Aging has been associated with a progressive decline of proteostasis, but how this process affects proteome composition remains largely unexplored. Here, we profiled more than 5,000 proteins along ...the lifespan of the nematode C. elegans. We find that one-third of proteins change in abundance at least 2-fold during aging, resulting in a severe proteome imbalance. These changes are reduced in the long-lived daf-2 mutant but are enhanced in the short-lived daf-16 mutant. While ribosomal proteins decline and lose normal stoichiometry, proteasome complexes increase. Proteome imbalance is accompanied by widespread protein aggregation, with abundant proteins that exceed solubility contributing most to aggregate load. Notably, the properties by which proteins are selected for aggregation differ in the daf-2 mutant, and an increased formation of aggregates associated with small heat-shock proteins is observed. We suggest that sequestering proteins into chaperone-enriched aggregates is a protective strategy to slow proteostasis decline during nematode aging.
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•Proteome profiling reveals loss of proteome balance during C. elegans aging•Proteome imbalances alter protein stoichiometries and cause proteostasis stress•Changes in protein abundance drive extensive protein aggregation during aging•Sequestration of surplus proteins in chaperone-associated aggregates is protective
Quantitative proteomic analysis in C. elegans reveals widespread proteome imbalance associated with aging. Extended lifespan is correlated with increased formation of chaperone-associated aggregates, suggesting that sequestering aberrant proteins delays proteostasis decline during aging.
The biological process of aging is believed to be the result of an accumulation of cellular damage to biomolecules. Although there are numerous studies addressing mutation frequencies, morphological ...or transcriptional changes in aging mammalian tissues, few have measured global changes at the protein level. Here, we present an in depth proteomic analysis of three brain regions as well as heart and kidney in mice aged 5 or 26 months, using stable isotope labeling of whole animals (SILAC mouse) and high resolution mass spectrometry. In the frontal cortex and hippocampal regions of the brain, more than 4200 proteins were quantitatively compared between age groups. Proteome differences between individual mice were observable within and between age groups. However, mean protein abundance changes of more than twofold between young and old mice were detected in less than 1% of all proteins and very few of these were statistically significant. Similar outcomes were obtained when comparing cerebellum, heart, and kidney between age groups. Thus, unexpectedly, our results indicate that aging-related effects on the tissue proteome composition at the bulk level are only minor and that protein homeostasis remains functional up to a relatively high age.
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Electrospun fibers emerged as promising drug delivery systems for various pharmaceutical applications due to their favorable properties. However, while for established drug delivery ...systems (e.g. tablets or capsules) standardized analytical procedures exist, the methodologies for characterization of electrospun fibers differ widely in the literature. Unfortunately, this situation impedes comparison of different studies and consequently hampers translation of the results into clinics. Thus, there is an urgent need for systematic studies evaluating different analytical techniques for their validity to characterize and differentiate different electrospun fibers.
In this study, we aimed to identify a predictive and robust toolset of complementary analytical techniques allowing for comprehensive and discriminative evaluation of electrospun fibers. For this purpose, we fabricated two drug-loaded model formulations with contrastive physico-chemical properties and drug release kinetics. Different analytical techniques were applied for physico-chemical characterization of the spinning solutions as well as of the fibers. Each analytical method was evaluated with regard to discriminative power and individual limitations. The introduction of novel analytical approaches such as automated low-volume release testing may further advance the field of electrospinning. By combining complementary analytical methods, including spectral composition analysis, morphology visualization, characterization of physico-chemical properties and drug release kinetics, as well as the application of multivariate data analysis, we were able to establish a robust and predictive toolset, which can support comparability of future electrospinning studies and the translation from the lab bench into clinics.
Pheochromocytoma is a rare but important tumor of chromaffin cells that is frequently considered in the evaluation of hypertension, arrhythmias, or panic disorder and in the follow-up of patients ...with particular genetic diseases. This report provides an update about the genetics, neurochemical diagnosis, localization by imaging, and surgical management of pheochromocytoma. Specific mutations of the RET proto-oncogene cause familial predisposition to pheochromocytoma in multiple endocrine neoplasia type II, and mutations in the von Hippel-Lindau tumor suppressor gene cause familial disposition to pheochromocytoma in von Hippel-Lindau disease. Recent findings demonstrating extraordinarily high sensitivity of plasma levels of metanephrines for detecting pheochromocytoma have led to an algorithm for clinical diagnostic steps. Nuclear imaging approaches, such as(123) I-metaiodobenzylguanidine scintigraphy and 6-(18) Ffluorodopamine positron emission tomography, enhance both diagnosis and localization of the tumor, as described in an algorithm for patients with positive biochemical test results. Since pheochromocytoma is often benign, surgical resection by laparoscopic adrenalectomy can be curative. Areas requiring further work include determining appropriate follow-up of patients with familial pheochromocytoma, elucidating the bases for phenotypic differences, improving both specificity and sensitivity of biochemical tests, optimizing cost-effectiveness of diagnostic imaging, and testing the risk for tumor recurrence after partial adrenalectomy.
One of the important challenges in condensed matter science is to understand ultrafast, atomic-scale fluctuations that dictate dynamic processes in equilibrium and non-equilibrium materials. Here, we ...report an important step towards reaching that goal by using a state-of-the-art perfect crystal based split-and-delay system, capable of splitting individual X-ray pulses and introducing femtosecond to nanosecond time delays. We show the results of an ultrafast hard X-ray photon correlation spectroscopy experiment at LCLS where split X-ray pulses were used to measure the dynamics of gold nanoparticles suspended in hexane. We show how reliable speckle contrast values can be extracted even from very low intensity free electron laser (FEL) speckle patterns by applying maximum likelihood fitting, thus demonstrating the potential of a split-and-delay approach for dynamics measurements at FEL sources. This will enable the characterization of equilibrium and, importantly also reversible non-equilibrium processes in atomically disordered materials.
In this paper we describe the OpenGeoSys (OGS) project, which is a scientific open-source initiative for numerical simulation of thermo-hydro-mechanical-chemical processes in porous media. The basic ...concept is to provide a flexible numerical framework (using primarily the Finite Element Method (FEM)) for solving multifield problems in porous and fractured media for applications in geoscience and hydrology. To this purpose OGS is based on an object-oriented FEM concept including a broad spectrum of interfaces for pre- and postprocessing. The OGS idea has been in development since the mid-eighties. We provide a short historical note about the continuous process of concept and software development having evolved through Fortran, C, and C++ implementations. The idea behind OGS is to provide an open platform to the community, outfitted with professional software-engineering tools such as platform-independent compiling and automated benchmarking. A comprehensive benchmarking book has been prepared for publication. Benchmarking has been proven to be a valuable tool for cooperation between different developer teams, for example, for code comparison and validation purposes (DEVOVALEX and CO
2
BENCH projects). On one hand, object-orientation (OO) provides a suitable framework for distributed code development; however, the parallelization of OO codes still lacks efficiency. High-performance-computing efficiency of OO codes is subject to future research.
We present high-resolution images of NGC 2071-IR in the J, H, and K bands and in the emission at 2.12 m of the v = 1-0 S(1) line of molecular hydrogen. We also present moderate-resolution K-band ...spectra of two young stellar objects, IRS 1 and IRS 3, within NGC 2071-IR, that are candidate sources of one or more of the outflows observed in the region. Two of the eight originally identified infrared point sources in NGC 2071-IR are binaries, and we identify two new sources, one coincident with the radio source Very Large Array-1 and highly reddened. The H2 Q(3)/S(1) line intensity ratios at IRS 1 and IRS 3 yield high and very high extinctions, respectively, to them, as is implied by their near-infrared colors and K-band continuum slopes. The spectra also reveal the presence of hot, dense circumstellar molecular gas in each, suggesting that both are strong candidates for having energetic molecular outflows. We agree with a previous suggestion that IRS 1 is the likely source of an east-west-oriented outflow and conclude that this outflow is probably largely out of the plane of the sky. We also conclude that if IRS 3 is the source of the large-scale northeast-southwest outflow, as has been previously suggested, its jet/wind must precess in order to explain the angular width of that outflow. We discuss the nature of the point sources and their possible contributions, if any, to the complex morphology of the H2 line emission.
Background
Transfers from one intensive care unit (ICU) to another ICU are associated with increased length of intensive care and hospital stay. Inter-hospital ICU transfers are carried out for three ...main reasons: clinical transfers, capacity transfers and repatriations. The aim of the study was to show that different ICU transfers differ in risk-adjusted mortality rate with repatriations having the least risk.
Results
Observational cohort study of adult patients transferred between Swedish ICUs during 3 years (2016–2018) with follow-up ending September 2019. Primary and secondary end-points were survival to 30 days and 180 days after discharge from the first ICU. Data from 75 ICUs in the Swedish Intensive Care Register, a nationwide intensive care register, were used for analysis (89% of all Swedish ICUs), covering local community hospitals, district general hospitals and tertiary care hospitals. We included adult patients (16 years or older) admitted to ICU and subsequently discharged by transfer to another ICU. Only the first admission was used. Exposure was discharge to any other ICU (ICU-to-ICU transfer), whether in the same or in another hospital. Transfers were grouped into three predefined categories: clinical transfer, capacity transfer, and repatriation. We identified 15,588 transfers among 112,860 admissions (14.8%) and analysed 11,176 after excluding 4112 repeat transfer of the same individual and 300 with missing risk adjustment. The majority were clinical transfers (62.7%), followed by repatriations (21.5%) and capacity transfers (15.8%). Unadjusted 30-day mortality was 25.0% among capacity transfers compared to 14.5% and 16.2% for clinical transfers and repatriations, respectively. Adjusted odds ratio (OR) for 30-day mortality were 1.25 (95% CI 1.06–1.49
p
= 0.01) for capacity transfers and 1.17 (95% CI 1.02–1.36
p
= 0.03) for clinical transfers using repatriation as reference. The differences remained 180 days post-discharge.
Conclusions
There was a large proportion of ICU-to-ICU transfers and an increased odds of dying for those transferred due to other reasons than repatriation.
Prehabilitation has been postulated as an effective preventive intervention to reduce postoperative complications, particularly for elderly patients with a relatively high risk of complications. To ...date, it remains to be determined whether prehabilitation increases physical capacity and reduces postoperative complications. The aim of this study was to assess the feasibility of a 4-week multimodal prehabilitation program consisting of a personalized, supervised training program and nutritional intervention with daily fresh protein-rich food for colorectal cancer patients aged over 64 years prior to surgery. The primary outcome was the feasibility of this prehabilitation program defined as ≥80% compliance with the exercise training program and nutritional intervention. The secondary outcomes were the organizational feasibility and acceptability of the prehabilitation program. A compliance rate of ≥80% to both the exercise and nutritional intervention was accomplished by 6 patients (66.7%). Attendance of ≥80% at all 12 training sessions was achieved by 7 patients (77.8%); all patients (100%) attended ≥80% of the available training sessions. Overall, compliance with the training was 91.7%. Six patients (66.7%) accomplished compliance of ≥80% with the nutritional program. The median protein intake was 1.2 (g/kg/d). No adverse events occurred. This multimodal prehabilitation program was feasible for the majority of patients.
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