bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pool‐Point Distribution of Zero‐Inventory Products
Authors: Geismar H. Neil , Dawande Milind , Sriskandarajah Chelliah 
Published: October 2010

We study zero‐inventory production‐distribution systems under pool‐point delivery. The zero‐inventory production and distribution paradigm is supported in a variety of industries in which a product cannot be inventoried because of its short shelf life. The advantages of pool‐point (or hub‐and‐spoke) distribution, explored extensively in the literature, include the efficient use of transportation resources and effective day‐to‐day management of operations. The setting of our analysis is as follows: A production facility (plant) with a finite production rate distributes its single product, which cannot be inventoried, to several pool points. Each pool point may require multiple truckloads to satisfy its customers' demand. A third‐party logistics provider then transports the product to individual customers surrounding each pool point. The production rate can be increased up to a certain limit by incurring additional cost. The delivery of the product is done by identical trucks, each having limited capacity and non‐negligible traveling time between the plant and the pool points. Our objective is to coordinate the production and transportation operations so that the total cost of production and distribution is minimized, while respecting the product lifetime and the delivery capacity constraints. This study attempts to develop intuition into zero‐inventory production‐distribution systems under pool‐point delivery by considering several variants of the above setting. These include multiple trucks, a modifiable production rate, and alternative objectives. Using a combination of theoretical analysis and computational experiments, we gain insights into optimizing the total cost of a production‐delivery plan by understanding the trade‐off between production and transportation.
Paris in Bogotá: Applying the Aid Effectiveness Agenda in Colombia
Authors: McGee Rosemary , García Heredia Irma 
Published: October 2010

SummaryRecent research in the field of development aid persuasively problematises aid relationships and begins to reveal their significance for the real‐life application and effectiveness of international development cooperation. Until insights from such research percolate through aid machineries such as the OECD DAC and its workings, the country‐level consequences of universal aid frameworks and prescriptions will continue to be insufficiently foreseen, and in some cases unexpectedly problematic.This paper is about an in‐depth, qualitative study of the application of the Paris Declaration (PD) on Aid Effectiveness in Colombia. This middle‐income, non‐aid‐dependent country with a prolonged and complex internal armed conflict and a poor human rights record, hitherto on the margins of international aid circles, has fast assumed a high‐profile role in them via its adoption of the PD. The study stemmed from a conviction that PD application in Colombia has unanticipated consequences, with under‐appreciated impacts on the strategies of donors and social actors. Donors are subject to an attempt to push them (back) into a technocratic corner. In this politically complex context where donors’ presence owes at least as much to concerns over Colombia's international human rights performance as to classic aid donor concerns with widespread extreme poverty, this is worrying and undesirable.It also has serious implications for the tripartite aid dialogue process established in 2003, involving Government, donors and social actors. This, for all its flaws and frustrations, is unique and important in a historic context of polarised, antagonistic and violent relationships between the state and left‐wing advocates of human rights and social democratic principles.It will require skilful and opportunistic responses by both donors and social organisations to turn this conjuncture to their favour, in the sense of strengthening their leverage on the Government in relation to human rights, poverty, conflict and democratic governance.
Potent Strategy To Inhibit HIV-1 by Binding both gp120 and gp41
Authors: Kagiampakis Ioannis , Gharibi Arbi , Mankowski Marie K. , Snyder Beth A. , Ptak Roger G. , Alatas Kristabelle , LiWang Patricia J. 
Published: October 2010

ABSTRACTThe development of an anti-HIV microbicide is critical in the fight against the spread of HIV. It is shown here that the covalent linking of compounds that bind gp120 with compounds that bind gp41 can inhibit HIV entry even more potently than individual inhibitors or noncovalent combinations. The most striking example involves griffithsin, a potent HIV inhibitor that binds to the surface of HIV gp120. While griffithsin inhibits HIV Env-mediated fusion in a CCR5-tropic cell-cell fusion assay with a 50% inhibitory concentration (IC50) of 1.31 ± 0.87 nM and the gp41-binding peptide C37 shows an IC50of 18.2 ± 7.6 nM, the covalently linked combination of griffithsin with C37 (Griff37) has an IC50of 0.15 ± 0.05 nM, exhibiting a potency 8.7-fold greater than that of griffithsin alone. Similarly, in CXCR4-tropic cell-cell fusion assays, Griff37 is 5.2-fold more potent than griffithsin alone. In viral assays, both griffithsin and Griff37 inhibit HIV replication at midpicomolar levels, but the linked compound Griff37 is severalfold more potent than griffithsin alone against both CCR5- and CXCR4-tropic virus strains. Another example of this strategy is the covalently linked combination of peptide C37 with a variant of the gp120-binding peptide CD4M33 (L. Martin et al., Nat. Biotechnol. 21:71-76, 2003). Also, nuclear magnetic resonance (NMR) spectra for several of these compounds are shown, including, to our knowledge, the first published NMR spectrum for griffithsin.
The Antibiotic Gentamicin Inhibits Specific Protein Trafficking Functions of the Arf1/2 Family of GTPases
Authors: Lin Lin , Wagner Mark C. , Cocklin Ross , Kuzma Alex , Harrington Maureen , Molitoris Bruce A. , Goebl Mark G. 
Published: October 2010

ABSTRACT

Gentamicin is a highly efficacious antibiotic against Gram-negative bacteria. However, its usefulness in treating infections is compromised by its poorly understood renal toxicity. Toxic effects are also seen in a variety of other organisms. While the yeast
Saccharomyces cerevisiae
is relatively insensitive to gentamicin, mutations in any one of ∼20 genes cause a dramatic decrease in resistance. Many of these genes encode proteins important for translation termination or specific protein-trafficking complexes. Subsequent inspection of the physical and genetic interactions of the remaining gentamicin-sensitive mutants revealed a network centered on chitin synthase and the Arf GTPases. Further analysis has demonstrated that some conditional
arf1
and
gea1
alleles make cells hypersensitive to gentamicin under permissive conditions. These results suggest that one consequence of gentamicin exposure is disruption of Arf-dependent protein trafficking.
Differential Effects of Paromomycin on Ribosomes ofLeishmania mexicanaand Mammalian Cells
Authors: Fernández Marisa M. , Malchiodi Emilio L. , Algranati Israel D. 
Published: October 2010

ABSTRACTParomomycin, an aminoglycoside antibiotic having low mammalian cell toxicity, is one of the drugs currently used in the chemotherapy of cutaneous and visceral leishmaniasis. In order to understand the mode of action of this antibiotic at the molecular level, we have investigated the effects of paromomycin on protein synthesis inLeishmaniaand its mammalian hosts. We were able to demonstrate thatin vivoprotein synthesis in the promastigote stage of the parasite and its proliferation rate are markedly inhibited by paromomycin while being only slightly affected by other aminoglycoside antibiotics, such as streptomycin and neomycin B. Furthermore, bothin vitropolypeptide synthesis induced by poly(U) as mRNA and accuracy of translation are significantly decreased by paromomycin in cell-free systems containing ribosomal particles ofLeishmaniapromastigotes. Conversely, when ribosomes from mammalian cells are used instead of the protozoan particles, polyphenylalanine synthesis is only barely reduced by the antibiotic and the translation misreading remains almost unaltered. Surface plasmon resonance analysis of the interaction between paromomycin and protozoan or mammalian cell ribosomal RNAs shows a strong binding of antibiotic to the parasite ribosomal decoding site and practically no interaction with the mammalian cell counterpart. Our results indicating differential effects of paromomycin on the translation processes of theLeishmaniaparasite and its mammalian hosts can explain the therapeutic efficiency of this antibiotic as an antileishmaniasis agent.
Structure of the
Mycobacterium tuberculosis
d
-Alanine:
d
-Alanine Ligase, a Target of the Antituberculosis Drug
d
-Cycloserine
Authors: Bruning John B. , Murillo Ana C. , Chacon Ofelia , Barletta Raúl G. , Sacchettini James C. 
Published: October 2010

ABSTRACT

d
-Alanine:
d
-alanine ligase (EC 6.3.2.4; Ddl) catalyzes the ATP-driven ligation of two
d
-alanine (
d
-Ala) molecules to form the
d
-alanyl:
d
-alanine dipeptide. This molecule is a key building block in peptidoglycan biosynthesis, making Ddl an attractive target for drug development.
d
-Cycloserine (DCS), an analog of
d
-Ala and a prototype Ddl inhibitor, has shown promise for the treatment of tuberculosis. Here, we report the crystal structure of
Mycobacterium tuberculosis
Ddl at a resolution of 2.1 Å. This structure indicates that Ddl is a dimer and consists of three discrete domains; the ligand binding cavity is at the intersection of all three domains and conjoined by several loop regions. The
M. tuberculosis
apo Ddl structure shows a novel conformation that has not yet been observed in Ddl enzymes from other species. The nucleotide and
d
-alanine binding pockets are flexible, requiring significant structural rearrangement of the bordering regions for entry and binding of both ATP and
d
-Ala molecules. Solution affinity and kinetic studies showed that DCS interacts with Ddl in a manner similar to that observed for
d
-Ala. Each ligand binds to two binding sites that have significant differences in affinity, with the first binding site exhibiting high affinity. DCS inhibits the enzyme, with a 50% inhibitory concentration (IC
50
) of 0.37 mM under standard assay conditions, implicating a preferential and weak inhibition at the second, lower-affinity binding site. Moreover, DCS binding is tighter at higher ATP concentrations. The crystal structure illustrates potential drugable sites that may result in the development of more-effective Ddl inhibitors.
Structural Features Governing the Activity of Lactoferricin-Derived Peptides That Act in Synergy with Antibiotics against
Pseudomonas aeruginosa In Vitro
and
In Vivo
Authors: Sánchez-Gómez Susana , Japelj Bostjan , Jerala Roman , Moriyón Ignacio , Fernández Alonso Mirian , Leiva José , Blondelle Sylvie E. , Andrä Jörg , Brandenburg Klaus , Lohner Karl , Martínez de Tejada Guillermo 
Published: October 2010

ABSTRACT

Pseudomonas aeruginosa
is naturally resistant to many antibiotics, and infections caused by this organism are a serious threat, especially to hospitalized patients. The intrinsic low permeability of
P. aeruginosa
to antibiotics results from the coordinated action of several mechanisms, such as the presence of restrictive porins and the expression of multidrug efflux pump systems. Our goal was to develop antimicrobial peptides with an improved bacterial membrane-permeabilizing ability, so that they enhance the antibacterial activity of antibiotics. We carried out a structure activity relationship analysis to investigate the parameters that govern the permeabilizing activity of short (8- to 12-amino-acid) lactoferricin-derived peptides. We used a new class of constitutional and sequence-dependent descriptors called PEDES (
pe
ptide
de
scriptors from
s
equence) that allowed us to predict (Spearman's ρ = 0.74;
P
< 0.001) the permeabilizing activity of a new peptide generation. To study if peptide-mediated permeabilization could neutralize antibiotic resistance mechanisms, the most potent peptides were combined with antibiotics, and the antimicrobial activities of the combinations were determined on
P. aeruginosa
strains whose mechanisms of resistance to those antibiotics had been previously characterized. A subinhibitory concentration of compound P2-15 or P2-27 sensitized
P. aeruginosa
to most classes of antibiotics tested and counteracted several mechanisms of antibiotic resistance, including loss of the OprD porin and overexpression of several multidrug efflux pump systems. Using a mouse model of lethal infection, we demonstrated that whereas P2-15 and erythromycin were unable to protect mice when administered separately, concomitant administration of the compounds afforded long-lasting protection to one-third of the animals.
Short Alkylated Peptoid Mimics of Antimicrobial Lipopeptides
Authors: Chongsiriwatana Nathaniel P. , Miller Tyler M. , Wetzler Modi , Vakulenko Sergei , Karlsson Amy J. , Palecek Sean P. , Mobashery Shahriar , Barron Annelise E. 
Published: October 2010

ABSTRACT

We report the creation of alkylated poly-
N
-substituted glycine (peptoid) mimics of antimicrobial lipopeptides with alkyl tails ranging from 5 to 13 carbons. In several cases, alkylation significantly improved the selectivity of the peptoids with no loss in antimicrobial potency. Using this technique, we synthesized an antimicrobial peptoid only 5 monomers in length with selective, broad-spectrum antimicrobial activity as potent as previously reported dodecameric peptoids and the antimicrobial peptide pexiganan.
Functional Antibodies Targeting IsaA of
Staphylococcus aureus
Augment Host Immune Response and Open New Perspectives for Antibacterial Therapy
Authors: Lorenz Udo , Lorenz Birgit , Schmitter Tim , Streker Karin , Erck Christian , Wehland Jürgen , Nickel Joachim , Zimmermann Bastian , Ohlsen Knut 
Published: October 2010

ABSTRACT

Staphylococcus aureus
is the most common cause of nosocomial infections. Multiple antibiotic resistance and severe clinical outcomes provide a strong rationale for development of immunoglobulin-based strategies. Traditionally, novel immunological approaches against bacterial pathogens involve antibodies directed against cell surface-exposed virulence-associated epitopes or toxins. In this study, we generated a monoclonal antibody targeting the housekeeping protein IsaA, a suggested soluble lytic transglycosylase of
S. aureus
, and tested its therapeutic efficacy in two experimental mouse infection models. A murine anti-IsaA antibody of the IgG1 subclass (UK-66P) showed the highest binding affinity in Biacore analysis. This antibody recognized all
S. aureus
strains tested, including hospital-acquired and community-acquired methicillin-resistant
S. aureus
strains. Therapeutic efficacy
in vivo
in mice was analyzed using a central venous catheter-related infection model and a sepsis survival model. In both models, anti-IsaA IgG1 conferred protection against staphylococcal infection.
Ex vivo
, UK-66P activates professional phagocytes and induces highly microbicidal reactive oxygen metabolites in a dose-dependent manner, resulting in bacterial killing. The study provides proof of concept that monoclonal IgG1 antibodies with high affinity to the ubiquitously expressed, single-epitope-targeting IsaA are effective in the treatment of staphylococcal infection in different mouse models. Anti-IsaA antibodies might be a useful component in an antibody-based therapeutic for prophylaxis or adjunctive treatment of human cases of
S. aureus
infections.
Heat Shock Factor 1 Protects Mice from Rapid Death duringListeria monocytogenesInfection by Regulating Expression of Tumor Necrosis Factor Alpha during Fever
Authors: Murapa Patience , Ward Martin R. , Gandhapudi Siva K. , Woodward Jerold G. , D'Orazio Sarah E. F. 
Published: October 2010

ABSTRACTHeat shock factor 1 (HSF1) is a stress-induced transcription factor that promotes expression of genes that protect mammalian cells from the lethal effects of severely elevated temperatures (>42°C). However, we recently showed that HSF1 is activated at a lower temperature (39.5°C) in T cells, suggesting that HSF1 may be important for preserving T cell function during pathogen-induced fever responses. To test this, we examined the role of HSF1 in clearance ofListeria monocytogenes, an intracellular bacterial pathogen that elicits a strong CD8+T cell response in mice. Using temperature transponder microchips, we showed that the core body temperature increased approximately 2°C inL. monocytogenes-infected mice and that the fever response was maintained for at least 24 h. HSF1-deficient mice cleared a low-dose infection with slightly slower kinetics than didHSF1+/+littermate controls but were significantly more susceptible to challenges with higher doses of bacteria. Surprisingly, HSF1-deficient mice did not show a defect in CD8+T cell responses following sublethal infection. However, when HSF1-deficient mice were challenged with high doses ofL. monocytogenes, increased levels of serum tumor necrosis factor alpha (TNF-α) and gamma interferon (IFN-γ) compared to those of littermate control mice were observed, and rapid death of the animals occurred within 48 to 60 h of infection. Neutralization of TNF-α enhanced the survival of HSF1-deficient mice. These results suggest that HSF1 is needed to prevent the overproduction of proinflammatory cytokines and subsequent death due to septic shock that can result following high-dose challenge with bacterial pathogens.
Granulocyte-Macrophage Colony-Stimulating Factor- and Tumor Necrosis Factor Alpha-Mediated Matrix Metalloproteinase Production by Human Osteoblasts and Monocytes after Infection withBrucella abortus
Authors: Scian Romina , Barrionuevo Paula , Giambartolomei Guillermo H. , Fossati Carlos A. , Baldi Pablo C. , Delpino M. Victoria 
Published: October 2010

ABSTRACTOsteoarticular complications are common in human brucellosis, but the pathogenic mechanisms involved are largely unknown. Since matrix metalloproteinases (MMPs) are involved in joint and bone damage in inflammatory and infectious diseases, we investigated the production of MMPs by human osteoblasts and monocytes, either uponBrucella abortusinfection or upon reciprocal stimulation with factors produced by each infected cell type.B. abortusinfection of the normal human osteoblastic cell line hFOB 1.19 triggered a significant release of MMP-2, which was mediated in part by granulocyte-macrophage colony-stimulating factor (GM-CSF) acting on these same cells. Supernatants from infected osteoblasts exhibited increased levels of monocyte chemoattractant protein 1 and induced the migration of human monocytes (THP-1 cell line). Infection withB. abortusinduced a high MMP-9 secretion in monocytes, which was also induced by heat-killedB. abortusand by the Omp19 lipoprotein fromB. abortus. These effects were mediated by Toll-like receptor 2 and by the action of tumor necrosis factor alpha (TNF-α) produced by these same cells. Supernatants fromB. abortus-infected monocytes induced MMP-2 secretion in uninfected osteoblasts, and this effect was mediated by TNF-α. Similarly, supernatants from infected osteoblasts induced MMP-9 secretion in uninfected monocytes. This effect was mediated by GM-CSF, which induced TNF-α production by monocytes, which in turn induced MMP-9 in these cells. These results suggest that MMPs could be potentially involved in the tissue damage observed in osteoarticular brucellosis.
Generation of a Neutralizing Human Monoclonal Antibody Fab Fragment to Surface Antigen 1 ofToxoplasma gondiiTachyzoites
Authors: Fu Yong-Feng , Feng Meng , Ohnishi Kenji , Kimura Tamon , Itoh Johbu , Cheng Xun-Jia , Tachibana Hiroshi 
Published: October 2010

ABSTRACTA combinatorial immunoglobulin gene library was constructed from lymphocytes in peripheral blood of a patient with toxoplasmosis and screened for production of human monoclonal antibody Fab fragments to recombinant surface antigen 1 (SAG1) ofToxoplasma gondii. Two Fab clones, Tox203 and Tox1403, which consisted of a common heavy chain and different light chains, showed positive staining on the entire surface of tachyzoites in confocal microscopy. Sequence analysis of the heavy-chain gene revealed that the closest germ line V segments were VH3-23. The germ line D segment was D1-7, and the closest germ line J segment was JH4. In the light-chain genes, the closest germ line V segment was Vκ1-17 with the Jκ1 or Jκ4 segments. The dissociation constants of these Fab fragments with recombinant SAG1 were 3.09 × 10−9M for Tox203 and 2.01 × 10−8M for Tox1403, indicating that the affinity of Tox203 was 7 times higher than that of Tox1403. Preincubation ofT. gondiitachyzoites with Tox203 significantly inhibited their attachment to cultured MDBK cells. Passive immunization of mice with Tox203 also significantly reduced mortality after challenge withT. gondiitachyzoites. This is the first report of bacterial expression of human monoclonal antibody Fab fragments to SAG1 ofT. gondii. These results also demonstrate that human Fab fragments to SAG1 might be applicable for immunoprophylaxis of toxoplasmosis.
Everyday ethics
Authors: Leeb Christine 
Published: October 2010

THIS series gives readers the opportunity to consider and contribute to the discussion of some of the ethical dilemmas that can arise in veterinary practice. Each month, a case scenario is presented, followed by discussion of some of the issues involved. In addition, a possible way forward is suggested; however, there is rarely a cut‐and‐dried answer in such cases, and readers may wish to suggest an alternative approach. This month's dilemma, entitled ‘A troubled vet abroad’, is presented and discussed by Christine Leeb. Readers with comments to contribute are invited to send them as soon as possible, so that they can be considered for publication in the next issue.The series is being coordinated by Siobhan Mullan, of the University of Bristol. It is hoped it will provide a framework that will help practices find solutions when facing similar dilemmas. On page 305, she comments on the ‘Conflicting co‐owners’ dilemma, which was published last month.
Everyday ethics
Authors: Forrest Niky 
Published: October 2010

THIS series gives readers the opportunity to consider and contribute to the discussion of some of the ethical dilemmas that can arise in veterinary practice. Each month, a case scenario is presented, followed by discussion of some of the issues involved. In addition, a possible way forward is suggested; however, there is rarely a cut‐and‐dried answer in such cases, and readers may wish to suggest an alternative approach. This month's dilemma, entitled ‘Veterinary nurse uneasy with vets' approach’, is presented and discussed by Niky Forrest. Readers with comments to contribute are invited to send them as soon as possible, so that they can be considered for publication in the next issue.The series is being coordinated by Siobhan Mullan, of the University of Bristol. It is hoped it will provide a framework that will help practices find solutions when facing similar dilemmas. On page 490, she comments on the dilemma, ‘Maliciously injured kitten’, which was published in the last issue.