Abstract Generalized uniformly invariant convex programming is an important optimization problem that has numerous practical applications, such as transportation planning, engineering optimization, ...etc. The study of its optimal conditions can help solve practical problems and improve efficiency. Optimality conditions serve as the foundation of optimization theory by aiding in understanding the nature and characteristics of problems and providing guidance for the design and analysis of optimization algorithms. Therefore, studying the optimality conditions of generalized uniformly invariant convex programming is highly significant for solving practical problems, promoting the development of optimization theory and algorithm design and analysis, as well as fostering interdisciplinary research. In this research, a novel type of generalized uniform η-V-I invexity function is defined through the use of the η - subdifferential. In the case of the new generalized convex functions, a certain of multiobjective programming with this generalized convexity is discussed, and the corresponding sufficient optimality conditions are obtained.
Serum calcium levels are tightly controlled by an integrated hormone-controlled system that involves active vitamin D 1,25(OH)(2)D, which can elicit calcium mobilization from bone when intestinal ...calcium absorption is decreased. The skeletal adaptations, however, are still poorly characterized. To gain insight into these issues, we analyzed the consequences of specific vitamin D receptor (Vdr) inactivation in the intestine and in mature osteoblasts on calcium and bone homeostasis. We report here that decreased intestinal calcium absorption in intestine-specific Vdr knockout mice resulted in severely reduced skeletal calcium levels so as to ensure normal levels of calcium in the serum. Furthermore, increased 1,25(OH)(2)D levels not only stimulated bone turnover, leading to osteopenia, but also suppressed bone matrix mineralization. This resulted in extensive hyperosteoidosis, also surrounding the osteocytes, and hypomineralization of the entire bone cortex, which may have contributed to the increase in bone fractures. Mechanistically, osteoblastic VDR signaling suppressed calcium incorporation in bone by directly stimulating the transcription of genes encoding mineralization inhibitors. Ablation of skeletal Vdr signaling precluded this calcium transfer from bone to serum, leading to better preservation of bone mass and mineralization. These findings indicate that in mice, maintaining normocalcemia has priority over skeletal integrity, and that to minimize skeletal calcium storage, 1,25(OH)(2)D not only increases calcium release from bone, but also inhibits calcium incorporation in bone.
The transcription factor Osterix (Osx) is required for osteoblast differentiation and bone formation during embryonic development, but it is not known whether Osx has an essential function in ...postnatal bone growth and in bone homeostasis. Conditional deletion of Osx at several time points postnatally revealed that Osx was essential for osteoblast differentiation and new bone formation in growing and adult bones. Additionally, inactivation of Osx in bones severely disrupted the maturation, morphology, and function of osteocytes. These findings identify Osx as having an essential role in the cell-specific genetic program of osteocytes. Interestingly, Osx inactivation also led to the massive accumulation of unresorbed calcified cartilage in a large area below the growth plate of endochondral bones. This specific area was also marked by an unanticipated almost complete lack of bone marrow cells and a marked decrease in the density and size of osteoclasts. This diminished density of osteoclasts could contribute to the lack of resorption of mineralized cartilage. In addition, we speculate that the abnormally accumulated, mainly naked cartilage represents an unfavorable substrate for osteoclasts. Our study identifies Osx as an essential multifunctional player in postnatal bone growth and homeostasis.
Evaluating the efficiency of health resource allocations is critical to improving China's rural three-level health service network.
This was a prospective panel data study.
Based on panel data of the ...medical and health resources of 31 provinces within rural China, collected from 2003 to 2020, this study uses a three-stage Data Envelopment Analysis–Malmquist index to analyze the evolution of efficiency and productivity.
The efficiency and productivity of county and county-level medical and health institutions rank highest, followed by township hospitals, whereas village clinics are shown to be in great need of improvement. A decline in technical advancement appears as a crucial factor exacerbating loss of factor productivity.
Policy makers should further optimize the efficiency of medical resource allocation and promote the coordinated development of rural health in China.
: Vibration of a new concrete bridge was monitored and change in the bridge structural stiffness was identified accordingly over a 5‐year period. This three‐span 111‐m long bridge is instrumented ...with 13 acceleration sensors at both the superstructure and the columns. The sensor data are transmitted to a server computer wirelessly. Modal parameters of the bridge, that is, the frequencies and the modal shapes were identified by processing 1,707 vibration data sets collected under traffic excitations, based on which the bridge structural parameters, stiffness and mass, and the soil spring values were identified by employing the neural network technique. The identified superstructure stiffness at the beginning of the monitoring was 97% of the stiffness value based on the design drawings. In the identified modal frequencies, a variation from −10% to +10% was observed over the monitoring period. In the identified stiffness values of the bridge superstructure, a variation from −3% to +3% was observed over the monitoring period. Based on the statistical analysis of the collected data for each year, 5% decrease in the first modal frequency and 2% decrease in the superstructure stiffness were observed over the 5‐year monitoring period. Probability density functions were obtained for stiffness values each year. Stiffness threshold values for the collapse of the bridge under the operational loading can be determined. Then the number of years can be assessed for which the area under the proposed probability density functions is greater than the threshold value. So the information obtained in this study is valuable for studying aging and long‐term performance assessment of similar bridges.
Osteoporosis, osteopenia, and pathological bone fractures are frequent complications of iron-overload conditions such as hereditary hemochromatosis, thalassemia, and sickle cell disease. Moreover, ...animal models of iron overload have revealed increased bone resorption and decreased bone formation. Although systemic iron overload affects multiple organs and tissues, leading to significant changes on bone modeling and remodeling, the cell autonomous effects of excessive iron on bone cells remain unknown. Here, to elucidate the role of cellular iron homeostasis in osteoclasts, we generated two mouse strains in which solute carrier family 40 member 1 (Slc40a1), a gene encoding ferroportin (FPN), the sole iron exporter in mammalian cells, was specifically deleted in myeloid osteoclast precursors or mature cells. The FPN deletion mildly increased iron levels in both precursor and mature osteoclasts, and its loss in precursors, but not in mature cells, increased osteoclastogenesis and decreased bone mass in vivo. Of note, these phenotypes were more pronounced in female than in male mice. In vitro studies revealed that the elevated intracellular iron promoted macrophage proliferation and amplified expression of nuclear factor of activated T cells 1 (Nfatc1) and PPARG coactivator 1β (Pgc-1β), two transcription factors critical for osteoclast differentiation. However, the iron excess did not affect osteoclast survival. While increased iron stimulated global mitochondrial metabolism in osteoclast precursors, it had little influence on mitochondrial mass and reactive oxygen species production. These results indicate that FPN-regulated intracellular iron levels are critical for mitochondrial metabolism, osteoclastogenesis, and skeletal homeostasis in mice.
Cholesterol reduction from statin therapy has been one of the greatest public health successes in modern medicine. Simvastatin is among the most commonly used prescription medications. A ...non‐synonymous coding single‐nucleotide polymorphism (SNP), rs4149056, in SLCO1B1 markedly increases systemic exposure to simvastatin and the risk of muscle toxicity. This guideline explores the relationship between rs4149056 (c.521T>C, p.V174A) and clinical outcome for all statins. The strength of the evidence is high for myopathy with simvastatin. We limit our recommendations accordingly.
Clinical Pharmacology & Therapeutics (2012); 92 1, 112–117. doi:10.1038/clpt.2012.57
Tumor cells preferentially adopt aerobic glycolysis for their energy supply, a phenomenon known as the Warburg effect. It remains a matter of debate as to how the Warburg effect is regulated during ...tumor progression. Here, we show that CHIP (carboxyl terminus of Hsc70-interacting protein), a U-box E3 ligase, suppresses tumor progression in ovarian carcinomas by inhibiting aerobic glycolysis. While CHIP is downregulated in ovarian carcinoma, induced expression of CHIP results in significant inhibition of the tumor growth examined by in vitro and in vivo experiments. Reciprocally, depletion of CHIP leads to promotion of tumor growth. By a SiLAD proteomics analysis, we identified pyruvate kinase isoenzyme M2 (PKM2), a critical regulator of glycolysis in tumors, as a target that CHIP mediated for degradation. Accordingly, we show that CHIP regulates PKM2 protein stability and thereafter the energy metabolic processes. Depletion or knockout of CHIP increased the glycolytic products in both tumor and mouse embryonic fibroblast cells. Simultaneously, we observed that CHIP expression inversely correlated with PKM2 levels in human ovarian carcinomas. This study reveals a mechanism that the Warburg effect is regulated by CHIP through its function as an E3 ligase, which mediates the degradation of PKM2 during tumor progression. Our findings shed new light into understanding of ovarian carcinomas and may provide a new therapeutic strategy for ovarian cancer.
Metallic osmium (Os) is one of the most exceptional elemental materials, having, at ambient pressure, the highest known density and one of the highest cohesive energies and melting temperatures. It ...is also very incompressible, but its high-pressure behaviour is not well understood because it has been studied so far only at pressures below 75 gigapascals. Here we report powder X-ray diffraction measurements on Os at multi-megabar pressures using both conventional and double-stage diamond anvil cells, with accurate pressure determination ensured by first obtaining self-consistent equations of state of gold, platinum, and tungsten in static experiments up to 500 gigapascals. These measurements allow us to show that Os retains its hexagonal close-packed structure upon compression to over 770 gigapascals. But although its molar volume monotonically decreases with pressure, the unit cell parameter ratio of Os exhibits anomalies at approximately 150 gigapascals and 440 gigapascals. Dynamical mean-field theory calculations suggest that the former anomaly is a signature of the topological change of the Fermi surface for valence electrons. However, the anomaly at 440 gigapascals might be related to an electronic transition associated with pressure-induced interactions between core electrons. The ability to affect the core electrons under static high-pressure experimental conditions, even for incompressible metals such as Os, opens up opportunities to search for new states of matter under extreme compression.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Irreversible hypofunction of salivary glands is a common side effect of radiotherapy for head and neck cancer and is difficult to remedy. Recent studies indicate that transient activation of Hedgehog ...signaling rescues irradiation-impaired salivary function in animal models, but the underlying mechanisms are largely unclear. Here, we show in mice that activation of canonical Gli-dependent Hedgehog signaling by Gli1 gene transfer is sufficient to recover salivary function impaired by irradiation. Salivary gland cells responsive to Hedgehog/Gli signaling comprised small subsets of macrophages, epithelial cells, and endothelial cells, and their progeny remained relatively rare long after irradiation and transient Hedgehog activation. Quantities and activities of salivary gland resident macrophages were substantially and rapidly impaired by irradiation and restored by Hedgehog activation. Conversely, depletion of salivary gland macrophages by clodronate liposomes compromised the restoration of irradiation-impaired salivary function by transient Hedgehog activation. Single-cell RNA sequencing and qRT-PCR of sorted cells indicated that Hedgehog activation greatly enhances paracrine interactions between salivary gland resident macrophages, epithelial progenitors, and endothelial cells through Csf1, Hgf, and C1q signaling pathways. Consistently, expression of these paracrine factors and their receptors in salivary glands decreased following irradiation but were restored by transient Hedgehog activation. These findings reveal that resident macrophages and their prorepair paracrine factors are essential for the rescue of irradiation-impaired salivary function by transient Hedgehog activation and are promising therapeutic targets of radiotherapy-induced irreversible dry mouth. SIGNIFICANCE: These findings illuminate a novel direction for developing effective treatment of irreversible dry mouth, which is common after radiotherapy for head and neck cancer and for which no effective treatments are available. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/24/5531/F1.large.jpg.
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