bluuebunny/crossref_metadata_2025 huggingface dataset:
Enhanced cytokine responsiveness in natural killer cells from a pilot cohort of uninfected seronegative women exposed to hepatitis C virus contaminated anti-D immunoglobulin
Authors: Robinson M. W. , Keane C. , Needham M. , Roche G. , Wallace E. , Connell J. , de Gascun C. F. , Naik A. , Fanning L. J. , Gardiner C. , Houlihan D. D. , O’Farrelly C.
Published: August 2019

Background

Some people exposed to hepatitis C virus (HCV) appear to be capable of preventing infection in the absence of detectable antibody responses. These ‘exposed seronegative (ESN)’ people appear naturally resistant to HCV infection. Here, we aimed to examine innate immune mechanisms in ESN individuals amongst rhesus negative Irish women exposed to HCV via contaminated anti-D immunoglobulin between 1977-79 and 1991-94.

Methods

A total of 16 ESN individuals were recruited, along with 9 age- and gender-matched healthy controls. All tested negative for HCV-specific antibodies using conventional diagnostic assays. Peripheral blood cells were analysed for presence of adaptive immune response markers, innate immune responsiveness and natural killer cell phenotype and function.

Results

The innate immune cell profile of ESN women in the present study was characterised by a significant decrease in monocyte frequency and elevated levels of interleukin-8 and -18 compared to age- and gender-matched healthy controls. NK cells from ESN women had normal expression of NK cell receptors but increased IFNγ-production upon cytokine and target cell stimulation as well as enhanced natural killer (NK) cell STAT3 phosphorylation in response to Type I IFN.

Conclusions

We describe for the first time ESN individuals amongst Irish women with past exposure to HCV via contaminated anti-D immunoglobulin. NK cells from these ESN individuals are more responsive to cytokine signalling compared with age- and gender-matched controls. Human ESN cohorts can provide unique insights into the biological mechanisms associated with antigen-independent natural resistance to viral infection.
The oldest freshwater crabs: claws on dinosaur bones
Authors: Robin Ninon , Bakel Barry W.M. van , Hyžný Matúš , Cincotta Aude , Garcia Géraldine , Charbonnier Sylvain , Godefroit Pascal , Valentin Xavier
Published: August 2019

With approximately 1,500 extant species, freshwater crabs (Decapoda: Brachyura) are among the most diverse decapod crustaceans. Nevertheless, their fossil record is extremely limited: only Potamidae, Potamonautidae and Trichodactylidae are reported up to the Eocene of the Neotropics so far. This work documents unusually large decapod claws from the Upper Cretaceous (Campanian) continental deposits of Velaux and vicinity (southern France), in close association with large vertebrate remains. In addition to (1) the systematic assignment of these claws, the study addresses (2) the salinity trends in the deposit environment from its faunal assemblage and the elementary chemical patterns of fossils, and (3) the likely scenario for their auto/allochtony in the Velaux fluvial system. These claws belong to a new taxon,Dinocarcinus velauciensisn. gen. n. sp., referred to as Portunoidea sensu lato, a group of “true” crabs nowadays linked to marine systems. However, the faunal assemblage, the claw taphonomy and the carbonates Y/Ho signatures support their ancient freshwater/terrestrial ecology, making them the oldest reported continental brachyurans and extending the presence of crabs in freshwater environments by 40 Ma. Either as primary or as secondary freshwater crabs, the occurrence of these portunoids in Velaux is an evidence for the independent colonizations of continental environments by multiple brachyuran clades over time, as early as the Campanian.
Integrating When and What Information in the Left Parietal Lobe Allows Language Rule Generalization
Authors: Orpella J , Ripollés P , Ruzzoli M , Amengual JL , Callejas A , Martinez-Alvarez A , Soto-Faraco S , de Diego-Balaguer R
Published: August 2019

A crucial aspect when learning a language is discovering the rules that govern how words are combined in order to convey meanings. Since rules are characterized by sequential co-occurrences between elements (e.g. ‘These cupcakes are unbelievable’), tracking the statistical relationships between these elements is fundamental. However, statistical learning alone cannot fully account for the ability to create abstract rule representations that can be generalized, a paramount requirement of linguistic rules. Here, we provide evidence that, after the statistical relations between words have been extracted, the engagement of goal-directed attention is key to enable rule generalization. Incidental learning performance during a rule-learning task on an artificial language revealed a progressive shift from statistical learning to goal-directed attention. In addition, and consistent with the recruitment of attention, fMRI analyses of late learning stages showed left parietal activity within a broad bilateral dorsal fronto-parietal network. Critically, rTMS on participants’ peak of activation within the left parietal cortex impaired their ability to generalize learned rules to a structurally analogous new language. No stimulation or rTMS on a non-relevant brain region did not have the same interfering effect on generalization. Performance on an additional attentional task showed that rTMS on the same parietal site hindered participants’ ability to integrate what (stimulus identity) and when (stimulus timing) information about an expected target. The present findings suggest that learning rules from speech is a two-stage process: following statistical learning, goal-directed attention –involving left parietal regions– integrates what and when stimulus information to facilitate rapid rule generalization.
Antisense inhibition of accA in E. coli suppressed luxS expression and increased antibiotic susceptibility
Authors: Hillman Tatiana
Published: August 2019

Bacterial multiple drug resistance is a significant issue for the medical community. Gram-negative bacteria exhibit higher rates of multi-drug resistance, partly due to the impermeability of the Gram-negative bacterial cell wall and double-membrane cell envelope, which limits the internal accumulation of antibiotic agents. The outer lipopolysaccharide membrane regulates the transport of hydrophobic molecules, while the inner phospholipid membrane controls influx of hydrophilic particles. In Escherichia coli, the gene accA produces the acetyl-CoA carboxylase transferase enzyme required for catalyzing synthesis of fatty acids and phospholipids that compose the inner membrane. To increase antibiotic susceptibility and decrease growth, this study interrupted fatty acid synthesis and disrupted the composition of the inner membrane through inhibiting the gene accA with antisense RNA. This inhibition suppressed expression of luxS, a vital virulence factor that regulates cell growth, transfers intercellular quorum-sensing signals mediated by autoinducer-2, and is necessary for biofilm formation. Bacterial cells in which accA was inhibited also displayed a greater magnitude of antibiotic susceptibility. These findings confirm accA as a potent target for developing novel antibiotics such as antimicrobial gene therapies.
BISON: Brain tISue segmentatiON pipeline using T1-weighted magnetic resonance images and a random forests classifier
Authors: Dadar Mahsa , Collins D. Louis
Published: August 2019

Introduction

Accurate differentiation of brain tissue types from T1-weighted magnetic resonance images (MRIs) is a critical requirement in many neuroscience and clinical applications. Accurate automated tissue segmentation is challenging due to the variabilities in the tissue intensity profiles caused by differences in scanner models and acquisition protocols, in addition to the varying age of the subjects and potential presence of pathology. In this paper, we present BISON (Brain tISue segmentatiON), a new pipeline for tissue segmentation.

Methods

BISON performs tissue segmentation using a random forests classifier and a set of intensity and location priors obtained based on T1-weighted images. The proposed method has been developed and cross-validated based on multi-center and multi-scanner manual labels of 72 subjects aging from 5-96 years old, ensuring the generalizability of the results to new data from various age ranges. In addition, we assessed the test-retest reliability of BISON on 2 datasets; a. using 20 subjects that had scan/re-scan MRIs and manual segmentations available, and b. using a human phantom dataset including 90 scans from a single individual acquired across 10 years.

Results

The results of the proposed method were compared against Atropos, a commonly used tissue classification method from ANTs. The proposed method yielded cross-validation Dice Kappa values of κGM= 0.88 ± 0.03, κWM= 0.85 ± 0.03, κCSF= 0.77 ± 0.11, outperforming ANTs Atropos (κGM= 0.79 ± 0.05, κWM= 0.84 ± 0.05, κCSF= 0.64 ± 0.22) as well as test-retest Dice Kappa values of κGM= 0.94 ± 0.006, κWM= 0.92 ± 0.006, κCSF= 0.77 ± 0.11 outperforming both manual (κGM= 0.92 ± 0.01, κWM= 0.91 ± 0.01, κCSF= 0.74 ± 0.03) and ANTs Atropos (κGM= 0.87 ± 0.001, κWM= 0.92 ± 0.001, κCSF= 0.79 ± 0.05). The human phantom dataset validations showed high generalizability for both Atropos (κGM= 0.97 ± 0.01, κWM= 0.96 ± 0.01, κCSF= 0.93 ± 0.02) and BISON (κGM= 0.95 ± 0.01, κWM= 0.94 ± 0.01, κCSF= 0.85 ± 0.03), while Atropos tended to consistently under-segment the cortical CSF. Finally, our assessment of BISON, Atropos, FAST from FSL, and SPM12 segmentations in presence of white matter hyperintensities (WMHs) showed that BISON outperforms the other three methods, correctly detecting WMHs as WM.

Conclusion

Our results show that BISON can provide accurate and robust segmentations in data from different age ranges and various scanner models, making it ideal for performing tissue classification in large multi-center and multi-scanner databases.
Chromosome-level hybrid de novo genome assemblies as an attainable option for non-model organisms
Authors: Jaworski Coline C. , Allan Carson W. , Matzkin Luciano M.
Published: August 2019

The emergence of third generation sequencing (3GS; long-reads) is making closer the goal of chromosome-size fragments in de novo genome assemblies. This allows the exploration of new and broader questions on genome evolution for a number of non-model organisms. However, long-read technologies result in higher sequencing error rates and therefore impose an elevated cost of sufficient coverage to achieve high enough quality. In this context, hybrid assemblies, combining short-reads and long-reads provide an alternative efficient and cost-effective approach to generate de novo, chromosome-level genome assemblies. The array of available software programs for hybrid genome assembly, sequence correction and manipulation is constantly being expanded and improved. This makes it difficult for non-experts to find efficient, fast and tractable computational solutions for genome assembly, especially in the case of non-model organisms lacking a reference genome or one from a closely related species. In this study, we review and test the most recent pipelines for hybrid assemblies, comparing the model organism Drosophila melanogaster to a non-model cactophilic Drosophila, D. mojavensis. We show that it is possible to achieve excellent contiguity on this non-model organism using the DBG2OLC pipeline.
Harnessing natural modularity of cellular metabolism to design a modular chassis cell for a diverse class of products by using goal attainment optimization
Authors: Garcia Sergio , Trinh Cong T.
Published: August 2019

Living cells optimize their fitness against constantly changing environments to survive. Goal attainment optimization is a mathematical framework to describe the simultaneous optimization of multiple conflicting objectives that must all reach a performance above a threshold or goal. In this study, we applied goal attainment optimization to harness natural modularity of cellular metabolism to design a modular chassis cell for optimal production of a diverse class of products, where each goal corresponds to the minimum biosynthesis requirements (e.g., yields and rates) of a target product. This modular cell design approach enables rapid generation of optimal production strains that can be assembled from a modular cell and various exchangeable production modules and hence accelerates the prohibitively slow and costly strain design process. We formulated the modular cell design problem as a blended or goal attainment mixed integer linear program, using mass-balance metabolic models as biological constraints. By applying the modular cell design framework for a genome-scale metabolic model of Escherichia coli, we demonstrated that a library of biochemically diverse products could be effectively synthesized at high yields and rates from a modular (chassis) cell with only a few genetic manipulations. Flux analysis revealed this broad modularity phenotype is supported by the natural modularity and flexible flux capacity of core metabolic pathways. Overall, we envision the developed modular cell design framework provides a powerful tool for synthetic biology and metabolic engineering applications such as industrial biocatalysis to effectively produce fuels, chemicals, and therapeutics from renewable and sustainable feedstocks, bioremediation, and biosensing.
The NanoZoomer Connectomics Pipeline for Tracer Injection Studies of the Marmoset Brain
Authors: Woodward Alexander , Gong Rui , Abe Hiroshi , Nakae Ken , Hata Junichi , Skibbe Henrik , Yamaguchi Yoko , Ishii Shin , Okano Hideyuki , Yamamori Tetsuo , Ichinohe Noritaka
Published: August 2019

We describe our connectomics pipeline for processing tracer injection data for the brain of the common marmoset (Callithrix jacchus). Brain sections were imaged using a batch slide scanner (NanoZoomer 2.0-HT) and we used artificial intelligence to precisely segment the anterograde tracer signal from the background in the fluorescence images. The shape of each brain was reconstructed by reference to a block-face and all data was mapped into a common 3D brain space with atlas and 2D cortical flat map. To overcome the effect of using a single template atlas to specify cortical boundaries, each brain was cytoarchitectonically annotated and used for making an individual 3D atlas. Registration between the individual and common brain cortical boundaries in the flat map space was done to absorb the variation of each brain and precisely map all tracer injection data into one cortical brain space. We describe the methodology of our pipeline and analyze tracer segmentation and brain registration accuracy. Results show our pipeline can successfully process and normalize tracer injection experiments into a common space, making it suitable for large-scale connectomics studies with a focus on the cerebral cortex.
Oral administration of an anti-CfaE secretory IgA antibody protects against EnterotoxigenicEscherichia colidiarrheal disease in a non-human primate model
Authors: Stoppato Matteo , Gaspar Carlos , Regeimbal James , Nunez Gladys , Giuntini Serena , Gawron Melissa A. , Pondish Jessica R. , Martin Joseph C. , Schneider Matthew , Schiller Zachary A. , Klempner Mark S. , Cavacini Lisa A. , Wang Yang
Published: August 2019

ABSTACT

EnterotoxigenicEscherichia coli(ETEC) is a leading cause of diarrhea-associated illness in developing countries. There is currently no vaccine licensed to prevent ETEC and the development of an efficacious prophylaxis would provide an intervention with significant impact. Recent studies suggested that effective protection could be achieved by inducing immunity to block colonization of ETEC. Here, we evaluated the efficacy of secretory (s) IgA2 and dimeric (d) IgA2 of an anti-colonization factor antigen antibody, 68-61, in theAotus nancymaaenon-human primate (NHP) ETEC challenge model via oral and parental delivery. Thirty-nine animals were distributed across 3 groups of 13, and challenged with 5.0×1011cfu of H10407 on Day 0. Group 1 received a dIgA2 68-61 subcutaneously on day 0. Group 2 received a SIgA2 68-61 orally on days −1, 0, and +1, and Group 3 received an irrelevant SIgA2 antibody orally on days −1, 0, and +1. All animals were observed for symptoms of diarrhea, and stools were collected for ETEC colony counts. SIgA2 treatment significantly lowered the attack rate, resulting in a protective efficacy of 71.4% (p=0.025) in Group 2 as compared to Group 3. Anti-CfaE dIgA2 treatment group reduced the diarrheal attack rate, although the reduction did not reach significance (57.1%; P=0.072) as compared to the irrelevant SIgA2 Group 3. Our results demonstrated the feasibility of oral administration of SIgA as a potential immunoprophylaxis against enteric infections. To our knowledge, this is the first study to demonstrate the efficacy of administrated SIgA in a non-human primate model.
Body height in young adult men and risk of dementia later in adult life
Authors: Jørgensen Terese Sara Høj , Christensen Gunhild Tidemann , Christensen Kaare , Sørensen Thorkild IA , Osler Merete
Published: August 2019

This study examined the relationship between body height and dementia and explored the impact of intelligence level, educational attainment, early life environment and familial factors. A total of 666,333 men, 70,608 brothers, and 7,388 twin brothers born 1939-1959 and examined at the conscript board were followed in Danish nationwide registers (1969-2016). Cox regression models were applied to analyze the association between body height and dementia. Within-brothers and within-twin pair analyses were conducted to explore the role of shared familial factors including partly shared genetics. In total, 10,599 men were diagnosed with dementia. The association between one z-score difference in body height and dementia (HR: 0.90, 95%CI: 0.89;0.90) was inverse and weakened slightly after adjustment for intelligence test scores and educational level. The within-brother analyses revealed a smaller estimate for dementia diagnosis the cohort analyses of brothers. The twin analysis showed similar, though less clear associations, which were not statistically significant.
Model-driven generation of artificial yeast promoters
Authors: Kotopka Benjamin J. , Smolke Christina D.
Published: August 2019

Promoters play a central role in controlling gene regulation; however, a small set of promoters is used for most genetic construct design in the yeast Saccharomyces cerevisiae. Generating and utilizing models that accurately predict protein expression from promoter sequences would enable rapid generation of novel useful promoters and facilitate synthetic biology efforts in this model organism. We measured the gene expression activity of over 675,000 unique sequences in a constitutive promoter library, and over 327,000 sequences in an inducible promoter library. Training an ensemble of convolutional neural networks jointly on the two datasets enabled very high (R2 > 0.79) predictive accuracies on multiple sequence-activity prediction tasks. We developed model-guided design strategies which yielded large, sequence-diverse sets of novel promoters exhibiting activities similar to current best-in-class sequences. In addition to providing large sets of new promoters, our results show the value of model-guided design as an approach for generating useful DNA parts.
Place cell map genesis via competitive learning and conjunctive coding in the dentate gyrus
Authors: Kim Soyoun , Jung Dajung , Royer Sébastien
Published: August 2019

Place cells exhibit spatially selective firing fields and collectively map the continuum of positions in environments; how such network pattern develops with experience remains unclear. Here, we recorded putative granule (GC) and mossy (MC) cells from the dentate gyrus (DG) over 27 days as mice repetitively ran through a sequence of objects fixed onto a treadmill belt. We observed a progressive transformation of GC spatial representations, from a sparse encoding of object locations and periodic spatial intervals to increasingly more single, evenly dispersed place fields, while MCs showed little transformation and preferentially encoded object locations. A competitive learning model of the DG reproduced GC transformations via the progressive integration of landmark-vector cells and grid cell inputs and required MC-mediated feedforward inhibition to evenly distribute GC representations, suggesting that GCs progressively encode conjunctions of objects and spatial information via competitive learning, while MCs help homogenize GC spatial representations.
Computational approaches for parametric imaging of dynamic PET data
Authors: Crisci S , Piana M , Ruggiero V , Scussolini M
Published: August 2019

Parametric imaging of nuclear medicine data exploits dynamic functional images in order to reconstruct maps of kinetic parameters related to the metabolism of a specific tracer injected in the biological tissue. From a computational viewpoint, the realization of parametric images requires the pixel-wise numerical solution of compartmental inverse problems that are typically ill-posed and nonlinear. In the present paper we introduce a fast numerical optimization scheme for parametric imaging relying on a regularized version of the standard affine-scaling Trust Region method. The validation of this approach is realized in a simulation framework for brain imaging and comparison of performances is made with respect to a regularized Gauss-Newton scheme and a standard nonlinear least-squares algorithm.
Prompt rewetting of drained peatlands reduces climate warming despite methane emissions
Authors: Günther Anke , Barthelmes Alexandra , Huth Vytas , Joosten Hans , Jurasinski Gerald , Koebsch Franziska , Couwenberg John
Published: August 2019

Peatlands are strategic areas for climate change mitigation because of their matchless carbon stocks. Drained peatlands release this carbon to the atmosphere as carbon dioxide (CO2). Peatland rewetting effectively stops these CO2 emissions, but also re-establishes the emission of methane (CH4).

Essentially, management must choose between CO2 emissions from drained or CH4 emissions from rewetted peatland. This choice must consider radiative effects and atmospheric lifetimes of both gases, with CO2 being a weak but persistent and CH4 a strong but short-lived greenhouse gas. The resulting climatic effects are, thus, strongly time-dependent. We used a radiative forcing model to compare forcing dynamics of global scenarios for future peatland management using areal data from the Global Peatland Database. Our results show that CH4 radiative forcing does not undermine the climate change mitigation potential of peatland rewetting. Instead, postponing rewetting increases the long-term warming effect of continued CO2 emissions. Warnings against CH4 emissions from rewetted peatlands are therefore unjustified and counterproductive.
Parallel channels for motion feature extraction in the pretectum and tectum of larval zebrafish
Authors: Wang Kun , Hinz Julian , Zhang Yue , Thiele Tod R. , Arrenberg Aristides B
Published: August 2019

Non-cortical visual areas in vertebrate brains extract different stimulus features, such as motion, object size and location, to support behavioural tasks. The optic tectum and pretectum, two primary visual areas, are thought to fulfil complementary biological functions in zebrafish to support prey capture and optomotor stabilisation behaviour. However, the adaptations of these brain areas to behaviourally relevant stimulus statistics are unknown. Here, we used calcium imaging to characterize the receptive fields of 1,926 motion-sensitive neurons in diencephalon and midbrain. We show that many caudal pretectal neurons have large receptive fields (RFs), whereas RFs of tectal neurons are smaller and mostly size-selective. RF centres of large-size RF neurons in the pretectum are predominantly located in the lower visual field, while tectal neurons sample the upper-nasal visual field more densely. This tectal visual field sampling matches the expected prey item locations, suggesting that the tectal magnification of the upper-nasal visual field might be an adaptation to hunting behaviour. Finally, we probed optomotor responsiveness and found that even relatively small stimuli drive optomotor swimming, if presented in the lower-temporal visual field, suggesting that the pretectum preferably samples information from this region on the ground to inform optomotor behaviour. Our characterization of the parallel processing channels for non-cortical motion feature extraction provides a basis for further investigation into the sensorimotor transformations of the zebrafish brain and its adaptations to habitat and lifestyle.
Are Sources of EEG and MEG rhythmic activity the same? An analysis based on BC-VARETA
Authors: Riaz Usama , Razzaq Fuleah A. , Paz-Linares Deirel , Areces-Gonzalez Ariosky , Huang Sunpei , Gonzalez-Moreira Eduardo , Bringas Vega Maria L. , Montes Eduardo Martinez , Iglesias José Enrique Alvarez , Valdés-Sosa Pedro A.
Published: August 2019

In the resting state (closed or open eyes) the electroencephalogram (EEG) and the magnetoencephalogram (MEG) exhibit rhythmic brain activity is typically the 10 Hz alpha rhythm. It has a topographic frequency spectral distribution that is, quite similar for both modalities--something not surprising since both EEG and MEG are generated by the same basic oscillations in thalamocortical circuitry. However, different physical aspects underpin the two types of signals. Does this difference lead to a different distribution of reconstructed sources for EEG and MEG rhythms? This question is important for the transferal of results from one modality to the other but has surprisingly received scant attention till now. We address this issue by comparing eyes open EEG source spectra recorded from 70 subjects from the Cuban Human Brain Mapping project with the MEG of 70 subjects from the Human Connectome Project. Source spectra for each voxel and frequencies between 0-50Hz with 100 frequency points were obtained via a novel sparse-covariance inverse method (BC-VARETA) based on individualized BEM head models with subject-specific regularization parameters (noise to signal ratio). We performed a univariate permutation-based rank test among sources of both modalities and found out no differences. To carry out an unbiased comparison we computed sources from eLORETA and LCMV, performed the same permutation-based comparison, and found the same results we got with BC-VARETA.
Associations of adverse lifetime experiences with brain structure in 7003 UK Biobank participants
Authors: Gheorghe Delia A. , Li Chenlu , Gallacher John , Bauermeister Sarah
Published: August 2019

Background

Experiences of chronic stress and trauma are major risk factors for psychiatric illness. Evidence suggests that adversity-related changes in brain structure and function accelerate this vulnerability. It is yet to be determined whether neuroendocrine effects on the brain are a result of the interference with neural development during sensitive periods or a consequence of cumulative lifetime adversity. To address this question, the present study investigated the associations between brain structure and self-reported data of childhood and adult adversity using machine learning techniques and structural equation models (SEM).

Methods

The UK Biobank resource was used to access Imaging Derived Phenotypes (IDPs) of grey matter and white matter tract integrity of 7003 participants, together with selected childhood and adult adversity data. Latent measures of adversity and imaging phenotypes were estimated to evaluate their associations using SEM.

Results

We demonstrated that increased incidence of childhood adversity events may be associated with smaller grey matter in frontal, insular, subcallosal and cerebellar regions of the brain. There were no significant associations between brain phenotypes and negative experiences during adulthood.

Conclusions

Using a large population cohort dataset, this study contributes to the suggestion that childhood adversity may determine grey matter reductions in brain regions, which are putatively sensitive to the neurotoxic effects of chronic stress. Furthermore, it provides novel evidence to support the “sensitive periods” model though which adversity affects the brain.
A multilayer perspective for inferring spatial and social functioning in animal movement networks
Authors: Mourier Johann , Lédée Elodie J. I. , Jacoby David M. P.
Published: August 2019

Animal movement patterns are increasingly analysed as spatial networks. Currently, structures of complex movements are typically represented as a single-layer (or monoplex) network. However, aggregating individual movements, to generate population-level inferences, considerably reduces information on how individual or species variability influences spatial connectivity and thus identifying the mechanisms driving network structure remains difficult.

Here, we propose incorporating the recent conceptual advances in multilayer network analyses with the existing movement network approach to improve our understanding of the complex interaction between spatial and/or social drivers of animal movement patterns.

Specifically, we explore the application and interpretation of this framework using an empirical example of shark movement data gathered using passive remote sensors in a coral reef ecosystem. We first show how aggregating individual movement networks can lead to the loss of information, potentially misleading our interpretation of movement patterns. We then apply multilayer network analyses linking individual movement networks (i.e. layers) to the probabilities of social contact between individuals (i.e. interlayer edges) in order to explore the functional significance of different locations to an animal’s ecology.

This approach provides a novel and holistic framework incorporating individual variability in behaviour and inter-individual interactions. We discuss how this approach can be used in applied ecology and conservation to better assess the ecological significance of variable space use by mobile animals within a population. Further, we argue that the uptake of multilayer networks will significantly broaden our understanding of long-term ecological and evolutionary processes, particularly in the context of information or disease transfer between individuals.
ZapA tetramerization is required for midcell localization and ZapB interaction in Escherichia coli
Authors: Meiresonne Nils Y. , den Blaauwen Tanneke
Published: August 2019

Bacterial cell division is guided by FtsZ treadmilling precisely at midcell. FtsZ itself is regulated by FtsZ associated proteins (Zaps) that couple it to different cellular processes. ZapA is known to enhance FtsZ bundling but also forms the synchronizing link with chromosome segregation through ZapB and matS bound MatP. ZapA exists as dimers and tetramers in the cell. Using the ZapAI83E mutant that only forms dimers, this paper investigates the effects of ZapA multimerization state on its interaction partners and cell division. By employing (fluorescence) microscopy and Förster Resonance Energy Transfer in vivo it is shown that; dimeric ZapA is unable to complement a zapA deletion strain and localizes diffusely through the cell but still interacts with FtsZ that is not part of the cell division machinery. Dimeric ZapA is unable to recruit ZapB, which localizes in its presence unipolarly in the cell. Interestingly, the localization profiles of the chromosome and unipolar ZapB anticorrelate. The work presented here confirms previously reported in vitro effects of ZapA multimerization in vivo and further places it in a broader context by revealing the strong implications for ZapB localization and ter linkage.
Accelerating Inflammation Resolution to Counteract Chemical Cutaneous Injury
Authors: Achanta Satyanarayana , Chintagari Narendranath Reddy , Balakrishna Shrilatha , Liu Boyi , Jordt Sven-Eric
Published: August 2019

Chemical exposure to vesicants such as sulfur mustard (SM), and electrophilic riot control agents such as 2-chlorobenzalmalononitrile (CS) tear gas agent, cause strong cutaneous inflammation. Classical anti-inflammatory treatments have focused on interference with target initiation and maintenance of inflammation, with mixed outcomes. Inflammation is broadly classified into three temporal phases, initiation, amplification and maintenance, and resolution. Resolution of inflammation was thought to be a passive process but the recent body of literature shows that resolution is an active process and is mediated by fatty acid-derived mediators (specialized pro-resolving mediators, SPMs). We hypothesized that accelerating resolution phase of inflammation may attenuate the exaggerated inflammatory response following chemical threat exposure, leading to decreased morbidity and improved recovery. In this study, SPMs, such as Resolvin D1 (RvD1) and Resolvin D2 (RvD2), were administered to mice at nanogram doses post-exposure to an SM analog, 2-chloroethyl-ethyl-sulfide (CEES) or CS tear gas agent. SPMs decreased edema (ear thickness and punch biopsy weights), pro-inflammatory cytokines (IL-1β, CXCL1/KC, MIP2) and protease marker (MMP-9), and vascular leakage (determined by IRDye 800 CW PEG) while improving histopathology in cutaneous chemical injury mouse models. These results support our hypothesis and pave the way for SPMs for further development as potential medical countermeasures for chemical threat agents-induced skin injuries.
Tertiary lymphoid tissue develops during normal aging in mice and humans
Authors: Ligon Marianne M. , Wang Caihong , Jennings Zoe , Schulz Christian , DeJong Erica N. , Lowder Jerry L. , Bowdish Dawn M. E. , Mysorekar Indira U.
Published: August 2019

Aging has multifaceted effects on the immune system in the context of systemic responses to specific vaccines and pathogens, but how aging affects tissue-specific immunity is not well-defined. Chronic bladder inflammation is highly prevalent in older women, but mechanisms by which aging promotes these pathologies remain unknown. Here we report distinct, age-associated changes to the immune compartment in the otherwise normal female (but not in male) mouse urinary bladder and parallel changes in older women with chronic bladder inflammation. In aged mice, the bladder epithelium became more permeable, and the homeostatic immune landscape shifted from a limited, innate immune-predominant surveillance to an inflammatory, adaptive immune-predominant environment. Strikingly, lymphoid cells were organized into tertiary lymphoid tissues, hereafter named bladder tertiary lymphoid tissue (bTLT). Analogous bTLTs were found in older women, many of whom had a history of recurrent urinary tract infection (UTI). Aged mice responded poorly to experimental UTI, experiencing spontaneous recurrences at higher rates than young mice. However, bTLT formation was dependent on aging and independent of infection. Furthermore, bTLTs in aged mice played a role inde novoantibody responses and urinary IgA production by recruitment of naive B cells that form germinal centers and mature into IgA-secreting plasma cells. Finally, TNFα was a key driver of bTLT formation, as aged TNFα-/-mice lacked bTLTs. Both aged TNFα-/-and wild type mice exhibited increased bladder permeability, suggesting that epithelial dysfunction may be an upstream mediator of chronic, age-associated bladder inflammation. Thus, bTLTs arise as a function of age and may underlie chronic, age-associated bladder inflammation. Our model establishes a platform for further investigation of age-association tissue inflammation and translation to new treatment strategies.

One Sentence Summary

Mice develop bladder tertiary lymphoid tissue (bTLT) during aging that is dependent on TNFα and independent of urinary tract infection.
The periphery and the core properties explain the omnigenic model in the human interactome
Authors: Wang Bingbo , Glass Kimberly , Röhl Annika , Santolini Marc , Croteau-Chonka Damien C. , Weiss Scott T. , Raby Benjamin A. , Sharma Amitabh
Published: August 2019

Understanding the connectivity patterns of genes in a localized disease neighborhood or disease module in a molecular interaction network (interactome) is a key step toward advancing the knowledge about molecular mechanisms underlying a complex disease. In this work, we introduce a framework that detects peripheral and core regions of a disease in the human interactome. We leverage gene expression data on 104 diseases and analyze the connectivity of differentially expressed genes (quantified by a p-value < 0.05) and their topological membership in the network to distinguish between peripheral and core genes. Per definition, peripheral and core genes are topologically different and we show that they also differ biologically. Core genes are more enriched for Genome-wide association study (GWAS) and Online Mendelian Inheritance in Man (OMIM) data, whereas peripheral genes are more shared across different disease states and their overlap helps predict disease proximity in the human interactome. Based on this observation, we propose a flower model to explain the organization of genes in the human interactome, with core genes of different diseases as the petals and the peripheral genes as the (shared) stem. We show that this network model is an important step towards finding novel drug targets and improving disease classification. Overall, we were able to demonstrate how perturbations percolate through the human interactome and contribute to peripheral and core regions, an important novel feature of the omnigenic model.
Defining variation in pre-human ecosystems can guide conservation: An example from a Caribbean coral reef
Authors: O’Dea Aaron , Lepore Mauro , Altieri Andrew H. , Chan Melisa , Morales-Saldaña Jorge Manuel , Muñoz Nicte-Ha , Pandolfi John M. , Toscano Marguerite A. , Zhao Jian-xin , Dillon Erin M.
Published: August 2019

There is a consensus that Caribbean coral reefs are a pale shadow of what they once were, yet a reef’s pre-human state is typically assumed or estimated using space-for-time substitution approaches. These approaches may fail to account for past variation before human impact which could mislead conservation priorities and actions. In this study we use a suite of fossilised mid-Holocene (7.2-5.6 ka) fringing reefs in Caribbean Panama to define the Historical Range of Variation (HRV) in coral community structure before human-impact to provide context for the states of modern reefs in the same area. Using the abundances of coral taxa to quantify communities, we found that most of the modern coral communities exist in novel ecosystem states with no fossil precedence. We do however identify one modern reef that is indistinguishable in coral community structure from the mid-Holocene reefs. Reef-matrix cores show that the community on this reef has remained in a stable state for over 760 years, suggesting long-term resistance to the region-wide shift to novel states. Without historical context this robust and stable reef would be overlooked since it does not fulfil expectations of what a “pristine” coral reef should look like. This example illustrates how defining past variation using the fossil record can place modern degradation in historical context and improve conservation recommendations.
Riluzole does not ameliorate disease caused by cytoplasmic TDP-43 in a mouse model of amyotrophic lateral sclerosis
Authors: Wright Amanda L. , Della Gatta Paul A. , Le Sheng , Berning Britt A. , Mehta Prachi , Jacobs Kelly R. , Gul Hossai , Gil Rebecca San , Hedl Thomas J. , Riddell Winonah R. , Watson Owen , Keating Sean S. , Venturato Juliana , Chung Roger S. , Atkin Julie D. , Lee Albert , Shi Bingyang , Blizzard Catherine A. , Morsch Marco , Walker Adam K.
Published: August 2019

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease commonly treated with riluzole, a small molecule that may act via modulation of glutamatergic neurotransmission. However, riluzole only modestly extends lifespan for people living with ALS and its precise mechanisms of action remain unclear. Most ALS cases are characterised by accumulation of cytoplasmic TAR DNA binding protein of 43 kDa (TDP-43), and understanding the effects of riluzole in models that closely recapitulate TDP-43 pathology may provide insights for development of improved therapeutics. We therefore investigated the effects of riluzole in transgenic mice that inducibly express nuclear localisation sequence (NLS)-deficient human TDP-43 in neurons (NEFH-tTA/tetO-hTDP-43ΔNLS, ‘rNLS’, mice). Riluzole treatment from the first day of hTDP-43ΔNLS expression did not alter disease onset, weight loss or performance on multiple motor behavioural tasks. Riluzole treatment also did not alter TDP-43 protein levels, solubility or phosphorylation. Although we identified a significant decrease in GluA2 and GluA3 proteins in the cortex of rNLS mice, riluzole did not ameliorate this disease-associated molecular phenotype. Likewise, riluzole did not alter the disease-associated atrophy of hindlimb muscle in rNLS mice. Finally, riluzole treatment beginning after disease onset in rNLS mice similarly had no effect on progression of late-stage disease or animal survival. Together, we demonstrate specific glutamatergic receptor alterations and muscle fibre-type changes reminiscent of ALS in rNLS mice, but riluzole had no effect on these or any other disease phenotypes. Future targeting of pathways directly related to accumulation of TDP-43 pathology may be needed to develop better treatments for ALS.

Significance Statement

Accumulation of cytoplasmic TDP-43 protein is the hallmark pathology of ALS. Riluzole is the most widely used drug for ALS treatment, but provides only a short extension of lifespan. We demonstrate here in the rNLS mouse model, which mimics TDP-43 pathology, that riluzole does not ameliorate progressive alterations in motor strength and coordination, muscle atrophy, glutamate receptor levels, or TDP-43 protein levels and solubility, and does not prolong animal survival. Riluzole similarly did not affect decreased levels of glutamate receptor subunits GluA2/GluA3 in rNLS mice. The inability of riluzole to rescue pathological or phenotypic changes in this TDP-43 model provides further impetus for the discovery of improved therapies targeting the key drivers of ALS pathogenesis.
Cloning of Two Gene Clusters Involved in the Catabolism of 2,4-Dinitrophenol byParaburkholderiasp. Strain KU-46 and Characterization of the Initial DnpAB Enzymes and a Two-Component Monooxygenase DnpC1C2
Authors: Yamamoto Taisei , Liu Yaxuan , Kohaya Nozomi , Hasegawa Yoshie , Lau Peter C.K. , Iwaki Hiroaki
Published: August 2019

Besides an industrial pollutant, 2,4-dinitrophenol (DNP) has been used illegally as a weight loss drug that had claimed human lives. Little is known about the metabolism of DNP, particularly among Gram-negative bacteria. In this study, two non-contiguous genetic loci ofParaburkholderia(formerlyBurkholderia) sp. strain KU-46 genome were identified and four key initial genes (dnpA,dnpB, anddnpC1C2) were characterized to provide molecular and biochemical evidence for the degradation of DNP via the formation of 4-nitrophenol (NP), a pathway that is unique among DNP utilizing bacteria. Reverse transcription PCR analysis indicated that thednpAgene encoding the initial hydride transferase (28 kDa), and thednpBgene encoding a nitrite-eliminating enzyme (33 kDa), are inducible by DNP and the two genes are organized in an operon. Purified DnpA and DnpB from overexpression clones inEscherichia colieffected the transformation of DNP to NP via the formation of hydride-Meisenheimer complex of DNP. The function of DnpB appears new since all homologs of DnpB sequences in the protein database are annotated as putative nitrate ABC transporter substrate-binding proteins. The gene cluster responsible for the degradation of DNP after NP formation was designateddnpC1C2DXFER.DnpC1 and DnpC2 were functionally characterized as the respective FAD reductase and oxygenase components of the two-component NP monooxygenase. Both NP and 4-nitrocatechol were shown to be substrates, producing hydroquinone and hydroxyquinol, respectively. Elucidation of thehqdA1A2BCDgene cluster allows the delineation of the final degradation pathway of hydroquinone to ß-ketoadipate prior to its entry to the tricarboxylic acid cycle.

Importance

This study fills a gap in our knowledge and understanding of the genetic basis and biochemical pathway for the degradation of 2,4-dinitrophenol (DNP) in Gram-negative bacteria, represented by the prototypicalParaburkholderiasp. strain KU-46 that metabolizes DNP through the formation of 4-nitrophenol, a pathway unseen by other DNP utilizers. The newly cloned genes could serve as DNA probes in biomonitoring as well as finding application in new biocatalyst development to access green chemicals. By and large, knowledge of the diverse strategies used by microorganisms to degrade DNP will contribute to the development of bioremediation solutions since DNP is an industrial pollutant used widely in the chemical industry for the synthesis of pesticides, insecticides, sulfur dyes, wood preservatives, and explosives, etc. (119 words)
aMpLiTuDe MoDuLaTeD noise for tinnitus suppression in tonal and noise-like tinnitus
Authors: Schoisswohl S. , Arnds J. , Schecklmann M. , Langguth B. , Schlee W. , Neff P.
Published: August 2019

Background

Acoustic stimulation offers a potential treatment approach for tinnitus but also in-sights in its basic mechanisms by short-term tinnitus suppression called residual inhibition (RI). The effects of RI were found to be depending on intensity, length or sound types covering the individual tinnitus characteristics. In patients with tonal tinnitus RI was increased with amplitude modulated (AM) pure tones at the individual tinnitus frequency while the effects of modulated noise sounds have not been systematically researched.

Objectives

The aim of the present study was to investigate whether in patients with noise-like tinnitus RI can be increased by AM noise-like stimuli according to the individual tinnitus frequency range.

Methods

For this purpose the individual tinnitus characteristics (noise-like and tonal tinnitus) were assessed via customizable noise-band matching, in order to generate bandpass filtered stimuli according to the individual tinnitus sound (individualized bandpass filtered sounds; IBP). Subsequent, various stimuli differing in bandpass filtering and AM were tested with respect to their potential to induce RI. Patients were acoustically stimulated with seven different types of stimuli for three minutes each and had to rate the loudness of their tinnitus after each stimuli.

Results

Results indicate a general efficacy of noise stimuli for the temporary suppression of tinnitus, but no significant differences between AM and unmodulated IBP. Significantly better effects were observed for the subgroup with noise-like tinnitus (n=14), especially directly after stimulation offset.

Conclusions

The study at hand provides further insights in potential mechanisms behind RI for different types of tinnitus. Beyond that, derived principles may qualify for new or extend current tinnitus sound therapies.