On the Complexity of Inverse Mixed Integer Linear Optimization

Inverse optimization is the problem of determining the values of missing input parameters for an associated forward problem that are closest to given estimates and that will make a given target vector optimal. This study is concerned with the relationship of a particular inverse mixed integer linear optimization problem (MILP) to both the forward problem and the separation problem associated with its feasible region. We show that a decision version of the inverse MILP in which a primal bound is verified is coNP-complete, whereas primal bound verification for the associated forward problem is NP-complete, and that the optimal value verification problems for both the inverse problem and the associated forward problem are complete for the complexity class D^P. We also describe a cutting-plane algorithm for solving inverse MILPs that illustrates the close relationship between the separation problem for the convex hull of solutions to a given MILP and the associated inverse problem. The inverse problem is shown to be equivalent to the separation problem for the radial cone defined by all inequalities that are both valid for the convex hull of solutions to the forward problem and binding at the target vector. Thus, the inverse, forward, and separation problems can be said to be equivalent

From regime-building to implementation: Harnessing the UN climate conferences to drive climate action

The gap between the internationally agreed climate objectives and tangible emissions reductions looms large. We explore how the supreme decision-making body of the United Nations Framework Convention on Climate Change (UNFCCC), the Conference of the Parties (COP), could develop to promote more effective climate policy. We argue that promoting implementation of climate action could benefit from focusing more on individual sectoral systems, particularly for mitigation. We consider five key governance functions of international institutions to discuss how the COP and the sessions it convenes could advance implementation of the Paris Agreement: guidance and signal, rules and standards, transparency and accountability, means of implementation, and knowledge and learning. In addition, we consider the role of the COP and its sessions as mega-events of global climate policy. We identify opportunities for promoting sectoral climate action across all five governance functions and for both the COP as a formal body and the COP sessions as conducive events. Harnessing these opportunities would require stronger involvement of national ministries in addition to the ministries of foreign affairs and environment that traditionally run the COP process, as well as stronger involvement of non-Party stakeholders within formal COP processes. This article is categorized under: Policy and Governance > International Policy Framework

Co-circulation of West Nile virus and distinct insect-specific flaviviruses in Turkey

Background: Active vector surveillance provides an efficient tool for monitoring the presence or spread of emerging or re-emerging vector-borne viruses. This study was undertaken to investigate the circulation of flaviviruses. Mosquitoes were collected from 58 locations in 10 provinces across the Aegean, Thrace and Mediterranean Anatolian regions of Turkey in 2014 and 2015. Following morphological identification, mosquitoes were pooled and screened by nested and real-time PCR assays. Detected viruses were further characterised by sequencing. Positive pools were inoculated onto cell lines for virus isolation. Next generation sequencing was employed for genomic characterisation of the isolates. Results: A total of 12,711 mosquito specimens representing 15 species were screened in 594 pools. Eleven pools (2%) were reactive in the virus screening assays. Sequencing revealed West Nile virus (WNV) in one Culex pipiens (s.l.) pool from Thrace. WNV sequence corresponded to lineage one clade 1a but clustered distinctly from the Turkish prototype isolate. In 10 pools, insect-specific flaviviruses were characterised as Culex theileri flavivirus in 5 pools of Culex theileri and one pool of Cx. pipiens (s.l.), Ochlerotatus caspius flavivirus in two pools of Aedes (Ochlerotatus) caspius, Flavivirus AV-2011 in one pool of Culiseta annulata, and an undetermined flavivirus in one pool of Uranotaenia unguiculata from the Aegean and Thrace regions. DNA forms or integration of the detected insect-specific flaviviruses were not observed. A virus strain, tentatively named as “Ochlerotatus caspius flavivirus Turkey”, was isolated from an Ae. caspius pool in C6/36 cells. The viral genome comprised 10,370 nucleotides with a putative polyprotein of 3,385 amino acids that follows the canonical flavivirus polyprotein organisation. Sequence comparisons and phylogenetic analyses revealed the close relationship of this strain with Ochlerotatus caspius flavivirus from Portugal and Hanko virus from Finland. Several conserved structural and amino acid motifs were identified. Conclusions: We identified WNV and several distinct insect-specific flaviviruses during an extensive biosurveillance study of mosquitoes in various regions of Turkey in 2014 and 2015. Ongoing circulation of WNV is revealed, with an unprecedented genetic diversity. A probable replicating form of an insect flavivirus identified only in DNA form was detected

Biallelic variants in ADAMTS15 cause a novel form of distal arthrogryposis

Purpose We aimed to identify the underlying genetic cause for a novel form of distal arthrogryposis. Methods Rare variant family-based genomics, exome sequencing, and disease-specific panel sequencing were used to detect ADAMTS15 variants in affected individuals. Adamts15 expression was analyzed at the single-cell level during murine embryogenesis. Expression patterns were characterized using in situ hybridization and RNAscope. Results We identified homozygous rare variant alleles of ADAMTS15 in 5 affected individuals from 4 unrelated consanguineous families presenting with congenital flexion contractures of the interphalangeal joints and hypoplastic or absent palmar creases. Radiographic investigations showed physiological interphalangeal joint morphology. Additional features included knee, Achilles tendon, and toe contractures, spinal stiffness, scoliosis, and orthodontic abnormalities. Analysis of mouse whole-embryo single-cell sequencing data revealed a tightly regulated Adamts15 expression in the limb mesenchyme between embryonic stages E11.5 and E15.0. A perimuscular and peritendinous expression was evident in in situ hybridization in the developing mouse limb. In accordance, RNAscope analysis detected a significant coexpression with Osr1, but not with markers for skeletal muscle or joint formation. Conclusion In aggregate, our findings provide evidence that rare biallelic recessive trait variants in ADAMTS15 cause a novel autosomal recessive connective tissue disorder, resulting in a distal arthrogryposis syndrome

Intrauterine growth restriction and placental angiogenesis

Background: Vascular endothelial growth factor (VEGF), basic-fibroblast growth factor (b-FGF), and endothelial nitric oxide synthase (eNOS) are factors that take part in placental angiogenesis. They are highly expressed during embryonic and fetal development, especially in the first trimester. In this study, we aimed to investigate the role of placental angiogenesis in the development of intrauterine growth restriction (IUGR) by comparing the levels of expression of VEGF-A, b-FGF, and eNOS in normal-term pregnancy and IUGR placentas.Methods: The expression of VEGF-A, b-FGF, and eNOS was studied using the avidin-biotin-peroxidase method in placental tissues diagnosed as normal (n = 55) and IUGR (n = 55). Results were evaluated in a semi-quantitative manner.Results: The expression of all the markers was significantly higher (p < 0.001) in cytotrophoblasts, syncytiotrophoblasts, extravillous trophoblasts, vascular smooth muscle cells, chorionic villous stromal cells, and villous vascular endothelial cells of the IUGR placentas when compared with those collected from normal-term pregnancies.Conclusion: Increased expression of VEGF-A, b-FGF, and eNOS may be the result of inadequate uteroplacental perfusion, supporting the proposal that abnormal angiogenesis plays a role in the pathophysiology of IUGR. © 2010 Barut et al; licensee BioMed Central Ltd

Characterization of magnesium requirement of human 5'-tyrosyl DNA phosphodiesterase mediated reaction

<p>Abstract</p> <p>Background</p> <p>Topo-poisons can produce an enzyme-DNA complex linked by a 3'- or 5'-phosphotyrosyl covalent bond. 3'-phosphotyrosyl bonds can be repaired by tyrosyl DNA phosphodiesterase-1 (TDP1), an enzyme known for years, but a complementary human enzyme 5'-tyrosyl DNA phosphodiesterase (hTDP2) that cleaves 5'-phosphotyrosyl bonds has been reported only recently. Although hTDP2 possesses both 3'- and 5'- tyrosyl DNA phosphodiesterase activity, the role of Mg²⁺in its activity was not studied in sufficient details.</p> <p>Results</p> <p>In this study we showed that purified hTDP2 does not exhibit any 5'-phosphotyrosyl phosphodiesterase activity in the absence of Mg²⁺/Mn²⁺, and that neither Zn²⁺or nor Ca²⁺can activate hTDP2. Mg²⁺also controls 3'-phosphotyrosyl activity of TDP2. In MCF-7 cell extracts and de-yolked zebrafish embryo extracts, Mg²⁺controlled 5'-phosphotyrosyl activity. This study also showed that there is an optimal Mg²⁺concentration above which it is inhibitory for hTDP2 activity.</p> <p>Conclusion</p> <p>These results altogether reveal the optimal Mg²⁺requirement in hTDP2 mediated reaction.</p

Investigation of the erosive potential of sour novelty sweets

Provides a background about the link between acidic beverages and dental erosion. Discusses the potential risk of developing dental erosion upon the frequent consumption of novelty sweets. Provides information which could be used by dental personnel in counselling patients who consume novelty sweets or at risk of developing dental erosion. Abstract Background The expansion of the novelty sweets market in the UK has major potential public health implications in children and young adults as they may cause dental erosion. Objective To investigate the erosive potential of the novelty sweets in term of their physiochemical properties and amount of enamel loss. Subjects and methods The pH of a variety of novelty sweets was tested in vitro using a pH meter and the neutralisable acidity was assessed by titrating the sweets against 0.1M NaOH. The viscosity of the novelty sweets was measured using a rotational viscometer. The wettability of enamel by each sweet was measured using dynamic contact angle analyser. Enamel loss was assessed using contact profilometry. Results The pH ranged from 1.8–3.2, the neutralisable acidity ranged from 9–201 ml of 0.1 NaOH. The viscosity of the novelty sweets that come in liquid form ranged from 2–594 mPa s. The surface enamel erosion ranged from 1.95–15.77 μm and from 2.5–17.6 μm with and without immersing in saliva for 1 hour before immersing in acidic solution respectively. The amount of subsurface enamel loss was ranged from 0.75 to 2.3 μm following ultrasonication at 0 min of acidic attack and from 0.23 to 0.85 μm at 60 minutes of acidic attack while immersed in saliva. The contact angle between enamel surface and four sweet was less than the angle formed between the orange juice and the enamel which caused more wettability of enamel. Conclusion The pH is lower than the critical value for enamel erosion (5.5), high neutralisable acidity and high sugar content strongly suggest that these sweets may cause significant amount of dental erosion clinically. In addition, the degree of wettability of enamel by solution is an important factor to consider in determining the enamel loss caused by acidic solution. Immediate tooth brushing would cause further enamel loss as a result of the mechanical removal of softened enamel. However, it has been suggested that postponing brushing after erosive attack should be reconsidered

Protonation States of Remote Residues Affect Binding-Release Dynamics of the Ligand but not the Conformation of apo Ferric Binding Protein

We have studied the apo (Fe3+ free) form of periplasmic ferric binding protein (FbpA) under different conditions and we have monitored the changes in the binding and release dynamics of H2PO4- that acts as a synergistic anion in the presence of Fe3+. Our simulations predict a dissociation constant of 2.2$\pm$0.2 mM which is in remarkable agreement with the experimentally measured value of 2.3$\pm$0.3 mM under the same ionization strength and pH conditions. We apply perturbations relevant for changes in environmental conditions as (i) different values of ionic strength (IS), and (ii) protonation of a group of residues to mimic a different pH environment. Local perturbations are also studied by protonation or mutation of a site distal to the binding region that is known to mechanically manipulate the hinge-like motions of FbpA. We find that while the average conformation of the protein is intact in all simulations, the H2PO4- dynamics may be substantially altered by the changing conditions. In particular, the bound fraction which is 20$\%$ for the wild type system is increased to 50$\%$ with a D52A mutation/protonation and further to over 90$\%$ at the protonation conditions mimicking those at pH 5.5. The change in the dynamics is traced to the altered electrostatic distribution on the surface of the protein which in turn affects hydrogen bonding patterns at the active site. The observations are quantified by rigorous free energy calculations. Our results lend clues as to how the environment versus single residue perturbations may be utilized for regulation of binding modes in hFbpA systems in the absence of conformational changes.Comment: 26 pages, 4 figure

Current trends in cannulation and neuroprotection during surgery of the aortic arch in Europe†‡

OBJECTIVES To conduct a survey across European cardiac centres to evaluate the methods used for cerebral protection during aortic surgery involving the aortic arch. METHODS All European centres were contacted and surgeons were requested to fill out a short, comprehensive questionnaire on an internet-based platform. One-third of more than 400 contacted centres completed the survey correctly. RESULTS The most preferred site for arterial cannulation is the subclavian-axillary, both in acute and chronic presentation. The femoral artery is still frequently used in the acute condition, while the ascending aorta is a frequent second choice in the case of chronic presentation. Bilateral antegrade brain perfusion is chosen by the majority of centres (2/3 of cases), while retrograde perfusion or circulatory arrest is very seldom used and almost exclusively in acute clinical presentation. The same pumping system of the cardio pulmonary bypass is most of the time used for selective cerebral perfusion, and the perfusate temperature is usually maintained between 22 and 26°C. One-third of the centres use lower temperatures. Perfusate flow and pressure are fairly consistent among centres in the range of 10-15 ml/kg and 60 mmHg, respectively. In 60% of cases, barbiturates are added for cerebral protection, while visceral perfusion still receives little attention. Regarding cerebral monitoring, there is a general tendency to use near-infrared spectroscopy associated with bilateral radial pressure measurement. CONCLUSIONS These data represent a snapshot of the strategies used for cerebral protection during major aortic surgery in current practice, and may serve as a reference for standardization and refinement of different approache