bluuebunny/crossref_metadata_2025 huggingface dataset:
Geometric analysis of airway trees shows that lung anatomy evolved to enable explosive ventilation and prevent barotrauma in cetaceans
Authors: Cieri Robert L. , Tawhai Merryn H. , Piscitelli-Doshkov Marina , Vogl A. Wayne , Shadwick Robert E.
Published: October 2024

Two new biomechanical challenges faced cetacean lungs compared to their terrestrial ancestors. First, hydrostatic pressures encountered during deep dives are sufficient to cause nearly full lung collapse, risking substantial barotrauma during surfacing if air is trapped in the fragile smaller airways. Second, rapid ventilation in large cetaceans requires correspondingly high ventilatory flow rates. In order to investigate how airway geometry evolved in response to these challenges, we characterized airway geometry from 12 species of cetaceans that vary in common dive depth and ventilatory behavior and a domestic pig using computed tomography. After segmenting the major airways, we generated centerline networks models for the larger airways and computed geometric parameters for each tree including mean branching angle, percent volume fraction, and Strahler branching, diameter, and length ratios. When airway geometry was regressed against ventilatory and diving parameters with phylogenetic least squares, neither average branching angle, percent volume fraction, Strahler length ratio or Strahler branching ratio significantly varied with common ventilatory mode or common diving depth. Higher Strahler diameter ratios were associated with slower ventilation and deeper diving depth, suggesting that cetacean lungs have responded to biomechanical pressures primarily with changes in airway diameter. High Strahler diameter ratios lungs in deeper diving species may help to facilitate more complete collapse of the delicate terminal airways by providing for a greater incompressible volume for air storage at depth. On the other hand, lungs with low Strahler diameter ratios would be better for fast ventilation because the gradual decrease in diameter moving distally should keep peripheral flow resistance low, maximizing ventilatory flow rates.
A brain-shuttled antibody targeting alpha synuclein aggregates for the treatment of synucleinopathies
Authors: An Sungwon , McInnis John J. , Kim Dongin , Li Yihang , Yilmaz Ozge , Ahn Jinhyung , Mackness Brian C , Park Jinyoung , Bonner Julia Maeve , Yun Hyesu , Dujardin Simon , Kim Donghwan , Kwon Seung-Hwan , Tang Yi , Pradier Laurent , Hyeon Sumin , Song Daehae , Sung Byungje , Krishnan Rajaraman , Spencer Brian , Rissman Robert , Sandhu Jagdeep K. , Haqqani Arsalan S. , Lee Hyeran , Jung Jinwon , You Weon-Kyoo , Star Alexandra T. , Delaney Christie E. , Stanimirovic Danica B. , Sardi Sergio Pablo , Lee Sang Hoon , Kayatekin Can
Published: October 2024

Parkinson’s disease and multiple system atrophy are members of a class of devastating neurodegenerative diseases called synucleinopathies, which are characterized by the presence of alpha-synuclein (α-Syn) rich aggregates in the brains of patients. Passive immunotherapy targeting these aggregates is an attractive disease-modifying strategy. Such an approach must not only demonstrate target selectivity towards α-Syn aggregates, but also achieve appropriate brain exposure to have the desired therapeutic effect. Here we present preclinical data for a next-generation antibody for the treatment of synucleinopathies. SAR446159 (ABL301) is a bispecific antibody composed of an α-Syn-binding immunoglobulin (IgG) and an engineered insulin-like growth factor receptor 1 (IGF1R) binding single-chain variable fragment (scFv), acting as a shuttle to transport an antibody across the blood-brain barrier (BBB). SAR446159 binds tightly and preferentially to α-Syn aggregates and prevents their seeding capacityin vitroandin vivo. Incubation with SAR446159 reduced α-Syn preformed fibrils (PFFs) uptake in neurons and facilitated uptake and clearance by microglia. In wild type mice injected in the striatum with α-Syn PFFs, treatment with SAR446159 reduced the spread of aSyn pathology as measured by phosphorylated α-Syn staining and lessened the severity of motor phenotypes. Additionally, in 9-month-old transgenic mice overexpressing α-Syn (mThy1-α-Syn, Line 61), repeated treatment with SAR446159 reduced markers of α-Syn aggregation in the brain. SAR446159 had significantly higher brain and CSF penetration over a sustained period than its monospecific counterpart (1E4) in rats and monkeys. The binding properties of SAR446159 combined with its brain-shuttle technology make it a potent, next-generation immunotherapeutic for treating synucleinopathies.
AI-QuIC: Machine Learning for Automated Detection of Misfolded Proteins in Seed Amplification Assays
Authors: Howey Kyle D. , Li Manci , Christenson Peter R. , Larsen Peter A. , Oh Sang-Hyun
Published: October 2024

Advancements in AI, particularly deep learning, have revolutionized protein folding modeling, offering insights into biological processes and accelerating drug discovery for protein misfolding diseases. However, detecting misfolded proteins associated with neurodegenerative disorders, such as Alzheimer’s, Parkinson’s, ALS, and prion diseases, relies on Seed Amplification Assays (SAAs) analyzed through manual, time-consuming, and potentially inconsistent methods. We introduce AI-QuIC, an AI-driven platform that automates the analysis of Real-Time Quaking- Induced Conversion (RT-QuIC) assay data, a type of SAA crucial for detecting misfolded proteins. Utilizing a well-labeled RT-QuIC dataset of over 8,000 wells—the largest curated dataset for chronic wasting disease prion detection—we applied various AI models to classify true positive, false positive, and negative reactions. Notably, our deep-learning-based model achieved over 98% sensitivity and 97% specificity. By learning directly from raw fluorescence data, deep learning simplifies the SAA-analysis workflow. Automating and standardizing SAA data interpretation with AI-QuIC provides robust, scalable, and consistent diagnostic solutions.
Characterization of antibiotic resistance development ofE. coliin synthetic and real wastewater
Authors: Sutradhar Indorica , Gross Neila , Ching Carly , Nahum Yanina , Desai Darash , Bowes Devin A. , Zaman Muhammad H.
Published: October 2024

Antimicrobial resistance (AMR) is a major threat to global health and resistant bacterial populations have been observed to develop and spread in and around wastewater. However,in vitrostudies on AMR development are typically conducted in ideal media conditions which can differ in composition and nutrient density from wastewater. In this study, we compare the growth and AMR development ofE. coliin standard LB broth to a synthetic wastewater recipe and autoclaved wastewater samples from the Massachusetts Water Resources Authority (MWRA). We found that synthetic wastewater and real wastewater samples both supported less bacterial growth compared to LB. Additionally, bacteria grown in synthetic wastewater and real wastewater samples had differing susceptibility to antibiotic pressure from Doxycycline, Ciprofloxacin, and Streptomycin. However, AMR development over time during continuous passaging under subinhibitory antibiotic pressure was similar in fold change across all media types. Thus, we find that while LB can act as a proxy for wastewater for AMR studies inE. coli, synthetic wastewater is a more accurate predictor of bothE.coligrowth and antibiotic resistance development. Moreover, we also show that antibiotic resistance can develop in real wastewater samples and components within wastewater likely have synergistic and antagonistic interactions with antibiotics.

Importance

Antimicrobial resistance (AMR) ranks among the leading global threats to public health and development. In 2019, bacterial AMR was estimated to have directly caused 1.27 million deaths worldwide and contributed to 4.95 million deaths overall (Murray, C. J., et al., (2022). Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis.The Lancet, 399(10325), 629–655.). With estimations of AMR only getting worse, it is imperative that we understand the complex dimensionalities that drive the genesis of antimicrobial resistance to where it begins–the environment. The paper investigates bacterial growth and AMR in real wastewater samples and highlights the importance of using a media that closely mimics real wastewater in AMR studies, compared to standard lab media like LB broth. This is crucial for understanding howE. coliand other bacteria develop AMR in environments similar to actual wastewater, which can inform more effective strategies to combat AMR in natural and engineered settings.
Statistical analysis of repertoire data demonstrates the influence of microhomology in V(D)J recombination
Authors: Russell Magdalena L , Trofimov Assya , Bradley Philip , Matsen Frederick A
Published: October 2024

V(D)J recombination generates the diverse B and T cell receptors essential for recognizing a wide array of antigens. This diversity arises from the combinatorial assembly of V(D)J genes and the junctional deletion and insertion of nucleotides. While previousin vitrostudies have shown that microhomology—–short stretches of sequence homology between gene ends—–can bias the recombination process, the extent of microhomology’s impactin vivo, particularly in humans, remains unknown. In this paper, we assess how germline-encoded microhomology influences trimming and ligation during V(D)J recombination using statistical inference on previously-published high-throughput TCRαrepertoire sequencing data. We find that microhomology increases both trimming and ligation probabilities, making it an important predictor of recombination outcomes. These effects are consistent across different receptor loci and sequence types. Further, we demonstrate that accounting for microhomology effects significantly alters sequence annotation probabilities and rankings, highlighting its practical importance for accurately inferring the V(D)J recombination events that generated an observed sequence. Together, these results enhance our understanding of how microhomologous nucleotides shape the human V(D)J recombination process.

Significance Statement

Humans rely on diverse adaptive immune receptor repertoires to effectively defend against infections. The receptor generation process, known as V(D)J recombination, is designed to create this diversity by stochastically joining V(D)J gene segments and modifying their junctions through nucleotide deletions and insertions. Previous studies, conducted in vitro, have suggested that short stretches of homologous nucleotides between gene segments can bias these recombination steps. In this study, we explore the extent to which these homologous nucleotides influence V(D)J recombination in humans using statistical inference on large-scale receptor repertoire sequencing data. Our findings reveal that microhomology significantly biases several recombination steps, with important practical implications for the analysis, processing, and interpretation of receptor sequences.
Simple models of non-random mating and environmental transmission bias standard human genetics statistical methods
Authors: Border Richard , Wang Jeremy , Caggiano Christa , Sankararaman Sriram , Schork Andrew J , Turley Patrick , Young Alexander S , Benjamin Daniel J , Dahl Andrew W , Zaitlen Noah
Published: October 2024

There is recognition among human complex-trait geneticists that not only are many common assumptions made for the sake of statistical tractability (e.g., random mating, independence of parent/offspring environments) unlikely to apply in many contexts, but that methods reliant on such assumptions can yield misleading results, even in large samples. Investigations of the consequences of violating these assumptions so far have focused on individual perturbations operating in isolation. Here, we analyze widely used estimators of genetic architectural parameters, including LD-score regression and both population-based and within-family GWAS, across a broad array of perturbations to classical assumptions, such as multivariate assortative mating and vertical transmission (parental effects on offspring phenotypes not mediated by genetic inheritance). We find that widely-used statistical approaches are unreliable across a broad range of perturbations, and that structural sources of confounding often operate synergistically to distort conclusions. For example, mild multivariate assortative mating and vertical transmission together can dramatically inflate heritability estimates and GWAS false positive rates. Further, GWAS will become progressively more polluted by off-target associations as sample sizes increase. Given these challenges, we introduce xftsim, a forward time simulation library capable of modeling a wide range of genetic architectures, mating regimes, and transmission dynamics, to facilitate the systematic comparison of existing approaches and the development of robust methods. Together, our findings illustrate the importance of comprehensive sensitivity analysis and present a valuable tool for future research.
Impact of mutations in theHEADING DATE 1gene on transcription and cell wall composition of rice
Authors: Biancucci Marco , Chirivì Daniele , Baldini Alessio , Badenhorst Eugene , Dobetti Fabio , Khahani Bahman , Formentin Elide , Eguen Tenai , Turck Franziska , Moore John P. , Tavakol Elahe , Wenkel Stephan , Schiavo Fiorella Lo , Ezquer Ignacio , Brambilla Vittoria , Horner David , Chiara Matteo , Perrella Giorgio , Betti Camilla , Fornara Fabio
Published: October 2024

Plants utilize environmental information to modify their developmental trajectories for optimal survival and reproduction. Over a century ago, day length (photoperiod) was identified as a major factor influencing developmental transitions, particularly the shift from vegetative to reproductive growth. In rice, exposure to day lengths shorter than a critical threshold accelerates flowering, while longer days inhibit this process. This response is mediated by HEADING DATE 1 (Hd1), a zinc finger transcription factor that is central in the photoperiodic flowering network. Hd1 acts as a repressor of flowering under long days but functions as a promoter of flowering under short days. However, the transcriptional organization of this dual function is still not fully understood. In this study, we utilized RNA-Seq to analyze the transcriptome ofhd1mutants under both long and short day conditions. We identified genes involved in the phenylpropanoid pathway that are deregulated under long days in the mutant. Quantitative profiling of cell wall components and abiotic stress assays suggest that Hd1 is involved in processes considered unrelated to flowering control. This indicates that day length perception and responses are intertwined with physiological processes beyond flowering.
Jasmonic acid signaling and glutathione coordinate plant recovery from high light stress
Authors: Kılıç Mehmet , Gollan Peter J. , Aro Eva-Mari , Rintamäki Eevi
Published: October 2024

High light-induced chloroplast retrograde signaling originates from the photosynthetic apparatus and regulates nuclear gene expression to enhance photoprotection and coordination of cell metabolism. Here, we analyzed the transcript profiles and accumulation of ROS, stress hormones and small molecule antioxidants to investigate the signaling mechanisms operating under HL stress, and in particular during plant recovery under growth conditions. Exposure to high light for 15 min induced a number of1O2- and H2O2-responsive genes and accumulation of an oxidative form of glutathione and ascorbate, the hallmarks of oxidative stress in cells. Prolonged exposure to high light resulted in accumulation of transcripts encoding oxylipin biosynthesis enzymes, leading to accumulation of 12-oxo-phytodienoic acid and jasmonic acid. However, the expression of several jasmonic acid -responsive genes, already induced by HL, peaked during the recovery together with accumulation of jasmonic acid, reduced glutathione and ascorbate, highlighting the critical role of jasmonic acid signaling in restoring chloroplast redox balance following high light stress. The involvement of jasmonic acid signaling in recovery-sustained gene expression was further confirmed by conducting experiments with jasmonic acid receptor mutants. High light exposure of only two min was sufficient to induce some recovery-sustained genes, indicating rapid response of plants to changing light conditions. We propose that ROS production at high light induces the signaling cascade for early oxylipin biosynthesis and 12-oxo-phytodienoic acid accumulation, while increased accumulation of jasmonic acid in recovery-phase activates the genes that fully restore the glutathione metabolism, and ultimately allow recovery from short-term high light stress.
The combination of optogenetic-induced protein aggregation and proximity biotinylation assays strongly implicates endolysosomal proteins in the early stages of α-synuclein aggregation
Authors: Teixeira Maxime , Sheta Razan , Musiol Dylan , Ranjakasoa Vetso , Loehr Jérémy , Lambert Jean-Phillippe , Oueslati Abid
Published: October 2024

Alpha-synuclein (α-syn) aggregation is a defining feature of Parkinson’s disease (PD) and related synucleinopathies. Despite significant research efforts focused on understanding α-syn aggregation mechanisms, the early stages of this process remain elusive, largely due to limitations in experimental tools that lack the temporal resolution to capture these dynamic events. Here, we introduce UltraID-LIPA, an innovative platform that combines the Light-Inducible Protein Aggregation (LIPA) system with the UltraID proximity-dependent biotinylation assay to identify α-syn-interacting proteins and uncover key mechanisms driving its oligomerization. UltraID-LIPA successfully identified 38 α-syn-interacting proteins, including both established and novel candidates, highlighting the accuracy and robustness of the approach. Notably, a strong interaction with endolysosomal and membrane-associated proteins was observed, supporting the hypothesis that interactions with membrane-bound organelles are pivotal in the early stages of α-syn aggregation. This powerful platform provides new insights into dynamic protein aggregation events, enhancing our understanding of synucleinopathies and other proteinopathies.
Federated deep learning enables cancer subtyping by proteomics
Authors: Cai Zhaoxiang , Boys Emma L , Noor Zainab , Aref Adel , Xavier Dylan , Lucas Natasha , Williams Steven G , Koh Jennifer M S , Poulos Rebecca C , Wu Yangxiu , Dausmann Michael , MacKenzie Karen L , Aguilar-Mahecha Adriana , Armengol Carolina , Barranco Maria M , Basik Mark , Bowman Elise D , Clifton-Bligh Roderick J , Connolly Elizabeth A , Cooper Wendy A , Dalal Bhavik , DeFazio Anna , Filipits Martin , Flynn Peter J , Graham J Dinny , George Jacob , Gill Anthony J , Gnant Michael , Habib Rosemary , Harris Curtis C , Harvey Kate , Horvath Lisa G , Jackson Christopher , Kohonen-Corish Maija R J , Lim Elgene , Liu Jia , Long Georgina , Lord Reginald V , Mann Graham J , McCaughan Geoffrey W , Morgan Lucy , Murphy Leigh C , Nagabushan Sumanth , Nagrial Adnan M , Navinés Jordi , Panizza Benedict J , Samra Jaswinder S , Scolyer Richard A , Souglakos Ioannis , Swarbrick Alexander , Thomas David M , Balleine Rosemary L , Hains Peter G , Robinson Phillip J , Zhong Qing , Reddel Roger R
Published: October 2024

Artificial intelligence applications in biomedicine face major challenges from data privacy requirements. To address this issue for clinically annotated tissue proteomic data, we developed a Federated Deep Learning (FDL) approach (ProCanFDL), training local models on simulated sites containing data from a pan-cancer cohort (n=1,260) and 29 cohorts held behind private firewalls (n=6,265), representing 19,930 replicate data-independent acquisition mass spectrometry (DIA-MS) runs. Local parameter updates were aggregated to build the global model, achieving a 43% performance gain on the hold-out test set (n=625) in 14 cancer subtyping tasks compared to local models, and matching centralized model performance. The approach’s generalizability was demonstrated by retraining the global model with data from two external DIA-MS cohorts (n=55) and eight acquired by tandem mass tag (TMT) proteomics (n=832). ProCanFDL presents a solution for internationally collaborative machine learning initiatives using proteomic data, e.g., for discovering predictive biomarkers or treatment targets, while maintaining data privacy.

Statement of Significance

A federated deep learning approach applied to human proteomic data, acquired using two distinct proteomic technologies from 40 tumor cohorts from eight countries, enabled accurate cancer histopathological subtyping while preserving data privacy. This approach will enable privacy-compliant development of large-scale proteomic AI models, including foundation models, across institutions globally.
Noninvasive optical monitoring of cerebral hemodynamics in a preclinical model of neonatal intraventricular hemorrhage
Authors: Jethe Jyoti V. , Shen YuBing Y. , LaGamma Edmund F. , Vinukonda Govindaiah , Fisher Jonathan A. N.
Published: October 2024

Intraventricular hemorrhage (IVH) is a common complication in premature infants and is associated with white matter injury and long-term neurodevelopmental disabilities. Standard diagnostic tools such as cranial ultrasound and MRI are widely used in both preclinical drug development and clinical practice to detect IVH. However, these methods only provide endpoint assessments of blood accumulation and lack real-time information about dynamic changes in ventricular blood flow. This limitation could potentially result in missed opportunities to advance drug candidates that may have protective effects against IVH. In this pilot study, we aimed to develop a noninvasive optical approach using diffuse correlation spectroscopy (DCS) to monitor real-time hemodynamic changes associated with hemorrhagic and sub-hemorrhagic events in a preclinical rabbit model of IVH. DCS measurements were conducted during the experimental induction of IVH, and results were compared with ultrasound and histological analysis to validate findings. Significant changes in hemodynamics were detected in all animals subjected to IVH-inducing procedures, including those that did not show clear positive results on ultrasound. The study revealed progressively elevated coefficients of variation in blood flow, particularly driven by increased oscillations within the 0.05-0.1 Hz frequency band. These hemodynamic changes were more pronounced in animals that developed IVH, as confirmed by ultrasound. Our findings suggest that real-time optical monitoring with DCS can provide critical insights into pathological blood flow changes, offering a more sensitive and informative tool for evaluating potential therapeutics in the context of IVH.
Virological characteristics of the SARS-CoV-2 XEC variant
Authors: Kaku Yu , Okumura Kaho , Kawakubo Shusuke , Uriu Keiya , Chen Luo , Kosugi Yusuke , Uwamino Yoshifumi , Begum MST Monira , Leong Sharee , Ikeda Terumasa , Sadamasu Kenji , Asakura Hiroyuki , Nagashima Mami , Yoshimura Kazuhisa ,   The Genotype to Phenotype Japan (G2P-Japan) Consortium, Ito Jumpei , Sato Kei
Published: October 2024

The SARS-CoV-2 JN.1 variant (BA.2.86.1.1), arising from BA.2.86.1 with spike protein (S) substitution S:L455S, outcompeted the previously predominant XBB lineages by the beginning of 2024. Subsequently, JN.1 subvariants including KP.2 (JN.1.11.1.2) and KP.3 (JN.1.11.1.3), which acquired additional S substitutions (e.g., S:R346T, S:F456L, and S:Q493E), have emerged concurrently. As of October 2024, KP.3.1.1 (JN.1.11.1.3.1.1), which acquired S:31del, outcompeted other JN.1 subvariants including KP.2 and KP.3 and is the most predominant SARS-CoV-2 variant in the world. Thereafter, XEC, a recombinant lineage of KS.1.1 (JN.13.1.1.1) and KP.3.3 (JN.1.11.1.3.3), was first identified in Germany on August 7, 2024. XEC acquired two S substitutions, S:T22N and S:F59S, compared with KP.3 through recombination, with a breakpoint at genomic position 21,738–22,599. We estimated the relative effective reproduction number (Re) of XEC using a Bayesian multinomial logistic model based on genome surveillance data from the USA, the United Kingdom, France, Canada, and Germany, where this variant has spread as of August 2024. In the USA, the Re of XEC is 1.13-fold higher than that of KP.3.1.1. Additionally, the other countries under investigation herein showed higher Re for XEC. These results suggest that XEC has the potential to outcompete the other major lineage including KP.3.1.1. We then assessed the virological properties of XEC using pseudoviruses. Pseudovirus infection assay showed that the infectivity of KP.3.1.1 and XEC was significantly higher than that of KP.3. Although S:T22N did not affect the infectivity of the pseudovirus based on KP.3, S:F59S significantly increased it. Neutralization assay was performed using three types of human sera: convalescent sera after breakthrough infection (BTI) with XBB.1.5 or KP.3.3, and convalescent sera after JN.1 infection. In all serum groups, XEC as well as KP.3.1.1 showed immune resistance when compared to KP.3 with statistically significant differences. In the cases of XBB.1.5 BTI sera and JN.1 infection sera, the 50% neutralization titers (NT50s) of XEC and KP.3.1.1 were comparable. However, we revealed that the NT50 of XEC was significantly (1.3-fold) lower than that of KP.3.1.1. Moreover, both S:T22N and S:F59S significantly (1.5-fold and 1.6-fold) increased the resistance to KP.3.3 BTI sera. Here we showed that XEC exhibited higher pseudovirus infectivity and higher immune evasion than KP.3. Particularly, XEC exhibited more robust immune resistance to KP.3.3 BTI sera than KP.3.1.1. Our data suggest that the higher Re of XEC than KP.3.1.1 is attributed to this property and XEC will be a predominant SARS-CoV-2 variant in the world in the near future.
Embryological cellular origins and hypoxia-mediated mechanisms inPIK3CA-Driven refractory vascular malformations
Authors: Torii Sota , Nagaharu Keiki , Nakanishi Nanako , Usui Hidehito , Hori Yumiko , Hirose Katsutoshi , Toyosawa Satoru , Morii Eiichi , Narushima Mitsunaga , Kubota Yoshiaki , Nakagawa Osamu , Imanaka-Yoshida Kyoko , Maruyama Kazuaki
Published: October 2024

Congenital vascular malformations, affecting 0.5% of the population, often occur in the head and neck, complicating treatment due to the critical functions in these regions. Our previous research identified distinct developmental origins for blood and lymphatic vessels in these areas, tracing them to the cardiopharyngeal mesoderm (CPM), which contributes to the development of the head, neck, and cardiovascular system in both mouse and human embryos.

In this study, we investigated the pathogenesis of these malformations by expressing Pik3caH1047Rin the CPM. Mice expressing Pik3caH1047Rin the CPM developed vascular abnormalities restricted to the head and neck. Single-cell RNA sequencing revealed that Pik3caH1047RupregulatesVegf-aexpression in endothelial cells through HIF-mediated hypoxia signaling. Human samples supported these findings, showing elevated HIF-1α and VEGF-A in malformed vessels. Notably, inhibition of HIF-1α and VEGF-A in the mouse model significantly reduced abnormal vasculature. These results highlight the role of embryonic origins and hypoxia-driven mechanisms in vascular malformations, providing a foundation for the development of therapies targeting these difficult-to-treat conditions.
Statins for Primary Prevention of Cardiovascular Disease in Germany: Benefits and Costs
Authors: Dressel Alexander , Fath Felix , Krämer Bernhard K. , Klose Gerald , März Winfried
Published: October 2024

Background

The reduction of LDL cholesterol lowers the risk of coronary and cerebrovascular events in individuals without manifest cardiovascular diseases. In Germany, statins may only be prescribed at the expense of statutory health insurance for patients with atherosclerosis-related diseases or those at high cardiovascular risk (over 20 percent event probability within the next 10 years, calculated using one of the “available risk calculators”). However, international guidelines recommend lower risk thresholds for the use of statins.

Methods

The health and economic impacts of different risk thresholds for statin use in primary prevention within the German population are estimated for thresholds of 7.5, 10, and 15 percent over 10 years, based on the USPooled Cohort Equation(PCE) which has been validated for Germany, using Markov models.

Findings

Cost-effectiveness increases with a rising risk threshold, while individual benefit decreases with age at the start of treatment. The use of statins at a risk of 7.5 percent or more is cost-effective at any age (cost per QALY between 410 and 2,100 euros). In none of the examined scenarios does the proportion of the population qualifying for statin therapy exceed 25 percent.

Interpretation

Lowering the threshold for statin therapy based on age to a risk of 7.5 percent, estimated with the US PCE, aligns statin prescription with international standards. There is no urgent rationale for applying age-stratified risk thresholds using the SCORE2 proposed for Europe, which tends to underestimate actual risks.
Identification of undetected SARS-CoV-2 infections by clustering of Nucleocapsid antibody trajectories
Authors: Zwerwer Leslie R. , Peto Tim E. A. , Pouwels Koen B. , Walker Ann Sarah ,   the COVID-19 Infection Survey team
Published: October 2024

During the COVID-19 pandemic, numerous SARS-CoV-2 infections remained undetected. Serological testing could potentially aid their identification. We combined results from routine monthly nose and throat swabs, and self-reported positive swab tests, from a UK household survey, linked to national swab testing programme data from England and Wales, together with Nucleocapsid (N-) antibody trajectories clustered using a longitudinal variation of K-means to estimate the number of infections undetected by either approach (N=185,646). After combining N-antibody (hypothetical) infections with swab-positivity, we estimated that 7.4% of all true infections would have remained undetected, 25.8% by swab-positivity-only and 28.6% by trajectory-based N-antibody classifications only. Congruence with swab-positivity was much poorer using a fixed threshold to define N-antibody infections. Additionally, using multivariable logistic regression N-antibody seroconversion was more likely as age increased between 30 and 60 years, in non-white participants, those less (recently/frequently) vaccinated, for lower Ct values in the range above 30, in symptomatic and Delta (vs BA.1) infections. Comparing swab-positivity data sources showed that routine monthly swabs were not sufficient to detect infections by swab-positivity only and incorporating national testing programme/self-reported data substantially increased detection rates. Overall, whilst N-antibody serosurveillance can identify infections undetected by swab-positivity, optimal use requires trajectory-based analysis.
Assessing the adherence of intervertebral disc degeneration clinical trial protocols to SPIRIT guidelines
Authors: Chemorion Francis , Bisotti Marc-Antonio
Published: October 2024

Introduction

Clinical trials are important for advancing medical knowledge and protocols are the core documents that facilitate their appraisal. The SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) checklist offers a framework for standardizing the quality and content of clinical trial protocols. Although there is a high growth in number of clinical trials investigating the efficacy and safety of various therapies, many still exhibit deficiencies in information contained in both their reports and protocols. The main objective for this study were to check the findability of intervertebral disc degeneration (IVD) clinical trial protocols and assessing their adherence to SPIRIT recommendations.

Methods

We included randomized controlled trials (RCTs) that investigated various therapeutic interventions for IVD provided they included a control group and reported at least one relevant clinical outcome. Studies were excluded if they were not recruiting, were observational, case reports, reviews, meta-analyses, editorials, or commentaries, or if they lacked complete data, such as missing results or a protocol. A search was conducted onClinicalTrials.govusing terms related to IVD, covering the period from January 2013 to the present, aligning with the post-SPIRIT recommendation publication period. Data extraction was performed using a reduced SPIRIT checklist to assess adherence to protocol guidelines, with compliance measured across 64 key items. A narrative synthesis was conducted to summarize study characteristics, adherence levels and patterns by intervention and sponsor type.

Results

Adherence rates vary from 28.13% to 98.44% with a median of 48.44%. Heatmaps revealed heterogeneity, highlighting areas of consistent adherence and regions requiring improvement. High adherence was noted in inclusion criteria and outcome measurement, while lower in research ethics and funding declarations. Industry-sponsored studies demonstrated highest adherence in ‘DRUG’ (79.69%) and ‘DEVICE’ (62.50%) categories, while non-industry sponsors were most adherent in ‘BIOLOGICAL’ (50.00%) and ‘OTHER’ intervention categories.

Discussion

Our findings shows a critical need for findability of clinical trial protocols to assist in appraisal of interventions and enhanced adherence to SPIRIT guidelines among IVD clinical trials, for greater transparency and accuracy. Adherence is essential for ensuring high-quality evidence that can inform clinical practice and patient care in managing IVD.
Mental Health Promotion in Victims of Colombian Armed conflict: a Scoping Review
Authors: Ballesteros Lina María González , Mojica Luis Eduardo , Marín Jennifer Clavijo , Ortiz Andrés Felipe , Ponce Mariana Vásquez , Pérez-Lalinde Sofía , Sanabria Nicolas León , Silva Luisa María Carrera , Álvarez Andrea Clavijo
Published: October 2024

Objective

To explore mental health promotion interventions for victims of Colombian armed conflict.

Design

Scoping review.

Methods

Searches were conducted using indexed and free terms regarding mental health promotion interventions for victims of Colombian armed conflict in different databases, including MEDLINE, EMBASE, Scielo, Cochrane Central Register of Controlled Trials, LiLACS, Google Scholar, and PsycArticles. We included primary and secondary research sources, including clinical trials, randomized controlled trials, qualitative research, online journals, meta-analyses, scoping reviews, and systematic reviews, as well as government reports and articles about implementing mental health promotion strategies for victims of Colombian armed conflict.

Results

Our search returned 317 identified articles through database exploration. Four more articles were included through literature research and another four records were included through gray literature and government reports. Retrieved citations were screened using Rayyan QCRI. A total of 259 records were left after duplicate removal. Members of the group then performed a paired-blind screening, which left us with 16 articles to be included in the analysis. Data analysis was conducted by authors in pairs using custom tools developed by the research team. After reviewing the articles, only six met the inclusion criteria established for this scoping review. Among these, two of the interventions addressed were randomized clinical trials that demonstrated effects on depression, anxiety, and post-traumatic stress disorder (PTSD). Additionally, one of these trials assessed impairments in functionality.

Conclusion

A total of six articles demonstrated the effectiveness of mental health promotion and primary prevention interventions in Colombian victims of armed conflict. However, only two of the studies were randomized clinical trials, and methodological limitations were evident, including loss in sample follow-up, challenges in comparing populations, and use of non-standardized scales across different studies. This hinders the possibility of a unified assessment of these interventions and highlights the need for bigger study samples and use of tools that facilitate access to programs and one-year follow-ups to enhance interventions government organizations employ to address these mental health needs.
The impact of health-system pharmacists on hospitalizations in heart failure: a systematic review and meta-analysis
Authors: Van der Linden Lorenz , Beavers Craig , Forsyth Paul , Vandenbriele Christophe , Tsuyuki Ross T. , Karapinar-Carkıt Fatma , Van Aelst Lucas
Published: October 2024

Background

Previous evidence has established the role of pharmacists in heart failure (HF) care. However, the specific role of health-system pharmacists within in- and outpatient settings for HF patients has been left unexplored. This systematic review and meta-analysis aimed to evaluate the impact of health-system pharmacy interventions on all-cause and HF hospitalizations.

Methods

A systematic literature search was performed using PUBMED and EMBASE, following PRISMA guidelines. Randomized controlled trials (RCTs) published up to May 2024 that evaluated the effects of health-system pharmacy interventions on hospitalizations in HF patients were included. The quality of the included RCTs was assessed using Cochrane’s risk-of-bias tool. Meta-analyses were performed using random-effects models, with odds ratios (OR) as summary measure. Heterogeneity was assessed using the I2statistic and Cochrane’s Q test.

Results

In total, 11 RCTs involving 3576 patients were included in our review. The meta-analysis of 9 RCTs assessing all-cause hospitalizations (3472 patients, 927 events) demonstrated a significant reduction with pharmacist care (OR 0.67, 95% CI: 0.49–0.92, p=0.0119). The second meta-analysis of also 9 RCTs, focusing on HF hospitalizations (3442 patients, 504 events), showed similar results (OR 0.64, 95% CI: 0.48–0.87, p=0.0038). Heterogeneity was moderate for both meta-analyses. Sensitivity analyses confirmed the robustness of the results. Subgroup analyses indicated greater effectiveness in outpatient settings and for extended interventions.

Conclusions

Health-system pharmacist interventions significantly reduce both all-cause and HF-specific hospitalizations in HF patients. Our findings highlight the importance of integrating pharmacists into multidisciplinary teams to improve HF management for in- and outpatients (PROSPERO: CRD42024593583).
TamL is a key player of the outer membrane homeostasis in Bacteroidetes
Authors: Giovannercole Fabio , de Smet Tom , Vences-Guzmán Miguel Angel , Lauber Frédéric , Dugauquier Rémy , Dieu Marc , Lizen Laura , Dehairs Jonas , Lima-Mendez Gipsi , Guan Ziqiang , Sohlenkamp Christian , Renzi Francesco
Published: October 2024

In Proteobacteria, the outer membrane protein TamA and the inner membrane-anchored protein TamB form the Translocation and Assembly Module (TAM) complex, which facilitates the transport of autotransporters, virulence factors, and likely lipids across the two membranes.

In Bacteroidetes TamA is replaced by TamL, a TamA-like lipoprotein with a lipid modification at its N-terminus that likely anchors it to the outer membrane. This structural difference suggests that TamL may have a distinct function compared to TamA. However, the role of TAM in bacterial phyla other than Proteobacteria remains unexplored.

Our study aimed to elucidate the functional importance of TamL inFlavobacterium johnsoniae, an environmental Bacteroidetes. Unlike its homologues in Proteobacteria, we found that TamL and TamB are essential inF. johnsoniae. Through genetic, phenotypic, proteomic, and lipidomic analyses, we discovered that TamL depletion severely compromises outer membrane integrity, as evidenced by reduced cell viability, altered cell shape, increased susceptibility to membrane-disrupting agents, and elevated levels of outer membrane lipoproteins. Notably, we did not observe any impact on outer membrane lipid composition.

Via pull-down protein assays, we confirmed that TamL interacts with TamB inF. johnsoniae, likely forming the TAM complex. Furthermore, ourin silicoanalysis revealed that the presence of TamL and TamB monocistronic genes is a shared genetic feature among Bacteroidetes members, including the human pathogenCapnocytophaga canimorsuswhere we also confirmed the essentiality of the TamL and TamB homologs.

To our knowledge, this study is the first to provide functional insights into a TAM subunit beyond Proteobacteria.

Significance

In Proteobacteria, the outer membrane (OM) protein TamA forms with the inner membrane (IM)-anchored protein TamB the Translocation and Assembly Module Complex (TAM). which contributes to efficient biogenesis of the OM. In Bacteroidetes TamA is replaced by TamL, a TamA-like lipoprotein of unknown role. In this work, we studied TamL in the BacteroidetesFlavobacterium johnsoniae. We found that TamL and TamB are essential for cell viability, and that TamL depletion disrupts outer membrane stability, increases outer membrane vesicle size, and lead to higher sensitivity to OM stressors. These findings highlight TamL critical role in maintaining OM structure in Bacteroidetes. To our surprise, we also identified multiple TamL, TamB and TamA homologs in Bacteroidetes. Altogether, our findings extend the current knowledge on TAM and provide novel insights into a field of research barely investigated outside Proteobacteria.
Fluorescent anionic cyanine plasma membrane probes for live cell andin vivoimaging
Authors: Danylchuk Dmytro I. , Khalin Igor , Suseela Yelisetty V. , Filser Severin , Plesnila Nikolaus , Klymchenko Andrey S.
Published: October 2024

Proper staining of cell plasma membrane is indispensable for fluorescence imaging. Herein, we present an array of five anionic cyanine-based turn-on plasma membrane probes with emission spanning from green to near infrared. They are analogous of commonly used MemBright probes family, where two zwitterionic anchor groups are replaced with anionic sulfonates with dodecyl chains. The developed probes provide selective wash-free staining of plasma membranes of live cells in vitro, featuring improved brightness and slower internalization inside the cells. In comparison to protein-based (wheat germ agglutinin) membrane markers, new membrane probes provide better staining in poorly assessable cell-cell contacts. A key challenge is to stain cell plasma membranes directly in vivo. Duringin vivobrain tissue imaging in living mice by two-photon microscopy, the anionic cyanine probes allowed us to visualize in detail the pyramidal neurons with high image quality, clearly resolving neuron soma, dendrites with dendritic spines and axons with axonal boutons. The developed anionic cyanine-based plasma membrane probes constitute an important extension of the toolbox of fluorescent probes for plasma membrane research.
Agent-Based Simulation of Cortical Microtubule Band Movement in theArabidopsisZygote
Authors: Nonoyama Tomonobu , Kang Zichen , Matsumoto Hikari , Nakagawa Sakumi , Ueda Minako , Tsugawa Satoru
Published: October 2024

Arabidopsis thalianazygotes form a circumferential cortical microtubule (CMT) band that stays at a constant position from the growing tip. CMT bands support zygote anisotropic growth that is essential to determine the apical-basal axis of the plant body, but how stable CMT bands are maintained remains unclear. We hypothesized that cell surface tension induces CMT reorientation of which the strength was defined as the directional cue (DC). We constructed an agent-based simulation model using the DC and its spatial distribution (DC zone) to determine the range of molecular parameters and the width and movement speed of the DC zone required to form the CMT band. We then developed a data–model correspondence method to determine the range of the parameters which are difficult to observe experimentally. We determined that the DC zone must move with an appropriate speed of mechanical change may exist to form a moving CMT band.
Abstract choice representations during stable choice-response associations
Authors: Quinn Katrina R. , Sandhaeger Florian , Noury Nima , Žeželić Ema , Siegel Markus
Published: October 2024

Perceptual decisions have long been framed in terms of the actions used to report a choice. Accordingly, studies of perceptual decision-making have historically relied on tasks with fixed choice-response mappings, in which choice and motor response are inextricably linked. Although several studies have since dissociated choice and response, they have typically involved dynamic switching of the choice-response mapping on a trial-by-trial basis. Thus, it remains unclear if abstract choice representations arise specifically when choice-response relationships change dynamically, or if they reflect a more general property of the decision-making process. Here, we show that in the human brain, choices are represented abstractly, even when the association between choice and motor response remains stable over time. We measured neural activity in humans using magnetoencephalography (MEG) while participants performed a motion discrimination task. Importantly, the associations between perceptual choice and motor response were balanced across experimental conditions and remained stable over many trials. We found neural information about the participants’ perceptual choice, independent of both the motor response and the visual stimulus. This abstract choice information increased during the stimulus period and peaked after the response had been made. Furthermore, choice and response information showed distinct cortical distributions, with strongest choice information in frontoparietal regions. Our results suggest that abstract choice representations are not restricted to action-independent contexts or those with dynamic choice-response associations and may therefore reflect a general role in perceptual decision-making.
Nanomaterials trigger functional responses in primary human immune cells
Authors: Mittelheisser Vincent , Lefebvre Olivier , Banerjee Mainak , Ghosh Shayamita , Dupas Amandine , Diringer Marie-Charlotte , Blumberger Juliette , Bochler Louis , Harlepp Sébastien , Larnicol Annabel , Pichot Angélique , Stemmelen Tristan , Molitor Anne , Moritz Chloé , Carapito Christine , Carapito Raphaël , Charbonnière Loïc J. , Lux François , Tillement Olivier , Goetz Jacky G. , Detappe Alexandre
Published: October 2024

Targeting the immune system with nanoparticles (NPs) to deliver immunomodulatory molecules emerged as a solution to address intra-tumoral immunosuppression and enhance therapeutic response. While the potential of nanoimmunotherapies in reactivating immune cells has been evaluated in several preclinical studies, the impact of drug-free nanomaterials on the immune system remains unknown. Here, we characterize the molecular and functional response of human NK cells and pan T cells to a selection of five NPs that are commonly used in biomedical applications. After a pre-screen to evaluate the toxicity of these nanomaterials on immune cells, we selected ultrasmall silica-based gadolinium (Si-Gd) NPs and poly(lactic-co-glycolic acid) (PLGA) NPs for further investigation. Bulk RNA-sequencing and flow cytometry analysis showcase that PLGA NPs trigger a transcriptional priming towards activation in NK and pan T cells. While PLGA NPs improved NK cells anti-tumoral functions in cytokines-deprived environment, Si-Gd NPs significantly impaired T cells activation as well as functional responses to a polyclonal antigenic stimulation. Altogether, we identified PLGAs NPs as suitable and promising candidates for further targeting approaches aiming to reactivate the immune system of cancer patients.