KSTAR: An algorithm to predict patient-specific kinase activities from phosphoproteomic data

Kinase inhibitors as targeted therapies have played an important role in improving cancer outcomes. However, there are still considerable challenges, such as resistance, non-response, patient stratification, polypharmacology, and identifying combination therapy where understanding a tumor kinase activity profile could be transformative. Here, we develop a graph- and statistics-based algorithm, called KSTAR, to convert phosphoproteomic measurements of cells and tissues into a kinase activity score that is generalizable and useful for clinical pipelines, requiring no quantification of the phosphorylation sites. In this work, we demonstrate that KSTAR reliably captures expected kinase activity differences across different tissues and stimulation contexts, allows for the direct comparison of samples from independent experiments, and is robust across a wide range of dataset sizes. Finally, we apply KSTAR to clinical breast cancer phosphoproteomic data and find that there is potential for kinase activity inference from KSTAR to complement the current clinical diagnosis of HER2 status in breast cancer patients

Tuning fluorescence and singlet oxygen quantum yields of subporphyrazines by axial functionalization

The axial functionalization of Subporphyrazines (SubPzs) with unreported alkoxy groups, carboxy and carboperoxy rests, as well as sulfanyl, aryl and amino groups, forming B−O, B−S, B−C, and B−N bonds, respectively, has been investigated. The studied oxygen nucleophiles include aromatic and sterically demanding aliphatic alcohols, along with carboxylic acids and peracids. In general, direct substitution of the chloro-SubPz by oxygen nucleophiles of diverse nature proceeds smoothly, with yields of the isolated alkoxy and carboxy-substituted SubPzs ranging from 49 to 100 %. Conversely, direct substitution with sulphur, carbon and nitrogen nucleophiles do not afford the corresponding substituted SubPzs. In these cases, a stepwise procedure involving an axial triflate-SubPz intermediate was employed, affording only the phenyl-SubPz in 8 % yield. The major compound under these conditions was the unreported SubPz μ-oxo dimer, presumably arising from substitution of the triflate-SubPz by the in situ generated hydroxy-SubPz. This result indicates a quite low reactivity of the TfO-SubPz intermediate with carbon, sulphur and nitrogen nucleophiles. All SubPzs prepared in this work exhibited fluorescence at 510–515 nm with quantum yields ranging from 0.1 to 0.24. Additionally, all SubPzs generated singlet oxygen, with ΦΔ values ranging from 0.15 to 0.57, which show no apparent correlation with the axial substituentsPID2020-116490GB-I00, TED2021-131255B-

Normative Minor Childhood Stress and Risk of Later Adult Psychopathology in Saudi Arabia

Chronic minor childhood stress in the form of corporal punishment predicts adult psychopathology in the United States but has not been demonstrated in a country where corporal punishment is normative. We tested whether adult psychopathology was predicted by recalled frequency of childhood corporal punishment and recalled controllability of punishment in Saudi Arabia. Two hundred and fifty nine Saudi men with substance addictions (who for cultural reasons were at risk for depression) completed a survey measuring: demographic variables, frequency of beating and controllability of punishment as a child, depression and borderline personality disorder symptoms (BPD). Beating frequency and punishment control were uncorrelated and unrelated to patients’ or parents’ education. 92 men (36%) had major depression (PHQ-9 ≥15). Compared to those never beaten, those experiencing infrequent beating (once or twice a year) were significantly more likely to have major depression and higher BPD symptoms, after controlling for demographic variables. Those experiencing frequent beating (monthly or more frequent) were more likely to have major depression and higher BDP symptoms compared to those never beaten, but only when perceived control was low. Perceived punishment control was not significantly related to outcome for those who never had or had infrequent corporal punishment. These results provide evidence in a culture where corporal punishment is normative that corporal punishment, even when infrequent, predisposes to adult psychopathology and that uncontrollability increases the pathogenic effect of frequent corporal punishment. These results support the hypothesis that frequent minor stressors in childhood act as kindling factor for later depression

A genetic algorithm for shortest path with real constraints in computer networks

The shortest path problem has many different versions. In this manuscript, we proposed a muti-constrained optimization method to find the shortest path in a computer network. In general, a genetic algorithm is one of the common heuristic algorithms. In this paper, we employed the genetic algorithm to find the solution of the shortest path multi-constrained problem. The proposed algorithm finds the best route for network packets with minimum total cost, delay, and hop count constrained with limited bandwidth. The new algorithm was implemented on four different capacity networks with random network parameters, the results showed that the shortest path under constraints can be found in a reasonable time. The experimental results showed that the algorithm always found the shortest path with minimal constraints

Lepton Polarization Asymmetry in B l l(bar) decays in R-parity violating Minimal Supersymmetric Standard Model

We study the implication of R-parity violating Rp Minimal Supersymmetric Standard Model (MSSM) model in lepton polarization asymmetry ALP in B l l(bar) decays . The analysis show that the ALP is significant in a certain phenomenological parametric region of Yukawa couplings. We have also placed indirect bounds on Lambda' lambda couplings as obtained from B t t(bar).Comment: 6 pages, 4 figures Changes of notation in Eq(8-11,17-19),Eq.20 adde

The metabolomic effects of tripeptide gut hormone infusion compared to Roux-en-Y gastric bypass and caloric restriction

Context: The gut-derived peptide hormones glucagon-like peptide-1 (GLP-1), oxyntomodulin (OXM), and peptide YY (PYY) are regulators of energy intake and glucose homeostasis, and are thought to contribute to the glucose-lowering effects of bariatric surgery. Objective: To establish the metabolomic effects of a combined infusion of GLP-1, OXM and PYY (tripeptide “GOP”) in comparison to a placebo infusion, Roux-en-Y gastric bypass (RYGB) surgery, and a very low-calorie diet (VLCD). Design and setting: Sub-analysis of a single-blind, randomised, placebo-controlled study of GOP infusion (ClinicalTrials.gov NCT01945840), including VLCD and RYGB comparator groups. Patients and interventions: 25 obese patients with type 2 diabetes or prediabetes were randomly allocated to receive a 4-week subcutaneous infusion of GOP (n=14) or 0.9% saline control (SAL; n=11). An additional 22 patients followed a VLCD, and 21 underwent RYGB surgery. Main outcome measures: Plasma and urine samples collected at baseline and 4 weeks into each intervention were subjected to cross-platform metabolomic analysis, followed by unsupervised and supervised modelling approaches to identify similarities and differences between the effects of each intervention. Results: Aside from glucose, very few metabolites were affected by GOP, contrasting with major metabolomic changes seen with VLCD and RYGB. Conclusions: Treatment with GOP provides a powerful glucose-lowering effect but does not replicate the broader metabolomic changes seen with VLCD and RYGB. The contribution of these metabolomic changes to the clinical benefits of RYGB remains to be elucidated