bluuebunny/crossref_metadata_2025 huggingface dataset:
ErbB2 enhances mammary tumorigenesis, oncogene-independent recurrence and metastasis in a model of IGF-IR-mediated mammary tumorigenesis
Authors: Campbell Craig I , Petrik James J , Moorehead Roger A
Published: September 2010

Background

The type I insulin-like growth factor receptor (IGF-IR) and ErbB2 (Her-2) are receptor tyrosine kinases implicated in human breast cancer. Both proteins are currently the subject of targeted therapeutics that are used in the treatment of breast cancer or which are in clinical trials. The focus of this study was to utilize our inducible model of IGF-IR overexpression to explore the interaction of these two potent oncogenes.

Results

ErbB2 was overexpressed in our RM11A cell line, a murine tumor cell line that overexpresses human IGF-IR in an inducible manner. ErbB2 conferred an accelerated tumor onset and increased tumor incidence after injection of RM11A cells into the mammary glands of syngeneic wild type mice. This was associated with increased proliferation immediately after tumor cell colonization of the mammary gland; however, this effect was lost after tumor establishment. ErbB2 overexpression also impaired the regression of established RM11A tumors following IGF-IR downregulation and enhanced their metastatic potential.

Conclusion

This study has revealed that even in the presence of vast IGF-IR overexpression, a modest increase in ErbB2 can augment tumor establishment in vivo, mediate resistance to IGF-IR downregulation and facilitate metastasis. This supports the growing evidence suggesting a possible advantage of using IGF-IR and ErbB2-directed therapies concurrently in the treatment of breast cancer.
Association of hypoglycemic symptoms with patients' rating of their health-related quality of life state: a cross sectional study
Authors: Alvarez-Guisasola Fernando , Yin Donald D , Nocea Gonzalo , Qiu Ying , Mavros Panagiotis
Published: September 2010

Background

To evaluate the association between patient-reported hypoglycemic symptoms with ratings of their health-related quality of life state and patient-reported adverse events in patients with type 2 diabetes mellitus (T2DM).

Methods

This observational, multicenter, cross sectional study was based on a sample of patients with T2DM from seven European countries who added sulfonylurea or thiazolidinedione to metformin monotherapy between January 2001 and January 2006. Included patients were required to have at least one hemoglobin A1c (HbA1c) measurement in the 12 months before enrollment and to not be receiving insulin. Demographic and clinical data from medical records were collected using case report forms. Questionnaires measured patient-reported hypoglycemic symptoms, health-related quality of life (EuroQol visual analogue scale, EQ-5D VAS), and treatment-related adverse events.

Results

A total of 1,709 patients were included in the study. Mean patient age was 63 years, 45% were female, mean HbA1c was 7.06%, and 28% were at HbA1c goal (HbA1c < 6.5%). Hypoglycemic symptoms during the 12 months before enrollment were reported by 38% of patients; among whom 68% reported their most severe symptoms were mild, 27% moderate, and 5% severe. Adjusted linear regression analyses revealed that patients reporting hypoglycemic symptoms had significantly lower EQ-5D VAS scores indicating worse patient-reported quality of life (mean difference -4.33, p < 0.0001). Relative to those not reporting symptoms, the adjusted decrement to quality of life increased with greater hypoglycemic symptom severity (mild: -2.68, p = 0.0039; moderate: -6.42, p < 0.0001; severe: -16.09, p < 0.0001). Patients with hypoglycemia reported significantly higher rates of shakiness, sweating, excessive fatigue, drowsiness, inability to concentrate, dizziness, hunger, asthenia, and headache (p < 0.0001 for each comparison).

Conclusions

Hypoglycemic symptoms and symptom severity have an adverse effect on patients' rating of their health related quality of life state. Hypoglycemic symptoms are correlated with treatment-related adverse effects. Minimizing the risk and severity of hypoglycemia may improve patients' quality of life and clinical outcomes. Results are subject to limitations associated with observational studies including the potential biases due to unobserved patient heterogeneity and the use of a convenience sample of patients.
Duodenal gastrointestinal stromal tumor resembling a pancreatic neuroendocrine tumor in a patient with neurofibromatosis type I (von Recklinghausen's disease): a case report
Authors: Ohtake Shinji , Kobayashi Noritoshi , Kato Shingo , Kubota Kensuke , Endo Itaru , Inayama Yoshiaki , Nakajima Atsushi
Published: September 2010

Introduction

Gastrointestinal stromal tumor is the most frequent nonepithelial tumor found in the gastrointestinal tract. One important clinical problem is that gastrointestinal stromal tumors, especially the extramural growth type, can be difficult to distinguish from other organ tumors. The case of a patient with an extramural gastrointestinal stromal tumor of the duodenum that mimicked a pancreatic head tumor has previously been reported. Here, we report a rare case of a patient with a duodenal gastrointestinal stromal tumor with extramural growth that mimicked a pancreatic neuroendocrine tumor. In this case, the gastrointestinal stromal tumor was also associated with neurofibromatosis type 1 (also known as von Recklinghausen's disease). To the best of our knowledge, this is the first report to describe the case of a patient with a duodenal gastrointestinal stromal tumor with neurofibromatosis type 1 in which the radiological findings resembled those of a pancreatic neuroendocrine tumor.

Case presentation

A 60-year-old Japanese woman with a history of neurofibromatosis type 1 was admitted to our hospital for the treatment of a tumor of her pancreas. She had no symptoms, but an abdominal ultrasonography screening examination had revealed a hypoechoic mass in the head of her pancreas. Laboratory data, including tumor markers, were within the normal ranges, and her insulin and glucagon levels were also within the normal ranges. However, her plasma gastrin level was elevated at 580 pg/mL (30 to 150 pg/mL). A computed tomography examination revealed a hypervascular tumor measuring 14 mm in diameter in the head of her pancreas. We diagnosed the patient as having a pancreatic neuroendocrine tumor and performed a tumor resection with a duodenal wedge resection. Microscopic analysis revealed spindle cell tumors in a trabecular pattern. The patient was finally diagnosed as having a duodenal gastrointestinal stromal tumor of the uncommitted type.

Conclusion

Extramural growth-type gastrointestinal stromal tumors can be difficult to distinguish from other organ tumors. In our case, a duodenal gastrointestinal stromal tumor was difficult to distinguish from a pancreatic neuroendocrine tumor based on radiological findings. When patients are identified as having hypervascular lesions that have adhered to the gastrointestinal tract, the possibility of an extramural growth-type gastrointestinal stromal tumor as a differential diagnosis should be considered in patients with neurofibromatosis type 1.
Experimental assessment of pro-lymphangiogenic growth factors in the treatment of post-surgical lymphedema following lymphadenectomy
Authors: Baker Amy , Kim Harold , Semple John L , Dumont Dan , Shoichet Molly , Tobbia Dalia , Johnston Miles
Published: September 2010

Introduction

Lymphedema is a frequent consequence of lymph node excision during breast cancer surgery. Current treatment options are limited mainly to external compression therapies to limit edema development. We investigated previously, postsurgical lymphedema in a sheep model following the removal of a single lymph node and determined that autologous lymph node transplantation has the potential to reduce or prevent edema development. In this report, we examine the potential of lymphangiogenic therapy to restore lymphatic function and reduce postsurgical lymphedema.

Methods

Lymphangiogenic growth factors (vascular endothelial growth factor C (VEGF-C)) and angiopoietin-2 (ANG-2) were loaded into a gel-based drug delivery system (HAMC; a blend of hyaluronan and methylcellulose). Drug release rates and lymphangiogenic signaling in target endothelial cells were assessed in vitro and vascular permeability biocompatibility tests were examined in vivo. Following, the removal of a single popliteal lymph node, HAMC with the growth factors was injected into the excision site. Six weeks later, lymphatic functionality was assessed by injecting 125Iodine radiolabeled bovine serum albumin (125I-BSA) into prenodal vessels and measuring its recovery in plasma. Circumferential leg measurements were plotted over time and areas under the curves used to quantify edema formation.

Results

The growth factors were released over a two-week period in vitro by diffusion from HAMC, with 50% being released in the first 24 hr. The system induced lymphangiogenic signaling in target endothelial cells, while inducing only a minimal inflammatory response in sheep. Removal of the node significantly reduced lymphatic functionality (nodectomy 1.9 ± 0.9, HAMC alone 1.7 ± 0.8) compared with intact groups (3.2 ± 0.7). In contrast, there was no significant difference between the growth factor treatment group (2.3 ± 0.73) and the intact group indicating improved function with the molecular factors. An increase in the number of regenerated lymphatic vessels at treatment sites was observed with fluoroscopy. Groups receiving HAMC plus growth factors displayed significantly reduced edema (107.4 ± 51.3) compared with nontreated groups (nodectomy 219.8 ± 118.7 and HAMC alone 162.6 ± 141).

Conclusions

Growth factor therapy has the potential to increase lymphatic function and reduce edema magnitude in an animal model of lymphedema. The application of this concept to lymphedema patients warrants further examination.
Non-Sentinel Node Risk Score (N-SNORE): A Scoring System for Accurately Stratifying Risk of Non-Sentinel Node Positivity in Patients With Cutaneous Melanoma With Positive Sentinel Lymph Nodes
Authors: Murali Rajmohan , Desilva Chitra , Thompson John F. , Scolyer Richard A.
Published: September 2010

Purpose

Sentinel node (SN) biopsy allows identification of patients with melanoma at risk of further metastatic disease in regional non-sentinel nodes (NSN). We investigated clinicopathologic factors that predict NSN positivity in an attempt to identify patients who may be safely spared completion lymph node dissection (CLND).

Patients and Methods

Clinicopathologic factors previously shown to be predictive of NSN positivity were analyzed in 409 patients with SN-positive disease (309 of whom underwent CLND) managed at a single melanoma center. A weighted score Non-Sentinel Node Risk Score [N-SNORE] incorporating predictive factors was derived, and the efficacy of N-SNORE at stratifying risk of NSN involvement was studied.

Results

Factors independently predictive of NSN positivity included primary tumor regression, proportion of harvested SNs involved by melanoma (%PosSN), sex (trend), and SN tumor burden indices (maximum size of largest deposit [MaxSize], % cross-sectional area of SN occupied by tumor, tumor penetrative depth, intranodal location of tumor) and perinodal lymphatic invasion (PLI). Of SN tumor burden criteria, MaxSize was the strongest predictor. N-SNORE was the sum of scores for five parameters: sex (female = 0, male = 1), regression (absent = 0, present = 2), %PosSN (absent = 0, present = 2), MaxSize (≤ 0.5 mm = 0, 0.51 to 2.00 mm = 1, 2.01 to 10.00 mm = 2, > 10.00 mm = 3), and PLI (absent = 0, present = 3). N-SNOREs of 0, 1 to 3, 4 to 5, 6 to 7, and ≥ 8 were associated with very low (0%), low (5% to 10%), intermediate (15% to 20%), high (40% to 50%), and very high (70% to 80%) risks of NSN involvement.

Conclusion

A weighted score (N-SNORE) based on clinicopathologic characteristics accurately stratifies risk of NSN involvement in patients with melanoma. If validated in future studies, N-SNORE will better predict prognosis, aid in management decisions, and stratify patient groups for entry into clinical trials.
Amateur Hour
Authors: Foote Stephanie
Published: September 2010

This essay explores the challenges of teaching a large introductory lecture class in the humanities.
Four KH domains of the C. elegans Bicaudal-C ortholog GLD-3 form a globular structural platform
Authors: Nakel Katharina , Hartung Sophia A. , Bonneau Fabien , Eckmann Christian R. , Conti Elena
Published: September 2010

Caenorhabditis elegans GLD-3 is a five K homology (KH) domain-containing protein involved in the translational control of germline-specific mRNAs during embryogenesis. GLD-3 interacts with the cytoplasmic poly(A)-polymerase GLD-2. The two proteins cooperate to recognize target mRNAs and convert them into a polyadenylated, translationally active state. We report the 2.8-Å-resolution crystal structure of a proteolytically stable fragment encompassing the KH2, KH3, KH4, and KH5 domains of C. elegans GLD-3. The structure reveals that the four tandem KH domains are organized into a globular structural unit. The domains are involved in extensive side-by-side interactions, similar to those observed in previous structures of dimeric KH domains, as well as head-to-toe interactions. Small-angle X-ray scattering reconstructions show that the N-terminal KH domain (KH1) forms a thumb-like protrusion on the KH2–KH5 unit. Although KH domains are putative RNA-binding modules, the KH region of GLD-3 is unable in isolation to cross-link RNA. Instead, the KH1 domain mediates the direct interaction with the poly(A)-polymerase GLD-2, pointing to a function of the KH region as a protein–protein interaction platform.
Epigenetic drugs for cancer treatment and prevention: mechanisms of action
Authors: Yu Xiao-Dan , Guo Z. Sheng
Published: September 2010

This review provides a brief overview of the basic principles of epigenetic gene regulation and then focuses on recent development of epigenetic drugs for cancer treatment and prevention with an emphasis on the molecular mechanisms of action. The approved epigenetic drugs are either inhibitors of DNA methyltransferases or histone deacetylases (HDACs). Future epigenetic drugs could include inhibitors for histone methyltransferases and histone demethylases and other epigenetic enzymes. Epigenetic drugs often function in two separate yet interrelated ways. First, as epigenetic drugsper se, they modulate the epigenomes of premalignant and malignant cells to reverse deregulated epigenetic mechanisms, leading to an effective therapeutic strategy (epigenetic therapy). Second, HDACs and other epigenetic enzymes also target non-histone proteins that have regulatory roles in cell proliferation, migration and cell death. Through these processes, these drugs induce cancer cell growth arrest, cell differentiation, inhibition of tumor angiogenesis, or cell death via apoptosis, necrosis, autophagy or mitotic catastrophe (chemotherapy). As they modulate genes which lead to enhanced chemosensitivity, immunogenicity or dampened innate antiviral response of cancer cells, epigenetic drugs often show better efficacy when combined with chemotherapy, immunotherapy or oncolytic virotherapy. In chemoprevention, dietary phytochemicals such as epigallocatechin-3-gallate and sulforaphane act as epigenetic agents and show efficacy by targeting both cancer cells and the tumor microenvironment. Further understanding of how epigenetic mechanisms function in carcinogenesis and cancer progression as well as in normal physiology will enable us to establish a new paradigm for intelligent drug design in the treatment and prevention of cancer.
Kinetic Properties and Functional Dynamics of Sodium Channels during Repetitive Spiking in a Slow Pacemaker Neuron
Authors: Milescu Lorin S. , Yamanishi Tadashi , Ptak Krzysztof , Smith Jeffrey C.
Published: September 2010

We examined the kinetic properties of voltage-gated Na+channels and their contribution to the repetitive spiking activity of medullary raphé neurons, which exhibit slow pacemaking and strong spiking adaptation. The study is based on a combination of whole-cell patch-clamp, modeling and real-time computation. Na+currents were recorded from neurons in brain slices obtained from male and female neonatal rats, using voltage-clamp protocols designed to reduce space-clamp artifacts and to emphasize functionally relevant kinetic features. A detailed kinetic model was formulated to explain the broad range of transient and stationary voltage-dependent properties exhibited by Na+currents. The model was tested by injecting via dynamic clamp a model-based current as a substitute for the native TTX-sensitive Na+currents, which were pharmacologically blocked. The model-based current reproduced well the native spike shape and spiking frequency. The dynamics of Na+channels during repetitive spiking were indirectly examined through this model. By comparing the spiking activities generated with different kinetic models in dynamic-clamp experiments, we determined that state-dependent slow inactivation contributes significantly to spiking adaptation. Through real-time manipulation of the model-based current, we established that suprathreshold Na+current mainly controls spike shape, whereas subthreshold Na+current modulates spiking frequency and contributes to the pacemaking mechanism. Since the model-based current was injected in the soma, the results also suggest that somatic Na+channels are sufficient to establish the essential spiking properties of raphé neuronsin vitro.
Proline-Rich Tyrosine Kinase 2 Regulates Hippocampal Long-Term Depression
Authors: Hsin Honor , Kim Myung Jong , Wang Chi-Fong , Sheng Morgan
Published: September 2010

Proline-rich tyrosine kinase 2 (PYK2), also known as cell adhesion kinase β or protein tyrosine kinase 2b, is a calcium-dependent signaling protein involved in cell migration. Phosphorylation of residue Y402 is associated with activation of PYK2 and leads to the recruitment of downstream signaling molecules. PYK2 was previously implicated in long-term potentiation (LTP); however, the role of PYK2 in long-term depression (LTD) is unknown. Here, we report that PYK2 is activated by NMDA receptor stimulation (chemical LTD) in cultured neurons. Small hairpin RNA-mediated knockdown of PYK2 blocks LTD, but not LTP, in hippocampal slice cultures. We find that the Y402 residue and, to a lesser extent, PYK2 kinase activity contribute to PYK2's role in LTD. Knockdown experiments indicate that PYK2 is required to suppress NMDA-induced extracellular signal-regulated kinase (ERK) phosphorylation. Overexpression of PYK2 depresses NMDA-induced ERK phosphorylation and inhibits LTP, but not LTD. Our data indicate that PYK2 is critical for the induction of LTD, possibly in part by antagonizing ERK signaling in hippocampal neurons.
Pyramidal Neurons Are Generated from Oligodendroglial Progenitor Cells in Adult Piriform Cortex
Authors: Guo Fuzheng , Maeda Yoshiko , Ma Joyce , Xu Jie , Horiuchi Makoto , Miers Laird , Vaccarino Flora , Pleasure David
Published: September 2010

Previous studies have shown that oligodendroglial progenitor cells (OPCs) can give rise to neuronsin vitroand in perinatal cerebral cortexin vivo. We now report that OPCs in adult murine piriform cortex express low levels of doublecortin, a marker for migratory and immature neurons. Additionally, these OPCs express Sox2, a neural stem cell marker, and Pax6, a transcription factor characteristic of progenitors for cortical glutamatergic neurons. Genetic fate-mapping by means of an inducible Cre–LoxP recombination system proved that these OPCs differentiate into pyramidal glutamatergic neurons in piriform cortex. Several lines of evidence indicated that these newly formed neurons became functionally integrated into the cortical neuronal network. Our data suggest that NG2+/PDGFRα+proteolipid protein promoter-expressing progenitors generate pyramidal glutamatergic neurons within normal adult piriform cortex.
Tumor Necrosis Factor-α (TNF-α) Regulates Shedding of TNF-α Receptor 1 by the Metalloprotease-Disintegrin ADAM8: Evidence for a Protease-Regulated Feedback Loop in Neuroprotection
Authors: Bartsch Jörg W. , Wildeboer Dirk , Koller Garrit , Naus Silvia , Rittger Andrea , Moss Marcia L. , Minai Yuji , Jockusch Harald
Published: September 2010

Tumor necrosis factor α (TNF-α) is a potent cytokine in neurodegenerative disorders, but its precise role in particular brain disorders is ambiguous. In motor neuron (MN) disease of the mouse, exemplified by the model wobbler (WR), TNF-α causes upregulation of the metalloprotease-disintegrin ADAM8 (A8) in affected brain regions, spinal cord, and brainstem. The functional role of A8 during MN degeneration in the wobbler CNS was investigated by crossing WR with A8-deficient mice: a severely aggravated neuropathology was observed for A8-deficient WR compared with WR A8+/−mice, judged by drastically reduced survival [7 vs 81% survival at postnatal day 50 (P50)], accelerated force loss in the forelimbs, and terminal akinesis.In vitroprotease assays using soluble A8 indicated specific cleavage of a TNF-α receptor 1 (p55 TNF-R1) but not a TNF-R2 peptide. Cleavage of TNF-R1 was confirmedin situ, because levels of soluble TNF-R1 were increased in spinal cords of standard WR compared with wild-type mice but not in A8-deficient WR mice. In isolated primary neurons and microglia, TNF-α-induced TNF-R1 shedding was dependent on the A8 gene dosage. Furthermore, exogenous TNF-α showed higher toxicity for cultured neurons from A8-deficient than for those from wild-type mice, demonstrating that TNF-R1 shedding by A8 is neuroprotective. Our results indicate an essential role for ADAM8 in modulating TNF-α signaling in CNS diseases: a feedback loop integrating TNF-α, ADAM8, and TNF-R1 shedding as a plausible mechanism for TNF-α mediated neuroprotectionin situand a rationale for therapeutic intervention.
Reduced Survival of Motor Neuron (SMN) Protein in Motor Neuronal Progenitors Functions Cell Autonomously to Cause Spinal Muscular Atrophy in Model Mice Expressing the Human Centromeric (SMN2) Gene
Authors: Park Gyu-Hwan , Maeno-Hikichi Yuka , Awano Tomoyuki , Landmesser Lynn T. , Monani Umrao R.
Published: September 2010

Spinal muscular atrophy (SMA) is a common (∼1:6400) autosomal recessive neuromuscular disorder caused by a paucity of the survival of motor neuron (SMN) protein. Although widely recognized to cause selective spinal motor neuron loss when deficient, the precise cellular site of action of the SMN protein in SMA remains unclear. In this study we sought to determine the consequences of selectively depleting SMN in the motor neurons of model mice. Depleting but not abolishing the protein in motor neuronal progenitors causes an SMA-like phenotype. Neuromuscular weakness in the model mice is accompanied by peripheral as well as central synaptic defects, electrophysiological abnormalities of the neuromuscular junctions, muscle atrophy, and motor neuron degeneration. However, the disease phenotype is more modest than that observed in mice expressing ubiquitously low levels of the SMN protein, and both symptoms as well as early electrophysiological abnormalities that are readily apparent in neonates were attenuated in an age-dependent manner. We conclude that selective knock-down of SMN in motor neurons is sufficient but may not be necessary to cause a disease phenotype and that targeting these cells will be a requirement of any effective therapeutic strategy. This realization is tempered by the relatively mild SMA phenotype in our model mice, one explanation for which is the presence of normal SMN levels in non-neuronal tissue that serves to modulate disease severity.
Aβ Oligomers Cause Localized Ca2+Elevation, Missorting of Endogenous Tau into Dendrites, Tau Phosphorylation, and Destruction of Microtubules and Spines
Authors: Zempel Hans , Thies Edda , Mandelkow Eckhard , Mandelkow Eva-Maria
Published: September 2010

Aggregation of amyloid-β (Aβ) and Tau protein are hallmarks of Alzheimer's disease (AD), and according to the Aβ-cascade hypothesis, Aβ is considered toxic for neurons and Tau a downstream target of Aβ. We have investigated differentiated primary hippocampal neurons for early localized changes following exposure to Aβ oligomers. Initial events become evident by missorting of endogenous Tau into the somatodendritic compartment, in contrast to axonal sorting in normal neurons. In missorted dendritic regions there is a depletion of spines and local increase in Ca2+, and breakdown of microtubules. Tau in these regions shows elevated phosphorylation at certain sites diagnostic of AD-Tau (e.g., epitope of antibody 12E8, whose phosphorylation causes detachment of Tau from microtubules, and AT8 epitope), and local elevation of certain kinase activities (e.g., MARK/par-1, BRSK/SADK, p70S6K, cdk5, but not GSK3β, JNK, MAPK). These local effects occur without global changes in Tau, tubulin, or kinase levels. Somatodendritic missorting occurs not only with Tau, but also with other axonal proteins such as neurofilaments, and correlates with pronounced depletion of microtubules and mitochondria. The Aβ-induced effects on microtubule and mitochondria depletion, Tau missorting, and loss of spines are prevented by taxol, indicating that Aβ-induced microtubule destabilization and corresponding traffic defects are key factors in incipient degeneration. By contrast, the rise in Ca2+levels, kinase activities, and Tau phosphorylation cannot be prevented by taxol. Incipient and local changes similar to those of Aβ oligomers can be evoked by cell stressors (e.g., H2O2, glutamate, serum deprivation), suggesting some common mechanism of signaling.
Ca2+and Ca2+-Activated K+Channels That Support and Modulate Transmitter Release at the Olivocochlear Efferent–Inner Hair Cell Synapse
Authors: Zorrilla de San Martín Javier , Pyott Sonja , Ballestero Jimena , Katz Eleonora
Published: September 2010

In the mammalian auditory system, the synapse between efferent olivocochlear (OC) neurons and sensory cochlear hair cells is cholinergic, fast, and inhibitory. This efferent synapse is mediated by the nicotinic α9α10 receptor coupled to the activation of SK2 Ca2+-activated K+channels that hyperpolarize the cell. So far, the ion channels that support and/or modulate neurotransmitter release from the OC terminals remain unknown. To identify these channels, we used an isolated mouse cochlear preparation and monitored transmitter release from the efferent synaptic terminals in inner hair cells (IHCs) voltage clamped in the whole-cell recording configuration. Acetylcholine (ACh) release was evoked by electrically stimulating the efferent fibers that make axosomatic contacts with IHCs before the onset of hearing. Using the specific antagonists for P/Q- and N-type voltage-gated calcium channels (VGCCs), ω-agatoxin IVA and ω-conotoxin GVIA, respectively, we show that Ca2+entering through both types of VGCCs support the release process at this synapse. Interestingly, we found that Ca2+entering through the dihydropiridine-sensitive L-type VGCCs exerts a negative control on transmitter release. Moreover, using immunostaining techniques combined with electrophysiology and pharmacology, we show that BK Ca2+-activated K+channels are transiently expressed at the OC efferent terminals contacting IHCs and that their activity modulates the release process at this synapse. The effects of dihydropiridines combined with iberiotoxin, a specific BK channel antagonist, strongly suggest that L-type VGCCs negatively regulate the release of ACh by fueling BK channels that are known to curtail the duration of the terminal action potential in several types of neurons.
Distinct Retinal Deficits in a Zebrafish Pyruvate Dehydrogenase-Deficient Mutant
Authors: Maurer Colette M. , Schönthaler Helia B. , Mueller Kaspar P. , Neuhauss Stephan C. F.
Published: September 2010

Mutations in ubiquitously expressed metabolic genes often lead to CNS-specific effects, presumably because of the high metabolic demands of neurons. However, mutations in omnipresent metabolic pathways can conceivably also result in cell type-specific effects because of cell-specific requirements for intermediate products. One such example is the zebrafishnoirmutant, which we found to be mutated in thepdhbgene, coding for the E1 β subunit of the pyruvate dehydrogenase complex. This vision mutant is described as blind and was isolated because of its vision defect-related darker appearance. A detailed morphological, behavioral, and physiological analysis of the phenotype revealed an unexpected specific effect on the retina. Surprisingly, the cholinergic amacrine cells of the inner retina are affected earlier than the photoreceptors. This might be attributable to the inability of these cells to maintain production of their neurotransmitter acetylcholine. This is reflected in an earlier loss of motion vision, followed only later by a general loss of light perception. Since both characteristics of the phenotype are attributable to a loss of acetyl-CoA production by pyruvate dehydrogenase, we used a ketogenic diet to bypass this metabolic block and could indeed partially rescue vision and prolong survival of the larvae. Thenoirmutant provides a case for a systemic disease with ocular manifestation with a surprising specific effect on the retina given the ubiquitous requirement for the mutated gene.
A Single Seizure Episode Leads to Rapid Functional Activation of KCC2 in the Neonatal Rat Hippocampus
Authors: Khirug Stanislav , Ahmad Faraz , Puskarjov Martin , Afzalov Ramil , Kaila Kai , Blaesse Peter
Published: September 2010

Functional expression of the K-Cl cotransporter KCC2 in developing central neurons is crucial for the maturation of Cl−-dependent, GABAAreceptor-mediated inhibitory responses. In pyramidal neurons of the rodent hippocampus, GABAergic postsynaptic responses are typically depolarizing and often excitatory during the first postnatal week. Here, we show that a single neonatal seizure episode induced by kainate injection during postnatal days 5–7 results in a fast increase in the Cl−extrusion capacity of rat hippocampal CA1 neurons, with a consequent hyperpolarizing shift of the reversal potential of GABAA-mediated currents (EGABA). A significant increase in the surface expression of KCC2 as well as the α2 subunit of the Na-K-ATPase parallels the seizure-induced increase in the Cl−extrusion capacity. Exposing hippocampal slices to kainate resulted in a similar increase in the neuronal Cl−extrusion and in the surface expression of KCC2. Both effects were blocked by the kinase inhibitor K252a. Hence, in the neonatal hippocampus the overall KCC2 expression level is high enough to promote a rapid functional activation of K-Cl cotransport and a consequent negative shift in EGABAclose to the adult level. The activity-dependent regulation of KCC2 function and its effect on GABAergic transmission may represent an intrinsic antiepileptogenic mechanism.
In VivoDevelopment of Outer Retinal Synapses in the Absence of Glial Contact
Authors: Williams Philip R. , Suzuki Sachihiro C. , Yoshimatsu Takeshi , Lawrence Owen T. , Waldron Steven J. , Parsons Michael J. , Nonet Michael L. , Wong Rachel O. L.
Published: September 2010

Astroglia secrete factors that promote synapse formation and maintenance. In culture, glial contact has also been shown to facilitate synaptogenesis. Here, we examined whether glial contact is important for establishing circuitsin vivoby simultaneously monitoring differentiation of glial cells and local synaptogenesis over time. Photoreceptor circuits of the vertebrate retina are particularly suitable for this study because of the relatively simple, laminar organization of their connectivity with their target neurons, horizontal cells and bipolar cells. Also, individual photoreceptor terminals are ensheathed within the outer plexiform layer (OPL) by the processes of one type of glia, Müller glia cells (MGs). We conductedin vivotime-lapse multiphoton imaging of the rapidly developing and relatively transparent zebrafish retina to ascertain the time course of MG development relative to OPL synaptogenesis. The emergence of synaptic triads, indicative of functional photoreceptor circuits, and structural association with glial processes were also examined across ages by electron microscopy. We first show that MG processes form territories that tile within the inner and outer synaptic layers. We then demonstrate that cone photoreceptor synapses are assembled before the elaboration of MG processes in the OPL. Using a targeted cell ablation approach, we also determined whether the maintenance of photoreceptor synapses is perturbed when local MGs are absent. We found that removal of MGs had no appreciable effect on the stability of newly formed cone synapses. Thus, in contrast to other CNS circuits, contact from glia is not necessary for the formation or immediate stabilization of outer retinal synapses.
The Role of Contralesional Dorsal Premotor Cortex after Stroke as Studied with Concurrent TMS-fMRI
Authors: Bestmann Sven , Swayne Orlando , Blankenburg Felix , Ruff Christian C. , Teo James , Weiskopf Nikolaus , Driver Jon , Rothwell John C. , Ward Nick S.
Published: September 2010

Contralesional dorsal premotor cortex (cPMd) may support residual motor function following stroke. We performed two complementary experiments to explore how cPMd might perform this role in a group of chronic human stroke patients. First, we used paired-coil transcranial magnetic stimulation (TMS) to establish the physiological influence of cPMd on ipsilesional primary motor cortex (iM1) at rest. We found that this influence became less inhibitory/more facilitatory in patients with greater clinical impairment. Second, we applied TMS over cPMd during functional magnetic resonance imaging (fMRI) in these patients to examine the causal influence of cPMd TMS on the whole network of surviving cortical motor areas in either hemisphere and whether these influences changed during affected hand movement. We confirmed that hand grip-related activation in cPMd was greater in more impaired patients. Furthermore, the peak ipsilesional sensorimotor cortex activity shifted posteriorly in more impaired patients. Critical new findings were that concurrent TMS-fMRI results correlated with the level of both clinical impairment and neurophysiological impairment (i.e., less inhibitory/more facilitatory cPMd-iM1 measure at rest as assessed with paired-coil TMS). Specifically, greater clinical and neurophysiological impairment was associated with a stronger facilitatory influence of cPMd TMS on blood oxygenation level-dependent signal in posterior parts of ipsilesional sensorimotor cortex during hand grip, corresponding to the posteriorly shifted sensorimotor activity seen in more impaired patients. cPMd TMS was not found to influence activity in other brain regions in either hemisphere. This state-dependent influence on ipsilesional sensorimotor regions may provide a mechanism by which cPMd supports recovered function after stroke.
Insights Into Species Divergence and the Evolution of Hermaphroditism From Fertile Interspecies Hybrids of Caenorhabditis Nematodes
Authors: Woodruff Gavin C , Eke Onyinyechi , Baird Scott E , Félix Marie-Anne , Haag Eric S
Published: September 2010

The architecture of both phenotypic variation and reproductive isolation are important problems in evolutionary genetics. The nematode genus Caenorhabditis includes both gonochoristic (male/female) and androdioecious (male/hermaprodite) species. However, the natural genetic variants distinguishing reproductive mode remain unknown, and nothing is known about the genetic basis of postzygotic isolation in the genus. Here we describe the hybrid genetics of the first Caenorhabditis species pair capable of producing fertile hybrid progeny, the gonochoristic Caenorhabditis sp. 9 and the androdioecious C. briggsae. Though many interspecies F1 arrest during embryogenesis, a viable subset develops into fertile females and sterile males. Reciprocal parental crosses reveal asymmetry in male-specific viability, female fertility, and backcross viability. Selfing and spermatogenesis are extremely rare in XX F1, and almost all hybrid self-progeny are inviable. Consistent with this, F1 females do not express male-specific molecular germline markers. We also investigated three approaches to producing hybrid hermaphrodites. A dominant mutagenesis screen for self-fertile F1 hybrids was unsuccessful. Polyploid F1 hybrids with increased C. briggsae genomic material did show elevated rates of selfing, but selfed progeny were mostly inviable. Finally, the use of backcrosses to render the hybrid genome partial homozygous for C. briggsae alleles did not increase the incidence of selfing or spermatogenesis relative to the F1 generation. These hybrid animals were genotyped at 23 loci, and significant segregation distortion (biased against C. briggsae) was detected at 13 loci. This, combined with an absence of productive hybrid selfing, prevents formulation of simple hypotheses about the genetic architecture of hermaphroditism. In the near future, this hybrid system will likely be fruitful for understanding the genetics of reproductive isolation in Caenorhabditis.
Genetic and Epigenetic Dynamics of a Retrotransposon After Allopolyploidization of Wheat
Authors: Kraitshtein Zina , Yaakov Beery , Khasdan Vadim , Kashkush Khalil
Published: September 2010

Allopolyploidy, or the combination of two or more distinct genomes in one nucleus, is usually accompanied by radical genomic changes involving transposable elements (TEs). The dynamics of TEs after an allopolyploidization event are poorly understood. In this study, we analyzed the methylation state and genetic rearrangements of a high copied, newly amplified terminal-repeat retrotransposon in miniature (TRIM) family in wheat termed Veju. We found that Veju insertion sites underwent massive methylation changes in the first four generations of a newly formed wheat allohexaploid. Hypomethylation or hypermethylation occurred in ∼43% of the tested insertion sites; while hypomethylation was significantly predominant in the first three generations of the newly formed allohexaploid, hypermethylation became predominant in the subsequent generation. In addition, we determined that the methylation state of Veju long terminal repeats (LTRs) might be correlated with the deletion and/or insertion of the TE. While most of the methylation changes and deletions of Veju occurred in the first generation of the newly formed allohexaploid, most Veju insertions were seen in the second generation. Finally, using quantitative PCR, we quantitatively assessed the genome composition of Veju in the newly formed allohexaploid and found that up to 50% of Veju LTRs were deleted in the first generation. Retrotransposition bursts in subsequent generations, however, led to increases in Veju elements. In light of these findings, the underlying mechanisms of TRIM rearrangements are discussed.
Effectiveness of the Brazilian influenza vaccination policy, a systematic review
Authors: Luna Expedito J.A. , Gattás Vera L.
Published: September 2010

Since 1999, Brazil has undertaken annual influenza vaccine campaigns, free of charge, targeting the elderly population, health professionals, and immune-deficient patients. We conducted a systematic review of literature in order to evaluate the effectiveness of the initiative. We used the keywords influenza, vaccine, Brazil and effectiveness to search the main databases. Thirty-one studies matched our inclusion and exclusion criteria. Influenza vaccine coverage among the elderly is high, though not as high as suggested by the official figures. Estimates on effectiveness are scarce. The majority come from ecological studies that show a modest reduction in mortality and hospital admissions due to influenza-related causes. Such reduction is not evident in the North and Northeastern states of Brazil, a finding that is probably related to the different seasonal pattern of influenza in equatorial and tropical regions. Brazilian epidemiologists still owe society better-designed studies addressing the effectiveness of influenza vaccine campaigns.
Lutzomyia longipalpis behavior and control at an urban visceral leishmaniasis focus in Argentina
Authors: Santini Maria Soledad , Salomón Oscar Daniel , Acardi Soraya Alejandra , Sandoval Enrique Adolfo , Tartaglino Lilian
Published: September 2010

During the earlier stages of visceral leishmaniasis transmission in Posadas City, Misiones, both the night activity and attraction to humans of Lutzomyia longipalpis were assessed, in order to provide preliminary recommendations. The impact of peridomestic deltamethrin spraying performed by local officials was also evaluated. Although Lu. longipalpis were found in traps located over a dog the entire night, 90% of the females were captured from 20.30h to 1.30h, and only landed on a human when he was at a distance of 1.5 m from the dog. Peridomestic spraying of deltamethrin (25 mg/m²) reduced the sand fly capture up to seven days post-intervention without dispersion in the border of the sprayed areas. These results support the recommendations about time-space focus of the protection measures: first half of the night, in the backyard, with pets and domestic animals kept at least 5 m from humans. The deltamethrin as it was used did not seem very effective in this scenario; neither did the eventual use of bed nets, at least in adults, due to the place/hour of sand fly higher activity. This study strengthens the need for a multidisciplinary approach to develop prevention strategies based both on biological and anthropological studies.
Edworthia Lerbekmoi, a New Primitive Paromomyid Primate from the Torrejonian (Early Paleocene) of Alberta, Canada
Authors: Fox Richard C. , Scott Craig S. , Rankin Brian D.
Published: September 2010

A primitive paromomyid plesiadapiform primate,Edworthia lerbekmoinew genus and species, is described from a recently discovered locality in the Paskapoo Formation, exposed at a road cut in Edworthy Municipal Park, Bow River Valley, Calgary, Alberta, Canada. The new taxon, probably middle Torrejonian (To2) in age, is based on two dentary fragments containing well-preserved dentitions that bracket p2-4, m1-3. With the exception of the basalParomomys, E. lerbekmoidiffers from all other paromomyids in retaining p2, but p2 in the new paromomyid is single-rooted, not two-rooted as inParomomys. E. lerbekmoidiffers further fromParomomysin having an enlarged anterior alveolus for a tooth immediately anterior to p2, hypothesized to be il. Unlike other paromomyids with an enlarged il, however, this tooth inE. lerbekmoiwas obliquely, not horizontally, oriented and its alveolus opens dorsally, in the alveolar row, not anteriorly, as in other paromomyids in which il is greatly enlarged. This suggests thatE. lerbekmoirepresents a previously unknown paromomyid lineage that evolved from an ancestor having obliquely oriented lower incisors as in the basal primatePurgatorius, not from an ancestor in which il was already subhorizontal in orientation, as inParomomys.If this working hypothesis is correct or whether in the future some other evolutionary scenario will better account for the unique anterior dentition inE. lerbekmoi, the new paromomyid nonetheless demonstrates that crucial aspects of the earliest history of the important plesiadapiform family Paromomyidae remain to be discovered.
Northeast Pacific Upper Cretaceous and Paleocene Glycymeridid Bivalves
Authors: Squires Richard L.
Published: September 2010

The Late Cretaceous to late Paleocene record of glycymeridid bivalves in the region extending from the Alaska Peninsula, southward to Baja California, Mexico is studied in detail for the first time.Glycymeris pacifica(Anderson, 1902), of late Cenomanian to late Turonian age, is the earliest known glycymeridid in the study area. Very locally, it is found with the middle to late TuronianGlycymeris yoloensisn. sp. The latter apparently represents some intermediate state between genusGlycymerisda Costa, 1778 and genusGlycymeritaFinlay and Marwick, 1937. In the study area,Glycymeritais represented byGlycymerita veatchii(Gabb, 1864), middle to late Turonian to late Campanian;Glycymerita banosensis(Anderson, 1958) new combination, late Campanian to latest Maastrichtian;Glycymerita aleutan. sp., known only from Alaska and of early Maastrichtian age; andGlycymerita major(Stanton, 1896) new combination, Selandian to Thanetian. All the studied species lived in warm-temperate, shallow-marine waters and were shallow burrowers in fine-grained siliciclastic sediments. Variability in morphology is common in sizeable populations of the various species, especiallyGlycymerita veatchii, which increased nearly fivefold in size during its 19.5 million-year-long range and culminated in shells up to 84 mm in length.
The Systematics of a New Upper Ordovician Edrioasteroid Pavement from Northern Kentucky
Authors: Sumrall Colin D.
Published: September 2010

A large, edrioasteroid-bearing hardground surface from the base of the Bellevue Member of the Grant Lake Formation near Maysville, Mason County, Kentucky is described. Four species are represented includingStreptaster vorticellatus(Hall),Carneyella ulrichiBassler and Shideler,Carneyella pilea(Hall), andCurvitriordo steckin. sp. Specimens ofS. vorticellatusandC. pileaadd little to the known morphologies of these species. However, prior to this studyC. ulrichiwas known from the unique holotype, andCurvitriordo steckin. sp. adds greatly to out understanding ofCurvitriordowhich was previously known from two species comprising three poorly preserved specimens.Curvitriordo steckishows a bimodal size frequency distribution suggesting seasonal breeding whereasCarneyella ulrichishows a left skewed size frequency suggesting low juvenile mortality.Streptaster vorticellatusshows a tight unimodal size frequency distribution suggestive of a single spat fall accumulation.
Late Guadalupian (Middle Permian) Fusuline Fauna from the Xiala Formation in Xainza County, Central Tibet: Implication of the Rifting Time of the Lhasa Block
Authors: Zhang Yi-Chun , Cheng Li-Ren , Shen Shu-Zhong
Published: September 2010

A fusuline fauna consisting of 9 species of 4 genera from the Xiala Formation of the Mujiucuo section, Xainza County, Tibet, China is described. The fusuline fauna is dominated byNankinellaandChusenellaand indicates a Midian (Late Guadalupian) age. The earliest record of fusuline fauna during the Midian in the Lhasa Block suggests that the block rifted later than the Qiangtang Block to the north and the Baoshan and Tengchong blocks to the east, all of which yield much earlier fusuline faunas of Yakhtashian (Artinskian) age, but had drifted away from Gondwana to a relatively warm temperate zone in the Late Guadalupian (Middle Permian).
The Sponge Family Guadalupiidae in the Texas Permian
Authors: Finks Robert M.
Published: September 2010

New and old species and genera of the family Guadalupiidae (spherulitic hypercalcified demosponges of the order Agelasida) are described or redescribed from the West Texas Permian. The entire family is reviewed and observations are made on the epibionts, growth patterns, functional morphology, ecological relationships, morphologic variability, modular structure, and evolutionary history of these largely reef-dwelling sponges. The stratigraphic distribution of species is also noted; many are limited and can define zones. The new genera Exovasa and Incisimura and the new species Guadalupia auricula, G. cupulosa, G. ramescens, G. microcamera, G. vasa, Cystothalamia megacysta, Lemonea simplex, Incisimura bella, and Exovasa cystauletoides are described. Almost all previously published taxa are redescribed and in some cases redefined. The Guadalupiidae are unique among hypercalcified sponges in having a modular thalamid layer (thalamidarium) covered on the exhalant surface by a non-modular stromatoporoid-like layer (trabecularium).