bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hypothesis-driven modeling of the human lung-ventilator system: A characterization tool for Acute Respiratory Distress Syndrome research
Authors: Stroh J.N. , Smith Bradford J. , Sottile Peter D. , Hripcsak George , Albers David J. 
Published: November 2022

AbstractMechanical ventilation is an essential tool in the management of Acute Respiratory Distress Syndrome (ARDS), but it exposes patients to the risk of ventilator-induced lung injury (VILI). The human lung-ventilator system (LVS) involves the interaction of complex anatomy with a mechanical apparatus, which limits the achievable flexibility and fidelity needed to provide individualized clinical support by modeling lung processes. This work proposes a hypothesis-driven strategy for LVS modeling, in which robust personalization is achieved using a pre-defined parameter basis in a non-physiological model. Model inversion, here via windowed data assimilation, forges observed waveforms into interpretable parameter values that characterize the data rather than quantifying physiological processes. Inference experiments performed on human pressure waveform data indicate the flexible model accurately estimates parameters for a variety of breath types, including breaths of markedly dyssynchronous LVSs. Parameter estimates generate static characterizations of the data that are 50–70% more accurate than breath-wise single-compartment model estimates. They also retain sufficient information to distinguish between the types of breath they represent. However, the fidelity and interpetability of model characterizations are tied to parameter definitions and model resolution. These additional factors must be considered in conjunction with the objectives of specific applications, such as identifying and tracking the development of human VILI.
Effect of Nrf2 Loss on Senescence and Cognition of Tau-Based P301S Mice
Authors: Riordan R. , Rong W. , Yu Z. , Ross G. , Valerio J. , Dimas-Muñoz J. , Heredia V. , Magnusson K. , Galvan V. , Perez V.I. 
Published: November 2022

AbstractCellular senescence may contribute to chronic inflammation involved in the progression of age-related diseases such as Alzheimer’s Disease (AD), and its removal prevents cognitive impairment in a model of tauopathy. Nrf2, the major transcription factor for damage response pathways and regulators of inflammation, declines with age. Our previous work showed that silencing Nrf2 gives rise to premature senescence in cells and mice. Others have shown that Nrf2 ablation can exacerbate cognitive phenotypes of some AD models. In this study we aimed to understand the relationship between Nrf2 elimination, senescence, and cognitive impairment in AD, by generating a mouse model expressing a mutant human tau transgene in an Nrf2 knockout (Nrf2KO) background. We assessed senescent cell burden and cognitive decline of P301S mice in the presence and absence of Nrf2. Lastly, we administered 4.5 month-long treatments with two senotherapeutic drugs to analyze their potential to prevent senescent cell burden and cognitive decline: the senolytic drugs Dasatinib and Quercetin (DQ) and the senomorphic drug rapamycin. Nrf2 loss accelerated the onset of hind-limb paralysis in P301S mice. At 8.5 months of age, P301S mice did not exhibit memory deficits, while P301S mice without Nrf2 were significantly impaired. However, markers of senescence were not elevated by Nrf2 ablation in any of tissues that we examined. Neither drug treatment improved cognitive performance, nor did it reduce expression of senescence markers in brains of P301S mice. Contrarily, rapamycin treatment at the doses used delayed spatial learning and led to a modest decrease in spatial memory. Taken together, our data suggests that the emergence of senescence may be causally associated with onset of cognitive decline in the P301S model, indicate that Nrf2 protects brain function in a model of AD through mechanisms that may include, but do not require the inhibition of senescence, and suggest possible limitations for DQ and rapamycin as therapies for AD.
YTHDF2 in dentate gyrus is the m6A reader mediating m6A modification in hippocampus-dependent learning and memory
Authors: Zhuang Mengru , Geng Xiaoqi , Han Peng , Liang Fanghao , Che Pengfei , Liu Chao , Yang Lixin , Yu Jun , Zhang Zhuxia , Dong Wei , Ji Sheng-Jian 
Published: November 2022

AbstractN6-methyladenosine (m6A) has been demonstrated to regulate learning and memory in mice. To investigate the mechanism by which m6A modification exerts its function through its reader proteins in the hippocampus, as well as to unveil the specific subregions of the hippocampus that are crucial for memory formation, we generated dentate gyrus (DG)-, CA3-, and CA1-specificYthdf1andYthdf2conditional knockout (cKO) mice, respectively. Surprisingly, we found that only the DG-specificYthdf2cKO mice displayed impaired memory formation, which is inconsistent with the previous report showing that YTHDF1 was involved in this process. YTHDF2 controls the stability of its target transcripts which encode proteins that regulate the elongation of mossy fibers (MF), the axons of granule cells in DG. DG-specificYthdf2ablation caused MF overgrowth and impairment of the MF-CA3 excitatory synapse development and transmission in the stratum lucidum. Thus, this study identifies the m6A reader YTHDF2 in dentate gyrus as the only regulator that mediates m6A modification in hippocampus-dependent learning and memory.
Calcium and Bicarbonate Signaling Pathways have Pivotal, Resonating Roles in Matching ATP Production to Demand
Authors: Greiser Maura , Karbowski Mariusz , Kaplan Aaron D. , Coleman Andrew K. , Mannella Carmen A. , Lederer W. J. , Boyman Liron 
Published: November 2022

AbstractMitochondrial ATP production in cardiac ventricular myocytes must be continually adjusted to rapidly replenish the ATP consumed by the working heart. Two systems are known to be critical in this regulation: mitochondrial matrix Ca2+([Ca2+]m) and blood flow that is tuned by local ventricular myocyte metabolic signaling. However, these two regulatory systems do not account for the large physiological range of ATP consumption observed. We report here on the identity, location, and signaling cascade of a controversial third regulatory system -- CO2/bicarbonate. CO2is generated in the mitochondrial matrix as a metabolic waste product produced by oxidation of nutrients which power the production of ATP. It is a lipid soluble gas that equilibrates with bicarbonate (HCO3−) in aqueous solutions. The bicarbonate level is tracked by a bicarbonate-activated adenylyl cyclase, soluble adenylyl cyclase (sAC). Using structural Airyscan super-resolution imaging and functional measurements we find that sAC is primarily inside the mitochondria of ventricular myocytes where it generates cAMP when activated by HCO3−. This cAMP signaling cascade is shown to operate inside the mitochondrial inter-membrane space (IMS) by activating local EPAC1 (ExchangeProtein directlyActivated bycAMP) which turns on Rap1 (Ras-related protein 1). Thus, mitochondrial ATP production is shown to be increased by bicarbonate-triggered sAC signaling through Rap1. Additional evidence is presented indicating that the cAMP signaling itself does not occur directly in the matrix. We also show that this third signaling process involving bicarbonate and sAC activates the cardiac mitochondrial ATP production machinery by working independently of, yet in conjunction with, [Ca2+]m-dependent ATP production to meet the energy needs of cellular activity in both health and disease. Thus, the resonant, or complementary effects of bicarbonate and [Ca2+]msignaling arms tune mitochondrial ATP production to match the full scale of energy consumption in cardiac ventricular myocytes.
Site of vulnerability on SARS-CoV-2 spike induces broadly protective antibody to antigenically distinct omicron SARS-CoV-2 subvariants
Authors: Changrob Siriruk , Halfmann Peter J. , Liu Hejun , Torres Jonathan L. , McGrath Joshua J.C. , Ozorowski Gabriel , Li Lei , Kuroda Makoto , Maemura Tadashi , Huang Min , Wilbanks G. Dewey , Zheng Nai-Ying , Turner Hannah L. , Erickson Steven A. , Fu Yanbin , Singh Gagandeep , Krammer Florian , Sather D. Noah , Ward Andrew B. , Wilson Ian A. , Kawaoka Yoshihiro , Wilson Patrick C. 
Published: November 2022

SummaryThe rapid evolution of SARS-CoV-2 Omicron variants has emphasized the need to identify antibodies with broad neutralizing capabilities to inform future monoclonal therapies and vaccination strategies. Herein, we identify S728-1157, a broadly neutralizing antibody (bnAb) targeting the receptor-binding site (RBS) and derived from an individual previously infected with SARS-CoV-2 prior to the spread of variants of concern (VOCs). S728-1157 demonstrates broad cross-neutralization of all dominant variants including D614G, Beta, Delta, Kappa, Mu, and Omicron (BA.1/BA.2/BA.2.75/BA.4/BA.5/BL.1). Furthermore, it protected hamsters againstin vivochallenges with wildtype, Delta, and BA.1 viruses. Structural analysis reveals that this antibody targets a class 1 epitope via multiple hydrophobic and polar interactions with its CDR-H3, in addition to common class 1 motifs in CDR-H1/CDR-H2. Importantly, this epitope is more readily accessible in the open and prefusion state, or in the hexaproline (6P)-stabilized spike constructs, as compared to diproline (2P) constructs. Overall, S728-1157 demonstrates broad therapeutic potential, and may inform target-driven vaccine design against future SARS-CoV-2 variants.
Excessive Firing of Dyskinesia-Associated Striatal Direct Pathway Neurons is Gated By Dopamine and Excitatory Synaptic Input
Authors: Ryan Michael B. , Girasole Allison E. , McGregor Matthew M. , Brakaj Rea , Paletzki Ronald F. , Gerfen Charles R. , Nelson Alexandra B. 
Published: November 2022

AbstractThe striatum integrates dopaminergic and glutamatergic inputs to select preferred versus alternative actions, but the precise mechanisms remain unclear. One way to study action selection is when it breaks down. Here, we explored the cellular and synaptic mechanisms of levodopa-induced dyskinesia (LID), a complication of Parkinson’s disease therapy characterized by involuntary movements. We used an activity-dependent tool (FosTRAP) in conjunction with a mouse model of LID to investigate functionally distinct subsets of striatal direct pathway medium spiny neurons (dMSNs).In vivo, levodopa differentially activates dyskinesia-associated (TRAPed) dMSNs compared to other dMSNs. This activation is likely to be driven by two cellular mechanisms we identified throughex vivoelectrophysiology: higher sensitivity to dopamine and stronger excitatory input from the motor cortex and thalamus. Together, these findings suggest how intrinsic and synaptic properties of heterogeneous dMSN subpopulations integrate to support action selection.
Core material and surface chemistry of Layer-by-Layer (LbL) nanoparticles independently direct uptake, transport, and trafficking in preclinical blood-brain barrier (BBB) models
Authors: Lamson Nicholas G. , Pickering Andrew J. , Wyckoff Jeffrey , Ganesh Priya , Straehla Joelle P. , Hammond Paula T. 
Published: November 2022

AbstractDevelopment of new treatments for neurological disorders, especially brain tumors and neurodegenerative diseases, is hampered by poor accumulation of new therapeutic candidates in the brain. Drug carrying nanoparticles are a promising strategy to deliver therapeutics, but there is a major need to understand interactions between nanomaterials and the cells of the blood-brain barrier (BBB), and to what degree these interactions can be predicted by preclinical models. Here, we use a library of eighteen layer-by-layer electrostatically assembled nanoparticles (LbL-NPs) to independently assess the impact of nanoparticle core stiffness and surface chemistry onin vitrouptake and transport in three common assays, as well as intracellular trafficking in hCMEC/D3 endothelial cells. We demonstrate that nanoparticle core stiffness impacts the magnitude of material transported, while surface chemistry influences how the nanoparticles are trafficked within the cell. Finally, we demonstrate that these factors similarly dictatein vivoBBB transport using intravital imaging through cranial windows in mice, and we discover that a hyaluronic acid surface chemistry provides an unpredicted boost to transport. Taken together, these findings highlight the importance of considering factors such as assay geometry, nanomaterial labelling strategies, and fluid flow in designing preclinical assays to improve nanoparticle screening throughput for drug delivery to the brain.
Improving quantitative structure models of trees inspired by pipe and metabolic scaling theory
Authors: Hackenberg Jan , Bontemps Jean-Daniel 
Published: November 2022

AbstractPurposeWe invent in this manuscript new tree parameters which can be derived from a single QSM. QSMs are topological ordered cylinder models of trees which describe the branching structure up to the tips. All new invented parameters have in common, that their defining point of view looks from the direction of the tips and not from the root along the tree.MethodsWe use new allometric power functions to predict the radius from the invented parameters. Then we improve the radii of the QMSs’ cylinders utilizing those functions.ResultsFor validation we use QSMs produced from an open point cloud data set of tree clouds with SimpleForest software. We compare the QSM volume against the harvested reference data for 65felled trees. We also found QSM data of TreeQSM, a competitive and broadly accepted QSM modeling tool. Our RMSE was less than 40 % of the TreeQSM RMSE. For other error measures, ther2adj.and theCCC, the relative improvement looked even better with reaching only 27 % and 21 % of the TreeQSM errors respectively.In a second validation part we show a way to run numerical tests against the West Brown Enquist (WBE) model. Expected power coefficients have been published for various allometric relations and we compare them to predicted values from QSM data. The deviation from the expected values ranges here from 8 % underestimation to 32 % overestimation.ConclusionsQuality -With the invention of the QSM radius filter technique we improve tree volume prediction capabilities utilizing QSMs.Quantity -More data can be collected with QSMs than with traditional methods.
Polarity and mixed-mode oscillations may underlie different patterns of cellular migration
Authors: Plazen Lucie , Rahbani Jalal Al , Brown Claire M. , Khadra Anmar 
Published: November 2022

AbstractIn mesenchymal cell motility, several migration patterns have been observed, including directional, exploratory and stationary. Two key members of the Rho-family of GTPases, Rac and Rho, along with an adaptor protein called paxillin, have been particularly implicated in the formation of such migration patterns and in regulating adhesion dynamics. Together, they form a key regulatory network that involves the mutual inhibition exerted by Rac and Rho on each other and the promotion of Rac activation by phosphorylated paxillin. Although this interaction is sufficient to generating wave-pinning that underscores cellular polarization comprised of cellular front (high active Rac) and back (high active Rho), it remains unclear how they interact collectively to induce other modes of migration detected in Chinese hamster Ovary (CHO-K1) cells. We previously developed a 6D reaction-diffusion model describing the interactions of these three proteins (in their active/phosphorylated and inactive/unphosphorylated forms) along with other auxiliary proteins, to decipher their role in generating wave-pinning. In this study, we explored, through computational modeling and image analysis, how differences in timescales within this molecular network can potentially produce the migration patterns in CHO-K1 cells and how switching between them could occur. To do so, the 6D model was reduced to an excitable 4D spatiotemporal model possessing three different timescales. The model produced not only wave-pinning in the presence of diffusion, but also mixed-mode oscillations (MMOs) and relaxation oscillations (ROs). Implementing the model using the Cellular Potts Model (CPM) produced outcomes in which protrusions in cell membrane changed Rac-Rho localization, resulting in membrane oscillations and fast directionality variations similar to those seen in CHO-K1 cells. The latter was assessed by comparing the migration patterns of CHOK1 cells with CPM cells using four metrics: instantaneous cell speed, exponent of mean square-displacement (calledα-value), directionality ratio and protrusion rate. Variations in migration patterns induced by mutating paxillin’s serine 273 residue was also captured by the model and detected by a machine classifier, revealing that this mutation alters the dynamics of the system from MMOs to ROs or nonoscillatory behaviour through variation in the concentration of an active form of an adhesion protein called p21-Activated Kinase 1 (PAK). These results thus suggest that MMOs and adhesion dynamics are the key ingredients underlying CHO-K1 cell motility.
Cut homeodomain transcription factor is a novel regulator of cortex glia morphogenesis and maintenance of neural niche
Authors: Yadav Vaishali , Mishra Ramkrishna , Das Papri , Arya Richa 
Published: November 2022

AbstractCortex glia inDrosophilacentral nervous system forms a niche around neural cells for necessary signals to establish cross-talk with their surroundings. These cells grow and expand their thin processes around neural cell bodies. Although essential for the development and function of the nervous system, how these cells make extensive and intricate connected networks remain largely unknown. Here we show that Cut, a homeodomain transcription factor, directly regulates the fate of the cortex glia, impacting NSC homeostasis. Focusing on the thoracic ventral nerve cord (tVNC), we found that Cut is required for normal growth and development of cortex glia and timely increase in DNA content to undergo endomitosis. Knockdown of Cut in cortex glia significantly reduces the growth of cellular processes, the network around NSCs, and their progeny’s cell bodies. Conversely, overexpression of Cut induces overall growth of the main processes at the expense of side ones. Whereas the Cut knockdown slowdown the timely increase of DNA, Cut overexpression results in a significant increase in nuclear size and volume and a threefold increase in DNA content of cortex glia. Further, we note that constitutively high Cut also interfered with nuclei separation during endomitosis. Since cortex glia form syncytial networks around neural cells, the finding identifies Cut as a novel regulator of glial growth and endomitosis to support a functional nervous system.Article SummaryCut homeodomain transcription factor is crucial for cortex glia growth and the formation of complex cellular processes around neural cells. This regulation ensures a timely increase in DNA content, allowing the cells to enter endomitosis. Constitutively high Cut levels increase the DNA content of these cells to several folds. The finding emphasizes the need to investigate if activated CUX1, the human homolog of Cut, in glioma enhances chromosomal instability and, in conjunction with other mutations, enhances their tumorigenic potential.
LRRK2 regulates synaptic function through BDNF signaling and actin cytoskeleton
Authors: Tombesi Giulia , Kompella Shiva , Favetta Giulia , Chen Chuyu , Zhao Yibo , Sevegnani Martina , Marte Antonella , Battisti Ilaria , Morosin Ester , Ornaghi Marta , Iannotta Lucia , Plotegher Nicoletta , Civiero Laura , Onofri Franco , Eickholt Britta J , Piccoli Giovanni , Arrigoni Giorgio , Beccano-Kelly Dayne , Manzoni Claudia , Parisiadou Loukia , Greggio Elisa 
Published: November 2022

AbstractParkinson’s disease (PD) is a multisystemic disorder that manifests through motor and non-motor symptoms. Motor dysfunction is the most debilitating and it is caused by the degeneration of dopamine-producing neurons in the substantia nigra pars compacta (SNpc). A body of evidence indicates that synapse demise precedes by years neuronal death. Still, early synaptic dysfunctions in PD are poorly deciphered.Here we combined literature metanalysis, proteomics and phosphoproteomics with biochemical, imaging and electrophysiological measurements in neurons, brains and synaptosomes from knockout and knockin mouse models, as well as human iPSC-derived neurons associated with the PD-kinase LRRK2.We show that phosphorylation of LRRK2 at Ser935, which controls LRRK2 subcellular localization, rapidly increases upon brain-derived neurotrophic factor (BDNF) stimulation of differentiated SH-SY5Y cells and primary mouse neurons. Affinity-purification coupled with mass spectrometry (AP-MS/MS) analysis revealed that LRRK2 interactome is significantly reshaped upon BDNF stimulation, with an interconnected network of actin cytoskeleton-associated proteins increasing their binding to LRRK2. Accordingly, LRRK2 knockout neurons exhibit decreased TrkB signaling and fail to induce BDNF-dependent spinogenesis.In vivo, one-month oldLrrk2knockout mice display defects in spine maturation, a phenotype that disappears with age. In human iPSC-derived cortical neurons, BDNF increases the frequency of miniature excitatory post-synaptic currents (mEPSC) in wild-type but not in the presence of LRRK2 knockout, functionally supporting a distinctive role of LRRK2 in BDNF-synaptic signaling. Finally, Lrrk2 G2019S PD mutant synaptosomes display differentially phosphorylated proteins enriched in categories related to postsynaptic structural organization.Taken together, our study discloses a critical function of LRRK2 in BDNF-dependent synaptic processes and identifies the postsynaptic actin cytoskeleton as a convergent site of LRRK2 pathophysiological activity.
Cancer treatment patterns and factors affecting receipt of treatment in older adults: results from the ASPREE Cancer Treatment Substudy (ACTS)
Authors: Muhandiramge Jaidyn , Warner Erica T. , Zalcberg John R. , Haydon Andrew , Polekhina Galina , van Londen G J. , Gibbs Peter , Bernstein Wendy B. , Tie Jeanne , Millar Jeremy L. , Mar Victoria J. , McNeil John J. , Woods Robyn L. , Orchard Suzanne G. ,   ASPREE Investigator Group
Published: November 2022

AbstractCancer treatment planning in older adults is complex and requires careful balancing of survival, quality of life benefits, and risk of treatment-related morbidity and toxicity. As a result, treatment selection in this cohort tend to differ from younger patients. However, there are very few studies describing cancer treatment patterns in older cohorts. We used data from the ASPirin in Reducing Events in the Elderly (ASPREE) trial and the ASPREE Cancer Treatment Substudy (ACTS) to describe cancer treatment patterns in the elderly. We used a multivariate logistic regression model to identify factors affecting receipt of treatment. Of 1,893 eligible Australian and United States (US) participants with incident cancer, 1,569 (81%) received some form of cancer treatment. Non-metastatic breast cancers most frequently received treatment (98%), while haematological malignancy received the lowest rates of treatment (60%). Factors associated with not receiving treatment were older age (OR 0.94, 95% CI 0.91-0.96), residence in the US (OR 0.35, 95% CI 0.22-0.56), smoking (OR 0.60, 95% CI 0.37-0.98), and diabetes (OR 0.58, 95% CI 0.41-0.82). After adjustment for treatment patterns in sex-specific cancers, sex did not impact receipt of treatment. This study is one of the first describing cancer treatment patterns and factors affecting receipt of treatment across common cancer types in older adults. We found that most older adults with cancer received some form of cancer treatment, typically surgery or systemic therapy, although this varied with factors including cancer type, age, sex, and country of residence.