Search for gravitational-lensing signatures in the full third observing run of the LIGO-Virgo network

Gravitational lensing by massive objects along the line of sight to the source causes distortions of gravitational wave-signals; such distortions may reveal information about fundamental physics, cosmology and astrophysics. In this work, we have extended the search for lensing signatures to all binary black hole events from the third observing run of the LIGO--Virgo network. We search for repeated signals from strong lensing by 1) performing targeted searches for subthreshold signals, 2) calculating the degree of overlap amongst the intrinsic parameters and sky location of pairs of signals, 3) comparing the similarities of the spectrograms amongst pairs of signals, and 4) performing dual-signal Bayesian analysis that takes into account selection effects and astrophysical knowledge. We also search for distortions to the gravitational waveform caused by 1) frequency-independent phase shifts in strongly lensed images, and 2) frequency-dependent modulation of the amplitude and phase due to point masses. None of these searches yields significant evidence for lensing. Finally, we use the non-detection of gravitational-wave lensing to constrain the lensing rate based on the latest merger-rate estimates and the fraction of dark matter composed of compact objects

Search for eccentric black hole coalescences during the third observing run of LIGO and Virgo

Despite the growing number of confident binary black hole coalescences observed through gravitational waves so far, the astrophysical origin of these binaries remains uncertain. Orbital eccentricity is one of the clearest tracers of binary formation channels. Identifying binary eccentricity, however, remains challenging due to the limited availability of gravitational waveforms that include effects of eccentricity. Here, we present observational results for a waveform-independent search sensitive to eccentric black hole coalescences, covering the third observing run (O3) of the LIGO and Virgo detectors. We identified no new high-significance candidates beyond those that were already identified with searches focusing on quasi-circular binaries. We determine the sensitivity of our search to high-mass (total mass M>70 M⊙) binaries covering eccentricities up to 0.3 at 15 Hz orbital frequency, and use this to compare model predictions to search results. Assuming all detections are indeed quasi-circular, for our fiducial population model, we place an upper limit for the merger rate density of high-mass binaries with eccentricities 0<e≤0.3 at 0.33 Gpc−3 yr−1 at 90\% confidence level

Ultralight vector dark matter search using data from the KAGRA O3GK run

Among the various candidates for dark matter (DM), ultralight vector DM can be probed by laser interferometric gravitational wave detectors through the measurement of oscillating length changes in the arm cavities. In this context, KAGRA has a unique feature due to differing compositions of its mirrors, enhancing the signal of vector DM in the length change in the auxiliary channels. Here we present the result of a search for U(1)B−L gauge boson DM using the KAGRA data from auxiliary length channels during the first joint observation run together with GEO600. By applying our search pipeline, which takes into account the stochastic nature of ultralight DM, upper bounds on the coupling strength between the U(1)B−L gauge boson and ordinary matter are obtained for a range of DM masses. While our constraints are less stringent than those derived from previous experiments, this study demonstrates the applicability of our method to the lower-mass vector DM search, which is made difficult in this measurement by the short observation time compared to the auto-correlation time scale of DM

Reprogramming of Polycomb-Mediated Gene Silencing in Embryonic Stem Cells by the miR-290 Family and the Methyltransferase Ash1l

Members of the miR-290 family are the most abundantly expressed microRNAs (miRNAs) in mouse embryonic stem cells (ESCs). They regulate aspects of differentiation, pluripotency, and proliferation of ESCs, but the molecular program that they control has not been fully delineated. In the absence of Dicer, ESCs fail to express mature miR-290 miRNAs and have selective aberrant overexpression of Hoxa, Hoxb, Hoxc, and Hoxd genes essential for body plan patterning during embryogenesis, but they do not undergo a full differentiation program. Introduction of mature miR-291 into DCR−/− ESCs restores Hox gene silencing. This was attributed to the unexpected regulation of Polycomb-mediated gene targeting by miR-291. We identified the methyltransferase Ash1l as a pivotal target of miR-291 mediating this effect. Collectively, our data shed light on the role of Dicer in ESC homeostasis by revealing a facet of molecular regulation by the miR-290 family

487 NC410, a fusion protein of LAIR-2 (Leukocyte Associated Immunoglobulin-like Receptor) with human IgG1 Fc, is safe & tolerable with evidence of immune modulation in subjects with advanced solid tumors

BackgroundCollagen and C1q in the extracellular matrix (ECM), are the predominant ligands for LAIR-1, an inhibitory receptor expressed on the cell surface of several immune cell subsets that inhibits immune activation and migration. LAIR-2, a soluble homolog of LAIR-1, competes for binding to collagen and C1q and serves as a natural decoy to promote immune function under normal conditions. Dysregulation of the ECM and increased expression of collagen and C1q within the tumor microenvironment (TME) plays a critical role in promoting tumor progression. NC410 was engineered to overcome this highly immunosuppressive environment by blocking LAIR-1 function, reversing immune suppression, and inducing ECM remodeling to promote immune cell infiltration within the TME.MethodsThis is a first in human, phase 1/2, open-label, single-armed dose-escalation study to determine the safety, tolerability, dose-limiting toxicity (DLT), maximum tolerated dose (MTD), recommended phase 2 dose, preliminary efficacy and to explore pharmacodynamic biomarkers of NC410 (figure 1). Key eligibility criteria include subjects with advanced or metastatic solid tumors with measurable disease based on RECIST v1.1.ResultsAs of 07/22/2021, a total of 16 patients have been enrolled, treated, and completed the DLT period. NC410 (up to 60 mg), was well tolerated, with no safety concerns, infusion-related toxicities, or DLT reported. No anti-drug antibody (ADA) was detected post-NC410 up to 60 mg treatment. As expected, the C1Q level decreased immediately after the NC410 infusion and was replenished after two hours. Evaluation from samples to date available up to cycle 5 suggests that there was no reduction in the baseline C1Q level with subsequent dosing (figure 2). LAIR-2 levels continued to increase in a dose-dependent fashion post-NC410 dosing and marginal increase pre-dose (figure 3). Interestingly, we observed an increase in soluble LAIR-1 over time in a similar pattern to LAIR-2 (figure 4). Furthermore, immunophenotyping of patient whole blood suggests a trend towards an increase in CD4+ and CD8+ T cells including LAIR-1+ T cells in cohort 4, although overall expression levels of LAIR-1 did not appear to increase (ongoing analysis). Cytokines, chemokines, and collagen degradation products (CDP) will be evaluated as potential pharmacodynamic biomarkers as we continue through higher dose cohorts.Abstract 487 Figure 1NC410: study schemaAbstract 487 Figure 2C1Q levels show immediate reduction after NC410 dosing with no accumulated depletionAbstract 487 Figure 3LAIR-2 levels show an increase in dose-dependent fashion after NC410 dosing with marginal increase pre-doseAbstract 487 Figure 4Soluble LAIR-1 levels show a similar pattern to LAIR-2 levelsConclusionsPreliminary evaluation of NC410 in subjects with advanced or metastatic solid tumors appears to be safe and well-tolerated with evidence of immune modulation consistent with predictive PK/PD modeling in a Phase 1/2 open-label study. Further evaluation will be done with increasing doses to confirm these initial findings.Trial RegistrationNCT04408599Ethics ApprovalThis study has been approved by the IRB of all the participating institutions, and all participants have given informed consent before taking part in the study.ConsentWritten informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal

CD55 Deficiency, Early-Onset Protein-Losing Enteropathy, and Thrombosis

BACKGROUND: Studies of monogenic gastrointestinal diseases have revealed molecular pathways critical to gut homeostasis and enabled the development of targeted therapies. METHODS: We studied 11 patients with abdominal pain and diarrhea caused by early-onset protein-losing enteropathy with primary intestinal lymphangiectasia, edema due to hypoproteinemia, malabsorption, and less frequently, bowel inflammation, recurrent infections, and angiopathic thromboembolic disease; the disorder followed an autosomal recessive pattern of inheritance. Whole-exome sequencing was performed to identify gene variants. We evaluated the function of CD55 in patients' cells, which we confirmed by means of exogenous induction of expression of CD55. RESULTS: We identified homozygous loss-of-function mutations in the gene encoding CD55 (decay-accelerating factor), which lead to loss of protein expression. Patients' T lymphocytes showed increased complement activation causing surface deposition of complement and the generation of soluble C5a. Costimulatory function and cytokine modulation by CD55 were defective. Genetic reconstitution of CD55 or treatment with a complement-inhibitory therapeutic antibody reversed abnormal complement activation. CONCLUSIONS: CD55 deficiency with hyperactivation of complement, angiopathic thrombosis, and protein-losing enteropathy (the CHAPLE syndrome) is caused by abnormal complement activation due to biallelic loss-of-function mutations in CD55. (Funded by the National Institute of Allergy and Infectious Diseases and others.)