bluuebunny/crossref_metadata_2025 huggingface dataset:
Does Experimental Philosophy Have a Role to Play in Carnapian Explication?
Authors: Pinder Mark
Published: May 2017

Shepherd and Justus argue that experimental philosophy has an important role to play in the method of Carnapian explication, facilitating the preparatory stage during which the concept to be explicated is clarified. I raise concerns about their specific proposal, before sketching an alternative. In particular, I suggest that experimental philosophy can directly aid the construction of fruitful concepts. This provides a clear practical role for experimental philosophy, both within the sciences and theoretical inquiry more generally. In this respect, experimental philosophy may rightly be construed as one aspect of applied philosophy.
Presentism, Redemption, and Moral Development
Authors: Pezet Robert Edward
Published: May 2017

This paper explores what could justify some intuitive temporal asymmetries regarding redemption and the distribution of ills and goods throughout an agent's lifespan. After exposing the inadequacies of causal explanations – based on our differential ability to affect the future, but not the past – a metaphysical explanation is outlined in relation to three competing temporal‐ontological profiles of agents, and their varying accounts of a being's development. Only one of those conceptions of agents – supported byPresentism, the thesis that everything is present – offers an account justifying the intuitive temporal asymmetries. Finally, consequences are then drawn for the possibility of true redemption.
Water quality implications of hydrologic restoration alternatives in the Florida Everglades, United States
Authors: Naja Melodie , Childers Daniel L. , Gaiser Evelyn E.
Published: May 2017

The use of models to generate future scenarios is an important tool for restoration planning. We used a scenario modeling approach to examine water quality implications of five options for Everglades hydrologic restoration. In oligotrophic Everglades wetlands, phosphorus (P) inputs exceeding 10 µg/L cause P accumulation in soils and a shift to cattail marsh. Everglades restoration seeks to improve wetland hydrology while ensuring that delivered water contains no more than 10 µg P/L (long‐term average). Outputs from a landscape‐scale ecological model, the Everglades Landscape Model (ELM), showed that P concentrations in new water inputs will be controlled by P uptake by constructed treatment wetlands and by the movement of legacy P. Benthic periphyton responds quickly to changes in P, initiating a eutrophication response cascade, so we used ELM output to drive periphyton response models that predicted abundance, quality, and composition. All five restoration scenarios had similar effects on these three attributes in Everglades National Park, but variable responses across the other wetland units depended on water delivery and legacy P mobilization. Periphyton biomass was considerably reduced in scenarios that maximized freshwater delivery, but predicted values for periphyton total P were below the legal P concentration maximum in most of the Everglades. Benthic algal edibility increased more than 4‐fold, with the greatest increases in the deeper water areas. To meet water quality standards for the five restoration scenarios, we estimated that Everglades restoration should include an additional 105–156 km2 of treatment marshes upstream of surface water inflows to the landscape.
Population Pharmacokinetic Model Linking Plasma and Peripheral Blood Mononuclear Cell Concentrations of Efavirenz and Its Metabolite, 8-Hydroxy-Efavirenz, in HIV Patients
Authors: Habtewold Abiy , Aklillu Eleni , Makonnen Eyasu , Yimer Getnet , Bertilsson Leif , Burhenne Jürgen , Owen Joel S.
Published: May 2017

The objectives of this study were to characterize the population pharmacokinetics (PK) of efavirenz (EFV) and 8-hydroxy-efavirenz (8OHEFV) in plasma and peripheral blood mononuclear cells (PBMCs) and to explore covariates affecting the PK parameters. Fifty-one patients had steady-state 0-to-24-h concentrations of EFV and 8OHEFV in plasma with corresponding concentrations in PBMCs, while 261 patients had one or two sparse concentrations at 16 ± 1 h postdose at weeks 4 and/or 16. The pharmacogenetic markers
CYP2B6*6
,
CYP3A5*3
,
CYP3A5*6
,
UGT2B7*2
,
ABCB1
(3435C→T, 3842A→G),
OATP1B1*1B
, and
OATP1B1*5
, the presence of a rifampin-based antituberculosis (anti-TB) regimen, baseline body weight and organ function values, and demographic factors were explored as covariates. EFV concentration data were well described by a two-compartment model with first-order absorption (

K
a

) and absorption lag time (
A
lag
) (

K
a

= 0.2 h
−1
;
A
lag
= 0.83 h; central compartment clearance [CL
c
/
F
] for
CYP2B6*1/*1
= 18 liters/h, for
CYP2B6*1/*6
= 14 liters/h, and for
CYP2B6*6/*6
= 8.6 liters/h) and PBMCs as a peripheral compartment. EFV transfer from plasma to PBMCs was first order (CL
p
/
F
= 32 liters/h), followed by capacity-limited return (
V
max
= 4,400 ng/ml/h;

K
m

= 710 ng/ml). Similarly, 8OHEFV displayed a first-order elimination and distribution to PBMCs, with a capacity-limited return to plasma. No covariate relationships resulted in a significant explanation of interindividual variability (IIV) on the estimated PK parameters of EFV and 8OHEFV, except for
CYP2B6*6
genotypes, which were consistent with prior evidence. Both EFV and 8OHEFV accumulated to higher concentrations in PBMCs than in plasma and were well described by first-order input and Michaelis-Menten kinetics removal from PBMCs.
CYP2B6*6
genotype polymorphisms were associated with decreased EFV and 8OHEFV clearance.
Aerosolized Polymyxin B for Treatment of Respiratory Tract Infections: Determination of Pharmacokinetic-Pharmacodynamic Indices for Aerosolized Polymyxin B against Pseudomonas aeruginosa in a Mouse Lung Infection Model
Authors: Lin Yu-Wei , Zhou Qi , Onufrak Nikolas J. , Wirth Veronika , Chen Ke , Wang Jiping , Forrest Alan , Chan Hak-Kim , Li Jian
Published: May 2017

Pulmonary administration of polymyxins is increasingly used for the treatment of respiratory tract infections caused by multidrug-resistant Gram-negative bacteria, such as those in patients with cystic fibrosis. However, there is a lack of pharmacokinetics (PK), pharmacodynamics (PD), and toxicity data of aerosolized polymyxin B to inform rational dosage selection. The PK and PD of polymyxin B following pulmonary and intravenous dosing were examined in neutropenic infected mice, and the data were analyzed by a population PK model. Dose fractionation study was performed for total daily doses between 2.06 and 24.8 mg base/kg of weight against
Pseudomonas aeruginosa
ATCC 27853, PAO1, and FADDI-PA022 (MIC of 1 mg/liter for all three strains). Histopathological examination of the lung was undertaken at 24 h posttreatment in both healthy and neutropenic infected mice. A two-compartment PK model was required for both epithelial lining fluid (ELF) and plasma drug exposure. The model consisted of central and peripheral compartments and was described by bidirectional first-order distribution clearance. The ratio of the area under the curve to the MIC (AUC/MIC) was the most predictive PK/PD index to describe the antimicrobial efficacy of aerosolized polymyxin B in treating lung infections in mice (
R
2
of 0.70 to 0.88 for ELF and 0.70 to 0.87 for plasma). The AUC/MIC targets associated with bacteriostasis against the three
P. aeruginosa
strains were 1,326 to 1,506 in ELF and 3.14 to 4.03 in plasma. Histopathological results showed that polymyxin B aerosols significantly reduced lung inflammation and preserved lung epithelial integrity. This study highlights the advantageous PK/PD characteristics of pulmonary delivery of polymyxin B over intravenous administration in achieving high drug exposure in ELF.
Penicillin Dried Blood Spot Assay for Use in Patients Receiving Intramuscular Benzathine Penicillin G and Other Penicillin Preparations To Prevent Rheumatic Fever
Authors: Page-Sharp Madhu , Coward Jonathan , Moore Brioni R. , Salman Sam , Marshall Lewis , Davis Timothy M. E. , Batty Kevin T. , Manning Laurens
Published: May 2017

Rheumatic heart disease (RHD) remains an important global health challenge. Administration of benzathine penicillin (BPG) every 3 to 4 weeks is recommended as a secondary prophylaxis to prevent recurrent episodes of acute rheumatic fever and subsequent RHD. Following intramuscular injection, BPG is hydrolyzed to penicillin G (benzylpenicillin). However, little is known of the pharmacokinetics (PK) of BPG in pediatric populations at high risk of RHD or of the pharmacokinetic-pharmacodynamic relationship between penicillin exposure and clinically relevant outcomes. Dried blood spot (DBS) assays can facilitate PK studies in situations where frequent venous blood sampling is logistically difficult. A liquid chromatography-mass spectroscopy assay for penicillin G in plasma and DBS was developed and validated. Application of the DBS assay for PK studies was confirmed using samples from adult patients receiving penicillin as part of an infection management plan. The limit of quantification for penicillin G in DBS was 0.005 mg/liter. Penicillin G is stable in DBS for approximately 12 h at room temperature (22°C), 6 days at 4°C, and >1 month at −20°C. Plasma and DBS penicillin G concentrations for patients receiving BPG and penicillin G given via bolus doses correlated well and had comparable time-concentration profiles. There was poor correlation for patients receiving penicillin via continuous infusions, perhaps as a result of the presence of residual penicillin in the peripherally inserted central catheter, from which the plasma samples were collected. The present DBS penicillin G assay can be used as a surrogate for plasma concentrations to provide valid PK data for studies of BPG and other penicillin preparations developed to prevent rheumatic fever and RHD.
Etest and Sensititre YeastOne Susceptibility Testing of Echinocandins against Candida Species from a Single Center in Austria
Authors: Aigner Maria , Erbeznik Thomas , Gschwentner Martin , Lass-Flörl Cornelia
Published: May 2017

Candida
species were tested for susceptibility to caspofungin, anidulafungin, and micafungin in order to evaluate the roles of Etest and Sensititre YeastOne in antifungal susceptibility testing for daily routines and to survey resistance. A total of 104
Candida
species isolates detected from blood cultures were investigated. With EUCAST broth microdilution as the reference method, essential agreement (EA), categorical agreement (CA), very major errors (VME), major errors (ME), and minor (MIN) errors were assessed by reading MICs at 18, 24, and 48 h. By use of EUCAST broth microdilution and species-specific clinical breakpoints (CBPs), echinocandin resistance was not detected during the study period. Using EUCAST CBPs, MIC readings at 24 h for the Etest and Sensititre YeastOne resulted in CA levels of 99% and 93% for anidulafungin and 99% and 97% for micafungin. Using revised CLSI CBPs for caspofungin, CA levels were 92% and 99% for Etest and Sensititre YeastOne. The Etest proved an excellent, easy-to-handle alternative method for testing susceptibility to anidulafungin and micafungin. Due to misclassifications, the Etest is less suitable for testing susceptibility to caspofungin (8% of isolates falsely tested resistant). The CA levels of Sensititre YeastOne were 93% and 97% for anidulafungin and micafungin (24 h) by use of EUCAST CBPs and increased to 100% for both antifungals if CLSI CBPs were applied and to 100% and 99% if Sensititre YeastOne epidemiological cutoff values (ECOFFs) were applied. No one echinocandin could be demonstrated to be superior to another
in vitro
. Since resistance was lacking among our
Candida
isolates, we cannot derive any recommendation from accurate resistance detection by the Etest and Sensititre YeastOne.
A Lower Baseline CD4/CD8 T-Cell Ratio Is Independently Associated with Immunodiscordant Response to Antiretroviral Therapy in HIV-Infected Subjects
Authors: Rosado-Sánchez I. , Herrero-Fernández I. , Álvarez-Ríos A. I. , Genebat M. , Abad-Carrillo M. A. , Ruiz-Mateos E. , Pulido F. , González-García J. , Montero M. , Bernal-Morell E. , Vidal F. , Leal M. , Pacheco Y. M.
Published: May 2017

We explored if baseline CD4/CD8 T-cell ratio is associated with immunodiscordant response to antiretroviral therapy in HIV-infected subjects. Comparing immunodiscordant and immunoconcordant subjects matched by pretreatment CD4 counts, we observed a lower pretreatment CD4/CD8 T-cell ratio in immunodiscordant subjects. Furthermore, pretreatment CD4/CD8 T-cell ratio, but not CD4 counts, correlated with the main immunological alterations observed in immunodiscordants, including increased regulatory T-cell (Treg) frequency and T-cell turnover-related markers. Then, in a larger cohort, only baseline CD4/CD8 T-cell ratio was independently associated with immunodiscordance, after adjusting by the viral CXCR4-tropic HIV variants. Our results suggest that the CD4/CD8 T-cell ratio could be an accurate biomarker of the subjacent immunological damage triggering immunodiscordance.
Simkania negevensis, an Example of the Diversity of the Antimicrobial Susceptibility Pattern among Chlamydiales
Authors: Vouga Manon , Baud David , Greub Gilbert
Published: May 2017

In past years, several
Chlamydia
-related bacteria have been discovered, including
Simkania negevensis
, the founding member of the
Simkaniaceae
family. We evaluated the antimicrobial susceptibility patterns of this emerging intracellular bacterium and highlighted significant differences, compared with related
Chlamydiales
members.
S. negevensis
was susceptible to macrolides, clindamycin, cyclines, rifampin, and quinolones. Importantly, unlike other
Chlamydiales
members, treatment with β-lactams and vancomycin did not induce the formation of aberrant bodies, leading to a completely resistant phenotype.
Peripheral T-Cell Reactivity to Heat Shock Protein 70 and Its Cofactor GrpE from Tropheryma whipplei Is Reduced in Patients with Classical Whipple's Disease
Authors: Trotta Lucia , Weigt Kathleen , Schinnerling Katina , Geelhaar-Karsch Anika , Oelkers Gerrit , Biagi Federico , Corazza Gino Roberto , Allers Kristina , Schneider Thomas , Erben Ulrike , Moos Verena
Published: May 2017

Classical Whipple's disease (CWD) is characterized by the lack of specific Th1 response toward
Tropheryma whipplei
in genetically predisposed individuals. The cofactor GrpE of heat shock protein 70 (Hsp70) from
T. whipplei
was previously identified as a B-cell antigen. We tested the capacity of Hsp70 and GrpE to elicit specific proinflammatory T-cell responses. Peripheral mononuclear cells from CWD patients and healthy donors were stimulated with
T. whipplei
lysate or recombinant GrpE or Hsp70 before levels of CD40L, CD69, perforin, granzyme B, CD107a, and gamma interferon (IFN-γ) were determined in T cells by flow cytometry. Upon stimulation with total bacterial lysate or recombinant GrpE or Hsp70 of
T. whipplei
, the proportions of activated effector CD4
+
T cells, determined as CD40L
+
IFN-γ
+
, were significantly lower in patients with CWD than in healthy controls; CD8
+
T cells of untreated CWD patients revealed an enhanced activation toward unspecific stimulation and
T. whipplei
-specific degranulation, although CD69
+
IFN-γ
+
CD8
+
T cells were reduced upon stimulation with
T. whipplei
lysate and recombinant
T. whipplei
-derived proteins. Hsp70 and its cofactor GrpE are immunogenic in healthy individuals, eliciting effective responses against
T. whipplei
to control bacterial spreading. The lack of specific T-cell responses against these
T. whipplei
-derived proteins may contribute to the pathogenesis of CWD.
The Disulfide Bond Formation Pathway Is Essential for Anaerobic Growth of Escherichia coli
Authors: Meehan Brian M. , Landeta Cristina , Boyd Dana , Beckwith Jonathan
Published: May 2017

Disulfide bonds are critical to the stability and function of many bacterial proteins. In the periplasm of
Escherichia coli
, intramolecular disulfide bond formation is catalyzed by the two-component disulfide bond forming (DSB) system. Inactivation of the DSB pathway has been shown to lead to a number of pleotropic effects, although cells remain viable under standard laboratory conditions. However, we show here that
dsb
strains of
E. coli
reversibly filament under aerobic conditions and fail to grow anaerobically unless a strong oxidant is provided in the growth medium. These findings demonstrate that the background disulfide bond formation necessary to maintain the viability of
dsb
strains is oxygen dependent. LptD, a key component of the lipopolysaccharide transport system, fails to fold properly in
dsb
strains exposed to anaerobic conditions, suggesting that these mutants may have defects in outer membrane assembly. We also show that anaerobic growth of
dsb
mutants can be restored by suppressor mutations in the disulfide bond isomerization system. Overall, our results underscore the importance of proper disulfide bond formation to pathways critical to
E. coli
viability under conditions where oxygen is limited.

IMPORTANCE
While the disulfide bond formation (DSB) system of
E. coli
has been studied for decades and has been shown to play an important role in the proper folding of many proteins, including some associated with virulence, it was considered dispensable for growth under most laboratory conditions. This work represents the first attempt to study the effects of the DSB system under strictly anaerobic conditions, simulating the environment encountered by pathogenic
E. coli
strains in the human intestinal tract. By demonstrating that the DSB system is essential for growth under such conditions, this work suggests that compounds inhibiting Dsb enzymes might act not only as antivirulents but also as true antibiotics.
Cysteine Biosynthesis Controls Serratia marcescens Phospholipase Activity
Authors: Anderson Mark T. , Mitchell Lindsay A. , Mobley Harry L. T.
Published: May 2017

Serratia marcescens
causes health care-associated opportunistic infections that can be difficult to treat due to a high incidence of antibiotic resistance. One of the many secreted proteins of
S. marcescens
is the PhlA phospholipase enzyme. Genes involved in the production and secretion of PhlA were identified by screening a transposon insertion library for phospholipase-deficient mutants on phosphatidylcholine-containing medium. Mutations were identified in four genes (
cyaA
,
crp
,
fliJ
, and
fliP
) that are involved in the flagellum-dependent PhlA secretion pathway. An additional phospholipase-deficient isolate harbored a transposon insertion in the
cysE
gene encoding a predicted serine
O
-acetyltransferase required for cysteine biosynthesis. The
cysE
requirement for extracellular phospholipase activity was confirmed using a fluorogenic phospholipase substrate. Phospholipase activity was restored to the
cysE
mutant by the addition of exogenous
l
-cysteine or
O
-acetylserine to the culture medium and by genetic complementation. Additionally,
phlA
transcript levels were decreased 6-fold in bacteria lacking
cysE
and were restored with added cysteine, indicating a role for cysteine-dependent transcriptional regulation of
S. marcescens
phospholipase activity.
S. marcescens
cysE
mutants also exhibited a defect in swarming motility that was correlated with reduced levels of
flhD
and
fliA
flagellar regulator gene transcription. Together, these findings suggest a model in which cysteine is required for the regulation of both extracellular phospholipase activity and surface motility in
S. marcescens
.

IMPORTANCE
Serratia marcescens
is known to secrete multiple extracellular enzymes, but PhlA is unusual in that this protein is thought to be exported by the flagellar transport apparatus. In this study, we demonstrate that both extracellular phospholipase activity and flagellar function are dependent on the cysteine biosynthesis pathway. Furthermore, a disruption of cysteine biosynthesis results in decreased
phlA
and flagellar gene transcription, which can be restored by supplying bacteria with exogenous cysteine. These results identify a previously unrecognized role for CysE and cysteine in the secretion of
S. marcescens
phospholipase and in bacterial motility.
Polyvalent Proteins, a Pervasive Theme in the Intergenomic Biological Conflicts of Bacteriophages and Conjugative Elements
Authors: Iyer Lakshminarayan M. , Burroughs A. Maxwell , Anand Swadha , de Souza Robson F. , Aravind L.
Published: May 2017

Intense biological conflicts between prokaryotic genomes and their genomic parasites have resulted in an arms race in terms of the molecular “weaponry” deployed on both sides. Using a recursive computational approach, we uncovered a remarkable class of multidomain proteins with 2 to 15 domains in the same polypeptide deployed by viruses and plasmids in such conflicts. Domain architectures and genomic contexts indicate that they are part of a widespread conflict strategy involving proteins injected into the host cell along with parasite DNA during the earliest phase of infection. Their unique feature is the combination of domains with highly disparate biochemical activities in the same polypeptide; accordingly, we term them polyvalent proteins. Of the 131 domains in polyvalent proteins, a large fraction are enzymatic domains predicted to modify proteins, target nucleic acids, alter nucleotide signaling/metabolism, and attack peptidoglycan or cytoskeletal components. They further contain nucleic acid-binding domains, virion structural domains, and 40 novel uncharacterized domains. Analysis of their architectural network reveals both pervasive common themes and specialized strategies for conjugative elements and plasmids or (pro)phages. The themes include likely processing of multidomain polypeptides by zincin-like metallopeptidases and mechanisms to counter restriction or CRISPR/Cas systems and jump-start transcription or replication. DNA-binding domains acquired by eukaryotes from such systems have been reused in XPC/RAD4-dependent DNA repair and mitochondrial genome replication in kinetoplastids. Characterization of the novel domains discovered here, such as RNases and peptidases, are likely to aid in the development of new reagents and elucidation of the spread of antibiotic resistance.

IMPORTANCE
This is the first report of the widespread presence of large proteins, termed polyvalent proteins, predicted to be transmitted by genomic parasites such as conjugative elements, plasmids, and phages during the initial phase of infection along with their DNA. They are typified by the presence of multiple domains with disparate activities combined in the same protein. While some of these domains are predicted to assist the invasive element in replication, transcription, or protection of their DNA, several are likely to target various host defense systems or modify the host to favor the parasite's life cycle. Notably, DNA-binding domains from these systems have been transferred to eukaryotes, where they have been incorporated into DNA repair and mitochondrial genome replication systems.
Functional Interaction between the N and C Termini of NhaD Antiporters from Halomonas sp. Strain Y2
Authors: Meng Yiwei , Yang Zhou , Cheng Bin , Nie Xinyu , Li Shannan , Yin Huijia , Xu Ping , Yang Chunyu
Published: May 2017

Two NhaD-type antiporters, NhaD1 and NhaD2, from the halotolerant and alkaliphilic
Halomonas
sp. strain Y2, exhibit different physiological functions in regard to Na
+
and Li
+
resistance, although they share high sequence identity. In the present study, the truncation of an additional 4 C-terminal residues from NhaD2 or an exchange of 39 N-terminal residues between these proteins resulted in the complete loss of antiporter activity. Interestingly, combining 39 N-terminal residues and 7 C-terminal residues of NhaD2 (N39D2-C7) partially recovered the activity for Na
+
and Li
+
expulsion, as well as complementary growth following exposure to 300 mM Na
+
and 100 mM Li
+
stress. The recovered activity of chimera N39D2-C7 indicated that the N and C termini are structurally dependent on each other and function synergistically. Furthermore, fluorescence resonance energy transfer (FRET) analysis suggested that the N and C termini are relatively close in proximity which may account for their synergistic function in ion translocation. In the N-terminal region of N39D2-C7, the replacement of Glu
38
with Pro abolished the recovered complementary and transport activities. In addition, this amino acid substitution in NhaD2 resulted in a drastically decreased complementation ability in
Escherichia coli
KNabc (level identical to that of NhaD1), as well as decreased activity and an altered pH profile.

IMPORTANCE
Limited information on NhaD antiporters supports speculation that these antiporters are important for resistance to high salinity and alkalinity. Moreover, only a few functional residues have been identified in NhaD antiporters, and there is limited literature on the molecular mechanisms of NhaD antiporter activity. The altered antiporter abilities of chimeras and mutants in this study implicate the functions of the N and C termini, especially Glu
38
, in pH regulation and ion translocation, and, most importantly, the essential roles of this negatively charged residue in maintaining the physiological function of NhaD2. These findings further our understanding of the molecular mechanism of NhaD antiporters for ion transport.
A Toxin Involved in
Salmonella
Persistence Regulates Its Activity by Acetylating Its Cognate Antitoxin, a Modification Reversed by CobB Sirtuin Deacetylase
Authors: VanDrisse Chelsey M. , Parks Anastacia R. , Escalante-Semerena Jorge C.
Published: May 2017

Bacterial toxin-antitoxin systems trigger the onset of a persister state by inhibiting essential cellular processes. The TacT toxin of
Salmonella enterica
is known to induce a persister state in macrophages through the acetylation of aminoacyl-tRNAs. Here, we show that the TacT toxin and the TacA antitoxin work as a complex that modulates TacT activity via the acetylation state of TacA. TacT acetylates TacA at residue K44, a modification that is removed by the NAD
+
-dependent CobB sirtuin deacetylase. TacA acetylation increases the activity of TacT, downregulating protein synthesis. TacA acetylation altered binding to its own promoter, although this did not change
tacAT
expression levels. These claims are supported by results from
in vitro
protein synthesis experiments used to monitor TacT activity,
in vivo
growth analyses, electrophoretic mobility shift assays, and quantitative reverse transcription-PCR (RT-qPCR) analysis. TacT is the first example of a Gcn5-related
N-
acetyltransferase that modifies nonprotein and protein substrates.

IMPORTANCE
During host infection, pathogenic bacteria can modulate their physiology to evade host defenses. Some pathogens use toxin-antitoxin systems to modulate a state of self-toxicity that can decrease their cellular activity, triggering the onset of a persister state. The lower metabolic activity of persister cells allows them to escape host defenses and antibiotic treatments. Hence a better understanding of the mechanisms used by pathogens to ingress and egress the persister state is of relevance to human health.
Endoplasmic Reticulum Stress Caused by Lipoprotein Accumulation Suppresses Immunity against Bacterial Pathogens and Contributes to Immunosenescence
Authors: Singh Jogender , Aballay Alejandro
Published: May 2017

The unfolded protein response (UPR) is a stress response pathway that is activated upon increased unfolded and/or misfolded proteins in the endoplasmic reticulum (ER), and enhanced ER stress response prolongs life span and improves immunity. However, the mechanism by which ER stress affects immunity remains poorly understood. Using the nematode
Caenorhabditis elegans
, we show that mutations in the lipoproteins vitellogenins, which are homologs of human apolipoprotein B-100, resulted in upregulation of the UPR. Lipoprotein accumulation in the intestine adversely affects the immune response and the life span of the organism, suggesting that it could be a contributing factor to immunosenescence. We show that lipoprotein accumulation inhibited the expression of several immune genes encoding proteins secreted by the intestinal cells in an IRE-1-independent manner. Our studies provide a mechanistic explanation for adverse effects caused by protein aggregation and ER stress on immunity and highlight the role of an IRE-1-independent pathway in the suppression of the expression of genes encoding secreted proteins.

IMPORTANCE
Increased accumulation of unfolded and/or misfolded proteins in the endoplasmic reticulum (ER) leads to enhanced ER stress. However, the mechanism(s) by which ER stress affects immunity remain understudied. Using the nematode
C. elegans
, we showed that mutations in lipoproteins lead to their accumulation in the intestine, causing ER stress and adversely affecting the life span of the organisms and their resistance to pathogen infection. Our results indicate that the ER stress caused by lipoprotein accumulation significantly reduced the levels of expression of genes encoding secreted immune effectors, contributing to immunosenescence. It is known that ER stress may suppress gene expression via IRE-1, which is a sensor of ER stress. The novel mechanism uncovered in our study is IRE-1 independent, which highlights the role of a novel process by which ER stress suppresses innate immunity.
Biphasic Metabolism and Host Interaction of a Chlamydial Symbiont
Authors: König Lena , Siegl Alexander , Penz Thomas , Haider Susanne , Wentrup Cecilia , Polzin Julia , Mann Evelyne , Schmitz-Esser Stephan , Domman Daryl , Horn Matthias
Published: May 2017

Chlamydiae are known as major bacterial pathogens of humans, causing the ancient disease trachoma, but they are also frequently found in the environment where they infect ubiquitous protists such as amoebae. All known chlamydiae require a eukaryotic host cell to thrive. Using the environmental chlamydia
Protochlamydia amoebophila
within its natural host,
Acanthamoeba castellanii
, we investigated gene expression dynamics
in vivo
and throughout the complete chlamydial developmental cycle for the first time. This allowed us to infer how a major virulence mechanism, the type III secretion system, is regulated and employed, and we show that the physiology of chlamydiae undergoes a complete shift regarding carbon metabolism and energy generation. This study provides comprehensive insights into the infection strategy of chlamydiae and reveals a unique adaptation to life within a eukaryotic host cell.
Rectosigmoid malakoplakia
Authors: Yen Jia Min , Soh Nicole Wei Ying , Petersson Fredrik , Pandya Garvi
Published: May 2017

We present a rare case of rectosigmoid malakoplakia treated with fluoroquinolone.
Hypercalcaemic encephalopathy due to metastatic parathyroid carcinoma
Authors: Sadacharan Dhalapathy , Mahadevan Shriraam , Ferdinant Jabamalai , Rakeshchandru Kaharin
Published: May 2017

A 49-year-old man presented in the emergency department with altered sensorium and renal failure and was placed on a ventilator. Evaluation with MRI of the brain showed enhancing lesion in the occipital lobe. Biochemical tests revealed elevated calcium and parathyroid hormone (PTH) levels. Further evaluation revealed multiple lesions at both lobes of the lungs and nodular lesion in the right inferior pole of the thyroid. Diagnosis of metastatic parathyroid carcinoma was suspected. Patient was stabilised with bisphosphonates and haemodialysis and planned for surgery. Intraoperatively a hard lesion was found in the right inferior parathyroid infiltrating the surrounding structures. En bloc resection was done. General condition of the patient improved and he was weaned from the ventilator. Histopathology confirmed the diagnosis of parathyroid carcinoma. Postoperatively, there was persistent elevation of PTH in spite of a fall in calcium levels indicating functioning brain and pulmonary metastases. Due to extensive metastases, the patient was given palliative cinacalcet and was kept under follow-up.
Alport’s syndrome with type 4 renal tubular acidosis
Authors: McDonnell Thomas , Chukwu Chukwuma , Wong Christopher
Published: May 2017

This case report details a 51-year-old man with Alport’s syndrome resulting in chronic nephritis with stable renal function and sensorineural deafness. The patient was being investigated for persistently raised potassium refractory to dietary and pharmacological modification. Subsequently, the patient was found to have type 4 renal tubular acidosis, and potassium normalised with the addition of fludrocortisone.
Ultimate limit state reliability-based design of augered cast-in-place piles considering lower-bound capacities
Authors: Reddy Seth C. , Stuedlein Armin W.
Published: May 2017

The use of augered cast-in-place (ACIP) piles for transportation infrastructure requires an appropriate reliability-based design (RBD) procedure. In an effort to improve the accuracy of an existing design model and calibrate appropriate resistance factors, this study presents a significantly revised RBD methodology for estimating the shaft and toe bearing capacity of ACIP piles using a large database consisting of static loading tests in predominately granular soils. The proposed design models are unbiased, as opposed to those currently recommended. Based on the reasonable assumption that a finite lower-bound resistance limit exists, lower-bound design lines are developed for shaft and toe bearing resistance by applying a constant ratio to the proposed design models. Resistance factors are calibrated at the strength or ultimate limit state (ULS) for ACIP piles loaded in compression and tension for two commonly used target probabilities of failure with and without lower-bound limits. For piles loaded in compression, separate resistance factors are calibrated for the proposed shaft and toe bearing resistance models. The inclusion of a lower-bound limit for piles loaded in tension results in a 24%–50% increase in the calibrated resistance factor. For piles loaded in compression, the application of a lower-bound limit results in a 20%–150% increase in the calibrated resistance factor, and represents a significant increase in useable pile capacity. Although the impact of a lower-bound limit on resistance factor calibration is directly dependent on the degree of uncertainty in the distribution of resistance, this effect is outweighed by the type of distribution selected (i.e., normal, lognormal) at more stringent target probabilities of failure due to differences in distribution shape at the location of the lower-bound limit. A companion paper explores the use of the revised ULS model in a reliability-based serviceability limit state design framework.
Reconstruction of interaction rate in holographic dark energy model with Hubble horizon as the infrared cut-off
Authors: Mamon Abdulla Al
Published: May 2017

This work is the reconstruction of the interaction rate of holographic dark energy whose infrared cut-off scale is set by the Hubble length. We have reconstructed the interaction rate between dark matter and the holographic dark energy for a specific parameterization of the effective equation-of-state parameter. We have obtained observational constraints on the model parameters using the latest type Ia supernova (SNIa), baryon acoustic oscillations (BAO) and cosmic microwave background (CMB) radiation datasets. We have found that for the present model, the interaction rate increases with expansion and remains positive throughout the evolution. For a comprehensive analysis, we have also compared the reconstructed results of the interaction rate with other well-known holographic dark energy models. The nature of the deceleration parameter, the statefinder parameters and the dark energy equation-of-state parameter have also been studied for the present model. It has been found that the deceleration parameter favors the past decelerated and recent accelerated expansion phase of the universe. It has also been found that the dark energy equation-of-state parameter shows a phantom nature at the present epoch.
OPENING UP THE R&D PROCESS IS RISKY — HOW FAR DO YOU HAVE TO GO IN ORDER TO BEAT YOUR COMPETITORS?
Authors: LANG ALEXANDER , TESCH ANNA-TERESA , LINDEMANN UDO
Published: May 2017

Looking into the research of the last 20 years, opening up the R&D process seems to help companies to be more successful. Looking for external ideas, based on market demands or external solutions to internal technical problems, helps to save time, reduce costs or find entirely new solutions. Having said that, opening up the R&D process also bears risks. If a company is willing to open up their R&D process, to what point should the process be opened? In a quantitative study with 100 German companies, followed by a qualitative study conducting interviews at 20 companies, an approach how to define this optimal point of openness was developed. First, the value of the real openness (RO) was measured directly; then the value for the virtual openness (VO) was calculated looking at risks and opportunities. Finally using the difference between the values of the RO and ideal opening (IO), recommendations to open the R&D process to an ideal level, the IO, can be derived.
Chalk reservoir of the Ockley accumulation, North Sea:
in situ
stresses, geology and implications for stimulation
Authors: Wynn T. J. , Kumar R. , Jones R. , Howell K. , Maxwell D. , Bailey P.
Published: May 2017

The Ockley discovery is a gas condensate accumulation contained within tight chalks of the Hod Formation. The observed faults and fractures are a combination of features radial to the main periclinal structure and parallel to the local structural grain 100° from north. Most natural fractures appear to be healed or cemented. The pore pressure gradient at Ockley is
c.
0.199 bar/m. The
in situ
stresses are estimated to all be within
c.
46 bar of each other, indicating a near-isotropic
in situ
stress system. Therefore the orientation of
S
Hmax
is hard to define and drilling optimally oriented wells to create transverse hydraulic fractures is difficult. The estimated intact rock fracture initiation pressure in a horizontal well would exceed all the
in situ
stress gradients. Therefore, even if a vertical planar induced fracture were created at the wellbore wall, it would probably exploit natural fractures and bedding planes, leading to complex fracture geometries. Acid fracture stimulations are plugged by the insoluble clay residue within the clay-rich Hod chalk, so this is not an optimal strategy. Proppant fracturing has more merit, but complex fracture geometries present significant challenges for successful treatment design while trying to avoid or minimize extremely costly early screen-outs.
Don’t Sit on the Fence
Authors: Alglave Jade , Kroening Daniel , Nimal Vincent , Poetzl Daniel
Published: May 2017

Modern architectures rely on memory fences to prevent undesired weakenings of memory consistency. As the fences’ semantics may be subtle, the automation of their placement is highly desirable. But precise methods for restoring consistency do not scale to deployed systems’ code. We choose to trade some precision for genuine scalability: our technique is suitable for large code bases. We implement it in our new musketeer tool and report experiments on more than 700 executables from packages found in Debian GNU/Linux 7.1, including memcached with about 10,000 LoC.
Cloning Agent-Based Simulation
Authors: Li Xiaosong , Cai Wentong , Turner Stephen J.
Published: May 2017

Simulation cloning is an efficient way to analyze multiple configurations in a parameter exploration task. A simulation model usually contains a set of tunable parameters for exploring different configurations of a system. To evaluate different design alternatives, multiple simulation instances need to be launched, each evaluating a different parameter configuration. It usually takes a considerable amount of time to execute these simulation instances. Simulation cloning is proposed to reuse computations among simulation instances and to shorten the overall execution time. It is a challenging task to design cloning strategies to explore the computation sharing among simulation instances while maintaining the correctness of execution. In this article, we propose two agent-based simulation (ABS) cloning strategies, the top-down cloning strategy and the bottom-up cloning strategy. The top-down cloning strategy is initially designed and can only be applied to limited scenarios. The bottom-up cloning strategy is an improved strategy to overcome the limitation of the top-down cloning strategy. In the experiments, the effectiveness of the two strategies is analyzed. To show the performance advantages and generality of the bottom-up cloning strategy, a large-scale ABS parameter exploration task is performed, and results are discussed in the article.
Fault-Tolerant Dynamic Task Mapping and Scheduling for Network-on-Chip-Based Multicore Platform
Authors: Chatterjee Navonil , Paul Suraj , Chattopadhyay Santanu
Published: May 2017

In Network-on-Chip (NoC)-based multicore systems, task allocation and scheduling are known to be important problems, as they affect the performance of applications in terms of energy consumption and timing. Advancement of deep submicron technology has made it possible to scale the transistor feature size to the nanometer range, which has enabled multiple processing elements to be integrated onto a single chip. On the flipside, it has made the integrated entities on the chip more susceptible to different faults. Although a significant amount of work has been done in the domain of fault-tolerant mapping and scheduling, existing algorithms either precompute reconfigured mapping solutions at design time while anticipating fault(s) scenarios or adopt a hybrid approach wherein a part of the fault mitigation strategy relies on the design-time solution. The complexity of the problem rises further for real-time dynamic systems where new applications can arrive in the multicore platform at any time instant. For real-time systems, the validity of computation depends both on the correctness of results and on temporal constraint satisfaction. This article presents an improved fault-tolerant dynamic solution to the integrated problem of application mapping and scheduling for NoC-based multicore platforms. The developed algorithm provides a unified mapping and scheduling method for real-time systems focusing on meeting application deadlines and minimizing communication energy. A predictive model has been used to determine the failure-prone cores in the system for which a fault-tolerant resource allocation with task redundancy has been performed. By selectively using a task replication policy, the reliability of the application, executing on a given NoC platform, is improved. A detailed evaluation of the performance of the proposed algorithm has been conducted for both real and synthetic applications. When compared with other fault-tolerant algorithms reported in the literature, performance of the proposed algorithm shows an average reduction of 56.95% in task re-execution time overhead and an average improvement of 31% in communication energy. Further, for time-constrained tasks, deadline satisfaction has also been achieved for most of the test cases by the developed algorithm, whereas the techniques reported in the literature failed to meet deadline in about 45% test cases.
Faster Statistical Model Checking for Unbounded Temporal Properties
Authors: Daca Przemysław , Henzinger Thomas A. , Křetínský Jan , Petrov Tatjana
Published: May 2017

We present a new algorithm for the statistical model checking of Markov chains with respect to unbounded temporal properties, including full linear temporal logic. The main idea is that we monitor each simulation run on the fly, in order to detect quickly if a bottom strongly connected component is entered with high probability, in which case the simulation run can be terminated early. As a result, our simulation runs are often much shorter than required by termination bounds that are computed a priori for a desired level of confidence on a large state space. In comparison to previous algorithms for statistical model checking our method is not only faster in many cases but also requires less information about the system, namely, only the minimum transition probability that occurs in the Markov chain. In addition, our method can be generalised to unbounded quantitative properties such as mean-payoff bounds.
The Chemical Approach to Typestate-Oriented Programming
Authors: Crafa Silvia , Padovani Luca
Published: May 2017

We introduce a novel approach to typestate-oriented programming based on the chemical metaphor: state and operations on objects are molecules of messages, and state transformations are chemical reactions. This approach allows us to investigate typestate in an inherently concurrent setting, whereby objects can be accessed and modified concurrently by several processes, each potentially changing only part of their state. We introduce a simple behavioral type theory to express in a uniform way both the private and the public interfaces of objects; describe and enforce structured object protocols consisting of possibilities, prohibitions, and obligations; and control object sharing.
Efficient Kernel Management on GPUs
Authors: Liang Yun , Li Xiuhong
Published: May 2017

Graphics Processing Units (GPUs) have been widely adopted as accelerators for compute-intensive applications due to its tremendous computational power and high memory bandwidth. As the complexity of applications continues to grow, each new generation of GPUs has been equipped with advanced architectural features and more resources to sustain its performance acceleration capability. Recent GPUs have been featured with concurrent kernel execution, which is designed to improve the resource utilization by executing multiple kernels simultaneously. However, it is still a challenge to find a way to manage the resources on GPUs for concurrent kernel execution. Prior works only achieve limited performance improvement as they do not optimize the thread-level parallelism (TLP) and model the resource contention for the concurrently executing kernels.

In this article, we design an efficient kernel management framework that optimizes the performance for concurrent kernel execution on GPUs. Our kernel management framework contains two key components: TLP modulation and cache bypassing. The TLP modulation is employed to adjust the TLP for the concurrently executing kernels. It consists of three parts: kernel categorization, static TLP modulation, and dynamic TLP modulation. The cache bypassing is proposed to mitigate the cache contention by only allowing a subset of a kernel’s blocks to access the L1 data cache. Experiments indicate that our framework can improve the performance by 1.51 × on average (energy-efficiency by 1.39 × on average), compared with the default concurrent kernel execution framework.
Wearable Computing
Authors: Siewiorek Daniel
Published: May 2017

When I started at Carnegie Mellon University (CMU) in 1972, I joined Gordon Bell's research group just as he started to explore multiprocessor systems. Later in 1972, Sam Fuller joined the research group and the Computer Module project was born. Cm* (Computer module replicated one or more times as indicated by the Kline star) was an extensible architecture with shared address space across a local bus, extending to a cluster bus, and to intercluster links realizing the first non-uniform memory access (NUMA) multiprocessor [18]. By the end of the 1970s, industry became very interested in multiprocessor systems and it became difficult for university design teams primarily composed of students to keep pace with professional engineering teams with more resources in designing higher speed and ever more complex logic.