The triglycerides and glucose index is associated with cardiovascular risk factors in metabolically obese normal-weight subjects.

PURPOSE: The aim of this study was to determine whether the triglycerides and glucose (TyG) index is associated with the presence of metabolically obese normal-weight (MONW) phenotype and related cardiovascular risk factors. METHODS: Apparently healthy men and non-pregnant women aged 20-65 years were enrolled in a population-based cross-sectional study. Overweight, obesity, smoking, alcohol consumption, pregnancy, diagnosis of hypertension, diabetes, cardiovascular disease, liver disease, renal disease, malignancy, and medical treatment were exclusion criteria. Subjects were allocated into the MONW or normal-weight groups. MONW phenotype was defined by normal weight and the presence of at least one of the following cardiovascular risk factors: elevated blood pressure, hyperglycemia, hypertriglyceridemia, and low HDL cholesterol. RESULTS: A total of 542 subjects were enrolled and allocated into the MONW (n = 354) and normal-weight (n = 188) groups. The adjusted logistic regression analysis showed that the elevated TyG index is significantly associated with the presence of MONW phenotype (OR = 11.14; 95% CI 6.04-20.57), hyperglycemia (OR = 3.18; 95% CI 1.95-5.21), hypertriglyceridemia (OR = 399.19; 95% CI 94.01-1694.98), and low HDL-C (OR = 2.60; 95% CI 1.74-3.87), but not with elevated blood pressure (OR = 1.55; 95% CI 0.93-2.60). CONCLUSION: Results of this study support that the TyG index may be a useful indicator to detect MONW phenotype and associated cardiovascular risk factors.

Direct and transdentinal biostimulatory effects of grape seed extract rich in proanthocyanidin on pulp cells.

AIM: To evaluate the potential biostimulatory effects of grape seed extract (GSE) on a primary culture of human pulp cells. METHODOLOGY: Human molars were used to obtain the primary pulp cell culture and 0.5-mm dentine discs. For GSE direct exposure, dose-response (0.0065-6.5%) and time response (1-60 min of contact) were examined. For transdentinal exposure, 0.65% of GSE was tested for 24 h. Cellular metabolism, nitric oxide and collagen production, and cell morphology alterations were assessed at periods of 24 and 72 h. After cell differentiation and direct exposure to GSE, the total protein production (TP), alkaline phosphatase activity (ALP) and formation of mineralization nodules (MN) were assessed. The results were analysed by parametric tests or non-parametric tests (α = 0.05). RESULTS: The lower concentration of GSE tested (0.0065%) was associated with an increase in cellular metabolism, a reduction in the production of nitric oxide and an increase in extracellular matrix synthesis (collagen). Distinct behaviours were observed for the different concentrations, without a reduction of cellular metabolism >10% compared with the control, either when applied directly or transdentinally. SEM revealed no significant change in cell morphology, except for the positive control (H2 O2 ). There was no difference in TP, ALP or MN between the control group and the group exposed to GSE. CONCLUSIONS: Treatment with grape seed extract, even at the highest concentration and longest period, caused neither direct nor transdentinal cytotoxic effects on human pulp cells. Grape seed extract components may play a biostimulatory role and protect dental pulp cells when in direct contact.

Influence on the saturable absorption of the induced losses by photodeposition of zinc nanoparticles in an optical fiber.

In this work, the influence of induced losses on the saturable absorption by zinc nanoparticles photodeposited onto the core of an optical fiber end is reported. Samples with different losses were obtained by the photodeposition technique using a continuous wave laser at 1550 nm. The nonlinear absorption of the saturable absorber was characterized by the P-scan technique using a high-gain pulsed erbium-doped fiber amplifier. The results have demonstrated that for optical fibers with variable induced losses by deposited nanoparticles, the modulation depth increases proportionally based on the nonlinear absorption coefficient. With induced losses fixed at 3 dB, it was demonstrated that the modulation depth increased as a function of the optical power used in the photodeposition process. The saturation intensity of the saturable absorber presents small shifts for higher intensities.

Interaction of foot-and-mouth disease virus nonstructural protein 3A with host protein DCTN3 is important for viral virulence in cattle.

UNLABELLED: Nonstructural protein 3A of foot-and-mouth disease virus (FMDV) is a partially conserved protein of 153 amino acids in most FMDVs examined to date. The role of 3A in virus growth and virulence within the natural host is not well understood. Using a yeast two-hybrid approach, we identified cellular protein DCTN3 as a specific host binding partner for 3A. DCTN3 is a subunit of the dynactin complex, a cofactor for dynein, a motor protein. The dynactin-dynein duplex has been implicated in several subcellular functions involving intracellular organelle transport. The 3A-DCTN3 interaction identified by the yeast two-hybrid approach was further confirmed in mammalian cells. Overexpression of DCTN3 or proteins known to disrupt dynein, p150/Glued and 50/dynamitin, resulted in decreased FMDV replication in infected cells. We mapped the critical amino acid residues in the 3A protein that mediate the protein interaction with DCTN3 by mutational analysis and, based on that information, we developed a mutant harboring the same mutations in O1 Campos FMDV (O1C3A-PLDGv). Although O1C3A-PLDGv FMDV and its parental virus (O1Cv) grew equally well in LFBK-αvß6, O1C3A-PLDGv virus exhibited a decreased ability to replicate in primary bovine cell cultures. Importantly, O1C3A-PLDGv virus exhibited a delayed disease in cattle compared to the virulent parental O1Campus (O1Cv). Virus isolated from lesions of animals inoculated with O1C3A-PLDGv virus contained amino acid substitutions in the area of 3A mediating binding to DCTN3. Importantly, 3A protein harboring similar amino acid substitutions regained interaction with DCTN3, supporting the hypothesis that DCTN3 interaction likely contributes to virulence in cattle. IMPORTANCE: The objective of this study was to understand the possible role of a FMD virus protein 3A, in causing disease in cattle. We have found that the cellular protein, DCTN3, is a specific binding partner for 3A. It was shown that manipulation of DCTN3 has a profound effect in virus replication. We developed a FMDV mutant virus that could not bind DCTN3. This mutant virus exhibited a delayed disease in cattle compared to the parental strain highlighting the role of the 3A-DCTN3 interaction in virulence in cattle. Interestingly, virus isolated from lesions of animals inoculated with mutant virus contained mutations in the area of 3A that allowed binding to DCTN3. This highlights the importance of the 3A-DCTN3 interaction in FMD virus virulence and provides possible mechanisms of virus attenuation for the development of improved FMD vaccines.

Foot-and-mouth disease virus modulates cellular vimentin for virus survival.

Foot-and-mouth disease virus (FMDV), the causative agent of foot-and-mouth disease, is an Aphthovirus within the Picornaviridae family. During infection with FMDV, several host cell membrane rearrangements occur to form sites of viral replication. FMDV protein 2C is part of the replication complex and thought to have multiple roles during virus replication. To better understand the role of 2C in the process of virus replication, we have been using a yeast two-hybrid approach to identify host proteins that interact with 2C. We recently reported that cellular Beclin1 is a natural ligand of 2C and that it is involved in the autophagy pathway, which was shown to be important for FMDV replication. Here, we report that cellular vimentin is also a specific host binding partner for 2C. The 2C-vimentin interaction was further confirmed by coimmunoprecipitation and immunofluorescence staining to occur in FMDV-infected cells. It was shown that upon infection a vimentin structure forms around 2C and that this structure is later resolved or disappears. Interestingly, overexpression of vimentin had no effect on virus replication; however, overexpression of a truncated dominant-negative form of vimentin resulted in a significant decrease in viral yield. Acrylamide, which causes disruption of vimentin filaments, also inhibited viral yield. Alanine scanning mutagenesis was used to map the specific amino acid residues in 2C critical for vimentin binding. Using reverse genetics, we identified 2C residues that are necessary for virus growth, suggesting that the interaction between FMDV 2C and cellular vimentin is essential for virus replication.

Polymorphisms in the GSTT1 and GSTM1 genes are associated with increased risk of preeclampsia in the Mexican mestizo population.

Preeclampsia is a pregnancy-specific disorder in humans and a major cause of maternal and neonatal morbidity and mortality. Increasing evidence suggests that oxidative stress plays an important role in the pathogenesis of preeclampsia. The aim of this study was to investigate the relationship between null alleles of the glutathione S-transferases (GST) M1 and T1 genes and the risk of preeclampsia. This case-control study involved 112 preeclamptic and 233 normoevolutive pregnant women. The null polymorphisms were genotyped by multiplex polymerase chain reaction (PCR). Our results showed an increased risk of preeclampsia in patients with the GSTT1 null genotype [odds ratio (OR) = 2.21; 95% confidence interval (CI) = 1.14-4.27; P = 0.018]. Our data further showed that a combination of deletion genotypes of the GSTM1 and GSTT1 genes conferred an even higher risk of preeclampsia (OR = 4.56, 95%CI = 1.59-13.09; P = 0.005). Our results provide the first evidence suggesting that a GSTT1 null polymorphism might be associated with preeclampsia in the Mexican mestizo population, and that this risk increases with the combination of both GSTT1 and GSTM1 null polymorphisms.

Foot-and-mouth disease virus nonstructural protein 2C interacts with Beclin1, modulating virus replication.

Foot-and-mouth disease virus (FMDV), the causative agent of foot-and-mouth disease, is an Apthovirus within the Picornaviridae family. Replication of the virus occurs in association with replication complexes that are formed by host cell membrane rearrangements. The largest viral protein in the replication complex, 2C, is thought to have multiple roles during virus replication. However, studies examining the function of FMDV 2C have been rather limited. To better understand the role of 2C in the process of virus replication, we used a yeast two-hybrid approach to identify host proteins that interact with 2C. We report here that cellular Beclin1 is a specific host binding partner for 2C. Beclin1 is a regulator of the autophagy pathway, a metabolic pathway required for efficient FMDV replication. The 2C-Beclin1 interaction was further confirmed by coimmunoprecipitation and confocal microscopy to actually occur in FMDV-infected cells. Overexpression of either Beclin1 or Bcl-2, another important autophagy factor, strongly affects virus yield in cell culture. The fusion of lysosomes to autophagosomes containing viral proteins is not seen during FMDV infection, a process that is stimulated by Beclin1; however, in FMDV-infected cells overexpressing Beclin1 this fusion occurs, suggesting that 2C would bind to Beclin1 to prevent the fusion of lysosomes to autophagosomes, allowing for virus survival. Using reverse genetics, we demonstrate here that modifications to the amino acids in 2C that are critical for interaction with Beclin1 are also critical for virus growth. These results suggest that interaction between FMDV 2C and host protein Beclin1 could be essential for virus replication.

Emergence of fairness in repeated group interactions.

Often groups need to meet repeatedly before a decision is reached. Hence, most individual decisions will be contingent on decisions taken previously by others. In particular, the decision to cooperate or not will depend on one's own assessment of what constitutes a fair group outcome. Making use of a repeated N-person prisoner's dilemma, we show that reciprocation towards groups opens a window of opportunity for cooperation to thrive, leading populations to engage in dynamics involving both coordination and coexistence, and characterized by cycles of cooperation and defection. Furthermore, we show that this process leads to the emergence of fairness, whose level will depend on the dilemma at stake.

The early pathogenesis of foot-and-mouth disease in cattle after aerosol inoculation. Identification of the nasopharynx as the primary site of infection.

To characterize the early events of foot-and-mouth disease virus (FMDV) infection in cattle subsequent to simulated natural exposure, 16 steers were aerosol inoculated with FMDV and euthanized at various times. Samples were collected from each steer antemortem (serum, nasal swabs, and oral swabs) and postmortem (up to 40 tissues per animal) and screened for FMDV by virus isolation and for FMDV RNA by real-time reverse transcription polymerase chain reaction. Tissues that tested positive for FMDV or viral RNA were examined by immunohistochemistry and multichannel immunofluorescence microscopy. In previremic steers, FMDV was most consistently localized to nasopharyngeal tissues, thereby indicating this region as the most important site of primary viral replication. The earliest site of microscopic localization of FMDV antigens was the lymphoid follicle-associated epithelium of the pharyngeal mucosa-associated lymphoid tissue of the nasopharynx at 6 hours postaerosolization. At early time points after aerosol inoculation, viral antigens colocalized with cytokeratin-positive pharyngeal epithelial cells; intraepithelial FMDV-negative, MHCII/CD11c-double-positive dendritic cells were present in close proximity to FMDV-positive cells. Onset of viremia coincided with marked increase of viral loads in pulmonary tissues and with substantial decrease of viral detection in nasopharyngeal tissues. These data indicate that subsequent to aerogenous exposure to FMDV, the temporally defined critical pathogenesis events involve (1) primary replication in epithelial cells of the pharyngeal mucosa-associated lymphoid tissue crypts and (2) subsequent widespread replication in pneumocytes in the lungs, which coincides with (3) the establishment of sustained viremia.

Cancer phenotype as the outcome of an evolutionary game between normal and malignant cells.

BACKGROUND: There is variability in the cancer phenotype across individuals: two patients with the same tumour may experience different disease life histories, resulting from genetic variation within the tumour and from the interaction between tumour and host. Until now, phenotypic variability has precluded a clear-cut identification of the fundamental characteristics of a given tumour type. METHODS: Using multiple myeloma as an example, we apply the principles of evolutionary game theory to determine the fundamental characteristics that define the phenotypic variability of a tumour. RESULTS: Tumour dynamics is determined by the frequency-dependent fitness of different cell populations, resulting from the benefits and costs accrued by each cell type in the presence of others. Our study shows how the phenotypic variability in multiple myeloma bone disease can be understood through the theoretical approach of a game that allows the identification of key genotypic features in a tumour and provides a natural explanation for phenotypic variability. This analysis also illustrates how complex biochemical signals can be translated into cell fitness that determines disease dynamics. CONCLUSION: The present paradigm is general and extends well beyond multiple myeloma, and even to non-neoplastic disorders. Furthermore, it provides a new perspective in dealing with cancer eradication. Instead of trying to kill all cancer cells, therapies should aim at reducing the fitness of malignant cells compared with normal cells, allowing natural selection to eradicate the tumour.

Targeted therapies for ROS1-rearranged non-small cell lung cancer.

ROS1 gene fusions account for approximately 1-2% of all cases of non-small cell lung cancer (NSCLC). Similarly to anaplastic lymphoma kinase (ALK)-positive NSCLC, patients with ROS1+ NSCLC tend to have minimal smoking and be of the female sex. In most cases, adenocarcinoma is the dominant histology. The ROS1 gene has homology to ALK and this structural similarity formed the basis for utilizing ALK inhibitors for ROS1+ NSCLC. On the basis of impressive progression-free survival of 19.2 months from the PROFILE 1001 trial, crizotinib obtained Food and Drug Administration (FDA) approval as first-line therapy for treatment of ROS1+ NSCLC. Since then, there has been a growing appreciation of the incidence of brain metastases in ROS1+ NSCLC and rates of central nervous system progression on crizotinib. Additionally, appreciation of novel resistance mechanisms to crizotinib has led to the development of newer tyrosine kinase inhibitors (TKIs). In this review, we highlight known and emerging TKIs for the management of ROS1+ NSCLC.

Early Detection of Foot-And-Mouth Disease Virus from Infected Cattle Using A Dry Filter Air Sampling System.

Foot-and-mouth disease (FMD) is a highly contagious livestock disease of high economic impact. Early detection of FMD virus (FMDV) is fundamental for rapid outbreak control. Air sampling collection has been demonstrated as a useful technique for detection of FMDV RNA in infected animals, related to the aerogenous nature of the virus. In the current study, air from rooms housing individual (n = 17) or two groups (n = 4) of cattle experimentally infected with FDMV A24 Cruzeiro of different virulence levels was sampled to assess the feasibility of applying air sampling as a non-invasive, screening tool to identify sources of FMDV infection. Detection of FMDV RNA in air was compared with first detection of clinical signs and FMDV RNA levels in serum and oral fluid. FMDV RNA was detected in room air samples 1-3 days prior (seven animals) or on the same day (four animals) as the appearance of clinical signs in 11 of 12 individually housed cattle. Only in one case clinical signs preceded detection in air samples by one day. Overall, viral RNA in oral fluid or serum preceded detection in air samples by 1-2 days. Six individually housed animals inoculated with attenuated strains did not show clinical signs, but virus was detected in air in one of these cases 3 days prior to first detection in oral fluid. In groups of four cattle housed together, air detection always preceded appearance of clinical signs by 1-2 days and coincided more often with viral shedding in oral fluid than virus in blood. These data confirm that air sampling is an effective non-invasive screening method for detecting FMDV infection in confined to enclosed spaces (e.g. auction barns, milking parlours). This technology could be a useful tool as part of a surveillance strategy during FMD prevention, control or eradication efforts.

Efficacy of a high potency O1 Manisa monovalent vaccine against heterologous challenge with foot-and-mouth disease virus of O/SEA/Mya-98 lineage in sheep.

Potency tests for commercial oil-adjuvanted foot-and-mouth disease (FMD) vaccines are usually carried out in cattle, using a full dose (2 ml) of vaccine and homologous virus challenge. However, in sheep the recommended vaccine dose is half of the cattle dose (1 ml) and most vaccines have not been potency tested for this species, especially with heterologous viruses. To determine the efficacy of a high potency (>6PD50) FMD virus (FMDV) O1Manisa vaccine in sheep, we carried out a study using a heterologous FMDV (FMDV O/SKR/2010 - Mya-98 strain) challenge. Groups of seven animals each were vaccinated with 2×, 1×, 1/2× or 1/4× dose (2 ml, 1 ml, 0.5 ml or 0.25 ml respectively) and challenged at 7 days post vaccination (dpv). Only 3 of the 7 sheep in the group vaccinated with 2 ml were protected. With 2 additional groups, receiving double or single doses and challenged at 14 dpv, 4 of 7 sheep were protected in each group. None of the sheep had measurable neutralising antibodies against the vaccine or challenge virus at 7 dpv. However, all vaccinated animals challenged at 14 dpv had a homologous neutralising response against FMDV O1 Manisa on the day of challenge and all but one animal also had a heterologous response to FMDV O/SKR/2010. Infectious FMDV and viral RNA could be found in nasal swabs between 1 and 6 days post challenge (dpc) in most vaccinated sheep, but those vaccinated with higher doses or challenged at 14 dpv showed significant decreases in the level of FMDV detection. Intermittent virus shedding was noticed between 1 and 35 dpc in all vaccinated groups, but persistent infection could be demonstrated only in 4 sheep (20%). This study showed that at the recommended dose, a high potency (>6 PD50) FMDV O1Manisa vaccine does not protect sheep against a heterologous challenge at 7 dpv. However, partial protection was observed when a double dose was used at 7 dpv or when double or single dose vaccinated sheep were challenged at 14 dpv.

An Integrative Analysis of Foot-and-Mouth Disease Virus Carriers in Vietnam Achieved Through Targeted Surveillance and Molecular Epidemiology.

Foot-and-mouth disease (FMD) is a major constraint to transboundary trade in animal products, yet much of its natural ecology and epidemiology in endemic regions is still poorly understood. To address this gap, a multidisciplinary, molecular and conventional epidemiological approach was applied to an investigation of endemic FMD in Vietnam. Within the study space, it was found that 22.3% of sampled ruminants had previously been infected with FMD virus (FMDV), of which 10.8% were persistent, asymptomatic carriers (2.4% of the total population). Descriptive data collected from targeted surveillance and a farm questionnaire showed a significantly lower prevalence of FMDV infection for dairy farms. In contrast, farms of intermediate size and/or history of infection in 2010 were at increased risk of FMD exposure. At the individual animal level, buffalo had the highest exposure risk (over cattle), and there was spatial heterogeneity in exposure risk at the commune level. Conversely, carrier prevalence was higher for beef cattle, suggesting lower susceptibility of buffalo to persistent FMDV infection. To characterize virus strains currently circulating in Vietnam, partial FMDV genomic (VP1) sequences from carrier animals collected between 2012 and 2013 (N = 27) and from FMDV outbreaks between 2009 and 2013 (N = 79) were compared by phylogenetic analysis. Sequence analysis suggested that within the study period, there were two apparent novel introductions of serotype A viruses and that the dominant lineage of serotype O in Vietnam shifted from SEA/Mya-98 to ME-SA/PanAsia. FMDV strains shared close ancestors with FMDV from other South-East Asian countries indicating substantial transboundary movement of the predominant circulating strains. Close genetic relationships were observed between carrier and outbreak viruses, which may suggest that asymptomatic carriers of FMDV contribute to regional disease persistence. Multiple viral sequences obtained from carrier cattle over a 1-year period had considerable within-animal genetic variation, indicating within-host virus evolution.

Graph topology plays a determinant role in the evolution of cooperation.

We study the evolution of cooperation in communities described in terms of graphs, such that individuals occupy the vertices and engage in single rounds of the Prisoner's Dilemma with those individuals with whom they are connected through the edges of those graphs. We find an overwhelming dominance of cooperation whenever graphs are dynamically generated through the mechanisms of growth and preferential attachment. These mechanisms lead to the appearance of direct links between hubs, which constitute sufficient conditions to sustain cooperation. We show that cooperation dominates from large population sizes down to communities with nearly 100 individuals, even when extrinsic factors set a limit on the number of interactions that each individual may engage in.

Infection Dynamics of Foot-and-Mouth Disease Virus in Cattle Following Intranasopharyngeal Inoculation or Contact Exposure.

For the purpose of developing an improved experimental model for studies of foot-and-mouth disease virus (FMDV) infection in cattle, three different experimental systems based on natural or simulated natural virus exposure were compared under standardized experimental conditions. Ante-mortem infection dynamics were characterized in cattle exposed to FMDV through a novel, simulated natural intranasopharyngeal (INP) inoculation system or through standardized and controlled systems of within- or between-species direct contact exposure (cattle-to-cattle or pig-to-cattle). All three systems were efficient in causing synchronous, generalized foot-and-mouth disease in cattle exposed to one of three different strains of FMDV representing serotypes O, A and Asia1. There was more within-group variation in the timing of clinical infection following natural and simulated natural virus exposure systems when compared with the conventionally used system of needle inoculation (intraepithelial lingual inoculation). However, the three optimized exposure systems described herein have the advantage of closely simulating field conditions by utilizing natural routes of primary infection, thereby facilitating engagement of mucosal host defence mechanisms. Overall, it is concluded that INP inoculation and standardized systems of direct contact exposure provide effective alternatives to conventional (needle) inoculation systems for studies in which it is desirable to simulate the natural biology of FMDV infection.

Detection of Foot-and-mouth Disease Virus RNA and Capsid Protein in Lymphoid Tissues of Convalescent Pigs Does Not Indicate Existence of a Carrier State.

A systematic study was performed to investigate the potential of pigs to establish and maintain persistent foot-and-mouth disease virus (FMDV) infection. Infectious virus could not be recovered from sera, oral, nasal or oropharyngeal fluids obtained after resolution of clinical infection with any of five FMDV strains within serotypes A, O and Asia-1. Furthermore, there was no isolation of live virus from tissue samples harvested at 28-100 days post-infection from convalescent pigs recovered from clinical or subclinical FMD. Despite lack of detection of infectious FMDV, there was a high prevalence of FMDV RNA detection in lymph nodes draining lesion sites harvested at 35 days post-infection, with the most frequent detection recorded in popliteal lymph nodes (positive detection in 88% of samples obtained from non-vaccinated pigs). Likewise, at 35 dpi, FMDV capsid antigen was localized within follicles of draining lymph nodes, but without concurrent detection of FMDV non-structural protein. There was a marked decline in the detection of FMDV RNA and antigen in tissue samples by 60 dpi, and no antigen or viral RNA could be detected in samples obtained at 100 dpi. The data presented herein provide the most extensive investigation of FMDV persistence in pigs. The overall conclusion is that domestic pigs are unlikely to be competent long-term carriers of infectious FMDV; however, transient persistence of FMDV protein and RNA in lymphoid tissues is common following clinical or subclinical infection.

Epidemic spreading and cooperation dynamics on homogeneous small-world networks.

We introduce a class of small-world networks--homogeneous small-worlds--which, in contrast with the well-known Watts-Strogatz small-worlds, exhibit a homogeneous connectivity distribution, in the sense that all nodes have the same number of connections. This feature allows the investigation of pure small-world effects, detached from any associated heterogeneity. Furthermore, we use at profit the remarkable similarity between the properties of homogeneous small worlds and the heterogeneous small-worlds of Watts-Strogatz to assess the separate roles of heterogeneity and small-world effects. We investigate the dependence on these two mechanisms of the threshold for epidemic outbreaks and also of the coevolution of cooperators and defectors under natural selection. With respect to the well-studied regular homogeneous limits, we find a subtle interplay between these mechanisms. While they both contribute to reduce the threshold for an epidemic outburst, they exhibit opposite behavior in the evolution of cooperation, such that the overall results mask the true nature of their individual contribution to this process.