Direct phase-sensitive identification of a d-form factor density wave in underdoped cuprates
Kazuhiro Fujita, Mohammad H. Hamidian, Stephen D. Edkins, Chung Koo Kim, Yuhki Kohsaka, Masaki Azuma, Mikio Takano, Hidenori Takagi, Hiroshi Eisaki, Shin-ichi Uchida, Andrea Allais, Michael J. Lawler, Eun-Ah Kim, Subir Sachdev, and J. C. Séamus Davis
High-temperature superconductivity emerges when holes are introduced into the antiferromagnetic, insulating CuO2 plane of the cuprates. Intervening between the insulator and the superconductor is the mysterious pseudogap phase. Evidence has been accumulating that this phase supports an exotic density wave state that may be key to its existence. By introducing visualization techniques that discriminate the electronic structure at the two oxygen sites with each CuO2 unit cell, we demonstrate (pp. E3026–E3032) that this density wave consists of periodic modulations maintaining a phase difference of π between every such pair of oxygen sites. Therefore, the cuprate pseudogap phase contains a previously unknown electronic state—a density wave with a d-symmetry form factor.
Structural basis for the binding and incorporation of nucleotide analogs with L-stereochemistry by human DNA polymerase λ
Rajan Vyas, Walter J. Zahurancik, and Zucai Suo
DNA polymerases are known to select against L-nucleotides, the enantiomers of natural D-nucleotides. However, the structural basis for D-stereoselectivity of a DNA polymerase has not been established, although two L-nucleoside analogs, lamivudine and emtricitabine, have been widely used as anti-HIV and anti-hepatitis B drugs. Here (pp. E3033–E3042), we report ternary crystal structures of human DNA polymerase λ in complex with DNA and L-deoxycytidine 5′-triphosphate, or its analogs (the triphosphates of lamivudine and emtricitabine). These structures reveal that unlike a polymerase-bound D-nucleotide, an L-nucleotide initially interacts with an active site arginine residue through hydrogen bonds and then pairs with the templating nucleotide. Our work provides a structural basis for the D-stereoselectivity of a polymerase and valuable insight toward design of less toxic antiviral nucleoside analogs.
Specific collagen XVIII isoforms promote adipose tissue accrual via mechanisms determining adipocyte number and affect fat deposition
Mari Aikio, Harri Elamaa, David Vicente, Valerio Izzi, Inderjeet Kaur, Lotta Seppinen, Helen E. Speedy, Dorota Kaminska, Sanna Kuusisto, Raija Sormunen, Ritva Heljasvaara, Emma L. Jones, Mikko Muilu, Matti Jauhiainen, Jussi Pihlajamäki, Markku J. Savolainen, Carol C. Shoulders, and Taina Pihlajaniemi
A previously unrecognized role is described for collagen XVIII—a ubiquitous, structurally complex basement membrane proteoglycan—in supporting preadipocyte differentiation and the maintenance of this differentiated state, and hence the size and lipid-clearing/storage functions of white adipose tissue depots. Specific lack of medium and long isoforms of this nonfibrillar collagen in mice led to reduced adiposity, ectopic deposition of fat in liver, and elevated very low-density lipoprotein-triglyceride levels (pp. E3043–E3052). The finding of a previously unidentified extracellular mechanism contributing to control of adipogenesis is expected to promote understanding of the molecular and functional bases of human hyperlipidemic syndromes associated with fatty liver.
Platelets guide the formation of early metastatic niches
Myriam Labelle, Shahinoor Begum, and Richard O. Hynes
Specialized microenvironments (or “niches”) are essential for metastasis, but how cancer cells and host cells contribute to their establishment remains poorly understood. Our study (pp. E3053–E3061) reveals that platelets and granulocytes are sequentially recruited to disseminated tumor cells to form “early metastatic niches” that promote metastatic progression. Importantly, the recruitment of granulocytes is not primarily due to tumor cell-derived signals but rather relies on platelet-derived CXCL5/7 chemokines. Prevention of granulocyte recruitment via inhibition of the CXCL5/7 receptor CXCR2, or depletion of either platelets or granulocytes inhibits metastasis, thereby uncovering a key role for platelet-to-granulocyte signaling in the establishment of metastases. Specific inhibition of platelet-to-granulocyte interactions may thus represent a valuable antimetastatic therapy in addition to cancer cell-centered treatments.
Synergistic tumor suppression by combined inhibition of telomerase and CDKN1A
Romi Gupta, Yuying Dong, Peter D. Solomon, Hiromi I. Wettersten, Christopher J. Cheng, JIn-Na Min, Jeremy Henson, Shaillay Kumar Dogra, Sung H. Hwang, Bruce D. Hammock, Lihua J. Zhu, Roger R. Reddel, W. Mark Saltzman, Robert H. Weiss, Sandy Chang, Michael R. Green, and Narendra Wajapeyee
Over 90% of cancer cells express telomerase, which is required for their survival. However, telomerase inhibitors alone have so far failed to provide any significant clinical benefit. Therefore, identifying and targeting genes that can enhance the effects of telomerase inhibitors will greatly benefit a large population of cancer patients. We find that simultaneous inhibition of p21 and telomerase synergistically suppresses tumor growth. We also show (pp. E3062–E3071) that our approach is useful for treating p53 mutant cancers, when used with therapies that restore the function of mutant p53. We anticipate that simultaneous targeting of p21 and telomerase will overcome the current limitation of single-agent telomerase therapeutics and provide an effective method to treat cancers that rely on telomerase activity for survival.
Immunosignature system for diagnosis of cancer
Phillip Stafford, Zbigniew Cichacz, Neal W. Woodbury, and Stephen Albert Johnston
Over much of the world, healthcare systems are facing an unprecedented challenge to meet the medical needs of an aging population while controlling costs. The early detection and treatment of diseases that are prevalent in older people is likely to be a key aspect of economically efficient, high-quality healthcare. In the case of cancer, the resection of a stage I or stage II tumor is often effectively a cure. An ideal diagnostic would allow early detection of disease on a single platform that could be used for any disease. Here (pp. E3072–E3080), we demonstrate that the immunosignature diagnosis platform could potentially meet the universal platform requirement. Ongoing work will address the early detection requirement separately.
Transcriptomics identified a critical role for Th2 cell-intrinsic miR-155 in mediating allergy and antihelminth immunity
Isobel S. Okoye, Stephanie Czieso, Eleni Ktistaki, Kathleen Roderick, Stephanie M. Coomes, Victoria S. Pelly, Yashaswini Kannan, Jimena Perez-Lloret, Jimmy L. Zhao, David Baltimore, Jean Langhorne, and Mark S. Wilson
The rising prevalence of allergic diseases throughout the world demands new approaches to treat this inflammatory disorder. CD4+ Th2 cells orchestrate the allergic cascade, stimulating IgE production, activating innate cells, and stimulating local tissue. This study (pp. E3081–E3090) took a comprehensive approach to identify the unique transcriptional features of pathogenic Th2 cells with the aim of identifying novel molecular regulators. Highly purified Th1, Th2, Th9, Th17, and Treg cells isolated from mice with allergy, infection, and autoimmunity identified unique mRNA and microRNAs (miRNAs) expressed in Th2 cells. Functional and mechanistic studies using miRNA-deficient mice, luciferase assays, miRNA inhibitors, and siRNA in combination with state-of-the-art adoptive transfer systems, identified a critical role for miR-155–regulated S1pr1 in the pathogenesis of Th2-mediated allergy.
Stromal response to Hedgehog signaling restrains pancreatic cancer progression
John J. Lee, Rushika M. Perera, Huaijun Wang, Dai-Chen Wu, X. Shawn Liu, Shiwei Han, Julien Fitamant, Phillip D. Jones, Krishna S. Ghanta, Sally Kawano, Julia M. Nagle, Vikram Deshpande, Yves Boucher, Tomoyo Kato, James K. Chen, Jürgen K. Willmann, Nabeel Bardeesy, and Philip A. Beachy
Preclinical studies have suggested that Hedgehog (Hh) pathway inhibition reduces growth and metastasis of pancreatic ductal adenocarcinoma (PDA), but ensuing clinical trials of Hh pathway antagonists combined with cytotoxic chemotherapy have not succeeded. Here, we find in three distinct genetically engineered mouse models that genetic and pharmacologic inhibition of Hh pathway activity actually accelerates PDA progression. Furthermore, we find that the acute modulation of pathway activity regulates the balance between epithelial and stromal elements, with inhibition causing suppression of desmoplasia and accelerated growth of epithelial elements and activation causing stromal hyperplasia and reduced growth of the neoplastic epithelium. Our study (pp. E3091–E3100) explains previous clinical trial results and suggests the possibility of novel types of therapeutic interventions.
Functional genomics of Lactobacillus casei establishment in the gut
Hélène Licandro-Seraut, Hélène Scornec, Thierry Pédron, Jean-François Cavin, and Philippe J. Sansonetti
Lactobacillus casei, a food bacterium recognized for its beneficial effects, was selected as a model microorganism to proceed to genomewide identification of the functions required for a symbiont to establish colonization in the gut. We recently have developed a mutagenesis tool that overcomes the barrier that prevented L. casei random mutagenesis (pp. E3101–E3109). After identifying 9,250 mutations, we assembled a library of 1,110 mutants disrupted in different genes and tested them for their ability to colonize an in vivo model, the rabbit ligated ileal loop. With this global functional genomic analysis of L. casei symbiosis (the first, to our knowledge), we identified a core of 47 L. casei genes necessary for its establishment in the gut.
Neurons in the human amygdala selective for perceived emotion
Shuo Wang, Oana Tudusciuc, Adam N. Mamelak, Ian B. Ross, Ralph Adolphs, and Ueli Rutishauser
Primates have a dedicated system to process faces. Neuroimaging, lesion, and electrophysiological studies find that the amygdala processes facial emotions. Here we recorded 210 neurons from 7 neurosurgical patients and asked whether amygdala responses are driven primarily by properties of the stimulus or by the perceptual judgments of the perceiver. Our finding shows (pp. E3110–E3119), for the first time to our knowledge, that neurons in the human amygdala encode the subjective judgment of emotions shown in face stimuli, rather than simply their stimulus features.
Acuity-independent effects of visual deprivation on human visual cortex
Chuan Hou, Mark W. Pettet, and Anthony M. Norcia
Deviation of the direction of two eyes (strabismus) or chronic optical blur (anisometropia) separately and together can disrupt the development of visual cortex. To shed new light on how these two forms of visual deprivation affect cortical development, we used event-related potentials coupled with a stimulation paradigm to study the temporal evolution of visual responses in patients who had experienced either strabismus or anisometropia early in life. Our results (pp. E3120–E3128) indicate that strabismus generates significant abnormalities at both early and later stages of cortical processing and, importantly, that these abnormalities are independent of visual-acuity deficits. The nonamblyopic eyes of anisometropic amblyopes, by contrast, are normal, suggesting that these two forms of visual deprivation are differentiated very early in visual cortex.
A dual role for planar cell polarity genes in ciliated cells
Camille Boutin, Paul Labedan, Jordane Dimidschstein, Fabrice Richard, Harold Cremer, Philipp André, Yingzi Yang, Mireille Montcouquiol, Andre M. Goffinet, and Fadel Tissir
Ependymal cilia are required for circulation of the cerebrospinal fluid and neurogenesis. To function properly, ependymal cilia must coordinate their beats in individual cells and across the tissue. Planar cell polarity (PCP) orients cilia in a given cell, thereby enabling their concerted beating. Here (pp. E3129–E3138), we describe previously unidentified functions for PCP in cilia organization at the cell and tissue levels. We show that PCP is important for the correct positioning of the primary cilium in radial progenitors and motile cilia in ependymal cells and provide evidence that cilia positioning is important for function. We also describe cytoskeletal changes during ependymal differentiation and shed light on mechanisms by which polarity is acquired by radial progenitors and passed on to ependymal cells.
Impaired excitability of somatostatin- and parvalbumin-expressing cortical interneurons in a mouse model of Dravet syndrome
Chao Tai, Yasuyuki Abe, Ruth E. Westenbroek, Todd Scheuer, and William A. Catterall
Dravet syndrome (DS) is an intractable childhood epilepsy syndrome accompanied by mental disability, behaviors similar to autism, and premature death. DS is caused by dominant loss-of-function mutations in the gene encoding the NaV1.1 sodium channel, SCN1A, which initiates electrical signals in the nerve cells of the brain. The physiological basis for this disease is largely unknown. Here we describe the functional effects of DS mutations on inhibitory neurons in the cerebral cortex in mice. Our results show (pp. E3139–E3148) that two major types of inhibitory neurons are impaired in generation of electrical signals by a DS mutation, whereas excitatory neurons are unaffected. The resulting imbalance of excitatory over inhibitory electrical signaling would contribute in an important way to the symptoms of DS.
Decreased dopamine brain reactivity in marijuana abusers is associated with negative emotionality and addiction severity
Nora D. Volkow, Gene-Jack Wang, Frank Telang, Joanna S. Fowler, David Alexoff, Jean Logan, Millard Jayne, Christopher Wong, and Dardo Tomasi
Marijuana abusers show lower positive and higher negative emotionality scores than controls, which is consistent, on one hand, with lower reward sensitivity and motivation and, on the other hand, with increased stress reactivity and irritability. To investigate this aspect of marijuana’s impact on the human brain, we compared the brain’s reactivity in marijuana abusers vs. controls when challenged with methylphenidate (MP). We found that marijuana abusers display attenuated dopamine (DA) responses to MP, including reduced decreases in striatal distribution volumes (pp. E3149–E3156). These deficits cannot be unambiguously ascribed to reduced DA release (because decreases in nondisplaceable binding potential were not blunted) but could reflect a downstream postsynaptic effect that in the ventral striatum (brain reward region) might contribute to marijuana’s negative emotionality and addictive behaviors.
Proteome-wide remodeling of protein location and function by stress
KiYoung Lee, Min-Kyung Sung, Jihyun Kim, Kyung Kim, Junghyun Byun, Hyojung Paik, Bongkeun Kim, Won-Ki Huh, and Trey Ideker
Protein location and function are dependent on diverse cell states. We develop a conditional function predictor (CoFP) for proteome-wide prediction of condition-specific locations and functions of proteins (pp. E3157–E3166). In addition to highly accurate retrieval of condition-dependent locations and functions in individual conditions, CoFP successfully discovers dynamic function changes of yeast proteins, including Tsr1, Caf120, Dip5, Skg6, Lte1, and Nnf2, under DNA-damaging stresses. Beyond specific predictions, CoFP reveals a global landscape of changes in protein location and function, highlighting a surprising number of proteins that translocate from the mitochondria to the nucleus or from endoplasmic reticulum to Golgi apparatus under stress. CoFP has the potential to discover previously unidentified condition-specific locations and functions under diverse conditions of cellular growth.