bluuebunny/crossref_metadata_2025_split huggingface dataset:
An adversarial collaboration to critically evaluate theories of consciousness
Authors:   Cogitate Consortium, Ferrante Oscar , Gorska-Klimowska Urszula , Henin Simon , Hirschhorn Rony , Khalaf Aya , Lepauvre Alex , Liu Ling , Richter David , Vidal Yamil , Bonacchi Niccolò , Brown Tanya , Sripad Praveen , Armendariz Marcelo , Bendtz Katarina , Ghafari Tara , Hetenyi Dorottya , Jeschke Jay , Kozma Csaba , Mazumder David R. , Montenegro Stephanie , Seedat Alia , Sharafeldin Abdelrahman , Yang Shujun , Baillet Sylvain , Chalmers David J. , Cichy Radoslaw M. , Fallon Francis , Panagiotaropoulos Theofanis I. , Blumenfeld Hal , de Lange Floris P , Devore Sasha , Jensen Ole , Kreiman Gabriel , Luo Huan , Boly Melanie , Dehaene Stanislas , Koch Christof , Tononi Giulio , Pitts Michael , Mudrik Liad , Melloni Lucia 
Published: June 2023

SummaryDifferent theories explain how subjective experience arises from brain activity1,2. These theories have independently accrued evidence, yet, confirmation bias and dependence on design choices hamper progress in the field3. Here, we present an open science adversarial collaboration which directly juxtaposes Integrated Information Theory (IIT)4,5and Global Neuronal Workspace Theory (GNWT)6–10, employing a theory-neutral consortium approach11,12. We investigate neural correlates of the content and duration of visual experience. The theory proponents and the consortium developed and preregistered the experimental design, divergent predictions, expected outcomes, and their interpretation12. 256 human subjects viewed suprathreshold stimuli for variable durations while neural activity was measured with functional magnetic resonance imaging, magnetoencephalography, and electrocorticography. We find information about conscious content in visual, ventro-temporal and inferior frontal cortex, with sustained responses in occipital and lateral temporal cortex reflecting stimulus duration, and content-specific synchronization between frontal and early visual areas. These results confirm some predictions of IIT and GNWT, while substantially challenging both theories: for IIT, a lack of sustained synchronization within posterior cortex contradicts the claim that network connectivity specifies consciousness. GNWT is challenged by the general lack of ignition at stimulus offset and limited representation of certain conscious dimensions in prefrontal cortex. Beyond challenging the theories themselves, we present an alternative approach to advance cognitive neuroscience through a principled, theory-driven, collaborative effort. We highlight the challenges to change people’s mind13and the need for a quantitative framework integrating evidence for systematic theory testing and building.
Oxysterol-liver X receptor signaling mediates CYFIP1 regulation of cortical neurogenesis
Authors: De La Fuente Daniel Cabezas , Tamburini Claudia , Stonelake Emily , Griffiths William J , Hall Jeremy , Owen Michael J. , Linden David E. J. , Pocklington Andrew , Wang Yuqin , Li Meng 
Published: June 2023

AbstractDysregulation in neural progenitor proliferation and neuronal differentiation has been increasingly recognised as a common pathology in neural cells harboring genetic risks to neuropsychiatric and neurodevelopmental disorders, yet the underlying molecular mechanisms remains largely unknown. Deletions and duplications of the 15q11.2 region containing the CYFIP1 gene have been associated with autism and schizophrenia. Using patient-derived iPSCs carrying 15q11.2 deletion and genetically manipulated hESCs with CYFIP1 gain- and loss-of-function (GoF and LoF), we show that 15q11.2 deletion and CYFIP1-LoF leads to premature neuronal differentiation while CYFIP1-GoF favours neural progenitor maintenance. We identified cholesterol biosynthesis and metabolism as a biological process disturbed by CYFIP1 dosage change, leading to altered neuro-oxysterol profiles. 24S,25-epoxycholesterol, which was decreased in CYFIP1-GoF and increased in CYFIP1-LoF and 15q11.2del neural cells, can mimic the 15q11.2del and CYFIP1-LoF phenotype by promoting cortical neuronal differentiation and restore the impaired neuronal differentiation of CYFIP1-GoF neural progenitors. Moreover, the neurogenic activity of 24S,25-epoxycholesterol is lost following genetic deletion of the brain expressed isoform of the liver X receptor LXRb while compound deletion of LXRb in CYFIP1-/- background rescued their premature neurogenesis. This work delineates LXR mediated oxysterol regulation of neurogenesis as a novel pathological mechanism in neural cells carrying 15q11.2CNV and provides a potential target for therapeutic strategies for genetic disorders associated with this risk locus.
Acquired Cross-resistance in Small Cell Lung Cancer due to Extrachromosomal DNA Amplification ofMYCparalogs
Authors: Choudhuri Shreoshi Pal , Girard Luc , Lim Jun Yi Stanley , Wise Jillian F. , Freitas Braeden , Yang Di , Wong Edmond , Hamilton Seth , Chien Victor D. , Gilbreath Collin , Zhong Jun , Phat Sarah , Myers David T. , Christensen Camilla L. , Stanzione Marcello , Wong Kwok-Kin , Farago Anna F. , Meador Catherine B. , Dyson Nicholas J. , Lawrence Michael S. , Wu Sihan , Drapkin Benjamin J. 
Published: June 2023

ABSTRACTSmall cell lung cancer (SCLC) presents as a highly chemosensitive malignancy but acquires cross-resistance after relapse. This transformation is nearly inevitable in patients but has been difficult to capture in laboratory models. Here we present a pre-clinical system that recapitulates acquired cross-resistance in SCLC, developed from 51 patient-derived xenografts (PDXs). Each model was tested forin vivosensitivity to three clinical regimens: cisplatin plus etoposide, olaparib plus temozolomide, and topotecan. These functional profiles captured hallmark clinical features, such as the emergence of treatment-refractory disease after early relapse. Serially derived PDX models from the same patient revealed that cross-resistance was acquired through aMYCamplification on extrachromosomal DNA (ecDNA). Genomic and transcriptional profiles of the full PDX panel revealed that this was not unique to one patient, asMYCparalog amplifications on ecDNAs were recurrent among cross-resistant models derived from patients after relapse. We conclude that ecDNAs withMYCparalogs are recurrent drivers of cross-resistance in SCLC.SIGNIFICANCESCLC is initially chemosensitive, but acquired cross-resistance renders this disease refractory to further treatment and ultimately fatal. The genomic drivers of this transformation are unknown. We use a population of PDX models to discover that amplifications ofMYCparalogs on ecDNA are recurrent drivers of acquired cross-resistance in SCLC.
A multi-layered integrative analysis reveals a cholesterol metabolic program in outer radial glia with implications for human brain evolution
Authors: Moriano Juan , Leonardi Oliviero , Vitriolo Alessandro , Testa Giuseppe , Boeckx Cedric 
Published: June 2023

AbstractThe definition of molecular and cellular mechanisms contributing to evolutionary divergences in brain ontogenetic trajectories is essential to formulate hypotheses about the emergence of our species. Yet the functional dissection of evolutionary modifications derived in theHomo sapienslineage at an appropriate level of granularity remains particularly challenging. Capitalizing on recent single-cell sequencing efforts that have massively profiled neural stem cells from the developing human cortex, we develop an integrative computational framework in which we perform (i) trajectory inference and gene regulatory network reconstruction, (ii) (pseudo)time-informed non-negative matrix factorization for learning the dynamics of gene expression programs, and (iii) paleogenomic analysis for a higher-resolution mapping of the regulatory landscape where our species acquired derived mutations in comparison to our closest relatives. We provide evidence for cell type-specific activation and regulation of gene expression programs during indirect neurogenesis. In particular, our analysis uncovers a zinc-finger transcription factor, KLF6, as a key regulator of a cholesterol metabolic program specifically in outer radial glia. Our strategy allows us to further probe whether the (semi)discrete gene expression programs identified have been under selective pressures in our species lineage. A cartography of the regulatory landscape impacted byHomo sapiens-derived transcription factor binding site disruptions reveals signals of selection clustering around regulatory regions associated withGLI3, a well-known regulator of the radial glial cell cycle. As a whole, our study contributes to the evidence of significant changes impacting metabolic pathways in recent human brain evolution.
Waste not, want not: Revisiting the analysis that called into question the practice of rarefaction
Authors: Schloss Patrick D. 
Published: June 2023

AbstractIn 2014, McMurdie and Holmes published the provocatively titled, “Waste not, want not: why rarefying microbiome data is inadmissible”. The claims of their study have significantly altered how microbiome researchers control for the unavoidable uneven sequencing depths that are inherent in modern 16S rRNA gene sequencing. Confusion over the distinction between the definitions of rarefying and rarefaction continues to cloud the interpretation of their results. More importantly, the authors made a variety of choices in designing and analyzing their simulations that were potentially problematic. I identified 11 factors that could have compromised the results of the original study. I reproduced the original simulation results and assessed the impact of those 11 factors on the underlying conclusion that rarefying data is inadmissible. Throughout, the design of the original study made choices that caused rarefying and rarefaction to appear to perform worse than they truly did. Most important were the approaches used to assess ecological distances, the removal of samples with low sequencing depth, and not accounting for conditions where sequencing effort is confounded with treatment group. Although the original study criticized rarefying for the arbitrary removal of valid data, repeatedly rarefying data many times (i.e., rarefaction) incorporates all the data. In contrast, it is the removal of rare taxa that would appear to remove valid data. Overall, I show that rarefaction is the most robust approach to control for uneven sequencing effort when considered across a variety of alpha and beta diversity metrics.ImportanceOver the past 10 years, the best method for normalizing the sequencing depth of samples characterized by 16S rRNA gene sequencing has been contentious. An often cited paper by McMurdie and Holmes forcefully argued that rarefying the number of sequence counts was “inadmissible” and should not be employed. However, I identified a number of problems with the design of their simulations and analysis that could compromise their results. In fact, when I reproduced and expanded upon their analysis, it was clear that rarefaction was actually the most robust approach for controlling for uneven sequencing effort across samples. Rarefaction limits the rate of falsely detecting and rejecting differences between treatment groups. Far from being “inadmissible”, rarefaction is a valuable tool for analyzing microbiome sequence data.
Size dependent diffusion and dispersion of particles in mucin
Authors: Kumar Parveen , Tamayo Joshua , Shiu Ruei-Feng , Chin Wei-Chun , Gopinath Arvind 
Published: June 2023

ABSTRACTMucus, composed significantly of glycosylated mucins, is a soft rheologically complex vis-coelastic material lining respiratory, reproductive, and gastrointestinal tracts in mammals. Mucus may present as a gel or as a fluid, and serves as a barrier to the transport of microbes including, harmful particles, and inhaled atmospheric pollutants. Studies on mucin gels have provided insight into swelling kinetics, and the diffusion and permeability of molecular constituents such as water. The transport and dispersion of micron and sub-micron tracer particles in mucin gels and solutions differs from the motion of molecular water since the much larger tracers may interact with microstructure and larger features of the mucin network. Here, using brightfield and florescence microscopy, high speed particle-tracking, and passive microrheology, we study the thermally driven stochastic movement of 0.5 − 5.0µm tracer particles in 10% mucin solutions at neutral pH, and in 10% mucin mixed with unmodified limestone rock dust, modified limestone, and crystalline silica. Particle trajectories, mean square displacements, and the displacement probability distributions, are used to assess tracer diffusion and transport. Complex moduli are concomitantly extracted using microrheology techniques. We find that under the conditions analyzed in our experiments the mucin solution present as a highly viscous, weakly viscoelastic fluid rather than as a viscoelastic gel. For small to moderately sized tracers with diameter than 2µm, effective diffusion coefficients follow predictions of classical Stokes-Einstein relationship. Diffusivity in rock-dust laden mucin is surprisingly larger than in bare mucin. Probability distributions of squared particle displacements indicate that heterogeneity, transient trapping, and electrostatic interactions impact tracer transport, especially for larger tracers. Our results prompt further exploration of physiochemical and rheological mechanisms mediating particle transport in soft, viscoelastic biopolymer networks and materials.
Not alpha power: prestimulus beta power predicts the magnitude of individual temporal order bias for audiovisual stimuli
Authors: Jiang Zeliang , wang Lu , An Xingwei , Liu Shuang , Yin Erwei , Yan Ye , Ming Dong 
Published: June 2023

AbstractIndividuals exhibit significant variations in audiovisual temporal order perception. Previous studies have investigated the neural mechanisms underlying these individual differences by analyzing ongoing neural oscillations using stimuli specific to each participant. This study explored whether these effects could extend to different paradigms with the same stimuli across subjects in each paradigm. The two human participants groups performed a temporal order judgment (TOJ) task in two experimental paradigms while recording EEG. One is the beep-flash paradigm, while the other is the stream-bounce paradigm. We focused on the correlation between individual temporal order bias (i.e., point of subjective simultaneity (PSS)) and spontaneous neural oscillations. In addition, we also explored whether the frontal cortex could modulate the correlation through a simple mediation model. We found that the beta band power in the auditory cortex could negatively predict the individual’s PSS in the beep-flash paradigm. Similarly, the same effects were observed in the visual cortex during the stream-bounce paradigm. Furthermore, the frontal cortex could influence the power in the sensory cortex and further shape the individual’s PSS. These results suggested that the individual’s PSS was modulated by auditory or visual cortical excitability depending on the experimental stimuli. The frontal cortex could shape the relation between sensory cortical excitability and the individual’s PSS in a top-down manner. In conclusion, our findings indicated that the prefrontal cortex could effectively regulate an individual’s temporal order bias, providing insights into audiovisual temporal order perception mechanisms and potential interventions for modulating temporal perception.
Maternal choline supplementation lessens the behavioral dysfunction produced by developmental manganese exposure in a rodent model of ADHD
Authors: Howard Shanna L. , Beaudin Stephane A. , Strupp Barbara J. , Smith Donald R. 
Published: June 2023

AbstractStudies in children have reported associations between elevated manganese (Mn) exposure and ADHD-related symptoms of inattention, impulsivity/hyperactivity, and psychomotor impairment. Maternal choline supplementation (MCS) during pregnancy/lactation may hold promise as a protective strategy because it has been shown to lessen cognitive dysfunction caused by numerous early insults. Our objectives were to determine whether (1) developmental Mn exposure alters behavioral reactivity/emotion regulation, in addition to impairing learning, attention, impulse control, and sensorimotor function, and (2) MCS protects against these Mn-induced impairments. Pregnant Long-Evans rats were given standard diet, or a diet supplemented with additional choline throughout gestation and lactation (G3 - PND 21). Male offspring were exposed orally to 0 or 50 mg Mn/kg/day over PND 1–21. In adulthood, animals were tested in a series of learning, attention, impulse control, and sensorimotor tasks. Mn exposure caused lasting dysfunction in attention, reactivity to errors and reward omission, learning, and sensorimotor function, recapitulating the constellation of symptoms seen in ADHD children. MCS lessened Mn-induced attentional dysfunction and partially normalized reactivity to committing an error or not receiving an expected reward but provided no protection against Mn-induced learning or sensorimotor dysfunction. In the absence of Mn exposure, MCS produces lasting offspring benefits in learning, attention, and reactivity to errors. To conclude, developmental Mn exposure produces a constellation of deficits consistent with ADHD symptomology, and MCS offered some protection against the adverse Mn effects, adding to the evidence that maternal choline supplementation is neuroprotective for offspring and improves offspring cognitive functioning.HighlightsDevelopmental Mn exposure causes lasting dysfunction consistent with ADHD symptomology.Maternal choline supplementation (MCS) protects against Mn-induced deficits in attention and behavioral reactivity.MCS in control animals produces lasting benefits to offspring in learning, attention, and error reactivity.These data support efforts to increase choline intake during pregnancy, particularly for individuals at risk of neurotoxicant exposure.
Luminal transport through intact endoplasmic reticulum limits the magnitude of localized Ca2+signals
Authors: Crapart Cécile C. , Scott Zubenelgenubi C. , Konno Tasuku , Sharma Aman , Parutto Pierre , Bailey David M. D. , Westrate Laura M. , Avezov Edward , Koslover Elena F. 
Published: June 2023

The endoplasmic reticulum (ER) forms an interconnected network of tubules stretching throughout the cell. Understanding how ER functionality relies on its structural organization is crucial for elucidating cellular vulnerability to ER perturbations, which have been implicated in several neuronal pathologies. One of the key functions of the ER is enabling Ca2+signalling by storing large quantities of this ion and releasing it into the cytoplasm in a spatiotemporally controlled manner. Through a combination of physical modeling and livecell imaging, we demonstrate that alterations in ER shape significantly impact its ability to support efficient local Ca2+releases, due to hindered transport of luminal content within the ER. Our model reveals that rapid Ca2+release necessitates mobile luminal buffer proteins with moderate binding strength, moving through a well-connected network of ER tubules. These findings provide insight into the functional advantages of normal ER architecture, emphasizing its importance as a kinetically efficient intracellular Ca2+delivery system.Significance StatementThe peripheral endoplasmic reticulum forms a continuous network of tubules extending through the entire cell. One of the key functional roles of the ER is the release of Ca2+ions into the cytosol to support a broad diversity of intracellular signaling processes. Such release events are enabled by the high Ca2+storage capacity of the ER. This work demonstrates that mobile Ca2+binding buffer proteins and a well-connected lattice-like architecture of the ER network are optimal to supply local Ca2+signals and that changes in ER structure can modulate Ca2+release. By linking transport kinetics to Ca2+release, we demonstrate a key functional role for the interconnected network architecture of the ER.
Synapsin E-domain is essential for α-synuclein function
Authors: Stavsky Alexandra , Parra-Rivas Leonardo A. , Tal Shani , Riba Jen , Madhivanan Kayalvizhi , Roy Subhojit , Gitler Daniel 
Published: June 2023

ABSTRACTThe cytosolic proteins synucleins and synapsins are thought to play cooperative roles in regulating synaptic vesicle (SV) recycling, but mechanistic insight is lacking. Here we identify the synapsin E-domain as an essential functional binding-partner of α-synuclein (α-syn). Synapsin E-domain allows α-syn functionality, binds to α-syn, and is necessary and sufficient for enabling effects of α-syn at the synapse. Together with previous studies implicating the E-domain in clustering SVs, our experiments advocate a cooperative role for these two proteins in maintaining physiologic SV clusters.
Locomotor effects of a fibrosis-based immune response in stickleback fish
Authors: Matthews David G. , Maciejewski Meghan F. , Wong Greta A. , Lauder George V. , Bolnick Daniel I. 
Published: June 2023

AbstractThe vertebrate immune system provides an impressively effective defense against parasites and pathogens. However, these benefits must be balanced against a range of costly side-effects including energy loss and risks of auto-immunity. These costs might include biomechanical impairment of movement, but little is known about the intersection between immunity and biomechanics. Here, we show that a fibrosis immune response in threespine stickleback (Gasterosteus aculeatus) has collateral effects on their locomotion. When freshwater stickleback are infected with the tapeworm parasite Schistocephalus solidus, they face an array of fitness consequences ranging from impaired body condition and fertility to an increased risk of mortality. To fight the infection, some stickleback will initiate a fibrosis immune response in which they produce excess collagenous tissue in their coelom. Although fibrosis is effective at reducing infection, some populations of stickleback actively suppress this immune response, possibly because the costs of fibrosis outweigh the benefits. Here we quantify the locomotor effects of the fibrosis immune response in the absence of parasites to investigate whether there are collateral costs of fibrosis that could help explain why some fish forego this effective defense. To do this, we induce fibrosis in stickleback and then test their C-start escape performance. Additionally, we measure the severity of fibrosis, body stiffness, and body curvature during the escape response. We were able to estimate performance costs of fibrosis by including these variables as intermediates in a structural equation model. This model reveals that among control fish without fibrosis, there is a performance cost associated with increased body stiffness. However, fish with fibrosis did not experience this cost but rather displayed increased performance with higher fibrosis severity. This result demonstrates that the adaptive landscape of immune responses can be complex with the potential for wide reaching and unexpected fitness consequences.
Hypoxia induced oxidative stress and endoplasmic reticulum stress promoted myocardial cell fibrosis
Authors: Jiang Zhan , Chun Zhang , Guang Xu 
Published: June 2023

SUMMARYMyocardial cells, fibroblasts and vascular cells in the heart are connected by a complex matrix mainly composed of fibrillar collagen, which helps to protect the integrity and compliance of the heart structure. Previous studies have shown that hypoxia can induce myocardial hypoxia, but the mechanism is still unclear. In this study, we found that hypoxia promotes TGF beta induced collagen deposition and myocardial fibrosis by inducing Endoplasmic reticulum stress and oxidative stress in cardiomyocytes. Moreover, we also found that antioxidant drugs can effectively alleviate hypoxia induced myocardial fibrosis. Therefore, our study provides an experimental basis for the treatment of myocardial fibrosis.