A simplified formula to estimate the load history due to ballistic impacts with bullet splash. Development and validation for finite element simulation of 9x21mm full metal jacket bullets

An original simplified formula is proposed to estimate the load history caused by ballistic impacts characterized by the so-called bullet splash phenomenon, consisting in the complete bullet fragmentation with no penetration of the target. The formula is based on the progressive momentum variation of the mass of the bullet impacting on a planar plate normal to the impact direction. The method aims at creating a simplified approach to assess the response of structures by means of explicit finite element simulations without the need of modelling the interaction between impactor and target. The results demonstrate that the proposed method can be used to estimate the forces generated by bullet-splash phenomena of 9x21mm full metal jacket bullets and effectively applied to finite element simulations allowing significant reductions in computational cost

A simplified constitutive model for a SEBS gel muscle simulant - Development and experimental validation for finite elements simulations of handgun and rifle ballistic impacts

An original simplified constitutive model is proposed to simulate the effects of ballistic impacts on blocks of synthetic muscle simulant based on mineral oil and styrene ethylene-butylene styrene polymers (SEBS) as a convenient substitute for Fackler ballistic gelatin. The model is based on a quasi-static elastic-plastic model associated with hydrodynamic properties regulated by a polynomial equation of state. The paper illustrates the development and experimental validation of the model to simulate 9x21mm FMJ round-nose, 7.62x39 mm FMJ, and 5.56x45 mm NATO bullets penetrating 145x145x400 mm gel blocks. All material parameters are provided to be implemented in built-in LS-Dyna keywords. The validation confirms the effectiveness of the model and suggests possible further developments. The work also confirms the tested synthetic gel as a valid and convenient substitute for Fackler 10% ballistic gelatin at 4 °C

Recovery of interleukin-17 production from interleukin-15-stimulated CD4+ mononuclear cells in HIV-1-infected patients with sustained viral suppression

Interleukin-17 (IL-17) is a pro-inflammatory cytokine that is mainly produced by CD4 + T cells. The role of Th17 during the human immunodeficiency virus (HIV)-1 infection is still unclear, but HIV-1 infection can cause a preferential depletion of Th17 cells. It has been shown that IL-15 elicits IL-17 production from human peripheral blood mononuclear cells. We studied the effect of IL-15 stimulation in vitro on IL-17 production from CD4 + mononuclear cells of HIV-infected patients. We observed that IL-15 triggers, in a dose-dependent manner, IL-17 secretion. This effect was blocked by anti-IL-15 monoclonal antibody (P = 0.01). Interestingly, IL-17 production was significantly lower in patients with detectable plasma viremia when compared with successfully treated HIV-infected patients (P = 0.02) and healthy controls, respectively (P < 0.001). We also noticed a significant difference in IL-17 production between naive HIV-infected patients and patients with virological failure on combined antiretroviral therapy (cART) (P = 0.02). Our results suggest that IL-15 can induce IL-17 production from peripheral CD4 + mononuclear cells of HIV-infected patients. Persistent HIV plasma viremia could cause a severe perturbation of IL-17 production from CD4 + mononuclear cells. IL-17 production in HIV-infected patients could be recovered through a sustained suppression of the viral replication in the peripheral blood through cART

A Simplified ALE model for finite element simulation of ballistic impacts with bullet splash – development and experimental validation

An original simplified finite element model is proposed to simulate the effects of non-penetrating ballistic impacts causing the so-called bullet splash phenomenon (complete bullet fragmentation), while no fragmentation is caused to the target. The model is based on the Arbitrary Lagrangian Eulerian formulation (ALE) and it simulates the impact as a fluid-structure interaction. The bullet splash phenomenon has been tested by experimental analyses of AISI 304L plates impacted by 9x21 FMJ (full metal jacket) bullets. The model has been developed with the aim of creating a simplified approach to be used in the industry and forensic sciences to simulate the non-penetrating interaction of soft impactors with hard targets. Comparisons between evidence and simulation results lead to the conclusion that the proposed approach can be used in a conservative way to estimate both local and global effects of bullet-splash phenomena

Endogenous CCL2 neutralization restricts HIV-1 replication in primary human macrophages by inhibiting viral DNA accumulation

Macrophages are key targets of HIV-1 infection. We have previously described that the expressionof CC chemokine ligand 2 (CCL2) increases during monocyte differentiation to macrophages and it is furtherup-modulated by HIV-1 exposure. Moreover, CCL2 acts as an autocrine factor that promotes viral replication ininfected macrophages. In this study, we dissected the molecular mechanisms by which CCL2 neutralization inhibitsHIV-1 replication in monocyte-derived macrophages (MDM), and the potential involvement of the innate restrictionfactors protein sterile alpha motif (SAM) histidine/aspartic acid (HD) domain containing 1 (SAMHD1) and apolipoproteinB mRNA-editing, enzyme-catalytic, polypeptide-like 3 (APOBEC3) family members.Results:CCL2 neutralization potently reduced the number of p24 Gag+cells during the course of either productive orsingle cycle infection with HIV-1. In contrast, CCL2 blocking did not modify entry of HIV-1 based Virus Like Particles, thusdemonstrating that the restriction involves post-entry steps of the viral life cycle. Notably, the accumulation of viralDNA, both total, integrated and 2-LTR circles, was strongly impaired by neutralization of CCL2. Looking for correlates ofHIV-1 DNA accumulation inhibition, we found that the antiviral effect of CCL2 neutralization was independent of themodulation of SAMHD1 expression or function. Conversely, a strong and selective induction of APOBEC3A expression,to levels comparable to those of freshly isolated monocytes, was associated with the inhibition of HIV-1 replicationmediated by CCL2 blocking. Interestingly, the CCL2 neutralization mediated increase of APOBEC3A expression was typeI IFN independent. Moreover, the transcriptome analysis of the effect of CCL2 blocking on global gene expressionrevealed that the neutralization of this chemokine resulted in the upmodulation of additional genes involved in thedefence response to viruses.Conclusions:Neutralization of endogenous CCL2 determines a profound restriction of HIV-1 replication in primaryMDM affecting post-entry steps of the viral life cycle with a mechanism independent of SAMHD1. In addition, CCL2blocking is associated with induction of APOBEC3A expression, thus unravelling a novel mechanism which mightcontribute to regulate the expression of innate intracellular viral antagonistsin vivo. Thus, our study may potentially leadto the development of new therapeutic strategies for enhancing innate cellular defences against HIV-1 and protecting macrophages from infection

Low mortality rates at two years in HIV-infected individuals undergoing systematic tuberculosis testing with rapid assays at initiation of antiretroviral treatment in Mozambique

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HIV-1 integrase inhibitors are substrates for the multidrug transporter MDR1-P-glycoprotein

BACKGROUND: The discovery of diketoacid-containing derivatives as inhibitors of HIV-1 Integrase (IN) (IN inhibitors, IINs) has played a major role in validating this enzyme as an important target for antiretroviral therapy. Since the in vivo efficacy depends on access of these drugs to intracellular sites where HIV-1 replicates, we determined whether the IINs are recognized by the multidrug transporter MDR1-P-glycoprotein (P-gp) thereby reducing their intracellular accumulation. To address the effect of IINs on drug transport, nine quinolonyl diketo acid (DKA) derivatives active on the HIV-1 IN strand transfer (ST) step and with EC50 ranging from 1.83 to >50 μm in cell-based assays were tested for their in vitro interaction with P-gp in the CEM-MDR cell system. IINs were investigated for the inhibition and induction of the P-gp function and expression as well as for multidrug resistance (MDR) reversing ability. RESULTS: The HIV-1 IINs act as genuine P-gp substrates by inhibiting doxorubicin efflux and inducing P-gp functional conformation changes as evaluated by the modulation of UIC2 mAb epitope. Further, IINs chemosensitize MDR cells to vinblastine and induce P-gp expression in drug sensitive revertants of CEM-MDR cells. CONCLUSION: To our knowledge, this is the first demonstration that HIV-1 IINs are P-gp substrates. This biological property may influence the absorption, distribution and elimination of these novels anti HIV-1 compounds

Dried blood spots for the quantitative evaluation of IgG isotypes and correlation with serum samples in HIV-exposed uninfected (HEU) infants

Background: The determination of IgG levels and their subclasses can provide clinically relevant information on the status of the immune system. Here we determined the sensitivity and reproducibility of the quantification of IgG subclasses from Dried Blood Spots (DBS) in Malawian uninfected infants exposed to HIV (HEU). Methods: Sixty paired samples of serum and DBS from HEU infants were used. Samples were collected from 1, 6, and 24-month old infants. IgGs concentrations from both serum and DBS were analyzed by BN ProSpec Siemens assay, using a different setting for sample dilutions. The reproducibility of the DBS method was tested on 10 samples run twice, starting from the DBS extraction process. To assess the systematic, proportional, and random differences, we computed the Passing-Bablok regression, and the Bland-Altman analysis to estimate the total mean bias between the two tests. Results: The IgG isotypes concentrations from serum and DBS showed significant differences in all the comparisons. Generally, the DBS method underestimated IgG subclasses' values showing a recovery range between 51.2% and 77.6%. Passing Bablok regression on age-based groups showed agreement for IgG, IgG1, and IgG2, but not for IgG3 and IgG4. The mean bias obtained with the Bland Altman test varied largely depending on IgG isotypes (−0.02–2.21 g/l) Coefficient of variation <7.0% was found in the repeated tests for IgG, IgG1, IgG3, and IgG4, while it was 12.4% for IgG2. Conclusions: Varying degrees of differences were seen in the IgGs measurement in the two different matrices. In IgGs analysis, the DBS method offers promise for population-based research, but the results should be carefully evaluated and considered as a relative value since they are not equivalent to the serum concentrations

Measurement of viral load by the automated Abbott real-time HIV-1 assay using dried blood spots collected and processed in Malawi and Mozambique

Background. The use of dried blood spots (DBS) for HIV-1 viral load quantification can greatly improve access to viral monitoring for HIV-infected patients receiving treatment in resource-limited settings.Objectives. To evaluate and validate HIV viral load measurement from DBS in sub-Saharan Africa, with a reliable, all-automated, standard commercial assay such as the Abbott m2000.Methods. A total of 277 DBS were collected in different health centres in Malawi and Mozambique and analysed for viral load determination using the Abbott m2000 assay with the corresponding plasma samples as gold standard. Samples were extracted using the m2000SP automatic extractor and then processed as the plasma samples using the specific 1.0 mL HIV-RNA DBS protocol.Results. Among samples with detectable HIV-RNA the correlation between viral load obtained from the paired 131 plasma and DBS samples was high (r=0.946). Overall, viral load values between DBS and plasma differed by less than 0.5 log unit in 90.1% of cases and by less than 1 log unit in 100% of cases. Using a threshold of 1 000 copies/mL (defining virological failure in resource-limited settings), sensitivity was 94.2% and specificity 98.6%, and both positive and negative predictive values were high (98.5% and 94.5%, respectively).Conclusion. DBS extracted and processed using the Abbott automated system can be reliably used in resource-limited setting to diagnose virological failure