bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cortical and subcortical mapping of the allostatic-interoceptive system in the human brain using 7 Tesla fMRI
Authors: Zhang Jiahe , Chen Danlei , Deming Philip , Srirangarajan Tara , Theriault Jordan , Kragel Philip A. , Hartley Ludger , Lee Kent M. , McVeigh Kieran , Wager Tor D. , Wald Lawrence L. , Satpute Ajay B. , Quigley Karen S. , Whitfield-Gabrieli Susan , Barrett Lisa Feldman , Bianciardi Marta 
Published: July 2023

AbstractThe brain continuously anticipates the energetic needs of the body and prepares to meet those needs before they arise, called allostasis. In support of allostasis, the brain continually models the sensory state of the body, called interoception. We replicated and extended a large-scale system supporting allostasis and interoception in the human brain using ultra-high precision 7 Tesla functional magnetic resonance imaging (fMRI) (N =90), improving the precision of subgenual and pregenual anterior cingulate topography combined with extensive brainstem nuclei mapping. We observed over 90% of the anatomical connections published in tract-tracing studies in non-human animals. The system also included regions of dense intrinsic connectivity broadly throughout the system, some of which were identified previously as part of the backbone of neural communication across the brain. These results strengthen previous evidence for a whole-brain system supporting the modeling and regulation of the internal milieu of the body.
Voluntary alcohol intake alters the motivation to seek intravenous oxycodone and neuronal activation during the reinstatement of oxycodone and sucrose seeking
Authors: Wilkinson Courtney S. , Blount Harrison L. , Davis Shane , Rojas Giselle , Wu Lizhen , Murphy Niall P. , Schwendt Marek , Knackstedt Lori A. 
Published: July 2023

AbstractOpioid-alcohol polysubstance use is prevalent and worsens treatment outcomes. Here we assessed whether co-consumption of oxycodone and alcohol would influence intake of one another, demand for oxycodone, and the neurocircuitry underlying cue-primed reinstatement of oxycodone-seeking. Male and female rats underwent oxycodone intravenous self-administration (IVSA) with access to either alcohol (20% v/v) and water or only water immediately after the IVSA session. Next, economic demand for intravenous oxycodone was assessed while access to alcohol and/or water continued. Control rats self-administered sucrose followed by access to alcohol and/or water. Rats underwent extinction training and brains were processed for c-fos mRNA expression immediately following a cue-primed reinstatement test. While both sexes decreased oxycodone intake if they had access to alcohol, and decreased alcohol intake if they had access to oxycodone, female oxycodone+alcohol rats exhibited decreased demand elasticity for intravenous oxycodone and increased cue-primed reinstatement while male rats did not. Spontaneous withdrawal signs were correlated with oxycodone intake while alcohol intake was correlated with anxiety-like behavior. Alcohol consumption increased the number of basolateral and central amygdala neurons activated during sucrose and oxycodone reinstatement and the number of ventral and dorsal striatum neurons engaged by sucrose reinstatement. Nucleus accumbens shell dopamine 1 receptor containing neurons displayed activation patterns consistent with oxycodone reinstatement. Thus, alcohol alters the motivation to seek oxycodone in a sex-dependent manner and alters the neural circuitry engaged by cue-primed reinstatement of sucrose and oxycodone-seeking.
Neural filtering of physiological tremor oscillations to spinal motor neurons mediates short-term acquisition of a skill learning task
Authors: Cabral Hélio V. , Cudicio Alessandro , Bonardi Alberto , Del Vecchio Alessandro , Falciati Luca , Orizio Claudio , Martinez-Valdes Eduardo , Negro Francesco 
Published: July 2023

AbstractThe acquisition of a motor skill involves adaptations of spinal and supraspinal pathways to alpha motoneurons. In this study, we estimated the shared synaptic contributions of these pathways to understand the neural mechanisms underlying the short-term acquisition of a new force-matching task. High-density surface electromyography (HDsEMG) was acquired from the first dorsal interosseous (FDI; 7 males and 6 females) and tibialis anterior (TA; 7 males and 4 females) during 15 trials of an isometric force-matching task. For two selected trials (pre-andpost-skillacquisition), we decomposed the HDsEMG into motor unit spike trains, tracked motor units between trials, and calculated the mean discharge rate and the coefficient of variation of inter-spike interval (CoVISI). We also quantified thepost/preratio of motor units’ coherence within delta, alpha, and beta bands. Improvements in force-matching were accompanied by a significant increase in the mean discharge rate and a decrease in CoVISIfor both muscles. Moreover, the area under the curve within alpha band decreased by ∼22% and ∼13% for the TA and FDI muscles, respectively, with no changes in the delta or beta bands. These reductions correlated significantly with increased coupling between force/neural drive and target oscillations. These results suggest that the short-term acquisition of a new force-matching skill is mediated by the attenuation of tremor oscillations in the shared synaptic inputs. In other words, the central nervous system acts as a matched filter to modulate the synaptic weights of shared inputs and suppress neural components unrelated to the specific task. Supported by simulations, a plausible mechanism behind these alpha band reductions may involve spinal interneurons’ phase-cancelling descending oscillations.
Brain and circulating steroids in an electric fish: relevance for non-breeding aggression
Authors: Zubizarreta Lucia , Jalabert Cecilia , Silva Ana C. , Soma Kiran K. , Quintana Laura 
Published: July 2023

AbstractSteroids play a crucial role in modulating brain and behavior. While traditionally it is considered that the brain is a target of peripheral hormones produced in endocrine glands, it has been discovered that the brain itself produces steroids, known as neurosteroids. Neurosteroids can be produced in brain regions involved in the regulation of social behaviors and can act locally regulating behaviors like reproduction and aggression. Here, for the first time in a teleost fish, we used liquid chromatography-tandem mass spectrometry (LC-MS/MS) to quantify a panel of 8 steroids in both plasma and brain. We use the weakly electric fishGymnotus omarorum, a species which shows non-breeding aggression in both sexes, to characterize these hormonal profiles in wild non-breeding adults. We show that: 1) systemic steroids in the non-breeding season are similar in both sexes, although only males have circulating 11-KT, 2) brain steroid levels are sexually dimorphic, as females display higher levels of AE, T and E1, and only males had 11-KT, 3) systemic androgens such as AE and T in the non-breeding season are potential precursors for neuroestrogen synthesis, and 4) estrogens, which play a key role in non-breeding aggression, are detectable in the brain (but not the plasma) in both sexes. These data fall in line with previous reports inG. omarorumwhich show that non-breeding aggression is dependent on the estrogenic pathway, as has also been shown in bird and mammal models. Overall, our results constitute a fundamental groundwork to understanding the complexity of hormonal modulation, its potential sex differences, the role of neurosteroids and the interplay between central and peripheral hormones in the regulation of behaviors.
RNAi-based screen for cuticle pigmentation inDrosophila melanogasterreveals novel regulators of brain dopamine
Authors: Deal Samantha L , Bei Danqing , Gibson Shelley B , Delgado-Seo Harim , Fujita Yoko , Wilwayco Kyla , Seto Elaine S , Yamamoto Shinya 
Published: July 2023

AbstractThe dopaminergic system has been extensively studied for its role in behavior in various animals as well as human neuropsychiatric and neurological diseases. However, we still know little about how dopamine levels are tightly regulatedin vivo. In order to identify novel regulators of dopamine levels, we utilizedDrosophila melanogastercuticle pigmentation as a readout, where dopamine is used as a precursor to melanin. First, we measured dopamine from classical mutants of genes that are known to be important for cuticle pigmentation to understand the relationship between dopamine levels and cuticle color. We then performed an RNAi-based screen to identify novel regulators of cuticle pigmentation. We identified 153 genes that were not only enriched for conserved homologs and disease-associated genes, but were unexpectedly enriched for multiple developmental signaling pathways and mitochondria-associated proteins. Upon measuring dopamine from 35 prioritized candidates from this cohort, we found 10 that caused significant reduction in dopamine in the head while one caused an increase. While most of these 11 genes are expressed in the fly brain, only two of them,cluandmask,altered dopamine levels specifically in the brain upon knockdown in dopaminergic cells. Interestingly,maskmay act as a hub of dopamine regulation since it is associated with three nodes found in our screen (Receptor tyrosine kinase/EGF signaling, Hippo signaling, and mitochondrial dynamics). Further examination suggests that Mask likely acts on dopamine synthesis by regulating transcription of the rate-limiting dopamine synthesis enzyme,tyrosine hydroxylase. In conclusion, this screen identified 11 new regulators of dopamine levels and provides molecular handles to investigate how dopamine levels are controlledin vivo, as well as revealed an unexpected relationship between fly pigmentation genes, developmental signaling and human neurological and neurodevelopmental disease genes.
Image Analysis Techniques for In Vivo Quantification of Cerebrospinal Fluid Flow
Authors: Kim Daehyun , Gan Yiming , Nedergaard Maiken , Kelley Douglas H. , Tithof Jeffrey 
Published: July 2023

AbstractOver the last decade, there has been a tremendously increased interest in understanding the neuro-physiology of cerebrospinal fluid (CSF) flow, which plays a crucial role in clearing metabolic waste from the brain. This growing interest was largely initiated by two significant discoveries: the glymphatic system (a pathway for solute exchange between interstitial fluid deep within the brain and the CSF surrounding the brain) and meningeal lymphatic vessels (lymphatic vessels in the layer of tissue surrounding the brain that drain CSF). These two CSF systems work in unison, and their disruption has been implicated in several neurological disorders including Alzheimer’s disease, stoke, and traumatic brain injury. Here, we present experimental techniques forin vivoquantification of CSF flow via direct imaging of fluorescent microspheres injected into the CSF. We discuss detailed image processing methods, including registration and masking of stagnant particles, to improve the quality of measurements. We provide guidance for quantifying CSF flow through particle tracking and offer tips for optimizing the process. Additionally, we describe techniques for measuring changes in arterial diameter, which is an hypothesized CSF pumping mechanism. Finally, we outline how these same techniques can be applied to cervical lymphatic vessels, which collect fluid downstream from meningeal lymphatic vessels. We anticipate that these fluid mechanical techniques will prove valuable for future quantitative studies aimed at understanding mechanisms of CSF transport and disruption, as well as for other complex biophysical systems.
Altered Fhod3 Expression Involved in Progressive High-Frequency Hearing Loss via Dysregulation of Actin Polymerization Stoichiometry in The Cuticular Plate
Authors: Boussaty Ely Cheikh , Ninoyu Yuzuru , Andrade Leo , Li Qingzhong , Takeya Ryu , Sumimoto Hideki , Ohyama Takahiro , Wahlin Karl J , Manor Uri , Friedman Rick A 
Published: July 2023

AbstractAge-related hearing loss (ARHL) is a common sensory impairment with complex underlying mechanisms. In our previous study, we performed a meta-analysis of genome-wide association studies (GWAS) in mice and identified a novel locus on chromosome 18 associated with ARHL specifically linked to a 32 kHz tone burst stimulus. Consequently, we investigated the role of Formin Homology 2 Domain Containing 3 (Fhod3), a newly discovered candidate gene for ARHL based on the GWAS results. We observed Fhod3 expression in auditory hair cells (HCs) and primarily localized at the cuticular plate (CP). To understand the functional implications of Fhod3 in the cochlea, we generated Fhod3 overexpression mice (Pax2-Cre+/-; Fhod3Tg/+) (TG) and HC-specific conditional knockout mice (Atoh1-Cre+/-; Fhod3fl/fl) (KO). Audiological assessments in TG mice demonstrated progressive high-frequency hearing loss, characterized by predominant loss of outer hair cells, and a decreased phalloidin intensities of CP. Ultrastructural analysis revealed shortened stereocilia in the basal turn cochlea. Importantly, the hearing and HC phenotype in TG mice were replicated in KO mice. These findings indicate that Fhod3 plays a critical role in regulating actin dynamics in CP and stereocilia. Further investigation of Fhod3 related hearing impairment mechanisms may facilitate the development of therapeutic strategies for ARHL in humans.
Tumor-reactive clonotype dynamics underlying clinical response to TIL therapy in melanoma
Authors: Chiffelle Johanna , Barras David , Pétremand Rémy , Orcurto Angela , Bobisse Sara , Arnaud Marion , Auger Aymeric , Rodrigo Blanca Navarro , Ghisoni Eleonora , Sauvage Christophe , Saugy Damien , Michel Alexandra , Murgues Baptiste , Fahr Noémie , Imbimbo Martina , Ochoa de Olza Maria , Latifyan Sofiya , Crespo Isaac , Benedetti Fabrizio , Genolet Raphael , Queiroz Lise , Schmidt Julien , Homicsko Krisztian , Zimmermann Stephan , Michielin Olivier , Bassani-Sternberg Michal , Kandalaft Lana E. , Dafni Urania , Corria-Osorio Jesus , Trueb Lionel , Laniti Denarda Dangaj , Harari Alexandre , Coukos George 
Published: July 2023

AbstractThe profiles, specificity and dynamics of tumor-specific clonotypes that are associated with clinical response to adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TILs) remain unclear. Using single-cell RNA/TCR-sequencing, we tracked TIL clonotypes from baseline tumors to ACT products and post-ACT blood and tumor samples in melanoma patients treated with TIL-ACT. Patients with clinical responses had baseline tumors enriched in tumor-reactive TILs, which were more effectively mobilized uponin vitroexpansion, yielding products with higher numbers of tumor-specific CD8+cells, which also preferentially infiltrated tumors post-ACT. Conversely, lack of clinical responses was associated with tumors devoid of tumor-reactive resident clonotypes, and with cell products mostly composed of blood-borne clonotypes mainly persisting in blood but not in tumors post-ACT. Upon expansion, tumor-specific TILs lost the specific signatures of states originally exhibited in tumors, including exhaustion, and in responders acquired an intermediate exhausted effector state after tumor engraftment, revealing important functional cell reinvigoration.
Addressing persistent challenges in digital image analysis of cancerous tissues
Authors: Prabhakaran Sandhya , Yapp Clarence , Baker Gregory J. , Beyer Johanna , Chang Young Hwan , Creason Allison L. , Krueger Robert , Muhlich Jeremy , Patterson Nathan Heath , Sidak Kevin , Sudar Damir , Taylor Adam J. , Ternes Luke , Troidl Jakob , Xie Yubin , Sokolov Artem , Tyson Darren R. ,   the Cell Imaging Hackathon 2022 Participants (Alphabetical authorship, apart from primary contributors)
Published: July 2023

AbstractThe National Cancer Institute (NCI) supports many research programs and consortia, many of which use imaging as a major modality for characterizing cancerous tissue. A trans-consortia Image Analysis Working Group (IAWG) was established in 2019 with a mission to disseminate imaging-related work and foster collaborations. In 2022, the IAWG held a virtual hackathon focused on addressing challenges of analyzing high dimensional datasets from fixed cancerous tissues. Standard image processing techniques have automated feature extraction, but the next generation of imaging data requires more advanced methods to fully utilize the available information. In this perspective, we discuss current limitations of the automated analysis of multiplexed tissue images, the first steps toward deeper understanding of these limitations, what possible solutions have been developed, any new or refined approaches that were developed during the Image Analysis Hackathon 2022, and where further effort is required. The outstanding problems addressed in the hackathon fell into three main themes: 1) challenges to cell type classification and assessment, 2) translation and visual representation of spatial aspects of high dimensional data, and 3) scaling digital image analyses to large (multi-TB) datasets. We describe the rationale for each specific challenge and the progress made toward addressing it during the hackathon. We also suggest areas that would benefit from more focus and offer insight into broader challenges that the community will need to address as new technologies are developed and integrated into the broad range of image-based modalities and analytical resources already in use within the cancer research community.
Adaptive therapy achieves long-term control of chemotherapy resistance in high grade ovarian cancer
Authors: Hockings Helen , Lakatos Eszter , Huang Weini , Mossner Maximilian , Khan Mohammed Ateeb , Metcalf Stephen , Nicolini Francesco , Smith Kane , Baker Ann-Marie , Graham Trevor A. , Lockley Michelle 
Published: July 2023

AbstractDrug resistance results in poor outcomes for most patients with metastatic cancer. Adaptive Therapy (AT) proposes to address this by exploiting presumed fitness costs incurred by drug-resistant cells when drug is absent, and prescribing dose reductions to allow fitter, sensitive cells to re-grow and re- sensitise the tumour. However, empirical evidence for treatment-induced fitness change is lacking. We show that fitness costs in chemotherapy-resistant ovarian cancer cause selective decline and apoptosis of resistant populations in low-resource conditions. Moreover, carboplatin AT caused fluctuations in sensitive/resistant tumour population sizein vitroand significantly extended survival of tumour-bearing mice. In sequential blood-derived cell-free DNA and tumour samples obtained longitudinally from ovarian cancer patients during treatment, we inferred resistant cancer cell population size through therapy and observed it correlated strongly with disease burden. These data have enabled us to launch a multicentre, phase 2 randomised controlled trial (ACTOv) to evaluate AT in ovarian cancer.
ChromatinHD connects single-cell DNA accessibility and conformation to gene expression through scale-adaptive machine learning
Authors: Saelens Wouter , Pushkarev Olga , Deplancke Bart 
Published: July 2023

1AbstractMachine learning methods that fully exploit the dual modality of single-cell RNA+ATAC-seq techniques are still lacking. Here, we developed ChromatinHD, a pair of models that uses the raw accessibility data, with-out peak-calling or windows, to predict gene expression and determine differentially accessible chromatin. We show how both models consistently outperform existing peak and window-based approaches, and find that this is due to a considerable amount of functional accessibility changes within and outside of putative cis-regulatory regions, both of which are uniquely captured by our models. Furthermore, ChromatinHD can delineate collaborating regions including their preferential genomic conformations that drive gene expression. Finally, our models also use changes in ATAC-seq fragment lengths to identify dense binding of transcription factors, a feature not captured by footprinting methods. Altogether, ChromatinHD, available athttps://deplanckelab.github.io/ChromatinHD, is a suite of computational tools that enables a data-driven understanding of chromatin accessibility at various scales and how it relates to gene expression.
Ultra-high density imaging arrays for diffuse optical tomography of human brain improve resolution, signal-to-noise, and information decoding
Authors: Markow Zachary E. , Trobaugh Jason W. , Richter Edward J. , Tripathy Kalyan , Rafferty Sean M. , Svoboda Alexandra M. , Schroeder Mariel L. , Burns-Yocum Tracy M. , Bergonzi Karla M. , Chevillet Mark. A. , Mugler Emily M. , Eggebrecht Adam T. , Culver Joseph P. 
Published: July 2023

ABSTRACTFunctional magnetic resonance imaging (fMRI) has dramatically advanced non-invasive human brain mapping and decoding. Functional near-infrared spectroscopy (fNIRS) and high-density diffuse optical tomography (HD-DOT) non-invasively measure blood oxygen fluctuations related to brain activity, like fMRI, at the brain surface, using more-lightweight equipment that circumvents ergonomic and logistical limitations of fMRI. HD-DOT grids have smaller inter-optode spacing (∼13 mm) than sparse fNIRS (∼30 mm) and therefore provide higher image quality, with spatial resolution ∼1/2 that of fMRI. Herein, simulations indicated reducing inter-optode spacing to 6.5 mm would further improve image quality and noise-resolution tradeoff, with diminishing returns below 6.5 mm. We then constructed an ultra-high-density DOT system (6.5-mm spacing) with 140 dB dynamic range that imaged stimulus-evoked activations with 30-50% higher spatial resolution and repeatable multi-focal activity with excellent agreement with participant-matched fMRI. Further, this system decoded visual stimulus position with 19-35% lower error than previous HD-DOT, throughout occipital cortex.
Conservation implications of diverse demographic histories: the case study of green peafowl (Pavo muticus, Linnaeus 1766)
Authors: Patil Ajinkya Bharatraj , Vijay Nagarjun 
Published: July 2023

AbstractThe green peafowl (Pavo muticus, Linnaeus 1766) is an endangered species native to the forests of tropical Southeast Asia. Although its morphological diversity and subspecies categorization is known and built upon traditional taxonomy, the intraspecific genetic structure has not been comprehensively addressed. To assess if phenotypic diversity is reflected at the molecular level, we used public whole-genome sequencing data of one blue peafowl and 52 green peafowls from multiple countries to characterize their genetic diversity, differentiation, identify Ancestry Informative Markers (AIMs) and compare their demographic histories. We found evidence of substantial population structure, with at least three distinct clusters and diverse demographic histories that may mirror different responses to various biogeoclimatic events. The genetic structure of native populations follows the pattern of the geographic distribution of the green peafowl with the highest autosomal pairwise FSTbetween Yunnan and Vietnam (∼0.1) and intermediate estimates for Thailand comparisons (∼0.077). We identify AIMs to distinguish between these three native populations. The captive green peafowls from Xinxing clustered with Vietnam and those from Qinhuangdao (QHD) formed a separate cluster. The two QHD individuals appear to have varying levels of blue peafowl ancestry based on PCA and admixture analysis and are mirrored in their demographic histories. Our study establishes the occurrence of genetically distinct natural populations of green peafowl that can be considered separate management units (MU) when planning conservation actions. Transboundary cooperation and concerted efforts to foster genetic diversity are imperative for Southeast Asian species at risk.