bluuebunny/crossref_metadata_2025 huggingface dataset:
A common neural network among state, trait, and pathological anxiety from whole-brain functional connectivity
Authors: Takagi Yu , Sakai Yuki , Abe Yoshinari , Nishida Seiji , Harrison Ben J. , Martínez-Zalacaín Ignacio , Soriano-Mas Carles , Narumoto Jin , Tanaka Saori C.
Published: July 2017

Anxiety is one of the most common mental states of humans. Although it drives us to avoid frightening situations and to achieve our goals, it may also impose significant suffering and burden if it becomes extreme. Because we experience anxiety in a variety of forms, previous studies investigated neural substrates of anxiety in a variety of ways. These studies revealed that individuals with high state, trait, or pathological anxiety showed altered neural substrates. However, no studies have directly investigated whether the different dimensions of anxiety share a common neural substrate, despite its theoretical and practical importance. Here, we investigated a neural network of anxiety shared by different dimensions of anxiety in a unified analytical framework using functional magnetic resonance imaging (fMRI). We analyzed different datasets in a single scale, which was defined by an anxiety-related neural network derived from whole brain. Through the fMRI task for provoking anxiety, we found a common neural network of state anxiety across participants (1,638 trials obtained from 10 participants). Then, using the resting-state fMRI in combination with the participants’ trait anxiety scale (879 participants from the Human Connectome Project), we demonstrated that trait anxiety also shared the same neural network as state anxiety. Furthermore, the common neural network between state and trait anxiety could detect patients with obsessive-compulsive disorder, which is characterized by pathological anxiety-driven behaviors (174 participants from multi-site datasets). Our findings provide direct evidence that different dimensions of anxiety are not completely independent but have a substantial biological inter-relationship. Our results also provide a biologically defined dimension of anxiety, which may promote further investigation of various human characteristics, including psychiatric disorders, from the perspective of anxiety.
Imaging and dynamic causal modelling reveal brain-wide changes in effective connectivity and synaptic dynamics during epileptic seizures
Authors: Rosch RE , Hunter PR , Baldeweg T , Friston KJ , Meyer MP
Published: July 2017

Pathophysiological explanations of epilepsy typically focus on either the micro/mesoscale (e.g. excitation-inhibition imbalance), or on the macroscale (e.g. network architecture). Linking abnormalities across spatial scales remains difficult, partly because of technical limitations in measuring neuronal signatures concurrently at the scales involved. Here we use light sheet imaging of the larval zebrafish brain during acute epileptic seizure induced with pentylenetetrazole. Empirically measured spectral changes of spontaneous neuronal activity during the seizure are then modelled using neural mass models, allowing Bayesian inference on changes in effective network connectivity and their underlying synaptic dynamics. This dynamic causal modelling of seizures in the zebrafish brain reveals concurrent changes in synaptic coupling at macro- and mesoscale. Fluctuations of synaptic connection strength and their temporal dynamics are both required to explain observed seizure patterns. These findings challenge a simple excitation-inhibition account of seizures, and highlight changes in synaptic transmission dynamics as a possible seizure generation pathomechanism.

Abbreviations

LFP

local field potential

PTZ

pentylenetetrazole

DCM

dynamic causal modelling

CSD

cross spectral densities

PEB

Parametric Empirical Bayes
A combined analysis of genetically correlated traits identifies 107 loci associated with intelligence
Authors: Hill W. D. , Davies G. , McIntosh A. M. , Gale C. R. , Deary I. J.
Published: July 2017

Intelligence, or general cognitive function, is phenotypically and genetically correlated with many traits, including many physical and mental health variables. Both education and household income are strongly genetically correlated with intelligence, at rg=0.73 and rg=0.70 respectively. This allowed us to utilize a novel approach, Multi-Trait Analysis of Genome-wide association studies (MTAG; Turley et al. 2017), to combine two large genome-wide association studies (GWASs) of education and household income to increase power in the largest GWAS on intelligence so far (Sniekers et al. 2017). This study had four goals: firstly, to facilitate the discovery of new genetic loci associated with intelligence; secondly, to add to our understanding of the biology of intelligence differences; thirdly, to examine whether combining genetically correlated traits in this way produces results consistent with the primary phenotype of intelligence; and, finally, to test how well this new meta-analytic data sample on intelligence predict phenotypic intelligence variance in an independent sample. We apply MTAG to three large GWAS: Sniekers et al (2017) on intelligence, Okbay et al. (2016) on Educational attainment, and Hill et al. (2016) on household income. By combining these three samples our functional sample size increased from 78 308 participants to 147 194. We found 107 independent loci associated with intelligence, implicating 233 genes, using both SNP-based and gene-based GWAS. We find evidence that neurogenesis may explain some of the biological differences in intelligence as well as genes expressed in the synapse and those involved in the regulation of the nervous system. We show that the results of our combined analysis demonstrate the same pattern of genetic correlations as a single measure/the simple measure of intelligence, providing support for the meta-analysis of these genetically-related phenotypes. We find that our MTAG meta-analysis of intelligence shows similar genetic correlations to 26 other phenotypes when compared with a GWAS consisting solely of cognitive tests. Finally, using an independent sample of 6 844 individuals we were able to predict 7% of intelligence using SNP data alone.
Orb-web spider color polymorphism through the eyes of multiple prey and predators
Authors: Ximenes Nathalia , Gawryszewski Felipe M.
Published: July 2017

The sensory drive theory predicts that signals, sensory systems, and signaling behavior should coevolve. Variation in the sensory systems of prey and predators may explain the diversity of color signals, such as color polymorphism. The spiderGasteracantha cancriformis(Araneidae) possesses several conspicuous color morphs. The aim of the present study was to assess whether the color polymorphism ofG. cancriformismay be maintained by pressure from multiple signal receivers, such as prey and predators with distinct color vision systems. Although, the multiple receivers world is a more realistic scenario, it has received little attention. In orb-web spiders, the prey attraction hypothesis states that conspicuous colors are prey lures that increase spider foraging success via flower mimicry. However, in highly defended species, conspicuous colors could also be a warning signal to predators. We used color vision modelling to estimate chromatic and achromatic contrast ofG. cancriformismorphs as perceived by potential prey and predator taxa. Our results revealed that individual prey and predator taxa perceive the conspicuousness of morphs differently. For instance, the red morph is perceived as quite conspicuous to lepidopteran prey and avian predators, but not by other insects. Therefore, the multiple prey and predator hypotheses may explain the evolution of color polymorphism inG. cancriformis. However, flower mimicry hypothesis was weakly corroborated. Other parameters that are not evaluated by color vision models, such as distance, shape, angle, and pattern geometry could also affect the perception of color morphs by both prey and predators and thereby influence morph survival.
Cortical area and subcortical volume mediate the effect of parental education and adverse experiences on cognitive performance in youth
Authors: Mehta Chintan M. , Malins Jeffrey G. , Noble Kimberly G. , Gruen Jeffrey R.
Published: July 2017

Early adversity and socioeconomic disadvantage are risk factors associated with diminished cognitive outcomes during development. Recent studies also provide evidence that upbringings characterized by stressful experiences and markers of disadvantage during childhood, such as lower parental education or household income, are associated with variation in brain structure. Although disadvantage often confers adversity, these are distinct risk factors whose differential influences on neurodevelopment and neurocognitive outcomes are not well characterized. We examined pathways linking parental education, adverse experiences, brain structure, and cognitive performances through an analysis of 1,413 typically-developing youth, ages 8 through 21, in the Philadelphia Neurodevelopmental Cohort. Parental education and adverse experiences had unique associations with cortical surface area and subcortical volume as well as cognitive performance across several domains. Associations between parental education and several cognitive tasks were explained, in part, by variation in cortical surface area. In contrast, associations between adversity and cognitive tasks were explained primarily by variation in subcortical volume. A composite neurodevelopmental factor derived from principal component analysis of cortical thickness, cortical surface area, and subcortical volume mediated independent associations between both parental education and adverse experiences with reading, geometric reasoning, verbal reasoning, attention, and emotional differentiation tasks. Our analysis provides novel evidence that socioeconomic disadvantage and adversity influence neurodevelopmental pathways associated with cognitive outcomes through independent mechanisms.
An aggrecan fragment drives osteoarthritis pain through Toll-like receptor 2
Authors: Miller Rachel E. , Miller Richard J. , Ishihara Shingo , Tran Phuong B. , Golub Suzanne B. , Last Karena , Fosang Amanda J. , Malfait Anne-Marie
Published: July 2017

Pain is the predominant symptom of osteoarthritis, but the connection between joint damage and the genesis of pain is not well understood. Loss of articular cartilage is a hallmark of osteoarthritis, and it occurs through enzymatic degradation of aggrecan by ADAMTS-4/5-mediated cleavage in the interglobular domain (E373-374A). Further cleavage by MMPs (N341-342F) releases a 32-amino-acid aggrecan fragment (32-mer). We investigated the role of this 32-mer in driving joint pain. We demonstrated that the 32-mer excites dorsal root ganglion (DRG) nociceptive neurons, both in culture and in intact explants. Treatment of cultured sensory neurons with the 32-mer induced them to express the pro-algesic chemokine, MCP-1/CCL2. These effects were mediated through Toll-like receptor (TLR)2, which we demonstrated was expressed by nociceptive neurons. In addition, intra-articular injection of the 32-mer provoked knee hyperalgesia in wild-type but notTlr2null mice. Blocking the production or action of the 32-mer in transgenic mice prevented the development of knee hyperalgesia in a murine model of osteoarthritis. These findings suggest that the aggrecan 32-mer fragment directly activates TLR2 on joint nociceptors and is an important mediator of the development of osteoarthritis-associated joint pain.
Flexible, Cluster-Based Analysis of the Electronic Medical Record of Sepsis with Composite Mixture Models
Authors: Mayhew Michael B. , Petersen Brenden K. , Sales Ana Paula , Greene John D. , Liu Vincent X. , Wasson Todd S.
Published: July 2017

The widespread adoption of electronic medical records (EMRs) in healthcare has provided vast new amounts of data for statistical machine learning researchers in their efforts to model and predict patient health status, potentially enabling novel advances in treatment. In the case of sepsis, a debilitating, dysregulated host response to infection, extracting subtle, uncataloged clinical phenotypes from the EMR with statistical machine learning methods has the potential to impact patient diagnosis and treatment early in the course of their hospitalization. However, there are significant barriers that must be overcome to extract these insights from EMR data. First, EMR datasets consist of both static and dynamic observations of discrete and continuous-valued variables, many of which may be missing, precluding the application of standard multivariate analysis techniques. Second, clinical populations observed via EMRs and relevant to the study and management of conditions like sepsis are often heterogeneous; properly accounting for this heterogeneity is critical. Here, we describe an unsupervised, probabilistic framework called a composite mixture model that can simultaneously accommodate the wide variety of observations frequently observed in EMR datasets, characterize heterogeneous clinical populations, and handle missing observations. We demonstrate the efficacy of our approach on a large-scale sepsis cohort, developing novel techniques built on our model-based clusters to track patient mortality risk over time and identify physiological trends and distinct subgroups of the dataset associated with elevated risk of mortality during hospitalization.

Abbreviations

EMR

electronic medical record

CMM

composite mixture model

KPNC

Kaiser Permanente Northern California

BIC

Bayesian information criterion

AIC

Akaike information criterion

PAM

partitioning around medoids

MICE

multivariate imputation using chained equations
Intraspecific variation in indirect plant-soil feedbacks as a driver of a wetland plant invasion
Authors: Allen Warwick J. , Meyerson Laura A. , Flick Andrew J. , Cronin James T.
Published: July 2017

Plant-soil feedbacks (PSFs) can influence plant competition via direct interactions with pathogens and mutualists or indirectly via apparent competition/mutualisms (i.e., spillover to cooccurring plants) and soil legacy effects. Presently, it is unknown how intraspecific variation in PSFs interacts with the environment (e.g., nutrient availability) to influence competition between native and invasive plants. We conducted a fully crossed multi-factor greenhouse experiment to determine the effects of soil biota, interspecific competition, and nutrient availability on biomass of replicate populations from one native and two invasive lineages of common reed (Phragmites australis) and a single lineage of native smooth cordgrass (Spartina alterniflora). Harmful soil biota consistently dominated PSFs involving all threeP. australislineages, reducing biomass by 10%, regardless of nutrient availability orS. alterniflorapresence as a competitor. Spillover of soil biota derived from the rhizosphere of the two invasiveP. australislineages reducedS. alterniflorabiomass by 7%, whereas soil biota from the nativeP. australislineage increasedS. alterniflorabiomass by 6%. Interestingly, regardless of lineage,P. australissoil biota negatively affectedS. alterniflorabiomass when grown alone (i.e., a soil legacy), but had a positive impact when grown withP. australis, suggesting thatP. australisis preferred by harmful generalist soil biota or facilitatesS. alternifloravia spillover (i.e., apparent mutualism). Soil biota also reduced the negative impacts of interspecific competition onS. alternifloraby 13%, although it remained competitively inferior toP. australisacross all treatments. Moreover, competitive interactions and the response to nutrients did not differ amongP. australislineages, indicating that interspecific competition and nutrient deposition may not be key drivers ofP. australisinvasion in North America. Taken together, although soil biota, interspecific competition, and nutrient availability appear to have no direct impact on the success of invasiveP. australislineages in North America, indirect spillover and soil legacies fromP. australisoccur and may have important implications for co-occurring native species and restoration of invaded habitats. Our study integrates multiple factors linked to plant invasions, highlighting that indirect interactions are likely commonplace in driving successful invasions and their impacts on the local community.
A broad role for YBX1 in defining the small non-coding RNA composition of exosomes
Authors: Shurtleff Matthew J. , Yao Jun , Qin Yidan , Nottingham Ryan M. , Temoche-Diaz Morayma , Schekman Randy , Lambowitz Alan M.
Published: July 2017

RNA is secreted from cells enclosed within extracellular vesicles (EVs). Defining the RNA composition of EVs is challenging due to their co-isolation with contaminants, a lack of knowledge of the mechanisms of RNA sorting into EVs and limitations of conventional RNA-seq methods. Here we present our observations using thermostable group II intron reverse transcriptase sequencing (TGIRT-seq) to characterize the RNA extracted from HEK293T cell EVs isolated by flotation gradient ultracentrifugation and from exosomes containing the tetraspannin CD63 further purified from the gradient fractions by immunoisolation. We found that EV-associated transcripts are dominated by full-length, mature tRNAs and other small non-coding RNAs encapsulated within vesicles. A substantial proportion of the reads mapping to protein-coding genes, long non-coding, and antisense RNAs were due to DNA contamination on the surface of vesicles. Nevertheless, sequences mapping to spliced mRNAs were identified within HEK293T cell EVs and exosomes, among the most abundant being transcripts containing a 5’ terminal oligopyrimidine (5’ TOP) motif. Our results indicate that the RNA-binding protein YBX1, which we showed previously is required for the sorting of selected miRNAs into exosomes, plays a role in the sorting of highly abundant small non-coding RNA species, including tRNAs, Y RNAs, and Vault RNAs. Finally, we obtained evidence for an EV-specific tRNA modification, perhaps indicating a role for post-transcriptional modification in the sorting of some RNA species into EVs. The identification of full-length small non-coding RNAs within EVs suggests a role for EVs in the export and possible intercellular functional transfer of abundant cellular transcripts.

Statement of Significance

Cells release vesicles containing selectively packaged cargo, including RNA, into the extracellular environment. Prior studies have identified RNA inside extracellular vesicles (EVs) but, due to limitations of conventional sequencing methods, highly structured and post-transcriptionally modified RNA species were not effectively captured. Using an alternative sequencing approach (TGIRT-seq), we found that EVs contain abundant small non-coding RNA species, including full-length tRNAs and Y RNAs. Using a knockout cell line, we obtained evidence that the RNA-binding protein YBX1 plays a role in sorting small non-coding RNAs into a subpopulation of extracellular vesicles termed exosomes. These experiments expand our understanding of EV-RNA composition and provide insights into how RNA is sorted into EVs for export from the cell.
Measuring the gut microbiome in birds: comparison of faecal and cloacal sampling
Authors: Videvall Elin , Strandh Maria , Engelbrecht Anel , Cloete Schalk , Cornwallis Charlie K.
Published: July 2017

The gut microbiomes of birds and other animals are increasingly being studied in ecological and evolutionary contexts. While methods for preserving samples and processing high-throughput sequence data to characterise bacterial communities have received considerable attention, there has been little evaluation of non-invasive sampling methods. Numerous studies on birds and reptiles have made inferences about gut microbiota using cloacal sampling, however, it is not known whether the bacterial community of the cloaca provides an accurate representation of the avian gut microbiome. We examined the accuracy with which cloacal swabs and faecal samples measure the microbiota in three different parts of the gastrointestinal tract (ileum, caecum, and colon) using a case study on juvenile ostriches,Struthio camelus, and high-throughput 16S rRNA sequencing. We found that faeces were significantly better than cloacal swabs in representing the bacterial community of the colon. Cloacal samples had a higher abundance of Gammaproteobacteria and fewer Clostridia relative to the gut and faecal samples. However, both faecal and cloacal samples were poor representatives of the microbial communities in the caecum and ileum. Furthermore, the accuracy of the sampling methods in measuring the abundance of different bacterial taxa was highly variable: Bacteroidetes was the most highly correlated phylum between all three gut sections and both methods, whereas colonic Actinobacteria correlated strongly only with faecal samples. This study demonstrates that sampling methods can have significant effects on the inferred gut microbiome in studies of birds. Based on our results, we recommend sampling faeces, whenever possible, as this provides the most accurate assessment of the colon microbiome. The fact that neither sampling technique portrayed the bacterial community of the ileum or the caecum illustrates the difficulty in non-invasively monitoring gut bacteria located further up in the gastrointestinal tract. These results have important implications for the interpretation of avian gut microbiome studies.
Association of Vancomycin with Lipid Vesicles
Authors: Hu Xiaohui , Tam Kin Yip
Published: July 2017

Antibiotics plays a pivotal role in modern medicine for the treatment of bacterial infection in patients. Membrane defines the boundary between single cell and its environment and is a main target for antibacterial agents. To better understand the mechanism of antibiotics action on microbes, we utilized liposome as membrane mimic model to study antibiotics interaction with bacterial membrane by variety of biophysical methods. Isothermal calorimetry and fluorescence photometry experiments were performed to examine interaction between antibiotics and liposome. We found that vancomycin, one of the most important antibiotics for the treatment of serious infections by gram-positive bacteria, binds to the liposome. The association between the drug and the liposome does not involve the tail part of the lipids. Moreover, the binding affinity increases along with the increment of liposome size. Of three major lipid components, phosphatidylglycerol is the preferential target for vancomycin binding. We also showed that vancomycin associates with vesicle derived fromStaphylococcus aureusmembrane in a similar manner as the binding to liposome. Our data suggested that vancomycin associates with bacterial membrane through direct interaction with lipid head groups with the extent of the association depending very much on specific type of lipids and curvature of local membrane structure.
Axe: rapid, competitive sequence read demultiplexing using a trie
Authors: Murray Kevin D. , Borevitz Justin O.
Published: July 2017

Here we implement a rapid algorithm for demultiplexing DNA sequence reads with in-read indices. Axe selects the optimal index present in a sequence read, even in the presence of sequencing errors. The algorithm is able to handle combinatorial indexing, indices of differing length, and several mismatches per index sequence.
A Novel, Fast and Efficient Single-Sensor Automatic Sleep-Stage Classification Based on Complementary Cross-Frequency Coupling Estimates
Authors: Dimitriadis Stavros I. , Salis Christos , Linden David
Published: July 2017

Objective

Limitations of the manual scoring of polysomnograms, which include data from electroencephalogram (EEG), electrooculogram (EOG), electrocardiogram (ECG) and electromyogram (EMG) channels, have long been recognised. Manual staging is resource-intensive and time-consuming and considerable efforts have to be spent to ensure inter-rater reliability. There is thus great interest in techniques based on signal processing and machine learning for a completely Automatic Sleep Stage Classification (ASSC).

Methods

In this paper, we present a single EEG-sensor ASSC technique based on dynamic reconfiguration of different aspects of cross-frequency coupling (CFC) estimated between predefined frequency pairs over 5s epoch lengths. The proposed analytic scheme is demonstrated using the PhysioNet Sleep European Data Format (EDF) Database using 20 healthy young adults with repeat recordings.

Results

We achieved very high classification sensitivity, specificity and accuracy of96.2 ± 2.2%, 94.2 ± 2.3%, and94.4 ± 2.2% across 20 folds, respectively and high mean F1-score (92%, range 90–94%) when multi-class Bayes Naive classifier was applied.

Conclusions

Our method outperformed the accuracy of previous studies on different datasets but also on the same database.

Significance

Single-sensor ASSC makes the whole methodology appropriate for longitudinal monitoring using wearable EEG in real world and lab-oriented environments.
Bayesian inference and simulation approaches improve the assessment of Elo-scores in the analysis of social behaviour
Authors: Goffe Adeelia S. , Fischer Julia , Sennhenn-Reulen Holger
Published: July 2017

The construction of rank hierarchies based on agonistic interactions between two individuals (“dyads”) is an important component in the characterization of the social structure of groups. To this end, winner-loser matrices are typically created, which collapse the outcome of dyadic interactions over time, resulting in the loss of all information contained in the temporal domain. Methods that track changes in the outcome of dyadic interactions (such as “Elo-scores”) are receiving increasing interest. Critically, individual scores are not just based on the succession of wins and losses, but depend on the values of starting scores and an update (“tax”) coefficient. Recent studies improved existing methods by introducing a point estimation of these auxiliary parameters on the basis of a maximum likelihood (ML) approach. For a sound assessment of the rank hierarchies generated this way, we argue that measures of uncertainty of the estimates, as well as a quantification of the robustness of the methods, are also needed.

We introduce a Bayesian inference (BI) approach using ‘‘partial pooling”, which rests on the assumption that all starting scores are samples from the same distribution. We compare the outcome of the ML approach to that of the BI approach using real-world data. In addition, we simulate different scenarios to explore in which way the Elo-score responds to social events (such as rank changes), and low numbers of observations.

Estimates of the starting scores based on ‘partial pooling” are more robust than those based on ML, also in scenarios where some individuals have only few observations. Our simulations show that assumed rank differences may fall well within the ‘uncertain” range, and that low sampling density, unbalanced designs, and coalitionary leaps involving several individuals within the hierarchy may yield unreliable results.

Our results support the view that Elo rating can be a powerful tool in the analysis of social behaviour, when the data meet certain criteria. Assessing the uncertainty greatly aids in the interpretation of results. We advocate running simulation approaches to test how well Elo scores reflect the (simulated) true structure and how sensitive the score is to true changes in the hierarchy.
Learning of Active Binocular Vision in a Biomechanical Model of the Oculomotor System
Authors: Klimmasch Lukas , Lelais Alexander , Lichtenstein Alexander , Shi Bertram E. , Triesch Jochen
Published: July 2017

We present a model for the autonomous learning of active binocular vision using a recently developed biome-chanical model of the human oculomotor system. The model is formulated in the Active Efficient Coding (AEC) framework, a recent generalization of classic efficient coding theories to active perception. The model simultaneously learns how to efficiently encode binocular images and how to generate accurate vergence eye movements that facilitate efficient encoding of the visual input. In order to resolve the redundancy problem arising from the actuation of the eyes through antagonistic muscle pairs, we consider the metabolic costs associated with eye movements. We show that the model successfully learns to trade off vergence accuracy against the associated metabolic costs, producing high fidelity vergence eye movements obeying Sherrington’s law of reciprocal innervation.
Pavement cells and the topology puzzle
Authors: Carter Ross , Sánchez-Corrales Yara E. , Grieneisen Verônica A. , Marée Athanasius F. M.
Published: July 2017

D’Arcy Thompson emphasised the importance of surface tension as a potential driving force in establishing cell shape and topology within tissues. Leaf epidermal pavement cells grow into jigsaw-piece shapes, highly deviating from such classical forms. We investigate the topology of developingArabidopsisleaves composed solely of pavement cells. Image analysis of around 50,000 cells reveals a clear and unique topological signature, deviating from previously studied epidermal tissues. This topological distribution is however established early during leaf development, already before the typical pavement cell shapes emerge, with topological homestasis maintained throughout growth and unaltered between division and maturation zones. Simulating graph models, we identify a heuristic cellular division rule that reproduces the observed topology. Our parsimonious model predicts how and when cells effectively place their division plane with respect to their neighbours. We verify the predicted dynamics through in vivo tracking of 800 mitotic events, and conclude that the distinct topology is not a direct consequence of the jigsaw-like shape of the cells, but rather owes itself to a strongly life-history-driven process, with limited impact from cell surface mechanics.

Summary statement

Development of theArabidopsisleaf epidermis topology is driven by deceptively simple rules of cell division, independent of surface tension, cell size and, often complex, cell shape.
Combining multiple functional annotation tools increases coverage of metabolic annotation
Authors: Griesemer Marc , Kimbrel Jeffrey , Zhou Carol , Navid Ali , D’haeseleer Patrik
Published: July 2017

Genome-scale metabolic modeling is a cornerstone of systems biology analysis of microbial organisms and communities, yet these genome-scale modeling efforts are invariably based on incomplete functional annotations. Annotated genomes typically contain 30-50% of genes without functional annotation, severely limiting our knowledge of the “parts lists” that the organisms have at their disposal. These incomplete annotations may be sufficient to derive a model of a core set of well-studied metabolic pathways that support growth in pure culture. However, pathways important for growth on unusual metabolites exchanged in complex microbial communities are often less understood, resulting in missing functional annotations in newly sequenced genomes. Here, we present results on a comprehensive reannotation of 27 bacterial reference genomes, focusing on enzymes with EC numbers annotated by KEGG, RAST, EFICAz, and the BRENDA enzyme database, and on membrane transport annotations by TransportDB, KEGG and RAST. Our analysis shows that annotation using multiple tools can result in a drastically larger metabolic network reconstruction, adding on average 40% more EC numbers, 3-8 times more substrate-specific transporters, and 37% more metabolic genes. These results are even more pronounced for bacterial species that are more phylogenetically distant from well-studied model organisms such as E. coli.
Adipose‐derived mesenchymal stem cells therapy for acute kidney injury induced by ischemia‐reperfusion in a rat model
Authors: Zhang Jian‐Bo , Wang Xiao‐Qiao , Lu Guo‐Lin , Huang Huan‐Sen , Xu Shi‐Yuan
Published: July 2017

Acute kidney injury (AKI) represents a group of complicated syndromes with a high mortality rate. The administration of adipose‐derived mesenchymal stem cells (ADMSCs) has been tested as a possible treatment method for AKI. The long‐term evaluation of AKI induced by ischemia/reperfusion (IR) and the probable renal protection of ADMSCs are limited. In this study we have established a rat AKI model induced by IR and investigated the possible protective effects of ADMSCs. Adult Sprague‐Dawley (SD) rats were divided into three groups (n = 6/each group). The MOCK group was as the normal control. Rats in the IR‐AKI and IR‐AKI+ADMSCs groups were subjected to IR injury by clamping both renal pedicles for 40 minutes. Rats in the MOCK and IR‐AKI groups were injected with PBS via the tail vein as negative treatment controls. Rats in the IR‐AKI+ADMSCs group received ADMSCs therapy (2 × 106 cells were injected into the rats via the tail vein). We found that ADMSC transplantation restored the pathologic morphology induced by IR‐AKI to normal compared with the MOCK group, suggesting the reparative function of ADMSCs in kidney tissues. Compared with IR‐induced AKI alone, ADMSC treatment significantly decreased the number of apoptotic cells, the level of total urinary protein and serum creatinine, the expression of pro‐inflammatory cytokines (IL‐6, TNF‐α, IL‐1β, IFN‐γ, TNF‐α, IFN‐γ, and TGF‐β), and the inflammation‐associated proteins (HGF and SDF1), but increased the expression of the anti‐inflammatory cytokine, IL‐10, and the anti‐apoptotic regulator, Bcl‐2. Our data have indicated that ADMSC transplantation may protect against IR‐induced AKI by anti‐apoptotic and anti‐inflammatory effects.
AQP4‐knockout aggravation of isoprenaline‐induced myocardial injury is mediated by p66Shc and endoplasmic reticulum stress
Authors: Cheng Yusi , Chao Jie , Dai Dezai , Dai Yin , Zhu Dongdong , Liu Bicheng
Published: July 2017

Aquaporin 4 (AQP4) is a type of water channel protein that maintains the water balance of cardiomyocytes. However, the physiological role of AQP4 in cardiovascular disease is poorly understood. We wanted to explore whether p66Shc and endoplasmic reticulum stress participates in AQP4 knockout (KO)‐mediated cardiac injury. There were two types of mice: AQP4 knockout and wild‐type mice. Each type was randomly divided into three groups: Control group, isoprenaline stimulation group (ISO, 1 mg/kg, s.c., 5 days), and apocynin treatment group (APO, 100 mg/kg, p.o., 3 days). H9c2 rat cardiomyocytes were cultured for RNA interference of AQP4. Results showed increased left ventricular weight index and more severe myocardial inflammation were induced in AQP4 knockout mice relative to wild‐type mice, accompanied by significantly increased levels of the oxidative stress biomarkers MDA and NOX4. In addition, the expressions of p66Shc, ER stress markers PERK, GRP78 and CHOP and proinflammatory factors such as ETA, IL6 and TNFα were upregulated in the myocardium of AQP4 knockout mice or AQP4 siRNA treated cardiomyocytes, whereas CASQ2 was downregulated. ISO stimulation aggravated these abnormalities, which were significantly attenuated by apocynin. This study showed that AQP4 knockout mice were susceptible to cardiac injury induced by ISO. The mechanism was closely connected with p66Shc and proinflammatory factors. Endoplasmic reticulum stress was also involved in the pathological process.
‘Hidden identities’: perceptions of sexual identity in Beijing
Authors: Miles‐Johnson Toby , Wang Yurong
Published: July 2017

This article draws upon responses given by volunteers who work in the Beijing LGBT Centre regarding perceptions of sexual identity, and how Chinese culture affects hidden or open sexual identities of Chinese lesbian and gay people in this region. The insights gained from those working carefully to create social change offers an important and original contribution to the field of gay and lesbian studies in China. The findings indicate the volunteers at the Beijing LGBT Centre are frustrated by the lack of acceptance of non‐heterosexual relationships among Chinese culture and society, and by the disregard of lesbian gay and bisexual (LGB) people by the Chinese government. The findings also illustrate stigmatization of homosexuality in China is enacted in structural terms (such as in the lack of policy, legislation and positive endorsement by governmental and socio‐political organizations), public expression (such as negative attitudes, beliefs or reactions towards LGB people) and internalized repression (through fear of stigmatization, and subsequent abuse due to negative societal attitudes and discrimination). Influenced by the Chinese tradition of conforming to group values, the findings from this study show that volunteers at the Beijing LGBT Centre believe LGB people in China are generally hesitant to disclose their sexual identities, and reject the idea that there had been a collective shift in Chinese culture regarding increased acceptance of LGB people. It also finds volunteers at the LGBT Centre in Beijing blame Chinese culture for its lack of acceptance of non‐heterosexual relationships, and state stigmatization of homosexuality in China is due to deep‐rooted cultural homophobia.
Does scatter‐hoarding of seeds benefit cache owners or pilferers?
Authors: GU Haifeng , ZHAO Qingjian , ZHANG Zhibin
Published: July 2017

The scatter‐hoarding behavior of granivorous rodents plays an important role in seed dispersal and seedling regeneration of trees, as well as the evolution of several well‐known mutualisms between trees and rodents in forest ecosystems. Because it is difficult to identify seed hoarders and pilferers under field conditions by traditional methods, the full costs incurred and benefits accrued by scatter‐hoarding have not been fully evaluated in most systems. By using infrared radiation camera tracking and seed tagging, we investigated the benefits and losses of scatter‐hoarded seeds (Camellia oleifera) for 3 sympatric rodent species (Apodemus draco, Niviventer confucianus and Leopoldamys edwardsi) in a subtropical forest of Southwest China during 2013 to 2015. We established the relationships between the rodents and the seeds at the individual level. For each rodent species, we calculated the cache recovery rate of cache owners, as well as conspecific and interspecific pilferage rates. We found that all 3 sympatric rodent species had a cache recovery advantage with rates that far exceeded average pilferage rates over a 30‐day tracking period. The smallest species (A. draco) showed the highest rate of scatter‐hoarding and the highest recovery advantage compared with the other 2 larger species (N. confucianus and L. edwardsi). Our results suggest that scatter‐hoarding benefits cache owners in food competition, supporting the pilferage avoidance hypothesis. Therefore, scatter‐hoarding behavior should be favored by natural selection, and plays a significant role in species coexistence of rodent community and in the formation of mutualism between seeds and rodents in forest ecosystems.
Insular mammalian fauna dynamics and paleogeography: A lesson from the Western Mediterranean islands
Authors: PALOMBO Maria Rita
Published: July 2017

Since the time of Darwin (1859) and Wallace (1869), islands have been regarded by scientists as a prime target for scrutinizing the forces that may influence evolution and diversification and important elements in biogeographic studies. This research aims to scrutinize whether and to what extent the composition and structure of past mammal insular faunas and their changes through time may provide sound clues for inferring the paleogeographical evolution of a region. As a case study, I critically analyzed the dynamics shown by the Plio–Pleistocene mammalian fauna of 3 Western Mediterranean insular districts, the Balearic Islands, Sardinia and Sicily, each characterized by its own peculiar paleobiogeographical evolutionary history. The revision of faunas and the critical analysis of the dispersal ability of the ancestors of island settlers have allowed hypothesizing on the time and mode of island colonization. The results obtained confirm that the early isolation of the Balearic Islands from the mainland led to the establishment of an endemic fauna since the pre‐Messinian Miocene (?Astaracian European Land Mammal Age, MN7/8), and that Sardinia has definitely been isolated since the Pliocene, although dispersal events led to some faunal turnovers during the Pleistocene. In addition, the results suggest for Sicily a complex, still imperfectly disentangled history of alternate phases of complete separation and sporadic, more or less difficult connections with southern Italy.
A physiologically based pharmacokinetic modelling approach to predict buprenorphine pharmacokinetics following intravenous and sublingual administration
Authors: Kalluri Hari V. , Zhang Hongfei , Caritis Steve N. , Venkataramanan Raman
Published: July 2017

Aims

Opioid dependence is associated with high morbidity and mortality. Buprenorphine (BUP) is approved by the Food and Drug Administration to treat opioid dependence. There is a lack of clear consensus on the appropriate dosing of BUP due to interpatient physiological differences in absorption/disposition, subjective response assessment and other patient comorbidities. The objective of the present study was to build and validate robust physiologically based pharmacokinetic (PBPK) models for intravenous (IV) and sublingual (SL) BUP as a first step to optimizing BUP pharmacotherapy.

Methods

BUP‐PBPK modelling and simulations were performed using SimCyp® by incorporating the physiochemical properties of BUP, establishing intersystem extrapolation factors‐based in vitro–in‐vivo extrapolation (IVIVE) methods to extrapolate in vitro enzyme activity data, and using tissue‐specific plasma partition coefficient estimations. Published data on IV and SL‐BUP in opioid‐dependent and non‐opioid‐dependent patients were used to build the models. Fourteen model‐naïve BUP‐PK datasets were used for inter‐ and intrastudy validations.

Results

The IV and SL‐BUP‐PBPK models developed were robust in predicting the multicompartment disposition of BUP over a dosing range of 0.3–32 mg. Predicted plasma concentration–time profiles in virtual patients were consistent with reported data across five single‐dose IV, five single‐dose SL and four multiple dose SL studies. All PK parameter predictions were within 75–137% of the corresponding observed data. The model developed predicted the brain exposure of BUP to be about four times higher than that of BUP in plasma.

Conclusion

The validated PBPK models will be used in future studies to predict BUP plasma and brain concentrations based on the varying demographic, physiological and pathological characteristics of patients.
Diminazene aceturate prevents nephropathy by increasing glomerular ACE2 and AT2 receptor expression in a rat model of type1 diabetes
Authors: Goru Santosh Kumar , Kadakol Almesh , Malek Vajir , Pandey Anuradha , Sharma Nisha , Gaikwad Anil Bhanudas
Published: July 2017

Background and Purpose

One of the protective actions of angiotensin converting enzyme‐2 (ACE2) is the inactivation of angiotensin II. Expression and activity of ACE2 was reduced in glomeruli of diabetic patients and in animal models of diabetes. Recently the potential role of recombinant ACE2 administration in preventing diabetic nephropathy (DN) has been shown. Here we have tested the effects of the ACE2 activator, diminazene aceturate (DIZE), in a model of DN.

Experimental Approach

Male Wistar rats were rendered diabetic using a single dose of streptozotocin (55 mg·kg−1, i.p.). After 4 weeks, diabetic animals were divided into experimental groups and treated with DIZE, at a low dose (5 mg·kg−1·day−1), a high dose (15 mg·kg−1·day−1) and the high dose with of the AT2 receptor antagonist PD123319 (10 mg·kg−1·day−1). At the end of the treatment , kidneys from all the groups were collected and processed separately for glomerular isolation, protein isolation, mRNA extraction and for immunohistochemical studies.

Key Results

Treatment with DIZE restored ACE2 expression in glomeruli and increased expression of AT2 receptors in whole kidney and isolated glomeruli of diabetic animals. DIZE administration reduced angiotensin II levels and increased angiotensin‐(1–7) levels in diabetic kidney. However, PD123319 treatment reversed all these actions of DIZE.

Conclusions and Implications

DIZE treatment reduced diabetes‐induced renal damage as shown by reduction of fibrosis and apoptosis. These protective actions of DIZE were blocked by the AT2 receptor antagonist. Taken together, these results suggest that DIZE protected against DN through the ACE2/angiotensin‐(1–7)/ AT2 receptor axis.
Inhibition of hyaluronan synthesis attenuates pulmonary hypertension associated with lung fibrosis
Authors: Collum Scott D , Chen Ning‐Yuan , Hernandez Adriana M , Hanmandlu Ankit , Sweeney Heather , Mertens Tinne C J , Weng Tingting , Luo Fayong , Molina Jose G , Davies Jonathan , Horan Ian P , Morrell Nick W , Amione‐Guerra Javier , Al‐Jabbari Odeaa , Youker Keith , Sun Wenchao , Rajadas Jayakumar , Bollyky Paul L , Akkanti Bindu H , Jyothula Soma , Sinha Neeraj , Guha Ashrith , Karmouty‐Quintana Harry
Published: July 2017

Background and Purpose

Group III pulmonary hypertension (PH) is a highly lethal and widespread lung disorder that is a common complication in idiopathic pulmonary fibrosis (IPF) where it is considered to be the single most significant predictor of mortality. While increased levels of hyaluronan have been observed in IPF patients, hyaluronan‐mediated vascular remodelling and the hyaluronan‐mediated mechanisms promoting PH associated with IPF are not fully understood.

Experimental Approach

Explanted lung tissue from patients with IPF with and without a diagnosis of PH was used to identify increased levels of hyaluronan. In addition, an experimental model of lung fibrosis and PH was used to test the capacity of 4‐methylumbeliferone (4MU), a hyaluronan synthase inhibitor to attenuate PH. Human pulmonary artery smooth muscle cells (PASMC) were used to identify the hyaluronan‐specific mechanisms that lead to the development of PH associated with lung fibrosis.

Key Results

In patients with IPF and PH, increased levels of hyaluronan and expression of hyaluronan synthase genes are present. Interestingly, we also report increased levels of hyaluronidases in patients with IPF and IPF with PH. Remarkably, our data also show that 4MU is able to inhibit PH in our model either prophylactically or therapeutically, without affecting fibrosis. Studies to determine the hyaluronan‐specific mechanisms revealed that hyaluronan fragments result in increased PASMC stiffness and proliferation but reduced cell motility in a RhoA‐dependent manner.

Conclusions and Implications

Taken together, our results show evidence of a unique mechanism contributing to PH in the context of lung fibrosis.