bluuebunny/crossref_metadata_2025 huggingface dataset:
40 Hz light stimulation restores early brain dynamics alterations and associative memory in Alzheimer’s disease model mice
Authors: Aguilera Matthieu , Mathis Chantal , Herbeaux Karin , Isik Amine , Faranda Davide , Battaglia Demian , Goutagny Romain
Published: October 2024

Visual gamma entrainment using sensory stimuli (vGENUS) is a promising non-invasive therapeutic approach for Alzheimer’s disease (AD), showing efficacy in improving memory function. However, its mechanisms of action remain poorly understood. Using young AppNL-F/MAPT double knock-in (dKI) mice, a model of early AD, we examined brain dynamics alterations before amyloid plaque onset. High-density EEG recordings and novel metrics from fields outside neuroscience were used to assess brain dynamics fluidity—a measure of the brain’s ability to transition between activity states. We revealed that dKI mice exhibit early, awake state-specific reductions in brain dynamics fluidity associated with cognitive deficits in complex memory tasks. Daily vGENUS sessions over two weeks restored brain dynamics fluidity and rescued memory deficits in dKI mice. Importantly, these effects built up during the stimulation protocol and persisted after stimulation ended, suggesting long-term modulation of brain function. Based on these results, we propose a “brain dynamics repair” mechanism for vGENUS that goes beyond current amyloid-centric hypotheses. This dual insight - that brain dynamics are both a target for repair and a potential diagnostic tool - provides new perspectives on early Alzheimer’s disease pathophysiology.

Significance Statement

Gamma ENtrainment Using Sensory stimuli (GENUS), involving 40 Hz rhythmic sensory stimulation, shows promise in improving memory function in Alzheimer’s disease (AD). We hypothesized that brain dynamics changes could be detected before plaque onset and modulated by vGENUS. Applying techniques from climate science to EEG recordings in young AD model mice, we found reduced brain dynamics fluidity associated with early cognitive deficits. Two weeks of vGENUS restored brain dynamics and improved memory, with effects persisting post-treatment. These findings challenge the amyloid-centric view of AD, introduce a potential early biomarker, and suggest vGENUS acts by “repairing” brain dynamics. Our approach offers new perspectives on early diagnosis and non-invasive interventions for AD and other neurological disorders with disrupted brain dynamics.
Visual objects refine head direction coding
Authors: Siegenthaler Dominique , Denny Henry , Skromne Carrasco Sofía , Mayer Johanna Luise , Levenstein Daniel , Peyrache Adrien , Trenholm Stuart , Macé Émilie
Published: October 2024

Animals use visual objects to guide navigation-related behaviors, from hunting prey, to escaping predators, to exploring the world. However, little is known about where visual objects are encoded in the mouse brain or how they impact processing in the spatial navigation system. Using functional ultrasound imaging in mice, we conducted a brain-wide screen and identified brain areas that were preferentially activated by images of objects compared to scrambled versions of the same images. While visual cortical areas did not show a significant preference, regions associated with spatial navigation were preferentially activated by visual objects. Electrophysiological recordings in postsubiculum, the primary cortical area of the head direction (HD) system, further confirmed a preference for visual objects, which was present in both HD cells and fast-spiking interneurons. Finally, we found that visual objects dynamically modulated HD cells, selectively increasing firing rates of HD cells aligned with a visual landmark’s direction, while decreasing activity in HD cells coding for other directions. These results reveal that visual objects refine population-level coding of head direction.
Proper reference selection and re-referencing to mitigate bias in single pulse electrical stimulation data
Authors: Huang Harvey , Adkinson Joshua A. , Jensen Michael A. , Hasen Mohammed , Danstrom Isabel A. , Bijanki Kelly R. , Gregg Nicholas M. , Miller Kai J. , Sheth Sameer A. , Hermes Dora , Bartoli Eleonora
Published: October 2024

Single pulse electrical stimulation experiments produce pulse-evoked potentials used to infer brain connectivity. The choice of recording reference for intracranial electrodes remains non-standardized and can significantly impact data interpretation. When the reference electrode is affected by stimulation or evoked brain activity, it can contaminate the pulse-evoked potentials recorded at all other electrodes and influence interpretation of findings. We highlight this specific issue in intracranial EEG datasets from two subjects recorded at separate institutions. We present several intuitive metrics to detect the presence of reference contamination and offer practical guidance on different mitigation strategies. Either switching the reference electrode or re-referencing to an adjusted common average effectively mitigated the reference contamination issue, as evidenced by increased variability in pulse-evoked potentials across the brain. Overall, we demonstrate the importance of clear quality checks and preprocessing steps that should be performed before analysis of single pulse electrical stimulation data.

Highlights

A reference electrode close to active tissue can contaminate intracranial EEG signals

Interpretation of pulse-evoked potentials can be biased by reference contamination

Low response variability between channels is indicative of reference contamination

Reference contamination can be resolved through data recollection or re-referencing
Space matters: virtual pedestrians with mobility constraints affect individuals’ avoidance behaviours
Authors: Nikmanesh Mohammadamin , Cinelli Michael E. , Marigold Daniel S.
Published: October 2024

Walking in urban settings requires people to negotiate crowds. In these situations, people typically want to maintain a level of personal space around themselves. Recent work on one-versus-one interactions demonstrated that whether one of the pedestrians looked distracted or interacted with an object (e.g., stroller, bike) predicted the medial-lateral separation between them as they walked past each other. However, this work did not distinguish between the type of object interaction (or mobility constraint) and thus, it is unclear whether different constraints have different effects on avoidance behaviours. Here we tested the hypothesis that the type of object an approaching pedestrian held or pushed would affect the extent of path deviation, which would also depend on whether that pedestrian was distracted. To address this hypothesis, we created an immersive virtual environment that consisted of a 3.5-m-wide paved urban path. Participants had to walk and avoid colliding with approaching virtual pedestrians that often held a shopping bag or pushed a bike or stroller while looking straight ahead or off to the side as if distracted. Distraction did not affect avoidance behaviours. However, participants increased medial-lateral separation with the virtual pedestrian at the time of crossing when a stroller was present compared to the other mobility constraints. The type of mobility constraint also differentially affected onset of deviation and rate of progression before and after a path deviation. These results support the idea that characteristics of the obstacle to avoid (in this case, a virtual pedestrian) influence collision avoidance behaviours.
Defining Cellular Diversity at the Swine Maternal-Fetal Interface Using Spatial Transcriptomics and Organoids
Authors: McCutcheon Cole R. , Caldwell Allyson , Yang Liheng (Henry) , Crisci Elisa , Pasternak J. Alex , Coyne Carolyn B.
Published: October 2024

The placenta is a dynamic, embryo-derived organ essential for fetal growth and development. While all eutherian mammals have placentas composed of fetal-derived trophoblasts that mediate maternal-fetal exchange, their anatomical and histological structures vary across species due to evolutionary divergence. Despite the cellular heterogeneity of porcine trophoblastsin vivo, understanding the mechanisms driving porcine placental development has been limited by the lack ofin vitromodels replicating this heterogeneity. In this study, we derived swine trophoblast organoids (sTOs) from full-term porcine placentas, retaining key transcriptional signatures ofin vivotrophoblasts. To identify conserved cell populations, we integrated Visium spatial transcriptomics from mid-gestation porcine placentas with single-cell transcriptomics from sTOs. Spatial transcriptomics revealed novel markers of the porcine uterus and placenta, enabling precise separation of histological structures at the maternal-fetal interface. The integration of tissue and sTO transcriptomics showed that sTOs spontaneously differentiate into distinct trophoblast populations, with conserved gene expression and cell communication programs. These findings demonstrate that sTOs recapitulate porcine placental trophoblast populations, offering a powerful model for advancing placentation research. Our work also provides a spatially resolved whole-transcriptome dataset of the porcine maternal-fetal interface, opening new avenues for discoveries in placental development, evolution, and health across mammals.
Spatial memory in Alzheimer’s disease 5XFAD mice is enhanced by XPO1 inhibitor KPT-330
Authors: Wong Shi Quan , Ouellette Adia , McNamara Avery , Tam Rachel A. , Alexandrov Alexander , Nawrocik-Madrid Acacia , Sanchez Jesus J. , Ginsburg Brett C. , Andrade Arturo A. , Lapierre Louis R.
Published: October 2024

The proteostatic decline in Alzheimer’s disease is well established and improvement in proteostasis could potentially delay cognitive impairment. One emerging entry point to modulate proteostasis is the regulation of nucleo-cytoplasmic partitioning of proteins across the nuclear pore via karyopherins. The nuclear exportin XPO1 is a key regulator of proteostasis by driving the assembly of ribosomes and by modulating the process of autophagy. We recently found that XPO1 inhibitor KPT-330 (Selinexor), an FDA approved drug against multiple myelomas, enhances proteostasis, leading to benefits in models of neurodegenerative diseases inC. elegansandDrosophila. Here, we find that KPT-330 increases autophagy in murine neuronal cells and improves spatial memory performance in a murine model of Alzheimer’s disease (5XFAD). Unexpectedly, general amyloid deposition in several brain regions was significantly increased by KPT-330, but specific regions, especially the thalamus, displayed significantly lower deposition, suggesting that XPO1 inhibition has regional-specific effects on proteostasis and amyloid plaque formation. Altogether, we conclude that XPO1 inhibition can improve cognition via spatially-specific reductions in amyloid deposition.
Benefits of combining individual and small group assessments as an instructional strategy
Authors: Arini Gabriel Santos , de Souza Almeida Israel , Torres Bayardo Baptista
Published: October 2024

Assessment is an essential curricular component despite being often seen only as a performance metric resource. However, its full potential can be harnessed if it is used as a formative instrument. The present study evaluated the benefits of combining individual and group assessments. Students’ perceptions of this type of strategy, assessed through a Likert scale questionnaire and semi-structured interviews, showed that students acknowledge the benefits of this procedure. We then carried out a dual assessment in an active learning environment. Students were given individual written tests and completed the same test immediately after, but now in a group. The average group scores were higher than the average individual scores, even for students who scored the highest within a group. Put together, these results indicate combining individual and group assessments can be an effective teaching tool in addition to simply measuring student performance.
Myeloid-derived β-hexosaminidase is essential for neuronal health and lysosome function: implications for Sandhoff disease
Authors: Tsourmas Kate I. , Butler Claire A. , Kwang Nellie E. , Sloane Zachary R. , Dykman Koby J. G. , Maloof Ghassan O. , Prekopa Christiana A. , Krattli Robert P. , El-Khatib Sanad M. , Swarup Vivek , Acharya Munjal M. , Hohsfield Lindsay A. , Green Kim N.
Published: October 2024

Lysosomal storage disorders (LSDs) are a large disease class involving lysosomal dysfunction, often resulting in neurodegeneration. Sandhoff disease (SD) is an LSD caused by a deficiency in the β subunit of the β-hexosaminidase enzyme (Hexb). AlthoughHexbexpression in the brain is specific to microglia, SD primarily affects neurons. To understand how a microglial gene is involved in maintaining neuronal homeostasis, we demonstrated that β-hexosaminidase is secreted by microglia and integrated into the neuronal lysosomal compartment. To assess therapeutic relevance, we treated SD mice with bone marrow transplant and colony stimulating factor 1 receptor inhibition, which broadly replacedHexb-/-microglia withHexb-sufficient cells. This intervention reversed apoptotic gene signatures, improved behavior, restored enzymatic activity andHexbexpression, ameliorated substrate accumulation, and normalized neuronal lysosomal phenotypes. These results underscore the critical role of myeloid-derived β- hexosaminidase in neuronal lysosomal function and establish microglial replacement as a potential LSD therapy.
An implementation study of the service model for genetic risk-based stratified breast cancer screening – Estonian results of the BRIGHT project
Authors: Tamm Madli , Padrik Peeter , Ojamaa Kristiina , Paas Anette , Lepland Anni , Kruuv-Käo Krista , Leitsalu Liis , Sõber Siim , Roht Laura , Pajusalu Sander , Kahre Tiina , Padrik Anna , Pindmaa Jagnar , Luga Kadri , Rootslane Ly , Ilves Anne , Ulp Sulev , Kallak Kersti , Tihamäe Ave-Triin , Tõnisson Neeme
Published: October 2024

Breast cancer (BC) remains the most common malignant tumor site and the leading cause of cancer-related deaths in women despite the wide availability of screening programs and personalized treatment options. The BRIGHT study tested a genetic risk-based personalized BC screening service model in women younger than 50 years, using telemedicine and home-based testing. Participants underwent polygenic risk score and monogenic pathogenic variant testing. This type of screening model demonstrated feasibility, clinical utility, and acceptability. It has the potential to enhance BC screening programs, particularly for younger women and those at higher genetic risk, while avoiding unnecessary interventions for low-risk individuals.
The role of the microbiota in respiratory virus-bacterial pathobiont relationships in the upper respiratory tract
Authors: Kelly Matthew S. , Shi Pixu , Boiditswe Sefelani C. , Qin Emily , Steenhoff Andrew P. , Mazhani Tiny , Patel Mohamed Z. , Cunningham Coleen K. , Rawls John F. , Luinstra Kathy , Gilchrist Jodi , Maciejewski Julia , Hurst Jillian H. , Seed Patrick C. , Bulir David , Smieja Marek
Published: October 2024

The mechanisms by which respiratory viruses predispose to secondary bacterial infections remain poorly characterized. Using 2,409 nasopharyngeal swabs from 300 infants in Botswana, we performed a detailed analysis of factors that influence the dynamics of bacterial pathobiont colonization during infancy. We quantify the extent to which viruses increase the acquisition ofHaemophilus influenzae,Moraxella catarrhalis, andStreptococcus pneumoniae. We provide evidence of cooperative interactions between these pathobionts while identifying host characteristics and environmental exposures that influence the odds of pathobiont colonization during early life. Using 16S rRNA gene sequencing, we demonstrate that respiratory viruses result in losses of putatively beneficialCorynebacteriumandStreptococcusspecies that are associated with a lower odds of pathobiont acquisition. These findings provide novel insights into viral-bacterial relationships in the URT of direct relevance to respiratory infections and suggest that the URT bacterial microbiota is a potentially modifiable mechanism by which viruses promote bacterial respiratory infections.
Moonlit Misconceptions: A South Florida Veterans’ Hospital Perspective on Full Moon Emergency Room Visits
Authors: VanMeter David J. , Strebel Timothy S. , Mastorides Stephen M. , Borkowski Andrew A.
Published: October 2024

The belief that the full moon influences human behavior and health outcomes has persisted for centuries despite limited scientific evidence. This study examined whether there is a correlation between the lunar cycle and emergency department (ED) visits and hospital admissions among veterans in South Florida from 2013-2023. Data on 465,838 ED visits resulting in 110,640 admissions and moon illumination fraction data were analyzed. The results showed no significant difference in the mean number of ED visits, admissions, or percentage of visits resulting in admission across different moon illumination fractions, including full moons. While some past studies have suggested links between the lunar cycle and health conditions like seizures and psychiatric issues, this study found no association between the full moon and ED utilization patterns in the South Florida veteran population over an 11-year period. The findings contradict the long-standing belief about the lunar effect on hospital services and do not support adapting staffing or resources based on the moon’s phase.
Infant gonadotropins predict spontaneous puberty in girls with Turner syndrome
Authors: Sawyer Alexandra , Bothwell Samantha , Swenson Karli , Travers Sharon , Davis Shanlee
Published: October 2024

Introduction

Hypergonadotropic hypogonadism is a characteristic clinical manifestation of Turner syndrome (TS). While up to 30% and 20% of people with TS will have spontaneous thelarche and menarche respectively, there is a lack of evidence to predict who will retain sufficient ovarian function to achieve these outcomes. The aim of this study was to determine if follicle-stimulation hormone (FSH) and/or luteinizing hormone (LH) concentrations measured in infancy would accurately predict later spontaneous thelarche or menarche.

Methods

Patients with a diagnosis of Turner syndrome with FSH and/or LH clinically measured prior to three years of age and now ≥10 years of age with documented pubertal assessment were included (n=33). Differences in infant gonadotropin values were determined for patients with vs without spontaneous thelarche/menarche using Kruskal-Wallis tests. The optimal threshold of infant LH and FSH to predict spontaneous thelarche and menarche was then determined by maximizing the sum of sensitivity and specificity.

Results

The prevalence of spontaneous thelarche and menarche were 21.2% and 15.2% respectively. An infant LH value greater than 0.5 mIU/mL predicted lack of spontaneous thelarche with an estimated accuracy of 94% and lack of spontaneous menarche with an estimated accuracy of 96%. An infant FSH value greater than 37.4 mIU/mL predicted lack of lack of spontaneous thelarche with an accuracy of 97% and lack of spontaneous menarche with an accuracy of 100%.

Conclusion

Infant gonadotropin concentrations accurately predict spontaneous later thelarche and menarche for persons with TS.
Association between TikTok use and the development of eating disorders in young Colombian adults between 18 and 25 years of age
Authors: Restrepo-Escudero Laura , McCormick Silvia , Cuevas Maria Isabel , Mosquera Sara , Vásquez Mariana , Correa Maria José , Patiño Maria Camila , Reyes Pablo , González Ballesteros Lina Maria
Published: October 2024

Background

Visual and appearance-based social media platforms like TikTok can establish unrealistic beauty standards and self-esteem issues, leading to the development of eating disorders (EDs). This study aims to evaluate the association between TikTok usage and the presence of EDs risk behaviors and body dissatisfaction among Colombian young adults aged between 18 and 25 years.

Methods

A cross-sectional descriptive study was conducted via an online survey through snowball sampling with 171 participants. The survey assessed demographic variables, social media use, content consumption, EDs risk behaviors, and body dissatisfaction through validated tools. Non-parametric tests and regression models were used for the data analysis.

Results

TikTok users showed significantly higher scores in ED risk behaviors (M = 14.91) and body dissatisfaction (M = 21.9) compared to non-users. Contributory usage, particularly collaborative content creation, was the most associated with increased risk. The multivariate regression model for ED risk explained 3% of the variance, while TikTok use accounted for 30% of the variance in the model for body dissatisfaction.

Discussion

Our study found a significant association between TikTok use and the development of ED risk behaviors and body dissatisfaction. These findings align with previous research and highlight the need for interventions that encourage mindful social media consumption.
A Normal Forced Vital Capacity Does Not Reliably or Equitably Exclude Restriction
Authors: Moffett Alexander T. , Balasubramanian Aparna , McCormack Meredith C. , Aysola Jaya , Halpern Scott D. , Weissman Gary E.
Published: October 2024

Background

European Respiratory Society and American Thoracic Society (ERS/ATS) guidelines for pulmonary function test (PFT) interpretation recommend the use of a normal forced vital capacity (FVC) to exclude restriction. However, this recommendation is based upon a single study from 1999, which was limited to White patients, and used race-specific reference equations that are no longer recommended by ERS/ATS. We sought to reassess the support for this recommendation by calculating the negative predictive value (NPV) of a normal FVC in a diverse, multicenter cohort using race-neutral reference equations.

Methods

We interpreted PFTs performed between 2000 and 2023 in two academic medical systems and in a national electronic health record (EHR) database. We calculated the NPV of a normal FVC to exclude restriction overall and among pre-specified racial and ethnic groups.

Results

We included PFTs from 85 990 patients. The prevalence of restriction was 35.1%. The overall NPV of a normal FVC to exclude restriction was 80.5% (95% CI 80.1% to 80.8%), compared to an NPV of 97.6% cited in support of ERS/ATS guidelines. The NPV ranged from 65.2% (95% CI 64.4% to 66.0%) among non-Hispanic Black patients to 85.9% (95% CI 85.6% to 86.3%) among non-Hispanic White patients. This difference was largely attributable to lower FVC z-scores among non-Hispanic Black patients.

Conclusions

The NPV of a normal FVC is lower than has been previously reported and varies by race and ethnicity. The approach to PFT interpretation recommended by ERS/ATS guidelines results in the under-recognition of restriction, particularly among non-Hispanic Black patients.
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

α-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 Figure

HIGHLIGHTS

Longitudinal α-synuclein pathology assessment in 1046 brain regions over 9 months

Linear diffusion modeling derivation of network vulnerability to α-synuclein pathology

PANGEA: assessment of over 19,000 genes in 302 brain regions

Group 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

In 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

Invasive 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

The 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

Best 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

Candida 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

Exploring 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

Cryptococcus 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

Background

Parkinson’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.

Objective

Investigate 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.

Methods

Using 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).

Results

Coincident 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.

Conclusions

These 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

Intracellular 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

Ketosis 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.
Polyphenol rewiring of the microbiome reduces methane emissions
Authors: McGivern Bridget B , Ellenbogen Jared B , Hoyt David W , Bouranis John A , Stemple Brooke P , Daly Rebecca A , Bosman Samantha H , Sullivan Matthew B , Hagerman Ann E , Chanton Jeffrey P , Tfaily Malak M , Wrighton Kelly C
Published: October 2024

Methane mitigation is regarded as a critical strategy to combat the scale of global warming. Currently, about 40% of methane emissions originate from microbial sources, which is causing strategies to suppress methanogens, either through direct toxic effects or by diverting their substrates and energy, to gain traction. Problematically, current microbial methane mitigation knowledge derives from rumen studies and lacks detailed microbiome-centered insights, limiting translation across ecosystems. Here we utilize genome-resolved metatranscriptomes and metabolomes to assess the impact of a proposed methane inhibitor, catechin, on greenhouse gas emissions for high-methane-emitting peatlands. In microcosms, catechin drastically reduced methane emissions by 72-84% compared to controls. Longitudinal sampling allowed for reconstruction of a novel catechin degradation pathway involving Actinomycetota and Clostridium, which break down catechin into smaller phenolic compounds within the first 21 days, followed by degradation of phenolic compounds by Pseudomonas_E from days 21 to 35. These genomes also co-expressed hydrogen-uptake genes, suggesting that hydrogenases may act as a hydrogen sink during catechin degradation, depriving methanogens of substrates. This was supported by decreased gene expression in hydrogenotrophic and hydrogen-dependent methylotrophic methanogens under catechin treatment. We also saw reduced gene expression from genomes inferred to be functioning syntrophically with hydrogen-utilizing methanogens. We propose that catechin metabolic redirection effectively starves hydrogen-utilizing methanogens, offering a potent avenue for curbing methane emissions across diverse environments including ruminants, landfills, and constructed or managed wetlands.
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

Recent 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

Despite 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.
Unraveling the architecture of major histocompatibility complex class II haplotypes in rhesus macaques
Authors: de Groot Nanine , van der Wiel Marit , Le Ngoc Giang , de Groot Natasja G. , Bruijnesteijn Jesse , Bontrop Ronald E.
Published: October 2024

The regions in the genome that encode components of the immune system are often featured by polymorphism, copy number variation, and segmental duplications. There is a need to thoroughly characterize these complex regions to gain insight into the impact of genomic diversity on health and disease. Here we resolve the organization of complete major histocompatibility complex (MHC) class II regions in rhesus macaques by using a long-read sequencing strategy (Oxford Nanopore Technologies) in concert with adaptive sampling. In particular, the expansion and contraction of the primateDRB-region appear to be a dynamic process that involves the rearrangement of different cassettes of paralogous genes. These chromosomal recombination events are propagated by a conserved pseudogene,DRB6, which features the integration of two retroviral elements. In contrast, theDRAlocus appears to be protected from rearrangements, which may be owing to the presence of an adjacently located truncated gene segment,DRB9. With our sequencing strategy, the annotation, evolutionary conservation, and potential function of pseudogenes can be reassessed, an aspect that was neglected by most genome studies in primates. Furthermore, our approach facilitates the characterization and refinement of an animal model essential to study human biology and disease.