bluuebunny/crossref_metadata_2025_split huggingface dataset:
Copper chelation inhibits TGF-βpathways and suppresses epithelial-mesenchymal transition in cancer
Authors: Poursani E. M. , Mercatelli D. , Raninga P. , Bell J. L. , Saletta F. , Kohane F. V. , Zheng Y. , Rouaen J. , Jue T. R. , Michniewicz F. T. , Kasiou E. , Tsoli M. , Cirillo G. , Waters S. , Shai-Hee T. , Valli E. , Brettle M. , Whan R. , Vahadat L. , Ziegler D. , Lock J. G. , Giorgi F. M. , Khanna K. K. , Vittorio O. 
Published: October 2022

AbstractCopper is a trace element essential to cellular function with elevated levels implicated in cancer progression. Clinical trials using copper chelators are associated with improved patient survival, however, the molecular mechanisms by which copper depletion inhibits tumor progression are poorly understood. This remains a major hurdle to the clinical translation of copper chelators. Epithelial-mesenchymal transition (EMT) is often exploited by malignant cells to promote growth and metastasis. Transforming growth factor (TGF)-βis a master regulator of EMT and facilitates cancer progression through changes in the tumor and its microenvironment. Herein, we report that a reduction of copper with the chelating agent tetraethylenepentamine (TEPA) inhibited EMTin vitroin three diverse cancer cell types; human triple-negative breast cancer (TNBC), neuroblastoma (NB), and diffuse intrinsic pontine glioma (DIPG) cell lines. Single-molecule imaging demonstrated EMT markers including Vimentin,β-catenin, ZEB1, and p-SMAD2 had increased expression with copper treatment and this pro-mesenchymal shift was rescued by the addition of TEPA. Moreover, SNAI1, ZEB1, and p-SMAD2 demonstrated increased accumulation in the cytoplasm after treating with TEPA. Transcriptomic analyses revealed a significant downregulation of the EMT pathway, including canonical (TGF-β/SMAD2&3) and non-canonical (TGF-β/PI3K/AKT and TGF-β/RAS/RAF/MEK/ERK) TGF signaling pathways. Matrix metalloproteinases MMP-9 and MMP-14 proteins which activate latent TGF-βcomplexes were also downregulated by TEPA treatment. These molecular changes are consistent with reduced plasma levels of TGF-βwe observed in cancer models treated with TEPA. Importantly, copper chelation reduced metastasis to the lung in a TNBC orthotopic syngeneic mouse model. Our studies suggest copper chelation therapy can be used to inhibit EMT-induced metastasis by targeting TGF-βsignalling. Because on-target anti-TGF-βtherapies are failing in the clinic, copper chelation presents itself as a potential therapy for targeting TGF-βin cancer.
Effect of Odor Stimulations on Physical Activity: A Systematic Review
Authors: Cournoyer Mathieu , Maldera Alice , Gauthier Alexandre-Charles , Maso Fabien Dal , Mathieu Marie-Eve 
Published: October 2022

AbstractFewer and fewer people are reaching physical activity recommendations. Therefore, it seems important to make the practice of physical activity more enjoyable to increase the participation rate. Several environmental factors have been studied to see their impact on sports practice, and some studies investigated the effect of odors. This systematic review aims to provide a thorough view of the literature on the effect of different odors on physical activity. The search strategy consisted of using index terms and keywords in MEDLINE, EMBASE, EBM Reviews – Cochrane Central Register of Controlled Trials, CINAHL, SPORTDiscus, and Web of Science search engine. Data from 19 studies that included 421 participants revealed that the odors had different results on strength, cardiovascular, precision, and postural balance tasks depending on the odors’ exposition. Among results, an important distinction was made between pleasant and unpleasant odors. Therefore, pleasant odors had better results on physical activity by improving participants’ feeling. Even though this review clarified evidence about the effect of odors on physical activity, better methodological consistency is needed across studies such as the odor administration method to produce more meaningful results.
Vaccines alone cannot slow the evolution of SARS-CoV-2
Authors: Van Egeren Debra , Stoddard Madison , White Laura F. , Hochberg Natasha S. , Rogers Michael S. , Zetter Bruce , Joseph-McCarthy Diane , Chakravarty Arijit 
Published: October 2022

AbstractThe rapid emergence of immune-evading viral variants of SARS-CoV-2 calls into question the practicality of a vaccine-only public health strategy for managing the ongoing COVID-19 pandemic. It has been suggested that widespread vaccination is necessary to prevent the emergence of future immune-evading mutants. Here we examine that proposition using stochastic computational models of viral transmission and mutation. Specifically, we look at the likelihood of emergence of immune escape variants requiring multiple mutations, and the impact of vaccination on this process. Our results suggest that the transmission rate of intermediate SARS-CoV-2 mutants will impact the rate at which novel immune-evading variants will appear. While vaccination can lower the rate at which new variants appear, other interventions that reduce transmission can also have the same effect. Crucially, relying solely on widespread and repeated vaccination (vaccinating the entire population multiple times a year) is not sufficient to prevent the emergence of novel immune-evading strains if transmission rates remain high within the population. Thus, vaccines alone are incapable of slowing the pace of evolution of immune evasion, and vaccinal protection against severe and fatal outcomes for COVID-19 patients is therefore not assured.
Association of upper respiratory Streptococcus pneumoniae colonization with SARS-CoV-2 infection among adults
Authors: Parker Anna M. , Jackson Nicole , Awasthi Shevya , Kim Hanna , Alwan Tess , Wyllie Anne L. , Baldwin Alisha B. , Brennick Nicole B. , Moehle Erica A. , Giannikopoulos Petros , Kogut Katherine , Holland Nina , Mora-Wyrobek Ana , Eskenazi Brenda , Riley Lee W. , Lewnard Joseph A. 
Published: October 2022

ABSTRACTBackgroundStreptococcus pneumoniae interacts with numerous viral respiratory pathogens in the upper airway. It is unclear whether similar interactions occur with SARS-CoV-2.MethodsWe collected saliva specimens from working-age adults receiving SARS-CoV-2 molecular testing at outpatient clinics and via mobile community-outreach testing between July and November 2020 in Monterey County, California. Following bacterial culture enrichment, we tested for pneumococci by quantitative polymerase chain reaction (qPCR) targeting the lytA and piaB genes, and measured associations with SARS-CoV-2 infection via conditional logistic regression.ResultsAnalyses included 1,278 participants, with 564 enrolled in clinics and 714 enrolled through outreach-based testing. Prevalence of pneumococcal carriage was 9.2% (117/1,278) among all participants (11.2% [63/564] clinic-based testing; 7.6% [54/714] outreach testing). Prevalence of SARS-CoV-2 infection was 27.4% (32/117) among pneumococcal carriers and 9.6% (112/1,161) among non-carriers (adjusted odds ratio [aOR]: 2.73; 95% confidence interval: 1.58-4.69). Associations between SARS-CoV-2 infection and pneumococcal carriage were enhanced in the clinic-based sample (aOR=4.01 [2.08-7.75]) and among symptomatic participants (aOR=3.38 [1.35-8.40]), when compared to findings within the outreach-based sample and among asymptomatic participants. Adjusted odds of SARS-CoV-2 co-infection increased 1.24 (1.00-1.55)-fold for each 1-unit decrease in piaB qPCR CT value among pneumococcal carriers. Last, pneumococcal carriage modified the association of SARS-CoV-2 infection with recent exposure to a suspected COVID-19 case (aOR=7.64 [1.91-30.7] and 3.29 [1.94-5.59]) among pneumococcal carriers and non-carriers, respectively).ConclusionsAssociations of pneumococcal carriage detection and density with SARS-CoV-2 suggest a synergistic relationship in the upper airway. Longitudinal studies are needed to determine interaction mechanisms between pneumococci and SARS-CoV-2.Key pointsIn an adult ambulatory and community sample, SARS-CoV-2 infection was more prevalent among pneumococcal carriers than non-carriers.Associations between pneumococcal carriage and SARS-CoV-2 infection were strongest among adults reporting acute symptoms and receiving SARS-CoV-2 testing in a clinical setting.
UBE2C promotes leptomeningeal dissemination and is a therapeutic target in brain metastatic disease
Authors: Paisana Eunice , Cascão Rita , Custódia Carlos , Qin Nan , Picard Daniel , Pauck David , Carvalho Tânia , Ruivo Pedro , Barreto Clara , Doutel Delfim , Cabeçadas José , Roque Rafael , Pimentel José , Miguéns José , Remke Marc , Barata João T. , Faria Claudia C. 
Published: October 2022

ABSTRACTDespite current improvements in systemic cancer treatment, brain metastases (BM) remain incurable, and there is an unmet clinical need for effective targeted therapies. Here, we sought common molecular events in brain metastatic disease. RNA sequencing of thirty human BM identified the upregulation of UBE2C, a gene that ensures the correct transition from metaphase to anaphase, across different primary tumor origins. Tissue microarray analysis of an independent BM patient cohort revealed that high expression of UBE2C was associated with decreased survival. UBE2C-driven orthotopic mouse models developed extensive leptomeningeal dissemination, likely due to increased migration and invasion. Early cancer treatment with dactolisib (dual PI3K/mTOR inhibitor) prevented the development of UBE2C-induced leptomeningeal metastases. Our findings reveal UBE2C as a key player in the development of metastatic brain disease and highlight PI3K/mTOR inhibition as a promising anticancer therapy to prevent late-stage metastatic brain cancer.
Intracellular helix-loop-helix domain modulates inactivation kinetics of mammalian TRPV5 and TRPV6 channels
Authors: Flores-Aldama Lisandra , Bustos Daniel , Cabezas-Bratesco Deny , Brauchi Sebastián E. 
Published: October 2022

AbstractTRPV5 and TRPV6 are calcium-selective ion channels expressed at the apical membrane of epithelial cells. Important for systemic calcium (Ca2+) homeostasis, these channels are considered as gatekeepers of this cation transcellular transport. Intracellular Ca2+ exerts a negative control over the activity of these channels by promoting inactivation. TRPV5 and TRPV6 inactivation has been divided into fast and slow phases based on their kinetics. While slow inactivation is common to both channels, fast inactivation is characteristic of TRPV6. It has been proposed that the fast phase depends on Ca2+ binding and that the slow phase depends on the binding of the Ca2+/Calmodulin complex to the internal gate of the channels. Here, by means of structural analyses, site-directed mutagenesis, electrophysiology, and molecular dynamic simulations, we identified a specific set of amino acids and interactions that determine the inactivation kinetics of mammalian TRPV5 and TRPV6 channels. We propose that the association between the intracellular helix-loop-helix (HLH) and the TRP helix (TDh) domains favors the faster inactivation kinetics observed in mammalian TRPV6 channels.
Resolving Complexities in Taxonomic Lineages of the Organellar and Nuclear Genomes of Galdieria through Comparative Phylogenomic Analysis
Authors: Iovinella Manuela , Lock Sarah C. L. , Downing Jessica M. , Morley Jennifer , Chew Yen Peng , Mackinder Luke C. M. , Chong James P. J. , Feichtinger Georg A. , Ashton Peter D. , James Sally , Jeffares Daniel , Ciniglia Claudia , Davis Seth J. 
Published: October 2022

AbstractExploration of life in extreme environments allows the discovery of intriguing organisms with extraordinary biotechnological potential. An example of extreme environments is represented by hot springs, where harsh conditions (pH < 1; Temperature > 50°C; high concentrations of metals) are prohibitive for most living organisms, except for archaea, bacteria and a few eukaryotes like the unicellular red alga Galdieria. Phylogenetic analysis based on a few plastid and nuclear genes highlighted the intricate genetic structure of Galdieria and the hypothesis of diverging clades within the G. sulphuraria species. To resolve enigmatic relationships between lineages, we used plastid, mitochondrial and nuclear genome-scale data obtained from numerous strains from around the world. The resulting phylogenomic analysis identified: i) the divergence of each of the mitochondrial, plastid, and nuclear genomes into the same six clear lineages; ii) the independent evolution of the lineages; iii) the incongruent interlineages relationships between the three genomes. Differential evolutionary pressure between the strains and the genomes were also highlighted by synonymous and non-synonymous substitutions.
Learning Free Energy Pathways through Reinforcement Learning of Adaptive Steered Molecular Dynamics
Authors: Ho Nicholas , Cava John Kevin , Vant John , Shukla Ankita , Miratsky Jake , Turaga Pavan , Maciejewski Ross , Singharoy Abhishek 
Published: October 2022

AbstractIn this paper, we develop a formulation to utilize reinforcement learning and sampling-based robotics planning to derive low free energy transition pathways between two known states. Our formulation uses Jarzynski’s equality and the stiffspring approximation to obtain point estimates of energy, and construct an informed path search with atomistic resolution. At the core of this framework, is our first ever attempt we use a policy driven adaptive steered molecular dynamics (SMD) to control our molecular dynamics simulations. We show that both the reinforcement learning and robotics planning realization of the RL-guided framework can solve for pathways on toy analytical surfaces and alanine dipeptide.
Control of spatio-temporal patterning via cell density in a multicellular synthetic gene circuit
Authors: Santorelli Marco , Bhamidipati Pranav S. , Kavanagh Andriu , MacKrell Victoria A. , Sondkar Trusha , Thomson Matt , Morsut Leonardo 
Published: October 2022

AbstractA major goal in synthetic development is to design and construct gene regulatory circuits that control the patterning and morphogenesis of synthetic multicellular structures. In natural development, an interplay between mechanical and chemical communication shapes the dynamics of gene regulatory circuits that underlie patterning and morphogenesis. However, for synthetic gene circuits, how the non-genetic properties of the growth environment impact circuit behavior remains poorly understood. Here, we describe an occurrence of mechano-chemical coupling in synthetic contact-dependent synNotch patterning circuits demonstrating that cell density modulates the transduction of signal between a sender and receiver cell. By exploiting density-dependent signaling, we construct multicellular signal propagation circuits with synNotch and control the patterning outcome both temporally and spatially via cell density gradients established in vitro via plating or small-molecule mediated modulation of proliferation. Our work demonstrates that synthetic gene circuits can be critically impacted by their context, providing an alternate means for programming multi-cellular circuit patterning outcomes.
Randomized, Double-Blind, Placebo-Controlled Trial of MUC1 Peptide Vaccine for Prevention of Recurrent Colorectal Adenoma
Authors: Schoen Robert E. , Boardman Lisa A. , Cruz-Correa Marcia , Bansal Ajay , Kastenberg David , Hur Chin , Dzubinski Lynda , Kaufman Sharon F. , Rodriguez Luz M. , Richmond Ellen , Umar Asad , Szabo Eva , Salazar Andres , McKolanis John , Beatty Pamela , Pai Reetesh K. , Singhi Aatur D. , Jacqueline Camille M. , Bao Riuye , Diergaarde Brenda , McMurray Ryan P. , Strand Carrie , Foster Nathan R. , Zahrieh David M. , Limburg Paul J. , Finn Olivera J. 
Published: October 2022

AbstractObjectiveVaccines against antigens expressed on adenomas could prevent new adenoma formation. We assessed whether a MUC1 peptide vaccine produces an immune response and prevents subsequent colonic adenoma formation.DesignMulticenter, double blind, placebo-controlled randomized trial in individuals age 40-70 with diagnosis of an advanced adenoma ≤1 year from randomization. Vaccine was administered at 0, 2, and 10 weeks with a booster injection at week 53. Adenoma recurrence was assessed ≥1 year from randomization. The primary endpoint was vaccine immunogenicity at 12 weeks defined by anti-MUC1 ratio ≥2.0.Results53 participants received the MUC1 vaccine and 50 placebo. 13/52 (25%) of MUC1 vaccine recipients had a ≥2-fold increase in MUC1 IgG (range 2.9-17.3) at week 12 vs. 0/50 placebo recipients (1-sided Fisher’s exact P<0.0001). Of the 13 responders at week 12, 11 (84.6%) had a ≥2-fold increase in MUC1 IgG with the booster and were considered immune responders. A recurrent adenoma was observed in 31 of 47 (66.0%) in the placebo group vs. 27 of 48 (56.3%) participants in the MUC1 group (adjusted relative risk (aRR) = 0.83 [95% CI, 0.60-1.14], P=0.25). Adenoma recurrence occurred in 3/11 (27.3%) immune responders, (aRR = 0.41 [95% CI, 0.15-1.11], P=0.08). Vaccine recipients had more injection site reactions than placebo recipients, but there was no difference in serious adverse events.ConclusionAn immune response was observed only in vaccine recipients. Overall adenoma recurrence was not different than placebo, but a 38% absolute reduction in adenoma recurrence was observed in immune responders.ClinicalTrials.gov Identifier: NCT02134925.https://clinicaltrials.gov/ct2/show/NCT02134925Key PointsWhat is already knownAntigens expressed on colonic adenomas are potential targets for immunopreventive vaccines. An effective vaccine could prevent subsequent adenoma formation.What this Study AddsIn this multicenter, double blind, placebo-controlled randomized trial, MUC1 vaccine recipients developed an immune response. Overall adenoma recurrence was not different than placebo, but a 38% absolute reduction in adenoma recurrence was observed in immune responders.How this study might affect research, practice or policyVaccine immunoprevention is a potential new frontier to colorectal cancer prevention.
The value of freedom: the introduction of option freedom in health-related capability wellbeing measurement
Authors: Ubels Jasper , Hernandez-Villafuerte Karla , Schlander Michael 
Published: October 2022

AbstractThe capability approach has been used to develop instruments. However, the capability concept by Sen has been argued to be ambiguous concerning some elements of freedom, such as the burdens that people experience whilst achieving capabilities. Developing instruments with a comprehensive definition of capability might increase their sensitivity to a broader range of constructs. Our study operationalizes a framework based on the comprehensive “option freedom” concept into measurable constructs and presents an illustrative instrument.For this, the Multi Instrument Comparison (MIC) database was used. Items from the MIC database were matched to themes from a framework that had been developed in an earlier qualitative study. Then, a measurement model was constructed with the selected items and model fit was assessed. Lastly, an illustrative instrument was created that shows how the selected constructs can be measured concisely.A measurement model was constructed with 57 items and 11 factors. Data-driven explorative adjustments were made to improve model fit. Based on this model an instrument was developed with three scales (“Reflective Wellbeing”, “Affective Wellbeing” and “Perceived Access to Options”) totaling 15 items. This instrument showed adequate psychometric characteristics in terms of reliability and fit index values.This study shows how the concept of option freedom can be operationalized for health-related wellbeing assessment. Furthermore, the analysis indicates that in the context of outcome measurement, information about both capabilities and functionings related to subjective wellbeing is required to assess the overall wellbeing of an individual. Further research is needed to validate the instrument.
Reward-related activation of fronto-striatal regions scaled negatively with C-reactive protein but showed no association with anhedonia in depression
Authors: Aruldass Athina R. , Kitzbichler Manfred G. , Lim Tsen Vei ,   Wellcome Trust Consortium for Neuroimmunology of Mood Disorders and Alzheimer’s Disease (NIMA), Cavanagh Jonathan , Cowen Phil , Pariante Carmine M. , Bullmore Edward T. , Harrison Neil A. 
Published: October 2022

AbstractDepression is characterized by divergent changes in positive and negative affect. Emerging roles of inflammation in depression portend avenues for novel immunomodulator-based monotherapy, targeting mechanistically distinct symptoms such as anhedonia and pessimism. To investigate fundamental links between these divergent affective components and inflammation, we used a probabilistic reinforcement-learning fMRI paradigm, testing for evidence of hyposensitivity to reward, and hypersensitivity to punishment in low-inflammation depression cases (loCRP depression; CRP ≤ mg/L; N=48), high-inflammation depression cases (hiCRP depression; CRP > 3mg/L; N=31), and healthy controls (HC; CRP ≤ mg/L; N=45). We aimed to (i) determine whether depression cases with high and low inflammation showed aberrant neural activation to monetary gains and losses compared to controls; (ii) examine if these alterations correlated with a continuous measure of C-reactive protein (CRP) in depression, (iii) test if neuroimaging responses to rewards and punishments scaled with indices of anhedonia and pessimism derived from behavioral instruments in depression. Voxel-wise activation was observed in key brain regions sensitive to monetary reward (ventromedial prefrontal cortex, vmPFC; nucleus accumbens, NAc) and punishment (insula) outcomes across all three groups. However, there was no significant difference in activation between groups. Within depression cases, increasing CRP scaled negatively with activation in the right vmPFC and left NAc but not insula cortex. However, there was no significant association between regional activation and severity of anhedonia or pessimism. Our results support the previously reported association between CRP and striatal reward reactivity in depression but do not extend this to processing of negatively valenced information.