bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mode-based morphometry: A multiscale approach to mapping human neuroanatomy
Authors: Cao Trang , Pang James C. , Segal Ashlea , Chen Yu-Chi , Aquino Kevin M. , Breakspear Michael , Fornito Alex 
Published: February 2023

AbstractVoxel-based morphometry (VBM) and surface-based morphometry (SBM) are two widely used neuroimaging techniques for investigating brain anatomy. These techniques rely on statistical inferences at individual points (voxels or vertices), clusters of points, or a priori regions-of-interest. They are powerful tools for describing brain anatomy, but offer little insights into the generative processes that shape a particular set of findings. Moreover, they are restricted to a single spatial resolution scale, precluding the opportunity to distinguish anatomical variations that are expressed across multiple scales. Drawing on concepts from classical physics, here we develop an approach, called mode-based morphometry (MBM), that can describe any empirical map of anatomical variations in terms of the fundamental, resonant modes––eigenmodes––of brain anatomy, each tied to a specific spatial scale. Hence, MBM naturally yields a multiscale characterization of the empirical map, affording new opportunities for investigating the spatial frequency content of neuroanatomical variability. Using simulated and empirical data, we show that the validity and reliability of MBM are either comparable or superior to classical vertex-based SBM for capturing differences in cortical thickness maps between two experimental groups. Our approach thus offers a robust, accurate, and informative method for characterizing empirical maps of neuroanatomical variability that can be directly linked to a generative physical process.
Multiscale Multimodal Characterization and Simulation of Structural Alterations in Failed Bioprosthetic Heart Valves
Authors: Tsolaki Elena , Corso Pascal , Zboray Robert , Avaro Jonathan , Appel Christian , Liebi Marianne , Bertazzo Sergio , Heinisch Paul Philipp , Carrel Thierry , Obrist Dominik , Herrmann Inge K. 
Published: February 2023

AbstractCalcific degeneration is the most frequent type of heart valve failure, with rising incidence due to the ageing population. The gold standard treatment to date is valve replacement. Unfortunately, calcification oftentimes re-occurs in bioprosthetic substitutes, with the governing processes remaining poorly understood. Here, we present a multiscale, multimodal analysis of disturbances and extensive mineralisation of the collagen network in failed bioprosthetic bovine pericardium valve explants with full histoanatomical context. In addition to highly abundant mineralized collagen fibres and fibrils, calcified micron-sized particles previously discovered in native valves were also prevalent on the aortic as well as the ventricular surface of bioprosthetic valves. The two mineral types (fibers and particles) were detectable even in early-stage mineralisation, prior to any macroscopic calcification. Based on multiscale multimodal characterisation and high-fidelity simulations, we demonstrate that mineral occurrence coincides with regions exposed to high haemodynamic and biomechanical indicators. These insights obtained by multiscale analysis of failed bioprosthetic valves may serve as groundwork for the evidence-based development of more durable alternatives.Graphical Abstract
Network-Level Changes in the Brain Underlie Fear Memory Strength
Authors: Haubrich Josue , Nader Karim 
Published: February 2023

AbstractThe strength of a fear memory significantly influences whether it drives adaptive or maladaptive behavior in the future. Yet, how mild and strong fear memories differ in underlying biology is not well understood. We hypothesized that this distinction may not be exclusively the result of changes within specific brain regions, but rather the outcome of collective changes in connectivity across multiple regions within the neural network. To test this, rats were fear conditioned in protocols of varying intensities to generate mild or strong memories. Neuronal activation driven by recall was measured using c-fos immunohistochemistry in 12 brain regions implicated in fear learning and memory. The interregional coordinated brain activity was computed and graph-based functional networks were generated to compare how mild and strong fear memories differ at the systems level. Our results show that mild fear recall is supported by a well-connected brain network with small-world properties in which the amygdala is well-positioned to be modulated by other regions. In contrast, this connectivity is disrupted in strong fear memories and the amygdala is isolated from other regions. These findings indicate that the neural systems underlying mild and strong fear memories differ, with implications for understanding and treating disorders of fear dysregulation.
2019-20 H1N1 clade A5a.1 viruses have betterin vitroreplication compared with the co-circulating A5a.2 clade
Authors: Swanson Nicholas J , Marinho Paula , Dziedzic Amanda , Jedlicka Anne , Liu Hsuan , Fenstermacher Katherine , Rothman Richard , Pekosz Andrew 
Published: February 2023

AbstractSurveillance for emerging human influenza virus clades is important for identifying changes in viral fitness and assessing antigenic similarity to vaccine strains. While fitness and antigenic structure are both important aspects of virus success, they are distinct characteristics and do not always change in a complementary manner. The 2019-20 Northern Hemisphere influenza season saw the emergence of two H1N1 clades: A5a.1 and A5a.2. While several studies indicated that A5a.2 showed similar or even increased antigenic drift compared with A5a.1, the A5a.1 clade was still the predominant circulating clade that season. Clinical isolates of representative viruses from these clades were collected in Baltimore, Maryland during the 2019-20 season and multiple assays were performed to compare both antigenic drift and viral fitness between clades. Neutralization assays performed on serum from healthcare workers pre- and post-vaccination during the 2019-20 season show a comparable drop in neutralizing titers against both A5a.1 and A5a.2 viruses compared with the vaccine strain, indicating that A5a.1 did not have antigenic advantages over A5a.2 that would explain its predominance in this population. Plaque assays were performed to investigate fitness differences, and the A5a.2 virus produced significantly smaller plaques compared with viruses from A5a.1 or the parental A5a clade. To assess viral replication, low MOI growth curves were performed on both MDCK-SIAT and primary differentiated human nasal epithelial cell cultures. In both cell cultures, A5a.2 yielded significantly reduced viral titers at multiple timepoints post-infection compared with A5a.1 or A5a. Receptor binding was then investigated through glycan array experiments which showed a reduction in receptor binding diversity for A5a.2, with fewer glycans bound and a higher percentage of total binding attributable to the top three highest bound glycans. Together these data indicate that the A5a.2 clade had a reduction in viral fitness, including reductions in receptor binding, that may have contributed to the limited prevalence observed after emergence.
Improving retinal vascular endothelial cell tropism through rational rAAV capsid design
Authors: Periasamy Ramesh , Patel Dwani D. , Boye Sanford L. , Boye Shannon E. , Lipinski Daniel M. 
Published: February 2023

AbstractVascular endothelial cells (VEC) are essential for retinal homeostasis and their dysfunction underlies pathogenesis in diabetic retinopathy (DR) and exudative age-related macular degeneration (AMD). Studies have shown that recombinant adeno-associated virus (rAAV) vectors are effective at delivering new genetic material to neural and glial cells within the retina, but targeting VECs remains challenging. To overcome this limitation, herein we developed rAAV capsid mutant vectors with improved tropism towards retinal VEC. rAAV2/2, 2/2[QuadYF-TV], and rAAV2/9 serotype vectors (n=9, capsid mutants per serotype) expressing GFP were generated by inserting heptameric peptides (7AA) designed to increase endothelial targeting at positions 588 (2/2 and 2/2[QuadYF-TV] or 589 (2/9) of the virus protein (VP 1-3). The packaging and transduction efficiency of the vectors were assessed in HEK293T and bovine VECs using Fluorescence microscopy and flow cytometry, leading to the identification of one mutant, termed EC5, that showed improved endothelial tropism when inserted into all three capsid serotypes. Intra-ocular and intravenous administration of EC5 mutants in C57Bl/6j mice demonstrated moderately improved transduction of the retinal vasculature, particularly surrounding the optic nerve head, and evidence of sinusoidal endothelial cell transduction in the liver. Most notably, intravenous administration of the rAAV2/2[QuadYF-TV] EC5 mutant led to a dramatic and unexpected increase in cardiac muscle transduction.
Coordinated growth of linked epithelia is mediated by the Hippo pathway
Authors: Friesen Sophia , Hariharan Iswar K. 
Published: February 2023

AbstractAn epithelium in a living organism seldom develops in isolation. Rather, most epithelia are tethered to other epithelial or non-epithelial tissues, necessitating growth coordination between layers. We investigated how two tethered epithelial layers of theDrosophilalarval wing imaginal disc, the disc proper (DP) and the peripodial epithelium (PE), coordinate their growth. DP growth is driven by the morphogens Hedgehog (Hh) and Dpp, but regulation of PE growth is poorly understood. We find that the PE adapts to changes in growth rates of the DP, but not vice versa, suggesting a “leader and follower” mechanism. Moreover, PE growth can occur by cell shape changes, even when proliferation is inhibited. While Hh and Dpp pattern gene expression in both layers, growth of the DP is exquisitely sensitive to Dpp levels, while growth of the PE is not; the PE can achieve an appropriate size even when Dpp signaling is inhibited. Instead, both the growth of the PE and its accompanying cell shape changes require the activity of two components of the mechanosensitive Hippo pathway, the DNA-binding protein Scalloped (Sd) and its co-activator (Yki), which could allow the PE to sense and respond to forces generated by DP growth. Thus, an increased reliance on mechanically-dependent growth mediated by the Hippo pathway, at the expense of morphogen-dependent growth, enables the PE to evade layer-intrinsic growth control mechanisms and coordinate its growth with the DP. This provides a potential paradigm for growth coordination between different components of a developing organ.
Methodology for inference of intercellular gene interactions
Authors: Modi Saurabh , Zurakowski Ryan , Gleghorn Jason P. 
Published: February 2023

AbstractTo govern organ size, shape, and function, cell-secreted diffusible molecules called morphogens spatially pattern cell differentiation, gene expression, and proliferation. Local morphogen concentration governs cell differentiation through gene regulatory networks (GRN). Previous inference methodologies tackle intercellular GRN inference between cells of one type. This is insufficient, as many developmental systems consist of cells of different types interacting with each other. Inference methodologies of GRNs between different cell types assume knowledge of diffusible morphogen identity and concentration. This makes their applicability limited in real biological systems. Here, we develop a computational methodology to infer the intercellular GRN derived from experiments that use fluorescence from reporter proteins for gene expression measurements. For validation, we demonstrate the methodologyin silicousing three case studies based on developmental and synthetic biology. The results show that, barring practical identifiability limitations, the methodology successfully infers the intercellular GRNs.
Stochastic bounds of aggregation dynamics distinguish near-wild-type from wild-type strains in social bacteria
Authors: Asp Merrill E. , Caro Eduardo A. , Welch Roy D. , Patteson Alison E. 
Published: February 2023

AbstractThe genotype-to-phenotype problem (G2P) for multicellular development asks how genetic inputs control collective phenotypic outputs. It is a difficult problem even to observe. On the genotype side, the phenotypic impact of mutation is often subtle due at least partly to gene redundancy and myriad other factors. On the phenotype side, biological and even technical developmental replicates can display significant phenotypic variation due at least in part to stochasticity, again with other factors. We attempt to partially resolve the G2P inputs and outputs from the obfuscating effects of factors like redundancy and stochasticity. As a model organism, we selected the biofilm-forming speciesMyxococcus xanthus, a motile self-organizing bacterium that forms three-dimensional cell aggregates that grow and mature into spore-filled fruiting bodies when under starvation stress. We developed data acquisition tools and analysis and visualization methods that can produce a topological map ofM. xanthusdevelopment. We demonstrate that even subtle effects on developmental dynamics caused by mutation can be identified, discriminated, characterized, and given statistical significance.
The Kinase Module of the Mediator regulates cell cycle re-entry and transcriptional response following DNA damage
Authors: Memişoğlu Gönen , Bohn Stefan , Krogan Nevan , Haber James E. , Ruthenburg Alexander J. 
Published: February 2023

ABSTRACTWhen faced with a DNA double strand break, cells activate an elaborate signaling cascade called the DNA damage response to protect genomic integrity. To identify novel factors that modulate the DNA damage response to DNA double strand breaks, we performed an epistatic miniarray profile (E-MAP) analysis of Mec1 and Rad53, two essential kinases that coordinate the DNA damage response in budding yeast. Through this analysis, we discovered a genetic interaction between the kinase module (CKM) of the Mediator of transcription and Rad53. We find that all four subunits of the CKM, as well as CKM’s kinase activity are critical for cell cycle re-entry following a DNA break, whereas the core Mediator subunits are dispensable. Notably, CKM mutants do not impair DNA repair by homologous recombination or confer sensitivity to DNA damaging reagents, suggesting that CKM specifically impinges on DNA damage signaling. In support of this, we find that Rad53 and CKM physically interact in response to DNA damage. Following the induction of a DNA break, CKM is a critical regulator of global transcription inhibition. In addition to this global effect, we illustrate that CKM functions locally at DNA breaks together with the core Mediator. In the absence of catalytically active CKM, the CKM-Mediator complexes at DNA breaks are replaced by RNAPII. Taken together, our results reveal a previously uncharacterized role for CKM in the DNA damage response.
Acetylcholine engages distinct amygdala microcircuits to gate internal theta rhythm
Authors: Bratsch-Prince Joshua X. , Warren James W. , Jones Grace C. , McDonald Alexander J. , Mott David D. 
Published: February 2023

SummaryAcetylcholine (ACh) is released from basal forebrain cholinergic neurons in response to salient stimuli and engages brain states supporting attention and memory. These high ACh states are associated with theta oscillations, which synchronize neuronal ensembles. Theta oscillations in basolateral amygdala (BLA) underlie emotional memory, yet their mechanism remains unclear. Using brain slice electrophysiology in mice, we show large ACh stimuli evoke prolonged theta oscillations in BLA local field potential that depend upon activation of cholecystokinin (CCK) interneurons (INs). Somatostatin (SOM) INs inhibit CCK INs and are themselves inhibited by ACh, gating BLA theta. ACh-induced theta activity is more readily evoked in BLA over cortex or hippocampus, suggesting preferential activation of BLA during high ACh states. These data reveal a SOM-CCK IN circuit in BLA that gates internal theta oscillations and suggest a mechanism by which salient stimuli acting through ACh switch the BLA into a network state enabling emotional memory.
Active maintenance of CD8+T cell naïvety through regulation of global genome architecture
Authors: Russ Brendan E. , Tsyganov Kirril , Quon Sara , Yu Bingfei , Li Jasmine , Lee Jason K. C. , Olshansky Moshe , He Zhaohren , Harrison Paul F. , Barugahare Adele , See Michael , Nussing Simone , Morey Alison E. , Udupa Vibha A. , Bennett Taylah .J , Kallies Axel , Murre Cornelis , Collas Phillipe , Powell David , Goldrath Ananda W. , Turner Stephen J. 
Published: February 2023

SUMMARYThe differentiation of naïve CD8+cytotoxic T lymphocytes (CTLs) into effector and memory states results in large scale changes in transcriptional and phenotypic profiles. Little is known about how large-scale changes in genome organisation reflect or underpin these transcriptional programs. We utilised Hi-C to map changes in the spatial organisation of long-range genome contacts within naïve, effector and memory virus-specific CD8+T cells. We observed that the architecture of the naive CD8+T cell genome was distinct from effector and memory genome configurations with extensive changes within discrete functional chromatin domains. However, deletion of the BACH2 or SATB1 transcription factors was sufficient to remodel the naïve chromatin architecture and engage transcriptional programs characteristic of differentiated cells. This suggests that the chromatin architecture within naïve CD8+T cells is preconfigured to undergo autonomous remodelling upon activation, with key transcription factors restraining differentiation by actively enforcing the unique naïve chromatin state.One Sentence SummaryCD8+T cell naïvety is actively maintained by transcription factors that enforce a distinct, naïve chromatin architecture.HighlightsCD8+T cell differentiation states are underscored by distinct chromatin looping architectures.Chromatin loops juxtapose CTL state appropriate enhancers, transcription factors and genes.Effector and memory CTLs have similar genome architectures, explaining rapid memory recall.CTL differentiation is restrained by BACH2 and SATB1, which enforce a naïve loop architecture.
Whole genome sequencing ofBorrelia burgdorferiisolates reveals linked clusters of plasmid-borne accessory genome elements associated with virulence
Authors: Lemieux Jacob E. , Huang Weihua , Hill Nathan , Cerar Tjasa , Freimark Lisa , Hernandez Sergio , Luban Matteo , Maraspin Vera , Bogovic Petra , Ogrinc Katarina , Ruzic-Sabljic Eva , Lapierre Pascal , Lasek-Nesselquist Erica , Singh Navjot , Iyer Radha , Liveris Dionysios , Reed Kurt D. , Leong John M. , Branda John A. , Steere Allen C. , Wormser Gary P. , Strle Franc , Sabeti Pardis C. , Schwartz Ira , Strle Klemen 
Published: February 2023

AbstractLyme disease is the most common vector-borne disease in North America and Europe. The clinical manifestations of Lyme disease vary based on the genospecies of the infectingBorrelia burgdorferispirochete, but the microbial genetic elements underlying these associations are not known. Here, we report the whole genome sequence (WGS) and analysis of 299 patient-derivedB. burgdorferisensu stricto (Bbss) isolates from patients in the Eastern and Midwestern US and Central Europe. We develop a WGS-based classification ofBbssisolates, confirm and extend the findings of previous single- and multi-locus typing systems, define the plasmid profiles of human-infectiousBbssisolates, annotate the core and strain-variable surface lipoproteome, and identify loci associated with disseminated infection. A core genome consisting of ∼800 open reading frames and a core set of plasmids consisting of lp17, lp25, lp36, lp28-3, lp28-4, lp54, and cp26 are found in nearly all isolates. Strain-variable (accessory) plasmids and genes correlate strongly with phylogeny. Using genetic association study methods, we identify an accessory genome signature associated with dissemination and define the individual plasmids and genes that make up this signature. Strains within the RST1/WGS A subgroup, particularly a subset marked by the OspC type A genotype, are associated with increased rates of dissemination. OspC type A strains possess a unique constellation of strongly linked genetic changes including the presence of lp56 and lp28-1 plasmids and a cluster of genes that may contribute to their enhanced virulence compared to other genotypes. The patterns of OspC type A strains typify a broader paradigm acrossBbssisolates, in which genetic structure is defined by correlated groups of strain-variable genes located predominantly on plasmids, particularly for expression of surface-exposed lipoproteins. These clusters of genes are inherited in blocks through strain-specific patterns of plasmid occupancy and are associated with the probability of invasive infection.
Characteristic differences in tibial subchondral bone changes in the post-traumatic knee osteoarthritis model
Authors: Arakawa Kohei , Takahata Kei , Usami Yuna , Kokubun Takanori 
Published: February 2023

ABSTRACTObjectiveMeniscus degeneration and subchondral bone changes contribute to the development and progression of knee OA. The purpose of this study was to reveal the relationship between medial meniscus degeneration and characteristics of subchondral bone changes in different modelsDesignWe used the anterior cruciate ligament transection (ACL-T) model, destabilization of the medial meniscus (DMM) model, controlled abnormal tibial translation (CATT) model and a controlled abnormal tibial rotation (CATR) model with different mechanical stresses. We performed histological analysis and micro computed tomography analysis, at 4 and 6 weeks. In addition, we divided the tibial subchondral bone into four compartments and set the regions of interestResultsMeniscus degeneration was observed in all groups, but there was no significant difference. The ACL-T group showed posterior displacement of the contact area, and the DMM and CATR groups showed lateral deviation of the medial meniscus. The region-specific subchondral bone changes in each model showed that changes in mechanical stress due to ACL and meniscus dysfunction, as well as changes in the contact area, affect the bony structure of the subchondral bone differently in each region.ConclusionsSubchondral bone changes in different models of mechanical stress were different in each region. In particular, changes in the contact area and increased compressive stress due to meniscus dysfunction were suggested to promote bone formation. The results of this study indicate that changes in alignment and contact area in the PTOA model may cause region-specific characteristics of the subchondral bone changes.