Limits on Isocurvature Perturbations from Non-Gaussianity in WMAP Temperature Anisotropies

We study the effect of primordial isocurvature perturbations on non-Gaussian properties of CMB temperature anisotropies. We consider generic forms of the non-linearity of isocurvature perturbations which can be applied to a wide range of theoretical models. We derive analytical expressions for the bispectrum and the Minkowski Functionals for CMB temperature fluctuations to describe the non-Gaussianity from isocurvature perturbations. We find that the isocurvature non-Gaussianity in the quadratic isocurvature model, where the isocurvature perturbation S is written as a quadratic function of the Gaussian variable sigma, S=sigma^2-, can give the same signal-to-noise as f_NL=30 even if we impose the current observational limit on the fraction of isocurvature perturbations contained in the primordial power spectrum alpha. We give constraints on isocurvature non-Gaussianity from Minkowski Functionals using WMAP 5-year data. We do not find a significant signal of the isocurvature non-Gaussianity. For the quadratic isocurvature model, we obtain a stringent upper limit on the isocurvature fraction alpha<0.070 (95% CL) for a scale invariant spectrum which is comparable to the limit obtained from the power spectrum.Comment: 13 pages, 5 figures, MNRAS accepte

Phenomenological Aspects of Gauge Mediation with Sequestered Supersymmetry Breaking in light of Dark Matter Detection

In a recent work, a model of gauge mediation with sequestered supersymmetry (SUSY) breaking was proposed. In this model, the mass of the gravitino is O(100) GeV without causing the flavor-changing neutral-current problem. In contrast to traditional gauge mediation, the gravitino is not the lightest SUSY particle and the neutralino is the candidate of the dark matter. In this paper, we investigate phenomenological aspects of this model and discuss the possibility of the direct detection of the dark matter. In particular, we focus on the light neutralino case and find that the light-Higgsino scenario such as the focus point is interesting, taking account of the recent CDMS result.Comment: 17 pages, 8 figures; v2:references added, some corrections; v3:version accepted for publication in JHE

RNA editing facilitates the enhanced production of neoantigens during the simultaneous administration of oxaliplatin and radiotherapy in colorectal cancer

Most cases of colorectal cancers (CRCs) are microsatellite stable (MSS), which frequently demonstrate lower response rates to immune checkpoint inhibitors (ICIs). RNA editing produces neoantigens by altering amino acid sequences. In this study, RNA editing was induced artificially by chemoradiation therapy (CRT) to generate neoantigens in MSS CRCs. Altogether, 543 CRC specimens were systematically analyzed, and the expression pattern of ADAR1 was investigated. In vitro and in vivo experiments were also performed. The RNA editing enzyme ADAR1 was upregulated in microsatellite instability-high CRCs, leading to their high affinity for ICIs. Although ADAR1 expression was low in MSS CRC, CRT including oxaliplatin (OX) treatment upregulated RNA editing levels by inducing ADAR1. Immunohistochemistry analyses showed the upregulation of ADAR1 in patients with CRC treated with CAPDX (capecitabine +OX) radiation therapy relative to ADAR1 expression in patients with CRC treated only by surgery (p <0.001). Compared with other regimens, CRT with OX effectively induced RNA editing in MSS CRC cell lines (HT29 and Caco2, p <0.001) via the induction of type 1 interferon-triggered ADAR1 expression. CRT with OX promoted the RNA editing of cyclin I, a neoantigen candidate. Neoantigens can be artificially induced by RNA editing via an OX-CRT regimen. CRT can promote proteomic diversity via RNA editing

Latent adrenal Ewing sarcoma family of tumors: A case report

Ewing sarcoma family of tumors (ESFT) is derived from the neural crest, which originates from basal embryo cells in the primitive neural tube. ESFT often arises at the bone, chest wall, and soft tissues of the thoracic region. However, ESFT that arises from the adrenal gland is much rarer and it is usually revealed by clinical symptoms. We report an autopsy case of suicidal hanging, in which adrenal ESFT was incidentally revealed. To our knowledge, this is the first case of latent ESFT arising from the adrenal gland. Autopsy can sometimes reveal latent disease. Some of these latent diseases are very rare and we would not be able to detect them without a complete autopsy. As forensic pathologists, we should attempt to perform a complete autopsy and report new discoveries for the development of medicine

Primordial fluctuations and non-Gaussianities from multifield DBI Galileon inflation

We study a cosmological scenario in which the DBI action governing the motion of a D3-brane in a higher-dimensional spacetime is supplemented with an induced gravity term. The latter reduces to the quartic Galileon Lagrangian when the motion of the brane is non-relativistic and we show that it tends to violate the null energy condition and to render cosmological fluctuations ghosts. There nonetheless exists an interesting parameter space in which a stable phase of quasi-exponential expansion can be achieved while the induced gravity leaves non trivial imprints. We derive the exact second-order action governing the dynamics of linear perturbations and we show that it can be simply understood through a bimetric perspective. In the relativistic regime, we also calculate the dominant contribution to the primordial bispectrum and demonstrate that large non-Gaussianities of orthogonal shape can be generated, for the first time in a concrete model. More generally, we find that the sign and the shape of the bispectrum offer powerful diagnostics of the precise strength of the induced gravity.Comment: 34 pages including 9 figures, plus appendices and bibliography. Wordings changed and references added; matches version published in JCA

Targeting miR-223 in neutrophils enhances the clearance of Staphylococcus aureus in infected wounds

Abstract Argonaute 2 bound mature microRNA (Ago2‐miRNA) complexes are key regulators of the wound inflammatory response and function in the translational processing of target mRNAs. In this study, we identified four wound inflammation‐related Ago2‐miRNAs (miR‐139‐5p, miR‐142‐3p, miR‐142‐5p, and miR‐223) and show that miR‐223 is critical for infection control. miR‐223Y/− mice exhibited delayed sterile healing with prolonged neutrophil activation and interleukin‐6 expression, and markedly improved repair of Staphylococcus aureus‐infected wounds. We also showed that the expression of miR‐223 was regulated by CCAAT/enhancer binding protein alpha in human neutrophils after exposure to S. aureus peptides. Treatment with miR‐223Y/−‐derived neutrophils, or miR‐223 antisense oligodeoxynucleotides in S. aureus‐infected wild‐type wounds markedly improved the healing of these otherwise chronic, slow healing wounds. This study reveals how miR‐223 regulates the bactericidal capacity of neutrophils at wound sites and indicates that targeting miR‐223 might be of therapeutic benefit for infected wounds in the clinic

Proteomic Biomarkers for Acute Interstitial Lung Disease in Gefitinib-Treated Japanese Lung Cancer Patients

Interstitial lung disease (ILD) events have been reported in Japanese non-small-cell lung cancer (NSCLC) patients receiving EGFR tyrosine kinase inhibitors. We investigated proteomic biomarkers for mechanistic insights and improved prediction of ILD. Blood plasma was collected from 43 gefitinib-treated NSCLC patients developing acute ILD (confirmed by blinded diagnostic review) and 123 randomly selected controls in a nested case-control study within a pharmacoepidemiological cohort study in Japan. We generated ∼7 million tandem mass spectrometry (MS/MS) measurements with extensive quality control and validation, producing one of the largest proteomic lung cancer datasets to date, incorporating rigorous study design, phenotype definition, and evaluation of sample processing. After alignment, scaling, and measurement batch adjustment, we identified 41 peptide peaks representing 29 proteins best predicting ILD. Multivariate peptide, protein, and pathway modeling achieved ILD prediction comparable to previously identified clinical variables; combining the two provided some improvement. The acute phase response pathway was strongly represented (17 of 29 proteins, p = 1.0×10−25), suggesting a key role with potential utility as a marker for increased risk of acute ILD events. Validation by Western blotting showed correlation for identified proteins, confirming that robust results can be generated from an MS/MS platform implementing strict quality control

Reduced FOXO1 Expression Accelerates Skin Wound Healing and Attenuates Scarring

The forkhead box O (FOXO) family has been extensively investigated in aging and metabolism, but its role in tissue-repair processes remains largely unknown. Herein, we clarify the molecular aspect of the FOXO family in skin wound healing. We demonstrated that Foxo1 and Foxo3a were both up-regulated during murine skin wound healing. Partial knockout of Foxo1 in Foxo1 +/- mice throughout the body led to accelerated skin wound healing with enhanced keratinocyte migration, reduced granulation tissue formation, and decreased collagen density, accompanied by an attenuated inflammatory response, but we observed no wound phenotype in Foxo3a-/- mice. Fibroblast growth factor 2, adiponectin, and notch1 genes were significantly increased at wound sites in Foxo1+/- mice, along with markedly altered extracellular signal-regulated kinase 1/2 and AKT phosphorylation. Similarly, transient knockdown of Foxo1 at the wound site by local delivery of antisense oligodeoxynucleotides enhanced skin wound healing. The link between FOXO1 and scarring extends to patients, in particular keloid scars, where we see FOXO1 expression markedly increased in fibroblasts and inflammatory cells within the otherwise normal dermis. This occurs in the immediate vicinity of the keloid by comparison to the center of the mature keloid, indicating that FOXO1 is associated with the overgrowth of this fibrotic response into adjacent normal skin. Overall, our data indicate that molecular targeting of FOXO1 may improve the quality of healing and reduce pathological scarring