Proteasomes, the primary mediators of ubiquitin-protein conjugate degradation, are regulated through complex and poorly understood mechanisms. Here we show that USP14, a proteasome-associated ...deubiquitinating enzyme, can inhibit the degradation of ubiquitin-protein conjugates both in vitro and in cells. A catalytically inactive variant of USP14 has reduced inhibitory activity, indicating that inhibition is mediated by trimming of the ubiquitin chain on the substrate. A high-throughput screen identified a selective small-molecule inhibitor of the deubiquitinating activity of human USP14. Treatment of cultured cells with this compound enhanced degradation of several proteasome substrates that have been implicated in neurodegenerative disease. USP14 inhibition accelerated the degradation of oxidized proteins and enhanced resistance to oxidative stress. Enhancement of proteasome activity through inhibition of USP14 may offer a strategy to reduce the levels of aberrant proteins in cells under proteotoxic stress.
To discover interordinal relationships of living and fossil placental mammals and the time of origin of placentals relative to the Cretaceous-Paleogene (K-Pg) boundary, we scored 4541 phenomic ...characters de novo for 86 fossil and living species. Combining these data with molecular sequences, we obtained a phylogenetic tree that, when calibrated with fossils, shows that crown clade Placentalia and placental orders originated after the K-Pg boundary. Many nodes discovered using molecular data are upheld, but phenomic signals overturn molecular signals to show Sundatheria (Dermoptera + Scandentia) as the sister taxon of Primates, a close link between Proboscidea (elephants) and Sirenia (sea cows), and the monophyly of echolocating Chiroptera (bats). Our tree suggests that Placentalia first split into Xenarthra and Epitheria; extinct New World species are the oldest members of Afrotheria.
We present Chandra and XMM-Newton X-ray observations of the Abell 3391/Abell 3395 intercluster filament. It has been suggested that the galaxy clusters Abell 3395, Abell 3391, and the galaxy group ...ESO-161 -IG 006 located between the two clusters, are in alignment along a large-scale intercluster filament. We find that the filament is aligned close to the plane of the sky, in contrast to previous results. We find a global projected filament temperature kT = keV, electron density cm−3, and M . The thermodynamic properties of the filament are consistent with that of the intracluster medium (ICM) of Abell 3395 and Abell 3391, suggesting that the filament emission is dominated by ICM gas that has been tidally disrupted during an early stage merger between these two clusters. We present temperature, density, entropy, and abundance profiles across the filament. We find that the galaxy group ESO-161 may be undergoing ram-pressure-stripping in the low-density environment at or near the virial radius of both clusters, due to its rapid motion through the filament.
Background Many laparoscopic procedures are currently performed on an outpatient basis. Laparoscopic appendectomy, however, continues to require postoperative hospitalization at most institutions. A ...treatment protocol for outpatient laparoscopic appendectomy was developed to determine if this could be successfully performed without increasing postoperative complications. We hypothesized that adopting an outpatient protocol for laparoscopic appendectomy will significantly increase the rate of outpatient management for uncomplicated appendicitis, without an increase in morbidity or mortality. Study Design We initiated a prospective outpatient protocol for laparoscopic appendectomy in July 2010 at our institution. All patients having laparoscopic appendectomy from July 2010 to March 2011 were included as protocol patients and were retrospectively reviewed. A separate group of patients having laparoscopic appendectomy from January to September 2009 were analyzed as historical controls. These 2 groups were compared for demographics, preoperative comorbidities, outpatient management, and postoperative morbidity by chi-square analysis, with a 0.95 confidence level for statistical significance. Results A total of 116 protocol patients were compared with 119 historical control patients. There were no significant differences in patient demographics, preoperative comorbidities, and pathologic findings between protocol patients and historical controls. Ninety-nine protocol patients (85.3%) had procedures as outpatients compared with 42 historical control patients (35.3%; p < 0.05). Postoperative morbidity occurred in 6 protocol patients (5.2%) and 10 historical controls (8.4%; p = NS). There were no readmissions or mortalities in the protocol group. Conclusions An outpatient protocol for laparoscopic appendectomy significantly increased the rate of outpatient management with no increase in morbidity or mortality. This practice has now become standard of care at our institution.
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The potential of poly (2-oxazoline) or POZ to be a versatile and broad based platform for drug delivery with wide utility in multiple therapeutic areas has long been recognized by ...experts in the field. This feature article provides a case study which describes the chemistry and preclinical studies underlying the Investigational New Drug Application for SER-214, a POZ conjugate of rotigotine, for the treatment of Parkinson’s disease. We report the chemistry, preclinical safety and pharmacology, and the early clinical safety, tolerability and pharmacokinetic data from the Phase I study in patients. SER-214 utilizes a POZ polymer and proprietary custom linker technology to deliver a sustained dose of rotigotine over a period of seven days following a single subcutaneous administration – a result not observed by any other polymer approach that we are aware of. As such, this candidate drug has the promise to be a major advancement in the treatment of Parkinson’s disease. Furthermore, this feature article also highlights the versatility of the POZ polymer platform (POZ™) to deliver cancer drugs by actively targeting cancer cells. Preclinical data reported in this feature showcase the polymer’s attributes in facilitating targeted delivery with folic acid and antibody targeting agents (ADCs). The ability of POZ to reliably delivery large payloads of anticancer drugs is of particular importance when pursuing low-receptor-density targets on the cancer cell. The data presented in this feature, much of it for the first time, establish the broad utility of the POZ polymer platform in drug development. Together with its ease of manufacture, ability to attach drugs to the polymer, and ability to administer an appropriate dose to patients, the results underscore the need to further explore and expand the untapped potential of POZ for the development of new therapeutics for unmet medical needs.
Perioperative neurocognitive disorders (PND) are common complications in older adults associated with increased 1-year mortality and long-term cognitive decline. One risk factor for worsened ...long-term postoperative cognitive trajectory is the Alzheimer's disease (AD) genetic risk factor APOE4. APOE4 is thought to elevate AD risk partly by increasing neuroinflammation, which is also a theorized mechanism for PND. Yet, it is unclear whether modulating apoE4 protein signaling in older surgical patients would reduce PND risk or severity.
MARBLE is a randomized, blinded, placebo-controlled phase II sequential dose escalation trial designed to evaluate perioperative administration of an apoE mimetic peptide drug, CN-105, in older adults (age≥60 years). The primary aim is evaluating the safety of CN-105 administration, as measured by adverse event rates in CN-105 versus placebo-treated patients. Secondary aims include assessing perioperative CN-105 administration feasibility and its efficacy for reducing postoperative neuroinflammation and PND severity.
201 patients undergoing non-cardiac, non-neurological surgery will be randomized to control or CN-105 treatment groups and receive placebo or drug before and every six hours after surgery, for up to three days after surgery. Chart reviews, pre- and postoperative cognitive testing, delirium screening, and blood and CSF analyses will be performed to examine effects of CN-105 on perioperative adverse event rates, cognition, and neuroinflammation. Trial results will be disseminated by presentations at conferences and peer-reviewed publications.
MARBLE is a transdisciplinary study designed to measure CN-105 safety and efficacy for preventing PND in older adults and to provide insight into the pathogenesis of these geriatric syndromes.
Abstract Lower serum chloride (Cl) levels are strongly associated with increased long-term mortality after admission for acute heart failure (AHF). However, the therapeutic implications of serum Cl ...levels during AHF are unknown. We sought to determine the short-term clinical response and post-discharge outcomes associated with serum Cl levels in AHF. Serum Cl was measured at randomization (N=358) and during hospitalization from patients with AHF in the in the Renal Optimization Strategies Evaluation in Acute Heart Failure (ROSE-AHF) trial. Outcomes included diuretic response and renal function at 72 hours and death and rehospitalization at 60 and 180-days. Baseline Cl tertiles were: 84-98 meq/L; 99-102 meq/L; and 103-117 meq/L. Baseline Cl level was associated with diuretic efficiency (P<.001), but not change in cystatin C (P=0.30) at 72 hours; and was associated with 60-day death (HR 0.86, P=0.029), 60-day death and rehospitalization (HR 0.90, P=0.01), and 180-day death (HR 0.91, P=0.049). These associations were attenuated with additional adjustment for loop diuretic dose (P>0.05). Chloride change correlated with weight change (rho 0.18, P=0.001), cystatin C change (rho -0.35, P<.001), and cumulative sodium excretion (rho -0.21, P<.001), but was not associated with any clinical outcomes (P>0.05 for all). In conclusion, serum Cl levels in AHF were inversely associated with loop diuretic response and were prognostic. However, changes in Cl levels were associated with parameters of decongestion, but not with clinical outcomes.
Alzheimer disease (AD) is one of several neurodegenerative diseases characterized by dysregulation, misfolding and accumulation of specific proteins in the CNS. The stable isotope labelling kinetics ...(SILK) technique is based on generating amino acids labelled with naturally occurring stable (that is, nonradioactive) isotopes of carbon and/or nitrogen. These labelled amino acids can then be incorporated into proteins, enabling rates of protein production and clearance to be determined in vivo and in vitro without the use of radioactive or chemical labels. Over the past decade, SILK studies have been used to determine the turnover of key pathogenic proteins amyloid-β (Aβ), tau and superoxide dismutase 1 (SOD1) in the cerebrospinal fluid of healthy individuals, patients with AD and those with other neurodegenerative diseases. These studies led to the identification of several factors that alter the production and/or clearance of these proteins, including age, sleep and disease-causing genetic mutations. SILK studies have also been used to measure Aβ turnover in blood and within brain tissue. SILK studies offer the potential to elucidate the mechanisms underlying various neurodegenerative disease mechanisms, including neuroinflammation and synaptic dysfunction, and to demonstrate target engagement of novel disease-modifying therapies.
Photosynthetic acclimation (photoacclimation) is the process whereby leaves alter their morphology and/or biochemistry to optimize photosynthetic efficiency and productivity according to long-term ...changes in the light environment. The three-dimensional architecture of plant canopies imposes complex light dynamics, but the drivers for photoacclimation in such fluctuating environments are poorly understood. A technique for high-resolution three-dimensional reconstruction was combined with ray tracing to simulate a daily time course of radiation profiles for architecturally contrasting field-grown wheat (Triticum aestivum) canopies. An empirical model of photoacclimation was adapted to predict the optimal distribution of photosynthesis according to the fluctuating light patterns throughout the canopies. While the photoacclimation model output showed good correlation with field-measured gas-exchange data at the top of the canopy, it predicted a lower optimal light-saturated rate of photosynthesis at the base. Leaf Rubisco and protein contents were consistent with the measured optimal light-saturated rate of photosynthesis. We conclude that, although the photosynthetic capacity of leaves is high enough to exploit brief periods of high light within the canopy (particularly toward the base), the frequency and duration of such sunflecks are too small to make acclimation a viable strategy in terms of carbon gain. This suboptimal acclimation renders a large portion of residual photosynthetic capacity unused and reduces photosynthetic nitrogen use efficiency at the canopy level, with further implications for photosynthetic productivity. It is argued that (1) this represents an untapped source of photosynthetic potential and (2) canopy nitrogen could be lowered with no detriment to carbon gain or grain protein content.
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