bluuebunny/crossref_metadata_2025 huggingface dataset:
Exopolysaccharide-Repressing Small Molecules with Antibiofilm and Antivirulence Activity against Pseudomonas aeruginosa
Authors: van Tilburg Bernardes Erik , Charron-Mazenod Laetitia , Reading David J. , Reckseidler-Zenteno Shauna L. , Lewenza Shawn
Published: February 2017

Biofilm formation is a universal virulence strategy in which bacteria grow in dense microbial communities enmeshed within a polymeric extracellular matrix that protects them from antibiotic exposure and the immune system.
Pseudomonas aeruginosa
is an archetypal biofilm-forming organism that utilizes a biofilm growth strategy to cause chronic lung infections in cystic fibrosis (CF) patients. The extracellular matrix of
P. aeruginosa
biofilms is comprised mainly of exopolysaccharides (EPS) and DNA. Both mucoid and nonmucoid isolates of
P. aeruginosa
produce the Pel and Psl EPS, each of which have important roles in antibiotic resistance, biofilm formation, and immune evasion. Given the central importance of the EPS for biofilms, they are attractive targets for novel anti-infective compounds. In this study, we used a high-throughput gene expression screen to identify compounds that repress expression of the
pel
genes. The
pel
repressors demonstrated antibiofilm activity against microplate and flow chamber biofilms formed by wild-type and hyperbiofilm-forming strains. To determine the potential role of EPS in virulence,
pel
/
psl
mutants were shown to have reduced virulence in feeding behavior and slow killing virulence assays in
Caenorhabditis elegans
. The antibiofilm molecules also reduced
P. aeruginosa
PAO1 virulence in the nematode slow killing model. Importantly, the combination of antibiotics and antibiofilm compounds increased killing of
P. aeruginosa
biofilms. These small molecules represent a novel anti-infective strategy for the possible treatment of chronic
P. aeruginosa
infections.
Deletion of
nudB
Causes Increased Susceptibility to Antifolates in Escherichia coli and Salmonella enterica
Authors: Li Kun , Li Ting , Yang Shan-shan , Wang Xu-De , Gao Lei-xin , Wang Rui-Qi , Gu Jing , Zhang Xian-En , Deng Jiao-Yu
Published: February 2017

Co-trimoxazole, a fixed-dose combination of sulfamethoxazole (SMX) and trimethoprim (TMP), has been used for the treatment of bacterial infections since the 1960s. Since it has long been assumed that the synergistic effects between SMX and TMP are the consequence of targeting 2 different enzymes of bacterial folate biosynthesis, 2 genes (
pabB
and
nudB
) involved in the folate biosynthesis of
Escherichia coli
were deleted, and their effects on the susceptibility to antifolates were tested. The results showed that the deletion of
nudB
resulted in a lag of growth in minimal medium and increased susceptibility to both SMX and TMP. Moreover, deletion of
nudB
also greatly enhanced the bactericidal effect of TMP. To elucidate the mechanism of how the deletion of
nudB
affects the bacterial growth and susceptibility to antifolates, 7,8-dihydroneopterin and 7,8-dihydropteroate were supplemented into the growth medium. Although those metabolites could restore bacterial growth, they had no effect on susceptibilities to the antifolates. Reverse mutants of the
nudB
deletion strain were isolated to further study the mechanism of how the deletion of
nudB
affects susceptibility to antifolates. Targeted sequencing and subsequent genetic studies revealed that the disruption of the tetrahydromonapterin biosynthesis pathway could reverse the phenotype caused by the
nudB
deletion. Meanwhile, overexpression of
folM
could also lead to increased susceptibility to both SMX and TMP. These data suggested that the deletion of
nudB
resulted in the excess production of tetrahydromonapterin, which then caused the increased susceptibility to antifolates. In addition, we found that the deletion of
nudB
also resulted in increased susceptibility to both SMX and TMP in
Salmonella enterica
. Since dihydroneopterin triphosphate hydrolase is an important component of bacterial folate biosynthesis and the tetrahydromonapterin biosynthesis pathway also exists in a variety of bacteria, it will be interesting to design new compounds targeting dihydroneopterin triphosphate hydrolase, which may inhibit bacterial growth and simultaneously potentiate the antimicrobial activities of antifolates targeting other components of folate biosynthesis.
In Vitro
and
In Vivo
Activity of Omadacycline against Two Biothreat Pathogens, Bacillus anthracis and Yersinia pestis
Authors: Steenbergen Judith , Tanaka S. Ken , Miller Lynda L. , Halasohoris Stephanie A. , Hershfield Jeremy R.
Published: February 2017

The
in vitro
activity and
in vivo
efficacy of omadacycline (OMC) were evaluated against the causative pathogens of anthrax and plague,
Bacillus anthracis
and
Yersinia pestis
, respectively. MICs of OMC were determined by broth microdilution according to CLSI guidelines for 30 isolates each of
Y. pestis
and
B. anthracis
. The
in vivo
efficacy of omadacycline was studied at a range of dosages in both a postexposure prophylaxis (PEP) murine model of anthrax and plague as well as in a delayed treatment model of inhalational anthrax. Omadacycline was active
in vitro
against
Y. pestis
(MIC
90
of 1 μg/ml) and
B. anthracis
(MIC
90
of 0.06 μg/ml). Omadacycline was less active
in vitro
than ciprofloxacin (CIP) against
Y. pestis
(CIP MIC
90
of 0.03 μg/ml) but was more potent
in vitro
against
B. anthracis
(CIP MIC
90
of 0.12 μg/ml). In the mouse model of infection, the survival curves for all treatment cohorts differed significantly from the vehicle control (
P
= 0.004). The median survival for the vehicle-treated controls was 6 days postchallenge, while all antibiotic-treated mice survived the entire study. Omadacycline treatment with 5, 10, or 20 mg/kg of body weight twice daily for 14 days had significant efficacy over the vehicle control in the treatment of aerosolized
B. anthracis
. Additionally, for postexposure prophylaxis treatment of mice infected with
Y. pestis
, the survival curves for omadacycline (40 mg/kg twice daily), ciprofloxacin, and doxycycline cohorts differed significantly from the vehicle control (
P
< 0.0001). Omadacycline is potent and demonstrates efficacy against both
B. anthracis
and
Y. pestis
. The well-characterized oral and intravenous pharmacokinetics, safety, and tolerability warrant further assessment of the potential utility of omadacycline in combating these serious biothreat organisms.
Vitamin K
3
Induces the Expression of the Stenotrophomonas maltophilia SmeVWX Multidrug Efflux Pump
Authors: Blanco P. , Corona F. , Sánchez M. B. , Martínez J. L.
Published: February 2017

Stenotrophomonas maltophilia
is an opportunistic pathogen with increasing prevalence, which is able to cause infections in immunocompromised patients or in those with a previous pathology. The treatment of the infections caused by this bacterium is often complicated due to the several intrinsic antibiotic resistance mechanisms that it presents. Multidrug efflux pumps are among the best-studied mechanisms of
S. maltophilia
antibiotic resistance. Some of these efflux pumps have a basal expression level but, in general, their expression is often low and only reaches high levels when the local regulator is mutated or bacteria are in the presence of an effector. In the current work, we have developed a yellow fluorescent protein (YFP)-based sensor with the aim to identify effectors able to trigger the expression of SmeVWX, an efflux pump that confers resistance to quinolones, chloramphenicol, and tetracycline when it is expressed at high levels. With this purpose in mind, we tested a variety of different compounds and analyzed the fluorescence signal given by the expression of YFP under the control of the
smeVWX
promoter. Among the tested compounds, vitamin K
3
, which is a compound belonging to the 2-methyl-1,4-naphthoquinone family, is produced by plants in defense against infection, and has increasing importance in human therapy, was able to induce the expression of the SmeVWX efflux pump. In addition, a decrease in the susceptibility of
S. maltophilia
to ofloxacin and chloramphenicol was observed in the presence of vitamin K
3
, in both wild-type and
smeW
-deficient strains.
Bactericidal and Fungicidal Activity of
N
-Chlorotaurine Is Enhanced in Cystic Fibrosis Sputum Medium
Authors: Gruber Martina , Moser Ivan , Nagl Markus , Lackner Michaela
Published: February 2017

Lung infections with multiresistant pathogens are a major problem among patients suffering from cystic fibrosis (CF).
N
-Chlorotaurine (NCT), a microbicidal active chlorine compound with no development of resistance, is well tolerated upon inhalation. The aim of this study was to investigate the
in vitro
bactericidal and fungicidal activity of NCT in artificial sputum medium (ASM), which mimics the composition of CF mucus. The medium was inoculated with bacteria (
Staphylococcus aureus
, including some methicillin-resistant
S. aureus
[MRSA] strains,
Pseudomonas aeruginosa
, and
Escherichia coli
) or spores of fungi (
Aspergillus fumigatus
,
Aspergillus terreus
,
Candida albicans
,
Scedosporium apiospermum
,
Scedosporium boydii
,
Lomentospora prolificans
,
Scedosporium aurantiacum
,
Scedosporium minutisporum
,
Exophiala dermatitidis
, and
Geotrichum
sp.), to final concentrations of 10
7
to 10
8
CFU/ml. NCT was added at 37°C, and time-kill assays were performed. At a concentration of 1% (10 mg/ml, 55 mM) NCT, bacteria and spores were killed within 10 min and 15 min, respectively, to the detection limit of 10
2
CFU/ml (reduction of 5 to 6 log
10
units). Reductions of 2 log
10
units were still achieved with 0.1% (bacteria) and 0.3% (fungi) NCT, largely within 10 to 30 min. Measurements by means of iodometric titration showed oxidizing activity for 1, 30, 60, and >60 min at concentrations of 0.1%, 0.3%, 0.5%, and 1.0% NCT, respectively, which matches the killing test results. NCT demonstrated broad-spectrum microbicidal activity in the milieu of CF mucus at concentrations ideal for clinical use. The microbicidal activity of NCT in ASM was even stronger than that in buffer solution; this was particularly pronounced for fungi. This finding can be explained largely by the formation, through transhalogenation, of monochloramine, which rapidly penetrates pathogens.
Expression of the
aac(6′)-Ib-cr
Gene in Class 1 Integrons
Authors: Raherison Sophie , Jove Thomas , Gaschet Margaux , Pinault Emilie , Tabesse Aurore , Torres Carmen , Ploy Marie-Cécile
Published: February 2017

aac(6′)-Ib-cr
is a plasmid-mediated quinolone resistance gene embedded within a gene cassette, most often within an integron. It confers resistance to quinolones and aminoglycosides. We investigated the role of a 101-bp fragment frequently present upstream of the
aac(6′)-Ib-cr
gene cassette and found that it contributes to the expression of
aac(6′)-Ib-cr
and provides an alternative start codon, confirming the length of the AAC(6′)-Ib-cr protein to 199 amino acids.
Chlamydia trachomatis Cellular Exit Alters Interactions with Host Dendritic Cells
Authors: Sherrid Ashley M. , Hybiske Kevin
Published: February 2017

The strategies utilized by pathogens to exit host cells are an area of pathogenesis which has received surprisingly little attention, considering the necessity of this step for infections to propagate. Even less is known about how exit through these pathways affects downstream host-pathogen interactions and the generation of an immune response.Chlamydia trachomatisexits host epithelial cells through two equally active mechanisms: lysis and extrusion. Studies have characterized the outcome of interactions between host innate immune cells, such as dendritic cells and macrophages, and free, extracellularChlamydiabacteria, such as those resulting from lysis. Exit via extrusion generates a distinct, host-membrane-bound compartment ofChlamydiaseparate from the original infected cell. In this study, we assessed the effect of containment within extrusions upon the interaction betweenChlamydiaand host dendritic cells. Extrusion dramatically affected the outcome ofChlamydia-dendritic cell interactions for both the bacterium and the host cell. Dendritic cells rapidly underwent apoptosis in response to engulfment of an extrusion, while uptake of an equivalent dose of freeChlamydiahad no such effect. Containment within an extrusion also prolonged bacterial survival within dendritic cells and altered the initial innate immune signaling by the dendritic cell.
Intact Pneumococci Trigger Transcription of Interferon-Related Genes in Human Monocytes, while Fragmented, Autolyzed Bacteria Subvert This Response
Authors: Skovbjerg Susann , Nordén Rickard , Martner Anna , Samuelsson Ebba , Hynsjö Lars , Wold Agnes E.
Published: February 2017

A peculiar trait of pneumococci (Streptococcus pneumoniae) is their propensity to undergo spontaneous lysis during stationary growth due to activation of the enzyme autolysin (LytA), which fragments the peptidoglycan cell wall. The fragments that are generated upon autolysis impair phagocytosis and reduce production of interleukin-12 (IL-12) and gamma interferon (IFN-γ) by human leukocytes in response to intact pneumococci, thereby impeding crucial host defenses. The objective was to identify additional monocyte genes whose transcription is induced by intact pneumococci and subverted by autolyzed bacteria. Monocytes were isolated from healthy blood donors and stimulated for 3 h with UV-inactivatedS. pneumoniae(Rx1PLY−LytA+strain), which is capable of autolyzing, its LytA−isogenic autolysin-deficient mutant, or a mixture of the two (containing twice the initial bacterial concentration). Gene expression was assessed by Illumina microarray, and selected findings were confirmed by reverse transcription-quantitative real-time PCR (RT-qPCR), enzyme-linked immunosorbent assay (ELISA), and flow cytometry. In all, we identified 121 genes that were upregulated to a significantly higher degree by intact than autolyzed pneumococci. These included IFNB1 and a large set of interferon-induced genes, such as IFIT3, RSAD2, CFCL1, and CXCL10 genes, as well as IL12B and CD40 genes. RT-qPCR revealed that transcription of these genes in response to intact pneumococci diminished when autolyzed pneumococci were admixed and that this pattern was independent of pneumolysin. Thus, transcription of interferon-related genes is triggered by intact pneumococci and subverted by fragments generated by spontaneous bacterial autolysis. We suggest that interferon-related pathways are important for elimination of pneumococci and that autolysis contributes to virulence by extinguishing these pathways.
Dynamic Expansion and Contraction ofcagACopy Number inHelicobacter pyloriImpact Development of Gastric Disease
Authors: Jang Sungil , Su Hanfu , Blum Faith C. , Bae Sarang , Choi Yun Hui , Kim Aeryun , Hong Youngmin A. , Kim Jinmoon , Kim Ji-Hye , Gunawardhana Niluka , Jeon Yeong-Eui , Yoo Yun-Jung , Merrell D. Scott , Ge Linhu , Cha Jeong-Heon
Published: February 2017

Infection withHelicobacter pyloriis a major risk factor for development of gastric disease, including gastric cancer. Patients infected withH. pyloristrains that express CagA are at even greater risk of gastric carcinoma. Given the importance of CagA, this report describes a new molecular mechanism by which thecagAcopy number dynamically expands and contracts inH. pylori. Analysis of strain PMSS1 revealed a heterogeneous population in terms of numbers ofcagAcopies; strains carried from zero to four copies ofcagAthat were arranged as direct repeats within the chromosome. Each of the multiple copies ofcagAwas expressed and encoded functional CagA; strains with morecagArepeats exhibited higher levels of CagA expression and increased levels of delivery and phosphorylation of CagA within host cells. This concomitantly resulted in more virulent phenotypes as measured by cell elongation and interleukin-8 (IL-8) induction. Sequence analysis of the repeat region revealed threecagAhomologous areas (CHAs) within thecagArepeats. Of these, CHA-ud flanked each of thecagAcopies and is likely important for the dynamic variation ofcagAcopy numbers. Analysis of a large panel of clinical isolates showed that 7.5% ofH. pyloristrains isolated in the United States harbored multiplecagArepeats, while none of the tested Korean isolates carried more than one copy ofcagA. Finally,H. pyloristrains carrying multiplecagAcopies were differentially associated with gastric disease. Thus, the dynamic expansion and contraction ofcagAcopy numbers may serve as a novel mechanism by whichH. pylorimodulates gastric disease development.

IMPORTANCESeverity ofH. pylori-associated disease is directly associated with carriage of the CagA toxin. Though the sequences of the CagA protein can differ across strains, previous analyses showed that virtually allH. pyloristrains carry one or no copies ofcagA. This study showed thatH. pylorican carry multiple tandem copies ofcagAthat can change dynamically. Isolates harboring morecagAcopies produced more CagA, thus enhancing toxicity to host cells. Analysis of 314H. pyloriclinical strains isolated from patients in South Korea and the United States showed that 7.5% of clinical strains in the United States carried multiplecagAcopies whereas none of the South Korean strains did. This study demonstrated a novel molecular mechanism by whichH. pyloridynamically modulatescagAcopy number, which affects CagA expression and activity and may impact downstream development of gastric disease.
The Source and Evolutionary History of a Microbial Contaminant Identified Through Soil Metagenomic Analysis
Authors: Olm Matthew R. , Butterfield Cristina N. , Copeland Alex , Boles T. Christian , Thomas Brian C. , Banfield Jillian F.
Published: February 2017

In this study, strain-resolved metagenomics was used to solve a mystery. A 6.4-Mbp complete closed genome was recovered from a soil metagenome and found to be astonishingly similar to that of
Delftia acidovorans
SPH-1, which was isolated in Germany a decade ago. It was suspected that this organism was not native to the soil sample because it lacked the diversity that is characteristic of other soil organisms; this suspicion was confirmed when PCR testing failed to detect the bacterium in the original soil samples.
D. acidovorans
was also identified in 16 previously published metagenomes from multiple environments, but detailed-scale single nucleotide polymorphism analysis grouped these into five distinct clades. All of the strains indicated as contaminants fell into one clade. Fragment length anomalies were identified in paired reads mapping to the contaminant clade genotypes only. This finding was used to establish that the DNA was present in specific size selection reagents used during sequencing. Ultimately, the source of the contaminant was identified as bacterial biofilms growing in tubing. On the basis of direct measurement of the rate of fixation of mutations across the period of time in which contamination was occurring, we estimated the time of separation of the contaminant strain from the genomically sequenced ancestral population within a factor of 2. This research serves as a case study of high-resolution microbial forensics and strain tracking accomplished through metagenomics-based comparative genomics. The specific case reported here is unusual in that the study was conducted in the background of a soil metagenome and the conclusions were confirmed by independent methods.

IMPORTANCE
It is often important to determine the source of a microbial strain. Examples include tracking a bacterium linked to a disease epidemic, contaminating the food supply, or used in bioterrorism. Strain identification and tracking are generally approached by using cultivation-based or relatively nonspecific gene fingerprinting methods. Genomic methods have the ability to distinguish strains, but this approach typically has been restricted to isolates or relatively low-complexity communities. We demonstrate that strain-resolved metagenomics can be applied to extremely complex soil samples. We genotypically defined a soil-associated bacterium and identified it as a contaminant. By linking together snapshots of the bacterial genome over time, it was possible to estimate how long the contaminant had been diverging from a likely source population. The results are congruent with the derivation of the bacterium from a strain isolated in Germany and sequenced a decade ago and highlight the utility of metagenomics in strain tracking.
Mutation of the N-Terminal Region of Chikungunya Virus Capsid Protein: Implications for Vaccine Design
Authors: Taylor Adam , Liu Xiang , Zaid Ali , Goh Lucas Y. H. , Hobson-Peters Jody , Hall Roy A. , Merits Andres , Mahalingam Suresh
Published: February 2017

Mosquito-transmitted chikungunya virus (CHIKV) is an arthritogenic alphavirus of the
Togaviridae
family responsible for frequent outbreaks of arthritic disease in humans. Capsid protein, a structural protein encoded by the CHIKV RNA genome, is able to translocate to the host cell nucleolus. In encephalitic alphaviruses, nuclear translocation induces host cell transcriptional shutoff; however, the role of capsid protein nucleolar localization in arthritogenic alphaviruses remains unclear. Using recombinant enhanced green fluorescent protein (EGFP)-tagged expression constructs and CHIKV infectious clones, we describe a nucleolar localization sequence (NoLS) in the N-terminal region of capsid protein, previously uncharacterized in CHIKV. Mutation of the NoLS by site-directed mutagenesis reduced efficiency of nuclear import of CHIKV capsid protein. In the virus, mutation of the capsid protein NoLS (CHIKV-NoLS) attenuated replication in mammalian and mosquito cells, producing a small-plaque phenotype. Attenuation of CHIKV-NoLS is likely due to disruption of the viral replication cycle downstream of viral RNA synthesis. In mice, CHIKV-NoLS infection caused no disease signs compared to wild-type CHIKV (CHIKV-WT)-infected mice; lack of disease signs correlated with significantly reduced viremia and decreased expression of proinflammatory factors. Mice immunized with CHIKV-NoLS, challenged with CHIKV-WT at 30 days postimmunization, develop no disease signs and no detectable viremia. Serum from CHIKV-NoLS-immunized mice is able to efficiently neutralize CHIKV infection
in vitro
. Additionally, CHIKV-NoLS-immunized mice challenged with the related alphavirus Ross River virus showed reduced early and peak viremia postchallenge, indicating a cross-protective effect. The high degree of CHIKV-NoLS attenuation may improve CHIKV antiviral and rational vaccine design.

IMPORTANCE
CHIKV is a mosquito-borne pathogen capable of causing explosive epidemics of incapacitating joint pain affecting millions of people. After a series of major outbreaks over the last 10 years, CHIKV and its mosquito vectors have been able to expand their range extensively, now making CHIKV a human pathogen of global importance. With no licensed vaccine or antiviral therapy for the treatment of CHIKV disease, there is a growing need to understand the molecular determinants of viral pathogenesis. These studies identify a previously uncharacterized nucleolar localization sequence (NoLS) in CHIKV capsid protein, begin a functional analysis of site-directed mutants of the capsid protein NoLS, and examine the effect of the NoLS mutation on CHIKV pathogenesis
in vivo
and its potential to influence CHIKV vaccine design. A better understanding of the pathobiology of CHIKV disease will aid the development of effective therapeutic strategies.
Uncovering the Horseshoe Effect in Microbial Analyses
Authors: Morton James T. , Toran Liam , Edlund Anna , Metcalf Jessica L. , Lauber Christian , Knight Rob
Published: February 2017

The horseshoe effect is often considered an artifact of dimensionality reduction. We show that this is not true in the case for microbiome data and that, in fact, horseshoes can help analysts discover microbial niches across environments.
Case of primary bilateral diffuse large B-cell lymphoma of the ovary with plasmablastic features in an HIV-negative female patient
Authors: Guvvala Suvarna L , Sakam Sailaja , Niazi Masooma , Alagkiozidis Ioannis , Skaradinskiy Yevgeniy
Published: February 2017

A 37-year-old woman from Puerto Rico was incidentally found to have bilateral ovarian masses during a laparoscopy for sterilization. CT of the abdomen and pelvis with contrast showed bilateral large heterogeneous adnexal masses with large ascites and right pleural effusion. Tumour markers CA 125 was 766 U/mL and lactate dehydrogenase was 654 U/L. She underwent total laparoscopy hysterectomy, bilateral salpingo-oophorectomy with pelvic lymph node dissection and partial omentectomy. Pathology of ovarian masses revealed a diffuse large B-cell lymphoma. The staging work-up was negative, which pointed towards the diagnosis of primary ovarian lymphoma. The patient completed 8 cycles of cyclophosphamide, doxorubicin, vincristine, prednisolone chemotherapy. After 18 months of chemotherapy completion, she remains in remission.
Case of a cerebral abscess caused byPorphyromonas gingivalisin a subject with periodontitis
Authors: Van der Cruyssen Frederic , Grisar Koenraad , Maes Honorine , Politis Constantinus
Published: February 2017

We report the case of a 65-year-old man presenting with generalised seizures after developing a right frontal brain abscess. Stereotactic aspiration and subsequent matrix assisted laser desorption/ionisation time-of-flight analyzer (MALDI-TOF) spectrometry revealedPorphyromonas gingivalisas the only causative anaerobe microorganism. Secondary incision and drainage was required due to neurological deterioration with increased dimensions of the abscess, intracranial pressure and formation of a subdural occipitoparietal empyema. Oral imaging was positive for apical periodontitis of multiple elements; therefore, the remaining dentition was removed. Targeted antibiotic treatment included intravenous ceftriaxone and ornidazole. The patient was discharged to our revalidation unit 59 days after admission to make a full recovery. To the best of our knowledge, this is the sixth reported case ofP. gingivaliscausing an intracranial abscess and the third case of a true intracerebral parenchymal abscess caused by this bacterium.
Triamcinolone emboli leading to central retinal artery occlusion: a multimodal imaging study
Authors: Gaur Nripen , Singh Pallavi , Chawla Rohan , Takkar Brijesh
Published: February 2017

A 19-year-old man presented with unilateral sudden onset vision loss following an intra-articular triamcinolone injection in the right temporomandibular joint. At fundus examination emboli of triamcinolone were visible in multiple retinal arteries. Choroidal ischaemia and occlusion of the central retinal artery and its branches were documented at fluorescein angiography. Optical coherence tomography revealed significant thickening of the inner retinal layers. Optical coherence tomography angiography clearly demonstrated an abrupt cut-off of flow in a vessel below the optic disc. Lack of perfusion of the superficial and deep retinal plexuses beyond the areas of embolisation and at the posterior pole was also appreciated. The visual outcome was poor despite treatment.
Periprocedural outcomes and early safety with the use of the Pipeline Flex Embolization Device with Shield Technology for unruptured intracranial aneurysms: preliminary results from a prospective clinical study
Authors: Martínez-Galdámez Mario , Lamin Saleh M , Lagios Konstantinos G , Liebig Thomas , Ciceri Elisa F , Chapot Rene , Stockx Luc , Chavda Swarupsinh , Kabbasch Christoph , Farago Giuseppe , Nordmeyer Hannes , Boulanger Thierry , Piano Mariangela , Boccardi Edoardo P
Published: February 2017

Background and purpose

The Pipeline Embolization Device (PED) has become a routine first-line option for treatment of intracranial aneurysms (IAs). We assessed the early safety and technical success of a new version of PED, Pipeline Flex Embolization Device with Shield Technology (Pipeline Shield), which has the same design and configuration but has been modified to include a surface synthetic biocompatible polymer.

Materials and methods

The Pipeline Flex Embolization Device with Shield Technology (PFLEX) study is a prospective, single-arm, multicenter study for the treatment of unruptured IAs using Pipeline Shield. The primary study endpoints included the occurrence of major stroke in the territory supplied by the treated artery or neurologic death at 1 year post-procedure. Secondary endpoints included the rate of Pipeline Shield-related or procedure-related serious or non-serious adverse events. Analyses were conducted to evaluate early safety findings in the 30-day post-procedure period as well as technical procedural success outcomes.

Results

Fifty patients with 50 unruptured target IAs were enrolled. Mean aneurysm diameter was 8.82±6.15 mm. Thirty-eight aneurysms (76%) were small (<10 mm). Device deployment was technically successful with 98% of devices. Complete wall apposition was achieved immediately post-procedure in 48 cases (96%). No major strokes or neurologic deaths were reported in the 30-day post-procedure period.

Conclusions

The results of this first experience with the new Pipeline Flex corroborate the early safety of the device. Mid-term and long-term follow-up examinations will provide data on safety outcomes at the 6-month and 1-year follow-up periods.

Clinical trial registration

NCT02390037.
Failure in anisotropic sensitive clays: finite element study of Perniö failure test
Authors: D’Ignazio Marco , Länsivaara Tim Tapani , Jostad Hans Petter
Published: February 2017

The railway network on coastal areas of Finland is predominantly located in soft clay areas. The undrained shear strength of such clays is generally low, highly anisotropic, and rate dependent, and it exhibits post-peak strain softening under undrained conditions. A full-scale failure test was performed by Tampere University of Technology in Perniö, Western Finland, in 2009. A shallow railway embankment built on a soft clay deposit was equipped with a loading structure and loaded to failure in about 30 h. The embankment collapsed 2 h after the last loading step. In this study, data collected from the experiment are used, together with laboratory test results on high-quality samples, to conduct advanced finite element analysis of the Perniö failure test. The NGI-ADPSoft model is used for this purpose, which is capable of simulating the strain-softening behavior of the clay. Even though the observed rate effect is not taken into account in the analyses, the failure load can be predicted reasonably well. Good agreement is also observed for calculated displacements and failure mechanism with experimental observations.
Undrained stability of rectangular tunnels where shear strength increases linearly with depth
Authors: Wilson Daniel W. , Abbo Andrew J. , Sloan Scott W. , Yamamoto Kentaro
Published: February 2017

This paper investigates the stability of a plane strain rectangular tunnel under undrained conditions, where the shear strength profile increases linearly with depth. The undrained stability of tunnels for a range of geometries and soil conditions is found using rigid-block upper bound methods as well as finite element limit analysis (FELA). The latter procedures employ a discrete form of the bound theorems of classical plasticity to formulate an optimization problem that is solved using a bespoke conic programming scheme. Rigorous solutions, obtained using adaptive re-meshing of the finite element mesh, generally bracket the true collapse load with upper and lower bound solutions to within 2%. Results from the parametric study are summarized in the form of stability charts.
Different electrophysiological effects of the levo- and dextro-rotatory isomers of mexiletine in isolated rabbit cardiac muscle
Authors: Gurabi Zsolt , Patocskai Bence , Györe Balázs , Virág László , Mátyus Péter , Papp Julius Gy. , Varró András , Koncz István
Published: February 2017

Racemic mexiletine is a widely used antiarrhythmic agent that blocks sodium channels. The effects of R-(−) and S-(+) mexiletine stereoisomers on maximum rate of depolarization ([Formula: see text]), conduction time, and repolarization have not yet been investigated in isolated cardiac preparations. We studied the effect of the R-(−) and S-(+) mexiletine on rabbit cardiac action potential parameters by using the conventional microelectrode technique. Both enantiomers at 20 μmol/L of therapeutically and experimentally relevant concentration, significantly depressed the [Formula: see text] at fast heart rates (BCLs 300–700 ms). R-(−) mexiletine has more potent inhibitory effect than S-(+) mexiletine. Both R-(−) and S-(+) mexiletine significantly inhibited the [Formula: see text] of early extrasystoles measured at 70 ms diastolic interval induced by S1–S2 stimuli. R-(−) mexiletine has more pronounced inhibitory effect than S-(+) mexiletine. Both R-(−) and S-(+) mexiletine increased significantly the ERP/APD90ratio. The time constant (τ) of recovery of [Formula: see text] was found to be τ = 376.0 ± 77.8 ms for R-(−) mexiletine and τ = 227.1 ± 23.4 ms for S-(+) mexiletine, which indicates a slower offset kinetics for R-(−) mexiletine from sodium channels than that of the S-(+) enantiomer. These data suggest that R-(−) mexiletine might be a more potent antiarrhythmic agent than S-(+) mexiletine.
Fuzzy Control for Walking Balance of the Biped Robot Using ZMP Criterion
Authors: Luat Tran Huu , Kim Yong-Tae
Published: February 2017

The dynamic walking stability of biped robot is a challenging research topic. In this paper, the fuzzy controller on zero movement point (ZMP) criterion is implemented to maintain the balance of dynamic walking. We designed a force sensitive resistor (FSR) sensor circuits to collect information from the sensors for the ZMP trajectory tracking. The robot walking has an imbalance when the ZMP shows the risk of moving out the footprint. The fuzzy controller is provided to drive the ZMP inside the ZMP reference area, by adjusting a suitable angle for the ankle and hip joint. In order to determine the ZMP reference, we compute the inverse kinematic and Jacobian coordinates from the biped robot model. In this research, we also introduce the biped robot configuration for control dynamic walking. A user interface is designed to conventionally observe the ZMP trajectory generation. The experimental results for stability of dynamic walking are presented to appreciate the proposed method.
Bis(hafnium(IV) stapled phthalocyanine) derivative complex. Synthesis and structure
Authors: Janczak Jan , Kubiak Ryszard
Published: February 2017

Thermal reaction of phthalonitrile with hafnium powder under iodine monobromide (IBr) yields a new type molecule: bis(hafnium(IV) stapled phthalocyanine) derivative complex. X-ray single crystal analysis shows that the complex molecule consists of two hafnium phthalocyanine units bridged by the unique internal ligand that stapled by two carbon–carbon [Formula: see text] bonds to both HfPc-units. The internal dianionic ligand consists of two fragments, each of them present the three fourth part of phthalocyaninate ring. Both fragments are linked together through the bridging 1,2-di[amine(imine)methyl]benzene. The X-ray conformation of the bis(hafnium(IV) stapled phthalocyanine) derivative complex cation is confirmed by DFT calculations. An absence of the Q-band in the UV-vis spectrum, the typical band for the fully delocalized [Formula: see text]-electron aromatic phthalocyaninato(2-) ring system, indicates on drastic modification of the chromophore in this Hf-phthalocyanine complex that was confirmed by TD DFT calculations.
The research progress of polyhedral oligomeric silsesquioxane (POSS) applied to electrical energy storage elements
Authors: Chen Hong-Li , Jiao Xiao-Ning , Zhou Jin-Tao
Published: February 2017

Polyhedral oligomeric silsesquioxane (POSS) is a kind of organic–inorganic hybrid nanoparticle. This paper introduces the research progress of different kind of POSS organic–inorganic hybrid nanoparticles applied to lithium-ion batteries, fuel batteries, and supercapacitors by researchers on mechanical properties, thermal properties and electrochemistry properties. The results showed that the ionic conductivity of POSS/Li-ion solid polymer electrolyte reached 3.26[Formula: see text][Formula: see text][Formula: see text]10[Formula: see text][Formula: see text]S/cm and mechanical properties were commendable. The proton conductivity of POSS hybrid proton exchange membranes came to the level of 6.46[Formula: see text][Formula: see text][Formula: see text]10[Formula: see text][Formula: see text]S/cm and the mechanical strength was 18[Formula: see text]MPa with less content of POSS. With the inorganic core of POSS, smaller and more uniform multi-pore electrode materials offer a new idea on the fabrication of supercapacitor electrode materials.
DOES ADOPTION OF MULTIPLE CLIMATE-SMART PRACTICES IMPROVE FARMERS’ CLIMATE RESILIENCE? EMPIRICAL EVIDENCE FROM THE NILE BASIN OF ETHIOPIA
Authors: TEKLEWOLD HAILEMARIAM , MEKONNEN ALEMU , KOHLIN GUNNAR , DI FALCO SALVATORE
Published: February 2017

There is a paucity of information on conditioning factors that hinder or promote adoption of multiple climate-smart practices and on the synergies among such practices in increasing household resilience by improving agricultural income. This study analyzes how heat, rainfall, and rainfall variability affect farmers’ choices of a portfolio of potential climate smart practices — agricultural water management, improved crop seeds, and fertilizer — and the impact of these practices on farm income in the Nile Basin of Ethiopia. We apply a multinomial endogenous switching regression approach by modeling combinations of practices and net farm income for each combination as depending on household and farm characteristics and on a set of climatic variables based on geo-referenced historical precipitation and temperature data. A primary result of this study is that farmers are less likely to adopt fertilizer (either alone or in combination with improved varieties) in areas of greater rainfall variability. However, even when there is high variability in rainfall, farmers are more likely to adopt these two yield-increasing inputs when they choose to (and are able to) include the third part of the portfolio: agricultural water management. Net farm income responds positively to agricultural water management, improved crop variety or fertilizer when they are adopted in isolation as well as in combination. But this effect is greater when these practices are combined. Simulation results suggest that a warming temperature and decreased precipitation in future decades will make it less likely that farmers will adopt practices in isolation but more likely that they will adopt a combination of practices. Hence, a package approach rather than a piecemeal approach is needed to maximize the synergies implicit in various climate smart practices.
Development of Data Acquisition Methods for an FPGA-Based Photon Counting Detector
Authors: Ambily S. , Sarpotdar Mayuresh , Mathew Joice , Sreejith A. G. , Nirmal K. , Prakash Ajin , Safonova Margarita , Murthy Jayant
Published: February 2017

MCP-based detectors are widely used in the ultraviolet (UV) region due to their low noise levels, high sensitivity and good spatial and temporal resolution. We have developed a compact near-UV (NUV) detector for high-altitude balloon and space flights, using off-the-shelf MCP, CMOS sensor, and optics. The detector is designed to be capable of working in the direct frame transfer mode as well in the photon counting mode for single photon event detection. The identification and centroiding of each photon event are done using an FPGA-based data acquisition and real-time processing system. In this paper, we discuss various algorithms and methods used in both operating modes, as well as their implementation on the hardware.
New Strategies and Tools in Quantitative Genetics: How to Go from the Phenotype to the Genotype
Authors: Bazakos Christos , Hanemian Mathieu , Trontin Charlotte , Jiménez-Gómez José M. , Loudet Olivier
Published: February 2017

Quantitative genetics has a long history in plants: It has been used to study specific biological processes, identify the factors important for trait evolution, and breed new crop varieties. These classical approaches to quantitative trait locus mapping have naturally improved with technology. In this review, we show how quantitative genetics has evolved recently in plants and how new developments in phenotyping, population generation, sequencing, gene manipulation, and statistics are rejuvenating both the classical linkage mapping approaches (for example, through nested association mapping) as well as the more recently developed genome-wide association studies. These strategies are complementary in most instances, and indeed, one is often used to confirm the results of the other. Despite significant advances, an emerging trend is that the outcome and efficiency of the different approaches depend greatly on the genetic architecture of the trait in the genetic material under study.
Plant Mitochondrial Genomes: Dynamics and Mechanisms of Mutation
Authors: Gualberto José M. , Newton Kathleen J.
Published: February 2017

The large mitochondrial genomes of angiosperms are unusually dynamic because of recombination activities involving repeated sequences. These activities generate subgenomic forms and extensive genomic variation even within the same species. Such changes in genome structure are responsible for the rapid evolution of plant mitochondrial DNA and for the variants associated with cytoplasmic male sterility and abnormal growth phenotypes. Nuclear genes modulate these processes, and over the past decade, several of these genes have been identified. They are involved mainly in pathways of DNA repair by homologous recombination and mismatch repair, which appear to be essential for the faithful replication of the mitogenome. Mutations leading to the loss of any of these activities release error-prone repair pathways, resulting in increased ectopic recombination, genome instability, and heteroplasmy. We review the present state of knowledge of the genes and pathways underlying mitochondrial genome stability.
Assessing Cartilage Biomechanical Properties: Techniques for Evaluating the Functional Performance of Cartilage in Health and Disease
Authors: Lakin Benjamin A. , Snyder Brian D. , Grinstaff Mark W.
Published: February 2017

Osteoarthritis (OA) affects millions of people and results in weakened hyaline cartilage due to overloading. During joint articulation, hyaline cartilage must withstand high loads while maintaining low friction to prevent wear and tissue loss. Thus, cartilage compressive stiffness and the coefficient of friction are important indicators of the tissue's functional performance. These mechanical properties are often measured ex vivo using mechanical testing regimens, but arthroscopic handheld probes (e.g., for indentation testing, ultrasound, and optical coherence tomography) and noninvasive imaging modalities (e.g., magnetic resonance imaging and computed tomography) provide opportunities for either direct or indirect in vivo assessment of cartilage mechanical properties. In this review, we examine the application of these techniques for evaluating cartilage, with a focus on measuring mechanical properties for early-stage OA diagnosis. For each approach, we discuss the advantages, disadvantages, current and potential clinical utility, and promising technological improvement.
Overcoming Immune Dysregulation with Immunoengineered Nanobiomaterials
Authors: Scott Evan A. , Karabin Nicholas B. , Augsornworawat Punn
Published: February 2017

The immune system is governed by an immensely complex network of cells and both intracellular and extracellular molecular factors. It must respond to an ever-growing number of biochemical and biophysical inputs by eliciting appropriate and specific responses in order to maintain homeostasis. But as with any complex system, a plethora of false positives and false negatives can occur to generate dysregulated responses. Dysregulated immune responses are essential components of diverse inflammation-driven pathologies, including cancer, heart disease, and autoimmune disorders. Nanoscale biomaterials (i.e., nanobiomaterials) have emerged as highly customizable platforms that can be engineered to interact with and direct immune responses, holding potential for the design of novel and targeted approaches to redirect or inhibit inflammation. Here, we present recent developments of nanobiomaterials that were rationally designed to target and modulate inflammatory cells and biochemical pathways for the treatment of immune dysregulation.
Sulfation of Glycosaminoglycans and Its Implications in Human Health and Disorders
Authors: Soares da Costa Diana , Reis Rui L. , Pashkuleva Iva
Published: February 2017

Sulfation is a dynamic and complex posttranslational modification process. It can occur at various positions within the glycosaminoglycan (GAG) backbone and modulates extracellular signals such as cell–cell and cell–matrix interactions; different sulfation patterns have been identified for the same organs and cells during their development. Because of their high specificity in relation to function, GAG sulfation patterns are referred to as the sulfation code. This review explores the role of GAG sulfation in different biological processes at the cell, tissue, and organism levels. We address the connection between the sulfation patterns of GAGs and several physiological processes and discuss the misregulation of GAG sulfation and its involvement in several genetic and metabolic disorders. Finally, we present the therapeutic potential of GAGs and their synthetic mimics in the biomedical field.
Antigen-Presenting Cells in the Skin
Authors: Kashem Sakeen W. , Haniffa Muzlifah , Kaplan Daniel H.
Published: February 2017

Professional antigen-presenting cells (APCs) in the skin include dendritic cells, monocytes, and macrophages. They are highly dynamic, with the capacity to enter skin from the peripheral circulation, patrol within tissue, and migrate through lymphatics to draining lymph nodes. Skin APCs are endowed with antigen-sensing, -processing, and -presenting machinery and play key roles in initiating, modulating, and resolving cutaneous inflammation. Skin APCs are a highly heterogeneous population with functionally specialized subsets that are developmentally imprinted and modulated by local tissue microenvironmental and inflammatory cues. This review explores recent advances that have allowed for a more accurate taxonomy of APC subsets found in both mouse and human skin. It also examines the functional specificity of individual APC subsets and their collaboration with other immune cell types that together promote adaptive T cell and regional cutaneous immune responses during homeostasis, inflammation, and disease.
Procedural Justice and Legal Compliance
Authors: Nagin Daniel S. , Telep Cody W.
Published: February 2017

This article reviews the evidence on whether procedurally just treatment of citizens by agents of the criminal justice system, usually the police, has the effect of increasing the citizen's compliance with the law. In brief, we find that perception-based studies consistently show that citizen perceptions of procedurally just treatment are closely tied to perceptions of police legitimacy, and that with only a few exceptions perceptions of legitimacy are strongly associated with legal compliance. However, what has not been established is whether these associations reflect a causal connection whereby changes in policies that are effective in changing actual procedurally just treatment of citizens by police and others lead to changes in legal compliance and perceived legitimacy. Three priority areas for future research are identified: (a) devising and testing a theory of the cumulative effects of experience and community and situational context on perceptions of procedurally just treatment and perceptions of legitimacy, (b) filling out and testing a theory of the circumstances in which improved perceptions of legitimacy translate into greater legal compliance, and (c) designing and evaluating policies and training protocols that are effective in translating the constituent components of procedurally just treatment into improved legal compliance.