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several tourist destinations in Manila of Philippines

The same things and places of the impact on different people imposing different. This is the reason someone else's trip can’t be copied, but also the charm of travel. Some people say that want to travel but do not know where to go. You can do a plan for a charming Philippine trip.There are several tourist destinations in Manila of Philippines.

Rizal Park is located in the heart of the city of Rojas, facing Manila Bay. There is a large fountain in the park, the heart of Manila residents rest. Rizhao Park flowers, green grass, quiet environment, sea breeze, is a good place for people to relax. The center of the park is erected with the bronze statue of José Rizal, the hero of the independent movement of the Philippines, where visitors can see the location of the island's 7107 islands. There are international gardens dedicated to planting Chinese, Japanese and Italian flowers on the north side. Twice a day of audio-visual performances, but also attracted the attention of many tourists. Many people came to watch a special trip. When the sunset, the sky color of the sea will be dyed golden brown, the shore of the coconut palms in the sea breeze blowing swaying, with the sunset, the sea matched, constitute a vigorous natural oil painting.

The Basilica Minore del Santo Nino was built in 1565 and is famous for its «holy baby» collection. It is said that when the indigenous patriarch Rajah Humabon and his wife Queen Juana were baptized, Magellan presented a black-skinned «holy image» to Queen Juana as a gift. 1565, Cebu fire Liaoyuan, April 27 a fire to Cebu razed to the ground, only this «holy baby like» intact, the locals call it miracles, and worship.

Wangcheng is located on the Pasig River, also known as the city center. Although some of the city walls have been decadent, but the distribution of the colonial atmosphere is its charm. In 1571 the Spaniards built the castle in order to rule the Philippines, an area of 1 square kilometers, known as the «urban city». The castle is surrounded by trenches and medieval walls, a total of seven gates, the city has a governor's residence and 12 churches. At the end of World War II, most of the castle was destroyed and now part of the repair. Here you can feel the time back, the old carriage to take visitors to travel in the streets, customs, ports, city walls, visiting a circle as if the 400 years of history of Manila old city tour it again. Here exudes the elegant atmosphere of Spain, retaining the ancient architectural features.

Pharmacokinetic-based drug design tool and method

Medicilon's structural biology department offers services supporting structure-based drug discovery from determination of novel targets to final structures. Our platform is one of the earliest established structural biology platforms in China and has been certified by the Shanghai Government. Email:[email protected] web:www.medicilon.com
The present invention relates to a pharmacokinetic-based design and selection tool (PK tool) and methods for predicting absoption of an administered compound of interest. The methods utilize the tools, and optionally a separately operable component or subsystem thereof. The PK tool includes as computer-readable components: (1) input/output system; (2) physiologic-based simulation model of one or more segments of a mammalian system of interest having one or more physiological barriers to absorption that is based on the selected route of administration; and (3) simulation engine having a differential equation solver. The invention also provides methods for optimizing as well as enabling minimal input requirements a physiologic-based simulation model for predicting in vivo absorption, and optionally one or more additional properties, from either in vitro or in vivo data. The PK tool of the invention may be provided as a computer system, as an article of manufacture in the form of a computer-readable medium, or a computer program product and the like. Subsystems and individual components of the PK tool also can be utilized and adapted in a variety of disparate applications for predicting the fate of an administered compound. The PK tool and methods of the invention can be used to screen and design compound libraries, select and de novo design drugs, as well as predict drug efficacy in mammals from in vitro and/or in vivo data of one or more compounds of interest. The PK tool and methods of the invention also find use in selecting, designing, and preparing drug compounds, and multi-compound drugs and drug formulations (i.e., drug delivery system) for preparation of medicaments for use in treating mammalian disorders.
The input/output system, simulation engine and simulation model of the PK tool are capable of working together to carry out the steps of (1) receiving as input data, the initial dose of a test compound at the site of administration and permeability and solubility, and optionally dissolution rate and transfer mechanism data; and (2) applying the simulation engine and the simulation model to generate as output data a simulated in vivo absoφtion profile for the test compound that reflects rate, extent and/or concentration of the test sample at a given sampling site for a selected route of administration in a mammalian system of interest. This includes uni- and multidimensional output profiles that collectively reflect parameters of absoφtion, which can be directly or indirectly utilized for characterizing in vivo absoφtion, as well as one or more additional bioavailability parameters including distribution, metabolism, elimination, and optionally toxicity.
The selected routes of administration include enteral (e.g., buccal or sublingual, oral (PO), rectal (PR)), parenteral (e.g., intravascular, intravenous bolus, intravenous infusion, intramuscular, subcutaneous injection), inhalation and transdermal (percutaneous). The preferred route of administration according to the method of the invention is oral administration. The selected route of administration determines the type and/or source of assay or structure-property parameters employed for obtaining a set of input data utilized for generating a simulated in vivo absoφtion profile. That is, artificial, cell or tissue preparations and the like derived from or representative of a physiological barrier to absoφtion for a selected route of administration are chosen to generate the relevant input data for use as input into the PK tool. For instance, input data for simulating fate of a test sample following oral administration can be based on cell culture and/or tissue assays that employ biological preparations derived from or representative of the gastrointestinal tract of a mammal of interest, e.g., gastrointestinal epithelial cell preparations for permeability and transfer mechanism data, and physiological/anatomical fluid and admixing conditions corresponding to the relevant portions of the gastrointestinal tract for solubility and dissolution rate assays. Assays for collecting input data for specialized physiological barriers such as the blood brain barrier may initially assume intravascular delivery and thus instantaneous absoφtion as a first step. In this situation an assay is selected to generate input data relative to the blood brain barrier, which include for instance cell culture and/or tissue assays that employ biological preparations derived from or representative of the interface between systemic blood and the endothelial cells of the microvessels of the brain for a mammal of interest, e.g., blood-brain-barrier microvessel endothelial cell preparations for permeability and transfer mechanism data, and physiological/anatomical fluid and admixing conditions corresponding to the relevant portions of the blood membrane barrier for solubility and dissolution rate assays. A series of assays may be employed to collect input data for two or more barriers to absoφtion. As an example, oral, hepatic, systemic and blood brain barrier assays may be utilized to obtain input data for screening compound libraries for orally delivered compounds that target brain tissue.
The sampling site relates to the point at which absoφtion parameters are evaluated for a test sample of interest. This is the site at which rate, extent and/or concentration of a test sample is determined relative to a selected site of administration, and is separated from the site of administration by at least one physiological barrier to absoφtion. For generating simulated absoφtion profiles, the sampling site preferably is separated from the site of administration by an individual primary barrier to absoφtion, which can be utilized to evaluate additional absoφtion events by secondary barriers to absoφtion so as to sequentially and collectively reflect the summation of absoφtion events at other sampling sites of interest. As an example, the sampling site selected for oral delivery may be the portal vein where the primary barrier to absoφtion is the gastrointestinal lumenal membrane, or systemic blood where a secondary barrier to systemic absoφtion is the liver after the test sample passes from the portal vein through the liver to systemic circulation. Thus the type of physiological barrier(s) residing between a site of administration and a sampling site reflects the type of assay(s) employed for generating the desired input data for use as input data into the PK tool of the invention.
As the selected route of administration determines the barrier(s) to absoφtion and the physiological parameters that affect absoφtion events following administration, it also determines the physiologic-based pharmacokinetic simulation model employed in the PK tool for generation of the simulated in vivo absoφtion profile. By way of example, if the proposed route of administration is oral, then a primary barrier to absoφtion is the lumenal membrane of the gastrointestinal tract, and a secondary event affecting systemic bioavailability is first pass metabolism by the liver. Thus, a given simulation model and its associated parameters for simulating the fate of a compound selected for oral delivery is chosen to represent this scenario. The model would include therefore relevant components of the gastrointestinal tract for administration and absoφtion (i.e., stomach, duodenum, jejunum, ileum, and colon) and a primary sampling site (i.e., portal vein) from which to evaluate a primary absoφtion event. In this instance a secondary barrier to absoφtion for oral delivery is the liver and a secondary sampling site is systemic blood/plasma. This basic approach to choosing a physiologic-based pharmacokinetic model also applies to models employed to simulate absoφtion by target organs and the like, where a physiological barrier to absoφtion is the tissue and/or membrane separating systemic blood from the target organ, such as the blood brain barrier. In this situation if oral delivery is selected as the preferred route of administration for a compound targeting brain tissue, then a gastrointestinal tract model and blood brain barrier model may be implemented separately and or combined through a complementary plasma component of the models for screening puφoses.
The physiological models are selected from a repository of delivery route- specific models stored in a memory, a database, or created de novo drug. Physiological models of the invention include those corresponding to common routes of administration or barriers to absoφtion, such as oral, ocular (eye), transdermal (skin), rectal, intravenous, rectal, subcutaneous, respiratory (nasal, lung), blood brain barrier and the like. For constructing a model de novo, the basic approach is to identify and isolate a primary barrier to a specific absoφtion event from secondary events so that each barrier to absoφtion can be tested and validated in isolation. This involves selecting a site of administration that is separated from a sampling site by a primary physiological barrier to absoφtion and then building a developmental physiological model that incoφorates rate process relations and limitations to describe the isolated absoφtion event. If desired, the secondary events can be added sequentially so that each additional layer of complexity to the model can be tested and validated in isolation from other components of the initial model.
The invention also relates to a method and PK tool for designing compounds based on absoφtion. This aspect of the invention utilizes output of the method and PK tool as the input to a structure-activity relationship (SAR) or quantitative SAR (QSAR) design/selection process, e.g., a SAR and/or QSAR computer-assisted design engineering/selection process. Output of the CAD process is then optionally used as input for the method and PK tool of the invention. SAR and QSAR information may then be incoφorated into a database for subsequent iterative design and selection in the CAD process. For instance, compounds designed using a CAD process may be tested in vitro and/or in vivo for absoφtion parameters such as permeability, solubility, dissolution, and transport mechanism, and optionally one or more additional bioavailability parameters, and the data employed as input into the PK tool and method of the invention (i.e., iterative design). Alternatively, the parameters can be predicted from SAR or QSAR information and utilized as input for the method and PK tool of the invention. In this aspect of the invention, the user also is allowed to vary input parameters for «What if analysis.

A portion of the disclosure of this patent document contains materia

Medicilon's structural biology department offers services supporting structure-based drug discovery from determination of novel targets to final structures. Our platform is one of the earliest established structural biology platforms in China and has been certified by the Shanghai Government. Email:[email protected] web:www.medicilon.com
A method of and apparatus are disclosed for evolving successive populations of molecular structures and evaluating each evolved structure of each population with desired physical and/or theoretical properties. An initial population of molecules is provided in terms of representations of a number of member molecules. Evaluation is performed by a fitness function, which compares the initial population and evolved generations of member representations with the set of desired properties to provide a numerical measure or value of fitness for each structure. That numerical value indicates how closely the compared member representation corresponds with the set of desired properties. The next population is generated by changing the structure of selected molecules of a population dependent upon the numerical measure of fitness, and the process repeats. Subsequent populations evolve towards ever-better fitness. The process is terminated when an acceptable molecule evolves.
A portion of the disclosure of this patent document contains material which is subject to copyright protection. The copyright owner has no objection to the facsimile reproduction by anyone of the patent document or the patent disclosure, as it appears in the Patent and Trademark Office patent file or records, but otherwise reserves all copyright rights whatsoever.
Many approaches have been used to discover new chemicals, which are suitable for particular purposes. Although most of this methodology has been directed at drug discovery, there are examples in almost every chemical field: agrochemicals, engineering (materials), fuels, perfumes, cosmetics, photography, semiconductors, non-linearoptics, and others. The goal of chemical discovery is to find chemicals, which have specific reactivities, biological activities, chemical and/or physical properties. In general, none of the available methods are considered satisfactory.
Chemical discovery methods fall into two general categories: random screening and rational design. Random screening methods are based on the ability to screen a very large number of compounds quickly with the goal of finding one or more «lead» compounds for further testing and refinement (typically by rational design). Disadvantages of random screening are that it is extremely expensive and its probability of success is relatively low. Most companies engaged in chemical discovery use random screening because it has the best track record historically and, for many problems, it is the only feasible approach. Random screening experiments often have a minor «rational» component, e.g., chemicals screened are not truly random, but are picked to be representative of a larger set of compounds.
Rational design is based on the ability to rationalize the activity of various chemicals in terms of their molecular structure. Attempts to build a rigorous framework for this purpose date back to 1930's, e.g., see «History and Objectives of Quantitative Drug Design», by Michael S. Tute, Comprehensive Medicinal Chemistry, pub. Pergamon Press plc, ISBN 0-08-037060-8, 1990. The field developed rapidly in the early 1960's with the advent of the QSAR (Quantitative Structure-Activity Relationship) method developed by Corwin Hansch. With QSAR, the activity of a molecule is related statistically to the position and physical parameters of its functional groups. A great deal of further development has been done along these lines. Along with the ability to visualize three-dimensional (3-D) structures using computer graphics systems, this has led to the field known as «molecular modeling».
Comprehensive Medicinal Chemistry, Vol 4 Quantitative Drug Design, (1990) provides a good description of the current state of the art. Overall, the methods that have been developed are techniques for analysis rather than discovery. Much work has been done on predicting how a new molecule will behave. Refining lead structures has received a great amount of attention. There has been little work done on methods which suggest new molecules from an universe of all possible molecules. The reason that there are no methods for direct chemical discovery is that the problem has appeared to be intractable. Even for a very limited chemical classes, there is an enormous number of molecular structures possible.
Current successful approaches for computer assisted methods of designing molecules include the DOCK program, which is described in, «A geometric approach to macromolecule--ligand interactions», I. D. Kuntz, J. M. Blaney, S. J. Oatley, R. Langridge, T. E. Ferrin, J. Mol. Biol., 161, 269 (1982); the GROW PROGRAM, which is described in «Computer design of bioactive molecules: a method for receptor-based de novo ligand design», J. B. Moon and W. J. Howe, Proteins: Struct. Funct. Genet., 11, 314 (1991); and the LUDI program, which is described in «The computer program LUDI: A new method for the de novo drug design of enzyme inhibitors», H. J. Bohm, J. Comp.-Aided Mol. Design, 6, 61 (1992). DOCK selects from a database molecules, which are complementary in shape and electrostatics to a receptor or active site, and has successfully identified lead compounds in several different drug discovery projects. DOCK relies on a predetermined database of chemical structures and does not perform de novo design. LUDI uses a database of chemical fragments and heuristic rules about fragment-receptor complementarily and geometry to assemble molecules that fit a receptor or active site. GROW assembles peptides from a database of amino acid sidechains into a binding site and has successfully grown peptides that bind tightly to a few different enzymes. These three approaches are the most ambitious and successful to date, but still fall short of the goal of true de novo design of molecules with no or limited constraints, e.g., synthetic feasibility, that fit a specific receptor site optimally.

Rainbow Village of Indonesia

We need to travel. If you do not touch the unknown, the feeling will become slow, our world is so little a little, even the curiosity will disappear. Life day after day, but also limited our experience of life, one day you will find that the life of this life is to have the dream as a price. Travel let us see more exciting scenes, Indonesia's poor villages can actually become a tourist attraction, and become a rainbow village in Indonesia.

Recently, a small village in Indonesia on the social networking site became popular. The village was once an unknown village in Lansa, the province of Islam, and now through the efforts of local residents and the government, it turned into a dazzling «Rainbow Village», attracting tourists from all over the world.

It is reported that the local residents spent 300 million Indonesian rupees to transform the village into a tourist attraction, visitors gradually increased. Local residents hand drawn 232 houses of the bare wall, after more than a month to complete, which the old little village into a dazzling «rainbow village», and therefore in the social media on a hit. «There are at least three colors in a house,» said the head of the department's department, «the locals are taking advantage of this opportunity to sell the local specialty to visitors who have visited it.» Now more than 230 houses have been completed. The Indonesian Building Association near Sambo City provided manpower and material support for the village.

This whimsical design project is run by 54-year-old junior high school principal of Slamet Widodo. The design took into account the renovation of at least three towns, using paint painting to transform at least 232 houses into works of art, use creative frescoes to rupture walls and narrow corridors, and to energize the entire village.

This once slum has become a tourist attraction in Indonesia, beautiful colors to attract people from all over the world came here. Gapensi Semarang, head of the arts and culture and sports department of the region, added: «Every house here is at least three colors, and we work with the road bureau, the bureau and other agencies to help develop Kampung.

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