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Tools for Writing Concise and Compelling Grants [HANDOUTS]

Michaela Kiernan
The handouts identify 8 recommended elements for writing concise and compelling specific aims. The 8 elements are designed to make it easy and efficient for National Institutes of Health (NIH) reviewers to evaluate the ‘Overall Impact’ of R01 grant applications. Examples of the 8 elements are included from previously awarded R01 grants across multiple NIH institutes and disciplines. Use a powerful visual strategy to determine which recommended elements still need to be addressed by color...

Data from: Genome sequencing highlights the dynamic early history of dogs

Adam H. Freedman, Ilan Gronau, Rena M. Schweizer, Diego Ortega-Del Vecchyo, Eunjung Han, Pedro M. Silva, Marco Galaverni, Zhenxin Fan, Peter Marx, Belen Lorente-Galdos, Holly Beale, Oscar Ramirez, Farhad Hormozdiari, Can Alkan, Carles Vilà, Kevin Squire, Eli Geffen, Josip Kusak, Adam R. Boyko, Heidi G. Parker, Clarence Lee, Vasisht Tadigotla, Adam Siepel, Carlos D. Bustamante, Timothy T. Harkins … & John Novembre
To identify genetic changes underlying dog domestication and reconstruct their early evolutionary history, we generated high-quality genome sequences from three gray wolves, one from each of the three putative centers of dog domestication, two basal dog lineages (Basenji and Dingo) and a golden jackal as an outgroup. Analysis of these sequences supports a demographic model in which dogs and wolves diverged through a dynamic process involving population bottlenecks in both lineages and post-divergence gene flow....

Data from: Chimpanzees breed with genetically dissimilar mates

Kara K. Walker, Rebecca S. Rudicell, Yingying Li, Beatrice H. Hahn, Emily Wroblewski & Anne E. Pusey
Inbreeding adversely affects fitness, whereas heterozygosity often augments it. Therefore, mechanisms to avoid inbreeding and increase genetic distance between mates should be advantageous in species where adult relatives reside together. Here we investigate mate choice for genetic dissimilarity in chimpanzees, a species in which many females avoid inbreeding through dispersal, but where promiscuous mating and sexual coercion can limit choice when related adults reside together. We take advantage of incomplete female dispersal in Gombe National...

Data from: Allogeneic HY antibodies detected 3 months after female-to-male HCT predict chronic GVHD and nonrelapse mortality in humans

Hideki Nakasone, Lu Tian, Bita Sahaf, Takakazu Kawase, Kelsi Schoenrock, Spenser Perloff, Christine E. Ryan, Jed Paul, Rakesh Popli, Fang Wu, Joanne M. Otani, John Coller, & David B. Miklos
Allogeneic antibodies against minor histocompatibility antigens encoded on the Y chromosome (HY-Abs) develop after hematopoietic cell transplant (HCT) of male recipients with female donors (F→M). However, the temporal association between HY-Ab development and chronic graft-versus-host disease (cGVHD) has yet to be elucidated. We studied 136 adult F→M HCT patients, with plasma prospectively collected through 3 years posttransplant, and measured immunoglobulin G against 6 H-Y antigens. Multiple HY-Abs were frequently detected beginning at 3 months posttransplant:...

Activity-based protein profiling for target identification of JCP276 in Mycobacterium tuberculosis

Brett Babin
The increasing incidence of antibiotic-resistant Mycobacterium tuberculosis infections is a growing global health threat necessitating the development of new antibiotics. Serine hydrolases (SHs) are a promising class of targets because of their importance for the synthesis of the mycobacterial cell envelope. We screened a library of small molecules containing serine-reactive electrophiles and identified a series of narrow spectrum inhibitors of M. tuberculous growth. Using these lead molecules we performed competitive activity-based protein profiling and identified...

A multi-ethnic epigenome-wide association study of leukocyte DNA methylation and blood lipids

Themistocles Assimes & Min A Jhun
We examined the association between DNA methylation in circulating leukocytes and blood lipids in a multi-ethnic sample of 16,265 subjects. We identified 148, 35, and 4 novel associations among Europeans, African Americans, and Hispanics, respectively, and an additional 186 novel associations through a trans-ethnic meta-analysis. We observed a high concordance in the direction of effects across racial/ethnic groups, a high correlation of effect sizes between high-density lipoprotein and triglycerides, a modest overlap of associations with...

Data from: Ranking and characterization of established BMI and lipid associated loci as candidates for gene-environment interactions

Dmitry Shungin, Wei Q. Deng, Tibor V. Varga, Jian'an Luan, Evelin Mihailov, Andres Metspalu, Andrew P. Morris, Nita G. Forouhi, Cecilia Lindgren, Patrik K. E. Magnusson, Nancy L. Pedersen, Göran Hallmans, Audrey Y. Chu, Anne E. Justice, Mariaelisa Graff, Thomas W. Winkler, Lynda M. Rose, Claudia Langenberg, L. Adrienne Cupples, Paul M. Ridker, Nicholas J. Wareham, Ken K. Ong, Ruth J. F. Loos, Daniel I. Chasman, Erik Ingelsson … & Paul W. Franks
Phenotypic variance heterogeneity across genotypes at a single nucleotide polymorphism (SNP) may reflect underlying gene-environment (G·E) or gene-gene interactions. We modeled variance heterogeneity for blood lipids and BMI in up to 44,211 participants and investigated relationships between variance effects (Pv), G·E interaction effects (with smoking and physical activity), and marginal genetic effects (Pm). Correlations between Pv and Pm were stronger for SNPs with established marginal effects (Spearman's ρ=0.401 for triglycerides, and ρ=0.236 for BMI) compared...

Data from: Evaporimeter and bubble-imaging measures of sweat gland secretion rates

Jeeyeon Kim, Miesha Farahmand, Colleen Dunn, Zoe Davies, Eric Frisbee, Carlos Milla & Jeffrey J. Wine
Beta-adrenergically-stimulated sweat rates determined by evaporimetry or by sweat bubble imaging are useful for measuring CFTR function because they provide a near-linear readout across almost the full range of CFTR function. They differentiate cystic fibrosis (CF) subjects from CF carriers and carriers from controls. However, evaporimetry, unlike bubble imaging, appears to be unable to detect improved levels of CFTR function in G551D subjects taking the CFTR modulator ivacaftor. Here, we quantify the sensitivity of evaporimetry...

Data from: Host species and environmental effects on bacterial communities associated with Drosophila in the laboratory and in the natural environment

Fabian Staubach, John F. Baines, Sven Künzel, Elisabeth M. Bik & Dmitri A. Petrov
The fruit fly Drosophila is a classic model organism to study adaptation as well as the relationship between genetic variation and phenotypes. Although associated bacterial communities might be important for many aspects of Drosophila biology, knowledge about their diversity, composition, and factors shaping them is limited. We used 454-based sequencing of a variable region of the bacterial 16S ribosomal RNA gene to characterize the bacterial communities associated with wild and laboratory Drosophila isolates. In order...

Human Responses to Visually Evoked Threat

Melis Yilmaz Balban, Erin Cafaro, Lauren Saue-Fletcher, Marlon Joseph Washington, Maryam Bijanzadeh, Andrew Moses Lee, Edward Chang & Andrew Huberman
Vision is the primary sense humans use to evaluate and respond to threats. Understanding the biological underpinnings of the human threat response has been hindered by lack of realistic in-lab threat paradigms. We established an immersive Virtual Reality (VR) platform to simultaneously measure behavior, physiological state and neural activity from the human brain using chronically implanted electrodes. Subjects with high anxiety showed increased visual scanning in response to threats as compared to healthy controls. In...

Toxplasma gondii wild-type vs. ASH4 knockout untargeted metabolomics raw data

Brett Babin & Matthew Bogyo
The intracellular protozoan parasite Toxoplasma gondii must scavenge cholesterol and other lipids from the host to facilitate intracellular growth and replication. Enzymes responsible for neutral lipid synthesis have been identified but there is no evidence for enzymes that catalyze lipolysis of cholesterol esters and esterified lipids. Here we characterize several T. gondii serine hydrolases with esterase and thioesterase activities that were previously thought to be depalmitoylating enzymes. We find they do not cleave palmitoyl thiol...

Data from: Chimpanzee fathers bias their behaviour towards their offspring

Carson M. Murray, Margaret A. Stanton, Elizabeth V. Lonsdorf, Emily E. Wroblewski & Anne E. Pusey
Promiscuous mating was traditionally thought to curtail paternal investment owing to the potential costs of providing care to unrelated infants. However, mounting evidence suggests that males in some promiscuous species can recognize offspring. In primates, evidence for paternal care exists in promiscuous Cercopithecines, but less is known about these patterns in other taxa. Here, we examine two hypotheses for paternal associations with lactating mothers in eastern chimpanzees (Pan troglodytes schweinfurthii): paternal effort, whereby males associate...

A human IgSF cell-surface interactome reveals a complex network of protein-protein interactions

Woj Wojtowicz, Jost Vielmetter, Ricardo Fernandes, Dirk Siepe, Catharine Eastman, Gregory Chisholm, Sarah Cox, Heath Klock, Paul Anderson, Sarah Rue, Jessica Miller, Scott Glaser, Melisa Bragstad, Julie Vance, Annie Lam, Scott Lesley, Kai Zinn & Christopher Garcia
Cell-surface protein-protein interactions (PPIs) mediate cell-cell communication, recognition and responses. We executed an interactome screen of 564 human cell-surface and secreted proteins, most of which are immunoglobulin superfamily (IgSF) proteins, using a high-throughput, automated ELISA-based screening platform employing a pooled-protein strategy to test all 318,096 PPI combinations. Screen results, augmented by phylogenetic homology analysis, revealed ~380 previously unreported PPIs. We validated a subset using surface plasmon resonance and cell binding assays. Observed PPIs reveal a...

Structure-activity mapping of ARHGAP36 reveals regulatory roles for its GAP homology and C-terminal domains

Patricia R. Nano, Taylor K. Johnson, Takamasa Kudo, Nancie A. Mooney, Jun Ni, Janos Demeter, Peter K. Jackson & James K. Chen
ARHGAP36 is an atypical Rho GTPase-activating protein (GAP) family member that drives both spinal cord development and tumorigenesis, acting in part through an N-terminal motif that suppresses protein kinase A and activates Gli transcription factors. ARHGAP36 also contains isoform-specific N-terminal sequences, a central GAP-like module, and a unique C-terminal domain, and the functions of these regions remain unknown. Here we have mapped the ARHGAP36 structure-activity landscape using a deep sequencing-based mutagenesis screen and truncation mutant...

Fitness maps to a large-effect locus in introduced stickleback populations

Dolph Schluter, Kerry Marchinko, Matt Arnegard, Haili Zhang, Shannon Brady, Felicity Jones, Michael Bell & David Kingsley
Mutations of small effect underlie most adaptation to new environments, but beneficial variants with large fitness effects are expected to contribute under certain conditions. Genes and genomic regions having large effects on phenotypic differences between populations are known from numerous taxa, but fitness effect sizes have rarely been estimated. We mapped fitness over a generation in an F2 intercross between a marine and a lake stickleback population introduced to a freshwater pond. A QTL map...

Data from: Long-term live imaging of the Drosophila adult midgut reveals real-time dynamics of division, differentiation, and loss

Judy Lisette Martin, Erin Nicole Sanders, Paola Moreno-Roman, Leslie Ann Jaramillo Koyama, Shruthi Balachandra, XinXin Du & Lucy Erin O'Brien
Organ renewal is governed by the dynamics of cell division, differentiation, and loss. To study these dynamics in real time, we present a platform for extended live imaging of the adult Drosophila midgut, a premier genetic model for stem cell-based organs. A window cut into a living animal allows the midgut to be imaged while intact and physiologically functioning. This approach prolongs imaging sessions to 12-16 hours and yields movies that document cell and tissue...

Data from: Mutual fitness benefits arise during coevolution in a nematode-defensive microbe model

Charlotte Rafaluk-Mohr, Ben Ashby, Dylan A. Dahan & Kayla C. King
Species interactions can shift along the parasitism-mutualism continuum. However, the consequences of these transitions for coevolutionary interactions remain unclear. We experimentally coevolved a novel species interaction between Caenorhabditis elegans hosts and a mildly parasitic bacterium, Enterococcus faecalis, with host-protective properties against virulent Staphylococcus aureus. Coinfections drove the evolutionary transition of the C.elegans-E. faecalis relationship towards a reciprocally beneficial interaction. As E. faecalis evolved to protect nematodes against S. aureus infection, hosts adapted by accommodating greater...

Lipidomic profiling of Mycobacterium tuberculosis treated with JCP276, BMB034, or THL

Brett Babin
The increasing incidence of antibiotic-resistant Mycobacterium tuberculosis infections is a growing global health threat necessitating the development of new antibiotics. Serine hydrolases (SHs) are a promising class of targets because of their importance for the synthesis of the mycobacterial cell envelope. We screened a library of small molecules containing serine-reactive electrophiles and identified a series of narrow spectrum inhibitors of M. tuberculous growth. Using these lead molecules we performed competitive activity-based protein profiling and identified...

Data from: Multiple pairwise analysis of non-homologous centromere coupling reveals preferential chromosome size-dependent interactions and a role for bouquet formation in establishing the interaction pattern

Philippe Lefrançois, Beth Rockmill, Pingxing Xie, G. Shirleen Roeder & Michael Snyder
During meiosis, chromosomes undergo a homology search in order to locate their homolog to form stable pairs and exchange genetic material. Early in prophase, chromosomes associate in mostly non-homologous pairs, tethered only at their centromeres. This phenomenon, conserved through higher eukaryotes, is termed centromere coupling in budding yeast. Both initiation of recombination and the presence of homologs are dispensable for centromere coupling (occurring in spo11 mutants and haploids induced to undergo meiosis) but the presence...

Data from: Sexually coercive male chimpanzees sire more offspring

Joseph T. Feldblum, Emily E. Wroblewski, Rebecca S. Rudicell, Beatrice H. Hahn, Thais Paiva, Mine Cetinkaya-Rundel, Anne E. Pusey & Ian C. Gilby
In sexually reproducing animals, male and female reproductive strategies often conflict. In some species, males use aggression to overcome female choice, but debate persists over the extent to which this strategy is successful. Previous studies of male aggression toward females among wild chimpanzees have yielded contradictory results about the relationship between aggression and mating behavior. Critically, however, copulation frequency in primates is not always predictive of reproductive success. We analyzed a 17-year sample of behavioral...

Data from: Differences in combinatorial calls among the 3 elephant species cannot be explained by phylogeny

Michael A. Pardo, Joyce H. Poole, Angela S. Stoeger, Peter H. Wrege, Caitlin E. O'Connell-Rodwell, Udaha Kapugedara Padmalal & Shermin De Silva
Understanding why related species combine calls in different ways could provide insight into the selection pressures on the evolution of combinatorial communication. African savannah elephants (Loxodonta africana), African forest elephants (Loxodonta cyclotis), and Asian elephants (Elephas maximus) all combine broadband calls (roars, barks, and cries) and low-frequency calls (rumbles) into single utterances known as “combination calls.” We investigated whether the structure of such calls differs among species and whether any differences are better explained by...

Data from: Lineage tracing of human B cells reveals the in vivo landscape of human antibody class switching

Felix Horns, Christopher Vollmers, Derek Croote, Sally F. Mackey, Gary E. Swan, Cornelia L. Dekker, Mark M. Davis & Stephen R. Quake
Antibody class switching is a feature of the adaptive immune system which enables diversification of the effector properties of antibodies. Even though class switching is essential for mounting a protective response to pathogens, the in vivo patterns and lineage characteristics of antibody class switching have remained uncharacterized in living humans. Here we comprehensively measured the landscape of antibody class switching in human adult twins using antibody repertoire sequencing. The map identifies how antibodies of every...

Chemical-genetic interrogation of RNA polymerase mutants reveals structure-function relationships and physiological tradeoffs

Anthony Shiver, Hendrik Osadnik, Jason Peters, Rachel Mooney, Peter Wu, Kemardo Henry, Hannes Braberg, Carol Gross, Kerwyn Huang, Robert Landick, Nevan Krogan & James Hu
The multi-subunit bacterial RNA polymerase (RNAP) and its associated regulators carry out transcription and integrate myriad regulatory signals. Numerous studies have interrogated the inner workings of RNAP, and mutations in genes encoding RNAP drive adaptation of Escherichia coli to many health- and industry-relevant environments, yet a paucity of systematic analyses has hampered our understanding of the fitness benefits and trade-offs from altering RNAP function. Here, we conduct a chemical-genetic analysis of a library of RNAP...

Data from: Hypothalamic circuitry underlying stress-induced insomnia and peripheral immunosuppression

Shi-Bin Li, Jeremy C Borniger, Hiroshi Yamaguchi, Julien Hédou, Brice Gaudilliere & Luis De Lecea
The neural substrates of insomnia/hyperarousal induced by stress remain unknown. Here, we show that restraint stress leads to hyperarousal associated with strong activation of corticotropin-releasing hormone neurons in the paraventricular nucleus of hypothalamus (CRHPVN) and hypocretin neurons in the lateral hypothalamus (HcrtLH). CRHPVN neurons directly innervate HcrtLH neurons and optogenetic stimulation of LH-projecting CRHPVN neurons elicits hyperarousal. CRISPR-Cas9-mediated knockdown of the crh gene in CRHPVN neurons abolishes hyperarousal induced by stimulating LH-projecting CRHPVN neurons. Genetic...

Imaging dataset for positron emission microscopy of patient-derived tumor organoids

Syamantak Khan & Guillem Pratx
Here, we present a microscopy method to image 18F-fluorodeoxyglucose and other radiotracers in patient-derived tumor organoids with spatial resolution up to 100-fold better than that of clinical positron emission tomography (PET). When combined with brightfield imaging, this metabolic imaging approach functionally mirrors clinical PET/CT scans and provides a quantitative readout of cell glycolysis other metabolic processes.

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