An optimal control for complete synchronization of 4D Rabinovich hyperchaotic systems

This paper derives new results for the complete synchronization of 4D identical Rabinovich hyperchaotic systems by using two strategies: active and nonlinear control. Nonlinear control strategy is considered as one of the powerful tool for controlling the dynamical systems. The stabilization results of error dynamics systems are established based on Lyapunov second method. Control is designed via the relevant variables of drive and response systems. In comparison with previous strategies, the current controller (nonlinear control) focuses on convergence speed and the minimum limits of relevant variables. Better performance is to achieve full synchronization by designing the control with fewer terms. The proposed control has certain significance for reducing the time and complexity for strategy implementation

Agro- Industrial Integration from an Accounting Perspective Study in General Company for Leather Industries/Baghdad

تعد الشركة العامة للصناعات الجلدية وحدة انتاجية اقتصادية تساهم في دعم الاقتصاد الوطني في مجال تصنيع الجلود الطبيعية واستغلالها بإنتاج الملابس والاحذية والحقائب اعتمادا على مبدا الحساب الاقتصادي وكفاءة استثمار الاموال العامة وفاعليتها في تحقيق اهداف الدولة ورفع مستويات الاداء للاقتصاد الوطني بما يحقق اهداف خطط التنمية  لذا هدف البحث الى تحديد المعوقات التي تواجه الشركة العامة للصناعات الجلدية /بغداد (عينة البحث) والتي تحول دون التكامل الزراعي الصناعي بفرعه الحيواني والتوجه نحو الجلود المستوردة لتحقيق اهدافها على الرغم من  وجود معامل دباغة في الشركة ذاتها وذلك من خلال اجراء مقارنة كلفوية للمنتج في حالة اعتمادها على الجلود المحلية وتطبيق التكامل الزراعي الصناعي  من جانب وفي حالة اذا كانت جلود مستوردة من جانب اخر ولأربعة موديلات من الاحذية الرجالية (7566,7639, ٦٧٣٠,7545) الواردة في سجلات الشركة في شهر تشرين الاول للعام 2014  ، ومن اهم ما توصل اليه البحث ان هنالك كثيرا من المعوقات التي تحول دون التكامل الزراعي الصناعي والتي تحتاج الى حلول حقيقية من الدولة وان تطبيقه لا يحقق اهداف الشركة من الارباح المخطط لها حتى وان كان على حساب الجودة .  The General Company for Leather Industries is an economic production unit that contributes to supporting the national economy in the field of manufacturing natural leather and exploiting it by producing clothes, shoes and bags based on the principle of economic account and efficiency of investing public funds and its effectiveness in achieving the objectives of the state and raising the performance levels of the national economy in order to achieve the goals of development plans, so the goal of the research is to identify the obstacles facing the General Company for Leather Industries / Baghdad (research sample) which transforms Without agricultural industrial integration with its animal branch and orientation towards imported leather to achieve its objectives despite the existence of tanning factories in the same company through a cost comparison of the product in case of dependence on local leather and application of agricultural industrial integration on the one hand and in case if the skins imported by another and four models of men's shoes (7566,7639, 6730,7545) contained in the company's records in October 2014, and one of the most important findings of the research is that there are many obstacles to agricultural industrial integration that need real solutions from the state and that its application does not achieve The company's objectives o

Characterisation of anticancer properties of a novel and naturally isolated bisindole alkaloid, conofolidine

Natural products play a pivotal role in the exploration of new cancer therapies of which the plant kingdom is a substantial source. Conofolidine is a novel bisindole alkaloid isolated from Malayan plant Tabernaemontana Corymbosa and belongs to the family of the known vinca alkaloid conophylline. To our knowledge, no published work existed at the time of commencement of this project. Herein, we report for the first time recognition of conofolidine’s exceptional anticancer activity, from a panel of Malayan bisindoles (namely leucophyllidine, bipleiophylline and alstonia macroline-sarpagine bisindoles) that were indiscriminately screened against various human-derived carcinoma cell lines. Preliminary data showed that conofolidine exerted remarkable inhibition of cell proliferation and colony formation of cancer cells (e.g. GI50 = 0.054 and IC50 < 0.1 μM in MCF-7) through either induction of apoptosis or senescence. Apoptosis was confirmed by accumulation of cleaved PARP and activation of caspases 3/7. Alternatively, increased β-galactosidase positive cells accompanied by transformation of cell shape to spindle like with enlarged cell size ascertained senescence induction. G1 cell cycle arrest and S-phase depletion were observed in the majority of tested cell lines. These cell cycle perturbations were confirmed by decreased expression of positive regulators (CDK2, cyclin A2 and c-Myc) and increased expression of CDK inhibitors p21WAF1/CIP1, p27KIP1 and p15INK4b. Conofolidine caused several aberrant mitotic phenotypes exemplified by multi-nucleation, mitotic slippage, changed polarity, membrane blebbing and DNA fragmentation. Compromised DNA integrity was confirmed by increased γ-H2AX foci and/or level indicating DNA double strand breaks. Conofolidine increased ROS production, which partly contributed to DNA damage, apoptosis- and senescence-induction. A proteomic study conducted following exposure of HT-29 cells to conofolidine (72 h; 0.602 µM) corroborated ROS generation by the increased expression of several ROS scavengers e.g. NQO1. Phospho-proteomics analyses revealed significant suppression of p-EGFR, p-Akt, p-ERK and p-STAT signal transduction. Such suppression caused c-Myc destabilisation with consequent eliciting of either apoptotic or senescent phenotypes. The variation in the basal phosphorylation levels of these signalling proteins in the different tested cell lines determined their fates. Additionally conofolidine down-regulated mutant-p53 at transcription, expression and post-translational levels in mutant-p53 (R273H) cell lines which could partly contribute to its suppressive actions on signalling pathways and cell cycle. Proteomic analyses showed decreased expressions of MCM (2-7) including MCM4 through which mutant-p53 (R273H) could drive initiation of DNA replication. Conofolidine’s ability to suppress MCM family (together with ROS production) provides an additional mechanism for conofolidine to induce DNA damage and genomic instability. Taken together, we present conofolidine in this study as potential anticancer candidate and provide mechanistic insight to its molecular targets and pathways, which encourage further future work

Concurrent reactive oxygen species generation and aneuploidy induction contribute to thymoquinone anticancer activity

Thymoquinone (TQ) is the main biologically active constituent of Nigella sativa. Many studies have confirmed its anticancer actions. Herein, we investigated the different anticancer activities of, and considered resistance mechanisms to, TQ. MTT and clonogenic data showed TQ’s ability to suppress breast MDA-MB-468 and T-47D proliferation at lower concentrations compared to other cancer and non-transformed cell lines tested (GI50 values ≤ 1.5 µM). Flow-cytometric analyses revealed that TQ consistently induced MDA-MB-468 and T-47D cell-cycle perturbation, specifically inducing pre-G1 populations. In comparison, less sensitive breast MCF-7 and colon HCT-116 cells exhibited only transient increases in pre-G1 events. Annexin V/PI staining confirmed apoptosis induction in MDA-MB-468 and HCT-116 cells, which was continuous in the former and transient in the latter. Experiments revealed the role of reactive oxygen species (ROS) generation and aneuploidy induction in MDA-MB-468 cells within the first 24 h of treatment. The ROS-scavenger NAD(P)H dehydrogenase (quinone 1) (NQO1; DT-diaphorase) and glutathione (GSH) were implicated in resistance to TQ. Indeed, western blot analyses showed that NQO1 is expressed in all cell lines in this study, except those most sensitive to TQ-MDA-MB-468 and T-47D. Moreover, TQ treatment increased NQO1 expression in HCT-116 in a concentration-dependent fashion. Measurement of GSH activity in MDA-MB-468 and HCT-116 cells found that GSH is similarly active in both cell lines. Furthermore, GSH depletion rendered these cells more sensitive to TQ’s antiproliferative actions. Therefore, to bypass putative inactivation of the TQ semiquinone metabolite, the benzylamine analogue was designed and synthesised following modification of TQ’s carbon-3 atom. However, the structural modification negatively impacted potency against MDA-MB-468 cells. In conclusion, we disclose the following: (i) The anticancer activity of TQ may be a consequence of ROS generation and aneuploidy; (ii) Early GSH depletion could substantially enhance TQ’s anticancer activity; (iii) Benzylamine substitution at TQ’s carbon-3 failed to enhance anticancer activity

Codrug Approach for the Potential Treatment of EML4-ALK Positive Lung Cancer

We report on the synergistic effect of PI3K inhibition with ALK inhibition for the possible treatment of EML4-ALK positive lung cancer. We have brought together ceritinib (ALK inhibitor) and pictilisib (PI3K inhibitor) into a single bivalent molecule (a codrug) with the aim of designing a molecule for slow release drug delivery that targets EML4-ALK positive lung cancer. We have joined the two drugs through a new, pH-sensitive linker where the resulting codrugs are hydrolytically stable at lower pH (pH 6.4) but rapidly cleaved at higher pH (pH 7.4). Compound (19), which was designed for optimal lung retention, demonstrated clean liberation of the drug payloads in vitro and represents a novel approach to targeted lung delivery

Mapping trait versus species turnover reveals spatiotemporal variation in functional redundancy and network robustness in a plant-pollinator community

Functional overlap among species (redundancy) is considered important in shaping competitive and mutualistic interactions that determine how communities respond to environmental change. Most studies view functional redundancy as static, yet traits within species—which ultimately shape functional redundancy—can vary over seasonal or spatial gradients. We therefore have limited understanding of how trait turnover within and between species could lead to changes in functional redundancy or how loss of traits could differentially impact mutualistic interactions depending on where and when the interactions occur in space and time. Using an Arctic bumblebee community as a case study, and 1277 individual measures from 14 species over three annual seasons, we quantified how inter- and intraspecific body-size turnover compared to species turnover with elevation and over the season. Coupling every individual and their trait with a plant visitation, we investigated how grouping individuals by a morphological trait or by species identity altered our assessment of network structure and how this differed in space and time. Finally, we tested how the sensitivity of the network in space and time differed when simulating extinction of nodes representing either morphological trait similarity or traditional species groups. This allowed us to explore the degree to which trait-based groups increase or decrease interaction redundancy relative to species-based nodes. We found that (i) groups of taxonomically and morphologically similar bees turn over in space and time independently from each other, with trait turnover being larger over the season; (ii) networks composed of nodes representing species versus morphologically similar bees were structured differently; and (iii) simulated loss of bee trait groups caused faster coextinction of bumblebee species and flowering plants than when bee taxonomic groups were lost. Crucially, the magnitude of these effects varied in space and time, highlighting the importance of considering spatiotemporal context when studying the relative importance of taxonomic and trait contributions to interaction network architecture. Our finding that functional redundancy varies spatiotemporally demonstrates how considering the traits of individuals within networks is needed to understand the impacts of environmental variation and extinction on ecosystem functioning and resilience

Conofolidine, a Natural Plant Alkaloid Causes Apoptosis and Senescence in Cancer Cells

Natural products contribute substantially to anticancer therapy; the plant kingdom provides an important source of molecules. Conofolidine is a novel Aspidosperma-Aspidosperma bisindole alkaloid isolated from the Malayan plant Tabernaemontana corymbosa. Herein, we report conofolidine’s anticancer activity together with that of three other bisindoles - conophylline, leucophyllidine and bipleiophylline against human-derived carcinoma cell lines. Remarkably, conofolidine was able to induce apoptosis (as observed in MDA-MB-468 breast cancer cells) or senescence (as detected in HT-29 colorectal carcinoma cells). Annexin V-FITC/PI, caspase activation and PARP cleavage confirmed the former while positive β-gal staining corroborated the latter. Evident cell cycle perturbations were observed comprising S-phase depletion, accompanied by downregulated CDK2, and cyclins (A2, D1) with p21 upregulation. Confocal imaging of HCT-116 cells revealed induction of aberrant mitotic phenotypes - multi-nucleation, membrane blebbing and DNA-fragmentation. The DNA integrity assessment of HCT-116 and MDA-MB-468 showed irreparable damage identified by increased fluorescent γ-H2AX during the G1 cell cycle phase. Furthermore, γ-H2AX foci were visually validated in HCT-116 and MDA-MB-468 cells using confocal microscopy. Conofolidine increased oxidative stress, preceding apoptosis- and senescence-induction in most carcinoma cell lines as seen by enhanced ROS levels accompanied by NQO1 expression. Collectively, we present conofolidine as a potential anticancer candidate capable of inducing heterogeneous modes of cancer cell death in vitro, encouraging further preclinical evaluation of this natural product

Discovery of a highly active anticancer analogue of cardamonin that acts as an inducer of caspase-dependent apoptosis and modulator of the mTOR pathway

Nineteen analogues of cardamonin were semi-synthesized and tested against A549 and HK1 cell lines. The analogues were fully characterized via IR and NMR analyses, while compound 19 (a Cu (II) complex of cardamonin) was further characterized via HRMS, ELEMENTAL ANALYSIS, TGA and UV-VIS spectroscopy. Results of the MTS cell viability assay showed that several derivatives possessed cytotoxic activities that were several-fold more potent than cardamonin. Compound 19 was the most potent analogue possessing IC50 values of 13.2 µM and 0.7 µM against A549 and HK1 cells, corresponding to a 5- and 32-fold increase in activity, respectively. Furthermore, the active analogues, especially 19, have generally demonstrated lower toxicity towards normal MRC5 cells. SAR analysis showed the importance of the ketone and alkene groups for bioactivity, while substituting cardamonin’s phenolic groups with more polar moieties resulted in activity enhancement. As part of the SAR study and further exploration of chemical space, the effect of metal coordination on cytotoxicity was also investigated, but it was only possible to successfully obtain the Cu (II) complex of cardamonin (19), and results showed that the metal ion enhanced activity. 19 was also able to significantly inhibit the migration of A549 and HK1 cells. Further studies have shown that the most active analogue, 19, induced DNA damage resulting in G2/M-phase cell-cycle arrest in both cell lines. These events further led to the induction of apoptosis by 19 via caspase-3/7 and caspase-9 activation, PARP cleavage and downregulation of Mcl-1 expression. Finally, 19 inhibited the expression levels of p-mTOR and p-4EBP1. These data indicated that 19 exerted its anticancer activity, at least in part, via inhibition of the mTOR signalling pathway

Lipophilic activated ester prodrug approach for drug delivery to the intestinal lymphatic system

The intestinal lymphatic system plays an important role in the pathophysiology of multiple diseases including lymphomas, cancer metastasis, autoimmune diseases, and human immunodeficiency virus (HIV) infection. It is thus an important compartment for delivery of drugs in order to treat diseases associated with the lymphatic system. Lipophilic prodrug approaches have been used in the past to take advantage of the intestinal lymphatic transport processes to deliver drugs to the intestinal lymphatics. Most of the approaches previously adopted were based on very bulky prodrug moieties such as those mimicking triglycerides (TG). We now report a study in which a lipophilic prodrug approach was used to efficiently deliver bexarotene (BEX) and retinoic acid (RA) to the intestinal lymphatic system using activated ester prodrugs. A range of carboxylic ester prodrugs of BEX were designed and synthesised and all of the esters showed improved association with chylomicrons, which indicated an improved potential for delivery to the intestinal lymphatic system. The conversion rate of the prodrugs to BEX was the main determinant in delivery of BEX to the intestinal lymphatics, and activated ester prodrugs were prepared to enhance the conversion rate. As a result, an 4-(hydroxymethyl)-1,3-dioxol-2-one ester prodrug of BEX was able to increase the exposure of the mesenteric lymph nodes (MLNs) to BEX 17-fold compared to when BEX itself was administered. The activated ester prodrug approach was also applied to another drug, RA, where the exposure of the MLNs was increased 2.4-fold through the application of a similar cyclic activated prodrug. Synergism between BEX and RA was also demonstrated in vitro by cell growth inhibition assays using lymphoma cell lines. In conclusion, the activated ester prodrug approach results in efficient delivery of drugs to the intestinal lymphatic system, which could benefit patients affected by a large number of pathological conditions

Morfologiskt processande i talad och skriven produktion : En explorativ studie om sambanden mellan morfologiska pauser, revideringar och fel i högstadieelevers muntliga och skriftliga produktioner

Bakgrund Morfologisk kunskap har visats gynna läsutvecklingen vilket lett till ökat forskningsintresse för hur morfologisk träning och medvetandegörande kan främja läsförmågan, framförallt bland elever med läs- och skrivsvårigheter. Hur morfologisk kunskap ter sig i typisk språkproduktion och huruvida morfologiska skillnader finns beroende på om produktionen utgörs av tal eller skrift är däremot mindre beforskat. En svårighet när det kommer till forskning om morfologisk produktion är att morfologiskt processande sannolikt sker under den språkliga förberedelsefasen vilken är svår att undersöka experimentellt. Ett sätt att fånga morfologiskt processande under produktion är att undersöka när personer möter svårigheter och hur de bearbetar dessa svårigheter.  Syfte Studiens syfte var att undersöka eventuella samband mellan morfologisk osäkerhet (dvs. pauser, revideringar och fel) i talat och skrivet språk samt undersöka om dessa osäkerheter avspeglas i ett morfologiskt kunskapstest. Metod Nitton högstadieelever fick genomföra en skrivuppgift, en muntlig uppgift samt ett nykonstruerat morfologiskt kunskapstest. Elevernas skrivprocess registrerades med hjälp av keystroke-logging för att analysera morfologisk osäkerhet under skrivande samt andel morfologiska fel och särskrivningar i den slutgiltiga elevtexten. Den muntliga uppgiften spelades in och analyserades med avseende på morfologisk osäkerhet under muntlig framställning. Morfologitestet, vilket bestod av sex deltester, genomfördes skriftligt och det sammanlagda resultatet för varje elev beräknades.  Resultat Ingen elev uppvisade morfologisk osäkerhet under muntlig produktion. Under skrivande noterades följande processer i morfemgränser på gruppnivå: pauser (10,21%), revideringar (1,31%), fel (0,49%) och särskrivningar (0,52%). Andel morfologiska osäkerheter under skriftlig produktion hade inget signifikant samband med resultatet på det morfologiska kunskapstestet. Post hoc-analys visade dock ett positivt samband mellan morfologiska pauser i skrivprocessen och antal poäng på ett deltest som undersöker morfologisk-syntaktisk kunskap.  Slutsatser Denna explorativa studie indikerar att morfologisk osäkerhet är ovanlig i talproduktion men att det kan förekomma i skrivprocessen, främst genom pauser i morfemgränser.  Resultatet antyder vidare att samband finns mellan pauser i morfemgränser under egen produktion och resultatet på ett test avsett att mäta morfologisk-syntaktisk kunskap. Resultatet bör dock tolkas aktsamt med hänsyn till det låga deltagarantalet och studiens explorativa angreppssätt