bluuebunny/crossref_metadata_2025_split huggingface dataset:
Spreading depolarization causes reperfusion failure after cerebral ischemia
Authors: Törteli Anna , Tóth Réka , Berger Sarah D. , Samardzic Sarah , Bari Ferenc , Menyhárt Ákos , Farkas Eszter 
Published: September 2022

AbstractBackgroundDespite successful recanalization to treat acute ischemic stroke, reperfusion failure associated with poor functional outcomes develops in half of the patients. The cause of reperfusion failure remains the subject of intensive research. Here, we explore the possibility that spreading depolarization (SD), a potent ischemic injury mechanism is a significant contributor and reliable predictor of reperfusion failure.MethodsYoung adult male and female C57BL/6 mice (n=69) were anesthetized with isoflurane (0.6-0.9%) and prepared for transcranial optical imaging. After 10 min of baseline, incomplete global forebrain ischemia was induced by transient (45 min) bilateral common carotid artery (CCA) occlusion, followed by 75 min reperfusion. SD and cerebral blood flow (CBF) changes were visualized with intrinsic optical signal imaging and laser speckle contrast imaging. To block SD, the irreversible NMDA receptor antagonist MK801 was applied (0.3 mg/kg, i.p., n=29). Neurological deficit was evaluated at baseline and post-ischemia with a composite Garcia Neuroscore scale. Collaterals of the circle of Willis were examined after loading the vasculature with carbon black ink. Ischemic neuronal injury was evaluated in hematoxylin-eosin-stained brain sections.ResultsSD emerged after ischemia onset in one or both hemispheres under a perfusion threshold (CBF drop to 21.1±4.6 vs. 33.6±4.4 %, SD vs. no SD). The failure of later reperfusion (44.4±12.5 %) was invariably linked to previous ischemic SD. In contrast, reperfusion was adequate (98.9±7.4 %) in hemispheres devoid of SD during ischemia. CBF reduced below the perfusion threshold of SD, when the P1 segment was absent in the circle of Willis. SD occurrence and the linked reperfusion failure were associated with poor neurologic function, and greater neuronal necrosis. The inhibition of SD with MK801 significantly improved reperfusion.ConclusionsSD occurrence during ischemia impairs later reperfusion, prognosticating poor functional outcomes. The increased likelihood of SD occurrence is predicted by inadequate collaterals.
A machine learning liver-on-a-chip system for safer drug formulation
Authors: Shi Yunhua , Lin Chih-Hsin , Reker Daniel , Steiger Christoph , Hess Kaitlyn , Collins Joy E. , Tamang Siddartha , Ishida Keiko , Lopes Aaron , Wainer Jacob , Hayward Alison M. , Walesky Chad , Goessling Wolfram , Traverso Giovanni 
Published: September 2022

AbstractDrug metabolism leads to biotransformations of pharmaceutical substances that alter drug efficacy, toxicity, as well as drug interactions. Modeling these processes ex vivo stands to greatly accelerate our capacity to develop safe and efficacious drugs and formulations. Recognizing the liver as the primary site of drug metabolism, here we report a novel whole-tissue ex vivo liver screening platform that enabled modeling of hepatic metabolism and tracking of hepatotoxic drug metabolites. We applied the system for the characterization of acetaminophen (APAP) metabolism and identified interactions that can mitigate the generation of toxic metabolites ex vivo. Combining our experimental platform with state-of-the-art machine learning, we validated two novel functional excipients that can prevent APAP hepatotoxicity in vivo in mice. To assess translational potential, we prototyped a novel solid dosage form with controlled release of both APAP and our functional excipients. Our this platform provides innovative potential access to actionable data on drug metabolism to support the development of new therapeutic approaches.
White matter structural bases for predictive tapping synchronization
Authors: García-Saldivar Pamela , de León Cynthia , Concha Luis , Merchant Hugo 
Published: September 2022

AbstractWe determined the intersubject association between rhythmic entrainment abilities of human subjects during a synchronization continuation tapping task (SCT) and the macro and microstructural properties of their superficial (SWM) and deep (dWM) white matter. Diffusion-weighted images were obtained from 32 subjects who also performed the SCT with auditory or visual metronomes and five tempos ranging from 550 to 950 ms. We developed a method to determine the fiber density of U-fibers running tangentially to the cortex. Notably, the right audiomotor system showed individual differences in the density of U-fibers that were correlated with the degree of predictive entrainment across subjects. These correlations were selective for the synchronization epoch with auditory metronomes and were specific for tempos around 1.5 Hz. In addition, there was a significant association between predictive rhythmic entrainment and the density and bundle diameter of the corpus callosum (CC), forming a chronotopic map where behavioural correlations of short and long intervals were found with the anterior and posterior portions of the CC. Finally, the fiber bundle cross-section of the arcuate fasciculus, the CC, and the Superior Longitudinal Fasciculus showed a significant correlation with the mean asynchronies of the auditory SCT. These findings suggest that the structural properties of the SWM and dWM in the audiomotor system support the predictive abilities of subjects during rhythmic tapping, where the density of cortical U-fibers are linked to the preferred tapping tempo, and the bundle properties of CC define an interval selective topography that has an anterior posterior gradient.
Heart Is Deceitful Above All Things: threat expectancy induces the illusory perception of increased heartrate
Authors: Parrotta Eleonora , Bach Patric , Perrucci Mauro Gianni , Costantini Marcello , Ferri Francesca 
Published: September 2022

AbstractThe perception of the internal milieu is thought to reflect beliefs and prior knowledge about the expected state of the body, rather than only actual interoceptive states. This study investigated whether heartbeat perception could be illusorily distorted towards prior subjective beliefs, such that threat expectations suffice to induce a false perception of increased heartbeat frequency. Participants were instructed to focus on their cardiac activity and report their heartbeat, either tapping along to it (Experiment 1) or silently counting (Experiment 2) while ECG was recorded. While completing this task, different cues provided valid predictive information about the intensity of an upcoming cutaneous stimulation (high- vs. low- pain). Results showed that participants expected a heart rate increase over the anticipation of high- vs. low-pain stimuli and that this belief was perceptually instantiated, as shown by their interoceptive reports. Importantly, the perceived increase was not mirrored by the real heart rate. Perceptual modulations were absent when participants executed the same task but with an exteroceptive stimulus (Experiment 3). The findings reveal, for the first time, an interoceptive illusion of increased heartbeats elicited by threat expectancy and shed new light on interoceptive processes through the lenses of Bayesian predictive processes, providing tantalizing insights into how such illusory phenomena may intersect with the recognition and regulation of people’s internal states.
Reorganizing Niche Architecture Still Preserves Organ Function in the Hair Follicle
Authors: Wei Haoyang , Du Shuangshuang , Parksong Jeeun , Pasolli H. Amalia , Regot Sergi , Gonzalez Lauren E. , Xin Tianchi , Greco Valentina 
Published: September 2022

SummaryStem cells’ ability to build and replenish tissues depends on support from their niche. While niche architecture varies across different organs, the functional importance of niche architecture is unclear. During hair follicle growth, multipotent epithelial progenitors build hair via crosstalk with their remodeling fibroblast niche, the dermal papilla, providing a powerful model to functionally interrogate different niche architectures. Through intravital imaging, we show that dermal papilla fibroblasts remodel both individually and collectively to form a polarized, structurally robust niche. Polarized TGFβ signaling precedes structural niche polarity, and loss of TGFβ signaling in dermal papilla fibroblasts leads them to progressively lose their stereotypic architecture and instead surround the epithelium. The reorganized niche relocates multipotent progenitors, but nevertheless supports their proliferation and differentiation. However, progenitor differentiation is completed prematurely, resulting in compromised hair production. Overall, our results reveal that niche architecture optimizes organ efficiency, but is not absolutely essential for organ function.
Bicistronic expression of a high-performance calcium indicator and opsin yields stable, robust cortical expression for holographic two-photon stimulation
Authors: LaFosse Paul K. , Zhou Zhishang , Friedman Nina G. , Deng Yanting , Akitake Bradley , Histed Mark H. 
Published: September 2022

AbstractPatterns of activity across many neurons are fundamental units of neural computation. Two-photon holographic photostimulation allows both delivering input to, and imaging responses from, patterns or populations of neurons. However, to make this method an easily-deployable tool, simple methods are needed to robustly and stably express opsins and indicators in the same cells. Here we describe a bicistronic adeno-associated virus (AAV) that in transfected cells expresses both the fast and bright calcium indicator GCaMP8s, and a soma-targeted (st) and two-photon-activatable opsin, ChrimsonR. With this method, in the visual cortex of mice, stChrimsonR stimulation with two-photon holography drives robust spiking in targeted cells, and neural responses to visual sensory stimuli and spontaneous activity are strong and easy to measure. stChrimsonR is a good choice of opsin when a balance is needed between stimulation-laser activatability and avoidance of imaging laser activation. This approach is a simple and robust way to prepare neurons in vivo for two-photon holography and imaging.Significance statementThe recent advent of holographic photostimulation methods in conjunction with standard two-photon calcium imaging promises unprecedented levels of control in manipulating and dissecting brain circuitry in vivo while reading out neural activity. These all-optical methods rely on a working synergy between optogenetic strategies to both measure calcium activity through genetically-encoded calcium indicators and modulate cell activity through light-activated opsins. Genetic strategies to achieve reliable and stable co-expression of opsin and indicator remain sparse and often challenging to execute. Here, we present a genetic tool to achieve robust co-expression of jGCaMP8s indicator and stChrimsonR opsin via a single injected virus to help facilitate experiments aiming to use holography to investigate the circuit principles underlying brain activity.
High-Frequency Stimulation Does Not Improve Comfort of Transcutaneous Spinal Cord Stimulation
Authors: Dalrymple Ashley N , Hooper Charli Ann , Kuriakose Minna G , Capogrosso Marco , Weber Douglas J 
Published: September 2022

ABSTRACTSpinal cord neuromodulation has gained much attention for demonstrating improved motor recovery in people with spinal cord injury, motivating the development of clinically applicable technologies. Among them, transcutaneous spinal cord stimulation (tSCS) is attractive because of its non-invasive profile. Many tSCS studies employ a high-frequency (10 kHz) carrier, which has been reported to reduce stimulation discomfort. However, these claims have come under scrutiny in recent years. The purpose of this study was to determine whether high-frequency tSCS is more comfortable at therapeutic amplitudes, which evoke posterior root-muscle (PRM) reflexes. In 16 neurologically intact participants, tSCS was delivered using a 1-ms long monophasic pulse with and without a high-frequency carrier. Stimulation amplitude and pulse duration were varied and PRM reflexes were recorded from the soleus, gastrocnemius, and tibialis anterior muscles. Participants rated their discomfort during stimulation from 0-10 at PRM reflex threshold. At PRM reflex threshold, high-frequency stimulation (0.87 ± 0.2) was equally comfortable as conventional stimulation (1.03 ± 0.18) but required approximately double the charge to evoke the PRM reflex (conventional: 32.4 ± 9.2 µC; high-frequency: 62.5 ± 11.1 µC). Strength-duration curves for high-frequency stimulation had a rheobase that was 4.8X greater and a chronaxie that was 5.7X narrower than the conventional monophasic pulse, indicating that high-frequency stimulation was less efficient in recruiting neural activity in spinal roots. High-frequency tSCS is equally as comfortable as conventional stimulation at amplitudes required to stimulate spinal dorsal roots.GRAPHICAL ABSTRACT
Wildfires change plant scents but not pollinator attraction in a Mediterranean palm
Authors: García Yedra , Clara Castellanos María , Pausas Juli G. 
Published: September 2022

AbstractNatural fire regimes are currently changing worldwide. These alterations may affect not only plant and animal species but also their interactions. Recently, a few studies have shown the effects of different disturbances on pollination through changes on plant fragrances mediating this interaction, yet no studies have focused on the effects of fires. Here, we assessed whether wildfires can modify plant scents and, in turn, pollinator attraction in a widespread palm in the western Mediterranean Basin. We studied the fireadapted palm Chamaerops humilis and its nursery (dominant in unburnt sites) and nonnursery (dominant in recently burnt sites) beetle pollinators. In nursery pollination systems, where pollinators develop inside their host plant, volatile organic compounds (VOCs) emitted by plants to attract pollinators can be crucial because of the tight interdependence among the interacting species. However, these systems can also involve non-nursery copollinators whose importance is context dependent, and potentially relevant for plant success after disturbance. We first compare scent composition between plants growing in burned and unburned sites after recent wildfires; then we conducted olfactory bioassays with the two beetle pollinators. Fires changed the palm’s scent composition; however, the two pollinators responded similarly to scent from burnt and unburnt areas which may ensure plant reproduction even after recent fire events. We show, for the first time, that wildfires can alter plant fragrances mediating mutualistic interactions, and that flexible pollinator responses to variable odourscapes can enhance resilience in plant performance.
Decoding Attended Spatial Location during Complex Scene Analysis with fNIRS
Authors: Ning Matthew , Yücel Meryem A. , Von Lühmann Alexander , Boas David A. , Sen Kamal 
Published: September 2022

AbstractWhen analyzing complex scenes, humans often focus their attention on an object at a particular spatial location. The ability to decode the attended spatial location would facilitate brain computer interfaces for complex scene analysis. Here, we investigated functional near-infrared spectroscopy’s (fNIRS) capability to decode audio-visual spatial attention in the presence of competing stimuli from multiple locations. We targeted dorsal frontoparietal network including frontal eye field (FEF) and intra-parietal sulcus (IPS) as well as superior temporal gyrus/planum temporal (STG/PT). They all were shown in previous functional magnetic resonance imaging (fMRI) studies to be activated by auditory, visual, or audio-visual spatial tasks. We found that fNIRS provides robust decoding of attended spatial locations for most participants and correlates with behavioral performance. Moreover, we found that FEF makes a large contribution to decoding performance. Surprisingly, the performance was significantly above chance level 1s after cue onset, which is well before the peak of the fNIRS response. Our results demonstrate that fNIRS is a promising platform for a compact, wearable technology that could be applied to decode attended spatial location and reveal contributions of specific brain regions during complex scene analysis.
Avoiding misleading estimates using mtDNA heteroplasmy statistics to study bottleneck size and selection
Authors: Giannakis Konstantinos , Broz Amanda K. , Sloan Daniel B. , Johnston Iain G. 
Published: September 2022

AbstractMitochondrial DNA (mtDNA) heteroplasmy samples can shed light on vital developmental and genetic processes shaping mtDNA populations. The sample mean and sample variance of a set of heteroplasmy observations are typically used both to estimate bottleneck sizes and to perform fits to the theoretical “Kimura” distribution in seeking evidence for mtDNA selection. However, each of these applications raises problems. Sample statistics do not generally provide optimal fits to the Kimura distribution and so can give misleading results in hypothesis testing, including false positive signals of selection. Using sample variance can give misleading results for bottleneck size estimates, particularly for small samples. These issues can and do lead to false positive results for mtDNA mechanisms – all published experimental datasets we re-analysed, reported as displaying departures from the Kimura model, do not in fact give evidence for such departures. Here we outline a maximum likelihood approach that is simple to implement computationally and addresses all of these issues. We advocate the use of maximum likelihood fits and explicit hypothesis tests, not fits and Kolmogorov-Smirnov tests via summary statistics, for ongoing work with mtDNA heteroplasmy.
Vitamin B12 produced by gut bacteria modulates excitatory neurotransmission
Authors: Kang Woo Kyu , Araya Antonia , Fox Bennett W. , Thackeray Andrea , Schroeder Frank C. , Walhout Albertha J.M. , Alkema Mark J. 
Published: September 2022

ABSTRACTA growing body of evidence indicates that gut microbiota influence brain function and behavior. However, the molecular basis of how gut bacteria modulate host nervous system function is largely unknown. Here we show that vitamin B12-producing bacteria that colonize the intestine can modulate excitatory synaptic transmission and behavior in the host Caenorhabditis elegans. We find that vitamin B12 reduces cholinergic signaling in the nervous system through rewiring of the methionine (Met)/S-Adenosylmethionine (SAM) cycle in the intestine. We identify a conserved metabolic crosstalk between the Met/SAM cycle and the choline oxidation pathway. We show that metabolic rewiring of these pathways by vitamin B12 reduces cholinergic transmission by limiting the availability of free choline required by neurons to synthesize acetylcholine. Our study reveals a gut-brain communication pathway by which enteric bacteria modulate host behavior and may affect mental health.
Rapidly Inferring Personalized Neurostimulation Parameters with Meta-Learning: A Case Study of Individualized Fiber Recruitment in Vagus Nerve Stimulation
Authors: Mao Ximeng , Chang Yao-Chuan , Zanos Stavros , Lajoie Guillaume 
Published: September 2022

AbstractObjectiveNeurostimulation is emerging as treatment for several diseases of the brain and peripheral organs. Due to variability arising from placement of stimulation devices, underlying neuroanatomy and physiological responses to stimulation, it is essential that neurostimulation protocols are personalized to maximize efficacy and safety. Building such personalized protocols would benefit from accumulated information in increasingly large datasets of other individuals’ responses.ApproachTo address that need, we propose a meta-learning family of algorithms to conduct few-shot optimization of key fitting parameters of physiological and neural responses in new individuals. While our method is agnostic to neurostimulation setting, here we demonstrate its effectiveness on the problem of physiological modeling of fiber recruitment during vagus nerve stimulation (VNS). Using data from acute VNS experiments, the mapping between amplitudes of stimulus-evoked compound action potentials (eCAPs) and physiological responses, such as heart rate and breathing interval modulation, is inferred.Main resultsUsing additional synthetic data sets to complement experimental results, we demonstrate that our meta-learning framework is capable of directly modeling the physiology-eCAP relationship for individual subjects with much fewer individually queried data points than standard methods.SignificanceOur meta-learning framework is general and can be adapted to many input-response neurostimulation mapping problems. Moreover, this method leverages information from growing data sets of past patients, as a treatment is deployed. It can also be combined with several model types, including regression, Gaussian processes with Bayesian optimization, and beyond.
Multivariate divergence in wild microbes: no evidence for evolution along a genetic line of least resistance
Authors: Gluck-Thaler Emile , Shaikh Muhammad , Wood Corlett W. 
Published: September 2022

AbstractTrait evolution depends both on the direct fitness effects of specific traits and on indirect selection arising from genetically correlated traits. Although well established in plants and animals, the role of trait correlations in microbial evolution remains a major open question. Here, we tested whether genetic correlations in a suite of metabolic traits are conserved between two sister lineages of fungal endophytes, and whether phenotypic divergence between lineages occurred in the direction of the multivariate trait combination containing the most genetic variance within lineages i.e., the genetic lines of least resistance. We found that while one lineage grew faster across nearly all substrates, lineages differed in their mean response to specific substrates and in their overall multivariate metabolic trait means. The structure of the genetic variance-covariance (G) matrix was conserved between lineages, yet to our surprise, divergence in metabolic phenotypes between lineages was nearly orthogonal to the major axis of genetic variation within lineages, indicating that divergence did not occur along the genetic lines of least resistance. Our findings suggest that the evolutionary genetics of trait correlations in microorganisms warrant further research, and highlight the extensive functional variation that exists at very fine taxonomic scales in host-associated microbial communities.