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The mass production paradigm on which much of the industry was based has changed. The market is increasingly demanding, requesting diversity and products that are more and more adapted to personal wishes and requirements. This implies producing a greater diversity of products in smaller quantities. Competitiveness is enormous, which forces most companies to be truly effective and efficient, taking care of product quality, delivery time, and final cost. Lean methodologies have been a valuable aid in this field. The diversity of Lean tools has been shown to have answers to the most diverse challenges, and companies are aware of this, increasingly adopting methodologies and processes that aim to progressively reduce waste and adapting their production paradigm to what the market requires. This work intends to provide a vision, as global as possible, of the pathway of Lean implementation in the Portuguese industry. For this purpose, a survey was carried out with a significant sample of Portuguese industrial companies from a wide range of activity sectors. The data collected through the survey were treated statistically, and then a SWOT analysis of the results was performed, which provided a collection of precious information on the evolution of industrial companies in Portugal.

We study the burden of the HIV viremia and of treatment efficacy in the severity of the patterns of the HIV/HCV coinfection. For this, we derive a simple non-integer-order (fractional-order) model for the coinfection dynamics. Fractional-order models have been proved in the literature to provide good fits to real data from patients suffering from several diseases, such as HIV, dengue fever, and others. We have computed the basic reproduction number and the stability of the disease-free equilibrium of the model. The numerical results suggest that the HIV viral load impacts impressively the severity of the HCV infection. The treatment efficacy is also found to influence the natural progression of HCV on the HIV/HCV coinfection. The latter is repeated for all values of the order of the fractional derivative. Moreover, the fractional derivative may pave the way to better understanding the individuals’ patients’ adjustments to treatment and to viremia.

Considering that mutations in known prostate cancer (PrCa) predisposition genes, including those responsible for hereditary breast/ovarian cancer and Lynch syndromes, explain less than 5% of early-onset/familial PrCa, we have sequenced 94 genes associated with cancer predisposition using next generation sequencing (NGS) in a series of 121 PrCa patients. We found monoallelic truncating/functionally deleterious mutations in seven genes, including ATM and CHEK2, which have previously been associated with PrCa predisposition, and five new candidate PrCa associated genes involved in cancer predisposing recessive disorders, namely RAD51C, FANCD2, FANCI, CEP57 and RECQL4. Furthermore, using in silico pathogenicity prediction of missense variants among 18 genes associated with breast/ovarian cancer and/or Lynch syndrome, followed by KASP genotyping in 710 healthy controls, we identified \"likely pathogenic\" missense variants in ATM, BRIP1, CHEK2 and TP53. In conclusion, this study has identified putative PrCa predisposing germline mutations in 14.9% of early-onset/familial PrCa patients. Further data will be necessary to confirm the genetic heterogeneity of inherited PrCa predisposition hinted in this study.

APRIL (A Proliferation-Inducing Ligand), a member of the TNF superfamily, was initially described for its ability to promote proliferation of tumor cells in vitro . Moreover, this cytokine has been related to the pathogenesis of different chronic inflammatory diseases, such as rheumatoid arthritis. This study aimed to evaluate the ability of APRIL in regulating B cell-mediated immune response in the antigen-induced arthritis (AIA) model in mice. AIA was induced in previously immunized APRIL-transgenic (Tg) mice and their littermates by administration of antigen (mBSA) into the knee joints. Different inflammatory cell populations in spleen and draining lymph nodes were analyzed using flow cytometry and the assay was performed in the acute and chronic phases of the disease, while cytokine levels were assessed by ELISA. In the acute AIA, APRIL-Tg mice developed a less severe condition and a smaller inflammatory infiltrate in articular tissues when compared with their littermates. We also observed that the total cellularity of draining lymph nodes was decreased in APRIL-Tg mice. Flow cytometry analysis revealed an increase of CD19 + IgM + CD5 + cell population in draining lymph nodes and an increase of CD19 + CD21 hi CD23 hi (B regulatory) cells in APRIL-Tg mice with arthritis as well as an increase of IL-10 and CXCL13 production in vitro .

Truncating pathogenic or likely pathogenic variants of CDH1 cause hereditary diffuse gastric cancer (HDGC), a tumour risk syndrome that predisposes carrier individuals to diffuse gastric and lobular breast cancer. Rare CDH1 missense variants are often classified as variants of unknown significance. We conducted a genotype–phenotype analysis in families carrying rare CDH1 variants, comparing cancer spectrum in carriers of pathogenic or likely pathogenic variants (PV/LPV; analysed jointly) or missense variants of unknown significance, assessing the frequency of families with lobular breast cancer among PV/LPV carrier families, and testing the performance of lobular breast cancer-expanded criteria for CDH1 testing. This genotype-first study used retrospective diagnostic and clinical data from 854 carriers of 398 rare CDH1 variants and 1021 relatives, irrespective of HDGC clinical criteria, from 29 institutions in ten member-countries of the European Reference Network on Tumour Risk Syndromes (ERN GENTURIS). Data were collected from Oct 1, 2018, to Sept 20, 2022. Variants were classified by molecular type and clinical actionability with the American College of Medical Genetics and Association for Molecular Pathology CDH1 guidelines (version 2). Families were categorised by whether they fulfilled the 2015 and 2020 HDGC clinical criteria. Genotype–phenotype associations were analysed by Student's t test, Kruskal-Wallis, χ2, and multivariable logistic regression models. Performance of HDGC clinical criteria sets were assessed with an equivalence test and Youden index, and the areas under the receiver operating characteristic curves were compared by Z test. From 1971 phenotypes (contributed by 854 probands and 1021 relatives aged 1–93 years), 460 had gastric and breast cancer histology available. CDH1 truncating PV/LPVs occurred in 176 (21%) of 854 families and missense variants of unknown significance in 169 (20%) families. Multivariable logistic regression comparing phenotypes occurring in families carrying PV/LPVs or missense variants of unknown significance showed that lobular breast cancer had the greatest positive association with the presence of PV/LPVs (odds ratio 12·39 [95% CI 2·66–57·74], p=0·0014), followed by diffuse gastric cancer (8·00 [2·18–29·39], p=0·0017) and gastric cancer (7·81 [2·03–29·96], p=0·0027). 136 (77%) of 176 families carrying PV/LPVs fulfilled the 2015 HDGC criteria. Of the remaining 40 (23%) families, who did not fulfil the 2015 criteria, 11 fulfilled the 2020 HDGC criteria, and 18 had lobular breast cancer only or lobular breast cancer and gastric cancer, but did not meet the 2020 criteria. No specific CDH1 variant was found to predispose individuals specifically to lobular breast cancer, although 12 (7%) of 176 PV/LPV carrier families had lobular breast cancer only. Addition of three new lobular breast cancer-centred criteria improved testing sensitivity while retaining high specificity. The probability of finding CDH1 PV/LPVs in patients fulfilling the lobular breast cancer-expanded criteria, compared with the 2020 criteria, increased significantly (AUC 0·92 vs 0·88; Z score 3·54; p=0·0004). CDH1 PV/LPVs were positively associated with HDGC-related phenotypes (lobular breast cancer, diffuse gastric cancer, and gastric cancer), and no evidence for a positive association with these phenotypes was found for CDH1 missense variants of unknown significance. CDH1 PV/LPVs occurred often in families with lobular breast cancer who did not fulfil the 2020 HDGC criteria, supporting the expansion of lobular breast cancer-centred criteria. European Reference Network on Genetic Tumour Risk Syndromes, European Regional Development Fund, Fundação para a Ciência e a Tecnologia (Portugal), Cancer Research UK, and European Union's Horizon 2020 research and innovation programme.

In this paper a complex-order van der Pol oscillator is considered. The complex derivative , with α , β ∈ R + is a generalization of the concept of integer derivative, where α =1, β =0. By applying the concept of complex derivative, we obtain a high-dimensional parameter space. Amplitude and period values of the periodic solutions of the two versions of the complex-order van der Pol oscillator are studied for variation of these parameters. Fourier transforms of the periodic solutions of the two oscillators are also analyzed.

We study exotic patterns appearing in a network of coupled Chen oscillators. Namely, we consider a network of two rings coupled through a “buffer” cell, with Z 3 × Z 5 symmetry group. Numerical simulations of the network reveal steady states, rotating waves in one ring and quasiperiodic behavior in the other, and chaotic states in the two rings, to name a few. The different patterns seem to arise through a sequence of Hopf bifurcations, period-doubling, and halving-period bifurcations. The network architecture seems to explain certain observed features, such as equilibria and the rotating waves, whereas the properties of the chaotic oscillator may explain others, such as the quasiperiodic and chaotic states. We use XPPAUT and MATLAB to compute numerically the relevant states.

Tomato mottle mosaic virus (ToMMV) is a tobamovirus found in a Solanum lycopersicum sample collected in Mexico in 2009. To assess the possible presence of ToMMV in Europe, accessions from a historic seed collection were tested by real-time RT-PCR and Illumina sequencing. ToMMV was identified in historical seed accessions produced in France, the Netherlands and Spain. Three different near complete genome sequences were obtained, each corresponding to the country in which the seeds had been produced. Positive samples from France and Spain could be related to the same production location and year, respectively, while the identical genome sequences from the Netherlands were obtained from samples produced in different locations and years between 1981 and 2007. The latter could be due to the fact that the Dutch seed accessions had been repacked in the past at the same location and time as accessions with a relatively high virus load from 2007. This indicates that possibly only the seeds from 2007 originated from ToMMV-infected plants, while the detection of ToMMV in the older seed accessions resulted from cross contamination. This data shows that ToMMV has been around in Europe before its first description and is possibly more widespread than currently known.