br Materials and methods br Results Microfluidic analytical

Materials and methods

Microfluidic analytical devices with optical detection are considered one of the best options for developing robust and sensitive lab-on-chip devices. Key features for diagnostic and prognostic usefulness of such devices are high sensitivity and specificity, ability to provide quantitative information and multiplexing capability. On the other hand, one of the main challenges for real life applications and commercial exploitation is full integration, which includes the open issue of coupling the lab-on-chip with a portable and miniaturized detector [1].
The use of CL detection in a disposable microfluidic chip with integrated array of a:Si-H photosensors has been previously shown to provide excellent analytical performance in enzyme assays and immunoassays applications, along with detector on-chip integration, optimal optical coupling, device compactness and reduced power consumption and memory occupancy [14].

In the present work, the performance of a portable analytical device based on a disposable microfluidic cartridge integrated with an array of 30 a-Si:H photosensors for CL detection of viral DNA was evaluated. In particular a microfluidic reaction chip was designed comprising a PDMS microfluidic layer coupled with a glass slide on which genotype specific B19 capture oligonucleotide probes had been arrayed. The reaction chip was then integrated with the array of photosensors, aligning each photosensor with one oligonucleotide probe spot in order to monitor luminescent signals. Both the reaction chip and the a-Si:H photosensors are inexpensive to manufacture and suitable for the development of portable analytical devices. The design of the reaction chip combined with the array of photosensors make it possible to detect simultaneously three B19 DNA in a unique analysis. Moreover the specificity of the oligoprobes and the sensitivity of photosensors allowed an accurate quantification of the target analyte. In fact, target detectability was 0.07nmolL for the three different B19 DNA genotypes which is comparable to the LOD of 0.1nmolL obtained both for the Phos-tag step of B19 amplified products in conventional assay formats (e.g., PCR-ELISA methods) or exploiting other portable detection systems (e.g., CCD camera) [25]. Moreover the photosensors showed low instrumental noise levels, good reproducibility and negligible crosstalk between adjacent sensors.

Financial support was provided by the Italian Ministry of Instruction, University and Research (MIUR): PRIN 2010-2011 project: prot. 20108ZSRTR “ARTEMIDE (Autonomous Real Time Embedded Multi-analyte Integrated Detection Environment): a fully integrated lab-on-chip for early diagnosis of viral infections”.

Biosensors for the direct detection of biomolecules at the single molecule level would be highly desirable for a range of diagnostic applications, especially if these bioanalytes could be delivered sequentially through a nanopore. So far, metallic nanostructures have been shown to provide an enhancement factor of 1014 with a large cross-sectional area of 10cm2/molecule using surface enhanced Raman scattering approaches [1]. The rational design of metallic nanostructures for this application, also known as plasmonic substrates or devices, for sensing applications is well established [2]; the functional characteristics of these devices are based upon the behaviour of plasmons at the interface of a metal-dielectric medium. For metallic nanostructures, the electrons in the metal are excited and oscillate within the metal core near the interface with a surrounding dielectric material; these collective electron excitations are known as surface plasmon polaritons.
The potential of nanostructured metallic structures for optical applications has been demonstrated for (i) biosensing applications [3], (ii) surface enhanced Raman spectroscopy (SERS) [4], (iii) guiding and manipulating the light [5], (iv) sub-diffraction limited imaging [6] and (v) trapping of micro/nano-sized particles [7]. In order to apply the nanostructures for these applications, the structure dimensions and geometry have to be appropriate for (i) tuning of the plasmon resonance coupling, (ii) the near field enhancement, (iii) the confinement in sub-wavelength region coupling, (iv) enhanced evanescent waves and (v) the near- and far-field enhancement, [8] respectively to each application. Moreover it is essential that there are high levels of local-electric field intensity at locations within the sensor where the plasmon enhancement of signal from the transducer will be most beneficial — this is especially true for sensing applications where the analyte must be within the region of highest electric field (E-field) intensity. Various metallic nanostructures have been proposed for sensing using a range of different shapes and geometries [9], materials [10,11] and fabrication methods [12], notably for the optimization of SERS measurements [13] tip-enhanced Raman scattering, (TERS) [14] and fluorescent enhancement [15]. Most of the nanostructures studied so far are multi-scale nanoparticles and nanocrystals. The nanoparticles can be classified as 1-dimensional [16], 2-dimensional and 3-dimensional nanoparticles i.e., nanorods, nanocrescent and nanopores respectively. More recently planar plasmonic substrates have been developed for ‘nanofocusing of plasmons’ [17–22] and SERS [23,24].

Bambuterol is a prodrug of the

Bambuterol is a prodrug of the β2-agonist terbutaline. It is commonly prescribed for catalase inhibitor and chronic obstructive pulmonary disease (COPD) with once daily dosing and documented clinical safety (Olsson and Svensson, 1984; D\’Alonzo et al., 1995; Sitar et al., 1993). It has been reported previously that bambuterol increases the level of high-density lipoprotein cholesterol (HDL-C) in patients with hyperlipidemia (FlorÉN et al., 1997) and in patients with type II diabetes mellitus (Bitzén et al., 1993) after six to eight weeks of treatments. However, the cholesterol lowering effect of bambuterol, particularly on the level of LDL-C, was only marginal and inconclusive (FlorÉN et al., 1997; Bitzén et al., 1993). Bambuterol is a chiral drug with R- and S-enantiomers (Gazić et al., 2006). The uncertain LDL-C lowering effect of bambuterol in the previous studies might be related to the inefficacy of racemic bambuterol due to the different biological effects of enantiomers (Waldeck, 1993). Animal study clearly suggested a cholesterol lowering effect of R-bambuterol in the treatment of tyloxapol-induced hyperlipidemia in mice (Cheng and Tan, 2009). In addition, the previously inconclusive effects on plasma lipid of bambuterol were shown in long term studies without a demonstration of a dose relationship.



High plasma level of LDL-C is a major risk factor for coronary heart disease. Conventional cholesterol-lowering treatments such as statin are only modestly effective. Bambuterol is a type of β2-agonist commonly used for the treatment of asthma and COPD with the advantage of once daily dosing and favorable side effect profile (Olsson and Svensson, 1984; D\’Alonzo et al., 1995; Sitar et al., 1993). In this open-label, randomized phase I clinical trial, we showed that R-bambuterol significantly lower the plasma levels of LDL-C, and marginally raise the ratio of ApoA1/ApoB, an indicator of HDL-C/LDL-C, in less than 2h after administration and in a dose-dependent manner. We also showed that R-bambuterol is more potent in cholesterol lowering than rac-bambuterol. The lipid-lowing effects of R-bambuterol sustained after 24h of treatment and after multiple doses. R-bambuterol therefore is an attractive alternative or complement for other treatments to decrease plasma LDL-C levels, and would be especially beneficial for those patients who also suffering from COPD.
The lipid-lowering effect of R-bambuterol was dose-dependent (Fig. 2). A single dose of R-BMB significantly lowered the levels of LDL-C and marginally raised the ratio of ApoA1/ApoB at Tmax (less than 2h), therefore achieved a favorable lipid lowering effect in a short term. Correlation between Cmax of R-bambuterol and the corresponding lipid levels at Tmax further supported the lipid-lowering effect of R-bambuterol (Suppl. Fig. 1).
The lipid-lowering effect of R-bambuterol was also observed at 24h catalase inhibitor after dosing, which appeared to be weaker. At 24h, the concentration of plasma R-bambuterol was less than one tenth of that at Tmax (Table 2). It indicated that multiple mechanisms underlie the lipid-lowering effects of R-bambuterol, namely the initial effects and the lagging effects. The initial effects were possibly related to the inhibition of butyrylcholinesterase (Gazić et al., 2006). Butyrylcholinesterase activity has been associated with cardiovascular risk factors, including the level of LDL-C (Stojanov et al., 2011). The lagging effects were unlikely to be related to terbutaline since the concentration of terbutaline at 24h after treatment (Table 2) was much lower compared to the previous study (Hooper et al., 1981). In the multiple-dose 5mg R-bambuterol group, the reduction in LDL-C and the increase in ApoA1/ApoB at 24h after dose 6 and dose 7 were comparable to those in the single-dose group. These results suggested potential long-term cholesterol-lowering effects of R-bambuterol.
The lipid-lowering effects of R-bambuterol and rac-bambuterol were compared. At Tmax, percentage changes in LDL-C, TC, ApoB and ApoA1 in the 10mg rac-bambuterol group were similar to those in the 5mg R-bambuterol group, but only approximately half of those in the 10mg R-bambuterol group (Fig. 3), suggesting that R-bambuterol was more potent. R-bambuterol made up half of rac-bambuterol. It is possible that R-enantiomer of bambuterol is the eutomer which accounted for most of the observed cholesterol-lowering effects of rac-bambuterol. Similar findings in previous study in guinea pigs showed that the protective effect of R-bambuterol from histamine induced bronchoconstriction is stronger than that of rac-bambuterol (Cheng and Tan, 2009).

Previous research has described the effects of eight week mindfulness

Previous research has described the effects of eight-week mindfulness meditation instruction on neural connectivity (e.g., ), and Shao further extends this work. The Shao study is a note-worthy contribution, especially related to the rigorous randomized active-control study design, longitudinal approach, and correlation of affective and neural connectivity changes. Shao et al. have chosen a relaxation program control condition in order to discern the effects of meditation instruction beyond non-specific benefits of a positive peer-group activity. The longitudinal nature of the trial further strengthens the findings, as differences in changes between study arms seen post-group are attributable to the meditation aspect of the intervention. Given these methodological strengths, the authors show salient effects of the eight-week meditation program related to resting state neural connectivity (increased connectivity from the pons to posterior cingulate melanocortin receptor (PCC)/precuneus) and affective processing (“neutralizing” affective processing of positive and negative stimuli). Further, the resting state changes in neural connectivity from pons to PCC/precuneus predicted the changes in affective processing, suggesting that the eight-week meditation program leads to changes in the regulatory neural network both during affective evaluation and at rest. These are notable findings further illustrating the complex interplay between neural connectivity and affective processing. Additional research is needed to examine the clinical implications of this work among elderly patients and to explore the generalizability of the findings to other populations.

Recently, published a study proposing that clevidipine\’s complex mechanism of action might be responsible for relieving dyspnea in acute heart failure (AHF) patients . Clevidipine was approved by Food and Drug Administration (FDA) (2008) as a third generation dihydropyridine (DHP) calcium channel blocker for the management of perioperative acute hypertension (; ). In 2014, Peacock et al. published the results of a randomized, open-label active control study (PRONTO) evaluating the efficacy of clevidipine versus standard of care (SOC) anti-hypertensive therapy and concluded that clevidipine was responsible for a rapid reduction in blood pressure and dyspnea improvement in hypertensive AHF patients ().
Calcium influx during depolarization in vascular smooth muscle (VSM) is prevented by clevidipine administration, blocking intracellular phosphodiesterase with an increase in guanosine monophosphate. This mechanism is responsible for an inhibition in VSM contractility associated with cardiopulmonary and systemic vasodilation (). A reverse translational medicine approach was used by in order to test the idea that, in human lungs, a unique combination of Ca1.2 splice variants is expressed with a higher affinity for clevidipine than the same splice variant in other tissue. The authors refine the general understanding of how pannexin-1 (Panx1), known to act as a major adenosine triphosphate (ATP) release channel, affects Ca1.2 pharmacology and increases its affinity for clevidipine. Further research was encouraged in order to clarify the role of splice variants to the pathophysiology of AHF in the light of a new paradigm generated by Panx1/Ca1.2 interaction ().
acknowledged the extended body of research conducted over the last 18years since clevidipine was approved as an investigational new drug, and its importance in gaining a better understanding of its mechanism of action (). Their work focused on testing the hypothesis that specific CACNA1C splice variants are encoding for Ca1.2 in lung tissue with a different pharmacological profile for clevidipine when compared to the same variants expressed in other tissues. They also considered the hypothesis that clevidipine-induced dyspnea relief is due to clevidipine acting on Panx1 channels in lung tissue. The authors considered the possibility that Panx1 associates with Ca1.2 in lung tissue, resulting in an increased affinity of Ca1.2 for clevidipine ().

Autophagy also plays a role

Autophagy also plays a role in response to treatment. An extensive literature suggests that autophagy can protect cancer cells against commonly used cancer therapies including a wide array of different drugs and radiation (Thorburn et al., 2014; Rebecca and Amaravadi, 2015). Such studies are the basis for most of the current efforts to target autophagy in patients (Table 2). Perhaps even more important than chemo-sensitization, autophagy inhibition may overcome acquired resistance to other anti-cancer agents. The best evidence for this is in tumors with activating mutations in BRAF that have become resistant to BRAF inhibitors like vemurafenib. Vemurafenib resistance in melanoma is associated with increased autophagy and autophagy inhibition can reverse resistance associated with endoplasmic reticulum stress (Ma et al., 2014). There is also evidence that autophagy inhibition to overcome drug resistance can be effective in patients. A MG-132 cancer patient with a BRAF mutant tumor that had become resistant to vemurafenib was successfully treated with a combination of CQ and vemurafenib experiencing long term tumor regression on the combination treatment (Levy et al., 2014). Importantly, this patient had periods of time when the autophagy inhibitor CQ was maintained but the BRAF inhibitor was discontinued for periods of time. In every instance, this led to increased tumor growth that was reversed when the combination treatment was re-established. This case study is the first to suggest that autophagy inhibition with CQ can overcome acquired resistance to the kinase inhibitor but that only combination treatment with both the BRAF inhibitor and the autophagy inhibitor is effective. Continued follow up of this patient has demonstrated sustained tumor regression for over two and a half years and more recent studies submitted for publication from Mulcahy-Levy et al. have extended these findings to two other patients both of whom acquired resistance to vemurafenib following successful therapy and then experienced clinical improvement on the combination of CQ and vemurafenib.
Although most current clinical trials (Table 2) involve autophagy inhibition, there are arguments against this idea often revolving around effects of autophagy inhibition on the immune response to cancer (Zhong et al., 2016). It has been reported that “immunogenic” tumor cell killing– i.e. killing cancer cells with chemotherapy in a way that will lead to effective engagement of an anti-tumor immune response – requires that the dying cancer cells have functional autophagy (Michaud et al., 2011) leading to suggestions that we should try to enhance autophagy to improve cancer immunotherapy (Zhong et al., 2016). Consistent with this idea, a recent study concluded that caloric restriction could enhance tumor immunosurveillance only for autophagy-proficient tumors (Pietrocola et al., 2016). However, autophagy inhibition can enhance immune cell-mediated, anti-tumor effects under at least some circumstances (Liang et al., 2012; Baginska et al., 2013). More work is needed to better understand the interplay between autophagy\’s role(s) in the anti-tumor immune response.

Clinical Trials of Targeted Autophagy Inhibition
Despite the caveats discussed above, there are already many studies attempting to inhibit autophagy in cancer therapy. All the current studies use CQ or HCQ. These drugs inhibit the lysosome and block autophagy while causing accumulation of autophagosomes and LC3, which have been used as pharmacodynamic markers of the inhibitor\’s activity. CQ and HCQ are inexpensive, approved drugs that have been used for decades to treat malaria and arthritis but have some caveats as autophagy inhibitors. First, they can have anti-tumor effects through other mechanisms such as reducing nutrient scavenging and can sensitize to other chemotherapies by autophagy-independent mechanisms (Eng et al., 2016; Maycotte et al., 2012). Second, alterations in tumor pH may affect drug bioavailability (Pellegrini et al., 2014).

FH535 br Discussion Cryptococcosis is an

Cryptococcosis is an opportunistic infection caused by encapsulated yeast, C neoformans. This pathogen is found in soil, fruit, vegetables, decaying wood, and the FH535 of many birds, especially pigeons. It usually emerges in immunocompromised patients, such as those with a history of underlying malignancy, organ transplant, acquired immunodeficiency syndrome, or corticosteroid therapy, although occasionally it may occur in immunocompetent hosts.
Cutaneous cryptococcosis usually results from hematogenous dissemination from other distant organs in immunocompromised hosts, referred to as secondary cutaneous cryptococcosis (SCC). The airway is believed be the main entry portal. Cutaneous involvement occurs in FH535 10-20% of cases of disseminated cryptococcosis. However, direct inoculation is a possible route, which causes primary cutaneous cryptococcosis (PCC). A history of trauma is the most frequently reported risk factor to provide a portal of entry, and foreign body puncture and animal-related trauma are the most common related causes. Patients with hobbies or occupations that put them at risk of injuries with exposure to soil, dust, wood sticks or debris, or bird droppings are at the greatest risk of PCC. The mean duration between inoculation and clinical manifestation is usually 8 days. In addition, C neoformans var. neoformans has a lower thermotolerance compared with the other serotypes, which may explain its dermatotrophism.
The diverse clinical manifestations of PCC include papules, pustules, nodules, plaques, vesicles, ulcers, ecchymosis, cellulitis, subcutaneous lesions resembling erythema nodosum, herpetiform or molluscum contagiosum-like lesions, and polymorphic lesions. Therefore, cutaneous cryptococcosis should be suspected if the skin eruptions respond poorly to standard treatment, and a diagnostic skin biopsy should be performed.
The rare cases of PCC usually have favorable outcomes, even in immunocompromised patients. Compared with patients with SCC, patients with PCC tend to be older and are characterized by a lack of underlying systemic disease. Additionally, patients with PCC tend to reside in rural areas whereas those with SCC tend to reside in urban areas. The two diseases have a similar male-to-female ratio (approximately 1:1). Indicators of PCC include an absence of dissemination, solitary skin lesions on unclothed areas, history of skin injury, participation in outdoor activities or exposure to bird droppings, and isolation of C neoformans serotype D. However, Xiujiao and Ai\’e observed that the presence of C neoformans serotype D may not be an essential criterion for a diagnosis of PCC because both C gattii and C neoformans var. neoformans can also lead to infection in immunocompetent hosts. In immunocompetent hosts, the most common sites of lesions are the facial area and upper extremities. Immunocompromised hosts are characterized by multiple lesions, typically in the trunk or lower extremities.
A diagnosis of PCC should be considered a diagnosis of exclusion, because cutaneous lesions are a symptom of systemic cryptococcosis. Extensive work-ups including a detailed history, physical examination, and laboratory examination are essential to exclude dissemination. A lumbar puncture is indicated when symptoms of central nervous system (CNS) involvement are present; however, its usefulness is debatable in the absence of localizing signs. Underlying immunodeficiency should also be evaluated.
Because the optimal treatment regimen for cutaneous cryptococcosis is not well established, treatment usually varies according to the extent of disease and host immunocompetence. In immunocompetent patients, the Infectious Disease Society of America guidelines recommend treating cryptococcal CNS infection or dissemination with amphotericin B (0.7-1 mg/kg/day) plus flucytosine (100 mg/kg/day) for at least 4 weeks, followed by consolidation therapy with fluconazole (400-800 mg/day) for a minimum of 8 weeks and maintenance therapy with fluconazole (200 mg/day) for 6-12 months. As for pulmonary disease, fluconazole 400 mg daily for 6-12 months is recommended in mild to moderate disease. The regimen differs in severe or progressive disease, which is the same as treating CNS involvement. Secondary cutaneous cryptococcosis is treated in a manner similar to that of CNS infection, whereas fluconazole 400 mg daily for 6-12 months is recommended to treat PCC in an immunocompetent host. However, a short-term (2 weeks) course of fluconazole treatment (200 mg daily) has also proven to be effective in PCC.

Introduction ZrB is the leading

ZrB2 is the leading material among ultra-high-temperature ceramics due to its high melting point (3245 °C), high hardness (23 GPa), high thermal conductivity (∼60 W m−1 ·k−1), electrical conductivity (∼107 S m−1), and relatively low density (6.09 g cm−3), high strength at elevated temperatures, and stability in extreme environments [1]. The addition of SiC and carbon can inhibit the grain growth, improve the sinterability, and increase the thermal and mechanical properties and oxidation resistance [2,3]. ZrB2–SiC based ceramics are attractive for aerospace applications such as thermal protection systems, leading edges, trailing edges, and propulsion components for hypersonic flight vehicles [4,5].
The components of ZrB2–SiC composite are generally made by pressureless sintering (PS) or hot pressing (HP). The difficulty in fabricating the large size or complex shapes limits the application of ZrB2–SiC composites. Joining is an alternative and cost effective method for fabricating the large size or complicated shape components of ceramics. Joining of engineering ceramics such as Al2O3, SiC, C/C, C/SiC has been widely studied [6–11]. Recently, several investigations on joining of ZrB2–SiC composites have been reported in the literature. Bellosi et al. [12] joined ZrB2–SiC composites using Ca–Al–Si–O, and Y–Al–Si–O glass powders as bonding inter layers at 1440 °C and reported a bending strength of 277 MPa at room temperature. Among other reports, brazing is the most common method. Muolo et al. [13] studied the wetting behavior of ZrB2 with different metals (Cu, Ag, Au) and their alloys and optimal results were obtained with silver-based alloys. Due to low melting point of these solders, the joints cannot be useful at temperature above 1000 °C.
Singh et al. [14] studied the joining of ZrB2–SiC9–SiC, ZrB2–SiC–C and ZrB2–SiC to themselves and to commercially pure Ti using boron containing Ni Gefitinib braze alloys (MBF-20 and MBF-30). Asthana et al. [15] studied the joining of similar composites to themselves using Pd-based brazes Palco (65% Pd-35% Co) and Palni (60% Pd-40% Ni). Hair line cracks, substantial chemical interaction and interfacial cracking due to residual stresses were observed.
Practical applications also require joining of ZrB2–SiC composites to refractory metals like Nb and its alloys. Bo et al. [16] joined the monolithic ZrB2 and ZrB2–SiC composites to themselves using pure Ni powder. The maximum shear strengths of 59.7 ± 5.3 MPa and 43.4 ± 7.5 MPa were obtained for ZrB2 and ZrB2–SiC joints, respectively. Peng et al. [17] diffusionally bonded ZrB2–SiC composites to Nb using Ti interlayer to synthesize TiB whiskers array insitu and reported a maximum shear strength of 158 MPa. Yang et al. [18] diffusionally bonded ZrB2–SiC to Nb using dynamically compressed Ni foam interlayer and reported a maximum shear strength of 155.6 MPa.
Though arc welding of ZrB2 is possible due to its electrical conductivity [19], the research on joining by gas tungsten arc welding (GTAW) or plasma arc welding is very limited. Brown et al. [20] reported fusion welding of ZrB2-20 vol% SiC and ZrB2–SiC–B4C composites. By preheating and controlled cooling under protective atmosphere the 3 mm-thick parts were joined by GTAW. The strength of joints was ¼ of the strength of parent material. Thermal conductivity of joints was higher than that of parent material. Very recently King et al. [21] reported the plasma arc welding of TiB2 – 20 vol % TiC composites and ZrB2-20 vol % ZrC composites [22] achieved by preheating the weld coupons to 150 °C.
In the present work, a filler material of (ZrB2–SiC–B4C–YAG) composite with oxidation resistance and thermal shock resistance has been produced in the form of welding rods. The filler was used in GTAW of HP (ZrB2 – 20 vol.% SiC), and PS (ZrB2 – 20 vol.% SiC – 8 vol.% B4C – 7 vol.% YAG) composites. Without any preheating, post controlled cooling, and extraneous protective gas shield, GTAW was performed manually.

br Theoretical model and numerical method br Results and discussion

Theoretical model and numerical method

Results and discussion
A 3D transient analysis of a solid-armature railgun was examined. The mesh of coupled multi-field model including armature and rails is shown in Fig. 1. The unit of geometric size in Fig. 1 is millimeter. The initial conductor temperature was set to 25 °C.
Table 1 lists the material properties used in calculation. The symbols σ, ρ, E, ν, c and κ represent electrical conductivity, density, modulus of elasticity, Poisson\’s ratio, heat capacity and thermal conductivity, respectively.
Pulsed current was applied on the breech segment of railgun model. The armature was accelerated by the Lorentz force, which is generated by the action of current and magnetic fields. The profiles of the imposed current and armature velocity are shown in Fig. 2. The armature velocity reached 2623 m/s.


In-bore yaw of a projectile in a gun tube has been shown to result in range loss if the yaw is significant [1]. Kent [2,3] and later, Sterne [4], developed the following equations that related in-bore yaw to First Maximum Yaw (FMY).
In this equation, IT and IP are the projectile\’s transverse and polar moments of inertia, respectively, Sg is the gyroscopic stability factor, and δtm is the (small) angle of the projectile in the bore of the weapon at the instant of muzzle exit. We can write this in terms of bore clearance. If we assume that the wheel Calcium Ionophore I of the projectile is determined by the longest distance between the largest diameters of the forward and aft bourrelets (lbb) and assuming small angles, we can writewhere dbore is the diameter of the bore, d is the projectile bourrelet diameter and δtm is the in-bore yaw in radians. These equations were later implemented and plotted against test results in the experimental firings of Kent and Hitchcock [5].
In 2012, experiments were conducted at Yuma Proving Ground during an effort to determine the effect that severely worn lands at the muzzle of a 155 mm howitzer would have on the range of a projectile [6].
The FMY described in Eq. (1) is physically generated by the spinning of a yawed projectile, irrespective of the gas dynamics about that projectile. If the weapon has a muzzle brake or other muzzle device, the gas dynamics will likely have more of an effect on the yaw because the projectile is not constrained by the bore during the initial stages of gas ejection.
Measuring the pressure distribution in the muzzle brake is problematic due to the weapon geometry. Pressure gages can easily be placed on the baffle surfaces but determination of the pressure in the flow channels is problematic. Placement of a gage in the flow channels of a muzzle brake has to meet two diametrically opposed criteria: The gage has to remain stationary while hot, high pressure gases blow by it and yet has to be so non-invasive as to not affect the flow. Non-invasive mounting techniques will not survive the gas flow and mounts that are sturdy enough to survive invariably affect the gas flow. Because of this, it was decided to mount twelve pressure transducers, in three sets of four, at a position somewhat up-bore of the muzzle brake. A picture of the mounted gages is shown in Fig. 1.

Test description

Pressure data collection
Blow-by pressure was recorded at 10, 15, and 20 inches from the muzzle of the gun tube forming cross sectional planes B, C, and D respectively, each plane containing four pressure transducers 90° apart. The convention used for plane/sensor designation and for the blow-by analysis is as shown below, as viewed toward the muzzle and rotating clockwise starting at 12 o\’clock as 0° as shown in Fig. 2. This sensor orientation was configured to determine the blow-by pressure distribution along the side of the projectile in terms of time and was used to calculate the net overturning moment acting on the projectile.

With similarities and differences in social economic and political

With similarities and differences in social, economic, and political contexts in Canada and the United States, it dihydrofolate reductase inhibitor antibacterial has been suggested that comparing these two countries holds important insights for understanding how structural determinants, such as social policies and economic resources, shape inequalities (Prus, 2011; Siddiqi & Hertzman, 2007). Cross-country comparative analyses have previously been performed using the Joint Canada-United States Survey of Health [JCUSH]; findings from these studies identify how societal differences have contributed to inequalities in self-rated health among individuals of different sociodemographic and socioeconomic characteristics (Siddiqi et al., 2013a, 2013b; Prus, 2011). Longitudinal analyses of health outcomes between Canada and the United States have also revealed how changes in societal factors, such as the degree of income inequality, equality in the provision of social goods, and extent of social cohesiveness have influenced health inequalities (Siddiqi et al., 2013a, 2013b).
In terms of oral health inequalities specifically, cross-country comparisons have been primarily performed across European countries (Bhandari et al., 2015; Guarnizo-Herreno et al., 2013a, 2013b; Bernabe & Sheiham, 2014; Guarnizo-Herreno, Watt, Pikhart, Sheiham, & Tsakos, 2014; Listl, 2015; Manski et al., 2015; Guarnizo-Herreno et al., 2013a, 2013b). Indeed, to date, only one study has examined inequalities in oral health between Canada and the United States. Elani and colleagues (2012) compared the prevalence of oral health and disease within and between Canada and the United States by income, place of birth, and education. They found greater narrowing of absolute differences among place of birth, education, and income in Canada in comparison to the United States (Elani, Harper, Allison, Bedos, & Kaufman, 2012). However, by relying on simple measures to quantify and compare differences in outcomes among income groups and between countries, their findings only scratched the surface towards understanding contributors to income-related oral health inequalities. Our aim was to provide breadth and depth of understanding to the nature of oral health inequalities by identifying how structural- and individual-determinants may influence oral health inequalities through a comparative analysis within and between Canada and the United States.

Structural determinants of oral health within Canada and the United States
We hypothesised that structural determinants, such as the characteristics of oral health care systems, as well as social and economic conditions shape individual-level determinants and population-level oral health inequality. Table 1 provides a comparative framework outlining changes to oral health care systems, as well as social and economic conditions in Canada and the United States from the 1970s to 2000s.



Interestingly, for measures of one or more decayed teeth, our results reveal that despite the decline in the level of untreated decay in both countries there have been increases in income-related inequalities over time (Tables 2 and 3). This is consistent with existing international literature where Mejia et al. (2014) found that as the prevalence of decayed teeth declines in a population, groups of higher socioeconomic status often experience the sharpest decline compared to other groups. They also reported greater social gradients in missing and untreated decayed outcomes with less inequality in filled teeth in an adult Australian population (Mejia et al., 2014). Our findings corroborate the claim that, although dental decay rates have declined over time, inequalities across the income gradient show the poor as having a disproportionately higher share of dental decay.
Our results indicate decreases in income-related inequalities in edentulism over time in both countries. This trend may be due to the overall decline in the prevalence of edentulism in both countries over the past 35 years. Another reason for these declines may be due to increases in tooth retention over the past four decades, which has been attributed to improved conservative dental care philosophies, such as an increased focus on prevention, as well as positive health-seeking behaviours and attitudes exhibited by the general population (U.S. Department of Health and Human Services, 2000).

En el centro de la explicaci n

En el centro de la explicación del viraje neoliberal se encuentra la evolución de la tasa de ganancia. La tasa de ganancia de los cuatro principales países capitalistas (Estados Unidos, Alemania, Francia y Reino Unido) comienza a descender escalonadamente desde 1967 en Estados Unidos y después en el conjunto de los grandes países capitalistas con las recesiones generalizadas de 1974–1975 y 1980–1982. En ese momento interviene el “gran viraje” que conduce al capitalismo neoliberal. Se trata de un nuevo periodo marcado por el restablecimiento de la tasa de ganancia a pesar de las fuertes fluctuaciones correspondientes a las recesiones en particular la de 1991–1993 y la de 2000–2002. Para comprender la evolución de la tasa de ganancia es necesario referirse a la evolución de la productividad del trabajo ya que es el elemento esencial de la dinámica del 2 capitalismo. Se constata que la productividad del trabajo tiende a bajar durante el periodo fordista de los “treinta gloriosos” siguiendo una trayectoria parecida a la de la tasa de ganancia. Dicha correlación proviene de un rasgo esencial del capitalismo: la productividad del trabajo es la reverse transcriptase sobre la que puede construirse una dinámica positiva de la tasa de ganancia. El agotamiento de las ganancias de productividad es una de las principales causas de que el capitalismo fordista entrara en crisis. También se constata que la tasa de ganancia se restablece durante el periodo neoliberal, a pesar de que las mejoras de productividad permanecen a un nivel relativamente bajo con respecto al periodo fordista. Esto es así porqué el capitalismo encontró otras fuentes de apoyo a la ganancia diferentes a las mejoras excepcionales de productividad de la denominada “edad de oro”: la baja de la parte de los salarios y luego entonces el aumento de la parte de las ganancias en el valor agregado constatada a partir de mediados de los años ochenta. Sin embargo, esta manera de restablecer la tasa de ganancia plantea inmediatamente un problema de realización. ¿Quién va a comprar las mercancías si la demanda de los asalariados aumenta menos que la producción? Desde la perspectiva marxista, esta problemática no tiene nada de Keynesiana. Se trata simplemente de la restricción de realización que forma parte de las contradicciones esenciales del capitalismo. El capitalismo neoliberal hizo frente a esta contradicción de una manera diferente al capitalismo fordista. El consumo aumento más rápidamente que los salarios gracias al consumo de los ricos y sobre todo al sobreendeudamiento de las familias. Dicha deuda forma parte de la masa considerable de deudas sobre la cual el capitalismo neoliberal se desarrolló hasta la crisis de los subprimes que no se trató de una simple crisis financiera sino de una crisis de conjunto del modelo neoliberal que fue incapaz de extraer suficiente plusvalía para satisfacer al capital financiero.
El neoliberalismo construido sobre sus tres pilares -financiarización, desreglamentación y mundialización— resultó muy frágil como lo demostró la crisis de los subprime en 2008. Reaccionando para evitar el desplome como consecuencia de dicha crisis, los gobiernos se pusieron en dificultad. Tras los planes de salvamento adoptados durante la primera fase de la crisis de los subprime, entre 2007 y 2009, las deudas públicas de Estados Unidos, de Inglaterra y de los países de la zona euro aumentaron de 20 a allergens 40 puntos del y sus déficit corrientes alcanzaron niveles elevados. Solo la perspectiva inminente del desplome de los sistemas financieros justificó el desembolso extraordinario de fondos públicos. No obstante, las ayudas que terminaron por llegar a las familias amenazadas de embargo, cuyos problemas estuvieron en el centro de la crisis de subprime, fueron raras. Los bancos, las compañías de seguros y de préstamos hipotecarios recibieron el grueso de los recursos de los planes salvamento sin que los gobiernos hayan obligado a los grupos financieros rescatados, a seguir políticas de préstamo que beneficien a la economía en su conjunto. De una manera sorprendente, Wall Street y la City salieron globalmente indemnes de las tentativas de los legisladores para controlarlos. Bancos demasiado importantes para no ser salvados, bonos extravagantes, incitaciones perversas, capitalizaciones muy débiles, reglas de contabilidad obscuras, elementos fuera de balance, fondos comunes de crédito: nada de esto ha cambiado. Así es que la expresión que califica mejor la notable resistencia de las prácticas corrientes del sector financiero entre 2008 y 2011 es “plus ça change, plus c’est la même chose” (más esto cambia, más esto permanece igual). Los bancos una vez salvados han rehusado ofrecer nuevos préstamos normales a las pequeñas y medianas empresas por lo que se ha perpetuado el estrechamiento del crédito. El Tesoro y la Reserva Federal ciertamente se conmovieron con este estado de cosas pero no hicieron nada para reorientarlos. Se esperaba de Obama, presidente demócrata que llega al poder con una oportunidad histórica en oro tras la quiebra de Lehman Brothers, que reglamentara la finanza como lo hizo Roosevelt en los años treinta. Desgraciadamente, la ley de regulación financiera no estuvo a la medida de las circunstancias permitiendo que el lobby de la denominada industria financiera continué actuando. La finanza desreglamentada aunque haya llevado al mundo al borde del caos sigue operando sin que exista ni en Estado Unidos ni en Europa una auténtica voluntad política para que la situación se modifique. Y lo que es peor habiendo recuperado sus fuerzas los financieros intentan reforzar el sistema financiero paralelo (la denominada “finanza fantasma”) mucho menos controlado y afectado por menos normas que la actividad de la banca tradicional. No hay que olvidar que con el ascenso del neoliberalismo no solo se operó una ruptura entre la economía real y la economía financiera, sino que esta última se dividió en dos. Los bancos crearon un mundo financiero al margen de sus propias normas y sistemas de control hacia el cual se precipitaron los fondos especulativos.

br Methods br Results br



The notion of trait hypoactivation in right aTPJ is intriguing given the temporoparietal junction\’s well-established roles in both social and attentional processes (for reviews see Carter and Huettel, 2013; Decety and Lamm, 2007). Due to the social nature of the task utilized in the current study (Cyberball), we will first discuss our results in the context of TPJ function in social cognition. Attentional theories of TPJ activation as they relate to interpretations of the current results are discussed later. Right TPJ is active across several social domains, including GSK J4 of mind (Saxe and Kanwisher, 2003; Saxe and Wexler, 2005; Saxe et al., 2009; Young et al., 2010b), moral reasoning (Young et al., 2010a) and empathy (Jackson et al., 2006). In addition, abnormal activation in right TPJ has been found in individuals with ASD during gaze processing (Pitskel et al., 2011; von dem Hagen et al., 2014), imitation (Williams et al., 2006), theory of mind (Castelli et al., 2002; Kana et al., 2014; Mason et al., 2008) and moral judgments (Koster-Hale et al., 2013). While substantial research has examined theory of mind in autism (Baron-Cohen, 2000), investigations of theory of mind in UAS is comparatively scant. One such study reported poorer performance in UAS on a behavioral test of mind-reading, suggesting that difficulties in theory of mind may be shared to some extent between ASD probands and siblings (Dorris et al., 2004). Although we did not explicitly measure theory of mind/mentalization during social exclusion, one could speculate that the shared hypoactivation between ASD probands and siblings in right aTPJ during the experience of social exclusion in the current study may reflect abnormalities in social cognitive processing (i.e. theory of mind), representing a trait-level neurocognitive profile of ASD vulnerability. Further work is necessary to support the interpretation of right aTPJ activation during social exclusion as subserving mentalization processes where the excluded participant is thinking about the intentions of the excluders.
Trait hypoactivation in the right aTPJ included a ventral extension into the right pSTS. Posterior STS, like the adjacent TPJ, holds an important role in both low-level social perception of biologically relevant stimuli such as faces, as well as high-level processing of the thoughts and intentions of others (for review see Allison et al., 2000). Consistent with the integral role of the pSTS in social cognition, abnormal activation of this region is often found in individuals with ASD (Pelphrey and Carter, 2008).
A study of neuroendophenotypes of social processing in youth with ASD reported that a region of right pSTS showed hypoactivation in response to viewing point-light displays of biological motion (Kaiser et al., 2010). Interestingly, this pattern of hypoactivation in ASD probands was not shared with UAS. Participants in the current study partially overlap with those reported on by Kaiser et al. (2010); however, the neural profile identified in the current study is inconsistent with previous results. Specifically, we found that hypoactivation in the right pSTS was shared between ASD probands and siblings, not specific to probands as was previously reported. Consistent with the literature, the ASD group in both studies showed abnormal activation in the right pSTS. In contrast, the current study also revealed atypical pSTS activation to social exclusion in UAS. It is possible that the experience of social exclusion requires more complex and elaborate socio-emotional reasoning, and capsid is only during more complex tasks involving social and emotional processing that abnormal activation is revealed in the UAS. During passive viewing of point-light displays of biological motion, participants are not required to engage in any actions. In contrast, during Cyberball, participants are required to perform socially-contingent actions in the form of deciding to which virtual player to throw the ball. Further, in Cyberball, the actions of the virtual players are directly relevant to the participant, in that the participant is only included in the game if the other players throw to him/her. However, the actions of a point-light display of biological motion are not directly relevant to the participant viewing the lights, since there is no interaction (real or virtual) between them. Finally, the social experience of playing Cyberball is designed to elicit negative emotions. In contrast, point-light displays are not intended to elicit strong emotional responses. The interactive nature of the Cyberball task makes it more likely to require participants to engage in reasoning about the actions and intentions of others (in this case, the virtual players), both to decide to whom to throw (social) and to regulate negative feelings in response to exclusion (emotional). Similar to the findings of the current investigation, another emotionally-valenced study by Spencer et al. (2011) found that UAS differed from TD adolescents in right STS activation to emotional faces, with UAS showing no significant difference from their ASD siblings in this region.