bluuebunny/crossref_metadata_2025_split huggingface dataset:
Network analysis of α-synuclein pathology progression reveals p21-activated kinases as regulators of vulnerability
Authors: Vatsa Naman , Brynildsen Julia K. , Goralski Thomas M. , Kurgat Kevin , Meyerdirk Lindsay , Breton Libby , DeWeerd Daniella , Brasseur Laura , Turner Lisa , Becker Katelyn , Gallik Kristin L. , Bassett Dani S. , Henderson Michael X. 
Published: October 2024

ABSTRACTα-Synuclein misfolding and progressive accumulation drives a pathogenic process in Parkinson’s disease. To understand cellular and network vulnerability to α-synuclein pathology, we developed a framework to quantify network-level vulnerability and identify new therapeutic targets at the cellular level. Full brain α-synuclein pathology was mapped in mice over 9 months. Empirical pathology data was compared to theoretical pathology estimates from a diffusion model of pathology progression along anatomical connections. Unexplained variance in the model enabled us to derive regional vulnerability that we compared to regional gene expression. We identified gene expression patterns that relate to regional vulnerability, including 12 kinases that were enriched in vulnerable regions. Among these, an inhibitor of group II PAKs demonstrated protection from neuron death and α-synuclein pathology, even after delayed compound treatment. This study provides a framework for the derivation of cellular vulnerability from network-based studies and identifies a promising therapeutic pathway for Parkinson’s disease.Abstract FigureHIGHLIGHTSLongitudinal α-synuclein pathology assessment in 1046 brain regions over 9 monthsLinear diffusion modeling derivation of network vulnerability to α-synuclein pathologyPANGEA: assessment of over 19,000 genes in 302 brain regionsGroup II PAK inhibitor prevents α-synuclein pathology and neuron death
Ancient DNA analyses of two Early Chalcolithic Individuals from the West Mound
Authors: Doğu Ayça , Kaptan Damla , Yüncü Eren , Gürün Kanat , Vural Kıvılcım Başak , Chylenski Maciej , Byrnes Jennifer , Götherström Anders , Özer Füsun , Somel Mehmet 
Published: October 2024

AbstractIn this chapter, we investigate the genetics of two Early Chalcolithic Çatalhöyük individuals, U.18333 and U.16835, the only two burials yet recovered from the West Mound. These were two neonates buried within the same building. Using shotgun-sequenced partial genomes (0.06x and 0.02x coverage) we identify both as females. Despite being recovered from the same building, we find no close genetic kinship between them, in line with previously published kinship results from Çatalhöyük. We also find that the two West Mound neonates shared the same gene pool with Neolithic Çatalhöyük and other Central and West Anatolian Neolithic populations, and they did not carry the Caucasus-related “eastern” gene flow signature observed in later-coming Chalcolithic Anatolian genomes. This indicates no large-scale admixture between East and West Mound Çatalhöyük, and possibly that the post-Neolithic “eastern” gene flow event into Anatolia may have initiated only by the mid-6th millennium BCE.
Chemotherapy resistance due to epithelial-to-mesenchymal transition is caused by abnormal lipid metabolic balance
Authors: Matsumoto Atsushi , Inoko Akihito , Hosoda Waki , Kojima Takahiro , Ohnishi Koji , Ikenouchi Junichi 
Published: October 2024

AbstractInvasive cancer is defined by the loss of epithelial cell traits resulting from the ectopic expression of epithelial-mesenchymal transition (EMT)-related transcription factors such as Snail. Although EMT is known to impart chemoresistance to cancer cells, the precise molecular mechanisms remain elusive. We found that Snail expression confers chemoresistance by upregulating the cholesterol efflux pump ABCA1 as a countermeasure to the excess of cytotoxic free cholesterol relative to its major interaction partner in cellular membranes, sphingomyelin. This imbalance is introduced by the transcriptional repression of enzymes involved in the biosynthesis of sphingomyelin by Snail. Inhibiting esterification of cholesterol, which renders it inert, selectively suppresses growth of a xenograft model of Snail-positive kidney cancer. Our findings offer a new perspective on lipid-targeting strategies for invasive cancer therapy.
SpotMAX: a generalist framework for multi-dimensional automatic spot detection and quantification
Authors: Padovani Francesco , Čavka Ivana , Neves Ana Rita Rodrigues , López Cristina Piñeiro , Al-Refaie Nada , Bolcato Leonardo , Chatzitheodoridou Dimitra , Chadha Yagya , Su Xiaofeng A. , Lengefeld Jette , Cabianca Daphne S. , Köhler Simone , Schmoller Kurt M. 
Published: October 2024

AbstractThe analysis of spot-like structures is a widespread task in microscopy-based cell biology. Existing solutions are typically specific to single applications and do not use multi-dimensional information from 5D datasets. Therefore, experimental scientists often resort to subjective manual annotation. Here, we present SpotMAX, a generalist AI-driven framework for automated spot detection and quantification. SpotMAX leverages the full scope of multi-dimensional datasets with an easy-to-use interface and an embedded framework for cell segmentation and tracking. SpotMAX outperforms state-of-the-art tools, and in some cases, even expert human annotators. We applied SpotMAX across diverse experimental questions, ranging from meiotic crossover events inC. elegansto mitochondrial DNA dynamics inS. cerevisiaeand telomere length in mouse stem cells, leading to new biological insights. With its flexibility in integrating AI workflows, we anticipate that SpotMAX will become the standard for spot analysis in microscopy data.Source code:https://github.com/SchmollerLab/SpotMAX
Interferon-mediated NK cell activation is associated with limited neutralization breadth during SARS-CoV-2 infection
Authors: de los Rios Kobara Izumi , Jayewickreme Radeesha , Lee Madeline J. , Wilk Aaron J. ,   Stanford COVID-19 Biobank, Blomkalns Andra L. , Nadeau Kari C. , Yang Samuel , Rogers Angela J. , Blish Catherine A. 
Published: October 2024

AbstractBest known for their ability to kill infected or malignant cells, natural killer (NK) cells are also underappreciated regulators of the antibody response to viral infection. In mice, NK cells can kill T follicular helper (Tfh) cells, decreasing somatic hypermutation and vaccine responses. Although human NK cell activation correlates with poor vaccine response, the mechanisms of human NK cell regulation of adaptive immunity are poorly understood. We found that in human ancestral SARS-CoV-2 infection, broad neutralizers, who were capable of neutralizing Alpha, Beta, and Delta, had fewer NK cells that expressed inhibitory and immaturity markers whereas NK cells from narrow neutralizers were highly activated and expressed interferon-stimulated genes (ISGs). ISG-mediated activation in NK cells from healthy donors increased cytotoxicity and functional responses to induced Tfh-like cells. This work reveals that NK cell activation and dysregulated inflammation may play a role in poor antibody response to SARS-CoV-2 and opens exciting avenues for designing improved vaccines and adjuvants to target emerging pathogens.
Single-Cell Transcriptomics Unveils Skin Cell Specific Antifungal Immune Responses and IL-1Ra-IL-1R Immune Evasion Strategies of Emerging Fungal PathogenCandida auris
Authors: Balakumar Abishek , Das Diprasom , Datta Abhishek , Mishra Abtar , Bryak Garrett , Ganesh Shrihari M , Netea Mihai G. , Kumar Vinod , Lionakis Michail S , Arora Devender , Thimmapuram Jyothi , Thangamani Shankar 
Published: October 2024

AbstractCandida aurisis an emerging multidrug-resistant fungal pathogen that preferentially colonizes and persists in skin tissue, yet the host immune factors that regulate the skin colonization ofC. auris in vivoare unknown. In this study, we employed unbiased single-cell transcriptomics of murine skin infected withC. auristo understand the cell type-specific immune response toC. auris. C. aurisskin infection results in the accumulation of immune cells such as neutrophils, inflammatory monocytes, macrophages, dendritic cells, T cells, and NK cells at the site of infection. We identified fibroblasts as a major non-immune cell accumulated in theC. aurisinfected skin tissue. The comprehensive single-cell profiling revealed the transcriptomic signatures in cytokines, chemokines, host receptors (TLRs, C-type lectin receptors, NOD receptors), antimicrobial peptides, and immune signaling pathways in individual immune and non-immune cells duringC. aurisskin infection. Our analysis revealed thatC. aurisinfection upregulates the expression of the IL-1RN gene (encoding IL-1R antagonist protein) in different cell types. We found IL-1Ra produced by macrophages duringC. aurisskin infection decreases the killing activity of neutrophils. Furthermore,C. aurisuses a unique cell wall mannan outer layer to evade IL-1R-signaling mediated host defense. Collectively, our single-cell RNA seq profiling identified the transcriptomic signatures in immune and non-immune cells duringC. aurisskin infection. Our results demonstrate the IL-1Ra and IL-1R-mediated immune evasion mechanisms employed byC. auristo persist in the skin. These results enhance our understanding of host defense and immune evasion mechanisms duringC. aurisskin infection and identify potential targets for novel antifungal therapeutics.
Linearizing and forecasting: a reservoir computing route to digital twins of the brain
Authors: Di Antonio Gabriele , Gili Tommaso , Gabrielli Andrea , Mattia Maurizio 
Published: October 2024

AbstractExploring the dynamics of a complex system, such as the human brain, poses significant challenges due to inherent uncertainties and limited data. In this study, we enhance the capabilities of noisy linear recurrent neural networks (lRNNs) within the reservoir computing framework, demonstrating their effectiveness in creating autonomous in silico replicas – digital twins – of brain activity. Our findings reveal that the poles of the Laplace transform of high-dimensional inferred lRNNs are directly linked to the spectral properties of observed systems and to the kernels of auto-regressive models. Applying this theoretical framework to resting-state fMRI, we successfully predict and decompose BOLD signals into spatiotemporal modes of a low-dimensional latent state space confined around a single equilibrium point. lRNNs provide an interpretable proxy for clustering among subjects and different brain areas. This adaptable digital-twin framework not only enables virtual experiments but also offers computational efficiency for real-time learning, highlighting its potential for personalized medicine and intervention strategies.
Phenotypic landscape of a fungal meningitis pathogen reveals its unique biology
Authors: Boucher Michael J. , Banerjee Sanjita , Joshi Meenakshi B. , Wei Angela L. , Huang Manning Y. , Lei Susan , Ciranni Massimiliano , Condon Andrew , Langen Andreas , Goddard Thomas D. , Caradonna Ippolito , Goranov Alexi I. , Homer Christina M. , Mortensen Yassaman , Petnic Sarah , Reilly Morgann C. , Xiong Ying , Susa Katherine J. , Pastore Vito Paolo , Zaro Balyn W. , Madhani Hiten D. 
Published: October 2024

SUMMARYCryptococcus neoformansis the most common cause of fungal meningitis and the top-ranked W.H.O. priority fungal pathogen. Only distantly related to model fungi,C. neoformansis also a powerful experimental system for exploring conserved eukaryotic mechanisms lost from specialist model yeast lineages. To decipher its biology globally, we constructed 4328 gene deletions and measured—with exceptional precision--the fitness of each mutant under 141 diverse growth-limitingin vitroconditions and during murine infection. We defined functional modules by clustering genes based on their phenotypic signatures. In-depth studies leveraged these data in two ways. First, we defined and investigated new components of key signaling pathways, which revealed animal-like pathways/components not predicted from studies of model yeasts. Second, we identified environmental adaptation mechanisms repurposed to promote mammalian virulence byC. neoformans, which lacks a known animal reservoir. Our work provides an unprecedented resource for deciphering a deadly human pathogen.
Impairment of Neuronal Activity in the Dorsolateral Prefrontal Cortex Occurs Early in Parkinsonism
Authors: Hjelle Noah , Mohanty Biswaranjan , Hubbard Tanner , Johnson Matthew D , Wang Jing , Johnson Luke A , Vitek Jerrold L 
Published: October 2024

AbstractBackgroundParkinson’s disease (PD) is often characterized by altered rates and patterns of neuronal activity in the sensorimotor regions of the basal ganglia thalamocortical network. Little is known, however, regarding how neuronal activity in the executive control network of the brain changes in the parkinsonian condition.ObjectiveInvestigate the impact of parkinsonism on neuronal activity in the dorsolateral prefrontal cortex (DLPFC), a key region in executive control, during a go/nogo reaching task.MethodsUsing a within-subject design, single and multi-unit neuronal activity was recorded in the DLPFC of a nonhuman primate before and after the induction of mild parkinsonism using the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).ResultsCoincident with development of mild parkinsonian motor signs, there was a marked reduction in the percentage of DLPFC cells with significant task-related firing rate modulation during go and nogo conditions.ConclusionsThese results suggest that DLPFC dysfunction may occur early in parkinsonism and contribute to cognitive impairments and disrupted executive function often observed in PD patients.
Arc mediates intercellular tau transmission via extracellular vesicles
Authors: Tyagi Mitali , Chadha Radhika , de Hoog Eric , Sullivan Kaelan R. , Walker Alicia C. , Northrop Ava , Fabian Balazs , Fuxreiter Monika , Hyman Bradley T. , Shepherd Jason D. 
Published: October 2024

AbstractIntracellular neurofibrillary tangles that consist of misfolded tau protein1cause neurodegeneration in Alzheimer’s disease (AD) and frontotemporal dementia (FTD). Tau pathology spreads cell-to-cell2but the exact mechanisms of tau release and intercellular transmission remain poorly defined. Tau is released from neurons as free protein or in extracellular vesicles (EVs)3–5but the role of these different release mechanisms in intercellular tau transmission is unclear. Here, we show that the neuronal gene Arc is critical for packaging tau into EVs. Brain EVs purified from human tau (hTau) transgenic rTg4510 mice (rTgWT) contain high levels of hTau that are capable of seeding tau pathology. In contrast, EVs purified from rTgWTcrossed with Arc knock-out mice (rTgArcKO) have significantly less hTau and cannot seed tau aggregation. Arc facilitates the release of hTau in EVs produced via the I-BAR protein IRSp53, but not free tau. Arc protein directly binds hTau to form a fuzzy complex that we identified in both mouse and human brain tissue. We find that pathological intracellular hTau accumulates in neurons in rTgArcKOmice, which correlates with accelerated neuron loss in the hippocampus. Finally, we find that intercellular tau transmission is significantly abrogated in Arc KO mice. We conclude that Arc-dependent release of tau in EVs plays a significant role in intracellular tau elimination and intercellular tau transmission.
Ketosis Elevates Antioxidants and Enhances Neural Function Through Improved Bioenergetics: A1H MR Spectroscopy Study
Authors: van Nieuwenhuizen Helena , Antal Botond B. , Hone-Blanchet Antoine , Lithen Andrew , McMahon Liam , Nikolaidou Sofia , Kuang Zeming , Clarke Kieran , Jenkins Bruce G. , Rothman Douglas L. , Mujica-Parodi Lilianne R. , Ratai Eva-Maria 
Published: October 2024

AbstractKetosis is known to alter the balance of neuroactive amino acids and enhance neural function when compared to a glycolytic condition. However, its influence on other metabolites, such as antioxidants and neural energy markers, and the mechanisms by which ketosis improves neural function remain unclear. Here, we measure the neurochemical effects of acute ketosis on the human brain using ultra-high-field1H MR Spectroscopy (MRS) and investigate the subsequent impact on neural function through resting-state functional magnetic resonance imaging (rsfMRI). In a within-subjects design, N = 63 healthy adults from across the lifespan underwent1H MRS and rsfMRI scans before and after consuming individually weight-dosed and calorically-matched ketone monoester or glucose drinks. Ketone monoester administration, but not glucose, significantly elevated cerebral antioxidants and energy markers while decreasing GABA, glutamate, and glutamine levels in the posterior cingulate cortex (PCC). Notably, increased bioenergetics, specifically an increase in total creatine, correlated with greater improvements in neural function as measured using rsfMRI. Our results integrate metabolic and functional neuroimaging findings, offering a comprehensive understanding of ketosis-induced changes in brain chemistry and functional network dynamics, yielding valuable insights into potential mechanisms by which ketosis imparts its neural benefits.
Child health, nutrition and gut microbiota development during the first two years of life; study protocol of a prospective cohort study from the Khyber Pakhtunkhwa, Pakistan
Authors: Shahzad Muhammad , Ismail Muhammad , Misselwitz Benjamin , Saidal Ahsan , Andrews Simon C , Iqbal Khalid , Egger Hatice Akarsu , Nabhani Ziad Al 
Published: October 2024

AbstractRecent evidence suggests that gut microbiota development during infancy impact several metabolic, immune and endocrine pathways in humans. An imbalance in the gut microbiota diversity or function, also known dysbiosis, not only affect early child growth and development, but also linked with the development of chronic, non-communicable diseases in later life. The CHAMP (ChildHealthAndMicrobiome develpment study –Pakistan) study aims to longitudinally assess gut microbiota development and associated factors (maternal, child and demographic) during early childhood, in populations residing in malnutrition endemic communities in Pakistan. A prospective cohort of mother-infant pairs (n=70) will be recruited from District Swat, Pakistan and followed for two years. Complete information about demographic characteristics, anti-natal and post-natal care, dietary intake and feeding practices and child health will be collected at baseline and 3, 6, 12, 18 and 24 months. Anthropometric measurements (height, weight, mid upper arm circumference and head circumference), dry blood spot and fecal samples will also be collected. Ethical approval of the study has been obtained from Khyber Medical University Pakistan. The study is also registered onclincaltrial.gov(Ref no:NCT05793294). The study finding will help researchers understand gut microbiota development, associated factors and its impact on longitudinal growth in infants during the first two years of life.
Novel Digital Markers of Sleep Dynamics: A Causal Inference Approach Revealing Age and Gender Phenotypes in Obstructive Sleep Apnea
Authors: Bechny Michal , Kishi Akifumi , Fiorillo Luigi , van der Meer Julia , Schmidt Markus , Bassetti Claudio , Tzovara Athina , Faraci Francesca 
Published: October 2024

ABSTRACTDespite evidence that sleep-disorders alter sleep-stage dynamics, clinical practice resists including these parameters in PSG-reports. Leveraging the matrix of sleep-stage transition proportions, we propose (i) a general framework to quantify sleep-dynamics, (ii) several novel markers of their alterations, and (iii) demonstrate our approach using Obstructive Sleep Apnea (OSA), the most prevalent sleep-disorder. Using causal inference techniques, we address confounding in an observational clinical database and estimate markers personalized by age, gender, and OSA-severity. Importantly, our approach adjusts for five categories of sleep-wake-related comorbidities, a factor overlooked in existing research but present in 48.6% of OSA-subjects in our high-quality dataset. Key markers, such as NREM-REM-oscillations and sleep-stage-specific fragmentations, were increased across all OSA-severities and demographic groups. Additionally, we identified distinct gender-phenotypes, suggesting that females may be more vulnerable to awakenings and REM-sleep-disruptions. External validation of the transition markers on the SHHS database confirmed their robustness in detecting sleep-disordered-breathing (average AUROC = 66.4%). With advancements in automated sleep-scoring and wearable devices, our approach holds promise for developing low-cost screening tools for sleep-, neurodegenerative-, and psychiatric-disorders exhibiting altered sleep patterns.
Intention to purchase sustainable food: the role of epistemic trust, credibility of science and scepticism about climate change
Authors: Pileri Jessica , Rocchi Giulia , Luciani Federica , Reho Matteo , Veneziani Giorgio , Lai Carlo 
Published: October 2024

PurposeThis study investigated the role of epistemic trust in shaping consumers intentions towards purchasing sustainable food products by examining the relationships between epistemic trust, credibility of science, scepticism about climate change and intentions to purchase sustainable food.Design/methodology/approachData were collected using a survey. A total of 391 consumers participated in the study. Structural equation modelling was employed for data analysis.FindingsThe results showed that the trust dimension was significantly and positively associated with credibility of science (p = 0.004) and negatively with scepticism about climate change (p = 0.018); mistrust was significantly and negatively associated with credibility of science (p = ≤0.001); credibility of science had a significant negative effect on scepticism about climate change (p = ≤0.001) and scepticism about climate change had a significant direct and negative impact on intention to purchase sustainable food (p = ≤0.001). Furthermore, results indicated that the link between trust, mistrust and intention to purchase sustainable food was significantly mediated by the credibility of science and scepticism about climate change.Practical implicationsThe results can preliminarily suggest policies promoting transparency and direct consumer experiences in organisational practices, with implications extending to other sectors like education and public information.Originality/valueFor the first time, epistemic trust is specifically considered as an antecedent of intentions to purchase sustainable food, while also examining its relationships with scepticism about climate change and the credibility of science.