Three-Dimensional Plasma Cell Survival Microniche in Multiple Myeloma

Multiple myeloma (MM) is an incurable malignancy characterized by the uncontrolled proliferation of long-lived plasma cells (PCs) in the bone marrow (BM), which constitute at least 10% of BM cellularity. Normally, long-lived plasma cells make up less than 1% of BM cells. Plasma cells become neoplastic when a clonal PC population produces a monoclonal immunoglobulin protein. A diagnosis of monoclonal gammopathy of undetermined significance (MGUS) is made when there is an increase in monoclonal PCs within the BM, but less than 10%, and the patient does not present with end-organ damage, which is associated with active MM. Though not considered pathological at this stage, individuals with MGUS are at an increased risk for developing MM. There are several challenging aspects in treating MM including the high clonal heterogeneity of MM cells and its clinical repercussions, thus making the malignancy difficult to treat. Further heterogeneity is found in regard to disease onset, disease progression, therapeutic resistance, and subsequent patient relapse. The purpose of this project is to investigate the microniche of PCs as they transition from premalignant to malignant myeloma cells in order to provide valuable insight which can be exploited to test current and novel therapeutic treatments. This project has demonstrated changes in the expression of fibronectin and morphological differences in plasma cells within core biopsies, which may support disease progression. Additionally, the purpose of this project is also to generate a long-term 3D in vitro culture models of MM using a high-throughput hydrogel platform. By using BM aspirates from MGUS and MM patients, results demonstrated that this 3D culturing system is capable of reproducing key features on long-lived PCs. Furthermore, these BM cultures maintained their abnormal phenotypes for at least five days of culture. This extended timeframe allows for better characterization of the mechanisms of action of current therapies and testing of emerging treatments for this incurable disease

Three-Dimensional Plasma Cell Survival Microniche in Multiple Myeloma

Multiple myeloma (MM) is an incurable malignancy characterized by the uncontrolled proliferation of long-lived plasma cells (PCs) in the bone marrow (BM), which constitute at least 10% of BM cellularity. Normally, long-lived plasma cells make up less than 1% of BM cells. Plasma cells become neoplastic when a clonal PC population produces a monoclonal immunoglobulin protein. A diagnosis of monoclonal gammopathy of undetermined significance (MGUS) is made when there is an increase in monoclonal PCs within the BM, but less than 10%, and the patient does not present with end-organ damage, which is associated with active MM. Though not considered pathological at this stage, individuals with MGUS are at an increased risk for developing MM. There are several challenging aspects in treating MM including the high clonal heterogeneity of MM cells and its clinical repercussions, thus making the malignancy difficult to treat. Further heterogeneity is found in regard to disease onset, disease progression, therapeutic resistance, and subsequent patient relapse. The purpose of this project is to investigate the microniche of PCs as they transition from premalignant to malignant myeloma cells in order to provide valuable insight which can be exploited to test current and novel therapeutic treatments. This project has demonstrated changes in the expression of fibronectin and morphological differences in plasma cells within core biopsies, which may support disease progression. Additionally, the purpose of this project is also to generate a long-term 3D in vitro culture models of MM using a high-throughput hydrogel platform. By using BM aspirates from MGUS and MM patients, results demonstrated that this 3D culturing system is capable of reproducing key features on long-lived PCs. Furthermore, these BM cultures maintained their abnormal phenotypes for at least five days of culture. This extended timeframe allows for better characterization of the mechanisms of action of current therapies and testing of emerging treatments for this incurable disease

Effects of Light, Food Availability and Temperature Stress on the Function of Photosystem II and Photosystem I of Coral Symbionts

Background: Reef corals are heterotrophic coelenterates that achieve high productivity through their photosynthetic dinoflagellate symbionts. Excessive seawater temperature destabilises this symbiosis and causes corals to "bleach," lowering their photosynthetic capacity. Bleaching poses a serious threat to the persistence of coral reefs on a global scale. Despite expanding research on the causes of bleaching, the mechanisms remain a subject of debate.\ud \ud Methodology/Principal Findings: This study determined how light and food availability modulate the effects of temperature stress on photosynthesis in two reef coral species. We quantified the activities of Photosystem II, Photosystem I and whole chain electron transport under combinations of normal and stressful growth temperatures, moderate and high light levels and the presence or absence of feeding of the coral hosts. Our results show that PS1 function is comparatively robust against temperature stress in both species, whereas PS2 and whole chain electron transport are susceptible to temperature stress. In the symbiotic dinoflagellates of Stylophora pistillata the contents of chlorophyll and major photosynthetic complexes were primarily affected by food availability. In Turbinaria reniformis growth temperature was the dominant influence on the contents of the photosynthetic complexes. In both species feeding the host significantly protected photosynthetic function from high temperature stress.\ud \ud Conclusions/Significance: Our findings support the photoinhibition model of coral bleaching and demonstrate that PS1 is not a major site for thermal damage during bleaching events. Feeding mitigates bleaching in two scleractinian corals, so that reef responses to temperature stresses will likely be influenced by the coinciding availabilities of prey for the host

Expanding the diversity of mycobacteriophages: insights into genome architecture and evolution.

Mycobacteriophages are viruses that infect mycobacterial hosts such as Mycobacterium smegmatis and Mycobacterium tuberculosis. All mycobacteriophages characterized to date are dsDNA tailed phages, and have either siphoviral or myoviral morphotypes. However, their genetic diversity is considerable, and although sixty-two genomes have been sequenced and comparatively analyzed, these likely represent only a small portion of the diversity of the mycobacteriophage population at large. Here we report the isolation, sequencing and comparative genomic analysis of 18 new mycobacteriophages isolated from geographically distinct locations within the United States. Although no clear correlation between location and genome type can be discerned, these genomes expand our knowledge of mycobacteriophage diversity and enhance our understanding of the roles of mobile elements in viral evolution. Expansion of the number of mycobacteriophages grouped within Cluster A provides insights into the basis of immune specificity in these temperate phages, and we also describe a novel example of apparent immunity theft. The isolation and genomic analysis of bacteriophages by freshman college students provides an example of an authentic research experience for novice scientists

Impact of the terrestrial-aquatic transition on disparity and rates of evolution in the carnivoran skull

Background: Which factors influence the distribution patterns of morphological diversity among clades? The adaptive radiation model predicts that a clade entering new ecological niche will experience high rates of evolution early in its history, followed by a gradual slowing. Here we measure disparity and rates of evolution in Carnivora, specifically focusing on the terrestrial-aquatic transition in Pinnipedia. We analyze fissiped (mostly terrestrial, arboreal, and semi-arboreal, but also including the semi-aquatic otter) and pinniped (secondarily aquatic) carnivorans as a case study of an extreme ecological transition. We used 3D geometric morphometrics to quantify cranial shape in 151 carnivoran specimens (64 fissiped, 87 pinniped) and five exceptionally-preserved fossil pinnipeds, including the stem-pinniped Enaliarctos emlongi. Range-based and variance-based disparity measures were compared between pinnipeds and fissipeds. To distinguish between evolutionary modes, a Brownian motion model was compared to selective regime shifts associated with the terrestrial-aquatic transition and at the base of Pinnipedia. Further, evolutionary patterns were estimated on individual branches using both Ornstein-Uhlenbeck and Independent Evolution models, to examine the origin of pinniped diversity. Results: Pinnipeds exhibit greater cranial disparity than fissipeds, even though they are less taxonomically diverse and, as a clade nested within fissipeds, phylogenetically younger. Despite this, there is no increase in the rate of morphological evolution at the base of Pinnipedia, as would be predicted by an adaptive radiation model, and a Brownian motion model of evolution is supported. Instead basal pinnipeds populated new areas of morphospace via low to moderate rates of evolution in new directions, followed by later bursts within the crown-group, potentially associated with ecological diversification within the marine realm. Conclusion: The transition to an aquatic habitat in carnivorans resulted in a shift in cranial morphology without an increase in rate in the stem lineage, contra to the adaptive radiation model. Instead these data suggest a release from evolutionary constraint model, followed by aquatic diversifications within crown families. Electronic supplementary material The online version of this article (doi:10.1186/s12862-015-0285-5) contains supplementary material, which is available to authorized users

Expanding the diversity of mycobacteriophages: insights into genome architecture and evolution.

Mycobacteriophages are viruses that infect mycobacterial hosts such as Mycobacterium smegmatis and Mycobacterium tuberculosis. All mycobacteriophages characterized to date are dsDNA tailed phages, and have either siphoviral or myoviral morphotypes. However, their genetic diversity is considerable, and although sixty-two genomes have been sequenced and comparatively analyzed, these likely represent only a small portion of the diversity of the mycobacteriophage population at large. Here we report the isolation, sequencing and comparative genomic analysis of 18 new mycobacteriophages isolated from geographically distinct locations within the United States. Although no clear correlation between location and genome type can be discerned, these genomes expand our knowledge of mycobacteriophage diversity and enhance our understanding of the roles of mobile elements in viral evolution. Expansion of the number of mycobacteriophages grouped within Cluster A provides insights into the basis of immune specificity in these temperate phages, and we also describe a novel example of apparent immunity theft. The isolation and genomic analysis of bacteriophages by freshman college students provides an example of an authentic research experience for novice scientists