bluuebunny/crossref_metadata_2025 huggingface dataset:
ProAffinity-GNN: A Novel Approach to Structure-based Protein-Protein Binding Affinity Prediction via a Curated Dataset and Graph Neural Networks
Authors: Zhou Zhiyuan , Yin Yueming , Han Hao , Jia Yiping , Koh Jun Hong , Kong Adams Wai-Kin , Mu Yuguang
Published: March 2024

Protein-protein interactions (PPIs) are crucial for understanding biological processes and disease mechanisms, contributing significantly to advances in protein engineering and drug discovery. The accurate determination of binding affinities, essential for decoding PPIs, faces challenges due to the substantial time and financial costs involved in experimental and theoretical methods. This situation underscores the urgent need for more effective and precise methodologies for predicting binding affinity. Despite the abundance of research on PPI modeling, the field of quantitative binding affinity prediction remains underexplored, mainly due to a lack of comprehensive data.

This study seeks to address these needs by manually curating pairwise interaction labels on all available 3D structures of proteins complexes, with experimentally determined binding affinities, creating the largest dataset for structure-based pairwise protein interaction with binding affinity to date. Subsequently, we introduce “ProAffinity-GNN”, a novel deep learning framework using protein language model and graph neural network (GNN) to improve the accuracy of prediction of structure-based protein-protein binding affinities. The evaluation results across several benchmark test sets demonstrate that ProAffinity-GNN not only outperforms existing models in terms of accuracy but also shows strong generalization capabilities.
Effects of Feed Processing Type, Protein Source, and Environmental Salinity onLitopenaeus vannameiFeeding Behaviour
Authors: Moss Amina S. , Brooker Adam J. , Ozioko Stella N. , Nederlof Marit A. J. , Debnath Sudip , Schrama Johan
Published: March 2024

In an 8-week trial, the effects of feed processing types (extruded vs. steamed pellets) and protein source (soya/pea vs. fish meal) onLitopenaeus vannameiwere studied under 30 ppt (first 30 days) and 5 ppt (last 15 days) salinity conditions. Diets included D1-SE soya/pea extruded, D2-SS soya/pea steamed, D3-FE fishmeal extruded, and D4 (FS) fishmeal steamed pellets. No significant weight differences were observed. Survival rates (80-97% at 30 ppt) decreased at reduced salinity and were significantly higher for shrimp fed steamed pellets (D2:80.00%, D4:76.67%) compared to extruded (D1: 50.00%, p<0.05). Shrimp fed D2-SS and D4-FS diets had increased lipid content (6.79%, 6.36%, p<0.05). Significantly lower lysine and isoleucine were noted in D2-SS. Behaviourally, at 30 ppt, D3-FE attracted significantly more shrimp (84.72%) than D1-SE (74.49%) and D2-SS (75.70%, p<0.05). Click analysis showed D1-SE and D2-SS with the shortest durations (17.97, 17.24ms, respectively), and D3-FE and D4-FS the longest (20.10, 23.89ms, respectively, p<0.05). Click frequency was also significantly higher in fishmeal–based diets, whereas the number of clicks was higher in shrimp fed extruded feed. Overall, extruded pellets and fishmeal diets were more favourable. These findings emphasize the importance of tailored feed strategies that consider nutritional content, feed physical properties and environmental factors for optimal shrimp feeding.
Construction of an Immunoinformatics-Based Multi-Epitope Vaccine Candidate targeting Kyasanur Forest Disease Virus
Authors: Kasibhatla Sunitha M. , Rajan Lekshmi S. , Shete Anita M. , Jani Vinod , Patil Savita , Joshi Yash , Sahay Rima R. , Patil Deepak Y. , Mohandas Sreelekshmy , Majumdar Triparna , Sonavane Uddhavesh , Joshi Rajendra , Yadav Pragya D.
Published: March 2024

Kyasanur Forest Disease (KFD) is one of the neglected tick-borne viral zoonoses. KFD virus was initially considered endemic to the Western Ghats region of Karnataka. Still, over the years, there have been reports of its spread to newer areas within and outside Karnataka. The absence of an effective treatment for KFD expedites the need for further research and development of novel vaccines. The present study was designed to develop a multi-epitope vaccine candidate against KFDV using immunoinformatic tools. After analyzing 74 complete KFDV genome sequences for genetic recombination and phylogeny, different prioritized B and T cell epitopes were combined using various linkers to construct the vaccine candidate. Docking analysis of the designed vaccine construct revealed a stable interaction with the TLR2-TLR6 receptor complex. After confirming the stability of the vaccine receptor complex, codon optimization was done to ensure the efficient translation of the designed multi-epitope vaccine in the prokaryotic host system, and the subsequentin-silicocloning into the pET30b(+) expression vector was carried out. Immunoinformatics analysis of the multi-epitope vaccine in the current study is satisfactory as it can significantly accelerate the initial stages of vaccine development by narrowing down potential vaccine candidates and providing insights into their design. Experimental validation of the potential multi-epitope vaccine candidate remains crucial to confirm effectiveness and safety in real-world conditions.
Antagonistic behavior of brain networks mediated by low-frequency oscillations: electrophysiological dynamics during internal–external attention switching
Authors: Hammer Jiri , Kajsova Michaela , Kalina Adam , Krysl David , Fabera Petr , Kudr Martin , Jezdik Petr , Janca Radek , Krsek Pavel , Marusic Petr
Published: March 2024

Antagonistic activity of brain networks likely plays a fundamental role in how the brain optimizes its performance by efficient allocation of computational resources. A prominent example involves externally/internally oriented attention tasks, implicating two anticorrelated, intrinsic brain networks: the default mode network (DMN) and the dorsal attention network (DAN). To elucidate electrophysiological underpinnings and causal interplay during attention switching, we recorded intracranial EEG (iEEG) from 25 epilepsy patients with electrode contacts localized in the DMN and DAN. We show antagonistic network dynamics of activation-related changes in high-frequency (> 50 Hz) and low-frequency (< 30 Hz) power. The temporal profile of information flow between the networks estimated by effective connectivity suggests that the activated network inhibits the other one, gating its activity by increasing the amplitude of the low-frequency oscillations. Insights about inter-network communication may have profound implications for various brain disorders in which these dynamics are compromised.
Differential Patterns of Cross-Protection against Antigenically Distinct Variants in Small Animal Models of SARS-CoV-2 Infection
Authors: Selvaraj Prabhuanand , Stauft Charles B. , Liu Shufeng , Sangare Kotou , Wang Tony T.
Published: March 2024

Continuous evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) will likely force more future updates of vaccine composition. Based on a series of studies carried out in human ACE2 transgenic mice (K18-hACE2) and Syrian hamsters, we show that immunity at the respiratory tract, acquired through either previous infection or vaccination with an in-house live attenuate virus, offers protection against antigenically distinct variants in the absence of variant spike-specific neutralizing antibodies. Interestingly, immunity acquired through infection of a modern variant (XBB.1.5) was insufficient in preventing brain infection by the ancestral virus (WA1/2020) in K18-hACE2 mice. Similarly, previous infection with WA1/2020 did not protect against brain infection by XBB.1.5. Our results highlight the importance of immune components other than neutralizing antibodies in maintaining protection against new variants in the respiratory tract, but also paint scenarios where a monovalent vaccine based on a contemporary variant may be less effective against the ancestral strain.

Importance

Many studies have assessed the cross neutralization of various SARS-CoV-2 variants induced by breakthrough infections or vaccine boosters. Few studies, however, have modeled a more severe type of breakthrough infection. Here, we show that immunity acquired through a previous infection by either a historical virus (WA1/2020) or a contemporary variant (XBB.1.5) failed to protect against brain infection of K18-hACE2 mice by an antigenically distinct virus, although it largely protected the respiratory tract. Our results provided a potential model to investigate the role of different immune components in curbing SARS-CoV-2 infection.
Global climate change effect on AsianMus musculus; Implication from last glacial maximum to the end of the 21stcentury
Authors: Afzali Yaser Amir
Published: March 2024

Global climate change poses unprecedented challenges to biodiversity, prompting urgent investigations into its effects on various species. This study focuses onMus musculus, a small rodent species and a crucial indicator of ecosystem health. Spanning from the last glacial maximum to the end of the 21stcentury, employed Species Distribution Models (SDMs) to assess the impacts of climate change onMus musculusand its four subspecies across Asia (M. m musculus,M. m domesticus,M. m castaneus, andM. m bactrianus). The SDMs reveal nuanced responses among subspecies, withM. m. domesticus,M. m. musculus, andM. m. castaneusfacing potential habitat contractions, whileM. m. bactrianusshows habitat expansion. Variable importance analysis highlights the significance of temperature-related variables, indicating the growing impact of rising temperatures on distribution patterns. Findings underscore the ecological implications of these shifts, emphasizing the need for tailored conservation strategies. The robustness of models, as indicated by high Area Under the Curve (AUC) values, enhances confidence in the reliability of predictions. Despite data limitations, this study contributes valuable insights into the complex dynamics between climate change andMus musculuspopulations, guiding future conservation efforts in the face of ongoing global environmental transformations.
Female-dominated disciplines have lower evaluated research quality and funding success rates, for men and women
Authors: James Alex , Buelow Franca , Gibson Liam , Brower Ann
Published: March 2024

We use data from 30 countries and find that the more women in a discipline, the lower quality the research in that discipline is evaluated to be and the lower the funding success rate is. This affects men and women, and is robust to age, number of research outputs, and bibliometric measures where such data are available. Our work builds on others’ findings that women’s work is valued less, regardless of who performs that work.
Late Miocene transformation of Mediterranean Sea biodiversity
Authors: Agiadi Konstantina , Hohmann Niklas , Gliozzi Elsa , Thivaiou Danae , Bosellini Francesca R. , Taviani Marco , Bianucci Giovanni , Collareta Alberto , Londeix Laurent , Faranda Costanza , Bulian Francesca , Koskeridou Efterpi , Lozar Francesca , Mancini Alan Maria , Dominici Stefano , Moissette Pierre , Campos Ildefonso Bajo , Borghi Enrico , Iliopoulos George , Antonarakou Assimina , Kontakiotis George , Besiou Evangelia , Zarkogiannis Stergios D. , Harzhauser Mathias , Sierro Francisco Javier , Coll Marta , Vasiliev Iuliana , Camerlenghi Angelo , García-Castellanos Daniel
Published: March 2024

Understanding deep-time marine biodiversity change under the combined effects of climate and connectivity changes is fundamental for predicting the impacts of modern climate change in semi-enclosed seas. We quantify the Late Miocene–Early Pliocene (11.63–3.6 Ma) taxonomic diversity of the Mediterranean Sea for calcareous nannoplankton, dinocysts, foraminifera, ostracods, corals, molluscs, bryozoans, echinoids, fishes, and marine mammals. During this time, marine biota was affected by global climate cooling and the restriction of the Mediterranean’s connection to the Atlantic Ocean that peaked with the Messinian Salinity Crisis. Although the net change in species richness from the Tortonian to the Zanclean varies by group, species turnover is greater than 30% in all cases. The results show clear perturbation already in the pre-evaporitic Messinian (7.25–5.97 Ma), with patterns differing among groups and sub-basins.
A Preliminary list of Birds from Laguna de Matusagarati: A Wildlife Refuge in Darien Province, Panama
Authors: Garzón Jorge L. , Pimentel-Peralta Gumercindo , Castillo-Caballero Pedro L. , Medina Jorge L. , Alfaro Yennifer , Carrera Jean Paul , Valderrama Anayansi
Published: March 2024

The wetland Laguna de Matusagarati, in the province of Darien, eastern Panama region, possesses an approximate extension of 56, 000 hectares, the largest wetland in Panama and one of the biggest of Central America. Despite 70% of this wetland is on protected areas by Ministerio de Ambiente Panama, there are areas where the anthropogenic impact is notable, livestock, rice and oil palm crops, logging and deforestation are the most intense activities that have led to habitat loss. As part of a comprehensive One Health initiative focused on the surveillance of emerging diseases in the Darien region, we have undertaken simultaneous investigation on the biodiversity (mosquitos, birds, mammals, reptiles and amphibians) of Matusagarati. Here we report the results of the avifauna diversity undertaken in October 2018 and June 2019. We used mist nests, direct observation with binoculars and photographic cameras to report the species. A total of 169 species were reported, 49 families and 19 orders that represent 17% of the birds from Panama. Here we present the first checklist of birds from the Humedal Laguna de Matusagarati, with this we expect to improve the knowledge of the biodiversity of this wetland and provide data to authorities to improve the policies of conservation in this unique ecosystem.
Single cell view of tumor microenvironment gradients in pleural mesothelioma
Authors: Giotti Bruno , Dolasia Komal , Zhao William , Cai Peiwen , Sweeney Robert , Merritt Elliot , Kiner Evgeny , Kim Grace , Bhagwat Atharva , Hegde Samarth , Fitzgerald Bailey , Shroff Sanjana , Dawson Travis , Garcia-barros Monica , Abdul-ghafar Jamshid , Chen Rachel , Gnjatic Sacha , Soto Alan , Brody Rachel , Kim-Schulze Seunghee , Chen Zhihong , Beaumont Kristin G. , Merad Miriam , Flores Raja , Sebra Robert , Horowitz Amir , Marron Thomas U , Tocheva Anna , Wolf Andrea , Tsankov Alexander M.
Published: March 2024

Immunotherapies have shown great promise in pleural mesothelioma (PM), yet most patients still do not achieve significant clinical response, highlighting the importance of improving understanding of the tumor microenvironment (TME). Here, we utilized high-throughput, single-cell RNA-sequencing tode novoidentify 54 expression programs and construct a comprehensive cellular catalogue of the PM TME. We found four cancer-intrinsic programs associated with poor disease outcome and a novel fetal-like, endothelial cell population that likely responds to VEGF signaling and promotes angiogenesis. Throughout cellular compartments, we observe substantial difference in the TME associated with a cancer-intrinsic sarcomatoid signature, including enrichment in fetal-like endothelial cells, CXCL9+ macrophages, cytotoxic, exhausted, and regulatory T cells, which we validated using imaging and bulk deconvolution analyses on two independent cohorts. Finally, we show, both computationally and experimentally, that NKG2A-HLA-E interaction between NK and tumor cells represents an important new therapeutic axis in PM, especially for epithelioid cases.

Statement of Significance

This manuscript presents the first single-cell RNA-sequencing atlas of pleural mesothelioma (PM) tumor microenvironment. Findings of translational relevance, validated experimentally and using independent bulk cohorts, include identification of gene programs predictive of survival, a fetal-like endothelial cell population, and NKG2A blockade as a promising new immunotherapeutic intervention in PM.
WISH-BONE: Whole-mount In Situ Histology, to label osteocyte mRNA and protein in 3D adult mouse bones
Authors: Meslier Quentin A. , Duerr Timothy J. , Nguyen Brian , Monaghan James R. , Shefelbine Sandra J.
Published: March 2024

Bone is a three dimensional and highly dynamic tissue under constant remodeling. Commonly used tools to investigate bone biology require sample digestion for biomolecule extraction or only provide two-dimensional spatial information. There is a need for 3D tools to investigate spatially preserved biomarker expression in osteocytes. In this work, we present a new method, WISH-BONE, to label osteocyte mRNA and protein in whole-mount mouse bone. For mRNA labeling, we used Hybridization Chain Reaction – FluorescenceIn SituHybridization to label genes of interest in osteocytes. For protein labeling, samples were preserved using an epoxy-based solution that protects tissue structure and biomolecular components. Then an enzymatic matrix permeabilization step was performed to enable antibody penetration. Immunostaining was used to label various proteins involved in bone homeostasis. We also demonstrate the use of customized fluorescent nanobodies to target and label proteins in the cortical bone. However, the relatively dim signal observed from nanobodies staining limited detection. In this study, we share protocols, highlight opportunities, and identify the challenges of this novel 3D labeling method. They are the first protocols for whole-mount osteocyte 3D labeling of mRNA and protein in mature mouse bones. WISH-BONE will allow the investigation of molecular signaling in bone cells in their 3D environment and could be applied to various bone-related fields of research.
Hour-long, Kilohertz Sampling Rate 3D Single-virus Tracking in Live Cells Enabled by StayGold Fluorescent Protein Fusions
Authors: Lin Yuxin , Exell Jack , Lin Haoting , Zhang Chen , Welsher Kevin D.
Published: March 2024

The viral infection process covers a large range of spatiotemporal scales. Tracking the viral infection process with fluorescent labels over long durations while maintaining a fast sampling rate requires bright and highly photostable labels. StayGold is a recently identified green fluorescent protein that has a greater photostability and higher signal intensity under identical illumination conditions as compared to existing fluorescence protein variants. Here, StayGold protein fusions were used to generate virus-like particles (StayGold-VLPs) to achieve hour-long 3D single-virus tracking (SVT) with one thousand localizations per second (kHz sampling rate) in live cells. The expanded photon budget from StayGold protein fusions prolonged the tracking duration, facilitating a comprehensive study of viral trafficking dynamics with high temporal resolution over long timescales. The development of StayGold-VLPs presents a simple and general VLP labeling strategy for better performance in SVT, enabling exponentially more information to be collected from single trajectories and allowing for the future possibility of observing the whole life cycle of a single virus.

Abstract Figure
Dissecting AlphaFold’s Capabilities with Limited Sequence Information
Authors: Gut Jannik Adrian , Lemmin Thomas
Published: March 2024

Protein structure prediction, a fundamental challenge in computational biology, aims to predict a protein’s 3D structure from its amino acid sequence. This structure is pivotal for elucidating protein functions, interactions, and driving innovations in drug discovery and enzyme engineering. AlphaFold2, a powerful deep learning model, has revolutionized this field by leveraging phylogenetic information from multiple sequence alignments (MSAs) to achieve remarkable accuracy in protein structure prediction. However, a key question remains: how well does AlphaFold2 understand protein structures? This study investigates AlphaFold2’s capabilities when relying primarily on high-quality template structures, without the additional information provided by MSAs. By designing experiments that probe local and global structural understanding, we aimed to dissect its dependence on specific features and its ability to handle missing information. Our findings revealed AlphaFold2’s reliance on sterically valid C-βatoms for correctly interpreting structural templates. Additionally, we observed its remarkable ability to recover 3D structures from certain perturbations and the negligible impact of the previous structure in recycling. Collectively, these results support the hypothesis that AlphaFold2 has learned an accurate local biophysical energy function. However, this function seems most effective for local interactions. Our work significantly advances understanding of how deep learning models predict protein structures and provides valuable guidance for researchers aiming to overcome limitations in these models. protein folding, alphafold, side-chain, interpretability
Common soil history is more important than plant history for arbuscular mycorrhizal community assembly in an experimental grassland diversity gradient
Authors: Albracht Cynthia , Solbach Marcel Dominik , Hennecke Justus , Bassi Leonardo , van der Ploeg Geert Roelof , Eisenhauer Nico , Weigelt Alexandra , Buscot François , Heintz-Buschart Anna
Published: March 2024

The relationship between biodiversity and ecosystem functioning strengthens with ecosystem age. However, the interplay between the plant diversity - ecosystem functioning relationship and Glomeromycotinian arbuscular mycorrhizal fungi (AMF) community assembly has not yet been scrutinized in this context, despite AMF’s role in plant survival and niche exploration.

We study the development of AMF communities by disentangling soil- and plant-driven effects from year effects. Within a long-term grassland biodiversity experiment, the pre-existing plant communities of varying plant diversity were re-established as split plots with combinations of common plant and soil histories: split plots with neither common plant nor soil history, with only soil but no plant history, and with both common plant and soil history.

We found that bulk soil AMF communities were primarily shaped by common soil history and additional common plant history had little effect. Further, the steepness of AMF diversity and plant diversity relationship did not strengthen over time, but AMF community evenness increased with common history. Specialisation of AMF towards plant species was low throughout giving no indication of AMF communities specialising or diversifying over time. The potential of bulk soil AMF as mediators of variation in plant and microbial biomass over time and hence as drivers of BEF relationships was low.

Our results suggest that soil processes may be key for the build-up of plant community-specific mycorrhizal communities with likely feedback effects on ecosystem productivity, but the plant-available mycorrhizal pool in bulk soil itself does not explain the strengthening of BEF relationships over time.
BMI Variability and Cardiovascular Outcomes Within Clinical Trial and Real-World Environments in Type 2 Diabetes: An IMI2 SOPHIA study
Authors: Massey Robert J , Chen Yu , Panova-Noeva Marina , Mattheus Michaela , Siddiqui Moneeza K , Schloot Nanette C , Ceriello Antonio , Pearson Ewan R , Dawed Adem Y
Published: March 2024

Aims

BMI variability has been associated with increased cardiovascular disease risk in individuals with type 2 diabetes, however comparison between clinical studies and real-world observational evidence has been lacking. Furthermore, it is not known whether BMI variability has an effect independent of HbA1c variability.

Methods and Results

We investigated the association between BMI variability and 3P-MACE risk in the Harmony Outcomes trial (n = 9198), and further analysed placebo arms of REWIND (n = 4440) and EMPA-REG OUTCOME (n = 2333) trials, followed by real-world data from the Tayside Bioresource (n = 6980) using Cox regression modelling. BMI variability was determined using average successive variability (ASV), with first major adverse cardiovascular event of non-fatal stroke, non-fatal myocardial infarction, and cardiovascular death (3P-MACE) as the primary outcome.

After adjusting for cardiovascular risk factors, a +1 SD increase in BMI variability was associated with increased 3P-MACE risk in Harmony Outcomes (HR 1.12, 95% CI 1.08 – 1.17, P < 0.001). The most variable quartile of participants experienced an 87% higher risk of 3P-MACE (P <0.001) relative to the least variable. Similar associations were found in REWIND and Tayside Bioresource. Further analyses in the EMPA-REG OUTCOME trial did not replicate this association. BMI variability’s impact on 3P-MACE risk was independent of HbA1c variability.

Conclusion

In individuals with type 2 diabetes, increased BMI variability was found to be an independent risk factor for 3P-MACE across cardiovascular outcome trials and real-world datasets. Future research should attempt to establish a causal relationship between BMI variability and cardiovascular outcomes.
Defining tumor growth in vestibular schwannomas: a volumetric inter-observer variability study in contrast-enhanced T1-weighted MRI
Authors: Cornelissen Stefan , Schouten Sammy M. , Langenhuizen Patrick P.J.H. , Lie Suan Te , Kunst Henricus P.M. , de With Peter H.N. , Verheul Jeroen B.
Published: March 2024

For patients with vestibular schwannomas (VS), a conservative observational approach is increasingly used. Therefore, the need for accurate and reliable volumetric tumor monitoring is important. Currently, a volumetric cutoff of 20% increase in tumor volume is widely used to define tumor growth in VS. The goal of this study is to investigate the tumor volume dependency on the limits of agreement (LoA) for volumetric measurements of VS by means of an inter-observer study.

This retrospective study included 100 VS patients who underwent contrast-enhanced T1-weighted MRI. Five observers volumetrically annotated the images. Observer agreement and reliability was measured using the LoA, estimated using the limits of agreement with the mean (LOAM) method, and the intraclass correlation coefficient (ICC). Influence of imaging parameters and tumor characteristics were assessed using univariable and multivariable linear regression analysis.

The 100 patients had an average median tumor volume of 903 mm3(IQR: 193-3101). Peritumoral cysts were found in 6 (6%) patients. Patients were divided into four volumetric size categories based on tumor volume quartile. The smallest tumor volume quartile showed a LOAM relative to the mean of 26.8% (95% CI: 23.7, 33.6), whereas for the largest tumor volume quartile this figure was found to be 7.3% (95% CI: 6.5, 9.7) and when excluding peritumoral cysts: 4.8% (95% CI: 4.2, 6.2). Of all imaging parameters and tumor characteristics, only tumor volume was associated with the LoA (adjusted B=-0.001 [95% CI: -0.001, 0.000;P=0.003]).

Agreement limits within volumetric annotation of VS are affected by tumor volume, since the LoA improves with increasing tumor volume. As a result, for tumors larger than 200 mm3, growth can reliably be detected at an earlier stage, compared to the currently widely used cutoff of 20%. However, for very small tumors, growth should be assessed with higher agreement limits than previously thought.
Comparative safety and effectiveness of Pfizer BA.4-5 versus Sanofi during the spring 2023 COVID-19 booster vaccination programme in England: a matched cohort study in OpenSAFELY-TPP
Authors: Andrews Colm D , Prestige Em , Parker Edward PK , Walker Venexia , Palmer Tom , Schaffer Andrea L , Green Amelia CA , Curtis Helen J , Walker Alex , Smith Rebecca M , Wood Christopher , Bates Chris , Mehrkar Amir , MacKenna Brian , Bacon Sebastian CJ , Goldacre Ben , Hernán Miguel A , Sterne Jonathan AC ,   the OpenSAFELY collaborative, Hulme William J
Published: March 2024

Introduction

The spring 2023 COVID-19 booster vaccination programme in England used both Pfizer BA.4-5 and Sanofi vaccines. All people aged 75 years or over and the clinically vulnerable were eligible to receive a booster dose. Direct comparisons of the effectiveness of these two vaccines in boosting protection against severe COVID-19 events have not been made in trials or observational data.

Methods

With the approval of NHS England, we used the OpenSAFELY-TPP database to compare effectiveness of the Pfizer BA.4-5 and Sanofi vaccines during the spring 2023 booster programme, between 1 April and 30 June 2023. We investigated two cohorts separately: those aged 75 or over (75+); and those aged 50 or over and clinically vulnerable (CV). In each cohort, vaccine recipients were matched on date of vaccination, COVID-19 vaccine history, age, and other characteristics. Effectiveness outcomes were COVID-19 hospital admission, COVID-19 critical care admission, and COVID-19 death up to 16 weeks after vaccination. Safety outcomes were pericarditis and myocarditis up to 4 weeks after vaccination. We report the cumulative incidence of each outcome, and compare safety and effectiveness using risk differences (RD), relative risks (RR), and incidence rate ratios (IRRs).

Results

492,642 people were 1-1 matched in the CV cohort, and 673,926 in the 75+ cohort, contributing a total of 7,423,251 and 10,173,230 person-weeks of follow-up, respectively. The incidence of COVID-19 hospital admission was higher for Sanofi than for Pfizer BA.4-5. In the CV cohort, 16-week risks per 10,000 people were 22.3 (95%CI 20.4 to 24.3) for Pfizer BA.4-5 and 26.4 (24.4 to 28.7) for Sanofi, with an IRR of 1.19 (95%CI 1.06 to 1.34). In the 75+ cohort, these were 17.5 (16.1 to 19.1) for Pfizer BA.4-5 and 20.4 (18.9 to 22.1) for Sanofi, with an IRR of 1.18 (1.05-1.32). These findings were similar across all pre-specified subgroups. More severe COVID-19 related outcomes (critical care admission and death), and safety outcomes at 4 weeks, were rare in both vaccines so we could not reliably compare effectiveness of the two vaccines.

Conclusion

This observational study comparing effectiveness of Pfizer BA.4-5 and Sanofi vaccine during the spring 2023 programme in England in the two main eligible cohorts – people aged 75 and over and in clinically vulnerable people – found some evidence of superior effectiveness against COVID-19 hospital admission for Pfizer BA.4-5 compared with Sanofi within 16 weeks after vaccination.
Extra-axial inflammatory signal and its relation to peripheral and central immunity in depression
Authors: Eiff Brandi , Bullmore Edward T. , Clatworthy Menna R. , Fryer Tim D. , Pariante Carmine M. , Mondelli Valeria , Maccioni Lucia , Hadjikhani Nouchine , Loggia Marco L. , Moskowitz Michael A. , Bruner Emiliano , Veronese Mattia , Turkheimer Federico E. ,   NIMA Consortium, Schubert Julia J.
Published: March 2024

Although both central and peripheral inflammation have been consistently observed in depression, the relationship between the two remains obscure. Extra-axial immune cells may play a role in mediating the connection between central and peripheral immunity. This study investigates the potential roles of calvarial bone marrow and parameningeal spaces in mediating interactions between central and peripheral immunity in depression.

Positron emission tomography was employed to measure regional TSPO expression in the skull and parameninges as a marker of inflammatory activity. This measure was correlated with brain TSPO expression and peripheral cytokine concentrations in a cohort enriched for heightened peripheral and central immunity comprising 51 individuals with depression and 25 healthy controls.

The findings reveal a complex relationship between regional skull TSPO expression and both peripheral and central immunity. Facial and parietal skull bone TSPO expression showed significant associations with both peripheral and central immunity. TSPO expression in the confluence of sinuses was also linked to both central and peripheral immune markers. Group dependant elevations in TSPO expression within the occipital skull bone marrow were also found to be significantly associated with central inflammation.

Significant associations between immune activity within the skull, parameninges, parenchyma, and periphery highlight the role of the skull bone marrow and venous sinuses as pivotal sites for peripheral and central immune interactions.
Large-Scale Longitudinal Assessment of Declining Memory Function Through Individualized Modeling of Episodic Memory
Authors: Hake Holly S. , van der Velde Maarten , Leonard Bridget , Grabowski Thomas , van Rijn Hedderik , Stocco Andrea
Published: March 2024

The detection and tracking of progressive memory impairments, particularly in the context of neurodegenerative disorders, relies predominantly on traditional neuropsychological assessment and short cognitive screening tools. These methods, however, are resource-intensive and lack the accessibility and/or the repeatability necessary for effective early identification and tracking interventions. This study addresses the critical need for reliable and efficient diagnostic tools to track and predict memory decline in clinical settings. We demonstrate that an online, remote model-based memory assessment, can identify individuals with Mild Cognitive Impairment (MCI) with an accuracy rate exceeding 84% in a single 8-minute session. Furthermore, the test can be repeated multiple times with increasing accuracy over multiple assessments. The system’s ability to monitor individual memory function inexpensively and longitudinally across various materials offers a robust and repeatable alternative to the static measures currently employed. Our findings show that traditional methods to assess memory decline could be replaced by adaptive, precise, and patient-friendly online tools based on computational modeling techniques. Moreover, our findings also open avenues for the proactive management of Alzheimer’s disease and other dementias, as well as sensitively tracking the effect of interventions in early disease.

Significance Statement

We introduce, for the first time, a dependable, reliable, and repeatable model-based system for the online assessment of clinical memory impairment. Our findings demonstrate that this system can efficiently detect memory impairments using only 8 minutes of data collected online, marking a significant improvement over traditional assessments that typically require 3 hours in a clinical setting. These findings open up the possibility of inexpensive population-level monitoring of memory function.
Machine Learning-Based Prediction of Hashimoto’s Thyroiditis Development Risk
Authors: de Oliveira Andrade Luís Jesuino , Matos de Oliveira Gabriela Correia , Matos de Oliveira Luisa Correia , Vinhaes Bittencourt Alcina Maria , Matos de Oliveira Luís
Published: March 2024

Introduction

Hashimoto’s Thyroiditis (HT) is a prevalent autoimmune disorder impacting thyroid function. Early detection allows for timely intervention and improved patient outcomes. Traditional diagnostic methods rely on clinical presentation and antibody testing, lacking a robust risk prediction tool.

Objective

To develop a high-precision machine learning (ML) model for predicting the risk of HT development.

Method

Data patients were acquired from PubMed. A binary classifier was constructed through data pre-processing, feature selection, and exploration of various ML models. Hyperparameter optimization and performance evaluation metrics (AUC-ROC, AUC-PR, sensitivity, specificity, precision, F1 score) were employed.

Results

Out of a total of 9,173 individuals, 400 subjects within this cohort exhibited normal thyroid function, while 436 individuals were diagnosed with HT. The mean patient age was 45 years, and 90% were female. The best performing model achieved an AUC-ROC of 0.87 and AUC-PR of 0.85, indicating high predictive accuracy. Additionally, sensitivity, specificity, precision, and F1 score reached 85%, 90%, 80%, and 83% respectively, demonstrating the model’s effectiveness in identifying individuals at risk of HT development. Hyperparameter tuning was optimized using a Random Search approach.

Conclusion

This study demonstrates the feasibility of utilizing ML for accurate prediction of HT risk. The high performance metrics achieved highlight the potential for this approach to become a valuable clinical tool for early identification and risk stratification of patients susceptible to HT.
IsGBA1T369M not a risk factor for Parkinson’s disease in the Swedish population?
Authors: Brolin Kajsa Atterling , Bäckström David , Wallenius Joel , Gan-Or Ziv , Puschmann Andreas , Hansson Oskar , Swanberg Maria
Published: March 2024

Variants inGBA1are important genetic risk factors in Parkinson’s disease (PD).GBA1T369M has been linked to an ∼80% increased PD risk but the reports are conflicting and the relevance ofGBA1variants in different populations varies. A lack of association between T369M and PD in the Swedish population was recently reported but needs further validation. We therefore investigated T369M in 1,808 PD patients and 2,183 controls and our results support that T369M is not a risk factor for PD in the Swedish population.
Assessing the Adequacy of Health Facilities for the Aging Population in Indian Cities
Authors: Anil Kumar A.H. Sruthi , Sarif Nawaj , Barman Papai
Published: March 2024

Objectives

The healthcare system in India is struggling to meet the needs of the current population, and the rising aging population is likely to exacerbate this problem. Therefore, this study tried to investigate the distribution of the older population’s access to improved health facilities in Indian cities.

Methods

The study uses data from the 2011 Census of India, which is the latest census round. An index was developed to understand the available health facilities and a geospatial approach was adopted to understand the aging pattern and access to health facilities across Indian cities.

Results

Despite similar aging scenarios, health infrastructure was not equally distributed across cities. The study revealed that advanced health facilities were more concentrated in specific pockets, particularly in metropolitan cities, while smaller cities lacked good health facilities and were not easily accessible.

Discussion

The results highlight the infrastructure gap in Indian cities which poses a significant challenge in achieving healthy aging.
Transcriptomic response to pyrethroid treatment in closely related bed bug strains varying in resistance
Authors: Haberkorn Chloé , Belgaidi Zaïnab , Lasseur Romain , Vavre Fabrice , Varaldi Julien
Published: March 2024

The common bed bug,Cimex lectularius, is one of the main human parasites. The world-wide resurgence of this pest is mainly due to globalization, and the spread of insecticide resistance. A few studies have compared the transcriptomes of susceptible and resistant strains. However, these studies usually relied on strains originating fromdistant locations, possibly explaining their extended candidate gene lists. Here, we compared the transcriptomes of two strains originating from the same location and showing low overall genetic differentiation (FST=0.018) but varying in their susceptibility to pyrethroids, before and after insecticide exposure. In sharp contrast with previous studies, only 24 genes showing constitutive differential expression between the strainswere identified. Interestingly, most of the genes with increased expression in the resistant strain encoded cuticular proteins. However, those changes were not associated with significant difference in cuticular thickness, suggesting that they might be involved in qualitative changes in the cuticle. In contrast, insecticide exposure induced the expression of a multitude of genes, mostly involved in detoxification. Finally, our set of transcriptome candidate loci showed little overlap with a set of loci strongly genetically differentiated in a previous study using the same strains. Several hypothesis explaining this discrepancy are discussed.
Non-prime- and Prime-side Profiling of Pro-Pro Endopeptidase Specificity Using Synthetic Combinatorial Peptide Libraries and Mass Spectrometry
Authors: Claushuis Bart , Cordfunke Robert A. , de Ru Arnoud H. , van Angeren Jordy , Baumann Ulrich , van Veelen Peter A. , Wuhrer Manfred , Corver Jeroen , Drijfhout Jan W. , Hensbergen Paul J.
Published: March 2024

A group of bacterial proteases, the Pro-Pro endopeptidases (PPEPs), possess the unique ability to hydrolyze proline-proline bonds in proteins. Since a protease’s function is largely determined by its substrate specificity, methods that can extensively characterize substrate specificity are valuable tools for protease research. Previously, we achieved an in-depth characterization of PPEP prime-side specificity. However, PPEP specificity is also determined by the non-prime-side residues in the substrate.

To gain a more complete insight into the determinants of PPEP specificity, we characterized the non-prime- and prime-side specificity of various PPEPs using a combination of synthetic combinatorial peptide libraries and mass spectrometry. With this approach, we deepened our understanding of the P3-P3’ specificities of PPEP-1 and PPEP-2, while identifying PPEP-2’s endogenous substrate as the most optimal substrate in our library data. Furthermore, by employing the library approach, we investigated the altered specificity of mutants of PPEP-1 and PPEP-2.

Additionally, we characterized a novel PPEP fromAnoxybacillus tepidamans, which we termed PPEP-4. Based on structural comparisons, we hypothesized that PPEP-4 displays a PPEP-1-like prime-side specificity, which was substantiated by the experimental data. Intriguingly, another putative PPEP fromClostridioides difficile, CD1597, did not display Pro-Pro endoproteolytic activity.

Collectively, we characterized PPEP specificity in detail using our robust peptide library method and, together with additional structural information, provide more insight into the intricate mechanisms that govern protease specificity.
Overlapping roles of Arabidopsis INCURVATA11 and CUPULIFORMIS2 as Polycomb Repressive Complex 2 accessory proteins
Authors: Nadi Riad , Juan-Vicente Lucía , Lup Samuel Daniel , Fernández Yolanda , Rubio Vicente , Micol José Luis
Published: March 2024

Polycomb Repressive Complex 2 (PRC2) catalyzes the trimethylation of lysine 27 of histone H3 (H3K27me3) and plays a key role in epigenetic repression of gene expression in plants and animals. PRC2 core components have all been identified inArabidopsis thaliana, with an expanding list of accessory proteins, some of which facilitate the recruitment of PRC2 to specific targets. INCURVATA11 (ICU11) is a 2-oxoglutarate and Fe2+-dependent dioxygenase that was previously shown to be a likely PRC2 accessory protein. In Tandem Affinity Purification (TAP)-based screens for interacting partners of ICU11 and its redundant paralog CUPULIFORMIS2 (CP2), we discovered that ICU11 interacts with four PRC2 core components, including EMBRYONIC FLOWER 2 (EMF2), and with the accessory proteins EMF1, TELOMERE REPEAT BINDING 1 (TRB1), TRB2, and TRB3. CP2 did not interact with PRC2 core components, nor with TRB1, TRB2, or TRB3, but did interact with TRB4 and TRB5. Both ICU11 and CP2 interacted with the nuclear proteins NAC DOMAIN CONTAINING PROTEIN 50 (NAC050), NAC052 and COP9 SIGNALOSOME SUBUNIT 1 (CSN1). Bimolecular Fluorescence Complementation (BiFC) assays revealed that ICU11 and CP2 both interact with the PRC2 core components CURLY LEAF and SWINGER, and the accessory proteins LIKE HETEROCHROMATIN PROTEIN 1, TRB1, and TRB3. ICU11 and CP2 did not interact with each other. Beyond their phenotypes, transcriptomic profiles revealed strong similarities betweenemf2-3and the double mutanticu11-5 cp2-1, as well as with mutants in PRC2 core components. A significant proportion of the genes mis-regulated inicu11-5 cp2-1are known to harbor H3K27me3 repressive marks in the wild type. Our results provide further evidence that ICU11 acts as a PRC2 accessory protein, and strongly suggest that CP2 plays a similar role.
Clostridium innocuum, an opportunistic gut pathogen, inactivates host gut progesterone and arrests ovarian follicular development
Authors: Chen Mei-Jou , Chou Chia-Hung , Hsiao Tsun-Hsien , Wu Tien-Yu , Li Chi-Ying , Chen Yi-Lung , Chao Kuang-Han , Lee Tzong-Huei , Gicana Ronnie , Shih Chao-Jen , Brandon-Mong Guo-Jie , Lai Yi-Li , Li Po-Ting , Tseng Yu-Lin , Wang Po-Hsiang , Chiang Yin-Ru
Published: March 2024

Levels of progesterone, an endogenous female hormone, increase after ovulation; progesterone is crucial in the luteal phase to maintain successful pregnancy and prevent early miscarriage. Both endogenous and exogenous progesterone are recycled between the liver and gut; thus, the gut microbiota regulate host progesterone levels by inhibiting enterohepatic progesterone circulation. Our data indicated Clostridium innocuum as a major species involved in gut progesterone metabolism in women with infertility. C. innocuum converts progesterone into the neurosteroid epipregnanolone (with negligible progestogenic activity). We purified and characterized the corresponding enzyme, namely NADPH-dependent 5beta-dihydroprogesterone reductase, which is highly oxygen sensitive and whose corresponding genes are prevalent in C. innocuum. Moreover, C. innocuum-administered female C57BL/6 mice (aged 7 weeks) exhibited decreased serum progesterone levels (~35%). Clostridium-specific antibiotics (metronidazole) restored low serum progesterone levels in these mice. Furthermore, prolonged C. innocuum administration (12 weeks) arrested ovarian follicular development in female mice. Cytological and histological analyses indicated that C. innocuum may cause luteal phase insufficiency and affect menstrual regularity. Our findings suggest C. innocuum as a causal factor of progesterone resistance in women taking progesterone.
Transcription of damage-induced RNA inArabidopsiswas frequently initiated from DSB loci within the genic regions
Authors: Kawaguchi Kohei , Satoh Soichirou , Obokata Junichi
Published: March 2024

DNA double-strand breaks (DSBs) are the most severe DNA lesions and need to be removed immediately to prevent loss of genomic information. Recently, it has been revealed that DSBs inducede novotranscription from the cleavage sites in various species, resulting in RNAs being referred to as damage-induced RNAs (diRNAs). While diRNA synthesis is an early event in the DNA damage response and plays an essential role in DSB repair activation, the location where diRNAs are newly generated in plant remains unclear, as does their transcriptional mechanism. Here, we performed RNA sequencing of diRNAs that emerged around all DSB loci inArabidopsis thalianaunder the expression of the exogenous restriction enzymeSbfI and observed 88 diRNAs in 360 DSB loci. Most of the detected diRNAs originated within the active genes and were transcribed from DSBs in a bidirectional manner. Furthermore, we found that diRNA elongation tends to terminate at the boundary of an endogenous gene located near DSB loci. Our results provide reliable evidence for understanding the importance ofde novotranscription at DSBs and show that diRNA is a crucial factor for successful DSB repair.