Autosomal Dominant Gain-of-function STAT1 Mutation is a Novel Genetic Etiology of Penicillium Marneffei Infection

Symposium / Free Paper 4: ImmunologyConference Theme: Inflammatory Basis of Perinatal and Childhood DiseasesBackground: Penicillium marneffei infection is indigenous to Southeast Asia. Majority of cases occur in patients with AIDS and secondary immunodeficiencies. We previously reported 4 HIV-negative children with chronic mucocutaneous candidiasis (CMC) and severe penicilliosis. Hyper-IgE syndrome was diagnosed in one of them, but extensive genetic studies on IL12-IFNγ axis, CARD9 and AIRE were unrevealing for the rest. Recently, STAT1 hyperphosphorylation causing defective Th1 and Th17 immunity is recognized as a cause of CMC. Objective: To investigate the genetic and functional defects of STAT1 signaling in children affected by penicilliosis. Methods: Targeted sequencing of STAT1 gene or total exome sequencing was performed in 3 patients with CMC and penicilliosis. PBMCs were isolated from patients and normal controls. Intracellular STAT1 phosphorylation (pSTAT1) towards interferon-α and interferon-γ stimulation was evaluated by flow cytometry. Cytokine production in PBMCs towards PMA and ionomycin stimulation was assessed. PBMCs were co-cultured with live Candida albicans and P. marneffei to evaluate interferon-γ response. Results: Heterozygous STAT1 missense mutations were identified in all 3 patients. Two mutations were located in the coiled-coil domain (P1 and P2) and one in the DNA-binding domain (P3). All 3 patients recovered from penicilliosis, but P1 eventually died of fulminant aspergillosis. The percentage of pSTAT1-positive PBMCs induced by interferon-α and interferon-γ was significantly higher in all 3 patients than normal controls, indicating that they had gain-of-function mutations. PBMCs from all patients displayed defective interferon-γ and interleukin-17 production towards PMA and PMA plus ionomycin, respectively. Interferon-γ production induced by C. albicans and P. marneffei in P2 was significantly lower than normal controls. Conclusions: For the first time, we demonstrated STAT1 gain-of-function mutation as an important and novel genetic etiology of invasive mycosis including penicilliosis and aspergillosis. Penicilliosis should be regarded as an indicator disease for primary immunodeficiencies in children without HIV infection unless proven otherwise.published_or_final_versio

National Surveillance of Home-Based HIV Testing Among Australian Gay and Bisexual Men, 2018–2020: Uptake After Commercial Availability of HIV Self-Tests

HIV self-testing allows people to collect samples and test themselves at home, addressing known barriers to facility-based testing. We aimed to measure the uptake of home HIV testing among Australian gay and bisexual men (GBM). Using national cross-sectional data from the Australian Gay Community Periodic Surveys, we assessed trends in home HIV testing among non-HIV positive GBM between 2018 and 2020. Overall, the use of home HIV testing was low, but slightly increased during 2018–2020 (from 0.3 to 0.8%, RR = 1.54, 95%CI = 1.23–1.92, p-trend < 0.001). Testing at home was more likely among non-HIV-positive GBM who were born overseas and recently arrived in Australia, at higher risk of HIV, and infrequent HIV testers. Given the greater use of home testing by men at higher risk of HIV, recent migrants and infrequent testers, all priority groups in Australia’s HIV epidemic, we recommend increasing access to HIV self-testing to enhance uptake in these and other groups of GBM

Towards 1H-MRSI of the human brain at 7T with slice-selective adiabatic refocusing pulses

Contains fulltext : 70576.pdf (publisher's version ) (Closed access)OBJECTIVE: To explore the possibilities of proton spectroscopic imaging (1H-MRSI) of the human brain at 7 Tesla with adiabatic refocusing pulses. MATERIALS AND METHODS: A combination of conventional slice selective excitation and two pairs of slice selective adiabatic refocusing pulses (semi-LASER) results in the formation of an echo from a localized volume. Depending on the used radio frequency (rf) coil efficiency and available rf power, the duration of the adiabatic full passage pulses (AFPs) is adapted to enable echo times down to 50 ms (head coil) or 30 ms (local surface coil). RESULTS: An AFP duration of 5 ms with a corresponding bandwidth of 5.1 kHz resulted in a chemical shift displacement error of 23% over 3.8 ppm at 7T. Using a local surface coil and an echo time down to 30 ms, we detected not only the three main metabolites (NAA, Cr and Cho), but also coupled signals from myo-inositol and glutamate/glutamine in spectra from 0.14 cc voxels with linewidths down to 10 Hz in 10 min measurement time. CONCLUSIONS: The semi-LASER pulse sequence enables 1H-MRSI of the human brain at 7T for larger parts of the brain as well as small localized areas with both a high spectral and spatial resolution

Penicillium marneffei infection and impaired IFN-γ immunity in humans with autosomal-dominant gain-of-phosphorylation STAT1 mutations

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The Galactic Magneto-ionic Medium Survey: moments of the Faraday spectra

Faraday rotation occurs along every line of sight in the Galaxy; rotation measure (RM) synthesis allows a 3D representation of the interstellar magnetic field. This study uses data from the Global Magneto-Ionic Medium Survey, a combination of single-antenna spectro-polarimetric studies, including northern sky data from the Dominion Radio Astrophysical Observatory (DRAO) 26 m telescope (1270-1750 MHz) and southern sky data from the Parkes 64 m telescope (300-480 MHz). From the synthesized Faraday spectral cubes we compute the zeroth, first, and second moments to find the total polarized emission, mean RM, and RM width of the polarized emission. From DRAO first moments we find a weak vertical field directed from Galactic North to South, but Parkes data reveal fields directed toward the Sun at high latitudes in both hemispheres: the two surveys clearly sample different volumes. DRAO second moments show feature widths in Faraday spectra increasing with decreasing positive latitudes, implying that longer lines of sight encounter more Faraday rotating medium, but this is not seen at negative latitudes. Parkes data show the opposite: at positive latitudes the second moment decreases with decreasing latitude, but not at negative latitudes. Comparing first moments with RMs of pulsars and extragalactic sources and a study of depolarization together confirm that the DRAO survey samples to larger distances than the Parkes data. Emission regions in the DRAO survey are typically 700-1000 pc away, slightly beyond the scale height of the magneto-ionic medium; emission detected in the Parkes survey is entirely within the magneto-ionic disk, less than 500 pc away

Production of phi mesons at mid-rapidity in sqrt(s_NN) = 200 GeV Au+Au collisions at RHIC

We present the first results of meson production in the K^+K^- decay channel from Au+Au collisions at sqrt(s_NN) = 200 GeV as measured at mid-rapidity by the PHENIX detector at RHIC. Precision resonance centroid and width values are extracted as a function of collision centrality. No significant variation from the PDG accepted values is observed. The transverse mass spectra are fitted with a linear exponential function for which the derived inverse slope parameter is seen to be constant as a function of centrality. These data are also fitted by a hydrodynamic model with the result that the freeze-out temperature and the expansion velocity values are consistent with the values previously derived from fitting single hadron inclusive data. As a function of transverse momentum the collisions scaled peripheral.to.central yield ratio RCP for the is comparable to that of pions rather than that of protons. This result lends support to theoretical models which distinguish between baryons and mesons instead of particle mass for explaining the anomalous proton yield.Comment: 326 authors, 24 pages text, 23 figures, 6 tables, RevTeX 4. To be submitted to Physical Review C as a regular article. Plain text data tables for the points plotted in figures for this and previous PHENIX publications are (or will be) publicly available at http://www.phenix.bnl.gov/papers.htm

Limits on WWZ and WW\gamma couplings from p\bar{p}\to e\nu jj X events at \sqrt{s} = 1.8 TeV

We present limits on anomalous WWZ and WW-gamma couplings from a search for WW and WZ production in p-bar p collisions at sqrt(s)=1.8 TeV. We use p-bar p -> e-nu jjX events recorded with the D0 detector at the Fermilab Tevatron Collider during the 1992-1995 run. The data sample corresponds to an integrated luminosity of 96.0+-5.1 pb^(-1). Assuming identical WWZ and WW-gamma coupling parameters, the 95% CL limits on the CP-conserving couplings are -0.33<lambda<0.36 (Delta-kappa=0) and -0.43<Delta-kappa<0.59 (lambda=0), for a form factor scale Lambda = 2.0 TeV. Limits based on other assumptions are also presented.Comment: 11 pages, 2 figures, 2 table

Through thick or thin: multiple components of the magneto-ionic medium towards the nearby H ɪɪ region Sharpless 2-27 revealed by Faraday tomography

Sharpless 2–27 (Sh2–27) is a nearby H ɪɪ region excited by ζOph. We present observations of polarized radio emission from 300 to 480 MHz towards Sh2–27, made with the Parkes 64 m Radio Telescope as part of the Global Magneto-Ionic Medium Survey. These observations have an angular resolution of 1.35°, and the data are uniquely sensitive to magneto-ionic structure on large angular scales. We demonstrate that background polarized emission towards Sh2–27 is totally depolarized in our observations, allowing us to investigate the foreground. We analyse the results of Faraday tomography, mapping the magnetized interstellar medium along the 165 pc path to Sh2–27. The Faraday dispersion function in this direction has peaks at three Faraday depths. We consider both Faraday thick and thin models for this observation, finding that the thin model is preferred. We further model this as Faraday rotation of diffuse synchrotron emission in the Local Bubble and in two foreground neutral clouds. The Local Bubble extends for 80 pc in this direction, and we find a Faraday depth of −0.8±0.4 rad m-2. This indicates a field directed away from the Sun with a strength of -2.5 ± 1.2 μG. The near and far neutral clouds are each about 30 pc thick, and we find Faraday depths of -6.6 ± 0.6 rad m-2 and +13.7 ± 0.8 rad m-2, respectively. We estimate that the line-of-sight magnetic strengths in the near and far cloud are B∥,near ≈ -15 μG and B∥,far ≈ + 30μG⁠. Our results demonstrate that Faraday tomography can be used to investigate the magneto-ionic properties of foreground features in front of nearby H ɪɪ regions

Search For Heavy Pointlike Dirac Monopoles

We have searched for central production of a pair of photons with high transverse energies in $p\bar p$ collisions at $\sqrt{s} = 1.8$ TeV using $70 pb^{-1}$ of data collected with the D\O detector at the Fermilab Tevatron in 1994--1996. If they exist, virtual heavy pointlike Dirac monopoles could rescatter pairs of nearly real photons into this final state via a box diagram. We observe no excess of events above background, and set lower 95% C.L. limits of $610, 870, or 1580 GeV/c^2$ on the mass of a spin 0, 1/2, or 1 Dirac monopole.Comment: 12 pages, 4 figure