bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Computational Model for Storing Memories in the Synaptic Structures of the Brain
Authors: George Vivek , Morar Vikash , Silva Gabriel 
Published: October 2022

Spike-timing dependent plasticity (STDP) is widely accepted as a mechanism through which the brain can learn information from different stimuli(1, 2). Basing synaptic changes on the timing between presynaptic and postsynaptic spikes enhances contributing edges within a network(3, 4). While STDP rules control the evolution of networks, most research focuses on spiking rates or specific activation paths when evaluating learned information(5–7). However, since STDP augments structural weights, synapses may also contain embedded information. While imaging studies demonstrate physical changes to synapses due to STDP, these changes have not been interrogated based on their embedding capacity of a stimulus(8–12). Here, we show that networks with biological features and STDP rules can embed information on their stimulus into their synaptic weights. We use a k-nearest neighbor algorithm on the synaptic weights of thousands of independent networks to identify their stimulus with high accuracy based on local neighborhoods, demonstrating that the network structure can store stimulus information. While spike rates and timings remain useful, structural embed-dings represent a new way to integrate information within a biological network. Our results demonstrate that there may be value in observing these changes directly. Beyond computational applications for monitoring these structural changes, this analysis may also inform investigation into neuroscience. Research is underway on the potential of astrocytes to integrate synapses in the brain and communicate that information elsewhere(13–15). In addition, observations of these synaptic embeddings may lead to novel therapies for memory disorders that are difficult to explain with current paradigms, such as transient epileptic amnesia.Significance StatementLearning in the brain is often achieved via spike-timing dependent plasticity changing the structure of synapses to augment the strength between neurons. Typically, these changes contribute to other behaviors in the network, such as spiking rates or spike timings. However, observing these changes themselves may be fruitful for interrogating the learning capability of networks in the brain. Using a computational model, we demonstrate that the synaptic weights contain an embedding of the stimulus after a certain amount of recurrent activity occurs. It is possible that networks in the brain embed information in a similar way and that external readers, such as astrocytes, can interrogate, integrate, and transport this synaptic weight information to process stimuli.
Spatiotemporal dynamics during niche remodeling by super-colonizing microbiota in the mammalian gut
Authors: Urtecho Guillaume , Moody Thomas , Huang Yiming , Sheth Ravi U. , Richardson Miles , Descamps Hélène C. , Kaufman Andrew , Lekan Opeyemi , Velez-Cortes Florencia , Qu Yiming , Cohen Lucas , Ricaurte Deirdre , Gibson Travis E. , Gerber Georg K. , Thaiss Christoph A. , Wang Harris H. 
Published: October 2022

ABSTRACTWhile fecal microbiota transplantation (FMT) has been shown to be effective in reversing gut dysbiosis, we lack an understanding for the fundamental processes underlying microbial engraftment in the mammalian gut. Here, we explored a murine gut colonization model leveraging natural inter-individual variations in gut microbiomes to elucidate the spatiotemporal dynamics of FMT. We identified a natural ‘super-donor’ consortium that universally engrafts into diverse recipients and resists reciprocal colonization. Temporal profiling of the gut microbiome showed an ordered succession of rapid engraftment by early colonizers within 72 hours followed by a slower emergence of late colonizers over 15-30 days. Moreover, engraftment was localized to distinct compartments of the gastrointestinal tract in a species-specific manner. Spatial metagenomic characterization suggested engraftment was mediated by simultaneous transfer of spatially co-localizing species from the super-donor consortia. These results offer a mechanism of super-donor colonization by which nutritional niches are expanded in a spatiotemporally- dependent manner.
BEST: a web application for comprehensive biomarker exploration on large-scale data in solid tumors
Authors: Liu Zaoqu , Liu Long , Weng Siyuan , Xu Hui , Xing Zhe , Ren Yuqing , Ge Xiaoyong , Wang Libo , Guo Chunguang , Li Lifeng , Cheng Quan , Luo Peng , Zhang Jian , Han Xinwei 
Published: October 2022

SummaryData mining from RNA-seq or microarray data has become an essential part of cancer biomarker exploration. Certain existing web servers are valuable and broadly utilized, but the meta-analysis of multiple datasets is absent. Most web servers only contain tumor samples from the TCGA database with only one cohort for each cancer type, which also means that the analysis results mainly derived from a single cohort are thin and unstable. Indeed, consistent performance across multiple independent cohorts is the foundation for an excellent biomarker. Moreover, many analytical functions researchers require remain adequately unmet by these tools. Thus, we introduce BEST (Biomarker Exploration for Solid Tumors), a web application for comprehensive biomarker exploration on large-scale data in solid tumors. BEST includes more than 50,000 samples of 27 cancer types. To ensure the comparability of genes between different sequencing technologies and the legibility of clinical traits, we re-annotated transcriptome data based on the GRCh38 patch 13 sequences and unified the nomenclature of clinical traits. BEST delivers fast and customizable functions, including clinical association, survival analysis, enrichment analysis, cell infiltration, immunomodulator, immunotherapy, candidate agents, and genomic alteration. Together, our web server provides multiple cleaned-up independent datasets and diverse analysis functionalities, helping unleash the value of current data resources. It is freely available athttps://rookieutopia.com/.The bigger pictureBioinformatics web servers enable researchers without computational programming skills to conduct various bioinformatics analyses. However, most web servers only contain tumor samples from the TCGA database with only one cohort for each cancer type, which also means that the analysis results mainly derived from a single cohort are thin and unstable. Thus, we introduce BEST (Biomarker Exploration for Solid Tumors), a web application for comprehensive biomarker exploration on large-scale data in solid tumors. BEST includes more than 50,000 samples of 27 cancer types that have been uniformly re-annotated based on the GRCh38 patch 13 sequences, which ensures the comparability of genes between different sequencing technologies. BEST also offers prevalent functions including clinical association, survival analysis, enrichment analysis, cell infiltration, immunomodulator, immunotherapy, candidate agents, and genomic alteration. Together, BEST provides a curated database and innovative analytical pipelines to explore cancer biomarkers at high resolution.
Patient-specific deep offline artificial pancreas for blood glucose regulation in type 1 diabetes
Authors: Deng Yixiang , Arao Kevin , Mantzoros Christos S. , Karniadakis George Em 
Published: October 2022

AbstractDue to insufficient insulin secretion, patients with type 1 diabetes mellitus (T1DM) are prone to blood glucose fluctuations ranging from hypoglycemia to hyperglycemia. While dangerous hypoglycemia may lead to coma immediately, chronic hyperglycemia increases patients’ risks for cardiorenal and vascular diseases in the long run. In principle, an artificial pancreas – a closed-loop insulin delivery system requiring patients manually input insulin dosage according to the upcoming meals – could supply exogenous insulin to control the glucose levels and hence reduce the risks from hyperglycemia. However, insulin overdosing in some type 1 diabetic patients, who are physically active, can lead to unexpected hypoglycemia beyond the control of common artificial pancreas. Therefore, it is important to take into account the glucose decrease due to physical exercise when designing the next-generation artificial pancreas. In this work, we develop a deep reinforcement learning algorithm using a T1DM dataset, containing data from wearable devices, to automate insulin dosing for patients with T1DM. In particular, we build patient-specific computational models using systems biology informed neural networks (SBINN), to mimic the glucose-insulin dynamics for a few patients from the dataset, by simultaneously considering patient-specific carbohydrate intake and physical exercise intensity.
A high-density 3-dimensional culture model of human glioblastoma for rapid screening of therapeutic resistance
Authors: Brown J , Zaben M , Ormonde C , Sharouf F , Spencer R , Bhatt H , Siebzehnrubl FA , Gray WP 
Published: October 2022

AbstractGlioblastoma is among the most lethal cancers, with no known cure. A multitude of therapeutics are being developed or in clinical trials, but currently there are no ways to predict which patient may benefit the most from which drug. Assays that allow prediction of the tumor’s response to anti-cancer drugs may improve clinical decision-making. Here, we present a high-density 3D primary cell culture model for short-term testing from resected glioblastoma tissue that is set up on the day of surgery, established within 7 days and viable for at least 3 weeks. High-density 3D cultures contain tumor and host cells, including microglia, and retain key histopathological characteristics of their parent tumors, including proliferative activity, expression of the marker GFAP, and presence of giant cells. This provides a proof-of-concept that 3D primary cultures may be useful to model tumor heterogeneity. Importantly, we show that high-density 3D cultures can be used to test chemotherapy response within a 2– 3-week timeframe and are predictive of patient response to Temozolomide therapy. Thus, primary high-density 3D cultures could be a useful tool for brain cancer research and prediction of therapeutic resistance.
Brain signatures of chronic gut inflammation
Authors: Hall Caitlin V. , Radford-Smith Graham , Savage Emma , Robinson Conor , Cocchi Luca , Moran Rosalyn J. 
Published: October 2022

ABSTRACTGut inflammation is thought to modify brain activity and behaviour via modulation of the gut-brain axis. However, how relapsing and remitting exposure to peripheral inflammation over the natural history of inflammatory bowel disease (IBD) contributes to altered brain dynamics is poorly understood. Here, we used electroencephalography (EEG) to characterise changes in spontaneous spatiotemporal brain states in Crohn’s Disease (CD) (n = 40) and Ulcerative Colitis (UC) (n = 30), compared to healthy individuals (n = 28). We first provide evidence of a significantly perturbed and heterogeneous microbial profile in CD, consistent with previous work showing enduring and long-standing dysbiosis in clinical remission. Results from our brain state assessment show that CD and UC exhibit alterations in the temporal properties of states implicating default-mode network, parietal, and visual regions, reflecting a shift in the predominance from externally to internally-oriented attentional modes. We investigated these dynamics at a finer sub-network resolution, showing a CD-specific and highly selective enhancement of connectivity between the insula and mPFC, regions implicated in cognitive-interoceptive appraisal mechanisms. Alongside overall higher anxiety scores in CD, we also provide preliminary support to suggest that the strength of chronic interoceptive hyper-signalling in the brain co-occurs with disease duration. Together, our results demonstrate that a long-standing diagnosis of CD is, in itself, a key factor in determining the risk of developing altered brain network signatures.
A tale of two paths: The evolution of mitochondrial recombination in bivalves with doubly uniparental inheritance
Authors: Smith Chase H. , Pinto Brendan J. , Kirkpatrick Mark , Hillis David M. , Pfeiffer John M. , Havird Justin C. 
Published: October 2022

AbstractIn most animals, mitochondrial DNA is strictly maternally inherited and non-recombining. One exception to these assumptions is called doubly uniparental inheritance (DUI): a phenomenon involving the independent transmission of female and male mitochondrial genomes. DUI is known only from the molluscan class Bivalvia. The phylogenetic distribution of male mitochondrial DNA in bivalves is consistent with several evolutionary scenarios, including multiple independent gains, losses, and varying degrees of recombination with female mitochondrial DNA. In this study, we use phylogenetic methods to test male mitochondrial DNA origination hypotheses and infer the prevalence of mitochondrial recombination in bivalves with DUI. Phylogenetic modeling using site concordance factors supported a single origin of male mitochondrial DNA in bivalves coupled with recombination acting over long evolutionary timescales. Ongoing mitochondrial recombination is present in Mytilida and Venerida, which results in a pattern of concerted evolution of female and male mitochondrial DNA. Mitochondrial recombination could be favored to offset the deleterious effects of asexual inheritance and maintain mitonuclear compatibility across tissues. Cardiida and Unionida have gone without recent recombination, possibly due to an extension of theCOX2gene in male mitochondrial DNA. The loss of recombination may be neutral but could be connected to the role of M mtDNA in sex determination or sexual development. Our results support recombination events in DUI species may occur throughout their genomes. Future investigations may reveal more complex patterns of inheritance of recombinants, which could explain the retention of signal for a single origination of male mitochondrial DNA in protein coding genes.
Distinction between small RNA-bound and free ARGONAUTE via an N-terminal protein-protein interaction site
Authors: Bressendorff Simon , Zobbe Sjøgaard Ida Marie , Prestel Andreas , Kragelund Birthe B. , Poulsen Christian , Brodersen Peter 
Published: October 2022

ABSTRACTARGONAUTE (AGO) proteins bind to small non-coding RNAs to form RNA Induced Silencing Complexes (RISCs). In the RNA-bound state, AGO proteins are stable while RNA-free AGOs turn over rapidly. Molecular determinants unique to RNA-free AGO that allow its specific recognition and degradation remain unknown. Here, we show that a confined, linear region in Arabidopsis AGO1, the N-coil, is accessible to antibodies preferentially in the RNA-free state of AGO1. Reanalysis of hydrogen-deuterium exchange data on human Ago2 indicates similar structural flexibility of the N-coil depending on small RNA binding. Unloaded Arabidopsis AGO1 interacts with the autophagy cargo receptor ATI1 via direct contact to specific amino acid residues in the N-coil, and mutation of residues required for ATI1 interaction reduces the degradation rate of unloaded AGO1in vivo. These results provide insight into the molecular basis for specific recognition and degradation of the RNA-free state of eukaryotic AGO proteins.
The ACE-2 receptor accelerates but is not biochemically required for SARS-CoV-2 membrane fusion
Authors: Cervantes Marcos , Hess Tobin , Morbioli Giorgio G. , Sengar Anjali , Kasson Peter M. 
Published: October 2022

ABSTRACTThe SARS-CoV-2 coronavirus infects human cells via the ACE-2 receptor. Circumstantial evidence suggests that ACE-2 may not just serve as an attachment factor but also help activate the SARS-CoV-2 spike protein for membrane fusion. Here, we test that hypothesis directly, using DNA-lipid tethering as a synthetic attachment factor in the place of ACE-2. We find that SARS-CoV-2 pseudovirus and viruslike particles are both capable of membrane fusion if attached in the absence of ACE-2 and activated with an appropriate protease. However, addition of soluble ACE-2 speeds the fusion reaction. This is observed for both the Wuhan strain and the B.1.1.529 Omicron variant. Kinetic analysis suggests that there are at least two rate-limiting steps for SARS-CoV-2 membrane fusion, one of which is ACE-2 dependent and one of which is not. These data establish that, in the presence of an alternative attachment factor, ACE-2 is not biochemically required for SARS-CoV-2 membrane fusion. Since ACE-2 serves as the high-affinity attachment factor on human cells, the possibility to replace it with other factors has implications for the evolvability of SARS-CoV-2 and the fitness landscape for future related coronaviruses.
Phenotypic alteration of low-density granulocytes in people with pulmonary post-acute sequalae of SARS-CoV-2 infection
Authors: Dean Logan S. , Devendra Gehan , Jiyarom Boonyanudh , Subia Natalie , Tallquist Michelle D. , Nerurukar Vivek R. , Chang Sandra P. , Chow Dominic C. , Shikuma Cecilia M. , Park Juwon 
Published: October 2022

AbstractLow-density granulocytes (LDGs) are a distinct subset of neutrophils whose increased abundance is associated with the severity of COVID-19. However, the long-term effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on LDG levels and phenotypic alteration remain unexplored. Using participants naïve to SARS-CoV-2 (NP), infected with SARS-CoV-2 with no residual symptoms (NRS), and infected with SARS-CoV-2 with chronic pulmonary symptoms (PPASC), we compared LDG levels and their phenotype by measuring the expression of markers for activation, maturation, and neutrophil extracellular trap (NET) formation using flow cytometry. The number of LDGs was significantly elevated in PPASC compared to NP. Individuals infected with SARS-CoV-2 (NRS and PPASC) demonstrated increased CD10+and CD16HI subset counts of LDGs compared to NP group. Further characterization of LDGs demonstrated that LDGs from PPASC displayed higher NET forming ability and aggregation with platelets compared to LDGs from NP and NRS. Our data demonstrates that mature neutrophils with a heightened activation phenotype remain in circulation long after initial SARS-CoV-2 infection. Persistent elevation of markers for neutrophil activation and NET formation on LDGs, as well as an enhanced proclivity for platelet-neutrophil aggregation (PNA) formation in individuals with PPASC may be associated with the development of long-term pulmonary sequelae.
Metformin use history and genome-wide DNA methylation profile: potential molecular mechanism for aging and longevity
Authors: Marra Pedro S. , Yamanashi Takehiko , Crutchley Kaitlyn J. , Wahba Nadia E. , Anderson Zoe-Ella M. , Modukuri Manisha , Chang Gloria , Tran Tammy , Iwata Masaaki , Cho Ryan , Shinozaki Gen 
Published: October 2022

AbstractBackgroundWhile there are medications that treat and manage age-related diseases, a compound that prolongs lifespan is yet to be discovered. Nonetheless, metformin, a commonly prescribed anti-diabetic medication, has repeatedly been shown to hinder aging in pre-clinical models and to be associated with lower mortality for humans, even among cancer patients. It is, however, not well understood how metformin can potentially prolong lifespan from a biological standpoint. We hypothesized that metformin’s potential mechanism of action for longevity is through its epigenetic modifications.MethodsTo test our hypothesis, we conducted a post-hoc analysis of available genome-wide DNA methylation (DNAm) data obtained from whole blood collected from inpatients with and without a history of metformin use. We assessed the methylation profile of 171 patients (first run) and only among 63 diabetic patients (second run) and compared the DNAm rates between metformin users and nonusers.ResultsEnrichment analysis from the Kyoto Encyclopedia of Genes and Genome (KEGG) showed pathways relevant to metformin’s mechanism of action, such as longevity, AMPK, and inflammatory pathways. We also identified several pathways related to delirium whose risk factor is aging. Moreover, top hits from the Gene Ontology (GO) included HIF-1α pathways. However, no individual CpG site showed genome-wide statistical significance (p<5E-08).ConclusionThis study may elucidate metformin’s potential role in longevity through epigenetic modifications and other possible mechanisms of action.
Anti-Inflammatory Tension-Activated Repair Patches Improve Repair After Intervertebral Disc Herniation
Authors: Peredo Ana P. , Gullbrand Sarah E. , Friday Chet S. , Orozco Briana S. , Bonnevie Edward D. , Hilliard Rachel L. , Zlotnick Hannah M. , Dodge George R. , Lee Daeyeon , Hast Michael W. , Schaer Thomas P. , Smith Harvey E. , Mauck Robert L. 
Published: October 2022

AbstractConventional treatment for intervertebral disc herniation alleviates pain but does not repair the annulus fibrosus (AF), resulting in a high incidence of recurrent herniation and persistent disfunction. The lack of repair and the acute inflammation that arise after injury further compromises the disc and can result in disc-wide degeneration in the long term. To address this clinical need, we developed tension-activated repair patches (TARPs) for annular repair and the local delivery of bioactive anti-inflammatory factors. TARPs transmit physiologic strains to mechanically-activated microcapsules (MAMCs) embedded within, which activate and release encapsulated biomolecules in response to physiologic loading. Here, we demonstrate that the TARP design modulates implant biomechanical properties and regulates MAMC mechano-activation. Next, the FDA-approved anti-inflammatory molecule, interleukin 1 receptor antagonist, Anakinra, was loaded in TARPs and the effects of TARP-mediated annular repair and Anakinra delivery was evaluated in a model of annular injury in the goat cervical spine. TARPs showed robust integration with the native tissue and provided structural reinforcement at the injury site that prevented disc-wide aberrant remodeling resulting from AF detensioning. The delivery of Anakinra via TARP implantation improved the retention of disc biochemical composition through increased matrix deposition and retention at the site of annular injury. Anakinra delivery additionally attenuated the inflammatory response associated by scaffold implantation, decreasing osteolysis in adjacent vertebrae and preserving disc cellularity and matrix organization throughout the AF. These results demonstrate the translational and therapeutic potential of this novel TARP system for the treatment of intervertebral disc herniations.One Sentence SummaryTension-activated repair patches delivering bioactive anti-inflammatory factors improve healing in an in vivo goat cervical disc injury model.