bluuebunny/crossref_metadata_2025 huggingface dataset:
Multidrug-Resistant Transporter Mdr1p-Mediated Uptake of a Novel Antifungal Compound
Authors: Sun Nuo , Li Dongmei , Fonzi William , Li Xin , Zhang Lixin , Calderone Richard
Published: September 2013

The activity of many anti-infectious drugs has been compromised by the evolution of multidrug-resistant (MDR) pathogens. For life-threatening fungal infections, such as those caused by
Candida albicans
, overexpression of
MDR1
, which encodes an MDR efflux pump of the major facilitator superfamily (MFS), often confers resistance to chemically unrelated substances, including the most commonly used azole antifungals. As the development of new and efficacious antifungals has lagged far behind the growing emergence of resistant strains, it is imperative to develop strategies to overcome multidrug resistance. Previous advances have been mainly to deploy combinational therapy to restore azole susceptibility, which, however, requires coordination of two or more compounds. We observed a unique phenotype in which Mdr1p facilitates the uptake of a specific class of compounds. Among them, we describe a novel antifungal small molecule, bis[1,6-a:5′,6′-g]quinolizinium 8-methyl-salt (BQM) (U.S. patent application no. 61/793,090,2013), that has potent and broad antifungal activity. Notably, BQM exploits the MDR phenotype in
C. albicans
to promote the inhibitory effect. Rather than causing an antagonism of MDR strains, it exhibits a highly potentiated activity against a collection of clinical isolates and lab strains that overexpress
MDR1
. The activity of BQM against
MDR1
-overexpressing isolates is due to its facilitated intracellular accumulation. Microarray comparisons showed an extensive upregulation of
MDR1
as well as polyamine transporter genes in a fluconazole-resistant strain. We then demonstrated that the polyamine transporters augment the accumulation of BQM. Importantly, BQM had greater activity than fluconazole and itraconazole against various fungal pathogens, including MDR
Aspergillus fumigatus
. Thus, our findings offer a paradigm shift to overcome MDR and the promise of improving antifungal treatment, especially in MDR pathogens.
Discovery of Inhibitors of 4′-Phosphopantetheine Adenylyltransferase (PPAT) To Validate PPAT as a Target for Antibacterial Therapy
Authors: de Jonge Boudewijn L. M. , Walkup Grant K. , Lahiri Sushmita D. , Huynh Hoan , Neckermann Georg , Utley Luke , Nash Tory J. , Brock Jesse , San Martin Maryann , Kutschke Amy , Johnstone Michele , Laganas Valerie , Hajec Laurel , Gu Rong-Fang , Ni Haihong , Chen Brendan , Hutchings Kim , Holt Elise , McKinney David , Gao Ning , Livchak Stephania , Thresher Jason
Published: September 2013

Inhibitors of 4′-phosphopantetheine adenylyltransferase (PPAT) were identified through high-throughput screening of the AstraZeneca compound library. One series, cycloalkyl pyrimidines, showed inhibition of PPAT isozymes from several species, with the most potent inhibition of enzymes from Gram-positive species. Mode-of-inhibition studies with
Streptococcus pneumoniae
and
Staphylococcus aureus
PPAT demonstrated representatives of this series to be reversible inhibitors competitive with phosphopantetheine and uncompetitive with ATP, binding to the enzyme-ATP complex. The potency of this series was optimized using structure-based design, and inhibition of cell growth of Gram-positive species was achieved. Mode-of-action studies, using generation of resistant mutants with targeted sequencing as well as constructs that overexpress PPAT, demonstrated that growth suppression was due to inhibition of PPAT. An effect on bacterial burden was demonstrated in mouse lung and thigh infection models, but further optimization of dosing requirements and compound properties is needed before these compounds can be considered for progress into clinical development. These studies validated PPAT as a novel target for antibacterial therapy.
Tools for Characterizing Bacterial Protein Synthesis Inhibitors
Authors: Orelle Cédric , Carlson Skylar , Kaushal Bindiya , Almutairi Mashal M. , Liu Haipeng , Ochabowicz Anna , Quan Selwyn , Pham Van Cuong , Squires Catherine L. , Murphy Brian T. , Mankin Alexander S.
Published: September 2013

Many antibiotics inhibit the growth of sensitive bacteria by interfering with ribosome function. However, discovery of new protein synthesis inhibitors is curbed by the lack of facile techniques capable of readily identifying antibiotic target sites and modes of action. Furthermore, the frequent rediscovery of known antibiotic scaffolds, especially in natural product extracts, is time-consuming and expensive and diverts resources that could be used toward the isolation of novel lead molecules. In order to avoid these pitfalls and improve the process of dereplication of chemically complex extracts, we designed a two-pronged approach for the
ch
aracterization of
i
nhibitors of
p
rotein
s
ynthesis (ChIPS) that is suitable for the rapid identification of the site and mode of action on the bacterial ribosome. First, we engineered antibiotic-hypersensitive
Escherichia coli
strains that contain only one rRNA operon. These strains are used for the rapid isolation of resistance mutants in which rRNA mutations identify the site of the antibiotic action. Second, we show that patterns of drug-induced ribosome stalling on mRNA, monitored by primer extension, can be used to elucidate the mode of antibiotic action. These analyses can be performed within a few days and provide a rapid and efficient approach for identifying the site and mode of action of translation inhibitors targeting the bacterial ribosome. Both techniques were validated using a bacterial strain whose culture extract, composed of unknown metabolites, exhibited protein synthesis inhibitory activity; we were able to rapidly detect the presence of the antibiotic chloramphenicol.
Hollow-Fiber Pharmacodynamic Studies and Mathematical Modeling To Predict the Efficacy of Amoxicillin for Anthrax Postexposure Prophylaxis in Pregnant Women and Children
Authors: Louie Arnold , VanScoy Brian , Liu Weiguo , Kulawy Robert , Drusano G. L.
Published: September 2013

Amoxicillin is considered an option for postexposure prophylaxis of
Bacillus anthracis
in pregnant and postpartum women who are breastfeeding and in children because of the potential toxicities of ciprofloxacin and doxycycline to the fetus and child. The amoxicillin regimen that effectively kills
B. anthracis
and prevents resistance is unknown. Fourteen-day dose range and dose fractionation studies were conducted in
in vitro
pharmacodynamic models to identify the exposure intensity and pharmacodynamic index of amoxicillin that are linked with optimized killing of
B. anthracis
and resistance prevention. Studies with dicloxacillin, a drug resistant to
B. anthracis
beta-lactamase, evaluated the role of beta-lactamase production in the pharmacodynamic indices for
B. anthracis
killing and resistance prevention. Dose fractionation studies showed that trough/MIC and not time above MIC was the index for amoxicillin that was linked to successful outcome through resistance prevention. Failure of amoxicillin regimens was due to inducible or stable high level expression of beta-lactamases. Studies with dicloxacillin demonstrated that a time above MIC of ≥94% was linked with treatment success when
B. anthracis
beta-lactamase activity was negated. Recursive partitioning analysis showed that amoxicillin regimens that produced peak concentrations of <10.99 μg/ml and troughs of >1.75 μg/ml provided a 100% success rate. Other amoxicillin peak and trough values produced success rates of 28 to 67%. For postpartum and pregnant women and children, Monte Carlo simulations predicted success rates for amoxicillin at 1 g every 8 h (q8h) of 53, 33, and 44% (30 mg/kg q8h), respectively. We conclude that amoxicillin is suboptimal for postexposure prophylaxis of
B. anthracis
in pregnant and postpartum women and in children.
Bacillus anthracis Has Two Independent Bottlenecks That Are Dependent on the Portal of Entry in an Intranasal Model of Inhalational Infection
Authors: Lowe David E. , Ernst Stephen M. C. , Zito Christine , Ya Jason , Glomski Ian J.
Published: September 2013

Bacillus anthracis
can cause inhalational anthrax. Murine inhalational
B. anthracis
infections have two portals of entry, the nasal mucosa-associated lymphoid tissue (NALT) and the lumen of the lungs. Analysis of the dissemination from these sites is hindered because infections are asynchronous and asymptomatic until the hosts near death. To further understand and compare how
B. anthracis
disseminates from these two different environments, clonal analysis was employed using a library of equally virulent DNA-tagged clones of a luminescent Sterne strain. Luminescence was used to determine the origin of the infection and monitor the dissemination
in vivo
. The number of clones and their proportions in the portals of entry, lymph nodes draining the portals, and kidneys were analyzed. Clonal analysis indicated a bottleneck for both portals of entry, yet the extent and location of the reduction in represented clones differed between the routes. In NALT-based infections, all clones were found to germinate in the NALT, but they underwent a bottleneck as the infection spread to the cervical lymph node. However, lung-based infections underwent a bottleneck in a focal region of growth within the lung lumen and did not need to spread through the mediastinal lymph nodes to cause a systemic infection. Further, the average number of clones found in the kidney and the rate at which genetic drift was affecting the disseminated populations were significantly higher in lung-based infections. Collectively, the data suggested that differences in the host environment alter dissemination of
B. anthracis
depending on the site of initial colonization and growth.
FimY Does Not Interfere with FimZ-FimW Interaction during Type 1 Fimbria Production by Salmonella enterica Serovar Typhimurium
Authors: Zeiner Sarah A. , Dwyer Brett E. , Clegg Steven
Published: September 2013

The production of type 1 fimbriae in
Salmonella enterica
serovar Typhimurium is controlled, in part, by three proteins, FimZ, FimY, and FimW. Amino acid sequence analysis indicates that FimZ belongs to the family of bacterial response regulators of two-component systems. In these studies, we have demonstrated that introducing a mutation mimicking phosphorylation of FimZ is necessary for activation of its target gene,
fimA
. In addition, the interaction of FimZ with FimW, a repressor of
fimA
expression, occurs only when FimZ is phosphorylated. Consequently, the negative regulatory effect of FimW is most likely due to downmodulation of the active FimZ protein. FimY does not appear to function as a response regulator, and its activity can be lost by mimicking the phosphorylation of FimY. Overproduction of FimY cannot alleviate the nonfimbriate phenotype in a FimZ mutant, whereas high levels of FimZ can overcome the nonfimbriate phenotype of a FimY mutant. It appears that FimY acts upstream of FimZ to activate
fimA
expression.
Global Transcriptome Analysis of Staphylococcus aureus Biofilms in Response to Innate Immune Cells
Authors: Scherr Tyler D. , Roux Christelle M. , Hanke Mark L. , Angle Amanda , Dunman Paul M. , Kielian Tammy
Published: September 2013

The potent phagocytic and microbicidal activities of neutrophils and macrophages are among the first lines of defense against bacterial infections. Yet
Staphylococcus aureus
is often resistant to innate immune defense mechanisms, especially when organized as a biofilm. To investigate how
S. aureus
biofilms respond to macrophages and neutrophils, gene expression patterns were profiled using Affymetrix microarrays. The addition of macrophages to
S. aureus
static biofilms led to a global suppression of the biofilm transcriptome with a wide variety of genes downregulated. Notably, genes involved in metabolism, cell wall synthesis/structure, and transcription/translation/replication were among the most highly downregulated, which was most dramatic at 1 h compared to 24 h following macrophage addition to biofilms. Unexpectedly, few genes were enhanced in biofilms after macrophage challenge. Unlike coculture with macrophages, coculture of
S. aureus
static biofilms with neutrophils did not greatly influence the biofilm transcriptome. Collectively, these experiments demonstrate that
S. aureus
biofilms differentially modify their gene expression patterns depending on the leukocyte subset encountered.
Periodontal Treatment Downregulates Protease-Activated Receptor 2 in Human Gingival Crevicular Fluid Cells
Authors: Euzebio Alves Vanessa Tubero , Bueno da Silva Henrique Aparecido , de França Bruno Nunes , Eichler Rosangela Santos , Saraiva Luciana , de Carvalho Maria Helena Catelli , Holzhausen Marinella
Published: September 2013

Protease-activated receptor 2 (PAR2) is implicated in the pathogenesis of chronic inflammatory diseases, including periodontitis; it can be activated by gingipain and produced by
Porphyromonas gingivalis
and by neutrophil protease 3 (P3). PAR2 activation plays a relevant role in inflammatory processes by inducing the release of important inflammatory mediators associated with periodontal breakdown. The effects of periodontal treatment on PAR2 expression and its association with levels of proinflammatory mediators and activating proteases were investigated in chronic periodontitis patients. Positive staining for PAR2 was observed in gingival crevicular fluid cells and was reflective of tissue destruction. Overexpression of PAR2 was positively associated with inflammatory clinical parameters and with the levels of interleukin-6 (IL-6), IL-8, tumor necrosis factor alpha, matrix metalloprotease 2 (MMP-2), MMP-8, hepatocyte growth factor, and vascular endothelial growth factor. Elevated levels of gingipain and P3 and decreased levels of dentilisin and the protease inhibitors secretory leukocyte protease inhibitor and elafin were also associated with PAR2 overexpression. Healthy periodontal sites from individuals with chronic periodontitis showed diminished expression of PAR2 mRNA and the PAR2 protein (
P
< 0.05). Furthermore, periodontal treatment resulted in decreased PAR2 expression and correlated with decreased expression of inflammatory mediators and activating proteases. We concluded that periodontal treatment resulted in decreased levels of proteases and that proinflammatory mediators are associated with decreased PAR2 expression, suggesting that PAR2 expression is influenced by the presence of periodontal infection and is not a constitutive characteristic favoring periodontal inflammation.
Prenatal diagnosis of i(18q) and dup(18q) cases by quantitative fluorescent PCR
Authors: Castro-Volio Isabel , Ortíz-Morales Fernando , Valle-Bourrouet Luisa , Malespín-Bendaña Wendy
Published: September 2013

Particular sonographic fetal malformations are common in chromosome 18 aberrations, requiring invasive prenatal tests to confirm the diagnosis. Karyotyping is the gold standard assay in these cases, although it is a high complexity, expensive and approximately 2 weeks turnaround time test. On the contrary, quantitative fluorescent PCR is considered an accurate, simple, low cost and rapid assay, particularly useful for the diagnosis of aneuploidies of chromosomes 13, 18 and 21 and for the detection of maternal cell contamination of the sample. Clinical presentation of two cases of rare chromosome 18 defects, diagnosed using both techniques. One case was an isochromosome and the other was a partial duplication. Quantitative fluorescent PCR was an invaluable tool for the cytogenetics laboratory
Acute urinary retention in an adolescent girl and important learning points
Authors: Christodoulidou Michelle , Kaba Rahim , Oates Jeremy , Wemyss-Holden Guy David
Published: September 2013

We presented a case of a 13-year-old girl who attended the emergency department with acute urinary retention and 1400 mL residual urine after catheterisation. She had no significant medical history, neurological examination was normal and she had not reached menarche. She was found to have a haematocolpos on ultrasound scan which was compressing the urinary bladder. Examination under anaesthesia confirmed an imperforate hymen and therefore an incision was performed and the haematocolpos drained. She managed to pass urine normally the day following her procedure. In this article, we emphasise on the differential diagnosis in this case and the learning points derived from it.
Dystypia in acute stroke not attributable to aphasia or neglect
Authors: Cook Fabian Alexander Blyth , Makin Stephen D J , Wardlaw Joanna , Dennis Martin S
Published: September 2013

A 68-year-old right-handed man had a sudden onset of impaired typing ability due to an ischaemic stroke that recovered over 2 months. The typing impairment was grossly out of proportion to his transient handwriting disturbance. Diffusion MRI showed a recent acute left temporoparietal infarct. There was no evidence of aphasia, alexia, agraphia, visuospatial inattention, sensory loss, neglect or poor coordination that could account for his isolated typing impairment. This example of a stroke that disproportionately affected typing more than handwriting abilities has practical implications for what deficits to look for in patients with stroke when assessing their fitness for work and rehabilitation requirements.
A patient with Loeys-Dietz syndrome treated with chemoradiotherapy for an oropharyngeal carcinoma
Authors: Chan Andrew K , Teoh Daren , Matthews Paul , Fresco Lydia
Published: September 2013

We present the first published case of a patient with Loeys-Dietz syndrome (LDS) who was treated with radical chemoradiotherapy for an oropharyngeal carcinoma. In view of this newly recognised connective tissue disease, the uncertainty of severe toxicity from chemoradiotherapy to treat a potentially curative cancer posed a management challenge. The patient was treated with chemoradiotherapy and remains well with no evidence of recurrence at 3 years. Furthermore, we have observed minimal late effects secondary to chemoradiotherapy at 3 years following the completion of treatment suggesting that the underlying pathogenesis of LDS may provide an interesting human model to further elucidate the complex interactions of transforming growth factor β1 (TGF-β1) and tissue fibrosis secondary to chemoradiotherapy. A review of LDS as well as the association of TGF-β1 expression and tissue fibrosis is presented.
Influence of midsole hardness of standard cushioned shoes on running-related injury risk
Authors: Theisen Daniel , Malisoux Laurent , Genin Joakim , Delattre Nicolas , Seil Romain , Urhausen Axel
Published: September 2013

Background

In this double-blind randomised controlled trial, we tested if leisure-time runners using shoes with less compliant midsoles have a higher running-related injury (RRI) risk.

Method

We provided 247 runners with standard running shoes having either a soft study shoes (soft-SS) or a hard study shoes (hard-SS) midsole and followed them prospectively for 5 months regarding RRI. All information about sports practice and injuries was uploaded on a dedicated internet platform and checked for consistency and completeness. RRI was defined as any first-time pain sustained during or as a result of running practice and impeding normal running activity for at least 1 day. Cox proportional hazards regressions were used to identify RRI risk factors.

Result

The type of study shoes used for running was not associated with RRIs (HR=0.92; 95% CI 0.57 to 1.48). The hard-SS had a 15% greater overall stiffness in the heel region. The two study groups were similar regarding personal and sports participation characteristics, except for years of running experience, which was higher (p<0.05) in the hard-SS group. Global RRI incidence was 12.1 RRI/1000 h of running. No between-group differences were found regarding injury location, type, severity or category. Nevertheless, the adjusted regression model revealed positive associations with RRI risk for body mass index (HR=1.126; 95% CI 1.033 to 1.227), previous injury (HR=1.735; 95% CI 1.037 to 2.902) and mean session intensity (HR=1.396; 95% CI 1.040 to 1.874). Protective factors were previous regular running activity (HR=0.422; 95% CI 0.228 to 0.779) and weekly volume of other sports activities (HR=0.702; 95% CI 0.561 to 0.879).

Conclusions

Midsole hardness of modern cushioned running shoes does not seem to influence RRI risk.
Internet-based hearing screening using speech-in-noise: validation and comparisons of self-reported hearing problems, quality of life and phonological representation
Authors: Molander Peter , Nordqvist Peter , Öberg Marie , Lunner Thomas , Lyxell Björn , Andersson Gerhard
Published: September 2013

Objectives

For the last decade a host of different projects have been launched to allow persons who are concerned about their hearing status to quickly and at a low cost test their hearing ability. Most often, this is carried out without collecting complementary information that could be correlated with hearing impairment. In this two-part study we first, present the development and validation of a novel Internet-based hearing test, and second, report on the associations between this test and phonological representation, quality of life and self-reported hearing difficulties.

Design

Cross-sectional study.

Setting

An opportunity sample of participants was recruited at the Stockholm central station for the first study. All parts of the second study were conducted via the Internet, with testing and self-report forms adapted for online use.

Participants

The first part of the study was carried out in direct contact with the participants, and participants from the second study were recruited by means of advertisements in newspapers and on webpages. The only exclusion criterion was that participants had to be over 18 years old. Most participants were between 60 and 69 years old. There were almost an equal number of men and women (total n=316).

Outcome measures

48 participants failed the Internet-based hearing screening test. The group failing the test reported more problems on the Amsterdam Inventory of Auditory Disability. In addition, they were found to have diminished phonological representational skills. However, no difference in quality of life was found.

Conclusions

Almost one in five participants was in need of contacting their local hearing clinic. This group had more complaints regarding tinnitus and hyperacusis, rated their own hearing as worse than those who passed, and had a poorer capability of generating accurate phonological representations. This study suggests that it is feasible to screen for hearing status online, and obtain valid data.
Evaluation of the HER2 amplification status in oesophageal adenocarcinoma by conventional and automated FISH: a tissue microarray study
Authors: Prins M J D , Ruurda J P , van Diest P J , van Hillegersberg R , ten Kate F J W
Published: September 2013

Introduction

The manual fluorescence in situ hybridisation (FISH) Human Epidermal Growth Factor Receptor 2 (HER2)/CEP17 testing method is frequently used, however, it is time consuming and liable to subjectivity. Automation of FISH might increase the throughput and accuracy.

Aim

To evaluate the agreement between automated and conventional FISH with regard to a reference test silver-enhanced in situ hybridization (SISH) for HER2 amplification, as well as its prognostic significance.

Material and methods

154 oesophageal adenocarcinomas were included in a tissue microarray. HER2/CEP17 gene amplification was assessed by automated FISH and was compared with conventional HER2/CEP17 testing methods.

Results

46.8% of patients showed HER2 amplified tumours by automated FISH (ratio ≥1.8) compared with 18.1% by conventional FISH. A high automated HER2/CEP17 ratio (≥1.8) was significantly associated with worse survival (HR 1.731; 95% CI 1.075 to 2.786; p=0.024). However, agreement between automated and conventional FISH was only 72.2% and 71.4% between automated FISH and SISH, compared with 94.6% for conventional FISH/SISH. Therefore, thresholds for HER2/CEP17 amplification were sequentially raised from HER2/CEP17 ratio 1.8 till 5.0. A HER2/CEP17 ratio threshold of ≥3.6 had similar prognostic significance as conventional FISH (HR 1.880; 95% CI 1.060 to 3.332; p=0.031 vs HR 1.828; 95% CI 1.102 to 3.033; p=0.020), yielded comparable amplification rates as conventional FISH (14.3% vs 18.1%) and comparable agreement to SISH/Immunohistochemistry (IHC).

Conclusions

Automation of HER2 FISH analysis in oesophageal cancer has not been performed before. Automated HER2 is feasible, but it seems that the HER2/CEP17 threshold should be adjusted to ≥3.6 to arrive at best comparability with other methods and prognostic value.
Paget's disease of bone: clinical review and update
Authors: Bolland Mark J , Cundy Tim
Published: September 2013

Paget's disease (PD) is a focal disorder of bone remodelling that occurs commonly in older people. In this article, we review clinical aspects of PD with an emphasis on recent findings. The epidemiology of PD appears to be changing rapidly, with several groups in different parts of the world reporting a marked reduction in the prevalence and incidence of PD, as well as in the severity of disease seen by clinicians. These findings seem most likely to be caused by changes in exposure to unknown environmental factors that have a role in the development of PD. However, genetic factors are also important. Mutations inSQSTM1occur in 25–50% of familial PD. Genotype–phenotype relationships are present, as PD develops at an earlier age and is more extensive and severe in those withSQSTM1mutations, and these findings are more pronounced in those with truncating mutations. However, the prevalence of PD in adults withSQSTM1mutations is uncertain, and it is not known how such mutations might cause PD. Ultimately, if the cause of PD is determined, it seems likely that it will include both genetic and environmental factors. Lastly, clinical trials have shown that potent bisphosphonates are highly effective treatments for active PD, and reduce pain, improve quality of life, normalise bone turnover and heal lytic lesions on radiographs. They can also induce sustained remission that persists for many years.
A study of α5 chain of collagen IV, caldesmon, placental alkaline phosphatase and smoothelin as immunohistochemical markers of gastrointestinal smooth muscle neoplasms
Authors: Wong Newton ACS , Wingate Jenny , Colling Richard
Published: September 2013

Aims

The histological distinction between gastrointestinal smooth muscle neoplasms (SMNs) and their differential diagnoses, especially gastrointestinal stromal tumours (GISTs), has important clinical management implications. This study aimed to investigate preliminary data suggesting that loss of the α5 chain of collagen IV (α5(IV)), placental acid phosphatase (PLAP) expression and smoothelin expression can be used diagnostically as markers of gastrointestinal SMNs. To aid this investigation, these potential markers were directly compared against caldesmon.

Methods

31 SMNs and 111 potential differential diagnoses (16 different neoplasm types) were immunostained for caldesmon, PLAP and smoothelin.

Results

A pilot study indicated that loss of α5(IV) positivity was neither a specific nor sensitive marker of SMN. Caldesmon, PLAP and smoothelin were expressed by all 31 SMNs though leiomyosarcomas showed some loss of staining proportion and/or intensity. Caldesmon positivity was commonly shown by GISTs, glomus tumours and angiomyolipomas. Cytoplasmic smoothelin positivity was commonly shown by glomus tumours and angiomyolipomas, whereas PLAP positivity was shown by one desmoplastic small round cell tumour studied and only infrequently shown by angiomyolipomas. Nuclear smoothelin positivity was seen among four leiomyosarcomas but also a wide range of non-SMNs.

Conclusions

α5(IV) immunohistochemistry with the A7 antibody is not a diagnostically useful marker of gastrointestinal SMNs. Both PLAP and smoothelin (cytoplasmic expression only) are as sensitive as but are more specific than caldesmon as such a marker. Further, PLAP and smoothelin immunostainings are technically reliable and can be reproducibly assessed.
NONPARAMETRIC BOOTSTRAP INTERVAL ESTIMATION OF SOFTWARE RELIABILITY AND ITS APPLICATION TO AN OPTIMAL RELEASE PROBLEM BASED ON A DISCRETIZED MODEL
Authors: INOUE SHINJI , YAMADA SHIGERU , MATSUNO HIRONORI
Published: September 2013

We discuss a simulation-based interval estimation method of software reliability and cost-optimal software release time based on a nonparametric bootstrap method via a discretized software reliability growth model. In general, it is very difficult to derive probability distributions of model parameters, software reliability assessment measures, and optimal software release time analytically even if we assume an asymptotic theory assuming a large number of samples. The bootstrap method overcomes the problem above by obtaining the probability distributions of the parameter based on the simulation-based approach. This paper includes numerical examples for confirming that our bootstrap approach yields simulation-based probability distributions of model parameters, software reliability assessment measures, and cost-optimal software release time from actual software fault-count data.
Meiobenthos in marine coastal sediments
Authors: Urban-Malinga Barbara
Published: September 2013

The term meiobenthos refers to a group of invertebrate organisms that are intermediate in size between macro- and microfauna, and inhabit all sediment types in all marine environments and in all climatic zones. They may occur at enormously high densities of millions of individuals per square metre; this means that 10 cm
3
of sediment in any given habitat may contain thousands of these organisms. Although meiobenthos in some extreme arctic habitats is uncommonly poor, the abundance and composition of the polar or subpolar meiobenthic assemblages are not essentially different from those found in boreal–tropical locations at corresponding sediments and depths.
Hybrid type legalization for a sparse SIMD instruction set
Authors: Asher Yosi Ben , Rotem Nadav
Published: September 2013

SIMD vector units implement only a subset of the operations used by vectorizing compilers, and there are multiple conflicting techniques to legalize arbitrary vector types into register-sized data types. Traditionally, type legalization is performed using a set of predefined rules, regardless of the operations used in the program. This method is not suitable to sparse SIMD instruction sets and often prevents the vectorization of programs. In this work we introduce a new technique for type legalization, namely vector element promotion, as well as a hybrid method for combining multiple techniques of type legalization. Our hybrid type legalization method makes decisions based on the knowledge of the available instruction set as well as the operations used in the program. Our experimental results demonstrate that program-dependent hybrid type legalization improves the execution time of vector programs, outperforms the existing legalization method, and allows the vectorization of workloads which were not vectorized before.
ASSURE
Authors: Sidiroglou Stelios , Laadan Oren , Perez Carlos , Viennot Nicolas , Nieh Jason , Keromytis Angelos D.
Published: September 2013

Software failures in server applications are a significant problem for preserving system availability. We present ASSURE, a system that introduces rescue points that recover software from unknown faults while maintaining both system integrity and availability, by mimicking system behavior under known error conditions. Rescue points are locations in existing application code for handling a given set of programmer-anticipated failures, which are automatically repurposed and tested for safely enabling fault recovery from a larger class of (unanticipated) faults. When a fault occurs at an arbitrary location in the program, ASSURE restores execution to an appropriate rescue point and induces the program to recover execution by virtualizing the program's existing error-handling facilities. Rescue points are identified using fuzzing, implemented using a fast coordinated checkpoint-restart mechanism that handles multi-process and multi-threaded applications, and, after testing, are injected into production code using binary patching. We have implemented an ASSURE Linux prototype that operates without application source code and without base operating system kernel changes. Our experimental results on a set of real-world server applications and bugs show that ASSURE enabled recovery for all of the bugs tested with fast recovery times, has modest performance overhead, and provides automatic self-healing orders of magnitude faster than current human-driven patch deployment methods.
Capo
Authors: Montesinos Pablo , Hicks Matthew , King Samuel T. , Torrellas Josep
Published: September 2013

While deterministic replay of parallel programs is a powerful technique, current proposals have shortcomings. Specifically, software-based replay systems have high overheads on multiprocessors, while hardware-based proposals focus only on basic hardware-level mechanisms, ignoring the overall replay system. To be practical, hardware-based replay systems need to support an environment with multiple parallel jobs running concurrently -- some being recorded, others being replayed and even others running without recording or replay. Moreover, they need to manage limited-size log buffers.

This paper addresses these shortcomings by introducing, for the first time, a set of abstractions and a software-hardware interface for practical hardware-assisted replay of multiprocessor systems. The approach, called
Capo
, introduces the novel abstraction of the
Replay Sphere
to separate the responsibilities of the hardware and software components of the replay system. In this paper, we also design and build
CapoOne
, a prototype of a deterministic multiprocessor replay system that implements Capo using Linux and simulated DeLorean hardware. Our evaluation of 4-processor executions shows that
CapoOne
largely records with the efficiency of hardware-based schemes and the flexibility of software-based schemes.
DMP
Authors: Devietti Joseph , Lucia Brandon , Ceze Luis , Oskin Mark
Published: September 2013

Current shared memory multicore and multiprocessor systems are nondeterministic. Each time these systems execute a multithreaded application, even if supplied with the same input, they can produce a different output. This frustrates debugging and limits the ability to properly test multithreaded code, becoming a major stumbling block to the much-needed widespread adoption of parallel programming.

In this paper we make the case for fully deterministic shared memory multiprocessing (DMP). The behavior of an arbitrary multithreaded program on a DMP system is only a function of its inputs. The core idea is to make inter-thread communication fully deterministic. Previous approaches to coping with nondeterminism in multithreaded programs have focused on replay, a technique useful only for debugging. In contrast, while DMP systems are directly useful for debugging by offering repeatability by default, we argue that parallel programs should execute deterministically in the field as well. This has the potential to make testing more assuring and increase the reliability of deployed multithreaded software. We propose a range of approaches to enforcing determinism and discuss their implementation trade-offs. We show that determinism can be provided with little performance cost using our architecture proposals on future hardware, and that software-only approaches can be utilized on existing systems.
Maximum benefit from a minimal HTM
Authors: Hofmann Owen S. , Rossbach Christopher J. , Witchel Emmett
Published: September 2013

A minimal, bounded hardware transactional memory implementation significantly improves synchronization performance when used in an operating system kernel. We add HTM to Linux 2.4, a kernel with a simple, coarse-grained synchronization structure. The transactional Linux 2.4 kernel can improve performance of user programs by as much as 40% over the non-transactional 2.4 kernel. It closes 68% of the performance gap with the Linux 2.6 kernel, which has had significant engineering effort applied to improve scalability.

We then extend our minimal HTM to a fast, unbounded transactional memory with a novel technique for coordinating hardware transactions and software synchronization. Overflowed transactions run in software, with only a minimal coupling between hardware and software systems. There is no performance penalty for overflow rates of less than 1%. In one instance, at 16 processors and an overflow rate of 4%, performance degrades from an ideal 4.3x to 3.6x.
Mixed-mode multicore reliability
Authors: Wells Philip M. , Chakraborty Koushik , Sohi Gurindar S.
Published: September 2013

Future processors are expected to observe increasing rates of hardware faults. Using Dual-Modular Redundancy (DMR), two cores of a multicore can be loosely coupled to redundantly execute a single software thread, providing very high coverage from many difference sources of faults. This reliability, however, comes at a high price in terms of per-thread IPC and overall system throughput.

We make the observation that a user may want to run both applications requiring high reliability, such as financial software, and more fault tolerant applications requiring high performance, such as media or web software, on the same machine at the same time. Yet a traditional DMR system must fully operate in redundant mode whenever any application requires high reliability.

This paper proposes a Mixed-Mode Multicore (MMM), which enables most applications, including the system software, to run with high reliability in DMR mode, while applications that need high performance can avoid the penalty of DMR. Though conceptually simple, two key challenges arise: 1) care must be taken to protect reliable applications from any faults occurring to applications running in high performance mode, and 2) the desire to execute additional independent software threads for a performance application complicates the scheduling of computation to cores. After solving these issues, an MMM is shown to improve overall system performance, compared to a traditional DMR system, by approximately 2X when one reliable and one performance application are concurrently executing.
ISOLATOR
Authors: Rajamani Sriram , Ramalingam G. , Ranganath Venkatesh Prasad , Vaswani Kapil
Published: September 2013

In this paper, we focus on concurrent programs that use locks to achieve isolation of data accessed by critical sections of code. We present ISOLATOR, an algorithm that guarantees isolation for well-behaved threads of a program that obey a locking discipline even in the presence of ill-behaved threads that disobey the locking discipline. ISOLATOR uses code instrumentation, data replication, and virtual memory protection to detect isolation violations and delays ill-behaved threads to ensure isolation. Our instrumentation scheme requires access only to the code of well-behaved threads. We have evaluated ISOLATOR on several benchmark programs and found that ISOLATOR can ensure isolation with reasonable runtime overheads. In addition, we present three general desiderata - safety, isolation, and permissiveness - for any scheme that attempts to ensure isolation, and formally prove that ISOLATOR satisfies all of these desiderata.
Commutativity analysis for software parallelization
Authors: Aleen Farhana , Clark Nathan
Published: September 2013

Extracting performance from many-core architectures requires software engineers to create multi-threaded applications, which significantly complicates the already daunting task of software development. One solution to this problem is automatic compile-time parallelization, which can ease the burden on software developers in many situations. Clearly, automatic parallelization in its present form is not suitable for many application domains and new compiler analyses are needed address its shortcomings.

In this paper, we present one such analysis: a new approach for detecting commutative functions. Commutative functions are sections of code that can be executed in any order without affecting the outcome of the application, e.g., inserting elements into a set. Previous research on this topic had one significant limitation, in that the results of a commutative functions must produce identical memory layouts. This prevented previous techniques from detecting functions like malloc, which may return different pointers depending on the order in which it is called, but these differing results do not affect the overall output of the application. Our new commutativity analysis correctly identify these situations to better facilitate automatic parallelization. We demonstrate that this analysis can automatically extract significant amounts of parallelism from many applications, and where it is ineffective it can provide software developers a useful list of functions that may be commutative provided semantic program changes that are not automatable.
Accelerating critical section execution with asymmetric multi-core architectures
Authors: Suleman M. Aater , Mutlu Onur , Qureshi Moinuddin K. , Patt Yale N.
Published: September 2013

To improve the performance of a single application on Chip Multiprocessors (CMPs), the application must be split into threads which execute concurrently on multiple cores. In multi-threaded applications, critical sections are used to ensure that only one thread accesses shared data at any given time. Critical sections can serialize the execution of threads, which significantly reduces performance and scalability.

This paper proposes Accelerated Critical Sections (ACS), a technique that leverages the high-performance core(s) of an Asymmetric Chip Multiprocessor (ACMP) to accelerate the execution of critical sections. In ACS, selected critical sections are executed by a high-performance core, which can execute the critical section faster than the other, smaller cores. As a result, ACS reduces serialization: it lowers the likelihood of threads waiting for a critical section to finish. Our evaluation on a set of 12 critical-section-intensive workloads shows that ACS reduces the average execution time by 34% compared to an equal-area 32T-core symmetric CMP and by 23% compared to an equal-area ACMP. Moreover, for 7 out of the 12 workloads, ACS improves scalability by increasing the number of threads at which performance saturates.
Producing wrong data without doing anything obviously wrong!
Authors: Mytkowicz Todd , Diwan Amer , Hauswirth Matthias , Sweeney Peter F.
Published: September 2013

This paper presents a surprising result: changing a seemingly innocuous aspect of an experimental setup can cause a systems researcher to draw wrong conclusions from an experiment. What appears to be an innocuous aspect in the experimental setup may in fact introduce a significant bias in an evaluation. This phenomenon is called measurement bias in the natural and social sciences.

Our results demonstrate that measurement bias is significant and commonplace in computer system evaluation. By significant we mean that measurement bias can lead to a performance analysis that either over-states an effect or even yields an incorrect conclusion. By commonplace we mean that measurement bias occurs in all architectures that we tried (Pentium 4, Core 2, and m5 O3CPU), both compilers that we tried (gcc and Intel's C compiler), and most of the SPEC CPU2006 C programs. Thus, we cannot ignore measurement bias. Nevertheless, in a literature survey of 133 recent papers from ASPLOS, PACT, PLDI, and CGO, we determined that none of the papers with experimental results adequately consider measurement bias.

Inspired by similar problems and their solutions in other sciences, we describe and demonstrate two methods, one for detecting (causal analysis) and one for avoiding (setup randomization) measurement bias.
Dynamic prediction of collection yield for managed runtimes
Authors: Wegiel Michal , Krintz Chandra
Published: September 2013

The growth in complexity of modern systems makes it increasingly difficult to extract high-performance. The software stacks for such systems typically consist of multiple layers and include managed runtime environments (MREs). In this paper, we investigate techniques to improve cooperation between these layers and the hardware to increase the efficacy of automatic memory management in MREs.

General-purpose MREs commonly implement parallel and/or concurrent garbage collection and employ compaction to eliminate heap fragmentation. Moreover, most systems trigger collection based on the amount of heap a program uses. Our analysis shows that in many cases this strategy leads to ineffective collections that are unable to reclaim sufficient space to justify the incurred cost. To avoid such collections, we exploit the observation that dead objects tend to cluster together and form large, never-referenced, regions in the address space that correlate well with virtual pages that have not recently been referenced by the application. We leverage this correlation to design a new, simple and light-weight, yield predictor that estimates the amount of reclaimable space in the heap using hardware page reference bits. Our predictor allows MREs to avoid low-yield collections and thereby improve resource management.

We integrate this predictor into three state-of-the-art parallel compactors, implemented in the HotSpot JVM, that represent distinct canonical heap layouts. Our empirical evaluation, based on standard Java benchmarks and open-source applications, indicates that inexpensive and accurate yield prediction can improve performance significantly.
Role of mitochondrial oxidative stress in hypertension
Authors: Dikalov Sergey I. , Ungvari Zoltan
Published: September 2013

Based on mosaic theory, hypertension is a multifactorial disorder that develops because of genetic, environmental, anatomical, adaptive neural, endocrine, humoral, and hemodynamic factors. It has been recently proposed that oxidative stress may contribute to all of these factors and production of reactive oxygen species (ROS) play an important role in the development of hypertension. Previous studies focusing on the role of vascular NADPH oxidases provided strong support of this concept. Although mitochondria represent one of the most significant sources of cellular ROS generation, the regulation of mitochondrial ROS generation in the cardiovascular system and its pathophysiological role in hypertension are much less understood. In this review, the role of mitochondrial oxidative stress in the pathophysiology of hypertension and cross talk between angiotensin II signaling, pathways involved in mechanotransduction, NADPH oxidases, and mitochondria-derived ROS are considered. The possible benefits of therapeutic strategies that have the potential to attenuate mitochondrial oxidative stress for the prevention/treatment of hypertension are also discussed.