bluuebunny/crossref_metadata_2025_split huggingface dataset:
Contribution of the microbiota and their secretory products to inflammation and colorectal cancer pathogenesis: the role of toll-like receptors
Authors: Sheikh Aadil , Taube Joseph , Greathouse K Leigh 
Published: July 2021

AbstractAlterations in diversity and function of the gut microbiome are associated with concomitant changes in immune response, including chronic inflammation. Chronic inflammation is a major risk factor for colorectal cancer (CRC). An important component of the inflammatory response system are the toll-like receptors (TLRs). TLRs are capable of sensing microbial components, including nucleic acids, lipopolysaccharides and peptidoglycans, as well as bacterial outer membrane vesicles (OMV). OMVs can be decorated with or carry as cargo these TLR activating factors. These microbial factors can either promote tolerance or activate signaling pathways leading to chronic inflammation. Herein we discuss the role of the microbiome and the OMVs that originate from intestinal bacteria in promoting chronic inflammation and the development of colitis-associated CRC. We also discuss the contribution of TLRs in mediating the microbiome-inflammation axis and subsequent cancer development. Understanding the role of the microbiome and its secretory factors in TLR response may lead to the development of better cancer therapeutics.
Does gut microbiota affect atrial rhythm? Causalities and speculations
Authors: Linz Dominik , Gawałko Monika , Sanders Prashanthan , Penders John , Li Na , Nattel Stanley , Dobrev Dobromir 
Published: July 2021

Abstract
Dietary intake has been shown to change the composition of gut microbiota and some changes in microbiota (dysbiosis) have been linked to diabetes, hypertension, and obesity, which are established risk factors for atrial fibrillation (AF). In addition, intestinal dysbiosis generates microbiota-derived bioactive metabolites that might exert proarrhythmic actions. Although emerging preclinical investigations and clinical observational cohort studies suggest a possible role of gut dysbiosis in AF promotion, the exact mechanisms through which dysbiosis contributes to AF remain unclear. This Viewpoint article briefly reviews evidence suggesting that abnormalities in the intestinal microbiota play an important and little-recognized role in the pathophysiology of AF and that an improved understanding of this role may open up new possibilities in the management of AF.
Behavioral Research in Cancer Prevention and Control: Emerging Challenges and Opportunities
Authors: Klein William M P , O’Connell Mary E , Bloch Michele H , Czajkowski Susan M , Green Paige A , Han Paul K J , Moser Richard P , Nebeling Linda C , Vanderpool Robin C 
Published: July 2021

AbstractIt is estimated that behaviors such as poor diet, alcohol consumption, tobacco use, sedentary behavior, and excessive ultraviolet exposure account for nearly one-half of all cancer morbidity and mortality. Accordingly, the behavioral, social, and communication sciences have been important contributors to cancer prevention and control research, with methodological advances and implementation science helping to produce optimally effective interventions. To sustain these contributions, it is vital to adapt to the contemporary context. Efforts must consider ancillary effects of the 2019 coronavirus disease pandemic, profound changes in the information environment and public understanding of and trust in science, renewed attention to structural racism and social determinants of health, and the rapidly increasing population of cancer survivors. Within this context, it is essential to accelerate reductions in tobacco use across all population subgroups; consider new models of energy balance (diet, physical activity, sedentary behavior); increase awareness of alcohol as a risk factor for cancer; and identify better communication practices in the context of cancer-related decisions such as screening and genetic testing. Successful integration of behavioral research and cancer prevention depends on working globally and seamlessly across disciplines, taking a multilevel approach where possible. Methodological and analytic approaches should be emphasized in research training programs and should use new and underused data sources and technologies. As the leadership core of the National Cancer Institute’s Behavioral Research Program, we reflect on these challenges and opportunities and consider implications for the next phase of behavioral research in cancer prevention and control.
A novel circular RNA, circPUS7 promotes cadmium-induced transformation of human bronchial epithelial cells by regulating Kirsten rat sarcoma viral oncogene homolog expression via sponging miR-770
Authors: Pan Shuya , Wang Qin , Zhang Qian , Zhou Mei , Li Luyao , Zhou Xue 
Published: July 2021

Abstract
Cadmium is a human carcinogen, which induces cancers by mechanisms that are not fully understood. Induction of oxidative stress, apoptosis resistance, genotoxic effects, and epigenetic modulations have been indicated to regulate cadmium-induced carcinogenesis. Circular RNAs are epigenetic regulators that have been recognized to play essential roles in carcinogenesis. Yet, the involvement of circular RNAs in cadmium carcinogenesis remains unclear. In this study, a novel circular RNA, circPUS7, was identified and described for the first time. CircPUS7 was significantly upregulated at week 12, 16, and 20 during the cadmium-induced transformation of human bronchial epithelial BEAS-2B cells. Knockdown of circPUS7 in cadmium-transformed BEAS-2B (T-BEAS-2B) cells significantly attenuated transformation markers including cell proliferation, migration, invasion, and anchorage-independent growth. Moreover, circPUS7 promoted malignant phenotypes by competitively binding with miR-770. Overexpression of miR-770 significantly inhibited the transformation properties of T-BEAS-2B cells while inhibition of miR-770 potently reversed the inhibitory effects of circPUS7 knockdown in proliferation, migration, invasion, and anchorage-independent growth of the T-BEAS-2B cells. Kirsten rat sarcoma viral oncogene homolog (KRAS), which was increased synchronically with circPUS7 during cadmium-induced cell transformation, was regulated by circPUS7 through sponging miR-770. In summary, our findings demonstrate that circPUS7 promotes cadmium-induced cell transformation through sponging miR-770 to regulate KRAS expression, providing a new perspective with the involvement of circular RNAs to further understand the mechanisms of cadmium carcinogenesis.
The IDentif.AI 2.0 Pandemic Readiness Platform: Rapid Prioritization of Optimized COVID-19 Combination Therapy Regimens
Authors: Blasiak Agata , Truong Anh T.L. , Remus Alexandria , Hooi Lissa , Seah Shirley Gek Kheng , Wang Peter , Chye De Hoe , Lim Angeline Pei Chiew , Ng Kim Tien , Teo Swee Teng , Tan Yee-Joo , Allen David Michael , Chai Louis Yi Ann , Chng Wee Joo , Lin Raymond T.P. , Lye David C.B. , Wong John Eu-Li , Tan Gek-Yen Gladys , Chan Conrad En Zuo , Chow Edward Kai-Hua , Ho Dean 
Published: July 2021

AbstractObjectivesWe aimed to harness IDentif.AI 2.0, a clinically actionable AI platform to rapidly pinpoint and prioritize optimal combination therapy regimens against COVID-19.MethodsA pool of starting candidate therapies was developed in collaboration with a community of infectious disease clinicians and included EIDD-1931 (metabolite of EIDD-2801), baricitinib, ebselen, selinexor, masitinib, nafamostat mesylate, telaprevir (VX-950), SN-38 (metabolite of irinotecan), imatinib mesylate, remdesivir, lopinavir, and ritonavir. Following the initial drug pool assessment, a focused, 6-drug pool was interrogated at 3 dosing levels per drug representing nearly 10,000 possible combination regimens. IDentif.AI 2.0 paired prospective, experimental validation of multi-drug efficacy on a SARS-CoV-2 live virus (propagated, original strain, B.1.351 and B.1.617.2 variants) and Vero E6 assay with a quadratic optimization workflow.ResultsWithin 3 weeks, IDentif.AI 2.0 realized a list of combination regimens, ranked by efficacy, for clinical go/no-go regimen recommendations. IDentif.AI 2.0 revealed EIDD-1931 to be a strong candidate upon which multiple drug combinations can be derived.ConclusionsIDentif.AI 2.0 rapidly revealed promising drug combinations for clinical translation. It pinpointed dose-dependent drug synergy behavior to play a role in trial design and realizing positive treatment outcomes. IDentif.AI 2.0 represents an actionable path towards rapidly optimizing combination therapy following pandemic emergence.Graphical AbstractHighlights-When novel pathogens emerge, the immediate strategy is to repurpose drugs.-Good drugs delivered together in suboptimal combinations and doses can yield low or no efficacy, leading to misperception that the drugs are ineffective.-IDentif.AI 2.0 does not use in silico modeling or pre-existing data.-IDentif.AI 2.0 pairs optimization with prospectively acquired experimental data using a SARS-CoV-2/Vero E6 assay.-IDentif.AI 2.0 pinpoints EIDD-1931 as a foundation for optimized anti-SARS-CoV-2 combination therapies.
The Genetic Architecture of Amygdala Nuclei
Authors: Mufford Mary S. , van der Meer Dennis , Kaufmann Tobias , Frei Oleksandr , Ramesar Raj , Thompson Paul M. , Jahanshad Neda , Morey Rajendra A. , Andreassen Ole A. , Stein Dan J. , Dalvie Shareefa 
Published: July 2021

AbstractBackgroundWhereas a number of genetic variants influencing total amygdala volume have been identified in previous research, genetic architecture of its distinct nuclei have yet to be thoroughly explored. We aimed to investigate whether increased phenotypic specificity through segmentation of the nuclei aids genetic discoverability and sheds light on the extent of shared genetic architecture and biological pathways between the nuclei and disorders associated with the amygdala.MethodsT1-weighted brain MRI scans (n=36,352, mean age= 64.26 years, 52% female) of trans-ancestry individuals from the UK Biobank were segmented into nine amygdala nuclei with FreeSurfer v6.1, and genome-wide association analyses were performed on the full sample and a European-only subset (n=31,690). We estimated heritability using Genome-wide Complex Trait Analysis, derived estimates of polygenicity, discoverability and power using MiXeR, and determined genetic correlations and shared loci between the nuclei using Linkage Disequilibrium Score Regression, followed by functional annotation using FUMA.ResultsThe SNP-based heritability of the nuclei ranged between 0.17-0.33, and the central nucleus had the greatest statistical power for discovery. Across the whole amygdala and the nuclei volumes, 38 novel significant (p < 5×10−9) loci were identified, with most loci mapped to the central nucleus. The mapped genes and associated pathways revealed both unique and shared effects across the nuclei, and immune-related pathways were particularly enriched across several nuclei.ConclusionsThese findings indicate that the amygdala nuclei volumes have significant genetic heritability, increased power for discovery compared to whole amygdala volume, may have unique and shared genetic architectures, and a significant immune component to their aetiology.
Alzheimer’s Disease Assessments Optimised for Diagnostic Accuracy and Administration Time
Authors: McCombe Niamh , Ding Xuemei , Prasad Girijesh , Gillespie Paddy , Finn David P. , Todd Stephen , McClean Paula L. , Wong-Lin KongFatt ,   Alzheimer’s Disease Neuroimaging Initiative
Published: July 2021

AbstractObjectiveDespite the potential of machine learning techniques to improve dementia diagnostic processes, research outcomes are often not readily translated to or adopted in clinical practice. Importantly, the time taken to administer diagnostic assessment has yet to be taken into account in feature-selection based optimisation for dementia diagnosis. We address these issues by considering the impact of assessment time as a practical constraint for feature selection of cognitive and functional assessments in Alzheimer’s disease diagnosis.MethodsWe use three different feature selection algorithms to select informative subsets of dementia assessment items from a large open-source dementia dataset. We use cost-sensitive feature selection to optimise our feature selection results for assessment time as well as diagnostic accuracy. To encourage clinical adoption and further evaluation of our proposed accuracy-vs-cost optimisation algorithms, we also implement a sandbox-like toolbox with graphical user interface to evaluate user-chosen subsets of assessment items.ResultsWe find that there are subsets of accuracy-cost optimised assessment items that can perform better in terms of diagnostic accuracy and/or total assessment time than most other standard assessments.DiscussionOverall, our analysis and accompanying sandbox tool can facilitate clinical users and other stakeholders to apply their own domain knowledge to analyse and decide which dementia diagnostic assessment items are useful, and aid the redesigning of dementia diagnostic assessments. Clinical Impact (Clinical Research): By optimising diagnostic accuracy and assessment time, we redesign predictive and efficient dementia diagnostic assessments and develop a sandbox interface to facilitate evaluation and testing by clinicians and non-specialists.
The Role of the Human Brain Neuron-Glia-Synaptic Composition in Forming Resting State Functional Connectivity Networks
Authors: Kahali Sayan , Raichle Marcus E. , Yablonskiy Dmitriy A. 
Published: July 2021

ABSTRACTWhile significant progress has been achieved in studying resting state functional networks in a healthy human brain and in a wide range of clinical conditions, many questions related to their relationship to the brain’s cellular constituents remain open. Herein we use quantitative Gradient-Recalled-Echo (qGRE) MRI for mapping human brain cellular composition, and BOLD (blood oxygen level dependent) MRI to explore how the brain cellular constituents relate to resting state functional networks. Results show that the BOLD-signal-defined synchrony of connections between cellular circuits in network-defined individual functional units is mainly associated with the regional neuronal density, while the between-functional-units connectivity strength is also influenced by the glia and synaptic components of brain tissue cellular constituents. These mechanisms lead to a rather broad distribution of resting state functional networks properties. Visual networks with the highest neuronal density (but lowest density of glial cells and synapses) exhibit the strongest coherence of BOLD signal, as well as the strongest intra-network connectivity. The Default Mode Network (DMN) is positioned near the opposite part of the spectrum with relatively low coherence of the BOLD signal but a remarkably balanced cellular content enabling DMN prominent role in the overall organization of the brain and the hierarchy of functional networks.
Suppression of sost/sclerostin and dickkopf-1 promote intervertebral disc structure in mice
Authors: Kroon Tori , Niziolek Paul , Edwards Daniel , Clinkenbeard Erica L , Robling Alexander , Holguin Nilsson 
Published: July 2021

AbstractIntervertebral disc (IVD) degeneration is a leading cause of low back pain and characterized by accelerated extracellular matrix breakdown and IVD height loss but there is no approved pharmacological therapeutic. Deletion of Wnt signaling receptor Lrp5 induces IVD degeneration and suggests that Wnt signaling in the IVD may be responsive to inhibition of Wnt signaling inhibitors sost(gene)/sclerostin(protein) or dickkopf-1 (dkk1). Anti-sclerostin antibody (Scl-Ab) is an FDA-approved bone therapeutic that activates Wnt signaling. We (1) determined if pharmacological neutralization of sclerostin, dkk1 or their combination stimulate Wnt signaling and promote IVD structure and (2) determined the extent of the response of the IVD to global, persistent deletion of sost. Nine-week-old C57Bl/6J female mice (n=6-7/grp) were subcutaneously injected 2x/wk for 5.5 wk with scl-Ab (25 mg/kg), dkk1-Ab (25 mg/kg), 3:1 scl-Ab/dkk1-Ab (18.75:6.25 mg/kg) or vehicle (Veh). Separately, IVD of sost KO and WT (wildtype) mice (n=8, grp) were harvested at 16 weeks of age. First, compared to vehicle, scl-Ab, dkk1-Ab and 3:1 scl-Ab/dkk1-Ab similarly increased lumbar IVD height and β-catenin gene expression. Despite these similarities, scl-Ab decreased cellular stress-related heat shock protein gene expressions while neither dkk1-Ab nor scl-Ab/dkk1-Ab altered the same. Genetically and compared to WT, sost KO increased MRI-determined hydration and proteoglycan staining in the IVD. Notably, persistent deletion of sost was compensated by upregulation of dkk1, which consequently reduced the cell nuclear fraction for Wnt signaling transcription factor β-catenin in whole IVD. Lastly, RNA-sequencing pathway analysis confirmed the compensatory suppression of Wnt signaling and determined a reduction of cellular stress pathways. Together, suppression of sost/sclerostin or dkk1 each promote IVD structure by stimulating Wnt signaling, but sclerostin and dkk1 may differentially regulate cellular stress pathways. Ultimately, postmenopausal women prescribed scl-Ab injections to prevent vertebral fracture may also benefit from a restoration of IVD height and health.Graphical abstractSuppression of Wnt signaling inhibitors by genetic or pharmacological approaches promotes intervertebral disc structure and hydration by Wnt signaling. However, persistent activation of Wnt signaling induces a compensatory reduction of Wnt signaling that shifts IVD cells toward a chondrocyte-like (CLC) phenotype. AF: annulus fibrosus, NC: notochordal cell, NP: nucleus pulposus, PG: proteoglycan
Mining all publicly available expression data to compute dynamic microbial transcriptional regulatory networks
Authors: Sastry Anand V. , Poudel Saugat , Rychel Kevin , Yoo Reo , Lamoureux Cameron R. , Chauhan Siddharth , Haiman Zachary B. , Al Bulushi Tahani , Seif Yara , Palsson Bernhard O. 
Published: July 2021

AbstractWe are firmly in the era of biological big data. Millions of omics datasets are publicly accessible and can be employed to support scientific research or build a holistic view of an organism. Here, we introduce a workflow that converts all public gene expression data for a microbe into a dynamic representation of the organism’s transcriptional regulatory network. This five-step process walks researchers through the mining, processing, curation, analysis, and characterization of all available expression data, usingBacillus subtilisas an example. The resulting reconstruction of theB. subtilisregulatory network can be leveraged to predict new regulons and analyze datasets in the context of all published data. The results are hosted athttps://imodulondb.org/, and additional analyses can be performed using the PyModulon Python package. As the number of publicly available datasets increases, this pipeline will be applicable to a wide range of microbial pathogens and cell factories.
Gaussian accelerated molecular dynamics reveals that a proline-rich signaling peptide frequently samples cis conformations when unbound
Authors: Alcantara Juan , Stix Robyn , Huang Katherine , Connor Acadia , East Ray , Jaramillo-Martinez Valeria , Stollar Elliott J. , Ball K. Aurelia 
Published: July 2021

AbstractDisordered proline-rich motifs are common across the proteomes of many species and are often involved in protein-protein interactions. Proline is a unique amino acid due to the covalent bond between the backbone nitrogen and the proline side chain. The resulting five-membered ring allows proline to sample the cis state about its peptide bond, which other residues cannot do as readily. Because proline-rich disordered sequences exist as ensembles that likely include structures with the proline peptide bond in cis, a robust methodology to accurately account for these conformations in the overall ensemble is crucial. Observing the cis conformations of proline in a disordered sequence is challenging both experimentally and computationally. Nitrogen-hydrogen NMR spectroscopy cannot directly observe proline residues, which lack an amide bond, and computational methods struggle to overcome the large kinetic barrier between the cis and trans states, since isomerization usually occurs on the order of seconds. In the current work, Gaussian accelerated molecular dynamics was used to overcome this free energy barrier and simulate proline isomerization in a tetrapeptide (KPTP) and in the 12-residue proline-rich SH3 binding peptide, ArkA. We found that Gaussian accelerated molecular dynamics, when combined with a lowered peptide bond dihedral angle potential energy barrier (15 kcal/mol), allowed sufficient sampling of the proline cis and trans states on a microsecond timescale. All ArkA prolines spend a significant fraction of time in cis, leading to a more compact ensemble with less polyproline II helix structure than an ArkA ensemble with all peptide bonds in trans. The ensemble containing cis prolines also matches more closely to in vitro circular dichroism data than the all-trans ensemble. The ability of the ArkA prolines to isomerize likely affects the peptide’s ability to bind its partner SH3 domain, and should be studied further. This is the first molecular dynamics simulation study of proline isomerization in a biologically relevant proline-rich sequence that we know of, and a similar protocol could be applied to study multi-proline isomerization in other proline-containing proteins to improve conformational diversity and agreement with in vitro data.
Evolution of the quorum sensing regulon in cooperating populations of Pseudomonas aeruginosa
Authors: Smalley Nicole E. , Schaefer Amy L. , Asfahl Kyle L. , Perez Crystal , Greenberg E. Peter , Dandekar Ajai A. 
Published: July 2021

AbstractThe bacterium Pseudomonas aeruginosa is an opportunistic pathogen and it thrives in many different saprophytic habitats. In this bacterium acyl-homoserine lactone quorum sensing (QS) can activate expression of over 100 genes, many of which code for extracellular products. P. aeruginosa has become a model for studies of cell-cell communication and coordination of cooperative activities. We hypothesized that long-term growth of bacteria under conditions where only limited QS-controlled functions were required would result in a reduction in the size of the QS-controlled regulon. To test this hypothesis, we grew P. aeruginosa for about 1000 generations in a condition in which expression of QS-activated genes is required for growth. We compared the QS regulons of populations after about 35 generations to those after about 1000 generations in two independent lineages by using quorum quenching and RNA-seq technology. In one evolved lineage the number of QS-activated genes identified was reduced by about 70% and in the other by about 45%. Our results lend important insights about the variations in the number of QS-activated genes reported for different bacterial strains and, more broadly, about the environmental histories of P. aeruginosa.