Microtubulin binding sites as target for developing anticancer agents

Microtubules (MTs) play important and diverse roles in eukaryotic cells. Their function and biophysical properties have made α−and β−tubulin, the main components of MTs, the subject of intense study. Interfering with normal MT dynamics, for example, by the addition of tubulin ligands, can cause the cell great distress and affect MT stability and functions, including mitosis, cell motion and intracellular organelle transport. It has been shown in the literature that tubulin is an important target molecule for developing anticancer drugs. Tubulin binding molecules have generated considerable interest after the successful introduction of the taxanes into clinical oncology and the widespread use of the vinca alkaloids vincristine and vinblastine. These compounds inhibit cell mitosis by binding to the protein tubulin in the mitotic spindle and preventing polymerization into the MTs. This mode of action is also shared with other natural agents eg colchicine and podophyllotoxin. However various tubulin isotypes have shown resistance to taxanes and other MT agents. Therefore, there is a strong need to design and develop new natural analogs as antimitotic agents to interact with tubulin at sites different from those of vinca alkaloids and taxanes. This minireview provides SAR on several classes of antimitotic agents reported in the literature. The structures and data given are essential to the scientists who are involved in drug design and development in the field of anticancer drugs.

Investigation of structural requirements of anticancer activity at the paclitaxel/tubulin binding site using CoMFA and CoMSIA

CoMFA and CoMSIA analysis were utilized in this investigation to define the important interacting regions in paclitaxel/tubulin binding site and to develop selective paclitaxel-like active compounds. The starting geometry of paclitaxel analogs was taken from the crystal structure of docetaxel. A total of 28 derivatives of paclitaxel were divided into two groups—a training set comprising of 19 compounds and a test set comprising of nine compounds. They were constructed and geometrically optimized using SYBYL v6.6. CoMFA studies provided a good predictability (q2 = 0.699, r2 = 0.991, PC = 6, S.E.E. = 0.343 and F = 185.910). They showed the steric and electrostatic properties as the major interacting forces whilst the lipophilic property contribution was a minor factor for recognition forces of the binding site. These results were in agreement with the experimental data of the binding activities of these compounds. Five fields in CoMSIA analysis (steric, electrostatic, hydrophobic, hydrogen-bond acceptor and donor properties) were considered contributors in the ligand–receptor interactions. The results obtained from the CoMSIA studies were: q2 = 0.535, r2 = 0.983, PC = 5, S.E.E. = 0.452 and F = 127.884. The data obtained from both CoMFA and CoMSIA studies were interpreted with respect to the paclitaxel/tubulin binding site. This intuitively suggested where the most significant anchoring points for binding affinity are located. This information could be used for the development of new compounds having paclitaxel-like activity with new chemical entities to overcome the existing pharmaceutical barriers and the economical problem associated with the synthesis of the paclitaxel analogs. These will boost the wide use of this useful class of compounds, i.e. in brain tumors as the most of the present active compounds have poor blood–brain barrier crossing ratios and also, various tubulin isotypes has shown resistance to taxanes and other antimitotic agents.

RuleOMS: A rule-based online management system

We propose an architecture for a rule-based online management systems (RuleOMS). Typically, many domain areas face the problem that stakeholders maintain databases of their business core information and they have to take decisions or create reports according to guidelines, policies or regulations. To address this issue we propose the integration of databases, in particular relational databases, with a logic reasoner and rule engine. We argue that defeasible logic is an appropriate formalism to model rules, in particular when the rules are meant to model regulations. The resulting RuleOMS provides an efficient and flexible solution to the problem at hand using defeasible inference. A case study of an online child care management system is used to illustrate the proposed architecture.

A qualitative exploration of parental experiences of stigma while living with HIV in Bangladesh

With much of the focus on the “risk” groups, families have often been less studied in HIV research. Further, because of a focus on the aetiology and epidemiology of HIV, the social impacts associated with HIV on families and neighbours are sometimes overlooked. This study examined parental experiences of stigma and discrimination while living with HIV within a family context in Bangladesh. A qualitative research design using a grounded theory approach was used for this research. Data was collected through in-depth interviews with 19 HIV-positive parents, recruited with the support of two self-help groups of HIV-positive people, in two settings namely Khulna and Dhaka in Bangladesh. The findings indicate that HIV-positive parents held the view that they continue to experience significant stigma and their narratives clearly show how this affected them and their children. A range of informal practices were enacted in everyday contexts by extended family and community members to identify, demarcate and limit the social interaction of HIV-positive parents. Parents highlighted a number of factors including negative thoughts and behaviours, rejection, isolation and derogatory remarks as manifestations of stigma and discrimination, impacting upon them and their children because of their association with HIV.

Numerical investigation of aerosol particle transport and deposition in realistic lung airway

Different human activities like combustion of fossil fuels, biomass burning, industrial and agricultural activities, emit a large amount of particulates into the atmosphere. As a consequence, the air we inhale contains significant amount of suspended particles, including organic and inorganic solids and liquids, as well as various microorganism, which are solely responsible for a number of pulmonary diseases. Developing a numerical model for transport and deposition of foreign particles in realistic lung geometry is very challenging due to the complex geometrical structure of the human lung. In this study, we have numerically investigated the airborne particle transport and its deposition in human lung surface. In order to obtain the appropriate results of particle transport and deposition in human lung, we have generated realistic lung geometry from the CT scan obtained from a local hospital. For a more accurate approach, we have also created a mucus layer inside the geometry, adjacent to the lung surface and added all apposite mucus layer properties to the wall surface. The Lagrangian particle tracking technique is employed by using ANSYS FLUENT solver to simulate the steady-state inspiratory flow. Various injection techniques have been introduced to release the foreign particles through the inlet of the geometry. In order to investigate the effects of particle size on deposition, numerical calculations are carried out for different sizes of particles ranging from 1 micron to 10 micron. The numerical results show that particle deposition pattern is completely dependent on its initial position and in case of realistic geometry; most of the particles are deposited on the rough wall surface of the lung geometry instead of carinal region.

A "Candidate-Interactome" Aggregate Analysis of Genome-Wide Association Data in Multiple Sclerosis

Though difficult, the study of gene-environment interactions in multifactorial diseases is crucial for interpreting the relevance of non-heritable factors and prevents from overlooking genetic associations with small but measurable effects. We propose a "candidate interactome" (i.e. a group of genes whose products are known to physically interact with environmental factors that may be relevant for disease pathogenesis) analysis of genome-wide association data in multiple sclerosis. We looked for statistical enrichment of associations among interactomes that, at the current state of knowledge, may be representative of gene-environment interactions of potential, uncertain or unlikely relevance for multiple sclerosis pathogenesis: Epstein-Barr virus, human immunodeficiency virus, hepatitis B virus, hepatitis C virus, cytomegalovirus, HHV8-Kaposi sarcoma, H1N1-influenza, JC virus, human innate immunity interactome for type I interferon, autoimmune regulator, vitamin D receptor, aryl hydrocarbon receptor and a panel of proteins targeted by 70 innate immune-modulating viral open reading frames from 30 viral species. Interactomes were either obtained from the literature or were manually curated. The P values of all single nucleotide polymorphism mapping to a given interactome were obtained from the last genome-wide association study of the International Multiple Sclerosis Genetics Consortium & the Wellcome Trust Case Control Consortium, 2. The interaction between genotype and Epstein Barr virus emerges as relevant for multiple sclerosis etiology. However, in line with recent data on the coexistence of common and unique strategies used by viruses to perturb the human molecular system, also other viruses have a similar potential, though probably less relevant in epidemiological terms. © 2013 Mechelli et al.

Advances in solid-catalytic and non-catalytic technologies for biodiesel production

The insecure supply of fossil fuel coerces the scientific society to keep a vision to boost investments in the renewable energy sector. Among the many renewable fuels currently available around the world, biodiesel offers an immediate impact in our energy. In fact, a huge interest in related research indicates a promising future for the biodiesel technology. Heterogeneous catalyzed production of biodiesel has emerged as a preferred route as it is environmentally benign needs no water washing and product separation is much easier. The number of well-defined catalyst complexes that are able to catalyze transesterification reactions efficiently has been significantly expanded in recent years. The activity of catalysts, specifically in application to solid acid/base catalyst in transesterification reaction depends on their structure, strength of basicity/acidity, surface area as well as the stability of catalyst. There are various process intensification technologies based on the use of alternate energy sources such as ultrasound and microwave. The latest advances in research and development related to biodiesel production is represented by non-catalytic supercritical method and focussed exclusively on these processes as forthcoming transesterification processes. The latest developments in this field featuring highly active catalyst complexes are outlined in this review. The knowledge of more extensive research on advances in biofuels will allow a deeper insight into the mechanism of these technologies toward meeting the critical energy challenges in future.

On the effect of Reynolds number for flow past three side-by-side square cylinders for unequal gap spacings

Flow patterns and aerodynamic characteristics behind three side-by-side square cylinders has been found depending upon the unequal gap spacing (g1 = s1/d and g2 = s2/d) between the three cylinders and the Reynolds number (Re) using the Lattice Boltzmann method. The effect of Reynolds numbers on the flow behind three cylinders are numerically studied for 75 ≤ Re ≤ 175 and chosen unequal gap spacings such as (g1, g2) = (1.5, 1), (3, 4) and (7, 6). We also investigate the effect of g2 while keeping g1 fixed for Re = 150. It is found that a Reynolds number have a strong effect on the flow at small unequal gap spacing (g1, g2) = (1.5, 1.0). It is also found that the secondary cylinder interaction frequency significantly contributes for unequal gap spacing for all chosen Reynolds numbers. It is observed that at intermediate unequal gap spacing (g1, g2) = (3, 4) the primary vortex shedding frequency plays a major role and the effect of secondary cylinder interaction frequencies almost disappear. Some vortices merge near the exit and as a result small modulation found in drag and lift coefficients. This means that with the increase in the Reynolds numbers and unequal gap spacing shows weakens wakes interaction between the cylinders. At large unequal gap spacing (g1, g2) = (7, 6) the flow is fully periodic and no small modulation found in drag and lift coefficients signals. It is found that the jet flows for unequal gap spacing strongly influenced the wake interaction by varying the Reynolds number. These unequal gap spacing separate wake patterns for different Reynolds numbers: flip-flopping, in-phase and anti-phase modulation synchronized, in-phase and anti-phase synchronized. It is also observed that in case of equal gap spacing between the cylinders the effect of gap spacing is stronger than the Reynolds number. On the other hand, in case of unequal gap spacing between the cylinders the wake patterns strongly depends on both unequal gap spacing and Reynolds number. The vorticity contour visualization, time history analysis of drag and lift coefficients, power spectrum analysis of lift coefficient and force statistics are systematically discussed for all chosen unequal gap spacings and Reynolds numbers to fully understand this valuable and practical problem.

Performance assessment in a heat exchanger tube fitted with double counter twisted tape inserts

The present study explored the effects of the double counter twisted tapes on heat transfer and fluid friction characteristics in a heat exchanger tube. The double counter twisted tapes were used as counter-swirl flow generators in the test section. The experiments were performed with double counter twisted tapes of four different twist ratios (y = 1.95, 3.85, 5.92 and 7.75) using air as the testing fluid in a circular tube turbulent flow regime where the Reynolds number was varied from 6950 to 50,050. The experimental results demonstrated that the Nusselt number, friction factor and thermal enhancement efficiency were increased with decreasing twist ratio. The results also revealed that the heat transfer rate in the tube fitted with double counter twisted tape was significantly increased with corresponding increase in pressure drop. In the range of the present work, heat transfer rate and friction factor were obtained to be around 60 to 240% and 91 to 286% higher than those of the plain tube values, respectively. The maximum thermal enhancement efficiency of 1.34 was achieved by the use of double counter twisted tapes at constant blower power. In addition, the empirical correlations for the Nusselt number, friction factor and thermal enhancement efficiency were also developed, based on the experimental data.

Socio-cultural influences on vehicle defects in the Omani heavy vehicle industry

With recent economic growth in Oman there is increased use of heavy vehicles, presenting an increase in heavy vehicle crashes, associated fatalities and injuries. Vehicle defects cause a significant number of heavy vehicle crashes in Oman and increase the likelihood of fatalities. The aim of this study is to explore factors contributing to driving with vehicle defects in the Omani heavy vehicle industry. A series of qualitative participants observations were conducted in Oman with 49 drivers. These observations also involved discussion and interviews with drivers. The observations occurred at two road-side locations where heavy vehicle drivers gather for eating, resting, vehicle check-up, etc. Data collection was conducted over a three week period. The data was analysed using thematic analysis. A broad number of factors were identified as contributing to the driving of vehicles with defects. Participants indicated that tyres and vehicle mechanical faults were a common issue in the heavy vehicle industry. Participants regularly reported that their companies use cheap, poor quality standards parts and conducted minimal maintenance. Drivers also indicated that they felt powerless to resist company pressure to drive vehicles with known faults. In addition, drivers reported that traffic police were generally in effective and lacked skill to appropriately conduct roadside inspection on trucks. Further, participants stated that it was possible for companies to avoid being fined during annual or roadside vehicle inspections if members of the company knew the traffic police officer conducting the inspection. Moreover, fines issued by police are generally directed to the individual driver rather than being applied to the company, thus providing no incentive for companies to address vehicle faults. The implications of the findings are discussed.

Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis. © 2011 Macmillan Publishers Limited. All rights reserved.

Thermodynamics of ligand (substrate end product) binding to endoxylanase from Chainia sp. (NCL-82-5-1): isothermal calorimetry and fluorescence titration studies

The binding of xylo-oligosaccharides to Chainia endoxylanase resulted in a decrease in fluorescence intensity of the enzyme with the formation of 1:1 complex. Equilibrium and thermodynamic parameters of ligand binding were determined by fluorescence titrations and titration calorimetry. The affinity of xylanase for the oligosaccharides increases in the order X-2 < X-3 < X-4 less than or equal to X-5. Contributions from the enthalpy towards the free energy change decreased with increasing chain length from X-2 to X-4, whereas an increase in entropy was observed, the change in enthalpy and entropy of binding being compensatory. The entropically driven binding process suggested that hydrophobic interactions as well as hydrogen bonds play a predominant role in ligand binding.

Wife beating: A measure to deal with marital disharmony or a license for misconduct

Wife beating is not a new phenomena rather it has been practiced from pre historic time till date. This was due to the fact that in all the civilizations and under all religions, woman was considered subjugated to men. Her natural physical weakness had also made her vulnerable for violence. Islam reinforced womanhood by protecting her rights and providing her respect in the family and society at large. However, it is not interpreted accurately in male dominant society due to the existence of a patriarchal social setup. Adding to the ignorance regarding the position of women in Islam, the presence of injustice and mal practices in contemporary Muslim societies has been taken up as a weak point of Islam by non Muslims as well by less informed Muslims. The reasons for denying women’s rights in Pakistani society could be summed up as lack of education, ignorance about Islamic teachings, feudal and tribal cultural traditions, male dominated patriarchal attitudes, poverty, unemployment and misinterpretations regarding precise teachings of Quran and Sunnah. There are many misconceptions regarding the stance of Islam on wife beating as well. It is commonly understood that Islam gives permission for wife beating in the Quranic verse 4:34. This article will describe the relationship between husband and wife in the light of Quranic verse4:34 and will explore the sanctions of wife beating and its dimensions. Furthermore, it will aim to remove misunderstandings and prejudged opinions related to the concerned issue, in the light of Quran and Sunnah.

Shariah perspective on marriage contract and practice in contemporary Muslim societies

Forced marriages are worldwide phenomena and also exist in Pakistani society. It involves the lack of free and full consent of at least one of the parties to a marriage. Mostly, females are victims of forced marriages. It is prevalent in the name of religion in many Muslim countries; however, it is purely a traditional and cultural phenomenon which has nothing to do with religion. Forced marriages are different from arranged marriages in which both parties freely consent to enter into marriage contract and they have no objection on the choice of partner selected by their parents. This study will highlights different forms of forced marriages in Pakistani society.

But if you desire God and His Messenger : The concept of choice in Sahih al-Bukhari

The aim of this dissertation is to discuss the concept of choice in the most important collection of Islamic traditions, Sahih al-Bukhari. The author of the collection, Muhammad ibn Isma'il al-Bukhari, lived between 810-870. My starting point is the collection of texts as it is now in its normative, established form. I read the hadiths as pieces of reality, not as statements about reality. The historicity of the texts has no role at all in my analysis. Part I sketches out the hagiography of the life and work of the author and provides a short history of the development of hadith literature and the processes of collecting and classifying the texts are discussed briefly. Part one ends with the presentation of my way of using rhetorical analysis as a methodological tool. Part II introduces my analysis of the concept of choice. It is divided into ten chapters, each concentrating on one hadith cluster. Part II ends with a discussion of the philosophy of free will and predestination in early Islam. Hadith literature is often considered as a representative of predestinarian theology compared to the Qur'an which emphasises the reponsibility of people of their own acts. In my conclusions I suggest that accoding to the texts in Sahih al-Bukhari, people do deal with real choices in their lives. The collection includes both strictly predestinarian texts but it also compises texts which claim that people are demanded to make real choices, even choices concerning life and death.