bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transduction of artificial transcriptional regulatory proteins into human cells
Authors: Yun Chae-Ok , Shin Hyun-Chul , Kim Tae-Dong , Yoon Wan-Hee , Kang Yoon-A , Kwon Heung-Sun , Kim Seong Keun , Kim Jin-Soo 
Published: July 2008

Abstract
Protein transduction (PT) is a method for delivering proteins into mammalian cells. PT is accomplished by linking a small peptide tag—called a PT domain (PTD)—to a protein of interest, which generates a functional fusion protein that can penetrate efficiently into mammalian cells. In order to study the functions of a transcription factor (TF) of interest, expression plasmids that encode the TF often are transfected into mammalian cells. However, the efficiency of DNA transfection is highly variable among different cell types and is usually very low in primary cells, stem cells and tumor cells. Zinc-finger transcription factors (ZF-TFs) can be tailor-made to target almost any gene in the human genome. However, the extremely low efficiency of DNA transfection into cancer cells, both in vivo and in vitro, limits the utility of ZF-TFs. Here, we report on an artificial ZF-TF that has been fused to a well-characterized PTD from the human immunodeficiency virus-1 (HIV-1) transcriptional activator protein, Tat. This ZF-TF targeted the endogenous promoter of the human VEGF-A gene. The PTD-attached ZF-TF was delivered efficiently into human cells in vitro. In addition, the VEGF-A-specific transcriptional repressor retarded the growth rate of tumor cells in a mouse xenograft experiment.
Urological surgery in patients aged 80 years and older: A 30‐year retrospective clinical study
Authors: Takao Tetsuya , Tsujimura Akira , Kiuchi Hiroshi , Komori Kazuhiko , Fujita Kazutoshi , Miyagawa Yasushi , Takada Shingo , Nonomura Norio , Okuyama Akihiko 
Published: July 2008

Objectives:  To investigate changes in the management of cases over time, we undertook a retrospective analysis of urological surgeries carried out in patients aged 80 years and older in a single institution over the last 30 years.Methods:  Between 1975 and 2004, 402 patients aged 80 years and older underwent 412 surgeries in our department. We reviewed the clinical records and analyzed changes in clinical data over time. We evaluated the observed comorbidities and postoperative complications in selected patients for whom complete clinical records were available. We then identified risk factors for postoperative complications by means of multiple logistic regression analysis.Results:  The number of surgeries carried out in patients aged 80 years and older increased every 5 years. Over time, the number of endourological and laparoscopic surgeries increased. Of 255 patients, 225 (88.3%) had at least one comorbidity, and 51 patients had postoperative complications. The number of observed comorbidities, such as cardiovascular disorder, central nervous system disorder, and diabetes mellitus, increased over the most recent 10‐year period. However, there were no differences in postoperative complications over time. Male sex and open surgery were found to be independent risk factors for postoperative complications.Conclusions:  Although elderly patients had various comorbidities, the postoperative morbidity rate was acceptable in our selected cases. This study may provide useful detailed information for patients 80 years and older who will undergo urological surgery.
Impact of long‐term treatment with neurotoxic dideoxynucleoside antiretrovirals: implications for clinical care in resource‐limited settings
Authors: Hung CF , Gibson SA , Letendre SL , Lonergan JT , Marquie‐Beck JA , Vaida F , Ellis RJ 
Published: July 2008

ObjectivesA minority of HIV‐infected patients taking an antiretroviral (ARV) regimen containing dideoxynucleosides (d‐drugs) such as stavudine (d4T) and didanosine (DDI) experiences dose‐limiting neuropathic pain and paraesthesias, usually within weeks of starting these drugs. Because d‐drugs are among the few affordable options available in developing countries, continuing d‐drug therapy would be a desirable strategy for many HIV‐infected individuals. Therefore, we evaluated the safety of continuing d‐drug therapy.MethodsIn a US cohort, we compared the rates of worsening neuropathic symptoms and signs in HIV‐infected individuals on stable ARV regimens that did (n=252) or did not (n=250) include d‐drugs. Rates of worsening were compared using proportional hazards model and the log‐rank test.ResultsThe risk ratios (RR) were not significantly larger for worsening neuropathy signs [0.94; 95% confidence interval (CI) 0.84–1.07] or symptoms (0.99; 95% CI 0.88–1.14) in patients taking d‐drugs continuously compared to those not taking d‐drugs.ConclusionsContinued d‐drug exposure among patients tolerating an initial trial did not increase the risk of worsening neuropathy compared to non‐d‐drug‐containing regimens. If applicable in developing countries, these findings suggest that in most patients d‐drugs can be continued safely in the long term without increasing the risk of worsening neuropathy.
Mother‐to‐child transmission of HIV‐1: association with malaria prevention, anaemia and placental malaria*
Authors: Naniche D , Lahuerta M , Bardaji A , Sigauque B , Romagosa C , Berenguera A , Mandomando I , David C , Sanz S , Aponte J , Ordi J , Alonso P , Menendez C 
Published: July 2008

ObjectivesMalaria infection may impact on mother‐to‐child transmission (MTCT) of HIV‐1. Prevention of malaria in pregnancy could thus potentially affect MTCT of HIV. We studied the impact of intermittent preventive treatment during pregnancy (IPTp) on HIV‐1 MTCT in southern Mozambique.MethodsA total of 207 HIV‐positive Mozambican pregnant women were enrolled in the study as part of a randomized placebo‐controlled trial of two‐dose sulfadoxine‐pyrimethamine (SP) IPTp in women receiving single‐dose nevirapine to prevent MTCT of HIV. HIV RNA viral load, maternal anaemia and peripheral and placental malaria were assessed at delivery. Infant HIV status was determined by DNA polymerase chain reaction (PCR) at 1 month of age.ResultsThere were 19 transmissions of HIV in 153 mother–infant pairs. IPTp with SP did not have a significant impact on MTCT (11.8% in the SP group vs. 13.2% in the placebo group; P=0.784) or on maternal HIV RNA viral load [16 312 (interquartile range {IQR} 4076–69 296) HIV‐1 RNA copies/mL in the SP group vs. 18 274 (IQR 5471–74 104) copies/mL in the placebo group; P=0.715]. In multivariate analysis, maternal HIV RNA viral load [adjusted odds ratio (AOR) 19.9; 95% confidence interval (CI) 2.3–172; P=0.006] and anaemia (haematocrit <33%; AOR 7.5; 95% CI 1.7–32.4; P=0.007) were independent risk factors for MTCT. Placental malaria was associated with a decrease in MTCT (AOR 0.23; 95% CI 0.06–0.89; P=0.034).ConclusionsIPTp with SP was not associated with a significant impact on MTCT of HIV. Maternal anaemia was an independent risk factor for MTCT.
A new proof of the non-tameness of the Nagata automorphism from the point of view of the Sarkisov program
Authors: Kishimoto Takashi 
Published: July 2008

AbstractThe Nagata automorphism is a kind of complicated automorphism on the affine 3-space ${\mathbb C}^3$. For a long time, it remained unknown whether or not the Nagata automorphism is tame until Shestakov and Umirbaev at last proved that it is not tame in 2004, by purely algebraic methods (e.g. Poisson algebra). In this paper, we consider a certain necessary condition for a given automorphism on ${\mathbb C}^3$ to be tame from the point of view of the Sarkisov program established by Corti. Furthermore, by using it, we shall give a new algebro-geometric proof of the non-tameness of the Nagata automorphism.
Varieties with quadratic entry locus, II
Authors: Ionescu Paltin , Russo Francesco 
Published: July 2008

AbstractWe continue the study, begun in [F. Russo, Varieties with quadratic entry locus. I, Preprint (2006), math. AG/0701889] , of secant defective manifolds having ‘simple entry loci’. We prove that such manifolds are rational and describe them in terms of tangential projections. Using also the work of [P. Ionescu and F. Russo, Conic-connected manifolds, Preprint (2006), math. AG/0701885], their classification is reduced to the case of Fano manifolds of high index, whose Picard group is generated by the hyperplane section class. Conjecturally, the former should be linear sections of rational homogeneous manifolds. We also provide evidence that the classification of linearly normal dual defective manifolds with Picard group generated by the hyperplane section should follow along the same lines.
Glycogen Synthase Kinase 3 Is a Potential Drug Target for African Trypanosomiasis Therapy
Authors: Ojo Kayode K. , Gillespie J. Robert , Riechers Aaron J. , Napuli Alberto J. , Verlinde Christophe L. M. J. , Buckner Frederick S. , Gelb Michael H. , Domostoj Mathias M. , Wells Susan J. , Scheer Alexander , Wells Timothy N. C. , Van Voorhis Wesley C. 
Published: July 2008

ABSTRACT

Development of a safe, effective, and inexpensive therapy for African trypanosomiasis is an urgent priority. In this study, we evaluated the validity of
Trypanosoma brucei
glycogen synthase kinase 3 (GSK-3) as a potential drug target. Interference with the RNA of either of two GSK-3 homologues in bloodstream-form
T. brucei
parasites led to growth arrest and altered parasite morphology, demonstrating their requirement for cell survival. Since the growth arrest after RNA interference appeared to be more profound for
T. brucei
GSK-3 “short” (Tb10.161.3140) than for
T. brucei
GSK-3 “long” (Tb927.7.2420), we focused on
T. brucei
GSK-3 short for further studies.
T. brucei
GSK-3 short with an N-terminal maltose-binding protein fusion was cloned, expressed, and purified in a functional form. The potency of a GSK-3-focused inhibitor library against the recombinant enzyme of
T. brucei
GSK-3 short, as well as bloodstream-form parasites, was evaluated with the aim of determining if compounds that inhibit enzyme activity could also block the parasites' growth and proliferation. Among the compounds active against the cell, there was an excellent correlation between activity inhibiting the
T. brucei
GSK-3 short enzyme and the inhibition of
T. brucei
growth. Thus, there is reasonable genetic and chemical validation of GSK-3 short as a drug target for
T. brucei
. Finally, selective inhibition may be required for therapy targeting the GSK-3 enzyme, and a molecular model of the
T. brucei
GSK-3 short enzyme suggests that compounds that selectively inhibit
T. brucei
GSK-3 short over the human GSK-3 enzymes can be found.
Antimalarial Activity of Phenylthiazolyl-Bearing Hydroxamate-Based Histone Deacetylase Inhibitors
Authors: Dow Geoffrey S. , Chen Yufeng , Andrews Katherine T. , Caridha Diana , Gerena Lucia , Gettayacamin Montip , Johnson Jacob , Li Qigui , Melendez Victor , Obaldia Nicanor , Tran Thanh N. , Kozikowski Alan P. 
Published: July 2008

ABSTRACT

The antimalarial activity and pharmacology of a series of phenylthiazolyl-bearing hydroxamate-based histone deacetylase inhibitors (HDACIs) was evaluated. In in vitro growth inhibition assays approximately 50 analogs were evaluated against four drug resistant strains of
Plasmodium falciparum
. The range of 50% inhibitory concentrations (IC
50
s) was 0.0005 to >1 μM. Five analogs exhibited IC
50
s of <3 nM, and three of these exhibited selectivity indices of >600. The most potent compound, WR301801 (YC-2-88) was shown to cause hyperacetylation of
P. falciparum
histones, which is a marker for HDAC inhibition in eukaryotic cells. The compound also inhibited malarial and mammalian HDAC activity in functional assays at low nanomolar concentrations. WR301801 did not exhibit cures in
P. berghei
-infected mice at oral doses as high as 640 mg/kg/day for 3 days or in
P. falciparum
-infected
Aotus lemurinus lemurinus
monkeys at oral doses of 32 mg/kg/day for 3 days, despite high relative bioavailability. The failure of monotherapy in mice may be due to a short half-life, since the compound was rapidly hydrolyzed to an inactive acid metabolite by loss of its hydroxamate group in vitro (half-life of 11 min in mouse microsomes) and in vivo (half-life in mice of 3.5 h after a single oral dose of 50 mg/kg). However, WR301801 exhibited cures in
P. berghei
-infected mice when combined at doses of 52 mg/kg/day orally with subcurative doses of chloroquine. Next-generation HDACIs with greater metabolic stability than WR301801 may be useful as antimalarials if combined appropriately with conventional antimalarial drugs.
Streptozocin-Induced Diabetic Mouse Model of Urinary Tract Infection
Authors: Rosen David A. , Hung Chia-Suei , Kline Kimberly A. , Hultgren Scott J. 
Published: July 2008

ABSTRACT

Diabetics have a higher incidence of urinary tract infection (UTI), are infected with a broader range of uropathogens, and more commonly develop serious UTI sequelae than nondiabetics. To better study UTI in the diabetic host, we created and characterized a murine model of diabetic UTI using the pancreatic islet β-cell toxin streptozocin in C3H/HeN, C3H/HeJ, and C57BL/6 mouse backgrounds. Intraperitoneal injections of streptozocin were used to initiate diabetes in healthy mouse backgrounds, as defined by consecutive blood glucose levels of >250 mg/dl. UTIs caused by uropathogenic
Escherichia coli
(UTI89),
Klebsiella pneumoniae
(TOP52 1721), and
Enterococcus faecalis
(0852) were studied, and diabetic mice were found to be considerably more susceptible to infection. All three uropathogens produced significantly higher bladder and kidney titers than buffer-treated controls. Uropathogens did not have as large an advantage in the Toll-like receptor 4-defective C3H/HeJ diabetic mouse, arguing that the dramatic increase in colonization seen in C3H/HeN diabetic mice may partially be due to diabetic-induced defects in innate immunity. Competition experiments demonstrated that
E. coli
had a significant advantage over
K. pneumoniae
in the bladders of healthy mice and less of an advantage in diabetic bladders. In the kidneys,
K. pneumoniae
outcompeted
E. coli
in healthy mice but in diabetic mice
E. coli
outcompeted
K. pneumoniae
and caused severe pyelonephritis. Diabetic kidneys contained renal tubules laden with communities of
E. coli
UTI89 bacteria within an extracellular-matrix material. Diabetic mice also had glucosuria, which may enhance bacterial replication in the urinary tract. These data support that this murine diabetic UTI model is consistent with known characteristics of human diabetic UTI and can provide a powerful tool for dissecting this infection in the multifactorial setting of diabetes.
Adaptation of
Francisella tularensis
to the Mammalian Environment Is Governed by Cues Which Can Be Mimicked In Vitro
Authors: Hazlett Karsten R. O. , Caldon Seth D. , McArthur Debbie G. , Cirillo Kerry A. , Kirimanjeswara Girish S. , Magguilli Micheal L. , Malik Meenakshi , Shah Aaloki , Broderick Scott , Golovliov Igor , Metzger Dennis W. , Rajan Krishna , Sellati Timothy J. , Loegering Daniel J. 
Published: July 2008

ABSTRACT

The intracellular bacterium
Francisella tularensis
survives in mammals, arthropods, and freshwater amoeba. It was previously established that the conventional media used for in vitro propagation of this microbe do not yield bacteria that mimic those harvested from infected mammals; whether these in vitro-cultivated bacteria resemble arthropod- or amoeba-adapted
Francisella
is unknown. As a foundation for our goal of identifying
F. tularensis
outer membrane proteins which are expressed during mammalian infection, we first sought to identify in vitro cultivation conditions that induce the bacterium's infection-derived phenotype. We compared
Francisella
LVS grown in brain heart infusion broth (BHI; a standard microbiological medium rarely used in
Francisella
research) to that grown in Mueller-Hinton broth (MHB; the most widely used
F. tularensis
medium, used here as a negative control) and macrophages (a natural host cell, used here as a positive control). BHI- and macrophage-grown
F. tularensis
cells showed similar expression of MglA-dependent and MglA-independent proteins; expression of the MglA-dependent proteins was repressed by the supraphysiological levels of free amino acids present in MHB. We observed that during macrophage infection, protein expression by intracellular bacteria differed from that by extracellular bacteria; BHI-grown bacteria mirrored the latter, while MHB-grown bacteria resembled neither. Naïve macrophages responding to BHI- and macrophage-grown bacteria produced markedly lower levels of proinflammatory mediators than those in cells exposed to MHB-grown bacteria. In contrast to MHB-grown bacteria, BHI-grown bacteria showed minimal delay during intracellular replication. Cumulatively, our findings provide compelling evidence that growth in BHI yields bacteria which recapitulate the phenotype of
Francisella
organisms that have emerged from macrophages.
Anti-Inflammatory Mechanisms of EntericHeligmosomoides polygyrusInfection against Trinitrobenzene Sulfonic Acid-Induced Colitis in a Murine Model
Authors: Sutton Thomas L. , Zhao Aiping , Madden Kathleen B. , Elfrey Justin E. , Tuft Blaine A. , Sullivan Carolyn A. , Urban Joseph F. , Shea-Donohue Terez 
Published: July 2008

ABSTRACTRecent studies showed that enteric helminth infection improved symptoms in patients with inflammatory bowel disease as well as in experimental models of colitis. The aim of this study was to determine the mechanism of the protective effect of helminth infection on colitis-induced changes in immune and epithelial cell function. BALB/c mice received an oral infection ofHeligmosomoides polygyrusthird-stage larvae, were given intrarectal saline or trinitrobenzene sulfonic acid (TNBS) on day 10 postinfection, and were studied 4 days later. Separate groups of mice received intrarectal saline or TNBS on day 10 and were studied on day 14. Muscle-free colonic mucosae were mounted in Ussing chambers to measure mucosal permeability and secretion. Expression of cytokines was assessed by quantitative real-time PCR, and mast cells were visualized by immunohistochemistry. TNBS-induced colitis induced mucosal damage, upregulated Th1 cytokines, and depressed secretory responses.Heligmosomoides polygyruselevated Th2 cytokine expression, increased mast cell infiltration and mucosal resistance, and also reduced some secretory responses. PriorH. polygyrusinfection prevented TNBS-induced upregulation of Th1 cytokines and normalized secretory responses to specific agonists. TNBS-induced colitis did not alterH. polygyrus-induced mast cell infiltration or upregulation of Th2 cytokine expression. The results indicate that the protective mechanism of enteric nematode infection against TNBS-induced colitis involves prevention of Th1 cytokine expression and improved colonic function by a mechanism that may involve mast cell-mediated protection of neural control of secretory function. Similar response patterns could account for the clinical improvement seen in inflammatory bowel disease with helminthic therapy.
Performance of raft foundations for high-rise buildings on the Bouldery Clay in Singapore
Authors: Wong I H , Ooi I K , Broms B B 
Published: July 2008

The Bouldery Clay in Singapore consists of sandstone boulders that are embedded in a matrix of very stiff to hard silty and sandy clay. The strength and deformation characteristics of the soil matrix are close to those of a weak rock or a heavily overconsolidated clay. The average value of the second cycle moduli from the pressuremeter tests and the plate load tests is 480 MPa, and the average value of the undrained shear strengh from in situ tests is 1000 kPa. The performance of raft foundations for six high-rise buildings founded on the Bouldery Clay has been vary satisfactory, and the measured maximum and differential settlements are within allowable limits. The average equivalent undrained modulus of elasticity back-calculated from settlement observations is 540 MPa, compared with the average modulus of 480 MPa from in situ tests after unloading and reloading. It is therefore recommended that unloading and reloading of at least two cycles should be carried out for in situ tests so that a more representative modulus of elasticity for the Bouldery Clay and other very stiff or hard soil can be obtained. Key words: raft foundations, Bouldery Clay, Young's modulus, settlement, high-rise buildings.
Loi de comportement thermo-hydromécanique pour les sols non saturés : identification in situ des indices de compression thermique
Authors: Devillers P , Saix C , El Youssoufi M S 
Published: July 2008

This paper deals with thermo-hydromechanical behaviour of nonsaturated soils. The constitutive relationship presented herein allows for the prediction of the settlement or swell of an unsaturated soil under nonisothermal oedometric conditions. Mechanical, hydraulic, and thermal compression indexes are considered for stress, capillary pressure, and temperature variables, respectively. The implementation of the relationship in a prediction scheme requires preliminary characterization of these indexes. The stressstrain and water volume change relationships are first presented from semiempirical point of view for a nonsaturated soil element under nonisothermal conditions. These relationships allow for the expression of a thermo-hydromechanical constitutive law for nonsaturated soils and propose a relationship for the change in the soil water content. The thermal compression indexes are then determined for a clayey silty sand, first using a reverse method and then a direct method. This determination is made from experimental data recorded on a prototype involving heat storage in an aquifer. The values of these thermal compression indexes are finally compared with the laboratory values obtained in a thermal triaxial cell on samples of the same soil. Key words: nonsaturated soils, thermo-hydromechanical, oedometer tests, thermal compression indexes, characterization, reverse method, direct method.[Journal Translation]
The angle of reach as a mobility index for small and large landslides
Authors: Corominas Jordi 
Published: July 2008

The relations between the angle of reach (fahrböschung) and other indexes expressing the mobility of landslides and vertical drop, horizontal reach, and volume of landslide mass have been analyzed by means of simplified plots and regression equations. Results for 204 landslides of all sizes show that whatever the mechanism of motion, all kinds of landslides experience a continuous reduction of the angle of reach with volume increase. This reduction starts from the smallest sizes. Scattering in this relation is mostly due to mechanisms of motion and to both obstacles and topographic constraints on the path. This synthesis indicates that small landslides (less than 0.5 × 106 m3), in relative terms, display excesses of travel distance similar to large landslides. Since most small landslides are not expected to develop any change in the mechanism of progression while moving, the decrease in the reach angle with volume suggests that scale effects should be taken into account. The angle of reach is found to be a proper indicator of the relative mobility of landslides and is not dependent on the height of fall. Key words: mass wasting, landslides, reach angle, runout distance, rock avalanches, shallow landslides.