Phylogenetic Analysis of the Mitochondrial Genomes from Leber Hereditary Optic Neuropathy Pedigrees

The nucleotide sequences of the mitochondrial genomes from patients with Leber hereditary optic neuropathy (LHON) were used for phylogenetic analysis to study the origin and population history of pathogenic mitochondrial mutations. Sequences of both the coding region (8300 bp) and the more rapidly evolving noncoding control region (1300 bp) were analyzed. Patients with the primary LHON mutations at nucleotides 3460, 11,778, and 14,484 were included in this study, as were LHON patients and non-LHON controls that lacked these primary mutations; some of the subjects also carried secondary LHON mutations. The phylogenetic analyses demonstrate that primary LHON mutations arose and were fixed multiple times within the population, even for the small set of LHON patients that was analyzed in these initial studies. In contrast, the secondary LHON mutations at nucleotides 4216, 4917, and 13,708 arose once: the mitochondrial genomes that carried these secondary mutations formed a well supported phylogenetic cluster that apparently arose 60,000 to 100,000 years ago. Previous studies found secondary LHON mutations at a higher frequency among LHON patients than among control subjects. However, this finding does not prove a pathogenetic role of these mutations in LHON. Instead, the increased frequency is more likely to reflect the population genetic history of secondary mutations relative to that of primary LHON mutations.     

Lipid-cholesterol interactions in the P beta' phase. Application of a statistical mechanical model.

We describe a statistical mechanical model for lipid-cholesterol mixtures in the P beta' (ripple) phase of lipid bilayers. The model is a simple extension of an earlier model for the ripple phase in pure lipid bilayers. The extension consists of adding a degree of freedom to allow for the occupation of underlying lattice sites by cholesterol molecules, and adding a lipid-cholesterol interaction term to the model Hamiltonian. The interaction term was constructed based on numerical calculations of lipid-cholesterol energies for several different packing juxtapositions of the two molecules. Other than the lipid-cholesterol interactions, the extended model uses the same parameter set as the earlier model, so that comparison of the properties of the extended model with experimental data serves as a test of the validity of the original model. Properties of the model were calculated using the Monte Carlo method. Results are displayed as snapshots of the ripple configurations at different cholesterol concentrations. The spacing of the ripples increases with increasing cholesterol concentration and the rate of increase compares very well with experimental data. The success of this model supports the conclusion drawn earlier that frustration arising from anisotropic packing interactions is responsible for the ripple phase in lipid bilayers. In the extended model these packing interactions are responsible for the selective partitioning of cholesterol in the regions between the ripples.     

NaCl homoeostasis as a factor for the survival of the evergreen halophyte Armeria maritima (Mill.) Willd. under salt stress in winter

The combination of NaCl and low temperature stress makes winter a critical time for evergreen halophytes at temperate latitudes. As part of a study of ecotypic differentiation of the evergreen Armeria maritima (Mill.) Willd., inland and salt-marsh populations were compared with respect to their growth and survival, osmotic adjustment and NaCl concentrations (based on dry weight) under salt stress in pot experiments in winter. Increased leaf necrosis in all populations under salt stress indicated a higher NaCl sensitivity in winter than in summer. Plants from inland populations were more sensitive than salt-marsh populations. Inland and salt-marsh populations showed similar capacities for seasonal osmotic adjustment, high seasonal increase of praline concentration and long-term betaine accumulation. Inland and salt-marsh populations allocated Na and Cl preferentially to the shoot. In inland populations, Na and Cl accumulated to high concentrations in leaves, whereas the much lower NaCl concentration in salt-marsh populations suggested that in these plants, Na uptake was regulated to match the growth-dependent ion demand of the shoot. The prevention of NaCl accumulation in times of slow growth by a NaCl homoeostasis system seemed to be an important adaptation with respect to the survival of evergreen plants in salt marshes.     

Protective immune response against foot-and-mouth disease.

The causative agents of foot-and-mouth disease (FMD) are small icosahedral viruses of the Aphthovirus group within the Picornaviridae family. There is no evidence that these viruses infect cells of the immune system or otherwise interfere detrimentally with their function; additionally, it has not been possible to relate cytotoxicity reactions against virus-infected cells to the efficacy of the immune response against FMD virus infection. In contrast, there is a close association between FMD virus antibody and the protective immune response (10, 14, 15, 20, 24, 25, 29-32). Induction of this antibody is dependent on the structure of the viral antigenic sites (7-9, 11, 18) and on the concomitant presence of Th-lymphocyte epitopes (4, 5, 7, 8), although a Th-lymphocyte-independent response has been reported (2). Recent work by Piatti et al. (26) showed that the immune response induced by FMD virus was only Th-lymphocyte dependent when low doses of antigen were used. This latter work was performed in mice, and it is not certain that a similar situation would be found in cattle. As for the major effector immune defense, this relies on the interaction between antibody-virus complexes and the phagocytic cells of the reticuloendothelial system (17, 19).     

Comparison of the mutagenicity of quinoline and all monohydroxyquinolines with a series of arene oxide, trans-dihydrodiol, diol epoxide, N-oxide and arene hydrate derivatives of quinoline in the Ames/Salmonella microsome test.

Fourteen new quinoline derivatives were synthesised and their mutagenicity compared in the Ames test using Salmonella typhimurium TA100 as indicator strain with and without (Aroclor-induced) S9 mix. None of the synthesised quinoline derivatives had to our knowledge been examined before in the Ames test. Quinoline and the monohydroxyquinolines were included as reference compounds. Three of the new derivatives, i.e., quinoline 7,8-oxide, N-methyl-quinoline 5,6-oxide and trans-quinoline-5,6,7,8-dioxide appeared to be mutagenic. Quinoline 7,8-oxide was positive only in the presence of S9 mix, the specific mutagenicity amounting to 2498 +/- 96 and 1289 +/- 120 revertants per mumole with 20 and 10% S9 in the mix, respectively. Both N-methyl-quinoline 5,6-oxide and trans-quinoline-5,6,7,8-dioxide were weakly positive, the former only in the presence of the S9 mix, and the latter irrespective of the presence of S9 mix, the specific mutagenicity amounting to 134 +/- 6 and 123 +/- 10 revertants per mumole, respectively. The mutagenic potency of quinoline 7,8-oxide was of the same order as that of quinoline itself and was distinctly lower than that of 8-hydroxyquinoline. Inconclusive results were obtained with trans-7,8-dihydroxy-7,8-dihydroquinoline, 5,6-dihydroxy-7,8-epoxy-5,6,7,8-tetrahydroquinoline and 8-hydroxyquinoline-N-oxide; if these compounds are mutagenic their mutagenic potency would be at least 20-30 times lower than that of the parent compounds. None of the other chemically synthesised quinoline derivatives showed mutagenic activity with TA100 either in the presence or in the absence of S9 mix. The results obtained with the reference compounds were in accordance with literature data.     

Possible association of the exetended MHC haplotype B44-SC30-DR4 with autism

We previously reported that the complement C4B null allele appears to be associated with infantile autism. Since the C4B null allele is known to be part of the extended or ancestral haplotype [B44-SC30-Dr4], we investigated the incidence of [B44-Sc30-DR4] in 21 autistic children and their parents. This extended haplotype was increased by almost six-fold in the autistic subjects as compared with healthy controls. Moreover, the total number of extended haplotypes expressed on chromosomes of autistic subjects was significantly increased as compared with those expressed on chromosomes of healthy subjects. We conclude that a gene related to, or included in, the extended major histocompatibility complex may be associated with autism.     

Differences in foliage quality of young jack pine (Pinus banksiana Lamb.) on burned and clearcut sites: effects on jack pine budworm (Choristoneura pinus pinus Freeman)

Summary Suitability of young jack pine as a host for jack pine budworm was examined on similarly-aged trees growing on two areas previously burned in wildfires and on two previously clearcut areas in northwest Wisconsin. Nitrogen, monoterpenes, and moisture levels of foliage, and xylem water potential were measured and related to larval survival and pupal weight of caged jack pine budworm larvae. Nitrogen, monoterpenes, needle weight, and needle moisture were higher in trees growing on clearcut sites than on burned area trees. Surival of budworms to early and late instar, pupation, and adult eclosion was greater for larvae caged on clearcut-area trees than on burned-area trees. Female pupal weight differed between older (ca 10 years old) and younger (ca 8 years old) trees, but not between clearcut and burned areas. Mean female pupal weight was greatest on lownitrogen trees, where larval survival was lowest. Foliar nitrogen was consistently included as a significant predictor in budworm survival regressions. Regressions indicated larval survival and pupal weight may be associated with different tree- and foliage-related traits. Results suggest long-lasting effects of previous forest disturbance may subsequently affect herbivorous insects such as jack pine budworm.     

Increased vital and total lung capacities in Tibetan compared to Han residents of Lhasa (3,658 m).

Larger chest dimensions and lung volumes have been reported for Andean high-altitude natives compared with sea-level residents and implicated in raising lung diffusing capacity. Studies conducted in Nepal suggested that lifelong Himalayan residents did not have enlarged chest dimensions. To determine if high-altitude Himalayans (Tibetans) had larger lung volumes than acclimatized newcomers (Han "Chinese"), we studied 38 Tibetan and 43 Han residents of Lhasa, Tibet Autonomous Region, China (elevation 3,658 m) matched for age, height, weight, and smoking history. The Tibetan compared with the Han subjects had a larger total lung capacity [6.80 +/- 0.19 (mean +/- SEM) vs 6.24 +/- 0.18 l BTPS, P less than 0.05], vital capacity (5.00 +/- 0.08 vs 4.51 +/- 0.10 1 BTPS, P less than 0.05), and tended to have a greater residual volume (1.86 +/- 0.12 vs 1.56 +/- 0.09 1 BTPS, P less than 0.06). Chest circumference was greater in the Tibetan than the Han subjects (85 +/- 1 vs 82 +/- 1 cm, P less than 0.05) and correlated with vital capacity in each group as well as in the two groups combined (r = 0.69, P less than 0.05). Han who had migrated to high altitude as children (less than or equal to 5 years old, n = 6) compared to Han adult migrants (greater than or equal to 18 years old, n = 26) were shorter but had similar lung volumes and capacities when normalized for body size. The Tibetans' vital capacity and total lung capacity in relation to body size were similar to values reported previously for lifelong residents of high altitude in South and North America. Thus, Tibetans, like North and South American high-altitude residents, have larger lung volumes. This may be important for raising lung diffusing capacity and preserving arterial oxygen saturation during exercise.     

β-Adrenergic blockade does not prevent polycythemia or decrease in plasma volume in men at 4300 m altitude

When humans ascend to high altitude (ALT) their plasma volume (PV) and total blood volume (BV) decrease during the first few days. With continued residence over several weeks, the hypoxia-induced stimulation of erythropoietin increases red cell production which tends to restore BV. Because hypoxia also activates the β-adrenergic system, which stimulates red blood cell production, we investigated the effect of adrenergic β-receptor inhibition with propranolol on fluid volumes and the polycythemic response in 11 healthy unacclimatized men (21–33 years old exposed to an ALT of 4300 m (barometric pressure 460 Torr) for 3 weeks on Pikes Peak, Colorado. PV was determined by the Evans blue dye method (PV_EB), BV by the carbon monoxide method (BV_CO), red cell volume (RCV) was calculated from hematocrit (Hct) and BV_CO, and serum erythropoietin concentration ([EPO]) and reticulocyte count, were also determined. All determinations were made at sea level and after 9–11 (ALT-10) and 19–20 (ALT-20) days at ALT. At sea level and ALT, six men received propranolol (pro, 240 mg · day⁻¹), and five received a placebo (pla). Effective β-blockade did not modify the mean (SE) maximal values of [EPO] [pla: 24.9 (3.5) vs pro: 24.5 (1.5) mU · ml⁻¹] or reticulocyte count [pla: 2.7 (0.7) vs pro: 2.2 (0.5)%]; nor changes in PV_EB [pla: −15.8 (3.8) vs pro: −19.9 (2.8)%], RCV_CO [pla: +7.0 (6.7) vs pro: +10.1 (6.1)%], or BV_CO [pla: −7.3 (2.3) vs pro: −7.1 (3.9)%]. In the absence of weight loss, a redistribution of body water with no net loss is implied. Hence, activation of the β-adrenergic system did not appear to affect the hypovolemic or polycythemic responses that occurred during 3 weeks at 4300 m ALT in these subjects. Accepted: 25 August 1997