Genomic donor cassette sharing during VLRA and VLRC assembly in jawless vertebrates

Lampreys possess two T-like lymphocyte lineages that express either variable lymphocyte receptor (VLR) A or VLRC antigen receptors. VLRA+ and VLRC+ lymphocytes share many similarities with the two principal T-cell lineages of jawed vertebrates expressing the αβ and γδ T-cell receptors (TCRs). During the assembly of VLR genes, several types of genomic cassettes are inserted, in step-wise fashion, into incomplete germ-line genes to generate the mature forms of antigen receptor genes. Unexpectedly, the structurally variable components of VLRA and VLRC receptors often possess partially identical sequences; this phenomenon of module sharing between these two VLR isotypes occurs in both lampreys and hagfishes. By contrast, VLRA and VLRC molecules typically do not share their building blocks with the structurally analogous VLRB receptors that are expressed by B-like lymphocytes. Our studies reveal that VLRA and VLRC germ-line genes are situated in close proximity to each other in the lamprey genome and indicate the interspersed arrangement of isotype-specific and shared genomic donor cassettes; these features may facilitate the shared cassette use. The genomic structure of the VLRA/VLRC locus in lampreys is reminiscent of the interspersed nature of the TCRA/TCRD locus in jawed vertebrates that also allows the sharing of some variable gene segments during the recombinatorial assembly of TCR genes

A fractional kinetic process describing the intermediate time behaviour of cellular flows

This paper studies the intermediate time behaviour of a small random perturbation of a periodic cellular flow. Our main result shows that on time scales shorter than the diffusive time scale, the limiting behaviour of trajectories that start close enough to cell boundaries is a fractional kinetic process: A Brownian motion time changed by the local time of an independent Brownian motion. Our proof uses the Freidlin-Wentzell framework, and the key step is to establish an analogous averaging principle on shorter time scales. As a consequence of our main theorem, we obtain a homogenization result for the associated advection-diffusion equation. We show that on intermediate time scales the effective equation is a fractional time PDE that arises in modelling anomalous diffusion

Selection of the lamprey VLRC antigen receptor repertoire

The alternative adaptive immune system of jawless vertebrates is based on different isotypes of variable lymphocyte receptors (VLRs) that are composed of leucine-rich repeats (LRRs) and expressed by distinct B- and T-like lymphocyte lineages. VLRB is expressed by B-like cells, whereas VLRA and VLRC are expressed by two T-like lineages that develop in the thymoid, a thymus-like structure in lamprey larvae. In each case, stepwise combinatorial insertions of different types of short donor LRR cassettes into incomplete germ-line genes are required to generate functional VLR gene assemblies. It is unknown, however, whether the diverse repertoires of VLRs that are expressed by peripheral blood lymphocytes are shaped by selection after their assembly. Here, we identify signatures of selection in the peripheral repertoire of VLRC antigen receptors that are clonally expressed by one of the T-like cell types in lampreys. Selection strongly favors VLRC molecules containing four internal variable leucine-rich repeat (LRRV) modules, although VLRC assemblies encoding five internal modules are initially equally frequent. In addition to the length selection, VLRC molecules in VLRC+ peripheral lymphocytes exhibit a distinct pattern of high entropy sites in the N-terminal LRR1 module, which is inserted next to the germ-line–encoded LRRNT module. This is evident in comparisons to VLRC gene assemblies found in the thymoid and to VLRC gene assemblies found in some VLRA+ cells. Our findings are the first indication to our knowledge that selection operates on a VLR repertoire and provide a framework to establish the mechanism by which this selection occurs during development of the VLRC+ lymphocyte lineage

The catalytic domains of thiamine triphosphatase and CyaB-like adenylyl cyclase define a novel superfamily of domains that bind organic phosphates

BACKGROUND: The CyaB protein from Aeromonas hydrophila has been shown to possess adenylyl cyclase activity. While orthologs of this enzyme have been found in some bacteria and archaea, it shows no detectable relationship to the classical nucleotide cyclases. Furthermore, the actual biological functions of these proteins are not clearly understood because they are also present in organisms in which there is no evidence for cyclic nucleotide signaling. RESULTS: We show that the CyaB like adenylyl cyclase and the mammalian thiamine triphosphatases define a novel superfamily of catalytic domains called the CYTH domain that is present in all three superkingdoms of life. Using multiple alignments and secondary structure predictions, we define the catalytic core of these enzymes to contain a novel α+β scaffold with 6 conserved acidic residues and 4 basic residues. Using contextual information obtained from the analysis of gene neighborhoods and domain fusions, we predict that members of this superfamily may play a central role in the interface between nucleotide and polyphosphate metabolism. Additionally, based on contextual information, we identify a novel domain (called CHAD) that is predicted to functionally interact with the CYTH domain-containing enzymes in bacteria and archaea. The CHAD is predicted to be an alpha helical domain, and contains conserved histidines that may be critical for its function. CONCLUSIONS: The phyletic distribution of the CYTH domain suggests that it is an ancient enzymatic domain that was present in the Last Universal Common Ancestor and was involved in nucleotide or organic phosphate metabolism. Based on the conservation of catalytic residues, we predict that CYTH domains are likely to chelate two divalent cations, and exhibit a reaction mechanism that is dependent on two metal ions, analogous to nucleotide cyclases, polymerases and certain phosphoesterases. Our analysis also suggests that the experimentally characterized members of this superfamily, namely adenylyl cyclase and thiamine triphosphatase, are secondary derivatives of proteins that performed an ancient role in polyphosphate and nucleotide metabolism

Zero-Reachability in Probabilistic Multi-Counter Automata

We study the qualitative and quantitative zero-reachability problem in probabilistic multi-counter systems. We identify the undecidable variants of the problems, and then we concentrate on the remaining two cases. In the first case, when we are interested in the probability of all runs that visit zero in some counter, we show that the qualitative zero-reachability is decidable in time which is polynomial in the size of a given pMC and doubly exponential in the number of counters. Further, we show that the probability of all zero-reaching runs can be effectively approximated up to an arbitrarily small given error epsilon > 0 in time which is polynomial in log(epsilon), exponential in the size of a given pMC, and doubly exponential in the number of counters. In the second case, we are interested in the probability of all runs that visit zero in some counter different from the last counter. Here we show that the qualitative zero-reachability is decidable and SquareRootSum-hard, and the probability of all zero-reaching runs can be effectively approximated up to an arbitrarily small given error epsilon > 0 (these result applies to pMC satisfying a suitable technical condition that can be verified in polynomial time). The proof techniques invented in the second case allow to construct counterexamples for some classical results about ergodicity in stochastic Petri nets.Comment: 20 page

Rights of passage: law and the biopolitics of dying

Deleuze and Law: Forensic Futures explores the relation between law and life and the advent of a politics of 'life'. How have recent events focused social, political and cultural attention on the living body and its maintenance and management? The central concept, through which the embodiment of the subject will be examined will be that of 'bio-power'. Articulated by Michel Foucault, but brought to attention more recently in the work of Giorgio Agamben, this concept recognises that the relation between life and law is both historical and necessary: the law must operate on bodies but can only do so by establishing a border between the body of the polity, and the mere life excepted from political concern. The contemporary advent of bio-politics occurs when the polity increasingly and invasively operates on this 'mere' life, and the body or organism – rather than the self – becomes the object of political management. The manner in which the body becomes the focus of contemporary power has led legal theory to explore new questions of the threshold between life and death and has led social theory to question the new extensions of the law and the polity into embodied life. The contributors explore the forensic shift in contemporary social theory and cultural sensibility from a number of perspectives. Description of book from publisher website at: http://www.palgrave.com