bluuebunny/crossref_metadata_2025 huggingface dataset:
Anticancer effects of resveratrol in canine hemangiosarcoma cell lines
Authors: Carlson A. , Alderete K. S. , Grant M. K. O. , Seelig D. M. , Sharkey L. C. , Zordoky B. N. M.
Published: December 2017

Hemangiosarcoma (HSA) is a highly malignant tumour with aggressive biological behaviour. HSAs are more common in dogs than other domestic animals. The median survival time of dogs with HSA remains short, even with chemotherapy and surgery. Therefore, there is a critical need to improve the adjuvant chemotherapeutic regimens to improve clinical outcomes in dogs with HSA. Resveratrol has been shown to possess strong anti‐proliferative and/or pro‐apoptotic properties in human cancer cell lines. Nevertheless, the potential anticancer effects of resveratrol have not been reported in canine HSAs. The objective of this study is to determine the growth inhibitory effects of resveratrol in HSA cells when used alone or in combination with doxorubicin, a commonly used chemotherapeutic agent. Frog and DD‐1 canine HSA cell lines were treated with varying concentrations of resveratrol with and without doxorubicin. Cell viability was measured by the MTT assay. The expression of apoptotic proteins, activation of p38 mitogen‐activated protein kinase (MAPK), AMP‐activated protein kinase (AMPK) and extracellular signal‐regulated kinase 1/2 (ERK1/2) were assessed by western blotting. Similar to human cancer cell lines, resveratrol markedly inhibited the growth and induced apoptosis in both HSA cell lines. Mechanistically, resveratrol activated p38 MAPK, but did not affect the AMPK or the ERK1/2 pathways. Additional experiments showed that resveratrol augmented the growth‐inhibitory and apoptotic effects of doxorubicin in both HSA cell lines. These findings suggest that resveratrol has pro‐apoptotic effects in canine HSA cells; therefore, its use as a potential adjunct therapy in canine HSA patients warrants further investigation.
Estimation of Maximum Pressure Stress Intensity in a Welding Tee
Authors: Blackman Martin
Published: December 2017

The required thickness of welding tees is neither specified in ASME (2012, “Factory-Made Wrought Buttwelding Fittings,” American Society of Mechanical Engineers, New York, Standard No. B16.9-2012) nor is a clear calculation method provided in codes such as ASME (2016, “Process Piping,” American Society of Mechanical Engineers, New York, Standard No. B31.3-2016). This can lead to uncertainty regarding the pressure capacity of a tee fitting, particularly one that has suffered from erosion or corrosion. Code methods including area replacement (ASME, 2016, “Process Piping,” American Society of Mechanical Engineers, New York, Standard No. B31.3-2016) or pressure-area (ASME, 2015, “Boiler and Pressure Vessel Code Section VIII Division 2,” American Society of Mechanical Engineers, New York, Standard No. BPVC-VIII-2-2015; BSI, 2014, “Unfired Pressure Vessels Part 3: Design,” BSI, London, UK, Standard No. BS EN 13445-3) do not directly account for the effect which the curvature of the crotch region may have on the stress state in the tee. The approach adopted in this work is to liken the geometry of the tee crotch to the intrados of a torus or pipe bend. The shell theory applicable to the torus is adapted for the tee in order to derive a relationship for circumferential membrane stress. An equivalent tube radius is assigned by determining the local radius of shell curvature in the plane passing through the crotch center of the curvature. The actual stresses in the tee crotch are significantly reduced by the adjoining straight portions. This effect is difficult to quantify theoretically and has thus been investigated by means of finite element analysis (FEA)-based assessments. An empirical relationship was then established providing a conservative correlation between the theoretical stresses and the program calculated local stress intensities.
Design and Evaluation of an Instrumented Wobble Board for Assessing and Training Dynamic Seated Balance
Authors: Williams Andrew D. , Boser Quinn A. , Kumawat Animesh Singh , Agarwal Kshitij , Rouhani Hossein , Vette Albert H.
Published: December 2017

Methods that effectively assess and train dynamic seated balance are critical for enhancing functional independence and reducing risk of secondary health complications in the elderly and individuals with neuromuscular impairments. The objective of this research was to devise and validate a portable tool for assessing and training dynamic seated balance. An instrumented wobble board was designed and constructed that (1) elicits multidirectional perturbations in seated individuals, (2) quantifies seated balance proficiency, and (3) provides real-time, kinematics-based vibrotactile feedback. After performing a technical validation study to compare kinematic wobble board measurements against a gold-standard motion capture system, 15 nondisabled participants performed a dynamic sitting task using the wobble board. Our results demonstrate that the tilt angle measurements were highly accurate throughout the range of wobble board dynamics. Furthermore, the posturographic analyses for the dynamic sitting task revealed that the wobble board can effectively discriminate between the different conditions of perturbed balance, demonstrating its potential to serve as a clinical tool for the assessment and training of seated balance. Vibrotactile feedback decreased the variance of wobble board tilt, demonstrating its potential for use as a balance training tool. Unlike similar instrumented tools, the wobble board is portable, requires no laboratory equipment, and can be adjusted to meet the user's balance abilities. While future work is warranted, obtained findings will aid in effective translation of assessment and training techniques to a clinical setting, which has the potential to enhance the diagnosis and prognosis for individuals with seated balance impairments.
Effect of carrier bandwidth on integration of simulations of acoustic and electric hearing within or across ears
Authors: Fu Qian-Jie , Galvin John J. , Wang Xiaosong
Published: December 2017

Differences in current spread and/or spread of excitation may differently affect integration of acoustic and electric hearing within (electric-acoustic stimulation, or EAS) or across ears (bimodal). In this study, vowel recognition was measured in normal-hearing subjects listening to simulations of cochlear implant (CI), EAS, and bimodal listening. Residual acoustic hearing was limited between 0.1 and 0.6 kHz. The carrier bandwidth in the CI simulations was varied across carriers: broad-band noise, narrow-band noise, and sine waves. Results showed that reducing the bandwidth (and the inherent noise fluctuations) in the CI simulations significantly affected CI-only and bimodal performance, but not EAS performance.
Thorase variants are associated with defects in glutamatergic neurotransmission that can be rescued by Perampanel
Authors: Umanah George K. E. , Pignatelli Marco , Yin Xiling , Chen Rong , Crawford Joshua , Neifert Stewart , Scarffe Leslie , Behensky Adam A. , Guiberson Noah , Chang Melissa , Ma Erica , Kim Jin Wan , Castro Cibele C. , Mao Xiaobo , Chen Li , Andrabi Shaida A. , Pletnikov Mikhail V. , Pulver Ann E. , Avramopoulos Dimitrios , Bonci Antonello , Valle David , Dawson Ted M. , Dawson Valina L.
Published: December 2017

Rare variants in the enzyme Thorase increase AMPAR expression, resulting in behavioral abnormalities in mice that can be rescued with Perampanel.
NRF2 much of a good thing
Authors: Shoemaker Ashley H.
Published: December 2017

Chronic hyperglycemia induces hypertension and renal injury through nuclear factor erythroid 2–related factor 2 (NRF2)–stimulation of the renin-angiotensin system.
Waltzing around Sacred Cows on the Way to the Future
Authors: Brecher Stephen M.
Published: December 2017

Our mostly manual, agar-based clinical microbiology laboratory is slowly but steadily being redefined by automation and innovation. Ironically, the oldest test, the Gram stain test, is still manually read and interpreted by trained personnel. In a proof-of-concept study, Smith et al. (J. Clin. Microbiol. 56:e01521-17, 2018,
https://doi.org/10.1128/JCM.01521-17
) used computer imaging with a deep convolutional neural network to examine and interpret Gram-stained slides from positive blood culture bottles. In light of the shortage of medical technologists/microbiologists and the need for results from positive blood culture bottles 24/7, this paper paves the way for the next innovations for the clinical microbiology laboratory of the future.
The Three-Fold Axis of the HIV-1 Capsid Lattice Is the Species-Specific Binding Interface for TRIM5α
Authors: Morger Damien , Zosel Franziska , Bühlmann Martin , Züger Sara , Mittelviefhaus Maximilian , Schuler Benjamin , Luban Jeremy , Grütter Markus G.
Published: December 2017

Rhesus TRIM5α (rhTRIM5α) potently restricts replication of human immunodeficiency virus type 1 (HIV-1). Restriction is mediated through direct binding of the C-terminal B30.2 domain of TRIM5α to the assembled HIV-1 capsid core. This host-pathogen interaction involves multiple capsid molecules within the hexagonal HIV-1 capsid lattice. However, the molecular details of this interaction and the precise site at which the B30.2 domain binds remain largely unknown. The human orthologue of TRIM5α (hsTRIM5α) fails to block infection by HIV-1 both
in vivo
and
in vitro
. This is thought to be due to differences in binding to the capsid lattice. To map the species-specific binding surface on the HIV-1 capsid lattice, we used microscale thermophoresis and dual-focus fluorescence correlation spectroscopy to measure binding affinity of rhesus and human TRIM5α B30.2 domains to a series of HIV-1 capsid variants that mimic distinct capsid arrangements at each of the symmetry axes of the HIV-1 capsid lattice. These surrogates include previously characterized capsid oligomers, as well as a novel chemically cross-linked capsid trimer that contains cysteine substitutions near the 3-fold axis of symmetry. The results demonstrate that TRIM5α binding involves multiple capsid molecules along the 2-fold and 3-fold interfaces between hexamers and indicate that the binding interface at the 3-fold axis contributes to the well-established differences in restriction potency between TRIM5α orthologues.

IMPORTANCE
TRIM5α is a cellular protein that fends off infection by retroviruses through binding to the viruses' protein shell surrounding its genetic material. This shell is composed of several hundred capsid proteins arranged in a honeycomb-like hexagonal pattern that is conserved across retroviruses. By binding to the complex lattice formed by multiple capsid proteins, rather than to a single capsid monomer, TRIM5α restriction activity persists despite the high mutation rate in retroviruses such as HIV-1. In rhesus monkeys, but not in humans, TRIM5α confers resistance to HIV-1. By measuring the binding of human and rhesus TRIM5α to a series of engineered HIV-1 capsid mimics of distinct capsid lattice interfaces, we reveal the HIV-1 capsid surface critical for species-specific binding by TRIM5α.
HLA Class I-Mediated HIV-1 Control in Vietnamese Infected with HIV-1 Subtype A/E
Authors: Chikata Takayuki , Tran Giang Van , Murakoshi Hayato , Akahoshi Tomohiro , Qi Ying , Naranbhai Vivek , Kuse Nozomi , Tamura Yoshiko , Koyanagi Madoka , Sakai Sachiko , Nguyen Dung Hoai , Nguyen Dung Thi , Nguyen Ha Thu , Nguyen Trung Vu , Oka Shinichi , Martin Maureen P. , Carrington Mary , Sakai Keiko , Nguyen Kinh Van , Takiguchi Masafumi
Published: December 2017

HIV-1-specific cytotoxic T cells (CTLs) play an important role in the control of HIV-1 subtype B or C infection. However, the role of CTLs in HIV-1 subtype A/E infection still remains unclear. Here we investigated the association of HLA class I alleles with clinical outcomes in treatment-naive Vietnamese infected with subtype A/E virus. We found that HLA-C*12:02 was significantly associated with lower plasma viral loads (pVL) and higher CD4 counts and that the HLA-A*29:01-B*07:05-C*15:05 haplotype was significantly associated with higher pVL and lower CD4 counts than those for individuals without these respective genotypes. Nine Pol and three Nef mutations were associated with at least one HLA allele in the HLA-A*29:01-B*07:05-C*15:05 haplotype, with a strong negative correlation between the number of HLA-associated Pol mutations and CD4 count as well as a positive correlation with pVL for individuals with these HLA alleles. The results suggest that the accumulation of mutations selected by CTLs restricted by these HLA alleles affects HIV control.

IMPORTANCE
Most previous studies on HLA association with disease progression after HIV-1 infection have been performed on cohorts infected with HIV-1 subtypes B and C, whereas few such population-based studies have been reported for cohorts infected with the Asian subtype A/E virus. In this study, we analyzed the association of HLA class I alleles with clinical outcomes for 536 HIV-1 subtype A/E-infected Vietnamese individuals. We found that HLA-C*12:02 is protective, while the HLA haplotype HLA-A*29:01-B*07:05-C*15:05 is deleterious. The individuals with HIV-1 mutations associated with at least one of the HLA alleles in the deleterious HLA haplotype had higher plasma viral loads and lower CD4 counts than those of individuals without the mutations, suggesting that viral adaptation and escape from HLA-mediated immune control occurred. The present study identifies a protective allele and a deleterious haplotype for HIV-1 subtype A/E infection which are different from those identified for cohorts infected with HIV-1 subtypes B and C.
Human Parvovirus B19 Utilizes Cellular DNA Replication Machinery for Viral DNA Replication
Authors: Zou Wei , Wang Zekun , Xiong Min , Chen Aaron Yun , Xu Peng , Ganaie Safder S. , Badawi Yomna , Kleiboeker Steve , Nishimune Hiroshi , Ye Shui Qing , Qiu Jianming
Published: December 2017

Human parvovirus B19 (B19V) infection of human erythroid progenitor cells (EPCs) induces a DNA damage response and cell cycle arrest at late S phase, which facilitates viral DNA replication. However, it is not clear exactly which cellular factors are employed by this single-stranded DNA virus. Here, we used microarrays to systematically analyze the dynamic transcriptome of EPCs infected with B19V. We found that DNA metabolism, DNA replication, DNA repair, DNA damage response, cell cycle, and cell cycle arrest pathways were significantly regulated after B19V infection. Confocal microscopy analyses revealed that most cellular DNA replication proteins were recruited to the centers of viral DNA replication, but not the DNA repair DNA polymerases. Our results suggest that DNA replication polymerase δ and polymerase α are responsible for B19V DNA replication by knocking down its expression in EPCs. We further showed that although RPA32 is essential for B19V DNA replication and the phosphorylated forms of RPA32 colocalized with the replicating viral genomes, RPA32 phosphorylation was not necessary for B19V DNA replication. Thus, this report provides evidence that B19V uses the cellular DNA replication machinery for viral DNA replication.

IMPORTANCE
Human parvovirus B19 (B19V) infection can cause transient aplastic crisis, persistent viremia, and pure red cell aplasia. In fetuses, B19V infection can result in nonimmune hydrops fetalis and fetal death. These clinical manifestations of B19V infection are a direct outcome of the death of human erythroid progenitors that host B19V replication. B19V infection induces a DNA damage response that is important for cell cycle arrest at late S phase. Here, we analyzed dynamic changes in cellular gene expression and found that DNA metabolic processes are tightly regulated during B19V infection. Although genes involved in cellular DNA replication were downregulated overall, the cellular DNA replication machinery was tightly associated with the replicating single-stranded DNA viral genome and played a critical role in viral DNA replication. In contrast, the DNA damage response-induced phosphorylated forms of RPA32 were dispensable for viral DNA replication.
Human Cytomegalovirus UL111A and US27 Gene Products Enhance the CXCL12/CXCR4 Signaling Axis via Distinct Mechanisms
Authors: Tu Carolyn C. , Arnolds Kathleen L. , O'Connor Christine M. , Spencer Juliet V.
Published: December 2017

Human cytomegalovirus (HCMV) is a prevalent pathogen that establishes lifelong infection in the host. Virus persistence is aided by extensive manipulation of the host immune system, particularly cytokine and chemokine signaling pathways. The HCMV UL111A gene encodes cmvIL-10, an ortholog of human interleukin-10 that has many immunomodulatory effects. We found that cmvIL-10 increased signaling outcomes from human CXCR4, a chemokine receptor with essential roles in hematopoiesis and immune cell trafficking, in response to its natural ligand CXCL12. Calcium flux and chemotaxis to CXCL12 were significantly greater in the presence of cmvIL-10 in monocytes, epithelial cells, and fibroblasts that express CXCR4. cmvIL-10 effects on CXCL12/CXCR4 signaling required the IL-10 receptor and Stat3 activation. Heightened signaling occurred both in HCMV-infected cells and in uninfected bystander cells, suggesting that cmvIL-10 may broadly influence chemokine networks by paracrine signaling during infection. Moreover, CXCL12/CXCR4 signaling was amplified in HCMV-infected cells compared to mock-infected cells even in the absence of cmvIL-10. Enhanced CXCL12/CXCR4 outcomes were associated with expression of the virally encoded chemokine receptor US27, and CXCL12/CXCR4 activation was reduced in cells infected with a deletion mutant lacking US27 (TB40/E-mCherry-US27Δ). US27 effects were Stat3 independent but required close proximity to CXCR4 in cell membranes of either HCMV-infected or US27-transfected cells. Thus, HCMV encodes two proteins, cmvIL-10 and US27, that exhibit distinct mechanisms for enhancing CXCR4 signaling. Either individually or in combination, cmvIL-10 and US27 may enable HCMV to exquisitely manipulate CXCR4 signaling to alter host immune responses and modify cell trafficking patterns during infection.

IMPORTANCEThe human chemokine system plays a central role in host defense, as evidenced by the many strategies devised by viruses for manipulating it. Human cytomegalovirus (HCMV) is widespread in the human population, but infection rarely causes disease except in immunocompromised hosts. We found that two different HCMV proteins, cmvIL-10 and US27, act through distinct mechanisms to upregulate the signaling activity of a cellular chemokine receptor, CXCR4. cmvIL-10 is a secreted viral cytokine that affects CXCR4 signaling in both infected and uninfected cells, while US27 is a component of the virus particle and impacts CXCR4 activity only in infected cells. Both cmvIL-10 and US27 promote increased intracellular calcium signaling and cell migration in response to chemokine CXCL12 binding to CXCR4. Our results demonstrate that HCMV exerts fine control over the CXCL12/CXCR4 pathway, which could lead to enhanced virus dissemination, altered immune cell trafficking, and serious health implications for HCMV patients.
Importance of Core Genome Functions for an Extreme Antibiotic Resistance Trait
Authors: Gallagher Larry A. , Lee Samuel A. , Manoil Colin
Published: December 2017

Extreme antibiotic resistance in bacteria is associated with the expression of powerful inactivating enzymes and other functions encoded in accessory genomic elements. The contribution of core genome processes to high-level resistance in such bacteria has been unclear. In the work reported here, we evaluated the relative importance of core and accessory functions for high-level resistance to the aminoglycoside tobramycin in the nosocomial pathogen
Acinetobacter baumannii
. Three lines of evidence establish the primacy of core functions in this resistance. First, in a genome scale mutant analysis using transposon sequencing and validation with 594 individual mutants, nearly all mutations reducing tobramycin resistance inactivated core genes, some with stronger phenotypes than those caused by the elimination of aminoglycoside-inactivating enzymes. Second, the core functions mediating resistance were nearly identical in the wild type and a deletion mutant lacking a genome resistance island that encodes the inactivating enzymes. Thus, most or all of the core resistance determinants important in the absence of the enzymes are also important in their presence. Third, reductions in tobramycin resistance caused by different core mutations were additive, and highly sensitive double and triple mutants (with 250-fold reductions in the MIC) that retained accessory resistance genes could be constructed. Core processes that contribute most strongly to intrinsic tobramycin resistance include phospholipid biosynthesis, phosphate regulation, and envelope homeostasis.

IMPORTANCE
The inexorable increase in bacterial antibiotic resistance threatens to undermine many of the procedures that transformed medicine in the last century. One strategy to meet the challenge antibiotic resistance poses is the development of drugs that undermine resistance. To identify potential targets for such adjuvants, we identified the functions underlying resistance to an important class of antibiotics for one of the most highly resistant pathogens known.
Disabling a Type I-E CRISPR-Cas Nuclease with a Bacteriophage-Encoded Anti-CRISPR Protein
Authors: Pawluk April , Shah Megha , Mejdani Marios , Calmettes Charles , Moraes Trevor F. , Davidson Alan R. , Maxwell Karen L.
Published: December 2017

CRISPR (clustered regularly interspaced short palindromic repeat)-Cas adaptive immune systems are prevalent defense mechanisms in bacteria and archaea. They provide sequence-specific detection and neutralization of foreign nucleic acids such as bacteriophages and plasmids. One mechanism by which phages and other mobile genetic elements are able to overcome the CRISPR-Cas system is through the expression of anti-CRISPR proteins. Over 20 different families of anti-CRISPR proteins have been described, each of which inhibits a particular type of CRISPR-Cas system. In this work, we determined the structure of type I-E anti-CRISPR protein AcrE1 by X-ray crystallography. We show that AcrE1 binds to the CRISPR-associated helicase/nuclease Cas3 and that the C-terminal region of the anti-CRISPR protein is important for its inhibitory activity. We further show that AcrE1 can convert the endogenous type I-E CRISPR system into a programmable transcriptional repressor.

IMPORTANCE
The CRISPR-Cas immune system provides bacteria with resistance to invasion by potentially harmful viruses, plasmids, and other foreign mobile genetic elements. This study presents the first structural and mechanistic insight into a phage-encoded protein that inactivates the type I-E CRISPR-Cas system in
Pseudomonas aeruginosa
. The interaction of this anti-CRISPR protein with the CRISPR-associated helicase/nuclease proteins Cas3 shuts down the CRISPR-Cas system and protects phages carrying this gene from destruction. This interaction also allows the repurposing of the endogenous type I-E CRISPR system into a programmable transcriptional repressor, providing a new biotechnological tool for genetic studies of bacteria encoding this type I-E CRISPR-Cas system.
Phylogenetics of a Fungal Invasion: Origins and Widespread Dispersal of White-Nose Syndrome
Authors: Drees Kevin P. , Lorch Jeffrey M. , Puechmaille Sebastien J. , Parise Katy L. , Wibbelt Gudrun , Hoyt Joseph R. , Sun Keping , Jargalsaikhan Ariunbold , Dalannast Munkhnast , Palmer Jonathan M. , Lindner Daniel L. , Marm Kilpatrick A. , Pearson Talima , Keim Paul S. , Blehert David S. , Foster Jeffrey T.
Published: December 2017

Globalization has facilitated the worldwide movement and introduction of pathogens, but epizoological reconstructions of these invasions are often hindered by limited sampling and insufficient genetic resolution among isolates.
Pseudogymnoascus destructans
, a fungal pathogen causing the epizootic of white-nose syndrome in North American bats, has exhibited few genetic polymorphisms in previous studies, presenting challenges for both epizoological tracking of the spread of this fungus and for determining its evolutionary history. We used single nucleotide polymorphisms (SNPs) from whole-genome sequencing and microsatellites to construct high-resolution phylogenies of
P. destructans
. Shallow genetic diversity and the lack of geographic structuring among North American isolates support a recent introduction followed by expansion via clonal reproduction across the epizootic zone. Moreover, the genetic relationships of isolates within North America suggest widespread mixing and long-distance movement of the fungus. Genetic diversity among isolates of
P. destructans
from Europe was substantially higher than in those from North America. However, genetic distance between the North American isolates and any given European isolate was similar to the distance between the individual European isolates. In contrast, the isolates we examined from Asia were highly divergent from both European and North American isolates. Although the definitive source for introduction of the North American population has not been conclusively identified, our data support the origin of the North American invasion by
P. destructans
from Europe rather than Asia.

IMPORTANCE
This phylogenetic study of the bat white-nose syndrome agent,
P. destructans
, uses genomics to elucidate evolutionary relationships among populations of the fungal pathogen to understand the epizoology of this biological invasion. We analyze hypervariable and abundant genetic characters (microsatellites and genomic SNPs, respectively) to reveal previously uncharacterized diversity among populations of the pathogen from North America and Eurasia. We present new evidence supporting recent introduction of the fungus to North America from a diverse Eurasian population, with limited increase in genetic variation in North America since that introduction.
T Cell Production of GM-CSF Protects the Host during Experimental Tuberculosis
Authors: Robinson Richard T.
Published: December 2017

Although classically associated with myelopoiesis, granulocyte-macrophage colony-stimulating factor (GM-CSF) is increasingly recognized as being important for tuberculosis (TB) resistance. GM-CSF is expressed by nonhematopoietic and hematopoietic lineages following infection withMycobacterium tuberculosisand is necessary to restrictM. tuberculosisgrowth in experimental models. Until the recent study by Rothchild et al. (mBio 8:e01514-17, 2017,https://doi.org/10.1128/mBio.01514-17), it was unknown whether GM-CSF-producing T cells contribute to TB resistance. Rothchild et al. identify which conventional and nonconventional T cell subsets produce GM-CSF during experimental TB, establish their protective nature using a variety of approaches, and provide a mechanistic basis for their ability to restrictM. tuberculosisgrowth. This commentary discusses the significance of these findings to basic and applied TB research. As translated to human disease, these findings suggest vaccine-mediated expansion of GM-CSF-producing T cells could be an effective prophylactic or therapeutic TB strategy.
Nitroimidazoles with a halogen-containing side-chain
Authors: Baird Ian R. , Patrick Brian O. , Skov Kirsten A. , James Brian R.
Published: December 2017

Syntheses are reported for: nine 2-nitroimidazoles, the abbreviated names all beginning with E, based on derivation from Etanidazole); five 2-methyl-5-nitroimidazoles (M compounds, derived from Metronidazole); and five 2-methyl-4-nitroimidazoles (labelled 2M4N compounds). The nitroimidazoles all have an amide side-chain at the N1 atom of the imidazole, with 17 of them containing one to five halogen atoms. The aim is to study compounds for comparison with EF5 (the number showing the presence of five F-atoms), a previously reported, pentafluoropropylacetamide derivative of 2-nitroimidazole that is currently used as a hypoxia marker drug to detect cancerous tumours. The new compounds are characterized by standard methods, including X-ray structural data for the fluorinated MF5, 2M4NF5, and 2M4NF1(−1) species, with the “–1” indicating two C-atoms in an alkylamide chain rather than the three C-atoms in the propylacetamide of EF5. Intra- and inter-molecular H-bonding is seen in the solid state structures, likely an important property in biological use; another key property of the nitroimidazoles is their reduction potentials, and the measured CV data confirm that 2NO2Im compounds with longer side-chains and more F-atoms (like EF5) are worth investigating for possible activity as hypoxia-selective, bioreductive agents.
Design Issues in Beam Structures for Performance Enhancement of MEMS Based Capacitive Accelerometer
Authors: Sanyal Keya , Biswas Kalyan
Published: December 2017

Structure of a MEMS based Capacitive Accelerometer has been analyzed in this paper. The symmetrical beam-mass structure with different interconnection has been investigated using Finite Element methodology. The simulation model is calibrated with the existing structure of H-shaped beam capacitive accelerometer. Then a rigorous simulation and analysis is carried out to propose new beam structure with improved sensitivity. Analytical model has been evaluated using MATLAB software. Output voltage of the device for a given acceleration is calculated and sensitivity of the device is also analyzed. To improve sensitivity of the device, two new connector structures such as Z-shaped beam and Ω-shaped beam capacitive accelerometer has been proposed. For a particular acceleration, displacement of the proof mass with new structures is increased almost 57% and 66% and the sensitivity has been improved from 7.71pF/g to 13.0pF/g and 13.8pF/g respectively. Parametric optimization of the Ω-shaped beam capacitive accelerometer has also been described for further improvement of device performance.
LP-HS Logic Evaluation on TSMC 0.18μm CMOS Technology
Authors: Saha Aloke , Kumar Sushil , Das Debajit , Chakraborty Mrinmoy
Published: December 2017

Present paper analyses different aspects of “Low Power-High Speed” (LP-HS) logic in favour of present day ULSI system focus. At first, the speed-power efficiency of LP-HS logic is investigated by designing some basic digital building blocks like Buffer, OR, AND, XOR etc. Next, the Voltage Transfer Characteristics (VTC), Noise Margin (NM) and the temperature effect on logic threshold with respect to LP-HS Buffer circuit are examined. The robustness and reliability of LP-HS Logic has been measured in terms of corner analysis with TT (Typical), FF (Fastest) and SS (Slowest) PVT (Process Voltage Temperature) variations on LP-HS XOR circuit. The worst case delay and PDP variation is recorded. Finally the 8:1 Multiplexer is designed, optimized and evaluated based on LP-HS Logic. The evaluated results are compared with some recent competitive designs to benchmark. To resolve reliability issue the corner analysis with PVT variation has been performed on designed 8:1 Multiplexor circuit. All the simulations are done on TSMC 0.18μm CMOS technology using Tanner EDA V.13 at 25°C temperature with 1.8V supply rail.
Improving AES Core Performance via an Advanced ASBUS Protocol
Authors: Yang Xiaokun , Wen Wujie , Fan Ming
Published: December 2017

Security is becoming a de-facto requirement of System-on-Chips (SoC), leading up to a significant share of circuit design cost. In this article, we propose an advanced SBUS protocol (ASBUS), to improve the data feeding efficiency of the Advanced Encryption Standard (AES) encrypted circuits. As a case study, the direct memory access (DMA) combined with AES engine and memory controller are implemented as our design-under-test (DUT) using field-programmable gate arrays (FPGA). The results show that our presented ASBUS structure outperforms the AXI-based design for cipher tests. As an example, the 32-bit ASBUS design costs less in terms of hardware resources and achieves higher throughput (1.30 ×) than the 32-bit AXI implementation, and the dynamic energy consumed by the ASBUS cipher test is reduced to 71.27% compared with the AXI test.
Formal Requirement Debugging for Testing and Verification of Cyber-Physical Systems
Authors: Dokhanchi Adel , Hoxha Bardh , Fainekos Georgios
Published: December 2017

A framework for the elicitation and debugging of formal specifications for Cyber-Physical Systems is presented. The elicitation of specifications is handled through a graphical interface. Two debugging algorithms are presented. The first checks for erroneous or incomplete temporal logic specifications without considering the system. The second can be utilized for the analysis of reactive requirements with respect to system test traces. The specification debugging framework is applied on a number of formal specifications collected through a user study. The user study establishes that requirement errors are common and that the debugging framework can resolve many insidious specification errors.
Host Control of Fungal Infections: Lessons from Basic Studies and Human Cohorts
Authors: Lionakis Michail S. , Levitz Stuart M.
Published: December 2017

In the last few decades, the AIDS pandemic and the significant advances in the medical management of individuals with neoplastic and inflammatory conditions have resulted in a dramatic increase in the population of immunosuppressed patients with opportunistic, life-threatening fungal infections. The parallel development of clinically relevant mouse models of fungal disease and the discovery and characterization of several inborn errors of immune-related genes that underlie inherited human susceptibility to opportunistic mycoses have significantly expanded our understanding of the innate and adaptive immune mechanisms that protect against ubiquitous fungal exposures. This review synthesizes immunological knowledge derived from basic mouse studies and from human cohorts and provides an overview of mammalian antifungal host defenses that show promise for informing therapeutic and vaccination strategies for vulnerable patients.
Biomimetic Structural Materials: Inspiration from Design and Assembly
Authors: Yaraghi Nicholas A. , Kisailus David
Published: December 2017

Nature assembles weak organic and inorganic constituents into sophisticated hierarchical structures, forming structural composites that demonstrate impressive combinations of strength and toughness. Two such composites are the nacre structure forming the inner layer of many mollusk shells, whose brick-and-mortar architecture has been the gold standard for biomimetic composites, and the cuticle forming the arthropod exoskeleton, whose helicoidal fiber-reinforced architecture has only recently attracted interest for structural biomimetics. In this review, we detail recent biomimetic efforts for the fabrication of strong and tough composite materials possessing the brick-and-mortar and helicoidal architectures. Techniques discussed for the fabrication of nacre- and cuticle-mimetic structures include freeze casting, layer-by-layer deposition, spray deposition, magnetically assisted slip casting, fiber-reinforced composite processing, additive manufacturing, and cholesteric self-assembly. Advantages and limitations to these processes are discussed, as well as the future outlook on the biomimetic landscape for structural composite materials.
Ultra Wideband Planar Microstrip Array Antennas for C-Band Aircraft Weather Radar Applications
Authors: Slimani Abdellatif , Bennani Saad Dosse , El Alami Ali , Terhzaz Jaouad
Published: December 2017

A miniaturized ultra wideband (UWB) planar array antennas for C-band aircraft weather RADAR applications is presented. Firstly, the effect of the ground plane is studied. Later, the realization and experimental validation of the geometry that has an UWB characteristic are discussed. This array antennas is composed of a twenty-four radiating element that is etched onto FR-4 substrate with an overall size of 162×100×1.58 mm3 and a dielectric constant of εr=4.4. The results show that this miniaturized array antennas gives us a bandwidth which is about 115% and a gain greater than 13 dB which are required in aircraft weather radar applications.
A 4‐Week Repeated‐Dose Oral Toxicity Study of Bojungikgi‐Tang in Crl:CD Sprague Dawley Rats
Authors: Yoo Sae-Rom , Ha Hyekyung , Lee Mee-Young , Shin Hyeun-Kyoo , Han Su-Cheol , Seo Chang-Seob
Published: December 2017

Traditional herbal medicines have been used for centuries in Asian countries. However, recent studies have led to increasing concerns about the safety and toxicity of herbal prescriptions. Bojungikgi‐tang (BJIGT), a herbal decoction, has been used in Korea to improve physical strength. To establish the safety information, BJIGT water extract was evaluated in a 4‐week repeated‐dose oral toxicity test in Crl:CD Sprague Dawley rats. BJIGT was orally administered in daily doses of 0, 500, 1000, and 2000 mg/kg/day for 4 weeks via oral gavage in male and female rats. We examined the mortality, clinical signs, body weight change, food intake, organ weights, hematology, serum biochemistry, and urinalysis parameters. No significant changes were observed in mortality, clinical sings, body weight, food intake, organ weights, hematology, serum biochemistry, and urinalysis parameters between the control group and the BJIGT‐treated groups in the rats of both sexes. The results indicate that BJIGT did not induce toxic effects at a dose level up to 2000 mg/kg in rats. Thus, this concentration is considered the nonobservable effect dose in rats and is appropriate for a 13‐week subchronic toxicity study.
Opposing Effects of Oxygen Regulation on Kallistatin Expression: Kallistatin as a Novel Mediator of Oxygen‐Induced HIF‐1‐eNOS‐NO Pathway
Authors: Chao Julie , Guo Youming , Li Pengfei , Chao Lee
Published: December 2017

Oxidative stress has both detrimental and beneficial effects. Kallistatin, a key component of circulation, protects against vascular and organ injury. Serum kallistatin levels are reduced in patients and animal models with hypertension, diabetes, obesity, and cancer. Reduction of kallistatin levels is inversely associated with elevated thiobarbituric acid‐reactive substance. Kallistatin therapy attenuates oxidative stress and increases endothelial nitric oxide synthase (eNOS) and NO levels in animal models. However, kallistatin administration increases reactive oxygen species formation in immune cells and bacterial killing activity in septic mice. High oxygen inhibits kallistatin expression via activating the JNK‐FOXO1 pathway in endothelial cells. Conversely, mild oxygen/hyperoxia stimulates kallistatin, eNOS, and hypoxia‐inducible factor‐1 (HIF‐1) expression in endothelial cells and in the kidney of normal mice. Likewise, kallistatin stimulates eNOS and HIF‐1, and kallistatin antisense RNA abolishes oxygen‐induced eNOS and HIF‐1 expression, indicating a role of kallistatin in mediating mild oxygen’s stimulation on antioxidant genes. Protein kinase C (PKC) activation mediates HIF‐1‐induced eNOS synthesis in response to hyperoxia/exercise; thus, mild oxygen through PKC activation stimulates kallistatin‐mediated HIF‐1 and eNOS synthesis. In summary, oxidative stress induces down‐ or upregulation of kallistatin expression, depending on oxygen concentration, and kallistatin plays a novel role in mediating oxygen/exercise‐induced HIF‐1‐eNOS‐NO pathway.
Origin and Geochemical Processes of Porewater in Clay-Rich Deposits in the North Jiangsu Coastal Plain, China
Authors: Ge Qin , Liang Xing , Jin Menggui , Li Jing , Liu Yan
Published: December 2017

The hydrogeochemical and stable isotope compositions of aquitard porewater samples from three boreholes were investigated to determine the origin, salinization, and hydrochemical evolution of water in the North Jiangsu coastal plain, China. Three porewater groups were identified based on the water-bearing subsystems. The total dissolved solids (TDS) of porewater samples highly varied from 0.03 to 26.1 g/L. Molar Cl/Br ratios and δ18O and δ2H data indicate that the source of Group 1 salinized porewater was the Holocene seawater, whereas Group 3 salinized samples were probably related to the remnant palaeoseawater of the Late Pleistocene. Group 2 samples had low salinity (TDS < 1 g/L) and undetectable Br− concentrations, which were probably recharged during a colder period and without evidence of seawater involvement. The salinized porewater was likely diluted by freshwater, as evidenced by its depleted isotopes and low salinity relative to standard seawater. The ionic ratios and ionic deltas indicate that considerable water-rock interactions (e.g., cation exchange and mineral weathering) also accounted for the hydrochemical constituents of porewaters, and cation exchange seems to be more noticeable at low salinity.
Cell Colonization Ability of a Commercialized Large Porous Alveolar Scaffold
Authors: Lemonnier S. , Bouderlique T. , Naili S. , Rouard H. , Courty J. , Chevallier N. , Albanese P. , Lemaire T.
Published: December 2017

The use of filling biomaterials or tissue-engineered large bone implant-coupling biocompatible materials and human bone marrow mesenchymal stromal cells seems to be a promising approach to treat critical-sized bone defects. However, the cellular seeding onto and into large porous scaffolds still remains challenging since this process highly depends on the porous microstructure. Indeed, the cells may mainly colonize the periphery of the scaffold, leaving its volume almost free of cells. In this study, we carry out an in vitro study to analyze the ability of a commercialized scaffold to be in vivo colonized by cells. We investigate the influence of various physical parameters on the seeding efficiency of a perfusion seeding protocol using large manufactured bone substitutes. The present study shows that the velocity of the perfusion fluid and the initial cell density seem to impact the seeding results and to have a negative effect on the cellular viability, whereas the duration of the fluid perfusion and the nature of the flow (steady versus pulsed) did not show any influence on either the fraction of seeded cells or the cellular viability rate. However, the cellular repartition after seeding remains highly heterogeneous.
Use of PRO Measures to Inform Tolerability in Oncology Trials: Implications for Clinical Review, IND Safety Reporting, and Clinical Site Inspections
Authors: Kim Janice , Singh Harpreet , Ayalew Kassa , Borror Kristina , Campbell Michelle , Johnson Laura Lee , Karesh Alyson , Khin Ni A. , Less Joanne R. , Menikoff Jerry , Minasian Lori , Mitchell Sandra A. , Papadopoulos Elektra J. , Piekarz Richard L. , Prohaska Kevin A. , Thompson Susan , Sridhara Rajeshwari , Pazdur Richard , Kluetz Paul G.
Published: December 2017

Cancer therapeutics frequently lead to symptomatic adverse events (AE) that can affect treatment tolerability. The NCI has developed the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) to assess symptomatic AEs by direct patient self-report. Although longitudinal assessment of patient-reported symptomatic AEs holds promise to better inform treatment tolerability, using patient-reported outcome (PRO) measures to assess symptomatic AEs has raised several regulatory and good clinical practice issues among those who conduct cancer clinical trials. These include concerns regarding trial monitoring, clinical review of PRO results by investigators and delegated clinical staff, whether PRO data on symptomatic AEs require investigational new drug (IND) safety reporting, and how the trial conduct and resultant PRO data will be assessed during clinical investigator site inspections. This article addresses current thinking regarding these issues in cancer clinical trials from the FDA, the NCI, and the Office for Human Research Protections. PRO measures, such as PRO-CTCAE, that assess symptomatic AEs in cancer trials are considered similar to other PRO assessments of symptoms, function, and health-related quality of life and can generate complementary data that may inform tolerability. Clarity on operational concerns related to incorporating PRO measures to inform tolerability is critical to continue the advancement of rigorous PRO assessment in cancer clinical trials. Clin Cancer Res; 24(8); 1780–4. ©2017 AACR.

See related commentary by Nipp and Temel, p. 1777
Multiple Socioeconomic Factors and Dental Caries in Swedish Children and Adolescents
Authors: André Kramer Ann-Catrin , Petzold Max , Hakeberg Magnus , Östberg Anna-Lena
Published: December 2017

The study aimed to explore associations between multiple socioeconomic factors and dental caries experience in Swedish children and adolescents (3-19 years old). Electronic dental records from 300,988, in a Swedish region (97.3% coverage) were collected using the DMFT indices (decayed, missing, filled teeth: dependent variables). Socioeconomic status (SES) data (ethnicity, wealth, parental education, and employment) for individuals, parents, and families were obtained from official registers. Principal component analysis was used to explore SES data. Scores based on the first factor were used as an independent aggregated socioeconomic variable in logistic regression analyses. Dental caries experience was low in the participants: 16% in 3- to 6-year-olds (deft index: decayed, extracted, filled teeth) and 47% in 7- to 19-year-olds (DFT index). Both separate and aggregated socioeconomic variables were consistently associated with the dental caries experience irrespective of the caries index used: the crude odds ratio (OR) for having at least 1 caries lesion in 3- to 6-year-olds (deft index) in the lowest SES quintile was 3.26 (95% confidence interval [CI] 3.09-3.43) and in ≥7-year-olds (DFT index) OR 1.80 (95% CI 1.75-1.84) compared with children in the 4 higher SES quintiles. Overall, associations were stronger in the primary dentition than in the permanent dentition. Large SES models contributed more to explaining the caries experience than slim models including fewer SES indicators. In conclusion, socioeconomic factors were consistently associated with dental caries experience in the children and adolescents both as single factors and as multiple factors combined in an index. Socioeconomic inequalities had stronger associations to caries experience in young children than in older children and adolescents.