74 Works

Lymph node metastases develop through a wider evolutionary bottleneck than distant metastases

Johannes Reiter, Wei-Ting Hung, I-Hsiu Lee, Shriya Nagpal, Peter Giunta, Sebastian Degner, Gang Liu, Emma Wassenaar, William Jeck, Martin Taylor, Alexander Farahani, Hetal Marble, Simon Knott, Onno Kranenburg, Jochen Lennerz & Kamila Naxerova
Genetic diversity among metastases is poorly understood but contains important information about disease evolution at secondary sites. Here we investigate inter- and intra-lesion heterogeneity for two types of metastases that associate with different clinical outcomes: lymph node and distant organ metastases in human colorectal cancer. We develop a rigorous mathematical framework for quantifying metastatic phylogenetic diversity. Distant metastases are typically monophyletic and genetically similar to each other. Lymph node metastases, in contrast, display high levels...

Data from: Conserved but flexible modularity in the zebrafish skull: implications for craniofacial evolvability

Kevin J. Parsons, Young H. Son, Amelie Crespel, Davide Thambithurai, Shaun Killen, Matthew P. Harris & R. Craig Albertson
Morphological variation is the outward manifestation of development and provides fodder for adaptive evolution. Because of this contingency, evolution is often thought to be biased by developmental processes and functional interactions among structures, which are statistically detectable through forms of covariance among traits. This can take the form of substructures of integrated traits, termed modules, which together comprise patterns of variational modularity. While modularity is essential to an understanding of evolutionary potential, biologists currently have...

Single molecule images for: An empirical energy landscape reveals mechanism of proteasome in polypeptide translocation

Ying Lu
The ring-like ATPase complexes in the AAA+ family perform diverse cellular functions that require coordination between the conformational transitions of their individual ATPase subunits. How the energy from ATP hydrolysis is captured to perform mechanical work by these coordinated movements is not known. In this study, we developed a novel approach for delineating the nucleotide-dependent free-energy landscape (FEL) of the proteasome's heterohexameric ATPase complex based on complementary structural and kinetic measurements. We used the FEL...

Data from: Health assessment of French university students and risk factors associated with mental health disorders

Antoine Tran, Laurie Tran, Nicolas Geghre, David Darmon, Marion Rampal, Diane Brandone, Jean-Michel Gozzo, Herve Haas, Karine Rebouillat-Savy, Herve Caci & Paul Avillach
Objective: The first year of university is a particularly stressful period and can impact academic performance and students’ health. The aim of this study was to evaluate the health and lifestyle of undergraduates and assess risk factors associated with psychiatric symptoms. Materials and methods: Between September 2012 and June 2013, we included all undergraduate students who underwent compulsory a medical visit at the university medical service in Nice (France) during which they were screened for...

Data from: Quantification of sensitivity and resistance of breast cancer cell lines to anti-cancer drugs using GR metrics

Marc Hafner, Laura M. Heiser, Elizabeth H. Williams, Mario Niepel, Nicholas J. Wang, James E. Korkola, Joe W. Gray & Peter K. Sorger
Traditional means for scoring the effects of anti-cancer drugs on the growth and survival of cell lines is based on relative cell number in drug-treated and control samples and is seriously confounded by unequal division rates arising from natural biological variation and differences in culture conditions. This problem can be overcome by computing drug sensitivity on a per-division basis. The normalized growth rate inhibition (GR) approach yields per-division metrics for drug potency (GR50) and efficacy...

Data from: A database of human exposomes and phenomes from the US National Health and Nutrition Examination Survey

Chirag J. Patel, Nam Pho, Michael McDuffie, Jeremy Easton-Marks, Cartik Kothari, Isaac S. Kohane & Paul Avillach
The National Health and Nutrition Examination Survey (NHANES) is a population survey implemented by the Centers for Disease Control and Prevention (CDC) to monitor the health of the United States whose data is publicly available in hundreds of files. This Data Descriptor describes a single unified and universally accessible data file, merging across 255 separate files and stitching data across 4 surveys, encompassing 41,474 individuals and 1,191 variables. The variables consist of phenotype and environmental...

Cognitive experience alters cortical involvement in goal-directed navigation

Charlotte Arlt
Neural activity in the mammalian cortex has been studied extensively during decision tasks, and recent work aims to identify under what conditions cortex is actually necessary for these tasks. We studied whether cognitive experience, beyond sensory or motor learning, affects cortical involvement in goal-directed navigation. To this aim, we first trained different cohorts of mice on either a simple goal-directed navigation task (“simple task”), or one of two complex tasks involving delay periods (“delay task”)...

Data from: Efficient in situ barcode sequencing using padlock probe-based BaristaSeq

Xiaoyin Chen, Yu-Chi Sun, George M. Church, Je Hyuk Lee & Anthony M. Zador
Cellular DNA/RNA tags (barcodes) allow for multiplexed cell lineage tracing and neuronal projection mapping with cellular resolution. Conventional approaches to reading out cellular barcodes trade off spatial resolution with throughput. Bulk sequencing achieves high throughput but sacrifices spatial resolution, whereas manual cell picking has low throughput. In situ sequencing could potentially achieve both high spatial resolution and high throughput, but current in situ sequencing techniques are inefficient at reading out cellular barcodes. Here we describe...

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: Ancient mitochondrial DNA provides high-resolution time scale of the peopling of the Americas

Bastien Llamas, Lars Fehren-Schmitz, Guido Valverde, Julien Soubrier, Swapan Mallick, Nadin Rohland, Susanne Nordenfelt, Cristina Valdiosera, Stephen M. Richards, Adam Rohrlach, Maria Inés Barreto Romero, Isabel Flores Espinoza, Elsa Tomasto Cagigao, Lucía Watson Jiménez, Krzysztof Makowski, Ilán Santiago Leboreiro Reyna, Josefina Mansilla Lory, Julio Alejandro Ballivián Torrez, Mario A. Rivera, Richard L. Burger, Maria Constanza Ceruti, Johan Reinhard, R. Spencer Wells, Gustavo Politis, Calogero M. Santoro … & Wolfgang Haak
The exact timing, route, and process of the initial peopling of the Americas remains uncertain despite much research. Archaeological evidence indicates the presence of humans as far as southern Chile by 14.6 thousand years ago (ka), shortly after the Pleistocene ice sheets blocking access from eastern Beringia began to retreat. Genetic estimates of the timing and route of entry have been constrained by the lack of suitable calibration points and low genetic diversity of Native...

Data from: Core genes evolve rapidly in the long-term evolution experiment with Escherichia coli

Rohan Maddamsetti, Philip J. Hatcher, Anna G. Green, Barry L. Williams, Debora S. Marks & Richard E. Lenski
Bacteria can evolve rapidly under positive selection owing to their vast numbers, allowing their genes to diversify by adapting to different environments. We asked whether the same genes that evolve rapidly in the long-term evolution experiment with Escherichia coli (LTEE) have also diversified extensively in nature. To make this comparison, we identified ~2000 core genes shared among 60 E. coli strains. During the LTEE, core genes accumulated significantly more nonsynonymous mutations than flexible (i.e., noncore)...

Data from: Investigation of parallel radiofrequency transmission for the reduction of heating in long conductive leads in 3 tesla magnetic resonance imaging

Clare E. McElcheran, Benson Yang, Laleh Golenstani-Rad & Simon J. Graham
Deep Brain Stimulation (DBS) is increasingly used to treat a variety of brain diseases by sending electrical impulses to deep brain nuclei through long, electrically conductive leads. Magnetic resonance imaging (MRI) of patients pre- and post-implantation is desirable to target and position the implant, to evaluate possible side-effects and to examine DBS patients who have other health conditions. Although MRI is the preferred modality for pre-operative planning, MRI post-implantation is limited due to the risk...

Data from: Transcriptional profiling at whole population and single cell levels reveals somatosensory neuron molecular diversity

Isaac M. Chiu, Lee B. Barrett, Erika Williams, David E. Strochlic, Seungkyu Lee, Andy D. Weyer, Shan Lou, Gregory Bryman, David P. Roberson, Nader Ghasemlou, Cara Piccoli, Ezgi Ahat, Victor Wang, Enrique J. Cobos, Cheryl L. Stucky, Qiufu Ma, Stephen D. Liberles, Clifford J. Woolf & Gregory S Bryman
The somatosensory nervous system is critical for the organism’s ability to respond to mechanical, thermal, and nociceptive stimuli. Somatosensory neurons are functionally and anatomically diverse but their molecular profiles are not well-defined. Here, we used transcriptional profiling to analyze the detailed molecular signatures of dorsal root ganglion (DRG) sensory neurons. We used two mouse reporter lines and surface IB4 labeling to purify three major non-overlapping classes of neurons: 1)IB4+SNS-Cre/TdTomato+, 2)IB4-SNS-Cre/TdTomato+, and 3)Parv-Cre/TdTomato+ cells, encompassing the...

Data from: Age influences the thermal suitability of Plasmodium falciparum transmission in the Asian malaria vector Anopheles stephensi

Courtney Murdock, Kerri Miazgowicz, Erin Mordecai, Sadie Ryan, Richard Hall, Harry Owen, Temitayo Adanlawo, Kavya Balaji, Marta Shocket, Oswaldo Villena, Leah Johnson, Blanka Tesla, Leah Demakovsky, Matt Bonds, Calistus Ngonghala & Melinda Brindley
Models predicting disease transmission are vital tools for long-term planning of malaria reduction efforts, particularly for mitigating impacts of climate change. We compared temperature-dependent malaria transmission models when mosquito life history traits were estimated from a truncated portion of the lifespan (a common practice) to traits measured across the full lifespan. We conducted an experiment on adult female Anopheles stephensi, the Asian urban malaria mosquito, to generate daily per capita values for mortality, egg production,...

Cell-autonomous light sensitivity via Opsin3 regulates fuel utilization in brown adipocytes

Mari Sato, Tadataka Tsuji, Kunyan Yang, Jonathan Dreyfuss, Tian Lian Huang, Chih-Hao Wang, Farnaz Shamsi, Luiz Leiria, Matthew Lynes, Yu-Hua Tseng, Xiaozhi Ren & King-Wai Yau
Opsin3 (Opn3) is a transmembrane heptahelical G-protein-coupled receptor (GPCR) with the potential to produce a non-visual photoreceptive effect. Interestingly, anatomical profiling of GPCRs reveals that Opn3 mRNA is highly expressed in adipose tissue. The photosensitive functions of Opn3 in mammals are poorly understood, and whether Opn3 has a role in fat is entirely unknown. In this study, we found that Opn3-knockout (Opn3-KO) mice were prone to diet-induced obesity and insulin-resistance. At the cellular level, Opn3-KO...

Risk factors for cardiovascular disease (CVD) in adults with type 1 diabetes: findings from prospective real-life T1D exchange registry

Nicole Foster, Viral N Shah, Ryan Bailey, Mengdi Wu, Rodica Pop-Busui, Michelle Katz, Jill Crandall, Fida Bacha, Kristen Nadeau, Ingrid Libman, Paul Hiers, Kara Mizokami-Stout, Linda A DiMeglio, Jennifer Sherr, Richard Pratley, Shivani Agarwal, Janet Snell-Bergeon, Eda Cengiz, Sarit Polsky & Sanjeev N Mehta
Context Cardiovascular disease (CVD) is a major cause of mortality in adults with type 1 diabetes. Objective We prospectively evaluated CVD risk factors in a large, contemporary cohort of adults with type 1 diabetes living in the United States. Design Observational study of CVD and CVD risk factors over a median of 5.3 years. Setting The T1D Exchange clinic network. Patients Adults (age ≥18 years) with type 1 diabetes and without known CVD diagnosed before...

Modernizing health information technology: lessons from healthcare delivery systems

Joseph Amlung, Hannah Huth, Theresa Cullen & Thomas Sequist
Abstract Objective To identify recurrent themes, insights, and process recommendations from stakeholders in US organizations during the health information technology (HIT) modernization of an existing electronic health record (EHR) to a commercial-off-the-shelf product in both resource-plentiful settings and in a resource-constrained environment, the US Indian Health Service. Materials and Methods Thirteen qualitative interviews with stakeholders in various organizations were conducted about HIT modernization efforts. Using a Theory of Change framework, recurring themes were identified and...

Functional architecture of neural circuits for leg proprioception in Drosophila

Chenghao Chen, Sweta Agrawal, Brandon Mark, Akira Mamiya, Anne Sustar, Jasper Phelps, Wei-Chung Lee, Barry Dickson, Gwyneth Card & John Tuthill
To effectively control their bodies, animals rely on feedback from proprioceptive mechanosensory neurons. In the Drosophila leg, different proprioceptor subtypes monitor joint position, movement direction, and vibration. Here, we investigate how these diverse sensory signals are integrated by central proprioceptive circuits. We find that signals for leg joint position and directional movement converge in second-order neurons, revealing pathways for local feedback control of leg posture. Distinct populations of second-order neurons integrate tibia vibration signals across...

Analysis of ancestry heterozygosity suggests that hybrid incompatibilities in threespine stickleback are environment-dependent

Ken Thompson, Catherine Peichel, Diana Rennison, Matthew McGee, Arianne Albert, Timothy Vines, Anna Greenwood, Abigail Wark, Yaniv Brandvain, Molly Schumer & Dolph Schluter
Hybrid incompatibilities occur when interactions between opposite-ancestry alleles at different loci reduce the fitness of hybrids. Most work on incompatibilities has focused on those that are 'intrinsic', meaning they affect viability and sterility in the laboratory. Theory predicts that ecological selection can also underlie hybrid incompatibilities, but tests of this hypothesis using sequence data are scarce. In this article, we compiled genetic data for F2 hybrid crosses between divergent populations of threespine stickleback fish (Gasterosteus...

MERFISH measurements in the mouse ileum

Jeffrey Moffitt, Rosalind Xu, Peter Kharchenko, Viktor Petukhov, Paolo Cadinu, Ruslan Soldatov & Konstantin Khodosevich
Spatial transcriptomics protocols based on in situ sequencing or multiplexed RNA fluorescent hybridization can reveal detailed tissue organization. However, distinguishing the boundaries of individual cells in such data is challenging, and can hamper downstream analysis. Current methods generally approximate cells positions using nuclei stains. We describe a segmentation method, Baysor, which optimizes 2D or 3D cell boundaries considering joint likelihood of transcriptional composition and cell morphology. While Baysor can take into account segmentation based on...

Cerebral Vasoregulation in Diabetes

Vera Novak & Laura Mendez
This observational study evaluated the effects of type 2 diabetes on cerebral vasoregulation and functional outcomes, measured by blood flow responses to hypocapnia and hypercapnia, Valsalva maneuver, head-up tilt, and sit-to-stand test. This dataset contains 37 diabetic participants and 49 controls (aged 55 to 75 years) with continuous measurements of cerebral blood flow using transcranial Doppler and MRI, heart rate, blood pressure, and respiratory parameters, balance, walking, laboratory and retinopathy measures.

Variation in the modality of a yeast signaling pathway is mediated by a single regulator

Julius Palme, Jue Wang & Michael Springer
Bimodal gene expression by genetically identical cells is a pervasive feature of signaling networks, and has been suggested to allow organisms to hedge their "bets" in uncertain conditions. In the galactose-utilization (GAL) pathway of Saccharomyces cerevisiae, gene induction is unimodal or bimodal depending on natural genetic variation and pre-induction conditions. Here, we find that this variation in modality arises from regulation of two features of the pathway response: the fraction of cells that show induction,...

Seasonal patterns of melatonin alter aggressive phenotypes of female Siberian hamsters

Nikki Rendon, Christopher Petersen, Kathleen Munley, Andrea Amez, Daniel Boyes, Marcy Kingsbury & Gregory Demas
Many animal species exhibit year-round aggression, a behaviour that allows individuals to compete for limited resources in their environment (e.g., food and mates). Interestingly, this high degree of territoriality persists during the non-breeding season, despite low levels of circulating gonadal steroids (i.e., testosterone [T] and oestradiol [E2]). Our previous work suggests that the pineal hormone melatonin mediates a ‘seasonal switch’ from gonadal to adrenal regulation of aggression in Siberian hamsters (Phodopus sungorus); solitary, seasonally breeding...

Data from: Quantification of motor speech impairment and its anatomic basis in primary progressive aphasia

Claire Cordella, Megan Quimby, Alexandra Touroutoglou, Michael Brickhouse, Bradford Clark Dickerson & Jordan R. Green
Objective: To evaluate whether a quantitative speech measure is effective in identifying and monitoring motor speech impairment (MSI) in patients with primary progressive aphasia (PPA), and to investigate the neuroanatomical basis of MSI in PPA. Methods: Sixty-four patients with PPA were evaluated at baseline, with a subset (N=39) evaluated longitudinally. Articulation rate (AR), a quantitative measure derived from spontaneous speech, was measured at each timepoint. MRI was collected at baseline. Differences in baseline AR were...

Data from: Identifying metabolic subpopulations from population level mass spectrometry

Christine M. DeGennaro, Yonatan Savir & Michael Springer
Metabolism underlies many important cellular decisions, such as the decisions to proliferate and differentiate, and defects in metabolic signaling can lead to disease and aging. In addition, metabolic heterogeneity can have biological consequences, such as differences in outcomes and drug susceptibilities in cancer and antibiotic treatments. Many approaches exist for characterizing the metabolic state of a population of cells, but technologies for measuring metabolism at the single cell level are in the preliminary stages and...

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  • Harvard Medical School
  • Harvard University
  • University of Washington
  • Stanford University
  • Boston University School of Medicine
  • Beth Israel Deaconess Medical Center
  • Massachusetts General Hospital
  • Boston Children's Hospital
  • University of California, San Diego
  • Indiana University