bluuebunny/crossref_metadata_2025 huggingface dataset:
The transcriptome of the leukemogenic homeoprotein HOXA9 in human hematopoietic cells
Authors: Dorsam Sheri Tinnell , Ferrell Christina M. , Dorsam Glenn P. , Derynck Mika Kakefuda , Vijapurkar Ulka , Khodabakhsh Daniel , Pau Bonnie , Bernstein Hillary , Haqq Christopher M. , Largman Corey , Lawrence H. Jeffrey
Published: November 2003

Hematopoietic defects in HOXA9–/– mice demonstrate a key role for this homeoprotein in blood cell development. Conversely, enforced HOXA9 expression is leukemogenic in mice, and HOXA9 is frequently activated in human acute myeloid leukemia (AML). Although HOXA9 is thought to function as a transcription factor, few downstream targets have been identified. We searched for early HOXA9 target genes by using a transient overexpression strategy in 3 hematopoietic cell lines (2 myeloid, 1 lymphoid). cDNA microarray analyses identified 220 genes whose expression was modulated at least 2-fold. Expression signatures in myeloid and lymphoid cells demonstrated that HOXA9 functions as both an activator and repressor of a variety of genes in cell-specific patterns suggesting that the transcriptional effects of HOXA9 are largely dependent on the cell context. Transient transcription assays and target gene expression patterns in HOXA9–/– marrow cells imply that we have identified direct physiologic targets. Many target genes are expressed in CD34+ stem cells or are members of gene families involved in proliferation or myeloid differentiation. Expression of 14 HOXA9 target genes correlated with high-level HOXA9 expression in primary AML. These data suggest that many genes identified in this survey may mediate the biologic effects of HOXA9 in normal and leukemic hematopoiesis.
Immunosuppressive regulatory T cells are abundant in the reactive lymphocytes of Hodgkin lymphoma
Authors: Marshall Neil A. , Christie Linsey E. , Munro Laura R. , Culligan Dominic J. , Johnston Peter W. , Barker Robert N. , Vickers Mark A.
Published: November 2003

Although immunosuppression has long been recognized in Hodgkin lymphoma (HL), the underlying basis for the lack of an effective immune response against the tumor remains unclear. The aim was to test our hypothesis that regulatory T cells dominate involved lymph nodes. The approach was to assay CD4+ T-cell function in HL-infiltrating lymphocytes (HLILs) and paired peripheral blood mononuclear cells (PBMCs) of 24 patients. Strikingly, unlike PBMCs, HLILs were anergic to stimulation with mitogen, primary, or recall antigens, mounting no proliferative responses and only rare T-helper 1 (Th1) or Th2 cytokine responses. Mixing paired HLILs and PBMCs showed the anergic effect was dominant and suppressed PBMC responses. Furthermore, flow cytometry demonstrated that HLILs contained large populations of both interleukin-10 (IL-10)–secreting T-regulatory 1 (Tr1) and CD4+CD25+ regulatory T cells. We found evidence for 3 mechanisms of action implicated in the suppressive functions of regulatory T cells: the inhibition of PBMCs by HLILs was ameliorated by neutralizing IL-10, by preventing cell-to-cell contact, and by blocking anti–cytotoxic T lymphocyte–associated antigen 4 (anti–CTLA-4). Thus, HLILs are highly enriched for regulatory T cells, which induce a profoundly immunosuppressive environment and so provide an explanation for the ineffective immune clearance of Hodgkin-Reed Sternberg cells.
Antibody-targeted MHC complex–directed expansion of HIV-1– and KSHV-specific CD8+ lymphocytes: a new approach to therapeutic vaccination
Authors: Stebbing Justin , Gazzard Brian , Patterson Steve , Bower Mark , Perumal Dhayaneethie , Nelson Mark , McMichael Andrew , Ogg Graham , Epenetos Agamemnon , Gotch Frances , Savage Philip
Published: November 2003

The ability of therapeutic vaccines to generate large numbers of CD8+ T lymphocytes that have specificity for HIV-1 or other virally infected cells has enormous potential clinical value. However, approaches to produce cytotoxic T lymphocytes (CTLs) in vivo via vaccine technology have thus far been disappointing and the ex vivo production of cells for adoptive transfer is labor intensive and expensive. We describe the results of a 2-step antibody-targeting system for the production of CD8+ T lymphocytes specific for HIV-1 and Kaposi sarcoma–associated herpesvirus (KSHV), suitable for use in vivo. In 8 consecutive human leukocyte antigen–A2 (HLA-A2)–positive HIV-1–infected individuals with Kaposi sarcoma, 2 cycles of this system resulted in more than 1 Log increases of specific anti-HIV and anti-KSHV CD8+ lymphocytes. These expanded cells have an effector phenotype that includes the ability to produce interferon-γ and CD45Ra+/CD69+ staining. We have shown that antibody-targeted B cells can function as effective antigen-presenting molecules and lead to sustained specific T-lymphocyte expansion from peripheral blood mononuclear cells (PBMCs) of immunosuppressed individuals. This approach, which offers an easy and effective protocol for the amplification of specific antiviral and antitumor CTLs, may offer significant advances for in vivo T-cell immunotherapeutic protocols.
Inhibition of Uncoupling Protein Expression during Lactation: Role of Leptin
Authors: Xiao Xiao Qiu , Grove Kevin L. , Grayson Bernadette E. , Smith M. Susan
Published: November 2003

Uncoupling proteins (UCPs) are mitochondrial proteins that play a role in regulation of energy expenditure by uncoupling respiration from ATP synthesis. Lactation is a physiological condition characterized by negative energy balance due to the loss of energy sources to the production of milk. The objective of the current study was to investigate whether UCP mRNA and protein expressions were altered during lactation compared with those after 48 h of fasting. Lactation significantly reduced serum leptin levels, and removal of pups for 48 h increased serum leptin to higher levels than those observed in control rats. Compared with control rats, mRNA expression of UCP1 and UCP3 in brown adipose tissue (BAT) was dramatically reduced during lactation and fasting. The reduction in mRNAs was reflected by a lowered UCP1 protein level, and to some extent, UCP3 protein. Treatment of lactating rats with exogenous leptin (3 mg/kg) or removal of pups for 48 h completely reversed the down-regulation of UCP1 and UCP3 mRNA expression in BAT, and pup removal led to a recovery of protein expression. In contrast to BAT, UCP3 expression in skeletal muscle was increased in fasted rats and decreased during lactation. Similar changes were observed in serum free fatty acid levels. These changes are consistent with the idea that the utilization of free fatty acids as a fuel source is spared during lactation. As in BAT, leptin treatment and removal of pups were able to restore changes in mRNA expression of UCP3 in skeletal muscle during lactation. The present results suggest that the inhibition of leptin secretion during lactation is involved in the down-regulation of UCP expression in BAT and skeletal muscle, which, in turn, is responsible for the decrease in metabolic fuel oxidation and thermogenesis.
Notch and Ras signaling pathway effector genes expressed in fusion competent and founder cells duringDrosophilamyogenesis
Authors: Artero Ruben , Furlong Eileen E. , Beckett Karen , Scott Matthew P. , Baylies Mary
Published: November 2003

Drosophila muscles originate from the fusion of two types of myoblasts, founder cells (FCs) and fusion-competent myoblasts (FCMs). To better understand muscle diversity and morphogenesis, we performed a large-scale gene expression analysis to identify genes differentially expressed in FCs and FCMs. We employed embryos derived from Toll10b mutants to obtain primarily muscleforming mesoderm, and expressed activated forms of Ras or Notch to induce FC or FCM fate, respectively. The transcripts present in embryos of each genotype were compared by hybridization to cDNA microarrays. Among the 83 genes differentially expressed, we found genes known to be enriched in FCs or FCMs,such as heartless or hibris, previously characterized genes with unknown roles in muscle development, and predicted genes of unknown function. Our studies of newly identified genes revealed new patterns of gene expression restricted to one of the two types of myoblasts, and also striking muscle phenotypes. Whereas genes such as phyllopod play a crucial role during specification of particular muscles, others such as tartan are necessary for normal muscle morphogenesis.
Na,K-ATPase is essential for embryonic heart development in the zebrafish
Authors: Shu Xiaodong , Cheng Karen , Patel Neil , Chen Fuhua , Joseph Elaine , Tsai Huai-Jen , Chen Jau-Nian
Published: November 2003

Na,K-ATPase is an essential gene maintaining electrochemical gradients across the plasma membrane. Although previous studies have intensively focused on the role of Na,K-ATPase in regulating cardiac function in the adults,little is known about the requirement for Na,KATPase during embryonic heart development. Here, we report the identification of a zebrafish mutant, heart and mind, which exhibits multiple cardiac defects, including the primitive heart tube extension abnormality, aberrant cardiomyocyte differentiation, and reduced heart rate and contractility. Molecular cloning reveals that the heart and mind lesion resides in the α1B1 isoform of Na,K-ATPase. Blocking Na,K-ATPase α1B1 activity by pharmacological means or by morpholino antisense oligonucleotides phenocopies the patterning and functional defects of heart and mind mutant hearts, suggesting crucial roles for Na,KATPase α1B1 in embryonic zebrafish hearts. In addition to α1B1, the Na,K-ATPase α2 isoform is required for embryonic cardiac patterning. Although the α1B1 andα2 isoforms share high degrees of similarities in their coding sequences, they have distinct roles in patterning zebrafish hearts. The phenotypes of heart and mind mutants can be rescued by supplementingα 1B1, but not α2, mRNA to the mutant embryos,demonstrating that α1B1 and α2 are not functionally equivalent. Furthermore, instead of interfering with primitive heart tube formation or cardiac chamber differentiation, blocking the translation of Na,KATPaseα2 isoform leads to cardiac laterality defects.
Regulation of outgrowth and apoptosis for the terminal appendage:external genitalia: development by concerted actions of BMP signaling
Authors: Suzuki Kentaro , Bachiller Daniel , Chen YiPing P. , Kamikawa Mami , Ogi Hidenao , Haraguchi Ryama , Ogino Yukiko , Minami Yasuhiro , Mishina Yuji , Ahn Kyung , Crenshaw E. Bryan , Yamada Gen
Published: November 2003

Extra-corporal fertilization depends on the formation of copulatory organs:the external genitalia. Coordinated growth and differentiation of the genital tubercle (GT), an embryonic anlage of external genitalia, generates a proximodistally elongated structure suitable for copulation, erection, uresis and ejaculation. Despite recent progress in molecular embryology, few attempts have been made to elucidate the molecular developmental processes of external genitalia formation.

Bone morphogenetic protein genes (Bmp genes) and their antagonists were spatiotemporally expressed during GT development. Exogenously applied BMP increased apoptosis of GT and inhibited its outgrowth. It has been shown that the distal urethral epithelium (DUE), distal epithelia marked by the Fgf8 expression, may control the initial GT outgrowth. Exogenously applied BMP4 downregulated the expression of Fgf8 and Wnt5a,concomitant with increased apoptosis and decreased cell proliferation of the GT mesenchyme. Furthermore, noggin mutants and Bmpr1a conditional mutant mice displayed hypoplasia and hyperplasia of the external genitalia respectively. noggin mutant mice exhibited downregulation of Wnt5aand Fgf8 expression with decreased cell proliferation. Consistent with such findings, Wnt5a mutant mice displayed GT agenesis with decreased cell proliferation. By contrast, Bmpr1a mutant mice displayed decreased apoptosis and augmented Fgf8 expression in the DUE associated with GT hyperplasia. These results suggest that some of the Bmp genes could negatively affect proximodistally oriented outgrowth of GT with regulatory functions on cell proliferation and apoptosis.

The DUE region can be marked only until 14.0 dpc (days post coitum) in mouse development, while GT outgrowth continues thereafter. Possible signaling crosstalk among the whole distal GT regions were also investigated.
Interplays of Gli2 and Gli3 and their requirement in mediating Shh-dependent sclerotome induction
Authors: Buttitta Laura , Mo Rong , Hui Chi-Chung , Fan Chen-Ming
Published: November 2003

Sonic hedgehog (Shh) signaling is essential for sclerotome development in the mouse. Gli2 and Gli3 are thought to be the primary transcriptional mediators of Shh signaling; however, their roles in Shh induction of sclerotomal genes have not been investigated. Using a combination of mutant analysis and in vitro explant assays, we demonstrate that Gli2 and Gli3 are required for Shh-dependent sclerotome induction. Gli2–/–Gli3–/–embryos exhibit a severe loss of sclerotomal gene expression, and somitic mesoderm from these embryos cannot activate sclerotomal genes in response to exogenous Shh. We find that one copy of either Gli2 or Gli3is required to mediate Shh induction of sclerotomal markers Pax1 and Pax9 in vivo and in vitro. Although Gli2 is generally considered an activator and Gli3 a repressor, our results also reveal a repressor function for Gli2 and an activator function for Gli3 in the developing somite. To further dissect the function of each Gli, we used adenovirus to overexpress Gli1, Gli2 and Gli3 in presomitic mesoderm explants. We find that each Gli preferentially activates a distinct set of Shh target genes, suggesting that the functions of Shh in patterning,growth and negative feedback are divided preferentially between different Gli proteins in the somite.
bullwinkleandsharkregulate dorsal-appendage morphogenesis inDrosophilaoogenesis
Authors: Tran David H. , Berg Celeste A.
Published: November 2003

bullwinkle (bwk) regulates embryonic anteroposterior patterning and, through a novel germline-to-soma signal, morphogenesis of the eggshell dorsal appendages. We screened for dominant modifiers of the bullwinkle mooseantler eggshell phenotype and identified shark, which encodes an SH2-domain, ankyrin-repeat tyrosine kinase. At the onset of dorsal-appendage formation, shark is expressed in a punctate pattern in the squamous stretch cells overlying the nurse cells. Confocal microscopy with cell-type-specific markers demonstrates that the stretch cells act as a substrate for the migrating dorsal-appendage-forming cells and extend cellular projections towards them. Mosaic analyses reveal that shark is required in follicle cells for cell migration and chorion deposition. Proper shark RNA expression in the stretch cells requires bwkactivity, while restoration of shark expression in the stretch cells suppresses the bwk dorsal-appendage phenotype. These results suggest that shark plays an important downstream role in the bwk-signaling pathway. Candidate testing implicates Src42Ain a similar role, suggesting conservation with a vertebrate signaling pathway involving non-receptor tyrosine kinases.
The glypican Dally-like is required for Hedgehog signalling in the embryonic epidermis ofDrosophila
Authors: Desbordes Sabrina C. , Sanson Bénédicte
Published: November 2003

The Drosophila genes dally and dally-like encode glypicans, which are heparan sulphate proteoglycans anchored to the cell membrane by a glycosylphosphatidylinositol link. Genetic studies have implicated Dally and Dally-like in Wingless signalling in embryos and imaginal discs. Here, we test the signalling properties of these molecules in the embryonic epidermis. We demonstrate that RNA interference silencing of dally-like, but not dally, gives a segment polarity phenotype identical to that of null mutations in wingless or hedgehog. Using heterologous expression in embryos, we uncoupled the Hedgehog and Wingless signalling pathways and found that Dally-like and Dally,separately or together, are not necessary for Wingless signalling. Dally-like,however, is strictly necessary for Hedgehog signal transduction. Epistatic experiments show that Dally-like is required for the reception of the Hedgehog signal, upstream or at the level of the Patched receptor.
Ni-Ankh-Sekhmet: first rhinologist in history
Authors: Pahor Ahmes L. , Farid Adel
Published: November 2003

Ni-Ankh-Sekhmet has always been referred to as the first rhinologist in history. Translations of the hieroglyphics depicted on all the illustrations accompanying previous publications do not substantiate this claim. The research presented is a result of an investigation of the original monument related to the doctor at its present location in the Egyptian Museum, Cairo. The research proves that Ni-Ankh-Sekhmet was the first rhinologist in history.
Use of audiotaped patient consultations in a head and neck oncology clinic and survey of patient attitudes to this facility
Authors: Bowden J. R. , Brennan P. A. , Butler-Keating R. , Zaki G. A.
Published: November 2003

The overall quality and delivery of patient care is becoming increasingly important, especially in those diagnosed with cancer. Multidisciplinary clinics are a valuable adjunct to this, but patients may not fully understand or comprehend all that is said to them. The use of audiotaping consultations has been studied in some settings, but not in head and neck cancer clinics. We report on a series of 50 consecutive head and neck patients to determine their views on the value of this facility. Thirty-nine patients (78 per cent) utilized the opportunity, of which 36 patients (92 per cent) found it beneficial. Over three quarters of the patients who used the facility thought that medical staff could benefit and learn from the tape recording. We recommend that audiotaping becomes a standard part of the multidisciplinary head and neck oncology clinic, helping to improve the overall quality of patient care.
A novel method for replacement of a blocked fine bore nasogastric tube
Authors: Panagamuwa C. , Gane S. , Hajioff D.
Published: November 2003

Nasogastric intubation is often difficult in patients with upper aero-digestive tract tumours. We present a new method for replacing obstructed fine-bore nasogastric tubes. This method eliminates the need for specialized equipment and skills, minimizes the risk of tracheal intubation and oesophageal trauma, and is better tolerated by patients.
Implementing a Customer Orientation: Extension of Theory and Application
Authors: Kennedy Karen Norman , Goolsby Jerry R. , Arnould Eric J.
Published: November 2003

The marketing literature affirms the value of a customer orientation to organizational performance, but it is relatively silent on the implementation of this orientation. This research reports the results of a paired-comparison ethnographic study of the dynamics of implementing a customer orientation in a major public school district. Changes at a progressing site are compared with those at a struggling site. The study provides answers to the question of how an organization adopts a customer orientation by refining understanding of the roles of leadership, interfunctional coordination, and the collection and dissemination of customer-focused data in the transformation process.
Synthesis, Characterization, and Nonlinear Optical Study of Metalloporphyrins
Authors: McEwan K. , Lewis K. , Yang G.‐Y. , Chng L.‐L. , Lee Y.‐W. , Lau W.‐P. , Lai K.‐S.
Published: November 2003

meso‐Tetrakis{4‐[2‐(trimethylsilyl)ethynyl]phenyl}porphyrin [TPP(4‐CCTMS)_H2] and its complexes with ZnII, NiII, GaIII, InIII, and SnIV were synthesized and characterized. Their nonlinear optical transmission characteristics were determined using a 532 nm, 5 ns pulsed laser at a repetition rate of 20 Hz. Stronger nonlinear absorption was obtained with the zinc derivative, ZnII‐meso‐tetrakis{4‐[2‐(trimethylsilyl)ethynyl]phenyl}porphyrin (TPP(4‐CCTMS)_Zn), than with the standard analogues, ZnII‐meso‐tetraphenylporphyrin (TPP_Zn), and ZnII‐meso‐tetratolyl‐porphyrin (TTP_Zn), indicating that the excited‐state absorption can be influenced via fine molecular modification on the para‐position of the meso‐phenyl rings, without changing the ground‐state absorption. The nonlinear optical response can be further enhanced via insertion of closed‐shell metal ions. In particular, InIIICl‐meso‐tetrakis{4‐[2‐(trimethylsilyl)ethynyl]phenyl}porphyrin (TPP(4‐CCTMS)_InCl), exhibited a larger change in transmission with increasing energy than C60 and a comparable change to the state‐of‐the‐art phthalocyanine dye, chloro(tetra(tert‐butyl)phthalocyanato)indium(III) (Pc(t‐Bu)_InCl).
Synthesis of Optically Complex Core–Shell Colloidal Suspensions: Pathways to Multiplexed Biological Screening
Authors: Lawrie G.A. , Battersby B.J. , Trau M.
Published: November 2003

The ability to generate enormous random libraries of DNA probes via split‐and‐mix synthesis on solid supports is an important biotechnological application of colloids that has not been fully utilized to date. To discriminate between colloid‐based DNA probes each colloidal particle must be ‘encoded’ so it is distinguishable from all other particles. To this end, we have used novel particle synthesis strategies to produce large numbers of optically encoded particles suitable for DNA library synthesis. Multi‐fluorescent particles with unique and reproducible optical signatures (i.e., fluorescence and light‐scattering attributes) suitable for high‐throughput flow cytometry have been produced. In the spectroscopic study presented here, we investigated the optical characteristics of multi‐fluorescent particles that were synthesized by coating silica ‘core’ particles with up to six different fluorescent dye shells alternated with non‐fluorescent silica ‘spacer’ shells. It was observed that the diameter of the particles increased by up to 20 % as a result of the addition of twelve concentric shells and that there was a significant reduction in fluorescence emission intensities from inner shells as an increasing number of shells were deposited.
AlxGa1–xN—A New Material System for Biosensors
Authors: Steinhoff G. , Purrucker O. , Tanaka M. , Stutzmann M. , Eickhoff M.
Published: November 2003

The applicability of the group III nitride material system for the fabrication of semiconductor‐based biosensors is demonstrated. The operation of ion‐sensitive field‐effect transistors (ISFETs) based on AlGaN/GaN heterostructures in aqueous electrolytes is shown to be characterized by high sensitivity and low drift. Fibroblasts in contact with oxidized and as‐deposited AlGaN surfaces are demonstrated to survive at least for 24 h, indicating that these surfaces are chemically robust and non‐toxic against living cells. Surface hydrophilization using thermal oxidation allows the deposition of highly mobile lipid membranes by vesicle fusion. The homogeneity and the diffusion properties of phospholipids with different net charges were analyzed by fluorescence microscopy and constant photobleaching, taking advantage of the optical transparency of the AlGaN material system. The obtained results reveal that AlGaN‐based devices are promising candidates for future multifunctional biosensors.
Solar Energy Materials
Authors: Granqvist C.G.
Published: November 2003

Solar energy materials have properties tailored to meet requirements set by the spectral distribution, angle of incidence, and intensity of the electromagnetic radiation prevailing in our natural surroundings. Specifically, the optimization can be performed with regard to solar irradiation, thermal emission, atmospheric absorption, visible light, and photosynthetic efficiency. Materials for thermal and electrical conversion of solar energy in man‐made collectors, as well as for energy‐efficient passive design in architecture, are typical examples. This paper reviews solar energy materials with emphasis on the thermal applications of a variety of types. Electrical applications are given a more cursory exposition, the reason being that a systems perspective—rather that a materials perspective—is most fruitful in this case.
Substrate‐Mediated Electronic Structure and Properties of Sexiphenyl Films
Authors: Ivanco J. , Winter B. , Netzer F.P. , Ramsey M.G.
Published: November 2003

It is shown that for organic film growth, the substrate conditions can lead to large differences in the electronic structure of the films. The significance for organic devices is illustrated with the band alignment of sexiphenyl films on Al(111), which is variable over almost 2 eV; 0.9 eV arising from differences in the planarity of the molecules in the films (see Figure) and up to 1 eV depending on the oxygen content at the interface.
A Continuous‐Flow Microcapillary Reactor for the Preparation of a Size Series of CdSe Nanocrystals
Authors: Yen B.K.H. , Stott N.E. , Jensen K.F. , Bawendi M.G.
Published: November 2003

A microcapillary flow reactor has been used to prepare a size series of colloidal CdSe nanocrystals (NCs). The continuous‐flow method (see Figure for schematic) produces samples with size distributions and quantum yields comparable to those prepared in conventional batch processes. The results obtained from the reactor provide insight into the kinetics of nucleation and growth for NC systems.
A 4 % Efficient Dye‐Sensitized Solar Cell Fabricated from Cathodically Electrosynthesized Composite Titania Films
Authors: Yamamoto J. , Tan A. , Shiratsuchi R. , Hayase S. , Chenthamarakshan C.R. , Rajeshwar K.
Published: November 2003

Cathodically electrosynthesized TiO2 films (see Figure) containing occluded Degussa P‐25 titania particles can yield short‐circuit current densities as high as 10.5 mA cm–2, an open‐circuit photovoltage of 690 mV, a fill factor of 57.3 %, and a photovoltaic efficiency of 4.13 % under simulated air mass 1.5 (100 mW cm–2) sunlight in a dye‐sensitized solar cell device.
Facile Synthesis of Hollow Nickel Submicrometer Spheres
Authors: Bao J. , Liang Y. , Xu Z. , Si L.
Published: November 2003

Hollow Ni spheres with average diameter of ∼370 nm have been prepared via redox reaction of NiSO4 with NaH2PO2 in a cyclohexane–water–polyglycol emulsion system. It is found that the composition of the reaction system has a significant influence on the formation of hollow Ni spheres. A mechanism of formation of the Ni hollow spheres is proposed.
Pyroelectricity in Highly Stressed Quasi‐Amorphous Thin Films
Authors: Lyahovitskaya V. , Zon I. , Feldman Y. , Cohen S.R. , Tagantsev A.K. , Lubomirsky I.
Published: November 2003

Quasi‐amorphous BaTiO3 thin films (see Figure) represent a polar ionic solid without spatial periodicity. Most probably, polarity of the quasi‐amorphous BaTiO3 is associated with directional ordering of crystal motifs formed in the steep temperature gradient and stabilized by high in‐plane mechanical stress. A remarkable characteristic of quasi‐amorphous BaTiO3 is expression of strong pyro‐ and piezoelectric effects in a low dielectric constant material.
Probing of Functionalized Mesoporous Silica Nanoparticles Using Transition Metal Clusters
Authors: Hermans S. , Sadasivan S. , Judkins C.M.G. , Johnson B.F.G. , Mann S. , Khushalani D.
Published: November 2003

Molecular clusters (homo‐ and bi‐metallic) have been used to gain structural information on nanoparticles of mesoporous silica (see Figure). Using scanning transmission electron microscopy, the spatial distribution of clusters has been imaged to determine the accessibility of the mesopores. The clusters are also used as “stains” to determine the exact location and number of functional sites within the substrates.
Hydrogel Formation via Cell Crosslinking
Authors: Lee K.Y. , Kong H.J. , Larson R.G. , Mooney D.J.
Published: November 2003

It is demonstrated that cells can be utilized as a crosslinker to form network structures from polymers. The properties of these systems can be interpreted with classical network theory. This approach can be useful to determine various parameters related to cell receptor–ligand binding (see Figure), such as the number of bonds, as well as to suggest a unique means to the delivery of cells for therapeutic purposes.
Higher‐Order Synthesis of Organoclay Pipes Using Self‐Assembled Lipid Templates
Authors: Patil A.J. , Muthusamy E. , Seddon A.M. , Mann S.
Published: November 2003

The template‐directed synthesis of helical ribbons and cylindrical micropipes (see Figure) of organically functionalized magnesium phyllosilicate clay is achieved by high fidelity decoration of self‐assembled phospholipid tubules. The replicas are produced by electrostatic interactions between the positively charged organoclay precursors and charged lipid headgroups exposed on the surfaces of the organic template.
1.3 μm to 1.55 μm Tunable Electroluminescence from PbSe Quantum Dots Embedded within an Organic Device
Authors: Steckel J.S. , Coe‐Sullivan S. , Bulović V. , Bawendi M.G.
Published: November 2003

Large area (mm2 in size) infrared electroluminescent devices are demonstrated using colloidally grown PbSe quantum dots (QDs) in organic host materials. By changing the QD size the electroluminescence is tuned from λ = 1.33–1.56 μm. The fabrication of this light‐emitting device (see Figure) combines the thin film processing techniques available to organic materials with the tunable optical properties of PbSe QDs.
Contact Printing of Metal Ions onto Carboxylate‐Terminated Self‐Assembled Monolayers
Authors: Yang K.‐L. , Cadwell K. , Abbott N.L.
Published: November 2003

The selective exchange of metals ions between salts inked onto the surfaces of polydimethylsiloxane (PDMS) stamps and sodium carboxylate‐terminated monolayers is reported. When Ni(ClO4)2 is inked onto a PDMS stamp and contacted with the monolayer, Ni2+ is transferred onto the surface and Na+ is transferred from the surface to the stamp (see Figure). Patterning of metals ions is demonstrated.
Large‐Area Nanowire Arrays of Molybdenum and Molybdenum Oxides: Synthesis and Field Emission Properties
Authors: Zhou J. , Xu N.‐S. , Deng S.‐Z. , Chen J. , She J.‐C. , Wang Z.‐L.
Published: November 2003

Well‐aligned nanowire arrays of Mo and its oxides have been synthesized. MoO2 nanowire arrays are first synthesized by thermal evaporation in a vacuum chamber. With further treatments in the growth chamber, the above nanowire arrays can be turned into MoO3 nanowire arrays or metallic Mo nanowire arrays (see Figure). The field emission properties of these nanowires are fully investigated.
Nanotubes Prepared by Layer‐by‐Layer Coating of Porous Membrane Templates
Authors: Liang Z. , Susha A.S. , Yu A. , Caruso F.
Published: November 2003

Polyelectrolyte (PE) (see Figure) and PE–nanoparticle hybrid nanotubes are prepared by the layer‐by‐layer deposition of oppositely charged species into the cylindrical pores of polycarbonate membrane templates. This method affords the preparation of compositionally complex tubes with nanometer‐level controllable tube wall thicknesses and enhanced structural stabilities.
Neue Antimalaria‐Wirkstoffe
Authors: Wiesner Jochen , Ortmann Regina , Jomaa Hassan , Schlitzer Martin
Published: November 2003

Etwa 40 % der Weltbevölkerung leben in Malariagebieten. Jährlich erkranken 300 bis 500 Millionen Menschen an Malaria, bis zu 2.5 Millionen sterben an den Krankheitsfolgen. Obwohl Malaria in vielen Teilen der Welt bereits als ausgerottet galt, nimmt die Zahl der Fälle auch in diesen Gebieten wieder zu. Der wichtigste Grund für diese bedrohliche Entwicklung ist die zunehmende Verbreitung von Resistenzen gegen Antimalaria‐Wirkstoffe, insbesondere gegen das am häufigsten verwendete Chloroquin. Seit Mitte der siebziger Jahre wurde die Entwicklung neuer Wirkstoffe vernachlässigt. Dafür ist neben dem Wegfall kolonialer und militärischer Interessen auch das beschränkte Marktpotenzial verantwortlich. Unterstützt durch öffentliche Förderprogramme werden erst seit kurzem wieder intensivere Forschungsaktivitäten unternommen. Fortschritte verspricht man sich vor allem von der Sequenzierung des Genoms von Plasmodium falciparum, dem Malaria‐Erreger, sowie von modernem Wirkstoff‐Design.
New Antimalarial Drugs
Authors: Wiesner Jochen , Ortmann Regina , Jomaa Hassan , Schlitzer Martin
Published: November 2003

Approximately 40 % of the world population live in areas with the risk of malaria. Each year, 300–500 million people suffer from acute malaria, and 0.5–2.5 million die from the disease. Although malaria has been widely eradicated in many parts of the world, the global number of cases continues to rise. The most important reason for this alarming situation is the rapid spread of malaria parasites that are resistant to antimalarial drugs, especially chloroquine, which is by far the most frequently used. The development of new antimalarial drugs has been neglected since the 1970s owing to the end colonialism, changes in the areas of military engagement, and the restricted market potential. Only in recent years, in part supported by public funding programs, has interest in the development of antimalarial drugs been renewed. New data available from the recently sequenced genome of the malaria parasite Plasmodium falciparum and the application of methods of modern drug design promise to bring significant development in the fight against this disease.
Cover Picture: Designing Permeable Molecular Crystals That React with External Agents To Give Crystalline Products (Angew. Chem. Int. Ed. 43/2003)
Authors: Brunet Philippe , Demers Eric , Maris Thierry , Enright Gary D. , Wuest James D.
Published: November 2003

Permeable molecular crystals can be specifically designed to let external agents enter, react, and produce single crystals of new substances with retention of the original crystalline architecture. Such topotactic processes can be made to cross‐link molecular crystals covalently, thus capturing temporary supramolecular constructs as permanent crystalline macromolecular replicas. The Communication by J. D. Wuest et al on page 5303 ff. describes how suitable dithiols react with exposed allyl groups in such a manner.
Coronary artery angiography in systemic lupus erythematosus patients with abnormal myocardial perfusion scintigraphy
Authors: Sella E. M. C. , Sato E. I. , Barbieri A.
Published: November 2003

Objective

According to published studies, 16–82% of systemic lupus erythematosus (SLE) patients have abnormal findings on myocardial perfusion tests, but it has not been established whether these patients also have abnormal findings on coronary angiography. The aim of this study was to evaluate the frequency of abnormal findings on coronary angiography in SLE patients in whom myocardial perfusion scintigraphy revealed abnormalities.

Methods

Ninety female SLE patients (ages 20–55 years, disease duration >5 years, and current or previous steroid treatment for ≥1 year) underwent myocardial perfusion scintigraphy with single‐photon–emission computed tomography using 99mTc‐sestamibi. Images were taken while the patient was at rest and after dipyridamole‐induced stress. Myocardial perfusion defects were identified in 30 patients (33%). Twenty‐one of these patients (mean ± SD age 42 ± 9; mean ± SD disease duration 132 ± 66 months) agreed to undergo coronary angiography.

Results

Atherosclerotic plaques were identified by angiography in 8 of the 21 patients (38%). The majority of coronary abnormalities were localized in the anterior descending artery. The mean ± SD number of risk factors for coronary artery disease (CAD) was significantly higher in the subgroup with (4.5 ± 0.8) compared with the subgroup without (2.5 ± 1.9) abnormal angiographic findings (P = 0.006). Arterial hypertension and postmenopause status were significantly associated with abnormal angiographic findings. Of the patients with at least 4 risk factors for CAD, coronary stenosis was present in 67% (P = 0.005). The number of American College of Rheumatology (ACR) criteria for SLE and scores on the SLE Disease Activity Index and the Systemic Lupus International Collaborating Clinics/ACR damage index were also higher in the subgroup with coronary stenosis (P < 0.05).

Conclusion

This is the first study to examine coronary angiography results in SLE patients with abnormal findings on myocardial scintigraphy. Our data suggest that myocardial scintigraphy can be used to screen SLE patients and that all patients with abnormal findings plus at least 4 risk factors for CAD should undergo coronary angiography.
Acceleration of the onset of collagen‐induced arthritis by a deficiency of platelet endothelial cell adhesion molecule 1
Authors: Tada Yoshifumi , Koarada Syuichi , Morito Fumitaka , Ushiyama Osamu , Haruta Yoshio , Kanegae Futoshi , Ohta Akihide , Ho Alexandra , Mak Tak W. , Nagasawa Kohei
Published: November 2003

Objective

Platelet endothelial cell adhesion molecule 1 (PECAM‐1; CD31) is a member of the immunoglobulin superfamily that is expressed in platelets, leukocytes, and endothelial cells. PECAM‐1 has been shown to play a role in transendothelial migration of leukocytes and contains immunoreceptor tyrosine‐based inhibitory motifs in its cytoplasmic tail and inhibits cellular responses. We examined the role of PECAM‐1 in the development of collagen‐induced arthritis (CIA).

Methods

CIA was induced in PECAM‐1–deficient DBA/1 mice. The incidence of arthritis and the arthritis index were examined. Anti–type II collagen (anti‐CII) antibody levels and interferon‐γ (IFNγ) production by lymph node cells and spleen cells were determined. Lymphocytes from arthritic PECAM‐1–deficient and wild‐type mice were labeled with dye, transferred to arthritic PECAM‐1+/− mice, and cell migration to inflamed joints was examined.

Results

PECAM‐1–deficient mice showed accelerated onset of arthritis and increased severity only during the early phase. Anti‐CII antibody levels were also increased during the early phase. IFNγ production by lymph node cells and spleen cells from PECAM‐1–deficient mice in response to CII was higher than that in wild‐type mice. Lymphocytes from arthritic PECAM‐1–deficient mice showed accelerated migration to inflamed joints, but not lymph nodes or spleen. The development of anti‐CII antibody–induced arthritis was similar in PECAM‐1–deficient and wild‐type mice.

Conclusion

These results indicate that PECAM‐1 negatively regulates humoral and cell‐mediated immune responses and lymphocyte migration into joints and, consequently, the development of CIA. In addition, the role of PECAM‐1 in the transendothelial migration of leukocytes appears to be redundant in this model.
Bone density threshold and other predictors of vertebral fracture in patients receiving oral glucocorticoid therapy
Authors: Van Staa T. P. , Laan R. F. , Barton I. P. , Cohen S. , Reid D. M. , Cooper C.
Published: November 2003

Objective

To evaluate predictors of vertebral fractures, including a threshold for bone mineral density (BMD), in patients receiving oral glucocorticoids (GCs).

Methods

Data were obtained from 2 randomized clinical trials (prevention and treatment trials of risedronate) using similar methods, but different inclusion criteria were applied with regard to prior exposure to GCs. Predictors of vertebral fracture in the placebo group were identified using Cox regression with forward selection. The BMD threshold analysis involved a comparison of the 1‐year fracture risk in postmenopausal women receiving placebo in the GC trials with that in postmenopausal women not taking GCs in 3 other trials.

Results

The study population comprised 306 patients with baseline and 1‐year followup data on vertebral fractures (111 receiving placebo and 195 receiving risedronate). In the placebo group, the statistically significant predictors of incident fracture were the baseline lumbar spine BMD (for each 1‐point decrease in T score, relative risk [RR] 1.85, 95% confidence interval [95% CI] 1.06–3.21) and the daily GC dose (for each 10‐mg dose increase, RR 1.62, 95% CI 1.11–2.36). In the BMD threshold analysis, compared with nonusers of GCs, patients receiving GCs were younger, had a higher BMD at baseline, and had fewer prevalent fractures; nevertheless, the risk of fracture was higher in the GC users compared with nonusers (adjusted RR 5.67, 95% CI 2.57–12.54). The increased risk of fracture was observed in GC users regardless of whether osteoporosis was present.

Conclusion

The daily, but not cumulative, GC dose was found to be a strong predictor of vertebral fracture in patients receiving GCs. At similar levels of BMD, postmenopausal women taking GCs, as compared with nonusers of GCs, had considerably higher risks of fracture.
Nitrite‐mediated protection against hypochlorous acid–induced chondrocyte toxicity: A novel cytoprotective role of nitric oxide in the inflamed joint?
Authors: Whiteman Matthew , Rose Peter , Siau Jia Ling , Halliwell Barry
Published: November 2003

Objective

To examine the potential consequences of overproduction of nitric oxide (NO) and nitrite (NO) in the inflamed rheumatoid joint.

Methods

Human articular chondrocytes in culture were exposed to HOCl (hypochlorous acid, a physiologic oxidant formed in increased amounts at sites of chronic inflammation), and assays of cell viability, intracellular ATP and glutathione (GSH), and lactate dehydrogenase (LDH) were performed. HOCl‐induced lipid peroxidation and activation of the MAP kinases ERK‐1/2, JNK‐1/2, and p38 were also measured. The modulatory effects of NO‐derived nitrite (NO) and nitrate (NO) on HOCl‐mediated chondrocyte toxicity were investigated.

Results

Exposure of human articular chondrocytes to HOCl resulted in a concentration‐ and time‐dependent loss of viability, decrease in ATP and GSH levels, LDH leakage, and cell death. HOCl induced significant lipid peroxidation as well as activation of the MAP kinases ERK‐1/2 and p38 but not JNK‐1/2. However, the presence of NO but not NO substantially decreased HOCl‐dependent cellular toxicity even when NO was added at low (μM) concentrations. In sharp contrast, NO (1 mM) did not inhibit superoxide‐, hydroxyl radical–, H2O2‐, or peroxynitrite‐mediated cytotoxicity. Furthermore, culture media from cells treated with interleukin‐1β (to generate NO and NO) offered significantly more protection against HOCl‐mediated cytotoxicity than culture media from untreated cells.

Conclusion

These data suggest that NO accumulation at chronically inflamed sites where both HOCl and NO are overproduced may be cytoprotective against damage induced by HOCl. Accumulation of NO could represent a novel cytoprotective role of NO in inflamed joints. A mechanism for this is suggested.
Extrasalivary lymphoma development in Sjögren's syndrome: Clonal evolution from parotid gland lymphoproliferation and role of local triggering
Authors: Gasparotto Daniela , De Vita Salvatore , De Re Valli , Marzotto Alessandra , De Marchi Ginevra , Scott Cathryn Ann , Gloghini Annunziata , Ferraccioli Gianfranco , Boiocchi Mauro
Published: November 2003

Objective

To characterize Sjögren's syndrome (SS)–related B cell lymphoproliferation at the premalignant stage and during the evolution to B cell lymphoma, and to better understand the pathobiologic mechanisms associated with clonal expansion and the possible influence of different microenvironments on neoplastic transformation.

Methods

We analyzed sequential parotid and lung biopsy specimens that were obtained from a single patient with SS at multiple time points over a 7‐year period. Polymerase chain reaction DNA amplification, cloning, and sequencing of the immunoglobulin heavy chain variable region showed clonality, somatic mutations, intraclonal heterogeneity, and genealogic relationships of the B cell clones in the different biopsy specimens.

Results

The evolution of a nonmalignant B cell clone that was present in the parotid gland and evolved into a B cell lymphoma was documented. During such a process, one subclone was selected that accumulated somatic mutations in a pattern consistent with the preservation of antigen receptor functionality, possibly attributable to continued hypermutation and selection. Intraclonal diversity indicated the presence of local triggers in both the parotid and lung microenvironments.

Conclusion

Molecular followup of B cell lymphoproliferation in SS, from nonmalignant stage to overt B cell lymphoma, indicated a role for B cell receptor engagement in clonal survival. The outgrowth of one subclone, with malignant transformation in the lung, a target organ different from the initial site of the lymphoproliferative process (the parotid gland), indicates that resident stimuli in different microenvironments may locally sustain ongoing lymphoproliferation and B cell transformation.
Comparison of rheumatoid arthritis clinical trial outcome measures: A simulation study
Authors: Anderson Jennifer J. , Bolognese James A. , Felson David T.
Published: November 2003

Objective

Isolated studies have suggested that continuous measures of response may be better than predefined, dichotomous definitions (e.g., the American College of Rheumatology 20% improvement criteria [ACR20]) for discriminating between rheumatoid arthritis (RA) treatments. Our goal was to determine the statistical power of predefined dichotomous outcome measures (termed “a priori”), compared with that of continuous measures derived from trial data in which there was no predefined response threshold (termed “data driven”), and to evaluate the sensitivity to change of these measures in the context of different treatments and early versus later‐stage disease. In order to generalize beyond results from a single trial, we performed simulation studies.

Methods

We obtained summary data from trials comparing disease‐modifying antirheumatic drugs (DMARDs) and from comparative coxib–placebo trials to test the power of 2 a priori outcomes, the ACR20 and improvement of the Disease Activity Score (DDAS), as well as 2 data‐driven outcomes. We studied patients with early RA and those with later‐stage RA (duration of <4 years and 4–9 years, respectively). We performed simulation studies, using the interrelationship of ACR core set measures in the trials to generate multiple trial data sets consistent with the original data.

Results

The data‐driven outcomes had greater power than did the a priori measures. The DMARD comparison was more powerful in early disease than in later‐stage disease (the sample sizes needed to achieve 80% power for the most powerful test were 64 for early disease versus 100 for later disease), but the coxib‐versus‐placebo comparison was less powerful in early disease than in later disease (the sample sizes needed to achieve 80% power were 200 and 100, respectively). When the effects of treatment on core set items were small and/or inconsistent, power was reduced, particularly for a less broadly based outcome (e.g., DDAS) compared with the ACR20.

Conclusion

The simulation studies demonstrate that data‐driven outcome definitions can provide better sensitivity to change than does the ACR20 or DDAS. Using such methods would improve power, but at the expense of trial standardization. The studies also show how patient population and treatment characteristics affect the power of specific outcome measures in RA clinical trials, and provide quantification of those effects.