bluuebunny/crossref_metadata_2025 huggingface dataset:
Pro-ictal, rather than pre-ictal, brain state marked by global critical slowing and local gamma power increase
Authors: Dallmer-Zerbe I. , Kopal J. , Pidnebesna A. , Curot J. , Denuelle M. , De Barros A. , Sol J.C. , Valton L. , Barbeau E.J. , Hlinka J.
Published: November 2024

The clinical workup during the pre-surgical evaluation for epilepsy relies on the electrophysiological recording of spontaneous seizures. The interval until first seizure occurrence is characterized by an increase in seizure likelihood caused by progressive drug dose decreases, during which the epileptic brain transitions from a state of low to a state of high seizure likelihood, so-calledpro-ictalstate. This study aimed to identify the dynamic brain changes characteristic of this transition from 386 ten-minute segments of intracranial EEG recordings of 29 patients with drug-refractory temporal lobe epilepsy, explored by stereoelectroencephalography, irregularly sampled between electrode implantation and first seizure. As measures of brain dynamics we studied mean phase coherence and relative power in the gamma frequency band, and autocorrelation function width. We further investigate the interaction of those brain dynamics with various susceptibility factors, such as the rate of interictal spikes and high frequency oscillations, circadian and multi-day cycles, and clinical outcomes. We observed a significant increase in relative gamma power in the epileptogenic zone, and an increase in critical slowing in both the epileptogenic zone as well as in presumably healthy cortex. These brain dynamic changes were linked with increases in spike and high frequency oscillations rate. While brain dynamic changes occurred on the slow time scale - from the beginning to the end of the multi-day interval - they did not change in the short-term during the pre-ictal interval. We thus highlight gamma power and critical slowing indices as markers of pro-ictal (as opposed to pre-ictal) brain states, as well as their potential to track the seizure-related brain mechanisms during the presurgical evaluation of epilepsy patients.

Key Points

We investigated the multi-day changes in brain dynamics during presurgical evaluation of patients with drug-resistant temporal lobe epilepsy, inside the epileptogenic zone as well as in healthy brain tissue.

This time interval of increasing seizure susceptibility is marked by increases in gamma band power in the epileptogenic zone and network-wide increase in critical slowing.

The identified multi-day changes were consistently linked to the changes in spikes and high-frequency oscillations (HFOs), while not to other factors like drug dose and circadian time.

While gamma power and critical slowing changed on the scale of days, there was no significant increase in the minutes before seizures, suggesting the brain dynamic changes during presurgical evaluation are likely a multi-day phenomenon associated with pro-ictal states.
When is the R = 1 epidemic threshold meaningful?
Authors: Parag Kris V , Cori Anne , Obolski Uri
Published: November 2024

Theeffective reproduction number Ris a predominant statistic for tracking the transmissibility of infectious diseases and informing public health policies. An estimatedR=1is universally interpreted as indicating epidemic stability and is a critical threshold for deciding whether new infections will grow (R>1) or fall (R<1). We demonstrate that this threshold, which is typically computed over coarse spatial scales, rarely signifies stability because those scales integrate infections from heterogeneous groups. Groups with falling and rising infections counteract and early-warning signals from resurging groups are lost in noisy fluctuations from stable groups with large infection counts. We prove that an estimatedR=1is consistent with a vast space of epidemiologically diverse scenarios, diminishing its predictive power and policymaking value. We show that a recent statistic,E, derived fromRvia experimental design theory provides a more meaningful stability threshold (E=1) by rigorously constraining this space of scenarios.
Racial and Ethnic Disparities in Prescribing of GLP-1 Receptor Agonists in the United States: A Retrospective Cohort Analysis
Authors: Kukhareva Polina V. , Facelli Julio C. , O’Brien Matthew J. , Gouripeddi Ram , Kawamoto Kensaku , Zhang Yue , Reddy Deepika , Malone Daniel C
Published: November 2024

Background

Type 2 diabetes (T2D) represents a major public health burden in the United States, with racial disparities in medication use potentially exacerbating inequities in health outcomes. This study examined racial/ethnic differences in the prescription of high-efficacy glucose-lowering medications for T2D using a large EHR network (TriNetX).

Methods

A retrospective cohort study included adults with uncomplicated T2D (ICD-10: E11.9), categorized as Hispanic or Latino (Hispanic) or non-Hispanic American Indian/Alaska Native (AI/AN), Asian, Black, Native Hawaiian/Pacific Islander (NH/PI), and White. Adjusted odds ratios for GLP-1 receptor agonist medications (tirzepatide, semaglutide, and dulaglutide) prescriptions in 2022-2023 were calculated by race/ethnicity, controlling for age, sex, and Charlson Comorbidity Index.

Findings

Among 57,320 patients included in the analysis, we observed significant racial disparities in the prescribing of GLP-1 medications. Compared to White patients, for tirzepatide, adjusted odds ratios prescriptions were 0.6 (95% CI: 0.4-0.9) for AI/AN, 0.3 (95% CI: 0.3-0.4) for Asian, 0.7 (95% CI: 0.6-0.9) for Black, 0.4 (95% CI: 0.3-0.5) for Hispanic, and 0.4 (95% CI: 0.3-0.6) for NH/PI. For semaglutide, adjusted odds ratios were 0.8 (95% CI: 0.7-0.9) for AI/AN, 0.5 (95% CI: 0.5-0.6) for Asian, 0.8 (95% CI: 0.7-0.9) for Black, 0.6 (95% CI: 0.6-0.7) for Hispanic, and 0.6 (95% CI: 0.5-0.8) for NH/PI. For dulaglutide, adjusted odds ratios were 1.2 (95% CI: 1.0-1.4) for AI/AN, 0.5 (95% CI: 0.4-0.5) for Asian, 1.0 (95% CI: 0.9-1.1) for Black, 0.9 (95% CI: 0.8-1.0) for Hispanic, and 0.5 (95% CI: 0.4-0.6) for NH/PI.

Interpretation

Racial disparities in high-efficacy diabetes medication prescriptions may contribute to unequal health outcomes in T2D, highlighting the need for targeted research and interventions for equitable diabetes care.
Proteomic analysis of the pyrenoid-traversing membranes ofChlamydomonas reinhardtiireveals novel components
Authors: Franklin Eric , Wang Lianyong , Cruz Edward Renne , Duggal Keenan , Ergun Sabrina L. , Garde Aastha , Jonikas Martin C.
Published: November 2024

Pyrenoids are algal CO2-fixing organelles that mediate approximately one-third of global carbon fixation and hold the potential to enhance crop growth if engineered into land plants. Most pyrenoids are traversed by membranes that are thought to supply them with concentrated CO2. Despite the critical nature of these membranes for pyrenoid function, they are poorly understood, with few protein components known in any species.

Here we identify protein components of the pyrenoid-traversing membranes from the leading model algaChlamydomonas reinhardtiiby affinity purification and mass spectrometry of membrane fragments. Our proteome includes previously-known proteins as well as novel candidates.

We further characterize two of the novel pyrenoid-traversing membrane-resident proteins, Cre10.g452250, which we name Pyrenoid Membrane Enriched 1 (PME1), and LCI16. We confirm their localization, observe that they physically interact, and find that neither protein is required for normal membrane morphology.

Taken together, our study identifies the proteome of pyrenoid-traversing membranes and initiates the characterization of a novel pyrenoid-traversing membrane complex, building toward a mechanistic understanding of the pyrenoid.
Neural basis of negative future mental imagery-based simulation in the bipolar disorder spectrum
Authors: Di Simplicio Martina , Visser Renee M. , Alfarano Giorgio , Ji Julie L. , Suri Sana , Holmes Emily A.
Published: November 2024

Objectives

Dysfunctional mental imagery-based simulations of emotional future events (episodic future simulation) - can contribute to emotional dysregulation in the bipolar disorder spectrum (BPDS). For example, vividly imaging social encounters having a disastrous outcome can trigger low mood. However, episodic future simulation may be perceptually modified to reduce their emotional intensity, which may in turn reduce BPDS mood instability. This study investigates the neural bases of perceptual and emotional characteristics of negative episodic future simulation in BPDS, and of perceptually manipulating such imagery.

Methods

Euthymic participants with BPDS (N=20) and healthy controls (HC, N=17) underwent an fMRI scan whilst generating, then perceptually modifying, negative episodic future imagery, and during rest.

Results

Negative episodic future imagery were rated as significantly morerealandunpleasantin the BPDS compared to HC group. Critically, perceptual manipulation of such imagery reduced ratings in the BPDS group to HC levels. Whole-brain analyses of task-based neural activity revealed greater activation in networks including right frontal pole, middle and inferior frontal gyrus and insula during episodic future simulation in BPSD versus HC. BPDS participants showed greater intrinsic resting state functional connectivity within the default mode network than HC participants.

Conclusions

Findings suggest dysfunctional episodic future simulation circuitry across default mode network, fronto-parietal and fronto-insular areas may represent a neural mechanism via which mental imagery amplifies emotion in BPDS. Perceptual modifications to dampen such imagery successfully abolished subjective and neural differences between groups, indicating promise as an intervention tool targeting mood instability.
Parenthood, Mental Disorders, and Symptoms Through Adulthood: A Total Population Study
Authors: Andersen ML , Sunde HF , Hart RK , Torvik FA
Published: November 2024

During recent decades, parenthood has declined in many Western countries. Simultaneously, mental disorders have become more prevalent. We investigated the link between parenthood and mental health in the entire Norwegian-born population aged 31 to 80 from 2006 to 2019 (n=2,234,087). We used logistic regression models on national register data and included sibling- and twin-matched analyses to address unobserved confounders. Parenthood was associated with a lower risk of mental disorders, including depressive and anxiety disorders. For symptoms related to mental disorders, fathers had a reduced risk, while mothers had a slightly elevated risk. Mental health disparities between parents and non-parents were greater among men than among women and persisted across adulthood, before reducing at older ages. Our main findings were largely consistent in sibling- and twin-matched designs. The disparity between parents and non-parents increased over the study period, suggesting stronger selection into parenthood. Our findings highlight parenthood as a significant indicator of mental health inequalities, with its importance growing over time.
The Whole Proteome, Phosphoproteome, and Glycoproteome Landscape of Pan-Cancer Cell Lines Profiled by Mass Spectrometry and Reverse Phase Protein Array
Authors: Wenhao Shi , Tianlong He , Wang Nan , Qian Annan , Liu Yuqiao , Shaojun Tang , Yiying Zhu
Published: November 2024

Mammalian cancer cell lines are essential model systems in biomedical research. We conducted multi-level proteomics analyses on 54 widely used cancer cell lines derived from various tissue-of-origins using two prominent proteomics technologies: mass spectrometry (MS) and reverse-phase protein array (RPPA). Our analysis identified 10,088 proteins, 33,609 phosphorylation sites across 7,289 phosphoproteins, and 56,350 site-specific glycans on 16,296 glycosylation sites from 5,966 glycoproteins, along with 305 drug-relevant protein and phosphoprotein targets. Our results reveal both consistent and distinct patterns in protein expression and modification between MS and RPPA, underscoring their complementary strengths as discovery tools. Additionally, we identified protein features that distinguish tissue origins across different cell line lineages. This dataset supports model system selection for drug target-related studies in vitro and provides valuable insights into key signaling pathways. Overall, this comprehensive resource enables new opportunities for exploration in cancer biology and offers significant value to research communities focused on biomarker profiling, drug target discovery, and understanding mechanisms across diverse cancer types.
Co-existence of ST-Segment Depression and Exaggerated Blood Pressure Response in Older Runners
Authors: Manabe Kazumasa , Beck Owen N. , Ortega Justus D. , Tanaka Hirofumi
Published: November 2024

Exercise stress tests are typically performed on symptomatic patients and those at elevated risks of ischemic heart disease. In more recent years, these tests are increasingly recommended for masters athletes who regularly perform exercise training. In the sample of apparently healthy physically active older adults who were recruited for a research study to evaluate exercise economy, we found the coexistence of ST-segment depression and exaggerated BP response in older runners. These findings are consistent with the notion that the screening and assessment of cardiovascular risks should be extended to masters athletes who vigorously train regularly and are seemingly healthy.
GENCODE: massively expanding the lncRNA catalog through capture long-read RNA sequencing
Authors: Kaur Gazaldeep , Perteghella Tamara , Carbonell-Sala Sílvia , Gonzalez-Martinez Jose , Hunt Toby , Mądry Tomasz , Jungreis Irwin , Arnan Carme , Lagarde Julien , Borsari Beatrice , Sisu Cristina , Jiang Yunzhe , Bennett Ruth , Berry Andrew , Cerdán-Vélez Daniel , Cochran Kelly , Vara Covadonga , Davidson Claire , Donaldson Sarah , Dursun Cagatay , González-López Silvia , Gopal Das Sasti , Hardy Matthew , Hollis Zoe , Kay Mike , Montañés José Carlos , Ni Pengyu , Nurtdinov Ramil , Palumbo Emilio , Pulido-Quetglas Carlos , Suner Marie-Marthe , Yu Xuezhu , Zhang Dingyao , Loveland Jane E. , Albà M. Mar , Diekhans Mark , Tanzer Andrea , Mudge Jonathan M. , Flicek Paul , Martin Fergal J , Gerstein Mark , Kellis Manolis , Kundaje Anshul , Paten Benedict , Tress Michael L. , Johnson Rory , Uszczynska-Ratajczak Barbara , Frankish Adam , Guigó Roderic
Published: November 2024

Accurate and complete gene annotations are indispensable for understanding how genome sequences encode biological functions. For twenty years, the GENCODE consortium has developed reference annotations for the human and mouse genomes, becoming a foundation for biomedical and genomics communities worldwide. Nevertheless, collections of important yet poorly-understood gene classes like long non-coding RNAs (lncRNAs) remain incomplete and scattered across multiple, uncoordinated catalogs, slowing down progress in the field. To address these issues, GENCODE has undertaken the most comprehensive lncRNAs annotation effort to date. This is founded on the manual annotation of full-length targeted long-read sequencing, on matched embryonic and adult tissues, of orthologous regions in human and mouse. Altogether 17,931 novel human genes (140,268 novel transcripts) and 22,784 novel mouse genes (136,169 novel transcripts) have been added to the GENCODE catalog representing a 2-fold and 6-fold increase in transcripts, respectively - the greatest increase since the sequencing of the human genome. Novel gene annotations display evolutionary constraints, have well-formed promoter regions, and link to phenotype-associated genetic variants. They greatly enhance the functional interpretability of the human genome, as they help explain millions of previously-mapped “orphan” omics measurements corresponding to transcription start sites, chromatin modifications and transcription factor binding sites. Crucially, our targeted design assigned human-mouse orthologs at a rate beyond previous studies, tripling the number of human disease-associated lncRNAs with mouse orthologs. The expanded and enhanced GENCODE lncRNA annotations mark a critical step towards deciphering the human and mouse genomes.
The fate of artificial transgenes inAcanthamoeba castellanii
Authors: Colp Morgan J. , Blais Cédric , Curtis Bruce A. , Archibald John M.
Published: November 2024

In this study, artificial transformation experiments were performed to investigate how theA. castellaniigenome responds to foreign DNA presented in both circular and linear plasmid form. Nanopore sequencing was used as a high throughput method to screen for transgene DNA in the resulting transformant cultures, and candidate transgene integrations were identified. Molecular biology experiments were performed to validate the sequence data and provide additional context on the fate of transgenes. A method was devised to estimate the rate of read chimerism in nanopore sequencing runs and accurately account for the effects of read chimerism in identifying putative transgene integrations. Based on the experimental data in hand, a potential mechanism for transgene maintenance inA. castellaniiis proposed, one in which incoming foreign DNA is tandemly duplicated and telomeres are added to the ends. This nascent linear molecule is maintained as a transgene-bearing minichromosome, while also allowing for chromosomal integration.
Optimal competitors: the balance of attraction and choices of mutualists, like pollinators, drives facilitation and may promote crop pollination
Authors: Dornhaus Anna , Houston Alasdair I.
Published: November 2024

When two species use the same resource, this typically leads to competition, such as when different plants aim to attract the same mutualist pollinators. However, more flowers may also attract more pollinators to the area. Depending on which process dominates, one or both ‘competitors’ may actually benefit from the other’s presence: a phenomenon called ‘pollination facilitation’ in plant ecology. For example, it has been argued that strips of wildflowers planted next to crops may attract pollinators who ‘spill over’ into the crop. Here we mathematically examine the tradeoff between facilitation and competition in consumer attraction. We show that contrary to previous claims, no accelerating benefits of densityper seare necessary for facilitation. Instead, under very general assumptions, an imbalance between local competition and joint attraction of consumers can generate a benefit to at least one ‘competitor’. This typically leads to maximal benefit to the crop at a low presence of highly attractive ‘wildflowers’ (i.e. plants that share pollinators with the crop). Our results generalize to many contexts where local competition may trade off with joint attraction of consumers. In such situations, the exact effect of competitor density on attraction of consumers can qualitatively shape outcomes, including facilitation or competition.
Modeling and Optimizing Deep Brain Stimulation to Enhance Gait in Parkinson’s Disease: Personalized Treatment with Neurophysiological Insights
Authors: Azgomi Hamid Fekri , Louie Kenneth H. , Bath Jessica E. , Presbrey Kara N. , Balakid Jannine P. , Marks Jacob H. , Wozny Thomas A. , Galifianakis Nicholas B. , Luciano Marta San , Little Simon , Starr Philip A. , Wang Doris D.
Published: November 2024

Although high-frequency deep brain stimulation (DBS) is effective at relieving many motor symptoms of Parkinson’s disease (PD), its effects on gait can be variable and unpredictable. This is due to 1) a lack of standardized and robust metrics for gait assessment in PD patients, 2) the challenges of performing a thorough evaluation of all the stimulation parameters space that can alter gait, and 3) a lack of understanding for impacts of stimulation on the neurophysiological signatures of walking. In this study, our goal was to develop a data-driven approach to identify optimal, personalized DBS stimulation parameters to improve gait in PD patients and identify the neurophysiological signature of improved gait. Local field potentials from the globus pallidus and electrocorticography from the motor cortex of three PD patients were recorded using an implanted bidirectional neural stimulator during overground walking. A walking performance index (WPI) was developed to assess gait metrics with high reliability. DBS frequency, amplitude, and pulse width on the “clinically-optimized” stimulation contact were then systemically changed to study their impacts on gait metrics and underlying neural dynamics. We developed a Gaussian Process Regressor (GPR) model to map the relationship between DBS settings and the WPI. Using this model, we identified and validated personalized DBS settings that significantly improved gait metrics. Linear mixed models were employed to identify neural spectral features associated with enhanced walking performance. We demonstrated that improved walking performance was linked to the modulation of neural activity in specific frequency bands, with reduced beta band power in the pallidum and increased alpha band pallidal-motor cortex coherence synchronization during key moments of the gait cycle. Integrating WPI and GPR to optimize DBS parameters underscores the importance of developing and understanding personalized, data-driven interventions for gait improvement in PD.
Protein associations and protein–metabolite interactions with depressive symptoms and the p-factor
Authors: Whipp Alyce M , Drouard Gabin , Rose Richard J , Pulkkinen Lea , Kaprio Jaakko
Published: November 2024

Despite increasing mental health problems among young people, few studies have examined associations between plasma proteins and mental health, and interactions between proteins and metabolites in association with mental health problems remain underexplored. In 730 twins, we quantified associations between plasma proteins measured at age 22 with 21 indicators representing either depressive symptoms or the p-factor, collected from questionnaires and interviews completed by different raters (e.g., self-report, teachers) through adolescence to young adulthood (12 to 22 years), and tested for interactions with metabolites. We found 47 proteins associated with depressive symptoms or the p-factor (FDR<0.2), 9 being associated with both. Two proteins, contactin-1 and mast/stem cell growth factor receptor kit, positively interacted with valine levels in explaining p-factor variability. In conclusion, our study demonstrates strong associations between plasma proteins and mental health and provides evidence for proteome– metabolome interactions in explaining higher levels of mental health problems.
Factors Associated with Measles Vaccine Immunogenicity in Children at University Teaching Hospitals, Lusaka, Zambia
Authors: Nkonde Gardner Priscilla , Sialubanje Cephas , Hangoma Jimmy , Chilengi Roma , Kapina Muzala , Chipoya Musole , Mwangilwa Kelvin , Lamba Lillian , Mwenechanya Musaku , Chilyabanyama Rodgers , Kasonde Mpanga , Young Soo , Simwaba Davie , Fwemba Isaac
Published: November 2024

Measles poses a significant global public health challenge, particularly in low-resource settings where vaccination coverage is limited. This study examined factors associated with measles vaccine immunogenicity in children aged 2 to 15 years at the University Teaching Children’s Hospital and the HIV Pediatric Centre of Excellence in Lusaka, Zambia. This was a comparative analytical cross-sectional study conducted from April to July 2024. Blood samples were collected using a questionnaire uploaded in Kobo. Data analysis was conducted in R-studio. Descriptive statistics were used to summarize respondent data. Bivariate analysis was conducted to test the association between the predictor and outcome variables, while multivariate logistic regression analysis measured the strength of association using adjusted odds ratios (AORs). A p-value < 0.05 was considered significant. Children aged 10 to 15 years were less likely to have retained immunity compared to those aged 2 to 4 years (AOR = 0.270, 95% CI [0.114–0.618], p = <0.002). HIV-positive children had lower odds of retaining immunity compared to HIV-negative children (AOR = 0.290, 95% CI [0.137–0.594], p = <0.001). Children who were breastfed had lower odds of waning immunity (AOR = 0.336; 95% CI [0.147–0.738], p = 0.007) compared to children who were not breastfed. Children residing in Lusaka were less likely to have retained immunity compared to those residing outside Lusaka (AOR = 0.250, 95% CI [0.066–0.859], p = 0.031). These findings show that age, breastfeeding, and HIV status significantly affect the retention of measles immunity in children aged 10-15 years. Younger, HIV-negative, and breastfed children show better immunity retention. These results highlight the protective role of breastfeeding and the need for booster doses to enhance immunity retention, especially for older and HIV-infected children.
Spatial Patterns of COVID-19 Mortality: Examining Socioeconomic Determinants in U.S. Counties Using Cluster Analysis
Authors: Wardrup Robert Ross
Published: November 2024

Aim

This study aims to investigate the spatial patterns of COVID-19 mortality across U.S. counties and identify the socioeconomic determinants that influence these mortality trends, using spatial epidemiological methods.

Subject and Methods

We conducted a spatial analysis of COVID-19 mortality data from over 3,000 U.S. counties, applying cluster detection techniques, including SatScan, to identify areas with significant mortality trends. Spatial regression models, including spatial lag and spatial error models, were employed to examine the impact of socioeconomic variables, such as race, income inequality, and insurance rates, on COVID-19 mortality. The analysis controlled for multicollinearity and spatial autocorrelation in the data.

Results

Counties with higher proportions of Black populations and higher uninsured rates exhibited significantly lower COVID-19 trends over the study period. Spatial clustering revealed regions in the northwestern and eastern/northeastern United States with a mix of positive and negative mortality rate trends. The spatial lag model showed the strongest fit, confirming the importance of spatial dependency in explaining mortality patterns.

Conclusion

This study highlights the significant spatial disparities in COVID-19 mortality across U.S. counties. The findings emphasize the need for targeted public health interventions in vulnerable regions to address these disparities.
Multicenter Comparison of AI Deep Learning Reconstruction, Iterative Reconstruction, and Filtered Back Projection for Coronary Artery Calcification Scoring
Authors: Winkler Alena R. , Campos June D. , Winkler Mark L.
Published: November 2024

Objective

To validate the feasibility of AI Deep Learning Reconstruction for Coronary Artery Calcification Scoring in order to decrease radiation exposure on a 4cm detector CT scanner. This is the first such validation on devices that are most commonly utilized for this procedure.

Methods

Data from 105 consecutive patients referred for Coronary Artery Calcification Scoring (CACS) in 4 centers was reconstructed with Filtered Back Projection (FBP), Iterative Reconstruction (Hybrid-IR), and AI Deep Learning Reconstruction (AI DLR), and analyzed both quantitatively and qualitatively to determine if AI DLR can be routinely used for this purpose. Additional phantom testing was performed to determine if further dose reduction can be accomplished with AI DLR while maintaining or improving image quality compared to current Hybrid-IR reconstruction.

Results

Quantitively, there was excellent agreement between the three reconstructions (FBP, Hybrid IR and AI DLR) with an interclass coefficient of 0.99. The mean CACS for Filtered Back Projection Reconstructions was 111.05. The mean CACS for Hybrid-IR was 91.30. The mean CACS for AI Deep Learning Reconstructions was 93.50. Qualitatively, image quality was consistently better with AI DLR than with Hybrid-IR at both soft tissue and lung windowing. Based on our phantom experiments, AI DLR allows for dose reduction of at least a 37% without any image quality penalty compared to Hybrid-IR.

Conclusions

The use of AI DLR for use in CACS on 4 cm coverage CT scanner has been quantitatively and qualitatively validated for use for the first time. AI DLR produces qualitatively and quantitively better image quality than Hybrid-IR at the same dose level, and produces good agreement in categorization of Agatston scores. In vivo and in vitro evaluations show that AI DLR will allow for an at least a 37% further dose reduction on a 4 cm coverage CT scanner.
Perspectives on the implementation of post-validation surveillance for lymphatic filariasis in the Pacific Islands: A Nominal Group Technique-based study protocol
Authors: Craig Adam T , Lawford Harriet , Viali Satupaitea , Tuitama George , Lau Colleen L
Published: November 2024

Introduction

Lymphatic filariasis (LF) is a neglected tropical disease caused by parasitic worms, transmitted via mosquito bites. Significant global efforts have led to the interruption of LF transmission, with eight of the 16 previously endemic Pacific Island countries and territories (PICTs) validated by WHO as having eliminated the disease as a public health problem. Post-validation surveillance (PVS) is recommended to verify the absence of a resurgence in transmission; however, there are no guidelines on how to implement such surveillance effectively.

Aim

This protocol outlines a research study that aims to explore, synthesise, and prioritise the perspectives of LF program staff from LF-eliminated PICTs. The study will focus on identifying the challenges faced in implementing PVS in the PICT settings and determining corresponding context-relevant operational research priorities.

Method

The study will employ a nominal group technique (NGT) involving representatives from LF-eliminated PICTs. The NGT will adhere to a structured process for generating, ranking, and prioritising ideas, followed by group discussions, debates, and the collation of shared views.

Discussion

The research will provide insights into the most significant challenges faced in implementing PVS in the PICTs. It will also identify priority areas where operational research is required to inform policy and practice. To our knowledge, this study is the first to apply a rigorous consensus group method to distil challenges and research priorities for LF PVS in PICTs. We expect this research to inform the development of national and regional LF guidelines.
Genomic surveillance and molecular evolution of fungicide resistance in European populations of wheat powdery mildew
Authors: Minadakis Nikolaos , Jigisha Jigisha , Cornetti Luca , Kunz Lukas , Müller Marion C. , Torriani Stefano F.F. , Menardo Fabrizio
Published: November 2024

Fungicides are used in agriculture to manage fungal infections and maintain crop yield and quality. In Europe, their application on cereals increased drastically starting from the mid 1970s, contributing to a significant improvement in yields. However, extensive usage has led to the rapid evolution of resistant pathogen populations within just a few years of fungicide deployment. Here we focus on wheat powdery mildew, a disease caused by the ascomycete fungusBlumeria graminis forma specialis tritici(Bgt). Previous research on Bgt documented the emergence of resistance to different fungicides and identified various resistance mechanisms. Yet, the frequency, distribution, and evolutionary dynamics of fungicide resistance in Bgt populations remain largely unexplored. In this study we leveraged extensive sampling and whole-genome sequencing of Bgt populations in Europe and the Mediterranean to investigate the population genetics and molecular epidemiology of fungicide resistance towards five major fungicide classes. We analyzed gene sequences and copy number variation of eight known fungicide target genes in 415 Bgt isolates sampled between 1980 and 2023. We observed that mutations conferring resistance to various fungicides increased in frequency over time, and had distinct geographic distributions, likely due to diverse deployment of fungicides across different regions. For demethylation inhibitor fungicides we identified multiple independent events of resistance emergence with distinct mutational profiles, and we tracked their rapid spread in the last decades. Overall, we revealed the evolutionary and epidemiological dynamics of fungicide resistance mutations in European Bgt populations. These results underscore the potential of genomic surveillance and population genetics to enhance our understanding of fungicide resistance.
Decoding words during sentence production: Syntactic role encoding and structure-dependent dynamics revealed by ECoG
Authors: Morgan Adam M. , Devinsky Orrin , Doyle Werner K. , Dugan Patricia , Friedman Daniel , Flinker Adeen
Published: November 2024

Sentence production is the uniquely human ability to transform complex thoughts into strings of words. Despite the importance of this process, language production research has primarily focused on single words. However, it remains a largely untested assumption that the principles of word production generalize to more naturalistic utterances like sentences. Here, we investigate this using high-resolution neurosurgical recordings (ECoG) and an overt production experiment where patients produced six words in isolation (picture naming) and in sentences (scene description). We trained machine learning classifiers to identify the unique brain activity patterns for each word during picture naming, and used these patterns to decode which words patients were processing while they produced sentences. Our findings confirm that words share cortical representations across tasks, but reveal a division of labor within the language network. In sensorimotor cortex, words were consistently activated in the order in which they were said in the sentence. However, in inferior and middle frontal gyri (IFG and MFG), the order in which words were processed depended on the syntactic structure of the sentence. Deeper analysis of this pattern revealed a spatial code for representing a word’s position in the sentence, with subjects selectively encoded in IFG and objects in MFG. Finally, we argue that the processes we observe in prefrontal cortex may impose a subtle pressure on language evolution, explaining why nearly all the world’s languages position subjects before objects.
Discriminative capacity of the 6-item Vision-related Quality of life and Limitations questionnaire (VQL-6)
Authors: Dol Vera Linde , Roelofs Antonius A. J. , Fuermaier Anselm B. M. , Vrijling Anne C. L. , Heutink Joost , Jansonius Nomdo M.
Published: November 2024

Purpose

The 6-item Vision-related Quality of life and Limitations questionnaire (VQL-6) is a screening instrument that signals a need for additional low vision care in patients with chronic ophthalmic diseases. This study aims to (1) determine the optimal scoring method for the VQL-6 and (2) evaluate its discriminative capacity for clinical use.

Methods

Patients with glaucoma and retina– and cornea-related disorders completed the VQL-6 and participated in an interview designed to distinguish between patients with and without a need of additional care. For the two subscales (general health and quality of life, HQOL, and vision-related limitations, VL) we compared a scoring model with equal item weights to a cross-validated model using regression weights. The optimal scoring method and discriminative capacity of the subscales were determined using receiver operating characteristics (ROC) analysis, with the interview outcome as gold standard. Sensitivities were evaluated at specificities of 90 and 95%.

Results

In 297 interview assessments, 96 patients (32%) appeared to need additional care. Both scoring models demonstrated very similar area under the ROC curves (AUC). The selected equal weight model yielded an AUC of 0.91 (95% confidence interval 0.87-0.94) for VL and 0.71 (0.65-0.77) for HQOL. For VL, sensitivity was 72 and 64% at 90 and 95% specificity, respectively. Corresponding HQOL sensitivities were 34 and 17%.

Conclusions

The subscale VL shows excellent discriminative capacity and outperformed HQOL. Future studies should explore the feasibility of the VQL-6 in clinical practice.
The effect of oxidative stress on the Adenosine A2a Receptor structure, activity and signalling
Authors: Company-Marin Idoia , Gunner Joseph , Poyner David , Simms John , Pitt Andrew R. , Spickett Corinne M.
Published: November 2024

The adenosine 2a receptor (A2aR) is a G-protein coupled receptor that has important anti-inflammatory effects in response to some agonists and consequently is considered a therapeutic target. Its activity is affected by local membrane lipid environment and presence of certain phospholipid classes, so studies should be conducted using extraction methods such as styrene maleic acid co-polymers (SMA) that retain the local lipids. Currently, little is known about the effect of oxidative stress, which may arise from inflammation, on the A2aR. Therefore it was over-expressed inPichia pastoris, SMA was used to extract the A2aR from cell membranes and its response to ligands was tested in the presence or absence of the radical initiator AAPH or reactive aldehyde acrolein. SMA-extracted A2aR was able to undergo conformational changes, measured by tryptophan fluorescence, in response to its ligands but oxidative treatments had no effect on the structural changes. Similarly, the treatments did not affect temperature-dependent protein unfolding. In contrast, in HEK293 cells expressing the A2aR, oxidative treatments increased cAMP levels in response to the agonist NECA, independently of adenylate cyclase activity. Thus, oxidative stress may be a homeostatic mechanism that abrogates inflammation via the A2aR signalling pathway. (max. 200 words - 194)
Chlamydia trachomatisTmeA promotes pedestal formation through N-WASP and TOCA-1 interactions
Authors: McCullough Alix , Jabeena C.A. , Steiert Brianna , Faris Robert , Weber Mary M.
Published: November 2024

Chlamydia trachomatis(C.t.) is the causative agent of several human diseases, including the sexually transmitted infection chlamydia and eye infection trachoma. As an obligate intracellular bacterial pathogen, invasion is essential for establishing infection and subsequent pathogenesis. To facilitate invasion,C.t.secretes effector proteins through its type III secretion system (T3SS). These effectors facilitate bacterial entry by manipulating multiple pathways involved in host actin cytoskeletal regulation. Previous studies have demonstrated that the T3SS effector protein TmeA is crucial forC.t.invasion, as it recruits and activates N-WASP. This interaction leads to recruitment and activation of the Arp2/3 complex, promoting cytoskeletal rearrangements at the invasion site to facilitateC.t.uptake. In this study, we define the role of the N-WASP CRIB domain in mediating this interaction, showing that TmeA acts as a functional mimic of Cdc42 in activating N-WASP. Additionally, we identified TOCA-1 as another host protein that directly interacts with TmeA. In other bacterial pathogens, notably EnterohemorrhagicE. coli, N-WASP and TOCA-1 are hijacked to mediate pedestal formation. Using siRNA to knockdown N-WASP and TOCA-1, followed by transmission electron microscopic, we observed that both N-WASP and TOCA-1 are important for inC.t.-mediated pedestal formation. Collectively, these findings reveal a unique mechanism of TmeA-mediated invasion, where direct interactions with N-WASP and TOCA-1 facilitate pedestal formation.

Importance

Chlamydia trachomatis(C.t.) is an obligate intracellular bacterial pathogen that poses a significant threat to human health, being associated with various diseases, including chlamydia— the most prevalent bacterial sexually transmitted infection—and trachoma. While Chlamydia infections are often asymptomatic, they can lead to serious complications such as sterility, ectopic pregnancy, and increased risk of cervical and ovarian cancers. Due to its intracellular nature, host cell invasion is essential forC.t.survival. Here, we present new data detailing the binding interactions between theC.t.invasion effector protein TmeA and host cell proteins N-WASP and TOCA-1, demonstrating that both N-WASP and TOCA-1 are involved in pedestal formation duringC.t.invasion. This research advances our understanding of TmeA-mediated host cell invasion, illuminating a key pathway required forC.t.-mediated pathogenesis.
Learning Allosteric Interactions in Gα Proteins from Molecular Dynamics Simulations
Authors: Yu Yiping , Yang Maohua , Wang Wenning
Published: November 2024

Gα is a key subunit of heterotrimeric guanine-nucleotide-binding regulatory proteins, yet its conformational dynamics are not fully understood. In this study, we developed a Transformer-based graph neural network framework, Dynamic-Mixed Transformer (DMFormer), to investigate conformational dynamics of Gαo. DMFormer achieved an AUC of 0.75 on the training set, demonstrating robustness in distinguishing active and inactive states. The interpretability of the model was enhanced using integrated gradients, identifying the Switch II as a critical motif in stabilizing the active state and revealing distinct movement patterns between GTPase and α-Helix domains. Our findings suggest that the conformational rigidity of the Q205L mutant in the Switch II segment leads to persistent activation. Overall, our study showcases DMFormer as an effective tool for analyzing protein conformational dynamics, offering valuable insights into activation mechanisms of Gα protein.
An intuitive method to visualize Boolean network attractors landscape based on probability distribution from trajectories
Authors: Chong Ket Hing
Published: November 2024

Motivation

Boolean network modeling is a coarse-grained modeling approach that has been highly valued for its simple abstract representation of biological regulation in molecular network. The simplified ‘On’ and ‘Off’ expression of gene or protein product is a qualitative representation of experimental findings for gene gets turned on or turned off. Boolean network constructed can be analyzed as having point attractor or cyclic attractor; however, current softwares can visualize the Boolean network attractors on a plane and not visualizing Boolean attractors’ landscape in a 3 dimensional view.

Results

Here, we propose an intuitive method to visualize Boolean network attractors land-scape based on probability distributionPof all possible trajectories in the state transition graph. We formulate a quasi-potential valueU= −ln Pthat enables us to plot the Boolean network attractors landscape in 3D. There are two types of attractors in Boolean network: cyclic attractor and point attractor. Our intuitive method can visualize Boolean network in a landscape with point attractor (node labeled with yellow color) and cyclic attractor (node labeled with pink color). In the 3D landscape the attractors are located at the bottom of the directed graphs. The propose method can be applied in the study of networks in general, for example applications in directed graph, social network for popular users or e-commerce store to find favorite products as identified by attractors.

Availability and implementation

The source code of Python implementation of the propose method can be downloaded fromBoolean-net-attractor-Land URL link.
Evolution of drug-binding residues in bacterial ribosomes
Authors: Ekemezie Chinenye L. , Chan Lewis I. , Brown Charlotte R. , Helena-Bueno Karla , Williams Tom A. , Melnikov Sergey V.
Published: November 2024

Ribosomes from certain bacteria possess divergent drug-binding sites compared to those ofEscherichia coli,leading to natural evasion or hypersensitivity to antibiotics. However, in the absence of systematic studies, it is unknown whether this observed divergence is a rare exception or a common occurrence among bacterial species. Here, we address this question by reconstructing the evolutionary history of drug-binding residues of the ribosome from the origin of bacteria to the present day. This analysis reveals the extent of natural diversity of ribosomal drug-binding sites between bacterial species, which may inform the development of species-specific antimicrobials and a more accurate and personalized choice of ribosome-targeting drugs for a given pathogen.
Glycoprotein K8.1 is Critical for Liver and Bone Marrow Tropism of Kaposi’s Sarcoma-Associated Herpesvirus (KSHV) in the Marmoset Infection Model
Authors: Stahl-Hennig Christiane , Roshani Berit , Schlagowski Sarah , Großkopf Anna K. , Mérida Ruíz Samuel Alberto , Vestweber Ramona , Bleyer Martina , Stolte-Leeb Nicole , Pöhlmann Stefan , Whitby Denise , Ensser Armin , Hahn Alexander S.
Published: November 2024

Kaposi’s sarcoma-associated herpesvirus (KSHV) is a human tumor virus with significant disease burden, particularly in Sub-Saharan Africa, where Kaposi’s sarcoma is prevalent. KSHV disproportionately affects immunocompromised individuals and men who have sex with men. A suitable animal model is critical for the development of a preventive vaccine, as it must replicate viral spread and immune interactions. The common marmoset (Callithrix jacchus) had previously been established as conducive to KSHV infection with non-BAC-derived virus via the intravenous (i.v.) route. We used this animal model to establish the ability to infect marmosets with bacterial artificial chromosome (BAC)-derived KSHV and to establish the role of individual glycoproteins (GPs) in the colonization of specific host tissues. We infected three groups of four animals each with BAC16-derived KSHV wild type (wt), KSHV gHASAELAAN, or KSHVΔK8.1. KSHV gHASAELAANcontains mutations in gH that interfere with binding to the EphA2 receptor, which normally forms a high-affinity complex with gH/gL, whereas KSHVΔK8.1 does not express GP K8.1. The KSHV gHASAELAANmutant was used at a relatively higher concentration to overcome its intrinsic defect and to allow for analysis of tissue tropism. While seroconversion to the KSHV LANA antigen was variable, all animals exhibited clearly detectable viral DNA load in many tissues. Highest loads were detected in spleen, liver, heart and bone marrow. Viral DNA loads in these four tissues did not significantly differ between groups infected with KSHV wt or with the gHASAELAANmutant. However, KSHVΔK8.1-infected animals exhibited significantly lower levels of viral DNA in liver and bone marrow, but not in spleen or heart. Analysis of immune cells demonstrated significant activation of CD4+and CD8+T-cells in KSHV wt-infected animals. In wt and gHASAELAAN-infected animals, different B cell subpopulations were found to expand after infection, which implies that the gH/gL glycoprotein complex may shape the host response to KSHV in unexpected ways. In summary, our findings demonstrate that neither the interaction with Eph family receptors nor GP K8.1 is essential for infection via the i.v. route but K8.1 plays a critical role for KSHV tissue tropism in vivo.