Do Major League Baseball Hitters Come Up Big in Their Contract Year?

In sports, especially baseball, there is a lot of talk about contract year performance. Beginning in spring training and continuing throughout the season, sports journalists and fans converse about how players in the last year of their contract will perform. Experts in the media, often ex-baseball players themselves, speculate contract year players will have break-out seasons in order to secure a better contract in upcoming contract negotiations. This leads to the question: do baseball players increase their effort and performance during their contract year to increase the value of their next contract

Paracrine IL-2 Is Required for Optimal Type 2 Effector Cytokine Production

IL-2 is a pleiotropic cytokine that promotes the differentiation of Th cell subsets, including Th1, Th2, and Th9 cells, but it impairs the development of Th17 and T follicular helper cells. Although IL-2 is produced by all polarized Th subsets to some level, how it impacts cytokine production when effector T cells are restimulated is unknown. We show in this article that Golgi transport inhibitors (GTIs) blocked IL-9 production. Mechanistically, GTIs blocked secretion of IL-2 that normally feeds back in a paracrine manner to promote STAT5 activation and IL-9 production. IL-2 feedback had no effect on Th1- or Th17-signature cytokine production, but it promoted Th2- and Th9-associated cytokine expression. These data suggest that the use of GTIs results in an underestimation of the presence of type 2 cytokine-secreting cells and highlight IL-2 as a critical component in optimal cytokine production by Th2 and Th9 cells in vitro and in vivo

K-band Spectroscopy of Clusters in NGC 4038/4039

Integral field spectroscopy in the K-band (1.9-2.4um) was performed on four IR-bright star clusters and the two nuclei in NGC 4038/4039 (``The Antennae''). Two of the clusters are located in the overlap region of the two galaxies, and together comprise ~25% of the total 15um and ~10% of the total 4.8 GHz emission from this pair of merging galaxies. The other two clusters, each of them spatially resolved into two components, are located in the northern galaxy, one in the western and one in the eastern loop of blue clusters. Comparing our analysis of Brgamma, CO band-heads, He I (2.058um), Halpha (from archival HST data), and V-K colors with stellar population synthesis models indicates that the clusters are extincted (A_V ~ 0.7 - 4.3 mags) and young, displaying a significant age spread (4-13 Myrs). The starbursts in the nuclei are much older (65 Myrs), with the nucleus of NGC 4038 displaying a region of recent star formation northward of its K-band peak. Using our derived age estimates and assuming the parameters of the IMF (Salpeter slope, upper mass cut-off of 100 M_sun, Miller-Scalo between 1 M_sun and 0.1 M_sun), we find that the clusters have masses between 0.5 and 5 * 10^6M_sun.Comment: 10 pages, 3 figures, ApJ accepte

Masses, Luminosities, and Orbital Coplanarities of the mu Orionis Quadruple Star System from PHASES Differential Astrometry

mu Orionis was identified by spectroscopic studies as a quadruple star system. Seventeen high precision differential astrometry measurements of mu Ori have been collected by the Palomar High-precision Astrometric Search for Exoplanet Systems (PHASES). These show both the motion of the long period binary orbit and short period perturbations superimposed on that caused by each of the components in the long period system being themselves binaries. The new measurements enable the orientations of the long period binary and short period subsystems to be determined. Recent theoretical work predicts the distribution of relative inclinations between inner and outer orbits of hierarchical systems to peak near 40 and 140 degrees. The degree of coplanarity of this complex system is determined, and the angle between the planes of the A-B and Aa-Ab orbits is found to be 136.7 +/- 8.3 degrees, near the predicted distribution peak at 140 degrees; this result is discussed in the context of the handful of systems with established mutual inclinations. The system distance and masses for each component are obtained from a combined fit of the PHASES astrometry and archival radial velocity observations. The component masses have relative precisions of 5% (component Aa), 15% (Ab), and 1.4% (each of Ba and Bb). The median size of the minor axes of the uncertainty ellipses for the new measurements is 20 micro-arcseconds. Updated orbits for delta Equulei, kappa Pegasi, and V819 Herculis are also presented.Comment: 12 Pages, Accepted for publication in A

TBX21 methylation as a potential regulator of immune suppression in CMS1 subtype colorectal cancer

Cytotoxic T lymphocyte (CTL) infiltration is associated with survival, recurrence, and therapeutic response in colorectal cancer (CRC). Immune checkpoint inhibitor (ICI) therapy, which requires CTLs for response, does not work for most CRC patients. Therefore, it is critical to improve our understanding of immune resistance in this disease. We utilized 2391 CRC patients and 7 omics datasets, integrating clinical and genomic data to determine how DNA methylation may impact survival and CTL function in CRC. Using comprehensive molecular subtype (CMS) 1 patients as reference, we found TBX21 to be the only gene with altered expression and methylation that was associated with CTL infiltration. We found that CMS1 patients with high TBX21 expression and low methylation had a significant survival advantage. To confirm the role of Tbx21 in CTL function, we utilized scRNAseq data, demonstrating the association of TBX21 with markers of enhanced CTL function. Further analysis using pathway enrichment found that the genes TBX21, MX1, and SP140 had altered expression and methylation, suggesting that the TP53/P53 pathway may modify TBX21 methylation to upregulate TBX21 expression. Together, this suggests that targeting epigenetic modification more specifically for therapy and patient stratification may provide improved outcomes in CRC

DNA methylome analysis in Burkitt and follicular lymphomas identifies differentially methylated regions linked to somatic mutation and transcriptional control

Although Burkitt lymphomas and follicular lymphomas both have features of germinal center B cells, they are biologically and clinically quite distinct. Here we performed whole-genome bisulfite, genome and transcriptome sequencing in 13 IG-MYC translocation-positive Burkitt lymphoma, nine BCL2 translocation-positive follicular lymphoma and four normal germinal center B cell samples. Comparison of Burkitt and follicular lymphoma samples showed differential methylation of intragenic regions that strongly correlated with expression of associated genes, for example, genes active in germinal center dark-zone and light-zone B cells. Integrative pathway analyses of regions differentially methylated in Burkitt and follicular lymphomas implicated DNA methylation as cooperating with somatic mutation of sphingosine phosphate signaling, as well as the TCF3-ID3 and SWI/SNF complexes, in a large fraction of Burkitt lymphomas. Taken together, our results demonstrate a tight connection between somatic mutation, DNA methylation and transcriptional control in key B cell pathways deregulated differentially in Burkitt lymphoma and other germinal center B cell lymphomas

Measuring the predictability of life outcomes with a scientific mass collaboration.

How predictable are life trajectories? We investigated this question with a scientific mass collaboration using the common task method; 160 teams built predictive models for six life outcomes using data from the Fragile Families and Child Wellbeing Study, a high-quality birth cohort study. Despite using a rich dataset and applying machine-learning methods optimized for prediction, the best predictions were not very accurate and were only slightly better than those from a simple benchmark model. Within each outcome, prediction error was strongly associated with the family being predicted and weakly associated with the technique used to generate the prediction. Overall, these results suggest practical limits to the predictability of life outcomes in some settings and illustrate the value of mass collaborations in the social sciences

A time-resolved proteomic and prognostic map of COVID-19

COVID-19 is highly variable in its clinical presentation, ranging from asymptomatic infection to severe organ damage and death. We characterized the time-dependent progression of the disease in 139 COVID-19 inpatients by measuring 86 accredited diagnostic parameters, such as blood cell counts and enzyme activities, as well as untargeted plasma proteomes at 687 sampling points. We report an initial spike in a systemic inflammatory response, which is gradually alleviated and followed by a protein signature indicative of tissue repair, metabolic reconstitution, and immunomodulation. We identify prognostic marker signatures for devising risk-adapted treatment strategies and use machine learning to classify therapeutic needs. We show that the machine learning models based on the proteome are transferable to an independent cohort. Our study presents a map linking routinely used clinical diagnostic parameters to plasma proteomes and their dynamics in an infectious disease

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe