Cholesterol oxides accumulate in human cataracts

Glucocorticoids induce hyperinsulinemia, hyperglycemia, and depress glucose transport by aortic endothelium. High glucocorticoid doses are used for many diseases, but with unknown effects on brain glucose transport or metabolism. This study tested the hypothesis that glucocorticoids affect glucose transport or metabolism by brain microvascular endothelium. Male rats received dexamethasone (DEX) s.c. with sucrose feeding for up to seven days. Cerebral microvessels from rats treated with DEX/sucrose demonstrated increased GLUT1 and brain glucose extraction compared to controls. Glucose transport in vivo correlated with hyperinsulinemia. Pre-treatment with low doses of streptozotocin blunted hyperinsulinemia and prevented increased glucose extraction induced by DEX. In contrast, isolated brain microvessels exposed to DEX in vitro demonstrated suppression of 2-deoxyglucose uptake and glucose oxidation. We conclude that DEX/sucrose treatment in vivo increases blood-brain glucose transport in a manner that requires the effects of chronic hyperinsulinemia. These effects override any direct inhibitory effects of either hyperglycemia or DEX.     

An exact method for determining the surface of a countercurrent heat exchanger when the tube side coefficient governs and is a parabolic function of temperature

The “Thermal effectiveness-Transfer unit” charts developed by the authors, for the countercurrent heat exchanger, assume that the overall heat transfer coefficient varies as a parabolic function of temperature; their use can lead to greater accuracy in calculating heat transfer areas.     

Design Optimization of Composite Prosthetic Tubes Using GA-ANN Algorithm Considering Tsai-Wu Failure Criteria

The investigation of possible failures in composite materials is a matter of very great importance, and the Tsai-Wu criterion is an effective criterion for analyzing those flaws in anisotropic materials and defining whether the material at a given load will or will not suffer structural failure. In this study, an optimization procedure is proposed to minimize the maximum value of Tsai-Wu of laminated composite tubes subject to axial loading. Artificial neural networks and genetic algorithms are chosen as optimization tools. The results of this study show that the developed algorithm converges faster. Then, the maximum Tsai-Wu value is used as the objective function and the fiber orientations are the constraints in the optimization process. The results yielded by them are compared and discussed. Optimal results are compared with respect to the usual initial design. The design approach is recommended for structures where composites are the key load-carrying members such as orthopedic prosthesis.     

Is neglected heterogeneity really an issue in binary and fractional regression models? A simulation exercise for logit, probit and loglog models

Theoretical and simulation analysis is performed to examine whether unobserved heterogeneity independent of the included regressors is really an issue in logit, probit and loglog models with both binary and fractional data. It is found that unobserved heterogeneity has the following effects. First, it produces an attenuation bias in the estimation of regression coefficients. Second, although it is innocuous for logit estimation of average sample partial effects, it may generate biased estimation of those effects in the probit and loglog models. Third, it has much more deleterious effects on the estimation of population partial effects. Fourth, it is only for logit models that it does not substantially affect the prediction of outcomes. Fifth, it is innocuous for the size of Wald tests for the significance of observed regressors but, in small samples, it substantially reduces their power.     

A methodology for the generation of planar models for multibody chain drives

To overcome the difficulty on building manually complex models of chain drives, this work proposes a comprehensive methodology to build multibody models of any general chain drive automatically from a minimal set of data. The proposed procedure also evaluates the initial positions and velocities of all components of the drive that are consistent with the kinematic joints or with the contact pairs used in the model. In this methodology, all links and sprockets are represented by rigid bodies connected to each other either by ideal or by clearance revolute joints. The clearance revolute joint contact is further extended to handle the contact between the chain rollers and the sprocket teeth exact profiles. A suitable cylindrical continuous contact law is applied to describe the interaction on all contact pairs. One of the complexities of the computational study of roller chain drives is the large number of bodies in the system and the dynamics of the successive engagement and disengagement of the rollers with the sprockets. Each time a roller engages or disengages with a sprocket tooth, the number of rigid bodies in contact changes. The search for the contact pairs is recognized as one of the most time consuming task in contact analysis. This work proposes a procedure to specify the contact pairs and their update during the dynamic analysis optimizing the computational efficiency of the contact search. The methodologies adopted result in a general computer program that is applied and demonstrated in a generic chain drive that can be used in industrial machines, vehicle engines or any other type of mechanical system.     

Ferroptosis Modulation: Potential Therapeutic Target for Glioblastoma Treatment

Glioblastoma multiforme is a lethal disease and represents the most common and severe type of glioma. Drug resistance and the evasion of cell death are the main characteristics of its malignancy, leading to a high percentage of disease recurrence and the patients’ low survival rate. Exploiting the modulation of cell death mechanisms could be an important strategy to prevent tumor development and reverse the high mortality and morbidity rates in glioblastoma patients. Ferroptosis is a recently described type of cell death, which is characterized by iron accumulation, high levels of polyunsaturated fatty acid (PUFA)-containing phospholipids, and deficiency in lipid peroxidation repair. Several studies have demonstrated that ferroptosis has a potential role in cancer treatment and could be a promising approach for glioblastoma patients. Thus, here, we present an overview of the mechanisms of the iron-dependent cell death and summarize the current findings of ferroptosis modulation on glioblastoma including its non-canonical pathway. Moreover, we focused on new ferroptosis-inducing compounds for glioma treatment, and we highlight the key ferroptosis-related genes to glioma prognosis, which could be further explored. Thereby, understanding how to trigger ferroptosis in glioblastoma may provide promising pharmacological targets and indicate new therapeutic approaches to increase the survival of glioblastoma patients.     

Loxin Reduced the Inflammatory Response in the Liver and the Aortic Fatty Streak Formation in Mice Fed with a High-Fat Diet

Oxidized low-density lipoprotein (ox-LDL) is the most harmful form of cholesterol associated with vascular atherosclerosis and hepatic injury, mainly due to inflammatory cell infiltration and subsequent severe tissue injury. Lox-1 is the central ox-LDL receptor expressed in endothelial and immune cells, its activation regulating inflammatory cytokines and chemotactic factor secretion. Recently, a Lox-1 truncated protein isoform lacking the ox-LDL binding domain named LOXIN has been described. We have previously shown that LOXIN overexpression blocked Lox-1-mediated ox-LDL internalization in human endothelial progenitor cells in vitro. However, the functional role of LOXIN in targeting inflammation or tissue injury in vivo remains unknown. In this study, we investigate whether LOXIN modulated the expression of Lox-1 and reduced the inflammatory response in a high-fat-diet mice model. Results indicate that human LOXIN blocks Lox-1 mediated uptake of ox-LDL in H4-II-E-C3 cells. Furthermore, in vivo experiments showed that overexpression of LOXIN reduced both fatty streak lesions in the aorta and inflammation and fibrosis in the liver. These findings were associated with the down-regulation of Lox-1 in endothelial cells. Then, LOXIN prevents hepatic and aortic tissue damage in vivo associated with reduced Lox-1 expression in endothelial cells. We encourage future research to understand better the underlying molecular mechanisms and potential therapeutic use of LOXIN.     

Diverse nearest neighbors queries using linear skylines

k-nearest neighbor (k-NN) queries are well-known and widely used in a plethora of applications. However, in the original definition of k-NN queries there is no concern regarding diversity of the answer set with respect to the user’s interests. For instance, travelers may be looking for touristic sites that are close to where they are, but that would also lead them to see different parts of the city. Likewise, if one is looking for restaurants close by, it may be more interesting to learn about restaurants of different categories or ethnicities which are nonetheless relatively close. The interesting novel aspect of this type of query is that there are two competing criteria to be optimized: closeness and diversity. We propose two approaches that leverage the notion of linear skyline queries in order to find the k diverse nearest neighbors within a radius r from a given query point, or (k, r)-DNNs for short. Our proposed approaches return a relatively small set containing all optimal solutions for any linear combination of the weights a user could give to the two competing criteria, and we consider three different notions of diversity: spatial, categorical and angular. Our experiments, varying a number of parameters and exploring synthetic and real datasets, in both Euclidean space and road networks, respectively, show that our approaches are several orders of magnitude faster than a straightforward approach.     

Col4a3-/- Mice on Balb/C Background Have Less Severe Cardiorespiratory Phenotype and SGLT2 Over-Expression Compared to 129x1/SvJ and C57Bl/6 Backgrounds

Alport syndrome (AS) is a hereditary renal disorder with no etiological therapy. In the preclinical Col4a3^-/- model of AS, disease progression and severity vary depending on mouse strain. The sodium-glucose cotransporter 2 (SGLT2) is emerging as an attractive therapeutic target in cardiac/renal pathologies, but its application to AS remains untested. This study investigates cardiorespiratory function and SGLT2 renal expression in Col4a3^-/- mice from three different genetic backgrounds, 129x1/SvJ, C57Bl/6 and Balb/C. male Col4a3^-/- 129x1/SvJ mice displayed alterations consistent with heart failure with preserved ejection fraction (HFpEF). Female, but not male, C57Bl/6 and Balb/C Col4a3^-/- mice exhibited mild changes in systolic and diastolic function of the heart by echocardiography. Male C57Bl/6 Col4a3^-/- mice presented systolic dysfunction by invasive hemodynamic analysis. All strains except Balb/C males demonstrated alterations in respiratory function. SGLT2 expression was significantly increased in AS compared to WT mice from all strains. However, cardiorespiratory abnormalities and SGLT2 over-expression were significantly less in AS Balb/C mice compared to the other two strains. Systolic blood pressure was significantly elevated only in mutant 129x1/SvJ mice. The results provide further evidence for strain-dependent cardiorespiratory and hypertensive phenotype variations in mouse AS models, corroborated by renal SGLT2 expression, and support ongoing initiatives to develop SGLT2 inhibitors for the treatment of AS.