The TimeGeo modeling framework for urban motility without travel surveys
Shan Jiang, Yingxiang Yang, Siddharth Gupta, Daniele Veneziano, Shounak Athavale, and Marta C. González
Individual mobility models are important in a wide range of application areas. Current mainstream urban mobility models require sociodemographic information from costly manual surveys, which are in small sample sizes and updated in low frequency. In this study, we propose an individual mobility modeling framework, TimeGeo, that extracts required features from ubiquitous, passive, and sparse digital traces in the information and communication technology era. The model is able to generate individual trajectories in high spatial–temporal resolutions, with interpretable mechanisms and parameters capturing heterogeneous individual travel choices. The modeling framework can flexibly adapt to input data with different resolutions, and be further extended for various modeling purposes. (See pp. E5370–E5378.)
Na+ coordination at the Na2 site of the Na+/I− symporter
Giuseppe Ferrandino, Juan Pablo Nicola, Yuly E. Sánchez, Ignacia Echeverria, Yunlong Liu, L. Mario Amzel, and Nancy Carrasco
The Na+/I− symporter (NIS) uses the Na+ electrochemical gradient to actively transport I− into the thyroid with a 2 Na+:1 I− stoichiometry. In NIS and related transporters, one of the two Na+ binding sites, Na2, includes a Ser and a Thr residue. We determined that, besides these residues, four other amino acids participate in binding Na+ at the Na2 site, at different stages of the transport cycle. These residues are conserved throughout the entirety of solute carrier family 5 (SLC5), to which NIS belongs. Replacing any of these residues has a marked effect on transport and on the dynamics of NIS. These results not only deepen our understanding of the mechanism of transport by NIS but are also relevant to the study of other Na+-driven cotransporters. (See pp. E5379–E5388.)
Comprehensive structural and dynamical view of an unfolded protein from the combination of single-molecule FRET, NMR, and SAXS
Mikayel Aznauryan, Leonildo Delgado, Andrea Soranno, Daniel Nettels, Jie-rong Huang, Alexander M. Labhardt, Stephan Grzesiek, and Benjamin Schuler
Proteins are the most versatile components of the molecular machinery of life. Synthesized as linear polymers of amino acids, proteins start out in their unfolded state and perform their function either in well-defined folded conformations or as intrinsically disordered proteins (IDPs) lacking tertiary structure. Both for the folding process and the properties of IDPs, a quantitative understanding of the conformational distributions and dynamics of unfolded proteins is thus essential. However, reaching this goal has been challenging owing to the large conformational heterogeneity and rapid dynamics of these systems. Here we combine three of the most powerful biophysical methods available to obtain a comprehensive view of an unfolded protein that would not be available from any of the individual methods. (See pp. E5389–E5398.)
Reg4+ deep crypt secretory cells function as epithelial niche for Lgr5+ stem cells in colon
Nobuo Sasaki, Norman Sachs, Kay Wiebrands, Saskia I. J. Ellenbroek, Arianna Fumagalli, Anna Lyubimova, Harry Begthel, Maaike van den Born, Johan H. van Es, Wouter R. Karthaus, Vivian S. W. Li, Carmen López-Iglesias, Peter J. Peters, Jacco van Rheenen, Alexander van Oudenaarden, and Hans Clevers
Stem cells crucially depend on their complex microenvironment, also called niche. The niche is defined as an anatomic site, consisting of specialized niche cells. These niche cells anchor stem cells and provide the stem cells with physical protection and essential growth and maintenance signals. In the murine small intestinal crypts, Paneth cells constitute an important part of cellular niche for Lgr5+ stem cells with which they are intermingled. Paneth cells provide molecules such as Wnt3, EGF, and Notch ligands to maintain intestinal stem cell. There exists no typical Paneth cell in the colon. Here, we show that Reg4-expressing deep crypt secretory cells function as the colon equivalent of Paneth cells. (See pp. E5399–E5407.)
MRG15 is required for pre-mRNA splicing and spermatogenesis
Naoki Iwamori, Kaoru Tominaga, Tetsuya Sato, Kevin Riehle, Tokuko Iwamori, Yasuyuki Ohkawa, Cristian Coarfa, Etsuro Ono, and Martin M. Matzuk
Pre-mRNA splicing generates protein diversity, is involved in the regulation of cellular differentiation, and can be epigenetically regulated by histone modifications. Chromatin binding proteins, which recognize histone modifications, recruit splicing regulators to methylated histones around tissue-specific splicing regions and regulate pre-mRNA splicing. However, the interplay of epigenetic factors and the splicing machinery during spermatogenesis remains unclear. Here, we show that epigenetic regulation of pre-mRNA splicing is required for spermatogenesis and male fertility. Thus, novel splicing diversity is important for spermatogenesis, and defects in this system may trigger disease. (See pp. E5408–E5415.)
Repeated replacement of an intrabacterial symbiont in the tripartite nested mealybug symbiosis
Filip Husnik and John P. McCutcheon
Mealybugs are plant sap-sucking insects with a nested symbiotic arrangement, where one bacterium lives inside another bacterium, which together live inside insect cells. These two bacteria, along with genes transferred from other bacteria to the insect genome, allow the insect to survive on its nutrient-poor diet. Here, we show that the innermost bacterium in this nested symbiosis was replaced several times over evolutionary history. These results show that highly integrated and interdependent symbiotic systems can experience symbiont replacement and suggest that similar dynamics could have occurred in building the mosaic metabolic pathways seen in mitochondria and plastids. (See pp. E5416–E5424.)
Parent-of-origin effects of A1CF and AGO2 on testicular germ-cell tumors, testicular abnormalities, and fertilization bias
Delphine Carouge, Valerie Blanc, Sue E. Knoblaugh, Robert J. Hunter, Nicholas O. Davidson, and Joseph H. Nadeau
Usually diagnosed in young men, testicular germ cell tumors (TGCTs) originate from abnormalities in germ cells during fetal development. Testicular cancer is a complex disease combining multiple genetic variants and environmental factors. The discovery of unconventional inheritance for TGCT risk both in humans and mice highlighted the major contribution of epigenetic mechanisms. The current work identifies two TGCT modifiers, the RNA-binding proteins apolipoprotein B mRNA-editing enzyme complex 1 (APOBEC1) complementation factor (A1CF) and Argonaute 2 (AGO2), respectively involved in RNA editing and RNA silencing. These results help us better understand the epigenetic control of germ-cell fate, urogenital development, and gamete functions. (See pp. E5425–E5433.)
Cd47-Sirpα interaction and IL-10 constrain inflammation-induced macrophage phagocytosis of healthy self-cells
Zhen Bian, Lei Shi, Ya-Lan Guo, Zhiyuan Lv, Cong Tang, Shuo Niu, Alexandra Tremblay, Mahathi Venkataramani, Courtney Culpepper, Limin Li, Zhen Zhou, Ahmed Mansour, Yongliang Zhang, Andrew Gewirtz, Koby Kidder, Ke Zen, and Yuan Liu
The present study reveals that macrophage phagocytosis toward healthy self-cells is controlled by a two-tier mechanism: a forefront activation mechanism requiring the inflammatory cytokine-stimulated protein kinase C (PKC)-spleen tyrosine kinase (Syk) pathway, to which IL-10 conversely regulates, and the subsequent self-target discrimination mechanism controlled by the CD47-signal regulatory protein α (SIRPα)–mediated inhibition. The findings significantly expand our understanding of macrophage phagocytic plasticity and behavior under different conditions and also provide insights into strategies for enhancing transplantation tolerance and macrophage-based cancer eradication, especially for cancers toward which therapeutic antibodies are yet unavailable. (See pp. E5434–E5443.)
IL2Rβ-dependent signals drive terminal exhaustion and suppress memory development during chronic viral infection
Jean-Christophe Beltra, Sara Bourbonnais, Nathalie Bédard, Tania Charpentier, Moana Boulangé, Eva Michaud, Ines Boufaied, Julie Bruneau, Naglaa H. Shoukry, Alain Lamarre, and Hélène Decaluwe
During chronic viral infection, CD8+ T cells are gradually deprived of their principal effector functions and irreversibly loose their plasticity to develop into memory populations, precluding the establishment of long-lasting protective immunity. Relevant host-derived factors directing this T-cell exhaustion process have remained elusive. Growing evidence suggests that the cytokine milieu dramatically impacts the outcome of chronic viral infection. However, it is unclear if cytokines directly promote CD8+ T-cell exhaustion and, if so, which specific cytokines are involved in this process. Here we demonstrate a critical role for two highly related cytokines, IL-2 and IL-15, in the terminal differentiation of highly exhausted CD8+ T cells and the lack of immunological memory observed during chronic viral infection. (See pp. E5444–E5453.)
Functional role of T-cell receptor nanoclusters in signal initiation and antigen discrimination
Sophie V. Pageon, Thibault Tabarin, Yui Yamamoto, Yuanqing Ma, John S. Bridgeman, André Cohnen, Carola Benzing, Yijun Gao, Michael D. Crowther, Katie Tungatt, Garry Dolton, Andrew K. Sewell, David A. Price, Oreste Acuto, Robert G. Parton, J. Justin Gooding, Jérémie Rossy, Jamie Rossjohn, and Katharina Gaus
T-cell activation requires the translation of antigen binding to the T-cell receptor (TCR) into intracellular signaling. However, how antigen recognition and signal transduction are mechanistically linked is poorly understood. Here, we used single-molecule localization microscopy to link TCR clustering to signaling. We found that the likelihood of a single receptor to initiate signaling upon ligand binding depended on receptor-to-receptor spacing, with TCRs in dense clusters having the highest signaling efficiency. This means that antigen recognition must first be translated into a spatial reorganization of receptors into dense, signaling-competent clusters before signaling can begin. Thus, the quality of an antigen in terms of signaling is given by its ability to densely cluster receptors. (See pp. E5454–E5463.)
Zinc-sensitive MRI contrast agent detects differential release of Zn(II) ions from the healthy vs. malignant mouse prostate
M. Veronica Clavijo Jordan, Su-Tang Lo, Shiuhwei Chen, Christian Preihs, Sara Chirayil, Shanrong Zhang, Payal Kapur, Wen-Hong Li, Luis M. De Leon-Rodriguez, Angelo J. M. Lubag, Neil M. Rofsky, and A. Dean Sherry
The normal prostate gland contains the most Zn(II) of all mammalian tissues, and there are marked differences in Zn(II) content between the healthy, malignant, and benign hyperplastic prostate. Given that multiparametric MRI does not always reliably distinguish between these tissue conditions, the release of Zn(II) ions from the prostate in response to an external stimulus may prove valuable as a specific biomarker of prostate cancer progression. In this work, we show that glucose stimulates the release of Zn(II) from intracellular stores in healthy prostate tissue and that Zn(II) secretion is reduced in a transgenic adenocarcinoma of the mouse prostate (TRAMP) model. (See pp. E5464–E5471.)
Metabolic features of chronic fatigue syndrome
Robert K. Naviaux, Jane C. Naviaux, Kefeng Li, A. Taylor Bright, William A. Alaynick, Lin Wang, Asha Baxter, Neil Nathan, Wayne Anderson, and Eric Gordon
Chronic fatigue syndrome is a multisystem disease that causes long-term pain and disability. It is difficult to diagnose because of its protean symptoms and the lack of a diagnostic laboratory test. We report that targeted, broad-spectrum metabolomics of plasma not only revealed a characteristic chemical signature but also revealed an unexpected underlying biology. Metabolomics showed that chronic fatigue syndrome is a highly concerted hypometabolic response to environmental stress that traces to mitochondria and was similar to the classically studied developmental state of dauer. This discovery opens a fresh path for the rational development of new therapeutics and identifies metabolomics as a powerful tool to identify the chemical differences that contribute to health and disease. (See pp. E5472–E5480.)
MYC-nick promotes cell migration by inducing fascin expression and Cdc42 activation
Sarah Anderson, Kumud Raj Poudel, Minna Roh-Johnson, Thomas Brabletz, Ming Yu, Nofit Borenstein-Auerbach, William N. Grady, Jihong Bai, Cecilia B. Moens, Robert N. Eisenman, and Maralice Conacci-Sorrell
The MYC family of transcription factors is deregulated in a broad range of cancers and drives the expression of genes that mediate biomass accumulation and promote cell proliferation and tumor initiation. We find that MYC can also trigger tumor cell migration and metastasis independently of its transcriptional activity, via its conversion to MYC-nick, a truncated form of MYC localized in the cytoplasm. MYC-nick promotes reorganization of the actin cytoskeleton by inducing expression of the actin-bundling protein fascin and by activating the Rho GTPase Cdc42, both of which lead to formation of filopodia, cellular structures known to drive cell migration. Our work links the repurposing of the MYC transcription factor to altered cytoskeletal structure and tumor cell metastatic behavior. (See pp. E5481–E5490.)
Merkel disc is a serotonergic synapse in the epidermis for transmitting tactile signals in mammals
Weipang Chang, Hirosato Kanda, Ryo Ikeda, Jennifer Ling, Jennifer J. DeBerry, and Jianguo G. Gu
The Merkel disc is a main type of tactile end organ for sensing gentle touch and is essential for sophisticated sensory tasks, including social interaction, environmental exploration, and tactile discrimination. Despite recent studies showing that Merkel cells in Merkel discs are main sites of mechanotransduction in response to tactile stimuli, it remains unclear how Merkel cells transmit tactile signals to Aβ-afferent endings, leading to tactile sensations. Here we show that Merkel discs are serotonergic synapses in the epidermis, that tactile stimuli trigger serotonin release from Merkel cells to excite their associated whisker Aβ-afferent endings, and that this epidermal serotonergic transmission is critical to both electrophysiological and behavioral responses to tactile stimulation. (See pp. E5491–E5500.)
Dopaminergic inputs in the dentate gyrus direct the choice of memory encoding
Huiyun Du, Wei Deng, James B. Aimone, Minyan Ge, Sarah Parylak, Keenan Walch, Wei Zhang, Jonathan Cook, Huina Song, Liping Wang, Fred H. Gage, and Yangling Mu
Reward boosts forms of learning and memory through dopamine-mediated neuromodulation in the brain. However, the influence of dopamine has been an underappreciated component of episodic information in the hippocampus. Using a cross-disciplinary approach, we demonstrate that dopaminergic input in the dentate gyrus, a hippocampal subregion critical for the formation of high-resolution memories, impairs subsequent learning by suppressing cortical inputs and ensemble neuronal activity in this area. This work reveals a mechanism by which dopamine signal biases memory storage of events leading to rather than subsequent to the reward. (See pp. E5501–E5510.)
A novel orvinol analog, BU08028, as a safe opioid analgesic without abuse liability in primates
Huiping Ding, Paul W. Czoty, Norikazu Kiguchi, Gerta Cami-Kobeci, Devki D. Sukhtankar, Michael A. Nader, Stephen M. Husbands, and Mei-Chuan Ko
A potent opioid analgesic without addictive and respiratory adverse effects has been a predominant goal for opioid medicinal chemistry since the isolation of morphine from opium in the 19th century. Here we report a functional profile of a unique analog, BU08028, targeting a combination of a classical and nonclassical opioid receptors in monkeys. By examining behavioral, physiological, and pharmacologic factors, the present study demonstrates that BU08028 exhibits full antinociception and antihypersensitivity without reinforcing effects (i.e., abuse liability), respiratory depression, pruritus, adverse cardiovascular events, or acute physical dependence. Because monkey models provide the most phylogenetically appropriate evaluation of opioid receptor functions and drug effects, these findings provide a translational bridge for such ligands as effective analgesics without safety and abuse liability concerns. (See pp. E5511–E5518.)
FERONIA interacts with ABI2-type phosphatases to facilitate signaling cross-talk between abscisic acid and RALF peptide in Arabidopsis
Jia Chen, Feng Yu, Ying Liu, Changqing Du, Xiushan Li, Sirui Zhu, Xianchun Wang, Wenzhi Lan, Pedro L. Rodriguez, Xuanming Liu, Dongping Li, Liangbi Chen, and Sheng Luan
Receptor-like kinase FERONIA (FER) not only serves as a receptor for growth-regulating rapid alkalinization factor (RALF) peptide but also acts as an important node in a variety of other signaling pathways, including plant responses to hormones, pathogens, and abiotic stresses. However, the mechanism underlying FER actions in these signaling cross-talks remain largely unknown. Our previous work identified a molecular relay that allows FER to inhibit abscisic acid (ABA) response through activation of a small G protein to enhance the activity of the clade A protein phosphatase type 2C (PP2C) ABA Insensitive 2 (ABI2), a repressor of ABA response. In this study, we found that ABI2 can directly interact and dephosphorylate FER, providing a feedback mechanism for RALF activation of FER. (See pp. E5519–E5527.)
Assessing intratumor heterogeneity and tracking longitudinal and spatial clonal evolutionary history by next-generation sequencing
Yuchao Jiang, Yu Qiu, Andy J. Minn, and Nancy R. Zhang
Cancer is a disease driven by rounds of genetic and epigenetic mutations that follow Darwinian evolution. The tumor for a given patient is often a mixture of multiple genotypically and phenotypically distinct cell populations. This contributes to failures of targeted therapies and to drug resistance, and thus it is important to study intratumor heterogeneity. Here, we propose Canopy, a statistical framework to reconstruct tumor phylogeny by next-generation sequencing data from temporally and/or spatially separated tumor resections from the same patient. We show that such analyses lead to the identification of potentially useful prognostic/diagnostic biomarkers and successfully recover the tumor’s evolutionary history, validated by single-cell sequencing. Canopy provides a rigorous foundation for statistical analysis of repeated sequencing data from evolving populations. (See pp. E5528–E5537.)