Pathologies in the sticky limit of hard-sphere-Yukawa models for colloidal fluids. A possible correction

A known `sticky-hard-sphere' model, defined starting from a hard-sphere-Yukawa potential and taking the limit of infinite amplitude and vanishing range with their product remaining constant, is shown to be ill-defined. This is because its Hamiltonian (which we call SHS2) leads to an {\it exact}second virial coefficient which {\it diverges}, unlike that of Baxter's original model (SHS1). This deficiency has never been observed so far, since the linearization implicit in the `mean spherical approximation' (MSA), within which the model is analytically solvable, partly {\it masks} such a pathology. To overcome this drawback and retain some useful features of SHS2, we propose both a new model (SHS3) and a new closure (`modified MSA'), whose combination yields an analytic solution formally identical with the SHS2-MSA one. This mapping allows to recover many results derived from SHS2, after a re-interpretation within a correct framework. Possible developments are finally indicated.Comment: 21 pages, 1 figure, accepted in Molecular Physics (2003

RNAseq analysis of heart tissue from mice treated with atenolol and isoproterenol reveals a reciprocal transcriptional response.

The transcriptional response to many widely used drugs and its modulation by genetic variability is poorly understood. Here we present an analysis of RNAseq profiles from heart tissue of 18 inbred mouse strains treated with the β-blocker atenolol (ATE) and the β-agonist isoproterenol (ISO). Differential expression analyses revealed a large set of genes responding to ISO (n = 1770 at FDR = 0.0001) and a comparatively small one responding to ATE (n = 23 at FDR = 0.0001). At a less stringent definition of differential expression, the transcriptional responses to these two antagonistic drugs are reciprocal for many genes, with an overall anti-correlation of r = -0.3. This trend is also observed at the level of most individual strains even though the power to detect differential expression is significantly reduced. The inversely expressed gene sets are enriched with genes annotated for heart-related functions. Modular analysis revealed gene sets that exhibit coherent transcription profiles across some strains and/or treatments. Correlations between these modules and a broad spectrum of cardiovascular traits are stronger than expected by chance. This provides evidence for the overall importance of transcriptional regulation for these organismal responses and explicits links between co-expressed genes and the traits they are associated with. Gene set enrichment analysis of differentially expressed groups of genes pointed to pathways related to heart development and functionality. Our study provides new insights into the transcriptional response of the heart to perturbations of the β-adrenergic system, implicating several new genes that had not been associated to this system previously

Evaluation of human chorionic gonadotropin as a replacement for GnRH in an ovulation synchronization protocol before fixed-time insemination

Two experiments were conducted to evaluate the difference between gonadotropinreleasing hormone (GnRH) and human chorionic gonadotropin (hCG) given at the beginning of a timed AI protocol and their effects on fertility. In Experiment 1, beef cows (n = 672) at six different locations were assigned randomly to treatments based on age, body condition, and days postpartum. On day −10, cattle were treated with GnRH or hCG and a progesterone-releasing controlled internal drug release (CIDR) insert was placed in the vagina. An injection of PGF2α was given and CIDR inserts were removed on day −3. Cows were inseminated at one fixed timed at 62 hr (day 0) after CIDR insert removal. Pregnancy was diagnosed at 33 days (range of 32 to 35) after insemination to determine pregnancy rates. For cows that were pregnant after the first insemination, a second pregnancy diagnosis was conducted 35 days (range of 33 to 37) after the first diagnosis to determine pregnancy survival. Pregnancy rates were reduced by the hCG injection compared with the GnRH injection (39.1 vs. 53.5%). In Experiment 2, cattle were assigned randomly to three treatments, balanced evenly across the two treatments (GnRH vs. hCG) applied in Experiment 1. Cows were injected with GnRH, hCG, or saline seven days before the first pregnancy diagnosis of cows inseminated in Experiment 1. At the time of pregnancy diagnosis, cattle found not pregnant (n = 328) were given PGF2α and inseminated 56 hours later. A second pregnancy diagnosis was conducted 35 days (range of 33 to 37) after the second insemination to determine pregnancy rate at the second AI. Injections of GnRH, hCG, or saline had no effect on pregnancy rates of cows already pregnant to the first insemination. Pregnancy rates after second insemination in cows given an injection of hCG or GnRH, however, tended to be reduced. Percentage of cows pregnant after two timed inseminations exceeded 60% without any need to detect estrus

Identification and validation of copy number variants using SNP genotyping arrays from a large clinical cohort.

BACKGROUND: Genotypes obtained with commercial SNP arrays have been extensively used in many large case-control or population-based cohorts for SNP-based genome-wide association studies for a multitude of traits. Yet, these genotypes capture only a small fraction of the variance of the studied traits. Genomic structural variants (GSV) such as Copy Number Variation (CNV) may account for part of the missing heritability, but their comprehensive detection requires either next-generation arrays or sequencing. Sophisticated algorithms that infer CNVs by combining the intensities from SNP-probes for the two alleles can already be used to extract a partial view of such GSV from existing data sets. RESULTS: Here we present several advances to facilitate the latter approach. First, we introduce a novel CNV detection method based on a Gaussian Mixture Model. Second, we propose a new algorithm, PCA merge, for combining copy-number profiles from many individuals into consensus regions. We applied both our new methods as well as existing ones to data from 5612 individuals from the CoLaus study who were genotyped on Affymetrix 500K arrays. We developed a number of procedures in order to evaluate the performance of the different methods. This includes comparison with previously published CNVs as well as using a replication sample of 239 individuals, genotyped with Illumina 550K arrays. We also established a new evaluation procedure that employs the fact that related individuals are expected to share their CNVs more frequently than randomly selected individuals. The ability to detect both rare and common CNVs provides a valuable resource that will facilitate association studies exploring potential phenotypic associations with CNVs. CONCLUSION: Our new methodologies for CNV detection and their evaluation will help in extracting additional information from the large amount of SNP-genotyping data on various cohorts and use this to explore structural variants and their impact on complex traits

A Phase I/II trial comparing autologous dendritic cell vaccine pulsed either with personalized peptides (PEP-DC) or with tumor lysate (OC-DC) in patients with advanced high-grade ovarian serous carcinoma.

Most ovarian cancer patients are diagnosed at a late stage with 85% of them relapsing after surgery and standard chemotherapy; for this reason, new treatments are urgently needed. Ovarian cancer has become a candidate for immunotherapy by reason of their expression of shared tumor-associated antigens (TAAs) and private mutated neoantigens (NeoAgs) and the recognition of the tumor by the immune system. Additionally, the presence of intraepithelial tumor infiltrating lymphocytes (TILs) is associated with improved progression-free and overall survival of patients with ovarian cancer. The aim of active immunotherapy, including vaccination, is to generate a new anti-tumor response and amplify an existing immune response. Recently developed NeoAgs-based cancer vaccines have the advantage of being more tumor specific, reducing the potential for immunological tolerance, and inducing robust immunogenicity. We propose a randomized phase I/II study in patients with advanced ovarian cancer to compare the immunogenicity and to assess safety and feasibility of two personalized DC vaccines. After standard of care surgery and chemotherapy, patients will receive either a novel vaccine consisting of autologous DCs pulsed with up to ten peptides (PEP-DC), selected using an agnostic, yet personalized, epitope discovery algorithm, or a sequential combination of a DC vaccine loaded with autologous oxidized tumor lysate (OC-DC) prior to an equivalent PEP-DC vaccine. All vaccines will be administered in combination with low-dose cyclophosphamide. This study is the first attempt to compare the two approaches and to use NeoAgs-based vaccines in ovarian cancer in the adjuvant setting. The proposed treatment takes advantage of the beneficial effects of pre-treatment with OC-DC prior to PEP-DC vaccination, prompting immune response induction against a wide range of patient-specific antigens, and amplification of pre-existing NeoAgs-specific T cell clones. Trial registration This trial is already approved by Swissmedic (Ref.: 2019TpP1004) and will be registered at http://www.clinicaltrials.gov before enrollment opens

The immunopeptidome landscape associated with T cell infiltration, inflammation and immune editing in lung cancer.

One key barrier to improving efficacy of personalized cancer immunotherapies that are dependent on the tumor antigenic landscape remains patient stratification. Although patients with CD3 <sup>+</sup> CD8 <sup>+</sup> T cell-inflamed tumors typically show better response to immune checkpoint inhibitors, it is still unknown whether the immunopeptidome repertoire presented in highly inflamed and noninflamed tumors is substantially different. We surveyed 61 tumor regions and adjacent nonmalignant lung tissues from 8 patients with lung cancer and performed deep antigen discovery combining immunopeptidomics, genomics, bulk and spatial transcriptomics, and explored the heterogeneous expression and presentation of tumor (neo)antigens. In the present study, we associated diverse immune cell populations with the immunopeptidome and found a relatively higher frequency of predicted neoantigens located within HLA-I presentation hotspots in CD3 <sup>+</sup> CD8 <sup>+</sup> T cell-excluded tumors. We associated such neoantigens with immune recognition, supporting their involvement in immune editing. This could have implications for the choice of combination therapies tailored to the patient's mutanome and immune microenvironment

Integrated proteogenomic deep sequencing and analytics accurately identify non-canonical peptides in tumor immunopeptidomes

Efforts to precisely identify tumor human leukocyte antigen (HLA) bound peptides capable of mediating T cell-based tumor rejection still face important challenges. Recent studies suggest that non-canonical tumor-specific HLA peptides that derive from annotated non-coding regions could elicit anti-tumor immune responses. However, sensitive and accurate mass-spectrometry (MS)-based proteogenomics approaches are required to robustly identify these non-canonical peptides. We present an MS-based analytical approach that characterizes the non-canonical tumor HLA peptide repertoire, by incorporating whole exome sequencing, bulk and single cell transcriptomics, ribosome profiling, and a combination of two MS/MS search tools. This approach results in the accurate identification of hundreds of shared and tumor-specific non-canonical HLA peptides and of an immunogenic peptide from a downstream reading frame in the melanoma stem cell marker gene ABCB5. It holds great promise for the discovery of novel cancer antigens for cancer immunotherapy

The Structure of Jupiter, Saturn, and Exoplanets: Key Questions for High-Pressure Experiments

We give an overview of our current understanding of the structure of gas giant planets, from Jupiter and Saturn to extrasolar giant planets. We focus on addressing what high-pressure laboratory experiments on hydrogen and helium can help to elucidate about the structure of these planets.Comment: Invited contribution to proceedings of High Energy Density Laboratory Astrophysics, 6. Accepted to Astrophysics & Space Science. 12 page

Search for displaced vertices arising from decays of new heavy particles in 7 TeV pp collisions at ATLAS

We present the results of a search for new, heavy particles that decay at a significant distance from their production point into a final state containing charged hadrons in association with a high-momentum muon. The search is conducted in a pp-collision data sample with a center-of-mass energy of 7 TeV and an integrated luminosity of 33 pb^-1 collected in 2010 by the ATLAS detector operating at the Large Hadron Collider. Production of such particles is expected in various scenarios of physics beyond the standard model. We observe no signal and place limits on the production cross-section of supersymmetric particles in an R-parity-violating scenario as a function of the neutralino lifetime. Limits are presented for different squark and neutralino masses, enabling extension of the limits to a variety of other models.Comment: 8 pages plus author list (20 pages total), 8 figures, 1 table, final version to appear in Physics Letters