bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of the IL-17A axis Protects against Immune-related Adverse Events while Supporting Checkpoint Inhibitor Anti-tumor Efficacy
Authors: Lechner Melissa G. , Patel Anushi Y. , Hugo Willy , Angell Trevor E. , Cheng Mandy I. , Pioso Marissa S. , Hoang Aline T. , Yakobian Natalie , McCarthy Ethan C. , Chen Ho-Chung , Rodriguez Eduardo D. , Guo Lily , Astourian Michael , Drakaki Alexandra , Famini Pouyan , Ribas Antoni , Su Maureen A. 
Published: January 2022

ABSTRACTCheckpoint inhibitor (ICI) immunotherapy leverages the body’s own immune system to attack cancer cells but leads to unwanted autoimmune side effects in up to 60% of patients. Such immune related adverse events (IrAE) may lead to treatment interruption, permanent organ dysfunction, hospitalization and premature death. Thyroiditis is one of the most common IrAE, but the cause of thyroid IrAE remains unknown. Here we present a novel mouse model in which checkpoint inhibitor therapy leads to multi-organ autoimmune infiltrates and show that activation and infiltration of Type 3 immune cells including IL17A+RORγt+CD4+(T helper 17 or Th17) and gamma delta 17 (γδT17) T cells promote thyroid IrAE development. IL-17A+T cells were similarly found in thyroid specimens from cancer patients treated with ICI who developed thyroid IrAE. Furthermore, antibody-based inhibition of IL-17A, a clinically available therapy, significantly reduced thyroid IrAE development in ICI-treated mice. Finally, combination of IL-17A neutralization with ICI treatment in multiple tumor models did not reduce ICI anti-tumor efficacy. These studies suggest that targeting Th17 and γδ17 function may reduce IrAE without impairing ICI anti-tumor efficacy and may be a generalizable strategy to address IL17-mediated IrAE.
Characterization of second-order mixing effects in reconstructed cross-spectra of random neural fields
Authors: Hindriks Rikkert 
Published: January 2022

AbstractFunctional connectivity in electroencephalography (EEG) and magnetoencephalography (MEG) data is commonly assessed by using measures that are insensitive to instantaneously interacting sources and as such would not give rise to false positive interactions caused by instantaneous mixing of true source signals (first-order mixing). Recent studies, however, have drawn attention to the fact that such measures are still susceptible to instantaneous mixing from lagged sources (i.e. second-order mixing) and that this can lead to a large number of false positive interactions. In this study we relate first- and second-order mixing effects on the cross-spectra of reconstructed source activity to the properties of the resolution operators that are used for the reconstruction. We derive two identities that relate first- and second-order mixing effects to the transformation properties of measurement and source configurations and exploit them to establish several basic properties of signal mixing. First, we provide a characterization of the configurations that are maximally and minimally sensitive to second-order mixing. It turns out that second-order mixing effects are maximal when the measurement locations are far apart and the sources coincide with the measurement locations. Second, we provide a description of second-order mixing effects in the vicinity of the measurement locations in terms of the local geometry of the point-spread functions of the resolution operator. Third, we derive a version of Lagrange’s identity for cross-talk functions that establishes the existence of a trade-off between the magnitude of first- and second-order mixing effects. It also shows that, whereas the magnitude of first-order mixing is determined by the inner product of cross-talk functions, the magnitude of second-order mixing is determined by a generalized cross-product of cross-talk functions (the wedge product) which leads to an intuitive geometric understanding of the trade-off. All results are derived within the general framework of random neural fields on cortical manifolds.
Brain-wide continuous functional ultrasound imaging for real-time monitoring of hemodynamics during ischemic stroke
Authors: Brunner Clément , Denis Nielsen Lagumersindez , Gertz Karen , Grillet Micheline , Montaldo Gabriel , Endres Matthias , Urban Alan 
Published: January 2022

AbstractIschemic stroke occurs with no warning, and therefore, very little is known about hemodynamic perturbations in the brain immediately after stroke onset. Here, functional ultrasound imaging was used to monitor variations in relative cerebral blood volume (rCBV) compared to baseline. rCBV levels were analyzed brain-wide and continuously at high spatiotemporal resolution (100μm, 2Hz) until 70mins after stroke onset in rats. We compared two stroke models, with either a permanent occlusion of the middle cerebral artery (MCAo) or a tandem occlusion of both the common carotid and middle cerebral arteries (CCAo+MCAo). We observed a typical hemodynamic pattern, including a quick drop of the rCBV after MCAo, followed by spontaneous reperfusion of several brain regions located in the vicinity of the ischemic core. The severity and location of the ischemia were highly variable between animals. Still, both parameters were, on average, in good agreement with the final ischemic lesion volume measured 24hrs after stroke onset for the MCAo but not the CCAo+MCAo model. For the latter, we observed that the infarct was extended to regions that were initially not ischemic and located rostrally of the ischemic core. These regions strongly colocalize with the origin of transient hemodynamic events associated with spreading depolarizations.
Therapeutic Interruption of T Cell Development Generates High-Affinity T Cells That Escape Exhaustion and Improve Cancer Immunotherapy
Authors: Dhuey Erica , Oldridge Olivia , Ravishankar Roshan , Dada Hannah , Yu Yongjun , Anderson Mark S. , Minn Andy J. 
Published: January 2022

SUMMARYAvailability of effective anti-tumor T cells is limited by cancer immunoediting, which depletes neoantigens, and central tolerance, which eliminates developing T cells with high-affinity T cell receptors (TCRs) against tumor self-antigens. Remaining tumor-reactive T cells are often exhausted after immune checkpoint blockade (ICB). Whether endogenous T cells with high- affinity TCRs against tumor self-antigens can be generated to circumvent exhaustion and reject neoantigen-poor tumors is unclear. We show that transiently interrupting central tolerance through RANKL blockade unleashes T cells possessing TCRs with self-reactive features that enable ICB to reject poorly immunogenic tumors. Upon recognition of tumor self-antigens, these T cells exhibit enhanced TCR signaling, enrichment in NFAT/AP-1 genes, and lymph node priming. Consequently, memory-precursor T cells against tumor self-antigens are generated, avoid exhaustion, and become effector-memory cells with transcriptional features associated with clinical ICB response. Thus, interrupting central tolerance provides T cells with tumor- directed autoreactivity that avoid exhaustion and improve immunotherapy.
Visualizing Synaptic Dopamine Efflux with a 2D Nanofilm
Authors: Bulumulla Chandima , Krasley Andrew T. , Walpita Deepika , Beyene Abraham G. 
Published: January 2022

AbstractChemical neurotransmission constitutes one of the fundamental modalities of communication between neurons. Monitoring release of these chemicals has traditionally been difficult to carry out at spatial and temporal scales relevant to neuron function. To understand chemical neurotransmission more fully, we need to improve the spatial and temporal resolutions of measurements for neurotransmitter release. To address this, we engineered a chemi-sensitive, two-dimensional nanofilm that facilitates subcellular visualization of the release and diffusion of the neurochemical dopamine with synaptic resolution, quantal sensitivity, and simultaneously from hundreds of release sites. Using this technology, we were able to monitor the spatiotemporal dynamics of dopamine release in dendritic processes, a poorly understood phenomenon. We found that dopamine release is broadcast from a subset of dendritic processes as hotspots that have a mean spatial spread of ≈3.2 µm (full width at half maximum) and are observed with a mean spatial frequency of 1 hotspot per ≈7.5 µm of dendritic length. Major dendrites of dopamine neurons and fine dendritic processes, as well as dendritic arbors and dendrites with no apparent varicose morphology participated in dopamine release. Remarkably, these release hotspots colocalized with Bassoon, suggesting that Bassoon may contribute to organizing active zones in dendrites, similar to its role in axon terminals.
Knockout of Bbs10 results in lack of cone electrical function and progressive retinal degeneration of rods and cones
Authors: Mayer Sara K. , Thomas Jacintha , Helms Megan , Kothapalli Aishwarya , Cherascu Ioana , Salesevic Adisa , Stalter Elliot , Wang Kai , Datta Poppy , Searby Charles , Seo Seongjin , Hsu Ying , Bhattarai Sajag , Sheffield Val C. , Drack Arlene V. 
Published: January 2022

ABSTRACTBardet Biedl Syndrome (BBS) is an autosomal recessive disorder caused by mutations in at least 22 different genes. A constant feature is early onset retinal degeneration leading to blindness, with variable central obesity, polydactyly, renal failure, and developmental anomalies. BBS type 10 (BBS10) is a common form caused by mutations in the BBS10 gene encoding a chaperonin-like protein. There are currently no treatments for the progressive vision loss. To aid in treatment development, a BBS10 mouse model was developed by knocking out the Bbs10 gene. Using optical coherence tomography (OCT), electroretinography (ERG), and a visually guided swim assay (VGSA), we demonstrate that Bbs10-/- mice have progressive retinal degeneration. Cone electrical function was absent although cones were anatomically present on histology and retained partial function based on VGSA. The retinal outer nuclear layer (photoreceptor nuclei) progressively thinned as demonstrated on OCT and histology, and rod electrical activity decreased over time on ERG. These phenotypes are more rapidly progressive than retinal degeneration in the Bbs1M390R/M390R knock-in mouse. They are consistent with a cone-rod dystrophy distinct from typical rod-cone degeneration in retinitis pigmentosa and recapitulate aspects of retinal degeneration observed in humans with BBS10. This study has implications for BBS10 gene therapy.
Framework for Denoising Monte Carlo Photon Transport Simulations Using Deep Learning
Authors: Ardakani Matin Raayai , Yu Leiming , Kaeli David R. , Fang Qianqian 
Published: January 2022

AbstractSignificanceThe Monte Carlo (MC) method is widely used as the gold-standard for modeling light propagation inside turbid media like human tissues, but combating its inherent stochastic noise requires one to simulate large number photons, resulting in high computational burdens.AimWe aim to develop an effective image denoising technique using deep learning (DL) to dramatically improve low-photon MC simulation result quality, equivalently bringing further acceleration to the MC method.ApproachWe have developed a cascade-network combining DnCNN with UNet, in the meantime, extended a range of established image denoising neural-network architectures, including DnCNN, UNet, DRUNet, and ResMCNet, in handling three-dimensional (3-D) MC data and compared their performances against model-based denoising algorithms. We have also developed a simple yet effective approach to create synthetic datasets that can be used to train DL based MC denoisers.ResultsOverall, DL based image denoising algorithms exhibit significantly higher image quality improvements over traditional model-based denoising algorithms. Among the tested DL denoisiers, our Cascade network yields a 14 - 19 dB improvement in signal-noise ratio (SNR), which is equivalent to simulating 25 × to 78 × more photons. Other DL-based methods yielded similar results, with our method performing noticeably better with low-photon inputs, and ResMCNet along with DRUNet performing better with high-photon inputs. Our Cascade network achieved the highest quality when denoising complex domains, including brain and mouse atlases.ConclusionIncorporating state-of-the-art DL denoising techniques can equivalently reduce the computation time of MC simulations by one to two orders of magnitude. Our open-source MC denoising codes and data can be freely accessed at http://mcx.space/.
Risk Factors for Delirium in Elderly Patients After Lumbar Spinal Fusion
Authors: Gold Colin , Ray Emanuel , Christianson David , Park Brian , Kournoutas Ioannis A , Kahn Taimur A , Perez Eli A. , Berger Joel I. , Sander Katie , Igram Cassim A. , Pugely Andrew , Olinger Catherine R. , Carnahan Ryan , Chen Pei-fu , Mueller Rashmi , Hitchon Patrick , Howard Matthew A. , Banks Matthew , Sanders Robert D. , Woodroffe Royce W. 
Published: January 2022

Background ContextPostoperative delirium is a clinically significant acute disorder of consciousness especially prevalent in older adult patients, of which more than 100,000 per year undergo spinal fusion surgery. There are no proven preventative therapies, and delirium is associated with increased postoperative complications, functional decline, morbidity, and mortality.PurposeTo identify perioperative risk factors for postoperative delirium (POD) after lumbar spinal fusion procedures in patients aged 65 or older.Study DesignRetrospective ReviewPatient Sample702 patients who underwent lumbar spinal fusion surgery from 11/13/2017 to 1/30/2021.Outcome MeasuresThe primary outcome was the presence of postoperative delirium assessed by the Delirium Observation Screening Scale (DOSS) and Confusion Assessment Method for the ICU (CAM-ICU).MethodsDemographic, surgical, and perioperative data were obtained from the electronic medical records. The primary outcome was presence of postoperative delirium. Univariate and multivariate analyses were performed. A binomial logistic regression model was designed using a custom written MATLAB script.ResultsOf the 702 patients included in the study, 173 (24.6%) developed POD. Our analysis revealed that older age (p < 0.001), lower preoperative hemoglobin (p < 0.001), and higher ASA grade (p < 0.001), were significant preoperative risk factors for developing POD. The only significant intraoperative risk factor was a higher number of spinal levels that were instrumented (p < 0.001). Higher pain scores on postoperative day 1 (p < 0.001), and lower postoperative hemoglobin (p < 0.001) were associated with increased POD; as were ICU admission (p < 0.001) and increased length of ICU stay (p < 0.001). Patients who developed POD had a longer hospital stay (p < 0.001) with lower rates of discharge to home as opposed to an inpatient facility (p < 0.001).ConclusionsRisk factors for older adults undergoing lumbar spinal fusion surgery include advanced age, lower preoperative and postoperative hemoglobin, higher ASA grade, greater extent of surgery, and higher postoperative pain scores. Patients with delirium had a higher incidence of postoperative ICU admission, increased length of stay, decreased likelihood of discharge to home and increased mortality, all consistent with prior studies. Further studies will determine whether adequate management of anemia and pain lead to a reduction in the incidence of postoperative delirium in these patients.
The relationship between work disability and subsequent suicide or self-harm: A systematic scoping review
Authors: Collie Alex , Gray Shannon Elise 
Published: January 2022

ABSTRACTBackgroundWork disability occurs when an injury, illness or other health condition limits the ability of a worker to participate in paid employment. Several lines of evidence suggest that people with work disability are also at increased risk of suicide and intentional self-harm, however the evidence on this relationship has not previously been the subject of systematic review.ObjectiveThis systematic scoping review aims to assess and summarise the research literature regarding the relationship between work disability and subsequent suicide or intentional self-harm.MethodsPeer-reviewed quantitative and qualitative studies published in English from 1st January 2000 were included if they reported suicide or self-harm outcomes in people aged 15 years or older with work disability. Narrative synthesis summarised findings according to the system of work disability income support.ResultsLiterature search yielded 859 records of which 47 eligible studies were included, including nine set in workers’ compensation, 20 in sickness absence, 13 in disability pension systems, and five from mixed cohorts. Of 44 quantitative studies, 41 reported a positive relationship between work disability and suicidal behaviour. The relationship is observed consistently across nations, work disability income support systems and in people with a range of health conditions. Several factors elevate risk of suicidal behaviour, including presence of mental health conditions and longer work disability duration. There were few quality studies in some nations and no suicide prevention interventions.ConclusionThe risk of suicide and intentional self-harm is elevated in people experiencing work disability. While further observational research is required to fill evidence gaps, this review suggests the need for governments, employers and those involved in the delivery of care and support to people with work disability to focus on identification and monitoring of those at greatest risk of suicidal behaviour, as well as suicide prevention.
Complex genetics cause and constrain fungal persistence in different parts of the mammalian body
Authors: Mullis Martin N. , Ghione Caleb , Lough-Stevens Michael , Goldstein Ilan , Matsui Takeshi , Levy Sasha F. , Dean Matthew D. , Ehrenreich Ian M. 
Published: January 2022

AbstractDetermining how genetic polymorphisms enable certain fungi to persist in mammalian hosts can improve understanding of opportunistic fungal pathogenesis, a source of substantial human morbidity and mortality. We examined the genetic basis of fungal persistence in mice using a cross between a clinical isolate and the lab reference strain of the budding yeastSaccharomyces cerevisiae. Employing chromosomally-encoded barcodes, we tracked the relative abundances of 822 genotyped, haploid segregants in multiple organs over time and performed linkage mapping of their persistence in hosts. Detected loci showed a mix of general and antagonistically pleiotropic effects across organs. General loci showed similar effects across all organs, while antagonistically pleiotropic loci showed contrasting effects in the brain and the kidneys, liver, and spleen. Persistence in an organ required both generally beneficial alleles and organ-appropriate pleiotropic alleles. This genetic architecture resulted in many segregants persisting in the brain or in non-brain organs, but few segregants persisting in all organs. These results show complex combinations of genetic polymorphisms collectively cause and constrain fungal persistence in different parts of the mammalian body.
Comparison of Two Individual Identification Algorithms for Snow Leopards after Automated Detection
Authors: Blount Drew , Bohnett Eve , Holmberg Jason , Parham Jason , Faryabi Sorosh Poya , Johansson Örjan , An Li , Ahmad Bilal , Khan Wajid , Ostrowski Stephane 
Published: January 2022

Abstract1. Photo-identification of individual snow leopards (Panthera uncia) is the primary technique for density estimation for the species. A high volume of images from multiple projects, combined with pre-existing historical catalogs, has made identifying snow leopard individuals within the images cost- and time-intensive. 2. To speed the classification among a high volume of photographs, we trained and evaluated image classification methods for PIE v2 (a triplet loss network), and we compared PIE’s accuracy to the HotSpotter algorithm (a SIFT based algorithm). Analyzed data were collected from a curated catalog of free-ranging snow leopards photographed across years (2012-2019) in Afghanistan and from samples in captivity provided by zoos from Finland, Sweden, Germany, and the United States. 3. Results show that PIE outperforms HotSpotter. We also found weaknesses in the initial PIE model, like a minor amount of background matching, which was addressed, although likely not fully resolved, by applying background subtraction (BGS) and left-right mirroring (LR) methods. The PIE BGS LR model combined with Hotspotter showed a Rank-1: 85%, Rank-5: 95%, Rank-20: 99%. 4. Overall, our results recommend implementing PIE v2 simultaneously with HotSpotter on Whiskerbook.org.
Imbalance of Neuregulin1-ErbB2/3 signaling underlies altered myelin homeostasis in models of Charcot-Marie-Tooth disease type 4H
Authors: El-Bazzal Lara , Ghata Adeline , Estève Clothilde , Quintana Patrice , Roeckel-Trévisiol Nathalie , Lembo Frédérique , Lenfant Nicolas , Mégarbané Andre , Borg Jean-Paul , Lévy Nicolas , Bartoli Marc , Poitelon Yannick , Roubertoux Pierre L. , Delague Valérie , Bernard-Marissal Nathalie 
Published: January 2022

AbstractCharcot Marie Tooth disease (CMT) is one of the most common inherited neurological disorders, affecting either axons from the motor and/or sensory neurons or Schwann cells (SC) of the peripheral nervous system, and caused by more than 100 genes. We previously identified mutations in FGD4, as responsible for CMT4H, an autosomal recessive demyelinating form of CMT. FGD4 encodes FRABIN a GDP/GTP nucleotide exchange factor (GEF), particularly for the small GTPase cdc42. Remarkably, nerves from patients with CMT4H display excessive redundant myelin called outfoldings that arise from focal hypermyelination, suggesting that FRABIN could play a role in the control of PNS myelination. To gain insights into the role of FGD4/FRABIN in SC myelination, we generated a knock-out mouse model, with conditional ablation of fgd4 in SC. We showed that the specific deletion of FRABIN in SCs leads to aberrant myelination in vitro, in dorsal root ganglion (DRG)/SCs cocultures as well in vivo, in distal sciatic nerves. We observed that those myelination defects are related to an upregulation of some interactors of the NRG1 type III/ErbB2/3 signaling pathway, which is known to ensure a proper level of myelination in the PNS. Based on a yeast two-hybrid screen, we identified SNX3 as a new partner of FRABIN, which is involved in the regulation of endocytic trafficking. Interestingly, we showed that loss of FRABIN impairs endocytic trafficking which may contribute to the defective NRG1 type III/ErbB2/3 signaling and myelination. Finally, we showed that the reestablishment of proper levels of the NRG1 type III/ErbB2/3 pathway using Niacin treatment reduces myelin outfoldings in nerves of CMT4H mice. Overall, our work reveals a new role of FRABIN in the regulation of NRG1 type III/ErbB2/3 NRG1signaling and myelination and opens future therapeutic strategies based on the modulation of NRG1 type III/ErbB2/3 NRG1to reduce CMT4H pathology and more generally others demyelinating CMT.