bluuebunny/crossref_metadata_2025 huggingface dataset:
A network based study of the dynamics ofAβand τ proteins in Alzheimer’s disease
Authors: Bianchi Stefano , Landi Germana , Marella Camilla , Tesi Maria Carla , Testa Claudia ,   Alzheimers Disease Neuroimaging Initiative
Published: October 2024

Due to the extreme complexity of Alzheimer’s disease (AD), the aetiology of which is not yet known, nor are there any known effective treatments, mathematical modelling can be very useful. Indeed, mathematical models, if deemed reliable, can be used to test medical hypotheses that could be difficult to verify directly. In this context, it is important to understand howAβandτproteins, which in abnormal aggregate conformations are hallmarks of the disease, interact and spread. We are particularly interested in this paper in studying the spreading of misfoldedτ. To this end, we present four different mathematical models, all on networks on which the protein evolves. The models differ in both the choice of network and diffusion operator. Through comparison with clinical data onτconcentration, that we carefully obtained with multimodal analysis techniques, we show that some models are more adequate than others to simulate the dynamics of the protein. This type of study may suggest that, when it comes to modelling certain pathologies, the choice of the mathematical setting must be made with great care if comparison with clinical data is considered decisive.
Frontoparietal theta synchronization causally links working memory with impulsive decision making
Authors: Kapetaniou Georgia E. , Vural Gizem , Soutschek Alexander
Published: October 2024

Delaying gratification in value-based decision making is canonically related to activation in the dorsolateral prefrontal cortex (dlPFC), but past research neglected that the dlPFC is part of a larger frontoparietal network. It is therefore unknown whether the dlPFC causally implements delay of gratification in concert with posterior parts of the frontoparietal network rather than in isolation. Here, we addressed this gap by testing the effects of frontoparietal theta synchronization and desynchronization on impulsive decision making using transcranial alternating current stimulation (tACS). Healthy participants performed an intertemporal choice task and a 3-back working memory task while left frontal and parietal cortices were stimulated with a 5 Hz theta frequency at in-phase (synchronization), anti-phase (desynchronization), or sham tACS. We found frontoparietal theta coupling to improve working memory performance, while in the decision task desynchronization was associated with more impulsive choices and stronger hyperbolic discounting of future rewards. Overall, our findings overcome the past focus of the dlPFC in isolation and show that patient decision making causally relies on synchronous activation in a frontoparietal network related to working memory.
Joint Protein Inference Analysis with PyProteinInference Elucidates Biological Understanding of Tandem Mass Spectrometry Data
Authors: Hinkle Trent B. , Bakalarski Corey E.
Published: October 2024

Selection and application of protein inference algorithms can have a significant impact on the data output from tandem mass spectrometry (MS/MS) experiments, yet its use is often an afterthought in proteomics research due to the inability to apply different inference algorithms in existing analysis systems today. PyProteinInference provides a comprehensive suite of tools to guide researchers through the application of multiple inference algorithms and computation of protein-level, set-based false discovery rates (FDR) from tandem mass spectrometry (MS/MS) data using a unified interface. Here, we describe the software and its application to a K562 whole-cell lysate as well as in a CRAF affinity-purification mass spectrometry experiment to demonstrate its utility in facilitating conclusions about underlying biological mechanisms in proteomic data.
Altered Proteasome Composition in Aging Brains, Genetic Proteasome Augmentation Mitigates Age-Related Cognitive Declines, and Acute Proteasome Agonist Treatment Rescues Age-Related Cognitive Deficits in Mice
Authors: Pickering Andrew M.
Published: October 2024

The aging brain experiences a significant decline in proteasome function, The proteasome is critical for many key neuronal functions including neuronal plasticity, and memory formation/retention. Treatment with proteasome inhibitors impairs these processes. Our study reveals a marked reduction in 20S and 26S proteasome activities in aged mice brains driven by reduced functionality of aged proteasome. This is matched by a decline in 20S proteasome but an increase in 26S proteasome. Our data suggests this may be a compensatory response to reduced functionality. By overexpressing the proteasome subunit PSMB5 in the neurons of mice, enhancing proteasome function, we slowed age-related declines in spatial learning and memory as well neuromuscular declines. We then showed acute treatment with a proteasome activator to rescue spatial learning and memory deficits in aged mice. These findings highlight the potential of proteasome augmentation as a therapeutic strategy to mitigate age-related cognitive declines.
sv-channels: filtering genomic deletions using one-dimensional convolutional neural networks
Authors: Santuari Luca , Georgievska Sonja , Kuzniar Arnold , Pedersen Brent S. , Shneider Carl , Mehrem Sarah , Ridder Lars , Kloosterman Wigard P. , de Ridder Jeroen
Published: October 2024

Structural variant (SV) detection in human genomes using short-read sequencing data is hindered by false positives, arising from sequencing and mapping artifacts that mimic genuine SV signals. Despite advances, state-of-the-art SV callers like GRIDSS and Manta exhibit trade-offs between precision and recall, with GRIDSS offering the highest precision and Manta excelling in recall. To address these limitations, we introduce sv-channels, a novel deep learning model designed to improve the precision of SV detection by leveraging read information at call sites. Our method effectively reduces false positives in Manta’s deletion callsets, achieving precision that surpasses GRIDSS while maintaining a recall rate comparable to Manta. This represents a significant improvement in SV detection, leveraging Manta’s high recall through deep learning and paving the way for more accurate genomic analyses. The sv-channels codebase is openly accessible on GitHub athttps://github.com/GooglingTheCancerGenome/sv-channelsenabling further research and application in the field.
CelFDrive: Artificial Intelligence assisted microscopy for automated detection of rare events
Authors: Brooks Scott , Toral-Pérez Sara , Corcoran David S. , Kilborn Karl , Bodensteiner Brian , Baumann Hella , Burroughs Nigel J. , McAinsh Andrew D. , Bretschneider Till
Published: October 2024

1

1.1

CelFDrive automates high-resolution 3D imaging cells of interest across a variety of fluorescence microscopes, integrating deep learning cell classification from auxiliary low resolution widefield images. CelFDrive enables efficient detection of rare events in large cell populations, such as the onset of cell division, and subsequent rapid switching to 3D imaging modes, increasing the speed for finding cells of interest by an order of magnitude.

1.2

Availability and Implementation

CelFDrive is available freely for academic purposes at the CelFDrive GitHub repository. and can be installed on Windows, macOS or Linux-based machines with relevant conda environments [1]. To interact with microscopy hardware requires additional software; we use SlideBook software from Intelligent Imaging Innovations (3i), but CelFDrive can be deployed with any microscope control software that can interact with a Python environment. Graphical Processing Units (GPUs) are recommended to increase the speed of application but are not required. On 3i systems the software can be deployed with a range of microscopes including their Lattice LightSheet microscope (LLSM) and spinning disk confocal (SDC).

1.3

Contact

s.brooks.2@warwick.ac.uk
Pathogenicity and intestinal barrier disruptive ability ofMalassezia furfurin an alternative model hostCaenorhabditis elegansis partially alleviated byLacticaseibacillus rhamnosus
Authors: Kishida Chiho , Tsuru Ayano , Takabayashi Satoka , Wu Xueyang , Tanimoto Yoshihiko , Kage-Nakadai Eriko
Published: October 2024

Malassezia furfuris associated with various diseases; however, the mechanisms underlying its pathogenicity remain largely unknown. In the present study,Caenorhabditis eleganswas used as the model host to evaluateM. furfurpathogenicity. Additionally, effects of lactic acid bacteria againstM. furfurpathogenicity were evaluated. Compared toEscherichia coliOP50 (OP, control), both live and heat-killedM. furfurreduced the lifespan and body size ofC. elegans, although heat-killedM. furfurwas less effective than liveM. furfurin lifespan shortening. Furthermore, unlike heat-killedM. furfur,liveM. furfurdisrupted the nematode intestinal barrier.nsy-1andsek-1loss-of-function mutants were susceptible toM. furfur, suggesting their involvement in the defense againstM. furfurinfection. Expression of genes involved in host defense and of those coding for C-type lectin domain-containing proteins and antimicrobial peptides was upregulated inM. furfur-infectedC. elegans.Lacticaseibacillus rhamnosus(LR) significantly ameliorated lifespan shortening and body size reduction inM. furfur-infectedC. elegansand protected against intestinal barrier disruption, suggesting that LR protects nematodes fromM. furfurvirulence. This study highlightsM. furfurpathogenicity and intestinal barrier disruptive ability inC. elegansand suggests that theM. furfurvirulence is partially attenuated by LR.

Importance

Infection withMalassezia furfurshortens the lifespan and disrupts the intestinal barrier in the model hostC. elegans. The probioticLacticaseibacillus rhamnosus(LR) attenuatesM. furfurvirulence, thus partially protecting the intestinal tract. Signaling of the innate immune response toM. furfurinC. elegansis mediated bynsy-1andsek-1, suggesting that the expression of genes involved in the biological defense response may be regulated downstream ofnsy-1andsek-1. This study enhances our understanding of the diseases associated withM. furfurand offers insights into potential preventive and therapeutic methods using probiotics.
Sugarcane yellow leaf virus impairs the transcriptomic defense responses of sugarcane to its new aphid vectorMelanaphis sorghi
Authors: Pimenta Ricardo José Gonzaga , Aono Alexandre Hild , Sforça Danilo Augusto , Melloni Maria Natália Guindalini , Gonçalves Marcos Cesar , Pinto Luciana Rossini , de Souza Anete Pereira
Published: October 2024

Sugarcane (Saccharumspp.) is a preeminent sugar and bioenergy crop and has great economic importance in tropical countries. A major disease affecting this crop is yellow leaf disease, which is caused by sugarcane yellow leaf virus (SCYLV,Polerovirus SCYLV,Solemoviridae). The sugarcane aphidMelanaphis sacchariis considered the main vector of SCYLV, and the closely related sorghum aphidMelanaphis sorghi,which has recently emerged as a pest of great relevance in sorghum, has also been suspected as a vector. Genetic resistance is an important resource for preventing yield losses caused by SCYLV and its vectors, but knowledge on the underlying molecular mechanisms is lacking. Therefore, the present work was aimed at investigating the transcriptomic responses of sugarcane to SCYLV andM. sorghi, which was reported to transmit this virus for the first time herein. Two sugarcane cultivars, one susceptible and one tolerant to SCYLV, were fed upon by aviruliferous and viruliferous aphids. The transcriptome of the plants was assessed by RNA-Seq using differential gene expression analyses and a gene coexpression network. The susceptible cultivar showed an incipient reaction to bothM. sorghiand SCYLV, with very few differentially expressed genes (DEGs) identified in comparison with aphid-free plants. The response of the tolerant cultivar to aviruliferousM. sorghiinvolved pathways typically associated with defense against herbivory, which were also enriched in coexpression network modules in which DEGs were overrepresented. Some of these genes were hubs in their respective modules, indicating they are potential key regulators of the defense responses. However, these responses were diminished when viruliferous aphids were used, and other processes linked to infection with SCYLV were altered. These results indicated that SCYLV could affect sugarcane defense responses to its vector, similar to other viruses of the same genus. Some possible implications for the epidemiology and impact of SCYLV andM. sorghiare discussed.
OfWRKY33 binds to the key linalool synthase geneOfTPS7to promote linalool synthesis inOsmanthus fragransflowers
Authors: Xi Wan , Jiang Meng-Yu , Zhu Lin-lin , Zeng Xu-Mei , Ju Huan , Yang Qin-Lian , Zhang Ting-Yu , Wang Cai-Yun , Zheng Ri-Ru
Published: October 2024

Volatile aroma compounds make significant contributions to human perception of flowers.Osmanthus fragransis a famous aroma plant and linalool along with its oxides are proved to be the dominant aroma active compounds. Although some terpene synthases (TPSs) have been characterized, a comprehensive study of the hub metabolic gene and its transcriptional regulation remain to be revealed. Here, we selected a specific cultivar Boyeyingui (BBYG) with the highest content of linalool among 20 wide-cultivated cultivars for genome and transcriptome sequencings. Among the 25 new putativeOfTPSs,onlyOfTPS6,OfTPS7could exclusively produce linaloolin planta. Biochemical analysis demonstrated that OfTPS6, OfTPS7 were able to catalyze geranyl diphosphate (GPP) into linalool and a small proportion of other monoterpenesin vitro. Spatial and temporal correlation analysis further confirmed the transcript level ofOfTPS7was closely associated with linalool content in diverse cultivars and different tissues, suggestingOfTPS7was the essential linalool synthase gene. Combined with yeast one-hybrid screen and weighted correlation network analysis (WGCNA), a nucleus-localized transcriptional factor OfWRKY33 was considered as a potential modulator. Y1H, dual-luciferase assay and electrophoretic mobility shift assay (EMSA) demonstrated that OfWRKY33 directly bound to the W-box ofOfTPS7promoter to stimulate its transcription. OfWRKY33 could coordinately induce the expressions ofOfTPS7,1-deoxy-d-xylulose 1(OfDXS1), thereby promoting the linalool formation. The results first revealed the hub linalool synthase geneOfTPS7and a novel TF participating in the complex transcriptional regulation of linalool biosynthesis inO. fragransflowers.
Glioblastoma Treatment by Systemic Actinium-225 α-particle Dendrimer-radioconjugates is Improved by Chemotherapy
Authors: Nair Rajiv Ranjit , Sarkar Aira , Hariharan Pooja , Gabrielson Kathleen L. , Wu Tony , Liu Chang , Santosh Anjalia , Liyanage Wathsala G.H.M , Bhujwalla Zaver M , Vidaver Marie-France Penet , Kannan Rangaramanujam M , Sofou Stavroula
Published: October 2024

RATIONALE

The poor prognosis of glioblastoma is largely due to drug resistance and tumor location that, together, make it difficult to treat aggressively without affecting the rest of the brain.

METHODOLOGY

High-energy, short-range (40-80µm) dendrimer-delivered α-particles could address both challenges, because (1) they cause complex, highly cytotoxic double-strand DNA breaks, and (2) irradiation of the neighboring brain is minimal, since dendrimers selectively delivers them to tumors. Since cancer cells that are not directly hit by α-particles will likely not be killed, the patterns of tumor irradiation affect efficacy. Systemically injected dendrimers extensively accumulate in glioblastomas, where they are taken up by tumor associated macrophages (TAMs), which tend to infiltrate tumors. We hypothesized that dendrimers labeled with α-particle emitters, when being carried by TAMs, could more evenly irradiate glioblastomas, improving survival. In this study, the efficacy of dendrimers radiolabeled with the α-particle emitter actinium-225 (dendrimer-radioconjugates) was evaluated when administered alone and/or after temozolomide, in a syngeneic immune-competent orthotopic GL261-C57BL/6 mouse model.

RESULTS

Systemically-administered dendrimer-radioconjugates, at activities that did not result in long-term toxicities, prolonged survival of mice with orthotopic GL261 tumors, compared to standard-of-care temozolomide (39 vs 31 days mean survival, p=0.0061) and non-treated animals (30 days, p=0.0009). Importantly, injection of temozolomide 24 hours before administration of dendrimer-radioconjugatesfurther improved survival remarkably(44 days). This improvement in efficacy was attributed to: (1) the significant increase (by 33%) in tumor absorbed doses delivered by dendrimer-radioconjugates when injected after chemotherapy, without altering normal organ dosimetry, while sparing the tumor-surrounding healthy brain; (2) the potentially deeper tumor penetration of dendrimer-radioconjugates, suggested by the enhancement of dendrimer penetration within GL261-spheroids, employed as model tumor-avascular regions and/or TAM-free regions; and/or (3) the formation of a more lethal cocktail when both modalities acted on same cancer cells, that was correlated with increased levels of dendrimer-radioconjugates associating with GL261 cellsin vitroand with greater incidences of karyomegalyin vivo.

CONCLUSIONS

This study demonstrates the potential of a ‘brain tumor targeted’ systemic actinium-225 radiopharmaceutical therapy that inhibits growth of glioblastoma cells and prolongs survival of mice with orthotopic brain tumors, further improved by standard-of-care temozolomide, without notable toxicities.
Optical Genome Mapping of the human reference iPSC line KOLF2.1J reveals new smaller structural variants in neurodevelopmental genes
Authors: Yang Madison James , Sedov Kamilla , Chen Max Y. , Zafar Faria , Schüle Birgitt
Published: October 2024

The INDI consortium curated the KOLF2.1J human iPSC line to create a reference cell line for neurological disease modeling. However, despite careful assessments, two separate studies found using SNP arrays identified five structural variants (SVs) with sizes >100kbp. Two heterozygous SVs overlap the genesJARID2, DTNBP1, andASTN2, raising concerns about KOLF2.1J’s suitability as a reference line. To investigate further, we screened KOLF2.1J for SVs smaller than 100kbp using optical genome mapping (OGM) to produce a high-resolution karyotype. OGM, validated by qPCR, indicated that one of the five known SVs contained a previously undetected overlap withRYBP. RYBP plays regulatory roles in neuronal differentiation, PAX6 expression and Notch signaling. Furthermore, OGM identified 11 SVs smaller than 100kbp, whose overlaps include the genesPER2, CSMD1,andPALS1. In summary, these mutations should be considered by researchers when using KOLF2.1J as a reference iPSC line for designing studies and experiments.
Collective dynamics ofEscherichia coligrowth under near-lethal acid stress
Authors: Segura Munoz Rafael R. , Sourjik Victor
Published: October 2024

Many neutralophilic bacteria, includingEscherichia coli, can withstand acidic conditions due to the action of several protective mechanisms. While the survival ofE. coliunder growth-inhibitory extreme acid stress is well understood, less is known about the physiology ofE. coligrowth under severe but permissive acidity. Here, we observed that growth ofE. coliMG1655 in a rich medium with pH of 4.1 to 4.4 exhibits a characteristic multi-phasic growth pattern, consisting of an initial exponential elongation in the absence of cell division, followed by growth arrest and subsequent resumption of exponential growth. The duration of the growth arrest phase was strongly dependent on the pH of the medium, but also on the initial cell density of the culture, suggesting the collective nature of this phenomenon. Cell-density dependent multiphasic growth at the near-lethal pH, including the initial increase in cell volume associated with either elongation or widening of the cell body, was also observed for all tested naturalE. coliisolates and forSalmonella entericaserovar Typhimurium. Such transient increase in volume apparently enables bacteria to induce acid resistance systems, including the lysine-dependent Cad system, to subsequently modify pH of the medium in the density-dependent manner. Consistent with the collective recovery, even a minor fraction of acid-tolerant cells could fully cross-protect acid-sensitive cells enabling them to resume growth in coculture. Thus, collective dynamics plays a central role in bacterial growth under near-lethal acid stress.

Importance

Since manyE. coliand other Enterobacteriaceae isolates are gastrointestinal pathogens for humans, it is important to understand their growth under acidic conditions imposed by the host physiology in the stomach, colon, and inside macrophages. Here we show thatE. coligrowth under near-lethal acidic conditions is a collective phenomenon that critically depends on cell density. This collective behavior is favored by changes in cell morphology as a response to high acidity. The observed density dependence might have implications for pathogen proliferation in the acidic environment of the human gastrointestinal tract and possibly also for their interactions with immune cells.
Information Technology in Screening and Identifying Unmet Social Needs: A Scoping Review
Authors: Sezgin Emre , Jackson Daniel I , Boch Samantha , Davenport Mattina , Skeens Micah , Dolce Millie , Franklin Bianca , Militello Lisa K. , Lyman Elizabeth , Kelleher Kelly
Published: October 2024

Background

Social determinants of health (SDOH) affect health outcomes, with unmet social needs like food insecurity, housing instability, and lack of services contributing to poor outcomes, health disparities, and higher healthcare costs. Identifying these needs is vital for improving health and achieving equity. Information technology has emerged as a tool for screening and identifying unmet social needs.

Objectives

This scoping review examines how information technology is used to screen and identify unmet social needs among vulnerable populations and its impact on the assessment process.

Methods

Following PRISMA-ScR guidelines, we searched databases including MEDLINE, Embase, Scopus, ACM Digital Library, and Web of Science for studies published from 2010 to 2023. Eligible studies used technology to screen for and identify unmet social needs in populations with health and socioeconomic challenges. Data extraction focused on the types of technology, screening processes, and social needs identified.

Results

Our findings highlight a limited yet evolving landscape of technological applications. We identified 13 studies using tools like self-assessment surveys, tablet-based systems, and electronic portals. These tools were applied across diverse groups, such as refugees and patients in emergency departments. Innovative approaches, such as chatbots and multi-dimensional risk appraisal systems for older adults, showed potential. However, challenges included single-site studies, small samples, and integration issues with medical records. Effectiveness varied. The effectiveness of these tools in screening for unmet social needs shows mixed outcomes.

Conclusions

Information technology plays a pivotal role in improving the identification of unmet social needs. The findings underscore the need for broader, more integrated research to fully understand the impact of technology-based assessments and screening processes for social needs. Future efforts should focus on facilitated screening using technology both within and outside of the visit, ensuring the linkage to appropriate resources and care.
Perceptual discrimination of complex objects: APOE e4 gene-dose effects in mid-life
Authors: Lancaster Claire , Berens Sam , Daly Jessica , Rusted Jennifer , Bird Chris M.
Published: October 2024

INTRODUCTION

Complex perceptual discrimination is supported by tau-vulnerable regions of the medial temporal lobe; notably the perirhinal cortex. This research tests whether there is a gene-dose effect of Apolipoprotein e4 on perceptual discrimination in mid-life.

METHODS

313 adults (45-65 years; grouped by APOE e4 gene-dose (142 APOE33, 135 APOE34, 36 APOE44)) completed a Greebles ‘odd-one-out’ task.

RESULTS

APOE44 carriers were significantly less accurate in their perceptual judgements than APOE33 and APOE34 individuals. There was a significant Age x APOE e4 gene-dose interaction in response speed, with the slope of age-related slowing increasing stepwise with the number of e4 alleles carried. Estimates suggest high-risk individuals are quicker than the APOE33 control group until age 54, but slower thereafter.

DISCUSSION

Perceptual disadvantages specific to APOE44 individuals suggest this high-risk group show compromised MTL-function by mid-life, potentially through accelerated tau-aggregation. Task performance in APOE34 carriers is relatively preserved across the studied age range.

Research in Context

Systematic review:A review of the literature (e.g., PubMed; Google Scholar databases) revealed perceptual discrimination is impaired in the mild to moderate stages of Alzheimer’s Disease. No prior study, however, tests for an effect of APOE e4 gene-dose in healthy adulthood.

Interpretation:Homozygous carriers of an APOE e4 genetic risk variant show perceptual disadvantages in mid-life. This may possibly reflect compromised MTL-function in this group, consistent with the theory perceptual discrimination will be vulnerable to early transentorhinal tau-accumulation. There is limited evidence of impairment in individuals carrying one copy of APOE e4 in mid-life.

Future directions:Whether transentorhinal and hippocampal tau mediates the relationship between APOE e4 gene-dose and perceptual discrimination remains to be established. Future research may also explore the utility of perceptual discrimination tasks in clinical trials targeting the preclinical stages of Alzheimer’s Disease.
Interdisciplinary modelling and forecasting of dengue
Authors: Mills Cathal , Kraemer Moritz U. G. , Donnelly Christl A.
Published: October 2024

Understanding the past, current, and future dynamics of dengue epidemics is challenging yet increasingly important. To date, many techniques across statistics, mathematics, and machine learning have provided us with quantitative tools for studying dengue epidemics. Here, using data from provinces in northern Peru across 2010 to 2021, we provide a new interdisciplinary pipeline that draws on a new and existing techniques to provide comprehensive understanding and robust prediction of dengue epidemic dynamics.

Wavelet analyses can unveil spatiotemporal patterns in epidemic dynamics across annual and multi-annual time periods. Here, these included climatic forcing and greater spatial similarity in large outbreak years. Space-varying epidemic drivers included climatic influences and shorter pairwise distances driving greater epidemic similarity in more northerly coastal provinces. Then, using a Bayesian model, we can probabilistically quantify the timing, structure, and intensity of such climatic influences on Dengue Incidence Rates (DIRs), while simultaneously considering other influences. Recognising that a single model is generally sub-optimal for any forecasting task, we demonstrate how to form trained and untrained probabilistic ensembles for forecasting dengue cases in settings reflective of real-world conditions. We introduce a suite of climate-informed and covariate-free deep learning approaches that leverage big data and foundational time series, temporal convolutional networks, and conformal inference. We complement these modern techniques with statistically principled training and assessment of ensemble frameworks, while explicitly considering strong benchmark models, computational costs, public health priorities, and data availability limitations. In doing so, we show how ensemble frameworks consistently outperform individual models across space and time, and produce sharp and accurate forecasts with robust, reliable descriptions of uncertainty. We report interpretable classification metrics for detection of outbreaks to communicate our outputs with the wider public and public health authorities.

Looking forward, whether the objective is to understand and/or to predict epidemic dynamics, our modelling pipeline can be used in any dengue setting to robustly inform the decision-making and planning of public health authorities.
Salivary IgG antibody response against SARS-CoV-2 differs between vaccinated children and adults
Authors: Badano María Noel , Keitelman Irene , Pereson Matías Javier , Aloisi Natalia , Sabbione Florencia , Baré Patricia
Published: October 2024

Studies comparing antibody responses against SARS-CoV-2 between children and adults show conflicting results in blood and are limited in the mucosa. Furthermore, as the results of studies comparing systemic and salivary immune responses are inconsistent, it is unclear whether determination of salivary antibodies against SARS-CoV-2 could be a non-invasive approach to evaluate the humoral immune response.

In this work, by studying and comparing systemic and salivary IgG antibody responses in vaccinated adults, we observed that the salivary immune response against SARS-CoV-2 in vaccinated adults largely reflects that observed at systemic levels. Higher salivary and systemic antibody concentrations were observed in adults who had schedules that included mRNA-based vaccines, a greater number of exposures, a shorter interval time between last exposure and saliva collection and had been exposed to SARS-CoV-2. Detection of salivary antibodies was associated with schedules that included mRNA-based vaccines, time between last exposure and sample collection, and systemic antibody concentrations. This suggests that salivary antibody detection might be compromised in subjects with lower systemic antibody levels.

Comparison of salivary antibody levels between vaccinated children and adults showed a stronger salivary antibody response against SARS-CoV-2 in vaccinated children. This also remained when antibody levels were compared between children and adults who had similar vaccination schedules or the same number of exposures or interval time between last exposure and saliva collection. A multivariable linear regression analysis confirmed these results showing that age, symptomatic exposure, number of vaccine doses and schedules that included mRNA-based vaccines associated with salivary anti-SARS-CoV-2 IgG antibody levels.

Determination of salivary antibodies against SARS-CoV-2 could be a non-invasive approach to evaluate the short-term immune response in children and adults with multiple exposures, especially in settings where blood sampling cannot be fulfilled. The higher levels of salivary anti-SARS-CoV- 2 IgG antibodies observed in children align with studies reporting stronger systemic antibody responses in children, suggesting their adaptive immune responses might be more efficient both locally and systemically. Further studies are required to characterize the salivary microenvironment for a better understanding of the difference observed in the local humoral immune response between children and adults.
Plasma acellular transcriptome contains Parkinson’s disease signatures that can inform clinical diagnosis
Authors: Beric Aleksandra , Cisterna-García Alejandro , Martin Charissa , Kumar Ravindra , Alfradique-Dunham Isabel , Boyer Kevin , Saliu Ibrahim Olabayode , Yamada Shinnosuke , Sanford Jessie , Western Daniel , Liu Menghan , Alvarez Ignacio , Perlmutter Joel S. , Norris Scott A. , Pastor Pau , Zhao Guoyan , Botia Juan , Ibanez Laura
Published: October 2024

We aimed to identify plasma cell-free transcripts (cfRNA) associated with Parkinson’s disease (PD) that also have a high predictive value to differentiate PD from healthy controls. Leveraging two independent populations from two different movement disorder centers we identified 2,188 differentially expressed cfRNAs after meta-analysis. The identified transcripts were enriched in PD relevant pathways, such as PD (p=9.26×10-4), ubiquitin-mediated proteolysis (p=7.41×10-5) and endocytosis (p=4.21×10-6). Utilizing in-house and publicly available brain, whole blood, and acellular plasma transcriptomic and proteomic PD datasets, we found significant overlap across dysregulated biological species in the different tissues and the different biological layers. We developed three predictive models containing increasing number of transcripts that can distinguish PD from healthy control with an area under the ROC Curve (AUC) ≥0.85. Finally, we showed that several of the predictive transcripts significantly correlate with symptom severity measured by UPDRS-III. Overall, we have demonstrated that cfRNA contains pathological signatures and has the potential to be utilized as biomarker to aid in PD diagnostics and monitoring.
Loss of Peripheral Retinal Vessels in Retinitis Pigmentosa
Authors: Ameri Hossein , Hong Alexander T. , Chwa Jason
Published: October 2024

Objective

Retinitis pigmentosa (RP) is the most common inherited retinal disease and a major cause of irreversible vision loss. The purpose of this study was to assess peripheral retinal vessels in RP.

Design

Cross-sectional study

Subjects

Patients with RP and age-matched controls.

Methods

Using ultra-wide field fundus images, the retina was divided into three zones: posterior, mid periphery, and far periphery. To evaluate vascularity of the retina, the vessels were counted at the border of posterior and mid peripheral zones (Z1/2) and the border of mid peripheral and far peripheral zones (Z2/3).

Main outcome measures

Vessel counts at Z1/2 and Z2/3

Results

181 eyes of 107 RP patients and 130 eyes of 84 controls were included. In the RP group, the median vessel counts at Z1/2 and Z2/3 were 8 and 3, respectively. These were strikingly lower than the control group with the median vessels of 42 and 43.5 at Z1/2 (p<0.001) and Z2/3 (p<0.001), respectively. 22% of RP eyes were entirely avascular in the far periphery and 7% were avascular in the mid periphery and far periphery. Only 5% of RP eyes had more than 25 vessels at Z2/3. There were significantly fewer vessels in the temporal retina at both Z1/2 (p=0.01) and Z2/3 (p<0.001) in RP eyes. Furthermore, eyes with visual acuity of 20/200 or worse had significantly fewer vessels at Z1/2 (p<0.001) and Z2/3 (p<0.001). There were no significant differences in the number of vessels at Z1/2 and 2/3 between the right and left eyes of RP patients with both eyes included in the study.

Conclusions

This study provides compelling evidence of substantial symmetrical peripheral retinal vascular loss in RP. This finding may aid in clinical diagnosis of the disease and have significant therapeutic implications.
Exploring social determinants of childhood vaccination based on the National Immunization Surveys Data
Authors: Pabon-Rodriguez Felix M.
Published: October 2024

Ensuring children receive vaccinations is essential for their health and community well-being, preventing serious diseases and fostering overall immunity. Nevertheless, the impact of social determinants of health on vaccination access underscores the urgent need for targeted interventions to address disparities and ensure equitable healthcare delivery for all children. This study investigates the impact of several social determinants on childhood vaccination in the United States using data from the National Immunization Surveys from 2010-2022. As a simple approach, ordinal logistic mixed-effect models is used to analyze vaccination patterns among children aged 19– 35 months as reported by parents or guardians. The study findings highlight associations between vaccination and key social factors, including the child’s age group, parents’ or guardians’ education level, and vaccination awareness due to the child being the firstborn. The results from this basic study provide insights into the nuanced relationships that influence vaccination practices.
Effect of Data Heterogeneity in Clinical MALDI-TOF Mass Spectra Profiles on Direct Antimicrobial Resistance Prediction through Machine Learning
Authors: Park Youngjun , Weig Michael , Noll Christine , Bader Oliver , Hauschild Anne-Christin
Published: October 2024

The matrix-assisted laser desorption-ionization time-of-flight mass spectrometry has become a powerful tool for accurate species identification in routine diagnostic microbiology. Recently, the application of machine learning models with MALDI-TOF mass spectra data indicated that rapid prediction of antimicrobial resistance patterns might facilitate even timelier and improved antimicrobial treatment. Although MALDI-TOF mass spectra data have proven valuable for clinical decision support, the issue of class imbalance in routine clinical data is often overlooked. This imbalance arises from factors such as local epidemiology, selective pressure from antibiotics, culture conditions, the methodology of phenotypic antimicrobial susceptibility testing, and sample preparation processes. Here, we provide a large mass spectra dataset, MS-UMG, for antimicrobial resistance prediction model training. With previously available public datasets, our dataset is evaluated and validated for usage in AMR prediction. We further explore the mass spectra data and identify informative regions on the spectra profile for AMR prediction. Moreover, we investigate the composition of this clinical dataset and present the implications of data heterogeneity on machine learning model performance. In conclusion, our findings highlight that accurate comprehension of clinical routine data and consideration of diverse hospital protocols are critical for effective clinical decision support systems with machine learning models.

Key Points

Introduced a large-scale clinical mass spectrometry dataset to the scientific community for research on antimicrobial resistance.

Conducted a comparison and evaluation of this dataset with other existing large-scale MS datasets, highlighting its value for developing and validating predictive models in clinical settings.

Demonstrated the robustness of machine learning models for antimicrobial resistance prediction using large-scale clinical mass spectra profiles.

Analyzed the impact of data heterogeneity on the training and performance of machine learning models, emphasizing the need to account for variability in clinical routine data to enhance model reliability and generalizability.
Endothelial cells stably infected with recombinant Kaposi’s sarcoma-associated herpesvirus display distinct viscoelastic and morphological properties
Authors: Shabangu Majahonkhe M , Blumenthal Melissa J , Sass Danielle T , Lang Dirk M , Schafer Georgia , Franz Thomas
Published: October 2024

Kaposi’s sarcoma-associated herpesvirus (KSHV) is a γ-herpesvirus that has a tropism for endothelial cells and leads to the development of Kaposi’s sarcoma, especially in people living with HIV. The present study aimed to quantify morphological and mechanical changes in endothelial cells after infection with KSHV to assess their potential as diagnostic and therapeutic markers. Vascular (HuARLT2) and lymphatic endothelial cells (LEC) were infected with recombinant KSHV (rKSHV) by spinoculation, establishing stable infections (HuARLT2-rKSHV and LEC-rKSHV). Cellular changes were assessed using mitochondria-tracking microrheology and morphometric analysis. rKSHV infection increased cellular deformability, indicated by higher mitochondrial mean squared displacement (MSD) for short lag times. Specifically, MSD at τ = 0.19 s was 49.4% and 42.2% higher in HuARLT2-rKSHV and LEC-rKSHV, respectively, compared to uninfected controls. There were 23.9% and 36.7% decreases in the MSD power law exponents for HuARLT2-rKSHV and LEC-rKSHV, respectively, indicating increased cytosolic viscosity associated with rKSHV infection. Infected cells displayed a marked spindloid phenotype with an increase in aspect ratio (29.7%) and decreases in roundness (26.1%) and circularity (25.7%) in HuARLT2-rKSHV, with similar changes observed in LEC-rKSHV. The quantification of distinct KSHV-induced morpho-mechanical changes in endothelial cells demonstrates the potential of these changes as diagnostic markers and therapeutic targets.
TORC2-regulated sterol redistribution mediates recovery from membrane perturbation by small amphipathic molecules.
Authors: Tettamanti Maria G. , Nowak Paulina , Kusmider Beata , Kefauver Jennifer M , Mercier Vincent , Roux Aurelien , Loewith Robbie
Published: October 2024

To maintain plasma membrane (PM) integrity, cells need to acutely regulate PM lipid composition. The Target Of Rapamycin (TOR) complex 2 is a protein kinase that acts as a central regulator of PM homeostasis, but the mechanisms by which it monitors and reacts to membrane stresses are poorly understood. To address this knowledge gap, we characterized a family of amphiphilic molecules that physically perturb PM organization and in doing so inhibit TORC2 in yeast and mammalian cells. Using fluorescent lipid associated reporters in budding yeast, we show that these small molecules first cause a transient increase in the amount of biochemically accessible ergosterol at the PM. Contemporaneous TORC2 inhibition stimulates a rapid removal of accessible ergosterol from the PM by the PM-ER sterol transporters Lam2 and Lam4, necessary for TORC2 reactivation. Thus, we show that TORC2 acts in a feedback loop to control active sterol levels at the PM and introduce sterols as possible TORC2 signalling modulators.
Nonlinear EEG Analysis for Distinguishing Mind Wandering and Focused Attention: A Machine Learning Approach
Authors: Kheiri Farshad , Sundaram Shyam , Bragin Anatol
Published: October 2024

This study uses nonlinear analysis techniques to distinguish between mind wandering (MW) and focused attention (FA) states using EEG data. EEG recordings from 21 sessions were segmented into intervals of 2, 3, 5, 6, 10, and 15 seconds, and seven nonlinear features were extracted to capture the brain’s dynamic complexity. Machine learning models, including gradient boosting trees, were applied to classify MW and FA states, with the highest accuracy of 75% achieved using 5-second segments.

Frequency-related features, particularly mean frequency and global frequency, were the most important in distinguishing between MW and FA. These findings emphasize the role of nonlinear EEG analysis in understanding the chaotic brain patterns underlying cognitive states. Future work should focus on temporal dynamics and personalized models to improve classification accuracy, with potential applications in cognitive enhancement and mental health.
Zebrahub-Multiome: Uncovering Gene Regulatory Network Dynamics During Zebrafish Embryogenesis
Authors: Kim Yang Joon , Vijay Kumar Shruthi , Iovino Benjamin , Granados Alejandro , Ancheta Sarah , Zhao Xiang , Awayan Kyle , Seng Amanda , Borja Michael , Paul Sheryl , Mekonen Honey , Arjyal Ritwicq , Detweiler Angela , Şenbabaoğlu Yasin , Gómez-Sjöberg Rafael , Neff Norma , Lange Merlin , Royer Loïc A.
Published: October 2024

During embryonic development, gene regulatory networks (GRNs) drive molecular differentiation of cell types. However, the temporal dynamics of these networks remain poorly understood. Here, we present Zebrahub-Multiome, a comprehensive, time-resolved atlas of zebrafish embryogenesis, integrating single-cell chromatin accessibility (scATAC-seq) and gene expression (scRNA-seq) from over 94,000 cells sampled across six key developmental stages (10 to 24 hours post-fertilization). Our analysis reveals early-stage GRNs shared across multiple lineages, followed by the emergence of lineage-specific regulatory programs during later stages. We also observe a shift in transcription factor (TF) influence from broad, multi-lineage roles in early development to more specialized, cell-type-specific functions as development progresses. Usingin silicogenetic perturbations, we highlight the dynamic role of TFs in driving cell fate decisions, emphasizing the gradual specialization of regulatory circuits. All data and analyses are made accessible through an interactive web portal, enabling users to explore zebrafish gene regulatory dynamics across time and cell types. This resource provides a foundation for hypothesis generation and deeper insights into vertebrate development.
Paused Polymerase synergises with transcription factors and RNA to enhance the transcriptional potential of promoters
Authors: Mann Rajat , Soota Deepanshu , Das Ayan , Podh Nitesh Kumar , Mehta Gunjan , Notani Dimple
Published: October 2024

Regulated pausing of RNA polymerase II (Pol II) is essential for enabling rapid and coordinated transcriptional responses to signalling cues. Pausing also contributes to the formation of nucleosome-free regions with the help of chromatin remodellers. However, if these nucleosome-free regions engage with transcription factors to stimulate the transcription potential of paused promoters is not known. In this study, we demonstrate that ligand-induced estrogen receptor-alpha (ERα) binding is stabilized at Pol II-paused sites. This stabilization results from an increased dwell time of ERα on chromatin, as revealed by single molecule tracking (SMT) experiments. Notably, short chromatin-associated RNAs generated by the paused Pol II contribute to enhancing ERα binding at paused promoters. We also observe that pausing increases histone H3K27 acetylation (H3K27ac) levels, which primes paused promoters for robust transcriptional activation upon release. Collectively, these findings suggest that paused Pol II plays a central role in enhancing transcription factor binding through an RNA-dependent mechanism. This, in turn, results in a more vigorous transcriptional response following pausing release, thus contributing to the fine-tuning of ERα-mediated gene regulation.
Wnt specifically induces FZD5/8 endocytosis and degradation and the involvement of RSPO-ZNRF3/RNF43 and DVL
Authors: Luo Dong , Zheng Jing , Lv Shuning , Sheng Ren , Chen Maorong , He Xi , Zhang Xinjun
Published: October 2024

Frizzled (FZD) proteins are the principal receptors of the Wnt signaling pathway. However, whether Wnt ligands induce FZD endocytosis and degradation remains elusive. The transmembrane E3 ubiquitin ligases ZNRF3 and RNF43 promote the endocytosis and degradation of FZD receptors to inhibit Wnt signaling, and their function is antagonized by R-spondin (RSPO) proteins. However, the dependency of RSPO-ZNRF3/RNF43-mediated FZD endocytosis and degradation on Wnt stimulation, as well as the specificity of this degradation for different FZD, remains unclear. Here, we demonstrated that Wnt specifically induces FZD5/8 endocytosis and degradation in a ZNRF3/RNF43-dependent manner. ZNRF3/RNF43 selectively targets FZD5/8 for degradation upon Wnt stimulation. RSPO1 enhances Wnt signaling by specifically stabilizing FZD5/8. Wnt promotes the interaction between FZD5 and RNF43. We further demonstrated that DVL proteins promote ligand-independent endocytosis of FZD but are dispensable for Wnt-induced FZD5/8 endocytosis and degradation. Our results reveal a novel negative regulatory mechanism of Wnt signaling at the receptor level and illuminate the mechanism by which RSPO-ZNRF3/RNF43 regulates Wnt signaling, which may provide new insights into regenerative medicine and cancer therapy.