bluuebunny/crossref_metadata_2025 huggingface dataset:
Endothelial expression of autocrine VEGF upon the uptake of tumor-derived microvesicles containing oncogenic EGFR
Authors: Al-Nedawi Khalid , Meehan Brian , Kerbel Robert S. , Allison Anthony C. , Rak Janusz
Published: February 2009

Activated EGF receptor (EGFR) plays an oncogenic role in several human malignancies. Although the intracellular effects of EGFR are well studied, its ability to induce and modulate tumor angiogenesis is less understood. We found previously that oncogenic EGFR can be shed from cancer cells as cargo of membrane microvesicles (MVs), which can interact with surfaces of other cells. Here we report that MVs produced by human cancer cells harboring activated EGFR (A431, A549, DLD-1) can be taken up by cultured endothelial cells, in which they elicit EGFR-dependent responses, including activation of MAPK and Akt pathways. These responses can be blocked by annexin V and its homodimer, Diannexin, both of which cloak phosphatidylserine residues on the surfaces of MVs. Interestingly, the intercellular EGFR transfer is also accompanied by the onset of VEGF expression in endothelial cells and by autocrine activation of its key signaling receptor (VEGF receptor-2). In A431 human tumor xenografts in mice, angiogenic endothelial cells stain positively for human EGFR and phospho-EGFR, while treatment with Diannexin leads to a reduction of tumor growth rate and microvascular density. Thus, we propose that oncogene-containing tumor cell-derived MVs could act as a unique form of angiogenesis-modulating stimuli and are capable of switching endothelial cells to act in an autocrine mode.
Spatiotemporal dynamics of the electrical network activity in the root apex
Authors: Masi E. , Ciszak M. , Stefano G. , Renna L. , Azzarello E. , Pandolfi C. , Mugnai S. , Baluška F. , Arecchi F. T. , Mancuso S.
Published: February 2009

The study of electrical network systems, integrated with chemical signaling networks, is becoming a common trend in contemporary biology. Classical techniques are limited to the assessment of signals from doublets or triplets of cells at a fixed temporal bin width. At present, full characteristics of the electrical network distribution and dynamics in plant cells and tissues has not been established. Here, a 60-channels multielectrode array (MEA) is applied to study spatiotemporal characteristics of the electrical network activity of the root apex. Both intense spontaneous electrical activities and stimulation-elicited bursts of locally propagating electrical signals have been observed. Propagation of the spikes indicates the existence of excitable traveling waves in plants, similar to those observed in non-nerve electrogenic tissues of animals. Obtained data reveal synchronous electric activities of root cells emerging in a specific root apex region. The dynamic electrochemical activity of root apex cells is proposed to continuously integrate internal and external signaling for developmental adaptations in a changing environment.
Multimodal neuroimaging provides a highly consistent picture of energy metabolism, validating
31
P MRS for measuring brain ATP synthesis
Authors: Chaumeil Myriam M. , Valette Julien , Guillermier Martine , Brouillet Emmanuel , Boumezbeur Fawzi , Herard Anne-Sophie , Bloch Gilles , Hantraye Philippe , Lebon Vincent
Published: February 2009

Neuroimaging methods have considerably developed over the last decades and offer various noninvasive approaches for measuring cerebral metabolic fluxes connected to energy metabolism, including PET and magnetic resonance spectroscopy (MRS). Among these methods,
31
P MRS has the particularity and advantage to directly measure cerebral ATP synthesis without injection of labeled precursor. However, this approach is methodologically challenging, and further validation studies are required to establish
31
P MRS as a robust method to measure brain energy synthesis. In the present study, we performed a multimodal imaging study based on the combination of 3 neuroimaging techniques, which allowed us to obtain an integrated picture of brain energy metabolism and, at the same time, to validate the saturation transfer
31
P MRS method as a quantitative measurement of brain ATP synthesis. A total of 29 imaging sessions were conducted to measure glucose consumption (CMRglc), TCA cycle flux (V
TCA
), and the rate of ATP synthesis (V
ATP
) in primate monkeys by using
18
F-FDG PET scan, indirect
13
C MRS, and saturation transfer
31
P MRS, respectively. These 3 complementary measurements were performed within the exact same area of the brain under identical physiological conditions, leading to: CMRglc = 0.27 ± 0.07 μmol·g
−1
·min
−1
, V
TCA
= 0.63 ± 0.12 μmol·g
−1
·min
−1
, and V
ATP
= 7.8 ± 2.3 μmol·g
−1
·min
−1
. The consistency of these 3 fluxes with literature and, more interestingly, one with each other, demonstrates the robustness of saturation transfer
31
P MRS for directly evaluating ATP synthesis in the living brain.
The potential for behavioral thermoregulation to buffer “cold-blooded” animals against climate warming
Authors: Kearney Michael , Shine Richard , Porter Warren P.
Published: February 2009

Increasing concern about the impacts of global warming on biodiversity has stimulated extensive discussion, but methods to translate broad-scale shifts in climate into direct impacts on living animals remain simplistic. A key missing element from models of climatic change impacts on animals is the buffering influence of behavioral thermoregulation. Here, we show how behavioral and mass/energy balance models can be combined with spatial data on climate, topography, and vegetation to predict impacts of increased air temperature on thermoregulating ectotherms such as reptiles and insects (a large portion of global biodiversity). We show that for most “cold-blooded” terrestrial animals, the primary thermal challenge is not to attain high body temperatures (although this is important in temperate environments) but to stay cool (particularly in tropical and desert areas, where ectotherm biodiversity is greatest). The impact of climate warming on thermoregulating ectotherms will depend critically on how changes in vegetation cover alter the availability of shade as well as the animals' capacities to alter their seasonal timing of activity and reproduction. Warmer environments also may increase maintenance energy costs while simultaneously constraining activity time, putting pressure on mass and energy budgets. Energy- and mass-balance models provide a general method to integrate the complexity of these direct interactions between organisms and climate into spatial predictions of the impact of climate change on biodiversity. This methodology allows quantitative organism- and habitat-specific assessments of climate change impacts.
Dynamics of the bacterial flagellar motor with multiple stators
Authors: Meacci Giovanni , Tu Yuhai
Published: February 2009

The bacterial flagellar motor drives the rotation of flagellar filaments and enables many species of bacteria to swim. Torque is generated by interaction of stator units, anchored to the peptidoglycan cell wall, with the rotor. Recent experiments [Yuan J, Berg HC (2008)
Proc Natl Acad Sci USA
105:1182–1185] show that at near-zero load the speed of the motor is independent of the number of stators. Here, we introduce a mathematical model of the motor dynamics that explains this behavior based on a general assumption that the stepping rate of a stator depends on the torque exerted by the stator on the rotor. We find that the motor dynamics can be characterized by two timescales: the moving-time interval for the mechanical rotation of the rotor and the waiting-time interval determined by the chemical transitions of the stators. We show that these two timescales depend differently on the load, and that their cross-over provides the microscopic explanation for the existence of two regimes in the torque-speed curves observed experimentally. We also analyze the speed fluctuation for a single motor by using our model. We show that the motion is smoothed by having more stator units. However, the mechanism for such fluctuation reduction is different depending on the load. We predict that the speed fluctuation is determined by the number of steps per revolution only at low load and is controlled by external noise for high load. Our model can be generalized to study other molecular motor systems with multiple power-generating units.
Induction of SOX4 by DNA damage is critical for p53 stabilization and function
Authors: Pan Xin , Zhao Jie , Zhang Wei-Na , Li Hui-Yan , Mu Rui , Zhou Tao , Zhang Hai-Ying , Gong Wei-Li , Yu Ming , Man Jiang-Hong , Zhang Pei-Jing , Li Ai-Ling , Zhang Xue-Min
Published: February 2009

DNA damage response (DDR) acts as a tumorigenesis barrier, and any defects in the DDR machinery may lead to cancer. SOX4 expression is elevated in many types of tumors; however, its role in DDR is still largely unknown. Here, we show that SOX4, a new DNA damage sensor, is required for the activation of p53 tumor suppressor in response to DNA damage. Notably, SOX4 interacts with and stabilizes p53 protein by blocking Mdm2-mediated p53 ubiquitination and degradation. Furthermore, SOX4 enhances p53 acetylation by interacting with p300/CBP and facilitating p300/CBP/p53 complex formation. In concert with these results, SOX4 promotes cell cycle arrest and apoptosis, and it inhibits tumorigenesis in a p53-dependent manner. Therefore, these findings highlight SOX4 as a potential key factor in regulating DDR-associated cancer.
Growing length and time scales in glass-forming liquids
Authors: Karmakar Smarajit , Dasgupta Chandan , Sastry Srikanth
Published: February 2009

The glass transition, whereby liquids transform into amorphous solids at low temperatures, is a subject of intense research despite decades of investigation. Explaining the enormous increase in relaxation times of a liquid upon supercooling is essential for understanding the glass transition. Although many theories, such as the Adam–Gibbs theory, have sought to relate growing relaxation times to length scales associated with spatial correlations in liquid structure or motion of molecules, the role of length scales in glassy dynamics is not well established. Recent studies of spatially correlated rearrangements of molecules leading to structural relaxation, termed “spatially heterogeneous dynamics,” provide fresh impetus in this direction. A powerful approach to extract length scales in critical phenomena is finite-size scaling, wherein a system is studied for sizes traversing the length scales of interest. We perform finite-size scaling for a realistic glass-former, using computer simulations, to evaluate the length scale associated with spatially heterogeneous dynamics, which grows as temperature decreases. However, relaxation times that also grow with decreasing temperature do not exhibit standard finite-size scaling with this length. We show that relaxation times are instead determined, for all studied system sizes and temperatures, by configurational entropy, in accordance with the Adam–Gibbs relation, but in disagreement with theoretical expectations based on spin-glass models that configurational entropy is not relevant at temperatures substantially above the critical temperature of mode-coupling theory. Our results provide new insights into the dynamics of glass-forming liquids and pose serious challenges to existing theoretical descriptions.
The advantages of linear information processing for cerebellar computation
Authors: Walter and Joy T. , Khodakhah Kamran
Published: February 2009

Purkinje cells can encode the strength of parallel fiber inputs in their firing by using 2 fundamentally different mechanisms, either as pauses or as linear increases in firing rate. It is not clear which of these 2 encoding mechanisms is used by the cerebellum. We used the pattern-recognition capacity of Purkinje cells based on the Marr–Albus–Ito theory of cerebellar learning to evaluate the suitability of the linear algorithm for cerebellar information processing. Here, we demonstrate the simplicity and versatility of pattern recognition in Purkinje cells linearly encoding the strength of parallel fiber inputs in their firing rate. In contrast to encoding patterns with pauses, Purkinje cells using the linear algorithm could recognize a large number of both synchronous and asynchronous input patterns in the presence or absence of inhibitory synaptic transmission. Under all conditions, the number of patterns recognized by Purkinje cells using the linear algorithm was greater than that achieved by encoding information in pauses. Linear encoding of information also allows neurons of deep cerebellar nuclei to use a simple averaging mechanism to significantly increase the computational capacity of the cerebellum. We propose that the virtues of the linear encoding mechanism make it well suited for cerebellar computation.
Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites
Authors: Wikoff William R. , Anfora Andrew T. , Liu Jun , Schultz Peter G. , Lesley Scott A. , Peters Eric C. , Siuzdak Gary
Published: February 2009

Although it has long been recognized that the enteric community of bacteria that inhabit the human distal intestinal track broadly impacts human health, the biochemical details that underlie these effects remain largely undefined. Here, we report a broad MS-based metabolomics study that demonstrates a surprisingly large effect of the gut “microbiome” on mammalian blood metabolites. Plasma extracts from germ-free mice were compared with samples from conventional (conv) animals by using various MS-based methods. Hundreds of features were detected in only 1 sample set, with the majority of these being unique to the conv animals, whereas ≈10% of all features observed in both sample sets showed significant changes in their relative signal intensity. Amino acid metabolites were particularly affected. For example, the bacterial-mediated production of bioactive indole-containing metabolites derived from tryptophan such as indoxyl sulfate and the antioxidant indole-3-propionic acid (IPA) was impacted. Production of IPA was shown to be completely dependent on the presence of gut microflora and could be established by colonization with the bacteriumClostridium sporogenes. Multiple organic acids containing phenyl groups were also greatly increased in the presence of gut microbes. A broad, drug-like phase II metabolic response of the host to metabolites generated by the microbiome was observed, suggesting that the gut microflora has a direct impact on the drug metabolism capacity of the host. Together, these results suggest a significant interplay between bacterial and mammalian metabolism.
Isolating highly enriched populations of circulating epithelial cells and other rare cells from blood using a magnetic sweeper device
Authors: Talasaz AmirAli H. , Powell Ashley A. , Huber David E. , Berbee James G. , Roh Kyung-Ho , Yu Wong , Xiao Wenzhong , Davis Mark M. , Pease R. Fabian , Mindrinos Michael N. , Jeffrey Stefanie S. , Davis Ronald W.
Published: February 2009

The enumeration of rare circulating epithelial cells (CEpCs) in the peripheral blood of metastatic cancer patients has shown promise for improved cancer prognosis. Moving beyond enumeration, molecular analysis of CEpCs may provide candidate surrogate endpoints to diagnose, treat, and monitor malignancy directly from the blood samples. Thorough molecular analysis of CEpCs requires the development of new sample preparation methods that yield easily accessible and purified CEpCs for downstream biochemical assays. Here, we describe a new immunomagnetic cell separator, the MagSweeper, which gently enriches target cells and eliminates cells that are not bound to magnetic particles. The isolated cells are easily accessible and can be extracted individually based on their physical characteristics to deplete any cells nonspecifically bound to beads. We have shown that our device can process 9 mL of blood per hour and captures >50% of CEpCs as measured in spiking experiments. We have shown that the separation process does not perturb the gene expression of rare cells. To determine the efficiency of our platform in isolating CEpCs from patients, we have isolated CEpCs from all 47 tubes of 9-mL blood samples collected from 17 women with metastatic breast cancer. In contrast, we could not find any circulating epithelial cells in samples from 5 healthy donors. The isolated CEpCs are all stored individually for further molecular analysis.
Multifunctionality and mechanism of ligand binding in a mosquito antiinflammatory protein
Authors: Calvo Eric , Mans Ben J. , Ribeiro José M. C. , Andersen John F.
Published: February 2009

The mosquito D7 salivary proteins are encoded by a multigene family related to the arthropod odorant-binding protein (OBP) superfamily. Forms having either one or two OBP domains are found in mosquito saliva. Four single-domain and one two-domain D7 proteins from
Anopheles gambiae
and
Aedes aegypti
(AeD7), respectively, were shown to bind biogenic amines with high affinity and with a stoichiometry of one ligand per protein molecule. Sequence comparisons indicated that only the C-terminal domain of AeD7 is homologous to the single-domain proteins from
A. gambiae
, suggesting that the N-terminal domain may bind a different class of ligands. Here, we describe the 3D structure of AeD7 and examine the ligand-binding characteristics of the N- and C-terminal domains. Isothermal titration calorimetry and ligand complex crystal structures show that the N-terminal domain binds cysteinyl leukotrienes (cysLTs) with high affinities (50–60 nM) whereas the C-terminal domain binds biogenic amines. The lipid chain of the cysLT binds in a hydrophobic pocket of the N-terminal domain, whereas binding of norepinephrine leads to an ordering of the C-terminal portion of the C-terminal domain into an α-helix that, along with rotations of Arg-176 and Glu-268 side chains, acts to bury the bound ligand.
A myocardium tropic adeno-associated virus (AAV) evolved by DNA shuffling and in vivo selection
Authors: Yang Lin , Jiang Jiangang , Drouin Lauren M. , Agbandje-Mckenna Mavis , Chen Chunlian , Qiao Chunping , Pu Dongqiuye , Hu Xiaoyun , Wang Da-Zhi , Li Juan , Xiao Xiao
Published: February 2009

To engineer gene vectors that target striated muscles after systemic delivery, we constructed a random library of adeno-associated virus (AAV) by shuffling the capsid genes of AAV serotypes 1 to 9, and screened for muscle-targeting capsids by direct in vivo panning after tail vein injection in mice. After 2 rounds of in vivo selection, a capsid gene named M41 was retrieved mainly based on its high frequency in the muscle and low frequency in the liver. Structural analyses revealed that the AAVM41 capsid is a recombinant of AAV1, 6, 7, and 8 with a mosaic capsid surface and a conserved capsid interior. AAVM41 was then subjected to a side-by-side comparison to AAV9, the most robust AAV for systemic heart and muscle gene delivery; to AAV6, a parental AAV with strong muscle tropism. After i.v. delivery of reporter genes, AAVM41 was found more efficient than AAV6 in the heart and muscle, and was similar to AAV9 in the heart but weaker in the muscle. In fact, the myocardium showed the highest gene expression among all tissues tested in mice and hamsters after systemic AAVM41 delivery. However, gene transfer in non-muscle tissues, mainly the liver, was dramatically reduced. AAVM41 was further tested in a genetic cardiomyopathy hamster model and achieved efficient long-term δ-sarcoglycan gene expression and rescue of cardiac functions. Thus, direct in vivo panning of capsid libraries is a simple tool for the de-targeting and retargeting of viral vector tissue tropisms facilitated by acquisition of desirable sequences and properties.
Positive regulation of minichromosome maintenance gene expression, DNA replication, and cell transformation by a plant retinoblastoma gene
Authors: Sabelli Paolo A. , Hoerster George , Lizarraga Lucina E. , Brown Sara W. , Gordon-Kamm William J. , Larkins Brian A.
Published: February 2009

Retinoblastoma-related (RBR) genes inhibit the cell cycle primarily by repressing adenovirus E2 promoter binding factor (E2F) transcription factors, which drive the expression of numerous genes required for DNA synthesis and cell cycle progression. The RBR-E2F pathway is conserved in plants, but cereals such as maize are characterized by having a complex RBR gene family with at least 2 functionally distinct members, RBR1 and RBR3. Although RBR1 has a clear cell cycle inhibitory function, it is not known whether RBR3 has a positive or negative role. By uncoupling RBR3 from the negative regulation of RBR1 in cultured maize embryos through a combination of approaches, we demonstrate that RBR3 has a positive and critical role in the expression of E2F targets required for the initiation of DNA synthesis, DNA replication, and the efficiency with which transformed plants can be obtained. Titration of endogenous RBR3 activity through expression of a dominant-negative allele with a compromised pocket domain suggests that these RBR3 functions require an activity distinct from its pocket domain. Our results indicate a cell cycle pathway in maize, in which 2 RBR genes have specific and opposing functions. Thus, the paradigm that RBR genes are negative cell cycle regulators cannot be considered universal.
Temperature- and age-dependent seizures in a mouse model of severe myoclonic epilepsy in infancy
Authors: Oakley John C. , Kalume Franck , Yu Frank H. , Scheuer Todd , Catterall William A.
Published: February 2009

Heterozygous loss-of-function mutations in the α subunit of the type I voltage-gated sodium channel Na
V
1.1 cause severe myoclonic epilepsy in infancy (SMEI), an infantile-onset epileptic encephalopathy characterized by normal development followed by treatment-refractory febrile and afebrile seizures and psychomotor decline. Mice with SMEI (mSMEI), created by heterozygous deletion of Na
V
1.1 channels, develop seizures and ataxia. Here we investigated the temperature and age dependence of seizures and interictal epileptiform spike-and-wave activity in mSMEI. Combined video-EEG monitoring demonstrated that mSMEI had seizures induced by elevated body core temperature but wild-type mice were unaffected. In the 3 age groups tested, no postnatal day (P)17–18 mSMEI had temperature-induced seizures, but nearly all P20–22 and P30–46 mSMEI had myoclonic seizures followed by generalized seizures caused by elevated core body temperature. Spontaneous seizures were only observed in mice older than P32, suggesting that mSMEI become susceptible to temperature-induced seizures before spontaneous seizures. Interictal spike activity was seen at normal body temperature in most P30–46 mSMEI but not in P20–22 or P17–18 mSMEI, indicating that interictal epileptic activity correlates with seizure susceptibility. Most P20–22 mSMEI had interictal spike activity with elevated body temperature. Our results define a critical developmental transition for susceptibility to seizures in SMEI, demonstrate that body temperature elevation alone is sufficient to induce seizures, and reveal a close correspondence between human and mouse SMEI in the striking temperature and age dependence of seizure frequency and severity and in the temperature dependence and frequency of interictal epileptiform spike activity.
Mapping the
Burkholderia cenocepacia
niche response via high-throughput sequencing
Authors: Yoder-Himes D. R. , Chain P. S. G. , Zhu Y. , Wurtzel O. , Rubin E. M. , Tiedje James M. , Sorek R.
Published: February 2009

Determining how an organism responds to its environment by altering gene expression is key to understanding its ecology. Here, we used RNA-seq to comprehensively and quantitatively assess the transcriptional response of the bacterial opportunistic cystic fibrosis (CF) pathogen and endemic soil dweller,
Burkholderia cenocepacia
, in conditions mimicking these 2 environments. By sequencing 762 million bases of cDNA from 2 closely related
B. cenocepacia
strains (one isolated from a CF patient and one from soil), we identified a number of potential virulence factors expressed under CF-like conditions, whereas genes whose protein products are involved in nitrogen scavenging and 2-component sensing were among those induced under soil-like conditions. Interestingly, 13 new putative noncoding RNAs were discovered using this technique, 12 of which are preferentially induced in the soil environment, suggesting that ncRNAs play an important role in survival in the soil. In addition, we detected a surprisingly large number of regulatory differences between the 2 strains, which may represent specific adaptations to the niches from which each strain was isolated, despite their high degree of DNA sequence similarity. Compared with the CF strain, the soil strain shows a stronger global gene expression response to its environment, which is consistent with the need for a more dynamic reaction to the heterogeneous conditions of soil.
The pro-inflammatory peptide LL-37 promotes ovarian tumor progression through recruitment of multipotent mesenchymal stromal cells
Authors: Coffelt Seth B. , Marini Frank C. , Watson Keri , Zwezdaryk Kevin J. , Dembinski Jennifer L. , LaMarca Heather L. , Tomchuck Suzanne L. , zu Bentrup Kerstin Honer , Danka Elizabeth S. , Henkle Sarah L. , Scandurro Aline B.
Published: February 2009

Bone marrow-derived mesenchymal stem cells or multipotent mesenchymal stromal cells (MSCs) have been shown to engraft into the stroma of several tumor types, where they contribute to tumor progression and metastasis. However, the chemotactic signals mediating MSC migration to tumors remain poorly understood. Previous studies have shown that LL-37 (leucine, leucine-37), the C-terminal peptide of human cationic antimicrobial protein 18, stimulates the migration of various cell types and is overexpressed in ovarian, breast, and lung cancers. Although there is evidence to support a pro-tumorigenic role for LL-37, the function of the peptide in tumors remains unclear. Here, we demonstrate that neutralization of LL-37 in vivo significantly reduces the engraftment of MSCs into ovarian tumor xenografts, resulting in inhibition of tumor growth as well as disruption of the fibrovascular network. Migration and invasion experiments conducted in vitro indicated that the LL-37-mediated migration of MSCs to tumors likely occurs through formyl peptide receptor like-1. To assess the response of MSCs to the LL-37-rich tumor microenvironment, conditioned medium from LL-37-treated MSCs was assessed and found to contain increased levels of several cytokines and pro-angiogenic factors compared with controls, including IL-1 receptor antagonist, IL-6, IL-10, CCL5, VEGF, and matrix metalloproteinase-2. Similarly, Matrigel mixed with LL-37, MSCs, or the combination of the two resulted in a significant number of vascular channels in nude mice. These data indicate that LL-37 facilitates ovarian tumor progression through recruitment of progenitor cell populations to serve as pro-angiogenic factor-expressing tumor stromal cells.
Secondary anchor polymorphism in the HA-1 minor histocompatibility antigen critically affects MHC stability and TCR recognition
Authors: Nicholls Sarah , Piper Karen P. , Mohammed Fiyaz , Dafforn Timothy R. , Tenzer Stefan , Salim Mahboob , Mahendra Premini , Craddock Charles , van Endert Peter , Schild Hansjörg , Cobbold Mark , Engelhard Victor H. , Moss Paul A. H. , Willcox Benjamin E.
Published: February 2009

T cell recognition of minor histocompatibility antigens (mHags) underlies allogeneic immune responses that mediate graft-versus-host disease and the graft-versus-leukemia effect following stem cell transplantation. Many mHags derive from single amino acid polymorphisms in MHC-restricted epitopes, but our understanding of the molecular mechanisms governing mHag immunogenicity and recognition is incomplete. Here we examined antigenic presentation and T-cell recognition of HA-1, a prototypic autosomal mHag derived from single nucleotide dimorphism (HA-1HversusHA-1R) in theHMHA1gene. The HA-1Hpeptide is restricted by HLA-A2 and is immunogenic inHA-1R/RintoHA-1Htransplants, whileHA-1Rhas been suggested to be a “null allele” in terms of T cell reactivity. We found that proteasomal cleavage and TAP transport of the 2 peptides is similar and that both variants can bind to MHC. However, the His>Arg change substantially decreases the stability and affinity of HLA-A2 association, consistent with the reduced immunogenicity of the HA-1Rvariant. To understand these findings, we determined the structure of an HLA-A2-HA-1Hcomplex to 1.3Å resolution. Whereas His-3 is accommodated comfortably in the D pocket, incorporation of the lengthy Arg-3 is predicted to require local conformational changes. Moreover, a soluble TCR generated from HA-1H-specific T-cells bound HA-1Hpeptide with moderate affinity but failed to bind HA-1R, indicating complete discrimination of HA-1 variants at the level of TCR/MHC interaction. Our results define the molecular mechanisms governing immunogenicity of HA-1, and highlight how single amino acid polymorphisms in mHags can critically affect both MHC association and TCR recognition.
Phonological awareness and early reading development in childhood apraxia of speech (CAS)
Authors: McNeill B. C. , Gillon G. T. , Dodd B.
Published: February 2009

Background: Childhood apraxia of speech (CAS) is associated with phonological awareness, reading, and spelling deficits. Comparing literacy skills in CAS with other developmental speech disorders is critical for understanding the complexity of the disorder.

Aims: This study compared the phonological awareness and reading development of children with CAS and children with inconsistent speech disorder (ISD).

Method & Procedures: Participants included twelve children with CAS aged 4–7 years. Their performance was compared with twelve children with ISD (and normal speech motor planning) and twelve children with typical development on tasks measuring phonological awareness, letter–sound knowledge, real and non‐word decoding, and access to underlying phonological representations of words. There was no significant difference in the age, gender, socio‐economic status, and receptive vocabulary of the groups. The two groups with speech disorder were matched for severity and inconsistency of their speech impairment.

Outcomes & Results: The results indicated that the CAS group had inferior phonological awareness than the ISD and typical development groups. The CAS group had a greater proportion of participants performing below their expected age level than the comparison groups on phonological awareness, letter–sound knowledge and decoding tasks. There was no difference in the performance of the CAS and ISD groups on the phonological representation task.

Conclusions & Implications: Children with CAS are particularly susceptible to phonological awareness and reading delay. Intervention for children with CAS must facilitate skills underlying reading development in addition to resolving speech deficits in order to improve the spoke and written language outcomes of this population.
Filling a data gap – Lake whitefish (Coregonus clupeaformis) index netting in the North Channel of Lake Huron
Authors: Carmichael Kimberley , Deary Caroline
Published: February 2009

The Anishinabek/Ontario Fisheries Resource Centre collaborated with the First Nation communities along the North Channel of Lake Huron – Aundeck-Omni-Kaning, Mississauga, Sagamok Anishnawbek, Serpent River and Wikwemikong Unceded – on a 5-year lake whitefish (Coregonus clupeaformis) index netting project. The impetus for this undertaking was concern that adequate information was not available for the derivation of the commercial catch quotas by the Ontario Ministry of Natural Resources. Traditional First Nation fishing waters were sampled from 2000 to 2004 using the Ontario Ministry of Natural Resources index netting methodology. A total of 2,760 lake whitefish were caught in 468 net sets, representing up to 17 year classes. The catch-per-unit-effort, as well as the number of year classes represented in the catch, was greater in Aundeck-Omni-Kaning than in the other four areas in the North Channel. The size and age at which 50% of lake whitefish are mature, ranged from 350 mm to 520 mm and 3 to 5 years, respectively. The data gathered from this study augmented the Ontario Ministry of Natural Resources biological catch data and was used in their statistical catch-at-age models for the derivation of lake whitefish commercial catch quotas in the North Channel.
Assessing historical versus contemporary mercury and lead contamination in Lake Huron sediments
Authors: Forsythe K. Wayne , Marvin Chris H.
Published: February 2009

This research utilized surficial sediment core sample data that were collected in 1969/1973 and 2002 from Lake Huron as part of the Environment Canada Great Lakes Sediment Assessment Program. Concentrations for mercury and lead were analyzed due their persistence in the lake ecosystem and their detrimental environmental effects. The analysis area included the main basin of Lake Huron, Georgian Bay, and the North Channel. Comprehending overall pollution levels strictly on the basis of point data is a difficult task, however spatial analysis techniques combined with Geographic Information Systems can be used to gain a better understanding of lake-wide trends. The Geostatistical Analyst extension of the ESRI ArcGIS software was used to carry out ordinary kriging analyses on the datasets. They produced statistically valid concentration estimates with log-normal data transformation procedures occasionally being performed to obtain suitable prediction estimates. Geospatial analysis (including kriging) allows for samples that vary in number and location to be analyzed and compared with each other based on areal estimates. Overall decreases in contamination levels were observed between the historical and contemporary surveys. Mercury has seen a dramatic reduction in concentrations from 1969/1973 to 2002, while the lead results indicate that high levels of contamination (compared to background concentrations) still persist in the contemporary dataset, although they have subsided from historic values. Higher contaminant concentrations were generally found in depositional basins. The interpolated kriging surfaces are more informative than i.e. conventional dot and/or proportional circle maps in the amount of information they present. They also provide an increased understanding of both the spatial distribution and temporal trends in sediment contamination in Lake Huron.
Diets of aquatic birds reflect changes in the Lake Huron ecosystem
Authors: Hebert Craig E. , Weseloh D. V. Chip , Idrissi Abde , Arts Michael T. , Roseman Edward
Published: February 2009

Human activities have affected the Lake Huron ecosystem, in part, through alterations in the structure and function of its food webs. Insights into the nature of food web change and its ecological ramifications can be obtained through the monitoring of high trophic level predators such as aquatic birds. Often, food web change involves alterations in the relative abundance of constituent species and/or the introduction of new species (exotic invaders). Diet composition of aquatic birds is influenced, in part, by relative prey availability and therefore is a sensitive measure of food web structure. Using bird diet data to make inferences regarding food web change requires consistent measures of diet composition through time. This can be accomplished by measuring stable chemical and/or biochemical “ecological tracers” in archived avian samples. Such tracers provide insights into pathways of energy and nutrient transfer.

In this study, we examine the utility of two groups of naturally-occurring intrinsic tracers (stable isotopes and fatty acids) to provide such information in a predatory seabird, the herring gull (Larus argentatus). Retrospective stable nitrogen and carbon isotope analysis of archived herring gull eggs identified declines in gull trophic position and shifts in food sources in Lake Huron over the last 25 years and changes in gull diet composition were inferred from egg fatty acid patterns. These independent groups of ecological tracers provided corroborating evidence of dietary change in this high trophic level predator. Gull dietary shifts were related to declines in prey fish abundance which suggests large-scale alterations to the Lake Huron ecosystem. Dietary shifts in herring gulls may be contributing to reductions in resources available for egg formation. Further research is required to evaluate how changes in resource availability may affect population sustainability in herring gulls and other waterbird species. Long-term biological monitoring programs are required to identify ecosystem change and evaluate its ecological significance.
Review of fish diversity in the Lake Huron basin
Authors: Roseman Edward F. , Schaeffer Jeffrey S. , Steen Paul J.
Published: February 2009

Lake Huron has a rich aquatic habitat diversity that includes shallow embayments, numerous tributaries, shallow mid-lake reef complexes, archipelagos, and profundal regions. These habitats provide support for warm, cool, and cold water fish communities. Diversity of fishes in Lake Huron reflects post-glaciation colonization events, current climate conditions, accidental and intentional introductions of non-indigenous species, and extinctions. Most extinction events have been largely associated with habitat alterations, exploitation of fisheries, and interactions with non-indigenous species. The most recent historical survey of extirpated and imperiled species conducted in the late 1970s identified 79 fish species in Lake Huron proper and about 50 additional species in tributaries. Of those 129 species, 20 are now considered extirpated or imperiled. Extirpated species include Arctic grayling, paddlefish, weed shiner, deepwater cisco, blackfin cisco, shortnose cisco, and kiyi. Six species have declined appreciably due to loss of clear-water stream habitat: the river redhorse, river darter, black redhorse, pugnose shiner, lake chubsucker, redside dace, eastern sand darter, and channel darter. While numerous agencies, universities, and other organizations routinely monitor nearshore and offshore fish distribution and abundance, there is a need for more rigorous examination of the distribution and abundance of less-common species to better understand their ecology. This information is critical to the development of management plans aimed at ecosystem remediation and restoration.
Biomass of deepwater demersal forage fishes in Lake Huron, 1994–2007: Implications for offshore predators
Authors: Roseman Edward F. , Riley Stephen C.
Published: February 2009

We estimated the biomass of deepwater demersal forage fishes (those species common in the diets of lake trout and Chinook salmon) in Lake Huron during the period 1994–2007. The estimated total lake-wide biomass of deepwater demersal fishes in 2007 was reduced by 87 percent of that observed in 1994. Alewife biomass remained near the record low observed in 2004. Biomass of young-of-the-year rainbow smelt was at a record high in 2005, but little recruitment appears to have occurred in 2006 or 2007. Record-high estimates of young-of-the-year bloater biomass were observed in 2005 and 2007, and an increase in the biomass of adult bloater in 2007 suggests that some recruitment may be occurring. The biomass of other potential deepwater demersal forage fish species (sculpins, ninespine stickleback, trout-perch and round goby) has also declined since 1994 and remained low in 2007. The forage fish community in 2007 was dominated by small (< 120 mm) bloater and rainbow smelt. These results suggest that lake trout and Chinook salmon in Lake Huron may face nutritional stress in the immediate future.
Development of ecological indicators for the U.S. Great Lakes coastal region – A summary of applications in Lake Huron
Authors: Niemi Gerald J. , Brady Valerie J. , Brown Terry N. , Ciborowski Jan J. H. , Danz Nicholas P. , Ghioca Dana M. , Hanowski JoAnn M. , Hollenhorst Tom P. , Howe Robert W. , Johnson Lucinda B. , Johnston Carol A. , Reavie Euan D.
Published: February 2009

Our overall goal was to develop indicators that both estimate ecological condition and suggest plausible causes of ecosystem degradation across the U.S. Great Lakes coastal region. Here we summarize data gathered along the U.S. Lake Huron coastline for breeding bird, diatom, fish, invertebrate, and wetland plant communities. We sampled these biotic communities on 88 sites in Lake Huron coastal wetlands, uplands, estuaries/bays, and high-energy shorelines. The sites were selected as part of a larger, stratified random design for the entire U.S. Great Lakes coastal region using gradients of anthropogenic stress that incorporated over 200 stressor variables (e.g. agriculture, land cover, human populations, and point source pollution). The U.S. Lake Huron coastal region exemplified wide variation in human-related stress relative to the entire U.S. Great Lakes coast. In general, levels of stress decreased from south to north partly reflecting the change in climate and physiography, but also due to the greater human influences in the southern region as compared with the north. The primary stressors in the southern region are due to agriculture and human development, while the northern region has substantially less agriculture and less human population. The biotic communities sampled were strongly related to the environmental stress gradients, especially agriculture and urbanization. The following indicators were developed based on responses to stress: 1) an index of biological condition for breeding bird communities corresponding to land use, 2) a diatom-inferred total phosphorus indicator corresponding to water quality, 3) exotic fish (carp [Cyprinus carpio] and goldfish [Carassius auratus]) corresponding to agriculture, and 4) a multi-taxa index for wetland plants corresponding to a cumulative stress index. These communities can all serve as useful indicators of the ecological condition of the Lake Huron coast. The ecological indicators provide a baseline on selected conditions for the U.S. Lake Huron coastal region and a means to detect change over time.
Recent changes in benthic macroinvertebrate populations in Lake Huron and impact on the diet of lake whitefish (coregonus clupeaformis)
Authors: Nalepa Thomas F. , Pothoven Steven A. , Fanslow David L.
Published: February 2009

Surveys of the benthic macroinvertebrate community were conducted in the main basin of Lake Huron in 2000 and 2003, and corresponding studies of lake whitefish diets were conducted in 2002-2004. Populations of three major benthic taxa, Diporeia spp., Sphaeriidae, and Chironomidae, declined dramatically between 2000 and 2003, with densities declining 57%, 74%, and 75% over this 3-year period. By 2003, Diporeia, an important food source for lake whitefish, was gone or rare at depths < 50 m except in the far northeastern portion of the lake. In contrast, densities of the Dreissena bugensis (quagga mussel) increased between 2000 and 2003, particularly at the 31-50 m depth interval, while densities of the zebra mussel Dreissena polymorpha remained stable. As expected, the diet of lake whitefish varied with fish size. Age-0 lake whitefish fed mainly zooplankton, most of which were Daphnia (98%). Medium lake whitefish (< 350 mm excluding age-0 fish) fed mainly on zooplankton, Chironomidae, and Dreissena bugensis, and large lake whitefish (350 to 688 mm) fed mainly on D. bugensis and Gastropoda. The diet of medium and large lake whitefish reflected the changing nature of the benthic community; that is, Diporeia was rarely found in the diet while D. bugensis played a prominent role. Since Diporeia has a much higher energy content than D. bugensis, contrasting density trends in the two organisms will have long term consequences to the relative health of lake whitefish populations in the lake.
Biodiversity and conservation of Lake Huron’s islands
Authors: Kraus Dan , Henson Bonnie , Ewert Dave
Published: February 2009

Lake Huron has the largest collection of freshwater islands in the world. These islands are a significant contributor to the biodiversity of the region. In this paper, we give preliminary results of a project that assembles mapping of over 23,000 islands and island groups and provides the most comprehensive biodiversity assessment of islands in Lake Huron to date. The number, extent and configuration of many islands, particularly small, low-lying systems, is very dynamic depending on lake-levels. Islands in Lake Huron can be divided into three general groups: 1) limestone and dolostone islands associated with and surrounding Manitoulin and Drummond Islands and the Bruce Peninsula, 2) dense archipelagos of small nearshore Precambrian Shield islands in eastern Georgian Bay and the North Channel and, 3) small groups of low-erodible islands in Saginaw Bay.

All three of these island groups are important for supporting colonial nesting waterbirds, endemic species and communities, and migratory birds. Lake Huron islands have been somewhat buffered from anthropogenic change due to their isolation and therefore support a rich and diverse sets of species and communities. Primary threats to island communities include development and invasive species. Threats are generally greater in many of the southern island regions where fewer islands are protected. Results from this project can be used to set priorities for conservation of key sites with high biodiversity values and conservation urgency.
Biodiversity in protected coastal wetlands along the west coast of Lake Huron
Authors: Burton Thomas M. , Uzarski Donald G.
Published: February 2009

Lake Huron protected (barrier-protected) wetlands occur within 1 km of the lake, in swales, interdunal ponds, and other shallow depressions. These wetlands are not directly connected via surface water to Lake Huron, although their hydrology is influenced by lake levels. Biodiversity in them has not been well documented. We compiled plant and animal species occurrence data from published and unpublished sources for the U.S. coast of Lake Huron. Many data sources were reports written by the authors and/or by scientists of the Michigan Natural Features Inventory. Species occurrence data were supplemented with data from published wetlands literature and dissertations and theses. We did not do a thorough compilation for Canadian wetlands and only added limited Canadian data from the “Ontario Great Lakes Coastal Wetlands Atlas”.

We estimate that total species richness exceeds 1400 species with about an equal number of plants and animals (600–700 species each). We documented the occurrence of 466 macrophytes in Lake Huron’s protected marshes, fens, and swamps and estimated total plant species richness to be > 600. Invertebrate species richness was estimated to be 500–600 with more than half of these being macroinvertebrates (> 0.5 mm) and the remainder being microinvertebrates (< 0.5 mm).

Vertebrate species richness was estimated to be > 200 as follows. Fish species richness was estimated to be < 10 because of low oxygen, periodic dry periods, and lack of surface water connection to Lake Huron. Amphibian species richness was estimated to be > 20 with 10 frogs and toads and 7 salamander species documented. Reptile species richness was estimated to be > 20 based on very limited data and published distribution maps with > 10 turtle species and > 10 snake species but no lizards in Lake Huron marshes (although 4–5 lizard species occur on sandy ridges near swale marshes). More than 50 mammal and 80 bird species were estimated to occur in protected wetlands. Occasional additional use by birds and other species combined with the addition of rare species as additional sampling occurs are likely to increase the number of vertebrate species to > 200.