bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of Recurrent Dynamics in Distributed Neural Populations
Authors: Osuna-Orozco Rodrigo , Castillo Edward , Harris Kameron Decker , Santacruz Samantha R. 
Published: June 2024

AbstractLarge-scale recordings of neural activity over broad anatomical areas with high spatial and temporal resolution are increasingly common in modern experimental neuroscience. Recently, recurrent switching dynamical systems have been used to tackle the scale and complexity of these data. However, an important challenge remains in providing insights into the existence and structure of recurrent linear dynamics in neural time series data. Here we test a scalable approach to time-varying autoregression with low-rank tensors to recover the recurrent dynamics in stochastic neural mass models with multiple stable attractors. We demonstrate that the sparse representation of time-varying system matrices in terms of temporal modes can recover the attractor structure of simple systems via clustering. We then consider simulations based on a human brain connectivity matrix in high and low global connection strength regimes, and reveal the hierarchical clustering structure of the dynamics. Finally, we explain the impact of the forecast time delay on the estimation of the underlying rank and temporal variability of the time series dynamics. This study illustrates that prediction error minimization is not sufficient to recover meaningful dynamic structure and that it is crucial to account for the three key timescales arising from dynamics, noise processes, and attractor switching.
The functional and pathogenic consequences of fibrinogen on human oligodendroglia
Authors: Blaszczyk Gabriela J. , Weng Chao , Mohammadnia Abdulshakour , Cui Qiao-Ling , Giurleo Arianna , Groh Adam M.R. , Plouffe Chloe , Sirois Julien , Piscopo Valerio E. C. , Yaqubi Moein , Taqvi Asad , Cassidy Erin , Hall Jeffery A. , Dudley Roy W.R. , Srour Myriam , Zandee Stephanie E J , Klement Wendy , Larouche Sandra , Prat Alexandre , Durcan Thomas M. , Stratton Jo Anne , Antel Jack P. , Moore G. R. Wayne 
Published: June 2024

AbstractObjectiveMultiple sclerosis is an inflammatory demyelinating disorder associated with blood-brain-barrier breakdown, where myelin repair is reduced and ultimately fails. Our aim was to investigate the effect of a systemically circulating molecule fibrinogen, which is abnormally present in the central nervous system as a result of blood-brain barrier breakdown on human oligodendrocyte lineage cells.MethodsIn situ immunofluorescence was performed using anti-fibrinogen and anti-SOX10 antibodies. Mature oligodendrocytes and late progenitors were derived from brain tissue from pediatric and adult donors. Early progenitors were generated from human induced pluripotent stem cells. Following fibrinogen addition to each of these cultures, cell viability and functional capacity was evaluated. Downstream signalling following fibrinogen exposure was confirmed by immunofluorescence microscopy and bulk RNA sequencing.ResultsIn situ studies showed fibrinogen on SOX10-positive oligodendroglia in multiple sclerosis, both in plaques and normal-appearing white matter, and white matter in amyotrophic lateral sclerosis. In response to in vitro exposure to fibrinogen, mature oligodendrocytes from adults showed increased ensheathment capacity and upregulation of lipid synthesis, whereas pediatric-age late oligodendrocyte precursors showed a decrease. Early precursors were unable to differentiate but expressed astrocytic markers and increased proliferation. Fibrinogen-exposed cells show bone morphogenetic protein signalling, more prominently in mature oligodendrocytes.InterpretationWe demonstrate that fibrinogen is deposited on oligodendrocytes in multiple sclerosis and has distinct functional consequences dependent on cell lineage stage. Our findings derived using human OL lineage cells suggest fibrinogen may benefit myelin maintenance by mature oligodendrocytes, while preventing earlier lineage cells from differentiating and repairing multiple sclerosis lesions.
Fibroblasts carrying intermediateC9orf72hexanucleotide repeat expansions from iNPH patients show impaired energy metabolism but no cell pathologies
Authors: Hoffmann Dorit , Korhonen Ville , Rostalski Hannah , Huber Nadine , Heikkinen Sami , Hietanen Tomi , Wittrahm Rebekka , Leskelä Stina , Hartikainen Päivi , Rauramaa Tuomas , Solje Eino , Portaankorva Anne M. , Hiltunen Mikko , Leinonen Ville , Haapasalo Annakaisa 
Published: June 2024

AbstractLongC9orf72hexanucleotide repeat expansions (C9-HRE) are the most common genetic cause of frontotemporal dementia (FTD), a group of neurodegenerative syndromes leading to cognitive dysfunction and frontal and temporal atrophy. FTD is a potential comorbidity of idiopathic normal pressure hydrocephalus (iNPH) and carrying the C9-HRE can modify the age-of-onset in iNPH patients. While intermediate-length C9-HRE (<30 repeats) are often considered non-pathogenic, the exact pathological cutoff is unclear. In this study, we assessed whether fibroblasts from iNPH patients carrying intermediate C9-HRE display C9-HRE-associated pathological hallmarks and changes in cellular function. C9-HRE-associated RNA foci were not detected in the intermediate carriers. The number of p62-positive puncta was significantly increased only in long C9-HRE carrier fibroblasts, in line with p62-positive intracellular inclusions observed in a brain biopsy from the patient. Specific parameters of mitochondrial respiration were significantly reduced in both the long and intermediate C9-HRE carrier fibroblasts. Fibroblasts from the intermediate C9-HRE carriers showed upregulated glycolytic activity, possibly to counteract the reduced mitochondrial respiration, which could not be observed in the long C9-HRE carriers. In conclusion, these data suggest that while the long C9-HRE leads to more severe cellular pathologies than intermediate C9-HRE, the latter might predispose cells to pathological changes.
Lattice ultrasensitivity amplifies signals inE. coliwithout fine-tuning
Authors: Sherry Derek M. , Graf Isabella R. , Bryant Samuel J. , Emonet Thierry , Machta Benjamin B. 
Published: June 2024

AbstractTheE. colichemosensory lattice, consisting of receptors, kinases, and adaptor proteins, is an important test case for biochemical signal processing. Kinase output is characterized by precise adaptation to a wide range of background ligand levels and large gain in response to small relative changes in concentration. Existing models of this lattice achieve their gain through allosteric interactions between either receptors or core units of receptors and kinases. Here we introduce a model which operates through an entirely different mechanism in which receptors gate inherently far from equilibrium enzymatic reactions between neighboring kinases. Our lattice model achieves gain through a mechanism more closely related to zero-order ultrasensitivity than to allostery. Thus, we call it lattice ultrasensitivity (LU). Unlike other lattice critical models, the LU model can achieve arbitrarily high gain through time-scale separation, rather than through finetuning. The model also captures qualitative experimental results which are difficult to reconcile with existing models. We discuss possible implementations in the lattice’s baseplate where long flexible linkers could potentially mediate interactions between neighboring core units.
EndoGPT: A Proof-of-concept Large Language Model Based Assistant for the Management of Thyroid Nodules
Authors: Shah Meghal , Kuo Eric J. , Kuo Jennifer H. , Hsu Shawn , McManus Catherine , Liou Rachel , Lee James A. , Sathe Tejas S. 
Published: June 2024

AbstractLarge language models (LLMs) are increasingly being explored for their potential to simulate clinical reasoning. Here, we demonstrate our initial experience using the GPT-4o LLM along with prompt engineering and knowledge retrieval to develop EndoGPT, a clinical decision support tool for the management of thyroid nodules. In a pilot study of 50 cases, EndoGPT demonstrated an 83% concordance rate with expert surgeons’ assessments and plans. The highest concordance was in diagnosis (93%), followed by the need for an operation (82%) and type of operation (69%). This work suggests that LLM-based assistants may play a useful role in assisting clinicians in the future.
Real-time breath metabolomics to assess early response to CFTR modulators in adults with cystic fibrosis: an open-label proof-of-concept study
Authors: Bardin Emmanuelle , Salvator Hélène , Roquencourt Camille , Lamy Elodie , Hunzinger Nicolas , Sermet-Gaudelus Isabelle , De Miranda Sandra , Grenet Dominique , Devillier Philippe , Grassin-Delyle Stanislas 
Published: June 2024

ABSTRACTBackgroundThe combination of CFTR modulators ivacaftor/tezacaftor/elexacaftor (ETI) achieves unprecedented improvements in clinical symptoms and respiratory function of people with cystic fibrosis. Yet, evaluation is difficult in people with high baseline lung function and the sweat test may vary depending on the type of CFTR mutation. Exhaled breath is a non-invasive sample, rich in personalised metabolic information and breathomics has emerged as a promising tool to monitor and assess therapeutic response. We hypothesised that ETI induces alterations in the breath composition and that these changes may correlate with clinical readouts.MethodsTen adults initiating ETI were enrolled in a prospective open-label study. Exhaled breath was analysed before, after one week and one month of treatment by real-time, proton transfer reaction-mass spectrometry. Clinical symptoms, lung function and sweat test results were recorded.ResultsA total of 29 breath samples were analysed; 108 volatile organic compounds (VOCs) were consistently detected. In responders (8/10), 21 VOCs were significantly modified, mostly hydrocarbons or small carbonyl compounds. At baseline, these VOCs exhibited significantly different concentrations compared to healthy young adults; throughout the first month of treatment, their level in CF breath evolved towards that of healthy volunteers. Eight of these also correlated with variations in lung function.ConclusionReal-time breath analysis identified alterations in the breath at the early stages of treatment that tended to normalise after one month. These changes exhibited correlations with clinical indicators, suggesting that breath VOCs may serve as early biomarkers useful for treatment monitoring.Trial registrationNCT05295524Key messagesWhat is already known on this topicAs efficient new generations of treatments are emerging for patients with CF, we are lacking early, non-invasive, personalised biomarkers associated with response to therapies. The previous generation of CFTR modulators modified the composition of breath within 3 months, yet nothing was known about the early impact of the newer combinations.What this study addsThe triple combination of CFTR modulators modifies the composition of breath in people with CF as soon as within one week of treatment and tends to normalise basal alterations in CF breath. These changes in breath composition may be captured with real-time mass spectrometry and correlate with clinical outcomes.How this study might affect research, practice or policyReal-time breath analysis may become useful in monitoring companion biomarkers associated with therapeutic response in patients with CF. Identification of related biological pathways could also help to elucidate the mode of action of these drugs.
Targeting complement C3a receptor resolves mitochondrial hyperfusion and subretinal microglial activation in progranulin-deficient frontotemporal dementia
Authors: Tan Li Xuan , Oertel Frederike Cosima , Cheng An , Cobigo Yann , Keihani Azeen , Bennett Daniel J , Abdelhak Ahmed , Montes Shivany Condor , Chapman Makenna , Chen Robert Y , Cordano Christian , Ward Michael E. , Casaletto Kaitlin , Kramer Joel H. , Rosen Howard J , Boxer Adam , Miller Bruce L , Green Ari J , Elahi Fanny M , Lakkaraju Aparna 
Published: June 2024

SUMMARYMutations in progranulin (GRN) cause frontotemporal dementia (GRN-FTD) due to deficiency of the pleiotropic protein progranulin.GRN-FTD exhibits diverse pathologies including lysosome dysfunction, lipofuscinosis, microgliosis, and neuroinflammation. Yet, how progranulin loss causes disease remains unresolved. Here, we report that non-invasive retinal imaging ofGRN-FTD patients revealed deficits in photoreceptors and the retinal pigment epithelium (RPE) that correlate with cognitive decline. Likewise,Grn−/−mice exhibit early RPE dysfunction, microglial activation, and subsequent photoreceptor loss. Super-resolution live imaging and transcriptomic analyses identified RPE mitochondria as an early driver of retinal dysfunction. Loss of mitochondrial fission protein 1 (MTFP1) inGrn−/−RPE causes mitochondrial hyperfusion and bioenergetic defects, leading to NF-kB-mediated activation of complement C3a-C3a receptor signaling, which drives further mitochondrial hyperfusion and retinal inflammation. C3aR antagonism restores RPE mitochondrial integrity and limits subretinal microglial activation. Our study identifies a previously unrecognized mechanism by which progranulin modulates mitochondrial integrity and complement-mediated neuroinflammation.
The Emergence of Non-Linear Evolutionary Trade-offs and the Maintenance of Genetic Polymorphisms
Authors: Hulse Samuel V. , Bruns Emily L. 
Published: June 2024

AbstractEvolutionary models of quantitative traits often assume trade-offs between beneficial and detrimental traits, requiring modelers to specify a function linking costs to benefits. The choice of trade-off function is often consequential; functions that assume diminishing returns (accelerating costs) typically lead to single equilibrium genotypes, while decelerating costs often lead to evolutionary branching. Despite their importance, we still lack a strong theoretical foundation to base the choice of trade-off function. To address this gap, we explore how trade-off functions can emerge from the genetic architecture of a quantitative trait. We developed a multi-locus model of disease resistance, assuming each locus had random antagonistic pleiotropic effects on resistance and fecundity. We used this model to generate genotype landscapes and explored how additive versus epistatic genetic architectures influenced the shape of the trade-off function. Regardless of epistasis, our model consistently led to accelerating costs. We then used our genotype landscapes to build an evolutionary model of disease resistance. Unlike other models with accelerating costs, our approach often led to genetic polymorphisms at equilibrium. Our results suggest that accelerating costs are a strong null model for evolutionary trade-offs and that the eco-evolutionary conditions required for polymorphism may be more nuanced than previously believed.
D-Serine inhibits non-ionotropic NMDA receptor signaling
Authors: Barragan Eden V. , Anisimova Margarita , Vijayakumar Vishnu , Coblentz Azariah C. , Park Deborah K. , Salaka Raghava Jagadeesh , Nisan Atheer F.K. , Petshow Samuel , Dore Kim , Zito Karen , Gray John A. 
Published: June 2024

AbstractNMDA-type glutamate receptors (NMDARs) are widely recognized as master regulators of synaptic plasticity, most notably for driving long-term changes in synapse size and strength that support learning. NMDARs are unique among neurotransmitter receptors in that they require binding of both neurotransmitter (glutamate) and co-agonist (e.g.d-serine) to open the receptor channel, which leads to the influx of calcium ions that drive synaptic plasticity. Over the past decade, evidence has accumulated that NMDARs also support synaptic plasticity via ion flux-independent (non-ionotropic) signaling upon the binding of glutamate in the absence of co-agonist, although conflicting results have led to significant controversy. Here, we hypothesized that a major source of contradictory results can be attributed to variable occupancy of the co-agonist binding site under different experimental conditions. To test this hypothesis, we manipulated co-agonist availability in acute hippocampal slices from mice of both sexes. We found that enzymatic scavenging of endogenous co-agonists enhanced the magnitude of LTD induced by non-ionotropic NMDAR signaling in the presence of the NMDAR pore blocker, MK801. Conversely, a saturating concentration ofd-serine completely inhibited both LTD and spine shrinkage induced by glutamate binding in the presence of MK801. Using a FRET-based assay in cultured neurons, we further found thatd-serine completely blocked NMDA-induced conformational movements of the GluN1 cytoplasmic domains in the presence of MK801. Our results support a model in whichd-serine inhibits ion flux-independent NMDAR signaling and plasticity, and thusd-serine availability could serve to modulate NMDAR signaling even when the NMDAR is blocked by magnesium.Significance StatementNMDARs are glutamate-gated cation channels that are key regulators of neurodevelopment and synaptic plasticity and unique in their requirement for binding of a co-agonist (e.g.d-serine) in order for the channel to open. NMDARs have been found to drive synaptic plasticity via non-ionotropic (ion flux-independent) signaling upon the binding of glutamate in the absence of co-agonist, though conflicting results have led to controversy. Here, we found thatd-serine inhibits non-ionotropic NMDAR-mediated LTD and LTD-associated spine shrinkage. Thus, a major source of the contradictory findings might be attributed to experimental variability ind-serine availability. In addition, the developmental regulation ofd-serine levels suggests a role for non-ionotropic NMDAR plasticity during critical periods of plasticity.
Optical Torque Calculations and Measurements for DNA Torsional Studies
Authors: Hong Yifeng , Ye Fan , Qian Jin , Gao Xiang , Inman James T. , Wang Michelle D. 
Published: June 2024

ABSTRACTThe angular optical trap (AOT) is a powerful instrument for measuring the torsional and rotational properties of a biological molecule. Thus far, AOT studies of DNA torsional mechanics have been carried out using a high numerical aperture oil-immersion objective, which permits strong trapping, but inevitably introduces spherical aberrations due to the glass-aqueous interface. However, the impact of these aberrations on torque measurements is not fully understood experimentally, partly due to a lack of theoretical guidance. Here, we present a numerical platform based on the finite element method to calculate forces and torques on a trapped quartz cylinder. We have also developed a new experimental method to accurately determine the shift in the trapping position due to the spherical aberrations by using a DNA molecule as a distance ruler. We found that the calculated and measured focal shift ratios are in good agreement. We further determined how the angular trap stiffness depends on the trap height and the cylinder displacement from the trap center and found full agreement between predictions and measurements. As further verification of the methodology, we showed that DNA torsional properties, which are intrinsic to DNA, could be determined robustly under different trap heights and cylinder displacements. Thus, this work has laid both a theoretical and experimental framework that can be readily extended to investigate the trapping forces and torques exerted on particles with arbitrary shapes and optical properties.SIGNIFICANCEWe developed a simulation platform based on the finite element method for force and torque calculation for particles in an angular optical trap (AOT), with considerations of tightly focused Gaussian beam, spherical aberrations, and optically anisotropic particles. Experimental measurements of focal shift ratio, force, and torque under multiple conditions were in good agreement with predictions from the simulations. We also demonstrated that intrinsic DNA torsional properties can be robustly measured under different AOT measurement conditions, strongly validating our simulations and calibrations. Our platform can facilitate trapping particle design for single-molecule assays using the AOT.
Behavioral impairments are linked to neuroinflammation in mice with Cerebral Cavernous Malformation disease
Authors: Offenberger Joseph , Chen Bianca , Rossitto Leigh-Ana , Jin Irisa , Conaboy Liam , Gallego-Gutierrez Helios , Nelsen Bliss , Frias-Anaya Eduardo , Gonzalez David J. , Anagnostaras Stephan , Lopez-Ramirez Miguel Alejandro 
Published: June 2024

AbstractBackgroundCerebral Cavernous Malformations (CCMs) are neurovascular abnormalities in the central nervous system (CNS) caused by loss of function mutations in KRIT1 (CCM1), CCM2, or PDCD10 (CCM3) genes. One of the most common symptoms in CCM patients is associated with motor disability, weakness, seizures, stress, and anxiety, and the extent of the symptom or symptoms may be due to the location of the lesion within the CNS or whether multiple lesions are present. Previous studies have primarily focused on understanding the pathology of CCM using animal models. However, more research has yet to explore the potential impact of CCM lesions on behavioral deficits in animal models, including effects on short-term and long-term memory, motor coordination, and function.MethodsWe used the accelerating RotaRod test to assess motor and coordination deficits. We also used the open field test to assess locomotor activity and pathology-related behavior and Pavlovian fear conditioning to assess short—and long-term memory deficits. Our behavioral studies were complemented by proteomics, histology, immunofluorescence, and imaging techniques. We found that neuroinflammation is crucial in behavioral deficits in male and female mice with neurovascular CCM lesions (Slco1c1-iCreERT2; Pdcd10fl/fl; Pdcd10BECKO).ResultsFunctional behavior tests in male and femalePdcd10BECKOmice revealed that CCM lesions cause sudden motor coordination deficits associated with the manifestation of profound neuroinflammatory lesions. Our findings indicate that maturation of CCM lesions inPdcd10BECKOmice also experienced a significant change in short- and long-term memory compared to their littermate controls,Pdcd10fl/flmice. Proteomic experiments reveal that as CCM lesions mature, there is an increase in pathways associated with inflammation, coagulation, and angiogenesis, and a decrease in pathways associated with learning and plasticity. Therefore, our study shows thatPdcd10BECKOmice display a wide range of behavioral deficits due to significant lesion formation in their central nervous system and that signaling pathways associated with neuroinflammation and learning impact behavioral outcomes.ConclusionsOur study found that CCM animal models exhibited behavioral impairments such as decreased motor coordination and amnesia. These impairments were associated with the maturation of CCM lesions that displayed a neuroinflammatory pattern.