Chemical Genetics of AGC-kinases Reveals Shared Targets of Ypk1, Protein Kinase A and Sch9

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Highlights

• •Acute inhibition of growth-regulatory AGC-kinases Sch9, PKA and Ypk1.
• •Phospho-proteomic profiling of 6373 phsopho-sites.
• •Ypk1 regulates phospho-sites in RRxS/T-context and functionally overlaps with PKA.
• •Ypk1 and PKA activate trehalase activity of Nth1.

     

Inflammatory Responses with Left Ventricular Compromise after Induction of Myocardial Infarcts in Sheep (Ovis aries)

Ischemic myocardial disease is a major cause of death among humans worldwide; it results in scarring and pallor of the myocardium and triggers an inflammatory response that contributes to impaired left ventricular function. This response includes and is evidenced by the production of several inflammatory cytokines including TNFα, IL1β, IL4, IFNγ, IL10 and IL6. In the current study, myocardial infarcts were induced in 6 mo old male castrated sheep by ligation of the left circumflex obtuse marginal arteries (OM 1 and 2). MRI was used to measure parameters of left ventricular function that include EDV, ESV, EF, SVI, dp/dt max and dp/dt min at baseline and at 4 wk and 3 mo after infarct induction. We also measured serum concentrations of an array of cytokines. Postmortem histologic findings corroborate the existence of left ventricular myocardial injury and deterioration. Our data show a correlation between serum cytokine concentrations and the development of myocardial damage and left ventricular functional compromise.

Heart failure is a globally significant problem in both humans and lower animals.^3,18 The medical literature is replete with predisposing causes of heart disease,¹³ yet the prevalence of heart failure remained high.^4,5,16 Regardless of the cause of myocardial damage and subsequent left ventricular compromise, the literature indicated that the proinflammatory response that occurs after myocardial infarction is an important contributor to the deterioration of the myocardium^{1,9,12,14,17,18,20,21} Sheep and pigs are excellent translational models of human cardiology because their hearts bear many physiologic and anatomic similarities to the human heart.^4,8,15 The primary use of these models in cardiology is primarily to study myocardial infarction^5,13,16 and to a lesser extent, physiologic processes that develop after myocardial insult.Our study measured some of the major proinflammatory cytokines that contribute to myocardial damage. Most of these cytokines, including: TNFα, IL6, and IFNγ, are important correlates of myocardial ischemia that contribute to a decline in left ventricular myocardial function.^1,9,14 In our study, we detected left ventricular compromise as early as 4 wk after the infarction, while the proinflammatory response was recorded at 48 h after the infarct and peaked at 4 wk. Cardiac functional parameters began to decline early in the study consistent with the proinflammatory response. The cardiac functional parameters continued to decline until 3 mo, which was the termination of the study. These findings may support antiinflammatory intervention as an important adjunct of any therapeutic regimen.     

Kinome Profiling of Primary Endometrial Tumors Using Multiplexed Inhibitor Beads and Mass Spectrometry Identifies SRPK1 as Candidate Therapeutic Target

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Highlights

• •SRPK1 is overexpressed in endometrial cancer and associated with poor survival.
• •SRPK1 promotes endometrial cancer cell growth under nutrient-deprived conditions.
• •Activation of EGFR-IGF1R-AKT signaling promotes resistance to SRPK1 inhibitors.
• •Co-targeting SRPK1 and EGFR-IGF1R synergize blocking endometrial cancer cell growth.

     

The Secretome Profiling of a Pediatric Airway Epithelium Infected with hRSV Identified Aberrant Apical/Basolateral Trafficking and Novel Immune Modulating (CXCL6, CXCL16, CSF3) and Antiviral (CEACAM1) Proteins

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Highlights

• •Proteome of airway secretions derived from mock- and hRSV-infected WD-PBEC cultures.
• •A polarised secretome in uninfected WD-PBECs, skewed in hRSV-infected cultures.
• •CXCL6, CXCL16, CECACAM1 and CSF3 induced only upon hRSV-infection.
• •Detection of CXCL6, CXCL16 and CSF3 in NPAs from hRSV-positive children.

     

Combining Precursor and Fragment Information for Improved Detection of Differential Abundance in Data Independent Acquisition

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Highlights

• •Modern DIA methods contain high quality MS1 and MS2.
• •We developed a statistical procedure incorporating MS1 and MS2.
• •Benchmarking, the combined method outperformed the individual use of MS1 or MS2.

     

Biclustering via sparse clustering

In identifying subgroups of a heterogeneous disease or condition, it is often desirable to identify both the observations and the features which differ between subgroups. For instance, it may be that there is a subgroup of individuals with a certain disease who differ from the rest of the population based on the expression profile for only a subset of genes. Identifying the subgroup of patients and subset of genes could lead to better-targeted therapy. We can represent the subgroup of individuals and genes as a bicluster, a submatrix, $\mathbf{U}$, of a larger data matrix, $\mathbf{X}$, such that the features and observations in $\mathbf{U}$ differ from those not contained in $\mathbf{U}$. We present a novel two-step method, SC-Biclust, for identifying $\mathbf{U}$. In the first step, the observations in the bicluster are identified to maximize the sum of the weighted between-cluster feature differences. In the second step, features in the bicluster are identified based on their contribution to the clustering of the observations. This versatile method can be used to identify biclusters that differ on the basis of feature means, feature variances, or more general differences. The bicluster identification accuracy of SC-Biclust is illustrated through several simulated studies. Application of SC-Biclust to pain research illustrates its ability to identify biologically meaningful subgroups.     

Mass Spectrometry Based Immunopeptidomics Leads to Robust Predictions of Phosphorylated HLA Class I Ligands

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Highlights

• •Curation of 2066 phosphorylated HLA class I peptides from immunopeptidomics data.
• •Determination of 22 HLA class I binding motifs for phosphorylated peptides.
• •Observation of a higher frequency of phosphorylated ligands binding HLA-C molecules.
• •Development of a predictor of phosphorylated peptide interactions with HLA class I.

     

Insect trace fossils in glyptodonts from Uruguay

Abstract

The association of vertebrate remains and invertebrate traces, although less studied than other bioerosion traces, provides important paleoecological information. This report describes Cubiculum ornatum Roberts, Rogers, and Foreman 2007 Roberts, E., R. Rogers, and B. Foreman. 2007. Continental insect borings in dinosaur bone: examples from the Late Cretaceous of Madagascar and Utah. Journal of Paleontology 81(1):201–208.[Crossref], [Web of Science ®] , [Google Scholar], Osteocallis Roberts, Rogers, and Foreman 2007 Roberts, E., R. Rogers, and B. Foreman. 2007. Continental insect borings in dinosaur bone: examples from the Late Cretaceous of Madagascar and Utah. Journal of Paleontology 81(1):201–208.[Crossref], [Web of Science ®] , [Google Scholar] and other unidentified insect traces from the dermal skeletal remains of glyptodonts found in Uruguay. They come from the Fray Bentos Formation (Late Oligocene), the Camacho Formation (Late Miocene) and the Dolores Formation (Late Pleistocene-Early Holocene). The reported traces were likely made by sarcosaprophagous beetles, which indicate depositional conditions with dry episodes in a warm climate for the referred stratigraphical units.     

Quantitative Proteomics Links the LRRC59 Interactome to mRNA Translation on the ER Membrane

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Highlights

• •Identification of subcellular protein interactomes via proximity labeling and quantitative multiplexed proteomics.
• •SEC61β and RPN1 interactomes overlap with translocon-associated protein networks.
• •SEC62 interacts with redox-linked proteins and ER luminal chaperones.
• •LRRC59 directly interacts with mRNA translation factors and SRP machinery on the ER.

     

A Cross-linking Mass Spectrometry Approach Defines Protein Interactions in Yeast Mitochondria

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Highlights

• •XL-MS reveals new PPIs in yeast mitochondria under glycerol and glucose condition.
• •Significant but limited results from quantitative XL-MS experiments.
• •Ndi1 participates in a CIII₂CIV₂ respiratory supercomplex.
• •Min8 promotes assembly of Cox12 into an intermediate complex IV.

     

Modulation of Natural HLA-B*27:05 Ligandome by Ankylosing Spondylitis-associated Endoplasmic Reticulum Aminopeptidase 2 (ERAP2)

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Highlights

• •HLA-B*27:05 and ERAP2 are risk factors for ankylosing spondylitis.
• •The effects of ERAP2 on the B*27:05 ligandome are defined.
• •P1, P2, P3, P7, and PΩ peptide positions are influenced by ERAP2.
• •These effects provide a basis for the association of ERAP2 with the autoimmune disease.