Mean Field Theory of Spherical Gravitating Systems

Important gaps remain in our understanding of the thermodynamics and statistical physics of self-gravitating systems. Using mean field theory, here we investigate the equilibrium properties of several spherically symmetric model systems confined in a finite domain consisting of either point masses, or rotating mass shells of different dimension. We establish a direct connection between the spherically symmetric equilibrium states of a self-gravitating point mass system and a shell model of dimension 3. We construct the equilibrium density functions by maximizing the entropy subject to the usual constraints of normalization and energy, but we also take into account the constraint on the sum of the squares of the individual angular momenta, which is also an integral of motion for these symmetric systems. Two new statistical ensembles are introduced which incorporate the additional constraint. They are used to investigate the possible occurrence of a phase transition as the defining parameters for each ensemble are altered

Targeting FcRn for immunomodulation: Benefits, risks, and practical considerations

The neonatal fragment crystallizable (Fc) receptor (FcRn) functions as a recycling mechanism to prevent degradation and extend the half-life of IgG and albumin in the circulation. Several FcRn inhibitors selectively targeting IgG recycling are now moving rapidly toward clinical practice in neurology and hematology. These molecules accelerate the destruction of IgG, reducing pathogenic IgG and IgG immune complexes, with no anticipated effects on IgA, IgM, IgE, complement, plasma cells, B cells, or other cells of the innate or adaptive immune systems. FcRn inhibitors have potential for future use in a much wider variety of antibody-mediated autoimmune diseases. Given the imminent clinical use, potential for broader utility, and novel mechanism of action of FcRn inhibitors, here we review data from 4 main sources: (a) currently available activity, safety, and mechanism-of-action data from clinical trials of FcRn inhibitors; (b) other procedures and treatments that also remove IgG (plasma donation, plasma exchange, immunoadsorption); (c) diseases resulting in loss of IgG; and (d) primary immunodeficiencies with potential mechanistic similarities to those induced by FcRn inhibitors. These data have been evaluated to provide practical considerations for the assessment, monitoring, and reduction of any potential infection risk associated with FcRn inhibition, in addition to highlighting areas for future research

Quasi-monocrystalline silicon for low-noise end mirrors in cryogenic gravitational-wave detectors

Mirrors made of silicon have been proposed for use in future cryogenic gravitational-wave detectors, which will be significantly more sensitive than current room-temperature detectors. These mirrors are planned to have diameters of ≈50 cm and a mass of ≈200 kg. While single-crystalline float-zone silicon meets the requirements of low optical absorption and low mechanical loss, the production of this type of material is restricted to sizes much smaller than required. Here we present studies of silicon produced by directional solidification. This material can be grown as quasi-monocrystalline ingots in sizes larger than currently required. We present measurements of a low room-temperature and cryogenic mechanical loss comparable with float-zone silicon. While the optical absorption of our test sample is significantly higher than required, the low mechanical loss motivates research into further absorption reduction in the future. While it is unclear if material pure enough for the transmissive detector input mirrors can be achieved, an absorption level suitable for the highly reflective coated end mirrors seems realistic. Together with the potential to produce samples much larger than ≈50 cm, this material may be of great benefit for realizing silicon-based gravitational-wave detectors

Defining the Critical Hurdles in Cancer Immunotherapy

ABSTRACT: Scientific discoveries that provide strong evidence of antitumor effects in preclinical models often encounter significant delays before being tested in patients with cancer. While some of these delays have a scientific basis, others do not. We need to do better. Innovative strategies need to move into early stage clinical trials as quickly as it is safe, and if successful, these therapies should efficiently obtain regulatory approval and widespread clinical application. In late 2009 and 2010 the Society for Immunotherapy of Cancer (SITC), convened an "Immunotherapy Summit" with representatives from immunotherapy organizations representing Europe, Japan, China and North America to discuss collaborations to improve development and delivery of cancer immunotherapy. One of the concepts raised by SITC and defined as critical by all parties was the need to identify hurdles that impede effective translation of cancer immunotherapy. With consensus on these hurdles, international working groups could be developed to make recommendations vetted by the participating organizations. These recommendations could then be considered by regulatory bodies, governmental and private funding agencies, pharmaceutical companies and academic institutions to facilitate changes necessary to accelerate clinical translation of novel immune-based cancer therapies. The critical hurdles identified by representatives of the collaborating organizations, now organized as the World Immunotherapy Council, are presented and discussed in this report. Some of the identified hurdles impede all investigators, others hinder investigators only in certain regions or institutions or are more relevant to specific types of immunotherapy or first-in-humans studies. Each of these hurdles can significantly delay clinical translation of promising advances in immunotherapy yet be overcome to improve outcomes of patients with cancer

Infection of Semen-Producing Organs by SIV during the Acute and Chronic Stages of the Disease

International audienceBACKGROUND: Although indirect evidence suggests the male genital tract as a possible source of persistent HIV shedding in semen during antiretroviral therapy, this phenomenon is poorly understood due to the difficulty of sampling semen-producing organs in HIV+ asymptomatic individuals. METHODOLOGY/PRINCIPAL FINDINGS: Using a range of molecular and cell biological techniques, this study investigates SIV infection within reproductive organs of macaques during the acute and chronic stages of the disease. We demonstrate for the first time the presence of SIV in the testes, epididymides, prostate and seminal vesicles as early as 14 days post-inoculation. This infection persists throughout the chronic stage and positively correlates with blood viremia. The prostate and seminal vesicles appear to be the most efficiently infected reproductive organs, followed by the epididymides and testes. Within the male genital tract, mostly T lymphocytes and a small number of germ cells harbour SIV antigens and RNA. In contrast to the other organs studied, the testis does not display an immune response to the infection. Testosteronemia is transiently increased during the early phase of the infection but spermatogenesis remains unaffected. CONCLUSIONS/SIGNIFICANCE: The present study reveals that SIV infection of the macaque male genital tract is an early event and that semen-producing organs display differential infection levels and immune responses. These results help elucidate the origin of HIV in semen and constitute an essential base to improving the design of antiretroviral therapies to eradicate virus from semen

Defining the critical hurdles in cancer immunotherapy

Scientific discoveries that provide strong evidence of antitumor effects in preclinical models often encounter significant delays before being tested in patients with cancer. While some of these delays have a scientific basis, others do not. We need to do better. Innovative strategies need to move into early stage clinical trials as quickly as it is safe, and if successful, these therapies should efficiently obtain regulatory approval and widespread clinical application. In late 2009 and 2010 the Society for Immunotherapy of Cancer (SITC), convened an "Immunotherapy Summit" with representatives from immunotherapy organizations representing Europe, Japan, China and North America to discuss collaborations to improve development and delivery of cancer immunotherapy. One of the concepts raised by SITC and defined as critical by all parties was the need to identify hurdles that impede effective translation of cancer immunotherapy. With consensus on these hurdles, international working groups could be developed to make recommendations vetted by the participating organizations. These recommendations could then be considered by regulatory bodies, governmental and private funding agencies, pharmaceutical companies and academic institutions to facilitate changes necessary to accelerate clinical translation of novel immune-based cancer therapies. The critical hurdles identified by representatives of the collaborating organizations, now organized as the World Immunotherapy Council, are presented and discussed in this report. Some of the identified hurdles impede all investigators; others hinder investigators only in certain regions or institutions or are more relevant to specific types of immunotherapy or first-in-humans studies. Each of these hurdles can significantly delay clinical translation of promising advances in immunotherapy yet if overcome, have the potential to improve outcomes of patients with cancer

Cosmological Synergies Enabled by Joint Analysis of Multi-probe data from WFIRST, Euclid, and LSST

WFIRST, Euclid, and LSST are all missions designed to perform dedicated cosmology surveys that offer unprecedented statistical constraining power and control of systematic uncertainties. There is a growing realization that these missions will be significantly more powerful when the data are processed and analyzed in unison

Classification of current anticancer immunotherapies

During the past decades, anticancer immunotherapy has evolved from a promising therapeutic option to a robust clinical reality. Many immunotherapeutic regimens are now approved by the US Food and Drug Administration and the European Medicines Agency for use in cancer patients, and many others are being investigated as standalone therapeutic interventions or combined with conventional treatments in clinical studies. Immunotherapies may be subdivided into “passive” and “active” based on their ability to engage the host immune system against cancer. Since the anticancer activity of most passive immunotherapeutics (including tumor-targeting monoclonal antibodies) also relies on the host immune system, this classification does not properly reflect the complexity of the drug-host-tumor interaction. Alternatively, anticancer immunotherapeutics can be classified according to their antigen specificity. While some immunotherapies specifically target one (or a few) defined tumor-associated antigen(s), others operate in a relatively non-specific manner and boost natural or therapy-elicited anticancer immune responses of unknown and often broad specificity. Here, we propose a critical, integrated classification of anticancer immunotherapies and discuss the clinical relevance of these approaches

Flanking sequence effects within the pyrimidine triple-helix motif characterized by affinity cleaving

Nearest neighbor interactions affect the stabilities of triple-helical complexes. Within a pyrimidine triple-helical motif, the relative stabilities of natural base triplets T·AT, C+GC, and G·TA, as well as triplets, D_3·TA and D_3·CG, containing the nonnatural deoxyribonucleoside 1-(2-deoxy-β-D-ribofuranosyl)-4-(3- benzamido)phenylimidazole (D_3) were characterized by the affinity cleaving method in the context of different flanking triplets (T·AT, T·AT; T·AT, C+GC; C+GC, T·AT; G+GC, C+GC). The T·AT triplet was shown to be insensitive to substitutions in either the 3' or 5' directions, while the relative stabilities of triple helices containing C+GC triplets decreased as the number of adjacent C+GC triplets increased. Triple helices incorporating a G·TA interaction were most stable when this triplet was flanked by two T·AT triplets and were adversely affected when a C+GC triplet was placed in the adjacent 5' direction. Similarly, complexes containing D_3·TA or D_3·CG triplets were most stable when the triplet was flanked by two T·AT triplets but were destabilized when the adjacent 3' neighbor position was occupied with a C+GC triplet. This information regarding sequence composition effects in triple-helix formation establishes a set of guidelines for targeting sequences of double-helical DNA by the pyrimidine triple-helix motif