Lower bounds for integer programming problems

Solving real world problems with mixed integer programming (MIP) involves efforts in modeling and efficient algorithms. To solve a minimization MIP problem, a lower bound is needed in a branch-and-bound algorithm to evaluate the quality of a feasible solution and to improve the efficiency of the algorithm. This thesis develops a new MIP model and studies algorithms for obtaining lower bounds for MIP. The first part of the thesis is dedicated to a new production planning model with pricing decisions. To increase profit, a company can use pricing to influence its demand to increase revenue, decrease cost, or both. We present a model that uses pricing discounts to increase production and delivery flexibility, which helps to decrease costs. Although the revenue can be hurt by introducing pricing discounts, the total profit can be increased by properly choosing the discounts and production and delivery decisions. We further explore the idea with variations of the model and present the advantages of using flexibility to increase profit. The second part of the thesis focuses on solving integer programming(IP) problems by improving lower bounds. Specifically, we consider obtaining lower bounds for the multi- dimensional knapsack problem (MKP). Because MKP lacks special structures, it allows us to consider general methods for obtaining lower bounds for IP, which includes various relaxation algorithms. A problem relaxation is achieved by either enlarging the feasible region, or decreasing the value of the objective function on the feasible region. In addition, dual algorithms can also be used to obtain lower bounds, which work directly on solving the dual problems. We first present some characteristics of the value function of MKP and extend some properties from the knapsack problem to MKP. The properties of MKP allow some large scale problems to be reduced to smaller ones. In addition, the quality of corner relaxation bounds of MKP is considered. We explore conditions under which the corner relaxation is tight for MKP, such that relaxing some of the constraints does not affect the quality of the lower bounds. To evaluate the overall tightness of the corner relaxation, we also show the worst-case gap of the corner relaxation for MKP. To identify parameters that contribute the most to the hardness of MKP and further evaluate the quality of lower bounds obtained from various algorithms, we analyze the characteristics that impact the hardness of MKP with a series of computational tests and establish a testbed of instances for computational experiments in the thesis. Next, we examine the lower bounds obtained from various relaxation algorithms com- putationally. We study methods of choosing constraints for relaxations that produce high- quality lower bounds. We use information obtained from linear relaxations to choose con- straints to relax. However, for many hard instances, choosing the right constraints can be challenging, due to the inaccuracy of the LP information. We thus develop a dual heuristic algorithm that explores various constraints to be used in relaxations in the Branch-and- Bound algorithm. The algorithm uses lower bounds obtained from surrogate relaxations to improve the LP bounds, where the relaxed constraints may vary for different nodes. We also examine adaptively controlling the parameters of the algorithm to improve the performance. Finally, the thesis presents two problem-specific algorithms to obtain lower bounds for MKP: A subadditive lifting method is developed to construct subadditive dual solutions, which always provide valid lower bounds. In addition, since MKP can be reformulated as a shortest path problem, we present a shortest path algorithm that uses estimated distances by solving relaxations problems. The recursive structure of the graph is used to accelerate the algorithm. Computational results of the shortest path algorithm are given on the testbed instances.Ph.D

O-GlcNAcylation of core components of the translation initiation machinery regulates protein synthesis

Protein synthesis is essential for cell growth, proliferation, and survival. Protein synthesis is a tightly regulated process that involves multiple mechanisms. Deregulation of protein synthesis is considered as a key factor in the development and progression of a number of diseases, such as cancer. Here we show that the dynamic modification of proteins by O-linked β-N-acetyl-glucosamine (O-GlcNAcylation) regulates translation initiation by modifying core initiation factors eIF4A and eIF4G, respectively. Mechanistically, site-specific O-GlcNAcylation of eIF4A on Ser322/323 disrupts the formation of the translation initiation complex by perturbing its interaction with eIF4G. In addition, O-GlcNAcylation inhibits the duplex unwinding activity of eIF4A, leading to impaired protein synthesis, and decreased cell proliferation. In contrast, site-specific O-GlcNAcylation of eIF4G on Ser61 promotes its interaction with poly(A)-binding protein (PABP) and poly(A) mRNA. Depletion of eIF4G O-GlcNAcylation results in inhibition of protein synthesis, cell proliferation, and soft agar colony formation. The differential glycosylation of eIF4A and eIF4G appears to be regulated in the initiation complex to fine-tune protein synthesis. Our study thus expands the current understanding of protein synthesis, and adds another dimension of complexity to translational control of cellular proteins

Molecular analysis of the diversity of vaginal microbiota associated with bacterial vaginosis

<p>Abstract</p> <p>Background</p> <p>Bacterial vaginosis (BV) is an ecological disorder of the vaginal microbiota that affects millions of women annually, and is associated with numerous adverse health outcomes including pre-term birth and the acquisition of sexually transmitted infections. However, little is known about the overall structure and composition of vaginal microbial communities; most of the earlier studies focused on predominant vaginal bacteria in the process of BV. In the present study, the diversity and richness of vaginal microbiota in 50 BV positive and 50 healthy women from China were investigated using culture-independent PCR-denaturing gradient gel electrophoresis (DGGE) and barcoded 454 pyrosequencing methods, and validated by quantitative PCR.</p> <p>Results</p> <p>Our data demonstrated that there was a profound shift in the absolute and relative abundances of bacterial species present in the vagina when comparing populations associated with healthy and diseased conditions. In spite of significant interpersonal variations, the diversity of vaginal microbiota in the two groups could be clearly divided into two clusters. A total of 246,359 high quality pyrosequencing reads was obtained for evaluating bacterial diversity and 24,298 unique sequences represented all phylotypes. The most predominant phyla of bacteria identified in the vagina belonged to <it>Firmicutes</it>, <it>Bacteroidetes</it>, <it>Actinobacteria </it>and <it>Fusobacteria</it>. The higher number of phylotypes in BV positive women over healthy is consistent with the results of previous studies and a large number of low-abundance taxa which were missed in previous studies were revealed. Although no single bacterium could be identified as a specific marker for healthy over diseased conditions, three phyla - <it>Bacteroidetes</it>, <it>Actinobacteria </it>and <it>Fusobacteria</it>, and eight genera including <it>Gardnerella</it>, <it>Atopobium</it>, <it>Megasphaera</it>, <it>Eggerthella</it>, <it>Aerococcus</it>, <it>Leptotrichia</it>/<it>Sneathia</it>, <it>Prevotella </it>and <it>Papillibacter </it>were strongly associated with BV (<it>p </it>< 0.05). These genera are potentially excellent markers and could be used as targets for clinical BV diagnosis by molecular approaches.</p> <p>Conclusions</p> <p>The data presented here have clearly profiled the overall structure of vaginal communities and clearly demonstrated that BV is associated with a dramatic increase in the taxonomic richness and diversity of vaginal microbiota. The study also provides the most comprehensive picture of the vaginal community structure and the bacterial ecosystem, and significantly contributes to the current understanding of the etiology of BV.</p

Porcine Deltacoronavirus Nucleocapsid Protein Suppressed IFN-β Production by Interfering Porcine RIG-I dsRNA-Binding and K63-Linked Polyubiquitination

Porcine deltacoronavirus (PDCoV) is a newly detected porcine coronavirus causing serious vomiting and diarrhea in piglets, especially newborn piglets. There has been an outbreak of PDCoV in worldwide since 2014, causing significant economic losses in the pig industry. The interferon (IFN)-mediated antiviral response is an important component of virus-host interactions and plays an essential role in inhibiting virus infection. However, the mechanism of PDCoV escaping the porcine immune surveillance is unclear. In the present study, we demonstrated that the PDCoV nucleocapsid (N) protein antagonizes porcine IFN-β production after vesicular stomatitis virus (VSV) infection or poly(I:C) stimulation. PDCoV N protein also suppressed the activation of porcine IFN-β promoter when it was stimulated by porcine RLR signaling molecules. PDCoV N protein targeted porcine retinoic acid-inducible gene I (pRIG-I) and porcine TNF receptor associated factor 3 (pTRAF3) by directly interacting with them. The N-terminal region (1–246 aa) of PDCoV N protein was important for interacting with pRIG-I and interfere its function. We confirmed that PDCoV N antagonizes IFN-β production by associating with pRIG-I to impede it from binding double-stranded RNA. Furthermore, porcine Riplet (pRiplet) was an important activator for pRIG-I by mediating the K63-linked polyubiquitination. However, PDCoV N protein restrained the pRiplet binding pRIG-I to inhibit pRIG-I K63-linked polyubiquitination. Taken together, our results revealed a novel mechanism by which PDCoV N protein interferes with the early activation of pRIG-I in the host antiviral response. The novel findings provide a new insight into PDCoV on evading the host innate immune response and may provide new therapeutic targets and more efficacious vaccines strategies for PDCoV infections

GSKJ4 Protects Mice Against Early Sepsis via Reducing Proinflammatory Factors and Up-Regulating MiR-146a

Sepsis, defined as life-threatening organ dysfunction, is one of the most common causes of mortality in intensive care units with limited therapeutic options. However, the mechanism underlying the regulation of epigenetics on sepsis remains largely undefined. Here we showed that JMJD3, the histone lysine demethylase, played a critical role in the epigenetic regulation of innate immunity during early sepsis. Pharmacological inhibition of JMJD3 by GSKJ4 protected mice against early septic death and reduced pro-inflammatory cytokine interleukin-1β (IL-1β) production as well as IL-6, tumor necrosis factor-α (TNF-α), and monocyte chemotactic protein-1 (MCP-1) expression. Interestingly, GSKJ4 up-regulated the transcription of anti-inflammatory microRNA-146a (miR-146a) in peritoneal macrophages from septic mice. Mechanistically, JMJD3 negatively regulated the transcription of miR-146a via its demethylation of H3K27me3 on the promoter of miR-146a. Moreover, the transcription of miR-146a was positively regulated by nuclear factor-κB (NF-κB) p65. Inhibition of NF-κB p65 promoted JMJD3 binding to miR-146a promoter and decreased the tri-methylation level of H3K27, while the inhibition of JMJD3 did not affect the recruitment of NF-κB p65 to miR-146a promoter. These results highlight an epigenetic mechanism by which JMJD3 was inhibited by NF-κB p65 from binding to miR-146a promoter to promote the anti-inflammatory response. Taken together, our findings uncover a key role for JMJD3 in modulating the miR-146a transcription and shed light on the JMJD3 inhibitors could be potential therapeutic agents for early sepsis therapy

Synchronous multiple primary malignancies of clear cell renal cell carcinoma with sarcomatoid, thyroid carcinoma: a case report

Multiple primary malignant neoplasms (MPMNs) are defined as the presence of two or more malignancies with different histologies in the same patient. MPMNs are rare, accounting for fewer than 4% of all tumor cases. Depending on the time interval between the diagnosis of the different malignancies, they are classified as either simultaneous or metachronous MPMNs, with simultaneous being rarer in MPMNs. Here, we present a 63-year-old female patient presenting with multiple primary renal and thyroid carcinomas and discuss the risk factors, treatment options, and prognosis of rare dual carcinomas. We focus on managing multidisciplinary teams and selecting individualized treatment options to deliver valuable treatment strategies to patients

Goose STING mediates IFN signaling activation against RNA viruses

Stimulator of the interferon gene (STING) is involved in mammalian antiviral innate immunity as an interferon (IFN) activator. However, there is still a lack of clarity regarding the molecular characterization of goose STING (GoSTING) and its role in the innate immune response. In the present study, we cloned GoSTING and performed a series of bioinformatics analyses. GoSTING was grouped into avian clades and showed the highest sequence similarity to duck STING. The in vitro experiments showed that the mRNA levels of GoSTING, IFNs, IFN-stimulated genes (ISGs), and proinflammatory cytokines were significantly upregulated in goose embryo fibroblast cells (GEFs) infected with Newcastle disease virus (NDV). Overexpression of GoSTING in DF-1 cells and GEFs strongly activated the IFN-β promoter as detected by a dual-luciferase reporter assay. Furthermore, overexpression of GoSTING induced the expression of other types of IFN, ISGs, and proinflammatory cytokines and inhibited green fluorescent protein (GFP)-tagged NDV (NDV-GFP) and GFP-tagged vesicular stomatitis virus (VSV) (VSV-GFP) replication in vitro. In conclusion, these data suggest that GoSTING is an important regulator of the type I IFN pathway and is critical in geese’s innate immune host defense against RNA viruses