The Staphylococcus aureus Peptidoglycan Protects Mice against the Pathogen and Eradicates Experimentally Induced Infection

Staphylococcus aureus, in spite of antibiotics, is still a major human pathogen causing a wide range of infections. The present study describes the new vaccine A170PG, a peptidoglycan-based vaccine. In a mouse model of infection, A170PG protects mice against a lethal dose of S. aureus. Protection lasts at least 40 weeks and correlates with increased survival and reduced colonization. Protection extends into drug-resistant (MRSA or VISA) and genetically diverse clinical strains. The vaccine is effective when administered - in a single dose and without adjuvant - by the intramuscular, intravenous or the aerosol routes and induces active as well as passive immunization. Of note, A170PG also displays therapeutic activity, eradicating staphylococci, even when infection is systemic. Sustained antibacterial activity and induction of a strong and rapid anti-inflammatory response are the mechanisms conferring therapeutic efficacy to A170PG

Zipf's Law in Short-Time Timbral Codings of Speech, Music, and Environmental Sound Signals

Timbre is a key perceptual feature that allows discrimination between different sounds. Timbral sensations are highly dependent on the temporal evolution of the power spectrum of an audio signal. In order to quantitatively characterize such sensations, the shape of the power spectrum has to be encoded in a way that preserves certain physical and perceptual properties. Therefore, it is common practice to encode short-time power spectra using psychoacoustical frequency scales. In this paper, we study and characterize the statistical properties of such encodings, here called timbral code-words. In particular, we report on rank-frequency distributions of timbral code-words extracted from 740 hours of audio coming from disparate sources such as speech, music, and environmental sounds. Analogously to text corpora, we find a heavy-tailed Zipfian distribution with exponent close to one. Importantly, this distribution is found independently of different encoding decisions and regardless of the audio source. Further analysis on the intrinsic characteristics of most and least frequent code-words reveals that the most frequent code-words tend to have a more homogeneous structure. We also find that speech and music databases have specific, distinctive code-words while, in the case of the environmental sounds, this database-specific code-words are not present. Finally, we find that a Yule-Simon process with memory provides a reasonable quantitative approximation for our data, suggesting the existence of a common simple generative mechanism for all considered sound sources

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment

Unbiased determination of the proton structure function F_2^p with faithful uncertainty estimation

We construct a parametrization of the deep-inelastic structure function of the proton F_2 based on all available experimental information from charged lepton deep-inelastic scattering experiments. The parametrization effectively provides a bias-free determination of the probability measure in the space of structure functions, which retains information on experimental errors and correlations. The result is obtained in the form of a Monte Carlo sample of neural networks trained on an ensemble of replicas of the experimental data. We discuss in detail the techniques required for the construction of bias-free parameterizations of large amounts of structure function data, in view of future applications to the determination of parton distributions based on the same method.We construct a parametrization of the deep-inelastic structure function of the proton F_2 based on all available experimental information from charged lepton deep-inelastic scattering experiments. The parametrization effectively provides a bias-free determination of the probability measure in the space of structure functions, which retains information on experimental errors and correlations. The result is obtained in the form of a Monte Carlo sample of neural networks trained on an ensemble of replicas of the experimental data. We discuss in detail the techniques required for the construction of bias-free parameterizations of large amounts of structure function data, in view of future applications to the determination of parton distributions based on the same method