Search results for: slow drug release

Authors: Jeanne Leblond, Warren Viricel, Amira Mbarek

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Although several products have reached the market, gene therapeutics are still in their first stages and require optimization. It is possible to improve their lacking efficiency by the use of carefully engineered vectors, able to carry the genetic material through each of the biological barriers they need to cross. In particular, getting inside the cell is a major challenge, because these hydrophilic nucleic acids have to cross the lipid-rich plasmatic and/or endosomal membrane, before being degraded into lysosomes. It takes less than one hour for newly endocytosed liposomes to reach highly acidic lysosomes, meaning that the degradation of the carried gene occurs rapidly, thus limiting the transfection efficiency. We propose to use a new pH-sensitive lipid able to change its conformation upon protonation at endosomal pH values, leading to the disruption of the lipidic bilayer and thus to the fast release of the nucleic acids into the cytosol. It is expected that this new pH-sensitive mechanism promote endosomal escape of the gene, thereby its transfection efficiency. The main challenge of this work was to design a preparation presenting fast-responding lipidic bilayer destabilization properties at endosomal pH 5 while remaining stable at blood pH value and during storage. A series of pH-sensitive lipids able to perform a conformational switch upon acidification were designed and synthesized. Liposomes containing these switchable lipids, as well as co-lipids were prepared and characterized. The liposomes were stable at 4°C and pH 7.4 for several months. Incubation with siRNA led to the full entrapment of nucleic acids as soon as the positive/negative charge ratio was superior to 2. The best liposomal formulation demonstrated a silencing efficiency up to 10% on HeLa cells, very similar to a commercial agent, with a lowest toxicity than the commercial agent. Using flow cytometry and microscopy assays, we demonstrated that drop of pH was required for the transfection efficiency, since bafilomycin blocked the transfection efficiency. Additional evidence was brought by the synthesis of a negative control lipid, which was unable to switch its conformation, and consequently exhibited no transfection ability. Mechanistic studies revealed that the uptake was mediated through endocytosis, by clathrin and caveolae pathways, as reported for previous lipid nanoparticle systems. This potent system was used for the treatment of hypercholesterolemia. The switchable lipids were able to knockdown PCSK9 expression on human hepatocytes (Huh-7). Its efficiency is currently evaluated on in vivo mice model of PCSK9 KO mice. In summary, we designed and optimized a new cationic pH-sensitive lipid for gene delivery. Its transfection efficiency is similar to the best available commercial agent, without the usually associated toxicity. The promising results lead to its use for the treatment of hypercholesterolemia on a mice model. Anticancer applications and pulmonary chronic disease are also currently investigated.

Keywords: liposomes, siRNA, pH-sensitive, molecular switch

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Authors: Agung Sugeng Widodo

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Water boiling system (WBS) using conventional gas stove (CGS) is relatively inefficient unless its mechanism being considered. In this study, an addition of ceramic stove cover (CSC) to a CGS and the gap between CSC and pan have been assessed. Parameters as energy produced by fuel, CSC temperature and water temperature were used to analyze the performance of a CGS. The gaps were varied by 1 – 7 mm in a step of 1 mm. The results showed that a CSC able to increase the performance of a CGS significantly. In certain fuel rate of 0.75 l/m, the efficiency of a CGS obtained in a gap of 4 mm. The best efficiency obtained in this study was 46.4 % due to the optimum condition that achieved simultaneously in convection and radiation heat transfer processes of the heating system. CSC also indicated a good characteristic for covering heat release at the initially of WBS.

Keywords: WBS, CSC, CGS, efficiency, gap

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Authors: Feiyu Yang, Chunfang Ni, Rong Wang, Yun Zou, Wenbin Liu, Chenggong Zhang, Fenjin Sun, Chun Wang

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Cocaine is the most frequently used illegal drug globally, with the global annual prevalence of cocaine used ranging from 0.3% to 0.4 % of the adult population aged 15–64 years. Growing consumption trend of abused cocaine and drug crimes are a great concern, therefore urine sample testing has become an important noninvasive sampling whereas cocaine and its metabolites (COCs) are usually present in high concentrations and relatively long detection windows. However, direct analysis of urine samples is not feasible because urine complex medium often causes low sensitivity and selectivity of the determination. On the other hand, presence of low doses of analytes in urine makes an extraction and pretreatment step important before determination. Especially, in gathered taking drug cases, the pretreatment step becomes more tedious and time-consuming. So developing a sensitive, rapid and high-throughput method for detection of COCs in human body is indispensable for law enforcement officers, treatment specialists and health officials. In this work, a new automated magnetic dispersive solid-phase extraction (MDSPE) sampling method followed by high performance liquid chromatography-mass spectrometry (HPLC-MS) was developed for quantitative enrichment of COCs from human urine, using prepared magnetic nanoparticles as absorbants. The nanoparticles were prepared by silanizing magnetic Fe3O4 nanoparticles and modifying them with divinyl benzene and vinyl pyrrolidone, which possesses the ability for specific adsorption of COCs. And this kind of magnetic particle facilitated the pretreatment steps by electromagnetically controlled extraction to achieve full automation. The proposed device significantly improved the sampling preparation efficiency with 32 samples in one batch within 40mins. Optimization of the preparation procedure for the magnetic nanoparticles was explored and the performances of magnetic nanoparticles were characterized by scanning electron microscopy, vibrating sample magnetometer and infrared spectra measurements. Several analytical experimental parameters were studied, including amount of particles, adsorption time, elution solvent, extraction and desorption kinetics, and the verification of the proposed method was accomplished. The limits of detection for the cocaine and cocaine metabolites were 0.09-1.1 ng·mL-1 with recoveries ranging from 75.1 to 105.7%. Compared to traditional sampling method, this method is time-saving and environmentally friendly. It was confirmed that the proposed automated method was a kind of highly effective way for the trace cocaine and cocaine metabolites analyses in human urine.

Keywords: automatic magnetic dispersive solid-phase extraction, cocaine detection, magnetic nanoparticles, urine sample testing

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Authors: Leda Maria Costa Pereira, Maria Denise Lopes, Nucharin Songsasen

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Mammalian ovaries contain thousands of follicles that eventually degenerate or die after culture in vitro. Caspase-3 is a key enzyme that regulating cell death. Our objective was to examine the influence of anti-apoptotic drug Z-VAD-FMK (pan-caspase inhibitor) on in vitro viability of dog follicles within the ovarian cortex. Ovaries were obtained from prepubertal (age, 2.5–6 months) and adult (age, 8 months to 2 years) bitches and ovarian cortical fragments were recovered. The cortices were then incubated on 1.5% (w/v) agarose gel blocks within a 24-wells culture plate (three cortical pieces/well) containing Minimum Essential Medium Eagle - Alpha Modification (Alpha MEM) supplemented with 4.2 µg/ml insulin, 3.8 µg/ml transferrin, 5 ng/ml selenium, 2 mM L-glutamine, 100 µg/mL of penicillin G sodium, 100 µg/mL of streptomycin sulfate, 0.05 mM ascorbic acid, 10 ng/mL of FSH and 0.1% (w/v) polyvinyl alcohol in humidified atmosphere of 5% CO2 and 5% O2. The cortices were divided in six treatment groups: 1) 10 ng/mL EGF (EGF V0); 2) 10 ng/mL of EGF plus 1 mM Z-VAD-FMK (EGF V1); 3) 10 ng/mL of EGF and 10 mM Z-VAD-FMK (EGF V10); 4) 1 mM Z-VAD-FMK; 5) 10 mM Z-VAD-FMK and (6) no EGF and Z-VAD-FMK supplementation. Ovarian follicles within the tissues were processed for histology and assessed for follicle density, viability (based on morphology) and diameter immediately after collection (Control) or after 3 or 7 days of in vitro incubation. Comparison among fresh and culture treatment group was performed using ANOVA test. There were no differences (P > 0.05) in follicle density and viability among different culture treatments. However, there were differences in this parameter between culture days. Specifically, culturing tissue for 7 days resulted in significant reduction in follicle viability and density, regardless of treatments. We found a difference in size between culture days when these follicles were cultured using 10 mM Z-VAD-FMK or 10 ng/mL EGF (EGF V0). In sum, the finding demonstrated that Z-VAD-FMK at the dosage used in the present study does not provide the protective effect to ovarian tissue during in vitro culture. Future studies should explore different Z-VAD-FMK dosages or other anti-apoptotic agent, such as surviving in protecting ovarian follicles against cell death.

Keywords: anti apoptotic drug, bitches, follicles, Z-VAD-FMK

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Authors: Michal Spilacek, Marian Brazdil, Otakar Stelcl, Jiri Pospisil

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This paper shows an experimental testing of a small unit for combustion of solid fuels, such as charcoal and wood logs, that can provide electricity. One of the concepts is that the unit does not require a qualified personnel for its operation. The unit itself is composed of two main parts. The design requires a heat producing stove and an electricity producing thermoelectric generator. After the construction the unit was tested and the results shows that the emission release is within the legislative requirements for emission production and environmental protection. That qualifies such unit for indoor application.

Keywords: micro-cogeneration, thermoelectric generator, biomass combustion, wood stove

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Authors: Xindong An, Kai Gu

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Urban intensification is regarded as the prevalent strategy in many cities of the world to ease the pressures of urban sprawl and deliver sustainable development through increasing the density of built form and activities. However, within the context of intensive development, planning and design control measures that help to maintain and promote the character of existing residential environments have been slow to develop. This causes the possible loss of the character of an area that makes a place unique and distinctive. The purpose of this paper is to explore the way of identifying the character of an urban area for the planning of urban landscape in the implementation of intensification. By employing the theory of urban morphology, the concept of morphological region is used for the analysis and characterisation of the spatial structure of the urban landscape in terms of ground plans, building types, and building and land utilisation. The morphological mapping of the character of urban landscape is suggested, which lays a foundation for more sensitive planning of urban landscape changes.

Keywords: character areas, urban intensification, urban morphology, urban landscape

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Authors: Krishna Dahiya

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Introduction: Labour pain has been described as the most severe pain experienced by women in their lives. Pain management in labour is one of the most important challenges faced by the obstetrician. The opioids are the primary treatment for patients with moderate and severe pain but these drugs are not always tolerated and are associated with dose-dependent side effects. Nonsteroidal anti-inflammatory drugs, too, are associated with variable adverse effects. Considering these factors, our study compared the efficacy and side effect of intravenous tramadol and paracetamol. Objective: To evaluate the efficacy and adverse effects of an intravenous infusion of 1000 mg of paracetamol as compared with an intravenous injection of 50mg of tramadol for intrapartum analgesia. Methods: In a randomized prospective study at Pt. BDS PGIMS, 200 women in active labor were allocated to received either paracetamol (n=100) or tramadol (n=100). The primary outcome was the efficacy of the drug to supply adequate analgesia as measured by a change in the visual analog scale (VAS) pain intensity score at various times after drug administration. The secondary outcomes included the need for additional rescue analgesia and the presence of adverse maternal or fetal events. Results: The mean age of cases were 25.55 ± 3.849 years and 25.60 ± 3.655 years respectively As recorded by the VAS score, there was significant pain reduction at 30 minutes, and at 1 and 2 hours in both groups (P<0.01). In comparison, between group I and II, a significantly higher rate of nausea and vomiting in tramadol group (14% vs 8%; P < 0.03) patients. Similarly, drowsiness (0% vs 11%; P<0.01), dry mouth (0% vs 8%; P<0.04) and dizziness (0% vs 9%; P<0.02) was also significant in group II. Conclusion: Due to difficulty in administering epidural analgesia to all parturients, administration of paracetamol and tramadol infusion for analgesia is simple and less invasive alternative. In the present study, both paracetamol and tramadol were equally effective for labour analgesia but paracetamol has emerged as safe alternative as compared to tramadol due to a low incidence of side effects.

Keywords: paracetamol, tramadol, labor, analgesia

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Authors: Meenakshi Chaudhary, V .S. Randhawa, M. Jais, R. Dutta

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Introduction: An outbreak of Multi drug resistant S. Typhi (i.e. resistance to chloramphenicol, ampicillin, and trimethoprim-sulfamethoxazole) occurred in 1990's in India which peaked in 1992-93 and resulted in the change of drug of choice from chloramphenicol to ciprofloxacin for enteric fever. Currently an emergence of Ciprofloxacin susceptible S. Typhi isolates in the region is being reported which appears to be chromosomally mediated. Methodology: Six hundred sixty four strains were randomly selected from the time period between January 2008-December 2011 at the National Salmonella Phage Typing Centre, LHMC, New Delhi. The strains were representative of the north, central and south zones of India. All isolates were subjected to serotyping, biotyping, phage typing and then to antimicrobial susceptibility testing by CLSI disk diffusion (CLSI) technique to Ciprofloxacin, Cefotaxime, Ampicillin, Chloramphenicol, Trimethoprim-Sulfomethoxazole and Tetracycline. Subsequently MIC of the isolates was determined by E-test (AB-Biodisc). Results: More than 80% of the tested strains had intermediate susceptibility to ciprofloxacin. The E test revealed the MIC (Ciprofloxacin) of these strains to be in the range of 0.12 to 0.5 µg/ml. Sixty nine percent of ciprofloxacin intermediate susceptible strains belonged to Phage type E1 and fourteen percent of these were Vi- Negative i.e these could not be typed by the phage typing scheme of Craigie and Yen. All the strains remained susceptible to cefotaxime. Conclusion: Predominant isolation of intermediate susceptible S. Typhi strains from India would alter the recommendations of empiric treatment of enteric fever in the region. Alternative to the low cost ciprofloxacin will have to be sought or increased dosage and/or duration of ciprofloxacin will have to be recommended. The reasons for the trend of increase in percentage of intermediate susceptible S. Typhi strains are not clear but may be attributed partly to the revision of CLSI guidelines in 2013.

Keywords: salmonella typhi, decreased ciprofloxacin susceptibility, ciprofloxacin, minimum inhibitory concentration

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Authors: Karem H. Alzoubi, Ahmad S. Alkofahi, Omar F. Khabour, Nizar M. Mhaidat

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Herbal medicinal products represent a major focus for drug development and industry and it holds a significant share in drug-market all over the globe. In here, selected medicinal plant extracts from Jordan with high antioxidative capacity were tested for their protective effect against oxidative DNA damage using in vitro 8-hydroxydeoxyguanisine and sister chromatid exchanges (SCEs) assays in cultured human lymphocytes. The following plant extracts were tested Cupressus sempervirens L., Psidium guajava (L.) Gaerth., Silybum marianum L., Malva sylvestris L., Varthemia iphionoides Boiss., Eminium spiculatum L. Blume, Pistachia palaestina Boiss., Artemisia herba-alba Asso, Ficus carica L., Morus alba Linn , Cucumis sativus L., Eucalyptus camaldulensis Dehnh., Salvia triloba L., Zizyphus spina-christi L. Desf., and Laurus nobilis L. A fractionation scheme for the active plant extracts of the above was followed. Plants extract fractions with best protective properties against DNA damage included hexane fraction of S. marianum L. (aerial parts), chloroform fractions of P. palaestina Boiss. (Fruits), ethanolic fractions of E. camaldulensis Dehnh (leaves), S. triloba L. (leaves), and ethanolic fractions of Z. spina-christi L. Desf. (Fruits/leaves). On the other hand, the ethanolic extracts of V. iphionoides Boiss was found to increase oxidative DNA damage. Results of the SCEs are undergoing. In conclusion, plant extracts with antioxidative DNA damage properties might have clinical applications in cancer prevention.

Keywords: medicinal plants extract, fractionation, oxidative DNA damage, 8-hydroxydeoxyguanisine, SCEs, Jordan

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Authors: Mohamed Moussaoui

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A series of thirty-one potential inhibitors targeting the epidermal growth factor receptor kinase (EGFR), derived from quinazoline, underwent 3D-QSAR analysis using CoMFA and CoMSIA methodologies. The training and test sets of quinazoline derivatives were utilized to construct and validate the QSAR models, respectively, with dataset alignment performed using the lowest energy conformer of the most active compound. The best-performing CoMFA and CoMSIA models demonstrated impressive determination coefficients, with R² values of 0.981 and 0.978, respectively, and Leave One Out cross-validation determination coefficients, Q², of 0.645 and 0.729, respectively. Furthermore, external validation using a test set of five compounds yielded predicted determination coefficients, R² test, of 0.929 and 0.909 for CoMFA and CoMSIA, respectively. Building upon these promising results, eighteen new compounds were designed and assessed for drug likeness and ADMET properties through in silico methods. Additionally, molecular docking studies were conducted to elucidate the binding interactions between the selected compounds and the enzyme. Detailed molecular dynamics simulations were performed to analyze the stability, conformational changes, and binding interactions of the quinazoline derivatives with the EGFR kinase. These simulations provided deeper insights into the dynamic behavior of the compounds within the active site. This comprehensive analysis enhances the understanding of quinazoline derivatives as potential anti-cancer agents and provides valuable insights for lead optimization in the early stages of drug discovery, particularly for developing highly potent anticancer therapeutics

Keywords: 3D-QSAR, CoMFA, CoMSIA, ADMET, molecular docking, quinazoline, molecular dynamic, egfr inhibitors, lung cancer, anticancer

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Authors: David Simpson, Kyle Nash

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There is considerable evidence linking slow, deliberative reasoning (system 2) with utilitarian judgments in dilemmas involving the sacrificing of another person for the greater good (other-sacrificial dilemmas). Joshua Greene has argued, based on this kind of evidence, that system 2 drives utilitarian judgments. However, the evidence on whether system 2 is associated with utilitarian judgments in self-sacrificial dilemmas is more mixed. We employed process dissociation to measure a self-sacrificial utilitarian (SU) parameter and an other-sacrificial (OU) utilitarian parameter. It was initially predicted that contra Greene, the cognitive reflection test (CRT) would only be positively correlated with the OU parameter and not the SU parameter. However, Greene’s hypothesis was corroborated: the CRT positively correlated with both the OU parameter and the SU parameter. By contrast, the CRT did not correlate with the other two moral parameters we extracted (altruism and deontology).

Keywords: dual-process model, utilitarianism, altruism, reason, emotion, process dissociation

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Authors: Muhammad Bello Ibrahim, M. Auwal Zakari, Aliyu Usman

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Hybrid concrete construction (HCC) combines all the benefits of pre-casting with the advantages of cast in-situ construction. Merging the two, as a hybrid structure, results in even greater construction speed, value, and the overall economy. Its variety of uses has gained popularity in the United States and in Europe due to its distinctive benefits. However, the increase of its application in some countries (including Nigeria) has been relatively slow. Several researches have shown that hybrid construction offers an ultra-high performance concrete that offers superior strength, durability and aesthetics with design flexibility and within sustainability credentials, based on the available and economically visible technologies. This paper examines and documents the criterion that will help inform the process of deciding whether or not to adopt hybrid concrete construction (HCC) technology rather than more traditional alternatives. It also the present situation of design, construction and research on hybrid structures.

Keywords: hybrid concrete construction, Nigeria, sustainable infrastructure development, design flexibility

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Authors: Salma A. El-Marasy, Reham M. Abd-Elsalam, Omar A. Ahmed-Farid

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Dementia is characterized by impairments in memory and other cognitive abilities. This study aims to elucidate the possible ameliorative effect of silymarin on scopolamine-induced dementia using the object recognition test (ORT). The study was extended to demonstrate the role of cholinergic activity, oxidative stress, neuroinflammation, brain neurotransmitters and histopathological changes in the anti-amnestic effect of silymarin in demented rats. Wistar rats were pretreated with silymarin (200, 400, 800 mg/kg) or donepezil (10 mg/kg) orally for 14 consecutive days. Dementia was induced after the last drug administration by a single intraperitoneal dose of scopolamine (16 mg/kg). Then behavioral, biochemical, histopathological, and immunohistochemical analyses were then performed. Rats pretreated with silymarin counteracted scopolamine-induced non-spatial working memory impairment in the ORT and decreased acetylcholinesterase (AChE) activity, reduced malondialdehyde (MDA), elevated reduced glutathione (GSH), restored gamma-aminobutyric acid (GABA) and dopamine (DA) contents in the cortical and hippocampal brain homogenates. Silymarin dose-dependently reversed scopolamine-induced histopathological changes. Immunohistochemical analysis showed that silymarin dose-dependently mitigated protein expression of a glial fibrillary acidic protein (GFAP) and nuclear factor kappa-B (NF-κB) in the brain cortex and hippocampus. All these effects of silymarin were similar to that of the standard anti-amnestic drug, donepezil. This study reveals that the ameliorative effect of silymarin on scopolamine-induced dementia in rats using the ORT maybe in part mediated by, enhancement of cholinergic activity, anti-oxidant and anti-inflammatory activities as well as mitigation in brain neurotransmitters and histopathological changes.

Keywords: dementia, donepezil, object recognition test, rats, silymarin, scopolamine

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Authors: Kimberley Rain Miner, Karl Kreutz, Larry LeBlanc

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During the period of 1950-1970 persistent organic pollutants such as DDT, dioxin and PCB were released in the atmosphere and distributed through precipitation into glaciers throughout the world. Recent abrupt climate change is increasing the melt rate of these glaciers, introducing the toxins to the watershed. Studies have shown the existence of legacy pollutants in glacial ice, but neither the impact nor quantity of these toxins on downstream populations has been assessed. If these pollutants are released at toxic levels it will be necessary to create a mitigation plan to lower their impact on the affected communities.

Keywords: climate change, adaptation, mitigation, risk management

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Authors: Vishnu Varthan Vaithiyalingamjagannathan, M. N. Sathishkumar, K. S. Lakhsmi, D. Satheeshkumar, Srividyaammayappanrajam

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Background:Naringenin, aglycone flavonoid possess certain activities like anti-oxidant, anti-estrogenic, anti-diabetic, cardioprotective, anti-obesity,anti-inflammatory, hepatoprotective and also have anti-cancer characteristics like carcinogenic inactivation, cell cycle arrest, anti-proliferation, apoptosis, anti-angiogenesis and enhances anti-oxidant activity. Methodology:The inhibitory effect of Naringenin in lung tumor progression estimated with adenocarcinoma (A549) cell lines (in vitro) and C57BL/6 mice injected with 5 X 106A549 cell lines (in vivo) in a tri-dose manner (Naringenin 100mg/kg,150mg/kg, and 200mg/kg) compared with standard chemotherapy drug cisplatin (7mg/kg). Results:The results of the present study revealed a dose-dependent activity in Naringenin and combination with cisplatin at a higher dose which showed decreased tumor progression in mice. In vitro studies carried out for estimation of cell survival and Nitric Oxide (NO) level, shows dose dependent action of Naringenin with IC50 value of 42µg/ml. In vivo studies were carried out in C57BL/6 mice. Naringenin satisfied the condition of an anti-cancer molecule with its characteristics in fragmentation assay, Zymography assay, anti-oxidant, and myeloperoxidase studies, than cisplatin which failed in anti-oxidant and myeloperoxidase effect. Both in vitro and in vivo establishes dose dependent decrease in NO levels. But whereas, Naringenin showed adverse results in Matrix Metalloproteinase (MMP) enzymatic levels with increase in dose levels. Conclusion:From the present study, Naringenin could suppress the lung tumor progression when given individually and also in combinatorial with standard chemotherapy drug.

Keywords: naringenin, in vitro, cell line, anticancer

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Authors: S. Ahmed John

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Marine forms-bacteria, actinobacteria, cynobacteria, fungi, microalgae, seaweeds mangroves and other halophytes an extremely important oceanic resources and constituting over 90% of the oceanic biomass. The marine natural products have lead to the discovery of many compounds considered worthy for clinical applications. The marine sources have the highest probability of yielding natural products. Natural derivatives play an important role to prevent the cancer incidences as synthetic drug transformation in mangrove. 28.12% of anticancer compound extracted from the mangroves. Exchocaria agollocha has the anti cancer compounds. The present investigation reveals the potential of the Exchocaria agollocha with biotechnological applications for anti cancer, antimicrobial drug discovery, environmental remediation, and developing new resources for the industrial process. The anti-cancer activity of Exchocaria agollocha was screened from 3.906 to 1000 µg/ml of concentration with the dilution leads to 1:1 to 1:128 following methanol and chloroform extracts. The cell viability in the Exchocaria agollocha was maximum at the lower concentration where as low at the higher concentration of methanol and chloroform extracts when compare to control. At 3.906 concentration, 85.32 and 81.96 of cell viability was found at 1:128 dilution of methanol and chloroform extracts respectively. At the concentration of 31.25 following 1:16 dilution, the cell viability was 65.55 in methanol and 45.55 in chloroform extracts. However, at the higher concentration, the cell viability 22.35 and 8.12 was recorded in the extracts of methanol and chloroform. The cell viability was more in methanol when compare to chloroform extracts at lower concentration. The present findings gives current trends in screening and the activity analysis of metabolites from mangrove resources and to expose the models to bring a new sustain for tackling cancer. Bioactive compounds of Exchocaria agollocha have extensive use in treatment of many diseases and serve as a compound and templates for synthetic modification.

Keywords: bio-active product, compounds, natural products and microalgae

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Authors: Kiran P. Chadayamuri, Saransh Bagdi, Sai Vinod Boddu

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Pollution has been a major problem that has haunted India for years. Large amounts of industrial, automobile and domestic waste have resulted in heavy contamination of air, land and water. The Taj Mahal, one of the Seven Wonders of the World, has been and continues to be India’s symbol of a rich history around the globe. Over the years, the beauty of Taj Mahal has also suffered from increasing pollution. Its shiny white exterior has started to turn yellow because of air pollution and acid rain. Illegal factories and uncontrolled construction have played a major role in worsening its condition. Rapid population growth in the city (Agra) meant more water requirement which has led to ground water deterioration under the historical monument making its wooden foundations dry and weak. Despite various measures by the state and central government, there hasn’t been any satisfactory result. This paper aims at studying the various causes and their impacts affecting the Taj Mahal and method that could slow down its deterioration.

Keywords: pollution, Taj Mahal, India, management

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Authors: S. Jayasinghe, W. G. D. Wickramasingha, V. Karunaratne, D. N. Karunaratne, A. Ekanayake

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Multi-drug resistant microbial pathogens are a serious global health problem, and hence, there is an urgent necessity for discovering new drug therapeutics. However, finding alternatives is a one of the biggest challenges faced by the global drug industry due to the spiraling high cost and serious side effects associated with modern medicine. On the other hand, plants and their secondary metabolites can be considered as good sources of scaffolds to provide structurally diverse bioactive compounds as potential therapeutic agents. 6β-hydroxy betunolic acid is a triterpenoid isolated from bark of Schumacheria castaneifolia which is an endemic plant to Sri Lanka which has shown antibacterial activity against both Staphylococcus aureus (ATCC 29213) and methicillin-resistant S. aureus with Minimum Inhibition Concentration (MIC) of 16 µg/ml. The objective of this study was to determine the anti-bacterial activity for the derivatives of 6β- hydroxy betunolic acid against standard strains of Staphylococcus aureus (ATCC 29213 and ATCC 25923), Enterococcus faecalis (ATCC 29212), Escherichia coli (ATCC 35218 and ATCC 25922), Pseudomonas aeruginosa (ATCC 27853), carbepenemas produce Kebsiella pneumonia (ATCC BAA 1705) and carbepenemas non produce Kebsiella pneumonia (ATCC BAA 1706) and four stains of clinically isolated methicillin resistance S. aureus and Acinetobacter. Structural analogues of 6β-hydroxy betunolic acid were synthesized by modifying the carbonyl group at C-3 to obtain olefin and oxime, the hydroxyl group at C-6 position to a ketone, the carboxylic acid at C-17 to obtain amide and halo ester and the olefin group at C-20 position to obtain epoxide. Chemical structures of the synthesized analogues were confirmed with spectroscopic data and antibacterial activity was determined through broth micro dilution assay. Results revealed that 6β- hydroxy betunolic acid shows significant antibacterial activity only against the Gram positive strains and it was inactive against all the tested Gram negative strains for the tested concentration range. However, structural modifications into oxime and olefin at C-3, ketone at C-6 and epoxide at C-20 decreased its antibacterial activity against the gram positive organisms and it was totally lost with the both modifications at C-17 into amide and ester. These results concluded that the antibacterial activity of 6β- hydroxy betunolic acid and derivatives is predominantly depending on the cell wall difference of the bacteria and the presence of carboxylic acid at C-17 is highly important for the antibacterial activity against Gram positive organisms.

Keywords: antibacterial activity, 6β- hydroxy betunolic acid, broth micro dilution assay, structure activity relationship

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Authors: Kirill M. Dubovikov, Ekaterina S. Marchenko, Gulsharat A. Baigonakova

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NiTi alloys are widely used as implants in medicine due to their unique properties such as superelasticity, shape memory effect and biocompatibility. However, despite these properties, one of the major problems is the release of nickel after prolonged use in the human body under dynamic stress. This occurs due to oxidation and cracking of NiTi implants, which provokes nickel segregation from the matrix to the surface and release into living tissues. As we know, nickel is a toxic element and can cause cancer, allergies, etc. One of the most popular ways to solve this problem is to create a corrosion resistant coating on NiTi. There are many coatings of this type, but not all of them have good biocompatibility, which is very important for medical implants. Coatings based on calcium phosphate phases have excellent biocompatibility because Ca and P are the main constituents of the mineral part of human bone. This fact suggests that a Ca-P coating on NiTi can enhance osteogenesis and accelerate the healing process. Therefore, the aim of this study is to investigate the structure of Ca-P coating on NiTi substrate. Plasma assisted radio frequency (RF) sputtering was used to obtain this film. This method was chosen because it allows the crystallinity and morphology of the Ca-P coating to be controlled by the sputtering parameters. It allows us to obtain three different NiTi samples with Ca-P coating. XRD, AFM, SEM and EDS were used to study the composition, structure and morphology of the coating phase. Scratch tests were carried out to evaluate the adhesion of the coating to the substrate. Wettability tests were used to investigate the hydrophilicity of the different coatings and to suggest which of them had better biocompatibility. XRD showed that the coatings of all samples were hydroxyapatite, but the matrix was represented by TiNi intermetallic compounds such as B2, Ti2Ni and Ni3Ti. The SEM shows that the densest and defect-free coating has only one sample after three hours of sputtering. Wettability tests show that the sample with the densest coating has the lowest contact angle of 40.2° and the largest free surface area of 57.17 mJ/m2, which is mostly disperse. A scratch test was carried out to investigate the adhesion of the coating to the surface and it was shown that all coatings were removed by a cohesive mechanism. However, at a load of 30N, the indenter reached the substrate in two out of three samples, except for the sample with the densest coating. It was concluded that the most promising sputtering mode was the third, which consisted of three hours of deposition. This mode produced a defect-free Ca-P coating with good wettability and adhesion.

Keywords: biocompatibility, calcium phosphate coating, NiTi alloy, radio frequency sputtering.

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Authors: Gurfateh Singh, Mu Khan, Razia Khanam, Govind Mohan

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Objective: The present study has been designed to investigate the beneficial role of Fenofibrate & Clofibrate in attenuated the cardioprotective effect of ischemic preconditioning (IPC) in hyperlipidemic rat hearts. Materials & Methods: Experimental hyperlipidemia was produced by feeding high fat diet to rats for a period of 28 days. Isolated langendorff’s perfused normal and hyperlipidemic rat hearts were subjected to global ischemia for 30 min followed by reperfusion for 120 min. The myocardial infarct size was assessed macroscopically using triphenyltetrazolium chloride staining. Coronary effluent was analyzed for lactate dehydrogenase (LDH) and creatine kinase-MB release to assess the extent of cardiac injury. Moreover, the oxidative stress in heart was assessed by measuring thiobarbituric acid reactive substance, superoxide anion generation and reduced form of glutathione. Results: The ischemia-reperfusion (I/R) has been noted to induce oxidative stress by increasing TBARS, superoxide anion generation and decreasing reduced form of glutathione in normal and hyperlipidemic rat hearts. Moreover, I/R produced myocardial injury, which was assessed in terms of increase in myocardial infarct size, LDH and CK-MB release in coronary effluent and decrease in coronary flow rate in normal and hyperlipidemic rat hearts. In addition, the hyperlipidemic rat hearts showed enhanced I/R-induced myocardial injury with high degree of oxidative stress as compared with normal rat hearts subjected to I/R. Four episodes of IPC (5 min each) afforded cardioprotection against I/R-induced myocardial injury in normal rat hearts as assessed in terms of improvement in coronary flow rate and reduction in myocardial infarct size, LDH, CK-MB and oxidative stress. On the other hand, IPC mediated myocardial protection against I/R-injury was abolished in hyperlipidemic rat hearts. However, Treatment with Fenofibrate (100 mg/kg/day, i.p.), Clofibrate (300mg/kg/day, i.p.) as a agonists of PPAR-α have not affected the cardioprotective effect of IPC in normal rat hearts, but its treatment markedly restored the cardioprotective potentials of IPC in hyperlipidemic rat hearts. Conclusion: It is noted that the high degree of oxidative stress produced in hyperlipidemic rat heart during reperfusion and consequent down regulation of PPAR-α may be responsible to abolish the cardioprotective potentials of IPC.

Keywords: Hyperlipidemia, ischemia-reperfusion injury, ischemic preconditioning, PPAR-α

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Authors: Mohamed A. Hammad, Dzul Azri Mohamed Noor, Syed Azhar Syed Sulaiman, Abeer Kharshid, Nor Azizah Aziz, Tarek M. Elsayed

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Medication safety is always an issue. In 2015, the National Pharmaceutical Control Bureau released a statement requesting all statins manufacturers in Malaysia to include the risk of diabetes information in the drug information leaflet in response to United States Food and Drug Administration (U.S. FDA) report. However, the data regarding this warning label in Malaysia is limited, so there is still some uncertainty whether such risk can also be observed in the Malaysian population or not. The study aims to determine the effect of statins on HbA1c% in type 2 diabetic outpatients in endocrine clinics at Hospital Pulau Pinang between June 2015 and May 2016 in Malaysia. In a prospective cohort study, records of 400 type 2 diabetic patients (control group 104 patients not using statin and treatment group 296 patients using statin) were reviewed to identify demographic criteria and lab tests. The prevalence of glycemic control (Glycated hemoglobin, HbA1C ≤ 7% for patient < 65 years, and < 8% for patient ≥ 65 years) was estimated, according to American Diabetes Association guidelines 2015. The results were presented as descriptive statistics. From 296 patients with Type 2 diabetes using statins cohort with a mean age of 57.52 ± 12.2 years, only 81 (27.4%) cases had controlled glycemia, and 215 (72.6%) had uncontrolled glycemia, CI: 95% (6.3–11.1). While the control group 104 diabetic patients had a mean age 46.1 ± 18 years and distributed among 59 (56.7%) patients with controlled diabetes and 45 (43.3%) cases, had uncontrolled glycemia, CI: 95% (5.2–10.3). The relative risk (RR) of uncontrolled glycemia in diabetic patients used statins was 1.68, and the excessive relative risk (ERR) was 68%. The absolute risk (AR) was 29.3%, and the number needed to harm (NNH) was 4. Diabetic patients using statins have more risk of uncontrolled glycemia than the patients with Type 2 diabetes non-using statins.

Keywords: diabetes mellitus, HbA1c, Malaysia, outpatients, statin, type 2, uncontrolled glycemia

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Authors: Birgul Hizlar, Sibel Karakaya

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Recently, increasing attention has been given to carotenoid bioaccessibility and bioavailability in the field of nutrition research. As a consequence of their lipophilic nature and their specific localization in plant-based tissues, carotenoid bioaccessibility and bioavailability is generally quite low in raw fruits and vegetables, since carotenoids need to be released from the cellular matrix and incorporated in the lipid fraction during digestion before being absorbed. Today’s approach related to improving the bioaccessibility is to design food matrix. Recently, the newest approach, excipient food, has been introduced to improve the bioavailability of orally administered bioactive compounds. The main idea is combining food and another food (the excipient food) whose composition and/or structure is specifically designed for improving health benefits. In this study, effects of food processing, food matrix and the addition of excipient foods on the carotenoid bioaccessibility of carrots were determined. Different excipient foods (olive oil, lemon juice and whey curd) and different food matrices (grating, boiling and mashing) were used. Total carotenoid contents of the grated, boiled and mashed carrots were 57.23, 51.11 and 62.10 μg/g respectively. No significant differences among these values indicated that these treatments had no effect on the release of carotenoids from the food matrix. Contrary to, changes in the food matrix, especially mashing caused significant increase in the carotenoid bioaccessibility. Although the carotenoid bioaccessibility was 10.76% in grated carrots, this value was 18.19% in mashed carrots (p<0.05). Addition of olive oil and lemon juice as excipients into the grated carrots caused 1.23 times and 1.67 times increase in the carotenoid content and the carotenoid bioaccessibility respectively. However, addition of the excipient foods in the boiled carrot samples did not influence the release of carotenoid from the food matrix. Whereas, up to 1.9 fold increase in the carotenoid bioaccessibility was determined by the addition of the excipient foods into the boiled carrots. The bioaccessibility increased from 14.20% to 27.12% by the addition of olive oil, lemon juice and whey curd. The highest carotenoid content among mashed carrots was found in the mashed carrots incorporated with olive oil and lemon juice. This combination also caused a significant increase in the carotenoid bioaccessibility from 18.19% to 29.94% (p<0.05). When compared the results related with the effect of the treatments on the carotenoid bioaccessibility, mashed carrots containing olive oil, lemon juice and whey curd had the highest carotenoid bioaccessibility. The increase in the bioaccessibility was approximately 81% when compared to grated and mashed samples containing olive oil, lemon juice and whey curd. In conclusion, these results demonstrated that the food matrix and addition of the excipient foods had a significant effect on the carotenoid content and the carotenoid bioaccessibility.

Keywords: carrot, carotenoids, excipient foods, food matrix

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Authors: Narin Ozturk, Xiao-Mei Li, Sylvie Giachetti, Francis Levi, Alper Okyar

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P-glycoprotein (P-gp, MDR1, ABCB1) is a transmembrane protein acting as an ATP-dependent efflux pump and functions as a biological barrier by extruding drugs and xenobiotics out of cells in healthy tissues especially in intestines, liver and brain as well as in tumor cells. The circadian timing system controls a variety of biological functions in mammals including xenobiotic metabolism and detoxification, proliferation and cell cycle events, and may affect pharmacokinetics, toxicity and efficacy of drugs. Selective mTOR (mammalian target of rapamycin) inhibitor everolimus is an immunosuppressant and anticancer drug that is active against many cancers, and its pharmacokinetics depend on P-gp. The aim of this study was to investigate the dosing time-dependent toxicity of everolimus with respect to the intestinal P-gp expression rhythms in mdr1a::Luc mice using Real Time-Biolumicorder (RT-BIO) System. Mdr1a::Luc male mice were synchronized with 12 h of Light and 12 h of Dark (LD12:12, with Zeitgeber Time 0 – ZT0 – corresponding Light onset). After 1-week baseline recordings, everolimus (5 mg/kg/day x 14 days) was administered orally at ZT1-resting period- and ZT13-activity period- to mdr1a::Luc mice singly housed in an innovative monitoring device, Real Time-Biolumicorder units which let us monitor real-time and long-term gene expression in freely moving mice. D-luciferin (1.5 mg/mL) was dissolved in drinking water. Mouse intestinal mdr1a::Luc oscillation profile reflecting P-gp gene expression and locomotor activity pattern were recorded every minute with the photomultiplier tube and infrared sensor respectively. General behavior and clinical signs were monitored, and body weight was measured every day as an index of toxicity. Drug-induced body weight change was expressed relative to body weight on the initial treatment day. Statistical significance of differences between groups was validated with ANOVA. Circadian rhythms were validated with Cosinor Analysis. Everolimus toxicity changed as a function of drug timing, which was least following dosing at ZT13, near the onset of the activity span in male mice. Mean body weight loss was nearly twice as large in mice treated with 5 mg/kg everolimus at ZT1 as compared to ZT13 (8.9% vs. 5.4%; ANOVA, p < 0.001). Based on the body weight loss and clinical signs upon everolimus treatment, tolerability for the drug was best following dosing at ZT13. Both rest-activity and mdr1a::Luc expression displayed stable 24-h periodic rhythms before everolimus and in both vehicle-treated controls. Real-time bioluminescence pattern of mdr1a revealed a circadian rhythm with a 24-h period with an acrophase at ZT16 (Cosinor, p < 0.001). Mdr1a expression remained rhythmic in everolimus-treated mice, whereas down-regulation was observed in P-gp expression in 2 of 4 mice. The study identified the circadian pattern of intestinal P-gp expression with an unprecedented precision. The circadian timing depending on the P-gp expression rhythms may play a crucial role in the tolerability/toxicity of everolimus. The circadian changes in mdr1a genes deserve further studies regarding their relevance for in vitro and in vivo chronotolerance of mdr1a-transported anticancer drugs. Chronotherapy with P-gp-effluxed anticancer drugs could then be applied according to their rhythmic patterns in host and tumor to jointly maximize treatment efficacy and minimize toxicity.

Keywords: circadian rhythm, chronotoxicity, everolimus, mdr1a::Luc mice, p-glycoprotein

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Authors: Mahmoud Huleihil

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In this study, the performance of a thermodynamic gas cycle of magnetohydrodynamic (MHD) power generation is considered and presented in terms of power efficiency curves. The dissipation mechanisms considered include: fluid friction modeled by means of the isentropic efficiency of the compressor, heat transfer leakage directly from the hot reservoir to the cold heat reservoir, and constant velocity of the MHD generator. The study demonstrates that power and efficiency vanish at the extremes of both slow and fast operating conditions. These points are demonstrated on power efficiency curves and the locus of efficiency at maximum power and the locus of maximum efficiency. Qualitatively, the considered loss mechanisms have a similar effect on the efficiency at maximum power operation and on maximum efficiency operation, thus these efficiencies are reduced, even for small values of the loss mechanisms.

Keywords: magnetohydrodynamic generator, electrical efficiency, maximum power, maximum efficiency, heat engine

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Authors: Naylya Djumaeva

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Since the end of 2019, the world has been shaken by an infection that has claimed the lives of more than six and a half million patients. Currently, SARS-CoV-2 not only causes acute damage but has long-term consequences affecting every organ and has brought a wave of a new chronic disabling condition called Long-Covid..This preliminary study describes an application of un-explored properties of low-level laser radiation with laser- light emitter in the field of which is placed Copegus (Ribavirin) with the aim of treatment of patients with Long-Covid syndrome. The difference from the traditional use of the drug is that Copegus was not prescribed to the patient by the traditional method - orally or intravenously, and the medicinal properties of the drug were introduced into the patient’s body using the un-explored properties of low-power laser radiation. Ninety eight patients with Long- Covid syndrome were observed. The obtained findings suggest that under the influence of the field formed into the laser- light emitter with a Copegus placed inside the field, the remote transfer of pharmacological properties of Сopegus occurs. Conclusions about the produced effect of exposure were made based on improvement in the condition of patients, the disappearance of complaints, and positive changes in various diagnostic tests performed by the patients. Biography: Djumaeva N completed her PhD from the Institute of Epidemiology, Microbiology and Infectious Diseases in 2000. In her dissertation work devoted to the treatment of patients with chronic hepatitis B virus infection, she presented data on the possible influence of Complex Homeopathic Preparations on the organization of bound intracellular water in the cells of the body. She is the Consultant (Neurologist) at the Scientific-Research Institute for Virology, Uzbekistan, and an expert in “medicament testing” method (30 years). She has published 43 papers, including 2 patents.

Keywords: long covid, low level laser, copegus, laser- light emmiter

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Authors: J. V. Thanikal, M. Torrijos, Philipe Sousbie, S. M. Rizwan, R. Senthil Kumar, Hatem Yezdi

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Co-digestion is one of the advantages of anaerobic digestion process because; several wastes having complimentary characteristics can be treated in a single process. The anaerobic co-digestion process, which can be defined as the simultaneous treatment of two –or more – organic biodegradable waste streams by anaerobic digestion offers great potential for the proper disposal of the organic fraction of solid waste coming from source or separate collection systems. The results of biogas production for sewage sludge, when used as a single substrate, were low (350ml/d), and also the biodegradation rate was slow. Sewage sludge as a co-substrate did not show much effect on biogas yield. The vegetable substrates (Potato, Carrot, Spinach) with a total charge of 27–36 g VS, with a HRT starting from 3 days and ending with 1 day, shown a considerable increase in biogas yield 3.5-5 l/d.

Keywords: anaerobic digestion, co-digestion, vegetable substrate, sewage sludge

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Authors: Djeddi Mabrouk

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The slow coming together between the Afro-Eurasia plates seems to be the main cause of the active deformation in the whole of North Africa which in consequence come true in Algeria with a large zone of deformation in an enough large limited band, southern through Saharan atlas and northern through tell atlas. Maghrebin and Atlassian Chain along North Africa are the consequence of this convergence. In junction zone, we have noticed a compressive regime NW-SE with a creases-faults structure and structured overthrust. From a geological point of view the north part of Algeria is younger then Saharan platform, it’s changing so unstable and constantly in movement, it’s characterized by creases openly reversed, overthrusts and reversed faults, and undergo perpetually complex movement vertically and horizontally. On structural level the north of Algeria it's a part of erogenous alpine peri-Mediterranean and essentially the tertiary age It’s spread from east to the west of Algeria over 1200 km.This oogenesis is extended from east to west on broadband of 100 km.The alpine chain is shaped by 3 domains: tell atlas in north, high plateaus in mid and Saharan atlas in the south In extreme south we find the Saharan platform which is made of Precambrian bedrock recovered by Paleozoic practically not deformed. The Algerian north and the Saharan platform are separated by an important accident along of 2000km from Agadir (Morocco) to Gabes (Tunisian). The seismic activity is localized essentially in a coastal band in the north of Algeria shaped by tell atlas, high plateaus, Saharan atlas. Earthquakes are limited in the first 20km of the earth's crust; they are caused by movements along faults of inverted orientation NE-SW or sliding tectonic plates. The center region characterizes Strong Earthquake Activity who locates mainly in the basin of Mitidja (age Neogene).The southern periphery (Atlas Blidéen) constitutes the June, more Important seism genic sources in the city of Algiers and east (Boumerdes region). The North East Region is also part of the tellian area, but it is characterized by a different strain in other parts of northern Algeria. The deformation is slow and low to moderate seismic activity. Seismic activity is related to the tectonic-slip earthquake. The most pronounced is that of 27 October 1985 (Constantine) of seismic moment magnitude Mw = 5.9. North-West region is quite active and also artificial seismic hypocenters which do not exceed 20km. The deep seismicity is concentrated mainly a narrow strip along the edge of Quaternary and Neogene basins Intra Mountains along the coast. The most violent earthquakes in this region are the earthquake of Oran in 1790 and earthquakes Orléansville (El Asnam in 1954 and 1980).

Keywords: alpine chain, seismicity north Algeria, earthquakes in Algeria, geophysics, Earth

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Authors: Pawan Kumar Gupta, Sumana Ghosh

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Parkinson's Disease (PD) is a long-term neurodegenerative movement disorder of the central nervous system with vast symptoms related to the motor system. The common symptoms of PD are tremor, rigidity, bradykinesia/akinesia, and postural instability, but the clinical symptom includes other motor and non‐motor issues. The motor symptoms of the disease are consequence of death of the neurons in a region of the midbrain known as substantia nigra pars compacta, leading to decreased level of a neurotransmitter known as dopamine. The cause of this neuron death is not clearly known but involves formation of Lewy bodies, an abnormal aggregation or clumping of the protein alpha-synuclein in the neurons. Unfortunately, there is no cure for PD, and the management of this disease is challenging. Therefore, it is critical for a patient to be diagnosed at early stages. A limited choice of drugs is available to improve the symptoms, but those become less and less effective over time. Apart from that, with rapid growth in the field of science and technology, other methods such as multi-area brain stimulation are used to treat patients. In order to develop advanced techniques and to support drug development for treating PD patients, an accurate mathematical model is needed to explain the underlying relationship of dopamine secretion in the brain with the hand tremors. There has been a lot of effort in the past few decades on modeling PD tremors and treatment effects from a computational point of view. These models can effectively save time as well as the cost of drug development for the pharmaceutical industry and be helpful for selecting appropriate treatment mechanisms among all possible options. In this review paper, an effort is made to investigate studies on PD modeling and analysis and to highlight some of the key advances in the field over the past centuries with discussion on the current challenges.

Keywords: Parkinson's disease, deep brain stimulation, tremor, modeling

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Authors: Dammar Bahadur Adhikari

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Mathematics teaching begins with human civilization. The rular used to choose mathematician as prime adviser in many tribes and country. Mathematics was powerful tool for understanding economial situation and strength of rular. In ancient Nepal teaching of mathematics starts with informal education provided by religious leaders there after in modern education system seems to follow the world’s educational system. The aim of this paper is to present a brief historical background of the Nepalese mathematicians up to nineteenth century and highlight the transformation in mathematical science in the line with modern world. Secondary data and formal papers and informal publications were studied to explore the present situation of education. The study concluded that there is remarcable change in quality of education and there are sufficient human powers in the mathematical sciences in Nepal.

Keywords: human development, mathematics, Nepal, science, traditional

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Authors: Sidra Shaw, Sarenna Shaw, Chae Joon Lee, Irimpan Mathews, Eric Koehn

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One of the biggest public health concerns of our time is increasing antimicrobial resistance. As of 2019, the CDC has documented more than 2.8 million serious antibiotic resistant infections in the United States. Currently, antibiotic resistant infections are directly implicated in over 750,000 deaths per year globally. On our current trajectory, British economist Jim O’Neill predicts that by 2050, an additional 10 million people (about half the population of New York) will die annually due to drug resistant infections. As a result, new biochemical pathways must be targeted to generate next generation antibiotic drugs that will be effective against drug resistant bacteria. One enticing target is the biosynthesis of DNA within bacteria, as few drugs interrupt this essential life process. Thymidylate synthase enzymes are essential for life as they catalyze the synthesis of a DNA building block, 2′-deoxythymidine-5′-monophosphate (dTMP). In humans, the thymidylate synthase enzyme (TSase) has been shown to be distinct from the flavin-dependent thymidylate synthase (FDTS) produced by many pathogenic bacteria. TSase and FDTS have distinct structures and mechanisms of catalysis, which should allow selective inhibition of FDTS over human TSase. Currently, C. diff is one of the most antibiotic resistant bacteria, and no drugs that target thymine biosynthesis exist for C. diff. Here we present the initial biochemical characterization of FDTS from C. diff. Specifically, we examine enzyme kinetics and binding features of this enzyme to determine the nature of interaction with ligands/inhibitors and understand the molecular mechanism of catalysis. This research will provide more insight into the targetability of the C. diff FDTS enzyme for novel antibiotic drugs.

Keywords: flavin-dependent thymidylate synthase, FDTS, clostridioides difficile, C. diff, antibiotic resistance, DNA synthesis, enzyme kinetics, binding features

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