bluuebunny/crossref_metadata_2025_split huggingface dataset:
Discovery of Potent Small-Molecule Inhibitors of Multidrug-Resistant
Plasmodium falciparum
Using a Novel Miniaturized High-Throughput Luciferase-Based Assay
Authors: Lucumi Edinson , Darling Claire , Jo Hyunil , Napper Andrew D. , Chandramohanadas Rajesh , Fisher Nicholas , Shone Alison E. , Jing Huiyan , Ward Stephen A. , Biagini Giancarlo A. , DeGrado William F. , Diamond Scott L. , Greenbaum Doron C. 
Published: June 2010

ABSTRACT

Malaria is a global health problem that causes significant mortality and morbidity, with more than 1 million deaths per year caused by
Plasmodium falciparum
. Most antimalarial drugs face decreased efficacy due to the emergence of resistant parasites, which necessitates the discovery of new drugs. To identify new antimalarials, we developed an automated 384-well plate screening assay using
P. falciparum
parasites that stably express cytoplasmic firefly luciferase. After initial optimization, we tested two different types of compound libraries: known bioactive collections (Library of Pharmacologically Active Compounds [LOPAC] and the library from the National Institute of Neurological Disorders and Stroke [NINDS]) and a library of uncharacterized compounds (ChemBridge). A total of 12,320 compounds were screened at 5.5 μM. Selecting only compounds that reduced parasite growth by 85% resulted in 33 hits from the combined bioactive collection and 130 hits from the ChemBridge library. Fifteen novel drug-like compounds from the bioactive collection were found to be active against
P. falciparum
. Twelve new chemical scaffolds were found from the ChemBridge hits, the most potent of which was a series based on the 1,4-naphthoquinone scaffold, which is structurally similar to the FDA-approved antimalarial atovaquone. However, in contrast to atovaquone, which acts to inhibit the
bc
1
complex and block the electron transport chain in parasite mitochondria, we have determined that our new 1,4-napthoquinones act in a novel, non-
bc
1
-dependent mechanism and remain potent against atovaquone- and chloroquine-resistant parasites. Ultimately, this study may provide new probes to understand the molecular details of the malaria life cycle and to identify new antimalarials.
Daptomycin-Oxacillin Combinations in Treatment of Experimental Endocarditis Caused by Daptomycin-Nonsusceptible Strains of Methicillin-Resistant
Staphylococcus aureus
with Evolving Oxacillin Susceptibility (the “Seesaw Effect”)
Authors: Yang Soo-Jin , Xiong Yan Q. , Boyle-Vavra Susan , Daum Robert , Jones Tiffanny , Bayer Arnold S. 
Published: June 2010

ABSTRACT

In vivo
development of daptomycin resistance (DAP
r
) among
Staphylococcus aureus
strains, especially methicillin-resistant
S. aureus
(MRSA) strains, in conjunction with clinical treatment failures, has emerged as a major problem. This has raised the question of DAP-based combination regimens to enhance efficacy against such strains. We studied five recent DAP-susceptible (DAP
s
)/DAP
r
clinical MRSA strain pairs obtained from patients who failed DAP monotherapy regimens, as well as one DAP
s
/DAP
r
MRSA strain pair in which the resistant strain was generated by
in vitro
passage in DAP. Of note, we identified a DAP-oxacillin (OX) “seesaw” phenomenon
in vitro
in which development of DAP
r
was accompanied by a concomitant fall in OX resistance, as demonstrated by 3- to 4-fold decreases in the OX MIC, a susceptibility shift by population analyses, and enhanced early killing by OX in time-kill assays. In addition, the combination of DAP and OX exerted modest improvement in
in vitro
bactericidal effects. Using an experimental model of infective endocarditis and two DAP
s
/DAP
r
strain pairs, we demonstrated that (i) OX monotherapy was ineffective at clearing DAP
r
strains from any target tissue in this model (heart valve, kidneys, or spleen) and (ii) DAP-OX combination therapy was highly effective in DAP
r
strain clearances from these organs. The mechanism(s) of the seesaw effect remains to be defined but does not appear to involve excision of the staphylococcal cassette chromosome
mec
(SCC
mec
) that carries
mecA
.
New Fixed-Dose Artesunate-Mefloquine Formulation against Multidrug-Resistant
Plasmodium falciparum
in Adults: a Comparative Phase IIb Safety and Pharmacokinetic Study with Standard-Dose Nonfixed Artesunate plus Mefloquine
Authors: Krudsood S. , Looareesuwan S. , Tangpukdee N. , Wilairatana P. , Phumratanaprapin W. , Leowattana W. , Chalermrut K. , Ramanathan S. , Navaratnam V. , Olliaro P. , Vaillant M. , Kiechel J. R. , Taylor W. R. J. 
Published: June 2010

ABSTRACT

A new fixed-dose artesunate (AS)-mefloquine (MQ) was assessed in adults hospitalized for 28 days with uncomplicated drug-resistant falciparum malaria. The patients (
n
= 25/arm) were treated with (i) two fixed-dose tablets (AS-MQ arm; 100 mg AS-200 mg MQ/tablet) daily for 3 days (days 0, 1, and 2) or (ii) nonfixed AS (AS-plus-MQ arm; 4 mg/kg of body weight/day for 3 days) plus MQ (15 mg/kg on day 1 and 10 mg/kg on day 2), dosed by weight. Clinical laboratory electrocardiogram (ECG), adverse events (AEs), efficacy, and pharmacokinetic parameters were assessed over 28 days. Both regimens were well tolerated. No AEs were drug related. Two serious AEs of malaria-induced hypotension occurring in the AS-MQ arm necessitated rescue treatment. There were no significant changes in hematology, biochemistry, or PR and QRS intervals. For all patients, mean Fridericia-corrected QT intervals were significantly (
P
≤ 0.0027) prolonged on day 3 (407 ms) and day 7 (399 ms) versus day 0 (389 ms), in parallel with significant (
P
≤ 0.0003) falls in heart rates (67 [day 3], 73 [day 7], and 83 [day 0] beats/minute). Fixed-nonfixed formulations were bioequivalent for MQ, but not for AS and dihydroartemisinin (DHA). One AS-MQ patient developed a new infection on day 28; his day 28 plasma MQ concentration was 503.8 ng/ml. Fixed-dose AS-MQ was well tolerated, had pharmacokinetic (PK) profiles broadly similar to those of nonfixed AS plus MQ, and is a suitable replacement.
Evaluation of a DNA Microarray, the Check-Points ESBL/KPC Array, for Rapid Detection of TEM, SHV, and CTX-M Extended-Spectrum β-Lactamases and KPC Carbapenemases
Authors: Naas T. , Cuzon G. , Truong H. , Bernabeu S. , Nordmann P. 
Published: June 2010

ABSTRACT

Extended-spectrum ß-lactamases (ESBLs) and
Klebsiella pneumoniae
carbapenemases (KPC carbepenemases) have rapidly emerged worldwide and require rapid identification. The Check-Points ESBL/KPC array, a new commercial system based on genetic profiling for the direct identification of ESBL producers (SHV, TEM, and CTX-M) and of KPC producers, was evaluated. Well-characterized Gram-negative rods (
Enterobacteriaceae
,
Pseudomonas aeruginosa
,
Acinetobacter baumannii
) expressing various ß-lactamases (KPC-2, SHV, TEM, and CTX-M types) were used as well as wild-type reference strains and isolates harboring ß-lactamase genes not detected by the assay. In addition, phenotypically confirmed ESBL producers isolated in clinical samples over a 3-month period at the Bicetre hospital were analyzed using the Check-Points ESBL/KPC array and by standard PCR. The Check-Points ESBL/KPC array allowed fast detection of all TEM, SHV, and CTX-M ESBL genes and of the KPC-2 gene. The assay allowed easy differentiation between non-ESBL TEM and SHV and their ESBL derivatives. None of the other tested ß-lactamase genes were detected, underlining its high specificity. The technique is suited for
Enterobacteriaceae
but also for
P. aeruginosa
and
A. baumannii
. However, for nonfermenters, especially
P. aeruginosa
, a 1:10 dilution of the total DNA was necessary to detect KPC-2 and SHV-2a genes reliably. The Check-Points ESBL/KPC array is a powerful high-throughput tool for rapid identification of ESBLs and KPC producers in cultures. It provided definitive results within the same working day, allowing rapid implementation of isolation measures and appropriate antibiotic treatment. It showed an interesting potential for routine laboratory testing.
Microbial Growth Inhibition by Alternating Electric Fields in Mice withPseudomonas aeruginosaLung Infection
Authors: Giladi Moshe , Porat Yaara , Blatt Alexandra , Shmueli Esther , Wasserman Yoram , Kirson Eilon D. , Palti Yoram 
Published: June 2010

ABSTRACTHigh-frequency, low-intensity electric fields generated by insulated electrodes have previously been shown to inhibit bacterial growthin vitro. In the present study, we tested the effect of these antimicrobial fields (AMFields) on the development of lung infection caused byPseudomonas aeruginosain mice. We demonstrate that AMFields (10 MHz) significantly inhibit bacterial growthin vivo, both as a stand-alone treatment and in combination with ceftazidime. In addition, we show that peripheral (skin) heating of about 2°C can contribute to bacterial growth inhibition in the lungs of mice. We suggest that the combination of alternating electric fields, together with the heat produced during their application, may serve as a novel antibacterial treatment modality.
Distribution and Phylogeny of Immunoglobulin-Binding Protein G in Shiga Toxin-Producing
Escherichia coli
and Its Association with Adherence Phenotypes
Authors: Merkel Viktor , Ohder Barbara , Bielaszewska Martina , Zhang Wenlan , Fruth Angelika , Menge Christian , Borrmann Erika , Middendorf Barbara , Müthing Johannes , Karch Helge , Mellmann Alexander 
Published: June 2010

ABSTRACT

eibG
in Shiga toxin-producing
Escherichia coli
(STEC) O91 encodes a protein (EibG) which binds human immunoglobulins G and A and contributes to bacterial chain-like adherence to human epithelial cells. We investigated the prevalence of
eibG
among STEC, the phylogeny of
eibG
, and
eibG
allelic variations and their impact on the adherence phenotype.
eibG
was found in 15.0% of 240
eae
-negative STEC strains but in none of 157
eae
-positive STEC strains. The 36
eibG
-positive STEC strains belonged to 14 serotypes and to eight multilocus sequence types (STs), with serotype O91:H14/H
−
and ST33 being the most common. Sequences of the complete
eibG
gene (1,527 bp in size) from
eibG
-positive STEC resulted in 21 different alleles with 88.11% to 100% identity to the previously reported
eibG
sequence; they clustered into three
eibG
subtypes (
eibG
-α,
eibG
-β, and
eibG
-γ). Strains expressing EibG-α and EibG-β displayed a mostly typical chain-like adherence pattern (CLAP), with formation of long chains on both human and bovine intestinal epithelial cells, whereas strains with EibG-γ adhered in short chains, a pattern we termed atypical CLAP. The same adherence phenotypes were displayed by
E. coli
BL21(DE3) clones containing the respective
eibG
-α,
eibG
-β, and
eibG-
γ subtypes. We propose two possible evolutionary scenarios for
eibG
in STEC: a clonal development of
eibG
in strains with the same phylogenetic background or horizontal transfer of
eibG
between phylogenetically unrelated STEC strains.
Sessile serrated adenomas: prevalence of dysplasia and carcinoma in 2139 patients
Authors: Lash Richard H , Genta Robert M , Schuler Christopher M 
Published: June 2010

Background and aimsSessile serrated adenomas (SSAs) are recognised as precursors to microsatellite unstable adenocarcinomas. This study attempts to estimate the progression rate of SSAs based upon the epidemiology of a large cohort as well as identify relationships to other colorectal polyps.MethodsPathological reports generated at Caris Diagnostics from 290 810 colonoscopic specimens on 179 111 patients were analysed using computerised algorithms.ResultsSSAs with or without dysplasia/carcinoma (SSA+/–) were identified in 2416 specimens from 2139 patients (54% women). The distribution of SSA+/– was: right-sided (81.2%); left-sided (11.2%); both right- and left-sided (3.2%); not specified (4.3%). There were 1816 (85%) patients without dysplasia (SSA–), 257 (12%) with low-grade dysplasia (SSA-LD), 45 (2%) with high-grade dysplasia (SSA-HD) and 21 (1%) with adenocarcinoma (SSA-CA). The difference in median age between almost all groups was significant (SSA–=61 years versus SSA-LD=66 years (p<0.001) vs SSA-HD=72 years (p=0.002) vs SSA-CA=76 years (p=0.07, NS)). Women comprised 53% of the SSA– group (968/1816), 57% of the SSA-LD group (147/257), 69% of the SSA-HD group (31/45) and 76% of the SSA-CA group (16/21), being more likely to have high-grade dysplasia (OR 1.94, 95% CI 1.03 to 3.67) and adenocarcinoma (OR 2.80, 95% CI 1.02 to 7.68).Conclusions1.7% of patients with mucosal polyps had SSAs (with and without dysplasia), more commonly in women and primarily in the right colon. Dysplasia or carcinoma was identified in 15% of patients and significantly disproportionately among women. Based on significant age differences between groups, there appears to be a stepwise progression of dysplasia and carcinoma in SSAs over 10 to 15 years, a period two to three times longer than that for conventional adenomas.
Associations between adolescent socioeducational status and use of snus and smoking
Authors: Øverland Simon , Tjora Tore , Hetland Jørn , Aarø Leif Edvard 
Published: June 2010

BackgroundFindings from studies on the association between smoking and socioeconomic status are mixed. While adolescent smoking is reduced in many countries, use of smokeless tobacco seems to increase. Associations between socioeducational status and smoking as well as use of snus (smokeless tobacco), and to what extent these associations had changed significantly from 2004 to 2007 (a period of relatively abrupt changes in tobacco use in Norway), were examined.MethodsData from two national representative cross-sectional studies of Norwegian 16–20 year olds, where participants were asked questions allowing us to construct indicators of socioeducational status, was used. Information was also collected about the adolescents' smoking and use of snus, as well as their intentions with regard to future use of these products.ResultsAdolescents with a lower socioeducational status had much higher odds for smoking compared to those with higher socioeducational status (ORs ranged from 2.9 to 3.8). There was no similar association between socioeducational status and snus use (ORs ranged from 0.6 to 1.2). No support was found for a change in the socioeducational status–smoking/snus use association from 2004 to 2007.ConclusionsAdolescents' socioeducational status was associated with smoking for boys and girls, while there was no similar association with snus use. This may indicate that snus truly deviates from how smoking is distributed across social strata or that snus is at a much earlier stage in the social diffusion process.
Incentive compatibility and dynamics of congestion control
Authors: Godfrey P. Brighten , Schapira Michael , Zohar Aviv , Shenker Scott 
Published: June 2010

his paper studies under what conditions congestion control schemes can be both efficient, so that capacity is not wasted, and incentive compatible, so that each participant can maximize its utility by following the prescribed protocol. We show that both conditions can be achieved if routers run strict priority queueing (SPQ) or weighted fair queueing (WFQ) and end-hosts run any of a family of protocols which we call Probing Increase Educated Decrease (PIED). A natural question is whether incentive compatibility and efficiency are possible while avoiding the per-flow processing of WFQ. We partially address that question in the negative by showing that any policy satisfying a certain "locality" condition cannot guarantee both properties.
Our results also have implication for convergence to some steady-state throughput for the flows. Even when senders transmit at a fixed rate (as in a UDP flow which does not react to congestion), feedback effects among the routers can result in complex dynamics which do not appear in the simple topologies studied in past work.
Qualitative properties of α-weighted scheduling policies
Authors: Shah Devavrat , Tsitsiklis John N. , Zhong Yuan 
Published: June 2010

We consider a switched network, a fairly general constrained queueing network model that has been used successfully to model the detailed packet-level dynamics in communication networks, such as input-queued switches and wireless networks. The main operational issue in this model is that of deciding which queues to serve, subject to certain constraints.
In this paper, we study qualitative performance properties of the well known α-weighted scheduling policies. The stability, in the sense of positive recurrence, of these policies has been well understood. We establish exponential upper bounds on the tail of the steady-state distribution of the backlog.
Along the way, we prove finiteness of the expected steady-state backlog when α<1, a property that was known only for α ≥ 1.
Finally, we analyze the excursions of the maximum backlog over a finite time horizon for α ≥ 1. As a consequence, for α ≥ 1, we establish the full state space collapse property.
A unified modeling framework for distributed resource allocation of general fork and join processing networks
Authors: Zhao Haiquan (Chuck) , Xia Cathy H. , Liu Zhen , Towsley Don 
Published: June 2010

This paper addresses the problem of distributed resource allocation in general fork and join processing networks. The problem is motivated by the complicated processing requirements arising from distributed data intensive computing. In such applications, the underlying data processing software consists of a rich set of semantics that include synchronous and asynchronous data fork and data join. The different types of semantics and processing requirements introduce complex interdependence between various data flows within the network.
We study the distributed resource allocation problem in such systems with the goal of achieving the maximum total utility of output streams. Past research has dealt with networks with specific types of fork/join semantics, but none of them included all four types. We propose a novel modeling framework that can represent all combinations of fork and join semantics, and formulate the resource allocation problem as a convex optimization problem on this model. We propose a shadow-queue based decentralized iterative algorithm to solve the resource allocation problem. We show that the algorithm guarantees optimality and demonstrate through simulation that it can adapt quickly to dynamically changing environments.
Distributed caching over heterogeneous mobile networks
Authors: Ioannidis Stratis , Massoulie Laurent , Chaintreau Augustin 
Published: June 2010

Sharing content over a mobile network through opportunistic contacts has recently received considerable attention.
In proposed scenarios, users store content they download in a local cache and share it with other users they meet, e.g., via Bluetooth or WiFi. The storage capacity of mobile devices is typically limited; therefore, identifying which content a user should store in her cache is a fundamental problem in the operation of any such content distribution system.
In this work, we propose Psephos, a novel mechanism for determining the caching policy of each mobile user. Psephos is fully distributed: users compute their own policies individually, in the absence of a central authority. Moreover, it is designed for a heterogeneous environment, in which demand for content, access to resources, and mobility characteristics may vary across different users. Most importantly, the caching policies computed by our mechanism are optimal: we rigorously show that Psephos maximizes the system's social welfare. Our results are derived formally using techniques from stochastic approximation and convex optimization; to the best of our knowledge, our work is the first to address caching with heterogeneity in a fully distributed manner.
The price of anarchy in parallel queues revisited
Authors: Anselmi Jonatha , Gaujal Bruno 
Published: June 2010

We consider a network of parallel, non-observable queues and analyze the Price of Anarchy (PoA) from the new point of view where the router has the memory of previous dispatching choices. In the regime where the demands grow with the network size, we provide an upper bound on the PoA by means of convex programming. To study the impact of non-Bernoulli routers, we introduce the Price of Forgetting (PoF) and prove that it is bounded from above by two.
Numerical experiments show that the benefit of having memory in the router is independent of the network size and heterogeneity, and monotonically depends on the network load only.
Typically-correct derandomization
Authors: Shaltiel Ronen 
Published: June 2010

A fundamental question in complexity theory is whether every randomized polynomial time algorithm can be simulated by a deterministic polynomial time algorithm (that is, whether BPP=P). A beautiful theory of derandomization was developed in recent years in attempt to solve this problem.
In this article we survey some recent work on relaxed notions of derandomization that allow the deterministic simulation to err on some inputs. We use this opportunity to also provide a brief overview to some results and research directions in "classical derandomization".
Algorithm for Solving a Generalized Mixed Equilibrium Problem with Perturbation in a Banach Space
Authors: Ceng Lu-Chuan , Kum Sangho , Yao Jen-Chih 
Published: June 2010

AbstractLet "Equation missing" be a real Banach space with the dual space "Equation missing". Let "Equation missing" be a proper functional and let "Equation missing" be a bifunction. In this paper, a new concept of "Equation missing"-proximal mapping of "Equation missing" with respect to "Equation missing" is introduced. The existence and Lipschitz continuity of the "Equation missing"-proximal mapping of "Equation missing" with respect to "Equation missing" are proved. By using properties of the "Equation missing"-proximal mapping of "Equation missing" with respect to "Equation missing", a generalized mixed equilibrium problem with perturbation (for short, GMEPP) is introduced and studied in Banach space "Equation missing". An existence theorem of solutions of the GMEPP is established and a new iterative algorithm for computing approximate solutions of the GMEPP is suggested. The strong convergence criteria of the iterative sequence generated by the new algorithm are established in a uniformly smooth Banach space "Equation missing", and the weak convergence criteria of the iterative sequence generated by this new algorithm are also derived in "Equation missing" a Hilbert space.
Oncogenic Partnerships: EWS-FLI1 Protein Interactions Initiate Key Pathways of Ewing's Sarcoma
Authors: Erkizan Hayriye V. , Uversky Vladimir N. , Toretsky Jeffrey A. 
Published: June 2010

AbstractTargeted therapy for cancer, which is specifically directed toward the cancer without any potential for effects outside of controlling the tumor, is a gold standard for treatment. Ewing's sarcoma contains the potential target EWS-FLI1, as a result of a pathognomonic chromosomal translocation. The EWS-FLI1 fusion protein includes the EWS domain, a potent transcriptional activator alongside the highly conserved FLI1 ets DNA-binding domain. Because of the combination of these domains, the EWS-FLI1 fusion protein acts as an aberrant transcription factor whose expression results in cellular transformation. EWS-FLI1 functions by binding to normal cellular protein partners in transcription and splicing, similar to how a virus would corrupt normal cellular machinery for virion production. Therefore, understanding the protein-protein interactions of EWS-FLI1 and the pathways that are regulated by these partnerships will inform both oncogenesis and therapeutics. This review describes the known protein partners and transcriptional targets of EWS-FLI1, while proposing strategies for exploiting these partnerships with targeted therapy. Clin Cancer Res; 16(16); 4077–83. ©2010 AACR.