bluuebunny/crossref_metadata_2025 huggingface dataset:
Human cerebrospinal fluid central memory CD4+T cells: Evidence for trafficking through choroid plexus and meninges via P-selectin
Authors: Kivisäkk Pia , Mahad Don J. , Callahan Melissa K. , Trebst Corinna , Tucky Barbara , Wei Tao , Wu Lijun , Baekkevold Espen S. , Lassmann Hans , Staugaitis Susan M. , Campbell James J. , Ransohoff Richard M.
Published: July 2003

Cerebrospinal fluid (CSF) from healthy individuals contains between 1,000 and 3,000 leukocytes per ml. Little is known about trafficking patterns of leukocytes between the systemic circulation and the noninflamed CNS. In the current study, we characterized the surface phenotype of CSF cells and defined the expression of selected adhesion molecules on vasculature in the choroid plexus, the subarachnoid space surrounding the cerebral cortex, and the cerebral parenchyma. Using multicolor flow cytometry, we found that CSF cells predominantly consisted of CD4+/CD45RA-/CD27+/CD69+-activated central memory T cells expressing high levels of CCR7 and L-selectin. CD3+T cells were present in the choroid plexus stroma in autopsy CNS tissue sections from individuals who died without known neurological disorders. P- and E-selectin immunoreactivity was detected in large venules in the choroid plexus and subarachnoid space, but not in parenchymal microvessels. CD4+T cells in the CSF expressed high levels of P-selectin glycoprotein ligand 1, and a subpopulation of circulating CD4+T cells displayed P-selectin binding activity. Intercellular adhesion molecule 1, but not vascular cell adhesion molecule 1 or mucosal addressin cell adhesion molecule 1, was expressed in choroid plexus and subarachnoid space vessels. Based on these findings, we propose that T cells are recruited to the CSF through interactions between P-selectin/P-selectin ligands and intercellular adhesion molecule 1/lymphocyte function-associated antigen 1 in choroid plexus and subarachnoid space venules. These results support the overall hypothesis that activated memory T cells enter CSF directly from the systemic circulation and monitor the subarachnoid space, retaining the capacity to either initiate local immune reactions or return to secondary lymphoid organs.
Neandertal faces were not long; modern human faces are short
Authors: Trinkaus Erik
Published: July 2003

Neandertal faces have been described as being derived with respect to their overall length or degree of anterior projection. A comparison of cranial and mandibular indicators of lower facial projection across archaic and modern
Homo
indicates that Neandertal facial lengths on average are similar to those of preceding archaic
Homo
and principally contrast with those of recent humans. Neandertal facial length is not derived. The shortness of recent human facial skeletons is the evolutionarily derived condition.
Does a betaretrovirus infection trigger primary biliary cirrhosis?
Authors: Xu Lizhe , Shen Zhiwei , Guo Linsheng , Fodera Brent , Keogh Adrian , Joplin Ruth , O'Donnell Barbara , Aitken James , Carman William , Neuberger James , Mason Andrew
Published: July 2003

Patients with primary biliary cirrhosis develop progressive ductopenia
associated with the production of antimitochondrial antibodies that react with
a protein aberrantly expressed on biliary epithelial cells and peri-hepatic
lymph nodes. Although no specific microbe has been identified, it is thought
that an infectious agent triggers this autoimmune liver disease in genetically
predisposed individuals. Previous serologic studies have provided evidence to
suggest a viral association with primary biliary cirrhosis. Here we describe
the identification of viral particles in biliary epithelium by electron
microscopy and the cloning of exogenous retroviral nucleotide sequences from
patients with primary biliary cirrhosis. The putative agent is referred to as
the human betaretrovirus because it shares close homology with the murine
mammary tumor virus and a human retrovirus cloned from breast cancer tissue.
In vivo
, we have found that the majority of patients with primary
biliary cirrhosis have both RT-PCR and immunohistochemistry evidence of human
betaretrovirus infection in lymph nodes. Moreover, the viral proteins
colocalize to cells demonstrating aberrant autoantigen expression.
In
vitro
, we have found that lymph node homogenates from patients with
primary biliary cirrhosis can induce autoantigen expression in normal biliary
epithelial cells in coculture. Normal biliary epithelial cells also develop
the phenotypic manifestation of primary biliary cirrhosis when cocultivated in
serial passage with supernatants containing the human betaretrovirus or the
murine mammary tumor virus, providing a model to test Koch's postulates
in
vitro
.
Water at DNA surfaces: Ultrafast dynamics in minor groove recognition
Authors: Pal Samir Kumar , Zhao Liang , Zewail Ahmed H.
Published: July 2003

Water molecules at the surface of DNA are critical to its equilibrium
structure, DNA–protein function, and DNA–ligand recognition. Here
we report direct probing of the dynamics of hydration, with femtosecond
resolution, at the surface of a DNA dodecamer duplex whose native structure
remains unperturbed on recognition in minor groove binding with the
bisbenzimide drug (Hoechst 33258). By following the temporal evolution of
fluorescence, we observed two well separated hydration times, 1.4 and 19 ps,
whereas in bulk water the same drug is hydrated with time constants of 0.2 and
1.2 ps. For comparison, we also studied calf thymus DNA for which the
hydration exhibits similar time scales to that of dodecamer DNA. However, the
time-resolved polarization anisotropy is very different for the two types of
DNA and clearly elucidates the rigidity in drug binding and difference in DNA
rotational motions. These results demonstrate that hydration at the surface of
the groove is a dynamical process with two general types of trajectories; the
slowest of them (≈20 ps) are those describing dynamically ordered water.
Because of their ultrafast time scale, the “ordered” water
molecules are the most weakly bound and are accordingly involved in the
entropic (hydration/dehydration) process of recognition.
The RNA–protein complex: Direct probing of the interfacial recognition dynamics and its correlation with biological functions
Authors: Xia Tianbing , Becker Hans-Christian , Wan Chaozhi , Frankel Adam , Roberts Richard W. , Zewail Ahmed H.
Published: July 2003

The N protein from bacteriophage λ is a key regulator of transcription antitermination. It specifically recognizes a nascent mRNA stem loop termedboxB, enabling RNA polymerase to read through downstream terminators processively. The stacking interaction between Trp-18 of WT N protein and A7 ofboxBRNA is crucial for efficient antitermination. Here, we report on the direct probing of the dynamics for this interfacial binding and the correlation of the dynamics with biological functions. Specifically, we examined the influence of structural changes in four peptides on the femtosecond dynamics ofboxBRNA (2-aminopurine labeled in different positions), through mutations of critical residues of N peptide (residues 1–22). We then compare theirin vivo(Escherichia coli) transcription antitermination activities with the dynamics. The results demonstrate that the RNA–peptide complexes adopt essentially two dynamical conformations with the time scale for interfacial interaction in the two structures being vastly different, 1 ps for the stacked structure and nanosecond for the unstacked one; only the weighted average of the two is detected in NMR by nuclear Overhauser effect experiments. Strikingly, the amplitude of the observed ultrafast dynamics depends on the identity of the amino acid residues that are one helical turn away from Trp-18 in the peptides and is correlated with the level of biological function of their respective full-length proteins.
Fluorescence bleaching reveals asymmetric compartment formation prior to cell division in
Caulobacter
Authors: Judd Ellen M. , Ryan Kathleen R. , Moerner W. E. , Shapiro Lucy , McAdams Harley H.
Published: July 2003

Asymmetric cell division in
Caulobacter crescentus
yields daughter
cells that have different cell fates. Compartmentalization of the
predivisional cell is a critical event in the establishment of the
differential distribution of regulatory factors that specify cell fate. To
determine when during the cell cycle the cytoplasm is compartmentalized so
that cytoplasmic proteins can no longer diffuse between the two nascent
progeny cell compartments, we designed a fluorescence loss in photobleaching
assay. Individual cells containing enhanced GFP were exposed to a bleaching
laser pulse tightly focused at one cell pole. In compartmentalized cells,
fluorescence disappears only in the compartment receiving the bleaching beam;
in noncompartmentalized cells, fluorescence disappears from the entire cell.
In a 135-min cell cycle, the cells were compartmentalized 18 ± 5 min
before the progeny cells separated. Clearance of the 22000 CtrA master
transcriptional regulator molecules from the stalked portion of the
predivisional cell is a controlling element of
Caulobacter
asymmetry.
Monitoring of a fluorescent marker for CtrA showed that the differential
degradation of CtrA in the nascent stalk cell compartment occurs only after
the cytoplasm is compartmentalized.
Human papillomavirus E6 and Myc proteins associate
in vivo
and bind to and cooperatively activate the telomerase reverse transcriptase promoter
Authors: Veldman Tim , Liu Xuefeng , Yuan Hang , Schlegel Richard
Published: July 2003

The papillomavirus E6 protein binds and directs the ubiquitin-dependent
degradation of the p53 tumor suppressor protein. Independent of this
p53-degradative function, however, E6 induces cellular telomerase activity.
This increase in enzyme activity reflects E6-enhanced transcription of the
human telomerase reverse transcriptase (hTERT) catalytic subunit, but the
molecular basis for this transactivation is unknown. In the present study, we
demonstrate that E6/Myc interactions regulate hTERT gene expression. Mad
protein, a specific antagonist of Myc, repressed E6-mediated transactivation
of the hTERT promoter and this repression was relieved by Myc overexpression.
The proximal Myc/ Max-binding element (E-box) in the hTERT promoter was the
major determinant of both E6 and Myc responsiveness in keratinocytes. E6 did
not alter Myc protein expression or Myc/Max association, and the induction of
hTERT by Myc/E6 was independent of Myc phosphorylation at Thr-58/Ser-62 within
the transactivation domain. However, immunoprecipitation studies demonstrated
that endogenous Myc protein coprecipitated with E6 protein and chromatin
immunoprecipitation analyses demonstrated that both E6 and Myc proteins bound
to a minimal 295-bp hTERT promoter. Only the “high-risk” E6
proteins bound to the hTERT promoter, consistent with their preferential
ability to induce telomerase. The observation that E6 associates with Myc
complexes and activates a Myc-responsive gene identifies a mechanism by which
this oncogene can modulate cell proliferation and differentiation.
MLL repression domain interacts with histone deacetylases, the polycomb group proteins HPC2 and BMI-1, and the corepressor C-terminal-binding protein
Authors: Xia Zhen-Biao , Anderson Melanie , Diaz Manuel O. , Zeleznik-Le Nancy J.
Published: July 2003

The
MLL
(
mixed-lineage leukemia
) gene is involved in many
chromosomal translocations associated with acute myeloid and lymphoid
leukemia. We previously identified a transcriptional repression domain in MLL,
which contains a region with homology to DNA methyltransferase. In chromosomal
translocations, the MLL repression domain is retained in the leukemogenic
fusion protein and is required for transforming activity of MLL fusion
proteins. We explored the mechanism of action of the MLL repression domain.
Histone deacetylase 1 interacts with the MLL repression domain, partially
mediating its activity; binding of Cyp33 to the adjacent MLL-PHD domain
potentiates this binding. Because the MLL repression domain activity was only
partially relieved with the histone deacetylase inhibitor trichostatin A, we
explored other protein interactions with this domain. Polycomb group proteins
HPC2 and BMI-1 and the corepressor C-terminal-binding protein also bind the
MLL repression domain. Expression of exogenous BMI-1 potentiates MLL
repression domain activity. Functional antagonism between Mll and Bmi-1 has
been shown genetically in murine knockout models for
Mll
and
Bmi-1
. Our new data suggest a model whereby recruitment of BMI-1 to
the MLL protein may be able to modulate its function. Furthermore, repression
mediated by histone deacetylases and that mediated by polycomb group proteins
may act either independently or together for MLL function
in
vivo
.
Neural and mammary gland defects in ErbB4 knockout mice genetically rescued from embryonic lethality
Authors: Tidcombe Hester , Jackson-Fisher Amy , Mathers Kathleen , Stern David F. , Gassmann Martin , Golding Jon P.
Published: July 2003

Mice lacking the epidermal growth factor receptor family member ErbB4
exhibit defects in cranial neural crest cell migration but die by embryonic
day 11 because of defective heart development. To examine later phenotypes, we
rescued the heart defects in ErbB4 mutant mice by expressing ErbB4 under a
cardiac-specific myosin promoter. Rescued ErbB4 mutant mice reach adulthood
and are fertile. However, during pregnancy, mammary lobuloalveoli fail to
differentiate correctly and lactation is defective. Rescued mice also display
aberrant cranial nerve architecture and increased numbers of large
interneurons within the cerebellum.
Nef increases the synthesis of and transports cholesterol to lipid rafts and HIV-1 progeny virions
Authors: Zheng Yong-Hui , Plemenitas Ana , Fielding Christopher J. , Peterlin B. Matija
Published: July 2003

HIV buds from lipid rafts and requires cholesterol for its egress from and
entry into cells. Viral accessory protein Nef plays a major role in this
process. In this study, it not only increased the biosynthesis of lipid rafts
and viral particles with newly synthesized cholesterol, but also enriched
them. Furthermore, via the consensus cholesterol recognition motif at its C
terminus, Nef bound cholesterol. When this sequence was mutated, Nef became
unable to transport newly synthesized cholesterol into lipid rafts and viral
particles. Interestingly, although its levels in lipid rafts were not
affected, this mutant Nef protein was poorly incorporated into viral
particles, and viral infectivity decreased dramatically. Thus, Nef also
transports newly synthesized cholesterol to the site of viral budding. As
such, it provides essential building blocks for the formation of viruses that
replicate optimally in the host.
Glucose-6-phosphate isomerase is necessary for embryo implantation in the domestic ferret
Authors: Schulz Laura Clamon , Bahr Janice M.
Published: July 2003

The mechanism of implantation in carnivores is poorly understood. However,
a previously unidentified 60-kDa protein has been shown to be necessary for
embryo implantation in ferrets. Here we identify this protein as
glucose-6-phosphate isomerase (GPI). GPI is expressed by the corpus luteum on
days 6–9 of pregnancy, the time at which implantation-promoting activity
has been found in corpora lutea. Passive immunization against GPI reduced the
number of implantation sites in pregnant ferrets in a dose-dependent manner.
GPI is a multifunctional protein. Although first identified for its role in
glycolysis, GPI has since been implicated in neural growth, lymphocyte
maturation, and metastasis. This study demonstrates a previously
uncharacterized function of this protein that may represent the natural
motility-stimulating activity that has been co-opted by tumor cells.
Disruption of the imprinted Grb10 gene leads to disproportionate overgrowth by an Igf2-independent mechanism
Authors: Charalambous Marika , Smith Florentia M. , Bennett William R. , Crew Tracey E. , Mackenzie Francesca , Ward Andrew
Published: July 2003

To investigate the function of the Grb10 adapter protein, we have generated
mice in which the
Grb10
gene was disrupted by a gene-trap insertion.
Our experiments confirm that
Grb10
is subject to genomic imprinting
with the majority of
Grb10
expression arising from the maternally
inherited allele. Consistent with this, disruption of the maternal allele
results in overgrowth of both the embryo and placenta such that mutant mice
are at birth ≈30% larger than normal. This observation establishes that
Grb10 is a potent growth inhibitor. In humans, GRB10 is located at chromosome
7p11.2–p12 and has been associated with Silver–Russell syndrome,
in which ≈10% of those affected inherit both copies of chromosome 7 from
their mother. Our results indicate that changes in GRB10 dosage could, in at
least some cases, account for the severe growth retardation that is
characteristic of Silver–Russell syndrome. Because Grb10 is a signaling
protein capable of interacting with tyrosine kinase receptors, we tested
genetically whether
Grb10
might act downstream of insulin-like growth
factor 2, a paternally expressed growth-promoting gene. The result indicates
that
Grb10
action is essentially independent of insulin-like growth
factor 2, providing evidence that imprinting acts on at least two major fetal
growth axes in a manner consistent with parent–offspring conflict
theory.
Molecular analysis of the evolutionary significance of ultraviolet vision in vertebrates
Authors: Shi Yongsheng , Yokoyama Shozo
Published: July 2003

Many fish, amphibians, reptiles, birds, and some mammals use UV vision for
such basic activities as foraging, mate selection, and communication. UV
vision is mediated by UV pigments in the short wavelength-sensitive type 1
(SWS1) group that absorb light maximally (λ
max
) at ≈360
nm. Reconstructed SWS1 pigments of most vertebrate ancestors have
λ
max
values of ≈360 nm, whereas the ancestral avian
pigment has a λ
max
value of 393 nm. In the nonavian lineage,
UV vision in many modern species is inherited directly from the vertebrate
ancestor, whereas violet vision in others has evolved by different amino acid
replacements at ≈10 specific sites. In the avian lineage, the origin of the
violet pigment and the subsequent restoration of UV pigments in some species
are caused by amino acid replacements F49V/F86S/L116V/S118A and S90C,
respectively. The use of UV vision is associated strongly with UV-dependent
behaviors of organisms. When UV light is not available or is unimportant to
organisms, the SWS1 gene can become nonfunctional, as exemplified by
coelacanth and dolphin.
Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma
Authors: Phan Giao Q. , Yang James C. , Sherry Richard M. , Hwu Patrick , Topalian Suzanne L. , Schwartzentruber Douglas J. , Restifo Nicholas P. , Haworth Leah R. , Seipp Claudia A. , Freezer Linda J. , Morton Kathleen E. , Mavroukakis Sharon A. , Duray Paul H. , Steinberg Seth M. , Allison James P. , Davis Thomas A. , Rosenberg Steven A.
Published: July 2003

Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is a critical immunoregulatory molecule (expressed on activated T cells and a subset of regulatory T cells) capable of down-regulating T cell activation. Blockade of CTLA-4 has been shown in animal models to improve the effectiveness of cancer immunotherapy. We thus treated 14 patients with metastatic melanoma by using serial i.v. administration of a fully human anti-CTLA-4 antibody (MDX-010) in conjunction with s.c. vaccination with two modified HLA-A*0201-restricted peptides from the gp100 melanoma-associated antigen, gp100:209–217(210M) and gp100:280–288(288V). This blockade of CTLA-4 induced grade III/IV autoimmune manifestations in six patients (43%), including dermatitis, enterocolitis, hepatitis, and hypophysitis, and mediated objective cancer regression in three patients (21%; two complete and one partial responses). This study establishes CTLA-4 as an important molecule regulating tolerance to “self” antigens in humans and suggests a role for CTLA-4 blockade in breaking tolerance to human cancer antigens for cancer immunotherapy.
The Role of c‐Jun N‐Terminal Kinase (JNK) in Parkinson's Disease
Authors: Peng Jun , Andersen Julie
Published: July 2003

Given the critical role that the c‐Jun N‐terminal kinase (JNK) pathway plays in regulating many of the cellular processes which are affected in Parkinson's disease (PD), the possible importance of JNK in disease pathogenesis is being increasingly recognized. Here we review recent findings implicating the JNK signaling pathway in animal models of Parkinson's disease and discuss the relationship between this pathway and the prominent pathological processes observed in the disease state. We suggest that regulation of the JNK signaling pathway may be a central facet in potential treatments for the disease. IUBMB Life, 55: 267‐271, 2003
Heterotachy and Functional Shift in Protein Evolution
Authors: Philippe Hervé , Casane Didier , Gribaldo Simonetta , Lopez Philippe , Meunier Julien
Published: July 2003

Study of structure/function relationships constitutes an important field of research, especially for modification of protein function and drug design. However, the fact that rational design (i.e. the modification of amino acid sequences by means of directed mutagenesis, based on knowledge of the three‐dimensional structure) appears to be much less efficient than irrational design (i.e. random mutagenesis followed by in vitro selection) clearly indicates that we understand little about the relationships between primary sequence, three‐dimensional structure and function. The use of evolutionary approaches and concepts will bring insights to this difficult question. The increasing availability of multigene family sequences that has resulted from genome projects has inspired the creation of novel in silico evolutionary methods to predict details of protein function in duplicated (paralogous) proteins. The underlying principle of all such approaches is to compare the evolutionary properties of homologous sequence positions in paralogs. It has been proposed that the positions that show switches in substitution rate over time‐‐i.e., 'heterotachous sites'‐‐are good indicators of functional divergence. However, it appears that heterotachy is a much more general process, since most variable sites of homologous proteins with no evidence of functional shift are heterotachous. Similarly, it appears that switches in substitution rate are as frequent when paralogous sequences are compared as when orthologous sequences are compared. Heterotachy, instead of being indicative of functional shift, may more generally reflect a less specific process related to the many intra‐ and inter‐molecular interactions compatible with a range of more or less equally viable protein conformations. These interactions will lead to different constraints on the nature of the primary sequences, consistently with theories suggesting the non‐independence of substitutions in proteins. However, a specific type of amino acid variation might constitute a good indicator of functional divergence: substitutions occurring at positions that are generally slowly evolving. Such substitutions at constrained sites are indeed much more frequent soon after gene duplication. The identification and analysis of these sites by complementing structural information with evolutionary data may represent a promising direction to future studies dealing with the functional characterization of an ever increasing number of multi‐gene families identified by complete genome analysis. IUBMB Life, 55: 257‐265, 2003
Medical Diagnosis by High Resolution NMR of Human Specimens
Authors: Smith Ian , Baert Racquel
Published: July 2003

NMR has progressed relatively recently from a technique used almost exclusively by chemists and physicists to a viable tool for medical diagnosis. NMR applications have developed from analysis of cells, tissues, and biological fluids, to in vivo analysis. We discuss some examples of its clinical successes, as well as some of the challenges encountered along the way. IUBMB Life, 55: 273‐277, 2003
4D Bioinformatics: A New Look at the Ribosome as an Example
Authors: Quon Gerald , Gordon Paul , Sensen Christoph
Published: July 2003

We have adapted the Java Molecular Viewer (JMV) to virtual reality display environments, through a number of extensions to the Java 3D code. Phylogenetic information derived from multiple alignments (temporal information) can be overlaid onto molecule structures (spatial information). The number of sequences included in the underlying multiple alignment can be changed instantaneously, resulting in dynamical updates of the displayed information. JMV was also extended to handle an infinite number of objects (molecules) in the same display. The objects can be manipulated in six degrees of freedom simultaneously or independently. We have used the small subunit ribosomal RNA to demonstrate the system (http://cave.ucalgary.ca), which can be used for any molecule with a resolved structure. IUBMB Life, 55: 279‐283, 2003
Two-dimensional magic numbers in mass abundances of photofragmented bimetallic clusters
Authors: Janssens Ewald , Tanaka Hiromasa , Neukermans Sven , Silverans Roger E , Lievens Peter
Published: July 2003

The stability of cationic gold clusters doped with one transition metal atom was investigated by a mass spectrometric analysis of fragments resulting from high fluence irradiation of a cluster beam. Strongly enhanced abundances are found for Au5X+, X = V, Mn, Cr, Fe, Co, Zn, which implies that these species are far more stable towards fragmentation than their neighbouring cluster sizes. Here we interpret the enhanced stability of these clusters within a shell model approach for two-dimensional (2D) systems: the number of delocalized electrons in Au5X+is six, which is a magic number for 2D systems. Quantum chemical calculations for AuNZn+(N= 2-6) predict planar structures that are stabilized by the influence of the dopant atom. Also, the main features of the calculated molecular orbitals are well reproduced by a simple electron-in-a-box model. The present report constitutes the first observation of 2D magic numbers in size dependent properties of metal clusters.
P2Y-like receptor, GPR105 (P2Y14), identifies and mediates chemotaxis of bone-marrowhematopoietic stem cells
Authors: Lee Byeong-Chel , Cheng Tao , Adams Gregor B. , Attar Eyal C. , Miura Nobuyuki , Lee Sean Bong , Saito Yoriko , Olszak Ivona , Dombkowski David , Olson Douglas P. , Hancock Julie , Choi Peter S. , Haber Daniel A. , Luster Andrew D. , Scadden David T.
Published: July 2003

Hematopoiesis in mammals undergoes a developmental shift in location from fetal liver to bone marrow accompanied by a gradual transition from highly proliferative to deeply quiescent stem cell populations. P2Y receptors are G-protein-coupled nucleotide receptors participating in vascular and immune responses to injury. We identified a P2Y-like receptor for UDP-conjugated sugars, GPR105 (P2Y14), with restricted expression on primitive cells in the hematopoietic lineage. Anti-GPR105 antibody selectively isolated a subset of hematopoietic cells within the fetal bone marrow, but not in the fetal liver, that was enriched for G0 cell cycle status and for in vitro stem-cell-like multipotential long-term culture capability. Conditioned media from bone marrowstroma induced receptor activation and chemotaxis that was sensitive to Gαi and anti-receptor antibody inhibition. GPR105 is a G-protein-coupled receptor identifying a quiescent, primitive population of hematopoietic cells restricted to bone marrow. It mediates primitive cell responses to specific hematopoietic microenvironments and extends the known immune system functions of P2Y receptors to the stem cell level. These data suggest a newclass of receptors participating in the regulation of the stem cell compartment.
cAMP promotes pancreatic β-cell survival via CREB-mediated induction of IRS2
Authors: Jhala Ulupi S. , Canettieri Gianluca , Screaton Robert A. , Kulkarni Rohit N. , Krajewski Stan , Reed John , Walker John , Lin Xueying , White Morris , Montminy Marc
Published: July 2003

The incretin hormone GLP1 promotes islet-cell survival via the second messenger cAMP. Here we show that mice deficient in the activity of CREB, caused by expression of a dominant-negative A-CREB transgene in pancreatic β-cells, develop diabetes secondary to β-cell apoptosis. Remarkably, A-CREB severely disrupted expression of IRS2, an insulin signaling pathway component that is shown here to be a direct target for CREB action in vivo. As induction of IRS2by cAMP enhanced activation of the survival kinase Akt in response to insulin and IGF-1, our results demonstrate a novel mechanism by which opposing pathways cooperate in promoting cell survival.
Formation of higher-order secondary and tertiary chromatin structures by genomic mouse mammary tumor virus promoters
Authors: Georgel Philippe T. , Fletcher Terace M. , Hager Gordon L. , Hansen Jeffrey C.
Published: July 2003

Agarose multigel electrophoresis has been used to characterize the structural features of isolated genomic mouse mammary tumor virus (MMTV) promoters. The mouse 3134cells used for these studies contain ∼200 stably integrated tandem repeats of a 2.4-kb MMTV promoter fragment. Inactive, basally active, and hormonally activated genomic promoters were liberated by restriction digestion of isolated nuclei, recovered in low-salt nuclear extracts, and electrophoresed in multigels consisting of nine individual agarose running gels. Specific bands were detected and characterized by Southern and Western blotting. We find that transcriptionally inactive promoters contain TBP and high levels of histone H1, and are present to varying extents in both untreated and dexamethasone (DEX)-treated 3134cells. In contrast, the basally active promoter, present in untreated cells, is bound to RNA Pol II, TBP, and Oct1, contains acetylated H3 tail domains, and is depleted of histone H1. The DEX-activated promoter possessed similar composition as the basal promoter, but also contains stably bound Brg1. Strikingly, all forms of the MMTV promoter condense into higher-order secondary and/or tertiary chromatin structures in vitro in the presence of Mg2+. Thus, genomic MMTV promoter chromatin retains the ability to form classical higher-order structures under physiological salt conditions, even after dissociation of H1 and binding of several transcription factors and multiprotein complexes. These results suggest that transcriptionally active eukaryotic promoters may function in a locally folded chromatin environment in vivo.
Werner syndrome protein limits MYC-induced cellular senescence
Authors: Grandori Carla , Wu Kou-Juey , Fernandez Paula , Ngouenet Celine , Grim Jonathan , Clurman Bruce E. , Moser Michael J. , Oshima Junko , Russell David W. , Swisshelm Karen , Frank Scott , Amati Bruno , Dalla-Favera Riccardo , Monnat Raymond J.
Published: July 2003

The MYC oncoprotein is a transcription factor that coordinates cell growth and division. MYC overexpression exacerbates genomic instability and sensitizes cells to apoptotic stimuli. Here we demonstrate that MYC directly stimulates transcription of the human Werner syndrome gene,WRN, which encodes a conserved RecQ helicase. Loss-of-function mutations inWRNlead to genomic instability, an elevated cancer risk, and premature cellular senescence. The overexpression of MYC in WRN syndrome fibroblasts or after WRN depletion from control fibroblasts led to rapid cellular senescence that could not be suppressed byhTERTexpression. We propose thatWRNup-regulation by MYC may promote MYC-driven tumorigenesis by preventing cellular senescence.
Cell fate decisions within the mouse organizer are governed by graded Nodal signals
Authors: Vincent Stéphane D. , Dunn N. Ray , Hayashi Shigemi , Norris Dominic P. , Robertson Elizabeth J.
Published: July 2003

It is well known that cell fate decisions in the mouse organizer region during gastrulation ultimately govern gut formation and patterning, left–right axis determination, and development of the central nervous system. Previous studies suggest that signaling pathways activated by Nodal, bone morphogenetic protein (BMP), and Wnt ligands coordinately regulate patterning of the streak and the formation of midline organizing tissues, but the specific contributions of these molecules within discrete cell lineages are poorly defined. Here we removedSmad2activity in the epiblast, using a conditional inactivation strategy. Abrogation ofSmad2does not compromise primitive streak (PS) formation or gastrulation movements, but rather results in a failure to correctly specify the anterior definitive endoderm (ADE) and prechordal plate (PCP) progenitors. To selectively lowerNodalactivity in the posterior epiblast, we generated a novel allele lacking the proximal epiblast enhancer (PEE) governingNodalexpression in the PS. As for conditional inactivation ofSmad2, germ-line deletion of the PEE selectively disrupts development of the anterior streak. In striking contrast, the node and its midline derivatives, the notochord and floor plate, develop normally in both categories of mutant embryos. Finally, we show that removal of one copy ofSmad3in the context of aSmad2-deficient epiblast results in a failure to specify all axial midline tissues. These findings conclusively demonstrate that gradedNodal/Smad2signals govern allocation of the axial mesendoderm precursors that selectively give rise to the ADE and PCP mesoderm.
PKCδ is essential for Dishevelled function in a noncanonical Wnt pathway that regulatesXenopusconvergent extension movements
Authors: Kinoshita Noriyuki , Iioka Hidekazu , Miyakoshi Akira , Ueno Naoto
Published: July 2003

Protein kinase C (PKC) has been implicated in the Wnt signaling pathway; however, its molecular role is poorly understood. We identified novel genes encoding δ-type PKC in theXenopusEST databases. Loss of PKCδ function revealed that it was essential for convergent extension during gastrulation. We then examined the relationship between PKCδ and the Wnt pathway. PKCδ was translocated to the plasma membrane in response to Frizzled signaling. In addition, loss of PKCδ function inhibited the translocation of Dishevelled and the activation of c-Jun N-terminal kinase (JNK) by Frizzled. Furthermore, PKCδ formed a complex with Dishevelled, and the activation of PKCδ by phorbol ester was sufficient for Dishevelled translocation and JNK activation. Thus, PKCδ plays an essential role in the Wnt/JNK pathway by regulating the localization and activity of Dishevelled.
The Sox9 transcription factor determines glial fate choice in the developing spinal cord
Authors: Stolt C. Claus , Lommes Petra , Sock Elisabeth , Chaboissier Marie-Christine , Schedl Andreas , Wegner Michael
Published: July 2003

The mechanism that causes neural stem cells in the central nervous system to switch from neurogenesis to gliogenesis is poorly understood. Here we analyzed spinal cord development of mice in which the transcription factor Sox9 was specifically ablated from neural stem cells by the CRE/loxPrecombination system. These mice exhibit defects in the specification of oligodendrocytes and astrocytes, the two main types of glial cells in the central nervous system. Accompanying an early dramatic reduction in progenitors of the myelin-forming oligodendrocytes, there was a transient increase in motoneurons. Oligodendrocyte progenitor numbers recovered at later stages of development, probably owing to compensatory actions of the related Sox10 and Sox8, both of which overlap with Sox9 in the oligodendrocyte lineage. In agreement, compound loss of Sox9 and Sox10 led to a further decrease in oligodendrocyte progenitors. Astrocyte numbers were also severely reduced in the absence of Sox9 and did not recover at later stages of spinal cord development. Taking the common origin of motoneurons and oligodendrocytes as well as V2 interneurons and some astrocytes into account, stem cells apparently fail to switch from neurogenesis to gliogenesis in at least two domains of the ventricular zone, indicating that Sox9 is a major molecular component of the neuron–glia switch in the developing spinal cord.
Insight into the effects of rotor downwash on engine jet
Authors: Cao Yihua , Su Yuan
Published: July 2003

An analytical method to predict the effects of rotor downwash on engine jet was proposed to investigate the flow pattern of helicopter engine jet. First, free wake analysis was carried out to calculate the rotor wake geometry and the downwash around the engine jet space. Then the engine jet path, cross section shape and physical variants were calculated and analyzed. Finally, an example was given to show the typical results for an insight into the influence of engine jet upon the temperature distribution around a helicopter. The method developed here can be used to predict rotor wake, engine jet and temperature distribution of a helicopter.
Transonic airfoil design and optimisation by using vibrational genetic algorithm
Authors: Hacıogˇlu Abdurrahman , Özkol I˙brahim
Published: July 2003

In this study, the power of vibrational genetic algorithm (VGA) for transonic airfoil design and optimisation problems, which are generally characterized by multi‐model topology in the design parameter space, has been introduced. This type of problem is characterized by search and computational time to achieve satisfying solutions. In order to obtain more robust and faster algorithm, vibration concept, our earlier study, is further developed. This developed VGA is coupled with a full potential flow‐field solver for inverse design and airfoil optimisation problem in transonic case. The performance of this implemented strategy is compared with that offered by a classical or more commonly used genetic algorithm.
Design for autonomous mission planning system
Authors: Rui Xu , Ping‐yuan Cui , Xiao‐fei Xu , Hu‐tao Cui
Published: July 2003

Because of indeterminateness of the environment and delay of the communication, deep space spacecraft is required to be autonomous. Planning technology is studied in order to realize the spacecraft autonomy. First, a multi‐agent planning system (MAPS) based on temporal constraint satisfaction is proposed for concurrency and distribution of spacecraft system. Second, timeline concept is used to describe simultaneous activity, continue time, resource and temporal constraints. Third, for every planning agent in the MAPS, its layered architecture is designed and planning algorithm based on the temporal constraint satisfaction is given in detail. Finally, taking some key subsystems of deep space explorer as an example, the prototype system of MAPS is implemented. The results show that with the communication and cooperation of the planning agents, the MAPS is able to produce complete plan for explorer mission quickly under the complex constraints of time and resource.
Lossless compression of radiographic images of aircraft components
Authors: Shark L‐K. , Lin X.Y. , Varley M.R. , Matuszewski B.J. , Smith J.P.
Published: July 2003

This paper presents an efficient lossless compression method to reduce the storage requirement and transmission time for radiographic non‐destructive testing images of aircraft components. The method is based on a combination of predictive coding and the integer wavelet transform. By using the component CAD model to divide the radiographic image of aircraft components into different regions with each region having the same material structure, the parameters of the predictors and the choice of the integer wavelet transform are optimised according to the specific image features contained in each region. Using a real radiographic image of a practical aircraft component as an example, the proposed method is presented and shown to offer a significantly higher compression ratio than other lossless compression schemes currently available.
Improving the performance of aerospace alloys
Authors: Thompson G.E. , Skeldon P. , Zhou X. , Shimizu K. , Habazaki H. , Smith C.J.E.
Published: July 2003

This paper reviews the role of alloying elements in aluminium and alloy fabrication on performance during surface treatment and surface finishing. Such elements may be present in solid solution as fine segregates, strengthening phase and equilibrium phases. For surface treatment and finishes, which generally proceed in the presence of alumina film, knowledge of the processes proceeding at the alloy/film and film/electrolyte interfaces, and those within anodic alumina films, gives rise to the possibility of controlling features of nanoscale dimensions, for improved performance, arises. Its influence on nanotextures at treated surfaces and compositionally and morphologically modified films is explained briefly.
The human side of organizational agility
Authors: Crocitto Madeline , Youssef Mohamed
Published: July 2003

Organizational agility may be considered the integration of organizational processes, characteristics, and members with advanced technology. Agility enhances the organization’s ability to provide high quality products and services and is, therefore, crucial to organizational competitiveness. Integrates the production/operations, general management, and sociotechnical views to develop a model of organizational agility. Briefly reviews the literature in these fields and offers a model of agility based on suppliers, organizational members, and customers united through information technology. It is proposed that these connections rest on a foundation of leadership, organization culture, and employee reward systems that create a relationship between people and technology. These relationships include involving people in decision making, creating process and product quality by offering enriched jobs, training in technology, and providing a reward system which reinforces agility‐promoting efforts.
A three‐stage model of requirements elicitation for Web‐based information systems
Authors: Yang Heng‐Li , Tang Jih‐Hsin
Published: July 2003

Although requirement elicitation is generally acknowledged to be very important in traditional information systems development (ISD), it does not get enough attention in most Web‐based information systems development (WISD). This paper highlighted the difference between ISD and WISD, and proposed a three‐stage model of user requirements elicitation for Web‐based information systems. This model divides the requirements definition into three stages: initial analysis, key user requirements elicitation and regular user responses. Most current WIS design methodologies consider only initial analysis, and neglect actual users’ requirements. Key user input is emphasized in this model, and social network analysis is proposed as a tool for identifying key users. Requirements analysis for WISD is no longer considered a one‐stop step, but is better regarded as a continuous evolving process. Finally, managerial implications are also provided in this paper.
The process and consequences of supply chain virtualization
Authors: Ho Danny C.K. , Au K.F. , Newton Edward
Published: July 2003

The recent rapid commercialization and adoption of Internet technologies has driven a process of supply chain virtualization, transforming conventional work practices across organizations. In an effort to provide a better understanding of this emerging phenomenon, this paper presents three key elements of supply chain virtualization, including: the formation of virtual trading communities; the emergence of virtual knowledge communities; and the relocation and integration of inter‐organizational business processes in the cyberspace. The transformations and consequences of virtualization are illustrated in the context of the Hong Kong textile and clothing industry. The experience of Hong Kong suggests that supply chain virtualization has propelled a structural change in buyers‐intermediaries‐sellers relationships, called for a novel approach to knowledge management, and accelerated internationalization of small‐ and medium‐sized enterprises. Managers and policy makers are advised to adopt new mindsets and practices in the face of these challenges.
Realizing a new e‐commerce tool for formation of a virtual enterprise
Authors: Davidrajuh Reggie
Published: July 2003

This paper presents a methodology for the development of a new tool for the formation of a virtual enterprise. The formation phase mainly deals with inviting potential collaborators to virtual enterprise, and developing a supply chain; supply chain development is done collaboratively by all the collaborating enterprises. The methodology for realizing a new e‐commerce tool is primarily aimed at satisfying the needs of small‐to‐medium‐sized enterprises, and has the following features: Web‐based; inexpensive; supports collaboration; and increases pipeline visibility and demand visibility.
A conceptual model of supply chain flexibility
Authors: Duclos Leslie K. , Vokurka Robert J. , Lummus Rhonda R.
Published: July 2003

This paper presents an integrated conceptual model of supply chain flexibility. It examines flexibility classification schemes and the commonalities of flexibility typologies published in the literature to create a theoretical foundation for analyzing the components of supply chain flexibility. Even though there has been a tremendous amount of research on the topic of flexibility, most of it has been confined to intra‐firm flexibility concerns. As supply chain management goes beyond a firm’s boundaries, the flexibility strategies must also extend beyond the firm. This paper identifies the cross‐enterprise nature of supply chain flexibility and the need to improve flexibility measures across firms. Opportunities are identified for future cross‐functional research that builds on this theoretical foundation and leads to more effective formulation of supply chain strategies.
Allocating health (and social care) expenditure in Wales
Authors: Beddow Tony , Cohen David
Published: July 2003

Devolution in the UK enables its four countries to pursue locally relevant policies. Healthcare is a key devolved subject on which the competency of the devolved governments will be judged. Mechanisms that enable political aspirations to be understood in terms of inputs, processes and outputs/outcomes – and delivered – are now needed. A model demonstrating such a mechanism is described. The model enables different investment options to be contrasted using several dimensions, including time lags, qualitative and quantitative changes, changes in different care settings, and changes in different care stages.
Understanding occupational (sub) culture – a precursor for reform
Authors: Barton Harry
Published: July 2003

Over the past two decades successive British governments, both Conservative and Labour, have attempted to implement reforms within the English and Welsh police service. The latest Labour government proposals have resulted in new legislation which paves the way for wide‐scale reforms of how the police are managed, financed and judged against specific performance targets. Further, the introduction of the UKs first “national policing plan” has led to the belief that this is a sign of the British government's intention to reduce/remove the historical, political neutrality identified through “constabulary independence”. Past experiences suggest that greater “nationalisation” of policing in the UK is unlikely to meet government expectations owing to the strength of police (sub) culture to adopt and yet resist reform and that the governments failure to pay attention to this may result in the failure of reform.
The diffusion of accounting practices in the new “managerial” public sector
Authors: Jackson Audrey , Lapsley Irvine
Published: July 2003

In the past two decades the public sector has experienced a transformation. A major feature of this change has been the displacement of the old style public administration by a “new public management” which focuses on results and measurement and in which accounting has a central role. This study reports on a survey of accountants in the public sector to determine the extent to which the changing public sector is accompanied by changes in accounting practices and to explore the process by which such changes are effected.