bluuebunny/crossref_metadata_2025 huggingface dataset:
Premature terminator analysis sheds light on a hidden world of bacterial transcriptional attenuation
Authors: Naville Magali , Gautheret Daniel
Published: September 2010

Background

Bacterial transcription attenuation occurs through a variety of cis-regulatory elements that control gene expression in response to a wide range of signals. The signal-sensing structures in attenuators are so diverse and rapidly evolving that only a small fraction have been properly annotated and characterized to date. Here we apply a broad-spectrum detection tool in order to achieve a more complete view of the transcriptional attenuation complement of key bacterial species.

Results

Our protocol seeks gene families with an unusual frequency of 5' terminators found across multiple species. Many of the detected attenuators are part of annotated elements, such as riboswitches or T-boxes, which often operate through transcriptional attenuation. However, a significant fraction of candidates were not previously characterized in spite of their unmistakable footprint. We further characterized some of these new elements using sequence and secondary structure analysis. We also present elements that may control the expression of several non-homologous genes, suggesting co-transcription and response to common signals. An important class of such elements, which we called mobile attenuators, is provided by 3' terminators of insertion sequences or prophages that may be exapted as 5' regulators when inserted directly upstream of a cellular gene.

Conclusions

We show here that attenuators involve a complex landscape of signal-detection structures spanning the entire bacterial domain. We discuss possible scenarios through which these diverse 5' regulatory structures may arise or evolve.
Three-dimensional interpretation of magnetic and gravity anomalies using the finite-difference similarity transform
Authors: Gerovska Daniela , Araúzo-Bravo Marcos J. , Whaler Kathryn , Stavrev Petar , Reid Alan
Published: September 2010

We present an automatic procedure for interpretation of magnetic or gravity gridded anomalies based on the finite-difference similarity transform (FDST). It is called MaGSoundFDST (magnetic and gravity sounding based on the finite-difference similarity transform) and uses a “focusing” principle in contrast to deriving multiple clusters of many solutions as in the widely used Euler deconvolution method. The source parameters are characterized by isolated solutions, and the interpreter obtains parallel images showing the horizontal position, depth, and structural index [Formula: see text] value. The underlying principle is that the FDST of a potential field anomaly becomes zero or linear at all observation points when the central point of similarity (CPS) of the transform coincides with a source field’s singular point and a correct [Formula: see text] value is used. The procedure involves calculating a 3D function that evaluates the linearity of the FDST for a series of [Formula: see text] values, using a moving window and sounding the subsurface along a verticalline under each window center. We then combine the 3D results for different [Formula: see text] values into a single map whose minima determine the horizontal position of the sources. The [Formula: see text] value and the CPS depth associated with each minimum determine the [Formula: see text] value and depth of the corresponding source. Only one estimate characterizes a simple source, which is a major advantage over other window-based procedures. MaGSoundFDST uses only the measured anomalous field and its upward continuation, thus avoiding the direct use of field derivatives. It is independent of the magnetization-vector direction in the magnetic data case. The procedure accounts for a linear background of local gravity or magnetic anomalies and has been applied effectively to several cases of synthetic and real data. MaGSoundFDST shares common features with the magnetic and gravity sounding based on the differential similarity transform (MaGSoundDST) but is more stable in estimating depth and structural index in the presence of random noise.
This issue of GEOPHYSICS
Authors: Grechka Vladimir
Published: September 2010

In this article, the Editor of Geophysics provides an overview of all technical articles in this issue of the journal.
Outcomes of Patients With Esophageal Cancer Staged With [18F]Fluorodeoxyglucose Positron Emission Tomography (FDG-PET): Can Postchemoradiotherapy FDG-PET Predict the Utility of Resection?
Authors: Monjazeb Arta Monir , Riedlinger Greg , Aklilu Mebea , Geisinger Kim R. , Mishra Girish , Isom Scott , Clark Paige , Levine Edward A. , Blackstock A. William
Published: September 2010

Purpose

To determine whether [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) can delineate patients with esophageal cancer who may not benefit from esophagectomy after chemoradiotherapy.

Patients and Methods

We reviewed records of 163 patients with histologically confirmed stage I to IVA esophageal cancer receiving chemoradiotherapy with or without resection with curative intent. All patients received surgical evaluation. Initial and postchemoradiotherapy FDG-PET scans and prognostic/treatment variables were analyzed. FDG-PET complete response (PET-CR) after chemoradiotherapy was defined as standardized uptake value ≤ 3.

Results

Eighty-eight patients received trimodality therapy and 75 received chemoradiotherapy. Surgery was deferred primarily due to medical inoperability or unresectable/metastatic disease after chemoradiotherapy. A total of 105 patients were evaluable for postchemoradiotherapy FDG-PET response. Thirty-one percent achieved a PET-CR. PET-CR predicted for improved outcomes for chemoradiotherapy (2-year overall survival, 71% v 11%, P < .01; 2-year freedom from local failure [LFF], 75% v 28%, P < .01), but not trimodality therapy. On multivariate analysis of patients treated with chemoradiotherapy, PET-CR is the strongest independent prognostic variable (survival hazard ratio [HR], 9.82, P < .01; LFF HR, 14.13, P < .01). PET-CR predicted for improved outcomes regardless of histology, although patients with adenocarcinoma achieved a PET-CR less often.

Conclusion

Patients treated with trimodality therapy found no benefit with PET-CR, likely because FDG-PET residual disease was resected. Definitive chemoradiotherapy patients achieving PET-CR had excellent outcomes equivalent to trimodality therapy despite poorer baseline characteristics. Patients who achieve a PET-CR may not benefit from added resection given their excellent outcomes without resection. These results should be validated in a prospective trial of FDG-PET–directed therapy for esophageal cancer.
On Voice Exchanges
Authors: Cutler Timothy
Published: September 2010

The voice exchange is an elementary concept that can help solve some of tonal music's most difficult analytical problems. Although many essays allude to the subject of voice exchanges, there have been few direct investigations of the topic. Why such an important compositional technique has remained on the analytical sidelines can be argued, but what is not debatable is that an understanding of this ubiquitous contrapuntal maneuver is a necessary component of an overall comprehension of tonal music. Featuring examples ranging from J. S. Bach to Puccini, this essay examines numerous aspects of the voice exchange and its analytical applications, including (1) the distinction between functional exchanges and pitch swaps that represent little more than optical illusions, (2) operative voice exchanges that are difficult or impossible to see in the literal score, (3) exchanges that underscore networks of motivic parallelisms, (4) long-range exchanges employed as persuasive and powerful organizing tools, (5) surface chromatic “chaos” explained by underlying exchanges, and (6) the relationship between voice exchanges and a relatively unexplored nuance of tonal analysis—the inverted cadential six-four chord.
Generalizing Musical Intervals
Authors: Tymoczko Dmitri
Published: September 2010

Taking David Lewin's work as a point of departure, this essay uses geometry to reexamine familiar music-theoretical assumptions about intervals and transformations. Section 1 introduces the problem of “transportability,” noting that it is sometimes impossible to say whether two different directions—located at two different points in a geometrical space—are “the same” or not. Relevant examples include the surface of the earth and the geometrical spaces representing n-note chords. Section 2 argues that we should not require that every interval be defined at every point in a space, since some musical spaces have natural boundaries. It also notes that there are spaces, including the familiar pitch-class circle, in which there are multiple paths between any two points. This leads to the suggestion that we might sometimes want to replace traditional pitch-class intervals with paths in pitch-class space, a more fine-grained alternative that specifies how one pitch class moves to another. Section 3 argues that group theory alone cannot represent the intuition that intervals have quantifiable sizes, proposing an extension to Lewin's formalism that accomplishes this goal. Finally, Section 4 considers the analytical implications of the preceding points, paying particular attention to questions about voice leading.
Anterograde Jelly belly ligand to Alk receptor signaling at developing synapses is regulated by Mind the gap
Authors: Rohrbough Jeffrey , Broadie Kendal
Published: September 2010

Bidirectional trans-synaptic signals induce synaptogenesis and regulate subsequent synaptic maturation. Presynaptically secreted Mind the gap (Mtg) molds the synaptic cleft extracellular matrix, leading us to hypothesize that Mtg functions to generate the intercellular environment required for efficient signaling. We show in Drosophila that secreted Jelly belly (Jeb) and its receptor tyrosine kinase Anaplastic lymphoma kinase (Alk) are localized to developing synapses. Jeb localizes to punctate aggregates in central synaptic neuropil and neuromuscular junction (NMJ) presynaptic terminals. Secreted Jeb and Mtg accumulate and colocalize extracellularly in surrounding synaptic boutons. Alk concentrates in postsynaptic domains, consistent with an anterograde, trans-synaptic Jeb-Alk signaling pathway at developing synapses. Jeb synaptic expression is increased in Alk mutants, consistent with a requirement for Alk receptor function in Jeb uptake. In mtg null mutants, Alk NMJ synaptic levels are reduced and Jeb expression is dramatically increased. NMJ synapse morphology and molecular assembly appear largely normal in jeb and Alk mutants, but larvae exhibit greatly reduced movement, suggesting impaired functional synaptic development. jeb mutant movement is significantly rescued by neuronal Jeb expression. jeb and Alk mutants display normal NMJ postsynaptic responses, but a near loss of patterned, activity-dependent NMJ transmission driven by central excitatory output. We conclude that Jeb-Alk expression and anterograde trans-synaptic signaling are modulated by Mtg and play a key role in establishing functional synaptic connectivity in the developing motor circuit.
TheC. elegansperoxidasin PXN-2 is essential for embryonic morphogenesis and inhibits adult axon regeneration
Authors: Gotenstein Jennifer R. , Swale Ryann E. , Fukuda Tetsuko , Wu Zilu , Giurumescu Claudiu A. , Goncharov Alexandr , Jin Yishi , Chisholm Andrew D.
Published: September 2010

Peroxidasins form a highly conserved family of extracellular peroxidases of unknown cellular function. We identified the C. elegans peroxidasin PXN-2 in screens for mutants defective in embryonic morphogenesis. We find that PXN-2 is essential for specific stages of embryonic morphogenesis and muscle-epidermal attachment, and is also required postembryonically for basement membrane integrity. The peroxidase catalytic activity of PXN-2 is necessary for these developmental roles. pxn-2 mutants display aberrant ultrastructure of the extracellular matrix, suggesting a role in basement membrane consolidation. PXN-2 affects specific axon guidance choice points in the developing nervous system but is dispensable for maintenance of process positions. In adults, loss of pxn-2 function promotes regrowth of axons after injury, providing the first evidence that C. elegans extracellular matrix can play an inhibitory role in axon regeneration. Loss of function in the closely related C. elegans peroxidasin pxn-1 does not cause overt developmental defects. Unexpectedly, pxn-2 mutant phenotypes are suppressed by loss of function in pxn-1 and exacerbated by overexpression of wild-type pxn-1, indicating that PXN-1 and PXN-2 have antagonistic functions. These results demonstrate that peroxidasins play crucial roles in development and reveal a new role for peroxidasins as extracellular inhibitors of axonal regeneration.
Cell-autonomous integrin control of Wnt and Notch signalling during somitogenesis
Authors: Rallis Charalampos , Pinchin Sheena M. , Ish-Horowicz David
Published: September 2010

Integrins act at signalling crossroads, and their interactions with other signal transduction pathways are key to the regulation of normal and pathological cell cytoarchitecture and behaviour. Here, we describe a signalling cascade that acts during the formation of the defining segmental features of the vertebrate body – the somites – in which β1-integrin activity regulates epithelialisation by controlling downstream Wnt and Notch activity crucial for somite border formation. Using in vivo transcriptional inhibition in the developing chick embryo, we show that β1-integrin in the anterior presomitic mesoderm activates canonical Wnt signalling in a cell-autonomous, `outside-inside' manner. Signalling is mediated by integrin-linked kinase (ILK), leading to modulation of glycogen synthase kinase 3β (GSK3β) phosphorylation, and activates Notch signalling in the anterior presomitic mesoderm. The two signalling pathways then cooperate to promote somite formation via cMESO1/Mesp2. Our results show that β1-integrin can regulate cell shape and tissue morphogenesis indirectly, by regulation of downstream signalling cascades.
Three-dimensional cartography of hematopoietic clusters in the vasculature of whole mouse embryos
Authors: Yokomizo Tomomasa , Dzierzak Elaine
Published: September 2010

Hematopoietic cell clusters in the aorta of vertebrate embryos play a pivotal role in the formation of the adult blood system. Despite their importance, hematopoietic clusters have not been systematically quantitated or mapped because of technical limitations posed by the opaqueness of whole mouse embryos. Here, we combine an approach to make whole mouse embryos transparent, with multicolor marking, to allow observation of hematopoietic clusters using high-resolution 3-dimensional confocal microscopy. Our method provides the first complete map and temporal quantitation of all hematopoietic clusters in the mouse embryonic vasculature. We show that clusters peak in number at embryonic day 10.5, localize to specific vascular subregions and are heterogeneous, indicating a basal endothelial to non-basal (outer cluster) hematopoietic cell transition. Clusters enriched with the c-Kit+CD31+SSEA1– cell population contain functional hematopoietic progenitors and stem cells. Thus, three-dimensional cartography of transparent mouse embryos provides novel insight into the vascular subregions instrumental in hematopoietic progenitor/stem cell development, and represents an important technological advancement for comprehensive in situ hematopoietic cluster analysis.
Atoh1a expression must be restricted by Notch signaling for effective morphogenesis of the posterior lateral line primordium in zebrafish
Authors: Matsuda Miho , Chitnis Ajay B.
Published: September 2010

The posterior lateral line primordium (pLLp) migrates caudally, depositing neuromasts to establish the posterior lateral line system in zebrafish. A Wnt-dependent FGF signaling center at the leading end of the pLLp initiates the formation of `proneuromasts' by facilitating the reorganization of cells into epithelial rosettes and by initiating atoh1a expression. Expression of atoh1a gives proneuromast cells the potential to become sensory hair cells, and lateral inhibition mediated by Delta-Notch signaling restricts atoh1a expression to a central cell. We show that as atoh1a expression becomes established in the central cell, it drives expression of fgf10 and of the Notch ligand deltaD, while it inhibits expression of fgfr1. As a source of Fgf10, the central cell activates the FGF pathway in neighboring cells, ensuring that they form stable epithelial rosettes. At the same time, DeltaD activates Notch in neighboring cells, inhibiting atoh1a expression and ensuring that they are specified as supporting cells. When Notch signaling fails, unregulated atoh1a expression reduces Fgfr1 expression, eventually resulting in attenuated FGF signaling, which prevents effective maturation of epithelial rosettes in the pLLp. In addition, atoh1a inhibits e-cadherin expression, which is likely to reduce cohesion and contribute to fragmentation of the pLLp. Together, our observations reveal a genetic regulatory network that explains why atoh1a expression must be restricted by Notch signaling for effective morphogenesis of the pLLp.
Notch signalling regulates left-right asymmetry through ciliary length control
Authors: Lopes Susana S. , Lourenço Raquel , Pacheco Luís , Moreno Nuno , Kreiling Jill , Saúde Leonor
Published: September 2010

The importance of cilia in embryonic development and adult physiology is emphasized by human ciliopathies. Despite its relevance, molecular signalling pathways behind cilia formation are poorly understood. We show that Notch signalling is a key pathway for cilia length control. In deltaD zebrafish mutants, cilia length is reduced in Kupffer's vesicle and can be rescued by the ciliogenic factor foxj1a. Conversely, cilia length increases when Notch signalling is hyperactivated. Short cilia found in deltaD mutants reduce the fluid flow velocity inside Kupffer's vesicle, thus compromising the asymmetric expression of the flow sensor charon. Notch signalling brings together ciliary length control and fluid flow hydrodynamics with transcriptional activation of laterality genes. In addition, our deltaD mutant analysis discloses an uncoupling between gut and heart laterality.
An interview with Irving Weissman at the 2010 ISSCR meeting
Authors: Amsen Eva
Published: September 2010

The International Society for Stem Cell Research (ISSCR) held their annual conference in San Francisco this June. At the time, the President of the society was Irving Weissman, who is currently on the board of directors of the ISSCR as past President. He is Professor of Pathology and Developmental Biology and also the Director of the Institute of Stem Cell Biology and Regenerative Medicine at Stanford University School of Medicine, where he works on the generation of myeloid and lymphoid lineages from haematopoietic stem cells. At the ISSCR meeting, we asked Professor Weissman about his role on the board of directors of the ISSCR, and also about the meeting and the field of stem cell research in general.
The ZFHX3 (ATBF1) transcription factor induces PDGFRB, which activates ATM in the cytoplasm to protect cerebellar neurons from oxidative stress
Authors: Kim Tae-Sun , Kawaguchi Makoto , Suzuki Mitsuko , Jung Cha-Gyun , Asai Kiyofumi , Shibamoto Yuta , Lavin Martin F. , Khanna Kum Kum , Miura Yutaka
Published: September 2010

Ataxia telangiectasia (A-T) is a neurodegenerative disease caused by mutations in the large serine-threonine kinase ATM. A-T patients suffer from degeneration of the cerebellum and show abnormal elevation of serum alpha-fetoprotein. Here, we report a novel signaling pathway that links ATM via cAMP-responsive-element-binding protein (CREB) to the transcription factor ZFHX3 (also known as ATBF1), which in turn promotes survival of neurons by inducing expression of platelet-derived growth factor receptor β (PDGFRB). Notably, AG1433, an inhibitor of PDGFRB, suppressed the activation of ATM under oxidative stress, whereas AG1433 did not inhibit the response of ATM to genotoxic stress by X-ray irradiation. Thus, the activity of a membrane-bound tyrosine kinase is required to trigger the activation of ATM in oxidative stress, independent of the response to genotoxic stress. Kainic acid stimulation induced activation of ATM in the cerebral cortex, hippocampus and deep cerebellar nuclei (DCN), predominately in the cytoplasm in the absence of induction of γ-H2AX (a marker of DNA double-strand breaks). The activation of ATM in the cytoplasm might play a role in autophagy in protection of neurons against oxidative stress. It is important to consider DCN of the cerebellum in the etiology of A-T, because these neurons are directly innervated by Purkinje cells, which are progressively lost in A-T.
Redox Behavior of Ruthenium(Bipyridine)(Terpyridine)(Carbonyl) Complex-modified Carbon Electrode and Reactivity toward Electrochemical Reduction of CO2
Authors: Tsukahara Yuhei , Wada Tohru , Tanaka Koji
Published: September 2010

Electrochemical reduction of a diazonium complex [Ru(bpy)(trpy-ph-N2+)(CO)](PF6)3 ([1](PF6)3) (bpy = 2,2′-bipyridine, trpy-ph-N2+ = 4-(2,2′:6′,2′′-terpyridine-4′-yl)benzenediazonium) using a GC electrode forms multilayer films of the complexes on the electrode surface, on which the reduced form of the complex showed strong affinity toward CO2.
A Pilot Randomized Clinical Trial Utilizing the Drug Burden Index to Reduce Exposure to Anticholinergic and Sedative Medications in Older People
Authors: Gnjidic Danijela , Couteur David G Le , Abernethy Darrell R , Hilmer Sarah N
Published: September 2010

Background:

The drug burden index (DBI) is an evidence-based tool that utilizes pharmacologic principles to calculate an individual's total exposure to anticholinergic and sedative medications. Higher DBI has been associated with functional impairment in observational studies of older people.

Objective:

To assess the impact of providing information about DBI to general practitioners (GPs) on prescribing for older people.

Methods:

This was a cluster randomized controlled trial with 3 months of follow-up. Participants were volunteers aged ≥70 years, living in self-care retirement villages in Sydney, Australia. The study intervention involved a letter and phone call to GPs, using DBI to prompt them to consider cessation or dose reduction of anticholinergic and sedative medications. The primary study outcome was to assess the impact of information about DBI on prescribing practices of the GPs.

Results:

A total of 115 participants were enrolled, 57 in the intervention group (from 6 sites) and 58 in the control group (from 6 sites). At baseline, 19 of 57 participants in the intervention group and 31 of 58 participants in the control group had a DBI >0 (p < 0.05). At follow-up, a DBI change was observed in 16 participants. DBI decreased in 12 participants, 6 (32%) in the intervention group, and 6 (19%) in the control group. GPs identified the following barriers to reducing anticholinergic and sedative drugs: uncomfortable altering prescriptions initiated by specialists; unable to influence patients' attitudes; unaware of patients' medications and strong clinical indication.

Conclusions:

The intervention targeting GPs' prescribing practices was less effective than anticipated in reducing anticholinergic and sedative drug exposure, and barriers were identified. Future studies should explore multidisciplinary interventions, engaging patients, specialists, GPs, and pharmacists.
In Situ Detection of Active Transglutaminases for Keratinocyte Type (TGase 1) and Tissue Type (TGase 2) Using Fluorescence-Labeled Highly Reactive Substrate Peptides
Authors: Itoh Miho , Kawamoto Tadafumi , Tatsukawa Hideki , Kojima Soichi , Yamanishi Kiyofumi , Hitomi Kiyotaka
Published: September 2010

Transglutaminase is a calcium-dependent enzyme that posttranslationally modifies proteins by cross-linking between glutamine and lysine residues or attachment of a primary amine to specific polypeptide-bound glutamine residues. Eight isozymes play essential roles in various mammalian biological processes. The authors have recently identified 12–amino acid preferred substrate peptide sequences that are highly reactive and act in an isozyme-specific manner. In this study, a rapid, isozyme-specific, and sensitive detection of active keratinocyte type (TGase 1) and tissue type (TGase 2) was successful using fluorescence-labeled peptides. This procedure involved using whole-body sections of a mouse to extensively analyze the tissue distribution of both enzymes that revealed clearly distinct patterns. Strong active TGase 1 was observed in epithelial tissues such as tongue, developing teeth, forestomach, and skin epidermis. Significantly active TGase 2 was observed in various types of tissues as predicted and at particularly higher levels in the intestinal mucosa, muscle membrane, and whole veins in the liver. This manuscript contains online supplemental material at http://www.jhc.org . Please visit this article online to view these materials.
Opioid Pharmacogenomics Using a Twin Study Paradigm: Methods and Procedures for Determining Familial Aggregation and Heritability
Authors: Angst Martin S. , Phillips Nicholas G. , Drover David R. , Tingle Martha , Galinkin Jeffrey L. , Christians Uwe , Swan Gary E. , Lazzeroni Laura C. , Clark J. David
Published: September 2010

Opioids are the cornerstone medication for the treatment of moderate to severe pain. However, analgesic opioid requirements and the propensity to suffer from aversive opioid effects, including fatal respiratory depression and addiction, vary widely among patients. The factors underlying the substantial response variance remain largely unknown and need clarification for using opioids more effectively in appropriately selected patients. This ongoing study takes advantage of the twin paradigm to estimate the genetic and environmental contributions to inter-individual differences in opioid responses. Evidence of significant heritability will justify more detailed and extensive genomic studies. The enrollment target is 80 monozygotic and 45 dizygotic twin pairs who undergo a target-controlled infusion of the opioid alfentanil and saline placebo in sequential but randomized order. In a laboratory-type setting, well-defined pharmacodynamic endpoints are measured to quantify pain sensitivity, analgesic opioid effects, and aversive opioid effects including respiratory depression, sedation and reinforcing affective responses. First results obtained in 159 participants provide evidence for the feasibility and utility of this interventional study paradigm to estimate familial aggregation and heritability components of relevant drug effects. Areas highlighted in this report include recruitment strategies, required infrastructure and personnel, selection of relevant outcome measures, drug infusion algorithm minimizing pharmacokinetic variability, and considerations for optimizing data quality and quantity without hampering feasibility. Applying the twin paradigm to complex and potentially harmful studies comprehensively characterizing pharmacological response profiles is without much precedent. Methods and first results including heritability estimates for heat and cold pain sensitivity should be of interest to investigators considering similar studies.
Body Mass Index and Breast Size in Women: Same or Different Genes?
Authors: Wade Tracey D. , Zhu Gu , Martin Nicholas G.
Published: September 2010

The objective of the current study was to investigate the heritability of breast size and the degree to which this heritability is shared with BMI. In a sample of 1010 females twins (mean age 35 years;SD= 2.1; range 28–40), self-report data pertaining to bra cup size and body mass index (BMI) was collected in the context of self-report data and an interview relating to disordered eating respectively. In a sample of 348 complete twin pairs who completed data collection (226 MZ pairs and 122 DZ pairs and 360 incomplete pairs (170 MZ and 190 DZ)), we found that the heritability of bra cup size was 56%. Of this genetic variance, one third is in common with genes influencing body mass index, and two thirds (41% of total variance) is unique to breast size, with some directional evidence of non-additive genetic variation. The implications of these findings with respect to previous research linking breast size with reproductive potential are discussed.
Determining Zygosity in the Vietnam Era Twin Registry: An Update
Authors: Forsberg Christopher W. , Goldberg Jack , Sporleder Jennifer , Smith Nicholas L.
Published: September 2010

Our work assessed the accuracy of the original zygosity classification in the Vietnam Era Twin (VET) Registry using new information from DNA markers on a subset of participants. We then constructed an updated zygosity classification algorithm. The VET Registry includes 7,375 male–male twin pairs who served in the military during the Vietnam era. During the mid-1980s 4,774 twin pairs completed a zygosity questionnaire of 20 items. Additionally, military record information, including blood group, was available. Items from the zygosity questionnaire and blood group were used in the original zygosity classification. Between 1990–2009 DNA was obtained from 612 twin pairs and concordance between co-twins was used to classify zygosity. Next logistic regression was used to construct predicted probabilities of zygosity using items from the zygosity questionnaire with this subsample. All twins were reclassified according to the new zygosity prediction model and compared with the original zygosity assignment. The original and new predicted probabilities of zygosity were highly correlated (r= 0.962) and concordance for the classification of zygosity was similarly high (kappa = 0.936). Errors in the original zygosity assignment were primarily due to monozygotic twins that were misclassified as dizygotic based on military record blood group data. Removing the military record blood group data markedly improved the accuracy of the original classification. Zygosity assignment based on a zygosity questionnaire was highly predictive of DNA-based zygosity. Augmentation of such a zygosity classification from administrative data, military records, or other records, should be done with caution.
Does Fetal Sex Influence the Risk of Preterm Delivery in Dichorionic Twin Pregnancies After Spontaneous Conception?
Authors: Klein Katharina , Worda Christof , Stammler-Safar Maria , Husslein Peter , Gleicher Norbert , Weghofer Andrea
Published: September 2010

Objective: The incidence of preterm delivery has been increasing, and our aim was to estimate the influence of fetal sex on the risk of preterm delivery in dichorionic twins after spontaneous conception.Methods: 125 spontaneously conceived dichorionic twin gestations, with viable fetuses, born after 24 weeks and delivered spontaneously before 37 weeks, were enrolled. The impact of fetal sex, previous preterm delivery, maternal age, body-mass-index, smoking, and parity on gestational age at birth were evaluated.Results: Despite similar baseline characteristics in all three groups, women with one or two male fetuses delivered significantly more often before 34 weeks than patients with two female fetuses, 48% (23/48) and 43% (19/44) vs 21% (7/33),p= .04. Regression analyses, including fetal sex, maternal age, maternal body-mass-index, smoking, previous preterm delivery and parity, revealed that only fetal sex was significantly associated with spontaneous preterm delivery (p= .03).Conclusion: Fetal sex appears to be a risk factor for preterm delivery in spontaneously conceived dichorionic twin gestations. Twin pregnancies with one or two male fetuses seem to be at higher risk for spontaneous preterm delivery than those with only females.
Brain Mediators of Predictive Cue Effects on Perceived Pain
Authors: Atlas Lauren Y. , Bolger Niall , Lindquist Martin A. , Wager Tor D.
Published: September 2010

Information about upcoming pain strongly influences pain experience in experimental and clinical settings, but little is known about the brain mechanisms that link expectation and experience. To identify the pathways by which informational cues influence perception, analyses must jointly consider both the effects of cues on brain responses and the relationship between brain responses and changes in reported experience. Our task and analysis strategy were designed to test these relationships. Auditory cues elicited expectations for barely painful or highly painful thermal stimulation, and we assessed how cues influenced human subjects' pain reports and brain responses to matched levels of noxious heat using functional magnetic resonance imaging. We used multilevel mediation analysis to identify brain regions that (1) are modulated by predictive cues, (2) predict trial-to-trial variations in pain reports, and (3) formally mediate the relationship between cues and reported pain. Cues influenced heat-evoked responses in most canonical pain-processing regions, including both medial and lateral pain pathways. Effects on several regions correlated with pretask expectations, suggesting that expectancy plays a prominent role. A subset of pain-processing regions, including anterior cingulate cortex, anterior insula, and thalamus, formally mediated cue effects on pain. Effects on these regions were in turn mediated by cue-evoked anticipatory activity in the medial orbitofrontal cortex (OFC) and ventral striatum, areas not previously directly implicated in nociception. These results suggest that activity in pain-processing regions reflects a combination of nociceptive input and top-down information related to expectations, and that anticipatory processes in OFC and striatum may play a key role in modulating pain processing.
CXCR4 Controls Ventral Migration of Sympathetic Precursor Cells
Authors: Kasemeier-Kulesa Jennifer C. , McLennan Rebecca , Romine Morgan H. , Kulesa Paul M. , Lefcort Frances
Published: September 2010

The molecular mechanisms that sort migrating neural crest cells (NCCs) along a shared pathway into two functionally discrete structures, the dorsal root ganglia and sympathetic ganglia (SGs), are unknown. We report here that this patterning is attributable in part to differential expression of the chemokine receptor, CXCR4. We show that (1) a distinct subset of ventrally migrating NCCs express CXCR4 and this subset is destined to form the neural core of the sympathetic ganglia, and (2) the CXCR4 ligand, SDF-1, is a chemoattractant for NCCsin vivoand is expressed adjacent to the future SGs. Reduction of CXCR4 expression in NCCs disrupts their migration toward the future SGs, whereas overexpression of CXCR4 in non-SG-destined NCCs induces them to migrate aberrantly toward the SGs. These data are the first to demonstrate a major role for chemotaxis in the patterning of NCC migration and demonstrate the neural crest is composed of molecularly heterogeneous cell populations.
Membrane Estrogen Receptors Stimulate Intracellular Calcium Release and Progesterone Synthesis in Hypothalamic Astrocytes
Authors: Kuo John , Hamid Naheed , Bondar Galyna , Prossnitz Eric R. , Micevych Paul
Published: September 2010

In hypothalamic astrocytes obtained from adult female rats, estradiol rapidly increased free cytoplasmic calcium concentrations ([Ca2+]i) that facilitate progesterone synthesis. The present study demonstrated that estradiol (1 nm) significantly and maximally stimulated progesterone synthesis within 5 min, supporting a rapid, nongenomic mechanism. The group I metabotropic glutamate receptor (mGluR1a) antagonist LY 367385 [(S)-(+)-a-amino-4-carboxy-2-methylbenzeneacetic acid] attenuated both the estradiol-induced [Ca2+]irelease and progesterone synthesis. To investigate membrane-associated estrogen receptors (mERs), agonists for ERα, ERβ, STX-activated protein, and GPR30 were compared. The selective ERα agonist propylpyrazole triole (PPT) and STX most closely mimicked the estradiol-induced [Ca2+]iresponses, where PPT was more potent but less efficacious than STX. Only high doses (100 nm) of selective ERβ agonist diarylpropionitrile (DPN) and GPR30 agonist G-1 induced estradiol-like [Ca2+]iresponses. With the exception of DPN (even at 100 nm), all agonists stimulated progesterone synthesis. The PPT- and STX-induced [Ca2+]irelease and progesterone synthesis were blocked by LY 367385. While the G-1-stimulated [Ca2+]irelease was blocked by LY 367385, progesterone synthesis was not. Since GPR30 was detected intracellularly but not in the membrane, we interpreted these results to suggest that G-1 could activate mGluR1a on the membrane and GPR30 on the smooth endoplasmic reticulum to release intracellular calcium. Although STX and G-1 maximally stimulated [Ca2+]irelease in astrocytes from estrogen receptor-α knock-out (ERKO) mice, estradiolin vivodid not stimulate progesterone synthesis in the ERKO mice. Together, these results indicate that mERα is mainly responsible for the rapid, membrane-initiated estradiol-signaling that leads to progesterone synthesis in hypothalamic astrocytes.
Manipulation of Adenosine Kinase Affects Sleep Regulation in Mice
Authors: Palchykova Svitlana , Winsky-Sommerer Raphaelle , Shen Hai-Ying , Boison Detlev , Gerling Andrea , Tobler Irene
Published: September 2010

Sleep and sleep intensity are enhanced by adenosine and its receptor agonists, whereas adenosine receptor antagonists induce wakefulness. Adenosine kinase (ADK) is the primary enzyme metabolizing adenosine in adult brain. To investigate whether adenosine metabolism or clearance affects sleep, we recorded sleep in mice with engineered mutations inAdk. Adk-tg mice overexpress a transgene encoding the cytoplasmic isoform of ADK in the brain but lack the nuclear isoform of the enzyme. Wild-type mice andAdk+/−mice that have a 50% reduction of the cytoplasmic and the nuclear isoforms of ADK served as controls.Adk-tg mice showed a remarkable reduction of EEG power in low frequencies in all vigilance states and in theta activity (6.25–11 Hz) in rapid eye movement (REM) sleep and waking.Adk-tg mice were awake 58 min more per day than wild-type mice and spent significantly less time in REM sleep (102 ± 3 vs 128 ± 3 min in wild type). After sleep deprivation, slow-wave activity (0.75–4 Hz), the intensity component of non-rapid eye movement sleep, increased significantly less inAdk-tg mice and their slow-wave energy was reduced. In contrast, the vigilance states and EEG spectra ofAdk+/−and wild-type mice did not differ. Our data suggest that overexpression of the cytoplasmic isoform of ADK is sufficient to alter sleep physiology. ADK might orchestrate neurotransmitter pathways involved in the generation of EEG oscillations and regulation of sleep.
LRRK2G2019S Mutation Induces Dendrite Degeneration through Mislocalization and Phosphorylation of Tau by Recruiting Autoactivated GSK3β
Authors: Lin Chin-Hsien , Tsai Pei-I , Wu Ruey-Meei , Chien Cheng-Ting
Published: September 2010

Intraneuronal tau aggregations are distinctive pathological features of Parkinson's disease (PD) with autosomal-dominant mutations inleucine-rich repeat kinase 2(LRRK2). The most prevalentLRRK2mutation, G2019S (glycine to serine substitution at amino acid 2019), causes neurite shrinkage through unclear pathogenetic mechanisms. We found that expression of G2019S mutant inDrosophiladendritic arborization neurons induces mislocalization of the axonal protein tau in dendrites and causes dendrite degeneration. G2019S-induced dendrite degeneration is suppressed by reducing the level of tau protein and aggravated by tau coexpression. Additional genetic analyses suggest that G2019S and tau function synergistically to cause microtubule fragmentation, inclusion formation, and dendrite degeneration. Mechanistically, hyperactivated G2019S promotes tau phosphorylation at the T212 site by theDrosophilaglycogen synthase kinase 3β homolog Shaggy (Sgg). G2019S increases the recruitment of autoactivated Sgg, thus inducing hyperphosphorylation and mislocalization of tau with resultant dendrite degeneration.
Phase Misalignment between Suprachiasmatic Neuronal Oscillators Impairs Photic Behavioral Phase Shifts But Not Photic Induction of Gene Expression
Authors: Schwartz Michael D. , Congdon Seth , de la Iglesia Horacio O.
Published: September 2010

The ability of the circadian pacemaker within the suprachiasmatic nucleus (SCN) to respond to light stimulation in a phase-specific manner constitutes the basis for photic entrainment of circadian rhythms. The neural basis for this phase specificity is unclear. We asked whether a lack of synchrony between SCN neurons, as reflected in phase misalignment between dorsomedial (dmSCN) and ventrolateral (vlSCN) neuronal oscillators in the rat, would impact the ability of the pacemaker to respond to phase-resetting light pulses. Light pulses delivered at maximal phase misalignment between the vlSCN and dmSCN oscillators increased expression ofPer1mRNA, regardless of the circadian phase of the dmSCN. However, phase shifts of locomotor activity were only observed when the vlSCN and dmSCN were phase aligned at the time of stimulation. Our results fit a model in which a vlSCN oscillator phase gates its own response to light and in turn relays light information to a dmSCN oscillator. This model predicts that the phase misalignment that results from circadian internal desynchronization could preserve the ability of light to induce gene expression within the master circadian clock but impair its ability to induce behavioral phase shifts.
Properties of Layer 6 Pyramidal Neuron Apical Dendrites
Authors: Ledergerber Debora , Larkum Matthew Evan
Published: September 2010

Layer 6 (L6) pyramidal neurons are the only neocortical pyramidal cell type whose apical dendrite terminates in layer 4 rather than layer 1. Like layer 5 pyramidal neurons, they participate in a feedback loop with the thalamus and project to other cortical areas. Despite their unique location in the cortical microcircuit, synaptic integration in dendrites of L6 neurons has never been investigated. Given that all other neocortical pyramidal neurons perform active integration of synaptic inputs via local dendritic spike generation, we were interested to establish the apical dendritic properties of L6 pyramidal neurons. We measured active and passive properties of the apical dendrites of L6 pyramidal neurons in the somatosensory region of rat cortical slices using dual patch-clamp recordings from somata and dendrites and calcium imaging. We found that L6 pyramidal neurons share many fundamental dendritic properties with other neocortical pyramidal neurons, including the generation of local dendritic spikes under the control of dendritic inhibition, voltage-dependent support of backpropagating action potentials, timing-dependent dendritic integration, distally locatedIhchannels, frequency-dependent Ca2+spike activation, and NMDA spike electrogenesis in the distal apical dendrite. The results suggest that L6 pyramidal neurons integrate synaptic inputs in layer 4 similar to the way other neocortical pyramidal neurons integrate input to layer 1. Thus, L6 pyramidal neurons can perform a similar associational task operating on inputs arriving at the granular and subgranular layers.
Evolution and Analysis of Minimal Neural Circuits for Klinotaxis inCaenorhabditis elegans
Authors: Izquierdo Eduardo J. , Lockery Shawn R.
Published: September 2010

Chemotaxis during sinusoidal locomotion in nematodes captures in simplified form the general problem of how dynamical interactions between the nervous system, body, and environment are exploited in the generation of adaptive behavior. We used an evolutionary algorithm to generate neural networks that exhibit klinotaxis, a common form of chemotaxis in which the direction of locomotion in a chemical gradient closely follows the line of steepest ascent. Sensory inputs and motor outputs of the model networks were constrained to match the inputs and outputs of theCaenorhabditis elegansklinotaxis network. We found that a minimalistic neural network, comprised of an ON-OFF pair of chemosensory neurons and a pair of neck muscle motor neurons, is sufficient to generate realistic klinotaxis behavior. Importantly, emergent properties of model networks reproduced two key experimental observations that they were not designed to fit, suggesting that the model may be operating according to principles similar to those of the biological network. A dynamical systems analysis of 77 evolved networks revealed a novel neural mechanism for spatial orientation behavior. This mechanism provides a testable hypothesis that is likely to accelerate the discovery and analysis of the biological circuitry for chemotaxis inC. elegans.
Flachheitsbasierter Vorsteuerungsentwurf für den Antriebsstrang eines Parallelhybriden
Authors: Gasper Rainer , Heßeler Frank , Abel Dirk
Published: September 2010

Hybridfahrzeuge finden eine immer größere Verbreitung, da sie das Potenzial bieten Kraftstoff einzusparen und den Schadstoffausstoß zu minimieren. Ein weiteres wichtiges Kriterium für die Kundenakzeptanz ist die Fahrbarkeit eines Hybridfahrzeuges, wobei Gangschaltungen und der Start des Verbrennungsmotors während des elektrischen Fahrens entscheidend sind. Da diese Vorgänge in einem Hybridfahrzeug automatisiert sind, würden Schwingungen im Fahrzeug vom Fahrer als unangenehm wahrgenommen. In diesem Beitrag werden Vorsteuerungen für den Antriebsstrang eines Parallelhybriden vorgestellt.
Identification of elements in the Smcp 5′ and 3′ UTR that repress translation and promote the formation of heavy inactive mRNPs in spermatids by analysis of mutations in transgenic mice
Authors: Bagarova Jana , Chowdhury Tamjid A , Kimura Mine , Kleene Kenneth C
Published: September 2010

The sperm mitochondria-associated cysteine-rich protein (Smcp) mRNA is transcribed in step 3 spermatids, and is stored in free mRNPs until translation begins ∼6 days later in step 11. To identify sequences that control the timing ofSmcpmRNA translation, mutations in both UTRs were analyzed in transgenic mice using green fluorescent protein (GFP), squashes of seminiferous tubules, and quantification of polysomal loading in adult and 21 dpp testes in sucrose and Nycodenz gradients. GFP fluorescence is first detected in step 9 spermatids in lines harboring a transgene containing theGfp5′ UTR andSmcp3′ UTR. Unexpectedly, this mRNA is stored in large, inactive mRNPs in early spermatids that sediment with polysomes in sucrose gradients, but equilibrate with the density of free mRNPs in Nycodenz gradients. Randomization of the segment 6–38 nt upstream of the firstSmcppoly(A) signal results in early detection of GFP, a small increase in polysomal loading in 21 dpp testis, inactivation of the formation of heavy mRNPs, and loss of binding of a Y-box protein. GFP is first detected in step 5 spermatids in a transgene containing theSmcp5′ UTR andGfp3′ UTR. Mutations in the start codons in the upstream reading frames eliminate translational delay by theSmcp5′ UTR. Collectively, these findings demonstrate thatSmcpmRNA translation is regulated by multiple elements in the 5′ UTR and 3′ UTR. In addition, differences in regulation betweenSmcp–GfpmRNAs containing oneSmcpUTR and the naturalSmcpmRNA suggest that interactions between the Smcp 5′ UTR and 3′ UTR may be required for regulation of theSmcpmRNA.