bluuebunny/crossref_metadata_2025 huggingface dataset:
The Characteristics of Health Care Workers with COVID-19 and Relationship Between COVID-19 Mortality and BCG/Tuberculosis History: a multi-center study
Authors: Torun Ş , Özkaya Ş , Şen N , Kanat F , Karaman I , Yosunkaya Ş , Dikiş Ö Ş , Asan A , Eroğlu S A , Atal S S , Ayten Ö , Aksel N , Ermiş H , Özçelik N , Demirelli M , Kara İ , Sümer Ş , Marakoğlu K , Üzer F , Uyar Y , Çiçek T , Ünsal Z E , Vatansev H , Yıldırım B B , Kuruoğlu T , Atilla A , Ersoy Y , Kandemir B , Durduran Y , Cihan F G , Demirbaş N , Yıldırım F , Akcay M S
Published: October 2020

Background

Today, COVID-19 pandemic has brought countries’ health services into sharp focus. Despite the low incidence of cases(1.2%) and high mortality rate(2.4%) among Turkish population, the low mortality rate(0.3%) despite the high incidence(11.5%) declared in healthcare workers drew our group’s attention. Therefore, we aimed to report the characteristics of infected health-care workers and investigate the relationship between BCG vaccine and tuberculosis history with COVID-19 mortality in infected health-care worker population.

Method

This study was conducted in three hospitals to assess the clinical presentations, disease severity and correlation with BCG vaccine and tuberculous history in COVID-19 positive health-care workers by an online questionnaire platform. The relationship between characteristics and tuberculosis history were investigated according to hospitalization status of the patients.

Result

Total of 465 infected healthcare workers included in the study. The rate of history of direct care and contact to tuberculosis patient, presence of previous tuberculosis treatment and BCG scar, presence of radiological infiltrations was significantly higher in hospitalized healthcare workers. The ratio of direct care and direct contact to the patient with tuberculosis, and presence of family history of tuberculosis were statistically significantly higher in patients with radiological infiltrations.

Conclusion

Although COVID-19 risk and incidence are higher among healthcare workers compared to the normal population due to higher virus load, this study brings evidence for the fact that the lower mortality rate seen in infected healthcare workers might be due to healthcare workers’ frequent exposure to tuberculosis bacillus and the mortality-reducing effects of BCG vaccine, despite the higher hospitalization rate and radiological infiltrations due to over-triggered immune system.
Examining Unit Costs for COVID-19 Case Management in Kenya
Authors: Barasa Edwine , Kairu Angela , Nganga Wangari , Maritim Marybeth , Were Vincent , Akech Samuel , Mwangangi Mercy
Published: October 2020

Introduction

Case management for COVID-19 patients is one of key interventions in country responses to the pandemic. Countries need information on the costs of case management to inform resource mobilization, planning and budgeting, purchasing arrangements, and assessments of the cost-effectiveness of interventions. We estimated unit costs for COVID-19 case management for patients with asymptomatic, mild to moderate, severe, and critical COVID-19 disease in Kenya.

Methods

We estimated per patient per day unit costs of COVID-19 case management for patients that are asymptomatic and those that have mild to moderate, severe, and critical symptoms. For asymptomatic and mild to moderate patients, we estimated unit costs for home-based care and institutional (hospitals and isolation centers). We used an ingredients approach, adopted a health system perspective and patient episode of care as our time horizon. We obtained data on inputs and their quantities from COVID-19 case management guidelines, home based care guidelines, and human resource guidelines, and augmented this with data provided by three public covid-19 treatment hospitals in Kenya. We obtained input prices for services from a recent costing survey of 20 hospitals in Kenya and for pharmaceuticals, non-pharmaceuticals, devices and equipment from market price databases for Kenya.

Results

Per day per patient unit cost for asymptomatic patients and patients with mild to moderate COVID-19 disease under home based care are KES 1,993.01 (USD 18.89) and 1995.17 (USD 18.991) respectively. When these patients are managed in an isolation center of hospital, the same unit costs for asymptomatic patients and patients with mild to moderate disease are 7,415.28 (USD 70.29) and 7,417.44 (USD 70.31) respectively. Per day unit costs for patients with severe COVID-19 disease managed in general hospital wards and those with critical COVID-19 disease admitted in intensive care units are 12,570.75 (USD 119.16) and 59,369.42 (USD 562.79).

Conclusion

COVID-19 case management costs are substantial. Unit costs for asymptomatic and mild to moderate COVID-19 patients in home-based care is 4-fold lower compared institutional care of the same patients. Kenya will not only need to mobilize substantial resources to finance COVID-19 case management but also explore additional service delivery adaptations that will reduce unit costs.
Functional connectivity directionality between large-scale resting-state networks in children and adolescence from the Healthy Brain Network sample
Authors: Lund Martina J. , Alnæs Dag , Rokicki Jaroslav , Schwab Simon , Andreassen Ole A. , Westlye Lars T. , Kaufmann Tobias
Published: October 2020

Mental disorders often emerge during adolescence and have been associated with age-related differences in connection strengths of brain networks (static functional connectivity), manifesting in non-typical trajectories of brain development. However, little is known about the direction of information flow (directed functional connectivity) in this period of functional brain progression. We employed dynamic graphical models (DGM) to estimate directed functional connectivity from resting state functional magnetic resonance imaging data on 1143 participants, aged 6 to 17 years from the healthy brain network (HBN) sample. We tested for effects of age, sex, cognitive abilities and psychopathology on estimates of direction flow. Across participants, we show a pattern of reciprocal information flow between visual-medial and visual-lateral connections, in line with findings in adults. Investigating directed connectivity patterns between networks, we observed a positive association for age and direction flow from the cerebellar to the auditory network, and for the auditory to the sensorimotor network. Further, higher cognitive abilities were linked to lower information flow from the visual occipital to the default mode network. Additionally, examining the degree networks overall send and receive information to each other, we identified age-related effects implicating the right frontoparietal and sensorimotor network. However, we did not find any associations with psychopathology. Our results revealed that the directed functional connectivity of large-scale brain networks is sensitive to age and cognition during adolescence, warranting further studies that may explore trajectories of development in more fine-grained network parcellations and in different populations.
Characterization of presumptive vancomycin-resistant enterococci recovered during infection control surveillance in Dallas, Texas
Authors: Ping Sara , Mayorga-Reyes Nancy , Price Valerie J. , Onuoha Michelle , Bhardwaj Pooja , Rodrigues Marinelle , Owen Jordan , Araya Dennise Palacios , Akins Ronda L. , Palmer Kelli L.
Published: October 2020

Enterococcus faecalis and E. faecium are Gram-positive bacteria that normally inhabit the human gastrointestinal tract. They are also opportunistic pathogens and can cause nosocomial infection outbreaks. To prevent the spread of nosocomial infections, hospitals may rely on screening methods to identify patients colonized with multidrug-resistant organisms including vancomycin-resistant enterococci (VRE). Spectra VRE agar (Remel) contains vancomycin and other medium components that select for VRE and phenotypically differentiate between faecalis and faecium species by colony color. We obtained 66 de-identified rectal swab cultures on Spectra VRE agar that were obtained during routine patient admission surveillance at a Dallas, Texas hospital. We analyzed 90 presumptive VRE from 61 of the Spectra VRE agar cultures using molecular and culture methods. Using ddl typing, 55 were found to be E. faecium and 32 were found to be E. faecalis. While most of the E. faecium were positive for the vanA gene by PCR (52 of 55 strains), few of the E. faecalis were positive for either vanA or vanB (5 of 32 strains). The 27 E. faecalis vanA- and vanB-negative strains could not be recultured on Spectra VRE agar. Overall, we found that Spectra VRE agar performed robustly for the identification of vancomycin-resistant E. faecium, but presumptive false positives were obtained for vancomycin-resistant E. faecalis.
Peripheral Blood DNA Methylation Changes after Omega-3 Fatty Acid Treatment Indicate Anti-inflammatory Effects and Individual Variability
Authors: Frankhouser David E , Steck Sarah , Sovic Michael G , Belury Martha A , Bundschuh Ralf , Yan Pearlly S , Yee Lisa D
Published: October 2020

Background

Omega-3 or n-3 polyunsaturated fatty acids (PUFAs) are widely studied for health benefits based on potential anti-inflammatory effects. However, the factors involved in mediating the anti-inflammatory responses to n-3 PUFAs are not fully understood; furthermore, many effects from n-3 PUFA treatment are not well characterized in humans. Of interest is the role of DNA methylation (DNAm) in mediating the effects of n-3 PUFAs on inflammation.

Objective

We aimed to characterize the effects of n-3 PUFA treatment on DNAm in inflammation-related signaling pathways in PBMCs of women at high risk of breast cancer

Methods

PBMCs of women at high risk of breast cancer were obtained at 0 and 6 months of n-3 PUFA treatment in a previously reported dose finding trial (n=10 matched pairs in the 5 g/day EPA+DHA dose arm).[53] DNA methylation of PBMCs were assayed using reduced representation bisulfite sequencing to obtain genome-wide methylation profiles on a single nucleotide level. Analyses were performed to investigate the effects of n-3 PUFA treatment on DNAm both genome-wide and within a set of candidate genes.

Results

A large number of differentially methylated CpGs (DMCs) in gene promoters (24,842 DMCs in 5507 genes) showed significant enrichment for hypermethylation in both the candidate gene and genome-wide analyses. Using these DNAm changes, pathway analysis identified significantly hypermethylated signaling networks after n-3 PUFA treatment, such as the Toll-like Receptor pathway. Based on analyses of data per individual, DNAm changes from n-3 PUFA treatment appear highly variable between study participants.

Conclusions

Dietary n-3 PUFA supplementation for six months is associated with DNAm changes in PBMCs with potential for anti-inflammatory effects. PBMC DNAm profiles may offer a novel means of assessing individual response to n-3 PUFAs. This observation warrants further investigation in future n-3 PUFA intervention studies.
COVID-19 serological survey using micro blood sampling
Authors: Matthews Melissa M. , Kim Tae Gyun , Shibata Satoshi , Shibata Noriko , Butcher Christian , Hyun Jaekyung , Kim Keon Young , Robb Theodore , Jheng Siang Sheng , Narita Masashi , Mori Tomoari , Collins Mary , Wolf Matthias
Published: October 2020

During August 2020, we carried out a serological survey among students and employees at the Okinawa Institute of Science and Technology Graduate University (OIST), Japan, testing for the presence of antibodies against SARS-CoV-2, the causative agent of COVID-19. We used a FDA-authorized 2-step ELISA protocol (1, 2) in combination with at-home self-collection of blood samples using a custom low-cost finger prick-based capillary blood collection kit. Although our survey did not find any COVID-19 seropositive individuals among the OIST cohort, it reliably detected all positive control samples obtained from a local hospital and excluded all negatives controls. We found that high serum antibody titers can persist for at least up to 6.5 months post infection. Among our controls, we found strong cross-reactivity of antibodies in samples from a serum pool from two MERS patients in the anti-SARS-CoV-2-S ELISA. Here we show that a centralized ELISA in combination with patient-based capillary blood collection using as little as one drop of blood can reliably assess the seroprevalence among communities. Anonymous sample tracking and an integrated website created a stream-lined procedure. Major parts of the workflow were automated on a liquid handler, demonstrating scalability. We anticipate this concept to serve as a prototype for reliable serological testing among larger populations.
Development and validation of the 4C Deterioration model for adults hospitalised with COVID-19
Authors: Gupta Rishi K , Harrison Ewen M , Ho Antonia , Docherty Annemarie B , Knight Stephen R , van Smeden Maarten , Abubakar Ibrahim , Lipman Marc , Quartagno Matteo , Pius Riinu , Buchan Iain , Carson Gail , Drake Thomas M , Dunning Jake , Fairfield Cameron J , Gamble Carrol , Green Christopher A , Halpin Sophie , Hardwick Hayley E , Holden Karl A , Horby Peter W , Jackson Clare , Mclean Kenneth A , Merson Laura , Nguyen-Van-Tam Jonathan S , Norman Lisa , Olliaro Piero L , Pritchard Mark G , Russell Clark D , Scott-Brown James , Shaw Catherine A , Sheikh Aziz , Solomon Tom , Sudlow Cathie , Swann Olivia V , Turtle Lance , Openshaw Peter JM , Baillie J Kenneth , Semple Malcolm G , Noursadeghi Mahdad
Published: October 2020

Prognostic models to predict the risk of clinical deterioration in acute COVID-19 are required to inform clinical management decisions. Among 75,016 consecutive adults across England, Scotland and Wales prospectively recruited to the ISARIC Coronavirus Clinical Characterisation Consortium (ISARIC4C) study, we developed and validated a multivariable logistic regression model for in-hospital clinical deterioration (defined as any requirement of ventilatory support or critical care, or death) using 11 routinely measured variables. We used internal-external cross-validation to show consistent measures of discrimination, calibration and clinical utility across eight geographical regions. We further validated the final model in held-out data from 8,252 individuals in London, with similarly consistent performance (C-statistic 0.77 (95% CI 0.75 to 0.78); calibration-in-the-large 0.01 (−0.04 to 0.06); calibration slope 0.96 (0.90 to 1.02)). Importantly, this model demonstrated higher net benefit than using other candidate scores to inform decision-making. Our 4C Deterioration model thus demonstrates unprecedented clinical utility and generalisability to predict clinical deterioration among adults hospitalised with COVID-19.
Mathematical formulation and application of kernel tensor decomposition based unsupervised feature extraction
Authors: Taguchi Y-h. , Turki Turki
Published: October 2020

In this work, we extended the recently developed tensor decomposition (TD) based unsupervised feature extraction (FE) to a kernel-based method through a mathematical formulation. Subsequently, the kernel TD (KTD) based unsupervised FE was applied to two synthetic examples as well as real data sets, and the findings were compared with those obtained previously using the TD-based unsupervised FE approaches. The KTD-based unsupervised FE outperformed or performed comparably with the TD-based unsupervised FE inlarge p small nsituations, which are situations involving a limited number of samples with many variables (observations). Nevertheless, the KTD-based unsupervised FE outperformed the TD-based unsupervised FE in nonlarge p small nsituations. In general, although the use of the kernel trick can help the TD-based unsupervised FE gain more variations, a wider range of problems may also be encountered. Considering the outperformance or comparable performance of the KTD-based unsupervised FE compared to the TD-based unsupervised FE when applied tolarge p small nproblems, it is expected that the KTD-based unsupervised FE can be applied in the genomic science domain, which involves manylarge p small nproblems, and, in which, the TD-based unsupervised FE approach has been effectively applied.
A Mathematical Model and Optimal Control for Listeriosis Disease from Ready-to-Eat Food Products
Authors: Chukwu Williams , Nyabadza Farai
Published: October 2020

Ready-to-eat food (RTE) are foods that are intended by the producers for direct human consumption without the need for further preparation. The primary source of human Listeriosis is mainly through ingestion of contaminated RTE food products. Thus, implementing control strategies for Listeriosis infectious disease is vital for its management and eradication. In the present study, a deterministic model of Listeriosis disease transmission dynamics with control measures was analyzed. We assumed that humans are infected with Listeriosis either through ingestion of contaminated food products or directly with Listeria Monocytogenes in their environment. Equilibrium points of the model in the absence of control measures were determined, and their local asymptotic stability established. We formulate an optimal control problem and analytically give sufficient conditions for the optimality and the transversality conditions for the model with controls. Numerical simulations of the optimal control strategies were performed to illustrate the results. The numerical findings suggest that constant implementation of the joint optimal control measures throughout the modelling time will be more efficacious in controlling or reducing the Listeriosis disease. The results of this study can be used as baseline measures in controlling Listeriosis disease from ready-to-eat food products.
Conservation status, threats, and information needs of small mammals in Alaska
Authors: Droghini A. , Christie K. S. , Kelty R. R. , Schuette P. , Gotthardt T. A.
Published: October 2020

Despite their diversity and ecological importance, small mammals are under-represented in conservation research relative to other mammals. We evaluated the conservation status of 36 small mammal species in Alaska, U.S.A. using a ranking system that we previously developed, the Alaska Species Ranking System (ASRS). We compared results from the ASRS with NatureServe’s subnational rankings. Finally, we surveyed taxonomic experts to identify recommended conservation actions and research priorities for 5 species of high conservation concern. In general, the ASRS and NatureServe agreed on the rankings of species in the highest and lowest risk categories. Species of highest conservation concern were taxa endemic to the state, including 2 island-endemic shrews, and taxa from the orders Chiroptera and Eulipotyphla. Because the ASRS includes information needs in its assessment, 15 of the 20 species considered lowest concern by NatureServe were considered intermediate concern by the ASRS. In the ASRS, most species (n= 24) were assessed to have low biological vulnerabilities, but high information needs. Population size and trends were unknown for all species; distributional limits and understanding of population dynamics were incomplete for all species except 4. Disease and climate change effects on habitat were perceived as important threats, but affected only 8 species. Taxonomic experts identified addressing data deficiencies and protecting habitat as important conservation actions; they identified monitoring population trends, modeling habitat, and researching species’ genetic diversity and adaptive capacity as high priorities. Conservation assessments that require accurate and current data on population trends or threats may lead to bias against data deficient groups such as small mammals. Our findings demonstrate the importance of accounting for data deficiencies in conservation status ranks to avoid conflation of sparse information with low conservation concern.
Light transport modeling in highly complex tissues using implicit mesh-based Monte Carlo algorithm
Authors: Yuan Yaoshen , Yan Shijie , Fang Qianqian
Published: October 2020

The mesh-based Monte Carlo (MMC) technique has grown tremendously since its initial publication nearly a decade ago. It is now recognized as one of the most accurate Monte Carlo (MC) methods, providing accurate reference solutions for the development of novel biophotonics techniques. In this work, we aim to further advance MMC to address a major challenge in biophotonics modeling, i.e. light transport within highly complex tissues, such as dense microvascular networks, porous media and multi-scale tissue structures. Although the current MMC framework is capable of simulating light propagation in such media given its generality, the run-time and memory usage grow rapidly with increasing media complexity and size. This greatly limits our capability to explore complex and multi-scale tissue structures. Here, we propose a highly efficient implicit mesh-based Monte Carlo (iMMC) method that incorporates both mesh- and shape-based tissue representations to create highly complex yet memory efficient light transport simulations. We demonstrate that iMMC is capable of providing accurate solutions for dense vessel networks and porous tissues while reducing memory usage by greater than a hundred- or even thousand-fold. In a sample network of microvasculature, the reduced shape complexity results in nearly 3x speed acceleration. The proposed algorithm is now available in our open-source MMC software athttp://mcx.space/#mmc.
Discovery of the first selective M4muscarinic acetylcholine receptor antagonists within vivoanti-parkinsonian and anti-dystonic efficacy
Authors: Moehle Mark S. , Bender Aaron M. , Dickerson Jonathan W. , Foster Daniel J. , Donsante Yuping , Peng Weimin , Bryant Zoey , Bridges Thomas M. , Chang Sichen , Watson Katherine J. , O’Neill Jordan C. , Engers Julie L. , Peng Li , Rodriguez Alice L. , Niswender Colleen M. , Lindsley Craig W. , Hess Ellen J. , Conn P. Jeffrey , Rook Jerri M.
Published: October 2020

Non-selective antagonists of muscarinic acetylcholine receptors (mAChRs) that broadly inhibit all five mAChR subtypes provide an efficacious treatment for some movement disorders, including Parkinson disease and dystonia. Despite their efficacy in these and other central nervous system disorders, anti-muscarinic therapy has limited utility due to severe adverse effects that often limit their tolerability by patients. Recent advances in understanding the roles that each mAChR subtype plays in disease pathology suggest that highly selective ligands for individual subtypes may underlie the anti-parkinsonian and anti-dystonic efficacy observed with the use of non-selective anti-muscarinic therapeutics. Our recent work has indicated that the M4muscarinic acetylcholine receptor has several important roles in opposing aberrant neurotransmitter release, intracellular signaling pathways, and brain circuits associated with movement disorders. This raises the possibility that selective antagonists of M4may recapitulate the efficacy of non-selective anti-muscarinic therapeutics and may decrease or eliminate the adverse effects associated with these drugs. However, this has not been directly tested due to lack of selective antagonists of M4. Here we utilize genetic mAChR knockout animals in combination with non-selective mAChR antagonists to confirm that the M4receptor underlies the locomotor-stimulating and anti-parkinsonian efficacy in rodent models. We also report the synthesis, discovery, and characterization of the first-in-class selective M4antagonists VU6013720, VU6021302, and VU6021625 and confirm that these optimized compounds have anti-parkinsonian and anti-dystonic efficacy in pharmacological and genetic models of movement disorders.
Conservation of dynamic characteristics of transcriptional regulatory elements in periodic biological processes
Authors: Motta Francis C. , Moseley Robert C. , Cummins Bree , Deckard Anastasia , Haase Steven B.
Published: October 2020

Cell and circadian cycles control a large fraction of cell and organismal physiology by regulating large periodic transcriptional programs that encompass anywhere from 15-80% of the genome. The gene-regulatory networks (GRNs) controlling these programs were largely identified by genetics and chromosome mapping approaches in model systems, yet it is unlikely that we have identified all of the core GRN components. Moreover, large periodic transcriptional programs controlling a variety of processes certainly exist in important non-model organisms where genetic approaches to identifying networks are expensive, time-consuming or intractable. Ideally, the core network components could be identified using data-driven approaches on the transcriptome dynamics data already available. Previous work used dynamic gene expression features to identify sets of genes with periodic behavior; our work goes further to distinguish genes by role: core versus their non-regulatory outputs. Here we present a quantitative approach that can identify nodes of GRNs controlling cell or circadian cycles across taxa. There are practical applications of the approach for network biologists, but our findings reveal something unexpected—that there are quantifiable and fundamental shared features of these unrelated GRNs controlling disparate periodic phenotypes.

Author summary

Circadian rhythms, cellular division, and the developmental cycles of a multitude of living creatures, including those responsible for infectious diseases, are among the many dynamic phenomena in the natural world that are known to be the eventual output of gene regulatory networks. Identifying the small number of specialized genes that control these dynamic behaviors is of fundamental importance to our understanding of life, and our treatment of disease, but is difficult because of the sheer size of the genomes. We show that the core genes in organisms separated by millions of years of evolution have remarkable similarities that can be used to identify them.
Design and development of a vortex ring generator to study the impact of the ring as a gust
Authors: Gupta Dipendra , Sane Sanjay P. , Arakeri Jaywant H.
Published: October 2020

We present a simple method to generate discrete aerodynamic gust under controlled laboratory condition in the form of a vortex ring which, unlike conventional methods of perturbation, is well studied and highly controllable. We characterized the flow properties of the vortex ring using flow visualization and novel light bead method. Reynolds number of the vortex ring, based on its average propagation velocity and nozzle exit diameter, was 16000. We demonstrate this method by studying the impact of head-on gust on freely flying soldier flies, Reynolds number of which, based on its wingtip velocity and mean wing chord, was 1100. We also present simple theoretical models to characterize the vortex ring based on generating conditions. The device can also be used to generate continuous gust in any direction and can be applied, in general, to study the gust response of natural fliers and swimmers, man-made micro aerial vehicles and aquatic plant lives.
Jurassic NLR: conserved and dynamic evolutionary features of the atypically ancient immune receptor ZAR1
Authors: Adachi Hiroaki , Sakai Toshiyuki , Kourelis Jiorgos , Pai Hsuan , Gonzalez Hernandez Jose L. , Maqbool Abbas , Kamoun Sophien
Published: October 2020

In plants, NLR immune receptors generally exhibit hallmarks of rapid evolution even at the intraspecific level. We used iterative sequence similarity searches coupled with phylogenetic analyses to reconstruct the evolutionary history of ZAR1, an atypically conserved NLR that traces its origin to early flowering plant lineages ∼220 to 150 million years ago (Jurassic period). We discovered 120 ZAR1 orthologs in 88 species, including the monocotColacasia esculenta, the magnoliidCinnamomum micranthumand the majority of eudicots, notably the early diverging eudicot speciesAquilegia coerulea. Ortholog sequence analyses revealed highly conserved features of ZAR1, including regions for pathogen effector recognition, intramolecular interactions and cell death activation. We functionally reconstructed the cell death activity of ZAR1 and its partner receptor-like cytoplasmic kinase (RLCK) from distantly related plant species, experimentally validating the hypothesis that ZAR1 has evolved to be a partner with RLCKs early in its evolution. In addition, ZAR1 acquired novel features, such as a C-terminal integration of a thioredoxin-like domain. ZAR1 duplicated into two paralog families, which underwent distinct evolutionary paths. We conclude that ZAR1 stands out among angiosperm NLRs for having experienced relatively limited gene duplication and expansion throughout its deep evolutionary history. Nonetheless, ZAR1 did also give rise to non-canonical NLR proteins with integrated domains and degenerated molecular features.
Between-subject correlation of heart rate variability predicts movie preferences
Authors: So Tsz Yan , Li Man Yi Erica , Lau Hakwan
Published: October 2020

We introduce a novel and simple method for assessing audiences’ emotional responses to audiovisuals (e.g. films). Viewers (N=21) watched movies and TV commercials from different genres while wearing photoplethysmography (PPG) optic sensors on their wrists. Heart rate variability (HRV) synchrony was observed among the audience. Based on this between-subject synchrony measure, we identified emotionally arousing segments from the materials. New participants (N=24;N=16) were then invited to watch these identified segments along with some randomly selected segments as control; they reported that the former was more engaging (effect sizew=.67;w=.5). This finding was confirmed in an online study with a larger cohort (N=300). While some specific effects varied depending on movie genre or gender, HRV-based editing generally performed better than the control. These findings suggest that HRV synchrony can be used as a new tool for audience psychology, and potentially also for automatically creating short trailers out of movies in a principled manner while taking into account the human perspective.
Synapse-specific direction selectivity in retinal bipolar cell axon terminals
Authors: Matsumoto Akihiro , Agbariah Weaam , Nolte Stella Solveig , Andrawos Rawan , Levi Hadara , Sabbah Shai , Yonehara Keisuke
Published: October 2020

The ability to encode the direction of image motion is fundamental to our sense of vision. Direction selectivity along the four cardinal directions is thought to originate in direction-selective ganglion cells (DSGCs), due to directionally-tuned GABAergic suppression by starburst cells. Here, by utilizing two-photon glutamate imaging to measure synaptic release, we reveal that direction selectivity along all four directions arises earlier than expected, at bipolar cell outputs. Thus, DSGCs receive directionally-aligned glutamatergic inputs from bipolar cell boutons. We further show that this bouton-specific tuning relies on cholinergic excitation and GABAergic inhibition from starburst cells. In this way, starburst cells are able to refine directional tuning in the excitatory visual pathway by modulating the activity of DSGC dendrites and their axonal inputs using two different neurotransmitters.
Development of an orally-administrable tumor vasculature-targeting therapeutic using annexin A1-binding D-peptides
Authors: Nonaka Motohiro , Mabashi-Asazuma Hideaki , Jarvis Donald L. , Yamasaki Kazuhiko , Akama Tomoya O. , Nagaoka Masato , Sasai Toshio , Kimura-Takagi Itsuko , Suwa Yoichi , Yaegashi Takashi , Huang Chun-Ten , Nishizawa-Harada Chizuko , Fukuda Michiko N.
Published: October 2020

IF7 peptide, which binds to the annexin A1 (ANXA1) N-terminal domain, functions as a tumor vasculature-targeted drug delivery vehicle after intravenous injection. To enhance IF7 stability in vivo, we undertook mirror-image peptide phage display using a synthetic D-peptide representing the Anxa1 N-terminus as target. Peptide sequences were identified, synthesized as D-amino acids, and designated as dTIT7, which was shown to bind the ANXA1 N-terminus. Whole body imaging of mouse brain tumors modeled with near infrared fluorescent IRDye-conjugated dTIT7 showed fluorescent signals in brain and kidney. Furthermore, orally-administered geldanamycin (GA)-conjugated dTIT7 suppressed brain tumor growth. Ours is a proof-of-concept experiment showing that Anxa1-binding D-peptide could be developed as an orally-administrable, tumor vasculature-targeted therapeutic.

Role of each author: MN designed and performed experiments, analyzed data, and wrote the manuscript; HMA and DLJ produced recombinant ANXA1 protein; KY conducted NMR analysis and data analysis; TOA designed, performed and analyzed LC-MS/MS data; MN, TS, IKT, YS, and TY analyzed peptide-binding assays and performed in silico structural analysis; CTU produced lentivirus for luciferase expression; CNH performed peptide binding assays, tissue culture and animal experiments; and MNF supervised the project and wrote the manuscript.
A protease protection assay for the detection of internalized alpha-synuclein pre-formed fibrils
Authors: Jarvela Timothy S. , Chaplot Kriti , Lindberg Iris
Published: October 2020

Alpha-synuclein pre-formed fibrils (PFFs) represent a promising model system for the study of cellular processes underlying cell-to-cell transmission of alpha-synuclein proteopathic aggregates. However, the ability to differentiate the fate of internalized PFFs from those which remain in the extracellular environment remains limited due to the propensity for PFFs to adhere to the cell surface. Removal of PFFs requires repeated washing and/or specific quenching of extracellular fluorescent PFF signals. In this paper we present a new method for analyzing the fate of internalized alpha-synuclein. We inserted a tobacco etch virus (TEV) protease cleavage site between alpha-synuclein and green fluorescent protein and subjected cells to brief treatment with TEV protease after incubation with tagged PFFs. As the TEV protease is highly specific, non-toxic, and active under physiological conditions, protection from TEV cleavage can be used to distinguish internalized PFFs from those which remain attached to the cell surface. Using this experimental paradigm, downstream intracellular events can be analyzed via live or fixed cell microscopy as well as by Western blotting. We suggest that this method will be useful for understanding the fate of PFFs after endocytosis under various experimental manipulations.
Relationship between personality and cognitive traits in domestic rabbits (Oryctolagus cuniculus)
Authors: GomezdelaTorre Clavel Macarena G. , Youngblood Mason , Lahti David
Published: October 2020

Domestication is the process by which species adapt to, and are artificially selected for, human-made environments. Few studies have explored how the process of domestication has affected the connection between behavioral traits and cognitive abilities in animals. This study investigated the relationship between personality and cognitive traits in domestic rabbits (Oryctolagus cuniculus). Fifteen individuals kept in a rabbit rescue facility were tested over a period of two months. We measured the linkage between behavioral traits (response to a novel object and exploration time) and cognitive performance. Our results suggest that there is no relationship between personality traits and problem solving abilities in domestic rabbits. In addition, our results suggest that exploration time is significantly repeatable at the individual level while latency to approach a novel object is not. Thus further research is needed to explore the relationship between cognitive and personality traits in domestic rabbits.
Using Machine Learning To Develop A Fully Automated Soybean Nodule Acquisition Pipeline (SNAP)
Authors: Jubery Talukder Zaki , Carley Clayton N. , Singh Arti , Sarkar Soumik , Ganapathysubramanian Baskar , Singh Asheesh K.
Published: October 2020

Nodules form on plant roots through the symbiotic relationship between soybean (Glycine maxL. Merr.) roots and bacteria (Bradyrhizobium japonicum), and are an important structure where atmospheric nitrogen (N2) is fixed into bio-available ammonia (NH3) for plant growth and developmental. Nodule quantification on soybean roots is a laborious and tedious task; therefore, assessment is done on a less informative qualitative scale. We report the Soybean Nodule Acquisition Pipeline (SNAP) for nodule quantification that combines RetinaNet and UNet deep learning architectures for object (i.e., nodule) detection and segmentation. SNAP was built using data from 691 unique roots from diverse soybean genotypes, vegetative growth stages, and field locations; and has a prediction accuracy of 99%. SNAP reduces the human labor and inconsistencies of counting nodules, while acquiring quantifiable traits related to nodule growth, location and distribution on roots. The ability of SNAP to phenotype nodules on soybean roots at a higher throughput enables researchers to assess the genetic and environmental factors, and their interactions on nodulation from an early development stage. The application of SNAP in research and breeding pipelines may lead to more nitrogen use efficient soybean and other legume species cultivars, as well as enhanced insight into the plant-Bradyrhizobiumrelationship.
Sustained nitrogen loss in a symbiotic association of ComammoxNitrospiraand Anammox bacteria
Authors: Gottshall Ekaterina Y. , Bryson Sam J. , Cogert Kathryn I. , Landreau Matthieu , Sedlacek Christopher J. , Stahl David A. , Daims Holger , Winkler Mari
Published: October 2020

The discovery of complete aerobic and anaerobic ammonia-oxidizing bacteria (Comammox and Anammox) significantly altered our understanding of the global nitrogen cycle. A high affinity for ammonia (Km(app),NH3≈ 63nM) and oxygen place the first described isolate, ComammoxNitrospira inopinatain the same trophic category as organisms such as some ammonia-oxidizing archaea. However,N. inopinatahas a relatively low affinity for nitrite (Km,NO2≈ 449.2μM) suggesting it would be less competitive for nitrite than other nitrite-consuming aerobes and anaerobes. We examined the ecological relevance of the disparate substrate affinities by coupling it with Anammox (Nitrospira inopinataandBrocadia anammoxidans, respectively). Synthetic communities were established in hydrogel granules in which Comammox grew in the aerobic outer layer to provide Anammox with nitrite in the inner anoxic core to form dinitrogen gas. This spatial organization was confirmed with FISH imaging, supporting a mutualistic or commensal relationship. Successful co-habitation of ComammoxN. inopinataand Anammox in synthetic granules broadens our limited understanding of the interplay between these two species and offers potential biotechnological applications to study any type of bacterial pairings in a systematic and reproducible manner.
Post-transcriptional regulation of redox homeostasis by the small RNA SHOxi in haloarchaea
Authors: Gelsinger Diego Rivera , Reddy Rahul , Whittington Kathleen , Debic Sara , DiRuggiero Jocelyne
Published: October 2020

Haloarchaea are highly resistant to oxidative stress, however, a comprehensive understanding of the processes regulating this remarkable response is lacking. Oxidative stress-responsive small non-coding RNAs (sRNAs) have been reported in the model archaeon,Haloferax volcanii, but targets and mechanisms have not been elucidated. Using a combination of high throughput and reverse molecular genetic approaches, we elucidated the functional role of the most up-regulated intergenic sRNA during oxidative stress inH. volcanii, namedSmall RNA inHaloferaxOxidative Stress (SHOxi). SHOxi was predicted to form a stable secondary structure with a conserved stem-loop region as the potential binding site for trans-targets. NAD-dependent malic enzyme mRNA, identified as a putative target of SHOxi, interacted directly with a putative “seed” region within the predicted stem loop of SHOxi. Malic enzyme is an enzyme of the tricarboxylic acid cycle that catalyzes the oxidative decarboxylation of malate into pyruvate using NAD+as a cofactor. The destabilization of malic enzyme mRNA, and the decrease in the NAD+/NADH ratio, resulting from the direct RNA-RNA interaction between SHOxi and its trans-target was essential for the survival ofH. volcaniito oxidative stress. These findings indicate that SHOxi likely regulates redox homeostasis during oxidative stress by the post-transcriptional destabilization of malic enzyme mRNA. SHOxi-mediated regulation provides evidence that the fine-tuning of metabolic cofactors could be a core strategy to mitigate damage from oxidative stress and confer resistance. This study is the first to establish the regulatory effects of sRNAs on mRNAs during the oxidative stress response in Archaea.
Expansion and transformation of the minor spliceosomal system in the slime moldPhysarum polycephalum
Authors: Larue Graham E. , Eliáš Marek , Roy Scott W.
Published: October 2020

Spliceosomal introns interrupt nuclear genes and are removed from RNA transcripts (“spliced”) by machinery called spliceosomes. While the vast majority of spliceosomal introns are removed by the so-called major spliceosome, diverse eukaryotes also contain a mysterious second form, the minor spliceosome, and associated introns [1–3]. In all characterized species, minor introns are distinguished by several features, including being rare in the genome (∼0.5% of all introns) [4–6], containing extended evolutionary-conserved splicing sites [4,5,7,8], being generally ancient [9,10] and being inefficiently spliced [11–13]. Here, we report a remarkable exception in the slime moldPhysarum polycephalum. TheP. polycephalumgenome contains > 20,000 minor introns—25 times more than any other species—with transformed splicing signals that have co-evolved with the spliceosome due to massive gain of efficiently spliced minor introns. These results reveal an unappreciated dynamism of minor spliceosomal introns and spliceosomal introns in general.
A dominant-negative variant in the dopamine transporter PDZ-binding motif is linked to parkinsonism and neuropsychiatric disease
Authors: Herborg Freja , Jensen Kathrine L. , Tolstoy Sasha , Arends Natascha V. , Posselt Leonie P. , Shekar Aparna , Aguilar Jenny , Lund Viktor K. , Erreger Kevin , Rickhag Mattias , Lykas Matthew D. , Lonsdale Markus N. , Rahbek-Clemmensen Troels , Sørensen Andreas T. , Newman Amy H. , Løkkegaard Annemette , Kjærulff Ole , Werge Thomas , Møller Lisbeth B. , Matthies Heinrich JG , Galli Aurelio , Hjermind Lena E. , Gether Ulrik
Published: October 2020

Dopaminergic dysfunction is central to movement disorders and mental diseases. The dopamine transporter (DAT) is essential for the regulation of extracellular dopamine but the genetic and mechanistic link between DAT function and dopamine-related pathologies remains elusive. Particularly, the pathophysiological significance of monoallelic missense mutations in DAT is unknown. Here we identify a novel coding DAT variant, DAT-K619N, in a patient with early-onset parkinsonism and comorbid neuropsychiatric disease and in 22 individuals from exome-sequenced samples of neuropsychiatric patients. The variant localizes to the critical C-terminal PDZ-binding motif of DAT and causes reduced uptake capacity, decreased surface expression, and accelerated turnover of DATin vitro.In vivo, we demonstrate that expression of DAT-K619N in mice anddropsophilaimposes impairments in dopamine transmission with accompanying changes in dopamine-directed behaviors. Importantly, both cellular studies and viral overexpression of DAT-K619N in mice show that DAT-K619N has a dominant-negative effect which collectively implies that a single dominant-negative genetic DAT variant can confer risk for neuropsychiatric disease and neurodegenerative early-onset parkinsonism.
Viral protein engagement of GBF1 induces host cell vulnerability through synthetic lethality
Authors: Navare Arti T , Mast Fred D , Olivier Jean Paul , Bertomeu Thierry , Neal Maxwell , Carpp Lindsay N , Kaushansky Alexis , Coulombe-Huntington Jasmin , Tyers Mike , Aitchison John D
Published: October 2020

Viruses co-opt host proteins to carry out their lifecycle. Repurposed host proteins may thus become functionally compromised; a situation analogous to a loss-of-function mutation. We term such host proteins viral-induced hypomorphs. Cells bearing cancer driver loss-of-function mutations have successfully been targeted with drugs perturbing proteins encoded by the synthetic lethal partners of cancer-specific mutations. Synthetic lethal interactions of viral-induced hypomorphs have the potential to be similarly targeted for the development of host-based antiviral therapeutics. Here, we use GBF1, which supports the infection of many RNA viruses, as a proof-of-concept. GBF1 becomes a hypomorph upon interaction with the poliovirus protein 3A. Screening for synthetic lethal partners of GBF1 revealed ARF1 as the top hit, disruption of which, selectively killed cells that synthesize poliovirus 3A. Thus, viral protein interactions can induce hypomorphs that render host cells vulnerable to perturbations that leave uninfected cells intact. Exploiting viral-induced vulnerabilities could lead to broad-spectrum antivirals for many viruses, including SARS-CoV-2.

Using a viral-induced hypomorph of GBF1, Navare et al., demonstrate that the principle of synthetic lethality is a mechanism to selectively kill virus-infected cells.
Targeted Degradation of Transcription Factors by TRAFTACs: Transcription Factor Targeting Chimeras
Authors: Samarasinghe Kusal T. G. , Jaime-Figueroa Saul , Dai Katherine , Hu Zhenyi , Crews Craig M.
Published: October 2020

Many diseases, including cancer, stem from aberrant activation and overexpression of oncoproteins that are associated with multiple signaling pathways. Although proteins with catalytic activity are able to be successfully drugged, the majority of other protein families, such as transcription factors, remain intractable due to their lack of ligandable sites. In this study, we report the development of TRAnscription Factor TArgeting Chimeras (TRAFTACs) as a generalizable strategy for targeted transcription-factor degradation. Herein, we show that TRAFTACs, which consist of a chimeric oligonucleotide that simultaneously binds to the transcription-factor of interest (TOI) and to HaloTag fused dCas9 protein, can induce degradation of the former via the proteasomal pathway. Application of TRAFTACs to two oncogenic TOIs, NF-κB and brachyury, suggests that TRAFTACs can be successfully employed for the targeted degradation of other DNA-binding proteins with minor changes to the chimeric oligonucleotide.
Brain-Restricted mTOR Inhibition with Binary Pharmacology
Authors: Zhang Ziyang , Fan Qiwen , Luo Xujun , Lou Kevin J. , Weiss William A. , Shokat Kevan M.
Published: October 2020

On-target-off-tissue drug engagement is an important source of adverse effects that constrains the therapeutic window of drug candidates. In diseases of the central nervous system, drugs with brain-restricted pharmacology are highly desirable. Here we report a strategy to achieve inhibition of mTOR while sparing mTOR activity elsewhere through the use of a brain-permeable mTOR inhibitor RapaLink-1 and brain-impermeable FKBP12 ligand RapaBlock. We show that this drug combination mitigates the systemic effects of mTOR inhibitors but retains the efficacy of RapaLink-1 in glioblastoma xenografts. We further present a general method to design cell-permeable, FKBP12-dependent kinase inhibitors from known drug scaffolds. These inhibitors are sensitive to deactivation by RapaBlock enabling the brain-restricted inhibition of their respective kinase targets.