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The role of RNA uptake in platelet heterogeneity

Wed, 05/24/2017 - 4:34pm

The role of platelets in regulating vascular homeostasis has expanded beyond mediation of haemostasis and thrombosis. The discovery of platelet RNA and the presence of subpopulations of platelets containing varying amounts of RNA suggest a role for platelet transcripts in vascular function. As the RNA in anucleated platelets is biologically functional and may transfer to other vascular cells, we hypothesised that platelet RNA diminishes over the lifespan of the platelet with diminishing platelet size due to horizontal cellular transfer. The purpose of this study is to determine if platelet RNA variance is the result of horizontal cellular transfer between platelets and other vascular cells. Utilising platelet sorting and RNA sequencing, we found that smaller platelets contained a more diverse set of transcripts than larger platelets. Further investigation using fluorescence imaging, gene expression analyses and in vitro and in vivo modelling revealed that platelets take up RNA from other vascular cells in a complex manner, revealing a dynamic role for platelets in modulating vascular homeostasis through bidirectional RNA transfer. The resultant RNA profile heterogeneity suggests unique functional roles for platelets dependent on size and complexity. This study expands our basic understanding of platelet function and heterogeneity and is the first to evaluate endogenous vascular RNA uptake and its relation to platelet processes. Our findings describe a novel endogenous phenomenon that can help elucidate the platelet's role in these non-thrombotic and haemostatic fields, as well as present potential for diagnostic and therapeutic development.

Integrating the UPRmt into the mitochondrial maintenance network

Wed, 05/24/2017 - 4:34pm

Mitochondrial function is central to many different processes in the cell, from oxidative phosphorylation to the synthesis of iron-sulfur clusters. Therefore, mitochondrial dysfunction underlies a diverse array of diseases, from neurodegenerative diseases to cancer. Stress can be communicated to the cytosol and nucleus from the mitochondria through many different signals, and in response the cell can effect everything from transcriptional to post-transcriptional responses to protect the mitochondrial network. How these responses are coordinated have only recently begun to be understood. In this review, we explore how the cell maintains mitochondrial function, focusing on the mitochondrial unfolded protein response (UPRmt), a transcriptional response that can activate a wide array of programs to repair and restore mitochondrial function.

Purposeful Pathway: Strategic Plan 2016-2020

Wed, 05/24/2017 - 3:19pm

Introduction: The Lamar Soutter Library (LSL) is a Purposeful Library. A purposeful library is one that engages its users and aligns its mission and goals to the larger institution. The LSL will fulfill its missions of service, education, and research by capitalizing on the strengths of its staff and collections. It will demonstrate leadership in its commitment to interdisciplinary activities that serve all its users and provide them the resources they need when they need it. LSL’s commitment to service is a programmatic approach using a purposeful plan of action that is both strategic and nimble enough to adapt to the rapidly changing health sciences, technology, and information environment. Having a purpose that is clear, meaningful, and intentional, while at the same time flexible, helps position LSL as the core knowledge and cultural base of UMMS. Preparing students for a career in the health professions, assisting faculty with their research and classroom activities, and providing evidence based information in support of patient care have always been important dimensions of LSL’s work. But in today’s world, these goals need to be achieved with greater focus and effectiveness. We believe this “Purposeful Pathway” gives meaning and relevance to LSL as we embark on our information pathway of the 21st century.

Percutaneous Transendocardial Delivery of Self-complementary Adeno-associated Virus 6 Achieves Global Cardiac Gene Transfer in Canines

Tue, 05/23/2017 - 4:52pm

Achieving efficient cardiac gene transfer in a large animal model has proven to be technically challenging. Previous strategies have used cardiopulmonary bypass or dual catheterization with the aid of vasodilators to deliver vectors, such as adenovirus, adeno-associated virus (AAV), or plasmid DNA. Although single-stranded AAV (ssAAV) vectors have shown the greatest promise, they suffer from delayed expression, which might be circumvented using self-complementary vectors. We sought to optimize cardiac gene transfer using a percutaneous transendocardial injection catheter to deliver adeno-associated viral vectors to the canine myocardium. Four vectors were evaluated-ssAAV9, self-complementary AAV9 (scAAV9), scAAV8, scAAV6-so that comparison could be made between single-stranded and self-complementary vectors as well as among serotypes 9, 8, and 6. We demonstrate that scAAV is superior to ssAAV and that AAV 6 is superior to the other serotypes evaluated. Biodistribution studies revealed that vector genome copies were 15-4,000 times more abundant in the heart than in any other organ for scAAV6. Percutaneous transendocardial injection of scAAV6 is a safe, effective method to achieve efficient cardiac gene transfer.

Recombinant AAV Serotype and Capsid Mutant Comparison for Pulmonary Gene Transfer of alpha-1-Antitrypsin Using Invasive and Noninvasive Delivery

Tue, 05/23/2017 - 4:52pm

Recombinant adeno-associated viral (rAAV) vectors have been widely used in pulmonary gene therapy research. In this study, we evaluated the transduction and expression efficiencies of several AAV serotypes and AAV2 capsid mutants with specific pulmonary targeting ligands in the mouse lung. The noninvasive intranasal delivery was compared with the traditional intratracheal lung delivery. The rAAV8 was the most efficient serotype at expressing alpha-1-antitrypsin (AAT) in the lung among all the tested serotypes and mutants. A dose of 1 x 1010 vg of rAAV8-CB-AAT transduced a high percentage of cells in the lung when delivered intratrachealy. The serum and the broncho-alveolar lavage fluid (BALF) levels of human AAT (hAAT) were about 6- and 2.5-fold higher, respectively, than those of rAAV5 group. Among the rAAV2 capsid mutants, the rAAV2 capsid mutants that display a peptide sequence from hAAT ("long serpin") indicated a twofold increase in transgene expression. For most vectors, the serum hAAT levels achieved after intranasal delivery were 1/2 to 1/3 of those with the intratracheal method. Overall, rAAV8 was the most promising vector for the future application in gene therapy of pulmonary diseases such as AAT deficiency-related emphysema.

Hypercalcemia due to Primary Hepatic Lymphoma

Tue, 05/23/2017 - 4:52pm

A 65-year-old female with a history of mixed connective tissue disease and pulmonary fibrosis on azathioprine, hydroxychloroquine, and prednisone (osteoporosis on teriparatide) presented with a 1-month history of hypercalcemia. After discontinuation of teriparatide, the patient's hypercalcemia persisted. Further evaluation revealed primary hepatic lymphoma as the source of her hypercalcemia.

Improved B cell development in humanized NOD-scid IL2Rgammanull mice transgenically expressing human stem cell factor, granulocyte-macrophage colony-stimulating factor and interleukin-3

Tue, 05/23/2017 - 4:52pm

INTRODUCTION: Immunodeficient mice engrafted with human immune systems support studies of human hematopoiesis and the immune response to human-specific pathogens. A significant limitation of these humanized mouse models is, however, a severely restricted ability of human B cells to undergo class switching and produce antigen-specific IgG after infection or immunization.

METHODS: In this study, we have characterized the development and function of human B cells in NOD-scid IL2Rgammanull (NSG) mice transgenically expressing human stem cell factor (SCF), granulocyte macrophage colony-stimulating factor (GM-CSF), and IL-3 (NSG-SGM3) following engraftment with human hematopoietic stem cells, autologous fetal liver, and thymic tissues (bone marrow, liver, thymus or BLT model). The NSG-SGM3 BLT mice engraft rapidly with human immune cells and develop T cells, B cells, and myeloid cells.

RESULTS: A higher proportion of human B cells developing in NSG-SGM3 BLT mice had a mature/naive phenotype with a corresponding decrease in immature/transitional human B cells as compared to NSG BLT mice. In addition, NSG-SGM3 BLT mice have higher basal levels of human IgM and IgG as compared with NSG BLT mice. Moreover, dengue virus infection of NSG-SGM3 BLT mice generated higher levels of antigen-specific IgM and IgG, a result not observed in NSG BLT mice.

CONCLUSIONS: Our studies suggest that NSG-SGM3 BLT mice show improved human B cell development and permit the generation of antigen-specific antibody responses to viral infection.

Society of Behavioral Medicine supports implementation of high quality lung cancer screening in high-risk populations

Tue, 05/23/2017 - 4:52pm

The Society of Behavioral Medicine (SBM) supports the United States Preventive Services Task Force (USPSTF) recommendation of low-dose computed tomography (LDCT) screening of the chest for eligible populations to reduce lung cancer mortality. Consistent with efforts to translate research findings into real-world settings, SBM encourages health-care providers and health-care systems to (1) integrate evidence-based tobacco treatment as an essential component of LDCT-based lung cancer screening, (2) examine the structural barriers that may impact screening uptake, and (3) incorporate shared decision-making as a clinical platform to facilitate consultations and engagement with individuals at high risk for lung cancer about the potential benefits and harms associated with participation in a lung cancer screening program. We advise policy makers and legislators to support screening in high-risk populations by continuing to (1) expand access to high quality LDCT-based screening among underserved high-risk populations, (2) enhance cost-effectiveness by integrating evidence-based tobacco treatments into screening in high-risk populations, and (3) increase funding for research that explores implementation science and increased public awareness and access of diverse populations to participate in clinical and translational research.

Exploratory analysis of osteoarthritis progression among medication users: data from the Osteoarthritis Initiative

Tue, 05/23/2017 - 4:52pm

BACKGROUND: We conducted an exploratory analysis of osteoarthritis progression among medication users in the Osteoarthritis Initiative to identify interventions or pathways that may be associated with disease modification and therefore of interest for future clinical trials.

METHODS: We used participants from the Osteoarthritis Initiative with annual medication inventory data between the baseline and 36-month follow-up visit (n = 2938). Consistent medication users were defined for each medication classification as a participant reporting at all four annual visits that they were regularly using an oral prescription medication at the time of the visit. The exploratory analysis focused on medication classes with 40 or more users. The primary outcome measures were medial tibiofemoral joint space width change and the Western Ontario and McMaster Universities Arthritis Index (WOMAC) knee pain score change (12-36-month visits). Within each knee, we explored eight comparisons between users and matched or unmatched nonusers (defined two ways). An effect size of each comparison was calculated. Medication classes had potential signals if (a) both knees had less progression among users compared with nonusers, or (b) there was less progression based on structure and symptoms in one knee.

RESULTS: We screened 28 medication classes. Six medication classes had signals for fewer structural changes and better knee pain changes: alpha-adrenergic blockers, antilipemic (excluding statins and fibric acid), anticoagulants, selective serotonin reuptake inhibitors, antihistamines, and antineoplastic agents. Four medication classes had signals for structural changes alone: anti-estrogen (median effect size = 0.28; range = -0.41-0.64), angiotensin-converting enzyme inhibitors (median effect size = 0.13; range = -0.08-0.28), beta-adrenergic blockers (median effect size = 0.09; range = 0.01-0.30), and thyroid agents (median effect size = 0.04; range = -0.05-0.14). Thiazide diuretics had evidence for symptom modification (median effect size = -0.12; range = -0.24-0.04).

CONCLUSIONS: Users of neurovascular, antilipemic, or hormonal interventions may have less disease progression compared with nonusers.

Adipose-derived human stem/stromal cells: comparative organ specific mitochondrial bioenergy profiles

Tue, 05/23/2017 - 4:52pm

BACKGROUND: Adipose-derived stem/stromal cells (ASCs) isolated from the stromal vascular fraction are a source of mesenchymal stem cells that have been shown to be beneficial in many regenerative medicine applications. ASCs are an attractive source of stem cells in particular, due to their lack of immunogenicity. This study examines differences between mitochondrial bioenergetic profiles of ASCs isolated from adipose tissue of five peri-organ regions: pericardial, thymic, knee, shoulder, and abdomen.

RESULTS: Flow cytometry showed that the majority of each ASC population isolated from the adipose tissue of 12 donors, with an n = 3 for each tissue type, were positive for MSC markers CD90, CD73, and CD105, and negative for hematopoietic markers CD34, CD11B, CD19, and CD45. Bioenergetic profiles were obtained for ASCs with an n = 4 for each tissue type and graphed together for comparison. Mitochondrial stress tests provided the following measurements: basal respiration rate (measured as oxygen consumption rate [pmol O2/min], ATP production, proton leak, maximal respiration, respiratory control ratio, coupling efficiency, and non-mitochondrial respiration. Glycolytic stress tests provided the following measurements: basal glycolysis rate (measured as extracellular acidification rate [mpH/min]), glycolytic capacity, glycolytic reserve, and non-glycolytic acidification.

CONCLUSIONS: The main goal of this manuscript was to provide baseline reference values for future experiments and to compare bioenergetic potentials of ASCs isolated from adipose tissue harvested from different anatomical locations. Through an investigation of mitochondrial respiration and glycolysis, it was demonstrated that bioenergetic profiles do not significantly differ by region due to depot-dependent and donor-dependent variability. Thus, although the physiological function, microenvironment and anatomical harvest site may directly affect the characteristics of ASCs isolated from different organ regions, the ultimate utility of ASCs remains independent of the anatomical harvest site.

The mammalian LINC complex regulates genome transcriptional responses to substrate rigidity

Tue, 05/23/2017 - 4:52pm

Mechanical integration of the nucleus with the extracellular matrix (ECM) is established by linkage between the cytoskeleton and the nucleus. This integration is hypothesized to mediate sensing of ECM rigidity, but parsing the function of nucleus-cytoskeleton linkage from other mechanisms has remained a central challenge. Here we took advantage of the fact that the LINC (linker of nucleoskeleton and cytoskeleton) complex is a known molecular linker of the nucleus to the cytoskeleton, and asked how it regulates the sensitivity of genome-wide transcription to substratum rigidity. We show that gene mechanosensitivity is preserved after LINC disruption, but reversed in direction. Combined with myosin inhibition studies, we identify genes that depend on nuclear tension for their regulation. We also show that LINC disruption does not attenuate nuclear shape sensitivity to substrate rigidity. Our results show for the first time that the LINC complex facilitates mechano-regulation of expression across the genome.

Oligosaccharyltransferase inhibition induces senescence in RTK-driven tumor cells

Tue, 05/23/2017 - 4:52pm

Asparagine (N)-linked glycosylation is a protein modification critical for glycoprotein folding, stability, and cellular localization. To identify small molecules that inhibit new targets in this biosynthetic pathway, we initiated a cell-based high-throughput screen and lead-compound-optimization campaign that delivered a cell-permeable inhibitor, NGI-1. NGI-1 targets oligosaccharyltransferase (OST), a hetero-oligomeric enzyme that exists in multiple isoforms and transfers oligosaccharides to recipient proteins. In non-small-cell lung cancer cells, NGI-1 blocks cell-surface localization and signaling of the epidermal growth factor receptor (EGFR) glycoprotein, but selectively arrests proliferation in only those cell lines that are dependent on EGFR (or fibroblast growth factor, FGFR) for survival. In these cell lines, OST inhibition causes cell-cycle arrest accompanied by induction of p21, autofluorescence, and cell morphology changes, all hallmarks of senescence. These results identify OST inhibition as a potential therapeutic approach for treating receptor-tyrosine-kinase-dependent tumors and provides a chemical probe for reversibly regulating N-linked glycosylation in mammalian cells.

Use of orbital atherectomy in acute myocardial infarction via the transradial approach

Tue, 05/23/2017 - 4:52pm

Severe coronary artery calcifications pose an ongoing challenge when performing percutaneous coronary interventions, resulting in an increased likelihood of procedural complications. Orbital atherectomy (OA) has emerged as a promising technology that helps improve outcomes in this complex patient population. Its safety and efficacy are yet to be demonstrated in the setting of acute myocardial infarction. We present a case of a patient with acute ST-elevation myocardial infarction (STEMI) evaluated with emergent transradial coronary angiography. The culprit lesion was a severely stenotic, heavily calcified, segment of the right coronary artery. The use of OA facilitated lesion expansion and implantation of a drug-eluting stent. Although OA should be considered as contraindicated for the management of soft-ruptured plaque, which accounts for the majority of STEMI presentations, it may be well applied to the small subset of patients with calcified nodule pathology, even in the acute setting.

Highlights from the 6th International Meeting on Emerging Diseases and Surveillance (IMED 2016) Vienna, Austria from Nov 3 to 7, 2016

Tue, 05/23/2017 - 4:52pm

Emerging infectious diseases remain at the center of the world's attention. The current threats posed by Zika, Yellow Fever, MERS-CoV, and pandemic influenza, the recent Ebola outbreak that devastated West Africa, and the realization that new infectious diseases may be recognized at any time, in any place, has dramatically increased public awareness of infectious diseases and underscored the need to understand emerging pathogens. As with each prior iteration, IMED 2016 fully embodied the “One Health” model of emerging diseases, recognizing the commonality of human, environmental and animal health by bringing together human and veterinary health clinicians, scientists, and policy makers from more than 100 countries. With more than 90 talks and 400 poster presentations, it's impossible to adequately summarize all of the important insights conveyed at IMED 2016. Here is a sampling of some of the topics that caught our interest.

Longitudinal changes in the dietary inflammatory index: an assessment of the inflammatory potential of diet over time in postmenopausal women

Tue, 05/23/2017 - 4:51pm

BACKGROUND/OBJECTIVES: The dietary inflammatory index (DII) measured at one time point is associated with risk of several chronic diseases, but disease risk may change with longitudinal changes in DII scores. Data are lacking regarding changes in DII scores over time; therefore, we assessed changes in the DII in the Women's Health Initiative (WHI).

SUBJECTS/METHODS: DII scores were calculated using data from repeated food frequency questionnaires in the WHI Observational Study (OS; n=76 671) at baseline and year 3, and the WHI Dietary Modification trial (DM; n=48482) at three time points. Lower DII scores represent more anti-inflammatory diets. We used generalized estimating equations to compare mean changes in DII over time, adjusting for multiple comparisons, and multivariable-adjusted linear regression analyses to determine predictors of DII change.

RESULTS: In the OS, mean DII decreased modestly from -1.14 at baseline to -1.50 at year 3. In the DM, DII was -1.32 in year 1, -1.60 in year 3 and -1.48 in year 6 in the intervention arm and was -0.65 in year 1, -0.94 in year 3 and -0.96 in year 6 in the control arm. These changes were modified by body mass index, education and race/ethnicity. A prediction model explained 22% of the variance in the change in DII scores in the OS.

CONCLUSIONS: In this prospective investigation of postmenopausal women, reported dietary inflammatory potential decreased modestly over time. Largest reductions were observed in normal-weight, highly educated women. Future research is warranted to examine whether reductions in DII are associated with decreased chronic disease risk.

Consensus Paper: Cerebellar Development

Tue, 05/23/2017 - 4:51pm

The development of the mammalian cerebellum is orchestrated by both cell-autonomous programs and inductive environmental influences. Here, we describe the main processes of cerebellar ontogenesis, highlighting the neurogenic strategies used by developing progenitors, the genetic programs involved in cell fate specification, the progressive changes of structural organization, and some of the better-known abnormalities associated with developmental disorders of the cerebellum.

The Yersinia pestis Effector YopM Inhibits Pyrin Inflammasome Activation

Tue, 05/23/2017 - 4:51pm

Type III secretion systems (T3SS) are central virulence factors for many pathogenic Gram-negative bacteria, and secreted T3SS effectors can block key aspects of host cell signaling. To counter this, innate immune responses can also sense some T3SS components to initiate anti-bacterial mechanisms. The Yersinia pestis T3SS is particularly effective and sophisticated in manipulating the production of pro-inflammatory cytokines IL-1beta and IL-18, which are typically processed into their mature forms by active caspase-1 following inflammasome formation. Some effectors, like Y. pestis YopM, may block inflammasome activation. Here we show that YopM prevents Y. pestis induced activation of the Pyrin inflammasome induced by the RhoA-inhibiting effector YopE, which is a GTPase activating protein. YopM blocks YopE-induced Pyrin-mediated caspase-1 dependent IL-1beta/IL-18 production and cell death. We also detected YopM in a complex with Pyrin and kinases RSK1 and PKN1, putative negative regulators of Pyrin. In contrast to wild-type mice, Pyrin deficient mice were also highly susceptible to an attenuated Y. pestis strain lacking YopM, emphasizing the importance of inhibition of Pyrin in vivo. A complex interplay between the Y. pestis T3SS and IL-1beta/IL-18 production is evident, involving at least four inflammasome pathways. The secreted effector YopJ triggers caspase-8- dependent IL-1beta activation, even when YopM is present. Additionally, the presence of the T3SS needle/translocon activates NLRP3 and NLRC4-dependent IL-1beta generation, which is blocked by YopK, but not by YopM. Taken together, the data suggest YopM specificity for obstructing the Pyrin pathway, as the effector does not appear to block Y. pestis-induced NLRP3, NLRC4 or caspase-8 dependent caspase-1 processing. Thus, we identify Y. pestis YopM as a microbial inhibitor of the Pyrin inflammasome. The fact that so many of the Y. pestis T3SS components are participating in regulation of IL-1beta/IL-18 release suggests that these effects are essential for maximal control of innate immunity during plague.

GW182-Free microRNA Silencing Complex Controls Post-transcriptional Gene Expression during Caenorhabditis elegans Embryogenesis

Tue, 05/23/2017 - 4:51pm

MicroRNAs and Argonaute form the microRNA induced silencing complex or miRISC that recruits GW182, causing mRNA degradation and/or translational repression. Despite the clear conservation and molecular significance, it is unknown if miRISC-GW182 interaction is essential for gene silencing during animal development. Using Caenorhabditis elegans to explore this question, we examined the relationship and effect on gene silencing between the GW182 orthologs, AIN-1 and AIN-2, and the microRNA-specific Argonaute, ALG-1. Homology modeling based on human Argonaute structures indicated that ALG-1 possesses conserved Tryptophan-binding Pockets required for GW182 binding. We show in vitro and in vivo that their mutations severely altered the association with AIN-1 and AIN-2. ALG-1 tryptophan-binding pockets mutant animals retained microRNA-binding and processing ability, but were deficient in reporter silencing activity. Interestingly, the ALG-1 tryptophan-binding pockets mutant phenocopied the loss of alg-1 in worms during larval stages, yet was sufficient to rescue embryonic lethality, indicating the dispensability of AINs association with the miRISC at this developmental stage. The dispensability of AINs in miRNA regulation is further demonstrated by the capacity of ALG-1 tryptophan-binding pockets mutant to regulate a target of the embryonic mir-35 microRNA family. Thus, our results demonstrate that the microRNA pathway can act independently of GW182 proteins during C. elegans embryogenesis.

Persistent Low-Level Replication of SIVDeltanef Drives Maturation of Antibody and CD8 T Cell Responses to Induce Protective Immunity against Vaginal SIV Infection

Tue, 05/23/2017 - 4:51pm

Defining the correlates of immune protection conferred by SIVDeltanef, the most effective vaccine against SIV challenge, could enable the design of a protective vaccine against HIV infection. Here we provide a comprehensive assessment of immune responses that protect against SIV infection through detailed analyses of cellular and humoral immune responses in the blood and tissues of rhesus macaques vaccinated with SIVDeltanef and then vaginally challenged with wild-type SIV. Despite the presence of robust cellular immune responses, animals at 5 weeks after vaccination displayed only transient viral suppression of challenge virus, whereas all macaques challenged at weeks 20 and 40 post-SIVDeltanef vaccination were protected, as defined by either apparent sterile protection or significant suppression of viremia in infected animals. Multiple parameters of CD8 T cell function temporally correlated with maturation of protection, including polyfunctionality, phenotypic differentiation, and redistribution to gut and lymphoid tissues. Importantly, we also demonstrate the induction of a tissue-resident memory population of SIV-specific CD8 T cells in the vaginal mucosa, which was dependent on ongoing low-level antigenic stimulation. Moreover, we show that vaginal and serum antibody titers inversely correlated with post-challenge peak viral load, and we correlate the accumulation and affinity maturation of the antibody response to the duration of the vaccination period as well as to the SIVDeltanef antigenic load. In conclusion, maturation of SIVDeltanef-induced CD8 T cell and antibody responses, both propelled by viral persistence in the gut mucosa and secondary lymphoid tissues, results in protective immune responses that are able to interrupt viral transmission at mucosal portals of entry as well as potential sites of viral dissemination.

Biophysical and Functional Characterization of Rhesus Macaque IgG Subclasses

Tue, 05/23/2017 - 4:51pm

Antibodies raised in Indian rhesus macaques [Macaca mulatta (MM)] in many preclinical vaccine studies are often evaluated in vitro for titer, antigen-recognition breadth, neutralization potency, and/or effector function, and in vivo for potential associations with protection. However, despite reliance on this key animal model in translation of promising candidate vaccines for evaluation in first in man studies, little is known about the properties of MM immunoglobulin G (IgG) subclasses and how they may compare to human IgG subclasses. Here, we evaluate the binding of MM IgG1, IgG2, IgG3, and IgG4 to human Fc gamma receptors (FcgammaR) and their ability to elicit the effector functions of human FcgammaR-bearing cells, and unlike in humans, find a notable absence of subclasses with dramatically silent Fc regions. Biophysical, in vitro, and in vivo characterization revealed MM IgG1 exhibited the greatest effector function activity followed by IgG2 and then IgG3/4. These findings in rhesus are in contrast with the canonical understanding that IgG1 and IgG3 dominate effector function in humans, indicating that subclass-switching profiles observed in rhesus studies may not strictly recapitulate those observed in human vaccine studies.