The vertical microdistribution of cyanobacteria and green algae within desert crusts and the development of the algal crusts

Substantial amounts of algal crusts were collected from five different desert experimental sites aged 42, 34, 17, 8 and 4 years, respectively, at Shapotou ( China) and analyzed at a 0.1 mm microscale of depth. It was found that the vertical distribution of cyanobacteria and microalgae in the crusts was distinctly laminated into an inorganic-layer (ca. 0.00 - 0.02 mm, with few algae), an algae-dense-layer ( ca. 0.02 - 1.0 mm) and an algae-sparse-layer ( ca. 1.0 - 5.0 mm). It was interesting to note that in all crusts Scytonema javanicum Born et Flah ( or Nostoc sp., cyanobacterium), Desmococcus olivaceus (Pers ex Ach., green alga) Laundon and Microcoleus vaginatus Gom. ( cyanobacterium) dominated at the depth of 0.02 - 0.05, 0.05 - 0.1 and 0.1 - 1.0 mm, respectively, from the surface. Phormidium tenue Gom. ( or Lyngbya cryptovaginatus Schk., cyanobacterium) and Navicula cryptocephala Kutz.( or Hantzschia amphioxys (Ehr.) Grun. and N. cryptocephala together, diatom) dominated at the depth of 1.0 - 3.0 and 3.5 - 4.0 mm, respectively, of the crusts from the 42 and 34 year old sites. It was apparent that in more developed crusts there were more green algae and the niches of Nostoc sp., Chlorella vulgaris Beij., M. vaginatus, N. cryptocephala and fungi were nearer to the surface. If lichens and mosses accounted for less than 41.5% of the crust surface, algal biovolume was bigger when the crust was older, but the opposite was true when the cryptogams other than algae covered more than 70%. In addition to detailed species composition and biovolume, analyses of soil physicochemical properties, micromorphologies and mineral components were also performed. It was found that the concentration of organic matter and nutrients, electric conductivity, silt, clay, secondary minerals were higher and there were more micro-beddings in the older crusts than the less developed ones. Possible mechanisms for the algal vertical microdistribtion at different stages and the impact of soil topography on crust development are discussed. It is concluded that biomethods ( such as fine species distribution and biovolume) were more precise than mineralogical approaches in judging algal crust development and thus could be a better means to measure the potentiality of algal crusts in desert amelioration.

Development of high-k gate dielectric materials

The traditional gate dielectric material Of SiO2 can not satisfy the need of the continuous downscaling of CMOS dimensions. High-K gate dielectric materials have attracted extensive research efforts recently and obtained great progress. In this paper, the developments of high-K gate materials were reviewed. Based on the author's background and research work in the area, the latest achievements of high-K gate dielectric materials on the recrystalization temperature, the low-K interface layer, and the dielectric breakdown and metal gate electrode were introduced in detail.

Organic/inorganic hybrid solar cells based on SnS/SnO nanocrystals and MDMO-PPV

SnS/SnO heterojunction structured nanocrystals with zigzag rod-like connected morphology were prepared by using a simple two-step method. Bulk heterojunction solar cells were fabricated using the SnS/SnO nanocrystals blended with poly(2-methoxy-5-(3',7'-dimethyloctyloxy)-1,4-phenylene vinylene) (MDMO-PPV) as the active layer. Compared with solar cells using SnS nanoparticles hybridized with MDMO-PPV as the active layer, the SnS/SnO devices showed better performance, with a power conversion efficiency higher by about one order in magnitude.

New development of organolanthanide complexes containing chalcogenide ligands

This article is to present and outline new approaches to chalcogen coordination chemistry from the organolanthanides point of view.

Relationships between nitrogen and phosphorus forms and ratios and the development of dinoflagellate blooms in the East China Sea

During late spring and early summer of 2005, large-scale (> 15 000 km(2)), mixed dinoflagellate blooms developed along the the coast of the East China Sea. Karenia mikimotoi was the dominant harmful algal bloom species in the first stage of the bloom (late May) and was succeeded by Prorocentrum donghaiense approximately 2 wk later. Samples were collected from different stations along both north-south and west-east transects, from the Changjiang River estuary to the south Zhejiang coast, during 3 cruises of the Chinese Ecology and Oceanography of Harmful Algal Blooms Program, before and during the bloom progression. Nitrogen isotope tracer techniques were used to measure rates of NO3-, NH4+, urea, and glycine uptake during the blooms. High inorganic nitrogen (N), but low phosphorus (P) loading from the Changjiang River led to high dissolved inorganic N:dissolved inorganic P ratios in the sampling area and indicate the development of P limitation. The rates of N-15-uptake experiments enriched with PO43- were enhanced compared to unamended samples, suggesting P limitation of the N-uptake rates. The bloom progression was related to the change in availability of both organic and inorganic N and P. Reduced N forms, especially NH4+, were preferentially taken up during the blooms, but different bloom species had different rates of uptake of organic N substrates. K mikimotoi had higher rates of urea uptake, while P. donghaiense had higher rates of glycine uptake. Changes in the availability of reduced N and the ratios of N:P in inorganic and organic forms were suggested to be important in the bloom succession. Nutrient ratios and specific uptake rates of urea were similar when compared to analogous blooms on the West Florida Shelf.

Development of an in vitro multicellular tumor spheroid model using microencapsulation and its application in anticancer drug screening and testing

In this study, an in vitro multicellular tumor spheroid model was developed using microencapsulation, and the feasibility of using the microencapsulated. multicellular tumor spheroid (MMTS) to test the effect of chemotherapeutic drugs was investigated. Human MCF-7 breast cancer cells were encapsulated in alginate-poly-L-lysine-alginate (APA) microcapsules, and a single multicellular spheroid 150 mu m in diameter was formed in the microcapsule after 5 days of cultivation. The cell morphology, proliferation, and viability of the MMTS were characterized using phase contrast microscopy, BrdU-Iabeling, MTT stain, calcein AM/ED-2 stain, and H&E stain. It demonstrated that the MMTS was viable and that the proliferating cells were mainly localized to the periphery of the cell spheroid and the apoptotic cells were in the core. The MCF-7 MMTS was treated with mitomycin C (MC) at a concentration of 0.1, 1, or 10 times that of peak plasma concentration (ppc) for up to 72 h. The cytotoxicity was demonstrated. clearly by the reduction in cell spheroid size and the decrease in cell viability. The MMTS was further used to screen the anticancer effect of chemotherapeutic drugs, treated with MC, adriamycin (ADM) and 5-fluorouracil (5-FU) at concentrations of 0.1, 1, and 10 ppc for 24, 48, and 72 h. MCF-7 monolayer culture was used as control. Similar to monolayer culture, the cell viability of MMTS was reduced after treatment with anticancer drugs. However, the inhibition rate of cell viability in MMTS was much lower than that in monolayer culture. The MMTS was more resistant to anticancer drugs than monolayer culture. The inhibition rates of cell viability were 68.1%, 45.1%, and 46.8% in MMTS and 95.1%, 86.8%, and 91.6% in monolayer culture treated with MC, ADM, and 5-FU at 10 ppc for 72 h, respectively. MC showed the strongest cytotoxicity in both MMTS and monolayer, followed by 5-FU and ADM. It demonstrated that the MMTS has the potential to be a rapid and valid in vitro model to screen chemotherapeutic drugs with a feature to mimic in vivo three-dimensional (3-D) cell growth pattern.

Influence of different neuroprotective drugs on dopamine neurotoxicity induced by 3,4-methylenedioxymethamphetamine and MPTP in mice

Introduction: Parkinson‟s disease (PD) is characterized by a chronic progressive loss of nigrostriatal dopaminergic neurons that is associated with chronic neuroinflammation. Current treatments for PD can significantly improve symptoms but do not cure the disease or slow its progression. An approach used in existing therapies is based on the inhibition of monoamine oxidase (MAO), enzyme involved in the metabolic degradation of dopamine. Although, preclinical studies showed that MAO-B inhibitors have neuroprotective activity in cellular and animal models of PD, clinical trials did not completely confirm this result. Therefore a large number of new molecules, with more potent MAO-B inhibitory activity and a possible neuroprotective effect, have been proposed to replace the pre-existing MAO-B inhibitors. The profile of the recent MAO inhibitor, SZV558, appears to be particularly interesting because of its pharmacodynamic, favorable for disease-modifying properties and its irreversible MAO-B enzyme bind. The enhancement of adult neurogenesis could be of great clinical interest in the management of neurodegenerative disorders. In line with this, the metformin, a well-known antidiabetic drug, has recently been proposed to promote neurogenesis and to have a neuroprotective effect on the neurodegenerative processes induced by the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in a mice PD model. Although, PD has multiple origins, one hypothesis is that amphetamine-related drugs may be part of the wide array of factors leading to the dopaminergic neuron degeneration that causes the disease. These hypothesis are supported by different results that showed a persistent, long-term dopaminergic toxicity induced by 3,4-methylenedioxymethamphetamine (MDMA) in mice. Moreover, the MDMA, altering the dopaminergic transmission, may affect neurogenesis and synaptogenesis. On these basis, considering that the young brain is particularly sensitive to drug-induced neurotoxicity, the consumption of MDMA during the adolescence might increase the vulnerability of dopaminergic neurons. However, the use of amphetamine-related drugs by adolescent and young people is often combined with caffeinated energy drinks in order to amplify their stimulant actions. Although caffeine use is safe, the combined treatment of caffeine and MDMA increases not only the DA release but also the microglia and astroglia activation. Aims: During my Ph.D. I studied the influence of neuroprotective drugs, such as MAO inhibitors and metformin, or substances, such as caffeine, on the neurodegenerative effects of two dopaminergic toxins, MDMA and MPTP, in mice. 1. In the first phase of my study, I evaluated the neuroprotective activity of the new MAO-B inhibitor SZV558, compared with well-known rasagiline, in a chronic mouse model of MPTP plus probenecid (MPTPp), which induces a progressive loss of nigrostriatal dopaminergic neurons. 2. Previous results showed that when MDMA is associated with caffeine, a more pronounced degeneration in adolescent compared with adult mice was observed. To better clarify the molecular mechanism at the base of the different neurotoxic effect of this drug association at different ages, I evaluated the neuronal nitric oxide synthase (nNOS) expression, which plays a critical role in the integration of dopaminergic and glutamatergic transmissions, in the CPu of adolescent or adult mice treated with MDMA, alone or in combination with caffeine. 3. Finally, I investigated the neuroprotective effect of metformin against dopaminergic neurotoxicity induced by MDMA in the CPu and SNc of adult mice. Conclusions: These results demonstrated that the dopaminergic neurodegenerative process may be induced or conditioned by environment stressors or substances which influence, through different ways, the development of neurodegenerative mechanisms. In the present study I evaluated the effects of 3 substances, known as potentially neuroprotective, in combination with two different neurotoxins that affect the nigrostriatal dopaminergic system. The SZV558 MAO-B inhibitor and the metformin protected the nigrostriatal pathway, usually affected in PD, by MPTP- and MDMA- induced neurotoxicity, respectively. On the other hand, caffeine, administrated with MDMA, showed a neurotoxic potential depending on the age of consumers, confirming the vulnerability of adolescent brain to consumption of drug and substances that affected the dopaminergic system. In conclusion, the study of neurodegenerative processes may be relevant to understand the human pharmacology, the origin and development of neurodegenerative disease and to predict the neurotoxic effect of drug abuse.

Application of mesoporous silica for the oral delivery of poorly water-soluble drugs

The objective of this thesis was to improve the dissolution rate of the poorly waters-soluble drug, fenofibrate by processing it with a high surface area carrier, mesoporous silica. The subsequent properties of the drug – silica composite were studied in terms of drug distribution within the silica matrix, solid state and release properties. Prior to commencing any experimental work, the properties of unprocessed mesoporous silica and fenofibrate were characterised (chapter 3), this allowed for comparison with the processed samples studied in later chapters. Fenofibrate was a highly stable, crystalline drug that did not adsorb moisture, even under long term accelerated storage conditions. It maintained its crystallinity even after SC-CO2 processing. Its dissolution rate was limited and dependent on the characteristics of the particular in vitro media studied. Mesoporous silica had a large surface area and mesopore volume and readily picked up moisture when stored under long term accelerated storage conditions (75% RH, 40 oC). It maintained its mesopore character after SC-CO2 processing. A variety of methods were employed to process fenofibrate with mesoporous silica including physical mixing, melt method, solvent impregnation and novel methods such as liquid and supercritical carbon dioxide (SC-CO2) (chapter 4). It was found that it was important to break down the fenofibrate particulate structure to a molecular state to enable drug molecules enter into the silica mesopores. While all processing methods led to some increase in fenofibrate release properties; the impregnation, liquid and SC-CO2 methods produced the most rapid release rates. SC-CO2 processing was further studied with a view to optimising the processing parameters to achieve the highest drug-loading efficiency possible (chapter 5). In this thesis, it was that SC-CO2 processing pressure had a bearing on drug-loading efficiency. Neither pressure, duration or depressurisation rate affected drug solid state or release properties. The amount of drug that could be loaded onto to the mesoporous silica successfully was also investigated at different ratios of drug mass to silica surface area under constant SC-CO2 conditions; as the drug – silica ratio increased, the drug-loading efficiency decreased, while there was no effect on drug solid state or release properties. The influence of the number of drug-loading steps was investigated (chapter 6) with a view to increasing the drug-loading efficiency. This multiple step approach did not yield an increase in drug-loading efficiency compared to the single step approach. It was also an objective in this chapter to understand how much drug could be loaded into silica mesopores; a method based on the known volume of the mesopores and true density of drug was investigated. However, this approach led to serious repercussions in terms of the subsequent solid state nature of the drug and its release performance; there was significant drug crystallinity and reduced release extent. The impact of in vitro release media on fenofibrate release was also studied (chapter 6). Here it was seen that media containing HCl led to reduced drug release over time compared to equivalent media not containing HCl. The key findings of this thesis are discussed in chapter 7 and included: 1. Drug – silica processing method strongly influenced drug distribution within the silica matrix, drug solid state and release. 2. The silica surface area and mesopore volume also influenced how much drug could be loaded. It was shown that SC-CO2 processing variables such as processing pressure (13.79 – 41.37 MPa), duration time (4 – 24 h) and depressurisation rate (rapid or controlled) did not influence the drug distribution within the SBA- 15 matrix, drug solid state form or release. Possible avenues of research to be considered going forward include the development and application of high resolution imaging techniques to visualise drug molecules within the silica mesopores. Also, the issues surrounding SBA-15 usage in a pharmaceutical manufacturing environment should be addressed.

Breast cancer therapies in development. A review of their pharmacology and clinical potential.

Although the management of breast cancer has improved over the past few decades, it remains an important challenge for the clinician. Cytotoxic chemotherapy and hormonotherapy, when given in the adjuvant setting, have a definitive though modest impact on the outcome of early-stage breast cancer. In metastatic disease, these therapies help to provide substantial palliation of symptoms but have a limited impact on survival. The discovery of vinorelbine and the taxanes, paclitaxel and docetaxel, certainly represented the most encouraging clinical development of the 1980s in breast cancer therapy. Several other new cytotoxic agents have been recognised for their potential in the treatment of this disorder. Many of them are only in a very early phase of their clinical development and it remains to be proven that they will have a major role in daily practice in the near future.

Economics of new oncology drug development.

PURPOSE: Review existing studies and provide new results on the development, regulatory, and market aspects of new oncology drug development. METHODS: We utilized data from the US Food and Drug Administration (FDA), company surveys, and publicly available commercial business intelligence databases on new oncology drugs approved in the United States and on investigational oncology drugs to estimate average development and regulatory approval times, clinical approval success rates, first-in-class status, and global market diffusion. RESULTS: We found that approved new oncology drugs to have a disproportionately high share of FDA priority review ratings, of orphan drug designations at approval, and of drugs that were granted inclusion in at least one of the FDA's expedited access programs. US regulatory approval times were shorter, on average, for oncology drugs (0.5 years), but US clinical development times were longer on average (1.5 years). Clinical approval success rates were similar for oncology and other drugs, but proportionately more of the oncology failures reached expensive late-stage clinical testing before being abandoned. In relation to other drugs, new oncology drug approvals were more often first-in-class and diffused more widely across important international markets. CONCLUSION: The market success of oncology drugs has induced a substantial amount of investment in oncology drug development in the last decade or so. However, given the great need for further progress, the extent to which efforts to develop new oncology drugs will grow depends on future public-sector investment in basic research, developments in translational medicine, and regulatory reforms that advance drug-development science.

The price of innovation: new estimates of drug development costs.

The research and development costs of 68 randomly selected new drugs were obtained from a survey of 10 pharmaceutical firms. These data were used to estimate the average pre-tax cost of new drug development. The costs of compounds abandoned during testing were linked to the costs of compounds that obtained marketing approval. The estimated average out-of-pocket cost per new drug is 403 million US dollars (2000 dollars). Capitalizing out-of-pocket costs to the point of marketing approval at a real discount rate of 11% yields a total pre-approval cost estimate of 802 million US dollars (2000 dollars). When compared to the results of an earlier study with a similar methodology, total capitalized costs were shown to have increased at an annual rate of 7.4% above general price inflation.

Development of universal antidotes to control aptamer activity.

With an ever increasing number of people taking numerous medications, the need to safely administer drugs and limit unintended side effects has never been greater. Antidote control remains the most direct means to counteract acute side effects of drugs, but, unfortunately, it has been challenging and cost prohibitive to generate antidotes for most therapeutic agents. Here we describe the development of a set of antidote molecules that are capable of counteracting the effects of an entire class of therapeutic agents based upon aptamers. These universal antidotes exploit the fact that, when systemically administered, aptamers are the only free extracellular oligonucleotides found in circulation. We show that protein- and polymer-based molecules that capture oligonucleotides can reverse the activity of several aptamers in vitro and counteract aptamer activity in vivo. The availability of universal antidotes to control the activity of any aptamer suggests that aptamers may be a particularly safe class of therapeutics.

Developing drugs for developing countries.

Infectious and parasitic diseases create enormous health burdens, but because most of the people suffering from these diseases are poor, little is invested in developing treatments. We propose that developers of treatments for neglected diseases receive a "priority review voucher." The voucher could save an average of one year of U.S. Food and Drug Administration (FDA) review and be sold by the developer to the manufacturer of a blockbuster drug. In a well-functioning market, the voucher would speed access to highly valued treatments. Thus, the voucher could benefit consumers in both developing and developed countries at relatively low cost to the taxpayer.

Pharmacogenomics in early-phase clinical development.

Pharmacogenomics (PGx) offers the promise of utilizing genetic fingerprints to predict individual responses to drugs in terms of safety, efficacy and pharmacokinetics. Early-phase clinical trial PGx applications can identify human genome variations that are meaningful to study design, selection of participants, allocation of resources and clinical research ethics. Results can inform later-phase study design and pipeline developmental decisions. Nevertheless, our review of the clinicaltrials.gov database demonstrates that PGx is rarely used by drug developers. Of the total 323 trials that included PGx as an outcome, 80% have been conducted by academic institutions after initial regulatory approval. Barriers for the application of PGx are discussed. We propose a framework for the role of PGx in early-phase drug development and recommend PGx be universally considered in study design, result interpretation and hypothesis generation for later-phase studies, but PGx results from underpowered studies should not be used by themselves to terminate drug-development programs.

Bioengineered human myobundles mimic clinical responses of skeletal muscle to drugs.

Existing in vitro models of human skeletal muscle cannot recapitulate the organization and function of native muscle, limiting their use in physiological and pharmacological studies. Here, we demonstrate engineering of electrically and chemically responsive, contractile human muscle tissues ('myobundles') using primary myogenic cells. These biomimetic constructs exhibit aligned architecture, multinucleated and striated myofibers, and a Pax7(+) cell pool. They contract spontaneously and respond to electrical stimuli with twitch and tetanic contractions. Positive correlation between contractile force and GCaMP6-reported calcium responses enables non-invasive tracking of myobundle function and drug response. During culture, myobundles maintain functional acetylcholine receptors and structurally and functionally mature, evidenced by increased myofiber diameter and improved calcium handling and contractile strength. In response to diversely acting drugs, myobundles undergo dose-dependent hypertrophy or toxic myopathy similar to clinical outcomes. Human myobundles provide an enabling platform for predictive drug and toxicology screening and development of novel therapeutics for muscle-related disorders.