bluuebunny/crossref_metadata_2025 huggingface dataset:
Bioengineered yeast tethered respiratory supercomplexes reveal mechanisms governing efficient substrate utilization
Authors: Eldeeb Mazzen H. , Cosner Zoe , Carlstrom Andreas , Mays Jeffri-Noelle , Rodriguez Gabriella F. , Berndtsson Jens , Ott Martin , Fontanesi Flavia
Published: December 2024

The mitochondrial respiratory chain (MRC) enzymatic complexes, essential for aerobic energy transduction in eukaryotic cells, are organized into evolutionarily conserved higher-order structures known as supercomplexes (SCs). The elucidation of the physiological relevance of respiratory SCs is essential for our understanding of mitochondrial function and cellular bioenergetics, yet it has been severely hampered by the limited availability of experimental models isolating SC formation as the sole variable. In the yeastSaccharomyces cerevisiae, where SCs are formed by the association of complexes III and IV into III2IV1and III2IV2configurations, compelling evidence suggests that SCs confer a competitive advantage by facilitating cytochromecdiffusion along the SC surface and enhancing respiratory rates. However, the significance of the proposed MRC plasticity and the role of distinct SC conformations in substrate utilization remain unresolved, leaving critical gaps in our understanding of mitochondrial bioenergetics and the adaptive evolution of energy transduction. To address these open questions, we engineered a yeast strain expressing a covalently linked III2IV2SC, whose high-resolution structure is virtually identical to wild-type. Exclusive expression of this tethered SC supports robust overall respiratory activity but selectively affects mitochondrial respiration of cytosolically-generated NADH. This is attributable to the preferential interaction of distinct SC species with mitochondrial NADH dehydrogenases. We propose that in yeast mitochondria, substrate-driven formation of defined respirasome-like SC organizations contributes to the optimization of electron fluxes across the MRC and support metabolic plasticity.
Non-continuous neuromodulation in awake, unrestrained felines increases bladder capacity
Authors: Ortiz-Lopez Miguel , Ouyang Zhonghua , Kotkar Anagha , Willen Maeve , Liu Richard , Olszewski Jordan , Stevens Miriam , Kennedy Eric , Offutt Sarah J. , Bittner Katie C. , Zirpel Lance , Bruns Tim M.
Published: December 2024

Objective

Neuromodulation is a standard therapy for bladder symptoms such as overactive bladder. Previous studies have demonstrated that non-continuous stimulation can increase bladder capacity, and that bladder pressure can be estimated from dorsal root ganglia (DRG) neural activity in anesthetized animal models. Our goal is to determine if non-continuous neuromodulation elicits similar bladder capacity effects as continuous neuromodulation and if bladder pressure can be estimated from DRG signals in an awake, unrestrained animal model.

Approach

We performed aseptic, chronic implant surgeries with seven adult, male felines. Three animals were used to establish procedures, three for experimental testing, and one did not yield data. Bipolar stimulating electrodes were placed on the ipsilateral pudendal nerve and sacral nerve. Microelectrode arrays were inserted in two ipsilateral sacral DRG. Two single-lumen catheters were implanted in the bladder dome for recording bladder pressure and infusing saline. Fixed-sequence, repeated bladder fills were performed in three awake test felines to evaluate the bladder capacity during no-stimulation, non-continuous stimulation, and continuous stimulation at either the pudendal or sacral nerve. Non-continuous stimulation was performed based on increases in bladder pressure estimated from DRG recordings or when 50% of the average no-stimulation bladder capacity was reached.

Main results

We observed similar bladder capacity increases for non-continuous stimulation (122 ± 32% of no-stimulation control) as for continuous stimulation (121 ± 33%) in the three test animals. Non-continuous stimulation paradigms reduced stimulation time by 44% on average. Median correlation coefficients of 0.46 and 0.64 (maximum 0.93) between neural activity and bladder pressure were obtained for awake trials with bladder units in two animals.

Significance

This study demonstrated the feasibility of using non-continuous neuromodulation to increase bladder capacity in awake, unrestrained felines and for decoding bladder pressure from DRG recordings. Further studies are needed to optimize non-continuous stimulation timing for clinical translation.
The Plantae Visualization Platform: a comprehensive web-based tool for the integration, visualization, and analysis of omic data across plant and related species
Authors: Santiago Antonio , Orduña Luis , Fernández José David , Vidal Álvaro , de Martín-Agirre Iñigo , Lisón Purificación , Vidal Elena A. , Navarro-Payá David , Matus José Tomás
Published: December 2024

The increasing availability of omic data from non-model plant species has created a need for centralized, user-friendly platforms that maximize the utility of these datasets. Here, we introduce PlantæViz, a web-based tool designed for the integration, visualization, and analysis of multi-omic data across a wide range of plant species. PlantæViz offers advanced functionalities including gene co-expression and regulatory networks, gene expression atlases, cistrome visualization and metabolomics-transcriptomics integration, providing a robust framework for hypothesis generation and biological interpretation. A suite of GeneCards applications tailored to each plant species provide both community curated and automatic functional annotation information. One of the main features of the platform is its big data approach, whereby large volumes of publicly available transcriptomic data have been processed and displayed, i.e. over 58,000 transcriptomic samples are included in total. In addition, a particular effort in the automatic classification and standardization of omic metadata through regular expressions and data mining has been made, with over 90% of transcriptomic runs being successfully classified according to sample tissue. This data has been used to build gene networks through computationally intensive approaches using different methods. PlantæViz connects genomic and functional understanding between model and non-model plant species and aims to expand its catalog of species in the future. Further developments will include the integration of enhanced data types, and novel tools to further support plant research across diverse biological contexts.
Kinase Plasticity in Response to Vandetanib Enhances Sensitivity to Tamoxifen and Identifies Co-Treatment Strategies in Estrogen Receptor Positive Breast Cancer
Authors: Kakati Rasha T. , Whitman Austin A. , Haase Santiago , Szenasi Attila T. , Thai Christine HNC , Brunk Elizabeth , Okumu Denis O. , East Michael P. , Perou Charles M. , Johnson Gary L. , Spanheimer Philip M.
Published: December 2024

Resistance to endocrine therapy (ET) is common in estrogen receptor (ER) positive breast cancer. Multiple studies have demonstrated that upregulation of MAPK signaling pathways contributes to ET resistance. Herein we show that vandetanib treatment enhances sensitivity to ET in ET-sensitive and –resistant ER+ breast cancer models. Using a CRISPR knockout model, we demonstrate that vandetanib effects are partially mediated by RET receptor tyrosine kinase. Vandetanib treatment alters the gene expression program of ER+ breast cancer cells resulting in a less proliferative and more estrogen responsive Luminal-A like character. Tyrosine kinase network reprogramming was assessed using multiplexed kinase inhibitor beads-mass spectrometry (MIB/MS) assay to identify adaptive resistance mechanisms to vandetanib treatment, which identified upregulation of HER2 activity. Co-treatment to inhibit HER2 with lapatinib enhanced sensitivity to vandetanib, demonstrating biologic activity of HER2 upregulation. Finally, we use our operating room-to-laboratory assay that measures drug response in individual primary tumor cells in short term cultures to demonstrate conserved gene expression changes, including increased HER2 activity signatures, in vandetanib treated cells, and identify features associated with vandetanib response. These results support future investigation of RET targeting strategies considering reprogrammed networks, such as activated HER2, in patients with ET resistant ER+ breast cancer.
Supplementing floral resources does not mitigate the negative effects of urbanisation on cavity-nesting bees and wasps
Authors: Ellis Emilie E. , Campbell Stuart A. , Edmondson Jill L.
Published: December 2024

Cavity-nesting bees and wasps provide essential ecosystem services such as pollination and pest control. Within urban environments, it is likely that cavity-nesting insects are using greenspaces to forage for food and nesting resources, and thus may benefit from urban greenspace management interventions, such as the addition of flower patches and “bee hotels” (trap nests).

In contrast to the relatively large body of work demonstrating the effects of wildflower provisioning on bees in an agricultural context, there have been few studies testing the benefits of floral provisioning, or the relative importance of nest site and food constraints on urban cavity-nesting bees and wasps. Consequently, we lack an empirical evidence base for optimising and informing conservation interventions for these taxa.

To understand how the addition of floral resources influences cavity-nesting insect communities, we conducted a 2-year study in urban greenspaces used for horticulture (allotments). We manipulated floral and nesting resources by adding nectar-rich flower patches and artificial trap nests, and compared nest colonisation by cavity-nesting bees and wasps in sites with floral additions and where no additions were made. Our sites were configured along an urbanisation gradient, allowing us to examine how surrounding urbanisation influenced these patterns.

Contrary to our predictions, we found no significant difference in trap nest uptake in sites where floral resources were added, compared to control sites. However, cavity-nesting insect abundance showed a 6-fold decrease over our urbanisation gradient. The addition of floral resources did not mitigate the negative effects of urbanisation on cavity-nesting insects.

Synthesis and Applications:Although enhancing floral resources in urban systems is a recognised strategy for conserving key pollinators such as social bees, our findings suggest that this approach alone does not address the challenges faced by cavity-nesting bees or wasps in urban landscapes. Our results suggest that accounting for the diversity of resource requirements and incorporating landscape-scale analysis is essential to ensure local conservation interventions will benefit a diversity of insect communities.
TEAD switches interacting partners along neural progenitor lineage progression to execute distinct functions
Authors: Perry Charles H. , Lavado Alfonso , Thulabandu Venkata , Ramirez Cody , Paré Joshua , Dixit Rajiv , Mishra Akhilesh , Yang Jiyuan , Yu Jiyang , Cao Xinwei
Published: December 2024

The TEAD family of transcription factors are best known as the DNA-binding factor in the Hippo pathway, where they act by interacting with transcriptional coactivators YAP and TAZ (YAP/TAZ). Despite the importance of the Hippo pathway, the in vivo functions of TEAD in mammals have not been well established. By comparing mouse mutants lacking TEAD1 and TEAD2 (TEAD1/2) to those lacking YAP/TAZ, we found that TEAD1/2 have both YAP/TAZ-dependent and -independent functions during ventral telencephalon development. TEAD1/2 loss and YAP/TAZ loss similarly disrupt neuroepithelial apical junctions. However, the impacts of their losses on progenitor lineage progression are essentially opposite: Whereas YAP/TAZ loss depletes early progenitors and increases later progenitors—consistent with their established function in promoting progenitor self-renewal and proliferation, TEAD1/2 loss expands early progenitors and reduces late progenitors, indicating that TEAD1/2 promote lineage progression. We further show that TEAD1/2 promote neural progenitor lineage progression by, at least in part, inhibiting Notch signaling and by cooperating with Insulinoma-associated 1 (INSM1). Orthologs of TEAD and INSM1 have been shown to cooperatively regulate neuronal cell fate decisions in worms and flies. Our study reveals a remarkable evolutionary conservation of the function of this transcription factor complex during metazoan neural development.
A Large Language Model Guides the Affinity Maturation of Variant Antibodies Generated by Combinatorial Optimization
Authors: Ashraf Faisal Bin , Zhang Zihao , Paco Karen , Mendivil Mariana P. , Lay Jordan A. , Ray Animesh , Lonardi Stefano
Published: December 2024

Machine learning-based antibody design and optimization by computational affinity maturation is emerging as a promising approach to combating infectious diseases. This has been possible because of significant advances in artificial intelligence methods and a surge in experimental datasets on antigen-antibody interaction. The ability of an antibody to bind an antigen with sufficient strength (measured bybinding affinity, the inverse of the equilibrium dissociation constant) and specificity are critical properties in the design of neutralizing antibodies. Here we introduce Ab-Affinity, a new large language model in conjunction with a genetic algorithm and simulated annealing for diversity generation and fitness optimization, which can accurately predict the binding affinity of specific antibodies against a target peptide within the SARS-CoV-2 spike protein. When trained on large datasets of existing antibodies that bind to certain antigens, we show that Ab-Affinity can generate novel antibodies with more than a 160-fold enhancement in binding affinities over those obtained experimentally. The predicted biophysical properties of the synthetic antibodies demonstrate their robustness. Molecular docking and molecular dynamics simulation of the binding interactions of the best candidate synthetic antibodies showed enhanced interactions and stability on the target peptide epitope. In general, antibodies generated by Ab-Affinity appear to be superior to those obtained with other existing computational methods.
A long-distance inhibitory system regulates haustoria numbers in parasitic plants
Authors: Kokla Anna , Leso Martina , Simura Jan , Wärdig Cecilia , Hayashi Marina , Nishii Naoshi , Tsuchiya Yuichiro , Ljung Karin , Melnyk Charles W.
Published: December 2024

The ability of parasitic plants to withdraw nutrients from their hosts depends on the formation of an infective structure known as the haustorium. How parasites regulate their haustoria numbers is poorly understood, and here, we uncovered that existing haustoria in the facultative parasitic plantsPhtheirospermum japonicumandParentucellia viscosasuppressed the formation of new haustoria on distant roots. UsingPhtheirospermum japonicum,we found that this effect depended on the formation of mature haustoria and could be induced through the application of external nutrients. To understand the molecular basis of this root plasticity, we analyzed hormone response and found that existing infections upregulated cytokinin responsive genes first at the haustoria and then more distantly inPhtheirospermumshoots. We observed that infections increased endogenous cytokinin levels inPhtheirospermumroots and shoots, and this increase appeared relevant since local treatments with exogenous cytokinins blocked the formation of both locally and distantly formed haustoria. In addition, local overexpression of a cytokinin degrading enzyme inPhtheirospermumprevented this systemic inter-haustoria repression and increased haustoria numbers locally. We propose that a long-distance signal produced by haustoria negatively regulates future haustoria, and inPhtheirospermum, such a signaling system is mediated by a local increase in cytokinin to regulate haustoria numbers and balance nutrient acquisition.
Order matters: Autocorrelation of temperature dictates extinction risk in populations with nonlinear thermal performance
Authors: Robey Alison J. , Vasseur David A.
Published: December 2024

Forecasting the risks caused by climate change often relies upon combining species’ thermal performance curves with expected statistical distributions of experienced temperatures, without consideration for the order in which those temperatures occur. Such averaging approaches may obscure the disproportionate impacts that extreme events like heatwaves have on fitness and survival. In this study, we instead incorporate thermal performance curves with population dynamical modeling to elucidate the relationship between the sequence of temperature events – driven by temporal autocorrelation – and extinction risk. We show that the permutation of temperatures determines the extent of risk; as thermal regimes grow warmer, more variable, and more autocorrelated, the risk of extinction grows non-linearly and is driven by interactions among our three treatment variables. Given that the mean, variance, and autocorrelation of temperatures are changing in nuanced ways across the globe, understanding these interactions is paramount for forecasting risk. Using empirical data from a benchmarked set of thermal performance curves, we demonstrate how extinction risk is impacted by the change in mean, variance, and autocorrelation, while controlling for seasonal and diurnal cycling. Our results and modeling approach offer new tools for testing the robustness of thermal performance curves and emphasize the importance of looking beyond temporally-blind metrics, like mean population size or average thermal distributions, for forecasting impending extinction risks.
Replication stress increases de novo CNVs across the malaria parasite genome
Authors: Brown Noah , Luniewski Aleksander , Yu Xuanxuan , Warthan Michelle , Liu Shiwei , Zulawinska Julia , Ahmad Syed , Congdon Molly , Santos Webster , Xiao Feifei , Guler Jennifer L
Published: December 2024

Changes in the copy number of large genomic regions, termed copy number variations (CNVs), contribute to important phenotypes in many organisms. CNVs are readily identified using conventional approaches when present in a large fraction of the cell population. However, CNVs that are present in only a few genomes across a population are often overlooked but important; if beneficial under specific conditions, a de novo CNV that arises in a single genome can expand during selection to create a larger population of cells with novel characteristics. While the reach of single cell methods to study de novo CNVs is increasing, we continue to lack information about CNV dynamics in rapidly evolving microbial populations. Here, we investigated de novo CNVs in the genome of thePlasmodiumparasite that causes human malaria. The highly AT-richP. falciparumgenome readily accumulates CNVs that facilitate rapid adaptation to new drugs and host environments. We employed a low-input genomics approach optimized for this unique genome as well as specialized computational tools to evaluate the de novo CNV rate both before and after the application of stress. We observed a significant increase in genome-wide de novo CNVs following treatment with a replication inhibitor. These stress-induced de novo CNVs encompassed genes that contribute to various cellular pathways and tended to be altered in clinical parasite genomes. This snapshot of CNV dynamics emphasizes the connection between replication stress, DNA repair, and CNV generation in this important microbial pathogen.
Fibrotic pulmonary dust foci is an advanced pneumoconiosis lesion in rats induced by titanium dioxide nanoparticles in a 2-year inhalation study
Authors: Yamano Shotaro , Umeda Yumi
Published: December 2024

Background

We have previously reported that inhalation exposure to titanium dioxide nanoparticles (TiO2NPs) for 13 weeks causes early pneumoconiosis lesions in the alveolar region of F344 rats. We defined these characteristic lesions as pulmonary dust foci (PDF). In this report, we re-evaluate and detail the histopathological data regarding particle-induced pneumoconiosis lesions, including progressive lesions of the early PDF lesions, that developed in F344 rats exposed TiO2NPs by whole body inhalation over a period of two years.

Methods

Male and female F344 rats were exposed to 0.5, 2, and 8 mg/m3anatase type TiO2NPs for 6 hours/day, 5 days/week for 104 weeks using a whole-body inhalation exposure system. After the final exposure, the rats were euthanized. In the present study, the collected lungs were re-evaluated macroscopically and histopathologically.

Results

Rats exposed to TiOL NPs developed macroscopic white lesions, primarily in the subpleural and hilar regions of the lung, which increased in size and number with exposure concentration. Histologically, two lesion types were identified: (1) Fibrotic Pulmonary Dust Foci (fPDF), characterized by collagen deposition, inflammatory infiltration, and disrupted alveolar epithelial differentiation, and (2) Dust Macules (DM), characterized by macrophage accumulation without significant fibrosis or inflammation. Immunohistochemical analysis revealed abnormal alveolar epithelial differentiation and reduced capillary density within fPDFs. Importantly, no histological connection was found between the pneumoconiosis lesions and the observed lung tumors, which resembled spontaneous, age-related neoplasms.

Conclusions

Chronic inhalation of TiOL NPs induces advanced pneumoconiosis characterized by fPDF and DM, with distinct pathological features. However, these lesions were not directly linked to lung tumor development. Therefore, in this study PDF lesions developed into fPDF lesions but did not lead to tumorigenesis. This study provides critical insights into the long-term pulmonary effects of TiOL NP exposure and the progression of pneumoconiosis lesions in the rats.
P2Y2 purinergic receptor and DNA sensor cGAS dictate ionizing radiation-mediated proinflammatory macrophage activation
Authors: Mostefa-Kara Ali , Nathan Aurélia Deva , Paoletti Audrey , Chapel Anais , Gutierrez-Mateyron Emie , Cao-Pham Thanh Trang , Ghosn Yara Bou , Allouch Awatef , Perfettini Jean-Luc
Published: December 2024

The reprogramming of tumor-associated macrophages (TAMs) by radiotherapy is associated with cancer patient’s response and sensitization to immune checkpoint blockade, but the molecular mechanisms involved remain largely unknown. Here, we show that following ionizing radiation (IR), macrophages accumulate single and double strand-DNA breaks and fragmented mitochondria in their cytosol, and stabilize the DNA sensor cyclic GMP-AMP synthase (cGAS). We demonstrate that mitochondrial fragmentation is induced by the activation of the dynamin-related protein 1 (DRP1), and controls the stabilization of cGAS and the proinflammatory activation of irradiated macrophages. Furthermore, pharmacological and genetic inhibitions of cGAS impair the proinflammatory activation of irradiated macrophages, thus revealing that cGAS is a central effector of IR-mediated proinflammatory macrophage activation. Interestingly, we also report that the purinergic receptor P2Y2 acts as an endogenous repressor of the proinflammatory macrophage activation and demonstrate that P2Y2 inactivation enhances the capacity of irradiated macrophages to undergo a proinflammatory activation. Our results thus define a new signaling pathway elicited in macrophages by IR directing mitochondrial dynamics, cytosolic DNA recognition by cGAS and proinflammatory phenotype, which is enhanced following P2Y2 inactivation.
Development of a novel risk prediction tool for emergency department patients with symptoms of coronary artery disease: A research study protocol
Authors: McRae Andrew D. , Macci Aysha J. , Holodinsky Jessalyn K. , Sajobi Tolulope , Andruchow James E. , Borgundvaag Bjug , Brooks Steven , Cheng Ivy , Deb Saswata , Fok Patrick , Kavsak Peter , Graham Michelle M. , Lee Jacques , McLeod Shelley L , Scheuermeyer Frank , Thiruganasambandamoorthy Venkatesh , Wiemer Hana , Yan Justin W. , Hohl Corinne M. ,   the Canadian Emergency Department Research Network (CEDRN) and the Network of Canadian Emergency Researchers (NCER)
Published: December 2024

Patients with chest pain and symptoms of acute coronary syndromes (ACS) account for over 600,000 emergency department (ED) visits annually in Canada. Over 80% of these patients do not have ACS, and most are discharged from the ED after a thorough evaluation. However, a large proportion of these patients are referred for outpatient objective cardiac testing after ED discharge, even though their short-term risk for major adverse cardiac events (MACE) such as death, new myocardial infarction or need for revascularization is very small. This contributes to substantial low-value healthcare utilization, and limits access for those patients who are more likely to benefit from objective testing.

Existing risk prediction tools were developed prior to the advent of high-sensitivity cardiac troponin assays, were derived in non-representative populations and, when applied to ED patients with low cardiac troponin concentrations, systematically overestimate short-term risk of (MACE).

This multicenter prospective cohort study will enrol ED patients with chest pain to derive and validate a novel risk prediction tool to accurately identify patients at low risk of MACE and not requiring additional cardiac testing from patients who are likely to benefit from additional cardiac testing. We will enroll 6500 patients at 13 Canadian EDs nd prospectively follow them for 30 days to ascertain a primary outcome of MACE. The risk prediction tool developed in this project will guide safe, efficient, appropriate referrals of ED patients with chest pain.
Evaluating digitally-enabled self-experiments in general practice to support patients managing persistent pain
Authors: Sturman Nancy , Nikles Jane , Worthy Peter , Fjaagesund Shauna , Elphinston Rachel , Andrews Nicole , Sterling Michele , Konigorski Stefan
Published: December 2024

Background

Despite somewhat limited evidence, non-pharmacological, self-management interventions are often recommended for general practice patients with persistent pain. StudyU is an open-source digital platform designed to help patients undertake self-experiments, using a single case experimental design, to test whether these interventions are personally effective.

Aim

To investigate the feasibility and acceptability of integrating digitally-enabled self-experiments in the general practice care of patients with persistent pain.

Design and setting

We will recruit 50 patients from a large Australian general practice. Participants trial a self-selected, self-management intervention (such as a physical activity, mindfulness practice, or online, self-guided cognitive behavioural therapy) approved by their general practitioner (GP), and use the StudyU app to rate the daily impact of their pain over the 10-week study period. The primary clinical outcome of the self-experiments is mean difference in pain interference (measured using the modified Brief Pain Inventory) between baseline (usual routine) and intervention conditions. Clinical reports are generated for the patient and their GP.

Method

We use validated measures of app usability and acceptance, pre/post measures of patient self-efficacy, quality of life, health service use and self-reported health, individual interviews informed by Normalisation Process Theory, and a nested process evaluation to examine the feasibility and acceptability for patients and practice staff of embedding these self-experiments in general practice care.

Conclusion

Digitally-enabled self-experiments testing non-pharmacological treatment effectiveness may empower patients to self-manage persistent pain, in partnership with their GPs, and provide a model for integrating other new technology for patients with other chronic conditions.

HOW THIS FITS IN

In spite of somewhat limited evidence, non-pharmacological, self-management interventions are generally recommended for general practice patients with persistent pain, a distressing and costly condition. Digitally-enabled single-case experimental designs may be a useful approach to assessing the individual effectiveness of self-management interventions. This research will provide evidence about the acceptability and feasibility (for patients, clinicians and other practice staff) of integrating digitally enabled self-experiments into general practice care.
PULSE PRESSURE IMPAIRS COGNITION VIA WHITE MATTER DISRUPTION
Authors: King Deborah L. O. , Henson Richard N. , Correia Marta , Rowe James B. , Tsvetanov Kamen A.
Published: December 2024

BACKGROUND

In older adults, elevated pulse pressure predicts cognitive decline, irrespective of overall blood pressure. It is proposed to compromise cerebrovascular integrity, potentially leading to brain damage, though the underlying mechanisms remain unclear. We hypothesized that pulse pressure affects cognition by disrupting white matter microstructure, and that it does so independently of other cardiovascular risk factors.

METHODS

Indices of pulse pressure, overall blood pressure and heart rate variability were estimated in a cross-sectional population-based cohort (n=708, aged 18-88 years). An indicator of white matter microstructure was derived from diffusion-weighted imaging, termed the “peak width of skeletonised mean diffusivity” (PSMD). Cognitive function was assessed using measures of processing speed.

RESULTS

In robust multiple linear regressions, pulse pressure significantly predicted PSMD. We also found that PSMD significantly predicted processing speed. Thus higher pulse pressure was associated with greater white matter disruption, and greater white matter disruption was associated with slower processing abilities.This motivated testing whether PSMD mediates the effects of pulse pressure on processing speed. We tested this using a number of structural equation models. PSMD significantly and substantially mediated the effect of pulse pressure on processing speed, over and above age and other cardiovascular factors. We then expanded the model to show that vascular-related changes in processing speed in turn drive changes in higher cognitive functions.

CONCLUSIONS

High pulse pressure disrupts microstructural integrity of white matter in the brain, leading to slower processing speed. We propose that better manament of pulse pressure could help to preserve white matter integrity and reduce cognitive decline in later life.
Quantifying the impact of the COVID-19 pandemic on the Scottish accident and emergency landscape
Authors: Teoh Hui Pheng , Banas Kasia , Oldnall Christopher Aldous
Published: December 2024

Background

The COVID-19 pandemic, declared in March 2020, is suspected to have greatly impacted Scotland’s accident and emergency (A&E) services. Stringent public health measures, including lockdowns, heightened pressures on A&E departments, but their long-term effects remain understudied. This study examines how the pandemic influenced A&E attendances over a broader time-frame.

Methods

Secondary data from Public Health Scotland (2018–2022) on monthly A&E attendances was analysed, standardised per 1,000 population using census data. Choropleth maps visualised A&E attendances and wait times across health boards during key pandemic periods. A Poisson generalised linear model (GLM) assessed the influence of COVID restrictions, demographics, and service factors on attendance rates.

Results

A&E attendances dropped from 2018 to 2022, with NHS Lanarkshire (-32.7%) and NHS Borders (-27.9%) seeing the largest declines. Despite reduced attendances, the percentage of patients seen within four hours also dropped (-29.4% in NHS Lanarkshire). The Poisson GLM confirmed that COVID-19 restrictions influenced attendance rates with a lower incident rate (IRR: 0.89, 95% CI: 0.88–0.90) during lockdowns and an increased incident rate (IRR: 1.04, 95% CI: 1.03–1.05) during easing periods. Health board-level effects varied substantially.

Discussion

COVID-19 disrupted A&E services, causing fluctuating attendances and worsening wait times. Large health board-level variations suggest local policies, behaviours, and existing pressures significantly influenced outcomes. These findings highlight the need to address systemic issues alongside localised strategies for future resilience.
HepatoPredict accurately selects hepatocellular carcinoma patients for liver transplantation regardless of tumor heterogeneity
Authors: Andrade Rita , Perez-Rojas Judith , Gomes da Silva Sílvia , Miskinyte Migla , Quaresma Margarida C. , Frazão Laura P. , Peixoto Carolina , Cubells Almudena , Montalva Eva M. , Figueiredo António , Cipriano Augusta , Gonçalves-Reis Maria , Proença Daniela , Folgado André , Pereira-Leal José B. , Oliveira Rui Caetano , Pinto-Marques Hugo , Tralhão José Guilherme , Berenguer Marina , Cardoso Joana
Published: December 2024

Background/Objectives

Hepatocellular carcinoma (HCC) is a major cause of cancer-related deaths rising worldwide. This is leading to an increased demand for liver transplantation (LT), the most effective treatment for HCC in its initial stages. However, current patient selection criteria are limited in predicting recurrence and raise ethical concerns about equitable access to care. This study aims to enhance patient selection by refining the HepatoPredict (HP) tool, a machine learning-based model that combines molecular and clinical data to forecast LT outcomes.

Methods

The updated HP algorithm was trained on a two-center dataset and assessed against standard clinical criteria. Its prognostic performance was evaluated through accuracy metrics, with additional analyses considering tumor heterogeneity and potential sampling bias.

Results

HP outperformed all clinical criteria, particularly regarding negative predictive value, addressing critical limitations in existing selection strategies. It also demonstrated improved differentiation of recurrence-free and overall survival outcomes. Importantly, the prognostic accuracy of HP remained largely unaffected by intra-nodule and intra-patient heterogeneity, indicating its robustness even when biopsies were taken from smaller or non-dominant nodules.

Conclusions

These findings support the usage of HP as a valuable tool for optimizing LT candidate selection, promoting fair organ allocation, and enhancing patient outcomes through integrated analysis of molecular and clinical data.

Simple Summary

Liver cancer is a leading cause of death, and liver transplants (LT) offer the best chance of survival for many patients. However, current methods to decide who should receive a transplant often fall short, leaving some patients without access to life-saving care. This research focuses on improving these decisions with HepatoPredict (HP). This new tool uses technology to combine tumor and patient data to predict how well someone will do after a transplant. HP was tested on a large group of patients and proved to be more accurate than current methods. It also performed well even when samples came from different parts of the tumor. These findings could help medical teams make fairer and more reliable transplant decisions, ultimately improving patient outcomes and advancing how liver cancer is managed in the medical community.
Integrative cross-omics analysis identifies DNA methylation signatures associated with bilateral hippocampal volume, asymmetry and atrophy rate in the general population
Authors: Liu Dan , Talevi Valentina , Tavares Juliana F. , Wang Ruiqi , Imtiaz Mohammed A , Melas Konstantinos , Teumer Alexander , Wittfeld Katharina , Hillary Robert F , Vojinovic Dina , Beekman Marian , Armstrong Nicola J , Estrada Santiago , Völzke Henry , Bülow Robin , Royle Natalie A. , Wardlaw Joanna M. , Wen Wei , Sachdev Perminder S. , Mather Karen A. , Slagboom P. Eline , Cox Simon R. , Grabe Hans Jörgen , Yang Qiong , Aziz N. Ahmad , Breteler Monique M.B.
Published: December 2024

The hippocampus exhibits volumetric differences between the left and right hemispheres (LHCV and RHCV) and asymmetry, yet the molecular mechanisms underlying these features remain unclear. In this study, we performed a meta-analysis of epigenome-wide association studies (EWAS) across six population-based cohorts (n=8,156; 53% women; mean age: 60.7 years) to identify blood-based methylation signatures associated with LHCV, RHCV, and hippocampal asymmetry. Integrative cross-omics analyses using individual-level genetic, methylation, and gene expression data (n > 2,624 participants from the Rhineland Study) revealed 15 CpG/DMR-gene expression pairs linked to LHCV and 18 pairs to RHCV, implicating pathways involved in neuronal differentiation and immune processes. Notably, baseline methylation at these loci predicted bilateral hippocampal atrophy rates, explaining over 10% of the variation. Four CpGs were consistently associated with hippocampal asymmetry cross-sectionally and longitudinally, exhibiting sex-specific differences. Additionally, adherence to healthy dietary patterns was associated with these methylation signatures, highlighting modifiable influences on hippocampal health and atrophy.
Integrating Ambient Mass Spectrometry Imaging and Spatial Transcriptomics on the Same Cancer Tissues to Identify Gene-Metabolite Correlations
Authors: Godfrey Trevor M. , Shanneik Yasmin , Zhang Wanqiu , Tran Thao , Verbeeck Nico , Patterson Nathan H. , Jackobs Faith E. , Nagi Chandandeep , Ramineni Maheshwari , Eberlin Livia S.
Published: December 2024

The combination of spatial metabolomics and spatial transcriptomics can reveal powerful connections between gene expression and metabolism in heterogeneous tissues, but section-to-section variability can convolute data integration. We present a novel method combining Desorption Electrospray Ionization Mass Spectrometry Imaging spatial metabolomics and spatial transcriptomics on the same tissue sections. We demonstrate this workflow on human breast and lung cancer tissues identifying correlations between metabolites and cancer-related RNA transcripts.
A quantum compatible classical continuum model explains mechanical responses of cell membranes and membrane crosslinkers
Authors: Kim Jichul
Published: December 2024

Both classical mechanics and quantum mechanics explain the Brownian motion. However, it is unclear whether they are compatible with each other as the physical and mathematical identity of the wavefunction in quantum mechanics has been elusive. Here, a continuum theory using grammars in classical mechanics modeling but compatible with the quantum wavefunction is introduced. The theory explains the confined Brownian motion of cell membrane inclusions interacting with extracellular matrices or cytoskeletons via elastic molecular crosslinkers. This crosslinker theory is combined into the Canham-Helfrich-Evans model for fluid membranes. Calculations through the provision of a finite element method for the combined theory reproduced measured data from adhesion molecular machineries and cell membranes. Overall, by providing physical and mathematical interpretations of the quantum wavefunction, the presented theoretical model provides improved capabilities for the realistic simulation of classical and quantum biomechanical aspects of cell membranes and membrane linker proteins.
Amyloid forming human lysozyme intermediates are stabilised by non-native amide-π interactions
Authors: Ahn Minkoo , Streit Julian O. , Waudby Christopher A. , Włodarski Tomasz , Figueiredo Angelo Miguel , Christodoulou John , Kumita Janet R.
Published: December 2024

Mutational variants of human lysozyme cause a rare but fatal hereditary form of systemic amyloidosis by populating an intermediate state that self-assembles into amyloid fibrils. Despite its significance in lysozyme amyloidosis, the intermediate state has been recalcitrant to detailed structural investigation as it is only transiently and sparsely populated. Here, we investigated the intermediate state of a mutational variant of human lysozyme (I59T) using CEST and CPMG RD NMR at low pH.15N CEST profiles probed the thermal unfolding of the native state into the denatured ensemble and revealed an additional state distinct from the two major states. Global fitting of15N CEST and CPMG data provided kinetic and thermodynamic parameters for the exchange between all three states, characterising the intermediate state populated at 0.6%.1H CEST data also confirmed the presence of the intermediate state displaying unusually high or low1HNchemical shifts. To further investigate the structural details of the intermediate state we used molecular dynamics (MD) simulations, which recapitulated the experimentally observed folding pathway and free energy landscape. A high-energy intermediate state with a locally disordered β-domain and C-helix was observed, revealing non-native hydrogen bonding and amide-π interactions. These interactions account for the anomalous1H chemical shifts and likely stabilise the transient intermediate state structure. Together, our NMR and MD data provide the first direct structural information on the intermediate state, offering insights into targeting lysozyme amyloidosis.
Inferring community architectures of multisensory pathways inDrosophilavia unsupervised network embedding
Authors: Sun Xiyang , Komaki Fumiyasu
Published: December 2024

Understanding the complex architecture and functions of neural circuits is central to unraveling the mechanisms of multisensory integration. In this study, we analyzed the structural properties of theDrosophilaadult brain to infer community structures within multisensory pathways. We adopt a network embedding method developed by ourselves, the Bidirectional Heterogeneous Graph Neural Network with Random Teleport (BHGNN-RT), designed to generate vector representations of neurons in a directed, heterogeneous brain connectome. This approach takes advantage of both structural connectivity and network heterogeneity features, enabling effective clustering of neurons and revealing hierarchical community architectures in olfactory and broader multisensory systems. We applied BHGNN-RT to the fly brain connectome to examine connectivity-based community organization in major neuronal classes along multisensory pathways, revealing distinct neural groups with unique connectivity patterns in the antennal lobe, lateral horn, mushroom body, and other brain regions. Further analysis showed how different neural groups contribute to the integration of sensory information in olfactory and multisensory systems. We also investigated the bilateral symmetry of the olfactory pathway, shedding light on how sensory signals are processed with ipsilateral and contralateral connections to ensure robust perception. Our findings demonstrate the utility of graph representation learning in analyzing the structural connectivity of complex neural systems. The insights gained from BHGNN-RT provide a deeper understanding of the community architecture in theDrosophilabrain and contribute to a broader comprehension of the mechanisms underlying multisensory integration.
Kabasura Kudineer Choornam, a medicinal polyherbal formulation, modulates human macrophage polarization and phagocytic function
Authors: Korkmaz Asli , Unuvar Duygu , Gunalp Sinem , Helvaci Derya Goksu , Sag Duygu
Published: December 2024

Background

Kabasura kudineer choornam(KKC) is a polyherbal formulation with 15 ingredients. It has been shown to have anti-inflammatory and anti-microbial properties and demonstrate efficacy in managing the symptoms of H1N1 swine flu and COVID-19. However, its mechanism of action is not fully comprehended.

Purpose

Herein, we examined the effect of theKKCon the polarization and function of primary human macrophages.

Methods

Human monocyte-derived macrophages (M0 macrophages) pre-treated withKKCextract were polarized into M1, M2a, or M2c subtypes. The expression of the M1/M2 polarization markers was analyzed by qPCR, flow cytometry, and ELISA, and the phagocytosis capacity of macrophages was analyzed by flow cytometry.

Results

Our data show that theKKCtreatment increased the expression of the M1 markers IDO1, IL-1β, IL-12a(p35), and TNF in both polarized and unpolarized macrophages at mRNA level. However, it decreased the secretion of IL-12 (p70) in M1 macrophages and increased the secretion of TNF in M0, M2a, and M2c macrophages. IL-10 secretion was increased in M0 and M2a macrophages, while it was decreased in M1 macrophages after theKKCtreatment. Interestingly, allKKC-treated macrophage phenotypes displayed a downregulation in the expression of the M1/M2 surface markers CD64, CD206, CD209, and CD163, which also play a role in phagocytosis. In accordance with this result, the phagocytic capacity of both polarized and unpolarized macrophages was decreased after theKKCtreatment.

Conclusion

In conclusion,KKCextract modulates macrophage inflammatory response and could be a potential supplement for the treatment of infectious and inflammatory diseases.
The angiosperm seed life cycle follows a developmental reverse hourglass
Authors: Sami Asif Ahmed , Bentsink Leónie , Artur Mariana A. S.
Published: December 2024

The seed life cycle is one of the most crucial stages in determining the ecological success of angiosperms. It broadly comprises three developmental phases - embryogenesis, maturation, and germination. Among these phases, seed maturation is particularly critical, serving as a bridge between embryo development and germination. During this phase, seeds accumulate nutrient reserves and acquire essential physiological traits, such as desiccation tolerance, vital for seed survival in diverse environments. Phylotranscriptomics inArabidopsis thalianahas shown that embryogenesis and germination follow an hourglass-like development, with high expression of older and conserved genes at the mid-developmental stages. However, unlike embryogenesis and germination, a phylotranscriptomic study of seed maturation has not yet been performed and a comprehensive overview of the phylotranscriptomic landscape throughout the entire seed life cycle is still lacking. Here, we combined existing RNA-seq data covering all three phases of theArabidopsisseed life cycle to construct a complete picture of the phylotranscriptomic pattern of the seed life cycle by generating transcriptome age index (TAI) and transcriptome divergence index (TDI) profiles. We found that the seed life cycle resembles a reverse hourglass-like pattern, with seed maturation exhibiting increased expression of younger genes with divergent expression patterns compared to embryogenesis and germination. Notably, this pattern of increased expression of younger genes during seed maturation is also conserved across both dicot and monocot species. Tissue-specific phylotranscriptomic analyses revealed that, in monocots, the increased expression of younger genes during maturation is largely driven by genes expressed in the endosperm. Overall, our findings highlight the major shifts in phylotranscriptomic patterns during the seed life cycle and establish seed maturation as a pivotal developmental phase enabling the expression of young and rapidly evolving genes critical for seeds’ adaptive capacity in their surrounding environment.