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1.  First report of Metarhizium anisopliae IP 46 pathogenicity in adult Anopheles gambiae s.s. and An. arabiensis (Diptera; Culicidae) 
Parasites & Vectors  2009;2:59.
The entomopathogenic fungus Metarhizium anisopliae isolate IP 46, originating from a soil sample collected in 2001 in the Cerrado of Central Brazil, was tested for its ability to reduce the survival of adult male and female Anopheles gambiae s.s. and An. arabiensis mosquitoes. A 6-h exposure to the fungus coated on test paper at a concentration of 3.3 × 106 conidia cm-2 reduced the daily survival of both mosquito species (HR = 3.14, p < 0.001), with higher risk of dying in An. gambiae s.s relative to An. arabiensis (HR = 1.38, p < 0.001). Fungal sporulation was observed in >95% of mosquito cadavers in the treatment groups. The results indicate that M. anisopliae IP 46 has the potential to be a bio-control agent for African malaria vector species, and is a suitable candidate for further research and development.
doi:10.1186/1756-3305-2-59
PMCID: PMC2791098  PMID: 19951426
2.  The impact of host species and vector control measures on the fitness of African malaria vectors 
Many malaria vector mosquitoes in Africa have an extreme preference for feeding on humans. This specialization allows them to sustain much higher levels of transmission than elsewhere, but there is little understanding of the evolutionary forces that drive this behaviour. In Tanzania, we used a semi-field system to test whether the well-documented preferences of the vectors, Anopheles arabiensis and Anopheles gambiae sensu stricto (s.s.) for cattle and humans, respectively, are predicted by the fitness they obtain from host-seeking on these species relative to other available hosts. Mosquito fitness was contrasted, when humans were fully exposed and when they were protected by a typical bednet. The fitness of both vectors varied between host species. The predicted relationship between host preference and fitness was confirmed in An. arabiensis, but not in An. gambiae s.s., whose fitness was similar on humans and other mammals. Use of typical, imperfect bednets generated only minor reductions in An. gambiae s.s. feeding success and fitness on humans, but was predicted to generate a significant reduction in the lifetime reproductive success of An. arabiensis on humans relative to cows. This supports the hypothesis that such human-protective measures could additionally benefit malaria control by increasing selection for zoophily in vectors.
doi:10.1098/rspb.2012.2823
PMCID: PMC3574332  PMID: 23303548
host specialization; selection; mosquito vectors; malaria; bednets
3.  Increased proportions of outdoor feeding among residual malaria vector populations following increased use of insecticide-treated nets in rural Tanzania 
Malaria Journal  2011;10:80.
Background
Insecticide-treated nets (ITNs) and indoor residual spraying (IRS) represent the front-line tools for malaria vector control globally, but are optimally effective where the majority of baseline transmission occurs indoors. In the surveyed area of rural southern Tanzania, bed net use steadily increased over the last decade, reducing malaria transmission intensity by 94%.
Methods
Starting before bed nets were introduced (1997), and then after two milestones of net use had been reached-75% community-wide use of untreated nets (2004) and then 47% use of ITNs (2009)-hourly biting rates of malaria vectors from the Anopheles gambiae complex and Anopheles funestus group were surveyed.
Results
In 1997, An. gambiae s.l. and An. funestus mosquitoes exhibited a tendency to bite humans inside houses late at night. For An. gambiae s.l., by 2009, nocturnal activity was less (p = 0.0018). At this time, the sibling species composition of the complex had shifted from predominantly An. gambiae s.s. to predominantly An. arabiensis. For An. funestus, by 2009, nocturnal activity was less (p = 0.0054) as well as the proportion biting indoors (p < 0.0001). At this time, An. funestus s.s. remained the predominant species within this group. As a consequence of these altered feeding patterns, the proportion (mean ± standard error) of human contact with mosquitoes (bites per person per night) occurring indoors dropped from 0.99 ± 0.002 in 1997 to 0.82 ± 0.008 in 2009 for the An. gambiae complex (p = 0.0143) and from 1.00 ± <0.001 to only 0.50 ± 0.048 for the An. funestus complex (p = 0.0004) over the same time period.
Conclusions
High usage of ITNs can dramatically alter African vector populations so that intense, predominantly indoor transmission is replaced by greatly lowered residual transmission, a greater proportion of which occurs outdoors. Regardless of the underlying mechanism, the residual, self-sustaining transmission will respond poorly to further insecticidal measures within houses. Additional vector control tools which target outdoor biting mosquitoes at the adult or immature stages are required to complement ITNs and IRS.
doi:10.1186/1475-2875-10-80
PMCID: PMC3084176  PMID: 21477321
4.  Changing character of cervical cancer in young women. 
BMJ : British Medical Journal  1989;298(6669):288-290.
To examine the hypothesis that the pattern of cervical cancer is changing data on women presenting with the disease over 34 years were studied retrospectively. During 1953-86, 2628 women with cervical cancer were referred to a large tertiary referral hospital in Sydney; 418 were aged 35 or less. During the period of review the proportion of young women with the disease increased from under 9% in the 1950s and 1960s to about 25% in the 1970s and 1980s; a similar but less pronounced trend was apparent for the whole of New South Wales in the 1970s and 1980s. The prevalence of less common morphological types of cervical cancer increased throughout the period, particularly in the young. Pelvic lymph node metastases were identified in younger patients with stage Ib and IIa tumours more commonly in the later years of the study, suggesting that the disease was becoming more severe. Overall rates of recurrence improved over time, but an apparent increase in early recurrences was observed in young patients with Ib and IIa tumours and without nodal disease. The results suggest that the clinical and pathological behaviour of cervical cancer changed over the period of review.
PMCID: PMC1835622  PMID: 2493898
5.  Mechanistic Consequences of Chiral Radical Clock Probes: Analysis of the Mononuclear Non-Heme Iron Enzyme HppE with 2-Hydroxy-3-methylenecyclopropyl Radical Clock Substrates 
(S)-2-Hydroxypropylphosphonic acid [(S)-HPP] epoxidase (HppE) is a mononuclear iron enzyme that catalyzes the last step in the biosynthesis of the antibiotic fosfomycin. HppE also processes the (R)-enantiomer of HPP but converts it to 2-oxo-propylphosphonic acid. In this study, all four stereoisomers of 3-methylenecyclopropyl-containing substrate analogues, (2R, 3R)-8, (2R, 3S)-8, (2S, 3R)-8, and (2S, 3S)-8, were synthesized and used as radical probes to investigate the mechanism of the HppE-catalyzed reaction. Upon treatment with HppE, (2S, 3R)-8 and (2S, 3S)-8 were converted via a C1 radical intermediate to the corresponding epoxide products, as anticipated. In contrast, incubation of HppE with (2R, 3R)-8 led to enzyme inactivation, and incubation of HppE with (2R, 3S)-8 yielded the 2-keto product. The former finding is consistent with the formation of a C2 radical intermediate, where the inactivation is likely triggered by radical-induced ring cleavage of the methylenecyclopropyl group. Reaction with (2R, 3S)-8 is predicted to also proceed via a C2 radical intermediate, but no enzyme inactivation and no ring-opened product were detected. These results strongly suggest that an internal electron transfer to the iron center subsequent to C–H homolysis competes with ring-opening in the processing of the C2 radical intermediate. The different outcomes of the reactions with (2R, 3R)-8 and (2R, 3S)-8 demonstrate the need to carefully consider the chirality of substituted cyclopropyl groups as radical reporting groups in studies of enzymatic mechanisms.
doi:10.1021/ja4100035
PMCID: PMC4004275  PMID: 24512048
6.  The impact of livestock on the abundance, resting behaviour and sporozoite rate of malaria vectors in southern Tanzania 
Malaria Journal  2015;14:17.
Background
Increases in the coverage of long-lasting insecticidal nets (LLINs) have significantly reduced the abundance of Anopheles gambiae sensu stricto in several African settings, leaving its more zoophagic sibling species Anopheles arabiensis as the primary vector. This study investigated the impact of livestock ownership at the household level on the ecology and malaria infection rate of vectors in an area of Tanzania where An. arabiensis accounts for most malaria transmission.
Methods
Mosquito vectors were collected resting inside houses, animal sheds and in outdoor resting boxes at households with and without livestock over three years in ten villages of the Kilombero Valley, Tanzania. Additionally, the abundance and sporozoite rate of vectors attempting to bite indoors at these households was assessed as an index of malaria exposure.
Results
The mean abundance of An. gambiae s.l. biting indoors was similar at houses with and without livestock. In all years but one, the relative proportion of An. arabiensis within the An. gambiae s.l. species complex was higher at households with livestock. Livestock presence had a significant impact on malaria vector feeding and resting behaviour. Anopheles arabiensis were generally found resting in cattle sheds where livestock were present, and inside houses when absent. Correspondingly, the human blood index of An. arabiensis and An. funestus s.l. was significant reduced at households with livestock, whereas that of An. gambiae s.s. was unaffected.
Whilst there was some evidence that sporozoite rates within the indoor-biting An. gambiae s.l population was significantly reduced at households with livestock, the significance of this effect varied depending on how background spatial variation was accounted for.
Conclusions
These results confirm that the presence of cattle at the household level can significantly alter the local species composition, feeding and resting behaviour of malaria vectors. However, the net impact of this livestock-associated variation in mosquito ecology on malaria exposure risk was unclear. Further investigation is required to distinguish whether the apparently lower sporozoite rates observed in An. gambiae s.l. at households with livestock is really a direct effect of cattle presence, or an indirect consequence of reduced risk within areas where livestock keepers choose to live.
Electronic supplementary material
The online version of this article (doi:10.1186/s12936-014-0536-8) contains supplementary material, which is available to authorized users.
doi:10.1186/s12936-014-0536-8
PMCID: PMC4311485  PMID: 25604150
Malaria transmission; Environmental management; Vector behaviour; Ecology; Zooprophylaxis; Kilombero Valley
7.  Gene Transfer of Mutant Mouse Cholinesterase Provides High Lifetime Expression and Reduced Cocaine Responses with No Evident Toxicity 
PLoS ONE  2013;8(6):e67446.
Gene transfer of a human cocaine hydrolase (hCocH) derived from butyrylcholinesterase (BChE) by 5 mutations (A199S/F227A/S287G/A328W/Y332G) has shown promise in animal studies for treatment of cocaine addiction. To predict the physiological fate and immunogenicity of this enzyme in humans, a comparable enzyme was created and tested in a conspecific host. Thus, similar mutations (A199S/S227A/S287G/A328W/Y332G) were introduced into mouse BChE to obtain a mouse CocH (mCocH). The cDNA was incorporated into viral vectors based on: a) serotype-5 helper-dependent adenovirus (hdAD) with ApoE promoter, and b) serotype-8 adeno-associated virus with CMV promoter (AAV-CMV) or multiple promoter and enhancer elements (AAV-VIP). Experiments on substrate kinetics of purified mCocH expressed in HEK293T cells showed 30-fold higher activity (U/mg) with 3H-cocaine and 25% lower activity with butyrylthiocholine, compared with wild type BChE. In mice given modest doses of AAV-CMV-mCocH vector (0.7 or 3×1011 particles) plasma hydrolase activity rose 10-fold above control for over one year with no observed immune response. Under the same conditions, transduction of the human counterpart continued less than 2 months and antibodies to hCocH were readily detected. The advanced AAV-VIP-mCocH vector generated a dose-dependent rise in plasma cocaine hydrolase activity from 20-fold (1010 particles) to 20,000 fold (1013 particles), while the hdAD vector (1.7×1012 particles) yielded a 300,000-fold increase. Neither vector caused adverse reactions such as motor weakness, elevated liver enzymes, or disturbance in spontaneous activity. Furthermore, treatment with high dose hdAD-ApoE-mCocH vector (1.7×1012 particles) prevented locomotor abnormalities, other behavioral signs, and release of hepatic alanine amino transferase after a cocaine dose fatal to most control mice (120 mg/kg). This outcome suggests that viral gene transfer can yield clinically effective cocaine hydrolase expression for lengthy periods without immune reactions or cholinergic dysfunction, while blocking toxicity from drug overdose.
doi:10.1371/journal.pone.0067446
PMCID: PMC3696080  PMID: 23840704
8.  Metabolic Abnormalities and Viral Replication is Associated with Biomarkers of Vascular Dysfunction in HIV-Infected Children 
HIV Medicine  2011;13(5):264-275.
Objectives
Human immunodeficiency virus (HIV)-infected children may be at risk for premature cardiovascular disease. We compared levels of biomarkers of vascular dysfunction among HIV-infected children with and without hyperlipidemia to HIV-exposed, uninfected children (HEU) enrolled in the Pediatric HIV/AIDS Cohort Study (PHACS), and determined factors associated with these biomarkers.
Design
Prospective cohort study
Methods
Biomarkers of inflammation (C-reactive protein (CRP), interleukin-6 (IL-6), and monocyte chemoattractant protein-1 (MCP1)); coagulant dysfunction (fibrinogen and P-selectin); endothelial dysfunction (soluble intracellular cell adhesion molecule-1 (sICAM), soluble vascular cell adhesion molecule-1 (sVCAM), and E-selectin); and metabolic dysfunction (adiponectin) were measured in 226 HIV-infected and 140 HEU children. Anthropometry, body composition, lipids, glucose, insulin, HIV disease severity, and antiretroviral therapy were recorded.
Results
The median ages were 12.3 y (HIV-infected) and 10.1 y (HEU). Body mass index (BMI) Z-scores, waist and hip circumference, and percent body fat were lower among HIV-infected. Total and non-HDL cholesterol and triglycerides were higher in HIV-infected children. HIV-infected children had higher MCP-1, fibrinogen, sICAM, and sVCAM levels. In multivariable analyses in the HIV-infected children alone, BMI z-score was associated with higher CRP and fibrinogen, but lower MCP-1 and sVCAM. Unfavorable lipid profiles were positively associated with IL6, MCP1, fibrinogen, and P- and E-selectin, whereas increased HIV viral load was associated with markers of inflammation (MCP1 and CRP) and endothelial dysfunction (sICAM and sVCAM).
Conclusions
HIV-infected children have higher levels of biomarkers of vascular dysfunction than do HEU children. Risk factors associated with higher biomarkers include unfavorable lipid levels and active HIV replication.
doi:10.1111/j.1468-1293.2011.00970.x
PMCID: PMC3297698  PMID: 22136114
Children; HIV/AIDS; vascular dysfunction; cardiovascular risk factors; biomarkers
9.  Anopheline and culicine mosquitoes are not repelled by surfaces treated with the entomopathogenic fungi Metarhizium anisopliae and Beauveria bassiana 
Parasites & Vectors  2010;3:80.
Background
Entomopathogenic fungi, Metarhizium anisopliae and Beauveria bassiana, are promising bio-pesticides for application against adult malaria mosquito vectors. An understanding of the behavioural responses of mosquitoes towards these fungi is necessary to guide development of fungi beyond the 'proof of concept' stage and to design suitable intervention tools.
Methods
Here we tested whether oil-formulations of the two fungi could be detected and avoided by adult Anopheles gambiae s.s., Anopheles arabiensis and Culex quinquefasciatus. The bioassays used a glass chamber divided into three compartments (each 250 × 250 × 250 mm): release, middle and stimulus compartments. Netting with or without fungus was fitted in front of the stimulus compartment. Mosquitoes were released and the proportion that entered the stimulus compartment was determined and compared between treatments. Treatments were untreated netting (control 1), netting with mineral oil (control 2) and fungal conidia formulated in mineral oil evaluated at three different dosages (2 × 1010, 4 × 1010 and 8 × 1010 conidia m-2).
Results
Neither fungal strain was repellent as the mean proportion of mosquitoes collected in the stimulus compartment did not differ between experiments with surfaces treated with and without fungus regardless of the fungal isolate and mosquito species tested.
Conclusion
Our results indicate that mineral-oil formulations of M. anisopliae and B. bassiana were not repellent against the mosquito species tested. Therefore, both fungi are suitable candidates for the further development of tools that aim to control host-seeking or resting mosquitoes using entomopathogenic fungi.
doi:10.1186/1756-3305-3-80
PMCID: PMC2939606  PMID: 20799937
10.  Infection of Anopheles gambiae mosquitoes with entomopathogenic fungi: effect of host age and blood-feeding status 
Parasitology Research  2010;108(2):317-322.
Physiological characteristics of insects can influence their susceptibility to fungal infection of which age and nutritional status are among the most important. An understanding of host–pathogen interaction with respect to these physiological characteristics of the host is essential if we are to develop fungal formulations capable of reducing malaria transmission under field conditions. Here, two independent bioassays were conducted to study the effect of age and blood-feeding status on fungal infection and survival of Anopheles gambiae s.s. Giles. Mosquitoes were exposed to 2 × 1010 conidia m−2 of oil-formulated Metarhizium anisopliae ICIPE-30 and of Beauveria bassiana I93-825, respectively, and their survival was monitored daily. Three age groups of mosquitoes were exposed, 2–4, 5–8, and 9–12 days since emergence. Five groups of different feeding status were exposed: non-blood-fed, 3, 12, 36, and 72 h post-blood feeding. Fungal infection reduced the survival of mosquitoes regardless of their age and blood-feeding status. Although older mosquitoes died relatively earlier than younger ones, age did not tend to affect mosquito susceptibility to fungal infection. Non-blood-fed mosquitoes were more susceptible to fungus infection compared to all categories of blood-fed mosquitoes, except for those exposed to B. bassiana 72 h post-blood feeding. In conclusion, formulations of M. anisopliae and B. bassiana can equally affect mosquitoes of different age classes, with them being relatively more susceptible to fungus infection when non-blood-fed.
doi:10.1007/s00436-010-2064-y
PMCID: PMC3024493  PMID: 20872014
11.  Understanding the Molecular Basis of the Interaction between NDPK-A and AMPK α1 
Molecular and Cellular Biology  2006;26(15):5921-5931.
Nucleoside diphosphate kinase (NDPK) (nm23/awd) belongs to a multifunctional family of highly conserved proteins (∼16 to 20 kDa) including two well-characterized isoforms (NDPK-A and -B). NDPK catalyzes the conversion of nucleoside diphosphates to nucleoside triphosphates, regulates a diverse array of cellular events, and can act as a protein histidine kinase. AMP-activated protein kinase (AMPK) is a heterotrimeric protein complex that responds to the cellular energy status by switching off ATP-consuming pathways and switching on ATP-generating pathways when ATP is limiting. AMPK was first discovered as an activity that inhibited preparations of acetyl coenzyme A carboxylase 1 (ACC1), a regulator of cellular fatty acid synthesis. We recently reported that NDPK-A (but not NDPK-B) selectively regulates the α1 isoform of AMPK independently of the AMP concentration such that the manipulation of NDPK-A nucleotide trans-phosphorylation activity to generate ATP enhanced the activity of AMPK. This regulation occurred irrespective of the surrounding ATP concentration, suggesting that “substrate channeling” was occurring with the shielding of NDPK-generated ATP from the surrounding medium. We speculated that AMPK α1 phosphorylated NDPK-A during their interaction, and here, we identify two residues on NDPK-A targeted by AMPK α1 in vivo. We find that NDPK-A S122 and S144 are phosphorylated by AMPK α1 and that the phosphorylation status of S122, but not S144, determines whether substrate channeling can occur. We report the cellular effects of the S122 mutation on ACC1 phosphorylation and demonstrate that the presence of E124 (absent in NDPK-B) is necessary and sufficient to permit both AMPK α1 binding and substrate channeling.
doi:10.1128/MCB.00315-06
PMCID: PMC1592779  PMID: 16847342
12.  On the origins of cells: a hypothesis for the evolutionary transitions from abiotic geochemistry to chemoautotrophic prokaryotes, and from prokaryotes to nucleated cells. 
All life is organized as cells. Physical compartmentation from the environment and self-organization of self-contained redox reactions are the most conserved attributes of living things, hence inorganic matter with such attributes would be life's most likely forebear. We propose that life evolved in structured iron monosulphide precipitates in a seepage site hydrothermal mound at a redox, pH and temperature gradient between sulphide-rich hydrothermal fluid and iron(II)-containing waters of the Hadean ocean floor. The naturally arising, three-dimensional compartmentation observed within fossilized seepage-site metal sulphide precipitates indicates that these inorganic compartments were the precursors of cell walls and membranes found in free-living prokaryotes. The known capability of FeS and NiS to catalyse the synthesis of the acetyl-methylsulphide from carbon monoxide and methylsulphide, constituents of hydrothermal fluid, indicates that pre-biotic syntheses occurred at the inner surfaces of these metal-sulphide-walled compartments, which furthermore restrained reacted products from diffusion into the ocean, providing sufficient concentrations of reactants to forge the transition from geochemistry to biochemistry. The chemistry of what is known as the RNA-world could have taken place within these naturally forming, catalyticwalled compartments to give rise to replicating systems. Sufficient concentrations of precursors to support replication would have been synthesized in situ geochemically and biogeochemically, with FeS (and NiS) centres playing the central catalytic role. The universal ancestor we infer was not a free-living cell, but rather was confined to the naturally chemiosmotic, FeS compartments within which the synthesis of its constituents occurred. The first free-living cells are suggested to have been eubacterial and archaebacterial chemoautotrophs that emerged more than 3.8 Gyr ago from their inorganic confines. We propose that the emergence of these prokaryotic lineages from inorganic confines occurred independently, facilitated by the independent origins of membrane-lipid biosynthesis: isoprenoid ether membranes in the archaebacterial and fatty acid ester membranes in the eubacterial lineage. The eukaryotes, all of which are ancestrally heterotrophs and possess eubacterial lipids, are suggested to have arisen ca. 2 Gyr ago through symbiosis involving an autotrophic archaebacterial host and a heterotrophic eubacterial symbiont, the common ancestor of mitochondria and hydrogenosomes. The attributes shared by all prokaryotes are viewed as inheritances from their confined universal ancestor. The attributes that distinguish eubacteria and archaebacteria, yet are uniform within the groups, are viewed as relics of their phase of differentiation after divergence from the non-free-living universal ancestor and before the origin of the free-living chemoautotrophic lifestyle. The attributes shared by eukaryotes with eubacteria and archaebacteria, respectively, are viewed as inheritances via symbiosis. The attributes unique to eukaryotes are viewed as inventions specific to their lineage. The origin of the eukaryotic endomembrane system and nuclear membrane are suggested to be the fortuitous result of the expression of genes for eubacterial membrane lipid synthesis by an archaebacterial genetic apparatus in a compartment that was not fully prepared to accommodate such compounds, resulting in vesicles of eubacterial lipids that accumulated in the cytosol around their site of synthesis. Under these premises, the most ancient divide in the living world is that between eubacteria and archaebacteria, yet the steepest evolutionary grade is that between prokaryotes and eukaryotes.
doi:10.1098/rstb.2002.1183
PMCID: PMC1693102  PMID: 12594918
13.  Synthesis and Pharmacological Evaluation Aminothiazolomorphinans at Mu and Kappa Opioid Receptors 
Journal of medicinal chemistry  2013;56(21):10.1021/jm401290y.
Previous studies with aminothiazolomorphinans suggested that this class of opioid ligands may be useful as a potential pharmacotherapeutic to decrease drug abuse. Novel aminothiazole derivatives of cyclorphan were prepared in order to evaluate a series of aminothiazolomorphinans with varying pharmacological properties at the MOR and KOR. This study was focused on exploring the regioisomeric analogs with the aminothiazole on the C-ring of the morphinan skeleton. Receptor binding and [35S]GTPγS binding assays were used to characterize the affinity and pharmacological properties of the aminothiazolomorphinans. Intracranial self-stimulation (ICSS) was used to compare effects of a representative aminothiazolomorphinan with the morphinan mixed KOR/MOR agonist butorphan (MCL-101) on brain stimulation reward.
doi:10.1021/jm401290y
PMCID: PMC3880591  PMID: 24107104
14.  Beyond Amyloid: Getting Real about Non-Amyloid Targets in Alzheimer’s Disease 
For decades, researchers have focused primarily on a pathway initiated by beta-amyloid (Aβ) aggregation, amyloid deposition, and accumulation in the brain as the key mechanism underlying the disease and the most important treatment target. However, evidence increasingly suggests that amyloid is deposited early in the course of disease, even prior to the onset of clinical symptoms; thus, targeting amyloid in mild-to-moderate patients, as past failed clinical trials have done, may be insufficient to halt further disease progression. Scientists are investigating other molecular and cellular pathways and processes that contribute to AD pathogenesis. Thus, the Alzheimer’s Association’s Research Roundtable convened a meeting in April 2012 to move beyond amyloid and explore AD as a complex multi-factorial disease, with the goal of using a more inclusive perspective to identify novel treatment strategies.
doi:10.1016/j.jalz.2013.01.017
PMCID: PMC3983562  PMID: 23809366
15.  Associations between objectively assessed child and parental physical activity: a cross-sectional study of families with 5–6 year old children 
BMC Public Health  2014;14:655.
Background
A number of studies have suggested that there is a need to increase the physical activity levels of children. Parents are important influences on children’s behaviour. There is a lack of information about whether there are associations between the physical activity levels of young children and their parents. The current study examined the associations between the physical activity (PA) of parents and their children at age five to six years old, and determined whether any associations differed by child or parent gender or between week and weekend days.
Methods
Cross-sectional study, with 1267 Year 1 pupils (five to six years of age) and at least one parent from 57 primary schools. Children and parents wore an accelerometer for five days and mean minutes of moderate-to-vigorous intensity physical activity (MVPA) per day were derived. We used multivariable linear regression to investigate whether parental and child time spent in MVPA was associated with each other. Each model was adjusted for age, child gender, parent BMI and neighbourhood deprivation with subgroup analysis by child gender.
Results
80% of parents met PA guidelines, however 29% of boys and 47% of girls aged five to six years failed to meet them. Fully-adjusted analyses suggested weak positive associations of parent’s and children’s time spent in MVPA. Every 10 additional minutes of parental MVPA were associated with one additional minute of child MVPA. There was no evidence of a difference in associations for boys and girls or between mothers and fathers.
Conclusions
29% of boys and 47% of girls aged five to six years did not meet PA guidelines indicating that these children would benefit from new approaches that focus on increasing physical activity. There were weak associations between the MVPA of 5–6 year old children and their parents, demonstrating that the time that children are active with their parents is not a major source of physical activity. Clinicians and public health professionals should encourage parents to create opportunities for their children to be active.
doi:10.1186/1471-2458-14-655
PMCID: PMC4091740  PMID: 24970045
Gender; Parent; Cross-sectional; Exercise
16.  Differential regulation of distinct Vps34 complexes by AMPK in nutrient stress and autophagy 
Cell  2013;152(1-2):290-303.
Summary
Autophagy is a stress response protecting cells from unfavorable conditions, such as nutrient starvation. The class III phosphatidylinositol-3 kinase, Vps34, forms multiple complexes and regulates both intracellular vesicle trafficking and autophagy induction. Here, we show that AMPK plays a key role in regulating different Vps34 complexes. AMPK inhibits the non-autophagy Vps34 complex by phosphorylating T163/S165 in Vps34, therefore suppresses overall PI(3)P production and protects cells from starvation. In parallel, AMPK activates the pro-autophagy Vps34 complex by phosphorylating S91/S94 in Beclin1 to induce autophagy. Atg14L, an autophagy essential gene present only in pro-autophagy Vps 34 complex, inhibits Vps34 phosphorylation but increases Beclin1 phosphorylation by AMPK. As such, Atg14L dictates the differential regulation (either inhibition or activation) of different Vps34 complexes in response to glucose starvation. Our study reveals an intricate molecular regulation of Vps34 complexes by AMPK in nutrient stress response and autophagy.
doi:10.1016/j.cell.2012.12.016
PMCID: PMC3587159  PMID: 23332761
17.  Alcohol and acetaldehyde in African fermented milk mursik – A possible etiological factor for high incidence of esophageal cancer in western Kenya 
Background
Esophageal cancer is unusually frequent in western Kenya, despite the low prevalence of classical risk factors such as heavy drinking and tobacco smoking. Among Kenyans consumption of fermented milk is an old tradition. Our hypothesis is that alcohol and acetaldehyde are produced during the fermentation process and that their carcinogenic potential contributes to the high incidence of esophageal cancer.
Methods
Eight samples of mursik milk starter cultures were collected from different Kalenjin families in the Rift Valley province, Western Kenya. A protocol provided by the families was used for milk fermentation. Ethanol and acetaldehyde levels were measured by gas chromatography. The microbial flora in starter cultures was identified by 16S and 18S sequencing.
Results
7/8 starter cultures produced mutagenic (>100 µM) levels of acetaldehyde and 4/8 starter cultures produced >1000 µM of acetaldehyde. The highest alcohol levels (mean 79.4 mM) were detected in the four fermented milks with highest acetaldehyde production. The mean number of microbial species in the starter cultures was 5 (range 2–8). Yeasts were identified in all starter cultures (mean 1.5 species/milk) but their proportion of the total microbial count varied markedly (mean 35%, range 7–90%). A combination of yeast and lactobacilli, especially Candida krusei with Lactobacillus kefiriwith the exclusion of other species, seemed to correlate with higher acetaldehyde and ethanol levels.
Conclusions
Significant levels of ethanol and acetaldehyde were produced during mursik fermentation.
Impact
When ingested several times daily the repeated exposure to carcinogenic levels of acetaldehyde may contribute to esophageal carcinogenesis.
doi:10.1158/1055-9965.EPI-12-0908
PMCID: PMC3538938  PMID: 23155139
Candida; carcinogenesis; ethanol; fermented milk; lactobacilli
18.  Lifetime Drinking Course of Driving-While-Impaired Offenders 
Addiction (Abingdon, England)  2012;107(11):1947-1956.
Aims
This retrospective study compared drinking histories of 283 men and 413 women convicted of driving while impaired (DWI) in New Mexico and interviewed 15 years following a first conviction and screening referral.
Design
We characterized drinking course and plotted drinking status (stable abstainers, abstainers, moderate, or risky drinkers) from age 15 to 60.
Setting
Pacific Institute for Research and Evaluation, Albuquerque, New Mexico.
Participants
Community sample of previously convicted DWI offenders.
Measurements
Psychiatric disorders from the Comprehensive International Diagnostic Interview; drinking histories from the Cognitive Lifetime Drinking History.
Findings
Risky drinking was prevalent at all ages for both genders. Almost half the population reported either a lifetime drinking course of risky drinking (19%) or resumed risky drinking after at least one interval of abstinence or moderate drinking (25%), while about one fifth followed a never-risky or risky-to-moderate drinking course. Offenders with a lifetime diagnosis of substance dependence more often transitioned to risky drinking, and those with lifetime alcohol dependence were more prone to transition to abstinence. Across time, those who began risky drinking at age 15 or later quit at double the rate of those who began before age 15. Women’s and men’s drinking courses were similar, but women began risky drinking at a later age and more often moved to abstinence.
Conclusions
Among people convicted of driving while impaired in the US, younger age of initiation of drinking and co-occurrence of psychiatric and substance use appear to be associated with a poorer trajectory of subsequent risky drinking behaviour. Women who are convicted of driving while impaired appear to start drinking later in life and be more likely subsequently to become abstainers.
doi:10.1111/j.1360-0443.2012.03963.x
PMCID: PMC3466340  PMID: 22681457
19.  The Mek1 phosphorylation cascade plays a role in meiotic recombination of Schizosaccharomyces pombe 
Cell Cycle  2010;9(23):4688-4702.
Mek1 is a Chk2/Rad53/Cds1-related protein kinase that is required for proper meiotic progression of Schizosaccharomyces pombe. However, the molecular mechanisms of Mek1 regulation and Mek1 phosphorylation targets are unclear. Here, we report that Mek1 is phosphorylated at serine-12 (S12), S14 and threonine-15 (T15) by Rad3 (ATR) and/or Tel1 (ATM) kinases that are activated by meiotic programmed double-strand breaks (DSBs). Mutations of these sites by alanine replacement caused abnormal meiotic progression and recombination rates. Phosphorylation of these sites triggers autophosphorylation of Mek1; indeed, alanine replacement mutations of Mek1-T318 and -T322 residues in the activation loop of Mek1 reduced Mek1 kinase activity and meiotic recombination rates. Substrates of Mek1 include Mus81-T275, Rdh54-T6 and Rdh54-T673. Mus81-T275 is known to regulate the Mus81 function in DNA cleavage, whereas Rdh54-T6A/T673A mutant cells showed abnormal meiotic recombination. Taken together, we conclude that the phosphorylation of Mek1 by Rad3 or Tel1, Mek1 autophosphorylation and Mus81 or Rdh54 phosphorylation by Mek1 regulate meiotic progression in S. pombe.
doi:10.4161/cc.9.23.14050
PMCID: PMC3048037  PMID: 21084840
Mek1; meiotic recombination; phosphorylation; Rdh54; Mus81
20.  Self-Reported Willingness to Have Cancer Screening and the Effects of Sociodemographic Factors 
Background
The relative effects of race/ethnicity and other sociodemographic factors, compared to those of attitudes and beliefs on willingness to have cancer screening, are not well understood.
Methods
We conducted telephone interviews with 1148 adults (31% African American, 27% Puerto Rican American, 43% white) from 3 cities in mainland United States and Puerto Rico. Respondents reported their sociodemographic characteristics, attitudes about barriers and facilitators of cancer screening, and willingness to have cancer screening under 4 scenarios: when done in the community vs one’s doctor’s office, and whether or not one had symptoms.
Results
Racial/ethnic minority status, age, and lower income were frequently associated with increased willingness to have cancer screening, even after including attitudes and beliefs about screening. Having screening nearby was important for community screening, and anticipation of embarrassment from screening for when there were no cancer symptoms. Associations varied across 4 screening scenarios, with the fewest predictors for screening by one’s doctor when there were symptoms.
Conclusions
Sociodemographic characteristics not only were related to willingness to have cancer screenings in almost all cases, but were generally much stronger factors than attitudinal barriers and facilitators. Cancer screening campaigns should affect attitudinal change where possible, but should also recognize that targeting screening to specific population groups may be necessary.
PMCID: PMC2920216  PMID: 20355351
cancer screening; knowledge, attitudes, and beliefs; minority health
21.  Neuroanatomical Correlates of Handedness for Tool Use in Chimpanzees (Pan troglodytes) 
Psychological science  2007;18(11):971-977.
It has been hypothesized that cognitive mechanisms underlying lateralized complex motor actions associated with tool use in chimpanzees may have set the stage for the evolution of left-hemisphere specialization for language and speech in humans. Here we report evidence that asymmetries in the homologues to Broca’s and Wernicke’s areas are associated with handedness for tool use in chimpanzees. These results suggest that the neural substrates of tool use may have served as a preadaptation for the evolution of language and speech in modern humans.
doi:10.1111/j.1467-9280.2007.02011.x
PMCID: PMC2662703  PMID: 17958711
22.  ATP Dependence of Na+-Driven Cl–HCO3 Exchange in Squid Axons 
The Journal of membrane biology  2008;222(3):107-113.
Squid giant axons recover from acid loads by activating a Na+-driven Cl–HCO3 exchanger. We internally dialyzed axons to an intracellular pH (pHi) of 6.7, halted dialysis and monitored the pHi recovery (increase) in the presence of ATP or other nucleotides, using cyanide to block oxidative phosphorylation. We computed the equivalent acid-extrusion rate (JH) from the rate of pHi increase and intracellular buffering power. In experimental series 1, we used dialysis to vary [ATP]i, finding that Michaelis-Menten kinetics describes JH vs. [ATP]i, with an apparent Vmax of 15.6 pmole cm−2 s−1 and Km of 124 µM. In series 2, we examined ATPγS, AMP-PNP, AMP-PCP, AMP-CPP, GMP-PNP, ADP, ADPβS and GDPβS to determine if any, by themselves, could support transport. Only ATPγS (8 mM) supported acid extrusion; ATPγS also supported the HCO3−-dependent 36Cl efflux expected of a Na+-driven Cl–HCO3 exchanger. Finally, in series 3, we asked whether any nucleotide could alter JH in the presence of a background [ATP]i of ~230 µM (control JH = 11.7 pmol cm−2 s−1). We found JH was decreased modestly by 8 mM AMP-PNP (JH = 8.0 pmol cm−2 s−1) but increased modestly by 1 mM ADPβS (JH = 16.0 pmol cm−2 s−1). We suggest that ATPγS leads to stable phosphorylation of the transporter or an essential activator.
doi:10.1007/s00232-008-9100-1
PMCID: PMC2905805  PMID: 18478173
Intracellular pH; Nucleotide analog; Dialysis; Kinetics
23.  RNA Polymerase I-Specific Subunit CAST/hPAF49 Has a Role in the Activation of Transcription by Upstream Binding Factor 
Molecular and Cellular Biology  2006;26(14):5436-5448.
Eukaryotic RNA polymerases are large complexes, 12 subunits of which are structurally or functionally homologous across the three polymerase classes. Each class has a set of specific subunits, likely targets of their cognate transcription factors. We have identified and characterized a human RNA polymerase I (Pol I)-specific subunit, previously identified as ASE-1 (antisense of ERCC1) and as CD3ɛ-associated signal transducer (CAST), and here termed CAST or human Pol I-associated factor of 49 kDa (hPAF49), after mouse orthologue PAF49. We provide evidence for growth-regulated Tyr phosphorylation of CAST/hPAF49, specifically in initiation-competent Pol Iβ complexes in HeLa cells, at a conserved residue also known to be important for signaling during T-cell activation. CAST/hPAF49 can interact with activator upstream binding factor (UBF) and, weakly, with selectivity factor 1 (SL1) at the rDNA (ribosomal DNA repeat sequence encoding the 18S, 5.8S, and 28S rRNA genes) promoter. CAST/hPAF49-specific antibodies and excess CAST/hPAF49 protein, which have no effect on basal Pol I transcription, inhibit UBF-activated transcription following functional SL1-Pol I-rDNA complex assembly and disrupt the interaction of UBF with CAST/hPAF49, suggesting that interaction of this Pol I-specific subunit with UBF is crucial for activation. Drawing on parallels between mammalian and Saccharomyces cerevisiae Pol I transcription machineries, we advance one model for CAST/hPAF49 function in which the network of interactions of Pol I-specific subunits with UBF facilitates conformational changes of the polymerase, leading to stabilization of the Pol I-template complex and, thereby, activation of transcription.
doi:10.1128/MCB.00230-06
PMCID: PMC1592716  PMID: 16809778
24.  Combining p-values in large scale genomics experiments 
Pharmaceutical statistics  2007;6(3):217-226.
Summary
In large-scale genomics experiments involving thousands of statistical tests, such as association scans and microarray expression experiments, a key question is: Which of the L tests represent true associations (TAs)? The traditional way to control false findings is via individual adjustments. In the presence of multiple TAs, p-value combination methods offer certain advantages. Both Fisher’s and Lancaster’s combination methods use an inverse gamma transformation. We identify the relation of the shape parameter of that distribution to the implicit threshold value; p-values below that threshold are favored by the inverse gamma method (GM). We explore this feature to improve power over Fisher’s method when L is large and the number of TAs is moderate. However, the improvement in power provided by combination methods is at the expense of a weaker claim made upon rejection of the null hypothesis – that there are some TAs among the L tests. Thus, GM remains a global test. To allow a stronger claim about a subset of p-values that is smaller than L, we investigate two methods with an explicit truncation: the rank truncated product method (RTP) that combines the first K ordered p-values, and the truncated product method (TPM) that combines p-values that are smaller than a specified threshold. We conclude that TPM allows claims to be made about subsets of p-values, while the claim of the RTP is, like GM, more appropriately about all L tests. GM gives somewhat higher power than TPM, RTP, Fisher, and Simes methods across a range of simulations.
doi:10.1002/pst.304
PMCID: PMC2569904  PMID: 17879330
multiple testing; p-value ranking; p-value combination; truncated product method; genetic association testing; microarray statistical testing
25.  In praise of tedious anatomy 
NeuroImage  2007;37(4):1033-1058.
Functional neuroimaging is fundamentally a tool for mapping function to structure, and its success consequently requires neuroanatomical precision and accuracy. Here we review the various means by which functional activation can be localized to neuroanatomy and suggest that the gold standard should be localization to the individual’s or group’s own anatomy through the use of neuroanatomical knowledge and atlases of neuroanatomy. While automated means of localization may be useful, they cannot provide the necessary accuracy, given variability between individuals. We also suggest that the field of functional neuroimaging needs to converge on a common set of methods for reporting functional localization including a common “standard” space and criteria for what constitutes sufficient evidence to report activation in terms of Brodmann’s areas.
doi:10.1016/j.neuroimage.2006.09.055
PMCID: PMC1986635  PMID: 17870621
neuroanatomy; localization; cytoarchitecture; neuroimaging

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