bluuebunny/crossref_metadata_2025 huggingface dataset:
A Comparison of the Polycation Receptors of Paramecium tetraurelia and Tetrahymena thermophila
Authors: ROBINETTE ERIC D. , GULLEY KEVIN T. , CASSITY KATHERINE J. , KING ERIN E. , NIELSEN AMBER J. , ROZELLE CRISTINE L. , WARREN TIMOTHY J. , MORROW JAMES M. , KURUVILLA HEATHER G.
Published: January 2008

ABSTRACT. Chemorepellents are compounds that cause ciliated protozoans to reorient their swimming direction. A number of chemorepellents have been studied in the ciliated protozoans, Paramecium and Tetrahymena. Chemorepellents, such as polycations, cause the organism to exhibit “avoidance behavior,” a swimming behavior characterized by jerky movements and other deviations from normal forward swimming, which result from ciliary reversal. One well‐characterized chemorepellent pathway in Tetrahymena is that of the proposed polycation receptor that is activated by lysozyme and pituitary adenylate cyclase activating polypeptide (PACAP). In this study, we compare the response of Paramecium to the chemorepellents lysozyme, vasoactive intestinal peptide (VIP), and PACAP to the previously studied polycation response in Tetrahymena. Our results indicate that lysozyme, VIP, and PACAP are all chemorepellents in Paramecium, just as they are in Tetrahymena. However, the signaling pathways involved appear to be different. While previous pharmacological characterization indicates that G‐proteins are involved in polycation signaling in Tetrahymena, we present evidence that similar reception in Paramecium involves activation of a tyrosine kinase pathway in order for lysozyme avoidance to occur. Polycation responses of both organisms are inhibited by neomycin sulfate. While PACAP is the most effective of the three chemorepellents in Tetrahymena, lysozyme is the most effective chemorepellent in Paramecium.
Pseudomonas aeruginosa Utilises Its Type III Secretion System to Kill the Free‐Living Amoeba Acanthamoeba castellanii
Authors: ABD HADI , WRETLIND BENGT , SAEED AMIR , IDSUND EVA , HULTENBY KJELL , SANDSTRÖM GUNNAR
Published: January 2008

ABSTRACT. Pseudomonas aeruginosa is a free‐living and common environmental bacterium. It is an opportunistic and nosocomial pathogen causing serious human health problems. To overcome its predators, such as macrophages and environmental phagocytes, it utilises different survival strategies, such as the formation of microcolonies and the production of toxins mediated by a type III secretion system (TTSS). The aim of this study was to examine interaction of TTSS effector proteins of P. aeruginosa PA103 with Acanthamoeba castellanii by co‐cultivation, viable count, eosin staining, electron microscopy, apoptosis assay, and statistical analysis. The results showed that P. aeruginosa PA103 induced necrosis and apoptosis to kill A. castellanii by the effects of TTSS effector proteins ExoU, ExoS, ExoT, and ExoY. In comparison, Acanthamoeba cultured alone and co‐cultured with P. aeruginosa PA103 lacking the known four TTSS effector proteins were not killed. The results are consistent with P. aeruginosa being a strict extracellular bacterium that needs TTSS to survive in the environment, because the TTSS effector proteins are able to kill its eukaryotic predators, such as Acanthamoeba.
Central nervous system involvement after herpes zoster ophthalmicus
Authors: Haargaard Birgitte , Lund‐Andersen Henrik , Milea Dan
Published: January 2008

Purpose:  To report central nervous system involvement after varicella zoster virus infection.

Methods:  We evaluated the frequency and type of neurological complications in patients initially presenting with ophthalmic herpes zoster at an ophthalmological department in a Danish university hospital, over a 7‐year period.

Results:  Of the 110 immunocompetent patients who presented with initial ophthalmic zoster, six (5.5%) suffered from neurological complications other than post‐herpetic neuralgia. Four experienced isolated cranial motor nerve palsies, one patient had meningitis with a favourable outcome and one patient had severe encephalitis with a poor clinical outcome.

Conclusions:  Central nervous system involvement after varicella zoster virus infection is an uncommon, but potentially life‐threatening, complication. Early recognition of neurological complications prompts acute, appropriate antiviral treatment.
Eye movements and binocular function in low birthweight teenagers
Authors: Lindqvist Susanne , Vik Torstein , Indredavik Marit S. , Skranes Jon , Brubakk Ann‐Mari
Published: January 2008

Purpose:  To assess eye movements and binocular function in 14‐year‐olds with very low birthweight (VLBW: birthweight ≤ 1500 g) and 14‐year‐olds born at term but small for gestational age (SGA: birthweight < 10th percentile) in a population‐based study.

Methods:  Ophthalmological examinations including measurements of heterophoria/tropia, near point of convergence, accommodative amplitude, stereopsis, nystagmus, saccades and smooth pursuit were performed in 51 adolescents with VLBW, 58 adolescents born SGA and in a control group consisting of 75 subjects of the same age.

Results:  Latent or manifest strabismus, poor stereopsis, poor convergence and nystagmus were all more frequent in the VLBW group than in the control group. The VLBW group did not differ from the control group regarding accommodative amplitude or saccades and smooth pursuit. The SGA population did not differ from the control group in the measured variables.

Conclusions:  Premature birth with VLBW affects binocular visual functions negatively in adolescence, whereas birth small for date at term does not appear to be a risk factor for impaired eye movements and binocular function.
Bone regeneration of dental implant dehiscence defects using a cultured periosteum membrane
Authors: Mizuno Daiki , Kagami Hideaki , Mizuno Hirokazu , Mase Junji , Usami Kazutada , Ueda Minoru
Published: January 2008

Objectives: This study aimed to demonstrate the feasibility of a cultured periosteum (CP) membrane for use in guided bone regeneration at sites of implant dehiscence.

Material and methods: Four healthy beagle dogs were used in this study. Implant dehiscence defects (4 × 4 × 3 mm) were surgically created at mandibular premolar sites where premolars had been extracted 3 months back. Dental implants (3.75 mm in diameter and 7 mm in length) with machined surfaces were placed into the defect sites (14 implants in total). Each dehiscence defective implant was randomly assigned to one of the following two groups: (1) PRP gel without cells (control) or (2) a periosteum membrane cultured on PRP gel (experimental). Dogs were killed 12 weeks after operation and nondecalcified histological sections were made for histomorphometric analyses including percent linear bone fill (LF) and bone‐to‐implant contact (BIC).

Results: Bone regeneration in the treatment group with a CP membrane was significantly greater than that in the control group and was confirmed by LF analysis. LF values in the experimental and the control groups were 72.36±3.14% and 37.03±4.63%, respectively (P<0.05). The BIC values in both groups were not significantly different from each other. The BIC values in the experimental and the control groups were 40.76±10.30% and 30.58±9.69%, respectively (P=0.25) and were similar to native bone.

Conclusion: This study demonstrated the feasibility of a CP membrane to regenerate bone at implant dehiscence defect.
Bone apposition around two different sandblasted and acid‐etched titanium implant surfaces: a histomorphometric study in canine mandibles
Authors: Bornstein Michael M. , Valderrama Pilar , Jones Archie A. , Wilson Thomas G. , Seibl Reinhart , Cochran David L.
Published: January 2008

Purpose: The aim of this study was to evaluate bone apposition to a modified sandblasted and acid‐etched (SLA) implant surface (modSLA) in the canine mandible as compared with the standard SLA surface.

Material and methods: In this experimental study, all mandibular premolars and first molars were extracted bilaterally in five foxhounds. After a healing period of 6 months, each side of the mandible received six randomly assigned dental implants alternating between the standard SLA and modSLA surface. The dogs were sacrificed at 2 weeks (n=2) or 4 weeks (n=3) after implant placement. Histologic and histomorphometric analyses were then performed for each implant.

Results: The microscopic healing patterns at weeks 2 and 4 for the two implant types with the standard SLA and modSLA surfaces showed similar qualitative findings. New bone tissue had already established direct contact with implant surfaces after 2 weeks of healing. The mean percentage of newly formed bone in contact with the implant (BIC) was significantly greater for modSLA (28.2±7.9%) than for SLA (22.2±7.3%) (P<0.05). This difference was no longer evident after 4 weeks. An increase in BIC for both implant surface types occurred from weeks 2 to 4. This increase was statistically significant when compared with SLA at 2 weeks (P<0.05), but not when compared with modSLA at 2 weeks.

Conclusion: The data from the present study demonstrate significantly more bone apposition for the modSLA surface than the standard SLA surface after 2 weeks of healing. This increased bone apposition may allow a further reduction of the healing period following implant placement for patients undergoing early loading procedures.
Changes in the pre‐surgical treatment planning using conventional spiral tomography
Authors: Diniz Ana Flávia N. , Mendonça Elismauro F. , Leles Claudio R. , Guilherme Adérico S. , Cavalcante Marcelo P. , Silva Maria Alves G. S.
Published: January 2008

Objective: To investigate variation in the pre‐surgical treatment planning after using conventional spiral tomography in addition to conventional radiographic exams.

Material and methods: Twenty‐nine partial or fully edentulous patients referred to implant therapy were selected and submitted to periapical, panoramic and conventional cross‐sectional tomography exams. Pre‐surgical treatment planning of 120 potential implant sites in 69 edentulous areas was performed by two independent experienced dental implant surgeons. After clinical examination, pre‐surgical planning was made using only periapical and panoramic exams. Examiners were requested to reformulated initial planning after assessing tomographic images. Four treatment parameters were evaluated: length and width of implants, need of bone grafting and need of other surgical procedures.

Results: Implant length and width remained unchanged in 60.2% and 87.2% of cases, respectively. No difference in length (P=0.576) and width (P=1) scores was observed in treatment planning with and without tomography. Variation in implant dimension was not affected by location of edentulous areas. Bone grafting and other surgical procedures significantly changed after tomograms (P<0.001), independent of the location of edentulous areas. In 15.8% and 5.3% of cases bone grafting and other procedures were planned only after tomograms, respectively. Significant differences were observed in all maxillary and mandibular regions.

Conclusion: Conventional spiral tomography plays an important role in pre‐surgical treatment planning, increasing clinician's certainty of the need of additional surgical procedures (bone grafting, sinus lifting, and others) in pre‐surgical treatment stage.
Comparing trophic position of stream fishes using stable isotope and gut contents analyses
Authors: Rybczynski S. M. , Walters D. M. , Fritz K. M. , Johnson B. R.
Published: January 2008

Abstract –  Stable isotope analysis (SIA) and gut contents analysis (GCA) are commonly used in food web studies, but few studies analyse these data in concert. We used SIA (δ15N) and GCA (% composition) to identify diets and trophic position (TP) of six stream fishes and to compare TP estimates between methods. Ordination analysis of gut contents identified two primary trophic groups, omnivores and predators. Significant differences in TPGCA and TPSIA were similar in direction among‐species and among‐trophic groups; neither method detected seasonal changes in omnivore diets. Within‐species TPGCA and TPSIA were similar except for one omnivore. TPGCA was less variable than TPSIA for predators, but variation between methods was similar for omnivores. While both methods were equally robust at discriminating trophic groups of fishes, TPSIA is less laborious to estimate and may facilitate cross‐stream comparisons of food web structure and energy flow.
Down‐regulation of epidermal growth factor receptor‐dependent signaling by Porphyromonas gingivalis lipopolysaccharide in life‐expanded human gingival fibroblasts
Authors: Quinchia‐Rios B. H. , Guerrero M. , Abozeid S. , Bainbridge B. , Darveau R. , Compton T. , Bertics P. J.
Published: January 2008

Background and Objective:  Human gingival fibroblasts exhibit proliferative responses following epidermal growth factor exposure, which are thought to enhance periodontal regeneration in the absence of bacterial products such as lipopolysacharide. However, lipopolysaccharide challenge activates human gingival fibroblasts to release several inflammatory mediators that contribute to the immune response associated with periodontitis and attenuate wound repair. We tested the hypothesis that Porphyromonas gingivalis lipopolysaccharide‐activated signaling pathways down‐regulate epidermal growth factor receptor‐dependent events.

Material and Methods:  To study lipopolysaccharide/epidermal growth factor interactions in human gingival fibroblasts, we introduced the catalytic subunit of human telomerase into human gingival fibroblasts, thereby generating a more long‐lived cellular model. These cells were characterized and evaluated for lipopolysaccharide/epidermal growth factor responsiveness and regulation of epidermal growth factor‐dependent pathways.

Results:  Comparison of human telomerase‐transduced gingival fibroblasts with human gingival fibroblasts revealed that both cell lines exhibit a spindle‐like morphology and express similar levels of epidermal growth factor receptor, CD14 and Toll‐like receptors 2 and 4. Importantly, human telomerase‐transduced gingival fibroblasts proliferation rates are increased 5–9 fold over human gingival fibroblasts and exhibit a longer life span in culture. In addition, human telomerase‐transduced gingival fibroblasts and human gingival fibroblasts exhibit comparable profiles of mitogen‐activated protein kinase kinase (extracellular signal‐regulated kinase 1/2) activation upon epidermal growth factor or P. gingivalis lipopolysaccharide administration. Interestingly, treatment with P. gingivalis lipopolysaccharide leads to a down‐regulation of epidermal growth factor‐dependent extracellular signal‐regulated kinase 1/2, p38 and cyclic‐AMP response element binding protein phosphorylation in both cell types.

Conclusion:  These studies demonstrate that human telomerase‐transduced gingival fibroblasts exhibit an extended life span and recapitulate human gingival fibroblasts biology. Moreover, this system has allowed for the first demonstration of lipopolysaccharide down‐regulation of epidermal growth factor activated pathways in human gingival fibroblasts and should facilitate the analysis of signaling events relevant to the pathogenesis and treatment of periodontitis.
Activation of hepatocyte growth factor activator zymogen (pro‐HGFA) by human kallikrein 1‐related peptidases
Authors: Mukai Shoichiro , Fukushima Tsuyoshi , Naka Daiji , Tanaka Hiroyuki , Osada Yukio , Kataoka Hiroaki
Published: January 2008

Hepatocyte growth factor activator (HGFA) is a serine protease and a potent activator of prohepatocyte growth factor/scatter factor (pro‐HGF/SF), a multifunctional growth factor that is critically involved in tissue morphogenesis, regeneration, and tumor progression. HGFA circulates as a zymogen (pro‐HGFA) and is activated in response to tissue injury. Although thrombin is considered to be an activator of pro‐HGFA, alternative pro‐HGFA activation pathways in tumor microenvironments remain to be identified. In this study, we examined the effects of kallikrein 1‐related peptidases (KLKs), a family of extracellular serine proteases, on the activation of pro‐HGFA. Among the KLKs examined (KLK2, KLK3, KLK4 and KLK5), we identified KLK4 and KLK5 as novel activators of pro‐HGFA. Using N‐terminal sequencing, the cleavage site was identified as the normal processing site, Arg407–Ile408. The activation of pro‐HGFA by KLK5 required a negatively charged substance such as dextran sulfate, whereas KLK4 could process pro‐HGFA without dextran sulfate. KLK5 showed more efficient pro‐HGFA processing than KLK4, and was expressed in 50% (13/25) of the tumor cell lines examined. HGFA processed by these KLKs efficiently activated pro‐HGF/SF, and led to cellular scattering and invasion in vitro. The activities of both KLK4 and KLK5 were strongly inhibited by HGFA inhibitor type 1, an integral membrane Kunitz‐type serine protease inhibitor that inhibits HGFA and other pro‐HGF/SF‐activating proteases. These data suggest that KLK4 and KLK5 mediate HGFA‐induced activation of pro‐HGF/SF within tumor tissue, which may thereafter trigger a series of events leading to tumor progression via the MET receptor.
Molecular characterization of gonad‐inhibiting hormone of Penaeus monodon and elucidation of its inhibitory role in vitellogenin expression by RNA interference
Authors: Treerattrakool Supattra , Panyim Sakol , Chan Siu‐Ming , Withyachumnarnkul Boonsirm , Udomkit Apinunt
Published: January 2008

One of the important peptide hormones that control reproduction in crustaceans is gonad‐inhibiting hormone (GIH). GIH is known to modulate gonad maturation by inhibiting synthesis of vitellogenin (Vg), the precursor of yolk proteins. In this study, a cDNA encoding a GIH (Pem‐GIH) from the eyestalk of Penaeus monodon was cloned using RT‐PCR and RACE techniques. Pem‐GIH cDNA is 861 bp in size with a single ORF of 288 bp. The deduced Pem‐GIH consists of a 17‐residue signal peptide and a mature peptide region of 79 amino acids with features typical of type II peptide hormones from the CHH family. Pem‐GIH transcript was detected in eyestalk, brain, thoracic and abdominal nerve cords of adult P. monodon. The gonad‐inhibiting activity of Pem‐GIH was investigated using the RNA interference technique. Double‐stranded RNA, corresponding to the mature Pem‐GIH sequence, can trigger a decrease in Pem‐GIH transcript levels both in eyestalk ganglia and abdominal nerve cord explant culture and in female P. monodon broodstock. The conspicuous increase in Vg transcript level in the ovary of GIH‐knockdown shrimp suggests a negative influence for Pem‐GIH on Vg gene expression, and thus implies its role as a gonad‐inhibiting hormone. This is the first report to demonstrate the use of double‐stranded RNA to elucidate the function of GIH in P. monodon.
The effects of RANTES/CCR5 promoter polymorphisms on HIV disease progression in HIV‐infected Koreans
Authors: Jang D. H. , Choi B.‐S. , Kim S. S.
Published: January 2008

Recent studies have reported that two single nucleotide polymorphisms (SNPs) in the RANTES gene promoter region, –403G/A and –28C/G, are associated with a slower rate of decline in CD4+ T‐cell number, whereas genetic polymorphisms within the CCR5 promoter are linked to acceleration of AIDS progression. In this study, we investigated the distribution of SNPs in the RANTES and CCR5 promoters and the association between these SNPs and HIV‐1 disease progression in HIV‐infected Koreans. Twenty‐seven long‐term non‐progressors (LTNPs), 29 AIDS patients and 39 HIV‐uninfected persons were enrolled in this study. SNPs for the RANTES and CCR5 promoters were determined by polymerase chain reaction–restriction fragment length polymorphism (PCR‐RFLP) and a direct sequencing method. In the analysis of RANTES promoter polymorphisms, the genotypic and allelic frequencies of the RANTES –28G mutation were significantly lower in HIV‐infected patients than in HIV‐uninfected persons (P = 0.005 and P = 0.001, respectively). The genotypic frequencies of RANTES –28G and –403A mutations did not differ significantly between LTNPs and AIDS patients. The frequencies of three CCR5 promoter polymorphisms, designated 59029 G/A, 59353T/C, and 59402G/A, did not differ significantly between HIV‐uninfected and HIV‐infected patients. However, the allelic frequency of CCR559353C was significantly higher in AIDS patients than in LTNPs (P = 0.003). These results suggest that RANTES‐28G and CCR5 59353C mutations might be associated with HIV infection or pathogenesis in the Korean population.
Diagnosing the site of gamma-ray burst prompt emission with spectral cut-off energy
Authors: Gupta Nayantara , Zhang Bing
Published: January 2008

The site and mechanism of gamma-ray burst (GRB) prompt emission is still unknown. Although internal shocks have been widely discussed as the emission site of GRBs, evidence supporting other emission sites, including the closer-in photosphere where the fireball becomes transparent and further-out radii near the fireball deceleration radius where magnetic dissipation may be important, have been also suggested recently. With the successful operation of the GLAST experiment, prompt high-energy emission spectra from many GRBs would be detected in the near future. We suggest that the cut-off energy of the prompt emission spectrum from a GRB depends on both the fireball bulk Lorentz factor and the unknown emission radius from the central engine. If the bulk Lorentz factor could be independently measured (e.g. from early afterglow observations), the observed spectral cut-off energy can be used to diagnose the emission site of gamma-rays. This would provide valuable information to understand the physical origin of GRB prompt emission.
Implications of very rapid TeV variability in blazars
Authors: Begelman Mitchell C. , Fabian Andrew C. , Rees Martin J.
Published: January 2008

We discuss the implications of rapid (few-minute) variability in the TeV flux of blazars, which has been observed recently with the HESS and MAGIC telescopes. The variability time-scales seen in PKS 2155−304 and Mrk 501 are much shorter than inferred light-crossing times at the black hole horizon, suggesting that the variability involves enhanced emission in a small region within an outflowing jet. The enhancement could be triggered by dissipation in part of the black hole magnetosphere at the base of the outflow, or else by instabilities in the jet itself. By considering the energetics of the observed flares, along with the requirement that TeV photons escape without producing pairs, we deduce that the bulk Lorentz factors in the jets must be ≳50. The distance of the emission region from the central black hole is less well-constrained. We discuss possible consequences for multi-wavelength observations.
Dielectronic recombination and stability of warm gas in active galactic nuclei
Authors: Chakravorty Susmita , Kembhavi Ajit K. , Elvis Martin , Ferland Gary , Badnell N. R.
Published: January 2008

Understanding the thermal equilibrium (stability) curve may offer insights into the nature of the warm absorbers often found in active galactic nuclei. Its shape is determined by factors such as the spectrum of the ionizing continuum and the chemical composition of the gas. We find that the stability curves obtained under the same set of the above-mentioned physical factors, but using recently derived dielectronic recombination rates, give significantly different results, especially in the regions corresponding to warm absorbers, leading to different physical predictions. Using the current rates we find a larger probability of having a thermally stable warm absorber at 105 K than previous predictions and also a greater possibility for its multiphase nature. The results obtained with the current dielectronic recombination rate coefficients are more reliable because the warm absorber models along the stability curve have computed coefficient values, whereas previous calculations relied on guessed averages for these because of a lack of available data.
An observation of a mutual event between two satellites of Uranus
Authors: Hidas M. G. , Christou A. A. , Brown T. M.
Published: January 2008

We present observations of the occultation of Umbriel by Oberon on 2007 May 4. We believe this is the first observed mutual event between satellites of Uranus. Fitting a simple geometric model to the light curve, we measure the mid-event time with a precision of 4 s. We assume previously measured values for the albedos of the two satellites, and measure the impact parameter to be 500 ± 80 km. These measurements are more precise than estimates based on current ephemerides for these satellites. Therefore observations of additional mutual events during the 2007–2008 Uranian equinox will provide improved estimates of their orbital and physical parameters.
SAR of Carbon‐Linked, 2‐Substituted Purines: Synthesis and Characterization of AP23451 as a novel Bone‐Targeted Inhibitor of Src Tyrosine Kinase With In Vivo Anti‐Resorptive Activity
Authors: Shakespeare William C. , Wang Yihan , Bohacek Regine , Keenan Terry , Sundaramoorthi Raji , Metcalf Chet , Dilauro Anne , Roeloffzen Sonya , Liu Shuangying , Saltmarsh Jennifer , Paramanathan Guru , Dalgarno David , Narula Surinder , Pradeepan Selvi , Van Schravendijk Marie Rose , Keats Jeff , Ram Mary , Liou Shuenn , Adams Susan , Wardwell Scott , Bogus Julie , Iuliucci John , Weigele Manfred , Xing Lianping , Boyce Brendan , Sawyer Tomi K.
Published: January 2008

Targeted disruption of the pp60src (Src) gene has implicated this tyrosine kinase in osteoclast‐mediated bone resorption and as a therapeutic target for the treatment of osteoporosis and other bone‐related diseases. Here, we describe structure activity relationships of a novel series of carbon‐linked, 2‐substituted purines that led to the identification of AP23451 as a potent inhibitor of Src tyrosine kinase with antiresorptive activity in vivo. AP23451 features the use of an arylphosphinylmethylphosphinic acid moiety which confers bone‐targeting properties to the molecule, thereby increasing local concentrations of the inhibitor to actively resorbing osteoclasts at the bone interface. AP23451 exhibited an IC50 = 68 nm against Src kinase; an X‐ray crystal structure of the molecule complexed with Src detailed the molecular interactions responsible for its Src inhibition. In vivo, AP23451 demonstrated a dose‐dependent decrease in PTH‐induced hypercalcemia. Moreover, AP23517, a structurally and biochemically similar molecule with comparable activity (IC50 = 73 nm) except devoid of the bone‐targeting element, demonstrated significantly reduced in vivo efficacy, suggesting that Src activity was necessary but not sufficient for in vivo activity in this series of compounds.
Tubulin‐Perturbing Naphthoquinone Spiroketals
Authors: Balachandran Raghavan , Hopkins Tamara D. , Thomas Catherine A. , Wipf Peter , Day Billy W.
Published: January 2008

Several natural and synthetic naphthoquinone spiroketals are potent inhibitors of the thioredoxin–thioredoxin reductase redox system. Based on the antimitotic and weak antitubulin actions noted for SR‐7 ([8‐(furan‐3‐ylmethoxy)‐1‐oxo‐1,4‐dihydronaphthalene‐4‐spiro‐2′‐naphtho[1″,8″‐de][1′,3′][dioxin]), a library of related compounds was screened for tubulin‐perturbing properties. Two compounds, TH‐169 (5′‐hydroxy‐4′H‐spiro[1,3‐dioxolane‐2,1′‐naphthalen]‐4′‐one) and TH‐223 (5′‐methoxy‐4′H‐spiro[1,3‐dioxane‐2,1′‐naphthalen]‐4′‐one), had substantial effects on tubulin assembly and were antiproliferative at low micromolar concentrations. TH‐169 was the most potent at blocking GTP‐dependent polymerization of 10 μmtubulinin vitrowith a remarkable 50% inhibitory concentration of ca. 400 nm. It had no effect on paclitaxel‐induced microtubule assembly and did not cause microtubule hypernucleation. TH‐169 failed to compete with colchicine for binding to β‐tubulin. The 50% antiproliferative concentration of TH‐169 against human cancer cells was at or slightly below 1 μm. Flow cytometry showed that 1 μmTH‐169 caused an increase in G2/M and hypodiploid cells. TH‐169 eliminated the PC‐3 cells’ polyploid population and increased their expression of p21WAF1and Hsp70 in a concentration‐dependent manner. The antiproliferative effect of TH‐169 was irreversible and independent of changes in caspases, actin, tubulin, glyceraldehyde phosphate dehydrogenase or Bcl‐xS/L. This structurally simple naphthoquinone spiroketal represents a small molecule, tubulin‐interactive agent with a novel apoptotic pathway and attractive biological function.
Rhodanine Derivatives as Selective Protease Inhibitors Against Bacterial Toxins
Authors: Johnson Sherida L. , Chen Li‐Hsing , Harbach Rebecca , Sabet Mojgan , Savinov Alexei , Cotton Naomi J. H. , Strongin Alex , Guiney Donald , Pellecchia Maurizio
Published: January 2008

In this study, we analyzed a series of rhodanine derivatives, as potential inhibitors of bacterial toxins, namely the proteases anthrax lethal factor and the botulinum neurotoxin type A. Conducting an extensive structure–activity relationship study on rhodanine derivatives, we profiled their selectivity against the two bacterial toxins and two related human metalloproteases using in vitro assays. In addition, we examined initial in vitro ADME‐Tox properties of selected compounds and their ability to protect lethal factor‐induced cell death of macrophages. These data allowed the selection of one additional drug candidate for which preliminary in vivo efficacy studies against anthrax spores were conducted. Integration of these results with our structure–activity relationship studies provides a framework for the development of potential drug candidates against anthrax and botulinum.
Trishomocubane Amino Acid as a β‐turn scaffold
Authors: Albericio Fernando , Arvidson Per I. , Bisetty Krishna , Giralt Ernest , Govender Thavendran , Jali Samuel , Kongsaeree Palangpon , Kruger Hendrik G. , Prabpai Samran
Published: January 2008

The synthesis and X‐ray structure of two diasteriomeric heptapeptides [Ac‐Ala‐Ala‐Ala‐(R/S)‐Cage‐Ala‐Ala‐Ala‐NH2] with a trishomocubane amino acid as a β‐turn scaffold are reported. The amino acid was synthesized as a racemate and two diastereomeric peptides were obtained. The two peptides were separated by preparative high‐pressure liquid chromatography and crystals suitable for X‐ray analysis were grown for both diasteriomeric peptides. In general, both the peptides satisfy the criteria for β‐turn conformations. Five of the six Ala residues of both cage peptide crystals satisfy the criteria for 310‐helix characteristics and the cage amino acid residue satisfied the α‐helix classification. These experimental results confirm previous theoretical studies in our laboratory which predicted that the cage moiety would be a strong/active β‐turn inducer.
Topliss Method in the Optimization of Salicylic Acid Derivatives as Potential Antimycobacterial Agents
Authors: Silva Márcia da , Menezes Carla Maria Souza , Ferreira Elizabeth Igne , Leite Clarice Queico Fujimura , Sato Daisy Nakamura , Correia Cristiane Cardoso , Pimenta Carolina Pereira , Botelho Kátia Cirlene Alves
Published: January 2008

The Topliss method was used to guide a synthetic path in support of drug discovery efforts toward the identification of potent antimycobacterial agents. Salicylic acid and its derivatives, p‐chloro, p‐methoxy, and m‐chlorosalicylic acid, exemplify a series of synthetic compounds whose minimum inhibitory concentrations for a strain of Mycobacterium were determined and compared to those of the reference drug, p‐aminosalicylic acid. Several physicochemical descriptors (including Hammett’s sigma constant, ionization constant, dipole moment, Hansch constant, calculated partition coefficient, Sterimol‐L and ‐B4 and molecular volume) were considered to elucidate structure–activity relationships. Molecular electrostatic potential and molecular dipole moment maps were also calculated using the AM1 semi‐empirical method. Among the new derivatives, m‐chlorosalicylic acid showed the lowest minimum inhibitory concentration. The overall results suggest that both physicochemical properties and electronic features may influence the biological activity of this series of antimycobacterial agents and thus should be considered in designing new p‐aminosalicylic acid analogs.
Social and Environmental Factors and Their Influence on Drug Use Vulnerability and Resiliency in Rural Populations
Authors: Dew Brian , Elifson Kirk , Dozier Michael
Published: January 2008

ABSTRACT: Findings from recent epidemiological investigations indicate that substance use in rural America has increased to the point where it nearly equals, if not exceeds, the rates found in suburban and urban areas. Although previous research has examined factors that have influenced use patterns, little attention has been devoted to the social and community contextual influences on these drug use trends. Based on a review of the literature, this article's purpose is to discuss distinctive features of rural communities, describe the impact of social and community influences on drug use, and explore implications for future research and interventions. Although rural areas have undergone tremendous economic and social change in the past 20 years, there remain unique social and community factors that serve to mediate alcohol and illicit drug use. In order to reduce drug use in rural areas, prevention and intervention efforts must consider social and environmental influences. Utilization of a multilevel social epidemiological approach could be particularly effective in developing a theoretical framework that best addresses these rising drug trends.
Rural‐Urban Differences in Substance Use Among African‐American Adolescents
Authors: Gibbons Frederick X. , Reimer Rachel A. , Gerrard Meg , Yeh Hsiu‐Chen , Houlihan Amy E. , Cutrona Carolyn , Simons Ron , Brody Gene
Published: January 2008

ABSTRACT: 
Purpose: To examine substance use differences among African‐American adolescents living in rural and more urban areas in Iowa and Georgia and factors thought to be related to those differences. Specifically, negative affect and perceived availability were examined as mediators of the relation between community size and alcohol, tobacco, and drug use. Methods: In‐home interviews with the adolescents (Time 1: N = 897, Mean age = 10.5) assessed their use, perceived substance availability, and negative affect across 3 waves. Their parents’ use was also assessed. Census data were used to determine community size (rural ≤ 2,500; urban ≥ 2,500). Findings: Perceived substance availability and use were both higher among the more urban adolescents. As expected, negative affect was a primary antecedent to use at each wave. Structural Equation Modeling indicated that the relation between population and use was mediated by perceived availability of the substances. Additional multigroup analyses indicated that the relations between negative affect and use were significantly stronger among the urban adolescents at all waves. Conclusions: Results suggest that stress or negative affect is an important antecedent to use among African‐American adolescents, especially when it occurs at an early age, but living in rural areas may be a buffer for both problems, in part, because exposure to this type of risk is lower in these environments.
Adapting Evidence‐Based Programs to New Contexts: What Needs to Be Changed?
Authors: Smith Edward , Caldwell Linda
Published: January 2008

ABSTRACT:  Evidence‐based substance use prevention programs have proliferated in schools and are being adopted by districts in rural settings and internationally. Little attention, however, has been paid to the adaptation process that occurs when these programs are moved to different contexts. In this commentary, the authors draw upon their experience with program adaptation to identify 6 areas for consideration when school‐based programs are introduced in rural areas and in other countries. A key conclusion that emerges is that evidence‐based programs should not be changed randomly but should be modified based on a careful review of program content, the theoretical underpinnings involved, and the context of the new environment.
Research on Rural Residence and Access to Drug Abuse Services: Where Are We and Where Do We Go?
Authors: Borders Tyrone F. , Booth Brenda M.
Published: January 2008

ABSTRACT: 
Context: Illicit drug use is common in rural areas, but very little research has investigated rural populations' access to drug abuse services. Purpose: To describe the current state of the scientific literature on access to drug abuse services in rural areas and suggest directions for future research. Methods: We performed a literature review of published articles on rural drug abuse services and summarized the findings according to potential, realized, accommodating, and acceptable access. Relevant articles on rural access to medical, alcohol, and mental health care were selected to supplement the scarce literature specific to drug abuse. Findings: A limited body of work indicates that rural populations have lower availability and utilize needed drug abuse services less frequently than their urban counterparts. Even less is known about the accommodation and acceptability of drug abuse programs serving rural populations. Conclusions: Research that investigates the existence and determinants of problems with access to drug abuse services is greatly needed to enable policy makers, drug treatment managers, and practitioners to better meet the needs of their rural clientele. As this field of inquiry advances, methodologies for constructing drug abuse service areas and measuring consumers' evaluations must be developed.
Social biology of rodents
Authors: WOLFF Jerry O.
Published: January 2008

Herein, I summarize some basic components of rodent social biology. The material in this paper is summarized and condensed from a recent book “Rodent Societies: An Ecological and Evolutionary Perspective” edited by J. O. Wolff and P. W. Sherman (2007). I describe the four basic spacing patterns and illustrate how female territoriality is a function of offspring defense and male mating tactics are a function of female defensibility. The vulnerability of young to infanticide shapes female spacing and mating behavior. Food does not appear to be a defensible resource for rodents, except for those species that larder hoard nonperishable items such as seeds. Philopatry and the formation of kin groups result in genetic sub‐structuring of the population, which in turn affects effective population size and genetic diversity. Dispersal is male biased and typically involves emigration from the maternal site to avoid female relatives and to seek unrelated mates. Scent marking is a major form of communication and is used in reproductive competition and to assess prospective mates, but it is also eavesdropped by predators to locate prey. Females do not appear to alter the sex ratio of litters in response to maternal condition but among arvicoline rodents daughters appear to be favored in spring and sons in autumn. Rodents are relatively monomorphic; however, females tend to be larger than males in the smallest species and smaller in the larger species. Predation risk results from an interaction among foraging time and vulnerability and in turn affects behavioral and life history characteristics.
Reproduction and population dynamics of Mastomys natalensis Smith, 1834 in an agricultural landscape in the Western Usambara Mountains, Tanzania
Authors: MAKUNDI Rhodes H. , MASSAWE Apia W. , MULUNGU Loth S.
Published: January 2008

The multimammate rat, Mastomys natalensis Smith 1834, is a dominant species in agro‐ecosystems in Sub‐Saharan Africa, but adapts quickly to changes in non‐agricultural landscape, particularly woodlands and forests. In this study we report on reproduction and population dynamics of M. natalensis in deforested high elevation localities in the Usambara Mountains, north‐east Tanzania. We conducted Capture‐Mark‐Recapture studies in 2002‐2004, and established that reproduction of M. natalensis takes place in the extended wet season between February and June, and the population density peaks in June‐August. Reproduction cease in July to January and population density drops from July onwards. Reproduction and population density fluctuations are linked to the duration and amount of rainfall. In years when rainfall was below average and the wet season was short, the population density was significantly lower (below 10 animals/ha and 60 animals/ha in 2003 and 2004 respectively, compared to >100 animals/ha in 2002 when rainfall was above the seasonal average) (Fdf 2,13= 9.092, p < 0.01 for in between years variations and Fdf 12,15= 5.389, p < 0.01 for effect of cumulative annual rainfall on population density). These densities were much lower than in the lowland savannah habitats in central and southwest Tanzania. A comparison between the farmland/fallow mosaic fields and agro–forestry areas showed higher population densities in the former, which have similarities to the preferred habitats in the lowland savannahs. The increasing abundance of M. natalensis in the Usambara could have some consequences: M. natalensis is major pest and is involved in the plague cycle in the western Usambara Mountains. Mastomys natalensis is also a strong competitor and the impact on endemic rodent species, e.g. Lophuromys flavopunctatus and Praomys delectorum is unknown.
Correlating rodent community structure with ecological integrity, Tussen‐die‐Riviere Nature Reserve, Free State province, South Africa
Authors: AVENANT Nico L. , CAVALLINI Paolo
Published: January 2008

Rodents form a vital component of Free State ecosystems and monitoring them may be a relatively quick and inexpensive method of indicating healthy or unhealthy ecosystem functioning. Using removal trapping, we have studied rodent seasonal abundance, species richness, Shannon diversity, and evenness of rodents in four habitats in the Tussen‐die‐Riviere Nature Reserve, inspected the most successful sampling method for these habitats, and report on their community structure and how it is related to an Ecological Index (≅ EI value of grassland). Both species richness and Shannon diversity increased significantly with EI value. The indicator species Mastomys coucha occurred at all plots, but contributed the largest proportion of the total captures (ca. 80%) at the plot with lowest EI value. Other results important for small mammal monitoring and collecting are that trap success and species richness was highest in autumn. This study also confirms that four days and nights continuous trapping is essential for the effective sampling of rodent communities in Free State grasslands. Our results partially support expectations that the number of specialist species increases with succession, M. coucha dominance acts as an indicator of habitat disturbance, rodent species richness conforms to Tilman's hump‐shaped curve model, and adds to a baseline of diversity indices in a variety of grassland habitats.
Pathogen evolution across the agro‐ecological interface: implications for disease management
Authors: Burdon Jeremy J. , Thrall Peter H.
Published: January 2008

Infectious disease is a major causal factor in the demography of human, plant and animal populations. While it is generally accepted in medical, veterinary and agricultural contexts that variation in host resistance and pathogen virulence and aggressiveness is of central importance to understanding patterns of infection, there has been remarkably little effort to directly investigate causal links between population genetic structure and disease dynamics, and even less work on factors influencing host–pathogen coevolution. The lack of empirical evidence is particularly surprising, given the potential for such variation to not only affect disease dynamics and prevalence, but also when or where new diseases or pathotypes emerge. Increasingly, this lack of knowledge has led to calls for an integrated approach to disease management, incorporating both ecological and evolutionary processes. Here, we argue that plant pathogens occurring in agro‐ecosystems represent one clear example where the application of evolutionary principles to disease management would be of great benefit, as well as providing model systems for advancing our ability to generalize about the long‐term coevolutionary dynamics of host–pathogen systems. We suggest that this is particularly the case given that agro‐ecological host–pathogen interactions represent a diversity of situations ranging from those that only involve agricultural crops through to those that also include weedy crop relatives or even unrelated native plant communities. We begin by examining some of the criteria that are important in determining involvement in agricultural pathogen evolution by noncrop plants. Throughout we use empirical examples to illustrate the fact that different processes may dominate in different systems, and suggest that consideration of life history and spatial structure are central to understanding dynamics and direction of the interaction. We then discuss the implications that such interactions have for disease management in agro‐ecosystems and how we can influence those outcomes. Finally, we identify several major gaps where future research could increase our ability to utilize evolutionary principles in managing disease in agro‐ecosystems.
The great opportunity: Evolutionary applications to medicine and public health
Authors: Nesse Randolph M. , Stearns Stephen C.
Published: January 2008

Evolutionary biology is an essential basic science for medicine, but few doctors and medical researchers are familiar with its most relevant principles. Most medical schools have geneticists who understand evolution, but few have even one evolutionary biologist to suggest other possible applications. The canyon between evolutionary biology and medicine is wide. The question is whether they offer each other enough to make bridge building worthwhile. What benefits could be expected if evolution were brought fully to bear on the problems of medicine? How would studying medical problems advance evolutionary research? Do doctors need to learn evolution, or is it valuable mainly for researchers? What practical steps will promote the application of evolutionary biology in the areas of medicine where it offers the most? To address these questions, we review current and potential applications of evolutionary biology to medicine and public health. Some evolutionary technologies, such as population genetics, serial transfer production of live vaccines, and phylogenetic analysis, have been widely applied. Other areas, such as infectious disease and aging research, illustrate the dramatic recent progress made possible by evolutionary insights. In still other areas, such as epidemiology, psychiatry, and understanding the regulation of bodily defenses, applying evolutionary principles remains an open opportunity. In addition to the utility of specific applications, an evolutionary perspective fundamentally challenges the prevalent but fundamentally incorrect metaphor of the body as a machine designed by an engineer. Bodies are vulnerable to disease – and remarkably resilient – precisely because they are not machines built from a plan. They are, instead, bundles of compromises shaped by natural selection in small increments to maximize reproduction, not health. Understanding the body as a product of natural selection, not design, offers new research questions and a framework for making medical education more coherent. We conclude with recommendations for actions that would better connect evolutionary biology and medicine in ways that will benefit public health. It is our hope that faculty and students will send this article to their undergraduate and medical school Deans, and that this will initiate discussions about the gap, the great opportunity, and action plans to bring the full power of evolutionary biology to bear on human health problems.