bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characteristics of patients presenting, and not presenting, to the emergency department during the early days of COVID-19
Authors: Westgard Bjorn C. , Morgan Matthew W. , Vazquez-Benitez Gabriela , Erickson Lauren O. , Zwank Michael D. 
Published: May 2020

AbstractObjectiveSocietal responses to the COVID-19 pandemic have had a substantial effect upon the number of patients seeking healthcare. An initial step in estimating the impact of these changes is characterizing the patients, visits, and diagnoses for whom care is being delayed or deferred.MethodsWe conducted an observational study, examining demographics and diagnoses for all patient visits to the ED of an urban Level-1 trauma center before and after the state declaration and compared them to visits from a similar period in 2019. We estimated the ratios of the before and after periods using Poisson regression, calculated the percent change with respect to 2019 for total ED visits, patient characteristics, and diagnoses, and then evaluated the interactions between each factor and the overall change in ED visits.ResultsThere was a significant 35.2% drop in overall ED visits after the state declaration. Disproportionate declines were seen in visits by pediatric and older patients, women, and Medicare recipients as well as for presentations of syncope, cerebrovascular accidents, urolithiasis, abdominal and back pain. Significantly disproportionate increases were seen in ED visits for potential symptoms of COVID-19, including URIs, shortness of breath, and chest pain.ConclusionsPatient concerns about health care settings and public health have significantly altered care-seeking during the COVID-19 pandemic. Overall and differential declines in ED visits for certain demographic groups and disease processes should prompt efforts to encourage care-seeking and research to monitor for the morbidity and mortality that is likely to result from delayed or deferred care.
Pontine Lesions Impair Visually Guided Eye and Hand Movements
Authors: Bunjes Friedemann , Thier Peter 
Published: May 2020

SummaryAlthough animal research and some rare human case reports suggest that lesions of the dorsal pons yield saccadic and smooth pursuit eye movement deficits, little is known about the functional topology of the human pontine nuclei (PN) and whether limb movements are similarly affected as eye movements. Saccadic as well as SP eye and pointing movements were measured in six patients with lesions in the PN region. Five patients of the six exhibited dysmetric saccades, whilst smooth pursuit gain was reduced in four. Pontine lesions also alter the relationship between amplitude, velocity, and velocity skewness of saccadic eye movements. Limb movement trajectories were more curved in four patients. The results suggest that the lesions impair a general calibration mechanism that uses the parallel fiber-Purkinjecell synapse in the cerebellar cortex to adjust the timing of muscle innervation in visually guided oculomotor as well as limb movement tasks.
Whole exome sequencing reveals a wide spectrum of ciliary gene mutations in nonsyndromic biliary atresia
Authors: Lam Wai-Yee , So Man-Ting , Hsu Jacob Shujui , Chung Patrick Ho-Yu , Ngo Diem Ngoc , Nguyen Pham Anh Hoa , Mitchison Hannah M. , Jenkins Dagan , O’Callaghan Christopher , Sham Pak-Chung , Garcia-Barceló Maria-Mercè , Lui Vincent Chi-Hang , Tang Clara Sze-Man , Tam Paul Kwong-Hang 
Published: May 2020

ABSTRACTBiliary atresia (BA) is the most common obstructive cholangiopathy in neonates, often progressing to end-stage cirrhosis. BA pathogenesis is believed to be multifactorial, but the genetic contribution remains poorly defined. We conducted exome sequencing on 89 nonsyndromic BA trios. In 31.5% of the patients, rare and deleterious de novo, homozygous recessive and/or compound heterozygous variants were detected in liver-expressed ciliary genes of diverse ciliary functions. Enrichment of deleterious mutations in liver-expressed ciliary geneset was significant compared to 148 control trios (OR 2.58, 95% CI 1.15-6.07). KIF3B, PCNT and TTC17 are essential for ciliogenesis. Reduced ciliary proteins expression were detected in the BA livers with KIF3B and TTC17 mutations. CRISPR/Cas9-engineered zebrafish knockouts of KIF3B, PCNT and TTC17 displayed reduced biliary flow. Our findings support a larger genetic contribution to nonsyndromic BA risk than expected. Ciliary gene mutations leading to cholangiocyte cilia malformation and dysfunction could be a key biological mechanism in BA pathogenesis.
AI based Chest X-Ray (CXR) Scan Texture Analysis Algorithm for Digital Test of COVID-19 Patients
Authors: Al-Karawi Dhurgham , Al-Zaidi Shakir , Polus Nisreen , Jassim Sabah 
Published: May 2020

AbstractChest Imaging in COVID-19 patient management is becoming an essential tool for controlling the pandemic that is gripping the international community. It is already indicated in patients with COVID-19 and worsening respiratory status. The rapid spread of the pandemic to all continents, albeit with a nonuniform community transmission, necessitates chest imaging for medical triage of patients presenting moderate-severe clinical COVID-19 features. This paper reports the development of innovative machine learning schemes for the analysis of Chest X-Ray (CXR) scan images of COVID-19 patients in almost real-time, demonstrating significantly high accuracy in identifying COVID-19 infection. The performance testing was conducted on a combined dataset comprising CXRs of positive COVID-19 patients, patients with various viral and bacterial infections, as well as persons with a clear chest. The test resulted in successfully distinguishing CXR COVID-19 infection from the other cases with an average accuracy of 94.43%, sensitivity 95% and specificity 93.86%.Key StrengthsThe development of efficient automatic AI texture analysis schemes for classification of chest X-Ray of COVID-19 patients with highest accuracy with equally low false negative and positive rates. Decisions would be supported by visual evidence viewable by clinician and help speed up the initial assessment process of new suspected cases, especially in a resource-constrained environment.
Causal inference for heritable phenotypic risk factors using heterogeneous genetic instruments
Authors: Wang Jingshu , Zhao Qingyuan , Bowden Jack , Hemani Gibran , Smith George Davey , Small Dylan S. , Zhang Nancy R. 
Published: May 2020

AbstractOver a decade of genome-wide association studies (GWAS) have led to the finding of extreme polygenicity of complex traits. The phenomenon that “all genes affect every complex trait” complicates Mendelian Randomization (MR) studies, where natural genetic variations are used as instruments to infer the causal effect of heritable risk factors. We reexamine the assumptions of existing MR methods and show how they need to be clarified to allow for pervasive horizontal pleiotropy and heterogeneous effect sizes. We propose a comprehensive framework GRAPPLE to analyze the causal effect of target risk factors with heterogeneous genetic instruments and identify possible pleiotropic patterns from data. By using GWAS summary statistics, GRAPPLE can efficiently use both strong and weak genetic instruments, detect the existence of multiple pleiotropic pathways, determine the causal direction and perform multivariable MR to adjust for confounding risk factors. With GRAPPLE, we analyze the effect of blood lipids, body mass index, and systolic blood pressure on 25 disease outcomes, gaining new information on their causal relationships and the potential pleiotropic pathways.
A mouse bio-electronic nose for sensitive and versatile chemical detection
Authors: Shor Erez , Herrero-Vidal Pedro , Dewan Adam , Uguz Ilke , Curto Vincenzo F. , Malliaras George G. , Savin Cristina , Bozza Thomas , Rinberg Dmitry 
Published: May 2020

AbstractWhen it comes to simultaneous versatility, speed, and specificity in detecting volatile chemicals, biological olfactory systems far outperform all artificial chemical detection devices. Consequently, the use of trained animals for chemical detection in security, defense, healthcare, agriculture, and other applications has grown astronomically. However, the use of animals in this capacity requires extensive training and behavior-based communication. Here we propose an alternative strategy, a bio-electronic nose, that capitalizes on the superior capability of the mammalian olfactory system, but bypasses behavioral output by reading olfactory information directly from the brain. We engineered a brain-machine interface that captures neuronal signals from an early stage of olfactory processing in awake mice, and used machine learning techniques to form a sensitive and selective chemical detector. We chronically implanted a grid electrode array on the surface of the mouse olfactory bulb and systematically recorded responses to a large battery of odorants and odorant mixtures across a wide range of concentrations. The bio-electronic nose has a comparable sensitivity to the trained animal and can detect odors on a variable background. We also introduce a novel genetic engineering approach designed to improve the sensitivity of our bio-electronic nose for specific chemical targets. Our bio-electronic nose outperforms current detection methods and unlocks a wide spectrum of civil, medical and environmental applications.
Nintedanib Targets KIT D816V Neoplastic Cells Derived from Induced Pluripotent Stem cells of Systemic Mastocytosis
Authors: Toledo Marcelo A. S. , Gatz Malrun , Sontag Stephanie , Gleixner Karoline V. , Eisenwort Gregor , Feldberg Kristina , Kluge Frederick , Guareschi Riccardo , Rossetti Giulia , Sechi Antonio S. , Dufva Olli M. J. , Mustjoki Satu M. , Maurer Angela , Schüler Herdit M. , Goetzke Roman , Braunschweig Till , Simonowski Anne , Panse Jens , Jawhar Mohamad , Reiter Andreas , Hilberg Frank , Ettmayer Peter , Wagner Wolfgang , Koschmieder Steffen , Brümmendorf Tim H. , Valent Peter , Chatain Nicolas , Zenke Martin 
Published: May 2020

AbstractTheKITD816V mutation is found in more than 80% of patients with systemic mastocytosis (SM) and is key to neoplastic mast cell (MC) expansion and accumulation in affected organs.KITD816V therefore represents a prime therapeutic target for SM. Here we generated a panel of patient-specificKITD816V induced pluripotent stem cells (iPSCs) from patients with aggressive SM (ASM) and mast cell leukemia (MCL) to develop a patient-specific SM disease model for mechanistic and drug discovery studies.KITD816V iPSCs differentiated into neoplastic hematopoietic progenitor cells and MCs with patient-specific phenotypic features, thereby reflecting the heterogeneity of the disease. CRISPR/Cas9n-engineeredKITD816V human embryonic stem cells (ESCs), when differentiated into hematopoietic cells, recapitulated the phenotype observed forKITD816V iPSC hematopoiesis.KITD816V causes constitutive activation of the KIT tyrosine kinase receptor and we exploited our iPSCs and ESCs to investigate new tyrosine kinase inhibitors targeting KIT D816V. Our study identified nintedanib as a novel KIT D816V inhibitor. Nintedanib selectively reduced the viability of iPSC-derivedKITD816V hematopoietic progenitor cells and MCs in the nanomolar range. Nintedanib was also active on primary samples of KIT D816V SM patients. Molecular docking studies show that nintedanib binds to the ATP binding pocket of inactive KIT D816V. Our results suggest nintedanib as a new drug candidate for KIT D816V targeted therapy of advanced SM.
Nicotinamide mononucleotide treatment increases NAD+ levels in an iPSC Model of Parkinson’s Disease
Authors: Fulleylove-Krause Brett K. , Sison Samantha L. , Ebert Allison D. 
Published: May 2020

AbstractParkinson’s disease (PD) is a common neurodegenerative disorder caused by the loss of dopaminergic neurons in the substantia nigra that leads to severe motor and non-motor deficits. Although the underlying mechanisms of dopaminergic neuron loss is not entirely clear, increasing evidence suggests mitochondrial malfunction as a key contributor to disease pathogenesis. Recently, we found that human PD patient stem cell-derived dopaminergic neurons exhibit reduced nicotinamide adenine dinucleotide (NAD+) levels, an essential cofactor in mitochondrial function and cellular metabolism. In addition, we found that sirtuins, a group of NAD+-dependent deacetylase enzymes that participate in the regulation of mitochondrial function, energy production, and cell survival, displayed decreased activity in PD dopaminergic neurons, thereby suggesting a potential mechanism for dopaminergic loss in PD. Thus, here we tested whether treatment of PD stem cell-derived dopaminergic neurons with an NAD+ precursor could increase NAD+ levels and improve sirtuin activity.
Different categories of fluorescent proteins result in GEVIs with similar characteristics
Authors: Platisa Jelena , Han Zhou , Pieribone Vincent A. 
Published: May 2020

AbstractThe latest generation of genetically encoded voltage indicators (GEVIs) is significantly advancing our ability to study electrical activity from large numbers of identified neurons. The further refinement of the technology will contribute to our understanding of behavior-evoked information perception, transfer and processing on a cellular level across brain regions. The development of GEVIs relies on synthetic biology which includes rational and random modifications of indicator sequence. One strategy in GEVI design is based on creating chimeras between voltage sensitive protein domains (VSDs) and fluorescent proteins (FPs). However, in this design scenario, the mechanistic details of voltage-induced fluorescence change that would inform rational design and improvements of GEVIs are still largely missing. Here we preformed a systematic study of how nature of the FP and altering the insertion site affects the characteristics ofCiona intestinalisvoltage-sensitive phosphatase-based GEVIs. Surprisingly, we found that regardless of vast difference in phylogenesis, biochemical properties, fluorophore structure, sequence and excitation/emission spectra between FPs, the resulting GEVIs exhibit virtually identical decrease in fluorescence intensity in response to depolarization. These results stand in strong contrast to studies demonstrating that small numbers of targeted mutations in the FP sequence cause dramatic changes in both signal size and polarity.
Selection for reducing energy cost of protein production drives the GC content and amino acid composition bias in gene transfer agents
Authors: Kogay Roman , Wolf Yuri I. , Koonin Eugene V. , Zhaxybayeva Olga 
Published: May 2020

AbstractGene transfer agents (GTAs) are virus-like elements integrated into bacterial genomes, particularly, those of Alphaproteobacteria. The GTAs can be induced under nutritional stress, incorporate random fragments of bacterial DNA into mini-phage particles, lyse the host cells and infect neighboring bacteria, thus enhancing horizontal gene transfer. We show that the GTA genes evolve under pronounced positive selection for the reduction of the energy cost of protein production as shown by comparison of the amino acid compositions with both homologous viral genes and host genes. The energy saving in GTA genes is comparable to or even more pronounced than that in the genes encoding the most abundant, essential bacterial proteins. In cases when viruses acquire genes from GTAs, the bias in amino acid composition disappears in the course of evolution, showing that reduction of the energy cost of protein is an important factor of evolution of GTAs but not bacterial viruses. These findings strongly suggest that GTAs are bacterial adaptations rather than selfish, virus-like elements. Because GTA production kills the host cell and does not propagate the GTA genome, it appears likely that the GTAs are retained in the course of evolution via kin or group selection. Therefore, we hypothesize that GTA facilitate the survival of bacterial populations under energy-limiting conditions through the spread of metabolic and transport capabilities via horizontal gene transfer and increase of nutrient availability resulting from the altruistic suicide of GTA-producing cells.ImportanceKin and group selection remain controversial topics in evolutionary biology. We argue that these types of selection are likely to operate in bacterial populations by showing that bacterial Gene Transfer Agents (GTAs), but not related viruses, evolve under positive selection for the reduction of the energy cost of a GTA particle production. We hypothesize that GTAs are dedicated devices for the survival of bacteria under the conditions of nutrient limitation. The benefits conferred by GTAs under nutritional stress appear to include horizontal dissemination of genes that could provide bacteria with enhanced capabilities for nutrient utilization and the increase of nutrient availability through the lysis of GTA-producing bacteria.
Polycistronic gene expression in the model micro-organismUstilago maydis
Authors: Müntjes Kira , Philipp Magnus , Hüsemann Lisa , Heucken Nicole , Weidtkamp-Peters Stefanie , Schipper Kerstin , Zurbriggen Matias D. , Feldbrügge Michael 
Published: May 2020

AbtractEukaryotic microorganisms transcribe monocistronic mRNAs to encode proteins. For synthetic biological approaches like metabolic engineering, precise co-expression of several proteins in space and time is advantageous. A straightforward approach is the application of viral 2A peptides to design synthetic polycistronic mRNAs in eukaryotes. Here, we establish such a system in the well-studied model microorganism Ustilago maydis. Using two fluorescence reporter proteins, we compared the activity of five viral 2A peptides. Their activity was evaluated in vivo using fluorescence microscopy and validated using fluorescence resonance energy transfer (FRET). Activity ranged from 20 to 100% and the best performing 2A peptide was P2A from porcine teschovirus-1. As proof of principle, we followed regulated gene expression efficiently over time and synthesised a tri-cistronic mRNA encoding biosynthetic enzymes to produce mannosylerythritol lipids (MELs). In essence, we evaluated 2A peptides in vivo and demonstrated the applicability of 2A peptide technology for U. maydis in basic and applied science.
Requirement for Anti-Apoptotic MCL-1 during Early Erythropoiesis
Authors: Turnis Meghan E. , Kaminska Ewa , Smith Kaitlyn H. , Kartchner Brittany J. , Vogel Peter , Laxton Jonathan D. , Ashmun Richard A. , Ney Paul A. , Opferman Joseph T. 
Published: May 2020

AbstractMature erythrocytes are under tight homeostatic control with the need for constant replacement from progenitors to replace damaged or obsolete red blood cells (RBCs). This process is regulated largely by erythropoietin (Epo) which promotes the survival of erythroid progenitors and facilitates their differentiation and proliferation. Ablation ofBcl2l1(which encodes BCL-xL) results in embryonic lethality with a lack of mature erythrocytes but does not perturb erythroid progenitors. Similarly, conditionalBcl2l1-deletion results in severe anemia with the death of late erythroid progenitors and induction of extramedullary erythropoiesis. While BCL-xL is critical to the survival of mature erythrocytes, it is still unclear whether other anti-apoptotic molecules mediate survival during earlier stages of erythropoiesis. Here, we demonstrate that erythroid-specificMcl1-deletion results in embryonic lethality due to severe anemia caused by a lack of mature RBCs.Mcl1-deleted embryos exhibit stunted growth, ischemic necrosis, and decreased RBCs in the blood. Furthermore, we demonstrate that the dependence on MCL-1 is only during early erythropoiesis, whereas during later stages the cells become MCL-1-independent and upregulate the expression of BCL-xL. Functionally, MCL-1 relies upon its ability to prevent apoptosis to promote erythroid development since co-deletion of the pro-apoptotic effectorsBaxandBakcan overcome the requirement for MCL-1 expression. Furthermore, ectopic expression of human BCL2 in erythroid progenitors can compensate forMcl1deletion, indicating redundancy between these two anti-apoptotic family members. These data clearly demonstrate a requirement for MCL-1 in promoting survival of early erythroid progenitors.
Addressing Inaccurate Nosology in Mental Health: A Multi Label Data Cleansing Approach for Detecting Label Noise from Structural Magnetic Resonance Imaging Data in Mood and Psychosis Disorders
Authors: Rokham Hooman , Pearlson Godfrey , Abrol Anees , Falakshahi Haleh , Plis Sergey , Calhoun Vince D. 
Published: May 2020

ABSTRACTBackgroundMental health diagnostic approaches are seeking to identify biological markers to work alongside advanced machine learning approaches. It is difficult to identify a biological marker of disease when the traditional diagnostic labels themselves are not necessarily valid.MethodsWe worked with T1 structural magnetic resonance imaging data collected from individuals with mood and psychosis disorders from over 1400 individuals comprising healthy controls, psychosis patients and their unaffected first-degree relatives including 176 bipolar probands, 134 schizoaffective probands, 240 schizophrenia proband, 581 patients relatives and 362 controls. We assumed there might be noise in the diagnostic labeling process. We detected label noise by classifying the data multiple times using a support vector machine classifier, and then we flagged those individuals in which all classifiers unanimously mislabeled those subjects. Next, we assigned a new diagnostic label to these individuals, based on the biological data (MRI), using iterative data cleansing approach.ResultsSimulation results showed our method was highly accurate in identifying label noise. Both diagnostic and Biotype categories showed about 65% and 63% respectively of noisy labels with the largest amount of relabeling occurring between the healthy control and bipolar and schizophrenia disorder individuals as well as in the unaffected close relatives. The extraction of imaging features highlighted regional brain changes associated with each group.ConclusionsThis approach represents an initial step towards developing strategies that need not assume existing mental health diagnostic categories are always valid, but rather allows us to leverage this information while also acknowledging that there are misassignments.