Lifestyle chemistries from phones for individual profiling
Amina Bouslimani, Alexey V. Melnik, Zhenjiang Xu, Amnon Amir, Ricardo R. da Silva, Mingxun Wang, Nuno Bandeira, Theodore Alexandrov, Rob Knight, and Pieter C. Dorrestein
This paper introduces the concept of skin-associated lifestyle chemistries found on personal belongings as a form of trace evidence. We propose a mass spectrometry-based approach to illuminate chemical traces recovered from personal objects. Using a chemical composite recovered froma swab of a phone, as a representative personal belonging, we can provide insights into personal lifestyle profile by predicting the kind of beauty product the individual uses, the food he/she eats, the medications he/she takes, or the places he/she has been. Therefore, the chemical interpretation of traces recovered from objects found on a crime scene can help a criminal investigator to learn about the lifestyle of the individual who used or touched these objects. (See pp. E7645–E7654.)
Unreasonable effectiveness of learning neural networks: From accessible states and robust ensembles to basic algorithmic schemes
Carlo Baldassi, Christian Borgs, Jennifer T. Chayes, Alessandro Ingrosso, Carlo Lucibello, Luca Saglietti, and Riccardo Zecchina
Artificial neural networks are some of the most widely used tools in data science. Learning is, in principle, a hard problem in these systems, but in practice heuristic algorithms often find solutions with good generalization properties. We propose an explanation of this good performance in terms of a nonequilibrium statistical physics framework: We show that there are regions of the optimization landscape that are both robust and accessible and that their existence is crucial to achieve good performance on a class of particularly difficult learning problems. Building on these results, we introduce a basic algorithmic scheme that improves existing optimization algorithms and provides a framework for further research on learning in neural networks. (See pp. E7655–E7662.)
Tissue-scale, personalized modeling and simulation of prostate cancer growth
Guillermo Lorenzo, Michael A. Scott, Kevin Tew, Thomas J. R. Hughes, Yongjie Jessica Zhang, Lei Liu, Guillermo Vilanova, and Hector Gomez
We perform a tissue-scale, personalized computer simulation of prostate cancer (PCa) growth in a patient, based on prostatic anatomy extracted from medical images. To do so, we propose a mathematical model for the growth of PCa. The model includes an equation for the reference biomarker of PCa: the prostate-specific antigen (PSA). Hence, we can link the results of our model to data that urologists can easily interpret. Our model reproduces features of prostatic tumor growth observed in experiments and clinical practice. It also captures a known shift in the growth pattern of PCa, from spheroidal to fingered geometry. Our results indicate that this shape instability is a tumor response to escape starvation, hypoxia, and, eventually, necrosis. (See pp. E7663–E7671.)
Life cycle greenhouse gas emissions and freshwater consumption associated with Bakken tight oil
Ian J. Laurenzi, Joule A. Bergerson, and Kavan Motazedi
The growth of production from tight oil plays such as the Bakken and Eagle Ford has prompted public interest in understanding the greenhouse gas (GHG) emissions and freshwater consumption associated with these resources, specifically with regard to hydraulic fracturing and flaring. Therefore, we conducted a comprehensive life cycle assessment of Bakken crude, using thousands of data from XTO Energy and other Bakken operators, establishing robust estimates of the footprint of current production practices. We conclude that flaring and hydraulic fracturing have a small impact on the life cycle (well to wheel) GHG emissions associated with Bakken and that these GHG emissions are comparable to those of other crudes. (See pp. E7672–E7680.)
The emergence of longevous populations
Fernando Colchero, Roland Rau, Owen R. Jones, Julia A. Barthold, Dalia A. Conde, Adam Lenart, Laszlo Nemeth, Alexander Scheuerlein, Jonas Schoeley, Catalina Torres, Virginia Zarulli, Jeanne Altmann, Diane K. Brockman, Anne M. Bronikowski, Linda M. Fedigan, Anne E. Pusey, Tara S. Stoinski, Karen B. Strier, Annette Baudisch, Susan C. Alberts, and James W. Vaupel
Public interest in social and economic equality is burgeoning. We examine a related phenomenon, lifespan equality, using data from charismatic primate populations and diverse human populations. Our study reveals three key findings. First, lifespan equality rises in lockstep with life expectancy, across primate species separated by millions of years of evolution and over hundreds of years of human social progress. Second, industrial humans differ more from nonindustrial humans in these measures than nonindustrial humans do from other primates. Third, in spite of the astonishing progress humans have made in lengthening the lifespan, a male disadvantage in lifespan measures has remained substantial—a result that will resonate with enduring public interest in male–female differences in many facets of life. (See pp. E7681–E7690.)
Molecular mechanisms of substrate-controlled ring dynamics and substepping in a nucleic acid-dependent hexameric motor
Nathan D. Thomsen, Michael R. Lawson, Lea B. Witkowsky, Song Qu, and James M. Berger
Hexameric, ring-shaped translocases are molecular motors that convert the chemical energy of ATP hydrolysis into the physical movement of protein and nucleic acid substrates. Structural studies of several distinct hexameric translocases have provided insights into how substrates are loaded and translocated; however, the range of structural changes required for coupling ATP turnover to a full cycle of substrate loading and translocation has not been visualized for any one system. Here, we combine low- and high-resolution structural studies of the Rho transcription termination factor, defining a set of conformational transitions that accompany substrate binding and translocations by a processive hexameric helicase. (See pp. E7691–E7700.)
Two familial ALS proteins function in prevention/repair of transcription-associated DNA damage
Sarah J. Hill, Daniel A. Mordes, Lisa A. Cameron, Donna S. Neuberg, Serena Landini, Kevin Eggan, and David M. Livingston
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease in which progressive dysfunction of motor neurons leads to paralysis and death. There is currently no known pathway of disease pathogenesis. However, many genes with varying functions have been linked to familial and sporadic forms of ALS suggesting multiple possible disease mechanisms. One set of gene products, including ALS-linked FUS and TDP43, functions in transcription and RNA processing. We find that defects in transcription due to loss of function of FUS or TDP43 can lead to DNA damage, including in primary human neuronal cells, and hypothesize that dysfunction in their RNA processing roles leads to DNA damage in motor neurons that, if incompletely resolved, could contribute to motor neuron death and ALS. (See pp. E7701–E7709.)
Notch1 controls development of the extravillous trophoblast lineage in the human placenta
Sandra Haider, Gudrun Meinhardt, Leila Saleh, Christian Fiala, Jürgen Pollheimer, and Martin Knöfler
Progenitor trophoblast cells of the human placenta either fuse to form a syncytium or develop into invasive trophoblasts invading the maternal uterus. However, regulatory pathways controlling their development and distinct differentiation programs are poorly understood. In the present study, we demonstrate that Notch1 is a critical regulator of early pregnancy, promoting development of the invasive, extravillous trophoblast lineage and survival of its progenitors. In vivo, Notch1 is detected in extravillous trophoblast progenitors and clusters of villous trophoblast initiating the invasive differentiation program. In vitro, Notch1 repressed genes involved in self-renewal of fusogenic precursors, but induced genes specifically expressed by extravillous trophoblast progenitors. Our data delineate Notch1 as a key regulator promoting development of the human extravillous trophoblast lineage. (See pp. E7710–E7719.)
Control of Hoxd gene transcription in the mammary bud by hijacking a preexisting regulatory landscape
Ruben Schep, Anamaria Necsulea, Eddie Rodríguez-Carballo, Isabel Guerreiro, Guillaume Andrey, Thi Hanh Nguyen Huynh, Virginie Marcet, Jozsef Zákány, Denis Duboule, and Leonardo Beccari
During vertebrate evolution, Hox gene function was coopted through the emergence of global enhancers outside the Hox gene clusters. Here, we analyze the regulatory modalities underlying Hoxd gene transcription into the developing mammary glands where Hox proteins are necessary. We report the existence of a long-distance acting mammary bud enhancer located near sequences involved in controlling Hox genes in the limbs. We argue that the particular constitutive chromatin structure found at this locus facilitated the emergence of this enhancer element in mammals by hijacking a regulatory context at work in other cell types, supporting a model wherein enhancer sequences tend to cluster into large regulatory landscapes due to an increased probability to evolve within a preexisting regulatory structure. (See pp. E7720–E7729.)
Origins of the current seventh cholera pandemic
Dalong Hu, Bin Liu, Lu Feng, Peng Ding, Xi Guo, Min Wang, Boyang Cao, Peter R. Reeves, and Lei Wang
Cholera, a major disease in human history, has terrorized the world through seven pandemics. The seventh pandemic started in Indonesia in 1961 and spread globally, currently infecting 3–5 million people annually. By combining all available historical records and genomic analysis of available preseventh pandemic and some early pandemic strains, we revealed the complex six-step evolution of the pandemic strain from its probable origin in South Asia to its nonpathogenic form in the Middle East in ∼1900 to Indonesia in ∼1925, where it evolved into a pandemic strain before becoming widespread in 1961. This pathway relates to human traffic routes, including the annual Hajj pilgrimage, and involved novel niches that provided gene sources and the driving forces for stepwise evolution. (See pp. E7730–E7739.)
Evolution of directional hearing in moths via conversion of bat detection devices to asymmetric pressure gradient receivers
Andrew Reid, Thibaut Marin-Cudraz, James F. C. Windmill, and Michael D. Greenfield
In most acoustic animals, directional hearing evolved alongside basic ear structure. Pyraloid moths differ because their ears generally function as simple bat detectors with little directional ability. Those pyraloid moths that broadcast mating calls represent a yet more special case, as these species localize sound but the ability evolved well after hearing and may be constrained by fundamental auditory features. Analyzing a species with male calling songs, we report a localization mechanism wherein the membrane structure of each ear affords sharp sensitivity to sound arriving from a distinct angle. Females can thereby track male calls but only via an indirect, curvilinear trajectory. Such inefficiency may characterize specialized perceptual traits that rely on general ones having already undergone extensive prior evolution. (See pp. E7740–E7748.)
Transposon mutagenesis identifies genes that cooperate with mutant Pten in breast cancer progression
Roberto Rangel, Song-Choon Lee, Kenneth Hon-Kim Ban, Liliana Guzman-Rojas, Michael B. Mann, Justin Y. Newberg, Takahiro Kodama, Leslie A. McNoe, Luxmanan Selvanesan, Jerrold M. Ward, Alistair G. Rust, Kuan-Yew Chin, Michael A. Black, Nancy A. Jenkins, and Neal G. Copeland
Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype. Despite extensive cancer genome-sequencing efforts, there is still an incomplete understanding of the genetic networks driving TNBC. Here, we used Sleeping Beauty transposon mutagenesis to identify genes that cooperate with mutant Pten in the induction of TNBC. We identified 12 candidate TNBC trunk drivers and a larger number of progression genes. Subsequent functional validation studies identified eight human TNBC tumor suppressor genes, including the GATA-like transcriptional repressor TRPS1, which was shown to inhibit lung metastasis by deregulating the expression of multiple serpin and epithelial-to-mesenchymal transition (EMT) pathway genes. Our study provides a better understanding of the genetic forces driving TNBC and discovered genes with clinical importance in TNBC. (See pp. E7749–E7758.)
Density of immunogenic antigens does not explain the presence or absence of the T-cell–inflamed tumor microenvironment in melanoma
Stefani Spranger, Jason J. Luke, Riyue Bao, Yuanyuan Zha, Kyle M. Hernandez, Yan Li, Alexander P. Gajewski, Jorge Andrade, and Thomas F. Gajewski
The T-cell–inflamed tumor microenvironment correlates with efficacy of immunotherapy. It is critical to understand whether non–T-cell–inflamed tumors lack antigens for T-cell recognition. In melanoma, no difference between inflamed and noninflamed tumors for multiple antigen classes was observed. Synthesized peptides corresponding to predicted HLA-A2 binding epitopes showed no differences between inflamed and noninflamed tumors. Extrapolation of a T-cell signature across The Cancer Genome Atlas showed no correlation between gene expression and mutational burden in any cancer type. These results indicate that lack of spontaneous immune infiltration in solid tumors is unlikely to be due to lack of antigens. Rather, transcriptional profiling suggests lack of Batf3-lineage dendritic cells. Our data suggest that strategies to restore T-cell entry into noninflamed tumors should be developed. (See pp. E7759–E7768.)
Association of PD-1/PD-L axis expression with cytolytic activity, mutational load, and prognosis in melanoma and other solid tumors
Ludmila Danilova, Hao Wang, Joel Sunshine, Genevieve J. Kaunitz, Tricia R. Cottrell, Haiying Xu, Jessica Esandrio, Robert A. Anders, Leslie Cope, Drew M. Pardoll, Charles G. Drake, and Janis M. Taube
The Cancer Genome Atlas datasets were used in the current study to explore the relationship of programmed death ligand-1 (PD-L1) expression, a cytotoxic T-cell gene signature, and mutational load to each other, to immunoactive factors, such as programmed cell death protein-1 (PD-1), PD-L2, and other checkpoint molecules, and to survival across multiple solid tumor types. We found that PD-L2 expression is more closely related to an ongoing host immune response in certain tumor types than PD-L1. Notably, mutational load was not immediately related to inflammation in any tumor type studied, and was inferior to an inflamed tumor microenvironment for predicting survival in patients with metastatic melanoma. Our findings also indicate the need for biomarker assays that are tumor-type–specific and include both expression studies and genomic profiling. (See pp. E7769–E7777.)
Trypanosoma brucei metabolite indolepyruvate decreases HIF-1α and glycolysis in macrophages as a mechanism of innate immune evasion
Anne F. McGettrick, Sarah E. Corcoran, Paul J. G. Barry, Jennifer McFarland, Cécile Crès, Anne M. Curtis, Edward Franklin, Sinéad C. Corr, K. Hun Mok, Eoin P. Cummins, Cormac T. Taylor, Luke A. J. O’Neill, and Derek P. Nolan
The parasite Trypanosoma brucei causes African sleeping sickness. This disease, which lacks effective treatments, affects millions of humans and livestock in sub-Saharan Africa. This paper reveals a mechanism by which the parasite can evade our immune response. Indolepyruvate is a metabolite produced by the parasite and it manipulates the immune cells, called macrophages, preventing them from becoming fully active. The selective advantage for the parasite of excretion of indolepyruvate is possible modulation of host inflammatory responses to prolong host survival, thereby potentiating transmission of the parasite to the tsetse fly vector and ensuring completion of the life cycle. This discovery could lead to new drug targets and better treatments. (See pp. E7778–E7787.)
Tethered IL-15 augments antitumor activity and promotes a stem-cell memory subset in tumor-specific T cells
Lenka V. Hurton, Harjeet Singh, Amer M. Najjar, Kirsten C. Switzer, Tiejuan Mi, Sourindra Maiti, Simon Olivares, Brian Rabinovich, Helen Huls, Marie-Andrée Forget, Vrushali Datar, Partow Kebriaei, Dean A. Lee, Richard E. Champlin, and Laurence J. N. Cooper
We describe an approach based on cytokine therapeutics to enhance the persistence and effectiveness of T-cell–based immunotherapies using chimeric antigen receptors (CARs). This strategy is effective without the use of high-dose exogenous cytokines that are typically associated with toxicities. Moreover, we report that the persistence of the least differentiated memory T cell, the T-memory stem cell, was promoted by signaling induced by a membrane-bound chimeric IL-15 cytokine-fusion molecule. These findings may contribute to improving the safety and therapeutic efficacy of CAR-based immunotherapies of patients with advanced cancer. (See pp. E7788–E7797.)
In vivo amelioration of endogenous antitumor autoantibodies via low-dose P4N through the LTA4H/activin A/BAFF pathway
Yu-Ling Lin, Nu-Man Tsai, Cheng-Hao Hsieh, Shu-Yi Ho, Jung Chang, Hsin-Yi Wu, Ming-Hua Hsu, Chia-Ching Chang, Kuang-Wen Liao, Tiffany L. B. Jackson, David E. Mold, and Ru Chih C. Huang
This study finds that a small-molecule drug (P4N) is able to inhibit tumor growth by augmentation of endogenous antitumor autoantibodies (EAAs). We show that the enhancement of EAA activity by P4N is mediated through activation of the leukotriene A4 hydrolase (LTA4H)/activin A/B-cell activating factor (BAFF) pathway, revealing a valuable method for developing new immune modulators of tumor growth via humoral immunity. Typically, the effects of the humoral response on tumor inhibition are modest; however, the results of this study demonstrate that by removing the impediment to cancer cell destruction posed by low-activity autoantibodies, the realization of new, more potent immunotherapies for cancer treatment may be possible. (See pp. E7798–E7807.)
Heparanase is required for activation and function of macrophages
Lilach Gutter-Kapon, Dror Alishekevitz, Yuval Shaked, Jin-Ping Li, Ami Aronheim, Neta Ilan, and Israel Vlodavsky
The tumor microenvironment is now considered to play a major role in cancer growth and metastasis. Heparanase is the only enzyme in mammals capable of cleaving heparan sulfate, an activity that is highly implicated in tumor growth, metastasis, and inflammation. Here we provide evidence that heparanase is critically required for the activation and function of macrophages, an important constituent of the tumor microenvironment. Mechanistically, we describe a linear cascade by which heparanase activates Erk, p38, and JNK signaling in macrophages, leading to increased c-Fos levels and induction of cytokine expression in a manner that apparently does not require heparanase enzymatic activity. These results identify heparanase as a key mediator of macrophage activation and function in tumorigenesis and cross-talk with the tumor microenvironment. (See pp. E7808–E7817.)
Role of nucleotide-binding oligomerization domain 1 (NOD1) and its variants in human cytomegalovirus control in vitro and in vivo
Yi-Hsin Fan, Sujayita Roy, Rupkatha Mukhopadhyay, Arun Kapoor, Priya Duggal, Genevieve L. Wojcik, Robert F. Pass, and Ravit Arav-Boger
Infection with human cytomegalovirus (HCMV) is a growing health problem, creating diagnostic and therapeutic challenges. Biomarkers for risk of infection are lacking, and the limited drugs that inhibit HCMV have major side effects. New strategies for virus control are needed. We report on the role of nucleotide-binding oligomerization domain 1 (NOD1), a cytoplasmic pattern recognition receptor, in HCMV suppression. NOD1 activation (through IKKα and IRF3) resulted in IFN response and HCMV inhibition. Specific mutations in NOD1 showed differential effects on HCMV replication in vitro. In a nested study of HCMV vaccine, specific polymorphisms in NOD1 were detected in HCMV-infected women compared with noninfected women. Our work provides direction for studies of innate immune response to HCMV and genetic susceptibility through NOD1. (See pp. E7818–E7827.)
VEGF preconditioning leads to stem cell remodeling and attenuates age-related decay of adult hippocampal neurogenesis
Tamar Licht, Gadiel Rothe, Tirzah Kreisel, Brachi Wolf, Ofra Benny, Alasdair G. Rooney, Charles ffrench-Constant, Grigori Enikolopov, and Eli Keshet
Generation of new neurons is maintained in the adult hippocampus throughout life. The process, which is driven by an exhaustible reservoir of neuronal stem cells (NSCs), greatly declines with age, however. We show that even a short, episodic exposure to the angiogenic factor VEGF and a resultant ramification/rejuvenation of the vasculature within the stem cell microenvironment (“niche”) is sufficient for neurogenesis to proceed at a markedly elevated rate for months later without accelerating the rate of NSC depletion. Importantly, this manipulation culminates in marked attenuation of age-dependent neurogenic decline. Long-term neurogenic enhancement via VEGF preconditioning was found to be associated with extensive NSC morphological remodeling resembling a “juvenile” pattern of NSC and blood vessel engagements. (See pp. E7828–E7836.)
Circadian rhythms identified in Caenorhabditis elegans by in vivo long-term monitoring of a bioluminescent reporter
María Eugenia Goya, Andrés Romanowski, Carlos S. Caldart, Claire Y. Bénard, and Diego A. Golombek
Endogenous circadian rhythms have been demonstrated in several model systems, including mammals, insects, and fungi, among many others. Cycles in behavior, physiology and gene expression have also been reported in the nematode Caenorhabditis elegans, although limited by experimental conditions. Here we report the application of a luciferase-based reporter to investigate circadian regulation in C. elegans. Our study demonstrates entrainable, endogenous, and temperature-dependent circadian rhythms in gene expression as well as part of the pathway for synchronization. Our results represent an innovative approach for the study of long-term gene expression in real time in this system, opening the way for novel research in neuroscience and molecular pathways in general, including the precise determination of its elusive circadian clock. (See pp. E7837–E7845.)
Control of seed dormancy in Arabidopsis by a cis-acting noncoding antisense transcript
Halina Fedak, Malgorzata Palusinska, Katarzyna Krzyczmonik, Lien Brzezniak, Ruslan Yatusevich, Zbigniew Pietras, Szymon Kaczanowski, and Szymon Swiezewski
Sequential developmental transitions in plant life cycle are tightly controlled by dynamic regulation of key genes. Seed dormancy release is probably the first developmental transition in a plant’s life cycle, and it is regulated by the Delay of Germination 1 (DOG1) gene. Here we demonstrate that a nonprotein-coding antisense transcript originating from a conserved at DNA—but not protein level—DOG1 region is a negative regulator of DOG1 expression and seed dormancy establishment. We show that this antisense transcript negatively regulates DOG1 expression in cis. This mechanism is presumably conserved across the Brassicaceae, given the evolutionary conservation of the antisense DOG1 promoter. (See pp. E7846–E7855.)
Statistics of natural reverberation enable perceptual separation of sound and space
James Traer and Josh H. McDermott
Sounds produced in the world reflect off surrounding surfaces on their way to our ears. Known as reverberation, these reflections distort sound but provide information about the world around us. We asked whether reverberation exhibits statistical regularities that listeners use to separate its effects from those of a sound’s source. We conducted a large-scale statistical analysis of real-world acoustics, revealing strong regularities of reverberation in natural scenes. We found that human listeners can estimate the contributions of the source and the environment from reverberant sound, but that they depend critically on whether environmental acoustics conform to the observed statistical regularities. The results suggest a separation process constrained by knowledge of environmental acoustics that is internalized over development or evolution. (See pp. E7856–E7865.)