Circadian Proteomic Analysis Uncovers Mechanisms of Post-Transcriptional Regulation in Metabolic Pathways.

Cell Syst. 2018 Nov 30;:

Authors: Hurley JM, Jankowski MS, De Los Santos H, Crowell AM, Fordyce SB, Zucker JD, Kumar N, Purvine SO, Robinson EW, Shukla A, Zink E, Cannon WR, Baker SE, Loros JJ, Dunlap JC

Abstract
Transcriptional and translational feedback loops in fungi and animals drive circadian rhythms in transcript levels that provide output from the clock, but post-transcriptional mechanisms also contribute. To determine the extent and underlying source of this regulation, we applied newly developed analytical tools to a long-duration, deeply sampled, circadian proteomics time course comprising half of the proteome. We found a quarter of expressed proteins are clock regulated, but >40% of these do not arise from clock-regulated transcripts, and our analysis predicts that these protein rhythms arise from oscillations in translational rates. Our data highlighted the impact of the clock on metabolic regulation, with central carbon metabolism reflecting both transcriptional and post-transcriptional control and opposing metabolic pathways showing peak activities at different times of day. The transcription factor CSP-1 plays a role in this metabolic regulation, contributing to the rhythmicity and phase of clock-regulated proteins.

PMID: 30553726 [PubMed - as supplied by publisher]

Influence of the T to S mutation at the STMK motif on antibiotic resistance of penicillin binding protein 1A: A comprehensive computational study.

J Mol Graph Model. 2018 Dec 07;87:185-191

Authors: Behmard E, Ahmadi A, Najafi A

Abstract
The emergence of antibiotic resistance has attracted the attention of scientists and scientific circles over the decades. β-Lactam antibiotics resistance is a worldwide therapeutic challenge in bacterial infections, mediated through several mechanisms of which mutations in Penicillin Binding Proteins (PBPs) are an important issue, making critical therapeutic problems in the human population. Accordingly, investigating the dynamic structures of mutant variants could result in a profound understanding of such a specific resistance. Therefore, this work investigated structural properties sampled by all-atom molecular dynamics (MD) simulations, umbrella sampling, and binding free energy calculations for both a wild-type and a cefotaxime-resistant T to S mutant of PBP1A. The T to S mutation significantly reduces the binding affinity of cefotaxime (a frequently clinically-administrated β-lactam antibiotic) as the PBP1A inhibitor. In the conventional MD simulations presented here, more fluctuations of the mutant's active site cleft margins were detected. The cleft of the mutant protein also opened remarkably more than the wild-type's cleft and displayed more flexibility. Thus, our findings have shown that flexibility of cleft margins of the active site in the mutant PBP1A immediately results in the catalytic cleft opening. In addition, binding free energy calculation suggests that reducing hydrophobic contacts and increasing the polar contribution in the binding energy may play an important role in cefotaxime resistance.

PMID: 30553158 [PubMed - as supplied by publisher]

Design and visualization of second generation cyanoisoindole based fluorescent strigolactone analogs.

Plant J. 2018 Dec 15;:

Authors: Van Overtveldt M, Braem L, Struk S, Kaczmarek AM, Boyer FD, Van Deun R, Gevaert K, Goormachtig S, Heugebaert TSA, Stevens CV

Abstract
Strigolactones (SLs) are a family of terpenoid allelochemicals that were recognized as plant hormones only a decade ago. They influence a myriad of both above- and belowground developmental processes, and are an important survival strategy for plants in nutrient-deprived soils. A rapidly emerging approach to gain knowledge on hormone signaling is the use of traceable analogs. A unique class of labeled SL analogs was constructed, where the original tricyclic lactone moiety of natural SLs is replaced by a fluorescent cyanoisoindole ring system. Biological evaluation as parasitic seed germination stimulant and hypocotyl elongation repressor proved the potency of the cyanoisoindole strigolactone analogs (CISA) to be comparable to the commonly accepted standard GR24. Additionally, via a SMXL6 protein degradation assay, we provided molecular evidence that the compounds elicit SL-like responses through the natural signaling cascade. All CISA analogs were shown to exhibit fluorescent properties, and the high quantum yield and Stokes shift of the pyrroloindole derivative CISA-7 also enabled in vivo visualization in plants. In contrast to the previously reported fluorescent analogs, CISA-7 displays a large similarity in shape and structure with natural SLs, which renders the analog a promising tracer to investigate the spatiotemporal distribution of SLs in plants and fungi. This article is protected by copyright. All rights reserved.

PMID: 30552776 [PubMed - as supplied by publisher]

Reply to 'Cardioimmunology of arrhythmias: the role of autoimmune and inflammatory cardiac channelopathies'.

Nat Rev Immunol. 2018 Dec 14;:

Authors: Swirski FK, Nahrendorf M

Abstract

PMID: 30552386 [PubMed - as supplied by publisher]

Successful Anti-PD-1 Cancer Immunotherapy Requires T Cell-Dendritic Cell Crosstalk Involving the Cytokines IFN-γ and IL-12.

Immunity. 2018 Nov 27;:

Authors: Garris CS, Arlauckas SP, Kohler RH, Trefny MP, Garren S, Piot C, Engblom C, Pfirschke C, Siwicki M, Gungabeesoon J, Freeman GJ, Warren SE, Ong S, Browning E, Twitty CG, Pierce RH, Le MH, Algazi AP, Daud AI, Pai SI, Zippelius A, Weissleder R, Pittet MJ

Abstract
Anti-PD-1 immune checkpoint blockers can induce sustained clinical responses in cancer but how they function in vivo remains incompletely understood. Here, we combined intravital real-time imaging with single-cell RNA sequencing analysis and mouse models to uncover anti-PD-1 pharmacodynamics directly within tumors. We showed that effective antitumor responses required a subset of tumor-infiltrating dendritic cells (DCs), which produced interleukin 12 (IL-12). These DCs did not bind anti-PD-1 but produced IL-12 upon sensing interferon γ (IFN-γ) that was released from neighboring T cells. In turn, DC-derived IL-12 stimulated antitumor T cell immunity. These findings suggest that full-fledged activation of antitumor T cells by anti-PD-1 is not direct, but rather involves T cell:DC crosstalk and is licensed by IFN-γ and IL-12. Furthermore, we found that activating the non-canonical NF-κB transcription factor pathway amplified IL-12-producing DCs and sensitized tumors to anti-PD-1 treatment, suggesting a therapeutic strategy to improve responses to checkpoint blockade.

PMID: 30552023 [PubMed - as supplied by publisher]

New views on the Malpighian tubule from post-genomic technologies.

Curr Opin Insect Sci. 2018 Oct;29:7-11

Authors: Dow JA, Pandit A, Davies SA

Abstract
Successful insect diversification depends at least in part on the ability to osmoregulate successfully across a broad range of ecological niches. First described in the 17th Century, and Malpighian tubules have been studied physiologically for 70 years. However, our understanding has been revolutionized by the advent of genomics, transcriptomics, proteomics and metabolomics. Such technologies are natural partners with (though do not obligatorily require) model organisms and transgenic technologies. This review describes the recent impact of multi-omic technologies on our understanding or renal function and control in insects.

PMID: 30551828 [PubMed - in process]

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Computational aspects underlying genome to phenome analysis in plants.

Plant J. 2018 Nov 30;:

Authors: Bolger AM, Poorter H, Dumschott K, Bolger ME, Arend D, Osorio S, Gundlach H, Mayer KF, Lange M, Scholz U, Usadel B

Abstract
Recent advances in genomics technologies have greatly accelerated progress in both fundamental plant science and applied breeding research. Concurrently, high throughput plant phenotyping is becoming widely adopted in the plant community, promising to alleviate the phenotypic bottleneck. Whilst these technological breakthroughs are significantly accelerating QTL and causal gene identification, challenges to enable even more sophisticated analyses remain. In particular, care needs to be taken to standardize, describe and conduct experiments robustly while relying on plant physiology expertise. Here we review the state of the art regarding genome assembly and the future potential of pangenomics in plant research We also describe the necessity of standardizing and describing phenotypic studies using the Minimum Information About a Plant Phenotyping Experiment (MIAPPE) standard in order to enable the reuse and integration of phenotypic data. In addition, we show how deep phenotypic data might yield novel trait-trait correlations and review how to link phenotypic data to genomic data. Finally, we provide perspectives on the golden future of machine learning and their potential in linking phenotypes to genomic features. This article is protected by copyright. All rights reserved.

PMID: 30500991 [PubMed - as supplied by publisher]

SCOPe: classification of large macromolecular structures in the structural classification of proteins-extended database.

Nucleic Acids Res. 2018 Nov 30;:

Authors: Chandonia JM, Fox NK, Brenner SE

Abstract
The SCOPe (Structural Classification of Proteins-extended, https://scop.berkeley.edu) database hierarchically classifies domains from the majority of proteins of known structure according to their structural and evolutionary relationships. SCOPe also incorporates and updates the ASTRAL compendium, which provides multiple databases and tools to aid in the analysis of the sequences and structures of proteins classified in SCOPe. Protein structures are classified using a combination of manual curation and highly precise automated methods. In the current release of SCOPe, 2.07, we have focused our manual curation efforts on larger protein structures, including the spliceosome, proteasome and RNA polymerase I, as well as many other Pfam families that had not previously been classified. Domains from these large protein complexes are distinctive in several ways: novel non-globular folds are more common, and domains from previously observed protein families often have N- or C-terminal extensions that were disordered or not present in previous structures. The current monthly release update, SCOPe 2.07-2018-10-18, classifies 90 992 PDB entries (about two thirds of PDB entries).

PMID: 30500919 [PubMed - as supplied by publisher]

Patients with systemic sclerosis-associated pulmonary arterial hypertension express a genomic signature distinct from patients with interstitial lung disease.

J Scleroderma Relat Disord. 2018 Oct;3(3):242-248

Authors: Moll M, Christmann RB, Zhang Y, Whitfield ML, Wang YM, Rice L, Stratton E, Lafyatis R, Farber HW

Abstract
Objective: Pulmonary arterial hypertension (PAH) and interstitial lung disease (ILD) are major causes of mortality in systemic sclerosis (SSc). We used a previously identified microarray biomarker to determine if SSc-PAH and SSc-ILD patients demonstrate distinct gene expression profiles.
Methods: PBMCs were collected from healthy controls (n=10), SSc (SSc) patients without pulmonary hypertension [SSc-noPAH, n=39], and SSc-PAH patients (n=21; mPAP≥25, PCWP≤15, PVR≥3WU) diagnosed by right heart catheterization (RHC). SSc-ILD patients were defined as those with evidence of fibrosis on chest CT and significant restriction (FVC<70% predicted, n = 11). SSc-PAH biomarker included 69 genes selected by unbiased statistical screening of 3 publicly available microarray studies. RNA levels were measured by Nanostring. Gene expression levels that were significantly correlated with PAH (multiple statistical measures) were chosen as inputs into a forward selection logistic regression model.
Results: When ILD patients were included (n=64), 4 genes (S100P, CD8B1, CCL2, TIMP1) and male sex predicted PAH with a high level of accuracy (AUC = 0.83). Without ILD patients (n=53), 2 genes (THBS1, CD8B1) and male sex predicted PAH with a high level of accuracy (AUC = 0.80). When examining SSc patients with borderline elevated pulmonary pressures (mPAP = 21-24 mmHg), gene expression changes closely resembled the SSc-PAH group, except for THBS1.
Conclusion: SSc-PAH and SSc-ILD have similar, but distinct, gene expression profiles. Many gene expression changes occur early in the disease course, potentially allowing for early detection. THBS1 appears to be an important mediator in the development of PAH-predominant phenotype. Further prospective investigation is warranted.

PMID: 30498788 [PubMed]

A scalable peptide-GPCR language for engineering multicellular communication.

Nat Commun. 2018 Nov 29;9(1):5057

Authors: Billerbeck S, Brisbois J, Agmon N, Jimenez M, Temple J, Shen M, Boeke JD, Cornish VW

Abstract
Engineering multicellularity is one of the next breakthroughs for Synthetic Biology. A key bottleneck to building multicellular systems is the lack of a scalable signaling language with a large number of interfaces that can be used simultaneously. Here, we present a modular, scalable, intercellular signaling language in yeast based on fungal mating peptide/G-protein-coupled receptor (GPCR) pairs harnessed from nature. First, through genome-mining, we assemble 32 functional peptide-GPCR signaling interfaces with a range of dose-response characteristics. Next, we demonstrate that these interfaces can be combined into two-cell communication links, which serve as assembly units for higher-order communication topologies. Finally, we show 56 functional, two-cell links, which we use to assemble three- to six-member communication topologies and a three-member interdependent community. Importantly, our peptide-GPCR language is scalable and tunable by genetic encoding, requires minimal component engineering, and should be massively scalable by further application of our genome mining pipeline or directed evolution.

PMID: 30498215 [PubMed - in process]

Understanding the microbial basis of body odor in pre-pubescent children and teenagers.

Microbiome. 2018 Nov 29;6(1):213

Authors: Lam TH, Verzotto D, Brahma P, Ng AHQ, Hu P, Schnell D, Tiesman J, Kong R, Ton TMU, Li J, Ong M, Lu Y, Swaile D, Liu P, Liu J, Nagarajan N

Abstract
BACKGROUND: Even though human sweat is odorless, bacterial growth and decomposition of specific odor precursors in it is believed to give rise to body odor in humans. While mechanisms of odor generation have been widely studied in adults, little is known for teenagers and pre-pubescent children who have distinct sweat composition from immature apocrine and sebaceous glands, but are arguably more susceptible to the social and psychological impact of malodor.
RESULTS: We integrated information from whole microbiome analysis of multiple skin sites (underarm, neck, and head) and multiple time points (1 h and 8 h after bath), analyzing 180 samples in total to perform the largest metagenome-wide association study to date on malodor. Significant positive correlations were observed between odor intensity and the relative abundance of Staphylococcus hominis, Staphylococcus epidermidis, and Cutibacterium avidum, as well as negative correlation with Acinetobacter schindleri and Cutibacterium species. Metabolic pathway analysis highlighted the association of isovaleric and acetic acid production (sour odor) from enriched S. epidermidis (teen underarm) and S. hominis (child neck) enzymes and sulfur production from Staphylococcus species (teen underarm) with odor intensity, in good agreement with observed odor characteristics in pre-pubescent children and teenagers. Experiments with cultures on human and artificial sweat confirmed the ability of S. hominis and S. epidermidis to independently produce malodor with distinct odor characteristics.
CONCLUSIONS: These results showcase the power of skin metagenomics to study host-microbial co-metabolic interactions, identifying distinct pathways for odor generation from sweat in pre-pubescent children and teenagers and highlighting key enzymatic targets for intervention.

PMID: 30497517 [PubMed - in process]