The Past and the Future of Vaccination

Antiviral drug, Ebola, Infection, Rabies, Virus,

PNAS this week celebrates 100 years of rabies vaccination by Louis Pasteur and Coworkers which took place already in 1885? We do not understand the counting as such but take the opportunity of the celebration anyhow. (From the editorial, and the featured articles it is not emerging why 100 years.) However, it was an tremendous achievement at that time and should be compared to the situation with the actual Ebola crisis: It took away the fear of fatal danger from the persons dealing with the disease and gave hope to those who were biten by mad animals.

The history of vaccination is dealt with by an nice article of Stanley Plotkin. There are additional papers on social matters of vaccination and one paper on NOD- and Toll-like agonists as adjuvants. These papers are free.

To come back to Ebola and the experimental treatment we mentioned before today 6 patients have been treated 4 improved but 2 have died from Ebola. The fatal rate would thus be 33 % versus 60 to 80 % if untreated. This is from nothing to something. However, this is no vaccination.

Review on stem cells for treating diseases

Cell physiology, Drug, Immunology, ,

This weeks Science features a review (DOI: 10.1126/science.1247391) on induced Pluripotent Stem Cells (PSC) and the treatment of diseases with their help. The disease treated in the paper are hematopoietic maladies, diabetes mellitus, liver diseases, neurological disorders,  muscular distrophy and heart diseases.

I was particular interested in diabetes and went to study the article. I was surprised to see that a paper was mentioned where immunotherapy, especially the induction of tolerance, was tried. I have explained the strategy behind in a separate article on this website.

The article, at least for the diabetes part, is highly instructive. You may find it in an University library.

The Proteasome adaptive response

Biochemistry, Cell physiology, ,

While you are most probably familiar with proteasomes (otherwise it is barrel-like structure with heptameric symmetry of four ring, holes at both end through which ubiquitin targets proteins to be digested during which process it produces peptides of seven to nine amino acids which are either digested or loaded into the peptide pockets of histocompatibility proteins) you would not have thought about how proteasomes themselves are regulated.  A free article in Molecular Cell (dx.doi.org/10.1016/j.molcel.2014.06.017) demonstrates that a protein Adc17 is induced in stress and helps to maintain adequate numbers of proteasomes. A nice piece of work!

Do bacteria still evolve? Yes, but…

Bacteria, Evolution, Genetics

There is a fascinating article in BMC Biology (doi:10.1186/s12915-014-0066-4, Open Source)which deals with bacterial evolution. It is an eye-opener for people not involved into the subject. Bacterial evolution is so fast via horizontal gene transfer (HGT) that there is almost no time for “normal” base exchange mechanisms. The predominant way of evolution is by gene loss, but occasionally via gene gain which may change the bacteria dramatically. This has also an impact of the charactization of bacteria whose genome  should be regarded as part of a pangenome or even supergenome. 

I wonder whether a given size (which is obviously maintained)  would limited horizontal transfer of larger parts of the genome.

Since this is open source I copy the conclusion entirely:

Conclusions
The reconstruction of short term genome dynamics events shows that microbial genomes exist in a state of perennial flux, gaining, losing, expanding and  contracting gene families. Typically, genome dynamics processes are rapid, with gains and losses of multiple gene families occurring within the time frame of a single nucleotide substitution per gene. Thus, gene flux is the dominant mode in microbial evolution such that microbes primarily differ from each other on the scale from static to highly dynamic. The rates of gene family gain and loss in most microbial groups are approximately an order of magnitude greater than the rates of expansion and contraction of pre-existing families, indicating that HGT is the principal source of new genes in prokaryote evolution. Overall, gene family loss notably prevails over gain, i.e. evolving genomes appear to spend more time contracting than  expanding. It seems most likely that the gradual gene loss is compensated for by episodes of rapid gene gain; most of such bursts are outside the evolutionary scale accessible through ATGCs although a few were detected. The absolute as well as relative rates of genome dynamics events show remarkable variance among bacteria, spanning almost two orders of magnitude, and do not significantly depend on the ATGC-wide dN/dS estimates, the taxonomic affinity of microbes or their life style. Conceivably, genome dynamics is highly sensitive to local ecological
factors the exact nature of which remains to be elucidated. The analysis of genome dynamics allowed us to estimate the size of microbial supergenomes which in the majority of the analyzed microbial groups turned out to be large but closed, exceeding the characteristic genome size by about an order of magnitude, but for a minority of microbes were appeared to be open.

Good to know!

GABA receptor structure revealed

Biochemistry, Brain, Cell physiology, Neurotransmitters

GABA (gamma-amino butyric acid) receptors belong to the group of pentameric ligand-gated ion channels as serotonin receptors or acetylcholin receptors. Since these membrane proteins have been impossible to chrystallize for a long time and there are still difficulties to determine their structure by X-ray spectometry. However, in recent years it became fashionable to analyze membrane receptors of different types, the determination of the GABA receptor is not a great surprise.

In this week Nature (doi:10.1038/nature13293) Miller and Aricescu from Oxford, UK, show the structure of the so-called β3-homopentamer. BTW that only two authors succeded in this task comes as a surprise.

The GABA receptor is involved in a number of diseases: epilepsy, insomnia, anxiety and panic disorders, has a role in alcohol abuse, binds to benzodiapines. Miller and Aricescu have chrystallized the receptor with a so far unkown agonist (a molecule to activate): benzamidine which allows predictions about the way ligands are bound and how they function.

The paper shows a abundance of beautiful  structural graphs which were drawn with Pymol a nice program used by myself in Hormone und Hormonsystem.

Tuberculosis in Peru – predating the contact with Europeans

Bacteria, History, Infection, Tuberculosis,

Devasting diseases have occured in indigenous populations of north and south America once they came in contact with Europeans. One disease, however, can no longer be attributed to this collection: tuberculosis.

In a Nature paper (doi:10.1038/nature13591) this week Bos, Harkins and colleagues demonstrate Mycobacterium tuberculosis isolates in Peruvian human skeletons from 1000 years ago i.e. 400 years before Columbus traveled to the Westindian islands. These mycobacteria do not ressemble the actual strains in Europe and America but are more closely related to those found in seals and sea lions proposing that human diseases could have spread via sea mammals before man themselves actually came in close contact. 

How to get rid of PCB!

Bacteria, Biochemistry, ,

PCB (PoylChlorinated Bisphenyls) are among the longlasting environmental toxins. They are present in varying degrees all over. It has been very difficult to identify bacteria which can degradate this chemical highly inert products enzymatically.

This weeks PNAS (doi: 10.1073/pnas.1404845111 ) describes for the first time the cultivation of organisms which can be reliably kept in culture and which feed on PCB. The authors show three Dehalococcoides mccartyi strains with different dechlorination potential and slight differences in the genome. The enzyme involved is a Reductive Dehalogenase which sequences have been determined and which are active in a bioassay removing chlorine from both PCB and PCE.

This may be a novel step in the search for decontamination, however, given that the process so far in under anaerobis conditions, it is mere speculation that this enzyme will work under ambient conditions.

Nicely done!

How microRNA work and influence tumour growth

Cell physiology, Genetics, Transformation

The analysis of tumour remains fascinating. While e.g. viruses, methylation of DNA, gene silencing, mutations and deletions have been recognized for some time to play major roles in tumour development, a new player has emerged only recently: microRNA or miRNA. An Open Access review in Current Biology ( http://dx.doi.org/10.1016/j.cub.2014.06.043) features this new class of molecules and describes how they act on tumours. A must read!

Ebola and the WHO

Antiviral drug, Drug, Infection, ,

It is remarkable how this pandemy threatens the rules seemingly carved in stone concerning untested medicines. What has been valid before i.e. never to use a medicine until a benefit could be proven is gone en face of the actual crisis. The Science magazine has reacted, too, and has put in the Open Access Paper that were published till now that dealt with Ebola. Among these now free papers is a decription how the rules of the WHO have changed. Martin Enserink from Amsterdam writes very clearly of the change of paradigmata at the WHO. Nice reading!

Seasonal Regulation of Endocrine Functions.

Biochemistry, Brain, Cell physiology, Endocrinology, Evolution, Hormones,

Almost any animal regulates its metabolism as well as its reproductive life according to the time of the year. (The fact that some domestic animals do not is the exception). This dependence on the season has long been a mystery for endocrinologists. Even then it was found that the Nucleus suprachiasmaticus in the hypothalamus controls and generates a circadian (daily) rhythm which is reflected in all animals analyzed the circannual (yearly) rhythm remained obcur.

Recent developments have shown that some pituitary cells in Pars tuberalis (PT; close to the pituitary stalk) measure the length of day via the melatonin they receive. Since melatonin is only produced in the dark, much melatonin means long nights and few melatonin means short nights. These cells therefore have been named calendar cells.

In an Open Access review in the Journal of Endocrinology Shona Wood and Andrew Loudon have summarized what is known about the physiology and biochemistry of this circannual regulation. They show that thyriod hormones and their conversion from thyroxine to triiodothyronine by deiodinase are an important part in the short day response. They analyse the melatonin response in the PT. They also show how clock genes are differential regulated during the seasons. Finally they show that a ancient gene, the eye absent protein 3 (EYA3) is specifically upregulated when the days get longer.

These genes are ancient and found in insects as well as in birds and mammals pointing to a very old mechanism.

Nice paper, worth studying!