554 research outputs found
Screening disability insurance applications
This paper investigates the effects of stricter screening of disability insurance applications. A large-scale experiment was setup where in two of the 26 Dutch regions case workers of the disability insurance administration were instructed to screen applications more stringently. The empirical results show that stricter screening reduces long-term sickness absenteeism and disability insurance applications. We find evidence for direct effects of stricter screening on work resumption during the period of sickness absence and for self-screening by potential disability insurance applicants. Stricter screening seems to improve targeting efficiency, without inducing negative spillover effects to the inflow into unemployment insurance. The costs of stricter screening are only a small fraction of the monetary benefits.Disability insurance; experiment; policy evaluation; sickness absenteeism; self-screening
A covalently crosslinked bioink for multi-materials drop-on-demand 3D bioprinting of three-dimensional cell cultures
In vitro three-dimensional (3D) cell models have been accepted to better recapitulate aspects of in vivo organ environment than 2D cell culture. Currently, the production of these complex in vitro 3D cell models with multiple cell types and microenvironments remains challenging and prone to human error. Here we report a versatile bioink comprised of a 4-arm PEG based polymer with distal maleimide derivatives as the main ink component and a bis-thiol species as the activator that crosslinks the polymer to form the hydrogel in less than a second. The rapid gelation makes the polymer system compatible with 3D bioprinting. The ink is combined with a drop-on-demand 3D bioprinting platform consisting of eight independently addressable nozzles and high-throughput printing logic for creating complex 3D cell culture models. The combination of multiple nozzles and fast printing logic enables the rapid preparation of many complex 3D structures comprising multiple hydrogel environments in the one structure in a standard 96-well plate format. The platform compatibility for biological applications was validated using pancreatic ductal adenocarcinoma cancer (PDAC) cells with their phenotypic responses controlled by tuning the hydrogel microenvironment
M1 muscarinic allosteric modulators slow prion neurodegeneration and restore memory loss
This is the final version of the article. Available from American Society for Clinical Investigation via the DOI in this record.The current frontline symptomatic treatment for Alzheimer’s disease (AD) is whole-body upregulation of cholinergic
transmission via inhibition of acetylcholinesterase. This approach leads to profound dose-related adverse effects. An
alternative strategy is to selectively target muscarinic acetylcholine receptors, particularly the M1 muscarinic acetylcholine
receptor (M1 mAChR), which was previously shown to have procognitive activity. However, developing M1 mAChR–selective orthosteric ligands has proven challenging. Here, we have shown that mouse prion disease shows many of the hallmarks
of human AD, including progressive terminal neurodegeneration and memory deficits due to a disruption of hippocampal
cholinergic innervation. The fact that we also show that muscarinic signaling is maintained in both AD and mouse prion
disease points to the latter as an excellent model for testing the efficacy of muscarinic pharmacological entities. The memory deficits we observed in mouse prion disease were completely restored by treatment with benzyl quinolone carboxylic acid (BQCA) and benzoquinazoline-12 (BQZ-12), two highly selective positive allosteric modulators (PAMs) of M1 mAChRs. Furthermore, prolonged exposure to BQCA markedly extended the lifespan of diseased mice. Thus, enhancing hippocampal muscarinic signaling using M1 mAChR PAMs restored memory loss and slowed the progression of mouse prion disease, indicating that this ligand type may have clinical benefit in diseases showing defective cholinergic transmission, such as AD.ABT, AC, and PMS received funding from a Wellcome Trust Collaborative
Award (201529/Z/16/Z). ABT, SJB, AJB, and TMH were
funded through a Medical Research Council programme leader
grant provided by the MRC Toxicology Unit. CCF, LMB, AJM, and
HES were funded by the Eli Lilly Company. JMB received funding
through a Lilly Research Award Program (LRAP) grant (Eli
Lilly). RP received funding from the Marie Curie grant “Extrabrain”
(European Commission). AC is a senior principal research
fellow and PMS a principal research fellow of the National Health
and Medical Research Council of Australia. Tissue samples were
from Randy Woltjer at the Oregon Alzheimer’s Disease Center.
The Oregon Alzheimer’s Disease Center is supported by NIH grant P30AG008017
The role of receptivity in the courtship behavior of Podocnemis erythrocephala in captivity
The courtship behavior of Podocnemis erythrocephala (Red-headed Amazon River Turtle) in captivity was studied to examine female receptivity and male response to female rejection. We observed 20 females and 39 males in 150 sessions (3–6 h/day for a total of 450 h). In 36% of the trials, there was no interaction between males and females, and 20% of the trials resulted in copulations. All males introduced into tanks approached females, and eventually there was aggression among the males. In 48% of the experiments, females also searched for or approached males. When males initially approached females, they either accepted the male’s advances (14%), rejected the male passively (38%), or rejected the male aggressively (48%). In 86% of the cases where males were rejected, 4% attempted to approach females again, and in 51% they were ultimately successful
Calcitonin gene-related peptide (CGRP) and its receptor components in human and rat spinal trigeminal nucleus and spinal cord at C1-level
<p>Abstract</p> <p>Background</p> <p>Calcitonin gene-related peptide (CGRP) has a key role in migraine pathophysiology and is associated with activation of the trigeminovascular system. The trigeminal ganglion, storing CGRP and its receptor components, projects peripheral to the intracranial vasculature and central to regions in the brainstem with Aδ- and C-fibers; this constitutes an essential part of the pain pathways activated in migraine attacks. Therefore it is of importance to identify the regions within the brainstem that processes nociceptive information from the trigeminovascular system, such as the spinal trigeminal nucleus (STN) and the C1-level of the spinal cord. Immunohistochemistry was used to study the distribution and relation between CGRP and its receptor components - calcitonin receptor-like receptor (CLR) and receptor activity modifying protein 1 (RAMP1) - in human and rat STN and at the C1-level, using a set of newly well characterized antibodies. In addition, double-stainings with CGRP and myelin basic protein (MBP, myelin), synaptophysin (synaptic vesicles) or IB4 (C-fibers in general) were performed.</p> <p>Results</p> <p>In the STN, the highest density of CGRP immunoreactive fibers were found in a network around fiber bundles in the superficial laminae. CLR and RAMP1 expression were predominately found in fibers in the spinal trigeminal tract region, with some fibers spanning into the superficial laminae. Co-localization between CGRP and its receptor components was not noted. In C1, CGRP was expressed in fibers of laminae I and II. The CGRP staining was similar in rat, except for CGRP positive neurons that were found close to the central canal. In C1, the receptor components were detected in laminae I and II, however these fibers were distinct from fibers expressing CGRP as verified by confocal microscopy.</p> <p>Conclusions</p> <p>This study demonstrates the detailed expression of CGRP and its receptor components within STN in the brainstem and in the spinal cord at C1-level, and shows the possibility of CGRP acting postjunctionally in these areas putatively involved in primary headaches.</p
Role of voiding and storage symptoms for the quality of life before and after treatment in men with voiding dysfunction
Previous studies on associations between voiding dysfunction and quality of life (QoL) have largely been limited to baseline data. Therefore, we have explored associations between Q (max) and voiding and storage sub-scores of the International Prostate Symptom Score (IPSS) before and after treatment with QoL. Analysis of a single-center database of 2,316 men with voiding dysfunction attributed to benign prostatic hyperplasia undergoing various medical and surgical treatment forms. Q (max) exhibited little correlation with QoL before or after treatment. IPSS inversely correlated with QoL at baseline and after treatment, and IPSS improvements correlated with those of QoL. The associations applied to both the voiding and storage sub-score of the IPSS, with the latter consistently exhibiting somewhat tighter associations. Our post-treatment data support the idea of a cause-effect relationship between voiding symptoms and QoL irrespective of treatment form. While both voiding and storage symptoms contribute to this relationship, storage symptoms play a somewhat greater rol
Active Site Mutations Change the Cleavage Specificity of Neprilysin
Neprilysin (NEP), a member of the M13 subgroup of the zinc-dependent endopeptidase family is a membrane bound peptidase capable of cleaving a variety of physiological peptides. We have generated a series of neprilysin variants containing mutations at either one of two active site residues, Phe563 and Ser546. Among the mutants studied in detail we observed changes in their activity towards leucine5-enkephalin, insulin B chain, and amyloid β1–40. For example, NEPF563I displayed an increase in preference towards cleaving leucine5-enkephalin relative to insulin B chain, while mutant NEPS546E was less discriminating than neprilysin. Mutants NEPF563L and NEPS546E exhibit different cleavage site preferences than neprilysin with insulin B chain and amyloid ß1–40 as substrates. These data indicate that it is possible to alter the cleavage site specificity of neprilysin opening the way for the development of substrate specific or substrate exclusive forms of the enzyme with enhanced therapeutic potential
Studying the Underlying Event in Drell-Yan and High Transverse Momentum Jet Production at the Tevatron
We study the underlying event in proton-antiproton collisions by examining
the behavior of charged particles (transverse momentum pT > 0.5 GeV/c,
pseudorapidity |\eta| < 1) produced in association with large transverse
momentum jets (~2.2 fb-1) or with Drell-Yan lepton-pairs (~2.7 fb-1) in the
Z-boson mass region (70 < M(pair) < 110 GeV/c2) as measured by CDF at 1.96 TeV
center-of-mass energy. We use the direction of the lepton-pair (in Drell-Yan
production) or the leading jet (in high-pT jet production) in each event to
define three regions of \eta-\phi space; toward, away, and transverse, where
\phi is the azimuthal scattering angle. For Drell-Yan production (excluding the
leptons) both the toward and transverse regions are very sensitive to the
underlying event. In high-pT jet production the transverse region is very
sensitive to the underlying event and is separated into a MAX and MIN
transverse region, which helps separate the hard component (initial and
final-state radiation) from the beam-beam remnant and multiple parton
interaction components of the scattering. The data are corrected to the
particle level to remove detector effects and are then compared with several
QCD Monte-Carlo models. The goal of this analysis is to provide data that can
be used to test and improve the QCD Monte-Carlo models of the underlying event
that are used to simulate hadron-hadron collisions.Comment: Submitted to Phys.Rev.
Precision measurement of the top quark mass from dilepton events at CDF II
We report a measurement of the top quark mass, M_t, in the dilepton decay
channel of
using an integrated luminosity of 1.0 fb^{-1} of p\bar{p} collisions collected
with the CDF II detector. We apply a method that convolutes a leading-order
matrix element with detector resolution functions to form event-by-event
likelihoods; we have enhanced the leading-order description to describe the
effects of initial-state radiation. The joint likelihood is the product of the
likelihoods from 78 candidate events in this sample, which yields a measurement
of M_{t} = 164.5 \pm 3.9(\textrm{stat.}) \pm 3.9(\textrm{syst.})
\mathrm{GeV}/c^2, the most precise measurement of M_t in the dilepton channel.Comment: 7 pages, 2 figures, version includes changes made prior to
publication by journa
Measurement of the Ratios of Branching Fractions B(Bs -> Ds pi pi pi) / B(Bd -> Dd pi pi pi) and B(Bs -> Ds pi) / B(Bd -> Dd pi)
Using 355 pb^-1 of data collected by the CDF II detector in \ppbar collisions
at sqrt{s} = 1.96 TeV at the Fermilab Tevatron, we study the fully
reconstructed hadronic decays B -> D pi and B -> D pi pi pi. We present the
first measurement of the ratio of branching fractions B(Bs -> Ds pi pi pi) /
B(Bd -> Dd pi pi pi) = 1.05 pm 0.10 (stat) pm 0.22 (syst). We also update our
measurement of B(Bs -> Ds pi) / B(Bd -> Dd pi) to 1.13 pm 0.08 (stat) pm 0.23
(syst) improving the statistical uncertainty by more than a factor of two. We
find B(Bs -> Ds pi) = [3.8 pm 0.3 (stat) pm 1.3 (syst)] \times 10^{-3} and B(Bs
-> Ds pi pi pi) = [8.4 pm 0.8 (stat) pm 3.2 (syst)] \times 10^{-3}.Comment: 7 pages, 2 figure
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