bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transcranial Functional Ultrasound Imaging Detects Focused Ultrasound Neuromodulation Induced Hemodynamic Changes in Mouse and Nonhuman Primate BrainsIn Vivo
Authors: Aurup Christian , Bendig Jonas , Blackman Samuel G. , McCune Erica P. , Bae Sua , Jimenez-Gambin Sergio , Ji Robin , Konofagou Elisa E. 
Published: March 2024

AbstractFocused ultrasound (FUS) is an emerging noinvasive technique for neuromodulation in the central nervous system (CNS). To evaluate the effects of FUS-induced neuromodulation, many studies used behavioral changes, functional magnetic resonance imaging (fMRI) or electroencephalography (EEG). However, behavioral readouts are often not easily mapped to specific brain activity, EEG has low spatial resolution limited to the surface of the brain and fMRI requires a large importable scanner that limits additional readouts and manipulations. In this context, functional ultrasound imaging (fUSI) holds promise to directly monitor the effects of FUS neuromodulation with high spatiotemporal resolution in a large field of view, with a comparatively simple and flexible setup. fUSI uses ultrafast Power Doppler Imaging (PDI) to measure changes in cerebral blood volume, which correlates well with neuronal activity and local field potentials. We designed a setup that aligns a FUS transducer with a linear array to allow immediate subsequent monitoring of the hemodynamic response with fUSI during and after FUS neuromodulation. We established a positive correlation between FUS pressure and the size of the activated area, as well as changes in cerebral blood volume (CBV) and found that unilateral sonications produce bilateral hemodynamic changes with ipsilateral accentuation in mice. We further demonstrated the ability to perform fully noninvasive, transcranial FUS-fUSI in nonhuman primates for the first time by using a lower-frequency transducer configuration.
GFPrint™: A MACHINE LEARNING TOOL FOR TRANSFORMING GENETIC DATA INTO CLINICAL INSIGHTS
Authors: Sanz-Martín Guillermo , Migliore Daniela Paula , del Campo Pablo Gómez , del Castillo-Izquierdo José , Domínguez Juan Manuel 
Published: March 2024

ABSTRACTThe increasing availability of massive genetic sequencing data in the clinical setting has triggered the need for appropriate tools to help fully exploit the wealth of information these data possess. GFPrint™is a proprietary streaming algorithm designed to meet that need. By extracting the most relevant functional features, GFPrint™transforms high-dimensional, noisy genetic sequencing data into an embedded representation, allowing unsupervised models to create data clusters that can be re-mapped to the original clinical information. Ultimately, this allows the identification of genes and pathways relevant to disease onset and progression. GFPrint™has been tested and validated using two cancer genomic datasets publicly available. Analysis of the TCGA dataset has identified panels of genes whose mutations appear to negatively influence survival in non-metastatic colorectal cancer (15 genes), epidermoid non-small cell lung cancer (167 genes) and pheochromocytoma (313 genes) patients. Likewise, analysis of the Broad Institute dataset has identified 75 genes involved in pathways related to extracellular matrix reorganization whose mutations appear to dictate a worse prognosis for breast cancer patients. GFPrint™is accessible through a secure web portal and can be used in any therapeutic area where the genetic profile of patients influences disease evolution.
Automated Identification of Germlinede novoMutations in Family Trios: A Consensus-Based Informatic Approach
Authors: Shadrina Mariya , Kalay Özem , Demirkaya-Budak Sinem , LeDuc Charles A. , Chung Wendy K. , Turgut Deniz , Budak Gungor , Arslan Elif , Semenyuk Vladimir , Davis-Dusenbery Brandi , Seidman Christine E. , Yost H. Joseph , Jain Amit , Gelb Bruce D. 
Published: March 2024

ABSTRACTAccurate identification of germlinede novovariants (DNVs) remains a challenging problem despite rapid advances in sequencing technologies as well as methods for the analysis of the data they generate, with putative solutions often involvingad hocfilters and visual inspection of identified variants. Here, we present a purely informatic method for the identification of DNVs by analyzing short-read genome sequencing data from proband-parent trios. Our method evaluates variant calls generated by three genome sequence analysis pipelines utilizing different algorithms—GATK HaplotypeCaller, DeepTrio and Velsera GRAF—exploring the assumption that a requirement of consensus can serve as an effective filter for high- quality DNVs. We assessed the efficacy of our method by testing DNVs identified using a previously established, highly accurate classification procedure that partially relied on manual inspection and used Sanger sequencing to validate a DNV subset comprising less confident calls. The results show that our method is highly precise and that applying a force-calling procedure to putative variants further removes false-positive calls, increasing precision of the workflow to 99.6%. Our method also identified novel DNVs, 87% of which were validated, indicating it offers a higher recall rate without compromising accuracy. We have implemented this method as an automated bioinformatics workflow suitable for large- scale analyses without need for manual intervention.
Evolutionary integration of the geography and pacing of the annual cycle in migratory birds
Authors: Winger Benjamin M. , La Sorte Frank A. , Hack Matthew D. , Pegan Teresa M. 
Published: March 2024

AbstractIn migratory species, the temporal phases of the annual cycle are intrinsically linked to seasonally shifting geographic ranges. Despite intense interest in the annual cycle ecology of migration, a synthetic understanding of the relationship between the biogeography and phenology of seasonal migration remains elusive. Here, we interrogate the spatiotemporal structure of the annual cycle in a novel phylogenetic comparative framework. We use eBird, a massive avian occurrence dataset, to demarcate and measure in a consistent manner among species the portions of the annual cycle when a geographic distribution is stationary versus dynamic due to migration. Through comparative analyses of the durations of annual cycle stages for 150 species of migratory birds breeding in North America, we show that the duration of the migratory periods is remarkably consistent among species and is unrelated to the distance between breeding and nonbreeding locations. In other words, the seasonal distributions of long-distance migrants shift between their geographically distant stationary phases in the same amount of time as short-distance migrants, suggesting that individuals of long-distance migratory species have more synchronous periods of migration and likely a faster individual migratory pace than short-distance migrants. Our results further show that the amount of time a species spends on the breeding grounds is strongly inversely related to time spent on the nonbreeding grounds, revealing the length of the breeding versus nonbreeding stationary period to be the primary source of species-level variation in the pacing of the annual cycle, as opposed to the time needed for the migratory period. Further, our study reveals that the amount of time spent annually on the breeding versus nonbreeding grounds predicts the distance between breeding and nonbreeding locations, demonstrating key linkages between the biogeography of the migratory cycle, its phenology, and the evolution of life history tradeoffs.
A Spatial Omnibus Test (SPOT) for Spatial Proteomic Data
Authors: Samorodnitsky Sarah , Campbell Katie , Ribas Antoni , Wu Michael C. 
Published: March 2024

AbstractSpatial proteomics can reveal the spatial organization of immune cells in the tumor immune microenvironment. Relating measures of spatial clustering, such as Ripley’s K or Besag’s L, to patient outcomes may offer important clinical insights. However, these measures require pre-specifying a radius in which to quantify clustering, yet no consensus exists on the optimal radius which may be context-specific. We propose a SPatial Omnibus Test (SPOT) which conducts this analysis across a range of candidate radii. At each radius, SPOT evaluates the association between the spatial summary and outcome, adjusting for confounders. SPOT then aggregates results across radii using the Cauchy combination test, yielding an omnibus p-value characterizing the overall degree of association. Using simulations, we verify that the type I error rate is controlled and show SPOT can be more powerful than alternatives. We also apply SPOT to an ovarian cancer study. An R package and tutorial is provided athttps://github.com/sarahsamorodnitsky/SPOT.
LINC complex alterations are a hallmark of sporadic and familial ALS/FTD
Authors: Sirtori Riccardo , Gregoire Michelle , Potts Emily , Collins Alicia , Donatelli Liviana , Fallini Claudia 
Published: March 2024

AbstractAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that primarily affects motor neurons, leading to progressive muscle weakness and loss of voluntary muscle control. While the exact cause of ALS is not fully understood, emerging research suggests that dysfunction of the nuclear envelope (NE) may contribute to disease pathogenesis and progression. The NE plays a role in ALS through several mechanisms, including nuclear pore defects, nucleocytoplasmic transport impairment, accumulation of mislocalized proteins, and nuclear morphology abnormalities. The LINC complex is the second biggest multi-protein complex in the NE and consists of the SUN1/2 proteins spanning the inner nuclear membrane and Nesprin proteins embedded in the outer membrane. The LINC complex, by interacting with both the nuclear lamina and the cytoskeleton, transmits mechanical forces to the nucleus regulating its morphology and functional homeostasis. In this study we show extensive alterations to the LINC complex in motor and cortical iPSC-derived neurons and spinal cord organoids carrying the ALS causative mutation in theC9ORF72gene (C9). Importantly, we show that such alterations are presentin vivoin a cohort of sporadic ALS and C9-ALS postmortem spinal cord and motor cortex biopsies. We also found that LINC complex disruption strongly correlated with nuclear morphological alterations occurring in ALS neurons, independently of TDP43 mislocalization. Altogether, our data establish morphological and functional alterations to the LINC complex as important events in ALS pathogenic cascade, making this pathway a possible target for both biomarker and therapy development.
Chromosome-scale genome assembly ofApocynum pictum, a drought-tolerant medicinal plant from the Tarim Basin
Authors: Xie Wenlong , Bai Baowei , Wang Yanqing 
Published: March 2024

AbstractApocynum pictumSchrenk is a semi-shrub of the Apocynaceae family with a wide distribution throughout the Tarim Basin that holds significant ecological, medicinal, and economic values. Here, we report the assembly of its chromosome-level reference genome using Nanopore long-read, Illumina HiSeq paired-end, and high-throughput chromosome conformation capture sequencing. The final assembly is 225.32 Mb in length with a scaffold N50 of 19.64 Mb. It contains 23,147 protein-coding genes across 11 chromosomes, 21,148 of which (91.36%) have protein functional annotations. Comparative genomics analysis revealed thatA. pictumdiverged from the closely related speciesApocynum venetumapproximately 2.2 million years ago and has not undergone additional polyploidizations after the core eudicot WGT-γ event. Karyotype evolution analysis was used to characterize interchromosomal rearrangements in representative Apocynaceae species and revealed that severalA. pictumchromosomes were derived entirely from single chromosomes of the ancestral eudicot karyotype. Finally, we identified 50 members of the well-known stress-responsive WRKY transcription factor family and used transcriptomic data to document changes in their expression at two stages of drought stress, identifying a number of promising candidate genes. Overall, this study provides high-quality genomic resources for evolutionary and comparative genomics of the Apocynaceae, as well as initial molecular insights into the drought adaptation of this valuable desert plant.
Spatially heterogeneous responses of planktonic foraminifera assemblages over 700,000 years of climate change
Authors: Mathes Gregor H. , Reddin Carl J. , Kiessling Wolfgang , Antell Gawain S. , Saupe Erin E. , Steinbauer Manuel J. 
Published: March 2024

AbstractAimTo determine the degree to which assemblages of planktonic foraminifera track thermal conditions.LocationThe world’s oceans.Time periodThe last 700,000 years of glacial-interglacial cycles.Major taxa studiedPlanktonic foraminifera.MethodsWe investigate assemblage dynamics in planktonic foraminifera in response to temperature changes using a global dataset of Quaternary planktonic foraminifera, together with a coupled Atmosphere–Ocean General Circulation Model (AOGCM) at 8,000-year resolution. We use ‘thermal deviance’ to assess assemblage responses to climate change, defined as the difference between the temperature at a given location and the bio-indicated temperature (i.e., the abundance-weighted average of estimated temperature optima for the species present).ResultsAssemblages generally tracked annual mean temperature changes through compositional turnover, but large thermal deviances are evident under certain conditions. The coldest-adapted species persisted in polar regions during warming but were not joined by additional immigrants, resulting in decreased assemblage turnover with warming. The warmest-adapted species persisted in equatorial regions during cooling. Assemblages at mid latitudes closely tracked temperature cooling and showed a modest increase in thermal deviance with warming.Main conclusionsPlanktonic foraminiferal assemblages were generally able to track or endure temperature changes: as climate warmed or cooled, bio-indicated temperature also became warmer or cooler, although to a variable degree. At polar sites under warming and at equatorial sites under cooling, the change in temperature predicted from assemblage composition was less than, or even opposite to, expectations based on estimated environmental change. Nevertheless, all species survived the accumulation of thermal deviance—a result that highlights the resilience and inertia of planktonic foraminifera on an assemblage level to the last 700,000 years of climate change, which might be facilitated by broad thermal tolerances or depth shifts.
Low-intensity focused ultrasound to the human insular cortex differentially modulates the heartbeat-evoked potential: a proof-of-concept study
Authors: Strohman Andrew , Isaac Gabriel , Payne Brighton , Verdonk Charles , Khalsa Sahib S. , Legon Wynn 
Published: March 2024

ABSTRACTBackgroundThe heartbeat evoked potential (HEP) is a brain response time-locked to the heartbeat and a potential marker of interoceptive processing. The insula and dorsal anterior cingulate cortex (dACC) are brain regions that may be involved in generating the HEP. Low-intensity focused ultrasound (LIFU) is a non-invasive neuromodulation technique that can selectively target sub-regions of the insula and dACC to better understand their contributions to the HEP.ObjectiveProof-of-concept study to determine whether LIFU modulation of the anterior insula (AI), posterior insula (PI), and dACC influences the HEP.MethodsIn a within-subject, repeated-measures design, healthy human participants (n=16) received 10 minutes of stereotaxically targeted LIFU to the AI, PI, dACC or Sham at rest during continuous electroencephalography (EEG) and electrocardiography (ECG) recording on separate days. Primary outcome was change in HEP amplitudes. Relationships between LIFU pressure and HEP changes were examined using linear mixed modelling. Peripheral indices of visceromotor output including heart rate and heart rate variability (HRV) were explored between conditions.ResultsRelative to sham, LIFU to the PI, but not AI or dACC, decreased HEP amplitudes; this was partially explained by increased LIFU pressure. LIFU did not affect time or frequency dependent measures of HRV.ConclusionsThese results demonstrate the ability to modulate HEP amplitudes via non-invasive targeting of key interoceptive brain regions. Our findings have implications for the causal role of these areas in bottom-up heart-brain communication that could guide future work investigating the HEP as a marker of interoceptive processing in healthy and clinical populations.
Explainable deep learning on 7500 whole genomes elucidates cancer-specific patterns of chromosomal instability
Authors: Ali al-Badri Mohamed , Cross William CH , Barnes Chris P 
Published: March 2024

AbstractChromosomal instability (CIN) refers to an increased rate of chromosomal changes within cells. It is highly prevalent in cancer cells and leads to abnormalities in chromosome number (aneuploidy) and structure. CIN contributes to genetic diversity within a tumour, which facilitates tumour progression, drug resistance, and metastasis. Here, we present a deep learning method and an exploration of the chromosome copy aberrations (CNAs) resultant from CIN, across 7,500 high-depth, whole genome sequences, representing 13 cancer types. We found that the types of CNAs can act as a highly specific classifier for primary site. Using an explainable AI approach, we revealed both established and novel loci that contributed to cancer type, and focusing on highly significant chromosome loci within cancer types, we demonstrated prognostic relevance. We outline how the developed methodology can provide several applications for researchers, including drug target and biomarker discovery, as well as the identification of cancers of unknown primary site.
Dopaminergic signaling regulates microglial surveillance and adolescent plasticity in the frontal cortex
Authors: Stowell Rianne , Wang Kuan Hong 
Published: March 2024

AbstractAdolescence is a sensitive period for frontal cortical development and cognitive maturation. The dopaminergic (DA) mesofrontal circuit is particularly malleable in response to changes in adolescent experience and DA activity. However, the cellular mechanisms engaged in this plasticity remain unexplored. Here, we report that microglia, the innate immune cells of the brain, are uniquely sensitive to adolescent mesofrontal DA signaling. Longitudinalin vivotwo-photon imaging in mice shows that frontal cortical microglia respond dynamically to plasticity-inducing behavioral or optogenetic DA axon stimulation with increased parenchymal and DA bouton surveillance. Microglial-axon contact precedes new bouton formation, and both D1 and D2-type DA receptors regulate microglial-bouton interactions and axonal plasticity. Moreover, D2 antagonism in adults reinstates adolescent plasticity, including increased microglial surveillance and new DA bouton formation. Our results reveal that DA signaling regulates microglial surveillance and axonal plasticity uniquely in the adolescent frontal cortex, presenting potential interventions for restoring plasticity in the adult brain.
Mechanisms of genomic instability dictate cytosolic DNA composition and dendritic cell mediated anti-tumor immunity
Authors: Mosley Shayla R. , Chen Angie , Doell David N.W. , Choi Siwon , Mowat Courtney , Meier-Stephenson Felix , Meier-Stephenson Vanessa , Baker Kristi 
Published: March 2024

AbstractPatients with microsatellite instable (MSI) colorectal cancers (CRC) face better prognosis than those with the more common chromosomal instable (CIN) subtype due to improved anti-tumor immune responses characterized by high cytotoxic T cell infiltration. Previous investigation identified the cytosolic DNA (cyDNA) sensor STING as necessary for chemokine-mediated T cell recruitment in MSI CRCs. Here, we find cyDNA from MSI CRC cells is inherently more capable of inducing STING activation and induces improved cytotoxic T cell activation by dendritic cells (DCs). Sequencing indicates MSI cyDNA is enriched for microsatellites, which upon DC uptake induce anti-tumor immunity in a manner consistent with clinical MSI CRCs. Radiation also modulates cyDNA stimulation capacity through larger cyDNA size and increased mitochondrial DNA content. Identifying highly stimulatory cyDNA arising from genomic instability such as in MSI CRCs allows for optimized development of DNA-based STING agonist therapies to improve responses of CIN CRC patients to immunotherapies.
Exploration of phosphoproteomic association during epimorphic regeneration
Authors: Banu Sarena , Anusha P V , Mandal Komal , Idris Mohammed M 
Published: March 2024

AbstractUnravelling the intricate patterns of site-specific protein phosphorylation during Epimorphic regeneration holds the key to unlocking the secrets of tissue complexity. Understanding these precise modifications and their impact on protein function could shed light on the remarkable regenerative capacity of tissues, with potential implications for therapeutic interventions. In this study we have systematically mapped the global phosphorylation modifications within regenerating tissue of zebrafish caudal fins, elucidating the intricate landscape of signalling pathway associate with the regeneration process. A total of 74 and 440 proteins were found undergoing differentially phosphorylated during the process of regeneration from 12hpa to 7dpa against control based on TiO2 column enrichment and immuno precipitation using phosphoserine, phosphothreonine and phosphotyrosine antibodies respectively. Interestingly 95% of the proteins identified from TiO2 enrichment method were also found to be identified through the phosphoprotein antibody pull down method impacting the high accuracy and significance of the methods and greater association of the 70 proteins undergoing differential phosphorylation during the process of regeneration. Whole mount immunohistochemistry analysis reveals high association of phosphorylation at 1dpa, 2dpa and 3 dpa regeneration time points. Based on network pathway analysis it was evident that Fc Receptor-mediated Phagocytosis in Macrophages and Monocytes, Actin cytoskeleton signaling, HGF signaling and Insulin receptor signaling are the most highly associated network pathways for regeneration through differential phosphorylation. This research enhances our comprehension on protein post-translational modification in the context of zebrafish caudal fin tissue regeneration, shedding light on its prospective application in the field of regenerative medicine.