bluuebunny/crossref_metadata_2025_split huggingface dataset:
A gated hydrophobic funnel within BAX binds long-chain alkenals to potentiate pro-apoptotic function
Authors: Gelles Jesse D. , Chen Yiyang , Luna-Vargas Mark P. A. , Follis Ariele Viacava , Bayiokos Stella G. , Mohammed Jarvier N. , Sebastian Tara M. , Al Noman M. Abdullah , Pham Ngoc Dung , Shi Yi , Kriwacki Richard W. , Chipuk Jerry E. 
Published: December 2024

ABSTRACTMitochondria maintain a biochemical environment that cooperates with BH3–only proteins (e.g., BIM) to potentiate BAX activation, the key event to initiate physiological and pharmacological forms of apoptosis. The sphingosine-1-phosphate metabolite 2-trans-hexadecenal (2t–hexadecenal) is one such component described to support BAX activation, but molecular mechanisms remain largely unknown. Here, we utilize complementary biochemical and biophysical techniques to reveal that 2t-hexadecenal non-covalently interacts with BAX, and cooperates with BIM to stimulate early-activation steps of monomeric BAX. Integrated structural and computational approaches reveal 2t–hexadecenal binds an undefined region – a hydrophobic cavity formed by core-facing residues of α5, α6, and gated by α8 – we now term the “BAX actuating funnel” (BAF). We define alkenal length and α8 mobility as critical determinants for 2t–hexadecenal synergy with BIM and BAX, and demonstrate that proline 168 allosterically regulates BAF function. Collectively, this work imparts detailed molecular insights advancing our fundamental knowledge of BAX regulation and identifies a regulatory region with implications for biological and therapeutic opportunities.
Investigating the Role of Glyoxalase 1 as a Therapeutic Target for Cocaine and Oxycodone Use Disorder
Authors: Alcantara Elizabeth , Doyle Michelle R. , Ortez Clara A. , Ilustrisimo Anne , Stromberg Bloom , Barkley-Levenson Amanda M. , Palmer Abraham A. 
Published: December 2024

AbstractMethylglyoxal (MG) is an endogenously produced non-enzymatic side product of glycolysis that acts as a partial agonist at GABAAreceptors. MG that is metabolized by the enzyme glyoxalase-1 (GLO1). Inhibition of GLO1 increases methylglyoxal levels, and has been shown to modulate various behaviors, including decreasing seeking of cocaine-paired cues and ethanol consumption. The goal of these studies was to determine if GLO1 inhibition could alter cocaine-or oxycodone-induced locomotor activation and/or conditioned place preference (CPP) to cocaine or oxycodone. We used both pharmacological and genetic manipulations of GLO1 to address this question. Administration of the GLO1 inhibitor s-bromobenzylglutathione cyclopentyl diester (pBBG) did not alter the locomotor response to cocaine or oxycodone. Additionally, pBBG had no significant effect on place preference for cocaine or oxycodone. Genetic knockdown ofGlo1, which is conceptually similar to pharmacological inhibition, did not have any significant effects on cocaine place preference, nor didGlo1overexpression affect locomotor response to cocaine. In summary, our results show that neither pharmacological nor genetic manipulations of GLO1 influence locomotor response or CPP to cocaine or oxycodone.
Setdb1 and Atf7IP form a hetero-trimeric complex that blocks Setdb1 nuclear export
Authors: Kariapper Leena , Marathe Ila A. , Niesman Ashley B. , Suino-Powell Kelly , Chook Yuh Min , Wysocki Vicki H. , Worden Evan J. 
Published: December 2024

AbstractHistone H3K9 methylation (H3K9me) by Setdb1 silences retrotransposons (rTE) by sequestering them in constitutive heterochromatin. Atf7IP is a constitutive binding partner of Setdb1 and is responsible for Setdb1 nuclear localization, activation and chromatin recruitment. However, structural details of the Setdb1/Atf7IP interaction have not been evaluated. We used Alphafold2 predictions and biochemical reconstitutions to show that one copy of Setdb1 and two copies of Atf7IP form a hetero-trimeric complexin vitroandin cells. We also find that Atf7IP self-associates, forming multimeric complexes that are resolved upon Setdb1 binding. Setdb1 binds to Atf7IP through coiled coil interactions that include both Setdb1 nuclear export signals (NES). Atf7IP directly competes with CRM1 to bind the Setdb1 NES motifs, explaining how Atf7IP prevents CRM1-mediated nuclear export of Setdb1. Setdb1 also forms hetero-trimeric complexes with the Atf7IP paralog Atf7IP2 and we show that Setdb1 can form mixed heterotrimers comprising one copy of each Setdb1, Atf7IP and Atf7IP2. Atf7IP and Atf7IP2 are co-expressed in many tissues suggesting that heterotrimers with different compositions of Atf7IP and Atf7IP2 may differentially regulate H3K9me by fine-tuning Setdb1 localization and activity.
N-Amino Peptide-Graphene Quantum Dot Loaded Small Extracellular Vesicles for Targeted Therapy of Tauopathies
Authors: Zhu Runyao , Kim Gaeun , Rajewski Benjamin H. , Angera Isaac J. , Del Valle Juan R. , Wang Yichun 
Published: December 2024

ABSTRACTTauopathies, a group of neurodegenerative disorders, are characterized by the abnormal aggregation of tau proteins into neurofibrillary tangles (NFTs), driving synaptic dysfunction, neuronal loss, and disease progression through tau aggregate propagation. Graphene quantum dots (GQDs) functionalized withD- cysteine (D-GQDs) have shown promise in inhibiting tau aggregation and transmissionviaπ-π stacking and electrostatic interactions with tau proteins. However, the non-specific binding of GQDs to various proteins in the physiological environment, such as serum albumin, limits their clinical translation. In this study, we aim to enhance the specificity ofD-GQDs toward tau protein by incorporating a tau-targeting N- amino peptide, mxyl-NAP2. The mxyl-NAP2/D-GQD complex demonstrated improved selectivity for tau protein over serum albumin, effectively enhancing the inhibition of tau aggregation. To further minimize off-target effects and optimize therapeutic delivery, we loaded the mxyl-NAP2/D-GQD complex into small extracellular vesicles (sEVs), followed by functionalization of sEVs with neuron targeting ligand, rabies viral glycoprotein peptides. This strategy not only reduced off-target effects, but also enhanced uptake by neuron cells, which further improved inhibition of tau transmission between neurons. Our results indicated that mxyl-NAP2/D-GQD-loaded sEVs hold great promise for overcoming the off-target limitations ofD- GQDs and advancing the development of precision therapeutics for neurodegenerative diseases.
Tumour-derived gliogenesis sustains dedifferentiation-dependent tumour growth in theDrosophilaCNS
Authors: Alvarez-Ochoa Edel , Dong Qian , Truong Hannah , Cheng Louise Y 
Published: December 2024

AbstractFate-restricted cells can acquire stem cell-like properties through dedifferentiation, enabling them to gain the plasticity required for differentiation into multiple lineages. Tumour plasticity is prominently observed in brain cancers, where transient cell state changes are linked to resistance to conventional therapies. In this study, we demonstrate that a sub-population of dedifferentiated tumour neural stem cells (NSCs) inDrosophila, induced by the knockdown ofprospero(pros), can generate its own glial niche. Temporal patterning, known to influence oncogenic competence and tumour malignancy, plays a key role in this process. Specifically, we show thatde novogliogenesis occurs in the more differentiated Syncrip+ (Syp+) NSC population. Modulating Syp levels alters the size of the glial niche, subsequently affecting tumour size. Furthermore, the tumour-associated glial niche expands through cell division and fails to cease proliferation on time due to dysregulated ecdysone signalling, contributing to niche expansion. Our findings reveal that tumours arising via dedifferentiation establish their own supportive glial microenvironment, which sustains tumour growth.
Novel interactions within the silent information regulator heterochromatin complex potentiate inter-subunit communication and gene repression
Authors: Kotz Jenna , Martz E. J. , Nelson Maya , Savoie Nicole , Schmitt Lauren , States Jordan , Holton Nathan , Hansen Kirk , Johnson Aaron M. 
Published: December 2024

ABSTRACTOrganisms with smaller genomes often perform multiple functions using one multi-subunit protein complex. TheS. cerevisiaeSilent Information Regulator complex (SIRc) carries out all of the core functions of heterochromatin. SIR complexes first drive the initiation and spreading of histone deacetylation in an iterative manner. Subsequently, the same complexes are incorporated stably with nucleosomes, driving compaction and repression of the underlying chromatin domain. These two distinct functions of SIRc have each been characterized in much detail, but the mechanism by which the dynamic spreading state switches to stable compaction is not well-understood. This incomplete knowledge of intra- complex communication is partly due to a lack of structural information of the complex as a whole; only structures of fragments have been determined to date. Using cross-linking mass spectrometry in solution, we identified a novel inter-subunit interaction that physically connects the two states of SIRc. The Sir2 deacetylase makes direct interactions with the scaffolding subunit Sir4 through its coiled-coil domain, which also interacts with the Sir3 compaction/repression subunit. Within the hub of interactions are conserved residues in Sir2 that can sense deacetylation state, as well as amino acids that likely diverged and co-evolved to interact with Sir4, promoting species-specific functions. Mutation of this interaction hub disrupts heterochromatic repression, potentially by disrupting a conserved mechanism that communicates completion of deacetylation to switch to compaction. Our work highlights how a single multi-functional chromatin regulatory complex can stage a step-wise mechanism that requires a major transition in activities to achieve epigenetic gene repression.
APOE4 Increases Susceptibility to Amyloid, Accelerating Episodic Memory Decline
Authors: Vanderlip Casey R. , Stark Craig E.L. ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: December 2024

AbstractApolipoprotein E4 (APOE4) is the strongest genetic risk factor for sporadic Alzheimer’s disease (AD). Individuals with one copy of APOE4 exhibit greater amyloid-beta (Aβ) deposition compared to noncarriers, an effect that is even more pronounced in APOE4 homozygotes. Interestingly, APOE4 carriers not only show more AD pathology but also experience more rapid cognitive decline, particularly in episodic memory. The underlying mechanisms driving this domain-specific vulnerability, however, remain unclear. In this study, we examined whether the accelerated decline in episodic memory among APOE4 carriers is due to increased Aβ deposition or heightened susceptibility to Aβ-related effects. Using data from the Alzheimer’s Disease Research Initiative, we modeled amyloid duration, the estimated number of years an individual has been amyloid-positive, and its impact on cognitive trajectories. Our findings reveal that APOE4 is associated with more rapid episodic memory decline as a function of amyloid duration. This decline was dose-dependent, with APOE4 homozygotes declining more rapidly than heterozygotes, and it was consistently observed across multiple episodic memory tasks and measures. Importantly, this pattern was not observed in other cognitive domains, such as processing speed, executive function, visuospatial skills, language, or crystallized intelligence. These results suggest that cognitive trajectories in AD differ by APOE genotype, with APOE4 conferring increased vulnerability to hippocampal dysfunction early in the disease course. Future research should investigate whether these cognitive differences stem from distinct pathological cascades in APOE4 carriers.
Restoring oxidative phosphorylation enhances osteogenesis in mitochondrial DNA translation defective human bone marrow stromal cells
Authors: Fernandez-Guerra Paula , Kjær Pernille Kirkegaard , Terp Simone Karlsson , Thomsen Jesper S. , Aldana Blanca I. , Renkema Herma , Smeitink Jan , Andersen Per H. , Palmfeldt Johan , Søe Kent , Andersen Thomas L. , Kassem Moustapha , Frost Morten , Frederiksen Anja L. 
Published: December 2024

AbstractBone formation is critical to maintain bone integrity. Here, we studied the importance of intact energy metabolism for bone formation in humans. The skeletal impact of impaired oxidative phosphorylation (OXPHOS) was investigated in adult individuals with genetically defective mitochondrial DNA translation (m.3243A>G). Although impaired mitochondrial ATP production in m.3243A>G human bone marrow stromal cells (hBMSC) was compensated by increased glycolytic ATP production (unchanged net ATP production), bothin vitroosteoblast differentiation andin vivoectopic bone formation were decreased. The impaired OXPHOS was associated with mitochondrial stress and disruption of the pro-osteogenic transcriptional program characteristic of hBMSC. Supporting OXPHOS pharmacologically in hBMSC restored mitochondrial ATP production, their transcriptional program and metabolism, leading to upregulation of osteogenic genes and restoration of bone formation capacity. These findings demonstrate a mitochondrial regulation mechanism of the osteogenic capacity of hBMSCs and identify OXPHOS as a potential target for increasing bone formation.
RiboTag-based RNA-Seq uncovers oligodendroglial lineage-specific inflammation in autoimmune encephalomyelitis
Authors: Wang Yuhang , Ghimire Sudeep , Mangalam Ashutosh , Kang Zizhen 
Published: December 2024

AbstractOligodendroglial lineage cells (OLCs) are critical for neuronal support functions, including myelination and remyelination. Emerging evidence reveals their active roles in neuroinflammation, particularly in conditions like Multiple Sclerosis (MS). This study explores the inflammatory translatome of OLCs during the early onset of experimental autoimmune encephalomyelitis (EAE), an established MS model. Using RiboTag-based RNA sequencing in genetically modified Olig2-Cre RiboTag mice, we identified 1,556 upregulated and 683 downregulated genes in EAE OLCs. Enrichment analysis indicated heightened immune-related pathways, such as cytokine signaling, interferon responses, and antigen presentation, while downregulated genes were linked to neuronal development and myelination. Notably, OLCs expressed cytokines/chemokines, and their receptor, highlighting their active involvement in neuroinflammatory signaling. Functional studies demonstrated that interferon-gamma (IFN-γ) signaling in OLCs exacerbates EAE pathology by enhancing antigen presentation and chemokine production, whereas interferon-beta (IFN-β) signaling showed minimal impact. These findings provide novel insights into the inflammatory role of OLCs in EAE and suggest therapeutic potential in targeting OLC-mediated neuroinflammation for MS and related disorders.
New isolate genomes and global marine metagenomes resolve ecologically relevant units of SAR11
Authors: Freel Kelle C. , Tucker Sarah J. , Freel Evan B. , Giovannoni Stephen J. , Eren A. Murat , Rappé Michael S. 
Published: December 2024

AbstractThe bacterial orderPelagibacterales(SAR11) is among the most abundant and widely distributed microbial lineages across the global surface ocean, where it forms an integral component of the marine carbon cycle. However, the limited availability of high-quality genomes has hampered comprehensive insights into the ecology and evolutionary history of this critical group. Here, we increase the number of complete SAR11 isolate genomes fourfold by describing 81 new SAR11 strains from seven distinct lineages isolated from coastal and offshore surface seawater of the tropical Pacific Ocean. We leveraged comprehensive phylogenomic insights afforded by these isolates to characterize 24 monophyletic, discrete ecotypes with unique spatiotemporal patterns of distribution across the global ocean, which we define as genera. Our data illustrate fine-scale differentiation in patterns of detection with ecologically-relevant gene content variation for some closely related genomes, demonstrating instances of ecological speciation within SAR11 genera. Our study provides unique insight into complex environmental SAR11 populations, and proposes an ecology-informed hierarchy to pave a path forward for the systematic nomenclature for this clade.
LeveragingDrosophilaModels to Explore AI-generated Synthetic Peptide’s Potential in Boosting Honeybee Health and Resilience
Authors: Sun Yanying , Jia Wenjie , Wei Yanan , Zhou Xinyue , Dong Ran , Lee Jihyeon , Bang Jeong Kyu , Ning Fangyong , Kim Woo Jae 
Published: December 2024

ABSTRACTThe integration of artificial intelligence (AI) and machine learning (ML) in peptide design has revolutionized the development of antimicrobial peptides (AMPs), which are essential components of innate immunity. In this study, we identified a novel synthetic peptide, PAN4 (GAYTFKIRRK), through genetic screening of AI-generated candidates inDrosophila melanogaster. PAN4 demonstrated robust antimicrobial activity, stress tolerance, and antitumor effects, significantly enhancing survival rates following bacterial infections and improving locomotor behaviors without adversely affecting lifespan. Furthermore, PAN4 expression in intestinal stem cells completely suppressed RasV12-induced tumor progression, indicating its potential role in cancer prevention. The peptide also mitigated gut barrier dysfunction associated with sleep deprivation and reduced inflammation in a dextran sulfate sodium (DSS)-induced colitis model. Mechanistically, PAN4’s antimicrobial activity was linked to its interaction with specific peptidoglycan recognition proteins (PGRPs), particularly PGRP-SC1a, while the Tak1-mediated immune signaling pathway was found to be non-essential for its efficacy. PAN4 showed promising effects on honeybee health, enhancing survival rates under bacterial stress. Furthermore, PAN4 expression demonstrated significant anti-tumor activity in theDrosophilagut tumor model. Our findings suggest that PAN4 serves as a versatile agent with significant implications for enhancing immune responses and combating diseases in honeybee populations, paving the way for future applications in agriculture and medicine.
Coevolution ofDrosophila-type Timeless with Partner Clock Proteins
Authors: Bullo Enrico , Chen Ping , Fiala Ivan , Smýkal Vlastimil , Doležel David 
Published: December 2024

SUMMARYDrosophila-type timeless (dTIM) is established key clock protein in fruit flies, regulating the rhythmicity and light-mediated entrainment. However, as indicated by functional experiments, its contribution to the clock differs in various insects. Therefore, we conducted a comprehensive phylogenetic analysis of dTIM across animals, dated its origin, gene duplications, and losses. We identified variable and conserved protein domains, and pinpointed animal lineages that underwent the biggest changes in the dTIM sequence. While dTIM modifications are only mildly affected by changes in the PER protein, even the complete loss of PER in echinoderms had no impact on dTIM. However, changes in dTIM always co-occur with the loss of CRYPTOCHROMES or JETLAG. This is exemplified by the remarkably accelerated evolution of dTIM in phylloxera and aphids. Finally, alternatived-timsplicing, characteristic ofD. melanogastertemperature-dependent function, is conserved at least to some extent in Diptera, albeit with unique alterations. Altogether, this study pinpoints major changes that shaped dTIM origin and evolution.
The natural HLA-Peptidome of Sezary Syndrome: uncovering antigens for T cell-based immunotherapy
Authors: Nyambura Lydon Wainaina , Textoris-Taube Kathrin , Walden Peter 
Published: December 2024

AbstractSezary syndrome (SS) is a rare and aggressive form of cutaneous T-cell lymphoma, that has a poor prognosis, with a median overall survival time of less than 3 years. Despite advances in its treatment, SS is a challenge to manage, often characterized by high rates of relapse and limited response to therapy in many patients. The main challenge for treatment, including vaccine development is its heterogeneity. In its molecular and genetic characteristics, clinical presentation, disease progression, and treatment response. Understanding the SS heterogeneity at the omics level is vital in developing T-cell mediated immunotherapeutic. In this study naturally presented HLA-I peptides were isolated from SS patients leukophoresis samples and analyzed using high performance liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS), and source proteins evaluated for immunotherapy application. The total number of HLA-I–restricted peptides and source proteins identified in SS leukophoresis patient samples was about the same, and they were heterogeneous and individualized. Only a small fraction of HLA-I peptides and source proteins was found to be shared between and among the patients. Peptide lengths were dominated by nanopeptides, with preferred processing by chymotrypsin. The source proteins were predominantly from the cytoplasm, and primarily involved in biosynthesis and regulation. Furthermore, the HLA-I peptides were presented from top 20 genes with somatic mutations in SS that include NCOR1, TRRAP, JAK3, PLCG1, TP53 and STAT3 (SS associated antigens-SAAs). These SAAs had; varying mutation types and frequencies-dominated by missense variant, allele-dependent immunogenicity-highest in HLA-A*11:01 and HLA-A*02:01 and lowest for HLA-A*01:01-with TRRAP showing high affinity peptides, low gene expression levels in normal tissue (except STAT3), significant protein interaction network-including JAK3 and STAT3 at primary level. This study findings, contributes to the overall understanding SS HLA-I peptidome landscape, and highlights potential T-cell mediated immunotherapeutic targets.
Evolution of genetic variance and its consequences on eco-evolutionary response in complex mutualistic networks
Authors: Baruah Gaurav , Wittmann Meike J. 
Published: December 2024

AbstractClimate change, especially rising temperatures, poses a threat to biodiversity and ecosystem resilience, for example, by disrupting phenological synchrony in plant-pollinator networks. These interactions, essential for ecosystem stability, are highly sensitive to temperature shifts, which can lead to mismatches in plant flowering and pollinator emergence, weakening species interactions and reducing resilience to environmental disturbances. In this study, we model species’ evolutionary responses to an abrupt temperature increase, examining one-dimensional adaptation in mean temperature optimum trait versus adaptation involving both the mean and trait variance. Our results indicate that networks where species can evolve in both dimensions exhibit greater resilience, especially those species with a larger number of interactions that enhance genetic variance and exhibit evolutionary rescue under strong selective pressures. Even specialist species benefit from increased resilience through interactions with highly connected generalists, which help stabilize adaptation of entire mutualistic network to a new environmental optimum. We observed the emergence of opposing selection pressures in such complex networks which consequently promotes increased genetic variance, or “evolvability,” enabling faster adaptation, and thus reducing trait lag, and boosting species survival. These findings highlights the critical role of evolving genetic variance and network architecture in mitigating the impacts of plant-pollinator phenotypic mismatches to rising environmental temperatures. This study provides valuable insights into the adaptive capacity of mutualistic networks, highlighting the importance of dynamical evolution of genetic variance in promoting resilience in the face of accelerating climate change.