text:
December 2004 Central limit theorem for sequential Monte Carlo methods and its application to Bayesian inference
Nicolas Chopin
The term "sequential Monte Carlo methods" or, equivalently, "particle filters," refers to a general class of iterative algorithms that performs Monte Carlo approximations of a given sequence of distributions of interest (πt). We establish in this paper a central limit theorem for the Monte Carlo estimates produced by these computational methods. This result holds under minimal assumptions on the distributions πt, and applies in a general framework which encompasses most of the sequential Monte Carlo methods that have been considered in the literature, including the resample-move algorithm of Gilks and Berzuini [J. R. Stat. Soc. Ser. B Stat. Methodol. 63 (2001) 127–146] and the residual resampling scheme. The corresponding asymptotic variances provide a convenient measurement of the precision of a given particle filter. We study, in particular, in some typical examples of Bayesian applications, whether and at which rate these asymptotic variances diverge in time, in order to assess the long term reliability of the considered algorithm.
Nicolas Chopin. "Central limit theorem for sequential Monte Carlo methods and its application to Bayesian inference." Ann. Statist. 32 (6) 2385 - 2411, December 2004. https://doi.org/10.1214/009053604000000698
Primary: 60F05, 62F15, 65C05
Secondary: 62L10, 82C80
Keywords: Markov chain Monte Carlo, particle filter, recursive Monte Carlo filter, resample-move algorithms, residual resampling, state-space model
Nicolas Chopin "Central limit theorem for sequential Monte Carlo methods and its application to Bayesian inference," The Annals of Statistics, Ann. Statist. 32(6), 2385-2411, (December 2004)


text:
Q: Subversion + Some other VCS (Git, Hg, etc) in the same working copy Here's the deal:
I just started a new job, and source control here is basically useless.
All of the devs (about 10 guys) test their code in the same dev site, and there's no way to test a change other than commiting the change to SVN, and then it automatically gets updated in the dev site. (Let's not even start talking about the headaches when someone else breaks something, and you have to figure why your stuff is now not working....)
So instead of doing like Ctrl+S, and refreshing the browser to see my changes, you have to Ctrl+S, svn commit, refresh the page.
Of course since everyone has to do this a million times every day, there's never any commit messages, so the svn history is useless.
Anyhow, since I'm the new guy, for now, for my own sanity, I want to use some other source control system locally, so that I can commit projects atomically, and be able to roll back easily.
Is it possible to use for example mercurial at the same time as svn?
I would use svn basically to see my changes, and mercurial to keep track of my changes.
Any alternative ideas are welcome too.
Thanks!
UPDATE-
Thanks for all the answers.
Unfortunately, none really suit me in this situation. Maybe I didn't explain it right.
I don't want sync between repos. What I need is to be able to have like two different repository checkouts living in the same place.
So if I do svn status I'm comparing against the regular company repo. But if I do hg status I'm comparing against my own personal repo to help me stay sane.
Thx guys

A: For Mercurial Stack Overflow has a guide which describes Subversion interaction choices in detail.  There are three current methods: hg convert, hgsubversion, and hgsvn.  See the guide for details.
(My own two cents is that hgsubversion doesn't handle all repositories properly but, when it does, handles them very smoothly.  When it doesn't I've had some success with hgsvn.)
UPDATE:
You said:

"Thanks for all the answers. Unfortunately, none really suit me in this situation. Maybe I didn't explain it right. I don't want sync between repos. What I need is to be able to have like two different repository checkouts living in the same place. So if I do svn status I'm comparing against the regular company repo. But if I do hg status I'm comparing against my own personal repo to help me stay sane."

Ah, I see.  In simplest terms, yes. but you probably don't want to.  You can checkout from Subversion, manually copy over your .hg directory from your Mercurial tree, and run commands from each.  You almost certainly want tosvn ignore the .hg* files and add **.svn to your .hgignore.  But you don't really want to do this unless the checkout is not being edited by you other than to occasionally svn update or hg pull from the original repositories.  If you are also doing edits you will make a mistake and you will end up with something checked in to one or the other repository that you didn't want there.
If I understand you correctly you would still benefit from using one of the Mercurial-Subversion bridges.  You can for example quite easily with hgsubversion do hg status to compare with your local Mercurial repository, and hg svn status to compare to the remote Subversion repository.  Even if you don't sync, and you just compare your files to one repository and the other, it's still much better to have a system that understands both, and won't spill unwanted state from one VCS into the other.

A: git svn is your friend.
git svn clone repository_url
# edit
git commit
# edit
git commit
# send all your changes to remote svn
git svn dcommit

A: You could use git, bazaar or mercurial along side of svn, though you would want to be sure that you exclude the .svn directories from your new scm, and vice versa so that they dont track each others meta data.
As far as IDE support, I know Eclipse will only let you have one active source control at a time. I am not sure about NetBeans or IntelliJ. In that case you could have the IDE control the svn and do yours from the command line.
Another option you might want to look into is branching with svn... could you not work from a branch locally and then merge into the common mainline as needed? That might just cause more pain.
Good luck and sorry to hear about your situation.

A: The hgsubversion extension to mercurial allows you to use mercurial as a svn client in the same way git svn does.
hg clone svn+http://python-nose.googlecode.com/svn nose-hg

after that your pushes and pulls will automatically go to/from the remote svn server too.

A: You could use git locally to manage your own changes, and then use git-svn to pull/push those changes to SVN.  http://flavio.castelli.name/howto_use_git_with_svn

A: You can use multiple VCSes in one working copy.  I tested both bazaar and git in one working copy which was actually tracked with SVN (my then main VCS).  So, I had a .svn, a .bzr and a .git directory in there.  No trouble at all.  Of course, smart ignore settings are needed.

redpajama_set_name: RedPajamaStackExchange


An incredibly powerful tool for finding and then converting ideal prospects remains the humble newsletter.
You can build, and maintain, top of mind brand awareness with it. You can establish or reinforce expert positioning with it. Your reach can be extraordinary – particularly so with an e-zine or email-based newsletter.
In the digital age it can – if done well – become almost viral. A small one-man-band can within a year have 1,600 target market prospects engaged by using a carefully structured and well positioned newsletter. All this for less than $4,000 per year. I am not making that number up: that is what happens in my business, with a newsletter.
That is a $2.50 cost per year per prospect that I am actively engaged with. And they are engaged because they choose to be. They are good prospects.
Now if that cost seems high to you then it is because I send a newsletter every 3 weeks. That's right – just 16 per year (we do have a little scheduled break over the Christmas season). It might seem a lot, but my target market live in an information filled world – they spend hours each day reading. So in order to simply be present and create that top-of-mind-awareness I have to be there regularly…but without being a pest about it.
The frequency of a newsletter is one of the factors that is critical to success, and finding that balance between being a nuisance and maintaining a presence with relevant information can be tricky. But if you know your target market well, and know what their issues and work habits and needs are, then you won't have too much trouble working out what the right balance is. Just put yourself in their shoes: what would you think is appropriate?
Not too many years ago all of this was an incredibly laborious task. It was drudgery. Running a bigger crew, with about 6,000 clients, and firmly committed to sending 3 newsletters per year. Just 3. But we'd spend hours and hours thinking and writing stuff, eventually settle on something and send it off to the printers. About a week later we would receive heaps of boxes of beautifully printed newsletters – thousands of them! Of course we hadn't been idle during the week the printers were doing their thing – we were printing up labels for every client, ordering in boxes of envelopes and then getting all the labels put on….and when the newsletters arrived we'd gather the entire office team around a few bottles of wine on a Friday afternoon and begin folding and stuffing envelopes….ah the good old days!
Little wonder that so many advisers veered away from committing to providing regular newsletters. And I am continually surprised at how few provide newsletters today. Of those advisers who DO actually provide newsletters, the blandness and lack of practical information that their prospects can use is striking. And all too often those who are using newsletters do not deliver consistently….they get a little lackadaisical on frequency.
If you have actually committed to providing regular service and contact with a newsletter, and are positioning to be THE person they turn to when they have money questions, why would you then deliver an infrequent service? How can they trust you to deliver on everything else you promise?
And if you provide generic, bland, economic drivel that they have already had flash across all of their device screens 2 weeks ago…well…how valuable are you to them? Yet so many of the few who do provide regular content do precisely that, and it makes no sense. Instead of being the "go to" with the answers to their problems, you become the specialist in yesterdays boring news stories.
It doesn't need to be like that at all because it is SOOOO easy...and so valuable if done correctly. It is easy to find interesting, quirky, fun stuff that is useful or entertaining. It is easy to produce content to reinforce your expertise and positioning. It is easy to find soothsayers predicting the future…it is actually easy to find anything to fit the approach and positioning you want to create. In fact it is because we (and our prospects) are swamped with content choices that you have the opportunity to be a trusted voice by delivering practical and on-point information that can make a difference to them. THAT is valuable to prospects.
Get the content right and maintain a consistent presence and you find that people share, refer friends, forward the newsletter to multiple addresses, click to share on social media….the market reach is extraordinary.
1. You don't have to write anything actually. Simply curate great content which is relevant for your audience.
2. The things you talk about all the time to existing clients will be of interest to other potential clients. If you find yourself having similar conversations with different clients – you have something to write about because it will appeal to other target market prospects, and it will appeal to many other clients.
3. There are some pretty safe and basic principles when it comes to working out what people like to read.
Having figured out what you are going to write about, it is not that hard to work out how to do it. Look at the image at the top of this post that was chosen deliberately. Begin with What, and work your way around in a clockwise fashion.
What do you want to be known for? That is, what position, or expertise are you trying to establish?
Who is it for? Who is the audience that you are trying to appeal to?
Why are you doing it? Your purpose (new leads; new sales; service; brand positioning; whatever…) will determine the style and approach.
Where does it fit in with all the other information they are exposed to? Do you want it to fit in, or to be deliberately different to other information they receive?
When is it going to be sent? The frequency, regularity, time of the day…they all matter to the impact and effectiveness.
How are you going to execute the strategy? What is needed; who is going to do what; what can be outsourced…or not….but how are you going to achieve it the strategic goal?
That is about all there is to it really.
Email newsletters remain one of the most under-utilised methods of social networking engagement with clients; one of the most cost effective; and one of the most effective prospecting tools available today. And in the age of compliance and audit trails, they can be quite magical in terms of demonstrating a level of customer service and the offer of ongoing advice.
Know your market well and it will be easy enough to work out what is the right balance, and what is relevant and meaningful content that they will pause and pay attention to (more often than not).
Prospecting is so hard that once you have a good one then it seems to make commercial sense to me to invest about $2.50 a year to stay engaged with them – that's loads cheaper than doing new advertising or marketing.
Besides….so few of your competitors are doing it well, so there is probably a great opportunity to grab their prospects too….
Great post Tony – done well, email newsletters are extremely powerful and the annualised cost is generally cheaper than one old snail mail letter.


Posted: Sat Aug 30, 2008 1:38 am Post subject: What Time Is It, In Ur World?
Its 3:37 am......tme 4 bed....gettng sleepy.
Wheelchair races.... Right. You have a fun imagination but I'm not likely to do them unless I really wanted to but I'm not THAT adventuress it could be called violation of property and being a ratbag really so.... It's not me hehe.
So, I went 2 bed @ 4:30 am lst nite....it ws fun.


text:
Q: How many colours do we at least need so that we can ensure all 250 countries have different flags. One for FN standardized flag consists of three horizontal rectangular fields.
If we assume that the middle field not are allowed to have the same colour
as the top or bottom field, how many colours do we at least need to be sure
that we can ensure that all $250$ countries have different flags.
My attempt at a solution:
If the number of colours are $f$, then the top field can consist of
$f$ different colours, the middle field $f-1$ and the bottom field $f-1$.
Hence, in total $f(f-1)^2$ colours.  We have that
$f(f-1)^2 > (f-1)^3$ and because $5^3 < 250 < 6^3$ we can be sure
if $f -1 = 6$, i.e. $f=7$.

A: You are correct that if there are $f$ colors available, then the number of different flags in which the middle field is not the same color as the top or bottom field is $f(f - 1)^2$.  Therefore, we require that $f(f - 1)^2 \geq 250$.
\begin{array}{c | c}
f & f(f - 1)^2\\ \hline
1 & 0\\
2 & 2\\
3 & 12\\
4 & 36\\
5 & 80\\
6 & 150\\
7 & 252
\end{array}
From the table, we see that the smallest value of $f$ that satisfies the inequality is $7$.
You attempted to estimate this value by using the observation that $f(f - 1)^2 \geq (f - 1)^3$.  You then wrote $5^3 < 250 < 6^3$, from which you concluded that we can be sure that if $f - 1 = 6$, then we have enough different flags, which led you to the correct conclusion, but your reasoning was incorrect.  Actually, $6^3 = 216 < 250 < 343 = 7^3$. If $f - 1 = 7$, then we may conclude that
$$250 < 7^3 = (f - 1)^3 < f(f - 1)^2 = 8(8 - 1)^2 = 392$$
that is, we may conclude that $8$ is an upper bound on the number of colors we need.  However, the calculations above show that $f = 7$ is sufficient.

A: So for the top and bottom we have $x$ colors. For the middle we can put all these colors but we must exclude on color in order to match requirements and not to go like $AAA$.
So sipmly: $x\cdot (x-1)\cdot x \geq 250$, $x\geq 7$.


text:
RussianPatents.com
New! → US patents search
Patent registration
Macrocyclic lactone, a pharmaceutical composition having antibiotic activity, and insecticide and acaricide composition
C07D493/22 - in which the condensed system contains four or more hetero rings
C07D315 - Heterocyclic compounds containing rings having one oxygen atom as the only ring hetero atom according to more than one of groups ; C07D0303000000-C07D0313000000
A61K31/71 -
A61K31/70 - Carbohydrates; Sugars; Derivatives thereof (sorbitol A61K0031047000)
A61K31/365 -
A01N43/90 - having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
(57) Abstract:
The compounds of formula (II):
< / BR>
and their salts, where R1represents methyl, ethyl or isopropyl group; OR4represents a hydroxyl group or a substituted hydroxyl group containing up to 25 carbon atoms. These compounds are used as antibiotics against Nemtsov or for pest control. 3 S. and 2 C.p. f-crystals, 3 tables.
The invention relates to new compounds of the antibiotic.
In the description of the patent in the UK N 2166436 considered getting antibiotics S541, which can be distinguished from the products of fermentation of Streptomyces species. Antibiotics S541 are a group of related compounds having the partial formula (I)
So, as presented in this description, identified an additional group of compounds with antibiotic activity, which can be obtained by separating them from the culture of microorganisms of the genus Streptomyces. The new compounds of the invention possess antibiotic activity and/or are used as intermediate products in the production of other active compounds and/or selecting or clearing the compounds ant is in S541.
Thus, in one embodiment, the invention proposes, in particular the compounds of formula (II)
where R1represents methyl, ethyl or isopropyl group; OR4represents a hydroxyl group or a substituted hydroxyl group having up to 25 carbon atoms and a salt thereof.
In the above compounds of formula (II) R1is preferably ISO-propyl group.
Group-OR4in the compounds of formula (II) is preferably a hydroxyl group.
Important active compounds of the invention are the compounds of formula (II) in which R1is methyl, ethyl or, in particular ISO-propyl group, R2and OR4represents a hydroxyl group.
Especially important active compounds of the invention are the compounds of formula (II) in which R1is ISO-propyl group, OR4represents a hydroxyl group.
As indicated, the compounds of the invention can be used as antibiotics and/or as intermediate compounds for other active compounds and/or selecting and clean the AMB as intermediates, -OR4can be protected hydroxyl groups. It is clear that such a group must have a minimum number of additional functional groups to avoid further reaction of the circuit should be such that it became possible to selectively restore from it a hydroxyl group. Examples of hydroxyl protective groups are known and described ("Protective groups in organic synthesis" in "Protective group in Organic Sinthesis" by Theodora W. Greene. Wiley-Interscience, New York, 1981; "Protective groups in organic chemistry" -"Protective group in Organic Chemistry" by J. F. W McOmie. Plenum Press, London, 1973).
Examples OR4protected hydroxyl groups include phenoxyacetate, similarsites, (for example, trimethyl-similarsearch and tert-butyldimethylsilyloxy), and silyloxy, for example, trimethylsilyloxy and tert-butyldimethylsilyloxy. The proposed compounds containing such groups will mainly be used as intermediate compounds.
The claimed compounds have antibiotic activity, for example, deworming, for example, against nematodes, in particular anti-endoparasites and anti-ectoparasitic activity.
Ectoparasites and endoparasites infecting people and a sheep, cattle, goats and poultry, horses and companion animals such as dogs and cats. Parasitic infection of livestock, leading to anemia, malnutrition and weight loss, is a major cause of economic losses worldwide.
Representatives of endoparasites infecting these animals and/or people are Ancylostoma, Ascaridia, Ascamis, Aspicularis, Brugia, Bunostomum, Capillavia, Chabertia, Cooperia, Dictyocaulus, Pirofilaria, Dracunculus, Enterobius, At, Hetevakis,Loa, Necator, Nmatodirus, Nmatospiroides, Heligomoroides, Nippostrongylus, Oesophagostomun, Onchocevca, Ostertagia, Oxyuvis, Pavascavis, Strongylus, Strongyloides, Syphacia, Toxascavis, Toxocava, Trichonema, Trichostrongylus, Trichinella, Trichuris, Uncinavia and Wuchaveria.
Examples of parasites that infect animals and/or people are arthropod ectoparasites, e.g., stinging insects, padolina fly, blocks, lice, ticks, sucking insects, ticks, and other two-winged insects.
Examples of these types of parasites that infect animals and/or people are Ambylomma, Boophilus, Chorioptes, Culliphore, Demodex, Demallenia, Dermatobia, Gastrophilus, Haematobia, Haematopinus, Haemophysalis, Hyalomma, Hyperderma, Ixodes, Linognathus, Lucilia, Melophagus, Oestrus, Otobius, Otodectes, Psorergates, Psoroptes, Rhipicephalus, Sarcoptes, Stomoxys and Tabanus.
Found that the proposed compounds have been effective both in vitro and in v active against nematodes, such as At the contortus, Ostertagia circu mcincta, Jrichostronyglus colubiformis, Dictyocaulus viviparis, Cooperia oncophera, ostertagia ostertagi, Nematospiroides dubues and Nippostrongylus braziliensis, and parasitic mites, such as Savcoptes sp. and Psoroptes sp. Thus, the proposed compounds find use in the treatment of animals and people with endoparasites and/or ectoparasitic infections.
Parasites vary in accordance with the host (animal) and the predominant site of infection. Therefore, for example, agents At contortus, Ostertagia circumcincta and Trichostrongylus colubiformis usually infect sheep and mostly localized in the stomach and the small intestine, while Dictyocaulus vivipavus, Cooperia oncophora and Ostertagia ostertagi usually infect cattle and mainly localized in the lungs, the intestines or the stomach, respectively.
The antibiotic activity of the proposed compounds can be demonstrated, for example, by their activity in vitro against free living of nematodes, for example, Caenorhabiditis elegans.
In addition, the claimed compounds are used as antifungal substances, for example, against such strains of Candida, such as Candida albicans and Candida glabvata, and yeasts, such as Sacchavomyces covls bergensis.
Join izobretatelnosti, forestry, health care and storage products. They can successfully handle pests, soil and agricultural crops, including cereals (e.g. wheat, barley, maize, rice), vegetables (e.g., soy), fruits (such as apples, grapes and citrus), along with root crops (e.g. sugar beet, potatoes). Typical examples of such pests are fruit mites and aphids, for example, Aphisfalue, Aulacorthum circumflexum, Myzuspersical, Nephotettix cincticeps, Nilpawata lugens, Panonychus ulmi, Phorodonhumuli, Phyllocoptruta oleivora, Tetramychus urticae and representatives of the genus Trialeuroides nematodes, for example, representatives of the genus Aphelencoides, Olobodera, Heterodera, Meloidogyne, and Panagrellus scaly, for example, Heliothis, Plutella and Spodpotira weevil-calandrino, such as Anthonomus grandis and Sitophilus granarius the larval flour, for example, Tribolium castoneum flies, for example Musca domestica ants Richter; moth-miners/number, such as Pear psylla; the tobacco thrips, such relic species, such as Blatella germanica and Periplaneta americana, mosquito, for example, Aedes aegypti.
In accordance with the proposed invention the compounds of formula (I), as mentioned above, which can be used as antibiotics. In particular, they can be used in the treatment of animals and people affected endoparasites, ectoparasitic and/or fungi farm, horticulture or forestry. They can be used, in addition, usually as pesticides in other circumstances, for example, in storage buildings or other public places or in places of localization of pests. Essentially, the proposed connection can be applied either to the host (animal or person, or to cultivated plants or other vegetation), or to the pests or their location.
The claimed compounds can be formed for reception in any convenient form for use in veterinary or medical practice. Thus, the invention includes within its scope pharmaceutical compositions containing the compound according to the claimed invention, suitable for use in veterinary medicine or therapy. Such compositions may be presented for use in the traditional manner using one or more suitable carriers or excipients. The proposed compositions are compositions in the form, especially suitable for parenteral (including the introduction inside the breast), oral, rectal, topical application in the form of the implant, for use in eye, ear or acquired, suitable for use in veterinary medicine or therapy, are the ways that are described in the patent of South Africa N 85/7049 for compounds of antibiotics S541.
The claimed compounds can be used in combination with other pharmaceutically active ingredients.
The total daily dose of the proposed compounds used in veterinary medicine and therapy, will be respectively in the range of 1-2000 mg/kg body weight, preferably 50-1000 mg/kg and above dose can be taken in fractional doses, for example, 1-4 times a day.
The claimed compounds can be in any convenient form suitable for farming or gardening. Thus, the invention includes within its scope compositions containing compound that is intended for use in agriculture or horticulture. Such formulations include dry or liquid form, for example, dusty, including pulverulent substrates or concentrates, powders, including soluble or wettable granules, including microspheres and dispersible granules, tablets, liquid substances, emulsions, for example, a diluted emulsion or emulsifiable concentrates, impregnating compositions, such as compositions for impregnation roots and injectii in the trunk, solutions or sprays, fumes and mists.
Suitable methods and agents for the preparation of the formulation of the proposed compounds for use in horticulture or agriculture include those disclosed in the patent of South Africa N 85/7049 for antibiotics S541.
When the formulation, the concentration of the active substance is usually from 0.01 up to 99.0 wt. and more preferably from 0.01 to 40.0 wt.
Industrial (commercial) products are usually prepared in the form of concentrated compositions that, when used diluted to the desired concentration, for example, from 0.001 to 0.0001 wt.
When used in veterinary medicine or in horticulture and agriculture in the case when the proposed compounds are products produced by fermentation, it is desirable to use the entire fermentation broth as a source of active compounds. In addition, you may be fit using dehydrated broth (containing mycelium or mycelium is separated from the broth and pasteurized, or more preferably dried. If desired, the specified broth or mycelium can be formed in the composition, as indicated above, including typical inert carriers, the change and be used in combination with other active ingredients.
In particular the proposed connection of the antibiotic can be used together with compounds of antibiotics S541 or in combination with other antibiotic compounds of the invention. This may occur, for example, when the crude products of fermentation interact according to the method of the invention without prior or subsequent branches; this may be preferred, for example, when using the compounds in agriculture, where it is important to ensure (save) low cost of production.
The claimed compounds of formula (II) can be obtained as follows:
oxidizing the corresponding compound of formula (III)
where OR5represents a hydroxyl group;
OR5represents a protected hydroxyl group,
and get the compound (II), where OR4represents an OH group, and the reaction is carried out with use of an oxidant capable of converting the secondary hydroxyl group in oxoprop in the presence of a solvent at a temperature of from -80 to +50oC and optional:
1) remove the protecting group in the compound of formula (II), where OR4protected hydroxy-group;
2) process the acid-base or not the 4 the hydroxy-group with hydroxyzinesee reagent to obtain the compound where OR4substituted hydroxyl group.
Suitable oxidizing agents include benzoquinoines operating in the presence of water, for example, 2,3-dichloro-5,6-dicyan-1,4-benzoquinone or 2,3,5,6-tetrachloro-1,4-benzoquinone; chromium (VI), for example, the bichromate of pyridine or triakis chromium in pyridine; manganese (IV) oxidant, such as manganese dioxide in dichloromethane; N-glowczewski, for example, N-chlorosuccinimide or N-bromosuccinimide; diallylsulfide, for example, dimethyl sulfoxide, in the presence of such activator as N,N'-dicyclohexylcarbodiimide or alloploidy, for example, oxanilide, or complex of sulfuric anhydride - pyridine).
A suitable solvent can be selected from the group consisting of a ketone, e.g. acetone; simple ether, for example diethyl ether, dioxane or tetrahydrofuran; hydrocarbons, such as hexane, halogen-substituted hydrocarbon, for example chloroform or methylene chloride; or a complex ester, e.g. ethyl acetate or substituted amide, such as dimethylformamide. The reaction can also use combinations of these solvents either in pure form or with water.
the invention proposes a method of producing compounds of the formula (II), where R2and R3together with the carbon atom to which they are attached, represent a group >C=O, OR4is hydroxyl or metaxylene group, including the stage of culturing a microorganism of the species Streptomyces, capable of forming at least one of the suggested compounds and, if desired, to extract the specified connection, and, in addition, if necessary, modify the group OR4by means described above.
Preferred microorganisms are capable of forming the above-mentioned substances are strains of a new species of the genus Streptomyces which are called Streptomyces thermoarchaensis. A sample of the microorganism, which is a soil culture, placed in storage (10.09.84,) in the permanent collection of the National collection of industrial and marine bacteria Torrh Research Station, Aberdeen, United Kingdom by assigning a registration number NCJB 12015. A mutant strain of Streptomyces thermoarchaensis NCJYB 12015 may also be advantageously used, and in the permanent culture collection of the National collection of industrial and marine bacteria deposited in the Depository storage (26.06.85 g) four strains of mutants that have been assigned a registration number NCJB 12111, NCJB 12112, NCJB 12113 and NCJB 12114.
The nitrogen sources usually include bababooey flour, tincture of wheat, solutions distillation, yeast extracts, flour from the seeds of cotton, gelatin, flour made from ground nuts, malt extract, molasses, casein, a mixture of amino acids, ammonia (gas or solution), ammonium salts and nitrates. You can also use urea and other amides. The nitrogen sources usually contain 0.1 to 10.0 wt. the fermentation medium.
Nutrient mineral salts that can be included in the culture medium contain commonly used salt, having the ability to give ions of sodium, potassium, ammonium, iron, magnesium, zinc, Nickel, cobalt, margarosanite Streptomyces the streptomycete is usually carried out at a temperature in the range of 20-50oC, preferably 25-40oC, more preferably about 34oC, preferably to accompany her aeration and agitation, such as shaking or intensive mixing. The environment can be initially inoculated with a small amount sporulirovannyh suspensions of microorganisms, but to avoid stunting can be cooked vegetable seed material of the microorganism by inoculation of a small amount of culture medium coroorate form specified body, when this plant inoculum, which is obtained may be transferred to the fermentation medium, or, more preferably, in one or more stages of sowing, where there is an additional growth before moving into the main fermentation medium.
The fermentation is usually conducted at a pH in the range of 5.5 to 8.5, preferably 5,5-7,5.
The fermentation can be carried out in a period of 2-10 days, for example about 5 days.
In the case where it is desirable to separate the material containing the compounds of the present invention from the whole fermentation broth or select any of the individual compounds mentioned can be done by conventional methods of extraction and separation of substances the broth and, thus, the technique of selection could also be applied to the fermentation broth after cleaning. It is clear that the method of selection of substances can have a wide variety.
The proposed connection can be selected and separated by various methods of fractionation, for example, elution, precipitation, fractional crystallization, extraction with solvent, which can be combined in different ways.
It is revealed that by solvent extraction and chromatography are most suited for the selection and separation of the proposed connections.
After fermentation, the mycelium can be assembled by traditional methods, for example, filtration or centrifugation. After that, for example, the compounds can be extracted from the mycelium of appropriate organic solvents such as ketones, for example acetone, methyl ethyl ketone or isobutyl ketone; hydrocarbons, such as hexane; halogen-substituted hydrocarbon, for example chloroform, carbontetrachloride, or methylene chloride; alcohols, such as methanol or ethanol; or esters, such as methyl acetate, or ethyl acetate. Clearly, if the mycelium contains significant College extract compounds usually desirable to carry out more than one extraction. Preferably the first extraction run using miscible with water solvent, such as methanol or acetone. Antibiotics can be extracted as the crude extract by solvent removal. Extracts solvent can then be extracted, if desired, after reduction of the volume of the solvent, e.g. by evaporation. At this stage it is preferable to use water-immiscible solvent, for example, hexane, chloroform, methylene chloride or ethyl acetate or a mixture thereof, thus to achieve good separation of the compounds of the antibiotic is introduced sufficient amount of water. When removing water-insoluble phase receive a product containing one or more compounds of the present invention, possibly together with the compounds of antibiotics S541.
Purification and/or separation of the proposed connection can be done by traditional methods, such as chromatography, including high-performance liquid chromatography on an appropriate substrate, such as silicon dioxide, non-functional macrostate adsorption resin, for example, cross-linked polystyrene resin, such as resin Amberlite XAD-2, XAD-4 or XAD-1180 (Rohm Haus Ltd) or resin S112 ((Kusteel Ltd) or the tea high-performance liquid chromatography on the substrate reverse phase, such as hydrocarbons deposited on the silicon dioxide, for example, C18cross-linked silica. The substrate may be in the form of a layer with a nozzle, fill the column. In the case of non-functional macrostate resins, for example, XAD-1180 or S112 (for elution, you can use a mixture of organic solvents, such as acetonitrile with water.
The solution of these compounds in an appropriate solvent is typically loaded into a chromatographic column of silica or Sephadex if desired, after first reducing the volume of the solvent. The column can be rinsed, and then washed with a suitable solvent polarity. In the case of columns of Sephadex and silica as solvents can be used alcohols, e.g. methanol; hydrocarbons such as hexane; acetonitrile; halogen-substituted hydrocarbons, for example chloroform or methylene chloride; esters, for example, ethylacetate.
Elution and separation/purification of the claimed compounds can be adjusted by using common methods, for example, thin-layer chromatography and high performance liquid chromatography or by using properties of the compounds described below.
Offer seat, such as chloroform: ethyl acetate, optionally with subsequent high-performance liquid chromatography. Thus obtained purified product is then subjected to chromatography on cephalexih columns, preferably by use of the eluate, for example, acetonitrile, and then claimed compounds may be selected liquid chromatography with high characteristic.
Using appropriate combinations of the above methods, compounds of formula (II), as revised now allocated as solids in almost pure form. It is clear that the sequence in which carry out the above stage of treatment, the choice of those who use, and the degree of purification achieved can be very different. These compounds can be used, but as mentioned, when the purity of their purpose. When used in medicine, it is desirable to have a purity of at least 90%, preferably more than 95% For veterinary and other applications sufficient to lower the degree of purity, for example, 50% or below.
The invention is further represented by the following preparations and examples. All temperatures are given at 0oC.
Connection oboznacheny
The factors A, B, C, D, E, F can be obtained by the method described in UK patent N 2166436.
Example 1. 5-Acetoxy-23-keto Factor A. the Solution oxalicacid (1,96 ml) in dry dichloromethane (25 ml) at -70oC in an atmosphere of nitrogen is treated dropwise with a solution of dimethylsulfoxide (3,19 ml) in dry dichloromethane (15 ml) and then dropwise a solution of 5-acetoxy Factor A (4,91 g) in dry dichloromethane (30 ml). The resulting solution was thoroughly stirred for 1.5 h at -70oC before processing dropwise a solution of triethylamine (of 12.6 ml) in dry dichloromethane (40 ml). The reaction mixture was stirred for 1.25 h without cooling and then poured into a mixture (1:1) with cold water and simple ether. The aqueous layer was extracted with simple ether. United organic layers washed with water, salt solution, dried and evaporated. The residual foam chromatographic on silica, using a mixture of dichloromethane with acetone (50:1) to give the titled compound (3.4 g); (CDCl3contains of 3.33 (M, 1H), 3,49 (m; 1H), 3,70 (d 10; 1H) and 5,52 (D. 5; 1H), m/z contains 652, 634, 609, 591, 574, 482, 263, 235 and 151.
Example 2. 23-keto Factor A. the Compound of example 1 (276 mg) in methanol (5 ml) at a temperature of 0oC handle on ka the support at a temperature of 5oC for 5 hours the Mixture is extracted with simple ether and ethyl acetate. United organic layers washed with brine, dried and evaporated to obtain a solid substance, which was purified preparative thin-layer chromatography, using as solvent a mixture with dichloromethane-acetone (10:1) to obtain the titled compound (140 mg); (CDCl3contains of 3.28 (m, 1H), 3,48 (m; 1H), 3,70 (d 10; 1H) and 4,28 (Tr; 1H), m/z includes 592, 549, 482, 370, 263, 235 and 151.
Example 2A. 23-keto Factor A. 0,41 ml coroorate suspension of Streptomyces thermoarchaensis NCJB 12015 10% glycerol used for inoculation in a 250 ml Erlenmyer flask (Erlenmeyer) containing 50 ml of culture medium consisting of (g/l D-glucose, 15.0 g/l of glycerol, 15,0 gL-1soy peptone, 3.0 g/l NaCl, 1.0 g/l CaCO3brought to the mark with distilled water. Before being placed in the autoclave pH was adjusted to 7.0 with an aqueous solution of NaOH.
The flask is incubated at a temperature of 28oC for 2 days on a pie rocking chair, running at a speed of 250 rpm with a 50 mm diameter orbit. Portions of a volume of 4 ml then use for inoculation of each of the four 2-liter bottles with a wide neck, each containing 200 ml of the same medium before income result for inoculation 70-liter fermenter, containing 40 liters of the same culture medium with the addition of propylene glycol 2000 (0,06%). Polypropylenglycol 2000 is introduced, as needed, throughout the fermentation process to control foaming. The fermentation is carried out at a temperature of 28oWith vigorous stirring and aeration sufficient to maintain the dissolved oxygen level is greater than 30% saturation. After 24 h of fermentation process 800-ml and 9-liter portions transferred into a 70-liter fermenter containing 40 l of culture medium, and 700-liter fermenter containing 450 l of culture medium, respectively. Both of these fermenters containing culture medium containing D-glucose and 2.5 gL-1, Malt dextrin (MD30E) 25,0 gL-1, Arkasy 50 12,5 gL-1, Bect Malasses 1,5 gL-1, K2HPO40,125 gL-1, CACO3(Ar) of 1.25 gL-1and 1520 silicone (Dow Corning) 0,6 gL-1given the norm of distilled water. Before sterilization pH is brought to 6.5 with an aqueous solution of H2SO4.
These fermentation processes performed when the temperature of the 34oC with vigorous stirring and aeration sufficient to maintain the level of dissolved oxygen is greater than 30% saturation. If necessary, add antispyware HSO4. The products of fermentation gather and unite in 4 days.
Mycelium (10 kg) of the collected liquid medium (423 l) is chosen in a Sharples centrifuge PS16AY. Mycelium intensively stirred in methanol (50 l) for 40 min and then filtered. The residue re-suspended in methanol (15 l) and again filtered. Joined the filtrates (55 l) was then mixed with water (27 l) and 60-80 petroleum ether (boiling point 60-80oC) (30 l) and stirred for 20 minutes
The resulting phases are separated in a centrifuge Westfalia MEM 1256, and the methanol phase (75 l) is mixed again with water (38 l) and 60-80 petroleum ether (30 l). After 20 min the phases are again separated in the centrifuge, and the phase of petroleum ether to break the resulting emulsion is injected acetone (2.0 l). The methanol phase (110 l) mixed with water (38 l) and 60-80 petroleum ether (30 l) for the third time, the phases are separated as before. Acetone (3 l) is added again to the petroleum ether phase for the destruction of the resulting emulsion.
Three phases of hexane unite (90 l) and concentrated at low pressure (temperature residue 25oC). Concentrate (9.8 l) dried with sodium sulfate (3 kg) and evaporated to oil.
The oil obtained is dissolved in dichloromethane (0.5 l) and filtered through Dical, raybaut dichloromethane (4 l) and elute with a mixture of chloroform with ethyl acetate (3:1). Fractions eluting between 14.6% and 33,3 l, concentrated to solids and dissolved in a mixture of chloroform with acetone (3:1).
The resulting solution was re-chromatographic on a column of silica with the same solvent. Fractions eluting between 14.5 and 31.5 l, dried to solids and dissolved in a mixture of chloroform with ethyl acetate (3:1). The resulting solution was again chromatographic on silica under the same conditions as before, then the elution fractions between 14 and 31 l dried to solid.
The solid is dissolved in 70% acetonitrile in water (1.23 l) with sufficient methanol is added to produce a light solution. This solution chromatographic in 5-ml portions on a column of Spherisorb CDS2. The contents of the column elute with 70% acetonitrile at a flow rate which increases from 20 to 34 ml/min after 24 minutes Fraction of each portion, which suirvey between 12,4 and 16.0, were collected and diluted with an equal volume of water. The resulting solution was then loaded into a column Montedison S112 (on the polystyrene with a mesh (2 l). The column was washed with 35% solution of the ptx2">
The solid is dissolved in acetonitrile (20 ml) and chromatographic on a column of Sephadex LH20 in the same solvent. Fractions eluting between 1.08 and 1,26, collected and dried to solid.
The solid is dissolved in 60% acetonitrile (10 ml) with a sufficient amount of methanol to be added to get a clear solution. The solution chromatographic in 2-ml portions again on a column of Spherisorb ODS2 and elute with 60% acetonitrile at 25 ml/min Fractions eluting between 0.95 and 1.08 l, collected together and dried to solids. The obtained solid is re-dissolved in chloroform (5 ml) and chromatographic on a column of Merck silica gel 60. The solution elute with chloroform at 10 ml/min and fractions eluting between 400 ml and 790 ml, dried to obtain the above compound (33 mg) in the form of solids, HNR spectrum corresponds contained 23-keto Factor A. E. I-mass spectroscopy gave ion molecules at 610 and characteristic fragments at 592, 549, 498, 482, 370, 263 and 151.
The sample is presented to compare the 23-keto Factor A, obtained by high-performance liquid chromatography with similar ketone formed during the chemical oxidation factor A.
Prip-dimethylformamide (10 ml) is stirred at a temperature of 20oC for 48 h and then poured into a mixture of ethyl acetate (50 ml) and 2N-hydrochloric acid (25 ml). The organic phase is washed with 2N-hydrochloric acid and saturated sodium bicarbonate, dried (magnesium sulfate) and evaporated to dryness. The residue is purified by chromatography on a column of Kieselgel 60 (25 g). Elution of the column with a mixture of petroleum ether:ethyl acetate (4:1) gives the titled compound (85 mg) as a colorless foam, []2D0+120o(1,05, CHCl3),max(EtOH) 245 nm ( 26500), Vmax(CHBr3) 3480 (OH), 1760 (CHLOROACETATE) and 1715 cm-1(ester and ketone), d (CDCl3includes 5.5 to 5.7 (m, 2H), 4,17 (s, 2H), and 3.72 (d, J 10 Hz, 1H), 2,50 (s, 2H) and of 0.85 (d, J 7 Hz, 3H), m/z 686 (M+, 35 Cl).
Example 5. Factor A, 5-methylcarbonate, 23-ketone (830 mg). []2D0+ 132o(0,82, CHCl3),max(EtOH) 245 nm (E 29800), Umax(CHBr3) and 3560 3500 (OH), 1745 (carbonate) and 1710 cm-1(ester), (CDCl3) consists of 5.40 (s, 1H), 4,80, and 4,70 (AB q, J 14 Hz, 2H), 4,28 (m, 1H), and 0.79 (g, J 7 Hz, 3H), from factor A, 23-ketone (916 mg) and methylformate (0,23 ml).
Example 6. Factor A, 5-benzylcarbamoyl, 23-ketone (57 mg). []2D0+ 99(0.4, CHCl3),max(EtOH) 245,5 nm (Et29600), (CHBr3) 3600, 3550 and 3480 (OH), 1740 (carbonate) and 1715 cm-1
Example 7. 5-acetoxy, 23-keto Factor D (152 mg). So pl. 228-230oC ()2D1+ 84max(c and 0.6, CHCl3), 244,5 nm (max31100), (CHBr3) 3500 (OH), 1732 and 1714 cm-1(ester and ketone), (CDCl3) 0,86 (d, 6 Hz, 3H), and 0.98 (d, 6 Hz, 3H), and 1.00 (t, 7 Hz, 3H), 1,49 (s, 3H), 1,67 (s, 3H), of 1.74 (s, 3H), and 2.14 (s, 3H), of 3.33 (m, 1H), 4,03 (d, 6 Hz, 1H) and 5.5 to 5.6 (m, 2H), m/z 638 (M+).
From 5-acetoxy Factor D (336 mg) in a similar manner to the compound of example 1.
Example 8. 23-keto Factor D (59 mg). []2D1+ 84(0.4, CHCl3)EtOmaxH244,5 nmmax28000,max(CHBr3) 3550 and 3500 (OH) and 1712 cm-1(ester and ketone), (CDCl3) 0,86 (d, 6 Hz, 3H), and 0.98 (d, 7 Hz, 3H), and 1.00 (t, 7 Hz, 3H), 1,50 (s, 3H), by 1.68 (s, 3H), of 1.86 (s, 3H), of 3.27 (m, 1H), of 3.73 (d, 10 Hz, 1H), 3,95 (d, 6 Hz, 1H) and 4,27 (t, 6 Hz, 1H), from 5-acetoxy-23-keto Factor D (96 mg), and similarly for compounds of example 2.
Spectral data characterizing compounds 1-6. The technique of mass-spectral analysis used for these compounds, usually given ion M+and not M+H. the Spectrum of proton magnetic resonance of these analogues is quite complex. Instead of a list of all heraldica to the ester carbonyl group in the NMR spectrum13C, which testify to the obvious presence of these two ester functionalities. Taken together, these data confirm the structure of the compounds (table.2).
New examples:
Example 9. 23-keto Factor B (160 mg), pl. 213-215o(Softening of about 209oC) [] 2D2+ 122(0,36, CHCl3),EtOmaxH238,5 (26,400), 244,5 (28,700) and 282 nm (max400);max(CHBr3) 3450 (OH) and 1710 cm-1(ester and ketone); (CDCl3includes 5,47 (6 Hz, 1H), was 4.02 (d 6 Hz, 1H), 3,95 (d 6 Hz; 1H), of 3.73 (d 10 Hz, 1H), 3,51 (s, 3H), and 3.31 (m, 1H), is 1.81 (s, 3H), 1.69 in (s, 3H), 1,67 (d 6 Hz, 3H), 1,50 (s, 3H), 0,97 (d 6 Hz, 3H) and 0.82 (d 7 Hz, 3H), m/z 596 (M+), factor B (559 mg) as a microcrystalline solid after crystallization from ether.
Example 10. 5-Tert-butyldimethylsilyloxy-23-keto Factor A
(i) 5-tert-butyldimethylsilyloxy Factor A
Factor A (2,144 g) in anhydrous ether (25 ml) and pyridine (2.5 ml) at 0oC in nitrogen atmosphere is treated, prokopeva t-butyldimethylsilyloxy chloride (1.2 g) in ether (10 ml). The mixture is stirred for 90 min at 0oWith them before processing by addition of acid chloride (1.10 g) in ether (10 ml). The mixture was stirred at 0o3includes 0,09 (C; 6N), 0,78 (D6; 3H), 0,90 (C; N), 0,93 (D6; 3H), 0,97 (D6; 3H), of 1.03 (D6; 3H) and 1.51 (s; 3H), 1.59 CI (s; 3H), 1,74 (s; 3H), of 3.32 (m, 1H), 3,52 (D10; 1H), to 3.64 (m, 1H), 3,74 (D10; 1H), 3,82 (m; 1H), 4,32 (s; 2H) and 5,57 (D5; 1H), m/z includes 784, 766, 748, 595, 577, 484, 466, 354, 314, 297, 265, 247, 237, 219 and 151.
(ii) Compound (i) (300 mg) in dry dimethylformamide (5 ml) at 22oWith is treated with pyridinium dichromate (we used the PDH) (1.40 g) and stirred for 3.5 hours Add we used the PDH (1.0 g) and continued stirring for 1 h the Mixture was poured into ice water and ether. The aqueous layer was washed thoroughly with ether. The combined organic layers washed with water and saline solution, dried and evaporated. The residue is purified using preparative TLC on silica using as eluent dichloromethane:acetone (40:1) to give a solid (150 mg), which, as shown by the MS/IHVR contains a named connection, m/C includes 782, 721, 592, 549, 370, 340, 263, 235 and 151.
Example 11. Factor A, 5-(2,2,2-trichloroethyl)carbonate, 23-ketone (65 mg) []2D2+ 98(C 1.07, and CHCl3),max(EtOH) 245,5 nm, ( 28,300), nmax(C(ABk, J 12 Hz, 2H), and 3.72 (d, J 10 Hz, 1H), of 2.51 (s, 2H) and 0.87 (d, J 7 Hz, 3H), m/z 784 (M+,35Cl), from Factor A, 5-(2,2,2-trichloroethyl)-carbonate (188 mg).
Example 12. 23-keto Factor A, 5-(4-chlorobenzoate) (150 mg) which crystallized when crushed into a powder with diisopropyl ether, so pl. 230-232oC []2D2+ 25(0,48, CHCl3);EtOmaxH245 (50,600) and 281,5 nm (max1,100),max(CHBr3) 3480 (OH) and 1718 cm-1(ester and ketone), (CDCl3includes 8,00 (d, 8 Hz, 2H), 7,40 (d, 8 Hz, 2H) and of 2.50 (s, 2H), m/z= 748, 750 (M+,35Cl37Cl), from Factor A, 5-(4-chlorobenzoate) (420 mg).
The following examples are examples of formulations according to this invention. The term "active ingredient" as used hereinafter means a compound of this invention and may be, for example, compound of example 2.
Mnogozonovaya parenteral injection, wt./about.
The active ingredient of 4.0 (range 0.1 to 7.5)
Benzyl alcohol 2,0
Glyceryl triacetate 30,0
Propylene glycol To 100.0
Dissolve the active ingredient in benzyl alcohol and glycerol the triacetate. Add the propylene glycol and bring to volume. To sterilize the product using conventional pharmaceutical techniques is Rosolini sprayer, wt./Mac:
The active ingredient of 0.1 (range of 0.01 to 2.0)
Trichloroethane 29,9
Trichlorofluoromethane 35,0
DICHLORODIFLUOROMETHANE 35,0
Mix the active ingredient with trichloroethane and fill in the aerosol container. To displace the free space above the product gas gas displacer and molded valve in position. Fill in the desired weight of liquid carrier gas under pressure through the valve. To install the drives and the safety valve caps.
A method of manufacturing wet granulation, mg:
The active ingredient 250
Magnesium stearate 4,5
Rice starch 22,5
Starch, glycolate sodium 9,0
Sodium lauryl sulfate 4,5
Microcrystalline cellulose To the weight of the core tablet 450
Add enough 10% starch paste to the active ingredient, to get suitable for wet granulation mass. To prepare granules and dried using a tray or a dryer with pseudo-liquefied layer. Sift through a sieve, add the remaining ingredients and compressed into tablets.
If you need to cover with a film grain tablets using hydroxypropylmethyl cellulose or other similar film-forming included a suitable plasticizer and a pigment.
Veterinary tablets for use in small/pet
A method of manufacturing a dry granulation, mg:
The active ingredient 50,0
Microcrystalline cellulose To the weight of the core tablet 75,0
Mix the active ingredient with magnesium stearate and microcrystalline cellulose. Compress the mixture into bars. Destroy blocks by passing through a rotary granulator to obtain Svobodnaya granules. Compress into tablets.
If necessary grain pellets can then be covered with a film, as described above.
Veterinary intramammary injection, mg/dose:
The active ingredient 150 mg (range of 0.05-1.0 g)
Polysorbate 60 3.0 wt./Mac
White beeswax to 6.0 wt./wt up to 3 g up to 3 or 15 g)
Peanut butter 91,0 wt./Mac
Heat peanut oil, white beeswax and Polysorbate 60 to 160oC under stirring. Kept at 160oC for 2 h and then cooled to room temperature under stirring. Aseptically add the active ingredient to the filler and dispersing using a high-speed mixer. Crushed by passing through a colloidal mill. Aseptically fill PR is the ingredient of 0.35 (range 0,01-2,0)
Polysorbate 85 5,0
Propylene glycol 30,0
Phosphate buffer At pH 6,0-6,5
Water Up to 100.0
Dissolve the active ingredient in Polysorbate 85, benzyl alcohol and polypropylenglycol. Add the proportion of water and bring the pH to 6.0-6.5 phosphate buffer, if necessary. Bring water to a final volume. To fill the product into the container of the device for infusion of medication into the oral cavity of the animal.
Veterinary oral paste, wt./Mac:
The active ingredient of 7.5 (range 1-30)
Saccharin 25,0
Distearate aluminum 5,0
Fractionated coconut oil To 100.0
Atomized distearate aluminum in fractionated coconut oil and Polysorbate 85 when heated. Cool to room temperature and dispersing saccharin in the oil filler. Dispersing the active ingredient in basis. Fill in plastic syringes.
Granules for veterinary use for administration in feed, wt./Mac:
Calcium sulfate, hemihydrate To 100.0
Mix the active ingredient with calcium sulfate. To produce granules using the method of wet granulation. Dry using a pallet or with whom, g:
The active ingredient 50
Anionic emulsifier (for example, phenyl sulfonate CALX) 40
Non-ionic emulsifier (for example, Syperonic NP13) 60
Aromatic solvents (for example Solvesso 100) To 1 litre
Mix all ingredients, stirring to dissolve.
Granules, g:
(a) Active ingredient 50
Extraction rosin 40
Granules of natural gypsum (20-60 mesh) (for example, Agsorb 100A) To 1 kg
(b) the Active ingredient 50
Syperonic NP13 40
Granules of natural gypsum (20-60 mesh) To 1 kg
Dissolve all ingredients in a volatile solvent, such as methylene chloride, add to the granules, processing in the mixer. Be dried to remove solvent.
In table. 3 assessed on insecticidally/acaricidal activity.
1. Macrocyclic lactone of General formula
where R1methyl, ethyl or isopropyl;
OR4OH, OCOR6where R6WITH1- C4-alkyl, possibly substituted by halogen, three, four1WITH4-alkylsalicylate, phenyl or aloevera, OCO2R6awhere R6aWITH1- C4-alkyl, possibly substituted by phenyl or halogen, OR7where R7WITH1WITH4-alkyl,
with antibiotikoterapiia group.
3. Connection on p. 1, where R1the isopropyl group and OR4- hydroxyl.
4. Pharmaceutical composition having antibiotic activity, including an active ingredient and a pharmaceutically acceptable carrier, wherein the active ingredient contains a compound of the formula I on p. 1, taken in an effective amount.
5. Insecticide and acaricide composition including the active ingredient is derived milbemycin and target additives, characterized in that as a derived milbemycin it contains a compound of the formula I, where R1- isopropyl, OR4HE R6where R6WITH1- C4-alkyl, substituted by one or more halogen atoms or phenyl, WITH3WITH6-cycloalkyl, in an effective amount.
Same patents:
Derivatives of 13-(substituted thio)acetoxypiperidine, the retrieval method, the insecticidal composition and method of plant protection // 2086552
The invention relates to a series of new derivatives of compounds known as "milbemycin", which are characterized by the presence of heterocyclic substituted mercaptoacetate group at the 13-position
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The invention relates to certain 13-alkyl-23-imino - 13-halogen-23-imino-LL-F28249-compounds and to their use for combating endo - and ectoparasitic infections and infestations in warm-blooded animals
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redpajama_set_name: RedPajamaCommonCrawl


I thought I would follow up my previous post on Brunelleschi's Il Badalone by looking at the stone used in the Duomo, or Santa Maria del Fiore, as it is officially known. According to Ross King in his highly readible Brunelleschi's Dome, the planners ordered three colors: verdi di Prato, marmum rubeum, and bianchi marmi—green, red, and white, respectively. Like many writers, King refers to the stone as marble. Only the white stone, however, is a true marble.
As the name implies, the first stone is green. It is a serpentine, quarried for centuries near the town of Figline, a few miles from Prato, northwest of Florence. The name comes from the stone's resemblance to a serpent's skin, or so say some, from the stone's use as a medicinal remedy against snake poison. In the building trade, serpentine is commonly called Verde Antique, or Verde Antico if the seller is feeling fancy. Serpentine forms from the metamorphism of magnesium-rich rock such as peridotite.
The red stone of the Duomo is a very fine grained limestone quarried in several locales near Florence. It was deposited in an open, marine environment around 190 million years ago. Geologists refer to this layer as the Rosso Ammonitico, due to the abundant ammonite fossils.
Bianchi marmi is better known as Carrara marble, the material that Brunelleschi's Il Badalone was supposed to carry up the Arno River. The Carrara began life as a fine-grained, calcite mud deposited in the same sea as Rosso Ammonitico but 10 million years later. It became marble around 27 million years ago when the Corsica-Sardinian microplate rammed into the Italian peninsula. As the plate's basalt, gabbro, and sediments piled on the limestone, it metamorphosed it into a marble that is almost 100 percent calcite.
King is not alone in using the term marble to describe non-marble stone. To the Romans, who called marble marmor, from the Greek adjective marmareos, meaning shining or shimmering, marble referred to any hard rock suitable for sculpture or architecture. Such "marbles" might include granite, breccia, porphyry, or serpentine. Go to any store selling architectural stone and you will find that the Roman tradition continues with a plethora of non-metamorphosed limestone labeled as "marble." I have no idea if any are good for snake bites.


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namespace shfb.helper.Properties {
    using System;

    /// <summary>
    ///   A strongly-typed resource class, for looking up localized strings, etc.
    /// </summary>
    // This class was auto-generated by the StronglyTypedResourceBuilder
    // class via a tool like ResGen or Visual Studio.
    // To add or remove a member, edit your .ResX file then rerun ResGen
    // with the /str option, or rebuild your VS project.
    [global::System.CodeDom.Compiler.GeneratedCodeAttribute("System.Resources.Tools.StronglyTypedResourceBuilder", "4.0.0.0")]
    [global::System.Diagnostics.DebuggerNonUserCodeAttribute()]
    [global::System.Runtime.CompilerServices.CompilerGeneratedAttribute()]
    internal class Resources {

        private static global::System.Resources.ResourceManager resourceMan;

        private static global::System.Globalization.CultureInfo resourceCulture;

        [global::System.Diagnostics.CodeAnalysis.SuppressMessageAttribute("Microsoft.Performance", "CA1811:AvoidUncalledPrivateCode")]
        internal Resources() {
        }

        /// <summary>
        ///   Returns the cached ResourceManager instance used by this class.
        /// </summary>
        [global::System.ComponentModel.EditorBrowsableAttribute(global::System.ComponentModel.EditorBrowsableState.Advanced)]
        internal static global::System.Resources.ResourceManager ResourceManager {
            get {
                if (object.ReferenceEquals(resourceMan, null)) {
                    global::System.Resources.ResourceManager temp = new global::System.Resources.ResourceManager("shfb.helper.Properties.Resources", typeof(Resources).Assembly);
                    resourceMan = temp;
                }
                return resourceMan;
            }
        }

        /// <summary>
        ///   Overrides the current thread's CurrentUICulture property for all
        ///   resource lookups using this strongly typed resource class.
        /// </summary>
        [global::System.ComponentModel.EditorBrowsableAttribute(global::System.ComponentModel.EditorBrowsableState.Advanced)]
        internal static global::System.Globalization.CultureInfo Culture {
            get {
                return resourceCulture;
            }
            set {
                resourceCulture = value;
            }
        }

        /// <summary>
        ///   Looks up a localized string similar to There was an error reading the schema file '{0}'..
        /// </summary>
        internal static string ExceptionBuilderCannotReadSchemaFile {
            get {
                return ResourceManager.GetString("ExceptionBuilderCannotReadSchemaFile", resourceCulture);
            }
        }

        /// <summary>
        ///   Looks up a localized string similar to There was an error reading the inline documentation XSLT file '{0}'..
        /// </summary>
        internal static string ExceptionBuilderCannotReadTransform {
            get {
                return ResourceManager.GetString("ExceptionBuilderCannotReadTransform", resourceCulture);
            }
        }

        /// <summary>
        ///   Looks up a localized string similar to There was an error constructing the schema set..
        /// </summary>
        internal static string ExceptionBuilderErrorBuildingSchemaSet {
            get {
                return ResourceManager.GetString("ExceptionBuilderErrorBuildingSchemaSet", resourceCulture);
            }
        }

        /// <summary>
        ///   Looks up a localized string similar to There was an error reading the external documentation file '{0}'..
        /// </summary>
        internal static string ExceptionBuilderErrorReadingExternalDocumentation {
            get {
                return ResourceManager.GetString("ExceptionBuilderErrorReadingExternalDocumentation", resourceCulture);
            }
        }

        /// <summary>
        ///   Looks up a localized string similar to There was an error transforming the inline documentation contained in the XML schema file '{0}'..
        /// </summary>
        internal static string ExceptionBuilderErrorTransformingInlineDocumentation {
            get {
                return ResourceManager.GetString("ExceptionBuilderErrorTransformingInlineDocumentation", resourceCulture);
            }
        }

        /// <summary>
        ///   Looks up a localized string similar to Unexpected schema object type '{0}'..
        /// </summary>
        internal static string ExceptionBuilderUnexpectedSchemaObjectType {
            get {
                return ResourceManager.GetString("ExceptionBuilderUnexpectedSchemaObjectType", resourceCulture);
            }
        }

        /// <summary>
        ///   Looks up a localized string similar to Unhandled case label '{0}'.
        /// </summary>
        internal static string ExceptionBuilderUnhandledCaseLabel {
            get {
                return ResourceManager.GetString("ExceptionBuilderUnhandledCaseLabel", resourceCulture);
            }
        }

        /// <summary>
        ///   Looks up a localized string similar to The attribute group '{0}' cannot be extended with attribute '{1}' as '{0}' does not contain an xs:anyAttribute element..
        /// </summary>
        internal static string ProblemReporterAttributeParentAttributGroupOffersNoExtension {
            get {
                return ResourceManager.GetString("ProblemReporterAttributeParentAttributGroupOffersNoExtension", resourceCulture);
            }
        }

        /// <summary>
        ///   Looks up a localized string similar to The complex type '{0}' cannot be extended with attribute '{1}' as '{0}' does not contain an xs:anyAttribute element..
        /// </summary>
        internal static string ProblemReporterAttributeParentComplexTypeOffersNoExtension {
            get {
                return ResourceManager.GetString("ProblemReporterAttributeParentComplexTypeOffersNoExtension", resourceCulture);
            }
        }

        /// <summary>
        ///   Looks up a localized string similar to The element '{0}' cannot be extended with attribute '{1}' as '{0}' does not contain an xs:anyAttribute element..
        /// </summary>
        internal static string ProblemReporterAttributeParentElementOffersNoExtension {
            get {
                return ResourceManager.GetString("ProblemReporterAttributeParentElementOffersNoExtension", resourceCulture);
            }
        }

        /// <summary>
        ///   Looks up a localized string similar to The complex type '{0}' cannot be extended with element '{1}' as '{0}' does not contain an xs:any element..
        /// </summary>
        internal static string ProblemReporterElementParentComplexTypeOffersNoExtension {
            get {
                return ResourceManager.GetString("ProblemReporterElementParentComplexTypeOffersNoExtension", resourceCulture);
            }
        }

        /// <summary>
        ///   Looks up a localized string similar to The element '{0}' cannot be extended with element '{1}' as '{0}' does not contain an xs:any element..
        /// </summary>
        internal static string ProblemReporterElementParentElementOffersNoExtension {
            get {
                return ResourceManager.GetString("ProblemReporterElementParentElementOffersNoExtension", resourceCulture);
            }
        }

        /// <summary>
        ///   Looks up a localized string similar to The group '{0}' cannot be extended with element '{1}' as '{0}' does not contain an xs:any element..
        /// </summary>
        internal static string ProblemReporterElementParentGroupOffersNoExtension {
            get {
                return ResourceManager.GetString("ProblemReporterElementParentGroupOffersNoExtension", resourceCulture);
            }
        }

        /// <summary>
        ///   Looks up a localized string similar to The '{0}' entity cannot be used as an extension. The only valid extension types are 'Element' and 'Attribute'..
        /// </summary>
        internal static string ProblemReporterInvalidExtensionType {
            get {
                return ResourceManager.GetString("ProblemReporterInvalidExtensionType", resourceCulture);
            }
        }

        /// <summary>
        ///   Looks up a localized string similar to The external doc file '{0}' contains a member URI with a value of '##Namespace' although the doc file was marked as documenting the schema set..
        /// </summary>
        internal static string ProblemReporterInvalidNamespaceUriInSchemaSet {
            get {
                return ResourceManager.GetString("ProblemReporterInvalidNamespaceUriInSchemaSet", resourceCulture);
            }
        }

        /// <summary>
        ///   Looks up a localized string similar to The URI '{0}' is used to indicate a preferred alternative over an obsolete entity but does not refer to a valid XML entity..
        /// </summary>
        internal static string ProblemReporterInvalidObsoleteUri {
            get {
                return ResourceManager.GetString("ProblemReporterInvalidObsoleteUri", resourceCulture);
            }
        }

        /// <summary>
        ///   Looks up a localized string similar to The '{0}' entity type cannot be used as the parent for an element extension. The only valid parent types are 'Element', 'Group', and 'ComplexType'..
        /// </summary>
        internal static string ProblemReporterInvalidParentForExtension {
            get {
                return ResourceManager.GetString("ProblemReporterInvalidParentForExtension", resourceCulture);
            }
        }

        /// <summary>
        ///   Looks up a localized string similar to The '{0}' entity type cannot be used as the parent for an attribute extension. The only valid parent types are 'Element', 'AttributeGroup', and 'ComplexType'..
        /// </summary>
        internal static string ProblemReporterInvalidParentForExtension1 {
            get {
                return ResourceManager.GetString("ProblemReporterInvalidParentForExtension1", resourceCulture);
            }
        }

        /// <summary>
        ///   Looks up a localized string similar to The URI '{0}' is used to indicate an extension parent but does not refer to a valid XML entity..
        /// </summary>
        internal static string ProblemReporterInvalidParentUri {
            get {
                return ResourceManager.GetString("ProblemReporterInvalidParentUri", resourceCulture);
            }
        }
    }
}

redpajama_set_name: RedPajamaGithub


The past two years have been exciting times for the Mental Health Association of Nebraska (MHA-NE). In February of 2015 we were awarded our first vocational and life skills grant through the Nebraska Department of Corrections. For the past 9 years we have primarily served individuals in the Behavioral Health System and this was our first attempt to serve people reentering their community after incarceration within the criminal justice system.
We provide a variety of reentry services including supported employment, outreach, transitional living, WRAP Support groups, and RentWise. All MHA-NE services are voluntary, person directed, recovery focused and all is provided by Certified Peer Specialists.
Peers in our supported employment program are offered a menu of services including assistance with job search, completing applications, creating resumes and interview skills; to name a few. We adhere to the evidenced based practice of supported employment which means competitive employment is the goal, supported employment is integrated with their treatment team (if they choose), Zero exclusion: Eligibility is based on choice, participant driven, benefits counseling is provided, job seeking begins immediately, employment specialists build relationships with employers of the participants' choice and follow-along supports continue until the participant chooses. People do amazing things when we as peers can provide hope and opportunity. For individuals coming out of incarceration the average time it takes to obtain employment is less than a week. Employers will now call us if they have any openings to see if we have a potential job match. Quality jobs with good benefits are a possibility for the people we serve.
Peer Outreach is provided to those who wish to have someone walk alongside them to navigate the resources of obtaining their basic needs of food, housing and clothing but also things such as bus passes, state identification and whatever else might assist them in moving forward. Our peer outreach worker has built incredible relationships with landlords, food nets, churches and community members in general. Peer Outreach Workers also meet individuals incarcerated in the county jail.
Honu Home is our up to 90-day peer-run transition home. Honu is a 5-bedroom home that focuses on providing peer support in a safe, learning environment. Many individuals have been incarcerated for long periods of time, sometimes 20-30 years, and learning how to become a spouse, family member, employee or friend again is often challenging. Honu provides an opportunity for people to be in the community while receiving peer support while they reacclimate to their new environment.
MHA-NE peers also provide services inside the state correctional facilities. We offer Wellness, Recovery, Action, Plan (WRAP) groups in which we facilitate the individuals to create their own plan for recovery. We facilitate these groups both in general population and in the restrictive housing unit. Once or twice a month I attend the Circle of Concerned Lifers Group to support them in their efforts and in the future hope to provide them with Intentional Peer Support Training so that they can provide support to others in the facilities.
In May, we had the privilege to travel to Albany NY and attend a meeting discussing the core principles of peer support within the Criminal Justice System facilitated by the Policy Research Institute. Two weeks later three MHA-NE Peer Specialists along with Sergeant John Walsh (Lincoln Police Department) traveled to Washington D.C. to speak with a group of 20-25 individuals working within the criminal justice system who were interested developing and implementing peer programs within their criminal justice systems.
In June, I traveled to California to visit San Quinten and a group of men incarcerated there. It was an incredible experience but also very re-assuring in that the experience affirmed our work here. No matter where we travel or who we meet, Peers just have a connection that is often just "understood" and we have a genuine care for one another and our experiences.
To date we have served approximately 650 people residing in or recently released from Nebraska state correctional facilities or in the county jail. The need is great but often just knowing they have someone they can relate to and walk with them along the journey is all they need. Recovery is the expectation and we are the evidence!


After approximately a four-week healing process following surgery, it is then time to activate the external component of the implant called the speech processor. Each child's speech processor must be individually programmed. This is sometimes referred to as setting the child's "map." This process typically requires an initial appointment with an audiologist at the hospital implant center and several subsequent appointments during the following weeks. It is necessary to adjust the program frequently in the beginning as the brain adapts to incoming sound. Once a stable program has been obtained, the hospital implant center will determine how often to monitor a child in the coming months and years to assure that the program continues to provide adequate responses to sound. A child may be seen every two to three months for the first year and every six months for the second and third years depending on the recommendation of the hospital implant center.
The basic components of determining a program include setting threshold levels (T levels), comfort levels (C Levels), and "flagging" (turning off) electrodes that may cause problems. A program is determined by setting each of the electrodes to be loud enough for a person to be aware of a sound, but not too loud as to cause discomfort.
For young children, setting the program(s) of the speech processor is as much an art as a science. It is important that the audiologist doing the programming have experience working with young children. In addition to behavioral observation testing to document the child's responses, objective assessment tools that do not require a child's participation may also be utilized. Each manufacturer has software to objectively measure the responses of the neural fibers to electrical stimulation. These measures can confirm that the internal device is functioning and can help assist in setting the program of the external speech processor when it is activated. Not all hospital centers check neural responses during surgery or programming.
Each manufacturer continues to update the design of its speech processors.
MED-EL-The speech processor are Sonnet, Opus: Opus 1: , and Opus 2 and a single unit speech processor called the Rondo.
As each manufacturer develops new speech processors, it may be possible for individuals to replace older model processors with newer model processors while still maintaining the older generation of the internal device. It will be necessary to communicate with the hospital implant center to determine if an individual is eligible for the upgrade and if insurance will cover the cost.
The speech processor converts sound to electrical impulses that represent speech. The cochlea is "tonotopic," with the base or bottom of the cochlea responsible for processing the high-frequency sounds and the apex of the cochlea responsible for processing the low-pitched sounds. The speech processor has the job of transforming sounds into electrical patterns to convey the sounds to the brain by stimulating the various parts of the cochlea. Each implant manufacturer uses speech processing strategies unique to its company.
The Cochlear Corporation speech processing package is called SmartSoundTM.
The MED-EL speech processing strategy is called Automatic Sound Management.
In addition to the implant device itself, there are many associated assistive listening devices that may be used in conjunction with each cochlear implant to enhance listening in noise, at a distance, and with electronic devices.
There are various assistive technologies available to improve listening in background noise and at a distance in school, public areas, and at home. Two types of systems are Frequency Modulation (FM) systems and infrared systems.
When using an FM system, a child may use either a soundfield FM system or a system that provides direct input to his or her cochlear implant. Both systems utilize a transmitter/microphone to transmit sound.
With the soundfield system, the sound is broadcast via a small speaker placed strategically near the child or elsewhere in the classroom. With this system, everyone in proximity of the system's speakers will be listening as well. This may be a benefit or a distraction to others. If a child uses a soundfield system, there are no additional parts needed to couple the speaker to the cochlear implant or settings to change on the implant itself.
With a direct audio input system, sound is transmitted directly into the child's cochlear implant. Depending on which speech processor a child is using, there are various connectors or setting changes involved in coupling the FM system to the child's implant. There are a variety of FM manufacturers available that couple with each cochlear implant. While the benefits may be great, the setting and monitoring of a direct audio input FM system requires close care by the child's implant audiologist, educational audiologist, teacher, family as well as feedback from the child to assure that both FM as well as cochlear implant components are functioning.


text:
Vol. 81 No. 2 (2021): Special Issue: Saudi Vision 2030 - Habitats for Sustainable Development /
Comparing the Sustainable Reuse of Historical Buildings
Dr. Silvia Mazzetto Prince Sultan University, College of Architecture and Design, Saudi Arabia
Heritage reuse, adaptive reuse, heritage safeguard, cultural values, national identity
The oil industry in Saudi Arabia and the wider Middle East has generated rapid urban growth and sparked a lively debate over the direction that such growth should take. While the construction of contemporary cities using innovative materials and technologies has been pursued, the need to preserve and maintain the nation's identity, rehabilitate national heritage, and establish new relationships with the local history and culture has also been recognised. This paper examines recently completed adaptive reuse projects and argues for the need to increasingly value local traditions and architecture. Based on data collected using mixed methods, and employing terms derived from reuse proposals, our analysis addresses each project's environmental, socio- economic, and socio-cultural aspects. Sustainability was identified as one of projects' common concerns. Broadly considered in terms of unity and harmony, the sustainability of the projects was further analysed in terms of the materials used, respect for the ecosystem, social aspects, and the required investments and costs related to the scale of interventions (urban-architectural). By presenting this assessment of the projects' innovative practices and overall sustainability, this study aims to promote new solutions for the restoration of architectural heritage in Saudi Arabia and the wider Middle East.
Requires Subscription or Fee DOWNLOAD PDF (USD 8.95)
Mazzetto, S. (2022). Comparing the Sustainable Reuse of Historical Buildings. Ekistics and The New Habitat, 81(2), 22–32. https://doi.org/10.53910/26531313-E2021812540
Vol. 81 No. 2 (2021): Special Issue: Saudi Vision 2030 - Habitats for Sustainable Development


A resident of Vienna since 1995, Laurie A. DiRocco has served as mayor since 2014. She was first elected to Town Council in 2009.
DiRocco previously served as chair of the Town of Vienna Planning Commission and vice chair of the Transportation Safety Commission. She currently is chair of the Northern Virginia Regional Commission and serves on the executive committee for the Virginia Municipal League. She is a member of the Rotary Club of Vienna and the Tysons Transportation Service District Advisory Board. DiRocco is a former adjunct professor at George Mason University's School of Management. She has served as treasurer of the Marshall Road Elementary School PTA, president of the Camelot Elementary School Hearing Association, and a member of James Madison High School PTSA.
Mayor DiRocco received a bachelor of science degree in finance from Virginia Tech University and a master of business administration from George Washington University. She and her husband, Rob, live in Vienna with their two children and are members of Vienna Presbyterian Church.


text:
Q: onchange submit but keep the first selected option So, whenever the user chooses "hightolow" and "1", it normally redirects to sortby=hightolow&availability=1. However, if a user changes availability to 0, it redirects to the FIRST of sortby and availability=0 (sortby=lowtohigh&availability=0)
I want the selected option to stay as it got chosen by the user (i.e: sortby=hightolow&availability=0), what's the best solution? Thanks.
I use express.js (node.js) as a back-end solution.
<form method="GET" onchange="submit()">
  Sort By

    <select name="sortby">
      <option value="lowtohigh">Price (Low to High)</option>
      <option value="hightolow">Price (Low to High)</option>
      <option value="new">Newest</option>
    </select>

  Availability

    <select name="availability">
      <option value="1">Available</option>
      <option value="0">Out of Season</option>
    </select>

</form>

A: That's because when you submit your form, the value will return to your original state (default to first element), therefore any subsequent change will only reflect to single select box, you can let me know what is your backend so I can write a sample code of handling
Hope it helps!
Edit: For express.js, you can do this in your handler (I didn't use any render middleware here)
function(req, res) {
    var selection = [{
        name: "sortby",
        label: "Sort By",
        options: [
            { value: "lowtohigh", label: "Price (Low to High)" },
            { value: "hightolow", label: "Price (High to Low)" },
            { value: "new", label: "Newest" }
        ]
    }, {
        name: "availability",
        label: "Availability",
        options: [
            { value: "1", label: "Available" },
            { value: "0", label: "Out of Season" }
        ]
    }];

    var html = "";

    selection.forEach(function(select) {
        html += `<label>${select.label}</label>`;
        html += `<div><select name="${select.name}">`;
        select.options.forEach(function(opt) {
            var selected = (opt.value == req.query[select.name]) ? "selected" : "";
            html += `<option value="${opt.value}" ${selected}>${opt.label}</option>`;
        });
        html += `</select></div>`;
    });

    res.send(`<form method="GET" onchange="submit()">${html}</form>`);
}


"Volatility and the Cross-section of Corporate Bond Returns," (with K. Chung and J. Wang), Journal of Financial Economics, forthcoming.
"Forecasting Corporate Bond Returns with a Large Set of Predictors: An Iterated Combination Approach," (with H. Lin and G. Zhou), Management Science, forthcoming.
"Repo Counterparty Risk and On-/Off-the-Run Treasury Spreads," (with S. Liu), Review of Asset Pricing Studies 7, 81-143, 2017.
"Predictions of Corporate Bond Returns," (with H. Lin and J. Wang), Journal of Financial Markets 21, 2014, 123-152.
"Price Discovery in the U.S. Treasury Market: Automation versus Intermediation," (with K. Man and J. Wang), Management Science 59, 2013, 695-714.
"Liquidity Risk and Expected Corporate Bond Returns," (with H. Lin and J. Wang), Journal of Financial Economics 99, 2011, 628-650.
"Reduced-Form Valuation of Callable Corporate Bonds: Theory and Evidence," (with R. Jarrow, H. Li, and S. Liu) , Journal of Financial Economics 95, 2010, 227-248.
"Are Liquidity and Information Risks Priced in the Treasury Bond Market?," (with H. Li, J. Wang and Y. He), Journal of Finance 64, 2009, 467-503.
"How Much of the Corporate Bond Spread Is Due to Personal Taxes?," (with S. Liu, J. Shi and J. Wang), Journal of Financial Economics 85, 2007, 599-636 (lead article).
"Daily Return Volatility, Bid-Ask Spreads and Information Flow: Analyzing the Information Content of Volume," (with J. Li), Journal of Business 79, 2006, 2697-2739.
"Personal Taxes, Endogenous Default and Corporate Bond Yield Spreads," (with S. Liu and H. Qi), Management Science 52, 2006, 939-954.
"The Role of Earnings Information in Corporate Dividend Decisions," (with J. Hsu and X. Wang), Management Science 44, 1998, S173-191.
"Rational Expectations, Information Signaling and Dividend Adjustment to Permanent Earnings," (with C. Kao) Review of Economics and Statistics 76, 1994, 490-502.
"Tests of Dividend Signaling Using the Marsh-Merton Model: A Generalized Friction Approach," (with C. Kao) Journal of Business 67, 1994, 45-68.
"Information Asymmetry and the Sinking Fund Provision," Journal of Financial and Quantitative Analysis 28, 1993, 399-416.
"Expectation Formation and the Financial Ratio Adjustment Processes," (with Cheng F. Lee), Accounting Review 63, 1988, 292-306; A Reply, Accounting Review 68, 1993, 953-955.
Consultant, Economic Development Institute, World Bank.
Executive Officer, Allied Social Science Association Meetings, 1997-2005.
President of the Society of Economics and Management in Pacific Basin Countries, 2000-2003.


Bring books in the car, on the train, on the bus. Life is busy and many of us spend a lot of time in transit. Reading can take place any time, any where.
Keep books by the front/back doors. Read a page or two while you're waiting to go somewhere or for someone or something.
Read at breakfast/lunch/dinner (especially if there is only one person eating).
Put a lamp next to your child's bed and give them extra time each night to read. Leave the light on extra minutes for reading (10, 20, 30 extra minutes - whatever works for you) or turn the light off at the regular time. Their choice. Most kids will choose to stay up later and read.
Carve out 10 minutes in the afternoon to read.
Show them reading. If you read, they will want to read, too. Whether it's books, magazines, newspapers - read side by side and see what happens.
Ask relatives/babysitters/caregivers to spend 15 minutes reading with your child.
Read aloud - no matter how old or what reading level your child is. According to a report by Scholastic, "83% of respondents ages 6 to 17 relish listening to their parents read them a tale." Also, until about 7th grade, kids' listening comprehension and reading comprehension are different - reading aloud helps bridge that gap.
Read only books your child is interested in. With millions of books to choose from, there is not enough time to read them all so let your child pick the ones they like best. It does not matter if you enjoy the book; it matters if they enjoy it (even Minecraft, Barbie and Spiderman!).
"My son looked forward to seeing his new selections every week and, for the first time, opted to take books in the car to read instead of his Nintendo."


text:
Latest News On Immigration – Home Office Immigration & Nationality Fees 2016
Posted on March 1, 2016 by Charlie in Expert Advisers UK, Fees changes, Immigration Advise, Immigration updates, Lifestyle in London, Lifestyle in UK, Living in the UK, Marriages, Partners, Student Visa, Studying in UK, Tier 1 Visas, Tier 2 Visas, Tier 4 Visas, Tier 5 Visas, Visiting UK
An Update on the latest news on immigration is that UK V&I's (UK Visas & Immigration) fees are going to rise again as expected and announced in January by the Home Office Immigration & Nationality Fees 2016 legislation.
It sets the maximum amounts that the Home Office can charge for visas, immigration and nationality applications. It also sets out the reasoning why the fees were increased by differing amounts.
The latest news on immigration is that further Legislation was laid by the Home Office, in Parliament, on 26 February, which will make changes to specific visa, immigration and nationality application fees.
The new fees will come into effect on 18 March with fees for the Isle of Man coming into effect on 6 April. The three reasons behind the latest immigration news on fees and the 1 Problem they missed (or glossed over) are that the key changes for 2016-17 as follows:
Visas linked to economic growth, e.g. students and workers (most of the PBS [Points Based System] applications), will be increased by 2%.
All Visit Visas will see an increase by 2%.
Fees for all sponsorship categories will be held at the current rates. Watch this space as this will be next for an increase.
"To achieve the government's objective of a fully self-funding border and immigration system, while maintaining competitiveness by protecting work, study and visit routes, larger fee increases will apply to other routes. These include:
Up to 25% increases for settlement, residence and nationality fees. These products deliver the most benefits to successful applicants, for example indefinite leave to enter or remain in the UK, full access to free healthcare and other public services, and unrestricted access to the labour market.
Up to 33% for optional premium services offered by the Home Office such as the super premium service and priority visa services overseas."
The 25% increase will see many migrants unhappy with a large increase in the road to Permanent Residence (PR)/Settlement and Citizenship. Whereas the Premium Service Increases will not mostly go unnoticed until you need a visa quickly.
The Home Office are confident that their fee increases strike the right balance between ensuring they achieve a fully-self funding border and immigration system and continuing to provide a competitive level of service, while maintaining a fees structure that remains attractive to businesses, migrants and visitors.
If you have any queries or comments about these increases, you can contact the Home Office directly at [email protected]
As we keep saying, if you want to make an application to the UK or any other country, planning is necessary. You should have an idea as to what the overall costs and the timescales involved in your stay.
At least this is the only significant latest news on immigration for the UK. Today is the Super Tuesday in the US, and luckily you don't have this guy to deal with too:
Donald Trump's Latest News On Immigration: "Build a Wall". Photo courtesy of Michael Vadon(CC ShareALike)
Seriously, there is no problem when it comes to UK immigration…. does anyone know the latest on the EU Referendum (Brexit) and how it will affect Visas and immigration to and from the UK?
500% Increase in Immigration Tribunal Fees Scrapped
Tier 2 and Tier 4 Visa Changes You Need to Know About
EU Citizens Staying in the UK After Brexit
Home Office Approach to English Language Testing…
latest news on immigration
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