The ion pathway through the opened Na(+),K(+)-ATPase pump

P-type ATPases pump ions across membranes, generating steep electrochemical gradients that are essential for the function of all cells. Access to the ion-binding sites within the pumps alternates between the two sides of the membrane to avoid the dissipation of the gradients that would occur during simultaneous access. In Na(+),K(+)-ATPase pumps treated with the marine agent palytoxin, this strict alternation is disrupted and binding sites are sometimes simultaneously accessible from both sides of the membrane, transforming the pumps into ion channels (see, for example, refs 2, 3). Current recordings in these channels can monitor accessibility of introduced cysteine residues to water-soluble sulphydryl-specific reagents. We found previously that Na(+),K(+) pump-channels open to the extracellular surface through a deep and wide vestibule that emanates from a narrower pathway between transmembrane helices 4 and 6 (TM4 and TM6). Here we report that cysteine scans from TM1 to TM6 reveal a single unbroken cation pathway that traverses palytoxin-bound Na(+),K(+) pump-channels from one side of the membrane to the other. This pathway comprises residues from TM1, TM2, TM4 and TM6, passes through ion-binding site II, and is probably conserved in structurally and evolutionarily related P-type pumps, such as sarcoplasmic- and endoplasmic-reticulum Ca(2+)-ATPases and H(+),K(+)-ATPases.     

Pleiotropic scaling of gene effects and the 'cost of complexity'

As perceived by Darwin, evolutionary adaptation by the processes of mutation and selection is difficult to understand for complex features that are the product of numerous traits acting in concert, for example the eye or the apparatus of flight. Typically, mutations simultaneously affect multiple phenotypic characters. This phenomenon is known as pleiotropy. The impact of pleiotropy on evolution has for decades been the subject of formal analysis. Some authors have suggested that pleiotropy can impede evolutionary progress (a so-called 'cost of complexity'). The plausibility of various phenomena attributed to pleiotropy depends on how many traits are affected by each mutation and on our understanding of the correlation between the number of traits affected by each gene substitution and the size of mutational effects on individual traits. Here we show, by studying pleiotropy in mice with the use of quantitative trait loci (QTLs) affecting skeletal characters, that most QTLs affect a relatively small subset of traits and that a substitution at a QTL has an effect on each trait that increases with the total number of traits affected. This suggests that evolution of higher organisms does not suffer a 'cost of complexity' because most mutations affect few traits and the size of the effects does not decrease with pleiotropy.     

Genetic variation in human NPY expression affects stress response and emotion

Understanding inter-individual differences in stress response requires the explanation of genetic influences at multiple phenotypic levels, including complex behaviours and the metabolic responses of brain regions to emotional stimuli. Neuropeptide Y (NPY) is anxiolytic and its release is induced by stress. NPY is abundantly expressed in regions of the limbic system that are implicated in arousal and in the assignment of emotional valences to stimuli and memories. Here we show that haplotype-driven NPY expression predicts brain responses to emotional and stress challenges and also inversely correlates with trait anxiety. NPY haplotypes predicted levels of NPY messenger RNA in post-mortem brain and lymphoblasts, and levels of plasma NPY. Lower haplotype-driven NPY expression predicted higher emotion-induced activation of the amygdala, as well as diminished resiliency as assessed by pain/stress-induced activations of endogenous opioid neurotransmission in various brain regions. A single nucleotide polymorphism (SNP rs16147) located in the promoter region alters NPY expression in vitro and seems to account for more than half of the variation in expression in vivo. These convergent findings are consistent with the function of NPY as an anxiolytic peptide and help to explain inter-individual variation in resiliency to stress, a risk factor for many diseases.     

Paleoclimate change recorded in the red earth and brown-yellow sediment of Late Quaternary for northeastern part of Guangdong Province, south to the Nanling Mountains, China

The paleoenvironment indicated by the geochronology, major oxides SiO2, Al2O3 and TOFE （Fe2O3 ＋ FeO）, and CIA （Chemical Index of Alteration） value of the red earth and brown-yellow silt primarily characterized by the Linjiang stratigraphic section, based on the geological investigation of Late Quaternary along the river banks of northeastern part of China＇s Guangdong Province, south to the Nanling Mountains, allow us to hypothesize that the red earth on the first terrace in northeastern part of Guangdong belongs to reticulated red clay developed in a hot-wet environment of the last interglacial period （132-73 ka BP）, similar to the monsoon environment in the northern margin of modern tropical zone, while the overlying brown-yellow silt layer mainly accumulated in a monsoon environment of warm temperate zone in the last glacial period （73-11 ka BP）, with the aeolian sand LJ3 representing an extreme period of worsening climate. Such a hypothesis corresponds well with predecessors＇ research on the paleoenvironment indicated by abundant fossils in both south and east to the Nanling Mountains. Hence, it follows that the bioclimatic zone did experience a large and rapid vicissitude in northeastern part of China＇s Guangdong Province, and even in the full extent of the region south to the Nanling Mountains from the last interglacial period to the last glacial period, with the red earth being replaced by the brown-yellow silty sediment, and even maybe with the Ailuropoda-Stegodon Fauna being replaced by the Penghu Fauna. This study may provide an important geological demonstration for the environmental response to global change in China＇s low latitudes on a 10 ka scale.