bluuebunny/crossref_metadata_2025_split huggingface dataset:
Longitudinal Awake Imaging of Mouse Deep Brain Microvasculature with Super-resolution Ultrasound Localization Microscopy
Authors: Wang Yike , Lowerison Matthew R. , Huang Zhe , You Qi , Lin Bing-Ze , Llano Daniel A. , Song Pengfei 
Published: September 2023

AbstractUltrasound localization microscopy (ULM) is an emerging imaging modality that resolves microvasculature in deep tissues with high spatial resolution. However, existing preclinical ULM applications are largely constrained to anesthetized animals, introducing confounding vascular effects such as vasodilation and altered hemodynamics. As such, ULM quantifications (e.g., vessel diameter, density, and flow velocity) may be confounded by the use of anesthesia, undermining the usefulness of ULM in practice. Here we introduce a method to address this limitation and achieve ULM imaging in awake mouse brain. Pupillary monitoring was used to support the presence of the awake state during ULM imaging. Vasodilation induced by isoflurane was observed by ULM. Upon recovery to the awake state, reductions in vessel density and flow velocity were observed across different brain regions. In the cortex, the effects induced by isoflurane are more pronounced on venous flow than on arterial flow. In addition, serialin vivoimaging of the same animal brain at weekly intervals demonstrated the highly robust longitudinal imaging capability of the proposed technique. The consistency was further verified through quantitative analysis on individual vessels, cortical regions of arteries and veins, and subcortical regions. This study demonstrates longitudinal ULM imaging in the awake mouse brain, which is crucial for many ULM brain applications that require awake and behaving animals.
The tumor microbiome reacts to hypoxia and can influence response to radiation treatment in colorectal cancer
Authors: Benej Martin , Hoyd Rebecca , Kreamer McKenzie , Wheeler Caroline E. , Grencewicz Dennis J. , Choueiry Fouad , Chan Carlos H.F. , Zakharia Yousef , Ma Qin , Dodd Rebecca D. , Ulrich Cornelia M. , Hardikar Sheetal , Churchman Michelle L. , Tarhini Ahmad A. , Robinson Lary A. , Singer Eric A. , Ikeguchi Alexandra P. , McCarter Martin D. , Tinoco Gabriel , Husain Marium , Jin Ning , Tan Aik Choon , Osman Afaf E.G. , Eljilany Islam , Riedlinger Gregory , Schneider Bryan P. , Benejova Katarina , Kery Martin , Papandreou Ioanna , Zhu Jiangjiang , Denko Nicholas , Spakowicz Daniel 
Published: September 2023

ABSTRACTTumor hypoxia has been shown to predict poor patient outcomes in several cancer types, partially because it reduces radiation’s ability to kill cells. We investigated whether some of the clinical effects of hypoxia could also be due to its impact on the tumor microbiome. We examined the RNA-seq data from the Oncology Research Information Exchange Network (ORIEN) database of colorectal cancer (CRC) patients treated with radiotherapy. For each tumor, we identified microbial RNAs and related them to the hypoxic gene expression scores calculated from host mRNA. Our analysis showed that the hypoxia expression score predicted poor patient outcomes and identified tumors enriched with certain microbes such asFusobacterium nucleatum. The presence of other microbes, such asFusobacterium canifelinum,predicted poor patient outcomes, suggesting a potential interaction between hypoxia, the microbiome, and radiation response. To investigate this concept experimentally, we implanted CT26 CRC cells into both immune-competent BALB/c and immune-deficient athymic nude mice. After growth, where tumors passively acquired microbes from the gastrointestinal tract, we harvested tumors, extracted nucleic acids, and sequenced host and microbial RNAs. We stratified tumors based on their hypoxia score and performed metatranscriptomic analysis of microbial gene expression. In addition to hypoxia-trophic and -phobic microbial populations, analysis of microbial gene expression at the strain level showed expression differences based on the hypoxia score. Hypoxia appears to not only associate with different microbial populations but also elicit an adaptive transcriptional response in intratumoral microbes.SIGNIFICANCETumor hypoxia reduces radiation’s ability to kill cells. We explored whether some of the clinical effects of hypoxia could also be due to interaction with the tumor microbiome. Hypoxic expression scores associated with certain microbes and elicited an adaptive transcriptional response in others.
Autometa 2: A versatile tool for recovering genomes from highly-complex metagenomic communities
Authors: Rees Evan R. , Uppal Siddharth , Clark Chase M. , Lail Andrew J. , Waterworth Samantha C. , Roesemann Shane D. , Wolf Kyle A. , Kwan Jason C. 
Published: September 2023

ABSTRACTIn 2019, we developed Autometa, an automated binning pipeline that is able to effectively recover metagenome-assembled genomes from complex environmental and non-model host-associated microbial communities. Autometa has gained widespread use in a variety of environments and has been applied in multiple research projects. However, the genome-binning workflow was at times overly complex and computationally demanding. As a consequence of Autometa’s diverse application, non-technical and technical researchers alike have noted its burdensome installation and inefficient as well as error-prone processes. Moreover its taxon-binning and genome-binning behaviors have remained obscure. For these reasons we set out to improve its accessibility, efficiency and efficacy to further enable the research community during their exploration of Earth’s environments. The highly augmented Autometa 2 release, which we present here, has vastly simplified installation, a graphical user interface and a refactored workflow for transparency and reproducibility. Furthermore, we conducted a parameter sweep on standardized community datasets to show that it is possible for Autometa to achieve better performance than any other binning pipeline, as judged by Adjusted Rand Index. Improvements in Autometa 2 enhance its accessibility for non-bioinformatic oriented researchers, scalability for large-scale and highly-complex samples and interpretation of recovered microbial communities.Graphical abstractAutometa: An automated taxon binning and genome binning workflow for single sample resolution of metagenomic communities.
Crossing host boundaries: the evolutionary drivers and correlates of viral host jumps
Authors: Tan Cedric C.S. , van Dorp Lucy , Balloux Francois 
Published: September 2023

AbstractMost emerging and re-emerging infectious diseases stem from viruses that naturally circulate in non-human vertebrates. When these viruses cross over into humans, they can cause disease outbreaks and epidemics. While zoonotic host jumps have been extensively studied from an ecological perspective, little attention has gone into characterising the evolutionary drivers and correlates underlying these events. To address this gap, we harnessed the entirety of publicly available viral genomic data, employing a comprehensive suite of network and phylogenetic analyses to investigate the evolutionary mechanisms underpinning recent viral host jumps. Notably, we challenge conventional assumptions about the directionality of host jumps, demonstrating that humans are as much a source as a sink for viral spillover events, insofar we infer more viral host jumps from humans to other animals, than from animals to humans. Moreover, we demonstrate heightened evolution in viral lineages that involve putative host jumps. We further observe that the extent of adaptation associated to a host jump is lower for viruses with broad host ranges. Finally, we show that the genomic targets of natural selection associated to host jumps vary across different viral families with either structural or auxiliary genes being the prime targets of selection. Collectively, our results illuminate some of the evolutionary drivers underlying viral host jumps that may contribute to mitigating viral threats across species boundaries.
Different sensory information is used for state estimation when stationary or moving
Authors: Wong Aaron L , Eyssalenne Alyssa N , Carter Luke , Therrien Amanda S 
Published: September 2023

ABSTRACTThe accurate estimation of limb state is necessary for movement planning and execution. While state estimation requires both feedforward and feedback information, we focus here on the latter. Prior literature has shown that integrating visual and proprioceptive feedback improves estimates of static limb position. However, differences in visual and proprioceptive feedback delays suggest that multisensory integration could be disadvantageous when the limb is moving. We formalized this hypothesis by modeling feedback-based state estimation using the longstanding maximum likelihood estimation model of multisensory integration, which we updated to account for sensory delays. Our model predicted that the benefit of multisensory integration was largely lost when the limb was passively moving. We tested this hypothesis in a series of experiments in human subjects that compared the degree of interference created by discrepant visual or proprioceptive feedback when estimating limb position either statically at the end of the movement or dynamically at movement midpoint. In the static case, we observed significant interference: discrepant feedback in one modality systematically biased sensory estimates based on the other modality. However, no interference was seen in the dynamic case: participants could ignore sensory feedback from one modality and accurately reproduce the motion indicated by the other modality. Together, these findings suggest that the sensory feedback used to compute a state estimate differs depending on whether the limb is stationary or moving. While the former may tend toward multimodal integration, the latter is more likely to be based on feedback from a single sensory modality.SIGNIFICANCE STATEMENTThe estimation of limb state involves feedforward and feedback information. While estimation based on feedback has been well studied when the limb is stationary, it is unknown if similar sensory processing supports limb position estimates when moving. Using a computational model and behavioral experiments, we show that feedback-based state estimation may involve multisensory integration in the static case, but it is likely based on a single modality when the limb is moving. We suggest that this difference may stem from visual and proprioceptive feedback delays.
Memory encoding and retrieval by retrosplenial parvalbumin interneurons is impaired in Alzheimer’s disease model mice
Authors: Park Kyerl , Kohl Michael M. , Kwag Jeehyun 
Published: September 2023

SummaryMemory deficits in Alzheimer’s disease (AD) show a strong link with GABAergic interneuron dysfunctions1–7. Ensemble dynamics of GABAergic interneurons are critical in memory encoding and retrieval8–12but how GABAergic interneuron dysfunction affects inhibitory ensemble dynamics in AD is unknown. As retrosplenial cortex (RSC) is a brain area critical for episodic memory13–16and affected by beta-amyloid accumulation in early AD17–21, we address this question by performing Ca2+imaging in RSC parvalbumin-expressing (PV) interneurons during a contextual fear memory (CFM) task in healthy control mice and the 5XFAD mouse model of AD. We found that subpopulations of PV interneurons that were responsive to aversive electric foot shocks during contextual fear conditioning (CFC) in the control mice significantly decreased in the 5XFAD mice, indicating a dysfunction in the recruitment of CFM-encoding PV interneurons. In control mice, CFC-responsive PV interneuron ensemble activities were selectively upregulated during the freezing epoch of the CFM retrieval, manifested by CFC-induced synaptic potentiation of PV interneuron-mediated inhibition. However, CFC-induced changes in PV interneuron ensemble dynamics during CFM retrieval and synaptic plasticity were both absent in the 5XFAD mice. Optogenetic silencing of PV interneurons during CFC in control mice mimicked the CFM deficits in 5XFAD mice, while optogenetic activation of PV interneurons during CFC in the 5XFAD mice restored CFM retrieval. These results demonstrate the necessity and sufficiency of CFC-responsive PV interneurons for CFM retrieval and suggest that synaptic dysfunction in CFM-encoding PV interneurons disrupt the inhibitory ensemble dynamics underlying CFM retrieval, subsequently leading to memory deficits in AD.
Topological evolution of sprouting vascular networks: from day-by-day analysis to general growth rules
Authors: Rojek Katarzyna O. , Wrzos Antoni , Żukowski Stanisław , Bogdan Michał , Lisicki Maciej , Szymczak Piotr , Guzowski Jan 
Published: September 2023

ABSTRACTEngineering tissues with an embedded vasculature of well-controlled topology remains one of the basic problems in biofabrication. Still, little is known about the evolution of topological characteristics of vascular networks over time. Here, we perform a high-throughput day-by-day analysis of tens of microvasculatures that sprout from endothelial-cell coated micrometric beads embedded in an external fibrin gel. We use the bead-assays to systematically analyze (i) ‘macroscopic’ observables such as the overall length and area of the sprouts, (ii) ‘microscopic’ observables such as the lengths of segments or the branching angles and their distributions, as well as (iii) general measures of network complexity such as the average number of bifurcations per branch. We develop a custom angiogenic image analysis toolkit and track the evolution of the networks for at least 14 days of culture under various conditions, e.g., in the presence of fibroblasts or with added endothelial growth factor (VEGF). We find that the evolution always consists of three stages: (i) an inactive stage in which cells remain bound to the beads, (ii) a sprouting stage in which the sprouts rapidly elongate and bifurcate, and (iii) the maturation stage in which the growth slows down. We show that higher concentrations of VEGF lead to an earlier onset of sprouting and to a higher number of primary branches, yet without significantly affecting the speed of growth of the individual sprouts. We find that the mean branching angle is weakly dependent on VEGF and typically in the range of 60-75 degrees suggesting that, by comparison with the available Laplacian growth models, the sprouts tend to follow local VEGF gradients. Finally, we observe an exponential distribution of segment lengths, which we interpret as a signature of stochastic branching at a constant bifurcation rate (per unit branch length). Our results, due to high statistical relevance, may serve as a benchmark for predictive models and reveal how the external means of control, such as VEGF concentration, could be used to control the morphology of the vascular networks. We provide guidelines for the fabrication of optimized microvasculatures with potential applications in drug testing or regenerative medicine.
evopython: a Python package for feature-focused, comparative genomic data exploration
Authors: Mick Steven T. , Fiszbein Ana 
Published: September 2023

AbstractMotivationSoftware such asLiftOverallows for the intra- and inter-species conversion of genomic coordinates between genome assemblies, but this coordinate-centric workflow is naive to sequence alterations underling the conversion. For instance, it does not clarify the location of any insertions or deletions that might have occurred.ResultsTo facilitate inter-species, sequence-based analyses, we developedevopython, a simple, object-oriented Python package that enables the sequence-aware resolution of genomic coordinates directly from pairwise and multiple whole-genome alignment data. The output is a Python dictionary storing all information relevant to the alignment: the participating species’ names, the position of the alignment in each species’ genome assembly, and the aligned sequences.Availability and implementationThe source code and documentation are available athttps://github.com/fiszbein-lab/evopython.Contactanafisz@bu.edu
Assessing the links between pollinators and the genetic and epigenetic features of plant species with contrasting distribution ranges
Authors: Valverde Javier , Medrano Mónica , Herrera Carlos M. , Alonso Conchita 
Published: September 2023

AbstractIn flowering plants, pollinators contribute to gene flow while they also respond to variation in plant traits together determined by genetic, epigenetic and environmental sources of variation. Consequently, a correlation between abundance and diversity of pollinators and the genetic and epigenetic characteristics of plant populations such as diversity or distinctiveness is to be expected, yet no study has explored such long-term dimensions of plant-pollinator interactions. Mediterranean narrow endemics often exhibit unexpectedly high levels of population (epi)genetic diversity. We hypothesize that pollinators may contribute to explain this pattern. Specifically, we expect a stronger association of pollinators with population (epi)genetic variability in narrow endemics than in widely distributed congeners. We studied five pairs of congeneric plant species, consisting of one narrow endemic with a restricted distribution and one widespread congener, found in the Sierra de Cazorla mountains (SE Spain). In up to three populations per species, a comprehensive characterisation of pollinators was carried out to estimate pollinator diversity and visitation rate. Genetic and epigenetic diversity and distinctiveness of each population was calculated using AFLP markers and methylation-sensitive AFLP markers (MSAP) respectively. The relationships with pollinator diversity and visitation rate were assessed. The diversity of pollinators did not vary according to the plant distribution range, whereas visitation rate was higher in widespread species. As predicted, only narrow endemics showed a significant association between pollinators and their population genetic and epigenetic characteristics. Specifically, higher pollinator diversity and visitation rates entailed higher population genetic diversity and lower epigenetic distinctiveness. This work shows the value of exploring the relationships between pollinator abundance and diversity and population (epi)genetics for understanding the evolution of plant rarity.
Magnetic nanocomplexes coupled with an external magnetic field modulate macrophage phenotype – a non-invasive strategy for bone regeneration
Authors: Kumar Harshini Suresh , Yi Zhongchao , Tong Sheng , Annamalai Ramkumar T. 
Published: September 2023

AbstractChronic inflammation is a major cause for the pathogenesis of musculoskeletal diseases such as fragility fracture, and nonunion. Studies have shown that modulating the immune phenotype of macrophages from proinflammatory to prohealing mode can heal recalcitrant bone defects. Current therapeutic strategies predominantly apply biochemical cues, which often lack target specificity and controlling their release kineticsin vivois challenging spatially and temporally. We show a magnetic iron-oxide nanocomplexes (MNC)-based strategy to resolve chronic inflammation in the context of promoting fracture healing. MNC internalized pro-inflammatory macrophages, when coupled with an external magnetic field, exert an intracellular magnetic force on the cytoskeleton, which promotes a prohealing phenotype switch. Mechanistically, the intracellular magnetic force perturbs actin polymerization, thereby significantly reducing nuclear to cytoplasm redistribution of MRTF-A and HDAC3, major drivers of inflammatory and osteogenic gene expressions. This significantly reducesNos2gene expression and subsequently downregulates the inflammatory response, as confirmed by quantitative PCR analysis. These findings are a proof of concept to develop MNC-based resolution-centric therapeutic intervention to direct macrophage phenotype and function towards healing and can be translated either to supplement or replace the currently used anti-inflammatory therapies for fracture healing.
Comparative epigenetic and genetic spatial structure in Mediterranean mountain plants: a multispecific comparison
Authors: Valverde Javier , Medrano Mónica , Herrera Carlos M. , Alonso Conchita 
Published: September 2023

AbstractEpigenetic information can be heritable, but also respond to key environmental variables in situ, endowing individuals with an additional capacity to adapt to environmental changes. Thus, it is likely that in sesile organisms such as plants, part of the spatial epigenetic variation found across individuals will reflect the environmental heterogeneity of populations. Analysing the departure of the spatial epigenetic structure from the baseline genetic variation can help in understanding the value of epigenetic regulation in species with different breath of optimal environmental conditions. We performed a multispecies study that considered seven pairs of congeneric plant species, each encompassing a narrow endemic with habitat specialization and a widespread species. In three populations per species we used AFLP and methylation-sensitive AFLP markers to characterise the spatial genetic and epigenetic structures. In contrast to widespread species, narrow endemics showed a significant and generalised lower epigenetic than genetic differentiation across species. Within most populations of narrow species, epigenetic variation was less spatially structured than the genetic variation. This pattern resulted from a lack of correlation between epigenetic and genetic information in populations of narrow endemics. We argue that the differences found between narrow endemics and widespread congeners reflect contrasting breaths of environmental requirements. We pose the hypothesis that in species with a narrow niche breath, epigenetic variation may be more similar across populations and among individuals within a population given the expected higher similarity in environmental requirements.
The simplicity of protein sequence-function relationships
Authors: Park Yeonwoo , Metzger Brian P.H. , Thornton Joseph W. 
Published: September 2023

AbstractHow complicated is the genetic architecture of proteins – the set of causal effects by which sequence determines function? High-order epistatic interactions among residues are thought to be pervasive, making a protein’s function difficult to predict or understand from its sequence. Most studies, however, used methods that overestimate epistasis, because they analyze genetic architecture relative to a designated reference sequence – causing measurement noise and small local idiosyncrasies to propagate into pervasive high-order interactions – or have not effectively accounted for global nonlinearity in the sequence-function relationship. Here we present a new reference-free method that jointly estimates global nonlinearity and specific epistatic interactions across a protein’s entire genotype-phenotype map. This method yields a maximally efficient explanation of a protein’s genetic architecture and is more robust than existing methods to measurement noise, partial sampling, and model misspecification. We reanalyze 20 combinatorial mutagenesis experiments from a diverse set of proteins and find that additive and pairwise effects, along with a simple nonlinearity to account for limited dynamic range, explain a median of 96% of total variance in measured phenotypes (and >92% in every case). Only a tiny fraction of genotypes are strongly affected by third- or higher-order epistasis. Genetic architecture is also sparse: the number of terms required to explain the vast majority of variance is smaller than the number of genotypes by many orders of magnitude. The sequence-function relationship in most proteins is therefore far simpler than previously thought, opening the way for new and tractable approaches to characterize it.