Sensitivity and performance of the Advanced LIGO detectors in the third observing run

On April 1st, 2019, the Advanced Laser Interferometer Gravitational-Wave Observatory (aLIGO), joined by the Advanced Virgo detector, began the third observing run, a year-long dedicated search for gravitational radiation. The LIGO detectors have achieved a higher duty cycle and greater sensitivity to gravitational waves than ever before, with LIGO Hanford achieving angle-averaged sensitivity to binary neutron star coalescences to a distance of 111 Mpc, and LIGO Livingston to 134 Mpc with duty factors of 74.6% and 77.0% respectively. The improvement in sensitivity and stability is a result of several upgrades to the detectors, including doubled intracavity power, the addition of an in-vacuum optical parametric oscillator for squeezed-light injection, replacement of core optics and end reaction masses, and installation of acoustic mode dampers. This paper explores the purposes behind these upgrades, and explains to the best of our knowledge the noise currently limiting the sensitivity of each detector

The Realm and Frontiers of Mycosis Fungoides

Objectives Chronic renal failure (CRF) is associated with altered systemic arterial tone and hypertension. Myogenic constriction and endothelium-derived hyperpolarizing factor (EDHF)-dependent relaxation represent major vasoregulatory mechanisms in small systemic arteries. Elevated myogenic response and impaired EDHF might participate in the development of essential hypertension; however, their role in CRF-related hypertension is unknown. We investigated whether myogenic response and EDHF are altered in subtotally nephrectornized (sNX) rats and whether these changes are modifiable by chronic treatment with angiotensin-converting enzyme (ACE) inhibitor. Methods In a pressure arteriograph, myogenic constriction and EDHF-mediated relaxation were evaluated in small mesenteric arteries isolated from male Wistar rats 15 weeks after either sham operation (n = 7) (SHAM), sNX (n = 12) or sNX followed by 9 weeks of treatment with lisinopril (sNX + LIS, 2.5 mg/kg, n = 13). Results Surprisingly, myogenic response was reduced in hypertensive CRF rats (maximal myogenic tone: 37 +/- 2 and 18 +/- 4%, P <0.01; peak myogenic index: -0.80 +/- 0.08 and -0.40 +/- 0.12%/mmHg, P <0.05 in SHAM and sNX respectively). At the same time EDHF-mediated relaxation was also impaired (maximal response: 92 +/- 2 and 77 +/- 5%, P <0.01; pD(2): 6.5 +/- 0.1 and 5.9 +/- 0.1, P <0.05). Both myogenic response and EDHF were inversely related to the severity of renal failure and restored by treatment with lisinopril to levels found in SHAM animals. Conclusion Major constrictive (myogenic) and dilatory (EDHF) mechanisms of small systemic arteries are impaired in hypertensive CRF rats. These alterations do not seem to participate in the development of hypertension, being rather directly related to the severity of renal impairment. Both systemic vascular changes might be restored by renoprotective treatment with ACE inhibitor

Potential Receptors for Targeted Imaging of Lymph Node Metastases in Penile Cancer

Imaging modalities using tumor-directed monoclonal antibodies may be of value to improve the pre- and intraoperative detection and resection of lymph node (LN) metastatic disease in penile squamous cell carcinoma (PSCC). We investigated the expression of prostate-specific membrane antigen (PSMA), vascular endothelial growth factor (VEGF), epidermal growth factor receptor (EGFR) and epithelial cell adhesion molecule (EpCAM) to analyze their potency for diagnostic applications. Antigen expression was determined in primary tumors and LNs with and without metastases of 22 patients with PSCC. The total immunostaining score (TIS, 0-12) was determined as the product of a proportion score (PS, 0-4) and an intensity score (IS, 0-3). EGFR and VEGF expression were high in primary tumor (median TIS 8) and LN metastases (median TIS 6 and 8, respectively). No EGFR expression was seen in LNs without metastases. However, LNs without metastases did show VEGF expression (median TIS 6). No EpCAM or PSMA expression was seen in PSCC. This study shows that VEGF and EGFR expression is moderate to high in LN metastases of PSCC. Both VEGF and EGFR warrant further clinical evaluation to determine their value as a target for pre- and intraoperative imaging modalities in the detection of LN metastases in PSCC

Author index for volume 286

Susceptibility to renal injury varies among individuals. Previously, we found that individual endothelial function of healthy renal arteries in vitro predicted severity of renal damage after 5/6 nephrectomy. Here we hypothesized that individual differences in endothelial function in vitro and renal perfusion in vivo predict the severity of renal damage in a model of adriamycin-induced nephropathy. In three separate studies, the following baseline parameters were measured in healthy male Wistar rats: (1) acetylcholine (ACh)-induced relaxation in small renal arteries in vitro (n = 16) and the contribution of prostaglandins, nitric oxide (NO) and endothelium-dependent hyperpolarizing factor (EDHF) to the relaxation; (2) glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) in spontaneously voiding rats in vivo (n = 16) and (3) the acute effect of the NO-synthase inhibitor N(G)-nitro-l-arginine methyl ester (L-NAME, n = 12) on renal blood flow (RBF) as compared to vehicle infusion (n = 9). Following these measurements, adriamycin (1.75 mg/kg i.v.) was injected and subsequent renal damage after 6 weeks was related to the baseline parameters. Total ACh-induced (r = 0.51, P <0.05) and EDHF-mediated relaxation (r = 0.68, P <0.05), as well as ERPF (r = 0.66, P <0.01), positively correlated with the severity of proteinuria 6 weeks after injection. In contrast, pronounced baseline NO-mediated dilation was associated with lower proteinuria (r = 0.71, P <0.01). Nevertheless, an acute L-NAME infusion, strongly reducing RBF by 22 +/- 8%, during adriamycin administration provided protection against the development of proteinuria. Individual animals with pronounced baseline endothelial dilatory ability measured in vitro and high ERPF in vivo are vulnerable to renal damage after the adriamycin injection. Acute inhibition of NO during adriamycin administration, resulting in a decrease of RBF, protects against renal injury, probably by limiting the delivery of the drug to the kidney. Therefore, interindividual variability in renal haemodynamics might be crucially involved in susceptibility to nephrotoxic renal damag

Sensitivity and performance of the Advanced LIGO detectors in the third observing run

On April 1st, 2019, the Advanced Laser Interferometer Gravitational-Wave Observatory (aLIGO), joined by the Advanced Virgo detector, began the third observing run, a year-long dedicated search for gravitational radiation. The LIGO detectors have achieved a higher duty cycle and greater sensitivity to gravitational waves than ever before, with LIGO Hanford achieving angle-averaged sensitivity to binary neutron star coalescences to a distance of 111 Mpc, and LIGO Livingston to 134 Mpc with duty factors of 74.6% and 77.0% respectively. The improvement in sensitivity and stability is a result of several upgrades to the detectors, including doubled intracavity power, the addition of an in-vacuum optical parametric oscillator for squeezed-light injection, replacement of core optics and end reaction masses, and installation of acoustic mode dampers. This paper explores the purposes behind these upgrades, and explains to the best of our knowledge the noise currently limiting the sensitivity of each detector. © 2020 authors. Published by the American Physical Society

Immune checkpoint inhibitor treatment induces colitis with heavy infiltration of CD8+T cells and an infiltration pattern that resembles ulcerative colitis

Colitis is a common, but poorly understood, adverse event of immune checkpoint inhibitors that are standard-of-care for an expanding range of cancer types. This explorative study aimed to describe the immune infiltrates in the colon from individuals developing checkpoint inhibitor colitis and compare them to well-known immunophenotypes of acute graft-versus-host disease, ulcerative colitis, and Crohn’s disease. Colon biopsies (n = 20 per group) of patients with checkpoint inhibitor colitis, acute graft-versus-host disease, ulcerative colitis and Crohn’s disease, all colitis treatment-naïve, and of individuals with a normal colon were analyzed using immunohistochemistry: CD8 for cytotoxic T cells, CD4 for T helper cells, and CD68 to identify cells of macrophage lineage. CD8 + T cell, CD4 + T cell, and CD68 + cell counts were performed. Cell infiltration was scored as scattered/patchy or band-like in the superficial and deep gut mucosa. Checkpoint inhibitor colitis was found to be heavily infiltrated by CD8 + T cells. Comparative analysis between groups showed that both CD8 + T cell counts (P < 0.01) and immune cell infiltration patterns in checkpoint inhibitor colitis were most similar to those observed in ulcerative colitis, with a deep band-like CD4 + T cell infiltration pattern and a superficial band-like CD68 + cell infiltration pattern in both. In conclusion, this is the first immunohistopathological study comparing infiltrate characteristics of checkpoint inhibitor colitis, acute graft-versus-host disease, ulcerative colitis, and Crohn’s disease. Checkpoint inhibitor colitis samples are heterogeneous, heavily infiltrated by CD8 + T cells, and show an immune cell infiltration pattern that is more similar to ulcerative colitis than to colonic acute graft-versus-host disease or colonic Crohn’s disease. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00428-021-03170-x

Sub-hertz optomechanically induced transparency with a kilogram-scale mechanical oscillator

Optical interferometers with suspended mirrors are the archetype of all current audio-frequency gravitational-wave detectors. The radiation pressure interaction between the motion of the mirrors and the circulating optical field in such interferometers represents a pristine form of light-matter coupling, largely due to 30 years of effort in developing high-quality optical materials with low mechanical dissipation. However, in all current suspended interferometers, the radiation pressure interaction is too weak to be useful as a resource, and too strong to be neglected. Here, we demonstrate a meter-long interferometer with suspended mirrors, of effective mass 125 g, where the radiation pressure interaction is enhanced by strong optical pumping to realize a cooperativity of 50. In conjunction with modest resolved-sideband operation, this regime is efficiently probed via optomechanically induced transparency of a weak on-resonant probe. The low resonant frequency and high-Q of the mechanical oscillator allows us to demonstrate transparency windows barely 100 mHz wide at room temperature. Together with a near-unity (≈99.9%) out-coupling efficiency, our system saturates the theoretical delay-bandwidth product, rendering it an optical buffer capable of seconds-long storage times

Homozygous whole body Cbs knockout in adult mice features minimal pathology during ageing despite severe homocysteinemia

Deficiencies in Cystathionine-β-synthase (CBS) lead to hyperhomocysteinemia (HHCy), which is considered a risk factor for cardiovascular, bone and neurological disease. Moreover, CBS is important for the production of cysteine, hydrogen sulfide (H2 S) and glutathione. Studying the biological role of CBS in adult mice has been severely hampered by embryological disturbances and perinatal mortality. To overcome these issues and assess the effects of whole-body CBS deficiency in adult mice, we engineered and characterized a Cre-inducible Cbs knockout model during ageing. No perinatal mortality occurred before Cbs-/- induction at 10 weeks of age. Mice were followed until 90 weeks of age and ablation of Cbs was confirmed in liver and kidney but not in brain. Severe HHCy was observed in Cbs-/- (289 ± 58 µM) but not in Cbs+/- or control mice (<10 µM). Cbs-/- showed impaired growth, facial alopecia, endothelial dysfunction in absence of increased mortality, and signs of liver or kidney damage. CBS expression in skin localized to sebaceous glands and epidermis, suggesting local effects of Cbs-/- on alopecia. Cbs-/- showed increased markers of oxidative stress and senescence but expression of other H2 S producing enzymes (CSE and 3-MST) was not affected. CBS deficiency severely impaired H2 S production capacity in liver, but not in brain or kidney. In summary, Cbs-/- mice presented a mild phenotype without mortality despite severe HHCy. The findings demonstrate that HHCy is not directly linked to development of end organ damage