Search results for: repetitive unit cell

Authors: Md. M. Hossain, Regan Roat, Jenica Christopherson, Colette Free, Zhiguang Guo

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Long noncoding RNA (lncRNA) mediated post-transcriptional gene regulation, and their epigenetic landscapes have been shown to be involved in many human diseases. However, their regulation in diabetes through governing islet’s β-cell function and survival needs to be elucidated. Due to the technical and ethical constraints, it is difficult to study their role in β-cell function and survival in human under in vivo condition. In this study, humanized mice have been developed through transplanting human pancreatic islet under the kidney capsule of NOD.SCID mice and induced β-cell death leading to diabetes condition to study lncRNA mediated regulation. For this, human islets from 3 donors (3000 IEQ, purity > 80%) were transplanted under the kidney capsule of STZ induced diabetic NOD.scid mice. After at least 2 weeks of normoglycecemia, lymphocytes from diabetic NOD mice were adoptively transferred and islet grafts were collected once blood glucose reached > 200 mg/dl. RNA from human donor islets, islet grafts from humanized mice with either adoptive lymphocyte transfer (ALT) or PBS control (CTL) were ribodepleted; barcoded fragment libraries were constructed and sequenced on the Ion Proton sequencer. lncRNA expression in isolated human islets, islet grafts from humanized mice with and without induced β-cell death and their regulation in human islets function in vitro under glucose challenge, cytokine mediated inflammation and induced apoptotic condition were investigated. Out of 3155 detected lncRNAs, 299 that highly expressed in islets were found to be significantly downregulated and 224 upregulated in ALT compared to CTL. Most of these are found to be collocated within 5 kb upstream and 1 kb downstream of 788 up- and 624 down-regulated mRNAs. Genomic Regions Enrichment of Annotations Analysis revealed deregulated and collocated genes are related to pancreas endocrine development; insulin synthesis, processing, and secretion; pancreatitis and diabetes. Many of them, that found to be located within enhancer domains for islet specific gene activity, are associated to the deregulation of known islet/βcell specific transcription factors and genes that are important for β-cell differentiation, identity, and function. RNA sequencing analysis revealed aberrant lncRNA expression which is associated to the deregulated mRNAs in β-cell function as well as in molecular pathways related to diabetes. A distinct set of candidate lncRNA isoforms were identified as highly enriched and specific to human islets, which are deregulated in human islets from donors with different BMIs and with type 2 diabetes. These RNAs show an interesting regulation in cultured human islets under glucose stimulation and with induced β-cell death by cytokines. Aberrant expression of these lncRNAs was detected in the exosomes from the media of islets cultured with cytokines. Results of this study suggest that the islet specific lncRNAs are deregulated in human islet with β-cell death, hence important in diabetes. These lncRNAs might be important for human β-cell function and survival thus could be used as biomarkers and novel therapeutic targets for diabetes.

Keywords: β-cell, humanized mouse, pancreatic islet, LncRNAs

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Authors: Qin Yang, Fan Zhang, Juan Du, Chongkui Sun, Krishna Kota, Yun-Ling Zheng

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Telomeres are specialized structures at chromosome ends consisting of tandem repetitive DNA sequences [(TTAGGG)n in humans] and associated proteins, which are necessary for telomere function. Telomere lengths are tightly regulated within a narrow range in normal human somatic cells, the basis of cellular senescence and aging. Previous studies have extensively focused on how short telomeres are extended and have demonstrated that telomerase plays a central role in telomere maintenance through elongating the short telomeres. However, the molecular mechanisms of regulating excessively long telomeres are unknown. Here, we found that telomerase enzymatic component hTERT plays a dual role in the regulation of telomeres length. We analyzed single telomere alterations at each chromosomal end led to the discoveries that hTERT shortens excessively long telomeres and elongates short telomeres simultaneously, thus maintaining the optimal telomere length at each chromosomal end for an efficient protection. The hTERT-mediated telomere shortening removes large segments of telomere DNA rapidly without inducing telomere dysfunction foci or affecting cell proliferation, thus it is mechanistically distinct from rapid telomere deletion. We found that expression of hTERT generates telomeric circular DNA, suggesting that telomere homologous recombination may be involved in this telomere shortening process. Moreover, the hTERT-mediated telomere shortening is required its enzymatic activity, but telomerase RNA component hTR is not involved in it. Furthermore, shelterin protein TPP1 interacts with hTERT and recruits it on telomeres to mediate telomere shortening. In addition, telomere-associated proteins, DKC1 and TCAB1 also play roles in this process. This novel hTERT-mediated telomere shortening mechanism not only exists in cancer cells, but also in primary human cells. Thus, the hTERT-mediated telomere shortening is expected to shift the paradigm on current molecular models of telomere length maintenance, with wide-reaching consequences in cancer and aging fields.

Keywords: aging, hTERT, telomerase, telomeres, human cells

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Authors: Myoung-Jin Kim, Yeong-Seop Ahn, Hyun-Jee Yang, Hyoung-Kyu Song

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This paper proposes the new cooperative communication scheme for the wireless communication system. When the receiver is located in the edge of coverage, the signal from the transmitter is distorted by the inter-cell interference (ICI) and power reduction by distance. In order to improve communication performance, the proposed scheme adds the relay. By using the relay, the receiver receives the signal from the transmitter and relay at the same time. Therefore, the new cooperative communication scheme obtains diversity gain and is improved by the relay.

Keywords: cooperative communication, diversity gain, OFDM, MIMO

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Authors: Andrew Hardman, Alistair T. McIlhagger, Edward Archer

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A degree of research has been undertaken in the determination of 3D textile preforms behaviour to compression with direct comparison to 2D counterparts. Multiscale simulations have been developed to try and accurately analyse the behaviour of varying architectures post-consolidation. However, further understanding is required to experimentally identify the mechanisms and deformations that exist upon conforming to a complex contour. Due to the complexity of 3D textile preforms, determination of yarn behaviour to a complex contour is assessed through consolidation by means of vacuum assisted resin transfer moulding (VARTM), and the resulting mechanisms are investigated by micrograph analysis. Varying architectures; with known areal densities, pic density and thicknesses are assessed for a cohesive study. The resulting performance of each is assessed qualitatively as well as quantitatively from the perspective of material in terms of the change in representative unit cell (RVE) across the curved beam contour, in crimp percentage, tow angle, resin rich areas and binder distortion. A novel textile is developed from the resulting analysis to overcome the observed deformations.

Keywords: comformability, compression, binder architecture, 3D weaving, textile preform

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Authors: Neil Erick Q. Madariaga, Noel B. Linsangan

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Body Mass Index (BMI) is one of the different ways to monitor the health of a person. It is based on the height and weight of the person. This study aims to compute for the BMI using an Android tablet by obtaining the height of the person by using a camera and measuring the weight of the person by using a weighing scale or load cell. The height of the person was estimated by applying background subtraction to the image captured and applying different processes such as getting the vanishing point and applying Artificial Neural Network. The weight was measured by using Wheatstone bridge load cell configuration and sending the value to the computer by using Gizduino microcontroller and Bluetooth technology after the amplification using AD620 instrumentation amplifier. The application will process the images and read the measured values and show the BMI of the person. The study met all the objectives needed and further studies will be needed to improve the design project.

Keywords: body mass index, artificial neural network, vanishing point, bluetooth, wheatstone bridge load cell

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Authors: Neda Sinaei, Davood Zare, Mehrdad Azin

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Polyhydroxyalkanoates (PHAs) are biocompatible and biodegradable polymers produced by a wide range of bacterial strains. These biopolymers are significantly studied for drug delivery and tissue engineering applications because of their fascinating physicochemical properties. Polyhydroxybutyrate (PHB) scaffold that has been extracted from a novel bacteria using oil wastewater was selected to study. Some physical parameters affecting scaffold properties such as PHB concentration, solvent evaporation speed, and ultrasonic time were investigated. Scanning electron microscopy was used to evaluate the porosity. Afterward, the biocompatibility of PHB scaffold was assessed. Initial results showed the highly porous PHB scaffold structure with a variety of pore sizes. Subsequent results indicated that more unique pore sizes can be obtained by optimizing physical factors. It would be noticed that the morphology of the pore structure was accordingly affected by ultrasonic time. Hence, In vitro cell viability tests on the PHB scaffold using human foreskin fibroblasts revealed strong cell attachment and proliferation supports. Therefore, it can be concluded that the cost-effective PHB scaffold has the potential using as a biomaterial cell adhesion substrate in therapeutic applications.

Keywords: Polyhydroxybutyrate, biocompatible, scaffold, porous, tissue engineering

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Authors: ZhenlinJu, Christopher P. Vellano, RehanAkbani, Yiling Lu, Gordon B. Mills

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The epithelial–mesenchymal transition (EMT) is a process by which epithelial cells acquire mesenchymal characteristics, such as profound disruption of cell-cell junctions, loss of apical-basolateral polarity, and extensive reorganization of the actin cytoskeleton to induce cell motility and invasion. A hallmark of EMT is its capacity to promote metastasis, which is due in part to activation of several transcription factors and subsequent downregulation of E-cadherin. Unfortunately, current approaches have yet to uncover robust protein marker sets that can classify tumors as possessing strong EMT signatures. In this study, we utilize reverse phase protein array (RPPA) data and consensus clustering methods to successfully classify a subset of cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) tumors into an EMT protein signaling group (EMT group). The overall survival (OS) of patients in the EMT group is significantly worse than those in the other Hormone and PI3K/AKT signaling groups. In addition to a shrinkage and selection method for linear regression (LASSO), we applied training/test set and Monte Carlo resampling approaches to identify a set of protein markers that predicts the EMT status of CESC tumors. We fit a logistic model to these protein markers and developed a classifier, which was fixed in the training set and validated in the testing set. The classifier robustly predicted the EMT status of the testing set with an area under the curve (AUC) of 0.975 by Receiver Operating Characteristic (ROC) analysis. This method not only identifies a core set of proteins underlying an EMT signature in cervical cancer patients, but also provides a tool to examine protein predictors that drive molecular subtypes in other diseases.

Keywords: consensus clustering, TCGA CESC, Silhouette, Monte Carlo LASSO

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Authors: Se-Mi Lim, Won-Jae Jung, Jin-Sup Kim, Jun-Seok Park, Hyung-Il Chae

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This paper presents a current-mode vertical hall device (VHD) structure using metal layers in a CMOS process. The proposed metal layer based vertical hall device (MLVHD) utilizes vertical connection among metal layers (from M1 to the top metal) to facilitate hall effect. The vertical metal structure unit flows a bias current Ibias from top to bottom, and an external magnetic field changes the current distribution by Lorentz force. The asymmetric current distribution can be detected by two differential-mode current outputs on each side at the bottom (M1), and each output sinks Ibias/2 ± Ihall. A single vertical metal structure generates only a small amount of hall effect of Ihall due to the short length from M1 to the top metal as well as the low conductivity of the metal, and a series connection between thousands of vertical structure units can solve the problem by providing NxIhall. The series connection between two units is another vertical metal structure flowing current in the opposite direction, and generates negative hall effect. To mitigate the negative hall effect from the series connection, the differential current outputs at the bottom (M1) from one unit merges on the top metal level of the other unit. The proposed MLVHD is simulated in a 3-dimensional model simulator in COMSOL Multiphysics, with 0.35 μm CMOS process parameters. The simulated MLVHD unit size is (W) 10 μm × (L) 6 μm × (D) 10 μm. In this paper, we use an MLVHD with 10 units; the overall hall device size is (W) 10 μm × (L)78 μm × (D) 10 μm. The COMSOL simulation result is as following: the maximum hall current is approximately 2 μA with a 12 μA bias current and 100mT magnetic field; This work was supported by Institute for Information & communications Technology Promotion(IITP) grant funded by the Korea government(MSIP) (No.R7117-16-0165, Development of Hall Effect Semiconductor for Smart Car and Device).

Keywords: CMOS, vertical hall device, current mode, COMSOL

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Authors: Neha Bhadauria, Indu Gaur, Shilpi Shilpi, Susmita Goswami, Prabir K. Paul

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The aerial surface of plants colonized by Human Enteric Pathogens ()has been implicated in outbreaks of enteric diseases in humans. Practice of organic farming primarily using animal dung as manure and sewage water for irrigation are the most significant source of enteric pathogens on the surface of leaves, fruits and vegetables. The present work aims to have an insight into the molecular mechanism of interaction of Human Enteric Pathogens or their metabolites with cell wall receptors in plants. Tomato plants grown under aseptic conditions at 12 hours L/D photoperiod, 25±1°C and 75% RH were inoculated individually with S. fonticola and K. pneumonia. The leaves from treated plants were sampled after 24 and 48 hours of incubation. The cell wall and cytoplasmic proteins were extracted and isocratically separated on 1D SDS-PAGE. The sampled leaves were also subjected to formaldehyde treatment prior to isolation of cytoplasmic proteins to study protein-protein interactions induced by Human Enteric Pathogens. Protein bands extracted from the gel were subjected to MALDI-TOF-TOF MS analysis. The foremost interaction of Human Enteric Pathogens on the plant surface was found to be cell wall bound receptors which possibly set ups a wave a critical protein-protein interaction in cytoplasm. The study revealed the expression and suppression of specific cytoplasmic and cell wall-bound proteins, some of them being important components of signaling pathways. The results also demonstrated HEP induced rearrangement of signaling pathways which possibly are crucial for adaptation of these pathogens to plant surface. At the end of the study, it can be concluded that controlling the over-expression or suppression of these specific proteins rearrange the signaling pathway thus reduces the outbreaks of food-borne illness.

Keywords: cytoplasmic protein, cell wall-bound protein, Human Enteric Pathogen (HEP), protein-protein interaction

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Authors: Seyedeh Mozhgan Seyed-Talebi, Weng-Kent Chan, Hsin-Yi Tiffany Chen

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Lead-free perovskite photovoltaic (PV) technology employing non-toxic tin halide perovskite absorbers is pivotal for advancing perovskite solar cell (PSC) commercialization. Despite challenges posed by perovskite sensitivity to oxygen and humidity, our study utilizes DFT calculations using VASP and NanoDCAL software and SCAPS-1D simulations to elucidate the charge transport mechanism at the interface of CsSnI₃-FASnI₃ heterojunction. Results reveal how inherent electric fields facilitate efficient carrier transport, reducing recombination losses. We predict optimized power conversion efficiencies (PCEs) and highlight the potential of CsSnI3-FASnI3 heterojunctions for cost-effective and efficient charge transport layer-free (CTLF) photovoltaic devices. Our study provides insights into the future direction of recognizing more efficient, nontoxic heterojunction perovskite devices.

Keywords: charge transport layer free, CsSnI₃-FASnI₃ heterojunction, lead-free perovskite solar cell, tin halide perovskite., Charge transport layer free

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Authors: Jui-Pin Hung, Qiao-Wen Chang, Kung-Da Wu, Yong-Run Chen

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This study was aimed to investigate the machining stability of a spindle tool with different preloaded amount. To this end, the vibration tests were conducted on the spindle unit with different preload to assess the dynamic characteristics and machining stability of the spindle unit. Current results demonstrate that the tool tip frequency response characteristics and the machining stabilities in X and Y direction are affected to change for spindle with different preload. As can be found from the results, a high preloaded spindle tool shows higher limited cutting depth at mid position, while a spindle with low preload shows a higher limited depth. This implies that the machining stability of spindle tool system is affected to vary by the machine frame structure. Besides, such an effect is quite different and varied with the preload of the spindle.

Keywords: bearing preload, dynamic compliance, machining stability, spindle

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Authors: Marlon Gallo, Eduardo Miguel, Laura Oca, Eneko Gonzalez, Unai Iraola

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The heat generation of an energy storage system is an essential topic when designing a battery pack and its cooling system. Heat generation estimation is used together with thermal models to predict battery temperature in operation and adapt the design of the battery pack and the cooling system to these thermal needs guaranteeing its safety and correct operation. In the present work, a comparison between the use of a heat flux sensor (HFS) for indirect measurement of heat losses in a cell and the widely used and simplified version of Bernardi’s equation for estimation is presented. First, a Li-ion cell is thermally characterized with an HFS to measure the thermal parameters that are used in a first-order lumped thermal model. These parameters are the equivalent thermal capacity and the thermal equivalent resistance of a single Li-ion cell. Static (when no current is flowing through the cell) and dynamic (making current flow through the cell) tests are conducted in which HFS is used to measure heat between the cell and the ambient, so thermal capacity and resistances respectively can be calculated. An experimental platform records current, voltage, ambient temperature, surface temperature, and HFS output voltage. Second, an equivalent circuit model is built in a Matlab-Simulink environment. This allows the comparison between the generated heat predicted by Bernardi’s equation and the HFS measurements. Data post-processing is required to extrapolate the heat generation from the HFS measurements, as the sensor records the heat released to the ambient and not the one generated within the cell. Finally, the cell temperature evolution is estimated with the lumped thermal model (using both HFS and Bernardi’s equation total heat generation) and compared towards experimental temperature data (measured with a T-type thermocouple). At the end of this work, a critical review of the results obtained and the possible mismatch reasons are reported. The results show that indirectly measuring the heat generation with HFS gives a more precise estimation than Bernardi’s simplified equation. On the one hand, when using Bernardi’s simplified equation, estimated heat generation differs from cell temperature measurements during charges at high current rates. Additionally, for low capacity cells where a small change in capacity has a great influence on the terminal voltage, the estimated heat generation shows high dependency on the State of Charge (SoC) estimation, and therefore open circuit voltage calculation (as it is SoC dependent). On the other hand, with indirect measuring the heat generation with HFS, the resulting error is a maximum of 0.28ºC in the temperature prediction, in contrast with 1.38ºC with Bernardi’s simplified equation. This illustrates the limitations of Bernardi’s simplified equation for applications where precise heat monitoring is required. For higher current rates, Bernardi’s equation estimates more heat generation and consequently, a higher predicted temperature. Bernardi´s equation accounts for no losses after cutting the charging or discharging current. However, HFS measurement shows that after cutting the current the cell continues generating heat for some time, increasing the error of Bernardi´s equation.

Keywords: lithium-ion battery, heat flux sensor, heat generation, thermal characterization

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Authors: Xinxiu Li, Chuqian Zheng, Yanyan Qian, Hong Fan

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Objectives: In hepatocellular carcinoma (HCC), oncogenes are continuously and robustly transcribed due to aberrant expression of essential components of the trans-acting super-enhancers (SE) complex. Preclinical and clinical trials are now being conducted on small-molecule inhibitors that target core-transcriptional components, including as transcriptional bromodomain protein 4 (BRD4) and cyclin-dependent kinase 7 (CDK7), in a number of malignant tumors. This study aims to explore whether co-overexpression of BRD4 and CDK7 is a potential marker of worse prognosis and a combined therapeutic target in HCC. Methods: The expression pattern of BRD4 and CDK7 and their correlation with prognosis in HCC were analyzed by RNA sequencing data and survival data of HCC patients from TCGA and GEO datasets. The protein levels of BRD4 and CDK7 were determined by immunohistochemistry (IHC), and survival data of patients were analyzed using the Kaplan-Meier method. The mRNA expression levels of genes in HCC cell lines were evaluated by quantitative PCR (q-PCR). CCK-8 and colony formation assays were conducted to assess cell proliferation of HCC upon treatment with BRD4 inhibitor JQ1 or/and CDK7 inhibitor THZ1. Results: It was shown that BRD4 and CDK7 were often overexpressed in HCCs and were associated with poor prognosis of HCC by analyzing the TCGA and GEO datasets. BRD4 or CDK7 overexpression was related to a lower survival rate. It's interesting to note that co-overexpression of CDK7 and BRD4 was a worse prognostic factor in HCC. Treatment with JQ1 or THZ1 alone had an inhibitory effect on cell proliferation; however, when JQ1 and THZ1 were combined, there was a more notable suppression of cell growth. At the same time, the combined use of JQ1 and THZ1 synergistically suppresses the expression of HCC driver genes. Conclusion: Our research revealed that BRD4 and CDK7 coupled can be a useful biomarker in HCC prognosis and the combination of JQ1 and THZ1 can be a promising therapeutic therapy against HCC.

Keywords: BRD4, CDK7, cell proliferation, combined inhibition

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Authors: Mohammad Kazem Mohammadi

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The use of anticancer agents forms an important part of the treatment of cancer of various types. Uranyl Complexes with DPHMP ligand have been used for the prevention and treatment of cancers. U(IV) metal complexes prepared by reaction of uranyl salt UO2 (NO3)2.6H2O with DPHMP in dry acetonitrile. Characterization of the ligand and its complexes was made by microanalyses, FT-IR, 1H NMR, 13C NMR and UV–Visible spectroscopy. These new complex showed excellent antitumor activity against two kinds of cancer cells that that are HT29:Haman colon adenocarcinoma cell line and T47D:human breast adenocarcinoma cell line.

Keywords: uranyl complexes, DPHMP ligand, antitumor activity, HT29, T47D

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Authors: Mohd Ali Abbas Zaidi, Meenu Sachdeva, Jonaki Sen

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In the vertebrate embryo, the forebrain anlagen develops from the anterior-most region of the neural tube which is the precursor of the central nervous system (CNS). The roof plate located at the dorsal midline region of the forebrain anlagen, acts as a source of several secreted molecules involved in patterning and morphogenesis of the forebrain. One such key morphogenetic event is the invagination of the forebrain roof plate which results in separation of the single forebrain vesicle into two cerebral hemispheres. Retinoic acid (RA) signaling plays a key role in this process. Blocking RA signaling at the dorsal forebrain midline inhibits dorsal invagination and results in the absence of certain key features of this region, such as thinning of the neuroepithelium and a lowering of cell proliferation. At present we are investigating the possibility of other signaling pathways acting in concert with RA signaling to regulate this process. We have focused on BMP signaling, which we found to be active in a mutually exclusive domain to that of RA signaling within the roof plate. We have also observed that there is a change in BMP signaling activity on modulation of RA signaling indicating an antagonistic relationship between the two. Moreover, constitutive activation of BMP signaling seems to completely inhibit thinning and partially affect invagination, leaving the lowering of cell proliferation in the midline unaffected. We are employing in-silico modeling as well as molecular manipulations to investigate the relative contribution if any, of regional differences in rates of cell proliferation and thinning of the neuroepithelium towards the process of invagination. We have found expression of certain cell adhesion molecules in forebrain roof-plate whose mRNA localization across the thickness of neuroepithelium is influenced by Bmp and RA signaling, giving regional rigidity to roof plate and assisting invagination. We also found expression of certain cytoskeleton modifiers in a localized small domains in invaginating forebrain roof plate suggesting that midline invagination is under control of many factors.

Keywords: bone morphogenetic signaling, cytoskeleton, cell adhesion molecules, forebrain roof plate, retinoic acid signaling

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Authors: Zahra Heydari

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Introduction: One of the major clinical issues is acute renal failure, which is caused by ischemia-reperfusion of the kidney and is associated with high mortality. Despite advances in this area, important issues such as tissue necrosis, cell apoptosis, and so on in damaged tissue are suggestive for more researches and study on this subject. Objective: Evaluation of the potential utility of Ezetimibe in reducing injuries and cell death induced by kidney ischemia/ reperfusion through inducing expression changes of different cellular pathways in adult Sprague-Dawley rats. Materials and methods: Forty rats weighing 180-200g were divided into 4 groups. For this purpose, the first right kidneys of the rats were removed during surgery. After 20 days, the left renal artery was closed with a soft clamp and reperfusion was performed. After 24 hours, blood samples were collected and sent to the laboratory with kidneys to measure bax and bcl-2 by Western blotting and histopathological tests. Results: Quantitative damage reviews of Kidney tissue indicates damage Acute and severe tubular lesions were observed in the ischemia group. Also, the amount of injury was significantly reduced in the treatment group. There was also a significant difference between the ischemia and sham groups. In general, the results show that a single dose of 1.2 mg/kg of ezetimibe can reduce the bax/ bcl-2 ratio compared to the ischemia group. In general, the results showed Ezetimibe is effective in reducing cell damage and death due to ischemia/ reperfusion after renal ischemia through changes in the expression of various cellular pathways in rats.

Keywords: acute renal failure, renal ischemia-reperfusion injury, ezetimibe, apoptosis

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Authors: M. Miriam Hernández-Arroyo, Ivonne Caro-Gonzales, Miguel Ángel Plascencia-Espinosa, Sergio R. Trejo-Estrada

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A large biodiversity of Lactobacillus strains has been detected in traditional foods and beverages from Mexico. A selected strain of Lactobacillus sp - PODI-20, used for the obtained from an artisanal fermented beverage was cultivated in different carbon sources in a complex medium, in order to define which carbon sourced induced more effectively the isomerization of arabinose by cell fractions obtained by fermentation. Four different carbon sources were tested in a medium containing peptone and yeast extract and mineral salts. Glucose, galactose, arabinose, and lactose were tested individually at three different concentrations: 3.5, 6, and 10% w/v. The biomass yield ranged from 1.72 to 17.6 g/L. The cell pellet was processed by mechanical homogenization. Both fractions, the cellular debris, and the lysis supernatant were tested for their ability to isomerize arabinose into ribulose. The highest yield of isomer was 12 % of isomerization in the supernatant fractions; whereas up to 9.3% was obtained by the use of cell debris. The isomerization of arabinose has great significance in the production of lactic acid by fermentation of complex carbohydrate hydrolysates.

Keywords: isomerase, tagatose, aguamiel, isomerization

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Authors: Katarína Koňariková, Georgios A. Perdikaris, Lucia Andrezálová, Zdeňka Ďuračková, Lucia Laubertová, Helena Gbelcová, Ingrid Žitňanová

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Introduction: The continuous demand for new anti-cancer drugs has stimulated chemotherapeutic research based on the use of essential metalloelements with the aim to develop potential drugs with lower toxicity and higher antiproliferative activity against tumors. Copper(II) and its complexes play an important role as suitable species for antiproliferative tests. Objectives: The central objective of the current study was to investigate the potential in vitro anti-proliferative effects of N-salicylidene-L-glutamato copper (II) complexes and molecular mechanism of apoptosis induced by tested complexes. In our project we tested N-salicylidene-L-glutamato copper (II) complexes ZK1 - [Cu(N-salicylidene-L-glutamato)(H2O)2].H2O; MK0 - ([Cu2(N-sal-D,L-glu)2(isoquinoline)2].2H2O); MK1 - [Cu(N-salicylidene-5-methyl-L-glutamato)(H2O)].H2O; MK3 - transbis(ethanol)tetrakis(imidazol)Cu(II)(2+)bis(N-salicylidene-D,L-glutamato-N,O)-KO:KO´-(imidazol); MK5 - [Cu(N-salicylidene-D,L- glutamato)(2-methylimidazol] at concentration range 0.001-100 µmol/L against human colon carcinoma cell line HT-29 and human breast carcinoma cell line MCF-7. Methods: Viability was assessed by direct counting of 0.4% trypan blue dye-excluding cells after 24, 48 and 72 hour cultivations with or without copper complex and by MTT assay. To analyze the type of cell death and its mechanism induced by our copper complex we used different methods. To distinguish apoptosis from necrosis we used electrophoretic analysis, to study the activity of caspases 8 and 9 – luminometric analysis and caspase activity 3 colorimetric assay. Results: The observed anti-proliferative effect of the copper complexes appeared to be dose-, time- and cell line- dependent. Human colon carcinoma cells HT-29 appeared to be more sensitive to the complex MK0 ([Cu2(N-sal-D,L-glu)2(isoquinoline)2].2H2O) than to ZK1 ([Cu(N-salicylidene-L-glutamato)(H2O)2].H2O) and MK1 ([Cu(N-salicylidene-5-methyl-L-glutamato)(H2O)].H2O)). Human colon carcinoma cells HT-29 appeared to be more sensitive to the complex than human breast carcinoma cells MCF-7. IC50 decreased with time of incubation (24, 48 and 72h) for HT-29, but increased for MCF-7. By electrophoresis we found apoptotic cell death induced by our copper complexes in HT-29 at concentrations 1, 10, 50 and 100 µmol/L after 48h (ZK1) and 72h (MK0, MK1) and in MCF-7 we did not find apoptosis. We also studied molecular mechanism of apoptosis in HT-29 induced by copper complexes. We found active caspase 9 in HT-29 after ZK1 ([Cu(N-salicylidene-L-glutamato)(H2O)2].H2O) and MK1 ([Cu(N-salicylidene-5-methyl-L-glutamato)(H2O)].H2O)) influence and active caspase 8 after MK0 ([Cu2(N-sal-D,L-glu)2(isoquinoline)2].2H2O) influence. Conclusion: Our copper complexes showed cytotoxic activities against human colon carcinoma cells HT-29 and breast cancer cell line MCF-7 in vitro. Apoptosis was activated by mitochondrial pathway (intrinsic pathway) in case of ZK1 [Cu(N-salicylidene-L-glutamato)(H2O)2].H2O; MK1 [Cu(N-salicylidene-5-methyl-L-glutamato)(H2O)].H2O; MK3 - transbis(ethanol)tetrakis(imidazol)Cu(II)(2+)bis(N-salicylidene-D,L-glutamato-N,O)-KO:KO´-(imidazol) and MK5 - [Cu(N-salicylidene-D,L- glutamato)(2-methylimidazol] copper complexes and by death receptors (extrinsic pathway) in case of MK0 [Cu2(N-sal-D,L-glu)2(isoquinoline)2].2H2O copper complex in HT-29.

Keywords: apoptosis, copper complex, cancer, carcinoma cell line

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Authors: Bhuwan C. Joshi, Atish Prakash, Ajudhia N. Kalia

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Ethnopharmacological relevance: The plant Urtica dioica L. (Urticaceae) is used in various diseases including hepatic ailments. Traditionally, the leaves and roots of the plant are used in jaundice. Objective: The aim of the present work was to evaluate hepatoprotective potential of potent antioxidant from Urtica dioica L. against CCl4 induced hepatotoxicity in-vitro and in-vivo model. Materials and methods: Antioxidant activity of hydro alcoholic extract and its fractions petroleum ether fraction (PEF), ethyl acetate fraction (EAF), n-butanol fraction (NBF) and aqueous fraction (AF) were determined by DPPH radicals scavenging assay. Fractions were subjected to in-vitro cell line study. Further, the most potent fraction (EAF) was subjected to in-vivo study. The in-vivo hepatoprotective active fraction was chromatographed on silica column to isolate the bioactive constituent(s). Structure elucidation was done by using various spectrophotometric techniques like UV, IR, 1H NMR, 13C NMR and MS spectroscopy. Results and conclusion: The ethyl acetate fraction (EAF) of Urtica. dioica L. possessed the potent antioxidant activity viz. DPPH (IC50 78.99 ± 0.17 µg/ml). The in-vitro cell line study showed EAF prevented the cell damage. The EAF significantly attenuated the increased liver enzymes activities in serum and tissue. Column chromatography of most potent antioxidant fraction (EAF) leads to the isolation of 4-hydroxy-3-methoxy cinnamic acid which is responsible for its hepatoprotective potential. Hence, the present study suggests that EAF has significant antioxidant and hepatoprotective potential on CCl4 induced hepatotoxicity in-vitro and in-vivo.

Keywords: Urtica dioica L., antioxidant, HepG2 cell line, hepatoprotective

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Authors: Niyada Naksuk, Thoetchai Peeraphatdit, Vitaly Herasevich, Peter A. Brady, Suraj Kapa, Samuel J. Asirvatham

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Introduction: Little is known about the safety of antipsychotic therapy for delirium in the coronary care unit (CCU). Our aim was to examine the effect of delirium and antipsychotic therapy among CCU patients. Methods: Pre-study Confusion Assessment Method-Intensive Care Unit (CAM–ICU) criteria were implemented in screening consecutive patients admitted to Mayo Clinic, Rochester, the USA from 2004 through 2013. Death status was prospectively ascertained. Results: Of 11,079 study patients, the incidence of delirium was 8.3% (n=925). Delirium was associated with an increased risk of in-hospital mortality (adjusted OR 1.49; 95% CI, 1.08-2.08; P=.02) and one-year mortality among patients who survived from CCU admission (adjusted HR 1.46; 95% CI, 1.12-1.87; P=.005). A total of 792 doses of haloperidol (5 IQR [3-10] mg/day) or quetiapine (25 IQR [13-50] mg/day) were given to 244 patients with delirium. The clinical characteristics of patients with delirium who did and did not receive antipsychotic therapy were not different (baseline corrected QT [QTc] interval 460±61 ms vs. 457±58 ms, respectively; P = 0.57). In comparison to baseline, mean QTc intervals after the first and third doses of the antipsychotics were not significantly prolonged in haloperidol (448±56, 458±57, and 450±50 ms, respectively) or quetiapine groups (459±54, 467±68, and 462±46 ms, respectively) (P > 0.05 for all). Additionally, in-hospital mortality (adjusted OR 0.67; 95% CI, 0.42-1.04; P=.07), ventricular arrhythmia (adjusted OR 0.87; 95% CI, 0.17-3.62; P=.85) and one-year mortality among the hospital survivors (adjusted HR 0.86; 95% CI 0.62-1.17; P = 0.34) were not different in patients with delirium irrespective of whether or not they received antipsychotics. Conclusions: In patients admitted to the CCU, delirium was associated with an increase in both in-hospital and one-year mortality. Low doses of haloperidol and quetiapine appeared to be safe, without an increase in risk of sudden cardiac death, in-hospital mortality, or one-year mortality in carefully monitored patients.

Keywords: arrhythmias, haloperidol, mortality, qtc interval, quetiapine

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Authors: Nima Samie, Batoul Sadat Haerian, Sekaran Muniandy, M. S. Kanthimathi

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Colon and breast cancers are categorized as the most prevalent types of cancer worldwide. Recently, the broad clinical application of metal complex compounds has led to the discovery of potential therapeutic drugs. The aim of this study was to evaluate the cytotoxic action of a selected nickel complex compound (NCC) against human colon and breast cancer cells. In this context, we determined the potency of the compound in the induction of apoptosis, cell cycle arrest, and cytoskeleton rearrangement. HT-29, WiDr, CCD-18Co, MCF-7 and Hs 190.T cell lines were used to determine the IC50 of the compound using the MTT assay. Analysis of apoptosis was carried out using immunofluorescence, acridine orange/ propidium iodide double staining, Annexin-V-FITC assay, evaluation of the translocation of NF-kB, oxygen radical antioxidant capacity, quenching of reactive oxygen species content , measurement of LDH release, caspase-3/-7, -8 and -9 assays and western blotting. The cell cycle arrest was examined using flowcytometry and gene expression was assessed using qPCR array. Results showed that our nickel complex compound displayed a potent suppressive effect on HT-29, WiDr, MCF-7 and Hs 190.T after 24 h of treatment with IC50 value of 2.02±0.54, 2.13±0.65, 3.76±015 and 3.14±0.45 µM respectively. This cytotoxic effect on normal cells was insignificant. Dipping in the mitochondrial membrane potential and increased release of cytochrome c from the mitochondria indicated induction of the intrinsic apoptosis pathway by the nickel complex compound. Activation of this pathway was further evidenced by significant activation of caspase 9 and 3/7.The nickel complex compound (NCC) was also shown activate the extrinsic pathways of apoptosis by activation of caspase-8 which is linked to the suppression of NF-kB translocation to the nucleus. Cell cycle arrest in the G1 phase and up-regulation of glutathione reductase, based on excessive ROS production were also observed. The results of this study suggest that the nickel complex compound is a potent anti-cancer agent inducing both intrinsic and extrinsic pathways as well as cell cycle arrest in colon and breast cancer cells.

Keywords: nickel complex, apoptosis, cytoskeletal rearrangement, colon cancer, breast cancer

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Authors: Hediyeh Talebi, Shokoofeh Ghiam, Changiz Eslahchi

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Traditionally, Alzheimer’s disease research has focused on genes with significant fold changes, potentially neglecting subtle but biologically important alterations. Our study introduces an integrative approach that highlights genes crucial to underlying biological processes, regardless of their fold change magnitude. Alzheimer's Single-cell RNA-seq data related to the peripheral blood mononuclear cells (PBMC) was extracted from the Gene Expression Omnibus (GEO). After quality control, normalization, scaling, batch effect correction, and clustering, differentially expressed genes (DEGs) were identified with adjusted p-values less than 0.05. These DEGs were categorized based on cell-type, resulting in four datasets, each corresponding to a distinct cell type. To distinguish between cells from healthy individuals and those with Alzheimer's, an adversarial autoencoder with a classifier was employed. This allowed for the separation of healthy and diseased samples. To identify the most influential genes in this classification, the weight matrices in the network, which includes the encoder and classifier components, were multiplied, and focused on the top 20 genes. The analysis revealed that while some of these genes exhibit a high fold change, others do not. These genes, which may be overlooked by previous methods due to their low fold change, were shown to be significant in our study. The findings highlight the critical role of genes with subtle alterations in diagnosing Alzheimer's disease, a facet frequently overlooked by conventional methods. These genes demonstrate remarkable discriminatory power, underscoring the need to integrate biological relevance with statistical measures in gene prioritization. This integrative approach enhances our understanding of the molecular mechanisms in Alzheimer’s disease and provides a promising direction for identifying potential therapeutic targets.

Keywords: alzheimer's disease, single-cell RNA-seq, neural networks, blood biomarkers

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Authors: Eleftheria Atta, Yianna Vovides, Marios Katsioloudes

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In the fusion of neoliberalism and globalization, Higher Education (HE) is becoming increasingly complex. The changing patterns of the economy worldwide caused the development of high value-added economy HE has been viewed as a social investment, significant for the development of knowledge-based societies and economies. In order to contribute to economic competitiveness universities are required to produce local and employable workers in order to fit into the neoliberal economic environment. The emergence of neoliberal performativity, which measures outcomes, is a key aspect in a neoliberal era. It facilitates the redesign of institutions making organizations and individuals to think about themselves in relation to their performance. Performativity and performance management systems lead academics to become more effective, professionally advance, improve and become better than others and therefore act competitively. Besides the aforementioned complexities, universities also encounter the challenge of maintaining a set of values to guide an institution’s actions and which have always been highly respected in developing a HE institution. The formulation of a clear set of values also determines the institutional culture which will be maintained. It is evident that values create a significant framework for the workplace and may determine positive institutional results. Universities are required to engage in activities for capacity building which will improve their students’ competence as well as offer opportunities to administrative and academic staff to professionally develop in light of neoliberal performativity. Additionally, the University is now considered as an innovation ecosystem playing a significant role in providing education, research and innovation to help create solutions to meet social, environmental and economic challenges. Thus, Universities become central in orchestrating multi-actor innovation networks. This presentation will discuss the establishment of an institutional unit entitled ‘Human Development Unit’ (HDU) in a European start-up university. The activities of the HDU are envisioned as drivers for innovation that would enable the university as a whole to maintain its position in a fast-changing world and be ready to face adaptive challenges. In addition, the HDU provides its students, staff, and faculty with opportunities to advance their academic and professional development through engagement in programs that align with institutional values. It also serves as a connector with the broader community. The presentation will highlight the functions of three centers which the unit will coordinate namely, the Student Development Center (SDC), the Faculty & Staff Development Center (FSDC) and the Continuing Education Center (CEC). The presentation aligns with the aim of the conference as it welcomes presentations to discuss innovations and challenges encountered in HE. Particularly, this presentation seeks to discuss the establishment of an innovative unit at a start-up university which will contribute to creating an institutional culture shaped by the value of academic excellence for students as well as for staff, shaping and defining the functions and activities of the unit. The establishment of the proposed unit is crucial in a start-up university both to differentiate from other competitors but also to sustain its presence given the pressures in a neoliberal HE context.

Keywords: academic excellence, globalization, human development unit, neoliberalism

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Authors: Isam M. Arafa, Mazin Y. Shatnawi, Yaser A. Yousef, Batool Zaid Al-Momani

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The present work describes the preparation, characterization, and luminescence of a series of fluorenone (FL) based luminophores grafted onto modified cellulose microfibers. The FL is condensed onto cellulose aldehyde using three diamine spacers (H₂N-NH₂, H₂N(CH₂)₂NH₂ and H₂N(CH₂)₃NH₂) to afford Cell=Spacer=FL. The obtained products were characterized by spectroscopic (FT-IR, UV–Vis), thermal gravimetric analysis (TGA), and microscopic (Optical, SEM) techniques. The UV-Vis spectra of the FL=N(CH₂)ₓNH₂ (x = 0, 2, 3) moieties show that they are transparent in the 375- 800 nm region while they exhibit intense absorption band below 350 nm attributed to n-π* and π-π* transitions. The solid-state photoluminescence (PLs-s) of the cold-pressed pellets of the FL=N(CH₂)ₓNH₂ and Cell=Spacer=FL placed in a quartz cuvette show strong emission in the 500-550 nm region upon irradiation with Xe lamp light (λex = 320 nm). The PLs-s green emission of the grafted Cell=Spacer=FL was evaluated relative to that of the FL-based precursor. These grafted conjugated products have the potential to be used as analyte sensors for typical nitroaromatics/aromatic amines and be further extended to immunoassay studies for aromatic amino acids such as phenylalanine and histidine.

Keywords: luminescence, cellulose, fluorenone, grafting, solid state

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Authors: Kolja Them, Johannes Salamon, Harald Ittrich, Michael Kaul, Tobias Knopp

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Superparamagnetic iron oxide nanoparticles (SPIONs) are nanoscale magnets which can be biologically functionalized for biomedical applications. Stem cell therapies to repair damaged tissue, magnetic fluid hyperthermia for cancer therapy and targeted drug delivery based on SPIONs are prominent examples where the visualization of a preferably low concentrated SPION distribution is essential. In 2005 a new method for tomographic SPION imaging has been introduced. The method named magnetic particle imaging (MPI) takes advantage of the nanoparticles magnetization change caused by an oscillating, external magnetic field and allows to directly image the time-dependent nanoparticle distribution. The SPION magnetization can be changed by the electron spin dynamics as well as by a mechanical rotation of the nanoparticle. In this work different calibration methods in MPI are investigated for image reconstruction of magnetically labeled stem cells. It is shown that a calibration using rotationally immobilized SPIONs provides a higher quality of stem cell images with fewer artifacts than a calibration using mobile SPIONs. The enhancement of the image quality and the reduction of artifacts enables the localization and identification of a smaller number of magnetically labeled stem cells. This is important for future medical applications where low concentrations of functionalized SPIONs interacting with biological matter have to be localized.

Keywords: biomedical imaging, iron oxide nanoparticles, magnetic particle imaging, stem cell imaging

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Authors: Monika Verma, Renuka Sharma, B. R. Gulati, Namita Singh

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In combination therapy, two chemotherapeutic agents work together in a collaborative action. It has appeared as one of the promising approaches to improve anti-cancer treatment efficacy. In the present investigation, piperine (P-NPS), paclitaxel (PTX NPS), and a combination of both, piperine-paclitaxel nanoparticle (Pip-PTX NPS), were made by the nanoprecipitation method and later characterized by PSA, DSC, SEM, TEM, and FTIR. All nanoparticles exhibited a monodispersed size distribution with a size of below 200 nm, zeta potential ranges from (-30-40mV) and a narrow polydispersity index (>0.3) of the drugs. The average encapsulation efficiency was found to be between 80 and 90%. In vitro release of drugs for nanoparticles was done spectrophotometrically. FTIR and DSC results confirmed the presence of the drug. The Pip-PTX NPS significantly inhibit cell proliferation as compared to the native drugs nanoparticles in the breast cancer cell line MCF-7. In addition, Pip-PTX NPS suppresses cells in colony formation and soft gel agar assay. Scratch migration and Transwell chamber invasion assays revealed that combined nanoparticles reduce the migration and invasion of breast cancer cells. Morphological studies showed that Pip-PTX NPS penetrates the cells and induces apoptosis, which was further confirmed by DNA fragmentation, SEM, and western blot analysis. Taken together, Pip-PTX NPS inhibits cell proliferation, anchorage dependent and anchorage independent cell growth, reduces migration and invasion, and induces apoptosis in cells. These findings support that combination therapy using Pip-PTX NPS represents a potential approach and could be helpful in the future for breast cancer therapy.

Keywords: piperine, paclitaxel, breast cancer, apoptosis

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Authors: Olfat A. Mohamed

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Rhamnolipids biosurfactants have distinct properties given them importance in many industrial applications, especially their great new future applications in cosmetic and pharmaceutical industries. These applications have encouraged the search for diverse and renewable resources to control the cost of production. The experimental results were then applied to find a suitable mathematical model for obtaining the design criteria of the batch bioreactor. This research aims to produce Rhamnolipids from different oily wastewater sources such as petroleum crude oil (PO) and vegetable oil (VO) by using Pseudomonas aeruginosa ATCC 9027. Different concentrations of the PO and the VO are added to the media broth separately are in arrangement (0.5 1, 1.5, 2, 2.5 % v/v) and (2, 4, 6, 8 and 10%v/v). The effect of the initial concentration of oil residues and the addition of glycerol and palmitic acid was investigated as an inducer in the production of rhamnolipid and the surface tension of the broth. It was found that 2% of the waste (PO) and 6% of the waste (VO) was the best initial substrate concentration for the production of rhamnolipids (2.71, 5.01 g rhamnolipid/l) as arrangement. Addition of glycerol (10-20% v glycerol/v PO) to the 2% PO fermentation broth led to increase the rhamnolipid production (about 1.8-2 times fold). However, the addition of palmitic acid (5 and 10 g/l) to fermentation broth contained 6% VO rarely enhanced the production rate. The experimental data for 2% initially (PO) was used to estimate the various kinetic parameters. The following results were obtained, maximum rate or velocity of reaction (Vmax) = 0.06417 g/l.hr), yield of cell weight per unit weight of substrate utilized (Yx/s = 0.324 g Cx/g Cs) maximum specific growth rate (μmax = 0.05791 hr⁻¹), yield of rhamnolipid weight per unit weight of substrate utilized (Yp/s)=0.2571gCp/g Cs), maintenance coefficient (Ms =0.002419), Michaelis-Menten constant, (Km=6.1237 gmol/l), endogenous decay coefficient (Kd=0.002375 hr⁻¹). Predictive parameters and advanced mathematical models were applied to evaluate the time of the batch bioreactor. The results were as follows: 123.37, 129 and 139.3 hours in respect of microbial biomass, substrate and product concentration, respectively compared with experimental batch time of 120 hours in all cases. The expected mathematical models are compatible with the laboratory results and can, therefore, be considered as tools for expressing the actual system.

Keywords: batch bioreactor design, glycerol, kinetic parameters, petroleum crude oil, Pseudomonas aeruginosa, rhamnolipids biosurfactants, vegetable oil

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Authors: Sujeet Poudyal

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Introduction: Renal cell carcinoma is the most common malignancy associated with Inferior vena cava (IVC) thrombosis. Radical nephrectomy with tumor thrombectomy provides durable cancer-free survival. Other renal malignancies like Wilms’ tumors are also associated with IVC thrombus. We describe our experience with the management of renal malignancies associated with IVC thrombus. Methods: This prospective study included 28 patients undergoing surgery for renal malignancies associated with IVC thrombus from February 2017 to March 2023. Demographics of patients, types of renal malignancy, level of IVC thrombus, intraoperative details, need for venovenous bypass, cardiopulmonary bypass and postoperative outcomes were all documented. Results: Out of a total of 28 patients, 24 patients had clear cell Renal Cell Carcinoma,1 had renal osteosarcoma and 3 patients had Wilms tumor. The levels. of thrombus were II in eight, III in seven, and IV in six patients. The mean age of RCC was 62.81±10.2 years, renal osteosarcoma was 26 years and Wilms tumor was 23 years. There was a need for venovenous bypass in four patients and cardiopulmonary bypass in four patients, and the Postoperative period was uneventful in most cases except for two mortalities, one in Level III due to pneumonia and one in Level IV due to sepsis. All cases followed up till now have no local recurrence and metastasis except one case of RCC with Level IV IVC thrombus, which presented with paraaortic nodal recurrence and is currently managed with sunitinib. Conclusion: The complexity in the management of renal malignancy with IVC thrombus increases with the level of IVC thrombus. As radical nephrectomy with tumor thrombectomy provides durable cancer-free survival in most cases, the surgery should be undertaken in an expert and experienced setup with a strong cardiovascular backup to minimize morbidity and mortality associated with the procedure.

Keywords: renal malignancy, IVC thrombus, radical nephrectomy with tumor thrombectomy, renal cell carcinoma

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Authors: Tarek S. Jamil, Ahmed M. Shaban, Eman S. Mansor, Ahmed A. Karim, Azza M. Abdel Aty

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In this manuscript, 35 m³/d NF unit was designed and applied for surface water treatment of river Nile water. Intake of Embaba drinking water treatment plant was selected to install that unit at since; it has the lowest water quality index value through the examined 6 sites in greater Cairo area. The optimized operating conditions were feed and permeate flow, 40 and 7 m³/d, feed pressure 2.68 bar and flux rate 37.7 l/m2.h. The permeate water was drinkable according to Egyptian Ministerial decree 458/2007 for the tested parameters (physic-chemical, heavy metals, organic, algal, bacteriological and parasitological). Single and double sand filters were used as pretreatment for NF membranes, but continuous clogging for sand filters moved us to use UF membrane as pretreatment for NF membrane.

Keywords: River Nile, NF membrane, pretreatment, UF membrane, water quality

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Authors: Marcel Verwey, Anna M. Joubert, Elsie M. Nolte, Wolfgang Dohle, Barry V. L. Potter, Anne E. Theron

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A tetrahydroisoquinolinone (THIQ) core can be used to mimic the A,B-ring of colchicine site-binding microtubule disruptors such as 2-methoxyestradiol in the design of anti-cancer agents. Steroidomimeric microtubule disruptors were synthesized by introducing C'2 and C'3 of the steroidal A-ring to C'6 and C'7 of the THIQ core and by introducing a decorated hydrogen bond acceptor motif projecting from the steroidal D-ring to N'2. For this in vitro study, four non-steroidal THIQ-based analogues were investigated and comparative studies were done between the non-sulphamoylated compound STX 3450 and the sulphamoylated compounds STX 2895, STX 3329 and STX 3451. The objective of this study was to investigate the modes of cell death induced by these four THIQ-based analogues in A549 lung carcinoma epithelial cells and metastatic breast adenocarcinoma MDA-MB-231 cells. Cytotoxicity studies to determine the half maximal growth inhibitory concentrations were done using spectrophotometric quantification via crystal violet staining and lactate dehydrogenase (LDH) assays. Microtubule integrity and morphologic changes of exposed cells were investigated using polarization-optical transmitted light differential interference contrast microscopy, transmission electron microscopy and confocal microscopy. Flow cytometric quantification was used to determine apoptosis induction and the effect that THIQ-based analogues have on cell cycle progression. Signal transduction pathways were elucidated by quantification of the mitochondrial membrane integrity, cytochrome c release and caspase 3, -6 and -8 activation. Induction of autophagic cell death by the THIQ-based analogues was investigated by morphological assessment of fluorescent monodansylcadaverine (MDC) staining of acidic vacuoles and by quantifying aggresome formation via flow cytometry. Results revealed that these non-steroidal microtubule disrupting analogues inhibited 50% of cell growth at nanomolar concentrations. Immunofluorescence microscopy indicated microtubule depolarization and the resultant mitotic arrest was further confirmed through cell cycle analysis. Apoptosis induction via the intrinsic pathway was observed due to depolarization of the mitochondrial membrane, induction of cytochrome c release as well as, caspase 3 activation. Potential involvement of programmed cell death type II was observed due to the presence of acidic vacuoles and aggresome formation. Necrotic cell death did not contribute significantly, indicated by stable LDH levels. This in vitro study revealed the induction of the intrinsic apoptotic pathway as well as possible involvement of autophagy after exposure to these THIQ-based analogues in both MDA-MB-231- and A549 cells. Further investigation of this series of anticancer drugs still needs to be conducted to elucidate the temporal, mechanistic and functional crosstalk mechanisms between the two observed programmed cell deaths pathways.

Keywords: apoptosis, autophagy, cancer, microtubule disruptor

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