464 research outputs found
Toward a Risk Management Strategy: A Narrative Review of Methods for Translation of Risk Assessment into Risk Management
Influence of molecular weight, temperature, and extensional rheology on melt blowing process stability for linear isotactic polypropylene
In this work, three linear isotactic polypropylenes with different weight-average molecular weights, M-w, and comparable polydispersities were used to produce nonwovens by melt blowing technology at two different temperatures, T. The air/polymer flow rate was changed to maintain the same average fiber diameter, resulting in a different broadness of fiber diameter distribution, which was quantified by the coefficient of variation, CV. The elasticity of the material was evaluated by the reptation-mode relaxation time, lambda(1), and the Rouse-mode reorientation time, lambda(2), determined from the deformation rate dependent shear viscosity data. Extensional rheology was evaluated using uniaxial extensional viscosity measured over a very wide range of strain rates (2 x 10(4) s(-1)-2 x 10(6) s(-1)) using entrance pressure drop and Gibson methods. An obtained plateau value of uniaxial extensional viscosity at the highest extensional strain rates, eta(E,infinity) (normalized by the three times zero-shear rate viscosity, eta(0)), and the minimum uniaxial extensional viscosity, eta(E,min), were related to M-w and T using simple equations. It has been found that the stability of fiber production captured by CV depends exclusively on the extensional properties of the polypropylene melts, namely, eta(E,U,)infinity/3 eta(0) and eta(E,U,min). These findings are important especially with regard to the stable production of polymeric nanofibers by melt blowing technology
A Digital Coach (E-Supporter 1.0) to Support Physical Activity and a Healthy Diet in People With Type 2 Diabetes:Acceptability and Limited Efficacy Testing
Eletrograma Intramiocárdico na Avaliaçao da Estimulaçao Biventricular para Miocardiopatia Dilatada
Um paciente masculino de 64 anos de idade, com miocardiopatia dilatada, fibrilaçao atrial e bloqueio intraventricular, teve implantado um sistema de marcapasso (MP) composto de um gerador de dupla-câmara Physios CTM 01 e de dois eletrodos: um eletrodo ventricular direito endocárdico modelo PX60-BP e um eletrodo de seio coronário (fixado na veia cardÃaca esquerda) modelo V336 (Biotronik, Berlim). Os eletrodos foram conectados respectivamente ao canal atrial e ventricular do MP, que foi programado em modo DDT com um atraso atrioventricular de 15 ms. A partir dos eletrogramas intracavitários
Eletrograma Intramiocárdico na Avaliaçao da Estimulaçao Biventricular para Miocardiopatia Dilatada
Um paciente masculino de 64 anos de idade, com miocardiopatia dilatada, fibrilaçao atrial e bloqueio intraventricular, teve implantado um sistema de marcapasso (MP) composto de um gerador de dupla-câmara Physios CTM 01 e de dois eletrodos: um eletrodo ventricular direito endocárdico modelo PX60-BP e um eletrodo de seio coronário (fixado na veia cardÃaca esquerda) modelo V336 (Biotronik, Berlim). Os eletrodos foram conectados respectivamente ao canal atrial e ventricular do MP, que foi programado em modo DDT com um atraso atrioventricular de 15 ms. A partir dos eletrogramas intracavitários
Gamma-ray observations of Tycho's SNR with VERITAS and Fermi
High-energy gamma-ray emission from supernova remnants (SNRs) has provided a
unique perspective for studies of Galactic cosmic-ray acceleration. Tycho's SNR
is a particularly good target because it is a young, type Ia SNR that is
well-studied over a wide range of energies and located in a relatively clean
environment. Since the detection of gamma-ray emission from Tycho's SNR by
VERITAS and Fermi-LAT, there have been several theoretical models proposed to
explain its broadband emission and high-energy morphology. We report on an
update to the gamma-ray measurements of Tycho's SNR with 147 hours of VERITAS
and 84 months of Fermi-LAT observations, which represents about a factor of two
increase in exposure over previously published data. About half of the VERITAS
data benefited from a camera upgrade, which has made it possible to extend the
TeV measurements toward lower energies. The TeV spectral index measured by
VERITAS is consistent with previous results, but the expanded energy range
softens a straight power-law fit. At energies higher than 400 GeV, the
power-law index is . It
is also softer than the spectral index in the GeV energy range, , measured by this study using
Fermi--LAT data. The centroid position of the gamma-ray emission is coincident
with the center of the remnant, as well as with the centroid measurement of
Fermi--LAT above 1 GeV. The results are consistent with an SNR shell origin of
the emission, as many models assume. The updated spectrum points to a lower
maximum particle energy than has been suggested previously.Comment: Accepted for publication in The Astrophysical Journa
Discovery of very-high-energy emission from RGB J2243+203 and derivation of its redshift upper limit
Very-high-energy (VHE; 100 GeV) gamma-ray emission from the blazar RGB
J2243+203 was discovered with the VERITAS Cherenkov telescope array, during the
period between 21 and 24 December 2014. The VERITAS energy spectrum from this
source can be fit by a power law with a photon index of , and a
flux normalization at 0.15 TeV of . The integrated
\textit{Fermi}-LAT flux from 1 GeV to 100 GeV during the VERITAS detection is
, which is an order of
magnitude larger than the four-year-averaged flux in the same energy range
reported in the 3FGL catalog, (). The detection with VERITAS
triggered observations in the X-ray band with the \textit{Swift}-XRT. However,
due to scheduling constraints \textit{Swift}-XRT observations were performed 67
hours after the VERITAS detection, not simultaneous with the VERITAS
observations. The observed X-ray energy spectrum between 2 keV and 10 keV can
be fitted with a power-law with a spectral index of , and the
integrated photon flux in the same energy band is . EBL model-dependent upper limits
of the blazar redshift have been derived. Depending on the EBL model used, the
upper limit varies in the range from z to z
Validation of Serum Neurofilament Light Chain as a Biomarker of Parkinson's Disease Progression
Background: The objective of this study
was to assess neurofilament light chain as a Parkinson’s
disease biomarker.
Methods: We quantified neurofilament light chain in
2 independent cohorts: (1) longitudinal cerebrospinal fluid
samples from the longitudinal de novo Parkinson’s disease cohort and (2) a large longitudinal cohort with serum
samples from Parkinson’s disease, other cognate/neurodegenerative disorders, healthy controls, prodromal conditions, and mutation carriers.
Results: In the Parkinson’s Progression Marker Initiative
cohort, mean baseline serum neurofilament light chain
was higher in Parkinson’s disease patients (13 � 7.2
pg/mL) than in controls (12 � 6.7 pg/mL), P = 0.0336.
Serum neurofilament light chain increased longitudinally in
Parkinson’s disease patients versus controls (P < 0.01).
Motor scores were positively associated with neurofilament light chain, whereas some cognitive scores
showed a negative association.
Conclusions: Neurofilament light chain in serum samples is increased in Parkinson’s disease patients versus healthy controls, increases over time and with age,
and correlates with clinical measures of Parkinson’s
disease severity. Although the specificity of neurofilament light chain for Parkinson’s disease is low, it
is the first blood-based biomarker candidate that could
support disease stratification of Parkinson’s disease
versus other cognate/neurodegenerative disorders,
track clinical progression, and possibly assess responsiveness to neuroprotective treatments. However, use of
neurofilament light chain as a biomarker of response
to neuroprotective interventions remains to be assessed
Individual influenza A virus mRNAs show differential dependence on cellular NXF1/TAP for their nuclear export
The influenza A virus RNA-dependent RNA polymerase produces capped and polyadenylated mRNAs in the nucleus of infected cells that resemble mature cellular mRNAs, but are made by very different mechanisms. Furthermore, only two of the 10 viral protein-coding mRNAs are spliced: most are intronless, while two contain unremoved introns. The mechanism(s) by which any of these mRNAs are exported from the nucleus is uncertain. To probe the involvement of the primary cellular mRNA export pathway, we treated cells with siRNAs against NXF1, Aly or UAP56, or with the drug 5,6-dichloro-1-β-d-ribofuranosyl-benzimidazole (DRB), an inhibitor of RNA polymerase II phosphorylation previously shown to inhibit nuclear export of cellular mRNA as well as influenza virus segment 7 mRNAs. Depletion of NXF1 or DRB treatment had similar effects, inhibiting the nuclear export of several of the viral mRNAs. However, differing degrees of sensitivity were seen, depending on the particular segment examined. Intronless HA mRNA and spliced M2 or unspliced M1 transcripts (all encoding late proteins) showed a strong requirement for NXF1, while intronless early gene mRNAs, especially NP mRNA, showed the least dependency. Depletion of Aly had little effect on viral mRNA export, but reduction of UAP56 levels strongly inhibited trafficking and/or translation of the M1, M2 and NS1 mRNAs. Synthesis of NS2 from the spliced segment 8 transcript was, however, resistant. We conclude that influenza A virus co-opts the main cellular mRNA export pathway for a subset of its mRNAs, including most but not all late gene transcripts
Targeting the glycine-rich domain of TDP-43 with antibodies prevents its aggregation in vitro and reduces neurofilament levels in vivo
Cytoplasmic aggregation and concomitant nuclear clearance of the RNA-binding protein TDP-43 are found in similar to 90% of cases of amyotrophic lateral sclerosis and similar to 45% of patients living with frontotemporal lobar degeneration, but no disease-modifying therapy is available. Antibody therapy targeting other aggregating proteins associated with neurodegenerative disorders has shown beneficial effects in animal models and clinical trials. The most effective epitopes for safe antibody therapy targeting TDP-43 are unknown. Here, we identified safe and effective epitopes in TDP-43 for active and potential future passive immunotherapy. We prescreened 15 peptide antigens covering all regions of TDP-43 to identify the most immunogenic epitopes and to raise novel monoclonal antibodies in wild-type mice. Most peptides induced a considerable antibody response and no antigen triggered obvious side effects. Thus, we immunized mice with rapidly progressing TDP-43 proteinopathy (rNLS8 model) with the nine most immunogenic peptides in five pools prior to TDP-43 Delta NLS transgene induction. Strikingly, combined administration of two N-terminal peptides induced genetic background-specific sudden lethality in several mice and was therefore discontinued. Despite a strong antibody response, no TDP-43 peptide prevented the rapid body weight loss or reduced phospho-TDP-43 levels as well as the profound astrogliosis and microgliosis in rNLS8 mice. However, immunization with a C-terminal peptide containing the disease-associated phosphoserines 409/410 significantly lowered serum neurofilament light chain levels, indicative of reduced neuroaxonal damage. Transcriptomic profiling showed a pronounced neuroinflammatory signature (IL-1 beta, TNF-alpha, Nf-kappa B) in rNLS8 mice and suggested modest benefits of immunization targeting the glycine-rich region. Several novel monoclonal antibodies targeting the glycine-rich domain potently reduced phase separation and aggregation of TDP-43 in vitro and prevented cellular uptake of preformed aggregates. Our unbiased screen suggests that targeting the RRM2 domain and the C-terminal region of TDP-43 by active or passive immunization may be beneficial in TDP-43 proteinopathies by inhibiting cardinal processes of disease progression
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