bluuebunny/crossref_metadata_2025_split huggingface dataset:
The anterior cingulate cortex and its role in controlling contextual fear memory to predatory threats
Authors: de Lima Miguel Antonio Xavier , Baldo Marcus Vinicius C. , Oliveira Fernando A. , Canteras Newton Sabino 
Published: February 2021

ABSTRACTPredator exposure is a life-threatening experience and elicits learned fear responses to the context in which the predator was encountered. The anterior cingulate area (ACA) occupies a pivotal position in a cortical network responsive to predatory threats, and it exerts a critical role in processing fear memory. Ours results revealed that the ACA is involved in both the acquisition and expression of contextual fear to predatory threat. Overall, the ACA can provide predictive relationships between the context and the predator threat and influences fear memory acquisition through projections to the basolateral amygdala and perirhinal region and the expression of contextual fear through projections to the dorsolateral periaqueductal gray. Our results expand previous studies based on classical fear conditioning and open interesting perspectives for understanding how the ACA is involved in processing contextual fear memory to ethologic threatening conditions that entrain specific medial hypothalamic fear circuits (i.e., predator- and conspecific-responsive circuits).
Mesophyll cells mediate systemic reactive oxygen signaling during wounding or heat stress
Authors: Zandalinas Sara I. , Mittler Ron 
Published: February 2021

ABSTRACTSensing of heat, high light (HL), or mechanical injury by a single leaf of a plant results in the activation of different systemic signals that reach systemic tissues within minutes and trigger systemic acquired acclimation (SAA) or systemic wound responses (SWRs), resulting in a heightened state of stress readiness of the entire plant. Among the different signals associated with rapid systemic responses to stress in plants are electric, calcium and reactive oxygen species (ROS) waves. These signals propagate from the stressed or injured leaf to the rest of the plant through the plant vascular bundles, and trigger SWRs and SAA in systemic tissues. However, whether they can propagate through other cell types, and whether or not they are interlinked, remain open questions. Here we report that in response to wounding or heat stress (HS), but not HL stress, the ROS wave can propagate through mesophyll cells ofArabidopsis thaliana. Moreover, we show that propagation of the ROS wave through mesophyll cells during these stresses is sufficient to restore SWR and SAA transcript accumulation in systemic leaves, as well as SAA to HS (but not HL). We further show that propagation of the ROS wave through mesophyll cells could contribute to systemic signal integration during HL&HS stress combination. Our findings reveal that the ROS wave can propagate through tissues other than the vascular bundles of plants, and that different stresses can trigger different types of systemic signals that propagate through different cell layers and induce stress-specific systemic responses.One-sentence summaryIn addition to vascular bundles, mesophyll cells can mediate the ROS wave during systemic responses to wounding or heat stress in Arabidopsis.
SpatialDWLS: accurate deconvolution of spatial transcriptomic data
Authors: Dong Rui , Yuan Guo-Cheng 
Published: February 2021

AbstractRecent development of spatial transcriptomic technologies has made it possible to systematically characterize cellular heterogeneity while preserving spatial information, which greatly enables the investigation of structural organization of a tissue and its impact on modulating cellular behavior. On the other hand, the technology often does not have sufficient resolution to distinguish neighboring cells which may belong to different cell types, therefore it is difficult to identify cell-type distribution directly from the data. To overcome this challenge, we have developed a computational method, called spatialDWLS, to quantitatively estimate the cell-type composition at each spatial location. We benchmarked the performance of spatialDWLS by comparing with a number of existing deconvolution methods using both real and simulated datasets, and we found that spatialDWLS outperformed the other methods in terms of accuracy and speed. By applying spatialDWLS to analyze a human developmental heart dataset, we observed striking spatial-temporal changes of cell-type composition which becomes increasing spatially coherent during development. As such, spatialDWLS provides a valuable computational tool for faithfully extracting biological information from spatial transcriptomic data.
Brain2Pix: Fully convolutional naturalistic video reconstruction from brain activity
Authors: Le Lynn , Ambrogioni Luca , Seeliger Katja , Güçlütürk Yağmur , van Gerven Marcel , Güçlü Umut 
Published: February 2021

AbstractReconstructing complex and dynamic visual perception from brain activity remains a major challenge in machine learning applications to neuroscience. Here we present a new method for reconstructing naturalistic images and videos from very large single-participant functional magnetic resonance imaging data that leverages the recent success of image-to-image transformation networks. This is achieved by exploiting spatial information obtained from retinotopic mappings across the visual system. More specifically, we first determine what position each voxel in a particular region of interest would represent in the visual field based on its corresponding receptive field location. Then, the 2D image representation of the brain activity on the visual field is passed to a fully convolutional image-to-image network trained to recover the original stimuli using VGG feature loss with an adversarial regularizer. In our experiments, we show that our method offers a significant improvement over existing video reconstruction techniques.
Cardiac fibroblast GSK-3α mediates adverse myocardial fibrosis via IL-11 and ERK pathway
Authors: Umbarkar Prachi , Tousif Sultan , Singh Anand P. , Anderson Joshua C. , Zhang Qinkun , Lal Hind 
Published: February 2021

AbstractBackgroundHeart failure is the leading cause of mortality, morbidity, and healthcare expenditures worldwide. Numerous studies have implicated Glycogen Synthase Kinase-3 (GSK-3) as a promising therapeutic target for cardiovascular diseases. GSK-3 isoforms appear to play overlapping, unique, and even opposing functions in the heart. Recently our group has identified cardiac fibroblast (CF) GSK-3β as a negative regulator of fibrotic remodeling in the ischemic heart. However, the role of CF-GSK-3α in myocardial fibrosis is unknown.Methods and ResultsHerein, we employed two entirely novel conditional fibroblast-specific and tamoxifen-inducible mouse models to define the role of CF-GSK-3α in fibroblast activation and myocardial fibrosis. Specifically, GSK-3α was deleted from cardiac fibroblasts or myofibroblasts with tamoxifen-inducible Tcf21- or periostin-promoter-driven Cre recombinase. At 2 months of age, WT and KO mice were subjected to cardiac injury, and heart functions were monitored by serial echocardiography. Histological analysis and morphometric studies were performed at 8 weeks post-injury. In both settings, GSK-3α deletion restricted fibrotic remodeling and improved cardiac function. To investigate underlying mechanisms, we examined the effect of GSK-3α deletion on myofibroblast transformation and pro-fibrotic TGFβ1-SMAD3 signalingin vitro. A significant reduction in cell migration, collagen gel contraction, and α-SMA expression in TGFβ1 treated GSK-3α KO MEFs confirmed that GSK-3α is required for myofibroblast transformation. Surprisingly, GSK-3α deletion did not affect SMAD3 activation, indicating the pro-fibrotic role of GSK-3α is SMAD3 independent. To further delineate the underlying mechanism, total proteins were isolated from CFs of WT and KO animals at 4 weeks post-injury, and kinome profiling was performed by utilizing PamStation®12 high throughput microarray platform. The kinome analysis identified the downregulation of RAF family kinase activity in GSK3α-KO-CFs. Moreover, mapping of significantly altered kinases against literature annotated interactions generated ERK-centric networks. Importantly, flow cytometric analysis of CFs confirmed a significant decrease in pERK levels in KO mice. Additionally, ourin vitrostudies demonstrated that GSK-3α deletion prevented TGFβ1 induced ERK activation thereby validating our findings from kinome analysis. Interestingly, IL-11, a fibroblast specific downstream effector of TGFβ1, was very low in GSK-3α KO MEFs as compared to WT and ERK inhibition further reduced IL-11 expression in them. All these results indicate that GSK-3α mediates pro-fibrotic response in the injured heart through IL-11 and ERK pathway.ConclusionCF-GSK-3α plays a causal role in myocardial fibrosis that could be therapeutically targeted for future clinical applications.
Characterization ofPoldip2knockout mice: avoiding incorrect gene targeting
Authors: Lassègue Bernard , Kumar Sandeep , Mandavilli Rohan , Wang Keke , Tsai Michelle , Kang Dong-Won , Hernandes Marina S. , Martín Alejandra San , Jo Hanjoong , Taylor W. Robert , Griendling Kathy K. 
Published: February 2021

AbstractPOLDIP2 is a multifunctional protein whose roles are only partially understood. Our laboratory previously reported physiological studies performed using a mouse gene trap model, which suffered from two limitations: perinatal lethality in homozygotes and constitutivePoldip2inactivation. To overcome these limitations, we developed a new conditional floxedPoldip2model. The first part of the present study shows that our initial floxed mice were affected by an unexpected mutation, which was not readily detected by Southern blotting and traditional PCR. It consisted of a 305 kb duplication aroundPoldip2with retention of the wild type allele and could be traced back to the original targeted ES cell clone. We offer simple suggestions to rapidly detect similar accidents, which may affect genome editing using both traditional and CRISPR-based methods. In the second part of the present study, correctly targeted floxedPoldip2mice were generated and used to produce a new constitutive knockout line by crossing with a Cre deleter. In contrast to the gene trap model, many homozygous knockout mice were viable, in spite of having no POLDIP2 expression. To further characterize the effects ofPoldip2ablation in the vasculature, an RNA-seq experiment was performed in constitutive knockout carotid arteries. Results support the involvement of POLDIP2 in multiple cellular processes and provide new opportunities for future in-depth study of its functions.
Cellular Reprogramming in Bursts and Phases
Authors: Alicea Bradly 
Published: February 2021

AbstractAs a biochemical process, direct cellular reprogramming is slow and complex. The early stages of this process is the most critical determinant of successful phenotypic conversion. This study provides insight into the statistical signatures that describe temporal structure in the reprogramming process. We examine two sources of variation in reprogramming cells: clonal instances from various tissues of origin and rate of expansion between these lines. Our analytical strategy involved modeling the potential of populations to reprogram, and then applying statistical models to capture this potential in action. This two-fold approach utilizes both conventional and novel techniques that allow us to infer and confirm a host of properties that define the phenomenon. These results can be summarized in a number of ways, and essentially suggest that reprogramming is organized around changes in gene expression phenotype (phases) which happens sporadically across a cellular population (bursts).
Evolutionary modelling of HCV subtypes provides rationale for their different disease outcomes
Authors: Zhang Hang , Quadeer Ahmed A. , McKay Matthew R. 
Published: February 2021

AbstractHepatitis C virus (HCV) is a leading cause of liver-associated disease and liver cancer. Of the major HCV subtypes, patients infected with subtype 1b have been associated with having a higher risk of developing chronic infection, cirrhosis and hepatocellular carcinoma. However, underlying reasons for this increased disease severity remain unknown. Here, we provide an evolutionary rationale, based on a comparative study of fitness landscape and in-host evolutionary models of the envelope glycoprotein 2 (E2) of HCV subtypes 1a and 1b. Our analysis demonstrates that a higher chronicity rate of subtype 1b may be attributed to lower fitness constraints, enabling 1b viruses to more easily escape antibody responses. More generally, our results suggest that differences in evolutionary constraints between HCV subtypes may be an important factor in mediating distinct disease outcomes. Our analysis also identifies antibodies that appear to be escape-resistant against both subtypes 1a and 1b, providing directions for the design of HCV vaccines having cross-subtype protection.
Life and work of researchers trapped in the COVID-19 pandemic vicious cycle
Authors: Ghaffarizadeh S. Aryan , Ghaffarizadeh S. Arman , Behbahani Amir H. , Mehdizadeh Mohammad , Olechowski Alison 
Published: February 2021

AbstractCOVID-19 has disrupted researchers’ work and posed challenges to their life routines. We have surveyed 740 researchers of which 66% experienced a decrease in productivity, 50% indicated increased workload, and 66% reported they have been feeling internal pressure to make progress. Those whose research required physical presence in a lab or the field experienced considerable disruption and productivity decrease. About 82% of this group will try to permanently reduce their work dependency on physical presence. Parents and those taking care of vulnerable dependents have been spending less time on research due to their role conflict. We further observed a gender gap in the overall disruption consequences; more female researchers have been experiencing a reduction in productivity and external pressure to make progress. The results of this study can help institution leaders and policymakers better understand the pandemic’s challenges for the research community and motivate appropriate measures to instill long-term solutions.
MTHFD2 is a Metabolic Checkpoint Controlling Effector and Regulatory T Cell Fate and Function
Authors: Sugiura Ayaka , Andrejeva Gabriela , Voss Kelsey , Heintzman Darren R. , Beier Katherine L. , Wolf Melissa M. , Greenwood Dalton , Ye Xiang , Shahi Shailesh K. , Freedman Samantha N. , Cameron Alanna M. , Foerch Patrik , Bourne Tim , Xu Xincheng , Garcia-Canaveras Juan C. , Mangalam Ashutosh K. , Rabinowitz Joshua D. , Rathmell Jeffrey C. 
Published: February 2021

SUMMARYAntigenic stimulation promotes T cells metabolic reprogramming to meet increased biosynthetic, bioenergetic, and signaling demands. We show that the one-carbon (1C) metabolism enzyme Methylenetetrahydrofolate Dehydrogenase-2 (MTHFD2) is highly expressed in inflammatory diseases and induced in activated T cells to promote proliferation and produce inflammatory cytokines. In pathogenic Th17 cells, MTHFD2 also prevented aberrant upregulation of FoxP3 and suppressive capacity. Conversely, MTHFD2-deficiency enhanced lineage stability of regulatory T (Treg) cells. Mechanistically, MTHFD2 maintained cellular 10-formyltetrahydrofolate forde novopurine synthesis and MTHFD2 inhibition led to accumulation of the intermediate 5-aminoimidazole carboxamide ribonucleotide that was associated with decreased mTORC1 signaling. MTHFD2 was also required for proper histone de-methylation in Th17 cells. Importantly, inhibiting MTHFD2in vivoreduced disease severity in Experimental Autoimmune Encephalomyelitis and Delayed-Type Hypersensitivity. MTHFD2 induction is thus a metabolic checkpoint for pathogenic effector cells that suppresses anti-inflammatory Treg cells and is a potential therapeutic target within 1C metabolism.
Large portion of essential genes is missed by screening either fly or beetle indicating unexpected diversity of insect gene function
Authors: Hakeemi Muhammad Salim , Ansari Salim , Teuscher Matthias , Weißkopf Matthias , Großmann Daniela , Kessel Tobias , Dönitz Jürgen , Siemanowski Janna , Wan Xuebin , Schultheis Dorothea , Frasch Manfred , Roth Siegfried , Schoppmeier Michael , Klingler Martin , Bucher Gregor 
Published: February 2021

AbstractMost gene functions were detected by screens in very few model organisms but it has remained unclear how comprehensive these data are. Here, we expanded our RNAi screen in the red flour beetleTribolium castaneumto cover more than half of the protein-coding genes and we compared the gene sets involved in several processes between beetle and fly.We find that around 50 % of the gene functions are detected in both species while the rest was found only in fly (~10%) or beetle (~40%) reflecting both technical and biological differences. We conclude that work in complementary model systems is required to gain a comprehensive picture on gene functions documented by the annotation of novel GO terms for 96 genes studied here. The RNAi screening resources developed in this project, the expanding transgenic tool-kit and our large-scale functional data makeT. castaneuman excellent model system in that endeavor.
‘Phytopathological strolls’ in the dual context of COVID-19 lockdown and IYPH2020: transforming constraints into an opportunity for public education about plant pathogens
Authors: Suffert Frédéric , Suffert Muriel 
Published: February 2021

AbstractThe experience presented here relates to 2020, a particularly timely year for plant disease-related communication (‘International Year of Plant Health’ IYPH2020), but also a unique year because of the COVID-19 pandemic. Our goal was to illustrate the diversity and beauty of fungal plant pathogens through a naturalist approach that could be followed by any amateur. We achieved this end through ‘phytopathological strolls’, in which we observed and determined the origin of symptoms on diseased plants found in our garden, in the local streets, in nearby open spaces, and sharing this matter with a broad public. The lockdown imposed in France created an additional motivation to take up the challenge, and to involve our children, even under strong constraints, such as movement restrictions. We observed and described fungal pathogens through hundreds of photographs, shared our findings with a large audience on Twitter, and received feedback. The material used was deliberately simple and transportable: a digital reflex camera, an old microscope, a mobile phone, some books and an Internet connexion. Between March 17, 2020 and June 20, 2021 we found 196 plant pathogens, including 97 rusts, 27 powdery mildews and 28 septoria-like diseases. We discuss here the importance of promoting searches for plant pathogens, their description and conservation, through a combination of classical approaches and digital tools in tune with the times, such as Twitter, by treating pathogen identification like a detective game and, more surprisingly, by making use of the addictive nature of collection approaches, drawing a parallel with Pokémon Go.
A programmable pAgo nuclease with universal guide and target specificity from the mesophilic bacteriumKurthia massiliensis
Authors: Kropocheva Ekaterina , Kuzmenko Anton , Aravin Alexei A. , Esyunina Daria , Kulbachinskiy Andrey 
Published: February 2021

ABSTRACTArgonaute proteins are programmable nucleases that are found in both eukaryotes and prokaryotes and provide defense against invading genetic elements. Although some prokaryotic Argonautes (pAgos) were shown to recognize RNA targetsin vitro, the majority of studied pAgos have strict specificity toward DNA, which limits their practical use in RNA-centric applications. Here, we describe a unique KmAgo nuclease from the mesophilic bacteriumKurthia massiliensisthat can be programmed with either DNA or RNA guides and can precisely cleave both DNA and RNA targets. KmAgo preferentially binds 16-20 nt long 5′-phosphorylated guide molecules with no strict specificity for their sequence and is active in a wide range of temperatures. In bacterial cells, KmAgo is loaded with small DNAs with no obvious sequence preferences suggesting that it can uniformly target genomic sequences. Target cleavage by KmAgo depends on the formation of secondary structure indicating that KmAgo can be used for structural probing of RNA targets. Mismatches between the guide and target sequences greatly affect the efficiency and precision of target cleavage, depending on the mismatch position and the nature of the reacting nucleic acid. These properties of KmAgo open the way for its use for highly specific nucleic acid detection and cleavage.
Three-dimensional interactions between integrated HPV genomes and cellular chromatin dysregulate host gene expression in early cervical carcinogenesis
Authors: Groves Ian J , Drane Emma LA , Michalski Marco , Monahan Jack M , Scarpini Cinzia G , Smith Stephen P , Bussotti Giovanni , Várnai Csilla , Schoenfelder Stefan , Fraser Peter , Enright Anton J , Coleman Nicholas 
Published: February 2021

AbstractDevelopment of cervical cancer is directly associated with integration of human papillomavirus (HPV) genomes into host chromosomes and subsequent modulation of HPV oncogene expression, which correlates with multi-layered epigenetic changes at the integrated HPV genomes. However, the process of integration itself and dysregulation of host gene expression at sites of integration in our model of HPV16 integrant clone natural selection has remained enigmatic. We now show, using a state-of-the-art ‘HPV integrated site capture’ (HISC) technique, that integration likely occurs through microhomology-mediated repair (MHMR) mechanisms via either a direct process, resulting in host sequence deletion (in our case, partially homozygously) or via a ‘looping’ mechanism by which flanking host regions become amplified. Furthermore, using our ‘HPV16-specific Region Capture Hi-C’ technique, we have determined that three-dimensional (3D) interactions between the integrated virus genome and host chromosomes, both at short- (<500 kbp) and long-range (>500 kbp), appear to drive host gene dysregulation through the disruption of local host:host 3D interactions known as topologically associating domains (TADs). This mechanism of HPV-induced host gene expression modulation indicates that integration of virus genomes near to or within a ‘cancer-causing gene’ is not essential to influence such genes within an entire TAD and that these modifications to 3D interactions could have a major role in selection of HPV integrants at the early stage of cervical neoplastic progression.