bluuebunny/crossref_metadata_2025_split huggingface dataset:
High variation in immune responses and parasite phenotypes in naturally acquiredTrypanosoma cruziinfection in a captive non-human primate breeding colony in Texas, USA
Authors: Padilla Angel M. , Yao Phil Y. , Landry Tre J. , Cooley Gretchen M. , Mahaney Susan M. , Ribeiro Isabela , VandeBerg John L. , Tarleton Rick L. 
Published: January 2021

AbstractTrypanosoma cruzi, the causative agent of human Chagas disease, is endemic to the southern region of the United States where it routinely infects many host species. The indoor/outdoor housing configuration used in many non-human primate research and breeding facilities in the southern U.S. provides the opportunity for infection byT. cruziand thus provides source material for in-depth investigation of host and parasite dynamics in a natural host species under highly controlled and restricted conditions. For cynomolgus macaques housed at such a facility, we used a combination of serial blood quantitative PCR (qPCR) and hemoculture to confirm infection in >92% of seropositive animals, although each method alone failed to detect infection in >20% of cases. Parasite isolates obtained from 43 of the 64 seropositive macaques were of 2 broad genetic types (discrete typing units, (DTU’s) I and IV); both within and between these DTU groupings, isolates displayed a wide variation in growth characteristics and virulence, elicited host immune responses, and susceptibility to drug treatment in a mouse model. Likewise, the macaques displayed a diversity in T cell and antibody response profiles that rarely correlated with parasite DTU type, length of infection, or age of the primate. This study reveals the complexity of infection dynamics, parasite phenotypes, and immune response patterns that can occur in a primate group, despite being housed in a uniform environment at a single location, and the limited time period over which theT. cruziinfections were established.Author SummaryWe evaluated naturally occurring infections ofTrypanosoma cruzi, the causative agent of human Chagas disease, in an indoor/outdoor primate colony at a breeding facility in Texas, USA. Using serial quantitative PCR and hemoculture, we confirmed infection in 92% of the 64 seropositive animals, but neither of these two methods confirmed more than 80% of the cases. Parasites by hemoculture fell into two genetic groups (discrete typing units I and IV), and displayed large variation in growth characteristics, elicited cellular and humoral immune responses as well as virulence and drug susceptibility when tested in mice. EKG abnormalities were found in 13 out of 51 qPCR-positive macaques. Our results demonstrate the complexity of these infection parameters in this colony in spite of the uniform and geographically constrained housing conditions of the macaques.
Quantifying the impact of electric fields on single-cell motility
Authors: Prescott TP , Zhu K , Zhao M , Baker RE 
Published: January 2021

ABSTRACTCell motility in response to environmental cues forms the basis of many developmental processes in multicellular organisms. One such environmental cue is an electric field (EF), which induces a form of motility known as electrotaxis. Electrotaxis has evolved in a number of cell types to guide wound healing, and has been associated with different cellular processes, suggesting that observed electrotactic behaviour is likely a combination of multiple distinct effects arising from the presence of an EF. In order to determine the different mechanisms by which observed electrotactic behaviour emerges, and thus to design EFs that can be applied to direct and control electrotaxis, researchers require accurate quantitative predictions of cellular responses to externally-applied fields. Here, we use mathematical modelling to formulate and parametrise a variety of hypothetical descriptions of how cell motility may change in response to an EF. We calibrate our model to observed data using synthetic likelihoods and Bayesian sequential learning techniques, and demonstrate that EFs bias cellular motility through only one of a selection of hypothetical mechanisms. We also demonstrate how the model allows us to make predictions about cellular motility under different EFs. The resulting model and calibration methodology will thus form the basis for future data-driven and model-based feedback control strategies based on electric actuation.SIGNIFICANCEElectrotaxis is attracting much interest and development as a technique to control cell migration due to the precision of electric fields as actuation signals. However, precise control of electrotactic migration relies on an accurate model of how cell motility changes in response to applied electric fields. We present and calibrate a parametrised stochastic model that accurately replicates experimental single-cell data and enables the prediction of input–output behaviour while quantifying uncertainty and stochasticity. The model allows us to elucidate and quantify how electric fields perturb the motile behaviour of the cell. This model and the associated simulation-based calibration methodology will be central to future developments in the control of electrotaxis.
Diversity of receptor expression in central and peripheral mouse neurons estimated from single cell RNA sequencing
Authors: Wangzhou Andi , Paige Candler , Ray Pradipta R. , Dussor Gregory , Price Theodore J. 
Published: January 2021

AbstractBecause somatosensory PNS neurons, in particular nociceptors, are specially tuned to be able to detect a wide variety of both exogenous and endogenous signals, it is widely assumed that these neurons express a greater variety of receptor genes. Because cells detect such signals via cell surface receptors, we sought to formally test the hypothesis that PNS neurons might express a broader array of cell surface receptors than CNS neurons using existing single cell RNA sequencing resources from mouse. We focused our analysis on ion channels, G-protein coupled receptors (GPCRS), receptor tyrosine kinase and cytokine family receptors. In partial support of our hypothesis, we found that mouse PNS somatosensory, sympathetic and enteric neurons and CNS neurons have similar receptor expression diversity in families of receptors examined, with the exception of GPCRs and cytokine receptors which showed greater diversity in the PNS. Surprisingly, these differences were mostly driven by enteric and sympathetic neurons, not by somatosensory neurons or nociceptors. Secondary analysis revealed many receptors that are very specifically expressed in subsets of PNS neurons, including some that are unique among neurons for nociceptors. Finally, we sought to examine specific ligand-receptor interactions between T cells and PNS and CNS neurons. Again, we noted that most interactions between these cells are shared by CNS and PNS neurons despite the fact that T cells only enter the CNS under rare circumstances. Our findings demonstrate that both PNS and CNS neurons express an astonishing array of cell surface receptors and suggest that most neurons are tuned to receive signals from other cells types, in particular immune cells.
Analysis ofDrosophilacardiac hypertrophy by micro-computerized tomography for genetic dissection of heart growth mechanisms
Authors: Petersen Courtney E , Tripoli Benjamin A , Schoborg Todd A , Smyth Jeremy T 
Published: January 2021

ABSTRACTHeart failure is often preceded by pathological cardiac hypertrophy, a thickening of the heart musculature driven by complex gene regulatory and signaling processes. TheDrosophilaheart has great potential as a genetic model for deciphering the underlying mechanisms of cardiac hypertrophy. However, current methods for evaluating hypertrophy of theDrosophilaheart are laborious and difficult to carry out reproducibly. Here we demonstrate that micro-computerized tomography (microCT) is an accessible, highly reproducible method for non-destructive, quantitative analysis ofDrosophilaheart morphology and size. To validate our microCT approach for analyzingDrosophilacardiac hypertrophy, we show that expression of constitutively active Ras (Ras85DV12), previously shown to cause hypertrophy of the fly heart, results in significant thickening of both adult and larval heart walls when measured from microCT images. We then show using microCT analysis that genetic upregulation of store-operated Ca2+entry (SOCE) driven by expression of constitutively active Stim (StimCA) or Orai (OraiCA) proteins also results in significant hypertrophy of theDrosophilaheart, through a process that specifically depends on Orai Ca2+influx channels. Intravital imaging of heart contractility revealed significantly reduced end diastolic dimensions in StimCAand OraiCAexpressing hearts, consistent with the hypertrophic phenotype. These results demonstrate that increased SOCE activity is an important driver of hypertrophic cardiomyocyte growth, and demonstrate how microCT analysis combined with tractable genetic tools inDrosophilacan be used to delineate molecular signaling processes that underlie cardiac hypertrophy and heart failure.NEW AND NOTEWORTHYGenetic analysis of cardiac hypertrophy inDrosophilaholds immense potential for the discovery of new therapeutic targets to prevent and treat heart failure. However, this potential has been hindered by a lack of rapid and effective methods for analysis of heart size in flies. Here we demonstrate that analysis of theDrosophilaheart with micro-computerized tomography yields accurate and highly reproducible heart size measurements that can be used to efficiently analyze heart growth and cardiac hypertrophy inDrosophila.
Fast but not furious: a streamlined selection method for genome edited cells
Authors: Ramachandran Haribaskar , Martins Soraia , Kontarakis Zacharias , Krutmann Jean , Rossi Andrea 
Published: January 2021

AbstractIn the last decade, Transcription Activator-Like Effector Nucleases (TALEN) and Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) based genome engineering have revolutionized our approach to biology. Due to their high efficiency and ease of use, the development of custom knock-out and knock-in animal or cell models is now within reach for almost every laboratory. Nonetheless, the generation of genetically modified cells often requires a selection step, usually achieved by antibiotics or fluorescent markers. The choice of the selection marker is based on the available laboratory resources, such as cell types, and parameters like time and cost should also be taken into consideration. Here, we present a new and fast strategy calledMAGECS(magnetic-activated genome edited cell sorting), to select genetically modified cells based on the ability to magnetically sort surface antigens (i.e. tCD19) present in Cas9 positive cells. By using MAGECS, we successfully generated and isolated genetically modified human induced pluripotent stem cells (hiPSCs), primary human fibroblasts, SH-SY5Y neuroblast-like cells, HaCaT and HEK293T cells.Our strategy expands the genome editing toolbox by offering a fast, cheap, and an easy to use alternative to the available selection methods.
Identification of genes associated with productivity traits and salinity tolerance from activation tagged lines of rice
Authors: Raja Kota Vamsee , Madhanasekhar Kalva , Reddy Vudem Dashavantha , Reddy Attipalli Ramachandra , Rao Khareedu Venkateswara 
Published: January 2021

AbstractWorld-wide crop productivity is hugely impacted by diverse eco-environmental conditions. In the present investigation, activation tagged (AT) lines of rice endowed with improved agronomic attributes have been analyzed for tolerance to salinity stress besides identification of genes associated with these attributes. Under salinity stress conditions, AT lines exhibited increased seed germination rates, improved plant growth and development at vegetative and reproductive stages as compared to wild-type (WT) plants. Furthermore, AT lines disclosed enhanced plant water content, photosynthetic efficiency, stomatal conductance, water use efficiency and maximum quantum yield when compared to WT plants, leading to improved yields and delayed onset of stress symptoms. Moreover, AT lines revealed effective antioxidant systems causing decreased accumulation of reactive oxygen species and delayed salinity stress symptoms compared to WT plants. Reduced accumulation of malondialdehyde with concomitant increases in proline and soluble sugars of AT lines further endorsing their improved stress tolerance levels. TAIL and qRT-PCR analyses of AT lines revealed Ds element integrations at different loci and respective overexpression of identified candidate genes involved in various aspects of plant development and stress tolerance. Accordingly, the AT lines plausibly serve as a rare genetic resource for fortifying stress tolerance and productivity traits of elite rice cultivars.HighlightActivation tagged lines of rice endowed with improved agronomic attributes have been analyzed for tolerance to salinity stress besides identification and expression analysis of genes associated with these attributes.
Human airway cells prevent SARS-CoV-2 multibasic cleavage site cell culture adaptation
Authors: Lamers Mart M. , Mykytyn Anna Z. , Breugem Tim I. , Wang Yiquan , Wu Douglas C. , Riesebosch Samra , van den Doel Petra B. , Schipper Debby , Bestebroer Theo , Wu Nicholas C. , Haagmans Bart L. 
Published: January 2021

AbstractVirus propagation methods generally use transformed cell lines to grow viruses from clinical specimens, which may force viruses to rapidly adapt to cell culture conditions, a process facilitated by high viral mutation rates. Upon propagation in VeroE6 cells, SARS-CoV-2 may mutate or delete the multibasic cleavage site (MBCS) in the spike protein that facilitates serine protease-mediated entry into human airway cells. We report that propagating SARS-CoV-2 on the human airway cell line Calu-3 - that expresses serine proteases - prevents MBCS mutations. Similar results were obtained using a human airway organoid-based culture system for SARS-CoV-2 propagation. Thus, in-depth knowledge on the biology of a virus can be used to establish methods to prevent cell culture adaptation.
Social prediction modulates activity of macaque superior temporal cortex
Authors: Roumazeilles Lea , Schurz Matthias , Lojkiewiez Mathilde , Verhagen Lennart , Schüffelgen Urs , Marche Kevin , Mahmoodi Ali , Emberton Andrew , Simpson Kelly , Joly Olivier , Khamassi Mehdi , Rushworth Matthew FS. , Mars Rogier B. , Sallet Jérôme 
Published: January 2021

AbstractThe ability to attribute thoughts to others, also called theory of mind (TOM), has been extensively studied. Computationally, the basis of TOM in humans has been interpreted within the predictive coding framework and associated with activity in the temporo-parietal junction (TPJ). However, the evolutionary origins of these human mindreading abilities have been challenged since the concept was coined. Here we identify a brain region in the Rhesus macaque that shares computational properties with the human TPJ. We revealed, using a non-linguistic task and functional magnetic resonance imaging, that activity in a region of the macaque middle superior temporal cortex was specifically modulated by the predictability of social interactions. As in human TPJ, this region could be distinguished from other temporal regions involved in face processing. Our result suggests the existence of a precursor for the theory of mind ability in the last common ancestor of human and old-world monkeys.
Dopamine transporter is a master regulator of dopaminergic neural network connectivity
Authors: Miller Douglas , Guenther Dylan T. , Maurer Andrew P. , Hansen Carissa A. , Zalesky Andrew , Khoshbouei Habibeh 
Published: January 2021

AbstractDopaminergic neurons of the substantia nigra (SNC) and ventral tegmental area (VTA) exhibit spontaneous firing activity. The dopaminergic neurons in these regions have been shown to exhibit differential sensitivity to neuronal loss and psychostimulants targeting dopamine transporter. However, it remains unclear whether these regional differences scale beyond individual neuronal activity to regional neuronal networks. Here we utilized live-cell calcium imaging to show that network connectivity greatly differs between SNC and VTA regions with higher incidence of hub-like neurons in the VTA. Specifically, the frequency of hub-like neurons was significantly lower in SNC dopamine neurons than in the adjacent VTA, consistent with the interpretation of a lower network resilience to SNC neuronal loss. We tested this hypothesis when activity of an individual dopaminergic neuron is suppressed, through whole-cell patch clamp electrophysiology, in either SNC, or VTA networks. Neuronal loss in the SNC decreased network clustering, whereas the larger number of hub-neurons in the VTA overcompensated by increasing network clustering in the VTA. We further show that network properties are regulatable via a dopamine transporter but not a D2 receptor dependent mechanism. Our results demonstrate novel regulatory mechanisms of functional network topology in dopaminergic brain regions.
Identification of a filamentous form of kunitz protease inhibitor inAsteraceae
Authors: Bratsch Sara , Olszewski Neil , Lockhart Benham 
Published: January 2021

AbstractFilamentous structures were observed in purified extracts from chrysanthemum, gerbera, sunflower and zinnia. When purified filament proteins were subjected to SDS-PAGE, the major protein associated with filaments from all three species has an apparent molecular mass of ≈25 kDa. Protein bands from chrysanthemum, gerbera, and zinnia were subjected to N-terminal protein sequencing while proteins from sunflower were sequenced by CID MS/MS. All of the sequences shared highest similarity to the kunitz trypsin inhibitor family. The sequencing results indicated that the proteins lacked the signal sequences. We tested the gerbera filament protein for glycosylation and found that it was a glycoprotein. Together these results indicate that the filaments are composed of mature KTI protein. This is the first report of a KTI assembling into filaments and the first report of a filament formingAsteraceaeenzyme.
Severe COVID-19 associated variants linked to chemokine receptor gene control in monocytes and macrophages
Authors: Stikker Bernard , Stik Grégoire , Hendriks Rudi W. , Stadhouders Ralph 
Published: January 2021

AbstractGenome-wide association studies have identified 3p21.31 as the main risk locus for severe disease in COVID-19 patients, although underlying biological mechanisms remain elusive. We performed a comprehensive epigenomic dissection of the 3p21.31 locus, identifying a CTCF-dependent tissue-specific 3D regulatory chromatin hub that controls the activity of several tissue-homing chemokine receptor (CCR) genes in monocytes and macrophages. Risk SNPs colocalized with regulatory elements and were linked to increased expression ofCCR1,CCR2andCCR5in monocytes and macrophages. As excessive organ infiltration of inflammatory monocytes and macrophages is a hallmark of severe COVID-19, our findings provide a rationale for the genetic association of 3p21.31 variants with elevated risk of hospitalization upon SARS-CoV-2 infection.
Temporal Self-Compression: Behavioral and neural evidence that past and future selves are compressed as they move away from the present
Authors: Brietzke Sasha , Meyer Meghan L. 
Published: January 2021

AbstractAlthough it is well-known that people feel disconnected from their past and future selves, the underlying mechanism supporting this phenomenon is unknown. To help fill this gap, we considered a basic principle of perception. As objects increase in distance from an observer, they also become logarithmically compressed in perception (i.e., not differentiated from one another), making them hard to distinguish. Here, we report four studies that suggest we may feel disconnected from distant selves, in part, because they are increasingly indiscriminable with temporal distance from the present self. In Studies 1-3, participants made trait ratings across various time points in the past and future. We found that participants compressed their past and future selves, relative to their present self. This effect was preferential to the self and could not be explained by the alternative possibility that individuals simply perceive arbitrary self-change with time irrespective of temporal distance. In Study 4, we tested for neural evidence of temporal self-compression by having participants complete trait ratings across time points while undergoing functional magnetic resonance imaging (fMRI). Representational similarity analysis (RSA) was used to determine if neural self-representations are compressed with temporal distance, as well. We found evidence of temporal self-compression in areas of the default network, including medial prefrontal cortex (MPFC) and posterior cingulate cortex (PCC). Specifically, neural pattern similarity between self-representations was logarithmically compressed with temporal distance. Taken together, these findings reveal a “temporal self-compression” effect, with temporal selves becoming increasingly indiscriminable with distance from the present.Significance StatementFor centuries, great thinkers have struggled to understand why we feel disconnected from our past and future selves. Insight may come from a basic principle of perception: as objects become distant, they also become less discriminable, or ‘compressed.’ In Studies 1-3, we demonstrate that people’s ratings of their own personality become increasingly less differentiated as they consider more distant past and future selves. In Study 4, we found neural evidence that the brain compresses self-representations with time, as well. When we peer out a window, objects close to us are in clear view whereas distant objects are hard to tell apart. We provide novel evidence that self-perception may operate similarly, with the nuance of distant selves increasingly harder to perceive.
Genetically independent phenotype analysis identifies LPA and VCAM1 as drug targets for human ageing
Authors: Timmers Paul R. H. J. , Tiys Evgeny S. , Sakaue Saori , Akiyama Masato , Kiiskinen Tuomo T. J. , Zhou Wei , Hwang Shih-Jen , Yao Chen ,   The Biobank Japan Project,   FinnGen Study, Deelen Joris , Levy Daniel , Ganna Andrea , Kamatani Yoichiro , Okada Yukinori , Joshi Peter K. , Wilson James F. , Tsepilov Yakov A. 
Published: January 2021

AbstractThe length and quality of life is important to us all, yet identification of promising drug targets for human ageing using genetics has had limited success. Here, we combine six large European-ancestry genome-wide association studies (GWAS) of human ageing traits—healthspan, father and mother lifespan, exceptional longevity, frailty index, and self-rated health—in a principal component framework that maximises their shared genetic architecture. The first principal component (GIP1) is more heritable than the original studies and shows strong genetic correlations with length of life as well as multiple indices of mental and physical wellbeing. We identify 27 genomic regions associated with GIP1, and provide additional, independent evidence for an effect on human ageing for loci nearHTTandMAML3using a study of Finnish and Japanese subject survival. Across the genome, GIP1 associations are enriched in genes involved in haem metabolism and pathways related to transcription, neurogenesis, homeostasis, proteolysis, intracellular signalling, immunity, and the muscle system. Finally, using proteome-wide two-sample Mendelian randomisation and colocalisation, we provide robust evidence for a detrimental effect of blood levels of apolipoprotein(a) (LPA) and vascular cell adhesion molecule 1 (VCAM1) on GIP1. Together, our results demonstrate that combining multiple ageing traits using genetic principal components enhances power to detect biological targets for human ageing.