bluuebunny/crossref_metadata_2025_split huggingface dataset:
Early Dynamics of Chronic Myeloid Leukemia on Nilotinib Predicts Deep Molecular Response
Authors: Okamoto Yuji , Hirano Mitsuhito , Morino Kai , Kajita Masashi K. , Nakaoka Shinji , Tsuda Mayuko , Sugimoto Kei-ji , Tamaki Shigehisa , Hisatake Junichi , Yokoyama Hisayuki , Igarashi Tadahiko , Shinagawa Atsushi , Sugawara Takeaki , Hara Satoru , Fujikawa Kazuhisa , Shimizu Seiichi , Yujiri Toshiaki , Wakita Hisashi , Nishiwaki Kaichi , Tojo Arinobu , Aihara Kazuyuki 
Published: February 2021

AbstractChronic myeloid leukemia (CML) is a myeloproliferative disorder caused by theBCR-ABL1tyrosine kinase1,2.ABL1-selective tyrosine kinase inhibitors (TKIs) including nilotinib have dramatically improved the prognosis of patients with CML3–7. The ultimate goal of CML treatment is likely to be TKI-free maintenance of deep molecular response (DMR), which is defined by quantitative measurement ofBCR-ABL1transcripts on the international scale (IS)8, and durable DMR is a prerequisite to reach this goal9. Thus, an algorithm to enable the early prediction of DMR achievement on TKI therapy is quite valuable. Here, we show that our mathematical framework based on a clinical trial dataset10can accurately predict the response to frontline nilotinib. We found that our simple dynamical model can predict nilotinib response by using two common laboratory findings (observation values): IS11,12and white blood cell (WBC) count. Furthermore, our proposed method identified patients who failed to achieve DMR with high fidelity according to the data collected only at three initial time points during nilotinib therapy. Since our model relies on the general properties of TKI response, our framework would be applicable to CML patients who receive frontline nilotinib or other TKIs in clinical practice.Significance StatementChronic myeloid leukemia (CML) is a myeloproliferative disorder caused by the BCR-ABL1 tyrosine kinase. The goal of this treatment is the sequential achievement of deep molecular response (DMR). Tyrosine kinase inhibitors (TKIs) are effective in the reduction because they inhibit CML cell proliferation. However, because of individual differences in the TKI efficacy, some patients are unable to achieve DMR, so that early prediction of DMR reachability is necessary for personalized medicine. By combining time series analysis and mathematical modeling, we developed a mathematical method that accurately predicts patients who do not achieve DMR in the early stages of TKI administration. Our prediction method gives a basis of effective personalized treatments for CML patients.
Hierarchical reactivation of transcription during mitosis-to-G1 transition by Brn2 and Ascl1 in neural stem cells
Authors: Soares Mário A. F. , Soares Diogo S. , Teixeira Vera , Bressan Raul Bardini , Pollard Steven M. , Oliveira Raquel A. , Castro Diogo S. 
Published: February 2021

SummaryDuring mitosis, chromatin condensation is accompanied by a global arrest of transcription. Recent studies suggest transcriptional reactivation upon mitotic exit occurs in temporally coordinated waves, but the underlying regulatory principles have yet to be elucidated. In particular, the contribution of sequence-specific transcription factors (TFs) remains poorly understood. Here we report that Brn2, an important regulator of neural stem cell identity, associates with condensed chromatin throughout cell division, as assessed by live-cell imaging of proliferating neural stem cells. By contrast, the neuronal fate determinant Ascl1 dissociates from mitotic chromosomes. ChIP-seq analysis reveals that Brn2 mitotic-chromosome binding does not result in sequence-specific interactions prior to mitotic exit, relying mostly on electrostatic forces. Nevertheless, surveying active transcription using single-molecule RNA-FISH against immature transcripts, indicates the differential presence of TF near chromatin when exiting mitosis is associated with early (anaphase) versus late (early G1) reactivation of key targets of Brn2 and Ascl1, respectively. Moreover, by using a mitotic-specific dominant negative approach, we show that competing with Brn2 binding during mitotic exit reduces the transcription of its target gene Nestin. Our study shows an important role for differential binding of TFs to mitotic chromosomes, governed by their electrostatic properties, in defining the temporal order of transcriptional reactivation during mitosis-to-G1 transition.
ATLASx: a computational map for the exploration of biochemical space
Authors: Mohammadi-Peyhani Homa , Hafner Jasmin , Sveshnikova Anastasia , Viterbo Victor , Hatzimanikatis Vassily 
Published: February 2021

AbstractMetabolic “dark matter” describes currently unknown metabolic processes, which form a blind spot in our general understanding of metabolism and slow down the development of biosynthetic cell factories and naturally derived pharmaceuticals. Mapping the dark matter of metabolism remains an open challenge that can be addressed globally and systematically by existing computational solutions. In this work, we use 490 generalized enzymatic reaction rules to map both known and unknown metabolic processes around a biochemical database of 1.5 million biological compounds. We predict over 5 million reactions and integrate nearly 2 million naturally and synthetically-derived compounds into the global network of biochemical knowledge, named ATLASx. ATLASx is available to researchers as a powerful online platform that supports the prediction and analysis of novel biochemical pathways and evaluates the biochemical vicinity of molecule classes (https://lcsbdatabases.epfl.ch/Atlas2).
Delayed induction of type I and III interferons mediates nasal epithelial cell permissiveness to SARS-CoV-2
Authors: Hatton Catherine F , Botting Rachel A , Dueñas Maria Emilia , Haq Iram J , Verdon Bernard , Thompson Benjamin J , Spegarova Jarmila Stremenova , Gothe Florian , Stephenson Emily , Gardner Aaron I , Murphy Sandra , Scott Jonathan , Garnett James P , Carrie Sean , Powell Jason , Khan C M Anjam , Huang Lei , Hussain Rafiqul , Coxhead Jonathan , Davey Tracey , Simpson A John , Haniffa Muzlifah , Hambleton Sophie , Brodlie Malcolm , Ward Chris , Trost Matthias , Reynolds Gary , Duncan Christopher J A 
Published: February 2021

AbstractThe nasal epithelium is a plausible entry point for SARS-CoV-2, a site of pathogenesis and transmission, and may initiate the host response to SARS-CoV-2. Antiviral interferon (IFN) responses are critical to outcome of SARS-CoV-2. Yet little is known about the interaction between SARS-CoV-2 and innate immunity in this tissue. Here we applied single-cell RNA sequencing and proteomics to a primary cell model of human nasal epithelium differentiated at air-liquid interface. SARS-CoV-2 demonstrated widespread tropism for nasal epithelial cell types. The host response was dominated by type I and III IFNs and interferon-stimulated gene products. This response was notably delayed in onset relative to viral gene expression and compared to other respiratory viruses. Nevertheless, once established, the paracrine IFN response began to impact on SARS-CoV-2 replication. When provided prior to infection, recombinant IFNβ or IFNλ1 induced an efficient antiviral state that potently restricted SARS-CoV-2 viral replication, preserving epithelial barrier integrity. These data suggest that the IFN-I/III response to SARS-CoV-2 initiates in the nasal airway and suggest nasal delivery of recombinant IFNs to be a potential chemoprophylactic strategy.
Gram-negative outer membrane proteins with multiple β-barrel domains
Authors: Solan Ron , Pereira Joana , Lupas Andrei N. , Kolodny Rachel , Ben-Tal Nir 
Published: February 2021

AbstractOuter membrane beta barrels (OMBBs) are found in the outer membrane of Gram-negative bacteria and eukaryotic organelles. OMBBs fold as antiparallel β-sheets that close onto themselves, forming pores that traverse the membrane. Currently known structures include only one barrel, of 8-36 strands, per chain. The lack of multi-OMBB chains is surprising, as most OMBBs form oligomers and some function only in this state. Using a combination of sensitive sequence-comparison methods and co-evolutionary analysis tools, we identify many proteins combining multiple beta barrels within a single chain; combinations that include 8-stranded barrels prevail. These multi-barrels seem to be the result of independent, lineage-specific fusion and amplification events. The absence of multi-barrels that are universally conserved in bacteria with an outer membrane, coupled with their frequentde novogenesis suggests that their functions are not essential, but rather beneficial in specific environments. Adjacent barrels of complementary function within the same chain may allow for new functions beyond those of the individual barrels.
Deletion of CD73 increases exercise power in mice
Authors: Aguiar Aderbal S , Speck Ana Elisa , Canas Paula M. , Cunha Rodrigo A. 
Published: February 2021

ABSTRACTEcto-5’-nucleotidase or CD73 is the main source of extracellular adenosine involved in the activation of adenosine A2Areceptors, responsible for the ergogenic effects of caffeine. We now investigated the role of CD73 in exercise by comparing female wild-type (WT) and CD73 knockout (KO) mice in a treadmill graded test to evaluate running power, oxygen uptake, and respiratory exchange ratio (RER) – the gold standards characterizing physical performance. Spontaneous locomotion in the open field and submaximal running power andin the treadmill were similar between CD73-KO and WT mice;also demonstrated equivalent aerobic power, but CD73-KO mice displayed a 43.7±4.2% larger critical power (large effect size, P<0.05) and 3.8±0.4% increase of maximum RER (small effect size, P<0.05). Thus, KO of CD73 was ergogenic, i.e., it increased physical performance.
Bioengineering of genetically encoded gene promoter repressed by flavonoids for constructing intracellular sensor for molecular events
Authors: Desmet Nicole M. , Dhusia Kalyani , Qi Wenjie , Doseff Andrea I. , Bhattacharya Sudin , Gilad Assaf A. 
Published: February 2021

AbstractIn recent years, Synthetic Biology has emerged as a new discipline where functions that were traditionally performed by electronic devices are replaced by “cellular devices”. Those are genetically encoded circuits, constructed of DNA that are built from biological parts (aka bio-parts). The cellular devices can be used for sensing and responding to natural and artificial signals. However, a major challenge in the field is that the crosstalk between many cellular signaling pathways use the same signaling endogenous molecules that can result in undesired activation. To overcome this problem, we utilized a specific promoter that can activate genes with a natural, non-toxic ligand at a highly-induced transcription level with low background or undesirable off-target expression. Here we used the orphan aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor that upon activation binds to specific AHR response elements (AHRE) of the Cytochrome P450, family 1, subfamily A, polypeptide 1 (CYP1A1) promoter. Flavonoids have been identified as AHR ligands. Data presented here shows successful creation of a synthetic gene “off” switch that can be monitored directly using an optical reporter gene. This is the first step towards bioengineering of a synthetic, nanoscale bio-part for constructing a sensor for molecular events.
Human breast milk enhances intestinal mucosal barrier function and innate immunity in a pediatric human enteroid model
Authors: Noel Gaelle , In Julie G. , Lemme-Dumit Jose M. , DeVine Lauren R. , Cole Robert N. , Guerrerio Anthony L. , Kovbasnjuk Olga , Pasetti Marcela F. 
Published: February 2021

ABSTRACTBreastfeeding has been associated with long lasting health benefits. Nutrients and bioactive components of human breast milk promote cell growth, immune development, and shield the infant gut from insults and microbial threats. The molecular and cellular events involved in these processes are ill defined. We have established human pediatric enteroids and interrogated maternal milk’s impact on epithelial cell maturation and function in comparison with commercial infant formula. Colostrum applied apically to pediatric enteroid monolayers reduced ion permeability, stimulated epithelial cell differentiation, and enhanced tight junction function by upregulating occludin expression. Breast milk heightened the production of antimicrobial peptide α-defensin 5 by goblet and Paneth cells, and modulated cytokine production, which abolished apical release of pro-inflammatory GM-CSF. These attributes were not found in commercial infant formula. Epithelial cells exposed to breast milk elevated apical and intracellular pIgR expression and enabled maternal IgA translocation. Proteomic data revealed a breast milk-induced molecular pattern associated with tissue remodeling and homeostasis. Using a novelex vivopediatric enteroid model, we have identified cellular and molecular pathways involved in human milk-mediated improvement of human intestinal physiology and immunity.
Force-Correction Analysis Method for Derivation of Multidimensional Free Energy Landscapes from Adaptively Biased Replica Simulations
Authors: Marinelli Fabrizio , Faraldo-Gómez José D. 
Published: February 2021

AbstractA methodology is proposed for the calculation of multidimensional free-energy landscapes of molecular systems, based on analysis of multiple Molecular Dynamics trajectories wherein adaptive biases have been applied to enhance the sampling of different collective variables. In this approach, which we refer to as Force Correction Analysis Method (FCAM), local averages of the total and biasing forces are evaluated post-hoc, and the latter are subtracted from the former to obtain unbiased estimates of the mean force across collective-variable space. Multidimensional free-energy surfaces and minimum free-energy pathways are then derived from integration of the mean force landscape through kinetic Monte Carlo algorithm. To evaluate the proposed method, a series of numerical tests and comparisons with existing approaches were carried out for small molecules, peptides, and proteins, based on all-atom trajectories generated with standard, concurrent and replica-exchange Metadynamics in collective-variable spaces ranging from one- to six-dimensional. The tests confirm the correctness of the FCAM formulation and demonstrate that calculated mean forces and free energies converge rapidly and accurately, outperforming other methods used to unbias this kind of simulation data.Abstract FigureTOC/Abstract Graphic
The P3b differentiates parallel physical and rule-based updating of a sensory model
Authors: Schwartze Michael , Bellotti Francesca I. , Kotz Sonja A. 
Published: February 2021

AbstractThe capacity to form and update mental representations of the type and timing of sensory events is a central tenet of adaptive behavior in a dynamically changing environment. An internal model of stimulus contingencies provides a means to optimize behavior through predictive adjustments based on past to future events. To this end, neural and cognitive processes rely on systematic relations between events and use these rules to optimize information processing. The P3 complex of the event-related potential of the electroencephalogram (ERP/EEG) is a well-established and extensively tested index of such mechanisms. Here we investigated the P3b sensitivity to auditory stimulus deviations associated with two updating operations: physical change (switching stimulus pitches) and rule change (switching additive and subtractive target stimulus counting). Participants listened to a variant of the classical oddball sequence consisting of frequent standard (600 Hz) and two equally probable less frequent deviant tones (660 Hz, 540 Hz), keeping count of the deviant tones and switching between addition and subtraction with a pitch change. The results indicate specific amplitude modulations, confirming the P3b as a context-sensitive marker of physical and cognitive components of an internal model. This suggests that the P3b can be used as a differential marker of predictive coding mechanisms.
Phagocytosed polyhedrin-cytokine co-crystal nanoparticles provide sustained secretion of bioactive cytokines from macrophages
Authors: Wendler Astrid , James Nicholas , Jones Michael H , Pernstich Christian 
Published: February 2021

AbstractMany cells possess the ability to engulf and incorporate particles by phagocytosis. This active process is characteristic of microorganisms as well as higher order species. In mammals, monocytes, macrophages and microglia are among so-called professional phagocytes. In addition, cells such as fibroblast and chondrocytes are classified as non-professional phagocytes. Professional phagocytes play important roles in both the innate and adaptive immune response, wound healing and tissue homeostasis. Consequently, these cells are increasingly studied as targets and vectors of therapeutic intervention to treat a range of diseases. Professional phagocytes are notoriously difficult to transfect limiting their study and manipulation. Consequently, efforts have shifted towards the development of nanoparticles to deliver a cargo to phagocytic cells via phagocytosis. However, this approach carries significant technical challenges, particularly for protein cargos. We have focused on the development of nanoscale co-crystalline protein depots, known as PODS®, that contain protein cargos, including cytokines. Here, we show that PODS are readily phagocytosed by non-professional as well as professional phagocytic cells and have attributes, such as highly sustained release of cargo, that suggest potential utility for the study and exploitation of phagocytic cells for drug delivery. Monocytes and macrophages that ingest PODS retain normal characteristics including a robust chemotactic response. Moreover, the PODS-cytokine cargo is secreted by the loaded cell at a level sufficient to modulate the behavior of surrounding non-phagocytic cells. The results presented here demonstrate the potential of PODS nanoparticles as a novel molecular tool for the study and manipulation of phagocytic cells and for the development of Trojan horse immunotherapy strategies to treat cancer and other diseases.
A genome-scale metabolic model ofSaccharomyces cerevisiaethat integrates expression constraints and reaction thermodynamics
Authors: Oftadeh Omid , Salvy Pierre , Masid Maria , Curvat Maxime , Miskovic Ljubisa , Hatzimanikatis Vassily 
Published: February 2021

AbstractEukaryotic organisms play an important role in industrial biotechnology, from the production of fuels and commodity chemicals to therapeutic proteins. To optimize these industrial systems, a mathematical approach can be used to integrate the description of multiple biological networks into a single model for cell analysis and engineering. One of the current most accurate models of biological systems include metabolism and expression (ME-models), and Expression and Thermodynamics FLux (ETFL) is one such formulation that efficiently integrates RNA and protein synthesis with traditional genome-scale metabolic models. However, ETFL is so far only applicable forE. coli. To therefore adapt this ME-model forSaccharomyces cerevisiae, we herein developed yETFL. To do this, we augmented the original formulation with additional considerations for biomass composition, the compartmentalized cellular expression system, and the energetic costs of biological processes. We demonstrated the predictive ability of yETFL to capture maximum growth rate, essential genes, and the phenotype of overflow metabolism. We envision that the extended ETFL formulation can be applied to ME-model development for a wide range of eukaryotic organisms. The utility of these ME-models can be extended into academic and industrial research.
TuMV infection alters miR168/AGO1 and miR403/AGO2 systems regulation in Arabidopsis
Authors: Manacorda Carlos Augusto , Tasselli Sabrina , Marano María Rosa , Asurmendi Sebastian 
Published: February 2021

AbstractPlant Argonaute proteins, chiefly AGO1 and 2, restrict viral infections. AGO1/2 also participate in developmental processes and are tightly regulated by microRNAs. Under viral infections, the regulatory loop comprising miR168/AGO1 is well studied, but much less so the miR403/AGO2 system. We studied both regulatory systems in TuMV-infected Arabidopsis plants. TuMV downregulated miRNAs precursor molecules, but mature miRNAs overaccumulated, without evidence of transcriptional alteration. AGO1 protein remained at basal levels whereas AGO2 overaccumulated. These results are in line with previous reports studying abiotic and biotic impact on microRNA biogenesis and AGO-dependent antiviral defense, expanding our knowledge of the miR403/AGO2 regulatory system.
Structural effects driven by rare point mutations in amylin hormone, the type II diabetes-associated peptide
Authors: Mendes Wendy S. , Franco Octavio L. , Alencar Sergio A. , Porto William F. 
Published: February 2021

AbstractBackgroundAmylin is a 37-amino-acid peptide hormone co-secreted with insulin, which participates in glucose homeostasis. This hormone is able to aggregate in a β-sheet conformation and deposit in islet amyloids, a hallmark in type II diabetes. Since amylin is a gene-encoded hormone, this peptide has variants caused by point mutations that can impact its functions.MethodsHere, we analyzed the structural effects caused by S20G and G33R point mutations which, according to the 1000 Genomes Project, have frequency in East Asian and European populations, respectively. The analyses were performed by means of aggrescan server, SNP functional effect predictors, and molecular dynamics.ResultsWe found that both mutations have aggregation potential and cause changes in the monomeric forms when compared with wild-type amylin. Furthermore, comparative analyses with pramlintide, an amylin drug analogue, allowed us to infer that second α-helix maintenance may be related to the aggregation potential.ConclusionsThe S20G mutation has been described as pathologically related, which is in agreement with our findings. In addition, our data suggest that the G33R mutation might have a deleterious effect. The data presented here also provide new therapy opportunities, whether for creating more effective drugs for diabetes or implementing specific treatment for patients with these mutations.General SignificanceOur data could help to better understand the impact of mutations on the wild-type amylin sequence, as a starting point for the evaluation and characterization of other variations. Moreover, these findings could improve the health of patients with type II diabetes.