bluuebunny/crossref_metadata_2025_split huggingface dataset:
Deep Bayesian networks for uncertainty estimation and adversarial resistance of white matter hyperintensity segmentation
Authors: Forooshani Parisa Mojiri , Biparva Mahdi , Ntiri Emmanuel E. , Ramirez Joel , Boone Lyndon , Holmes Melissa F. , Adamo Sabrina , Gao Fuqiang , Ozzoude Miracle , Scott Christopher J.M. , Dowlatshahi Dar , Lawrence-Dewar Jane M. , Kwan Donna , Lang Anthony E. , Marcotte Karine , Leonard Carol , Rochon Elizabeth , Heyn Chris , Bartha Robert , Strother Stephen , Tardif Jean-Claude , Symons Sean , Masellis Mario , Swartz Richard H. , Moody Alan , Black Sandra E. , Goubran Maged 
Published: August 2021

AbstractWhite matter hyperintensities (WMH) are frequently observed on structural neuroimaging of elderly populations and are associated with cognitive decline and increased risk of dementia. Many existing WMH segmentation algorithms produce suboptimal results in populations with vascular lesions or brain atrophy, or require parameter tuning and are computationally expensive. Additionally, most algorithms do not generate a confidence estimate of segmentation quality, limiting their interpretation. MRI-based segmentation methods are often sensitive to acquisition protocols, scanners, noise-level, and image contrast, failing to generalize to other populations and out-of-distribution datasets. Given these concerns, we propose a novel Bayesian 3D Convolutional Neural Network (CNN) with a U-Net architecture that automatically segments WMH, provides uncertainty estimates of the segmentation output for quality control and is robust to changes in acquisition protocols. We also provide a second model to differentiate deep and periventricular WMH. 432 subjects were recruited to train the CNNs from four multi-site imaging studies. A separate test set of 158 subjects was used for evaluation, including an unseen multi-site study. We compared our model to two established state-of-the-art techniques (BIANCA and DeepMedic), highlighting its accuracy and efficiency. Our Bayesian 3D U-Net achieved the highest Dice similarity coefficient of 0.89 ± 0.08 and the lowest modified Hausdorff distance of 2.98 ± 4.40 mm. We further validated our models highlighting their robustness on ‘clinical adversarial cases’ simulating data with low signal-to-noise ratio, low resolution, and different contrast (stemming from MRI sequences with different parameters). Our pipeline and models are available at:https://hypermapp3r.readthedocs.io
L-DOPA enhances hippocampal direction signals in younger and older adults
Authors: Koch Christoph , Bäuchl Christian , Glöckner Franka , Riedel Philipp , Petzold Johannes , Smolka Michael , Li Shu-Chen , Schuck Nicolas W. 
Published: August 2021

AbstractPrevious studies indicate a role of dopamine in hippocampus-dependent spatial navigation. Although neural representations of direction are an important aspect of spatial cognition, it is not well understood whether dopamine directly affects these representations, or only impacts other aspects of spatial brain function. Moreover, both dopamine and spatial cognition decline sharply during age, raising the question which effect dopamine has on directional signals in the brain of older adults. To investigate these questions, we used a double-blind cross-over L-DOPA/Placebo intervention design in which 43 younger and 37 older adults navigated in a virtual spatial environment while undergoing functional magnetic resonance imaging (fMRI). We studied the effect of L-DOPA, a DA precursor, on fMRI activation patterns that encode spatial walking directions that have previously been shown to lose specificity with age. This was done in predefined regions of interest, including the early visual cortex, retrosplenial cortex, and hippocampus. Classification of brain activation patterns associated with different walking directions was improved in the hippocampus and the retrosplenial cortex following L-DOPA administration. This suggests that DA enhances the specificity of neural representations of walking direction in these areas. In the hippocampus these results were found in both age groups, while in the RSC they were only observed in younger adults. Taken together, our study provides evidence for a mechanistic link between DA and the specificity of neural responses during spatial navigation.Significance StatementThe sense of direction is an important aspect of spatial navigation, and neural representations of direction can be found throughout a large network of space-related brain regions. But what influences how well these representations track someone’s true direction? Using a double-blind cross-over L-DOPA/Placebo intervention design, we find causal evidence that the neurotransmitter dopamine impacts the fidelity of direction selective neural representations in the human hippocampus and retrosplenial cortex. Interestingly, the effect of L-DOPA was either equally present or even smaller in older adults, despite the well-known age related decline of dopamine. These results provide novel insights into how dopamine shapes the neural representations that underlie spatial navigation.
Perinatal Inflammation Disturbs Secondary Germinal Zone Neurogenesis and Gliogenesis Producing Deficits in Sociability
Authors: Velloso Fernando Janczur , Wadhwa Anna , Kumari Ekta , Carcea Ioana , Gunal Ozlem , Levison Steven W. 
Published: August 2021

AbstractEpidemiologic studies have demonstrated that infections during pregnancy increase the risk of offspring developing Schizophrenia, Autism, Depression and Bipolar Disorder and have implicated interleukin-6 (IL-6) as a causal agent. However, other cytokines have been associated with psychiatric disorders; therefore, it remains to be established whether elevating IL-6 is sufficient to alter the trajectory of neural development. Furthermore, most rodent studies have manipulated the maternal immune system at mid-gestation, which affects the stem cells and progenitors in both the primary and secondary germinal matrices. Therefore, a question that remains to be addressed is whether elevating IL-6 when the secondary germinal matrices are most active will affect brain development. Here, we have increased IL-6 from postnatal days 3-6, when the secondary germinal matrices are rapidly expanding. Using Nestin-CreERT2 fate mapping we show that this transient increase in IL-6 decreased neurogenesis in the dentate gyrus of the dorsal hippocampus, reduced astrogliogenesis in the prefrontal cortex and amygdala and decreased oligodendrogenesis in the body and splenium of the corpus callosum all by ∼50%. Moreover, the IL-6 treatment elicited behavioral changes classically associated with neurodevelopmental disorders. As adults, IL-6 injected male mice lost social preference in the social approach test, spent ∼30% less time socially engaging with sexually receptive females and produced ∼50% fewer ultrasonic vocalizations during mating. They also engaged ∼50% more time in self-grooming behavior and had an increase in inhibitory avoidance. Altogether, these data provide new insights into the biological mechanisms linking perinatal immune activation to complex neurodevelopmental brain disorders.Significance statementIn these studies, we doubled circulating IL-6 levels in mice from postnatal days 3-6 to test the hypothesis that this would be sufficient to disturb neural development. More specifically, we hypothesized that IL-6 would affect postnatal neural stem cell and progenitor expansion and specification. We show that this transient increase in IL-6 decreases the numbers of granule neurons in the dorsal hippocampus, astrocytes in the prefrontal cortex and amygdala and oligodendrocytes in the corpus callosum. Importantly, this transient increase in IL-6 changes the sociability, communication and repetitive behaviors of the treated mice as adults, which are core symptoms pertinent to several neurodevelopmental psychiatric disorders.
Metabolic control of adult neural stem cell self-renewal by the mitochondrial protease YME1L
Authors: Wani Gulzar A. , Sprenger Hans-Georg , Ndoci Kristiano , Chandragiri Srikanth , Acton Richard James , Schatton Désirée , Kochan Sandra M.V. , Sakthivelu Vignesh , Jevtic Milica , Seeger Jens M. , Müller Stefan , Giavalisco Patrick , Rugarli Elena I. , Motori Elisa , Langer Thomas , Bergami Matteo 
Published: August 2021

AbstractThe transition between quiescence and activation in neural stem and progenitor cells (NSPCs) is coupled to reversible changes in energy metabolism with key implications for life-long NSPC self-renewal and neurogenesis. How this metabolic plasticity is ensured between NSPC activity states is unclear. We found that a state-dependent rewiring of the mitochondrial proteome by the peptidase YME1L is required to preserve NSPC self-renewal in the adult brain. YME1L-mediated proteome rewiring regulates the rate of fatty acid oxidation (FAO) for replenishing Krebs cycle intermediates and dNTP precursors, which are required to sustain NSPC amplification. Yme1l deletion irreversibly shifts the metabolic profile of NSPCs away from a FAO-dependent state resulting in defective self-renewal, premature differentiation and NSPC pool depletion. Our results disclose an important role for YME1L in coordinating the switch between metabolic states of NSPCs and suggest that NSPC fate is regulated by compartmentalized changes in protein network dynamics.
Subpopulations of soluble, misfolded proteins commonly bypass chaperones: How it happens at the molecular level
Authors: Halder Ritaban , Nissley Daniel A. , Sitarik Ian , O’Brien Edward P. 
Published: August 2021

ABSTRACTSubpopulations of soluble, misfolded proteins can bypass chaperones within cells. The scope of this phenomenon and the lifetimes of these states have not been experimentally quantified, and how such misfolding happens at the molecular level is poorly understood. We address the first issue through a meta-analysis of the experimental literature. We find that in all quantitative protein refolding-function studies, there is always a subpopulation of soluble but misfolded and less-functional protein that does not fold in the presence of one or more chaperones. This subpopulation ranges from 8% to 50% of the soluble protein molecules in solution. Fitting the experimental time traces to a kinetic model, we find these chaperone-bypassing misfolded states take months or longer to fold and function in the presence of different chaperones. We next addressed how, at the molecular level, some misfolded proteins can evade chaperones by simulating six different proteins interacting withE. coli’s GroEL and HtpG chaperones when those proteins are in folded, unfolded, or long-lived, soluble, misfolded states. We observe that both chaperones strongly bind the unfolded state and weakly bind the folded and misfolded states to a similar degree. Thus, these chaperones cannot distinguish between the folded and long-lived misfolded states of these proteins. A structural analysis reveals the misfolded states are highly similar to the native state – having a similar size, amount of exposed hydrophobic surface area, and level of tertiary structure formation. These results demonstrate thatin vitroit is common for appreciable subpopulations of proteins to remain misfolded, soluble, and evade the refolding action of chaperones for very long times. Further, these results suggest that this happens because these misfolded subpopulations are near-native and therefore interact with chaperones to a similar extent as properly folded proteins. More broadly, these results indicate a mechanism in which long-time scale changes in protein structure and function can persist in cells because some protein’s non-native states can bypass components of the proteostasis machinery.TEASERNear-native, misfolded protein conformations explain why some soluble proteins fail to refold in the presence of chaperones.
A genealogical estimate of genetic relationships
Authors: Fan Caoqi , Mancuso Nicholas , Chiang Charleston W.K. 
Published: August 2021

AbstractThe application of genetic relationships among individuals, characterized by a genetic relationship matrix (GRM), has far-reaching effects in human genetics. However, the current standard to calculate the GRM generally does not take advantage of linkage information and does not reflect the underlying genealogical history of the study sample. Here, we propose a coalescent-informed framework to infer the expected relatedness between pairs of individuals given an ancestral recombination graph (ARG) of the sample. Through extensive simulations we show that the eGRM is an unbiased estimate of latent pairwise genome-wide relatedness and is robust when computed using genealogies inferred from incomplete genetic data. As a result, the eGRM better captures the structure of a population than the canonical GRM, even when using the same genetic information. More importantly, our framework allows a principled approach to estimate the eGRM at different time depths of the ARG, thereby revealing the time-varying nature of population structure in a sample. When applied to genotyping data from a population sample from Northern and Eastern Finland, we find that clustering analysis using the eGRM reveals population structure driven by subpopulations that would not be apparent using the canonical GRM, and that temporally the population model is consistent with recent divergence and expansion. Taken together, our proposed eGRM provides a robust tree-centric estimate of relatedness with wide application to genetic studies.
DNA Origami Voltage Sensors for Transmembrane Potentials with Single-Molecule Sensitivity
Authors: Ochmann Sarah E. , Joshi Himanshu , Büber Ece , Franquelim Henri G. , Stegemann Pierre , Saccà Barbara , Keyser Ulrich F. , Aksimentiev Aleksei , Tinnefeld Philip 
Published: August 2021

ABSTRACTSignal transmission in neurons goes along with changes in the transmembrane potential. To report them, different approaches including optical voltage-sensing dyes and genetically encoded voltage indicators have evolved. Here, we present a DNA nanotechnology-based system. Using DNA origami, we incorporate and optimize different properties such as membrane targeting and voltage sensing modularly. As a sensing unit, we use a hydrophobic red dye anchored to the membrane and an anionic green dye at the DNA connecting the DNA origami and the membrane dye anchor. Voltage-induced displacement of the anionic donor unit is read out by changes of Fluorescence Resonance Energy Transfer (FRET) of single sensors attached to liposomes. They show a FRET change of ∼5% for ΔΨ=100 mV and allow adapting the potential range of highest sensitivity. Further, the working mechanism is rationalized by molecular dynamics simulations. Our approach holds potential for the application as non-genetically encoded sensors at membranes.
Interaction between spike protein of SARS-CoV-2 and human virus receptor ACE2 using two-color fluorescence cross-correlation spectroscopy
Authors: Fujimoto Ai , Yidan Lyu , Kinjo Masataka , Kitamura Akira 
Published: August 2021

AbstractInfection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), is initiated by the interaction between a receptor protein, angiotensin-converting enzyme type 2 (ACE2) on the cell surface, and the viral spike (S) protein. This interaction is similar to the mechanism in SARS-CoV, a close relative of SARS-CoV-2, which was identified in 2003. Drugs and antibodies that inhibit the interaction between ACE2 and S proteins could be key therapeutic methods for preventing viral infection and replication in COVID-19. Here, we demonstrate the interaction between human ACE2 and a fragment of the S protein (S1 subunit) derived from SARS-CoV-2 and SARS-CoV using two-color fluorescence cross-correlation spectroscopy (FCCS), which can detect the interaction of fluorescently labeled proteins. The S1 subunit of SARS-CoV-2 interacted in solution with soluble ACE2, which lacks a transmembrane region, more strongly than that of SARS-CoV. Furthermore, one-to-one stoichiometry of the two proteins during the interaction was indicated. Thus, we propose that this FCCS-based interaction detection system can be used to analyze the interaction strengths of various mutants of the S1 subunit that have evolved during the worldwide pandemic, and also offers the opportunity to screen and evaluate the performance of drugs and antibodies that inhibit the interaction.
CRISPR activation screening identifies VGLL3 and GATA2 as transcriptional regulators of PD-L1
Authors: Wijdeven Ruud H. , Cabukusta Birol , Qiu Xueer , Borras Daniel M. , Liang Yun , Neefjes Jacques 
Published: August 2021

AbstractThe PD-L1/2 – PD-1 immune checkpoint is essential for the proper induction of peripheral tolerance and limits autoimmunity, whereas tumor cells exploit their expression to promote immune evasion. Many different cell types express PD-L1/2, either constitutively or upon stimulation, but the factors driving this expression are often not defined. Here, using genome-wide CRISPR-activation screening, we identified three factors that upregulate PD-L1 expression; GATA2, MBD6, and VGLL3. GATA2 and VGLL3 act as transcriptional regulators and their expression induced PD-L1 in many different cell types. Conversely, loss of VGLL3 impaired IFNγ-induced PD-L1/2 expression in keratinocytes. Mechanistically, by performing a second screen to identify proteins acting together with VGLL3, we found that VGLL3 forms a complex with TEAD1 and RUNX1/3 to drive expression of PD-L1/2. Collectively, our work identified a new transcriptional network controlling PD-L1/2 expression and suggests that VGLL3, in addition to its known role in the expression of pro-inflammatory genes, can balance inflammation by upregulating the anti-inflammatory factors PD-L1 and PD-L2.
Aβ toxicity rescued by protein retention in the ER
Authors: Catterson James H , Minkley Lucy , Aspe Salomé , Judd-Mole Sebastian , Moura Sofia , Dyson Miranda C , Rajasingam Arjunan , Woodling Nathaniel S , Atilano Magda L , Ahmad Mumtaz , Durrant Claire S , Spires-Jones Tara L , Partridge Linda 
Published: August 2021

AbstractAccumulation of Aβ in the brain is one of the hallmarks of Alzheimer’s disease (AD). In the adult Drosophila brain, human Aβ over-expression is toxic and leads to deterioration of climbing ability and shortened lifespan. However, it remains unknown if Aβ is inherently toxic or if it triggers toxic downstream pathways that lead to neurodegeneration. Here, we describe a novel, and previously unidentified, protective role of intracellular laminin chain accumulation. Despite high Aβ levels, over-expression of the extracellular matrix protein subunit Laminin B1 (LanB1) resulted in a robust rescue of toxicity, highlighting a potential protective mechanism of resistance to Aβ. Over-expression of other Laminin subunits and a Collagen IV subunit also significantly rescued Aβ toxicity, while combining LanB1 with these subunits led to an even larger rescue. Imaging revealed that LanB1 was retained in the ER but had no effect on the secretion of Aβ into the extracellular milieu. LanB1 rescued toxicity independently of the IRE1α/XBP1-mediated branch of the ER stress response. Interestingly, over-expression of ER-targeted GFP also rescued Aβ toxicity, indicating a potentially broader benefit of ER protein retention. Finally, in proof-of-principle lentiviral transduction experiments using murine organotypic hippocampal slice cultures, over-expression of mouse Lamb1 resulted in ER-retention in transduced cells, highlighting a conserved mechanism. Typically, retention of proteins in the ER is detrimental to cellular health, but in the context of neuronal Aβ toxicity it may prove to be beneficial and a new therapeutic avenue for AD.
How the insect central complex could coordinate multimodal navigation
Authors: Sun Xuelong , Yue Shigang , Mangan Michael 
Published: August 2021

AbstractThe central complex of the insect midbrain is thought to coordinate insect guidance strategies. Computational models can account for specific behaviours but their applicability across sensory and task domains remains untested. Here we assess the capacity of our previous model explaining visual navigation to generalise to olfactory navigation and its coordination with other guidance in flies and ants. We show that fundamental to this capacity is the use of a biologically-realistic neural copy-and-shift mechanism that ensures sensory information is presented in a format compatible with the insect steering circuit regardless of its source. Moreover, the same mechanism is shown to transfer cues from unstable/egocentric to stable/geocentric frames of reference providing a first account of the mechanism by which foraging insects robustly recover from environmental disturbances. We propose that these circuits can be flexibly repurposed by different insect navigators to address their unique ecological needs.
Macrophages in the reticuloendothelial system inhibit the propagation phase of mouse apolipoprotein A-II amyloidosis
Authors: Miyahara Hiroki , Dai Jian , Li Ying , Xiaoran Cui , Takeuchi Hibiki , Hachiya Naomi , Kametani Fuyuki , Yazaki Masahide , Mori Masayuki , Higuchi Keiichi 
Published: August 2021

AbstractAmyloidosis refers to a group of degenerative diseases that are characterized by the deposition of misfolded protein fibrils in various organs. Deposited amyloid may be removed by a phagocyte-dependent innate immune system; however, the precise mechanisms during disease progression remain unclear. We herein investigated the properties of macrophages that contribute to amyloid degradation and disease progression using transmissible apolipoprotein A-II amyloidosis model mice. Intravenously injected AApoAII amyloid was efficiently engulfed by reticuloendothelial macrophages in the liver and spleen and disappeared by 24 h. While cultured murine macrophages degraded AApoAII via the endosomal-lysosomal pathway, AApoAII fibrils reduced cell viability and phagocytic capacity. Furthermore, the depletion of reticuloendothelial macrophages prior to the induction of AApoAII markedly increased hepatic and splenic AApoAII deposition. These results highlight the physiological role of reticuloendothelial macrophages against inter-individual amyloid propagation and suggest the maintenance of phagocytic integrity as a therapeutic strategy to inhibit disease progression.
Systemic host inflammation induces stage-specific transcriptomic modification and slower maturation in malaria parasites
Authors: Lansink Lianne I.M. , Engel Jessica A. , Lee Hyun Jae , Soon Megan S.F. , Williams Cameron G. , SheelaNair Arya , Pernold Clara P.S. , Laohamonthonkul Pawat , Akter Jasmin , Stoll Thomas , Hill Michelle M. , Talman Arthur M. , Russell Andrew , Lawniczak Mara , Davenport Miles P. , Khoury David S. , Haque Ashraful 
Published: August 2021

AbstractMaturation rate of malaria parasites within red blood cells (RBC) can be influenced by host nutrient status or circadian rhythm. Here, we observed in mice that systemic host inflammation, induced by lipopolysaccharide (LPS) conditioning or ongoing acute malaria infection, slowed the progression of a single cohort of parasites from one generation of RBC to the next. LPS-conditioning and acute infection both triggered substantial changes to the metabolomic composition of plasma in which parasites circulated. This altered plasma directly slowed parasite maturation in a manner that could not be rescued by supplementation, consistent with the presence of inhibitory factors. Single-cell transcriptomic assessment of mixed parasite populations, exposed to a short period of systemic host inflammation in vivo, revealed specific impairment in the transcriptional activity and translational capacity of trophozoites compared to rings or schizonts. Thus, we provide in vivo evidence of transcriptomic and phenotypic plasticity of asexual blood-stage Plasmodium parasites when exposed to systemic host inflammation.