This work presents integer programming techniques to tackle the problem of the International Nurse Rostering Competition. Starting from a compact and monolithic formulation in which the current ...generation of solvers performs poorly, improved cut generation strategies and primal heuristics are proposed and evaluated. A large number of computational experiments with these techniques produced the following results: the optimality of the vast majority of instances was proved, the best known solutions were improved by up to 15 % and strong dual bounds were obtained. In the spirit of reproducible science, all code was implemented using the Computational Infrastructure for Operations Research.
The project scheduling problem (PSP) is the subject of several studies in computer science, mathematics, and operations research because of the hardness of solving it and its practical importance. ...This work tackles an extended version of the problem known as the multimode resource-constrained multiproject scheduling problem. A solution to this problem consists of a schedule of jobs from various projects, so that the job allocations do not exceed the stipulated limits of renewable and nonrenewable resources. To accomplish this, a set of execution modes for the jobs must be chosen, as the jobs’ duration and amount of needed resources vary depending on the mode selected. Finally, the schedule must also consider precedence constraints between jobs. This work proposes heuristic methods based on integer programming to solve the PSP considered in the
Multidisciplinary International Scheduling Conference: Theory and Applications
(MISTA) 2013 Challenge. The developed solver was ranked third in the competition, being able to find feasible and competitive solutions for all instances and improving best known solutions for some problems.
Corynebacterium pseudotuberculosis, a facultative intracellular bacterial pathogen, is the etiological agent of caseous lymphadenitis (CLA), an infectious disease that affects sheep and goats and it ...is responsible for significant economic losses. The disease is characterized mainly by bacteria-induced caseous necrosis in lymphatic glands. New vaccines are needed for reliable control and management of CLA. Thus, the putative virulence factors SpaC, SodC, NanH, and PknG from C. pseudotuberculosis FRC41 may represent new target proteins for vaccine development and pathogenicity studies.
SpaC, PknG and NanH presented better vaccine potential than SodC after in silico analyses. A total of 136 B and T cell epitopes were predicted from the four putative virulence factors. A cluster analysis was performed to evaluate the redundancy degree among the sequences of the predicted epitopes; 57 clusters were formed, most of them (34) were single clusters. Two clusters from PknG and one from SpaC grouped epitopes for B and T-cell (MHC I and II). These epitopes can thus potentially stimulate a complete immune response (humoral and cellular) against C. pseudotuberculosis. Several other clusters, including two from NanH, grouped B-cell epitopes with either MHC I or II epitopes. The four target proteins were expressed in Escherichia coli. A purification protocol was developed for PknG expression.
In silico analyses show that the putative virulence factors SpaC, PknG and NanH present good potential for CLA vaccine development. Target proteins were successfully expressed in E. coli. A protocol for PknG purification is described.
The tumor suppressor tuberin, encoded by the Tuberous Sclerosis Complex (TSC) gene
TSC2, negatively regulates the mammalian target of rapamycin (mTOR) pathway, which plays a key role in the control ...of cell growth and proliferation. In addition to naturally occurring mutations, several kinases including Akt, RSK1, and ERK are known to phosphorylate and inactivate tuberin. We demonstrate a novel mechanism of tuberin inactivation through ubiquitination by Pam, a putative RING finger-containing E3 ubiquitin (Ub) ligase in mammalian cells. We show that Pam associates with E2 ubiquitin-conjugating enzymes, and tuberin can be ubiquitinated by Pam through its RING finger domain. Tuberin ubiquitination is independent of its phosphorylation by Akt, RSK1, and ERK kinases. Pam is also self-ubiquitinated through its RING finger domain. Moreover, the TSC1 protein hamartin, which forms a heterodimer with tuberin, protects tuberin from ubiquitination by Pam. However, TSC1 fails to protect a disease-associated missense mutant of TSC2 from ubiquitination by Pam. Furthermore, Pam knockdown by RNA interference (RNAi) in rat primary neurons elevates the level of tuberin, and subsequently inhibits the mTOR pathway. Our results provide novel evidence that Pam can function as an E3 Ub ligase toward tuberin and regulate mTOR signaling, suggesting that Pam can in turn regulate cell growth and proliferation as well as neuronal function through the TSC/mTOR pathway in mammalian cells.
•The 3-D diffusion equation is solved by a new MPFA scheme with a diamond stencil.•The MPFA method handles highly non-homogeneous and non-isotropic media.•It reproduces piecewise linear solutions ...exactly.•Second order accuracy for the scalar variable and first order accurate for fluxes.
In this paper, we propose a non-orthodox Multipoint Flux Approximation scheme with a “Diamond” stencil (MPFA-D) for the solution of the 3-D steady state diffusion equation. Following the work of GAO and WU (2011), in our method, the auxiliary vertex unknowns are eliminated by a novel explicit interpolation that is flux conservative and is constructed under the Linearity-Preserving Criterion (LPC). The MPFA-D is able to reproduce piecewise linear solutions exactly on challenging heterogeneous and anisotropic media, even in cases with some severely distorted meshes. Furthermore, our new scheme presentssecond order accuracy for the scalar unknown and, at least, first order accuracy for fluxes, considering unstructured tetrahedral meshes and arbitrarily anisotropic diffusion tensors. In order to validate our numerical scheme, we perform different test cases, involving 3-D benchmarks on diffusion problems. We compare the performance with other schemes found in literature. We also compare our Linearity-Preserving Explicit Weight (LPEW) interpolation with other interpolations strategies to evaluate its robustness to handle anisotropic and heterogeneous, possibly discontinuous diffusion tensors. In general, our linear preserving MPFA-D method performs well, however it is not monotone, particularly for very distorted meshes and highly anisotropic diffusion tensors.
Tuberous sclerosis complex is caused by mutations in tumor suppressor genes TSC1 or TSC2 and is characterized by the presence of hamartomas in many organs. Although tuberous sclerosis complex is a ...tumor suppressor gene syndrome with classic "second hits" detectable in renal tumors, conventional genetic analysis has not revealed somatic inactivation of the second allele in the majority of human brain lesions. We demonstrate a novel mechanism of post-translational inactivation of the TSC2 protein, tuberin, by physiologically inappropriate phosphorylation, which is specific to tuberous sclerosis complex-associated brain lesions. Additional analysis shows that tissue specificity is due to abnormal activation of the Akt and mitogen-activated protein kinase pathways in brain but not in renal tumors. These results have widespread implications for understanding the tissue specificity of tumor suppressor gene phenotypes.
Noroviruses are a leading cause of epidemic and pandemic acute gastroenteritis (AGE) worldwide, and contaminated food and water are important routes for its transmission. Raw sewage has been used for ...viral surveillance to monitor the emergence of new norovirus strains with the potential to cause epidemics. In this study, we investigated norovirus occurrence and norovirus RNA levels in 156 samples collected from May 2013 to May 2014, across three different stages (52 samples each) of a wastewater treatment plant (WWTP) in Rio de Janeiro, Brazil. We also explored norovirus GII diversity in raw sewage samples by next-sequencing generation (NGS). In addition, we examined norovirus prevalence and molecular epidemiology from acute gastroenteritis cases. Using RT-qPCR, norovirus GI and GII was detected in 38.5% and 96.1% of raw sewage samples, 40.4% and 96.1% of primary effluent samples and 1.9% and 5.8% of final effluent samples, respectively. Norovirus RNA levels varied from 4 to 6.2 log10 genome copies per litre (gc L−1) for GI and from 4.4 to 7.3 log10 gc L−1 for GII. Using MiSeq NGS, we identified 13 norovirus genotypes over the one-year period, with six dominant capsid genotypes, including GII.4, GII.17, GII.5, GII.2, GII.3 and GII.1. GII.4 noroviruses were the most prevalent in wastewater samples (68.5%), and a similar trend was observed in AGE cases (71%). The emergent GII.17 was the second most prevalent genotype (14.3%) identified in the raw sewage samples, however, it was not detected in clinical cases. Due to the high burden of norovirus outbreaks and the lack of vaccine and antiviral drugs, it is essential to understand the genotypic diversity of norovirus at the population level. Complementary data obtained from both clinical and environmental (sewage) samples proved to be an effective strategy to monitor the circulation and emergence of norovirus epidemic genotypes.
•We identified 13 norovirus genotypes in the raw sewage using deep sequencing.•Major and minor norovirus GII genotypes were detected from raw sewage.•Norovirus GII.17 genotype was detected prior to its detection in clinical cases.•Secondary sewage treatment decreased norovirus RNA levels to undetected levels.•Autumn/winter seasonality was observed only for norovirus GI.
We described the detection of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) in stool samples from patients presenting only acute gastroenteritis (AGE) symptoms. From January to July ...2020, 121 AGE stool samples were screened by quantitative reverse‐transcription polymerase chain reaction. We detected SARS‐CoV‐2 in 27.5% of samples received during the epidemic period. No infectious viruses were observed in Vero E6 cells.
In this paper, we prove that a free nilpotent group of finite rank is transitive self-similar. In contrast, we prove that a free metabelian group of rank
r
≥
2
is not transitive self-similar.
Genome annotation of the plant pathogen Xanthomonas axonopodis pv. citri (Xac), identified flagellar genes in a 15.7 kb gene cluster. However, FlgN, a secretion chaperone for hook-associated proteins ...FlgK and FlgL, was not identified. We performed extensive screening of the X. axonopodis pv. citri genome with the yeast two-hybrid system to identify a protein with the characteristics of the flagellar chaperone FlgN. We found a candidate (XAC1990) encoded by an operon for components of the flagellum apparatus that interacted with FlgK. In order to further support this finding, Xac FlgK and XAC1990 were cloned, expressed, and purified. The recombinant proteins were characterized by spectroscopic methods and their interaction in vitro confirmed by pull-down assays. We, therefore, conclude that XAC1990 and its homologs in other Xanthomonas species are, in fact, FlgN proteins. These observations extend the sequence diversity covered by this family of proteins.
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