Comparison of the oxidative reactivity of recombinant fetal and adult human hemoglobin: implications for the design of hemoglobin-based oxygen carriers.

Hemoglobin based oxygen carriers (HBOCs) have been engineered to replace or augment the oxygen carrying capacity of erythrocytes. However, clinical results have generally been disappointing due, in part due to the intrinsic oxidative toxicity of hemoglobin. The most common HBOC starting material is adult human or bovine hemoglobin. However, it has been suggested that fetal hemoglobin may offer advantages due to decreased oxidative reactivity. Large scale manufacturing of a HBOC will likely ultimately require recombinant sources of human proteins. We therefore directly compared the functional properties and oxidative reactivity of recombinant fetal (rHbF) and recombinant adult (rHbA) hemoglobin. rHbA and rHbF produced similar yields of purified functional protein. No differences were seen in the two proteins in: autoxidation rate; the rate of hydrogen peroxide reaction; NO scavenging dioxygenase activity; and the NO producing nitrite reductase activity. The rHbF protein was: less damaged by low levels of hydrogen peroxide; less damaging when added to human umbilical vein endothelial cells (HUVEC) in the ferric form; and had a slower rate of intrinsic heme loss. The rHbA protein was: more readily reducible by plasma antioxidants such as ascorbate in both the reactive ferryl and ferric states; less readily damaged by lipid peroxides; and less damaging to phosphatidylcholine liposomes. In conclusion in terms of oxidative reactivity there are advantages and disadvantages to the use of recombinant adult or fetal Hb as the basis for an effective HBOC

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

Inarticulate Forgiveness

Influentially, Pamela Hieronymi has argued that any account of forgiveness must be both articulate and uncompromising. It must articulate the change in judgement that results in the forgiver’s loss of resentment without excusing or justifying the misdeed, and without comprising a commitment to the transgressor=s responsibility, the wrongness of the action, and the transgressed person=s self-worth. Non-articulate accounts of forgiveness, which rely on indirect strategies for reducing resentment (for example, reflecting on the transgressor’s bad childhood) are said to fail to explain forgiveness. I argue that the articulateness condition is not a necessary condition for forgiveness. I respond to numerous objections advanced against non-articulate accounts, including the claim that the resentment-mitigating practices they involve amount to excusing. Appealing to P.F. Strawson=s distinction between objective and participant attitudes, I argue that forgivers can take transgressors to be detrimentally causally shaped by their past while holding him them to be morally responsible

Quorum Sensing in the Dimorphic Fungus \u3ci\u3eCandida albicans\u3c/i\u3e Is Mediated by Farnesol

The inoculum size effect in the dimorphic fungus Candida albicans results from production of an extracellular quorum-sensing molecule (QSM). This molecule prevents mycelial development in both a growth morphology assay and a differentiation assay using three chemically distinct triggers for germ tube formation (GTF): L-proline, N-acetylglucosamine, and serum (either pig or fetal bovine). In all cases, the presence of QSM prevents the yeast-to-mycelium conversion, resulting in actively budding yeasts without influencing cellular growth rates. QSM exhibits general cross-reactivity within C. albicans in that supernatants from strain A72 are active on five other strains of C. albicans and vice versa. The QSM excreted by C. albicans is farnesol (C15H26O; molecular weight, 222.37). QSM is extracellular, and is produced continuously during growth and over a temperature range from 23 to 43°C, in amounts roughly proportional to the CFU/milliliter. Production is not dependent on the type of carbon source nor nitrogen source or on the chemical nature of the growth medium. Both commercial mixed isomer and (E,E)-farnesol exhibited QSM activity (the ability to prevent GTF) at a level sufficient to account for all the QSM activity present in C. albicans supernatants, i.e., 50% GTF at ca. 30 to 35 mM. Nerolidol was ca. two times less active than farnesol. Neither geraniol (C10), geranylgeraniol (C20), nor farnesyl pyrophosphate had any QSM activity

A Rare Case of Primary Cutaneous Signet-Ring Cell Melanoma With Discrepant Findings on Gene Expression Profiling and Chromosomal Microarray Analysis

ABSTRACT: Melanoma with signet ring cell features is an exceptionally rare variant of primary cutaneous and metastatic melanoma. The molecular mechanisms underlying this unusual cytologic phenotype in malignant melanocytes are largely unknown. In this report, we aim to add to the literature by describing the histomorphological, immunophenotypic, gene expression, and cytogenetic findings in 1 recently encountered case

On Eliciting Intelligence from Human Sources: Contextualizing the Scharff-Technique

Three techniques for eliciting intelligence from human sources were examined. Two versions of the Scharff-technique (conceptualized as four tactics) were compared against the Direct Approach (open and direct questions). The Scharff confirmation technique used correct claims to elicit information, and the Scharff disconfirmation/confirmation technique used a mix of correct and incorrect claims. The participants (N = 119) took the role of ‘sources’ holding information about a terrorist attack and tried not to reveal too much or too little information during an interview. The Scharff confirmation resulted in more new information than the Scharff disconfirmation/confirmation and the Direct Approach. The sources in the Scharff conditions had a more difficult time reading the interviewer’s information objectives. The sources in the Scharff conditions underestimated, whereas sources in the Direct Approach overestimated, how much new information they revealed. The study advances previous work and shows that the Scharff-technique is a promising intelligence gathering technique