bluuebunny/crossref_metadata_2025_split huggingface dataset:
Altered PVN-to-CA2 hippocampal oxytocin pathway and reduced number of oxytocin-receptor expressing astrocytes in heart failure rats
Authors: Althammer Ferdinand , Roy Ranjan K. , Lefevre Arthur , Najjar Rami , Schoenig Kai , Bartsch Dusan , Eliava Marina , Feresin Rafaela , Hammock Elizabeth , Murphy Anne Z. , Charlet Alexandre , Grinevich Valery , Stern Javier E. 
Published: March 2022

AbstractOxytocinergic actions within the hippocampal CA2 are important for neuromodulation, memory processing and social recognition. However, the source of the OTergic innervation, the cellular targets expressing the OT receptors (OTRs) and whether the PVN-to-CA2 OTergic system is altered during heart failure (HF), a condition recently associated with cognitive and mood decline, remains unknown. Using immunohistochemistry along with retrograde monosynaptic tracing, RNAscope and a novel OTR-Cre rat line, we show that the PVN (but not the supraoptic nucleus) is an important source of OTergic innervation to the CA2. These OTergic fibers were found in many instances in close apposition to OTR expressing cells within the CA2. Interestingly, while only a small proportion of neurons were found to express OTRs (∼15%), this expression was much more abundant in CA2 astrocytes (∼40%), an even higher proportion that was recently reported for astrocytes in the central amygdala. Using an established ischemic rat heart failure (HF) model, we found that HF resulted in robust changes in the PVN-to-CA2 OTergic system, both at the source and target levels. Within the PVN, we found an increased OT immunoreactivity, along with a diminished OTR expression in PVN neurons. Within the CA2 of HF rats, we observed a blunted OTergic innervation, along with a diminished OTR expression, which appeared to be restricted to CA2 astrocytes. Taken together, our studies highlight astrocytes as key cellular targets mediating OTergic PVN inputs to the CA2 hippocampal region. Moreover, provides the first evidence for an altered PVN-to-CA2 OTergic system in HF rats, which could potentially contribute to previously reported cognitive and mood impairments in this animal model.
Beneficial effects of prolonged 2-phenylethyl alcohol inhalation on chronic distress-induced anxio-depressive-like phenotype in female mice
Authors: Ramadan Bahrie , Cabeza Lidia , Cramoisy Stéphanie , Houdayer Christophe , Andrieu Patrice , Millot Jean-Louis , Haffen Emmanuel , Risold Pierre-Yves , Peterschmitt Yvan 
Published: March 2022

AbstractChronic distress-induced hypothalamic-pituitary-adrenal axis deregulations have been associated with the development of neuropsychiatric disorders such as anxiety and depression. Currently available drugs treating such pathological conditions have limited efficacy and diverse side effects, revealing the need of new safer strategies. Aromatic plant-based compounds are largely used in herbal medicine due to their therapeutic properties on mood, physiology, and general well-being. The purpose of this study was to investigate the effects of 2-phenylethyl alcohol (PEA), one of the pharmacologically active constituents of rose essential oil, on chronic corticosterone (CORT)-induced behavioral and neurobiological changes in female mice. Animals followed a prolonged PEA inhalation exposure (30 min per day) for 15 consecutive days prior to behavioral evaluation with open-field, forced swim and novelty-suppressed feeding tests. CORT treatment induced an anxio-depressive-like phenotype, evidenced by a reduced locomotor activity in the open-field, and an increased latency to feed in the novelty-suppressed feeding paradigms. To elucidate the neural correlates of our behavioral results, cerebral cFos expression analysis was further performed to provide a global map of neuronal activity. The altered feeding behavior was accompanied by a significant decrease in the number of cFos-positive cells in the olfactory bulb, and altered brain connectivity as shown by cross-correlation-based network analysis. CORT-induced behavioral and neurobiological alterations were reversed by prolonged PEA inhalation, suggesting a therapeutic action that allows regulating the activity of neural circuits involved in sensory, emotional and feeding behaviors. These findings might contribute to better understand the therapeutic potential of PEA on anxio-depressive symptoms.
Spatio-temporal modeling reveals a layer of tunable control circuits for the distribution of cytokines in tissues
Authors: Brunner Patrick , Kiwitz Lukas , Thurley Kevin 
Published: March 2022

AbstractCytokines are diffusible mediators of cell-cell communication among immune cells with critical regulatory functions for cell differentiation and proliferation. Previous studies have revealed considerable spatial inhomogeneities in the distribution of cytokine molecules in tissues, potentially shaping the efficacy and range of paracrine cytokine signals. How such cytokine gradients emerge and are controlled within cell populations is incompletely understood. In this work, we employed a spatial reaction-diffusion model to systematically investigate the formation and influence of spatial cytokine gradients. We found the fraction of cytokine secreting cells to be the main source of spatial inhomogeneity and subsequent activation. Positive feedback from local cytokine levels upon cytokine receptor expression leads to further increased spatial cytokine inhomogeneities. By exploring the effect of co-clustering cytokine secreting cells and cells with large amounts of receptor expression, as in the presence of regulatory T cells in the vicinity of antigen-presenting cells, we found that such constrained tissue architecture can have profound effects on the range of paracrine cytokine signals.
Peripheral and central employment of acid-sensing ion channels during early bilaterian evolution
Authors: Martí-Solans Josep , Børve Aina , Bump Paul , Hejnol Andreas , Lynagh Timothy 
Published: March 2022

AbstractNervous systems are endowed with rapid chemosensation and intercellular signaling by ligand-gated ion channels (LGICs). While a complex, bilaterally symmetrical nervous system is a major innovation of bilaterian animals, the employment of specific LGICs during early bilaterian evolution is poorly understood. We therefore questioned bilaterian animals’ employment of acid-sensing ion channels (ASICs), LGICs that mediate fast excitatory responses to decreases in extracellular pH in vertebrate neurons. Our phylogenetic analysis identified an earlier emergence of ASICs from the overarching DEG/ENaC superfamily than previously thought and suggests that ASICs were a bilaterian innovation. Our broad examination of ASIC gene expression and biophysical function in each major bilaterian lineage of Xenacoelomorpha, Protostomia, and Deuterostomia, suggests that the earliest bilaterian ASICs were probably expressed in the periphery, before being incorporated into the brain as it emerged independently in certain deuterostomes and xenacoelomorphs. The loss of certain peripheral cells from Ecdysozoa when they split from other protostomes likely explains their loss of ASICs, and thus the absence of ASICs in model organismsDrosophilaandC. elegans. Thus, our use of diverse bilaterians in the investigation of LGIC expression and function offers a unique hypothesis on the employment of LGICs in early bilaterian evolution.
Causal Inference on Neuroimaging Data with Mendelian Randomisation
Authors: Taschler Bernd , Smith Stephen M. , Nichols Thomas E. 
Published: March 2022

AbstractWhile population-scale neuroimaging studies offer the promise of discovery and characterisation of subtle risk factors, massive sample sizes increase the power for both meaningful associations and those attributable to confounds. This motivates the need for causal modelling of observational data that goes beyond statements of association and towards deeper understanding of complex relationships between individual traits and phenotypes, clinical biomarkers, genetic variation, and brain-related measures of health. Mendelian randomisation (MR) presents a way to obtain causal inference on the basis of genetic data and explicit assumptions about the relationship between genetic variables, exposure and outcome. In this work, we provide an introduction to and overview of causal inference methods based on Mendelian randomisation, with examples involving imaging-derived phenotypes from UK Biobank to make these methods accessible to neuroimaging researchers. We motivate the use of MR techniques, lay out the underlying assumptions, introduce common MR methods and focus on several scenarios in which modelling assumptions are potentially violated, resulting in biased effect estimates. Importantly, we give a detailed account of necessary steps to increase the reliability of MR results with rigorous sensitivity analyses.
Lack of self-medication by fungus infected Lasius platythorax ants in a multitrophic experiment
Authors: Rissanen Jason , Helanterä Heikki , Will Torsten , Freitak Dalial 
Published: March 2022

AbstractAnts live in dense colonies with low genetic diversity between nestmates, creating favourable conditions for the spread of diseases. Due to the constant pressure by infectious disease, ants have evolved different mechanisms to cope with it. One way to combat pathogens is via consumption of biologically active compounds, which can inhibit the growth of the microbes or eliminate them. Although ants are known to respond to pathogen infections by altering their foraging to incorporate reactive oxygen species (ROS) into their diet to successfully combat disease under laboratory conditions, it is still unknown how ants would self-medicate in the wild. By designing a multitrophic environment, we try for the first time to identify potential sources of medicinal compounds for ants to use against fungal infections under natural conditions to better understand how the behaviour is expressed in nature. We investigated whether a bean plant suffering from an infestation of Megoura viciae aphids would be a source of ROS which the ant could use for self-medication, and whether the ant Lasius platythorax changes its foraging behaviour on bean plants if exposed to infectious spores of the entomopathogenic fungus Beauveria bassiana. We found no clear evidence that the ants significantly change their foraging behaviour on extrafloral nectaries in response to the pathogen or that the nectar produced by aphid stressed plants contains ROS. The aphids contained ROS in levels which ants could potentially use, however Megoura viciae is considered unpalatable to ants and we saw no evidence of predation on the aphids. Our results mean that the combination of species of the ant – plant – aphid interactions which we studied does result in a detectable self-medication response in ants. Therefore, we suggest that alternative species of aphids as well as other natural sources of ROS should be studied for self-medication.
Tissue-adjusted pathway analysis of cancer (TPAC)
Authors: Frost H. Robert 
Published: March 2022

AbstractWe describe a novel single sample pathway analysis method for cancer transcriptomics data named tissue-adjusted pathway analysis of cancer (TPAC). The TPAC method leverages information about the normal tissue-specificity of human genes to compute a robust multivariate distance score that quantifies pathway dysregulation in each profiled tumor. Because the null distribution of the TPAC scores has an accurate gamma approximation, both population and sample-level inference is supported. As we demonstrate through an analysis of gene expression data from The Cancer Genome Atlas (TCGA), TPAC pathway scores are more strongly associated with both patient prognosis and tumor stage than the scores generated by existing single sample pathway analysis methods. An R package implementing the TPAC method can be found athttps://hrfrost.host.dartmouth.edu/TPAC.
Understandable Multifunctionality Measures Using Hill Numbers
Authors: Byrnes Jarrett E. K. , Roger Fabian , Bagchi Robert 
Published: March 2022

AbstractIn ecology, multifunctionality measures the simultaneous performance of multiple ecosystem functions. If species diversity describes the variety of species that together build the ecosystem, multifunctionality attempts to describe the variety of functions these species perform. A range of methods have been proposed to quantify multifunctionality, successively attempting to alleviate problems that have been identified with the previous methods. This has led to a proliferation of more-or-less closely related metrics which, however, lack an overarching theoretical framework. Here we borrow from the comprehensive framework of species diversity to derive a new metric of multifunctionality. Analogously to the effective number of species used to quantify species diversity, the metric we propose is influenced both by the number of functions as well as, crucially, the evenness of performance levels across functions. In addition, the effective multifunctionality also considers the average level at which the functions are performed. The result is a measure of the cumulative performance of the system were all functions provided equally. The framework allows for the inclusion of the correlation structure among functions, thus allowing it to account for non-independence between functions. We show that the average metric is a special case of the newly proposed metric when all functions are uncorrelated and performed at equal levels. We hope that by providing a new metric of multifunctionality anchored in the rigorous framework of species diversity based on effective numbers, we will overcome the considerable skepticism that the larger community of ecologists has built against indices of multifunctionality. We thereby hope to help popularize this important concept which, as biological diversity, describes a fundamental property of ecosystems and thus lies at the heart of ecology.
Influence of perceptual load on attentional orienting in post-stroke fatigue: a study of auditory evoked potentials
Authors: De Doncker William , Kuppuswamy Annapoorna 
Published: March 2022

AbstractObjectiveIncreasing perceptual load alters behavioural outcomes in post-stroke fatigue. While the effect of perceptual load on top-down attentional processing is known, here we investigate if increasing perceptual load modulates bottom-up attentional processing in a fatigue dependent manner.MethodsIn this cross-sectional observational study, in twenty-nine first-time non-depressed stroke survivors, an auditory oddball task consisting of target, standard and novel tones was performed in conditions of low and high perceptual load. Electroencephalography was used to measure auditory evoked potentials. Perceived effort was rated using the visual analog scale at regular intervals during the experiment. Fatigue was measured using the fatigue severity scale. The effect of fatigue and perceptual load on behaviour (response time, accuracy, and effort rating) and auditory evoked potentials (amplitude and latency) was examined using mixed model ANOVAS.ResultsResponse time was prolonged with greater perceptual load and fatigue. There was no effect of load or fatigue on accuracy. Greater effort was reported with higher perceptual load both in high and low fatigue. p300a amplitude of auditory evoked potentials (AEP) for novel stimuli was attenuated in high fatigue with increasing load when compared to low fatigue. Latency of p300a was longer in low fatigue with increasing load when compared to high fatigue. There were no effects on p300b components, with smaller N100 in high load conditions.InterpretationHigh fatigue specific modulation of p300a component of AEP with increasing load is indicative of distractor driven alteration in orienting response, suggestive of compromise in bottom-up selective attention in post-stroke fatigue.
Heterocyclic aromatic amines (HAAs) target mitochondrial physiology
Authors: Sammi Shreesh Raj , Syeda Tauqeerunnisa , Foguth Rachel , Cannon Jason 
Published: March 2022

AbstractHeterocyclic aromatic amines (HAA) may be found naturally in plants or are formed through the Maillard reaction when meat is cooked at high temperatures. Previous studies have indicated HAAs are especially toxic to dopaminergic neurons, whereas specific exposures may also affect other neuronal populations such as cholinergic neurons. Biochemical mechanisms of neurotoxic action implicate elevated oxidative stress and afflicted mitochondria. Notably, these mechanisms are of importance in Alzheimer’s disease (AD) and Parkinson’s disease (PD). Most neurodegenerative disease cases are sporadic, where environmental and dietary factors may modulate risk. To further investigate HAA neurotoxicity, we tested the effect of common HAA (harmane, harmine, norharmane, PhIP, and HONH-PhIP) exposure on mitochondrial physiology, a key pathogenic target in AD and PD. Upon assessing mitochondrial bioenergetics, we observed a significant reduction in basal respiration, ATP production, maximal respiratory capacity, and non-mitochondrial respiration, indicating that HAA negatively impacts mitochondrial respiration. Followed by more specific studies on individual mitochondrial complexes, it was found that harmane, harmine, norharmane specifically inhibit complex I enzyme activity, whereas HONH-PhiP, a reactive metabolite of PhIP, inhibits Complex III enzyme activity. Our findings provide significant advancement with respect to underlying mechanisms of toxicity, though also validating HAA exposure as a potential risk factor for AD and PD.
Maternal separation induces autism spectrum disorder in young rhesus monkeys
Authors: Ren Xiao-Feng , Wu Shi-Hao , Zhou Hui , Lv Long-Bao , Qiu Zi-Long , Feng Xiao-Li , Hu Xin-Tian 
Published: March 2022

AbstractAutism spectrum disorder (ASD) is a class of severe neurodevelopmental disorders with a high incidence in young children, and its pathogenesis remains elusive. There is no effective treatment, and ASD children usually have a hard time in integrating into society and leading a normal life, which places a heavy burden on the families and society. Studies have shown that in addition to genetic factors, environmental factors are another important risk contributing to the pathogenesis of ASD. Early environmental adversity, which can lead to abnormal brain development and affect cognition and behavior, greatly increases the incidence of a variety of brain developmental diseases including ASD. However, studies on this aspect are inadequate at present, and no clear conclusions can be drawn. We explored whether early adversity could trigger ASD core clinical symptoms in macaques by modeling early adversity through maternal separation. In this study, we conducted a rigorous behavioral analysis of 12 male macaques (1.5-2 years old) that underwent maternal separation and 9 male normal macaques of the same age that had been mother raised, and found that maternal separation could induce a small number of the young individuals to develop three core symptoms of ASD, including social impairment, stereotyped behaviors, and restricted interest simultaneously. According to DSM-V and ASD clinical diagnostic criteria, these individuals should be ASD macaques for having all the three core ASD symptoms at the same time., For the first time, this study reveals that early environmental adversity can lead to ASD pathogenesis in monkeys, and provides a new approach for future ASD studies and modeling ASD monkeys.
Molecular determinants of the Bacillus subtilis chromosome origin basal unwinding system
Authors: Pelliciari Simone , Burnham Daniel R. , Merces George , Yardimci Hasan , Murray Heath 
Published: March 2022

SUMMARYGenome duplication is essential for cell proliferation and DNA synthesis is generally initiated by dedicated replication proteins at specific loci termed origins. During DNA replication initiation in bacteria, the ubiquitous DnaA protein engages both double-strand DNA (dsDNA) and single-stranded DNA (ssDNA) at the chromosome origin (oriC) to promote DNA duplex unwinding. While the molecular basis for DnaA binding to a specific dsDNA element (“DnaA-box”) has been established, the mechanism for DnaA binding to a specific ssDNA motif (“DnaA-trio”) is unclear. Here we define specific steps of DnaA-trio engagement by Bacillus subtilis DnaA. Single-molecule total internal reflection fluorescence microscopy indicates that DnaA proteins are loaded onto DnaA-trios using DnaA-boxes located on a shared DNA polymer. Chemical modification of either the phosphodiester backbone or the nucleobases revealed that three DnaA-trio repeats proximal to DnaA-boxes are necessary and sufficient to promote DnaA-dependent strand separation, and that the amino group from the central nucleobase of the DnaA-trio is critical for this reaction. Finally, based on electrophoretic mobility shift assays, we propose that during replication initiation DnaA progresses from DnaA-boxes to nucleobase recognition at DnaA-trios before engaging the phosphodiester backbone and destabilizing the DNA duplex. These results provide new molecular insight into DnaA-dependent Bacterial Unwinding System (BUS) activity at a bacterial chromosome origin.
Novel repertoire of tau biosensors to monitor pathological tau transformation and seeding activity in living cells
Authors: Cecon Erika , Oishi Atsuro , Luka Marine , Ndiaye-Lobry Delphine , François Arnaud , Lescuyer Mathias , Panayi Fany , Dam Julie , Machado Patricia , Jockers Ralf 
Published: March 2022

ABSTRACTAggregates of the tau protein are a well-known hallmark of several neurodegenerative diseases, collectively referred as tauopathies, including frontal temporal dementia and Alzheimer’s disease (AD). Monitoring the transformation process of tau from physiological monomers into pathological oligomers or aggregates in a high-throughput, quantitative manner and in a cellular context is still a major challenge in the field. Identifying molecules able to interfere with those processes is of high therapeutic interest. Here, we developed a series of inter- and intramolecular tau biosensors based on the highly sensitive Nanoluciferase (Nluc) binary technology (NanoBiT) able to monitor the pathological conformational change and self-interaction of tau in living cells. Our repertoire of tau biosensors reliably reporti.molecular proximity of physiological full-length tau at microtubules;ii.changes in tau conformation and self-interaction associated with tau phosphorylation, as well asiii.tau interaction induced by seeds of recombinant tau or from mouse brain lysates of a mouse model of tau pathology. By comparing biosensors comprising different tau forms (i.e.full-length or short fragments, wild-type or the disease-associated tau(P301L) variant) further insights in the tau transformation process are obtained. Proof-of-concept data for the high-throughput suitability and identification of molecules interfering with the pathological tau transformation processes are presented. This novel repertoire of tau biosensors is aimed to boost the disclosure of molecular mechanisms underlying pathological tau transformation in living cells and to discover new drug candidates for tau-related neurodegenerative diseases.