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In this article, we focus on a class of a fractional interval multivalued programming problem. For the solution concept, LU-Pareto optimality and LS-Pareto, optimality are discussed, and some nontrivial concepts are also illustrated with small examples. The ideas of LU-V-invex and LS-V-invex for a fractional interval problem are introduced. Using these invexity suppositions, we establish the Karush–Kuhn–Tucker optimality conditions for the problem assuming the functions involved to be gH-differentiable. Non-trivial examples are discussed throughout the manuscript to make a clear understanding of the results established. Results obtained in this paper unify and extend some previously known results appeared in the literature.

Bioluminescent imaging (BLI) is a powerful tool in biomedical research to measure gene expression and tumor growth. The current study examined factors that influence the BLI signal, specifically focusing on the tissue distribution of two luciferase substrates, D-luciferin and CycLuc1. D-luciferin, a natural substrate of firefly luciferase, has been reported to have limited brain distribution, possibly due to the efflux transporter, breast cancer resistance protein (Bcrp), at the blood-brain barrier. CycLuc1, a synthetic analog of D-luciferin, has a greater BLI signal at lower doses than D-luciferin, especially in the brain. Our results indicate that limited brain distribution of D-luciferin and CycLuc1 is predominantly dictated by their low intrinsic permeability across the cell membrane, where the efflux transporter, Bcrp, plays a relatively minor role. Both genetic ablation and pharmacological inhibition of Bcrp decreased the systemic clearance of both luciferase substrates, significantly increasing exposure in the blood and, hence, in organs and tissues. These data also indicate that the biodistribution of luciferase substrates can be differentially influenced in luciferase-bearing tissues, leading to a “tissue-dependent” BLI signal. The results of this study point to the need to consider multiple mechanisms that influence the distribution of luciferase substrates.SIGNIFICANCE STATEMENTBioluminescence is used to monitor many biological processes, including tumor growth. This study examined the pharmacokinetics, brain distribution, and the role of active efflux transporters on the luciferase substrates D-luciferin and CycLuc1. CycLuc1 has a more sustained systemic circulation time (longer half-life) that can provide an advantage for the superior imaging outcome of CycLuc1 over D-luciferin. The disparity in imaging intensities between brain and peripheral sites is due to low intrinsic permeability of these luciferase substrates across the blood-brain barrier.

ATM is a key mediator of radiation response, and pharmacological inhibition of ATM is a rational strategy to radiosensitize tumors. AZD1390 is a brain-penetrant ATM inhibitor and a potent radiosensitizer. This study evaluated the spectrum of radiosensitizing effects and the impact of TP53mutation status in a panel of IDH1wild-type (WT) glioblastoma (GBM) patient-derived xenografts (PDXs). AZD1390 suppressed radiation-induced ATM signaling, abrogated G0-G1arrest, and promoted a proapoptotic response specifically in p53-mutant GBM in vitro. In a preclinical trial using 10 orthotopic GBM models, AZD1390/RT afforded benefit in a cohort of TP53-mutant tumors but not in TP53-WT PDXs. In mechanistic studies, increased endogenous DNA damage and constitutive ATM signaling were observed in TP53-mutant, but not in TP53-WT, PDXs. In plasmid-based reporter assays, GBM43 (TP53-mutant) showed elevated DNA repair capacity compared with that in GBM14 (p53-WT), whereas treatment with AZD1390 specifically suppressed homologous recombination (HR) efficiency, in part, by stalling RAD51 unloading. Furthermore, overexpression of a dominant-negative TP53(p53DD) construct resulted in enhanced basal ATM signaling, HR activity, and AZD1390-mediated radiosensitization in GBM14. Analyzing RNA-seq data from TCGA showed up-regulation of HR pathway genes in TP53-mutant human GBM. Together, our results imply that increased basal ATM signaling and enhanced dependence on HR represent a unique susceptibility of TP53-mutant cells to ATM inhibitor–mediated radiosensitization.

The room temperature chemiresistive response of n-type ZnO nanowire (ZnO NWs) films modified with different thicknesses of p-type cobalt phthalocyanine (CoPc) has been studied. With increasing thickness of CoPc (>15 nm), heterojunction films exhibit a transition from n- to p-type conduction due to uniform coating of CoPc on ZnO. The heterojunction films prepared with a 25 nm thick CoPc layer exhibit the highest response (268% at 10 ppm of H2S) and the fastest response (26 s) among all samples. The X-ray photoelectron spectroscopy and work function measurements reveal that electron transfer takes place from ZnO to CoPc, resulting in formation of a p–n junction with a barrier height of 0.4 eV and a depletion layer width of ∼8.9 nm. The detailed XPS analysis suggests that these heterojunction films with 25 nm thick CoPc exhibit the least content of chemisorbed oxygen, enabling the direct interaction of H2S with the CoPc molecule, and therefore exhibit the fastest response. The improved response is attributed to the high susceptibility of the p–n junctions to the H2S gas, which manipulates the depletion layer width and controls the charge transport.

SummaryIf you want your students to graph a cubic polynomial, it is best to give them one with rational roots and critical points. In this paper, we describe completely all such cubics and explain how to generate them.

Integrins are transmembrane heterodimeric receptors responsible for transducing and modulating signals between the extracellular matrix and cytoskeleton, ultimately influencing cell functions such as adhesion and migration. Integrin α9β1 is classified within a two member sub-family of integrins highlighted in part by its specialized role in cell migration. The importance of this role is demonstrated by its regulation of numerous biological functions including lymphatic valve morphogenesis, lymphangiogenesis, angiogenesis and hematopoietic homeostasis. Compared to other integrins the signaling mechanisms that transduce α9β1-induced cell migration are not well described. We have recently shown that Src tyrosine kinase plays a key proximal role to control α9β1 signaling. Specifically it activates inducible nitric oxide synthase (iNOS) and in turn nitric oxide (NO) production as a means to transduce cell migration. Furthermore, we have also described a role for FAK, Erk and Rac1 in α9β1 signal transduction. Here we provide an over view of known integrin α9β1 signaling pathways and highlight its roles in diverse biological conditions.

This Correspondence addresses the use of LAM and LAM-derived cells in Issaka et al. (Am J Pathol 2009,175: 1410–1420)

The superconducting properties of RuSr2GdCu2O8Ru1212 superconductor strongly depend on the processing conditions. In this report we have made an investigation on the influence of processing method and heat treatments on the superconducting properties, as well as normal state resistivity of RuSr2GdCu2O8Ru1212 compound. The samples were prepared using solidstate reaction of high purity oxides and carbonates of constituents cations through direct method, precursor method, and standard method used for the synthesis of Ru1212 compounds. These samples were then subjected to different annealing treatments in different atmosphere oxygen and air for 120 h. They have been investigated by Xray diffraction, dc resistivity and scanning electron microscopy. The normal state resistivity has been studied on the basis of various conduction mechanisms.

Lymphangioleiomyomatosis (LAM) is a potentially fatal lung disease characterized by nodules of proliferative smooth muscle-like cells. The exact nature of these LAM cells and their proliferative stimuli are poorly characterized. Herein we report the novel findings that the lymphangiogenic vascular endothelial growth factors (VEGF) C and D induce LAM cell proliferation through activation of their cognate receptor VEGF-R3 and activation of the signaling intermediates Akt/mTOR/S6. Furthermore, we identify expression of the proteoglycan NG2, a marker of immature smooth muscle cells, as a characteristic of LAM cells both in vitroand in human lung tissue. VEGF-C-induced LAM cell proliferation was in part a result of autocrine stimulation that resulted from cross talk with lymphatic endothelial cells. Ultimately, these findings identify the lymphangiogenic VEGF proteins as pathogenic growth factors in LAM disease and at the same time provide a novel pharmacotherapeutic target for a lung disease that to date has no known effective treatment.

Genes that code for proteins expressed at high and low levels in plants were classified into separate data sets. The two data sets were analysed to identify the conserved nucleotide sequences that may characterize genes with contrasting levels of expression. The AUG context that characterized the highly expressed genes is (A/C)N2AAN3(A/T)T(A/C) AACAATGGCTNCC(T/A)CNA(C/T)(A/C). The data set of highly expressed genes shows overrepresentation of codons for alanine at the second position and serine at the third and fourth positions after the translation initiation codon. The characteristic transcription initiation site in the highly expressed genes is CAN(A/C)(A/C)(C/A)C(C/A)N2A(C/A). The promoter region is characterized by two tandemly repeated TATA elements, sometimes with one and rarely with two point mutations in the highly expressed genes. Besides the two tandemly repeated TATA elements, the promoter context in the highly expressed genes is overrepresented by C, C and G at the -3, -1 and+9 positions respectively. The characteristic TATA motif in the highly expressed plant genes is (T/C)(T/A)N2TCACTATATATAG. Most of these features are not present in the genes ubiquitously expressed at low levels in plants.

Despite a history of successful applications to operational-level problems, the vale of OR/MS modelling techniques as aids in policy/strategy formulation has not been widely demonstrated. In this paper, we suggest that the language of traditional OR/MS model structures is too restrictive to deal with issues typically confronted in policy-making. Differences between operational-level decision-making processes and policy/strategy formulation processes are discussed; alternative model structures are described and classified; and a modelling language for addressing issues of policy and strategy is proposed. The language is presented in set-theoretic terms, and the resulting structure implies that certain model classes accommodate policy-level management needs better than others. Furthermore, policy-level models must serve a role distinct from the prediction and optimization role typically served by operational-level models.

An information society is one in which informational (or interactional) as opposed to material entities represent the dominant form of social and economic transaction. This paper argues that in such an information-rich environment, the conventional view of the systems approach may no longer be relevant, and may in fact be a serious barrier to the development and implementation of creative management technologies. We present an alternative perspective on the systems approach that emphasizes the primacy of informational concepts as opposed to the primacy of matter/energy concepts. This alternative focuses on interactions, on the logic of change, on circular causality, and on multiple concepts of time. There are important implications for organizational design, managerial control and information systems.

This article is concerned with the effects of alternative forms of surplus and shortage cost functions and also with the effects of alternative forms of probability density function of demand in an inventory control situation.

Frequently, companies face the problem of allocating a given marketing budget in order to maximize their total returns. In this paper we examine the problem of allocating marketing effort, such as advertising, among Psubstitutional products, distributed in Ndifferent sales territories. Two models are discussed. In the first model it is assumed that at most one product is promoted in each sales territory. It is shown that a simple algorithm leads to at least a local optimum in a finite number of steps. In the second model, the restriction of one product per territory is eliminated. Applying a concept of effective effort, the model is transformed to an equivalent separable programming problem, solvable by a “single-pass” algorithm for various forms of response functions. Furthermore, a concept of successive modifications of the objective function is discussed.

The use of "optimality" as an operational research criterion is insufficiently discriminating. Ample evidence exists that for many problems simple optimization (particularly profit maximization) does not represent the aims of management. In this paper we discuss the nature of the problem situations for which alternative decision criteria are more appropriate. In particular the structure of strategic planning problems is analysed. The provisional commitment involved in a plan (in contrast to the irrevocable commitment of a decision) leads to the development of a particular criterion, robustness—a measure of the flexibility which an initial decision of a plan maintains for achieving near-optimal states in conditions of uncertainty. The robustness concept is developed through the case study of a sequential factory location problem.

Approximately 12% of diffuse large B cell lymphoma (DLBCL) are double-hit lymphomas (DHL) with translocations in both MYC (MYC/8q24) and BCL2 (14;18) (q32; q21) and/or BCL6 (3q27) and prognosis is generally poor. Triple hit lymphomas (THL) are a subset of DHL exhibiting simultaneous gene translocations of MYC, BCL2and BCL6,and demonstrate aggressive behavior, worse than that of DHL. Currently, there are no guidelines for the treatment of this group of patients, and disease remains challenging to treat. Bromodomain and external domain (BET) proteins are known as “epigenetic readers” and are enriched at the regions regulating transcription of oncogenes and many BET inhibitors (BETi) are now being clinically evaluated in several cancers.

Gadd45 expression, which is stress inducible, has been associated with growth arrest, but the exact role of gadd45 family genes in apoptosis still remains unclear. We have found that myeloid progenitor cells from gadd45a and gadd45b-deficient mice are more sensitive to ultra-violet radiation, VP-16 or daunorubicin induced apoptosis. indicating that gadd45a or gadd45b protect haematopoetic cells from DNA damaging agents. To determine, how gadd45a or gadd45b proteins exert their anti-apoptotic function, bone marrow cells from wild-type and gadd45a or gadd45b deficient mice were exposed to ultraviolet radiation (UV) and analyzed for expression of stress responsive kinases, including JNK and p38. It was observed that P38 and JNK were activated in wt bone marrow cells in response to UV but not in bone marrow cells defecient in gadd45a. Also, the transcription factor NF-kB was activated in wt bone marrow cells, but not in gadd45a−/− cells. The pharmacological inhibitor SB203580 specific for p38, increased apoptosis in reponse to UV, indicating that p38 is implicated in signaling myeloid cell survival. SB203580 was observed also to inhibit the expression of certain NF-kB target genes, including cIAP-1, c-IAP-2, bcl-2 and bcl-xl, in gadd45a+/+ cells but not in gadd45a deficient bone marrow cells. Taken together this data provides first evidence for the role gadd45a plays in the control of hematopoietic cell survival in response to UV, via modulation of P38 MAPK and NF-kB signaling pathways. Unlike in gadd45a−/− bone marrow cells, p38 activation appeared not to be impaired in gadd45b−/− cells, indicating that gadd45b is not involved in p38 activation in myeloid cells. However, UV induced JNK activation was sustained in gadd45b−/− myeloid cells compared to wt cells, indicating that gadd45b is a negative modulator of UV induced JNK signaling in myeloid cells. UV induced activation of MKK4 an upstream regulator of JNK also was impaired in gadd45b−/−. NF-kB was also found activated in wt cells, but not in gadd45b−/− cells. This data indicates that in bone marrow cells exposed to UV, NF-kB induced expression of Gadd45b plays a protective role against UV induced apoptosis via inhibition of MKK4 kinase which in turn results in suppression of JNK activity. Taken together this data provides evidence that Gadd45a and Gadd45b protect haematopoetic cells from genotoxic-stress induced apoptosis via distinct signaling pathways.

Growth arrest and DNA damage, Gadd45 gene family members are rapidly induced by genotoxic agents as well as by apoptosis and differentiation inducing cytokines. Their role in hemetopoiesis, wherein proliferation, differentiation and apoptosis integrate to maintain cellular homeostasis, is not clear. Using bone marrow cells from gadd45a or gadd45b deficient and wild type littermate mice we have investigated the role of Gadd45 proteins in cytokine induced myeloid cell differentiation in vitro. Bone marrow cells obtained from either gadd45a or gadd45b deficient mice displayed compromised cytokines (IL3, GM-CSF, M-CSF or G-CSF) induced myelopoiesis, resulting in a quantitatively decreased population of mature myeloid cells. Immuno-phenotyping with antibodies to cell surface molecules associated with myeloid cell maturation confirmed impaired myeloid cell maturation in Gadd45a or b deficient bone marrow cells treated with the above cytokines. Analysis of apoptosis by annexin-V and PI staining followed by FACS analysis showed a substantially higher apoptosis in Gadd45a−/− as well as gadd45b−/− cells compared to wild type cells after treatment with M-CSF or G-CSF. Gadd45a−/− as well as gadd45b−/− bone marrow cells were found to be less clonogenic in methylcellulose medium. Morphologically compact and round colonies consisting of immature myeloid cells prevailed over dispersed- colonies consisting of mature myeloid cells in gadd45- deficient cells cultured in methyl cellulose containing IL-3. Furthermore, colony re-plating assay showed better self-renewal abilities in gadd45a−/− as well as gadd45b−/− progenitors, compared to wild type progenitor cells. Altered myelopoiesis in gadd45 a or b deficient mice was further confirmed in vivo by intra-peritoneal administration of sodium casienate - a known inducer of inflammatory response and myelopoiesis in mice bone marrow. Sodium casienate failed to enhance myelopoiesis in gadd45a or gadd45b deficient mice bone marrow, while wild type littermate mice showed a rapid induction of myelopoiesis. Simultaneously peritoneal exudates collected from gadd45 deficient mice consisted of 2–3 fold less myeloid cells compared to age matched wild type control mice after sodium casienate treatment. Gadd45a−/− or gadd45b−/− mice showed a slow recovery after myelo-suppressive effect of antimetabolite 5-Fluorouracil, which further confirmed that gadd45 deficiency leads to delayed myelopoiesis in mouse. Mechanistic aspects of Gadd45 deficiency, which results in impaired myelopoiesis are under investigation.

GADD45 (Growth arrest and DNA damge) regulates cell growth following exposure to diverse stimuli. It has been shown that, mice lacking the gadd45a gene exhibit genomic instability and increased carcinogenesis, but the exact role of the gadd45 family genes still remains unclear. In this study we have aimed at determining the effect of gadd45a or gadd45b deficiency on the response of bone marrow derived myeloid cells to genotoxic stress agents by using gadd45a or gadd45b null mice. We have found that myeloid progenitor cells from gadd45a or gadd45b-null mice are more sensitive to ultraviolet-radiation (UV), VP-16 or daunorubicin induced apoptosis. Introduction of wild-type gadd45 into gadd45-deficient bone marrow cells restored the wild-type apoptotic phenotype. In-vitro colony formation following stress responses has shown that bone marrow cells from gadd45a or gadd45b-deficient mice have a decreased ability to form haematopoetic colonies. Gadd45a or gadd45b-deficient bone marrow cells also displayed defective G2/M cell cycle checkpoint following exposure to either UV and V-16 but were still able to undergo G2/M arrest following exposure to daunorubicin, indicating the existence of different G2/M checkpoints in response to these anticancer agents. Taken together these findings identify gadd45a or gadd45b as anti-apoptotic gene(s), and suggests that the absence of gadd45a or gadd45b results in higher susceptibility of haematopoetic cells to UV radiation and certain anticancer drugs.