bluuebunny/crossref_metadata_2025_split huggingface dataset:
WEBNG: A templating tool for weighted ensemble sampling of rule-based models
Authors: Saglam Ali Sinan , Faeder James R. 
Published: November 2022

AbstractTime scales for biological processes span many orders of magnitude, forcing modelers to tackle coupled processes that have large time scale gaps. This results in rare events, which take longer to occur than the fastest processes in the model. Efficient generation of rare events has been a focus of modelers for a long time and multiple software packages implement various rare event sampling algorithms. However, these packages frequently require expertise to get started with, making it harder for researchers to start using them. WEBNG (short for Weighted Ensemble–BioNetGen) is an open source software framwework that bridges the open source software packages WESTPA, which implements the weighted ensemble method for sampling rare events, and BioNetGen, which facilitates the specification and simulation of biochemical reaction network models following a rule-based approach. WEBNG simplifies rare event sampling in simulations of rule-based models by taking a model specified in the BioNetGen language (BNGL) and generating a WESTPA simulation folder ready to simulate with default parameters selected to match model observables. WEBNG is written in Python with dependencies only on proven, open-source packages that are in active development, which makes WEBNG easy to install and maintain. Here, we describe the architecture and features of WEBNG and demonstrate its capabilities through application to a two-gene model of cell fate transitions.
Mechanically manipulate glymphatic transportation by ultrasound combined with microbubbles
Authors: Ye Dezhuang , Chen Si , Liu Yajie , Weixel Charlotte , Hu Zhongtao , Chen Hong 
Published: November 2022

AbstractThe glymphatic system is a perivascular fluid transport system for waste clearance. Glymphatic transportation is believed to be driven by the perivascular pumping effect generated by arterial wall pulsation induced by the cardiac cycle. Ultrasound sonication of circulating microbubbles in the cerebral vasculature induces volumetric expansion and contraction of microbubbles that push and pull on the vessel wall to generate a microbubble pumping effect. The objective of this study was to evaluate whether glymphatic transportation can be mechanically manipulated by focused ultrasound (FUS) sonication of microbubbles. The glymphatic pathway in intact mouse brains was studied using intranasal administration of fluorescently labeled albumin as a fluid tracer followed by FUS sonication at a deep brain target (thalamus) in the presence of intravenously injected microbubbles. Three-dimensional confocal microscopy imaging of optically cleared brain tissue revealed that FUS sonication enhanced the transport of fluorescently labeled albumin tracer in the perivascular space along microvessels, primarily the arterioles. We also obtained evidence of FUS-enhanced penetration of the albumin tracer from the perivascular space into the interstitial space. This study revealed that ultrasound combined with circulating microbubbles could noninvasively enhance glymphatic transportation in the brain.Significance StatementThe glymphatic system is a waste clearance system in the brain analogous to the lymphatic system in peripheral organs. Glymphatic system impairment might contribute to brain disease pathologies, including those in neurodegenerative diseases, traumatic brain injury, and stroke. This study revealed that ultrasound could mechanically enhance glymphatic transportation. This result opens opportunities for using ultrasound to probe the role of the glymphatic system in brain function and brain diseases. Findings from this study suggest that ultrasound can be utilized as a noninvasive/nonpharmacological approach to mitigate brain diseases caused by impaired glymphatic function.
Analyzing the covariance structure of plasma signaling proteins in relation to the diagnosis of dementia
Authors: Guan Calvin , Au Rhoda , Ang Alvin , Gangopadhyay Ashis 
Published: November 2022

AbstractNumerous studies have shown that individuals with dementia have exhibited activation of inflammatory pathways in their brains. Typically, these studies use traditional and well-established regression methods for data analysis. In this paper, a new approach is introduced that utilizes the analysis of the covariance structure using methods related to the principal component analysis (PCA) theory. Eleven biomarkers related to neuroinflammation were used to determine the association with the onset of dementia. Various demographic covariates were adjusted to account for possible confounding effects of the covariance structure. Three hypothesis testing methods were considered to discern differences between partial covariance matrices for comparing power and Type I errors through simulation studies. Application of hypothesis testing methods using data from Framingham Heart Study (FHS) found significant differences in covariance matrices between the non-dementia and dementia groups.
Networks and genes modulated by posterior hypothalamic stimulation in patients with aggressive behaviours: Analysis of probabilistic mapping, normative connectomics, and atlas-derived transcriptomics of the largest international multi-centre dataset
Authors: Gouveia Flavia Venetucci , Germann Jürgen , Elias Gavin JB , Boutet Alexandre , Loh Aaron , Lopez Rios Adriana Lucia , Torres Diaz Cristina V , Contreras Lopez William Omar , Martinez Raquel CR , Fonoff Erich T , Benedetti-Isaac Juan C , Giacobbe Peter , Arango Pava Pablo M , Yan Han , Ibrahim George M , Lipsman Nir , Lozano Andres M , Hamani Clement 
Published: November 2022

ABSTRACTDeep brain stimulation targeting the posterior hypothalamus (pHyp-DBS) is being investigated as treatment for refractory aggressive behaviour, but its mechanisms of action remain elusive. We conducted an integrated imaging analysis of a large multi-centre dataset, incorporating volume of activated tissue modeling, probabilistic mapping, normative connectomics, and atlas-derived transcriptomics. 91% of the patients responded positively to treatment, with a more striking improvement recorded in the pediatric population. Probabilistic mapping revealed an optimized surgical target within the posterior-inferior-lateral posterior hypothalamic area and normative connectomic analyses identified fiber tracts and interconnected brain areas associated with sensorimotor function, emotional regulation, and monoamine production. Functional connectivity between the target, periaqueductal gray and the amygdala – together with patient age – was highly predictive of treatment outcome. Finally, transcriptomic analysis showed that genes involved in mechanisms of aggressive behaviour, neuronal communication, plasticity and neuroinflammation may underlie this functional network.SIGNIFICANCE STATEMENTThis study investigated the brain mechanisms associated with symptom improvement following deep brain stimulation of the posterior hypothalamus for severe and refractory aggressive behavior. Conducting an integrated imaging analysis of a large international multi-center dataset of patients treated with hypothalamic deep brain stimulation, we were able to show for the first time that treatment is highly efficacious across various patients with an average improvement greater than 70%. Leveraging this unique dataset allowed us to demonstrate that some patient characteristics are important for treatment success, describe the optimal target zone for maximal benefit, that engagement of distinct fiber tracts and networks within the emotional neurocircuitry are key for positive outcome, and - using imaging transcriptomics - elucidate some potential molecular underpinnings. The provided optimal stimulation site allows for direct clinical application.
Alveolar epithelial type 1 cells serve as a cell of origin for lung adenocarcinoma with distinct molecular and phenotypic presentation
Authors: Yang Minxiao , Shen Hua , Flodby Per , Koss Michael D. , Bassiouni Rania , Liu Yixin , Jashashvili Tea , Stueve Theresa R. , Mullen Daniel J. , Ryan Amy L. , Carpten John , Castaldi Alessandra , Wallace W. Dean , Zhou Beiyun , Borok Zea , Marconett Crystal N. 
Published: November 2022

ABSTRACTLung adenocarcinoma (LUAD) is the most common subtype of cancer arising in the distal lung. LUAD encompasses several pathologic subtypes, each with differing clinical outcomes and biological behaviors. However, the molecular and cellular underpinnings of the different subtypes are largely unknown. Understanding which cell populations in the distal lung contribute to LUAD could provide insights into the marked heterogeneity in pathologic features, clinical presentation and responses to therapy of LUAD. Differential expression analysis of lung adenocarcinoma transcriptomes from The Cancer Genome Atlas revealed distinct alveolar epithelial type 1 (AT1) and alveolar epithelial type 2 (AT2) cell signatures within human LUAD with significantly different survival outcomes between tumors expressing AT2 and AT1 gene signatures, suggesting AT1 cells might contribute to a subset of LUAD cases. To address this, we tested the ability of AT1 cells to give rise to LUAD following induction of KrasG12D, a known oncogenic driver of human LUAD. Activation of KrasG12Din Gram-domain containing 2 (Gramd2)+AT1 cells gave rise to multiple LUAD lesions, primarily of papillary histology. In contrast, activation of KrasG12Din surfactant protein C (Sftpc+) AT2 cells resulted in LUAD lesions of lepidic histology. Immunohistochemistry established thatGramd2:KrasG12Dlesions were of primary lung origin and not metastatic events. Spatial transcriptomic profiling revealed distinct pathway alterations within Gramd2- and Sftpc-derived LUAD. Immunofluorescence confirmed differences observed in the spatial transcriptomic analysis in expression patterns and distribution of cell-specific markers depending on cell of origin, while universal upregulation of the Krt8 intermediate cell state marker was observed. Our results are consistent with Gramd2+AT1 cells serving as a putative cell of origin for LUAD and suggest that LUAD may be a collection of adenocarcinomas that share a common location within the distal lung but arise from different cells of origin.
The entry of pinewood nematode is linked to programmed tracheal development of vector beetles
Authors: Tang Xuan , Koski Tuuli-Marjaana , Sun Jianghua 
Published: November 2022

AbstractThe transmission of some pathogens by insect vectors often requires fine-tuned biological synchronization and communication between the two parties. However, the role of tissue development in mediating this pathogen-vector coordination remains elusive. Here we investigated the association between tracheal development ofMonochamus alternatusbeetle and a notorious plant parasitic pine wood nematodeBursaphelenchus xylophilus, which enter and inhabit inside the tracheal system after adult beetle eclosion and then were transmitted to pine trees (Pinusspp.) by the beetle. We found that the tracheal systems of newly emerged adult beetles underwent morphological changes during the adult sclerotization, characterized by a remarkable increase of diameter of thoracic tracheal dorsal tubes. Consistently, comparative transcriptomics further revealed dramatic changes in gene expression occurring within five days after eclosion, demonstrating sequential regulation of tracheal genes. Genes controlling primary branching were up-regulated soon after eclosion, whereas those controlling terminal branching and branch fusion were up-regulaed at the later stage. Interestingly, during tracheal maturation, genes involved in biosynthesis of Juvenile Hormone (JH) and ecdysteroids were activated. Nematode loading assay further revealed that the entry of nematodes to beetle tracheae was initiated earliest after three days post eclosion, implying that nematode entry is reliant on the formation of the vector’s primary tracheal branches and is perhaps stimulated by production of insect hormones or their precursors. In addition, specific regulation on secreted proteins, such as Defensin-1-like and membrane proteins, at later stages of tracheal maturation may further facilitate the entry of nematodes by improving their retention. Therefore, this study highlights vital role of programed tracheal development on nematode entry into its vector beetle, and suggests a potential roles of insect genes and metabolites in manipulation of interspecific biological developmental synchronization between parasites and their insect vectors.
Feasibility of Ultra-Short Term Analysis of Heart Rate and Systolic Arterial Pressure Variability at Rest and During Stress via Time-domain and Entropy-based Measures
Authors: Volpes Gabriele , Barà Chiara , Busacca Alessandro , Stivala Salvatore , Javorka Michal , Faes Luca , Pernice Riccardo 
Published: November 2022

AbstractHeart Rate Variability (HRV) and Blood Pressure Variability (BPV) are widely employed tools for characterizing the complex behavior of cardiovascular dynamics. Usually, HRV and BPV analyses are carried out through short-term (ST) measurements, which exploit ∼5 minute-long recordings. Recent research efforts are focused on reducing the time series length, assessing whether and to what extent Ultra-Short Term (UST) analysis is capable of extracting information about cardiovascular variability from very short recordings. In this work, we compare ST and UST measures computed on electrocardiographic R-R intervals and systolic arterial pressure time series obtained at rest and during both postural and mental stress. Standard time-domain indices are computed, together with entropy-based measures able to assess regularity and complexity of cardiovascular dynamics, on time series lasting up to 60 samples, employing either a faster linear parametric estimator or a more reliable but time-consuming model-free method based on nearest neighbor estimates. Our results evidence that shorter time series up to 120 samples still exhibit an acceptable agreement with the ST reference, and can be exploited to discriminate between stress and rest as well. Moreover, although neglecting nonlinearities inherent to short-term cardiovascular dynamics, the faster linear estimator is still capable of detecting differences among the conditions, thus resulting suitable to be implemented on wearable devices.
Prefrontal allopregnanolone mediates the adverse effects of acute stress in a mouse model of tic pathophysiology
Authors: Cadeddu Roberto , Van Zandt Meghan , Odeh Karen , Anderson Collin J , Flanagan Deirdre , Nordkild Peter , Pittenger Christopher J , Bortolato Marco 
Published: November 2022

AbstractAmple evidence suggests that acute stress can worsen symptom severity in Tourette syndrome (TS); however, the neurobiological underpinnings of this phenomenon remain poorly understood. We previously showed that acute stress exacerbates tic-like and other TS-associated responses via the neurosteroid allopregnanolone (AP) in an animal model of repetitive behavioral pathology. To verify the relevance of this mechanism to tic pathophysiology, here we tested the effects of AP in a mouse model recapitulating the partial depletion of cholinergic interneurons (CINs) in the striatum seen inpostmortemstudies of TS. Mice underwent targeted depletion of striatal CINs during adolescence and were tested in young adulthood. Compared with controls, CIN-depleted male mice exhibited several TS-relevant abnormalities, including deficient prepulse inhibition (PPI) and increased grooming stereotypies after a 30-min session of spatial confinement, a mild acute stressor that increases AP synthesis in the prefrontal cortex (PFC). These effects were not seen in females. Systemic and intra-PFC AP administration dose-dependently worsened grooming stereotypies and PPI deficits in CIN-depleted males. Conversely, both AP synthesis inhibition and pharmacological antagonism reduced the effects of stress. These results further suggest that AP in the PFC mediates the adverse effects of stress on the severity of tics and other TS manifestations. Future studies will be necessary to confirm these mechanisms in patients and define the circuitry responsible for the effects of AP on tics.
Cross-attractor modeling of resting-state functional connectivity in psychiatric disorders
Authors: Sun Yinming , Zhang Mengsen , Saggar Manish 
Published: November 2022

AbstractResting-state functional connectivity (RSFC) is altered across various psychiatric disorders. Brain network modeling (BNM) has the potential to reveal the neurobiological underpinnings of such abnormalities by dynamically modeling the structure-function relationship and examining biologically relevant parameters after fitting the models with real data. Although innovative BNM approaches have been developed, two main issues need to be further addressed. First, previous BNM approaches are primarily limited to simulating noise-driven dynamics near a chosen attractor (or a stable brain state). An alternative approach is to examine multi(or cross)-attractor dynamics, which can be used to better capture non-stationarity and switching between states in the resting brain. Second, previous BNM work is limited to characterizing one disorder at a time. Given the large degree of co-morbidity across psychiatric disorders, comparing BNMs across disorders might provide a novel avenue to generate insights regarding the dynamical features that are common across (vs. specific to) disorders. Here, we address these issues by (1) examining the layout of the attractor repertoire over the entire multi-attractor landscape using a recently developed cross-attractor BNM approach; and (2) characterizing and comparing multiple disorders (schizophrenia, bipolar, and ADHD) with healthy controls using an openly available and moderately large multimodal dataset from the UCLA Consortium for Neuropsychiatric Phenomics. Both global and local differences were observed across disorders. Specifically, the global coupling between regions was significantly decreased in schizophrenia patients relative to healthy controls. At the same time, the ratio between local excitation and inhibition was significantly higher in the schizophrenia group than the ADHD group. In line with these results, the schizophrenia group had the lowest switching costs (energy gaps) across groups for several networks including the default mode network. Paired comparison also showed that schizophrenia patients had significantly lower energy gaps than healthy controls for the somatomotor and visual networks. Overall, this study provides preliminary evidence supporting transdiagnostic multi-attractor BNM approaches to better understand psychiatric disorders’ pathophysiology.
A multi-omics analysis of glioma chemoresistance using a hybrid microphysiological model of glioblastoma
Authors: Shojaei Shahla , Basso João , Amereh Meitham , Alizadeh Javad , Dehesh Tania , De Silva Rosa Simone , Clark Courtney , Hassan Misha , Tomczyk Mateuz , Cole Laura , Hatch Grant , Dolinsky Vern , Pasco Chris , Schibli David , Dhingra Sanjiv , Srivastava Abhay , Ravandi Amir , Vitorino Rui , Ghavami Saeid , Akbari Mohsen 
Published: November 2022

AbstractChemoresistance is a major clinical challenge in the management of glioblastoma (GBM) Temozolomide (TMZ) is the chemotherapeutic drug of choice for GBM; however, the therapeutic effect of TMZ is limited due to the development of resistance. Recapitulating GBM chemoresistance in a controlled environment is thus essential in understanding the mechanism of chemoresistance. Herein, we present a hybrid microphysiological model of chemoresistant GBM-on-a-chip (HGoC) by directly co-culturing TMZ-resistant GBM spheroids with healthy neurons to mimic the microenvironment of both the tumor and the surrounding healthy tissue. We characterized the model with proteomics, lipidomics, and secretome assays. The results showed that our artificial model recapitulated the molecular signatures of recurrent GBM in humans. Both showed alterations in vesicular transport and cholesterol pathways, mitotic quiescence, and a switch in metabolism to oxidative phosphorylation associated with a transition from mesenchymal to amoeboid. This is the first report to unravel the interplay of all these molecular changes as a mechanism of chemoresistance in glioblastoma. Moreover, we have shown that the acquisition of resistance increases invasiveness and the presence of neurons decreases this property.
Whole-brain modeling of the differential influences of Amyloid-Beta and Tau in Alzheimer’s Disease
Authors: Patow Gustavo , Stefanovski Leon , Ritter Petra , Deco Gustavo , Kobeleva Xenia ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: November 2022

AbstractBackgroundAlzheimer’s Disease is a neurodegenerative condition associated with the accumulation of two misfolded proteins, amyloid-beta (Aβ) and tau. We study their effect on neuronal activity, with the aim of assessing their individual and combined impact.MethodsWe use a whole-brain dynamic model to find the optimal parameters that best describe the effects of Aβand tau on the excitation-inhibition balance of the local nodes.ResultsWe found a clear dominance of Aβover tau in the early disease stages (MCI), while tau dominates over Aβin the latest stages (AD). We identify crucial roles for Aβand tau in complex neuronal dynamics and demonstrate the viability of using regional distributions to define models of large-scale brain function in AD.ConclusionsOur study provides further insight into the dynamics and complex interplay between these two proteins, opening the path for further investigations on biomarkers and candidate therapeutic targets in-silico.
Instantaneous visual genotyping and facile site-specific transgenesis via CRISPR-Cas9 and phiC31 integrase
Authors: Ma Junyan , Zhang Weiting , Sun Zhengwang , Parvez Saba , Peterson Randall T. , Yeh Jing-Ruey Joanna 
Published: November 2022

AbstractThe zebrafishDanio reriohas become a popular model in functional genomics and genetic disease studies. However, when a zebrafish mutant line must be propagated as heterozygotes due to homozygous lethality, using standard genotyping methods to identify a population of homozygous mutant embryos is time-consuming and sometimes impractical due to downstream applications such as large-scale chemical screens. Here, we introduce ‘TICIT’,TargetedIntegration byCRISPR-Cas9 andIntegraseTechnologies, which utilizes the site-specific DNA recombinase – phiC31 integrase – to insert fluorescent markers into CRISPR-Cas9-generated mutant alleles. It allows instantaneous determination of a zebrafish’s genotype simply by examining its color. This technique, which relies on first knocking in a 39-basepair phiC31 landing site via CRISPR-Cas9, enables researchers to insert large DNA fragments at the same genomic location repeatedly and with high precision and efficiency. We demonstrated that TICIT could also be used to create reporter fish driven by an endogenous promoter. Additionally, we created a landing site located in thetyrosinasegene that could support transgene expression in a broad spectrum of tissue and cell types, acting as a putative safe harbor locus. Hence, TICIT can yield predictable and reproducible transgene expression, facilitate diverse applications in zebrafish, and may be applicable to cells in culture and other model organisms.