Is haploid gene expression possible for sperm antigens?

The development of a spermatozoon (sperm) from a spermatid involves a complex process of differentiation during which a variety of new gene products appear. It has been generally assumed that no genetic transcription occurs after meiosis and, if this were so, that all the new sperm proteins would have to be transcribed from stored messenger RNA. However, the biochemical evidence suggests that there is no abrupt change in the rate of RNA synthesis during meiosis and that qualitative changes in RNA synthesis, to the extent that they are known, favor the likelihood of continuing messenger RNA synthesis. Experimental analyses of distorted transmission ratios of t-alleles and unbalanced chromosomal states in males also suggest that genes are expressed in haploid nuclei after meiosis. It is probable that spermatozoa are functionally equivalent in most respects because of intercellular bridges that create a continuous cytoplasm between developing spermatozoa, facilitating an exchange of most post-meiotic gene products. Plasma membrane proteins which are potential antigens might not be shared across the intercellular bridges but the evidence to date for haploid expression of sperm antigens is poor.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/24267/1/0000532.pd

HST NICMOS Observations of the Polarization of NGC 1068

We have observed the polarized light at 2 micron in the center of NGC 1068 with HST NICMOS Camera 2. The nucleus is dominated by a bright, unresolved source, polarized at a level of 6.0 pm 1.2% with a position angle of 122degr pm 1.5degr. There are two polarized lobes extending up to 8'' northeast and southwest of the nucleus. The polarized flux in both lobes is quite clumpy, with the maximum polarization occurring in the southwest lobe at a level of 17% when smoothed to 0.23'' resolution. The perpendiculars to the polarization vectors in these two lobes point back to the intense unresolved nuclear source to within one 0.076'' Camera 2 pixel, thereby confirming that this is the illuminating source of the scattered light and therefore the probable AGN central engine. Whereas the polarization of the nucleus is probably caused by dichroic absorption, the polarization in the lobes is almost certainly caused by scattering, with very little contribution from dichroic absorption. Features in the polarized lobes include a gap at a distance of about 1'' from the nucleus toward the southwest lobe and a ``knot'' of emission about 5'' northeast of the nucleus. Both features had been discussed by ground-based observers, but they are much better defined with the high spatial resolution of NICMOS. The northeast knot may be the side of a molecular cloud that is facing the nucleus, which cloud may be preventing the expansion of the northeast radio lobe at the head of the radio synchrotron-radiation-emitting jet. We also report the presence of two ghosts in the Camera 2 polarizers. These had not been detected previously (Hines et al. 2000) because they are relatively faint and require observations of a source with a large dynamic range.Comment: 17 pages, 4 figure

The On-Orbit Performance of the Galaxy Evolution Explorer

We report the first year on-orbit performance results for the Galaxy Evolution Explorer (GALEX), a NASA Small Explorer that is performing a survey of the sky in two ultraviolet bands. The instrument comprises a 50 cm diameter modified Ritchey-Chretien telescope with a 1.25 degree field of view, selectable imaging and objective grism spectroscopic modes, and an innovative optical system with a thin-film multilayer dichroic beam splitter that enables simultaneous imaging by a pair of photon counting, microchannel plate, delay line readout detectors. Initial measurements demonstrate that GALEX is performing well, meeting its requirements for resolution, efficiency, astrometry, bandpass definition and survey sensitivity.Comment: This paper will be published as part of the Galaxy Evolution Explorer (GALEX) Astrophysical Journal Letters Special Issu

A phase I study of CPI-613 (devimistat) in combination with chemoradiation in patients with pancreatic adenocarcinoma

Background: Local tumor progression is a cause of significant mortality and morbidity in patients with unresectable pancreatic ductal adenocarcinoma (PDAC). Effective approaches to achieve durable local control are urgently needed. Metabolic reprogramming and enhanced mitochondrial function, both hallmarks of PDAC, are known contributors to chemo- and radio-resistance. CPI-613, a lipoic acid analog that selectively inhibits components of the Krebs cycle in tumors, showed promising preclinical synergy in combination with gemcitabine and radiation therapy (gem-RT). Methods: We describe a single-arm, single-center, open-label, phase I study designed to determine the maximumtolerated dose of CPI-613 when used concomitantly with gemcitabine and intensity modulated radiation therapy (IMRT) for local control of PDAC. CPI-613 will be administered once weekly by intravenous infusion over approximately 2 hours at a starting dose of 500 mg/m2 and dose-escalated/de-escalated using a Bayesian optimal interval design. Gemcitabine will be given once weekly at 400 mg/m2 dosage and IMRT as 54 Gray (Gy) in 30 fractions (1.8 Gy per fraction) with five fractions given per week. Up to 24 patients will be enrolled for the study after meeting the following main eligibility criteria, which include: pathologically confirmed PDAC; inoperable disease that by institutional pancreatic multidisciplinary tumor board or multidisciplinary review are considered to benefit from definitive local control of the primary tumor; ECOG of 0-2; and adequate organ and marrow function after completion of intended systemic chemotherapy. The secondary objectives are to determine the recommended phase II dose of CPI-613 when used with gem-RT, safety and tolerability of CPI-613-gem-RT, overall survival, local progression-free survival (PFS), overall PFS, patient-reported quality of life after treatment, and late gastrointestinal toxicities following treatment with CPI-613-gem-RT

Patterns of fatigue in adolescents receiving chemotherapy

Abstract: Purpose/Objectives: To describe patterns of fatigue in adolescents and the impact of fatigue during one month of chemotherapy, to explore variables that affect fatigue, and to explore the feasibility of collecting daily selfreport data in this population. Design: Longitudinal, descriptive. Setting: Two pediatric oncology centers in central Virginia. Sample: 20 adolescents with a variety of cancer diagnoses receiving chemotherapy. Methods: Adolescents described daily fatigue for one month using rating scales and qualitative diaries Main Research Variables: Fatigue severity. Finding: Adolescents commonly reported a peak in fatigue in the days immediately following chemotherapy administration. The most common pattern for adolescents who received chemotherapy on a schedule every three to four weeks was a "declining rollercoaster" pattern, with fatigue severity alternating on a daily basis but gradually declining until chemotherapy was scheduled again. Adolescents who received chemotherapy weekly showed more frequent peaks and troughs (the "yo-yo" pattern) that did not diminish in severity over the weeks of the study. Adolescents associated fatigue with other symptoms, particularly sleep-wake disturbances, pain, and nausea, and frequently reported that fatigue interfered with daily activities. Conclusions: Fatigue commonly bothers adolescents receiving chemotherapy, particularly in the days following chemotherapy administration and when other symptoms are present. Although fatigue interfered with the adolescents' abilities to maintain their usual lifestyles, many still participated in the typical activities of adolescence. Implications for Nursing: Fatigue is a complex and dynamic symptom. Oncology clinicians and researchers should frequently assess fatigue in adolescents receiving chemotherapy and apply timely and tailored interventions to match the factors that contribute to fatigue and influence fatigue severity. Management of fatigue during treatment will help adolescents stay involved in age-related activities and meet developmental milestones. Article: Adolescents diagnosed with cancer represent a group of patients with a unique cancer epidemiology, development profile, and research needs. The population's most common cancers include lymphoma, leukemia, central nervous system cancers, endocrine and germ cell tumors, and sarcomas--a spectrum of cancers different than that seen in adults or in younger childre

A Dynamic Pathway for Calcium-Independent Activation of CaMKII by Methionine Oxidation

SummaryCalcium/calmodulin (Ca2+/CaM)-dependent protein kinase II (CaMKII) couples increases in cellular Ca2+ to fundamental responses in excitable cells. CaMKII was identified over 20 years ago by activation dependence on Ca2+/CaM, but recent evidence shows that CaMKII activity is also enhanced by pro-oxidant conditions. Here we show that oxidation of paired regulatory domain methionine residues sustains CaMKII activity in the absence of Ca2+/CaM. CaMKII is activated by angiotensin II (AngII)-induced oxidation, leading to apoptosis in cardiomyocytes both in vitro and in vivo. CaMKII oxidation is reversed by methionine sulfoxide reductase A (MsrA), and MsrA−/− mice show exaggerated CaMKII oxidation and myocardial apoptosis, impaired cardiac function, and increased mortality after myocardial infarction. Our data demonstrate a dynamic mechanism for CaMKII activation by oxidation and highlight the critical importance of oxidation-dependent CaMKII activation to AngII and ischemic myocardial apoptosis

Amplified B Lymphocyte CD40 Signaling Drives Regulatory B10 Cell Expansion in Mice

Aberrant CD40 ligand (CD154) expression occurs on both T cells and B cells in human lupus patients, which is suggested to enhance B cell CD40 signaling and play a role in disease pathogenesis. Transgenic mice expressing CD154 by their B cells (CD154(TG)) have an expanded spleen B cell pool and produce autoantibodies (autoAbs). CD22 deficient (CD22(-/-)) mice also produce autoAbs, and importantly, their B cells are hyper-proliferative following CD40 stimulation ex vivo. Combining these 2 genetic alterations in CD154(TG)CD22(-/-) mice was thereby predicted to intensify CD40 signaling and autoimmune disease due to autoreactive B cell expansion and/or activation.CD154(TG)CD22(-/-) mice were assessed for their humoral immune responses and for changes in their endogenous lymphocyte subsets. Remarkably, CD154(TG)CD22(-/-) mice were not autoimmune, but instead generated minimal IgG responses against both self and foreign antigens. This paucity in IgG isotype switching occurred despite an expanded spleen B cell pool, higher serum IgM levels, and augmented ex vivo B cell proliferation. Impaired IgG responses in CD154(TG)CD22(-/-) mice were explained by a 16-fold expansion of functional, mature IL-10-competent regulatory spleen B cells (B10 cells: 26.7×10(6)±6 in CD154(TG)CD22(-/-) mice; 1.7×10(6)±0.4 in wild type mice, p<0.01), and an 11-fold expansion of B10 cells combined with their ex vivo-matured progenitors (B10+B10pro cells: 66×10(6)±3 in CD154(TG)CD22(-/-) mice; 6.1×10(6)±2 in wild type mice, p<0.01) that represented 39% of all spleen B cells.These results demonstrate for the first time that the IL-10-producing B10 B cell subset has the capacity to suppress IgG humoral immune responses against both foreign and self antigens. Thereby, therapeutic agents that drive regulatory B10 cell expansion in vivo may inhibit pathogenic IgG autoAb production in humans