bluuebunny/crossref_metadata_2025 huggingface dataset:
‘FAS’t inhibition of malaria
Authors: SUROLIA Avadhesha , RAMYA T. N. C. , RAMYA V. , SUROLIA Namita
Published: October 2004

Malaria, a tropical disease caused by Plasmodium sp., has been haunting mankind for ages. Unsuccessful attempts to develop a vaccine, the emergence of resistance against the existing drugs and the increasing mortality rate all call for immediate strategies to treat it. Intense attempts are underway to develop potent analogues of the current antimalarials, as well as a search for novel drug targets in the parasite. The indispensability of apicoplast (plastid) to the survival of the parasite has attracted a lot of attention in the recent past. The present review describes the origin and the essentiality of this relict organelle to the parasite. We also show that among the apicoplast specific pathways, the fatty acid biosynthesis system is an attractive target, because its inhibition decimates the parasite swiftly unlike the ‘delayed death’ phenotype exhibited by the inhibition of the other apicoplast processes. As the enzymes of the fatty acid biosynthesis system are present as discrete entities, unlike those of the host, they are amenable to inhibition without impairing the operation of the host-specific pathway. The present review describes the role of these enzymes, the status of their molecular characterization and the current advancements in the area of developing inhibitors against each of the enzymes of the pathway.
The 161TT genotype in the exon 6 of the peroxisome-proliferator-activated receptor γ gene is associated with premature acute myocardial infarction and increased lipid peroxidation in habitual heavy smokers
Authors: CHAO Ting-Hsing , LI Yi-Heng , CHEN Jyh-Hong , WU Hua-Lin , SHI Guey-Yueh , LIU Ping-Yen , TSAI Wei-Chuan , GUO How-Ran
Published: October 2004

PPAR (peroxisome-proliferator-activated receptor) is a nuclear receptor. Activation of PPARγ by its ligands could modulate gene transcription, thereby leading to multiple anti-atherogenic and fibrinolytic effects. However, the association between the 161T allele in exon 6 of the PPARγ gene and premature AMI (acute myocardial infarction) is not clear. We recruited 146 patients with premature AMI (onset age ≤50 years) and 146 controls. The C161T polymorphism was examined using PCR and restriction-fragment-length polymorphism. Plasma levels of Ab-ox-LDL (antibody against oxidized low-density lipoprotein) were measured in 27 male smokers, whose genotypes have been identified. The frequency of the PPARγ TT genotype among patients with AMI was significantly higher than that in controls [13% compared with 5.5%; OR (95% CI) 2.7, (1.1–6.5), where OR and CI are odds ratio and confidence interval respectively]. This association was not observed in CC or CT genotypes. Using multivariate logistic regression analyses, we found that the homozygous TT genotype [OR (95% CI), 3.1 (1.2–7.9)], smoking [OR (95% CI), 3.5, (2.1–6.0)], hypertension [OR (95% CI), 3.6, (1.9–6.9)] and diabetes mellitus [OR (95% CI), 3.5 (1.5–8.4)] were independent risk factors for premature AMI. Plasma levels of Ab-ox-LDL were significantly higher in healthy volunteers with the TT genotype compared with those with the CC genotype (49.3±18.1 compared with 24.2±15.2 units/l respectively; P=0.02). Therefore in our study we observed an association between the PPARγ 161 TT genotype and premature AMI. Lipid peroxidation was significantly influenced by the 161T allele.
Lack of association of a 9 bp insertion/deletion polymorphism within the bradykinin 2 receptor gene with myocardial infarction
Authors: FISCHER Marcus , LIEB Wolfgang , MAROLD Daniel , BERTHOLD Matthias , BAESSLER Andrea , LOWEL Hannelore , HENSE Hans-Werner , HENGSTENBERG Christian , HOLMER Stephan , SCHUNKERT Heribert , ERDMANN Jeanette
Published: October 2004

The BK (bradykinin) B2 receptor is the major cellular mediator of the effects of BK. A 9 bp deletion in the promoter of the receptor gene represents an allelic variant that is associated with enhanced mRNA expression levels. We tested whether this polymorphism is associated with the prevalence of MI (myocardial infarction) or with echocardiographically determined left ventricular function in post-MI patients. Patients with documented MI (n=484), matched controls and controls without evidence of coronary heart disease (n=1363) constituted cases and controls. MI patients and controls were carefully matched for age, gender and cardiovascular risk factors. Genotype distributions of the 9 bp insertion/deletion polymorphism were similar across the groups: −9/−9, −9/+9 and +9/+9 were 22.1, 49.5 and 28.5% in MI patients, and 23.0, 44.6 and 32.5% in matched control subjects respectively. The lack of association was also observed in selected subgroups, stratified by age, gender and cardiovascular risk factors. Furthermore, there was no relation between this polymorphism and left ventricular systolic function in post-MI patients. These findings indicate that the 9 bp insertion/deletion polymorphism of the BK B2 receptor gene is neither related to the prevalence of MI nor to left ventricular function after MI.
The procyanidin-induced pseudo laminar shear stress response: a new concept for the reversal of endothelial dysfunction
Authors: CORDER Roger , WARBURTON Richard C. , KHAN Noorafza Q. , BROWN Ruth E. , WOOD Elizabeth G. , LEES Delphine M.
Published: October 2004

Reduced endothelium-dependent vasodilator responses with increased synthesis of ET-1 (endothelin-1) are characteristics of endothelial dysfunction in heart failure and are predictive of mortality. Identification of treatments that correct these abnormalities may have particular benefit for patients who become refractory to current regimens. Hawthorn preparations have a long history in the treatment of heart failure. Therefore we tested their inhibitory effects on ET-1 synthesis by cultured endothelial cells. These actions were compared with that of GSE (grape seed extract), as the vasoactive components of both these herbal remedies are mainly oligomeric flavan-3-ols called procyanidins. This showed extracts of hawthorn and grape seed were equipotent as inhibitors of ET-1 synthesis. GSE also produced a potent endothelium-dependent vasodilator response on preparations of isolated aorta. Suppression of ET-1 synthesis at the same time as induction of endothelium-dependent vasodilation is a similar response to that triggered by laminar shear stress. Based on these results and previous findings, we hypothesize that through their pharmacological properties procyanidins stimulate a pseudo laminar shear stress response in endothelial cells, which helps restore endothelial function and underlies the benefit from treatment with hawthorn extract in heart failure.
High pressure-temperature Raman measurements of H2O melting to 22 GPa and 900 K
Authors: Lin Jung-Fu , Militzer Burkhard , Struzhkin Viktor V. , Gregoryanz Eugene , Hemley Russell J. , Mao Ho-kwang
Published: October 2004

The melting curve of H2O has been measured by in situ Raman spectroscopy in an externally heated diamond anvil cell up to 22 GPa and 900 K. The Raman-active OH-stretching bands and the translational modes of H2O as well as optical observations are used to directly and reliably detect melting in ice VII. The observed melting temperatures are higher than previously reported x-ray measurements and significantly lower than recent laser-heating determinations. However, our results are in accord with earlier optical determinations. The frequencies and intensities of the OH-stretching peaks change significantly across the melting line while the translational mode disappears altogether in the liquid phase. The observed OH-stretching bands of liquid water at high pressure are very similar to those obtained in shock-wave Raman measurements.
Fourier transform microwave spectroscopy and Fourier transform microwave–millimeter wave double resonance spectroscopy of the ClOO radical
Authors: Suma Kohsuke , Sumiyoshi Yoshihiro , Endo Yasuki
Published: October 2004

Pure rotational spectra of the ClOO radical for the Cl35 and Cl37 isotopomers have been observed using Fourier transform microwave and Fourier transform microwave–millimeter wave double resonance spectroscopy. The rotational, centrifugal, spin-rotation coupling, and hyperfine coupling constants have been determined by least-squares fits of the observed transition frequencies. The molecular constants indicate that the electronic ground state is A″3. The r0 structure is determined to be r0(ClO)=2.075 Å, r0(OO)=1.227 Å, and θ0(ClOO)=116.4°. Several highly accurate ab initio calculations have also been performed. Some of them turned out to be inaccurate because it is necessary to take into account both static and dynamic electronic correlations. Only multireference (single and double) configuration interaction calculations with large basis sets reproduce the present experimental results. The anharmonic force constants obtained by the ab initio calculations are used to determine the re structure, re(ClO)=2.084(1) Å, re(OO)=1.206(2) Å, and θe(ClOO)=115.4(1)°. Unique features of the ClOO radical have become clear by the present experiment and the ab initio calculations.
Experimental and theoretical investigations of rate coefficients of the reaction S(3P)+O2 in the temperature range 298–878 K
Authors: Lu Chih-Wei , Wu Yu-Jong , Lee Yuan-Pern , Zhu R. S. , Lin M. C.
Published: October 2004

Rate coefficients of the reaction S+O2 with Ar under 50 Torr in the temperature range 298–878 K were determined with the laser photolysis technique. S atoms were generated by photolysis of OCS with a KrF excimer laser at 248 nm; their concentration was monitored via resonance fluorescence excited by atomic emission of S produced from microwave-discharged SO2. Our measurements show that k(298 K)=(1.92±0.29)×10−12 cm3 molecule−1 s−1, in satisfactory agreement with previous reports. New data determined for 505–878 K show non-Arrhenius behavior; combining our results with data reported at high temperatures, we derive an expression k(T)=(9.02±0.27)×10−19T2.11±0.15 exp[(730±120)/T] cm3 molecule−1 s−1 for 298⩽T⩽3460 K. Theoretical calculations at the G2M (RCC2) level, using geometries optimized with the B3LYP/6-311+G(3df) method, yield energies of transition states and products relative to those of the reactants. Rate coefficients predicted with multichannel RRKM calculations agree satisfactorily with experimental observations; the reaction channel via SOO(1A′) dominates at T<500 K, whereas channels involving formation of SOO(3A″) followed by isomerization to SO2 before dissociation, and formation of SOO(1A″) followed by direct dissociation, become important at high temperatures, accounting for the observed rapid increase in rate coefficient.
On the interatomic Coulombic decay in the Ne dimer
Authors: Scheit S. , Averbukh V. , Meyer H.-D. , Moiseyev N. , Santra R. , Sommerfeld T. , Zobeley J. , Cederbaum L. S.
Published: October 2004

The interatomic Coulombic decay (ICD) in the Ne dimer is discussed in view of the recent experimental results. The ICD electron spectrum and the kinetic energy release of the Ne+ fragments resulting after Coulomb explosion of Ne22+ are computed and compared to the measured ones. A very good agreement is found, confirming the dynamics predicted for this decay mechanism. The effect of the temperature on the electron spectrum is briefly investigated.
Formally exact quantization condition for nonrelativistic quantum systems
Authors: Ou Y. C. , Cao Zhuangqi , Shen Qishun
Published: October 2004

Based on the standard transfer matrix, a formally exact quantization condition for arbitrary potentials, which outflanks and unifies the historical approaches, is derived. It can be used to find the exact bound-state energy eigenvalues of the quantum system without solving an equation of motion for the system wave functions.
Collisional line shapes for low frequency vibrations of adsorbates on a metal surface
Authors: Vega J. L. , Guantes R. , Miret-Artés S. , Micha D. A.
Published: October 2004

The dynamics of atoms or molecules adsorbed on a metal surface, and excited by collisions with an atomic beam, are treated within a theory that includes energy dissipation into lattice vibrations by means of a frequency and temperature dependent friction function. The theory provides dynamic structure factors for energy transfer derived from collisional time correlation functions. It describes the relaxation of a vibrationally excited atom or molecule within a model of a damped quantum harmonic oscillator bilinearly coupled to a bath of lattice oscillators. The collisional time correlation function is generalized to include friction effects and is applied to the vibrational relaxation of the frustrated translation mode of Na adsorbed on a Cu(001) surface, CO on Cu(001), and CO on Pt(111), following excitation by collisions with He atoms. Results for the frequency shift and width of line shapes versus surface temperature are in very good agreement with experimental measurements of inelastic He atom scattering. Our interpretation of the experimental results provides insight on the relative role of phonon versus electron-hole relaxation.
Structure and stability of Al13I clusters
Authors: Han Young-Kyu , Jung Jaehoon
Published: October 2004

We have performed density functional calculations for the structures and stabilities of Al13I at the scalar relativistic pseudopotential and all-electron levels of theory. The Al13 moiety in Al13I is significantly distorted and structurally similar to an Al13 cation, where the natural population is −0.27e for the I atom. Unlike other Al13-M (M=H, alkali metals, and coinage metals) clusters, a Cs-ontop structure was found to be the most stable form. The Al13I cluster has a large Al13-I binding energy of 3.11 eV and is more stable, as charge transfer to the electronegative I atom is larger.
Solvent effects on the n→π* electronic transition in formaldehyde: A combined coupled cluster/molecular dynamics study
Authors: Kongsted Jacob , Osted Anders , Mikkelsen Kurt V. , Åstrand Per-Olof , Christiansen Ove
Published: October 2004

We present a study of the blueshift of the n→π* electronic transition in formaldehyde in aqueous solution using a combined coupled cluster/molecular mechanics model including mutual polarization effects in the Hamiltonian. In addition, we report ground and excited state dipole moments. Configurations are generated from molecular dynamics simulations with two different force fields, one with and one without an explicit polarization contribution. A statistical analysis using 1200 configurations is presented. Effects of explicit polarization contributions are found to be significant. It is found that the main difference in the effects on the excitation energies arises from the fact that the two force fields result in different liquid structures, and thus a different set of configurations is generated for the coupled cluster/molecular mechanics calculations.
Convergence of excitatory and inhibitory hair cell transmitters shapes vestibular afferent responses
Authors: Holstein Gay R. , Rabbitt Richard D. , Martinelli Giorgio P. , Friedrich Victor L. , Boyle Richard D. , Highstein Stephen M.
Published: October 2004

The vestibular semicircular canals respond to angular acceleration that is integrated to angular velocity by the biofluid mechanics of the canals and is the primary origin of afferent responses encoding velocity. Surprisingly, some afferents actually report angular acceleration. Our data indicate that hair-cell/afferent synapses introduce a mathematical derivative in these afferents that partially cancels the biomechanical integration and results in discharge rates encoding angular acceleration. We examined the role of convergent synaptic inputs from hair cells to this mathematical differentiation. A significant reduction in the order of the differentiation was observed for low-frequency stimuli after γ-aminobutyric acid type B receptor antagonist administration. Results demonstrate that γ-aminobutyric acid participates in shaping the temporal dynamics of afferent responses.
Local modulation of plus-end transport targets herpesvirus entry and egress in sensory axons
Authors: Smith G. A. , Pomeranz L. , Gross S. P. , Enquist L. W.
Published: October 2004

The core structures of many viruses move within cells by association with host cytoskeletal motor proteins; however, the mechanisms by which intracellular viral particles are transported toward sites of replication or the cell periphery at distinct stages of infection remain to be understood. The regulation of herpesvirus directional transport in sensory neurons was examined by tracking individual viral capsids within axons at multiple frames per s. After entry into axons, capsids underwent bidirectional and saltatory movement to the cell body independently of endosomes. A comparison of entry transport to a previous analysis of capsid axonal transport during egress revealed that capsid targeting in and out of cells occurs by modulation of plus-end, but not minus-end, motion. Entry transport was unperturbed by the presence of egressing virus from a prior infection, indicating that transport direction is not modulated globally by viral gene expression, but rather directly by a component of the viral particle.
A β-oxidation-resistant lipoxin A4analog treats hapten-induced colitis by attenuating inflammation and immune dysfunction
Authors: Fiorucci Stefano , Wallace John L. , Mencarelli Andrea , Distrutti Eleonora , Rizzo Giovanni , Farneti Silvana , Morelli Antonio , Tseng Jih-Lie , Suramanyam Babu , Guilford William J. , Parkinson John F.
Published: October 2004

Lipoxins and aspirin-triggered 15-epi-lipoxins (ATL) are counter-regulatory eicosanoids with potent antiinflammatory actions. Oral efficacy and mechanism of action of ZK-192, a β-oxidation-resistant 3-oxa-ATL analog, were examined in trinitrobenzenesulphonate (TNBS)-induced colitis. When dosed orally once daily, 300 and 1,000 μg/kg ZK-192 markedly attenuated TNBS colitis in rodents both in preventive and therapeutic regimens. ZK-192 attenuated weight loss, macroscopic and histologic colon injury, mucosal neutrophil infiltration, and colon wall thickening. ZK-192 was as effective as 3–10 mg/kg oral prednisolone. ZK-192 decreased mucosal mRNA levels for several inflammatory mediators: inducible nitric oxide synthase, cyclooxygenase 2, and macrophage inflammatory protein 2. ZK-192 also decreased mucosal mRNA and protein levels of T helper 1 effector cytokines: tumor necrosis factor α, IL-2, and IFN-γ. Systemic levels of these cytokines were also dramatically attenuated. CD3/CD28-mediated costimulation of T helper 1 effector cytokine release in lamina propria mononuclear cells was markedly inhibited by ZK-192ex vivoandin vitro. ZK-192 also prevented colitis in lymphocyte-deficient severe combined immunodeficient mice, with ≈75% inhibition of mucosal tumor necrosis factor α and IL-2 levels. The results are further evidence that innate immune cells function as triggers for hapten-induced colitis. The combined antiinflammatory and immunomodulatory effects of ZK-192 in TNBS colitis suggest that ATL analogs may be an attractive oral treatment approach for inflammatory bowel diseases.
Emergence of complex dynamics in a simple model of signaling networks
Authors: Amaral Luís A. N. , Díaz-Guilera Albert , Moreira Andre A. , Goldberger Ary L. , Lipsitz Lewis A.
Published: October 2004

Various physical, social, and biological systems generate complex fluctuations with correlations across multiple time scales. In physiologic systems, these long-range correlations are altered with disease and aging. Such correlated fluctuations in living systems have been attributed to the interaction of multiple control systems; however, the mechanisms underlying this behavior remain unknown. Here, we show that a number of distinct classes of dynamical behaviors, including correlated fluctuations characterized by 1/
f
scaling of their power spectra, can emerge in networks of simple signaling units. We found that, under general conditions, complex dynamics can be generated by systems fulfilling the following two requirements, (
i
) a “small-world” topology and (
ii
) the presence of noise. Our findings support two notable conclusions. First, complex physiologic-like signals can be modeled with a minimal set of components; and second, systems fulfilling conditions
i
and
ii
are robust to some degree of degradation (i.e., they will still be able to generate 1/
f
dynamics).
Barrier-limited, microsecond folding of a stable protein measured with hydrogen exchange: Implications for downhill folding
Authors: Meisner W. Kevin , Sosnick Tobin R.
Published: October 2004

Folding experiments are conducted to test whether a covalently cross-linked coiled-coil folds so quickly that the process is no longer limited by a free-energy barrier. This protein is very stable and topologically simple, needing merely to “zipper up,” while having an extrapolated folding rate of
k
f
= 2 × 10
5
s
-1
. These properties make it likely to attain the elusive “downhill folding” limit, at which a series of intermediates can be characterized. To measure the ultra-fast kinetics in the absence of denaturant, we apply NMR and hydrogen-exchange methods. The stability and its denaturant dependence for the hydrogen bonds in the central part of protein equal the values calculated for whole-molecule unfolding. Like-wise, their closing and opening rates indicate that these hydrogen bonds are broken and reformed in a single cooperative event representing the folding transition from the fully unfolded state to the native state. Additionally, closing rates for these hydrogen bonds agree with the extrapolated barrier-limited folding rate observed near the melting transition. Therefore, even in the absence of denaturant, where Δ
G
eq
≈ -6 kcal·mol
-1
(1 cal = 4.18 J) and τ
f
≈ 6 μs, folding remains cooperative and barrier-limited. Given that this prime candidate for downhill folding fails to do so, we propose that protein folding will remain barrier-limited for proteins that fold cooperatively.
Three distinct suppressors of RNA silencing encoded by a 20-kb viral RNA genome
Authors: Lu Rui , Folimonov Alexey , Shintaku Michael , Li Wan-Xiang , Falk Bryce W. , Dawson William O. , Ding Shou-Wei
Published: October 2004

Viral infection in both plant and invertebrate hosts requires a virus-encoded function to block the RNA silencing antiviral defense. Here, we report the identification and characterization of three distinct suppressors of RNA silencing encoded by the ≈20-kb plus-strand RNA genome of citrus tristeza virus (CTV). When introduced by genetic crosses into plants carrying a silencing transgene, both p20 and p23, but not coat protein (CP), restored expression of the transgene. Although none of the CTV proteins prevented DNA methylation of the transgene, export of the silencing signal (capable of mediating intercellular silencing spread) was detected only from the F
1
plants expressing p23 and not from the CP- or p20-expressing F
1
plants, demonstrating suppression of intercellular silencing by CP and p20 but not by p23. Thus, intracellular and intercellular silencing are each targeted by a CTV protein, whereas the third, p20, inhibits silencing at both levels. Notably, CP suppresses intercellular silencing without interfering with intracellular silencing. The novel property of CP suggests a mechanism distinct to p20 and all of the other viral suppressors known to interfere with intercellular silencing and that this class of viral suppressors may not be consistently identified by
Agrobacterium
coinfiltration because it also induces RNA silencing against the infiltrated suppressor transgene. Our analyses reveal a sophisticated viral counter-defense strategy that targets the silencing antiviral pathway at multiple steps and may be essential for protecting CTV with such a large RNA genome from antiviral silencing in the perennial tree host.
Growth and hydraulic (not mechanical) constraints govern the scaling of tree height and mass
Authors: Niklas Karl J. , Spatz Hanns-Christof
Published: October 2004

The size-dependent variations of plant height
L
and mass
M
with respect to basal stem diameter
D
are important to the analysis of a broad range of ecological and evolutionary phenomena. Prior examination of some of the world's largest trees suggests that the scaling relationships
L
α
D
2/3
and
M
α
D
8/3
hold true, ostensibly as functional adaptations for mechanical stability. This concept remains engrained in the literature in the form of null hypotheses (or predictive models), despite numerous examples showing that the 2/3 and 8/3 rules are violated by small and intermediate-sized plants. Here, we present a growth-hydraulic model that provides more accurate and biologically realistic predictions of
L
and
M
. This model also sheds light on why
L
,
D
, and
M
scale differently across species and habitats as a result of differences in absolute size.
Integration of reproductive meristem fates by a
SEPALLATA
-like MADS-box gene
Authors: Uimari Anne , Kotilainen Mika , Elomaa Paula , Yu Deyue , Albert Victor A. , Teeri Teemu H.
Published: October 2004

Reproductive transition, inflorescence architecture, meristem patterning, and floral organ identity have been studied as distinct research areas in plant science. By using the ornamental plant
Gerbera
, we demonstrate that all of these keystone aspects of reproductive meristematic fate are integrated genetically by a single
SEPALLATA
-like MADS-box gene from a functional class designated previously as “floral homeotic” or “organ identity.” This extended regulatory network has not been elaborated in the model plant systems, which have a floral design and inflorescence-determinacy state that obscures these relationships.
Induction of long-term potentiation and depression is reflected by corresponding changes in secretion of endogenous brain-derived neurotrophic factor
Authors: Aicardi Giorgio , Argilli Emanuela , Cappello Silvia , Santi Spartaco , Riccio Massimo , Thoenen Hans , Canossa Marco
Published: October 2004

Neurotrophins play an important role in modulating activity-dependent neuronal plasticity. In particular, threshold levels of brain-derived neurotrophic factor (BDNF) are required to induce long-term potentiation (LTP) in acute hippocampal slices. Conversely, the administration of exogenous BDNF prevents the induction of long-term depression (LTD) in the visual cortex. A long-standing missing link in the analysis of this modulatory role of BDNF was the determination of the time-course of endogenous BDNF secretion in the same organotypic preparation in which LTP and LTD are elicited. Here, we fulfilled this requirement in slices of perirhinal cortex. Classical theta-burst stimulation patterns evoking LTP lasting >180 min elicited a large increase in BDNF secretion that persisted 5-12 min beyond the stimulation period. Weaker theta-burst stimulation patterns leading only to the initial phase of LTP (≈35 min) were accompanied by a smaller increase in BDNF secretion lasting <1 min. Sequestration of BDNF by TrkB-IgG receptor bodies prevented LTP. Low-frequency stimulations leading to LTD were accompanied by reductions in BDNF secretion that never lasted beyond the duration of the stimulation.
Sole BCR-ABL inhibition is insufficient to eliminate all myeloproliferative disorder cell populations
Authors: Wong S. , McLaughlin J. , Cheng D. , Zhang C. , Shokat K. M. , Witte O. N.
Published: October 2004

Protein kinase inhibitors can be effective in treating selected cancers, but most suppress several kinases. Imatinib mesylate has been useful in the treatment of Philadelphia chromosome-positive chronic myelogenous leukemia and B cell acute lymphoblastic leukemia through the inhibition of BCR-ABL tyrosine kinase activity. Imatinib mesylate has also been shown to inhibit KIT, ARG, and platelet-derived growth factor receptors α and β, and potentially other tyrosine kinases. We have produced a mutant allele of BCR-ABL (T315A) that is uniquely inhibitable by the small molecule 4-amino-1-
tert
-butyl-3-(1-naphthyl)pyrazolo[3,4-
d
]pyrimidine and used it to demonstrate that sole suppression of BCR-ABL activity was insufficient to eliminate BCR-ABL
+
KIT
+
-expressing immature murine myeloid leukemic cells. In contrast, imatinib mesylate effectively eliminated BCR-ABL
+
KIT
+
-expressing leukemic cells. In the cellular context of mature myeloid cells and Pro/Pre B cells that do not express KIT, monospecific BCR-ABL inhibition was quantitatively as effective as imatinib mesylate in suppressing cell growth and inducing apoptosis. These results suggest that the therapeutic effectiveness of small molecule drugs such as imatinib mesylate could be due to the inhibitor's ability to suppress protein kinases in addition to the dominant target.
Antigen-independent memory CD8 T cells do not develop during chronic viral infection
Authors: Wherry E. John , Barber Daniel L. , Kaech Susan M. , Blattman Joseph N. , Ahmed Rafi
Published: October 2004

Memory T cells can persist for extended periods in the absence of antigen, and long-term T cell immunity is often seen after acute infections. Paradoxically, there have been observations suggesting that T cell memory may be antigen-dependent during chronic infections. To elucidate the underlying mechanisms we have compared memory CD8 T cell differentiation during an acute versus chronic infection by using the mouse model of infection with lymphocytic choriomeningitis virus. We found that during a chronic infection virus-specific CD8 T cells failed to acquire the cardinal memory T cell property of long-term antigen-independent persistence. These chronically stimulated CD8 T cells were unable to undergo homeostatic proliferation, responded poorly to IL-7 and IL-15, and expressed reduced levels of the IL-7 and IL-15 receptors, thus providing a possible mechanism for the inability of these cells to persist long term in the absence of antigen. In striking contrast, virus-specific memory CD8 T cells that developed after an acute lymphocytic choriomeningitis virus infection could persist without antigen, were capable of self-renewal because of homeostatic proliferation, responded efficiently to IL-7 and IL-15, and expressed high levels of receptors for these two cytokines. Thus, memory CD8 T cells generated after acute infections are likely to have a competitive advantage over CD8 T cells that develop during chronic infections. These findings raise concerns about using vaccines that may persist and also suggest that there may be limitations and challenges in designing effective immunological interventions for the treatment of chronic infections and tumors.
Business Failure and the Agenda of Business History
Authors: Fridenson Patrick
Published: October 2004

Is it really useful to focus the interest of business historians on major companies that failed in recent years, like Parmalat in Italy or Enron in the United States? What can we learn from studying cases like that of the French company Schneider, a first mover in metallurgy, armaments, and nuclear energy, which for almost 150 years dominated the company town Le Creusot, where the Business History Conference held its fiftieth anniversary meeting in 2004, but which has now disappeared?
Dynamical origin of quantum probabilities
Authors: Valentini Antony , Westman Hans
Published: October 2004

We study the origin of the Born probability ruleρ= |ψ|2in the de Broglie–Bohm pilot–wave formulation of quantum theory. It is argued that quantum probabilities arise dynamically, and have a status similar to thermal probabilities in ordinary statistical mechanics. This is illustrated by numerical simulations for a two–dimensional system. We show that a simple initial ensemble, with a non–standard distributionρ≠ |ψ|2of particle positions, evolves towards the quantum distribution to high accuracy. The relaxation processρ→|ψ|2is quantified in terms of a coarse–grainedH–function (equal to minus the relative entropy ofρwith respect to |ψ|2), which is found to decrease approximately exponentially over time, with a time constant that accords with a simple theoretical estimate.
Assessing the quality of molecular divergence time estimates by fossil calibrations and fossil–based model selection
Authors: Near Thomas J. , Sanderson Michael J.
Published: October 2004

Estimates of species divergence times using DNA sequence data are playing an increasingly important role in studies of evolution, ecology and biogeography. Most work has centred on obtaining appropriate kinds of data and developing optimal estimation procedures, whereas somewhat less attention has focused on the calibration of divergences using fossils. Case studies with multiple fossil calibration points provide important opportunities to examine the divergence time estimation problem in new ways. We discuss two cross–validation procedures that address different aspects of inference in divergence time estimation. ‘Fossil cross–validation’ is a procedure used to identify the impact of different individual calibrations on overall estimation. This can identify fossils that have an exceptionally large error effect and may warrant further scrutiny. ‘Fossil–based model cross–validation’ is an entirely different procedure that uses fossils to identify the optimal model of molecular evolution in the context of rate smoothing or other inference methods. Both procedures were applied to two recent studies: an analysis of monocot angiosperms with eight fossil calibrations and an analysis of placental mammals with nine fossil calibrations. In each case, fossil calibrations could be ranked from most to least influential, and in one of the two studies, the fossils provided decisive evidence about the optimal molecular evolutionary model.
Global climate and the distribution of plant biomes
Authors: Woodward F. I. , Lomas M. R. , Kelly C. K.
Published: October 2004

Biomes are areas of vegetation that are characterized by the same life–form. Traditional definitions of biomes have also included either geographical or climatic descriptors. This approach describes a wide range of biomes that can be correlated with characteristic climatic conditions, or climatic envelopes. The application of remote sensing technology to the frequent observation of biomes has led to a move away from the often subjective definition of biomes to one that is objective. Carefully characterized observations of life–form, by satellite, have been used to reconsider biome classification and their climatic envelopes. Five major tree biomes can be recognized by satellites based on leaf longevity and morphology: needleleaf evergreen, broadleaf evergreen, needleleaf deciduous, broadleaf cold deciduous and broadleaf drought deciduous. Observations indicate that broadleaf drought deciduous vegetation grades substantially into broadleaf evergreen vegetation. The needleleaf deciduous biome occurs in the world's coldest climates, where summer drought and therefore a drought deciduous biome are absent.

Traditional biome definitions are quite static, implying no change in their life–form composition with time, within their particular climatic envelopes. However, this is not the case where there has been global ingress of grasslands and croplands into forested vegetation. The global spread of grasses, a new super–biome, was probably initiated 30–45 Myr ago by an increase in global aridity, and was driven by the natural spread of the disturbances of fire and animal grazing. These disturbances have been further extended over the Holocene era by human activities that have increased the land areas available for domestic animal grazing and for growing crops. The current situation is that grasses now occur in most, if not all biomes, and in many areas they dominate and define the biome. Croplands are also increasing, defining a new and relatively recent component to the grassland super–biome. In the case of both grassland and croplands, various forms of disturbance, particularly frequent disturbance, lead to continued range extensions of the biomes.
Multiple Miocene Melastomataceae dispersal between Madagascar, Africa and India
Authors: Renner Susanne S.
Published: October 2004

Melastomataceae
sensu stricto
(excluding Memecylaceae) comprise some 3000 species in the neotropics, 1000 in Asia, 240 in Africa, and 230 in Madagascar. Previous family–wide morphological and DNA analyses have shown that the Madagascan species belong to at least three unrelated lineages, which were hypothesized to have arrived by trans–oceanic dispersal. An alternative hypothesis posits that the ancestors of Madagascan, as well as Indian, Melastomataceae arrived from Africa in the Late Cretaceous. This study tests these hypotheses in a Bayesian framework, using three combined sequence datasets analysed under a relaxed clock and simultaneously calibrated with fossils, some not previously used. The new fossil calibration comes from a re–dated possibly Middle or Upper Eocene Brazilian fossil of Melastomeae. Tectonic events were also tentatively used as constraints because of concerns that some of the family's fossils are difficult to assign to nodes in the phylogeny. Regardless of how the data were calibrated, the estimated divergence times of Madagascan and Indian lineages were too young for Cretaceous explanations to hold. This was true even of the oldest ages within the 95% credibility interval around each estimate. Madagascar's Melastomeae appear to have arrived from Africa during the Miocene.
Medinilla
, with some 70 species in Madagascar and two in Africa, too, arrived during the Miocene, but from Asia.
Gravesia
, with 100 species in Madagascar and four in east and west Africa, also appears to date to the Miocene, but its monophyly has not been tested. The study afforded an opportunity to compare divergence time estimates obtained earlier with strict clocks and single calibrations, with estimates based on relaxed clocks and different multiple calibrations and taxon sampling.
Mechanisms and tempo of evolution in the African Guineo–Congolian rainforest
Authors: Plana Vanessa
Published: October 2004

This paper reviews how and when African rainforest diversity arose, presenting evidence from both plant and animal studies. Preliminary investigations show that these African forests are an assemblage of species of varying age. Phylogenetic evidence, from both African rainforest angiosperms and vertebrates, suggest a Tertiary origin for the major lineages in some of these groups. In groups where savannah species are well represented and rainforest species are a minority, the latter appear to be relicts of a Mid–Tertiary rainforest. By contrast, species that are primarily adapted to rainforest have arisen in the past 10 Myr with the main morphological innovations dating from the Late Miocene, and Quaternary speciation dominating in large, morphologically homogeneous groups. The small number of species–level phylogenies for African rainforest plants hinders a more incisive and detailed study into the historical assembly of these continental forests.
Historical biogeography of two cosmopolitan families of flowering plants: Annonaceae and Rhamnaceae
Authors: Richardson J. E. , Chatrou L. W. , Mols J. B. , Erkens R. H. J. , Pirie M. D.
Published: October 2004

Annonaceae are a pantropically distributed family found predominantly in rainforests, so they are megathermal taxa, whereas Rhamnaceae are a cosmopolitan family that tend to be found in xeric regions and may be classified as mesothermal. Phylogenetic analyses of these families are presented based onrbcLandtrnL–F plastid DNA sequences. Likelihood ratio tests revealed rate heterogeneity in both phylogenetic trees and they were therefore made ultrametric using non–parametric rate smoothing and penalized likelihood. Divergence times were then estimated using fossil calibration points. The historical biogeography of these families that are species rich in different biomes is discussed and compared with other published reconstructions. Rhamnaceae and most lineages within Annonaceae are too young to have had their distribution patterns influenced by break–up of previously connected Gondwanan landmasses. Contrasts in the degree of geographical structure between these two families may be explained by differences in age and dispersal capability. In both groups, long–distance dispersal appears to have played a more significant role in establishing modern patterns than had previously been assumed. Both families also contain examples of recent diversification of species–rich lineages. An understanding of the processes responsible for shaping the distribution patterns of these families has contributed to our understanding of the historical assembly of the biomes that they occupy.
Patterns in the assembly of temperate forests around the Northern Hemisphere
Authors: Donoghue Michael J. , Smith Stephen A.
Published: October 2004

Recent studies of Northern Hemisphere biogeography have highlighted potentially significant differences between disjunction patterns in plants versus animals. To assess such differences, we compiled a larger sample of relevant plant phylogenies from which disjunction patterns, ancestral areas and directions of movement could be inferred. We considered 66 plant clades with species variously endemic today to eastern Asia (EA), Europe (including southwestern Asia), eastern North America (ENA), and/or western North America (WNA). Within these clades we focused on 100 disjunctions among these major areas, for 33 of which absolute divergence times have also been inferred. Our analyses uphold the view that disjunctions between EA and ENA are exceptionally common in plants, apparently more so than in animals. Compared with animals, we find few disjunctions between EA and WNA, consistent with increased extinction in WNA or failure of some groups to colonize that region. Taken at face value, our data also support the view that many temperate forest plant groups originated and diversified within EA, followed by movement out of Asia at different times, but mostly during the last 30 Myr. This favours Beringia over a North Atlantic land bridge as the primary path between the Old World and the New World. Additional studies are needed, especially to evaluate the impacts of differential extinction on these patterns, to more confidently establish divergence times, and to assess the statistical significance of these findings. Fortunately, many more plant groups show relevant disjunction patterns and could soon be added to such analyses.
Introduction and synthesis: plant phylogeny and the origin of major biomes
Authors: Pennington R. Toby , Cronk Quentin C. B. , Richardson James A.
Published: October 2004

Phylogenetic trees based upon DNA sequence data, when calibrated with a dimension of time, allow inference of: (i) the pattern of accumulation of lineages through time; (ii) the time of origin of monophyletic groups; (iii) when lineages arrived in different geographical areas; (iv) the time of origin of biome–specific morphologies. This gives a powerful new view of the history of biomes that in many cases is not provided by the incomplete plant fossil record. Dated plant phylogenies for angiosperm families such as Leguminoaceae (Fabaceae), Melastomataceaesensu stricto, Annonaceae and Rhamnaceae indicate that long–distance, transoceanic dispersal has played an important role in shaping their distributions, and that this can obscure any effect of tectonic history, previously assumed to have been the major cause of their biogeographic patterns. Dispersal from other continents has also been i mportant in the assembly of the Amazonian rainforest flora and the Australian flora. Comparison of dated biogeographic patterns of plants and animals suggests that recent long–distance dispersal might be more prevalent in plants, which has major implications for community assembly and coevolution. Dated plant phylogenies also reveal the role of past environmental changes on the evolution of lineages in species–rich biomes, and show that recent Plio–Pleistocene diversification has contributed substantially to their current species richness. Because of the critical role of fossils and morphological characters in assigning ages to nodes in phylogenetic trees, future studies must include careful morphological consideration of fossils and their extant relatives in a phylogenetic context. Ideal study systems will be based upon DNA sequence data from multiple loci and multiple fossil calibrations. This allows cross–validation both of age estimates from different loci, and from different fossil calibrations. For a more complete view of biome history, future studies should emphasize full taxon sampling in ecologically important groups, and should focus on geographical areas for which few species–level phylogenies are available, such as tropical Africa and Asia. These studies are urgent because understanding the history of biomes can both inform conservation decisions, and help predict the effects of future environmental changes at a time when biodiversity is being impacted on an unprecedented scale.
A DINOFLAGELLATE CYST FROM ANTARCTIC SEA ICE1
Authors: Buck Kurt R. , Bolt Patricia A. , Bentham Wilfred N. , Garrison David L.
Published: October 2004

The small (< 15 μm) hypnozygote of an autotrophic athecate dinofiagellate found in association with Antarctic sea ice had an external covering composed of approximately 60 plates, each of which was bounded by sutural ridging and possessed an intratabular process. A cingulum and sulcus were also evident. The ultrastructure of the cyst was increasingly dominated by storage bodies as the cyst matured, and the cell wall thickened from 0.2 to 0.8 μm over 2 months. This cyst has been encountered often but usually at low abundances (103−104 cells·L−1); however, the maximum abundances observed (106 cells·L−1) indicate that the formation of this cyst may play an important part in the ecology of sea ice communities.
PHOTOSYNTHESIS AND PHOTOSYNTHESIS‐COUPLED RESPIRATION IN NATURAL BIOFILMS QUANTIFIED WITH OXYGEN MICROSENSORS1
Authors: Glud Ronnie Nøhr , Ramsing Niels Birger , Revsbech Niels Peter
Published: October 2004

Photosynthesis and respiration were analyzed in natural biofilms by use of O2 microsensors. Depth profiles of gross photosynthesis were obtained from the rate of decrease in O2 concentration during the first few seconds following extinction of light, and net photosynthesis of the photic zone was calculated from O2 concentration gradients measured at steady state. Respiration within the photic zone was calculated as the difference between gross and net photosynthesis. Two types of biofilms were investigated: one dominated by diatoms, and one dominated by cyanobacteria. High O2/CO2 ratios caused increased respiration especially within the diatom biofilm, which could indicate that photorespiration was a dominant O2‐consuming process. The rate of respiration was constant within both biofilms during the first 4.6 s following extinction of light, even when respiration was stimulated by high O2/CO2 ratio. The assumption of a constant rate of respiration during the dark period is an essential one for the determination of gross photosynthetic activity by use of O2 microsensors. We here present the first evidence to substantiate this assumption. The results strongly suggest that gross photosynthesis as measured by use of O2 microsensors may include carbon equivalents that are subsequently lost through photorespiration. Computer modeling of photosynthesis profiles measured after 1.1, 1.6, and 2.6 s of dark incubation illustrated how the actual photosynthesis profile could have appeared if it had been possible to do the determination at time 0. Diffusion of O2 during the up to 4.6‐s long dark incubations did not affect gross photosynthetic rate when integrated over all depths, but the apparent vertical distribution of the photosynthetic activity was strongly affected.