Increased stability and intracellular antioxidant activity of chlorogenic acid depend on its molecular interaction with wheat gluten hydrolysate.

Food Chem. 2020 Apr 23;325:126873

Authors: He D, Peng X, Xing YF, Wang Y, Zeng W, Su N, Zhang C, Lu DN, Xing XH

Abstract
Gastrointestinal stability and cell entry efficiency affect the biological accessibility of chlorogenic acid (CGA). Here, wheat gluten hydrolysate (WGH) was proven to improve the stability of CGA during simulated gastrointestinal digestion, promote the intestinal epithelial cell entry efficiency of CGA, and increase its intracellular antioxidant activity. The interaction between WGH and CGA was studied by fluorescence quenching and molecular dynamics simulations. The thermodynamic parameters and molecular dynamics simulation analysis showed that the interaction between WGH and CGA was dependent on hydrogen bonding and hydrophobic and electrostatic interactions. Analyses of the binding sites of WGH showed that Arg12, Arg49, Lys54, and Pro74-Gln89 had strong interactions with CGA molecules. This interaction between CGA and WGH was related to both electrostatic interactions and their respective concentrations. Taken together, the stability, intestinal epithelial cell entry, and antioxidant activity of CGA can be increased by its molecular interactions with WGH.

PMID: 32387948 [PubMed - as supplied by publisher]

Characterizing diversity in the tumor-immune microenvironment of distinct subclasses of gastroesophageal adenocarcinomas.

Ann Oncol. 2020 May 06;:

Authors: Derks S, de Klerk LK, Xu X, Fleitas T, Liu KX, Liu Y, Dietlein F, Margolis C, Chiaravalli AM, Da Silva AC, Ogino S, Akarca FG, Freeman GJ, Rodig SJ, Hornick JL, van Allen E, Li B, Liu SX, Thorsson V, Bass AJ

Abstract
BACKGROUND: Gastroesophageal adenocarcinomas (GEA) are heterogeneous cancers where immune checkpoint inhibitors (ICI) have robust efficacy in heavily inflamed microsatellite instability (MSI) or Epstein-Barr Virus (EBV) positive subtypes. ICI responses are markedly lower in diffuse/genome-stable (GS) and chromosomal instable (CIN) GEAs. In contrast to EBV and MSI subtypes, the tumor microenvironment of CIN and GS GEAs have not been fully characterized to date, which limits our ability to improve immunotherapeutic strategies.
PATIENTS AND METHODS: Here we aimed to identify tumor-immune cell association across GEA subclasses using data from The Cancer Genome Atlas (TCGA) (N=453 GEAs) and archival GEA resection specimen (N=63). TCGA RNAseq data were used for computational inferences of immune cell subsets, which were correlated to tumor characteristic within and between subtypes. Archival tissues were used for more spatial immune characterization spanning immunohistochemistry and mRNA expression analyses.
RESULTS: Our results confirmed substantial heterogeneity in TME between distinct subtypes. While MSI-high and EBV+ GEAs harbored most intense T cell infiltrates, the GS group showed enrichment of CD4+T cells, macrophages and B cells and, in ∼50% of cases, evidence for tertiary lymphoid structures (TLSs). In contrast, CIN cancers possessed CD8+T cells predominantly at the invasive margin while tumor associated macrophages (TAMs) showed tumor infiltrating capacity. Relatively T cell-rich 'hot' CIN GEAs were often from Western patients, while immunological 'cold' CIN GEAs showed enrichment of MYC and cell cycle pathways, including amplification of CCNE1.
CONCLUSION: These results reveal the diversity of immune phenotypes of GEA. Half of GS GCs have TLSs and are therefore promising candidates for immunotherapy. The majority of CIN GEAs, however, exhibit T cell exclusion and infiltrating macrophages. Associations of immune-poor CIN GEAs with MYC activity and CCNE1 amplification may enable new studies to determine precise mechanisms of immune evasion, ultimately inspiring new therapeutic modalities.

PMID: 32387455 [PubMed - as supplied by publisher]

Antimicrobial peptides as a promising treatment option against Acinetobacter baumannii infections.

Microb Pathog. 2020 May 05;:104238

Authors: Neshani A, Sedighian H, Mirhosseini SA, Ghazvini K, Zare H, Jahangiri A

Abstract
BACKGROUND: With the increasing rate of antibiotic resistance in Acinetobacter, the World Health Organization introduced the carbapenem-resistant isolates in the priority pathogens list for which innovative new treatments are urgently needed. Antimicrobial peptides (AMPs) are one of the antimicrobial agents with high potential to produce new anti-Acinetobacter drugs. This review aims to summarize recent advances and compare AMPs with anti-Acinetobacter baumannii activity.
METHODS: Active AMPs against Acinetobacter were considered, and essential features, including structure, mechanism of action, anti-A. baumannii potent, and other prominent characteristics, were investigated and compared to each other. In this regard, the Google Scholar search engine and databases of PubMed, Scopus, and Web of Science were used.
RESULTS: Forty-six anti-Acinetobacter peptides were identified and classified into ten groups: Cathelicidins, Defensins, Frog AMPs, Melittin, Cecropins, Mastoparan, Histatins, Dermcidins, Tachyplesins, and computationally designed AMPs. According to the Minimum Inhibitory Concentration (MIC) reports, six peptides of Melittin, Histatin-8, Omega76, AM-CATH36, Hymenochirin, and Mastoparan have the highest anti-A. baumannii power against sensitive and antibiotic-resistant isolates. All anti-Acinetobacter peptides except Dermcidin have a net positive charge. Most of these peptides have alpha-helical structure; however, β-sheet and other structures have been observed among them. The mechanism of action of these antimicrobial agents is divided into two categories of membrane-based and intracellular target-based attack.
CONCLUSION: Evidence from this review indicates that AMPs would be likely among the main anti-A. baumannii drugs in the post-antibiotic era. Also, the application of computer science to increase anti-A. baumannii activity and reduce toxicity could be helpful.

PMID: 32387392 [PubMed - as supplied by publisher]

Metabolomic Markers of Kidney Function Decline in Patients With Diabetes: Evidence From the Chronic Renal Insufficiency Cohort (CRIC) Study.

Am J Kidney Dis. 2020 May 05;:

Authors: Kwan B, Fuhrer T, Zhang J, Darshi M, Van Espen B, Montemayor D, de Boer IH, Dobre M, Hsu CY, Kelly TN, Raj DS, Rao PS, Saraf SL, Scialla J, Waikar SS, Sharma K, Natarajan L, CRIC Study Investigators

Abstract
RATIONALE & OBJECTIVE: Biomarkers that provide reliable evidence of future diabetic kidney disease (DKD) are needed to improve disease management. In a cross-sectional study, we previously identified 13 urine metabolites that had levels reduced in DKD compared with healthy controls. We evaluated associations of these 13 metabolites with future DKD progression.
STUDY DESIGN: Prospective cohort.
SETTING & PARTICIPANTS: 1,001 Chronic Renal Insufficiency Cohort (CRIC) participants with diabetes with estimated glomerular filtration rates (eGFRs) between 20 and 70mL/min/1.73m2 were followed up prospectively for a median of 8 (range, 2-10) years.
PREDICTORS: 13 urine metabolites, age, race, sex, smoked more than 100 cigarettes in lifetime, body mass index, hemoglobin A1c level, blood pressure, urinary albumin, and eGFR.
OUTCOMES: Annual eGFR slope and time to incident kidney failure with replacement therapy (KFRT; ie, initiation of dialysis or receipt of transplant).
ANALYTICAL APPROACH: Several clinical metabolite models were developed for eGFR slope as the outcome using stepwise selection and penalized regression, and further tested on the time-to-KFRT outcome. A best cross-validated (final) prognostic model was selected based on high prediction accuracy for eGFR slope and high concordance statistic for incident KFRT.
RESULTS: During follow-up, mean eGFR slope was-1.83±1.92 (SD) mL/min/1.73m2 per year; 359 (36%) participants experienced KFRT. Median time to KFRT was 7.45 years from the time of entry to the CRIC Study. In our final model, after adjusting for clinical variables, levels of metabolites 3-hydroxyisobutyrate (3-HIBA) and 3-methylcrotonyglycine had a significant negative association with eGFR slope, whereas citric and aconitic acid were positively associated. Further, 3-HIBA and aconitic acid levels were associated with higher and lower risk for KFRT, respectively (HRs of 2.34 [95% CI, 1.51-3.62] and 0.70 [95% CI, 0.51-0.95]).
LIMITATIONS: Subgroups for whom metabolite signatures may not be optimal, nontargeted metabolomics by flow-injection analysis, and 2-stage modeling approaches.
CONCLUSIONS: Urine metabolites may offer insights into DKD progression. If replicated in future studies, aconitic acid and 3-HIBA could identify individuals with diabetes at high risk for GFR decline, potentially leading to improved clinical care and targeted therapies.

PMID: 32387023 [PubMed - as supplied by publisher]

Coronavirus Lockdown: Forced Inactivity for the Oldest Old?

J Am Med Dir Assoc. 2020 Apr 28;:

Authors: Valenzuela PL, Santos-Lozano A, Lista S, Serra-Rexach JA, Emanuele E, Lucia A

PMID: 32386843 [PubMed - as supplied by publisher]

Single-Cell Analysis of Human Retina Identifies Evolutionarily Conserved and Species-Specific Mechanisms Controlling Development.

Dev Cell. 2020 Apr 28;:

Authors: Lu Y, Shiau F, Yi W, Lu S, Wu Q, Pearson JD, Kallman A, Zhong S, Hoang T, Zuo Z, Zhao F, Zhang M, Tsai N, Zhuo Y, He S, Zhang J, Stein-O'Brien GL, Sherman TD, Duan X, Fertig EJ, Goff LA, Zack DJ, Handa JT, Xue T, Bremner R, Blackshaw S, Wang X, Clark BS

Abstract
The development of single-cell RNA sequencing (scRNA-seq) has allowed high-resolution analysis of cell-type diversity and transcriptional networks controlling cell-fate specification. To identify the transcriptional networks governing human retinal development, we performed scRNA-seq analysis on 16 time points from developing retina as well as four early stages of retinal organoid differentiation. We identified evolutionarily conserved patterns of gene expression during retinal progenitor maturation and specification of all seven major retinal cell types. Furthermore, we identified gene-expression differences between developing macula and periphery and between distinct populations of horizontal cells. We also identified species-specific patterns of gene expression during human and mouse retinal development. Finally, we identified an unexpected role for ATOH7 expression in regulation of photoreceptor specification during late retinogenesis. These results provide a roadmap to future studies of human retinal development and may help guide the design of cell-based therapies for treating retinal dystrophies.

PMID: 32386599 [PubMed - as supplied by publisher]

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Robustness and parameter geography in post-translational modification systems.

PLoS Comput Biol. 2020 May 04;16(5):e1007573

Authors: Nam KM, Gyori BM, Amethyst SV, Bates DJ, Gunawardena J

Abstract
Biological systems are acknowledged to be robust to perturbations but a rigorous understanding of this has been elusive. In a mathematical model, perturbations often exert their effect through parameters, so sizes and shapes of parametric regions offer an integrated global estimate of robustness. Here, we explore this "parameter geography" for bistability in post-translational modification (PTM) systems. We use the previously developed "linear framework" for timescale separation to describe the steady-states of a two-site PTM system as the solutions of two polynomial equations in two variables, with eight non-dimensional parameters. Importantly, this approach allows us to accommodate enzyme mechanisms of arbitrary complexity beyond the conventional Michaelis-Menten scheme, which unrealistically forbids product rebinding. We further use the numerical algebraic geometry tools Bertini, Paramotopy, and alphaCertified to statistically assess the solutions to these equations at ∼109 parameter points in total. Subject to sampling limitations, we find no bistability when substrate amount is below a threshold relative to enzyme amounts. As substrate increases, the bistable region acquires 8-dimensional volume which increases in an apparently monotonic and sigmoidal manner towards saturation. The region remains connected but not convex, albeit with a high visibility ratio. Surprisingly, the saturating bistable region occupies a much smaller proportion of the sampling domain under mechanistic assumptions more realistic than the Michaelis-Menten scheme. We find that bistability is compromised by product rebinding and that unrealistic assumptions on enzyme mechanisms have obscured its parametric rarity. The apparent monotonic increase in volume of the bistable region remains perplexing because the region itself does not grow monotonically: parameter points can move back and forth between monostability and bistability. We suggest mathematical conjectures and questions arising from these findings. Advances in theory and software now permit insights into parameter geography to be uncovered by high-dimensional, data-centric analysis.

PMID: 32365103 [PubMed - as supplied by publisher]

How will farmed populations of freshwater fish deal with the extreme climate scenario in 2100? Transcriptional responses of Colossoma macropomum from two Brazilian climate regions.

J Therm Biol. 2020 Apr;89:102487

Authors: Fé-Gonçalves LM, Araújo JDA, Santos CHDAD, Val AL, Almeida-Val VMF

Abstract
Tambaqui (Colossoma macropomum Cuvier, 1818) is an endemic fish of the Amazon and Orinoco basins, and it is the most economically important native species in Brazil being raised in five climatically distinct regions. In the face of current global warming, environmental variations in farm ponds represent additional challenges that may drive new adaptive regional genetic variations among broodstocks of tambaqui. In an experimental context based on the high-emission scenario of the 5th Intergovernmental Panel on Climate Change (IPCC) report, we used two farmed tambaqui populations to test this hypothesis. RNA-seq transcriptome analysis was performed in the liver of juvenile tambaqui from northern (Balbina Experimental Station, Balbina, AM) and southeastern (Brumado Fish Farming, Mogi Mirim, SP) Brazilian regions kept for 30 days in artificial environmental rooms mimicking the current and extreme climate scenarios. Three Illumina MiSeq runs produced close to 120 million 500 bp paired-end reads; 191,139 contigs were assembled with N50 = 1595. 355 genes were differentially expressed for both populations in response to the extreme scenario. After enrichment analysis, each population presented a core set of genes to cope with climate change. Northern fish induced genes related to the cellular response to stress, activation of MAPK activity, response to unfolded protein, protein metabolism and cellular response to DNA damage stimuli. Genes biologically involved in regulating cell proliferation, protein stabilisation and protein ubiquitination for degradation through the ubiquitin-proteasome system were downregulated. Genes associated with biological processes, including the cellular response to stress, MAPK cascade activation, homeostatic processes and positive regulation of immune responses were upregulated in southeastern fish. The downregulated genes were related to cytoskeleton organisation, energy metabolism, and the regulation of transcription and biological rhythms. Our findings reveal the signatures of promising candidate genes involved in the regional plasticity of each population of tambaqui in dealing with upcoming climate changes.

PMID: 32364997 [PubMed - as supplied by publisher]

Genomic and epigenomic EBF1 alterations modulate TERT expression in gastric cancer.

J Clin Invest. 2020 May 04;:

Authors: Xing M, Ooi WF, Tan J, Qamra A, Lee PH, Li Z, Xu C, Padmanabhan N, Lim JQ, Guo YA, Yao X, Amit M, Ng LM, Sheng T, Wang J, Huang KK, Anene-Nzelu CG, Ho SWT, Ray M, Ma L, Fazzi G, Lim KJ, Wijaya GC, Zhang S, Nandi T, Yan T, Chang MM, Das K, Isa ZFA, Wu J, Poon PSY, Lam YN, Lin JS, Tay ST, Lee MH, Tan ALK, Ong X, White K, Rozen SG, Beer M, Foo RSY, Grabsch HI, Skanderup AJ, Li S, Teh BT, Tan P

Abstract
Transcriptional reactivation of telomerase catalytic subunit (TERT) is a frequent hallmark of cancer, occurring in 90% of human malignancies. However, specific mechanisms driving TERT reactivation remain obscure for many tumor types and in particular gastric cancer (GC), a leading cause of global cancer mortality. Here, through comprehensive genomic and epigenomic analysis of primary GCs and GC cell lines, we identified the transcription factor early B cell factor 1 (EBF1) as a TERT transcriptional repressor and inactivation of EBF1 function as a major cause of TERT upregulation. Abolishment of EBF1 function occurs through 3 distinct (epi)genomic mechanisms. First, EBF1 is epigenetically silenced via DNA methyltransferase, polycomb-repressive complex 2 (PRC2), and histone deacetylase activity in GCs. Second, recurrent, somatic, and heterozygous EBF1 DNA-binding domain mutations result in the production of dominant-negative EBF1 isoforms. Third, more rarely, genomic deletions and rearrangements proximal to the TERT promoter remobilize or abolish EBF1-binding sites, derepressing TERT and leading to high TERT expression. EBF1 is also functionally required for various malignant phenotypes in vitro and in vivo, highlighting its importance for GC development. These results indicate that multimodal genomic and epigenomic alterations underpin TERT reactivation in GC, converging on transcriptional repressors such as EBF1.

PMID: 32364535 [PubMed - as supplied by publisher]

Genome-Scale Metabolic Modeling of Glioblastoma Reveals Promising Targets for Drug Development.

Front Genet. 2020;11:381

Authors: Larsson I, Uhlén M, Zhang C, Mardinoglu A

Abstract
Glioblastoma (GBM) is an aggressive type of brain cancer with a poor prognosis for affected patients. The current line of treatment only gives the patients a survival time of on average 15 months. In this work, we use genome-scale metabolic models (GEMs) together with other systems biology tools to examine the global transcriptomics-data of GBM-patients obtained from The Cancer Genome Atlas (TCGA). We reveal the molecular mechanisms underlying GBM and identify potential therapeutic targets for effective treatment of patients. The work presented consists of two main parts. The first part stratifies the patients into two groups, high and low survival, and compares their gene expression. The second part uses GBM and healthy brain tissue GEMs to simulate gene knockout in a GBM cell model to find potential therapeutic targets and predict their side effect in healthy brain tissue. We (1) find that genes upregulated in the patients with low survival are linked to various stages of the glioma invasion process, and (2) identify five essential genes for GBM, whose inhibition is non-toxic to healthy brain tissue, therefore promising to investigate further as therapeutic targets.

PMID: 32362913 [PubMed]

Arabidopsis Lectin EULS3 Is Involved in ABA Signaling in Roots.

Front Plant Sci. 2020;11:437

Authors: Dubiel M, Beeckman T, Smagghe G, Van Damme EJM

Abstract
The Arabidopsis thaliana lectin ArathEULS3 is upregulated in particular stress conditions and upon abscisic acid (ABA) treatment. ABA is a plant hormone important for plant growth and stress responses. During stress ABA is perceived by PYR/PYL/RCAR receptors, inhibiting protein phosphatases PP2Cs thereby enabling SNRK2s kinases to start downstream phosphorylation cascades and signaling. PYL9, one of the ABA receptors was identified as an interacting partner for ArathEULS3. Promoter::GUS activity studies revealed the expression of ArathEULS3 in the central root cylinder and the cells flanking young lateral root primordia, and showed enhanced expression in root tips after ABA treatment. Transcript levels for ArathEULS3 increased after exposure to ABA and osmotic treatments. ArathEULS3 CRISPR KO mutants served as a tool to expand the knowledge on the role of ArathEULS3 in plant development. KO lines revealed a longer root system compared to WT plants, and showed reduced sensitivity to ABA, salt, and osmotic conditions. Additionally it was noted that the KO mutants had more emerged lateral roots when grown in high osmotic conditions. Together these data suggest that ArathEULS3 may be an important player in ABA responses in roots.

PMID: 32362905 [PubMed]

Editorial overview: Network analysis and experimental models for the understanding of multifactorial human diseases.

Curr Opin Biotechnol. 2020 Apr 30;:

Authors: Vanoni M, Palumbo P

PMID: 32362517 [PubMed - as supplied by publisher]

A Dynamical Paradigm for Molecular Cell Biology.

Trends Cell Biol. 2020 Apr 30;:

Authors: Tyson JJ, Novak B

Abstract
The driving passion of molecular cell biologists is to understand the molecular mechanisms that control important aspects of cell physiology, but this ambition is often limited by the wealth of molecular details currently known about these mechanisms. Their complexity overwhelms our intuitive notions of how molecular regulatory networks might respond under normal and stressful conditions. To make progress we need a new paradigm for connecting molecular biology to cell physiology. We suggest an approach that uses precise mathematical methods to associate the qualitative features of dynamical systems, as conveyed by 'bifurcation diagrams', with 'signal-response' curves measured by cell biologists.

PMID: 32362451 [PubMed - as supplied by publisher]

Dissecting the interaction of photosynthetic electron transfer with mitochondrial signalling and hypoxic response in the Arabidopsis rcd1 mutant.

Philos Trans R Soc Lond B Biol Sci. 2020 Jun 22;375(1801):20190413

Authors: Shapiguzov A, Nikkanen L, Fitzpatrick D, Vainonen JP, Gossens R, Alseekh S, Aarabi F, Tiwari A, Blokhina O, Panzarová K, Benedikty Z, Tyystjärvi E, Fernie AR, Trtílek M, Aro EM, Rintamäki E, Kangasjärvi J

Abstract
The Arabidopsis mutant rcd1 is tolerant to methyl viologen (MV). MV enhances the Mehler reaction, i.e. electron transfer from Photosystem I (PSI) to O2, generating reactive oxygen species (ROS) in the chloroplast. To study the MV tolerance of rcd1, we first addressed chloroplast thiol redox enzymes potentially implicated in ROS scavenging. NADPH-thioredoxin oxidoreductase type C (NTRC) was more reduced in rcd1. NTRC contributed to the photosynthetic and metabolic phenotypes of rcd1, but did not determine its MV tolerance. We next tested rcd1 for alterations in the Mehler reaction. In rcd1, but not in the wild type, the PSI-to-MV electron transfer was abolished by hypoxic atmosphere. A characteristic feature of rcd1 is constitutive expression of mitochondrial dysfunction stimulon (MDS) genes that affect mitochondrial respiration. Similarly to rcd1, in other MDS-overexpressing plants hypoxia also inhibited the PSI-to-MV electron transfer. One possible explanation is that the MDS gene products may affect the Mehler reaction by altering the availability of O2. In green tissues, this putative effect is masked by photosynthetic O2 evolution. However, O2 evolution was rapidly suppressed in MV-treated plants. Transcriptomic meta-analysis indicated that MDS gene expression is linked to hypoxic response not only under MV, but also in standard growth conditions. This article is part of the theme issue 'Retrograde signalling from endosymbiotic organelles'.

PMID: 32362253 [PubMed - in process]