bluuebunny/crossref_metadata_2025 huggingface dataset:
Using practical supergain for passive imaging with noise
Authors: Siderius Martin
Published: December 2011

Recent work has shown that endfire beamforming of ocean noise can be used to produce images of the seabed layering [Siderius et al., J. Acoust. Soc. Am. 120, 1315–1323 (2006)]. This initial noise imaging technique used conventional beamforming and was later extended to adaptive beamforming that is theoretically optimal. However, there can be problems with adaptive methods, which include extreme sensitivity to random errors, the required averaging time, and computational complexity. Here, the concept of supergain is used to show that delay and sum beamforming can produce nearly the same results as the optimal adaptive methods without the drawbacks.
Triggering Actin Comets Versus Membrane Ruffles: Distinctive Effects of Phosphoinositides on Actin Reorganization
Authors: Ueno Tasuku , Falkenburger Björn H. , Pohlmeyer Christopher , Inoue Takanari
Published: December 2011

The ability of phosphoinositides to produce functionally diverse effects may depend on the relative concentrations of different species.
H
2
S-Induced Sulfhydration of the Phosphatase PTP1B and Its Role in the Endoplasmic Reticulum Stress Response
Authors: Krishnan Navasona , Fu Cexiong , Pappin Darryl J. , Tonks Nicholas K.
Published: December 2011

Reversible inactivation by sulfhydration of the protein tyrosine phosphatase PTP1B activates the kinase PERK to promote the ER stress response.
Pharmacokinetics and Pharmacodynamics of TMC207 and Its
N
-Desmethyl Metabolite in a Murine Model of Tuberculosis
Authors: Rouan Marie-Claude , Lounis Nacer , Gevers Tom , Dillen Lieve , Gilissen Ron , Raoof Araz , Andries Koen
Published: December 2011

TMC207 is a first-in-class diarylquinoline with a new mode of action against mycobacteria targeting the ATP synthase. It is metabolized to an active derivative,
N
-desmethyl TMC207, and both compounds are eliminated with long terminal half-lives (50 to 60 h in mice) reflecting slow release from tissues such as lung and spleen.
In vitro
, TMC207 is 5-fold more potent against
Mycobacterium tuberculosis
than
N
-desmethyl TMC207, and the effects of the two compounds are additive. The pharmacokinetic and pharmacodynamic (PK-PD) response was investigated in the murine model of tuberculosis (TB) infection following oral administration of different doses of TMC207 or
N
-desmethyl TMC207 at 5 days per week for 4 weeks starting the day after intravenous infection with
M. tuberculosis
and following administration of different doses of TMC207 at various dosing frequencies for 6 weeks starting 2 weeks after infection. Upon administration of
N
-desmethyl TMC207, maximum plasma concentration (
C
max
), area under the plasma concentration-time curve from time zero to 168 h postdose (AUC
168h
), and minimum plasma concentration (
C
min
) were approximately dose proportional between 8 and 64 mg/kg, and the lung CFU counts were strongly correlated with these pharmacokinetic parameters using an inhibitory sigmoid maximum effect (
E
max
) model. Administration of the highest dose (64 mg/kg) produced a 4.0-log
10
reduction of the bacillary load at an average exposure (average concentration [
C
avg
] or AUC
168h
divided by 168) of 2.7 μg/ml. Upon administration of the highest dose of TMC207 (50 mg/kg) 5 days per week for 4 weeks, the total reduction of the bacillary load was 4.7 log
10
. TMC207 was estimated to contribute to a 1.8-log
10
reduction and its corresponding exposure (
C
avg
) was 0.5 μg/ml. Optimal bactericidal activity with
N
-desmethyl TMC207 was reached at a high exposure compared to that achieved in humans, suggesting a minor contribution of the metabolite to the overall bactericidal activity in TB-infected patients treated with TMC207. Following administration of TMC207 at a total weekly dose of 15, 30, or 60 mg/kg fractionated for either 5 days per week, twice weekly, or once weekly, the bactericidal activity was correlated to the total weekly dose and was not influenced by the frequency of administration. Exposures (AUC
168h
) to TMC207 and
N
-desmethyl TMC207 mirrored this dose response, indicating that the bactericidal activity of TMC207 is concentration dependent and that AUC is the main PK-PD driver on which dose optimization should be based for dosing frequencies up to once weekly. The PK-PD profile supports intermittent administration of TMC207, in agreement with its slow release from tissues.
Impact of Spores on the Comparative Efficacies of Five Antibiotics for Treatment of Bacillus anthracis in an
In Vitro
Hollow Fiber Pharmacodynamic Model
Authors: Louie Arnold , VanScoy Brian D. , Brown David L. , Kulawy Robert W. , Heine Henry S. , Drusano George L.
Published: December 2011

Bacillus anthracis
, the bacterium that causes anthrax, is an agent of bioterrorism. The most effective antimicrobial therapy for
B. anthracis
infections is unknown. An
in vitro
pharmacodynamic model of
B. anthracis
was used to compare the efficacies of simulated clinically prescribed regimens of moxifloxacin, linezolid, and meropenem with the “gold standards,” doxycycline and ciprofloxacin. Treatment outcomes for isogenic spore-forming and non-spore-forming strains of
B. anthracis
were compared. Against spore-forming
B. anthracis
, ciprofloxacin, moxifloxacin, linezolid, and meropenem reduced the
B. anthracis
population by 4 log
10
CFU/ml over 10 days. Doxycycline reduced the population of this
B. anthracis
strain by 5 log
10
CFU/ml (analysis of variance [ANOVA]
P
= 0.01 versus other drugs). Against an isogenic non-spore-forming strain, meropenem killed the vegetative
B. anthracis
the fastest, followed by moxifloxacin and ciprofloxacin and then doxycycline. Linezolid offered the lowest bacterial kill rate. Heat shock studies using the spore-producing
B. anthracis
strain showed that with moxifloxacin, ciprofloxacin, and meropenem therapies the total population was mostly spores, while the population was primarily vegetative bacteria with linezolid and doxycycline therapies. Spores have a profound impact on the rate and extent of killing of
B. anthracis
. Against spore-forming
B. anthracis
, the five antibiotics killed the total (spore and vegetative) bacterial population at similar rates (within 1 log
10
CFU/ml of each other). However, bactericidal antibiotics killed vegetative
B. anthracis
faster than bacteriostatic drugs. Since only vegetative-phase
B. anthracis
produces the toxins that may kill the infected host, the rate and mechanism of killing of an antibiotic may determine its overall
in vivo
efficacy. Further studies are needed to examine this important observation.
Frequentist and Bayesian Pharmacometric-Based Approaches To Facilitate Critically Needed New Antibiotic Development: Overcoming Lies, Damn Lies, and Statistics
Authors: Ambrose Paul G. , Hammel Jeffrey P. , Bhavnani Sujata M. , Rubino Christopher M. , Ellis-Grosse Evelyn J. , Drusano George L.
Published: December 2011

Antimicrobial drug development has greatly diminished due to regulatory uncertainty about the magnitude of the antibiotic treatment effect. Herein we evaluate the utility of pharmacometric-based analyses for determining the magnitude of the treatment effect. Frequentist and Bayesian pharmacometric-based logistic regression analyses were conducted by using data from a phase 3 clinical trial of tigecycline-treated patients with hospital-acquired pneumonia (HAP) to evaluate relationships between the probability of microbiological or clinical success and the free-drug area under the concentration-time curve from time zero to 24 h (AUC
0-24
)/MIC ratio. By using both the frequentist and Bayesian approaches, the magnitude of the treatment effect was determined using three different methods based on the probability of success at free-drug AUC
0-24
/MIC ratios of 0.01 and 25. Differences in point estimates of the treatment effect for microbiological response (method 1) were larger using the frequentist approach than using the Bayesian approach (Bayesian estimate, 0.395; frequentist estimate, 0.637). However, the Bayesian credible intervals were tighter than the frequentist confidence intervals, demonstrating increased certainty with the former approach. The treatment effect determined by taking the difference in the probabilities of success between the upper limit of a 95% interval for the minimal exposure and the lower limit of a 95% interval at the maximal exposure (method 2) was greater for the Bayesian analysis (Bayesian estimate, 0.074; frequentist estimate, 0.004). After utilizing bootstrapping to determine the lower 95% bounds for the treatment effect (method 3), treatment effect estimates were still higher for the Bayesian analysis (Bayesian estimate, 0.301; frequentist estimate, 0.166). These results demonstrate the utility of frequentist and Bayesian pharmacometric-based analyses for the determination of the treatment effect using contemporary trial endpoints. Additionally, as demonstrated by using pharmacokinetic-pharmacodynamic data, the magnitude of the treatment effect for patients with HAP is large.
Antibacterial Activity of Sphingoid Bases and Fatty Acids against Gram-Positive and Gram-Negative Bacteria
Authors: Fischer Carol L. , Drake David R. , Dawson Deborah V. , Blanchette Derek R. , Brogden Kim A. , Wertz Philip W.
Published: December 2011

There is growing evidence that the role of lipids in innate immunity is more important than previously realized. How lipids interact with bacteria to achieve a level of protection, however, is still poorly understood. To begin to address the mechanisms of antibacterial activity, we determined MICs and minimum bactericidal concentrations (MBCs) of lipids common to the skin and oral cavity—the sphingoid basesd-sphingosine, phytosphingosine, and dihydrosphingosine and the fatty acids sapienic acid and lauric acid—against four Gram-negative bacteria and seven Gram-positive bacteria. Exact Kruskal-Wallis tests of these values showed differences among lipid treatments (P< 0.0001) for each bacterial species exceptSerratia marcescensandPseudomonas aeruginosa.d-Sphingosine (MBC range, 0.3 to 19.6 μg/ml), dihydrosphingosine (MBC range, 0.6 to 39.1 μg/ml), and phytosphingosine (MBC range, 3.3 to 62.5 μg/ml) were active against all bacteria exceptS. marcescensandP. aeruginosa(MBC > 500 μg/ml). Sapienic acid (MBC range, 31.3 to 375.0 μg/ml) was active againstStreptococcus sanguinis,Streptococcus mitis, andFusobacterium nucleatumbut not active againstEscherichia coli,Staphylococcus aureus,S. marcescens,P. aeruginosa,Corynebacterium bovis,Corynebacterium striatum, andCorynebacterium jeikeium(MBC > 500 μg/ml). Lauric acid (MBC range, 6.8 to 375.0 μg/ml) was active against all bacteria exceptE. coli,S. marcescens, andP. aeruginosa(MBC > 500 μg/ml). Complete killing was achieved as early as 0.5 h for some lipids but took as long as 24 h for others. Hence, sphingoid bases and fatty acids have different antibacterial activities and may have potential for prophylactic or therapeutic intervention in infection.
Evolution of an Incompatibility Group IncA/C Plasmid Harboring
bla
CMY-16
and
qnrA6
Genes and Its Transfer through Three Clones of Providencia stuartii during a Two-Year Outbreak in a Tunisian Burn Unit
Authors: Arpin C. , Thabet L. , Yassine H. , Messadi A. A. , Boukadida J. , Dubois V. , Coulange-Mayonnove L. , Andre C. , Quentin C.
Published: December 2011

During a 2-year period in 2005 and 2006, 64 multidrug-resistant
Providencia stuartii
isolates, including 58 strains from 58 patients and 6 strains obtained from the same tracheal aspirator, were collected in a burn unit of a Tunisian hospital. They divided into four antibiotypes (ATB1 to ATB4) and three SmaI pulsotypes (PsA to PsC), including 49 strains belonging to clone PsA (48 of ATB1 and 1 of ATB4), 11 strains to clone PsB (7 of ATB2 and 4 of ATB3), and 4 strains to clone PsC (ATB3). All strains, except for the PsA/ATB4 isolate, were highly resistant to broad-spectrum cephalosporins due to the production of the plasmid-mediated CMY-16 β-lactamase. In addition, the 15 strains of ATB2 and ATB3 exhibited decreased quinolone susceptibility associated with QnrA6. Most strains (ATB1 and ATB3) were gentamicin resistant, related to an AAC(6′)-Ib′ enzyme. All these genes were located on a conjugative plasmid belonging to the incompatibility group IncA/C
2
of 195, 175, or 100 kb. Despite differences in size and in number of resistance determinants, they derived from the same plasmid, as demonstrated by similar profiles in plasmid restriction analysis and strictly homologous sequences of

repAIncA/C
2

, unusual antibiotic resistance genes (e.g.,
aphA-6
), and their genetic environments. Further investigation suggested that deletions, acquisition of the IS
CR1
insertion sequence, and integron cassette mobility accounted for these variations. Thus, this outbreak was due to both the spread of three clonal strains and the dissemination of a single IncA/C
2
plasmid which underwent a remarkable evolution during the epidemic period.
Safe and Sustained Vaginal Delivery of Pyrimidinedione HIV-1 Inhibitors from Polyurethane Intravaginal Rings
Authors: Johnson Todd J. , Srinivasan Priya , Albright Theodore H. , Watson-Buckheit Karen , Rabe Lorna , Martin Amy , Pau Chou-Pong , Hendry R. Michael , Otten Ron , McNicholl Janet , Buckheit Robert , Smith James , Kiser Patrick F.
Published: December 2011

The potent antiretroviral pyrimidinediones IQP-0528 (PYD1) and IQP-0532 (PYD2) were formulated in polyurethane intravaginal rings (IVRs) as prophylactic drug delivery systems to prevent the sexual transmission of HIV-1. To aid in the selection of a pyrimidinedione candidate and the optimal loading of the drug in the IVR delivery system, four pyrimidinedione IVR formulations (PYD1 at 0.5 wt% [PYD1
0.5wt%
], PYD1
1wt%
, PYD2
4wt%
, and PYD2
14wt%
) were evaluated in pigtail macaques over 28 days for safety and pyrimidinedione vaginal biodistribution. Kinetic analysis of vaginal proinflammatory cytokines, native microflora, and drug levels suggested that all formulations were safe, but only the high-loaded PYD2
14wt%
IVR demonstrated consistently high pyrimidinedione vaginal fluid and tissue levels over the 28-day study. This formulation delivered drug in excess of 10 μg/ml to vaginal fluid and 1 μg/g to vaginal tissue, a level over 1,000 times the
in vitro
50% effective concentration. The
in vitro
release of PYD1 and PYD2 under nonsink conditions correlated well with
in vivo
release, both in amount and in kinetic profile, and therefore may serve as a more biologically relevant means of evaluating release
in vitro
than typically employed sink conditions. Lastly, the pyrimidinediones in the IVR formulation were chemically stable after 90 days of storage at elevated temperature, and the potent nanomolar-level antiviral activity of both molecules was retained after
in vitro
release. Altogether, these results point to the successful IVR formulation and vaginal biodistribution of the pyrimidinediones and demonstrate the usefulness of the pigtail macaque model in evaluating and screening antiretroviral IVR formulations prior to preclinical and clinical evaluation.
Characterization of Nasal and Blood Culture Isolates of Methicillin-Resistant Staphylococcus aureus from Patients in United States Hospitals
Authors: Tenover Fred C. , Tickler Isabella A. , Goering Richard V. , Kreiswirth Barry N. , Mediavilla José R. , Persing David H. ,   for the MRSA Consortium
Published: December 2011

A total of 299 nares and 194 blood isolates of methicillin-resistant
Staphylococcus aureus
(MRSA), each recovered from a unique patient, were collected from 23 U.S. hospitals from May 2009 to March 2010. All isolates underwent
spa
and staphylococcal cassette chromosome
mec
element (SCC
mec
) typing and antimicrobial susceptibility testing; a subset of 84 isolates was typed by pulsed-field gel electrophoresis (PFGE) using SmaI. Seventy-six
spa
types were observed among the isolates. Overall, for nasal isolates,
spa
type t002-SCC
mec
type II (USA100) was the most common strain type (37% of isolates), while among blood isolates,
spa
type t008-SCC
mec
type IV (USA300) was the most common (39%). However, the proportion of all USA100 and USA300 isolates varied by United States census region. Nasal isolates were more resistant to tobramycin and clindamycin than blood isolates (55.9% and 48.8% of isolates versus 36.6% and 39.7%, respectively; for both,
P
< 0.05). The USA300 isolates were largely resistant to fluoroquinolones. High-level mupirocin resistance was low among all
spa
types (<5%). SCC
mec
types III and VIII, which are rare in the United States, were observed along with several unusual PFGE types, including CMRSA9, EMRSA15, and the PFGE profile associated with sequence type 239 (ST239) isolates. Typing data from this convenience sample suggest that in U.S. hospitalized patients, USA100 isolates of multiple
spa
types, while still common in the nares, have been replaced by USA300 isolates as the predominant MRSA strain type in positive blood cultures.
Phenotypic Modulation of the Virulent Bvg Phase Is Not Required for Pathogenesis and Transmission of Bordetella bronchiseptica in Swine
Authors: Nicholson Tracy L. , Brockmeier Susan L. , Loving Crystal L. , Register Karen B. , Kehrli Marcus E. , Stibitz Scott E. , Shore Sarah M.
Published: December 2011

The majority of virulence gene expression in
Bordetella
is regulated by a two-component sensory transduction system encoded by the
bvg
locus. In response to environmental cues, the BvgAS regulatory system controls expression of a spectrum of phenotypic phases, transitioning between a virulent (Bvg
+
) phase and a nonvirulent (Bvg
−
) phase, a process referred to as phenotypic modulation. We hypothesized that the ability of
Bordetella bronchiseptica
to undergo phenotypic modulation is required at one or more points during the infectious cycle in swine. To investigate the Bvg phase-dependent contribution to pathogenesis of
B. bronchiseptica
in swine, we constructed a series of isogenic mutants in a virulent
B. bronchiseptica
swine isolate and compared each mutant to the wild-type isolate for its ability to colonize and cause disease. We additionally tested whether a BvgAS system capable of modulation is required for direct or indirect transmission. The Bvg
−
phase-locked mutant was never recovered from any respiratory tract site at any time point examined. An intermediate phase-locked mutant (Bvg
i
) was found in numbers lower than the wild type at all respiratory tract sites and time points examined and caused limited to no disease. In contrast, colonization of the respiratory tract and disease caused by the Bvg
+
phase-locked mutant and the wild-type strain were indistinguishable. The Bvg
+
phase-locked mutant transmitted to naïve pigs by both direct and indirect contact with efficiency equal to that of the wild-type isolate. These results indicate that while full activation of the BvgAS regulatory system is required for colonization and severe disease, it is not deleterious to direct and indirect transmission. Overall, our results demonstrate that the Bvg
+
phase is sufficient for respiratory infection and host-to-host transmission of
B. bronchiseptica
in swine.
Experimental Cerebral Malaria Develops Independently of Caspase Recruitment Domain-Containing Protein 9 Signaling
Authors: Hafalla Julius Clemence R. , Burgold Jan , Dorhoi Anca , Gross Olaf , Ruland Jürgen , Kaufmann Stefan H. E. , Matuschewski Kai
Published: December 2011

The outcome of infection depends on multiple layers of immune regulation, with innate immunity playing a decisive role in shaping protection or pathogenic sequelae of acquired immunity. The contribution of pattern recognition receptors and adaptor molecules in immunity to malaria remains poorly understood. Here, we interrogate the role of the caspase recruitment domain-containing protein 9 (CARD9) signaling pathway in the development of experimental cerebral malaria (ECM) using the murine
Plasmodium berghei
ANKA infection model.
CARD9
expression was upregulated in the brains of infected wild-type (WT) mice, suggesting a potential role for this pathway in ECM pathogenesis. However,
P. berghei
ANKA-infected
Card9
−/−
mice succumbed to neurological signs and presented with disrupted blood-brain barriers similar to WT mice. Furthermore, consistent with the immunological features associated with ECM in WT mice,
Card9
−/−
mice revealed (i) elevated levels of proinflammatory responses, (ii) high frequencies of activated T cells, and (iii) CD8
+
T cell arrest in the cerebral microvasculature. We conclude that ECM develops independently of the CARD9 signaling pathway.
ON THE SUM OF CONSECUTIVE INTEGERS IN SEQUENCES
Authors: TSAI MU-TSUN , ZAHARESCU ALEXANDRU
Published: December 2011

Let A be a set of natural numbers, rA(n) be the number of ways to represent n as a sum of consecutive elements in A, and MA(x) := ∑n ≤ xrA(n). Under various circumstances, we show that Mℕ(x) ~ ∑ MAi(x), where ℕ = ⊔ Aiis a partition of ℕ. In particular, we prove that the asymptotic formula holds when the Ai's are chosen such that Ai= {n ∈ ℕ : f(n) = i}, where f(n) can be one of the following: (1) f(n) = Ω(n), (2) f(n) = d(n), (3) f(n) = rℕ(n), (4) (assuming the Riemann Hypothesis) f(n) = ‖n‖ := min {∣n - p∣ : p ∈ ℙ} (the distance to the set of primes).
Merger Waves: Theory and Evidence
Authors: Yan Jinghua
Published: December 2011

This paper presents a model that incorporates product market competition into the standard neoclassical framework. The model explains why value-maximizing firms conduct mergers that appear to lower shareholder value. In a Cournot setting, the model demonstrates a prisoners' dilemma for merging firms in a merger wave. Consistent with the model's implications, the paper empirically documents that horizontal mergers are followed by substantially worse performance when they occur during waves. Moreover, further empirical tests show that the empirical relation between performance and merger waves is independent of the method of payment and increasing in the acquirer's managerial ownership. These findings are difficult to reconcile with alternative interpretations from existing theories.
The deep-sea microfossil record of macroevolutionary change in plankton and its study
Authors: Lazarus David B.
Published: December 2011

The deep-sea planktonic microfossil record (foraminifera, coccolithophores, diatoms, radiolaria and dinoflagellates) provides a unique resource for palaeobiology. Despite some geographical gaps due to poor regional preservation, and intermittant time intervals lost to erosion, most time periods for each Cenozoic planktonic biogeographical province are preserved. Vast numbers of specimens and numerous deep-sea cores provide abundant material and the opportunity to tightly integrate macroevolutionary and palaeoenvironmental data. Current documentation of this record is mixed. Catalogues for foraminifera and coccolithophores offer nearly complete species-level clade histories, but taxonomy for siliceous microfossils is incomplete. Published occurrence data is primarily stratigraphic and covers only a fraction of the total preserved diversity. Age models for some sections are excellent (accuracy
c
. 100 kya) but for many other sections are still poor. Taxonomic errors, age model errors and reworking displace fossil occurrences in time, complicating palaeobiological analysis. With additional taxonomic work, careful collection of whole fauna/floral assemblage occurrence data, improved age models, and the development of better data filtering and analysis tools to deal with data outliers the deep-sea microfossil record can deliver its promise of providing the most complete, detailed record of macroevolutionary change available to science.

Supplementary material:

Supplementary Appendix is available at
http://www.geolsoc.org.uk/SUP18485
Collateral mammal diversity loss associated with late Quaternary megafaunal extinctions and implications for the future
Authors: Barnosky Anthony D. , Carrasco Marc A. , Graham Russell W.
Published: December 2011

Using data from two palaeontological databases, MIOMAP and FAUNMAP (now linked as NEOMAP), we explore how late Quaternary species loss compared in large and small mammals by determining palaeospecies-area relationships (PSARs) at 19 temporal intervals ranging from
c.
30 million to 500 years ago in 10 different biogeographical provinces in the USA. We found that mammalian diversity of both large and small mammals remained relatively stable from 30 million years ago up until both crashed near the Pleistocene–Holocene transition. The diversity crash had two components: the well-known megafaunal extinction that amounted to
c.
21% of the pre-crash species, and collateral biodiversity loss due to biogeographical range reductions. Collateral loss resulted in large mammal diversity regionally falling an additional 6–31% above extinction loss, and small mammal diversity falling 16–51%, even though very few small mammals suffered extinction. These results imply that collateral losses due to biogeographical range adjustments may effectively double the regional diversity loss during an extinction event, substantially magnifying the ecological ramifications of the extinctions themselves. This is of interest in forecasting future ecological impacts of mammal extinctions, given that
c.
8% of USA mammal species, and 22% of mammal species worldwide, are now considered ‘Threatened’ by the IUCN.
Disentangling palaeodiversity signals from a biased sedimentary record: an example from the Early to Middle Miocene of Central Paratethys Sea
Authors: Zuschin Martin , Harzhauser Mathias , Mandic Oleg
Published: December 2011

Changes in molluscan diversity across the 3rd order sequence boundary from the Lower to the Middle Miocene of the Paratethys were evaluated in the context of environmental bias. Taken at face value, quantitative data from nearshore and sublittoral shell beds suggest a transition from low-diversity Karpatian (Upper Burdigalian) to highly diverse Badenian (Langhian and Lower Serravallian) assemblages, but environmental affiliation of samples reveals a strong facies shift across the sequence boundary. Ordination methods show that benthic assemblages of the two stages, including 4 biozones and four 3rd order depositional sequences over less than four million years, are developed along the same depth-related environmental gradient. Almost all samples are from highstand systems tracts, but Karpatian faunas are mostly from nearshore settings, and Badenian faunas are strongly dominated by sublittoral assemblages. This study emphasizes the importance of highly resolved stratigraphic and palaeoenvironmental frameworks for deciphering palaeodiversity patterns at regional scales and highlights the effort required to reach the asymptote of the collector's curve. Abundance data facilitate the recognition of ecological changes in regional biota and it is suggested that in second and higher order sequences the facies covered within systems tracts will drive observed diversity patterns.
SpiNNaker
Authors: Plana Luis A. , Clark David , Davidson Simon , Furber Steve , Garside Jim , Painkras Eustace , Pepper Jeffrey , Temple Steve , Bainbridge John
Published: December 2011

The design and implementation of globally asynchronous locally synchronous systems-on-chip is a challenging activity. The large size and complexity of the systems require the use of computer-aided design (CAD) tools but, unfortunately, most tools do not work adequately with asynchronous circuits. This article describes the successful design and implementation of SpiNNaker, a GALS multicore system-on-chip. The process was completed using commercial CAD tools from synthesis to layout. A hierarchical methodology was devised to deal with the asynchronous sections of the system, encapsulating and validating timing assumptions at each level. The crossbar topology combined with a pipelined asynchronous fabric implementation allows the on-chip network to meet the stringent requirements of the system. The implementation methodology constrains the design in a way that allows the tools to complete their tasks successfully. A first test chip, with reduced resources and complexity was taped-out using the proposed methodology. Test chips were received in December 2009 and were fully functional. The methodology had to be modified to cope with the increased complexity of the SpiNNaker SoC. SpiNNaker chips were delivered in May 2011 and were also fully operational, and the interconnect requirements were met.
Compositional Shape Analysis by Means of Bi-Abduction
Authors: Calcagno Cristiano , Distefano Dino , O’Hearn Peter W. , Yang Hongseok
Published: December 2011

The accurate and efficient treatment of mutable data structures is one of the outstanding problem areas in automatic program verification and analysis. Shape analysis is a form of program analysis that attempts to infer descriptions of the data structures in a program, and to prove that these structures are not misused or corrupted. It is one of the more challenging and expensive forms of program analysis, due to the complexity of aliasing and the need to look arbitrarily deeply into the program heap. This article describes a method of boosting shape analyses by defining a compositional method, where each procedure is analyzed independently of its callers. The analysis algorithm uses a restricted fragment of separation logic, and assigns a collection of Hoare triples to each procedure; the triples provide an over-approximation of data structure usage. Our method brings the usual benefits of compositionality---increased potential to scale, ability to deal with incomplete programs, graceful way to deal with imprecision---to shape analysis, for the first time.

The analysis rests on a generalized form of abduction (inference of explanatory hypotheses), which we call
bi-abduction
. Bi-abduction displays abduction as a kind of inverse to the frame problem: it jointly infers anti-frames (missing portions of state) and frames (portions of state not touched by an operation), and is the basis of a new analysis algorithm. We have implemented our analysis and we report case studies on smaller programs to evaluate the quality of discovered specifications, and larger code bases (e.g., sendmail, an imap server, a Linux distribution) to illustrate the level of automation and scalability that we obtain from our compositional method.

This article makes number of specific technical contributions on proof procedures and analysis algorithms, but in a sense its more important contribution is holistic: the explanation and demonstration of how a massive increase in automation is possible using abductive inference.
Randomized Shellsort
Authors: Goodrich Michael T.
Published: December 2011

In this article, we describe a
randomized Shellsort
algorithm. This algorithm is a simple, randomized, data-oblivious version of the Shellsort algorithm that always runs in
O
(
n
log
n
) time and succeeds in sorting any given input permutation with very high probability. Taken together, these properties imply applications in the design of new efficient privacy-preserving computations based on the secure multiparty computation (SMC) paradigm. In addition, by a trivial conversion of this Monte Carlo algorithm to its Las Vegas equivalent, one gets the first version of Shellsort with a running time that is provably
O
(
n
log
n
) with very high probability.
Climate Change Impacts on Marine Ecosystems
Authors: Doney Scott C. , Ruckelshaus Mary , Emmett Duffy J. , Barry James P. , Chan Francis , English Chad A. , Galindo Heather M. , Grebmeier Jacqueline M. , Hollowed Anne B. , Knowlton Nancy , Polovina Jeffrey , Rabalais Nancy N. , Sydeman William J. , Talley Lynne D.
Published: December 2011

In marine ecosystems, rising atmospheric CO2 and climate change are associated with concurrent shifts in temperature, circulation, stratification, nutrient input, oxygen content, and ocean acidification, with potentially wide-ranging biological effects. Population-level shifts are occurring because of physiological intolerance to new environments, altered dispersal patterns, and changes in species interactions. Together with local climate-driven invasion and extinction, these processes result in altered community structure and diversity, including possible emergence of novel ecosystems. Impacts are particularly striking for the poles and the tropics, because of the sensitivity of polar ecosystems to sea-ice retreat and poleward species migrations as well as the sensitivity of coral-algal symbiosis to minor increases in temperature. Midlatitude upwelling systems, like the California Current, exhibit strong linkages between climate and species distributions, phenology, and demography. Aggregated effects may modify energy and material flows as well as biogeochemical cycles, eventually impacting the overall ecosystem functioning and services upon which people and societies depend.
M. tuberculosisin Lymph Node Biopsy Paraffin-Embedded Sections
Authors: Eshete Abdurehman , Zeyinudin Ahmed , Ali Solomon , Abera Solomon , Mohammed Mona
Published: December 2011

Background. Tuberculosis lymphadenitis is one of the most common forms of all extrapulmonary tuberculosis.Objective. To evaluate the magnitude ofM. tuberculosisfrom lymph node biopsy paraffin-embedded sections among suspected patients visiting the Jimma University Specialized Hospital.Method. A cross-sectional study design of histological examination among lymph node biopsy paraffin-embedded sections by Ziehl-Neelsen and hematoxylin/eosin staining technique was conducted from December, 2009, to October, 2010, at the Department of Medical Laboratory Science and Pathology.Result. Histopathological examination of the specimens by hematoxylin and eosin staining technique revealed the presence of granulomas. But for the caseation and necrosis they were present in 85% cases of nodal tissue biopsies. From those, 56.7% were from females. The presence of acid-fast bacilli was microscopically confirmed by ZN staining in 37 (61.7%) of the nodal tissue biopsies.Conclusion and Recommendation. Tuberculosis lymphadenitis is significantly more common in females. Hence, attention should be given for control and prevention of extrapulmonary tuberculosis.
A Community Outbreak of Cryptosporidiosis in Sydney Associated with a Public Swimming Facility: A Case-Control Study
Authors: Mayne Darren J. , Ressler Kelly-Anne , Smith Diane , Hockey Gareth , Botham Susan J. , Ferson Mark J.
Published: December 2011

In February, 2008, the South Eastern Sydney Illawarra Public Health Unit investigated an outbreak of cryptosporidiosis within the south east region of Sydney, Australia. Thirty-one cases with laboratory-confirmed cryptosporidiosis and 97 age- and geographically matched controls selected by random digit dialling were recruited into a case-control study and interviewed for infection risk factors. Cryptosporidiosis was associated with swimming at Facility A (matched odds ratio = 19.4, 95% confidence interval: 3.7–100.8) and exposure to household contacts with diarrhoea (matched odds ratio = 7.7, 95% confidence interval: 1.9–31.4) in multivariable conditional logistic regression models. A protective effect for any animal contact was also found (matched odds ratio = 0.2, 95% confidence interval: 0.1–0.7).Cryptosporidium hominissubtype IbA10G2 was identified in 8 of 11 diagnostic stool samples available for cases. This investigation reaffirms the importance of public swimming pools as potential sources ofCryptosporidiuminfection and ensuring their compliance with water-quality guidelines. The protective effect of animal contact may be suggestive of past exposure leading to immunity.
α2 Integrin-Dependent Suppression of Pancreatic Adenocarcinoma Cell Invasion Involves Ectodomain Regulation of Kallikrein-Related Peptidase-5
Authors: Lee Chia-Yao , Marzan David , Lin Grace , Goodison Steve , Silletti Steve
Published: December 2011

Previous reports demonstrate that the α2-integrin (α2) mediates pancreatic ductal adenocarcinoma (PDAC) cell interactions with collagens. We found that while well-differentiated cells use α2 exclusively to adhere and migrate on collagenI, poorly differentiated PDAC cells demonstrate reduced reliance on, or complete loss of, α2. Since well-differentiated PDAC lines exhibit reducedin vitroinvasion and α2-blockade suppressed invasion of well-differentiated lines exclusively, we hypothesized that α2 may suppress the malignant phenotype in PDAC. Accordingly, ectopic expression of α2 retardedin vitroinvasion and maintenance on collagenI exacerbated this effect. Affymetrix profiling revealed that kallikrein-related peptidase-5 (KLK5) was specifically upregulated by α2, and reduced α2 and KLK5 expression was observed in poorly differentiated PDAC cellsin situ. Accordingly, well-differentiated PDAC lines express KLK5, and KLK5 blockade increased the invasion of KLK5-positive lines. The α2-cytoplasmic domain was dispensable for these effects, demonstrating that the α2-ectodomain and KLK5 coordinately regulate a less invasive phenotype in PDAC.
Effect of Age and Diabetes on the Response of Mesenchymal Progenitor Cells to Fibrin Matrices
Authors: Stolzing A. , Colley H. , Scutt A.
Published: December 2011

Mesenchymal stem cells are showing increasing promise in applications such as tissue engineering and cell therapy. MSC are low in number in bone marrow, and thereforein vitroexpansion is often necessary.In vivo, stem cells often reside within a niche acting to protect the cells. These niches are composed of niche cells, stem cells, and extracellular matrix. When blood vessels are damaged, a fibrin clot forms as part of the wound healing response. The clot constitutes a form of stem cell niche as it appears to maintain the stem cell phenotype while supporting MSC proliferation and differentiation during healing. This is particularly appropriate as fibrin is increasingly being suggested as a scaffold meaning that fibrin-based tissue engineering may to some extent recapitulate wound healing. Here, we describe how fibrin modulates the clonogenic capacity of MSC derived from young/old human donors and normal/diabetic rats. Fibrin was prepared using different concentrations to modulate the stiffness of the substrate. MSC were expanded on these scaffolds and analysed. MSC showed an increased self-renewal on soft surfaces. Old and diabetic cells lost the ability to react to these signals and can no longer adapt to the changed environment.
Distribution and Genetic Diversity ofSalmonella entericain the Upper Suwannee River
Authors: Rajabi Masoumeh , Jones Melissa , Hubbard Michael , Rodrick Gary , Wright Anita C.
Published: December 2011

The Suwannee River spans the Florida/Georgia border to the Gulf of Mexico, and contributes to regional irrigation and recreational activities. Association ofSalmonella entericawith these resources may result in the contamination of produce and disease outbreaks. Therefore, surface water was examined for the distribution ofS. entericaat multiple time points from 4 sites on the upper Suwannee River. Isolates were confirmed by detection of theinvAgene, and 96% of all samples were positive for the bacterium. Most probable number enumeration ranged from <18 to 5400 MPN/100 mL. Genetic diversity of these isolates (n=110) was compared to other environmental (n=47) or clinical (n=28) strains and to an online library (n=314) using DiversiLab rep-PCR. All strains showed >60% similarity and distributed into 16 rep-PCR genogroups. Most (74%) of the Suwannee River isolates were clustered into two genogroups that were comprised almost exclusively (97%) of just these isolates. Conversely, 85% of the clinical reference strains clustered into other genogroups. However, some Suwannee River isolates (12%) were clustered with these primarily clinically-associated genogroups, supporting the hypothesis that river water can serve as a disease reservoir and that pathogenic strains may persist or possibly originate from environmental sources.
Liposomes for Targeted Delivery of Active Agents against Neurodegenerative Diseases (Alzheimer's Disease and Parkinson's Disease)
Authors: Spuch Carlos , Navarro Carmen
Published: December 2011

Neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease represent a huge unmet medical need. The prevalence of both diseases is increasing, but the efficacy of treatment is still very limited due to various factors including the blood brain barrier (BBB). Drug delivery to the brain remains the major challenge for the treatment of all neurodegenerative diseases because of the numerous protective barriers surrounding the central nervous system. New therapeutic drugs that cross the BBB are critically needed for treatment of many brain diseases. One of the significant factors on neurotherapeutics is the constraint of the blood brain barrier and the drug release kinetics that cause peripheral serious side effects. Contrary to common belief, neurodegenerative and neurological diseases may be multisystemic in nature, and this presents numerous difficulties for their potential treatment. Overall, the aim of this paper is to summarize the last findings and news related to liposome technology in the treatment of neurodegenerative diseases and demonstrate the potential of this technology for the development of novel therapeutics and the possible applications of liposomes in the two most widespread neurodegenerative diseases, Alzheimer's disease and Parkinson's disease.
Mobile Music Distribution: A Multichannel Approach
Authors: Furini Marco
Published: December 2011

In contrast to what is happening in the Internet-based scenario, the music market in the mobile scenario is far from being considered a large success. Several studies state that excessive downloading time and high cost are the main burdens. Motivated by the growth of social and mobile applications, in this paper we propose an approach that aims at reducing both the downloading time and the cost to get digital music when acquired in the mobile scenario. The proposed architecture exploits the usage of personal communication technologies embedded in cellphones (e.g., Bluetooth and Wi-Fi) to couple the current distribution model (mainly based on 3G networks), so as to provide a multichannel distribution model where users are free to redistribute digital music. The architecture includes a license-based security mechanism that prevents unauthorized usage of digital music, and makes use of an incentive mechanism to stimulate and reward the music distribution among customers. By analyzing pros and cons of the music distribution chain, results show that the proposed architecture might help in reducing both the downloading time and the cost to get digital music when acquired in the mobile scenario. Therefore, it might be helpful to the success of the mobile music scenario.
Stability and Performance of First‐Order Linear Time‐Delay Feedback Systems: An Eigenvalue Approach
Authors: He Shu-An , Fong I-Kong
Published: December 2011

Linear time‐delay systems with transcendental characteristic equations have infinitely many eigenvalues which are generally hard to compute completely. However, the spectrum of first‐order linear time‐delay systems can be analyzed with the Lambert function. This paper studies the stability and state feedback stabilization of first‐order linear time‐delay system in detail via the Lambert function. The main issues concerned are the rightmost eigenvalue locations, stability robustness with respect to delay time, and the response performance of the closed‐loop system. Examples and simulations are presented to illustrate the analysis results.
A Class of Bridges of Iterated Integrals of Brownian Motion Related to Various Boundary Value Problems Involving the One-Dimensional Polyharmonic Operator
Authors: Lachal Aimé
Published: December 2011

Let be the linear Brownian motion and the -fold integral of Brownian motion, with being a positive integer: for any In this paper we construct several bridges between times and of the process involving conditions on the successive derivatives of at times and . For this family of bridges, we make a correspondence with certain boundary value problems related to the one-dimensional polyharmonic operator. We also study the classical problem of prediction. Our results involve various Hermite interpolation polynomials.
The Novel CFTR Mutation A457P in a Male with a Delayed Diagnosis of Cystic Fibrosis
Authors: Cole Kate H. , Sosnay Patrick R. , Yarmus Lonny B. , Zuckerman Jonathan B.
Published: December 2011

Cystic fibrosis (CF) is an autosomal recessive disease that may be caused by more than 1000 different mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. We describe the case of a CF patient who was initially diagnosed at 16 years of age after presenting with mild respiratory compromise and pancreatic sufficiency. When genetic testing was first performed using a CF mutation panel, only a single F508del CFTR allele was identified. We subsequently performed testing, which revealed a previously unreported mutation: A457P (p.Ala457Pro, c.1369G>C). The patient's clinical course through adulthood is described, and genotype-phenotype correlation is discussed. The A457P mutation appears to confer a relatively mild phenotype, as is usually observed with CFTR class IV–VI defects. With the advent of more comprehensive and widely available genetic testing techniques, identification of CF genotypes in patients with milder disease variants may help stratify patients for targeted therapy and prevent late complications of the disease.
Silver Orthophosphate Immobilized on Flaky Layered Double Hydroxides as the Visible-Light-Driven Photocatalysts
Authors: Cui Xianlu , Li Yaogang , Zhang Qinghong , Wang Hongzhi
Published: December 2011

Flaky layered double hydroxide (FLDH) was prepared by the reconstruction of its oxide in alkali solution. The composites with FLDH/Ag3PO4mass ratios at 1.6 : 1 and 3 : 1 were fabricated by the coprecipitation method. The powders were characterized by X-ray diffraction, field-emission scanning electron microscopy, transmission electron microscope, and UV-vis diffuse reflectance spectroscopy. The results indicated that the well-distributed Ag3PO4in a fine crystallite size was formed on the surface of FLDH. The photocatalytic activities of the Ag3PO4immobilized on FLDH were significantly enhanced for the degradation of acid red G under visible light irradiation compared to bare Ag3PO4. The composite with the FLDH/Ag3PO4mass ratio of 3 : 1 showed a higher photocatalytic efficiency.
Flavonoids Isolated from KoreaCitrus aurantiumL. Induce G2/M Phase Arrest and Apoptosis in Human Gastric Cancer AGS Cells
Authors: Lee Do-Hoon , Park Kwang-Il , Park Hyeon-Soo , Kang Sang-Rim , Nagappan Arulkumar , Kim Jin-A , Kim Eun-Hee , Lee Won-Sup , Hah Young-Sool , Chung Hyon-Jong , An Su-Jin , Kim Gon-Sup
Published: December 2011

Aim of the Study. Citrus species is used in traditional medicine as medicinal herb in several Asian countries including Korea. Flavonioids became known as various properties, such as anti-oxidants, anti-inflammation and anti-cancer, and so forth. The present study, the anti-cancer effect of flavonioids isolated fromCitrus aurantiumL. in human gastric cancer AGS cells has been investigated.Materials and Methods. The anti-proliferative activity was assayed using MTT assay. Cell cycle analysis was done using flow cytometry and apoptosis detection was done using by hoechst fluorescent staining and Annexin V-propidium iodide double staining. Western blot was used to detect the expression of protein related with cell cycle and apoptosis.Results. Flavonoids isolated fromCitrus aurantiumL. have the effect of anti proliferation on AGS cells with IC50 value of 99 μg/mL. Flavonoids inhibited cell cycle progression in the G2/M phase and decrease expression level of cyclin B1, cdc 2, cdc 25c. Flavonoids induced apoptosis through activate caspase and inactivate PARP.Conclusions. Flavonoids isolated fromCitrus aurantiumL. induced G2/M phase arrest through the modulation of cell cycle related proteins and apoptosis through activation caspase. These finding suggest flavonoids isolated fromCitrus aurantiumL. were useful agent for the chemoprevention of gastric cancer.