bluuebunny/crossref_metadata_2025 huggingface dataset:
Arabidopsis
Ethylene Signaling Pathway
Authors: Stepanova Anna N. , Alonso Jose M.
Published: March 2005

In plants, ethylene gas functions as a potent endogenous growth regulator. In the model system
Arabidopsis thaliana
, the molecular mechanisms that underlie perception and transduction of the ethylene signal to the nucleus, where the transcription of hundreds of genes is altered, are being elucidated. In the current view, ethylene is sensed by a family of five receptors that show similarity to the bacterial two-component histidine kinases, and in plants function as negative regulators of the pathway. Binding of the ethylene gas turns off the receptors, resulting in the inactivation of another negative regulator of ethylene signaling, CTR1, a Raf-like protein kinase that directly interacts with the receptors. EIN2, a protein of unknown biochemical activity that functions as a positive regulator of the pathway, acts downstream of CTR. Derepression of EIN2 by ethylene upon disabling of the receptors and CTR1 leads to the activation of EIN3 and EIN3-like transcription factors. In the absence of ethylene, the levels of EIN3 protein are extremely low because of the function of two F-box-containing proteins, EBF1 and EBF2, that target EIN3 for proteosome-mediated degradation. In the presence of ethylene, the EIN3 protein accumulates in the nucleus and initiates a transcriptional cascade, resulting in the activation and repression of hundreds of genes. To date, the only empirically demonstrated direct target of EIN3 is the APETALA2 (AP2)-domain–containing transcription factor gene
ERF1
. The coregulation of
ERF1
by another plant hormone, jasmonic acid, illustrates how a transcriptional cascade could be utilized in a combinatorial fashion to generate a large diversity of responses using a limited number of input signals. As new components and points of intersection with other pathways are identified, the Connections Map will be updated.
Candida albicansperitonitis in a patient with Felty’s syndrome: Figure 1
Authors: Thomas D W , Munuswamy P , Adu-Poku K , Holgate C S , Hickling P , Lambert A , Prentice A G
Published: March 2005

A 53 year old man with Felty’s syndrome presented with abdominal pain and fever. He underwent a laparotomy after starting broad spectrum antibiotics. An intestinal biopsy showed skip ulcers with fungal hyphae. Peritoneal exudates grewCandida albicans. He was started on intravenous fluconazole and then switched to liposomal amphotericin to which he showed a good clinical response. After one month at home he was readmitted with candidosis and died of a myocardial infarction.
Detection of BRAF mutations in colorectal tumours and peritoneal washings using a mismatch ligation assay
Authors: Busby K , Morris A
Published: March 2005

Aims:To detect cells bearing BRAF mutations in colorectal tumour samples and peritoneal washings, using a mismatch ligation assay (MLA).

Methods:DNA from 46 colorectal tumours was studied. Part of exon 15 of the BRAF gene was amplified using the polymerase chain reaction, and T→A mutations at codon 600 were detected using MLA. When a mutation was detected, the same mutation was sought in peritoneal washings from that patient.

Results:BRAF mutations were detected in five of the 45 analysable tumour samples. In four cases, this result was confirmed by sequencing analysis. More tumours with BRAF mutations were Dukes’ stage C or D rather than A or B (p < 0.02). Dilution experiments revealed that one mutant cell could be detected in 1000 normal cells. Cells with the same BRAF mutation were present in the peritoneal washing taken at the start of the operation in four of the five patients.

Conclusions:MLA is a suitable technique for the detection of BRAF mutations, and allows the detection of small numbers of isolated tumour cells shed from the primary tumour.
Pseudospirochaetosis of the urinary bladder
Authors: Chitale S , Burgess N , Barker T H W , Roberts P F
Published: March 2005

This report describes an elderly patient with urinary symptoms who showed surface colonisation of the transitional mucosa of the bladder by an unusual haematoxophilic microorganism superficially resembling the “blue fuzz” seen in colonic biopsies showing intestinal spirochaetosis. Special stains showed that the organisms were Gram and Giemsa positive, weakly argyrophilic, and Ziehl-Nielsen negative. Immunostains were negative forHelicobacter pyloriand electron microscopy revealed curious curved bodies, which were difficult to classify. Therefore, this condition was described as pseudospirochaetosis of the urinary bladder. The urinary symptoms regressed on treatment with ciprofloxacin. The clinicopathological relevance of these findings is discussed in the report.
Significant expression of IGFBP2 in breast cancer compared with benign lesions
Authors: Busund L-T , Richardsen E , Busund R , Ukkonen T , Bjørnsen T , Busch C , Stalsberg H
Published: March 2005

Background/Aim:Insulin-like growth factors (IGFs) and IGF binding proteins (IGFBPs) play a role in the normal development of breast tissue, and possibly in breast cancer aetiology. IGFBP2, one of six members of the IGFBP superfamily, acts as regulator of the IGFs and has pleiotropic effects in normal and neoplastic tissues. Because IGFs have mitogenic effects on mammary epithelia, this study investigated IGFBP2 expression in mammary tissues of different benign and malignant entities.

Methods:Immunohistochemistry was used to study correlations between the presence and intensity of IGFBP2 staining and tumour type and grade, in addition to steroid hormone receptor status, in 120 breast specimens. Expression was measured by quantitative colour video image analysis and semiquantitative evaluation, and the measurements correlated well (r = 0.92; p<0.05).

Results:Both methods found no significant expression of IGFBP2 in normal glandular cells and hyperplasia (group I). Atypical hyperplasia showed a slightly increased cytoplasmic expression of IGFBP2, and carcinoma in situ showed a distinctive, membrane associated and cytoplasmic expression (group II). Infiltrating carcinomas strongly expressed cytoplasmic IGFBP2 (group III). There were significant differences between group I and II, and between group II and III. There were no significant differences between invasive lobular and invasive ductal carcinoma, or between grades I, II, and III within these entities. There was no significant correlation between IGFBP2 immunostaining and oestrogen or progesterone receptor positivity within the malignant group.

Conclusions:IGFBP2 mitogenic signals of autocrine/paracrine regulatory mechanisms may be responsible for the growth of breast carcinomas and IGFBP2 may be an independent indicator of malignancy.
Histological features used in the diagnosis of melanoma are frequently found in benign melanocytic naevi
Authors: Urso C , Rongioletti F , Innocenzi D , Batolo D , Chimenti S , Fanti P L , Filotico R , Gianotti R , Lentini M , Tomasini C , Pippione M
Published: March 2005

Aims:The histological features used in the diagnosis of melanoma may be present in benign naevi, but quantitative data are not available. The aim of this study was to establish the real prevalence of such features in naevi.

Methods:Ten dermatopathologists, from nine Italian institutions, studied a series of naevi. Eleven histological parameters currently used in melanoma diagnosis were analysed: asymmetry, poor circumscription, predominance of single melanocytes, irregular confluent nests, suprabasal melanocytes, hair follicle involvement, absence of maturation, cytological atypia, dermal lymphocytic infiltrate, mitoses, and necrosis.

Results:Ninety one naevi were examined: 22 junctional, 59 compound, and 10 intradermal. None of the studied parameters was seen in 22 of the benign naevi studied. One or more investigated features were found in 69 naevi. Poor circumscription was found in 49 cases, single melanocytic predominating in 42, asymmetry in 41, irregular confluent nests in 16, cytological atypia in 14, suprabasal melanocytes in seven, and hair follicle involvement in seven; absence of maturation, mitoses and necrosis were not found.

Conclusions:The histological features used for the histological diagnosis of melanoma are often present in benign melanocytic naevi. This suggests a critical, non-mechanical use of them in melanoma diagnosis.
Differences in growth characteristics and elementary body associated cytotoxicity betweenChlamydia trachomatisoculogenital serovars D and H andChlamydia muridarum
Authors: Lyons J M , Ito J I , Peña A S , Morré S A
Published: March 2005

Aim:In vitro growth and elementary body (EB) associated cytotoxicity of twoChlamydia trachomatisstrains belonging to serovars D and H andC muridarumwere compared to identify difference(s) that correlate with virulence variations between these strains in the mouse model of human female genital tract infection, and phenotypic characteristics that could explain human epidemiological data on serovar prevalence and levels of shedding during serovar D and H infection.

Methods:Replication cycle kinetics, inclusion characteristics, and EB associated cytotoxicity were assessed in McCoy cell monolayers using culture, light microscopy, and lactate dehydrogenase release.

Results:Over 72 hours, more rapid production and release of inclusion forming units (ifu) allowedC muridarumto initiate two replication rounds, resulting in 4–8 times more ifu/input unit of infection than with serovars D and H. AlthoughC muridarumEBs were significantly more cytotoxic to McCoy cell monolayers than serovar D at moderate and high multiplicity of infection ratios (MOI), serovar H EBs were significantly more cytotoxic thanC muridarum, even at the lowest MOI tested.

Conclusions:These phenotypic differences are consistent with the more invasive course and severe pathological outcome of infection in mice infected withC muridarum, providing an objective basis for questioning the appropriateness ofC muridarumas a surrogate for the human biovar ofC trachomatisin the murine model of female genital tract infection. The differences seen between the human strains could help explain human epidemiological data relating to differences in prevalence and level of shedding that occurs during infection with oculogenital serovars D and H.
Bone marrow biopsy morbidity: review of 2003: Table 1
Authors: Bain B J
Published: March 2005

Background:Although some hazards are recognised, in general, bone marrow aspiration and trephine biopsy are thought to be safe procedures. Until recently, no attempt had been made to quantify any attendant risks. For this reason, documentation of adverse events was begun in 2001, under the auspices of the British Society for Haematology. Three consecutive years have now been surveyed, the results for 2003 being presented here and compared with earlier results.

Methods:Members of the British Society of Haematology were requested to document adverse events associated with diagnostic bone marrow aspirates and trephine biopsies between 1 January and 31 December, 2003. Data were collected early in 2004.

Results:In total, 19 259 procedures were reported from 63 hospitals, 13 147 being combined procedures and 6112 aspirates without a trephine biopsy. Sixteen adverse events were reported, representing 0.08% of total reported procedures. The major adverse event was haemorrhage, which comprised 11 of the 16 adverse events. Although infrequent, adverse events were associated with significant morbidity and three were judged as very serious. The major risk factors for haemorrhage, in order of frequency, were diagnosis of a myeloproliferative disorder, aspirin treatment, other putative platelet dysfunctions, and thrombocytopenia.

Conclusions:Adverse events following trephine biopsies and bone marrow aspirates are rare, but nevertheless can have considerable impact on individual patients.
Diagnostic cues for natural killer cell lymphoma: primary nodal presentation and the role of in situ hybridisation for Epstein-Barr virus encoded early small RNA in detecting occult bone marrow involvement
Authors: Chim C-S , Ma E S K , Loong F , Kwong Y-L
Published: March 2005

Natural killer (NK) cell lymphomas are rare, and atypical features might lead to diagnostic pitfalls. This report describes an unusual patient in whom lymphoma occurred initially as isolated lymph node involvement, an exceptional presentation of an almost exclusively extranodal disease. Furthermore, during the terminal haemophagocytosis in the bone marrow, lymphoma cells lost the expression of the NK cell marker, CD56, making the histopathological diagnosis of bone marrow involvement difficult. This was resolved by in situ hybridisation for Epstein-Barr virus encoded small RNA, which detected occult bone marrow infiltration.
The Gurvich waveform has lower defibrillation threshold than the rectilinear waveform and the truncated exponential waveform in the rabbit heart
Authors: Qu Fujian , Zarubin Fidel , Wollenzier Brian , Nikolski Vladimir P , Efimov Igor R
Published: March 2005

Implantable cardioverter defibrillator studies have established the superiority of biphasic waveforms over monophasic waveforms. However, external defibrillator studies of biphasic waveforms are not as widespread. Our objective was to compare the defibrillation efficacy of clinically used biphasic waveforms, i.e., truncated exponential, rectilinear, and quasi-sinusoidal (Gurvich) waveforms in a fibrillating heart model. Langendorff-perfused rabbit hearts (n = 10) were stained with a voltage-sensitive fluorescent dye, Di-4-ANEPPS. Transmembrane action potentials were optically mapped from the anterior epicardium. We found that the Gurvich waveform was significantly superior (p < 0.05) to the rectilinear and truncated exponential waveforms. The defibrillation thresholds (mean ± SE) were as follows: Gurvich, 0.25 ± 0.01 J; rectilinear-1, 0.34 ± 0.01 J; rectilinear-2, 0.33 ± 0.01 J; and truncated exponential, 0.32 ± 0.02 J. Using optically recorded transmembrane responses, we determined the shock-response transfer function, which allowed us to predict the cellular response to waveforms at high accuracy. The passive parallel resistor-capacitor model (RC-model) predicted polarization superiority of the Gurvich waveform in the myocardium with a membrane time constant (τm) of less than 2 ms. The finding of a lower defibrillation threshold with the Gurvich waveform in an in vitro model of external defibrillation suggests that the Gurvich waveform may be important for future external defibrillator designs.Key words: defibrillation, optical mapping, biphasic waveform, Gurvich waveform.
Cardiac chymase: pathophysiological role and therapeutic potential of chymase inhibitors
Authors: Doggrell Sheila A , Wanstall Janet C
Published: March 2005

On release from cardiac mast cells, α-chymase converts angiotensin I (Ang I) to Ang II. In addition to Ang II formation, α-chymase is capable of activating TGF-β1 and IL-1β, forming endothelins consisting of 31 amino acids, degrading endothelin-1, altering lipid metabolism, and degrading the extracellular matrix. Under physiological conditions the role of chymase in the mast cells of the heart is uncertain. In pathological situations, chymase may be secreted and have important effects on the heart. Thus, in animal models of cardiomyopathy, pressure overload, and myocardial infarction, there are increases in both chymase mRNA levels and chymase activity in the heart. In human diseased heart homogenates, alterations in chymase activity have also been reported. These findings have raised the possibility that inhibition of chymase may have a role in the therapy of cardiac disease. The selective chymase inhibitors developed to date include TY-51076, SUN-C8257, BCEAB, NK320, and TEI-E548. These have yet to be tested in humans, but promising results have been obtained in animal models of myocardial infarction, cardiomyopathy, and tachycardia-induced heart failure. It seems likely that orally active inhibitors of chymase could have a place in the treatment of cardiac diseases where injury-induced mast cell degranulation contributes to the pathology.Key words: cardiac chymase, pathophysiological role, inhibition.
Effect of BM 17.0744, a PPARα ligand, on the metabolism of perfused hearts from control and diabetic mice
Authors: Aasum Ellen , Cooper Marie , Severson David L , Larsen Terje S
Published: March 2005

Peroxisome proliferator-activated receptor-α (PPARα) regulates the expression of fatty acid (FA) oxidation genes in liver and heart. Although PPARα ligands increased FA oxidation in cultured cardiomyocytes, the cardiac effects of chronic PPARα ligand administration in vivo have not been studied. Diabetic db/db mouse hearts exhibit characteristics of a diabetic cardiomyopathy, with altered metabolism and reduced contractile function. A testable hypothesis is that chronic administration of a PPARα agonist to db/db mice will normalize cardiac metabolism and improve contractile function. Therefore, a PPARα ligand (BM 17.0744) was administered orally to control and type 2 diabetic (db/db) mice (37.9 ± 2.5 mg/(kg·d) for 8 weeks), and effects on cardiac metabolism and contractile function were assessed. BM 17.0744 reduced plasma glucose in db/db mice, but no change was observed in control mice. FA oxidation was significantly reduced in BM 17.0744 treated db/db hearts with a corresponding increase in glycolysis and glucose oxidation; glucose and FA oxidation in control hearts was unchanged by BM 17.0744. PPARα treatment did not alter expression of PPARα target genes in either control or diabetic hearts. Therefore, metabolic alterations in hearts from PPARα-treated diabetic mice most likely reflect indirect mechanisms related to improvement in diabetic status in vivo. Despite normalization of cardiac metabolism, PPARα treatment did not improve cardiac function in diabetic hearts.Key words: PPAR, cardiac metabolism and function, diabetes.
MULTIFRACTAL PROPERTIES OF R90 CELLULAR AUTOMATON WITH MEMORY
Authors: SÁNCHEZ JUAN R. , ALONSO-SANZ RAMÓN
Published: March 2005

Standard Cellular Automata (CA) are ahistoric (memoryless Markov process), i.e., the new state of a cell depends on the neighborhood configuration only at the preceding time step. This article considers the fractal and multifractal properties of an extension to the standard framework of CA implemented by the inclusion of memory capabilities. Thus, in CA with memory, while the update rules of the CA remain unaltered, historic memory of all past iterations is retained by featuring each cell by a summary of all its past states. A study is made of the effect of historic memory on the multifractal dynamical characteristics of one-dimensional cellular automata operating under one of the most studied rules, rule 90, which is well known to display a rich complex behavior.
THE CRITICAL BEHAVIOR OF THE 2D SPIN-1 ISING MODEL WITH THE BILINEAR AND POSITIVE BIQUADRATIC NEAREST NEIGHBOR INTERACTIONS ON A CELLULAR AUTOMATON
Authors: SOLAK A. , KUTLU B.
Published: March 2005

The two-dimensional BEG model with nearest neighbor bilinear and positive biquadratic interaction is simulated on a cellular automaton, which is based on the Creutz cellular automaton for square lattice. Phase diagrams characterizing phase transitions of the model are presented for comparison with those obtained from other calculations. We confirm the existence of the tricritical points over the phase boundary for D/K>0. The values of static critical exponents (α, β, γ and ν) are estimated within the framework of the finite size scaling theory along D/K=-1 and 1 lines. The results are compatible with the universal Ising critical behavior except the points over phase boundary.
Kinetic characterization of tetrapropylammonium inhibition reveals how ATP and Pi alter access to the Na+-K+-ATPase transport site
Authors: Gatto Craig , Helms Jeff B. , Prasse Megan C. , Arnett Krista L. , Milanick Mark A.
Published: March 2005

Current models of the Na+-K+-ATPase reaction cycle have ATP binding with low affinity to the K+-occluded form and accelerating K+ deocclusion, presumably by opening the inside gate. Implicit in this situation is that ATP binds after closing the extracellular gate and thus predicts that ATP binding and extracellular cation binding to be mutually exclusive. We tested this hypothesis. Accordingly, we needed a cation that binds outside and not inside, and we determined that tetrapropylammonium (TPA) behaves as such. TPA competed with K+ (and not Na+) for ATPase, TPA was unable to prevent phosphoenzyme (EP) formation even at low Na+, and TPA decreased the rate of EP hydrolysis in a K+-competitive manner. Having established that TPA binding is a measurement of extracellular access, we next determined that TPA and inorganic phosphate (Pi) were not mutually exclusive inhibitors of para-nitrophenylphosphatase (pNPPase) activity, implying that when Pi is bound, the transport site has extracellular access. Surprisingly, we found that ATP and TPA also were not mutually exclusive inhibitors of pNPPase activity, implying that when the cation transport site has extracellular access, ATP can still bind. This is consistent with a model in which ATP speeds up the conformational changes that lead to intracellular or extracellular access, but that ATP binding is not, by itself, the trigger that causes opening of the cation site to the cytoplasm.
Expression and functional properties of four slow skeletal troponin T isoforms in rat muscles
Authors: Kischel P. , Bastide B. , Muller M. , Dubail F. , Offredi F. , Jin J. P. , Mounier Y. , Martial J.
Published: March 2005

We investigated the expression and functional properties of slow skeletal troponin T (sTnT) isoforms in rat skeletal muscles. Four sTnT cDNAs were cloned from the slow soleus muscle. Three isoforms were found to be similar to sTnT1, sTnT2, and sTnT3 isoforms described in mouse muscles. A new rat isoform, with a molecular weight slightly higher than that of sTnT3, was discovered. This fourth isoform had never been detected previously in any skeletal muscle and was therefore called sTnTx. From both expression pattern and functional measurements, it appears that sTnT isoforms can be separated into two classes, high-molecular-weight (sTnT1, sTnT2) and low-molecular-weight (sTnTx, sTnT3) isoforms. By comparison to the apparent migration pattern of the four recombinant sTnT isoforms, the newly described low-molecular-weight sTnTx isoform appeared predominantly and typically expressed in fast skeletal muscles, whereas the higher-molecular-weight isoforms were more abundant in slow soleus muscle. The relative proportion of the sTnT isoforms in the soleus was not modified after exposure to hindlimb unloading (HU), known to induce a functional atrophy and a slow-to-fast isoform transition of several myofibrillar proteins. Functional data gathered from replacement of endogenous troponin complexes in skinned muscle fibers showed that the sTnT isoforms modified the Ca2+ activation characteristics of single skeletal muscle fibers, with sTnT2 and sTnT1 conferring a similar increase in Ca2+ affinity higher than that caused by low-molecular-weight isoforms sTnTx and sTnT3. Thus we show for the first time the presence of sTnT in fast muscle fibers, and our data show that the changes in neuromuscular activity on HU are insufficient to alter the sTnT expression pattern.
Bisphosphonates stimulate an endogenous nonselective cation channel in Xenopus oocytes: potential mechanism of action
Authors: Shao Weijian , Orlando Roy C. , Awayda Mouhamed S.
Published: March 2005

The mechanisms of action of bisphosphonates (BPs) have been poorly determined. Besides their actions on osteoclasts, these agents exhibit gastrointestinal complications. They have also recently been described as affecting various preparations that express an epithelial Na+ channel (ENaC). To understand the effects of BP on ion channels and the ENaC in particular, we used the Xenopus oocyte expression system. Alendronate, and similarly risedronate, two aminobisphosphonates, caused a large stimulation of an endogenous nonselective cation conductance (NSCC). This stimulation averaged 63 ± 12 μS ( n = 18) 60 min after the addition of 2 mM alendronate. The effects on the endogenous NSCC were blocked by extracellular acidification to pH 6.4. On the other hand, alendronate caused a small inhibition of ENaC conductance at pH 7.4 and 6.4, but the effects at pH 6.4 were more readily observed in the absence of changes of the endogenous conductance. The effects on membrane capacitance were also markedly different, with a clear decrease at pH 6.4 and no consistent changes at pH 7.4. The effects on the endogenous channel were further augmented by genistein and were inhibited by a tyrosine phosphatase inhibitor, indicating the involvement of the tyrosine kinase pathway. Stimulation of NSCC with BP is expected to cause membrane depolarization and may explain, in part, its mechanisms of action in inhibiting osteoclasts.
Etk/Bmx mediates expression of stress-induced adaptive genes VEGF, PAI-1, and iNOS via multiple signaling cascades in different cell systems
Authors: Chau Cindy H. , Clavijo Carlos A. , Deng Hong-Tao , Zhang Qunzhou , Kim Kwang-Jin , Qiu Yun , Le Anh D. , Ann David K.
Published: March 2005

We recently showed that Etk/Bmx, a member of the Tec family of nonreceptor protein tyrosine kinases, promotes tight junction formation during chronic hypoxic exposure and augments normoxic VEGF expression via a feedforward mechanism. Here we further characterized Etk's role in potentiating hypoxia-induced gene expression in salivary epithelial Pa-4 cells. Using transient transfection in conditionally activated Etk (ΔEtk:ER) cells, we demonstrated that Etk enhances hypoxia-response element-dependent reporter activation in normoxia and hypoxia. This Etk-driven reporter activation is ameliorated by treatment with wortmannin or LFM-A13. Using lentivirus-mediated gene delivery and small interfering RNA, we provided direct evidence that hypoxia leads to transient Etk and Akt activation and hypoxia-mediated Akt activation is Etk dependent. Northern blot analyses confirmed that Etk activation led to induction of steady-state mRNA levels of endogenous VEGF and plasminogen activator inhibitor (PAI)-1, a hallmark of hypoxia-mediated gene regulation. We also demonstrated that Etk utilizes a phosphatidylinositol 3-kinase/Akt pathway to promote reporter activation driven by NF-κB, another oxygen-sensitive transcription factor, and to augment cytokine-induced inducible nitric oxide synthase expression in endothelial cells. To establish the clinical relevance of Etk-induced, hypoxia-mediated gene regulation, we examined Etk expression in keloid, which has elevated VEGF and PAI-1. We found that Etk is overexpressed in keloid (but not normal skin) tissues. The differential steady-state Etk protein levels were further confirmed in primary fibroblast cultures derived from these tissues, suggesting an Etk role in tissue fibrosis. Our results provide further understanding of Etk function within multiple signaling cascades to govern adaptive cytoprotection against extracellular stress in different cell systems, salivary epithelial cells, brain endothelial cells, and dermal fibroblasts.
Parathyroid hormone treatment induces dissociation of type IIa Na+-Pi cotransporter-Na+/H+ exchanger regulatory factor-1 complexes
Authors: Déliot Nadine , Hernando Nati , Horst-Liu Zeya , Gisler Serge M. , Capuano Paola , Wagner Carsten A. , Bacic Desa , O'Brien Stephen , Biber Jürg , Murer Heini
Published: March 2005

The type IIa Na+-Pi cotransporter (NaPi-IIa) and the Na+/H+ exchanger regulatory factor-1 (NHERF1) colocalize in the apical membrane of proximal tubular cells. Both proteins interact in vitro. Herein the interaction between NaPi-IIa and NHERF1 is further documented on the basis of coimmunoprecipitation and co-pull-down assays. NaPi-IIa is endocytosed and degraded in lysosomes upon parathyroid hormone (PTH) treatment. To investigate the effect of PTH on the NaPi-IIa-NHERF1 association, we first compared the localization of both proteins after PTH treatment. In mouse proximal tubules and OK cells, NaPi-IIa was removed from the apical membrane after hormonal treatment; however, NHERF1 remained at the membrane. Moreover, PTH treatment led to degradation of NaPi-IIa without changes in the amount of NHERF1. The effect of PTH on the NaPi-IIa-NHERF1 interaction was further studied using coimmunoprecipitation. PTH treatment reduced the amount of NaPi-IIa coimmunoprecipitated with NHERF antibodies. PTH-induced internalization of NaPi-IIa requires PKA and PKC; therefore, we next analyzed whether PTH induces changes in the phosphorylation state of either partner. NHERF1 was constitutively phosphorylated. Moreover, in mouse kidney slices, PTH induced an increase in NHERF1 phosphorylation; independent activation of PKA or PKC also resulted in increased phosphorylation of NHERF1 in kidney slices. However, NaPi-IIa was not phosphorylated either basally or after exposure to PTH. Our study supports an interaction between NHERF1 and NaPi-IIa on the basis of their brush-border membrane colocalization and in vitro coimmunoprecipitation/co-pull-down assays. Furthermore, PTH weakens this interaction as evidenced by different in situ and in vivo behavior. The PTH effect takes place in the presence of increased phosphorylation of NHERF1.
Modeling the Effects of Transcranial Magnetic Stimulation on Cortical Circuits
Authors: Esser Steve K. , Hill Sean L. , Tononi Giulio
Published: March 2005

Transcranial magnetic stimulation (TMS) is commonly used to activate or inactivate specific cortical areas in a noninvasive manner. Because of technical constraints, the precise effects of TMS on cortical circuits are difficult to assess experimentally. Here, this issue is investigated by constructing a detailed model of a portion of the thalamocortical system and examining the effects of the simulated delivery of a TMS pulse. The model, which incorporates a large number of physiological and anatomical constraints, includes 33,000 spiking neurons arranged in a 3-layered motor cortex and over 5 million intra- and interlayer synaptic connections. The model was validated by reproducing several results from the experimental literature. These include the frequency, timing, dose response, and pharmacological modulation of epidurally recorded responses to TMS (the so-called I-waves), as well as paired-pulse response curves consistent with data from several experimental studies. The modeled responses to simulated TMS pulses in different experimental paradigms provide a detailed, self-consistent account of the neural and synaptic activities evoked by TMS within prototypical cortical circuits.
Contribution of the Motor Cortex to the Structure and the Timing of Hindlimb Locomotion in the Cat: A Microstimulation Study
Authors: Bretzner Frédéric , Drew Trevor
Published: March 2005

We used microstimulation to examine the contribution of the motor cortex to the structure and timing of the hindlimb step cycle during locomotion in the intact cat. Stimulation was applied to the hindlimb representation of the motor cortex in 34 sites in three cats using either standard glass-insulated microelectrodes (16 sites in 1 cat) or chronically implanted microwire electrodes (18 sites in 2 cats). Stimulation at just suprathreshold intensities with the cat at rest produced multijoint movements at a majority of sites (21/34, 62%) but evoked responses restricted to a single joint, normally the ankle, at the other 13/34 (38%) sites. Stimulation during locomotion generally evoked larger responses than the same stimulation at rest and frequently activated additional muscles. Stimulation at all 34 sites evoked phase-dependent responses in which stimulation in swing produced transient increases in activity in flexor muscles while stimulation during stance produced transient decreases in activity in extensors. Stimulation with long (200 ms) trains of stimuli in swing produced an increased level of activity and duration of flexor muscles without producing changes in cycle duration. In contrast, stimulation during stance decreased the duration of the extensor muscle activity and initiated a new and premature period of swing, resetting the step cycle. Stimulation of the pyramidal tract in two of these three cats as well as in two additional ones produced similar effects. The results show that the motor cortex is capable of influencing hindlimb activity during locomotion in a similar manner to that seen for the forelimb.
Electrical Coupling in Sustentacular Cells of the Mouse Olfactory Epithelium
Authors: Vogalis Fivos , Hegg Colleen C. , Lucero Mary T.
Published: March 2005

Sustentacular cells (SCs) line the apical surface of the olfactory epithelium (OE) and provide trophic, metabolic, and mechanical support for olfactory receptor neurons. Morphological studies have suggested that SCs possess gap junctions, although physiological evidence for gap junctional communication in mammalian SCs is lacking. In the present study we investigated whether coupling exists between SCs situated in tissue slices of OE from neonatal (P0–P4) mice. Using whole cell and cell-attached patch recordings from SCs, we demonstrate that SCs are electrically coupled by junctional resistances on the order of 300 MΩ. Under whole cell recording conditions, Alexa 488 added to the pipette solution failed to reveal dye coupling between SCs. Electrical coupling was deduced from the biexponential decay of capacitive currents recorded from SCs and from the bell-shaped voltage dependency of a P2Y-receptor–activated current, both of which were abolished by 18β-glycyrrhetinic acid (20–50 μM), a blocker of gap junctions. These data provide strong evidence for functional coupling between SCs, the physiological importance of which is discussed.
Remapping the Remembered Target Location for Anti-Saccades in Human Posterior Parietal Cortex
Authors: Medendorp W. Pieter , Goltz Herbert C. , Vilis Tutis
Published: March 2005

We used functional magnetic resonance imaging (fMRI) to investigate the role of the human posterior parietal cortex (PPC) in anti-saccades. To do so, we exploited the laterality of a subregion of the PPC for remembered target location. Using an event-related design, we tracked fMRI signal changes in this region while subjects remembered the location of a flashed target, then were instructed to plan either an anti- or pro-saccade to that location, and finally were instructed to execute the movement. At first, the region responded preferentially to the memory of a target location presented in the contralateral visual field. However, when an anti-cue specified a saccadic response into the opposite visual field, we observed a dynamic shift in cortical activity from one hemisphere to the other. This shows that this region within the human posterior parietal cortex codes the target location for an upcoming saccade, rather than the location of the remembered visual stimulus in an anti-saccade task.
Primate Memory Saccade Amplitude After Intervened Motion Depends on Target Distance
Authors: Li Nuo , Wei Min , Angelaki Dora E.
Published: March 2005

To keep a stable internal representation of the visual world as our eyes, head, and body move around, humans and monkeys must continuously adjust neural maps of visual space using extraretinal sensory or motor cues. When such movements include translation, the amount of body displacement must be weighted differently in the updating of far versus near targets. Using a memory-saccade task, we have investigated whether nonhuman primates can benefit from this geometry when passively moved sideways. We report that monkeys made appropriate memory saccades, taking into account not only the amplitude and nature (rotation vs. translation) of the movement, but also the distance of the memorized target: i.e., the amplitude of memory saccades was larger for near versus far targets. The scaling by viewing distance, however, was less than geometrically required, such that memory saccades consistently undershot near targets. Such a less-than-ideal scaling of memory saccades is reminiscent of the viewing distance–dependent properties of the vestibuloocular reflex. We propose that a similar viewing distance–dependent vestibular signal is used as an extraretinal compensation for the visuomotor consequences of the geometry of motion parallax by scaling both memory saccades and reflexive eye movements during motion through space.
Pulse Pressure and Effects of Losartan or Atenolol in Patients With Hypertension and Left Ventricular Hypertrophy
Authors: Fyhrquist Frej , Dahlöf Björn , Devereux Richard B. , Kjeldsen Sverre E. , Julius Stevo , Beevers Gareth , de Faire Ulf , Ibsen Hans , Kristianson Krister , Lederballe-Pedersen Ole , Lindholm Lars H. , Nieminen Markku S. , Omvik Per , Oparil Suzanne , Hille Darcy A. , Lyle Paulette A. , Edelman Jonathan M. , Snapinn Steven M. , Wedel Hans
Published: March 2005

In the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study, the primary composite end point of cardiovascular death, stroke, and myocardial infarction was reduced by losartan versus atenolol in patients with hypertension and left ventricular hypertrophy. The objective of this post hoc analysis was to determine the influence of pulse pressure on outcome. Patients were divided into quartiles of baseline pulse pressure. Cox regression, including baseline Framingham risk score as a covariate, was used to compare risk in the quartiles. In the atenolol group, there were significantly higher risks in the highest versus lowest quartile for the composite end point 28% (confidence interval [CI], 2% to 62%;
P
=0.035), stroke 84% (CI, 32% to 157%;
P
<0.001), and total mortality 41% (CI, 7% to 84%;
P
=0.013). Risk for myocardial infarction was 44% higher (CI, −5% to 120%;
P
=0.089). The risks in the losartan group also increased with increasing quartile, but were lower than in the atenolol group, and differences between the highest and lowest quartiles were not significant: composite end point 12% (CI, −13% to 44%;
P
>0.2), stroke −5% (CI, −34% to 37%;
P
>0.2), myocardial infarction 30% (CI, −13% to 94%;
P
>0.2), and total mortality 32% (CI, −1% to 76%;
P
=0.062). In patients with hypertension and left ventricular hypertrophy in the LIFE study, there were significantly higher risks, adjusted for the Framingham risk score, for the primary composite end point, stroke, and total mortality in the highest versus lowest quartile of pulse pressure with atenolol-based treatment. The risks in the losartan group also increased with increasing pulse pressure quartile, but were lower than those in the atenolol group, and were not significant.
Dorsal and Ventral Stream Interaction: Contributions from Optic Ataxia
Authors: Himmelbach Marc , Karnath Hans-Otto
Published: March 2005

In monkeys and humans, two functionally specialized cortical streams of visual processing emanating from V1 have been proposed: a dorsal, action-related system and a ventral, perception-related pathway. Traditionally, a separate organization of the two streams is assumed; the extent of functional interaction is unknown. After lesions of the dorsal stream in patients with optic ataxia, it has recently been shown that the ventral perception-related system might contribute to visuo-motor processing if movements rely on remembered target positions. The ventral pathway thus seemed to participate in goal-directed movements, a function that previously has been assigned exclusively to the dorsal stream. We wondered whether different types of pointing movements are controlled by switching between two separated cortical pathways or whether a variable interaction of interconnected systems should be assumed. Our study investigated two acute stroke patients with optic ataxia following lesions of the dorsal stream in a delayed pointing task. The delays ranged from 0 to 10 sec. The patients' pointing error decreased in a linear manner with the length of time. The finding suggests a gradual change between dorsal and ventral control of reaching behavior, rather than a sudden switch between two separated cortical processing streams. Although our observations with two patients require further validation, the results suggest that the ventral and dorsal systems interact closely in the sensorimotor control of reaching behavior.
To Look or Not to Look? Typical and Atypical Development of Oculomotor Control
Authors: Scerif Gaia , Karmiloff-Smith Annette , Campos Ruth , Elsabbagh Mayada , Driver Jon , Cornish Kim
Published: March 2005

The ability to inhibit saccades toward suddenly appearing peripheral stimuli (prosaccades) and direct them to contralateral locations instead (antisaccades) is a crucial marker of eye movement control. Typically developing infants as young as 4-month-olds can learn to inhibit reflexive saccades to peripheral stimuli, but they do not produce antisaccades, whose development later in infancy and its underlying neural computations remain unexplored. Here we tested oculomotor control in typically developing toddlers and toddlers with fragile X syndrome (FXS), a disorder of known genetic origin that allows the investigation of the neuro-computational properties contributing to the development of saccadic control. Typically developing toddlers decreased looking toward peripheral cues that predicted contralateral rewards, whose appearance they anticipated. Furthermore, this correlated with age, indicating a gradual development of saccadic control. In contrast with the typical case, toddlers with FXS did not decrease their looks to peripheral onsets that predicted contralateral events. Importantly, the atypical pattern of performance was also evident in the elimination of the correlation with mental or chronological age found in controls. Taken together, the findings suggest that control of saccades and its developmental trajectory is atypical in toddlers with FXS, consistent with inhibitory deficits previously shown at later ages in this condition. Potential implications for the neural mechanisms underlying the typical and atypical development of oculomotor control are discussed.
Common Mechanisms for Working Memory and Attention: The Case of Perseveration with Visible Solutions
Authors: Stedron Jennifer Merva , Sahni Sarah Devi , Munakata Yuko
Published: March 2005

Everyone perseverates at one time or another, repeating previous behaviors when they are no longer appropriate. Such perseveration often occurs in situations with working memory demands, and the ability to overcome perseveration has been linked to brain regions critical for working memory. Many theories thus explain perseveration in terms of working memory deficits. However, perseveration also occurs in situations without apparent working memory demands, in which the visible environment specifies appropriate behavior. Such findings appear to challenge working memory accounts of perseveration. To evaluate this challenge, a neural network model of a working memory account of perseveration was tested on tasks with visible solutions. With advances in the mechanisms that support working memory, networks became increasingly able to attend to relevant information in the environment. These developments led to improvements in performance on tasks with visible solutions, paralleling the developmental progression observed in infants. The simulations demonstrate how mechanisms of working memory can subserve perseveration and success on tasks with and without obvious memory demands. In both types of tasks, controlled processing occurs through the activation of task-relevant representations, which provide top-down biasing of other processing pathways. More generally, the simulations demonstrate how common mechanisms can support working memory and attention.
The Constitutional Court of the Republic of Lithuania and the Death Penalty: A Note on the Judgment of 9 December 1988
Authors:   Vaicaitis
Published: March 2005

No Abstract
Minority Shareholder Rights in the Current Macedonian Legislation
Authors:   Koevski
Published: March 2005

No Abstract
Synoptic Disturbances over the Equatorial South China Sea and Western Maritime Continent during Boreal Winter
Authors: Chang C-P. , Harr P. A. , Chen H-J.
Published: March 2005

During boreal winter, the Maritime Continent is a region of deep cumulus convection and heavy precipitation systems that play a major role in several global- and regional-scale processes. Over the western part of this region, the synoptic-scale Borneo vortex, the northeast cold surge, and the intraseasonal Madden–Julian oscillation (MJO) contribute to the variability in deep convection. This work studies the impact on deep convection due to interactions among these three different motion systems. Furthermore, the role of the unique topography of the region is examined with respect to the variability in the synoptic-scale cold surge and Borneo vortex.

On the synoptic scale, the interaction of northeast winds with local topography and the dynamic response to the change in latitude contribute to the turning of the winds and localized patterns of deep convection. In days without a Borneo vortex, deep convection tends to be suppressed over the South China Sea and Borneo and enhanced downstream over the landmasses on the western and southern peripheries of the equatorial South China Sea. The pattern is reversed in days with a vortex. The presence of a cold surge enhances this contrast. The surge also interacts with the Borneo vortex, in that the vortex is strengthened and the vortex center shifts from over the South China Sea to be located over the western coast of Borneo.

The frequency of cold surges and vortex days is reduced during periods when the MJO is present. Composites of large-scale circulation and outgoing longwave radiation are used to show that often the MJO-related circulation patterns oppose the synoptic-scale cold-surge and vortex circulations. Thus, a primary impact of the MJO is to inhibit weak cold-surge events, which then produces a secondary impact on the Borneo vortex via interactions between the cold-surge winds and the vortex.
Conservative Semi-Lagrangian Transport on a Sphere and the Impact on Vapor Advection in an Atmospheric General Circulation Model
Authors: Peng Xindong , Xiao Feng , Ohfuchi Wataru , Fuchigami Hiromitsu
Published: March 2005

A conservative semi-Lagrangian scheme with rational function for interpolation is implemented in spherical geometry and tested in an atmospheric general circulation model (AGCM). The new scheme, different from the conventional semi-Lagrangian method, is conservative and oscillation free. By introducing polar mixing and a time split computation of divergence, the scheme can compute advection transport correctly over the polar regions. Idealized advection tests with various velocity fields were carried out to demonstrate numerical accuracy and conservation in comparison with the spectral schemes. The impact of the advection computation on water vapor circulation in an AGCM is also investigated with numerical simulations on the Earth Simulator. Both pure advection tests and general circulation experiments show that the presented scheme is effective in improving the tracer transport property and the precipitation field in comparison with the leapfrog-spectral method.