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"Blanchard, Kenneth R"
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Delayed vaginal SHIV infection in VRC01 and anti-α4β7 treated rhesus macaques
VRC01 protects macaques from vaginal SHIV infection after a single high-dose challenge. Infusion of a simianized anti-α4β7 mAb (Rh-α4β7) just prior to, and during repeated vaginal exposures to SIVmac251 partially protected macaques from vaginal SIV infection and rescued CD4+ T cells. To investigate the impact of combining VRC01 and Rh-α4β7 on SHIV infection, 3 groups of macaques were treated with a suboptimal dosing of VRC01 alone or in combination with Rh-α4β7 or with control antibodies prior to the initiation of weekly vaginal exposures to a high dose (1000 TCID50) of SHIVAD8-EO. The combination Rh-α4β7-VRC01 significantly delayed SHIVAD8-EO vaginal infection. Following infection, VRC01-Rh-α4β7-treated macaques maintained higher CD4+ T cell counts and exhibited lower rectal SIV-DNA loads compared to controls. Interestingly, VRC01-Rh-α4β7-treated macaques had fewer IL-17-producing cells in the blood and the gut during the acute phase of infection. Moreover, higher T cell responses to the V2-loop of the SHIVAD8-EO envelope in the VRC01-Rh-α4β7 group inversely correlated with set point viremia. The combination of suboptimal amounts of VRC01 and Rh-α4β7 delayed infection, altered antiviral immune responses and minimized CD4+ T cell loss. Further exploration of the effect of combining bNAbs with Rh-α4β7 on SIV/HIV infection and antiviral immune responses is warranted and may lead to novel preventive and therapeutic strategies.
Journal Article
Male homosexuality and maternal immune responsivity to the Y-linked protein NLGN4Y
We conducted a direct test of an immunological explanation of the finding that gay men have a greater number of older brothers than do heterosexual men. This explanation posits that some mothers develop antibodies against a Y-linked protein important in male brain development, and that this effect becomes increasingly likely with each male gestation, altering brain structures underlying sexual orientation in their later-born sons. Immune assays targeting two Y-linked proteins important in brain development—protocadherin 11 Y-linked (PCDH11Y) and neuroligin 4 Y-linked (NLGN4Y; isoforms 1 and 2)—were developed. Plasma from mothers of sons, about half of whom had a gay son, along with additional controls (women with no sons, men) was analyzed for male protein-specific antibodies. Results indicated women had significantly higher anti-NLGN4Y levels than men. In addition, after statistically controlling for number of pregnancies, mothers of gay sons, particularly those with older brothers, had significantly higher anti-NLGN4Y levels than did the control samples of women, including mothers of heterosexual sons. The results suggest an association between a maternal immune response to NLGN4Y and subsequent sexual orientation in male offspring.
Journal Article
Interrupting bedtime to reverse frailty levels in acute care: a study protocol for the Breaking Bad Rest randomized controlled trial
Background
Hospitalized older patients spend most of the waking hours in bed, even if they can walk independently. Excessive bedrest contributes to the development of frailty and worse hospital outcomes. We describe the study protocol for the
Breaking Bad Rest Study
, a randomized clinical trial aimed to promoting more movement in acute care using a novel device-based approach that could mitigate the impact of too much bedrest on frailty.
Methods
Fifty patients in a geriatric unit will be randomized into an intervention or usual care control group. Both groups will be equipped with an activPAL (a measure of posture) and StepWatch (a measure of step counts) to wear throughout their entire hospital stay to capture their physical activity levels and posture. Frailty will be assessed via a multi-item questionnaire assessing health deficits at admission, weekly for the first month, then monthly thereafter, and at 1-month post-discharge. Secondary measures including geriatric assessments, cognitive function, falls, and hospital re-admissions will be assessed. Mixed models for repeated measures will determine whether daily activity differed between groups, changed over the course of their hospital stay, and impacted frailty levels.
Discussion
This randomized clinical trial will add to the evidence base on addressing frailty in older adults in acute care settings through a devices-based movement intervention. The findings of this trial may inform guidelines for limiting time spent sedentary or in bed during a patient’s stay in geriatric units, with the intention of scaling up this study model to other acute care sites if successful.
Trial Registration
The protocol has been registered at clinicaltrials.gov (identifier: NCT03682523).
Journal Article
Host Genetic Variation Impacts SARS-CoV-2 Vaccination Response in the Diversity Outbred Mouse Population
The COVID-19 pandemic led to the rapid and worldwide development of highly effective vaccines against SARS-CoV-2. However, there is significant individual-to-individual variation in vaccine efficacy due to factors including viral variants, host age, immune status, environmental and host genetic factors. Understanding those determinants driving this variation may inform the development of more broadly protective vaccine strategies. While host genetic factors are known to impact vaccine efficacy for respiratory pathogens such as influenza and tuberculosis, the impact of host genetic variation on vaccine efficacy against COVID-19 is not well understood. To model the impact of host genetic variation on SARS-CoV-2 vaccine efficacy, while controlling for the impact of non-genetic factors, we used the Diversity Outbred (DO) mouse model. We found that DO mice immunized against SARS-CoV-2 exhibited high levels of variation in vaccine-induced neutralizing antibody responses. While the majority of the vaccinated mice were protected from virus-induced disease, similar to human populations, we observed vaccine breakthrough in a subset of mice. Importantly, we found that this variation in neutralizing antibody, virus-induced disease, and viral titer is heritable, indicating that the DO serves as a useful model system for studying the contribution of genetic variation of both vaccines and disease outcomes.
Journal Article
A guide to modelling priorities for managing land-based impacts on coastal ecosystems
Pollution from land‐based run‐off threatens coastal ecosystems and the services they provide, detrimentally affecting the livelihoods of millions people on the world's coasts. Planning for linkages among terrestrial, freshwater and marine ecosystems can help managers mitigate the impacts of land‐use change on water quality and coastal ecosystem services. We examine the approaches used for land‐sea planning, with particular focus on the models currently used to estimate the impacts of land‐use change on water quality and fisheries. Our findings could also be applied to other ecosystem services. This Review encompasses modelling of: large scale drivers of land‐use change; local activities that cause such change; run‐off, dispersal and transformation of pollutants in the coastal ocean; ecological responses to pollutants; socio‐economic responses to ecological change; and finally, the design of a planning response. We find that there is a disconnect between the dynamical models that can be used to link land to sea processes and the simple tools that are typically used to inform planning. This disconnect may weaken the robustness of plans to manage dynamic processes. Land‐sea planning is highly interdisciplinary, making the development of effective plans a challenge for small teams of managers and decision makers. Synthesis and applications. We propose some guiding principles for where and how dynamic land‐sea connections can most effectively be built into planning tools. Tools that can capture pertinent processes are needed, but they must be simple enough to be implemented in regions with limited resources for collecting data, developing models and developing integrated land‐sea plans. We propose some guiding principles for where and how dynamic land‐sea connections can most effectively be built into planning tools. Tools that can capture pertinent processes are needed, but they must be simple enough to be implemented in regions with limited resources for collecting data, developing models and developing integrated land‐sea plans.
Journal Article
Delayed vaginal SHIV infection in VRC01 and anti-alpha4beta7 treated rhesus macaques
VRC01 protects macaques from vaginal SHIV infection after a single high-dose challenge. Infusion of a simianized anti-[alpha].sub.4 [beta].sub.7 mAb (Rh-[alpha].sub.4 [beta].sub.7) just prior to, and during repeated vaginal exposures to SIVmac251 partially protected macaques from vaginal SIV infection and rescued CD4.sup.+ T cells. To investigate the impact of combining VRC01 and Rh-[alpha].sub.4 [beta].sub.7 on SHIV infection, 3 groups of macaques were treated with a suboptimal dosing of VRC01 alone or in combination with Rh-[alpha].sub.4 [beta].sub.7 or with control antibodies prior to the initiation of weekly vaginal exposures to a high dose (1000 TCID.sub.50) of SHIV.sub.AD8-EO . The combination Rh-[alpha].sub.4 [beta].sub.7 -VRC01 significantly delayed SHIV.sub.AD8-EO vaginal infection. Following infection, VRC01-Rh-[alpha].sub.4 [beta].sub.7 -treated macaques maintained higher CD4.sup.+ T cell counts and exhibited lower rectal SIV-DNA loads compared to controls. Interestingly, VRC01-Rh-[alpha].sub.4 [beta].sub.7 -treated macaques had fewer IL-17-producing cells in the blood and the gut during the acute phase of infection. Moreover, higher T cell responses to the V2-loop of the SHIV.sub.AD8-EO envelope in the VRC01-Rh-[alpha].sub.4 [beta].sub.7 group inversely correlated with set point viremia. The combination of suboptimal amounts of VRC01 and Rh-[alpha].sub.4 [beta].sub.7 delayed infection, altered antiviral immune responses and minimized CD4.sup.+ T cell loss. Further exploration of the effect of combining bNAbs with Rh-[alpha].sub.4 [beta].sub.7 on SIV/HIV infection and antiviral immune responses is warranted and may lead to novel preventive and therapeutic strategies.
Journal Article
Maternal circulating miRNAs contribute to negative pregnancy outcomes by altering placental transcriptome and fetal vascular dynamics
Circulating miRNAs the in blood are promising biomarkers for predicting pregnancy complications and adverse birth outcomes. Previous work identified 11 gestationally elevated maternal circulating miRNAs ( HEa miRNAs) that predicted infant growth deficits following prenatal alcohol exposure and regulated epithelial–mesenchymal transition in the placenta. Here we show that a single intravascular administration of pooled murine-conserved HEa miRNAs to pregnant mice on gestational day 10 (GD10) attenuates umbilical cord blood flow during gestation, explaining the observed intrauterine growth restriction (IUGR), specifically decreased fetal weight, and morphometric indices of cranial growth. Moreover, RNAseq of the fetal portion of the placenta demonstrated that this single exposure has lasting transcriptomic changes, including upregulation of members of the Notch pathway ( Dll4 , Rfng , Hey1 ), which is a pathway important for trophoblast migration and differentiation. Weighted gene co-expression network analysis also identified chemokine signaling, which is responsible for regulating immune cell-mediated angiogenesis in the placenta, as an important predictor of fetal growth and head size. Our data suggest that HEa miRNAs perturb the expression of placental genes relevant for angiogenesis, resulting in impaired umbilical cord blood flow and subsequently, IUGR.
Journal Article
