Matching isotopic distributions from metabolically labeled samples

Motivation: In recent years stable isotopic labeling has become a standard approach for quantitative proteomic analyses. Among the many available isotopic labeling strategies, metabolic labeling is attractive for the excellent internal control it provides. However, analysis of data from metabolic labeling experiments can be complicated because the spacing between labeled and unlabeled forms of each peptide depends on its sequence, and is thus variable from analyte to analyte. As a result, one generally needs to know the sequence of a peptide to identify its matching isotopic distributions in an automated fashion. In some experimental situations it would be necessary or desirable to match pairs of labeled and unlabeled peaks from peptides of unknown sequence. This article addresses this largely overlooked problem in the analysis of quantitative mass spectrometry data by presenting an algorithm that not only identifies isotopic distributions within a mass spectrum, but also annotates matches between natural abundance light isotopic distributions and their metabolically labeled counterparts. This algorithm is designed in two stages: first we annotate the isotopic peaks using a modified version of the IDM algorithm described last year; then we use a probabilistic classifier that is supplemented by dynamic programming to find the metabolically labeled matched isotopic pairs. Such a method is needed for high-throughput quantitative proteomic metabolomic experiments measured via mass spectrometry

Anti-tumor activity and mechanistic characterization of APE1/Ref-1 inhibitors in bladder cancer

Bladder cancer is the ninth most common cause of cancer-related deaths worldwide. Although cisplatin is used routinely in treating bladder cancer, refractory disease remains lethal for many patients. The recent addition of immunotherapy has improved patient outcomes; however, a large cohort of patients does not respond to these treatments. Therefore, identification of innovative molecular targets for bladder cancer is crucial. Apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1) is a multifunctional protein involved in both DNA repair and activation of transcription factors through reduction-oxidation (redox) regulation. High APE1/Ref-1 expression is associated with shorter patient survival time in many cancer types. In this study, we found high APE1/Ref-1 expression in human bladder cancer tissue relative to benign urothelium. Inhibition of APE1/Ref-1 redox signaling using APE1/Ref-1-specific inhibitors attenuates bladder cancer cell proliferation in monolayer, in three-dimensional cultures, and in vivo. This inhibition corresponds with an increase in apoptosis and decreased transcriptional activity of NF-κB and STAT3, transcription factors known to be regulated by APE1/Ref-1, resulting in decreased expression of downstream effectors survivin and Cyclin D1 in vitro and in vivo. We also demonstrate that in vitro treatment of bladder cancer cells with APE1/Ref-1 redox inhibitors in combination with standard-of-care chemotherapy cisplatin is more effective than cisplatin alone at inhibiting cell proliferation. Collectively, our data demonstrate that APE1/Ref-1 is a viable drug target for the treatment of bladder cancer, provide a mechanism of APE1/Ref-1 action in bladder cancer cells, and support the use of novel redox-selective APE1/Ref-1 inhibitors in clinical studies. SIGNIFICANCE: This work identifies a critical mechanism for APE1/Ref-1 in bladder cancer growth and provides compelling preclinical data using selective redox activity inhibitors of APE1/Ref-1 in vitro and in vivo

The likelihood of extinction of iconic and dominant herbivores and detritivores of coral reefs: the parrotfishes and surgeonfishes

Parrotfishes and surgeonfishes perform important functional roles in the dynamics of coral reef systems. This is a consequence of their varied feeding behaviors ranging from targeted consumption of living plant material (primarily surgeonfishes) to feeding on detrital aggregates that are either scraped from the reef surface or excavated from the deeper reef substratum (primarily parrotfishes). Increased fishing pressure and widespread habitat destruction have led to population declines for several species of these two groups. Species-specific data on global distribution, population status, life history characteristics, and major threats were compiled for each of the 179 known species of parrotfishes and surgeonfishes to determine the likelihood of extinction of each species under the Categories and Criteria of the IUCN Red List of Threatened Species. Due in part to the extensive distributions of most species and the life history traits exhibited in these two families, only three (1.7%) of the species are listed at an elevated risk of global extinction. The majority of the parrotfishes and surgeonfishes (86%) are listed as Least Concern, 10% are listed as Data Deficient and 1% are listed as Near Threatened. The risk of localized extinction, however, is higher in some areas, particularly in the Coral Triangle region. The relatively low proportion of species globally listed in threatened Categories is highly encouraging, and some conservation successes are attributed to concentrated conservation efforts. However, with the growing realization of man's profound impact on the planet, conservation actions such as improved marine reserve networks, more stringent fishing regulations, and continued monitoring of the population status at the species and community levels are imperative for the prevention of species loss in these groups of important and iconic coral reef fishes

Coordinated Cellular Neighborhoods Orchestrate Antitumoral Immunity at the Colorectal Cancer Invasive Front.

Antitumoral immunity requires organized, spatially nuanced interactions between components of the immune tumor microenvironment (iTME). Understanding this coordinated behavior in effective versus ineffective tumor control will advance immunotherapies. We re-engineered co-detection by indexing (CODEX) for paraffin-embedded tissue microarrays, enabling simultaneous profiling of 140 tissue regions from 35 advanced-stage colorectal cancer (CRC) patients with 56 protein markers. We identified nine conserved, distinct cellular neighborhoods (CNs)-a collection of components characteristic of the CRC iTME. Enrichment of PD-1+CD4+ T cells only within a granulocyte CN positively correlated with survival in a high-risk patient subset. Coupling of tumor and immune CNs, fragmentation of T cell and macrophage CNs, and disruption of inter-CN communication was associated with inferior outcomes. This study provides a framework for interrogating how complex biological processes, such as antitumoral immunity, occur through concerted actions of cells and spatial domains

Multiomics modeling of the immunome, transcriptome, microbiome, proteome and metabolome adaptations during human pregnancy.

MotivationMultiple biological clocks govern a healthy pregnancy. These biological mechanisms produce immunologic, metabolomic, proteomic, genomic and microbiomic adaptations during the course of pregnancy. Modeling the chronology of these adaptations during full-term pregnancy provides the frameworks for future studies examining deviations implicated in pregnancy-related pathologies including preterm birth and preeclampsia.ResultsWe performed a multiomics analysis of 51 samples from 17 pregnant women, delivering at term. The datasets included measurements from the immunome, transcriptome, microbiome, proteome and metabolome of samples obtained simultaneously from the same patients. Multivariate predictive modeling using the Elastic Net (EN) algorithm was used to measure the ability of each dataset to predict gestational age. Using stacked generalization, these datasets were combined into a single model. This model not only significantly increased predictive power by combining all datasets, but also revealed novel interactions between different biological modalities. Future work includes expansion of the cohort to preterm-enriched populations and in vivo analysis of immune-modulating interventions based on the mechanisms identified.Availability and implementationDatasets and scripts for reproduction of results are available through: https://nalab.stanford.edu/multiomics-pregnancy/.Supplementary informationSupplementary data are available at Bioinformatics online

On the origin of aurorae on Mars

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/95268/1/grl20829.pd

Precision Measurement of the Ds∗+−Ds+D_s^{*+}- D_s^+ Mass Difference

We have measured the vector-pseudoscalar mass splitting $M(D_s^{*+})-M(D_s^+) = 144.22\pm 0.47\pm 0.37 MeV$, significantly more precise than the previous world average. We minimize the systematic errors by also measuring the vector-pseudoscalar mass difference $M(D^{*0})-M(D^0)$ using the radiative decay $D^{*0}\rightarrow D^0\gamma$, obtaining $[M(D_s^{*+})-M(D_s^+)]-[M(D^{*0})-M(D^0)] = 2.09\pm 0.47\pm 0.37 MeV$. This is then combined with our previous high-precision measurement of $M(D^{*0})-M(D^0)$, which used the decay $D^{*0}\rightarrow D^0\pi^0$. We also measure the mass difference $M(D_s^+)-M(D^+)=99.5\pm 0.6\pm 0.3$ MeV, using the $\phi\pi^+$ decay modes of the $D_s^+$ and $D^+$ mesons.Comment: 18 pages uuencoded compressed postscript (process with uudecode then gunzip). hardcopies with figures can be obtained by sending mail to: [email protected]

Observation of a New Charmed Strange Meson

Using the CLEO-II detector, we have obtained evidence for a new meson decaying to $D^0 K^+$. Its mass is $2573.2^{+1.7}_{-1.6}\pm 0.8\pm 0.5$ {}~MeV/$c^2$ and its width is $16^{+5}_{-4}\pm 3$~MeV/$c^2$. Although we do not establish its spin and parity, the new meson is consistent with predictions for an $L=1$, $S=1$, $J_P=2^+$ charmed strange state.Comment: 9 pages uuencoded compressed postscript (process with uudecode then gunzip). hardcopies with figures can be obtained by sending mail to: [email protected]

Semileptonic Branching Fraction of Charged and Neutral B Mesons

An examination of leptons in ${\Upsilon (4S)}$ events tagged by reconstructed $B$ decays yields semileptonic branching fractions of $b_-=(10.1 \pm 1.8\pm 1.4)\%$ for charged and $b_0=(10.9 \pm 0.7\pm 1.1)\%$ for neutral $B$ mesons. This is the first measurement for charged $B$. Assuming equality of the charged and neutral semileptonic widths, the ratio $b_-/b_0=0.93 \pm 0.18 \pm 0.12$ is equivalent to the ratio of lifetimes. A postscript version is available through World-Wide-Web in http://w4.lns.cornell.edu/public/CLNS/1994Comment: 9 pages (in REVTEX format) Preprint CLNS94-1286, CLEO 94-1