14 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 2020/05/04

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.

Model-based detection of whole-genome duplications in a phylogeny.

Mol Biol Evol. 2020 May 02;:

Authors: Zwaenepoel A, Van de Peer Y

Abstract
Ancient whole-genome duplications (WGDs) leave signatures in comparative genomic data sets that can be harnessed to detect these events of presumed evolutionary importance. Current statistical approaches for the detection of ancient WGDs in a phylogenetic context have two main drawbacks. The first is that unwarranted restrictive assumptions on the 'background' gene duplication and loss rates make inferences unreliable in the face of model violations. The second is that most methods can only be used to examine a limited set of a priori selected WGD hypotheses; and cannot be used to discover WGDs in a phylogeny. In this study we develop an approach for WGD inference using gene count data that seeks to overcome both issues. We employ a phylogenetic birth-death model that includes WGD in a flexible hierarchical Bayesian approach, and use reversible-jump MCMC to perform Bayesian inference of branch-specific duplication, loss and WGD retention rates accross the space of WGD configurations. We evaluate the proposed method using simulations, apply it to data sets from flowering plants and discuss the statistical intricacies of model-based WGD inference.

PMID: 32359154 [PubMed - as supplied by publisher]

Upregulation of Cell Surface GD3 Ganglioside Phenotype is Associated with Human Melanoma Brain Metastasis.

Mol Oncol. 2020 May 02;:

Authors: Ramos RI, Bustos MA, Wu J, Jones P, Chang SC, Kiyohara E, Tran K, Zhang X, Stern SL, Izraely S, Sagi-Assif O, Witz IP, Davies MA, Mills GB, Kelly DF, Irie RF, Hoon DSB

Abstract
Melanoma metastasis to the brain is one of the most frequent extracranial brain tumors. Cell surface gangliosides are elevated in melanoma metastasis; however, the metabolic regulatory mechanisms that govern these specific changes are poorly understood in melanoma particularly brain metastases (MBM) development. We found ganglioside GD3 levels significantly upregulated in MBM compared to lymph node metastasis (LNM) but not for other melanoma gangliosides. Moreover, we demonstrated an upregulation of ST8SIA1 (GD3 synthase) as melanoma progresses from melanocytes to MBM cells. Using RNA-ISH on FFPE specimens, we evaluated ST8SIA1 expression in primary melanomas (PRM) (n=23), LNM and visceral metastasis (n=45), and MBM (n=39). ST8SIA1 was significantly enhanced in MBM compared to all other specimens. ST8SIA1 expression was assessed in clinically well-annotated melanoma patients from multicenters with AJCC stage III B-D LNM (n=58) with 14 year follow-up. High ST8SIA1 expression was significantly associated with poor overall survival (HR=3.24; 95% CI, 1.19-8.86, p=0.02). In a nude mouse human xenograft melanoma brain metastasis model, MBM variants had higher ST8SIA1 expression than their respective cutaneous melanoma variants. Elevated ST8SIA1 expression enhances levels of cell surface GD3, a phenotype that favors MBM development; hence associated with very poor prognosis. Functional assays demonstrated that ST8SIA1 overexpression enhanced cell proliferation and colony formation whereby, ST8SIA1 knockdown had opposite effects. Icaritin, a plant-derived phytoestrogen treatment significantly inhibited cell growth in high GD3 positive MBM cells through targeting the canonical NFκB-pathway. The study demonstrates GD3 phenotype associates with melanoma progression and poor outcome.

PMID: 32358995 [PubMed - as supplied by publisher]

DIP/Dpr interactions and the evolutionary design of specificity in protein families.

Nat Commun. 2020 May 01;11(1):2125

Authors: Sergeeva AP, Katsamba PS, Cosmanescu F, Brewer JJ, Ahlsen G, Mannepalli S, Shapiro L, Honig B

Abstract
Differential binding affinities among closely related protein family members underlie many biological phenomena, including cell-cell recognition. Drosophila DIP and Dpr proteins mediate neuronal targeting in the fly through highly specific protein-protein interactions. We show here that DIPs/Dprs segregate into seven specificity subgroups defined by binding preferences between their DIP and Dpr members. We then describe a sequence-, structure- and energy-based computational approach, combined with experimental binding affinity measurements, to reveal how specificity is coded on the canonical DIP/Dpr interface. We show that binding specificity of DIP/Dpr subgroups is controlled by "negative constraints", which interfere with binding. To achieve specificity, each subgroup utilizes a different combination of negative constraints, which are broadly distributed and cover the majority of the protein-protein interface. We discuss the structural origins of negative constraints, and potential general implications for the evolutionary origins of binding specificity in multi-protein families.

PMID: 32358559 [PubMed - as supplied by publisher]

SGLT2 inhibition modulates NLRP3 inflammasome activity via ketones and insulin in diabetes with cardiovascular disease.

Nat Commun. 2020 May 01;11(1):2127

Authors: Kim SR, Lee SG, Kim SH, Kim JH, Choi E, Cho W, Rim JH, Hwang I, Lee CJ, Lee M, Oh CM, Jeon JY, Gee HY, Kim JH, Lee BW, Kang ES, Cha BS, Lee MS, Yu JW, Cho JW, Kim JS, Lee YH

Abstract
Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce cardiovascular events in humans with type 2 diabetes (T2D); however, the underlying mechanism remains unclear. Activation of the NLR family, pyrin domain-containing 3 (NLRP3) inflammasome and subsequent interleukin (IL)-1β release induces atherosclerosis and heart failure. Here we show the effect of SGLT2 inhibitor empagliflozin on NLRP3 inflammasome activity. Patients with T2D and high cardiovascular risk receive SGLT2 inhibitor or sulfonylurea for 30 days, with NLRP3 inflammasome activation analyzed in macrophages. While the SGLT2 inhibitor's glucose-lowering capacity is similar to sulfonylurea, it shows a greater reduction in IL-1β secretion compared to sulfonylurea accompanied by increased serum β-hydroxybutyrate (BHB) and decreased serum insulin. Ex vivo experiments with macrophages verify the inhibitory effects of high BHB and low insulin levels on NLRP3 inflammasome activation. In conclusion, SGLT2 inhibitor attenuates NLRP3 inflammasome activation, which might help to explain its cardioprotective effects.

PMID: 32358544 [PubMed - as supplied by publisher]

PBRM1 loss defines a nonimmunogenic tumor phenotype associated with checkpoint inhibitor resistance in renal carcinoma.

Nat Commun. 2020 May 01;11(1):2135

Authors: Liu XD, Kong W, Peterson CB, McGrail DJ, Hoang A, Zhang X, Lam T, Pilie PG, Zhu H, Beckermann KE, Haake SM, Isgandrova S, Martinez-Moczygemba M, Sahni N, Tannir NM, Lin SY, Rathmell WK, Jonasch E

Abstract
A non-immunogenic tumor microenvironment (TME) is a significant barrier to immune checkpoint blockade (ICB) response. The impact of Polybromo-1 (PBRM1) on TME and response to ICB in renal cell carcinoma (RCC) remains to be resolved. Here we show that PBRM1/Pbrm1 deficiency reduces the binding of brahma-related gene 1 (BRG1) to the IFNγ receptor 2 (Ifngr2) promoter, decreasing STAT1 phosphorylation and the subsequent expression of IFNγ target genes. An analysis of 3 independent patient cohorts and of murine pre-clinical models reveals that PBRM1 loss is associated with a less immunogenic TME and upregulated angiogenesis. Pbrm1 deficient Renca subcutaneous tumors in mice are more resistance to ICB, and a retrospective analysis of the IMmotion150 RCC study also suggests that PBRM1 mutation reduces benefit from ICB. Our study sheds light on the influence of PBRM1 mutations on IFNγ-STAT1 signaling and TME, and can inform additional preclinical and clinical studies in RCC.

PMID: 32358509 [PubMed - as supplied by publisher]

SYNERGISTIC ON AUXIN AND CYTOKININ 1 positively regulates growth and attenuates soil pathogen resistance.

Nat Commun. 2020 May 01;11(1):2170

Authors: Hurný A, Cuesta C, Cavallari N, Ötvös K, Duclercq J, Dokládal L, Montesinos JC, Gallemí M, Semerádová H, Rauter T, Stenzel I, Persiau G, Benade F, Bhalearo R, Sýkorová E, Gorzsás A, Sechet J, Mouille G, Heilmann I, De Jaeger G, Ludwig-Müller J, Benková E

Abstract
Plants as non-mobile organisms constantly integrate varying environmental signals to flexibly adapt their growth and development. Local fluctuations in water and nutrient availability, sudden changes in temperature or other abiotic and biotic stresses can trigger changes in the growth of plant organs. Multiple mutually interconnected hormonal signaling cascades act as essential endogenous translators of these exogenous signals in the adaptive responses of plants. Although the molecular backbones of hormone transduction pathways have been identified, the mechanisms underlying their interactions are largely unknown. Here, using genome wide transcriptome profiling we identify an auxin and cytokinin cross-talk component; SYNERGISTIC ON AUXIN AND CYTOKININ 1 (SYAC1), whose expression in roots is strictly dependent on both of these hormonal pathways. We show that SYAC1 is a regulator of secretory pathway, whose enhanced activity interferes with deposition of cell wall components and can fine-tune organ growth and sensitivity to soil pathogens.

PMID: 32358503 [PubMed - as supplied by publisher]

Serum triglycerides in Alzheimer disease: Relation to neuroimaging and CSF biomarkers.

Neurology. 2020 May 01;:

Authors: Bernath MM, Bhattacharyya S, Nho K, Barupal DK, Fiehn O, Baillie R, Risacher SL, Arnold M, Jacobson T, Trojanowski JQ, Shaw LM, Weiner MW, Doraiswamy PM, Kaddurah-Daouk R, Saykin AJ, Alzheimer's Disease Neuroimaging Initiative and Alzheimer's Disease Metabolomics Consortium

Abstract
OBJECTIVE: To investigate the association of triglyceride (TG) principal component scores with Alzheimer disease (AD) and the amyloid, tau, neurodegeneration, and cerebrovascular disease (A/T/N/V) biomarkers for AD.
METHODS: Serum levels of 84 TG species were measured with untargeted lipid profiling of 689 participants from the Alzheimer's Disease Neuroimaging Initiative cohort, including 190 cognitively normal older adults (CN), 339 with mild cognitive impairment (MCI), and 160 with AD. Principal component analysis with factor rotation was used for dimension reduction of TG species. Differences in principal components between diagnostic groups and associations between principal components and AD biomarkers (including CSF, MRI and [18F]fluorodeoxyglucose-PET) were assessed with a generalized linear model approach. In both cases, the Bonferroni method of adjustment was used to correct for multiple comparisons.
RESULTS: The 84 TGs yielded 9 principal components, 2 of which, consisting of long-chain, polyunsaturated fatty acid-containing TGs (PUTGs), were significantly associated with MCI and AD. Lower levels of PUTGs were observed in MCI and AD compared to CN. PUTG principal component scores were also significantly associated with hippocampal volume and entorhinal cortical thickness. In participants carrying the APOE ε4 allele, these principal components were significantly associated with CSF β-amyloid1-42 values and entorhinal cortical thickness.
CONCLUSION: This study shows that PUTG component scores were significantly associated with diagnostic group and AD biomarkers, a finding that was more pronounced in APOE ε4 carriers. Replication in independent larger studies and longitudinal follow-up are warranted.

PMID: 32358220 [PubMed - as supplied by publisher]

Quantitative Proteomics of All 14 Renal Tubule Segments in Rat.

J Am Soc Nephrol. 2020 May 01;:

Authors: Limbutara K, Chou CL, Knepper MA

Abstract
BACKGROUND: Previous research has used RNA sequencing in microdissected kidney tubules or single cells isolated from the kidney to profile gene expression in each type of kidney tubule epithelial cell. However, because proteins, not mRNA molecules, mediate most cellular functions, it is desirable to know the identity and amounts of each protein species to understand function. Recent improvements in the sensitivity of mass spectrometers offered us the ability to quantify the proteins expressed in each of 14 different renal tubule segments from rat.
METHODS: We manually dissected kidney tubules from rat kidneys and subjected samples to protein mass spectrometry. We used the "proteomic ruler" technique to estimate the number of molecules of each protein per cell.
RESULTS: Over the 44 samples analyzed, the average number of quantified proteins per segment was 4234, accounting for at least 99% of protein molecules in each cell. We have made the data publicly available online at the Kidney Tubule Expression Atlas website (https://esbl.nhlbi.nih.gov/KTEA/). Protein abundance along the renal tubule for many commonly studied water and solute transport proteins and metabolic enzymes matched expectations from prior localization studies, demonstrating the overall reliability of the data. The site features a "correlated protein" function, which we used to identify cell type-specific transcription factors expressed along the renal tubule.
CONCLUSIONS: We identified and quantified proteins expressed in each of the 14 segments of rat kidney tubules and used the proteomic data that we obtained to create an online information resource, the Kidney Tubule Expression Atlas. This resource will allow users throughout the world to browse segment-specific protein expression data and download them for their own research.

PMID: 32358040 [PubMed - as supplied by publisher]

Data-Driven Modeling Identifies TIRAP-Independent MyD88 Activation Complex and Myddosome Assembly Strategy in LPS/TLR4 Signaling.

Int J Mol Sci. 2020 Apr 26;21(9):

Authors: Li X, Zhong CQ, Yin Z, Qi H, Xu F, He Q, Shuai J

Abstract
TLR4 complexes are essential for the initiation of the LPS-induced innate immune response. The Myddosome, which mainly contains TLR4, TIRAP, MyD88, IRAK1/4 and TRAF6 proteins, is regarded as a major complex of TLR4. Although the Myddosome has been well studied, a quantitative description of the Myddosome assembly dynamics is still lacking. Furthermore, whether some unknown TLR4 complexes exist remains unclear. In this study, we constructed a SWATH-MS data-based mathematical model that describes the component assembly dynamics of TLR4 complexes. In addition to Myddosome, we suggest that a TIRAP-independent MyD88 activation complex is formed upon LPS stimulation, in which TRAF6 is not included. Furthermore, quantitative analysis reveals that the distribution of components in TIRAP-dependent and -independent MyD88 activation complexes are LPS stimulation-dependent. The two complexes compete for recruiting IRAK1/4 proteins. MyD88 forms higher-order assembly in the Myddosome and we show that the strategy to form higher-order assembly is also LPS stimulation-dependent. MyD88 forms a long chain upon weak stimulation, but forms a short chain upon strong stimulation. Higher-order assembly of MyD88 is directly determined by the level of TIRAP in the Myddosome, providing a formation mechanism for efficient signaling transduction. Taken together, our study provides an enhanced understanding of component assembly dynamics and strategies in TLR4 complexes.

PMID: 32357531 [PubMed - as supplied by publisher]

16 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 2020/05/02

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 2020/05/01

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.

27 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 2020/04/30

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.

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 2020/04/29

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.

23 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 2020/04/29

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.

58 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 2020/04/28

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.

57 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 2020/04/28

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.

Deciphering MET-dependent modulation of global cellular responses to DNA damage by quantitative phosphoproteomics.

Mol Oncol. 2020 Apr 26;:

Authors: Bensimon A, Koch JP, Francica P, Roth SM, Riedo R, Glück AA, Orlando E, Blaukat A, Aebersold DM, Zimmer Y, Aebersold R, Medová M

Abstract
Increasing evidence suggests that interference with growth factor receptor tyrosine kinases (RTKs) signaling can affect DNA damage response (DDR) networks, with a consequent impact on cellular responses to DNA-damaging agents widely used in cancer treatment. In that respect, the MET RTK is deregulated in abundance and/or activity in a variety of human tumors. Using two proteomic techniques, we explored how disrupting MET signaling modulates global cellular phosphorylation response to ionizing radiation (IR). Following an immunoaffinity-based phosphoproteomic discovery survey we selected candidate phosphorylation sites for extensive characterization by targeted proteomics focusing on phosphorylation sites in both signaling networks. Several substrates of the DDR were confirmed to be modulated by sequential MET inhibition and IR, or MET inhibition alone. Upon combined treatment, for two substrates, NUMA1 S395 and CHEK1 S345, the gain and loss of phosphorylation, respectively, were recapitulated using in vivo tumor models by immunohistochemistry, with possible utility in future translational research. Overall, we have corroborated phosphorylation sites at the intersection between MET and the DDR signaling networks, and suggest that these represent a class of proteins at the interface between oncogene-driven proliferation and genomic stability.

PMID: 32336009 [PubMed - as supplied by publisher]

The effect of female sex steroid hormones on osteogenic differentiation of endometrial stem cells.

Mol Biol Rep. 2020 Apr 25;:

Authors: Soltanyzadeh M, Salimi A, Halabian R, Ghollasi M

Abstract
Bone regeneration is a significant and crucial health issue worldwide. Tissue bioengineering has shown itself to be the best substitute for common clinical treatment of bone loss. The suitable cell source is human endometrial stem cells (hEnSCs) which have several suitable characteristics for this approach. Since sex steroid hormones are involved in expansion and conservation of the skeleton, the effect of two sex steroid hormones known as estrogen (17-β estradiol) and progesterone on osteogenic differentiation of hEnSCs were examined. For this purpose, hEnSCs were treated with 17-β estradiol and progesterone separately (1 × 10-6 M) and simultaneously (1 × 10-7 M). Osteogenic differentiation tests including measurement of total mineral calcium content, Alizarin Red staining, the quantitative expression levels of some osteogenic markers by Real-time RT-PCR, and immunofluorescence staining were performed at 7 and 14 days of differentiation. To exhibit the morphology of the cells in osteogenic and culture medium, the hEnSCs were stained with Acridine Orange (AO) solution. In this research, MTT assay and AO staining revealed progesterone and 17-β estradiol increase the proliferation of hEnSCs in a dose-dependent manner. Furthermore, the results of calcium content analysis, Real-time RT-PCR assay, and all tests of differentiation staining have shown that 17-β estradiol and progesterone cannot induce hEnSCs' osteogenic differentiation. In conclusion, it is indicated that 17-β estradiol and progesterone do not have positive effects on hEnSCs' osteogenic differentiation in vitro.

PMID: 32335804 [PubMed - as supplied by publisher]

Tracing incorporation of heavy water into proteins for species-specific metabolic activity in complex communities.

J Proteomics. 2020 Apr 23;:103791

Authors: Starke R, Oliphant K, Jehmlich N, Schäpe SS, Sachsenberg T, Kohlbacher O, Allen-Vercoe E, von Bergen M

Abstract
Stable isotope probing (SIP) approaches are a suitable tool to identify active organisms in bacterial communities, but adding isotopically labeled substrate can alter both the structure and the functionality of the community. Here, we validated and demonstrated a substrate-independent protein-SIP protocol using isotopically labeled water that captures the entire microbial activity of a community. We found that 18O yielded a higher incorporation rate into peptides and thus comprised a higher sensitivity. We then applied the method to an in vitro model of a human distal gut microbial ecosystem grown in two medium formulations, to evaluate changes in microbial activity between a high-fiber and high-protein diet. We showed that only little changes are seen in the community structure but the functionality varied between the diets. In conclusion, our approach can detect species-specific metabolic activity in complex bacterial communities and more specifically to quantify the amount of amino acid synthesis. Heavy water makes possible to analyze the activity of bacterial communities for which adding an isotopically labeled energy and nutrient sources is not easily feasible. SIGNIFICANCE: Heavy stable isotopes allow for the detection of active key players in complex ecosystems where many organisms are thought to be dormant. Opposed to the labelling with energy or nutrient sources, heavy water could be a suitable replacement to trace activity, which has been shown for DNA and RNA. Here we validate, quantify and compare the incorporation of heavy water either labeled with deuterium or 18‑oxygen into proteins of Escherichia coli K12 and of an in vitro model of a human gut microbial ecosystem. The significance of our research is in providing a freely available pipeline to analyze the incorporation of deuterium and 18‑oxygen into proteins together with the validation of the applicability of tracing heavy water as a proxy for activity. Our approach unveils the relative functional contribution of microbiota in complex ecosystems, which will improve our understanding of both animal- and environment-associated microbiomes and in vitro models.

PMID: 32335296 [PubMed - as supplied by publisher]