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1.  Neonatal Abstinence Syndrome: Treatment and Pediatric Outcomes 
Recent rise in rates of opiate replacement therapy among pregnant women have resulted in increasing number of infants requiring treatment for neonatal abstinence syndrome. Short- and long-term developmental outcomes associated with prenatal opiate exposure are discussed, including symptoms and severity of neonatal abstinence syndrome (NAS), and early cognitive and motor delays. Maternal and infant risk factors are discussed, and include patterns of maternal substance use during pregnancy, genetic risk, polysubstance exposure pharmacologic treatment for NAS and breastfeeding. The importance of characterizing corollary environmental risk factors is also considered.
doi:10.1097/GRF.0b013e31827feea4
PMCID: PMC3589586  PMID: 23314720
Neonatal Abstinence Syndrome; maternal opiate dependence; pharmacological treatment for opiate addiction; neonatal and long-term developmental outcomes
2.  Can we protect the kidneys after hypertensive pregnancy? 
doi:10.1503/cmaj.130007
PMCID: PMC3576435  PMID: 23339153
3.  The Ecological and Geographic Context of Morphological and Genetic Divergence in an Understorey-Dwelling Bird 
PLoS ONE  2014;9(2):e85903.
Advances in understanding the process of species formation require an integrated perspective that includes the evaluation of spatial, ecological and genetic components. One approach is to focus on multiple stages of divergence within the same species. Species that comprise phenotypically different populations segregated in apparently distinct habitats, in which range is presently continuous but was putatively geographically isolated provide an interesting system to study the mechanisms of population divergence. Here, we attempt to elucidate the role of ecology and geography in explaining observed morphological and genetic variation in an understorey-dwelling bird endemic to southeastern Africa, where two subspecies are recognized according to phenotype and habitat affinity. We carried out a range-wide analysis of climatic requirements, morphological and genetic variation across southeast Africa to test the hypothesis that the extent of gene flow among populations of the brown scrub-robin are influenced by their distinct climatic niches. We recovered two distinct trends depending on whether our analyses were hierarchically structured at the subspecies or at the within subspecies level. Between subspecies we found pronounced morphological differentiation associated with strong reproductive isolation (no gene flow) between populations occupying divergent climatic niches characterized by changes in the temperature of the warmest and wettest month. In contrast, within subspecies, we recovered continuous morphological variation with extensive gene flow among populations inhabiting the temperate and sub-tropical forests of southern Africa, despite divergence along the climate axis that is mainly determined by minimum temperature and precipitation of the coldest months. Our results highlight the role of niche divergence as a diversifying force that can promote reproductive isolation in vertebrates.
doi:10.1371/journal.pone.0085903
PMCID: PMC3917827  PMID: 24516521
4.  Increased glutamate concentration in the auditory cortex of persons with autism and first-degree relatives: A 1H-MRS study 
Lay Abstract
We investigated brain chemistry of the primary region of the brain involved in auditory processing in adults with autism spectrum disorder (ASD). Due to the highly heritable nature of ASD and the lack of prior brain chemistry data on unaffected first-degree relatives, we also enrolled parents of children with ASD (pASD), comparing both groups to a healthy adult control group. The technique used to quantify chemical signals was magnetic resonance spectroscopy (MRS), which we used to assess the concentration of auditory glutamate, the primary excitatory brain neurotransmitter, as well as other metabolites that assess neuronal integrity and metabolism. We found significantly higher levels of auditory glutamate in persons with ASD. In addition, increases in two other metabolites, n-acetyl-aspartate (NAA), and creatine (Cr), were observed in the ASD group. No differences were observed in the pASD group in any MRS measurement. We interpret the glutamate finding as suggestive of an increase in brain excitability, and the NAA and Cr findings as indicative of a change in brain energy metabolism in ASD.
Scientific Abstract
Increased glutamate levels have been reported in the hippocampal and frontal regions of persons with autism using proton magnetic resonance spectroscopy (1H-MRS). Although autism spectrum disorders (ASD) are highly heritable, MRS studies have not included relatives of persons with ASD. We therefore conducted a study to determine if glutamate levels are elevated in people with autism and parents of children with autism.
Single-voxel, point resolved spectroscopy (PRESS) data were acquired at 3T for left and right hemisphere auditory cortical voxels in 13 adults with autism, 15 parents of children with autism, and 15 adult control subjects. The primary measure was Glx. Additional measures included n-acetyl-aspartate (NAA), choline (Cho), myoinositol (mI) and creatine (Cr).
The autism group had significantly higher Glx, NAA and Cr concentrations than the control subjects. Parents did not differ from control subjects on any measures. No significant differences in Cho or mI levels were seen among groups. No reliable correlations between autism symptom measures and MRS variables were seen after Bonferroni correction for multiple comparisons.
The elevation in Glx in autism is consistent with prior MRS data in the hippocampus and frontal lobe and may suggest increased cortical excitability. Increased NAA and Cr may indicate brain metabolism disturbances in autism. In the current study, we found no reliable evidence of a familial effect for any spectroscopy measure. This may indicate that these metabolites have no heritable component in autism, the presence of a compensatory factor in parents, or sample specific limitations such the participation of singleton families.
doi:10.1002/aur.1260
PMCID: PMC3580156  PMID: 23166003
glutamate; n-acetyl-aspartate; creatine; spectroscopy; auditory cortex
5.  Effects of the Botanical Insecticide, Toosendanin, on Blood Digestion and Egg Production by Female Aedes aegypti (Diptera: Culicidae): Topical Application and Ingestion 
Journal of medical entomology  2013;50(1):112-121.
Botanical insecticides offer novel chemistries and actions that may provide effective mosquito control. Toosendanin (TSN, 95% purity) is one such insecticide used to control crop pests in China, and in this study, it was evaluated for lethal and sublethal effects on larvae and females of the yellowfever mosquito, Aedes aegypti (L.). TSN was very toxic to first instar larvae after a 24 h exposure (LC50 = 60.8 μg/ml) and to adult females up to 96 h after topical treatment (LD50 = 4.3 μg/female) or ingestion in a sugar bait (LC50 = 1.02 μg/μl). Treatment of first instars for 24 h with a range of sublethal doses (6.3–25 μg/ml) delayed development to pupae by 1 to 2 d. Egg production and larval hatching from eggs were dose dependently reduced (>45%) by TSN doses (1.25–10.0 μg) topically applied to females 24 h before or 1 h after a bloodmeal. Ingestion of TSN (0.031–0.25 μg/μl of sugar bait) by females 24 h before a bloodmeal also greatly reduced egg production and larval hatch; no eggs were oviposited by females ingesting the highest dose. Further studies revealed that topical or ingested TSN dose-dependently disrupted yolk deposition in oocytes, blood ingestion and digestion, and ovary ecdysteroid production in blood-fed females. Overall, our results indicate that TSN is an effective insecticide for Ae. aegypti larvae and adults, because of its overt toxicity at high doses and disruption of development and reproduction at sublethal doses.
PMCID: PMC3893133  PMID: 23427659
mosquito; reproduction; toxicity
6.  Influence of Age and Nutritional Status on Flight Performance of the Asian Tiger Mosquito Aedes albopictus (Diptera: Culicidae) 
Insects  2013;4(3):10.3390/insects4030404.
The Asian tiger mosquito, Aedes albopictus, is a competent vector for arboviruses and recently was implicated as the vector of the first autochthonous cases of dengue and chikungunya in southern Europe. The objective of this study was to analyze the flight performance of female Ae. albopictus of different ages that were starved, sugar-fed, or sugar-fed and blood-fed, using flight mills. After three days of starvation post emergence, females flew an average distance of 0.7 ± 0.5 km in 1.9 ± 1.5 h during a 16 h trial period, whereas sugar- or sugar- and blood-fed females of this age covered a significantly higher distance of around 3 km with a mean total flight time of around 6 h. The age of females (up to four weeks) had no effect on performance. The average of maximal continuous flight segments of sugar-fed (2.14 ± 0.69 h) and blood-fed (3.17 ± 0.82 h) females was distinctly higher than of starved females (0.38 ± 0.15 h) of which most flyers (83%) performed maximal flight segments that lasted no longer than 0.5 h. Overall, the results for the laboratory monitored flight performance of Ae. albopictus confirm their ability to disperse a few kilometres between breeding site and host.
doi:10.3390/insects4030404
PMCID: PMC3882092  PMID: 24404384
Aedes albopictus; flight potential; distance; vector; mosquito
7.  The Gut Bacterial Community of Mammals from Marine and Terrestrial Habitats 
PLoS ONE  2013;8(12):e83655.
After birth, mammals acquire a community of bacteria in their gastro-intestinal tract, which harvests energy and provides nutrients for the host. Comparative studies of numerous terrestrial mammal hosts have identified host phylogeny, diet and gut morphology as primary drivers of the gut bacterial community composition. To date, marine mammals have been excluded from these comparative studies, yet they represent distinct examples of evolutionary history, diet and lifestyle traits. To provide an updated understanding of the gut bacterial community of mammals, we compared bacterial 16S rRNA gene sequence data generated from faecal material of 151 marine and terrestrial mammal hosts. This included 42 hosts from a marine habitat. When compared to terrestrial mammals, marine mammals clustered separately and displayed a significantly greater average relative abundance of the phylum Fusobacteria. The marine carnivores (Antarctic and Arctic seals) and the marine herbivore (dugong) possessed significantly richer gut bacterial community than terrestrial carnivores and terrestrial herbivores, respectively. This suggests that evolutionary history and dietary items specific to the marine environment may have resulted in a gut bacterial community distinct to that identified in terrestrial mammals. Finally we hypothesize that reduced marine trophic webs, whereby marine carnivores (and herbivores) feed directly on lower trophic levels, may expose this group to high levels of secondary metabolites and influence gut microbial community richness.
doi:10.1371/journal.pone.0083655
PMCID: PMC3875473  PMID: 24386245
8.  Genetic Variability of the Neogregarine Apicystis bombi, an Etiological Agent of an Emergent Bumblebee Disease 
PLoS ONE  2013;8(12):e81475.
The worldwide spread of diseases is considered a major threat to biodiversity and a possible driver of the decline of pollinator populations, particularly when novel species or strains of parasites emerge. Previous studies have suggested that populations of introduced European honeybee (Apis mellifera) and bumblebee species (Bombus terrestris and Bombus ruderatus) in Argentina share the neogregarine parasite Apicystis bombi with the native bumblebee (Bombus dahlbomii). In this study we investigated whether A. bombi is acting as an emergent parasite in the non-native populations. Specifically, we asked whether A. bombi, recently identified in Argentina, was introduced by European, non-native bees. Using ITS1 and ITS2 to assess the parasite’s intraspecific genetic variation in bees from Argentina and Europe, we found a largely unstructured parasite population, with only 15% of the genetic variation being explained by geographic location. The most abundant haplotype in Argentina (found in all 9 specimens of non-native species) was identical to the most abundant haplotype in Europe (found in 6 out of 8 specimens). Similarly, there was no evidence of structuring by host species, with this factor explaining only 17% of the genetic variation. Interestingly, parasites in native Bombus ephippiatus from Mexico were genetically distant from the Argentine and European samples, suggesting that sufficient variability does exist in the ITS region to identify continent-level genetic structure in the parasite. Thus, the data suggest that A. bombi from Argentina and Europe share a common, relatively recent origin. Although our data did not provide information on the direction of transfer, the absence of genetic structure across space and host species suggests that A. bombi may be acting as an emergent infectious disease across bee taxa and continents.
doi:10.1371/journal.pone.0081475
PMCID: PMC3855659  PMID: 24324696
9.  Pathological and Evolutionary Implications of Retroviruses as Mobile Genetic Elements 
Genes  2013;4(4):573-582.
Retroviruses, a form of mobile genetic elements, have important roles in disease and primate evolution. Exogenous retroviruses, such as human immunodeficiency virus (HIV), have significant pathological implications that have created a massive public health challenge in recent years. Endogenous retroviruses (ERVs), which are the primary focus of this review, can also be pathogenic, as well as being beneficial to a host in some cases. Furthermore, retroviruses may have played a key role in primate evolution that resulted in the incorporation of these elements into the human genome. Retroviruses are mobile genetic elements that have important roles in disease and primate evolution. We will further discuss the pathogenic potential of retroviruses, including their role in cancer biology, and will briefly summarize their evolutionary implications.
doi:10.3390/genes4040573
PMCID: PMC3927575
transposon; mobile genetic element; virology
10.  Cultivation and Complete Genome Sequencing of Gloeobacter kilaueensis sp. nov., from a Lava Cave in Kīlauea Caldera, Hawai'i 
PLoS ONE  2013;8(10):e76376.
The ancestor of Gloeobacter violaceus PCC 7421T is believed to have diverged from that of all known cyanobacteria before the evolution of thylakoid membranes and plant plastids. The long and largely independent evolutionary history of G. violaceus presents an organism retaining ancestral features of early oxygenic photoautotrophs, and in whom cyanobacteria evolution can be investigated. No other Gloeobacter species has been described since the genus was established in 1974 (Rippka et al., Arch Microbiol 100:435). Gloeobacter affiliated ribosomal gene sequences have been reported in environmental DNA libraries, but only the type strain's genome has been sequenced. However, we report here the cultivation of a new Gloeobacter species, G. kilaueensis JS1T, from an epilithic biofilm in a lava cave in Kīlauea Caldera, Hawai'i. The strain's genome was sequenced from an enriched culture resembling a low-complexity metagenomic sample, using 9 kb paired-end 454 pyrosequences and 400 bp paired-end Illumina reads. The JS1T and G. violaceus PCC 7421T genomes have little gene synteny despite sharing 2842 orthologous genes; comparing the genomes shows they do not belong to the same species. Our results support establishing a new species to accommodate JS1T, for which we propose the name Gloeobacter kilaueensis sp. nov. Strain JS1T has been deposited in the American Type Culture Collection (BAA-2537), the Scottish Marine Institute's Culture Collection of Algae and Protozoa (CCAP 1431/1), and the Belgian Coordinated Collections of Microorganisms (ULC0316). The G. kilaueensis holotype has been deposited in the Algal Collection of the US National Herbarium (US# 217948). The JS1T genome sequence has been deposited in GenBank under accession number CP003587. The G+C content of the genome is 60.54 mol%. The complete genome sequence of G. kilaueensis JS1T may further understanding of cyanobacteria evolution, and the shift from anoxygenic to oxygenic photosynthesis.
doi:10.1371/journal.pone.0076376
PMCID: PMC3806779  PMID: 24194836
11.  Early detection of neuropathophysiology using diffusion-weighted magnetic resonance imaging in asymptomatic cats with feline immunodeficiency viral infection 
Journal of neurovirology  2011;17(4):341-352.
HIV infection results in a highly prevalent syndrome of cognitive and motor disorders designated as HIV-associated dementia (HAD). Neurologic dysfunction resembling HAD has been documented in cats infected with strain PPR of the feline immunodeficiency virus (FIV), whereas another highly pathogenic strain (C36) has not been known to cause neurologic signs. Animals experimentally infected with equivalent doses of FIV-C36 or FIV-PPR, and uninfected controls were evaluated by magnetic resonance diffusion-weighted imaging (DW-MRI) and spectroscopy (MRS) at 17.5 – 18 weeks post-infection, as part of a study of viral clade pathogenesis in FIV infected cats. Goals of the MR imaging portion of the project were to determine whether this methodology was capable of detecting early neuropathophysiology in the absence of outward manifestation of neurological signs, and to compare MR imaging results for the two viral strains expected to have differing degrees of neurologic effects. We hypothesized that there would be increased diffusion, evidenced by the apparent diffusion coefficient as measured by DW-MRI, and altered metabolite ratios measured by MRS, in the brains of FIV-PPR infected cats relative to C36-infected cats and uninfected controls. Increased apparent diffusion coefficients were seen in the white matter, gray matter, and basal ganglia of both the PPR and C36 infected (asymptomatic) cats. Thalamic MRS metabolite ratios did not differ between groups. The equivalently increased diffusion by DW-MRI suggests similar indirect neurotoxicity mechanisms for the two viral genotypes. DW-MRI is a sensitive tool to detect neuropathophysiological changes in vivo that could be useful during longitudinal studies of FIV.
doi:10.1007/s13365-011-0040-7
PMCID: PMC3749835  PMID: 21786078
Lentiviral neuropathology; HIV-associated dementia (HAD); Magnetic Resonance Spectroscopy (MRS); Diffusion-Weighted Imaging (DW-MRI); Apparent Diffusion Coefficient (ADC); FIV-PPR; FIV-C36
12.  Location of the CD8 T Cell Epitope within the Antigenic Precursor Determines Immunogenicity and Protection against the Toxoplasma gondii Parasite 
PLoS Pathogens  2013;9(6):e1003449.
CD8 T cells protect the host from disease caused by intracellular pathogens, such as the Toxoplasma gondii (T. gondii) protozoan parasite. Despite the complexity of the T. gondii proteome, CD8 T cell responses are restricted to only a small number of peptide epitopes derived from a limited set of antigenic precursors. This phenomenon is known as immunodominance and is key to effective vaccine design. However, the mechanisms that determine the immunogenicity and immunodominance hierarchy of parasite antigens are not well understood.
Here, using genetically modified parasites, we show that parasite burden is controlled by the immunodominant GRA6-specific CD8 T cell response but not by responses to the subdominant GRA4- and ROP7-derived epitopes. Remarkably, optimal processing and immunodominance were determined by the location of the peptide epitope at the C-terminus of the GRA6 antigenic precursor. In contrast, immunodominance could not be explained by the peptide affinity for the MHC I molecule or the frequency of T cell precursors in the naive animals. Our results reveal the molecular requirements for optimal presentation of an intracellular parasite antigen and for eliciting protective CD8 T cells.
Author Summary
Toxoplasma gondii is a widespread intracellular parasite that can cause severe disease in immunocompromised individuals and lead to fetal abnormalities if contracted during pregnancy. Establishment of protective immunity relies on CD8 T cells, which recognize antigenic peptides presented by MHC class I molecules on the surface of T. gondii-infected cells. Intriguingly, while the proteome of T. gondii is large, CD8 T cell responses target a very limited set of peptides. These peptides can be ranked according to the magnitude of the associated CD8 response (from immunodominant down to subdominant). Yet, little is known about the rules that define their immunogenicity and the hierarchy of the associated T cell responses. Using a panel of genetically modified T. gondii where the GRA6 dominant antigen was mutated, we show that the C-terminal location of the epitope within the source antigen is the critical parameter for immunodominance. Interestingly, when placed at the C-terminus of GRA6, the subdominant status of an epitope can be overturned. Our results unravel the mechanisms that make parasite antigens accessible for the MHC I presentation pathway. They may help to ameliorate natural immune responses and improve vaccine design against intravacuolar pathogens.
doi:10.1371/journal.ppat.1003449
PMCID: PMC3688528  PMID: 23818852
13.  A Focused Small-Molecule Screen Identifies 14 Compounds with Distinct Effects on Toxoplasma gondii 
Antimicrobial Agents and Chemotherapy  2012;56(11):5581-5590.
Toxoplasma gondii is a globally ubiquitous pathogen that can cause severe disease in immunocompromised humans and the developing fetus. Given the proven role of Toxoplasma-secreted kinases in the interaction of Toxoplasma with its host cell, identification of novel kinase inhibitors could precipitate the development of new anti-Toxoplasma drugs and define new pathways important for parasite survival. We selected a small (n = 527) but diverse set of putative kinase inhibitors and screened them for effects on the growth of Toxoplasma in vitro. We identified and validated 14 noncytotoxic compounds, all of which had 50% effective concentrations in the nanomolar to micromolar range. We further characterized eight of these compounds, four inhibitors and four enhancers, by determining their effects on parasite motility, invasion, and the likely cellular target (parasite or host cell). Only two compounds had an effect on parasite motility and invasion. All the inhibitors appeared to target the parasite, and interestingly, two of the enhancers appeared to rather target the host cell, suggesting modulation of host cell pathways beneficial for parasite growth. For the four inhibitors, we also tested their efficacy in a mouse model, where one compound proved potent. Overall, these 14 compounds represent a new and diverse set of small molecules that are likely targeting distinct parasite and host cell pathways. Future work will aim to characterize their molecular targets in both the host and parasite.
doi:10.1128/AAC.00868-12
PMCID: PMC3486605  PMID: 22908155
14.  Osteolysis following resorbable poly-l-lactide-co-d, l-lactide PLIF cage use: a review of cases 
European Spine Journal  2011;21(3):449-454.
Study design
Report of case series
Objective
To report a problem with bioabsorbable poly-l-lactide-co-d, l-lactide, PLDLLA, posterior lumbar instrumented fusion (PLIF) cage implants.
Summary of background data
Synthetic bioabsorbable implants have recently been introduced to spinal surgery and their indications and applications are still being explored. There is evidence that the use of bioabsorbable cages may be of benefit in interbody spinal fusion.
Methods
We present a case series of nine patients who have undergone PLIF with bioabsorbable cages in the lumbar spine.
Results
At follow-up over at least 1 year, four of these patients were found to have osteolysis around the implant on CT scanning. One of these patients underwent an operation to remove the cage and histology sent during surgery suggested that the implant had caused the bone loss and there was no evidence of infection. Another patient had ongoing pain in relation to the lysis, while the other two patients with lysis remained asymptomatic.
Conclusions
PLDLLA cage, which has high osteolytic nature, is considered not suitable as a fusion cage.
doi:10.1007/s00586-011-2002-4
PMCID: PMC3296858  PMID: 21881864
Bioabsorbable cage; PLIF; Osteolysis
15.  Phylogenetic Investigation of Peptide Hormone and Growth Factor Receptors in Five Dipteran Genomes 
Peptide hormones and growth factors bind to membrane receptors and regulate a myriad of processes in insects and other metazoans. The evolutionary relationships among characterized and uncharacterized (“orphan”) receptors can provide insights into receptor-ligand biology and narrow target choices in deorphanization studies. However, the large number and low sequence conservation of these receptors make evolutionary analysis difficult. Here, we characterized the G-protein-coupled receptors (GPCRs), receptor guanylyl cyclases (RGCs), and protein kinase receptors (PKRs) of mosquitoes and select other flies by interrogating the genomes of Aedes aegypti, Anopheles gambiae, Culex quinquefasciatus, Drosophila melanogaster, and D. mojavensis. Sequences were grouped by receptor type, clustered using the program CLANS, aligned using HMMR, and phylogenetic trees built using PhyML. Our results indicated that PKRs had relatively few orphan clades whereas GPCRs and RGCs had several. In addition, more than half of the Class B secretin-like GPCRs and RGCs remained uncharacterized. Additional studies revealed that Class B GPCRs exhibited more gain and loss events than other receptor types. Finally, using the neuropeptide F family of insect receptors and the neuropeptide Y family of vertebrate receptors, we also show that functional sites considered critical for ligand binding are conserved among distinct family members and between distantly related taxa. Overall, our results provide the first comprehensive analysis of peptide hormone and growth factor receptors for a major insect group.
doi:10.3389/fendo.2013.00193
PMCID: PMC3863949  PMID: 24379806
GPCR; receptor tyrosine kinase; guanylyl cyclase; serine/threonine kinase; neuropeptide; protein hormone
16.  NUTRIENT TRANSPORT IN HUMAN ANNULUS FIBROSUS IS AFFECTED BY COMPRESSIVE STRAIN AND ANISOTROPY 
Annals of biomedical engineering  2012;40(12):2551-2558.
The avascular intervertebral disc (IVD) receives nutrition via transport from surrounding vasculature; poor nutrition is believed to be a main cause of disc degeneration. In this study, we investigated the effects of mechanical deformation and anisotropy on the transport of two important nutrients – oxygen and glucose – in human annulus fibrosus (AF). The diffusivities of oxygen and glucose were measured under three levels of uniaxial confined compression – 0%, 10%, and 20% – and in three directions – axial, circumferential, and radial. The glucose partition coefficient was also measured at three compression levels. Results for glucose and oxygen diffusivity in AF ranged from 4.46×10−7 to 9.77×10−6 cm2/s and were comparable to previous studies; the glucose partition coefficient ranged from 0.71 to 0.82 and was also similar to previous results. Transport properties were found to decrease with increasing deformation, likely caused by fluid exudation during tissue compression and reduction in pore size. Furthermore, diffusivity in the radial direction was lower than in the axial or circumferential directions, indicating that nutrient transport in human AF is anisotropic. This behavior is likely a consequence of the layered structure and unique collagen architecture of AF tissue. These findings are important for better understanding nutritional supply in IVD and related disc degeneration.
doi:10.1007/s10439-012-0606-4
PMCID: PMC3509223  PMID: 22669503
glucose; oxygen; nutrition; diffusion; partitioning; solubility; intervertebral disc
17.  Insulin-like peptides in the mosquito Anopheles stephensi: identification and expression in response to diet and infection with Plasmodium falciparum 
Insulin-like peptides (ILPs) regulate a multitude of biological processes, including metabolism and immunity to infection, and share similar structural motifs across widely divergent taxa. Insulin/insulin-like growth factor signaling (IIS) pathway elements are similarly conserved. We have shown that IIS regulates reproduction, innate immunity, and lifespan in female Anopheles stephensi, a major mosquito vector of human malaria. To further explore IIS regulation of these processes, we identified genes encoding five ILPs in this species and characterized their expression in tissues. Antisera to ILP homologs in Anopheles gambiae were used to identify cellular sources in An. stephensi females by immunocytochemistry. We analyzed tissue-specific ILP transcript expression in young and older females, in response to different feeding regimens, and in response to infection with Plasmodium falciparum with quantitative reverse transcriptase-PCR assays. While some ILP transcript changes were evident in older females and in response to blood feeding, significant changes were particularly notable in response to hormonal concentrations of ingested human insulin and to P. falciparum infection. These changes suggest that ILP secretion and action may be similarly responsive in Plasmodium-infected females and potentially alter metabolism and innate immunity.
doi:10.1016/j.ygcen.2011.06.005
PMCID: PMC3153599  PMID: 21703270
insect; mosquito; insulin signaling; malaria; Anopheles; Plasmodium
18.  3D FINITE ELEMENT ANALYSIS OF NUTRIENT DISTRIBUTIONS AND CELL VIABILITY IN THE INTERVERTEBRAL DISC: EFFECTS OF DEFORMATION AND DEGENERATION 
Background
The intervertebral disc (IVD) receives important nutrients, such as glucose, from surrounding blood vessels. Poor nutritional supply is believed to play a key role in disc degeneration. Several investigators have presented finite element models of the IVD to investigate disc nutrition; however, none has predicted nutrient levels and cell viability in the disc with a realistic 3D geometry and tissue properties coupled to mechanical deformation. Understanding how degeneration and loading affect nutrition and cell viability is necessary for elucidating the mechanisms of disc degeneration and low back pain. The objective of this study was to analyze the effects of disc degeneration and static deformation on glucose distributions and cell viability in the IVD using finite element analysis.
Method of Approach
A realistic 3D finite element model of the IVD was developed based on mechano-electrochemical mixture theory. In the model, the cellular metabolic activities and viability were related to nutrient concentrations, and transport properties of nutrients were dependent on tissue deformation. The effects of disc degeneration and mechanical compression on glucose concentrations and cell density distributions in the IVD were investigated. To examine effects of disc degeneration, tissue properties were altered to reflect those of degenerated tissue, including reduced water content, fixed charge density, height, and endplate permeability. Two mechanical loading conditions were also investigated: a reference (undeformed) case and a 10% static deformation case.
Results
In general, nutrient levels decreased moving away from the nutritional supply at the disc periphery. Minimum glucose levels were at the interface between the nucleus and annulus regions of the disc. Deformation caused a 6.2% decrease in the minimum glucose concentration in the normal IVD, while degeneration resulted in an 80% decrease. Although cell density was not affected in the undeformed normal disc, there was a decrease in cell viability in the degenerated case, in which averaged cell density fell 11% compared with the normal case. This effect was further exacerbated by deformation of the degenerated IVD.
Conclusions
Both deformation and disc degeneration altered the glucose distribution in the IVD. For the degenerated case, glucose levels fell below levels necessary for maintaining cell viability, and cell density decreased. This study provides important insight into nutrition-related mechanisms of disc degeneration. Moreover, our model may serve as a powerful tool in the development of new treatments for low back pain.
doi:10.1115/1.4004944
PMCID: PMC3318943  PMID: 22010741
glucose; annulus fibrosus; nucleus pulposus; mechanical loading; cell density
19.  Global biogeography of SAR11 marine bacteria 
Metagenomic samples from oceans around the globe were used to examine the biogeography of the dominant marine heterotrophic bacterial clade, SAR11. Analysis uncovers evidence of adaptive radiation in response to environmental parameters, particularly temperature.
By generating 37 new Antarctic metagenomes and analysing the internal transcribed spacer (ITS) regions of the SAR11 clade in a total of 128 surface marine metagenomes, we identified phylotype distributions that strongly correlated with temperature and latitude.By assembling SAR11 genomes from Antarctic metagenome data, we identified specific genes, biases in gene functions and signatures of positive selection in the genomes of the polar SAR11—genomic signatures of adaptive radiation.Our data demonstrate the importance of adaptive radiation in an organism's ability to proliferate throughout the world's oceans, and describe genomic traits characteristic of different phylotypes in specific marine biomes.These bacteria are important marine heterotrophs and have a fundamental role in oceanic nutrient cycling. These findings, therefore, have important implications for our ability to predict how changes in ocean temperature may affect bacterial ecology.
The ubiquitous SAR11 bacterial clade is the most abundant type of organism in the world's oceans, but the reasons for its success are not fully elucidated. We analysed 128 surface marine metagenomes, including 37 new Antarctic metagenomes. The large size of the data set enabled internal transcribed spacer (ITS) regions to be obtained from the Southern polar region, enabling the first global characterization of the distribution of SAR11, from waters spanning temperatures −2 to 30°C. Our data show a stable co-occurrence of phylotypes within both ‘tropical' (>20°C) and ‘polar' (<10°C) biomes, highlighting ecological niche differentiation between major SAR11 subgroups. All phylotypes display transitions in abundance that are strongly correlated with temperature and latitude. By assembling SAR11 genomes from Antarctic metagenome data, we identified specific genes, biases in gene functions and signatures of positive selection in the genomes of the polar SAR11—genomic signatures of adaptive radiation. Our data demonstrate the importance of adaptive radiation in the organism's ability to proliferate throughout the world's oceans, and describe genomic traits characteristic of different phylotypes in specific marine biomes.
doi:10.1038/msb.2012.28
PMCID: PMC3421443  PMID: 22806143
adaptive radiation; Antarctica; metagenome; Pelagibacter; phylotype distribution
20.  An integrative study of a meromictic lake ecosystem in Antarctica 
The ISME journal  2010;5(5):879-895.
In nature, the complexity and structure of microbial communities varies widely, ranging from a few species to thousands of species, and from highly structured to highly unstructured communities. Here, we describe the identity and functional capacity of microbial populations within distinct layers of a pristine, marine-derived, meromictic (stratified) lake (Ace Lake) in Antarctica. Nine million open reading frames were analyzed, representing microbial samples taken from six depths of the lake size fractionated on sequential 3.0, 0.8 and 0.1 μm filters, and including metaproteome data from matching 0.1 μm filters. We determine how the interactions of members of this highly structured and moderately complex community define the biogeochemical fluxes throughout the entire lake. Our view is that the health of this delicate ecosystem is dictated by the effects of the polar light cycle on the dominant role of green sulfur bacteria in primary production and nutrient cycling, and the influence of viruses/phage and phage resistance on the cooperation between members of the microbial community right throughout the lake. To test our assertions, and develop a framework applicable to other microbially driven ecosystems, we developed a mathematical model that describes how cooperation within a microbial system is impacted by periodic fluctuations in environmental parameters on key populations of microorganisms. Our study reveals a mutualistic structure within the microbial community throughout the lake that has arisen as the result of mechanistic interactions between the physico-chemical parameters and the selection of individual members of the community. By exhaustively describing and modelling interactions in Ace Lake, we have developed an approach that may be applicable to learning how environmental perturbations affect the microbial dynamics in more complex aquatic systems.
doi:10.1038/ismej.2010.185
PMCID: PMC3105772  PMID: 21124488
metagenomics/metaproteomics; Antarctic meromictic lake; green sulfur bacteria; virus/phage; nutrient cycle; Lotka–Volterra predator–prey model
21.  Genetic diversity, parasite prevalence and immunity in wild bumblebees 
Inbreeding and a consequent loss of genetic diversity threaten small, isolated populations. One mechanism by which genetically impoverished populations may become extinct is through decreased immunocompetence and higher susceptibility to parasites. Here, we investigate the relationship between immunity and inbreeding in bumblebees, using Hebridean island populations of Bombus muscorum. We sampled nine populations and recorded parasite prevalence and measured two aspects of immunity: the encapsulation response and levels of phenoloxidase (PO). We found that prevalence of the gut parasite Crithidia bombi was higher in populations with lower genetic diversity. Neither measure of immune activity was correlated with genetic diversity. However, levels of PO declined with age and were also negatively correlated with parasite abundance. Our results suggest that as insect populations lose heterozygosity, the impact of parasitism will increase, pushing threatened populations closer to extinction.
doi:10.1098/rspb.2010.1550
PMCID: PMC3049068  PMID: 20926436
inbreeding; social insects; heterozygosity; disease; immune defence
22.  Cryptic Bumblebee Species: Consequences for Conservation and the Trade in Greenhouse Pollinators 
PLoS ONE  2012;7(3):e32992.
Commercial greenhouse growers in both Japan and China are increasingly using reared orange-tailed bumblebees known previously as Bombus hypocrita Pérez as pollinators. Phylogenetic analysis of the DNA (COI) barcodes with Bayesian methods shows that this “species” is a long-standing confusion of two cryptic species. We find that the orange-tailed bumblebees in North China are actually part of the widespread Russian (otherwise white-tailed) B. patagiatus Nylander (as B. patagiatus ganjsuensis Skorikov, n. comb.), whereas the orange-tailed bees in Japan are true B. hypocrita. This situation has been further complicated because two other cryptic species from North China that were previously confused with the Russian B. patagiatus are now recognised as separate: B. lantschouensis Vogt n. stat. and B. minshanensis Bischoff n. stat.. As demand for pollination services by greenhouse growers inevitably increases, these bees are more likely to be transported between countries. In order to conserve genetic resources of pollinator species for their option value for future food security, we advocate preventing trade and movement of B. patagiatus from China into Japan and of B. hypocrita from Japan into China.
doi:10.1371/journal.pone.0032992
PMCID: PMC3302899  PMID: 22427924
23.  The Impact of Sleep-Disordered Breathing on Body Mass Index (BMI): The Sleep Heart Health Study (SHHS) 
Introduction
It is well known that obesity is a risk factor for sleep-disordered breathing (SDB). However, whether SDB predicts increase in BMI is not well defined. Data from the Sleep Heart Health Study (SHHS) were analyzed to determine whether SDB predicts longitudinal increase in BMI, adjusted for confounding factors.
Methods
A full-montage unattended home polysomnogram (PSG) and body anthropometric measurements were obtained approximately five years apart in 3001 participants. Apnea-hypopnea index (AHI) was categorized using clinical thresholds: < 5 (normal), ≥ 5 to <15 (mild sleep apnea), and ≥ 15 (moderate to severe sleep apnea). Linear regression was used to examine the association between the three AHI groups and increased BMI. The model included age, gender, race, baseline BMI, and change in AHI as covariates.
Results
Mean (SD) age was 62.2 years (10.14), 55.2% were female and 76.1% were Caucasian. Five-year increase in BMI was modest with a mean (SD) change of 0.53 (2.62) kg/m2 (p=0.071). A multivariate regression model showed that subjects with a baseline AHI between 5–15 had a mean increase in BMI of 0.22 kg/m2 (p=0.055) and those with baseline AHI ≥ 15 had a BMI increase of 0.51 kg/m2 (p<0.001) compared to those with baseline AHI of <5.
Conclusion
Our findings suggest that there is a positive association between severity of SDB and subsequent increased BMI over approximately 5 years. This observation may help explain why persons with SDB have difficulty losing weight.
PMCID: PMC3266949  PMID: 22288025
Sleep Apnea; Weight Gain; Obesity
24.  Colour Patterns Do Not Diagnose Species: Quantitative Evaluation of a DNA Barcoded Cryptic Bumblebee Complex 
PLoS ONE  2012;7(1):e29251.
Cryptic diversity within bumblebees (Bombus) has the potential to undermine crucial conservation efforts designed to reverse the observed decline in many bumblebee species worldwide. Central to such efforts is the ability to correctly recognise and diagnose species. The B. lucorum complex (Bombus lucorum, B. cryptarum and B. magnus) comprises one of the most abundant and important group of wild plant and crop pollinators in northern Europe. Although the workers of these species are notoriously difficult to diagnose morphologically, it has been claimed that queens are readily diagnosable from morphological characters. Here we assess the value of colour-pattern characters in species identification of DNA-barcoded queens from the B. lucorum complex. Three distinct molecular operational taxonomic units were identified each representing one species. However, no uniquely diagnostic colour-pattern character state was found for any of these three molecular units and most colour-pattern characters showed continuous variation among the units. All characters previously deemed to be unique and diagnostic for one species were displayed by specimens molecularly identified as a different species. These results presented here raise questions on the reliability of species determinations in previous studies and highlights the benefits of implementing DNA barcoding prior to ecological, taxonomic and conservation studies of these important key pollinators.
doi:10.1371/journal.pone.0029251
PMCID: PMC3253071  PMID: 22238595
25.  Parasite and host assemblages: embracing the reality will improve our knowledge of parasite transmission and virulence 
Interactions involving several parasite species (multi-parasitized hosts) or several host species (multi-host parasites) are the rule in nature. Only a few studies have investigated these realistic, but complex, situations from an evolutionary perspective. Consequently, their impact on the evolution of parasite virulence and transmission remains poorly understood. The mechanisms by which multiple infections may influence virulence and transmission include the dynamics of intrahost competition, mediation by the host immune system and an increase in parasite genetic recombination. Theoretical investigations have yet to be conducted to determine which of these mechanisms are likely to be key factors in the evolution of virulence and transmission. In contrast, the relationship between multi-host parasites and parasite virulence and transmission has seen some theoretical investigation. The key factors in these models are the trade-off between virulence across different host species, variation in host species quality and patterns of transmission. The empirical studies on multi-host parasites suggest that interspecies transmission plays a central role in the evolution of virulence, but as yet no complete picture of the phenomena involved is available. Ultimately, determining how complex host–parasite interactions impact the evolution of host–parasite relationships will require the development of cross-disciplinary studies linking the ecology of quantitative networks with the evolution of virulence.
doi:10.1098/rspb.2010.1163
PMCID: PMC2992712  PMID: 20667874
multi-parasitized hosts; multi-host parasites; intrahost competition; immune system; interspecies transmission; epidemiology

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