bluuebunny/crossref_metadata_2025 huggingface dataset:
Existence theorems for some boundary value problems in the nonlinear theory of annular elastic membranes
Authors: Grabmüller Hans , Pirner Robert
Published: July 2009

A simplified version of Reissner's theory of thin shells of revolution suffering small strains but arbitrarily large deflections and rotations reduces, when specialized to axi-symmetric deformations of annular membranes under a vertical surface load, to a nonlinear ordinary differential equation which is free of Poisson'ratio. Within this framework the questions of existence and non-existence of non-negative solutions of the associated stress and displacement boundary value problem are brought to a final answer. Progress in this direction was made in an earlier study (Grabmüller & Pirner 1987). In this paper a continuous monotone curve is constructed which effects a subdivision of the respective ranges of boundary data into complementary domains of existence and non-existence of strictly positive solutions
On a self-similar solution for the decay of turbulent bursts
Authors: Hastings S. P. , Peletier L. A.
Published: July 2009

We discuss the self-similar solutions of the second kind associated with the propagation of turbulent bursts in a fluid at rest. Such solutions involve an eigenvalue parameter μ, which cannot be determined from dimensional analysis. Existence and uniqueness are established and the dependence of μ on a physical parameter λ in the problem is studied: estimates are obtained and the asymptotic behaviour as λ → ∞ is established.
On Hele–Shaw flow of power-law fluids
Authors: Aronsson Gunnar , Janfalk Ulf
Published: July 2009

This paper reviews the governing equations for a plane Hele–Shaw flow of a power-law fluid. We find two closely related partial differential equations, one for the pressure and one for the stream function. Some mathematical results for these equations are presented, in particular some exact solutions and a representation theorem. The results are applied to Hele–Shaw flow. It is then possible to determine the flow near an arbitrary corner for any power-law fluid. Other examples are also given.
Nonclassical symmetry reductions and exact solutions of the Zabolotskaya–Khokhlov equation
Authors: Clarkson Peter A. , Hood Simon
Published: July 2009

In this paper, new non-classical symmetry reductions and exact solutions for the 2+1- dimensional, time-independent and time-dependent, dissipative Zabolotskaya-Khokhlov equations in both cartesian and cylindrical coordinates, are presented. These are obtained using the Direct Method, which was originally developed by Clarkson & Kruskal (1989) to study symmetry reductions of the Boussinesq equation, and which involves no group theoretic techniques. In particular, we derive exact solutions of these Zabolotskaya-Khokhlov equations expressible in terms of elementary functions, Weierstrass elliptic and zeta functions, Weber-Hermite functions and Airy functions. Additionally, it is shown that some previously known solutions of these equations actually arise from non-classical symmetries.
Transgenerational association: extending the notion of the person - RETRACTION
Authors: Armatrudo Anthony
Published: July 2009

This paper develops the idea of transgenerational association. It addresses intrapersonal distributions of wellbeing over time. It develops the notion of temporal distributions between generations, and posits that it is possible to overcome the problems that obstruct ethical individualism. It argues that corporate personality allows us to compare distributions between generations to distributions between the stages of one person.
Corruption, the Southern African Development Community Anti-corruption Protocol and the principal–agent–client model
Authors: Carr Indira
Published: July 2009

Since the 1990s, a number of anti-corruption conventions have been adopted due to pressure from international financial institutions, donor countries and governments of major industrialised nations. One of these conventions is the Anti-corruption Protocol adopted by the Southern African Development Community. This article examines this Convention against the backdrop of the principal–agent–client (PAC) model which influences much of the current anti-corruption measures ranging from legal and civil service reform through to privatisation of the public sector. In focusing on the efforts to fight and prevent corruption through legal and public sector reform, this paper highlights the limitations of externally imposed solutions largely driven by donors. Using Tanzania, a country that has seen extensive technical input from donor agencies in reforming the law and bureaucratic structures, as an illustration, this article argues that the limited success of such donor-driven anti-corruption strategies is attributable to a number of reasons ranging from reform policies of donors and paternalistic attitudes to political shifts and antipathy towards external demands for reforms that are fuelled by the colonial past. This paper recommends that for a recipient country to take ownership of the anti-corruption strategies it is important to tailor the PAC model to the cultural, social and political context of the recipient country so that the solutions are seen as an indigenous initiative, thus enabling sustainable change in attitudes and behaviour.
Minimising medical litigation: a review of key tort and legal reforms
Authors: Tan Harold
Published: July 2009

The traditional tort system in medical malpractice is increasingly perceived as being incapable of addressing the mismatch between claims and negligent injuries. Tort reforms have been introduced in various developed countries in an attempt to bring about greater fairness and economic sustainability in the compensation of medical injuries and to reduce the overall rate of medical litigation. This paper reviews the key tort reforms that have been used in various countries, notably the US and the UK, and discusses the arguments that had been put forth by advocates and opponents of such reforms. The impact of these tort reforms, where studied and available, is also reviewed and discussed in the paper.
Impact of the subtropical mode water biogeochemical properties on primary production in the North Atlantic: New insights from an idealized model study
Authors: Krémeur A.‐S. , Lévy M. , Aumont O. , Reverdin G.
Published: July 2009

An idealized biophysical model of the North Atlantic was designed to investigate the setting and variability of the subtropical mode water (STMW) biogeochemical properties and its impact on surface primary production in the North Atlantic. The model solution first emphasizes that the exact timing of STMW formation versus the timing of the spring bloom is of primary importance for setting the STMW biogeochemical properties. The surface primary production reaches its maximum in March in the STMW formation region just before its subduction. Thus the spring bloom consumes nitrate at the surface before STMW subducts, and STMW leaves the upper layers depleted in nutrients and fueled in organic matter. This spring consumption explains the low nutrient content of STMW observed near its source region by J. B. Palter et al. (2005). Furthermore, the model suggests that STMW plays a key role in exporting dissolved organic matter (DOM) at subsurface. The spring bloom produces a significant amount of DOM sequestrated in the mode waters after its subduction. This large pool of DOM is then remineralized with time along the transit of STMW through the subtropical gyre. Consequently, the nutrient content of STMW increases as it moves away from its source region. Finally, the model shows also that STMW is very important in controlling primary production in the western boundary current (WBC) region. Indeed, STMW remains isolated from the surface along its trajectory within the subtropical gyre. It joins the mixed layer by obduction in the WBC region only. This nutrient‐rich old STMW irrigates and fertilizes the euphotic zone primarily in the WBC and then spreads along the boundary between the two gyres by advection.
How robust are observed and simulated precipitation responses to tropical ocean warming?
Authors: John Viju O. , Allan Richard P. , Soden Brian J.
Published: July 2009

Robust responses and links between the tropical energy and water cycles are investigated using multiple datasets and climate models over the period 1979–2006. Atmospheric moisture and net radiative cooling provide powerful constraints upon future changes in precipitation. While moisture amount is robustly linked with surface temperature, the response of atmospheric net radiative cooling, derived from satellite data, is less coherent. Precipitation trends and relationships with surface temperature are highly sensitive to the data product and the time‐period considered. Data from the Special Sensor Microwave Imager (SSM/I) produces the strongest trends in precipitation and response to warming of all the datasets considered. The tendency for moist regions to become wetter while dry regions become drier in response to warming is captured by both observations and models.
Statistical uncertainty of changes in winter storms over the North Atlantic and Europe in an ensemble of transient climate simulations
Authors: Della‐Marta Paul M. , Pinto Joaquim G.
Published: July 2009

Winter storms are among the most important natural hazards affecting Europe. We quantify changes in storm frequency and intensity over the North Atlantic and Europe under future climate scenarios in terms of return periods (RPs) considering uncertainties due to both sampling and methodology. RPs of North Atlantic storms' minimum central pressure (CP) and maximum vorticity (VOR) remain unchanged by 2100 for both the A1B and A2 scenarios compared to the present climate. Whereas shortened RPs for VOR of all intensities are detected for the area between British Isles/North‐Sea/western Europe as early as 2040. However, the changes in storm VOR RP may be unrealistically large: a present day 50 (20) year event becomes approximately a 9 (5.5) year event in both A1B and A2 scenarios by 2100. The detected shortened RPs of storms implies a higher risk of occurrence of damaging wind events over Europe.
Why is there a minimum in projected warming in the tropical North Atlantic Ocean?
Authors: Leloup Julie , Clement Amy
Published: July 2009

In IPCC projections for the 21st Century, the sea surface temperature (SST) shows several regions of minimum warming in the tropical oceans. These patterns appear both in fully coupled ocean‐atmosphere general circulation models (GCMs) and also in atmospheric GCMs coupled to mixed‐layer ocean models, and are robust across a multi‐model ensemble. The present study focuses on the minimum warming in the tropical North Atlantic, as it has implications for the influence of greenhouse gas‐induced climate change on hurricane development. The surface heat budget is analyzed in order to determine the causes for this minimum warming. It is found that the primary contribution is through the influence of the climatological mean wind speed on the efficiency of latent heat flux. In regions of high wind speed, radiative heating can be balanced by latent heat flux with a smaller change in SST than in other regions of the tropics.
Spectral analysis of ionospheric electron density and mesospheric neutral wind diurnal nonmigrating tides observed by COSMIC and TIMED satellites
Authors: Wu Q. , Solomon S. C. , Kuo Y.‐H. , Killeen T. L. , Xu Jiyao
Published: July 2009

We use two‐dimensional spectral analysis method to extract diurnal eastward zonal wavenumber 3 (E3) and westward zonal wavenumber 2 (W2) nonmigrating tide in the mesospheric winds from TIMED TIDI instrument and ionosphere density from the COSMIC six satellite cluster GPS data to study seasonal and inter‐annual variations. In the case of the diurnal E3 component our results show that the ionospheric electron density feature has the same inter‐annual variation trend as the symmetric mode of the mesospheric wind E3 component. The mesospheric wind E3 antisymmetric mode has the opposite inter‐annual trend and less influence on the ionosphere. The diurnal W2 component show less clear correlation between the mesosphere and the ionosphere. Quasi‐Biennial Oscillation (QBO) influences on both the mesosphere and ionosphere are implied.
Down‐welling circulation of the northwest European continental shelf: A driving mechanism for the continental shelf carbon pump
Authors: Holt Jason , Wakelin Sarah , Huthnance John
Published: July 2009

Annually integrated measurements of pCO2 have demonstrated that seasonally stratified regions of temperate shelf seas can be an important sink of atmospheric CO2. A key process to support this sink is the transport of carbon from shelf seas to below the permanent pycnocline of the deep ocean. Using a hydrodynamic model simulation of the northwest European Continental shelf, we find that both the large scale circulation and frictional processes support the off‐shelf transport of carbon sufficiently quickly to remove ∼40% of the carbon sequestered by one growing season before the onset of the next. This transport is highly heterogeneous, with some regions being only weakly flushed. Only 52% of this exported carbon is transported below the permanent pycnocline, hence the shelf sea and open ocean carbon cycles are intrinsically coupled.
A Study on the Origin of Peroxisomes: Possibility of Actinobacteria Symbiosis
Authors: Narendra Duhita , Satoshi Saruhashi , Kazuo Hamada , Daisuke Miyata , Tokumasa Horiike , Takao Shinozawa
Published: July 2009

Withdrawn
EDHF: an update
Authors: Félétou Michel , Vanhoutte Paul M.
Published: July 2009

The endothelium controls vascular tone not only by releasing NO and prostacyclin, but also by other pathways causing hyperpolarization of the underlying smooth muscle cells. This characteristic was at the origin of the term ‘endothelium-derived hyperpolarizing factor’ (EDHF). However, this acronym includes different mechanisms. Arachidonic acid metabolites derived from the cyclo-oxygenases, lipoxygenases and cytochrome P450 pathways, H2O2, CO, H2S and various peptides can be released by endothelial cells. These factors activate different families of K+ channels and hyperpolarization of the vascular smooth muscle cells contribute to the mechanisms leading to their relaxation. Additionally, another pathway associated with the hyperpolarization of both endothelial and vascular smooth muscle cells contributes also to endothelium-dependent relaxations (EDHF-mediated responses). These responses involve an increase in the intracellular Ca2+ concentration of the endothelial cells, followed by the opening of SKCa and IKCa channels (small and intermediate conductance Ca2+-activated K+ channels respectively). These channels have a distinct subcellular distribution: SKCa are widely distributed over the plasma membrane, whereas IKCa are preferentially expressed in the endothelial projections toward the smooth muscle cells. Following SKCa activation, smooth muscle hyperpolarization is preferentially evoked by electrical coupling through myoendothelial gap junctions, whereas, following IKCa activation, K+ efflux can activate smooth muscle Kir2.1 and/or Na+/K+-ATPase. EDHF-mediated responses are altered by aging and various pathologies. Therapeutic interventions can restore these responses, suggesting that the improvement in the EDHF pathway contributes to their beneficial effect. A better characterization of EDHF-mediated responses should allow the determination of whether or not new drugable targets can be identified for the treatment of cardiovascular diseases.
Gliomas induce and exploit microglial MT1-MMP expression for tumor expansion
Authors: Markovic D. S. , Vinnakota K. , Chirasani S. , Synowitz M. , Raguet H. , Stock K. , Sliwa M. , Lehmann S. , Kälin R. , van Rooijen N. , Holmbeck K. , Heppner F. L. , Kiwit J. , Matyash V. , Lehnardt S. , Kaminska B. , Glass R. , Kettenmann H.
Published: July 2009

Diffuse infiltration of glioma cells into normal brain tissue is considered to be a main reason for the unfavorable outcomes of patients with malignant gliomas. Invasion of glioma cells into the brain parenchyma is facilitated by metalloprotease-mediated degradation of the extracellular matrix. Metalloproteases are released as inactive pro-forms and get activated upon cleavage by membrane bound metalloproteases. Here, we show that membrane type 1 metalloprotease (MT1-MMP) is up-regulated in glioma-associated microglia, but not in the glioma cells. Overexpression of MT1-MMP is even lethal for glioma cells. Glioma-released factors trigger the expression and activity of MT1-MMP via microglial toll-like receptors and the p38 MAPK pathway, as deletion of the toll-like receptor adapter protein MyD88 or p38 inhibition prevented MT1-MMP expression and activity in cultured microglial cells. Microglial MT1-MMP in turn activates glioma-derived pro-MMP-2 and promotes glioma expansion, as shown in an ex vivo model using MT1-MMP-deficient brain tissue and a microglia depletion paradigm. Finally, MyD88 deficiency or microglia depletion largely attenuated glioma expansion in 2 independent in vivo models.
Why kinesin is so processive
Authors: Toprak Erdal , Yildiz Ahmet , Hoffman Melinda Tonks , Rosenfeld Steven S. , Selvin Paul R.
Published: July 2009

Kinesin I can walk on a microtubule for distances as long as several micrometers. However, it is still unclear how this molecular motor can remain attached to the microtubule through the hundreds of mechanochemical cycles necessary to achieve this remarkable degree of processivity. We have addressed this issue by applying ensemble and single-molecule fluorescence methods to study the process of kinesin stepping, and our results lead to 4 conclusions. First, under physiologic conditions, ≈75% of processively moving kinesin molecules are attached to the microtubule via both heads, and in this conformation, they are resistant to dissociation. Second, the remaining 25% of kinesin molecules, which are in an “ATP waiting state” and are strongly attached to the microtubule via only one head, are intermittently in a conformation that cannot bind ATP and therefore are resistant to nucleotide-induced dissociation. Third, the forward step in the kinesin ATPase cycle is very fast, accounting for <5% of the total cycle time, which ensures that the lifetime of this ATP waiting state is relatively short. Finally, by combining nanometer-level single-molecule fluorescence localization with higher ATP concentrations than used previously, we have determined that in this ATP waiting state, the ADP-containing head of kinesin is located 8 nm behind the attached head, in a location where it can interact with the microtubule lattice. These 4 features reduce the likelihood that a kinesin I motor will dissociate and contribute to making this motor so highly processive.
SLP-76-ADAP adaptor module regulates LFA-1 mediated costimulation and T cell motility
Authors: Wang Hongyan , Wei Bin , Bismuth Georges , Rudd Christopher E.
Published: July 2009

Although adaptor ADAP (FYB) and its binding to SLP-76 has been implicated in TcR-induced “inside-out” signaling for LFA-1 activation in T cells, little is known regarding its role in LFA-1-mediated “outside-in” signaling. In this study, we demonstrate that ADAP and SLP-76-ADAP binding are coupled to LFA-1 costimulation of IL-2 production, F-actin clustering, cell polarization, and T cell motility. LFA-1 enhancement of anti-CD3-induced IL-2 production was completely dependent on SLP-76-ADAP binding. Further, anti-CD3 was found to require CD11a ligation by antibody or ICAM1 to cause T cell polarization. ADAP augmented this polarization induced by anti-CD3/CD11a, but not by anti-CD3 alone. ADAP expression with LFA-1 ligation alone was sufficient to polarize T cells directly and to increase T cell motility whereas the loss of ADAP inADAP−/− primary T cells reduced motility. A mutant lacking SLP-76-binding sites (M12) blocked LFA-1 costimulation of IL-2 production, polarization, and motility. LFA-1-ADAP polarization was also dependent on src kinases, Rho GTPases, phospholipase C, and phosphoinositol 3-kinase. Our findings provide evidence of an obligatory role for the SLP-76-ADAP module in LFA-1-mediated costimulation in T cells.
Anti-VEGF single-chain antibody GLAF-1 encoded by oncolytic vaccinia virus significantly enhances antitumor therapy
Authors: Frentzen Alexa , Yu Yong A. , Chen Nanhai , Zhang Qian , Weibel Stephanie , Raab Viktoria , Szalay Aladar A.
Published: July 2009

We previously reported that the replication-competent vaccinia virus (VACV) GLV-1h68 shows remarkable oncolytic activity and efficacy in different animal models as a single treatment modality and also in combination with chemotherapy [Yu YA, et al. (2009)
Mol Cancer Ther
8:141–151]. Here, we report the construction of 3 VACV strains encoding GLAF-1, a previously undescribed engineered single-chain antibody (scAb). This unique scAb is transcribed from 3 vaccinia promoters (synthetic early, early/late, and late) and directed against both human and murine VEGFs. The expression of GLAF-1 was demonstrated in cell cultures. Also, the replication efficiency of all GLAF-1–expressing VACV strains in cell culture was similar to that of the parental GLV-1h68 virus. Successful tumor-specific delivery and continued production of functional scAb derived from individual VACV strains were obtained in tumor xenografts following a single intravenous injection of the virus. The VACV strains expressing the scAb exhibited significantly enhanced therapeutic efficacy in comparison to treatment of human tumor xenografts with the parental virus GLV-1h68. This enhanced efficacy was comparable to the concomitant treatment of tumors with a one-time i.v. injection of GLV-1h68 and multiple i.p. injections of Avastin. Taken together, the VACV-mediated delivery and production of immunotherapeutic anti-VEGF scAb in colonized tumors may open the way for a unique therapy concept: tumor-specific, locally amplified drug therapy in humans.
A remote prolyl isomerization controls domain assembly via a hydrogen bonding network
Authors: Weininger Ulrich , Jakob Roman P. , Eckert Barbara , Schweimer Kristian , Schmid Franz X. , Balbach Jochen
Published: July 2009

Prolylcis/transisomerizations determine the rates of protein folding reactions and can serve as molecular switches and timers. In the gene-3-protein of filamentous phage, Pro-213trans→cisisomerization in a hinge region controls the assembly of the 2 domains N1 and N2 and, in reverse, the activation of the phage for infection. We elucidated the structural and energetic basis of this proline-limited domain assembly at the level of individual residues by real-time 2D NMR. A local cluster of inter-domain hydrogen bonds, remote from Pro-213, is stabilized up to 3,000-fold bytrans→cisisomerization. This network of hydrogen bonds mediates domain assembly and is connected with Pro-213 by rigid backbone segments. Thus, prolinecis/transswitching is propagated in a specific and directional fashion to change the protein structure and stability at a distant position.
On the regulation of photosynthesis by excitonic interactions between carotenoids and chlorophylls
Authors: Bode Stefan , Quentmeier Claudia C. , Liao Pen-Nan , Hafi Nour , Barros Tiago , Wilk Laura , Bittner Florian , Walla Peter J.
Published: July 2009

Selective 2-photon excitation (TPE) of carotenoid dark states, Car S
1
, shows that in the major light-harvesting complex of photosystem II (LHCII), the extent of electronic interactions between carotenoid dark states (Car S
1
) and chlorophyll (Chl) states, φ
Coupling

Car S
1
−Chl

, correlates linearly with chlorophyll fluorescence quenching under different experimental conditions. Simultaneously, a linear correlation between both Chl fluorescence quenching and φ
Coupling

Car S
1
−Chl

with the intensity of red-shifted bands in the Chl Q
y
and carotenoid absorption was also observed. These results suggest quenching excitonic Car S
1
−Chl states as origin for the observed effects. Furthermore, real time measurements of the light-dependent down- and up-regulation of the photosynthetic activity and φ
Coupling

Car S
1
−Chl

in wild-type and mutant (
npq1
,
npq2
,
npq4
,
lut2
and
WT
+
PsbS
)
Arabidopsis thaliana
plants reveal that also in vivo the quenching parameter NPQ correlates always linearly with the extent of electronic Car S
1
–Chl interactions in any adaptation status. Our in vivo measurements with
Arabidopsis
variants show that during high light illumination, φ
Coupling

Car S
1
−Chl

depends on the presence of PsbS and zeaxanthin (Zea) in an almost identical way as NPQ. In summary, these results provide clear evidence for a very close link between electronic Car S
1
–Chl interactions and the regulation of photosynthesis. These findings support a photophysical mechanism in which short-living, low excitonic carotenoid–chlorophyll states serve as traps and dissipation valves for excess excitation energy.
Droplet microfluidic technology for single-cell high-throughput screening
Authors: Brouzes Eric , Medkova Martina , Savenelli Neal , Marran Dave , Twardowski Mariusz , Hutchison J. Brian , Rothberg Jonathan M. , Link Darren R. , Perrimon Norbert , Samuels Michael L.
Published: July 2009

We present a droplet-based microfluidic technology that enables high-throughput screening of single mammalian cells. This integrated platform allows for the encapsulation of single cells and reagents in independent aqueous microdroplets (1 pL to 10 nL volumes) dispersed in an immiscible carrier oil and enables the digital manipulation of these reactors at a very high-throughput. Here, we validate a full droplet screening workflow by conducting a droplet-based cytotoxicity screen. To perform this screen, we first developed a droplet viability assay that permits the quantitative scoring of cell viability and growth within intact droplets. Next, we demonstrated the high viability of encapsulated human monocytic U937 cells over a period of 4 days. Finally, we developed an optically-coded droplet library enabling the identification of the droplets composition during the assay read-out. Using the integrated droplet technology, we screened a drug library for its cytotoxic effect against U937 cells. Taken together our droplet microfluidic platform is modular, robust, uses no moving parts, and has a wide range of potential applications including high-throughput single-cell analyses, combinatorial screening, and facilitating small sample analyses.
TCR-inducible PLZF transcription factor required for innate phenotype of a subset of γδ T cells with restricted TCR diversity
Authors: Kreslavsky Taras , Savage Adam K. , Hobbs Robin , Gounari Fotini , Bronson Roderick , Pereira Pablo , Pandolfi Pier Paolo , Bendelac Albert , von Boehmer Harald
Published: July 2009

Some γδ and αβ T lymphocytes exhibit an “innate” phenotype associated with rapid cytokine responses. The PLZF transcription factor is essential for the innate phenotype of NKT cells. This report shows that PLZF is likewise responsible for the innate, NKT-like phenotype of Vγ1+Vδ6.3/Vδ6.4+ cells. TCR cross-linking induced PLZF expression in all polyclonal immature γδ thymocytes, suggesting that agonist selection might be required for PLZF induction. Transgenic expression of Vγ1Vδ6.4 TCR was sufficient to support the development of large numbers of PLZF+ T cells, further supporting the importance of the TCR for PLZF induction. Interestingly, expression of this TCR transgene led to the development of spontaneous dermatitis.
Sparse and stable Markowitz portfolios
Authors: Brodie Joshua , Daubechies Ingrid , De Mol Christine , Giannone Domenico , Loris Ignace
Published: July 2009

We consider the problem of portfolio selection within the classical Markowitz mean-variance framework, reformulated as a constrained least-squares regression problem. We propose to add to the objective function a penalty proportional to the sum of the absolute values of the portfolio weights. This penalty regularizes (stabilizes) the optimization problem, encourages sparse portfolios (i.e., portfolios with only few active positions), and allows accounting for transaction costs. Our approach recovers as special cases the no-short-positions portfolios, but does allow for short positions in limited number. We implement this methodology on two benchmark data sets constructed by Fama and French. Using only a modest amount of training data, we construct portfolios whose out-of-sample performance, as measured by Sharpe ratio, is consistently and significantly better than that of the naïve evenly weighted portfolio.
Plant sex and the evolution of plant defenses against herbivores
Authors: Johnson Marc T. J. , Smith Stacey D. , Rausher Mark D.
Published: July 2009

Despite the importance of plant–herbivore interactions to the ecology and evolution of terrestrial ecosystems, the evolutionary factors contributing to variation in plant defenses against herbivores remain unresolved. We used a comparative phylogenetic approach to examine a previously untested hypothesis (Recombination-Mating System Hypothesis) that posits that reduced sexual reproduction limits adaptive evolution of plant defenses against arthropod herbivores. To test this hypothesis we focused on the evening primrose family (Onagraceae), which includes both sexual and functionally asexual species. Ancestral state reconstructions on a 5-gene phylogeny of the family revealed between 18 and 21 independent transitions between sexual and asexual reproduction. Based on these analyses, we examined susceptibility to herbivores on 32 plant species representing 15 independent transitions. Generalist caterpillars consumed 32% more leaf tissue, gained 13% greater mass, and experienced 21% higher survival on functionally asexual than on sexual plant species. Survival of a generalist feeding mite was 19% higher on asexual species. In a field experiment, generalist herbivores consumed 64% more leaf tissue on asexual species. By contrast, a specialist beetle fed more on sexual than asexual species, suggesting that a tradeoff exists between the evolution of defense to generalist and specialist herbivores. Measures of putative plant defense traits indicate that both secondary compounds and physical leaf characteristics may mediate this tradeoff. These results support the Recombination-Mating System Hypothesis and suggest that variation in sexual reproduction among plant species may play an important, yet overlooked, role in shaping the macroevolution of plant defenses against arthropod herbivores.
A hyperfused mitochondrial state achieved at G
1
–S regulates cyclin E buildup and entry into S phase
Authors: Mitra Kasturi , Wunder Christian , Roysam Badrinath , Lin Gang , Lippincott-Schwartz Jennifer
Published: July 2009

Mitochondria undergo fission–fusion events that render these organelles highly dynamic in cells. We report a relationship between mitochondrial form and cell cycle control at the G
1
–S boundary. Mitochondria convert from isolated, fragmented elements into a hyperfused, giant network at G
1
–S transition. The network is electrically continuous and has greater ATP output than mitochondria at any other cell cycle stage. Depolarizing mitochondria at early G
1
to prevent these changes causes cell cycle progression into S phase to be blocked. Inducing mitochondrial hyperfusion by acute inhibition of dynamin-related protein-1 (DRP1) causes quiescent cells maintained without growth factors to begin replicating their DNA and coincides with buildup of cyclin E, the cyclin responsible for G
1
-to-S phase progression. Prolonged or untimely formation of hyperfused mitochondria, through chronic inhibition of DRP1, causes defects in mitotic chromosome alignment and S-phase entry characteristic of cyclin E overexpression. These findings suggest a hyperfused mitochondrial system with specialized properties at G
1
–S is linked to cyclin E buildup for regulation of G
1
-to-S progression.
Capillary morphogenesis protein-2 is the major receptor mediating lethality of anthrax toxin in vivo
Authors: Liu Shihui , Crown Devorah , Miller-Randolph Sharmina , Moayeri Mahtab , Wang Hailun , Hu Haijing , Morley Thomas , Leppla Stephen H.
Published: July 2009

Anthrax toxin, a major virulence factor of
Bacillus anthracis
, gains entry into target cells by binding to either of 2 von Willebrand factor A domain-containing proteins, tumor endothelium marker-8 (TEM8) and capillary morphogenesis protein-2 (CMG2). The wide tissue expression of TEM8 and CMG2 suggest that both receptors could play a role in anthrax pathogenesis. To explore the roles of TEM8 and CMG2 in normal physiology, as well as in anthrax pathogenesis, we generated TEM8- and CMG2-null mice and TEM8/CMG2 double-null mice by deleting TEM8 and CMG2 transmembrane domains. TEM8 and CMG2 were found to be dispensable for mouse development and life, but both are essential in female reproduction in mice. We found that the lethality of anthrax toxin for mice is mostly mediated by CMG2 and that TEM8 plays only a minor role. This is likely because anthrax toxin has approximately 11-fold higher affinity for CMG2 than for TEM8. Finally, the CMG2-null mice are also shown to be highly resistant to
B. anthracis
spore infection, attesting to the importance of both anthrax toxin and CMG2 in anthrax infections.
Direct evidence for a dry molten globule intermediate during the unfolding of a small protein
Authors: Jha Santosh Kumar , Udgaonkar Jayant B.
Published: July 2009

Little is known about how proteins begin to unfold. In particular, how and when water molecules penetrate into the protein interior during unfolding, thereby enabling the dissolution of specific structure, is poorly understood. The hypothesis that the native state expands initially into a dry molten globule, in which tight packing interactions are broken, but whose hydrophobic core has not expanded sufficiently to be able to absorb water molecules, has very little experimental support. Here, we report our analysis of the earliest observable events during the unfolding of single chain monellin (MNEI), a small plant protein. Far- and near-UV circular dichroism measurements of GdnHCl-induced unfolding indicate that a molten globule intermediate forms initially, before the major slow unfolding reaction commences. Steady-state fluorescence resonance energy transfer measurements show that the C-terminal end of the single helix of MNEI initially moves rapidly away from the single tryptophan residue that is close to the N-terminal end of the helix. The average end-to-end distance of the protein also expands during unfolding to the molten globule intermediate. At this time, water has yet to penetrate the protein core, according to the evidence from intrinsic tryptophan fluorescence and 8-anilino-1-naphthalenesulfonic acid fluorescence-monitored kinetic unfolding measurements. Our results therefore provide direct evidence for a dry molten globule intermediate at the initial stage of unfolding. Our results further suggest that the structural transition between the native and dry molten globule states could be an all-or-none transition, whereas further swelling of the globule appears to occur gradually.
High frequency of hotspot mutations in core genes of Escherichia coli due to short-term positive selection
Authors: Chattopadhyay Sujay , Weissman Scott J. , Minin Vladimir N. , Russo Thomas A. , Dykhuizen Daniel E. , Sokurenko Evgeni V.
Published: July 2009

Core genes comprising the ubiquitous backbone of bacterial genomes are not subject to frequent horizontal transfer and generally are not thought to contribute to the adaptive evolution of bacterial pathogens. We determined, however, that at least one-third and possibly more than one-half of the core genes in
Escherichia coli
genomes are targeted by repeated replacement substitutions in the same amino acid positions—hotspot mutations. Occurrence of hotspot mutations is driven by positive selection, as their rate is significantly higher than expected by random chance alone, and neither intragenic recombination nor increased mutability can explain the observed patterns. Also, commensal
E. coli
strains have a significantly lower frequency of mutated genes and mutations per genome than pathogenic strains.
E. coli
strains causing extra-intestinal infections accumulate hotspot mutations at the highest rate, whereas the highest total number of mutated genes has been found among
Shigella
isolates, suggesting the pathoadaptive nature of such mutations. The vast majority of hotspot mutations are of recent evolutionary origin, implying short-term positive selection, where adaptive mutations emerge repeatedly but are not sustained in natural circulation for long. Such pattern of dynamics is consistent with source-sink model of virulence evolution.
The Ccr4–Not Deadenylase Subunits CNOT7 and CNOT8 Have Overlapping Roles and Modulate Cell Proliferation
Authors: Aslam Akhmed , Mittal Saloni , Koch Frederic , Andrau Jean-Christophe , Winkler G. Sebastiaan
Published: July 2009

Accurate gene expression requires the precise control of mRNA levels, which are determined by the relative rates of nuclear (pre-)mRNA synthesis and processing, and cytoplasmic mRNA turnover. A key step in mRNA degradation is the removal of the poly(A) tail, which involves several deadenylases including components of the Ccr4–Not complex. Here, we focused on the role of the human paralogues CNOT7 (hCaf1/Caf1a) and CNOT8 (hPop2/Caf1b/Calif), which possess deadenylase activity mediated by DEDD nuclease domains. We show that efficient proliferation requires both subunits, although combined knockdown of CNOT7 and CNOT8 further reduces cell proliferation indicating partial redundancy between these proteins. Interestingly, the function of CNOT7 in cell proliferation partly depends on its catalytic activity. On the other hand, the interaction between CNOT7 and BTG2, a member of the antiproliferative BTG/Tob family involved in transcription and mRNA decay appears less important for proliferation of MCF7 cells, suggesting that CNOT7 does not function solely in conjunction with BTG2. Further analysis of gene expression profiles of CNOT7 and/or CNOT8 knockdown cells underscores the partial redundancy between these subunits and suggests that regulation of several genes, including repression of the antiproliferative genes MSMB and PMP22, by the Ccr4–Not complex contributes to cell proliferation.
Peroxisome Size Provides Insights into the Function of Autophagy-related Proteins
Authors: Nazarko Taras Y. , Farré Jean-Claude , Subramani Suresh
Published: July 2009

Autophagy is a major pathway of intracellular degradation mediated by formation of autophagosomes. Recently, autophagy was implicated in the degradation of intracellular bacteria, whose size often exceeds the capacity of normal autophagosomes. However, the adaptations of the autophagic machinery for sequestration of large cargos were unknown. Here we developed a yeast model system to study the effect of cargo size on the requirement of autophagy-related (Atg) proteins. We controlled the size of peroxisomes before their turnover by pexophagy, the selective autophagy of peroxisomes, and found that peroxisome size determines the requirement of Atg11 and Atg26. Small peroxisomes can be degraded without these proteins. However, Atg26 becomes essential for degradation of medium peroxisomes. Additionally, the pexophagy-specific phagophore assembly site, organized by the dual interaction of Atg30 with functionally active Atg11 and Atg17, becomes essential for degradation of large peroxisomes. In contrast, Atg28 is partially required for all autophagy-related pathways independent of cargo size, suggesting it is a component of the core autophagic machinery. As a rule, the larger the cargo, the more cargo-specific Atg proteins become essential for its sequestration.
Glucosidase II β Subunit ModulatesN-Glycan Trimming in Fission Yeasts and Mammals
Authors: Stigliano Ivan D. , Caramelo Julio J. , Labriola Carlos A. , Parodi Armando J. , D'Alessio Cecilia
Published: July 2009

Glucosidase II (GII) plays a key role in glycoprotein biogenesis in the endoplasmic reticulum (ER). It is responsible for the sequential removal of the two innermost glucose residues from the glycan (Glc3Man9GlcNAc2) transferred to Asn residues in proteins. GII participates in the calnexin/calreticulin cycle; it removes the single glucose unit added to folding intermediates and misfolded glycoproteins by the UDP-Glc:glycoprotein glucosyltransferase. GII is a heterodimer whose α subunit (GIIα) bears the glycosyl hydrolase active site, whereas its β subunit (GIIβ) role is controversial and has been reported to be involved in GIIα ER retention and folding. Here, we report that in the absence of GIIβ, the catalytic subunit GIIα of the fission yeast Schizosaccharomyces pombe (an organism displaying a glycoprotein folding quality control mechanism similar to that occurring in mammalian cells) folds to an active conformation able to hydrolyze p-nitrophenyl α-d-glucopyranoside. However, the heterodimer is required to efficiently deglucosylate the physiological substrates Glc2Man9GlcNAc2(G2M9) and Glc1Man9GlcNAc2(G1M9). The interaction of the mannose 6-phosphate receptor homologous domain present in GIIβ and mannoses in the B and/or C arms of the glycans mediates glycan hydrolysis enhancement. We present evidence that also in mammalian cells GIIβ modulates G2M9 and G1M9 trimming.
Pericentromeric Sister Chromatid Cohesion Promotes Kinetochore Biorientation
Authors: Ng Tessie M. , Waples William G. , Lavoie Brigitte D. , Biggins Sue
Published: July 2009

Accurate chromosome segregation depends on sister kinetochores making bioriented attachments to microtubules from opposite poles. An essential regulator of biorientation is the Ipl1/Aurora B protein kinase that destabilizes improper microtubule–kinetochore attachments. To identify additional biorientation pathways, we performed a systematic genetic analysis between the ipl1-321 allele and all nonessential budding yeast genes. One of the mutants, mcm21Δ, precociously separates pericentromeres and this is associated with a defect in the binding of the Scc2 cohesin-loading factor at the centromere. Strikingly, Mcm21 becomes essential for biorientation when Ipl1 function is reduced, and this appears to be related to its role in pericentromeric cohesion. When pericentromeres are artificially tethered, Mcm21 is no longer needed for biorientation despite decreased Ipl1 activity. Taken together, these data reveal a specific role for pericentromeric linkage in ensuring kinetochore biorientation.
Motif discovery and motif finding from genome-mapped DNase footprint data
Authors: Kulakovskiy Ivan V. , Favorov Alexander V. , Makeev Vsevolod J.
Published: July 2009

Motivation: Footprint data is an important source of information on transcription factor recognition motifs. However, a footprinting fragment can contain no sequences similar to known protein recognition sites. Inspection of genome fragments nearby can help to identify missing site positions.

Results: Genome fragments containing footprints were supplied to a pipeline that constructed a position weight matrix (PWM) for different motif lengths and selected the optimal PWM. Fragments were aligned with the SeSiMCMC sampler and a new heuristic algorithm, Bigfoot. Footprints with missing hits were found for ∼50% of factors. Adding only 2 bp on both sides of a footprinting fragment recovered most hits. We automatically constructed motifs for 41 Drosophila factors. New motifs can recognize footprints with a greater sensitivity at the same false positive rate than existing models. Also we discuss possible overfitting of constructed motifs.

Availability: Software and the collection of regulatory motifs are freely available at http://line.imb.ac.ru/DMMPMM.

Contact:  ivan.kulakovskiy@gmail.com

Supplementary information:  http://line.imb.ac.ru/DMMPMM
Probabilistic resolution of multi-mapping reads in massively parallel sequencing data using MuMRescueLite
Authors: Hashimoto Takehiro , de Hoon Michiel J.L. , Grimmond Sean M. , Daub Carsten O. , Hayashizaki Yoshihide , Faulkner Geoffrey J.
Published: July 2009

Summary: Multi-mapping sequence tags are a significant impediment to short-read sequencing platforms. These tags are routinely omitted from further analysis, leading to experimental bias and reduced coverage. Here, we present MuMRescueLite, a low-resource requirement version of the MuMRescue software that has been used by several next generation sequencing projects to probabilistically reincorporate multi-mapping tags into mapped short read data.

Availability and implementation: MuMRescueLite is written in Python; executables and documentation are available from http://genome.gsc.riken.jp/osc/english/software/.

Contact:  geoff.faulkner@roslin.ed.ac.uk
Seasonality Role on the Phenolics from Cultivated Baccharis dracunculifolia
Authors: de Sousa João Paulo B. , Leite Mateus F. , Jorge Renata F. , Resende Dimas O. , da Silva Filho Ademar A. , Furtado Niege A. J. C. , Soares Ademilson E. E. , Spadaro Augusto C. C. , de Magalhães Pedro Melillo , Bastos Jairo K.
Published: July 2009

Baccharis dracunculifolia is the source of Brazilian green propolis (BGP). Considering the broad spectrum of biological activities attributed to green proplis, B. dracunculifolia has a great potential for the development of new cosmetic and pharmaceutical products. In this work, the cultivation of 10 different populations of native B. dracunculifolia had been undertaken aiming to determine the role of seasonality on its phenolic compounds. For this purpose, fruits of this plant were collected from populations of 10 different regions, and 100 individuals of each population were cultivated in an experimental area of 1800 m2. With respect to cultivation, the yields of dry plant, essential oil and crude extract were measured monthly resulting in mean values of 399 ± 80 g, 0.6 ± 0.1% and 20 ± 4%, respectively. The HPLC analysis allowed detecting seven phenolic compounds: caffeic acid, ferulic acid, aromadendrin‐4′‐methyl ether (AME), isosakuranetin, artepillin C, baccharin and 2‐dimethyl‐6‐carboxyethenyl‐2H‐1‐benzopyran acid, which were the major ones throughout the 1‐year monthly analysis. Caffeic acid was detected in all cultivated populations with mean of 4.0%. AME displayed the wide variation in relation to other compounds showing means values of 0.65 ± 0.13% at last quarter. Isosakuranetin and artepillin C showed increasing concentrations with values between 0% and 1.4% and 0% and 1.09%, respectively. The obtained results allow suggesting that the best time for harvesting this plant, in order to obtain good qualitative and quantitative results for these phenolic compounds, is between December and April.
KIOM‐79, an Inhibitor of AGEs–Protein Cross‐linking, Prevents Progression of Nephropathy in Zucker Diabetic Fatty Rats
Authors: Kim Young Sook , Kim Junghyun , Kim Chan-Sik , Sohn Eun Jin , Lee Yun Mi , Jeong Il-Ha , Kim Hyojun , Jang Dae Sik , Kim Jin Sook
Published: July 2009

Advanced glycation end products (AGEs) have been implicated in the development of diabetic complications, including diabetic nephropathy. KIOM‐79, an 80% ethanolic extract obtained from parched Puerariae Radix, gingered Magnolia Cortex, Glycyrrhiza Radix and Euphorbia Radix, was investigated for its effects on the development of renal disease in Zucker diabetic fatty rats, an animal model of type 2 diabetes. In vitro inhibitory effect of KIOM‐79 on AGEs cross‐linking was examined by enzyme‐linked immunosorbent assay (ELISA). KIOM‐79 (50 mg/kg/day) was given to Zucker diabetic fatty rats for 13 weeks. Body and kidney weight, blood glucose, glycated hemoglobin, urinary albumin and creatinine excretions were monitored. Kidney histopathology, collagen accumulation, fibrinogen and transforming growth factor‐beta 1 (TGF‐β1) expression were also examined. KIOM‐79 reduced blood glucose, kidney weight, histologic renal damage and albuminuria in Zucker diabetic fatty rats. KIOM‐79 prevented glomerulosclerosis, tubular degeneration, collagen deposition and podocyte apoptosis. In the renal cortex, TGF‐β1, fibronectin mRNA and protein were significantly reduced by KIOM‐79 treatment. KIOM‐79 reduces AGEs accumulation in vivo, AGE–protein cross‐linking and protein oxidation. KIOM‐79 could be beneficial in preventing the progression of diabetic glomerularsclerosis in type 2 diabetic rats by attenuating AGEs deposition in the glomeruli.