bluuebunny/crossref_metadata_2025 huggingface dataset:
Cylicodiscus gabunensis(FABACEAE) aqueous stem bark extract mediated silver nanoparticle enhance anti-inflammation on Wistar rats
Authors: Meva Francois Eya’ane , Mponge Pamela Nguadie , Koube Juliette , Nyuyfoni Gildas Fonye , Hzounda Fokou Jean Baptiste , Ntoumba Agnes Antoinette , Yen Beglau Thi Hai , Tako Djimefo Alex Kevin , Djuidje Annie Guilaine , Tchatchouang Geordamie Chimi , Wounang Ariane Laure , Danielle Evouna Madeleine Ines , Chameni Nkouankam Maeva Jenna , Dada Youte Yolaine Pamela , Ndotti Hassana Moussa , Ebanda Kedi Philippe Belle , Bertin Sone Enone , Janiak Christoph
Published: December 2024

Introduction

Plants are a source of bioactive ingredient that can play a key role in development of new drugs. In recent years, plant mediated-biological synthesis of nanoparticles has gained importance due to its simplicity, cost effectiveness and eco-friendly nature. To the best of our readings, nanoparticule fromCylicodiscus gabunensisstem bark is still untaped. This work therefore aimed at assessing the anti-inflammatory properties of the silver nanoparticles obtained from the aqueous extract of the stem bark ofCylicodiscus gabunensis(Cg).

Methodology

Cylicodiscus gabunensisextract was prepared by infusion-followed by the biosynthesis of silver nanoparticles. The synthesis was monitored by color and UV-Vis spectrophotometry. Infrared spectroscopy aimed at revealing the functional groups present at the surface of the nanoparticles. Structural elucidation was done by powder X-ray crystallography, while microstructure and elemental mapping was performed with scanning electron microscopy and energy dispersive X-ray spectroscopy. In vitro anti-inflammatory test was done using the BSA denaturation based test. The acute toxicity was done using the OEDC 425 guideline. carrageenan-induced rat paw oedema model was used to ascertain thein vivoanti-inflammatory effects.

Results

Phytochemical screening of the aqueous extract ofCylicodiscus gabunensisrevealed the presence of polyphenols, flavonoids, alkaloids, coumarins, saponins, triterpenes, steroids, reducing sugar, tannins, and the absence of anthraquinone. The surface Plasmon resonance peak in the UV-Vis spectrum shows absorption spectra between 380 and 550 nm. Stability studies done over time showed that the nanoparticles were stable even after two months of synthesis. IR spectroscopy revealed the presence of O-H, N-H, C≡C, C=C, C-O, and C=O groups. PXRD confirms the formation of silvernanoparticles (AgNPs) while nanograins of various forms were visualized by SEM and EDX. No toxic sign was observed. The maximum inhibitory percentages were 95% at 200 µg/mL and 91% at 400 μg/Kg forin vitroandin vivoanti-inflammatory effects, respectively.

Conclusion

This paper spot the light on silver nanoparticle fromCylicodiscus gabunensisaqueous stem bark for their anti-inflammatory effect on paw oedema model.
Rare habitats, rare species, and invasive predators highlight management complexities in the Colorado River system
Authors: Hossack Blake R. , Stemp Kenzi M. , Goldberg Caren S. , Duke Alexandra C. K. , Preston Taryn N. , Arnold Jeff L. , Ray Andrew M.
Published: December 2024

Long-term drought caused Lake Powell, a reservoir on the Colorado River (USA), to decline to its lowest elevation in >50 years during 2022–2023, allowing warm water to pass through intakes of Glen Canyon Dam and facilitating invasion by non-native Smallmouth Bass (Micropterus dolomieu). Establishment of bass downstream of the dam could threaten persistence of several native fishes, including two federally listed species. Subsequent detection of larval Smallmouth Bass in a spring-fed slough (river mile -12 slough) connected to the river in Glen Canyon National Recreation Area (NRA) increased urgency to stem further invasion. The National Park Service is evaluating proposed actions to limit effects from non-native predators on native species in the Colorado River, including potentially channelizing the slough. This locally rare, spring-fed waterbody provides habitat for other species, including Western Tiger Salamanders (Ambystoma mavortiumsubsp.) of uncertain origin. We found salamanders from the slough had two distinct mitochondrial DNA haplotypes identical to sequences from nearby Arizona Tiger Salamander (A. m. nebulosum) populations, confirming they are the native genotype. We detected Red-spotted Toads (Anaxyrus punctatus) and Woodhouse’s Toads (A. woodhousii) from three other sites in Glen Canyon NRA and 34 sites in adjacent, downstream Grand Canyon National Park (spanning ∼464 km of river) with environmental DNA and traditional surveys. However, we did not detect salamanders elsewhere, matching prior information that salamanders are rare in the Colorado River corridor below Glen Canyon Dam. Based on this information, we discuss management options for the local population of Arizona Tiger Salamanders.
dsRNAmax: a Multi-Target Chimeric dsRNA Designer for Safe And Effective Crop Protection
Authors: Fletcher Stephen J , Lawrence Jai , Sawyer Anne , Manzie Narelle , Gardiner Donald , Mitter Neena , Brosnan Christopher
Published: December 2024

Crop protection is undergoing significant evolution, transitioning toward sustainable approaches that minimise impacts on the environment and human health. Exogenous application of double-stranded RNA (dsRNA) that silences pest or pathogen genes via RNAi (RNA interference) has promise as a safe and effective next generation crop protection platform without the need for genetic modification. However, exogenous dsRNA application at scale presents challenges. Specifically, a single dsRNA sequence needs to balance targeting the standing variation in a target pest or pathogen group against the potential for adverse impacts in a vast array of non-target and beneficial organisms at the application site and broader environment. To address these competing demands, we present dsRNAmax (https://github.com/sfletc/dsRNAmax), a software package that employsk-mer based assembly of chimeric dsRNA sequences to target multiple related RNA sequences, to broaden the target spectrum. The package ensures designed dsRNAs have no defined contiguous sequence homology with any off-target sequences, which can range from single transcriptomes through to metagenome sequence data and beyond. The efficacy of this package is demonstrated by a dsRNAmax-designed dsRNA that inhibits multiple root-knot nematode species but not a non-target nematode species, despite its susceptibility to environmental RNAi and high homology of the target gene.

GRAPHICAL ABSTRACT
ChatGPT as a decision-support tool for better self-monitoring of hearing
Authors: Pastucha Małgorzata , Ratuszniak Anna , Ganc Małgorzata , Piłka Edyta , Drohobycka Iryna , Skarżyński Henryk , Jedrzejczak W. Wiktor
Published: December 2024

Background

The rapid development of large language model chatbots, such as ChatGPT, has created new possibilities for healthcare support. This study investigates the feasibility of integrating self-monitoring of hearing (via a mobile app) with ChatGPT’s decision-making capabilities to assess whether specialist consultation is required. In particular, the study evaluated how ChatGPT’s accuracy to make a recommendation changed over periods of up to 12 months.

Methods

ChatGPT-4.0 was tested on a dataset of 1,000 simulated cases, each containing monthly hearing threshold measurements over periods of up to 12 months. Its recommendations were compared to the opinions of 5 experts using percent agreement and Cohen’s Kappa. A multiple-response strategy, selecting the most frequent recommendation from 5 trials, was also analyzed.

Results

ChatGPT aligned strongly with the experts’ judgments, with agreement scores ranging from 0.80 to 0.84. Accuracy scores improved to 0.87 when the multiple-query strategy was employed. In those cases where all 5 experts unanimously agreed, ChatGPT achieved a near-perfect agreement score of 0.99. It adapted its decision-making criteria with extended observation periods, seemingly accounting for potential random fluctuations in hearing thresholds.

Conclusions

ChatGPT has significant potential as a decision-support tool for monitoring hearing, able to match expert recommendations and adapting effectively to time-series data. Existing hearing self-testing apps lack capabilities for tracking and evaluating changes over time; integrating ChatGPT could fill this gap. While not without its limitations, ChatGPT offers a promising complement to self-monitoring. It can enhance decision-making processes and potentially encourage patients to seek clinical expertise when needed.

Graphical abstract
Maladaptive response of an endemic California oak to climatic warming is previewed by interannual variation in growth and survival
Authors: Goetz Alexander R. B. , Ochoa Marissa E. , Wright Jessica W. , Sork Victoria L.
Published: December 2024

Climate change poses a major threat to long-lived tree populations by shifting environmental conditions away from those to which species are adapted. One of the biggest concerns is that individuals that are adapted to current conditions will become maladapted to new conditions due to a reduction in fitness. If tree populations are already maladapted to their current environments, climate change may put them at even greater risk. Valley oak (Quercus lobata), a foundational California endemic tree species, has already lost much of its range to anthropogenic activities and has been shown to demonstrate patterns of climatic maladaptation. Given the rapid pace of climate change, predicting the future of a species requires quantifying the extent to which contemporary populations are adapted or maladapted to current climates. Here, we tested the extent and variability of maladaptation in valley oak using a ten-year, range-wide provenance study of 3,371 half-sib juvenile trees from 658 maternal lineages. We compared growth rates and multiplicative fitness functions (height * survival; MFF) across families sourced from sites with differing climates relative to the gardens, as well as against annual phenological records. We found evidence that valley oak trees are most adapted to temperatures beyond the coolest limit of the current species range. Within and across years, trees sourced from hotter localities had higher growth and fitness in the gardens, and the relationship was more pronounced in hotter years. Trees showed persistent maladaptation after ten years, suggesting that the role of phenotypic plasticity in immediate environmental response is superseded by underlying genotypes. Finally, trees with earlier leaf phenology (associated with warmer source climates) consistently showed higher growth rates, further demonstrating a maladaptive pattern. Our results suggest that short-term variation in fitness shows immediate short-term response to climate warming, “previewing” a concerning range of species-level responses to increasing temperature.
Human RNase H2 upregulation counteracts oncogene- and chemotherapy-induced replication stress
Authors: Wilkins Rosanna J. , Kannan Abirami , Plass Siobhan A. , Wilson Claire , Kelly Richard D. W. , Tang Claire H. M. , Kotsantis Panagiotis , Reijns Martin A. M. , Kanhere Aditi , Petermann Eva
Published: December 2024

RNase H2 is a heterotrimeric endoribonuclease that resolves RNA:DNA hybrids and genome-embedded ribonucleotides, which are implicated in DNA replication stress and cancer development. Protein and/or mRNA levels of individual RNase H2 subunits are elevated in some cancers, but little is known about the mechanisms or consequences of RNase H2 upregulation. We report that RNase H2 subunits are upregulated at the protein level in response to replication stress induced by oncogenes and chemotherapy drugs in human cancer and non-cancer cell lines. We show that inducible overexpression of the RNASEH2B subunit increases levels of the active RNase H2 heterotrimer. While causing only subtle changes to gene expression, RNASEH2B overexpression is unexpectedly associated with increased RNA:DNA hybrid levels. RNASEH2B overexpression prevents further increases in RNA:DNA hybrid levels by camptothecin or hydroxyurea and reduces replication fork stalling in presence of these drugs. Surprisingly, RNase H2 levels do not strongly impact survival of chemotherapy treatments but appear to have more subtle effects on genome instability and innate immune signalling. In contrast, increased RNase H2 levels in presence of oncogenic HRAS limit not only RAS-induced replication fork stalling but also cell death. Our findings shed new light on the functions of RNase H2 and suggest that upregulation of RNase H2 may be an important aspect of replication stress responses in cancer.
Efficient microbial glucose-fructose conversion at ambient temperature through adaptive laboratory evolution and application for D-allulose production
Authors: Lehnert Alexander , Gentile Rocco , Tahiraj Claudia , Wirtz Astrid , Baumgart Meike , Polen Tino , Gohlke Holger , Bott Michael
Published: December 2024

Glucose and fructose, the major monosaccharides in nature, are metabolically interconverted in phosphorylated form by glucose 6-phosphate isomerase. An enzyme specifically evolved for interconversion of the non-phosphorylated forms has not been discovered yet. Xylose isomerase catalyzes the conversion as a side reaction, but with very low activity at ambient temperatures. Here, we developed a microbial catalyst enabling the efficient interconversion of glucose and fructose at 30°C. Using adaptive laboratory evolution (ALE) of a selection strain dependent on xylose isomerase activity for growth, we obtained enzyme variants with up to ten-fold improved catalytic efficiency. Fast growth additionally required a mutation in the transporter IolT1, boosting sugar uptake and increasing the intracellular substrate concentration. During engineering of a strain unable to grow on glucose, we identified mutations in the sucrose transporter PtsS, presumably converting it into a transporter for glucose and fructose. Molecular dynamics simulations of the transporter and xylose isomerase variants suggested mechanistic consequences of the mutations. Our novel strains enabled the microbial conversion of glucose to the low-calorie sweetener D-allulose with a yield of 15%.

Graphical abstract
High-dimensional mediation analysis to elucidate the role of metabolites in the association between PFAS exposure and reduced SARS-CoV-2 IgG in pregnancy
Authors: Guan Haibin , Chen Jia , Kaur Kirtan , Amreen Bushra , Lesseur Corina , Dolios Georgia , Andra Syam S. , Narasimhan Srinivasan , Pulivarthi Divya , Midya Vishal , De Witte Lotje D. , Bergink Veerle , Rommel Anna-Sophie , Petrick Lauren M.
Published: December 2024

Objective

We previously found that per- and polyfluoroalkyl substances (PFAS) mixture exposure is inversely associated with SARS-CoV-2 IgG (IgG) antibody levels in pregnant individuals. Here, we aim to identify metabolites mediating this relationship to elucidate the underlying biological pathways.

Methods

We included 59 pregnant participants from a US-based pregnancy cohort. Untargeted metabolomic profiling was performed using Liquid Chromatography-High Resolution Sass spectrometry (LC-HRMS), and weighted Quantile Sum (WQS) regression was applied to assess the PFAS and metabolites mixture effects on IgG. Metabolite indices positively or negatively associated with IgG levels were constructed separately and their mediation effects were examined independently and jointly.

Results

The PFAS-index was negatively associated with IgG levels (beta=-0.273, p=0.002), with PFHpS and PFHxS as major contributors. Two metabolite-indices were constructed, one positively (beta=1.260, p<0.001) and one negatively (beta=-0.997, p<0.001) associated with IgG. Key contributors for these indices included protoporphyrin, 5-hydroxytryptophan, n-acetylproline, and tyrosine. Analysis of single mediator showed that 48.9% (95%CI: 21.9%,125.0%) and 50.1% (95% CI: 8.1%, 90.1%) of the PFAS index-IgG total effect were mediated by the negative and positive metabolite-indices, respectively. Joint analysis of the metabolite-indices indicated a cumulative mediation effect of 73.6% (95%CI: 44.9%, 116.4%). Enriched pathways associated with these metabolites indices were phenylalanine, tyrosine, and tryptophan biosynthesis and arginine metabolism.

Conclusions

We observed significant mediation effects of plasma metabolites on the PFAS-IgG relationship, suggesting that PFAS disrupts the balance of plasma metabolites that contributes to reduced plasma IgG production.
Cell cycle-regulated transcriptional pausing ofDrosophilareplication-dependent histone genes
Authors: Kemp James P. , Geisler Mark S. , Hoover Mia , Cho Chun-Yi , O’Farrell Patrick H. , Marzluff William F. , Duronio Robert J.
Published: December 2024

Coordinated expression of replication-dependent (RD) histones genes occurs within the Histone Locus Body (HLB) during S phase, but the molecular steps in transcription that are cell cycle regulated are unknown. We report thatDrosophilaRNA Pol II promotes HLB formation and is enriched in the HLB outside of S phase, including G1-arrested cells that do not transcribe RD histone genes. In contrast, the transcription elongation factor Spt6 is enriched in HLBs only during S phase. Proliferating cells in the wing and eye primordium express full-length histone mRNAs during S phase but express only short nascent transcripts in cells in G1 or G2 consistent with these transcripts being paused and then terminated. Full-length transcripts are produced when Cyclin E/Cdk2 is activated as cells enter S phase. Thus, activation of transcription elongation by Cyclin E/Cdk2 and not recruitment of RNA pol II to the HLB is the critical step that links histone gene expression to cell cycle progression inDrosophila.
Clinical and Biological Stratification in 121,560 Antidepressant Prescription Trajectories using Unsupervised Modelling and Clustering
Authors: Herrero-Zazo Maria , Fitzgerald Tomas , Banasik Karina , Louloudis Ioannis , Vassos Evangelos , Colón-Ruiz Critóbal , Segura-Bedmar Isabel , Kessing Lars V. , Ostrowski Sisse R. , Pedersen Ole B. , Schork Andrew J. , Sørensen Erik , Ullum Henrik , Werge Thomas M. , Bruun Mie T. , Christoffersen Lea AN. , Didriksen Maria , Erikstrup Christian , Aagaard Bitten , Mikkelsen Christina ,   DBDS Genomic Consortium, Lewis Cathryn M. , Brunak Søren , Birney Ewan
Published: December 2024

Major depressive disorder is a complex condition with diverse presentations and polygenic underpinnings. Leveraging large biobanks linked to primary care prescription data, we developed a data-driven approach based on antidepressant prescription trajectories for patient stratification and novel phenotype identification. We extracted quantitative prescription trajectories for 56,951 UK Biobank (UKB) and 64,609 Danish National Biobank (CHB+DBDS) individuals. Using Hidden Markov Models and K-means clustering, we identified five and six patient clusters, respectively. Multinomial logistic regression and non-parametric association tests, using clinical information, enabled patient group characterization. We consistently identified three common patient groups across cohorts: first, a majority group of individuals with mild to moderate depression; second, those with severe mental illness (i.e., a group with a higher likelihood of psychiatric diagnoses, such as bipolar depression, with odds ratios: ORUKB= 1.87 [95% CI = 1.48, 2.35], p = 2.7e-6; ORCHB+DBDS= 1.69 [95% CI = 1.41, 2.02], p = 2.3e-7); and third, patients with less severe forms of depression or receiving treatment for conditions other than depression (i.e., a group with a lower likelihood of depression diagnosis: ORUKB= 0.80 [95% CI = 0.74, 0.85], p = 3e-10; ORCHB+DBDS= 0.77 [95% CI = 0.73, 0.82], p < 1e-10). Genome-wide association studies (GWAS) revealed 14 significant loci, includingUSP4andBCHEon chromosome 3, as well as a locus associated with the drug metabolising enzymeCYP2D6. These findings, and the reproducibility across cohorts, demonstrate the power of unsupervised phenotyping from primary care prescriptions for patient stratification and pharmacogenetics research.
Population comparisons reveal more social interactions are correlated with larger brains in the Lake Tanganyikan cichlidNeolamprologus brevis
Authors: Ma Bin , Dunster Boyd , Lein Etienne , Zhu Boshan , Li Weiwei , Goverts Zoë , Jordan Alex
Published: December 2024

The Social Brain Hypothesis (SBH) proposes that complex social environments drive the evolution of larger brains and specific neuroanatomical adaptations. This relationship can be difficult to study in the wild, because species that differ in social organization may also diverge in morphology, ecology, phylogeny, and other life history parameters. Here we use two populations of the shell-dwelling cichlidNeolamprologus breviswith contrasting social environments to test whether increased social complexity is associated with larger brain sizes or specific regional adaptations. Behavioral observations revealed similarly low feeding rates in both populations, but significantly more frequent social interaction frequencies in the population one of the populations. This population had larger total brain volumes relative to body size, with a disproportionately larger telencephalon and a smaller hypothalamus, suggesting region-specific adaptations to social demands. By integrating behavioral quantification and neuroanatomical analysis, our study highlights the importance of sociality as a driver of brain evolution and demonstrates the utility of cichlid fish as a model for testing the SBH in non-mammalian systems. These findings provide empirical support for the SBH and underscore the value of combining behavioral and morphological data in evolutionary neuroethology.
Global Stability and Tipping Point Prediction of the Coral Reef Ecosystem
Authors: Xu Li , Patterson Denis , Levin Simon Asher , Wang Jin
Published: December 2024

Coral reefs are highly diverse and important marine ecosystems, with the potential for multiple stable states and critical transitions between alternative states. Using landscape-flux theory, we explore the dynamics of these systems in the face of stochastic perturbations. We quantified the average flux as the non-equilibrium driving force and the entropy production rate as the nonequilibrium thermodynamic cost. We also compute the nonequilibrium free energy and time irreversibility from the cross-correlation functions as early warning signals for critical transitions. These early warning signals, characterized by turning points in the middle of two bifurcations, can provide predictions for both left and right bifurcations, much earlier than critical slowing down, a more traditional indicator that is evident only closer to the bifurcation point(s).
Small molecule activation of the tumor suppressor kinase LKB1
Authors: Kretschmer Lin Song , Mitchell Dominique C. , Liu Jin , Wang LeeAnn , Wang Zheng , He Changliang , Ding Luo , Adler Marc , Turnham Rigney E. , Kellett Timothy , Keith Aidan , Hwang Yeonjoo C. , Chan Gary K. L. , Li Weicheng , Ramamoorthi Roopa , Lively Sarah , Drakas Robert A. , Ramani Vijay , Qing Tingting , Verba Kliment A. , Ostrem Jonathan M. L. , Beresis Richard T. , Gordan John D.
Published: December 2024

The ability to identify and target oncogenic signals has transformed clinical oncology. Drug development for targeted therapies has historically focused on the inhibition of oncogenic kinases and GTPases. However, many cancer patients do not benefit from targeted approaches because their tumors lack targetable mutations. Therapeutic augmentation of tumor suppressive signaling could be a viable alternative but poses challenges. Specifically, designing compounds capable of stimulating kinase activity is more structurally challenging than inhibitor design, and most kinases lack targetable allosteric pockets. Inactivation of the liver kinase B1 (LKB1) tumor suppressor kinase is associated with poor prognosis and therapeutic resistance. Thus, augmented LKB1 function could be beneficial for cancer patients whose tumors retain intact copies of the gene. LKB1 signals as part of an obligate trimer including the scaffolding protein Mouse protein-25 (MO25) and the pseudokinase (PSK) STE20-related kinase adapter protein (STRAD). As STRAD binds but does not metabolize ATP, it provides the opportunity for a novel activation strategy. We have developed STRAD-binding compounds capable of activating LKB1 and demonstrate the therapeutic benefits of LKB1 activation in a target-dependent manner within cancer cell lines.
Improving whole biodiversity monitoring and discovery with environmental DNA metagenomics
Authors: Curto Manuel , Veríssimo Ana , Riccioni Giulia , Santos Carlos D. , Ribeiro Filipe , Jentoft Sissel , Alves Maria Judite , Gante Hugo F.
Published: December 2024

Environmental DNA (eDNA) metagenomics sequences all DNA molecules present in environmental samples and has the potential of identifying virtually any organism from which they are derived. However, due to unacceptable levels of false positives and negatives, this approach is underexplored as a tool for biodiversity monitoring across the tree of life, particularly for non-microscopic eukaryotes. We present SEQIDIST, a framework that combines multilocus BLAST matches against several reference databases followed by analysis of sequence identity distribution patterns to disentangle false positives while revealing new biodiversity and increasing the accuracy of metagenomic approaches. We tested SEQIDIST on an eDNA metagenomic dataset from a riverine site and compare the results to those obtained with an eDNA metabarcoding approach for benchmarking purposes. We start by characterizing the biological community (∼ 2000 taxa) across the tree of life at low taxonomic levels and show that eDNA metagenomics has a higher sensitivity than eDNA metabarcoding in discovering new diversity. We show that limited representation of whole genome sequences in reference databases can lead to false positives. For non-microscopic eukaryotes, eDNA metagenomic data often consist of a few sparse, anonymous sequences scattered across the genome, making metagenome assembly methods unfeasible. Finally, we infer eDNA source and residency time using read length distributions as a measure of decay status. The higher accuracy of SEQIDIST opens the discussion of the archival potential of eDNA metagenomics and its implementation in biodiversity monitoring actions at large planetary and temporal scales.
Fitness translocation: improving variant effect prediction with biologically-grounded data augmentation
Authors: Mialland Adrien , Fukunaga Shuzo , Katsuki Riku , Dong Yunfei , Yamaguchi Hideki , Saito Yutaka
Published: December 2024

Navigating the protein fitness landscape is critical for understanding sequence-function relationships and improving variant effect prediction. However, the limited availability of experimentally measured functional data poses a significant bottleneck. To address this, we present a novel data augmentation strategy called fitness translocation, which leverages fitness landscapes from related proteins to enhance the performance of variant effect predictors on a target protein. Using embeddings from protein language models and by translocating the features within the sequence space, we transfer the fitness information from homologous protein datasets to a target protein to augment its dataset. Our approach was evaluated across diverse protein species, including IGPS orthologs, GFP orthologs, and SARS-CoV-2 spike proteins strains for cell entry and ACE2 binding. The results demonstrate consistent and substantial improvements in predictive performances, particularly for datasets with limited training data. Furthermore, we introduce a systematic selection framework for identifying the most beneficial protein datasets for augmentation and optimizing predictive gains. This study highlights the potential of related protein fitness translocation to advance protein engineering and variant effect prediction. The implementation of the method is available athttps://github.com/adrienmialland/ProtFitTrans.
Diversity and productivity of a natural grassland decline with the number of global change factors
Authors: Wang Jianyong , Liu Yingxia , Oduor Ayub M.O. , Kleunen Mark van , Liu Yanjie
Published: December 2024

Grasslands are highly diverse ecosystems providing important ecosystem services, but they currently face a variety of anthropogenic stressors simultaneously. Quantifying grassland responses to global change factors (GCFs) is crucial for developing effective strategies to mitigate the negative impacts of global change on grassland communities and to promote their resilience in the face of future environmental challenges. We conducted a field experiment in the Songnen grassland, northeastern China, to test the combined effects of 0, 1, 2, 4, 6, and 8 GCFs, including fungicide, herbicide, insecticide, antibiotic stress, heavy metal pollution, light pollution, microplastic pollution, nitrogen deposition, tillage disturbance, and increased precipitation. We found that within one year, the increasing number of GCFs negatively impacts on both the productivity and diversity of grassland communities. In comparison to exposure to a single GCF, exposure to 8 GCFs led to a reduction in productivity and species richness by 42.8% and 42.9%, respectively. Furthermore, these negative effects seem to be linked to the reduction of dominant species and the concurrent increase in neonative species. The results of hierarchical diversity-interaction modeling suggested that the adverse impacts of an increasing number of GCFs on community productivity and diversity are attributable to both the specific identities of GCFs involved and their unique pairwise interactions. The results suggest that grasslands may quickly loose stability and degrade more rapidly in response to multiple co-occurring GCFs. Greater efforts should be made to conserve the functions and services of grassland ecosystems by reducing the impacts of human activities.
The proteasome activator PA200 regulates tumor cell invasion
Authors: Yazgili Ayse Seda , Živković Dušan , Dafun Angelique Sanchez , Giotopoulou Georgia G. , Behrend Sabine , Koops Frauke , Zemke Linda , Stacher-Priehse Elvira , Goldmann Torsten , Reiling Norbert , Stathopoulos Georgios T. , Marcoux Julien , Bousquet Marie-Pierre , Meiners Silke
Published: December 2024

The proteasome is a well-identified therapeutic target for cancer treatment but the efficacy of proteasome inhibitors for solid tumors is severely hampered by cytotoxic side effects due to broad proteasome inhibition in non-tumor tissues. We and others observed significant upregulation of proteasome activator 200 (PA200) specifically in non-small cell lung cancer (NSCLC) tissues correlating with poor prognosis. To understand the functional role of PA200, we genetically depleted PA200 in two different NSCLC cell lines and characterized its functional effectsin vitroandin vivo.Of note, we observed a striking disparity in proteasome regulation, cellular growth, and transcriptome regulation upon deletion of PA200 in the two lung cancer cell lines. A common response to PA200 depletion, however, was the concerted impairment of tumor cell migration and invasionin vitroand diminished flank tumor growthin vivo. These data strongly suggest that the function of PA200 in tumor cells depends on the cellular context but has a conserved effect on tumor cell migration. Furthermore, using anin vitrodrug screening system with purified 20S and recombinantly expressed PA200, we were able to identify a PA200 inhibitor. This compound inhibits the activity of PA200-proteasome complexes but only marginally interferes with the catalytic activity of the 20S proteasome core. The drug showed inhibitory activity in cell extracts and reduced the invasive capacity of A549 lung cancer cells. Taken together, our data uncover PA200 as a potential target for lung cancer therapy and identify Prest2-M17 as a potential PA200 inhibitor.
Exploring Genetic Interactions with Rare Variants Reveals Gene Networks Susceptible to Complex Diseases
Authors: Jiang Hui , Tang Bin , Li Kun , Zhang Liubing , Liang Junhao , Tang Clara Sze-Man , Tam Paul Kwong-Hang , Wang Binbin , Song Youqiang , Wang Qiang , Li Mulin Jun , Huang Hailiang , Li Miaoxin
Published: December 2024

Genetic interactions play a crucial role in understanding the susceptibility and etiology of complex human diseases. However, existing methods for analyzing gene-gene interactions are often limited to common variants and may not capture the effects of rare variants. In this study, we propose a novel method called GGI-RUNNER that is specifically designed for analyzing gene-gene interactions of rare variants. GGI-RUNNER evaluates the enrichment of rare variant interaction burden in patients relative to baselines in the general population. The baselines are estimated for pairwise genes by a recursive truncated negative-binomial regression model on multiple genomic features available from public data. Intensive simulations demonstrate that GGI-RUNNER exhibits substantially higher statistical power than alternative epistasis tests and maintains reasonable type I error rates even in stratified populations. Applied to real data, GGI-RUNNER identified significant rare variant interactions associated with Alzheimer’s disease, Hirschsprung’s disease, Ulcerative colitis and Crohn’s disease. Furthermore, we found that these identified genes for each trait can form interconnected networks, which may provide valuable insights into the underlying molecular mechanisms.
mitoXplorer 3.0, a web tool for exploring mitochondrial dynamics in single-cell RNA-seq data
Authors: Haering Margaux , del Bondio Andrea , Puccio Helene , Habermann Bianca H.
Published: December 2024

Mitochondria are important eukaryotic organelles, best known for their function in ATP production and in cellular metabolism and signalling. It is widely accepted that their structure, composition and function differ across cell types. However, little is known about mitochondrial variability within the same cell type. To truly understand mitochondrial function and dynamics, we need to study individual cell types, as well as mitochondrial variability on a single-cell level.

Based on our mitoXplorer 2.0 web tool, we introduce mitoXplorer 3.0 with new features adapted for analysing single-cell sequencing data, focusing only on mitochondria. We provide a formatting script, scXplorer to generate mitoXplorer 3.0 compatible files for upload. This script creates pseudo-bulk transcriptomes of cell types from scRNA-seq data for differential expression analysis and subsequent mitochondria-centric analysis with mitoXplorer classical interfaces. It also creates a single-cell expression matrix only containing mitochondria-associated genes (mito-genes), which can be analysed for cell-to-cell variability with novel, interactive interfaces created for mitoXplorer 3.0: these new interfaces help to identify sub-clusters of cell types based only on mito-genes and offer in-depth mitochondria-centric analysis of subpopulations. We demonstrate the usability and predictive power of mitoXplorer 3.0 using single-cell transcriptome data from a single-cell study of Spinocerebellar Ataxia Type 1. We identified several mito-processes and mito-genes that are majorly affected in SCA1 Purkinje cells and which might contribute to our understanding of mitochondrial decline and subsequent Purkinje cell loss in this disease.

MitoXplorer 3.0 is freely available athttps://mitoxplorer3.ibdm.univ-amu.fr.
What makes human cortical pyramidal neurons functionally complex
Authors: Aizenbud Ido , Yoeli Daniela , Beniaguev David , de Kock Christiaan PJ , London Michael , Segev Idan
Published: December 2024

Humans exhibit unique cognitive abilities within the animal kingdom, but the neural mechanisms driving these advanced capabilities remain poorly understood. Human cortical neurons differ from those of other species, such as rodents, in both their morphological and physiological characteristics. Could the distinct properties of human cortical neurons help explain the superior cognitive capabilities of humans? Understanding this relationship requires a metric to quantify how neuronal properties contribute to the functional complexity of single neurons, yet no such standardized measure currently exists. Here, we propose the Functional Complexity Index (FCI), a generalized, deep learning-based framework to assess the input-output complexity of neurons. By comparing the FCI of cortical pyramidal neurons from different layers in rats and humans, we identified key morpho-electrical factors that underlie functional complexity. Human cortical pyramidal neurons were found to be significantly more functionally complex than their rat counterparts, primarily due to differences in dendritic membrane area and branching pattern, as well as density and nonlinearity of NMDA-mediated synaptic receptors. These findings reveal the structural-biophysical basis for the enhanced functional properties of human neurons.
Characterizing particle dynamics in live imaging through stochastic physical models and machine learning
Authors: Nardi G. , Sano M. Santos , Bilay M. , Brelot A. , Olivo-Marin J.-C. , Lagache T.
Published: December 2024

Particle dynamics determine the orchestration of molecular signaling in cellular processes. A wide range of subdiffusive motions has been described at the cell interior and membrane, corresponding to different environmental constraints. However, the standard methods for motion analysis, embedded in a diffusion-based framework, lack robustness for capturing the complexity of stochastic dynamics. This work develops a classification method to detect the five main stochastic laws modeling particle dynamics accurately. The method builds on machine-learning techniques that use features properly designed to capture the intrinsic geometric properties of trajectories governed by the different processes. This guarantees the accurate classification of observed dynamics in an interpretable and explainable framework. The main asset of this approach is its capability to distinguish different subdiffusive behaviors making it a privileged tool for biological investigations. The robustness to localization error and motion composition is proven, ensuring its reliability on experimental data. Moreover, the classification of composed trajectories is investigated, showing that the method can uncover the path’s mono-vs bi-dynamics nature. The method is used to study the dynamics of membrane receptors CCR5, involved in HIV infection. Comparing the basal state to an agonist-bound state which displays potent anti-HIV-1 activity, we show that the latter affects the natural dynamic state of receptors, thus clarifying the link between movement and receptor activation.
Ready-to-load MHC-I Nanoparticles for High-throughput T cell Screening Studies
Authors: Phan Hoang Anh T. , Hwang Daniel , Young Michael C. , Sun Shirley M. , Monos Dimitri S. , Sgourakis Nikolaos G.
Published: December 2024

MHC-I proteins present epitopic peptides to CD8+ T cells to elicit multifaceted adaptive immune responses. The affinity and avidity of interactions between peptide-MHC molecules and T-cell receptors (TCR) are fundamental parameters that contribute to the induction of activated or anergic T cell states. Here, we present a loadable system, VLP-Open HLA, featuring a virus-like particle (VLP) that can accommodate up to 60 loadable HLA (HLA – human leukocyte antigen) molecules. HLA nanoparticles, pre-loaded with a placeholder ligand, allow efficient peptide exchange upon incubation with target peptides. We show that fluorescently tagged VLP-Open HLA particles can be used to stain antigen-specific CD8+ T cells, providing a screening tool for novel TCRs. Finally, we demonstrate that our system can induce activation of T cells in an antigen-specific manner. Our platform can be adapted to encompass multiple HLA allotypes and co-stimulatory molecules as mosaic nanoparticles, to enable a range of applications in experimental immunology.
Activation and signaling characteristics of the hydroxy-carboxylic acid 3 receptor identified in human neutrophils through a microfluidic flow cell technique
Authors: Forsman Huamei , Li Wenyan , Levin Neele K. , Karlsson Roger , Karlsson Anders , Dahlgren Claes , Sundqvist Martina
Published: December 2024

Human neutrophils express numerous G protein-coupled receptors (GPCRs) of importance for immune regulation. Several of the functionally known neutrophil GPCRs, are not part of the human neutrophil proteome. To identify GPCRs not earlier shown to be expressed in human neutrophils, we utilized a microfluidic flow cell technique in combination with subcellular granule fractionation and liquid chromatography-tandem mass spectrometry (LC-MS/MS). This approach added the hydroxy-carboxylic acid 3 receptor (HCA3R) to the human neutrophil proteome. The β-oxidation intermediate 3-hydroxy-octanoic acid (3-OH-C8) is the primary endogenous agonist for this receptor which is highly expressed in adipocytes where it has anti-lipolytic effects. Literature describing the role and function of HCA3R in human neutrophils is scarce. We now show that 3-OH-C8 as well the synthetic HCA3R agonist IBC 293 activate human neutrophils determined as an increase in the intracellular concentration of free calcium ions ([Ca2+]i) and activation of the NADPH oxidase. However, in contrast to the rise in [Ca2+]iwhich could be triggered in naïve neutrophils, pre-treatment of neutrophils was required for HCA3Rs to activate the NADPH oxidase. That is, the HCA3R-mediated NADPH oxidase activation occurred only in neutrophils pre-treated with either an actin cytoskeleton disrupter or an allosteric modulator targeting the GPCR termed free fatty acid receptor 2 (FFA2R). Our findings demonstrate that HCA3R is not only a new member of the human neutrophil proteome, but also exhibits functional activity with complex signaling pathways when stimulated with endogenous and synthetic HCA3R agonists.
Association of Epigenetic Age Acceleration with Early Stage Heart Failure: Sex-Specific Effects in the Project Baseline Health Study
Authors: Ashar Perisa , Cauwenberghs Nicholas , Kottilil Kalyani , Chatterjee Ranee , Pagidipati Neha , Douglas Pamela S. , Plowman R. Scooter , Hernandez Adrian F. , Mahaffey Kenneth W. , Haddad Francois , Shah Svati H. , Kwee Lydia Coulter ,   the Project Baseline Health Study Group
Published: December 2024

Background

Epigenetic age acceleration (EAA), defined as blood DNA methylation-derived biological age exceeding chronological age, has emerged as a potential biomarker of cardiovascular health and disease. EAA has been associated with symptomatic heart failure (HF); however, its connection to early-stage HF remains unclear. Moreover, the association of EAA with cardiovascular disease may differ by sex.

Methods

We analyzed participants from the Project Baseline Health Study, a deeply-phenotyped longitudinal cohort. HF staging was performed using echocardiographic measures and clinical criteria, classifying participants into stage 0/B0 (no HF risk factors), stage A (HF risk factors only, without structural cardiac abnormalities), and stage B1 (structural changes without HF symptoms). EAA was calculated as the residual of Horvath methylation epigenetic age regressed on chronological age. We compared EAA across HF stages using ANOVA models adjusted for sex, and in secondary analyses, investigated associations between EAA and echocardiographic parameters as well as sex-specific differences.

Results

Among 1,338 participants (mean age: 49.2±15.4 years; 53.5% female), 41.7% were stage 0/B0 (n=558), 39.4% were stage A (n=527), and 18.9% were stage B1 (n=253). EAA tended to differ across HF stages (p=0.07), with higher EAA in stage B1 participants compared to those in stage 0/B0 or A. Sex-stratified models suggested that this trend was more pronounced in males than females. Among individual echocardiographic parameters, greater left ventricular posterior wall thickness was associated with higher EAA (p=0.046). In analyses restricted to stage A and B1 participants, higher EAA in B1 approached significance only in males (p=0.051).

Conclusions

These findings suggest that elevated EAA may occur even in the early, asymptomatic stages of HF, potentially reflecting underlying biological aging processes associated with early cardiac structural abnormalities. The effects may be sex-specific, with males showing a stronger relationship between EAA and stage B1 HF. Although validation through larger, longitudinal studies is necessary, our results support EAA as a potential biomarker for early cardiovascular risk assessment and underscore the need of considering sex differences in early HF pathophysiology.
Functional outcome, return to work and quality of life in patients with non-aneurysmal subarachnoid hemorrhage
Authors: Dronkers Wouter J. , Germans Menno R. , Post René , Coert Bert A. , Coutinho Jonathan M. , van den Berg René , Vandertop W. Peter , Verbaan Dagmar
Published: December 2024

Background

Non-aneurysmal, non-traumatic subarachnoid hemorrhage (nSAH) refers to cases where a causative aneurysm cannot be identified. We studied six-months’ outcomes in nSAH patients.

Methods

From a prospective SAH registry of all nSAH patients admitted between 2012 and 2023, relevant complications and outcomes were collected. Functional outcome and return-to-work at six months were assessed using the modified Rankin Scale (mRS), quality of life with the EuroQol-5Dimensions (EQ-5D) and Hospital Anxiety & Depression Scale (HADS), and an institutional 14-item questionnaire for assessment of residual symptoms.

Results

325 consecutive nSAH patients were included (191 non-perimesencephalic, non-aneurysmal subarachnoid hemorrhage [NPSAH]; 134 perimesencephalic subarachnoid hemorrhage [PMSAH]). 303 (93%; 179 NPSAH and 124 PMSAH) were available at follow-up (7 patients died). Favorable functional outcome (mRS-score 0-2) was reported in 271 (89%) patients and did not differ between NPSAH- and PMSAH. 141 (77%) patients returned to work, whereas only 71 (39%) patients reached their previous level of work. PMSAH patients were more likely to return to work (68/96 (71%) NPSAH and 73/87 (84%) PMSAH, respectively, p=0.01). Furthermore, PMSAH patients were more likely to fully return to work (p=.034). The mean (SD) EQ-5D and EQ-VAS scores were 0.827 (0.184) and 74 (16), respectively. The HADS-A and -D scores were deviant (score >7 points) in 53 (23%) and 48 (21%) patients, respectively. Only 39 patients (16%) denied experiencing residual symptoms. Increased fatigue (n=164; 68%), increased concentration difficulties (n=130; 54%), and increased forgetfulness (n=121; 50%) were the most frequently reported residual symptoms.

Conclusions

This study reveals that the majority of nSAH patients reports residual symptoms and did not return to their previous level of work at six months follow-up, despite a favorable functional outcome. These findings nuance the perception of a good outcome, as suggested in previous studies, warranting further research on possible rehabilitative interventions and counseling in these patients.