A
bstract
We describe a proposal to add a set of very forward detectors to the CMS experiment for the high-luminosity era of the Large Hadron Collider to search for beyond the standard model ...long-lived particles, such as dark photons, heavy neutral leptons, axion-like particles, and dark Higgs bosons. The proposed subsystem is called
FACET
for
F
orward-
A
perture
C
MS
E
x
T
ension, and will be sensitive to any particles that can penetrate at least 50 m of magnetized iron and decay in an 18 m long, 1 m diameter vacuum pipe. The decay products will be measured in detectors using identical technology to the planned CMS Phase-2 upgrade.
We have recently identified apoptosis-antagonizing transcription factor (AATF), tumor-susceptibility gene 101 (TSG101) and zipper-interacting protein kinase (ZIPK) as novel coactivators of the ...androgen receptor (AR). The mechanisms of coactivation remained obscure, however. Here we investigated the interplay and interdependence between these coactivators and the AR using the endogenous prostate specific antigen (PSA) gene as model for AR-target genes. Chromatin immunoprecipitation in combination with siRNA-mediated knockdown revealed that recruitment of AATF and ZIPK to the PSA enhancer was dependent on AR, whereas recruitment of TSG101 was dependent on AATF. Association of AR and its coactivators with the PSA enhancer or promoter occurred in cycles. Dissociation of AR-transcription complexes was due to degradation because inhibition of the proteasome system by MG132 caused accumulation of AR at enhancer/promoter elements. Moreover, inhibition of degradation strongly reduced transcription, indicating that continued and efficient transcription is based on initiation, degradation and reinitiation cycles. Interestingly, knockdown of ZIPK by siRNA had a similar effect as MG132, leading to reduced transcription but enhanced accumulation of AR at androgen-response elements. In addition, knockdown of ZIPK, as well as overexpression of a dominant-negative ZIPK mutant, diminished polyubiquitination of AR. Furthermore, ZIPK cooperated with the E3 ligase Mdm2 in AR-dependent transactivation, assembled into a single complex on chromatin and phosphorylated Mdm2 in vitro. These results suggest that ZIPK has a crucial role in regulation of ubiquitination and degradation of the AR, and hence promoter clearance and efficient transcription.
The objective of the study was to assess the effects of a dog‐appeasing pheromone (DAP) collar in reducing sound‐induced fear and anxiety in a laboratory model of thunderstorm simulation. Twenty‐four ...beagle dogs naïve to the current test were divided into two treatment groups (DAP and placebo) balanced on their fear score in response to a thunderstorm recording. Each group was then exposed to two additional thunderstorm simulation tests on consecutive days. Dogs were video‐assessed by a trained observer on a 6‐point scale for active, passive and global fear and anxiety (combined). Both global and active fear and anxiety scores were significantly improved during and following thunder compared with placebo on both test days. DAP significantly decreased global fear and anxiety across ‘during’ and ‘post’ thunder times when compared with baseline. There was no significant improvement in the placebo group from baseline on the test days. In addition, the DAP group showed significantly greater use of the hide box at any time with increased exposure compared with the placebo group. The DAP collar reduced the scores of fear and anxiety, and increased hide use in response to a thunder recording, possibly by counteracting noise‐related increased reactivity.
The current study describes both Aβ and tau abnormalities that accumulate in the brains of aged (16–21 years), but not young (<4 years) clinically characterized cats. Diffuse plaques that were ...morphologically different from what is typically observed in the human brain could be detected with 4G8 (Aβ17–24) or an Aβ1–42-specific antibody but not with N-terminal Aβ or an Aβ1–40-specific antibody. SELDI-TOF mass spectrometry experiments indicated that cat brain Aβ consisted almost entirely of Aβ1–42. Markers of tau hyperphosphorylation (AT8 and PHF-1) labeled a subset of neurons in two aged animals. In the hilus of the hippocampus, a subset of AT8 positive neurons showed a sprouting morphology similar to that observed in human brain. Western blot analysis with antibodies against hyperphosphorylated tau indicated that tau is hyperphosphorylated in the aged cat and contains many of the same epitopes found in Alzheimer's disease (AD) brain. Thus, the aged cat brain develops AD-related lesions with important morphological and biochemical differences compared to human brain.
OBJECTIVES
The management of concomitant coronary and carotid artery disease is still in evolution. The surgical options are staged approach-carotid endarterectomy (CEA), followed by coronary artery ...bypass grafting (CABG) or a reversed-staged approach, or combined approach-CEA and CABG under the same anaesthesia. In view of the percutaneous carotid artery stenting option, we have reviewed our short- and long-term experience with combined CEA and CABG to define the role of this procedure.
METHODS
From January 1992 to December 2006, we operated on 80 patients performing combined carotid endarterctomy and myocardial revascularization. Short- and long-term results were reviewed.
RESULTS
Operative mortality was 3.7%. Perioperative cerebrovascular accident (CVA) occurred in 2 patients (2.5%). Perioperative myocardial infarction (MI) occurred in 3 patients (3.7%). Combined complications of death + MI + CVA = 10%. During the mean follow-up of 10 ± 3.2 years (1-14 years), 6 patients (7.6%) had neurological events. Freedom from neurological events for 10 years was 92 ± 4%. Nearly 17 (21.5%) had cardiac events. The 5-year and 10-year survival rates were 74 ± 5 and 62 ± 6%, respectively.
CONCLUSIONS
Although the short-term results of the non-surgical carotid therapeutic alternative is similar to our surgical results, there are limitations to carotid artery stenting: the need for aggressive antiplatelets therapy, and the haemodynamic changes during the procedure that may be unacceptable for patients with unstable coronary artery disease. Therefore, there is still a role for concomitant surgical CEA and CABG to the results of which the other options should be compared.
With increasing age, dogs develop a form of neurodegenerative disease which has many similarities to age related cognitive impairment and Alzheimer's disease in humans. A decline in learning and ...memory can be demonstrated in dogs beginning as young as 7 years of age using a variety of neuropsychological tests. However, clinical cases of cognitive dysfunction syndrome are seldom identified until the age of 11 years or older. This is likely due to the fact that the owners are relying on clinical observations such as house-soiling, sleep–wake cycles and disorientation, rather than tests of learning and memory. On the other hand, dogs that are trained to more exacting tasks such as guide dogs for the visually impaired, or bomb detection and agility trained dogs might be noticed to have a decline in performance at a much earlier age. Through the use of standardized neuropsychological testing protocols, a number of drugs, natural products and supplement formulations have been developed for use in dogs with cognitive dysfunction and, in some cases clinical trials have validated their efficacy. Furthermore, the testing of products currently licensed and in the pipeline for the treatment of cognitive decline and Alzheimer's in humans, may provide additional therapeutic agents for the treatment of senior dogs, as well as provide insight as to the potential for the efficacy of these compounds in humans. This review will examine those products that are now marketed along with some that might be considered for use in senior dogs with cognitive dysfunction as well as the research that has been used to validate the efficacy (or lack thereof) of these compounds.
Aims: To determine whether appropriate dosage adjustments are made in patients with significant renal impairment for drugs with a high fractional renal clearance.
Methods: Evaluation of dosage ...adjustment was performed in patients who were admitted to a 480‐bed metropolitan hospital (Princess Alexandra Hospital, Brisbane, Australia) with an estimated creatinine clearance of ≤40 mL/min. All drugs had a high fractional renal excretion. A prescribed dose within 30% of the calculated dose was considered appropriate.
Results: Doses were found to be inappropriately high in 105 (42.2%) of 249 admission prescriptions of the targeted drugs. Doses were appropriately reduced in hospital in 32 patients (30.4%). Seventy‐three (29.3%) prescriptions were continued with excessive doses. Only 34 prescriptions for the target drugs were initiated in hospital, of which 88.2% were appropriately dosed.
Conclusions: A significant percentage of patients with renal impairment are admitted to hospital on inappropriately high doses of drugs, with a high fractional renal excretion and low therapeutic index. Doses are appropriately reduced in hospital in some patients but there is still room for improvement. (Intern Med J 2003; 33: 10−13)
The hysteretic thermal behavior of two amorphous semi-aromatic polyamides, subjected to cyclic loading at high stress levels, has been investigated. The two polymers, called 1I and 1.8T, were ...selected with regards to chain mobility and plastic deformability considerations. This work reports the exothermal response of these materials to high level cyclic stress (of the order of
σ
y), with emphasis on the initial thermal peak, normally observed in commercial polycarbonate (PC) and not in commercial polymethylmethacrylate (PMMA). The investigated materials exhibit noticeable initial thermal peaks, which are similar, to some extent, to those observed in PC. The present results suggest that chain mobility may indeed be partially responsible for the initial exothermal peak, thus supporting the hypothesis that it may be related to the transition from shear deformation zones to chain disentanglement crazing.
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