Inducible DNA Interstrand Cross-linking Agents: Design, Synthesis, Mechanism, and Biomedical Applications

DNA is the carrier of genetic information, making its chemical reactivity and function extremelyimportant. DNA interstrand cross-links (ICL) leads to covalent bind of two strands, which prevents the separation of double helix. DNA ICLs are the sources of the cytotoxicity of antitumor and anticancer agents. This thesis focuses on investigating the reactivity of a varieties of aromatic compounds towards DNA. Some of these molecules can be activated by photo irradiation to induce DNA ICL formation via alkylation. Others undergo activation by H2O2 to release DNA cross-linking agents. We investigated the mechanism of function of these inducible DNA cross-linking agents as well as their biomedical application. The first part of this thesis is focusing on design, synthesis, and mechanism investigation of the anthracene analogues as photo-inducible DNA cross-linking agents. In an effort to increase the efficiency of photo-inducible DNA cross-linking formation by bifunctional aromatic compounds for biological applications, we used a well-known DNA intercalator anthracene for this study. We synthesized a series of bifunctional compounds containing the 9,10-anthryl core structure, and various benzylic leaving groups and investigated their photo reactivity towards DNA at 350 nm. The efficiency of DNA ICL formation strongly depends on the leaving groups and compound solubility. Compounds 1a-c with bromo, trimethyl ammonium salts or triphenyl phosphonium salts as leaving groups showed faster reaction rate and higher DNA cross-linking efficiency than the remaining compounds. Compounds containing amine (1d and 1e), acetate (1f), or ether groups (1g-j) as leaving groups showed very low DNA ICL efficiency and low reaction rate. DNA ICL formation induced by 1b was inhibited by both radical and cation trapping agents, indicating that both free radicals and cations are involved in DNA crosss-linking process. However, none of the trapping agents was able to inhibit ICL completely even with very high concentration, which might be due to the intercalating interaction between anthracene moiety and duplex DNA. The free radical trapping adducts y-z were detected in the photoreaction of 1b with TEMPO, suggesting the generation of free radicals x in photo-induced DNA cross-linking process of 1b-z. We also observed formation the cation trapping adducts n that provide direct evidence for the generation of carbocation m in the photo-induced DNA ICL formation induced by 1b-c. Collectively, these data suggested that both both free radicals and carbo cations may have been involved in photo-induced DNA ICL formation by these anthracene analogues. The second part of this thesis is focusing on in vivo study of H2O2-activated DNA alkylating agents. We investigated the in vivo efficacy and safety of H2O2-activated nitrogen mustard prodrug 11. The CD-1 mice and athymic nude mice were used for the safety and in vivo efficacy study, respectively. We tested the cytotoxicity of 11 against triple negative breast cancer cell line (MDA-MB-468) and a few renal cancer cell lines (UO-31, SN-12C, A498, TK-10 and CAKI-1). Repeated dose toxicity study was used to identify the safe doses for in-vivo efficacy study. The athymic nude mice were xenografted with MDA-MB-468 breast cancer cell line. We observed that 11 greatly reduced tumor size (\u3e50%) without any obvious side effects such as no obvious weight loss and other unusual behaviors for mice. We did not observe the changes of normal tissues including lung, liver, spleen, brain etc. Pharmacokinetic study showed that duration time of 11 is double of the parent molecule x. In addition, we observed that 11 showed better efficacy but less toxic to mice than the clinically used DNA alkylating agent chlorambucil. Further study suggested that the breast cancer MDA-MB-468 cells showed high H2O2 level and quenching the H2O2 level decreased the anticancer activity of 11, which indicated that there is a correlation between the anticancer activity of 11 and ROS level in cancer cells. Metabolite extraction study was also conducted on cell culture in an effort to identify activated metabolite

Directional flow of solitons with asymmetric potential wells: Soliton diode

We study the flow of bright solitons through two asymmetric potential wells. The scattering of a soliton by certain type of single potential wells, e.g., Gaussian or Rosen-Morse, is distinguished by a critical velocity above which solitons can transmit almost completely and below which solitons can reflect nearly perfectly. For two such wells in series with certain parameter combinations, we find that there is an appreciable velocity range for which solitons can propagate in one direction only. Our study shows that this directional propagation or diode behavior is due to a combined effect of the sharp transition in the transport coefficients at the critical velocity and a slight reduction in the center-of-mass speed of the soliton while it travels across a potential well.Comment: 7 pages, 5 figure

Groundwater Abstraction from Aquitard, Aquiclude and Thin Aquifer in Barind

Barind is the land where the quality of life is inextricably linked to the availability of water. We are trying to help the section of people of such area where water is considered only from the viewpoint of quantity; they do not have the scope to think from quality aspect for their survival. The scale of poverty level here is normally measured on the basis of per capita income; however, to give a better indication about the quality of life, the accessibility for food, education, health, safe drinking water, sanitation, medicine and social empowerment for decision-making should also be included in these figures. Moreover, availability of drinking water is one of the basic human rights, and therefore should not be considered as a privilege. The presence of an aquifer is the prerequisite for the installation of any type of well. In certain areas of Barind tract there is no screenable aquifer. Hence, surface water of ponds and river is being used as the source of drinking water as well as the source of bathing of villagers and their domestic animals, cleaning of house hold utensils and also used as source to meet the needs for supplementary irrigation. There are also many areas where there is no source of surface water and a totally water-bearing strata (aquifer), an essential element for well construction, is absent. The nature and cause of concern are as follows: (a) no aquifer, sometimes only aquitard and aquiclude (b) very deep static water table say deeper than sixty feet- which leads to a twofold resultpeople in neighboring areas lead inhuman life style and suffer from water borne diseases of mainly skin and stomach. Academically we define: Aquifer: a formation, group of formation, or part of a formation that contains sufficient saturated permeable material to yield economical quantities of water to wells and springs. Aquitard: A geologic formation, group of formations, or part of formation through which virtually no water moves. Aquiclude: A saturated, but poorly permeable bed, formation, or group of formations that does not yield water freely to a well or springs. However, an aquiclude may transmit appreciable water to or from adjacent aquifers. (Groundwater and wells of Johnson Division, USA, 1987) However, the dug wells are installed at a depth of around one hundred feet having absolutely no aquifer. The cement rings are being used as well casing. Practically these wells are installed within the aquitard and aquiclude zone. The lithological classifications of the encountered layers are of pure clay-to-clay loam. The discharge from these wells is very small say ranging from 1 to 4 liter per second. This discharge is meeting the need of household water supply pumping in the water tank located on the roof of second floor. The homestead gardening, nursery maintenance and supplementary irrigation to rice and wheat are also being observed. In the recent past a new type of short well in respect of depth having very thin aquifer has been invented/introduced with a quite reasonable discharge say around three cusec equivalent to 84 liter per second. This is something unique invention, projecting the well screens of four numbers in upward direction along the wall of well casing. The shortest well of only 73 feet total well configuration depth produces 84 liter per second. This type of well number is presently around three hundred are working for irrigation successfully for the last ten to fifteen years. These are locally known as Inverted well and favored and preferred by the farmers. The continuous test pumping for ninety-two hours has been conducted to assess the hydrogeological parameter and sustainability of the encountered aquifer. In conclusion this type of well has been proved to be wonderfully successful

Recycling of Steel Scraps as a Strength Enhancement Material in Concrete

The cement industry is very energy consumptive and produces CO2 and also generates greenhouse gases which are the major cause of global warming. The production of cement and the use of concrete are both rising daily. So, to protect the environment, alternate materials are required. The construction industry has several constructional byproducts and wastes as a variant of traditionally used products. In the process of production and working with steel, steel chips are formed as waste material. The best way to reduce environmental pollution and improve waste recycling is to partially replace concrete with steel chips. Due to these factors and the abundance of material, steel chips were used as a partial cement replacement at 0.5%, 1%, 1.5%, and 2% by the volume of cement. The properties such as compressive strength, split tensile strength, flexural beam strength, and modulus of elasticity are checked after 7, 14, and 28 days. Comparing these qualities to those of control molds showed that by raising the percentage of steel chips in the concrete up to 1.5%, mechanical characteristics are improved; however, when the percentage is increased to 2%, mechanical properties are also affected

Tuning the structural and dynamical properties of a dipolar Bose-Einstein condensate: Ripples and instability islands

It is now well established that the stability of aligned dipolar Bose gases can be tuned by varying the aspect ratio of the external harmonic confinement. This paper extends this idea and demonstrates that a Gaussian barrier along the strong confinement direction can be employed to tune both the structural properties and the dynamical stability of an oblate dipolar Bose gas aligned along the strong confinement direction. In particular, our theoretical mean-field analysis predicts the existence of instability islands immersed in otherwise stable regions of the phase diagram. Dynamical studies indicate that these instability islands, which can be probed experimentally with present-day technology, are associated with the going soft of a Bogoliubov--de Gennes excitation frequency with radial breathing mode character. Furthermore, we find dynamically stable ground state densities with ripple-like oscillations along the radial direction. These structured ground states exist in the vicinity of a dynamical radial roton-like instability.Comment: 9 pages, 11 figure

Effect of Different Salinity Level on Tomato (Lycopersicon esculentum) Production under Climate Change Condition in Bangladesh

Tomato is a crop with the greatest economic importance in the world and salinity stress causes are reduction in the quantity and quality of crop production. Today the main challenge in world agriculture is to sustain the continuously growing global population, and this becomes more difficult due to climatic change, as this imposes further abiotic stress. The aim of this study was to find out the salinity effect on tomato production. The study was initiated at the Irrigation and Water Management (IWM) research field of Bangladesh Agricultural University (BAU), Bangladesh during October 2007 to April 2008 cropping season. The experiment was carried out in a randomized complete block design (RCBD) with 3 replications. The treatments were: T1= Irrigation with fresh water, T2= Irrigation with saline water containing 4 dS m−1 of Electrical conductivity (Seawater cannot hold as much dissolved oxygen as freshwater due to its high salinity. Conductivity and salinity have a strong correlation.), T3= Irrigation with saline water containing 6 dS m−1 of Electrical conductivity, T4= Irrigation with saline water containing 8 dS m−1 of Electrical conductivity and T5= Irrigation with saline water containing 10 dS m−1 of Electrical conductivity. We found that the plants irrigated with the T1 treatment (Irrigation with fresh water) was the highest fruit yield plant-1 (1.52 kg) whereas the lowest yield (0.667 kg) was obtained from the higher level of saline water treatment T5 (10 dS m−1). When the fruit yield was considered the effective treatment for the highest total fruit yield (36.57 t ha-1) was produced by the T1 treatment (Irrigation with fresh water) and the lowest fruit yield (21.87 t ha-1) was found from the treatment T5 (10 dS m−1). The effect of different salinity levels of irrigation such as fresh water, 4 dS m−1, 6 dS m−1, 8 dS m−1 and 10 dS m−1 on total soluble solid was significantly influenced. The highest total soluble solid (2.53) was shown in T5 treatment (10 dS m−1) whereas the lowest (2.00) in Irrigation with fresh water treatment

Dipolar Bose-Einstein condensate soliton on a two-dimensional optical lattice

Using a three-dimensional mean-field model we study one-dimensional dipolar Bose-Einstein condensate (BEC) solitons on a weak two-dimensional (2D) square and triangular optical lattice (OL) potentials placed perpendicular to the polarization direction. The stabilization against collapse and expansion of these solitons for a fixed dipolar interaction and a fixed number of atoms is possible for short-range atomic interaction lying between two critical limits. The solitons collapse below the lower limit and escapes to infinity above the upper limit. One can also stabilize identical tiny BEC solitons arranged on the 2D square OL sites forming a stable 2D array of interacting droplets when the OL sites are filled with a filling factor of 1/2 or less. Such an array is unstable when the filling factor is made more than 1/2 by occupying two adjacent sites of OL. These stable 2D arrays of dipolar superfluid BEC solitons are quite similar to the recently studied dipolar Mott insulator states on 2D lattice in the Bose-Hubbard model by Capogrosso-Sansone et al. [B. Capogrosso-Sansone, C. Trefzger, M. Lewenstein, P. Zoller, G. Pupillo, Phys. Rev. Lett. 104 (2010) 125301].Comment: 8 pages, 5 figures and 2 table

Comparison of CMIP6 and CMIP5 model performance in simulating historical precipitation and temperature in Bangladesh: a preliminary study

The relative performance of global climate models (GCMs) of phases 5 and 6 of the coupled model intercomparison project (CMIP5 and CMIP6, respectively) was assessed in this study based on their ability to simulate annual and seasonal mean rainfall and temperature over Bangladesh for the period 1977–2005. Multiple statistical metrics were used to measure the performance of the GCMs at 30 meteorological observation stations. Two robust multi-criteria decision analysis methods were used to integrate the results obtained using different metrics for an unbiased ranking of the GCMs. The results revealed MIROC5 as the most skillful among CMIP5 GCMs and ACCESS-CM2 among CMIP6 GCMs. Overall, CMIP6 MME showed a significant improvement in simulating rainfall and temperature over Bangladesh compared to CMIP5 MME. The highest improvements were found in simulating cold season (winter and post-monsoon) rainfall and temperature in higher elevated areas. The improvement was relatively more for rainfall than for temperature. The models could capture the interannual variability of annual and seasonal rainfall and temperature reliably, except for the winter rainfall. However, systematic wet and cold/warm biases still exist in CMIP6 models for Bangladesh. CMIP6 GCMs showed higher spatial correlations with observed data, but the higher difference in standard deviations and centered root mean square errors compared to CMIP5 GCMs indicates better performance in simulating geographical distribution but lower performance in simulating spatial variability of most of the climate variables except for minimum temperature at different timescales. In terms of Taylor skill score, the CMIP6 MME showed higher performance in simulating rainfall but lower performance in simulating temperature than CMIP5 MME for most of the timeframes. The findings of this study suggest that the added value of rainfall and temperature simulations in CMIP6 models is not consistent among the climate models used in this research. However, it sets a precedent for future research on climate change risk assessment for the scientific community

Effects of Long-Range Nonlinear Interactions in Double-Well Potentials

We consider the interplay of linear double-well-potential (DWP) structures and nonlinear longrange interactions of different types, motivated by applications to nonlinear optics and matter waves. We find that, while the basic spontaneous-symmetry-breaking (SSB) bifurcation structure in the DWP persists in the presence of the long-range interactions, the critical points at which the SSB emerges are sensitive to the range of the nonlocal interaction. We quantify the dynamics by developing a few-mode approximation corresponding to the DWP structure, and analyze the resulting system of ordinary differential equations and its bifurcations in detail. We compare results of this analysis with those produced by the full partial differential equation, finding good agreement between the two approaches. Effects of the competition between the local self-attraction and nonlocal repulsion on the SSB are studied too. A far more complex bifurcation structure involving the possibility for not only supercritical but also subcritical bifurcations and even bifurcation loops is identified in that case.Comment: 12 pages, 9 figure