bluuebunny/crossref_metadata_2025 huggingface dataset:
Looking back and looking forward: contributions of electron microscopy to the structural cell biology of gametes and fertilization
Authors: Ravi Ravi Teja , Leung Miguel Ricardo , Zeev-Ben-Mordehai Tzviya
Published: September 2020

Mammalian gametes—the sperm and the egg—represent opposite extremes of cellular organization and scale. Studying the ultrastructure of gametes is crucial to understanding their interactions, and how to manipulate them in order to either encourage or prevent their union. Here, we survey the prominent electron microscopy (EM) techniques, with an emphasis on considerations for applying them to study mammalian gametes. We review how conventional EM has provided significant insight into gamete ultrastructure, but also how the harsh sample preparation methods required preclude understanding at a truly molecular level. We present recent advancements in cryo-electron tomography that provide an opportunity to image cells in a near-native state and at unprecedented levels of detail. New and emerging cellular EM techniques are poised to rekindle exploration of fundamental questions in mammalian reproduction, especially phenomena that involve complex membrane remodelling and protein reorganization. These methods will also allow novel lines of enquiry into problems of practical significance, such as investigating unexplained causes of human infertility and improving assisted reproductive technologies for biodiversity conservation.
Techno-economic assessment of animal cell-based meat
Authors: Risner Derrick , Li Fangzhou , Fell Jason S. , Pace Sara A. , Siegel Justin B. , Tagkopoulos Ilias , Spang Edward S.
Published: September 2020

Interest in animal cell-based meat (ACBM) or laboratory grown meat has been increasing, however the economic viability of these potential products has not been thoroughly vetted. Recent studies suggest monoclonal antibody production technology can be adapted for the industrialization of ACBM production. This study provides a scenario-based assessment of the projected cost per kilogram of ACBM based on cellular metabolic requirements and process/chemical engineering conventions. A sensitivity analysis of the model identified the nine most influential cost factors for ACBM production out of 67 initial parameters. The results indicate that technological performance will need to approach technical limits for ACBM to achieve profitably as a commodity. However, the model also suggests that low-volume high-value specialty products could be viable based on current technology.

One Sentence Summary

A model based upon cellular metabolism and engineering conventions was created to examine the economic viability of animal cell-based meat.

Significance statement

Animal cell-based meat (ACBM) has received a significant amount of media attention (as well as corporate investment) in recent years based on its perceived potential to displace traditional meat production, whether beef, poultry, or fish. However, a robust techno-economic assessment (TEA) of these potential products is not publicly available. Our study examined the capital and operating expenditures for potential ACBM products based upon fundamental cellular attributes, the use of proposed near-term/existing technology, and process engineering conventions. Our findings suggest that the current production pathways are far from producing cost-competitive ACBM products, as well as highlight the technical metrics that must be achieved for an ACBM product to become economically viable.
A Motion Correction Strategy for Multi-Contrast based 3D parametric imaging: Application to Inhomogeneous Magnetization Transfer (ihMT)
Authors: Soustelle Lucas , Lamy Julien , Le Troter Arnaud , Hertanu Andreea , Guye Maxime , Ranjeva Jean-Philippe , Varma Gopal , Alsop David C. , Pelletier Jean , Girard Olivier , Duhamel Guillaume
Published: September 2020

Purpose

To propose an efficient retrospective image-based method for motion correction of multi-contrast acquisitions with a low number of available images (MC-MoCo) and evaluate its use in 3D inhomogeneous Magnetization Transfer (ihMT) experiments in the human brain.

Methods

A framework for motion correction, including image pre-processing enhancement and rigid registration to an iteratively improved target image, was developed. The proposed method was compared to Motion Correction with FMRIB’s Linear Image Registration Tool (MCFLIRT) function in FSL over 13 subjects. Native (pre-correction) and residual (post-correction) motions were evaluated by means of markers positioned at well-defined anatomical regions over each image.

Results

Both motion correction strategies significantly reduced inter-image misalignment, and the MC-MoCo method yielded significantly better results than MCFLIRT.

Conclusion

MC-MoCo is a high-performance method for motion correction of multi-contrast volumes as in 3D ihMT imaging.
Wireless Ensembles of Sub-mm Microimplants Communicating as a Network near 1 GHz in a Neural Application
Authors: Lee Jihun , Leung Vincent , Lee Ah-Hyoung , Huang Jiannan , Asbeck Peter , Mercier Patrick P. , Shellhammer Stephen , Larson Lawrence , Laiwalla Farah , Nurmikko Arto
Published: September 2020

Multichannel electrophysiological sensors and stimulators, especially those used for studying the nervous system, are most commonly based on monolithic microelectrode arrays. Such architecture limits the spatial flexibility of individual electrode placement, posing constraints for scaling to a large number of nodes, particularly across non-contiguous locations. We describe the design and fabrication of sub-millimeter size electronic microchips (“Neurograins”) which autonomously perform neural sensing or electrical microstimulation, with emphasis on their wireless networking and powering. An ∼1 GHz electromagnetic transcutaneous link to an external telecom hub enables bidirectional communication and control at the individual neurograin level. The link operates on a customized time division multiple access (TDMA) protocol designed to scale up to 1000 neurograins. The system is demonstrated as a cortical implant in a small animal (rat) model with anatomical limitations restricting the implant to 48 neurograins. We suggest that the neurograin approach can be generalized to overcome many scalability issues for wireless sensors and actuators as implantable microsystems.
A snap shot of space and time dynamics of COVID-19 risk in Malawi. An application of spatial temporal model
Authors: Ngwira Alfred , Kumwenda Felix , Munthali Eddons , Nkolokosa Duncan
Published: September 2020

Background

COVID-19 has been the greatest challenge the world has faced since the second world war. The aim of this study was to investigate the distribution of COVID-19 in both space and time in Malawi.

Methods

The study used publicly available data of COVID-19 cases for the period from 24th June to 20th August, 2020. Semiparametric spatial temporal models were fitted to the number of weekly confirmed cases as an outcome data, with time and location as independent variables.

Results

The study found significant main effect of location and time with the two interacting. The spatial distribution of COVID-19 showed major cities being at greater risk than rural areas. Over time the COVID-19 risk was increasing then decreasing in most districts with the rural districts being consistently at lower risk.

Conclusion

Future or present strategies to avert the spread of COVID-19 should target major cities by limiting international exposure. In addition, the focus should be on time points that had shown high risk.
Environment influences SARS-CoV-2 transmission in the absence of non-pharmaceutical interventions
Authors: Smith Thomas P. , Flaxman Seth , Gallinat Amanda S. , Kinosian Sylvia P. , Stemkovski Michael , Unwin H. Juliette T. , Watson Oliver J. , Whittaker Charles , Cattarino Lorenzo , Dorigatti Ilaria , Tristem Michael , Pearse William D.
Published: September 2020

As COVID-19 continues to spread across the world, it is increasingly important to understand the factors that influence its transmission. Seasonal variation driven by responses to changing environment has been shown to affect the transmission intensity of several coronaviruses. However, the impact of the environment on SARS-CoV-2 remains largely unknown, and thus seasonal variation remains a source of uncertainty in forecasts of SARS-CoV-2 transmission. Here we address this issue by assessing the association of temperature, humidity, UV radiation, and population density with estimates of transmission rate (R). Using data from the United States of America, we explore correlates of transmission across USA states using comparative regression and integrative epidemiological modelling. We find that policy intervention (‘lockdown’) and reductions in individuals’ mobility are the major predictors of SARS-CoV-2 transmission rates, but in their absence lower temperatures and higher population densities are correlated with increased SARS-CoV-2 transmission. Our results show that summer weather cannot be considered a substitute for mitigation policies, but that lower autumn and winter temperatures may lead to an increase in transmission intensity in the absence of policy interventions or behavioural changes. We outline how this information may improve the forecasting of COVID-19, its future seasonal dynamics, and inform intervention policies.
Ancestry May Confound Genetic Machine Learning: Candidate-Gene Prediction of Opioid Use Disorder as an Example
Authors: Hatoum Alexander S. , Wendt Frank R. , Galimberti Marco , Polimanti Renato , Neale Benjamin , Kranzler Henry R. , Gelernter Joel , Edenberg Howard J. , Agrawal Arpana
Published: September 2020

Background

Machine learning (ML) models are beginning to proliferate in psychiatry, however machine learning models in psychiatric genetics have not always accounted for ancestry. Using an empirical example of a proposed genetic test for OUD, and exploring a similar test for tobacco dependence and a simulated binary phenotype, we show that genetic prediction using ML is vulnerable to ancestral confounding.

Methods

We utilize five ML algorithms trained with 16 brain reward-derived “candidate” SNPs proposed for commercial use and examine their ability to predict OUD vs. ancestry in an out-of-sample test set (N=1000, stratified into equal groups of n=250 cases and controls each of European and African ancestry). We rerun analyses with 8 random sets of allele-frequency matched SNPs. We contrast findings with 11 genome-wide significant variants for tobacco smoking. To document generalizability, we generate and test a random phenotype.

Results

None of the 5 ML algorithms predict OUD better than chance when ancestry was balanced but were confounded with ancestry in an out-of-sample test. In addition, the algorithms preferentially predicted admixed subpopulations. Random sets of variants matched to the candidate SNPs by allele frequency produced similar bias. Genome-wide significant tobacco smoking variants were also confounded by ancestry. Finally, random SNPs predicting a random simulated phenotype show that the bias attributable to ancestral confounding could impact any ML-based genetic prediction.

Conclusions

Researchers and clinicians are encouraged to be skeptical of claims of high prediction accuracy from ML-derived genetic algorithms for polygenic traits like addiction, particularly when using candidate variants.
Clinical characteristics and outcomes of patients with COVID-19 and ARDS admitted to a third level health institution in Mexico City
Authors: Cárdenas Carmen M. Hernández , Sotelo Carlos Torruco , Jurado Felipe , Serna-Secundino Héctor , Aguilar Cristina , García-Olazarán José G. , García Diana Hernández , Goytia Gustavo Lugo
Published: September 2020

Background

In December 2019, the first cases of severe pneumonia associated with a new coronavirus were reported in Wuhan, China. Severe respiratory failure requiring intensive care was reported in up to 5% of cases. There is, however, limited information available in Mexico.

Objectives

The purpose of this study was to describe the clinical manifestations, and outcomes in a COVID-19 cohort attended to from March to May 2020 in our RICU. In addition, we explored the association of clinical variables with mortality.

Methods

The first consecutive patients admitted to the RICU from March 3, 2020, to Jun 24, 2020, with confirmed COVID-19 were investigated. Clinical and laboratory data were obtained. Odds ratios (ORs) were calculated using a logistic regression model. The survival endpoint was mortality at discharge from the RICU.

Results

Data from 68 consecutive patients were analyzed. Thirty-eight patients survived, and 30 died (mortality: 44.1 %). Of the 16 predictive variables analyzed, only 6 remained significant in the multivariate analysis [OR (95% confidence interval)]: no acute kidney injury (AKI)/AKI 1: [.61 (.001;.192)]; delta lymphocyte count: [.061 (.006;.619)]; delta ventilatory ratio: [8.19 (1.40;47.8)]; norepinephrine support at admission: [34.3 (2.1;550)]; body mass index: [1.41 (1.09;1.83)]; and bacterial coinfection: [18.5 (1.4;232)].

Conclusions

We report the characteristics and outcome of patients with ARDS and COVID-19. We found six independent factors associated with the mortality risk: delta lymphocyte count, delta ventilatory ratio, BMI, norepinephrine support, no AKI/AKI 1, and bacterial coinfection.
The impact of natural disasters on the spread of COVID-19: a geospatial, agent based epidemiology model
Authors: Van Wyk de Vries Maximillian , Rambabu Lekaashree
Published: September 2020

Background

Natural disasters and infectious diseases are global issues, resulting in widespread disruption to human health and livelihood. At the scale of a global pandemic, the cooccurrence of natural disasters is inevitable. However, the impact of natural disasters on the spread of COVID-19 has not been extensively evaluated using agent based epidemiology models.

Methods

We create an agent-based epidemiology model based on both COVID-19 clinical and epidemiological data and geographic data. We first model 35 scenarios with varying natural disaster timing and duration for a COVID-19 outbreak in a theoretical region. We then evaluate the potential effect of an eruption of Vesuvius volcano on the spread of COVID-19 in Campania, Italy. Our objective is to determine if the occurrence of a natural disaster during the COVID-19 pandemic is likely to increase infection cases and disease related fatalities.

Results

In a majority of cases, the occurrence of a natural disaster increases the number of disease related fatalities. When the natural disaster occurs at the beginning of the outbreak within a given region, there is little to no increase in the progression of disease spread. However, the occurrence of a natural disaster close to the peak of infections may increase the number of fatalities by more than five-fold. In a theoretical test case, for a natural disaster that occurred fifty days after first infection case, the median increase in fatalities is 2%, 59%, and 180% for a 2, 14, and 31-day long natural disaster respectively, when compared to the no natural disaster scenario.

Conclusion

We propose that the compound risk from natural disasters is greatest in the case of already widespread disease outbreak. The key risk factors for increase in spread of infection and disease related fatalities are the timing of the natural disaster relative to the peak in infections and the duration of the natural disaster.
Context influences how individuals with misophonia respond to sounds
Authors: Edelstein M. , Monk B. , Ramachandran V.S. , Rouw R.
Published: September 2020

Misophonia is a newly researched condition in which specific sounds cause an intense, aversive response in individuals, characterized by negative emotions and autonomic arousal. Although virtually any sound can become a misophonic “trigger,” the most common sounds appear to be bodily sounds related to chewing and eating as well as other repetitive sounds. An intriguing aspect of misophonia is the fact that many misophonic individuals report that they are triggered more, or even only, by sounds produced by specific individuals, and less, or not at all, by sounds produced by animals (although there are always exceptions).

In general, anecdotal evidence suggests that misophonic triggers involve a combination of sound stimuli and contextual cues. The aversive stimulus is more than just a sound and can be thought of as a Gestalt of features which includes sound as a necessary component as well as additional contextual information. In this study, we explore how contextual information influences misophonic responses to human chewing, as well as sonically similar sounds produced by non-human sources. The current study revealed that the exact same sound can be perceived as being much more or less aversive depending on the contextual information presented alongside the auditory information. The results of this study provide a foundation for potential cognitive based therapies.
The chaos in calibrating crop models
Authors: Wallach Daniel , Palosuo Taru , Thorburn Peter , Hochman Zvi , Gourdain Emmanuelle , Andrianasolo Fety , Asseng Senthold , Basso Bruno , Buis Samuel , Crout Neil , Dibari Camilla , Dumont Benjamin , Ferrise Roberto , Gaiser Thomas , Garcia Cecile , Gayler Sebastian , Ghahramani Afshin , Hiremath Santosh , Hoek Steven , Horan Heidi , Hoogenboom Gerrit , Huang Mingxia , Jabloun Mohamed , Jansson Per-Erik , Jing Qi , Justes Eric , Kersebaum Kurt Christian , Klosterhalfen Anne , Launay Marie , Lewan Elisabet , Luo Qunying , Maestrini Bernardo , Mielenz Henrike , Moriondo Marco , Nariman Zadeh Hasti , Padovan Gloria , Olesen Jørgen Eivind , Poyda Arne , Priesack Eckart , Pullens Johannes Wilhelmus Maria , Qian Budong , Schütze Niels , Shelia Vakhtang , Souissi Amir , Specka Xenia , Srivastava Amit Kumar , Stella Tommaso , Streck Thilo , Trombi Giacomo , Wallor Evelyn , Wang Jing , Weber Tobias K.D. , Weihermüller Lutz , de Wit Allard , Wöhling Thomas , Xiao Liujun , Zhao Chuang , Zhu Yan , Seidel Sabine J.
Published: September 2020

Calibration, the estimation of model parameters based on fitting the model to experimental data, is among the first steps in many applications of system models and has an important impact on simulated values. Here we propose and illustrate a novel method of developing guidelines for calibration of system models. Our example is calibration of the phenology component of crop models. The approach is based on a multi-model study, where all teams are provided with the same data and asked to return simulations for the same conditions. All teams are asked to document in detail their calibration approach, including choices with respect to criteria for best parameters, choice of parameters to estimate and software. Based on an analysis of the advantages and disadvantages of the various choices, we propose calibration recommendations that cover a comprehensive list of decisions and that are based on actual practices.

Highlights

We propose a new approach to deriving calibration recommendations for system models

Approach is based on analyzing calibration in multi-model simulation exercises

Resulting recommendations are holistic and anchored in actual practice

We apply the approach to calibration of crop models used to simulate phenology

Recommendations concern: objective function, parameters to estimate, software used
Three-dimensional Printing of Customized Bioresorbable Airway Stents
Authors: Paunović Nevena , Bao Yinyin , Coulter Fergal Brian , Masania Kunal , Geks Anna Karoline , Klein Karina , Rafsanjani Ahmad , Cadalbert Jasmin , Kronen Peter W. , Kleger Nicole , Karol Agnieszka , Luo Zhi , Rüber Fabienne , Brambilla Davide , von Rechenberg Brigitte , Franzen Daniel , Studart André R. , Leroux Jean-Christophe
Published: September 2020

Central airway obstruction is a life-threatening disorder causing a high physical and psychological burden to patients due to severe breathlessness and impaired quality of life. Standard-of-care airway stents are silicone tubes, which cause immediate relief, but are prone to migration, especially in growing patients, and require additional surgeries to be removed, which may cause further tissue damage. Customized airway stents with tailorable bioresorbability that can be produced in a reasonable time frame would be highly needed in the management of this disorder. Here, we report poly(D,L-lactide-co-ε-caprolactone) methacrylate blends-based biomedical inks and their use for the rapid fabrication of customized and bioresorbable airway stents. The 3D printed materials are cytocompatible and exhibit silicone-like mechanical properties with suitable biodegradability.In vivostudies in healthy rabbits confirmed biocompatibility and showed that the stents stayed in place for 7 weeks after which they became radiographically invisible. The developed biomedical inks open promising perspectives for the rapid manufacturing of the customized medical devices for which high precision, tuneable elasticity and predictable degradation are sought-after.
The impact of digital contact tracing on the SARS-CoV-2 pandemic - a comprehensive modelling study
Authors: Pollmann Tina R , Pollmann Julia , Wiesinger Christoph , Haack Christian , Shtembari Lolian , Turcati Andrea , Neumair Birgit , Meighen-Berger Stephan , Zattera Giovanni , Neumair Matthias , Apel Uljana , Okolie Augustine , Müller Johannes , Schönert Stefan , Resconi Elisa
Published: September 2020

Contact tracing is one of several strategies employed in many countries to curb the spread of SARS-CoV-2. Digital contact tracing (DCT) uses tools such as cell-phone applications to improve tracing speed and reach. We model the impact of DCT on the spread of the virus for a large epidemiological parameter space consistent with current literature on SARS-CoV-2. We also model DCT in combination with random testing (RT) and social distancing (SD).

Modelling is done with two independently developed individual-based (stochastic) models that use the Monte Carlo technique, benchmarked against each other and against two types of deterministic models.

For current best estimates of the number of asymptomatic SARS-CoV-2 carriers (approximately 40%), their contagiousness (similar to that of symptomatic carriers), the reproductive number before interventions (R0 at least 3) we find that DCT must be combined with other interventions such as SD and/or RT to push the reproductive number below one. At least 60% of the population would have to use the DCT system for its effect to become significant. On its own, DCT cannot bring the reproductive number below 1 unless nearly the entire population uses the DCT system and follows quarantining and testing protocols strictly. For lower uptake of the DCT system, DCT still reduces the number of people that become infected.

When DCT is deployed in a population with an ongoing outbreak where of the population have already been infected, the gains of the DCT intervention come at the cost of requiring up to 15% of the population to be quarantined (in response to being traced) on average each day for the duration of the epidemic, even when there is sufficient testing capability to test every traced person.
Alternative or Complementary Role of Serological Rapid Antibody Test in the Management of Possible COVID-19 Cases
Authors: Yildirim Fatma , Gulhan Pınar Yildiz , Diken Ozlem Ercen , Capraz Aylin , Simsek Meltem , Yildirim Berna Botan , Taysi Muhammet Ridvan , Ozturk Sakine Yilmaz , Demirtas Nurcan , Ergil Julide , Dirican Adem , Uzar Tugce , Karaman Irem , Ozkaya Sevket
Published: September 2020

Background

Although the gold diagnostic method for COVID-19 is accepted as the detection of viral particles by reverse transcription polymerase chain reaction (RT-PCR), serology testing for SARS-CoV-2 is at increased demand. A primary aim for utilization of serological tests are to better quantify the number of COVID-19 cases including those RT-PCR samples were negative but showing clinical and radiological signs of COVID-19. In this study, we aimed to report the features of the patients that were diagnosed and treated as possible COVID-19 cases whose multiple nasopharyngeal swab samples were negative by RTPCR but serological IgM/IgG antibody against SARS-CoV-2 were detected by rapid antibody test.

Method

We retrospectively analyzed eighty suspected COVID-19 cases that have at least two negative consecutive COVID-19 PCR test and were subjected to serological rapid antibody test.

Result

The specific antibodies against SARS-CoV-2 were detected as positive in twenty-two patients. The mean age of patient group was 63.2 ± 13.1 years old with male /female ratio 11/11. Cough was the most common symptom with 90.9%. Most common presenting chest CT findings were bilateral ground glass opacities (77.2%) and alveolar consolidations (50.09%). The mean duration from symptom initiation to hospital admission, to hospitalization, to treatment initiation and to detection of antibody positivity were 8.6 ± 7.2, 11.2 ± 5.4, 7.9 ± 3.2 and 24 ± 17 days, respectively.

Conclusion

Our study demonstrated the feasibility of COVID-19 diagnosis based on rapid antibody test in the cases of patients whose RT-PCR samples were negative. We suggest that the detection of antibodies against SARS-CoV-2 with rapid antibody test should be included in the diagnostic algorithm in suspected COVID-19 patients.
Heritability of ethanol consumption and pharmacokinetics in a genetically diverse panel of Collaborative Cross mouse strains and their inbred founders
Authors: Bagley Jared R. , Chesler Elissa J. , Philip Vivek M. ,   Center for the Systems Genetics of Addiction, Jentsch James D.
Published: September 2020

Background

Inter-individual variation in voluntary ethanol consumption and ethanol response is partially influenced by genetic variation. Discovery of the genes and allelic variants that affect these phenotypes may clarify the etiology and pathophysiology of problematic alcohol use, including alcohol use disorder. Genetically diverse mouse populations also demonstrate heritable variation in ethanol consumption and can be utilized to discover the genes and gene networks that influence this trait. The Collaborative Cross (CC) recombinant inbred strains, Diversity Outbred (DO) population and their eight founder strains are complementary mouse resources that capture substantial genetic diversity and can demonstrate expansive phenotypic variation in heritable traits. These populations may be utilized to discover candidate genes and gene networks that moderate ethanol consumption and other ethanol-related traits.

Methods

We characterized ethanol consumption, preference and pharmacokinetics in the eight founder strains and ten CC strains in 12-hour drinking sessions during the dark phase of the circadian cycle.

Results

Ethanol consumption was found to be substantially heritable, both early in ethanol access and over a chronic intermittent access schedule. Ethanol pharmacokinetics were also found to be heritable; however, no association between strain-level ethanol consumption and pharmacokinetics was detected. The PWK/PhJ strain was found to be the highest drinking strain, with consumption substantially exceeding C57BL/6J, a strain commonly used as a model of “high” or “binge” drinking. Notably, we found strong evidence that sex moderated genetic effects on voluntary ethanol drinking.

Conclusions

Collectively, this research may serve as a foundation for expanded genetic study of ethanol consumption in the CC/DO and related populations; moreover, we have identified reference strains with extreme consumption phenotypes that effectively represent polygenic models of hazardous ethanol use.
nanoDoc: RNA modification detection using Nanopore raw reads with Deep One-Class Classification
Authors: Ueda Hiroki
Published: September 2020

Advances in Nanopore single-molecule direct RNA sequencing (DRS) have presented the possibility of detecting comprehensive post-transcriptional modifications (PTMs) as an alternative to experimental approaches combined with high-throughput sequencing. It has been shown that the DRS method can detect the change in the raw electric current signal of a PTM; however, the accuracy and reliability still require improvement. Here, I present a new software program, named as nanoDoc, for detecting PTMs from DRS data using a deep neural network. Current signal deviations caused by PTMs are analyzed via Deep One-Class Classification with a convolutional neural network. Using a ribosomal RNA dataset, the software archive displayed an area under the curve (AUC) accuracy of 0.96 for detecting 23 different types of modifications inEscherichia coliandSaccharomyces cerevisiae. Furthermore, I demonstrated a tentative classification of PTMs using unsupervised clustering. Finally, I applied this software to severe acute respiratory syndrome coronavirus 2 data and identified commonly modified sites among three groups. nanoDoc is an open source software (GPLv3) available athttps://github.com/uedaLabR/nanoDoc

Author Summary

RNA post-transcriptional modifications (PTMs) is regulate multiple aspects of RNA function, including alternative splicing, export, stability, and translation, and the method to identify multiple types of PTMs is required for further advancement of this fields called ‘epitranscriptomics’. Nanopore singlemolecule direct RNA sequencing (DRS) can detect such PTMs, however the accuracy of the method needs to be improved. Detecting PTMs can be solved as a One-Class Classification problem, which is widely used in machine learning fields. Thus, a novel software named ‘nanoDoc’ for detecting PTMs was developed. The nanoDoc use convolutional neural network to extract the feature signal from nanopore sequencer and Deep One-Class Classification to detect PTMs as an anomaly. The software archive displayed an area under the curve (AUC) accuracy of 0.96 for detecting 23 different types of modifications inEscherichia coliandSaccharomyces cerevisiae.This software is applicable to different samples, and tested on severe acute respiratory syndrome coronavirus 2, and human transcript data as well.
The new kid on the block: A dominant-negative mutation of phototropin1 enhances carotenoid content in tomato fruits
Authors: Kilambi Himabindu Vasuki , Dindu Alekhya , Sharma Kapil , Nizampatnam Narasimha Rao , Gupta Neha , Thazath Nikhil Padmanabhan , Dhanya Ajayakumar Jaya , Tyagi Kamal , Sharma Sulabha , Kumar Sumit , Sharma Rameshwar , Sreelakshmi Yellamaraju
Published: September 2020

Phototropins, the UVA-blue light photoreceptors, endow plants to detect the direction of light and optimize photosynthesis by regulating chloroplasts positioning and stomatal gas exchange. Little is known about their functions in other developmental responses. A tomatoNon-phototropic seedling1(Nps1) mutant, bearing an Arg495His substitution in the vicinity of LOV2 domain in phototropin1, dominant-negatively blocks phot1 and phot2 responses. The fruits ofNps1mutant were enriched in carotenoids, particularly lycopene, than its parent, Ailsa Craig. Contrarily, CRISPR/CAS9-edited loss of functionphototropin1mutants displayed subdued carotenoids than the parent. The enrichment of carotenoids inNps1fruits is genetically linked with the mutation and exerted in a dominant-negative fashion.Nps1also altered volatile profiles with high levels of lycopene-derived 6-methyl 5-hepten2-one. The transcript levels of several MEP and carotenogenesis pathways genes were upregulated inNps1.Nps1fruits showed altered hormonal profiles with subdued ethylene emission and reduced respiration. Proteome profiles showed a causal link between higher carotenogenesis and increased levels of protein protection machinery, which may stabilize proteins contributing to MEP and carotenogenesis pathways. Given the enhancement of carotenoid content byNps1in a dominant-negative fashion, it offers a potential tool for high lycopene-bearing hybrid tomatoes.

One-sentence summary

A dominant-negative phototropin1 mutation enhances carotenoid levels, alters metabolite homeostasis, and protein quality control machinery in tomato fruits.
Accurate prediction of residue-residue contacts across homo-oligomeric protein interfaces through deep leaning
Authors: Yan Yumeng , Huang Sheng-You
Published: September 2020

Protein-protein interactions play a fundamental role in all cellular processes. Therefore, determining the structure of protein-protein complexes is crucial to understand their molecular mechanisms and develop drugs targeting the protein-protein interactions. Recently, deep learning has led to a breakthrough in intraprotein contact prediction, achieving an unusual high accuracy in recent CASP structure prediction challenges. However, due to the limited number of known homologous protein-protein interactions and the challenge to generate joint multiple sequence alignments (MSA) of two interacting proteins, the advances in inter-protein contact prediction remain limited. Here, we have proposed a deep learning model to predict inter-protein residue-residue contacts across homo-oligomeric protein interfaces, named as DeepHomo, by integrating evolutionary coupling, sequence conservation, distance map, docking pattern, and physic-chemical information of monomers. DeepHomo was extensively tested on both experimentally determined structures and realistic CASP-CAPRI targets. It was shown that DeepHomo achieved a high accuracy of >60% for the top predicted contact and outperformed state-of-the-art direct-coupling analysis (DCA) and machine learning (ML)-based approaches. Integrating predicted contacts into protein docking with blindly predicted monomer structures also significantly improved the docking accuracy. The present study demonstrated the success of DeepHomo in inter-protein contact prediction. It is anticipated that DeepHomo will have a far-reaching implication in the inter-protein contact and structure prediction for protein-protein interactions.
Bacterial processing of glucose modulatesC. eleganslifespan and healthspan
Authors: Kingsley Samuel F. , Seo Yonghak , Allen Calista , Ghanta Krishna S. , Finkel Steven , Tissenbaum Heidi A.
Published: September 2020

Intestinal microbiota play an essential role in the health of a host organism. Here, we define how commensalEscherichia coli (E. coli)alters its host after long term exposure to glucose using aC. elegans-E. colisystem. Our data reveal that bacterial processing of glucose, rather than direct ingestion by the animal, results in reduced lifespan and healthspan, including reduced locomotion, oxidative stress resistance, and heat stress resistance inC. elegans. Chronic exposure ofE. colito glucose produces growth defects and increased advanced glycation end products within theE. coli.These negative effects are abrogated when theE. coliis not able to process the additional glucose and by the addition of the anti-glycation compound carnosine. Physiological changes of the hostC. elegansare accompanied by dysregulation of detoxifying genes including glyoxalase, glutathione-S-transferase, and superoxide dismutase. Loss ofgst-4shortensC. eleganslifespan and blunts the animal’s response to a glucose-fed bacteria diet. Taken together, we reveal that added dietary sugar may alter intestinal microbialE. colito decrease lifespan and healthspan of the host and define the critical role of detoxification genes in maintaining health during a chronic high-sugar diet.
Genes with 5′ terminal oligopyrimidine tracts preferentially escape global suppression of translation by the SARS-CoV-2 Nsp1 protein
Authors: Rao Shilpa , Hoskins Ian , Tonn Tori , Garcia P. Daniela , Ozadam Hakan , Cenik Elif Sarinay , Cenik Can
Published: September 2020

Viruses rely on the host translation machinery to synthesize their own proteins. Consequently, they have evolved varied mechanisms to co-opt host translation for their survival. SARS-CoV-2 relies on a non-structural protein, Nsp1, for shutting down host translation. However, it is currently unknown how viral proteins and host factors critical for viral replication can escape a global shutdown of host translation. Here, using a novel FACS-based assay called MeTAFlow, we report a dose-dependent reduction in both nascent protein synthesis and mRNA abundance in cells expressing Nsp1. We perform RNA-Seq and matched ribosome profiling experiments to identify gene-specific changes both at the mRNA expression and translation level. We discover a functionally-coherent subset of human genes are preferentially translated in the context of Nsp1 expression. These genes include the translation machinery components, RNA binding proteins, and others important for viral pathogenicity. Importantly, we uncovered a remarkable enrichment of 5′ terminal oligo-pyrimidine (TOP) tracts among preferentially translated genes. Using reporter assays, we validated that 5’ UTRs from TOP transcripts can drive preferential expression in the presence of NSP1. Finally, we found that LARP1, a key effector protein in the mTOR pathway may contribute to preferential translation of TOP transcripts in response to Nsp1 expression. Collectively, our study suggests fine tuning of host gene expression and translation by Nsp1 despite its global repressive effect on host protein synthesis.
The impact of vaccination on Neisseria gonorrhoeae antimicrobial resistance and prevalence in men who have sex with men: a mathematical modelling study
Authors: Heijne Janneke C.M. , Xiridou Maria , Turner Katy M.E. , Basten Maartje , Visser Maartje , van Benthem Birgit , Low Nicola
Published: September 2020

Background

Neisseria gonorrhoeae (gonorrhoea) and antimicrobial-resistant (AMR) gonorrhoea infections disproportionately affect men who have sex with men (MSM). Vaccine development is challenging, but a N. meningitidis (group B) vaccine given to children and young adults was associated with a ca. ~30% reduction in gonorrhoea diagnoses. We investigated the impact of vaccination on N. gonorrhoeae AMR development and transmission in MSM.

Methods

We developed a compartmental model of N. gonorrhoeae transmission among MSM. AMR to ceftriaxone was incorporated as a stepwise increases in minimum inhibitory concentrations and eventual resistance (MIC drift). We estimated the impact of a partially protective vaccine (reducing susceptibility; 2-years protection) targeting high sexual activity MSM on AMR and prevalence until 2050. We performed sensitivity analyses assuming different levels of vaccine effectiveness (VE) and other modes of vaccine action.

Findings

Gonorrhoea model prevalence was 3·4% (95% credible interval 3·2% – 3·8%) in all MSM, 12·5% (95% credible interval 12·1% – 12·7%) in high sexual activity MSM. A vaccine with 30% VE cannot prevent AMR, even with high uptake or durable protection. However, it increases time to AMR development by several years. For a fixed uptake of 40% a vaccine needs a minimum VE of 90% to prevent AMR development completely. A vaccine providing complete protection to infection for those vaccinated was most effective in reducing population prevalence and preventing AMR.

Interpretation

A vaccine that has limited efficacy for the prevention of gonorrhoea could delay AMR development in MSM, providing time for developing new antimicrobials and more efficacious vaccines.

Funding

None
Psychometric properties of the Depression Stigma Scale in the Portuguese population and its association with gender and depressive symptomatology
Authors: Conceição Virgínia da , Rothes Inês , Severo Milton , Griffiths Kathleen , Hegerl Ulrich , Gusmão Ricardo
Published: September 2020

Background

Stigma is one of the most significant constraints on people living with depression. There is a lack of validated scales in Portugal to measure depression stigma; therefore, validation of the Depression Stigma Scale (DSS) is an essential step to the depression stigma research in Portugal.

Methods

We developed the adaptation process with the ITC Guidelines for Translation and Adapting Tests taken into consideration. We collected the sample as part of the OSPI program – Optimizing suicide prevention programs and their implementation in Europe, specifically within the application in Portugal, and included 1693 participants. Floor-ceiling effects and response ranges were analyzed, and we calculated Cronbach alphas, conducted a Principal Component Analysis and Confirmatory Analysis. Validity evidence was tested with two well-documented hypotheses, using data on gender and depression symptoms.

Results

The sample was well comparable with the general Portuguese population, indicating its representativeness. We identified a three-factor structure in each subscale (personal and perceived stigma): weak-not-sick, discrimination, and dangerous/unpredictable. The Cronbach’s alphas were satisfactory, and validity was confirmed.

Conclusions

This study established the validity and demonstrated good psychometric properties of the DSS in the Portuguese population. The validation of the DSS can be beneficial in exploring stigma predictors and evaluating the effectiveness of stigma reduction interventions.
Ablation of STAT3 in Purkinje Cells Reorganizes Cerebellar Synaptic Plasticity in Long-Term Fear Memory Network
Authors: Han Jeong-Kyu , Kwon Sun-Ho , Kim Yong Gyu , Choi Jaeyong , Kim Jong-Il , Lee Yong-Seok , Ye Sang-Kyu , Kim Sang Jeong
Published: September 2020

Emotional memory processing, such as fear memory, engages a large neuronal network of brain regions including the cerebellum. However, the molecular and cellular mechanisms of the cerebellar cortex modulating the fear memory network is largely unknown. Here, we illustrate a novel mechanism by which synaptic signaling in cerebellar Purkinje cells (PCs)viaSTAT3 regulates long-term fear memory. Firstly, we generated PC-specific STAT3 knockout (STAT3PKO) mice. Transcriptome analyses revealed that STAT3 deletion results in transcriptional changes that lead to an increase in the expression of glutamate receptors. The amplitude of AMPA receptor-mediated excitatory postsynaptic currents at parallel fiber to PC synapses was larger in STAT3PKOmice than in wild-type littermates. Conditioning at the parallel fiber induced long-term depression of parallel fiber-PC synapses in STAT3PKOmice while the same manipulation induced long-term potentiation in wild-type littermates. Interestingly, STAT3PKOmice showed an aberrantly enhanced long-term fear memory. Neuronal activity in fear-related regions increased in fear-conditioned STAT3PKOmice. Our data suggest that STAT3-dependent molecular regulation in PCs is indispensable for proper expression of fear memory processing.
How to build a water-splitting machine: structural insights into photosystem II assembly
Authors: Zabret Jure , Bohn Stefan , Schuller Sandra K. , Arnolds Oliver , Möller Madeline , Meier-Credo Jakob , Liauw Pasqual , Chan Aaron , Tajkhorshid Emad , Langer Julian D. , Stoll Raphael , Krieger-Liszkay Anja , Engel Benjamin D. , Rudack Till , Schuller Jan M. , Nowaczyk Marc M.
Published: September 2020

Biogenesis of photosystem II (PSII), nature’s water splitting catalyst, is assisted by auxiliary proteins that form transient complexes with PSII components to facilitate stepwise assembly events. Using cryo-electron microscopy, we solved the structure of such a PSII assembly intermediate with 2.94 Å resolution. It contains three assembly factors (Psb27, Psb28, Psb34) and provides detailed insights into their molecular function. Binding of Psb28 induces large conformational changes at the PSII acceptor side, which distort the binding pocket of the mobile quinone (QB) and replace bicarbonate with glutamate as a ligand of the non-heme iron, a structural motif found in reaction centers of non-oxygenic photosynthetic bacteria. These results reveal novel mechanisms that protect PSII from damage during biogenesis until water splitting is activated. Our structure further demonstrates how the PSII active site is prepared for the incorporation of the Mn4CaO5cluster, which performs the unique water splitting reaction.

One Sentence Highlight

The high-resolution Cryo-EM structure of the photosystem II assembly intermediate PSII-I reveals how nature’s water splitting catalyst is assembled, protected and prepared for photoactivation by help of the three assembly factors Psb27, Psb28 and Psb34.
Human INCL fibroblasts display abnormal mitochondrial and lysosomal networks and heightened susceptibility to ROS-induced cell death
Authors: Balouch Bailey , Nagorsky Halle , Pham Truc , LaGraff Thai , Chu-LaGraff Quynh
Published: September 2020

Infantile Neuronal Ceroid Lipofuscinosis (INCL) is a pediatric neurodegenerative disorder characterized by progressive retinal and central nervous system deterioration during infancy. This lysosomal storage disorder results from a deficiency in the Palmitoyl Protein Thioesterase 1 (PPT1) enzyme - a lysosomal hydrolase which cleaves fatty acid chains such as palmitate from lipid-modified proteins. In the absence of PPT1 activity, these proteins fail to be degraded, leading to the accumulation of autofluorescence storage material in the lysosome. The underlying molecular mechanisms leading to INCL pathology remain poorly understood. A role for oxidative stress has been postulated, yet little evidence has been reported to support this possibility. Here we present a comprehensive cellular characterization of human PPT1-deficient fibroblast cells harboring Met1Ile and Tyr247His compound heterozygous mutations. We detected autofluorescence storage material and observed distinct organellar abnormalities of the lysosomal and mitochondrial structures, which supported previous postulations about the role of ER, mitochondria and oxidative stress in INCL. An increase in the number of lysosomal structures was found in INCL patient fibroblasts, which suggested an upregulation of lysosomal biogenesis, and an association with endoplasmic reticulum stress response. The mitochondrial network also displayed abnormal spherical punctate morphology instead of normal elongated tubules with extensive branching, supporting the involvement of mitochondrial and oxidative stress in INCL cell death. Autofluorescence accumulation and lysosomal pathologies can be mitigated in the presence of conditioned wild type media suggesting that a partial restoration via passive introduction of the enzyme into the cellular environment may be possible. We also demonstrated, for the first time, that human INCL fibroblasts have a heightened susceptibility to exogenous reactive oxygen species (ROS)-induced cell death, which suggested an elevated basal level of endogenous ROS in the mutant cell. Collectively, these findings support the role of intracellular organellar networks in INCL pathology, possibly due to oxidative stress.