bluuebunny/crossref_metadata_2025 huggingface dataset:
Age-associated changes in expression of small, noncoding RNAs, including microRNAs, in C. elegans
Authors: Kato Masaomi , Chen Xiaowei , Inukai Sachi , Zhao Hongyu , Slack Frank J.
Published: August 2011

Small, noncoding RNAs (sncRNAs), including microRNAs (miRNAs), impact diverse biological events through the control of gene expression and genome stability. However, the role of these sncRNAs in aging remains largely unknown. To understand the contribution of sncRNAs to the aging process, we performed small RNA profiling by deep-sequencing over the course of Caenorhabditis elegans (C. elegans) aging. Many small RNAs, including a significant number of miRNAs, change their expression during aging in C. elegans. Further studies of miRNA expression changes under conditions that modify lifespan demonstrate the tight control of their expression during aging. Adult-specific loss of argonaute-like gene-1 (alg-1) activity, which is necessary for miRNA maturation and function, resulted in an abnormal lifespan, suggesting that miRNAs are, indeed, required in adulthood for normal aging. miRNA target prediction algorithms combined with transcriptome data and pathway enrichment analysis revealed likely targets of these age-associated miRNAs with known roles in aging, such as mitochondrial metabolism. Furthermore, a computational analysis of our deep-sequencing data identified additional age-associated sncRNAs, including miRNA star strands, novel miRNA candidates, and endo-siRNA sequences. We also show an increase of specific transfer RNA (tRNA) fragments during aging, which are known to be induced in response to stress in several organisms. This study suggests that sncRNAs including miRNAs contribute to lifespan regulation in C. elegans, and indicates new connections between aging, stress responses, and the small RNA world.
Maintenance Immunosuppression with Intermittent Intravenous IL-2 Receptor Antibody Therapy in Renal Transplant Recipients
Authors: Gabardi Steven , Catella Jennifer , Martin Spencer T , Perrone Ronald , Chandraker Anil , Magee Colm C , McDevitt-Potter Lisa M
Published: August 2011

Objective:

To report what we believe to be the first 2 cases of long-term (>24 months) intermittent intravenous interleukin-2 receptor antibody (IL-2RA) therapy for maintenance immunosuppression following renal transplantation.

Case Summary:

The first patient is a 52-year-old female with a history of intolerance to calcineurin inhibitors (CNIs) and sirolimus. Following her second transplant, the patient received mycophenolate mofetil 100 mg twice daily, a tapering corticosteroid regimen (initial dose of methylprednisoIona 500 mg tapered over 1 week to prednisone 30 mg/day), and biweekly intravenous daclizumab 1-1.2 mg/kg/dose; 33 months after transplant the IL-2RA was changed to intravenous basiliximab 40 mg once a month. At 40 months after transplant, the patient continued to have stable renal function (estimated glomerular filtration rate 48 mL/min/1.73 m2) with excellent tolerability. The second patient is a 59-year-old female also intolerant to CNIs and sirolimus who required intermittent maintenance therapy with intravenous basiliximab 20 mg/dose. Despite an initial rejection episode, the patient tolerated more than 2 years of basiliximab therapy with good renal function (estimated glomerular filtration rate 103 months after transplant 69 mL/min/1.73 m2) and no adverse events.

Discussion:

The IL-2RAs basiliximab and daclizumab possess several characteristics of ideal maintenance immunosuppressive agents (ie, nondepleting long half-lives, limited adverse events). Based on a MEDLINE search (through December 31, 2010) using the search terms basiliximab, daclizumab, organ transplant, immunosuppression, and/or maintenance immunosuppression, and an advanced search in the published abstracts from the American Transplant Congress and World Transplant Congress (2000-2010), it appears that IL-2RAS have been used successfully as short-term therapy in both renal and extrarenal transplant recipients to allow for renal recovery following CNI-induced nephrotoxicity. In heart transplant recipients, the IL-2RAs have been used for <24 months as maintenance immunosuppression in patients intolerant of CNIs or sirolimus.

Conclusions:

To the best of our knowledge, these 2 cases are the first to demonstrate that IL-2RAs can be used as an alternative to a CNI in a de novo immunosuppressive regimen. Also, this is the first report to illustrate successful long-term use of IL-2RAS in renal transplant recipients. This alternative approach was well tolerated by our patients, with no apparent adverse events. Although the efficacy of such regimens cannot be determined with 2 case reports, the fact that intermittent intravenous IL-2RA administration was successfully accomplished in these patients provides impetus to evaluate this treatment modality in prospective studies.
A series of tetranuclear [2 × 2] grid complexes derived from an asymmetric ligand: Structural differences based on metal ion affinities
Authors: Shiga Takuya , Noguchi Mao , Matsumoto Takuto , Sato Hiroki , Tahira Hirotaka , Newton Graham N. , Oshio Hiroki
Published: August 2011

A series of tetranuclear grid-type complexes were prepared by the reaction of the asymmetric multidentate ligand HL (HL = 2-[3-(2-hydroxyphenyl)-1H-pyrazol-5-yl]-6-pyridine carboxylic acid ethylester) with different metal sources. The tetranuclear copper complex, [Cu4(L1)4(NO3)4(H2O)4]·Et2O·2MeOH (1, HL1 = 2-[3-(2-hydroxyphenyl)-1H-pyrazol-5-yl]-6-pyridine carboxylic acid methyl ester) consists of four ligands, four copper ions, four nitrate ions and four water molecules, forming a [2 × 2] grid structure, in which all four copper ions have the same coordination environment. On the other hand, the corresponding nickel and cobalt complexes, [M4(L2)4(H2O)4]·4MeOH·6H2O (M = Ni (2) and Co (3), (H2L2 = 6-[1,3-dioxo-3-(2-phenyl)propionyl]pyridine-2-carboxylic acid)), have a similar grid core structure to the copper complex with four metal ions, four ligand molecules, and four water molecules, however, in these clusters there are two kinds of coordination site for the metal ions. Temperature-dependent magnetic susceptibility measurements for all complexes demonstrated that antiferromagnetic interactions between the metal ions were in operation. The magnetic susceptibility data of the copper and nickel complexes were analyzed using a tetranuclear model based on H = –2J(S1S2+S2S3+S3S4+S4S1) to give best-fit parameters of g = 2.11(1), J = –1.39(3) cm–1 and g = 2.19(1), J = –0.44(2) cm–1, respectively.
Changing paradigm for drug development: A case study of natural products
Authors:   Atta-ur-Rahman, Choudhary M. Iqbal , Khan Naik Tameen
Published: August 2011

Natural products have been a rich source of lead identification for drug discovery and development. Over the last two decades, the impetus for natural product-based lead discovery in pharmaceutical industry has declined, resulting in a productivity and innovation crisis. Most of the focus is now on high-throughput screening of synthetic libraries of compounds against defined biological targets; however, discovery of new molecular entities (NMEs) is still declining in this postgenomic era. With the availability of modern purification, characterization, and yield optimization techniques, and with an established intellectual property rights (IPR) regime, it is now possible to circumvent the problems once associated with natural product-based drug discovery. Our work demonstrates that natural products can lead to cost-effective identification of lead molecules against a defined molecular target. During our recent studies, novel classes of urease and α-glucosidase inhibitors were initially obtained from medicinal plants, and based on these novel structural leads, synthetic libraries of structural analogues were synthesized for structure–activity relationship (SAR) studies. These synthetic analogues have shown potent inhibitory activities against the target enzymes, and their mechanisms of action were studied by kinetic, computational, and NMR-based methods.
A Poem of Philes to Makarios Chrysokephalos? The Case of Poem Florentinus 58
Authors: Bazzani Marina
Published: August 2011

Manuel Philes dedicated countless occasional poems to his many benefactors to praise their qualities and ask for all sorts of assistance, both spiritual and material. This article analyses one of these compositions, namely poem Flor. 58, and offers a commentary of its language and content. On the basis of the imagery, repetitions and allusions present in the text, it is argued that this untitled poem was in fact dedicated to the scholar and metropolitan of Philadelphia Makarios Chrysokephalos to request the gift of a hat. The detailed reading of the text aims at showing the presence of several layers of meaning which characterise the whole poem, as well as illustrating Philes' sophisticated poetic technique.
ProcopiusDe aedificiis4.2.1–22 on the Thermopylae Frontier
Authors: Cherf William J.
Published: August 2011

This article compares topographical and archaeological remains of the Thermopylae frontier with the ancient testimonia of the sixth century historian Procopius of Caesareia (De aedificiis4.2.1.–22). It was revealed that: many of the frontier fortifications described were initially built before the sixth century; the fortified κλεισούρα mentioned should be equated with the Dhéma Pass; and the commercial settlement of Myropóles is best identified with the modern village of Káto Dhió Vouná. Written in Attic prose, this passage represents a rhetorical exercise, the climax of which turned not on the ancient battlefield of Thermopylae, but rather on a mountain pass and it's highway that neutralized the Thermopylae defenses if they were ever controlled by the enemy. We were told that only the Emperor Justinian's wisdom could grasp this critical fact. Additionally, Procopius employed many rhetorical devices in this narrative: τóπος, χρóνος,, ἄγαλμα, ἔκφρασις, πανηγρικóς and employed imperial propaganda, praise, and exaggeration as well. In short, the passage is a classic example of selective story telling that may have found its inspiration in the Hunnic raid of 539/540 and the Herodotean account of the Persian invasion of 480 BC. While Procopius' account remains our best topographical description of the late antique Thermopylae frontier, one can only say that more archaeological questions were left unanswered than were resolved. In short, as an archaeological source, theDe aedificiisis a disappointing and vexing resource filled with equivocations. Finally, one may doubt that Procopius ever did visit the Thermopylae frontier, even though during his career he certainly had ample opportunity to do so. His account, therefore, must have been based upon secondary sources, whether imperial archival material, itineraries, or military staff reports and were not the result of personal autopsy.
Theophanes Continuatus VI and De Cerimoniis
Authors: Featherstone Jeffrey Michael
Published: August 2011

Though parts of the text traditionally called Theophanes Continuatus go back to the time of Constantine VII, it is in fact a compilation of various texts put together by a later redactor in the reign of Nicephorus Phokas. Likewise, the original parts of text known as the De Cerimoniis were produced in the reign of Constantine, but the text has come down to us in a later redaction, apparently also from the time of Phokas. In the case of the De Cerimoniis, the final redactor has been identified as Basil the parakoimomenos, the bastard son of Romanus I Lecapenus. Similar interests and coincidences of composition in the two texts, particularly in Book VI of Theophanes Continuatus and chapter I, 96 of the De Cerimoniis, suggest that the compiling of Theophanes Continuatus was also the work of Basil.
The TermKandaulos/Kandylosin theLexiconof Photius and theCommentarii ad Homeri Iliademof Eustathius of Thessalonica
Authors: Kokoszko Maciej , Gibel-Buszewska Katarzyna
Published: August 2011

The present article analyzes Photius'Lexiconand Eustathius of Thessalonica'sCommentarii ad Homeri Iliademin order to trace the history and reconstruct the recipe of a dish called kandaulos/kandylos. It was a Greek delicacy, which appears to have been developed in Lydia before the middle of the VI th c. B.C. It is known to have been named after king Candaules, who ruled the Lydian territory in the VII th c. B.C. The dish was (via the Ionians) borrowed by the Helens and established itself in Greece sometime in the V th c. B.C. It became popular in the Hellenistic period

The testimony provided by Photius and Eustathius of Thessalonica contributes to our better knowledge of two varieties ofkandaulos/kandylos. The first was savoury and consisted of cooked meat, stock, Phrygian cheese, breadcrumbs and dill (or fennel). The other included milk, animal fat, cheese and honey. The dish is reported to have been costly, prestigious and indicated the social status of those who would eat it.

Though there is much evidence suggesting its popularity in antiquity, we lack any solid proof thatkandaulos/kandyloswas eaten in Byzantine times. On the other hand, Byzantine authors preserved the most detailed literary data on the delicacy.
A Rhetorical Declamation of Sophonias the Monk and Paraphrast
Authors: Searby Denis M. , Sjörs Ambjörn
Published: August 2011

Codex Marcianus Graecus 266 contains a declamation in the character of Paul speaking before the Athenian Areopagus that is attributed to the learned monk Sophonias. This previously unpublished text is valuable both as an example of late Byzantine rhetoric and as additional testimony to the Sophonias known through historical sources to have acted as a representative of Emperor Andronikos II Palaeologos and to whom a paraphrase of Aristotelian works is attributed. The text is introduced, edited and translated for the first time.
Ein Griechischer Doppelvers Sulṭān Walads Neu Gelesen
Authors: Theodoridis Dimitri
Published: August 2011

The Greek poetry of Sulṭān Walad poses two main problems for Greek philology: the fact that the texts were written and passed on in Arabic writing, and that they were composed in the perished colloquial Greek of the city Ikonion/ Konya (13th / 14th centuries). A final edition of these poems therefore requires a stepwose approach regarding reading and interpretation of these trxts.

The article attempts to reconstruct a double verse by Sulṭān Walad and to interpret it with the help of ist Islamic background.
Extracellular Signal-Regulated Kinase Signaling in the Ventral Tegmental Area Mediates Cocaine-Induced Synaptic Plasticity and Rewarding Effects
Authors: Pan Bin , Zhong Peng , Sun Dalong , Liu Qing-song
Published: August 2011

Drugs of abuse such as cocaine induce long-term synaptic plasticity in the reward circuitry, which underlies the formation of drug-associated memories and addictive behavior. We reported previously that repeated cocaine exposurein vivofacilitates long-term potentiation (LTP) in dopamine neurons of the ventral tegmental area (VTA) by reducing the strength of GABAergic inhibition and that endocannabinoid-dependent long-term depression at inhibitory synapses (I-LTD) constitutes a mechanism for cocaine-induced reduction of GABAergic inhibition. The present study investigated the downstream signaling mechanisms and functional consequences of I-LTD in the VTA in the rat. Extracellular signal-regulated kinase (ERK) signaling has been implicated in long-term synaptic plasticity, associative learning, and drug addiction. We tested the hypothesis that VTA ERK activity is required for I-LTD and cocaine-induced long-term synaptic plasticity and behavioral effects. We show that the activation of receptors required for I-LTD increased ERK1/2 phosphorylation and inhibitors of ERK activation blocked I-LTD. We further demonstrate that ERK mediates cocaine-induced reduction of GABAergic inhibition and facilitation of LTP induction. Finally, we show that cocaine conditioned place preference (CPP) training (15 mg/kg; four pairings) increased ERK1/2 phosphorylation in the VTA, while bilateral intra-VTA injections of a CB1antagonist or an inhibitor of ERK activation attenuated ERK1/2 phosphorylation and the acquisition, but not the expression, of CPP to cocaine. Our study has identified the CB1and ERK signaling cascade as a key mediator of several forms of cocaine-induced synaptic plasticity and provided evidence linking long-term synaptic plasticity in the VTA to rewarding effects of cocaine.
Mirror-Image Sensitivity and Invariance in Object and Scene Processing Pathways
Authors: Dilks Daniel D. , Julian Joshua B. , Kubilius Jonas , Spelke Elizabeth S. , Kanwisher Nancy
Published: August 2011

Electrophysiological and behavioral studies in many species have demonstrated mirror-image confusion for objects, perhaps because many objects are vertically symmetric (e.g., a cup is the same cup when seen in left or right profile). In contrast, the navigability of a scene changes when it is mirror reversed, and behavioral studies reveal high sensitivity to this change. Thus, we predicted that representations in object-selective cortex will be unaffected by mirror reversals, whereas representations in scene-selective cortex will be sensitive to such reversals. To test this hypothesis, we ran an event-related functional magnetic resonance imaging adaptation experiment in human adults. Consistent with our prediction, we found tolerance to mirror reversals in one object-selective region, the posterior fusiform sulcus, and a strong sensitivity to these reversals in two scene-selective regions, the transverse occipital sulcus and the retrosplenial complex. However, a more posterior object-selective region, the lateral occipital sulcus, showed sensitivity to mirror reversals, suggesting that the sense information that distinguishes mirror images is represented at earlier stages in the object-processing hierarchy. Moreover, one scene-selective region (the parahippocampal place area or PPA) was tolerant to mirror reversals. This last finding challenges the hypothesis that the PPA is involved in navigation and reorientation and suggests instead that scenes, like objects, are processed by distinct pathways guiding recognition and action.
The Importance of Having Arc: Expression of the Immediate-Early Gene Arc Is Required for Hippocampus-Dependent Fear Conditioning and Blocked by NMDA Receptor Antagonism
Authors: Czerniawski Jennifer , Ree Fredrick , Chia Chester , Ramamoorthi Kartik , Kumata Yayoi , Otto Timothy A.
Published: August 2011

Long-lasting, experience-dependent changes in synaptic strength are widely thought to underlie the formation of memories. Many forms of learning-related plasticity are likely mediated by NMDA receptor activation and plasticity-related gene expression in brain areas thought to be important for learning and memory, including the hippocampus. Here, we examined the putative role of activity-regulated cytoskeletal-associated protein (Arc), an immediate-early gene (IEG) whose expression is tightly linked to the induction and maintenance of some forms of neuronal plasticity, in hippocampus-dependent and hippocampus-independent forms of learning. The extent to which learning-induced Arc expression may depend on NMDA receptor activation was also assessed. First, we observed an increase in Arc gene and protein products in both dorsal hippocampus (DH) and ventral hippocampus (VH) of male Sprague Dawley rats after hippocampus-dependent trace and contextual fear conditioning, but not after hippocampus-independent delay fear conditioning. Specific knockdown of Arc using antisense oligodeoxynucleotides (ODNs) in DH or VH attenuated the learning-related expression of Arc protein, and resulted in a dramatic impairment in trace and contextual, but not delay, fear conditioning. Finally, pretraining infusions of the NMDA receptor antagonist APV into the DH or VH blocked the learning-induced enhancement of Arc in a regionally selective manner, suggesting that NMDA receptor activation and Arc translation are functionally coupled to support hippocampus-dependent memory for fear conditioning. Collectively these results provide the first evidence suggesting that NMDA receptor-dependent expression of the IEG Arc in both DH and VH likely underlies the consolidation of a variety of forms of hippocampus-dependent learning.
Role of Drp1, a Key Mitochondrial Fission Protein, in Neuropathic Pain
Authors: Ferrari Luiz F. , Chum Adrienne , Bogen Oliver , Reichling David B. , Levine Jon D.
Published: August 2011

While oxidative stress has been implicated in small-fiber painful peripheral neuropathies, antioxidants are only partially effective to treat patients. We have tested the hypothesis that Drp1 (dynamin-related protein 1), a GTPase that catalyzes the process of mitochondrial fission, which is a mechanism central for the effect and production of reactive oxygen species (ROS), plays a central role in these neuropathic pain syndromes. Intrathecal administration of oligodeoxynucleotide antisense against Drp1 produced a decrease in its expression in peripheral nerve and markedly attenuated neuropathic mechanical hyperalgesia caused by HIV/AIDS antiretroviral [ddC (2′,3′-dideoxycytidine)] and anticancer (oxaliplatin) chemotherapy in male Sprague Dawley rats. To confirm the role of Drp1 in these models of neuropathic pain, as well as to demonstrate its contribution at the site of sensory transduction, we injected a highly selective Drp1 inhibitor, mdivi-1, at the site of nociceptive testing on the dorsum of the rat's hindpaw. mdivi-1 attenuated both forms of neuropathic pain. To evaluate the role of Drp1 in hyperalgesia induced by ROS, we demonstrated that intradermal hydrogen peroxide produced dose-dependent hyperalgesia that was inhibited by mdivi-1. Finally, mechanical hyperalgesia induced by diverse pronociceptive mediators involved in inflammatory and neuropathic pain—tumor necrosis factor α, glial-derived neurotrophic factor, and nitric oxide—was also inhibited by mdivi-1. These studies provide support for a substantial role of mitochondrial fission in preclinical models of inflammatory and neuropathic pain.
Arrangement of Subunits in Functional NMDA Receptors
Authors: Salussolia Catherine L. , Prodromou Michael L. , Borker Priya , Wollmuth Lonnie P.
Published: August 2011

Ionotropic glutamate receptors (iGluRs), including the NMDA receptor subtype, are ligand-gated ion channels critical to fast signaling in the CNS. NMDA receptors are obligate heterotetramers composed of two GluN1 and typically two GluN2 subunits. However, the arrangement of GluN subunits in functional receptors—whether like subunits are adjacent to (N1/N1/N2/N2) or diagonal to (N1/N2/N1/N2) one another—remains unclear. Recently, a crystal structure of a homomeric AMPA receptor revealed that the four identical subunits adopt two distinct and subunit-specific conformations termed A/C and B/D with subunits of like conformations (e.g., A/C) diagonal to one another. In the structure, the two conformers were notable at the level of the linkers (S1–M1, M3–S2, and S2–M4) that join the ligand-binding domain to the transmembrane ion channel with the M3–S2 linker positioned more proximal to the central axis of the channel pore in the A/C conformation and S2–M4 more proximal in the B/D conformation. Using immunoblots and functional assays, we show that introduced cysteines in the M3/M3–S2 linker of GluN1, but not GluN2, show dimer formation and oxidation-induced changes in current amplitudes predictive of the A/C conformation. Conversely, introduced cysteines in the S2–M4 linker of GluN2, but not GluN1, showed similar functional effects, suggesting that the GluN2 subunit adopts the B/D conformation. Thus, we show that NMDA receptors, like AMPA receptors, possess distinct subunit-specific conformations with GluN1 approximating the A/C and GluN2 the B/D conformation. GluN subunits are therefore positioned in a N1/N2/N1/N2 arrangement in functional NMDA receptors.
Characterizing the Spontaneous Blink Generator: An Animal Model
Authors: Kaminer Jaime , Powers Alice S. , Horn Kyle G. , Hui Channing , Evinger Craig
Published: August 2011

Although spontaneous blinking is one of the most frequent human movements, little is known about its neural basis. We developed a rat model of spontaneous blinking to identify and better characterize the spontaneous blink generator. We monitored spontaneous blinking for 55 min periods in normal conditions and after the induction of mild dry eye or dopaminergic drug challenges. The normal spontaneous blink rate was 5.3 ± 0.3 blinks/min. Dry eye or 1 mg/kg apomorphine significantly increased and 0.1 mg/kg haloperidol significantly decreased the blink rate. Additional analyses revealed a consistent temporal organization to spontaneous blinking with a median 750 s period that was independent of the spontaneous blink rate. Dry eye and dopaminergic challenges significantly modified the regularity of the normal pattern of episodes of frequent blinking interspersed with intervals having few blinks. Dry eye and apomorphine enhanced the regularity of this pattern, whereas haloperidol reduced its regularity. The simplest explanation for our data is that the spinal trigeminal complex is a critical element in the generation of spontaneous blinks, incorporating reflex blinks from dry eye and indirect basal ganglia inputs into the blink generator. Although human subjects exhibited a higher average blink rate (17.6 ± 2.4) than rats, the temporal pattern of spontaneous blinking was qualitatively similar for both species. These data demonstrate that rats are an appropriate model for investigating the neural basis of human spontaneous blinking and suggest that the spinal trigeminal complex is a major element in the spontaneous blink generator.
Progranulin Deficiency Decreases Gross Neural Connectivity But Enhances Transmission at Individual Synapses
Authors: Tapia Lucia , Milnerwood Austen , Guo Aobo , Mills Fergil , Yoshida Eileen , Vasuta Cristina , Mackenzie Ian R. , Raymond Lynn , Cynader Max , Jia William , Bamji Shernaz X.
Published: August 2011

Frontotemporal dementia (FTD) has been linked to mutations in the progranulin gene (GRN) that lead to progranulin (PGRN) haploinsufficiency. Thus far, our understanding of the effects of PGRN depletion in the brain has been derived from investigation of gross pathology, and more detailed analyses of cellular function have been lacking. We report that knocking down PGRN levels in rat primary hippocampal cultures reduces neural connectivity by decreasing neuronal arborization and length as well as synapse density. Despite this, the number of synaptic vesicles per synapse and the frequency of mEPSCs are increased in PGRN knockdown cells, suggesting an increase in the probability of release at remaining synapses. Interestingly, we demonstrate that the number of vesicles per synapse is also increased in postmortem brain sections from FTD patients with PGRN haploinsufficiency, relative to controls. Our observations show that PGRN knockdown severely alters neuronal connectivityin vitroand that the synaptic vesicle phenotype observed in culture is consistent with that observed in the hippocampus of FTD patients.
Suppression of a Neocortical Potassium Channel Activity by Intracellular Amyloid-β and Its Rescue with Homer1a
Authors: Yamamoto Kenji , Ueta Yoshifumi , Wang Li , Yamamoto Ryo , Inoue Naoko , Inokuchi Kaoru , Aiba Atsu , Yonekura Hideto , Kato Nobuo
Published: August 2011

It is proposed that intracellular amyloid-β (Aβ), before extracellular plaque formation, triggers cognitive deficits in Alzheimer disease (AD). Here we report how intracellular Aβ affects neuronal properties. This was done by injecting Aβ protein into rat and mouse neocortical pyramidal cells through whole-cell patch pipettes and by using 3xTg AD model mice, in which intracellular Aβ is accumulated innately. In rats, intracellular application of a mixed Aβ1-42preparation containing both oligomers and monomers, but not a monomeric preparation of Aβ1-40, broadened spike width and augmented Ca2+influx via voltage-dependent Ca2+channels in neocortical neurons. Both effects were mimicked and occluded by charybdotoxin, a blocker of large-conductance Ca2+-activated K+(BK) channels, and blocked by isopimaric acid, a BK channel opener. Surprisingly, augmented Ca2+influx was caused by elongated spike duration, but not attributable to direct Ca2+channel modulation by Aβ1-42. The Aβ1-42-induced spike broadening was blocked by electroconvulsive shock (ECS), which we previously showed to facilitate BK channel opening via expression of the scaffold protein Homer1a. In young 3xTg and wild mice, we confirmed spike broadening by Aβ1-42, which was again mimicked and occluded by charybdotoxin and blocked by ECS. In Homer1a knock-out mice, ECS failed to block the Aβ1-42effect. Single-channel recording on BK channels supported these results. These findings suggest that the suppression of BK channels by intracellular Aβ1-42is a possible key mechanism for early dysfunction in the AD brain, which may be counteracted by activity-dependent expression of Homer1a.
Identification of somatostatin receptor type 5 gene polymorphisms associated with acromegaly
Authors: Ciganoka Darja , Balcere Inga , Kapa Ivo , Peculis Raitis , Valtere Andra , Nikitina-Zake Liene , Lase Ieva , Schiöth Helgi B , Pirags Valdis , Klovins Janis
Published: August 2011

Objective

The aim of this study was to characterize the genetic variance of somatostatin receptor 5 (SSTR5) and investigate the possible correlation of such variants with acromegaly risk and different disease characteristics.

Design and methods

The SSTR5 gene coding region and 2000 bp upstream region was sequenced in 48 patients with acromegaly and 96 control subjects. Further, three single nucleotide polymorphisms (SNPs) were analyzed in the same group of acromegaly patients and in an additional group of 475 age- and sex-matched controls.

Results

In total, 19 SNPs were identified in the SSTR5 gene locus by direct sequencing. Three SNPs (rs34037914, rs169068, and rs642249) were significantly associated with the presence of acromegaly using the initial controls. The allele frequencies were significantly (P<0.01) different between the acromegaly patients and the additional large control group. rs34037914 and rs642249 remained significantly associated with acromegaly after Bonferroni correction and permutation tests (odds ratio (OR)=3.38; 95% confidence interval (CI), 1.78–6.42; P=0.00016 and OR=2.41; 95% CI, 1.41–4.13; P=0.0014 respectively). Haplotype reconstruction revealed two possible risk haplotypes determined by rs34037914 (633T) and rs642249 (1044A) alleles. Both haplotypes were found in significantly higher frequency in acromegaly patients compared with controls (P<0.001). In addition, the 663T allele was significantly associated with a younger age of acromegaly diagnosis (unstandardized regression coefficient β=−10.4; P=0.002), increased body mass index (β=4.1; P=0.004), higher number of adenoma resection (P<0.001) and lack of observable tumor shrinkage after somatostatin analog treatment (P=0.014).

Conclusions

Our results demonstrate a previously undetected strong association of two SSTR5 SNPs with acromegaly. The data also suggest a possible involvement of SSTR5 variants in decreased suppression of GH production and increased tumor proliferation.
In silico and in vitro analysis of rare germline allelic variants of RET oncogene associated with medullary thyroid cancer
Authors: Cosci B , Vivaldi A , Romei C , Gemignani F , Landi S , Ciampi R , Tacito A , Molinaro E , Agate L , Bottici V , Cappagli V , Viola D , Piaggi P , Vitti P , Pinchera A , Elisei R
Published: August 2011

Germline and somaticREToncogene mutations are found in 98% hereditary and 40% sporadic medullary thyroid carcinomas. Our aim was to analyse byin silicoandin vitroassays the transforming activity of six rareRETmutations (T338I, V648I, M918V, A883T, S904F and M848T). Six knownRETmutations were used as controls. Thein silicoanalysis showed the highest score value (i.e. 65) for S904F, M848T, M918T and C634R, whereas L790F, G691S, T338I and V648I had 0 score. Intermediate score values were obtained by A883T (score=55), M918V, V804M and Y791F (score=15). Thein vitrofocus formation assay showed that cells transfected with S904F, M918T, M848T or C634R generated the largest number of focus formation units (FFU). Intermediate numbers of FFU were observed in cells transfected with M918V, V804M, Y791F or A883T, while cells transfected with L790F, G691S, T338I or V648I showed a number of FFU similar to control cells. A positive correlation between thein silicoscore andin vitroFFU was found (P=0.0005). Only cells transfected with M918T or C634R grew faster and generated higher number of colonies in soft agar than control cells. However, the cells that were transfected with V804M produced an intermediate number of colonies. In conclusion, two of the six rareRETmutations, S904F and M848T possessed a relatively high transforming activity but a low aggressiveness; the other four mutations T338I, V648I, M918V and A883T were low or non-transforming, and their ability to induce tumoural transformation might be related to particular genetic conditions.
Dynamic expression of bone morphogenetic protein 4 in reproductive organs of female mice
Authors: Tanwar Pradeep S , McFarlane James R
Published: August 2011

Various members of the bone morphogenetic protein (BMP) family have been shown to regulate mammalian follicular development by affecting granulosa cell proliferation and steroidogenesis.In situhybridization studies have shown expression of BMPR1A, BMPR1B, and BMPR2 in the granulosa cells and oocyte of most of the follicles in the ovary, suggesting that these cells have the capacity to respond to BMP signaling. Although much is known about BMP4 signaling, its expression pattern in the female reproductive tract (FRT) is still unclear. The objective of the current study was to characterize the expression of BMP4 and its downstream target proteins (pSMAD1/5/8) in the FRT. In the ovary, BMP4 protein was detected in all the stages of follicular development. Staining for pSMAD1/5/8 was observed in granulosa cells and oocytes of all the stages of follicular development including primordial follicles, suggesting that these follicles are responsive to autocrine/paracrine BMP signaling. In the uterus, BMP4 and pSMAD1/5/8 staining was observed in all three compartments and strongest expression was observed during the estrus phase. BMP4- and pSMAD1/5/8-specific staining was also observed in oviductal epithelium. Different forms (apparent MW: 50, 35, and 15 kDa) of BMP4 were detected in mouse ovary by western blot analysis. In conclusion, these results have defined BMP4 and pSMAD1/5/8 protein expression in the mouse FRT and highlighted the importance of BMP4 in folliculogenesis.
Forkhead transcription factors in ovarian function
Authors: Uhlenhaut Nina Henriette , Treier Mathias
Published: August 2011

Since the discovery of the conserved forkhead (Fkh) DNA binding domain more than 20 years ago, members of the Fkh or forkhead box (FOX) family of transcription factors have been shown to act as important regulators of numerous developmental and homeostatic processes. The human genome contains 44 Fkh genes, several of which have recently been reported to be essential for female fertility. In this review, we highlight the roles of specific FOX proteins in ovarian folliculogenesis and present our current understanding of their molecular function. In particular, we describe what we have learned from loss-of-function studies using mouse models as well as human genetics and illustrate how different stages of folliculogenesis, both in oocytes and in somatic granulosa and theca cells, are regulated by FOXC1, FOXL2, and FOXO subfamily members.
The potential role of ductoscopy in modern breast diagnostics and therapy
Authors: Mátrai Zoltán , Tóth László , Bidlek Mária , Szabó Éva , Farkas Emil , Sávolt Ákos , Góbor László , Bartal Alexandra , Kásler Miklós
Published: August 2011

Mammary ductoscopy is a modern, minimally invasive procedure that enables direct, in vivo observation of the mammary ductal system, primarily by nipple discharge. The rapidly developing device is suitable for aimed biopsy for further cytological or molecular examinations. High-tech equipments facilitate polypectomy or laser vaporization of certain intraluminal lesions, and play an important role in the direct surgical excision of the duct or the so-called terminal duct-lobular unit. The above listed facilitate the early diagnosis of malignancies even before imaging could detect them, and the control of high risk patients. Ductoscopy can foster surgical removal of ductal in situ tumors as anatomical units, thus enabling the optimization of radicality of breast conserving surgeries. Authors give a detailed description of the surgical techniques, and provide a wide review of the literature, for the first time in Hungarian language. Orv. Hetil., 2011, 152, 1284–1293.
Low vitamin D levels among patients at Semmelweis University: retrospective analysis during a one-year period
Authors: Vásárhelyi Barna , Sátori Anna , Olajos Ferenc , Szabó András , Bekő Gabriella
Published: August 2011

Even in developed countries the prevalence of subjects with suboptimal vitamin D levels is high. The aim of this retrospective data analysis was to evaluate the prevalence of severe and moderate vitamin D deficiencies (defined as vitamin D levels <15 ng/ml and 15–30 ng/ml, respectively) among patients evaluated at Semmelweis University during a period between April, 2009 and March, 2010. Methods and results: The average vitamin D level of 5808 subjects (3936 women and 1872 men) was 25.5 ± 10.9 ng/ml. The prevalence of moderate and severe vitamin D deficiency in whole population was 72% and 12%, respectively. Higher than normal vitamin D levels were measured in 0.8% of subjects. Female gender, older age and winter season were independent risk factors for vitamin D deficiency. Vitamin D levels were measured repeatedly in 1307 subjects. Interestingly, vitamin D levels measured later were lower compared to those measured at the first time (27.07±13.2 vs. 25.9±9.11 ng/ml, p < 0.001). The prevalence of severe and moderate vitamin D deficiency was 8.1 and 71.5 per cent when vitamin D levels were measured at the second time. Of the 110 patients with severe vitamin D deficiency measured repeatedly only 11 patients (10%) presented with normal vitamin D levels at the second time. Conclusions: These data indicate that severe and moderate vitamin D deficiencies are common in patients evaluated at Semmelweis University. Repeated measurements of vitamin D levels raise the notion that the efficacy of supplementation used for correction of vitamin D levels is not optimal. Orv. Hetil., 2011, 152, 1272–1277.
New Details on the Clefted Uvular Muscle: Analyzing Its Role at Histological Scale by Model-Based Deformation Analyses
Authors: Landes Constantin A. , Weichert Frank , Steinbauer Thomas , Schröder Andreas , Walczak Lars , Fritsch Helga , Wagner Mathias
Published: August 2011

Objective

As an initial step to a complex reconstruction model for virtual surgery, the present study was carried out to provide data on the prenatal cleft lip and palate uvular muscle in eight specimens.

Method

Serial sections of viscerocrania of 18 aborted embryos and fetuses were studied microscopically and segmented manually. Registration, three-dimensional reconstruction, and finite element analyses were conducted.

Results

Incompletely clefted uvulae showed anterior fusion and dorsal fission of the bilateral uvular muscle bodies. A complete cleft lip and palate specimen evidenced single bilateral uvular muscle bodies lying medially and orally below the cleft shelf, its central longitudinal fibers running beneath the oral-median mucosa. In incompletely clefted uvulae, 10% to 50% of circular peripheral fibers crossed the midline within the central third of the anterioposterior muscle, behind the levator loop. Of the fibers, 30% to 60% crossed to the ipsilateral palatopharyngeus muscle. Fibers inserted into the uvular basal membrane in a 60% nasal and 40% oral distribution at the middle third of the macroscopically clefted uvula. The macroscopic uvula itself consisted of loose connective tissue and salivary glands. Deformation analysis did disclose local stress, suggesting the uvular muscle contributes to velopharyngeal closure in normal anatomy and extends the cleft edges in cleft palate.

Conclusion

Cleft lip and palate reconstruction should reasonably use the uvular muscle to augment the velar midline bulk. Uvular muscle deformation calculation was successful, permitting functional insight on the basis of microanatomical specimens, so far a bigger complete velar model can be ventured.
Rheological behaviour of reconstituted pyroclastic debris flow
Authors: SCOTTO DI SANTOLO A. , PELLEGRINO A.M. , EVANGELISTA A. , COUSSOT P.
Published: August 2011

An experimental study of the rheological behaviour of three natural pyroclastic soils with different depositional processes remixed with water was carried out with the help of a rotational rheometer and inclined plane tests. A homogeneous fluid-like behaviour is obtained only within a very narrow range of concentrations, typically not more than 10%. Below this range the material sedimentates rapidly; above this range it behaves like a solid. In the fluid-like range the typical rheological behaviour of these suspensions is that of a yield stress fluid exhibiting a static yield stress larger than its dynamic yield stress. This effect probably finds its origin in a ‘local' sedimentation effect: that is, the particles sedimentate just as necessary to form a structure more jammed than the structure during flow. As a result the flow of such materials is usually unstable: they will start to flow beyond a critical stress, but just beyond this value will reach a high shear rate associated with a high flowing velocity. The static and dynamic yield stresses of these materials increase widely from very low to very large values (several orders of magnitude). Inclined-plane tests were shown to provide reasonable although still approximate values for the static and dynamic yield stresses. These results suggest that in the field a small change in solid fraction will cause a slight decrease of the static yield stress, readily inducing a rapid flow that will stop only when the dynamic yield stress is reached, namely on a much smoother slope. This can explain the in situ observed post-failure behaviour of pyroclastic debris flows, which are able to flow over very long distances, even on smooth slopes.
Designing a Peanut Ideotype for a Target Environment Using the CSM‐CROPGRO‐Peanut Model
Authors: Suriharn B. , Patanothai A. , Boote K. J. , Hoogenboom Gerrit
Published: August 2011

Crop simulation models have potential for evaluating the effects of plant traits leading to the design of a crop ideotype for a target environment. The objective of this study was to design a large‐seeded and a small‐seeded peanut (Arachis hypogaea L.) ideotype for Thailand using the cropping system model (CSM)‐CROPGRO‐Peanut model. The sensitivity analysis was performed, utilizing the cultivar coefficients of a large‐seeded line (L‐line) and a small‐seeded peanut line (S‐line) as initial values, by changing the value of each coefficient for consecutive runs of model simulation over 10 locations for three growing seasons and 30 yr. The durations of the developmental phases were adjusted first to maximize seed yield within a fixed life cycle duration. Then the growth and the partitioning parameters were adjusted to maximize biomass and seed yield, respectively. The final outcomes were the designed peanut ideotypes with the following characteristics: early flowering, long duration from beginning seed to maturity and from first flower to end of leaf expansion, large leaf size, high specific leaf area, high leaf photosynthetic rate, high partitioning of assimilates to pods and seeds, more determinate growth habit, and moderately long seed filling duration. Seed yield improvements of 4.03 and 52.91% were achieved over the L‐ and S‐lines, respectively. This study demonstrates the capability of the CSM‐CROPGRO‐Peanut model for evaluating the effects of different genetic traits and for designing a crop ideotype for a target environment.
Estimated N2–Fixation of Cool‐Season Annual Clovers by the Difference Method
Authors: Evers G. W. , Parsons M. J.
Published: August 2011

Information on the N2–fixation (NF) capacity of cool‐season annual clovers in the southeastern United States is lacking. Estimates of NF were determined on arrowleaf (Trifolium vesiculosum Savi), crimson (Trifolium incarnatum L.), rose (Trifolium hirtum All.), and subterranean (Trifolium subterraneum L.) clovers using the difference in N accumulation of the clovers and annual ryegrass (Lolium multiflorum Lam.) as the nonfixing plant at 2‐wk intervals for 2 yr. Initial estimates of NF were negative because N accumulation in ryegrass exceeded that in clovers. The general trend was for NF and percent plant N from NF to increase as dry matter (DM) yield increased. Percentage of plant N fixed from the atmosphere exceeded 75% for all clover species at some point in spring. The 2 yr average maximum NF values using herbage mass (HM) were 296 kg N ha−1 for arrowleaf clover, 189 kg N ha−1 for crimson clover, 215 kg N ha−1 for rose clover, and 192 kg n ha−1 for subterranean clover. Using HM plus roots increased maximum NF values from 4 to 12 kg N ha−1. The root NF contribution was greatest during the winter after NF values turned positive ranging from 8 to 83% of plant NF. Then they decreased with plant maturity from 1 to 9% of total plant NF. Crimson clover had the greatest NF values until mid March after which the later‐maturing arrowleaf clover had the greatest NF value.
Relationship between Herbage Intake and Sward Structure of Grazed Temperate Grasses
Authors: Brink Geoffrey E. , Soder Kathy J.
Published: August 2011

Temperate grasses differ in sward structure, which may influence herbage intake of grazing cattle. We compared herbage intake of meadow fescue [Schedonorus pratensis (Huds.) P. Beauv.], orchardgrass (Dactylis glomerata L.), quackgrass [Elymus repens (L.) Gould], and reed canarygrass (Phalaris arundinacea L.) grazed by dairy heifers, and determined its relationship with sward structure. Grasses were grazed at vegetative stage for 24 h over 5‐d periods in the spring, summer, and fall of 2 yr. Forage dry matter (DM) allowance was a minimum of two times expected daily intake (11 kg animal−1 d−1). Sward characteristics were measured before grazing (height, mass, vertical distribution of leaf and stem bulk density and nutritive value). Herbage DM intake was estimated daily (pregraze minus postgraze herbage mass). Despite species differences in pregraze sward height (range of 29–49 cm across seasons), herbage mass (range of 1480–2540 kg DM ha−1), and neutral detergent fiber (NDF) digestibility (range of 713–843 g kg−1 NDF), no differences in leaf bulk density and herbage intake were found among grasses during four of six grazing seasons. Herbage intake differences during two seasons were related to either sward leaf bulk density (r = 0.79) or stem bulk density (r = −0.84), and the associated changes in leaf and stem mass of the canopy layers grazed by cattle, indicating that these sward characteristics were the primary determinants of grazed herbage intake in vegetative meadow fescue, orchardgrass, quackgrass, and reed canarygrass.