bluuebunny/crossref_metadata_2025 huggingface dataset:
Menin and RNF20 recruitment is associated with dynamic histone modifications that regulate signal transducer and activator of transcription 1 (STAT1)-activated transcription of the interferon regulatory factor 1 gene (IRF1)
Authors: Buro Lauren J , Chipumuro Edmond , Henriksen Melissa A
Published: September 2010

Background

Signal transducer and activator of transcription (STAT) activation of gene expression is both rapid and transient, and when properly executed it affects growth, differentiation, homeostasis and the immune response, but when dysregulated it contributes to human disease. Transcriptional activation is regulated by alterations to the chromatin template. However, the role of histone modification at gene loci that are activated for transcription in response to STAT signaling is poorly defined.

Results

Using chromatin immunoprecipitation, we profiled several histone modifications during STAT1 activation of the interferon regulatory factor 1 gene (IRF1). Methylated lysine histone proteins H3K4me2, H3K4me3, H3K79me3, H3K36me3 and monoubiquitinated histone ubH2B are dynamic and correlate with interferon (IFN)γ induction of STAT1 activity. Chemical inhibition of H3K4 methylation downregulatesIRF1transcription and decreases RNA polymerase II (Pol II) occupancy at theIRF1promoter. MEN1, a component of a complex proteins associated with Set1 (COMPASS)-like complex and the hBRE1 component, RNF20, are localized toIRF1in the uninduced state and are further recruited whenIRF1is activated. RNAi-mediated depletion of RNF20 lowers both ubH2B and H3K4me3, but surprisingly, upregulates IFNγ inducedIRF1transcription. The dynamics of phosphorylation in the C-terminal domain (CTD) of Pol II are disrupted during gene activation as well.

Conclusions

H2B monoubiquitination promotes H3K4 methylation, but the E3 ubiquitin ligase, RNF20, is repressive of inducible transcription at theIRF1gene locus, suggesting that ubH2B can, directly or indirectly, affect Pol II CTD phosphorylation cycling to exert control on ongoing transcription.
Dynamic combinatorial chemistry at the phospholipid bilayer interface
Authors: Mansfeld Friederike M , Au-Yeung Ho Yu , Sanders Jeremy KM , Otto Sijbren
Published: September 2010

Background

Molecular recognition at the environment provided by the phospholipid bilayer interface plays an important role in biology and is subject of intense investigation. Dynamic combinatorial chemistry is a powerful approach for exploring molecular recognition, but has thus far not been adapted for use in this special microenvironment.

Results

Thioester exchange was found to be a suitable reversible reaction to achieve rapid equilibration of dynamic combinatorial libraries at the egg phosphatidyl choline bilayer interface. Competing thioester hydrolysis can be minimised by judicial choice of the structure of the thioesters and the experimental conditions. Comparison of the library compositions in bulk solution with those in the presence of egg PC revealed that the latter show a bias towards the formation of library members rich in membrane-bound building blocks. This leads to a shift away from macrocyclic towards linear library members.

Conclusions

The methodology to perform dynamic combinatorial chemistry at the phospholipid bilayer interface has been developed. The spatial confinement of building blocks to the membrane interface can shift the ring-chain equilibrium in favour of chain-like compounds. These results imply that interfaces may be used as a platform to direct systems to the formation of (informational) polymers under conditions where small macrocycles would dominate in the absence of interfacial confinement.
Bortezomib Plus Dexamethasone Is Superior to Vincristine Plus Doxorubicin Plus Dexamethasone As Induction Treatment Prior to Autologous Stem-Cell Transplantation in Newly Diagnosed Multiple Myeloma: Results of the IFM 2005-01 Phase III Trial
Authors: Harousseau Jean-Luc , Attal Michel , Avet-Loiseau Hervé , Marit Gerald , Caillot Denis , Mohty Mohamad , Lenain Pascal , Hulin Cyrille , Facon Thierry , Casassus Philippe , Michallet Mauricette , Maisonneuve Hervé , Benboubker Lotfi , Maloisel Frédéric , Petillon Marie-Odile , Webb Iain , Mathiot Claire , Moreau Philippe
Published: September 2010

Purpose

To compare efficacy and safety of bortezomib plus dexamethasone and vincristine plus doxorubicin plus dexamethasone (VAD) as induction before stem-cell transplantation in previously untreated myeloma.

Patients and Methods

Four hundred eighty-two patients were randomly assigned to VAD (n = 121), VAD plus dexamethasone, cyclophosphamide, etoposide, and cisplatin (DCEP) consolidation (n = 121), bortezomib plus dexamethasone (n = 121), or bortezomib plus dexamethasone plus DCEP (n = 119), followed by autologous stem-cell transplantation. Patients not achieving very good partial response (VGPR) required a second transplantation. The primary end point was postinduction complete response/near complete response (CR/nCR) rate.

Results

Postinduction CR/nCR (14.8% v 6.4%), at least VGPR (37.7% v 15.1%), and overall response (78.5% v 62.8%) rates were significantly higher with bortezomib plus dexamethasone versus VAD; CR/nCR and at least VGPR rates were higher regardless of disease stage or adverse cytogenetic abnormalities. Response rates were similar in patients who did and did not receive DCEP. Post first transplantation, CR/nCR (35.0% v 18.4%) and at least VGPR (54.3% v 37.2%) rates remained significantly higher with bortezomib plus dexamethasone. Median progression-free survival (PFS) was 36.0 months versus 29.7 months (P = .064) with bortezomib plus dexamethasone versus VAD; respective 3-year survival rates were 81.4% and 77.4% (median follow-up, 32.2 months). The incidence of severe adverse events appeared similar between groups, but hematologic toxicity and deaths related to toxicity (zero v seven) were more frequent with VAD. Conversely, rates of grade 2 (20.5% v 10.5%) and grades 3 to 4 (9.2% v 2.5%) peripheral neuropathy during induction through first transplantation were significantly higher with bortezomib plus dexamethasone.

Conclusion

Bortezomib plus dexamethasone significantly improved postinduction and post-transplantation CR/nCR and at least VGPR rates compared with VAD and resulted in a trend for longer PFS. Bortezomib plus dexamethasone should therefore be considered a standard of care in this setting.
Light Chain–Induced Acute Renal Failure Can Be Reversed by Bortezomib-Doxorubicin-Dexamethasone in Multiple Myeloma: Results of a Phase II Study
Authors: Ludwig Heinz , Adam Zdenek , Hajek Roman , Greil Richard , Tóthová Elena , Keil Felix , Autzinger Eva Maria , Thaler Josef , Gisslinger Heinz , Lang Alois , Egyed Miklós , Womastek Irene , Zojer Niklas
Published: September 2010

Purpose

To assess the efficacy of bortezomib-doxorubicin-dexamethasone (BDD) therapy in patients with multiple myeloma with light chain–induced acute renal failure.

Patients and Methods

Sixty-eight patients with light chain–induced acute renal failure and glomerular filtration rate (GFR) less than 50 mL/min received bortezomib (1.0 mg/m2on days 1, 4, 8, and 11), doxorubicin (9 mg/m2on days 1 and 4), and dexamethasone (40 mg on days 1, 4, 8, and 11); if well tolerated after two cycles, bortezomib could be increased to 1.3 mg/m2and doxorubicin administered on days 1, 4, 8, and 11.

Results

By intent-to-treat analysis a myeloma response was obtained in 72% of 18 previously and 50 not previously treated patients (complete response [CR]/near CR [nCR], 38%; very good partial response [VGPR], 15%; partial response [PR], 13%; minor response [MR], 6%). Renal response was achieved in 62% of patients (renal CR, 31%; renal PR, 7%; renal MR, 24%). Median GFR increased from 20.5 to 48.4 mL/min. GFR improvement correlated with tumor response; the greatest increase to 59.6 mL/min was seen in the group of patients with CR/nCR/VGPR. Median progression-free survival was 12.1 months. One- and 2-year survival rates were 72% and 58%, respectively. Survival did not differ between patients with and without renal response but was inferior in previously treated patients (P < .001). In multivariate analysis, baseline GFR and tumor response correlated with renal response, and pretreatment status, lactate dehydrogenase, and myeloma response correlated with survival. The most common grade 3 or 4 toxicities were infection (19.1%), thrombocytopenia (14.7%), neutropenia (14.7%), fatigue/weakness (10.3%), and polyneuropathy (8.8%).

Conclusion

BDD induced a high rate of myeloma and renal responses, and treatment was well tolerated.
Reading with an “Inveterate Hypochondriac”
Authors: Wooden Shannon R. , Spiegel Maura , DasGupta Sayantani
Published: September 2010

Narrative medicine, designed to develop empathic listening skills in healthcare professionals, also helps literature teachers discuss ethics without sacrificing critical rigor. Reading the distasteful narrator of Dostoevsky's challenging story as the notorious “hated patient/unreliable historian” of clinical practice, we demonstrate how students can practice reading empathically as a fundamentally ethical act.
The Heat of Composition
Authors: Palmer Heather
Published: September 2010

This essay explores how the “heat of composition” is inexorably linked to ethos and also how writers, student or otherwise, might seek to create and intensify pleasure through a sustained textual becoming. I consider how this ethics of affect is an unfolding, an exteriorization of the intensities and forces of becoming writers, student or otherwise, who engage with the movements of desire.
Far from the Truth
Authors: Siebler Kay
Published: September 2010

At many levels of the educational system, teachers use Sojourner Truth's speech “Ain't I a Woman” as a powerful example of women's rhetoric. This article examines the politics of privileging one version of the speech. The author makes a call to teachers to teach multiple versions and talk about the politics of transcription, gender, and race.
Page and Screen
Authors: Goldstein David S.
Published: September 2010

Courses on ethnic American literature can unintentionally reinscribe students' preconceptions and stereotypes about ethnic American subgroups or create the false impression that each ethnic group is homogeneous. A student with limited experience with people of color might think she now understands an ethnic group after reading an ethnic American novel, for example. By using fiction and non-fiction film, teachers can destabilize students' oversimplified views of ethnic groups and of the concepts of race and ethnicity themselves. The course described here started with Toni Morrison's short story, “Recitatif,” which ingeniously leads readers to examine their own racial preconceptions. Then, novels (Love Medicine by Louise Erdrich, Sent for You Yesterday by John Wideman, The House on Mango Street by Sandra Cisneros, and Mona in the Promised Land by Gish Jen) are paired with films to demonstrate that greater diversity exists within any ethnic group than between any two. Students also engage a few key articles about canon formation so they can understand ethnic literature in the context of American literary traditions. By the end of the course, students have a healthy uncertainty regarding race and ethnicity, their oversimplifications having been undermined by their work with diverse texts.
Nachmanovitch'sFree Playas a Context for Experimental Writing
Authors: Holm Janis Butler
Published: September 2010

Stephen Nachmanovitch's Free Play: Improvisation in Life and Art offers a compelling view of creativity as playful practice, a model that engaged and motivated my initially apprehensive experimental writing class. Nachmanovitch's erudition, provocative examples, and narratives of personal experience make his book a good choice for university students. Especially useful are his chapters addressing the nature of inspiration, the nature of play, the importance of practice (of continually and playfully doing), and the cultural tendency to associate play with childhood. In particular, the “Childhood's End” chapter, which discusses how some aspects of schooling and the media block our inherent creativity, resonated among my students. After sharing their tragicomic experiences of institutional obstacles, they welcomed the course's strange readings and even stranger writing exercises as invitations to recover some “raw creativity.” And I found their enthusiasm contagious.
Biology, politics and performance management: tackling healthcare-associated infections in the NHS in England
Authors: Duerden Brian
Published: September 2010

Infection is different from other aspects of medical care and clinical practice because it spreads. That is the defining characteristic of infection and it means that for every infected patient who needs treatment for their illness, there are two further questions – where has the infection come from, and where (to whom) may it have spread? The study of infection is a fascinating biological interaction between microbial populations and human populations with a variety of influencing factors linked to human behaviour. This includes the behaviour of patients, their relatives and, importantly, their healthcare attendants, particularly doctors and nurses. These factors have critical importance in relation to healthcare-associated infections. These infections are complications of a patient's underlying, primary illness or of the treatment they have received for that illness. They used to be called ‘hospital infections’ but they know no boundaries across health and social care because the bacteria move with people (both patients and staff) and these infections affect all health and social care settings. Therefore, responsibility for infection prevention and control lies across the whole health and social care community.
Medicolegal pitfalls in the management of chest pain
Authors: Gallagher Sean , Knight Charles , Wragg Andrew
Published: September 2010

Chest pain is a common reason for patients to present to either general practice or hospital. It is the presenting symptom of a number of disorders, including potentially life-threatening conditions such as acute coronary syndrome, pulmonary embolus and aortic dissection. The initial evaluation of patients with chest pain is not straightforward, and failure to diagnose and treat patients with chest pain appropriately and expeditiously can have serious consequences. Included in those consequences are potential medicolegal liabilities. In this article we review the management of common causes of acute chest pain, with special emphasis placed upon the management of life-threatening causes of chest pain. We also highlight potential medicolegal pitfalls in the management of patients presenting with chest pain, and make suggestions to help avoid these pitfalls in everyday practice.
Trimethoprim/Sulfamethoxazole Pharmacokinetics in Two Patients Undergoing Continuous Venovenous Hemodiafiltration
Authors: Curkovic Ivanka , Lüthi Beatrice , Franzen Daniel , Ceschi Alessandro , Rudiger Alain , Corti Natascia
Published: September 2010

Objective:

To determine the extent of elimination of trimethoprim (TMP) and sulfamethoxazole (SMX) via continuous venovenous hemodiafiltration (CVVHDF) in 2 critically ill patients with renal failure.

Case Summary:

A 62-year-old woman with Pneumocystis jirovecii pneumonia (PCP) was admitted to our intensive care unit for severe acute respiratory distress syndrome. A 77-year-old man was admitted for aortic root replacement and developed septic shock and nosocomial pneumonia due to Stenotrophomonas maltophilia. Both patients developed acute renal failure, necessitating CVVHDF. They were treated with intravenous TMP/SMX adapted to renal function. The first patient received TMP 6.4 mg/kg/day and SMX 32 mg/kg/day, corresponding to 50% of the recommended high-dose TMP/SMX regimen in PCP patients. The second patient received TMP 1.7 mg/kg/day and SMX 8.6 mg/kg/day, corresponding to 50% of the usual dose in bacterial infections. We determined peak and trough serum TMP and SMX concentrations and the extent of TMP/SMX CVVHDF clearance at steady-state while the patients were still anuric and oliguric.

Discussion:

Data on TMP and SMX pharmacokinetics in CVVHDF are lacking and dosing recommendations are inconclusive. In both patients, CVVHDF clearance of TMP ranged from 21.5 to 28.9 mL/min, corresponding with normal renal clearance (20–80 mL/min). SMX clearance in CVVHDF showed high variability (18.7, 26.7, and 42.6 mL/min) and exceeded renal clearance values in normal renal function (1–5 mL/min). Accordingly, peak TMP serum concentrations were within the recommended range in the patient treated with a reduced TMP/SMX dose for PCP, whereas her SMX peak concentrations were only one third of recommended target concentrations.

Conclusions:

Our data indicate that both TMP and SMX are removed by CVVHDF to a significant degree, and dose reduction of TMP/SMX in CVVHDF bears the risk of underdosing. Given variability in drug exposure in critically ill patients, therapeutic drug monitoring is advisable in anuric or oliguric patients undergoing continuous renal replacement therapy to ensure optimal TMP/SMX dosing.
A fresh look at the Ramachandran plot and the occurrence of standard structures in proteins
Authors: Hollingsworth Scott A. , Karplus P. Andrew
Published: September 2010

The Ramachandran plot is among the most central concepts in structural biology, seen in publications and textbooks alike. However, with the increasing numbers of known protein structures and greater accuracy of ultra-high resolution protein structures, we are still learning more about the basic principles of protein structure. Here, we use high-fidelity conformational information to explore novel ways, such as geo-style and wrapped Ramachandran plots, to convey some of the basic aspects of the Ramachandran plot and of protein conformation. We point out the pressing need for a standard nomenclature for peptide conformation and propose such a nomenclature. Finally, we summarize some recent conceptual advances related to the building blocks of protein structure. The results for linear groups imply the need for substantive revisions in how the basics of protein structure are handled.
Competing Streams at the Cocktail Party: Exploring the Mechanisms of Attention and Temporal Integration
Authors: Xiang Juanjuan , Simon Jonathan , Elhilali Mounya
Published: September 2010

Processing of complex acoustic scenes depends critically on the temporal integration of sensory information as sounds evolve naturally over time. It has been previously speculated that this process is guided by both innate mechanisms of temporal processing in the auditory system, as well as top-down mechanisms of attention and possibly other schema-based processes. In an effort to unravel the neural underpinnings of these processes and their role in scene analysis, we combine magnetoencephalography (MEG) with behavioral measures in humans in the context of polyrhythmic tone sequences. While maintaining unchanged sensory input, we manipulate subjects' attention to one of two competing rhythmic streams in the same sequence. The results reveal that the neural representation of the attended rhythm is significantly enhanced in both its steady-state power and spatial phase coherence relative to its unattended state, closely correlating with its perceptual detectability for each listener. Interestingly, the data reveal a differential efficiency of rhythmic rates of the order of few hertz during the streaming process, closely following known neural and behavioral measures of temporal modulation sensitivity in the auditory system. These findings establish a direct link between known temporal modulation tuning in the auditory system (particularly at the level of auditory cortex) and the temporal integration of perceptual features in a complex acoustic scene, while mediated by processes of attention.
Nanodomain Control of Exocytosis Is Responsible for the Signaling Capability of a Retinal Ribbon Synapse
Authors: Jarsky Tim , Tian Miao , Singer Joshua H.
Published: September 2010

Primary sensory circuits encode both weak and intense stimuli reliably, requiring that their synapses signal over a wide dynamic range. In the retinal circuitry subserving night vision, processes intrinsic to the rod bipolar (RB) cell presynaptic active zone (AZ) permit the RB synapse to encode signals generated by the absorption of single photons as well as by more intense stimuli. In a study using anin vitroslice preparation of the mouse retina, we provide evidence that the location of Ca channels with low open probability within nanometers of the release sites is a critical determinant of the physiological behavior of the RB synapse. This gives rise to apparent one-to-one coupling between Ca channel opening and vesicle release, allowing presynaptic potential to be encoded linearly over a wide dynamic range. Further, it permits a transition from univesicular to multivesicular release (MVR) when two Ca channels/AZ open at potentials above the threshold for exocytosis. MVR permits small presynaptic voltage changes to elicit postsynaptic responses larger than quantal synaptic noise.
Plexin A-Semaphorin-1a Reverse Signaling Regulates Photoreceptor Axon Guidance inDrosophila
Authors: Yu Li , Zhou Yating , Cheng Songting , Rao Yong
Published: September 2010

While it is well established that Semaphorin family proteins function as axon guidance ligands in invertebrates and vertebrates, several recent studies indicate that theDrosophilaSemaphorin-1a (Sema1a), a transmembrane Semaphorin, can also function as a receptor during neural development. The regulator of Sema1a reverse signaling, however, remains unknown. In this study, we show that like Sema1a, the well known Semaphorin receptor Plexin A (PlexA), is required for the proper guidance of photoreceptor (R cell) axons in theDrosophilavisual system. Loss ofPlexA, like loss ofsemala, disrupted the association of R-cell growth cones in the optic lobe. Conversely, overexpression ofPlexA, like overexpression ofsema1a, induced the hyperfasciculation of R-cell axons. Unlike Sema1a, however, the cytoplasmic domain of PlexA is dispensable. Epistasis analysis suggests thatPlexAfunctions upstream ofsemala.AndPlexAandsema1ainteract genetically withRho1.We propose that PlexA regulates Semala reverse signaling in theDrosophilavisual system.
Nerve Growth Factor Induces Axonal Filopodia through Localized Microdomains of Phosphoinositide 3-Kinase Activity That Drive the Formation of Cytoskeletal Precursors to Filopodia
Authors: Ketschek Andrea , Gallo Gianluca
Published: September 2010

The initiation of axonal filopodia is the first step in the formation of collateral branches and synaptic structures. In sensory neurons, nerve growth factor (NGF) promotes the formation of axonal filopodia and branches. However, the signaling and cytoskeletal mechanisms of NGF-induced initiation of axonal filopodia are not clear. Axonal filopodia arise from precursor axonal cytoskeletal structures termed filamentous actin (F-actin) patches. Patches form spontaneously and are transient. Although filopodia emerge from patches, only a fraction of patches normally gives rise to filopodia. Using chicken sensory neurons and live imaging of enhanced yellow fluorescent protein (eYFP)–actin dynamics, we report that NGF promotes the formation of axonal filopodia by increasing the rate of F-actin patch formation but not the fraction of patches that give rise to filopodia. We also demonstrate that activation of the phosphatidylinositol 3-kinase (PI3K)–Akt pathway is sufficient and required for driving the formation of axonal F-actin patches, filopodia, and axon branches. Using the green fluorescent protein–plekstrin homology domain of Akt, which targets to PI3K-generated phosphatidylinositol-3,4,5-triphosphate (PIP3), we report localized microdomains of PIP3accumulation that form in synchrony with F-actin patches and that NGF promotes the formation of microdomains of PIP3and patches. Finally, we find that, in NGF, F-actin patches form in association with axonal mitochondria and oxidative phosphorylation is required for patch formation. This investigation demonstrates that surprisingly NGF promotes formation of axonal filopodia by increasing the formation of cytoskeletal filopodial precursors (patches) through localized microdomains of PI3K signaling but not the emergence of filopodia from patches.
Dynamic Spike Thresholds during Synaptic Integration Preserve and Enhance Temporal Response Properties in the Avian Cochlear Nucleus
Authors: Howard MacKenzie A. , Rubel Edwin W
Published: September 2010

Neurons of the cochlear nuclei are anatomically and physiologically specialized to optimally encode temporal and spectral information about sound stimuli, in part for binaural auditory processing. The avian cochlear nucleus magnocellularis (NM) integrates excitatory eighth nerve inputs and depolarizing GABAergic inhibition such that temporal fidelity is enhanced across the synapse. The biophysical mechanisms of this depolarizing inhibition, and its role in temporal processing, are not fully understood. We used whole-cell electrophysiology and computational modeling to examine how subthreshold excitatory inputs are integrated and how depolarizing IPSPs affect spike thresholds and synaptic integration by chick NM neurons. We found that both depolarizing inhibition and subthreshold excitatory inputs cause voltage threshold accommodation, nonlinear temporal summation, and shunting. Inhibition caused such large changes in threshold that subthreshold excitatory inputs were followed by a refractory period. We hypothesize that these large shifts in threshold eliminate spikes to asynchronous inputs, providing a mechanism for the enhanced temporal fidelity seen across the eighth nerve/cochlear nucleus synapse. Thus, depolarizing inhibition and threshold shifting hone the temporal response properties of this system so as to enhance the temporal fidelity that is essential for auditory perception.
Activation of the Liver X Receptor Increases Neuroactive Steroid Levels and Protects from Diabetes-Induced Peripheral Neuropathy
Authors: Cermenati Gaia , Giatti Silvia , Cavaletti Guido , Bianchi Roberto , Maschi Omar , Pesaresi Marzia , Abbiati Federico , Volonterio Alessandro , Saez Enrique , Caruso Donatella , Melcangi Roberto Cosimo , Mitro Nico
Published: September 2010

Neuroactive steroids act in the peripheral nervous system as physiological regulators and as protective agents for acquired or inherited peripheral neuropathy. In recent years, modulation of neuroactive steroids levels has been studied as a potential therapeutic approach to protect peripheral nerves from damage induced by diabetes. Nuclear receptors of the liver X receptor (LXR) family regulate adrenal steroidogenesis via their ability to control cholesterol homeostasis. Here we show that rat sciatic nerve expresses both LRXα and β isoforms and that these receptors are functional. Activation of liver X receptors using a synthetic ligand results in increased levels of neurosteroids and protection of the sciatic nerve from neuropathy induced by diabetes. LXR ligand treatment of streptozotocin-treated rats increases expression in the sciatic nerve of steroidogenic acute regulatory protein (a molecule involved in the transfer of cholesterol into mitochondria), of the enzyme P450scc (responsible for conversion of cholesterol into pregnenolone), of 5α-reductase (an enzyme involved in the generation of neuroactive steroids) and of classical LXR targets involved in cholesterol efflux, such as ABCA1 and ABCG1. These effects were associated with increased levels of neuroactive steroids (e.g., pregnenolone, progesterone, dihydroprogesterone and 3α-diol) in the sciatic nerve, and with neuroprotective effects on thermal nociceptive activity, nerve conduction velocity, and Na+, K+-ATPase activity. These results suggest that LXR activation may represent a new pharmacological avenue to increase local neuroactive steroid levels that exert neuroprotective effects in diabetic neuropathy.
Induced Loss of ADAR2 Engenders Slow Death of Motor Neurons from Q/R Site-Unedited GluR2
Authors: Hideyama Takuto , Yamashita Takenari , Suzuki Takeshi , Tsuji Shoji , Higuchi Miyoko , Seeburg Peter H. , Takahashi Ryosuke , Misawa Hidemi , Kwak Shin
Published: September 2010

GluR2 is a subunit of the AMPA receptor, and the adenosine for the Q/R site of its pre-mRNA is converted to inosine (A-to-I conversion) by the enzyme called adenosine deaminase acting on RNA 2 (ADAR2). Failure of A-to-I conversion at this site affects multiple AMPA receptor properties, including the Ca2+permeability of the receptor-coupled ion channel, thereby inducing fatal epilepsy in mice (Brusa et al., 1995; Feldmeyer et al., 1999). In addition, inefficient GluR2 Q/R site editing is a disease-specific molecular dysfunction found in the motor neurons of sporadic amyotrophic lateral sclerosis (ALS) patients (Kawahara et al., 2004). Here, we generated genetically modified mice (designated as AR2) in which the ADAR2 gene was conditionally targeted in motor neurons using the Cre/loxP system. These AR2 mice showed a decline in motor function commensurate with the slow death of ADAR2-deficient motor neurons in the spinal cord and cranial motor nerve nuclei. Notably, neurons in nuclei of oculomotor nerves, which often escape degeneration in ALS, were not decreased in number despite a significant decrease in GluR2 Q/R site editing. All cellular and phenotypic changes in AR2 mice were prevented when the mice carried endogenous GluR2 alleles engineered to express edited GluR2 without ADAR2 activity (Higuchi et al., 2000). Thus, loss of ADAR2 activity causes AMPA receptor-mediated death of motor neurons.
White Matter Fiber Degradation Attenuates Hemispheric Asymmetry When Integrating Visuomotor Information
Authors: Schulte Tilman , Müller-Oehring Eva M. , Rohlfing Torsten , Pfefferbaum Adolf , Sullivan Edith V.
Published: September 2010

Degradation of white matter fibers can affect the transmission of signals in brain circuits that normally enable integration of highly lateralized visual and motor processes. Here, we used diffusion tensor imaging tractography in combination with functional magnetic resonance imaging to examine the specific contributions of interhemispheric and intrahemispheric white matter fibers to functional measures of hemispheric transfer and parallel information processing using bilateral and unilateral left and right visual field stimulation in normal and compromised systems. In healthy adults, a greater degree of bilateral processing advantage with the left (nondominant) hand correlated with higher integrity of callosal fibers connecting occipital cortices, whereas less unilateral processing advantage with the right hand correlated with higher integrity of left-hemispheric posterior cingulate fibers. In contrast, alcoholics who have compromised callosal integrity showed less bilateral processing advantage than controls when responding with the left hand and greater unilateral processing advantage when responding with the right hand. We also found degraded left posterior cingulate and posterior callosal fibers in chronic alcoholics, which is consistent with functional imaging results of less left posterior cingulate and extrastriate cortex activation in alcoholics than controls when processing bilateral compared with unilateral visual field stimulation. Together, our results demonstrated that interhemispheric and intrahemispheric white matter fiber pathways mediate visuomotor integration asymmetrically and that subtle white matter fiber degradation in alcoholism attenuated the normal pattern of hemispheric asymmetry, which may have ramifications for the efficiency of visual information processing and fast response execution.
Photic Entrainment ofPeriodMutant Mice is Predicted from Their Phase Response Curves
Authors: Pendergast Julie S. , Friday Rio C. , Yamazaki Shin
Published: September 2010

A fundamental property of circadian clocks is that they entrain to environmental cues. The circadian genes,Period1andPeriod2, are involved in entrainment of the mammalian circadian system. To investigate the roles of thePeriodgenes in photic entrainment, we constructed phase response curves (PRC) to light pulses for C57BL/6J wild-type,Per1−/−,Per2−/−, andPer3−/−mice and tested whether the PRCs accurately predict entrainment to non-24 light–dark cycles (T-cycles) and constant light (LL). The PRCs of wild-type andPer3−/−mice are similar in shape and amplitude and have relatively large delay zones and small advance zones, resulting in successful entrainment to 26 h T-cycles (T26), but not T21, with similar phase angles.Per1−/−mice have a high-amplitude PRC, resulting in entrainment to a broad range of T-cycles.Per2−/−mice also entrain to a wide range of T-cycles because the advance portion of their PRC is larger than wild types. Period aftereffects following entrainment to T-cycles were similar among all genotypes. We found that the ratio of the advance portion to the delay portion of the PRC accurately predicts the lengthening of the period of the activity rhythm in LL. Wild-type,Per1−/−, andPer3−/−mice had larger delay zones than advance zones and lengthened (>24 h) periods in LL, whereasPer2−/−mice had delay and advance zones that were equal in size and no period lengthening in LL. Together, these results demonstrate that PRCs are powerful tools for predicting and understanding photic entrainment of circadian mutant mice.
Visual Motion Processing by Neurons in Area MT of Macaque Monkeys with Experimental Amblyopia
Authors: El-Shamayleh Yasmine , Kiorpes Lynne , Kohn Adam , Movshon J. Anthony
Published: September 2010

Early experience affects the development of the visual system. Ocular misalignment or unilateral blur often causes amblyopia, a disorder that has become a standard for understanding developmental plasticity. Neurophysiological studies of amblyopia have focused almost entirely on the first stage of cortical processing in striate cortex. Here we provide the first extensive study of how amblyopia affects extrastriate cortex in nonhuman primates. We studied macaque monkeys (Macaca nemestrina) for which we have detailed psychophysical data, directly comparing physiological findings to perceptual capabilities. Because these subjects showed deficits in motion discrimination, we focused on area MT/V5, which plays a central role in motion processing. Most neurons in normal MT respond equally to visual stimuli presented through either eye; most recorded in amblyopes strongly preferred stimulation of the nonamblyopic (fellow) eye. The pooled responses of neurons driven by the amblyopic eye showed reduced sensitivity to coherent motion and preferred higher speeds, in agreement with behavioral measurements. MT neurons were more limited in their capacity to integrate motion information over time than expected from behavioral performance; neurons driven by the amblyopic eye had even shorter integration times than those driven by the fellow eye. We conclude that some, but not all, of the motion sensitivity deficits associated with amblyopia can be explained by abnormal development of MT.
Enhanced Function of Prefrontal Serotonin 5-HT2Receptors in a Rat Model of Psychiatric Vulnerability
Authors: Benekareddy Madhurima , Goodfellow Nathalie M. , Lambe Evelyn K. , Vaidya Vidita A.
Published: September 2010

Prefrontal serotonin 5-HT2receptors have been linked to the pathogenesis and treatment of affective disorders, yet their function in psychiatric vulnerability is not known. Here, we examine the effects of 5-HT2receptors in a rat model of psychiatric vulnerability using electrophysiology, gene expression, and behavior. Following the early stress of chronic maternal separation, we found that serotonin has atypical 5-HT2receptor-mediated excitatory effects in the adult prefrontal cortex that were blocked by the 5-HT2Areceptor antagonist MDL 100907. In the absence of a serotonergic agonist, the intrinsic excitability of the prefrontal cortex was not enhanced relative to controls. Yet, in response to stimulation of 5-HT2receptors, adult animals with a history of early stress exhibit heightened prefrontal network activityin vitro, enhanced immediate early gene expressionin vivo, and potentiated head shake behavior. These changes arise in the absence of any major alteration of prefrontal 5-HT2A/CmRNA expression or 5-HT2receptor binding. Our microarray results and quantitative PCR validation provide insight into the molecular changes that accompany such enhanced 5-HT2receptor function in adult animals following early stress. We observed persistent prefrontal transcriptome changes, with significant enrichment of genes involved in cellular developmental processes, regulation of signal transduction, and G-protein signaling. Specific genes regulated by early stress were validated in an independent cohort, and several altered genes were normalized by chronic blockade of 5-HT2receptors in adulthood. Together, our results demonstrate enhanced prefrontal 5-HT2receptor function and persistent alterations in prefrontal gene expression in a rat model of psychiatric vulnerability.
Tissue Culture-Induced Novel Epialleles of aMybTranscription Factor Encoded bypericarp color1in Maize
Authors: Rhee Yong , Sekhon Rajandeep S , Chopra Surinder , Kaeppler Shawn
Published: September 2010

Plants regenerated from tissue culture often display somaclonal variation, that is, somatic and often meiotically heritable phenotypic variation that can result from both genetic and epigenetic modifications. To better understand the molecular basis of somaclonal variation, we have characterized four unique tissue culture-derived epialleles of the pericarp color1 (p1) gene of maize (Zea mays L.). The progenitor p1 allele, P1-wr, is composed of multiple head-to-tail tandemly arranged copies of the complete gene unit and specifies brick-red phlobaphene pigmentation in the cob glumes. The novel epialleles identified in progeny plants regenerated from tissue culture showed partial to complete loss of p1 function indicated by pink or colorless cob glumes. Loss of pigmentation was correlated with nearly complete loss of p1 steady-state transcripts. DNA gel-blot analysis and genomic bisulfite sequencing showed that silencing of the epialleles was associated with hypermethylation of a region in the second intron of P1-wr. Presence of Unstable factor for orange1 (Ufo1), an unlinked epigenetic modifier of p1, restored the cob glume pigmentation in the silenced alleles, and such reactivation was accompanied by hypomethylation of the p1 sequence. This observation confirmed that silencing of the epialleles is indeed due to epigenetic modifications and that the p1 epialleles were capable of functioning in the presence of the correct trans-acting factors. While the low-copy regions of the genome generally undergo hypomethylation during tissue culture, our study shows that the tandemly repeated genes are also prone to hypermethylation and epigenetic silencing.
Botulism in Brazil, 2000-2008: epidemiology, clinical findings and laboratorial diagnosis
Authors: Rowlands Ruth Estela Gravato , Ristori Christiane Asturiano , Lopes Giselle Ibette S. Lopez , Paula Ana Maria Ramalho de , Sakuma Harumi , Grigaliunas Raquel , Lopreato Filho Roberto , Gelli Dilma Scala , Eduardo Maria Bernadete de Paula , Jakabi Miyoko
Published: September 2010

Botulism is a rare and potentially lethal illness caused by Clostridium botulinum neurotoxin. We describe the findings of a laboratorial investigation of 117 suspected cases of botulism reported to the surveillance system in Brazil from January 2000 to October 2008. Data on the number and type of samples analyzed, type of toxins identified, reporting of the number of botulism cases and transmission sources are discussed. A total of 193 clinical samples and 81 food samples were analyzed for detection and identification of the botulism neurotoxin. Among the clinical samples, 22 (11.4%) presented the toxin (nine type A, five type AB and eight with an unidentified type); in food samples, eight (9.9%) were positive for the toxin (five type A, one type AB and two with an unidentified type). Of the 38 cases of suspected botulism in Brazil, 27 were confirmed by a mouse bioassay. Laboratorial botulism diagnosis is an important procedure to elucidate cases, especially food-borne botulism, to confirm clinical diagnosis and to identify toxins in food, helping sanitary control measures.
Deciduous Premolars of Paleocene Litopterns of São José De Itaboraí Basin, Rio De Janeiro, Brasil
Authors: Bergqvist Lílian Paglarelli
Published: September 2010

The order Litopterna is represented in the São José de Itaboraí basin by four species belonging to the families Protolipternidae (Protolipterna ellipsodontoides, Miguelsoria parayirunhorandAsmithwoodwardia scotti) and Proterotheriidae (Paranisolambda prodromus). Only the deciduous teeth ofP. prodromusare known so far. Isolated milk premolars are described forP. ellipsodontoidesandM. parayirunhor.The known specimens assigned toP. prodromusare redescribed. No milk teeth are known forA. scotti.The upper and lower milk teeth of Protolipternidae, especially dP3, are more molarized than their successors, resembling, in several features later Proterotheriidae. They provide new support for the placement of this family within the order Litopterna. The analysis of the wear level of dp2-4/dP2-4 and X-ray images of the lower jaw ofP. prodromussuggests that the second teeth of the premolar series, in upper and lower jaw, are retained milk premolars. Some information on tooth replacement pattern ofP. ellipsodontoidesandP. prodromusare also provided.
Early Evolution of Phyllocarid Arthropods: Phylogeny and Systematics of Cambrian-Devonian Archaeostracans
Authors: Collette Joseph H. , Hagadorn James W.
Published: September 2010

A phylogenetic analysis and review of Paleozoic phyllocarid systematics is presented using morphology-based characters from Cambrian to modern taxa. The resulting cladograms of the Phyllocarida suggest that the suborder Ceratiocaridina as traditionally defined (families Ceratiocarididae and Caryocarididae) is paraphyletic. Caryocarididae is subsequently elevated to subordinal rank with the erection of Caryocaridina n. suborder, resulting in two monophyletic suborders.Haplocarisn. gen. is erected to contain Caryocarididae taxa without triangular spine-like projections of the anterior telson margin. Emended diagnoses, quantified with morphometrics where appropriate, are integrated into this analysis, and result in synonymy of many Cambrian—Silurian caryocaridids and ceratiocaridids with pre-existing taxa. Two representatives of the Leptostraca are included in this analysis. A visual key of well-established representatives of the Ceratiocaridina is presented and suggestions are offered that will help to improve the long-term stability of the Archaeostraca.
A New Early Campanian Rudist Fauna from San Luis Potosi in Mexico and Its Taxonomic and Stratigraphic Significance
Authors: Pons Jose Maria , Vicens Enric , Pichardo Yolanda , Aguilar Javier , Oviedo Angélica , Alencaster Gloria , García-Barrera Pedro
Published: September 2010

A rudist fauna composed of the radiolitids Potosites tristantorresi new genus, new species and Radiolites acutocostata (Adkins), the hippuritids Barrettia cf. ruseae Chubb, Torreites sanchezi (Douvillé), and Vaccinites vermunti Mac Gillavry, plagioptychids, and antillocaprinids is described from a rudist limestone succession in the central Mexican State of San Luis Potosí. The previously known species, one radiolitid from Texas and three hippuritids from the Caribbean Biogeographic Province, indicate the early Campanian. The new genus is a large radiolitid with a coiled and canaliculated left valve. New observations on R. acutocostata and V. vermunti shell morphology and variability are provided. Observations made on well preserved specimens of the latter species clarify the outer shell layer structure of the hippuritids right valve and has taxonomic implications. This is the first report of genus Torreites in Mexico and one of the northernmost records of genus Barrettia, already reported in southern Mexico from Chiapas State. This rudist limestone succession (informally ‘Temazcal limestones’ herein) is an easy-to-recognize cartographical unit; up to now it and Santonian and Turonian units have been mapped as the El Abra Formation in most available geological maps. Recognition of the successive carbonate platform intervals, between El Abra and Cardenas formations, improves the geological mapping and the understanding of the Mexican Gulf western margin evolution during the Late Cretaceous.
A New Species ofProtamphisopusNicholls (Crustacea, Isopoda, Phreatoicidea) from Middle Triassic Luoping Fauna of Yunnan Province, China
Authors: Fu Wan-Lu , Wilson George D. F. , Jiang Da-Yong , Sun Yuan-Lin , Hao Wei-Cheng , Sun Zuo-Yu
Published: September 2010

Fossil isopod crustaceans in the suborder Phreatoicidea have a known stratigraphic range from the Carboniferous to the Jurassic. Until now, all Mesozoic records of this group were thought to occur in fresh water habitats. A new phreatoicidean isopod fossil of the Triassic Luoping marine fauna, Yunnan Province, China, is described. The new species, based on several exceptionally complete specimens, is assigned to the genusProtamphisopusNicholls and the family Amphisopidae Nicholls. This Chinese record is the first report of a Mesozoic-age phreatoicidean isopod outside of Gondwanan terranes, requiring a revision of known biogeographic patterns of the Phreatoicidea. Whether this record is from a marine habitat or is the result of a secondary deposition is not certain.SottyellaRacheboef, Schram and Vidal from the Carboniferous (Stephanian) Lagerstätte of Montceaules-Mines that was assigned to this suborder may be a decapod. Therefore, it has no relationship to this new species.
Role of PTPRJ genotype in papillary thyroid carcinoma risk
Authors: Iuliano Rodolfo , Palmieri Dario , He Huiling , Iervolino Angela , Borbone Eleonora , Pallante Pierlorenzo , Cianflone Alessandra , Nagy Rebecca , Alder Hansjuerg , Calin George A , Trapasso Francesco , Giordano Carla , Croce Carlo M , de la Chapelle Albert , Fusco Alfredo
Published: September 2010

The strong genetic predisposition to papillary thyroid carcinoma (PTC) might be due to a combination of low-penetrance susceptibility variants. Thus, the research into gene variants involved in the increase of susceptibility to PTC is a relevant field of investigation. The gene coding for the receptor-type tyrosine phosphatase PTPRJ has been proposed as a cancer susceptibility gene, and its role as a tumor suppressor gene is well established in thyroid carcinogenesis. In this study, we want to ascertain the role of PTPRJ genotype in the risk for PTC. We performed a case–control study in which we determined the PTPRJ genotype for the non-synonymous Gln276Pro and Asp872Glu polymorphisms by PCR amplification and sequencing. We calculated allele and genotype frequencies for the considered polymorphisms of PTPRJ in a total sample of 299 cases (PTC patients) and 339 controls (healthy subjects) selected from Caucasian populations. We observed a significantly higher frequency of homozygotes for the Asp872 allele in the group of PTC patients than in the control group (odds ratio=1.61, 95% confidence interval 1.15–2.25, P=0.0053). We observed a non-significant increased frequency of homozygotes for Gln276Pro polymorphism in PTC cases in two distinct Caucasian populations. Therefore, the results reported here show that the homozygous genotype for Asp872 of PTPRJ is associated with an increased risk to develop PTC.