Unresolved Gamma-Ray Sky through its Angular Power Spectrum.

The gamma-ray sky has been observed with unprecedented accuracy in the last decade by the Fermi -large area telescope (LAT), allowing us to resolve and understand the high-energy Universe. The nature of the remaining unresolved emission [unresolved gamma-ray background (UGRB)] below the LAT source detection threshold can be uncovered by characterizing the amplitude and angular scale of the UGRB fluctuation field. This Letter presents a measurement of the UGRB autocorrelation angular power spectrum based on eight years of Fermi-LAT Pass 8 data products. The analysis is designed to be robust against contamination from resolved sources and noise systematics. The sensitivity to subthreshold sources is greatly enhanced with respect to previous measurements. We find evidence (with ∼3.7σ significance) that the scenario in which two classes of sources contribute to the UGRB signal is favored over a single class. A double power law with exponential cutoff can explain the anisotropy energy spectrum well, with photon indices of the two populations being 2.55±0.23 and 1.86±0.15.

Search for Cosmic-Ray Electron and Positron Anisotropies with Seven Years of Fermi Large Area Telescope Data.

The Large Area Telescope on board the Fermi Gamma-ray Space Telescope has collected the largest ever sample of high-energy cosmic-ray electron and positron events since the beginning of its operation. Potential anisotropies in the arrival directions of cosmic-ray electrons or positrons could be a signature of the presence of nearby sources. We use almost seven years of data with energies above 42 GeV processed with the Pass 8 reconstruction. The present data sample can probe dipole anisotropies down to a level of 10^{-3}. We take into account systematic effects that could mimic true anisotropies at this level. We present a detailed study of the event selection optimization of the cosmic-ray electrons and positrons to be used for anisotropy searches. Since no significant anisotropies have been detected on any angular scale, we present upper limits on the dipole anisotropy. The present constraints are among the strongest to date probing the presence of nearby young and middle-aged sources.

Search for Spectral Irregularities due to Photon-Axionlike-Particle Oscillations with the Fermi Large Area Telescope.

We report on the search for spectral irregularities induced by oscillations between photons and axionlike-particles (ALPs) in the γ-ray spectrum of NGC 1275, the central galaxy of the Perseus cluster. Using 6 years of Fermi Large Area Telescope data, we find no evidence for ALPs and exclude couplings above 5×10^{-12} GeV^{-1} for ALP masses 0.5≲m_{a}≲5 neV at 95% confidence. The limits are competitive with the sensitivity of planned laboratory experiments, and, together with other bounds, strongly constrain the possibility that ALPs can reduce the γ-ray opacity of the Universe.

Resolving the Extragalactic γ-Ray Background above 50 GeV with the Fermi Large Area Telescope.

The Fermi Large Area Telescope (LAT) Collaboration has recently released a catalog of 360 sources detected above 50 GeV (2FHL). This catalog was obtained using 80 months of data re-processed with Pass 8, the newest event-level analysis, which significantly improves the acceptance and angular resolution of the instrument. Most of the 2FHL sources at high Galactic latitude are blazars. Using detailed Monte Carlo simulations, we measure, for the first time, the source count distribution, dN/dS, of extragalactic γ-ray sources at E>50 GeV and find that it is compatible with a Euclidean distribution down to the lowest measured source flux in the 2FHL (∼8×10^{-12} ph cm^{-2} s^{-1}). We employ a one-point photon fluctuation analysis to constrain the behavior of dN/dS below the source detection threshold. Overall, the source count distribution is constrained over three decades in flux and found compatible with a broken power law with a break flux, S_{b}, in the range [8×10^{-12},1.5×10^{-11}] ph cm^{-2} s^{-1} and power-law indices below and above the break of α_{2}∈[1.60,1.75] and α_{1}=2.49±0.12, respectively. Integration of dN/dS shows that point sources account for at least 86_{-14}^{+16}% of the total extragalactic γ-ray background. The simple form of the derived source count distribution is consistent with a single population (i.e., blazars) dominating the source counts to the minimum flux explored by this analysis. We estimate the density of sources detectable in blind surveys that will be performed in the coming years by the Cherenkov Telescope Array.

Searching for Dark Matter Annihilation from Milky Way Dwarf Spheroidal Galaxies with Six Years of Fermi Large Area Telescope Data.

The dwarf spheroidal satellite galaxies (dSphs) of the Milky Way are some of the most dark matter (DM) dominated objects known. We report on γ-ray observations of Milky Way dSphs based on six years of Fermi Large Area Telescope data processed with the new Pass8 event-level analysis. None of the dSphs are significantly detected in γ rays, and we present upper limits on the DM annihilation cross section from a combined analysis of 15 dSphs. These constraints are among the strongest and most robust to date and lie below the canonical thermal relic cross section for DM of mass ≲100 GeV annihilating via quark and τ-lepton channels.

Inferred cosmic-ray spectrum from Fermi large area telescope γ-ray observations of Earth's limb.

Recent accurate measurements of cosmic-ray (CR) species by ATIC-2, CREAM, and PAMELA reveal an unexpected hardening in the proton and He spectra above a few hundred GeV, a gradual softening of the spectra just below a few hundred GeV, and a harder spectrum of He compared to that of protons. These newly discovered features may offer a clue to the origin of high-energy CRs. We use the Fermi Large Area Telescope observations of the γ-ray emission from Earth's limb for an indirect measurement of the local spectrum of CR protons in the energy range ∼90 GeV-6 TeV (derived from a photon energy range 15 GeV-1 TeV). Our analysis shows that single power law and broken power law spectra fit the data equally well and yield a proton spectrum with index 2.68±0.04 and 2.61±0.08 above ∼200 GeV, respectively.

Measurement of separate cosmic-ray electron and positron spectra with the fermi large area telescope.

We measured separate cosmic-ray electron and positron spectra with the Fermi Large Area Telescope. Because the instrument does not have an onboard magnet, we distinguish the two species by exploiting Earth's shadow, which is offset in opposite directions for opposite charges due to Earth's magnetic field. We estimate and subtract the cosmic-ray proton background using two different methods that produce consistent results. We report the electron-only spectrum, the positron-only spectrum, and the positron fraction between 20 and 200 GeV. We confirm that the fraction rises with energy in the 20-100 GeV range. The three new spectral points between 100 and 200 GeV are consistent with a fraction that is continuing to rise with energy.

Constraining dark matter models from a combined analysis of Milky Way satellites with the Fermi Large Area Telescope.

Satellite galaxies of the Milky Way are among the most promising targets for dark matter searches in gamma rays. We present a search for dark matter consisting of weakly interacting massive particles, applying a joint likelihood analysis to 10 satellite galaxies with 24 months of data of the Fermi Large Area Telescope. No dark matter signal is detected. Including the uncertainty in the dark matter distribution, robust upper limits are placed on dark matter annihilation cross sections. The 95% confidence level upper limits range from about 10(-26) cm3 s(-1) at 5 GeV to about 5×10(-23) cm3 s(-1) at 1 TeV, depending on the dark matter annihilation final state. For the first time, using gamma rays, we are able to rule out models with the most generic cross section (∼3×10(-26) cm3 s(-1) for a purely s-wave cross section), without assuming additional boost factors.

Investigating the Nature of Late-Time High-Energy GRB Emission Through Joint Fermi /Swift Observations.

We use joint observations by the Neil Gehrels Swift X-ray Telescope (XRT) and the Fermi Large Area Telescope (LAT) of gamma-ray burst (GRB) afterglows to investigate the nature of the long-lived high-energy emission observed by Fermi LAT. Joint broadband spectral modeling of XRT and LAT data reveal that LAT non-detections of bright X-ray afterglows are consistent with a cooling break in the inferred electron synchrotron spectrum below the LAT and/or XRT energy ranges. Such a break is sufficient to suppress the high-energy emission so as to be below the LAT detection threshold. By contrast, LAT-detected bursts are best fit by a synchrotron spectrum with a cooling break that lies either between or above the XRT and LAT energy ranges. We speculate that the primary difference between GRBs with LAT afterglow detections and the non-detected population may be in the type of circumstellar environment in which these bursts occur, with late-time LAT detections preferentially selecting GRBs that occur in low wind-like circumburst density profiles. Furthermore, we find no evidence of high-energy emission in the LAT-detected population significantly in excess of the flux expected from the electron synchrotron spectrum fit to the observed X-ray emission. The lack of excess emission at high energies could be due to a shocked external medium in which the energy density in the magnetic field is stronger than or comparable to that of the relativistic electrons behind the shock, precluding the production of a dominant synchrotron self-Compton (SSC) component in the LAT energy range. Alternatively, the peak of the SSC emission could be beyond the 0.1-100 GeV energy range considered for this analysis.

Expression of myeloid cell phenotypes by a novel adult T-cell leukemia/lymphoma cell line.

BACKGROUND: Human T-cell leukemia virus type 1 (HTLV-1) can infect a number of cells of different lineages in vitro, yet the immunophenotypes of most adult T-cell leukemia/lymphomas (ATLs) are restricted to CD4+. The apparent discrepancy between these findings is still largely unknown. PURPOSE: We report on a unique case of ATL in which the leukemia cells were positive for both T-cell and myeloid cell antigens. To characterize these cells, we isolated cell lines from this patient with ATL. METHODS: The fresh leukemia cells were cultured without the addition of interleukin-2. Cell cloning was carried out by limiting dilution. RESULTS: A cell line (MU) and its clonal sublines were established. MU cells showed the same chromosomal abnormalities and T-cell receptor beta-chain gene rearrangement pattern as those of fresh leukemia cells. MU cells were exclusively positive for a myeloid cell marker (CD13) but not for T-cell markers, despite the presence of T-cell receptor gene rearrangement. CONCLUSION: The established ATL cell line showed both T-cell and myeloid cell characteristics, which seems to be the first evidence for the close association of ATL cells with both lymphoid and myeloid features. The cell line may provide a new insight for the targets of HTLV-1 infection and transformation in vivo.

Methods for immunoblot detection and electron microscopic localization of septin subunits in mammalian nervous systems.

The minimal functional units of the mammalian septin system are diverse heterooligomers of SEPT1-14 subunits, which are most abundantly and differentially expressed in postmitotic neurons and glia. The subunit compositions of such heterooligomers are thought to differentiate their affinity for other proteins and lipids, and subcellular localization. Thus, high-precision quantification and mapping of each subunit is necessary to understand their subcellular functions and physiological roles. However, systematic information on the localization of individual septin subunits in the mammalian nervous system is limited. Here, we present our experimental workflows for the study of septin expression and localization in the rodent brain by immunoblot and serial section immunoelectron microscopy. Our protocols, based on standard methods, have been rigorously optimized and simplified for universality and reproducibility to aid non-experts in the field.

Immunochemical determinant and serological specificity of Candida krusei.

We have investigated the chemical structure of the antigenic determinant of Candida krusei cell-wall mannan. Acetolysis of the mannan, obtained by extraction with alkali and purified as copper complex, gave five oligosaccharides (from mono- to pentasaccharide) and a minor amount of an octasaccharide. Partial acetolysis of the mannan gave a large amount of mannooctaose. We have examined the inhibition by these oligosaccharides of the precipitin reaction between anti-Candida krusei serum and homologous mannan, and found that the mannooctaose was the most effective inhibitor. Results obtained by proton magnetic resonance spectroscopy, methylation analysis, and other structural studies of Candida krusei mannan, suggest that the octasaccharide possesses six alpha (1-2) linkages and one alpha (1-6) linkage located in the middle of the chain, and that this mannooctaose may be responsible for the specificity of Candida krusei cell-wall mannan.

Apoptosis of pregnancy-dependent mammary tumor and transplantable pregnancy-dependent mammary tumor in mice.

Pregnancy-dependent mammary tumors (PDMT) of GR/A mice and transplantable PDMT (TPDMT-4 line) in DDD mice, are exceptionally stable in hormone dependence, continue to grow until parturition and regress soon after delivery. In order to study the regression mechanism of PDMT and TPDMT-4, morphological and biochemical changes were examined in the tumors removed on day 18 (TPDMT-4) or day 20 (PDMT) of pregnancy, and on the expected parturient and the following postpartum days. DNA fragmentation occurred from day 18 (TPDMT-4) or day 20 (PDMT) of pregnancy to the day after parturition. Apoptotic cells were demonstrated by an in situ 3'-end labeling method, and the plateau of the number of apoptotic cells was observed on the parturient day in PDMT and on the day after parturition in TPDMT-4. Reverse transcriptase polymerase chain reaction showed that expression of Fas was slightly increased but that of bcl-2 was decreased during the process of involution of TPDMT-4 and PDMT. These results suggest that both an increase in expression of Fas and decrease in expression of bcl-2 are involved in the apoptosis of pregnancy-dependent mammary tumor cells after parturition.

Mouse anococcygeus muscle: sexual dimorphism and responsiveness to sex hormones.

The anococcygeus muscle (AcM) is one of a pair of thin sheets of smooth muscle inserting on the rectum, having a tendinous origin largely on sacral vertebrae. The cross-sectional area of AcM in the juxtarectal region in 90-day-old male mice was significantly larger than that in females of three strains: BALB/cCrgl, ICR/Jcl and C57BL/Tw. The AcM area in female mice showed strain differences: BALB/c > ICR > C57BL. Five daily injections of testosterone into newborn ICR mice from the day of birth significantly increased the areas of AcM in both sexes at 30 days of age, but five daily injections of oestradiol-17 beta (OE) decreased them. The AcM area in 60-day-old ICR male mice castrated at 30 days of age was significantly smaller than in intact males, and that in ovariectomized females was significantly larger than in intact females. In both sexes, implantation of a testosterone pellet (12 mg) into gonadectomized mice on the day of gonadectomy stimulated the growth of AcM, and implantation of an OE pellet (12 mg) inhibited the growth of AcM. The AcM in both ICR and C57BL strains showed positive androgen receptor and oestrogen receptor immunostaining at 15 days. Female ICR mice exposed neonatally to diethylstilboestrol (DES) had significantly larger AcM than controls; ovariectomy at 30 days of age did not change the AcM area in 60-day-old DES-exposed mice. However, male mice exposed neonatally to DES had significantly smaller AcM than controls; castration at 30 days of age nullified this inhibition. These results suggest that both androgen and oestrogen play an important role in sexual dimorphism of the mouse AcM. Neonatal exposure to DES (but not to oestradiol) had an irreversible stimulatory effect on the AcM area in female mice.

Effects of sex hormones on oncogene expression in the vagina and on development of sexual dimorphism of the pelvis and anococcygeus muscle in the mouse.

Neonatal treatment of female mice with diethystilbestrol (DES) is known to induce ovary-independent persistent proliferation and cornification of vaginal epithelium. This irreversibly changed vaginal epithelium persistently expressed higher levels of c-jun and c-fos mRNAs, which was not altered by postpubertal estrogen. Sexual dimorphism was encountered in mouse pelvis and anococcygeus muscle. Postpubertal estrogen changed the shape of the pelvis to the female type and postpubertal androgen changed it to the male type. Neonatal exposure to DES and to the antiestrogen tamoxifen altered the developmental pattern of the pelvis, which contained lower concentrations of calcium and phosphorus than controls. The size of anococcygeus muscle was increased by postpubertal androgen but decreased by postpubertal estrogen. However, neonatal estrogen (DES) exposure permanently enlarged the anococcygeus muscle. Thus, neonatal treatment of mice with estrogen and antiestrogen results in irreversible changes in nonreproductive as well as reproductive structures.

Apoptosis in thyroid tissue from patients with Hashimoto's thyroiditis.

To clarify whether apoptosis of thyroid follicular epithelial cells occurs at the tissue level in autoimmune thyroiditis, 17 specimens of thyroid tissues with Hashimoto's thyroiditis were stained for fragmented DNA. Almost all nuclei of follicular epithelial cells forming atrophic thyroid follicles surrounded by mononuclear cell infiltration and fibrosis showed positive staining. With increasing distance from lymphoid cell follicles, the percentage of follicular epithelial cells with DNA fragmentation-positive nuclei decreased (30-80%). Electron microscopic study revealed the existence of epithelial cells with shrunk and condensed nuclei. The frequency of those cells in different areas was almost compatible with that of cells with fragmentation-positive nuclei. These findings suggest that apoptosis plays an important role in the thyroid tissue injury in autoimmune thyroiditis.

Effects of proteasome inhibitors on the synaptic localization of Vesl-1S/Homer-1a proteins.

The Vesl-1S/Homer-1a proteins are upregulated during seizure and long-term potentiation, but are rapidly degraded by ubiquitin-proteasome systems under normal conditions. We examined the distribution of Vesl-1S proteins in cultured hippocampal neurons. Application of proteasome inhibitors caused accumulation of Vesl-1S immunoreactivity in the neurons which showed a punctate distribution in the cortical regions of the cells, and these puncta were found to be juxtaposed with synaptophysin, a presynaptic, synapse-specific protein. These results suggest that Vesl-1S protein is synaptically targeted.

Antigen-specific suppression of antibody responses by T lymphocytes cytotoxic for antigen-presenting cells.

In this study we demonstrated an alternative model of the antigen (Ag)-specific suppression of antibody response in mice. Splenocytes that were taken from BALB/c mice immunized by i.v. injection of soluble human serum albumin (HSA) or ovalbumin exhibited MHC-restricted Ag-specific cytotoxicity for the respective antigen-presenting cells (APC). When HSA-primed splenocytes cultured with Ag and interleukin-2 (IL-2) were treated with anti-CD4 or anti-CD8 monoclonal antibody (mAb) plus complement, CD8+ and CD4+ T cells exhibited nearly the same level of cytotoxicity against APC. Furthermore, HSA-primed CD4+ and CD8+ T cells released the same amount of interferon-gamma (IFN-gamma) when stimulated with Ag and IL-2. Recombinant IFN-gamma was shown to suppress the in vitro plaque-forming cell (PFC) response to sheep red blood cells (SRBC) only when it was added within 24 h after addition of Ag. The supernatants from both HSA-primed CD4+ and CD8+ T cells suppressed the PFC response to SRBC in vitro, and the suppressive activity was abrogated by anti-IFN-gamma mAb, but increased by anti-IL 4 mAb. These results suggest that in our system the effector cells for Ag-specific suppression of the antibody response in mice are both the cytotoxic type 1 clones (IFN-gamma-producing) of CD4+ and CD8+ T cells for APC, and that IFN-gamma is a major extracellular effector molecule for such suppression.

Multiple mechanisms are involved in apoptotic cell death in the mouse uterus and vagina after ovariectomy.

Withdrawal of sex hormones by gonadectomy results in rapid involution of mouse reproductive organs. To study the regression mechanism in the uterus and vagina after ovariectomy, histologic and biochemical changes were examined. Apoptotic cells were detected by in situ 3'-DNA nick end labeling method and electron microscopy, while the number of cells showing incorporation of bromo-deoxyuridine (BrdU) decreased in the uterus and vagina after ovariectomy. DNA fragmentation in the uterus was observed even at estrus and the degree of fragmentation increased after ovariectomy. DNA fragmentation in the vagina occurred 1-5 days after ovariectomy. Semi-quantitative RT-PCR revealed that expression of Fas-ligand and tumor necrosis factor-alpha (TNF-alpha) mRNA in the uterus and vagina was increased by ovariectomy. These results suggest that apoptotic cell death is induced by ovariectomy through the mediation of both Fas and TNF-alpha in the mouse uterus and vagina; however, uterine and vaginal cells in CBA lpr(cg)/lpr(cg) mice lacking functional Fas showed apoptosis, indicating that Fas is not the sole regulator of apoptosis in female reproductive organs in mice.

Effect of estrogen on ontogenic expression of progesterone and estrogen receptors in rat uterus.

The ontogenic expression of progesterone and estrogen receptors (PR and ER) and effect of estrogen on these receptors were investigated immunohistochemically in rat uterus from the day of birth ( = 0 day) to 30 days of age. Uterine epithelial and stromal cells showed a negative PR immunoreaction at 0 day. The PR in the epithelial cell nuclei appeared by 5 days, while the stromal cells showed a negative PR reaction until 12 days. The staining of the stromal cells appeared from 12 to 15 days. In both the epithelial and stromal cells, the initiation of the PR appearance was not affected by ovariectomy performed at 0 day or 5 days prior to the appearance of PR in the epithelial and stromal cells. Estrogen injections from 0 day failed to initiate the appearance of PR in the epithelial cells, regardless of doses of estradiol-17 beta (0.1, 1 and 10 micrograms daily), but induced PR in the stromal cells. The staining of ER appeared at 5 days in the epithelial cells and at 1 day in the stromal cells, respectively. ER appeared after 2-3 daily injections of estrogen from 0 day depending upon the doses. These results suggest that steroid hormones secreted from neonatal ovary do not play any important role in ontogenic expression of PR during the postnatal uterine maturation.