The biogenesis of mitochondria 26

Summary The vegetative segregation of parental and recombinant mitochondrial (cytoplasmic) genomes of Saccharomyces cerevisiae were compared by experiments involving the micromanipulation of early zygotic buds. Recombinant mitochondrial genomes are formed rapidly upon zygote formation and initial zygote buds are frequently composed of varying proportions of recombinant and parental type gnomes, which then all segregate in a similar fashion. Evidence suggesting that some formation of recombinant genomes can continue in the early zygote progeny is presented, but the possibility that recombination is restricted to the zygote has not been excluded. Polarity phenomena appear to be determined by the mechanism of the mitochondrial recombination events rather than by the mechanism of distribution of recombinant genomes to zygote progeny.     

Emerging tobacco hazards in China: 1. Retrospective proportional mortality study of one million deaths

ObjectiveTo assess the hazards at an early phase of the growing epidemic of deaths from tobacco in China.DesignSmoking habits before 1980 (obtained from family or other informants) of 0.7 million adults who had died of neoplastic, respiratory, or vascular causes were compared with those of a reference group of 0.2 million who had died of other causes.Setting24 urban and 74 rural areas of China.SubjectsOne million people who had died during 1986-8 and whose families could be interviewed.ResultsAmong male smokers aged 35-69 there was a 51% (SE 2) excess of neoplastic deaths, a 31% (2) excess of respiratory deaths, and a 15% (2) excess of vascular deaths. All three excesses were significant (P<0.0001). Among male smokers aged ⩾70 there was a 39% (3) excess of neoplastic deaths, a 54% (2) excess of respiratory deaths, and a 6% (2) excess of vascular deaths. Fewer women smoked, but those who did had tobacco attributable risks of lung cancer and respiratory disease about the same as men. For both sexes, the lung cancer rates at ages 35-69 were about three times as great in smokers as in non-smokers, but because the rates among non-smokers in different parts of China varied widely the absolute excesses of lung cancer in smokers also varied. Of all deaths attributed to tobacco, 45% were due to chronic obstructive pulmonary disease and 15% to lung cancer; oesophageal cancer, stomach cancer, liver cancer, tuberculosis, stroke, and ischaemic heart disease each caused 5-8%. Tobacco caused about 0.6 million Chinese deaths in 1990 (0.5 million men). This will rise to 0.8 million in 2000 (0.4 million at ages 35-69) or to more if the tobacco attributed fractions increase.ConclusionsAt current age specific death rates in smokers and non-smokers one in four smokers would be killed by tobacco, but as the epidemic grows this proportion will roughly double. If current smoking uptake rates persist in China (where about two thirds of men but few women become smokers) tobacco will kill about 100 million of the 0.3 billion males now aged 0-29, with half these deaths in middle age and half in old age.

Key messages

• Of the Chinese deaths now being caused by tobacco, 45% are from chronic lung disease, 15% from lung cancer, and 5-8% from each of oesophageal cancer, stomach cancer, liver cancer, stroke, ischaemic heart disease, and tuberculosis
• Tobacco now causes 13% (and will probably eventually cause about 33%) of deaths in men but only 3% (and perhaps eventually about 1%) of deaths in women as the proportion of young women who smoke has become small
• Two thirds of men now become smokers before age 25; few give up, and about half of those who persist will be killed by tobacco in middle or old age
• If present smoking patterns continue about 100 million of the 0.3 billion Chinese males now aged 0-29 will eventually be killed by tobacco
• Tobacco caused 0.6 million deaths in 1990 and will cause at least 0.8 million in 2000 (0.7 million in men) and about 3 million a year by the middle of the century on the basis of current smoking patterns

     

A comparative study of incisor procumbency and mandibular morphology in vampire bats

The three species of vampire bats (Phyllostomidae: Desmodontinae), Desmodus rotundus, Diaemus youngi, and Diphylla ecaudata, are the only mammals that obtain all nutrition from vertebrate blood (sanguinivory). Because of the unique challenges of this dietary niche, vampire bats possess a suite of behavioral, physiological, and morphological specializations. Morphological specializations include a dentition characterized by small, bladelike, non‐occlusive cheek teeth, large canines, and extremely large, procumbent, sickle‐shaped upper central incisors. The tips of these incisors rest in cuplike pits in the mandible behind the lower incisors (mandibular pits). Here, we use microCT scanning and high‐resolution radiography to describe the morphology of the mandible and anterior dentition in vampire bats, focusing on the relationship between symphyseal fusion, mandibular pit size, incisor size, and procumbency. In Desmodus and Diaemus, highly procumbent upper incisors are associated with relatively small mandibular pits, an unfused mandibular symphysis with substantial bony interdigitations linking the dentaries, and a diastema between the lower central incisors that helps to facilitate the lapping of blood from a wound. In Diphylla, less procumbent upper incisors are associated with relatively large mandibular pits, a completely fused mandibular symphysis, and a continuous lower toothrow lacking a central diastema. We hypothesize that symphyseal morphology and the presence or absence of the diastema are associated with the angle of upper incisor procumbency and mandibular pit development, and that spatial constraints influence the morphology of the symphysis. Finally, this morphological variation suggests that Diphylla utilizes a different feeding strategy as compared to Desmodus and Diaemus, possibly resulting from the functional demands of specialization on avian, rather than mammalian, blood. J. Morphol., 2010. © 2010 Wiley‐Liss, Inc.     

HLA-DPB1 supertype-associated protection from childhood leukaemia: relationship to leukaemia karyotype and implications for prevention

Most childhood B cell precursor (BCP) acute lymphoblastic leukaemia (ALL) cases carry the reciprocal translocation t(12;21)(p13;q22) (∼25%), or a high hyperdiploid (HeH) karyotype (30%). The t(12;21) translocation leads to the expression of a novel fusion gene, TEL-AML1 (ETV6-RUNX1), and HeH often involves tri- and tetrasomy for chromosome 21. The presence of TEL-AML1+ and HeH cells in utero prior to the development of leukaemia suggests that these lesions play a critical role in ALL initiation. Based on our previous analysis of HLA-DP in childhood ALL, and evidence from in vitro studies that TEL-AML1 can activate HLA-DP-restricted T cell responses, we hypothesised that the development of TEL-AML1+ ALL might be influenced by the child’s DPB1 genotype. To test this, we analysed the frequency of six HLA-DPB1 supertypes in a population-based series of childhood leukaemias (n = 776) classified by their karyotype (TEL-AML1+, HeH and others), in comparison with newborn controls (n = 864). One DPB1 supertype (GKD) conferred significant protection against TEL-AML1+ ALL (odds ratio (OR), 95% confidence interval (95% CI): 0.42, 0.22–0.81; p < 0.005) and HeH ALL (OR; 95% CI: 0.44, 0.30–0.65; p < 0.0001). These negative associations were almost entirely due to a single allele, DPB1*0101. Our results suggest that DPB1*0101 may afford protection from the development of TEL-AML1+ and HeH BCP ALL, possibly as the result of a DP-restricted immune response to BCP ALL-associated antigen(s), the identification of which could have important implications for the design of prophylactic vaccines.     

Genetic suppressors of the Lotus japonicus har1-1 hypernodulation phenotype

Lotus japonicus har1 mutants respond to inoculation with Mesorhizobium loti by forming an excessive number of nodules due to genetic lesions in the HAR1 autoregulatory receptor kinase gene. In order to expand the repertoire of mutants available for the genetic dissection of the root nodule symbiosis (RNS), a screen for suppressors of the L. japonicus har1-1 hypernodulation phenotype was performed. Of 150,000 M2 plants analyzed, 61 stable L. japonicus double-mutant lines were isolated. In the context of the har1-1 mutation, 26 mutant lines were unable to form RNS, whereas the remaining 35 mutant lines carried more subtle symbiotic phenotypes, either forming white ineffective nodules or showing reduced nodulation capacity. When challenged with Glomus intraradices, 18 of the 61 suppressor lines were unable to establish a symbiosis with this arbuscular mycorrhiza fungus. Using a combined approach of genetic mapping, targeting induced local lesions in genomics, and sequencing, all non-nodulating mutant lines were characterized and shown to represent new alleles of at least nine independent symbiotic loci. The class of mutants with reduced nodulation capacity was of particular interest because some of them may specify novel plant functions that regulate nodule development in L. japonicus. To facilitate mapping of the latter class of mutants, an introgression line, in which the har1-1 allele was introduced into a polymorphic background of L. japonicus ecotype MG20, was constructed.     

Self-awareness of impairment and the decision to drive after an extended period of wakefulness

Fatigue is an increasingly noted factor in road accidents. The ability to predict and be aware of impairment in terms of driving capability is important for potential legal liability and road safety. However, to date, there have been few studies that have investigated the accuracy of individuals in predicting how safely they could drive during conditions of sleep loss. Research has demonstrated that individuals rate themselves as better than the population average in a number of domains, including driving-related skills. Therefore, this study also aimed to investigate self-ratings of predicted driving ability during extended wakefulness and compare them to ratings made of a hypothetical other person under the same conditions. Thirty-two participants remained awake for a period of 40 h. Every 2 h, they completed the Psychomotor Vigilance Task (PVT) and rated on a seven-point scale how well they thought they could drive safely, react quickly in an emergency, and stay in their own lane. They were also asked to assess how they thought someone else in their own position could drive. The participants rated their driving ability as becoming significantly poorer at the same time that their PVT performance became significantly slower. Self-ratings indicating a qualitative assessment of poorer than neutral driving occurred at 03:00 h for both the “drive safely” and “react quickly” questions, after 19 h of continuous wakefulness (starting at 08:00 h). This occurred at 05:00 h for the “keep in my lane” question. Previous studies with a similar protocol demonstrated that under these conditions, individuals exhibit a performance decrements equivalent to someone with a blood alcohol concentration of 0.05% (the legal driving limit in Australia). Participants consistently rated the ability of others to drive as poorer than their own. The main implication from this study for road safety and legal liability is that it is reasonable to focus on a person's perception of the situation, as it does align with objective reality to a certain extent. A concern in terms of road safety is potential overconfidence, indicated by rating others consistently poorer than themselves.     

A new Rac/PAK/GC/cGMP signaling pathway

Guanosine 3′,5′-cyclic monophosphate (cGMP) and small GTPase Rac are critical regulators of cell functions. Recently, Rac has been shown to use its downstream effector p21-activated kinase (PAK) to directly activate transmembrane guanylyl cyclases (GCs). This novel Rac/PAK/GC/cGMP signaling pathway bridges Rac and cGMP, and provides a general molecular mechanism for diverse receptors to regulate physiological functions such as cell migration through elevating the cellular cGMP level.     

Population genomic analysis of strain variation in Leptospirillum group II bacteria involved in acid mine drainage formation

Deeply sampled community genomic (metagenomic) datasets enable comprehensive analysis of heterogeneity in natural microbial populations. In this study, we used sequence data obtained from the dominant member of a low-diversity natural chemoautotrophic microbial community to determine how coexisting closely related individuals differ from each other in terms of gene sequence and gene content, and to uncover evidence of evolutionary processes that occur over short timescales. DNA sequence obtained from an acid mine drainage biofilm was reconstructed, taking into account the effects of strain variation, to generate a nearly complete genome tiling path for a Leptospirillum group II species closely related to L. ferriphilum (sampling depth approximately 20x). The population is dominated by one sequence type, yet we detected evidence for relatively abundant variants (>99.5% sequence identity to the dominant type) at multiple loci, and a few rare variants. Blocks of other Leptospirillum group II types ( approximately 94% sequence identity) have recombined into one or more variants. Variant blocks of both types are more numerous near the origin of replication. Heterogeneity in genetic potential within the population arises from localized variation in gene content, typically focused in integrated plasmid/phage-like regions. Some laterally transferred gene blocks encode physiologically important genes, including quorum-sensing genes of the LuxIR system. Overall, results suggest inter- and intrapopulation genetic exchange involving distinct parental genome types and implicate gain and loss of phage and plasmid genes in recent evolution of this Leptospirillum group II population. Population genetic analyses of single nucleotide polymorphisms indicate variation between closely related strains is not maintained by positive selection, suggesting that these regions do not represent adaptive differences between strains. Thus, the most likely explanation for the observed patterns of polymorphism is divergence of ancestral strains due to geographic isolation, followed by mixing and subsequent recombination.     

Endogenous RGS proteins attenuate Galpha(i)-mediated lysophosphatidic acid signaling pathways in ovarian cancer cells

Lysophosphatidic acid is a bioactive phospholipid that is produced by and stimulates ovarian cancer cells, promoting proliferation, migration, invasion, and survival. Effects of LPA are mediated by cell surface G-protein coupled receptors (GPCRs) that activate multiple heterotrimeric G-proteins. G-proteins are deactivated by Regulator of G-protein Signaling (RGS) proteins. This led us to hypothesize that RGS proteins may regulate G-protein signaling pathways initiated by LPA in ovarian cancer cells. To determine the effect of endogenous RGS proteins on LPA signaling in ovarian cancer cells, we compared LPA activity in SKOV-3 ovarian cancer cells expressing G(i) subunit constructs that are either insensitive to RGS protein regulation (RGSi) or their RGS wild-type (RGSwt) counterparts. Both forms of the G-protein contained a point mutation rendering them insensitive to inhibition with pertussis toxin, and cells were treated with pertussis toxin prior to experiments to eliminate endogenous G(i/o) signaling. The potency and efficacy of LPA-mediated inhibition of forskolin-stimulated adenylyl cyclase activity was enhanced in cells expressing RGSi G(i) proteins as compared to RGSwt G(i). We further showed that LPA signaling that is subject to RGS regulation terminates much faster than signaling thru RGS insensitive G-proteins. Finally, LPA-stimulated SKOV-3 cell migration, as measured in a wound-induced migration assay, was enhanced in cells expressing Galpha(i2) RGSi as compared to cells expressing Galpha(i2) RGSwt, suggesting that endogenous RGS proteins in ovarian cancer cells normally attenuate this LPA effect. These data establish RGS proteins as novel regulators of LPA signaling in ovarian cancer cells.     

Cell entry by human pathogenic arenaviruses

The arenaviruses Lassa virus (LASV) in Africa and Machupo (MACV), Guanarito (GTOV) and Junin viruses (JUNV) in South America cause severe haemorrhagic fevers in humans with fatality rates of 15–35%. The present review focuses on the first steps of infection with human pathogenic arenaviruses, the interaction with their cellular receptor molecules and subsequent entry into the host cell. While similarities exist in genomic organization, structure and clinical disease caused by pathogenic Old World and New World arenaviruses these pathogens use different primary receptors. The Old World arenaviruses employ α-dystroglycan, a cellular receptor for proteins of the extracellular matrix, and the human pathogenic New World arenaviruses use the cellular cargo receptor transferrin receptor 1. While the New World arenavirus JUNV enters cells via clathrin-dependent endocytosis, evidence occurred for clathrin-independent entry of the prototypic Old World arenavirus lymphocytic choriomeningitis virus. Upon internalization, arenaviruses are delivered to the endosome, where pH-dependent membrane fusion is mediated by the envelope glycoprotein (GP). While arenavirus GPs share characteristics with class I fusion GPs of other enveloped viruses, unusual mechanistic features of GP-mediated membrane fusion have recently been discovered for arenaviruses with important implications for viral entry.