bluuebunny/crossref_metadata_2025 huggingface dataset:
Central Role of Tumor-Associated CD8+ T Effector/Memory Cells in Restoring Systemic Antitumor Immunity
Authors: Kilinc Mehmet O. , Gu Tao , Harden Jamie L. , Virtuoso Lauren P. , Egilmez Nejat K.
Published: March 2009

Sustained delivery of IL-12 and GM-CSF to tumors induces the activation of tumor-resident CD8+ T effector/memory cells (Tem) followed by cytotoxic CD8+ T effector cell expansion. To determine whether the secondary effectors expanded from tumor-associated Tem or were primed de novo, activation kinetics of tumor-draining lymph node (TDLN) CD8+ T cells were analyzed. Treatment promoted a 4-fold increase in the numbers of TDLN CD8+ T cells displaying a CD69+CCR5+CD62L− periphery-homing effector phenotype by day 4 posttherapy. Pulse labeling of tumor and TDLN T cells with BrdU confirmed that proliferation occurred exclusively within the draining lymph nodes between days 1 and 4 with subsequent migration of primed CD8+ T effectors to tumors on day 7. Day 4 CD8+ T effector cells preferentially homed to and lysed experimental, but not control, tumors, establishing tumor specificity. To determine whether the secondary CD8+ T effector cell response was dependent on activation of tumor-resident CD8+ Tem, mice that were selectively depleted of tumor-infiltrating CD8+ T cells were treated and monitored for T effector priming. In the absence of tumor-resident CD8+ Tem, T effector cell expansion was completely abrogated in the TDLN, revealing that restoration of CD8+ Tem function was critical to the induction of secondary T effectors. T cell priming failed to occur in IFN-γ or perforin knockout mice, demonstrating that the requirement for Tem activation was associated with induction of Tem cytotoxicity. These data confirm that intratumoral IL-12 plus GM-CSF induces de novo priming of tumor-specific CD8+ T effector cells in the TDLN and establish the critical role of preexisting intratumoral CD8+ Tem in driving this process.
Anti-CD25 Antibody-Mediated Depletion of Effector T Cell Populations Enhances Susceptibility of Mice to Acute but Not Chronic Toxoplasma gondii Infection
Authors: Couper Kevin N. , Lanthier Paula A. , Perona-Wright Georgia , Kummer Lawrence W. , Chen Wangxue , Smiley Stephen T. , Mohrs Markus , Johnson Lawrence L.
Published: March 2009

Natural regulatory T cells (Tregs) constitutively express the IL-2R α-chain (CD25) on their surface. Consequently, administration of anti-CD25 Abs is a commonly used technique to deplete Treg populations in vivo. However, activated effector T cells may also transiently express CD25, and are thus also potential targets for anti-CD25 Abs. In this study using Toxoplasma gondii as a model proinflammatory infection, we have examined the capacity of anti-CD25 Abs to target effector T cell populations during an inflammatory episode, to determine to what extent that this action may modulate the outcome of disease. Anti-CD25 Ab-treated C57BL/6 mice displayed significantly reduced CD4+ T cell IFN-γ production during acute T. gondii infection and exhibited reduced weight loss and liver pathology during early acute infection; aspects of infection previously associated with effector CD4+ T cell responses. In agreement, anti-CD25 Ab administration impaired parasite control and caused mice to succumb to infection during late acute/early chronic stages of infection with elevated tissue parasite burdens. In contrast, anti-CD25 Ab treatment of mice with established chronic infections did not markedly affect brain parasite burdens, suggesting that protective T cell populations do not express CD25 during chronic stages of T. gondii infection. In summary, we have demonstrated that anti-CD25 Abs may directly abrogate effector T cell responses during an inflammatory episode, highlighting important limitations of the use of anti-CD25 Ab administration to examine Treg function during inflammatory settings.
Intestinal T Cell Responses to Gluten Peptides Are Largely Heterogeneous: Implications for a Peptide-Based Therapy in Celiac Disease
Authors: Camarca Alessandra , Anderson Robert P. , Mamone Gianfranco , Fierro Olga , Facchiano Angelo , Costantini Susan , Zanzi Delia , Sidney John , Auricchio Salvatore , Sette Alessandro , Troncone Riccardo , Gianfrani Carmen
Published: March 2009

The identification of gluten peptides eliciting intestinal T cell responses is crucial for the design of a peptide-based immunotherapy in celiac disease (CD). To date, several gluten peptides have been identified to be active in CD. In the present study, we investigated the recognition profile of gluten immunogenic peptides in adult HLA-DQ2+ celiac patients. Polyclonal, gliadin-reactive T cell lines were generated from jejunal mucosa and assayed for both proliferation and IFN-γ production in response to 21 peptides from wheat glutenins and α-, γ-, and ω-gliadins. A magnitude analysis of the IFN-γ responses was performed to assess the hierarchy of peptide potency. Remarkably, 12 of the 14 patients recognized a different array of peptides. All α-gliadin stimulatory peptides mapped the 57–89 N-terminal region, thus confirming the relevance of the known polyepitope 33-mer, although it was recognized by only 50% of the patients. By contrast, γ-gliadin peptides were collectively recognized by the great majority (11 of 14, 78%) of CD volunteers. A 17-mer variant of 33-mer, QLQPFPQPQLPYPQPQP, containing only one copy of DQ2-α-I and DQ2-α-II epitopes, was as potent as 33-mer in stimulating intestinal T cell responses. A peptide from ω-gliadin, QPQQPFPQPQQPFPWQP, although structurally related to the α-gliadin 17-mer, is a distinct epitope and was active in 5 out of 14 patients. In conclusion, these results showed that there is a substantial heterogeneity in intestinal T cell responses to gluten and highlighted the relevance of γ- and ω-gliadin peptides for CD pathogenesis. Our findings indicated that α-gliadin (57–73), γ-gliadin (139–153), and ω-gliadin (102–118) are the most active gluten peptides in DQ2+ celiac patients.
Novel Subset of CD8α+ Dendritic Cells Localized in the Marginal Zone Is Responsible for Tolerance to Cell-Associated Antigens
Authors: Qiu Chun-Hong , Miyake Yasunobu , Kaise Hitomi , Kitamura Hiroshi , Ohara Osamu , Tanaka Masato
Published: March 2009

Apoptotic cell clearance by dendritic cells (DCs) plays a crucial role in the maintenance of self-tolerance. In spleen, CD8α+ DCs are thought to be responsible for this phenomenon by phagocytosing circulating apoptotic cells. However, as CD8α+ DCs are believed to be predominantly localized in the T cell zone, it remains unclear how these DCs phagocytose blood-borne apoptotic cells accumulated in the marginal zone (MZ). In this study, we identified a subpopulation of CD8α+ DCs responsible for tolerance induction to cell-associated Ags. Among splenic CD8α+ DCs, the CD103+,CD207+ subset was preferentially localized in the MZ and dominantly phagocytosed blood-borne apoptotic cells. After phagocytosis of apoptotic cells, this DC subset migrated into the T cell zone for cross-presentation of cell-associated Ags. Stimulation of TLRs induced the disappearance of this DC subset. Consequently, CD8α+ DCs neither phagocytosed injected apoptotic cells nor presented cell-associated Ags in mice treated with TLR ligands. Transient ablation of this DC subset by cytochrome c injection resulted in a failure of tolerance induction to cell-associated Ags, indicating that this DC subset is essential for tolerance induction by apoptotic cell clearance.
Modulation of T Lymphocyte Replicative Senescence via TNF-α Inhibition: Role of Caspase-3
Authors: Parish Stanley T. , Wu Jennifer E. , Effros Rita B.
Published: March 2009

Expanded populations of CD8+ T lymphocytes lacking CD28 expression are associated with a variety of deleterious clinical outcomes, including early mortality in the elderly, more rapid progression to AIDS, cardiovascular disease, and enhanced tumor cell growth. In cell culture, irreversible loss of CD28 expression correlates with increased production of TNF-α as CD8+ T cells are driven to the nonproliferative end stage of replicative senescence by multiple rounds of Ag-driven cell division. Interestingly, in patients with rheumatoid arthritis, inhibition or neutralization of TNF-α reduces the proportion of T cells lacking CD28 in the disease joints, consistent with studies showing a direct involvement of this cytokine in CD28 gene transcription. Here, we show that modulation of TNF-α levels in long-term cultures of human CD8+ T lymphocytes, by chronic exposure either to a neutralizing Ab or to an inhibitor of the TNF-α receptor-1, increases proliferative potential, delays loss of CD28 expression, retards cytokine profile changes, and enhances telomerase activity. We also show that constitutive caspase-3, one of the downstream effectors of TNF-αR1 binding, increases in parallel with the loss of CD28 in long-term cultures, but this effect is blunted in the presence of the TNF-α inhibitors. Consistent with the in vitro culture data, CD8+CD28− T lymphocytes tested immediately ex vivo also show significantly higher levels of caspase-3 compared with their CD28+ counterparts. These findings help elucidate the complex nature of CD28 gene regulation, and may ultimately lead to novel therapeutic approaches for diseases associated with increased proportions of CD28− T lymphocytes.
Cutting Edge: Acute Lung Allograft Rejection Is Independent of Secondary Lymphoid Organs
Authors: Gelman Andrew E. , Li Wenjun , Richardson Steven B. , Zinselmeyer Bernd H. , Lai Jiaming , Okazaki Mikio , Kornfeld Christopher G. , Kreisel Friederike H. , Sugimoto Seiichiro , Tietjens Jeremy R. , Dempster John , Patterson G. Alexander , Krupnick Alexander S. , Miller Mark J. , Kreisel Daniel
Published: March 2009

It is the prevailing view that adaptive immune responses are initiated in secondary lymphoid organs. Studies using alymphoplastic mice have shown that secondary lymphoid organs are essential to initiate allograft rejection of skin, heart, and small bowel. The high immunogenicity of lungs is well recognized and allograft rejection remains a major contributing factor to poor outcomes after lung transplantation. We show in this study that alloreactive T cells are initially primed within lung allografts and not in secondary lymphoid organs following transplantation. In contrast to other organs, lungs are acutely rejected in the absence of secondary lymphoid organs. Two-photon microscopy revealed that recipient T cells cluster predominantly around lung-resident, donor-derived CD11c+ cells early after engraftment. These findings demonstrate for the first time that alloimmune responses following lung transplantation are initiated in the graft itself and therefore identify a novel, potentially clinically relevant mechanism of lung allograft rejection.
Vitamin D-Directed Rheostatic Regulation of Monocyte Antibacterial Responses
Authors: Adams John S. , Ren Songyang , Liu Philip T. , Chun Rene F. , Lagishetty Venu , Gombart Adrian F. , Borregaard Niels , Modlin Robert L. , Hewison Martin
Published: March 2009

The active form of vitamin D, 1,25-dihydroxyvitamin D (1,25(OH)2D) enhances innate immunity by inducing the cathelicidin antimicrobial peptide (hCAP). In monocytes/macrophages, this occurs primarily in response to activation of TLR, that induce expression of the vitamin D receptor and localized synthesis of 1,25(OH)2D from precursor 25-hydroxyvitamin D3 (25OHD). To clarify the relationship between vitamin D and innate immunity, we assessed changes in hCAP expression in vivo and ex vivo in human subjects attending a bone clinic (n = 50). Of these, 38% were vitamin D-insufficient (<75 nM 25OHD) and received supplementation with vitamin D (50,000 IU vitamin D2 twice weekly for 5 wk). Baseline 25OHD status or vitamin D supplementation had no effect on circulating levels of hCAP. Therefore, ex vivo changes in hCAP for each subject were assessed using peripheral blood monocytes cultured with 10% autologous serum (n = 28). Under these vitamin D “insufficient” conditions the TLR2/1 ligand 19 kDa lipopeptide or the TLR4 ligand LPS, monocytes showed increased expression of the vitamin D-activating enzyme CYP27b1 (5- and 5.5-fold, respectively, both p < 0.01) but decreased expression of hCAP mRNA (10-fold and 30-fold, both p < 0.001). Following treatment with 19 kDa, expression of hCAP: 1) correlated with 25OHD levels in serum culture supplements (R = 0.649, p < 0.001); 2) was significantly enhanced by exogenous 25OHD (5 nM); and 3) was significantly enhanced with serum from vivo vitamin D-supplemented patients. These data suggest that a key role of vitamin D in innate immunity is to maintain localized production of antibacterial hCAP following TLR activation of monocytes.
Vascular Endothelial Growth Factor C Facilitates Immune Tolerance and Endovascular Activity of Human Uterine NK Cells at the Maternal-Fetal Interface
Authors: Kalkunte Satyan S. , Mselle Teddy F. , Norris Wendy E. , Wira Charles R. , Sentman Charles L. , Sharma Surendra
Published: March 2009

Although replete with cytotoxic machinery, uterine NK (uNK) cells remain tolerant at the maternal-fetal interface. The mechanisms that facilitate the uNK cell tolerance are largely unknown. In this study, we demonstrate that vascular endothelial growth factor (VEGF) C, a proangiogenic factor produced by uNK cells, is responsible for their noncytotoxic activity. VEGF C-producing uNK cells support endovascular processes as demonstrated in a three-dimensional coculture model of capillary tube formation on Matrigel. Peripheral blood NK cells fail to produce VEGF C and remain cytotoxic. This response can be reversed by exogenous VEGF C. We show that cytoprotection by VEGF C can be related to induction of the TAP-1 expression and MHC class I assembly in target cells. Small interfering RNA-mediated silencing of TAP-1 expression abolished the VEGF C-imparted protection. Overall, these results demonstrate that empowerment of uNK cells with angiogenic factors keeps them noncytotoxic. This phenotype is critical to their pregnancy-compatible immunovascular role during placentation and fetal development.
Uneven Colonization of the Lymphoid Periphery by T Cells That Undergo Early TCRα Rearrangements
Authors: Hendricks Deborah W. , Fink Pamela J.
Published: March 2009

A sparse population of thymocytes undergoes TCRα gene rearrangement early in development, before the double-positive stage. The potential of these cells to contribute to the peripheral T cell pool is unknown. To examine the peripheral T cell compartment expressing a repertoire biased to early TCR gene rearrangements, we developed a mouse model in which TCRα rearrangements are restricted to the double-negative stage of thymocyte development. These mice carry floxed RAG2 alleles and a Cre transgene driven by the CD4 promoter. As expected, conventional T cell development is compromised in such Cre+ RAG2fl/fl mice, and the TCRαβ+ T cells that develop are limited in their TCRα repertoire, preferentially using early rearranging Vα genes. In the gut, the Thy-1+TCRαβ+ intraepithelial lymphocyte (IEL) compartment is surprisingly intact, whereas the Thy-1−TCRαβ+ subset is almost completely absent. Thus, T cells expressing a TCRα repertoire that is the product of early gene rearrangements can preferentially populate distinct IEL compartments. Despite this capacity, Cre+ RAG2fl/fl T cell progenitors cannot compete with wild-type T cell progenitors in mixed bone marrow chimeras, suggesting that in normal mice, there is only a small contribution to the peripheral T cell pool by cells that have undergone early TCRα rearrangements. In the absence of wild-type competitors, aggressive homeostatic proliferation in the IEL compartment can promote a relatively normal Thy-1+ TCRαβ+ T cell pool from the limited population derived from Cre+ RAG2fl/fl progenitors.
Cutting Edge: TLR-Dependent Viral Recognition Along with Type I IFN Positive Feedback Signaling Masks the Requirement of Viral Replication for IFN-α Production in Plasmacytoid Dendritic Cells
Authors: Kumagai Yutaro , Kumar Himanshu , Koyama Shohei , Kawai Taro , Takeuchi Osamu , Akira Shizuo
Published: March 2009

Plasmacytoid dendritic cells (pDCs) recognize RNA virus infection via TLRs and consequently produce vast amounts of type I IFN. Because nucleic acid-sensing TLRs reside in the intracellular membrane compartment, it is presumable that pDCs do not require cytoplasmic viral replication to recognize the infection. By checking Newcastle disease virus (NDV) RNA abundance in GFP+ and GFP− pDCs from Ifna6gfp mice, we found that NDV replication was not detected in IFN-producing pDCs. GFP+ pDC was induced in response to replication-incompetent NDV. In contrast, the replication-incompetent NDV failed to induce IFN-producing pDCs in type I IFNR-deficient mice. The lack of IFNR signaling led to the replication of NDV and the subsequent RIG-I-like helicase-dependent IFN-α production in pDCs. These results showed that detection of viruses via TLRs together with a type I IFN feedback system circumvents the requirement for viral replication-dependent recognition in pDCs.
Subtle Affinity-Enhancing Mutations in a Myelin Oligodendrocyte Glycoprotein-Specific TCR Alter Specificity and Generate New Self-Reactivity
Authors: Udyavar Akshata , Alli Rajshekhar , Nguyen Phuong , Baker Lesley , Geiger Terrence L.
Published: March 2009

We describe a simple iterative approach to augment TCR affinity, which we studied using a myelin oligodendrocyte glycoprotein-specific TCR. We hypothesized that single amino acid modifications in TCR CDR3 could enhance TCR sensitivity through focal interactions with antigenic peptide while minimizing the risk of cross-reactivity observed previously in TCR more broadly mutagenized using in vitro evolution techniques. We show that this iterative method can indeed generate TCR with Ag sensitivity 100-fold greater than the parental receptor and can endow TCR with coreceptor independence. However, we also find that single amino acid mutations in the CDR3 can alter TCR fine specificity, affecting recognition requirements for Ag residues over most of the length of the MHC binding groove. Furthermore, minimal changes in surface-exposed CDR3 amino acids, even the addition of a single hydroxyl group or conversion of a methyl or sulfhydryl moiety to a hydroxyl, can confer modified Ag-specific TCR with new self-reactivity. In vivo modeling of modified TCR through retroviral TCR gene transfer into Rag−/− mice confirmed the biological significance of these altered reactivities, although it also demonstrated the feasibility of producing Ag-specific, positively selecting, coreceptor-independent receptors with markedly increased Ag sensitivity. These results affirm the possibility of readily generating affinity-enhanced TCR for therapeutic purposes but demonstrate that minimal changes in TCR CDR3 structure can promote self reactivity and thereby emphasize the importance of caution in validating receptors with even subtle alterations before clinical application.
pH‐Responsive Flower‐Type Micelles Formed by a Biotinylated Poly(2‐vinylpyridine)‐block‐poly(ethylene oxide)‐block‐poly(ε‐caprolactone) Triblock Copolymer
Authors: Van Butsele Kathy , Cajot Sébastien , Van Vlierberghe Sandra , Dubruel Peter , Passirani Catherine , Benoit Jean‐Pierre , Jérôme Robert , Jérôme Christine
Published: March 2009

In the present work, a method is proposed to assemble pH‐responsive, flower‐like micelles that can expose a targeting unit at their periphery upon a decrease in pH. The micelles are composed of a novel biotinylated triblock copolymer of poly(εε‐caprolactone)‐block‐poly(ethylene oxide)‐block‐poly(2‐vinylpyridine) (PCL‐b‐PEO‐b‐P2VP) and the non‐biotinylated analogue. The block copolymers are synthesized by sequential anionic and ring‐opening polymerization. The pH‐dependent micellization behaviour in aqueous solution of the triblock copolymers developed is studied using dynamic light scattering, zeta potential, transmission electron microscopy (TEM), and fluorimetric measurements. The shielding of the biotin at neutral pH and their availability at the micelle surface upon protonation is established by TEM and surface plasmon resonance with avidin and streptavidin‐coated gold surfaces. The preliminary stealthy behavior of these pH‐responsive micelles is examined using the complement activation (CH50) test.
Polymer Films Composed of Surface‐Bound Nanofilaments with a High Aspect Ratio, Molecularly Imprinted with Small Molecules and Proteins
Authors: Linares Ana Valvanuz , Vandevelde Fanny , Pantigny Jacques , Falcimaigne‐Cordin Aude , Haupt Karsten
Published: March 2009

Hierarchically nanostructured materials that combine two or more levels of structuring and that exhibit a combination of useful features have gained considerable interest over recent years. Here, the generation of surface‐bound nanofilaments with a high aspect ratio by nanomolding on a nanoporous template surface is described. The filaments, at the same time, carry molecularly imprinted binding sites. The dye fluorescein and the protein myoglobin are used as model templates for imprinting. The surfaces exhibit specific binding as revealed by fluorescence microscopy. The wetting properties of the surfaces depend on the dimensions of the nanofilaments and on the nature of the polymer. It is believed that these materials can potentially be useful for applications in biosensors and biochips.
Randomized sequential trial of valproic acid in amyotrophic lateral sclerosis
Authors: Piepers Sanne , Veldink Jan H. , De Jong Sonja W. , Van Der Tweel Ingeborg , Van Der Pol W‐Ludo , Uijtendaal Esther V. , Schelhaas H. Jurgen , Scheffer Hans , De Visser Marianne , De Jong J. M. B. Vianney , Wokke John H. J. , Groeneveld Geert Jan , Van Den Berg Leonard H.
Published: March 2009

Objective

To determine whether valproic acid (VPA), a histone deacetylase inhibitor that showed antioxidative and antiapoptotic properties and reduced glutamate toxicity in preclinical studies, is safe and effective in amyotrophic lateral sclerosis (ALS) using a sequential trial design.

Methods

Between April 2005 and January 2007, 163 ALS patients received VPA 1,500mg or placebo daily. Primary end point was survival. Secondary outcome measure was decline of functional status measured by the revised ALS Functional Rating Scale. Analysis was by intention to treat and according to a sequential trial design. This trial was registered with ClinicalTrials.gov (number NCT00136110).

Results

VPA did not affect survival (cumulative survival probability of 0.72 in the VPA group [standard error (SE), 0.06] vs 0.88 in the placebo group [SE, 0.04] at 12 months, and 0.59 in the VPA group [SE, 0.07] vs 0.68 in the placebo group [SE, 0.08] at 16 months) or the rate of decline of functional status. VPA intake did not cause serious adverse reactions.

Interpretation

Our finding that VPA, at a dose used in epilepsy, does not show a beneficial effect on survival or disease progression in patients with ALS has implications for future trials with histone deacetylase inhibitors in ALS and other neurodegenerative diseases. The use of a sequential trial design allowed inclusion of only half the number of patients required for a classic trial design and prevented patients from unnecessarily continuing potentially harmful study medication. Ann Neurol 2009;66:227–234
Digit‐specific aberrations in the primary somatosensory cortex in Writer's cramp
Authors: Nelson Aimee J. , Blake David T. , Chen Robert
Published: March 2009

Objective

One approach to the treatment of focal hand dystonia (FHD) is via sensory‐based training regimes. It is known that FHD patients demonstrate a reduced distance between the representations of digits 1 and 5 and also digits 2 and 5 in primary somatosensory cortex. However, we lack information on the spatial relationships among digits, such as reduced inter‐digit spacing or shifts of representations within the cortical areas, and whether aberrations are specific to symptomatic digits. Our aim was to characterize the spatial relationships among individual digits to determine the types of aberrations that exist and whether these are specific to symptomatic digits only.

Methods

Using high‐resolution fMRI over a limited volume and surface‐based mapping techniques, the cortical representations of all digits of the dystonia‐affected hand within the sub‐regions of the postcentral gyrus were mapped in patients with task‐specific Writer's cramp (WC).

Results

In area 3b, digits directly involved in writing (D1, D2 and D3) show reduced inter‐digit separation, reversals, and overlapping activation. The thumb representation occupies territory normally occupied by digit 2 in controls. Asymptomatic digits 4 and 5 preserve their inter‐digit separation yet shift towards the D1/D2/D3 cluster, suggesting that reduced spacing, not simply digit shifts, are associated with dystonia symptoms. Area 3a was less responsive to sensory input in WC patients providing evidence of reduced afferent drive or top‐down modulation to this sub‐region.

Interpretation

Therapeutic regimes aimed at facilitating inter‐digit separation of digits 1, 2 and 3 may promote beneficial plasticity in WC patients. Ann Neurol 2009;66:146–154.
SNCA variants are associated with increased risk for multiple system atrophy
Authors: Scholz Sonja W. , Houlden Henry , Schulte Claudia , Sharma Manu , Li Abi , Berg Daniela , Melchers Anna , Paudel Reema , Gibbs J. Raphael , Simon‐Sanchez Javier , Paisan‐Ruiz Coro , Bras Jose , Ding Jinhui , Chen Honglei , Traynor Bryan J. , Arepalli Sampath , Zonozi Ryan R. , Revesz Tamas , Holton Janice , Wood Nick , Lees Andrew , Oertel Wolfgang , Wüllner Ullrich , Goldwurm Stefano , Pellecchia Maria Teresa , Illig Thomas , Riess Olaf , Fernandez Hubert H. , Rodriguez Ramon L. , Okun Michael S. , Poewe Werner , Wenning Gregor K. , Hardy John A. , Singleton Andrew B. , Gasser Thomas
Published: March 2009

To test whether the synucleinopathies Parkinson's disease and multiple system atrophy (MSA) share a common genetic etiology, we performed a candidate single nucleotide polymorphism (SNP) association study of the 384 most associated SNPs in a genome‐wide association study of Parkinson's disease in 413 MSA cases and 3,974 control subjects. The 10 most significant SNPs were then replicated in additional 108 MSA cases and 537 controls. SNPs at the SNCA locus were significantly associated with risk for increased risk for the development of MSA (combined p = 5.5 × 1012; odds ratio 6.2). Ann Neurol 2009;65:610–614
Closed and Open Clamlike Structures Formed by Hydrogen‐Bonded Pairs of Cyclotricatechylene Anions that Contain Cationic “Meat”
Authors: Abrahams Brendan F. , FitzGerald Nicholas J. , Hudson Timothy A. , Robson Richard , Waters Tom
Published: March 2009

Clamming up: The hexaphenolic compound cyclotricatechylene, which has a bowl‐shaped cavity, forms clamlike pairs that encapsulate cations (see picture). Variable hydrogen bonding allows two linked cyclotricatechylene clamshells to be in a closed arrangement when smaller cations such Rb+ or Cs+ provide the clam meat, whereas larger cations such as NMe4+ and NEt4+ cause the clam to be partially opened.

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Perfluoropentaphenylborole: A New Approach to Lewis Acidic, Electron‐Deficient Compounds
Authors: Huynh Keith , Vignolle Joan , Tilley T. Don
Published: March 2009

Zirconocene is the key: A new synthetic method, which utilizes zirconocene‐mediated coupling of alkynes, has been developed for the preparation of a new class of highly Lewis acidic boroles (see scheme). Such compounds hold potential for applications in catalysis and the field of electron‐deficient organic materials.

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Preparation of novel axially chiral NHC–Pd(II) complexes and their application in oxidative kinetic resolution of secondary alcohols
Authors: Liu Shi‐Jia , Liu Lian‐jun , Shi Min
Published: March 2009

Novel axially chiral N‐heterocyclic carbene (NHC) Pd(II) complexes were prepared from optically active 1,1′‐binaphthalenyl‐2,2′‐diamine (BINAM) and H8‐BINAM and their crystal structures were unambiguously determined by X‐ray diffraction. These chiral N‐heterocyclic carbene (NHC) Pd(II) complexes were applied in the oxidative kinetic resolution of secondary alcohols using molecular oxygen as a terminal oxidant or under aerobic conditions, affording the corresponding sec‐alcohols in good yields with moderate to good enantioselectivities. Copyright © 2009 John Wiley & Sons, Ltd.
Poly(2‐(methacryloyloxy) ethyl phosphorylcholine)‐functionalized multi‐walled carbon nanotubes: Preparation, characterization, solubility, and effects on blood coagulation
Authors: Zhu Leize , Jin Qiao , Xu Jianping , Ji Jian , Shen Jiacong
Published: March 2009

Water‐soluble multi‐walled carbon nanotubes (MWNTs) were prepared via surface‐initiated atom transfer radical polymerization (ATRP) of 2‐(methacryloyloxy) ethyl phosphorylcholine (MPC) from carbon nanotubes (CNTs). The success of the surface functionalization of MWNTs with poly(2‐(methacryloyloxy) ethyl phosphorylcholine) (pMPC) was ascertained using fourier transform infrared spectrophotometry (FTIR), thermogravimetric analysis (TGA), hydrogen nuclear magnetic resonance (1H‐NMR), and transmission electron microscopy (TEM). Different from the results of the previous work, in our work, we demonstrate that the amount of pMPC on CNTs can be easily regulated by ATRP approach. In addition, from TGA results, a linear relationship between the weight loss fraction of MWNT‐pMPC and the weight of MPC fed and as high as 48.1% weight loss of MWNT‐pMPC (MWNTs grafted by pMPC) are observed. Through TEM, the core‐shell structure of MWNT‐pMPC is clearly observed, which is also different from the previous report. The pMPC‐modified MWNTs are highly soluble, which can also resist pH and saline concentration changes and remain stable in physiological environment. PMPC‐modified MWNT does not significantly affect the blood coagulation as demonstrated in plasma recalcification time (PRT) test. These highly soluble MWNTs are expected to enable their wide use in biomedical areas. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009
Electromagnetic and electrical properties of coated cotton fabric with barium ferrite doped polyaniline film
Authors: Akşit Aysun Cireli , Onar Nurhan , Ebeoglugil M. Faruk , Birlik Isil , Celik Erdal , Ozdemir, Ismail
Published: March 2009

In this study, we aimed to produce fabrics with microwave absorbing properties in broad band. For this purpose, the cotton fabrics were coated with polyaniline (PAni) by using chemical oxidative polymerization method. Firstly, the type of protonic acid used, the polymerization time, the type and concentration of dopant, and the number of coating layer were varied as parameters. The effect of these parameters on resistance values of coated fabrics was investigated. We determined the most appropriate process conditions to provide the lowest resistance values. Secondly, the fabric was coated with PAni by adding barium ferrite powder as filler with different ratios. Morphological properties, electrical, and electromagnetic properties of coated fabrics were determined. As a result, we obtained 350 Ω of the minimum resistance values of coated fabric using 1M HCl, 0.5M aniline and 0.5M ammonium persulphate by chemical oxidative polymerization method for totally 4 h of polymerization time. The results of electromagnetic parameters showed that the absorption values of the fabric coated PAni was average 48% in the frequency range of 6–14 GHz. It was concluded that microwave absorber for a textile material can be successfully produced by this process. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009
Sorption and transport properties of the semi‐interpenetrating network based on crosslinked poly(vinyl alcohol) and poly(styrene sulfonic acid‐co‐maleic anhydride) as proton‐conducting membranes
Authors: Huang Y. F. , Hwang B. J. , Lin C. W.
Published: March 2009

This study investigates the sorption and transport properties of hydrocarbon membranes based on poly(vinyl alcohol) network and poly(styrene sulfonic acid‐co‐maleic acid) (PSSA‐MA). The water and methanol self‐diffusion coefficients through an 80 wt % PSSA‐MA interpenetrating SIPN‐80 membrane measured 3.75 × 10−6 and 5.47 × 10−7 cm2/s, respectively. These results are lower than the corresponding values of Nafion® 115 (8.89 × 10−6 cm2/s for water and 8.63 × 10−6 cm2/s for methanol). The methanol permeability of SIPN‐80 membrane is 4.1 × 10−7 cm2/s, or about one‐fourth that of Nafion® 115. The difference in self‐diffusion behaviors of Nafion® 115 and SIPN‐80 membranes is well correlated with their sorption characteristics. The solvent uptake of Nafion® 115 increased as the methanol concentration increased up to a methanol mole fraction of 0.63, and then decreased. However, the solvent uptake of the SIPN‐80 membranes decreased sluggishly as the methanol concentration increased. The λ values of water and methanol (i.e., λ and λ) in Nafion® 115 are quite close, indicating no sorption preference between water and methanol. In contrast, the λ value is only one‐third λ for a SIPN‐80 membrane. Accordingly, the SIPN membranes are regarded as candidates for direct methanol fuel cell applications. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009
Preparation and properties of bio‐based epoxy montomorillonite nanocomposites derived from polyglycerol polyglycidyl ether and ε‐polylysine
Authors: Takada Yoshiro , Shinbo Kiyomi , Someya Yoshihiro , Shibata Mitsuhiro
Published: March 2009

Glycerol polyglycidyl ether (GPE) and polyglycerol polyglycidyl ether (PGPE) were cured with ε‐poly(L‐lysine) (PL) using epoxy/amine ratios of 1 : 1 and 2 : 1 to create bio‐based epoxy cross‐linked resins. When PGPE was used as an epoxy resin and the epoxy/amine ratio was 1 : 1, the cured neat resin showed the greatest glass transition temperature (Tg), as measured by differential scanning calorimetry. Next, the mixture of PGPE, PL, and montomorillonite (MMT) at an epoxy/amine ratio of 1 : 1 in water was dried and cured finally at 110°C to create PGPE‐PL/MMT composites. The X‐ray diffraction and transmission electron microscopy measurements revealed that the composites with MMT content 7–15 wt % were exfoliated nanocomposites and the composite with MMT content 20 wt % was an intercalated nanocomposite. The Tg and storage modulus at 50–100°C for the PGPE‐PL/MMT composites measured by DMA increased with increasing MMT content until 15 wt % and decreased at 20 wt %. The tensile strength and modulus of the PGPE‐PL/MMT composites (MMT content 15 wt %: 42 and 5300 MPa) were much greater than those of the cured PGPE‐PL resin (4 and 6 MPa). Aerobic biodegradability of the PGPE‐PL in an aqueous medium was ∼ 4% after 90 days, and the PGPE‐PL/MMT nanocomposites with MMT content 7–15 wt % showed lower biodegradability. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009
Toughening of poly(L‐lactide) by melt blending with rubbers
Authors: Ishida Sachiko , Nagasaki Reiko , Chino Keisuke , Dong Tungalag , Inoue Yoshio
Published: March 2009

Poly(L‐lactide) (PLA) was melt‐blended with four rubber components—ethylene–propylene copolymer, ethylene–acrylic rubber, acrylonitrile–butadiene rubber (NBR), and isoprene rubber (IR)—in an effort to toughen PLA. All the blend samples exhibited distinct phase separation. Amorphous PLA constituted a topologically continuous matrix in which the rubber particles were dispersed. According to Izod impact testing, toughening was achieved only when PLA was blended with NBR, which showed the smallest particle size in its blend samples. In agreement with the morphological analysis, the value of the interfacial tension between the PLA phase and the NBR phase was the lowest, and this suggested that rubber with a high polarity was more suitable for toughening PLA. Under the tensile stress conditions for NBR and IR blend samples, these rubbers displayed no crosslinking and showed a high ability to induce plastic deformation before the break as well as high elongation properties; this suggested that the intrinsic mobility of the rubber was important for the dissipation of the breaking energy. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009
Exploring the interactions of gliadins with model membranes: Effect of confined geometry and interfaces
Authors: Banc Amélie , Desbat Bernard , Renard Denis , Popineau Yves , Mangavel Cécile , Navailles Laurence
Published: March 2009

Mechanisms leading to the assembly of wheat storage proteins into proteins bodies within the endoplasmic reticulum (ER) of endosperm cells are unresolved today. In this work, physical chemistry parameters which could be involved in these processes were explored. To model the confined environment of proteins within the ER, the dynamic behavior of γ‐gliadins inserted inside lyotropic lamellar phases was studied using FRAP experiments. The evolution of the diffusion coefficient as a function of the lamellar periodicity enabled to propose the hypothesis of an interaction between γ‐gliadins and membranes. This interaction was further studied with the help of phospholipid Langmuir monolayers. γ‐ and ω‐gliadins were injected under DMPC and DMPG monolayers and the two‐dimensional (2D) systems were studied by Brewster angle microscopy (BAM), polarization modulation infrared reflection‐absorption spectroscopy (PM‐IRRAS), and surface tension measurements. Results showed that both gliadins adsorbed under phospholipid monolayers, considered as biological membrane models, and formed micrometer‐sized domains at equilibrium. However, their thicknesses, probed by reflectance measurements, were different: ω‐gliadins aggregates displayed a constant thickness, consistent with a monolayer, while the thickness of γ‐gliadins aggregates increased with the quantity of protein injected. These different behaviors could find some explanations in the difference of aminoacid sequence distribution: an alternate repeated ‐ unrepeated domain within γ‐gliadin sequence, while one unique repeated domain was present within ω‐gliadin sequence. All these findings enabled to propose a model of gliadins self‐assembly via a membrane interface and to highlight the predominant role of wheat prolamin repeated domain in the membrane interaction. In the biological context, these results would mean that the repeated domain could be considered as an anchor for the interaction with the ER membrane and a nucleus point for the formation and growth of protein bodies within endosperm cells. © 2009 Wiley Periodicals, Inc. Biopolymers 91: 610–622, 2009.

This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com
Individual‐based and stochastic modeling of cell population dynamics considering substrate dependency
Authors: Lee Min Woo , Vassiliadis Vassilios S. , Park Jong Moon
Published: March 2009

In this article, we propose an individual‐based and stochastic modeling approach that is capable of describing the bacterial cell population dynamics during a batch culture. All stochastic nature inherent in intracellular molecular level reactions and cell division processes were considered in a single model framework by embedding a sub‐model describing individual cell's growth kinetics in a discrete event simulation algorithm. The resultant unique feature of the model is that the effects of the stochasticities on the cell population dynamics can be investigated for different substrate‐dependent cell growth kinetics. When Monod kinetics was used as the sub‐model, the stochasticities only slightly affected the cell mass increase and substrate consumption profiles during the batch culture although they were still important in describing the changes of cell population distributions. When Andrews substrate inhibition kinetics was used, however, it was revealed that the overall cell population dynamics could be seriously influenced by the stochasticities. Under a critical initial substrate level, the cell population could proliferate against the substrate inhibition only when the stochasticities were considered. Biotechnol. Bioeng. 2009;103: 891–899. © 2009 Wiley Periodicals, Inc.
Development of a method for the determination of vardenafil in human plasma by high performance liquid chromatography with UV detection
Authors: Carlucci Giuseppe , Palumbo Paola , Iuliani Piera , Palumbo Giancarlo
Published: March 2009

A simple high‐performance liquid chromatographic (HPLC) method with photometric detection is described for the determination of vardenafil hydrochloride, a phosphodiesterase V inhibitor, in human plasma. Chromatographic separation of the analyte and internal standard was achieved on an analytical 250 × 4.6 mm i.d. reversed‐phase Kromasil KR 100 C18 (5 µm particle size) column using a mobile phase of acetonitrile–potassium dihydrogen phosphate (30:70 v/v). The run time was less than 15 min. Column eluate was monitored at 230 nm. The linearity over the concentration range of 10–1500 ng/mL for vardenafil was obtained and the limit of quantification (LOQ) was 10 ng/mL. The method has been applied to analysis of the vardenafil concentrations for application in pharmacokinetic studies. Copyright © 2009 John Wiley & Sons, Ltd.
Reversed‐phase liquid chromatography method for the determination of total plasma thiols after derivatization with 1‐benzyl‐2‐chloropyridinium bromide
Authors: Kuśmierek Krzysztof , Bald Edward
Published: March 2009

A high‐performance liquid chromatography method was developed for simultaneous detection and quantitation of total cysteine, glutathione, homocysteine and cysteinylglycine in human plasma. The two key steps in the analysis are reduction of disulfides and treatment with 1‐benzyl‐2‐chloropyridinium bromide, which rapidly and quantitatively reacts with thiol groups to form stable S‐pyridinium derivatives with intense UV absorption. The derivatives are well separated on a Zorbax SB C18 column using reversed‐phase high‐performance liquid chromatography and monitored at 315 nm. The calibration graphs were linear over concentration ranges covering most experimental and clinical cases with a regression coefficients better than 0.999. The detection and quantitation limits for all analytes were 0.2 and 0.5 µmol/L, respectively. The recoveries were 99.25–101.68%. The intra‐ and interassay imprecisions were 0.88–4.24 and 1.68–5.14%, respectively. The method was applied for plasma samples donated by apparently healthy volunteers. Copyright © 2009 John Wiley & Sons, Ltd.
Computer technology for enhancing teaching and learning modules of engineering mechanics
Authors: Deliktas Babur
Published: March 2009

Improving the quality of learning and teaching has always been in the interest of instructors in all fields of study. There have been tremendous efforts to this end. In this article, learning and teaching modules enhanced with computer technology are introduced. This approach is based on concept questioning and scenario building aided with interactive animation, simulation, and rich graphical content. Modules for the engineering mechanics course covering fundamental topics in Statics, Strength of Materials, and Dynamics are prepared by using the proposed approach. Some examples of the prepared modules are presented. Design of the course module and its evaluation from student's perspective are discussed. Based on evaluations using questionnaires by the students it can be inferred that this approach to teaching and learning helps students to increase their capacity to understand and instructors to convey their ideas more conveniently. © 2009 Wiley Periodicals, Inc. Comput Appl Eng Educ 19: 421–432, 2011
Rhodium‐Catalyzed Formation of Stereocontrolled Trisubstituted Alkenes from Baylis–Hillman Adducts
Authors: Gendrineau Thomas , Demoulin Nicolas , Navarre Laure , Genet Jean‐Pierre , Darses Sylvain
Published: March 2009

Efficient and general conditions for the formation of stereodefined trisubstituted alkenes by using the rhodium‐catalyzed reaction of unactivated Baylis–Hillman adducts with either organoboronic acids or potassium trifluoro(organo)borates are reported (see scheme).

magnified image

We report here efficient and general conditions for the formation of stereodefined trisubstituted alkenes using the rhodium‐catalyzed reaction of unactivated Baylis–Hillman adducts with either organoboronic acids and potassium trifluoro(organo)borates. The use of the [{Rh(cod)OH}2] precursor gave very fast coupling reactions under low catalyst loading, very mild reaction conditions (from room temperature up to 50 °C) and without the need of additional phosphane ligands. Based on the new reaction conditions, the reaction, originally limited to Baylis–Hillman adducts derived from esters, could be extended to a large variety of Baylis–Hillman adducts, bearing either keto, cyano or amido functionalities. Moreover, the reaction of Baylis–Hillman adducts bearing esters functionality was improved and could be conducted at lower temperature using lower catalyst loading.
Use of Emergency Medical Services in Patients with Acute Myocardial Infarction in China
Authors: Zhang Shouyan , Hu Dayi , Wang Xian , Yang Jingang
Published: March 2009

Background

Although guidelines strongly recommend use of the Emergency Medical Systems (EMS) by patients with acute myocardial infarction (AMI), it remains underutilized in western countries. Information about its current use in China is unclear. The objective of this study was to examine the use of the EMS by patients with AMI in China, and investigate factors affecting its use.

Methods

A prospective survey study, which included 803 patients with AMI who were admitted to 21 hospitals in China between November 1, 2005 and December 31, 2006.

Results

Only 39.5% of patients called up the EMS at the onset of symptoms (EMS group, n = 317), whereas the rest presented to the hospital by some other means (self‐transport group, n = 486, 60.5%). Predictors of EMS users were older age, symptom onset at evening, unbearable symptoms, having received training and acquired knowledge on heart attack, as well as having a higher income and medical history of heart failure or stroke. Prehospital delay (median 110 min vs. 143 min, p < 0.001), door to needle time (median 85 min vs. 93 min, p < 0.005) and door‐to‐balloon time (median 118 min vs. 160 min, p < 0.001) were significantly shorter in the EMS group. The early reperfusion rate was also significantly higher in the EMS group (84.8% vs. 78.2%, p = 0.019), mainly because of a greater incidence of primary percutaneous coronary intervention (68.1% vs. 61.7%, p = 0.046).

Conclusions

The emergency medical services are underutilized by patients with AMI in China. Use of the EMS may be advantageous in view of greater administration of reperfusion therapy. New public health strategies should be developed to facilitate greater use of the EMS for AMI. Copyright © 2009 Wiley Periodicals, Inc.