1,757 research outputs found
Single Molecule Statistics and the Polynucleotide Unzipping Transition
We present an extensive theoretical investigation of the mechanical unzipping
of double-stranded DNA under the influence of an applied force. In the limit of
long polymers, there is a thermodynamic unzipping transition at a critical
force value of order 10 pN, with different critical behavior for homopolymers
and for random heteropolymers. We extend results on the disorder-averaged
behavior of DNA's with random sequences to the more experimentally accessible
problem of unzipping a single DNA molecule. As the applied force approaches the
critical value, the double-stranded DNA unravels in a series of discrete,
sequence-dependent steps that allow it to reach successively deeper energy
minima. Plots of extension versus force thus take the striking form of a series
of plateaus separated by sharp jumps. Similar qualitative features should
reappear in micromanipulation experiments on proteins and on folded RNA
molecules. Despite their unusual form, the extension versus force curves for
single molecules still reveal remnants of the disorder-averaged critical
behavior. Above the transition, the dynamics of the unzipping fork is related
to that of a particle diffusing in a random force field; anomalous,
disorder-dominated behavior is expected until the applied force exceeds the
critical value for unzipping by roughly 5 pN.Comment: 40 pages, 18 figure
New Therapeutic Strategies for Systemic Sclerosis—a Critical Analysis of the Literature
Systemic sclerosis (SSc) is a multi-system disease characterized by skin
fibrosis and visceral disease. Therapy is organ and pathogenesis targeted. In
this review, we describe novel strategies in the treatment of SSc. Utilizing the
MEDLINE and the COCHRANE REGISTRY, we identified open trials, controlled
trials, for treatment of SSc from 1999 to April 2005. We used the terms scleroderma,
systemic sclerosis, Raynaud's phenomenon, pulmonary hypertension,
methotrexate, cyclosporin, tacrolimus, relaxin, low-dose penicillamine, IVIg,
calcium channel blockers, losartan, prazocin, iloprost, N-acetylcysteine, bosentan,
cyclophosphamide, lung transplantation, ACE inhibitors,
anti-thymocyte globulin, and stem cell transplantation. Anecdotal reports were
omitted
Particles and fields in fluid turbulence
The understanding of fluid turbulence has considerably progressed in recent
years. The application of the methods of statistical mechanics to the
description of the motion of fluid particles, i.e. to the Lagrangian dynamics,
has led to a new quantitative theory of intermittency in turbulent transport.
The first analytical description of anomalous scaling laws in turbulence has
been obtained. The underlying physical mechanism reveals the role of
statistical integrals of motion in non-equilibrium systems. For turbulent
transport, the statistical conservation laws are hidden in the evolution of
groups of fluid particles and arise from the competition between the expansion
of a group and the change of its geometry. By breaking the scale-invariance
symmetry, the statistically conserved quantities lead to the observed anomalous
scaling of transported fields. Lagrangian methods also shed new light on some
practical issues, such as mixing and turbulent magnetic dynamo.Comment: 165 pages, review article for Rev. Mod. Phy
Polypharmacy among anabolic-androgenic steroid users: A descriptive metasynthesis
Background: As far as we are aware, no previous systematic review and synthesis of the qualitative/descriptive literature on polypharmacy in anabolic-androgenic steroid(s) (AAS) users has been published. Method: We systematically reviewed and synthesized qualitative/descriptive literature gathered from searches in electronic databases and by inspecting reference lists of relevant literature to investigate AAS users' polypharmacy. We adhered to the recommendations of the UK Economic and Social Research Council's qualitative research synthesis manual and the PRISMA guidelines. Results: A total of 50 studies published between 1985 and 2014 were included in the analysis. Studies originated from 10 countries although most originated from United States (n = 22), followed by Sweden (n = 7), England only (n = 5), and the United Kingdom (n = 4). It was evident that prior to their debut, AAS users often used other licit and illicit substances. The main ancillary/supplementary substances used were alcohol, and cannabis/cannabinoids followed by cocaine, growth hormone, and human chorionic gonadotropin (hCG), amphetamine/meth, clenbuterol, ephedra/ephedrine, insulin, and thyroxine. Other popular substance classes were analgesics/opioids, dietary/nutritional supplements, and diuretics. Our classification of the various substances used by AAS users resulted in 13 main groups. These non-AAS substances were used mainly to enhance the effects of AAS, combat the side effects of AAS, and for recreational or relaxation purposes, as well as sexual enhancement. Conclusions: Our findings corroborate previous suggestions of associations between AAS use and the use of other licit and illicit substances. Efforts must be intensified to combat the debilitating effects of AAS-associated polypharmacy
Colors of 2625 Quasars at 0<z<5 Measured in the Sloan Digital Sky Survey Photometric System
We present an empirical investigation of the colors of quasars in the Sloan
Digital Sky Survey (SDSS) photometric system. The sample studied includes 2625
quasars with SDSS photometry. The quasars are distributed in a 2.5 degree wide
stripe centered on the Celestial Equator covering square degrees.
Positions and SDSS magnitudes are given for the 898 quasars known prior to SDSS
spectroscopic commissioning. New SDSS quasars represent an increase of over
200% in the number of known quasars in this area of the sky. The ensemble
average of the observed colors of quasars in the SDSS passbands are well
represented by a power-law continuum with (). However, the contributions of the bump
and other strong emission lines have a significant effect upon the colors. The
color-redshift relation exhibits considerable structure, which may be of use in
determining photometric redshifts for quasars. The range of colors can be
accounted for by a range in the optical spectral index with a distribution
(95% confidence), but there is a red tail in the
distribution. This tail may be a sign of internal reddening. Finally, we show
that there is a continuum of properties between quasars and Seyfert galaxies
and we test the validity of the traditional division between the two classes of
AGN.Comment: 66 pages, 15 figures (3 color), accepted by A
Chronic exposure to outdoor air pollution and diagnosed cardiovascular disease: meta-analysis of three large cross-sectional surveys
BACKGROUND: Higher exposure to outdoor air pollution is associated with increased cardiopulmonary deaths, but there is limited evidence about the association between outdoor air pollution and diagnosed cardiovascular disease. Our study aimed to estimate the size of the association between long term exposure to outdoor air pollution and prevalent cardiovascular disease.
METHODS: We carried out a cross-sectional analysis of data on more than 19,000 white adults aged 45 and older who participated in three representative surveys of the English population in 1994, 1998 and 2003, examining the relationship between self-reported doctor-diagnosed cardiovascular disease and exposure to outdoor air pollutants using multilevel regression techniques and meta-analysis.
RESULTS: The combined estimates suggested that an increase of 1 microg m-3 in concentration of particulate matter less than 10 microns in diameter was associated with an increase of 2.9% (95% CI -0.6% to 6.5%) in prevalence of cardiovascular disease in men, and an increase of 1.6% (95%CI -2.1% to 5.5%) in women. The year-specific analyses showed strongly positive associations in 2003 between odds of cardiovascular disease in both men and women and exposure to particulate matter but not in 1994 or 1998. We found no consistent associations between exposure to gaseous air pollutants and doctor-diagnosed cardiovascular disease.
CONCLUSION: The associations of prevalent cardiovascular disease with concentration of particulate matter less than 10 microns in diameter, while only weakly positive, were consistent with the effects reported in cohort studies. The results provide evidence of the size of the association between particulate air pollution and the prevalence of cardiovascular disease but no evidence for an association with gaseous pollutants. We found strongly positive associations between particulate matter and cardiovascular disease in 2003 only, which highlights the importance of replicating findings in more than one population
Gene therapy restores dopamine transporter expression and ameliorates pathology in iPSC and mouse models of infantile parkinsonism
Most inherited neurodegenerative disorders are incurable, and often only palliative treatment is available. Precision medicine has great potential to address this unmet clinical need. We explored this paradigm in dopamine transporter deficiency syndrome (DTDS), caused by biallelic loss-of-function mutations in SLC6A3, encoding the dopamine transporter (DAT). Patients present with early infantile hyperkinesia, severe progressive childhood parkinsonism, and raised cerebrospinal fluid dopamine metabolites. The absence of effective treatments and relentless disease course frequently leads to death in childhood. Using patient-derived induced pluripotent stem cells (iPSCs), we generated a midbrain dopaminergic (mDA) neuron model of DTDS that exhibited marked impairment of DAT activity, apoptotic neurodegeneration associated with TNFα-mediated inflammation, and dopamine toxicity. Partial restoration of DAT activity by the pharmacochaperone pifithrin-μ was mutation-specific. In contrast, lentiviral gene transfer of wild-type human SLC6A3 complementary DNA restored DAT activity and prevented neurodegeneration in all patient-derived mDA lines. To progress toward clinical translation, we used the knockout mouse model of DTDS that recapitulates human disease, exhibiting parkinsonism features, including tremor, bradykinesia, and premature death. Neonatal intracerebroventricular injection of human SLC6A3 using an adeno-associated virus (AAV) vector provided neuronal expression of human DAT, which ameliorated motor phenotype, life span, and neuronal survival in the substantia nigra and striatum, although off-target neurotoxic effects were seen at higher dosage. These were avoided with stereotactic delivery of AAV2.SLC6A3 gene therapy targeted to the midbrain of adult knockout mice, which rescued both motor phenotype and neurodegeneration, suggesting that targeted AAV gene therapy might be effective for patients with DTDS
Upregulation of the cell-cycle regulator RGC-32 in Epstein-Barr virus-immortalized cells
Epstein-Barr virus (EBV) is implicated in the pathogenesis of multiple human tumours of lymphoid and epithelial origin. The virus infects and immortalizes B cells establishing a persistent latent infection characterized by varying patterns of EBV latent gene expression (latency 0, I, II and III). The CDK1 activator, Response Gene to Complement-32 (RGC-32, C13ORF15), is overexpressed in colon, breast and ovarian cancer tissues and we have detected selective high-level RGC-32 protein expression in EBV-immortalized latency III cells. Significantly, we show that overexpression of RGC-32 in B cells is sufficient to disrupt G2 cell-cycle arrest consistent with activation of CDK1, implicating RGC-32 in the EBV transformation process. Surprisingly, RGC-32 mRNA is expressed at high levels in latency I Burkitt's lymphoma (BL) cells and in some EBV-negative BL cell-lines, although RGC-32 protein expression is not detectable. We show that RGC-32 mRNA expression is elevated in latency I cells due to transcriptional activation by high levels of the differentially expressed RUNX1c transcription factor. We found that proteosomal degradation or blocked cytoplasmic export of the RGC-32 message were not responsible for the lack of RGC-32 protein expression in latency I cells. Significantly, analysis of the ribosomal association of the RGC-32 mRNA in latency I and latency III cells revealed that RGC-32 transcripts were associated with multiple ribosomes in both cell-types implicating post-initiation translational repression mechanisms in the block to RGC-32 protein production in latency I cells. In summary, our results are the first to demonstrate RGC-32 protein upregulation in cells transformed by a human tumour virus and to identify post-initiation translational mechanisms as an expression control point for this key cell-cycle regulator
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