bluuebunny/crossref_metadata_2025 huggingface dataset:
Word embeddings trained on published case reports are lightweight, effective for clinical tasks, and free of protected health information
Authors: Flamholz Zachary N. , Ungar Lyle H. , Weissman Gary E.
Published: December 2019

Rationale

Word embeddings are used to create vector representations of text data but not all embeddings appropriately capture clinical information, are free of protected health information, and are computationally accessible to most researchers.

Methods

We trained word embeddings on published case reports because their language mimics that of clinical notes, the manuscripts are already de-identified by virtue of being published, and the corpus is much smaller than those trained on large, publicly available datasets. We tested the performance of these embeddings across five clinically relevant tasks and compared the results to embeddings trained on a large Wikipedia corpus, all publicly available manuscripts, notes from the MIMIC-III database using fastText, GloVe, and word2vec, and using different dimensions. Tasks included clinical applications of lexicographic coverage, semantic similarity, clustering purity, linguistic regularity, and mortality prediction.

Results

The embeddings trained using the published case reports performed as well as if not better on most tasks than those using other corpora. The embeddings trained using all published manuscripts had the most consistent performance across all tasks and required a corpus with 100 times as many tokens as the corpus comprised of only case reports. Embeddings trained on the MIMIC-III dataset had small but marginally better scores on the clustering tasks which was also based on clinical notes from the MIMIC-III dataset. Embeddings trained on the Wikipedia corpus, although containing almost twice as many tokens as all available published manuscripts, performed poorly compared to those trained on medical and clinical corpora.

Conclusion

Word embeddings trained on freely available published case reports performed well for most clinical task, are free of protected health information, and are small compared to commonly used embeddings trained on larger clinical and non-clinical corpora. The optimal corpus, dimension size, and which embedding model to use for a given task involves tradeoffs in privacy, reproducibility, performance, and computational resources.
Severe volcanic SO2 exposure and respiratory morbidities in the Icelandic population – a register study
Authors: Carlsen Hanne Krage , Valdimarsdóttir Unnur , Briem Haraldur , Dominici Francesca , Finnbjornsdottir Ragnhildur Gudrun , Jóhannsson Thorsteinn , Aspelund Thor , Gislason Thorarinn , Gudnason Thorolfur
Published: December 2019

Background

The Holuhraun volcanic eruption September 2014 to February 2015 emitted large amounts of sulfur dioxide (SO2).

Objectives

The aim of this study was to determine the association between volcanic SO2 gases on general population respiratory health in the Icelandic capital area some 250 km from the eruption site.

Methods

Respiratory health outcomes were: asthma medication dispensing (AMD) from the Icelandic Medicines Register, medical doctor consultations in primary care (PCMD) and hospital emergency department visits (HED) in Reykjavík (population: 215 000) for respiratory disease from 1 January 2010 to 31 December 2014. The associations between daily counts of health events,and daily mean SO2 concentration and high SO2 levels (24-hour mean SO2>125µg/m3) were analyzed using generalized additive models.

Results

After the eruption began, AMD was higher than before (129.4 vs. 158.4 individuals per day, p<0.05). Increases in SO2 concentration were associated with an estimated increase in AMD by 1.05% (95% CI 0.48 - 1.62%) per 10 µg/m3 at lag 0-2, 1.51% (95% CI 0.63 – 2.40%) increase in individuals under 18 years of age. PCMD for respiratory causes increased by 1.52% (95% CI 1.04 -2.00%) per 10 µg/m3 SO2 at lag 0-2. For HED, only effect estimated for individuals aged 64 years and older were significantly increased, by 1.541% (95% CI 0.02-3.07%) per 10 µg/m3 SO2 at lag 0-2. Following days with SO2 levels above 125 µg/m3, AMD and PCMD were increased in all age groups, in AMD mostly so in individuals under 18 by 20.4%(95%CI 4.8 – 23.4%), and adult PCMD visits by 24.1%(95%CI 16.8 – 31.3%). HED was significantly increased in elderly by 26.3% (95%CI 5.56-47.0).

Discussion

High levels of volcanic SO2 are associated with increases in dispensing of AMD, and health care utilization in primary and tertiary care. Individuals with prevalent respiratory disease may be particularly susceptible.

Funding

The study was funded by the Icelandic Ministry of Health.
Predictors of health related quality of life among diabetic patients on follow up at Nekemte Specialized Hospital, Western Ethiopia: A cross sectional study
Authors: Feyisa Bikila Regassa , Yilma Mekdes Tigistu , Tolessa Belachew Etana
Published: December 2019

Objective

To assess health related quality of life (HRQoL) and its predictors among diabetic patients on follow up at Nekemte Specialized Hospital (NSH) in Western Ethiopia.

Design, setting and participants

This facility based cross sectional study was conducted among 224 diabetic patients on follow up at one of the public hospitals in western Ethiopia.

Main outcome measured

HRQoL was measured by using the Medical Outcome Study 36-item Short Form Health Survey from 15th April to 5th June. Structured questionnaire was used for data the collection from participants selected by systematic random sampling. Multiple linear regression was used for final model.

Result

A total of 215 diabetic patients were involved in the study with the response rate of 96%. The mean score of the overall HRQoL of the study participants was found to be 50.30 ± 18.08 with highest mean score in physical functioning and lowest mean score in general health domain. Age, education status, history of smoking, feeling of stigmatized and Body mass index (BMI) were inversely associated while being male, being married, absence of co morbidity and absence of chronic complications related to diabetes mellitus were found to be positively associated with overall HRQoL.

Conclusion

The overall HRQoL of diabetic patients on follow up at the study area was found to be moderate. General health, mental health, bodily pain and vitality were the most affected domains. Both the mental and physical components need to be considered when caring the diabetic patients on follow up beyond provision of treatment.

Strength and limitations of this study

The study was the first of its kind in assessing the predictors of health-related quality of life (HRQoL) among both diabetes mellitus type I and type II in Ethiopia.

The tools used was validated across different cultures

Eight domains of HRQoL and two component summary scores were used to make the measurement more specific.

The cross sectional nature of the study design made the result of the study difficult to identify either the cause or the effect comes first.
Null effect of circulating sphingomyelins on risk for breast cancer: a Mendelian randomization report using Breast Cancer Association Consortium (BCAC) data
Authors: Adams Charleen D.
Published: December 2019

Background

Changes in cellular metabolism are a hallmark of cancer and are linked with sphingolipid synthesis. Due to immense interest in how sphingolipids influence chemoresistance, more is known about the impact of sphingolipids during cancer treatment and progression than about the potential role of sphingolipids in the induction of tumors in humans.

Methods

Because estrogen triggers sphingolipid signaling cascades, the causal role of circulating levels of sphingomyelin (a type of sphingolipid) on breast cancer was investigated with a well-powered Mendelian randomization design.

Results

The results reveal a null effect (OR = 0.94; 95% CI = 0.85, 1.05; P = 0.30).

Conclusion

Despite the role sphingomyelins play during chemoresistance and cancer progression, circulating sphingomyelins do not appear to initiate or protect from breast cancer.

Impact

This finding comprises the first causal report in humans that sphingomyelins on breast cancer initiation is null. Future investigations of risk in other cancer types are needed to further explore the potential role of sphingolipid biology in cancer etiology.
The genetic and clinical landscape of nanophthalmos in an Australian cohort
Authors: Siggs Owen M , Awadalla Mona S , Souzeau Emmanuelle , Staffieri Sandra E , Kearns Lisa S , Laurie Kate , Kuot Abraham , Qassim Ayub , Edwards Thomas L , Coote Michael A , Mancel Erica , Walland Mark J , Dondey Joanne , Galanopoulous Anna , Casson Robert J , Mills Richard A , MacArthur Daniel G , Ruddle Jonathan B , Burdon Kathryn P , Craig Jamie E
Published: December 2019

Purpose

Refractive error is caused by a disparity between the axial length and focusing power of the eye. Nanophthalmos is a rare ocular abnormality in which both eyes are abnormally small, typically causing extreme hyperopic refractive error, and associated with an increased risk of angle-closure glaucoma.

Methods

A cohort of 40 individuals from 13 unrelated nanophthalmos kindreds were recruited, with 11 probands subjected to exome sequencing.

Results

Nine probands (69.2%) were assigned a genetic diagnosis, with variants in PRSS56 (4), MFRP (3), and previously reported variants in TMEM98 (1) and MYRF (1). Two of the four PRSS56 probands harboured the previously described c.1066dupC frameshift variant implicated in over half of all reported PRSS56 kindreds, with surrounding haplotypes distinct from each other, and from a previously reported Tunisian c.1066dupC haplotype. Individuals with a genetic diagnosis had shorter mean axial lengths (P=7.22×10−9) and more extreme hyperopia (P=0.0005) than those without a genetic diagnosis, with recessive forms associated with the shortest axial lengths and highest hyperopia. All individuals with an axial length below 18 mm in their smaller eye (17/17) were assigned a genetic diagnosis.

Conclusions

These findings detail the genetic architecture of nanophthalmos in an Australian cohort of predominantly European ancestry, their relative clinical phenotypes, and highlight the shared genetic architecture of rare and common disorders of refractive error.
Measuring Tibial Forces is More Useful than Varus-Valgus Laxities for Identifying and Correcting Overstuffing in Kinematically Aligned Total Knee Arthroplasty
Authors: Roth Joshua D. , Howell Stephen M. , Hull Maury L.
Published: December 2019

Identifying and correcting varus-valgus (V-V) malalignment of the tibial component is important when balancing a kinematically aligned total knee arthroplasty (TKA). Accordingly, the primary objective was to determine whether the tibial forces or V-V laxities are more sensitive to, and thus more useful for identifying and correcting, V-V malalignments of the tibial component that overstuff a compartment. Calipered kinematically aligned TKA was performed on nine human cadaveric knees. Medial and lateral tibial forces and V-V laxities were measured from 0° to 120° flexion with an unmodified reference tibial component and modified tibial components that introduced ±1° and ±2° V-V malalignments from the reference component to overstuff either the medial or lateral compartment. Changes in the tibial forces were most sensitive to V-V malalignments at 0° flexion (medial = 118±34 N/deg valgus malalignment and lateral = 79±20 N/deg varus malalignment). The varus and valgus laxities were most sensitive to V-V malalignments at 30° flexion (−0.6±0.1 deg/deg varus malalignment) and 120° flexion (−0.4±0.2 deg/deg valgus malalignment), respectively. The maximum average signal-to-noise ratios of the sensitivities to changes in tibial forces and V-V laxities were 8.4 deg-1 and 0.9 deg-1, respectively, based on reported measurement errors (i.e., noise) using current intraoperative technologies (14 N and 0.7°). Because of the greater signal-to-noise ratios, measuring tibial forces is more useful than V-V laxities for identifying and correcting V-V malalignments of the tibial component that overstuff a compartment.

Clinical Significance

The sensitivities of tibial forces provide objective guidance to surgeons performing V-V recuts of the tibia.
Sporadic activation of an oxidative stress-dependent NRF2–p53 signaling network in breast epithelial spheroids and premalignancies
Authors: Pereira Elizabeth J. , Burns Joseph S. , Lee Christina Y. , Marohl Taylor , Calderon Delia , Wang Lixin , Atkins Kristen A. , Wang Chun-Chao , Janes Kevin A.
Published: December 2019

Breast–mammary epithelial cells experience different local environments during tissue development and tumorigenesis. Microenvironmental heterogeneity gives rise to distinct cell-regulatory states whose identity and importance are just beginning to be appreciated. Cellular states diversify when clonal 3D spheroids are cultured in basement membrane, and prior transcriptomic analyses identified a state associated with stress tolerance and poor response to anticancer therapeutics. Here, we examined the regulation of this state and found that it is jointly coordinated by the NRF2 and p53 pathways, which are co-stabilized by spontaneous oxidative stress within the 3D cultures. Inhibition of NRF2 or p53 individually disrupts some of the transcripts defining the regulatory state but does not yield a notable phenotype in nontransformed breast epithelial cells. In contrast, combined perturbation prevents 3D growth in an oxidative stress-dependent manner. By integrating systems models of NRF2 and p53 signaling together as a single oxidative-stress network, we recapitulate these observations and make predictions about oxidative stress profiles during 3D growth. Similar coordination of NRF2 and p53 signaling is observed in normal breast epithelial tissue and hormone-negative ductal carcinoma in situ lesions. However, the pathways are uncoupled in triple-negative breast cancer, a subtype in which p53 is usually mutated. Using the integrated model, we reconcile the different NRF2-knockdown phenotypes of triple-negative cancer lines with their inferred handling of oxidative stress. Our results point to an oxidative stress-tolerance network that is important for single cells during glandular development and the early stages of breast cancer.

One Sentence Summary

Reactive oxygen species co-stabilize a non-oncogene and a tumor suppressor for triple-negative breast cancer when cells are surrounded by basement-membrane ECM.
Investigating the Role of Hypoxia-Induced Migration in Glioblastoma Growth Rates
Authors: Curtin Lee , Hawkins-Daarud Andrea , van der Zee Kristoffer G. , Swanson Kristin R. , Owen Markus R.
Published: December 2019

We analyze the wave-speed of the Proliferation Invasion Hypoxia Necrosis Angiogenesis (PIHNA) model that was previously created and applied to simulate the growth and spread of glioblastoma (GBM), a particularly aggressive primary brain tumor. We extend the PIHNA model by allowing for different hypoxic and normoxic cell migration rates and study the impact of these differences on the wave-speed dynamics. Through this analysis, we find key variables that drive the outward growth of the simulated GBM. We find a minimum tumor wave-speed for the model; this depends on the migration and proliferation rates of the normoxic cells and is achieved under certain conditions on the migration rates of the normoxic and hypoxic cells. If the hypoxic cell migration rate is greater than the normoxic cell migration rate above a threshold, the wave-speed increases above the predicted minimum. This increase in wave-speed is explored through an eigenvalue and eigenvector analysis of the linearized PIHNA model, which yields an expression for this threshold. The PIHNA model suggests that an inherently faster-diffusing hypoxic cell population can drive the outward growth of a GBM as a whole, and that this effect is more prominent for faster proliferating tumors that recover relatively slowly from a hypoxic phenotype.
Measurement and models accounting for cell death capture hidden variation in compound response
Authors: Bae Song Yi , Guan Ning , Yan Rui , Warner Katrina , Meyer Aaron S
Published: December 2019

Cancer cell sensitivity or resistance is almost universally quantified through a direct or surrogate measure of cell number. However, compound responses can occur through many distinct phenotypic outcomes including changes in cell growth, apoptosis, and non-apoptotic cell death. These outcomes have distinct effects on the tumor microenvironment, immune responses, and resistance mechanisms. Here, we show that quantifying cell viability alone is insufficient to distinguish between these compound responses. Using an alternative assay and drug response analysis amenable to high-throughput measurement, we find that compounds with identical viability outcomes can have very different effects on cell growth and death. Moreover, compound pairs with additive cell growth and death effects can appear synergistic when only assessed by viability. Overall, these results demonstrate an approach to incorporating measurements of cell death when characterizing a pharmacologic response.

Summary Points

Measurements of solely live cell numbers mask important differences in compound effects.

Additive effects on growth and death rates can appear synergistic when analyzed solely via live cell number.

Automated imaging can provide reasonable throughput to analyze cell response in terms of cell growth and death, and endpoint analysis is similarly informative.
EpitoCore: mining conserved epitope vaccine candidates in the core proteome of multiple bacteria strains
Authors: Fiuza T.S. , Lima J.P.M.S. , de Souza G.A.
Published: December 2019

In reverse vaccinology approaches, complete proteomes of bacteria are submitted to multiple computational prediction steps in order to filter proteins that are possible vaccine candidates. Most available tools perform such analysis only in a single strain, or a very limited number of strains. But the vast amount of genomic data had shown that most bacteria contain pangenomes, i.e. their genomic information contains core, conserved genes, and random accessory genes specific to each strain. Therefore, it is of the utmost importance to define core proteins, and also core epitopes, in reverse vaccinology methods. EpitoCore is a decision-tree pipeline developed to fulfill that need. It provides surfaceome prediction of proteins from related strains, defines clusters of core proteins within those, calculate the immunogenicity of such clusters, predicts epitopes for a given set of MHC alleles defined by the user, and then reports if epitopes are located extracellularly and if they are conserved among the core homologues. Pipeline performance is illustrated by mining peptide vaccine candidates inMycobacterium avium hominissuisstrains. From a total proteome of approximately 4,800 proteins per strain, EpitoCore mined 103 highly immunogenic core homologues located at cell surface, many of those related to virulence and drug resistance. Conserved epitopes identified among these homologues allows the users to define sets of peptides with potential to immunize the largest coverage of tested HLA alleles using peptide-based vaccines. Therefore, EpitoCore is able to provide automated identification of conserved epitopes in bacterial pangenomic datasets.
Pay to know me in your eyes: A computational account and oxytocin modulation of social evaluation
Authors: Wang Danyang , Ma Yina
Published: December 2019

People are eager to know and recast the self in the eyes of others, even at a personal cost. However, it remains unknown what drives people to pursue costly evaluations of the self. Here, we propose that the evaluation of the self is valuable and that such subjective value placed on evaluation drives the costly-to-know behavior. By measuring the amount of money that individuals would forgo for the opportunity to know evaluations from other people (social evaluation) or a computer program (non-social evaluation), we quantified the subjective value individuals assigned to the evaluation on the self. The results from 5 studies (n= 375) lent cognitive and computational support for this hypothesis. Furthermore, the subjective value was modulated by the source and valence of the evaluation. Participants equally valued positive and negative non-social evaluations, characterized by a shared unknown aversion computation. However, individuals computed independent unknown aversion towards positive and negative social evaluations and placed a higher value on the opportunity to know another person’s evaluation on positive than negative aspects. Such a valence-dependent valuation of the social evaluation was facilitated by oxytocin, a neuropeptide linked to linked to social feedback learning and valuation processes, which decreased the value ascribed to negative social evaluation. Taken together, the current study reveals the psychological and computational processes underlying self-image formation and updating and suggests a role of oxytocin in modulating the value of social evaluation.
End-to-end multitask learning, from protein language to protein features without alignments
Authors: Elnaggar Ahmed , Heinzinger Michael , Dallago Christian , Rost Burkhard
Published: December 2019

Correctly predicting features of protein structure and function from amino acid sequence alone remains a supreme challenge for computational biology. For almost three decades, state-of-the-art approaches combined machine learning and evolutionary information from multiple sequence alignments. Exponentially growing sequence databases make it infeasible to gather evolutionary information for entire microbiomes or meta-proteomics. On top, for many important proteins (e.g. dark proteome and intrinsically disordered proteins) evolutionary information remains limited. Here, we introduced a novel approach combining recent advances of Language Models (LMs) with multi-task learning to successfully predict aspects of protein structure (secondary structure) and function (cellular component or subcellular localization) without using any evolutionary information from alignments. Our approach fused self-supervised pre-training LMs on an unlabeled big dataset (UniRef50, corresponding to 9.6 billion words) with supervised training on labelled high-quality data in one single end-to-end network. We provided a proof-of-principle for the novel concept through the semi-successful per-residue prediction of protein secondary structure and through per-protein predictions of localization (Q10=69%) and the distinction between integral membrane and water-soluble proteins (Q2=89%). Although these results did not reach the levels obtained by the best available methods using evolutionary information from alignments, these less accurate multi-task predictions have the advantage of speed: they are 300-3000 times faster (where HHblits needs 30-300 seconds on average, our method needed 0.045 seconds). These new results push the boundaries of predictability towards grayer and darker areas of the protein space, allowing to make reliable predictions for proteins which were not accessible by previous methods. On top, our method remains scalable as it removes the necessity to search sequence databases for evolutionary related proteins.
Topographic Signatures of Global Object Perception in Human Visual Cortex
Authors: Stoll Susanne , Finlayson Nonie J. , Schwarzkopf D. Samuel
Published: December 2019

Our visual system readily groups dynamic fragmented input into global objects. How the brain represents such perceptual grouping remains however unclear. To address this question, we recorded brain responses using functional magnetic resonance imaging whilst observers perceived a dynamic bistable stimulus that could either be perceived globally (i.e., as a grouped and coherently moving shape) or locally (i.e., as ungrouped and incoherently moving elements). We further estimated population receptive fields and used these to back-project the brain activity during stimulus perception into visual space via a searchlight procedure. Global perception resulted in non-topographic suppression of responses in lower visual cortex accompanied by wide-spread enhancement in higher object-sensitive cortex. However, follow-up experiments indicated that higher object-sensitive cortex is suppressed if global perception lacks shape grouping, and that grouping-related suppression can be diffusely confined to stimulated sites once stimulus size is reduced. These results speak against a rigid between-area response amplitude code acting as a generic grouping mechanism and point to a within-area response amplitude code mediating the perception of figure and ground.
Increased yields of duplex sequencing data by a series of quality control tools
Authors: Povysil Gundula , Heinzl Monika , Salazar Renato , Stoler Nicholas , Nekrutenko Anton , Tiemann-Boege Irene
Published: December 2019

Duplex sequencing is currently the most reliable method to identify ultra-low frequency DNA variants by grouping sequence reads derived from the same DNA molecule into families with information on the forward and reverse strand. However, only a small proportion of reads are assembled into duplex consensus sequences, and reads with potentially valuable information are discarded at different steps of the bioinformatics pipeline, especially reads without a family. We developed a bioinformatics tool-set that analyses the tag and family composition with the purpose to understand data loss and implement modifications to maximize the data output for the variant calling. Specifically, our tools show that tags contain PCR and sequencing errors that contribute to data loss and lower DCS yields. Our tools also identified chimeras, which result in unpaired families that do not form DCS. Finally, we also developed a tool called Variant Analyzer that re-examines variant calls from raw reads and provides different summary data that categorizes the confidence level of a variant call by a tier-based system. We demonstrate that this tool identified false positive variants tagged by the tier-based classification. Furthermore, with this tool we can include reads without a family and check the reliability of the call, which increases substantially the sequencing depth for variant calling, a particular important advantage for low-input samples or low-coverage regions.
Demographic history and genomics of local adaptation in blue tit populations
Authors: Charles Perrier , Quentin Rougemont , Anne Charmantier
Published: December 2019

Understanding the genomic processes underlying local adaptation is a central aim of modern evolutionary biology. This task requires identifying footprints of local selection but also estimating spatio-temporal variation in population demography and variation in recombination rate and diversity along the genome. Here, we investigated these parameters in blue tit populations inhabiting deciduous versus evergreen forests and insular versus mainland areas, in the context of a previously described strong phenotypic differentiation. Neighboring population pairs of deciduous and evergreen habitats were weakly genetically differentiated (FST = 0.004 on average), nevertheless with a statistically significant effect of habitat type on the overall genetic structure. This low differentiation was consistent with the strong and long-lasting gene flow between populations, inferred by demographic modeling. In turn, insular and mainland populations were moderately differentiated (FST = 0.08 on average), in line with the inference of moderate ancestral migrations, followed by isolation since the end of the last glaciation. Effective population sizes were overall large, yet smaller on the island than on the mainland. Weak and non-parallel footprints of divergent selection between deciduous and evergreen populations were consistent with their high connectivity and the probable polygenic nature of local adaptation in these habitats. In turn, stronger footprints of divergent selection were identified between long isolated insular versus mainland birds, and were more often found in regions of low recombination as expected from theory. Lastly, we identified a genomic inversion on the mainland, spanning 2.8Mb. These results provide insights into the demographic history and genetic architecture of local adaptation in blue tit populations at multiple geographic scales.
Why the tumor cell metabolism is not that abnormal
Authors: Jacquet Pierre , Stéphanou Angélique
Published: December 2019

The cell energy metabolism is a multifactorial and evolving process that we address with a theoretical approach in order to decipher the functioning of the core system of the glycolysis-OXPHOS relationship. The model is based on some key experimental observations and well established facts. It emphasizes the role of lactate as a substrate, as well as the central role of pyruvate in the regulation of the metabolism. The simulations show how imposed environmental constraints and imposed energy requirements push the cell to adapt its metabolism to sustain its needs. The results highlight the cooperativeness of the two metabolic modes and allows to revisit the notions ofmetabolic switchandmetabolic reprogramming. Our results thus tend to show that the Warburg effect is not an inherent characteristic of the tumor cell, but a spontaneous and transitory adaptation mechanism to a disturbed environment. This means that the tumor cell metabolism is not fundamentally different from that of a normal cell. This has implications on the way therapies are being considered. The quest to normalize the tumor acidity could be a good strategy.

Author Summary

Cancer cells metabolism focuses the interest of the cancer research community. Although this process is intensely studied experimentally, there exists very few theoretical models that tackle this issue. One main reason is the extraordinary complexity of the metabolism that involves many inter-related regulation networks which makes it illusory to recreate computationally this complexity. In this study we propose a simplified model of the metabolism which focuses on the interrelation of the three main energetic metabolites that are oxygen, glucose and lactate with the aim to better understand the dynamic of the core system of the glycolysis-OXPHOS relationship. However simple, the model highlights the main rules that allow the cell to dynamically adapt its metabolism to its changing environment. It moreover allows to address this impact at the tissue scale. Simulations performed in a spheroid exhibit non-trivial spatial heterogeneity of the energy metabolism. It further reveals that the metabolic features that are commonly assigned to cancer cells are not necessarily due to cell intrinsic abnormality. They can emerge spontaneously because of the disregulated over-acidic environment.
Prolonged inflammation leads to ongoing damage after spinal cord injury
Authors: Kwiecien Jacek M. , Dabrowski Wojciech , Dąbrowska-Bouta Beata , Sulkowski Grzegorz , Oakden Wendy , Kwiecien-Delaney Christian J. , Yaron Jordan R. , Zhang Liqiang , Schutz Lauren , Marzec-Kotarska Barbara , Stanisz Greg J. , Karis John P. , Struzynska Lidia , Lucas Alexandra R.
Published: December 2019

The pathogenesis of spinal cord injury (SCI) remains poorly understood and treatment remains limited. Emerging evidence indicates the severity of post-SCI inflammation and an ongoing controversy in the roles of astrocytes with studies identifying astrocytes as associated both with ongoing inflammation and damage as well as potentially having a protective role. We have completed an extensive systematic study with MRI, histopathology, proteomics and ELISA analyses designed to further define the severe protracted and damaging inflammation after SCI in a rat model. We have identified 3 distinct phases of SCI: acute (first 2 days), inflammatory (starting day 3) and resolution (>3 months) in 16 weeks follow up. Actively phagocytizing, CD68+/CD163- macrophages infiltrate myelin-rich necrotic areas converting them into cavities of injury (COI) when deep in the spinal cord. Alternatively, superficial SCI areas are infiltrated by granulomatous tissue, or arachnoiditis where glial cells are obliterated. In the COI, CD68+/CD163- macrophage numbers reach a maximum in the first 4 weeks and then decline. Myelin phagocytosis is present at 16 weeks indicating ongoing inflammatory damage. The COI and arachnoiditis are defined by a wall of progressively hypertrophied astrocytes. MR imaging indicates persistent spinal cord edema that is linked to the severity of inflammation. Microhemorrhages in the spinal cord around the lesion are eliminated, presumably by reactive astrocytes within the first week post-injury. Acutely increased levels of TNF-α, IL-1β, IFN-γ and other pro-inflammatory cytokines, chemokines and proteases decrease and anti-inflammatory cytokines increase in later phases. In this study we elucidated a number of fundamental mechanisms in pathogenesis of SCI and have demonstrated a close association between progressive astrogliosis and reduction in the severity of inflammation.
MicroRNA miR-100 decreases glioblastoma growth by targeting SMARCA5 and ErbB3 in tumor-initiating cells
Authors: Alrfaei Bahauddeen M. , Vemuganti Raghu , Kuo John S.
Published: December 2019

Glioblastoma multiforme (GBM) is the most aggressive and most frequently diagnosed malignant human glioma. Despite the best available standard of care (surgery, radiation, and chemotherapy), the median survival of GBM patients is less than 2 years. Many recent studies have indicated that microRNAs (miRNAs) are important for promoting or reducing/limiting GBM growth. In particular, we previously showed that GBMs express decreased levels of miR-100 relative to control tissue and that restoring miR-100 expression reduced GBM tumorigenicity by modulating SMRT/NCOR2 (Nuclear Receptor Corepressor 2). Here, we demonstrate that miR-100 overexpression decreases expression of the stem cell markers, nestin and L1CAM, and decreases proliferation of GBM tumor-initiating cells (GBM stem-like cells). We further show that miR-100-mediated anti-tumorigenic activity limits the activity of SMARCA5 and its downstream target STAT3 (known as mTOR-STAT3-Notch pathway). In addition, we report ErbB3 (Her3) as a putative miR-100 target, including inhibition of its downstream AKT and ERK signaling pathways.
Room without a view – den construction in relation to body size in brown bears
Authors: Shiratsuru Shotaro , Friebe Andrea , Swenson Jon E. , Zedrosser Andreas
Published: December 2019

Hibernation is an adaptive strategy to survive harsh winter conditions and food shortage. The use of well-insulated winter dens helps animals minimize energy loss during hibernation. Brown bears (Ursus arctos) commonly use excavated dens for hibernation. Physical properties of excavated dens, such as the amount of space between a bear and the inner wall, wall/roof thickness, and bedding materials, are expected to impact heat retention and energy conservation of bears. The objective of this study was to examine the impact of physical properties of excavated dens on energy conservation in hibernating bears. Our hypothesis was that bears excavate dens in a way to minimize heat loss and optimize energy conservation during hibernation. We predicted that physical properties of excavated dens would significantly affect the bears’ post-hibernation body condition. To test our hypothesis and prediction, we analyzed data collected from brown bears in Sweden with linear mixed effects models, examining (i) what factors affect den-excavation behavior and (ii) if physical properties of excavated dens affect post-hibernation body condition. We found that bears excavated a den cavity in relation to their body size, that older bears tended to excavate better-fitting den cavities compared to young bears, and that the physical properties of excavated dens did not significantly affect a bears’ post-hibernation body condition. Older bears excavated better-fitting den cavities, suggesting a potentially experience-based shift with age in den-excavation behavior and an optimum cavity size relative to a bear’s body size. The strong year effect shown by the most parsimonious model for post-hibernation body condition suggests that variations in physical properties of excavated dens are possibly negligible, compared to the large annual variations in biotic and abiotic factors affecting pre-hibernation body condition and heat loss during hibernation.
Epiviz File Server: Query, Transform and Interactively Explore Data from Indexed Genomic Files
Authors: Kancherla Jayaram , Yang Yifan , Chae Hyeyun , Bravo Hector Corrada
Published: December 2019

Genomic data repositories like The Cancer Genome Atlas (TCGA), Encyclopedia of DNA Elements (ENCODE), Bioconductor’s AnnotationHub and ExperimentHub etc., provide public access to large amounts of genomic data as flat files. Researchers often download a subset of files data from these repositories to perform their data analysis. As these data repositories become larger, researchers often face bottlenecks in their exploratory data analysis. Based on the concepts of a NoDB paradigm, we developed epivizFileServer, a Python library that implements an in-situ data query system for local or remotely hosted indexed genomic files, not only for visualization but also data manipulation. The File Server library decouples data from analysis workflows and provides an abstract interface to define computations independent of the location, format or structure of the file.
Bipartite Tight Spectral Clustering (BiTSC) Algorithm for Identifying Conserved Gene Co-clusters in Two Species
Authors: Sun Yidan Eden , Zhou Heather J. , Li Jingyi Jessica
Published: December 2019

Gene clustering is a widely-used technique that has enabled computational prediction of unknown gene functions within a species. However, it remains a challenge to refine gene function prediction by leveraging evolutionarily conserved genes in another species. This challenge calls for a new computational algorithm to identify gene co-clusters in two species, so that genes in each co-cluster exhibit similar expression levels in each species and strong conservation between the species. Here we develop the bipartite tight spectral clustering (BiTSC) algorithm, which identifies gene co-clusters in two species based on gene orthology information and gene expression data. BiTSC novelly implements a formulation that encodes gene orthology as a bipartite network and gene expression data as node covariates. This formulation allows BiTSC to adopt and combine the advantages of multiple unsupervised learning techniques: kernel enhancement, bipartite spectral clustering, consensus clustering, tight clustering, and hierarchical clustering. As a result, BiTSC is a flexible and robust algorithm capable of identifying informative gene co-clusters without forcing all genes into co-clusters. Another advantage of BiTSC is that it does not rely on any distributional assumptions. Beyond cross-species gene co-clustering, BiTSC also has wide applications as a general algorithm for identifying tight node co-clusters in any bipartite network with node covariates. We demonstrate the accuracy and robustness of BiTSC through comprehensive simulation studies. In a real data example, we use BiTSC to identify conserved gene co-clusters of D. melanogaster and C. elegans, and we perform a series of downstream analysis to both validate BiTSC and verify the biological significance of the identified co-clusters.
Massively parallel discovery of human-specific substitutions that alter neurodevelopmental enhancer activity
Authors: Uebbing Severin , Gockley Jake , Reilly Steven K. , Kocher Acadia A. , Geller Evan , Gandotra Neeru , Scharfe Curt , Cotney Justin , Noonan James P.
Published: December 2019

Genetic changes that altered the function of gene regulatory elements have been implicated in the evolution of the human brain. However, identifying the particular changes that modified regulatory activity during neurodevelopment remains challenging. Here we used massively parallel enhancer assays in human neural stem cells to measure the impact of 32,776 human-specific substitutions on enhancer activity in 1,363 Human Accelerated Regions (HARs) and 3,027 Human Gain Enhancers (HGEs), which include enhancers with novel activities in humans. We found that 31.9% of active HARs and 36.4% of active HGEs exhibited differential activity between human and chimpanzee. This enabled us to isolate the effects of 401 human-specific substitutions from other types of genetic variation in HARs and HGEs. Substitutions acted in both an additive and non-additive manner to alter enhancer activity. Human-specific substitutions altered predicted binding sites for a specific set of human transcription factors (TFs) that were a subset of TF binding sites associated with enhancer activity in our assay. Substitutions within HARs, which are overall highly constrained compared to HGEs, showed smaller effects on enhancer activity, suggesting that the impact of human-specific substitutions may be buffered in enhancers with constrained ancestral functions. Our findings yield insight into the mechanisms by which human-specific genetic changes impact enhancer function and provide a rich set of candidates for experimental studies of regulatory evolution in humans.
Clair: Exploring the limit of using a deep neural network on pileup data for germline variant calling
Authors: Luo Ruibang , Wong Chak-Lim , Wong Yat-Sing , Tang Chi-Ian , Liu Chi-Man , Leung Chi-Ming , Lam Tak-Wah
Published: December 2019

Single-molecule sequencing technologies have emerged in recent years and revolutionized structural variant calling, complex genome assembly, and epigenetic mark detection. However, the lack of a highly accurate small variant caller has limited the new technologies from being more widely used. In this study, we present Clair, the successor to Clairvoyante, a program for fast and accurate germline small variant calling, using single molecule sequencing data. For ONT data, Clair achieves the best precision, recall and speed as compared to several competing programs, including Clairvoyante, Longshot and Medaka. Through studying the missed variants and benchmarking intentionally overfitted models, we found that Clair may be approaching the limit of possible accuracy for germline small variant calling using pileup data and deep neural networks. Clair requires only a conventional CPU for variant calling and is an open source project available at https://github.com/HKU-BAL/Clair.
Set1/COMPASS repels heterochromatin invasion at euchromatic sites by disrupting Suv39/Clr4 activity and nucleosome stability
Authors: Greenstein R.A. , Barrales Ramon R. , Sanchez Nicholas A. , Bisanz Jordan E. , Braun Sigurd , Al-Sady Bassem
Published: December 2019

Protection of euchromatin from invasion by gene-repressive heterochromatin is critical for cellular health and viability. In addition to constitutive loci such as pericentromeres and subtelomeres, heterochromatin can be found interspersed in gene-rich euchromatin, where it regulates gene expression pertinent to cell fate. While heterochromatin and euchromatin are globally poised for mutual antagonism, the mechanisms underlying precise spatial encoding of heterochromatin containment within euchromatic sites remain opaque. We investigated ectopic heterochromatin invasion by manipulating the fission yeast mating type locus boundary using a single-cell spreading reporter system. We found that heterochromatin repulsion is locally encoded by Set1/COMPASS on certain actively transcribed genes and that this protective role is most prominent at heterochromatin islands, small domains interspersed in euchromatin that regulate cell fate specifiers. Sensitivity to invasion by heterochromatin, surprisingly, is not dependent on Set1 altering overall gene expression levels. Rather, the gene-protective effect is strictly dependent on Set1's catalytic activity. H3K4 methylation, the Set1 product, antagonizes spreading in two ways: directly inhibiting catalysis by Suv39/Clr4 and locally disrupting nucleosome stability. Taken together, these results describe a mechanism for spatial encoding of euchromatic signals that repel heterochromatin invasion.
Striving for sustainable graduate careers
Authors: Donald William E. , Baruch Yehuda , Ashleigh Melanie J.
Published: December 2019

Purpose

The purpose of this paper is to conceptually articulate the differing needs of graduates and graduate employers, which can be competing or complementary in nature. Drawing from theoretical frameworks of career ecosystems and the new psychological contract, a set of propositions are presented using three themes: career management, development of talent and technological change.

Design/methodology/approach

A conceptual design offering a conceptual model through adopting the career ecosystem and new psychological contract as a framework.

Findings

These propositions offer a new conceptual model, which provides a practical contribution by articulating sustainability of graduates’ careers through employability at the graduate level and competitive advantage at the employer level.

Originality/value

The paper offers important contributions to theory by connecting career management and vocational career literature through acknowledging shared constructs of life-long learning and sustainable employability for graduates. These two streams are often developed in parallel, thus this paper helps to bridge the gaps in respective research agendas. This paper therefore has the originality of helping to advance the fields of career theory and sustainable human resource management.
Effect of finite wall thickness on entropy generation and natural convection in a nanofluid-filled partially heated square cavity
Authors: Ishak Muhamad Safwan , Alsabery Ammar I. , Chamkha A. , Hashim Ishak
Published: December 2019

Purpose

The purpose of this paper is to study the effects of finite wall thickness on the natural convection and entropy generation in a square cavity filled with Al2O3–water nanofluid in the presence of bottom heat source.

Design/methodology/approach

The moving isothermal heater was placed on the bottom solid wall. The vertical walls (left and right walls) were fully maintained at low temperatures. The rest of the bottom solid wall along with the top horizontal wall was kept adiabatic. The boundaries of the domain are assumed to be impermeable; the fluid within the cavity is a water-based nanofluid having Al2O3 nanoparticles. The Boussinesq approximation is applicable. The dimensionless governing equations subject to the selected boundary conditions are solved using the finite difference method. The current proposed numerical method is proven excellent through comparisons with the existing experimental and numerical published studies.

Findings

Numerical results were demonstrated graphically in several forms including streamlines, isotherms and local entropy generation, as well as the local and average Nusselt numbers. The results reveal that the thermal conductivity and thickness of the solid wall are important control parameters for optimization of heat transfer and Bejan number within the partially heated square cavity.

Originality/value

According to the past research studies mentioned above and to the best of the authors’ knowledge, the gap regarding the problem with entropy generation analysis and natural convection in partially heated square cavity has yet to be filled. Because of this, this study aims to investigate the entropy generation analysis as well as the natural convection in nanofluid-filled square cavity which was heated partially. A square cavity with an isothermal heater located on the bottom solid horizontal wall of the cavity and partly cold sidewalls are essential problems in thermal processing applications. Hence, the authors believe that this present work will be a valuable contribution in improving the thermal performance.