Effects of Novel Synthetic Nucleosides as Anti-Tumor Agents on Human Acute Promyelocytic Leukemia Cell Line (HL-60)

Nucleosides and their analogs are considered a clinically proven class of therapeutic agents possessing anticancer and antiviral activity. Several trifluoromethyl-substituted pyrazole N-nucleosides (coded NIA, NIIA and NIIA) and their nucleobases were synthesized and tested for the ability to induce apoptosis in acute human promyelocytic cell line (HL-60). The growth and proliferation of HL-60 was more effectively inhibited by NIA, NIIA and their nucleobases compared to NIIIA and its nucleobase. In addition, DNA fragmentation was detected in a concentration-dependent manner as a result of nucleosides treatment. A caspase-3-dependent apoptosis was observed based on the Western blot analysis of poly-ADP-ribose polymerase (PARP) and caspase-3. Nucleosides and nucleobases also trigger the release of cytochrome-c from the mitochondria by disruption of mitochondrial membrane potential and ROS formation. Furthermore, the use of zDEVD-fmk (caspase-3 inhibitor) and zLEHD-fmk (caspase-9 inhibitor) resulted in an inhibition of the activity of caspase-3 and 9, accompined with no change in the activity of caspase-8 after the use of zIETD-fmk (casapse-8 inhibitor). These findings implicate the involvement of the caspase-9-dependent mitochondrial pathway. Treatment with nucleosides also resulted in a concentration-dependent upregulation and translocation of the proapoptotic molecule Bax, increased expression of other proapoptotic proteins Bad, Bak, decreased expression of antiapoptotic proteins (i.e. Bcl-2 and Bcl-xL), and enhancement of p53 expression. Moreover, treatment with these agents resulted in accumulation of cells in the G0-G1 phase of the cell cycle, indicating the degradation of the cellular DNA. Interestingly, these nucleosides were found to posses anti-histone deacetyl transferase(s) (HDACs) potential, which is an exciting turn in cancer therapy. This conclusion was based on the observed decease in the expressed level of HDAC-1, -2 and -3. Our results suggest that these novel synthetic nucleosides can induce apoptosis via the mitochondrial pathway, and therefore they could be considered as candidate anti-tumor agents

Characterizing of Robo downstream signalling to promote direct neurogenesis

The size and degree of folding of the mammalian cortex are pivotal factors that affect species’ cognitive abilities and sensorimotor skills. The cerebral cortex is the main region in the mammalian brain that governs complex cognitive behaviors. The development of the cortex depends on the amplification of neural stem cells (NSCs), neural progenitors (NPs) and the generation and differentiation of postmitotic neurons. There are two main types of NPs in the mouse neocortex (NCx): apical radial glia (aRGCs) and intermediate progenitor cells (IPCs). Robo receptors play an important role in regulating the amplification of cortical progenitors. The absence of Robo receptor signalling plus the alteration of the Notch signalling pathway in the mouse NCx leads to an overproduction of poorly functional IPCs. Ancient amniotic cortices exhibit a predominance of direct neurogenesis during development, where aRGCs produce neurons directly. Intriguingly, Robo receptors as well as Notch signalling play a major role in attenuating the mode of neurogenesis. This hypothesis was validated in several brain structures with phyletic antiquity, confirming that Robo receptors are essential in the shift towards indirect neurogenesis during the evolution and expansion of the cerebral cortex. However, little is known about the precise signalling cascade or interactors employed by Robo to initiate direct neurogenesis. In this thesis, we demonstrated the transcriptomic differences between the developing mouse NCx and OB (where direct neurogenesis is predominant in the OB vs NCx) using single cell RNA sequencing (scRNA). We showed aRGCs populations that are differently enriched between these regions. We traced lineage trajectories of indirect and direct neurogenesis, as well as validating the expression of several differentially expressed genes between the two regions. We used Robo intracellular domain (ICD)—this region is considered a constitutively active form of Robo receptor—and demonstrated the protein interactors that bind it. Following that, we demonstrated Robo ICD localization to the nucleus. We discovered that Robo conserved cytoplasmic domains play an important role in Robo ICD nucleocytoplasmic localization and direct neurogenesis induction in the mouse NCx. Next, we showed that Robo ICD localizes to chromatin, and causes transcriptional changes that occur upon the experimental gain of function of Robo ICD in the NCx and in vitro. Additionally, we showed that loss of function of Nup107, a nuclear pore complex (NPC) protein and one of Robo ICD protein interactors, induces direct neurogenesis in mouse NCx and chick lateral pallium. Taken together, our findings suggest the transcriptional role Robo ICD exerts by binding DNA and, consequently, its conserved role in moderating direct neurogenesis. El tamaño y el grado de plegamiento de la corteza cerebral son factores fundamentales que afectan a las capacidades cognitivas y habilidades sensoriomotoras de los mamíferos. La corteza cerebral es la principal región del cerebro que gobierna conductas cognitivas complejas. El desarrollo de la corteza depende de la amplificación de células madre neurales (CMN), progenitores neurales (PN) y de la generación y diferenciación de neuronas postmitóticas. Hay dos tipos principales de PN en la neocorteza o neocórtex (NCx) del ratón: las células de glía radial apical (CGRa) y las células progenitoras intermedias (CPI). Los receptores Robo juegan un papel importante en la regulación de la amplificación de los progenitores corticales. La ausencia de señalización del receptor Robo sumada a la alteración de la vía de señalización de Notch en el NCx de ratón conduce a una sobreproducción de CPI poco funcionales. La corteza de especies amniotas anteriores en la evolución a los mamíferos (como los reptiles y las aves) exhiben un predominio de neurogénesis directa durante el desarrollo, por el cual las CGRa producen neuronas directamente. Curiosamente, los receptores Robo, así como la señalización de Notch, desempeñan un papel importante en la atenuación de esta modalidad de neurogénesis a lo largo de la evolución. Esta hipótesis ha sido validada en varias estructuras cerebrales con antigüedad filética, confirmando que los receptores Robo son esenciales en el cambio hacia la neurogénesis indirecta durante la evolución y la consecuente expansión de la corteza cerebral. Sin embargo, se sabe poco sobre la cascada de señalización de Robo, así como de los mensajeros secundarios empleados por este receptor para iniciar el proceso de neurogénesis directa. En esta tesis, demostramos las diferencias transcriptómicas que existen entre el NCx y el bulbo olfatorio (BO) de ratón en desarrollo (sabiendo que la neurogénesis directa es predominante en BO frente al NCx). Para ello usamos la técnica de secuenciación de ARN de células individuales (single-cell RNA sequencing (scRNAseq) en inglés). Mostramos que hay poblaciones de RGCa que están diferentemente enriquecidas entre estas regiones. Trazamos trayectorias de linaje de neurogénesis indirecta y directa y validamos la expresión de varios genes expresados diferencialmente entre las dos regiones. Utilizamos el dominio intracelular (DIC) de Robo (esta región se considera una forma constitutivamente activa del receptor) y demostramos los mensajeros secundarios que se unen. Después, demostramos la localización del DIC de Robo en el núcleo. Descubrimos que sus dominios citoplasmáticos, muy conservados a lo largo de la evolución, tienen un papel importante en la localización núcleo-citoplasmática del DIC y la inducción directa de neurogénesis en el NCx de ratón. A continuación, mostramos que una vez en el núcleo, el DIC se une a la cromatina y provoca cambios transcripcionales que tienen como resultado una la ganancia de función de Robo tanto en el NCx como in vitro. Además, demostramos que la pérdida de función de Nup107, una proteína que forma parte del complejo del poro nuclear (CPN) además de ser una proteína de interacción del DIC de Robo, induce neurogénesis directa en el NCx de ratón y en el palio lateral de pollo. En conjunto, nuestros resultados sugieren el papel de modulación transcripcional que ejerce el DIC de Robo al unirse al ADN y, en consecuencia, su rol conservado a lo largo de la evolución en la disminución de la neurogénesis directa

Variation Orders in Building Projects in Khartoum State-Sudan: The Causes and the Impact on Projects Performance

"Occurrence of variation orders (VOs) is a common phenomenon in building projects and a challenging feature. Opinions and feedback of the stakeholders of building projects at Khartoum State – Sudan were investigated to identify and rank the key factors that cause VOs and evaluate their consequent impact on projects’ performance. 10 projects were thoroughly analyzed to determine how their performance was affected by the occurrence of VOs and in conjunction with this an industry wide survey that was conducted to determine the frequency of occurrence of a previously compiled list of factors. 130 respondents -contractors, consultants, projects’ owners and project managers-took part in the survey. Considering the frequency of occurrence and the strength of their impact, the relative importance index from the participants’ feedback was calculated allowing the ranking of the factors causing VOs. It was found that the main causes for VOs emerged from the owners’ side and are mainly attributed to changing his needs or scope of work. It was also confirmed that there is a significant relationship between the occurrence of VOs and projects’ time extension (by 22-200%) and cost overrun (by 2.67-42.86).

New Policies For The Development Of Informal Settlements

Most urban areas of the world suffer from many urban problems resulting from population inflation and urban growth. Urban areas have seen many developments in the past decades, such as the migration of people from rural to urban areas, and the subsequent deterioration. Urbanization is growing rapidly, with no parallel investment in urban services, and housing policies, planning and land management systems failing to meet the needs of society. The concept of “informal” is usually defined negatively and simply, unlike typical “formal” characteristics, where it represents illegal, unauthorized, unplanned and unregulated characteristics. In recent years, land-use change and urban growth models have become important tools for city planners, economists, ecologists, and resource managers. In most models, future land use changes, urban sprawl and limb expansion are expected. Today, urban areas use smart growth strategies. The study illustrates the use of urban infill as a new approach to dealing with informal areas. It considers the transfer of incompatible land uses beyond the city limits, the redevelopment, improvement and renovation of old urban areas, worn-out fabric and the reuse of abandoned land in new urban development. The problem of informal settlements is one of the key issues. It is an economic, social and urban problem affecting the region itself and its surroundings. Informal areas have been imposed themselves as a form of planning for the majority of urban residents. The extreme neglect of this problem amplified it as it grew at more rates than the city itself. The promotion and development of informal settlements have become self-imposed in national developmentpolicies. Although there are several ways to address them, their problems remain, and development projects continue to suffer from many deficiencies in their performance. Therefore, the importance of the study was to use a new policy to deal with informal areas in Egypt such as the urban infill policy as a new approach to deal with it and try to use and implement it and try to reach solutions to reduce the problem and increase the resulting problems

Investigating the mechanisms of action of the SNF2-homolog protein Fun30

In eukaryotes, the manipulation of chromatin structure represents a means of regulating access to genetic information. One way in which this can be achieved is via the action of ATP-dependent chromatin remodelling complexes related to the S.cerevisiae Snf2 proteins. The Fun30 protein (Function unknown now 30) shares sequence homology with the Snf2 family of chromatin remodelling proteins. Here the activities and roles of Fun30 have been investigated further. In this study, Fun30 was found to exist predominantly as a homodimer with an apparent molecular weight of 250 KDa. Fun30 binds to DNA, mononucleosomes and nucleosomal arrays. Moreover, Fun30 was shown to cause ATP-dependent alterations to nucleosome structure. This can involve increasing the accessibility of DNA, octamer displacement by sliding in cis or transfer to separate DNA molecules.However, Fun30 was shown to be proficient in catalysing the exchange of histone dimers. Deletion of fun30 was observed to increases resistance to UV, IR and 6-azauracil raising the possibility that this protein has functions in DNA repair. Deletion of fun30 was also found to result in temperature sensitivity. At the non permissive temperature cells were found to accumulate in the S-phase of the cell cycle. Under these conditions Rad53 was found to be phosphorylated which is consistent with the activation of the S-phase checkpoint. In order to investigate the role of Fun30 in DNA replication samples were prepared to map the genome-wide locations of Fun30 at different stages in the cell cycle. Preliminary analysis of this data suggests that there is a transient enrichment of Fun30 protein within the vicinity of replication origins during S-phase.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Staphylococcal infections among leukemic patients

Staphylococcus are cause hospital community acquired infection and they are an important cause of health –care associated infection.The Coagulase positive Staphylococcus are Staphylococcus aureus which can implicated in toxic shock syndrome. Methicillin and Vancomycin Staphylococcus aureus resistant (MRSA, VRSA) become major cause of hospital- acquired infection and community acquired infection.Coagulase negative staphylococcus emerged as major cause of infection in immunocompromised patients.The main objective of this study was to evaluate the distribution of Staphylococci among leukemic patients since it is well known that leukemic patients are prone to be infected easily due to their immunosuppressed status.This study was undertaken between oct. 2009 and Jun 2010 at Iraqi center of hematology and medical genetics. 140 clinical specimen(aspirated wound,superficial wound,urine, blood) have deen collected carefully from leukemic patients and subjected to well known established microbiological methods for diagnosis and identification of the isolates .All isolates were tested for their susceptibility to antimicrobials according to Kirby –Bauer technique.Out of 140 clinical specimen collected from leukemic patients, it was possible to obtain( 63) bacterial isolates form which(43) of Coagulase negative staphylococci (CONS) and (20) of Coagulase positive staphylococci. Out of 43(CONS) isolates has been found that S.epidermidis constitutes (28)the highest of all isolates. Antimicrobial susceptibility reveald that S.aureus is highly sensitive to Gentamycin (85%), Erythromycin (80%), while it is resistant to the drugs Cefotaxim (45%), Choramphenicol(40%),and Tetracycline(20%). S.epidermidis show highly sensitive to Erythromycin(100%),Vancomycin (100%), and Cefotaxim(70%) and highly resistant to the drugs Chloromphenicol(45%), Augmentin(45%),Gentamycin (10%), and Tetracycline(10%).It is concluded that S.epidemidis rankes the first( 28)among the isolates and S.aureus ranke the 2nd .All isolates were highly resistant to Chloramphenicol and highly sensitive to Erythromycine

Eco-friendly Concrete Using Local Materials From Sudan

This study is aimed at investigating the potentiality for utilizing some locally available eco-friendly materials to replace some concrete constituents as a possible opportunity to introduce sustainable construction in Sudan. Six suggested scenarios were explored to visualize the possible outcomes : (1) 100% recycled aggregates (RA) and natural pozzolana in replacement of coarse aggregates (2) steel slag replacing fine aggregate or cement (3) treated sawdust replacing fine aggregates (4) sawdust ash in partial replacement of cement (5) meta-kaolin (MK) in partial substitution for ordinary Portland cement (OPC) (6) quarry dust (QD) in partial replacement of sand or cement. Laboratory experiments were conducted and concrete workability and compressive strength were determined. The results confirmed the suitability of RA for full replacement of natural coarse aggregates. Steel slag was more appropriate in replacing sand than cement when added in small percentages not exceeding 15%. Sawdust needed treatment to eliminate the unfavorable properties before using it as a substitute for sand but when the ash was used to replace cement, it was not possible to achieve the required strength at early ages and better results were achieved in 28 days. With a chemical composition comparable to cement, MK showed impressive results when used in partial replacement of OPC. The addition of QD in replacement of 15% of sand offered a reasonable workability but the compressive strength was only approaching the targeted value. According to these results, it could be inferred that the tested options offer reasonable evidence to confirm their potentiality for producing green concrete in Sudan

Explainable AI by BAPC -- Before and After correction Parameter Comparison

By means of a local surrogate approach, an analytical method to yield explanations of AI-predictions in the framework of regression models is defined. In the case of the AI-model producing additive corrections to the predictions of a base model, the explanations are delivered in the form of a shift of its interpretable parameters as long as the AI- predictions are small in a rigorously defined sense. Criteria are formulated giving a precise relation between lost accuracy and lacking model fidelity. Two applications show how physical or econometric parameters may be used to interpret the action of neural network and random forest models in the sense of the underlying base model. This is an extended version of our paper presented at the ISM 2020 conference, where we first introduced our new approach BAPC