mRNA quality control: Marking the message for life or death

A protein complex deposited upstream of exon-exon junctions after pre-mRNA splicing may serve a dual role in mRNA quality control by directing mRNA nuclear export and, possibly, serving as a downstream 'mark' for nonsense-mediated decay.     

Interactions of tight junctions with membrane channels and transporters

Tight junctions are unique organelles in epithelial cells. They are localized to the apico-lateral region and essential for the epithelial cell transport functions. The paracellular transport process that occurs via tight junctions is extensively studied and is intricately regulated by various extracellular and intracellular signals. Fine regulation of this transport pathway is crucial for normal epithelial cell functions. Among factors that control tight junction permeability are ions and their transporters. However, this area of research is still in its infancy and much more needs to be learned about how these molecules regulate tight junction structure and functions. In this review we have attempted to compile literature on ion transporters and channels involved in the regulation of tight junctions.     

Interactions of tight junctions with membrane channels and transporters

Tight junctions are unique organelles in epithelial cells. They are localized to the apico-lateral region and essential for the epithelial cell transport functions. The paracellular transport process that occurs via tight junctions is extensively studied and is intricately regulated by various extracellular and intracellular signals. Fine regulation of this transport pathway is crucial for normal epithelial cell functions. Among factors that control tight junction permeability are ions and their transporters. However, this area of research is still in its infancy and much more needs to be learned about how these molecules regulate tight junction structure and functions. In this review we have attempted to compile literature on ion transporters and channels involved in the regulation of tight junctions.     

Antigen presentation: peptides and proteins scramble for the exit

The fate of peptides that fail to bind to major histocompatibility complex class I molecules in the endoplasmic reticulum (ER)has remained unclear. A recent study has revealed that these peptides exit the ER via the Sec61 channel and compete for this pathway with misfolded proteins.     

Hierarchical models of intra-specific competition: scramble versus contest

Hierarchical structured models for scramble and contest intraspecific competition are derived. The dynamical consequences of the two modes of competition are studied under the assumption that both populations divide up the same amount of a limiting resource at equal population levels. A comparison of equilibrium levels and their resiliences is made in order to determine which mode of competition is more advantageous. It is found that the concavity of the resource uptake rate is an important determining factor. Under certain circumstances contest competition is more advantageous for a population while under other circumstances scramble competition is more advantageous.Supported by NSF grant DMS-9306271     

CFTR and TMEM16A are separate but functionally related Cl- channels

Previous reports point out to a functional relationship of the cystic fibrosis transmembrane conductance regulator (CFTR) and Ca(2+) activated Cl(-) channels (CaCC). Recent findings showing that TMEM16A forms the essential part of CaCC, prompted us to examine whether CFTR controls TMEM16A. Inhibition of endogenous CaCC by activation of endogenous CFTR was found in 16HBE human airway epithelial cells, which also express TMEM16A. In contrast, CFBE airway epithelial cells lack of CFTR expression, but express TMEM16A along with other TMEM16-proteins. These cells produce CaCC that is inhibited by overexpression and activation of CFTR. In HEK293 cells coexpressing TMEM16A and CFTR, whole cell currents activated by IMBX and forskolin were significantly reduced when compared with cells expressing CFTR only, while the halide permeability sequence of CFTR was not changed. Expression of TMEM16A, but not of TMEM16F, H or J, produced robust CaCC, which that were inhibited by CaCCinh-A01 and niflumic acid, but not by CFTRinh-172. TMEM16A-currents were attenuated by additional expression of CFTR, and were completely abrogated when additionally expressed CFTR was activated by IBMX and forskolin. On the other hand, CFTR-currents were attenuated by additional expression of TMEM16A. CFTR and TMEM16A were both membrane localized and could be coimmunoprecipitated. Intracellular Ca(2+) signals elicited by receptor-stimulation was not changed during activation of CFTR, while ionophore-induced rise in [Ca(2+)](i) was attenuated after stimulation of CFTR. The data indicate that both CFTR and TMEM16 proteins are separate molecular entities that show functional and molecular interaction.     

The scramble for Africa: pan-temperate elements on the African high mountains

The composition of isolated floras has long been thought to be the result of relatively rare long-distance dispersal events. However, it has recently become apparent that the recruitment of lineages may be relatively easy and that many dispersal events from distant but suitable habitats have occurred, even at an infraspecific level. The evolution of the flora on the high mountains of Africa has been attributed to the recruitment of taxa not only from the African lowland flora or the Cape Floristic Region, but also to a large extent from other areas with temperate climates. We used the species rich, pan-temperate genera Carex, Ranunculus and Alchemilla to explore patterns in the number of recruitment events and region of origin. Molecular phylogenetic analyses, parametric bootstrapping and ancestral area optimizations under parsimony indicate that there has been a high number of colonization events of Carex and Ranunculus into Africa, but only two introductions of Alchemilla. Most of the colonization events have been derived from Holarctic ancestors. Backward dispersal out of Africa seems to be extremely rare. Thus, repeated colonization from the Northern Hemisphere in combination with in situ radiation has played an important role in the composition of the flora of African high mountains.     

Shall organized medicine be unified, or separate?

MEMBERS OF THE CALIFORNIA MEDICAL ASSOCIATION ARE TO BE CALLED UPON IN SEPTEMBER TO BALLOT ON A QUESTION OF GREAT IMPORTANCE TO THE FUTURE OF ORGANIZED MEDICINE: Shall membership in organized medicine-county medical society, California Medical Association, American Medical Association-be unified, or shall such membership be separate?In the July issue we published statements pro and con which the Informed Membership Poll Committee had prepared from statements of position on both sides of the question that the committee had solicited from county societies and individuals.Here, for the fuller information of our readers on this momentous question, we are presenting material representative of the arguments that the Committee digested in the statements printed in the July issue.     

Orangutan pantomime: elaborating the message

We present an exploratory study of forest-living orangutan pantomiming, i.e. gesturing in which they act out their meaning, focusing on its occurrence, communicative functions, and complexities. Studies show that captive great apes may elaborate messages if communication fails, and isolated reports suggest that great apes occasionally pantomime. We predicted forest-living orangutans would pantomime spontaneously to communicate, especially to elaborate after communication failures. Mining existing databases on free-ranging rehabilitant orangutans'' behaviour identified 18 salient pantomimes. These pantomimes most often functioned as elaborations of failed requests, but also as deceptions and declaratives. Complexities identified include multimodality, re-enactments of past events and several features of language (productivity, compositionality, systematicity). These findings confirm that free-ranging rehabilitant orangutans pantomime and use pantomime to elaborate on their messages. Further, they use pantomime for multiple functions and create complex pantomimes that can express propositionally structured content. Thus, orangutan pantomime serves as a medium for communication, not a particular function. Mining cases of complex great ape communication originally reported in functional terms may then yield more evidence of pantomime.     

Contest and scramble competitions inCallosobruchus maculatus (Coleoptera: Bruchidae)

Larval competition curves and resource sharing patterns of 5 strains of Callosobruchus maculatus (iQ, yQ, aaQ, wQ, and tQ) were examined. Offspring emergences as a function of the initial larval density were recorded to construct competition curves. Elytron length of emerged adults was used as the indicator of resource sharing patterns among competing larvae inside a bean. In the large beans, strain iQ showed a saturated competition curve and tQ strain showed a humped curve. Competition curves of the other 3 strains (yQ, aaQ, and wQ) were between those two extremes. In the small beans, strains iQ and tQ also showed a saturated and a humped competition curves, respectively, whereas the competition curves of the 3 intermediate scramble strains could not be distinguished from that of the iQ strain. Thus, the classification based on competition curves was sensitive to the resource condition (bean size). In both the large and the small beans, the elytron lengths of iQ strain remained constant irrespective of initial larval density. On the contrary, the elytron lengths of the 4 other strains decreased monotonically with higher initial larval density. Thus, the judgment based on the resource sharing pattern was shown to be robust. Only iQ strain should be designated as a contest type, and the remaining strains as scaramble types. Contest and scramble types in C. maculatus were also compared with those observed in C. analis and C. phaseoli using competition curves, resource sharing patterns, and other physiological characters.     

Random mutagenesis screening indicates the absence of a separate H+-sensor in the pH-sensitive Kir channels

Several inwardly-rectifying (Kir) potassium channels (Kir1.1, Kir4.1 and Kir4.2) are characterised by their sensitivity to inhibition by intracellular H⁺ within the physiological range. The mechanism by which these channels are regulated by intracellular pH has been the subject of intense scrutiny for over a decade, yet the molecular identity of the titratable pH-sensor remains elusive. In this study we have taken advantage of the acidic intracellular environment of S. cerevisiae and used a K⁺-auxotrophic strain to screen for mutants of Kir1.1 with impaired pH-sensitivity. In addition to the previously identified K80M mutation, this unbiased screening approach identified a novel mutation (S172T) in the second transmembrane domain (TM2) that also produces a marked reduction in pH-sensitivity through destabilization of the closed-state. However, despite this extensive mutagenic approach, no mutations could be identified which removed channel pH-sensitivity or which were likely to act as a separate H⁺-sensor unique to the pH-sensitive Kir channels. In order to explain these results we propose a model in which the pH-sensing mechanism is part of an intrinsic gating mechanism common to all Kir channels, not just the pH-sensitive Kir channels. In this model, mutations which disrupt this pH-sensor would result in an increase, not reduction, in pH-sensitivity. This has major implications for any future studies of Kir channel pH-sensitivity and explains why formal identification of these pH-sensing residues still represents a major challenge.Key words: pH-sensitivity, Kir channel, pH-sensor, potassium channel, Kir1.1     

The electrophysiology of gap junctions and gap junction channels and their mathematical modelling

In most tissues of vertebrates, gap junctions control the exchange of ions and small molecules between adjacent cells, thus co-ordinating the cellular activities. The application of the dual voltage-clamp method to cell pair preparations enables one to elucidate the electrical properties of gap junctions and gap junction channels. The conductive and kinetic data obtained at the multichannel and single channel level led to a generalised concept for the operation of gap junction channels. Based on the biological data gained in this way, a mathematical model has been developed. This model is versatile and allows to simulate the electrophysiological behaviour of different types of vertebrate gap junctions.     

Bipolar cells use kainate and AMPA receptors to filter visual information into separate channels

Unlike cone photoreceptors, whose light responses have a uniform time course, retinal ganglion cells are tuned to respond to different temporal components in a changing visual scene. The signals in a mammalian cone flow to three to five morphologically distinct "OFF" bipolar cells at a sign-conserving, glutamatergic synapse. By recording simultaneously from pairs of synaptically connected cones and OFF bipolar cells, I now show that each morphological type of OFF bipolar cell receives its signal through a different AMPA or kainate receptor. The characteristic rate at which each receptor recovers from desensitization divides the cone signal into temporal components. Temporal processing begins at the first synapse in the visual system.