bluuebunny/crossref_metadata_2025 huggingface dataset:
Beta-Propiolactone Inactivation of Coxsackievirus A16 Induces Structural Alteration and Surface Modification of Viral Capsids
Authors: Fan Chen , Ye Xiaohua , Ku Zhiqiang , Kong Liangliang , Liu Qingwei , Xu Cong , Cong Yao , Huang Zhong
Published: February 2017

Beta-propiolactone (BPL) is an inactivating agent that is widely used in the vaccine industry. However, its effects on vaccine protein antigens and its mechanisms of action remain poorly understood. Here we present cryo-electron microscopy (cryo-EM) structures of BPL-treated coxsackievirus A16 (CVA16) mature virions and procapsids at resolutions of 3.9 Å and 6.5 Å, respectively. Notably, both particles were found to adopt an expanded conformation resembling the 135S-like uncoating intermediate, with characteristic features including an opened 2-fold channel, the externalization of the N terminus of VP1 capsid protein, and the absence of pocket factor. However, major neutralizing epitopes are very well preserved on these particles. Further biochemical analyses revealed that BPL treatment impairs the abilities of CVA16 particles to bind to the attachment receptor heparan sulfate and to a conformation-dependent monoclonal antibody in a BPL dose-dependent manner, indicating that BPL is able to modify surface-exposed amino acid residues. Taken together, our results demonstrate that BPL treatment may induce alteration of the overall structure and surface properties of a nonenveloped viral capsid, thus revealing a novel mode of action of BPL.

IMPORTANCE
Beta-propiolactone (BPL) is commonly used as an inactivating reagent to produce viral vaccines. It is recognized that BPL inactivates viral infectivity through modification of viral nucleic acids. However, its effect on viral proteins remains largely unknown. Here, we present high-resolution cryo-EM structures of BPL-treated coxsackievirus A16 (CVA16) mature virions and procapsids, which reveals an expanded overall conformation and characteristic features that are typical for the 135S-like uncoating intermediate. We further show that the BPL concentration affects the binding of inactivated CVA16 particles to their receptor/antibody. Thus, BPL treatment can alter the overall structure and surface properties of viral capsids, which may lead to antigenic and immunogenic variations. Our findings provide important information for future development of BPL-inactivated vaccines.
Neurovirulent Murine Coronavirus JHM.SD Uses Cellular Zinc Metalloproteases for Virus Entry and Cell-Cell Fusion
Authors: Phillips Judith M. , Gallagher Tom , Weiss Susan R.
Published: February 2017

The coronavirus (CoV) S protein requires cleavage by host cell proteases to mediate virus-cell and cell-cell fusion. Many strains of the murine coronavirus mouse hepatitis virus (MHV) have distinct, S-dependent organ and tissue tropisms despite using a common receptor, suggesting that they employ different cellular proteases for fusion. In support of this hypothesis, we found that inhibition of endosomal acidification only modestly decreased entry, and overexpression of the cell surface protease TMPRSS2 greatly enhanced entry, of the highly neurovirulent MHV strain JHM.SD relative to their effects on the reference strain, A59. However, TMPRSS2 overexpression decreased MHV structural protein expression, release of infectious particles, and syncytium formation, and endogenous serine protease activity did not contribute greatly to infection. We therefore investigated the importance of other classes of cellular proteases and found that inhibition of matrix metalloproteinase (MMP)- and a disintegrin and metalloprotease (ADAM)-family zinc metalloproteases markedly decreased both entry and cell-cell fusion. Suppression of virus by metalloprotease inhibition varied among tested cell lines and MHV S proteins, suggesting a role for metalloprotease use in strain-dependent tropism. We conclude that zinc metalloproteases must be considered potential contributors to coronavirus fusion.

IMPORTANCE
The family
Coronaviridae
includes viruses that cause two emerging diseases of humans, severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), as well as a number of important animal pathogens. Because coronaviruses depend on host protease-mediated cleavage of their S proteins for entry, a number of protease inhibitors have been proposed as antiviral agents. However, it is unclear which proteases mediate
in vivo
infection. For example, SARS-CoV infection of cultured cells depends on endosomal acid pH-dependent proteases rather than on the cell surface acid pH-independent serine protease TMPRSS2, but Zhou et al. (Antiviral Res 116:76–84, 2015, doi:10.1016/j.antiviral.2015.01.011) found that a serine protease inhibitor was more protective than a cathepsin inhibitor in SARS-CoV-infected mice. This paper explores the contributions of endosomal acidification and various proteases to coronavirus infection and identifies an unexpected class of proteases, the matrix metalloproteinase and ADAM families, as potential targets for anticoronavirus therapy.
Inactivated Recombinant Rabies Viruses Displaying Canine Distemper Virus Glycoproteins Induce Protective Immunity against Both Pathogens
Authors: da Fontoura Budaszewski Renata , Hudacek Andrew , Sawatsky Bevan , Krämer Beate , Yin Xiangping , Schnell Matthias J. , von Messling Veronika
Published: February 2017

The development of multivalent vaccines is an attractive methodology for the simultaneous prevention of several infectious diseases in vulnerable populations. Both canine distemper virus (CDV) and rabies virus (RABV) cause lethal disease in wild and domestic carnivores. While RABV vaccines are inactivated, the live-attenuated CDV vaccines retain residual virulence for highly susceptible wildlife species. In this study, we developed recombinant bivalent vaccine candidates based on recombinant vaccine strain rabies virus particles, which concurrently display the protective CDV and RABV glycoprotein antigens. The recombinant viruses replicated to near-wild-type titers, and the heterologous glycoproteins were efficiently expressed and incorporated in the viral particles. Immunization of ferrets with beta-propiolactone-inactivated recombinant virus particles elicited protective RABV antibody titers, and animals immunized with a combination of CDV attachment protein- and fusion protein-expressing recombinant viruses were protected from lethal CDV challenge. However, animals that were immunized with only a RABV expressing the attachment protein of CDV vaccine strain Onderstepoort succumbed to infection with a more recent wild-type strain, indicating that immune responses to the more conserved fusion protein contribute to protection against heterologous CDV strains.

IMPORTANCERabies virus and canine distemper virus (CDV) cause high mortality rates and death in many carnivores. While rabies vaccines are inactivated and thus have an excellent safety profile and high stability, live-attenuated CDV vaccines can retain residual virulence in highly susceptible species. Here we generated recombinant inactivated rabies viruses that carry one of the CDV glycoproteins on their surface. Ferrets immunized twice with a mix of recombinant rabies viruses carrying the CDV fusion and attachment glycoproteins were protected from lethal CDV challenge, whereas all animals that received recombinant rabies viruses carrying only the CDV attachment protein according to the same immunization scheme died. Irrespective of the CDV antigens used, all animals developed protective titers against rabies virus, illustrating that a bivalent rabies virus-based vaccine against CDV induces protective immune responses against both pathogens.
Extreme Mutation Tolerance: Nearly Half of the Archaeal Fusellovirus Sulfolobus Spindle-Shaped Virus 1 Genes Are Not Required for Virus Function, Including the Minor Capsid Protein Gene
vp3
Authors: Iverson Eric A. , Goodman David A. , Gorchels Madeline E. , Stedman Kenneth M.
Published: February 2017

Viruses infecting the
Archaea
harbor a tremendous amount of genetic diversity. This is especially true for the spindle-shaped viruses of the family
Fuselloviridae
, where >90% of the viral genes do not have detectable homologs in public databases. This significantly limits our ability to elucidate the role of viral proteins in the infection cycle. To address this, we have developed genetic techniques to study the well-characterized fusellovirus Sulfolobus spindle-shaped virus 1 (SSV1), which infects
Sulfolobus solfataricus
in volcanic hot springs at 80°C and pH 3. Here, we present a new comparative genome analysis and a thorough genetic analysis of SSV1 using both specific and random mutagenesis and thereby generate mutations in all open reading frames. We demonstrate that almost half of the SSV1 genes are not essential for infectivity, and the requirement for a particular gene correlates well with its degree of conservation within the
Fuselloviridae
. The major capsid gene
vp1
is essential for SSV1 infectivity. However, the universally conserved minor capsid gene
vp3
could be deleted without a loss in infectivity and results in virions with abnormal morphology.

IMPORTANCE
Most of the putative genes in the spindle-shaped archaeal hyperthermophile fuselloviruses have no sequences that are clearly similar to characterized genes. In order to determine which of these SSV genes are important for function, we disrupted all of the putative genes in the prototypical fusellovirus, SSV1. Surprisingly, about half of the genes could be disrupted without destroying virus function. Even deletions of one of the known structural protein genes that is present in all known fuselloviruses,
vp3
, allows the production of infectious viruses. However, viruses lacking
vp3
have abnormal shapes, indicating that the
vp3
gene is important for virus structure. Identification of essential genes will allow focused research on minimal SSV genomes and further understanding of the structure of these unique, ubiquitous, and extremely stable archaeal viruses.
Impact of rapid ultrafiltration rate on changes in the echocardiographic left atrial volume index in patients undergoing haemodialysis: a longitudinal observational study
Authors: Kim Jwa-Kyung , Song Young Rim , Park GunHa , Kim Hyung Jik , Kim Sung Gyun
Published: February 2017

Objective

Optimal fluid management is essential when caring for a patient on haemodialysis (HD). However, if the fluid removal is too rapid, the resultant higher ultrafiltration rate (UFR) disadvantageously promotes haemodynamic instability and cardiac injury. We evaluated the effects of a rapid UFR on changes in the echocardiographic left atrial volume index (LAVI) over a period of time.

Design

Longitudinal observational study.

Setting and participants

A total of 124 new patients on HD.

Interventions

Echocardiography was performed at baseline and repeated after 19.7 months (range 11.3–23.1 months). Changes in LAVI (ΔLAVI/year, mL/m2/year) were calculated. The UFR was expressed in mL/hour/kg, and we used the mean UFR over 30 days (∼12–13 treatments).

Main outcome measures

The 75th centile of the ΔLAVI/year distribution was regarded as a ‘pathological’ increment.

Results

The mean interdialytic weight gain was 1.73±0.94 kg, and the UFR was 8.01±3.87 mL/hour/kg. The significant pathological increment point in ΔLAVI/year was 4.89 mL/m2/year. Correlation analysis showed that ΔLAVI/year was closely related to the baseline blood pressure, haemoglobin level, residual renal function and UFR. According to the receiver operating characteristics curve, the ‘best’ cut-off value of UFR for predicting the pathological increment was 10 mL/hour/kg, with an area under the curve of 0.712. In multivariate analysis, systolic blood pressure, a history of coronary artery disease, haemoglobin <10 g/dL and high UFR were significant predictors. An increase of 1 mL/hour/kg in the UFR was associated with a 22% higher risk of a worsening LAVI (OR 1.22, 95% CI 1.05 to 1.41).

Conclusions

An increased haemodynamic load could affect left atrial remodelling in incident patients on HD. Thus, close monitoring and optimal control of UFR are needed.
Influence of spin–phonon interactions and spin-reorientation transitions on the phonon properties of RCrO3
Authors: Apostolov A. T. , Apostolova I. N. , Wesselinowa J. M.
Published: February 2017

Using a microscopic model and a Green’s function technique we calculate the renormalized phonon energy in multiferroic RCrO3 (R = Sm, Dy, Er, Pr, Gd and Y) compounds as a function of temperature, magnetic field and R-ionic radius. We explain the observed anomalies in the temperature dependence of the phonon spectra based on a detailed analysis of the influence of the magnetic sublattices, the interaction between them and the spin-reorientation (SR) transition on lattice vibrations via spin–phonon interactions. When the rare earth ions are magnetic we investigate their essential role for the anomalies around the SR temperature. For the case when R is nonmagnetic, for example YCrO3, we propose a new microscopic model. We define an induced Dzyaloshinskii–Moriya (IDM) vector as a consequence from the spontaneous polarization. This IDM interaction is responsible for the appearance of a temperature-driven SR transition, which itself is responsible for the phonon anomalies at low temperatures. The numerical calculations are in good qualitative agreement with the experimental data.
Phase transformations of severely plastically deformed Ti–Ni–Pd high-temperature shape memory alloys
Authors: Tulić Semir , Kerber Michael , Matsuda Mitsuhiro , Waitz Thomas
Published: February 2017

Severe plastic deformation of a Ti[Formula: see text]Ni[Formula: see text]Pd[Formula: see text] high-temperature shape memory alloy yields a nanoscale mixture of an amorphous phase and retained lamellae of the parent B19 martensite. The thermal stability of the deformed martensite is significantly enhanced. Upon heating, B2 austenite occurs within the martensite and by crystallization of the amorphous phase, concomitant with recovery and the formation of an ultrafine grained structure. In the small grains, the B2 austenite to B19 martensitic transformation is shifted to lower temperatures and incomplete.
Shear stress induces Gαq/11 activation independently of G protein-coupled receptor activation in endothelial cells
Authors: dela Paz Nathaniel G. , Melchior Benoît , Frangos John A.
Published: February 2017

Mechanochemical signal transduction occurs when mechanical forces, such as fluid shear stress, are converted into biochemical responses within the cell. The molecular mechanisms by which endothelial cells (ECs) sense/transduce shear stress into biological signals, including the nature of the mechanosensor, are still unclear. G proteins and G protein-coupled receptors (GPCRs) have been postulated independently to mediate mechanotransduction. In this study, we used in situ proximity ligation assay (PLA) to investigate the role of a specific GPCR/Gαq/11 pair in EC shear stress-induced mechanotransduction. We demonstrated that sphingosine 1-phosphate (S1P) stimulation causes a rapid dissociation at 0.5 min of Gαq/11 from its receptor S1P3, followed by an increased association within 2 min of GPCR kinase-2 (GRK2) and β-arrestin-1/2 with S1P3 in human coronary artery ECs, which are consistent with GPCR/Gαq/11 activation and receptor desensitization/internalization. The G protein activator AlF4 resulted in increased dissociation of Gαq/11 from S1P3, but no increase in association between S1P3 and either GRK2 or β-arrestin-1/2. The G protein inhibitor guanosine 5′-(β-thio) diphosphate (GDP-β-S) and the S1P3 antagonist VPC23019 both prevented S1P-induced activation. Shear stress also caused the rapid activation within 7 s of S1P3/Gαq/11. There were no increased associations between S1P3 and GRK2 or S1P3 and β-arrestin-1/2 until 5 min. GDP-β-S, but not VPC23019, prevented dissociation of Gαq/11 from S1P3 in response to shear stress. Shear stress did not induce rapid dephosphorylation of β-arrestin-1 or rapid internalization of S1P3, indicating no GPCR activation. These findings suggest that Gαq/11 participates in the sensing/transducing of shear stress independently of GPCR activation in ECs.
Glucose elicits cephalic-phase insulin release in mice by activating KATPchannels in taste cells
Authors: Glendinning John I. , Frim Yonina G. , Hochman Ayelet , Lubitz Gabrielle S. , Basile Anthony J. , Sclafani Anthony
Published: February 2017

The taste of sugar elicits cephalic-phase insulin release (CPIR), which limits the rise in blood glucose associated with meals. Little is known, however, about the gustatory mechanisms that trigger CPIR. We asked whether oral stimulation with any of the following taste stimuli elicited CPIR in mice: glucose, sucrose, maltose, fructose, Polycose, saccharin, sucralose, AceK, SC45647, or a nonmetabolizable sugar analog. The only taste stimuli that elicited CPIR were glucose and the glucose-containing saccharides (sucrose, maltose, Polycose). When we mixed an α-glucosidase inhibitor (acarbose) with the latter three saccharides, the mice no longer exhibited CPIR. This revealed that the carbohydrates were hydrolyzed in the mouth, and that the liberated glucose triggered CPIR. We also found that increasing the intensity or duration of oral glucose stimulation caused a corresponding increase in CPIR magnitude. To identify the components of the glucose-specific taste-signaling pathway, we examined the necessity of Calhm1, P2X2+P2X3, SGLT1, and Sur1. Among these proteins, only Sur1 was necessary for CPIR. Sur1 was not necessary, however, for taste-mediated attraction to sugars. Given that Sur1 is a subunit of the ATP-sensitive K+channel (KATP) channel and that this channel functions as a part of a glucose-sensing pathway in pancreatic β-cells, we asked whether the KATPchannel serves an analogous role in taste cells. We discovered that oral stimulation with drugs known to increase (glyburide) or decrease (diazoxide) KATPsignaling produced corresponding changes in glucose-stimulated CPIR. We propose that the KATPchannel is part of a novel signaling pathway in taste cells that mediates glucose-induced CPIR.
Subfunctionalization of COX4 paralogs in fish
Authors: Porplycia Danielle , Lau Gigi Y. , McDonald Jared , Chen Zhilin , Richards Jeffrey G. , Moyes Christopher D.
Published: February 2017

Cytochrome c oxidase (COX) subunit 4 has two paralogs in most vertebrates. The mammalian COX4-2 gene is hypoxia responsive, and the protein has a disrupted ATP-binding site that confers kinetic properties on COX that distinguish it from COX4-1. The structure-function of COX4-2 orthologs in other vertebrates remains uncertain. Phylogenetic analyses suggest the two paralogs arose in basal vertebrates, but COX4-2 orthologs diverged faster than COX4-1 orthologs. COX4-1/4-2 protein levels in tilapia tracked mRNA levels across tissues, and did not change in hypoxia, arguing against a role for differential post-translational regulation of paralogs. The heart, and to a lesser extent the brain, showed a size-dependent shift from COX4-1 to COX4-2 (transcript and protein). ATP allosterically inhibited both velocity and affinity for oxygen in COX assayed from both muscle (predominantly COX4-2) and gill (predominantly COX4-1). We saw some evidence of cellular and subcellular discrimination of COX4 paralogs in heart. In cardiac ventricle, some non-cardiomyocyte cells were COX positive but lacked detectible COX4-2. Within heart, the two proteins partitioned to different mitochondrial subpopulations. Cardiac subsarcolemmal mitochondria had mostly COX4-1 and intermyofibrillar mitochondria had mostly COX4-2. Collectively, these data argue that, despite common evolutionary origins, COX4-2 orthologs of fish show unique patterns of subfunctionalization with respect to transcriptional and posttranslation regulation relative to the rodents and primates that have been studied to date.
Sport-related concussion induces transient cardiovascular autonomic dysfunction
Authors: Dobson John L. , Yarbrough Mary Beth , Perez Jose , Evans Kelsey , Buckley Thomas
Published: February 2017

Recent evidence suggests that concussions may disrupt autonomic cardiovascular control. This study investigated the initial effects of concussion on cardiovascular function using three autonomic reflex tests. Twenty-three recreational athletes (12 women, 11 men) were divided into concussed ( n = 12) and control ( n = 11) groups. Concussed participants performed forced breathing, standing, and Valsalva autonomic tests four times: 1) within 48 h of injury; 2) 24 h later; 3) 1 wk after injury; and 4) 2 wk after injury. The controls performed the same tests on the same schedule. Differences in heart rate (HR), systolic blood pressure (SBP), and diastolic blood pressure (DBP) responses to the tests were continuously measured using finger photoplethysmography and were analyzed using repeated-measures multivariate ANOVAs and ANOVAs. Within 48 h of injury, the concussed group had significantly greater resting SBP ( t21= 2.44, P = 0.02, d = 1.03), HR ( t21= 2.33, P = 0.03, d = 1.01), and SBP responses to standing ( t21= 2.98, P = 0.01, d = 1.24), and 90% SBP normalization times ( t21= 2.64, P = 0.02, d = 1.10) after the Valsalva, but those group differences subsided 24 h later. There was also a significant interaction with the HR responses to forced breathing ( F3,60= 4.13, P = 0.01, ηp2= 0.17), indicating the concussed responses declined relative to the control’s over time. The results demonstrate that concussion disrupted autonomic cardiovascular control, and that autonomic reflex tests are practical means by which to evaluate that dysfunction.
Ammonia Transporters and Their Role in Acid-Base Balance
Authors: Weiner I. David , Verlander Jill W.
Published: February 2017

Acid-base homeostasis is critical to maintenance of normal health. Renal ammonia excretion is the quantitatively predominant component of renal net acid excretion, both under basal conditions and in response to acid-base disturbances. Although titratable acid excretion also contributes to renal net acid excretion, the quantitative contribution of titratable acid excretion is less than that of ammonia under basal conditions and is only a minor component of the adaptive response to acid-base disturbances. In contrast to other urinary solutes, ammonia is produced in the kidney and then is selectively transported either into the urine or the renal vein. The proportion of ammonia that the kidney produces that is excreted in the urine varies dramatically in response to physiological stimuli, and only urinary ammonia excretion contributes to acid-base homeostasis. As a result, selective and regulated renal ammonia transport by renal epithelial cells is central to acid-base homeostasis. Both molecular forms of ammonia, NH3and NH4+, are transported by specific proteins, and regulation of these transport processes determines the eventual fate of the ammonia produced. In this review, we discuss these issues, and then discuss in detail the specific proteins involved in renal epithelial cell ammonia transport.
The Contribution of Small Airway Obstruction to the Pathogenesis of Chronic Obstructive Pulmonary Disease
Authors: Hogg James C. , Paré Peter D. , Hackett Tillie-Louise
Published: February 2017

The hypothesis that the small conducting airways were the major site of obstruction to airflow in normal lungs was introduced by Rohrer in 1915 and prevailed until Weibel introduced a quantitative method of studying lung anatomy in 1963. Green repeated Rohrer's calculations using Weibels new data in 1965 and found that the smaller conducting airways offered very little resistance to airflow. This conflict was resolved by seminal experiments conducted by Macklem and Mead in 1967, which confirmed that a small proportion of the total lower airways resistance is attributable to small airways <2 mm in diameter. Shortly thereafter, Hogg, Macklem, and Thurlbeck used this technique to show that small airways become the major site of obstruction in lungs affected by emphysema. These and other observations led Mead to write a seminal editorial in 1970 that postulated the small airways are a silent zone within normal lungs where disease can accumulate over many years without being noticed. This review provides a progress report since the 1970s on methods for detecting chronic obstructive pulmonary disease, the structural nature of small airways' disease, and the cellular and molecular mechanisms that are thought to underlie its pathogenesis.
Temporomandibular Joint Anatomy Assessed by CBCT Images
Authors: Caruso Silvia , Storti Ennio , Nota Alessandro , Ehsani Shideh , Gatto Roberto
Published: February 2017

Aim. Since cone beam computed tomography (CBCT) has been used for the study of craniofacial morphology, the attention of orthodontists has also focused on the mandibular condyle. The purpose of this brief review is to summarize the recent 3D CBCT images of mandibular condyle. Material and Methods. The eligibility criteria for the studies are (a) studies aimed at evaluating the anatomy of the temporomandibular joint; (b) studies performed with CBCT images; (c) studies on human subjects; (d) studies that were not clinical case-reports and clinical series; (e) studies reporting data on children, adolescents, or young adults (data from individuals with age ≤ 30 years). Sources included PubMed from June 2008 to June 2016. Results. 43 full-text articles were initially screened for eligibility. 13 full-text articles were assessed for eligibility. 11 articles were finally included in qualitative synthesis. The main topics treated in the studies are the volume and surface of the mandibular condyle, the bone changes on cortical surface, the facial asymmetry, and the optimum position of the condyle in the glenoid fossa. Conclusion. Additional studies will be necessary in the future, constructed with longitudinal methodology, especially in growing subjects. The limits of CBCT acquisitions are also highlighted.
The Effects of Intravenous Dexmedetomidine Injections on IOP in General Anesthesia Intubation: A Meta-Analysis
Authors: Zhou Chengmao , Zhu Yu , Liu Zhen , Ruan Lin
Published: February 2017

Objective. The aim of this meta-analysis is to evaluate the effects of dexmedetomidine on intraocular pressure (IOP) in patients with general anesthesia administered via intubation. Methods. We searched randomized controlled trials (RCT) on the effects of intravenous injection of dexmedetomidine on IOP in patients with general anesthesia administered via intubation. Results. The meta-analysis study showed that (1) a statistically significant difference [WMD = −3.40 mmHg, 95% CI (−4.76, −2.04), P<0.00001] was found between IOP of the two groups. (2) The IOP of the dexmedetomidine group that was administrated succinylcholine was lower than that of placebo group which was administrated succinylcholine [WMD = −4.13 mmHg, 95% CI (−6.01, −2.25), P<0.0001]. (3) Compared with the IOP of patients in the placebo group, patients with intubation in the dexmedetomidine group maintained a lower IOP [WMD = −3.10 mmHg, 95% CI (−5.12, −1.07), P=0.003]. However, for incidences of bradycardia, the use of dexmedetomidine was higher than that of the placebo [RR = 0.23, 95% CI (0.07, 0.76), P=0.02]. Conclusion. This meta-analysis showed that, in many cases, dexmedetomidine can lower the IOP of patients with general anesthesia administered by intubation.
Differential Site-Based Expression of Pentose Phosphate Pathway-Related Proteins among Breast Cancer Metastases
Authors: Cha Yoon Jin , Jung Woo Hee , Koo Ja Seung
Published: February 2017

Purpose. We aimed to investigate the expression of pentose phosphate pathway- (PPP-) related proteins in metastatic breast cancer and its relationship with clinicopathologic factors.Methods. Tissue samples from 126 metastatic breast cancers were included in a tissue microarray. Expression of PPP-related proteins [glucose-6-phosphate dehydrogenase (G6PDH), 6-phosphogluconolactonase (6PGL), 6-phosphogluconate dehydrogenase (6PGDH), and nuclear factor erythroid 2-related factor (NRF2)] was determined by immunohistochemistry.Results. G6PDH (p=0.011) and cytoplasmic NRF2 (p=0.001) showed the highest expression in brain metastases. Human epidermal growth factor receptor (HER-2) positivity was associated with G6PDH (p<0.001) and cytoplasmic NRF2 (p=0.015) positivity. A high Ki-67 labeling index (LI) was correlated with nuclear NRF2 positivity (p=0.037), and HER-2-positive luminal B type was associated with G6PDH positivity (p=0.001). On multivariate Cox analysis, independent risk factors of short overall survival were 6PGL positivity in bone metastasis (HR 4.180, 95% CI 1.160–15.06,p=0.029) and low Ki-67 LI in lung metastasis (HR 11.853, 95% CI 1.841–76.30,p=0.009).Conclusion. Differential expression of PPP-related proteins correlated with different prognoses and metastatic sites, with the highest expression in brain metastases, and could be a potential therapeutic target.
The Protective Effect of Chrysanthemum indicum Extract against Ankylosing Spondylitis in Mouse Models
Authors: Dong Mei , Yu Dongsheng , Duraipandiyan Veeramuthu , Abdullah Al-Dhabi Naif
Published: February 2017

In traditional Chinese and Korean homeopathic medicine, Chrysanthemum indicum Linné (Asteraceae) is a time-honored herb, prescribed for the resolution of symptoms associated with inflammatory and hypertensive conditions as well as those affecting the lungs and its associated structures. The goal of this work is to investigate the defensive role of Chrysanthemum indicum extract in fighting ankylosing spondylitis (AS) using mouse models, through which the manifestation and extent of the disease progression were measured with quantitative analysis of the intervertebral joints. Markers of inflammation as well as oxidative stress were also analysed. Western blot was used to quantify the levels of Nuclear Factor-κB (NF-κB) p65, Dickkopf-1 (DKK-1), and sclerostin (SOST). Consequently, the findings of this experiment demonstrated that AS in mice that were given Chrysanthemum indicum extract had lower level of TNF-α, IL-1β, and IL-6 (P<0.05) and increased level of catalase (CAT), glutathione peroxidase (GSH-PX), and superoxide dismutase (SOD) (P<0.05). The results also revealed that Chrysanthemum indicum supplemented with diet contributed to a decrease in Nuclear Factor-κB (NF-κB) p65 protein expression (P<0.05) and higher levels of DKK-1 and SOST proteins (P<0.05). Therefore, we concluded that the beneficial role of Chrysanthemum indicum in AS is manifested through downregulating oxidative stress, inhibiting inflammatory mediators and NF-κB, and increasing DKK-1 and SOST levels.
Effect of Harvesting Stage on Sweet Sorghum (Sorghum bicolor L.) Genotypes in Western Kenya
Authors: Oyier Moses Owuor , Owuoche James O. , Oyoo Maurice E. , Cheruiyot Erick , Mulianga Betty , Rono Justice
Published: February 2017

Harvesting stage of sweet sorghum (Sorghum bicolor L. Moench) cane is an important aspect in the content of sugar for production of industrial alcohol. Four sweet sorghum genotypes were evaluated for harvesting stage in a randomized complete block design. In order to determine sorghum harvest growth stage for bioethanol production, sorghum canes were harvested at intervals of seven days after anthesis. The genotypes were evaluated at different stages of development for maximum production of bioethanol from flowering to physiological maturity. The canes were crushed and juice fermented to produce ethanol. Measurements of chlorophyll were taken at various stages as well as panicles from the harvested canes. Dried kernels at 14% moisture content were also weighed at various stages. Chlorophyll, grain weight, absolute ethanol volume, juice volume, cane yield, and brix showed significant (p=0.05) differences for genotypes as well as the stages of harvesting. Results from this study showed that harvesting sweet sorghum at stages IV and V (104 to 117 days after planting) would be appropriate for production of kernels and ethanol. EUSS10 has the highest ethanol potential (1062.78 l ha−1) due to excellent juice volume (22976.9 l ha−1) and EUSS11 (985.26 l ha−1) due to its high brix (16.21).
Experimental Study on Strain Reliability of Embroidered Passive UHF RFID Textile Tag Antennas and Interconnections
Authors: Chen Xiaochen , Liu Aruhan , Wei Zhigang , Ukkonen Leena , Virkki Johanna
Published: February 2017

We present embroidered antennas and interconnections in passive UHF RFID textile tags and test their strain reliability. Firstly, we fabricate tag antennas on two different stretchable fabric substrates by five different embroidery patterns and choose the most stretchable ones for testing. Next, the tag ICs are attached by sewing and gluing, and the tag reliability during repeated stretching cycles is evaluated through wireless measurements. Initially, the chosen tags achieve read ranges of 6–8 meters and can strain up to 140–150% of their original length. After 100 stretching cycles to 80% of their maximum strain, the read ranges of the tags with glued interconnections are similar to the initial values. In addition, also the read ranges of the tags with sewed interconnections are still more than 70%–85% of their initial values. However, some challenges with the reproducibility need to be solved next.
A Dynamic Stackelberg Game of Supply Chain for a Corporate Social Responsibility
Authors: Ferrara Massimiliano , Khademi Mehrnoosh , Salimi Mehdi , Sharifi Somayeh
Published: February 2017

In this paper, we establish a dynamic game to allocate CSR (Corporate Social Responsibility) to the members of a supply chain. We propose a model of a supply chain in a decentralized state which includes a supplier and a manufacturer. For analyzing supply chain performance in decentralized state and the relationships between the members of the supply chain, we formulate a model that crosses through multiperiods with the help of a dynamic discrete Stackelberg game which is made under two different information structures. We obtain an equilibrium point at which both the profits of members and the level of CSR taken up by supply chains are maximized.
Impairments in Brain Perfusion, Metabolites, Functional Connectivity, and Cognition in Severe Asymptomatic Carotid Stenosis Patients: An Integrated MRI Study
Authors: Wang Tao , Xiao Feng , Wu Guangyao , Fang Jian , Sun Zhenmeng , Feng Hongliang , Zhang Junjian , Xu Haibo
Published: February 2017

Carotid artery stenosis without transient ischemic attack (TIA) or stroke is considered as “asymptomatic.” However, recent studies have demonstrated that these asymptomatic carotid artery stenosis (aCAS) patients had cognitive impairment in tests of executive function, psychomotor speed, and memory, indicating that “asymptomatic” carotid stenosis may not be truly asymptomatic. In this study, when 19 aCAS patients compared with 24 healthy controls, aCAS patients showed significantly poorer performance on global cognition, memory, and executive function. By utilizing an integrated MRI including pulsed arterial spin labeling (pASL) MRI, Proton MR Spectroscopy (MRS), and resting-state functional MRI (R-fMRI), we also found that aCAS patients suffered decreased cerebral blood flow (CBF) mainly in the Left Frontal Gyrus and had decreased NAA/Cr ratio in the left hippocampus and decreased connectivity to the posterior cingulate cortex (PCC) in the anterior part of default mode network (DMN).
Acute Nonspecific Mesenteric Lymphadenitis: More Than “No Need for Surgery”
Authors: Helbling Rossana , Conficconi Elisa , Wyttenbach Marina , Benetti Cecilia , Simonetti Giacomo D. , Bianchetti Mario G. , Hamitaga Flurim , Lava Sebastiano A. G. , Fossali Emilio F. , Milani Gregorio P.
Published: February 2017

Acute nonspecific, or primary, mesenteric lymphadenitis is a self-limiting inflammatory condition affecting the mesenteric lymph nodes, whose presentation mimics appendicitis or intussusception. It typically occurs in children, adolescents, and young adults. White blood count and C-reactive protein are of limited usefulness in distinguishing between patients with and without mesenteric lymphadenitis. Ultrasonography, the mainstay of diagnosis, discloses 3 or more mesenteric lymph nodes with a short-axis diameter of 8 mm or more without any identifiable underlying inflammatory process. Once the diagnosis is established, supportive care including hydration and pain medication is advised. Furthermore, it is crucial to reassure patients and families by explaining the condition and stating that affected patients recover completely without residuals within 2–4 weeks.
Clinical Dosing Regimen of Selinexor Maintains Normal Immune Homeostasis and T-cell Effector Function in Mice: Implications for Combination with Immunotherapy
Authors: Tyler Paul M. , Servos Mariah M. , de Vries Romy C. , Klebanov Boris , Kashyap Trinayan , Sacham Sharon , Landesman Yosef , Dougan Michael , Dougan Stephanie K.
Published: February 2017

Selinexor (KPT-330) is a first-in-class nuclear transport inhibitor currently in clinical trials as an anticancer agent. To determine how selinexor might affect antitumor immunity, we analyzed immune homeostasis in mice treated with selinexor and found disruptions in T-cell development, a progressive loss of CD8 T cells, and increases in inflammatory monocytes. Antibody production in response to immunization was mostly normal. Precursor populations in bone marrow and thymus were unaffected by selinexor, suggesting that normal immune homeostasis could recover. We found that a high dose of selinexor given once per week preserved nearly normal immune functioning, whereas a lower dose given 3 times per week did not restore immune homeostasis. Both naïve and effector CD8 T cells cultured in vitro showed impaired activation in the presence of selinexor. These experiments suggest that nuclear exportins are required for T-cell development and function. We determined the minimum concentration of selinexor required to block T-cell activation and showed that T-cell–inhibitory effects of selinexor occur at levels above 100 nmol/L, corresponding to the first 24 hours post-oral dosing. In a model of implantable melanoma, selinexor treatment at 10 mg/kg with a 4-day drug holiday led to intratumoral IFNγ+, granzyme B+ cytotoxic CD8 T cells that were comparable with vehicle-treated mice. Overall, selinexor treatment leads to transient inhibition of T-cell activation, but clinically relevant once and twice weekly dosing schedules that incorporate sufficient drug holidays allow for normal CD8 T-cell functioning and development of antitumor immunity. Mol Cancer Ther; 16(3); 428–39. ©2017 AACR.

See related article by Farren et al., p. 417
Prognostic Relevance of Tumor Purity and Interaction with MGMT Methylation in Glioblastoma
Authors: Schulze Heuling Eva , Knab Felix , Radke Josefine , Eskilsson Eskil , Martinez-Ledesma Emmanuel , Koch Arend , Czabanka Marcus , Dieterich Christoph , Verhaak Roel G. , Harms Christoph , Euskirchen Philipp
Published: February 2017

Promoter methylation status of O-6-methylguanine-DNA methyltransferase (MGMT), a DNA repair enzyme, is a critical biomarker in glioblastoma (GBM), as treatment decisions and clinical trial inclusion rely on its accurate assessment. However, interpretation of results is complicated by poor interassay reproducibility as well as a weak correlation between methylation status and expression levels of MGMT. This study systematically investigates the influence of tumor purity on tissue subjected to MGMT analysis. A quantitative, allele-specific real-time PCR (qAS-PCR) assay was developed to determine genotype and mutant allele frequency of telomerase promoter (pTERT) mutations as a direct measure of tumor purity. We studied tumor purity, pTERT mutation by Sanger sequencing, MGMT methylation by pyrosequencing, IDH1 mutation status, and clinical parameters in a cohort of high-grade gliomas (n = 97). The qAS-PCR reliably predicted pTERT genotype and tumor purity compared with independent methods. Tumor purity positively and significantly correlated with the extent of methylation in MGMT methylated GBMs. Extent of MGMT methylation differed significantly with respect to pTERT mutation hotspot (C228T vs. C250T). Interestingly, frontal lobe tumors showed greater tumor purity than those in other locations. Above all, tumor purity was identified as an independent prognostic factor in GBM. In conclusion, we determined mutual associations of tumor purity with MGMT methylation and pTERT mutations and found that the extent of MGMT methylation reflects tumor purity. In turn, tumor purity is prognostic in IDH1 wild-type GBM.

Implications: Tumor purity is an independent prognostic marker in glioblastoma and is associated with the extent of MGMT methylation. Mol Cancer Res; 15(5); 532–40. ©2017 AACR.
Prediction of major and clinically relevant bleeding in patients with VTE treated with edoxaban or vitamin K antagonists
Authors: Raskob Gary , Büller Harry , Grosso Michael , Zhang George , Winters Shannon , Cohen Alexander , Di Nisio Marcello
Published: February 2017

Better understanding of risk factors for major bleeding events during anticoagulant treatment for venous thromboembolism (VTE) may help physicians when deciding on intensity and duration of treatment. The primary aim of this study was to identify risk factors for major and clinically relevant bleeding in patients receiving the oral factor Xa inhibitor edoxaban or warfarin for the treatment of acute VTE. We analysed data from 8240 patients who received ≥1 dose of study drug in the Hokusai-VTE study. Bleeding risk factors were evaluated in 4118 patients who received edoxaban and significant variables were combined in a prediction model. We used the C-statistic to estimate model discrimination and bootstrap techniques for internal validation. Major bleeding occurred in 56/4118 (1.4 %) patients given edoxaban and in 66/4122 (1.6 %) patients given warfarin. Clinically relevant bleeding occurred in 349 (8.5 %) and 423 (10.3 %), respectively. Significant risk factors for major bleeding during edoxaban treatment were female sex, concomitant antiplatelet therapy, haemoglobin ≤10 g/dl, history of arterial hypertension, and systolic blood pressure >160 mmHg. The discrimination of the model was high (C-statistic: 0.71) for major bleeding, lower for clinically relevant bleeding (C-statistic: 0.62) and when the model was applied to patients receiving warfarin (C-statistic 0.60). In conclusion, we identified five main predictors of major bleeding in patients receiving edoxaban for the treatment of acute VTE. A risk model based on these factors predicted an increased risk of bleeding with good discrimination.

Supplementary Material to this article is available online at www.thrombosis-online.com.
Sex Differences in 1-Year All-Cause Rehospitalization in Patients After Acute Myocardial Infarction
Authors: Dreyer Rachel P. , Dharmarajan Kumar , Kennedy Kevin F. , Jones Philip G. , Vaccarino Viola , Murugiah Karthik , Nuti Sudhakar V. , Smolderen Kim G. , Buchanan Donna M. , Spertus John A. , Krumholz Harlan M.
Published: February 2017

Background:

Compared with men, women are at higher risk of rehospitalization in the first month after discharge for acute myocardial infarction (AMI). However, it is unknown whether this risk extends to the full year and varies by age. Explanatory factors potentially mediating the relationship between sex and rehospitalization remain unexplored and are needed to reduce readmissions. The aim of this study was to assess sex differences and factors associated with 1-year rehospitalization rates after AMI.

Methods:

We recruited 3536 patients (33% women) ≥18 years of age hospitalized with AMI from 24 US centers into the TRIUMPH study (Translational Research Investigating Underlying Disparities in Acute Myocardial Infarction Patients’ Health Status). Data were obtained by medical record abstraction and patient interviews, and a physician panel adjudicated hospitalizations within the first year after AMI. We compared sex differences in rehospitalization using a Cox proportional hazards model, following sequential adjustment for covariates and testing for an age-sex interaction.

Results:

One-year crude all-cause rehospitalization rates for women were significantly higher than men after AMI (hazard ratio, 1.29 for women; 95% confidence interval, 1.12−1.48). After adjustment for demographics and clinical factors, women had a persistent 26% higher risk of rehospitalization (hazard ratio, 1.26; 95% confidence interval, 1.08−1.47). However, after adjustment for health status and psychosocial factors (hazard ratio, 1.14; 95% confidence interval, 0.96−1.35), the association was attenuated. No significant age-sex interaction was found for 1-year rehospitalization, suggesting that the increased risk applied to both older and younger women.

Conclusions:

Regardless of age, women have a higher risk of rehospitalization compared with men over the first year after AMI. Although the increased risk persisted after adjustment for clinical factors, the poorer health and psychosocial state of women attenuated the difference.
Retro-Engineering and Alternative Histories: Possible Roads toward Media Archaeological Reconstruction
Authors: Stricot Morgane
Published: February 2017

This article gives insight into research on media archaeological reconstruction of media and digital artworks. This experimental approach, illustrated by two practical cases, results in a duplication of the artworks within their original machines and languages. Based on retro-engineering, this approach is becoming a way to investigate the known, unknown and alternative stories by and for the machines, the goal being to produce archives, witnesses of the machines’ related history and inherent imaginary.
Toxicity of ethanol solutions and vapours against Meloidogyne incognita
Authors: Silva Julio C.P. , Campos Vicente P. , Freire Eduardo S. , Terra Willian C. , Lopez Liliana E.
Published: February 2017

Ethanol (EtOH) is less harmful to humans than currently available nematicide molecules. This study evaluated the efficacy of EtOH in controllingMeloidogyne incognitain vitroand in lettuce plants under glasshouse conditions. Aqueous EtOH solutions (5-70% volume) and their vapours caused an acute nematicidal effectin vitroin second-stage juveniles (J2) ofM. incognitaand reduced hatching of J2. There was a large reduction of galls and eggs in the root system when 40 ml of EtOH was applied toM. incognita-infested soil at concentrations of 40 and 70%. Water exposed to EtOH vapours for 1 h became toxic, and a 12-h exposure caused 100% J2 mortality. Use of a plastic cover did not increase the efficiency of EtOH in controllingM. incognitain lettuce plants. The observed EtOH effects indicate its prospective use in controlling plant-parasitic nematodes, especially in glasshouses.
Uroptychus atlanticus, a new species of squat lobster (Crustacea: Decapoda: Anomura: Chirostylidae) from the western Atlantic Ocean
Authors: BABA KEIJI , WICKSTEN MARY K.
Published: February 2017

A new species of squat lobster, Uroptychus atlanticus, is described on the basis of a female specimen taken at a depth of 713–841 m in the southeastern Gulf of Mexico. The new species is readily distinguished from all known species of the genus from the western Atlantic by the very spinose carapace and pereopods, and a transverse row of spines on each of the abdominal tergites 1 and 2.