bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of mutant IDH1 promotes cycling of acute myeloid leukemia stem cells
Authors: Gruber Emily , So Joan , Lewis Alexander C. , Franich Rheana , Cole Rachel , Martelotto Luciano G. , Rogers Amy J. , Vidacs Eva , Fraser Peter , Stanley Kym , Jones Lisa , Trigos Anna , Thio Niko , Li Jason , Nicolay Brandon , Daigle Scott , Tron Adriana E. , Hyer Marc L. , Shortt Jake , Johnstone Ricky W. , Kats Lev M. 
Published: April 2022

ABSTRACTAcute myeloid leukemias (AML) are comprised of multiple cell types with distinct capabilities to propagate the disease and resist therapy. Approximately 20% of AML patients carry gain- of-function mutations in IDH1 or IDH2 that result in over-production of the onco-metabolite 2-HG. Although IDH inhibitors can induce complete morphological remission, almost all patients eventually relapse. Analysis of clinical samples suggests that a population of IDH mutant cells is able to persist during treatment eventually acquiring 2-HG independence and drug resistance. Herein we characterized the molecular and cellular responses to the clinical IDH1 inhibitor AG-120 at high resolution using a novel multi-allelic mouse model of IDH1 mutant AML. We demonstrate that AG-120 exerts cell type-dependent effects on leukemic cells promoting delayed disease regression. Although IDH1 inhibition alone was not able to fully eradicate the disease, we uncovered that it increases cycling of rare leukemic stem cells and triggers transcriptional upregulation of the pyrimidine salvage pathway. Accordingly, AG-120 sensitized IDH1 mutant AML to azacitidine with the combination of AG-120 and azacitidine showing vastly improved efficacy in vivo. Our data highlight the impact of non- genetic heterogeneity on treatment response and provide mechanistic rationale for a drug combination that is being tested in clinical trials.STATEMENT OF SIGNIFICANCEInhibition of mutant IDH1 in AML is insufficient to eliminate the disease but promotes proliferation of quiescent leukemic stem cells. Our data provide a mechanistic explanation for the observed synergy between IDH inhibitors and azacitidine and suggest that IDH inhibitors may also synergize with other drugs that preferentially target actively dividing cells.
Secreted dengue virus NS1 from infection is predominantly dimeric and in complex with high-density lipoprotein
Authors: Chew Bing Liang Alvin , Ngoh An Qi , Phoo Wint Wint , Chan Kitti Wing Ki , Ser Zheng , Tulsian Nikhil K , Lim Shiao See , Weng Mei Jie Grace , Watanabe Satoru , Choy Milly M. , Low Jenny G. , Ooi Eng Eong , Ruedl Christiane , Sobota Radoslaw M. , Vasudevan Subhash G. , Luo Dahai 
Published: April 2022

AbstractSevere dengue infections are characterized by endothelial dysfunction shown to be associated with the secreted nonstructural protein 1 (sNS1), making it an attractive vaccine antigen and biotherapeutic target. To uncover the biologically relevant structure of sNS1, we obtained infection-derived sNS1 (isNS1) from DENV-infected Vero cells through immunoffinity purification instead of recombinant sNS1 (rsNS1) overexpressed in insect or mammalian cell lines. We found that isNS1 appeared as an approximately 250 kDa complex of NS1 and ApoA1 and further determined the cryoEM structures of isNS1 and its complex with a monoclonal antibody/Fab. Indeed, we found that the major species of isNS1 is a complex of the NS1 dimer partially embedded in a High-Density Lipoprotein (HDL) particle. Cross-linking mass spectrometry (XL-MS) studies confirmed that the isNS1 interacts with the major HDL component ApoA1 through interactions that map to the NS1 wing and hydrophobic domains. Furthermore, our studies demonstrated that the sNS1 in sera from DENV-infected mice and a human patient form a similar complex as isNS1. Our results report the molecular architecture of a biological form of sNS1 which may have implications for the molecular pathogenesis of dengue.SummaryCryoEM structures of secreted dengue virus NS1 protein reveal dimers in complex with high-density lipoprotein.
Bio-electric potentials in superior plants: electric collective behaviour
Authors: Chiolerio Alessandro , Dehshibi Mohammad Mahdi , Vitiello Giuseppe , Bernard Alessandro , Ceretto Paolo , Arvat Massimo , Adamatzky Andrew 
Published: April 2022

ABSTRACTElectrical activity is used by plants in long term signalling and information transfer between the distant parts of the plant. Biopotential recordings from trees in a natural environment have been so far less discussed in scientific literature. Here we present our data about the open science experiment TRee-hUMAn iNterface (TRUMAN) located in Paneveggio forest (Valle di Fiemme, Trento, Italy), cultivated since one thousand years for the production of harmonic wood from Picea abies (red fir). We show that: i) biopotential features based on xylem can be correlated with the solar (and lunar) cycle ii) dead tree logs show an electrical activity that is correlated with that of neighbouring trees iii) statistical features of the spike-like peaks are evidenced, including amplitude, frequency, propagation speed, entropy iv) a quantum field theory is presented to highlight the collective behaviour of the forest, supported by preliminar correlation analyses between electrical signal Kolmogorov entropy and thermographies Shannon entropy.
LILAC: Enhanced actin imaging with an optogenetic Lifeact
Authors: Kroll Kourtney L. , French Alexander R. , Sosnick Tobin R. , Rock Ronald S. 
Published: April 2022

AbstractWe have designed an improved Lifeact variant that binds to actin under the control of light using the LOV2 protein. Light control enables one to subtract the pre-illumination signal of the unbound label, yielding an enhanced view of F-actin dynamics in cells. Furthermore, the tool eliminates actin network perturbations and cell sickness caused by Lifeact overexpression.
Recycling of uridylated mRNAs in starfish embryos
Authors: Yamazaki Haruka , Furuichi Megumi , Katagiri Mikoto , Kajitani Rei , Itoh Takehiko , Chiba Kazuyoshi 
Published: April 2022

AbstractIn eukaryotes, mRNAs with long poly(A) tails are translationally active, whereas deadenylation of the tails decreases translation and uridylation of the short poly(A) tails causes the mRNA to be degraded. In this study, we confirmed that maternalcyclin BmRNAs with long poly(A) tails in blastula embryos of invertebrate starfish were deadenylated and uridylated, followed by decay. In starfish oocytes, however,cyclin BmRNAs with uridylated short poly(A) tails are stable. They are polyadenylated and translationally active immediately following hormonal stimulation for resumption of meiosis. Similarly, maternal ribosomal protein mRNAs,Rps29andRpl27a, which become uridylated following deadenylation upon hormonal stimulation, remain stable even after fertilisation and early development. At the morula stage, the uridylated maternal ribosomal protein mRNAs are modified to yield non-canonical poly (A) tails rich in U and G residues in the 5’ region and in A residues at the 3’ end, rendering them translationally active. These results indicate that the fates of uridylated mRNAs in starfish are decay and/or recycling.
The production of diverse brGDGTs by an Acidobacterium allows a direct test of temperature and pH controls on their distribution
Authors: Chen Yufei , Zheng Fengfeng , Yang Huan , Yang Wei , Wu Ruijie , Liu Xinyu , Liang Huayang , Chen Huahui , Pei Hongye , Zhang Chuanlun , Pancost Richard D. , Zeng Zhirui 
Published: April 2022

AbstractMicrobial lipid biomarkers preserved in geological archives can be used to explore past climate changes. Branched glycerol dialkyl glycerol tetraethers (brGDGTs) are unique bacterial biomarkers that have been used as molecular tools for the quantitative determination of terrestrial temperatures and the pH of depositional environments over a range of geological timescales. However, the exact biological source organisms – especially of the entire suite of brGDGTs found in the environment – remains unclear; by extension, so do the mechanisms that govern these proxies. Here, we identified a brGDGT-producing strainCandidatus Solibacter usitatusEllin6076, by identifying archaeal tetraether synthase homologs in bacterial genomes. This strain synthesizes diverse brGDGTs, including regular C5-methylated and cyclic brGDGTs, and brGDGTs comprise up to 66% of the major lipids, far exceeding the proportions found in previous studies. The degree of C5-methylation in cultured strain Ellin6076 is primarily determined by temperature, whereas cyclization appears to be influenced by multiple factors. Consequently, culture-derived paleoclimate indices are in agreement with the global soil-derived MBT’5ME(methylation index of C5-methyl brGDGTs) proxy for temperature but not the CBT5ME(cyclization index of C5-methyl brGDGTs) proxy for pH. Our findings provide important insights from a physiological perspective into the underlying mechanism of brGDGT-based proxies.Significance StatementBranched glycerol dialkyl glycerol tetraethers (brGDGTs) are biomarkers widely used for the quantitative estimation of past climatic changes due to their ubiquitous occurrence in the environment and the relationships between their distributions and temperature and pH. However, the ecophysiology of brGDGT-producing bacteria and the mechanistic basis for brGDGT-based climate proxies remain unknown. Here, we identify a brGDGT-producing Acidobacterium and present a physiological study of brGDGTs in response to cultivation variables, which provides pivotal insights into how brGDGT producers modulate methylation and cyclization under different culturing conditions. Our study represents a significant advancement in understanding the physiological role of lipid structures in microbial adaptation and helps us interpret the relationships between brGDGT-based proxies and environmental conditions of the geological environment.
AGC: Compact representation of assembled genomes
Authors: Deorowicz Sebastian , Danek Agnieszka , Li Heng 
Published: April 2022

AbstractHigh-quality sequence assembly is the ultimate representation of complete genetic information of an individual. Several ongoing pangenome projects are producing collections of high-quality assemblies of various species. Here, we show how to represent the sequenced genomes in 2–3 orders of magnitude smaller space, allowing easy and fast extraction of any contig or its part.
ARP2/3 complex associates with peroxisomes to participate in pexophagy in plants
Authors: Martinek Jan , Cifrová Petra , Vosolsobě Stanislav , Krtková Jana , Sikorová Lenka , Malínská Kateřina , Mauerová Zdeňka , Leaves Ian , Sparkes Imogen , Schwarzerová Kateřina 
Published: April 2022

ABSTRACTARP2/3 is a heteroheptameric protein complex evolutionary conserved in all eukaryotic organisms. Its conserved role is based on the induction of actin polymerization at the interface between membranes and the cytoplasm. Plant ARP2/3 has been reported to participate in actin reorganization at the plasma membrane during polarized growth of trichomes and at the plasma membrane-endoplasmic reticulum contact sites. We demonstrate here that individual plant subunits of ARP2/3 fused to fluorescent proteins form motile dot-like structures in the cytoplasm that are associated with plant peroxisomes. ARP2/3 dot structure is found at the peroxisome periphery and contains assembled ARP2/3 complex and WAVE/SCAR complex subunit NAP1. This dot occasionally colocalizes with the autophagosome, and under conditions that affect the autophagy, colocalization between ARP2/3 and the autophagosome increases. ARP2/3 subunits co-immunoprecipitate with ATG8f marker. Since mutants lacking functional ARP2/3 complex have more peroxisomes than WT, we link the ARP2/3 complex on peroxisomes to the process of peroxisome degradation by autophagy called pexophagy. Additionally, several other peroxisomal proteins colocalize with ARP2/3 dot on plant peroxisomes. Our results suggest a specific role of ARP2/3 and actin in the peroxisome periphery, presumably in membrane remodelling. We hypothesize that this role of ARP2/3 aids processes at the peroxisome periphery such as peroxisome degradation through autophagy or regulation of peroxisomal proteins localization or function.Significance statementARP2/3 complex-positive dots associate exclusively with peroxisomes in plant cells, where it colocalizes with autophagosome marker ATG8f and several other proteins. Our experiments link ARP2/3 to pexophagy: colocalization between ARP2/3 dots and autophagosome increases when autophagy processes are induced or inhibited; ARP2/3 and ATG8f colocalize and co-immunoprecipitate, and finally, ARP2/3 mutants’ cells contain more peroxisomes than WT. Our results suggest a novel role of ARP2/3 in peroxisome structure and function regulation.
Plant N-glycan breakdown by human gut Bacteroides
Authors: Crouch Lucy I. , Urbanowicz Paulina A. , Baslé Arnaud , Cai Zhi-Peng , Liu Li , Voglmeir Josef , Diaz Javier M. Melo , Benedict Samuel T. , Spencer Daniel I.R. , Bolam David N. 
Published: April 2022

AbstractThe major nutrients available to the human colonic microbiota are complex glycans derived from the diet. To degrade this highly variable mix of sugar structures, gut microbes have acquired a huge array of different carbohydrate-active enzymes (CAZymes), predominantly glycoside hydrolases, many of which have specificities that can be exploited for a range of different applications. Plant N-glycans are prevalent on proteins produced by plants and thus components of the diet, but the breakdown of these complex molecules by the gut microbiota has not been explored. Plant N-glycans are also well characterised allergens in pollen and some plant-based foods, and when plants are used in heterologous protein production for medical applications, the N-glycans present can pose a risk to therapeutic function and stability. Here we use a novel genome association approach for enzyme discovery to identify a breakdown pathway for plant complex N-glycans encoded by a gut Bacteroides species and biochemically characterise five CAZymes involved, including structures of the PNGase and GH92 α-mannosidase. These enzymes provide a toolbox for the modification of plant N-glycans for a range of potential applications. Furthermore, the keystone PNGase also has activity against insect-type N-glycans, which we discuss from the perspective of insects as a nutrient source.
Streptococcus Pneumoniae Promotes Lung Tumorigenesis by Activating PI3K/AKT and NF-kB Pathways via Binding PspC to PAFR
Authors: Li Ning , Zhou Huifen , Holden Van K , Deepak Janaki , Dhilipkannah Pushpa , Todd Nevins W , Jiang Feng 
Published: April 2022

AbstractStreptococcus pneumoniae (SP) is associated with lung cancer, yet its role in the tumorigenesis remains uncertain. Herein we find that SP attaches to lung cancer cells via binding pneumococcal surface protein C (PspC) to platelet-activating factor receptor (PAFR), a receptor overexpressed in lung tumors. Interaction between PspC and PAFR stimulates cell proliferation and activates PI3K/AKT and NF-kB signaling pathways, which triggers a pro-inflammatory response. Lung cancer cells infected with SP rapidly form larger tumors in BALB/C mice compared to untreated cells. Mice treated with tobacco carcinogen and SP develop more lung tumors and had shorter survival than mice treated with the carcinogen alone. Mutating PspC or deleting PAFR abolishes the tumor-promoting effects of SP. Overabundance of SP is found in lung tumors of patients with lung cancer and associated with the survival. SP plays a driving role in lung tumorigenesis by activating PI3K/AKT and NF-kB pathways via binding PspC to PAFR and provides a microbial target for diagnosis and treatment of the disease.
Probing the role of macromolecular crowding in cell volume regulation using fluorescence anisotropy
Authors: Biswas Parijat , Ray Dipanjan , Jana Subhamoy , Das Jibitesh , Sinha Bidisha , Sinha Deepak Kumar 
Published: April 2022

AbstractCytoplasmic macromolecular crowding (MMC) influences multiple cellular functions. Using fluorescence anisotropy of EGFP, we explore the homeostasis of MMC in the cytoplasm and its role in cell volume regulation. Individual cells of different lineages maintain a distinctly unique average cytoplasmic MMC for considerably long durations. Despite diffusion, actin cytoskeleton facilitates spatially heterogeneous MMC in the cytoplasm. While hypertonic-stress triggers regulatory volume increase (RVI), other methods of increasing cytoplasmic MMC fail to start RVI, suggesting that cells lack capabilities for MMC homeostasis. During spreading or microtubule-depolymerized state, cells neglect changes in cytoplasmic MMC to undergo volume regulation. Inhibition of TNFR1 increases the membrane tension and deprives cells of their ability to undergo volume regulation. Current understanding contemplates that cytoplasmic MMC, the mechanical state of the plasma membrane or the actin cytoskeleton, could be sensors for cell volume regulation. Our observations establish the irrelevance of cytoplasmic MMC and the significance of plasma membrane tension in setting off the cell volume regulation machinery.
Extended functional connectivity of convergent structural alterations among individuals with PTSD: A neuroimaging meta-analysis
Authors: Pankey Brianna S. , Riedel Michael C. , Cowan Isis , Bartley Jessica E. , Lobo Rosario Pintos , Hill-Bowen Lauren D. , Salo Taylor , Musser Erica D. , Sutherland Matthew T. , Laird Angela R. 
Published: April 2022

AbstractBackgroundPost-traumatic stress disorder (PTSD) is a debilitating disorder defined by the onset of intrusive, avoidant, negative cognitive or affective, and/or hyperarousal symptoms after witnessing or experiencing a traumatic event. Previous voxel-based morphometry studies have provided insight into structural brain alterations associated with PTSD with notable heterogeneity across these studies. Furthermore, how structural alterations may be associated with brain function, as measured by task-free and task-based functional connectivity, remains to be elucidated.MethodsUsing emergent metaanalytic techniques, we sought to first identify a consensus of structural alterations in PTSD using the anatomical likelihood estimation (ALE) approach. Next, we generated functional profiles of identified convergent structural regions utilizing resting-state functional connectivity (rsFC) and meta-analytic coactivation modeling (MACM) methods. Finally, we performed functional decoding to examine mental functions associated with our ALE, rsFC, and MACM brain characterizations.ResultsWe observed convergent structural alterations in a single region located in the medial prefrontal cortex. The resultant rsFC and MACM maps identified functional connectivity across a widespread, whole-brain network that included frontoparietal and limbic regions. Functional decoding revealed overlapping associations with attention, memory, and emotion processes.ConclusionsConsensus-based functional connectivity was observed in regions of the default mode, salience, and central executive networks, which play a role in the tripartite model of psychopathology. Taken together, these findings have important implications in understanding the neurobiological mechanisms associated with PTSD.
Long lifespan is maintained by a unique Heat Shock Factor in reproductive ants
Authors: Glastad Karl M. , Roessler Julian , Gospocic Janko , Berger Shelley L. 
Published: April 2022

AbstractAmong eusocial insects, reproductive females show longer lifespan than non-reproductive female workers despite high genetic similarity. Using an ant species (Harpegnathos saltator, Hsal) featuring inducible worker reproduction and correlated extended lifespan, we find that long-lived reproductive individuals (called “gamergates”) show elevated expression of heat shock response (HSR) genes specifically in the absence of heat stress. This HSR gene elevation is driven in part by gamergate-specific constitutive upregulation of a heat shock transcription factor gene most similar to mammalian HSF2 (called hsalHSF2). In sterile workers hsalHSF2 is bound to DNA only upon heat stress, but in gamergates hsalHSF2 binds to DNA in the absence of heat stress, and correlates with caste-biased gene expression of a subset of heat-inducible genes, thus showing natural bias to gamergates. Remarkably, ectopic expression in D. melanogaster of hsalHSF2 leads to enhanced survival compared to hsalHSF1 following heat stress, as well as extended lifespan. Molecular characterization of these longer-lived flies illustrates multiple parallels between long-lived flies and gamergates, underscoring the centrality of hsalHSF2 to extended lifespan in gamergates. Hence, ant caste-specific heat stress resilience and excessive longevity is, remarkably, transferrable to flies via a specialized ant heat shock factor, HSF2. These findings reinforce the critical role of proteostasis to health and to aging, and reveal novel mechanisms underlying facultative lifespan extension.
A generic framework for hierarchical de novo protein design
Authors: Harteveld Zander , Bonet Jaume , Rosset Stéphane , Yang Che , Sesterhenn Fabian , Correia Bruno E. 
Published: April 2022

AbstractDe novo protein design enables the exploration of novel sequences and structures absent from the natural protein universe. De novo design also stands as a stringent test to our understanding of the underlying physical principles of protein folding and may lead to the development of proteins with unmatched functional characteristics. The first fundamental challenge of de novo design is to devise “designable” structural templates leading to sequences that will adopt the predicted fold. Here, we built on the TopoBuilder de novo design method to automatically assemble structural templates with native-like features starting from string descriptors that capture the overall topology of proteins. Our framework eliminates the dependency of hand-crafted and fold-specific rules through an iterative, data-driven approach that extracts geometrical parameters from structural tertiary motifs. We evaluated the TopoBuilder framework by designing sequences for a set of five protein folds and experimental characterization revealed that several sequences were folded and stable in solution. The TopoBuilder de novo design framework will be broadly useful to guide the generation of artificial proteins with customized geometries, enabling the exploration of the protein universe.
Oncogenic signalling is coupled to colorectal cancer cell differentiation state
Authors: Sell Thomas , Klotz Christian , Fischer Matthias M. , Astaburuaga-García Rosario , Krug Susanne , Drost Jarno , Clevers Hans , Morkel Markus , Blüthgen Nils 
Published: April 2022

AbstractColorectal cancer progression is intrinsically linked to stepwise deregulation of the intestinal differentiation trajectory. In this process, sequential mutations of APC/Wnt, KRAS, TP53 and SMAD4 stepwisely enable an oncogenic signalling network. Here, we developed a novel mass cytometry antibody panel to analyse colorectal cancer cell differentiation and signalling in human isogenic colorectal cancer organoids and in patient-derived cultures. We define a differentiation axis following EphrinB2 abundance in all tumour progression states from normal to cancer. We show that during colorectal cancer progression, oncogenes decrease dependence on external factors and shape distribution of cells along the differentiation axis. In this regard, subsequent mutations can have stem cell-promoting or restricting effects. Individual nodes of the signalling network remain coupled to the differentiation state, regardless of the presence of oncogenic signals. Our work underscores the key role of cell plasticity as a hallmark of cancer that is gradually unlocked during colorectal cancer progression.