bluuebunny/crossref_metadata_2025 huggingface dataset:
Detailed and atypical HLA-E peptide binding motifs revealed by a novel peptide exchange binding assay
Authors: Walters Lucy C. , McMichael Andrew J. , Gillespie Geraldine M.
Published: May 2020

Diverse SIV epitopes that bind the rhesus homologue of HLA-E, Mamu-E, have recently been identified in SIV-vaccine studies using a recombinant Rhesus cytomegalovirus (RhCMV 68-1) vector, where unprecedented protection against SIV challenge was achieved. Additionally, severalMycobacterialpeptides identified both algorithmically and following elution from infected cells, are presented to CD8+T cells by HLA-E in humans. Yet, a comparative and comprehensive analysis of relative HLA-E peptide binding strength via a reliable, high throughputin vitroassay is currently lacking. To address this we developed and optimised a novel, highly sensitive peptide exchange ELISA-based assay that relatively quantitates peptide binding to HLA-E. Using this approach we screened multiple peptides, including peptide panels derived from HIV, SIV and Mtb predicted to bind HLA-E. Our results indicate that although HLA-E preferentially accommodates canonical MHC class I leader peptides, many non-canonical, sequence diverse, pathogen-derived peptides also bind HLA-E, albeit generally with lower relative binding strength. Additionally, our screens demonstrate that the majority of peptides tested, including some key Mtb and SIV epitopes which have been shown to elicit strong Mamu-E-restricted T cell responses, either bind HLA-E extremely weakly or give signals that are indistinguishable from the negative, peptide-free controls.
SIGAR: Inferring features of genome architecture and DNA rearrangements by split read mapping
Authors: Feng Yi , Beh Leslie Y. , Chang Wei-Jen , Landweber Laura F.
Published: May 2020

Ciliates are microbial eukaryotes with distinct somatic and germline genomes. Post-zygotic development involves extensive remodeling of the germline genome to form somatic chromosomes. Ciliates therefore offer a valuable model for studying the architecture and evolution of programmed genome rearrangements. Current studies usually focus on a few model species, where rearrangement features are annotated by aligning reference germline and somatic genomes. While many high-quality somatic genomes have been assembled, a high quality germline genome assembly is difficult to obtain due to its smaller DNA content and abundance of repetitive sequences. To overcome these hurdles, we propose a new pipeline SIGAR (SplitreadInference ofGenomeArchitecture andRearrangements) to infer germline genome architecture and rearrangement features without a germline genome assembly, requiring only short germline DNA sequencing reads. As a proof of principle, 93% of rearrangement junctions identified by SIGAR in the ciliateOxytricha trifallaxwere validated by the existing germline assembly. We then applied SIGAR to six diverse ciliate species without germline genome assemblies, includingIchthyophthirius multifilii,a fish pathogen. Despite the high level of somatic DNA contamination in each sample, SIGAR successfully inferred rearrangement junctions, short eliminated sequences and potential scrambled genes in each species. This pipeline enables pilot surveys or exploration of DNA rearrangements in species with limited DNA material access, thereby providing new insights into the evolution of chromosome rearrangements.
Evidence for a behaviourally measurable perseverance trait
Authors: Määttänen Ilmari , Makkonen Emilia , Jokela Markus , Närväinen Johanna , Väliaho Julius , Seppälä Vilja , Kylmälä Julia , Henttonen Pentti
Published: May 2020

The aim of this exploratory study was to create a behavioural measure for trait(s) that reflect the ability and motivation to continue an unpleasant behaviour, i.e. perseverance or persistence, and to measure its correlates to several variables.

We utilised six different tasks with 54 subjects to measure the perseverance-trait: cold pressor task, hand grip endurance task, impossible anagram task, impossible verbal reasoning task, thread and needle task and boring video task.

According to our results, the task performances formed two perseverance factors that could be roughly described as “physical” and “mental” perseverance. Together, the two-factor solution is responsible for the common variance constituting 37.3 % of the total variance in the performances i.e. performance times. Excluding the impossible anagram task, the performance in any given task was better explained by performances in the other tasks (i.e. “trait”, η2range = 0.131–0.253) than by rank order variable (“depletion”, i.e. getting tired from the previous tasks, η2range = 0–0.096).

Highlights

Behavioural perseverance of individuals can be measured behaviourally

Behavioural perseverance forms a two-factor structure

Perseverance trait is better predictor of performance than depletion of individuals’ personal resources in a task
Anti-inflammatory dopamine- and serotonin-based endocannabinoid epoxides reciprocally regulate cannabinoid receptors and the TRPV1 channel
Authors: Arnold William R. , Carnevale Lauren N. , Xie Zili , Baylon Javier L. , Tajkhorshid Emad , Hu Hongzhen , Das Aditi
Published: May 2020

The endocannabinoid (eCB) system is a promising target to mitigate pain as the eCBs are endogenous ligands of the pain-mediating receptors—cannabinoid receptors 1 and 2 (CB1 and CB2) and TRPV1. Here we report on a novel class of lipids formed by the epoxidation of N-arachidonoyl-dopamine (NADA) and N-arachidonoyl serotonin (NA5HT) by cytochrome P450 (CYP) epoxygenases. These epoxides (epoNADA and epoNA5HT) are dual-functional rheostat modulators (varying strength of agonism or antagonism) of the eCB-TRPV1 axis. In fact, epoNADA is a 6-fold stronger agonist of TRPV1 than NADA while epoNA5HT is a 30-fold stronger antagonist of TRPV1 than NA5HT and displays a significantly stronger inhibition on TRPV1-mediated responses in primary afferent neurons. Moreover, epoNA5HT is a full CB1 agonist. The epoxides reduce the pro-inflammatory biomarkers IL-6, IL-1β, TNF-α and nitrous oxide (NO) and raise anti-inflammatory IL-10 in activated microglial cells. The epoxides are spontaneously generated by activated microglia cells and their formation is potentiated in the presence of another eCB, anandamide (AEA). We provide evidence for the direct biochemical mechanism of this potentiation using human CYP2J2, a CYP epoxygenase in the human brain, using detailed kinetics studies and molecular dynamics simulations. Taken all together, inflammation leads to an increase in the metabolism of NADA, NA5HT and other eCBs by CYP epoxygenases to form the corresponding epoxides. The epoxide metabolites are bioactive lipids that are more potent, multi-faceted endogenous molecules, capable of influencing the activity of CB1, CB2 and TRPV1 receptors. The identification of these molecules will serve as templates for the synthesis of new multi-target therapeutics for the treatment of inflammatory pain.
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

Objective

Societal 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.

Methods

We 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.

Results

There 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.

Conclusions

Patient 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

Although 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

Biliary 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

Chest 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 Strengths

The 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

Over 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

When 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

TheKITD816V 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

Parkinson’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

The 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

Gene 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.

Importance

Kin 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

Abtract

Eukaryotic 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

Mature 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

Background

Mental 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.

Methods

We 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.

Results

Simulation 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.

Conclusions

This 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.
Breakage of Hydrophobic Contacts Limits the Rate of Passive Lipid Exchange Between Membranes
Authors: Rogers Julia R. , Geissler Phillip L.
Published: May 2020

The maintenance of heterogeneous lipid compositions among cellular membranes is key to biological function. Yet, even the simplest process that could be responsible for maintaining proper lipid distributions, passive lipid exchange of individual molecules between membranes, has eluded a detailed understanding, due in part to inconsistencies between experimental findings and molecular simulations. We resolve these discrepancies by discovering the reaction coordinate for passive lipid exchange, which enables a complete biophysical characterization of the rate limiting step for lipid exchange. Our approach to identify the reaction coordinate capitalizes on our ability to harvest over 1,000 unbiased trajectories of lipid insertion, an elementary step of passive lipid transport, using all-atom and coarse-grained molecular dynamics simulations. We find that the reaction coordinate measures the formation and breakage of hydrophobic contacts between the membrane and exchanging lipid. Consistent with experiments, free energy profiles as a function of our reaction coordinate exhibit a substantial barrier for insertion. In contrast, lipid insertion was predicted to be a barrier-less process by previous computational studies, which incorrectly presumed the reaction coordinate to be the displacement of the exchanging lipid from the membrane. Utilizing our newfound knowledge of the reaction coordinate, we formulate an expression for the lipid exchange rate to enable a quantitative comparison with experiments. Overall, our results indicate that the breakage of hydrophobic contacts is rate limiting for passive lipid exchange and provide a foundation to understand the catalytic function of lipid transfer proteins.
Impact of Concatenating fMRI Data on Reliability for Functional Connectomics
Authors: Cho Jae Wook , Korchmaros Annachiara , Vogelstein Joshua T , Milham Michael , Xu Ting
Published: May 2020

Compelling evidence suggests the need for more data per individual to reliably map the functional organization of the human connectome. As the notion that ‘more data is better’ emerges as a golden rule for functional connectomics, researchers find themselves grappling with the challenges of how to obtain the desired amounts of data per participant in a practical manner, particularly for retrospective data aggregation. Increasingly, the aggregation of data across all fMRI scans available for an individual is being viewed as a solution, regardless of scan condition (e.g., rest, task, movie). A number of open questions exist regarding the aggregation process and the impact of different decisions on the reliability of resultant aggregate data. We leveraged the availability of highly sampled test-retest datasets to systematically examine the impact of data aggregation strategies on the reliability of cortical functional connectomics. Specifically, we compared functional connectivity estimates derived after concatenating from: 1) multiple scans under the same state, 2) multiple scans under different states (i.e. hybrid or general functional connectivity), and 3) subsets of one long scan. We also varied connectivity processing (i.e. global signal regression, ICA-FIX, and task regression) and estimation procedures. When the total number of time points is equal, and the scan state held constant, concatenating multiple shorter scans had a clear advantage over a single long scan. However, this was not necessarily true when concatenating across different fMRI states (i.e. task conditions), where the reliability from the aggregate data varied across states. Concatenating fewer numbers of states that are more reliable tends to yield higher reliability. Our findings provide an overview of multiple dependencies of data concatenation that should be considered to optimize reliability in analysis of functional connectivity data.
Gamma rhythms and visual information in mouse V1 specifically modulated by somatostatin-positive neurons in reticular thalamus
Authors: Hoseini Mahmood S. , Higashikubo Bryan , Cho Frances S. , Chang Andrew H. , Clemente-Perez Alexandra , Lew Irene , Stryker Michael , Paz Jeanne T.
Published: May 2020

Visual perception in natural environments depends on the ability to focus on salient stimuli while ignoring distractions. This kind of selective visual attention is associated with gamma activity in the visual cortex. While the nucleus reticularis thalami (nRT) has been implicated in selective attention, its role in modulating visual perception remains unknown. Here we show that somatostatin-(SOM) but not parvalbumin-expressing (PV) neurons in the nRT preferentially project to visual thalamic nuclei. In freely behaving mice, single-unit and field recordings reveal powerful modulation of both visual information transmission and gamma activity in primary visual cortex (V1), as well as in the dorsal lateral geniculate nucleus (dLGN). These findings pinpoint the SOM neurons in nRT as powerful modulators of the visual information encoding accuracy in V1, and represent a novel circuit through which the nRT can influence representation of visual information.
Physiological characterization of nitrate ammonifying bacteria isolated from rice paddy soil via a newly developed high-throughput screening method
Authors: Heo Hokwan , Kwon Miye , Song Bongkeun , Yoon Sukhwan
Published: May 2020

Dissimilatory nitrate/nitrite reduction to ammonium (DNRA) has recently gained attention as a nitrogen retention pathway that may potentially be harnessed to alleviate nitrogen loss resulting from denitrification. Until recently, ecophysiology of DNRA bacteria inhabiting agricultural soils has remained largely unexplored, due to the difficulty in targeted enrichment and isolation of DNRA microorganisms. In this study, >100 microbial isolates capable of DNRA have been isolated from rice paddy soil with apparent dominance of denitrification using a novel high-throughput screening method. Six of these isolates, each assigned to a disparate genus, was examined to improve understanding of DNRA physiology. All isolates carriednrfAand/ornirB, and an isolate affiliated toBacilluspossessed a clade IInosZgene and was capable of N2O reduction. A common prominent physiological feature observed in all DNRA isolates was NO2−accumulation observed before NH4+production, which was further examined withCitrobactersp. DNRA3 (possessingnrfAandnirB)andEnterobactersp. DNRA5 (possessing onlynirB). In both organisms, NO2−-to-NH4+reduction was inhibited by submillimolar NO3−, andnrfAornirBtranscription was down-regulated when NO3−was being reduced to NO2−. Both batch and chemostat incubations of these isolates with excess organic electron donors produced NH4+from reduction of NO3−; however, incubation with excess NO3−resulted in NO2−buildup but no substantial NH4+production, presumably due to NO3−presence. This previously overlooked link between NO3−repression of NO2−-to-NH4+reduction and the C-to-N ratio regulation of DNRA activity may be a key mechanism underpinning denitrification-vs-DNRA competition in soil.

IMPORTANCE

Dissimilatory nitrate/nitrite reduction to ammonium (DNRA) is an anaerobic microbial pathway that competes with denitrification for common substrates NO3−and NO2−. Unlike denitrification leading to nitrogen loss and N2O emission, DNRA reduces NO3−and NO2−to NH4+, a reactive nitrogen with higher tendency to be retained in soil matrix. Therefore, stimulation of DNRA has often been proposed as a strategy to improve fertilizer efficiency and reduce greenhouse gas emissions. Such attempts have been hampered by lack of insights into soil DNRA ecophysiology. Here, we have developed a novel high-throughput screening method for isolating DNRA-catalyzing organisms from agricultural soils without apparent DNRA activity. Physiological characteristics of six DNRA isolates were closely examined, disclosing a previously overlooked link between NO3−repression of NO2−-to-NH4+reduction and the C-to-N ratio regulation of DNRA activity, which may be key to understanding why significant DNRA activity is rarely observed in nitrogen-rich agricultural soils.
Clinical Performance of SARS-CoV-2 Molecular Testing
Authors: Green Daniel A. , Zucker Jason , Westblade Lars F. , Whittier Susan , Rennert Hanna , Velu Priya , Craney Arryn , Cushing Melissa , Liu Dakai , Sobieszczyk Magdalena , Boehme Amelia K. , Sepulveda Jorge L.
Published: May 2020

Molecular testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the gold standard for diagnosis of coronavirus disease 2019 (COVID-19), but the test clinical performance is poorly understood. From 3/10/2020-5/1/2020 NewYork-Presbyterian laboratories performed 27,377 SARS-CoV-2 molecular assays from 22,338 patients. Repeat testing was performed in 3,432 patients, of which 2,413 had negative and 1,019 had positive first day results. Repeat-tested patients were more likely to be older, male, African-American or Hispanic, and to have severe disease. Among the patients with initially negative results, 18.6% became positive upon repeat-testing. Only 58.1% of any-time positive patients had a result of “detected” on the first test. The clinical sensitivity of COVID-19 molecular assays is estimated between 66.2 % and 95.6%, depending on the unknown number of false negative results in single-tested patients. Conversion to a negative result is unlikely to occur before 15 to 20 days after initial testing or 20-30 days after the onset of symptoms, with 50% conversion occurring at 28 days after initial testing. Forty-nine initially-positive patients converted to negative and then back to positive in subsequent days. Conversion from first day negative to positive results increased linearly with each day of testing, reaching 25% probability in 20 days. In summary, our study provides estimates of the clinical performance of SARS-CoV-2 molecular assays and suggests time frames for appropriate repeat testing, namely 15 to 20 days after a positive test and the same or next 2 days after a negative test in a patient with high suspicion for COVID-19.
Transcriptomic response of an Antarctic yeastRhodotorulasp. USM-PSY62 to temperature changes
Authors: Chai Cleo-Nicole , Yam Hok-Chai , Rosli Nurlina , Azlan Azali , Azzam Ghows , Halim Mardani Abdul , Najimudin Nazalan
Published: May 2020

Rhodotorulasp. (USM-PSY62) is a psychrophilic yeast isolated from Antarctic sea ice and it grows optimally at 15 °C. This study was set up to observe how USM-PSY62 adapted to fluctuations in temperature. During cold adaptation, an elevated transcription of the CorA magnesium transporter gene in USM-PSY62 indicated a higher requirement for magnesium ions in order to gain additional enzyme cofactors or maintain cytoplasmic fluidity. The HepA homologue coding for DNA/RNA helicase was also over-expressed in cold condition possibly to reorganize secondary structures of DNA and RNA. An up-regulation of the catalase gene was also observed reflecting an increment in the concentration of reactive oxygen species and fluctuations in the associated antioxidant system. TheYOP1gene, which encodes a membrane protein associated with protein transport and membrane traffic, was the most down-regulated under cold shock condition. The genes responsible for the structural maintenance of chromosome (SMC) were also down-regulated when the temperature was shifted to 0 °C. Upon cold shock, the gene for heat shock factor protein 1 (HSF1) was also down-regulated. Hsf1 is a transcriptional regulator which regulate the heat shock responses. Although USM-PSY62 showed some common adaptive strategies as in several other psychrophilic organisms, new mechanisms were also uncovered.
Pattern recognition receptors confer plant salt tolerance via WRKY18/WRKY40 transcription factors
Authors: Loo Eliza P. , Tajima Yuri , Yamada Kohji , Hirase Taishi , Ariga Hirotaka , Fujiwara Tadashi , Tanaka Keisuke , Taji Teruaki , Somssich Imre E. , Parker Jane E. , Saijo Yusuke
Published: May 2020

Pattern recognition receptors (PRRs) bind microbe- and damage-associated molecular patterns (MAMPs/DAMPs, respectively) to enhance host immunity in animals and plants. Here, we report that PRRs also confer salt tolerance in the model plantArabidopsis thalianafollowing recognition of cognate ligands, such as bacterial flagellin and EF-Tu and the endogenous Pep peptides. Pattern-triggered salt tolerance (PTST) requires the PRR-associated kinasesBAK1andBIK1, and the NADPH oxidaseRBOHD. Transcriptome profiling reveals an inventory of PTST target genes, which increase or acquire salt responsiveness following an exposure to immunogenic patterns. In their regulatory DNA sequences, specific binding sites for a subset of WRKY transcription factors are over-represented. Accordingly, PTST requiresWRKY40andWRKY18, which activate salt tolerance-related genes but attenuate pathogen defense-related genes, including theEDS1immunity activator. PRR signaling leads to sustained WRKY40/WRKY18 accumulation under salt stress and utilizes bothWRKYs for salt tolerance. The PRR-WRKY40/WRKY18 module also confers salt tolerance after challenge with non-pathogenic bacteria. Our findings give molecular insight into signaling plasticity underlying biotic-abiotic stress cross-tolerance in plants conferred by PRRs.
Third generation indexing for third generation sequencing
Authors: Jighly Abdulqader
Published: May 2020

Indexing of DNA sequences is the art of sorting massive genomic data in a user-friendly structure to enable rapid accessing and comparing of different patterns in the data. Current genome assemblers use general algorithms for string indexing that do not exploit the special structural arrangement of genomes. Here, I am proposing a new algorithm that indexes only the configuration of microsatellite motifs along reads assuming that the order of microsatellites will be the same in overlapped sequences. The index size is >1000 times smaller than currently used indices and it has higher tolerance to the high error rates produced by third generation sequencing platforms. The results showed that the proposed algorithm can rapidly detect overlaps among considerable proportion of uncorrected long reads (~50% of all simulated base pairs with average read size of 8.16 kb and total error rates of 14.4%) to build large initial contigs. Unassembled reads can be then mapped to these contigs or can be assembled with them with currently used algorithms. Thus, the proposed algorithm can efficiently be used as an initial stage to significantly reduce the number of pairwise sequence comparisons among reads and/or references and improve the performance of different software but not replacing them. The algorithm was also useful for comparative genomics and detect large locally colinear blocks and structural variations among tensaccharomyces cerevisiaestrains. The proposed algorithm has the power to make de novo assembly of individuals as routine activity which can lead to more accurate variant calling and pan genomics.
RAN translation of the expanded CAG repeats in the SCA3 disease context
Authors: Jazurek-Ciesiolka Magdalena , Ciesiolka Adam , Komur Alicja A. , Urbanek-Trzeciak Martyna O. , Fiszer Agnieszka
Published: May 2020

Spinocerebellar ataxia type 3 (SCA3) is a progressive neurodegenerative disorder caused by a CAG repeat expansion in theATXN3gene encoding the ataxin-3 protein. Despite extensive research the exact pathogenic mechanisms of SCA3 are still not understood in depth. In the present study, to gain insight into the toxicity induced by the expanded CAG repeats in SCA3, we comprehensively investigated repeat-associated non-ATG (RAN) translation in various cellular models expressing translated or non-canonically translatedATXN3sequences with an increasing number of CAG repeats. We demonstrate that two SCA3 RAN proteins, polyglutamine (polyQ) and polyalanine (polyA), are found only in the case of CAG repeats of pathogenic length. Despite having distinct cellular localization, RAN polyQ and RAN polyA proteins are very often coexpressed in the same cell, impairing nuclear integrity and inducing apoptosis. We provide for the first time mechanistic insights into SCA3 RAN translation indicating thatATXN3sequences surrounding the repeat region have an impact on SCA3 RAN translation initiation and efficiency. We revealed that RAN translation of polyQ proteins starts at non-cognate codons upstream of the CAG repeats, whereas RAN polyA proteins are likely translated within repeats. Furthermore, integrated stress response activation enhances SCA3 RAN translation. We suggest that RAN translation in SCA3 is a common event substantially contributing to SCA3 pathogenesis and that theATXN3sequence context plays an important role in triggering this unconventional translation.
Why is cyclic dominance so rare?
Authors: Park Hye Jin , Pichugin Yuriy , Traulsen Arne
Published: May 2020

Natural populations can contain multiple types of coexisting individuals. How does natural selection maintain such diversity within and across populations? A popular theoretical basis for the maintenance of diversity is cyclic dominance, illustrated by the rock-paper-scissor game. However, it appears difficult to find cyclic dominance in nature. Why is this case? Focusing on continuously produced novel mutations, we theoretically addressed the rareness of cyclic dominance. We developed a model of an evolving population and studied the formation of cyclic dominance. Our results showed that the chance for cyclic dominance to emerge is lower when the newly introduced type is similar to existing types, whereas the introduction of an unrelated type improves these chances. This suggests that cyclic dominance is more likely to evolve through the assembly of unrelated types whereas it rarely evolves within a community of similar types.