QCB Special Seminar | Dr. Vsevolod (Seva) Katritch

Dr. Vsevolod Katritch

Assistant Professor, USC Dept. of Biological Sciences, QCB

Lab Website

GPCR modeling: from structure to function to rational design of new receptors and ligands

Thursday, October 1 @ 2 PM

Zoom Meeting ID: 984 8270 9945 | Passcode: 329869

Abstract: Comprising the largest protein superfamily in human, 800 G-protein Coupled Receptors (GPCRs) play key regulatory roles in most physiological processes and serve as a target for about a third of all therapeutic drugs. Over the last few years, a flow of structural information from crystallography and cryo-EM helped to establish a solid framework for computational modelling inquiry into GPCR functional mechanisms and 3D pharmacology of GPCR ligands. The quantitative understanding of atomistic details of GPCR structure-function is also directly applicable to the rational design of both receptors and ligands with new properties. This talk will describe several new approaches to GPCR computational modelling and design developed in my lab. Using sequence-based, structure-based, and machine-learning approaches we developed the CompoMug software for predicting stabilizing mutations in GPCRs, which has already helped to crystallize more than a dozen receptors.  Discovery of new allosteric co-factors, including highly conserved sodium ion in the center of the 7TM bundle in Class A GPCRs, has opened a venue for rational design of highly potent bitopic ligands with unusual signalling properties. This design approach has yielded novel opioid receptor probes and can be applied to many GPCRs.  Finally, we develop a conceptually new Virtual SYNTon Hierarchical Enumeration Screening approach, V SYNTHES, which enables fast and accurate screening in combinatorial REadily AvailabLe (REAL) chemical space as large as 10 Billion compounds and more. Tested in prospective screening for Cannabinoid receptor ligands, V-SYNTHES yielded 20 novel submicromolar ligands, while showing more than 100-fold improved speed and better hit rates than the traditional virtual ligand screening. The approach is scalable to the rapidly growing combinatorial libraries beyond 1010-1013 compounds, yielding better hits and also streamlining their optimization.  We apply these computational tools to the key receptors in inflammation, sleep and pain modulation pathways, facilitating discovery of novel GPCR ligands with desirable functional profiles as molecular probes and lead candidates.

Hosts: Dr. Charles McKenna and Dr. Remo Rohs

MEB Seminar | Dr. Nicole Ratib

Dr. Nicole Ratib
Post-Doc, USC, MEB (PI: Dr. Cameron Thrash)
Research Profile

Genomic and physiological characterization of Escherichia coli evolving in long-term batch culture

Tuesday, March 10, 12 PM, AHF 153 (Torrey Webb Room)

Abstract: In most natural environments, bacteria spend much of their time under conditions of starvation and stress. Long-term batch cultures are an excellent laboratory system to study adaptation during nutrient stress because cells are incubated for relatively long periods of time, months to years, without the addition of nutrients. During long-term batch culture cells adapt to acquire energy from cellular detritus creating a complex and dynamic environment for mutants of increased relative fitness to exploit. To characterize the population dynamics and identify beneficial alleles, we analyzed the genomes of 1117 clones isolated from a single long-term batch culture inoculated with a single clone and incubated for 1200 days. A total of 679 mutations were identified including single nucleotide polymorphisms, indels, movement of mobile genetic elements, large deletions up to 64kbp and amplifications up to ~500kbp. During the 3.3-year incubation, two main lineages diverge and continuously evolve. There is evidence of at least two instances of a fixed mutation reverting back to the wild type allele, suggesting beneficial mutations may later become maladaptive. Most of the mutated genes encode proteins involved in metabolism, transport, or transcriptional regulation. Clones from the two lineages are physiologically distinct based on outgrowth in fresh medium and competition against the parental strain. Similar population dynamics and mutated genes were detected in three parallel populations sequenced through day 60 providing evidence for positive selection. These data provide new insight into the population structure and mutations that may be beneficial during periods of starvation in evolving bacterial communities.

QCB Faculty Candidate Seminar | Dr. Geoffrey Fudenberg

Dr. Geoffrey Fudenberg
Bioinformatics Fellow, UCSF, Gladstone Institute
Research Profile

Genomes in 3D: connecting structure and function

Thursday, March 5, 2 PM, RRI 101

Abstract: How are micron-long chromosomes spatially organized by molecular interactions between proteins at the nanometer scale? Acting as a molecular microscope, genome-wide chromosome conformation capture (Hi-C) reveals that genomes are intricately folded in 3D. Here I describe how biophysical simulations and machine learning approaches enable interpretation of these large-scale genomic datasets. First, I describe converging theoretical and experimental evidence arguing that Cohesin-mediated loop extrusion with CTCF-defined barriers plays a crucial role in interphase. Second, I describe how convolutional neural networks enable accurate predictions of genome folding from DNA sequence alone. Together, these advance our understanding of the proteins driving and the sequences underpinning 3D genome folding.

QCB Faculty Candidate Seminar | Dr. Assaf Amitai

Dr. Assaf Amitai
Post-Doctoral Researcher, MIT
Research Website

Geometry and stochastic dynamics in biological systems

Thursday, February 27, 2 PM, RRI 101

Abstract: The interaction of proteins with chromatin regulates many cellular functions. Most DNA-binding proteins interact both non-specifically and transiently with many chromatin sites, as well as specifically and more stably with cognate binding sites. These interactions and chromatin structure are important in governing protein dynamics. By analyzing the motion of CTCF, a DNA binding protein responsible for chromosomal organization, we inferred that it interacts with a new type of small nuclear domains. These domains, composed of RNA, are central in guiding CTCF to find its cognate binding site. Hence, weak transient interactions govern chromatin organization and dynamics. In the second part of the talk, I will describe recent advances in the development of a universal vaccine for the influenza virus. Using coarse-grained molecular dynamics simulations and a population scale models of the adaptive immune system, we study the immune response to nanoparticles presenting flu proteins at unique geometries and compositions. We show that these nanoparticles can direct the immune response in distinct evolutionary paths, and elicit the creation of antibodies of high breadth - capable of neutralizing multiple flu strains.

QCB Faculty Candidate Seminar | Dr. David Zeevi

Dr. David Zeevi
Independent Fellow, Rockerfeller University, Center for Studies in Physics & Biology
Research Website

Mining the marine microbiome for remediation targets: lessons from the human microbiome

Thursday, February 20, 2 PM, RRI 101

Abstract: Microbial communities can have an immense effect on their environment and are strongly affected by it. Using new methods for metagenomic sequencing analysis, we systematically identified microbial genomic structural variants and found them to be highly prevalent in the gut microbiome and to correlate with disease risk factors (Zeevi et al., Nature 2019). Our results suggest that these variants facilitate adaptation to environmental stress. Exploring genes that are clustered in the same variant, we uncovered potential mechanistic links between microbiome and its host. Inspired by our discovery of potential microbial adaptation to host pressures, I developed a strategy for mining marine microbiome samples for novel bioremediation genes. To this end, we devised a high-throughput evolutionary analysis, and revealed an unexpected insight into the structure of our genetic code (Shenhav and Zeevi, bioRxiv 2019). Our primary analyses uncovered overwhelmingly strong purifying selective pressure across marine microbial life. This selection was highly correlated with nutrient concentrations and has led us to explore robustness in the genetic code, common to nearly all life forms. We show that the structure of the genetic code, along with amino acid choices across all kingdoms of Life, confers robustness to mutations that incorporate additional nitrogen and carbon into protein sequences. By accounting for this nutrient-conservation-driven purifying selection, we will be able to expose a new layer of selection associated with marine pollution.

MEB Seminar | Dr. Leslie Babonis

Dr. Leslie Babonis
Research Assistant Scientist, University of Florida, Whitney Lab for Marine Bioscience
Research Profile

Understanding biodiversity, one cell at a time

Thursday, February 6, 12 PM, AHF 153 (Torrey Webb Room)

Abstract: I study novelty. Specifically, I am interested in understanding the factors that drive the origin and diversification of novel cell types. More than just taxon-specific oddities, novel cell types can promote niche specialization and facilitate speciation events; thus, studying novelty is critical for understanding the evolution of biodiversity. One of my favorite projects focuses on understanding the mechanisms driving morphological and functional specialization of cnidocytes (stinging cells) across cnidarians (corals, jellyfish, and their kin). Using a combination of observational and functional techniques, I have constructed a cnidocyte gene regulatory network that I use to test hypotheses about the evolutionary origin of this truly bizarre lineage of cells. Surprisingly, the fate of this novel cell lineage seems to have been acquired through recycling and reorganization of an old gene regulatory network, rather that the origin of a novel regulation strategy.

MEB Seminar | Dr. Allie Graham

Dr. Allie Graham
NSF PRFB Fellow, Oregon State University
Research Website

From the Mountains to the Sea: Comparative Genomics of Mechanisms Underlying the Physiological Response to Low Oxygen

Tuesday, January 28, 12 PM, AHF 153 (Torrey Webb Room)

Abstract: Environmental variables can exert a considerable selective pressure across the entire organism – from their genome to their physiology. Organisms living in extreme environmental conditions provide excellent systems to investigate numerous basic questions about the limits of an organism's ability to adapt, to understanding the inherent repeatability of molecular adaptation, and thus the origins of biodiversity, by examining both phenotypic and genotypic novelty. My work uses both integrative and comparative approaches to understand the mechanisms underpinning the response to such environmental variables, with a focus on oxygen availability (i.e. hypoxia). This talk will journey through my previous work on high-altitude adaptation in Andean duck species, to my current work on hypoxia in copepods (and other crustaceans), and conclude with how my discoveries opened up numerous exciting avenues for future work in aquatic invertebrates.

Marine & Environmental Biology Seminar | Dr. Phillip Cleves

Dr. Phillip Cleves
Post-Doctoral Research Fellow, Stanford University
Research Profile |

Molecular and cellular bases of cnidarian-dinoflagellate symbiosis and its breakdown

Tuesday, January 21, 12 PM, AHF 153 (Torrey Webb Room)

Abstract: The symbiosis between corals and dinoflagellate algae is essential to the energetic requirements of coral-reef ecosystems. However, coral reefs are in danger due to elevated ocean temperatures and other stresses that lead to the breakdown of this symbiosis and coral "bleaching". Despite the importance of coral reefs, the molecular basis of how corals maintain a healthy symbiosis and avoid bleaching is poorly understood, in part because of the lack of a tractable genetic model system. The small anemone Aiptasia is symbiotic with algal strains like those in reef-building corals but has many experimental advantages, making it an attractive laboratory model for cnidarian symbiosis.  To explore the transcriptional basis of heat-induced bleaching, we used RNAseq to identify genes that are differentially expressed during a time course of heat stress of symbiotic and aposymbiotic Aiptasia strains. We observed a strong upregulation of hundreds of genes at times long before bleaching begins in symbiotic anemones. The putative promoters of these early stress-response genes are enriched for binding sites for the NFB and HSF1 transcription factors, suggesting that many of these genes share core transcriptional control. The overall expression patterns were similar between the symbiotic and aposymbiotic anemones, indicating that many of the expression changes are not specific to the presence of the algae. Nonetheless, reducing HSF1 activity with a pharmacological inhibitor resulted in more severe bleaching, suggesting that this symbiont-independent stress response is protective against bleaching.
           
Genetic tools are needed to allow rigorous functional testing of the roles of candidate genes in symbiosis and bleaching. Recently, we have developed methods for knocking down and overexpressing genes of interest in Aiptasia. Meanwhile, we have successfully used the CRISPR/Cas9 technology to create genetic changes in embryos of the coral Acropora millepora. We used this technology to knock out HSF1 and demonstrated its role in coral heat tolerance. Through the establishment of both gain-of-function and loss-of-function methods in both Aiptasia and corals, it will be possible to exploit the year-round spawning of Aiptasia to perform initial tests of gene function in cnidarian-algal symbiosis and then further test the discoveries made using similar technologies in corals.

Quantitative & Computational Biology Faculty Candidate Seminar | Yang Yang

Yang Yang
Ph.D. Candidate, Carnegie Mellon University, Computational Biology
Research Website

Computational Methods for Multi-Species Comparison of 3D Genome Structure and Function

Thursday, January 23, 2 PM, RRI 101

Abstract: Recent development in chromatin interaction mapping technologies have greatly advanced the study of three-dimensional (3D) genome organization, which is closely related to vital genome functions such as DNA replication timing (RT) and transcription. However, the principles underlying 3D genome organization and the detailed patterns on how the 3D genome has changed in mammalian evolution remain largely unclear. In this talk, I will primarily introduce two probabilistic models that I have developed during my Ph.D. research: Phylo-HMGP and Phylo-HMRF, which provide the new generic frameworks for genome-wide comparison of continuous genomic features, including RT and Hi-C data for 3D genome structures. The methods incorporate the temporal dependencies of species in the context of evolution with the spatial dependencies of genomic loci, to identify genome-wide evolutionary patterns of continuous genomic features. Real data applications to the RT data and Hi-C data from multiple primate species demonstrated the effectiveness of the models and offered high resolution characterization of evolutionary patterns of 3D genome structure and function. Together, the methods have the potential to help reveal genomic regions with conserved or species-specific structural and regulatory roles, and provide key insights into nuclear organization and function through cross-species comparisons.

MEB Seminar | Dr. Casey Mueller

Dr. Casey Mueller
Assistant Professor, CSUSM, Biology
Lab Website

Thermal physiology: exploring themes of development and variability in different animal models

Tuesday, Dec. 3, 12 PM, AHF 153 (Torrey Webb Room)

Abstract: Dr. Mueller will present some of her lab’s data on copepods, as well as some work on chorus frogs and possibly rainbow trout.  Many of the ideas can be applied to marine organisms.

HEB Seminar | Dr. Caitlin O'Connell

Dr. Caitlin O'Connell
Post-Doctoral Scholar/Teaching Fellow, USC, Dept. of Biological Sciences
Research Profile

The Costs and Benefits of Sociality Explored in the Semi-Solitary Orangutan

Monday, Nov. 18, 12 PM, AHF 153 (Torrey Webb Room)

Abstract: Social relationships are an integral part of primate life for humans and nonhumans
alike, but the extent to which a primate devotes its time and energy to
socializing can vary tremendously within and between species. With a semisolitary
social system, orangutans present a unique opportunity to examine both
social and solitary conditions within a single population to test predictions
regarding the costs and benefits of sociality. While the socioecological model
predicts that orangutans display reduced sociality compared to other apes, this
should affect individuals differently across life history stages. This research
examines the variation in social behavior among age-sex classes in wild
orangutans using social interactions, behavioral and hormonal indicators of stress,
and intestinal parasites to evaluate the reasons orangutans socialize or remain
solitary at different times. Adolescent females were found to socialize the most, to
suffer the lowest physiological cost from socializing, and to employ unique
behavioral strategies to mitigate potentially risky social situations. My findings
highlight the adolescent period as behaviorally distinct and socially rich for
female orangutans who face unique challenges as members of a socially dispersed
species with high levels of sexual coercion.

MEB Seminar | Dr. Jeff Bowman

Dr. Jeff Bowman
Assistant Professor, UCSD, Scripps Institute of Oceanography, Integrative Oceanography Division
Lab Website

Trials, tribulations, and transcriptomes: Understanding microbial ecosystem processes along the western Antarctic Peninsula

Tuesday, Nov. 5, 12 PM, AHF 153 (Torrey Webb Room)

Abstract: The western Antarctic Peninsula (WAP) is a dynamic marine environment defined by contrasting onshore and offshore water masses, rapidly shifting sea ice conditions, and strong season cycles of light and temperature.  The region is well known for its charismatic megafauna, but the charisma of its marine microbes is just beginning to emerge.  I’ll describe some of our efforts over the last several years to understand the dynamics of marine microbial communities along the WAP, culminating in our ongoing effort to use metatranscriptomics to understand the carbon and energy transfers associated with the winter-spring seasonal transition.  This transitional period is dominated by lipid metabolisms among a surprisingly diverse group of marine phytoplankton.  Given the variability in timing of the annual sea ice retreat, and the importance of lipid-rich phytoplankton in regional foodwebs, we anticipate implications for metabolic energy budgets across trophic levels.

HEB Seminar | Dr. Lindsey Schier

HEB Seminar Schier by uscbiscgrad on Scribd

MEB Seminar | Dr. Alyson Santoro

Dr. Alyson Santoro
Assistant Professor, UCSB, EEMB
Lab Website

Nitrification as a window on the mesopelagic

Tuesday, October 7
12 PM
AHF 153 (Torrey Webb Room)

Abstract: The mesopelagic ocean--often called the “twilight zone”--is a critical area for the microbial processing of sinking organic matter. Our lab studies some of the most abundant members of the mesopelagic microbial community, the ammonia-oxidizing archaea and nitrite-oxidizing bacteria. Together, these organisms carry out the biogeochemical process of nitrification and are responsible for producing the vast deep ocean nitrate reservoir. They also play an underappreciated role in carbon and trace metal cycling. My talk will describe combining laboratory cultures with field rate measurements to understand the critical role of nitrifiers in the intertwined geochemical cycles of carbon, nitrogen, and trace metals in the dark ocean.

MEB Seminar | Dr. Rebecca Albright

Dr. Rebecca Albright
California Academy of Sciences, Invertebrate Zoology
Research Profile

Coral Reefs in a Changing Climate: Challenges and Reasons for Hope

Tuesday, October 1
12 PM
AHF 153 (Torrey Webb Room)

Abstract: Already under severe pressure from a number of stressors, including overfishing and pollution, coral reefs are also among the most vulnerable ecosystems to climate change and ocean acidification: We have lost an estimated 50% of the world's coral reefs over the last several decades and are projected to lose more than 90% by 2050. While acute disturbances such as temperature-induced coral bleaching are largely responsible for accelerated reef decline in recent years, chronic disturbances like ocean acidification erode a reef’s capacity to recover by slowing growth and reproduction. In this talk, I will give an overview to the challenges that reefs are currently facing, focusing on the impacts of changing seawater chemistry on various aspects of coral reef biology, ecology, and biogeochemistry.  We will also explore some of the novel and exciting ideas that are emerging to address the coral reef crisis. We'll highlight strengths and limitations of current approaches and discuss next steps towards saving these valuable ecosystems.

MEB Seminar | Dr. Eric Boyd

Dr. Eric Boyd
Associate Professor, Montana State Univ., Microbiology and Immunology
Lab Website

Tuesday, September 24
12 PM
AHF 153 (Torrey Webb Room)

Abstract: Feedbacks between biological and geological processes drove the co-evolution of life and the environment. Yet, little is known of the nature of these feedbacks and the time scales over which they occurred. Here we describe a series of geobiological feedbacks that have played out over the past ~1.1 to 0.8 Ga and that shaped the co-evolution of thermoacidophiles and their acidic hot spring habitats. Future experimentation will evaluate kinetic controls on the acid-generating reactions and the physiological adaptations that allowed microbes to exploit these reactions to fuel their metabolisms.

MEB Seminar | Dr. Randie Bundy

Dr. Randie Bundy
Assistant Professor, University of Washington, Chemical Oceanography
Lab Website

The impact of organic compounds on the cycling of trace metals in the ocean

Tuesday, September 10, 2019
12 PM
AHF 153 (Torrey Webb Room)

Abstract: Trace metals such as iron are essential nutrients for phytoplankton and bacteria, impacting primary productivity in many regions of the ocean. Our understanding of the iron cycle has improved dramatically since the dawn of the international GEOTRACES program, with the chemical speciation of iron emerging as a key control on the oceanic inventory of iron. The speciation of dissolved iron in seawater is dominated by complexation to a diverse pool of organic compounds which impact the bioavailability and reactivity of this scarce nutrient, yet the identity of these compounds are largely unknown. In this talk I will discuss how we determine the identity of these compounds in seawater with novel analytical tools, and why these organic ligands are important for trace metal cycling.

MEB Seminar | Dr. Matthew Church

Dr. Matthew Church
Associate Professor, University of Montana, Flathead Lake Biological Station
Lab Website | Abstract

Eddy-driven variability in nitrification in the subtropical North Pacific Ocean

Tuesday, September 3
12 PM
AHF 153 (Torrey Webb Room)

Abstract: Nitrification is a key step in the marine nitrogen cycle, controlling oxidation of reduced nitrogen in the ocean. Mesoscale eddies, which vertically perturb isopycnal surfaces within the main pycnocline, are thought to play important roles in upper ocean biogeochemical processes; however, potential impacts of eddies on microbial nitrogen cycling in the dimly-lit mesopelagic waters remains largely unknown. In this talk I will summarize on-going work examining how eddies influence the export of particulate nitrogen (PN), rates of nitrification, and the abundances and spatial distributions of nitrifying Archaea (using the ammonia-monooxygenase gene [amoA] as a biomarker) in the oligotrophic waters of the North Pacific Ocean. Eddies influence upper ocean nutrient pools and fluxes, shape the distributions of nitrifying microorganisms and rates of nitrification in the mesopelagic waters. These results suggest that eddy-mediated changes to the upper ocean can have important roles in modifying nitrogen transformation in the interior waters of the ocean.

MEB Seminar | Dr. Sheila Kitchen

Dr. Sheila Kitchen
Post-Doc, California Institute of Technology, PI: Dr. Joseph Parker
Research Website

Adaptive potential and limits in Caribbean acroporid corals

Tuesday, August 27
12 PM
AHF 153 (Torrey Webb Room)

Abstract: Reef-building corals are currently threatened by rapid changes in local and global stressors, and hybridization offers a potential shortcut for rapid adaptation and evolutionary rescue in these species. The sympatric corals Acropora palmata and A. cervicornis form the hybrid, A. prolifera, whose abundance has continued to increase while the parental species decline. Previous work indicates that weakened prezygotic isolation mechanisms in A. cervicornis but not A. palmata could allow for continuous unidirectional gene flow between the two species. Furthermore, asymmetric introgression from A. palmata to A. cervicornis has been recorded in three nuclear loci. In contrast, we found evidence for bidirectional introgession across three hybrid zones, although the frequency of hybrids and backcrosses differs across the range. Genome assemblies of A. palmataand A. cervicornis were compared to other corals to identify orthologs uniquely shared by the Caribbean acroporids. Genomic sequence data from the two parental species and their hybrids was used to further characterize the patterns of genomic synteny, divergence and introgression across hybrid zones. Combined, these approaches elucidate genomic hotspots of introgression and parallel evolution with implications for how hybridization may shape adaptation in these important foundation species across the Caribbean and North-West Atlantic.

Host: Dr. Carly Kenkel

MBBO Ph.D. Dissertation Defense | Erin McParland

Erin McParland
Ph.D. Candidate, MBBO Graduate Program (PI: Dr. Naomi Levine)

The dynamic regulation of DMSP production by marine phytoplankton

Wednesday, May 8, 2019
10 AM
AHF 153 (Torrey Webb Room)

Abstract: Dimethylsulfoniopropionate (DMSP) is a labile sulfur and carbon metabolite that significantly contributes to both the cycling of marine dissolved organic carbon and the balance of Earth’s albedo. DMSP is produced by the majority of eukaryotic marine phytoplankton and by many prokaryotes, but despite decades of research, the cellular mechanism and environmental drivers of DMSP production remain unknown. My thesis confirms that the cellular mechanism of DMSP is differentiated by the cellular concentrations of DMSP in different producers, where high DMSP producers (e.g. dinoflagellates and haptophytes) constitutively produce DMSP and low DMSP producers (e.g. cyanobacteria and diatoms) actively regulate DMSP production in response to environmental stress. However, with natural community experiments and global model predictions, my thesis demonstrates that variability of in situ DMSP production is driven by the biomass of high producers. My thesis highlights the potential for predicting in situ DMSP concentrations with a high DMSP producer marker gene and demonstrates the importance of accurately capturing the sub-dominant community for prediction of DMSP, or other similar metabolites produced by a small fraction of the marine microbial community.