Observations of Shock Diffusion and Interactions in Supersonic Freestreams with Counterflowing Jets

One of the technical challenges in long-duration space exploration and interplanetary missions is controlled entry and re-entry into planetary and Earth atmospheres, which requires the dissipation of considerable kinetic energy as the spacecraft decelerates and penetrates the atmosphere. Efficient heat load management of stagnation points and acreage heating remains a technological challenge and poses significant risk, particularly for human missions. An innovative approach using active flow control concept is proposed to significantly modify the external flow field about the spacecraft in planetary atmospheric entry and re-entry in order to mitigate the harsh aerothermal environments, and significantly weaken and disperse the shock-wave system to reduce aerothermal loads and wave drag, as well as improving aerodynamic performance. To explore the potential benefits of this approach, we conducted fundamental experiments in a trisonic blow down wind tunnel to investigate the effects of counterflowing sonic and supersonic jets against supersonic freestreams to gain a better understanding of the flow physics of the interactions of the opposing flows and the resulting shock structure

NF-κB activation is critical for bacterial lipoprotein tolerance-enhanced bactericidal activity in macrophages during microbial infection

Tolerance to bacterial components represents an essential regulatory mechanism during bacterial infection. Bacterial lipoprotein (BLP)-induced tolerance confers protection against microbial sepsis by attenuating inflammatory responses and augmenting antimicrobial activity in innate phagocytes. It has been well-documented that BLP tolerance-attenuated proinflammatory cytokine production is associated with suppressed TLR2 signalling pathway; however, the underlying mechanism(s) involved in BLP tolerance-enhanced antimicrobial activity is unclear. Here we report that BLP-tolerised macrophages exhibited accelerated phagosome maturation and enhanced bactericidal activity upon bacterial infection, with upregulated expression of membrane-trafficking regulators and lysosomal enzymes. Notably, bacterial challenge resulted in a strong activation of NF-κB pathway in BLP-tolerised macrophages. Importantly, activation of NF-κB pathway is critical for BLP tolerance-enhanced antimicrobial activity, as deactivation of NF-κB in BLP-tolerised macrophages impaired phagosome maturation and intracellular killing of the ingested bacteria. Finally, activation of NF-κB pathway in BLP-tolerised macrophages was dependent on NOD1 and NOD2 signalling, as knocking-down NOD1 and NOD2 substantially inhibited bacteria-induced activation of NF-κB and overexpression of Rab10 and Acp5, two membrane-trafficking regulators and lysosomal enzymes contributed to BLP tolerance-enhanced bactericidal activity. These results indicate that activation of NF-κB pathway is essential for BLP tolerance-augmented antimicrobial activity in innate phagocytes and depends primarily on both NOD1 and NOD2

The Dynamics of Shock Dispersion and Interactions in Supersonic Freestreams with Counterflowing Jets

An active flow control concept using counterflowing jets to significantly modify the external flowfields and strongly weaken or disperse the shock-waves of supersonic and hypersonic vehicles to reduce the aerothermal loads and wave drag was investigated. Experiments were conducted in a trisonic blow-down wind-tunnel, complemented by pre-test computational fluid dynamics (CFD) analysis of a 2.6% scale model of Apollo capsule, with and without counterflowing jets, in Mach 3.48 and 4.0 freestreams, to assess the potential aerothermal and aerodynamic benefits of this concept. The model was instrumented with heat flux gauges, thermocouples and pressure taps, and employed five counterflowing jet nozzles (three sonic and other two supersonic with design Mach numbers of 2.44 and 2.94) and nozzle exit diameters ranging from 0.25 to 0.5 inch. Schlieren data show that at low jet flow rates of 0.05 and 0.1lb(sub m)/sec, the interactions result in a long penetration mode (LPM) jet, while the short penetration mode (SPM) jet is observed at flow rates greater than 0.1 lb(sub m)/sec., consistent with the pre-test CFD predictions. For the LPM, the jet appears to be nearly fully-expanded, resulting in a very unsteady and oscillatory flow structure in which the bow shock becomes highly dispersed such that it is no longer discernable. Higher speed camera Schlieren data reveal the shock to be dispersed into striations of compression waves, which suddenly coalesce to a weaker bow shock with a larger standoff distance as the flow rate reached a critical value. The pronounced shock dispersion could significantly impact the aerodynamic performance (L/D) and heat flux reduction of spacecraft in atmospheric entry and re-entry, and could also attenuate the entropy layer in hypersonic blunt body flows. For heat transfer, the results show significant reduction in heat flux, even giving negative heat flux for some of the SPM interactions, indicating that the flow wetting the model is cooling, instead of heating the model, which could significantly impact the requirements and design of thermal protection system. These findings strongly suggest that the application of counterflowing jets as active flow control could have strong impact on supersonic and hypersonic vehicle design and performance

Elite Suppressors Harbor Low Levels of Integrated HIV DNA and High Levels of 2-LTR Circular HIV DNA Compared to HIV+ Patients On and Off HAART

Elite suppressors (ES) are a rare population of HIV-infected individuals that are capable of naturally controlling the infection without the use of highly active anti-retroviral therapy (HAART). Patients on HAART often achieve viral control to similar (undetectable) levels. Accurate and sensitive methods to measure viral burden are needed to elucidate important differences between these two patient populations in order to better understand their mechanisms of control. Viral burden quantification in ES patients has been limited to measurements of total DNA in PBMC, and estimates of Infectious Units per Million cells (IUPM). There appears to be no significant difference in the level of total HIV DNA between cells from ES patients and patients on HAART. However, recovering infectious virus from ES patient samples is much more difficult, suggesting their reservoir size should be much smaller than that in patients on HAART. Here we find that there is a significant difference in the level of integrated HIV DNA in ES patients compared to patients on HAART, providing an explanation for the previous results. When comparing the level of total to integrated HIV DNA in these samples we find ES patients have large excesses of unintegrated HIV DNA. To determine the composition of unintegrated HIV DNA in these samples, we measured circular 2-LTR HIV DNA forms and found ES patients frequently have high levels of 2-LTR circles in PBMC. We further show that these high levels of 2-LTR circles are not the result of inefficient integration in ES cells, since HIV integrates with similar efficiency in ES and normal donor cells. Our findings suggest that measuring integration provides a better surrogate of viral burden than total HIV DNA in ES patients. Moreover, they add significantly to our understanding of the mechanisms that allow viral control and reservoir maintenance in this unique patient population

A Tribute to the Mind, Methodology and Mentoring of Wayne Velicer

Wayne Velicer is remembered for a mind where mathematical concepts and calculations intrigued him, behavioral science beckoned him, and people fascinated him. Born in Green Bay, Wisconsin on March 4, 1944, he was raised on a farm, although early influences extended far beyond that beginning. His Mathematics BS and Psychology minor at Wisconsin State University in Oshkosh, and his PhD in Quantitative Psychology from Purdue led him to a fruitful and far-reaching career. He was honored several times as a high-impact author, was a renowned scholar in quantitative and health psychology, and had more than 300 scholarly publications and 54,000+ citations of his work, advancing the arenas of quantitative methodology and behavioral health. In his methodological work, Velicer sought out ways to measure, synthesize, categorize, and assess people and constructs across behaviors and time, largely through principal components analysis, time series, and cluster analysis. Further, he and several colleagues developed a method called Testing Theory-based Quantitative Predictions, successfully applied to predicting outcomes and effect sizes in smoking cessation, diet behavior, and sun protection, with the potential for wider applications. With $60,000,000 in external funding, Velicer also helped engage a large cadre of students and other colleagues to study methodological models for a myriad of health behaviors in a widely applied Transtheoretical Model of Change. Unwittingly, he has engendered indelible memories and gratitude to all who crossed his path. Although Wayne Velicer left this world on October 15, 2017 after battling an aggressive cancer, he is still very present among us

Relationships of PBMC microRNA expression, plasma viral load, and CD4+ T-cell count in HIV-1-infected elite suppressors and viremic patients

<p>Abstract</p> <p>Background</p> <p>HIV-1-infected elite controllers or suppressors (ES) maintain undetectable viral loads (< 50 copies/mL) without antiretroviral therapy. The mechanisms of suppression are incompletely understood. Modulation of HIV-1 replication by miRNAs has been reported, but the role of small RNAs in ES is unknown. Using samples from a well-characterized ES cohort, untreated viremic patients, and uninfected controls, we explored the PBMC miRNA profile and probed the relationships of miRNA expression, CD4+ T-cell counts, and viral load.</p> <p>Results</p> <p>miRNA profiles, obtained using multiple acquisition, data processing, and analysis methods, distinguished ES and uninfected controls from viremic HIV-1-infected patients. For several miRNAs, however, ES and viremic patients shared similar expression patterns. Differentially expressed miRNAs included those with reported roles in HIV-1 latency (miR-29 family members, miRs -125b and -150). Others, such as miR-31 and miR-31*, had no previously reported connection with HIV-1 infection but were found here to differ significantly with uncontrolled HIV-1 replication. Correlations of miRNA expression with CD4+ T-cell count and viral load were found, and we observed that ES with low CD4+ T-cell counts had miRNA profiles more closely related to viremic patients than controls. However, expression patterns indicate that miRNA variability cannot be explained solely by CD4+ T-cell variation.</p> <p>Conclusions</p> <p>The intimate involvement of miRNAs in disease processes is underscored by connections of miRNA expression with the HIV disease clinical parameters of CD4 count and plasma viral load. However, miRNA profile changes are not explained completely by these variables. Significant declines of miRs-125b and -150, among others, in both ES and viremic patients indicate the persistence of host miRNA responses or ongoing effects of infection despite viral suppression by ES. We found no negative correlations with viral load in viremic patients, not even those that have been reported to silence HIV-1 in vitro, suggesting that the effects of these miRNAs are exerted in a focused, cell-type-specific manner. Finally, the observation that some ES with low CD4 counts were consistently related to viremic patients suggests that miRNAs may serve as biomarkers for risk of disease progression even in the presence of viral suppression.</p

Activation of both TLR and NOD signaling confers host innate immunity-mediated protection against microbial infection

The detection of microbial pathogens relies on the recognition of highly conserved microbial structures by the membrane sensor Toll-like receptors (TLRs) and cytosolic sensor NOD-like receptors (NLRs). Upon detection, these sensors trigger innate immune responses to eradicate the invaded microbial pathogens. However, it is unclear whether TLR and NOD signaling are both critical for innate immunity to initiate inflammatory and antimicrobial responses against microbial infection. Here we report that activation of both TLR and NOD signaling resulted in an augmented inflammatory response and the crosstalk between TLR and NOD led to an amplified downstream NF-kB activation with increased nuclear transactivation of p65 at TNF-a and IL-6 promoters. Furthermore, co-stimulation of macrophages with TLR and NOD agonists maximized antimicrobial activity with accelerated phagosome maturation. Importantly, administration of both TLR and NOD agonists protected mice against polymicrobial sepsis-associated lethality with increased serum levels of inflammatory cytokines and accelerated bacterial clearance from the circulation and visceral organs. These results demonstrate that activation of both TLR and NOD signaling synergizes to induce efficient inflammatory and antimicrobial responses, thus conferring protection against microbial infection

Preterm birth and reduced birthweight in first and second teenage pregnancies: a register-based cohort study

<p>Abstract</p> <p>Background</p> <p>Higher risks of preterm birth and small for gestational age babies have been reported in teenagers. The aim of this study was to investigate the relationship between first and second teenage pregnancies and preterm birth, birthweight and small for gestational age (SGA).</p> <p>Methods</p> <p>All women aged 14 to 29 yrs who gave birth to live singletons in the North Western Region of England between January 1st 2004 and December 31st 2006 were identified. Women were classified in three groups; 14-17 yrs, 18-19 yrs and 20-29 yrs (reference group). The outcome measures were preterm birth, very preterm birth, birthweight, SGA (< 5^thpercentile), very SGA (VSGA< 3^rdpercentile). We compared these outcome measures in teenagers' first and second pregnancies with those of mothers aged 20 to 29 yrs.</p> <p>Results</p> <p>The risk of preterm birth was increased in first (OR = 1.21, [95% CI: 1.01-1.45]) and second (OR = 1.93, [95% CI: 1.38-2.69]) time mothers aged 14-17 yrs compared to the reference group. Birthweight was reduced in the first (mean difference = -24 g; [95% CI: -40, -7]) and second (mean difference = -80 g; [95% CI: -115, -46]) time mothers aged 14-17 yrs compared to the reference group. There was some evidence of a protective effect against VSGA in 14-17 yr old first time mothers (OR = 0.79, [95% CI: 0.63-0.99]).</p> <p>Conclusions</p> <p>Teenage mothers are at increased risk of preterm birth compared to adult mothers and this risk is further increased in second time teen pregnancies. This study highlights the importance of ensuring pregnant teenagers have appropriate antenatal care. A first pregnancy may be the first and only time a pregnant teenager interacts with health services and this opportunity for health education and the promotion of contraception should not be overlooked.</p

Targeted Killing of Virally Infected Cells by Radiolabeled Antibodies to Viral Proteins

BACKGROUND: The HIV epidemic is a major threat to health in the developing and western worlds. A modality that targets and kills HIV-1-infected cells could have a major impact on the treatment of acute exposure and the elimination of persistent reservoirs of infected cells. The aim of this proof-of-principle study was to demonstrate the efficacy of a therapeutic strategy of targeting and eliminating HIV-1-infected cells with radiolabeled antibodies specific to viral proteins in vitro and in vivo. METHODS AND FINDINGS: Antibodies to HIV-1 envelope glycoproteins gp120 and gp41 labeled with radioisotopes bismuth 213 ((213)Bi) and rhenium 188 ((188)Re) selectively killed chronically HIV-1-infected human T cells and acutely HIV-1-infected human peripheral blood mononuclear cells (hPBMCs) in vitro. Treatment of severe combined immunodeficiency (SCID) mice harboring HIV-1-infected hPBMCs in their spleens with a (213)Bi- or (188)Re-labeled monoclonal antibody (mAb) to gp41 resulted in a 57% injected dose per gram uptake of radiolabeled mAb in the infected spleens and in a greater than 99% elimination of HIV-1-infected cells in a dose-dependent manner. The number of HIV-1-infected thymocytes decreased 2.5-fold in the human thymic implant grafts of SCID mice treated with the (188)Re-labeled antibody to gp41 compared with those treated with the (188)Re-control mAb. The treatment did not cause acute hematologic toxicity in the treated mice. CONCLUSIONS: The current study demonstrates the effectiveness of HIV-targeted radioimmunotherapy and may provide a novel treatment option in combination with highly active antiretroviral therapy for the eradication of HIV