bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Impact of Brief Monocular Retinal Inactivation on the Central Visual System During Postnatal Development
Authors: Duffy Kevin R. , Crowder Nathan A. , Heynen Arnold J. , Bear Mark F. 
Published: August 2022

AbstractDuring a critical period of postnatal life, monocular deprivation (MD) of kittens by eyelid closure reduces the size of neurons in layers of the dorsal lateral geniculate nucleus (dLGN) connected to the deprived eye, and shifts cortical ocular dominance in favor of the non-deprived eye, modeling deprivation amblyopia in humans. Following long-term MD, temporary retinal inactivation of the non-deprived eye with microinjection of tetrodotoxin can promote superior recovery from MD, and at older ages, in comparison to conventional occlusion therapy. This suggests that monocular inactivation (MI) is a more potent approach to producing neural plasticity than occlusion. In the current study we assessed the modification of neuron size in the dLGN as a means of measuring the impact of a brief period of MI imposed at different ages during postnatal development. The biggest impact of inactivation was observed when it occurred at the peak of the critical period for ocular dominance plasticity. The effect of MI was evident in both the binocular and monocular segments of the dLGN, distinguishing it from MD that produces changes only within the binocular segment. With increasing age, the capacity for inactivation to alter postsynaptic cell size diminished but was still significant beyond the classic critical period. In comparison to MD, inactivation consistently produced effects that were about double in magnitude, and inactivation exhibited efficacy to produce neural modifications at older ages than MD. Notwithstanding the large neural alterations precipitated by inactivation, its anatomical effects were remediated with a short period of binocular visual experience, and vision through the previously inactivated eye fully recovered after washout of TTX. Our results demonstrate that MI is a potent means of modifying the visual pathway, and does so beyond the age at which occlusion is effective. The magnitude and longevity of inactivation to evoke neural modification highlights its potential to ameliorate disorders of the visual system such as amblyopia.
Incorporating sampling bias into permutation tests for niche and distribution models
Authors: Warren Dan L. , Kass Jamie M. , Casadei-Ferreira Alexandre , Economo Evan P. 
Published: August 2022

AbstractRandomization tests are often used with species niche and distribution models to estimate model performance, test hypotheses, and measure methodological biases. Many of these tests involve building null models representing the hypothesis that there is no association between the species’ occurrences and the environmental predictors, then comparing the empirical model to null distributions built from these models. These null models are commonly based on points randomly selected with a uniform probability from the study area. However, spatial sampling bias, a near-universal feature of the occurrence data used to build niche and distribution models, results in a non-uniform probability of observing species in different areas even when species occurrences are unrelated to environmental predictors. Failing to account for this bias in randomization tests results in null distributions that do not accurately represent the null hypothesis, potentially leading to incorrect conclusions. In this study, we use simulations to demonstrate that uniform sampling in randomization tests can lead to unacceptable rates of type I error and poor estimates of methodological bias when spatial sampling bias is present in the occurrence data. We present a new method that incorporates a bias estimate into replicate simulations for these randomization tests, and show that this adjustment can reduce type I error rates to an acceptable level.
Development of a Scoring Function for Comparing Simulated and Experimental Tumor Spheroids
Authors: Herold Julian , Behle Eric , Rosenbauer Jakob , Ferruzzi Jacopo , Schug Alexander 
Published: August 2022

AbstractEnormous progress continues in the field of cancer biology, yet much remains to be unveiled regarding the mechanisms of cancer invasion. In particular, complex biophysical mechanisms enable a tumor to remodel the surrounding extracellular matrix (ECM), thus allowing cells to escape and invade alone or as multicellular collectives. Tumor spheroids cultured in collagen represent a simplified, reproducible 3D model system, which is sufficiently complex to recapitulate the evolving internal organization of cells and external interaction with the ECM that occur during invasion. Recent experimental approaches enable high resolution imaging and quantification of the internal structure of invading tumor spheroids. Concurrently, computational modeling enables simulations of complex multicellular aggregates based on first principles. The comparison between real and simulated spheroids represents a way to fully exploit both data sources, but remains a challenging task. We hypothesize that comparing any two spheroids requires first the extraction of basic features from the raw data, and second the definition of key metrics to match such features. Here, we present a novel data-agnostic method to compare spatial features of spheroids in 3D. To do so, we define and extract features from spheroid point cloud data, which we simulated using Cells in Silico (CiS), a high-performance framework for large-scale tissue modeling previously developed by our group. We then define metrics to compare features between individual spheroids, and combine all metrics into an overall deviation score. Finally, we use our features to compare experimental data on invading spheroids in increasing collagen densities. We propose that our approach represents the basis for defining improved metrics to compare large 3D data sets. Moving forward, this approach will enable informingin silicospheroids based on theirin vitrocounterparts, and vice versa, thus enabling both basic and applied researchers to close the loop between modeling and experiments in cancer research.Author summaryCells within a tumor use various methods to escape and thereby invade into healthy parts of the body. These methods are studied experimentally by examining tumor spheroids, spherical aggregates of hundreds to thousands of individual cells. Such spheroids can also be simulated, and the comparison of simulation and experiment is desirable. Here, we present an analysis strategy for the comparison of tumor spheroids, a widely used workhorse of cancer research. Using this strategy, we aim to improve the collaborative potential between experimentalists and theorists.
Ancient DNA reveals interstadials as a driver of the common vole population dynamics during the last glacial period
Authors: Baca Mateusz , Popović Danijela , Lemanik Anna , Bañuls-Cardona Sandra , Conard Nicholas J. , Cuenca-Bescós Gloria , Desclaux Emmanuel , Fewlass Helen , Garcia Jesus T. , Hadravova Tereza , Heckel Gerald , Horáček Ivan , Knul Monika Vlasta , Lebreton Loïc , López-García Juan Manuel , Luzi Eliza , Marković Zoran , Lenardić Jadranka Mauch , Murelaga Xabier , Noiret Pierre , Petculescu Alexandru , Popov Vasil , Rhodes Sara E. , Ridush Bogdan , Royer Aurélien , Stewart John R. , Stojak Joanna , Talamo Sahra , Wang Xuejing , Wójcik Jan M. , Nadachowski Adam 
Published: August 2022

1AbstractAimThe common vole is a temperate rodent widespread across Europe. It was also one of the most abundant small mammal species throughout the Late Pleistocene. Phylogeographic studies of its extant populations suggested the Last Glacial Maximum (LGM, 26.5–19 ka ago) as one of the main drivers of the species’ population dynamics. However, analyses based solely on extant genetic diversity may not recover the full complexity of past population history. The main aim of this study was to investigate the evolutionary history and identify the main drivers of the common vole population dynamics during the Late Pleistocene.LocationEuropeTaxonCommon vole (Microtus arvalis)MethodsWe generated a dataset comprising 4.2 kb-long fragment of mitochondrial DNA from 148 ancient and 51 modern specimens sampled from multiple localities across Europe and covering the last 60 thousand years (ka). We used Bayesian inference to reconstruct their phylogenetic relationships and to estimate the age of specimens that were not directly dated.ResultsWe estimate the time to the most recent common ancestor of all Last Glacial and extant common vole lineages to 90 ka ago and the divergence of the main mtDNA lineages present in extant populations to between 55 and 40 ka ago, earlier than previous estimates. We find multiple lineage turnovers in Europe in the period of high climate variability at the end of Marine Isotope Stage 3 (MIS 3; 57–29 ka ago) in addition to those found previously around the Pleistocene/Holocene transition. Conversely, data from the Western Carpathians suggest continuity throughout the LGM even at high latitudes.Main conclusionsOur results suggest that the main factor affecting the common vole populations during the last glacial period was the reduction of open habitats during the interstadial periods while the climate deterioration during the LGM had little impact on species’ population dynamics.
The genetic and environmental etiology of blood-based biomarkers related to risk of Alzheimer’s Disease in a population-based sample of early old-age men
Authors: Gillespie Nathan A. , Rissman Robert A. , Elman Jeremy A. , McKenzie Ruth E. , Tu Xin M. , Xian Hong , Reynolds Chandra A. , Panizzon Matthew S. , Lyons Michael J. , Eglit Graham M.L. , Neale Michael C. , Franz Carol , Kremen William S. 
Published: August 2022

AbstractThe amyloid-tau-neurodegeneration (ATN) framework has led to an increased focus on Alzheimer’s disease (AD) biomarkers. The cost and invasiveness of obtaining biomarkers via cerebrospinal fluid has motivated efforts to develop sensitive blood-based biomarkers. Although AD is highly heritable, the biometric genetic and environmental etiology of blood-based biomarkers has never been explored. We therefore, analyzed plasma beta-amyloid (Aβ40, Aβ42, Aβ42/40), total tautau (t-tautau), and neurofilament light (NFL) biomarkers in a sample of 1,050 men aged 60 to 73 years (m=68.2, SD=2.5) from the Vietnam Era Twin Study of Aging (VETSA). Unlike Aβ and tautau, NFL does not define AD; however, as a biomarker of neurodegeneration it serves as the N component in the ATN framework. Univariate estimates suggest that familial aggregation in Aβ42, Aβ42/40, t-tau, and NFL is entirely explained by additive genetic influences accounting for 40%-58% of the total variance. All remaining variance is associated with unshared or unique environmental influences. For Aβ40, a additive genetic (31%), shared environmental (44%), and unshared environmental (25%) influences contribute to the total variance. In the more powerful multivariate analysis of Aβ42, Aβ40, t-tau, and NFL, heritability estimates range from 32% to 58%. Aβ40 and Aβ42 are statistically genetically identical (rg = 1.00, 95%CI = 0.92,1.00) and are also moderately environmentally correlated (re = 0.66, 95%CI = 0.59, 0.73). All other genetic and environmental associations were non-significant or small. Our results suggest that plasma biomarkers are heritable and that Aβ40 and Aβ42 share the same genetic influences, whereas the genetic influences on plasma t-tau and NFL are mostly unique and uncorrelated with plasma Aβ in early old-age men.
Comparison of Three Transcytotic Pathways for Distribution to Brain Metastases of Breast Cancer
Authors: Khan Imran , Gril Brunilde , Paranjape Anurag , Robinson Christina , Difilippantonio Simone , Biernat Wojciech , Bieńkowski Michał , Pęksa Rafał , Duchnowska Renata , Jassem Jacek , Brastianos Priscilla K. , Metellus Philippe , Bialecki Emilie , Woodroofe Carolyn C. , Wu Haitao , Swenson Rolf , Steeg Patricia S. 
Published: August 2022

AbstractAdvances in drug treatments for brain metastases of breast cancer have improved progression free survival but new, more efficacious strategies are needed. Most chemotherapeutic drugs infiltrate brain metastases by moving between brain capillary endothelial cells, paracellular distribution, resulting in heterogeneous distribution, lower than that to systemic metastases. Herein, we tested three well-known transcytotic pathways through brain capillary endothelial cells as potential avenues for drug access: Transferrin receptor (TfR) peptide, Low density lipoprotein receptor 1 (LRP1) peptide, Albumin. Each was far-red labeled, injected into two hematogenous models of brain metastases, circulated for two different times, and their uptake quantified in metastases and uninvolved (nonmetastatic) brain. Surprisingly, all three pathways demonstrated distinct distribution patternsin vivo.Two were suboptimal: TfR distributed to uninvolved brain but poorly in metastases, while LRP1 was poorly distributed. Albumin distributed to virtually all metastases in both model systems, significantly greater than in uninvolved brain (P <0.0001). Further experiments revealed that albumin entered both macrometastases and micrometastases, the targets of treatment and prevention translational strategies. Albumin uptake into brain metastases was not correlated with the uptake of a paracellular probe (biocytin). We identified a novel mechanism of albumin endocytosis through the endothelia of brain metastases consistent with clathrin-independent endocytosis (CIE), involving the neonatal Fc receptor (FcRn), galectin-3 (Gal-3) and glycosphingolipids. Components of the CIE process were found on metastatic endothelial cells in human craniotomies. The data suggest a reconsideration of albumin as a translational mechanism for improved drug delivery to brain metastases and possibly other CNS cancers.Statement of SignificanceDrug therapy for brain metastasis needs improvements. We surveyed transcytotic pathways as potential delivery systems in brain-tropic models and found that albumin has optimal properties. Albumin used a novel mechanism for endocytosis.
‘High-Density-SleepCleaner’: An open-source, semi-automatic artifact removal routine tailored to high-density sleep EEG
Authors: Leach Sven , Sousouri Georgia , Huber Reto 
Published: August 2022

AbstractBackgroundWith up to 256 channels, high-density electroencephalography (hd-EEG) has become essential to the sleep research field. The vast amount of data resulting from this magnitude of channels in overnight EEG recordings complicates the removal of artifacts.New MethodWe present a new, semi-automatic artifact removal routine specifically designed for sleep hd-EEG recordings. By employing a graphical user interface (GUI), the user assesses epochs in regard to four sleep quality markers (SQMs). Based on their topography and underlying EEG signal, the user eventually removes artifactual values. To identify artifacts, the user is required to have basic knowledge of the typical (patho-)physiological EEG they are interested in, as well as artifactual EEG. The final output consists of a binary matrix (channels x epochs). Channels affected by artifacts can be restored in afflicted epochs using epoch-wise interpolation, a function included in the online repository.ResultsThe routine was applied in 54 overnight sleep hd-EEG recordings. The proportion of bad epochs highly depends on the number of channels required to be artifact-free. Between 95% and 100% of bad epochs could be restored using epoch-wise interpolation. We furthermore present a detailed examination of two extreme cases (with few and many artifacts). For both nights, the topography and cyclic pattern of delta power look as expected after artifact removal.Comparison with Existing MethodsNumerous artifact removal methods exist, yet their scope of application usually targets short wake EEG recordings. The proposed routine provides a transparent, practical, and efficient approach to identify artifacts in overnight sleep hd-EEG recordings.ConclusionsThis method reliably identifies artifacts simultaneously in all channels and epochs.
The basolateral amygdala-anterior cingulate pathway contributes to depression and its comorbidity with chronic pain
Authors: Becker Léa J , Fillinger Clémentine , Waegaert Robin , Hener Pierre , Ayazgok Beyza , Humo Muris , Journée Sarah H , Karatas Meltem , Degiorgis Laetitia , des Neiges Santin Marie , Mondino Mary , Barrot Michel , Ibrahim El Chérif , Turecki Gustavo , Belzeaux Raoul , Veinante Pierre , Harsan Laura A , Hugel Sylvain , Lutz Pierre-Eric , Yalcin Ipek 
Published: August 2022

AbstractWhile depression and chronic pain are frequently comorbid, underlying neuronal circuits, and their relevance for the understanding of psychopathology, remain poorly defined. Here we show in mice that hyperactivity of the neuronal pathway linking the basolateral amygdala to the anterior cingulate cortex is essential for chronic pain-induced depression. In naive animals, we demonstrate that activation of this pathway is sufficient to trigger depressive-like behaviors, as well as transcriptomic alterations that recapitulate core molecular features of depression in the human brain. These alterations notably impact gene modules related to myelination and the oligodendrocyte lineage. Among these, we show that Sema4a, a hub gene significantly upregulated in both mice and humans in the context of altered mood, is necessary for the emergence of depressive-like behaviors. Overall, these results place the BLA-ACC pathway at the core of pain and depression comorbidity, and unravel the role of impaired myelination and Sema4a in mood control.
The birth-death diffusion leading to present-day Mammal diversity
Authors: Quintero Ignacio , Lartillot Nicolas , Morlon Hélène 
Published: August 2022

AbstractDramatic spatial, temporal and taxonomic variation in biodiversity is ultimately explained by differences in speciation and extinction rates. Mammals represent a ∼200 My old radiation that resulted in over 6500 extant species, with stark temporal, spatial and taxonomic heterogeneity in biodiversity. Throughout their history, every mammal lineage is expected to have undergone diversification rates that vary instantaneously in time resulting from the complex interplay of context-specific extrinsic factors (e.g., K-Pg mass extinction event, rise of angiosperms) with their evolving ecologies (e.g., body size, diet). When studying the diversification history of a clade, however, mathematical and computational limitations have hindered inference of such a flexible birth-death model where speciation and extinction rates evolve continuously along a phylogenetic tree. Here we overcome these challenges by implementing a series of phylogenetic models in which speciation and extinction rates are inherited and diffuse following a latent Geometric Brownian motion process. We enable full Bayesian inference using data augmentation techniques to sample from the posterior distribution of model parameters, including augmented phylogenetic trees and validate using simulations. Using a genome-informed time-calibrated tree for over 4000 Mammals species, we are able to estimate a complete and fine-grained picture of the variation in diversification rates that captures both global and lineage specific effects. We find that, contrary to the idea of a suppressed mammalian diversification before the K-Pg mass extinction event (i.e., explosive- or delayed-rise), mammal speciation rates dramatically increased around 10-20 My before the K-Pg. Our new model opens exciting possibilities in disentangling the drivers behind variation in diversification and assaying how small-scale processes scale-up to macroevolutionary dynamics.
Formation of secondary allo-bile acids by novel enzymes from gut Firmicutes
Authors: Lee Jae Won , Cowley Elise S. , Wolf Patricia G. , Doden Heidi L. , Murai Tsuyoshi , Olivos Caicedo Kelly Yovani , Ly Lindsey K. , Sun Furong , Takei Hajime , Nittono Hiroshi , Daniel Steven L. , Cann Isaac , Gaskins H. Rex , Anantharaman Karthik , Alves João M. P. , Ridlon Jason M. 
Published: August 2022

ABSTRACTThe gut microbiome of vertebrates is capable of numerous biotransformations of bile acids, which are responsible for intestinal lipid digestion and function as key nutrient-signaling molecules. The human liver produces bile acids from cholesterol predominantly in the A/B-transorientation in which the sterol rings are “kinked”, as well as small quantities of A/B-cisoriented “flat” stereoisomers known as “primary allo-bile acids”. While the complex multi-step bile acid 7α-dehydroxylation pathway has been well-studied for conversion of “kinked” primary bile acids such as cholic acid (CA) and chenodeoxycholic acid (CDCA) to deoxycholic acid (DCA) and lithocholic acid (LCA), respectively, the enzymatic basis for the formation of “flat” stereoisomers allo-deoxycholic acid (allo-DCA) and allo-lithocholic acid (allo-LCA) by Firmicutes has remained unsolved for three decades. Here, we present a novel mechanism by which Firmicutes generate the “flat” bile acids allo-DCA and allo-LCA. The BaiA1 was shown to catalyze the final reduction from 3-oxo-allo-DCA to allo-DCA and 3-oxo-allo-LCA to allo-LCA. Phylogenetic and metagenomic analyses of human stool samples indicate that BaiP and BaiJ are encoded only in Firmicutes and differ from membrane-associated bile acid 5α-reductases recently reported in Bacteroidetes that indirectly generate allo-LCA from 3-oxo-Δ4-LCA. We further map the distribution ofbaiPandbaiJamong Firmicutes in human metagenomes, demonstrating an increased abundance of the two genes in colorectal cancer (CRC) patients relative to healthy individuals.SIGNIFICANCE STATEMENTBile acid synthesis by vertebrates is central to digestion and nutrient signaling. Gut bacteria have evolved enzymes capable of converting primary bile acids to hundreds of secondary bile acids. While bile acid microbiology has been focused on the metabolism of ring hydroxyl groups and the carboxylated side-chain, very little is known about how bacteria alter the shape of the steroid ring system. Here, we describe enzymes expressed by Firmicutes that convert the “kinked” primary bile acid into “flat” secondary bile acids. Decades of research indicate that increased levels of secondary bile acids are risk factors for colorectal cancer. Hidden Markov Models developed from the BaiP and BaiJ enzyme sequences revealed significant enrichment in metagenomes of subjects with colorectal cancer.
Enhancing adult neuroplasticity by epigenetic regulation of Parvalbumin-expressing GABAergic cells
Authors: Lavertu-Jolin Marisol , Chattopadhyaya Bidisha , Chehrazi Pegah , Carrier Denise , Wünnemann Florian , Leclerc Séverine , Dumouchel Félix , Robertson Derek , Affia Hicham , Saba Kamal , Gopal Vijaya , Patel Anant Bahadur , Andelfinger Gregor , Pineyro Graçiela , Di Cristo Graziella 
Published: August 2022

AbstractFailure of inhibiting fear in response to harmless stimuli contributes to anxiety disorders. Extinction training only temporarily suppresses fear memories in adults, but it is highly effective in juveniles. GABAergic parvalbumin-positive (PV+) cells restrict plasticity in adult brains, thus increasing PV+ cell plasticity could promote the suppression of fear memories following extinction training in adults. Histone deacetylase 2 (Hdac2) restrains both structural and functional synaptic plasticity; however, whether and how Hdac2 controls adult PV+ cell plasticity is unknown. Here, we report that Hdac2 deletion or pharmacological inhibition in PV+ cells attenuate spontaneous recovery of fear memory after fear extinction learning in adults. These manipulations promote a temporally restricted downregulation of Acan, a critical perineuronal net component expressed exclusively by PV+ cells in medial prefrontal cortex. Finally, we show that Acan transient downregulation before extinction training but after fear memory acquisition is sufficient to reduce spontaneous fear memory recovery in wild-type mice.