An economic order quantity stochastic dynamic optimization model in a logistic 4.0 environment

This paper proposes a stock dynamic sizing optimization under the Logistic 4.0 environment. The safety stock is conceived to fill up the demand variability, providing continuous stock availability. Logistic 4.0 and the smart factory topics are considered. It focuses on vertical integration to implement flexible and reconfigurable smart production systems using the information system integration in order to optimize material flow in a 4.0 full-service approach. The proposed methodology aims to reduce the occurring stock-out events through a link among the wear-out items rate and the downstream logistic demand. The failure rate items trend is obtained through life-cycle state detection by a curve fitting technique. Therefore, the optimal safety stock size is calculated and then validated by an auto-tuning iterative modified algorithm. In this study, the reorder time has been optimized. The case study refers to the material management of a very high-speed train

An analysis of task assignment and cycle times when robots are added to human-operated assembly lines, using mathematical programming models

Abstract Adding robots to a human-operated assembly line influences both the short- and long-term operation of the line. However, the effects of robots on assembly line capacity and on cycle time can only be studied if appropriate task assignment models are available. This paper shows how traditional assembly line balancing models can be changed in order to determine the optimal number of workstations and cycle time when robots with different technological capabilities are able to perform a predetermined set of tasks. The mathematical programming models for the following three cases are presented and analysed: i) only workers are assigned to the workstations; ii) either a worker or a robot is assigned to a workstation; iii) a robot and a worker are also assigned to specific workstations. The data of an assembly line producing power inverters is used to illustrate the proposed calculations. Both the assignment of tasks and the changes of cycle time are analysed within the AIMMS modelling environment. The computational characteristics of the proposed mathematical programming models are also examined and tested using benchmark problems. The models presented in this paper can assist operations management in making decisions relating to assembly line configuration

Discovery of a Potent and Orally Active Dual GPBAR1/CysLT1R Modulator for the Treatment of Metabolic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are two highly prevalent human diseases caused by excessive fat deposition in the liver. Although multiple approaches have been suggested, NAFLD/NASH remains an unmet clinical need. Here, we report the discovery of a novel class of hybrid molecules designed to function as cysteinyl leukotriene receptor 1 (CysLT1R) antagonists and G protein bile acid receptor 1 (GPBAR1/TGR5) agonists for the treatment of NAFLD/NASH. The most potent of these compounds generated by harnessing the scaffold of the previously described CystLT1R antagonists showed efficacy in reversing liver histopathology features in a preclinical model of NASH, reshaping the liver transcriptome and the lipid and energy metabolism in the liver and adipose tissues. In summary, the present study described a novel orally active dual CysLT1R antagonist/GPBAR1 agonist that effectively protects against the development of NAFLD/NASH, showing promise for further development

Single-Cell Redox Imaging Demonstrates a Distinctive Response of Dopaminergic Neurons to Oxidative Insults

Producción CientíficaAims: The study of the intracellular oxido-reductive (redox) state is of extreme relevance to the dopamine (DA) neurons of the substantia nigra pars compacta. These cells possess a distinct physiology intrinsically associated with elevated reactive oxygen species production, and they selectively degenerate in Parkinson's disease under oxidative stress conditions. To test the hypothesis that these cells display a unique redox response to mild, physiologically relevant oxidative insults when compared with other neuronal populations, we sought to develop a novel method for quantitatively assessing mild variations in intracellular redox state. Results: We have developed a new imaging strategy to study redox variations in single cells, which is sensitive enough to detect changes within the physiological range. We studied DA neurons' physiological redox response in biological systems of increasing complexity--from primary cultures to zebrafish larvae, to mammalian brains-and identified a redox response that is distinctive for substantia nigra pars compacta DA neurons. We studied simultaneously, and in the same cells, redox state and signaling activation and found that these phenomena are synchronized. Innovation: The redox histochemistry method we have developed allows for sensitive quantification of intracellular redox state in situ. As this method is compatible with traditional immunohistochemical techniques, it can be applied to diverse settings to investigate, in theory, any cell type of interest. Conclusion: Although the technique we have developed is of general interest, these findings provide insights into the biology of DA neurons in health and disease and may have implications for therapeutic intervention

Cabozantinib After a Previous Immune Checkpoint Inhibitor in Metastatic Renal Cell Carcinoma: A Retrospective Multi-Institutional Analysis

Background: Angiogenesis has been recognized as the most important factor for tumor invasion, proliferation, and progression in metastatic renal cell carcinoma (mRCC). However, few clinical data are available regarding the efficacy of cabozantinib following immunotherapy. Objective: To describe the outcome of cabozantinib in patients previously treated with immunotherapy. Patients and methods: Patients with mRCC who received cabozantinib immediately after nivolumab were included. The primary endpoint was to assess the outcome in terms of efficacy and activity. Results: Eighty-four mRCC patients met the criteria to be included in the final analysis. After a median follow-up of 9.4 months, median overall survival was 17.3 months. According to the IMDC criteria, the rates of patients alive at 12 months in the good, intermediate, and poor prognostic groups were 100%, 74%, and 33%, respectively (p < 0.001). The median progression-free survival (PFS) was 11.5 months (95% CI 8.3-14.7); no difference was found based on duration of previous first-line therapy or nivolumab PFS. The overall response rate was 52%, stable disease was found as the best response in 25.3% and progressive disease in 22.7% of patients. Among the 35 patients with progressive disease on nivolumab, 26 (74.3%) patients showed complete/partial response or stable disease with cabozantinib as best response after nivolumab. The major limitations of this study are the retrospective nature and the short follow-up. Conclusions: Cabozantinib was shown to be effective and active in patients previously receiving immune checkpoint inhibitors. Therefore, cabozantinib can be considered a valid therapeutic option for previously treated mRCC patients, irrespective of the type and duration of prior therapies

Heavy Metals Concentrations in Fish from Sicily (Mediterranean Sea) and Evaluation of Possible Health Risks to Consumers

Cadmium, lead, mercury and chromium concentrations in fish muscle tissue taken from various Sicilian areas were detected. Fish caught in Siracusa, nearby a petrochemical industrial area, were more contaminated by cadmium, lead and chromium (respectively 0.366, 0.32, 0.72 μg/g) than those from the other sites. In the Sicily Channel, we found the highest bioaccumulation of mercury (0.31 μg/g). Although some metals concentrations exceed the limits set by the European regulation, the estimated weekly intake was below the Provisional Tolerable Weekly Intake established by the European Food and Safety Authority, and the Target Hazard Quotient values indicate that there is no carcinogenic risk for humans

Cardiac teleconsulting in the time of COVID-19 global pandemic: The "Antonio Cardarelli" Hospital project.

Dear Editor, Teleconsulting - defined as real-time consultation between doctors by exploiting video conferencing technology over the Internet network - is exponentially being implemented through the western world lastly triggered by COVID-19 pandemic..

Discovery That Theonellasterol a Marine Sponge Sterol Is a Highly Selective FXR Antagonist That Protects against Liver Injury in Cholestasis

Background: The farnesoid-x-receptor (FXR) is a bile acid sensor expressed in the liver and gastrointestinal tract. Despite FXR ligands are under investigation for treatment of cholestasis, a biochemical condition occurring in a number of liver diseases for which available therapies are poorly effective, mice harboring a disrupted FXR are protected against liver injury caused by bile acid overload in rodent models of cholestasis. Theonellasterol is a 4-methylene-24-ethylsteroid isolated from the marine sponge Theonella swinhoei. Here, we have characterized the activity of this theonellasterol on FXR-regulated genes and biological functions. Principal Findings: Interrogation of HepG2 cells, a human hepatocyte cell line, by microarray analysis and transactivation assay shows that theonellasterol is a selective FXR antagonist, devoid of any agonistic or antagonistic activity on a number of human nuclear receptors including the vitamin D receptor, PPARs, PXR, LXRs, progesterone, estrogen, glucorticoid and thyroid receptors, among others. Exposure of HepG2 cells to theonellasterol antagonizes the effect of natural and synthetic FXR agonists on FXR-regulated genes, including SHP, OSTa, BSEP and MRP4. A proof-of-concept study carried out to investigate whether FXR antagonism rescues mice from liver injury caused by the ligation of the common bile duct, a model of obstructive cholestasis, demonstrated that theonellasterol attenuates injury caused by bile duct ligation as measured by assessing serum alanine aminostrasferase levels and extent of liver necrosis at histopathology. Analysis of genes involved in bile acid uptake and excretion by hepatocytes revealed that theonellasterol increases the liver expression of MRP4, a basolateral transporter that is negatively regulated by FXR. Administering bile duct ligated mice with an FXR agonist failed to rescue from liver injury and downregulated the expression of MRP4. Conclusions: FXR antagonism in vivo results in a positive modulation of MRP4 expression in the liver and is a feasible strategy to target obstructive cholestasis

The effect of autistic traits on disembedding and mental rotation in neurotypical women and men

Funder: Autism Research TrustFunder: Templeton World Charitable FundFunder: NIHR Cambridge Biomedical Research Centre; doi: http://dx.doi.org/10.13039/501100018956Funder: National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health ResearchFunder: Care East of England at Cambridgeshire and Peterborough NHS Foundation TrustAbstractRecent data has revealed dissociations between social and non-social skills in both autistic and neurotypical populations. In the present study, we investigated whether specific visuospatial abilities, such as figure disembedding and mental rotation, are differently related to social and non-social autistic traits, in neurotypical women and men. University students (N = 426) completed the Autism Spectrum Quotient (AQ), figure disembedding and mental rotation of two-dimensional figures tasks. AQ social skills (AQ-social) and attention-to-details (AQ-attention) subscales were used as measures of social and non-social autistic traits, respectively. Mental rotation was affected by a significant interaction between sex, social and non-social traits. When non-social traits were above the mean (+ 1 SD), no sex differences in mental rotation were found. Instead, below this value, sex differences depended on the social traits, with men on average outperforming women at middle-to-high social traits, and with a comparable performance, and with women on average outperforming men, at lower social traits. A small positive correlation between figure disembedding and social traits was observed in the overall sample. These results are interpreted in terms of the hyper-systemizing theory of autism and contribute to the evidence of individual differences in the cognitive style of autistic people and neurotypical people with autistic traits.</jats:p