WNK4 regulates the balance between renal NaCl reabsorption and K+ secretion

A key question in systems biology is how diverse physiologic processes are integrated to produce global homeostasis. Genetic analysis can contribute by identifying genes that perturb this integration. One system orchestrates renal NaCl and K+ flux to achieve homeostasis of blood pressure and serum K+ concentration. Positional cloning implicated the serine-threonine kinase WNK4 in this process; clustered mutations in PRKWNK4, encoding WNK4, cause hypertension and hyperkalemia (pseudohypoaldosteronism type II, PHAII) by altering renal NaCl and K+ handling. Wild-type WNK4 inhibits the renal Na-Cl cotransporter (NCCT); mutations that cause PHAII relieve this inhibition. This explains the hypertension of PHAII but does not account for the hyperkalemia. By expression in Xenopus laevis oocytes, we show that WNK4 also inhibits the renal K+ channel ROMK. This inhibition is independent of WNK4 kinase activity and is mediated by clathrin-dependent endocytosis of ROMK, mechanisms distinct from those that characterize WNK4 inhibition of NCCT. Most notably, the same mutations in PRKWNK4 that relieve NCCT inhibition markedly increase inhibition of ROMK. These findings establish WNK4 as a multifunctional regulator of diverse ion transporters; moreover, they explain the pathophysiology of PHAII. They also identify WNK4 as a molecular switch that can vary the balance between NaCl reabsorption and K+ secretion to maintain integrated homeostasis.     

Archaean ultra-depleted komatiites formed by hydrous melting of cratonic mantle

Komatiites are ultramafic volcanic rocks containing more than 18 per cent MgO (ref. 1) that erupted mainly in the Archaean era (more than 2.5 gigayears ago). Although such compositions occur in later periods of Earth history (for example, the Cretaceous komatiites of Gorgona Island), the more recent examples tend to have lower MgO content than their Archaean equivalents. Komatiites are also characterized by their low incompatible-element content, which is most consistent with their generation by high degrees of partial melting (30-50 per cent). Current models for komatiite genesis include the melting of rock at great depth in plumes of hot, diapirically rising mantle or the melting of relatively shallow mantle rocks at less extreme, but still high, temperatures caused by fluxing with water. Here we report a suite of ultramafic lava flows from the Commondale greenstone belt, in the southern part of the Kaapvaal Craton, which represents a previously unrecognized type of komatiite with exceptionally high forsterite content of its igneous olivines, low TiO(2)/Al(2)O(3) ratio, high silica content, extreme depletion in rare-earth elements and low Re/Os ratio. We suggest a model for their formation in which a garnet-enriched residue left by earlier cratonic volcanism was melted by hydration from a subducting slab.     

Role of experience and oscillations in transforming a rate code into a temporal code

In the vast majority of brain areas, the firing rates of neurons, averaged over several hundred milliseconds to several seconds, can be strongly modulated by, and provide accurate information about, properties of their inputs. This is referred to as the rate code. However, the biophysical laws of synaptic plasticity require precise timing of spikes over short timescales (<10 ms). Hence it is critical to understand the physiological mechanisms that can generate precise spike timing in vivo, and the relationship between such a temporal code and a rate code. Here we propose a mechanism by which a temporal code can be generated through an interaction between an asymmetric rate code and oscillatory inhibition. Consistent with the predictions of our model, the rate and temporal codes of hippocampal pyramidal neurons are highly correlated. Furthermore, the temporal code becomes more robust with experience. The resulting spike timing satisfies the temporal order constraints of hebbian learning. Thus, oscillations and receptive field asymmetry may have a critical role in temporal sequence learning.     

Epistatic interaction between KIR3DS1 and HLA-B delays the progression to AIDS

Natural killer (NK) cells provide defense in the early stages of the innate immune response against viral infections by producing cytokines and causing cytotoxicity. The killer immunoglobulin-like receptors (KIRs) on NK cells regulate the inhibition and activation of NK-cell responses through recognition of human leukocyte antigen (HLA) class I molecules on target cells KIR and HLA loci are both highly polymorphic, and some HLA class I products bind and trigger cell-surface receptors specified by KIR genes. Here we report that the activating KIR allele KIR3DS1, in combination with HLA-B alleles that encode molecules with isoleucine at position 80 (HLA-B Bw4-80Ile), is associated with delayed progression to AIDS in individuals infected with human immunodeficiency virus type 1 (HIV-1). In the absence of KIR3DS1, the HLA-B Bw4-80Ile allele was not associated with any of the AIDS outcomes measured. By contrast, in the absence of HLA-B Bw4-80Ile alleles, KIR3DS1 was significantly associated with more rapid progression to AIDS. These observations are strongly suggestive of a model involving an epistatic interaction between the two loci. The strongest synergistic effect of these loci was on progression to depletion of CD4(+) T cells, which suggests that a protective response of NK cells involving KIR3DS1 and its HLA class I ligands begins soon after HIV-1 infection.     

Performance constraints in decathletes

Physical performance by vertebrates is thought to be constrained by trade-offs between antagonistic pairs of ecologically relevant traits and between conflicting specialist and generalist phenotypes, but there is surprisingly little evidence to support this reasoning. Here we analyse the performance of world-class athletes in standardized decathlon events and find that it is subject to both types of trade-off, after correction has been made for differences between athletes in general ability across all 10 events. These trade-offs may have imposed important constraints on the evolution of physical performance in humans and other vertebrates.     

Circadian variation of serum testosterone in the adult male rat with a late morning acrophase

Summary Serum testosterone concentrations were measured in adult male Sprague-Dawley rats. A significant circadian testosterone rhythm (p<0.01) was found with peak values at 10.00 and 13.00 h.Supported in part by NIH, NCI Grant No. CA 15062 and NIH, NIAMDD Grant No. 5 RO1 AM11376.The authors would like to acknowledge the excellent technical assistance of Ms.Kris Strom.     

Urogastrone-epidermal growth factor is trophic to the intestinal epithelium of parenterally fed rats

Summary The weight of the stomach, small intestine and colon and the mucosal crypt cell production rate of these tissues were significantly decreased after 10 days on an isocaloric TPN diet when compared to orally fed controls. Continuous infusion of recombinant beta urogastrone, at a dose below that needed to inhibit gastric acid secretion, largely prevented this decrease in crypt cell production rate and gastrointestinal tissue weights.     

Phenolic content of sugarcane in relation to red rot disease

Zusammenfassung Hohe Konzentrationen an phenolischen Substanzen in Zuckerrohrpflanzen hemmen die durch den ParasitenCollectotrichum falcatum Went verursachte Pilzfäule.