Stress granules (SGs) are mRNA-protein aggregates induced during stress, which accumulate in many neurodegenerative diseases. Previously, the autophagy-lysosome pathway and valosin-containing protein ...(VCP), key players of the protein quality control (PQC), were shown to regulate SG degradation. This is consistent with the idea that PQC may survey and/or assist SG dynamics. However, despite these observations, it is currently unknown whether the PQC actively participates in SG assembly. Here, we describe that inhibition of autophagy, lysosomes and VCP causes defective SG formation after induction. Silencing the VCP co-factors UFD1L and PLAA, which degrade defective ribosomal products (DRIPs) and 60S ribosomes, also impaired SG assembly. Intriguingly, DRIPs and 60S, which are released from disassembling polysomes and are normally excluded from SGs, were significantly retained within SGs in cells with impaired autophagy, lysosome or VCP function. Our results suggest that deregulated autophagy, lysosomal or VCP activities, which occur in several neurodegenerative (VCP-associated) diseases, may alter SG morphology and composition.
The U.S. Army has a vested interest in retaining the skilled personnel necessary to achieve its mission and strategic goals. A wealth of research has investigated the retention process and what ...influences service member decisions to stay in the military. While families are an important influence on soldier retention decisions, research on the mechanism by which this happens is lacking. This report explores the relationship between spouse attitudes and perceptions, resource use, and soldier retention almost two years later, using a proposed theoretical model. Our results generally support our model, with the important change that resource use and unmet needs and stress were not directly associated with specific attitudes toward staying in the military as we had expected. Instead, the association was accounted for by relationship with general attitudes toward the military. Spouses whose needs were unmet after seeking help from available resources experienced greater stress, and spouse unmet needs and reports of greater stress were associated with worse general attitudes toward the military; worse general attitudes toward the military were associated with less inclination to stay a military family; which in turn predicted soldier turnover almost two years later. As the research in this report shows, providing benefits to military spouses is also associated with a tangible and important outcome for the military: improved service member retention.
Over the last years the zebrafish imposed itself as a powerful model to study skeletal diseases, but a limit to its use is the poor characterization of collagen type I, the most abundant protein in ...bone and skin. In tetrapods collagen type I is a trimer mainly composed of two α1 chains and one α2 chain, encoded by COL1A1 and COL1A2 genes, respectively. In contrast, in zebrafish three type I collagen genes exist, col1a1a, col1a1b and col1a2 coding for α1(I), α3(I) and α2(I) chains. During embryonic and larval development the three collagen type I genes showed a similar spatio-temporal expression pattern, indicating their co-regulation and interdependence at these stages. In both embryonic and adult tissues, the presence of the three α(I) chains was demonstrated, although in embryos α1(I) was present in two distinct glycosylated states, suggesting a developmental-specific collagen composition. Even though in adult bone, skin and scales equal amounts of α1(I), α3(I) and α2(I) chains are present, the presented data suggest a tissue-specific stoichiometry and/or post-translational modification status for collagen type I. In conclusion, this data will be useful to properly interpret results and insights gained from zebrafish models of skeletal diseases.
Large-amplitude (geometrically nonlinear) forced vibrations of a stainless-steel thin rectangular plate carrying different concentrated masses are experimentally studied. The experimental boundary ...conditions are close to those of a clamped plate. The plate is vertically and horizontally tested in order to investigate the gravity effect. Harmonic excitation is applied by using electrodynamic exciter and the plate vibration is measured by using a laser Doppler vibrometer with displacement decoder. The harmonic excitation is controlled in closed-loop in order to keep constant the desired force and is increased (or decreased) by very small discrete steps. Numerical simulations on reduced-order models, obtained by using Von Kármán nonlinear plate theory and global discretization, are also carried out and compared to experiments in order to better understand the system. Results show that concentrated masses have no effect on the trend of nonlinearity of the vertical plate, while they play a role in case of horizontal plate due to the static flexural deflection caused by gravity, which reduces the hardening-type nonlinearity. Initial geometric imperfection (deviation from flat surface in vertical position) of the plate is measured and taken into account; it plays a significant role.
► Comparison of numerical and experimental results. ► Negligible effect of masses on hardening nonlinearity in the absence of gravity. ► With gravity, hardening nonlinearity is reduced increasing the mass. ► Damping increases nonlinearly with the vibration amplitude. ► Geometric imperfections reduce the hardening nonlinearity.
Nonlinear forced vibrations and postbuckling of isotropic rectangular plates subjected to thermal variations are studied. Geometric imperfections are taken into account since they play a fundamental ...role. The plate is modelled by using the Von Kármán hypothesis and the equations of motion are obtained by using an energy approach. Plates with fixed edges and additional rotational elastic constraint are considered. A pseudo-arclength continuation method is used in order to obtain numerical results. Laboratory experiments have been performed on two plates of different thickness.
Purpose
First-generation somatostatin analogs, octreotide (OCT) and lanreotide, are the cornerstone for the medical treatment of growth hormone (GH)-secreting pituitary tumors. A new multireceptor ...analog, such as pasireotide (PAS), showed better activity than OCT in long-term treatment of patients with acromegaly, but modulation of intracellular key processes is still unclear in vitro. In this study, we evaluated the antitumor activity of OCT and PAS in two GH-secreting pituitary tumor cell lines, GH3 and GH4C1, after a long-term incubation.
Methods
The effects of PAS and OCT on the cell viability, cell cycle, apoptosis, GH secretion, and tumor-induced angiogenesis have been evaluated through a colorimetric method (MTS Assay), DNA flow cytometry with propidium iodide, and Annexin V-FITC/propidium iodide staining, ELISA assay and zebrafish platform, respectively.
Results
PAS showed a more potent antitumor activity compared to OCT in GH3 cell line exerted through inhibition of cell viability, perturbation of cell cycle progression, and induction of apoptosis after 6 days of incubation. A concomitant decrease in GH secretion has been observed after 2 days of incubation only with PAS. No effect on tumor-induced angiogenesis has been reported after treatment with OCT or PAS in zebrafish/tumor xenograft model.
Conclusion
Long-term incubation with PAS showed a more potent antitumor activity than that reported after OCT in GH3 cells, mainly modulated by a cell cycle perturbation and a relevant induction in apoptosis.
The U.S. Air Force asked RAND Project AIR FORCE (PAF) to help assess the well-being of its wounded members and the quality of services provided to facilitate their recovery and reintegration. RAND ...PAF fielded a survey in the fall of 2016 to assess wounded airmen's functioning in the domains of physical health, mental health, interpersonal relationships, unemployment, and financial status, as well as their utilization and perceptions of Air Force nonmedical programs for wounded airmen. The authors of this study invited all 713 wounded airmen enrolled in the Air Force Wounded Warrior program to complete the survey, and 270 airmen (38 percent) completed it. One-third of airmen reported difficulty obtaining care for physical or mental health conditions, and one-quarter expressed dissatisfaction with coordination of care. Similar proportions of airmen reported barriers to care for physical and mental health conditions. Difficulty scheduling appointments was the most commonly endorsed barrier for both types of conditions. Small but notable proportions of airmen reported potential social support deficits, unemployment, and financial problems. For many of the Air Force's programs for wounded airmen, over 80 percent of program users reported overall program satisfaction. The authors recommend that the Air Force consider focusing on improving care coordination, increasing health care system capacity, continuing employment assistance, and improving marketing of programs with low uptake.
To ensure its service members have the requisite physical fitness to serve, the Department of the Air Force (DAF) has established a variety of medical and physical standards. The DAF also recognizes ...that building a more comprehensive understanding of how different factors influence exercise habits, test preparation, and the perceived importance of fitness is critical to promoting a ready and deployable force. The authors evaluate Air Force (AF) data relevant to the Tier 1 fitness assessment (FA) from all AF-FAs completed by active duty officers and enlisted personnel from fiscal year (FY) 2005 to FY 2018 to examine the fitness of the AF's active component. The Tier 1 FA consists of four components: a 1.5-mile run or 2.0-kilometer walk, designed to measure cardiorespiratory fitness; an abdominal circumference (AC) measurement for body composition; and push-ups and sit-ups, which assess muscular fitness. In this study, the authors explore the relationships between component fitness scores with career and health outcomes and examine airmen's perceptions of current fitness policies and the culture of fitness across the DAF. They conclude by recommending several strategies to improve the rationale for and the validity and acceptance of the AF-FA.
A finite element formulation for vibration analysis of rotating thick plates is developed. Mindlin plate theory combined with second order strain–displacement assumptions are applied for plate ...modeling. Kane dynamic method is employed for the derivation of nonlinear governing equations of motion, which include Coriolis effects and the couplings between in-plane and out of plane deformations. The nonlinear equations of motion are linearized using the conventional quasi static method and frequency results are obtained. The effects of different parameters including aspect ratio, thickness ratio, hub radius ratio and rotation speed on dimensionless natural frequencies are investigated and discussed. In addition, the differences between linear and nonlinear approaches toward in-plane vibration analysis of rotating plates are studied. Tune speeds are observed for the in-plane vibration frequencies. The results are in good agreement with those of other theories and experiments.
Purpose
Neuroendocrine neoplasms can occur as part of inherited disorders, usually in the form of well-differentiated, slow-growing tumors (NET). The main predisposing syndromes include: multiple ...endocrine neoplasias type 1 (MEN1), associated with a large spectrum of gastroenteropancreatic and thoracic NETs, and type 4 (MEN4), associated with a wide tumour spectrum similar to that of MEN1; von Hippel-Lindau syndrome (VHL), tuberous sclerosis (TSC), and neurofibromatosis 1 (NF-1), associated with pancreatic NETs. In the present review, we propose a reappraisal of the genetic basis and clinical features of gastroenteropancreatic and thoracic NETs in the setting of inherited syndromes with a special focus on molecularly targeted therapies for these lesions.
Methods
Literature search was systematically performed through online databases, including MEDLINE (via PubMed), and Scopus using multiple keywords’ combinations up to June 2022.
Results
Somatostatin analogues (SSAs) remain the mainstay of systemic treatment for NETs, and radiolabelled SSAs can be used for peptide-receptor radionuclide therapy for somatostatin receptor (SSTR)-positive NETs. Apart of these SSTR-targeted therapies, other targeted agents have been approved for NETs: the mTOR inhibitor everolimus for lung, gastroenteropatic and unknown origin NET, and sunitinib, an antiangiogenic tyrosine kinase inhibitor, for pancreatic NET. Novel targeted therapies with other antiangiogenic agents and immunotherapies have been also under evaluation.
Conclusions
Major advances in the understanding of genetic and epigenetic mechanisms of NET development in the context of inherited endocrine disorders have led to the recognition of molecular targetable alterations, providing a rationale for the implementation of treatments and development of novel targeted therapies.
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