bluuebunny/crossref_metadata_2025 huggingface dataset:
Untargeted lipidomics of non-small cell lung carcinoma shows differentially abundant lipid classes in cancer vs non-cancer tissue
Authors: Mitchell Joshua M , Flight Robert M , Lane Andrew N , Moseley Hunter N.B.
Published: March 2021

Lung cancer is the leading cause of cancer death worldwide and non-small cell lung carcinoma (NSCLC) represents 85% of newly diagnosed lung cancers. The high mortality rate of lung cancer is due in part to the lack of effective treatment options for advanced disease. A major limitation in the development of effective treatment options is our incomplete understanding of NSCLC metabolism at a molecular level, especially lipids. Improvements in mass spectrometry combined with our untargeted assignment tool SMIRFE enable the systematic and less biased examination of NSCLC lipid metabolism.
Lipids were extracted from paired tumorous and non-tumorous lung tissue samples from 86 patients with suspected resectable stage I or IIa primary NSCLC and were analyzed using ultra-high resolution Fourier transform mass spectrometry. Pathological examination of the samples revealed that the majority of the samples were primary NSCLC; however, the disease group does include examples of metastases of other cancers and several granulomas. Information-content-informed (ICI) Kendall tau correlation analysis revealed correlation and co-occurrence patterns consistent with significant changes in lipid profiles between disease and non-disease samples. Lipids assigned using the program SMIRFE (Mitchell et al., 2019) were analyzed for differential abundance, followed by machine learning to classify the SMIRFE formula assignments into lipid categories. At the lipid category level, sterol abundances were consistently higher in diseased versus non-diseased lung tissues at statistically significant levels.
The statistically significant increase in sterol abundances in primary NSCLC compared with non-cancerous lung tissue suggests for treatment of primary NSCLC a possible therapeutic role for statins and nitrogenous bisphosphonates, pharmaceuticals that inhibit endogenous sterol biosynthesis. This hypothesis is consistent with previous epidemiological studies that have identified a therapeutic role for statins in the treatment of NSCLC but were unable to identify a molecular mechanism for this effect. Additionally, the majority of the consistently increased sterol abundances belong to the sterol ester subcategory, suggesting increased SCD1 and ACAT1 activity. SCD1 expression is a known negative prognostic indicator for survival in NSCLC. In our study, a large fraction of the NSCLC samples displayed this phenotype; however, SCD1 mutants would be unexpected in all of these samples. This suggests that this metabolic phenotype may be shared across multiple genetic subtypes of NSCLC. Thus, inhibitors of SCD1 and other enzymes involved in the production of this metabolic phenotype could have utility in the treatment of many genetic subtypes of NSCLC.
“This is about the coolest thing I’ve ever seen is that you just showed right up.” COVID-19 testing and vaccine acceptability among homeless-experienced adults: Qualitative data from two samples
Authors: Knight Kelly Ray , Duke Michael R. , Carey Caitlin A. , Pruss Graham , Garcia Cheyenne M. , Lightfoot Marguerita , Imbert Elizabeth , Kushel Margot
Published: March 2021

Background

Homeless-experienced populations are at increased risk of exposure to SARS CoV-2 due to their living environments and face increased risk of severe COVID-19 disease due to underlying health conditions. Little is known about COVID-19 testing and vaccination acceptability among homeless-experienced populations.

Objective

To understand the facilitators and barriers to COVID-19 testing and vaccine acceptability among homeless-experienced adults.

Design

We conducted in-depth interviews with participants from July-October 2020. We purposively recruited participants from 1) a longitudinal cohort of homeless-experienced older adults in Oakland, CA (n=37) and 2) a convenience sample of people (n=57) during a mobile outreach COVID-19 testing event in San Francisco.

Participants

Adults with current or past experience of homelessness.

Approach

We asked participants about their experiences with and attitudes towards COVID-19 testing and their perceptions of COVID-19 vaccinations. We used participant observation techniques to document the interactions between testing teams and those approached for testing. We audio-recorded, transcribed and content analyzed all interviews and identified major themes and subthemes.

Key Results

Participants found incentivized COVID-19 testing administered in unsheltered settings and supported by community health outreach workers (CHOWs) to be acceptable. The majority of participants expressed positive inclination toward vaccine acceptability, citing a desire to return to routine life and civic responsibility. Those who expressed hesitancy cited a desire to see trial data, concerns that vaccines included infectious materials, and mistrust of the government.

Conclusions

Participants expressed positive evaluations of the incentivized, mobile COVID-19 testing supported by CHOWs in unsheltered settings. The majority of participants expressed positive inclination toward vaccination. Vaccine hesitancy concerns must be addressed when designing vaccine delivery strategies that overcome access challenges. Based on the successful implementation of COVID-19 testing, we recommend mobile delivery of vaccines using trusted CHOWs to address concerns and facilitate wider access to and uptake of the COVID vaccine.
A Queuing Model for Ventilator Capacity Management during the COVID-19 Pandemic
Authors: Zimmerman Samantha L. , Rutherford Alexander R. , van der Waall Alexa , Norena Monica , Dodek Peter
Published: March 2021

We applied a queuing model to inform ventilator capacity planning during the first wave of the COVID-19 epidemic in the province of British Columbia (BC), Canada. The core of our framework is a multiclass Erlang loss model that represents ventilator use by both COVID-19 and non-COVID-19 patients. Input for the model includes COVID-19 case projections, and our analysis incorporates projections with different levels of transmission due to public health measures and social distancing. We incorporated data from the BC Intensive Care Unit Database to calibrate and validate the model. Using discrete event simulation, we projected ventilator access, including when capacity would be reached and how many patients would be unable to access a ventilator. Simulation results were compared with three numerical approximation methods, namely pointwise stationary approximation, modified offered load, and fixed point approximation. Using this comparison, we developed a hybrid optimization approach to efficiently identify required ventilator capacity to meet access targets. Model projections demonstrate that public health measures and social distancing potentially averted up to 50 deaths per day in BC, by ensuring that ventilator capacity was not reached during the first wave of COVID-19. Without these measures, an additional 173 ventilators would have been required to ensure that at least 95% of patients can access a ventilator immediately. Our model provides a tool for policy makers to quantify the interplay between public health measures, necessary critical care resources, and performance indicators for patient access.
Learning from the Experiences of COVID-19 Survivors: A Descriptive Study
Authors: Prioleau Temiloluwa
Published: March 2021

Background

There are still many unanswered questions about the novel coronavirus, however, a largely underutilized source of knowledge are the millions of people who have recovered after contracting the virus. This includes majority of undocumented cases of the COVID-19 which are classified as mild or moderate and received little to no clinical care during the course of illness.

Objective

To document and glean insights from the experiences of persons with first-hand experience with coronavirus, especially the so-called mild to moderate cases that self-resolved in isolation.

Methods

This online-based survey study called C19 Insider Scoop recruited adult participants that are 18-years or older who reside in the United States and tested positive for COVID-19 or antibodies. Participants were recruited through various methods including online support groups for COVID-19 survivors, advertisement in local news outlets, and advertisement through professional and other networks. The main outcomes measured include knowledge on contraction/transmission of the virus, symptoms, and personal experiences on road to recovery.

Results

A total of 72 participants (53 females/19 males, ages 18 - 73 yrs. old, mean = 41-yrs.) from 22 U.S. states participated in this study. We found that the top known source of how people contracted the COVID-19 virus was through a family or household member (n=26 or 35%). This was followed by essential workers contracting the virus through the workplace (n=13 or 18%).

Participants reported up to 27 less-documented symptoms that they experienced during their illness such as brain/memory fog, palpitations, ear pain/discomfort and neurological problems. In addition, 47 out of 72 participants (65%) reported that their symptoms lasted longer than the commonly cited 2-weeks even for mild cases of COVID-19. In our study, the mean recovery time was 4.5-weeks, and exactly one-half of survivors (50%) still experienced lingering symptoms of COVID-19 after an average of 65-days following illness onset. Additionally, 37 participants (51%) reported that they experienced stigma associated with having COVID-19.

Conclusion

This study presents preliminary findings which suggests that emphasis on family/household spread of COVID-19 may be lacking and there is a general underestimation of the recovery time even for mild cases of the virus. Although a larger study is needed to validate these results, it is important to note that as more people experience COVID-19, insights from prior survivors can enable a more informed public, pave the way for others who may be affected, and guide further research.
Effects of wearing face masks under moderate physical effort
Authors: Martin Eberhart , Stefan Orthaber , Reinhold Kerbl
Published: March 2021

Due to the COVID-19 pandemic, face masks have become part of daily life and work. Only few studies have investigated potential negative effects of this measure. It was aim of this study to evaluate whether face masks may affect oygen saturation and heart reate under moderate physical effort. Ten healthy volunteers were asked to climb up four floors (96 steps) with and without a face mask. Oxygen saturation and heart rate were recorded before and after this procedure.

Physical activity lead to a slight decrease of oxygen saturation of 3.0% (± 3.1) without and 3.7% (± 3.8) with face masks (p= 0.28). Heart rate increased by 31.0 (±18.7) and 33.3 (± 15.9) beats per minute (p= 0.39). Desaturation was more pronounced in individuals > 40 years, however was uncritical in all cases.

This study shows that in healthy adults the use of face masks does not significantly affect oxygen supply nor cause additional cardiac load.
Bridging cell-scale simulations and radiologic images to explain short-time intratumoral oxygen fluctuations
Authors: Kingsley Jessica L. , Costello James R. , Raghunand Natarajan , Rejniak Katarzyna A.
Published: March 2021

Radiologic images provide a way to monitor tumor development and its response to therapies in a longitudinal and minimally invasive fashion. However, they operate on a macroscopic scale (average value per voxel) and are not able to capture microscopic scale (cell level) phenomena. Nevertheless, to examine the causes of frequent fast fluctuations in tissue oxygenation, the models simulating individual cells’ behavior are needed. Here, we provided a link between the average data value recorded for radiologic image voxels and the cellular and vascular architecture of the tissue that fills these voxels. Using hybrid agent-based modeling, we generated a set of tissue morphologies capable of reproducing tissue oxygenation levels observed in radiologic images. We applied this approach to investigate whether oxygen fluctuations can be explained by changes in vascular oxygen supply or by modulations in cellular oxygen absorption. Our studies showed that intravascular changes in oxygen supply can reproduce the observed fluctuations in tissue oxygenation in all considered regions of interest. However, large magnitude fluctuations cannot be recreated by modifications in cellular absorption of oxygen in biologically feasible manner. Additionally, we developed a procedure to identify plausible tissue morphologies for a given temporal series of average data from radiology images. In future applications this approach can be used to generate a set of tissues representative for radiology images and to simulate tumor response to various anti-cancer treatments on the tissue-scale level.

Authors Summary

Low levels of oxygen, called hypoxia, are observable in many solid tumors. They are associated with more aggressive malignant cells which are resistant to chemo-, radio- and immunotherapies. Recently developed imaging techniques provide a way to measure the magnitude of frequent short-term oxygen fluctuation, however they operate on a macro-scale voxel level. To examine the causes of rapid oxygen fluctuations on the cell level, we developed a hybrid agent-based mathematical model. We tested two different mechanisms that could be responsible for these cyclic effects in tissue oxygenation: variations in vascular influx of oxygen and modulations in cellular oxygen absorption. Additionally, we developed a procedure to identify plausible tissue morphologies from data collected from radiological images. This will also provide a bridge between the micro-scale simulations with individual cells and the longitudinal medical images containing average voxel values. In the future applications, this approach can be used to generate a set of tissues representative of radiology images and to simulate tumor response to various anticancer treatments on the cell-scale level.
Multimodal characterization of Yucatan minipig behavior and physiology through maturation
Authors: Netzley Alesa H. , Hunt Ryan D. , Franco-Arellano Josue , Arnold Nicole , Munoz Kirk A. , Colbath Aimee C. , Bush Tamara Reid , Pelled Galit
Published: March 2021

Brain injuries that are induced by external forces are particularly challenging to model experimentally. In recent decades, the domestic pig has been gaining popularity as a highly relevant animal model to address the pathophysiological mechanisms and the biomechanics associated with head injuries. Understanding cognitive, motor, and sensory aspects of pig behavior throughout development is crucial for evaluating cognitive and motor deficits after injury. We have developed a comprehensive battery of tests to characterize the behavior and physiological function of the Yucatan minipig throughout maturation. Behavioral testing included assessments of learning and memory, executive functions, circadian rhythms, gait analysis, and level of motor activity. We applied traditional behavioral apparatus and analysis methods, as well as state-of-the-art sensor technologies to report on motion and activity, and artificial intelligent approaches to analyze behavior. We studied pigs from 16 weeks old through sexual maturity at 35 weeks old. The results show multidimensional characterization of minipig behavior, and how it develops and changes with age. This animal model may capitulate the biomechanical consideration and phenotype of head injuries in the developing brain and can drive forward the field of understanding pathophysiological mechanisms and developing new therapies to accelerate recovery in children who have suffered head trauma.
Assortative Mating Biases Marker-based Heritability Estimators
Authors: Border Richard , O’Rourke Sean , de Candia Teresa , Goddard Michael E. , Visscher Peter M. , Yengo Loic , Jones Mathew , Keller Matthew C.
Published: March 2021

Many complex traits are subject to assortative mating (AM), with recent molecular genetic findings confirming longstanding theoretical predictions that AM alters genetic architecture by inducing long range dependence across causal variants. However, all marker-based heritability estimators assume mating is random. We provide mathematical and simulation-based evidence demonstrating that both method-of-moments estimators and likelihood-based estimators produce biased estimates in the presence of AM and that common approaches to account for population structure fail to mitigate this bias. Then, examining height and educational attainment in the UK Biobank, we demonstrate that these biases affect real world traits. Finally, we derive corrected heritability estimators for traits under equilibrium AM.
SC1: A Tool for Interactive Web-Based Single Cell RNA-Seq Data Analysis
Authors: Moussa Marmar , Măndoiu Ion I.
Published: March 2021

Single cell RNA-Seq (scRNA-Seq) is critical for studying cellular function and phenotypic heterogeneity as well as the development of tissues and tumors. Here, we presentSC1a web-based highly interactive scRNA-Seq data analysis tool publicly accessible athttps://sc1.engr.uconn.edu. The tool presents an integrated workflow for scRNA-Seq analysis, implements a novel method of selecting informative genes based on Term-Frequency Inverse-Document-Frequency (TF-IDF) scores, and provides a broad range of methods for clustering, differential expression analysis, gene enrichment, interactive visualization, and cell cycle analysis. The tool integrates other single cell omics data modalities like TCR-Seq and supports several single cell sequencing technologies. In just a few steps, researchers can generate a comprehensive analysis and gain powerful insights from their scRNA-Seq data.
Plasticity in gustatory and nociceptive neurons controls decision making inC. eleganssalt navigation
Authors: Dekkers Martijn P.J. , Salfelder Felix , Sanders Tom , Umuerri Oluwatoroti , Cohen Netta , Jansen Gert
Published: March 2021

A conventional understanding of perception assigns sensory organs the role of capturing the environment. Better sensors result in more accurate encoding of stimuli, allowing for cognitive processing downstream. Here we show that plasticity in sensory neurons mediates a behavioral switch inC. elegansbetween attraction to NaCl in naïve animals and avoidance of NaCl in preconditioned animals, called gustatory plasticity. Ca2+imaging in ASE and ASH NaCl sensing neurons reveals multiple cell-autonomous and distributed circuit adaptation mechanisms. A computational model quantitatively accounts for observed behaviors and reveals roles for sensory neurons in the control and modulation of motor behaviors, decision making and navigational strategy. Sensory adaptation dynamically alters the encoding of the environment. Rather than encoding the stimulus directly, therefore, we propose that theseC. eleganssensors dynamically encode a context-dependent value of the stimulus. Our results demonstrate how adaptive sensory computation can directly control an animal’s behavioral state.
More pests but less treatments: ambivalent effect of landscape complexity on Conservation Biological Control
Authors: Zamberletti Patrizia , Sabir Khadija , Opitz Thomas , Bonnefon Olivier , Gabriel Edith , Papaïx Julien
Published: March 2021

In agricultural landscapes, the amount and organization of crops and semi-natural habitats (SNH) have the potential to promote a bundle of ecosystem services due to their influence on ecological community at multiple spatio-temporal scales. SNH are relatively undisturbed and are often source of complementary resources and refuges, supporting more diverse and abundant natural pest enemies. However, the nexus of SNH proportion and organization with pest suppression is not trivial. It is thus crucial to understand how the behavior of pest and auxiliary species, the underlying landscape structure, and their interaction may influence conservation biological control (CBC). Here, we develop a generative stochastic landscape model to simulate realistic agricultural landscape compositions and configurations of fields and linear elements. Generated landscapes are used as spatial support over which we simulate a spatially explicit predator-prey dynamic model. We find that SNH boost predator population, but predator movement from hedges to fields is fundamental for an efficient pest regulation by auxiliaries and to decrease pesticide treatments. Moreover landscape elements may lead to different effects on pest reduction depending on the considered scale. Integration of species behaviors and traits with landscape structure at multiple scales are needed to provide useful insights for CBC.
Predicting TCR-epitope Binding Specificity Using Deep Metric Learning and Multimodal Learning
Authors: Luu Alan M. , Leistico Jacob R. , Miller Tim , Kim Somang , Song Jun S.
Published: March 2021

Understanding the recognition of specific epitopes by cytotoxic T cells is a central problem in immunology. Although predicting binding between peptides and the class I Major Histocompatibility Complex (MHC) has had success, predicting interactions between T cell receptors (TCRs) and MHC class I-peptide complexes (pMHC) remains elusive. This paper utilizes a convolutional neural network model employing deep metric learning and multimodal learning to perform two critical tasks in TCR-epitope binding prediction: identifying the TCRs that bind a given epitope from a TCR repertoire, and identifying the binding epitope of a given TCR from a list of candidate epitopes. Our model can perform both tasks simultaneously and reveals that inconsistent preprocessing of CDR3B sequences can confound binding prediction. Applying a neural network interpretation method identifies key amino acid sequence patterns and positions within the TCR important for binding specificity. Contrary to the common assumption, known crystal structures of TCR-pMHC complexes show that the predicted salient amino acid positions are not necessarily the closest to the epitopes, implying that physical proximity may not be a good proxy for importance in determining TCR-epitope specificity. Our work thus provides insight into the learned predictive features of TCR-epitope binding specificity and advances associated classification tasks.
Automated Spatially Targeted Optical Micro Proteomics (AutoSTOMP) 2.0 identifies proteins enriched within inflammatory lesions in tissue sections and human clinical biopsies
Authors: Yin Bocheng , Caggiano Laura R , Li Rung-Chi , McGowan Emily , Holmes Jeffery W , Ewald Sarah E
Published: March 2021

Tissue microenvironment properties like blood flow, extracellular matrix or proximity to immune infiltrate are important regulators of cell biology. However, methods to study regional protein expression in context of the native tissue environment are limited. To address this need we have developed a novel approach to visualize, purify and measure proteins in situ using Automated Spatially Targeted Optical Micro Proteomics (AutoSTOMP) 2.0. We previously implemented AutoSTOMP to identify proteins localized to the vacuoles of obligate intracellular microbes at the 1-2 μm scale within infected host cells1. Here we report custom codes in SikuliX to specify regions of heterogeneity in a tissue section and then biotin tag and identify proteins belonging to specific cell types or structures within those regions. To enrich biotinylated targets from fixed tissue samples we developed a biochemical protocol compatible with LC-MS. These tools were applied to a) identify inflammatory proteins expressed by CD68+ macrophages in rat cardiac infarcts and b) characterize inflammatory proteins enriched in IgG4+ lesions in esophageal tissue. These data indicate that AutoSTOMP is a flexible approach to determine regional protein expression in situ on a range of primary tissues and clinical biopsies where current tools are limited.
CCL28 modulates neutrophil responses during infection with mucosal pathogens
Authors: Perez-Lopez Araceli , Silva Steven , Lee Michael H. , Dillon Nicholas , Brandt Stephanie L. , Gerner Romana R. , Melchior Karine , Walker Gregory T. , Sosa-Hernandez Victor A. , Cervantes-Diaz Rodrigo , Romero-Ramirez Sandra , Maravillas-Montero Jose L. , Nuccio Sean-Paul , Nizet Victor , Raffatellu Manuela
Published: March 2021

The chemokine CCL28 is highly expressed in mucosal tissues, but its role during infection is not well understood. Here we show that CCL28 promotes neutrophil accumulation to the gut of mice infected withSalmonellaand to the lung of mice infected withAcinetobacter. Neutrophils isolated from the infected mucosa expressed the CCL28 receptors CCR3 and, to a lesser extent, CCR10, on their surface. The functional consequences of CCL28 deficiency were different between the two infections, asCcl28-/-mice were highly susceptible toSalmonellagut infection, but highly resistant to otherwise lethalAcinetobacterlung infection.In vitro, unstimulated neutrophils harbored pre-formed intracellular CCR3 that was rapidly mobilized to the cell surface following phagocytosis or inflammatory stimuli. Moreover, CCL28 stimulation enhanced neutrophil antimicrobial activity, production of reactive oxygen species, and formation of extracellular traps, all processes that were largely dependent on CCR3. Consistent with the different outcomes in the two infection models, neutrophil stimulation with CCL28 boosted the killing ofSalmonellabut not ofAcinetobacter. CCL28 thus plays a critical role in the immune response to mucosal pathogens by increasing neutrophil accumulation and activation, which can enhance pathogen clearance but also exacerbate disease depending on the mucosal site and the infectious agent.
An equine tendon model for studying intra-tendinous shear in tendons that have more than one muscle contribution
Authors: Yin Nai-Hao , McCarthy Ian , Birch Helen L.
Published: March 2021

Human Achilles tendon is composed of three smaller sub-tendons and exhibits non-uniform internal displacements, which decline with age and after injury, suggesting a potential role in the development of tendinopathies. Studying internal sliding behaviour is therefore important but difficult in human Achilles tendon. Here we propose the equine deep digital flexor tendon (DDFT) and its accessory ligament (AL) as a model to understand the sliding mechanism. The AL-DDFT has a comparable sub-bundle structure, is subjected to high and frequent asymmetric loads and is a natural site of injury similar to human Achilles tendons. Equine AL-DDFT were collected and underwent whole tendon level (n=7) and fascicle level (n=7) quasi-static mechanical testing. Whole tendon level testing was performed by sequentially loading through the proximal AL and subsequently through the proximal DDFT and recording regional strain in the free structures and joined DDFT and AL. Fascicle level testing was performed with focus on the inter-sub-bundle matrix between the two structures at the junction. Our results demonstrate a significant difference in the regional strain between the joined DDFT and AL and a greater transmission of force from the AL to the DDFT than vice versa. These results can be partially explained by the mechanical properties and geometry of the two structures and by differences in the properties of the interfascicular matrices. In conclusion, this tendon model successfully demonstrates that high displacement discrepancy occurs between the two structures and can be used as an easy-access model for study intra-tendinous shear mechanics at the sub-tendon level.
Effects of cover crops on beetle assemblages in tea plantations
Authors: Chen Li-Lin , Pozsgai Gabor , Li Xiang-Yu , Li Lei , Reddy Gadi V.P. , You Min-Sheng
Published: March 2021

Beetles are visible members of food webs in tea plantations, with high species richness and abundance. Many tea pests, as well as natural enemies, are members of this order, so a knowledge of how groundcovers affect beetles can aid pest management. We collected beetles in a replicated field experiment in the Wuyi Mountains, Fujian Province China. Tea was intercropped withPaspalum notatumorChamaecrista rotundifolia,or rows were cleared to bare ground, or in the control they were left unmanaged to allow weeds to grow naturally. Sampling, done by sweep netting and vegetation beating, was conducted monthly, between May 2006 and April 2008, and Coleoptera abundance, biomass, species richness and assemblage structures were compared between groundcover treatments. Total beetle abundance and species richness were significantly higher in tea intercropped withC. rotundifoliaand bare ground than in naturally grown weedy control. Whilst there was no difference between predator assemblages among treatments for any measure, herbivores were more abundant, weighed more, and were more diverse inC. rotundifoliatreatments than in weedy control. Biomass and species richness were also greater in plots withP. notatumgroundcover than those in weedy control. We found that beetle assemblages varied both seasonally and with ground cover treatment, but the potential pest control impact of more species-rich beetle assemblages was mixed, and further work is needed to gain information on trophic groups with potential benefits for use in non-insecticidal pest management.
The middle lipin (M-Lip) domain is a new dimeric protein fold that binds membranes
Authors: Gu Weijing , Gao Shujuan , Wang Huan , Fleming Kaelin D. , Hoffmann Reece M. , Yang Jong Won , Patel Nimi M. , Choi Yong Mi , Burke John E. , Reue Karen , Airola Michael V.
Published: March 2021

Phospholipid synthesis and fat storage as triglycerides is regulated by lipin phosphatidic acid phosphatases (PAPs), whose enzymatic PAP function requires association with cellular membranes. Using hydrogen deuterium exchange mass spectrometry, we find mouse lipin 1 binds membranes through an N-terminal amphipathic helix and a middle lipin (M-Lip) domain that is conserved in mammalian and mammalian-like lipins. Crystal structures of the M-Lip domain reveal a previously unrecognized and novel protein fold that dimerizes. The isolated M-Lip domain binds membranes both in vitro and in cells through conserved basic and hydrophobic residues. Deletion of the M-Lip domain in full-length lipin 1 influences PAP activity, membrane binding, subcellular localization, oligomerization, and adipocyte differentiation, but does not affect transcriptional co-activation. This establishes the M-Lip domain as a new dimeric protein fold that binds membranes and is critical for full functionality of mammalian lipins.
A Weighted Network Analysis Framework for the Hourglass Effect — and its Application in the C. Elegans Connectome
Authors: Batta Ishaan , Yao Qihang , Sabrin Kaeser M. , Dovrolis Constantine
Published: March 2021

Understanding hierarchy and modularity in natural as well as technological networks is of utmost importance. A major aspect of such analysis involves identifying the nodes that are crucial to the overall processing structure of the network. More recently, the approach of hourglass analysis has been developed for the purpose of quantitatively analyzing whether only a few intermediate nodes mediate the information processing between a large number of inputs and outputs of a network. We develop a new framework for hourglass analysis that takes network weights into account while identifying the core nodes and the extent of hourglass effect in a given weighted network. We use this framework to study the structural connectome of theC. elegansand identify intermediate neurons that form the core of sensori-motor pathways in the organism. Our results show that the neurons forming the core of the connectome show significant differences across the male and hermaphrodite sexes, with most core nodes in the male concentrated in sex-organs while they are located in the head for the hermaphrodite. Our work demonstrates that taking weights into account for network analysis framework leads to emergence of different network patterns in terms of identification of core nodes and hourglass structure in the network, which otherwise would be missed by unweighted approaches.
EffectorO: motif-independent prediction of effectors in oomycete genomes using machine learning and lineage-specificity
Authors: Nur Munir , Wood Kelsey , Michelmore Richard
Published: March 2021

Oomycete plant pathogens cause a wide variety of diseases, including late blight of potato, sudden oak death, and downy mildews of plants. These pathogens are major contributors to loss in numerous food crops. Oomycetes secrete effector proteins to manipulate their hosts to the advantage of the pathogen. Plants have evolved to recognize effectors, resulting in an evolutionary cycle of defense and counter-defense in plant–microbe interactions. This selective pressure results in highly diverse effector sequences that can be difficult to computationally identify using only sequence similarity. We developed a novel effector prediction tool, EffectorO, that uses two complementary approaches to predict effectors in oomycete pathogen genomes: (1) a machine learning-based pipeline that predicts effector probability based on the biochemical properties of the N-terminal amino acid sequence of a protein and (2) a pipeline based on lineage-specificity to find proteins that are unique to one species or genus, a sign of evolutionary divergence due to adaptation to the host. We tested EffectorO onBremia lactucae, which causes lettuce downy mildew, andPhytophthora infestans, which causes late blight of potato and tomato, and predicted many novel effector candidates, while recovering the majority of known effector candidates. EffectorO will be useful for discovering novel families of oomycete effectors without relying on sequence similarity to known effectors.
Tardigrades exhibit robust inter-limb coordination across walking speeds
Authors: Nirody Jasmine A , Duran Lisset A. , Johnston Deborah , Cohen Daniel J.
Published: March 2021

Tardigrades must negotiate heterogeneous, fluctuating environments, and accordingly utilize locomotive strategies capable of dealing with variable terrain. We analyze the kinematics and inter-leg coordination of freely walking tardigrades (species:Hypsibius dujardini). We find that tardigrade walking replicates several key features of walking in insects despite disparities in size, skeleton, and habitat. To test the effect of environmental changes on tardigrade locomotor control circuits, we measure kinematics and inter-leg coordination during walking on two substrates of different stiffnesses. We find that the phase offset between contralateral leg pairs is flexible, while ipsilateral coordination is preserved across environmental conditions. This mirrors similar results in insects and crustaceans. We propose that these functional similarities in walking co-ordination between tardigrades and arthropods is either due to a generalized locomotor control circuit common to panarthropods, or to independent convergence onto an optimal strategy for robust multi-legged control in small animals with simple circuitry. Our results highlight the value of tardigrades as a comparative system towards understanding the mechanisms – neural and/or mechanical – underlying coordination in panarthropod locomotion.
Membrane-MEDYAN: Simulating Deformable Vesicles Containing Complex Cytoskeletal Networks
Authors: Ni Haoran , Papoian Garegin A.
Published: March 2021

The plasma membrane defines the shape of the cell and plays an indispensable role in bridging intra- and extra-cellular environments. Mechanochemical interactions between plasma membrane and cytoskeleton are vital for cell biomechanics and mechanosensing. A computational model that comprehensively captures the complex, cell-scale cytoskeleton-membrane dynamics is still lacking. In this work, we introduce a triangulated membrane model that accounts for membrane’s elastic properties, as well as for membrane-filament steric interactions. The corresponding force-field was incorporated into the active biological matter simulation platform, MEDYAN (“Mechanochemical Dynamics of Active Networks”). Simulations using the new model shed light on how actin filament bundling affects generation of tubular membrane protrusions. In particular, we used membrane-MEDYAN simulations to investigate protrusion initiation and dynamics while varying geometries of filament bundles, membrane rigidities and local G-Actin concentrations. We found that bundles’ protrusion propensities sensitively depend on the synergy between bundle thickness and inclination angle at which the bundle approaches the membrane. The new model paves the way for simulations of biological systems involving intricate membrane-cytoskeleton interactions, such as occurring at the leading edge and the cortex, eventually helping to uncover the fundamental principles underlying the active matter organization in the vicinity of the membrane.
Critical interactions for SARS-CoV-2 spike protein binding to ACE2 identified by machine learning
Authors: Pavlova Anna , Zhang Zijian , Acharya Atanu , Lynch Diane L. , Pang Yui Tik , Mou Zhongyu , Parks Jerry M. , Chipot Chris , Gumbart James C.
Published: March 2021

Both SARS-CoV and SARS-CoV-2 bind to the human ACE2 receptor. Based on high-resolution structures, the two viruses bind in practically identical conformations, although several residues of the receptor-binding domain (RBD) differ between them. Here we have used molecular dynamics (MD) simulations, machine learning (ML), and free energy perturbation (FEP) calculations to elucidate the differences in RBD binding by the two viruses. Although only subtle differences were observed from the initial MD simulations of the two RBD-ACE2 complexes, ML identified the individual residues with the most distinctive ACE2 interactions, many of which have been highlighted in previous experimental studies. FEP calculations quantified the corresponding differences in binding free energies to ACE2, and examination of MD trajectories provided structural explanations for these differences. Lastly, the energetics of emerging SARS-CoV-2 mutations were studied, showing that the affinity of the RBD for ACE2 is increased by N501Y and E484K mutations but is slightly decreased by K417N.
Challenges in defining Long COVID: Striking differences across literature, Electronic Health Records, and patient-reported information
Authors: Rando Halie M. , Bennett Tellen D. , Byrd James Brian , Bramante Carolyn , Callahan Tiffany J. , Chute Christopher G. , Davis Hannah E. , Deer Rachel , Gagnier Joel , Koraishy Farrukh M , Liu Feifan , McMurry Julie A. , Moffitt Richard A. , Pfaff Emily R. , Reese Justin T. , Relevo Rose , Robinson Peter N. , Saltz Joel H. , Solomonides Anthony , Sule Anupam , Topaloglu Umit , Haendel Melissa A.
Published: March 2021

Since late 2019, the novel coronavirus SARS-CoV-2 has introduced a wide array of health challenges globally. In addition to a complex acute presentation that can affect multiple organ systems, increasing evidence points to long-term sequelae being common and impactful. The worldwide scientific community is forging ahead to characterize a wide range of outcomes associated with SARS-CoV-2 infection; however the underlying assumptions in these studies have varied so widely that the resulting data are difficult to compareFormal definitions are needed in order to design robust and consistent studies of Long COVID that consistently capture variation in long-term outcomes. Even the condition itself goes by three terms, most widely “Long COVID”, but also “COVID-19 syndrome (PACS)” or, “post-acute sequelae of SARS-CoV-2 infection (PASC)”. In the present study, we investigate the definitions used in the literature published to date and compare them against data available from electronic health records and patient-reported information collected via surveys. Long COVID holds the potential to produce a second public health crisis on the heels of the pandemic itself. Proactive efforts to identify the characteristics of this heterogeneous condition are imperative for a rigorous scientific effort to investigate and mitigate this threat.
Water yield modelling, sensitivity analysis and validation: a study for Portugal
Authors: Almeida Bruna , Cabral Pedro
Published: March 2021

The spatially explicit assessment of freshwater is key to introduce the ecosystem service (ES) concept into decision-making processes. Many tools are being developed to model water balance and to analyse the effects of meteorological conditions on water ES behaviours at multiple spatial scales. Nevertheless, there is a lack of studies that analyse the sensitivity of these models and estimate the model’s accuracy. The current research uses the InVEST Water Yield Model (WYM) to assess freshwater ES between 1990 and 2018 at River Basin District (RBD) level in mainland Portugal. The methodology included sensitivity analysis simulations to test different parameters of the model over two different sources of meteorological data. We validated the model with the European Environment Agency (EEA) database on the quantity of Europe’s freshwater resources. To evaluate the models’ sensitivity, Pearson’s correlation coefficients and statistical methods were calculated for each simulation. The model which obtained the best performance in the sensitivity tests was retained for further analysis and calibration and its accuracy was assessed by comparing the mean estimated water yield (WY) with mean observed values for 2018. Results at the national level show a correlation coefficient of 0.803 with statistical significance for 0.01 one-tail. The WY in the RBDs of the North of the country was underestimated by 56.5 mm/ha/year and for the RBDs in the South of Portugal, the WY was overestimated by 58.1 mm/ha/year. This difference was explained through the spatial-temporal assessment of the main climatic variables used as input. This study contributes to a methodology to assess the level of confidence in WYM outputs and can be used to support the trustworthiness of water availability studies at sub-watershed, watershed, or RBD, using open access data and software.
Internal microbial zonation assists in the massive growth of marimo, a lake ball ofAegagropila linnaeiin Lake Akan
Authors: Nakai Ryosuke , Wakana Isamu , Niki Hironori
Published: March 2021

Marimo (lake ball) is an uncommon ball-like aggregation of the green alga,Aegagropila linnaei.AlthoughA. linnaeiis broadly distributed in fresh and brackish waters in the northern hemisphere, marimo colonies are found only in particular habitats. The colonies have been gradually shrinking in recent years. Nevertheless, it is not clear how and whyA. linnaeiforms such massive spherical aggregations. Here, we report the bacterial microbiomes inside various sizes and aggregating structures of natural marimo collected from Lake Akan, Japan. We observed multi-layers composed of sediment particles only in the sizeable radial-type marimo with a >20 cm diameter, not in the tangled-type marimo. The deeper layers were enriched byNitrospira, potential novel sulphur-oxidizing bacteria, and sulphate-reducingDesulfobacteraceaebacteria. The sulphur cycle-related bacteria are unique to Lake Akan due to sulphur deposits from the nearby volcanic mountains. Some of them were also recovered from lake sediments. Microorganisms of the multi-layers would form biofilms incorporating nearby sediment, which would function as microbial “seals” within large radial-type marimo. We propose that the layer structure provides habitats for diverse bacterial communities, promotes airtightness of the marimo, and finally contributes to the massive growth of the aggregation. These findings provide a clue to deciphering the massive growth of endangered marimo aggregates.
The circadian clock component BMAL1 regulates SARS-CoV-2 entry and replication in lung epithelial cells
Authors: Zhuang Xiaodong , Tsukuda Senko , Wrensch Florian , Wing Peter AC , Schilling Mirjam , Harris James M , Borrmann Helene , Morgan Sophie B , Cane Jennifer L , Mailly Laurent , Thakur Nazia , Conceicao Carina , Sanghani Harshmeena , Heydmann Laura , Bach Charlotte , Ashton Anna , Walsh Steven , Tan Tiong Kit , Schimanski Lisa , Huang Kuan-Ying A , Schuster Catherine , Watashi Koichi , Hinks Timothy SC , Jagannath Aarti , Vausdevan Sridhar R , Bailey Dalan , Baumert Thomas F , McKeating Jane A
Published: March 2021

The COVID-19 pandemic, caused by SARS-CoV-2 coronavirus, is a global health issue with unprecedented challenges for public health. SARS-CoV-2 primarily infects cells of the respiratory tract, via Spike glycoprotein binding angiotensin-converting enzyme (ACE2). Circadian rhythms coordinate an organism’s response to its environment and can regulate host susceptibility to virus infection. We demonstrate a circadian regulation of ACE2 in lung epithelial cells and show that silencing BMAL1 or treatment with a synthetic REV-ERB agonist SR9009 reduces ACE2 expression and inhibits SARS-CoV-2 entry. Treating infected cells with SR9009 limits viral replication and secretion of infectious particles, showing that post-entry steps in the viral life cycle are influenced by the circadian system. Transcriptome analysis revealed that Bmal1 silencing induced a wide spectrum of interferon stimulated genes in Calu-3 lung epithelial cells, providing a mechanism for the circadian pathway to dampen SARS-CoV-2 infection. Our study suggests new approaches to understand and improve therapeutic targeting of SARS-CoV-2.
A bidirectional corticoamygdala circuit for the encoding and retrieval of detailed reward memories
Authors: Sias Ana C. , Morse Ashleigh K. , Wang Sherry , Greenfield Venuz Y. , Goodpaster Caitlin M. , Wrenn Tyler M. , Wikenheiser Andrew M. , Holley Sandra M. , Cepeda Carlos , Levine Michael S. , Wassum Kate M.
Published: March 2021

Adaptive reward-related decision making often requires accurate and detailed representation of potential available rewards. Environmental reward-predictive stimuli can facilitate these representations, allowing one to infer which specific rewards might be available and choose accordingly. This process relies on encoded relationships between the cues and the sensory-specific details of the reward they predict. Here we interrogated the function of the basolateral amygdala (BLA) and its interaction with the lateral orbitofrontal cortex (lOFC) in the ability to learn such stimulus-outcome associations and use these memories to guide decision making. Using optical recording and inhibition approaches, Pavlovian cue-reward conditioning, and the outcome-selective Pavlovian-to-instrumental transfer (PIT) test in male rats, we found that the BLA is robustly activated at the time of stimulus-outcome learning and that this activity is necessary for sensory-specific stimulus-outcome memories to be encoded, so they can subsequently influence reward choices. Direct input from the lOFC was found to support the BLA in this function. Based on prior work, activity in BLA projections back to the lOFC was known to support the use of stimulus-outcome memories to influence decision making. By multiplexing optogenetic and chemogenetic inhibition we performed a serial circuit disconnection and found that the lOFC→BLA and BLA→lOFC pathways form a functional circuit regulating the encoding (lOFC→BLA) and subsequent use (BLA→lOFC) of the stimulus-dependent, sensory-specific reward memories that are critical for adaptive, appetitive decision making.