Mosaic HIV-1 vaccination induces anti-viral CD8+ T cell functionality in the phase 1/2a clinical trial APPROACH.

IMPORTANCE: The functionality of CD8+ T cells against human immunodeficiency virus-1 (HIV-1) antigens is indicative of HIV-progression in both animal models and people living with HIV. It is, therefore, of interest to assess CD8+ T cell responses in a prophylactic vaccination setting, as this may be an important component of the immune system that inhibits HIV-1 replication. T cell responses induced by the adenovirus serotype 26 (Ad26) mosaic vaccine regimen were assessed previously by IFN-γ ELISpot and flow cytometric assays, yet these assays only measure cytokine production but not the capacity of CD8+ T cells to inhibit replication of HIV-1. In this study, we demonstrate direct anti-viral function of the clinical Ad26 mosaic vaccine regimen through ex vivo inhibition of replication of diverse clades of HIV-1 isolates in the participant's own CD4+ T cells.

Enabling the evaluation of COVID-19 vaccines with correlates of protection.

In February 2023, a meeting about correlates of protection (CoPs) against COVID-19 was organized by the International Alliance for Biological Standardization, the European Plotkin Institute for Vaccinology, and Vaccinopolis. The meeting aimed at reviewing the evidence, drawing conclusions, and identifying knowledge gaps. Collection of evidence is not straightforward. Neutralizing antibodies correlate with protection and are used for immunobridging studies within and between vaccine platforms for approval of new COVID-19 vaccines. In preparation for the next pandemic, it is vital that rapidly authorized initial vaccines are available to perform immunobridging studies very early. Additional components of the immune response likely contribute to protection against symptomatic infection. Current evidence is strongest for T lymphocytes and binding antibodies. Further studies are needed to consolidate this evidence and define their potential role in the evaluation of vaccines. For evaluation of mucosal vaccines, identifying CoPs against infection and transmission is key; further research is needed to identify and standardize methods suitable for clinical studies. CoPs for broadly protective beta-coronavirus vaccines remain a critical area of research. The knowledge, expertise, and capacity exist to conduct clinical studies using different designs in different populations to discover and validate CoPs, facilitating and accelerating evaluation of novel vaccines/vaccination platforms.

A Biomechanical Comparison of the Back Squat and Hexagonal Barbell Deadlift.

ABSTRACT: Stahl, CA, Regni, G, Tanguay, J, McElfresh, M, Trihy, E, Diggin, D, and King, DL. A biomechanical comparison of the back squat and hexagonal barbell deadlift. J Strength Cond Res 38(5): 815-824, 2024-Coaches often use different exercises to encourage similar strength adaptations and limit monotony. Anecdotally, the hexagonal barbell deadlift (HBD) exhibits similarities to the back squat (BS). To date, research has not examined the empirical differences between these exercises. This study examined kinematic and kinetic differences between the BS and the HBD across different loads. Sixteen resistance-trained individuals (6 men and 10 women) volunteered to participate. Subjects performed 1-repetition maximum (1RM) testing under BS and HBD conditions. Kinematic and kinetic data were collected during performance of both exercises at submaximal (warm-up sets) and maximal (1RM) loads using a 3D motion capture and force-plate system. Results showed that subjects lifted greater 1RM loads in the HBD relative to the BS (p < 0.05; d = -1.75). Kinematic data indicated that subjects exhibited greater maximum forward lean of the trunk and decreased maximum knee flexion while performing the HBD compared with the BS. The BS resulted in higher maximum extension moments at the hip joint than the HBD. Maximum extension moments at the knee joint showed no difference between the exercises. Data suggest that bar design and position facilitate balanced moment arm length at hip and knee joints during performance of the HBD. By contrast, bar position during performance of the BS increases moment arm length at the hip joint, making it a hip-dominant exercise. The present data have implications for the programming of both exercises. Future research should examine differences in muscle-activation strategies between the 2 exercises.

Infection with multiple HIV-1 founder variants is associated with lower viral replicative capacity, faster CD4+ T cell decline and increased immune activation during acute infection.

HIV-1 transmission is associated with a severe bottleneck in which a limited number of variants from a pool of genetically diverse quasispecies establishes infection. The IAVI protocol C cohort of discordant couples, female sex workers, other heterosexuals and men who have sex with men (MSM) present varying risks of HIV infection, diverse HIV-1 subtypes and represent a unique opportunity to characterize transmitted/founder viruses (TF) where disease outcome is known. To identify the TF, the HIV-1 repertoire of 38 MSM participants' samples was sequenced close to transmission (median 21 days post infection, IQR 18-41) and assessment of multivariant infection done. Patient derived gag genes were cloned into an NL4.3 provirus to generate chimeric viruses which were characterized for replicative capacity (RC). Finally, an evaluation of how the TF virus predicted disease progression and modified the immune response at both acute and chronic HIV-1 infection was done. There was higher prevalence of multivariant infection compared with previously described heterosexual cohorts. A link was identified between multivariant infection and replicative capacity conferred by gag, whereby TF gag tended to be of lower replicative capacity in multivariant infection (p = 0.02) suggesting an overall lowering of fitness requirements during infection with multiple variants. Notwithstanding, multivariant infection was associated with rapid CD4+ T cell decline and perturbances in the CD4+ T cell and B cell compartments compared to single variant infection, which were reversible upon control of viremia. Strategies aimed at identifying and mitigating multivariant infection could contribute toward improving HIV-1 prognosis and this may involve strategies that tighten the stringency of the transmission bottleneck such as treatment of STI. Furthermore, the sequences and chimeric viruses help with TF based experimental vaccine immunogen design and can be used in functional assays to probe effective immune responses against TF.

Service learning: Nursing students' civic engagement with diverse populations of children with special needs.

PURPOSE: There is limited knowledge of nursing students' perspectives about engagement with special needs populations. The purpose of this study was to identify the advantages/benefits and disadvantages/challenges of nursing students' engagement experience with children with special mental and physical disabilities. Recommendations to enhance student engagement experiences were also provided. METHODS: A descriptive, qualitative design was employed. Undergraduate nursing students (N = 28) responded to open-ended questions about their civic engagement experiences at a community-based, respite care program for children with special needs. Student accounts underwent directed content analysis, with coding, category and theme development according to the Theory of Planned Behavior. The Atlas.Ti computer program was used to manage the data. RESULTS: Advantages/Benefits: Filling cognitive and experiential learning gaps, rewarding connections/relationships, positive emotions, perceptions and interactions, and fun and stress relief. Disadvantage/challenges: Managing negative/uncomfortable emotions and uncertainty, witnessing and managing disruptive behaviors, negative perceptions of program operations/expectations. CONCLUSIONS: Students experienced cognitive, emotional, interpersonal and educational advantages and/or disadvantages while engaging with this defined population. PRACTICE IMPLICATIONS: To enhance engagement faculty can provide education and anticipatory guidance, detail responsibilities and expectations, and/or utilize simulation for student preparation. Nurses and researchers can utilize community based participatory methods to guide discussions with community-based organizations to collaboratively develop strategies to institute, evaluate and enhance student engagement during service learning experiences with children who have special needs.

Viewpoint of a WHO Advisory Group Tasked to Consider Establishing a Closely-monitored Challenge Model of Coronavirus Disease 2019 (COVID-19) in Healthy Volunteers.

WHO convened an Advisory Group (AG) to consider the feasibility, potential value, and limitations of establishing a closely-monitored challenge model of experimental severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and coronavirus disease 2019 (COVID-19) in healthy adult volunteers. The AG included experts in design, establishment, and performance of challenges. This report summarizes issues that render a COVID-19 model daunting to establish (the potential of SARS-CoV-2 to cause severe/fatal illness, its high transmissibility, and lack of a "rescue treatment" to prevent progression from mild/moderate to severe clinical illness) and it proffers prudent strategies for stepwise model development, challenge virus selection, guidelines for manufacturing challenge doses, and ways to contain SARS-CoV-2 and prevent transmission to household/community contacts. A COVID-19 model could demonstrate protection against virus shedding and/or illness induced by prior SARS-CoV-2 challenge or vaccination. A limitation of the model is that vaccine efficacy in experimentally challenged healthy young adults cannot per se be extrapolated to predict efficacy in elderly/high-risk adults.

Pelvic MRI in spinal cord injury patients: incidence of muscle signal change and early heterotopic ossification.

STUDY DESIGN: Prospective observational study. OBJECTIVE: To evaluate pelvic MRI muscle signal changes and their association with early heterotopic ossification (HO) in patients with spinal cord injuries. SETTING: National Spinal Injuries Unit, Stoke Mandeville, UK. METHODS: Forty patients were imaged with at least two interval magnetic resonance (MR) studies of the pelvis in the first 6 months following a spinal cord injury. Scans were reviewed and scored for heterotopic ossification, muscle signal change and extent of muscle involvement. RESULTS: Muscle signal change was present in 28 (70%) on the initial MRI and 31 (77%) by the second study. Six patients developed MR changes of prodromal or immature heterotopic ossification (15%). No restricted diffusion was demonstrated and no patient developed mature HO. Patients developing MR changes of early HO were more likely to have grade 3 muscle changes. CONCLUSION: Increased T2 muscle signal is common following cord injury, is frequently progressive in the subacute period and is associated with complete injury and early MR signs of heterotopic ossification.

Effect of Varying Self-myofascial Release Duration on Subsequent Athletic Performance.

ABSTRACT: Phillips, J, Diggin, D, King, DL, and Sforzo, GA. Effect of varying self-myofascial release duration on subsequent athletic performance. J Strength Cond Res 35(3): 746-753, 2021-Self-myofascial release (SMR) treatments can enhance joint range-of-motion and restore movement function. The effects of different SMR durations on athletic performance have yet to be examined. Twenty-four volunteers had ankle and knee joint range-of-motion assessed using modified weight-bearing and kneeling lunge (KL) tests. Vertical jump and pro-agility sprint performance were also examined. All tests were conducted before and immediately after 1 (SMR_1) and 5 minutes (SMR_5) of foam rolling, and immediately after a control (CONTR) condition. Results showed KL scores increased after SMR_5 (16.4%; effect size [ES] = 0.85) when compared with SMR_1 (12.5%; ES = 0.58). Weight-bearing lunge scores showed little change after either SMR treatment. The CONTR condition exhibited little effect on joint range-of-motion. Vertical jump performance decreased after SMR_5 (5.1%; ES = 0.26) but changed little after SMR_1 (0.7%; ES = 0.03) and CONTR (1.9%; ES = 0.10) conditions. Pro-agility performance improved slightly after SMR_1 (1.1%) but deteriorated after CONTR (1.2%) and SMR_5 (0.5%). Effect size calculations for changes in pro-agility sprint times were trivial across all conditions (0.06-0.15). Data suggest that extended periods of SMR may be recommended, should improvements in joint range-of-motion be required. If power output is a critical requirement of subsequent exercise/performance tasks, prolonged SMR treatment (i.e., 5 minutes) should be avoided. Practitioners should be cautious when implementing SMR treatments within warm-ups.

IceSense Proof of Concept: Calibrating an Instrumented Figure Skating Blade to Measure On-Ice Forces.

Competitive figure skaters often suffer from overuse injuries, which may be due to the high impact forces endured during jump repetitions performed in practice and competition. However, to date, forces during on-ice figure skating have not been quantified due to technological limitations. The purpose of this study was to determine the optimal calibration procedure for a previously developed instrumented figure skating blade (IceSense). Initial calibration was performed by collecting data from the blade while 11 skaters performed off-ice jumps, landing on a force plate in the lab. However, mean peak force measurements from the blade were greater than the desired error threshold of ±10%. Therefore, we designed a series of controlled experiments which included measuring forces from a load cell rigidly attached to the top of the blade concurrently with strain data from the strain gauges on the blade. Forces were applied to the blade by adding weight to a drop tower or by manually applying force in a quasi-static manner. Both methods showed similar accuracy, though using the drop tower allowed precise standardization. Therefore, calibration was performed using the weighted drop method. This calibration was applied to strain gauge data from out-of-sample drop trials, resulting in acceptable estimates of peak force (less than 10% error). Using this calibration, we collected data on one figure skater and present results from an exemplar on-ice double flip jump. Using the IceSense device to quantify on-ice forces in a research setting may help inform training, technique, and equipment design.

Broadly Neutralizing Antibodies Display Potential for Prevention of HIV-1 Infection of Mucosal Tissue Superior to That of Nonneutralizing Antibodies.

Definition of the key parameters mediating effective antibody blocking of HIV-1 acquisition within mucosal tissue may prove critical to effective vaccine development and the prophylactic use of monoclonal antibodies. Although direct antibody-mediated neutralization is highly effective against cell-free virus, antibodies targeting different sites of envelope vulnerability may display differential activity against mucosal infection. Nonneutralizing antibodies (nnAbs) may also impact mucosal transmission events through Fc-gamma receptor (FcγR)-mediated inhibition. In this study, a panel of broadly neutralizing antibodies (bnAbs) and nnAbs, including those associated with protection in the RV144 vaccine trial, were screened for the ability to block HIV-1 acquisition and replication across a range of cellular and mucosal tissue models. Neutralization potency, as determined by the TZM-bl infection assay, did not fully predict activity in mucosal tissue. CD4-binding site (CD4bs)-specific bnAbs, in particular VRC01, were consistent in blocking HIV-1 infection across all cellular and tissue models. Membrane-proximal external region (MPER) (2F5) and outer domain glycan (2G12) bnAbs were also efficient in preventing infection of mucosal tissues, while the protective efficacy of bnAbs targeting V1-V2 glycans (PG9 and PG16) was more variable. In contrast, nnAbs alone and in combinations, while active in a range of cellular assays, were poorly protective against HIV-1 infection of mucosal tissues. These data suggest that tissue resident effector cell numbers and low FcγR expression may limit the potential of nnAbs to prevent establishment of the initial foci of infection. The solid protection provided by specific bnAbs clearly demonstrates their superior potential over that of nonneutralizing antibodies for preventing HIV-1 infection at the mucosal portals of infection. IMPORTANCE: Key parameters mediating effective antibody blocking of HIV-1 acquisition within mucosal tissue have not been defined. While bnAbs are highly effective against cell-free virus, they are not induced by current vaccine candidates. However, nnAbs, readily induced by vaccines, can trigger antibody-dependent cellular effector functions, through engagement of their Fc-gamma receptors. Fc-mediated antiviral activity has been implicated as a secondary correlate of decreased HIV-1 risk in the RV144 vaccine efficacy trial, suggesting that protection might be mediated in the absence of classical neutralization. To aid vaccine design and selection of antibodies for use in passive protection strategies, we assessed a range of bnAbs and nnAbs for their potential to block ex vivo challenge of mucosal tissues. Our data clearly indicate the superior efficacy of neutralizing antibodies in preventing mucosal acquisition of infection. These results underscore the importance of maintaining the central focus of HIV-1 vaccine research on the induction of potently neutralizing antibodies.

Spirituality attenuates the association between depression symptom severity and meaning in life.

OBJECTIVES: This cross-sectional study examined whether spirituality moderates the association between depression symptom severity and meaning in life among treatment-seeking adults. METHOD: Participants were 55 adults (≥60 years of age) newly seeking outpatient mental health treatment for mood, anxiety, or adjustment disorders. Self-report questionnaires measured depression symptom severity (Patient Health Questionnaire-9), spirituality (Spirituality Transcendence Index), and meaning in life (Geriatric Suicide Ideation Scale-Meaning in Life subscale). RESULTS: Results indicated a significant interaction between spirituality and depression symptom severity on meaning in life scores (ß = .26, p = .02). A significant negative association between depression symptom severity and meaning in life was observed at lower but not the highest levels of spirituality. CONCLUSION: In the presence of elevated depressive symptomatology, those participants who reported high levels of spirituality reported comparable levels of meaning in life to those without elevated depressive symptomatology. Assessment of older adult patients' spirituality can reveal ways that spiritual beliefs and practices can be can be incorporated into therapy to enhance meaning in life.

Discrete partitioning of HIV-1 Env forms revealed by viral capture.

BACKGROUND: The structure of HIV-1 envelope glycoprotein (Env) is flexible and heterogeneous on whole virions. Although functional Env complexes are thought to require trimerization of cleaved gp41/gp120 heterodimers, variable processing can result in the potential incorporation of non-functional uncleaved proteins (gp160), non-trimeric arrangements of gp41/gp120 heterodimers, and gp120 depleted gp41 stumps. The potential distribution of functional and non-functional Env forms across replication-competent viral populations may have important implications for neutralizing and non-neutralizing antibody functions. This study applied an immuno-bead viral capture assay (VCA) to interrogate the potential distribution (heterologous vs homologous) of functional and non-functional forms of virion associated Env. RESULTS: The VCA revealed a significant association between depletion of infectious virions and virion Env incorporation, but not between infectivity and p24-gag. Three distinct subpopulations of virions were identified within pools of genetically homogenous viral particles. Critically, a significant subpopulation of infectious virions were exclusively captured by neutralizing antibodies (nAbs) indicative of a homologous distribution of functional trimeric Env forms. A second infectious subpopulation bound both neutralizing and non-neutralizing antibodies (nnAbs) representative of a heterologous distribution of Env forms, while a third non-infectious subpopulation was predominantly bound by nnAbs recognizing gp41 stumps. CONCLUSIONS: The observation that a distinct and significant subpopulation of infectious virions is exclusively captured by neutralizing antibodies has important implications for understanding antibody binding and neutralization, as well as other antibody effector functions.

Adapting interpersonal psychotherapy for older adults at risk for suicide.

OBJECTIVE: To pilot a psychological intervention adapted for older adults at risk for suicide. DESIGN: A focused, uncontrolled, pre-to-post-treatment psychotherapy trial. All eligible participants were offered the study intervention. SETTING: Outpatient mental health care provided in the psychiatry department of an academic medical center in a mid-sized Canadian city. PARTICIPANTS: Seventeen English-speaking adults 60 years or older, at risk for suicide by virtue of current suicide ideation, death ideation, and/or recent self-injury. INTERVENTION: A 16-session course of Interpersonal Psychotherapy (IPT) adapted for older adults at risk for suicide who were receiving medication and/or other standard psychiatric treatment for underlying mood disorders. MEASUREMENTS: Participants completed a demographics form, screens for cognitive impairment and alcohol misuse, a semi-structured diagnostic interview, and measures of primary (suicide ideation and death ideation) and secondary study outcomes (depressive symptom severity, social adjustment and support, psychological well-being), and psychotherapy process measures. RESULTS: Participants experienced significant reductions in suicide ideation, death ideation, and depressive symptom severity, and significant improvement in perceived meaning in life, social adjustment, perceived social support, and other psychological well-being variables. CONCLUSIONS: Study participants experienced enhanced psychological well-being and reduced symptoms of depression and suicide ideation over the course of IPT adapted for older adults at risk for suicide. Larger, controlled trials are needed to further evaluate the impact of this novel intervention and to test methods for translating and integrating focused interventions into standard clinical care with at-risk older adults.

HPV Vaccine Public Awareness Campaigns: An Environmental Scan.

Human papillomavirus (HPV) vaccination rates are significantly lower than recommended targets. Public awareness campaigns can raise awareness of the severity and prevalence of HPV infection and the cancer prevention benefits of the vaccine. We conducted an environmental scan of HPV vaccine public awareness campaigns during the summer of 2014. We used online search strategies and expert input to identify candidate campaigns. Multiple study investigators reviewed all data abstraction and analysis. After applying our inclusion criteria, we identified 14 campaigns with parents or teenagers as the target audience. We characterized campaign messages according to constructs of the Health Belief Model. Most messages focused on the cancer prevention benefits of HPV vaccine; few addressed psychological or practical barriers to getting or completing the vaccine. Four of 14 campaigns had pre- or postcampaign data readily available, only 2 used vaccine outcomes in their evaluations. We concluded there was a high prevalence of HPV vaccine public awareness campaigns but little available evidence on their impact on intermediate or vaccine outcomes.

Reliability of Using a Handheld Tablet and Application to Measure Lower-Extremity Alignment Angles.

CONTEXT: Landing kinematics have been identified as a risk factor for knee injury. Detecting atypical kinematics in clinical settings is important for identifying individuals at risk for these injuries. OBJECTIVE: To determine the reliability of a handheld tablet and application (app) for measuring lower-extremity kinematics during drop vertical-jump landings. DESIGN: Measurement reliability. SETTING: Laboratory. PARTICIPANTS: 23 healthy young adults with no lower-extremity injuries and no contraindications for jumping and landing. INTERVENTION: Subjects performed 6 drop vertical jumps that were captured with an iPad2 and analyzed with a KinesioCapture app by 2 novice and 2 experienced raters. Three trials each were captured in the frontal and sagittal planes. MAIN OUTCOME MEASURES: Frontal-plane projection angles, knee flexion, and hip flexion at initial contact and maximum knee flexion were measured. ICC and SEM were calculated to determine intertrial and interrater reliability. One-way ANOVAs were used to examine differences between the measured angles of the raters. RESULTS: Average intertrial reliability ranged from .71 to .98 for novice raters and .77 to .99 for experienced raters. SEMs were 2.3-4.3° for novice raters and 1.6-3.9° for experienced raters. Interrater ICC2,1 was.39-.98 for the novice raters and .69-.93 for the experienced raters. SEMs were smallest with the experiences raters, all less than 1.5°. CONCLUSION: A handheld tablet and app is promising for evaluating landing kinematics and identifying individuals at risk for knee injury in a clinical setting. Intertrial reliability is good to excellent when using average trial measures. Interrater reliability is fair to excellent depending on experience level. Multiple trials should be assessed by a single rater when assessing lower-extremity mechanics with a handheld tablet and app, and results may vary with experience level or training.

Validity and Intrarater Reliability of 2-Dimensional Motion Analysis Using a Handheld Tablet Compared to Traditional 3-Dimensional Motion Analysis.

CONTENT: Lower extremity landing mechanics have been implicated as a contributing factor in knee pain and injury, yet cost effective and clinically accessible methods for evaluating movement mechanics are limited. The identification of valid, reliable, and readily accessible technology to assess lower extremity alignment could be an important tool for clinicians, coaches, and strength and conditioning specialists. OBJECTIVE: The purpose of this study was to examine the validity and reliability of using a hand-held tablet and movement analysis application (app) for assessing lower extremity alignment during a drop vertical jump task. DESIGN: Concurrent Validation. SETTING: Laboratory. PARTICIPANTS: Twenty-two healthy college aged subjects (11 female and 11 male, mean age = 21 ± 1.4 years; mean height: 1.73 ± .12 m, mean mass: 71 ± 13 kg) with no lower extremity pathology that prevented safe landing from a drop jump. INTERVENTION: Subjects performed six drop vertical jumps which were recorded simultaneously using a 3D motion capture system and a hand-held tablet. MAIN OUTCOME MEASURES: Angles on the tablet were calculated using a motion analysis app and from the 3D motion capture system using Visual 3D. Hip and knee angles were measured and compared between both systems. RESULTS: Significant correlations between the tablet and 3D measures for select frontal and sagittal plane ranges of motion (ROM) and angles at maximum knee flexion (MKF) ranged from r = 0.48 (P = .036) for frontal plane knee angle at MKF to r = .77 (P<.001) for knee flexion at MKF. CONCLUSION: Results of this study suggest that a hand-held tablet and app may be a reliable method for assessing select lower extremity joint alignments during drop vertical jumps, but this technology should not be used to measure absolute joint angles. However, sports medicine specialists could use a hand-held tablet to reliably record and evaluate lower extremity movement patterns on the field or in the clinic.

Aggregate complexes of HIV-1 induced by multimeric antibodies.

BACKGROUND: Antibody mediated viral aggregation may impede viral transfer across mucosal surfaces by hindering viral movement in mucus, preventing transcytosis, or reducing inter-cellular penetration of epithelia thereby limiting access to susceptible mucosal CD4 T cells and dendritic cells. These functions may work together to provide effective immune exclusion of virus from mucosal tissue; however little is known about the antibody characteristics required to induce HIV aggregation. Such knowledge may be critical to the design of successful immunization strategies to facilitate viral immune exclusion at the mucosal portals of entry. RESULTS: The potential of neutralizing and non-neutralizing IgG and IgA monoclonals (mAbs) to induce HIV-1 aggregation was assessed by Dynamic light scattering (DLS). Although neutralizing and non-neutralizing IgG mAbs and polyclonal HIV-Ig efficiently aggregated soluble Env trimers, they were not capable of forming viral aggregates. In contrast, dimeric (but not monomeric) IgA mAbs induced stable viral aggregate populations that could be separated from uncomplexed virions. Epitope specificity influenced both the degree of aggregation and formation of higher order complexes by dIgA. IgA purified from serum of uninfected RV144 vaccine trial responders were able to efficiently opsonize viral particles in the absence of significant aggregation, reflective of monomeric IgA. CONCLUSIONS: These results collectively demonstrate that dIgA is capable of forming stable viral aggregates providing a plausible basis for testing the effectiveness of aggregation as a potential protection mechanism at the mucosal portals of viral entry.

Mucosal tissue tropism and dissemination of HIV-1 subtype B acute envelope-expressing chimeric virus.

Human immunodeficiency virus type 1 (HIV-1) transmission results from infection with one or a small number of variants from the donor quasispecies. Transmitted/founder (T/F) viruses have recently been identified from acutely infected patients, but the way in which they interact with primary targets of HIV-1 infection is poorly understood. We have conducted a biological characterization of a panel of subtype B T/F acute and chronic envelope (Env)-expressing chimeric virus in primary human target cells and mucosal tissues. Both acute and chronic Envs preferentially replicated in peripheral blood mononuclear cells (PBMC) and a CD4 T-cell line compared to monocyte-derived macrophages, or dendritic cells (DC). In a model of trans infection from monocyte-derived dendritic cells to T cells, chimeric virus from acute Envs achieved significantly lower titers compared to chronic Envs. Challenge of primary human mucosal tissues revealed significantly higher levels of replication in chronic Env-expressing virus in rectal tissue compared to cervical and penile tissues and enhanced replication in tonsillar tissue relative to acute Envs. In agreement with data from the DC to T-cell trans infection assay, chronic Env-chimeric virus pools were transmitted more efficiently by migratory cells from cervical and penile tissues to CD4(+) T cells than individual acute Env chimeras. These data indicate that virus with HIV-1 Envs of transmitted acute infections preferentially replicate in T cells rather than macrophages or dendritic cells and are less efficiently transmitted from antigen-presenting cells to CD4 T cells than chronic Envs. Such properties together with chemokine (C-C motif) receptor 5 (CCR5) use may confer an advantage for transmission.

A novel running mechanic's class changes kinematics but not running economy.

A novel method of running technique instruction, Midstance to Midstance Running (MMR), was studied to determine how MMR affected kinematics and running economy (RE) of recreational runners. An experimental pre-post randomized groups design was used. Participants (n = 18) were recreational runners who ran at least 3 days a week and 5 km per run. All testing was performed on a treadmill at 2.8 m·s. The intervention group (n = 9) completed 8 weeks of instruction in MMR; the control group (n = 9) continued running without instruction. The MMR group showed significant decreases in stride length (SL) (p = 0.02) and maximum knee flexion velocity in stance (p = 0.01), and a significant increase in stride rate (SR) (p = 0.02) after 8 weeks. No significant changes were found in heart rate, rating of perceived exertion, or RE. Midstance to Midstance Running was effective in changing SR and SL, but was not effective in changing other kinematic variables such as foot contact position and maximum knee flexion during swing. Midstance to Midstance Running did not affect RE. Evidence suggests that MMR may be an appropriate instructional method for recreational runners trying to decrease SL and increase SR.

Dynamic electrophoretic fingerprinting of the HIV-1 envelope glycoprotein.

BACKGROUND: Interactions between the HIV-1 envelope glycoprotein (Env) and its primary receptor CD4 are influenced by the physiological setting in which these events take place. In this study, we explored the surface chemistry of HIV-1 Env constructs at a range of pH and salinities relevant to mucosal and systemic compartments through electrophoretic mobility (EM) measurements. Sexual transmission events provide a more acidic environment for HIV-1 compared to dissemination and spread of infection occurring in blood or lymph node. We hypothesize functional, trimeric Env behaves differently than monomeric forms. RESULTS: The dynamic electrophoretic fingerprint of trimeric gp140 revealed a change in EM from strongly negative to strongly positive as pH increased from that of the lower female genital tract (pHx) to that of the blood (pHy). Similar findings were observed using a trimeric influenza Haemagglutinin (HA) glycoprotein, indicating that this may be a general attribute of trimeric viral envelope glycoproteins. These findings were supported by computationally modeling the surface charge of various gp120 and HA crystal structures. To identify the behavior of the infectious agent and its target cells, EM measurements were made on purified whole HIV-1 virions and primary T-lymphocytes. Viral particles had a largely negative surface charge, and lacked the regions of positivity near neutral pH that were observed with trimeric Env. T cells changed their surface chemistry as a function of activation state, becoming more negative over a wider range of pH after activation. Soluble recombinant CD4 (sCD4) was found to be positively charged under a wide range of conditions. Binding studies between sCD4 and gp140 show that the affinity of CD4-gp140 interactions depends on pH. CONCLUSIONS: Taken together, these findings allow a more complete model of the electrochemical forces involved in HIV-1 Env functionality. These results indicate that the influence of the localized environment on the interactions of HIV with target cells are more pronounced than previously appreciated. There is differential chemistry of trimeric, but not monomeric, Env under conditions which mimic the mucosa compared to those found systemically. This should be taken into consideration during design of immunogens which targets virus at mucosal portals of entry.