bluuebunny/crossref_metadata_2025 huggingface dataset:
Two Novel Thio-Arsenosugars in Scallops Identified with HPLC - ICPMS and HPLC - ESMS
Authors: Kahn Markus , Raml Reingard , Schmeisser Ernst , Vallant Birgit , Francesconi Kevin A. , Goessler Walter
Published: September 2005

Environmental Context. A new group of arsenic compounds, namely thio-arsenosugars, has recently been discovered in some marine samples, including seafood products. We do not yet understand how these arsenic compounds are produced by living organisms, nor do we know their implications for human health. Their unusual chromatographic properties are the reason that they are difficult to detect by existing methods. We present a new method for finding these thio-arsenosugars, and we also report two new thio-arsenosugars.
Abstract. Two new thio-arsenosugars were identified in aqueous and methanol extracts from the gonad and the muscle of the great scallop by using high-performance liquid chromatography–inductively coupled plasma mass spectrometry (HPLC–ICPMS) and HPLC–electrospray ionization mass spectrometry (ESMS). The gonad of the scallops contained thio-arsenosugar–sulfonate [0.067 mg (As) kg−1; dry mass ± 3.7%] and thio-arsenosugar–sulfate [0.267 mg (As) kg−1; dry mass ± 1.2%]. The muscle also contained both thio-arsenosugar–sulfonate [0.030 mg (As) kg−1; dry mass ± 2.6%] and thio-arsenosugar–sulfate [0.200 mg (As) kg−1; dry mass ± 2.6%]. Methanol increased the extraction efficiency threefold for the two thio-arsenosugars as compared to water. Fresh and freeze-dried samples from both parts of the scallop showed no significant difference with respect to the concentration of the two thio-arsenosugars. In order to confirm the presence of the thio-arsenosugars, a new method for their determination with HPLC–ESMS was developed. Under optimized conditions [Hamilton PRP-X100; 150 by 1.0 mm; 20 mM NH4HCO3 with 55% (v/v) methanol at pH 10.3] we succeeded in determining the pseudomolecular ions of thio-arsenosugar–glycerol, thio-arsenosugar–phosphate, thio-arsenosugar–sulfonate, and thio-arsenosugar–sulfate at concentrations less than 5 µg (As) dm−3 in standard solutions and real samples.
Drifting or walking? Colonisation routes used by different instars and species of lotic, macroinvertebrate filter feeders
Authors: Downes Barbara J. , Bellgrove Alecia , Street Jodie L.
Published: September 2005

Many views of stream invertebrate populations centre on drift as the major route of larval dispersal, but few studies have presented unambiguous information about the role of drift. We present the results from an experiment designed to determine whether the major route of colonisation of substrata by hydropsychid larvae (commonly found in the drift) is by drifting directly onto substrata or by walking along the stream bottom. The experimental design contained four treatments: substrata open to drifters and walkers; fenced substrata open to drifters only; and two treatments open to drifters and walkers that provided forms of fence controls. Fifteen replicates of each treatment were set out at random locations within a riffle at each of three sites, with each site on a different river (the Little River, the Steavenson River and the Acheron River) in the Acheron River catchment. The experiment was run twice, once during autumn (April 1999) and once during early summer (January 2000). Both experiments were colonised by three species of hydropsychids, Asmicridea sp. AV1, and Smicrophylax sp. AV1 and AV2. We found that 2nd/3rd instars of Asmicridea sp. AV1 walked as well as drifted, whereas all others primarily drifted. No relation between numbers of recruits and water speed was found when substrata were open only to drifters, whereas substrata open also to walkers gained more recruits in faster flows. Additionally, larvae more frequently abandoned nets in slow than fast flows, indicating that drifting into unfavourable flow environments may result in mortality or redispersal of larvae. These findings demonstrate that, although drift is important, it is not necessarily the only method used by hydropsychids to colonise substrata. Larvae may have more capacity to choose substrata in fast flows when they colonise substrata by walking. Spot measures of hydropsychid distribution cannot distinguish between these explanations. The finding that walkers can sometimes comprise significant numbers of recruits raises the prospect that hydropsychids can be sourced locally and have not inevitably drifted in from upstream locations.
Measuring fragmentation of seagrass landscapes: which indices are most appropriate for detecting change?
Authors: Sleeman Jai C. , Kendrick Gary A. , Boggs Guy S. , Hegge Bruce J.
Published: September 2005

Many indices are available for assessment of spatial patterns in landscape ecology, yet there is presently no consensus about which ones effectively quantify habitat fragmentation. Research that has been carried out to date has evaluated indices primarily using computer-simulated models of terrestrial environments, but how they perform when applied to real landscapes, particularly in the marine environment, has received little attention. Eleven indices that are commonly used for quantifying habitat fragmentation were assessed for their abilities to measure different levels of fragmentation in 16-ha landscape windows of mapped seagrass. The landscape windows were grouped into five categories, from highly fragmented to continuous seagrass landscapes. Nested within the fragmentation categories were high and low levels of seagrass cover. Hierarchical analysis of variance techniques were used to differentiate between the different fragmentation categories and levels of seagrass cover within the fragmentation categories. Principal component analysis was also employed to determine strong correlations between the indices. The results suggest that (1) landscape division and (2) area-weighted mean perimeter to area ratio were the most appropriate indices for differentiating between independent levels of seagrass fragmentation. The splitting index may also be useful when the detection of small differences in cover is important.
Role and efficacy of marine protected areas for the South African rock lobster, Jasus lalandii
Authors: Mayfield Stephen , Branch George M. , Cockcroft Andrew C.
Published: September 2005

Protected areas for the South African rock lobster, Jasus lalandii, were sampled by using divers, traps and ringnets at sites within and adjacent to four protected areas (St Helena Bay, Saldanha Bay and Table Bay rock lobster sanctuaries and the Betty’s Bay marine reserve), over two years. Virtually no rock lobsters were found in St Helena Bay sanctuary, probably because of periodic harmful algal blooms. Abundance was greater in Saldanha Bay sanctuary than in adjacent fished areas, but only once in two years. Sizes were, however, larger in this sanctuary than the fished areas. By an order of magnitude, fewer and smaller rock lobsters were caught within the Table Bay sanctuary than in adjacent areas. Only at Betty’s Bay were rock lobster sizes and abundance consistently greater inside than outside the reserve. Fecundity was similar among sites, with females in protected areas contributing no more to egg production than would be expected by the proportional area occupied by protected areas. Rock lobsters do benefit from protection in Betty’s Bay reserve, but the west coast sanctuaries appear poorly located and seemingly contain large areas of unsuitable substrate. They clearly need relocation to be effective.
Transmembrane glycine zippers: Physiological and pathological roles in membrane proteins
Authors: Kim Sanguk , Jeon Tae-Joon , Oberai Amit , Yang Duan , Schmidt Jacob J. , Bowie James U.
Published: September 2005

We have observed a common sequence motif in membrane proteins, which we call a glycine zipper. Glycine zipper motifs are strongly overrepresented and conserved in membrane protein sequences, and mutations in glycine zipper motifs are deleterious to function in many cases. The glycine zipper has a significant structural impact, engendering a strong driving force for right-handed packing against a neighboring helix. Thus, the presence of a glycine zipper motif leads directly to testable structural hypotheses, particularly for a subclass of glycine zipper proteins that form channels. For example, we suggest that the membrane pores formed by the amyloid-β peptide
in vitro
are constructed by glycine zipper packing and find that mutations in the glycine zipper motif block channel formation. Our findings highlight an important structural motif in a wide variety of normal and pathological processes.
Notch interferes with the scaffold function of JNK-interacting protein 1 to inhibit the JNK signaling pathway
Authors: Kim Jin Woo , Kim Myung Jin , Kim Kwang Je , Yun Hee Jae , Chae Ji Soo , Hwang Sang Gil , Chang Tong-Shin , Park Hee-Sae , Lee Kang-Woo , Han Pyung-Lim , Cho Ssang-Goo , Kim Tae-Wan , Choi Eui-Ju
Published: September 2005

The transmembrane protein Notch is cleaved by γ-secretase to yield an active form, Notch intracellular domain (Notch-IC), in response to the binding of ligands, such as Jagged. Notch-IC contributes to the regulation of a variety of cellular events, including cell fate determination during embryonic development as well as cell growth, differentiation, and survival. We now show that Notch1-IC suppresses the scaffold activity of c-Jun N-terminal kinase (JNK)-interacting protein 1 (JIP1) in the JNK signaling pathway. Notch1-IC physically associated with the JNK binding domain of JIP1 and thereby interfered with the interaction between JIP1 and JNK. JIP1 mediated the activation of JNK1 induced by glucose deprivation in mouse embryonic fibroblasts, and ectopic expression of Notch1-IC inhibited JNK activation and apoptosis triggered by glucose deprivation. Taken together, these findings suggest that Notch1-IC negatively regulates the JNK pathway by disrupting the scaffold function of JIP1.
C-type natriuretic peptide inhibits leukocyte recruitment and platelet-leukocyte interactions via suppression of P-selectin expression
Authors: Scotland Ramona S. , Cohen Marc , Foster Paul , Lovell Matthew , Mathur Anthony , Ahluwalia Amrita , Hobbs Adrian J.
Published: September 2005

The multifaceted process of immune cell recruitment to sites of tissue injury is key to the development of an inflammatory response and involved in the pathogenesis of numerous cardiovascular disorders. We recently identified C-type natriuretic peptide (CNP) as an important endothelium-derived mediator that regulates vascular tone and protects against myocardial ischemia/reperfusion injury. Herein, we investigated whether CNP inhibits leukocyte recruitment and platelet aggregation and thereby exerts a potential antiinflammatory influence on the blood vessel wall. We assessed the effects of CNP on leukocyte-endothelial cell interactions in mouse mesenteric postcapillary venulesin vivoin animals with high basal leukocyte activation (endothelial nitric oxide synthase knockout mice, eNOS-/-) or under acute inflammatory conditions (induced by interleukin-1β or histamine). CNP suppressed basal leukocyte rolling in eNOS-/-mice in a rapid, reversible, and concentration-dependent manner. These effects of CNP were mimicked by the selective natriuretic peptide receptor-C agonist cANF4-23. CNP also suppressed leukocyte rolling induced by IL-1β or histamine, inhibited platelet-leukocyte interactions, and prevented thrombin-induced platelet aggregation of human blood. Furthermore, analysis of human umbilical vein endothelial cells, leukocytes, and platelets revealed that CNP selectively attenuates expression of P-selectin. Thus, CNP is a modulator of acute inflammation in the blood vessel wall characterized by leukocyte and platelet activation. These antiinflammatory effects appear to be mediated, at least in part, via suppression of P-selectin expression. These observations suggest that endothelial CNP might maintain an anti-atherogenic influence on the blood vessel wall and represent a target for therapeutic intervention in inflammatory cardiovascular disorders.
Targeting angiogenesis: Structural characterization and biological properties of a
de novo
engineered VEGF mimicking peptide
Authors: D'Andrea Luca Domenico , Iaccarino Guido , Fattorusso Roberto , Sorriento Daniela , Carannante Concetta , Capasso Domenica , Trimarco Bruno , Pedone Carlo
Published: September 2005

Modulating angiogenesis is an attractive goal because many pathological conditions depend on the growth of new vessels. Angiogenesis is mainly regulated by the VEGF, a mitogen specific for endothelial cells. In the last years, many efforts have been pursued to modulate the angiogenic response targeting VEGF and its receptors. Based on the x-ray structure of VEGF bound to the receptor, we designed a peptide, QK, reproducing a region of the VEGF binding interface: the helix region 17–25. NMR conformation analysis of QK revealed that it adopts a helical conformation in water, whereas the peptide corresponding to the α-helix region of VEGF, VEGF15, is unstructured. Biological assays
in vitro
and on bovine aorta endothelial cells suggested that QK binds to the VEGF receptors and competes with VEGF. VEGF15 did not bind to the receptors indicating that the helical structure is necessary for the biological activity. Furthermore, QK induced endothelial cells proliferation, activated cell signaling dependent on VEGF, and increased the VEGF biological response. QK promoted capillary formation and organization in an
in vitro
assay on matrigel. These results suggested that the helix region 17–25 of VEGF is involved in VEGF receptor activation. The peptide designed to resemble this region shares numerous biological properties of VEGF, thus suggesting that this region is of potential interest for biomedical applications, and molecules mimicking it could be attractive for therapeutic and diagnostic applications.
Extracting subnanometer single shells from ultralong multiwalled carbon nanotubes
Authors: Hong Byung Hee , Small Joshua P. , Purewal Meninder S. , Mullokandov Asher , Sfeir Matthew Y. , Wang Feng , Lee Ju Young , Heinz Tony F. , Brus Louis E. , Kim Philip , Kim Kwang S.
Published: September 2005

We report a simple but powerful method for engineering multi-walled carbon nanotubes (MWNTs) by using manipulation by an atomic-force microscope. The successive shell-by-shell extraction process of ultralong MWNTs allows the exposure of the innermost single-walled carbon nanotubes (SWNTs), which have diameters as small as ≈0.4 nm. The inner-shell extraction process changes the electrical characteristics of the MWNTs. Whereas the outer hollowed-out nanotubes show either metallic or semiconducting character, the innermost SWNTs of small diameter exhibit predominantly metallic transport properties.
A positive feedback loop of phosphodiesterase 3 (PDE3) and inducible cAMP early repressor (ICER) leads to cardiomyocyte apoptosis
Authors: Ding Bo , Abe Jun-ichi , Wei Heng , Xu Haodong , Che Wenyi , Aizawa Toru , Liu Weimin , Molina Carlos A. , Sadoshima Junichi , Blaxall Burns C. , Berk Bradford C. , Yan Chen
Published: September 2005

cAMP plays crucial roles in cardiac remodeling and the progression of heart failure. Recently, we found that expression of cAMP hydrolyzing phosphodiesterase 3A (PDE3A) was significantly reduced in human failing hearts, accompanied by up-regulation of inducible cAMP early repressor (ICER) expression. Angiotensin II (Ang II) and the β-adrenergic receptor agonist isoproterenol (ISO) also induced persistent PDE3A down-regulation and concomitant ICER up-regulation
in vitro
, which is important in Ang II- and ISO-induced cardiomyocyte apoptosis. We hypothesized that interactions between PDE3A and ICER may constitute an autoregulatory positive feedback loop (PDE3A-ICER feedback loop), and this loop would cause persistent PDE3A down-regulation and ICER up-regulation. Here, we demonstrate that ICER induction repressed PDE3A gene transcription. PDE3A down-regulation activated cAMP/PKA signaling, leading to ICER up-regulation via PKA-dependent stabilization of ICER. With respect to Ang II, the initiation of the PDE3A-ICER feedback loop depends on activation of Ang II type 1 receptor (AT1R), classical PKC(s), and CREB (cAMP response element binding protein). We further show that the PDE3A-ICER feedback loop is essential for Ang II-induced cardiomyocyte apoptosis. ISO and PDE3 inhibitors also induced the PDE3A-ICER feedback loop and subsequent cardiomyocyte apoptosis, highlighting the importance of this PDE3A-ICER feedback loop and cAMP signaling in cardiomyocyte apoptosis. Our findings may provide a therapeutic paradigm to prevent cardiomyocyte apoptosis and the progression of heart failure by inhibiting the PDE3A-ICER feedback loop.
Nonlinear system theory: Another look at dependence
Authors: Wu Wei Biao
Published: September 2005

Based on the nonlinear system theory, we introduce previously undescribed dependence measures for stationary causal processes. Our physical and predictive dependence measures quantify the degree of dependence of outputs on inputs in physical systems. The proposed dependence measures provide a natural framework for a limit theory for stationary processes. In particular, under conditions with quite simple forms, we present limit theorems for partial sums, empirical processes, and kernel density estimates. The conditions are mild and easily verifiable because they are directly related to the data-generating mechanisms.
Elucidation of IgH intronic enhancer functions via germ-line deletion
Authors: Perlot Thomas , Alt Frederick W. , Bassing Craig H. , Suh Heikyung , Pinaud Eric
Published: September 2005

Studies of chimeric mice demonstrated that the core Ig heavy chain (
IgH
) intronic enhancer (iEμ) functions in V(D)J and class switch recombination at the
IgH
locus. To more fully evaluate the role of this element in these and other processes, we generated mice homozygous for germ-line mutations in which the core sequences of iEμ (cEμ) were either deleted (cEμ
Δ/Δ
mice) or replaced with a

pgk-Neo
R

cassette (cEμ
N/N
mice). The cEμ
Δ/Δ
mice had reduced B cell numbers, in association with impaired D to J
H
and V
H
to DJ
H
rearrangement, whereas cEμ
N/N
mice had a complete block in
IgH
V(D)J
H
recombination, confirming that additional cis elements cooperate with iEμ to enforce D to J
H
recombination. In addition, developing cEμ
Δ/Δ
and cEμ
N/N
B lineage cells had correspondingly decreased levels of germ-line transcripts from the J
H
region of the
IgH
locus (μ0 and Iμ transcripts); although both had normal levels of germ-line V
H
transcripts, suggesting that cEμ may influence
IgH
locus V(D)J recombination by influencing accessibility of J
H
proximal regions of the locus. Consistent with chimera studies, peripheral cEμ
Δ/Δ
B cells had normal surface Ig and relatively normal class switch recombination. However, cEμ
Δ/Δ
B cells also had relatively normal somatic hypermutation of their
IgH
variable region genes, showing unexpectedly that the cEμ is not required for this process. The availability of mice with the iEμ mutation in their germ line will facilitate future studies to elucidate the roles of iEμ in V
H
(D)J
H
recombination in the context of
IgH
chromatin structure and germ-line transcription.
Detection of a bioluminescent milky sea from space
Authors: Miller Steven D. , Haddock Steven H. D. , Elvidge Christopher D. , Lee Thomas F.
Published: September 2005

On many occasions over the centuries, mariners have reported witnessing surreal nocturnal displays where the surface of the sea produces an intense, uniform, and sustained glow that extends to the horizon in all directions. Although such emissions cannot be fully reconciled with the known features of any light-emitting organism, these so-called “milky seas” are hypothesized to be manifestations of unusually strong bioluminescence produced by colonies of bacteria in association with a microalgal bloom in the surface waters. Because of their ephemeral nature and the paucity of scientific observations, an explanation of milky seas has remained elusive. Here, we report the first satellite observations of the phenomenon. An ≈15,400-km
2
area of the northwestern Indian Ocean, roughly the size of the state of Connecticut, was observed to glow over 3 consecutive nights, corroborated on the first night by a ship-based account. This unanticipated application of satellite remote-sensing technology provides insights pertaining to the formation and scale of these poorly understood events.
Mechanisms of SEPA 0009-Induced Tumorigenesis in v-rasHa Transgenic Tg.AC Mice
Authors: Fuhrman Jill , Shafer Laura , Repertinger Susan , Chan Tom , Hansen Laura A.
Published: September 2005

Genetically engineered mouse models with altered oncogene or tumor suppressor gene activity have been utilized recently for carcinogen identification. The v -rasHa transgenic Tg.AC mouse, with its enhanced susceptibility to skin tumorigenesis, is thought to be well suited for examining the carcinogenicity of topically applied agents. Tg.AC mice were used to examine the carcinogenicity of SEPA 0009, a rationally designed organic molecule designed to enhance drug penetration through the skin. Fifty mg SEPA 0009/kg body weight, 1500 mg SEPA 0009/kg body weight, or the vehicle alone was applied daily to the skin of Tg.AC mice. Nontransgenic FVB/N mice were also treated with the vehicle alone or 1500 mg SEPA 0009. Daily application of a high-dose of SEPA 0009 caused severe and chronic irritation by 1 week that was maintained throughout the experiment. The irritation was accompanied by increased proliferation, increased apoptosis, and expression of the wound-associated keratin 6. High-dose SEPA 0009 induced squamous papillomas in Tg.AC, but not in nontransgenic mice, by 6 weeks. In mice treated with the high dose SEPA 0009, transgene expression was detected in papillomas at week 9, well after the onset of skin irritation and hyperplasia. In contrast, low-dose SEPA 0009 was not irritating to the skin and did not induce papillomas. Thus, SEPA 0009-induced tumorigenesis was associated with chronic and severe irritation. We propose that SEPA 0009-induced tumorigenesis in Tg.AC mice proceeds through an indirect mechanism that is secondary to cutaneous irritation.
Topical Application of Representative Multifunctional Acrylates Produced Proliferative and Inflammatory Lesions in F344/N Rats and B6C3F1 Mice, and Squamous Cell Neoplasms in Tg.AC Mice
Authors: Doi Adriana M. , Hailey James R. , Hejtmancik Milton , Toft John D. , Vallant Molly , Chhabra Rajendra S.
Published: September 2005

Widespread human exposure to multifunctional acrylates is of concern, due to their inherent reactivity and irritating properties. Trimethylolpropane triacrylate (TMPTA) and pentaerythritol triacrylate (PETA) are industrially important representatives of multifunctional acrylates. The current studies characterized the toxicity of 3-month topical administration of technical grade TMPTA and PETA in F344/N rats and B6C3F1 mice, and evaluated the carcinogenic potential of TMPTA and PETA in hemizygous Tg.AC (v-Ha-ras) transgenic mice. Administration of 0.75, 1.5, 3, 6, and 12 mg/kg TMPTA and PETA for 3 months resulted in hyperplastic, degenerative, and necrotic lesions, accompanied by chronic inflammation of the skin, with severities generally increasing with dose. Lesions were slightly more severe in rats, when compared with mice, and illustrate the irritant potential of TMPTA and PETA. A similar dosage regimen was used for the 6-month study with Tg.AC mice. Topical application of TMPTA and PETA to Tg.AC mice showed dose-dependent increases in squamous cell papillomas at the site of application, with decreases in the latency of their appearance in mice receiving 3 mg/kg or greater. Papillomas, the reporter phenotype in Tg.AC mice, were accompanied by a few squamous cell carcinomas, along with hyperplastic and inflammatory lesions. Although chronic inflammation might have contributed to the development of the skin lesions, the dose-related nature of the induction of the skin papillomas in Tg.AC mice by TMPTA and PETA may reflect a potential for carcinogenicity.
The Development of Mouse APECED Models Provides New Insight into the Role of AIRE in Immune Regulation
Authors: Pereira Lara E. , Bostik Pavel , Ansari Aftab A.
Published: September 2005

Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy is a rare
recessive autoimmune disorder caused by a defect in a single gene called AIRE
(autoimmune regulator). Characteristics of this disease include a variable
combination of autoimmune endocrine tissue destruction, mucocutaneous
candidiasis and ectodermal dystrophies. The development of Aire‐knockout
mice has provided an invaluable model for the study of this disease. The aim
of this review is to briefly highlight the strides made in APECED research using
these transgenic murine models, with a focus on known roles of Aire in
autoimmunity. The findings
thus far are compelling and prompt additional areas of study which are discussed.
Antiphospholipid Antibodies Bind ATP: A putative Mechanism for the Pathogenesis of Neuronal Dysfunction
Authors: Chapman J. , Soloveichick L. , Shavit S. , Shoenfeld Y. , Korczyn A. D.
Published: September 2005

Antiphospholipid antibodies (aPL) generated in experimental animals
cross‐react with ATP. We therefore examined the possibility that aPL IgG from
human subjects bind to ATP by affinity column and an enzyme linked
immunosorbent assay (ELISA). Sera with high levels of aPL IgG were collected
from 12 patients with the antiphospholipid syndrome (APS). IgG fractions from
10 of 12 APS patients contained aPL that could be affinity‐bound to an ATP
column and completely eluted with NaCl 0.5 M. A significant (>50%) inhibition
of aPL IgG binding by ATP 5 mM was found in the majority. Similar inhibition
was obtained with ADP but not with AMP or cAMP. All the affinity purified
anti‐ATP antibodies also bound β2‐glycoprotein‐I (β2‐GPI, also known as
apolipoprotein H) suggesting that, similar to most pathogenic aPL, their binding
depends on this serum cofactor. We further investigated this possibility and found
that the binding of β2‐GPI to the ATP column was similar to that of aPL IgG in
that most was reversed by NaCl 0.5 M. Furthermore, addition of β2‐GPI to aPL
IgG significantly increased the amount of aPL binding to an ATP column. We
conclude that aPL IgG bind ATP, probably through β2‐GPI. This binding could
interfere
with the normal extracellular function of ATP and similar neurotransmitters.
New Therapeutic Strategies for Systemic Sclerosis—a Critical Analysis of the Literature
Authors: Zandman-Goddard Gisele , Tweezer-Zaks Nurit , Shoenfeld Yehuda
Published: September 2005

Systemic sclerosis (SSc) is a multi‐system disease characterized by skin
fibrosis and visceral disease. Therapy is organ and pathogenesis targeted. In
this review, we describe novel strategies in the treatment of SSc. Utilizing the
MEDLINE and the COCHRANE REGISTRY, we identified open trials, controlled
trials, for treatment of SSc from 1999 to April 2005. We used the terms scleroderma,
systemic sclerosis, Raynaud′s phenomenon, pulmonary hypertension,
methotrexate, cyclosporin, tacrolimus, relaxin, low‐dose penicillamine, IVIg,
calcium channel blockers, losartan, prazocin, iloprost, N‐acetylcysteine, bosentan,
cyclophosphamide, lung transplantation, ACE inhibitors,
anti‐thymocyte globulin, and stem cell transplantation. Anecdotal reports were
omitted.

Methotrexate, cyclosporin, tacrolimus, relaxin, low‐dose penicillamine,
and IVIg may be beneficial in improving the skin tightness in SSc. Calcium
channel blockers, the angiotensin II receptor type 1 antagonist losartan,
prazocin, the prostacyclin analogue iloprost, N‐acetylcysteine and the dual
endothelin‐receptor antagonist bosentan may be beneficial for Raynaud′s
phenomenon. Epoprostenol and bosentan are approved for therapy of
pulmonary hypertension (PAH). Other options under investigation include
intravenous or aerolized iloprost. Cyclophosphamide (CYC) pulse therapy
is effective in suppressing active alveolitis. Stem cell and lung transplantation
is a viable option for carefully selected patients. Renal crisis can be effectively
managed when hypertension is aggressively controlled with angiotensin converting
enzyme (ACE) inhibitors. Patients should continue taking ACE inhibitors even after
beginning dialysis in hope of discontinuing dialysis. Anti‐thymocyte globulin and
mycophenolate mofetil appear safe in SSc. The improvement in skin score and
the apparent stability of systemic disease during the treatment period suggest
that controlled studies of these agents are justified. Stem cell transplantation is
under investigation for severe disease. Novel therapies are currently being tested
in the treatment of SSc and have the potential of modifying the disease process
and overall
clinical outcome. The evaluation of these studies is still a difficult process.
The Diagnostic Utility of Anti‐cyclic Citrullinated Peptide Antibodies, Matrix Metalloproteinase‐3, Rheumatoid Factor, Erythrocyte Sedimentation Rate, and C‐reactive Protein in Patients with Erosive and Non‐erosive Rheumatoid Arthritis
Authors: Shovman O. , Gilburd B. , Zandman-Goddard G. , Sherer Y. , Orbach H. , Gerli R. , Shoenfeld Y.
Published: September 2005

Objective: To compare the diagnostic utility of laboratory variables,
including matrix metalloproteinase‐3 (MMP‐3), anti‐cyclic citrullinated peptide
(CCP) antibodies, rheumatoid factor (RF), erythrocyte sedimentation rate (ESR),
and C‐reactive protein (CRP) in
patients with erosive and non‐erosive rheumatoid arthritis (RA).

Methods: We assembled a training set, consisting of 60 patients with RA,
all fulfilling the revised criteria of the American College of Rheumatology. A
commercial enzyme linked immunosorbent assay (ELISA) was used both to
test for anti‐CCP antibodies (second generation ELISA kit) and MMP; RF were
detected by latex‐enhanced immunonephelometric assay. CRP
was measured by latex turbidimetric immunoassay.

Results: The levels of anti‐CCP antibody titers and ESR were significantly
higher in patients with erosive disease than those in non‐erosive RA patients
(p < 0.001 and 0.0341) respectively. Moreover, a higher frequency of elevated
titers of anti‐CCP antibodies was found in RA patients with erosions compared
to patients with non‐erosive RA (78.3% vs. 43.2% respectively). The ROC curves
of anti‐CCP passed closer to the upper left corner than those other markers and
area under the curve (AUC) of anti‐CCP was significantly larger than AUC of other
markers (0.755 for anti‐CCP,
0.660 for ESR, 0.611 for CRP, 0.577 for RF, and 0.484 for MMP‐3 female).

A positive predictive value was higher for anti‐CCP antibodies in comparison to
other markers. We did not find significant statistical correlation between anti‐CCP
antibody titers and inflammatory markers such as ESR or CRP. However, we
confirmed the correlation of elevated titers of anti‐CCP antibodies and RF in both
groups of patients whereas
the degree of correlation was more significant in non‐erosive patients.

Conclusion: The results of our study suggest that the presence of elevated
anti‐CCP antibody titers have better diagnostic
performance than MMP‐3, RF, CRP and ESR in patients with erosive RA.
The effect of interference in the early processing stages on response inhibition in the stop signal task
Authors: Verbruggen Frederick , Liefooghe Baptist , Vandierendonck André
Published: September 2005

In the present study, the relation between interference at the early processing stages and response inhibition was investigated. In previous studies, response stopping appeared to be slowed down when irrelevant distracting information was presented. The purpose of the present study was to further explore the relationship between interference control and response inhibition. In Experiment 1, a stop signal paradigm was combined with a global/local task. The typical global-to-local interference effect is generally attributed to early processing stages, such as stimulus perception and identification. Results of this experiment demonstrated a congruency effect for both reaction time data and stopping performance. In Experiment 2, these results were replicated with a flanker task that used stimulus-incongruent but response-congruent flankers. Results of both experiments suggest that response inhibition and interference at the early processing stages interact.
Mental representation in visual/haptic crossmodal memory: evidence from interference effects
Authors: Lacey Simon , Campbell Christine
Published: September 2005

Two experiments used visual-, verbal-, and haptic-interference tasks during encoding (Experiment 1) and retrieval (Experiment 2) to examine mental representation of familiar and unfamiliar objects in visual/haptic crossmodal memory. Three competing theories are discussed, which variously suggest that these representations are: (a) visual; (b) dual-code—visual for unfamiliar objects but visual and verbal for familiar objects; or (c) amodal. The results suggest that representations of unfamiliar objects are primarily visual but that crossmodal memory for familiar objects may rely on a network of different representations. The pattern of verbal-interference effects suggests that verbal strategies facilitate encoding of unfamiliar objects regardless of modality, but only haptic recognition regardless of familiarity. The results raise further research questions about all three theoretical approaches.
EPS Mid-Career Award 2004: Brain mechanisms of attention
Authors: Duncan John
Published: September 2005

There are many varieties of “attention”, to some extent separate yet working together to produce coherent perception, thought, and behaviour. Using data from human behaviour, functional neuroimaging, and single-cell recording in the behaving monkey, I consider different levels of attention and their basis in physiological mechanisms of biased competition. Beginning with visual attention, I suggest that processing is competitive in many brain systems that code visual input. Competition is biased towards stimuli that match task requirements and is integrated between systems coding different object properties. The result is flexible, object-based attentional selection. In the second part of the paper, I describe recent experiments on attentional competition within and between sensory modalities. Though competition is often modality specific, more global levels of interference are also easy to demonstrate. In the third part of the paper, I move to frontoparietal cortex and to a pattern of similar brain regions recruited by many different cognitive demands. This multiple-demand (MD) pattern, I suggest, reflects neurons with highly flexible response properties, adapting to represent the information and events of many different tasks. Biased competition in MD regions may play a central role in broad attentional capacity limits and attentional focusing. More generally, I suggest that biased competition is characteristic of many different cognitive domains and brain systems. Coherent “attention” develops as different systems converge to work on related cognitive content.
Arginase I in myeloid suppressor cells is induced by COX-2 in lung carcinoma
Authors: Rodriguez Paulo C. , Hernandez Claudia P. , Quiceno David , Dubinett Steven M. , Zabaleta Jovanny , Ochoa Juan B. , Gilbert Jill , Ochoa Augusto C.
Published: September 2005

Myeloid suppressor cells (MSCs) producing high levels of arginase I block T cell function by depleting l-arginine in cancer, chronic infections, and trauma patients. In cancer, MSCs infiltrating tumors and in circulation are an important mechanism for tumor evasion and impair the therapeutic potential of cancer immunotherapies. However, the mechanisms that induce arginase I in MSCs in cancer are unknown. Using the 3LL mouse lung carcinoma, we aimed to characterize these mechanisms. Arginase I expression was independent of T cell–produced cytokines. Instead, tumor-derived soluble factors resistant to proteases induced and maintained arginase I expression in MSCs. 3LL tumor cells constitutively express cyclooxygenase (COX)-1 and COX-2 and produce high levels of PGE2. Genetic and pharmacological inhibition of COX-2, but not COX-1, blocked arginase I induction in vitro and in vivo. Signaling through the PGE2 receptor E-prostanoid 4 expressed in MSCs induced arginase I. Furthermore, blocking arginase I expression using COX-2 inhibitors elicited a lymphocyte-mediated antitumor response. These results demonstrate a new pathway of prostaglandin-induced immune dysfunction and provide a novel mechanism that can help explain the cancer prevention effects of COX-2 inhibitors. Furthermore, an addition of arginase I represents a clinical approach to enhance the therapeutic potential of cancer immunotherapies.
Conditional deletion reveals a cell-autonomous requirement of SLP-76 for thymocyte selection
Authors: Maltzman Jonathan S. , Kovoor Lisa , Clements James L. , Koretzky Gary A.
Published: September 2005

The SH2 domain containing leukocyte phosphoprotein of 76 kD (SLP-76) is critical for pre-TCR–mediated maturation to the CD4+CD8+ double positive (DP) stage in the thymus. The absolute block in SLP-76null mice at the CD4−CD8−CD44−CD25+ (double-negative 3, DN3) stage has hindered our understanding of the role of this adaptor in αβ TCR-mediated signal transduction in primary thymocytes and peripheral T lymphocytes. To evaluate the requirements for SLP-76 in these events, we used a cre-loxP approach to generate mice that conditionally delete SLP-76 after the DN3 checkpoint. These mice develop DP thymocytes that express the αβ TCR on the surface, but lack SLP-76 at the genomic DNA and protein levels. The DP compartment has reduced cellularity in young mice and fails to undergo positive selection to CD4+ or CD8+ single positive (SP) cells in vivo or activation-induced cell death in vitro. A small number of CD4+SP thymocytes are generated, but these cells fail to flux calcium in response to an αβ TCR-generated signal. Peripheral T cells are reduced in number, lack SLP-76 protein, and have an abnormal surface phenotype. These studies show for the first time that SLP-76 is required for signal transduction through the mature αβ TCR in primary cells of the T lineage.
SNPselector: a web tool for selecting SNPs for genetic association studies
Authors: Xu Hong , Gregory Simon G. , Hauser Elizabeth R. , Stenger Judith E. , Pericak-Vance Margaret A. , Vance Jeffery M. , Züchner Stephan , Hauser Michael A.
Published: September 2005

Summary: Single nucleotide polymorphisms (SNPs) are commonly used for association studies to find genes responsible for complex genetic diseases. With the recent advance of SNP technology, researchers are able to assay thousands of SNPs in a single experiment. But the process of manually choosing thousands of genotyping SNPs for tens or hundreds of genes is time consuming. We have developed a web-based program, SNPselector, to automate the process. SNPselector takes a list of gene names or a list of genomic regions as input and searches the Ensembl genes or genomic regions for available SNPs. It prioritizes these SNPs on their tagging for linkage disequilibrium, SNP allele frequencies and source, function, regulatory potential and repeat status. SNPselector outputs result in compressed Excel spreadsheet files for review by the user.

Availability: SNPselector is freely available at

Contact:  mike.hauser@duke.edu
Noise and rank-dependent geometrical filter improves sensitivity of highly specific discovery by microarrays
Authors: Fathallah-Shaykh Hassan M.
Published: September 2005

Summary: MASH is a mathematical algorithm that discovers highly specific states of expression from genomic profiling by microarrays. The goal at the outset of this analysis was to improve the sensitivity of MASH. The geometrical representations of microarray datasets in the 3D space are rank-dependent and unique to each dataset. The first filter (F1) of MASH defines a zone of instability whose F1-sensitive ratios have large variations. A new filter (Fs) constructs in the 3D space rank-dependent lower and upper-bound contour surfaces, which are modeled based on the geometry of the unique noise intrinsic to each dataset. As compared with MASH, Fs increases sensitivity significantly without lowering the high specificity of discovery. Fs facilitates studies in functional genomics and systems biology.

Contact:  hfathall@rush.edu

Supplementary information:
Doelan: a solution for quality control monitoring of microarray production
Authors: Jourdren Laurent , Le Crom Stéphane
Published: September 2005

Summary: Doelan is an automated tool designed to monitor the quality of DNA microarray production. The software executes a series of quality control tests on hybridizations to validate batches of chips. The reports generated by Doelan should help microarray platforms aiming at quality labels, such as ISO 9001 certification. The Doelan application is written in Java and works with a plug-in system that allows everyone to add custom validation tests.

Availability: The Doelan application is distributed under the GNU General Public License at

Contact:  lecrom@biologie.ens.fr

Supplementary information: Complete documentation, source code and screenshots are available at
Validation of a search technique for crystal structure prediction of flexible molecules by application to piracetam
Authors: Nowell Harriott , Price Sarah L.
Published: September 2005

A new approach to the crystal structure prediction of flexible molecules is presented. It is applied to piracetam, whose conformational polymorphs exhibit a variety of hydrogen-bond motifs but lack the intramolecular hydrogen bond found in the gas-phase ab initio optimized conformer. Stable crystal packing can result when favourable intermolecular interactions are made possible when the molecule distorts from the gas-phase conformation. If the resulting intermolecular lattice energy is sufficiently favourable to compensate for the intramolecular energy penalty associated with the suboptimal gas-phase conformation, then the crystal structure may be experimentally feasible. The new approach involves searching for low-energy crystal structures using a large number of rigid conformers, firstly to systematically explore which regions of conformational space could give rise to low-energy hydrogen-bonded crystal structures, and then to refine the search using crystallographic insight to optimize particular intermolecular interactions. The timely discovery of a new polymorph (form IV) by an independent experimental team allowed this approach to be validated by way of a `blind test' of crystal structure prediction. Form IV was successfully identified as the most favourable computed crystal structure with a conformation very distinct from that in the previously known polymorphs.
Morphotropism: link between the isostructurality, polymorphism and (stereo)isomerism of organic crystals
Authors: Kálmán Alajos
Published: September 2005

An ongoing analysis of the supramolecular self-assembly of disubstituted cycloalkanes has led to the discovery of seven packing patterns built up from hydrogen-bonded homo- and heterochiral chains of racemic molecules, associated in either antiparallel or parallel arrays [Kálmán et al. (2001). Acta Cryst. B57, 539–550]. Two further patterns have been revealed in the close packing of analogous alicyclic β-amino acids [Fábián et al. (2005). Cryst. Growth Des.
5, 773–782]. Since each pattern is represented by at least one crystal structure, the chemical similarity and crystallographic forms of these crystals have facilitated the recognition that these patterns differ by one or two rotation(s) of the common motifs (e.g. dimers, tetramers, helices etc.), or the whole pattern may rotate through 180° in an oblique unit cell. Such non-crystallographic – with the exception of polymorphism – virtual rotations as a whole may be denoted by the expression morphotropism. According to Kitaigorodskii [(1961), Organic Chemical Crystallography, pp. 222–231. New York: Consultants Bureau], morphotropism is an attempt to keep the packing coefficient above 0.6 whenever there are alternative possibilities for the structures of closely related molecules. It has been found that crystals of stereoisomers are also frequently related by such virtual rotations. Similarly, non-crystallographic rotations effect bridges between homostructural crystals [Kálmán et al. (1993b). Acta Cryst. B49, 1039–1049] and occasionally hallmark the polymorphism of organic compounds [Kálmán et al. (2003) J. Am. Chem. Soc.
125, 34–35]. In polymorphs, however, such rotations really transform one molecule into another in order to achieve a better packing mediated by solvents, temperature etc.
Reversible pressure-induced structure changes in turbostratic BN–C solid solutions
Authors: Solozhenko Vladimir L. , Kurakevych Oleksandr O.
Published: September 2005

The results obtained by Rietveld analysis and numerical modeling of B–C–N layered clusters with various types of lattice defects explain the evolution of diffraction patterns of turbostratic graphite-like BN–C solid solutions which are experimentally observed at room temperature at pressures up to 30 GPa. Above 20 GPa a reversible diffusionless transformation of the initial turbostratic structure takes place, giving a high-pressure phase formed by close-packed buckled layers having a diamond-like structure.
Conformational isomers of a peptide–class II major histocompatibility complex
Authors: Lovitch Scott B. , Unanue Emil R.
Published: September 2005

Summary:  The relative plasticity of peptide binding to class II major histocompatibility complex (MHC) molecules permits formation of multiple conformational isomers by the same peptide and MHC molecule; such conformers are specifically recognized by distinct subsets of T cells. Here, we review current knowledge and recent advances in our understanding of peptide–class II MHC conformational isomerism and the mechanisms that generate distinct MHC–peptide conformers. We focus on our studies of two T‐cell subsets, type A and B, which recognize distinct conformers of the dominant epitope of hen egg white lysozyme presented by I‐Ak. These conformers form via different pathways and in distinct intracellular vesicles: the type A conformer forms in late endosomes upon processing of native protein, while the more flexible type B conformer forms in early endosomes and at the cell surface. In this process, H2‐DM acts as a conformational editor, eliminating the type B conformer in late endosomes. Type B T cells constitute a significant component of the naïve T‐cell repertoire; furthermore, self‐reactive type B T cells escape negative selection and are present in abundance in the periphery. Ongoing studies should elucidate the role of type B T cells in immunity to pathogens and in autoimmune pathology.