bluuebunny/crossref_metadata_2025_split huggingface dataset:
Data acquisition strategies to reduce cardiac-induced noise in brain maps of R2* and magnetic susceptibility
Authors: Raynaud Quentin , Dardano Thomas , Oliveira Rita , Di Domenicantonio Giulia , Kober Tobias , Roy Christopher W. , van Heeswijk Ruud B. , Lutti Antoine 
Published: August 2024

AbstractPurposeCardiac pulsation increases the noise level in brain MR images. Maps of the transverse relaxation rate R2* and magnetic susceptibility (QSM) are particularly affected by cardiac-induced noise as they are computed from gradient-echo data acquired at multiple echo times. Here, we introduce two data acquisition strategies to mitigate the impact of cardiac-induced noise in brain maps of R2* and QSM.MethodsThe proposed strategies are based on the higher level of cardiac-induced noise near the k-space centre. Using a pseudo-spiral sampling trajectory, the first strategy allows for the acquisition of a specific number of averages at each k-space location, set from the local level of cardiac-induced noise. The second strategy synchronizes the acquisition with the cardiac cycle in real time. We compared in 10 healthy volunteers, the variability of data acquired across 4 repetitions and in the same session, using both strategies and with a standard linear trajectory.ResultsCompared to linear sampling, the pseudo-spiral trajectory reduced the variability of R2* and QSM maps across repetitions by 26/28/22% and 19/18/16% in the brainstem/cerebellum/whole brain, for a 14% increase in scan time. The pseudo-spiral sampling also reduced the level of aliasing artifacts from pulsating blood vessels. The cardiac-triggered trajectory did not reduce the variability of R2* or QSM maps.ConclusionPseudo-spiral k-space trajectories can be designed to mitigate cardiac-induced noise in brain maps of the MRI parameters R2* and QSM. Synchronization of the acquisition with the cardiac cycle in real time did not lead to any reduction in cardiac-induced noise.
Evidence for belief updating in decision-variable space: past decisions with finer granularity attract future ones more strongly
Authors: Lee Heeseung , Lim Jaeseob , Lee Sang-Hun 
Published: August 2024

AbstractEssential to adaptive intelligence is the ability to create mental spaces where knowledge from past experiences cumulates and integrates with newly acquired information. When engaged in decision-making tasks, humans are known to create such a space and therein form decision variables, which integrate task-essential information from multiple sources in a generalizable form. Much effort has focused on the cognitive and neural processes involved in forming decision variables. However, there is limited understanding of how decision variables, once formed, are utilized to adapt to the environment. Considering the abstract and generalizable nature of decision variables, we reason that decision-makers would benefit from shaping and updating probabilistic knowledge—known asbelief—within the decision-variable space. As one such belief updating, we hypothesize that an act of decision commitment restricts the current belief about the decision variable to a range of states corresponding to that decision. This implies that past decisions not only attract future ones but also exert a greater pull when those decisions are made with finer granularity—dubbed ‘the granularity effect.’ Here, we present the findings of seven psychophysical experiments that consistently confirm these implications while ruling out the stimulus and action space as potential loci of the granularity effect. Further, as a principled and unified account of the granularity effect and other history effects found in various perceptual tasks, we offer a Bayesian model where beliefs are updated separately in the stimulus and decision-variable spaces. Our work demonstrates how humans leverage the abstract and generalizable nature of the decision-variable space to effectively adapt to their surroundings, expanding the gamut of human intellect.
Angiotensin Converting Enzyme Hub Model of Peptide Flux Relating Calculated AT1 Receptor and Aldosterone Levels
Authors: Westwood Brian M. , Chappell Mark C. 
Published: August 2024

ABSTRACTUtilizing data from the Vitamin C, Thiamine, and Steroids in Sepsis (VICTAS) Trial, this hub model was developed to limit seventeen Renin-Angiotensin-Aldosterone System (RAAS) components as three entrance and four exits, to facilitate the calculation of a model as one egress unknown, the angiotensin type 1 (AT1) receptor. Following previous evidence relating renin levels to mortality, this study found controls were more like sepsis patients with levels < renin quartile 1 (Q1) for calculated AT1, while more like sepsis patients with renin levels > quartile 3 (Q4) for measured aldosterone levels. Additionally differential discrete correlate summation (DCS) analysis indicates AT1, aldosterone and renin as major hub nodes in this independent DCS model of metabolic data inputs.
Extracellular Vesicle-Associated Neutrophil Elastase Activates Hepatic Stellate Cells and Promotes Liver Fibrogenesis via ERK1/2 Pathway
Authors: Oshins Regina , Greenberg Zachary , Tai Yun-Ling , Zhao Derrick , Wang Xuan , Mehrad Borna , He Mei , Patel Ishan , Khartabil Laith , Zhou Huiping , Brantly Mark , Khodayari Nazli 
Published: August 2024

AbstractLiver fibrosis associated with increased mortality is caused by activation of hepatic stellate cells and excessive production and accumulation of extracellular matrix in response to fibrotic insults. It has been shown that in addition to liver inflammation, systemic inflammation also contributes to liver fibrogenesis. A deeper understanding of mechanisms that control liver fibrotic response to intra- and extra-hepatic inflammation is essential to develop novel clinical strategies against this disease. Extracellular vesicles (EV) have been recognized as immune mediators that facilitate activation of hepatic stellate cells. In inflammatory diseases, activated neutrophils release neutrophil elastase (NE) bound to EV, which has been identified as a significant contributor to inflammation by promoting immune cell activation. Here, we aimed to explore the role of inflammation derived plasma EV-associated NE in liver fibrogenesis and its potential mechanisms. We show EV-associated NE induces activation, proliferation and migration of hepatic stellate cells by promoting activation of the ERK1/2 signaling pathway. This effect did not occur through EV without surface NE, and Sivelestat, a NE inhibitor, inhibited activation of the ERK1/2 signaling pathway mediated by EV-associated NE. Moreover, we found plasma EV-associated NE increases deposition of collagen1 and α-smooth muscle actin in the liver of a mouse model of liver fibrosis (Mdr2-/-). Notably, this effect does not occur in control mice without preexisting liver disease. These data suggest that EV-associated NE is a pro-fibrogenic factor for hepatic stellate cell activation via the ERK1/2 signaling pathway in pre-existing liver injuries. Inhibition of the plasma EV-associated NE in inflammatory conditions may be a therapeutic target for liver fibrosis in patients with inflammatory diseases.
Protein stability models fail to capture epistatic interactions of double point mutations
Authors: Dieckhaus Henry , Kuhlman Brian 
Published: August 2024

AbstractThere is strong interest in accurate methods for predicting changes in protein stability resulting from amino acid mutations to the protein sequence. Recombinant proteins must often be stabilized to be used as therapeutics or reagents, and destabilizing mutations are implicated in a variety of diseases. Due to increased data availability and improved modeling techniques, recent studies have shown advancements in predicting changes in protein stability when a single point mutation is made. Less focus has been directed toward predicting changes in protein stability when there are two or more mutations, despite the significance of mutation clusters for disease pathways and protein design studies. Here, we analyze the largest available dataset of double point mutation stability and benchmark several widely used protein stability models on this and other datasets. We identify a blind spot in how predictors are typically evaluated on multiple mutations, finding that, contrary to assumptions in the field, current stability models are unable to consistently capture epistatic interactions between double mutations. We observe one notable deviation from this trend, which is that epistasis-aware models provide marginally better predictions on stabilizing double point mutations. We develop an extension of the ThermoMPNN framework for double mutant modeling as well as a novel data augmentation scheme which mitigates some of the limitations in available datasets. Collectively, our findings indicate that current protein stability models fail to capture the nuanced epistatic interactions between concurrent mutations due to several factors, including training dataset limitations and insufficient model sensitivity.SignificanceProtein stability is governed in part by epistatic interactions between energetically coupled residues. Prediction of these couplings represents the next frontier in protein stability modeling. In this work, we benchmark protein stability models on a large dataset of double point mutations and identify previously overlooked limitations in model design and evaluation. We also introduce several new strategies to improve modeling of epistatic couplings between protein point mutations.
Fecal microbiota transplantation promotes immunotherapy sensitivity in refractory gastrointestinal cancer patients: open label, single-arm, single center, phase 1 study
Authors: Zhang Yifan , Xu Xiaomin , Wang Shulin , Yin Xiaochen , Zhang Bohan , Zhu Zhengnong , Ji Rujie , Zhu Jing , He Hermione , Cheng Siyuan , Han Zihan , Xie Tong , Zhang Xiaotian , Wang Yakun , Shen Si , Kou Yan , Bao Siyu , Liu Yingyu , Cao Baoran , Bonny Christophe , Segal Eran , Tan Yan , Shen Lin , Peng Zhi 
Published: August 2024

AbstractBackgroundThe discovery and therapeutic application of immune checkpoint inhibitors (ICIs) has significantly improved clinical outcomes in cancer treatment. However, the response rate is still low in gastrointestinal (GI) cancers. The gut microbiome’s impact on immune modulation is a promising area for enhancing ICI efficacy.MethodsThis study (NCT04130763) is an open label, single-arm, single center, phase 1 study assessing the safety and efficacy of fecal microbiota transplantation (FMT) from healthy donors in ten advanced GI cancer patients resistant to anti-PD-(L)1 treatment. Patients received initial FMT treatment via oral capsules, followed by a combination therapy phase, where maintenance FMT was paired with nivolumab at 3mg/kg every two weeks for six cycles. Serial biomarker assessments were conducted through both fecal and blood sampling.FindingsThe combination of FMT and anti-PD1 treatment was well tolerated with no serious adverse reactions observed among all 10 patients. The objective response rate was 20% and the disease control rate was 40%. The progression-free survival of these two responders were 15 and more than 19 months respectively. Clinical benefits were associated with colonization of donor-derived immunogenic microbes, and an activated immune status reflected by peripheral immune cell populations. Responder-enriched microbes interacted closely as a butyrate-functional guild, while non-responder-enriched microbes interacted sparsely and had higher fraction of oral-originated microbes. Donor-specific microbial traits that influence clinical efficacy of FMT were validated in an independent cohort.InterpretationThe current study demonstrates the feasibility of FMT for ICI-refractory GI cancer patients and provides a foundation for live biotherapeutic product (LBP) development to enhance ICI efficacy.
Capacity and limitations of microfluidic flow to increase solute transport in three-dimensional cell cultures
Authors: Bonneuil Willy V. , Katiyar Neeraj , Tenje Maria , Bagheri Shervin 
Published: August 2024

AbstractCulturing living cells in three-dimensional (3D) environments increases the biological relevance of laboratory experiments, but has the caveat of requiring solutes to overcome a diffusion barrier to reach the center of cellular constructs. We present a theoretical and numerical investigation that brings a mechanistic understanding of how microfluidicculture conditions, including chamber size, inlet fluid velocity, and spatial confinement, affect solute distribution within 3D cellular constructs. Contact with the culture chamber reduces the maximally achievable construct radius by 15%. In practice, finite diffusion and convection kinetics in the microfluidic chamber further lower that limit. The benefits of external convection are greater if transport rates across diffusion-dominated areas are high. Those are omnipresent and include the diffusive boundary layer growing from the fluid-construct interface and regions near corners where fluid is recirculating. Less convection is required to approach an ideal maximally-supplied state when diffusion within the constructs is slow. Our results contribute to defining the conditions where complete solute transport into an avascular 3D cell construct is achievable and demonstrate how flow velocity must evolve with construct radius in order to maintain a given solute penetration depth.
Tumor suppressor p53 controls thymic NKT17 development
Authors: Celli Sofia , Watanabe Masashi , Hodes Richard J. 
Published: August 2024

ABSTRACTThe tumor suppressor p53 antagonizes tumorigenesis, notably including the suppression of T cell lymphomas while its role on physiological T cell biology including thymic T cell development has not been fully understood. Invariant natural killer T (iNKT) cells develop in the thymus as innate-like αβ-T cells which consist of NKT1, NKT2 and NKT17 subsets. We found that the tumor suppressor p53 regulates specifically thymic NKT17 development. p53 is highly expressed in NKT17 relative to other T cell populations. Loss of p53 in the T cell lineage resulted in increased thymic NKT17 cell number with retention of lineage specific cytokine production, while development of NKT1, NKT2 and conventional T cells was not affected. Of interest, γH2AX expression was higher in NKT17 than NKT1 and NKT2 at steady state, and it was further increased in p53-deficient NKT17, suggesting that NKT17 development involves selectively greater DNA damage or genomic instability and that p53 expression might be in response to these damage signals. Taken together, our results indicated that the tumor suppressor p53 is active in selectively controlling thymic NKT17 development, with absence of p53 leading to an increase in thymic NKT17 cells expressing high levels of DNA damage response.
Functional imaging and connectome analyses reveal organizing principles of taste circuits inDrosophila
Authors: Li Jinfang , Dhaliwal Rabiah , Stanley Molly , Junca Pierre , Gordon Michael D. 
Published: August 2024

AbstractTaste is crucial for many innate and learned behaviors. In the fly, taste impacts feeding, oviposition, locomotion, mating, and memory formation, to name a few. These diverse roles may necessitate the apparent distributed nature of taste responses across different circuits in the fly brain, leading to complexity that has hindered attempts to deduce unifying principles of taste processing and coding. Here, we combine information from the whole brain connectome with functional calcium imaging to examine the neural representation of taste at early steps of processing. We find that the representation of taste quality remains largely segregated in cholinergic and GABAergic local interneurons (LNs) that are directly postsynaptic to taste sensory neurons of the labellum. Although some taste projection neurons (TPNs) projecting to superior protocerebrum receive direct inputs from sensory neurons, many receive primarily indirect taste inputs via cholinergic LNs. Moreover, we found that cholinergic interneurons appear to function as nodes to convey feedforward information to dedicated sets of morphologically similar TPNs. Examining a small number of representative TPNs suggests that taste information remains mostly segregated at this level as well. Together, these studies suggest a previously unappreciated logic in the organization of fly taste circuits.
TAF1-dependent transcriptional dysregulation underlies multiple sclerosis
Authors: Rodríguez-López Claudia , Hernández Ivó H. , Terrón-Bautista José , Agirre Eneritz , Lozano-Muñoz David , Pose-Utrilla Julia , García-Ortiz Inés , Lucas-Santamaría Miriam , Ruiz-Blas Irene , González-Bermejo María , Ortega María C. , Chara Juan C. , Martínez Zara , Pérez-Cerdá Fernando , Fransen Nina L. , Martínez-Jiménez Miriam , Sancho-González Beatriz , Pérez-Samartín Alberto , Kabbe Mukund , Zheng Chao , Casado-Barbero Marcos , Santos-Galindo María , Borroto Aldo , Alarcón Balbino , Clemente Diego , Toma Claudio , Matute Carlos , Cortés-Ledesma Felipe , Castelo-Branco Gonçalo , Lucas José J. 
Published: August 2024

AbstractMultiple sclerosis (MS) is characterized by neuroinflammation and demyelination of the central nervous system (CNS), leading to disablility1, 2. Genetic variants that confer MS risk implicate genes involved in immune function3, while variants related to severity of the disease are associated with genes preferentially expressed within the CNS4. Current MS therapies decrease relapse rates by preventing immune-mediated damage of myelin, but they ultimately fail to slow long-term disease progression, which apparently depends on CNS intrinsic processes. The molecular events that trigger progressive MS are still unknown. Here we report that the C-terminal region of TAF1 (the scaffolding subunit of the general transcription factor TFIID) is underrepresented in postmortem brain tissue from individuals with MS. Furthermore, we demonstratein vivo,in genetically modified mice, that C-terminal alteration of TAF1 suffices to induce an RNA polymerase II (RNAPII)-elongation deficit that particularly affects oligodendroglial myelination-related genes and results in an MS-like brain transcriptomic signature, including increased expression of proinflammatory genes. This transcriptional profile is accompanied by CNS-resident inflammation, robust demyelination and MS-like motor phenotypes. We also identify numerous interactors of C-terminal TAF1 that participate in RNAPII-promoter escape, of which two show evidence for genetic association to MS3, 4. Our study reveals that TAF1 dysfunction converges with genetic susceptibility to cause transcriptional dysregulation in CNS cell types, such as oligodendrocytes, to ultimately trigger MS.
Using dynamic ultrasound to assess Achilles tendon mechanics during running: the effect on running pattern and muscle-tendon junction tracking
Authors: Schallig Wouter , Sloot Ytjanda , van der Schaaf Milou M. , Bus Sicco A. 
Published: August 2024

ABSTRACTAchilles tendon strain can be quantified using dynamic ultrasound, but its use in running is limited. Minimal effects on running pattern and acceptable test-retest reliability of muscle-tendon junction (MTJ) tracking are prerequisites for ultrasound use during running. We aimed to assess (i) the effect of wearing an ultrasound transducer on running pattern and (ii) the test-retest reliability of MTJ tracking during running. Sixteen long-distance runners (nine injury-free, seven with Achilles tendinopathy) ran at different speeds on an instrumented treadmill with a 10-camera system tracking skin-mounted retroreflective markers, first without and then with an ultrasound transducer attached to the lower leg to track the MTJ of the gastrocnemius medialis. Spatiotemporal parameters, joint kinematics and kinetics were compared between conditions using mixed ANOVAs and paired t-tests. MTJ tracking was performed manually twice by three raters in ten participants. Variability and standard error of measurement (SEM) quantified the inter- and intra-tester test-retest reliability. The running pattern was not affected by wearing the ultrasound transducer, except for significantly less knee flexion during midstance (1.6°) and midswing (2.9°) found when wearing the transducer. Inter-rater and intra-rater SEMs for MTJ tracking to assess the tendon strain (0.43%, and 0.56%, respectively) were about four times as low as between-group differences presented in literature. The minimal effects found on the running pattern and acceptable test-retest reliability indicates that dynamic ultrasound during running can be appropriately used to study Achilles tendon mechanics and thereby help improve our understanding of Achilles tendon behavior during running, injury development and recovery.
Dynamic alterations of dural and bone marrow B cells in an animal model of progressive multiple sclerosis
Authors: Florescu Alexandra , Zuo Michelle , Wang Angela A. , Champagne-Jorgensen Kevin , Noor Mohammed Ariyan , Ward Lesley A. , van Puijenbroek Erwin , Klein Christian , Gommerman Jennifer L. 
Published: August 2024

AbstractIn multiple sclerosis (MS), the leptomeninges (LM) are populated with immune cell aggregates that correlate with disease progression. The impact of LM inflammation on the adjacent dura is largely unknown. Using a mouse model of MS that induces brain LM inflammation and age-dependent disease progression, we found that encephalitogenic T cells and B220highB cells accumulate substantially in the brain LM and parenchyma of both young and aged mice, while the adjacent dura remains relatively inert. We also observed a population of anti-CD20 resistant B220lowB cells in the dura and bone marrow that virtually disappear at disease onset and accumulate in the brain of young mice concomitant with disease remission. In contrast, aged mice show a paucity of brain-resident B220lowB cells at the expense of class-switched B220highB cells concomitant with severe, chronic disease. In summary, dynamic changes in brain, LM and dural B cells are associated with age-dependent disease severity in an animal model of progressive MS.Short SummaryFlorescuet al. investigate the temporal accumulation of immune cells within distinct meningeal compartments in an animal model of progressive MS and uncover a population of anti-CD20 resistant dural B cells that remain in the brain parenchyma at disease remission.
Ecosystem stability relies on diversity difference between trophic levels
Authors: Liu Yizhou , Hu Jiliang , Gore Jeff 
Published: August 2024

AbstractThe stability of ecological communities has a profound impact on humans, ranging from individual health influenced by the microbiome to ecosystem services provided by fisheries. A long-standing goal of ecology is the elucidation of the interplay between biodiversity and ecosystem stability, with some ecologists warning of instability due to loss of species diversity while others arguing that greater diversity will instead lead to instability. Here, by considering a minimal two-level ecosystem with multiple predator and prey species, we show that stability does not depend on absolute diversity but rather on diversity differences between levels. We discovered that increasing diversity in either level first destabilizes but then stabilizes the community (i.e., a re-entrant stability transition). We therefore find that it is the diversity difference between levels that is the key to stability, with the least stable communities having similar diversities in different levels. An analytical stability criterion is derived, demonstrating quantitatively that the critical diversity difference is determined by the correlation between how one level affects another and how it is affected in turn. Our stability criterion also applies to consumer-resource models with other forms of interaction such as cross-feeding. Finally, we show that stability depends on diversity differences in ecosystems with three trophic levels. Our finding of a non-monotonic dependence of stability on diversity provides a natural explanation for the variety of diversity-stability relationships reported in the literature, and emphasizes the significance of level structure in predicting complex community behaviors.