Atomic-level Motion May Drive Bacteria’s Ability To Evade Immune System Defenses

I wish you all a Merry Christmas!

Separation of a highly fluorescent anthranilic acid derivative from the reaction mixture.

The upper organic layer dissolved almost completely my compound from the reaction mixture and could be separated in one step. A good point was that the compound had a really strong fluorescence and if I placed an UV lamp next to the separation funnel it was easily observed that the water phase contained almost none of the title compound. 

Antibody Therapy Creates New Opportunities For Treating Brain Diseases

Immunotherapy has proven to be effective against many serious diseases. But to treat diseases in the brain, the antibodies must first get past the obstacle of the blood-brain barrier. In a new study, a research group at Uppsala University describes their development of a new antibody design that increases brain uptake of antibodies almost 100-fold.

Immunotherapy entails treatment with antibodies; it is the fastest growing field in pharmaceutical development. In recent years, immunotherapy has successfully been used to treat cancer and rheumatoid arthritis, and the results of clinical studies look very promising for several other diseases. Antibodies are unique in that they can be modified to strongly bind to almost any disease-causing protein. In other words, major potential exists for new antibody-based medicines.

The problem with immunotherapy for diseases affecting the brain is that the brain is protected by a very tight layer of cells, called the blood-brain barrier. The blood-brain barrier effectively prevents large molecules, such as antibodies, from passing from the bloodstream into the brain. It has therefore been difficult to use immunotherapy to treat Alzheimer’s and Parkinson’s disease, which affect the brain, as well as cancerous tumours in the brain.

It has been known for a long time that some large proteins are actively transported across the blood-brain barrier. These include a protein called transferrin, whose primary task is to bind to iron in the blood and then transport it to the brain. The research group behind this new study has taken advantage of this process and modified the antibodies they want to transport into the brain using components that bind to the transferrin receptor. Then, like a Trojan horse, the receptor transports antibodies into the brain. The number of modifications to and placement of the antibodies have proven to be important factors for making this process as effective as possible.

“Bivalent Brain Shuttle Increases Antibody Uptake by Monovalent Binding to the Transferrin Receptor” by Greta Hultqvist, Stina Syvänen, Xiaotian T Fang, Lars Lannfelt, and Dag Sehlin in Theranostics. Published online January 2017 doi:10.7150/thno.17155

The green antibody is modified using two components that bind to the transferrin receptor and enable the antibody to pass through the blood-brain barrier. The components are placed in such a way that prevents them from being able to bind simultaneously. The placement is important, because otherwise the antibody would not detach on the far side of the blood-brain barrier. NeuroscienceNews.com image is credited to Greta Hultqvist.

Thorny life of new-born neurons

Even in adult brains, new neurons are generated throughout a lifetime. In a publication in the scientific journal PNAS, a research group led by Goethe University describes plastic changes of adult-born neurons in the hippocampus, a critical region for learning: frequent nerve signals enlarge the spines on neuronal dendrites, which in turn enables contact with the existing neural network.

Practise makes perfect, and constant repetition promotes the ability to remember. Researchers have been aware for some time that repeated electrical stimulation strengthens neuron connections (synapses) in the brain. It is similar to the way a frequently used trail gradually widens into a path. Conversely, if rarely used, synapses can also be removed – for example, when the vocabulary of a foreign language is forgotten after leaving school because it is no longer practised. Researchers designate the ability to change interconnections permanently and as needed as the plasticity of the brain.

Plasticity is especially important in the hippocampus, a primary region associated with long-term memory, in which new neurons are formed throughout life. The research groups led by Dr Stephan Schwarzacher (Goethe University), Professor Peter Jedlicka (Goethe University and Justus Liebig University in Gießen) and Dr Hermann Cuntz (FIAS, Frankfurt) therefore studied the long-term plasticity of synapses in new-born hippocampal granule cells. Synaptic interconnections between neurons are predominantly anchored on small thorny protrusions on the dendrites called spines. The dendrites of most neurons are covered with these spines, similar to the thorns on a rose stem.

In their recently published work, the scientists were able to demonstrate for the first time that synaptic plasticity in new-born neurons is connected to long-term structural changes in the dendritic spines: repeated electrical stimulation strengthens the synapses by enlarging their spines. A particularly surprising observation was that the overall size and number of spines did not change: when the stimulation strengthened a group of synapses, and their dendritic spines enlarged, a different group of synapses that were not being stimulated simultaneously became weaker and their dendritic spines shrank.

“This observation was only technically possible because our students Tassilo Jungenitz and Marcel Beining succeeded for the first time in examining plastic changes in stimulated and non-stimulated dendritic spines within individual new-born cells using 2-photon microscopy and viral labelling,” says Stephan Schwarzacher from the Institute for Anatomy at the University Hospital Frankfurt. Peter Jedlicka adds: “The enlargement of stimulated synapses and the shrinking of non-stimulated synapses was at equilibrium. Our computer models predict that this is important for maintaining neuron activity and ensuring their survival.”

The scientists now want to study the impenetrable, spiny forest of new-born neuron dendrites in detail. They hope to better understand how the equilibrated changes in dendritic spines and their synapses contribute the efficient storing of information and consequently to learning processes in the hippocampus.

Complement Pathways

Components of complement pathways of the immune system. 

Classical Pathway: binds to the pathogen surface

C1 binds to phosphocholine on bacteria, which activates C1r to cleave C1s.

Activated C1s cleaves C4 to C4a and C4b.

C4b binds to the microbial surface and also binds C2.

C2 is cleaved to C2a and C2b by C1s, forming the C4bC2a complex.

The C4bC2a complex cleaves C3 to C3a and C3b.

C3b binds to the surface and causes opsonization.

MB-Lectin Pathway: uses mannin-binding lectin to bind to mannose-containing carbohydrates on the pathogen surface

Mannin-binding lectin (MBL) binds to the pathogen surface and activates MASP-2.

MASP-2 cleaves C4 to C4a and C4b.

C4b binds to the microbial surface and also binds C2.

C2 is cleaved to C2a and C2b by MASP-2, forming the C4bC2a complex.

The C4bC2a complex cleaves C3 to C3a and C3b.

C3b binds to the surface and causes opsonization.

Alternative Pathway: binds to the pathogen surface with spontaneously activated complement, amplifies C3b

C3b deposited by the C3 convertase binds to factor B.

Factor B is cleaved by factor D into Ba and Bb, forming the C3bBb complex.

The C3bBb complex cleaves C3 into C3a and C3b.

C3 spontaneously hydrolyzes to C3(H2O).

C3(H2O) binds to factor B, and factor D cleaves factor B.

Upon factor B cleavage, the C3(H2O)Bb complex is formed.

The C3(H2O)Bb complex cleaves C3 into C3a and C3b.

Factor B binds to C3b on the surface and is cleaved to Bb.

Today is UN International Day of Women and Girls in Science!

We’ve pulled together this collection of quotes from inspiring women who have made huge contributions in their scientific fields.

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How are elements created in space, stars, and in laboratories? The latest edition of #PeriodicGraphics in C&EN takes a look! http://bit.ly/2UXWoPD http://bit.ly/2YbuBNE

Stephanie Kwolek was born #OTD in 1923. She’s most famous for inventing the bulletproof polymer Kevlar: wp.me/p4aPLT-3dv

Molecule of the Day: VX

VX (C11H26NO2PS) is a colourless, odourless, oily liquid under room temperatures. It is a member of the V-series of nerve agents, and is an extremely potent poison - only 0.01 grams of it is needed to kill a person by skin contact. VX was recently implicated in the assassination of Kim Jong-nam, the half-brother of the North Korean leader Kim Jong-un, in Malaysia.

VX is a potent inhibitor of acetylcholinesterase, which breaks down the neurotransmitter acetylcholine into acetic acid and choline. The normal function of the enzyme is to regulate the concentration of acetylcholine within the synaptic cleft, so as to control the frequency of binding of acetylcholine to cholinergic receptors on the postsynaptic cell membrane and hence the transmission of impulses across the synapse.

Consequently, the inhibition of acetylcholinesterase results in a rapid increase in the synaptic concentration of acetylcholine, as the presynaptic knob continues to synthesise it and secrete it into the synaptic cleft. As a result, the cholinergic receptors on the postsynaptic cell membrane are continually stimulated, and a rapid series of action potentials are triggered. This results in muscle spasms and eventual paralysis, leading to death by asphyxiation due to paralysis of the diaphragm.

VX exposure is usually treated using an injection of atropine and pralidoxime. Atropine inhibits certain cholinergic receptors, reducing the binding of acetylcholine to receptors and thus the triggering of action potentials. On the other hand, one end of pralidoxime binds to acetylcholinesterase and the other binds to the phosphate group of VX, which causes the VX molecule to detach from the enzyme together with the pralidoxime molecule (see below). This restores the ability of acetylcholinesterase to hydrolyse acetylcholine, hence reducing its synaptic levels.

VX is synthesised from phosphorus trichloride over multiple steps; first, it is methylated, reacted with ethanol, then transesterified with N,N-diisopropylaminoethanol to produce QL. This is then oxidised with sulfur, and isomerised via heating to produce VX.

Fungal tissues – the fungal mantle around the root tip and the fungal network of tendrils that penetrates the root of plants, or Hartig Net, between Pinus sylvestris plant root cells – in green. Ectomycorrhizal (ECM) fungi help trees tolerate drought and boost the productivity of bioenergy feedstock trees, including poplar and willow.

Via Berkeley Lab: The sclerotia are in the soil!

More: How Fungi Help Trees Tolerate Drought (Joint Genome Institute)