bluuebunny/crossref_metadata_2025 huggingface dataset:
AA147 Alleviates Symptoms in a Mouse Model of Multiple Sclerosis by Reducing Oligodendrocyte Loss
Authors: Aksu Metin , Kaschke Kevin , Podojil Joseph R. , Chiang MingYi , Steckler Ian , Bruce Kody , Cogswell Andrew C. , Schulz Gwen , Kelly Jeffery , Wiseman R. Luke , Miller Stephen , Popko Brian , Chen Yanan
Published: January 2025

Inflammation induced oligodendrocyte death and CNS demyelination, are key features of multiple sclerosis (MS). Inflammation-triggered endoplasmic reticulum (ER) stress and oxidative stress promote tissue damage in MS and in its preclinical animal model, experimental autoimmune encephalitis (EAE). Compound AA147 is a potent activator of the ATF6 signaling arm of the unfolded protein response (UPR) that can also induce antioxidant signaling through activation of the NRF2 pathway in neuronal cells. Previous work showed that AA147 protects multiple tissues against ischemia/reperfusion damage through ATF6 and/or NRF2 activation; however, its therapeutic potential in neuroinflammatory disorders remains unexplored. Here, we demonstrate that AA147 ameliorated the clinical symptoms of EAE and reduced ER stress, oligodendrocyte loss, and demyelination. Additionally, AA147 suppressed T cells in the CNS without altering the peripheral immune response. Importantly, AA147 significantly increased the expressions ofGrp78, an ATF6 target gene, in oligodendrocytes, while enhancing levels ofGrp78as well asHo-1, an NRF2 target gene, in microglia. In cultured oligodendrocytes, AA147 promoted nuclear translocation of ATF6, but not NRF2. Intriguingly, AA147 altered the microglia activation profile, possibly by triggering the NRF2 pathway. AA147 was not therapeutically beneficial during the acute EAE stage in mice lacking ATF6 in oligodendrocytes, indicating that protection primarily involves ATF6 activation in these cells. Overall, our results suggest AA147 as a potential therapeutic opportunity for MS by promoting oligodendrocyte survival and regulating microglia status through distinct mechanisms.
Exacerbated salmonellosis in poly(ADP-ribose) polymerase 14 deficient mice
Authors: Vedantham Madhukar , Polari Lauri , Rissanen Tiia , Pulliainen Arto Tapio
Published: January 2025

Salmonella entericasubspeciesentericaserovar Typhimurium (S.Typhimurium) is an enteropathogen annually causing millions of acute infections ranging from gastroenteritis to life-threatening invasive systemic disease. Strong mucosal inflammation is characteristic for the infection driven by the innate immune receptor activation but also directly by the invading bacterium. It remains unknown how and at which point the mucosal inflammation turns anti-bacterial and how the tissue homeostasis is restored. Here, we investigated the expression and function of poly(ADP-ribose)polymerase (Parp14), a known cytoplasmic and nuclear regulatory protein of immune cells, in the mouse streptomycin-pretreatment model ofS.Typhimurium infection. In the infected mice, Parp14 expressing cells, some of which were macrophages, were detected throughout the gastrointestinal tract. However, the most strongly Parp14 expressing cells were the epithelial cells. Based on small intestine single cell RNA-Seq analysis of different epithelial cell types, the expression ofparp14was pronounced in the enterocytes and Tuft cells. Mice with a body-wide genetic deficiency of Parp14 suffered from exacerbatedS.Typhimurium colitis. The histopathological analysis of the large intestine revealed increased immune cell infiltration, Goblet cell loss, and epithelial erosion. At the same time lower numbers of viable bacteria were detected. Based on a bulk tissue RNA-Seq analysis, transcriptional signatures either missing or down-regulated in the infected Parp14 deficient mice were detected. These signatures were enriched with genes related to cell adhesion, cell division and cytoskeletal rearrangements, and genes related to infection and immune responses. It appears that Parp14 has potential functions in the regulation of tissue architecture and mucosal inflammation in the large intestine ofS.Typhimurium infected mice.
Investigating sodium homeostasis of structural brain hubs in focal epilepsy using 7T MRI
Authors: Gauer Lucas , Haast Roy AM , Azilinon Mikhael , El Mendili Mohamed Mounir , Scholly Julia , Dary Hugo , Dinkelacker Vera , Ranjeva Jean-Philippe , Zaaraoui Wafaa , Bartolomei Fabrice , Guye Maxime
Published: January 2025

Besides their crucial role in cerebral connectivity, brain hubs are regions vulnerable to the energy deficit associated with various brain disorders. Changes in sodium homeostasis of cortical regions have been observed in focal epilepsy and may reflect energy failure. We investigated whether nodal structural connectivity is differently affected within the hub and non-hub regions by ionic perturbations associated with focal epilepsy. Our hypothesis was that the metabolic demands of hub regions may be associated with a distinct ionic profile detectable by sodium MRI and that this profile is altered in focal epilepsy.

We recruited 23 patients with drug-resistant focal epilepsy and 21 age- and gender-matched healthy controls. Anatomical, diffusion-weighted, and sodium imaging was performed using a 7 Tesla MRI scanner. Patients underwent pre-surgical work-up, including stereo-electroencephalographic recordings for defining the epileptogenic regions. Anatomical parcellation and multimodal coregistration allowed the use of parcels as nodes of whole-brain structural connectomes, linking structural connectivity measures to epileptogenicity and sodium parameters. Sodium parameters in patients were z-scored concerning homologous parcels in controls to allow comparison across regions of interest.

Hub regions had higher total sodium concentration (TSC) than non-hub regions in both patients and controls, and this difference was not observed for sodium signal fraction (f, a proxy of intracellular sodium homeostasis). Compared to controls, patients showed increased TSC in both epileptogenic and non-epileptogenic zones, and this increase in TSC was consistent in both hub and non-hub regions. On the opposite,fwas increased only within the epileptogenic zones and was not affected by the hubness of a region.

Our results confirm the whole brain increase in TSC and the local increase of thefvalue within epileptogenic zones previously observed in focal epilepsy patients. Therefore, we propose that that sodium imaging can probe distinct tissue properties: TSC appears sensitive to microstructural alterations, whilefcould reflect homeostatic disruptions specific to epileptogenic regions.
Forecasting invasive mosquito abundance in the Basque Country, Spain using machine learning techniques
Authors: Steindorf Vanessa , Hamna Mariyam K. B. , Stollenwerk Nico , Cevidanes Aitor , Barandika Jesús F. , Vazquez Patricia , García-Pérez Ana L. , Aguiar Maíra
Published: January 2025

Mosquito-borne diseases cause millions of deaths each year and are increasingly spreading from tropical and subtropical regions into temperate zones, creating significant public health risks. The establishment of mosquito species in new areas increases the risk of local transmission (autochthonous cases), driven by both rising mosquito populations and viremic imported cases, infected travelers who can spark local transmission. Such developments present new challenges for public health systems in non-endemic regions.

In Spain, in the Basque Country region, the spread of mosquitoes, driven by changing climatic conditions, has enhanced mosquito adaptation alongside an increase in imported cases of dengue, Zika, and chikungunya. By employing a model that captures the complexities of the mosquito life cycle driven by the interaction with weather variables, including temperature, precipitation, and humidity, and leveraging machine learning techniques, this study aims to predictAedesinvasive mosquito abundance in provinces of the Basque Country, using egg count as a proxy and the weather features as key independent variables.

Statistical analyses explored the impact of temperature, precipitation, and humidity on mosquito egg abundance. Using lagged climate variables and ovitrap egg counts, models were evaluated using Root Mean Squared Error (RMSE) and Mean Absolute Error (MAE) metrics. The Random Forest (RF) model demonstrated the highest accuracy, followed by the Seasonal Autoregressive Integrated Moving Average (SARIMAX) model. Lastly, the best models were implemented to forecastAedesinvasive mosquito abundance in the Basque Country provinces. This forecasting tool aids vector control strategies in regions with expanding mosquito populations, highlighting the need for ongoing entomological surveillance to improve mosquito spread assessments.
Proposing a Weight-Based Expectation-Maximization Algorithm for Estimating Discrete-Time Markov Transition Probability Matrices with a Proof-of-Concept Example in Health Technology Assessment
Authors: Bollée Marc , Majumdar Abhirup Dutta
Published: January 2025

Discrete-time Markov cohort-state transition models are now well-established as the preferred choice of analysts across application areas including health technology assessment. This preference arises out of its relative intuition and its capability to strike a fine balance between complex disease pathways, statistical precision, and parsimony although being criticized by a wide variety of stakeholders. Transition probability matrices (TPMs) are the “heart and soul” of such models responsible for estimating patient dispositions. However, estimating such TPMs comes with its own set of challenges. In some situations, the transition data may be censored such that the health state of a patient is unknown for multiple time steps before the next observation or data immaturity especially in rare diseases. Craig and Sendi proposed the expectation-maximization (EM) algorithm using uniform weights as a solution for unequal estimation intervals for partially observed data. However, this typically comes at the cost of increased within-state output variations with no optimization technique available in the literature.

The objective of this paper is to explore an optimized weighted version of the original EM algorithm, that aims to estimate the set of weights which minimizes the uncertainty of the estimated TPM against a target objective function. The weighting reduces the uncertainty of the estimate by considering the difference in temporal sparsity of the data when there are missing time steps. Further, we demonstrate the applicability of this weighting method using a fictitious cost-effectiveness model with our approach, showing a fine but definitive change over the original approach.
The atypical filament assembly underpins the inflammasome-independent functions of IFI16
Authors: Garg Archit , Niedzialkowska Ewa , Zhou Jeffrey J. , Moh Jasper , Egelman Edward H. , Sohn Jungsan
Published: January 2025

Inflammasomes trigger cell death upon sensing various intracellular maladies. These supra-structures relay upstream signals by sequentially assembling architecturally congruent filaments via their pyrin domains (PYDs). Interferon Inducible Protein 16 (IFI16) is an innate immune sensor that detects dysregulated nucleic acids. Once presumed as an inflammasome receptor due to its PYD, the role of IFI16 has been much more appreciated in other innate immune pathways such as regulating interferon production and viral replication restriction. Here, a cryo-EM structure of the filament assembled by the PYD of IFI16(PYD)shows a helical architecture distinct from inflammasome PYD filaments.In silico Rosettainteraction energy calculations suggest that the helical architecture of the IFI16PYDfilament is incompatible with those assembled by the central inflammasome adaptor ASC and its interacting partners. Cellular experiments further support that IFI16 fails to interact with ASC. Together, we provide the structural basis for the inflammasome-independent functions of IFI16.
The Biorepository and Integrative Genomics resource for inclusive genomics: insights from a diverse pediatric and admixed cohort
Authors: Buonaiuto Silvia , Marsico Franco , Mohammed Akram , Chinthala Lokesh K , Amos−Abanyie Ernestine K , Center Regeneron Genetics , Prins Pjotr , Mozhui Kyobeni , Rooney Robert J , Williams Robert W , Davis Robert L , Finkel Terri H , Brown Chester W , Colonna Vincenza
Published: January 2025

The Biorepository and Integrative Genomics (BIG) Initiative in Tennessee has developed a pioneering resource to address gaps in genomic research by linking genomic, phenotypic, and environmental data from a diverse Mid-South population, including underrepresented groups. We analyzed 13,152 exomes from BIG and found significant genetic diversity, with 50% of participants inferred to have non-European or several types of admixed ancestry. Ancestry within the BIG cohort is stratified, with distinct geographic and demographic patterns, as African ancestry is more common in urban areas, while European ancestry is more common in suburban regions. We observe ancestry-specific rates of novel genetic variants, which are enriched for functional or clinical relevance. Disease prevalence analysis linked ancestry and environmental factors, showing higher odds ratios for asthma and obesity in minority groups, particularly in the urban area. Finally, we observe discrepancies between self-reported race and genetic ancestry, with related individuals self-identifying in differing racial categories. These findings underscore the limitations of race as a biomedical variable. BIG has proven to be an effective model for community-centered precision medicine. We integrated genomics education, and fostered great trust among the contributing communities. Future goals include cohort expansion, and enhanced genomic analysis, to ensure equitable healthcare outcomes.
Development and Validation of a Nutrient Profiling Model for Shopping Baskets: The Grocery Basket Score (GBS)
Authors: Marcon Sandro , Naef André , Faeh David , Windisch Paul
Published: January 2025

Background

Rating someone’s diet as a whole as opposed to rating individual food items could help to better inform people about their nutrition and its health properties, e.g. by considering possible deficiencies. The goal of this project was to develop an automated rating of shopping baskets based on their health properties that can be deployed on top of existing loyalty or digital shopping basket programs by retailers without knowing for how long a basket will last or how many people consume it.

Methods

We developed a model that uses nutrient densities as opposed to absolute quantities based on self-reported food intake from the National Health and Nutrition Examination Survey (NHANES) as well as mortality follow-up data and conducted a validation against the Nutri-Score as well as the Alternate Healthy Eating Index (AHEI).

Results

The model we obtained punishes consuming calories from sugar and saturated fats, high salt intake, as well as consuming calories from beverages. Furthermore, a penalty is applied to a nutrition that is deficient in protein, vitamin C, or iron. Fiber consumption is rewarded. The model showed a high degree of correlation with the Nutri-Score (Pearson correlation coefficient: 0.60) and the AHEI (Pearson correlation coefficient: -0.62 for the AHEI without the protective effect of moderate alcohol consumption and -0.60 with it).

Conclusions

The proposed model is aligned with the recommendations formulated in nutritional guidelines, which is indicated by a high degree of correlation with the AHEI. Product-level profiling systems such as the Nutri-Score also exhibit a correlation with the model and can be used in combination.
Quantifying Device Type and Handedness Biases in a Remote Parkinson’s Disease AI-Powered Assessment
Authors: Tumpa Zerin Nasrin , Shahriar Zawad Md Rahat , Sollis Lydia , Parab Shubham , Chen Irene , Washington Peter
Published: January 2025

Early detection of Parkinson’s Disease (PD) can enable early access to care, improving patient outcomes. We investigate the use of machine learning to predict PD using data recorded from a web application measuring structured mouse and keypress data through tests assessing finger and hand movement patterns. We evaluate the impact of demographic bias and bias related to device type and handedness, which are particularly relevant to our application. We collected data from 251 participants (99 PD, 152 Non-PD). Using a random forest model, we observed an 84% F1 score, 86% sensitivity, and 92% specificity. When examining only F1-score differences across groups, no significant bias appears. However, conducting a more in-depth analysis using algorithmic fairness metrics uncovers bias regarding the positive prediction and error rates. In particular, we found that sex and ethnicity have no statistically significant impact on receiving a PD prediction. However, we observe biases regarding device type and dominant hand in terms of receiving a PD diagnosis, as evidenced by disparate impact and equalized odds fairness metrics. This work demonstrates that remote digital health diagnostics using consumer devices like desktops or laptops can exhibit nontraditional yet significant biases concerning understudied factors in algorithmic fairness such as device type and handedness.
Freeze-drying as a novel concentrating method for wastewater detection of SARS-CoV-2
Authors: Dong Rui , Noriega Landa Elizabeth , Ouellet Hugues , Lee Wen-Yee , Xiao Chuan
Published: January 2025

Extracting and detecting viral RNA in wastewater has proven to be a rapid and cost-effective approach for community-level monitoring during the recent global Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic. Various sample concentrating methods, such as centrifugal ultrafiltration, have been utilized in wastewater SARS-CoV-2 detection studies. However, freeze drying, a promising technique commonly used for concentrating and preserving various biological samples, has yet to be explored in this field. This study compared the performance of freeze-drying and the widely used centrifugal ultrafiltration method in terms of recovery rate, detection limit, and other key parameters for concentrating 72 wastewater samples collected from four facilities in El Paso, TX. Statistical analyses revealed that the freeze-drying method demonstrated higher overall recovery efficiency (20.33% vs 13.00%), a superior detection ratio (68.4% vs. 31.6%), and lower detection limits (0.06copies/mL vs 0.35copis/mL) than centrifugal ultrafiltration, particularly during the early stages of the pandemic. Despite its longer processing time than centrifugal ultrafiltration, freeze-drying offers several notable advantages, including eliminating pretreatment steps, providing flexible sample storage options, preventing signal loss and sample degradation, and reducing labor and exposure risks. Freeze-drying also does not require intensive training for concentrating sewage water. These benefits, combined with its efficient capture of viral RNA, position freeze-drying as a promising alternative for wastewater virus detection, especially in resource-constrained lab settings at local wastewater treatment plants. The protocol and findings reported here provide a baseline for further development of freeze-drying-based methods for enabling community-level early warning and surveillance against emerging viral threats in the future.
Postprandial glycaemic response to white and wholemeal bread consumption between normal weight and overweight/obese healthy adults
Authors: Dong Honglin , Colosimo Abbie , Xu Yizhi
Published: January 2025

Obesity and the increased postprandial glycaemic response (PPGR) are risk factors for type 2 diabetes. Few studies have explored the association of body weight with PPGRs. The study aimed to investigate the PPGR between healthy adults with normal weight and overweight/obesity to two commercially available breads (white and wholemeal) with different dietary fibre contents. In this acute randomised crossover trial, 20 healthy adults (10 normal weight, 10 overweight/obese) consumed two slices of white (100 g, fibre 3.6 g) or wholemeal bread (88 g, fibre 5.6 g) alongside 150 ml of orange juice and 10 g butter on separate visits in random order after fasting for 8-12 hours. The blood glucose concentration was measured fasted, 30 min, 60 min, 90 min and 120 min postprandially by finger pricks. Information on age, gender, ethnicity, body mass index (BMI), and body fat percentage were collected. Two-way repeated measures ANCOVA was used for controlling for age, gender, ethnicity and body fat percentage, and results showed no significant difference was observed in fasting blood glucose concentrations (F(1, 14)=2.968, P=0.107), incremental areas under the curve (iAUCs) (F (1, 14) = 0.702, P=0.416) and peak values (PVs) (F (1, 14) = 0.507, P=0.488) between participants with normal weight and overweight/obesity, or in fasting blood glucose concentrations (F(1, 14)=0.007, P=0.964), iAUCs (F (1, 14) = 0.008, P=0.929) and PVs (F (1, 14) = 0.036, P=0.851) between white and wholemeal bread consumption. The BMI or body fat percentage was not associated with iAUCs or PVs regardless of bread type adjusted by age, gender and ethnicity. Our results did not find that body weight is associated with PPGR in healthy adults, and the wholemeal bread used in the current study did not deliver the health benefit of attenuating PPGR compared with white bread consumption despite the higher dietary fibre content.
An Enhanced Conditional Variational Autoencoder-Based Normative Model for Neuroimaging Analysis
Authors: Ho Mai P. , Song Yang , Sachdev Perminder S. , Jiang Jiyang , Wen Wei
Published: January 2025

Normative modelling in neuroimaging provides a powerful framework for quantifying individual deviations from expected brain measures as a function of relevant covariates. While most established approaches have focused on analysing distinct variables in isolation, there is a growing need for deep learning-based methods capable of handling multiple response variables simultaneously. Conditional variational autoencoders (cVAEs) have previously been applied in this context; however, existing inference methods still face challenges in providing reliable probabilistic predictions.

In this study, we introduce an enhanced cVAE-based framework for normative modelling of neuroimaging data. Our key contribution is the development of a novel inference method that integrates latent space sampling and bootstrapping. This method directly leverages the generative nature of cVAEs to estimate the conditional distributions of brain measures. We demonstrate the effectiveness of this approach using white matter hyperintensity (WMH) volumes as a test case for developing, testing, and validating the model. Our dataset includes 8,551 normotensive and 18,180 hypertensive participants from the UK Biobank. We evaluated our method against three well-established and popular normative modelling techniques, including Generalised Additive Models for Location, Scale, and Shape (GAMLSS), Multivariate Fractional Polynomial Regression (MFPR), and Hierarchical Bayesian Regression (HBR).

Our results indicate that the proposed cVAE-based framework achieves comparable performance across various metrics, while capturing individual deviations that correlate with the severity of hypertension. The model is particularly well-suited for high-dimensional, non-linear data, making it a robust tool for assessing individual deviations in brain structure. This enhanced normative modelling architecture paves the way for more nuanced and reliable assessments of brain health, with potential implications for personalised medicine and early detection of neurological disorders.
MISO Regulates Mitochondria Dynamics and mtDNA Homeostasis by Establishing Inner Membrane Subdomains
Authors: Zhang Yue , Xia Yuchen , Wang Xinhui , Wu Shang , Li Jianshuang , Guo Xuan , Zhou Qinghua , He Li
Published: January 2025

Mitochondrial dynamics and mtDNA homeostasis are critical in various biological processes, including cell fate determination, metabolism, and aging. Although specialized mitochondrial membrane subdomains linking these two aspects have recently been reported, their structural and molecular characteristics have remained elusive. In this study, we discover MISO (MitochondrialInner membraneSubdomainOrganizer), a novel protein that initiates the formation of distinctMISO-EnrichedMitochondrialSubdomains (MEMS) within the inner mitochondrial membrane. Our data demonstrate that MISO is an evolutionary conserved protein that regulates mitochondrial dynamics inDrosophilaintestinal stem cells (ISCs)in vivoand various human and mouse cell linesin vitro. The functions of MISO depend on the formation of MEMS, which promote mitochondrial fission while inhibiting fusion, likely through the modulation of FIS1-DRP1 and OPA1 respectively. Further investigation reveals that MEMS recruit mtDNA nucleoids, facilitating their degradation via peripheral mitochondrial division. Additionally, we show that MISO orchestrates the assembly of MEMS through oligomerization mediated by its C-terminal domain, which drives contact between inner mitochondrial membranes to generate locally multilayered structures. Our findings collectively elucidate the molecular identity and functional mechanisms of specific mitochondrial subdomains bothin vivoandin vitro, revealing a structural link between the regulation of mitochondrial dynamics and mtDNA homeostasis.
Manipulating Environmental Affordances via Intrinsic Measurement: Evidence from Sensorimotor Brain Dynamics
Authors: Wang Sheng
Published: January 2025

According to the view of ecological psychology, affordances are perceived directly through the interaction between the observer and the environment, and thus body-scaled. Considering the actions from different object-agent distances, Tosoni and colleagues have provided a conceptual distinction concerning two types of affordances: macro affordances (also called environmental affordance) and micro affordances. Both of these two types of affordances have been investigated in psychological research since the beginning of this century. However, most of the environmental affordances have not yet been manipulated with a body-scaled setting in the prior research protocol. Inspired by the intrinsic measurement introduced by ecological psychologist Warren (1984) and focusing on environmental affordances, the present study adapted the task of Djebbara et al. (2019) by defining transitional affordance as the body-door height ratios. The current results from subjective data, EEG data and behavioral data showed that affordance can be manipulated intrinsically and covaried with agents’ experience, perception and motor interaction. The perception of environmental affordances was based on intrinsic optical information for the relationship between environmental properties and capacities of the observer’s own action system. It thus provides empirical support for the need to link ecological psychology and neuro-architecture in experimental protocols.
Irinotecan-induced mucositis is associated with variation in the expression of regulatory compounds associated with goblet cells
Authors: Thorpe Daniel W , Mayo Bronwen , Bresland John , Stringer Andrea
Published: January 2025

Alimentary mucositis (AM) is a common side effect of antineoplastic treatment and a key reason for cessation of treatment, compromising the chance of remission. Gastrointestinal mucin secretion is associated with regulatory compounds nitric oxide and its respective synthases inducible, epithelial and neural nitric oxide synthase (iNOS, eNOS and nNOS, respectively), vasoactive intestinal polypeptide (VIP), and prostaglandin E2 (PGE2). Changes in secretion during mucositis have been demonstrated in numerous studies, however no secretory regulatory signals have been associated in mucositis induced secretory change. The aim of this study is to investigate regulator factors in the gastrointestinal tract involved in mucin secretion, VIP, NOS, and PGE2, which are suspected of being involved in mucositis, specifically through alteration of neural or goblet cells. Tumour-bearing Dark Agouti rats received a single dose of 175 mg/kg of irinotecan (i.p.) and 0.01mg/kg atropine. (s.c.). Rats were killed post treatment at 6, 24, 48, 72, 96 and 120 hours. Samples were collected, immunohistochemistry and real time PCR were performed to analyse the expression of iNOS, eNOS, nNOS, VIP, and PGE2. Following irinotecan treatment, staining intensity for iNOS positive goblet cells in the crypts of the jejunum decreased significantly at 48 h (p < 0.05). VIP, and PGE2 positive goblet cell numbers showed no change. mRNA expression in iNOS, eNOS, and nNOS showed no change. Irinotecan-induced mucositis is associated with altered secretory regulatory compounds; this may affect mucin secretion increasing the severity of irinotecan induced mucositis.
Enhanced yield and subtype identity of hPSC-derived midbrain dopamine neuron by modulation of WNT and FGF18 signaling
Authors: Kim Tae Wan , Piao Jinghua , Bocchi Vittoria D , Koo So Yeon , Choi Se Joon , Chaudhry Fayzan , Yang Donghe , Cho Hyein S , Hergenreder Emiliano , Perera Lucia Ruiz , Joshi Subhashini , Mrad Zaki Abou , Claros Nidia , Donohue Shkurte Ademi , Frank Anika K. , Walsh Ryan , Mosharov Eugene V. , Betel Doron , Tabar Viviane , Studer Lorenz
Published: January 2025

While clinical trials are ongoing using human pluripotent stem cell-derived midbrain dopamine (mDA) neuron precursor grafts in Parkinson’s disease (PD), current protocols to derive mDA neurons remain suboptimal. In particular, the yield of TH+ mDA neurons afterin vivografting and the expression of some mDA neuron and subtype-specific markers can be further improved. For example, characterization of mDA grafts by single cell transcriptomics has yielded only a small proportion of mDA neurons and a considerable fraction of contaminating cell populations.

Here we present an optimized mDA neuron differentiation strategy that builds on our clinical grade (“Boost”) protocol but includes the addition of FGF18 and IWP2 treatment (“Boost+”) at the mDA neurogenesis stage. We demonstrate that Boost+ mDA neurons show higher expression of EN1, PITX3 and ALDH1A1. Improvements in both mDA neurons yield and transcriptional similarity to primary mDA neurons is observed both in vitro and in grafts. Furthermore, grafts are enriched in authentic A9 mDA neurons by single nucSeq. Functional studiesin vitrodemonstrate increased dopamine production and release and improved electrophysiological properties.In vivoanalyses show increased percentages of TH+ mDA neurons resulting in efficient rescue of amphetamine induced rotation behavior in the 6-OHDA rat model and rescue of some motor deficits in non-drug induced assays, including the ladder rung assay that is not improved by Boost mDA neurons. The Boost+ conditions present an optimized protocol with advantages for disease modeling and mDA neuron grafting paradigms.
Toward a privacy-preserving predictive foundation model of single-cell transcriptomics with federated learning and tabular modeling
Authors: Ding Jiayuan , Lin Jianhui , Jiang Shiyu , Wang Yixin , Miao Ziyang , Fang Zhaoyu , Tang Jiliang , Li Min , Qiu Xiaojie
Published: January 2025

The ability to pre-train on vast amounts of data to build foundation models (FMs) has achieved remarkable success in numerous domains, including natural language processing, computer vision, and, more recently, single-cell genomics—epitomized by GeneFormer, scGPT, and scFoundation. However, as single-cell FMs begin to train on increasingly large corpora, significant privacy and ethical concerns arise. Moreover, unlike text data, single-cell data is unordered and exhibits a unique tabular structure that most existing single-cell FMs overlook. In this study, we propose Tabula, a privacy-preserving and tabular-structure aware FM designed with federated learning (FL) and tabular modeling. Tabula combines the advantages of FMs and FL, enabling collaborative model training across multiple clients without compromising data privacy. In contrast to earlier single-cell FMs—which treat single-cell data like natural language (viewing cells as “words” defined by genes)—Tabula introduces a novel pretraining strategy that explicitly models the tabular structure of single-cell data. Extensive experimental results show that Tabula outperforms state-of-the-art methods in various downstream tasks (including cell type annotation, gene imputation, gene perturbation, multi-batch integration, and multi-omics integration) while requiring only half the data for pretraining and preserving data privacy. Furthermore, Tabula accurately reveals pairwise and even combinatorial regulatory logic across diverse biological systems, including hematopoiesis, pancreatic endogenesis, neurogenesis, and cardiogenesis. Thus, Tabula provides a new foundation model that explicitly incorporates the tabular nature of single-cell data alongside FL, paving the way for creating a “virtual cell” for human health under critical privacy preservation.
Temporal and Notch identity determine layer targeting and synapse location of medulla neurons
Authors: Holguera I. , Chen Y-C. , Chen Y-C-D. , Simon F. , Gaffney A.G. , Rodas J.D. , Córdoba S. , Desplan C.
Published: January 2025

How specification mechanisms that generate neural diversity translate into specific neuronal targeting, connectivity, and function in the adult brain is not understood. In the medulla region of theDrosophilaoptic lobe, neural progenitors generate different neurons in a fixed order by sequentially expressing a series of temporal transcription factors as they age. Then, Notch signaling in intermediate progenitors further diversifies neuronal progeny. By establishing the birth order of medulla neurons, we found that their temporal identity correlates with the depth of neuropil targeting in the adult brain, for both local interneurons and projection neurons. We show that this temporal identity-dependent targeting of projection neurons unfolds early in development and is genetically determined. By leveraging the Electron Microscopy reconstruction of the adult fly brain, we determined the synapse location of medulla neurons in the different optic lobe neuropils and find that it is significantly associated with both their temporal identity and Notch status. Moreover, we show that all the putative medulla neurons with the same predicted function share similar neuropil synapse location, indicating that ensembles of neuropil layers encode specific visual functions. In conclusion, we show that temporal identity and Notch status of medulla neurons can predict their neuropil synapse location and visual function, linking their developmental patterning with their specific connectivity and functional features in the adult brain.
In vivo imaging of inferior olive neurons reveals roles of co-activation and cerebellar feedback in olivocerebellar signaling
Authors: Guo Da , Uusisaari Marylka Yoe
Published: January 2025

Complex spikes (CSs), generated by inferior olive (IO) neurons, are foundational to most theories of cerebellar function and motor learning. Despite their importance, recordings from IO neurons in living animals have been limited to single-electrode methods, providing no insights into multineuron dynamics within intact circuits. Here, we used a novel ventral surgical approach that allows calcium imaging-based monitoring of multicellular activity in the IO of anesthetized mice. This method provides direct optical access to the ventral medulla, enabling simultaneous recording of spontaneous and sensory-evoked activity within localized clusters of IO neurons, specifically in the principal (PO) and dorsal accessory olives (DAO).

Our findings reveal that spontaneous activity rates and event magnitudes differ between the PO and DAO, consistent with observations from cerebellar cortex recordings in zebrin-positive (Z+) and zebrin-negative (Z-) zones, respectively. We further demonstrate that spontaneous event amplitudes are influenced by co-activation among neighboring neurons, so that events occurring in clusters are larger than single ones. Event co-activation is more pronounced in the PO than in the DAO, potentially explaining the differences in complex spike sizes observed in Z+ and Z-zones. Sensory-evoked events induced by periocular airpuff stimulation were larger than spontaneous ones, as expected. However, this difference diminishes when accounting for the higher levels of co-activation during sensory stimulation. By comparing spontaneous and sensory-evoked events categorized as clustered or single, we find no intrinsic differences in amplitudes, emphasizing the role of co-activation in shaping event magnitude. Next, we optogenetically activated cerebellar nucleo-olivary (N-O) axons, a pathway central to theories of CS generation. To our surprise, while this robustly suppressed spontaneous IO activity, sensory-evoked events showed no reduction in either their probability or waveform. Our findings suggest that the traditional view of the N-O pathway as purely inhibitory or desynchronizing might be complemented with selective suppression of background activity while preserving sensory-driven responses. Together with the role of local co-activation in shaping IO event magnitudes, this work offers new insight into the timing and variation in complex spikes and their functional significance for behavior.
Inspiral-merger-ringdown waveforms in Einstein-scalar-Gauss-Bonnet gravity within the effective-one-body formalism
Authors: Julié Félix-Louis , Pompili Lorenzo , Buonanno Alessandra
Published: January 2025

Gravitational waves (GWs) provide a unique opportunity to test general relativity (GR) in the highly dynamical, strong-field regime. So far, the majority of the tests of GR with GW signals have been carried out following parametrized, theory-independent approaches. An alternative avenue consists in developing inspiral-merger-ringdown (IMR) waveform models in specific beyond-GR theories of gravity, by combining analytical and numerical-relativity results. In this work, we provide the first example of a full IMR waveform model in a beyond-GR theory, focusing on Einstein-scalar-Gauss-Bonnet (ESGB) gravity. This theory has attracted particular attention due to its rich phenomenology for binary black-hole (BH) mergers, thanks to the presence of nontrivial scalar fields. Starting from the state-of-the-art, effective-one-body (EOB) multipolar waveform model for spin-precessing binary BHs , we include theory-specific corrections to the EOB Hamiltonian, the metric and scalar energy fluxes, the GW modes, the quasinormal-mode (QNM) spectrum and the mass and spin of the remnant BH. We also propose a way to marginalize over the uncertainty in the merger morphology with additional nuisance parameters. Interestingly, we observe that changes in the frequency of the ringdown waveform due to the final mass and spin corrections are significantly larger than those due to ESGB corrections to the QNM spectrum. By performing Bayesian parameter estimation for the GW events GW190412, GW190814, and GW230529_181500, we place constraints on the fundamental coupling of the theory (αGB≲0.31  km at 90% confidence). The bound could be improved by one order of magnitude by observing a single “golden” binary system with next-generation ground-based GW detectors. Our model can be used to improve constraints on modifications of GR with upcoming GW observations, and to provide forecasts for future GW detectors on the ground and in space.

Published by the American Physical Society
2025
Black holes, cavities, and blinking islands
Authors: Ageev Dmitry S. , Aref’eva Irina Ya. , Rusalev Timofei A.
Published: January 2025

Placing a black hole in a cavity provides a natural framework for exploring gravitational scales, thermodynamic instabilities, and effective gravity theories. In this paper, we examine the evolution of entanglement entropy and entanglement islands in a two-sided extension of the Schwarzschild black hole in a cavity. By introducing a reflecting boundary in the eternal black hole exteriors, we regulate the infrared modes of Hawking radiation, finding that the entanglement entropy eventually saturates at a constant value. This value can be lower than the black hole’s thermodynamic entropy, thus avoiding the Page formulation of the information paradox. Regarding entanglement islands, we identify a universal effect induced by the boundary, which we term the “blinking island”—where the entanglement island temporarily disappears, resulting in a short-time information paradox.

Published by the American Physical Society
2025
Systematic integral evaluation for spin-resummed binary dynamics
Authors: Chen Gang , Kim Jung-Wook , Wang Tianheng
Published: January 2025

Computation of spin-resummed observables in post-Minkowskian dynamics typically involve evaluation of Feynman integrals deformed by an exponential factor, where the exponent is a linear sum of the momenta being integrated. Such integrals can be viewed as tensor integral generating functions, which provide alternative approaches to tensor reduction of Feynman integrals. We develop a systematic method to evaluate tensor integral generating functions using multiloop integration techniques. The spin-resummed aligned-spin eikonal at second post-Minkowskian order is considered as a phenomenologically relevant example where evaluation of tensor integral generating functions is necessary.

Published by the American Physical Society
2025
Managerial ability, overseas investment performance of emerging market countries – based on the perspective of intangible knowledge resources
Authors: Wu Yuqi , Zhan Huiwen , Hong Lianying , Hu Weijie
Published: January 2025

Purpose

From the perspective of intangible knowledge resources, this paper clarifies the impact of managerial ability on the performance of overseas investment subsidiaries. It explains the dilemma that the rapid growth of overseas investment by enterprises in emerging markets has not brought about the corresponding expected performance.

Design/methodology/approach

This paper uses matching data between the parent companies and overseas subsidiaries of Chinese A-share listed companies from 2007 to 2022 to study the impact of managerial ability on the performance of overseas investment subsidiaries and its mechanism.

Findings

The results show that there is a significant positive correlation between managerial ability and the performance of overseas subsidiaries. However, the impact of managerial ability exhibits heterogeneous, which is more significant in non-state-owned enterprises, investments in high-income economies and M&A investment. Managerial ability promotes mainly the performance of overseas subsidiaries through R&D knowledge resources, marketing knowledge resources and internationalization experience; managerial ability significantly impacts the performance of overseas subsidiaries in the case of CEO two-job separation, low CEO shareholding level, the executive team with overseas background and female.

Originality/value

This paper introduces managerial ability as a critical intangible knowledge resource in the study of overseas investment performance, enriching and expanding the connotation and theoretical foundation of managerial ability. It clarifies the impact mechanism of managerial ability on overseas investment performance from three dimensions: R&D knowledge resources, marketing knowledge resources and internationalization experience. It provides new empirical evidence and management enlightenment for promoting overseas investment performance and high-quality development in emerging market countries.
Female entrepreneurship: systematic literature review and research framework
Authors: Deng Wei , Zhou Wenxin , Song Rui , Li Jie , Zhang Jing
Published: January 2025

Purpose

The rise of digitalization brings new opportunities and challenges to female entrepreneurship (FE). This paper aims to systematically review the intellectual landscape of FE research, identifying gaps and proposing future directions.

Design/methodology/approach

A systematic literature review was conducted on 1,918 highly relevant articles on FE, which were retrieved from the Scopus and Web of Science up to 2023.

Findings

While cyberfeminism is a rising perspective, the impact of digitalization on FE remains underexplored. Antecedents of FE are predominantly examined at the individual, family, organizational and environmental levels, overlooking team-level factors. Studies predominantly focus on outcomes at a single level and within a country, neglecting FE’s cross-level and cross-national complexity and diversity. The static analysis of mediating mechanisms in existing research fails to capture the dynamic process of FE. Furthermore, contextualization research often isolates family, institutional, social and mixed embeddedness, neglecting the simultaneous multiple contexts in which female entrepreneurs operate.

Originality/value

To bridge gaps in existing literature, this paper introduces an integrated research framework for FE. It suggests future research directions encompassing the impact of digital intelligence, heterogeneity of different groups of female entrepreneurs, the multiple contextual embedded nature of FE, dynamic process mechanisms for FE and cross-cultural comparisons. The proposed framework aims to inspire new insights and contribute to the evolving field of FE research.
When does ownership concentration improve franchise store performance?
Authors: Gill Pushpinder , Kim Stephen K. , Kaur Preetinder
Published: January 2025

Purpose

This study aims to examine the performance outcomes of a store’s ownership concentration within a multi-unit franchise (MUF) network, emphasizing the nuanced effects under varying competitive conditions.

Design/methodology/approach

This study conducted a comprehensive analysis of all stores within the McDonald’s chain over an eight-year span. The research methodology incorporated a review of over 11 million customer evaluations to discern patterns in customer satisfaction and sales growth in relation to the store’s ownership concentration.

Findings

Stores with a pronounced ownership concentration showcased enhanced outcomes in both customer satisfaction and sales growth. However, the magnitude of these effects was moderated by the nature of competitive conditions, specifically focal market competition, non-focal market competition and legal safeguards.

Research limitations/implications

The study’s concentration on McDonald’s stores introduces a specificity that might limit the universal applicability of the findings to all franchise models or sectors. Additionally, the emphasis on the store level of analysis potentially overlooks broader systemic factors.

Practical implications

For managers and franchise owners, understanding the nuanced roles of ownership concentration can provide strategic insights. Recognizing how different competitive conditions can moderate the effects of ownership concentration can help in making informed decisions about power dynamics and competitive positioning.

Social implications

A store’s ownership concentration can have broader societal ramifications, potentially shaping consumer perceptions, community engagement and overall market health. As an owner’s stores concentrate spatially, they can contribute to a healthier market ecosystem, benefitting consumers and communities alike.

Originality/value

While the vertical power between the franchisor and franchisee owners have been studied, this study extends the discourse to power between MUF owners. This study provides novel insights by showing customer centric and firm centric performance outcomes of ownership concentration.