bluuebunny/crossref_metadata_2025_split huggingface dataset:
Analysis and Identification of Necroptosis Landscape on Therapy and Prognosis in Bladder Cancer
Authors: Zhao Zihan , Jiang Ning , Zhang Yulin , Bai Yuhao , Liu Tianyao , Li Tianhang , Guo Hongqian , Yang Rong 
Published: May 2022

AbstractBladder cancer (BLCA) is one of the most common malignant tumors of the urinary system, but current therapeutic strategy based on chemotherapy and immune checkpoint inhibitors (ICIs) therapy cannot meet the treatment needs, which mainly owing to the endogenous or acquired apoptotic resistance of cancer cells. Targeting necroptosis provides a novel strategy for chemotherapy, targeted drugs, and improves the efficacy of ICIs because of strong immunogenicity of necroptosis. Therefore, we systemically analyzed necroptosis landscape on therapy and prognosis in BLCA. We firstly divided BLCA patients from The Cancer Genome Atlas (TCGA) database into two necroptosis-related clusters (C1 and C2). Necroptosis C2 showed a significantly better prognosis than C1, and the differential genes of C2 and C1 were mainly related to the immune response according to GO and KEGG analysis. Next, we constructed a novel necroptosis related genes (NRGs) signature consisting of SIRT6, FASN, GNLY, FNDC4, SRC, ANXA1, AIM2, and IKBKB to predict the survival of TCGA-BLCA cohort, the accuracy of NRGsocre was also verified by external datasets. In addition, a nomogram combining NRGscore and several clinicopathological features was established to predict the BLCA patient’s OS more accurately and conveniently. We also found that NRGscore was significantly related to the infiltration levels of CD8 T cells, NK cells, and iDC cells, the gene expression of CTLA4, PD1, TIGIT, and LAG3 of TME, the sensitivity to chemotherapy and targeted agents in BLCA patients. In conclusion, the NRGscore has an excellent performance in evaluating the prognosis, clinicopathologic features, tumor microenvironment (TME) and therapeutic sensitivity of BLCA patients, which could be utilized as a guide for chemotherapy, ICIs therapy, and combination therapy.
Glutamine 666 renders murine ADAM10 an inefficient S. aureus α-toxin receptor
Authors: von Hoven Gisela , Meyenburg Martina , Neukirch Claudia , Siedenschnur Daniel , Husmann Matthias 
Published: May 2022

AbstractS. aureus is one of the most important causes of infectious diseases in hospitalized individuals and outpatients. The majority of clinical isolates secretes large amounts of the small membrane pore-forming α-toxin, alias α-hemolysin, which serves as an important virulence factor of this organism. The identification of A Disintegrin And Metalloprotease (ADAM10) as its high affinity receptor held great promise for a better understanding of the processes underlying membrane damage by α-toxin. Twelve years on however, the molecular details of initial toxin binding to target cells remain elusive. Because we noted that several murine cell lines were resilient to α-toxin, we considered the possibility that murine ADAM10 could be less efficient a receptor, as compared to human or bovine orthologues. Accordingly, we sought to identify amino acid residues in ADAM10, which could explain species-dependent functionality as receptor for α-toxin. Our work led to the finding that replacement of a single glutamine residue (Q666) in murine ADAM10 with corresponding glutamic acid (E665) of human or bovine ADAM10 enhances significantly the binding and consequent cytotoxicity of α-toxin. Consistently, a synthetic peptide comprising E665 mitigated α-toxin-dependent hemolysis. In multicellular organisms, E665 is highly conserved, but mice and several other members of the taxon glires evolved glutamine at the corresponding position. The residue is located in a short membrane proximal, extracellular region of ADAM10. Taken together, available structural information, in silico docking, and functional data suggests that α-toxin monomers could bind to cellular membranes via this so-called stalk region of ADAM10 and phosphocholine.
Sleep does not influence schema-facilitated motor memory consolidation
Authors: Reverberi S. , Dolfen N. , van Roy A. , Albouy G. , King B.R. 
Published: May 2022

AbstractStudy ObjectivesNovel information is rapidly learned when it is compatible with previous knowledge. This “schema” effect, initially described for declarative memories, was recently extended to the motor memory domain. Importantly, this beneficial effect was only observed 24 hours – but not immediately – following motor schema acquisition. Given the established role of sleep in memory consolidation, we hypothesized that sleep following the initial learning of a schema is necessary for the subsequent rapid integration of novel motor information.MethodsTwo experiments were conducted to investigate the effect of diurnal and nocturnal sleep on schema-mediated motor sequence memory consolidation. In Experiment 1, participants first learned an 8-element motor sequence through repeated practice (Session 1). They were then afforded a 90-minute nap opportunity (N=25) or remained awake (N=25) before learning a second motor sequence (Session 2) which was highly compatible with that learned prior to the sleep/wake interval. Experiment 2 was similar; however, Sessions 1 and 2 were separated by a 12-hour interval that included nocturnal sleep (N=28) or only wakefulness (N=29).ResultsFor both experiments, we found no group differences in motor sequence performance (reaction time and accuracy) following the sleep/wake interval. Furthermore, in Experiment 1, we found no correlation between sleep features (non-REM sleep duration, spindle and slow wave activity) and post-sleep behavioral performance.ConclusionsThe results of this research suggest that integration of novel motor information into a cognitive-motor schema does not specifically benefit from post-learning sleep.
FAMetA: a mass isotopologue-based tool for the comprehensive analysis of fatty acid metabolism
Authors: Alcoriza-Balaguer María Isabel , García-Cañaveras Juan Carlos , Benet Marta , Vidal Oscar Juan , Lahoz Agustín 
Published: May 2022

AbstractThe use of stable isotope tracers and mass spectrometry (MS) is the gold standard method for the analysis of fatty acids (FAs) metabolism. Yet current state-of-the-art tools provide limited and difficult to interpret information about FA biosynthetic routes. Here we present FAMetA, an R-package and a web-based application (www.fameta.es) that use 13C mass-isotopologue profiles to estimate FA import, de novo lipogenesis, elongation, and desaturation in a user-friendly platform. The FAMetA workflow covers all the functionalities needed for MS data analyses. To illustrate its utility, different in vitro and in vivo experimental settings are used in which FA metabolism is modified. Thanks to the comprehensive characterisation of FA biosynthesis and the easy-to-interpret graphical representations compared to previous tools, FAMetA discloses unnoticed insights into how cells reprogramme their FA metabolism and, when combined with FASN, SCD1 and FADS2 inhibitors, it enables the straightforward identification of new FAs by the metabolic reconstruction of their synthesis route.
Genome assembly and analysis of the flavonoid and phenylpropanoid biosynthetic pathways in Fingerroot ginger (Boesenbergia rotunda)
Authors: Taheri Sima , How Teo Chee , Heslop-Harrison John S. , Schwarzacher Trude , Seong Tan Yew , Yee Wee Wei , Khalid Norzulaani , Biswas Manosh Kumar , Mutha Naresh V R , Mohd-Yusuf Yusmin , Gan Han Ming , Harikrishna Jennifer Ann 
Published: May 2022

AbstractBoesenbergia rotunda(Zingiberaceae), is a high-value culinary and ethno-medicinal plant of Southeast Asia. The rhizomes of this herb have high flavanone and chalcone content. Here we report genome analysis ofB. rotundatogether with a complete genome sequence as a hybrid assembly.B. rotundahas an estimated genome size of 2.4 Gb which was assembled as 27,491 contigs with N50 size of 12.386 Mb. The highly heterozygous genome encodes 71,072 protein-coding genes and has 72% repeat content, with class I TEs occupying ∼67% of the assembled genome. FluorescenceIn SituHybridization of the 18 chromosome pairs at metaphase showed six sites of 45S rDNA and two sites of 5S rDNA. SSR analysis identified 238,441 gSSRs and 4,604 EST-SSRs with 49 SSR markers common among related species. Genome-wide methylation percentages ranged from 73% CpG, 36% CHG and 34% CHH in leaf to 53% CpG, 18% CHG and 25% CHH in embryogenic callus. Panduratin A biosynthetic unigenes were most highly expressed in watery callus.B rotundahas a relatively large genome with high heterozygosity and TE content. This assembly and data (PRJNA71294) comprise a source for further research on the functional genomics ofB. rotunda, the evolution of the ginger plant family and the potential genetic selection or improvement of gingers.
DNA double strand breaks lead to de novo transcription and translation of damage-induced long RNAs in planta
Authors: Schreiber Tom , Tripathee Sunita , Iwen Thomas , Prange Anja , Vahabi Khabat , Grützner Ramona , Horn Claudia , Marillonnet Sylvestre , Tissier Alain 
Published: May 2022

ABSTRACTDNA double strand breaks (DSBs) are lethal threats that need to be repaired. Although many of the proteins involved in the early steps of DSB repair have been characterized, recent reports indicate that damage induced long and small RNAs also play an important role in DSB repair. Here, using a Nicotiana benthamiana transgenic line originally designed as a reporter for targeted knock-ins, we show that DSBs generated by Cas9 induce the transcription of long stable RNAs (damage-induced long RNAs - dilRNAs) that are translated into proteins. Using an array of single guide RNAs we show that the initiation of transcription takes place in the vicinity of the DSB. Single strand DNA nicks are not able to induce transcription, showing that cis DNA damage-induced transcription is specific for DSBs. Our results support a model in which a default and early event in the processing of DSBs is transcription into RNA which, depending on the genomic and genic context, can undergo distinct fates, including translation into protein, degradation or production of small RNAs. Our results have general implications for understanding the role of transcription in the repair of DSBs and, reciprocally, reveal DSBs as yet another way to regulate gene expression.
Comprehensive analysis of gene regulatory dynamics, fitness landscape, and population evolution during sexual reproduction
Authors: Okubo Kenji , Kaneko Kunihiko 
Published: May 2022

AbstractThe fitness landscape is a critical concept in evolutionary biology and genetics that depicts fitness in the genotype space and visualizes the relationship between genotype and fitness. However, the fitness landscape is challenging to characterize because the quantitative relationships between genotype and phenotype and their association to fitness has not been comprehensively well described. To address this challenge, we adopted gene regulatory networks to determine gene expression dynamics. We analyzed how phenotype and fitness are shaped by the genotype in two-gene networks. A two-by-two matrix provided the two-gene regulatory network in which a vector with two angle values (Θ) was introduced to characterize the genotype. Mapping from this angle vector to phenotypes allowed for the classification of steady-state expression patterns of genes into seven types. We then studied all possible fitness functions given by the Boolean output from the on/off expression of the two genes. The possible fitness landscapes were obtained as a function of the genetic parameters Θ. Finally, the evolution of the population distribution under sexual reproduction was investigated in the obtained landscape. We found that the distribution was restricted to a convex region within the landscape, resulting in the branching of population distribution, including the speciation process.
A mechanism for the elimination of IgE plasma cells
Authors: Wade-Vallance Adam K. , Yang Zhiyong , Libang Jeremy B. , Robinson Marcus J. , Tarlinton David M. , Allen Christopher D. C. 
Published: May 2022

ABSTRACTThe proper regulation of IgE production safeguards against allergic disease, highlighting the importance of mechanisms that restrict IgE plasma cell (PC) survival. IgE PCs have unusually high surface B cell receptor (BCR) expression, yet the functional consequences of ligating this receptor are unknown. Here, we found that BCR ligation induced BCR signaling in IgE PCs followed by their elimination. In cell culture, exposure of IgE PCs to cognate antigen or anti-BCR antibodies induced apoptosis. IgE PC depletion correlated with the affinity, avidity, amount, and duration of antigen exposure and required the BCR signalosome components Syk, BLNK, and PLCγ2. In mice with a PC-specific impairment of BCR signaling, the abundance of IgE PCs was selectively increased. Conversely, BCR ligation by injection of cognate antigen or anti-IgE depleted IgE PCs. These findings establish a mechanism for the elimination of IgE PCs through BCR ligation. This has important implications for allergen tolerance and immunotherapy as well as anti-IgE monoclonal antibody treatments.
Multi-Omic Integration by Machine Learning (MIMaL) Reveals Protein-Metabolite Connections and New Gene Functions
Authors: Dickinson Quinn , Aufschnaiter Andreas , Ott Martin , Meyer Jesse G. 
Published: May 2022

AbstractCells respond to environments by regulating gene expression to exploit resources optimally. Recent advances in technologies allow the ability to gather information of cellular states of its components, measuring abundances of transcripts, their translation, the accumulation of proteins, lipids and metabolites. These highly complex datasets reflect the state of the different layers in a biological system. Multi-omics is the integration of these disparate methods and data to gain a clearer picture of the biological state. Multi-omic studies of the proteome and metabolome are becoming more common as mass spectrometry technology continues to be democratized. However, knowledge extraction through integration of these data remains challenging. Here we show that connections between omic layers can be discovered through a combination of machine learning and model interpretation. We find that model interpretation values connecting proteins to metabolites are valid experimentally and reveal also largely new connections. Further, clustering the magnitudes of protein control over all metabolites enabled prediction of gene five gene functions, each of which was validated experimentally. We accurately predicted that two uncharacterized genes in yeast modulate mitochondrial translation, YJR120W and YLD157C.We also predict and validate functions for several incompletely characterized genes, including SDH9, ISC1, and FMP52. Our work demonstrates that multi-omic analysis with machine learning (MIMaL) views multi-omic data through a new lens to reveal new insight that was not possible using existing methods.
Mitochondrial Pyruvate Carrier Inhibition Initiates Metabolic Crosstalk to Stimulate Branched Chain Amino Acid Catabolism
Authors: Ferguson Daniel , Eichler Sophie J. , Yiew Nicole K.H. , Colca Jerry R. , Cho Kevin , Patti Gary J. , Lutkewitte Andrew J. , McCommis Kyle S. , Niemi Natalie M. , Finck Brian N. 
Published: May 2022

ABSTRACTObjectiveThe mitochondrial pyruvate carrier (MPC) has emerged as a therapeutic target for treating insulin resistance, type 2 diabetes, and nonalcoholic steatohepatitis (NASH). We evaluated whether MPC inhibitors (MPCi) might correct impairments in branched chain amino acid (BCAA) catabolism, which are predictive of developing diabetes and NASH.MethodsCirculating BCAA concentrations were measured in people with NASH and type 2 diabetes, who participated in a recent randomized, placebo-controlled Phase IIB clinical trial to test the efficacy and safety of the MPCi MSDC-0602K (EMMINENCE;NCT02784444). In this 52-week trial, patients were randomly assigned to placebo (n = 94) or 250 mg MSDC-0602K (n = 101). Human hepatoma cell lines were used to test the direct effects of various MPCi on BCAA catabolism in vitro. Lastly, we investigated how hepatocyte-specific deletion of MPC2 affects BCAA catabolism in the liver of obese mice.ResultsIn patients with NASH, MSDC-0602K treatment, which led to marked improvements in insulin sensitivity and diabetes, decreased plasma concentrations of BCAAs compared to baseline while placebo had no effect. The rate-limiting enzyme in BCAA catabolism is the mitochondrial branched chain ketoacid dehydrogenase (BCKDH), which is deactivated by phosphorylation. In multiple human hepatoma cell lines, MPCi markedly reduced BCKDH phosphorylation and stimulated branched chain keto acid catabolism; an effect that required the BCKDH phosphatase PPM1K. Mechanistically, the effects of MPCi were linked to activation of the energy sensing AMP-dependent protein kinase (AMPK) and mechanistic target of rapamycin (mTOR) kinase signaling cascades. Finally, BCKDH phosphorylation was reduced in liver of obese, hepatocyte-specific MPC2 knockout (LS-Mpc2-/-) mice compared to wild-type controls concomitant with activation of mTOR signaling in vivo.ConclusionsThese data demonstrate novel cross talk between mitochondrial pyruvate and BCAA metabolism and suggest that MPC inhibition leads to lower plasma BCAA concentrations and BCKDH phosphorylation by activating the AMPK/mTOR axis.
The homodimeric structure of the LARGE1 dual glycosyltransferase
Authors: Katz Michael , Diskin Ron 
Published: May 2022

AbstractLARGE1 is a bifunctional glycosyltransferase responsible for generating a long linear polysaccharide termed matriglycan that links the cytoskeleton and the extracellular matrix and is required for proper muscle function. This matriglycan polymer is made with an alternating pattern of xylose and glucuronic acid monomers. Mutations in the LARGE1 gene have been shown to cause life-threatening dystroglycanopathies through the inhibition of matriglycan synthesis. Despite its major role in muscle maintenance, the structure of the LARGE1 enzyme and how it assembles in the Golgi are unknown. Here we present the structure of LARGE1, obtained by a combination of X-ray crystallography and single-particle cryo-EM. We found that LARGE1 homo-dimerizes in a configuration that is dictated by its coiled-coil stem domain. The structure shows that this enzyme has two canonical GT-A folds with each of its catalytic domains. In the context of its dimeric structure, the two types of catalytic domains are brought into close proximity from opposing monomers to allow efficient shuttling of the substrate between the two domains. Together with putative retention of matriglycan by electrostatic interactions, this dimeric organization offers a possible mechanism for the high processivity of LARGE1. The structural information further reveals the mechanisms in which disease-causing mutations disrupt the activity of LARGE1. Collectively, these data shed light on how matriglycan is synthesized alongside the functional significance of glycosyltransferase oligomerization.
Effect on the conformations of spike protein of SARS-CoV-2 due to mutation
Authors: Gupta Aayatti Mallick , Chakrabarti Jaydeb 
Published: May 2022

ABSTRACTThe spike protein of SARS CoV-2 mediates receptor binding and cell entry and is the key immunogenic target for virus neutralization and the present attention of many vaccine layouts. It exhibits significant conformational flexibility. We study the structural fluctuations of spike protein among the most common mutations appeared in variant of concerns (VOC). We report the thermodynamics of conformational changes in mutant spike protein with respect to the wildtype from the distributions of the dihedral angles obtained from the equilibrium configurations generated via all-atom molecular dynamics simulations. We find that the mutation causes the increase in distance between N-terminal domain and receptor binding domain leading to an obtuse angle cosine θ distribution in the trimeric structure in spike protein. Thus, increase in open-state is conferred to the more infectious variants of SARS-CoV-2. The thermodynamically destabilized and disordered residues of receptor binding motif among the mutant variants of spike protein are proposed to serve as better binding sites for host factor. We identify a short stretch of region connecting the N-terminal domain and receptor binding domain forming linker loop where many residues undergo stabilization in the open state compared to the closed one.
Ena/VASP clustering at microspike tips involves Lamellipodin but not I-BAR proteins, and absolutely requires unconventional Myosin-X
Authors: Pokrant Thomas , Hein Jens Ingo , Körber Sarah , Disanza Andrea , Pich Andreas , Scita Giorgio , Rottner Klemens , Faix Jan 
Published: May 2022

AbstractSheet-like membrane protrusions at the leading edge, termed lamellipodia, drive 2D-cell migration using active actin polymerization. Microspikes comprise actin-filament bundles embedded within lamellipodia, but the molecular mechanisms driving their formation and their potential functional relevance have remained elusive. Microspike formation requires the specific activity of clustered Ena/VASP proteins at their tips to enable processive actin assembly in the presence of capping protein, but the factors and mechanisms mediating Ena/VASP clustering are poorly understood. Systematic analyses of B16-F1 melanoma mutants lacking potential candidate proteins revealed that neither inverse BAR-domain proteins, nor lamellipodin or Abi are essential for clustering, although they differentially contribute to lamellipodial VASP accumulation. In contrast, unconventional myosin-X (MyoX) identified here as proximal to VASP was obligatory for Ena/VASP clustering and microspike formation. Interestingly, and despite the invariable distribution of other relevant marker proteins, the width of lamellipodia in MyoX-KO mutants was significantly reduced as compared to B16-F1 control, suggesting that microspikes contribute to lamellipodium stability. Consistently, MyoX removal caused marked defects in protrusion and random 2D-cell migration. Strikingly, Ena/VASP-deficiency also uncoupled MyoX cluster dynamics from actin assembly in lamellipodia, establishing their tight functional association in microspike formation.Significance StatementUnlike filopodia that protrude well beyond the cell periphery and are implicated in sensing, morphogenesis and cell-to-cell communication, the function of microspikes consisting of actin-filament bundles fully embedded within lamellipodia is less clear. Microspike formation involves specific clustering of Ena/VASP family members at filament-barbed ends to enable processive actin polymerization in the presence of capping protein, but the factors and mechanisms mediating Ena/VASP clustering have remained unknown. Here, we systematically analyzed these processes in genetic knockout mutants derived from B16-F1 cells and show that Ena/VASP clustering at microspike tips involves Lamellipodin, but not inverse BAR-domain proteins, and strictly requires unconventional Myosin-X. Complete loss of microspikes was confirmed with CRISPR/Cas9-mediated MyoX knockout in Rat2 fibroblasts, excluding cell type-specific effects.