Overview of the SAMPL6 host-guest binding affinity prediction challenge.

J Comput Aided Mol Des. 2018 Nov 10;:

Authors: Rizzi A, Murkli S, McNeill JN, Yao W, Sullivan M, Gilson MK, Chiu MW, Isaacs L, Gibb BC, Mobley DL, Chodera JD

Abstract
Accurately predicting the binding affinities of small organic molecules to biological macromolecules can greatly accelerate drug discovery by reducing the number of compounds that must be synthesized to realize desired potency and selectivity goals. Unfortunately, the process of assessing the accuracy of current computational approaches to affinity prediction against binding data to biological macromolecules is frustrated by several challenges, such as slow conformational dynamics, multiple titratable groups, and the lack of high-quality blinded datasets. Over the last several SAMPL blind challenge exercises, host-guest systems have emerged as a practical and effective way to circumvent these challenges in assessing the predictive performance of current-generation quantitative modeling tools, while still providing systems capable of possessing tight binding affinities. Here, we present an overview of the SAMPL6 host-guest binding affinity prediction challenge, which featured three supramolecular hosts: octa-acid (OA), the closely related tetra-endo-methyl-octa-acid (TEMOA), and cucurbit[8]uril (CB8), along with 21 small organic guest molecules. A total of 119 entries were received from ten participating groups employing a variety of methods that spanned from electronic structure and movable type calculations in implicit solvent to alchemical and potential of mean force strategies using empirical force fields with explicit solvent models. While empirical models tended to obtain better performance than first-principle methods, it was not possible to identify a single approach that consistently provided superior results across all host-guest systems and statistical metrics. Moreover, the accuracy of the methodologies generally displayed a substantial dependence on the system considered, emphasizing the need for host diversity in blind evaluations. Several entries exploited previous experimental measurements of similar host-guest systems in an effort to improve their physical-based predictions via some manner of rudimentary machine learning; while this strategy succeeded in reducing systematic errors, it did not correspond to an improvement in statistical correlation. Comparison to previous rounds of the host-guest binding free energy challenge highlights an overall improvement in the correlation obtained by the affinity predictions for OA and TEMOA systems, but a surprising lack of improvement regarding root mean square error over the past several challenge rounds. The data suggests that further refinement of force field parameters, as well as improved treatment of chemical effects (e.g., buffer salt conditions, protonation states), may be required to further enhance predictive accuracy.

PMID: 30415285 [PubMed - as supplied by publisher]

Autoregulation and repair in microtubule homeostasis.

Curr Opin Cell Biol. 2018 Nov 08;56:80-87

Authors: Gasic I, Mitchison TJ

Abstract
Even in the face of damaging insults, most cells maintain stability over time through multiple homeostatic pathways, including maintenance of the microtubule cytoskeleton that is fundamental to numerous cellular processes. The dynamic instability-perpetual growth and shrinkage-is the best-known microtubule regulatory pathway, which allows rapid rebuilding of the microtubule cytoskeleton in response to internal or external cues. Much less investigated is homeostatic regulation through availability of α-β tubulin heterodimers-microtubules' main building blocks-which influences total mass and dynamic behavior of microtubules. Finally, the most recently discovered is microtubule homeostasis through self-repair, where new GTP-bound tubulin heterodimers replace the lost ones in the microtubule lattice. In this review we try to integrate our current knowledge on how dynamic instability, regulation of tubulin mass, and self-repair work together to achieve microtubule homeostasis.

PMID: 30415186 [PubMed - as supplied by publisher]

The Min Oscillator Defines Sites of Asymmetric Cell Division in Cyanobacteria during Stress Recovery.

Cell Syst. 2018 Oct 29;:

Authors: Liao Y, Rust MJ

Abstract
When resources are abundant, many rod-shaped bacteria reproduce through precise, symmetric divisions. However, realistic environments entail fluctuations between restrictive and permissive growth conditions. Here, we use time-lapse microscopy to study the division of the cyanobacterium Synechococcus elongatus as illumination intensity varies. We find that dim conditions produce elongated cells whose divisions follow a simple rule: cells shorter than ∼8 μm divide symmetrically, but above this length divisions become asymmetric, typically producing a short ∼3-μm daughter. We show that this division strategy is implemented by the Min system, which generates multi-node patterns and traveling waves in longer cells that favor the production of a short daughter. Mathematical modeling reveals that the feedback loops that create oscillatory Min patterns are needed to implement these generalized cell division rules. Thus, the Min system, which enforces symmetric divisions in short cells, acts to strongly suppress mid-cell divisions when S. elongatus cells are long.

PMID: 30414921 [PubMed - as supplied by publisher]

Misinterpretation risks of global stochastic optimisation of kinetic models revealed by multiple optimisation runs.

Math Biosci. 2018 Nov 08;:

Authors: Stalidzans E, Landmane K, Sulins J, Sahle S

Abstract
One of use cases for metabolic network optimisation of biotechnologically applied microorganisms is the in silico design of new strains with an improved distribution of metabolic fluxes. Global stochastic optimisation methods (genetic algorithms, evolutionary programing, particle swarm and others) can optimise complicated nonlinear kinetic models and are friendly for unexperienced user: they can return optimisation results with default method settings (population size, number of generations and others) and without adaptation of the model. Drawbacks of these methods (stochastic behavior, undefined duration of optimisation, possible stagnation and no guaranty of reaching optima) cause optimisation result misinterpretation risks considering the very diverse educational background of the systems biology and synthetic biology research community. Different methods implemented in the COPASI software package are tested in this study to determine their ability to find feasible solutions and assess the convergence speed to the best value of the objective function. Special attention is paid to the potential misinterpretation of results. Optimisation methods are tested with additional constraints that can be introduced to ensure the biological feasibility of the resulting optimised design: 1) total enzyme activity constraint (called also amino acid pool constraint) to limit the sum of enzyme concentrations and 2) homeostatic constraint limiting steady state metabolite concentration corridor around the steady state concentrations of metabolites in the original model. Impact of additional constraints on the performance of optimisation methods and misinterpretation risks is analysed.

PMID: 30414874 [PubMed - as supplied by publisher]

11 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"systems biology"

These pubmed results were generated on 2018/11/11

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Developmental exposure to environmentally relevant concentrations of bifenthrin alters transcription of mTOR and ryanodine receptor-dependent signaling molecules and impairs predator avoidance behavior across early life stages in inland silversides (Menidia beryllina).

Aquat Toxicol. 2018 Oct 24;206:1-13

Authors: Frank DF, Brander SM, Hasenbein S, Harvey DJ, Lein PJ, Geist J, Connon RE

Abstract
Altered transcription of calcium-dependent signaling cascades involving the ryanodine receptor (RyR) and mechanistic target of rapamycin (mTOR) in response to environmental exposures have been described in model vertebrates, including zebrafish, while the relevance for wild fishes remains unknown. To address this knowledge gap, we exposed the euryhaline model species Menidia beryllina (inland silversides) to the insecticide bifenthrin, a known modulator of calcium signaling. The main objectives of this study were to determine: (1) whether exposure of developing silversides to environmentally relevant concentrations of bifenthrin alters their behavior; and (2) whether behavioral changes correlate with altered expression of genes involved in RyR and mTOR-dependent signaling pathways. At six hours post fertilization (hpf), inland silversides were exposed to bifenthrin at 3, 27 and 122 ng/L until 7 days post fertilization (dpf, larvae hatched at 6dpf), followed by a 14-day recovery period in uncontaminated water. Transcriptional responses were measured at 5, 7 and 21 dpf; locomotor behavior following external stimuli and response to an olfactory predator cue were assessed at 7 and 21 dpf. Bifenthrin elicited significant non-monotonic transcriptional responses in the majority of genes examined at 5 dpf and at 21 dpf. Bifenthrin also significantly altered predator avoidance behavior via olfactory mechanisms with main effects identified for animals exposed to 3 and 27 ng/L. Behavioral effects were not detected in response to visual stimuli during acute exposure, but were significant in the predator-cue assessment following the recovery period, suggesting delayed and long-term effects of early developmental exposures to bifenthrin. Our findings demonstrate that at picomolar (pM) concentrations, which are often not represented in ecotoxicological studies, bifenthrin perturbs early development of inland silversides. These developmental impacts are manifested behaviorally at later life stages, specifically as altered patterns of predator avoidance behavior, which have been correlated with population decline. Collectively, these data suggest that bifenthrin may be negatively impacting wild fish populations.

PMID: 30414561 [PubMed - as supplied by publisher]

Identification of gene products that control lipid droplet size in yeast using a high-throughput quantitative image analysis.

Biochim Biophys Acta Mol Cell Biol Lipids. 2018 Nov 07;:

Authors: Lv X, Liu J, Qin Y, Liu Y, Jin M, Dai J, Chua BT, Yang H, Li P

Abstract
Lipid droplets (LDs) are important organelles involved in energy storage and expenditure. LD dynamics has been investigated using genome-wide image screening methods in yeast and other model organisms. For most studies, genes were identified using two-dimensional images with LD enlargement as readout. Due to imaging limitation, reduction of LD size is seldom explored. Here, we aim to set up a screen that specifically utilizes reduced LD size as the readout. To achieve this, a novel yeast screen is set up to quantitatively and systematically identify genes that regulate LD size through a three-dimensional imaging-based approach. Cidea which promotes LD fusion and growth in mammalian cells was overexpressed in a yeast knockout library to induce large LD formation. Next, an automated, high-throughput image analysis method that monitors LD size was utilized. With this screen, we identified twelve genes that reduced LD size when deleted. The effects of eight of these genes on LD size were further validated in fld1 null strain background. In addition, six genes were previously identified as LD-regulating genes. To conclude, this methodology represents a promising strategy to screen for players in LD size control in both yeast and mammalian cells to aid in the investigation of LD-associated metabolic diseases.

PMID: 30414449 [PubMed - as supplied by publisher]

Human and computational models of atopic dermatitis: a review and perspectives by an expert panel of the International Eczema Council.

J Allergy Clin Immunol. 2018 Nov 07;:

Authors: Eyerich K, Brown SJ, Perez White BE, Tanaka RJ, Bissonette R, Dhar S, Bieber T, Hijnen DJ, Guttman-Yassky E, Irvine A, Thyssen JP, Vestergaard C, Werfel T, Wollenberg A, Paller AS, Reynolds NJ

Abstract
Atopic dermatitis (AD) is a prevalent disease worldwide associated with systemic co-morbidities, representing a significant burden on individuals, their families and society. Therapeutic options for AD remain limited, in part due to lack of well-characterised animal models. To better define pathophysiological mechanisms and to identify novel therapeutic targets and biomarkers that predict therapeutic response, there has been increasing interest in developing experimental approaches to study the pathogenesis of human AD in vivo, in vitro, and in silico. This review critically appraises a range of models including: genetic mutations relevant to AD; experimental challenge of human skin in vivo; tissue culture models; integration of "omic" datasets; and the development of predictive computational models. Whilst no one individual model recapitulates the complex AD pathophysiology, our review highlights insights gained into key elements of cutaneous biology, molecular pathways and therapeutic target identification through each approach. Recent developments in computational analysis, including the application of machine learning and a systems approach to data integration and predictive modelling, highlight the applicability of these methods to AD subclassification (endotyping), therapy development and precision medicine. Such predictive modelling will highlight knowledge gaps, further inform refinement of biological models, and support new experimental and systems approaches to AD.

PMID: 30414395 [PubMed - as supplied by publisher]

Reduction in Albuminuria With Dapagliflozin Cannot Be Predicted by Baseline Clinical Characteristics or Changes in Most Other Risk Markers.

Diabetes Obes Metab. 2018 Nov 09;:

Authors: Heerspink HJL, Sjöström CD, Inzucchi SE, Hallow MK, Cain VA, Rossing P, Stefansson BV, Sartipy P

Abstract
The sodium glucose co-transporter 2 inhibitor dapagliflozin has been shown to decrease urinary albumin:creatinine ratio (UACR). This effect, however, varies among individual patients. In this study, we assessed the baseline characteristics and concurrent changes in other cardiovascular risk markers that might be associated with UACR response to dapagliflozin. A pooled analysis of 11 phase 3 randomized, controlled clinical trials was performed. UACR change from baseline after 24 weeks treatment with dapagliflozin 10 mg/day in 531 patients with type 2 diabetes and UACR ≥30 mg/g at baseline was determined. UACR response was defined as >30% reduction from baseline at 24-weeks, whereas UACR non-response was defined as ≤30% reduction at 24-weeks. A total of 288 (54%) patients were classified as responders and 243 (46%) as non-responders. At 24-weeks, the UACR adjusted mean change from baseline was -71.2% and 25.9% in responders and non-responders, respectively. Baseline characteristics were similar between both groups. Changes in HbA1c and body weight were comparable across groups. Responders showed a numerically larger reduction in eGFR and SBP versus non-responders. UACR reduction to dapagliflozin is an individual characteristic that cannot be predicted by baseline clinical features or changes in metabolic parameters. Whether UACR response would improve long-term renal and cardiovascular outcomes remains to be determined. This article is protected by copyright. All rights reserved.

PMID: 30414240 [PubMed - as supplied by publisher]

Following Transcriptome to Uncover FOXO Biological Functions.

Methods Mol Biol. 2019;1890:219-227

Authors: Liang R, Menon V, Ghaffari S

Abstract
Two and half million red blood cells (RBC) are generated every second in a healthy adult. The process of RBC production known as erythropoiesis requires a meticulous synchrony between signaling processes and the activity of many transcription factor complexes. FOXO3 is a transcription factor that is responsive to signaling processes and essential for the erythroid proliferation and maturation, RBC formation, and lifespan. Here, we discuss how using an integrated computational and experimental systems biology approach new and unanticipated FOXO3 functions in terminal erythropoiesis were uncovered. These combinatory approaches identified FOXO3 as a key regulator of terminal erythropoiesis. As a result, a new mode of FOXO3 participation in erythroid transcription complex formation has been proposed.

PMID: 30414157 [PubMed - in process]

Analysis of the Genome and Metabolome of Marine Myxobacteria Reveals High Potential for Biosynthesis of Novel Specialized Metabolites.

Sci Rep. 2018 Nov 09;8(1):16600

Authors: Amiri Moghaddam J, Crüsemann M, Alanjary M, Harms H, Dávila-Céspedes A, Blom J, Poehlein A, Ziemert N, König GM, Schäberle TF

Abstract
Comparative genomic/metabolomic analysis is a powerful tool to disclose the potential of microbes for the biosynthesis of novel specialized metabolites. In the group of marine myxobacteria only a limited number of isolated species and sequenced genomes is so far available. However, the few compounds isolated thereof so far show interesting bioactivities and even novel chemical scaffolds; thereby indicating a huge potential for natural product discovery. In this study, all marine myxobacteria with accessible genome data (n = 5), including Haliangium ochraceum DSM 14365, Plesiocystis pacifica DSM 14875, Enhygromyxa salina DSM 15201 and the two newly sequenced species Enhygromyxa salina SWB005 and SWB007, were analyzed. All of these accessible genomes are large (~10 Mb), with a relatively small core genome and many unique coding sequences in each strain. Genome analysis revealed a high variety of biosynthetic gene clusters (BGCs) between the strains and several resistance models and essential core genes indicated the potential to biosynthesize antimicrobial molecules. Polyketides (PKs) and terpenes represented the majority of predicted specialized metabolite BGCs and contributed to the highest share between the strains. BGCs coding for non-ribosomal peptides (NRPs), PK/NRP hybrids and ribosomally synthesized and post-translationally modified peptides (RiPPs) were mostly strain specific. These results were in line with the metabolomic analysis, which revealed a high diversity of the chemical features between the strains. Only 6-11% of the metabolome was shared between all the investigated strains, which correlates to the small core genome of these bacteria (13-16% of each genome). In addition, the compound enhygrolide A, known from E. salina SWB005, was detected for the first time and structurally elucidated from Enhygromyxa salina SWB006. The here acquired data corroborate that these microorganisms represent a most promising source for the detection of novel specialized metabolites.

PMID: 30413766 [PubMed - in process]

Unlocking conserved and diverged metabolic characteristics in cassava carbon assimilation via comparative genomics approach.

Sci Rep. 2018 Nov 09;8(1):16593

Authors: Siriwat W, Kalapanulak S, Suksangpanomrung M, Saithong T

Abstract
Globally, cassava is an important source of starch, which is synthesized through carbon assimilation in cellular metabolism whereby harvested atmospheric carbon is assimilated into macromolecules. Although the carbon assimilation pathway is highly conserved across species, metabolic phenotypes could differ in composition, type, and quantity. To unravel the metabolic complexity and advantage of cassava over other starch crops, in terms of starch production, we investigated the carbon assimilation mechanisms in cassava through genome-based pathway reconstruction and comparative network analysis. First, MeRecon - the carbon assimilation pathway of cassava was reconstructed based upon six plant templates: Arabidopsis, rice, maize, castor bean, potato, and turnip. MeRecon, available at http://bml.sbi.kmutt.ac.th/MeRecon, comprises 259 reactions (199 EC numbers), 1,052 proteins (870 genes) and 259 metabolites in eight sub-metabolisms. Analysis of MeRecon and the carbon assimilation pathways of the plant templates revealed the overall topology is highly conserved, but variations at sub metabolism level were found in relation to complexity underlying each biochemical reaction, such as numbers of responsible enzymatic proteins and their evolved functions, which likely explain the distinct metabolic phenotype. Thus, this study provides insights into the network characteristics and mechanisms that regulate the synthesis of metabolic phenotypes of cassava.

PMID: 30413726 [PubMed - in process]

Phenotype loss is associated with widespread divergence of the gene regulatory landscape in evolution.

Nat Commun. 2018 Nov 09;9(1):4737

Authors: Roscito JG, Sameith K, Parra G, Langer BE, Petzold A, Moebius C, Bickle M, Rodrigues MT, Hiller M

Abstract
Detecting the genomic changes underlying phenotypic changes between species is a main goal of evolutionary biology and genomics. Evolutionary theory predicts that changes in cis-regulatory elements are important for morphological changes. We combined genome sequencing, functional genomics and genome-wide comparative analyses to investigate regulatory elements in lineages that lost morphological traits. We first show that limb loss in snakes is associated with widespread divergence of limb regulatory elements. We next show that eye degeneration in subterranean mammals is associated with widespread divergence of eye regulatory elements. In both cases, sequence divergence results in an extensive loss of transcription factor binding sites. Importantly, diverged regulatory elements are associated with genes required for normal limb patterning or normal eye development and function, suggesting that regulatory divergence contributed to the loss of these phenotypes. Together, our results show that genome-wide decay of the phenotype-specific cis-regulatory landscape is a hallmark of lost morphological traits.

PMID: 30413698 [PubMed - in process]

High-resolution ultramicroscopy of the developing and adult nervous system in optically cleared Drosophila melanogaster.

Nat Commun. 2018 Nov 09;9(1):4731

Authors: Pende M, Becker K, Wanis M, Saghafi S, Kaur R, Hahn C, Pende N, Foroughipour M, Hummel T, Dodt HU

Abstract
The fruit fly, Drosophila melanogaster, is an important experimental model to address central questions in neuroscience at an organismic level. However, imaging of neural circuits in intact fruit flies is limited due to structural properties of the cuticle. Here we present a novel approach combining tissue clearing, ultramicroscopy, and data analysis that enables the visualisation of neuronal networks with single-cell resolution from the larval stage up to the adult Drosophila. FlyClear, the signal preserving clearing technique we developed, stabilises tissue integrity and fluorescence signal intensity for over a month and efficiently removes the overall pigmentation. An aspheric ultramicroscope set-up utilising an improved light-sheet generator allows us to visualise long-range connections of peripheral sensory and central neurons in the visual and olfactory system. High-resolution 3D reconstructions with isotropic resolution from entire GFP-expressing flies are obtained by applying image fusion from orthogonal directions. This methodological integration of novel chemical, optical, and computational techniques allows a major advance in the analysis of global neural circuit organisation.

PMID: 30413688 [PubMed - in process]

Inhibiting Inflammation with Myeloid Cell-Specific Nanobiologics Promotes Organ Transplant Acceptance.

Immunity. 2018 Oct 30;:

Authors: Braza MS, van Leent MMT, Lameijer M, Sanchez-Gaytan BL, Arts RJW, Pérez-Medina C, Conde P, Garcia MR, Gonzalez-Perez M, Brahmachary M, Fay F, Kluza E, Kossatz S, Dress RJ, Salem F, Rialdi A, Reiner T, Boros P, Strijkers GJ, Calcagno CC, Ginhoux F, Marazzi I, Lutgens E, Nicolaes GAF, Weber C, Swirski FK, Nahrendorf M, Fisher EA, Duivenvoorden R, Fayad ZA, Netea MG, Mulder WJM, Ochando J

Abstract
Inducing graft acceptance without chronic immunosuppression remains an elusive goal in organ transplantation. Using an experimental transplantation mouse model, we demonstrate that local macrophage activation through dectin-1 and toll-like receptor 4 (TLR4) drives trained immunity-associated cytokine production during allograft rejection. We conducted nanoimmunotherapeutic studies and found that a short-term mTOR-specific high-density lipoprotein (HDL) nanobiologic treatment (mTORi-HDL) averted macrophage aerobic glycolysis and the epigenetic modifications underlying inflammatory cytokine production. The resulting regulatory macrophages prevented alloreactive CD8+ T cell-mediated immunity and promoted tolerogenic CD4+ regulatory T (Treg) cell expansion. To enhance therapeutic efficacy, we complemented the mTORi-HDL treatment with a CD40-TRAF6-specific nanobiologic (TRAF6i-HDL) that inhibits co-stimulation. This synergistic nanoimmunotherapy resulted in indefinite allograft survival. Together, we show that HDL-based nanoimmunotherapy can be employed to control macrophage function in vivo. Our strategy, focused on preventing inflammatory innate immune responses, provides a framework for developing targeted therapies that promote immunological tolerance.

PMID: 30413362 [PubMed - as supplied by publisher]

26 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"systems biology"

These pubmed results were generated on 2018/11/10

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

40 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"systems biology"

These pubmed results were generated on 2018/11/09

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

20 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"systems biology"

These pubmed results were generated on 2018/11/08

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

20 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"systems biology"

These pubmed results were generated on 2018/11/08

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

34 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

"systems biology"

These pubmed results were generated on 2018/11/07

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.