across majority of the functional dimensions.

Originality/value

In the Indian healthcare system, public hospitals provide low-cost healthcare targeted toward low to middle socio-economic population whereas, large corporate private hospitals provide high-cost healthcare targeted toward high-income group. So the comparison between them produces an obvious result indicating better service quality in private hospitals. Present study minimizes this gap by comparing the service quality of public and private medical college hospitals. Medical colleges ensure access to health services for a larger group of people. Thus, similarity in the segment of population receiving medical services in public and private medical colleges is higher, making the comparison of perceived service quality fairer.
Benchmarking the performance of dairy products in Chinese dairy industry
Authors: Wibowo Santoso , Yang Rongbin , Ramsaran Roshnee
Published: January 2019

Purpose

The purpose of this paper is to present a review of the main factors that are important to consumers of dairy products and develop a new product performance index for evaluating and benchmarking the performance of dairy products. This helps dairy product companies understand their dairy products’ overall performance level, relative to other dairy products in the market.

Design/methodology/approach

A new product performance index is developed for evaluating and benchmarking the performance of dairy products with respect to multiple criteria. Seven important criteria are identified for evaluating and benchmarking the performance of dairy products. To deal with the subjective assessments of qualitative performance measures, linguistic terms approximated by fuzzy numbers are used. Based on the concept of the degree of dominance, a fuzzy multicriteria group decision-making approach is developed to obtain a product performance index for each dairy product.

Findings

The proposed multicriteria group decision-making approach is found to be useful and effective in evaluating and benchmarking the performance of dairy products. The approach is capable of adequately considering the presence of multiple decision makers, the multi-dimensional nature of the performance evaluation problem, and modeling the subjectiveness and imprecision of the performance evaluation process.

Research limitations/implications

The outcome of the multicriteria group decision-making approach is dependent on the subjective inputs provided by the decision makers.

Practical implications

This product performance index will provide useful insights for companies understand their strengths and weaknesses in terms of their products’ performance criteria, and identify relevant areas for continuous improvement. This product performance index is also applicable for dealing with the general multicriteria decision-making problems.

Social implications

The proposed multicriteria group decision-making approach can be used as a decision-making tool for providing various decision makers in dairy product companies and general consumers with useful information regarding the performance of different dairy products.

Originality/value

This paper highlights the important factors for evaluating and benchmarking dairy products and develops a new product performance index for evaluating and benchmarking the performance of dairy products in China.
Quality assessment of city bus service based on subjective and objective service quality dimensions
Authors: Deb Saikat , Ahmed Mokaddes Ali
Published: January 2019

Purpose

The purpose of this paper is to estimate and compare the service quality of the city bus service measured by two different approaches which are subjective service quality dimensions and objective service quality dimensions.

Design/methodology/approach

The objective service quality dimensions have been estimated based on the benchmarking technique provided by the Ministry of Urban Development, India. For the analysis of subjective service quality dimensions, a questionnaire survey has been conducted to measure the users’ satisfaction and dissatisfaction about the service. The questionnaire consists of users’ socioeconomic characteristics and 23 questions related to city bus service quality dimensions. Questionnaire data have been analyzed by factor analysis, regression analysis and path analysis to find out the indicators representing subjective service quality dimensions. Finally, the overall service quality of the bus service has been determined based on both the measures.

Findings

The study indicates that the overall service quality of the bus service is different for subjective and objective analyses. While the objective measures show that the service quality is very good, the subjective measures indicate that the service is not doing well.

Research limitations/implications

The analysis of the subjective dimensions is complicated. Analysis of the subjective dimensions needed more expertise and resources than the objective analysis.

Originality/value

In this study, the estimated service quality of the bus service is more reliable than the other methods as it comprises of both operators’ perspective and passengers’ expectations from the service.