bluuebunny/crossref_metadata_2025_split huggingface dataset:
AVJ16 inhibits the RNA binding protein IGF2BP1 in lung adenocarcinomas and prevents tumor growth in mice
Authors: Wallis Nadav , Gershon Tehila , Shaaby Sojod , Oberman Froma , Grunewald Myriam , Duran Deborah , Singh Amandeep , Vainer Gilad , Spiegelman Vladimir S. , Sharma Arun K. , Yisraeli Joel K. 
Published: August 2024

ABSTRACTIGF2BP1 is an oncofoetal RNA binding protein that is expressed in many tumors. We have recently described a small molecule inhibitor of IGF2BP1, termed AVJ16, that prevents binding of the protein to its RNA targets by directly associating with the protein. Here, using a multi-omics approach, we have analyzed the effects of this inhibition on RNA binding, RNA expression, and protein expression. AVJ16 treatment downregulates RNAs encoding members of several pro-oncogenic signaling pathways, including Hedgehog, Wnt, and PI3K-Akt, and there is a strong correlation between IGF2BP1 RNA binding, RNA expression, and protein expression. AVJ16 treatment of lung adenocarcinoma (LUAD) cells in culture causes a strong reduction in proliferation, colony formation, invasion, and spheroid growth while enhancing apoptosis and cell death. All of these effects are limited to cells expressing IGF2BP1. LUAD cells treated with AVJ16 show a pronounced reduction in vital dye efflux, often correlated with enhanced chemosensitivity. In syngeneic LUAD xenografts in mice, IP injection of AVJ16 prevents tumor growth, and incubation with AVJ16 induces cell death in human organoids derived from IGF2BP1-expressing LUADs but not from healthy lung tissue. These results suggest that AVJ16 is a promising candidate for mono- and/or adjuvant therapy directed against tumors expressing IGF2BP1.
A genetically engineered therapeutic lectin inhibits human influenza A virus infection and sustains robust virus-specific CD8 T cell expansion
Authors: Yu Meng , Lin Ang , Baharom Faezzah , Li Shuijie , Legendre Maureen , Covés-Datson Evelyn , Sohlberg Ebba , Schlisio Susanne , Loré Karin , Markovitz David M. , Smed-Sörensen Anna 
Published: August 2024

ABSTRACTNative banana lectin (BanLec) is antiviral but highly mitogenic, which limits its therapeutic value. In contrast, the genetically engineered H84T BanLec (H84T) is not mitogenic but remains effective against influenza A virus (IAV) infection in mouse models. However, the potency and effect of H84T on human immune cells and IAV-specific immune responses is undetermined. We found that H84T efficiently inhibited IAV replication in human dendritic cells (DCs) from blood and tonsils, which preserved DC viability and allowed acquisition and presentation of viral antigen. Consequently, H84T-treated DCs initiated effective expansion of IAV-specific CD8 T cells. Furthermore, H84T preserved the capacity of IAV-exposed DCs to present a second non-IAV antigen and induce robust CD8 T cell expansion. This supports H84T as a potent antiviral in humans as it effectively inhibits IAV infection without disrupting DC function, and preserves induction of antigen-specific adaptive immune responses against diverse antigens, which likely is clinically beneficial.
Unlocking Protein Evolution Insights: Efficient and Interpretable Mutational Effect Predictions with GEMME
Authors: Carbone A. , Laine E. , Lombardi G. 
Published: August 2024

AbstractThe Global Epistatic Model for predicting Mutational Effects (GEMME) is a computational method that reconstructs protein mutational landscapes using sequence data alone. In this article, we delve into the broader biological questions that GEMME can address beyond mere landscape reconstruction. We provide several examples to guide users in maximizing the utility of GEMME. Additionally, we discuss recent advancements that enhance GEMME’s predictive accuracy and extend its capabilities by integrating sequence data with structural information and allele frequency data, when available. These innovations enable GEMME to answer new biological questions and offer deeper insights into protein evolution and function.
The evolution of signalling and monitoring in plant-fungal networks
Authors: Scott Thomas W. , Kiers E. Toby , West Stuart A. 
Published: August 2024

AbstractExperiments have shown that when one plant is attacked by a pathogen or herbivore, this can lead to other plants connected to the same mycorrhizal network upregulating their defence mechanisms. It has been hypothesised that this represents signalling, with attacked plants producing a signal to warn other plants of impending harm. We examined the evolutionary plausibility of this and other hypotheses theoretically. We found that the evolution of plant signalling about an attack requires restrictive conditions, and so will rarely be evolutionarily stable. The problem is that signalling about an attack provides a benefit to competing neighbours, even if they are kin, and so reduces the relative fitness of signalling plants. Indeed, selection is often more likely to push plant behaviour in the opposite direction – with plants signalling dishonestly about an attack that has not occurred, or by suppressing a cue that they have been attacked. Instead, we show that there are two viable alternatives that could explain the empirical data: (1) the process of being attacked leads to a cue (information about the attack) which is too costly for the attacked plant to fully suppress; (2) mycorrhizal fungi monitor their host plants, detect when they are attacked, and then the fungi signal this information to warn other plants in their network. Our results suggest the empirical work that would be required to distinguish between these possibilities.Significance statementExperiments have shown that when one plant is attacked by a herbivore, this can lead to other plants connected to the same mycorrhizal network upregulating their defence mechanisms. It has been hypothesised that this represents signalling, with attacked plants producing a signal to warn other plants of impending harm. We found theoretically that plant warning signals are rarely evolutionarily stable. Instead, we identify two viable alternatives that could explain the empirical data: (1) being attacked leads to a cue (information about the attack) which is too costly for the attacked plant to suppress; (2) mycorrhizal fungi monitor their host plants, detect when they are attacked, and then the fungi signal this information to warn other plants in their network.
Formation of giant ER sheets by pentadecanoic acid causes lipotoxicity in fission yeast
Authors: Hoshikawa Yojiro , Shirota Natsuho , Tsugawa Hiroshi , Kimura Satoshi , Matsuyama Akihisa , Yashiroda Yoko , Kakeya Hideaki , Arita Makoto , Iizumi Reiko , Yoshida Minoru , Nishimura Shinichi 
Published: August 2024

AbstractExcess amounts of saturated fatty acids are toxic to organisms, a condition termed lipotoxicity, which is often accompanied by pleiotropic cellular and tissue dysfunction. Here we show that pentadecanoic acid (C15:0) exerts toxicity on the fission yeastSchizosaccharomyces pombeby generating an aberrantly planar endoplasmic reticulum (ER) structure, which we named a “giant ER sheet.” Untargeted lipidomics revealed that C15:0 is incorporated into complex lipids depending on an acyl-CoA ligase Lcf1 and an acyl-CoA transferase Slc1, thereby increasing the saturation level of the acyl chains. The toxicity and giant ER sheet formation were abolished by deleting Lcf1 or Slc1, indicating that the incorporation of C15:0 into glycerophospholipids causes giant ER sheet formation. The giant ER sheets disrupted the correct migration of Mid1, a protein determining the cell division site, and physically blocked septum formation, hindering correct cell separation. Our results suggest that the ER is the primary site targeted by saturated fatty acids, leading to lipotoxicity.
Myosin forces elicit an F-actin structural landscape that mediates mechanosensitive protein recognition
Authors: Carl Ayala G. , Reynolds Matthew J. , Gurel Pinar S. , Phua Donovan Y.Z. , Sun Xiaoyu , Mei Lin , Hamilton Keith , Takagi Yasuharu , Noble Alex J. , Sellers James R. , Alushin Gregory M. 
Published: August 2024

AbstractCells mechanically interface with their surroundings through cytoskeleton-linked adhesions, allowing them to sense physical cues that instruct development and drive diseases such as cancer. Contractile forces generated by myosin motor proteins mediate these mechanical signal transduction processes through unclear protein structural mechanisms. Here, we show that myosin forces elicit structural changes in actin filaments (F-actin) that modulate binding by the mechanosensitive adhesion protein α-catenin. Using correlative cryo-fluorescence microscopy and cryo-electron tomography, we identify F-actin featuring domains of nanoscale oscillating curvature at cytoskeleton-adhesion interfaces enriched in zyxin, a marker of actin-myosin generated traction forces. We next introduce a reconstitution system for visualizing F-actin in the presence of myosin forces with cryo-electron microscopy, which reveals morphologically similar superhelical F-actin spirals. In simulations, transient forces mimicking tugging and release of filaments by motors produce spirals, supporting a mechanistic link to myosin’s ATPase mechanochemical cycle. Three-dimensional reconstruction of spirals uncovers extensive asymmetric remodeling of F-actin’s helical lattice. This is recognized by α-catenin, which cooperatively binds along individual strands, preferentially engaging interfaces featuring extended inter-subunit distances while simultaneously suppressing rotational deviations to regularize the lattice. Collectively, we find that myosin forces can deform F-actin, generating a conformational landscape that is detected and reciprocally modulated by a mechanosensitive protein, providing a direct structural glimpse at active force transduction through the cytoskeleton.
Integrative genomics approach identifies glial transcriptomic dysregulation and risk in the cortex of individuals with Alcohol Use Disorder
Authors: Warden Anna S. , Salem Nihal A. , Brenner Eric , Sutherland Greg T. , Stevens Julia , Kapoor Manav , Goate Alison M. , Dayne Mayfield R. 
Published: August 2024

AbstractAlcohol use disorder (AUD) is a prevalent neuropsychiatric disorder that is a major global health concern, affecting millions of people worldwide. Past molecular studies of AUD used underpowered single cell analysis or bulk homogenates of postmortem brain tissue, which obscures gene expression changes in specific cell types. Here we performed single nuclei RNA-sequencing analysis of 73 post-mortem samples from individuals with AUD (N=36, Nnuclei= 248,873) and neurotypical controls (N=37, Nnuclei= 210,573) in both sexes across two institutional sites. We identified 32 clusters and found widespread cell type-specific transcriptomic changes across the cortex in AUD, particularly affecting glia. We found the greatest dysregulation in novel microglial and astrocytic subtypes that accounted for the majority of differential gene expression and co-expression modules linked to AUD. Analysis for cell type-specific enrichment of aggregate genetic risk for AUD identified subtypes of microglia and astrocytes as potential key players not only affected by but causally linked to the progression of AUD. These results highlight the importance of cell-type specific molecular changes in AUD and offer opportunities to identify novel targets for treatment.
Multipartite complexity of the lichen symbiosis revealed by metagenome and transcriptome analysis ofXanthoria parietina
Authors: Tagirdzhanova Gulnara , Scharnagl Klara , Sahu Neha , Yan Xia , Bucknell Angus , Bentham Adam R. , Jégousse Clara , Ament-Velásquez Sandra Lorena , Onuț-Brännström Ioana , Johannesson Hanna , MacLean Dan , Talbot Nicholas J. 
Published: August 2024

AbstractLichens are composite symbiotic associations of fungi, algae, and bacteria that result in large, anatomically complex organisms adapted to many of the world’s most challenging environments. How such intricate, self-replicating lichen architectures develop from simple microbial components remains unknown because of their recalcitrance to experimental manipulation. Here we report a metagenomic and metatranscriptomic analysis of the lichenXanthoria parietinaat different developmental stages. We identified 168 genomes of symbionts and lichen-associated microbes within a lichen thallus, including representatives of green algae, three different classes of fungi, and 14 bacterial phyla. By analyzing occurrence of individual species across lichen thalli from diverse environments, we defined both substrate-specific and core microbial components of the lichen. Meta-transcriptomic analysis of the principal fungal symbiont from three different developmental stages of a lichen, compared to axenically grown fungus, revealed differential gene expression profiles indicative of lichen-specific transporter functions, specific cell signalling, transcriptional regulation and secondary metabolic capacity. Putative immunity-related proteins and lichen-specific structurally conserved secreted proteins resembling fungal pathogen effectors were also identified, consistent with a role for immunity modulation in lichen morphogenesis.
Ribosome-inactivation by a class of widely distributed C-tail anchored membrane proteins
Authors: Njenga Robert , Boele Julian , Drepper Friedel , Sinha Kasturica , Marouda Eirini , Huesgen Pitter F. , Blaby-Haas Crysten , Koch Hans-Georg 
Published: August 2024

SummaryRibosome hibernation is a commonly used strategy that protects ribosomes under unfavorable conditions and regulates developmental processes. Multiple ribosome-hibernation factors have been identified in all domains of life, but due to their structural diversity and the lack of a common inactivation mechanism, it is currently unknown how many different hibernation factors exist. Here, we show that the YqjD/ElaB/YgaM paralogs, initially discovered as membrane-bound ribosome binding proteins inE. coli,constitute an abundant class of ribosome-hibernating proteins, which are conserved across all proteobacteria and some other bacterial phyla. Our data demonstrate that they inhibitin vitroprotein synthesis by interacting with the 50S ribosomal subunit.In vivocross-linking combined with mass spectrometry reveals their specific interactions with proteins surrounding the ribosomal tunnel exit and even their penetration into the ribosomal tunnel. Thus, YqjD/ElaB/YgaM inhibit translation by blocking the ribosomal tunnel and thus mimic the activity of antimicrobial peptides and macrolide antibiotics.
Improved Zika virus plaque assay using Vero/TMPRSS2 cell line
Authors: Oluwasemowo Olukunle O. , Graham Monica E. , Murugesh Deepa K. , Borucki Monica K. 
Published: August 2024

ABSTRACTPlaque assay is the gold standard for the quantification of viable cytopathic viruses like Zika virus (ZIKV). Some strains of ZIKV produce plaques that are very difficult to accurately visualize and count on the commonly used Vero cell line. From data generated in our lab, we became curious if Vero/TMPRSS2 cells may be a better alternative, therefore we compared the plaque forming units (PFU) of two strains of ZIKV on Vero/TMPRSS2 cells to those produced by Vero cells. We also compared the virus stock titer generated on Vero/TMPRSS2 cells to that generated by the Vero cell line. Although Vero cells generated higher quantity of ZIKV stocks, Vero/TMPRSS2 cells produced plaques with significantly improved morphology and visibility and may therefore be a better alternative to use for performing plaque assays for strains of ZIKV that are more difficult to titer on regular Vero cells.
Crosslinked agarose-gelatine beads as a substrate for investigating biofilms of bacterial pathogens
Authors: Roizman Dan , Herzog Maren , Nath Arpita , Pachaimuthu Nivetha , Hujeirat Ahmad , Kuropka Benno , Rolff Jens , Rodríguez-Rojas Alexandro 
Published: August 2024

AbstractTreating chronic bacterial infections is challenging due to the formation of biofilms, making bacteria less susceptible to antimicrobials.In vitromodels have limitations in replicating biofilm physiology. To address this problem, we have created a hydrogel substrate that combines crosslinked agarose and gelatine presented as beads, providing stability and resistance to autoclaving. Bacterial pathogens rapidly colonise these biogel beads when submerged in liquid culture. The substrate was tested withEscherichia coli,Pseudomonas aeruginosa, andStaphylococcus aureus, showing more robust biofilm growth than its glass bead counterpart. Additionally, this led to increased virulence factor production and served as a reservoir for biofilm quorum sensing molecules. These features closely resemble clinical situations, suggesting a more accurate representation of biofilm-associated infections than current approaches. This new substrate offers a practical and convenient model for studying biofilms of bacterial pathogens, providing an efficient solution to the research community and holding promise for future breakthroughs.
Antiviral Library Screening Leads to Discovery of Novel and Potent Anticlostridial Compounds
Authors: Stolz Brice Jasarino , Seleem Mohamed N. , Abouelkhair Ahmed A 
Published: August 2024

Clostridium difficile(C. difficile) is a major cause of nosocomial infections, often associated with individuals who have gut dysbiosis from previous antibiotic therapies.C. difficileinfections have a high recurrence rate and impose significant financial and mortality burdens on the healthcare system. Novel anti-C. difficiledrugs are urgently needed to treat and reduce the severity and recurrence of infection. In this study, we screened a library of 618 antiviral drugs to identify a potential candidate for repurposing as novel anti-C. difficiletreatments. Following our preliminary screening, we identified 9 novel compounds that inhibitC. difficileat a concentration of 16 µM or lower. Among these, 4 antiviral compounds demonstrated the most potent anti-C. difficileactivity against a panel of 15C. difficileisolates, with minimum inhibitory concentrations (MICs) comparable to the drug of choice, vancomycin. These include rottlerin (MIC50 = 0.25 µg/mL), α-mangostin (MIC50 = 1 µg/mL), dryocrassin ABBA (MIC50 = 1 µg/mL), and obefazimod (MIC50 = 4 µg/mL). All exhibited minimal to no activity against representative members of the gut microbiota. Interestingly, α-mangostin, a natural xanthone derived from the mangosteen fruit, exhibited strong bactericidal action, clearing a high inoculum ofC. difficilein less than an hour. All other drugs exhibited bacteriostatic activity. Given the characteristics of these compounds, they show great promise as novel treatments forC. difficileinfections.
A rapid growth rate underpins the dominance ofHanseniaspora uvarumin spontaneous grape juice fermentations
Authors: Onetto Cristobal A. , McCarthy Jane , Schmidt Simon A. 
Published: August 2024

AbstractHanseniaspora uvarumis consistently observed as the dominant non-Saccharomycesspecies in spontaneous grape juice fermentations. However, the physiological mechanisms and physicochemical variables influencing the prevalence ofH. uvarumover other non-Saccharomycesspecies remain unclear. We tested the physicochemical parameters contributing toH. uvarumdominance by inoculating a chemically diverse set of grape juices with a mock community whose composition was defined following a comprehensive microbial survey of spontaneous fermentations. Our findings indicated that the chemical composition of grape juice had minimal impact on the microbial dynamics of fermentation, withH. uvarumemerging as the dominant non-Saccharomycesspecies in nearly all conditions tested. Grape juice composition primarily influenced the total yeast abundance of the mock community. Flow cytometry analysis confirmed thatH. uvarumhas a faster growth rate thanSaccharomyces cerevisiaeand several otherHanseniaspora spp.. Moreover, its growth was not affected by the presence ofS. cerevisiae, explaining its rapid dominance in spontaneous fermentations. The rapid growth ofH. uvarumnegatively impacted the growth ofS. cerevisiae, with significant implications for fermentation performance and sugar consumption. The results of this study suggest that the fast growth rate ofH. uvarumenables it to quickly dominate the grape juice environment during the early stages of fermentation. This physiological advantage indicates that the initial abundance ofH. uvarummay be critical to the outcome of spontaneous fermentations, as evidenced by its direct impact on the growth ofS. cerevisiaeand fermentation performance.
Clu1/Clu form mitochondria-associated granules upon metabolic transitions and regulate mitochondrial protein translation via ribosome interactions
Authors: Miller-Fleming Leonor , Au Wing Hei , Raik Laura , Guiomar Pedro , Schmitz Jasper , Cho Ha Yoon , Czako Aron , Whitworth Alexander J 
Published: August 2024

ABSTRACTMitochondria perform essential metabolic functions and respond rapidly to changes in metabolic and stress conditions. As the majority of mitochondrial proteins are nuclear-encoded, intricate post-transcriptional regulation is crucial to enable mitochondria to adapt to changing cellular demands. The eukaryotic Clustered mitochondria protein family has emerged as an important regulator of mitochondrial function during metabolic shifts. Here, we show that theDrosophila melanogasterandSaccharomyces cerevisiaeClu/Clu1 proteins form dynamic, membraneless granules adjacent to mitochondria in response to metabolic changes. Yeast Clu1 regulates the translation of a subset of nuclear-encoded mitochondrial protein by interacting with their mRNAs while these are engaged in translation. We further show that Clu1 regulates translation by interacting with polysomes, independently of whether it is in a diffuse or granular state. Our results demonstrate remarkable functional conservation with other members of the Clustered mitochondria protein family and suggests that Clu/Clu1 granules isolate and concentrate ribosomes engaged in translating their mRNA targets, thus, integrating metabolic signals with the regulation of mitochondrial protein synthesis.
CAG repeat-selective compounds reduce abundance of expanded CAG RNAs in patient cell and murine models of SCAs
Authors: Shorrock Hannah K. , Aliyeva Asmer , Frias Jesus A. , DeMeo Victoria A. , Lennon Claudia D. , DeMeo Cristina C. , Mascorro Amy K. , Shaughnessy Sharon , Mazdiyasni Hormoz , Cleary John D. , Reddy Kaalak , Vangaveti Sweta , Shin Damian S. , Berglund J. Andrew 
Published: August 2024

SummarySpinocerebellar ataxias (SCAs) are a genetically heterogenous group of devastating neurodegenerative conditions for which clinical care currently focuses on managing symptoms. Across these diseases there is an unmet need for therapies that address underlying disease mechanisms. We utilised the shared CAG repeat expansion mutation causative for a large subgroup of SCAs, to develop a novel disease-gene independent and mechanism agnostic small molecule screening approach to identify compounds with therapeutic potential across multiple SCAs. Using this approach, we identified the FDA approved microtubule inhibitor Colchicine and a novel CAG-repeat binding compound that reduce expression of disease associated transcripts across SCA1, 3 and 7 patient derived fibroblast lines and theAtxn1154Q/2QSCA1 mouse model in a repeat selective manner. Furthermore, our lead candidate rescues dysregulated alternative splicing inAtxn1154Q/2Qmice. This work provides the first example of small molecules capable of targeting the underlying mechanism of disease across multiple CAG SCAs.