Synthetic Formulations Research Articles

Progesterone treatment for the prevention of preterm birth

Preterm birth (PTB) is defined as birth before 37 completed weeks of gestation, which occurs in approximately 10% of all pregnancies. Prior PTB history and short cervical length (CL) are the most significant predictors of PTB. Prior PTB history can increase the risk of recurrence of PTB more than two-fold in the next pregnancy. A short CL of less than 25 mm as measured by ultrasound between 16 and 24 weeks of gestation has been shown to be the most reliable predictor of an increased risk of PTB. Progesterone is one of the few proven effective methods of preventing PTB in women with a previous history of spontaneous PTB and women with a short CL. Progestins are available in natural micronized or synthetic formulations for intramuscular or vaginal (tablet or gel) administration. Several studies have reported that 17 hydroxyprogesterone caproate injection can prevent recurrent PTB in women with a previous history of PTB. Vaginal micronized natural progesterone has also been shown to be effective in preventing PTB in women with previous PTB history or with a short CL. At present, we are performing a multi-center, randomized trial in Korea (a multicenter, randomized, open-label, investigator-initiated trial of vaginal compared with intramuscular progesterone for the prevention of PTB in high-risk pregnant women: VICTORIA protocol) to compare the efficacy between vaginal progesterone and intramuscular injection of progesterone in women with a previous preterm history or short CL. This study will provide important information to both obstetricians and patients on whether a vaginal or intramuscular regimen is better for prevention of a recurrent PTB.

Cortisol Response in Healthy and Diseased Dogs after Stimulation with a Depot Formulation of Synthetic ACTH.

BackgroundThe ACTH stimulation test is used to evaluate the adrenocortical reserve. Recently, the availability of the synthetic ACTH formulation was limited, causing major problems in clinical practice.ObjectivesThe objective of this study was to evaluate poststimulation peak cortisol concentrations and the duration of the stimulatory effect of a depot ACTH preparation in dogs.AnimalsTwenty‐two healthy dogs, 10 dogs with suspected hypoadrenocorticism (HA) and 15 dogs with suspected hyperadrenocorticism (HC).MethodsProspective study. An ACTH stimulation test using a synthetic depot tetracosactide, administered intramuscularly (5 μg/kg or at least 0.1 mL) was performed. Blood samples for determination of cortisol were taken immediately before and 1, 2, 3, 4, 6, and 24 hours after stimulation.ResultsPeak cortisol concentrations were reached after 2–4 hours in all dogs. Cortisol concentrations 1 hour after stimulation were >9 μg/dL in all healthy dogs and >5 μg/dL in all dogs in which HA was excluded. None of the dogs with HA showed a cortisol‐increase above the detection‐limit of the assay. After 6 hours, cortisol concentrations had decreased in the healthy and HC group and were back to baseline after 24 hours.Conclusions and Clinical ImportanceThe depot formulation can be used in place of the short‐acting ACTH to evaluate the adrenocortical reserve. Blood for peak cortisol concentrations should be drawn 3 hours after stimulation in cases in which HC is suspected; in HA‐suspected cases, blood sampling can take place after 1 hour. As the stimulatory effect is gone after 24 hours, interference with other hormonal tests is unlikely after that time.

An Extension of the Hawkins and Simon Condition Characterizing Viable Techniques

This paper discusses an extended version of the Hawkins and Simon condition which constitutes a synthetic formulation of the mathematical properties that viable economies must satisfy in single production models. The new version is implicit in the economic interpretations offered by them of the Hawkins and Simon condition, once a correction is introduced in one of those interpretations. Moreover, the paper details the meaning of the extended version following the interpretation of the original version proposed by Dorfman, Samuelson, and Solow. It also introduces a characteristic property of indecomposable matrices that has not previously been published.

Abstract 5540: Antitumor efficacy of synthetic formulations of active components in Arum palaestinum extracts in head and neck squamous cell carcinoma

Abstract Head and neck squamous cell carcinoma (HNSCC) have a propensity for aggressive growth and metastasis, with high morbidity and low 5-year survival rates. Despite advances in treatment, the overall survival rate has only modestly improved over the past several years. Herbal tea extract from the root and leaves of Arum palaestinum has been used to prevent and facilitate treatment of cancer in Palestine. Very few studies have addressed the mechanisms and antitumor efficacy of this neutraceutical. Here we tested the antitumor efficacy of synthetic formulations of Arum palaestinum extract (GZ17-S, -05.00 and -06.02) in preclinical models of HNSCC. Our preliminary data demonstrates that these formulations have antitumor efficacy in several tumor types including HNSCC, lung and ovarian cancer cells. We hypothesized that GZ17-06.02 inhibits phosphorylation of key molecules that mitigate HNSCC progression and induce apoptotic cell death. Cytotoxicity of all the formulations was investigated on two HNSCC cell lines, OSC19 and UMSCC1. The GZ17-06.02 and -05.00 were found to be highly efficacious with low ED50 values (11.85 μg/ml and 16.40 μg/ml, respectively) for OSC19 and (10.86 μg/ml and 11.60 μg/ml, respectively) UMSCC1 cells at 72h. We determined the efficacy of GZ17 formulations in mitigating HNSCC invasion and migration. Among the formulations tested, GZ17-06.02 was most efficacious in significantly reducing invasion (37.33%) and migration (12.66%) of OSC19 cells compared to vehicle control (p<0.001). Further, GZ17-06.02 induced cytotoxicity through Caspase-3 and PARP cleavage in HNSCC cells. Flow cytometric analyses of GZ17-06.02 treated HNSCC revealed a significant reduction in cells in the G1 phase and increased apoptosis compared to vehicle control treated cells. In order to determine the molecular mechanism regulating these effects, we assessed the levels of phosphorylated proteins. It was observed that phosphorylation of several signal transducing molecules including MAPK, EGFR, Akt 1/2/3, checkpoint kinase (chk2), proto oncogene tyrosine-kinase (Src) and signal transducer and activator of transcription2 (STAT2) were reduced in OSC19 cells treated with GZ17-06.02 compared to vehicle control. Further, we tested the in vivo antitumor efficacy of all formulations on HNSCC xenografts. All formulations demonstrated antitumor efficacy up on intratumoral administration of 15 mg/kg/d. GZ17-06.02 was most efficacious in significantly reducing the tumor volume compared to the vehicle control treated tumors (p<0.001). All formulations were well tolerated. We are now testing the antitumor efficacy of GZ17-06.02 on systemic delivery (oral gavage) in a patient-derived xenograft model of HNSCC. In conclusion, the synthetic versions of Arum Palaestinum demonstrate potent therapeutic potential in HNSCC through down-regulation of key signaling molecules and the induction of apoptosis. Citation Format: Vikalp Vishwakarma, Kyle Crooker, Vusala Snyder, Jeffrey Straub, Caitlin Cole, Annie Lee, Lisa Stehno Bittel, Sufi Thomas. Antitumor efficacy of synthetic formulations of active components in Arum palaestinum extracts in head and neck squamous cell carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5540. doi:10.1158/1538-7445.AM2015-5540

A synthetic formulation for the Italian seismic hazard and code implications for the seismic risk

The paper contains two parts. In the first one, the seismic hazard on the Italian territory, as given by the current Italian structural design code, published in 2008, is discussed. Hazard curves, given by the Italian code in a tabular form, are fitted with a single non-linear model and it is shown that a more compact, simple and user-ready territorial hazard description can be applied. The model is valid for both the bedrock and the surface seismic hazards, and is accurate. The surface seismic hazard is computed with a local amplification mapping, which is now well detailed over the entire territory. Departing from these results, in the second part the territorial seismic risk for the ultimate limit state is computed via a parametric fragility curve. From the results, it can be inferred that the codes need further factors calibration, with the aims of guaranteeing both territorially uniform reliability levels, and the traditionally assumed target reliability levels, e.g. those stated in the Eurocodes.

S-Nitrosated Polypropylene Sulfide Nanoparticles for Thiol-Dependent Transnitrosation and Toxicity Against Adult Female Filarial Worms.

A synthetic polymer nanoparticle formulation utilizing the physiological nitrosothiol chemistry for nitric oxide delivery is shown. Toxicity of S-nitroso nanoparticles against adult female Brugia malayi worms, which are responsible for lymphatic filariasis, is dependent on nitric oxide release through transnitrosation as S-nitrosocysteine, a potent endogenous nitric oxide donor.

Coupling salinity reduction to aquatic animal well-being and ecosystem representativeness at the Biodôme de Montréal

This paper presents a case study of a locally adapted sustainable strategy of salinity reduction applied to the Saint Lawrence maritime ecosystem at the Biodome de Montreal. In conformity with the standards of the CAZA (Canadian Aquarium and Zoos Association), this procedure was implemented to reconcile animal well-being, ecosystem representativeness and control of costs under the operational environment of a cold seawater recirculation system featuring the Golfe du Saint Laurent Ecosystem (GSLE) and its associated live collection. A simple methodology to carry out safe salinity reduction procedures of artificial seawater environments (from 28 to 24 Practical Salinity Units) is proposed and detailed. Adapted salinity challenge tests at 14, 21 and 24 were conducted beforehand and simple adapted indicators were used on a selection of key species (thorny skate: Raja radiate ; little skate: R. erinacea ; barndoor skate: R. laevis ; Atlantic cod: Gadus morhua ; green urchins: Strongylocentrolus droebachien and American lobster: Homarus americanus ) to evaluate the well-being and mortality risks associated with both a lower operational salinity (long-term exposure) and an unavoidable salinity drop (short-term exposure) observed during routine large-scale water renewal operations. Economic gains achieved through reduction in the use of costly synthetic salt formulation were calculated. The savings achieved during three years of operation at 24 PSU have been applied to the improvement of the water quality control management capacities of the GLSE exhibit such as a sulphur-based denitrification unit, additional ozonation and protein skimming capacities.

Synthesis of sodium dodecyl sulfate-supported nanocomposite cation exchanger: removal and recovery of Cu2+ from synthetic, pharmaceutical and alloy samples

A new surfactant-based nanocomposite cation exchanger, sodium dodecyl sulfate–Th(IV) tungstate (SDS–TT) was prepared by the sol–gel method. The SDS–TT was characterized by FTIR, XRD, TGA, SEM, EDS and TEM. The distribution studies for various metal ions on SDS–TT were performed in different acidic mediums. On the basis of distribution coefficient values, SDS–TT was found to be selective for Cu2+ metal ion. SDS–TT was successfully used for the quantitative separation of Cu2+ from the synthetic mixture, pharmaceutical formulation and brass sample. The regeneration studies were performed which showed a decrease in the recovery of Cu2+ from 88 to 70 % after seven consecutive cycles.

Essential oil based polymeric patch development and evaluating its repellent activity against mosquitoes

Essential oil based insect repellents are environment friendly and provide dependable personal protection against the bites of mosquitoes and other blood-sucking insects. In the present study, optimized mixture of three essential oils was embedded into the ethylcellulose (EC) and polyvinylpyrrolidone (PVP K-30) polymers to develop essential oils based patch type mosquito repellent formulation. The developed formulation was characterized for various physico-chemical properties, oil release efficiency and essential oil–polymer interaction. Repellent activity of the formulation was evaluated against Ae. (S) albopictus mosquitoes and compared with commercially available synthetic insecticide based mosquito repellent cream Odomos® in the laboratory. The developed patches were 100% flat and there was no interaction between oil components and the excipients. Patches were smooth, homogenous and provided excellent mosquito repellent activity comparable to Odomos® under laboratory condition. Morphological and physico-chemical characterization indicated that the formulation was stable and suitable with the polymeric combination. The patch formulation did not show any inhalation toxicity in experimental Wistar rat. The repellent patches developed and evaluated currently, may provide a suitable, eco-friendly, acceptable and safe alternative to the existing synthetic repellent formulations for achieving protection against mosquitoes.

Assessment of biologically active GAC and complementary technologies for gray water treatment

The reuse of gray water for applications ranging from irrigation to showering is a viable means to reduce net water demand when water supplies are stressed. The objective of this study was to investigate the treatment of gray water using biologically active granular-activated carbon (GAC) and complementary technologies. Technologies were challenged individually or in combination using a synthetic gray water formulation based on NSF/ANSI Standard 350. Specific technologies included: GAC; biologically active GAC (BAC); a newly developed intermittently operated BAC (IOBAC) process; ion exchange (IX); coagulation with a cationic polymer; microfiltration; ultrafiltration (UF); and multi-barrier combinations thereof. For control of organic contaminants such as surfactants, BAC and IOBAC performed well over test periods as long as 6 months. Combinations of IOBAC treatment with coagulation pretreatment and UF post-treatment resulted in sustained chemical oxidant demand and turbidity value reductions in excess of 90 and 99.5%, respectively. Such an approach would be useful for gray water treatment for low tier applications like irrigation or toilet flushing, or as a pretreatment system upstream of reverse osmosis (RO) membranes and/or advanced oxidation processes for high tier reuse applications such as showering.

Synthetic nucleic acid delivery systems: present and perspectives.

Self-assembled synthetic gene delivery systems represent the bottom-up approach to gene delivery and gene silencing, in which scientists are designing novel cationic and procationic amphiphiles that can pack, transport, and deliver nucleic acids to various targets in the body in a controlled manner. These supramolecular assemblies are safer than viruses, but they are lagging behind them in efficiency. We are presenting recent progress that has narrowed this gap through better understanding the delivery barriers and incorporation of this knowledge in the design of novel synthetic amphiphiles, formulations, and revolutionary screening and optimization processes. Structure-properties and structure-activity relationships were drawn within each amphiphile class, presenting the cellular and animal models used to generate them. We are also revealing pertinent in vitro/in vivo correlations that emphasize promising amphiphiles and successful formulation optimization efforts for efficient in vivo nucleic acid delivery, together with main organ targets and diseases treatable with these revolutionary technologies.

The Lipid Portion of Activated Platelet-Rich Plasma Significantly Contributes to Its Wound Healing Properties.

Objective: Platelet-rich plasma (PRP) is a popular choice for the treatment of chronic wounds. Current dogma attributes these healing properties to the peptide growth factors of PRP. However, PRP is also rich in bioactive lipids whose contribution to healing has not been characterized and warrants investigation due to the protease-rich environment of chronic wounds. Approach: The lipid fraction of PRP was tested with respect to proliferation and migration of primary adult human dermal fibroblasts (HDFa)±exposure to chronic wound fluid (CWF). This fraction was also characterized via LC-MS/MS for bioactive lipids. A synthetic formulation of the bioactive lipid composition was developed and tested for the ability to overcome proliferative growth arrest induced by CWF. Results: The data demonstrate the ability of the lipid fraction of PRP to significantly enhance the migration and proliferation of HDFa, and to overcome the proliferative growth arrest induced by CWF. Furthermore, the synthetic lipid formulation generated following characterization of the PRP lipidome demonstrated a similar ability to overcome proliferative arrest of HDFa in the presence of CWF. Innovation: For the first time, we demonstrate the relevance of the lipid fraction of PRP toward the biology of wound healing. These studies open the possibility of altering the lipid profile of PRP via diet or exogenous pathway manipulation to obtain a better healing outcome. Conclusion: The lipid fraction of PRP is under investigated and yet relevant component in wound healing. The current study demonstrates the relevance of this fraction in wound healing by PRP.

Analytical Quality by Design Approach to Test Method Development and Validation in Drug Substance Manufacturing

Pharmaceutical industry has been emerging rapidly for the last decade by focusing on product Quality, Safety, and Efficacy. Pharmaceutical firms increased the number of product development by using scientific tools such as QbD (Quality by Design) and PAT (Process Analytical Technology). ICH guidelines Q8 to Q11 have discussed QbD implementation in API synthetic process and formulation development. ICH Q11 guidelines clearly discussed QbD approach for API synthesis with examples. Generic companies are implementing QbD approach in formulation development and even it is mandatory for USFDA perspective. As of now there is no specific requirements for AQbD (Analytical Quality by Design) and PAT in analytical development from all regulatory agencies. In this review, authors have discussed the implementation of QbD and AQbD simultaneously for API synthetic process and analytical methods development. AQbD key tools are identification of ATP (Analytical Target Profile), CQA (Critical Quality Attributes) with risk assessment, Method Optimization and Development with DoE, MODR (method operable design region), Control Strategy, AQbD Method Validation, and Continuous Method Monitoring (CMM). Simultaneous implementation of QbD activities in synthetic and analytical development will provide the highest quality product by minimizing the risks and even it is very good input for PAT approach.

Identification of Lactobacillus Fermentum Strains with Potential against Colorectal Cancer by Characterizing Short Chain Fatty Acids Production, Anti-Proliferative Activity and Survival in an Intestinal Fluid: In Vitro Analysis

The use of probiotics as preventive agents in colorectal cancer (CRC), as widely suggested in many clinical and pre-clinical studies, was often linked to the potency of short chain fatty acids (SCFAs) in the gut. However, there remains an incomplete understanding of the fatty-acid-producing activity of certain probiotics and their cancer preventive potential. In the current study, L. fermentum strains were investigated for their potential use with CRC treatments. Using cell-free extracts, L. fermentum NCIMB -5221, - 2797, and -8829 were first compared based on their SCFAs production and anti-proliferative activity against Caco-2 colon cancer cells. The corresponding SCFAs synthetic formulations, similar to the ones produced by the bacteria, were prepared and compared with the latter to determine the role and efficacy of naturally produced SCFAs in inhibiting the proliferation of colon cancer cells. Subsequently, the bioactivity and stability of L. fermentum bacterial strains in a simulated intestinal fluid (SIF) was determined. Results showed that L. fermentum NCIMB -5221 and -8829 were the most potent in producing SCFAs, in particular, acetic (192.3 ± 4 mg/L minimum), propionic (69.2 ± 1.6 mg/L minimum), and butyric (35.4 ± 2.9 mg/L minimum) acids. They were also found to inhibit the growth of Caco-2 cells (53.4 ± 1.6%, 72 h, p = 0.021) in comparison with L. acidophilus ATCC 314. Additionally, they showed resistance to SIF (16.3 ± 1.9% minimum, 72 h, p = 0.006) and produced SCFAs in SIF at concentrations high enough to significantly inhibit Caco-2 proliferation (74.73 ± 2.1%, 72 h). Based on characteristics related to bacterial cell survival, SCFA production, and anti-proliferative activity, L. fermentum NCIMB -5221 and - 2797 could potentially be considered as biotherapeutic agents against CRC.

Screening and In-Vitro Analysis of Lactobacillus reuteri Strains for Short Chain Fatty Acids Production, Stability and Therapeutic Potentials in Colorectal Cancer

The use of probiotics as preventive agents in colorectal cancer is widely reported in the literature. However, the bioactivity of specific bacterial strains is only partially understood. Here, we identified Lactobacillus reuteri strains with anti-proliferative activity against colorectal cancer cells. We investigated the bioavailability and the efficacy of short chain fatty acids secreted by distinct Lactobacillus reuteri strains on the inhibition of colorectal cancer cells growth. Five L. reuteri strains were screened based on the short chain fatty acids bio-production and anti-proliferative effects on Caco-2 colon cancer cells. The composition of probiotic short chain fatty acids in cell culture conditioned medium was used to prepare short chain fatty acid synthetic formulations that were compared with the L. reuteri cell culture conditioned media. Later, the bio-stability of the bacteria in a simulated intestinal fluid was determined. Results showed that the production of short chain fatty acids was strain-dependent. L. reuteri NCIMB -11951, -701359 and -702656 were the most potent in producing total short chain fatty acids (402.2 ± 23. 5, p < 0.05 compared with the rest of strains) and inhibiting Caco-2 (by 56.7 ± 1.6 % compared to untreated cells at 72 h, p < 0.001). Comparing the inhibitory effect of the probiotic cell culture conditioned medium and the corresponding short chain fatty acid synthetic formulation showed that the role and relevance of short chain fatty acid production in colorectal cancer cell growth suppression was strain-dependent. L. reuteri NCIMB -702656 and -701359 showed resistance in simulated intestinal fluid (104.6 ± 0.6 % and 105.7 ± 4.1 % of viability at 4 h, respectively) and produced high amounts of total short chain fatty acids (1245.49 ± 0.49 - 1391.58 ± 4.84 mg/ L at 24 h, respectively). Depending partly on short chain fatty acid bio-production, specific L. reuteri strains demonstrated growth inhibitory activity and may be considered as a potential chemopreventive agent against colorectal cancer.

Iron bioavailability from commercially available iron supplements

Iron deficiency anaemia (IDA) is a global public health problem. Treatment with the standard of care ferrous iron salts may be poorly tolerated, leading to non-compliance and ineffective correction of IDA. Employing supplements with higher bioavailability might permit lower doses of iron to be used with fewer side effects, thus improving treatment efficacy. Here, we compared the iron bioavailability of ferrous sulphate tablets with alternative commercial iron products, including three liquid-based supplements. Iron bioavailability was measured using Caco-2 cells with ferritin formation as a surrogate marker for iron uptake. Statistical analysis was performed using one-way ANOVA followed by either Dunnett's or Tukey's multiple comparisons tests. Spatone Apple(®) (a naturally iron-rich mineral water with added ascorbate) and Iron Vital F(®) (a synthetic liquid iron supplement) had the highest iron bioavailability. There was no statistical difference between iron uptake from ferrous sulphate tablets, Spatone(®) (naturally iron-rich mineral water alone) and Pregnacare Original(®) (a multimineral/multivitamin tablet). In our in vitro model, naturally iron-rich mineral waters and synthetic liquid iron formulations have equivalent or better bioavailability compared with ferrous iron sulphate tablets. If these results are confirmed in vivo, this would mean that at-risk groups of IDA could be offered a greater choice of more bioavailable and potentially better tolerated iron preparations.

Characterization of a purified decolorizing detergent-stable peroxidase from Streptomyces griseosporeus SN9

A novel extracellular lignin peroxidase (called LiP-SN) was produced and purified from a newly isolated Streptomyces griseosporeus strain SN9. The findings revealed that the pure enzyme was a monomeric protein with an estimated molecular mass of 43kDa and a Reinheitzahl value of 1.63. The 19 N-terminal residue sequence of LiP-SN showed high homology with those of Streptomyces peroxidases. Its optimum pH and temperature were pH 8.5 and 65°C, respectively. The enzyme was inhibited by sodium azide and potassium cyanide, suggesting the presence of heme components in its tertiary structure. Its catalytic efficiency was higher than that of the peroxidase from Streptomyces albidoflavus strain TN644. Interestingly, LiP-SN showed marked dye-decolorization efficiency and stability toward denaturing, oxidizing, and bleaching agents, and compatibility with EcoVax and Dipex as laundry detergents for 48h at 40°C. These properties make LiP-SN a potential candidate for future applications in distaining synthetic dyes and detergent formulations.

Trends in Language Formalization in Architecture

Alberti’s first attempt to theorize architecture as a formalized language, condensed in its concept of concinnitas, is used as a pretext for the subject of this paper. The path to formalization is a homo sapiens ‘must’. At first, in the everyday use, from primitive pre-discursive languages to the modern dominant language system – speech or discursive semi-formal languages; and since classical Greece, with logical-deductive languages, scientific languages and our age’s zenith of mental representations of the world – theory. Almost every domain of human activity has been subjected to the effort of applying those new methodologies. Architecture could not remain an isolated case. After analyzing some properties of formalized languages, three domains, interior to the architectural activities, are presented. Structures is an architectural field of early formalization (but two millenniums after the first – geometry). Its development has suffered all the pains of growing up, thus having a great diversity of very interesting stories to learn from – the need and difficulties of making epistemological cuts in the open ocean of phenomena, defining the important concepts and ignoring the others, penetrating the essence of reality in very reduced, abstract and synthetic formulations, that, although absolutely general and abstract, don’t loose any semantic or concrete power. It’s what science and theoretical science do. The history and practice of structural science also rise the ‘theory versus methodology’ issue. The second field is real-time building management (the case of intelligent buildings). This is the domain where the more recent advances in formal languages (such as discrete maths, theory of computation, logics, language theory, higher algebras, decision theory) have been applied more often and profoundly. Several particular developments are mentioned, that could be relevant to other fields of architecture – multi-agent optimization, the great complexity of the problem with thousands of interrelated discrete variables, the community of many (human and machine) languages that have to coexist and communicate, the need for a common semantic ground, through ontologies – base for several grammars development. Finally, some remarks on current paths of formalization in the core business of architectural global design, specially on space syntaxes (one of the three major approachs,along with space grammars and architectural ontologies, in the contemporary research). Those remarks concern the problems of empiric vs theoretic; the expressiveness of denotational semantics (relations with other sciences – social, cultural, ideologies); the sophistication of connotational semantics. The question is what is the state of the art – how extensively can they address the global human problems of the city and the building; how their concepts address intensively, in a core minimal theory, the essence of the interaction of architectural action with its environment.

Linear Programming-Based Optimization of Synthetic Fertilizers Formulation

Linear least-cost programming was used in formulating three NPK labeled synthetic fertilizers. Linear Programming technique was selected to formulate the appropriate composition of the three synthetic fertilizers mixes with least costs of production and optimum potential to increase yield of crops and soil fertility. Data about fertilizers specifications and constraints imposed on the fertilizers components were collected from 30 synthetic fertilizers plants. Costs of ingredients used in fertilizers formulation were obtained from the prevailing market prices. The results of the study prevailed that the least cost synthetic fertilizer combinations of the three studied fertilizer mixes among many calculated combinations was 672 JDs for the first mix with NPK label of 20-20-20, 669 JDs for the second mix with NPK label of 15-30-15, and 754 JDs for the third mix with NPK label of 12-12-36. These all three costs are lower by nearly 5-10% than those imposed by the market. These results confirm the importance of using techniques such as LP to formulate least cost products in industries such as synthetic fertilizers industry.

Targeted in vivo delivery of siRNA and an endosome-releasing agent to hepatocytes.

The discoveries of RNA interference (RNAi) and short interfering RNAs (siRNAs) have provided the opportunity to treat diseases in a fundamentally new way: by co-opting a natural process to inhibit gene expression at the mRNA level. Given that siRNAs must interact with the cells' natural RNAi machinery in order to exert their silencing effect, one of the most fundamental requirements for their use is efficient delivery to the desired cell type and, specifically, into the cytoplasm of those cells. Numerous research efforts involving the testing of a large number of delivery approaches using various carrier molecules and inventing several distinct formulation technologies during the past decade illustrate the difficulty and complexity of this task. We have developed synthetic polymer formulations for in vivo siRNA delivery named Dynamic PolyConjugates™ (DPCs) that are designed to mimic the features viruses possess for efficient delivery of their nucleic acids. These include small size, long half-life in circulation, capability of displaying distinct host cell tropism, efficient receptor binding and cell entry, disassembly in the endosome and subsequent release of the nucleic acid cargo to the cytoplasm. Here we present an example of this delivery platform composed of a hepatocyte-targeted endosome-releasing agent and a cholesterol-conjugated siRNA (chol-siRNA). This delivery platform forms the basis of ARC-520, an siRNA-based therapeutic for the treatment of chronic hepatitis B virus (HBV) infection. In this chapter, we provide a general overview of the steps in developing ARC-520 and detailed protocols for two critical stages of the discovery process: (1) verifying targeted in vivo delivery to hepatocytes and (2) evaluating in vivo drug efficacy using a mouse model of chronic HBV infection.