Induction and organization of Ca2+ waves by enteric neural reflexes.

The motility of the gastrointestinal tract consists of local, non-propulsive mixing (pendular or segmental) and propulsive (peristaltic) movements. It is generally considered that mixing movements are produced by intrinsic pacemakers which generate rhythmic contractions, and peristalsis by intrinsic excitatory and inhibitory neural reflex pathways, but the relationship between mixing and peristalsis is poorly understood. Peristalsis is compromised in mice lacking interstitial cells of Cajal, suggesting that these pacemaker cells may also be involved in neural reflexes. Here we show that mixing movements within longitudinal muscle result from spontaneously generated waves of elevated internal calcium concentration which originate from discrete locations (pacing sites), spread with anisotropic conduction velocities in al directions, and terminate by colliding with each other or with adjacent neurally suppressed regions. Excitatory neural reflexes control the spread of excitability by inducing new pacing sites and enhancing the overall frequency of pacing, whereas inhibitory reflexes suppress the ability of calcium waves to propagate. We provide evidence that the enteric nervous system organizes mixing movements to generate peristalsis, linking the neural regulation of pacemakers to both types of gut motility.     

Mechanism of antigen-driven selection in germinal centres

The high affinity of antibodies produced during responses to T-cell-dependent antigens is associated with somatic mutation in the variable region of the immunoglobulin. Indirect evidence indicates that: (1) this arises by a process of hypermutation, acting selectively on rearranged immunoglobulin variable-region genes, which is activated in centroblasts within germinal centres; and (2) centrocytes, the progeny of centroblasts, undergo selection on the basis of their ability to receive a positive signal from antigen. We have now performed experiments analysing this selection process, and found that, on culture, centrocytes isolated from human tonsil kill themselves within a few hours by apoptosis. This is not a feature of other tonsillar B cells. Centrocytes can be prevented from entering apoptosis if they are activated both through their receptors for antigen and a surface glycoprotein recognized by CD40 antibodies.     

Evolutionary speed limits inferred from the fossil record.

The dynamics of extinction and diversification determine the long-term effects of extinction episodes. If rapid bursts of extinction are offset by equally rapid bursts of diversification, their biodiversity consequences will be transient. But if diversification rates cannot accelerate rapidly enough, pulses of extinction will lead to long-lasting depletion of biodiversity. Here I use spectral analysis of the fossil record to test whether diversification rates can accelerate as much as extinction rates, over both short and long spans of geological time. I show that although the long-wavelength variability of diversification rates equals or exceeds that of extinctions, diversification rates are markedly less variable than extinction rates at wavelengths shorter than roughly 25 million years. This implies that there are intrinsic speed limits that constrain how rapidly diversification rates can accelerate in response to pulses of extinction.     

Conservation of position and exclusive expression of mouse Xist from the inactive X chromosome

X-chromosome inactivation in mammals is a regulatory phenomenon whereby one of the two X chromosomes in female cells is genetically inactivated, resulting in dosage compensation for X-linked genes between males and females. In both man and mouse, X-chromosome inactivation is thought to proceed from a single cis-acting switch region or inactivation centre (XIC/Xic). In the human, XIC has been mapped to band Xq13 (ref. 6) and in the mouse to band XD (ref. 7), and comparative mapping has shown that the XIC regions in the two species are syntenic. The recently described human XIST gene maps to the XIC region and seems to be expressed only from the inactive X chromosome. We report here that the mouse Xist gene maps to the Xic region of the mouse X chromosome and, using an interspecific Mus spretus/Mus musculus domesticus F1 hybrid mouse carrying the T(X;16)16H translocation, show that Xist is exclusively expressed from the inactive X chromosome. Conservation between man and mouse of chromosomal position and unique expression exclusively from the inactive X chromosome lends support to the hypothesis that XIST and its mouse homologue are involved in X-chromosome inactivation.     

A comparison of pyridoxal 5′-phosphate dependent decarboxylase and transaminase enzymes at a molecular level

Pyridoxal 5′-phosphate is a coenzyme for a number of enzymes which catalyse reactions at C^α of amino acid substrates including transaminases, decarboxylases and serine hydroxymethyltransferase. Using the X-ray coordinates for a transaminase, aspartate aminotransferase, and the results of stereochemical and mechanistic studies for decarboxylases and serine hydroxymethyltransferase, an active-site structure for the decarboxylase group is constructed. The structure of the active-site is further refined through active-site pyridoxyllysine peptide sequence comparison and a 3-D catalytic mechanism for the L-α-amino acid decarboxylases is proposed. The chemistry of serine hydroxymethyltransferase is re-examined in the light of the proposed decarboxylase mechanism.     

A comparison of pyridoxal 5'-phosphate dependent decarboxylase and transaminase enzymes at a molecular level.

Pyridoxal 5'-phosphate is a coenzyme for a number of enzymes which catalyse reactions at C alpha of amino acid substrates including transaminases, decarboxylases and serine hydroxymethyltransferase. Using the X-ray coordinates for a transaminase, aspartate aminotransferase, and the results of stereochemical and mechanistic studies for decarboxylases and serine hydroxymethyltransferase, an active-site structure for the decarboxylase group is constructed. The structure of the active-site is further refined through active-site pyridoxyllysine peptide sequence comparison and a 3-D catalytic mechanism for the L-alpha-amino acid decarboxylases is proposed. The chemistry of serine hydroxymethyltransferase is re-examined in the light of the proposed decarboxylase mechanism.     

A bayesian forecasting model for sequential bidding

In this paper we consider the problem facing a company in selecting the values of bids to submit on a sequence of contracts put out to tender. A simple-to-implement Bayesian forecasting model is presented, based on a steady Dirichlet process whose states are indexed by the possible bid decisions open to the company. The model gives an explicit algorithm for calculating the state probabilities, needing only data on the lowest bid made by the company's competitors. The flexibility of the basic model makes it a potentially powerful forecasting system for use by companies bidding for contracts.