bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of Quality Improvement Education in Diabetic Retinopathy on Routine Clinical Practice Patterns of Optometrists
Authors: Maatouk Christopher M. , Hentati Firas , Urbano Catherine A. , Greenlee Tyler E. , Conti Thais F. , Hom Grant L. , Immler Wes K. , Babiuch Amy S. , Singh Rishi P.
Published: October 2020

SIGNIFICANCE

Optometrists play a preventive role in diabetic care by detecting early signs of diabetic retinopathy (DR), a leading cause of blindness in adults. This study demonstrates that additional training can improve optometrists' ability to assess the presence and severity of DR in individuals with diabetes.

PURPOSE

This study aimed to determine the impact of a quality improvement intervention involving education, assessment, and feedback on improving the evaluation and referral patterns of optometrists with regard to their patients with diabetes.

METHODS

A pre-interventional and post-interventional analysis of optometrist practices was conducted through a retrospective chart review of diabetic patient encounters from July 2018 to March 2019. Dilated fundus examination (DFE) documentation, follow-up scheduling, referral practices, and usage of various imaging modalities were collected from patient records. Concordance of DR severity recordings between DFE findings, assessment and plan notes, and International Classification of Diseases codes was calculated.

RESULTS

After intervention, the proportion of optometrists who conducted a DFE significantly increased from 79.5 (95% confidence interval [CI], 77.3 to 81.7%) to 84.4% (95% CI, 82.4 to 86.4%). In addition, the rate of improper follow-up instructions decreased from 13.8 (95% CI, 12.0 to 15.7%) to 10.8% (95% CI, 9.2 to 12.6%), and the decrease was significant (P = .02). Although overall referrals decreased from 19.8 (95% CI, 17.6 to 21.9%) to 14.6% (95% CI, 12.6 to 16.5%), optometrists were as likely to refer to retinal specialists. Finally, concordance between documented DFE findings, assessment and plan notes, and International Classification of Diseases codes significantly increased from 78.8 (95% CI, 76.5 to 81.0%) to 88.7% (95% CI, 86.9 to 90.4%).

CONCLUSIONS

Providing optometrists education in screening and assessing DR is effective in improving diabetic patient care.
Use of Cardiac Point-of-Care Ultrasound in the Pediatric Emergency Department
Authors: Miller Andrew F. , Arichai Piyawat , Gravel Cynthia A. , Vieira Rebecca L. , Neal Jeffrey T. , Neuman Mark I. , Monuteaux Michael C. , Levy Jason A.
Published: October 2020

Objectives

We sought to describe the test characteristics of cardiac point-of-care ultrasound (POCUS) performed by pediatric emergency medicine (PEM) physicians after structured cardiac POCUS training.

Methods

We evaluated the use of clinically indicated cardiac POCUS by PEM physicians in a single tertiary care pediatric emergency department after implementation of a focused cardiac POCUS training curriculum. The test characteristics of the sonologist interpretation were compared with expert POCUS review, by PEM physicians who have completed PEM POCUS fellowship training, for the assessment of both pericardial effusion and left ventricular systolic dysfunction.

Results

A total of 1241 cardiac POCUS examinations were performed between July 2015 and December 2017, of which 456 were clinically indicated and underwent expert POCUS review and comprised the study sample. These examinations were performed by 33 different PEM attending sonologists. Chest pain (52%), dyspnea (20%), and tachycardia (18%) were the most common indications for cardiac POCUS. Prevalence of pericardial effusion and global systolic dysfunction based on expert POCUS review were 11% (48/443) and 4% (16/435), respectively. Real-time cardiac POCUS interpretation had a sensitivity and specificity of 100% and 99.5%, respectively, for both pericardial effusion and left ventricular systolic dysfunction when compared with expert POCUS review.

Conclusions

Cardiac POCUS is both sensitive and specific for identifying pericardial effusion and left ventricular systolic dysfunction when performed by PEM attendings with focused training.
Back to the Future: Whole Blood Resuscitation of the Severely Injured Trauma Patient
Authors: McCoy Christopher Cameron , Brenner Megan , Duchesne Juan , Roberts Derek , Ferrada Paula , Horer Tal , Kauvar David , Khan Mansoor , Kirkpatrick Andrew , Ordonez Carlos , Perreira Bruno , Priouzram Artai , Cotton Bryan A.
Published: October 2020

Following advances in blood typing and storage, whole blood transfusion became available for the treatment of casualties during World War I. While substantially utilized during World War II and the Korean War, whole blood transfusion declined during the Vietnam War as civilian centers transitioned to blood component therapies. Little evidence supported this shift, and recent conflicts in Iraq and Afghanistan have renewed interest in military and civilian applications of whole blood transfusion. Within the past two decades, civilian trauma centers have begun to study transfusion protocols based upon cold-stored, low anti-A/B titer type O whole blood for the treatment of severely injured civilian trauma patients. Early data suggests equivalent or improved resuscitation and hemostatic markers with whole blood transfusion when compared to balanced blood component therapy. Additional studies are taking place to define the optimal way to utilize low-titer type O whole blood in both prehospital and trauma center resuscitation of bleeding patients.
Examining the Effects of Multitiered Oral Narrative Language Instruction on Reading Comprehension and Writing
Authors: Petersen Douglas B. , Mesquita Meredith W. , Spencer Trina D. , Waldron Jessica
Published: October 2020

This early-stage feasibility study investigated the effects of a multitiered oral narrative language intervention on oral language, reading comprehension, and writing. Twenty-eight second-grade students participated in this quasi-experimental control group study with assignment at the classroom level. The independent variable was large- and small-group oral narrative language intervention that required students to retell increasingly complex stories that were strategically crafted to include academic language typically found in grade-level reading material. Story grammar, causal adverbial subordinate clauses, elaborated noun phrases, adverbs, and the acquisition of word meanings through context were explicitly taught. Students' performance on proximal measures of oral narrative retells, as well as distal measures of reading comprehension and writing, was assessed at pretest and posttest. Statistically significant differences between the treatment and control groups were found on all outcome measures using nonparametric analyses. Large- and small-group multitiered oral narrative instruction improved not only oral narrative language but also reading comprehension and written composition.
Expanding the Catatonia Tent
Authors: Fink Max
Published: October 2020

Catatonia is a motor and mood disorder of behavior increasingly recognized in systemic medically ill. Neuroleptic malignant syndrome, delirious mania, self injurious behaviors in autism, and limbic encephalitis are conditions in which ECT-responsive catatonia is increasingly recognized and effectively treated.
Pseudoxanthomonas winnipegensis sp. nov., derived from human clinical materials and recovered from cystic fibrosis and other patient types in Canada, and emendation of Pseudoxanthomonas spadix Young et al. 2007
Authors: Bernard Kathryn A. , Vachon Alicia , Pacheco Ana Luisa , Burdz Tamara , Wiebe Deborah , Beniac Daniel R. , Hiebert Shannon L. , Booth Tim , Doyle Dena Annie , Lawson Paul , Bernier Anne-Marie
Published: October 2020

Twelve isolates recovered from 10 cystic fibrosis/other patient types and a variety of clinical sources, were referred to Canada's National Microbiology Laboratory over 7 years. These were assignable to the genus

Pseudoxanthomonas

but were unidentifiable to species level. Patients included five males and five females from two geographically separated provinces, ranging in age from 2 months to 84 years. In contrast, most

Pseudoxanthomonas

species described to date have been derived from water, plants or contaminated soils. By 16S rRNA gene sequencing, the patient strains had ≥99.4 % similarity to each other but only 97.73–98.29 % to their closest relatives,

Pseudoxanthomonas spadix

or

Pseudoxanthomonas helianthi

. Bacteria were studied by whole genome sequencing using average nucleotide identity by Blastn, digital DNA–DNA hybridization, average amino acid identity, core genome and single nucleotide variant analyses, MALDI-TOF, biochemical and cellular fatty acid analyses, and by antimicrobial susceptibility testing. Bacterial structures were assessed using scanning and transmission electron microscopy. Strains were strict aerobes, yellowish-pigmented, oxidative, non-motile, Gram-stain-negative bacilli and generally unable to reduce nitrate. Strains were susceptible to most of the antibiotics tested; some resistance was observed towards carbapenems, several cephems and uniformly to nitrofurantoin. The single taxon group observed by 16S rRNA gene sequencing was supported by whole genome sequencing; genomes ranged in size from 4.36 to 4.73 Mb and had an average G+C content of 69.12 mol%. Based on this study we propose the name Pseudoxanthomonas winnipegensis sp. nov. for this cluster.

Pseudoxanthomonas spadix

DSM 18855T, acquired for this study, was found to be non-motile phenotypically and by electron microscopy; we therefore propose the emendation of

Pseudoxanthomonas spadix

Young et al. 2007 to document that observation.
Behaviour of two species of psittacine birds at wild bird feeding sites in Australia
Authors: Plant Michelle R. , Vankan Dianne , Baxter Gregory , Hall Evelyn , Phalen David
Published: October 2020

This study investigated how Crimson RosellasPlatycercus elegans(CR) and Australian King-ParrotsAlisterus scapularis(AKP) used provisioned seed at two public bird feeding sites in Australia. A total of 197 CR and 72 AKP were trapped and colour-banded. Observational data was collected every 10mins between 08:00-16:00 for three consecutive days during autumn and spring. Foraging effort was described using five metrics that quantified the birds’ visiting frequency and foraging duration over each day and observation period. Seed selection (over 5mins) and intake (over 10mins) were determined, and the energy intake was calculated. Total counts and population estimates were calculated for each species. Individual, species, seasonal and geographic variation in the use of provisioned seed was demonstrated by the metric summaries and Restricted Maximum Likelihood Modelling. Both species fed as part of large mixed species flocks that would not naturally congregate together to forage. Overall, CR were found to have higher foraging effort and feed in greater numbers than AKP, but a spectrum of use was observed for both species. Individuals were observed using the provisioned seed between 0-3 days/observation period. When birds used the provisioned seed, they were found to make between 1-8 visits/day, with most lasting 10-30mins. Few daily durations lasted longer than 50mins. Within a 10-minute interval, it was possible for a CR and AKP to obtain between 1.73-62.91% and 6.84-88.54% of their daily energy requirements, respectively. In a visit, either species could fill their crop and meet most, if not all, of their daily energy requirements. A small percentage of birds (6.5%) were found to use the feeding sites daily and for long durations (up to 160mins). It is likely that a proportion of the birds using the provisioned seed at both sites were dependent on the food source and would be at risk if the seed supply were suddenly reduced. The study also provided evidence that wild bird feeding provided an advantage to one or more species, as well as evidence that the food source did not affect the study species’ seasonal dispersal patterns or juveniles’ ability to forage on natural food sources.
Magnetoencephalographic Signatures of Conscious Processing Before Birth
Authors: Moser Julia , Schleger Franziska , Weiss Magdalene , Sippel Katrin , Semeia Lorenzo , Preissl Hubert
Published: October 2020

The concept of fetal consciousness is a widely discussed topic. In this study, we applied a hierarchical rule learning paradigm to investigate the possibility of fetal conscious processing during the last trimester of pregnancy. We used fetal magnetoencephalography, to assess fetal brain activity in 56 healthy fetuses between gestational week 25 and 40, during an auditory oddball paradigm containing first- and second-order regularities. The comparison of fetal brain responses towards standard and deviant tones revealed that the investigated fetuses show signs of hierarchical rule learning, and thus the formation of a memory trace for the second-order regularity. This ability develops over the course of the last trimester of gestation, in accordance with processes in physiological brain development and was only reliably present in fetuses older than week 35 of gestation. Analysis of fetal autonomic nervous system activity replicates findings in newborns, showing importance of activity state for cognitive processes. On the whole, our results support the assumption that fetuses in the last weeks of gestation are capable of consciously processing stimuli that reach them from outside the womb.
Accurate Prediction of Breast Cancer Survival through Coherent Voting Networks with Gene Expression Profiling
Authors: Pellegrini Marco
Published: October 2020

We describe a novel machine learning methodology which we call Coherent Voting Network (CVN) and we demonstrate its usefulness by building a 5-years prognostic predictor for post-surgery breast cancer patients based on CVNs. Coherent Voting Network (CVN) is a supervised learning paradigm designed explicitly to uncover non-linear, combinatorial patterns in complex data, within a statistical robust framework. Breast Cancer patients after surgery may receive several types of post-surgery adjuvant therapeutic regimen (endocrine, radio- or chemo-therapy, and combinations thereof) aiming at reducing relapse and the formation of metastases, and thus favouring log term survival. We wish to predict the outcome of adjuvant therapy using just small molecular fingerprints (mRNA) of the patient’s transcriptome. Our aim is to have simultaneously high scores for PPV (positive predictive value) and NPV (negative predictive value) as these are important indices for the final clinical applications of the predictor. A Training-validate-test protocol is applied onto CVN built on patient data from the Metabric Consortium (about 2000 patients). For the testing pool of 82 lymph node positive patients we obtain PPV 0.77 and NPV 0.78 (Odds Ratio 11.50); for the pool of 61 lymph node negative patients we obtain PPV 0.68 and NPV 0.88 (Odds Ratio 16.07). Improved results are obtained on some specific sub-types of BC. For the testing pool of 16 TNBC patients we obtain PPV 1.0 and NPV 0.83 (Odds Ratio 45.00). For the testing pool of 18 HER2+ patients we obtain PPV 0.91 and NPV 1.0 (Odds Ratio 40.00). For the testing pool of 41 Luminal B patients we obtain PPV 0.75 and NPV 0.95 (Odds Ratio 60.00). Effectiveness of the selected fingerprints is confirmed also on several independent data sets (for a total of 601 patients) from the NCBI Gene Expression Omnibus (GEO).
Direct Measurement of Unsteady Microscale Stokes Flow Using Optically Driven Microspheres
Authors: Bruot Nicolas , Cicuta Pietro , Bloomfield-Gadêlha Hermes , Goldstein Raymond E. , Kotar Jurij , Lauga Eric , Nadal François
Published: October 2020

A growing body of work on the dynamics of eukaryotic flagella has noted that their oscillation frequencies are sufficiently high that the viscous penetration depth of unsteady Stokes flow is comparable to the scales over which flagella synchronize. Incorporating these effects into theories of synchronization requires an understanding of the global unsteady flows around oscillating bodies. Yet, there has been no precise experimental test on the microscale of the most basic aspects of such unsteady Stokes flow: the orbits of passive tracers and the position-dependent phase lag between the oscillating response of the fluid at a distant point and that of the driving particle. Here, we report the first such direct Lagrangian measurement of this unsteady flow. The method uses an array of 30 submicron tracer particles positioned by a time-shared optical trap at a range of distances and angular positions with respect to a larger, central particle, which is then driven by an oscillating optical trap at frequencies up to 400 Hz. In this microscale regime, the tracer dynamics is considerably simplified by the smallness of both inertial effects on particle motion and finite-frequency corrections to the Stokes drag law. The tracers are found to display elliptical Lissajous figures whose orientation and geometry are in agreement with a low-frequency expansion of the underlying dynamics, and the experimental phase shift between motion parallel and orthogonal to the oscillation axis exhibits a predicted scaling form in distance and angle. Possible implications of these results for synchronization dynamics are discussed.
BC-store: a program for mgiseq barcode sets analysis
Authors: Bulusheva Irina , Belova Vera , Nikashin Boris , Korostin Dmitriy
Published: October 2020

Here we present the devised BC-store – a program for analyzing and selecting sets of barcodes for sequencing on platforms manufactured by MGI Tech (China). The app is available as an open source in Python3 and as a desktop version. The application allows analyzing the compatibility of barcodes on a single lane of a flow cell in a set in the case of equal and arbitrary fractions. In addition, with the help of this tool barcodes can be added to an existing set with custom share options. In this paper we describe how BC-store works for different tasks and consider the effectiveness of using BC-store in sequence lab routine tasks.

Author summary

The performance of modern NGS machines allows considerable amount of data to be obtained which exceed the data required for one specific sample. To pool multiple samples on a single lane of the flow cell, barcoding is used – adapters carrying a unique nucleotide sequence are introduced by ligation [1]. Adapters are sequenced from their specific primers. Their sequences are used for demultiplexing the sequencing results for individual fastq files by programs like zebracall [2] or bcl2fastq [3]. The task of selecting the adapters for a set is similar to sequencing low diversity libraries [4]: if all adapters on the lane have the same nucleotide during this sequencing cycle, the quality of its reading drops dramatically. Therefore, manufacturers recommend grouping the adapters by sets. However, the sets offered by MGI Tech [5] are far from routine practice, as they do not allow for non-equimolar sample pooling by default, and they have other disadvantages (more on them later in the text). To overcome these problems, we created the BC-store program, which allows analyzing the sets of MGI Tech barcodes entered by the user to be further used in sequencing. This tool also provides the opportunity to vary the number of simultaneously sequenced samples, to use reagents more efficiently, and, as a result, to correctly distribute reads across samples, which helps to increase both the quality of sequencing and the level of data interpretation.
5-amino levulinic acid inhibits SARS-CoV-2 infection in vitro
Authors: Sakurai Yasuteru , Ngwe Tun Mya Myat , Kurosaki Yohei , Sakura Takaya , Inaoka Daniel Ken , Fujine Kiyotaka , Kita Kiyoshi , Morita Kouichi , Yasuda Jiro
Published: October 2020

The current COVID-19 pandemic requires urgent development of effective therapeutics. 5-amino levulinic acid (5-ALA) is a naturally synthesized amino acid and has been used for multiple purposes including as an anticancer therapy and as a dietary supplement due to its high bioavailability. In this study, we demonstrated that 5-ALA treatment potently inhibited infection of SARS-CoV-2, a causative agent of COVID-19. The antiviral effects could be detected in both human and non-human cells, without significant cytotoxicity. Therefore, 5-ALA is a candidate as an oral antiviral drug for COVID-19.
Modulating Intra-Nuclear LC3 with Small Molecules Rescues Cells from a Docetaxel-Induced Phenotype
Authors: Rosenberg Daniel P. , Kolla Likhitha , Heo David S. , Cassio Emily E. , Veenstra Matthew J. , Vakaki Marianna , Zhang Jibo , Anyetei-Anum Cyril , Allison Lizabeth A. , Buchser William J.
Published: October 2020

Nucleus-associated autophagy has been described as a cellular metabolic response by which nuclear material is actively degraded. This degradation occurs after stress, such as nuclear damage or the onset of tumorigenesis. Here we describe a nucleus-associated autophagic process distinct from other forms of selective autophagy in human cell lines. We found that although nuclear localization of MAP1LC3B (LC3) is not dependent on particular nuclear importins, knockdown of nuclear importins, which causes nuclear stress, can induce a nuclear autophagic response. Our characterization of this autophagic phenomenon was facilitated by chemical modulation of the process via two compounds discovered previously in a high content analysis. These small molecules bidirectionally regulate nuclear LC3 in human renal, pancreatic, and bladder cell lines. One molecule (NSC31762 orDTEP)enhancesnuclear LC3 puncta and increases lysosomal targeting of LC3. This compound also decreases the nuclear envelope protein LaminB1. Another molecule (NSC279895 orDIHI)reducesthe nuclear localization of LC3. Finally, we applied these chemical tools in the setting of mitotic-disruptor induced nuclear stress. The compound DIHI, shown to reduce nuclear autophagic puncta, diminished the mitotic disruptor effect. These new tools will allow for deeper exploration of nucleus-associated autophagies, and could serve as proof-of-principle in guiding new therapies for diseases involving nuclear stress.
Microtissue geometry and cell-generated forces drive patterning of liver progenitor cell differentiation in 3D
Authors: Berg Ian C. , Mohagheghian Erfan , Habing Krista , Wang Ning , Underhill Gregory H.
Published: October 2020

Towards understanding the impact of mechanical signaling on progenitor cell differentiation in three dimensional (3D) microenvironments, we implemented a hydrogel based microwell platform to produce arrays of multicellular microtissues in constrained geometries, which cause distinct profiles of mechanical signals. We applied this to a model liver development system to investigate the impact of geometry and stress on early liver progenitor cell fate. We fabricated 3D liver progenitor cell microtissues of varied geometries, including cylinder and toroid, and used image segmentation to track individual single cell fate. We observed patterning of hepatocytic makers to the outer shell of the microtissues, except at the inner diameter surface of the toroids. Biliary markers were distributed throughout the interior regions and was increased in toroid tissues compared to cylinder tissues. Finite element models of predicted stress distributions demonstrated that cell-cell tension correlated with hepatocytic fate, while compression correlated with decreased hepatocytic and increased biliary fate. This combined approach integrating microfabrication, imaging and analysis, and mechanical modeling demonstrate of how microtissue geometry can drive patterning of mechanical stresses that regulate cell differentiation trajectories. It also can serve as a platform for the further investigation of signaling mechanisms in the liver and other systems.
Phosphorylation triggers presynaptic phase separation of Liprin-α3 to control active zone structure
Authors: Emperador-Melero Javier , Wong Man Yan , Wang Shan Shan H. , de Nola Giovanni , Kirchhausen Tom , Kaeser Pascal S.
Published: October 2020

Liquid-liquid phase separation enables the assembly of membrane-less subcellular compartments, but testing its biological functions has been difficult. The presynaptic active zone, protein machinery in nerve terminals that defines sites for neurotransmitter release, may be organized through phase separation. Here, we discover that the active zone protein Liprin-α3 rapidly and reversibly undergoes phase separation upon phosphorylation by PKC at a single site. RIM and Munc13 are co-recruited to membrane-attached condensates, and phospho-specific antibodies establish Liprin-α3 phosphorylation in vivo. At synapses of newly generated Liprin-α2/α3 double knockout mice, RIM, Munc13 and the pool of releasable vesicles were reduced. Re-expression of Liprin-α3 restored these defects, but mutating the Liprin-α3 phosphorylation site to abolish phase condensation prevented rescue. Finally, PKC activation acutely increased RIM, Munc13 and neurotransmitter release, which depended on the presence of phosphorylatable Liprin-α3. We conclude that Liprin-α3 phosphorylation rapidly triggers presynaptic phase separation to modulate active zone structure and function.
Prevalence and Associated Factors of Agricultural Technology Adoption and Teff Productivity in Basso Liben District, East Gojjame Zone, North west Ethiopia
Authors: Elemineh Demelash Abewa , Merie Hayimero Edmealem , Kassa Mulusew
Published: October 2020

Teff productivity and Teff technology adoption in Ethiopia is low and it requiring immediate attention for policymakers and decision-makers. This study was conducted to identify the determinant factors that affect Teff technology adoption and Teff productivity in Basso Liben district, East Gojjam Zone, Northwest Ethiopia. A cross-sectional study design was conducted among 190 households. Multivariable linear and logistic regressions were employed to identify the factors associated with Teff production and Teff technology adoption respectively. Of a total of 190 households considered in the study, 77.9% were Teff technology adopter. Household head gender (male) (OR=7.644), family size (OR=1.149), age of household head (OR=0.873), row planting (use)(OR=257.2), credit access (yes)(OR=3.141), manure(use)(OR=0.042) were significance associated with Teff technology adoption in the study area. Age of household head (β= 0.079), Education level (primary)(β= −0.612), total land holding (β= 5.107), annual income(β=0.0051), extension service (no)(β= −0.635), row planting (yes) (β= 1.409), organic fertilizer (no)(β= −0.946) were significance associated with teff production in the study area. In this study, a low prevalence of agricultural technology adoption and Teff production and various associated agricultural technology adoption and Teff production factors have been identified in the study area. Thus, the concerned stockholders should intervene in agricultural technology adoption and Teff production via different extension service and by considering household size, community-based household head education, and efficient use landholding in hectare.
SARS-CoV-2 replication triggers an MDA-5-dependent interferon production which is unable to efficiently control replication
Authors: Antoine Rebendenne , Valadão Ana Luiza Chaves , Marine Tauziet , Ghizlane Maarifi , Boris Bonaventure , Rémi Planès , Joe McKellar , Sébastien Nisole , Mary Arnaud-Arnould , Olivier Moncorgé , Caroline Goujon
Published: October 2020

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the third highly pathogenic coronavirus to spill over to humans in less than 20 years, after SARS-CoV-1 in 2002-2003 and Middle East respiratory syndrome (MERS)-CoV in 2012. SARS-CoV-2 is the etiologic agent of coronavirus disease 19 (COVID-19), which ranges from mild respiratory symptoms to severe lung injury and death in the most severe cases. The COVID-19 pandemic is currently a major health issue worldwide. Immune dysregulation characterized by altered innate cytokine responses is thought to contribute to the pathology of COVID-19 patients, which is a testimony of the fundamental role of the innate immune response against SARS-CoV-2. Here, we further characterized the host cell antiviral response against SARS-CoV-2 by using primary human airway epithelia and immortalized model cell lines. We mainly focused on the type I and III interferon (IFN) responses, which lead to the establishment of an antiviral state through the expression of IFN-stimulated genes (ISGs). Our results demonstrate that both primary airway epithelial cells and model cell lines elicit a robust immune response characterized by a strong induction of type I and III IFN through the detection of viral pathogen molecular patterns (PAMPs) by melanoma differentiation associated gene (MDA)-5. However, despite the high levels of type I and III IFNs produced in response to SARS-CoV-2 infection, the IFN response was unable to control viral replication, whereas IFN pre-treatment strongly inhibited viral replication andde novoproduction of infectious virions. Taken together, these results highlight the complex and ambiguous interplay between viral replication and the timing of IFN responses.
Phosphorothioate Substitutions in RNA Structure Studied by Molecular Dynamics Simulations, QM/MM Calculations and NMR Experiments
Authors: Zhang Zhengyue , Vögele Jennifer , Mráziková Klaudia , Kruse Holger , Cang Xiaohui , Wöhnert Jens , Krepl Miroslav , Šponer Jiří
Published: October 2020

Phosphorothioates (PTs) are important chemical modifications of the RNA backbone where a single non-bridging oxygen of the phosphate is replaced with a sulphur atom. PT can stabilize RNAs by protecting them from hydrolysis and is commonly used as tool to explore their function. It is, however, unclear what basic physical effects PT has on RNA stability and electronic structure. Here, we present Molecular Dynamics (MD) simulations, quantum mechanical (QM) calculations, and NMR spectroscopy measurements, exploring the effects of PT modifications in the structural context of the Neomycin-sensing riboswitch (NSR). The NSR is the smallest biologically functional riboswitch with a well-defined structure stabilized by a U-turn motif. Three of the signature interactions of the U-turn; an H-bond, an anion-π interaction and a potassium binding site; are formed by RNA phosphates, making the NSR an ideal model for studying how PT affects RNA structure and dynamics. By comparing with high-level QM calculations, we reveal the distinct physical properties of the individual interactions facilitated by the PT. The sulphur substitution, besides weakening the direct H-bond interaction, reduces the directionality of H-bonding while increasing its dispersion and induction components. It also reduces the induction and increases dispersion component of the anion-π stacking. The sulphur force-field parameters commonly employed in the literature do not reflect these distinctions, leading to unsatisfactory description of PT in simulations of the NSR. We show that it is not possible to accurately describe the PT interactions using one universal set of van der Waals sulphur parameters and provide suggestions for improving the force-field performance.
Characterization of spatial dynamics of fMRI data in white matter using diffusion-informed white matter harmonics
Authors: Behjat Hamid , Aganj Iman , Abramian David , Eklund Anders , Westin Carl-Fredrik
Published: October 2020

In this work, we leverage the Laplacian eigenbasis of voxelwise white matter (WM) graphs derived from diffusion-weighted MRI data, dubbedWM harmonics, to characterize the spatial structure of WM fMRI data. Our motivation for such a characterization is based on studies that show WM fMRI data exhibit a spatial correlational anisotropy that coincides with underlying fiber patterns. By quantifying the energy content of WM fMRI data associated with subsets of WM harmonics across multiple spectral bands, we show that the data exhibits notable subtle spatial modulations under functional load that are not manifested during rest. WM harmonics provide a novel means to study the spatial dynamics of WM fMRI data, in such way that the analysis is informed by the underlying anatomical structure.
Striking parallels between dorsoventral patterning inDrosophilaandGryllusreveal a complex evolutionary history behind a model gene regulatory network
Authors: Pechmann Matthias , Kenny Nathan James , Pott Laura , Heger Peter , Chen Yen-Ta , Buchta Thomas , Özüak Orhan , Lynch Jeremy , Roth Siegfried
Published: October 2020

Dorsoventral pattering relies on Toll and BMP signalling in all insects studied so far, with variations in the relative contributions of both pathways.Drosophilaand the beetleTriboliumshare extensive dependence on Toll, while representatives of more distantly related lineages like the waspNasoniaand bugOncopeltusrely more strongly on BMP signalling. Here, we show that in the cricketGryllus bimaculatus, an evolutionarily distant outgroup, Toll has, like inDrosophila, a direct patterning role for the ventral half of the embryo. In addition Toll polarizes BMP signalling, although this does not involve the conserved BMP inhibitor Sog/Chordin. Finally, Toll activation relies on ovarian patterning mechanisms with striking similarity toDrosophila.Our data suggest two surprising hypotheses: 1) that Toll’s patterning function inGryllusandDrosophilais the result of convergent evolution or 2) aDrosophila-likesystem arose early in insect evolution, and was extensively altered in multiple independent lineages.
The propofol binding sites of prokaryotic voltage-gated sodium channels
Authors: Yang Elaine , Bu Weiming , Suma Antonio , Carnevale Vincenzo , Grasty Kimberly C. , Loll Patrick , Woll Kellie , Bhanu Natarajan , Garcia Benjamin A. , Eckenhoff Roderic G. , Covarrubias Manuel
Published: October 2020

Propofol, one of the most commonly used intravenous general anesthetics, modulates neuronal function by interacting with ion channels. The mechanisms that link propofol binding to the modulation of distinct ion channel states, however, are not understood. To tackle this problem, we investigated prokaryotic ancestors of eukaryotic voltage-gated Na+channels (Navs) using unbiased photoaffinity labeling with a photoacitivatable propofol analog (AziPm), electrophysiological methods and mutagenesis. The results directly demonstrate conserved propofol binding sites involving the S4 voltage sensors and the S4-S5 linkers in NaChBac and NavMs, and also suggest state-dependent changes at these sites. Then, using molecular dynamics simulations to elucidate the structural basis of propofol modulation, we show that the S4 voltage sensors and the S4-S5 linkers shape two distinct propofol binding sites in a conformation-dependent manner. These interactions help explain how propofol binding promotes activation-coupled inactivation to inhibit Nav channel function.
Altered neural oscillations and behavior in a genetic mouse model of NMDA receptor hypofunction
Authors: Aguilar David D. , Radzik Leana K. , Schiffino Felipe L. , Folorunso Oluwarotimi , Zielinski Mark R. , Coyle Joseph T. , Balu Darrick T. , McNally James M.
Published: October 2020

Introduction

Abnormalities in electroencephalographic (EEG) biomarkers occur in patients with schizophrenia and those clinically at high risk for transition to psychosis and are associated with cognitive impairment. While the pathophysiology of schizophrenia remains poorly understood, converging evidence suggestsN-methyl-D-aspartate receptor (NMDAR) hypofunction plays a central role and likely contributes to biomarker impairments. Thus, the characterization of such biomarkers is of significant interest for both the early diagnosis of schizophrenia and the development of novel treatments.

Methods

We utilized an established model of chronic NMDAR hypofunction, serine racemase knockout (SRKO) mice.In vivoEEG recording and behavioral analyses were performed on adult male and female SRKO mice and wild-type littermates to determine the impact of chronic NMDAR hypofunction on a battery of translationally-relevant electrophysiological biomarkers.

Results

SRKO mice displayed impairments in investigation-elicited gamma power that corresponded with reduced short-term social recognition. This impairment was associated with enhanced background (pre-investigation) broadband gamma activity that only appeared during social task performance. Additionally, SRKO mice exhibited sensory gating impairments, in both gamma power and event-related potential amplitude. However, other biomarkers such as the auditory steady-state response, sleep spindles, and state-specific power spectral density were generally neurotypical.

Conclusions

SRKO mice provide a useful model to understand how chronic NMDAR hypofunction contributes to deficits in a subset of translationally-relevant EEG biomarkers that are altered in schizophrenia. Importantly, our gamma band findings support the hypothesis that an aberrant signal-to-noise ratio impairing cognition occurs with NMDAR hypofunction, which may be tied to impaired taskdependent alteration in functional connectivity.
Modulation of polyamine metabolism inArabidopsis thalianaby salicylic acid
Authors: Rossi Franco R. , Gárriz Andrés , Marina María , Pieckenstain Fernando L.
Published: October 2020

Polyamines (PAs) play important roles in plant defense against pathogens, but the regulation of PA metabolism by hormone-mediated defense signaling pathways has not been studied in depth. In this study, the modulation of PA metabolism in Arabidopsis by salicylic acid (SA) was analyzed, by combining the exogenous application of this hormone with the use of PA biosynthesis and SA synthesis/signaling mutants. SA induced notable modifications of polyamine metabolism, mainly consisting in putrescine accumulation both in whole-plant extracts and apoplastic fluids. Put was accumulated at the expense of increased biosynthesis by arginine decarboxylase 2 and decreased oxidation by copper amine oxidase. Enhancement of Put levels by SA was independent of the regulatory protein Non-Expressor of Pathogenesis Related 1 (NPR1) and the signaling kinases MKK4 and MPK3, but depended on MPK6. On its part, plant infection byPseudomonas syringaepv.tomatoDC3000 elicited Put accumulation in a SA-dependent way. The present study demonstrates a clear connection between SA signaling and plant PA metabolism in Arabidopsis and contributes to understand the mechanisms by which SA modulates PA levels during plant-pathogen interactions.

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Salicylic acid modulates polyamine biosynthesis and catabolism in Arabidopsis. Regulatory effects of salicylic acid are independent of the master regulator NPR1 and are mediated by the MPK6 kinase.
Evaluation of Methods for Protein Representation Learning: A Quantitative Analysis
Authors: Unsal Serbulent , Ataş Heval , Albayrak Muammer , Turhan Kemal , Acar Aybar C. , Doğan Tunca
Published: October 2020

Data-centric approaches have been utilized to develop predictive methods for elucidating uncharacterized aspects of proteins such as their functions, biophysical properties, subcellular locations and interactions. However, studies indicate that the performance of these methods should be further improved to effectively solve complex problems in biomedicine and biotechnology. A data representation method can be defined as an algorithm that calculates numerical feature vectors for samples in a dataset, to be later used in quantitative modelling tasks. Data representation learning methods do this by training and using a model that employs statistical and machine/deep learning algorithms. These novel methods mostly take inspiration from the data-driven language models that have yielded ground-breaking improvements in the field of natural language processing. Lately, these learned data representations have been applied to the field of protein informatics and have displayed highly promising results in terms of extracting complex traits of proteins regarding sequence-structure-function relations. In this study, we conducted a detailed investigation over protein representation learning methods, by first categorizing and explaining each approach, and then conducting benchmark analyses on;(i)inferring semantic similarities between proteins,(ii)predicting ontology-based protein functions, and(iii)classifying drug target protein families. We examine the advantages and disadvantages of each representation approach over the benchmark results. Finally, we discuss current challenges and suggest future directions. We believe the conclusions of this study will help researchers in applying machine/deep learning-based representation techniques on protein data for various types of predictive tasks. Furthermore, we hope it will demonstrate the potential of machine learning-based data representations for protein science and inspire the development of novel methods/tools to be utilized in the fields of biomedicine and biotechnology.
HiC-ACT: Improved Detection of Chromatin Interactions from Hi-C Data via Aggregated Cauchy Test
Authors: Lagler Taylor M. , Yang Yuchen , Abnousi Armen , Hu Ming , Li Yun
Published: October 2020

Genome-wide chromatin conformation capture technologies such as Hi-C are commonly employed to study chromatin spatial organization. In particular, to identify statistically significant long-range chromatin interactions from Hi-C data, most existing methods such as Fit-Hi-C/FitHiC2 and HiCCUPS assume that all chromatin interactions are statistically independent. Such an independence assumption is reasonable at low resolution (e.g., 40Kb bin), but is invalid at high resolution (e.g., 5 or 10Kb bins) since spatial dependency of neighboring chromatin interactions is non-negligible at high resolution. Our previous hidden Markov random field based methods accommodate spatial dependency but are computationally intensive. It is urgent to develop approaches that can model spatial dependence, in a computationally efficient and scalable manner. Here, we develop HiC-ACT, an aggregated Cauchy test (ACT) based approach, to improve the detection of chromatin interactions by post-processing results from methods assuming independence. To benchmark the performance of HiC-ACT, we re-analyzed deeply sequenced Hi-C data from a human lymphoblastoid cell line GM12878 and mouse embryonic stem cell line (mESC). Our results demonstrate advantages of HiC-ACT in improving sensitivity with controlled type-I error. By leveraging information from neighboring chromatin interactions, HiC-ACT enhances the power to detect interactions with lower signal to noise ratio and similar (if not stronger) epigenetic signatures that suggest regulatory roles. We further demonstrate that HiC-ACT peaks show higher overlap with known enhancers than Fit-Hi-C/FitHiC2 peaks, in both GM12878 and mESC. HiC-ACT, effectively a summary statistic based approach, is computationally efficient (~6 minutes and ~2GB memory to process 25,000 pairwise interactions).
Synaptic propagation in neuronal networks with finite-support space dependent coupling
Authors: Erazo Toscano Ricardo , Osan Remus
Published: October 2020

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Traveling waves of electrical activity are ubiquitous in biological neuronal networks. Traveling waves in the brain are associated with sensory processing, phase coding, and sleep. The neuron and network parameters that determine traveling waves’ evolution are synaptic space constant, synaptic conductance, membrane time constant, and synaptic decay time constant. We used an abstract neuron model to investigate the propagation characteristics of traveling wave activity. We formulated a set of evolution equations based on the network connectivity parameters. We numerically investigated the stability of the traveling wave propagation with a series of perturbations with biological relevance.
Using EngineeredEscherichia colito Synthesize Squalene with Optimized Manipulation of Squalene Synthase and Mevalonate Pathway
Authors: Sun Chenhao , Ding Yuancheng , Cheng Bingjing , Zong Yeqing
Published: October 2020

Squalene is the metabolic precursor of sterols and naturally synthesized in the deep-dea shark liver and human sebum. The utilization of squalene is wide such as food, cosmetical, and pharmaceutical industries. This experiment used engineered Escherichia coli to construct the gene circuit for the biosynthesis of squalene. Human squalene synthase (hSQS) efficiently catalyzes the synthesis of squalene. Also, mevalonate (MVA) pathway would increase the yield of the precursor of squalene, farnesyl diphosphate, which then increased the yield of squalene. Meanwhile, the regulation of MVA pathway via different inducer IPTG concentrations and creation of selection pressure by antibiotics were investigated.
Genomic surveillance and improved molecular typing ofBordetella pertussisusing wgMLST
Authors: Weigand Michael R. , Peng Yanhui , Pouseele Hannes , Kania Dane , Bowden Katherine E. , Williams Margaret M. , Tondella M. Lucia
Published: October 2020

Multi-Locus Sequence Typing (MLST) provides allele-based characterization of bacterial pathogens in a standardized framework. However, current MLST schemes forBordetella pertussis, the causative agent of whooping cough, seldom reveal diversity among the small number of gene targets and thereby fail to delineate population structure. To improve discriminatory power of allele-based molecular typing ofB. pertussis, we have developed a whole-genome MLST (wgMLST) scheme from 214 reference-quality genome assemblies. Iterative refinement and allele curation resulted in a scheme of 3,506 coding sequences and covering 81.4% of theB. pertussisgenome. This wgMLST scheme was further evaluated with data from a convenience sample of 2,389B. pertussisisolates sequenced on Illumina instruments, including isolates from known outbreaks and epidemics previously characterized by existing molecular assays, as well as replicates collected from individual patients. wgMLST demonstrated concordance with whole-genome single nucleotide polymorphisms (SNP) profiles, accurately resolved outbreak and sporadic cases in a retrospective comparison, and clustered replicate isolates collected from individual patients during diagnostic confirmation. Additionally, a re-analysis of isolates from two statewide epidemics using wgMLST reconstructed the population structures of circulating strains with increased resolution, revealing new clusters of related cases. Comparison with an existing core-genome (cgMLST) scheme highlights the genomic stability of this bacterium and forms the initial foundation for necessary standardization. These results demonstrate the utility of wgMLST for improvingB. pertussischaracterization and genomic surveillance during the current pertussis disease resurgence.
Infant functional connectivity fingerprints predict long-term language and pre-literacy outcomes
Authors: Yu Xi , Ferradal Silvina , Sliva Danielle D. , Dunstan Jade , Carruthers Clarisa , Sanfilippo Joseph , Zuk Jennifer , Zöllei Lilla , Boyd Emma , Gagoski Borjan , Grant P. Ellen , Gaab Nadine
Published: October 2020

Functional brain networks undergo extensive development within the first few years of life. Previous studies have linked infant functional connectivity to cognitive abilities in toddlerhood. However, little is known regarding the long-term relevance of functional connections established in infancy for the protracted development of higher-order abilities of language and literacy. Employing a five-year longitudinal imaging project starting in infancy, this study utilizes resting-state functional MRI to demonstrate prospective associations between infant functional connectivity fingerprints and subsequent language and foundational literacy skills at a mean age of 6.5. These longitudinal associations are preserved when key environmental influences are controlled for and are independent of emergent language abilities in infancy, suggesting early development of functional network characteristics in supporting the acquisition of high-order language and pre-literacy skills. Altogether, the current results highlight the importance of functional organization established in infancy as a neural scaffold underlying the learning process of complex cognitive functions.