Malaria parasite carbonic anhydrase:inhibition of aromatic/heterocyclic sulfonamides and its therapeutic potential

Plasmodium falciparum(P.falciparum) is responsible for the majority of life-threatening cases of human malaria,causing 1.5-2.7 million annual deaths.The global emergence of drug-resistant malaria parasites necessitates identification and characterisation of novel drug targets and their potential inhibitors.We identified the carbonic anhydrase(CA) genes in P.falciparum.The pfGA gene encodes an α-carbonic anhydrase,a Zn^(2+)-metalloenzme,possessing catalytic properties distinct from that of the human host CA enzyme.The amino acid sequence of the pfCA enzyme is different from the analogous protozoan and human enzymes.A library of aromatic/heterocyclic sulfonamides possessing a large diversity of scaffolds were found to be very good inhibitors for the malarial enzyme at moderate-low micromolar and submicromolar inhibitions.The structure of the groups substituting the aromatic-ureido-or aromatic-azomethine fragment of the molecule and the length of the parent sulfonamide were critical parameters for the inhibitory properties of the sulfonamides.One derivative,that is,4-(3,4-dichlorophenylureido)thioureidobcnzcnesulfonamide(compound 10) was the most effective in vitro Plasmodium falciparum CA inhibitor,and was also the most effective antimalarial compound on the in vitro P.falciparum growth inhibition.The compound 10 was also effective in vivo antimalarial agent in mice infected with Plasmodium berghei,an animal model of drug testing for human malaria infection. It is therefore concluded that the sulphonamide inhibitors targeting the parasite CA may have potential for the development of novel therapies against human malaria.

Estimation of Hourly and Daily Global Solar Radiation at Clear Days Using an Approach Based on Modified Version of Gaussian Distribution

The performance of two models,Jam and Baig,based on the modified version of Gaussian distribution function in estimating the daily total of global solar radiation and its distribution through the hours of the day from sunrise to sunset al any clear day is evaluated with our own measured data in the period from June 1992 to May 1993 in Qena Egypt The results show a high relative deviation of calculated values from measured ones,especially for Jain model,in the most hours of the day,except for those near to local noon.This misfit behavior is quite obvious in the early morning and late afternoon A new approach has been proposed in this paper to estimate the daily and hourly global solar radiation This model performs with very high accuracy on the recorded data in our region.The validity of this approach was verified with new measurements in some clear days in June and August 1994.The resultant very low relative deviation of the calculated values of global solar radiation from the measured ones confirms the high performance of the approach proposed in this work

A unique insertion of low complexity amino acid sequence underlies protein-protein interaction in human malaria parasite orotate phosphoribosyltransferase and orotidine 5'-monophosphate decarboxylase

Objective:To investigate the multienzyine complex formation of human malaria parasite Plasmodium falciparum[P.falciparum)orotate phosphoribosyltransferase(OPRT)and orotidine5'-monophosphate decarboxylase(OMPDC),the fifth and sixth enzyme of the de novo pyrimidine biosynthetic palhway.Previously,we have clearly established that the two enzymes in the malaria parasite exist physically as a heterotetrameric(OPRT)_2(OMPDG)_2 complex containing two subunits each of OPRT and OMPDC.and that the complex have catalytic kinetic advantages over the monofunetional enzyme.Methods:Both enzymes were cloned and expressed as recombinant proteins.The protein-protein interaction in the enzyme complex was identified using bifunctionul chemical cross-linker,liquid chromatography-mass spectrometric analysis and homology modeling,Results:The unique insertions of low complexity region at the a 2 and a 5 helices of the parasite OMPDC,characterized by single amino acid repeat sequence which was not found in homologous proteins from other organisms,was located on the OPRT-OMPDC interface.The structural models for the protein-prolein interaction of the helerotetrameric(OPRT)_2(OMPDC)_2multienzyme complex were proposed.Conclusions:Based on the proteomic data and structural modeling,it is surmised that the human malaria parasite low complexity region is responsible for the OPRT-OMPDC interaction.The structural complex of the parasite enzymes,thus,represents an efficient functional kinetic advantage,which in line with co-localization principles of evolutional origin,and allosteric control in protein-protein-interactions.

In vitro cytotoxicity of Indonesian stingless bee products against human cancer cell lines

Objective:To screen crude extracts of propolis,bee pollen and honey from four stingless bee species[Trigona incisa(T.incisa)],Timia apicalis,Trigona fuso-baltata and Trigona filscibasis)native to East Kalimantan.Indonesia for cytotoxic activity against five human cancer cell lines(HepG2,SW620,ChaGo-1,KATO-Ⅲand BT474).Methods:All samples were extracted with methanol,and then subpartitioned with n-hexane and ethyl acetate.Each crude extract was screened at 20μg/mL for in vitro cytotoxicity against the cell lines using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay.Tn addition,four previously shown bioactive components from propolis(apigenin,cafieic acid phenyl ester,kaempferol and naringenin)and two chemotherapeutic drugs(doxorubicin and 5-fluorouracil)were used to evaluate the sensitivity of the cell lines.Results:Overall,crude extracts from propolis and honey had higher cytotoxic activities than bee pollen,but the activity was dependent upon the extraction solvent,bee species and cell line.Propolis extracts from T.incisa and Tarda apicalis showed the highest and lowest cytotoxic activity,respectively.Only the HepG2 cell line was broadly sensitive to the honey extracts.For pure compounds,doxorubicin was the most cytotoxic,the four propolis compounds the least,but the ChaGo-I cell line was sensitive to kaempferol at 10μg/mL and KATO-Ⅲwas sensitive to kaempferol and apigenin at 10μg/mL,.All pure compounds were effective against the BT474 cell line.Conclusions:Propolis from f,incisa and Trigona fusco-balteata contain an in vitro cytotoxic activity against human cancer cell lines.Further study is required,including the isolation and characterization of the active antiproliferative agent(s).

Antimicrobial activity of latex silver nanoparticles using Calotropis procera

Objective:To synthesize silver nanoparticles(AgNPs) by green methods using scrum latex of Calotropis procera at 80 ℃ and evaluate them against bacteria,dermatophytes and phytopathogenic fungi comparing with the activity of untreated latex.Methods:The synthesis of AgNPs was performed by mixing 3%latex scrum extract with the same volume of silver nitrate(2 mmol/L) solution in round flask and heating in water bath at80 ℃.Characterization of silver particles were determined using UV-vis spectrophotometer,transmission electron microscopy(TEM),X-ray diffraction and Fourier transform infrared spectroscopy.The antimicrobial activity of the green synthesized AgNPs was determined against bacteria,dermatophytes and phytopathogenic fungi and compared to the crude untreated latex by agar-well diffusion methods.Results:Biosynthesis of latex silver nanoparticles was successfully obtained by green method.The formation of AgNPs has been confirmed by UV-vis,TEM microscopy.X-ray diffraction and Fourier transform infrared spectroscopy.TEM analysis showed that synthesized AgNPs are highly stable spherical shaped particles,well dispersed with a diameter ranged from 4 nm up to 25 nm and an average size of 12.33 nm.AgNPs showed strong antibacterial activity against Gram-negative bacteria(Escherichia coli,Pseudomonas aeruginosa and Serratia sp.) and antifungal activity against Trichophyton rubrum,Candida albicans and Aspergillus terreus.Conclusions:It can be concluded that serum latex of Calotropis pmcera was found to display strong potential for the synthesis of AgNPs as antimicrobial agents through rapid reduction of silver ions(Ag^+ to Ag^0).The green synthesized AgNPs were found to show higher antimicrobial efficacy than crude latex.

Deadly oasis:Recurrent annihilation of Cretaceous desert bryophyte colonies;the role of solar,climate and lithospheric forcing

Many oases(wet interdunes)are sedimentary systems characterized by high-frequency water-level oscillations,marked changes in salinity and intense biological activity at their margins.They are considered to be one of the most challenging environments on Earth for ecosystem development.These dynamic,depositional settings are usually unfavourable for fossilization and subsequent preservation of vegetal remains.This paper describes bryophyte(liverwort)assemblages occurring in three successive horizons interpreted to represent(i)recurrent early successional phases of biological soil crust colonization of wet interdune margins or(ii)exceptional preservation of floating or riparian liverworts in oasis pond waters associated with a progressive fall of the interdune water level.The record of in situ colonization surfaces characterized by delicate(e.g.lignin-free)three-dimensional structures represents an exceptional type of preservation herein associated with a rapid variation in phreatic interdune water level and the subsequent establishment of anoxic and reducing conditions.The occurrence of exceptionally preserved liverwort colonies coincides with the sedimentary record of,at least,three seismite levels in the oasis.Data gathered from the site suggests that the water table of the oasis was controlled by a combination of(i)a positive creation of accommodation space due to subsidence associated with movement on syn-sedimentary extensional faults,and(ii)the rise and fall of the oasis water table controlled by the oscillations of the groundwater system due to orbital changes which appear to drive the variability of the climate system.Rising groundwater levels flooded the oasis soil crusts and lead to the exceptional recurrent preservation of liverwort colonies at the oasis margins.Alternatively,considering the hypothesis of floating or riparian liverworts in the oasis pond waters,the fall in the level of the oasis water table placed the floating liverworts in contact with the oasis bottom sediments.This fall in the level of the oasis water table could indicate a cessation of accommodation space by syn-sedimentary extensional faults and/or a regional lowering of the groundwater system level associated with drought periods.Preliminary results indicate that oasis lamination between liverwort colonies records decadal and sub-decadal cyclicity,related with 11-year Schwabe sunspot and sub-decadal NAO cyclicities,conferring for every sedimentary cycle between liverwort colonies a duration of approximately 200 years,that otherwise matches the expected recurrence period for the De Vries cycle of solar activity.

Rock composition and origin of the Duwi Formation calcareous rocks, Upper Egypt

Upper Cretaceous phosphorite beds of the Duwi Formation, Upper Egypt, are intercalated with limestone, sandy limestone, marl, calcareous shales, and calcareous sandstone. Calcareous intercalations were subjected to field and detailed petrographic, mineralogical and geochemical investigations in order to constrain their rock composition and origin.; Mineralogically, dolomite, calcite, quartz, francolite and feldspars are the non-clay minerals. Smectite, kaolinite and illite represent the clay minerals. Major and trace elements can be classified as the detrital and carbonate fractions based on their sources. The detrital fraction includes the elements that are derived from detrital sources, mainly clay minerals and quartz, such as Si, Al, Fe, Ti, K, Ba, V, Ni, Co, Cr, Zn, Cu, Zr, and Mo. The carbonate fraction includes the elements that are derived from carbonates, maily calcite and dolomite, such as Ca, Mg and Sr. ; Dolomite occurs as being dense, uniform, mosaic, very fine-to-fine, non-ferroan, and non-stoichiometrical, suggesting its early diagenetic formation in a near-shore oxidizing shallow marine environment. The close association and positive correlation between dolomite and smectite indicates the role of clay minerals in the formation of dolomite as a source of Mg{2}-rich solutions.; Calcareous rocks were deposited in marine, oxidizing and weakly alkaline conditions, marking a semi-arid climatic period. The calcareous/argillaceous alternations are due to oscillations in clay/carbonate ratio.

Modeling seasonal leptospirosis transmission and its association with rainfall and temperature in Thailand using time-series and ARIMAX analyses

Objective:To study the number of leptospirosis cases in relations to the seasonal pattern,and its association with climate factors.Methods:Time series analysis was used to study the time variations in the number of leptospirosis cases.The Autoregressive Integrated Moving Average (ARIMA) model was used in data curve fitting and predicting the next leptospirosis cases. Results:We found that the amount of rainfall was correlated to leptospirosis cases in both regions of interest,namely the northern and northeastern region of Thailand,while the temperature played a role in the northeastern region only.The use of multivariate ARIMA(ARIMAX) model showed that factoring in rainfall(with an 8 months lag) yields the best model for the northern region while the model,which factors in rainfall(with a 10 months kg) and temperature(with an 8 months lag) was the best for the northeaslern region.Conclusions:The models are able to show the trend in leptospirosis cases and closely fit the recorded data in both regions.The models can also be used to predict the next seasonal peak quite accurately.

Geochemical characteristics and spectrometric prospecting in the muscovite-bearing pegmatites and granites, southeastern Aswan, Egypt

Rare metal mineralization of Sn, Nb-Ta and W is encountered in the Gebel Dihmit area (GDA), south- eastern Aswan, Egypt. The mineralization is related to muscovite granites and their pegmatite derivatives. The peg- matites are divided into three types according to their main mineral assemblages: K-feldspar-muscovite-tourmaline, K-feldspar-albite-muscovite and albite-K-feldspar-lepidolite veins. Petrogenetic studies indicate that Sn and Nb-Ta mineralization extends from the late-magmatic stage to the pegmatite and hydrothermal stages of the (GDA) suite. The albite-K-feldspar-lepidolite granite is composed dominantly of albite, lepidolote, and quartz, with topaz, K-feldspar and amblygonite. The accessory minerals are zircon, monazite, pollucite, columbite-tantalite, microlite and Ta-rich cassiterite. Phenocrysts of quartz, topaz and K-feldspar contain abundant inclusions of albite laths and occasional lepidolite crystals along growth zones (snowball texture), indicating simultaneous crystallization from a subsolvus, residual magma. The origin of the pegmatites is attributed to extreme differentiation by fractional crystal- lization of a granitic magma. The economic potential for rare metals was evaluated in the geochemical discrimination diagrams. Accordingly, some of the pegmatites are not only highly differentiated in terms of alkalis, but also the promising targets for small-scale Ta and, to a less extent, Sn. The pegmatites also provide the first example of Fe-Mn and Nb-Ta fractionation in successive generations of granites to cassiterite-bearing pegmatites, which perfectly ex- hibit similar fractionation trends established for primary columbite-tantalite in the corresponding categories of peg- matites. Uranium and Th of magmatic origin are indicated by the presence of thorite and allanite, whereas evidence of hydrothermal mineralization is the alteration of rock- foring minerals such as feldspar and the formation of sec- ondary minerals such as uranophane..

Current perspectives on dengue episode in Malaysia

To Prevalence of dengue transmission has been alarmed by an estimate of 390 million infections per annum.Urban encroachment,ecological disruption and poor sanitation are all contributory factors of increased epidemiology.Complication however arises from the fact that dengue virus inherently exists as four different serotypes.Secondary infection is often manifested in the more severe form,such that antibody-dependent enhancement(ADE) could aggravate ailment by allowing pre-existing antibodies to form complexes with infecting viruses as means of intrusion.Consequently,increased viraemic litter and suppression of antiviral response are observed.Deep concerns are thus expressed in regards to escalating trend of hospitalisation and mortality rates.In Malaysia,situation is exacerbated by improper clinical management and pending vector control operations.As a preparedness strategy against the potential deadly dengue pandemic,the call for development of a durable and costeffective dengue vaccine against all infecting serotypes is intensified.Even though several vaccine candidates are currently being evaluated in clinical trials,uncertainties in regards to serotypes interference,incomplete protection and dose adequacy have been raised.Instead of sole reliance on outsourcing,production of local vaccine should be considered in coherent to government's efforts to combat against dengue.

The structure of superabundant semigroups

A structure theorem for superabundant semigroups in terms of semilattices of normalized Rees matrix semigroups over some cancellative monoids is obtained. This result not only provides a construction method for superabundant semigroups but also generalizes the well-known result of Petrich on completely regular semigroups. Some results obtained by Fountain on abundant semigroups are also extended and strengthened.

The Asymptotics of the Heat Semigroup for a General Bounded Domain with Mixed Boundary Conditions

Small-time asymptotics of the trace of the heat semigroup θ（t）=Σv=1x exp（-tμv）. where {μv} are the eigenvalues of the uegative Laplacian -Δ= -Σβ=12（/xβ）2 in the （x1, x2）-plane. is studied for a general bounded domain Ω with a smooth boundary Ω. where a finite number of Dirichlet. Neumann and Robin boundary conditions, on the piecewise smooth parts Γi（i=1, ..., n） of )Ω such that)Ω=∪i=1nΓ are considered. Some geometrical properties associated with Ω are determined

Highly efficient one-pot synthesis of dihydropyran heterocycles

Diammonium hydrogen phosphate and potassium carbonate-catalyzed one-pot synthesis of 1,4- phenylene-bis（2-amino-4H-pyran-3-carbonitrile and 2-amino-4-aryl-4H-pyran-3-carbonitrile deriva- tives has been achieved by a three-component cyclocondensation of aldehydes, malononitrile, and different nucleophiles in aqueous medium in high yields.

Effects of chemical reaction and heat generation/absorption on magnetohydrodynamic(MHD)Casson fluid flow over an exponentially accelerated vertical plate embedded in porous medium with ramped wall temperature and ramped surface concentration

This article studies effects of heat generation/absorption and chemical reaction on the unsteady magnetohydrodynamic(MHD)Casson fluid flow past over exponentially accelerated vertical plate embedded in porous medium.It is assumed that the bounding plate has ramped temperature with ramped surface concentration and isothermal temperature with ramped surface concentration.This phenomenon is modeled in the form of system of partial differential equations with initial and boundary conditions.The goveming dimensionless equations are solved using Laplace transfom technique and expressions for velocity,temperature and concentration profiles are obtained.Expressions for skin friction,Nusselt number and Sherwood number are also derived and represented in tabular form.Effect of pertinent parameters on velocity,temperature and concentration profiles are presented through graphically.

On Certain Classes of Univalent Functions with Negative and Missing Coefficients

Let p~*(A,B,k,a,β) be the class of functions f(z)=a_1-sum from n=k to ∞(|a_n|Z^n) (a_1>0,k≥2) regular and univalent in the unit disc U={z:|z|<1}and satis-fying where and We denote by P_o(A,B,k, α,β,z_o) and p_1(A,k,α,β,z_o), two suoclasses of p~*(A,B,k,α,β), consisting of the functions which satisfy f(z_n)=z_n and f′(z_n)=1,respectively, here In this paper we obtain ooefficient estimates,distortion and closure theorems and radius of convexity of order p (0≤ρ<1)for the classes P_o(A,B,k, α,β,z_0) and P_1(A,B,k,α,β,z_o).