Optimal Control of State Constrained Integral Equations

We consider the optimal control problem of a class of integral equations with initial and final state constraints, as well as running state constraints. We prove Pontryagin’s principle, and study the continuity of the optimal control and of the measure associated with first order state constraints. We also establish the Lipschitz continuity of these two functions of time for problems with only first order state constraints.Fil: Bonnans, J. Frederic. Institut National de Recherche en Informatique et en Automatique; FranciaFil: Sanchez Fernandez de la Vega, Constanza Mariel. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Matemática; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Investigaciones Matemáticas "Luis A. Santaló"; Argentin

A Robust AFPTAS for Online Bin Packing with Polynomial Migration

In this paper we develop general LP and ILP techniques to find an approximate solution with improved objective value close to an existing solution. The task of improving an approximate solution is closely related to a classical theorem of Cook et al. in the sensitivity analysis for LPs and ILPs. This result is often applied in designing robust algorithms for online problems. We apply our new techniques to the online bin packing problem, where it is allowed to reassign a certain number of items, measured by the migration factor. The migration factor is defined by the total size of reassigned items divided by the size of the arriving item. We obtain a robust asymptotic fully polynomial time approximation scheme (AFPTAS) for the online bin packing problem with migration factor bounded by a polynomial in $\frac{1}{\epsilon}$. This answers an open question stated by Epstein and Levin in the affirmative. As a byproduct we prove an approximate variant of the sensitivity theorem by Cook at el. for linear programs

The T Box Transcription Factor TBX2 Promotes Epithelial-Mesenchymal Transition and Invasion of Normal and Malignant Breast Epithelial Cells

The T box transcription factor TBX2, a master regulator of organogenesis, is aberrantly amplified in aggressive human epithelial cancers. While it has been shown that overexpression of TBX2 can bypass senescence, a failsafe mechanism against cancer, its potential role in tumor invasion has remained obscure. Here we demonstrate that TBX2 is a strong cell-autonomous inducer of the epithelial-mesenchymal transition (EMT), a latent morphogenetic program that is key to tumor progression from noninvasive to invasive malignant states. Ectopic expression of TBX2 in normal HC11 and MCF10A mammary epithelial cells was sufficient to induce morphological, molecular, and behavioral changes characteristic of EMT. These changes included loss of epithelial adhesion and polarity gene (E-cadherin, ß-catenin, ZO1) expression, and abnormal gain of mesenchymal markers (N-cadherin, Vimentin), as well as increased cell motility and invasion. Conversely, abrogation of endogenous TBX2 overexpression in the malignant human breast carcinoma cell lines MDA-MB-435 and MDA-MB-157 led to a restitution of epithelial characteristics with reciprocal loss of mesenchymal markers. Importantly, TBX2 inhibition abolished tumor cell invasion and the capacity to form lung metastases in a Xenograft mouse model. Meta-analysis of gene expression in over one thousand primary human breast tumors further showed that high TBX2 expression was significantly associated with reduced metastasis-free survival in patients, and with tumor subtypes enriched in EMT gene signatures, consistent with a role of TBX2 in oncogenic EMT. ChIP analysis and cell-based reporter assays further revealed that TBX2 directly represses transcription of E-cadherin, a tumor suppressor gene, whose loss is crucial for malignant tumor progression. Collectively, our results uncover an unanticipated link between TBX2 deregulation in cancer and the acquisition of EMT and invasive features of epithelial tumor cells

Nucleases of Metallo-Beta-Lactamase and Protein Phosphatase Families in DNA Repair

24 páginas, 5 figuras, 3 tablas -- PAGS nros. 211-234, Capítulo 11DNA repair is fundamental to all cell types to maintain genomic stability. A collection of cutting-edge reviews, DNA Repair - On the pathways to fixing DNA damage and errors covers major aspects of the DNA repair processes in a large variety of organisms, emphasizing foremost developments, questions to be solved and new directions in this rapidly evolving area of modern biology. Written by researchers at the vanguard of the DNA repair field, the chapters highlight the importance of the DNA repair mechanisms and their linkage to DNA replication, cell-cycle progression and DNA recombination. Major topics include: base excision repair, nucleotide excision repair, mismatch repair, double-strand break repair, with focus on specific inhibitors and key players of DNA repair such as nucleases, ubiquitin-proteasome enzymes, poly ADP-ribose polymerase and factors relevant for DNA repair in mitochondria and embryonic stem cells. This book is a journey into the cosmos of DNA repair and its frontiersThe authors will like to acknowledge financial support from grants PET2008_0101 and BFU2010-22260-C02-02 from the Spanish Ministry of Science and Innovation (MICINN) to MCV. FJF and MLE were supported by the MICINN grant PET2008-0101 and a fellowship (ME-517217) from the Spanish Ministry of Education, respectivelyPeer reviewe

The UlaG protein family defines novel structural and functional motifs grafted on an ancient RNase fold

Background: Bacterial populations are highly successful at colonizing new habitats and adapting to changing environmental conditions, partly due to their capacity to evolve novel virulence and metabolic pathways in response to stress conditions and to shuffle them by horizontal gene transfer (HGT). A common theme in the evolution of new functions consists of gene duplication followed by functional divergence. UlaG, a unique manganese-dependent metallo-b-lactamase (MBL) enzyme involved in L-ascorbate metabolism by commensal and symbiotic enterobacteria, provides a model for the study of the emergence of new catalytic activities from the modification of an ancient fold. Furthermore, UlaG is the founding member of the so-called UlaG-like (UlaGL) protein family, a recently established and poorly characterized family comprising divalent (and perhaps trivalent)metal-binding MBLs that catalyze transformations on phosphorylated sugars and nucleotides. Results: Here we combined protein structure-guided and sequence-only molecular phylogenetic analyses to dissect the molecular evolution of UlaG and to study its phylogenomic distribution, its relatedness with present-day UlaGL protein sequences and functional conservation. Phylogenetic analyses indicate that UlaGL sequences are present in Bacteria and Archaea, with bona fide orthologs found mainly in mammalian and plant-associated Gramnegative and Gram-positive bacteria. The incongruence between the UlaGL tree and known species trees indicates exchange by HGT and suggests that the UlaGL-encoding genes provided a growth advantage under changing conditions. Our search for more distantly related protein sequences aided by structural homology has uncovered that UlaGL sequences have a common evolutionary origin with present-day RNA processing and metabolizing MBL enzymes widespread in Bacteria, Archaea, and Eukarya. This observation suggests an ancient origin for the UlaGL family within the broader trunk of the MBL superfamily by duplication, neofunctionalization and fixation. Conclusions: Our results suggest that the forerunner of UlaG was present as an RNA metabolizing enzyme in the last common ancestor, and that the modern descendants of that ancestral gene have a wide phylogenetic distribution and functional roles. We propose that the UlaGL family evolved new metabolic roles among bacterial and possibly archeal phyla in the setting of a close association with metazoans, such as in the mammalian gastrointestinal tract or in animal and plant pathogens, as well as in environmental settings. Accordingly, the major evolutionary forces shaping the UlaGL family include vertical inheritance and lineage-specific duplication and acquisition of novel metabolic functions, followed by HGT and numerous lineage-specific gene loss events

Insulin-like growth factor I sensitization rejuvenates sleep patterns in old mice

Sleep disturbances are common during aging. Compared to young animals, old mice show altered sleep structure, with changes in both slow and fast electrocorticographic (ECoG) activity and fewer transitions between sleep and wake stages. Insulin-like growth factor I (IGF-I), which is involved in adaptive changes during aging, was previously shown to increase ECoG activity in young mice and monkeys. Furthermore, IGF-I shapes sleep architecture by modulating the activity of mouse orexin neurons in the lateral hypothalamus (LH). We now report that both ECoG activation and excitation of orexin neurons by systemic IGF-I are abrogated in old mice. Moreover, orthodromical responses of LH neurons are facilitated by either systemic or local IGF-I in young mice, but not in old ones. As orexin neurons of old mice show dysregulated IGF-I receptor (IGF-IR) expression, suggesting disturbed IGF-I sensitivity, we treated old mice with AIK3a305, a novel IGF-IR sensitizer, and observed restored responses to IGF-I and rejuvenation of sleep patterns. Thus, disturbed sleep structure in aging mice may be related to impaired IGF-I signaling onto orexin neurons, reflecting a broader loss of IGF-I activity in the aged mouse brain.This work was funded by a grant from Ciberned and is part of the project SAF2016-76462 funded by MCIN/AEI/https://doi.org/10.13039/501100011033. J.A. ZegarraValdivia acknowledges the fnancial support of the National Council of Science, Technology and Technological Innovation (CONCYTEC, Perú) through the National Fund for Scientifc and Technological Development (FONDECYT, Perú). J. Fernandes received a post-doc fellowship from Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP: # 2017/14742–0; # 2019/03368–5)

Silicic Acid and Beer Consumption Reverses the Metal Imbalance and the Prooxidant Status Induced by Aluminum Nitrate in Mouse Brain

The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link.Abstract: Background: Emerging evidence suggests that by affecting mineral balance, aluminum (Al) may enhance some events associated with neurodegenerative diseases. Aim: To examine the effect of Al(NO3)3 exposure on brain Al, cooper (Cu), iron (Fe), magnesium (Mg), manganese (Mn), silicon (Si), and zinc (Zn) levels, and the metal-change implication in brain oxidant and inflammatory status. Methods: Four groups of six-week-old male NMRI mice were treated for three months: i) controls, administrated with deionized water; ii) Al, which received Al(NO3)3; iii) Al+silicic acid, which were given Al(NO3)3 plus silicic acid; and iv) Al+beer, which received Al(NO3)3 plus beer. Results: Brain Al and TBARS levels and TNFα and GPx expressions increased, while Cu, Mn, and Zn levels, and catalase and CuZn-SOD expression decreased (at least, p < 0.05) in Al versus control animals. Al, Si, and TBARS levels and TNFα expression decreased (p < 0.05) in Al+silicic acid and Al+beer specimens while Cu, Mn, and Zn levels and antioxidant expression increased versus the Al group. Brain Al levels correlated negatively with those of Cu, Fe, Mn, and Zn, and catalase, CuZn-SOD, and GPx enzyme expressions but positively with Si and TBARS levels and TNFα expression. Two components of the principal component analysis (PCA) explained 71.2% of total data variance (p < 0.001). PCA connected the pro-oxidant markers with brain Al content, while brain Zn and Cu levels were closer to antioxidant enzyme expression. Conclusion: Administration of Al(NO3)3 induced metal imbalance, inflammation, and antioxidant status impairment in the brain. Those effects were blocked to a significant extent by silicic acid and beer administration

The phase diagram of water at high pressures as obtained by computer simulations of the TIP4P/2005 model: the appearance of a plastic crystal phase

In this work the high pressure region of the phase diagram of water has been studied by computer simulation by using the TIP4P/2005 model of water. Free energy calculations were performed for ices VII and VIII and for the fluid phase to determine the melting curve of these ices. In addition molecular dynamics simulations were performed at high temperatures (440K) observing the spontaneous freezing of the liquid into a solid phase at pressures of about 80000 bar. The analysis of the structure obtained lead to the conclusion that a plastic crystal phase was formed. In the plastic crystal phase the oxygen atoms were arranged forming a body center cubic structure, as in ice VII, but the water molecules were able to rotate almost freely. Free energy calculations were performed for this new phase, and it was found that for TIP4P/2005 this plastic crystal phase is thermodynamically stable with respect to ices VII and VIII for temperatures higher than about 400K, although the precise value depends on the pressure. By using Gibbs Duhem simulations, all coexistence lines were determined, and the phase diagram of the TIP4P/2005 model was obtained, including ices VIII and VII and the new plastic crystal phase. The TIP4P/2005 model is able to describe qualitatively the phase diagram of water. It would be of interest to study if such a plastic crystal phase does indeed exist for real water. The nearly spherical shape of water makes possible the formation of a plastic crystal phase at high temperatures. The formation of a plastic crystal phase at high temperatures (with a bcc arrangements of oxygen atoms) is fast from a kinetic point of view occurring in about 2ns. This is in contrast to the nucleation of ice Ih which requires simulations of the order of hundreds of ns

Scheduling periodic tasks in a hard real-time environment

We consider a real-time scheduling problem that occurs in the design of software-based aircraft control. The goal is to distribute tasks $au_i=(c_i,p_i)$ on a minimum number of identical machines and to compute offsets $a_i$ for the tasks such that no collision occurs. A task $au_i$ releases a job of running time $c_i$ at each time $a_i + kcdot p_i,k in mathbb{N}_0$ and a collision occurs if two jobs are simultaneously active on the same machine. We shed some light on the complexity and approximability landscape of this problem. Although the problem cannot be approximated within a factor of $n^{1-varepsilon}$ for any $varepsilon>0$, an interesting restriction is much more tractable: If the periods are dividing (for each $i,j$ one has $p_i | p_j$ or $p_j | p_i$), the problem allows for a better structured representation of solutions, which leads to a 2-approximation. This result is tight, even asymptotically