168 research outputs found
The impact of dose calculation algorithms on partial and whole breast radiation treatment plans
Correction to: The novel compound PBT434 prevents iron mediated neurodegeneration and alpha-synuclein toxicity in multiple models of Parkinson's disease.
Following publication of the original article [1], the author identified an error in Fig. 4E. The data and statistics were correct, but the synaptophysin blot was incorrect. The incorrect (Fig. 1) and correct figure (Fig. 2) are shown in this correction article. (Figure presented.)
The novel compound PBT434 prevents iron mediated neurodegeneration and alpha-synuclein toxicity in multiple models of Parkinson's disease
Elevated iron in the SNpc may play a key role in Parkinson's disease (PD) neurodegeneration since drug candidates with high iron affinity rescue PD animal models, and one candidate, deferirpone, has shown efficacy recently in a phase two clinical trial. However, strong iron chelators may perturb essential iron metabolism, and it is not yet known whether the damage associated with iron is mediated by a tightly bound (eg ferritin) or lower-affinity, labile, iron pool. Here we report the preclinical characterization of PBT434, a novel quinazolinone compound bearing a moderate affinity metal-binding motif, which is in development for Parkinsonian conditions. In vitro, PBT434 was far less potent than deferiprone or deferoxamine at lowering cellular iron levels, yet was found to inhibit iron-mediated redox activity and iron-mediated aggregation of α-synuclein, a protein that aggregates in the neuropathology. In vivo, PBT434 did not deplete tissue iron stores in normal rodents, yet prevented loss of substantia nigra pars compacta neurons (SNpc), lowered nigral α-synuclein accumulation, and rescued motor performance in mice exposed to the Parkinsonian toxins 6-OHDA and MPTP, and in a transgenic animal model (hA53T α-synuclein) of PD. These improvements were associated with reduced markers of oxidative damage, and increased levels of ferroportin (an iron exporter) and DJ-1. We conclude that compounds designed to target a pool of pathological iron that is not held in high-affinity complexes in the tissue can maintain the survival of SNpc neurons and could be disease-modifying in PD
Predictors of Hospitalization for Injection Drug Users Seeking Care for Soft Tissue Infections
BACKGROUND: Soft tissue infections (STIs) from injection drug use are a common cause of Emergency Department visits, hospitalizations, and operating room procedures, yet little is known about factors that may predict the need for these costly medical services. OBJECTIVE: To describe a cohort of injection drug users seeking Emergency Department care for STIs and to identify risk factors associated with hospitalization. We hypothesized that participants who delayed seeking care would be hospitalized more often than those who did not. DESIGN: Cohort study using in-person structured interviews and medical record review. Logistic regression assessed the association between hospital admission and delay in seeking care as well as other demographic, clinical, and psychosocial factors. PARTICIPANTS: Injection drug users who sought Emergency Department care for STIs from May 2001 to March 2002. RESULTS: Of the 136 participants, 55 (40%) were admitted to the hospital. Delay in seeking care was not associated with hospital admission. Participants admitted for their infection were significantly more likely to be living in a shelter (P = .01) and to report being hospitalized 2 or more times in the past year (P < .01). CONCLUSIONS: We identified a subpopulation of injection drug users, mostly living in shelters, who were hospitalized frequently in the past year and who were more likely to be hospitalized for their current infections compared to others. As members of this subpopulation can be easily identified and located, they may benefit from interventions to reduce the health care utilization resulting from these infections
Changed epitopes drive the antigenic drift for influenza A (H3N2) viruses
<p>Abstract</p> <p>Background</p> <p>In circulating influenza viruses, gradually accumulated mutations on the glycoprotein hemagglutinin (HA), which interacts with infectivity-neutralizing antibodies, lead to the escape of immune system (called antigenic drift). The antibody recognition is highly correlated to the conformation change on the antigenic sites (epitopes), which locate on HA surface. To quantify a changed epitope for escaping from neutralizing antibodies is the basis for the antigenic drift and vaccine development.</p> <p>Results</p> <p>We have developed an epitope-based method to identify the antigenic drift of influenza A utilizing the conformation changes on epitopes. A changed epitope, an antigenic site on HA with an accumulated conformation change to escape from neutralizing antibody, can be considered as a "key feature" for representing the antigenic drift. According to hemagglutination inhibition (HI) assays and HA/antibody complex structures, we statistically measured the conformation change of an epitope by considering the number of critical position mutations with high genetic diversity and antigenic scores. Experimental results show that two critical position mutations can induce the conformation change of an epitope to escape from the antibody recognition. Among five epitopes of HA, epitopes A and B, which are near to the receptor binding site, play a key role for neutralizing antibodies. In addition, two changed epitopes often drive the antigenic drift and can explain the selections of 24 WHO vaccine strains.</p> <p>Conclusions</p> <p>Our method is able to quantify the changed epitopes on HA for predicting the antigenic variants and providing biological insights to the vaccine updates. We believe that our method is robust and useful for studying influenza virus evolution and vaccine development.</p
E-readers and the death of the book: or, new media and the myth of the disappearing medium
The recent emergence of e-readers and e-books has b
rought the death of the book to the centre of
current debates on new media. In this article, we a
nalyse alternative narratives that surround the
possibility of the disappearance of print books, do
minated by fetishism, fears about the end of
humanism, and ideas of techno-fundamentalist progre
ss. We argue that, in order to comprehend
such narratives, we need to inscribe them in the br
oader history of media. The emergence of new
media, in fact, has often been accompanied by narra
tives about the possible disappearance of
older media: the introduction of television, for in
stance, inspired claims about the forthcoming
death of film and radio. As a recurrent narrative s
haping the reception of media innovation, the
myth of the disappearing medium helps us to make se
nse of the transformations that media
change provokes in our everyday life
Parasites in the mangrove oyster Crassostrea rhizophorae cultivated in the estuary of the Graciosa River in Taperoá, Bahia
Copper binding to the Alzheimer’s disease amyloid precursor protein
Alzheimer’s disease is the fourth biggest killer in developed countries. Amyloid precursor protein (APP) plays a central role in the development of the disease, through the generation of a peptide called Aβ by proteolysis of the precursor protein. APP can function as a metalloprotein and modulate copper transport via its extracellular copper binding domain (CuBD). Copper binding to this domain has been shown to reduce Aβ levels and hence a molecular understanding of the interaction between metal and protein could lead to the development of novel therapeutics to treat the disease. We have recently determined the three-dimensional structures of apo and copper bound forms of CuBD. The structures provide a mechanism by which CuBD could readily transfer copper ions to other proteins. Importantly, the lack of significant conformational changes to CuBD on copper binding suggests a model in which copper binding affects the dimerisation state of APP leading to reduction in Aβ production. We thus predict that disruption of APP dimers may be a novel therapeutic approach to treat Alzheimer’s disease
Genetic Structure of Human A/H1N1 and A/H3N2 Influenza Virus on Corsica Island: Phylogenetic Analysis and Vaccine Strain Match, 2006–2010
Background: The aim of this study was to analyse the genetic patterns of Hemagglutinin (HA) genes of influenza A strains circulating on Corsica Island during the 2006-2009 epidemic seasons and the 2009-2010 pandemic season. [br/]
Methods: Nasopharyngeal samples from 371 patients with influenza-like illness (ILI) were collected by General Practitioners (GPs) of the Sentinelles Network through a randomised selection routine. [br/]
Results: Phylogenetic analysis of HA revealed that A/H3N2 strains circulating on Corsica were closely related to the WHO recommended vaccine strains in each analyzed season (2006-2007 to 2008-2009). Seasonal Corsican influenza A/H1N1 isolated during the 2007-2008 season had drifted towards the A/Brisbane/59/2007 lineage, the A/H1N1 vaccine strain for the 2008-2009 season. The A/H1N1 2009 (A/H1N1pdm) strains isolated on Corsica Island were characterized by the S220T mutation specific to clade 7 isolates. It should be noted that Corsican isolates formed a separate sub-clade of clade 7 as a consequence of the presence of the fixed substitution D222E. The percentages of the perfect match vaccine efficacy, estimated by using the p(epitope) model, against influenza viruses circulating on Corsica Island varied substantially across the four seasons analyzed, and tend to be highest for A/H1N1 compared with A/H3N2 vaccines, suggesting that cross-immunity seems to be stronger for the H1 HA gene. [br/]
Conclusion: The molecular analysis of the HA gene of influenza viruses that circulated on Corsica Island between 2006-2010 showed for each season the presence of a dominant lineage characterized by at least one fixed mutation. The A/H3N2 and A/H1N1pdm isolates were characterized by multiples fixation at antigenic sites. The fixation of specific mutations at each outbreak could be explained by the combination of a neutral phenomenon and a founder effect, favoring the presence of a dominant lineage in a closed environment such as Corsica Island
TESS Hunt for Young and Maturing Exoplanets (THYME). III. A Two-planet System in the 400 Myr Ursa Major Group
Exoplanets can evolve significantly between birth and maturity as their
atmospheres, orbits, and structures are shaped by their environment. Young
planets (1 Gyr) offer the opportunity to probe these sculpting processes.
However, most of the known young planets orbit prohibitively faint stars. We
present the discovery of two planets transiting HD 63433 (TOI 1726, TIC
130181866), a young Sun-like () star. Through kinematics,
lithium abundance, and rotation, we confirm that HD 63433 is a member of the
Ursa Major moving group ( Myr). Based on the TESS light curve
and updated stellar parameters, the planet radii are and
, the orbital periods are 7.11 and 20.55 days, and the
orbital eccentricities are lower than abut 0.2. Using HARPS-N velocities, we
measure the Rossiter-McLaughlin signal of the inner planet, demonstrating the
orbit is prograde. Since the host star is bright (V=6.9), both planets are
amenable to transmission spectroscopy, radial velocity measurements of their
masses, and more precise determination of the stellar obliquity. This system is
therefore poised to play an important role in our understanding of planetary
system evolution in the first billion years after formation
- …