ALBERT

Description: The dimensions that influence the establishment of business process management (BPM) practices and the progression to higher levels of process maturity derive from exploring the dimensions of process orientation of organizations. Small and medium-sized clothing enterprises (SME’s) are characterized by various specifics that can affect the degree of process orientation adoption and the pace of transition from lower to higher levels of process maturity. According to these specifics, the acceptance of the process approach may be differently affected. For the purpose of adequate evaluation and prioritization of the most influential dimensions, a new integrated multicriteria decision-making (MCDM) model that combines classical and fuzzy theory was developed. First, the full consistency method (FUCOM) method was applied, followed by the fuzzy pivot pairwise relative criteria importance assessment (fuzzy PIPRECIA) method to obtain more accurate criteria values. Prioritization of the most influential BPM dimension contributes to highlighting the area of business that needs to be primarily strengthened by appropriate actions for successful establishment of BPM in apparel industry SMEs. Within this research, the prioritized dimension refers to human resource management in accordance with the specific aspects of business within the apparel industry.

Description: Deregulated c-MYC is found in a variety of cancers where it promotes proliferation as well as apoptosis. In many hematologic malignancies, enhanced NF-κB exerts prosurvival functions. Here we investigated the role of NF-κB in mouse and human c-MYC–transformed lymphomas. The NF-κB pathway is extinguished in murine lymphoma cells, and extrinsic stimuli typically inducing NF-κB activity fail to activate this pathway. Genetic activation of the NF-κB pathway induces apoptosis in these cells, whereas inhibition of NF-κB by an IκBα superrepressor provides a selective advantage in vivo. Furthermore, in human Burkitt lymphoma cells we find that NF-κB activation induces apoptosis. NF-κB up-regulates Fas and predisposes to Fas-induced cell death, which is caspase-8 mediated and can be prevented by CFLAR overexpression. We conclude that c-MYC overexpression sensitizes cells to NF-κB–induced apoptosis, and persistent inactivity of NF-κB signaling is a prerequisite for MYC-mediated tumorigenesis. We could also show that low immunogenicity and Fas insensitivity of MYC-driven lymphoma cells are reversed by activation of NF-κB. Our observations provide a molecular explanation for the described absence of the NF-κB signaling in Burkitt lymphoma and question the applicability of NF-κB inhibitors as candidates for treatment of this cancer.

Description: Healthcare systems worldwide are facing problems in providing health care to patients in a pandemic caused by the SARS-CoV-2 virus (COVID-19). The pandemic causes an extreme disease to spread with fluctuating needs among patients, which significantly affect the capacity and overall performance of healthcare systems. In addition, its impact on the sustainability of the entire economic and social system is enormous and certain sustainable management strategies need to be selected. To meet the challenges of the COVID-19 pandemic and ensure sustainable performance, national healthcare systems must adapt to new circumstances. This paper proposes an original multi-criteria methodology for the sustainable selection of strategic guidelines for the reorganization of a healthcare system under the conditions of the COVID-19 pandemic. The selection of an appropriate strategic guideline is made on the basis of defined criteria and depending on infection capacity and pandemic spread risk. The criteria for the evaluation of strategic guidelines were defined on the basis of a survey in which the medical personnel engaged in the crisis response team during the COVID-19 pandemic in the Republic of Serbia participated. The Level-Based Weight Assessment (LBWA) model and Measuring Attractiveness by a Categorical-Based Evaluation Technique (MACBETH) method were used to determine the weight coefficient criteria, while a novel fuzzy Ranking of Alternatives through Functional Mapping of Criterion Subintervals into a Single Interval (RAFSI) model was used to evaluate the strategic guidelines. The proposed multi-criteria methodology was tested in a case study in the Republic of Serbia. The validity of the proposed methodology is shown through the simulation of changes in input parameters of Bonferroni aggregation functions and through a comparison with other multi-criteria methodologies.

Description: Reactive oxygen species (ROS) are toxic byproducts of oxidative metabolism implicated in many debilitating human disorders including hematological malignancies and aging. ROS are also generated by growth factors and cytokine stimulation and play critical functions in normal cellular signaling. However, not much is known of how ROS impact physiological processes in normal and diseased states. We and others have recently shown critical functions for box (O) family of forkhead transcription factors (Fox)O in the regulation of physiological ROS in primitive hematopoietic cells. In particular, FoxO3 has emerged as the principal FoxO whose regulation of ROS is essential for the maintenance of hematopoietic stem cell pool. Although FoxO3’s activity is constitutively repressed by several oncoproteins that play critical roles in myeloproliferative disorders the role of FoxO3 in the regulation of primitive hematopoietic progenitors remains elusive. FoxO’s function is restrained by AKT serine threonine protein kinase. AKT supports growth, survival and proliferation by promoting inhibition of FoxO and activation of the mammalian target of rapamycin (mTOR) and its downstream target p70 S6 Kinase (S6K) through phosphorylation. We demonstrate that loss of FoxO3 leads to a myeloproliferative-like syndrome characterized by leukocytosis, splenomegaly, enhanced generation of primitive progenitors including colony-forming-unit-spleen (CFU-S) in hematopoietic organs and hypersensitivity of hematopoietic progenitor cells to cytokines in FoxO3 null mice. These findings were intriguing since we had not found FoxO3 null hematopoietic stem cells to exhibit enhanced cycling in vivo or to generate excessive hematopoietic progenitors ex vivo (Yalcin et al., JBC, 2008). To investigate the mechanism of enhanced myeloproliferation, we interrogated cytokine-mediated activation of signaling pathways in freshly isolated FoxO3 null versus wild type bone marrow cells enriched for hematopoietic progenitors. To our surprise we found that stimulation with cytokines including IL-3 led to hyperphosphorylation of AKT, mTOR and S6K but not STAT5 proteins in FoxO3 null as compared to wild type cytokine-starved hematopoietic progenitors. In agreement with these results, in vivo administration of the mTOR inhibitor rapamycin resulted in significant reduction of FoxO3 null- but not wild type-derived CFU-Sd12 in lethally irradiated hosts. These unexpected results suggested that AKT/mTOR signaling pathway is specifically overactivated as part of a feedback loop mechanism and mediates enhanced generation of FoxO3 null primitive multipotential hematopoietic progenitors in vivo. We further showed that phosphorylation of AKT/mTOR/S6K is highly sensitive to ROS scavenger N-Acetyl-Cysteine (NAC) in vivo and ex vivo in both wild type and FoxO3 null primitive hematopoietic progenitors indicating that ROS are involved in cytokine signaling in primary hematopoietic progenitor cells. Interestingly, in vivo administration of NAC normalized the number of FoxO3 null-derived CFU-Sd12 in lethally irradiated hosts without any impact on wild type CFU-Sd12 strongly suggesting that ROS mediate specifically enhanced generation of primitive hematopoietic progenitors in FoxO3 null mice. In this context, we were surprised to find similar levels of ROS concentrations in FoxO3 mutant as compared to control hematopoietic progenitors. Thus, we asked whether the increase in FoxO3 null primitive hematopoietic progenitor compartment is due to an increase sensitivity of cytokine signaling to ROS as opposed to increased ROS build up per se in these cells. In search for a mechanism we found the expression of Lnk, a negative regulator of cytokine signaling, to be highly reduced in FoxO3 null primitive hematopoietic progenitor cells. We further demonstrated that retroviral reintroduction of Lnk but not vector control in FoxO3 null primitive bone marrow cells reduced significantly the number of FoxO3 null-derived CFU-Sd12in vivo. Collectively, these results suggest that reduced expression of Lnk hypersensitizes FoxO3-deficient hematopoietic progenitors to ROS generated by cytokine signaling leading to myeloproliferation. These cumulative findings uncover a mechanism by which deregulation of cellular sensitivity to physiological ROS leads to hematopoietic malignancies specifically in disorders in which FoxO play a role.

Description: The conditions of globalization often dictate the functioning of transport markets, so it is necessary to conduct frequent research in order to achieve sustainable business. This is achieved through adequate risk and safety management at all levels. The research carried out in this paper includes determining the state of railway traffic safety in a total of nine railway sections in Bosnia and Herzegovina (B&H). The aim of this paper is to develop a new integrated Entropy-Fuzzy PIPRECIA (PIvot Pairwise RElative Criteria Importance Assessment)-DEA (Data Envelopment Analysis) model for determining the state of safety in B&H under particular conditions of uncertainty. Additionally, the aim is to combine the advantages of linear programming (DEA), an objective method (Entropy), and a subjective method (Fuzzy PIPRECIA). In this way, an integrated objective–subjective model is created that provides accurate and balanced decision-making through their integration. Eleven sustainable criteria were defined and divided into six inputs and five outputs. The Entropy model was used to determine the weight values of the inputs, while due to the nature of the outputs, Fuzzy PIPRECIA was used to evaluate them. After the application of the two methods, the way of averaging their values was defined. The DEA model, which implies an input- and output-oriented model, was applied to determine which railway sections have satisfactory performance in terms of safety. Two sections were eliminated from further computation due to extremely poor performance and high risk. Then, the weighted overall efficiency ranking method was applied to determine the final ranking of the railway sections. The results obtained were verified through a sensitivity analysis, which involved changing the impact of the five most significant criteria and a comparison with two Multi-Criteria Decision-Making (MCDM) methods.

Description: The finite element method (FEM) has deservedly gained the reputation of the most powerful, highly efficient, and versatile numerical method in the field of structural analysis. Though typical application of FE programs implies the so-called “off-line” computations, the rapid pace of hardware development over the past couple of decades was the major impetus for numerous researchers to consider the possibility of real-time simulation based on FE models. Limitations of available hardware components in various phases of developments demanded remarkable innovativeness in the quest for suitable solutions to the challenge. Different approaches have been proposed depending on the demands of the specific field of application. Though it is still a relatively young field of work in global terms, an immense amount of work has already been done calling for a representative survey. This paper aims to provide such a survey, which of course cannot be exhaustive.

Description: Reactive oxygen species (ROS) such as superoxide anions and hydrogen peroxides are byproducts of normal oxidative metabolism that play an important role in regulating the proliferation of many cell types including hematopoietic cells. However, excess production of ROS induces damage to cellular components including DNA, maintains cellular transformation, apoptosis and senescence, and is associated with leukemias. Therefore highly regulated mechanisms are required for balancing ROS production during normal hematopoiesis. In particular, erythroid cells require an efficient scavenging mechanism for ROS because of high exposure to oxidative stress as a result of an abundance of heme iron. Specifically, deficiencies in erythroid ROS scavenging enzymes are associated with malignancies and other hematopoietic disorders such as sideroblastic anemia. We have recently shown that Erythropoietin (Epo)-induced activation of the PI3-kinase/AKT signaling pathway supports differentiation and maturation of primary erythroid progenitor cells (Zhao et al., Blood 2006; Ghaffari et al., Blood 2006). FOXO forkhead transcription factors constitute one of downstream targets of the PI3-kinase/AKT signaling pathway. In response to Epo, activation of PI3-kinase/AKT signaling pathway results in rapid phosphorylation of FOXO proteins triggering its translocation to the cytosol where, away from their transcriptional targets, FOXO are inhibited. FOXO proteins play many fundamental functions including protecting cells against oxidative insults by controlling the expression of ROS scavenging enzymes manganese superoxide dismutase and catalase. Here we show that Foxo3 is the most abundant FOXO protein in erythroid cells whose expression is upregulated several fold during maturation of mouse primary fetal liver erythroid progenitor cells. Using immunofluorescent staining and reporter gene assay, we show that Foxo3 enters the nucleus and becomes transcriptionally active as fetal liver erythroblasts mature. Notably, Foxo3 activation is concomitant with downregulation of Epo receptor (EpoR) on maturing erythroblasts. We further demonstrate that Foxo3 regulates levels of ROS in adult erythroid cells. In particular, eight to twelve week old Foxo3-deficient mice (kindly provided by Dr. Ron DePinho, Harvard Medical School) exhibit hemolysis that is responsive to in vivo therapy by N-Acetyl- l-Cysteine, a generic scavenger of ROS, suggesting that Foxo3−/ − hemolysis is induced by ROS. In addition, Foxo3−/ − hemolysis is characterized by enhanced concentration of erythroid ROS as determined by dichlorofluorescein assay and significantly decreased expression of ROS scavenging enzymes, leading to protein oxidation and shortened erythrocyte lifespan. In agreement with these results, Foxo3−/ − mice are highly sensitive to oxidative stress and, in contrast to their wild type counterparts, do not survive treatment with phenylhydrazine which reacts with hemoglobin to generate ROS. These results demonstrate that Foxo3 is required for protecting erythroid cells from oxidative stress. Finally, our data further support an important function for Foxo3 in coordinating cell cycle and differentiation of primary erythroblasts that is mediated by a ROS-regulated mechanism. Collectively, these findings establish Foxo3, a transcription factor targeted by EpoR signaling, as a regulator of oxidative stress in primary erythropoiesis.

Description: AKT serine threonine kinase of the protein kinase B (PKB) family plays essential roles in cell survival, growth, metabolism, and differentiation. In the erythroid system, AKT is known to be rapidly phosphorylated and activated in response to erythropoietin (Epo) engagement of Epo receptor (EpoR) and to sustain survival signals in cultured erythroid cells. Here we demonstrate that activated AKT complements EpoR signaling and supports erythroid-cell differentiation in wild-type and JAK2-deficient fetal liver cells. We show that erythroid maturation of AKT-transduced cells is not solely dependent on AKT-induced cell survival or proliferation signals, suggesting that AKT transduces also a differentiation-specific signal downstream of EpoR in erythroid cells. Down-regulation of expression of AKT kinase by RNA interference, or AKT activity by expression of dominant negative forms, inhibits significantly fetal liver–derived erythroid-cell colony formation and gene expression, demonstrating that AKT is required for Epo regulation of erythroid-cell maturation.