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The long-awaited need for more comprehensive pharmacokinetic investigations of insulin glargine in humans is addressed by the two accompanying articles by Bolli and colleagues ( BOBS from SKECHERSHighlights Set Sail 7bQSh
, Giuseppe Zanotti I770069 JlRhcQBbTD
). From a clinical point of view, it is essential to provide information about the circulating concentrations of the parent compound and its active metabolites using adequate methodologies. These two studies present the first such data in individuals with both type 1 ( 1 ) and type 2 ( 2 ) diabetes using a newly developed specific assay method involving liquid chromatography-tandem mass spectrometry capable of providing discrete measurements of insulin glargine and its metabolites M1 and M2 after their extraction from human plasma using immunoaffinity columns. Insulin glargine was administered to individuals with type 1 diabetes by bolus subcutaneous injection at both therapeutic and supratherapeutic doses (0.3, 0.6, and 1.2 units/kg) in a euglycemic clamp used to define the glucodynamic changes over the study period of 30 h. Each participant received a single dose of insulin glargine. The parent compound, insulin glargine, and the metabolite M2 were rarely detected in plasma above the lower limit of detection at 33 pmol/L (∼6 μU/mL) regardless of the dose (up to 1.2 units/kg). M1 was detected in plasma in a dose-related fashion correlating with the observed glucodynamic changes observed. Importantly, insulin glargine was not detected in plasma at the higher dosage. Essentially similar findings were seen in the type 2 study after the administration of insulin glargine at only a single dose of 0.4 units/kg, with the metabolite M1 being predominant in the plasma with little or no parent insulin glargine or the second metabolite M2 detectable by involving liquid chromatography-tandem mass spectrometry ( 2 ). A similar plasma insulin profile was observed when the radioimmunoassay was used, indirectly confirming the major contribution by the M1 metabolite. There is acknowledgment by the authors that it is also necessary and advisable to examine the metabolism of insulin glargine after prolonged exposure and at even higher doses, which are sometimes used in obese and insulin-resistant individuals.

Therefore, the virtual absence of the parent compound insulin glargine in the circulation after its subcutaneous injection invalidates the submission that the in vitro findings of enhanced IGF-1 binding and mitogenicity of insulin glargine has a clinical correlate, especially as insulin glargine is extensively and quickly metabolized in the subcutaneous tissue and in the systemic circulation to its metabolites M1 and M2, both of which have lesser metabolic and similar mitogenic potency to human insulin ( 15 , 26 ).

The important and definitive findings by Bolli and colleagues ( 1 , 2 ) represent a critical piece of evidence in support of the recent findings of the ORIGIN trial ( 3 ) and the French National Healthcare Insurance Database ( 27 ), neither of which observed an excess risk of cancer during long-term exposure to insulin glargine. It is, however, surprising that it has taken almost 12 years since insulin glargine was first introduced to start to truly understand its metabolic fate in humans after subcutaneous administration despite the early observations by Kuerzel et al. ( 11 ).

In VS Code, we default the language support for a file based on its filename extension. However, at times you may wish to change language modes, to do this click on the language indicator - which is located on the right hand of the Status Bar. This will bring up the Select Language Mode drop-down where you can select another language for the current file.

Select Language Mode

Tip : You can get the same drop-down by running the Change Language Mode command ( Ctrl+K M ).

Change Language Mode

VS Code associates a language mode with a specific language identifier so that various VS Code features can be enabled based on the current language mode.

A language identifier is often (but not always) the lowercased programming language name. Note that casing matters for exact identifier matching ('Markdown' != 'markdown'). Unknown language files have the language identifier plaintext .

You can see the list of currently installed languages and their identifiers in the Change Language Mode ( Ctrl+K M ) drop-down.

You can find a list of known identifiers in the language identifier reference .

You can add new file extensions to an existing language with the files.associations setting .

For example, the setting below adds the .myphp file extension to the php language identifier:

IntelliSense ( Ctrl+Space ) will show you the available language identifiers.

Now you know that VS Code has support for the languages you care about. Read on...

Q: Can I contribute my own language service?

A: Yes you can! Check out the example language server in the VS Code Extension Authoring documentation.

Q: What if I don't want to create a full language service, can I reuse existing TextMate bundles?

A: Yes, you can also add support for your favorite language through TextMate colorizers. See Themes, Snippets, and Colorizers topic in the Extension Authoring section to learn how to integrate TextMate .tmLanguage syntax files into VS Code.

Q: Can I map additional file extensions to a language?

A: Yes, with the files.associations setting you can map file extensions to an existing language either globally or per workspace.

Here is an example that will associate more file extensions to the PHP language:

You can also configure full file paths to languages if needed. The following example associates all files in a folder somefolder to PHP:

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in The Biology Files

An inordinate fondness for systematics

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In an earlier post, I introduced you all to the fusulinids, a group of complex foraminiferans that were abundant during the later Palaeozoic. In that post, I alluded to the complex array of terminology that can be used when describing fusulinids but said that I would rather not cover it at that time. Well, this time I'm going to be dredging some of it up because I've drawn the Fusulinellidae as the topic for today's post. The Fusulinellidae as recognised by Vachard (2013) are a family of fusulinids with fusiform or oblong tests known from the Middle to Late Pennsylvanian (during the later part of the Carboniferous). One genus, , persists into the early Permian (Ross 1999). They are a part of the larger superfamily Fusulinoidea, a group of fusulinids characterised by what is known as a diaphanotheca. This is a thick, more or less translucent layer in the test wall. As noted in my earlier post, such a test structure may have functioned to allow light through to symbiotic microalgae (or possibly captured chloroplasts from algal prey) sheltered within. Fusulinellids are distinguished from other fusulinoids by the structure of the septa dividing chambers within the test, which are mostly flat except for some folding near the poles of the test (in the Fusulinidae, in contrast, the septal walls were folded throughout). As the test developed, sections of the septa were resorbed to form tunnels connecting adjacent chabers (and presumably allowing the transmission of materials between chambers in life). The course of the tunnels is commonly delimited within the chambers by chomata, discrete ridges of shell material. In other species, the chomata are absent but axial fillings of calcite were formed in the chambers instead. Being so widespread and abundant when they lived, fusulinellids are commonly used as index fossils for identifying when a deposit was formed. However, this process is complicated somewhat by ongoing debates about fusulinid systematics. Rauzer-Chernousova (1996) proposed a classification of fusulinids that represented an extensive modification from previous systems. Part of this was simply a question of ranking, with Rauzer-Chernousova recognising many groups at higher ranks than previously (so, for instance, recognising the separate family Fusulinellidae as opposed to its previous recognition as a subfamily of Fusulinidae). Nevertheless, some subsequent authors have felt that Rauzer-Chernousova and their followers attribute too much significance to relatively minor variations. For instance, Kobayashi (2011) synonymised several genera under that Rauzer-Chernousova regarded as belonging to distinct families (and Vachard 2013 even placed in separate superfamilies). Some of the features regarded by Rauzer-Chernousova as indicating separate genera were regarded by Kobayashi as representing variation within a single species. Indeed, there have even been arguments that some 'significant' features may represent post-mortem preservation artefacts (I've come across the term 'taphotaxa' used to refer to taxa based on such features). At present, my impression is that there is something of a geographical divide in preferred systems with eastern European authors following the lead of Rauzer-Chernousova whereas authors from elsewhere may keep to a more conservative arrangement. The Berlin Wall may be down but the Fusulinid Cold War continues. Kobayashi, F. 2011. Two species of ( and ), early Moscovian (Pennsylvanian) fusulines from southern Turkey and subdivision of primitive groups of the family Fusulinidae. 117 (1): 29–37. Rauzer-Chernousova, D. M., F. R. Bensh, M. V. Vdovenko, N. B. Gibshman, E. Y. Leven, O. A. Lipina, E. A. Reitlinger, M. N. Solovieva I. O. Chedija. 1996. . Rossijskaâ Akademiâ Nauk, Geologičeskij Institut, Moskva "Nauka". Ross, C. A. 1999. Classification of the Upper Paleozoic superorders Endothyroida and Fusulinoida as part of the class Foraminifera. 29 (3): 291–305. Vachard, D., K. Krainer S. G. Lucas. 2013. Pennsylvanian (Late Carboniferous) calcareous microfossils from Cedro Peak (New Mexico, USA). Part 2: smaller foraminifers and fusulinids. 99: 1–42.

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Next, let’s make the movement of turtles use up some of the turtle’s energy.

As each turtle wanders, it will lose one unit of energy at each step.

You’ll see the patches turn black as turtles travel over them.

Next you will create two monitors in the Interface tab with the toolbar. (You make them just like buttons and sliders, using the Add icon on the toolbar.) Let’s make the first monitor now.

A dialog box will appear.

turtles is an “agentset”, the set of all turtles. count tells us how many agents are in that set.

Let’s make the second monitor now:

Here we’re using count again to see how many agents are in an agentset. John VarvatosWaverly Covered Chelsea Jq1m9XDr
is the set of all the patches, but we don’t just want to know how many patches there are total, we want to know how many of them are green. That’s what with does; it makes a smaller agentset of just those agents for whom the condition in the brackets is true. The condition is pcolor = green , so that gives us just the green patches.

Now we have two monitors that will report how many turtles and green patches we have, to help us track what’s going on in our model. As the model runs, the numbers in the monitors will automatically change.

The turtles aren’t just turning the patches black. They’re also gaining and losing energy. As the model runs, try using a turtle monitor to watch one turtle’s energy go up and down.

It would be nicer if we could see every turtle’s energy all the time. We will now do exactly that, and add a switch so we can turn the extra visual information on and off.

A dialog will appear.

The eat-grass procedure introduces the ifelse command. Look at the code carefully. Each turtle, when it runs these new commands, checks the value of show-energy? (determined by the switch). If the switch is on, comparison is true and the turtle will run the commands inside the first set of brackets. In this case, it assigns the value for the energy to the label of the turtle. If the comparison is false (the switch is off) then the turtle runs the commands inside the second set of brackets. In this case, it removes the text labels (by setting the label of the turtle to be nothing).

(In NetLogo, a piece of text is called a “string”, short for string of characters. A string is a sequence of letters or other characters, written between double quotes. Here we have two double quotes right next to each other, with nothing in between them. That’s an empty string. If a turtle’s label is an empty string, no text is attached to the turtle.)

When the switch is on, you’ll see the energy of each turtle go up each time it eats grass. You’ll also see its energy going down whenever it moves.

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