bluuebunny/crossref_metadata_2025 huggingface dataset:
Plasma lipid and liporotein biomarkers in LBC1936: Do they predict general cognitive ability and brain structure?
Authors: Harris Sarah E. , Ritchie Stuart J , Correia Gonçalo D S , Jiménez Beatriz , Fawns-Ritchie Chloe , Pattie Alison , Corley Janie , Maniega Susana Muñoz , Hernández Maria Valdés , Starr John M. , Hill Derek , Wren Paul , Bastin Mark E. , Lewis Matthew R , Wardlaw Joanna M. , Deary Ian J.
Published: July 2020

Identifying predictors of cognitive ability and brain structure in later life is an important step towards understanding the mechanisms leading to cognitive decline and dementia. This study used ultra-performance liquid chromatography mass spectrometry (UPLC-MS) and nuclear magnetic resonance (NMR) to measure targeted and untargeted metabolites, mainly lipids and lipoproteins, in ∼600 members of the Lothian Birth Cohort 1936 (LBC1936) at aged ∼73 years. Penalized regression models (LASSO) were then used to identify sets of metabolites that predict variation in general cognitive ability and structural brain variables. UPLC-MS-POS measured lipids, together predicted 19% of the variance in total brain volume and 17% of the variance in both grey matter and normal appearing white matter volumes. Multiple subclasses of lipids were included in the predictor, but the best performing lipid was the sphingomyelin SM(d18:2/14:0) which occurred in 100% of iterations of all three significant models. No metabolite set predicted cognitive ability, or white matter hyperintensities or connectivity. Future studies should concentrate on identifying specific lipids as potential cognitive and brain-structural biomarkers in older individuals.
DNA methylation site loss for plasticity-led novel trait genetic fixation
Authors: Katsumura Takafumi , Sato Suguru , Yamashita Kana , Oda Shoji , Gakuhari Takashi , Tanaka Shodai , Fujitani Kazuko , Nishimaki Toshiyuki , Imai Tadashi , Yoshiura Yasutoshi , Takeshima Hirohiko , Hashiguchi Yasuyuki , Sekita Yoichi , Mitani Hiroshi , Ogawa Motoyuki , Takeuchi Hideaki , Oota Hiroki
Published: July 2020

Many organisms exhibit phenotypic plasticity that changes their traits in response to their environment. Whether or not this plasticity contributes to adaptive evolution is a fundamental question in evolutionary biology because various studies report that natural populations adapt to rapid environmental changes via plasticity, which often “triggers” novel adaptive traits. While such alternative phenotypes could be induced by nongenetic perturbations that include gene expression noise or epigenetic modification caused by environmental change, it remains unknown what molecular mechanism genetically fix the alternative phenotypes as adaptive traits passed into the next generation. Here we show that a decrease in methylated CpG sites leads to loss of plasticity, which triggers genetic fixation of novel traits, in medaka fish (Oryzias latipes). We found that the gut length was correlated with the number of methylated CpG sites upstream of thePlxnb3gene. The medaka, in which the methylated DNA region is deleted by CRISPR/Cas9, showed a loss of plasticity in gut length.

Moreover, standing variation in the promoter region of another gene,Ppp3r1, made a longer gut stably in wild medaka groups that lost the gut-length plasticity. Furthermore, our phylogenetic analysis revealed the timing of these evolutionary events, indicating that the loss of phenotypic plasticity by nucleotide substitutions initiates the process of genetic fixation of the novel trait. That is, while phenotypic plasticity plays a role as a buffer of evolution and contributes to environmental adaptation, as previously thought, our molecular data suggest that mutation on CpG site causing the loss of phenotypic plasticity, is the trigger for a generation of novel traits.
TAXON INCOMPLETENESS AND DISCRETE TIME BINS AFFECT CHARACTER CHANGE RATES IN SIMULATED DATA
Authors: Flores Jorge R.
Published: July 2020

Estimating how fast or slow morphology evolves through time (phenotypic change rate; PR) has become common in macroevolutionary studies, and has been important for clarifying key evolutionary events. However, the inclusion of incompletely scored taxa (e.g., fossils) could affect PR estimates and potentially mask real PR patterns. This effect being also affected by the usage of arbitrary discrete time bins. Here, the impact of taxon incompleteness (unscored data) on PR estimates is assessed in simulated data. Three different time bin series were likewise evaluated: bins evenly spanning the tree length (i), a shorter middle bin (ii), and a longer middle bin (iii). The results indicate that PR values decrease as taxon incompleteness increases. Statistical significant PR values, and the dispersion among PR values, depended on the time bins. These outcomes imply that taxon incompleteness can undermine our capacity to infer morphology evolutionary dynamics and that these estimates are also influenced by our choice of discrete time bins. More importantly, the present results stress the need for a better approach to deal with taxon incompleteness and arbitrary discrete time bins.
A self-aligning end-effector robot for individual joint training of the human arm
Authors: Balasubramanian Sivakumar , Guguloth Sandeep , Mohammed Javeed Shaikh , Sujatha S.
Published: July 2020

Abstract

Current evidence indicates that individual joint training with robotic devices can be as effective as multi-joint training for the arm. This makes a case for developing simpler and more compact robots for training individual joints of the arm. Such robots have the highest potential for clinical translation. To this end, the current work presents the kinematic design and optimization of a six degrees-of-freedom (dof) end-effector robot with three actuateddofand three non-actuated self-aligningdoffor safe assisted training of the individual joints (shoulder or elbow) of the human arm, with relaxed constraints of the relative positioning of the human limb with respect to the robot. Further, we present a simple estimation procedure to automatically identify the kinematic parameters of the human limb essential for control of the human-robot closed kinematic chain.
Multiple parietal pathways are associated with rTMS-induced hippocampal network enhancement and episodic memory changes
Authors: Freedberg Michael , Cunningham Catherine A. , Fioriti Cynthia M. , Murillo Jorge Dorado , Reeves Jack A. , Taylor Paul A. , Sarlls Joelle E. , Wassermann Eric M.
Published: July 2020

Repetitive transcranial magnetic stimulation (rTMS) of the inferior parietal cortex (IPC) increases resting-state functional connectivity (rsFC) of the hippocampus with the precuneus and other posterior cortical areas and causes proportional improvement of episodic memory. The anatomical pathway responsible for the propagation of these effects from the IPC is unknown and may not be direct. Using diffusion tensor imaging, we examined whether individual differences in fractional anisotropy (FA), a tensor-derived quantity related to white matter properties, in pathways between the IPC and medial temporal lobe (MTL), via the parahippocampal cortex and the precuneus, accounted for individual differences in hippocampal rsFC and memory change after rTMS. FA in the IPC-parahippocampal pathway was associated with rsFC change in a few small cortical clusters, while FA in the IPC-precuneus pathway was strongly linked to widespread changes in rsFC. FA in both pathways was related to episodic memory, but not to procedural memory. These results implicate pathways to the MTL and to the precuneus in the enhancing effect of parietal rTMS on hippocampal rsFC and memory.
Replication-competent vesicular stomatitis virus vaccine vector protects against SARS-CoV-2-mediated pathogenesis
Authors: Case James Brett , Rothlauf Paul W. , Chen Rita E. , Kafai Natasha M. , Fox Julie M. , Shrihari Swathi , McCune Broc T. , Harvey Ian B. , Smith Brittany , Keeler Shamus P. , Bloyet Louis-Marie , Winkler Emma S. , Holtzman Michael J. , Fremont Daved H. , Whelan Sean P.J. , Diamond Michael S.
Published: July 2020

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused millions of human infections and hundreds of thousands of deaths. Accordingly, an effective vaccine is of critical importance in mitigating coronavirus induced disease 2019 (COVID-19) and curtailing the pandemic. We developed a replication-competent vesicular stomatitis virus (VSV)-based vaccine by introducing a modified form of the SARS-CoV-2 spike gene in place of the native glycoprotein gene (VSV-eGFP-SARS-CoV-2). Immunization of mice with VSV-eGFP-SARS-CoV-2 elicits high titers of antibodies that neutralize SARS-CoV-2 infection and target the receptor binding domain that engages human angiotensin converting enzyme-2 (ACE2). Upon challenge with a human isolate of SARS-CoV-2, mice expressing human ACE2 and immunized with VSV-eGFP-SARS-CoV-2 show profoundly reduced viral infection and inflammation in the lung indicating protection against pneumonia. Finally, passive transfer of sera from VSV-eGFP-SARS-CoV-2-immunized animals protects naïve mice from SARS-CoV-2 challenge. These data support development of VSV-eGFP-SARS-CoV-2 as an attenuated, replication-competent vaccine against SARS-CoV-2.
Discriminating Mild from Critical COVID-19 by Innate and Adaptive Immune Single-cell Profiling of Bronchoalveolar Lavages
Authors: Wauters Els , Van Mol Pierre , Garg Abhishek D. , Jansen Sander , Van Herck Yannick , Vanderbeke Lore , Bassez Ayse , Boeckx Bram , Malengier-Devlies Bert , Timmerman Anna , Van Brussel Thomas , Van Buyten Tina , Schepers Rogier , Heylen Elisabeth , Dauwe Dieter , Dooms Christophe , Gunst Jan , Hermans Greet , Meersseman Philippe , Testelmans Dries , Yserbyt Jonas , Matthys Patrick , Tejpar Sabine ,   CONTAGIOUS collaborators, Neyts Johan , Wauters Joost , Qian Junbin , Lambrechts Diether
Published: July 2020

How innate and adaptive lung immune responses to SARS-CoV-2 synchronize during COVID-19 pneumonitis and regulate disease severity is poorly established. To address this, we applied single-cell profiling to bronchoalveolar lavages from 44 patients with mild or critical COVID-19versusnon-COVID-19 pneumonia as control. Viral RNA-tracking delineated the infection phenotype to epithelial cells, but positioned mainly neutrophils at the forefront of viral clearance activity during COVID-19. In mild disease, neutrophils could execute their antiviral function in an immunologically ‘controlled’ fashion, regulated by fully-differentiated T-helper-17 (TH17)-cells, as well as T-helper-1 (TH1)-cells, CD8+resident-memory (TRM) and partially-exhausted (TEX) T-cells with good effector functions. This was paralleled by ‘orderly’ phagocytic disposal of dead/stressed cells by fully-differentiated macrophages, otherwise characterized by anti-inflammatory and antigen-presenting characteristics, hence facilitating lung tissue repair. In critical disease, CD4+TH1- and CD8+TEX-cells were characterized by inflammation-associated stress and metabolic exhaustion, while CD4+TH17- and CD8+TRM-cells failed to differentiate. Consequently, T-cell effector function was largely impaired thereby possibly facilitating excessive neutrophil-based inflammation. This was accompanied by impaired monocyte-to-macrophage differentiation, with monocytes exhibiting an ATP-purinergic signalling-inflammasome footprint, thereby enabling COVID-19 associated fibrosis and worsening disease severity. Our work represents a major resource for understanding the lung-localised immunity and inflammation landscape during COVID-19.
GRIDSS2: comprehensive characterisation of somatic structural variation using single breakend variants and structural variant phasing
Authors: Cameron Daniel L. , Baber Jonathan , Shale Charles , Valle-Inclan Jose Espejo , Besselink Nicolle , Hoeck Arne van , Janssen Roel , Cuppen Edwin , Priestley Peter , Papenfuss Anthony T.
Published: July 2020

GRIDSS2 is the first structural variant caller to explicitly report single breakends - breakpoints in which only one side can be unambiguously determined. By treating single breakends as a fundamental genomic rearrangement signal on par with breakpoints, GRIDSS2 can explain 47% of somatic centromeric copy number changes using single breakends to non-centromeric sequence, with chromosome 1 exhibiting a unique centromeric rearrangement signature. On a cohort of 3,782 deeply sequenced metastatic cancers, GRIDSS2 achieved an unprecedented 3.1% false negative rate and identified a novel 32-100bp duplication signature. Somatic structural variants are highly clustered with GRIDSS2 phasing 16% using just paired-end sequencing.
Bioinformatic and Reactivity-Based Discovery of Linaridins
Authors: Georgiou Matthew A. , Dommaraju Shravan R. , Guo Xiaorui , Mitchell Douglas A.
Published: July 2020

Linaridins are members of the ribosomally synthesized and post-translationally modified peptide (RiPP) family of natural products. Five linaridins have been reported, which are defined by the presence of dehydrobutyrine, a dehydrated threonine residue. This work describes the development of a linaridin specific scoring module for Rapid ORF Description and Evaluation Online (RODEO), a genome-mining tool tailored towards RiPP discovery. Upon mining publicly accessible genomes available in the NCBI database, RODEO identified 561 (382 non-redundant) linaridin biosynthetic gene clusters (BGCs). Linaridin BGCs with unique gene architectures and precursor sequences markedly different from previous predictions were uncovered during these efforts. To aid in dataset validation, two new linaridins, pegvadin A and B, were detected through reactivity-based screening (RBS) and isolated from Streptomyces noursei and Streptomyces auratus, respectively. RBS involves the use of a reactive chemical probe that chemoselectively modifies a functional group present in the natural product. The dehydrated amino acids present in linaridins as α/β-unsaturated carbonyls were appropriate electrophiles for nucleophilic 1,4 addition using a thiol-functionalized probe. The data presented within significantly expands the number of predicted linaridin BGCs and serves as a road map for future work in the area. The combination of bioinformatics and RBS is a powerful approach to accelerate natural product discovery.
Psychological state and family functioning of University of Ibadan students during the COVID-19 lockdown
Authors: Ojewale Lucia Yetunde
Published: July 2020

Background

The curtailment of social gatherings as well as lack of online academic engagement, due to the COVID-19 lockdown, could have potentially damaging effects on the psychological state of university students in Nigeria. This study examined the prevalence of anxiety and depression, including associated factors and coping methods among undergraduate students in a Nigerian university. It also examined the association between psychological state and family functioning.

Methods

The study design was cross sectional and involved 386 undergraduate students across the main faculties. The university’s ethical review board approved the study with approval number UI/EC/20/0242. An online questionnaire, using Google form, was circulated among the students through their faculty representatives. The Hospital Anxiety and Depression scale (HADs) was used in assessing anxiety and depression, while family functioning was assessed using the McMaster Family Assessment Device, (FAD). Data was entered into Statistical Package for Social Sciences (SPSS), and analysis carried out using descriptive statistics, chi-square, independent t-test, Analysis of Variance (ANOVA), Post-Hoc analysis and linear logistics regression, at α 0.05.

Results

The mean age was 21±2.9 years, with a female population of 60.1%. Prevalence of anxiety and depression were 41.5% and 31.9% respectively. Students in health-related faculties were significantly less anxious than those in other faculties. Inability to afford three square meals, negative family functioning, having a chronic illness and living in a State/Region with a high incidence of COVID-19, was significantly associated with depression. These factors jointly accounted for 14% of depression seen in undergraduate students. Most of the students coped by engaging themselves in social media, watching television/movies and participating in other online skill development programmes.

Conclusion

There was a high prevalence of anxiety and depression among university students with poor family functioning, inability to afford three meals/day, living in a state with a high incidence of COVID-19 and having a chronic illness, contributing to depression. Measures need to be taken to support undergraduate students and their families to prevent negative consequences of poor mental health.
A flexible COVID-19 model to assess mitigation, “reopening”, virus mutation and other changes
Authors: Bienstock Sergio
Published: July 2020

The COVID-19 epidemic which began in China last year has expanded worldwide. A flexible SEIRD epidemiological model with time-dependent parameters is applied to modeling the pandemic. The value of the effective reproduction ratio is varied to quantify the impact of quarantines and social distancing on the number of infections and deaths, on their daily changes. and on the maxima in these daily rates expected during the epidemic. The effect of changing Reff is substantial. It ought to inform policy decisions around resource allocation, mitigation strategies and their duration, and economic tradeoffs. The model can also calculate the impact of changes in infectiousness or morbidity as the virus mutates, or the expected effects of a new therapy or vaccine assumed to arrive at a future date. The paper concludes with a discussion of a potential endemic end of COVID-19, which might involve times of about 100 years.
Modeling and Preparedness: The Transmission Dynamics of COVID-19 Outbreak in Provinces of Ecuador
Authors: Bustamante-Orellana Carlos , Cevallos-Chavez Jordy , Montalvo-Clavijo Cesar , Sullivan Jeff , Michael Edwin , Mubayi Anuj
Published: July 2020

Coronavirus disease 2019 (COVID-19), a novel infectious disease first identified in December 2019 in the city of Wuhan of China’s Hubei province, is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The disease has become a pandemic in just a few months and spread globally with more than 2.89 million cases and 203,000 deaths across 185 countries, as of April 26th, 2020. Ecuador has reported one of the highest rates of COVID-19 in Latin America, with more than 10K cases and 500 deaths in a country of approximately 17 million people. The dynamics of the outbreak is being observed quite different in different provinces of Ecuador with high reported prevalence in some low population density provinces. In this study, we aim to understand variations in outbreaks between provinces and provide assistance in essential preparedness planning in order to respond effectively to ongoing COVID-19 outbreak. The study estimated the critical level of quarantine rate along with corresponding leakage in order to avoid overwhelming the local health care system. The results suggest that provinces with high population density can avoid a large disease burden provided they initiate early and stricter quarantine measures even under low isolation rate. To best of our knowledge, this study is first from the region to determine which provinces will need much preparation for current outbreak in fall and which might need more help.
The diagnostic accuracy of nucleic acid point-of-care test for human coronavirus: A systematic review and meta-analysis
Authors: Subsoontorn Pakpoom , Lohitnavy Manupat , Kongkaew Chuenjid
Published: July 2020

Many recent studies reported coronavirus point of care tests (POCTs) based on isothermal amplification. However, the performances of these tests have not been systematically evaluated. We searched databases for studies that provide data to calculate sensitivity, specificity and diagnostic odds ratio (DOR). We included 43 studies on 5204 specimens. Most studies had high risk of patient selection and index test bias but low risk in other domains. Most studies (n = 21) used reverse transcribed loop mediated isothermal amplification (RT-LAMP) to diagnose Coronavirus disease 2019 (COVID-19). Summary estimated ln(DOR) for RT-LAMP of RNA purified COVID-19 samples is 6.50 (95%CI 5.25-7.76), similar to previously reported value for RT-LAMP of other RNA virus. RT-LAMP from crude samples has significantly lower ln(DOR) at 4.46 (95%CI 3.53-5.38). SAMBA-II has the highest ln(DOR) at 8.00 (95%CI 6.14-9.87). Abbott ID Now performance is similar to RT-LAMP of crude sample. The performances of CRISPR diagnosis and RT-LAMP are not significantly different. Types of coronaviruses and publication status have no significant effect on diagnosis performance. Existing nucleic acid POCTs, particularly RT-LAMP, CRISPR diagnosis and SAMBA-II, have good diagnostic performance. Future work should focus on improving a study design to minimize the risk of biases.
A Bayesian Model for Prediction of Rheumatoid Arthritis from Risk Factors
Authors: Lufkin Leon , Budišić Marko , Mondal Sumona , Sur Shantanu
Published: July 2020

Rheumatoid arthritis (RA) is a chronic autoimmune disorder that typically manifests as destructive joint inflammation but also affects multiple other organ systems. The pathogenesis of RA is complex where a variety of factors including comorbidities, demographic, and socioeconomic variables are known to influence the incidence and progress of the disease. In this work, we aimed to predict RA from a set of 11 well-known risk factors and their interactions using Bayesian logistic regression. We considered up to third-order interactions between the risk factors and implemented factor analysis of mixed data (FAMD) to account for both the continuous and categorical natures of these variables. The predictive model was further optimized over the area under the receiver operating characteristic curve (AUC) using a genetic algorithm (GA). We use data from the National Health and Nutrition Examination Survey (NHANES). Our optimal predictive model has a smoothed AUC of 0.826 (95% CI: 0.801–0.850) on a validation dataset and 0.805 (95% CI: 0.781–0.829) on a holdout test dataset. Our model identified multiple second- and third-order interactions that demonstrate a strong association with RA, implying the potential role of risk factor interactions in the disease mechanism. Interestingly, we find that the inclusion of higher-order interactions in the model only marginally improves overall predictive ability. Our findings on the contribution of RA risk factors and their interaction on disease prediction could be useful in developing strategies for early diagnosis of RA, thus opening potential avenues for improved patient outcomes and reduced healthcare burden to society.
Genomic Mutations and Changes in Protein Secondary Structure and Solvent Accessibility of SARS-CoV-2 (COVID-19 Virus)
Authors: Nguyen Thanh Thi , Pathirana Pubudu N. , Nguyen Thin , Hung Nguyen Quoc Viet , Bhatti Asim , Nguyen Dinh C. , Nguyen Dung Tien , Nguyen Ngoc Duy , Creighton Douglas , Abdelrazek Mohamed
Published: July 2020

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly pathogenic virus that has caused the global COVID-19 pandemic. Tracing the evolution and transmission of the virus is crucial to respond to and control the pandemic through appropriate intervention strategies. This paper reports and analyses genomic mutations in the coding regions of SARS-CoV-2 and their probable protein secondary structure and solvent accessibility changes, which are predicted using deep learning models. Prediction results suggest that mutation D614G in the virus spike protein, which has attracted much attention from researchers, is unlikely to make changes in protein secondary structure and relative solvent accessibility. Based on 6,324 viral genome sequences, we create a spreadsheet dataset of point mutations that can facilitate the investigation of SARS-CoV-2 in many perspectives, especially in tracing the evolution and worldwide spread of the virus. Our analysis results also show that coding genes E, M, ORF6, ORF7a, ORF7b and ORF10 are most stable, potentially suitable to be targeted for vaccine and drug development.
Influence of plant host and organ, management strategy, and spore traits on microbiome composition
Authors: Gdanetz Kristi , Noel Zachary , Trail Frances
Published: July 2020

Microbiomes from maize and soybean were characterized in a long-term three-crop rotation research site, under four different land management strategies, to begin unraveling the effects of common farming practices on microbial communities. The fungal and bacterial communities of leaves, stems, and roots in host species were characterized across the growing season using amplicon sequencing and compared with the results of a similar study on wheat. Communities differed across hosts, and among plant growth stages and organs, and these effects were most pronounced in the bacterial communities of the wheat and maize phyllosphere. Roots consistently showed the highest number of bacterial OTUs compared to above-ground organs, whereas the alpha diversity of fungi was similar between above- and below-ground organs. Network analyses identified putatively influential members of the microbial communities of the three host plant species. The fungal taxa specific to roots, stems, or leaves were examined to determine if the specificity reflected their life histories based on previous studies. The analysis suggests that fungal spore traits are drivers of organ specificity in the fungal community. Identification of influential taxa in the microbial community and understanding how community structure of specific crop organs is formed, will provide a critical resource for manipulations of microbial communities. The ability to predict how organ specific communities are influenced by spore traits will enhance our ability to introduce them sustainably.
dMSCC: A microfluidic platform for microbial single-cell cultivation under dynamic environmental medium conditions
Authors: Täuber Sarah , Golze Corinna , Ho Phuong , von Lieres Eric , Grünberger Alexander
Published: July 2020

In nature and in technical systems, microbial cells are often exposed to rapidly fluctuating environmental conditions. These conditions can vary in quality, e.g., existence of a starvation zone, and quantity, e.g., average residence time in this zone. For strain development and process design, cellular response to such fluctuations needs to be systematically analysed. However, the existing methods for physically emulating rapidly changing environmental conditions are limited in spatio-temporal resolution. Hence, we present a novel microfluidic system for cultivation of single cells and small cell clusters under dynamic environmental conditions (dynamic microfluidic single-cell cultivation (dMSCC)). This system enables to control nutrient availability and composition between two media with second to minute resolution. We validate our technology using the industrially relevant model organismCorynebacterium glutamicum. The organism was exposed to different oscillation frequencies between nutrient excess (feasts) and scarcity (famine). Resulting changes in cellular physiology, such as the colony growth rate and cell morphology were analysed and revealed significant differences with growth rate and cell length between the different conditions. dMSCC also allows to apply defined but randomly changing nutrient conditions, which is important for reproducing more complex conditions from natural habitats and large-scale bioreactors. The presented system lays the foundation for the cultivation of cells under complex changing environmental conditions.
Robust three-dimensional expansion of human adult alveolar stem cells and SARS-CoV-2 infection
Authors: Youk Jeonghwan , Kim Taewoo , Evans Kelly V. , Jeong Young-Il , Hur Yongsuk , Hong Seon Pyo , Kim Je Hyoung , Yi Kijong , Kim Su Yeon , Na Kwon Joong , Bleazard Thomas , Kim Ho Min , Ivory Natasha , Mahbubani Krishnaa T. , Saeb-Parsy Kourosh , Kim Young Tae , Koh Gou Young , Choi Byeong-Sun , Ju Young Seok , Lee Joo-Hyeon
Published: July 2020

Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), which is the cause of a present global pandemic, infects human lung alveolar cells (hACs). Characterising the pathogenesis is crucial for developing vaccines and therapeutics. However, the lack of models mirroring the cellular physiology and pathology of hACs limits the study. Here, we develop a feeder-free, long-term three-dimensional (3D) culture technique for human alveolar type 2 (hAT2) cells, and investigate infection response to SARS-CoV-2. By imaging-based analysis and single-cell transcriptome profiling, we reveal rapid viral replication and the increased expression of interferon-associated genes and pro-inflammatory genes in infected hAT2 cells, indicating robust endogenous innate immune response. Further tracing of viral mutations acquired during transmission identifies full infection of individual cells effectively from a single viral entry. Our study provides deep insights into the pathogenesis of SARS-CoV-2, and the application of long-term 3D hAT2 cultures as models for respiratory diseases.
Cognitive and Neural State Dynamics of Story Comprehension
Authors: Song Hayoung , Park Bo-yong , Park Hyunjin , Shim Won Mok
Published: July 2020

Understanding a story involves a constant interplay of the accumulation of narratives and its integration into a coherent structure. This study characterizes cognitive state dynamics during story comprehension and the corresponding network-level reconfiguration of the whole brain. We presented movie clips of temporally scrambled sequences, eliciting fluctuations in subjective feelings of understanding. An understanding occurred when processing events with high causal relations to previous events. Functional neuroimaging results showed that, during moments of understanding, the brain entered into a functionally integrated state with increased activation in the default mode network (DMN). Large-scale neural state transitions were synchronized across individuals who comprehended the same stories, with increasing occurrences of the DMN-dominant state. The time-resolved functional connectivities predicted changing cognitive states, and the predictive model was generalizable when tested on new stories. Taken together, these results suggest that the brain adaptively reconfigures its interactive states as we construct narratives to causally coherent structures.
Shape-invariant perceptual encoding of dynamic facial expressions across species
Authors: Taubert N. , Stettler M. , Siebert R. , Spadacenta S. , Sting L. , Dicke P. , Thier P. , Giese Martin A.
Published: July 2020

Dynamic facial expressions are crucial for communication in primates. Due to the difficulty to control shape and dynamics of facial expressions across species, it is unknown how species-specific facial expressions are perceptually encoded and interact with the representation of facial shape. While popular neural-network theories predict a joint encoding of facial shape and dynamics, the neuromuscular control of faces evolved more slowly than facial shape, suggesting a separate encoding. To investigate this hypothesis, we developed photo-realistic human and monkey heads that were animated with motion-capture data from monkeys and human. Exact control of expression dynamics was accomplished by a Bayesian machine-learning technique. Consistent with our hypothesis, we found that human observers learned cross-species expressions very quickly, where face dynamics was represented independently of facial shape. This result supports the co-evolution of the visual processing and motor-control of facial expressions, while it challenges popular neural-network theories of dynamic expression-recognition.
A prion accelerates proliferation at the expense of lifespan
Authors: Garcia David M. , Campbell Edgar A. , Jakobson Christopher M. , Tsuchiya Mitsuhiro , DiNardo Acadia , Kaeberlein Matt , Jarosz Daniel F.
Published: July 2020

Organisms often commit to one of two strategies: living fast and dying young or living slow and dying old. In fluctuating environments, however, switching between these two strategies could be advantageous. Lifespan is often inversely correlated with cell size and proliferation, which are both limited by protein synthesis. Here we report that a highly conserved RNA-modifying enzyme, the pseudouridine synthase Pus4/TruB, can act as a prion, endowing yeast with greater proliferation rates at the cost of a shortened lifespan. Cells harboring the prion can grow larger and exhibit altered protein synthesis. This epigenetic state, [BIG+] (better ingrowth), allows cells to heritably yet reversibly alter their translational program, leading to the differential expression of hundreds of proteins, including many that regulate proliferation and aging. Our data reveal a functional role for aggregation of RNA-modifying enzymes in driving heritable epigenetic states that transform cell growth and survival.
Regulation of GluA1 Phosphorylation by D-amphetamine and Methylphenidate in the Cerebellum
Authors: Cutando Laura , Puighermanal Emma , Castell Laia , Tarot Pauline , Bertaso Federica , Bonnavion Patricia , de Kerchove d’Exaerde Alban , Isingrini Elsa , Galante Micaela , Dallerac Glenn , Pascoli Vincent , Luscher Christian , Giros Bruno , Valjent Emmanuel
Published: July 2020

Prescription stimulants, such as d-amphetamine or methylphenidate, are potent dopamine (DA) and norepinephrine (NE) releasers used to treat children and adults diagnosed for attention-deficit/hyperactivity disorder (ADHD). Although increased phosphorylation of the AMPA receptor subunit GluA1 at Ser845 (pS845-GluA1) in the striatum has been identified as an important cellular effector for the actions of these drugs, regulation of this posttranslational modification in the cerebellum has never been recognized. Here, we demonstrate that d-amphetamine and methylphenidate increase pS845-GluA1 in the membrane fraction in both vermis and lateral hemispheres of the mouse cerebellum. This regulation occurs selectively in Bergmann Glia Cells and requires intact norepinephrine release since the effects were abolished in mice lacking the vesicular monoamine transporter-2 selectively in NE neurons. Moreover, d-amphetamine-induced pS845-GluA1 was prevented by β1-adenoreceptor antagonist, whereas the blockade of dopamine D1 receptor had no effect. Additionally, we identified transcriptional alterations of several regulators of the cAMP/PKA pathway, which might account for the absence of pS845-GluA1 desensitization in mice repeatedly exposed to d-amphetamine or methylphenidate. Together, these results point to norepinephrine transmission as a key regulator of GluA1 phosphorylation in Bergmann Glial Cells, which may represent a new target for the treatment of ADHD.
Age-dependent ribosomal DNA variations and their effect on cellular function in mammalian cells
Authors: Watada Eriko , Li Sihan , Hori Yutaro , Fujiki Katsunori , Shirahige Katsuhiko , Inada Toshifumi , Kobayashi Takehiko
Published: July 2020

The ribosomal RNA gene, which consists of tandem repetitive arrays (rDNA repeat), is one of the most unstable regions in the genome. The rDNA repeat in the budding yeast is known to become unstable as the cell ages. However, it is unclear how the rDNA repeat changes in ageing mammalian cells. Using quantitative analyses, we identified age-dependent alterations in rDNA copy number and levels of methylation in mice. The degree of methylation and copy number of rDNA from bone marrow cells of 2-year-old mice were increased by comparison to 4-week-old mice in two mouse strains, BALB/cA and C57BL/6. Moreover, the level of pre-rRNA transcripts was reduced in older BALB/cA mice. We also identified many sequence variations among the repeats with two mutations being unique to old mice. These sequences were conserved in budding yeast and equivalent mutations shortened the yeast chronological lifespan. Our findings suggest that rDNA is also fragile in mammalian cells and alterations within this region have a profound effect on cellular function.

Author Summary

The ribosomal RNA gene (rDNA) is one of the most unstable regions in the genome due to its tandem repetitive structure. rDNA copy number in the budding yeast increases and becomes unstable as the cell ages. It is speculated that the rDNA produces an “aging signal” inducing senescence and death. However, it is unclear how the rDNA repeat changes during the aging process in mammalian cells. In this study, we attempted to identify the age-dependent alteration of rDNA in mice. Using quantitative single cell analysis, we show that rDNA copy number increases in old mice bone marrow cells. By contrast, the level of ribosomal RNA production was reduced because of increased levels of DNA methylation that represses transcription. We also identified many sequence variations in the rDNA. Among them, three mutations were unique to old mice and two of them were found in the conserved region in budding yeast. We then established a yeast strain with the old mouse-specific mutations and found this shortened the lifespan of the cells. These findings suggest that rDNA is also fragile in mammalian cells and alteration to this region of the genome affects cellular senescence.
Host adaptation and microbial competition driveRalstonia solanacearumphylotype I evolution in South Korea
Authors: Prokchorchik Maxim , Pandey Ankita , Moon Hayoung , Kim Wanhui , Jeon Hyelim , Poole Stephen , Segonzac Cécile , Sohn Kee Hoon , McCann Honour C.
Published: July 2020

Bacterial wilt caused by theRalstonia solanacearumspecies complex (RSSC) threatens the the cultivation of important crops worldwide. The exceptional diversity of type III secreted effector (T3E) families, high rates of recombination and broad host range of the RSSC hinder sustainable disease management strategies. We sequenced 30 phylotype I RSSC strains isolated from pepper (Capsicum annuum) and tomato (Solanum lycopersicum) in South Korea. These isolates span the diversity of phylotype I, have extensive effector repertoires and are subject to frequent recombination. Recombination hotspots among South Korean phylotype I isolates include multiple predicted contact-dependent inhibition loci, suggesting microbial competition plays a significant role inRalstoniaevolution. Rapid diversification of secreted effectors present challenges for the development of disease resistant plant varieties. We identified potential targets for disease resistance breeding by testing for allele-specific host recognition of T3Es present among South Korean phyloype I isolates. The integration of pathogen population genomics and molecular plant pathology contributes to the development of location-specific disease control and development of plant cultivars with durable resistance to relevant threats.

Repositories

All genome sequences obtained in this study are deposited to NCBI GeneBank under BioProject number PRJNA593908
Investigating hospitalMycobacterium chelonaeinfection using whole genome sequencing and hybrid assembly
Authors: Gu Christopher H. , Zhao Chunyu , Hofstaedter Casey , Tebas Pablo , Glaser Laurel , Baldassano Robert , Bittinger Kyle , Mattei Lisa M. , Bushman Frederic D.
Published: July 2020

Mycobacterium chelonaeis a rapidly growing nontuberculous mycobacterium that is a common cause of nosocomial infections. Here we describe investigation of a possible nosocomial transmission ofM. chelonaeat the Hospital of the University of Pennsylvania (HUP).M. chelonaestrains with similar high-level antibiotic resistance patterns were isolated from two patients who developed post-operative infections at HUP in 2017, suggesting a possible point source infection. The isolates, along with other clinical isolates from other patients, were sequenced using the Illumina and Oxford Nanopore technologies. The resulting short and long reads were hybrid assembled into draft genomes. The genomes were compared by quantifying single nucleotide variants in the core genome and assessed using a control dataset for identity. We show that that allM. chelonaeisolates tested were highly divergent, consistent with environmental acquisition. Additionally, antibiotic resistance genes were predicted for our isolates, and several single nucleotide variants identified with the potential to modulated drug susceptibility, providing candidate resistance mechanisms.
Quality of life of people seeking for acupuncture treatment
Authors: Silva-Filho Reginaldo , Koike Marcia Kiyomi , da Silva Gizelda Monteiro
Published: July 2020

Background

The use of Acupuncture, part of Chinese Medicine, has grown as well as the need to understand its effects. The Quality of Life (QOL) assessment is an important way to have a global view of the patient.

Objective

To assess the QoL of people who seek acupuncture at the outpatient clinic of an acupuncture school.

Methods

QOL assessment using WHOQOL-BREF applied only once to people who voluntarily sought for acupuncture at the general outpatient clinic of Faculdade EBRAMEC in 2016.

Results

People who sought for acupuncture treatment presented lower mean QoL value in all domains compared to normative values for Brazil, with physical domain presenting lower values than the other domains. It was also observed that male patients had higher values in the physical, psychological domains and general QOL compared to women.

Conclusion

Our data demonstrated that people seeking for acupuncture treatment presented lower values of QOL in comparison to a referential study with a Brazilian population, providing for the first time reference values measured by WHOQOL-bref, for patients seeking for acupuncture in the city of São Paulo.
Cryo-EM structure of Pol κ−DNA−PCNA holoenzyme and implications for polymerase switching in DNA lesion bypass
Authors: Lancey Claudia , Tehseen Muhammad , Takahashi Masateru , Sobhy Mohamed A. , Ragan Timothy J. , Crehuet Ramon , Hamdan Samir M. , De Biasio Alfredo
Published: July 2020

Replacement of the stalled replicative polymerase (Pol δ) at a DNA lesion by the error-prone DNA polymerase κ (Pol κ) restarts synthesis past the lesion to prevent genome instability. The switching from Pol δ to Pol κ is mediated by the processivity clamp PCNA but the structural basis of this mechanism is unknown. We determined the Cryo-EM structures of human Pol κ–DNA–PCNA complex and of a stalled Pol δ–DNA–PCNA complex at 3.9 and 4.7 Å resolution, respectively. In Pol κ complex, the C-terminus of the PAD domain docks the catalytic core to one PCNA protomer in an angled orientation, bending the DNA exiting Pol κ active site through PCNA. In Pol δ complex, the DNA is disengaged from the active site but is retained by the thumb domain. We present a model for polymerase switching facilitated by Pol κ recruitment to PCNA and Pol κ conformational sampling to seize the DNA from stalled Pol δ assisted by PCNA tilting.
The Amyloid Structure of Mouse RIPK3 (Receptor Interacting Protein Kinase 3) in Cell Necroptosis
Authors: Wu Xia-lian , Hu Hong , Dong Xing-qi , Zhang Jing , Wang Jian , Schwieters Charles D. , Liu Jing , Wu Guo-xiang , Li Bing , Lin Jing-yu , Wang Hua-yi , Lu Jun-xia
Published: July 2020

RIPK3 amyloid complex plays crucial roles in execution of TNF-induced necroptosis and in response to immune defense in both human and mouse. We have structurally characterized the mouse RIPK3 homogeneous self-assembly using solid-state NMR, illustrating a well-ordered N-shaped amyloid core structure featured with 3 parallel in-registerβ-sheets. The structure is different from previously published human RIPK1/RIPK3 hetero-amyloid complex. Functional studies indicate both RIPK1-RIPK3 binding and RIPK3 amyloid formation are essential but not sufficient for RIPK3-mediated necroptosis. The structural integrity of RIPK3 fibril with three β-strands is necessary for the signaling. Molecular dynamics simulation of the mouse RIPK1/RIPK3 model indicates less stable for the hetero-amyloid to adopt RIPK3 fibril conformation, suggesting a structural transformation of RIPK3 from RIPK1-RIPK3 binding to RIPK3 amyloid formation. This structural transformation is revealed for the first time, providing a missing link connecting RIPK1-RIPK3 binding to RIPK3 homo-oligomer formation in the signal transduction.
A formin-mediated cell wall- plasma membrane- cytoskeleton continuum is required for symbiotic infections inMedicago truncatula
Authors: Liang Pengbo , Schmitz Clara , Lace Beatrice , Ditengou Franck Anicet , Keller Jean , Libourel Cyril , Delaux Pierre-Marc , Ott Thomas
Published: July 2020

Plant cell infections are tightly orchestrated by cell wall (CW) alterations, plasma membrane (PM) resident signalling processes and dynamic remodelling of the cytoskeleton. During root nodule symbiosis these processes result in morpho-dynamic responses including root hair swelling and curling, PM invagination and polar growth of a tubular infection structure, the infection thread (IT). However, the molecular details driving and guiding these PM remodelling events remain to be unravelled. Here, we studied a formin protein (SYFO1) inM. truncatulathat is specifically induced during rhizobial infection. Phenotypical analysis ofsyfo1mutants clearly indicates that the encoded protein is required for efficient rhizobial colonization of root hairs. SYFO1 itself creates a proteinaceous bridge between the CW and the polarized cytoskeleton. It binds to CW components via a proline-rich N-terminal segment, which is indispensable for its function. On the cytoplasmic side of the PM SYFO1 is associated with actin accumulations supporting the hypothesis that it contributes to cell polarizationin vivo. This is further sustained by the fact that cell shape changes can be induced in a stimulus-dependent manner in root protoplasts expressing SYFO1. Taken together we provide evidence for the evolutionary re-wiring of a generic cytoskeleton modulator into a symbiosis-specific response.
Male and female reproductive fitness costs of an immune response in natural populations
Authors: De Lisle Stephen P. , Bolnick Daniel I.
Published: July 2020

Parasites can mediate host fitness both directly, via effects on survival and reproduction, or indirectly by inducing host immune defense with costly side-effects. The evolution of immune defense is determined by a complex interplay of costs and benefits of parasite infection and immune response, all of which may differ for male and female hosts in sexual lineages. Here, we examine fitness costs associated with an inducible immune defense in a fish-cestode host-parasite system. Cestode infection induces peritoneal fibrosis in threespine stickleback (Gasterosteus aculeatus), constraining cestode growth and sometimes encasing and killing the parasite. Surveying two wild populations of stickleback, we confirm that the presence of fibrosis scar tissue is associated with reduced parasite burden in both male and female fish. However, fibrotic fish had lower foraging success and reproductive fitness (reduced female egg production and male nesting success), indicating strong costs of the lingering immunopathology. We show that these substantial sexually-concordant fitness effects of immune response act to align multivariate selection across the sexes, masking the signature of sexual antagonism that acted on morphology alone. Although both sexes experienced costs of fibrosis, the net impacts are unequal because in the two study populations females had higher cestode exposure. To evaluate whether this difference in risk should drive sex-specific immune strategies, we analyze a quantitative genetic model of host immune response to a trophically transmitted parasite. The model and empirical data illustrate how shared costs and benefits of immune response lead to shared evolutionary interests of male and female hosts, despite unequal infection risks across the sexes.