Tumor Vasculature in Young and Old Hosts: Scanning Electron Microscopy of Microcorrosion Casts with Microangiography, Light Microscopy and Transmission Electron Microscopy

Tumor growth in vivo is dependent upon new blood vessel formation. When B16-F10 melanoma cells are implanted subcutaneously in young (3 mo) and old (24 mo) C57BL/6 mice the rate of growth is dependent on the age of the mice. This study involved a wide range of histological and microscopic techniques but was limited primarily to the initial phase of tumor growth. Stereological point counting from light microscopy (LM) of standard histological sections has been used to yield data regarding blood content. Tumor-bearing mice were perfused through the aorta with a fixation solution and were infused with a low-viscosity radiopaque gel (Microfil) or resin (Mercox). Soft x-rays of the whole animal were used for identifying the feeding vessels to the tumor. Tumors with Microfil were sliced and used for microangiography and light-microscopic observation while those with resin were used to make corrosion casts for scanning electron microscopy (SEM). The different characteristics of the tumor blood vessels in different aged mice were most obvious through SEM of vascular corrosion casts. In comparison with tumors in young mice those of similar size in old hosts had more necrosis, reduced presence of angiogenic features, decreased vessel density, reduced penetration into the tumor, and enhanced tortuosity of the vessel lumen. Transmission electron microscopy (TEM) revealed incompletely developed wall structure of the vessels regardless of host. The above results are consistent with the hypothesis that retarded angiogenesis may be responsible in part for the limited growth of tumors in old hosts

High-Temperature Deformation During Continental-Margin Subduction & Exhumation: The Ultrahigh-Pressure Western Gneiss Region of Norway

A new dataset for the high-pressure to ultrahigh-pressure Western Gneiss Region allows the definition of distinct structural and petrological domains. Much of the study area is an E-dipping homocline with E-plunging lineations that exposes progressively deeper, more strongly deformed, more eclogite-rich structural levels westward. Although eclogites crop out across the WGR, Scandian deformation is weak and earlier structures are well preserved in the southeastern half of the study area. The Scandian reworking increases westward, culminating in strong Scandian fabrics with only isolated pockets of older structures; the dominant Scandian deformation was coaxial E–W stretching. The sinistrally sheared Møre–Trøndelag Fault Complex and Nordfjord Mylonitic Shear Zone bound these rocks to the north and south. There was moderate top-E, amphibolite-facies deformation associated with translation of the allochthons over the basement along its eastern edge, and the Nordfjord–Sogn Detachment Zone underwent strong lower amphibolite-facies to greenschist-facies top-W shearing. A northwestward increase in exhumation-related melting is indicated by leucosomes with hornblende, plagioclase, and Scandian sphene. In the western 2/3 of the study area, exhumation-related, amphibolite-facies symplectite formation in quartzofeldspathic gneiss postdated most Scandian deformation; further deformation was restricted to slip along biotite-rich foliation planes and minor local folding. That the Western Gneiss Region quartzofeldspathic gneiss exhibits a strong gradient in degree of deformation, implies that continental crust in general need not undergo pervasive deformation during subduction

AD51B in Familial Breast Cancer

Common variation on 14q24.1, close to RAD51B, has been associated with breast cancer: rs999737 and rs2588809 with the risk of female breast cancer and rs1314913 with the risk of male breast cancer. The aim of this study was to investigate the role of RAD51B variants in breast cancer predisposition, particularly in the context of familial breast cancer in Finland. We sequenced the coding region of RAD51B in 168 Finnish breast cancer patients from the Helsinki region for identification of possible recurrent founder mutations. In addition, we studied the known rs999737, rs2588809, and rs1314913 SNPs and RAD51B haplotypes in 44,791 breast cancer cases and 43,583 controls from 40 studies participating in the Breast Cancer Association Consortium (BCAC) that were genotyped on a custom chip (iCOGS). We identified one putatively pathogenic missense mutation c.541C>T among the Finnish cancer patients and subsequently genotyped the mutation in additional breast cancer cases (n = 5259) and population controls (n = 3586) from Finland and Belarus. No significant association with breast cancer risk was seen in the meta-analysis of the Finnish datasets or in the large BCAC dataset. The association with previously identified risk variants rs999737, rs2588809, and rs1314913 was replicated among all breast cancer cases and also among familial cases in the BCAC dataset. The most significant association was observed for the haplotype carrying the risk-alleles of all the three SNPs both among all cases (odds ratio (OR): 1.15, 95% confidence interval (CI): 1.11–1.19, P = 8.88 x 10−16) and among familial cases (OR: 1.24, 95% CI: 1.16–1.32, P = 6.19 x 10−11), compared to the haplotype with the respective protective alleles. Our results suggest that loss-of-function mutations in RAD51B are rare, but common variation at the RAD51B region is significantly associated with familial breast cancer risk

Sensitivity of the Advanced LIGO detectors at the beginning of gravitational wave astronomy

The Laser Interferometer Gravitational Wave Observatory (LIGO) consists of two widely separated 4 km laser interferometers designed to detect gravitational waves from distant astrophysical sources in the frequency range from 10 Hz to 10 kHz. The first observation run of the Advanced LIGO detectors started in September 2015 and ended in January 2016. A strain sensitivity of better than 10−23/Hz−−−√ was achieved around 100 Hz. Understanding both the fundamental and the technical noise sources was critical for increasing the astrophysical strain sensitivity. The average distance at which coalescing binary black hole systems with individual masses of 30  M⊙ could be detected above a signal-to-noise ratio (SNR) of 8 was 1.3 Gpc, and the range for binary neutron star inspirals was about 75 Mpc. With respect to the initial detectors, the observable volume of the Universe increased by a factor 69 and 43, respectively. These improvements helped Advanced LIGO to detect the gravitational wave signal from the binary black hole coalescence, known as GW150914

Search for post-merger gravitational waves from the remnant of the binary neutron star merger GW170817

In Advanced LIGO, detection and astrophysical source parameter estimation of the binary black hole merger GW150914 requires a calibrated estimate of the gravitational-wave strain sensed by the detectors. Producing an estimate from each detector's differential arm length control loop readout signals requires applying time domain filters, which are designed from a frequency domain model of the detector's gravitational-wave response. The gravitational-wave response model is determined by the detector's opto-mechanical response and the properties of its feedback control system. The measurements used to validate the model and characterize its uncertainty are derived primarily from a dedicated photon radiation pressure actuator, with cross-checks provided by optical and radio frequency references. We describe how the gravitational-wave readout signal is calibrated into equivalent gravitational-wave-induced strain and how the statistical uncertainties and systematic errors are assessed. Detector data collected over 38 calendar days, from September 12 to October 20, 2015, contain the event GW150914 and approximately 16 of coincident data used to estimate the event false alarm probability. The calibration uncertainty is less than 10% in magnitude and 10 degrees in phase across the relevant frequency band 20 Hz to 1 kHz

Localization and Broadband Follow-Up of the Gravitational-Wave Transient GW150914

A gravitational-wave (GW) transient was identified in data recorded by the Advanced Laser InterferometerGravitational-wave Observatory (LIGO) detectors on 2015 September 14. The event, initially designated G184098and later given the name GW150914, is described in detail elsewhere. By prior arrangement, preliminary estimatesof the time, significance, and sky location of the event were shared with 63 teams of observers covering radio,optical, near-infrared, X-ray, and gamma-ray wavelengths with ground- and space-based facilities. In this Letter wedescribe the low-latency analysis of the GW data and present the sky localization of the first observed compactbinary merger. We summarize the follow-up observations reported by 25 teams via private Gamma-rayCoordinates Network circulars, giving an overview of the participating facilities, the GW sky localizationcoverage, the timeline, and depth of the observations. As this event turned out to be a binary black hole merger,there is little expectation of a detectable electromagnetic (EM) signature. Nevertheless, this first broadbandcampaign to search for a counterpart of an Advanced LIGO source represents a milestone and highlights the broadcapabilities of the transient astronomy community and the observing strategies that have been developed to pursueneutron star binary merger events. Detailed investigations of the EM data and results of the EM follow-upcampaign are being disseminated in papers by the individual teams

Gata4 Is Required for Formation of the Genital Ridge in Mice

In mammals, both testis and ovary arise from a sexually undifferentiated precursor, the genital ridge, which first appears during mid-gestation as a thickening of the coelomic epithelium on the ventromedial surface of the mesonephros. At least four genes (Lhx9, Sf1, Wt1, and Emx2) have been demonstrated to be required for subsequent growth and maintenance of the genital ridge. However, no gene has been shown to be required for the initial thickening of the coelomic epithelium during genital ridge formation. We report that the transcription factor GATA4 is expressed in the coelomic epithelium of the genital ridge, progressing in an anterior-to-posterior (A-P) direction, immediately preceding an A-P wave of epithelial thickening. Mouse embryos conditionally deficient in Gata4 show no signs of gonadal initiation, as their coelomic epithelium remains a morphologically undifferentiated monolayer. The failure of genital ridge formation in Gata4-deficient embryos is corroborated by the absence of the early gonadal markers LHX9 and SF1. Our data indicate that GATA4 is required to initiate formation of the genital ridge in both XX and XY fetuses, prior to its previously reported role in testicular differentiation of the XY gonadHoward Hughes Medical Institut

Respondent-driven sampling to assess mental health outcomes, stigma and acceptance among women raising children born from sexual violence-related pregnancies in eastern Democratic Republic of Congo

Objectives: Assess mental health outcomes among women raising children from sexual violence-related pregnancies (SVRPs) in eastern Democratic Republic of Congo and stigma toward and acceptance of women and their children. Design: Participants were recruited using respondent-driven sampling. Setting: Bukavu, Democratic Republic of Congo in 2012. Participants: 757 adult women raising children from SVRPs were interviewed. A woman aged 18 and older was eligible for the study if she self-identified as a sexual violence survivor since the start of the conflict (∼1996), conceived an SVRP, delivered a liveborn child and was currently raising the child. A woman was ineligible for the study if the SVRP ended with a spontaneous abortion or fetal demise or the child was not currently living or in the care of the biological mother. Intervention Trained female Congolese interviewers verbally administered a quantitative survey after obtaining verbal informed consent. Outcome measures Symptom criteria for major depressive disorder, post-traumatic stress disorder, anxiety and suicidality were assessed, as well as stigma toward the woman and her child. Acceptance of the woman and child from the spouse, family and community were analysed. Results: 48.6% met symptom criteria for major depressive disorder, 57.9% for post-traumatic stress disorder, 43.3% for anxiety and 34.2% reported suicidality. Women who reported stigma from the community (38.4%) or who reported stigma toward the child from the spouse (42.9%), family (31.8%) or community (38.1%) were significantly more likely to meet symptom criteria for most mental health disorders. Although not statistically significant, participants who reported acceptance and acceptance of their children from the spouse, family and community were less likely to meet symptom criteria. Conclusions: Women raising children from SVRPs experience symptoms of mental health disorders. Programming addressing stigma and acceptance following sexual violence may improve mental health outcomes in this population

Mitochondrial Ubiquitin Ligase MARCH5 Promotes TLR7 Signaling by Attenuating TANK Action

The signaling of Toll-like receptors (TLRs) is the host's first line of defense against microbial invasion. The mitochondrion is emerging as a critical platform for antiviral signal transduction. The regulatory role of mitochondria for TLR signaling remains to be explored. Here, we show that the mitochondrial outer-membrane protein MARCH5 positively regulates TLR7 signaling. Ectopic expression or knockdown of MARCH5 enhances or impairs NF-κB-mediated gene expression, respectively. MARCH5 interacts specifically with TANK, and this interaction is enhanced by R837 stimulation. MARCH5 catalyzes the K63-linked poly-ubiquitination of TANK on its Lysines 229, 233, 280, 302 and 306, thus impairing the ability of TANK to inhibit TRAF6. Mislocalization of MARCH5 abolishes its action on TANK, revealing the critical role of mitochondria in modulating innate immunity. Arguably, this represents the first study linking mitochondria to TLR signaling