High fat diets and sedentary lifestyles are becoming major concerns for Western countries. They have led to a growing incidence of obesity, dyslipidemia, high blood pressure, and a condition known as ...the insulin-resistance syndrome or metabolic syndrome. These health conditions are well known to develop along with, or be precursors to atherosclerosis, cardiovascular disease, and diabetes. Recent studies have found that most of these disorders can also be linked to an increased risk of Alzheimer's disease (AD). To complicate matters, possession of one or more apolipoprotein E epsilon4 (APOE epsilon4) alleles further increases the risk or severity of many of these conditions, including AD. ApoE has roles in cholesterol metabolism and Abeta clearance, both of which are thought to be significant in AD pathogenesis. The apparent inadequacies of ApoE epsilon4 in these roles may explain the increased risk of AD in subjects carrying one or more APOE epsilon4 alleles. This review describes some of the physiological and biochemical changes that the above conditions cause, and how they are related to the risk of AD. A diversity of topics is covered, including cholesterol metabolism, glucose regulation, diabetes, insulin, ApoE function, amyloid precursor protein metabolism, and in particular their relevance to AD. It can be seen that abnormal lipid, cholesterol and glucose metabolism are consistently indicated as central in the pathophysiology, and possibly the pathogenesis of AD. As diagnosis of mild cognitive impairment and early AD are becoming more reliable, and as evidence is accumulating that health conditions such as diabetes, obesity, and coronary artery disease are risk factors for AD, appropriate changes to diets and lifestyles will likely reduce AD risk, and also improve the prognosis for people already suffering from such conditions.
ABSTRACT We describe the motivation, design, and implementation of the CORNISH survey, an arcsecond-resolution radio continuum survey of the inner galactic plane at 5 GHz using the Very Large Array ...(VLA). It is a blind survey coordinated with the northern Spitzer GLIMPSE I region covering 10° < l < 65° and |b| < 1° at similar resolution. We discuss in detail the strategy that we employed to control the shape of the synthesised beam across this survey, which covers a wide range of fairly low declinations. Two snapshots separated by 4h kept the beam elongation to less that 1.5 over 75% of the survey area and less than 2 over 98% of the survey. The prime scientific motivation is to provide an unbiased survey for ultra-compact H II regions to study this key phase in massive star formation. A sensitivity around 2 mJy will allow the automatic distinction between radio-loud and radio-quiet mid-IR sources found in the Spitzer surveys. This survey has many legacy applications beyond star formation, including evolved stars, active stars and binaries, and extragalactic sources. The CORNISH survey for compact ionized sources complements other Galactic plane surveys that target diffuse and nonthermal sources, as well as atomic and molecular phases to build up a complete picture of the interstellar medium in the Galaxy.
Swallowing therapy is commonly provided as a treatment to lessen the risk or severity of dysphagia secondary to radiotherapy (RT) for head and neck cancer (HNC); however, best practice is not yet ...established. This trial will compare the effectiveness of prophylactic (high and low intensity) versus reactive interventions for swallowing in patients with HNC undergoing RT.
This multi-site, international randomized clinical trial (RCT) will include 952 adult patients receiving radiotherapy for HNC and who are at high risk for post-RT dysphagia. Participants will be randomized to receive one of three interventions for swallowing during RT: RE-ACTIVE, started promptly if/when dysphagia is identified; PRO-ACTIVE EAT, low intensity prophylactic intervention started before RT commences; or, PRO-ACTIVE EAT+EXERCISE, high intensity prophylactic intervention also started before RT commences. We hypothesize that the PRO-ACTIVE therapies are more effective than late RE-ACTIVE therapy; and, that the more intensive PRO-ACTIVE (EAT + EXERCISE) is superior to the low intensive PRO-ACTIVE (EAT). The primary endpoint of effectiveness is duration of feeding tube dependency one year post radiation therapy, selected as a pragmatic outcome valued equally by diverse stakeholders (e.g., patients, caregivers and clinicians). Secondary outcomes will include objective measures of swallow physiology and function, pneumonia and weight loss, along with various patient-reported swallowing-related outcomes, such as quality of life, symptom burden, and self-efficacy.
Dysphagia is a common and potentially life-threatening chronic toxicity of radiotherapy, and a priority issue for HNC survivors. Yet, the optimal timing and intensity of swallowing therapy provided by a speech-language pathologist is not known. With no clearly preferred strategy, current practice is fraught with substantial variation. The pragmatic PRO-ACTIVE trial aims to specifically address the decisional dilemma of when swallowing therapy should begin (i.e., before or after a swallowing problem develops). The critical impact of this dilemma is heightened by the growing number of young HNC patients in healthcare systems that need to allocate resources most effectively. The results of the PRO-ACTIVE trial will address the global uncertainty regarding best practice for dysphagia management in HNC patients receiving radiotherapy.
The protocol is registered with the US Patient Centered Outcomes Research Institute, and the PRO-ACTIVE trial was prospectively registered at ClinicalTrials.gov , under the identifier NCT03455608 ; First posted: Mar 6, 2018; Last verified: Jun 17, 2021. Protocol Version: 1.3 (January 27, 2020).
The RNA helicase p68 (DDX5) is an established co-activator of the p53 tumour suppressor that itself has a pivotal role in orchestrating the cellular response to DNA damage. Although several factors ...influence the biological outcome of p53 activation, the mechanisms governing the choice between cell-cycle arrest and apoptosis remain to be elucidated. In the present study, we show that, while p68 is critical for p53-mediated transactivation of the cell-cycle arrest gene p21(WAF1/CIP1), it is dispensable for induction of several pro-apoptotic genes in response to DNA damage. Moreover, p68 depletion results in a striking inhibition of recruitment of p53 and RNA Pol II to the p21 promoter but not to the Bax or PUMA promoters, providing an explanation for the selective effect on p21 induction. Importantly, these findings are mirrored in a novel inducible p68 knockout mouse model in which p68 depletion results in a selective inhibition of p21 induction in several tissues. Moreover, in the bone marrow, p68 depletion results in an increased sensitivity to γ-irradiation, consistent with an increased level of apoptosis. These data highlight a novel function of p68 as a modulator of the decision between p53-mediated growth arrest and apoptosis in vitro and in vivo.
Polycyclic aromatic hydrocarbons (PAHs) are carbon-based molecules that are ubiquitous in a variety of astrophysical objects and environments. In this work we use JWST/MIRI MRS spectroscopy of three ...Seyferts to compare their nuclear PAH emission with that of star-forming (SF) regions. This study represents the first of its kind to use sub-arcsecond angular resolution data of local luminous Seyferts (
L
bol
> 10
44.46
erg s
−1
) with a wide wavelength coverage (4.9–28.1 μm). We present an analysis of their nuclear PAH properties by comparing the observed ratios with PAH diagnostic model grids derived from theoretical spectra. Our results show that a suite of PAH features is present in the innermost parts of luminous Seyfert galaxies (∼0.45″ at 12 μm; in the inner ∼142–245 pc). We find that the nuclear regions of active galactic nuclei (AGN) lie at different positions of the PAH diagnostic diagrams, whereas the SF regions are concentrated around the average values of SF galaxies. In particular, we find that the nuclear PAH emission mainly originates in neutral PAHs. In contrast, PAH emission originating in the SF regions favours ionised PAH grains. The observed PAH ratios in the nuclear region of the AGN-dominated galaxy NGC 6552 indicate the presence of larger PAH molecules compared with those of the SF regions. Therefore, our results provide evidence that the AGN have a significant impact on the ionisation state (and probably the size) of the PAH grains on scales of ∼142–245 pc.
•Domex 355MC steel plates modelled in LS-DYNA.•Load applied as experimental load curves and using MMALE.•Validated model used to derive energy equivalent uniform impulse.•Parametric study shows ...strong correlation between plate deformation and energy equivalent impulse.
Recent experimental work by the current authors has provided highly spatially and temporally resolved measurements of the loading imparted to, and the subsequent dynamic response of, structures subjected to near-field explosive loading 1. In this article we validate finite element models of plates subjected to near-field blast loads and perform a parametric study into the relationship between imparted load and peak and residual plate deformation. The energy equivalent impulse is derived, based on the theory of upper bound kinetic energy uptake introduced herein, which accounts for the additional energy imparted to a structure from a spatially non-uniform blast load. Whilst plate deflection is weakly correlated to total impulse, there is shown to be a strong positive correlation between deflection and energy equivalent impulse. The strength of this correlation is insensitive to loading distribution and mode of response. The method developed in this article has clear applications for the generation of fast-running engineering tools for the prediction of structural response to near-field explosions.
Abstract
Using photometry collected with the Zwicky Transient Facility, we are conducting an ongoing survey for binary systems with short orbital periods (
with the goal of identifying new ...gravitational-wave sources detectable by the upcoming Laser Interferometer Space Antenna (LISA). We present a sample of 15 binary systems discovered thus far, with orbital periods ranging from 6.91 to 56.35 minutes. Of the 15 systems, seven are eclipsing systems that do not show signs of significant mass transfer. Additionally, we have discovered two AM Canum Venaticorum systems and six systems exhibiting primarily ellipsoidal variations in their lightcurves. We present follow-up spectroscopy and high-speed photometry confirming the nature of these systems, estimates of their LISA signal-to-noise ratios, and a discussion of their physical characteristics.
The CLSI epidemiological cutoff values (ECVs) of antifungal agents are available for various Candida spp., Aspergillus spp., and the Mucorales. However, those categorical endpoints have not been ...established for Fusarium spp., mostly due to the difficulties associated with collecting sufficient CLSI MICs for clinical isolates identified according to the currently recommended molecular DNA-PCR-based identification methodologies. CLSI MIC distributions were established for 53 Fusarium dimerum species complex (SC), 10 F. fujikuroi, 82 F. proliferatum, 20 F. incarnatum-F. equiseti SC, 226 F. oxysporum SC, 608 F. solani SC, and 151 F. verticillioides isolates originating in 17 laboratories (in Argentina, Australia, Brazil, Canada, Europe, Mexico, and the United States). According to the CLSI guidelines for ECV setting, ECVs encompassing ≥97.5% of pooled statistically modeled MIC distributions were as follows: for amphotericin B, 4 μg/ml (F. verticillioides) and 8 μg/ml (F. oxysporum SC and F. solani SC); for posaconazole, 2 μg/ml (F. verticillioides), 8 μg/ml (F. oxysporum SC), and 32 μg/ml (F. solani SC); for voriconazole, 4 μg/ml (F. verticillioides), 16 μg/ml (F. oxysporum SC), and 32 μg/ml (F. solani SC); and for itraconazole, 32 μg/ml (F. oxysporum SC and F. solani SC). Insufficient data precluded ECV definition for the other species. Although these ECVs could aid in detecting non-wild-type isolates with reduced susceptibility to the agents evaluated, the relationship between molecular mechanisms of resistance (gene mutations) and MICs still needs to be investigated for Fusarium spp.
Summary Objectives To investigate the regulation of sclerostin (SOST) in osteoarthritis (OA) and its potential effects on articular cartilage degradation. Methods SOST and other Wnt-β-catenin ...components were immuno-localised in osteochondral sections of surgically-induced OA in knees of sheep and mice, and human OA samples obtained at arthroplasty. Regulation of SOST mRNA and protein expression by ovine chondrocytes in response to interleukin-1α (IL-1α) or tumour necrosis factor-α (TNFα) was examined in explant cultures. The effect of 25 or 250 ng/ml recombinant SOST alone or in combination with IL-1α, on ovine articular cartilage explant aggrecan degradation, and chondrocyte gene expression of Wnt-β-catenin pathway proteins, metalloproteinases and their inhibitors, and cartilage matrix proteins was quantified. Results Contrary to being an osteocyte-specific protein, SOST was expressed by articular chondrocytes, and mRNA levels were upregulated in vitro by IL-1α but not TNFα. Chondrocyte SOST staining was significantly increased only in the focal area of cartilage damage in surgically-induced OA in sheep and mice, as well as end-stage human OA. In contrast, osteocyte SOST was focally decreased in the subchondral bone in sheep OA in association with bone sclerosis. SOST was biologically active in chondrocytes, inhibiting Wnt-β-catenin signalling and catabolic metalloproteinase matrix metalloproteinases (MMP) and distintegrin and metalloproteinase with thrombospndin repeats (ADAMTS) expression, but also decreasing mRNA levels of aggrecan, collagen II and tissue inhibitors of metalloproteinaes (TIMPs). Despite this mixed effect, SOST dose-dependently inhibited IL-1α-stimulated cartilage aggrecanolysis in vitro. Conclusions These results implicate SOST in regulating the OA disease processes, but suggest opposing effects by promoting disease-associated subchondral bone sclerosis while inhibiting degradation of cartilage.
We previously reported decreased transfusions and donor exposures in preterm infants randomized to Darbepoetin (Darbe) or erythropoietin (Epo) compared with placebo. As these ...erythropoiesis-stimulating agents (ESAs) have shown promise as neuroprotective agents, we hypothesized improved neurodevelopmental outcomes at 18 to 22 months among infants randomized to receive ESAs.
We performed a randomized, masked, multicenter study comparing Darbe (10 μg/kg, 1×/week subcutaneously), Epo (400 U/kg, 3×/week subcutaneously), and placebo (sham dosing 3×/week) given through 35 weeks' postconceptual age, with transfusions administered according to a standardized protocol. Surviving infants were evaluated at 18 to 22 months' corrected age using the Bayley Scales of Infant Development III. The primary outcome was composite cognitive score. Assessments of object permanence, anthropometrics, cerebral palsy, vision, and hearing were performed.
Of the original 102 infants (946 ± 196 g, 27.7 ± 1.8 weeks' gestation), 80 (29 Epo, 27 Darbe, 24 placebo) returned for follow-up. The 3 groups were comparable for age at testing, birth weight, and gestational age. After adjustment for gender, analysis of covariance revealed significantly higher cognitive scores among Darbe (96.2 ± 7.3; mean ± SD) and Epo recipients (97.9 ± 14.3) compared with placebo recipients (88.7 ± 13.5; P = .01 vs ESA recipients) as was object permanence (P = .05). No ESA recipients had cerebral palsy, compared with 5 in the placebo group (P < .001). No differences among groups were found in visual or hearing impairment.
Infants randomized to receive ESAs had better cognitive outcomes, compared with placebo recipients, at 18 to 22 months. Darbe and Epo may prove beneficial in improving long-term cognitive outcomes of preterm infants.
PDF
