Dark Matter at the Center and in the Halo of the Galaxy

All presently known stellar-dynamical constraints on the size and mass of the supermassive compact dark object at the Galactic center are consistent with a ball of self-gravitating, nearly non-interacting, degenerate fermions with mass between 76 and 491 keV, for degeneracy factor g=2. Sterile neutrinos of 76 keV mass, which are mixed with at least one of the active neutrinos with a mixing angele ~10^{-7}, are produced in about the right amount in the early Universe by incoherent resonant and non-resonant scattering of active neutrinos having asymmetry of ~0.01. The former process yields sterile neutrinos with a quasi-degenerate spectrum while the latter leads to a thermal spectrum. As the production mechanism of the sterile neutrino is consistent with the constraints from large scale structure formation, core collapse supernovae, and diffuse X-ray background, it could be the dark matter particle of the Universe.Comment: 6 pages, to appear in the Beyond 2003 conference proceeding

Validation of an arterial tortuosity measure with application to hypertension collection of clinical hypertensive patients

<p>Abstract</p> <p>Background</p> <p>Hypertension may increase tortuosity or twistedness of arteries. We applied a centerline extraction algorithm and tortuosity metric to magnetic resonance angiography (MRA) brain images to quantitatively measure the tortuosity of arterial vessel centerlines. The most commonly used arterial tortuosity measure is the distance factor metric (DFM). This study tested a DFM based measurement’s ability to detect increases in arterial tortuosity of hypertensives using existing images. Existing images presented challenges such as different resolutions which may affect the tortuosity measurement, different depths of the area imaged, and different artifacts of imaging that require filtering.</p> <p>Methods</p> <p>The stability and accuracy of alternative centerline algorithms was validated in numerically generated models and test brain MRA data. Existing images were gathered from previous studies and clinical medical systems by manually reading electronic medical records to identify hypertensives and negatives. Images of different resolutions were interpolated to similar resolutions. Arterial tortuosity in MRA images was measured from a DFM curve and tested on numerically generated models as well as MRA images from two hypertensive and three negative control populations. Comparisons were made between different resolutions, different filters, hypertensives versus negatives, and different negative controls.</p> <p>Results</p> <p>In tests using numerical models of a simple helix, the measured tortuosity increased as expected with more tightly coiled helices. Interpolation reduced resolution-dependent differences in measured tortuosity. The Korean hypertensive population had significantly higher arterial tortuosity than its corresponding negative control population across multiple arteries. In addition one negative control population of different ethnicity had significantly less arterial tortuosity than the other two.</p> <p>Conclusions</p> <p>Tortuosity can be compared between images of different resolutions by interpolating from lower to higher resolutions. Use of a universal negative control was not possible in this study. The method described here detected elevated arterial tortuosity in a hypertensive population compared to the negative control population and can be used to study this relation in other populations.</p

Baryon Washout, Electroweak Phase Transition, and Perturbation Theory

We analyze the conventional perturbative treatment of sphaleron-induced baryon number washout relevant for electroweak baryogenesis and show that it is not gauge-independent due to the failure of consistently implementing the Nielsen identities order-by-order in perturbation theory. We provide a gauge-independent criterion for baryon number preservation in place of the conventional (gauge-dependent) criterion needed for successful electroweak baryogenesis. We also review the arguments leading to the preservation criterion and analyze several sources of theoretical uncertainties in obtaining a numerical bound. In various beyond the standard model scenarios, a realistic perturbative treatment will likely require knowledge of the complete two-loop finite temperature effective potential and the one-loop sphaleron rate.Comment: 25 pages, 9 figures; v2 minor typos correcte

Dominant stop-loss <em>HNRNPA1</em> variants in juvenile-onset myopathy

\ua9 2024 The Author(s). Muscle &amp; Nerve published by Wiley Periodicals LLC. Introduction/Aims: Heterogeneous nuclear ribonucleoprotein A1 is involved in nucleic acid homeostatic functions. The encoding gene HNRNPA1 has been associated with several neuromuscular disorders including an amyotrophic lateral sclerosis-like phenotype, distal hereditary motor neuropathy, multisystem proteinopathy, and various myopathies. We report two unrelated individuals with monoallelic stop loss variants affecting the same codon of HNRNPA1. Methods: Two individuals with unsolved juvenile-onset myopathy were enrolled under approved institutional protocols. Phenotype data were collected and genetic analyses were performed, including whole-exome sequencing (WES). Results: The two probands (MNOT002-01 and K1440-01) showed a similar onset of slowly progressive extremity and facial weakness in early adolescence. K1440-01 presented with facial weakness, winged scapula, elevated serum creatine kinase (CK) levels, and mild neck weakness. MNOT002-01 also exhibited elevated CK levels along with facial weakness, cardiomyopathy, respiratory dysfunction, pectus excavatum, a mildly rigid spine, and loss of ambulation. On quadriceps muscle biopsy, K1440-01 displayed rounded myofibers, mild variation in fiber diameter, and type 2 fiber hypertrophy, while MNOT002-01 displayed rimmed vacuoles. Monoallelic stop-loss variants in HNRNPA1 were identified for both probands: c.1119A&gt;C p.*373Tyrext*6 (K1440-01) and c.1118A&gt;C p.*373Serext*6 (MNOT002-01) affect the same codon and are both predicted to lead to the addition of six amino acids before termination at an alternative stop codon. Discussion: Both stop-loss variants in our probands are likely pathogenic. Our findings contribute to the disease characterization of pathogenic variants in HNRNPA1. This gene should be screened in clinical diagnostic testing of unsolved cases of sporadic or dominant juvenile-onset myopathy

Prospective study of intratumoral microvessel density, p53 expression and survival in colorectal cancer

Adjuvant treatment of patients with colorectal cancer is hampered by a lack of reliable prognostic factors in addition to the clinicopathological staging system. A poorly defined but considerable fraction of Astler–Coller stage B patients will experience tumour recurrence, and some of the stage C patients will probably survive for a prolonged time after surgery without adjuvant treatment. Assessing parameters related to tumour angiogenesis has provided valuable prognostic information in different tumour types. The formation of new microvessels is part of the malignant phenotype in the majority of tumours. Alterations in tumour-suppressor genes, such as the p53 gene, or oncogenes, such as the ras gene, have been found to be responsible for changing the local balance of pro- and antiangiogenic factors in favour of the former. In this prospective study, intratumoral microvessel density (IMD) was assessed by immunostaining tissue sections for CD31 and counting individual microvessels in selected and highly vascular regions in specimens of 145 colorectal cancer patients. p53 protein overexpression was semiquantitatively determined after immunohistochemistry. In both uni- and multivariate analysis, high IMD was significantly associated with shorter survival in the patients undergoing surgery with curative intent (Astler–Coller stages A–C). p53 added prognostic power to IMD, both in Astler–Coller stage B and stage C patients. An association between IMD and mode of metastasis was also noted. High IMD was strongly associated with the incidence of haematogenous metastasis during follow-up, but not with the presence of lymphogenic metastasis observed at surgery. This study confirms the results of previous retrospective analyses of IMD and survival in colorectal cancer and warrants a clinical validation by randomizing stage B tumour patients with high IMD and p53 overexpression between adjuvant treatment or not. © 1999 Cancer Research Campaig

The stellar halo of the Galaxy

Stellar halos may hold some of the best preserved fossils of the formation history of galaxies. They are a natural product of the merging processes that probably take place during the assembly of a galaxy, and hence may well be the most ubiquitous component of galaxies, independently of their Hubble type. This review focuses on our current understanding of the spatial structure, the kinematics and chemistry of halo stars in the Milky Way. In recent years, we have experienced a change in paradigm thanks to the discovery of large amounts of substructure, especially in the outer halo. I discuss the implications of the currently available observational constraints and fold them into several possible formation scenarios. Unraveling the formation of the Galactic halo will be possible in the near future through a combination of large wide field photometric and spectroscopic surveys, and especially in the era of Gaia.Comment: 46 pages, 16 figures. References updated and some minor changes. Full-resolution version available at http://www.astro.rug.nl/~ahelmi/stellar-halo-review.pd

Direct Observation of Defects and Increased Ion Permeability of a Membrane Induced by Structurally Disordered Cu/Zn-Superoxide Dismutase Aggregates

Interactions between protein aggregates and a cellular membrane have been strongly implicated in many protein conformational diseases. However, such interactions for the case of Cu/Zn superoxide dismutase (SOD1) protein, which is related to fatal neurodegenerative disorder amyotrophic lateral sclerosis (ALS), have not been explored yet. For the first time, we report the direct observation of defect formation and increased ion permeability of a membrane induced by SOD1 aggregates using a supported lipid bilayer and membrane patches of human embryonic kidney cells as model membranes. We observed that aggregated SOD1 significantly induced the formation of defects within lipid membranes and caused the perturbation of membrane permeability, based on surface plasmon resonance spectroscopy, atomic force microscopy and electrophysiology. In the case of apo SOD1 with an unfolded structure, we found that it bound to the lipid membrane surface and slightly perturbed membrane permeability, compared to other folded proteins (holo SOD1 and bovine serum albumin). The changes in membrane integrity and permeability were found to be strongly dependent on the type of proteins and the amount of aggregates present. We expect that the findings presented herein will advance our understanding of the pathway by which structurally disordered SOD1 aggregates exert toxicity in vivo

The effects of tea extracts on proinflammatory signaling

BACKGROUND: Skin toxicity is a common side effect of radiotherapy for solid tumors. Its management can cause treatment gaps and thus can impair cancer treatment. At present, in many countries no standard recommendation for treatment of skin during radiotherapy exists. In this study, we explored the effect of topically-applied tea extracts on the duration of radiation-induced skin toxicity. We investigated the underlying molecular mechanisms and compared effects of tea extracts with the effects of epigallocatechin-gallate, the proposed most-active moiety of green tea. METHODS: Data from 60 patients with cancer of the head and neck or pelvic region topically treated with green or black tea extracts were analyzed retrospectively. Tea extracts were compared for their ability to modulate IL-1β, IL-6, IL-8, TNFα and PGE(2 )release from human monocytes. Effects of tea extracts on 26S proteasome function were assessed. NF-κB activity was monitored by EMSAs. Viability and radiation response of macrophages after exposure to tea extracts was measured by MTT assays. RESULTS: Tea extracts supported the restitution of skin integrity. Tea extracts inhibited proteasome function and suppressed cytokine release. NF-κB activity was altered by tea extracts in a complex, caspase-dependent manner, which differed from the effects of epigallocatechin-gallate. Additionally, both tea extracts, as well as epigallocatechin-gallate, slightly protected macrophages from ionizing radiation CONCLUSION: Tea extracts are an efficient, broadly available treatment option for patients suffering from acute radiation-induced skin toxicity. The molecular mechanisms underlying the beneficial effects are complex, and most likely not exclusively dependent on effects of tea polyphenols such as epigallocatechin-gallate