James Scott-Brown

Why Python

2015-03-23T00:00:00+00:00

Why Python

Python has recently become my default language for new projects. There are several reasons to use python.

Because it is very readable, and “can be seen as either a practical (better libraries) version of Scheme, or as a cleaned-up (no $@&% characters) version of Perl” (Norvig). Treating incorrect indentation as a syntax error is very helpful when working with people who would otherwise indent code at random.

Because it is good at a wide range of tasks, it is causing the “The homogenization of scientific computing . . . steadily eating other languages’ lunch”, and is “all a scientist needs”. In contrast, MATLAB feels extremely powerful within one domain (essentially anything involving a matrix), but extremely clunky outside it (particularly anything involving a string).

Because IPython notebooks are awesome for rapid prototyping, as well as communicating with others. But, if you’d prefer a GUI that looks a bit more like MATLAB, there’s also spyder.

Because there are many other reasons to “push for Python”.

Bookmarklet for Oxford Off-Campus Journal Access

2015-03-23T00:00:00+00:00

Bookmarklet for Oxford Off-Campus Journal Access

I often want to read academic papers that are behind paywalls on my laptop when it is not connected to an internal university network.

Whilst I could use the university VPN, I may not want to route all of my network traffic through it - I just want a proxy for a single URL.

When I was at Cambridge they advertised a useful bookmarklet for Off-Campus Journal Access - you could add it to your bookmarks menu, then:

“When on a journal page that should provide full text access under a Cambridge subscription, click on the ‘Reload URL for off campus access’ text in your browsers’ bookmark bar to reload the page via our proxy server. You may be prompted to login with a Raven username and password.”

I tried to find an equivalent bookmarklet for Oxford, but couldn’t, so resorted to modifying the Cambridge one. I present it here to help anyone else Googling for it.

The URL to bookmark is:

javascript:void(location.href=%22http://ezproxy.ouls.ox.ac.uk:2048/login?url=%22+location.href)

Or you can simply drag this link to your bookmarks bar: Oxford Off-Campus Access.

Short links - 2015-03-1

2015-03-01T00:00:00+00:00

Short links - 2015-03-1

Following the example of Geeking with Greg and the O’Reilly Radar, I thought I would start periodically posting a round-up of links to things I found interesting.

Science

Nature has a poster on CRISPR-Cas
The University of California has announced a new journal Collabraoa, which will have several nice features: open access, optional Open Peer Review, payments for reviewers and editors.
Video of session from SB6 on Assessing Risk and Managing Biocontainment At 1.13 “Hi, I’m with the FBI and I guess I would be the higher authority”

Tech:

A good example of building a better interface around publicly released data - the Handsome Atlas (via Dr. Bunsen)
Similarly, online tools provide a better interface for working out how to use Unix tools: .bashrc calculator, file permissions calculator, regex builder and tester, crontab calculator
Devising efficient representations for things makes them easier to remember - Hacking Scrabble (Related - the Mnemonic Encoder)
The Facebook Demetricator is “a web browser extension that hides all the metrics on Facebook”
To fulfil it’s aim of Making Wrong Code Look Wrong Hungarian notation needs to indicate the kind of value a variable stores, not its type
Distributed chat is possible using an RC airplane to relay messages between two computers that it can’t simultaneously see
Forecast.io cleans up weather radar by segmenting images, then classifying each blob as either signal or noise with a 25-neuron neural network.
Cirqoid described itself as ‘your PCB lab on your desk’ - “Cirqoid can do insulation milling of your PCB (aka mechanical etching), drill holes, dispense solder paste and even populate the board with SMD components. That’s right - complete production cycle of a printed circuit board”

My Setup

2015-03-01T00:00:00+00:00

My Setup

I use three computers - an iMac, a MacBook pro, and a DigitalOcean VPS. The iMac is connected to an external monitor in portrait orientation (as is the MacBook, when on my desk at work) - the marketing term for monitors that can switch between portrait and landscape is pivot, not rotate.

Folders that I use frequently are kept in sync between the iMac and MacBook using unison.

Papers are stored in I, Librarian. This is installed on both my MacBook and VPS, but papers are only ever imported into the installation on the VPS: if I can’t access this, it’s because I don’t have an Internet connection, so can’t download any new papers anyway. The library subfolder on the VPS is frequently backed up to my MacBook using rsync, so I can still read papers and annotations when offline.

I use FastMail for email (and contacts, and calendars), and back this up locally with OfflineIMAP. Given DuckDuckGo and OpenStreetMap, I am largely independent of Google’s services: some reasons why this is a Good Thing are given by Scott Lowe and Marco Arment.

RSS feeds are read using Miniflux on the VPS. Miniflux is Good Enough: it can import OPML, doesn’t need MySQL/postgres (it uses SQLite), has a reasonable interface that works on mobile devices as well as desktops, and can send links to pinboard or instapaper but has no social media integration. There seem to be a lot of feed readers available, and so there may well be an alternative that is ‘better’, but looking for the optimum rather than just satisfying seemed like a waste of time.

I keep notes in NValt. A script commits changes to a .git repository, which are then pushed to a remote on the VPS. This gives version control over my notes, as well as sync (which is done over SSH, whereas simplenote sync is done in plain text). A second script extracts structrued information, and constructs HTML tables indexing the recipes, books, and talks I’ve made notes on.

I use homebrew and homebrew cask as package managers: they’ve been used to install several of the programs I’ve mentioned, as well as several useful unix ffmpeg, imagemagick, graphviz, the_silver_searcher, and youtube-dl (particularly useful in letting me download long videos so I can play them back at 1.5-2x speed in VLC). I also use several Mac-specific utilities: QuickSilver, flux, caffeine, DoublePane, iTerm2, and jitouch.

Many of my documents are written as markdown, then converted to PDF via LaTeX using pandoc. This has all the advantages of LaTeX, whilst having source files that are clearer to read and faster to type. If I want to do something like include a listing of source code from another file, I use MarkdownPP.

My blog is also written in markdown, using the static site generator with Jekyll. The resulting HTML is then scp‘d to the VPS.

Most things are thus stored on more than one of my three machines, giving some redundancy against failure or loss of any one of them. Assuming it has jsut been synced, the contents of my MacBook are a strict subset of the contents of my iMac. My iMac is backed up to an external HDD (using Time Machine), which is stored off-site.

Papers

I have been a user of Mekentosj’s Papers since the initial Public Preview in 2007. However, reviews on blogs suggested some problems with Papers 3. Most annoyingly, syncing between two computers (eg. desktop and laptop) could only be done though Dropbox - and my papers library was larger than the 2GB limit of Dropbox’s free plan.

Things may have improved since, but this was enough for me to look for alternative options rather than upgrading. By now, several of the most popular programs are owned by huge publishing conglomerates:

Papers (Springer)
Mendeley (Elsevier)
ReadCube (Macmillan ¹)

In addition to this, there’s EndNote (non-free, clunky), Zotero (a browser extension, then converted into a Standalone application using XULRunner), and various competitors.

In the end I opted for I, Librarian, which runs in the browser. It is available as a hosted service, or can be hosted yourself (PHP, backed by a sqlite database, so no need to install MySQL or Postgres).

Because it runs in the browser, if I am reading/annotating several PDFs at once, I can organize them into multiple windows, not just tabs.

It’s open-source and, importantly, implemented in a language (PHP) with which I am familiar. In principle, this means it should continue being useful to me even if it were abandoned by its developer; in practice it’s allowed me to make a few small tweaks.

I was able to write a python script to export my library from Papers to i-Librarian (both store libraries as directories of PDFs, with metadata stored in SQLite). This is rather rough, but can share it if it would be useful to others.

Macmillan have invested in Labtiva via DigitalScience, but I don’t know the extent of this investment. ↩

Recording PDFs read in Skim

2013-05-09T00:00:00+00:00

Recording PDFs read in Skim

I have a large number of reference PDFs, only some of which I have actually referred to.

I wanted a quick way to record which I had referred to, when, and why, in a single text file that I could easily review or grep through.

My solution was the following Applescript, which I associated with a keyboard shortcut using Quicksilver’s Triggers feature.

tell application "Skim"
	set page_no to current page of document 1
end tell
display dialog "Description" default answer "p." & (index of page_no)
set the str_descr to the text returned of the result

tell (current date) to get (it's year as integer) & "-" & (it's month as integer) & "-" & day
set str_date to the result as text

tell application "Skim"
	set str_pdf to name of document 1
end tell

set str_details to (str_date) & "	" & str_pdf & "	" & str_descr & return
set file_name to (((path to home folder) as string) & "PDFs Read")

set the file_name to the file_name as string
set the open_target_file to open for access file file_name with write permission
write str_details to the open_target_file starting at eof
close access the open_target_file

When run, this identifies the file in the Skim window that currently has focus, brings up a dialog prompting for a comment (pre-filled with the page number), then appends a line formatted as <date>\t<filename>\t<comment> to a text file named “PDFs Read” in your home directory.

Good Lecture Notes

2013-05-09T00:00:00+00:00

Good Lecture Notes

Over the past three years, I’ve attended a lot of lectures, given by a large number of lecturers from several departments.

Generally, these have been courses for scientists and engineers, with fairly complete handouts.

However, there are certain desiderata that are not always met, and so are worth listing explicitly. Ideally, all hand-outs should:

Include your email address, so that you can be sent corrections or suggestions.
Include suggestions of appropriate readings on the cover-page.
Include page numbers on every page.
State the source of all figures (if these mostly come from one source, include a comment like ‘Figures are from Molecular Biology of the Cell/Introduction to Neural Science/etc. unless otherwise noted’)
Not include every intermediate state of a powerpoint transition unless this is necessary for clarification, or to provide space for annotations

If possible, handouts should be hole-punched, so they can be immediately filed after the lecture, rather than being carried loose.

Lecture notes should be given out at the start of a lecture. Lecture notes help the audience to think about what is being said, by removing the need to frantically transcribe everything; this is not possible if they are withheld until after the lecture.

Some lecture notes include gaps to be filled in during lectures. This strategy might help to discouraging students from skipping lectures, or falling asleep during them. On the other hand, such students might just copy from their friends’ notes later. When it comes to revision it is certainly reassuring to have a set of notes which are known to be complete, legible, and free from transcription errors.

Compiling a comprehensive biomedical/chemical spell-check dictionary

2013-01-10T00:00:00+00:00

Compiling a comprehensive biomedical/chemical spell-check dictionary

I often type biomedical or chemical terms which are not recognised by default spell-checkers.

When all technical terms are highlighted as being misspelt, it is much harder to spot where you have actually made typos.

A while ago, I therefore programmatically created a large word-list of technical terms. This was derived from a number of sources:

The NCBI SPECIALIST Lexicon
OpenMedSpel - 48,729 entries
ChemiDic - 166,611 entries

The NCBI lexicon contains lexical details of words (part of speech, etc.), so I extracted only the words with a regex. I then concatenated the files, sorted them with sort, and remove duplicates with uniq. A little additional processing was also performed.

The result is a single file with 371,261 entries. This includes almost all the terms that I am likely to use, plus many that I am not. There are some gene names that possibly shouldn’t be there (whsc1l2p), but I’ve resisted the urge to manually delete entries.

The file is long enough that, after concatenating it to the end of ~/Library/Spelling/LocalDictionary on my mac, and logging-out and -in again, almost all of the spurious squiggly lines disappear. Even more useful, I now get suggestions for how to spell obscure words like woytkowskii or wiedemann-rautenstrauch.

Single day Hall Menu for Trinity today

2012-12-20T00:00:00+00:00

Trinity College provides copies of its Hall menus online. These are in the form of PDF files, each representing the menu for one week as a table with one column per day.

It would be more convenient to be able to see just the menu choices for the current day, so I created a page to do this.

My first thoughts were that I could write a script to download the menu for the coming week, and then use ImageMagick to extract rectangular regions corresponding to each day. However, the width and height of columns in the table changes, so it is necessary to find the positions of the line in the table separately for each PDF. This task is greatly simplified by the fact that the lines are horizontal or vertical, and their length is a large proportion of the height/width of the image. This suggests that they can be found by looking for rows and columns in the image containing a large number of black pixels.

To test if this idea was feasible, I downloaded a menu, and converted it to a png with ImageMagick (convert -density 600x600 menu.pdf menu.png), then did some investigating with Matlab:

I = imread('menu.png');  % Load the image
imggrey = I(:,:,1);      % Extract only the blue channel (the menu is B&W, so each pixel has equal values of R/G/B) 
plot(sum(imggrey,1));    % Plot the sum of the values in imggrey down each column 
plot(sum(imggrey,2));    % Plot the sum of the values in imggrey across each row

Repeating this for a few menus and looking at the resulting plots confirm that the lines can be easily located by summing the intensities all pixels in each row and column, then identifying the sums that are below a threshold.

To actually do the processing, I wrote a small program in C++, using the CImg library, a “small, open source, C++ toolkit for image processing”. I chose this library because it is lightweight and portable: there is a single header file to include in my program, with no dependencies or library installation problems to contend with.

How I keep notes

2012-12-11T00:00:00+00:00

How I keep notes

I keep a large number of notes in Notational Velocity, which has two key advantages: entering and subsequently retrieving notes is very fast, and notes can be stored as individual text files in a directory.

Speed

Creating a new note requires no mouse-clicks, and only a few key-presses: Cmd-space to open Quicksilver, “no” to select notational velocity, and enter to launch it. Then Cmd-L moves the cursor to the title area, and I can type the title for the new note. Hitting enter moves to the body of the note, so I can type the note itself, then hit Cmd-Q to close the application and go back to whatever I was doing.

This is incredibly fast, and makes note-taking minimally disruptive to other tasks.

Searching notes is similarly fast: typing anything in the title area displays a filtered list of notes. You can click on the desired note directly, or move through the list with Cmd-J/Cmd-K.

Syncing

Notational Velocity can sync its notes with simplenote, so that they can be accessed and edited in a web browser or the iPhone/iPad app. This allows me to taking notes with the simplenote app on my iPad during a talk, and have them be searchable in Notational Velocity as soon as I get back to my room. It also means that I have all of my notes with me wherever I am (which would not be true if I had separate paper notebooks).

Directory of text files

By default, Notational Velocity saves notes in a single file, but it also offers the option of saving one plain-text file per note (Notational Velocity -> Preferences -> Notes -> Storage). By default, these are saved in ~/Library/Application Support/Notational Data/.

I have a cron script on my computer that commits this directory into a Git repository every 15 minutes. Not only does this give me some protection against accidentally deleting or overwriting part of a note, but it also allows me to go back and check exactly when I edited each note and how they changed over time.

At the top of some notes, I also attach metadata. This is ignored by Notational Velocity and Simplenote, but is very useful to me. For example, a recipe may begin:

Title: Herman the Friendship Cake
Type: Baking
Tried: Rachel made it; it was good
#recipe

For several common types of notes (recipes, talks etc.) I have snippets set up in TextExpander. This means that I can just type “;recipe” and have an appropriate template appear, ready to be filled in.

I wrote a series of ruby scripts that goes through each file, and does useful things with the metadata that I’ve added. For example, I can view a random recipe (note containing “#recipe”) with ./NVrandom.rb recipe. Alternatively, I can produce a tab-separated values file containing one row per recipe, and one column per key (eg. title, type, tried): ./NVtabulate.rb recipe > recipes.tsv. Then I can open this file in Excel: open -a "Microsoft Excel" recipes.tsv.

Note that the metadata system is very flexible: the keys do not have to be predefined. If I wanted to add a new key to one recipe to mark it as vegetarian, I can just type “Vegetarian: yes” at the top of the note, then rerun ./NVtabulate.rb. A column will appear labelled ‘Vegetarian’, even though it is empty for all but one note.

Notational Velocity allows you to add links from one note to another (with the same [[target]] syntax as Wikipedia/MediaWiki). I have another script that lets me see the network of links by outputting a .dot file that can be opened by GraphViz.

What we don't know

2012-12-10T00:00:00+00:00

What we don’t know

Last year, whilst going through lecture notes for the BMB and CDB courses at Cambridge, I decided to collate the comments about things that were not known.

The result is this list of some of the things we don’t know about biochemisty/molecular biology/cell biology.

Each bullet point is a direct quotation from lecture notes; comments in square brackets were added by me as explanation.

Things ‘Unknown’:

Analysis of Arabidopsis genome sequence identified 450 genes for PPR proteins – all predicted to be targeted to chloroplasts or mitochondria. Roles of most unknown, but some shown to be important for splicing, translation, and editing of chloroplast transcripts.
b559 is cytochrome of unknown function.
However, cloning of the receptor revealed a thrombin-cleavage site close to the N terminus, and functional studies showed that thrombin clipped off a short peptide (whose function is unknown), revealing a new N-terminus with the sequence Ser-Phe-Leu-Leu-Arg—-. This peptide binds to the receptor, activating it conventionally.
The location of the secretion “signal” in the structurally-diverse proteins targeted through the Type II pathway is unknown.
The default state for var genes is to be silenced; this property is conferred by telomeric location and by an unknown mechanism involving sequences in the intron and exon 2 and probably involves chromatin remodelling during replication
A common way of making E. coli competent is to treat them with CaCl2, which works by an unknown mechanism to permit them to take up DNA when they are subjected to a heat shock.
The detailed mechanism of plasmid partition is unknown but some years ago a plausible scenario was described in the pre-pairing model (Fig. 12) which proposes that a monomeric protein binds to a centromere-like site on individual plasmids.
In any case, selective retrograde transport by COPI vesicles must play an import role for intra-Golgi sorting; the necessary sorting signals however are still largely unknown.
Later in development, the GLP-l protein is involved a second time in signalling that is required for anterior pharynx formation. GLP-l acts as the receptor on the ABa derived cells for the unknown ligand from the MS cell.
Live cell imaging shows that this secretion is mediated by tubular carriers, which are “pulled” out of the TGN by molecular motors. Surprisingly, these carriers have not been characterised in detail, and it is still not known what protein coat (if any) they require.
The basis for the different affinities [of Erd2 for its cargo] in the ER and ERGIC is not known; it seems plausible that differences in pH and ionic environment could be accountable.
Cloning strategies have allowed a large number of novel receptors to be identified as orphans, i.e. their ligand is not known.
The role of SRC in the normal cell cycle is not known
The active component of the germ plasm is not known, but it is interesting that the germ plasm contains the homologues of some genes that are expressed in the pole plasm of Drosophila
Use of a dominant-negative receptor shows that activin-like signalling is required for normal mesoderm formation, but it is not known which of the above factors is most important in this process.
What is the molecular nature of the trigger that initiates the activation of Cdk1. The precise nature of the trigger is not known but it is believed it is centred on the spindle pole body/centrosome.

Things ‘Unclear’:

Other types of activation domain have more recently been discovered (“glutamine-rich”; “proline-rich); significance unclear.
Whether both branches [of PS1] are active is unclear.
Kinetochore MTs shorten by the net loss of tubulin from their kinetochore ends. Yet, how MT depolymerization at the kinetochore drives chromosome movement (without MTs letting go of the kinetochores!) remains unclear.
Inactivation of AS160 in response to insulin signalling results in increased Rab GTP loading and thus allows translocation to the plasma membrane. However the exact mechanism remains unclear.
The actual composition of the pore is controversial and still unclear, but a key component is probably the adenine nucleotide translocator, which forms a pore when high levels of calcium bind to the matrix side of the translocator.
Very recent genomic research provides accumulating evidence for many more narrowly defined origins and initiation zones, many of which are located in the vicinity of active gene promoters. However, the genetic and epigenetic factors that determine an active origin, or that determine its activation timing are still unclear.
Brefeldin is a very useful drug for disrupting Golgi apparatus integrity, even though it is not clear what physiological significance the Golgi-derived tubules have.
Not clear whether it [Z DNA] exists in vivo
In solution, DNA is usually B-form and this is the major form in the cell. Dehydration (in fibres, many crystals) produces A-form; not clear whether any significant stretches of A-DNA exist in vivo (although RNA-DNA hybrids are A-form).
In summary, in eukaryotes supercoiling could be generated locally by transcription. Not clear that there is a role for it in driving transcription, e.g. by promoter unwinding.
The H+/2e- stoichiometry of complex I is 4, but the mechanism of proton coupling is not clear.
However the causes and mechanistic basis of type 2 diabetes are not clear.
Curiously, the active sites [in TIM barrel proteins] are found at the C-‐termini of the β-‐strands and N-‐termini of the helices; it is not clear that this can always be explained in terms of helix dipoles or divergent evolution.
Several receptor specific kinases are known, but it is not clear whether all 7TM receptors are susceptible to their action.

Things ‘Not Understood’:

Sorting into regulated secretory vesicles is not understood in detail. It is likely to involve kin recognition, as well as retrograde sorting of unwanted proteins from budded immature secretory vesicles.
Di-acidic sequence motifs (DXD, DXE, EXE) in the cytoplasmic domains of integral membrane proteins are known to mediate incorporation into COPII vesicles; they are recognised by the Sec23/Sec24 dimer. Generally, however, the sorting signals necessary for ER exit are not well understood.

Uncertainty that ‘Remains’:

It has also been proposed that RI- and RII-containing isoforms of PKA may be regulated by different ligands in the same cell type, implying that these may be expressed in different compartments within the cell. The basis for this remains to be established.
The relationship between IP4 and Ca2+ entry remains contentious after many years.
PI-3 K can also phosphorylate PI and PIP at the 3 position, generating novel isoforms of PIP and PIP2. Whether these lipids serve a signalling function remains to be seen.
The regulation of cPLA2 remains unclear.
It is interesting that carbon monoxide (CO) appears to couple to GC in the same way. (This might be anticipated, given the known binding of CO to haem in haemoglobin.) Any physiological significance of the action of CO remains to be established.
Whether the fly centromere is a good model for other eukaryotic centromeres remains to be seen.

A complete index for XKCD

2010-09-11T00:00:00+00:00

A complete index for XKCD

When searching for a particular image that had appeared in XKCD to show a friend, I wondered if there was an index of all the XKCD comics, and all their associated meta-data (Title, URL, Image URL for hot-linking, Description, and the hover-text). There wasn’t. So I created one.

~~View it as a tab-separated file as a ~~github Gist~~, or a Google Spreadsheet.~~

Update: the google spreadsheet is automatically updated by a perl script using Net::Google::Spreadsheets, which is called by cron. My script originally parsed HTML pages, until I realised that XKCD has a JSON interface.

Update 2 (2015-03-24): This has been replaced by a a simple table

Drugs and History

2009-09-16T00:00:00+00:00

Drugs and History

The following is a transcript of a short talk which I recently gave.

Last term, I was reminded of a quote by Les Iversen: ‘‘It was amazing to find out how much they influenced our lives in the 20th Century’’¹

He was talking about the amphetamines, but he could have been referring to any of many different drugs just as truthfully. Today, I’d like to describe how a few have influenced the modern world. The importance of medicines to maintaining health and extending life is obvious, so I won’t discuss it further. Instead, I’ll talk about more subtle effects.

This image shows a protein. Specifically, it’s the Nicotinic Acetycholine receptor. There are actually two slightly different forms of this protein: one found in muscle cells, the other in nerve cells.

Consequently, nictotine will bind to the receptors in the brain, but not in the muscles. If it bound to both, it would have the same effect as venom in the fangs of a cobra, or curare on the tip of an arrow - it would kill you, very quickly. But it doesn’t, and so smokers live long enough to get addicted². This turns out to be extremely important, not only because it has caused countless millions of excess deaths, but also because it has enabled those who produce tobacco to make billions.

Those who profited included settlers in the Colony of Virginia. Despite what some people may tell you, the first permanent settlers in America were not puritans seeking religious freedom in Massachusetts, but pragmatists wanting to make a quick buck in Virginia.

First, they tried mining, but that wasn’t profitable. Then they tried growing silk; but that wasn’t profitable either. Finally John Rolfe, the husband of Pocahontas, grew tobacco, and the economic security of Virginia was established.

Interestingly, some realised the dangers of tobacco at the time: King James wrote a pamphlet calling it a ‘noxious weed’ that was ‘hateful to the Nose, harmful to the brain, dangerous to the Lungs’³. These comments were remarkably prescient, coming 350 years before the British Doctors Study was to provide conclusive evidence of a link between smoking and diseases such as lung cancer and heart attack.

As well as establishing a foothold for British colonies in America, Virginia was important to the American war of independence. It was in Virginia, at Yorktown, that the british general Cornwallis surrendered, ending the conflict on land. And during the war, Virignia’s Governor was Thomas Jefferson, the principal author of the Declaration of independence.

And now, back to amphetamine. It’s been used by a lot of writers, including Jack Kerouac (whilst writing On The Road) and Philip K. Dick⁴.

Mathematicians, too: Paul Erdos⁵, one of the most prolific mathematicians of the twentieth century, used to take it. Had he not, a lot of people would probably have rather higher Erdos Numbers.

Much has been written about amphetamine use by soldiers, especially special forces, both in non-fictional accounts in the medical literature, and in novels, such as Cruel Sea. But it’s also been used by politicians. Most notably, Prime minister Eden started taking it after a botched operation on his intestine. It is believed to have altered his personality, making him more paranoid, and ultimately contributing to his decision to become involved in the Tripartite Aggression⁶. The idea was that control of the Suez canal could be wrested from the Egyptian government if the Israelis invaded the Sinai, and then British and French troops entered as ‘peace-keepers’. This was an absurd idea, and, predictably, failed, after both the US and UN refused to support it.

The black discolouration of this rye is due to a fungus called Claviceps purpurea; or, more commonly, ergot.

During the middle ages, there were periodic epidemics of St. Anthony’s fire, a gangrenous disease caused by eating the fungus. In it’s more acute form, ergot poisoning has symptoms including seizures, vomiting, and hallucinations. Most hallucinogens have been used for ritual purposes, and ergot is probably no exception. Several bodies recovered from peat bogs - most notably Graubelle Man and Tollund Man, which were found in Denmark - seem to have been force fed ergot before their death.

Some historians have suggested that the girls whose allegations of witchcraft led to the Salem Witch Trials were suffering from the effects of ergotism⁷. However, this idea is controversial, and others claim that if it were true, there would be records of the girls vomiting, and others in the village would have also shown symptoms⁸.

Several centuries later, a swiss chemist produced a number of drug candidates from ergot. He decided to repeat the synthesis of one, ingested some, and had one of the most interesting bicycle rides home in history. The chemist’s name was Albert Hoffmann; the drug’s, LSD. Very soon, a lot of people were very interested in using LSD, including psychiatrists trying to improve the effectiveness of psychoanalysis and treatment for alcohol addiction, hippies wanting to ‘‘turn on, tune in, drop out’’ - and the CIA.

The CIA were very interested in using LSD to make uncooperative captives talk, and to modify the behaviour of foreign leaders. Its MK-ULTRA project included the administration of LSD to a variety of subjects, many without their knowledge or consent. At least two of them - Harold Blauer and Frank Olson - died as a result.

Such experimentation was in violation of the Nurenberg Code, which had been established after the trials of German doctors who’d conducted medical experiments on prisoners during the second World War. The US government had sentenced those doctors to death, and yet - just a few decades later -its own employees were conducting similar experiments. And, after 9-11, the CIA began to use interrogation techniques such as water-boarding, which it had considered a war-crime, when it had been conducted against, rather than by, US citizens.

Similar duplicity occurs not only in international relations, and the operating procedures of intelligence agents, but also in the enforcement of drugs policy. In January, for example, the government upgraded cannabis from a Class C to a Class B drug, against the advice of the Home Office Advisory Council on the Misuse of Drugs[^fnref9]. At the same time, it does nothing to increase the price of alcohol, despite the advice of experts that this would be the most effective way to reduce alcohol related deaths.

The CIA mis-stepped because it fixated on fantasy applications for LSD, ignoring the ethical implications of its experiments. Gordon Brown mis-stepped because he chose policies based on their appeal to voters, rather than their effect on public health. If there is a moral to this assembly, it is that little things can have big effects, and we should not lose sight of what is truly important when confronted with decisions. But you knew that already. Thank-you for listening.

T[^fnref9]: his advice was expressed in a report entitled Cannabis: Classification and Public Health. The Chairman’s covering letter noted that ‘You will note that, after a most careful scrutiny of the totality of the available evidence, the majority of the Council’s members consider, based on its harmfulness to individuals and society, that cannabis should remain a Class C substance.’

Personal correspondence, 5 Jun 2007 ↩
Xiu et al. Nicotine binding to brain receptors requires a strong cation-pi interaction. Nature (2009) vol. 458 (26 March 2009) pp. 534-537 ↩
A Counterblaste to Tobacco, King James I, 1603 ↩
Williams. The true story of Philip K Dick. Rolling Stone (1975) (November 6) pp. 44-48, 50, 88, 91, 93-4 ↩
Hoffman. The Man Who Loves Only Numbers. The Atlantic Monthly (1987) (November 1987) pp. 60-74 ↩
Leslie Iversen Speed, Ecstasy, Ritalin: The Science of Amphetamines, Oxford University Press ↩
Caporael. Ergotism: The Satan Loosed in Salem?. Science (1976) vol. 192 (4234) pp. 21-26 ↩
Spanos and Gottlieb. Ergotism and the Salem village Witch Trials. Science (1976) vol. 194 (4272) pp. 1390-94 ↩

Kite Diagrams

2009-09-05T00:00:00+00:00

Kite Diagrams

In ecology, measurements of abundance made along a transect are often represented on kite diagrams. Essentially, these are line graphs, in which each line is translated vertically so that it does not overlap the others, and reflected in its x-axis. The space between the reflections is then shaded.

Unfortunately, these are awkward to draw by hand. They are frequently plotted on graph paper in its landscape orientation, requiring that several sheets be stuck together in order to represent the full set of measurements. This is messy, and results in a low information density. Consequently, it is desirable to produce kite diagrams with a computer, rather than ruler and pen. Some suitable software exists, but mostly as plugins for Excel (EasyStats, Merlin), a proprietary software package with a long history of computational errors and inadequacies.

I therefore wrote my own program to draw kite diagrams. It accepts the name of a CSV file as its only argument. The first line of this file is a header specifying the labels to print at each tick on the x-axis. Subsequent lines consist of a species name, then list of measurements. Output is written to a file as postscript.

Example input file:

` 0,5,10,15,20,25,30,35,40,45,50,55,60,65,70,75,80 Sea pink, 0,0,0,0,3,0,0,6,6,3,0,0,8,22,0,0,0 Sea lavendar,0,0,0,0,0,0,0,4,0,0,30,0,16,16,17,0,0 Saltmarsh grass,0,0,0,0,0,15,0,0,0,0,50,100,49,50,83,100,0 Glasswort,10,0,35,5,0,40,8,4,0,0,20,0,11,1,0,0,0 Sea plantain,0,0,0,0,0,0,0,0,38,0,0,0,0,0,0,0,0 Sea Purslane,0,1,4,77,0,27,52,0,0,0,0,0,12,11,0,0,0 Sea rush,0,0,0,0,0,18,38,34,6,0,0,0,0,0,0,0,0 Sea couch,0,0,0,0,52,0,0,0,0,0,0,0,0,0,0,0,0 Cord Grass,22,0,5,0,0,0,0,0,0,0,0,0,0,0,0,0,0 `

Becomes:

(PDF available.)

The perl script can be downloaded here. After downloading, change the extension from .txt to .pl .

Using perl to find words in the periodic table

2009-08-30T00:00:00+00:00

Using perl to find words in the periodic table

I’ve just come back from a ‘Lower Sixth Chemistry Olympiad Event’ that the RSC hosted at St. Catherine’s College, Cambridge. Over dinner on the first night, one of the organisers asked us for the longest word we could write using just the symbols of the elements. After a few people suggested a few, fairly short, words, I said that the only sensible way to solve the problem was with a perl script. But Bryant Tan proved me wrong with a C++ program. After I provided a dictionary file (2of12.txt from 12dicts) and list of elemental symbols, we concluded that the longest were probably OVErSUPErSTiTiOUSNeSS (at 21 letters) and CONSUBSTaNTiAtION (at 17).

On the second day, Bryant commented that it was surprising that the word ‘chemistry’, nine letters long, contained no repeated letters. By writing a perl script, I found one such word 14 letters long (ambidextrously).

Arrows

2009-08-20T00:00:00+00:00

Arrows

Arrows have been used to communicate an enormous variety of different concepts. They can represent almost any relation between two objects (or sets of objects). For clarity, when different relations must be shown in close proximity to one another, they are depicted by visually distinct arrows; over time many specific styles of arrow have acquired particular meanings.

These meanings are often idiomatic to a particular field: the curly arrows that indicate electron movement, or the double arrows showing that a reaction stops at equilibrium rather than going to completion, are not used outside of chemistry. The US military uses a large set of arrows (at least 30) to depict specific troop movements and attacks in their tactical mission graphics. Chemists use fewer: I have tabulated some of the most commonly used below.

Some arrows have very different meanings in different contexts: in mathematics, the double arrow represents logical implication (‘if X is true, then Y must be true too’); in chemistry, it is the retrosynthetic arrow, (‘X can be produced from Y’).

A few arrows do not represent relationships, but things themselves. For example, an arrow may represent a vector (such as a force or velocity) in a diagram.

Recipeconverter

2009-08-06T00:00:00+00:00

Recipeconverter

I’ve written a utility to convert lightly formatted text files (like this) into a LaTeX snippet coding for a pretty graphical layout:

The code is in a, GitHub repository.

Has man lost the battle against infectious disease?

2009-08-03T00:00:00+00:00

Has man lost the battle against infectious disease?

It is often said that humans are losing the battle against disease. I disagree. Our opportunities are ongoing, progress continues, and we are winning the battle. The efforts of human to control infection have a long history, though in the past they were often ineffective. Early efforts control the plague failed, because they were based on the flawed belief that it was caused by a ‘bad air’ or miasma, rather than recognising that it was caused by an infectious agent transmitted by fleas carried by rats. However, after the acceptance of the germ-theory of disease, many effective interventions were developed. Lister’s use of carbonic acid to reduce infections during surgery set a precedent for the sterilization of surgical theatres and instruments, which has undoubtably saved countless lives.

There are many cases in which epidemics have been ended by careful interventions, such as cleaning water in areas where water-bourne infections are occurring (however, the popular belief that John Snow ended London’s 1854 cholera epidemic by disabling the Broad street pump is false; the epidemic was already drawing to a close). Other infections have been only partially controlled: no ‘treatment’ has been developed for HIV/AIDS, but Anti-Retroviral Therapy can extend life (and reduce infectiousness), Post-Exposure Prophylaxis can help prevent those exposed to HIV by needle-stick injuries from developing the disease, and the latex condom provides an effective barrier to its transmission via sexual intercourse.

More remarkably, some diseases (most notably smallpox) have been completely eradicated due to vaccination programs. Unfortunately, such programs are not universally successful: efforts to produce a effacious vaccine against HIV/AIDs have thus far failed; efforts to eradicate polio have stalled, and whilst it has been removed from most countries, there are still a few in which it remains stubbornly endemic. Public concern about vaccine safety hinder such programs—these concerns often lack a solid evidential basis, and occur not only in Africa, but also in the UK, as illustrated by the media hype surrounding Andrew Wakefield’s suggestion that the MMR vaccine could cause autism.

Alexander Fleming’s discovery of penicillin’s antibiotic effect (and the subsequent work of Florey and Chain) led to the first effective chemotherapeutic treatment for those suffering from bacterial disease. The class of antibiotics that includes penicillin (the beta-lactams) now has dozens of members, and many other classes have been developed. Unfortunately, the over-use of antibiotics imposed a selection pressure that led to the development of resistance in many organisms. There are many mechanisms by which resistance may occur, including production of enzymes that metabolize the antibiotic (such as beta-lactamases, which break open the beta-lactam ring), and pumps that remove them from bacterial cells. This is particularly concerning given the facility with which bacteria can exchange genetic material. At present, the most prevalent diseases caused by drug-resistant pathogens are multi-drug-resistant tuberculosis and Methicillin Resistance Stapylococcus Aureas (MRSA). A study, published last year in the journal Science, found that many common soil bacteria were able not only to survive at high concentrations of antibiotics, but also to use them as a nutrient-source¹. As many of these bacteria are similar to pathogens, this is highly concerning. Nonetheless, there has been progress: it has been shown that using two beta-lactams in combination can be effective in killing drug-resistant-TB²: one of the beta-lactams is broken down very slowly, and effectively acts as a beta-lactamase inhibitor. Conveniently, both drugs are already in use, avoiding both regulatory hurdles in the licensing process, and difficulties in synthesis scale-up.

As antibiotic resistance has increased, development of new antibiotic classes has slowed. This is due partly to the fact that low-hanging fruit has been exhausted, and there are few easy targets remaining for new drugs to hit. There are also economic reasons: only a single course of antibiotics is prescribed at a time, but whilst a patient is put on some other types of drug (eg. statins) they will likely continue taking it for the rest of their lives. For these two reasons, antibiotic development is expensive, and does not result in high revenues. Nonetheless, there has been some progress: two new drugs with the potential for use as anti-tuberculosis agents have been recently described in the literature: one, a imidazole, acts by causing the formation of NO. This occurs only in infected cells, avoiding damage to healthy host cells, as it is dependent on an enzyme produced by the TB pathogen³

However, there is increasing awareness that drugs need not actually kill pathogens in order to cure a patient: rather, it may be sufficient to the expression of virulence factors. A recent paper in Science described a drug that prevented cholera bacteria from producing cholera toxin, and thus also from causing symptoms. At the same time, pilus formation was impaired, hindering entrance to cells of the intestinal epithelium. As the bacterium is not being killed by the drug, there is likely to be a weaker pressure driving selection for resistance. Similar approaches may be found to be useful against other pathogens⁴

In future, administering antibodies may have a greater role in treating infection. The approach was pioneered by Pasteur, who used transplants of blood form a succession of animals (including a rabbit and a horse) to treat a boy who had been infected with rabies by a dog-bite. As it is harder to demonstrate the indistinguishability of two complex proteins than it would be for a conventional small-molecule medicine, there is a higher regulatory barrier to the production of ‘generic’ biologics. The manufacturer of a biologic therapeutic agent may thus enjoy a monopoly maintained not only by intellectual property law, but also regulatory & safety law, making the development of biologics commercially appealing . Antibodies are used to treat some diseases (the most widely known is probably Hercepetin, which is used in some cases of breast cancer). In the last few months, researchers have been able to produce a modified version of Herceptin with affinity for a second antigen: this is the first example of antibodies with high affinities for two different biomolecules⁵. A team at Scripps research institute have produced an antibody that binds to the ‘tail’ of one of influenza’s surface proteins (hemagglutinin), a region which mutates more slowly that the ‘head’⁶. This targeting of a more stable epitope could allow the development of ‘flu vaccines that do not have to be re-formulated every-year as the result of epitope mutation/serotypic-shift. It could also, perhaps, allow the stockpiling of antibodies that could be administered directly to infected persons.

Surprisingly, gene therapy may be useful in treating not only genetic, but also infectious, diseases. The entry of HIV into white-blood cells is facilitated by a protein (CCR5) on its surface. A mutation (Delta-32) in this protein prevents HIV form binding to it, hindering infection. It was found that after a bone marrow transplant from a donor with the mutation, the recipient was able to come off anti-retrovirals, and has not since suffered viral rebound (the case was reported in the New England Journal of Medicine⁷. This is a promising result, but bone-marrow transplant procedures have an high morbidity and mortality. It would thus be desirable to bring about the change in blood-cell phenotype by gene therapy instead.

In conclusion, drug resistance is an increasing problem, and some vaccination programs have stalled (polio), whilst others have failed to get off the ground (HIV). However, there are now cures for many disease that were previously incurable, and new developments continue to be made. Many of these provide entire new paradigms for treatment, such as gene therapy (for HIV), carefully designed antibodies (for ‘flu), cleverer combination therapies (for TB), and inhibition of virulence factor formation (for cholera). Clearly, the battle is not lost—it still continues.

Dantas et al. Bacteria subsisting on antibiotics. Science (2008) vol. 320 (5872) pp. 100-3 doi:10.1126/science.1155157 ↩
Hugonnet et al. Meropenem-Clavulanate Is Effective Against Extensively Drug-Resistant Mycobacterium tuberculosis. Science (2009) vol. 323 (5918) pp. 1215 doi:10.1126/science.1167498 ↩
Singh et al. PA-824 Kills Nonreplicating Mycobacterium tuberculosis by Intracellular NO Release. Science (2008) vol. 322 (5906) pp. 1392. doi:10.1126/science.1164571 ↩
Hung et al. Small-Molecule Inhibitor of Vibrio cholerae Virulence and Intestinal Colonization. Science (2005) vol. 310 (5748) pp. 670 10.1126/science.1116739 ↩
Bostrom et al. Variants of the Antibody Herceptin That Interact with HER2 and VEGF at the Antigen Binding Site. Science (2009) vol. 323 (5921) pp. 1610 doi:10.1126/science.1165480 ↩
Ekiert et al. Antibody Recognition of a Highly Conserved Influenza Virus Epitope. Science (2009) vol. 324 (5924) pp. 246 doi:10.1126/science.1171491 ↩
Hutter et al. Long-Term Control of HIV by CCR5 Delta32/Delta32 Stem-Cell Transplantation. The New England Journal of Medicine (2009) vol. 360 (7) pp. 692 doi:10.1056/NEJMoa0802905 ↩

Aspirin

2009-07-31T00:00:00+00:00

Aspirin

The medicinal use of willow bark is mentioned in Egyptian papyri, as well as the works of Hippocrates, Galen and Pliny the Elder. It was then largely ignored by western medicine, before being ‘rediscovered’ in 1736 by Reverend Stone, who sent the Royal Society a paper that described using it to treat ague (a fever). The active ingredient in willow bark was shown to be salicin in the 19th century. Rafaele Pina was able to convert this into a second compound, salicyclic acid. Unfortunately, salicyclic acid irritated the stomach, a problem solved by acetylation: the resulting acetylsalicyclic acid is today more commonly known as aspirin. Aspects of the history of this drug are outlined in the graphic above.

In 1971, John Robert Vane discovered the mechanism by which aspirin acts. Eleven years later, he, along with Sune Bergstrom and Bengt Samuelsson, was rewarded with the 1982 Nobel Prize for Physiology and Medicine. Aspirin reduces the rate at which prostaglandins (lipids that are involved in inflammation) are produced from arachidonic acid. It does this by permanently inactivating cyclooxygenase enzymes, by acetylating one of their serine residues (an -OH group is converted to -O(COCH3) )

Capsaicin

2009-07-30T00:00:00+00:00

Capsaicin

Capsaicin, and other closely related compounds (the capsainoids) are responsible for the heat of chillis. For some time, scientists have thought that Chillis produce capsacin in order to protect themselves from fungal infection. This hypothesis seems quite reasonable: after all, capsaicin has no obvious function in the plant, and so may have evolved to have an effect on other organisms, perhaps to protect the chillis from being eaten. Furthermore, Chillis are dependent on many animals to disperse their seeds, and any defense that developed against vertebrates would be likely to interfere with this, having a detrimental effect on the plant. In contrast, no microorganisms feeding on the chillis benefit them.

But the strongest evidence for this idea was presented in a paper in the Aug 19 2008 issue of Science ¹. The authors showed that fungal infections are indeed a major cause of damage to chillis, and that there is a correlation between number of insect bites in a particular fruit and the severity of subsequent fungal infections. The effect of additional insect bites is less significicant for peppers producing more capsaicin, which also contain less fungus, suggesting that capsaicin has a protective effect. To show that it was indeed capsaicin that was responsible for this difference, the scientists then grew fungus in two media, differing only in amount of capsaicin and dihydrocapsaicin - these compounds reduced fungal growth by 33%. Finally, they compared chillis growing across an area of 1,600 square kilometers in Bolivia. The scientists expected that in areas where chillis have more insect bites, they are exposed to the fungus more frequently, and will therefore be more likely to produce capsicin to protect themselves. And that is exactly what fieldwork found.

Not all chilis are equally hot, and their heat is compared with the Scoville Scale, developed by Wilbur Scoville. Each chilli pepper, or chilli sauce, can be given a score according to the number of times it must be diluted with water before its heat is no longer felt by a panel of taste-testers. The problem with this method is that it is time consuming, and the testers must be representative to the population. Some have tried to use more objective techniques from analytical chemistry, but initially had little success. High Performance Liquid Chromatography was tried, but its use was limited by its high cost. Last year, Richard Compton and his colleagues at Oxford University announced² that they had developed a technique for the voltammetric measurement of capsaicin concentration. In short, they placed electrodes into the sample, and measured how the current flowing between them varied as they changed the voltage across them. By repeating this several times, they could assign a Scoville score to the sample. This method is potentially much cheaper and more widely usable than existing methods.

The reason why capsaicin tastes hot is that it binds to a receptor called TRPV1 on specific nerve cells. This permits the entry of sodium or calcium ions into the cell, resulting in the transmission of an electrical signal to the brain. The opening of this recptor could have another application: the targeted entry of anesthetics. The local anesthetics currently used by dentists target all nerve cells in the mouth, not just the pain-causing nociceptors. Consequently, they make the mouth feel numb, and speech slurred, for hours after the operation. A study³ conducted on rats by scientists in Massachusetts found that when an anaesthetic called QX-314 was applied after capsaicin, it would enter nociceptors through the TRPV1 channel, reducing pain, but have no effect on other nerve cells. Capsaicin has also be used alone as a local anaesthtic.

Some have suggested that people initially began eating chillis as medication, because of their anti-fungal properties. And as the paper by Compton observes they have “antioxidant power, in addition to anti-tumoral, anti-mutagenic, antibacterial and anticarcinogenic properties. . . protective effects against cholesterol and obesity”. Despite their usefulness in healing, they are also used to harm: many of the less-than-lethal pepper sprays used to disperse crowds or disable attackers contain capsainoids as their active ingredients.

Tewksbury et al. Evolutionary ecology of pungency in wild chilies. Proceedings of the National Academy of Sciences of the United States of America (2008) vol. 105 (33) pp. 11808-11 doi:10.1073/pnas.0802691105 ↩
Kachoosangi et al. Carbon nanotube-based electrochemical sensors for quantifying the ‘heat’ of chilli peppers: the adsorptive stripping voltammetric determination of capsaicin. Analyst (2008) pp. 15 doi:10.1039/b803588a ↩
Binshtok et al. Inhibition of nociceptors by TRPV1-mediated entry of impermeant sodium channel blockers. Nature (2007) doi:10.1038/nature06191 ↩ ↩

Antibiotics - their history and future

2009-03-23T00:00:00+00:00

Antibiotics - their history and future

These are a few notes written to accompany a talk I recently gave.

The history of antibiotics

Inorganic arsenic arsenic compounds have probably been used since prehistory: coloured arsenic oxides may have been used in cosmetics, leading to the serendipitous discovery of their ability to treat skin complaints. Atoxy was so named because it was about many times (perhaps as much as 40 times) less toxic than inorganic arsenic compounds. Initially, its structure was misassigned as a anilide, rather than as an amino arsenic acid, an error rectified by Ehrlich (or his collaborator Bertheim). The first structure proposed for Salversan was also in error: more recent evidence suggests that it does not contain a double As=As bond, and is instead a mixture of a trimer and pentamer.

A 2005 article in chemotherapy provides a good 9-page introduction to the history of Salvarsan ¹.

Biological role of antibiotics

Given that man uses some natural antibiotics to treat disease by killing bacteria, it is tempting to fall into a post-hoc ergo propter hoc fallacy, and conclude that this must be the reason why they are produced by microorganisms. But the doses at which many of these compounds have an antibiotic effect is far higher than the concentrations at which they are secreted, and it now appears that many fulfill other roles, such as signaling/quorum-sensing/bio-film formation².

Antibiotic resistance

Antibiotic resistant bacteria are now a major problem: the most notable diseases that it causes are Methicillin-Resistant Staphylococcus aureus (MRSA), Clostridium difficile, and multi-drug resistant Tuberculosis (TB).

It can arise via a variety of mechanisms including enzymatic degradation of antibiotics, efflux mechanisms that remove antibiotics from the cell, decreased cell wall/membrane permeability to antibiotics, and changes to the target of the antibiotic. A 2008 paper in Science found numerous strains of soil bacteria that were not only resistant to many antibiotics, but were able to subsist on them as their sole carbon source. Worryingly, many of these bacteria are closely related to human pathogens³.

Anti-virulence therapies

Nature Reviews Microbiology published a good review of the potential for treatments that make bacteria less virulent without killing them (antivirulence therapies) in 2008⁴. Virstatin’s effects on production of Cholora Toxin by Vibrio Cholerae were first reported in 2005⁵. It was identified by genetically modifying the O395 strain of Vibrio Cholerae so that the tetracycline resistance gene tetA was places under the same promotor (ctx) as the Cholera Toxin. Thus, whenever cholera toxin was being produced, so was the tetracycline resistance protein. So the bacteria were ordinarily resistant to the antibiotic tetracycline, but if a drug stopped the production of the Cholera Toxin, it would make the bacterium susceptible to the antibiotic. The scientists screened 50,000 compounds by adding them to bacteria along with tetracycline: if the bacteria died, they concluded that the compound might prevent toxin production. Further experiments confirmed that Virstatin did indeed inhibit toxin production without killing the bacteria, and was an effective treatment for cholera in mice. Subsequent work by the same investigators suggests that it may act by preventing dimerization of the transcriptional activator ToxT⁶.

Phage Therapy

In the former USSR (especially Georgia), bacteriophages—viruses that infect and kill bacteria—are an established treatment for bacterial infections. However, they have both practical and regulatory problems that limit there use in the rest of the world: they act with extreme specificity, requiring the stockpiling of large numbers of different strains, and the careful determination of which bacteria are responsible for an infection; and they are biologic agents (which are harder to characterize than small-molecules), and undergo unpredictable changes due to mutation. Some also have short half-lives in the body, though this can be improved by serial selection

Riethmiller. From Atoxyl to Salvarsan: searching for the magic bullet Chemotherapy (2005) vol. 51 (5) pp. 234-42. doi:10.1159/000087453 ↩
Mlot. Antibiotics in Nature: Beyond Biological Warfare. Science (2009) vol. 324 (5935) pp. 1637 doi:10.1126/science.324_1637 ↩
Dantas et al. Bacteria subsisting on antibiotics. Science (2008) vol. 320 (5872) pp. 100-3 doi:10.1126/science.1155157 ↩
Cegelski et al. The biology and future prospects of antivirulence therapies. Nature reviews Microbiology (2008) vol. 6 (1) pp. 17 doi:10.1038/nrmicro1818 (There is an open-access manuscript of this paper available at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2211378/</a>) ↩
Hung et al. Small-Molecule Inhibitor of Vibrio cholerae Virulence and Intestinal Colonization. Science (2005) vol. 310 (5748) pp. 670 doi:10.1126/science.1116739 ↩
Shakhnovich et al. Virstatin inhibits dimerization of the transcriptional activator ToxT. Proceedings of the National Academy of Sciences of the United States of America (2007) vol. 104 (7) pp. 2372-7 doi:10.1073/pnas.0611643104 ↩

James Scott-Brown

Why Python

Why Python

Bookmarklet for Oxford Off-Campus Journal Access

Bookmarklet for Oxford Off-Campus Journal Access

Short links - 2015-03-1

Short links - 2015-03-1

Science

Tech:

Social

My Setup

My Setup

Papers

Recording PDFs read in Skim

Recording PDFs read in Skim

Good Lecture Notes

Good Lecture Notes

Compiling a comprehensive biomedical/chemical spell-check dictionary

Compiling a comprehensive biomedical/chemical spell-check dictionary

Single day Hall Menu for Trinity today

Single day Hall Menu for Trinity today

How I keep notes

How I keep notes

Speed

Syncing

Directory of text files

What we don't know

What we don’t know

Things ‘Unknown’:

Things ‘Unclear’:

Things ‘Not Understood’:

Uncertainty that ‘Remains’:

A complete index for XKCD

A complete index for XKCD

Drugs and History

Drugs and History

Kite Diagrams

Kite Diagrams

Using perl to find words in the periodic table

Using perl to find words in the periodic table

Arrows

Arrows

Recipeconverter

Recipeconverter

Has man lost the battle against infectious disease?

Has man lost the battle against infectious disease?

Aspirin

Aspirin

Capsaicin

Capsaicin

Antibiotics - their history and future

Antibiotics - their history and future

The history of antibiotics

Biological role of antibiotics

Antibiotic resistance

Anti-virulence therapies

Phage Therapy