bluuebunny/crossref_metadata_2025_split huggingface dataset:
Proteasome Inhibition Enhances Lysosome-mediated Targeted Protein Degradation
Authors: Elshazly Ahmed M. , Hosseini Nayyerehalsadat , Shen Shanwei , Neely Victoria , Harada Hisashi , Grant Steven , Radhakrishnan Senthil K. 
Published: February 2025

ABSTRACTProteasome inhibitor drugs are currently used in the clinic to treat multiple myeloma and mantle cell lymphoma. These inhibitors cause accumulation of undegraded proteins, thus inducing proteotoxic stress and consequent cell death. However, cancer cells counteract this effect by activating an adaptive response through the transcription factor Nuclear factor erythroid 2-related factor 1 (NRF1, also known as NFE2L1). NRF1 induces transcriptional upregulation of proteasome and autophagy/lysosomal genes, thereby reducing proteotoxic stress and diminishing the effectiveness of proteasome inhibition. While suppressing this protective autophagy response is one potential strategy, here we investigated whether this heightened autophagy could instead be leveraged therapeutically. To this end, we designed an autophagy-targeting chimera (AUTAC) compound to selectively degrade the anti-apoptotic protein Mcl1 via the lysosome. Our results show that this lysosome-mediated targeted degradation is significantly amplified in the presence of proteasome inhibition, in a NRF1-dependent manner. The combination of the proteasome inhibitor carfilzomib and Mcl1 AUTAC synergistically promoted cell death in both wild-type and proteasome inhibitor-resistant multiple myeloma and lung cancer cells. Thus, our work offers a novel strategy for enhancing proteasome inhibitor efficacy by exploiting the adaptive autophagy response. More broadly, our study establishes a framework for amplifying lysosome-mediated targeted protein degradation, with potential applications in cancer therapeutics and beyond.
Critical Assessment of MetaProteome Investigation 2 (CAMPI-2): Multi-laboratory assessment of sample processing methods to stabilize fecal microbiome for functional analysis
Authors: Tanca Alessandro , Schallert Kay , Grenga Lucia , Peters Samantha L. , Abbondio Marcello , De Diego Laura , Deledda Maria Antonietta , Haange Sven-Bastiaan , Miotello Guylaine , Sáenz Johan S. , Wolf Maximilian , Bastida Felipe , Devos Simon , Hernandez-Raquet Guillermina , Seifert Jana , Wilmes Paul , Van Den Bossche Tim , Kunath Benoit J. , Heyer Robert , Jehmlich Nico , Benndorf Dirk , Hettich Robert L. , Armengaud Jean , Uzzau Sergio 
Published: February 2025

AbstractBackgroundFecal samples are widely used as a proxy for studying gut microbiome composition in both human and animal research. Fecal metaproteomics provides valuable insights by tracking changes in the relative abundance of microbial taxa and their protein functions. To ensure reliable results, it is crucial to minimize alterations in the metaproteome occurring from sample collection to protein extraction. Therefore, employing effective stabilization methods is essential to preserve the integrity of the fecal metaproteome from sample collection to laboratory analysis, particularly over long distances or when rapid freezing options are not readily available. In line with these needs, the second edition of the Critical Assessment of MetaProteome Investigation (CAMPI-2) was specifically focused on improving sample stabilization prior to metaproteomic analysis.ResultsThis collaborative multicenter study assessed the ability of five different stabilization methods, based on two commercial devices and three specific reagents (acetone, lithium dodecyl sulfate, and an RNAlater-like buffer), respectively, to stabilize the fecal metaproteome during room-temperature storage (14 days) and shipment to mass spectrometry facilities. The five methods were tested simultaneously by eight different laboratories across Europe, using aliquots from the same fecal sample. After protein extraction and digestion, duplicate aliquots of the resulting peptides were analyzed independently by two mass spectrometry facilities at distinct international locations. Analysis of the mass spectrometric data using two different search engines revealed that the fecal metaproteome profile differed considerably depending on the stabilization method used in terms of richness, alpha and beta diversity, reproducibility, and quantitative distribution of main taxa and functions. Although each method showed unique strengths and weaknesses, a commercial swab-based device stood out for its remarkable reproducibility and ranked highest for most of the metrics measured.ConclusionsCAMPI-2 allowed a robust evaluation of five different methods for preserving fecal metaproteome samples. The present investigation provides useful data for the design of metaproteomics and multi-omics studies where fecal sampling cannot be immediately followed by long-term storage at −80°C. Further optimization of the tested protocols is necessary to improve stabilization efficiency and control bias in the taxonomic and functional profile of the gut microbiome.
Promoter-Driven Modulation of Flagellin Expression and Motility inEscherichia coli
Authors: Bayana Karima Bharati , Wang Xinyue 
Published: February 2025

AbstractSynthetic biology offers powerful tools to engineer biological systems for diverse applications. However, key challenges persists before achieving real-world applications like environmental bioremediation or therapeutic microrobots for targeted drug delivery. This study aimed to precisely control bacterial movement by modulating gene expression using engineered promoters in Escherichia coli. We focused on Escherichia coli, a model organism, and manipulated its motility by engineering the expression of flagellin, a crucial protein for bacterial movement. To achieve this, specific genetic promoters were employed to regulate the production of flagellin, thereby dictating the movement capabilities of these bacteria. The promoters enabled targeted adjustments to flagellin expression, which in turn allowed for the enhancement or suppression of bacterial locomotion. Interestingly, the relationship between promoter design parameters and gene expression levels was non-linear, highlighting complex underlying dynamics. Optimal bacterial motility occurred at 30°C, illustrating the influence of environmental factors. Our findings demonstrate the ability to effectively regulate complex microbial phenotypes like motility using genetic engineering strategies. The results not only extend our understanding of bacterial gene regulation but also highlight the transformative potential of synthetic biology in creating functional and adaptable microbial phenotypes for diverse biotechnological applications.Abstract Figure
Adaptive strategies of Caribbean sponge holobionts beyond the mesophotic zone
Authors: Paix Benoît , Thivet Alexane , Domingos Celso , Erol Özlem , van der Windt Niels , Choi Young H. , de Voogd Nicole J. 
Published: February 2025

AbstractMarine sponges and their microbiomes function together as holobionts, playing essential roles in ecosystem dynamics and exhibiting remarkable adaptability across depth gradients. This study utilized a multi-omics approach, integrating microbiome and metabolome analyses, to investigate adaptive strategies in sponge holobionts inhabiting the mesophotic (80-125 m), upper-rariphotic (125-200 m), and lower-rariphotic (200-305 m) zones of Curaçao. We hypothesized that depth-related environmental factors drive distinct adaptive strategies, similar to patterns observed in fish and coral assemblages.Results revealed major differences in holometabolomes and microbial communities between Demospongiae and Hexactinellida sponges, reflecting class-specific adaptive strategies. Notably, phospholipid homeoviscous adaptation to temperature and pressure emerged as a key mechanism in phosphorus metabolism. Adaptations in nitrogen metabolism were linked to diverse ammonia oxidizing archaea (AOA) symbionts, and dissolved organic matter cycling. Hexactinellid microbiomes exhibited intra-specific heterogeneity; however, species-specific associations with AOA symbionts such asCenarchaeumandNitrosopumiluswere observed. Additionally, the lower-rariphotic hexactinellid holometabolomes highlighted the significance of the nested ecosystem concept through the identification of secondary metabolites produced by their associated fauna (aphrocallistins by zoanthids, and xanthurenic acid by shrimp).This study highlights the ecological significance of sponge holobionts in mesophotic and rariphotic ecosystems, revealing diverse adaptations to unique physicochemical conditions and biotic interactions.
TRAF6 integrates innate immune signals to regulate glucose homeostasis via Parkin-dependent and -independent mitophagy
Authors: Levi-D’Ancona Elena , Walker Emily M. , Zhu Jie , Deng Yamei , Sidarala Vaibhav , Stendahl Ava M. , Reck Emma C. , Henry-Kanarek Belle A. , Lietzke Anne C. , Pasmooij Mabelle B. , Hubers Dre L. , Basrur Venkatesha , Ghosh Sankar , Stiles Linsey , Nesvizhskii Alexey I. , Shirihai Orian S. , Soleimanpour Scott A. 
Published: February 2025

ABSTRACTActivation of innate immune signaling occurs during the progression of immunometabolic diseases, including type 2 diabetes (T2D), yet the impact of innate immune signaling on glucose homeostasis is controversial. Here, we report that the E3 ubiquitin ligase TRAF6 integrates innate immune signals following diet-induced obesity to promote glucose homeostasis through the induction of mitophagy. Whereas TRAF6 was dispensable for glucose homeostasis and pancreatic β-cell function under basal conditions, TRAF6 was pivotal for insulin secretion, mitochondrial respiration, and increases in mitophagy following metabolic stress in both mouse and human islets. Indeed, TRAF6 was critical for the recruitment and function of machinery within both the ubiquitin-mediated (Parkin-dependent) and receptor-mediated (Parkin-independent) mitophagy pathways upon metabolic stress. Intriguingly, the effect of TRAF6 deficiency on glucose homeostasis and mitophagy was fully reversed by concomitant Parkin deficiency. Thus, our results implicate a role for TRAF6 in the cross-regulation of both ubiquitin- and receptor- mediated mitophagy through the restriction of Parkin. Together, we illustrate that β-cells engage innate immune signaling to adaptively respond to a diabetogenic environment.
Polyamine biosynthesis dysregulation in Alzheimer’s disease and Down syndrome cellular models
Authors: Sola Andres , Sandberg Alex , Pham Caitlin , Revier Alexandra , Hebinck Mia , Penney Alexandra , Caviedes Pablo , Kumar Sunil , Granholm Ann-Charlotte , Linseman Daniel A. , Paredes Daniel A. 
Published: February 2025

ABSTRACTBACKGROUNDIndividuals with Down Syndrome (DS) frequently develop early onset Alzheimer’s disease (AD) with pathological hallmarks closely resembling AD due to several triplicated genes on chromosome 21. Polyamines are small, organic molecules that play a pivotal role for growth and differentiation, and a dysregulation of polyamine pathways is implicated in AD pathology. However, their role in DS-associated AD is unclear.METHODSWe analyzed polyamines and their metabolite levels in mouse hippocampal cells and human DS-AD and AD hippocampal tissue and assessed the effects of the ODC inhibitor difluoromethylornithine (DFMO) on Aβ42 aggregation and protein expression in DS fibroblasts.RESULTSAmyloid-β42 increased polyamine levels via ornithine decarboxylase (ODC) activation in a dose-dependent manner. DFMO reduced Aβ42 aggregation, decreased amyloid precursor protein (APP) levels, and normalized proteins linked to AD pathology in DS fibroblasts. Polyamine levels were elevated in DS-AD hippocampal tissue, with colocalization of ODC and Aβ42 aggregates.CONCLUSIONThese findings suggest that polyamine biosynthesis may exacerbate Aβ42 toxicity and APP expression, contributing to AD progression in DS. The ability of DFMO to reduce Aβ42 aggregation and restore protein homeostasis presents the polyamine pathway as a therapeutic target for DS-AD management.
Early posttranscriptional response to tetracycline exposure in a gram-negative soil bacterium reveals unexpected attenuation mechanism of a DUF1127 gene
Authors: Kothe Jennifer A.F. , Sauerwein Till , Dietz Theresa , Scheuer Robina , Elhossary Muhammad , Barth-Weber Susanne , Wähling Jan , Förstner Konrad U. , Evguenieva-Hackenberg Elena 
Published: February 2025

AbstractThe Gram-negative, soil-dwelling plant symbiontSinorhizobium melilotishares its free-living habitat with antibiotic producers. To learn about early steps of its adaptation to antibiotics, we analyzed transcriptome changes after 10 min exposure to subinhibitory amount of tetracycline (Tc). RNA-seq revealed 297 differentially expressed genes. Besides ten upregulated ribosomal genes, there was no recognizable functional pattern in the observed changes. Instead, upregulated genes were mostly first in operons and often small, while downregulated genes were downstream in operons. Furthermore, we detected mRNA stabilization upon Tc exposure for several up- and down-regulated genes. Thus, mRNA stabilization contributed to increased mRNA levels, but for downstream genes its effect was counteracted by premature transcriptional termination caused by disrupted coupling between transcription and translation. Using reporter constructs, we found that a DUF1127 gene, showing highest mRNA increase, is controlled by transcription attenuation depending on the translation of an upstream ORF (uORF). Our data suggest the following model: The attenuation strongly depends on the accessibility of C-rich codons at the begin of the uORF. The accessibility is guaranteed by translation of the uORF, and is possible in a time window after a ribosome moves downstream and before a next ribosome occupies the ribosomal binding site (RBS). The accessibility is blocked either by impaired translation initiation or, in the absence of ribosome binding, by base-pairing between the RBS and the C-rich codons. We propose that this is used by bacteria to monitor ribosome availability and translation efficiency, and to ensure reciprocal expression of the DUF1127 gene.
Mapping the GDF15 Arm of the Integrated Stress Response in Human Cells and Tissues
Authors: Smith Janell LM , Tanner Kamaryn , Devine Jack , Monzel Anna S , Cohen Alan A , Picard Martin 
Published: February 2025

AbstractMitochondrial stress activates the integrated stress response (ISR) and triggers cell-cell communication through secretion of the metabokine growth differentiation factor 15 (GDF15). However, the gene network underlying the ISR remains poorly defined, particularly across metabolically diverse cellular states and tissues. Using RNAseq data from fibroblasts subjected to metabolic perturbations, we develop anISRGDF15indexquantifying the GDF15 arm of the ISR activation in human cells. Validation ofISRGDF15indexacross 44 postmortem human tissues illustrates how this index can be applied to investigate tissue-specific and age-related ISR activation.
Regulation of early-stage tomato fruit growth by the splicing factor RS2Z36
Authors: Vraggalas Stavros , Rosenkranz Remus RE , Keller Mario , Pérez-Pérez Yolanda , Bachiri Samia , Zehl Kerstin J , Bold Jessica , Simm Stefan , Ghatak Arindam , Weckwerth Wolfram , Afjehi-Sadat Leila , Chaturvedi Palak , Testillano Pilar S , Müller-McNicoll Michaela , Zarnack Kathi , Fragkostefanakis Sotirios 
Published: February 2025

AbstractFruit size and shape are determined by cell division and expansion. In tomato, the model plant for fleshy fruit development, both processes are associated with changes in gene expression, including transcription and RNA processing. While several transcription factors have been identified as regulators of genes involved in fruit development, the contribution of splicing regulators remains unknown. Profiling of RNA splicing-related genes revealed stage-preferential expression of several factors, including RS2Z36, a serine/arginine-rich splicing factor highly expressed during the early stages of fruit development. Mutations in RS2Z36 lead to smaller ellipsoid fruits than the wild type, with histological analysis showing elongated pericarp cells in the ovaries along the longitudinal axis. RNA-seq analysis uncovered numerous alternatively spliced genes involved in different biological processes. Complementary proteome analysis identified proteins with altered abundance and peptides corresponding to novel RNA splice isoforms, underscoring the role of RS2Z36 in shaping both transcriptome and proteome diversity. Immunofluorescence screening of cell wall proteins further demonstrated an increased abundance of LM6-recognized arabinan epitopes of rhamnogalacturonan-I pectins and arabinogalactan protein (AGP) epitopes inrs2z36.1pericarp cells compared to the wild type. These findings highlight RS2Z36 as a critical regulator of alternative splicing, impacting fruit development through diverse transcriptome and proteome changes.
Discovery of a distinct BAM complex in the Bacteroidetes
Authors: Silale Augustinas , Madej Mariusz , Mikruta Katarzyna , Frey Andrew M. , Hart Adam J. , Baslé Arnaud , Scavenius Carsten , Enghild Jan J. , Trost Matthias , Hirt Robert P. , van den Berg Bert 
Published: February 2025

AbstractThe BAM (β-barrel assembly machinery) complex is an evolutionarily conserved, multiprotein machine that catalyses the folding and membrane insertion of newly synthesised β-barrel outer membrane (OM) proteins in Gram-negative bacteria. Based on Proteobacteria, bacterial BAM is also structurally conserved, with an essential BamAD core and up to three auxiliary periplasmic lipoproteins of poorly defined function. Here we show, using structural biology, quantitative proteomics and functional assays, that the BAM complex is radically different within the Bacteroidetes, a large and important phylum widely distributed within the environment and animal microbiomes. Cryogenic electron microscopy (cryo-EM) structures of BAM complexes from the human gut symbiontBacteroides thetaiotaomicronand the human oral pathogenPorphyromonas gingivalisshow similar, seven-component complexes of ∼325 kDa in size with most of the mass in the extracellular space. In addition to canonical BamA and BamD, the complexes contain an integral OM protein named BamF that is essential and intimately associated with BamA, as well as four surface-exposed lipoproteins (SLPs) named BamG-J. Together, BamF-J form a large, extracellular dome that likely serves as an assembly cage for the β-barrel-SLP complexes that are a hallmark of the Bacteroidetes. Our data suggest that BAM functionality in Bacteroidetes is substantially expanded from that in Proteobacteria and underscores the importance of studying other phyla for a more complete understanding of fundamental biological processes.
Progesterone regulation of cervix ripening in preterm and term birth
Authors: Yellon Steven M. , Ward Daylan , Thompson Ashley , Vazquez Brigitte M. , Daniel Baldwin D. , Oldford Elaine J. , Kirby Michael A. 
Published: February 2025

AbstractThe cervix functions both as gatekeeper barrier to maintain pregnancy and virtually vanish for birth at term in mammals. The period of remodeling well-before term is characterized by an inflammatory process associated with reduced cell nuclei density and cross-linked collagen, as well as increased density of resident macrophages in cervix stroma. Contemporarily, progesterone (P4) is at or near peak concentrations in maternal circulation. The functional or actual loss of response to P4 is thought to drive the process that enhances uterine contractile activity for labor and parturition at term. The objective of the present study was to determine if actual or functional loss of P4 regulated cytomorphological characteristics associated with prepartum cervix ripening at term and with preterm birth. On day 16 of pregnancy. Ovaries were removed to eliminate the main source of P4 production and a silastic capsule implanted (with vehicle or P4, Ovx or Ovx+P4, respectively).Controls received a vehicle-filled capsule, while a P4 capsule was implanted into an addition group of Intact mice to ensure sustained concentrations throughout pregnancy (Intact+P4). Pups were born in controls at term (days 19-20 postbreeding), but deliveries were preterm in Ovx mice within 24h (day 17). In the Ovx+P4 group, births were delayed to term and post-term in most Intact+P4 mice with adverse pregnancy outcomes commonplace. Characteristics of cell nuclei and degradation of cross-linked collagen were advanced with preterm birth in Ovx mice compared to controls that gave birth by at term. Treatment of Ovx mice with P4 blocked preterm birth, but parturition was complicated by dystocia. In addition, P4 given to ovary-intact mice sustained peak pregnancy concentrations, but had minimal effects on cytoarchitecture of the prepartum cervix stroma except term birth was forestalled with dystocia and fetal morbidity. Density of resident macrophages in the cervix stroma in term Ovx+P4 mice was reduced along with area of macrophage stain versus postpartum controls. Thus, analyses of cervix cellular cytoarchitecture provided useful biomarkers of local inflammation to assessment the ripening process for preterm and term parturition. Collectively, findings suggest a functional loss of prepartum cervix responses to progesterone are part of a final common mechanism for parturition across mammals.SummaryLoss of response to progesterone withdrawal is associated with cervix ripening while some cytoarchitectural characteristics of remodeling are regulated to block preterm birth and dystocia at term
The impact of emotional cues on the information-gathering willingness of paid knowledge users
Authors: Cao Youjing , Deng Xiaozhao 
Published: February 2025

PurposeThis study aims to explore the impact of emotional cues in knowledge product descriptions on users’ willingness to gather information. It specifically focuses on how different types of textual emotional cues, including heuristic cues like “emotional titles” and systematic cues like “emotional synopses,” influence users’ information-gathering willingness and examines the mediating role of emotional arousal in this process.Design/methodology/approachA conceptual model was developed by integrating the heuristic-systematic model with cue utilization theory. The experimental design employed knowledge product descriptions from the “Knowledge Column” section of the Zhihu platform. A controlled experiment was conducted to investigate the effect of varying emotional cues in these descriptions on participants’ willingness to gather information.FindingsThe study identified two types of emotional cues – heuristic cues, such as “emotional titles,” and systematic cues, such as “emotional synopses” – that significantly and positively influence users' information-gathering willingness. Additionally, emotional arousal was found to mediate the relationship between emotional cues and users’ willingness to gather information in the context of knowledge payments.Originality/valueThis study confirms that emotional cues in knowledge product descriptions, mediated by emotional arousal, can enhance the information-gathering willingness of knowledge payment users. The research deepens the theoretical exploration of information behavior among online knowledge payment users, providing valuable insights for knowledge producers on effectively leveraging emotional cues to attract potential customers as well as offering guidance for knowledge payment users in their information-gathering practices.