bluuebunny/crossref_metadata_2025 huggingface dataset:
Inhibition of histone deacetylase 6 attenuates intestinal inflammation and apoptosis in a rodent model of hemorrhagic shock
Authors: Chang Panpan , Bhatti Umar F. , Williams Aaron M. , Dennahy Isabel S. , Liu Baoling , Li Yongqing , Alam Hasan B.
Published: December 2018

BACKGROUND

Intestinal inflammation is a mediator of multiorgan failure in trauma. We have previously shown that histone deacetylase (HDAC6) inhibitors, including ACY1083, improve survival and preserve intestinal tight junction integrity in a rodent model of hemorrhagic shock (HS). However, mechanisms leading to this alleviation in intestinal injury remain poorly defined. In this study, we sought to determine whether HDAC6 inhibition by ACY1083 can attenuate intestinal inflammation and apoptosis in rats subjected to HS.

METHODS

Sprague Dawley rats were subjected to hemorrhage (40% of total blood volume) followed by intravenous injection of either ACY1083 (30 mg/kg) dissolved in cyclodextrin or cyclodextrin only (vehicle group). Three hours after hemorrhage, blood samples were collected, and small bowel was harvested. Histological effects of ACY1083 on small bowel were examined. Myeloperoxidase (MPO) levels were assessed as a marker for neutrophil infiltration. Whole cell lysates were analyzed for acetylated α-tubulin, metalloproteinase (ADAM) 17, TNF-α, IL-6, and cleaved caspase 3 using Western blot. The levels of ADAM17, TNF-α, and IL-6 in serum were also examined using enzyme-linked immunosorbent assay.

RESULTS

ACY1083 treatment significantly attenuated HS-induced intestinal injury and MPO production. Both systemic and intestinal TNF-α and IL-6 levels were attenuated following ACY1083 administration. Increased acetylation of α-tubulin was observed in rats treated with ACY1083, along with a significantly decreased expression of cleaved caspase 3 following hemorrhage.

CONCLUSION

Inhibition of HDAC6 with ACY1083 provides intestinal protection by attenuating both the inflammatory and apoptotic responses during HS.
Identifying A- and P-site locations on ribosome-protected mRNA fragments using Integer Programming
Authors: Ahmed Nabeel , Sormanni Pietro , Ciryam Prajwal , Vendruscolo Michele , Dobson Christopher M. , O’Brien Edward P.
Published: December 2018

Identifying the A- and P-site locations on ribosome-protected mRNA fragments from Ribo-Seq experiments is a fundamental step in the quantitative analysis of transcriptome-wide translation properties at the codon level. Many analyses of Ribo-Seq data have utilized heuristic approaches applied to a narrow range of fragment sizes to identify the A-site. In this study, we use Integer Programming to identify A-site by maximizing an objective function that reflects the fact that the ribosome’s A-site on ribosome-protected fragments must reside between the second and stop codons of an mRNA. This identifies the A-site location as a function of the fragment’s size and its 5□ end reading frame in Ribo-Seq data generated from S. cerevisiae and mouse embryonic stem cells. The correctness of the identified A-site locations is demonstrated by showing that this method, as compared to others, yields the largest ribosome density at established stalling sites. By providing greater accuracy and utilization of a wider range of fragment sizes, our approach increases the signal-to-noise ratio of underlying biological signals associated with translation elongation at the codon length scale.
Computational Discovery of Evolutionary Conserved Enterovirus 71 RNA Secondary Structures
Authors: Fridlyand Nathan , Lukashev Alexander N , Chursov Andrey , Venanzi Franco M , Yewdell Jonathan W , Sufianov Albert A , Shneider Alexander
Published: December 2018

Viral RNAs store information in their sequence and structure. Little, however is known about the contribution of RNA structure to viral replication and evolution. We previously described RNA ISRAEU to computationally identify structured regions in viral RNA based on evolutionary conservation of predicted structures. Here, we apply RNA GUESS (Generator of Uniformly Evolved Secondary Structures) to better understand enterovirus 71, a highly pathogenic human picornavirus. RNA GUESS identified previously known evolutionarily conserved picornavirus RNA structures, and uniquely predicted RNA structures with significant structural conservation despite the lack of an obvious sequence conservation. One structure consists of a stretch of obligatorily unpaired nucleotides that can potentially interact with RNA-binding proteins and siRNAs. Another, forms a potential RNA switch that can form two alternative structures while the third and fourth constitute hairpin-like structures. These findings provide a launching point for physical and genetic studies regarding the function and structures of these RNA elements.
Differential adaptation to visual motion allows robust encoding of optic flow in the dragonfly
Authors: Evans Bernard J E , O'Carroll David C , Fabian Joseph M , Wiederman Steven D
Published: December 2018

An important task for any aerial creature is the ability to ascertain their own movement (ego-motion) through their environment. Neurons thought to underlie this behaviour have been well-characterised in many insect models including flies, moths and bees. However, dragonfly wide-field motion pathways remain undescribed. Some species of Dragonflies, such as Hemicordulia tau, engage in hawking behaviour, hovering in a single area for extended periods of time whilst also engaging in fast-moving patrols and highly dynamic pursuits of prey and conspecifics. These varied flight behaviours place very different constraints on establishing ego-motion from optic flow cues hinting at a sophisticated wide-field motion analysis system capable of detecting both fast and slow motion. We characterised wide-field motion sensitive neurons via intracellular recordings in Hemicordulia dragonflies finding similar properties to those found in other species. We found that the spatial and temporal tuning properties of these neurons were broadly similar but differed significantly in their adaptation to sustained motion. We categorised a total of three different subclasses, finding differences between subclasses in their motion adaptation and response to the broadband statistics of natural images. The differences found correspond well with the dynamics of the varied behavioural tasks hawking dragonflies perform. These findings may underpin the exquisite flight behaviours found in dragonflies. They also hint at the need for the great complexity seen in dragonfly early visual processing.
Clinical implications of identifying pathogenic variants in aortic dissection patients with whole exome sequencing
Authors: Wolford Brooke N. , Hornsby Whitney E.
Published: December 2018

Background

Thoracic aortic dissection is an emergent life-threatening condition. Routine screening for genetic variants causing thoracic aortic dissection is not currently performed for patients or their family members.

Methods

We performed whole exome sequencing of 240 patients with thoracic aortic dissection (n=235) or rupture (n=5) and 258 controls matched for age, sex, and ancestry. Blinded to case-control status, we annotated variants in 11 genes for pathogenicity.

Results

Twenty-four pathogenic variants in 6 genes (COL3A1, FBN1, LOX, PRKG1, SMAD3, TGFBR2) were identified in 26 individuals, representing 10.8% of aortic cases and 0% of controls. Among dissection cases, we compared those with pathogenic variants to those without and found that pathogenic variant carriers had significantly earlier onset of dissection (41 vs. 57 years), higher rates of root aneurysm (54% vs. 30%), less hypertension (15% vs. 57%), lower rates of smoking (19% vs. 45%), and greater incidence of aortic disease in family members. Multivariable logistic regression showed significant risk factors associated with pathogenic variants are age <50 [odds ratio (OR) = 5.5; 95% CI: 1.6-19.7], no history of hypertension (OR=5.6; 95% CI: 1.4-22.3) and family history of aortic disease (mother: OR=5.7; 95% CI: 1.4-22.3, siblings: OR=5.1; 95% CI 1.1-23.9, children: OR=6.0; 95% CI: 1.4-26.7).

Conclusions

Clinical genetic testing of known hereditary thoracic aortic dissection genes should be considered in patients with aortic dissection, followed by cascade screening of family members, especially in patients with age-of-onset of aortic dissection <50 years old, family history of aortic disease, and no history of hypertension.
Enhanced nitrous oxide production in denitrifying Dechloromonas aromatica strain RCB under salt and alkaline conditions
Authors: Han Heejoo , Song Bongkeun , Song Min Joon , Yoon Sukhwan
Published: December 2018

Salinity and pH are important environmental parameters with direct and indirect impacts on the viability and metabolic activities of microorganisms. In this study, the effects of salt and alkaline stresses on the kinetic balance between nitrous oxide (N2O) production and consumption in the denitrification pathway of Dechloromonas aromatica strain RCB were examined. N2O accumulated transiently only in insignificant amounts at low salinity (≤0.5% NaCl) and circumneutral pH (7.0 and 7.5). Incubation at 0.7% salinity resulted in substantially longer lag phase and slower growth rate, along with the increase in the amounts of transiently accumulated N2O (15.8±2.8 μmoles N2O-N/vessel). Incubation at pH 8.0 severely inhibited growth and resulted in permanent accumulation of 29.9±1.3 μmoles N2O-N/vessel from reduction of 151±20 μmoles NO3-. The transcription analyses observed decreased nosZ/(nirS1+nirS2) ratios coinciding with N2O accumulation. The N2O consumption rates of resting D. aromatica cells subjected to the salt and alkaline stress conditions were significantly lower than the rates of N2O production from NO2- reduction at N2O / NO2- concentration of 0.1 mM, but not at a higher concentration (1.0 mM). These results indicate that alteration in N2O consumption kinetics was another cause of enhanced N2O production observed under the stress conditions. The findings in this study suggest that canonical denitrifiers may become a significant N2O source when faced with abrupt environmental changes.
Acute effects of systemic inflammation upon neurovascular unit and cerebrovascular function.
Authors: Brezzo Gaia , Simpson Julie , Ameen-Ali Kamar E , Berwick Jason , Martin Chris
Published: December 2018

Background: Brain health relies on a tightly regulated system known as neurovascular function whereby the cellular constituents of the neurovascular unit (NVU) regulate cerebral haemodynamics in accordance with neuronal metabolic demand. Disruption of neurovascular function impairs brain health and is associated with the development of disease, including Alzheimer's disease (AD). The NVU is the site of action of neuroinflammatory responses and contributes to the transition of systemic inflammation to neuroinflammatory processes. Thus, systemic inflammatory challenges may cause a shift in the NVU focus, prioritising neuroimmune over neurovascular actions leading to altered neurovascular function.
Methods: Rats were injected with lipopolysaccharide (LPS) (2mg/kg) or vehicle and haemodynamic responses to sensory and non-sensory (hypercapnia) stimuli were assessed in vivo. Following imaging, animals were perfused and their brain extracted to histologically characterise components of the NVU to determine the association between underlying pathology to altered blood flow regulation in vivo.
Results: LPS-treated animals showed altered haemodynamic function and cerebrovascular dynamics 6 hours after LPS administration. Histological assessment identified a significant increase in astrogliosis, microgliosis and endothelial activation in LPS-treated animals.
Conclusions: Our data shows that an acutely induced systemic inflammatory response is able to rapidly alter in-vivo haemodynamic function and is associated with significant changes in the cellular constituents of the NVU. We suggest that these effects are initially mediated by endothelial cells, which are directly exposed to the circulating inflammatory stimulus and have been implicated in regulating functional hyperaemia.
Species Tree Inference on Data with Paralogs is Accurate Using Methods Intended to Deal with Incomplete Lineage Sorting
Authors: Yan Zhi , Smith Megan L. , Du Peng , Hahn Matthew W. , Nakhleh Luay
Published: December 2018

Abstract

Many recent phylogenetic methods have focused on accurately inferring species trees when there is gene tree discordance due to incomplete lineage sorting (ILS). For almost all of these methods, and for phylogenetic methods in general, the data for each locus is assumed to consist of orthologous, single-copy sequences. Loci that are present in more than a single copy in any of the studied genomes are excluded from the data. These steps greatly reduce the number of loci available for analysis. The question we seek to answer in this study is: What happens if one runs such species tree inference methods on data where paralogy is present, in addition to or without ILS being present? Through simulation studies and analyses of two large biological data sets, we show that running such methods on data with paralogs can still provide accurate results. We use multiple different methods, some of which are based directly on the multispecies coalescent (MSC) model, and some of which have been proven to be statistically consistent under it. We also treat the paralogous loci in multiple ways: from explicitly denoting them as paralogs, to randomly selecting one copy per species. In all cases the inferred species trees are as accurate as equivalent analyses using single-copy orthologs. Our results have significant implications for the use of ILS-aware phylogenomic analyses, demonstrating that they do not have to be restricted to single-copy loci. This will greatly increase the amount of data that can be used for phylogenetic inference.
Forecasting dengue epidemics using a hybrid methodology
Authors: Chakraborty Tanujit , Chattopadhyay Swarup , Ghosh Indrajit
Published: December 2018

Dengue case management is an alarmingly important global health issue. The effective allocation of resources is often difficult due to external and internal factors imposing nonlinear fluctuations in the prevalence of dengue fever. We aimed to construct an early-warning system that could accurately forecast subsequent dengue cases in three dengue endemic regions, namely San Juan, Iquitos, and the Philippines. The problem is solely regarded as a time series forecasting problem ignoring the known epidemiology of dengue fever as well as the other meteorological variables. Autoregressive integrated moving average (ARIMA) model is a popular classical time series model for linear data structures whereas with the advent of neural networks, nonlinear structures in the dataset can be handled. In this paper, we propose a novel hybrid model combining ARIMA and neural network autoregressive (NNAR) model to capture both linearity and nonlinearity in the datasets. The ARIMA model filters out linear tendencies in the data and passes on the residual values to the NNAR model. The proposed hybrid approach is applied to three dengue time-series data sets and is found to give better forecasting accuracy in comparison to the state-of-the-art. The results of this study indicate that dengue cases can be accurately forecasted over a sufficient time period using the proposed hybrid methodology.
Microhomology-mediated CRISPR/Cas9-based method for genome editing in fission yeast
Authors: Hayashi Aki , Tanaka Katsunori
Published: December 2018

The CRISPR/Cas9 system enables the editing of genomes of numerous organisms through the induction of the double-strand breaks (DSB) at specific chromosomal targets. We improved the CRISPR/Cas9 system to ease the direct introduction of a point mutation or a tagging sequence into the chromosome by combining it with the microhomology mediated end joining (MMEJ)-based genome editing in fission yeast. We constructed convenient cloning vectors, which possessed a guide RNA (gRNA) expression module, or the humanized Streptococcus pyogenes Cas9 gene that is expressed under the control of an inducible promoter to avoid the needless expression, or both a gRNA and Cas9 gene. Using this system, we attempted the MMEJ-mediated genome editing and found that the MMEJ-mediated method provides high-frequency genome editing at target loci without the need of a long donor DNA. Using short oligonucleotides, we successfully introduced point mutations into two target genes at high frequency. We also precisely integrated the sequences for epitope and GFP tagging using donor DNA possessing microhomology into the target loci, which enabled us to obtain cells expressing N-terminally tagged fusion proteins. This system could expedite genome editing in fission yeast, and could be applicable to other organisms.
Access COI barcode efficiently using high throughput Single-End 400 bp sequencing
Authors: Yang Chentao , Tan Shangjin , Meng Guangliang , Bourne David G. , O’Brien Paul A. , Xu Junqiang , Liao Sha , Chen Ao , Chen Xiaowei , Liu Shanlin
Published: December 2018

Over the last decade, the rapid development of high-throughput sequencing platforms has accelerated species description and assisted morphological classification through DNA barcoding. However, constraints in barcoding costs led to unbalanced efforts which prevented accurate taxonomic identification for biodiversity studies.

We present a high throughput sequencing approach based on the HIFI-SE pipeline which takes advantage of Single-End 400 bp (SE400) sequencing data generated by BGISEQ-500 to produce full-length Cytochrome c oxidase subunit I (COI) barcodes from pooled polymerase chain reaction amplicons. HIFI-SE was written in Python and included four function modules of filter, assign, assembly and taxonomy.

We applied the HIFI-SE to a test plate which contained 96 samples (30 corals, 64 insects and 2 blank controls) and delivered a total of 86 fully assembled HIFI COI barcodes. By comparing to their corresponding Sanger sequences (72 sequences available), it showed that most of the samples (98.61%, 71/72) were correctly and accurately assembled, including 46 samples that had a similarity of 100% and 25 of ca. 99%.

Our approach can produce standard full-length barcodes cost efficiently, allowing DNA barcoding for global biomes which will advance DNA-based species identification for various ecosystems and improve quarantine biosecurity efforts.
NASC-seq monitors RNA synthesis in single cells
Authors: Hendriks Gerardus , Jung Lisa A , Larsson Anton JM , Andersson Forsman Oscar , Lidschreiber Michael , Lidschreiber Katja , Cramer Patrick , Sandberg Rickard
Published: December 2018

Sequencing of newly synthesized RNA can monitor transcriptional dynamics with great sensitivity and high temporal resolution, but is currently restricted to populations of cells. Here, we developed newly synthesized alkylation-dependent single-cell RNA sequencing (NASC-seq), to monitor both newly synthesized and pre-existing RNA in single cells. We validated the method on pre-alkylated exogenous spike-in RNA, and by demonstrating that more newly synthesized RNA was detected for genes with known high mRNA turnover. Importantly, NASC-seq reveals rapidly up- and down-regulated genes during the T-cell activation, and RNA sequenced for induced genes were essentially only newly synthesized. Moreover, the newly synthesized and pre-existing transcriptomes after T-cell activation were distinct confirming that we indeed could simultaneously measure gene expression corresponding to two time points in single cells. Altogether, NASC-seq is a powerful tool to investigate transcriptional dynamics and it will enable the precise monitoring of RNA synthesis at flexible time periods during homeostasis, perturbation responses and cellular differentiation.
Maintenance of active chromatin states by Hmgn1 and Hmgn2 is required for stem cell identity:
Authors: Garza-Manero Sylvia , Sindi Abdulmajeed A. A. , Mohan Gokula , Rehbini Ohoud , Jeantet Valentine H. M. , Bailo Mariarca , Abdul Latif Faeezah , West Maureen , Gurden Ross , Finlayson Lauren , Svambaryte Silvija , West Adam G. , West Katherine
Published: December 2018

Chromatin plasticity is thought to be fundamental to the pluripotency of embryonic stem cells. Hmgn proteins modulate chromatin structure and are highly expressed during early development and in neural stem/progenitor cells of the developing and adult brain. Here, we show that loss of Hmgn1 or Hmgn2 in pluripotent embryonal carcinoma cells leads to increased levels of spontaneous neuronal differentiation. This is accompanied by the loss of pluripotency markers and increased expression of the pro-neural transcription factors Neurog1 and Ascl1. Neural stem cells derived from these Hmgn-knockout lines also show increased spontaneous neuronal differentiation and Neurog1 expression. The loss of Hmgn2 is associated with the disruption of active chromatin states at specific classes of gene. The levels of H3K4me3, H3K9ac, H3K27ac and H3K122ac are considerably reduced at the pluripotency genes Nanog and Oct4, which impacts transcription. At endodermal/mesodermal lineage-specific genes, the loss of Hmgn2 leads to a switch from a bivalent to a repressive chromatin configuration. However, at the neuronal lineage genes Neurog1 and Ascl1, no epigenetic changes are observed and their bivalent states are retained. We conclude that Hmgn proteins play important roles in maintaining chromatin plasticity in stem cells, and are essential for maintaining stem cell identity and pluripotency.
Baloxavir Marboxil Susceptibility of Influenza Viruses from the Asia-Pacific, 2012-2018.
Authors: Koszalka Paulina , Tilmanis Danielle , Roe Merryn , Vijaykrishna Dhanasekaran , Hurt Aeron
Published: December 2018

Baloxavir Marboxil (BXM) is an influenza polymerase inhibitor antiviral that binds to the endonuclease region in the PA subunit of influenza A and B viruses. To establish the baseline susceptibility of viruses circulating prior to licensure of BXM and to monitor for susceptibility post-BXM use, a cell culture-based focus reduction assay was developed to determine the susceptibility of 286 circulating seasonal influenza viruses, A(H1N1)pdm09, A(H3N2), B (Yamagata/Victoria) lineage viruses, including neuraminidase inhibitor (NAI) resistant viruses, to Baloxavir Acid (BXA), the active metabolic form of BXM. BXA was effective against all influenza subtypes tested with mean EC50 values (minimum-maximum) of 0.7 ± 0.5 nM (0.1-2.1 nM), 1.2 ± 0.6 nM (0.1- 2.4), 7.2 ± 3.5 nM (0.7-14.8), and 5.8 ± 4.5 nM (1.8-15.5) obtained for A(H1N1)pdm09, A(H3N2), B(Victoria lineage), and B(Yamagata lineage) influenza viruses, respectively. Using reverse genetics, amino acid substitutions known to alter BXA susceptibility were introduced into the PA protein resulting in EC50 fold change increases that ranged from 2 to 65. Our study demonstrates that currently circulating viruses are susceptible to BXA and that the newly developed focus reduction assay is well suited to susceptibility monitoring in reference laboratories.
Functional and Optogenetic Approaches to Discovering Stable Subtype-Specific Circuit Mechanisms in Depression
Authors: Grosenick Logan , Shi Tracey C , Gunning Faith , Dubin Marc J , Downar Jonathan , Liston Conor
Published: December 2018

Background: Using canonical correlation analysis (CCA), hierarchical clustering, and machine learning methods, we recently identified four subtypes of depression defined by distinct patterns of abnormal functional connectivity in depression-related brain networks, which in turn predicted differing clinical symptom profiles and individual differences in treatment response. However, whether and how dysfunction in specific circuits may give rise to specific depressive symptoms and behaviors remains unclear. Furthermore, this approach assumes that there are robust and stable canonical correlations between functional connectivity and depressive symptoms--an assumption that was not extensively tested in our earlier work.
Methods: First, we comprehensively re-evaluate the stability of canonical correlations between functional connectivity and symptoms, using optimized approaches for large-scale statistical testing, and we validate methods for improving stability. Next, we illustrate one approach to formulating hypotheses regarding subtype-specific circuit mechanisms driving depressive symptoms and behaviors and then testing them in animal models using optogenetic fMRI. We review recent work in this field and describe one example of this approach.
Results: Correlations between connectivity features and clinical symptoms are robustly significant, and CCA solutions tested repeatedly on held-out data generalize, but they are sensitive to data quality, preprocessing decisions, and clinical sample heterogeneity, which can reduce effect sizes. Generalization can be markedly improved by adding L2-regularization to CCA, which decreases variance, increases canonical correlations in left-out data, and stabilizes feature selection. This approach, in turn, can be used to identify candidate circuits for optogenetic interrogation in rodent models.
Conclusions: Multi-view approaches like CCA are a conceptually useful framework for discovering stable patient subtypes by synthesizing multiple clinical and functional measures. Optogenetic fMRI holds substantial promise for testing hypotheses regarding subtype-specific mechanisms driving specific symptoms and behaviors in depression.
Integrative analysis of Dupuytren’s disease identifies novel risk locus and reveals a shared genetic etiology with BMI
Authors: Major Megan , Freund Malika K , Burch Kathryn S , Mancuso Nicholas , Ng Michael , Furniss Dominic , Pasaniuc Bogdan , Ophoff Roel
Published: December 2018

Dupuytren’s disease is the common inherited tissue-specific fibrotic disorder. It’s characterized by progressive and irreversible fibroblastic proliferation affecting the palmar fascia of the hand, with an onset typically in the sixth decade of life. Although genome-wide association studies (GWAS) have identified 24 genomic regions associated with Dupuytren’s risk, the biological mechanisms driving signal at these regions remain elusive. We identify potential biological mechanisms for Dupuytren’s disease by integrating the most recent, largest GWAS (ncases = 3,871, ncontrols = 4,686) with eQTLs (47 tissue panels from five consortia, total n = 3,975) to perform a transcriptome-wide association study (TWAS). We identify 43 tissue-specific gene associations with Dupuytren’s risk, one of which resides at least 0.5 Mb away from the 24 risk regions previously identified. We also estimate the genome-wide genetic correlation between Dupuytren’s disease and 45 complex traits and find significant genetic correlations between Dupuytren’s disease and body mass index (, P = 1.6 × 10−6), type II diabetes (, P = 1.7 × 10−4), triglycerides (, P = 3.5 × 10−4), and high-density lipoprotein (, P = 4.1 × 10−4), which suggests a shared genetic etiology. We further refine the genome-wide genetic correlation signal to identify 8 regions significantly negatively correlated with BMI and 3 regions significantly correlated (1 positively and 2 negatively correlated) with HDL; none of these regions contained the novel gene association identified by TWAS. Our results are consistent with previous epidemiological findings which show that lower BMI increases risk for Dupuytren’s disease. These 12 novel risk regions provide new insight into the biological mechanisms of Dupuytren’s disease and serve as a starting point for functional validation.
AAV-mediated gene transfer restores a normal muscle transcriptome in a canine model of X-linked myotubular myopathy
Authors: Dupont Jean-Baptiste , Guo Jianjun , Lawlor Michael W. , Grange Robert W. , Gray John T. , Buj-Bello Ana , Childers Martin K. , Mack David L.
Published: December 2018

Multiple clinical trials employing recombinant adeno-associated viral (rAAV) vectors have been initiated for neuromuscular disorders, including Duchenne and limb-girdle muscular dystrophies, spinal muscular atrophy, and recently X-linked myotubular myopathy (XLMTM). Previous work from our laboratory on a canine model of XLMTM showed that a single rAAV8-cMTM1 systemic infusion corrects structural abnormalities within the muscle and restores contractile function, with affected dogs surviving more than four years post injection. This exceptional therapeutic efficacy presents a unique opportunity to identify the downstream molecular drivers of XLMTM pathology, and to what extent the whole muscle transcriptome is restored to normal after gene transfer. Herein, RNA-sequencing was used to examine the transcriptomes of the Biceps femoris and Vastus lateralis in a previously-described canine cohort showing dose-dependent clinical improvements after rAAV8-cMTM1 gene transfer. Our analysis confirmed several dysregulated genes previously observed in XLMTM mice, but also identified new transcripts linked to XLMTM pathology. We demonstrated XLMTM transcriptome remodeling and dose-dependent normalization of gene expression after gene transfer and created new metrics to pinpoint potential biomarkers of disease progression and correction.
Multiple species drive flexible lake food webs with warming
Authors: Bartley Timothy J. , Tunney Tyler D. , Lester Nigel P. , Shuter Brian J. , Hanner Robert H. , McCann Kevin S.
Published: December 2018

Climate change is rewiring the food webs that determine the fate of diverse ecosystems. Mobile generalist consumers are responding to climate change by rapidly shifting their behaviour and foraging, driving food webs to flex. Although these responsive generalists form a key stabilizing module in food web structure, the extent to which they are present throughout whole food webs is largely unknown. Here, we show that multiple species comprising key trophic roles drive flexible lake food webs with warming. By examining lakes that span a 7°C air temperature gradient, we found significant reductions in nearshore derived carbon and nearshore habitat use with increased temperature in three of four fish species. We also found evidence that the response of lake trout to increased temperatures may reduce their biomass and cascade to release their preferred prey, the pelagic forage fish cisco. Our results suggest that climate warming will shift lake food webs toward increased reliance on offshore habitats and resources. We argue that species across trophic levels broadly couple lake macrohabitats, suggesting that potentially stabilizing responsive consumers are present throughout food webs. However, climate change appears to limit their ability to responsively forage, critically undermining a repeated stabilizing mechanism in food webs.
Discovery of Hierarchical Representations for Efficient Planning
Authors: Tomov Momchil S. , Yagati Samyukta , Kumar Agni , Yang Wanqian , Gershman Samuel J.
Published: December 2018

We propose that humans spontaneously organize environments into clusters of states that support hierarchical planning, enabling them to tackle challenging problems by breaking them down into sub-problems at various levels of abstraction. People constantly rely on such hierarchical presentations to accomplish tasks big and small – from planning one’s day, to organizing a wedding, to getting a PhD – often succeeding on the very first attempt. We formalize a Bayesian model of hierarchy discovery that explains how humans discover such useful abstractions. Building on principles developed in structure learning and robotics, the model predicts that hierarchy discovery should be sensitive to the topological structure, reward distribution, and distribution of tasks in the environment. In five simulations, we show that the model accounts for previously reported effects of environment structure on planning behavior, such as detection of bottleneck states and transitions. We then test the novel predictions of the model in eight behavioral experiments, demonstrating how the distribution of tasks and rewards can influence planning behavior via the discovered hierarchy, sometimes facilitating and sometimes hindering performance. We find evidence that the hierarchy discovery process unfolds incrementally across trials. We also find that people use uncertainty to guide their learning in a way that is informative for hierarchy discovery. Finally, we propose how hierarchy discovery and hierarchical planning might be implemented in the brain. Together, these findings present an important advance in our understanding of how the brain might use Bayesian inference to discover and exploit the hidden hierarchical structure of the environment.
Measuring graded changes in consciousness through multi-target filling-in
Authors: Davidson Matthew J , Graafsma Irene , Tsuchiya Naotsugu , van Boxtel Jeroen
Published: December 2018

Perceptual filling-in (PFI) occurs when a physically-present visual target disappears from conscious perception, with its location filled in by the surrounding visual background. Compared to other visual illusions, these perceptual changes are crisp and simple, and can occur for multiple spatially-separated targets simultaneously. Contrasting neural activity during the presence or absence of PFI may complement other multistable phenomena to reveal the neural correlates of consciousness (NCC). We presented four peripheral targets over a background dynamically updating at 20 Hz. While participants reported on target disappearances/reappearances via button press/release, we tracked neural activity entrained by the background during PFI using steady-state visually evoked potentials (SSVEPs) recorded in the electroencephalogram. We found background SSVEPs closely correlated with subjective report, and increased with an increasing amount of PFI. Unexpectedly, we found that as the number of filled-in targets increased, the duration of target disappearances also increased, suggesting facilitatory interactions exist between targets in separate visual quadrants. We also found distinct spatiotemporal correlates for the background SSVEP harmonics. Prior to genuine PFI, the response at the second harmonic (40 Hz) increased before the first (20 Hz), which we tentatively link to an attentional effect. There was no difference between harmonics for physically removed stimuli. These results demonstrate that PFI can be used to study multi-object perceptual suppression when frequency-tagging the background of a visual display, and because there are distinct neural correlates for endogenously and exogenously induced changes in consciousness, that it is ideally suited to study the NCC.

Highlights

Perceptual filling-in (PFI) has distinct advantages for investigating the neural correlates of consciousness.

Participants can accurately report graded changes in consciousness using four simultaneous buttons.

Frequency-tagging of visual background information tracks changes in visual perception.

Spatiotemporal EEG responses differentiate PFI from phenomenally matched physical disappearances.
Impact of branching on the conformational heterogeneity of the lipopolysaccharide from Klebsiella pneumoniae: Implications for vaccine design
Authors: Aytenfisu Asaminew , Simon Raphael , MacKerell Alexander
Published: December 2018

Resistance of Klebsiella pneumoniae (KP) to antibiotics has motivated the development of an efficacious KP human vaccine that would not be subject to antibiotic resistance. Klebsiella lipopolysaccharide (LPS) associated O polysaccharide (OPS) types have provoked broad interest as a vaccine antigen as there are only 4 that predominate worldwide (O1, O2a, O3, O5). Klebsiella O1 and O2 OPS are polygalactans that share a common D-Gal-I structure, for which a variant D-Gal-III was recently discovered. To understand the potential impact of this variability on antigenicity, a detailed molecular picture of the conformational differences associated with the addition of the D-Gal-III (1?4)Gal branch is presented using enhanced-sampling molecular dynamics simulations. In D-Gal-I two major conformational states are observed while the presence of the 1?4 branch in D-Gal-III resulted in only a single dominant extended state. Stabilization of the more folded states in D-Gal-I is due to a O4-H…O2 hydrogen bond in the linear backbone that cannot occur in D-Gal-III as the O4 is in the Galp(1?4)Galp glycosidic linkage. The impact of branching in D-Gal-III also significantly decreases the accessibility of the monosaccharides in the linear backbone region of D-Gal-I, while the accessibility of the terminal D-Gal-II region of the OPS is not substantially altered. The present results suggest that a vaccine that targets both the D-Gal-I and D-Gal-III LPS can be developed by using D-Gal-III as the antigen combined with cross-reactivity experiments using the Gal-II polysaccharide to assure that this region of the LPS is the primary epitope of the antigen.
Incommensurate structures of the [CH3NH3][Co(COOH)3] compound
Authors: Canadillas-Delgado Laura , Mazzuca Lidia , Fabelo Oscar , Rodriguez-Velamazan J. Alberto , Rodriguez-Carvajal Juan
Published: December 2018

The present article is devoted to the characterization of the structural phase transitions of the [CH3NH3][Co(COOH)3] (1) perovskite-like metal–organic compound through variable-temperature single-crystal neutron diffraction. At room temperature, compound1crystallizes in the orthorhombic space groupPnma(phaseI). A decrease in temperature gives rise to a first phase transition from the space groupPnmato an incommensurate phase (phaseII) at approximately 128 K. At about 96 K, this incommensurate phase evolves into a second phase with a sharp change in the modulation vector (phaseIII). At lower temperatures (ca78 K), the crystal structure again becomes commensurate and can be described in the monoclinic space groupP21/n(phaseIV). Although phasesIandIVhave been reported previously [Bočaet al.(2004).Acta Cryst.C60, m631–m633; Gómez-Aguirreet al.(2016).J. Am. Chem. Soc.138, 1122–1125; Mazzucaet al.(2018).Chem. Eur. J.24, 388–399], phasesIIIandIVcorresponding to thePnma(00γ)0s0 space group have not yet been described. These phase transitions involve not only the occurrence of small distortions in the three-dimensional anionic [Co(HCOO)3]−framework, but also the reorganization of the [CH3NH3]+counter-ions in the cavities of the structure, which gives rise to an alteration of the hydrogen-bonded network, modifying the electrical properties of compound1.
Deformation pathway and defect generation in crystals: a combined group theory and graph theory description
Authors: Gao Yipeng , Wang Yunzhi , Zhang Yongfeng
Published: December 2018

The generation and motion of crystalline defects during plastic deformation are critical processes that determine the mechanical properties of a crystal. The types of defect generated are not only related to the symmetry of a crystal but also associated with the symmetry-breaking process during deformation. Proposed here is a new mathematical framework to capture the intrinsic coupling between crystal symmetry and deformation-induced symmetry breaking. Using a combination of group theory and graph theory, a general approach is demonstrated for the systematic determination of the types of crystalline defect induced by plastic deformation, through the construction of a crystal deformation group and a deformation pathway graph. The types of defect generated in the deformation of a face-centered cubic crystal are analyzed through the deformation pathway graph and compared with experimental observations.
Crystal structures of two PCN pincer iridium complexes and one PCP pincer carbodiphosphorane iridium intermediate: substitution of one phosphine moiety of a carbodiphosphorane by an organic azide
Authors: Partl Gabriel Julian , Nussbaumer Felix , Schuh Walter , Kopacka Holger , Wurst Klaus , Peringer Paul
Published: December 2018

The structure of [Ir{(4-Cl-C6H4N3)C(dppm)-κ3
P,C,N}(dppm-κ2
P,P′)]Cl·1.5CH2Cl2·0.5C7H8 (C57H48Cl2IrN3P4·1.5CH2Cl2·0.5C7H8) (2), dppm = bis(diphenylphosphino)methane {systematic name: [7-(4-chlorophenyl)-1,1,3,3-tetraphenyl-5,6,7-triaza-κN
7-1,3λ4-diphospha-κP
1-hepta-4,6-dien-4-yl][methylenebis(diphenylphosphine)-κ2
P,P′]iridium(I) chloride–dichloromethane–toluene (2/3/1)}, resulting from the reaction of [IrClH{C(dppm)2-κ3
P,C,P)(MeCN)]Cl (1a) with 1-azido-4-chlorobenzene, shows a monocationic five-coordinate IrI complex with a distorted trigonal–bipyramidal geometry. In 2, the iridium centre is coordinated by the neutral triazeneylidenephosphorane (4-Cl-C6H4N3)C(dppm) acting as a PCN pincer ligand, and a chelating dppm unit. The structure of the coordination compound [IrCl(CN)H(C(dppm)2-κ3
P,C,P)]·CH3CN, (C52H45ClIrNP4·CH3CN) (1b) [systematic name: chloridocyanidohydrido(1,1,3,3,5,5,7,7-octaphenyl-1,3λ5,5λ4,7-tetraphospha-κ2
P
1,P
7-hept-3-en-4-yl)iridium(III) acetonitrile monosolvate], prepared from 1a and KCN, reveals an octahedral IrIII central atom with a meridional PCP pincer carbodiphosphorane (CDP) ligand; the chloride ligand is located trans to the central carbon of the CDP functionality while the hydrido and cyanido ligands are situated trans to each other. The chiral coordination compound [Ir(CN)((4-Cl-C6H4N3)CH(CH(P(Ph)2)2)-κ3
P,C,N)(dppm-κ2
P,P′)]·2CH3OH, (C58H48ClIrN4P4·2CH3OH) (3) (systematic name: {4-[3-(4-chlorophenyl)triazenido-κN
3]-1,1,3,3-tetraphenyl-1,3λ5-diphospha-κP
1-but-2-en-4-yl}cyanido[methylenebis(diphenylphosphine)-κ2
P,P′]iridium(III) methanol disolvate), formed via prolonged reaction of 1-azido-4-chlorobenzene with 1b, features a six-coordinate IrIII central atom. The iridium centre is coordinated by the dianionic facial PCN pincer ligand [(4-Cl-C6H4N3)CH(CH(P(Ph2)2)2)], a cyanido ligand trans to the central carbon of the PCN pincer ligand and a chelating dppm unit. Complex 2 exhibits a 2:1 positional disorder of the Cl− anion. The CH2Cl2 and C7H8 solvent molecules show occupational disorder, with the toluene molecule exhibiting additional 1:1 positional disorder with some nearly overlying carbon atoms.
Resolving conflict in organizations – achieving results through a harmonization process
Authors: Nguyen Thuc-Doan
Published: December 2018

Purpose

Conflict is inevitable in organizational life. On the one hand, it can bring creativity and enhance problem-solving. On the other, it can hinder effective problem-solving, increase defensiveness and member dissatisfaction, and create a destructive work environment. This paper aims to outline four important components of harmonization that help to enhance conflict-management capability.

Design/methodology/approach

Based on Nguyen and Belk’s (2013) harmonization framework, the author adds their own comments and places in the context of resolving conflict in organization.

Findings

The harmonization process synthesizes multiple goals and balances differences to achieve better solutions without discounting any of these elements. Harmonization provides better understanding of important issues and why they are critical to each party. Each party will feel better about the situation after having heard the other side’s position. There might be anger, anxiety, or frustration at the beginning. However, when people successfully go through the harmonization process, they feel happy, connected to others and proud of the results they get. These processes require communicating with others, learning others’ perspectives, understanding and empathizing with others, and being willing to adjust.

Practical implications

The paper outlines four skills in which organizations can train their employees to improve conflict management.

Originality/value

Harmonization process is applied to conflict management in organization.
When institutions matter: a gravity model for Chinese meat imports
Authors: Hasiner Eva , Yu Xiaohua
Published: December 2018

Purpose

In international trade differences in political and legal systems confront trading partners with relatively greater information asymmetry and contract enforcement problems than in domestic trade, resulting in higher transaction costs. Nevertheless, well-functioning institutions in the exporting country could prove beneficial for the agricultural importer, as institutions generally establish food and product regulations and ensure that they are enforced and serve as a last resort for dispute resolution and contract enforcement. Given China’s increasingly stricter control of its food supply chain and its rising imports of meat products, the purpose of this paper is to analyze whether institutions in the exporting country matter for Chinese meat imports.

Design/methodology/approach

To analyze the effect of the exporters’ institutions on Chinese meat imports, the authors estimate a gravity model for the 1990-2013 period. The authors apply the method suggested by Helpmanet al.(2008) to correct for sample selection and firm heterogeneity. To estimate the effect of time-invariant variables, the authors apply the Fixed Effects Vector Decomposition method proposed by Plümper and Troeger (2007).

Findings

The results show that institutions affect Chinese trade flows. In particular, the authors find that China imports more meat products from countries who host qualitatively better institutions and are geographically closer, and that the country’s imports rise with its GDP level. This confirms our hypothesis that institutions in the exporting country are positively associated with meat exports to China.

Originality/value

The importance of the exporters’ institutions for Chinese meat imports has not been studied so far and is of great interest given China’s rising role as a sizable importer. Furthermore, Chinese meat imports have attracted much attention recently due to the country’s potentially significant impact on world food security and sustainable development. Hence, this paper aims to make a substantial contribution to the literature, both from a scientific and a policy perspective.
Why multinational enterprises may be causing more inequality than we think
Authors: Giuliani Elisa
Published: December 2018

Purpose

This paper aims to discuss the ways in which multinational enterprises (MNEs) may contribute to growing inequality.

Design/methodology/approach

By showing some macroscopic evidence of business-related human rights infringements, this paper claims that the negative impacts of MNEs has been largely overlooked.

Findings

The extent to which MNEs contribute to income-based inequality through the abnormal accumulation of wealth by chief executive officers (CEOs), top managers and shareholders is known, and almost nothing is known about whether this is connected to MNEs’ track record of human rights infringements.

Originality/value

This paper suggest that there might be a connection between MNEs’ human rights infringements and the abnormal accumulation of wealth by companies’ CEOs, top managers and shareholders. It calls for more international business research investigating this link.