bluuebunny/crossref_metadata_2025_split huggingface dataset:
Autophagy in DG engrams mediates Rac1-dependent forgetting via TLR2/4 signals in microglia
Authors: Wang Zhilin , Chen Ruyan , Lin Qing , Jiang Yan , Le Qiumin , Liu Xing , Ma Lan , Wang Feifei 
Published: August 2021

AbstractBACKGROUNDEngrams are considered to be substrates for memory storage, and the adaptive plasticity remolding that switch engrams to an inaccessible state cause forgetting. The normal function of engrams is ensured by the crosstalk between neurons and microglia, the major immune cells in the brain implicated in synapse remodeling and memory processing. However, the cellular processes and molecular mediators between engrams and microglia underlying forgetting are poorly understood.METHODSWe utilized doxycycline (Dox)-dependent robust activity marking (RAM) system to label and manipulate DG engrams encoding contexture fear memory in mice. Combining optogenetics, microglia-specific transcriptomics, fluorescence in situ hybridization and spine morphology analysis, we investigated the potential mechanisms of information exchange between engrams and microglia mediating memory forgetting.RESULTSThe expression of Rac1 in dentate gyrus (DG) engrams upregulated memory encoding. Increased Rac1 activity in DG engrams accelerated forgetting, upregulated autophagy influx and the expression of autophagy protein 7 (Atg7). The elevated ATG7 expression in the engrams activated of DG microglia and promoted forgetting. In addition, the Toll-like receptor (TLR) signal in DG microglia was upregulated when overexpressing ATG7 or activating Rac1 in DG engrams, and mediated the ATG7-dependent synapse remodeling and Rac1-dependent forgetting.CONCLUSIONSIn this study, we found that Rac1 increases ATG7-dependent autophagy in DG engrams, which activated microglia via TLR2/4, to promote spine remodeling and forgetting. These results unravel a novel pathway mediating memory forgetting, and provide a potential therapeutic strategy in the treatment of cognitive disorders such as Alzheimer’s disease.
Alterations in rhythmic and non-rhythmic resting-state EEG activity and their link to cognition in older age
Authors: Cesnaite Elena , Steinfath Paul , Idaji Mina Jamshidi , Stephani Tilman , Kumral Deniz , Haufe Stefan , Sander Christian , Hensch Tilman , Hegerl Ulrich , Riedel-Heller Steffi , Röhr Susanne , Schroeter Matthias L. , Witte A. Veronica , Villringer Arno , Nikulin Vadim V. 
Published: August 2021

AbstractWhile many structural and biochemical changes in the brain have been previously associated with aging, the findings concerning electrophysiological signatures, reflecting functional properties of neuronal networks, remain rather controversial. To try resolve this issue, we took advantage of a large population study (N=1703) and comprehensively investigated the association of multiple EEG biomarkers (power of alpha and theta oscillations, individual alpha peak frequency (IAF), the slope of 1/f power spectral decay), aging, and aging and cognitive performance. Cognitive performance was captured with three factors representing processing speed, episodic memory, and interference resolution. Our results show that not only did IAF decline with age but it was also associated with interference resolution over multiple cortical areas. To a weaker extent, 1/f slope of the PSD showed age-related reductions, mostly in frontal brain regions. Finally, alpha power was negatively associated with the speed of processing in the right frontal lobe, despite the absence of age-related alterations. Our results thus demonstrate that multiple electrophysiological features, as well as their interplay, should be considered when investigating the association between age, neuronal activity, and cognitive performance.
The human-baited host decoy trap (HDT) is an efficient sampling device for exophagic malaria mosquitoes within irrigated lands in southern Malawi
Authors: Zembere Kennedy , Chirombo James , Nasoni Peter , McDermott Daniel P. , Tchongwe-Divala Lizzie , Hawkes Frances M. , Jones Christopher M. 
Published: August 2021

AbstractIrrigation schemes provide an ideal habitat for Anopheles mosquitoes particularly during the dry season. Reliable estimates of outdoor host-seeking behaviour are needed to assess the impact of vector control options and this is particularly the case for Anopheles arabiensis which displays a wide range of behaviours that circumvent traditional indoor-insecticide based control. In this study we compared the Host Decoy Trap (HDT) with the Human Landing Catch (HLC) and Suna trap in a repeated Latin square design in two villages on an irrigated sugar estate in southern Malawi. Over the course of 18 trapping nights we caught 379 female Anopheles, the majority of which were identified as An. arabiensis. Overall, the HDT and HLC caught a similar number of Anopheles per night with both methods catching significantly higher densities than the Suna trap across both villages. Regardless of the density of Anopheles mosquitoes in each village the HLC and HDT demonstrated broadly similar sampling efficacy. We conclude that the HDT is an effective sampling device for outdoor host seeking An. arabiensis in southern Malawi. The presence of An. arabiensis in irrigated lands during the dry season poses a challenge for ongoing indoor vector control efforts.
Gene regulatory network analysis identifies key genes and regulatory mechanisms involved in acute myocardial infarction using bulk and single cell RNA-seq data
Authors: Luo Jiaxin , Wu Lin , Liu Dinghui , Xiong Zhaojun , Wang Linli , Qian Xiaoxian , Sun Xiaoqiang 
Published: August 2021

AbstractCardiovascular and cerebrovascular diseases are leading causes of death worldwide, accounting for more than 40% of all deaths in China. Acute myocardial infarction (AMI) is a common cardiovascular disease and traditionally divided into ST-segment (STEMI) and non-ST-segment elevation myocardial infarction (NSTEMI), which are known with different prognoses and treatment strategies. However, key regulatory genes and pathways involved in AMI that may be used as potential biomarker for prognosis are unknown. In this study, we constructed weighted gene co-expression networks for differential expressed genes between STEMI and NSTEMI patients based on whole-blood RNA-seq transcriptomics. Network topological attributes (e.g., node degree, betweenness) were analyzed to identify key genes involved in different functional network modules. Furthermore, we used single-cell RNA-seq data to construct multilayer signaling network to infer regulatory mechanisms of the above key genes. PLAUR (receptor for urokinase plasminogen activator) was found to play a vital role in transducing inter-cellular signals from endothelial cells and fibroblast cells to intra-cellular pathways of myocardial cells, leading to gene expression involved in cellular response to hypoxia. Our study sheds lights on identifying molecular biomarkers for diagnosis and prognosis of AMI, and provides candidate key regulatory genes for further experimental validation.
Using Continuous Directed Evolution to Improve Enzymes for Plant Applications
Authors: García-García Jorge D. , Van Gelder Kristen , Joshi Jaya , Bathe Ulschan , Leong Bryan J. , Bruner Steven D. , Liu Chang C. , Hanson Andrew D. 
Published: August 2021

AbstractContinuous directed evolution of enzymes and other proteins in microbial hosts is capable of outperforming classical directed evolution by executing hypermutation and selection concurrently in vivo, at scale, with minimal manual input. Provided that a target enzyme’s activity can be coupled to growth of the host cells, the activity can be improved simply by selecting for growth. Like all directed evolution, the continuous version requires no prior mechanistic knowledge of the target. Continuous directed evolution is thus a powerful new way to modify plant or non-plant enzymes for use in plant metabolic research and engineering. Here, we first describe the basic features of theSaccharomyces cerevisiaeOrthoRep system for continuous directed evolution and compare it briefly with other systems. We then give a step-by-step account of three ways in which OrthoRep can be deployed to evolve primary metabolic enzymes, using a THI4 thiazole synthase as an example and illustrating the mutational outcomes obtained. We close by outlining applications of OrthoRep that serve growing demands (i) to change the characteristics of plant enzymes destined for return to plants, and (ii) to adapt (‘plantize’) enzymes from prokaryotes – especially exotic prokaryotes – to function well in mild, plant-like conditions.One-sentence summaryContinuous directed evolution using the yeast OrthoRep system is a powerful new way to improve enzymes for use in plant engineering as illustrated by ‘plantizing’ a bacterial thiamin synthesis enzyme..
Retinoschisin deficiency induces persistent aberrant waves of activity affecting neuroglial signaling in the retina
Authors: Eleftheriou Cyril G. , Corona Carlo , Khattak Shireen , Ivanova Elena , Bianchimano Paola , Liu Yang , Sun Duo , Singh Rupesh , Batoki Julia C. , McAnany Jason J. , Peachey Neal S. , Romano Carmelo , Sagdullaev Botir T. 
Published: August 2021

AbstractGenetic disorders which present during development make treatment strategies particularly challenging because there is a need to disentangle primary pathophysiology from downstream dysfunction caused at key developmental stages. To provide a deeper insight into this question, we studied a mouse model of X-linked juvenile retinoschisis (XLRS), an early onset inherited condition caused by mutations in the RS1 gene encoding retinoschisin (RS1) and characterized by cystic retinal lesions and early visual deficits. Using an unbiased approach in expressing the fast intracellular calcium indicator GCaMP6f in neuronal, glial, and vascular cells of the retina of mice lacking RS1, we found that initial cyst formation is paralleled by the appearance of aberrant spontaneous neuro-glial signals as early as postnatal day 13. These presented as glutamate-driven wavelets of neuronal activity and sporadic radial bursts of activity by Müller glia, spanning all retinal layers and disrupting light-induced signaling. This study highlights a critical role for RS1 in early retinal development with a potential to disrupt circuit formation to central targets. Additionally, it confers a functional role to RS1 beyond the scope of an adhesion molecule and identifies an early onset for dysfunction, a potential temporal target for therapeutic intervention and diagnosis.Significance Statement/ HighlightsPhotoreceptor inner segments express Rs1 at P5, after which RS1 protein is detected in the inner segments by P9 and throughout the retina at later ages, with structural abnormalities observed by optical coherence tomography at P13 in Rs1 mutant mouse models.Aberrant glutamate-driven wavelets identified by GCaMP6f-based analyses are a novel pathophysiological feature of RS1 deficient mice that emerge after maximal RS1 expression.Müller glia display abnormal radial glutamate-driven coordinated and sporadic bursts of activity in RS1-deficient mice.These data identify a novel pathophysiological feature of RS1-deficient mice and define a window where treatments might be most effective.Graphical Abstract
Mathematical modeling reveals a complex network of signaling and apoptosis pathways in the survival of memory plasma cells
Authors: Burt Philipp , Cornelis Rebecca , Geißler Gustav , Hahne Stefanie , Radbruch Andreas , Chang Hyun-Dong , Thurley Kevin 
Published: August 2021

AbstractThe long-term survival of memory plasma cells is conditional on the signals provided by dedicated survival niches in the bone marrow organized by mesenchymal stromal cells. Recently, we could show that plasma cell survival requires secreted factors such as APRIL and direct contact to stromal cells, which act in concert to activate NF-kB- and PI3K-dependent signaling pathways to prevent cell death. However, the precise dynamics of the underlying regulatory network are confounded by the complexity of potential interaction and cross-regulation pathways. Here, based on flow-cytometric quantification of key signaling proteins in the presence or absence of the required survival signals, we generated a quantitative model of plasma cell survival. Our model emphasizes the non-redundant and essential nature of the two plasma cell survival signals APRIL and stromal cell contact, providing resilience to endoplasmic reticulum stress and mitochondrial stress, respectively. Importantly, the modeling approach allowed us to unify distinct data sets and derive a consistent picture of the intertwined signaling and apoptosis pathways regulating plasma cell survival.
Mapping of single-cell landscape of acral melanoma and analysis of molecular regulatory network of tumor microenvironment
Authors: He Zan , Xin Zijuan , Fang Xiangdong , Zhao Hua 
Published: August 2021

AbstractMelanoma is a type of skin malignant tumor with high invasiveness, high metastasis, and poor prognosis. The incidence of melanoma continues to increase. Among them, the subtype of acral melanoma (AM) is more common in Asian populations. AM has higher degree, low immunotherapy response rate. With the help of single-cell sequencing technology provides new technical means for tumor microenvironment research, so that we can more easily explore specific tumor types suitable immunotherapy targets. However, no complete single-cell level differentiation map exists for the AM tumor microenvironment (TME). In this study, we used AM related sample and used the 10× Genomics single-cell transcriptome platform to draw a specific single-cell map of AM, understand the cell composition of AM, and analyze the interaction and molecular regulation of AM TME. Nine cell types were identified, of which malignant cells accounted for the largest proportion, followed by fibroblasts. And the cell interaction network shows that malignant cells, macrophages, B, T and fibroblasts play an important role in AM TME. Our research provides systematic theoretical guidance for the diagnosis and treatment of acral melanoma.
Colorectal cancer risk in bowel adenomas based on lifestyle exposures, tissue preconditioning and DNA methylation
Authors: Sutton Jaim , Moorghen Morgan , Wang Lai Mun , Thirlwell Christina , Pipinikas Christodoulos , Lorincz Attila 
Published: August 2021

AbstractBackgroundColorectal cancer (CRC) is associated with patient demographics, lifestyle exposures and molecular alterations. However, it is not possible to determine which adenomas will progress to CRC, as ethically it is unacceptable to leave and follow adenomas. We hypothesised that certain lifestyle exposures at high levels could precondition exposed bowel tissue by changing and aging it, increasing the risks of deleterious DNA methylation and genetic alterations. We used a novel study design comparing adenomas with concurrent CRC (thus more likely exposed to deleterious lifestyle effects) to single adenomas in bowels with no history of CRC; we called these high (HR) and low-risk (LR) adenomas respectively.MethodsWe carried out a discovery and replication epigenome-wide association study (EWAS) on 106 HR and 111 LR adenomas, profiled with MethylationEPIC BeadChips. In order, to identify differentially methylated positions (DMP), regions (DMR), and DNAm (DNAmethylation) lifestyle exposures and risks, with adjustment for confounders, and gene ontology (GO) and pathway enrichment. Then, two open-source gene expression omnibus (GEO) validation datasets (52, 57 and 49, 48 HR and LR normal bowel tissues respectively) were analysed for these DNAm lifestyle exposures and risks, with adjustment for confounders.ResultsOur EWAS found 5 Bonferroni significant DMPs with absolute delta betas ≥ 5%, and 14 significant DMRs with absolute mean DMR delta betas ≥ 5%, replicated in the GPX7, RGS3 and TMEM135 cancer-associated genes. DNAm high alcohol exposures were strongly associated with increased risk of HR adenomas (odds ratio (OR) per standard deviation (SD) = 2.16 (95% confidence interval (CI) 1.55 - 3.09, p-value = 9.7 × 10-6)). In the validation datasets, DNAm high alcohol (ORperSD = 2.12 (95% CI 1.35 - 3.55, p-value = 2.0 × 10-3) and ORperSD = 1.79 (95% CI 1.14 - 2.96, p-value = 1.7 × 10-2)), and high body mass index (BMI) exposures (ORperSD = 1.72 (95% CI 1.13 - 2.73, p-value = 1.5 × 10-2)) were associated with increased risk of HR normal bowel tissues.ConclusionsHigh alcohol and BMI exposures may precondition normal bowel tissues and adenomas for increased risk of DNA methylation alterations associated with CRC progression. The DNAm exposure signatures and our newly identified genes may be useful epigenetic biomarkers for CRC prevention.
Methylation at CpG sites in genomes of aphid Acyrtosiphon pisum and its endosymbiont Buchnera
Authors: Clément Mathilde , Rocha Martine Da , Agnel Sandra , Raddatz Guenter , Robichon Alain , Bailly-Bechet Marc 
Published: August 2021

AbstractPea aphid Acyrtosiphon pisum, a sap-feeding insect, has established a mutualistic relationship with an endosymbiotic bacteria (Buchnera aphidicola) that constitutes an evolutionary successful symbiosis to synthetize complex chemical compounds from a nutrient deprived diet. In this study, led by the presence of DNMT1 and a putative DNMT3 methylase in the aphid genome, we investigated the distribution of the methyl groups on 5’cytosine in CpG motifs on the whole genomes of host and endosymbiont, and looked into their correlation with gene expression. The DNA methylation turned to be present at low level in aphid (around 3% of total genomic cytosine) compared to mammals and plants, but increased to ∼9% in genes. Interestingly, the reduced genome of the endosymbiont Buchnera also shows global low level of methyl cytosine despite the fact that its genome does not shelter any DNA methylase. This finding argues for the import of DNA methylase from the host to the endosymbiont. The observed differences in methylation patterns between two clonal variants (host plus endosymbiont) are reported along with the differences in their transcriptome profiles. Our data allowed to decipher a dynamic combinatorial DNA methylation and epigenetic cross talk between host and symbiont in a clonality context that might count for the aphid adaptation to environment.
Dissociating the Neural Correlates of Planning and Executing Tasks with Nested Task Sets
Authors: Cookson Savannah L. , Schumacher Eric H. 
Published: August 2021

AbstractTask processing (e.g., the preparation and execution of responses) and task representation (e.g., the activation and maintenance of stimulus-response and context information) are two facets of cognitive control supported by lateral frontal cortex (LFC). However, the mechanistic overlap (or distinction) between these two facets is unknown. We explored this by combining a complex task mapping with a pre-cueing procedure. Participants made match/non-match judgments on pairs of stimuli during fMRI recording. Pre-cues on each trial gave variable amounts of information to the participant in anticipation of the stimulus. Our results demonstrated that regions throughout LFC were more active at the stimulus (when responses could be executed) than at the cue (when they could only be prepared), indicating that they supported execution of the task agnostic to the specific task representation. A subset of regions in left caudal LFC showed increased activity with more cue information at the cue and the reverse at the stimulus, suggesting their involvement in reducing uncertainty within the task representation. These results suggest that one component of task processing is preparing and executing the task according to the relevant representation, confined to left caudal LFC, while non-representational functions that occur primarily during execution are supported by different regions throughout the rest of LFC. We further conducted an exploratory investigation of connectivity between the two groups of regions in this study and their potential relationship to the fronto-parietal and cingulo-opercular networks. Regions with both patterns of activity appear to be part of the fronto-parietal network.
Gene signature of circulating platelet-bound neutrophils is associated with poor prognosis in cancer patients
Authors: Lecot Pacôme , Ardin Maude , Dussurgey Sébastien , Alcazer Vincent , Moudombi Lyvia , Hubert Margaux , Swalduz Aurélie , Hernandez-Vargas Hector , Viari Alain , Caux Christophe , Michallet Marie-Cécile 
Published: August 2021

AbstractBeyond their critical role in hemostasis, platelets physically interact with neutrophils to form neutrophil-platelet aggregates (NPAs), enhancing neutrophil effector functions during inflammation. NPAs may also promote disease worsening in various inflammatory diseases. However, characterization of NPAs in cancer remains totally unexplored. Using ImageStream®X (ISX) imaging flow cytometer, we were not only allowed able to detect CD15+ CD14− CD36+ ITGA2B+ NPAs in both healthy donors’ (HDs) and cancer patients’ bloods, but we also showed that NPAs result from the binding of platelets preferentially to low-density neutrophils (LDNs) as opposed to normal-density neutrophils (NDNs). By re-analyzing two independent public scRNAseq data of whole blood leukocytes from cancer patients and HDs, we could identify a subset of neutrophils with high platelet gene expression that may correspond to NPAs. Moreover, we showed that cancer patients’ derived NPAs possessed a distinct molecular signature compared with the other neutrophil subsets, independently of platelet genes. Gene ontology (GO) term enrichment analysis of this NPAs-associated neutrophil transcriptomic signature revealed a significant enrichment of neutrophil degranulation, chemotaxis and trans-endothelial migration GO terms. Lastly, using The Cancer Genome Atlas (TCGA), we could show by multivariate Cox analysis that the NPAs-associated neutrophil transcriptomic signature was associated with a worse patient prognosis in several cancer types. These results suggest that neutrophils from NPAs are systemically primed by platelets empowering them with cancer progression capacities once at tumor site. NPAs may therefore hold clinical utility as novel non-invasive blood prognostic biomarker in cancer patients with solid tumors.Novelty and ImpactPlatelets physically interact with peripheral blood neutrophils to form neutrophil-platelet aggregates (NPAs), known to promote disease worsening in various inflammatory diseases. However, characterization of NPAs in cancer remains totally unexplored. We showed that NPAs-associated neutrophils were a yet-unreported unique subset of circulating neutrophils associated with a worse patient prognosis in several cancer types. NPAs may hold clinical utility as novel non-invasive blood prognostic biomarker in cancer patients with solid tumors.
Cryo-ET of a human GBP coatomer governing cell-autonomous innate immunity to infection
Authors: Zhu Shiwei , Bradfield Clinton J. , Mamińska Agnieszka , Park Eui-Soon , Kim Bae-Hoon , Kumar Pradeep , Huang Shuai , Zhang Yongdeng , Bewersdorf Joerg , MacMicking John D. 
Published: August 2021

AbstractAll living organisms deploy cell-autonomous defenses to combat infection. In plants and animals, these activities generate large supramolecular complexes that recruit immune proteins for protection. Here, we solve the native structure of a massive antimicrobial complex generated by polymerization of 30,000 human guanylate-binding proteins (GBPs) over the entire surface of virulent bacteria. Construction of this giant nanomachine takes ∼1-3 minutes, remains stable for hours, and acts as a cytokine and cell death signaling platform atop the coated bacterium. Cryo-ET of this “coatomer” revealed thousands of human GBP1 molecules undergo ∼260 Å insertion into the bacterial outer membrane, triggering lipopolysaccharide release that activates co-assembled caspase-4. Together, our results provide a quasi-atomic view of how the GBP coatomer mobilizes cytosolic immunity to combat infection in humans.One-Sentence SummaryThousands of GBPs coat cytosolic bacteria to engineer an antimicrobial signaling platform inside human cells.