bluuebunny/crossref_metadata_2025_split huggingface dataset:
Compression-based Network Interpretability Schemes
Authors: Warrell Jonathan , Mohsen Hussein , Gerstein Mark 
Published: October 2020

AbstractDeep learning methods have achieved state-of-the-art performance in many domains of artificial intelligence, but are typically hard to interpret. Network interpretation is important for multiple reasons, including knowledge discovery, hypothesis generation, fairness and establishing trust. Model transformations provide a general approach to interpreting a trained network post-hoc: the network is approximated by a model, which is typically compressed, whose structure can be more easily interpreted in some way (we call such approachesinterpretability schemes). However, the relationship between compression and interpretation has not been fully explored: How much should a network be compressed for optimal extraction of interpretable information? Should compression be combined with other criteria when selecting model transformations? We investigate these issues using two different compression-based schemes, which aim to extract orthogonal kinds of information, pertaining to feature and data instance-based groupings respectively. The first (rank projection trees) uses a structured sparsification method such that nested groups of features can be extracted having potential joint interactions. The second (cascaded network decomposition) splits a network into a cascade of simpler networks, allowing groups of training instances with similar characteristics to be extracted at each stage of the cascade. We use predictive tasks in cancer and psychiatric genomics to assess the ability of these approaches to extract informative feature and data-point groupings from trained networks. We show that the generalization error of a network provides an indicator of the quality of the information extracted; further we derive PAC-Bayes generalization bounds for both schemes, which we show can be used as proxy indicators, and can thus provide a criterion for selecting the optimal compression. Finally, we show that the PAC-Bayes framework can be naturally modified to incorporate additional criteria alongside compression, such as prior knowledge based on previous models, which can enhance interpretable model selection.
The Influence of Pre-Supplementary Motor Area Targeted High-Definition Transcranial Direct Current Stimulation on Inhibitory Control
Authors: DeLaRosa Bambi L. , Spence Jeffrey S. , Motes Michael A. , To Wing , Vanneste Sven , Hart John , Kraut Michael A. 
Published: October 2020

AbstractThe neural underpinnings of inhibitory control, an executive cognitive control function, has been a topic of interest for several decades due to both its clinical significance and the maturation of cognitive science disciplines. Behavioral, imaging, and electrophysiological studies suggest that the pre-supplementary motor area (preSMA) serves as a primary hub in a network of regions engaged in inhibition. High-definition transcranial direct current stimulation (HD-tDCS) allows us to modulate neural function to assess cortical contribution to cognitive functioning. The present study targeted HD-tDCS modulation of preSMA to affect inhibition. Participants were randomly assigned to receive 20 min of Sham, Anodal, or Cathodal stimulation prior to completing a semantically cued go/nogo task while electroencephalography (EEG) data were recorded. Both anodal and cathodal stimulation improved inhibitory performance as measured by faster reaction times and increased (greater negative) N2 event-related potentials (ERPs). In contrast, the Sham group did not show such changes. We did not find support for the anodal/cathodal dichotomy for HD neural stimulation. These findings constitute an early investigation into role of the preSMA in inhibitory control and in exploring application of HD-tDCS to the preSMA in order to improve inhibitory control.
A multivariate method to correct for batch effects in microbiome data
Authors: Wang Yiwen , Lê Cao Kim-Anh 
Published: October 2020

AbstractMicrobial communities are highly dynamic and sensitive to changes in the environment. Thus, microbiome data are highly susceptible to batch effects, defined as sources of unwanted variation that are not related to, and obscure any factors of interest. Existing batch correction methods have been primarily developed for gene expression data. As such, they do not consider the inherent characteristics of microbiome data, including zero inflation, overdispersion and correlation between variables. We introduce a new multivariate and non-parametric batch correction method based on Partial Least Squares Discriminant Analysis. PLSDA-batch first estimates treatment and batch variation with latent components to then subtract batch variation from the data. The resulting batch effect corrected data can then be input in any downstream statistical analysis. Two variants are also proposed to handle unbalanced batch x treatment designs and to include variable selection during component estimation. We compare our approaches with existing batch correction methods removeBatchEffect and ComBat on simulated and three case studies. We show that our three methods lead to competitive performance in removing batch variation while preserving treatment variation, and especially when batch effects have high variability. Reproducible code and vignettes are available on GitHub.
Neuropixels 2.0: A miniaturized high-density probe for stable, long-term brain recordings
Authors: Steinmetz Nicholas A. , Aydin Cagatay , Lebedeva Anna , Okun Michael , Pachitariu Marius , Bauza Marius , Beau Maxime , Bhagat Jai , Böhm Claudia , Broux Martijn , Chen Susu , Colonell Jennifer , Gardner Richard J. , Karsh Bill , Kostadinov Dimitar , Mora-Lopez Carolina , Park Junchol , Putzeys Jan , Sauerbrei Britton , van Daal Rik J. J. , Vollan Abraham Z. , Welkenhuysen Marleen , Ye Zhiwen , Dudman Joshua , Dutta Barundeb , Hantman Adam W. , Harris Kenneth D. , Lee Albert K. , Moser Edvard I. , O’Keefe John , Renart Alfonso , Svoboda Karel , Häusser Michael , Haesler Sebastian , Carandini Matteo , Harris Timothy D. 
Published: October 2020

AbstractTo study the dynamics of neural processing across timescales, we require the ability to follow the spiking of thousands of individually separable neurons over weeks and months, during unrestrained behavior. To address this need, we introduce the Neuropixels 2.0 probe together with novel analysis algorithms. The new probe has over 5,000 sites and is miniaturized such that two probes plus a headstage, recording 768 sites at once, weigh just over 1 g, suitable for implanting chronically in small mammals. Recordings with high quality signals persisting for at least two months were reliably obtained in two species and six different labs. Improved site density and arrangement combined with new data processing methods enable automatic post-hoc stabilization of data despite brain movements during behavior and across days, allowing recording from the same neurons in the mouse visual cortex for over 2 months. Additionally, an optional configuration allows for recording from multiple sites per available channel, with a penalty to signal-to-noise ratio. These probes and algorithms enable stable recordings from >10,000 sites during free behavior in small animals such as mice.
Suppressing STAT3 activity protects the endothelial barrier from VEGF-mediated vascular permeability
Authors: Wang Li , Astone Matteo , Alam Sk. Kayum , Zhu Zhu , Pei Wuhong , Frank David A. , Burgess Shawn M. , Hoeppner Luke H. 
Published: October 2020

ABSTRACTVascular permeability triggered by inflammation or ischemia promotes edema, exacerbates disease progression, and impairs tissue recovery. Vascular endothelial growth factor (VEGF) is a potent inducer of vascular permeability. VEGF plays an integral role in regulating vascular barrier function physiologically and in pathologies, such as cancer, ischemic stroke, cardiovascular disease, retinal conditions, and COVID-19-associated pulmonary edema and sepsis, which often leads to acute lung injury, including acute respiratory distress syndrome. However, after initially stimulating permeability, VEGF subsequently mediates angiogenesis to repair damaged tissue. Consequently, understanding temporal molecular regulation of VEGF-induced vascular permeability will facilitate developing therapeutics that achieve the delicate balance of inhibiting vascular permeability while preserving tissue repair. Here, we demonstrate that VEGF signals through signal transducer and activator of transcription 3 (STAT3) to promote vascular permeability. Specifically, we show that genetic STAT3 ablation reduces vascular permeability in STAT3-deficient endothelium of mice and VEGF-inducible zebrafish crossed with CRISPR/Cas9 generated genomic STAT3 knockout zebrafish. Importantly, STAT3 deficiency does not impair vascular development and function in vivo. We identify intercellular adhesion molecule 1 (ICAM-1) as a STAT3-dependent transcriptional regulator and show VEGF-dependent STAT3 activation is regulated by JAK2. Pyrimethamine, an FDA-approved anti-microbial agent that inhibits STAT3-dependent transcription, substantially reduces VEGF-induced vascular permeability in zebrafish, mouse, and human endothelium. Indeed, pharmacologically targeting STAT3 increases vascular barrier integrity using two additional compounds, atovaquone and C188-9. Collectively, our findings suggest that the VEGF, VEGFR-2, JAK2, and STAT3 signaling cascade regulates vascular barrier integrity, and inhibition of STAT3-dependent activity reduces VEGF-induced vascular permeability in vertebrate models.Key PointsGenetic STAT3 deficiency in VEGF-inducible zebrafish and mice reveals that VEGF signals through STAT3 to promote vascular permeabilityPyrimethamine, a clinically available agent that inhibits STAT3 activity, reduces VEGF-induced vascular permeability in preclinical models
Kinetic isotope tracing of glycerol and de novo proteogenic amino acids in Human Lung Carcinoma cells using [U-13C6]glucose
Authors: Akram Subia , Thakur Jyotika , Shree Manu , Masakapalli Shyam K. , Nanda Ranjan Kumar 
Published: October 2020

Abstract13C based Isotopic tracers of the media components can be used to kinetically track their contribution in the cell systems. A tracer ([U-13C6] glucose) was used to monitor its contribution into the central carbon metabolic pathways of human lung carcinoma (A549) cells by Gas chromatography-mass spectrometry (GC-MS) based mass isotopomer analysis. Calculated average 13C of methanolic extracts (glycerol: 5.46±3.53 % and lactate: 74.4±2.65 %), protein acid hydrolysates (serine: 4.51±0.21 %, glycine: 2.44±0.31 %, alanine: 24.56±0.59 %, glutamate: 8.81±0.85 %, proline: 6.96±0.53 % and aspartate: 10.72±0.95 %) and the culture filtrate (glycerol: 43.14±1.45 % and lactate: 81.67±0.91 %), showed significant contribution of 13C glucose. We observed the Warburg effect with higher levels of 13C lactate in the culture filtrate. 13C glycerol levels in culture supernatant showed significant increase with time and amino acids of glucogenic origin also contributed cellular protein biomass. The workflow adopted in this study for 13C analysis could be useful for the metabolic phenotyping of other mammalian cell systems under normal and perturbed (cancer and infection) conditions.
A Darwinian outlook on schistosomiasis elimination
Authors: Van den Broeck Frederik , Vanoverbeeke Joost , Polman Katja , Huyse Tine 
Published: October 2020

SUMMARYSchistosomiasis is a poverty-related chronic disease that affects over 240 million people across 78 countries worldwide. In order to control the disease, the World Health Organization (WHO) recommends the drug praziquantel against all forms of schistosomiasis. Mass Drug Administration (MDA) programs with praziquantel are successful on the short-term as they reduce the prevalence and infection intensity after treatment, and thus instantly relieve the patient from the burden of its disease. However, epidemiological and genetic studies suggest that current school-based interventions may have little or no long-term impact on parasite transmission. Here, we adopt a Darwinian approach to understand the impact of MDA on the neutral evolution ofSchistosomaparasites and assess its potential to eliminate schistosomiasis. We develop a finite island model to simulate the impact of repeated treatments on the genetic diversity of schistosome populations locally (within each host, i.e. infrapopulation) and regionally (within all hosts combined, i.e. component population). We show that repeated treatments induced strong and lasting declines in parasite infrapopulation sizes, resulting in concomitant genetic bottlenecks within the treated individuals. However, parasite genetic diversity recovered quickly in a few generations due to re-infection, and there was little or no impact of treatment on the genetic diversity of the component population when treatment coverage was 95% or lower. This was mainly due to parasite infrapopulations of the untreated host individuals that acted as reservoirs of genetic diversity, sustaining the diversity of the component population. Hence, lasting declines in parasite genetic diversity were only observed when coverage of treatment was 100%, resulting in population crashes after a minimum of six treatment rounds. We argue that achieving a full coverage of treatment is highly challenging for most endemic regions in sub-Saharan Africa, and conclude that MDA alone has little potential to achieve elimination within a conceivable time frame. Our results raise skepticism about the current WHO goals of elimination of schistosomiasis by 2025.
Genetically-Modified Macrophages Accelerate Myelin Repair
Authors: Aigrot Marie-Stephane , Barthelemy Clara , Moyon Sarah , Dufayet-Chaffaud Gaelle , Izagirre-Urizar Leire , Gillet-Legrand Beatrix , Bayón-Cordero Laura , Tada Satoru , Chara Juan-Carlos , Matute Carlos , Cartier Nathalie , Lubetzki Catherine , Tepavčević Vanja 
Published: October 2020

ABSTRACTPreventing neurodegeneration-associated disability progression in patients with multiple sclerosis (MS) remains an unmet therapeutic need. As remyelination prevents degeneration of demyelinated axons, promoting this process in patients might halt the development of permanent disability. In demyelinating mouse lesions, local overexpression of Semaphorin 3F (Sema3F), an oligodendrocyte progenitor cell (OPC) attractant, increases OPC recruitment and remyelination. However, molecular targeting to MS lesions is a challenge because these are disseminated in the central nervous system.We hypothesized that a clinically-relevant paradigm to deliver Sema3F to demyelinating lesions and increase OPC recruitment may be to use blood-derived macrophages as vehicles. Thus, we chose transplantation of genetically-modified hematopoietic stem cells (HSCs) as means of obtaining circulating monocytes that overexpress Sema3F. We first demonstrated that the supernatant from Sema3F-lentiviral vector transduced HSCs stimulates OPC migration in Neuropilin 2 (Nrp2, Sema3F receptor)-dependent fashion. We then investigated whether OPCs remain responsive to Sema3F with age. While Sema3F expression in the lesions of middle-aged and old mice (characterized by decreased efficiency of OPC recruitment and remyelination) was decreased, middle-aged OPCs retained Nrp2 expression and migrated in response to both recombinant Sema3F and Sema3F-transduced cell supernatant in vitro. We then investigated whether blood cells engineered to overexpress Sema3F can target demyelinating CNS lesions and improve remyelination. Thus, we transplanted Sema3F-transduced HSCs and obtained chimeric mice (with Sema3F overexpression in blood cells), in which we induced demyelinating spinal cord lesions. Transgene-carrying cells, predominantly macrophages, quickly infiltrated lesions in both control and Sema3F chimeras. While infiltration of Sema3F-expressing cells did not alter the inflammatory status of the lesions nor OPC survival, it increased OPC recruitment, which accelerated the onset of remyelination. Our results provide a proof-of-concept that blood cells, particularly monocyte-derived macrophages, can be used to deliver pro-remyelinating agents “at the right time and place”, suggesting novel means for remyelination-promoting strategies.
Assortative Mating, Autistic Traits, Empathizing, and Systemizing
Authors: Richards Gareth , Baron-Cohen Simon , Stokes Holly , Warrier Varun , Mellor Ben , Winspear Ellie , Davies Jessica , Gee Laura , Galvin John 
Published: October 2020

AbstractIt has been suggested that the children of parents with particular interests and aptitude for understanding systems via input-operation-output rules (i.e. systemizing) are at increased likelihood of developing autism. Furthermore, assortative mating (i.e. a non-random pattern in which individuals are more likely to pair with others who are similar to themselves) is hypothesised to occur in relation to systemizing, and so romantic couples may be more similar on this variable than chance would dictate. However, no published study has yet tested this hypothesis. We therefore examined intra-couple correlations for a measure of autistic traits (Autism Spectrum Quotient [AQ]), self-report measures of empathizing (Empathy Quotient [EQ]), and systemizing (Systemizing Quotient-Revised [SQ-R]), as well as the Reading the Mind in the Eyes Test (RMET) and Embedded Figures Task (EFT). We observed positive intra-couple correlations of small-to-medium magnitude for all measures except EQ. Further analyses suggest that these effects are attributable to people pairing with those who are more similar to themselves than chance (initial assortment) rather than becoming more alike over the course of a relationship (convergence), and to seeking out self-resembling partners (active assortment) rather than pairing in this manner due to social stratification increasing the likelihood of similar people meeting in the first place (social homogamy). Additionally, we found that the difference in scores for the AQ, SQ-R, RMET and EFT of actual couples were smaller (i.e. more similar) than the average difference scores calculated from all other possible male-female pairings within the dataset. The current findings therefore provide clear evidence in support of the assortative mating theory of autism.
Quantitative Behavioural Phenotyping to Investigate Anaesthesia-Induced Neurobehavioural Impairment
Authors: Nambyiah Pratheeban , Brown Andre EX 
Published: October 2020

AbstractBackgroundVertebrate animal experiments have suggested that anaesthesia exposure to the developing nervous system causes neuroapoptosis and behavioural impairment. Mechanistic understanding is limited, and target-based approaches are challenging. High-throughput methods may be an important parallel approach to drug-discovery and mechanistic research. The nematode wormCaenorhabditis elegansis an ideal candidate as a model for this. A rich subset of its behaviour can be studied, and hundreds of morphological and behavioural features can be quantified, then aggregated to yield a ‘signature’. Perturbation of this behavioural signature may provide a tool that can be used to quantify the effects of anaesthetic regimes, and act as an outcome marker for drug screening and molecular target research.MethodsLarvalC. eleganswere exposed to: isoflurane, ketamine, morphine, dexmedetomidine, and lithium (and combinations). Behaviour was recorded, and videos analysed with automated algorithms to extract behavioural and morphological features.ResultsAnaesthetic exposure during early development leads to persisting morphological and behavioural variation (in total, 125 features/exposure combinations). Higher concentrations, and combinations of isoflurane with ketamine, lead to more feature ‘hits’. Morphine and dexmedetomidine do not appear to lead to behavioural impairment. Lithium rescues the neurotoxic phenotype produced by isoflurane.ConclusionsFindings correlate well with vertebrate research: impairment is dependent on agent, is concentration-specific, is more likely with combination therapies, and can potentially be rescued by lithium. These results suggest thatC. elegansmay be an appropriate model with which to pursue phenotypic screens for drugs that mitigate the neurobehavioural impairment. Some possibilities are suggested for how high-throughput platforms might be organised in service of this field.
Cycling hypoxia selects for constitutive HIF stabilization
Authors: Pressley Mariyah , Gallaher Jill A. , Brown Joel S. , Tomaszewski Michal R. , Borad Punit , Damaghi Mehdi , Gillies Robert J. , Whelan Christopher J. 
Published: October 2020

AbstractTumors experience temporal and spatial fluctuations in oxygenation. Hypoxia inducible transcription factors (HIF-α) in tumor cells are stabilized in response to low levels of oxygen and induce angiogenesis to re-supply oxygen. HIF-α stabilization is typically facultative, induced by hypoxia and reduced by normoxia. In some cancers, however, HIF-α stabilization becomes constitutive even under normoxia, a condition known aspseudohypoxia. Herein, we develop a mathematical model that predicts the effects of fluctuating levels of oxygen availability on stabilization of HIF-α and its client proteins based on fitness. The model shows that facultative regulation of HIF-α always promotes greater cell fitness than constitutive regulation. However, cell fitness is nearly identical regardless of HIF-α regulation strategy when there are rapid periodic fluctuations in oxygenation. Furthermore, the model predicts that stochastic changes in oxygenation favor facultative HIF-α regulation. We conclude that rapid and regular cycling of oxygenation levels selects for pseudohypoxia.
“The frog in the pan”: relational transformation of public values in the UK tax authority
Authors: Closs-Davies Sara C. , Bartels Koen P.R. , Merkl-Davies Doris M. 
Published: October 2020

PurposeThe authors aim to contribute to conceptual and empirical understanding of publicness in public sector accounting research by analysing how accounting technologies facilitated the transformation of public values of the UK tax authority.Design/methodology/approachThe authors develop a conceptual framework for analysing public values in terms of relational power. Combining governmentality and actor–network theory, the authors focus on the complex relationships through which human and non-human actors interact and the public values that emerge from these evolving socio-material networks. Based on a critical-interpretivist ethnographic study of interviews, documents and secondary survey data, the authors identify the emergent properties of accounting technologies in their case study.FindingsThe authors explain how accounting technologies facilitated the transformation of public values in the tax authority by reshaping relational power. Traditional public values were eroded and replaced by neoliberal values through a gradual change process (“frog in the pan”) of (1) disconnecting workers and citizens both spatially and socially; (2) losing touch with the embodied nature of tax administration; and (3) yielding to a dehumanising performance management system. Neoliberal accounting technologies transformed the texture of relationships in such a way that workers and citizens became disempowered from effective, accountable and humane tax administration.Research limitations/implicationsFurther research is needed that gains wider access to tax authority workers, extends the scope of the empirical data and provides comparisons with other tax authorities and public sector organisations.Social implicationsThe authors show that a relational approach to public values enables identification of what is “valuable” and how public sector organisations can become “value-able”.Originality/valueThe authors offer an interdisciplinary conceptualisation of publicness based on public administration literature, develop a relational conceptualisation of public values and provide original empirical evidence about the changing publicness of the UK tax authority.