bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pre-MEASURE:FLT3-ITD and mutatedNPM1measurable residual disease before allogeneic transplant in adults with AML in first remission
Authors: Dillon Laura W , Gui Gege , Ravindra Niveditha , Wong Zoë , Andrew Georgia , Mukherjee Devdeep , Zeger Scott L. , El Chaer Firas , Spellman Stephen , Howard Alan , Chen Karen , Auletta Jeffery , Devine Steven M. , Jimenez Jimenez Antonio Martin , De Lima Marcos J.G. , Litzow Mark Robert , Kebriaei Partow , Saber Wael , Weisdorf Daniel Jordan , Page Kristin M. , Hourigan Christopher S. 
Published: October 2022

AbstractBackgroundPrevention of relapse for adults with Acute Myeloid Leukemia (AML) in first remission (CR1) is the most common indication for allogeneic hematopoietic cell transplantation (alloHCT). Measurable residual disease (MRD) detection has been associated with higher relapse rates, but testing is not standardized. Establishment of validated AML MRD criteria would allow harmonization across centers facilitating clinical trials and generalizable practice guidelines.MethodsPatients aged 18 or older who underwent first alloHCT forFLT3, NPM1, IDH1, IDH2and/orKITmutated AML in CR1 were eligible for this multicenter study. Residual mutations detected in remission using ultra-deep error-corrected next-generation DNA-sequencing (NGS-MRD) associated with increased relapse risk were validated in a second independent cohort. The impact of baseline characteristics on NGS-MRD results was evaluated.ResultsPre-conditioning CR1 blood samples from 1075 patients were tested. Detection of residualNPM1and/orFLT3-ITD mutations before alloHCT was associated with worse outcomes after transplantation in both discovery (patients transplanted 2013-2017) and validation (patients transplanted 2018-2019) cohorts. In multivariate Cox regression analysis detection of residualNPM1m (relapse; HR: 4.9, 3.5-7.0, P<0.0001, survival; HR: 2.9, 2.2-4.0, P<0.0001), residualFLT3-ITD (relapse: HR: 4.2, 3.1-5.7, P<0.0001, survival; HR: 2.6, 2.0-3.6, P<0.0001), and receipt of non-melphalan containing reduced intensity conditioning were associated with inferior clinical outcomes.ConclusionsDetection of residualNPM1and/orFLT3-ITD mutations in the blood of patients undergoing alloHCT for AML in CR1 is associated with increased relapse and worse survival. In those undergoing reduced intensity conditioning, melphalan may reduce the risk associated with testing NGS-MRD positive prior to transplantation.
Population serum proteomics uncovers prognostic protein classifier and molecular mechanisms for metabolic syndrome
Authors: Cai Xue , Xue Zhangzhi , Zeng Fang-Fang , Tang Jun , Yue Liang , Wang Bo , Ge Weigang , Xie Yuting , Miao Zelei , Gou Wanglong , Fu Yuanqing , Li Sainan , Gao Jinlong , Shuai Menglei , Zhang Ke , Xu Fengzhe , Tian Yunyi , Xiang Nan , Zhou Yan , Shan Peng-Fei , Zhu Yi , Chen Yu-ming , Zheng Ju-Sheng , Guo Tiannan 
Published: October 2022

ABSTRACTMetabolic syndrome (MetS) is a complex metabolic disorder with a global prevalence of 20-25%. Early identification and intervention would help minimize the global burden on healthcare systems. Here, we measured over 400 proteins from ∼20,000 proteomes using data-independent acquisition mass spectrometry for 7890 serum samples from a longitudinal cohort of 3840 participants with two follow-up time points over ten years. We then built a machine learning model for predicting the risk of developing MetS within ten years. Our model, composed of 11 proteins and the age of the individuals, achieved an area under the curve of 0.784 in the discovery cohort (n=855) and 0.774 in the validation cohort (n=242). Using linear mixed models, we found that apolipoproteins, immune-related proteins, and coagulation-related proteins best correlated with MetS development. This population-scale proteomics study broadens our understanding of MetS, and may guide the development of prevention and targeted therapies for MetS.
Intergenic regions of Saccharomycotina yeasts are enriched in potential to form transmembrane domains
Authors: Tassios Emilios , Nikolaou Christoforos , Vakirlis Nikolaos 
Published: October 2022

AbstractIntergenic genomic regions have essential regulatory and structural roles that impose constraints on their sequences. But regions that do not currently encode proteins, also carry the potential to do so in the future. De novo gene emergence, the evolution of novel genes out of previously non-coding sequences has now been established as a potent force for genomic novelty. Recently, it was shown that intergenic regions in the genome ofS. cerevisiaeharbor pervasive cryptic potential to, if theoretically translated, form transmembrane domains (TM domains) more frequently than expected by chance, a property that we refer to as TM-forming enrichment. The source and biological relevance of this property is unknown. Here we expand the investigation into the TM-forming potential of intergenic regions to the entire Saccharomycotina budding yeast subphylum, in an effort to explain this property and understand its importance. We find pervasive but variable enrichment in TM-forming potential across the subphylum, regardless of the composition and average size of intergenic regions. This cryptic property is evenly spread across the genome, cannot be explained by the hydrophobic content of the sequence, and does not appear to localize to regions containing regulatory motifs. This TM-forming enrichment specifically, and not the actual TM-forming potential, is associated, across genomes, with more TM domains in evolutionarily young genes. Our findings shed light on this newly discovered feature of yeast genomes and constitute a first step towards understanding its evolutionary importance.
Inferring assembly-curving trends of bacterial micro-compartment shell hexamers from crystal structure arrangements
Authors: Garcia-Alles Luis F. , Soldan Vanessa , Custovic Irma , Castaño-Cerezo Sara , Balor Stéphanie , Fuentes-Cabrera Miguel , Truan Gilles , Lesniewska Eric , Reguera David 
Published: October 2022

ABSTRACTBacterial microcompartments (BMC) are complex macromolecular assemblies that participate to varied chemical processes in about one fourth of bacterial species. BMC-encapsulated enzymatic activities are segregated from other cell contents by means of semipermeable shells, justifying why BMC are viewed as prototype nano-reactors for biotechnological applications. Herein, we undertook a comparative study of trends of self-assembly of BMC hexamers (BMC-H), the most abundant shell constituents. Published and new microscopy data show that some BMC-H, likeβ-carboxysomal CcmK, tend to assemble flat whereas other BMC-H often build curved-implying objects. Inspection of available crystal structures presenting BMC-H in tiled arrangements permitted to identify two major assembly modes with a striking connection with experimental trends. All-atom molecular dynamics (MD) supported that BMC-H bending is triggered robustly only from the disposition adopted by BMC-H that form curved objects experimentally, conducting to almost identical arrangements to those found in structures of recomposed BMC shells. Simulations on ensembles of planar-behaving hexamers, which were previously reconfigured to comply with such disposition, confirmed that bending is defined by assembly details, rather than by BMC-H identity. Finally, although no common atomic determinants could be identified as responsible of BMC-H spontaneous curvature, an inter-hexamer ionic pair was pinpointed as contributor to hold a subset of BMC-H in low bending dispositions. These results are expected to improve our understanding of the variable mechanisms of biogenesis characterized for BMC, and of possible strategies to regulate BMC size and shape.
Modulation of type I interferon responses potently inhibits SARS-CoV-2 replication and inflammation in rhesus macaques
Authors: Hoang Timothy N. , Viox Elise G. , Upadhyay Amit A. , Strongin Zachary , Tharp Gregory K. , Pino Maria , Nchioua Rayhane , Hirschenberger Maximilian , Gagne Matthew , Nguyen Kevin , Harper Justin L. , Marciano Shir , Boddapati Arun K. , Pellegrini Kathryn L. , Tisoncik-Go Jennifer , Whitmore Leanne S. , Karunakaran Kirti A. , Roy Melissa , Kirejczyk Shannon , Curran Elizabeth H. , Wallace Chelsea , Wood Jennifer S. , Connor-Stroud Fawn , Kasturi Sudhir P. , Levit Rebecca D. , Gale Michael , Vanderford Thomas H. , Silvestri Guido , Busman-Sahay Kathleen , Estes Jacob D. , Vaccari Monica , Douek Daniel C. , Sparrer Konstantin M.J. , Kirchhoff Frank , Johnson R. Paul , Schreiber Gideon , Bosinger Steven E. , Paiardini Mirko 
Published: October 2022

AbstractType-I interferons (IFN-I) are critical mediators of innate control of viral infections, but also drive recruitment of inflammatory cells to sites of infection, a key feature of severe COVID-19. Here, and for the first time, IFN-I signaling was modulated in rhesus macaques (RMs) prior to and during acute SARS-CoV-2 infection using a mutated IFNα2 (IFN-modulator; IFNmod), which has previously been shown to reduce the binding and signaling of endogenous IFN-I. In SARS-CoV-2-infected RMs, IFNmod reduced both antiviral and inflammatory ISGs. Notably, IFNmod treatment resulted in a potent reduction in (i) SARS-CoV-2 viral load in Bronchoalveolar lavage (BAL), upper airways, lung, and hilar lymph nodes; (ii) inflammatory cytokines, chemokines, and CD163+MRC1-inflammatory macrophages in BAL; and (iii) expression of Siglec-1, which enhances SARS-CoV-2 infection and predicts disease severity, on circulating monocytes. In the lung, IFNmod also reduced pathogenesis and attenuated pathways of inflammasome activation and stress response during acute SARS-CoV-2 infection. This study, using an intervention targeting both IFN-α and IFN-β pathways, shows that excessive inflammation driven by type 1 IFN critically contributes to SARS-CoV-2 pathogenesis in RMs, and demonstrates the potential of IFNmod to limit viral replication, SARS-CoV-2 induced inflammation, and COVID-19 severity.
Gene Gain and Loss from the Asian Corn Borer W Chromosome
Authors: Dai Wenting , Mank Judith E. , Ban Liping 
Published: October 2022

AbstractWe built a chromosome-level genome assembly of the Asian corn borer,Ostrinia furnacalisGuenée (Lepidoptera: Pyralidae, Pyraloidea), an economically important pest in corn, from a female, including both the Z and W chromosome. Despite deep conservation of the Z chromosome across Lepidoptera, our chromosome-level W assembly reveals little conservation with available W chromosome sequence in related species or with the Z chromosome, consistent with a non-canonical origin of the W chromosome. The W chromosome has accumulated significant repetitive elements and experienced rapid gene gain from the remainder of the genome, with most genes exhibiting pseudogenization after duplication to the W. The genes that retain significant expression are largely enriched for functions in DNA recombination, the nucleosome, chromatin and DNA binding, likely related to meiotic and mitotic processes within the female gonad.
The homeodomain transcriptional regulator DVE-1 directs a program for synapse elimination during circuit remodeling
Authors: Alexander Kellianne D , Ramachandran Shankar , Biswas Kasturi , Lambert Christopher M , Russell Julia , Oliver Devyn B , Armstrong William , Rettler Monika , Doitsidou Maria , Bénard Claire , Francis Michael M 
Published: October 2022

AbstractAn important step in brain development is the remodeling of juvenile neural circuits to establish mature connectivity. The elimination of juvenile synapses is a critical step in this process; however, the molecular mechanisms directing synapse elimination activities and their timing are not fully understood. We identify here a conserved transcriptional regulator, DVE-1, that shares homology with mammalian special AT-rich sequence-binding (SATB) family members and directs the elimination of juvenile synaptic inputs onto remodelingC. elegansGABAergic neurons. Dorsally localized juvenile acetylcholine receptor clusters and apposing presynaptic sites are eliminated during maturation of wild type GABAergic neurons but persist into adulthood indve-1mutants. The persistence of juvenile synapses indve-1mutants does not impede synaptic growth during GABAergic remodeling and therefore produces heightened motor connectivity and a turning bias during movement. DVE-1 is localized to GABAergic nuclei prior to and during remodeling and DVE-1 nuclear localization is required for synapse elimination to proceed, consistent with DVE-1’s function as a transcriptional regulator. Pathway analysis of DVE-1 targets and proteasome inhibitor experiments implicate transcriptional control of the ubiquitin-proteasome system in synapse elimination. Together, our findings demonstrate a new role for a SATB family member in the control of synapse elimination during circuit remodeling through transcriptional regulation of ubiquitin-proteasome signaling.Contributions SummaryKDA generated strains, transgenic lines, molecular constructs, confocal microscopy images and analysis, performed optogenetic behavioral experiments, photoconversion experiments, modencode ChIP-seq analysis and pathway analysis. SR performed all calcium imaging experiments/analysis and conducted single worm tracking. KB performed all Bortezomib inhibitor experiments and analysis. CL generated most vectors and constructs. JR assisted with generation of CRISPR/Cas9 generated strains. WA and MR assisted with aldicarb behavioral assay. DO assisted with EMS screen and isolation ofdve-1mutant. CB and MD aided in CloudMap bioinformatic analysis of theuf171mutant. MMF and KDA designed and interpreted results of all experiments and wrote the manuscript.
The line bisection bias stems from left-side underawareness, not from right-side hyperattention
Authors: Smaczny S. , Klein E. , Jung S. , Moeller K. , Karnath H.-O. 
Published: October 2022

AbstractIt is still a matter of scientific debate whether the line bisection bias frequently observed in patients with spatial neglect is due to attentional underawareness of the left end of the line, attentional hyperattention towards the right end, or a logarithmically compressed perception of the line. To address this question, neglect patients who showed a line bisection bias were administered additional tasks involving horizontal lines (e.g., number line estimation tasks). Their performance was compared to neglect patients not showing a line bisection bias, patients with right hemisphere damage without neglect, and healthy controls. Results indicated that patients with a line bisection bias tended to overestimate lefthand segments when they had to dissect lines into three or four equal parts. This is congruent with both the notions of an underawareness of lefthand segments as well as a logarithmic compression of the line. However, when these patients had to imagine the lines as bounded fraction number lines ranging from 0-1, the results were mixed. When the number lines ranged from 0-10, these patients showed rightward overestimation biases for the numbers 4 and 5. Additionally, all patient groups, but not healthy controls, tended to place number 1 too far to the left and number 9 too far to the right, suggesting a general bias towards endpoints. In sum, this seems more congruent with attentional accounts than a perceptual one. Spatial-numerical associations could be ruled out, as all participants showed a verbal number bisection bias towards smaller numbers (i.e., the ‘left’ of the mental number line). Therefore, these findings seem to indicate that the line bisection bias is most likely due to underawareness of the left end rather than hyperattention towards the right or a logarithmic perception of the line.
Vector-clustering Multiple Sequence Alignment: Aligning into the twilight zone of protein sequence similarity with protein language models
Authors: McWhite Claire D. , Singh Mona 
Published: October 2022

ABSTRACTMultiple sequence alignment is a critical step in the study of protein sequence and function. Typically, multiple sequence alignment algorithms progressively align pairs of sequences and combine these alignments with the aid of a guide tree. These alignment algorithms use scoring systems based on substitution matrices to measure amino-acid similarities. While successful, standard methods struggle on sets of proteins with low sequence identity - the so-called twilight zone of protein alignment. For these difficult cases, another source of information is needed. Protein language models are a powerful new approach that leverage massive sequence datasets to produce high-dimensional contextual embeddings for each amino acid in a sequence. These embeddings have been shown to reflect physicochemical and higher-order structural and functional attributes of amino acids within proteins. Here, we present a novel approach to multiple sequence alignment, based on clustering and ordering amino acid contextual embeddings. Our method for aligning semantically consistent groups of proteins circumvents the need for many standard components of multiple sequence alignment algorithms, avoiding initial guide tree construction, intermediate pairwise alignments, gap penalties, and substitution matrices. The added information from contextual embeddings leads to higher accuracy alignments for structurally similar proteins with low amino-acid similarity. We anticipate that protein language models will become a fundamental component of the next generation of algorithms for generating MSAs.Software availability:https://github.com/clairemcwhite/vcmsa
Macrophage phenotype transitions in a stochastic gene-regulatory network model
Authors: Frank Anna-Simone , Larripa Kamila , Ryu Hwayeon , Röblitz Susanna 
Published: October 2022

ABSTRACTPolarization is the process by which a macrophage cell commits to a phenotype based on external signal stimulation. To know how this process is affected by random fluctuations and events within a cell is of utmost importance to better understand the underlying dynamics and predict possible phenotype transitions. For this purpose, we develop a stochastic modeling approach for the macrophage polarization process. We classify phenotype states using the Robust Perron Cluster Analysis and quantify transition pathways and probabilities by applying Transition Path Theory. Depending on the model parameters, we identify four bistable and one tristable phenotype configuration. We find that bistable transitions are fast but their states less robust. In contrast, phenotype transitions in the tristable situation have a comparatively long time duration, which reflects the robustness of the states. The results indicate parallels in the overall transition behavior of macrophage cells with other heterogeneous and plastic cell types, such as cancer cells. Our approach allows for a probabilistic interpretation of macrophage phenotype transitions and biological inference on phenotype robustness. In general, the methodology can easily be adapted to other systems where random state switches are known to occur.
Monopolization at the cost of desiccation: Reduced waterproofing cuticular hydrocarbons impairs nestmate discrimination in an ant
Authors: Pierre-André Eyer , Helms Anjel M. , Moran Megan N. , Vargo Edward L. 
Published: October 2022

SummaryAfter humans, social insects represent one of the most complex groups of social organisms, relying on a well-organized communication system among colony members. The transfer of information among individuals is primarily based on cuticular hydrocarbons (CHC). These chemical compounds, produced by all insects, initially evolved to prevent water loss1. They were subsequently co-opted as semiochemicals to communicate various types of information. This includes nestmate recognition in social insects2,3, enabling different colonies to partition resources by ousting conspecific competitors. In this study, we report the near complete loss of CHC production by workers of the antNylanderia fulva. This absence of CHCs is a double-edged sword. It represents a causative agent in the ecological success of this ant species — enabling the development of a large supercolony in its invasive range through limited ability to differentiate nestmates— but increases the risk of suffering ecological stress through desiccation.
FANCJ DNA helicase is recruited to the replisome by AND-1 to ensure genome stability
Authors: Boavida Ana , Napolitano Luisa M. R. , Santos Diana , Cortone Giuseppe , Onesti Silvia , Jegadesan Nanda K. , Branzei Dana , Pisani Francesca M. 
Published: October 2022

AbstractFANCJ is a DNA helicase linked to Fanconi anemia and frequently mutated in breast and ovarian cancers. If and how FANCJ is recruited to the replisome is unknown. Here, we report that FANCJ directly binds to AND-1 (the vertebrate ortholog of budding yeast Ctf4), a homo-trimeric protein adaptor that connects the CDC45/MCM2-7/GINS replicative DNA helicase with DNA polymerase α and several factors at DNA replication forks. We find that the interaction between FANCJ and AND-1 requires the integrity of an evolutionarily conserved Ctf4-interacting protein (CIP) box located between the FANCJ helicase motifs IV and V. Disruption of the FANCJ CIP box significantly reduces FANCJ association with the replisome, causing enhanced DNA damage, decreased replication fork recovery and fork asymmetry in stressful conditions. Cancer-relevant FANCJ CIP box variants display reduced AND-1-binding, a finding that suggests a potential role of the mutatedFANCJalleles in cancer predisposition.
Molecular early burst associated with the diversification of birds at the K–Pg boundary
Authors: Berv Jacob S. , Singhal Sonal , Field Daniel J. , Walker-Hale Nathanael , McHugh Sean W. , Shipley J. Ryan , Miller Eliot T. , Kimball Rebecca T. , Braun Edward L. , Dornburg Alex , Parins-Fukuchi C. Tomomi , Prum Richard O. , Winger Benjamin M. , Friedman Matt , Smith Stephen A. 
Published: October 2022

AbstractComplex patterns of genome and life-history evolution associated with the end-Cretaceous (K– Pg) mass extinction event limit our understanding of the early evolutionary history of crown group birds [1-9]. Here, we assess molecular heterogeneity across living birds using a technique enabling inferred sequence substitution models to transition across the history of a clade [10]. Our approach identifies distinct and contrasting regimes of molecular evolution across exons, introns, untranslated regions, and mitochondrial genomes. Up to fifteen shifts in the mode of avian molecular evolution map to rapidly diversifying clades near the Cretaceous-Palaeogene boundary, demonstrating a burst of genomic disparity early in the evolutionary history of crown birds [11-13]. Using simulation and machine learning techniques, we show that shifts in developmental mode [14] or adult body mass [4] best explain transitions in the mode of nucleotide substitution. These patterns are related, in turn, to macroevolutionary shifts in the allometric scaling relationship between basal metabolic rate and body mass [15, 16]. In agreement with theoretical predictions, this scaling relationship appears to have weakened across the end-Cretaceous transition. Overall, our study provides evidence that the Chicxulub bolide impact [17] triggered integrated patterns of evolution across avian genomes, physiology, and life history that structured the evolutionary potential of modern birds.