bluuebunny/crossref_metadata_2025_split huggingface dataset:
Synaptic and circuit mechanisms prevent detrimentally precise correlation in developing visual system
Authors: Tikidji-Hamburyan Ruben A. , Govindaiah Gubbi , Guido William , Colonnese Matthew T. 
Published: November 2022

AbstractDuring development, retinal axons create broad and imprecise connections in the thalamus. This topology, very different from adults, supplies developing thalamic neurons with locally homogeneous synaptic currents and should cause spike correlation between thalamocortical neurons on a millisecond timescale. Such correlations have not been observedin vivo, at these ages, and would likely be maladaptive. Here, we use a biophysical model of the visual thalamus with the membrane and synaptic properties of 7-10 day-old mice to show that the developmentally appropriate dominance of NMDA-receptor currents and absence of strong recurrent inhibitory and excitatory connections prevents precise correlation and preserves topographic information in thalamic spikes. We illustrate possible reasons for this desynchronization using a phenomenological cortical model, which shows impaired network diversity when driven with precisely correlated inputs. Our results suggest that developing synapses and circuits evolved mechanisms to compensate for detrimental, “parasitic” correlation arising from the unrefined and immature circuit.
Behavioral dissection of hunger states inDrosophila
Authors: Weaver KJ , Raju S , Rucker RA , Chakraborty TS , Holt RA , Pletcher SD 
Published: November 2022

AbstractHunger is a motivational drive that promotes feeding, and it can be generated by the physiological need to consume nutrients as well as the hedonic properties of food. Brain circuits and mechanisms that regulate feeding have been described, but which of these contribute to the generation of motive forces that drive feeding is unclear. Here, we describe our first efforts at behaviorally and neuronally distinguishing hedonic from homeostatic hunger states inDrosophila melanogasterand propose that this system can be used as a model to dissect the molecular mechanisms that underlie feeding motivation. We visually identify and quantify behaviors exhibited by hungry flies and find that increased feeding duration is a behavioral signature of hedonic feeding motivation. Using a genetically-encoded marker of neuronal activity, we find that the mushroom body (MB) lobes are activated by hedonic food environments, and we use optogenetic inhibition to implicate a dopaminergic neuron cluster (PAM) to α’/β’ MB circuit in hedonic feeding motivation. The identification of discrete hunger states in flies and the development of behavioral assays to measure them offers a framework to begin dissecting the molecular and circuit mechanisms that generate motivational states in the brain.
Cyclic Loading Induces Anabolic and Catabolic Gene Expression in ACLs in a Load-Dependent and Sex-Specific Manner
Authors: Paschall Lauren , Carrozzi Sabrina , Tabdanov Erdem , Dhawan Aman , Szczesny Spencer 
Published: November 2022

AbstractAnterior cruciate ligament (ACL) injuries are historically thought to be a result of a single acute overload or traumatic event. However, recent studies suggest that ACL failure may be a consequence of fatigue damage. Additionally, the remodeling response of ACLs to fatigue loading is unknown. Therefore, the objective of this study was to investigate the remodeling response of ACLs to cyclic loading. Furthermore, given that women have an increased rate of ACL rupture, we investigated whether this remodeling response is sex specific. ACLs were harvested from male and female New Zealand white rabbits and cyclically loaded in a tensile bioreactor mimicking the full range of physiological loading (2, 4, and 8 MPa). Expression of markers for anabolic and catabolic tissue remodeling, as well as inflammatory cytokines, was quantified using RT-qPCR. We found that the expression of markers for tissue remodeling of the ACL is dependent on the magnitude of loading and is sex specific. Male ACLs activated a tissue remodeling response to cyclic loading below 4 MPa loads but turned off remodeling at 8 MPa. These data support the hypothesis that noncontact ACL injury is a consequence of failed tissue remodeling and inadequate repair of microtrauma resulting from fatigue loading. Conversely, female ACLs downregulate genes responsible for tissue remodeling in response to cyclic loading at all magnitudes, which may explain the increased rate of ACL tears in women. Together, these data provide insight into the remodeling response of ACLs in vivo and potentially offer novel approaches for preventing ACL rupture.
Glucocerebrosidase activity and lipid levels are related to protein pathologies in Parkinson’s disease
Authors: Leyns Cheryl E. G. , Prigent Alice , Beezhold Brenna , Yao Lihang , Hatcher Nathan , Tao Peining , Kang John , Suh EunRan , Van Deerlin Vivianna M , Trojanowski John Q. , Lee Virginia M.Y. , Kennedy Matthew , Fell Matthew , Henderson Michael X. 
Published: November 2022

ABSTRACTParkinson’s disease (PD) and dementia with Lewy bodies (DLB) are progressive neurodegenerative diseases characterized by the accumulation of misfolded α-synuclein in the form of Lewy pathology. While most cases are sporadic, there are rare genetic mutations that cause disease and more common variants that increase incidence of disease. The most prominent genetic mutations for PD and DLB are in theGBA1andLRRK2genes.GBA1mutations are associated with decreased glucocerebrosidase activity and lysosomal accumulation of its lipid substrates, glucosylceramide and glucosylsphingosine. Previous studies have shown a link between this enzyme and lipids even in sporadic PD. However, it is unclear how the protein pathologies of disease are related to enzyme activity and glycosphingolipid levels. To address this gap in knowledge, we examined quantitative protein pathology, glucocerebrosidase activity and lipid substrates in parallel from 4 regions of 91 brains with no neurological disease, idiopathic,GBA1-linked, orLRRK2-linked PD and DLB. We find that several biomarkers are altered with respect to mutation and disease severity. We found mild association of glucocerebrosidase activity with disease, but a strong association of glucosylsphingosine with α-synuclein pathology, irrespective of genetic mutation. This association suggests that Lewy pathology precipitates changes in lipid levels related to disease severity.
Emergent Electrical Activity, Tissue Heterogeneity, and Robustness in a Calcium Feedback Regulatory Model of the Sinoatrial Node
Authors: Moise Nicolae , Weinberg Seth H. 
Published: November 2022

AbstractThe sinoatrial node (SAN) is the primary pacemaker of the heart. SAN activity emerges at an early point in life and maintains a steady rhythm for the lifetime of the organism. The ion channel composition and currents of SAN cells can be influenced by a variety of factors. Therefore, the emergent activity and long-term stability imply some form of dynamical feedback control of SAN activity. We adapt a recent feedback model - previously utilized to describedion conductances in neurons - to a model of SAN cells and tissue. The model describes a minimal regulatory mechanism of ion channel conductances via feedback between intracellular calcium and an intrinsic target calcium level. By coupling a SAN cell to the calcium feedback model, we show that spontaneous electrical activity emerges from quiescence and is maintained at steady-state. In a 2D SAN tissue, spatial variability in intracellular calcium targets lead to significant, self-organized heterogeneous ion channel expression and calcium transients throughout the tissue. Further, multiple pacemaking regions appear, which interact and lead to time-varying cycle length, demonstrating that variability in heart rate is an emergent property of the feedback model. Finally, we demonstrate that the SAN tissue is robust to the silencing of leading cells or ion channel knockouts. Thus, the calcium feedback model can reproduce and explain many fundamental emergent properties of activity in the SAN that have been observed experimentally based on a minimal description of intracellular calcium and ion channel regulatory networks.Key Points SummaryThe robust function of the sinoatrial node (SAN) is reproduced in an intracellular calcium feedback model governing ion channel conductancesThe feedback model predicts the emergence and long-term maintenance of spontaneous oscillatory electrical activityIntegrating the feedback model into a 2D SAN tissue leads to emergent spatial heterogeneity, multiple pacemaking regions, and variable cycle lengthSAN cells and tissue with feedback are robust to cell injury and channel knock-outs
Brain-wide representations of behavior spanning multiple timescales and states inC. elegans
Authors: Atanas Adam A. , Kim Jungsoo , Wang Ziyu , Bueno Eric , Becker McCoy , Kang Di , Park Jungyeon , Estrem Cassi , Kramer Talya S. , Baskoylu Saba , Mansingkha Vikash K. , Flavell Steven W. 
Published: November 2022

SUMMARYChanges in an animal’s behavior and internal state are accompanied by widespread changes in activity across its brain. However, how neurons across the brain encode behavior and how this is impacted by state is poorly understood. We recorded brain-wide activity and the diverse motor programs of freely-movingC. elegansand built probabilistic models that explain how each neuron encodes quantitative features of the animal’s behavior. By determining the identities of the recorded neurons, we created, for the first time, an atlas of how the defined neuron classes in theC. elegansconnectome encode behavior. Many neuron classes have conjunctive representations of multiple behaviors. Moreover, while many neurons encode current motor actions, others encode recent actions. Changes in behavioral state are accompanied by widespread changes in how neurons encode behavior, and we identify these flexible nodes in the connectome. Our results provide a global map of how the cell types across an animal’s brain encode its behavior.
3D-bioprinted, phototunable hydrogel models for studying adventitial fibroblast activation in pulmonary arterial hypertension
Authors: Davis-Hall Duncan , Thomas Emily , Peña Brisa , Magin Chelsea M. 
Published: November 2022

AbstractPulmonary arterial hypertension (PAH) is a progressive disease of the lung vasculature, characterized by elevated pulmonary blood pressure, remodeling of the pulmonary arteries, and ultimately right ventricular failure. Therapeutic interventions for PAH are limited in part by the lack ofin vitroscreening platforms that accurately reproduce dynamic arterial wall mechanical properties. Here we present a 3D-bioprinted model of the pulmonary arterial adventitia comprised of a phototunable poly(ethylene glycol) alpha methacrylate (PEG-αMA)-based hydrogel and primary human pulmonary artery adventitia fibroblasts (HPAAFs). This unique biomaterial emulates PAH pathogenesisin vitrothrough a two-step polymerization reaction. First, PEG-αMA macromer was crosslinked off-stoichiometry by 3D bioprinting an acidic bioink solution into a basic gelatin support bath initiating a base-catalyzed thiol-ene reaction with synthetic and biodegradable crosslinkers. Then, matrix stiffening was induced by photoinitiated homopolymerization of unreacted αMA end groups. A design of experiments approach produced a hydrogel platform that exhibited an initial elastic modulus (E) within the range of healthy pulmonary arterial tissue (E = 4.7 ± 0.09 kPa) that was stiffened to the pathologic range of hypertensive tissue (E = 12.8 ± 0.47 kPa) and supported cellular proliferation over time. A higher percentage of HPAAFs cultured in stiffened hydrogels expressed the fibrotic marker alpha-smooth muscle actin than cells in soft hydrogels (88 ± 2% versus 65 ± 4%). Likewise, a greater percentage of HPAAFs were positive for the proliferation marker 5-ethynyl-2’-deoxyuridine (EdU) in stiffened models (66 ± 6%) compared to soft (39 ± 6%). These results demonstrate that 3D-bioprinted, phototunable models of pulmonary artery adventitia are a tool that enable investigation of fibrotic pathogenesisin vitro.
SUMO2 Protects Against Tau-induced Synaptic and Cognitive Dysfunction
Authors: Orsini Franca , Argyrousi Elentina , Restelli Elena , Ford Lenzie K. , Takamura Hironori , Matsuzaki Shinsuke , Zentilin Lorena , Pascente Rosaria , Kanaan Nicholas M , Soni Rajesh , Katayama Taiichi , Chiesa Roberto , Forloni Gianluigi , Kosik Kenneth S. , Kandel Eric R. , Fraser Paul E. , Arancio Ottavio , Fioriti Luana 
Published: November 2022

SummaryAbnormal intracellular accumulation of Tau aggregates is a hallmark of Alzheimer’s disease (AD) and other Tauopathies, such as Frontotemporal dementia (FTD), which can be caused by mutations of Tau. Mutated and pathological Tau can undergo a range of post-translational modifications (PTMs) that might trigger or modulate disease pathology. Recent studies indicate that modification of wild type Tau bySmallubiquitin-likemodifier SUMO isoform 1 (SUMO1) controls Tau hyperphosphorylation and aggregation, suggesting that SUMOylation acts as a central regulator of Tau’s biochemical properties. Besides SUMO1, Tau is modified by SUMO2/3, however the consequences of this modification have not been investigated. Here, using viral approaches on primary hippocampal neurons, transgenic mice expressing mutant Tau and SUMO2, and iPSC-derived neurons from FTD patients, we evaluated whether SUMO2/3 conjugation modifies the neurodegenerative disease pathology associated with the aggregation-prone mutant Tau P301L, P301S, and R406W variants. We found that mutant forms of Tau are targets of SUMO2/3, and SUMO2/3 conjugation is neuroprotective. Importantly, expression of mutant Tau is accompanied by a significant reduction of SUMO2/3 conjugation levels, and restoring levels of SUMO2 reduces mutant Tau aggregation and phosphorylation in all model systems Furthermore, overexpression of SUMO2 restores levels of pre- and post-synaptic markers, associated with a complete rescue of the LTP and memory deficits in transgenic mice expressing mutant Tau. These findings bring to light the potential therapeutic implication of manipulating SUMO conjugation to detoxify Tau through PTM-based approaches.
Hemodynamic timing in resting-state and breathing-task BOLD fMRI
Authors: Gong Jingxuan , Stickland Rachael C. , Bright Molly G. 
Published: November 2022

AbstractThe blood flow response to a vasoactive stimulus demonstrates regional heterogeneity across both the healthy brain and in cerebrovascular pathology. The timing of a regional hemodynamic response is emerging as an important biomarker of cerebrovascular dysfunction, as well as a confound within fMRI analyses. Previous research demonstrated that hemodynamic timing is more robustly characterized when a larger systemic vascular response is evoked by a breathing challenge, compared to when only spontaneous fluctuations in vascular physiology are present (i.e., in resting-state data). However, it is not clear whether hemodynamic delays in these two conditions are physiologically interchangeable, and how methodological signal-to-noise factors may limit their agreement. To address this, we generated whole-brain maps of hemodynamic delays in nine healthy adults. We assessed the agreement of voxel-wise gray matter (GM) hemodynamic delays between two conditions: resting-state and breath-holding. We found that delay values demonstrated poor agreement when considering all GM voxels, but increasingly greater agreement when limiting analyses to voxels showing strong correlation with the GM mean time-series. Voxels showing the strongest agreement with the GM mean time-series were primarily located near large venous vessels, however these voxels explain some, but not all, of the observed agreement in timing. Increasing the degree of spatial smoothing of the fMRI data enhanced the correlation between individual voxel time-series and the GM mean time-series. These results suggest that signal-to-noise factors may be limiting the accuracy of voxel-wise timing estimates and hence their agreement between the two data segments. In conclusion, caution must be taken when using voxel-wise delay estimates from resting-state and breathing-task data interchangeably, and additional work is needed to evaluate their relative sensitivity and specificity to aspects of vascular physiology and pathology.
Differential modulation of cellular phenotype and drug sensitivity by extracellular matrix proteins in primary and metastatic pancreatic cancer cells
Authors: Usman Olalekan H , Kumar Sampath , Walker Reddick R , Xie Gengqiang , Sumajit Hyeje , Jalil AbdelAziz R. , Ramakrishnan Subramanian , Dooling Lawrence J , Wang Yue Julia , Irianto Jerome 
Published: November 2022

AbstractPancreatic cancer adenocarcinoma (PDAC) is reported to be the third highest cause of cancer-related deaths in the United States. PDAC is known for its high proportion of stroma, which accounts for 90% of the tumor mass. The stroma is made up of extracellular matrix (ECM) and non-malignant cells such as inflammatory cells, cancer-associated fibroblasts, and lymphatic and blood vessels. Here, we decoupled the effects of the ECM on PDAC cell lines by culturing cells on surfaces coated with different ECM proteins. Our data show that the primary tumor-derived cell lines have different morphology depending on the ECM proteins on which they are cultured, while metastatic lesion-derived PDAC lines’ morphology does not change with respect to the different ECM proteins. Similarly, ECM proteins modulate the proliferation rate and the gemcitabine sensitivity of the primary tumor PDAC cell lines, but not the metastatic PDAC lines. Lastly, transcriptomics analysis of the primary tumor PDAC cells cultured on different ECM proteins reveals the regulation of various pathways, such as cell cycle, cell adhesion molecules, and focal adhesion, including the regulation of several integrin genes that are essential for ECM recognition.
Characterizing microplastic ingestion, transformation, and excretion in insects using fluorescent plastics
Authors: Ritchie Marshall W. , Cheslock Alexandra , Bourdages Madelaine P.T. , Hamilton Bonnie M. , Provencher Jennifer F. , Allison Jane E. , MacMillan Heath A. 
Published: November 2022

AbstractPlastic pollution is a growing threat to our natural environment. Plastic waste/pollution results from high emissions of both macro (> 5 mm) and microplastics (MPs; < 5 mm) as well as environmental fractioning of macroplastics into microplastics. Microplastics have been shown to have a range of negative impacts on biota. Harmonized methods to accurately measure and count MPs from animal samples are limited, but what methods exist are not ideal for a controlled laboratory environment where plastic ingestion, transformation, and elimination can be quantified and related to molecular, physiological, and organismal traits. Here we propose a complete method for isolating and characterizing fluorescent MPs by combining several previously reported approaches into one comprehensive workflow. We combine tissue dissection, organic material digestion, sample filtering, and automated imaging techniques to show how fluorescently-labelled MPs provided to animals (e.g. in their diet) in a laboratory setting can be isolated, identified, and quantified. As a proof of concept, we fed crickets (Gryllodes sigillatus) a diet of 2.5% (w/w) fluorescently-labelled plastics and isolated and characterized plastic particles within the gut and frass.
Phenotypic, genomic, and transcriptomic heterogeneity in a pancreatic cancer cell line
Authors: Xie Gengqiang , Zhang Liting , Usman Olalekan H , Kumar Sampath , Modak Chaity , Patel Dhenu , Kavanaugh Megan , Mallory Xian , Wang Yue Julia , Irianto Jerome 
Published: November 2022

AbstractObjectivesTo evaluate the suitability of the MIA PaCa-2 cell line for studying pancreatic cancer intratumor heterogeneity, we aim to further characterize the nature of MIA PaCa-2 cells’ phenotypic, genomic, and transcriptomic heterogeneity.MethodsMIA PaCa-2 single-cell clones were established through flow cytometry. For the phenotypic study, we quantified the cellular morphology, proliferation rate, migration potential, and drug sensitivity of the clones. The chromosome copy number and transcriptomic profiles were quantified using SNPa and RNA-seq, respectively.ResultsFour MIA PaCa-2 clones showed distinctive phenotypes, with differences in cellular morphology, proliferation rate, migration potential, and drug sensitivity. We also observed a degree of genomic variations between these clones in form of chromosome copy number alterations and single nucleotide variations, suggesting the genomic heterogeneity of the population, and the intrinsic genomic instability of MIA PaCa-2 cells. Lastly, transcriptomic analysis of the clones also revealed gene expression profile differences between the clones, including the uniquely regulatedITGAV, which dictates the morphology of MIA PaCa-2 clones.ConclusionsMIA PaCa-2 is comprised of cells with distinctive phenotypes, heterogeneous genomes, and differential transcriptomic profiles, suggesting its suitability as a model to study the underlying mechanisms behind pancreatic cancer heterogeneity.
Individual regional associations between Aβ-, tau- and neurodegeneration (ATN) with microglial activation in patients with primary and secondary tauopathies
Authors: Finze Anika , Biechele Gloria , Rauchmann Boris-Stephan , Franzmeier Nicolai , Palleis Carla , Katzdobler Sabrina , Weidinger Endy , Guersel Selim , Schuster Sebastian , Harris Stefanie , Schmitt Julia , Beyer Leonie , Gnörich Johannes , Lindner Simon , Albert Nathalie L. , Wetzel Christian , Rupprecht Rainer , Rominger Axel , Danek Adrian , Burow Lena , Kurz Carolin , Tato Maia , Utecht Julia , Papazov Boris , Zaganjori Mirlind , Trappmann Lena-Katharina , Goldhardt Oliver , Grimmer Timo , Haeckert Jan , Janowitz Daniel , Buerger Katharina , Keeser Daniel , Stoecklein Sophia , Dietrich Olaf , Morenas-Rodriguez Estrella , Barthel Henryk , Sabri Osama , Bartenstein Peter , Simons Mikael , Haass Christian , Höglinger Günter U. , Levin Johannes , Perneczky Robert , Brendel Matthias 
Published: November 2022

ABSTRACTβ-amyloid (Aβ) and tau aggregation as well as neuronal injury and atrophy (ATN) are the major hallmarks of Alzheimer’s disease (AD), and biomarkers for these hallmarks have been linked to neuroinflammation. However, the detailed regional associations of these biomarkers with microglial activation in individual patients remain to be elucidated.We investigated a cohort of 55 patients with AD and primary tauopathies and 10 healthy controls that underwent TSPO-, A-, tau-, and perfusion-surrogate-PET, as well as structural MRI. Z-score deviations for 246 brain regions were calculated and biomarker contributions of Aβ (A), tau (T), perfusion (N1) and gray matter atrophy (N2) to microglial activation (TSPO, I) were calculated for each individual subject. Individual ATN-related microglial activation was correlated with clinical performance and CSF soluble TREM2 (sTREM2) concentrations.In typical and atypical AD, regional tau was stronger and more frequently associated with microglial activation when compared to regional A (AD: βT= 0.412±0.196 vs. βA= 0.142±0.123, p < 0.001; AD-CBS: βT= 0.385±0.176 vs. βA= 0.131±0.186, p = 0.031). The strong association between regional tau and microglia reproduced well in primary tauopathies (βT= 0.418±0.154). Stronger individual associations between tau and microglial activation were associated with poorer clinical performance. In patients with 4RT, sTREM2 levels showed a positive association with tau-related microglial activation.Tau pathology has strong regional associations with microglial activation in primary and secondary tauopathies. An index of tau- and Aβ-associated microglia activation accounts for regional heterogeneity and allows for clinical and biomarker correlations with ATN-specific neuroinflammation.