MYH9 is associated with nondiabetic end-stage renal disease in African Americans

As end-stage renal disease (ESRD) has a four times higher incidence in African Americans compared to European Americans, we hypothesized that susceptibility alleles for ESRD have a higher frequency in the West African than the European gene pool. We carried out a genome-wide admixture scan in 1,372 ESRD cases and 806 controls and found a highly significant association between excess African ancestry and nondiabetic ESRD (lod score = 5.70) but not diabetic ESRD (lod = 0.47) on chromosome 22q12. Each copy of the European ancestral allele conferred a relative risk of 0.50 (95% CI = 0.39-0.63) compared to African ancestry. Multiple common SNPs (allele frequencies ranging from 0.2 to 0.6) in the gene encoding nonmuscle myosin heavy chain type II isoform A (MYH9) were associated with two to four times greater risk of nondiabetic ESRD and accounted for a large proportion of the excess risk of ESRD observed in African compared to European Americans.     

Go protein as signal transducer in the pertussis toxin-sensitive phosphatidylinositol pathway

Receptors stimulating phospholipase C do so through heterotrimeric GTP-binding proteins to produce two second messengers, inositol 1,4,5-trisphosphate (InsP3) and diacylglycerol. In spite of the detailed understanding of phospholipase C structure and phosphatidyl inositol signalling, the identity of the GTP-binding protein involved is so far unknown. To address this issue, we have used the Xenopus oocyte in which muscarinic receptors couple to phospholipase C through a pertussis toxin-sensitive GTP-binding protein. In this cell, InsP3 mobilizes intracellular Ca2+ to evoke a Cl- current. The magnitude of this Cl- current is proportional to the amount of InsP3 in the cell, and therefore can be used as an assay for InsP3 production. We report here that the activated alpha-subunit of the GTP-binding protein GO, when directly injected into oocytes, evokes a Cl- current by mobilizing Ca2+ from intracellular InsP3-sensitive stores. We also show that holo-GO, when injected into oocytes, can specifically enhance the muscarinic receptor-stimulated Cl- current. These data indicate that GO can serve as the signal transducer of the receptor-regulated phospholipase C in Xenopus oocytes.     

UV guided dendritic growth patterns and the networking of melanocytes

Whole skin organ cultures of vitiliginous, skin show that the marginal melanocytes are highly sensitive to a pulse of UV exposure (210–380 nm) during the G₂ phase of the cell cycle, as seen by prominent dendricity. Melanocytes are highly dendritic in the epidermis overlying rapidly growing tumors, as well as within proliferative lesions such as basal cell carcinomas and aggressive seborrheic keratosis. In the organ cultures the dendrites extend towards the source of UV, i.e. the surface, while the main body lies along the basement membrane. The epidermal melanocytes overlying tumors lie, almost vertically, dendrites aligned towards the underlying tumor on one side and the surface on the other. Within tumors dendritic elongation is guided by mitotic and PCNA positive (S-phase) tumor cells, which are a source of ultraweak UV emissions in the range of 210–330 nm. These observations indicate that ultraweak biophoton emissions from neighbouring cells can simulate environmental cues and contribute to the plasticity of networks such as the melanocytes or the visual pathways.     

The G protein-gated atrial K+ channel is stimulated by three distinct Gi alpha-subunits

The guanine nucleotide-binding protein, Gi, which inhibits adenylyl cyclase, has recently been shown to have three subtypes of the alpha-subunit, termed Gi alpha-1, Gi alpha-2 and Gi alpha-3. They share 87-94% amino-acid sequence homology and so are difficult to separate from one another. Among other functions, purified preparations activate K+ channels but there is confusion over which of the subtypes activates the muscarinic K+ channels of the atrial muscle of the heart: Gi alpha-3, also termed Gk, has been shown to activate this channel but it is not clear whether Gi alpha-1 does or does not. To clarify this problem, we expressed the subtypes separately in Escherichia coli to eliminate contamination by other subtypes and tested the recombinant alpha- chains on atrial muscarinic K+ channels. Although we anticipated that only Gi alpha-3 would have Gk activity, to our surprise all three recombinant subtypes were active, from which we deduce that the Gi subtypes are multifunctional.     

Stimulation and inhibition of adenylyl cyclases mediated by distinct regulatory proteins

Adenylyl cyclases are under positive and negative control by guanine nucleotides and hormones. Stimulatory responses are mediated by a guanine nucleotide- and Mg-binding regulatory component (Ns), a protein that has been purified to homogeneity. Inhibitory responses have been hypothesized to be mediated by an analogous regulatory component (Ni) distinct from Ns, but definitive proof for this is lacking and these effects may result from modulation of Ns activity. Recently, Bordetella pertussis toxin has been shown to ADP-ribosylate a peptide that is not part of Ns, and this coincides with attenuation of hormonal inhibition of adenylyl cyclase. We show here that cyc- S49 cells contain a substrate for ADP-ribosylation by pertussis toxin and that the toxin alters GTP dependent inhibition of cyc- adenyl cyclase activity. As cyc- S49 cells do not contain Ns by several criteria, we conclude that Ni is a distinct and separate regulatory component of adenylyl cyclase.     

The germ cell — oncogenic and embryogenic correlates

Summary This study is based on 100 consecutive germ cell tumors of the gonads, received during a 5-year period. Benign teratomas, with totipotent differentiation are the commonest ovarian germ cell tumors, whereas the nullipotent germinomas from the bulk of the testicular tumors. Differentiation in the rapidly proliferating testicular teratomas, occurs in the form of embryoid bodies and organoid structures. From an analysis of the germ cell tumors it is evident that the ovum confers differentiating functions on the zygote, while the spermatozoon confers functions of organization and proliferation. This difference in the behavior of the 2 germ cells is due to local feedbacks within the cortical and medullary zones of the gonads.Acknowledgments. I wish to thank Dr S. K. Lal, Maulana Azad Medical College, New Delhi, for his valuable suggestions concerning gonadal functions. Reprint requests to B. I., B-72, Pandara Road, New Delhi-110003 (India).     

Sarcolemma-localized nNOS is required to maintain activity after mild exercise

Many neuromuscular conditions are characterized by an exaggerated exercise-induced fatigue response that is disproportionate to activity level. This fatigue is not necessarily correlated with greater central or peripheral fatigue in patients, and some patients experience severe fatigue without any demonstrable somatic disease. Except in myopathies that are due to specific metabolic defects, the mechanism underlying this type of fatigue remains unknown. With no treatment available, this form of inactivity is a major determinant of disability. Here we show, using mouse models, that this exaggerated fatigue response is distinct from a loss in specific force production by muscle, and that sarcolemma-localized signalling by neuronal nitric oxide synthase (nNOS) in skeletal muscle is required to maintain activity after mild exercise. We show that nNOS-null mice do not have muscle pathology and have no loss of muscle-specific force after exercise but do display this exaggerated fatigue response to mild exercise. In mouse models of nNOS mislocalization from the sarcolemma, prolonged inactivity was only relieved by pharmacologically enhancing the cGMP signal that results from muscle nNOS activation during the nitric oxide signalling response to mild exercise. Our findings suggest that the mechanism underlying the exaggerated fatigue response to mild exercise is a lack of contraction-induced signalling from sarcolemma-localized nNOS, which decreases cGMP-mediated vasomodulation in the vessels that supply active muscle after mild exercise. Sarcolemmal nNOS staining was decreased in patient biopsies from a large number of distinct myopathies, suggesting a common mechanism of fatigue. Our results suggest that patients with an exaggerated fatigue response to mild exercise would show clinical improvement in response to treatment strategies aimed at improving exercise-induced signalling.     

Indoleamines and the UV-light-sensitive photoperiodic responses of the melanocyte network: a biological calendar?

The pineal, serotoninergic and pigmented neurons are associated with light-dependent sleep/arousal, serving as a biological clock with a circadian rhythm. This rhythm is maintained by melatonin which serves to recognise the dark phase. The neural network that responds to seasonal variations in day/night length has not been identified. The present study demonstrates that melanocytes in human skin respond to changes in the duration of UV exposure, and can serve as a biological calendar. These responses are mediated by two indoleamines, serotonin and melatonin. Higher melatonin levels correspond to long nights and long days (short UV pulse), while high serotonin levels in the presence of melatonin reflect short nights and long days (long UV exposure). This response recapitulates the sleep/arousal patterns in animals exposed to large variations in day/night cycle that cause changes in coat colour from pure white in winter to complete repigmentation in summer.     

Paternal inheritance of a female moth's mating preference

Females of the arctiid moth Utetheisa ornatrix mate preferentially with larger males, receiving both direct phenotypic and indirect genetic benefits. Here we demonstrate that the female's mating preference is inherited through the father rather than the mother, indicating that the preference gene or genes lie mostly or exclusively on the Z sex chromosome, which is strictly paternally inherited by daughters. Furthermore, we show that the preferred male trait and the female preference for that trait are correlated, as females with larger fathers have a stronger preference for larger males. These findings are predicted by the protected invasion theory, which asserts that male homogametic sex chromosome systems (ZZ/ZW) found in lepidopterans and birds promote the evolution of exaggerated male traits through sexual selection. Specifically, the theory predicts that, because female preference alleles arising on the Z chromosome are transmitted to all sons that have the father's attractive trait rather than to only a fraction of the sons, such alleles will experience stronger positive selection and be less vulnerable to chance loss than would autosomal alleles.