Soluble guanylate cyclase as an alternative target for bronchodilator therapy in asthma
Arnab Ghosh, Cynthia J. Koziol-White, Kewal Asosingh, Georgina Cheng, Lisa Ruple, Dieter Groneberg, Andreas Friebe, Suzy A. A. Comhair, Johannes-Peter Stasch, Reynold A. Panettieri Jr., Mark A. Aronica, Serpil C. Erzurum, and Dennis J. Stuehr
Asthmatics depend on β-agonist bronchodilator drugs, but a majority develop resistance to these drugs in their lifetime, and new ways to bronchodilate are needed. We show that brochodilation can be triggered in normal human and asthmatic mouse airways through an alternative signaling pathway, using new pharmacologic agents that directly activate the soluble guanylate cyclase (sGC) enzyme. Because an sGC-based drug was recently approved to treat pulmonary arterial hypertension, our findings imply that such drugs could become new bronchodilators in asthma. Our work also provides insight on how the sGC signaling enzyme becomes desensitized toward NO in inflammatory asthma, and thus helps to explain why NO is an ineffective bronchodilator in this disease. (See pp. E2355–E2362.)
Function and regulation of TRPP2 ion channel revealed by a gain-of-function mutant
Mahmud Arif Pavel, Caixia Lv, Courtney Ng, Lei Yang, Parul Kashyap, Clarissa Lam, Victoria Valentino, Helen Y. Fung, Thomas Campbell, Simon Geir Møller, David Zenisek, Nathalia G. Holtzman, and Yong Yu
Mutations in transient receptor potential polycystin 2 (TRPP2) and polycystin-1 account for autosomal dominant polycystic kidney disease (ADPKD). TRPP2 is a cation channel and plays a crucial role in coupling extracellular stimuli to cellular responses in cells. The activation mechanism of TRPP2 is unknown, which significantly limits its study. Here, we report a gain-of-function (GOF) mutation that causes constitutive activity of TRPP2. This mutant was applied to investigation of the TRPP2 channel properties, the functional effects of ADPKD pathogenic TRPP2 mutations, and the in vivo function of the GOF TRPP2 in zebrafish embryos. From our results, we conclude that the GOF TRPP2 is a powerful tool for TRPP2 study, and has potential therapeutic applications in ADPKD treatment. (See pp. E2363–E2372.)
The tandem duplicator phenotype as a distinct genomic configuration in cancer
Francesca Menghi, Koichiro Inaki, XingYi Woo, Pooja A. Kumar, Krzysztof R. Grzeda, Ankit Malhotra, Vinod Yadav, Hyunsoo Kim, Eladio J. Marquez, Duygu Ucar, Phung T. Shreckengast, Joel P. Wagner, George MacIntyre, Krishna R. Murthy Karuturi, Ralph Scully, James Keck, Jeffrey H. Chuang, and Edison T. Liu
In this study, we provide the first detailed molecular characterization, to our knowledge, of a distinct cancer genomic configuration, the tandem duplicator phenotype (TDP), that is significantly enriched in the molecularly related triple-negative breast, serous ovarian, and endometrial carcinomas. We show here that TDP represents an oncogenic configuration featuring (i) genome-wide disruption of cancer genes, (ii) loss of cell cycle control and DNA damage repair, and (iii) increased sensitivity to cisplatin chemotherapy both in vitro and in vivo. Therefore, the TDP is a systems strategy to achieve a protumorigenic genomic configuration by altering a large number of oncogenes and tumor suppressors. The TDP arises in a molecular context of joint genomic instability and replicative drive, and is consequently associated with enhanced sensitivity to cisplatin. (See pp. E2373–E2382.)
Induction of autoimmune disease by deletion of CTLA-4 in mice in adulthood
Katrin Klocke, Shimon Sakaguchi, Rikard Holmdahl, and Kajsa Wing
Cytotoxic T lymphocyte antigen-4 (CTLA-4), up-regulated by activated conventional T cells and constitutively expressed by Foxp3+ regulatory T cells, is essential for immunological self-tolerance. Because of early fatality in germ-line CTLA-4–deficient mice, the role in adulthood remains unclear. We abrogated CTLA-4 expression in adult mice and compared their phenotype with congenitally CTLA-4–deleted mice. We found that the two modes of CTLA-4 deficiency differed in resulting autoimmune disease phenotype and severity. Additionally, although CTLA-4–deficient mice had more severe collagen-induced arthritis, they were protected against peptide-induced experimental autoimmune encephalomyelitis (EAE). However, onset of protein-induced EAE was only delayed. These results taken together indicate that CTLA-4 deficiency affects both central and peripheral tolerance and Treg cell-mediated suppression. (See pp. E2383–E2392.)
Immuno-Navigator, a batch-corrected coexpression database, reveals cell type-specific gene networks in the immune system
Alexis Vandenbon, Viet H. Dinh, Norihisa Mikami, Yohko Kitagawa, Shunsuke Teraguchi, Naganari Ohkura, and Shimon Sakaguchi
Correlation of expression between genes can offer useful hints regarding their function or underlying regulatory mechanism. Today, large amounts of expression data are publicly available, allowing researchers to estimate expression correlation over thousands of samples. However, extracting information from correlation data is not straightforward, because underlying expression data are generated by different laboratories working on different cell types and under different conditions. Here we present Immuno-Navigator, a database for correlation of expression in cells of the immune system, which addresses these issues. We present examples of ways our database can be used for generating hypotheses for further experimental analysis. We demonstrate how it recapitulates known facts in immunology and successfully predicts key regulators in naturally occurring regulatory T cells. (See pp. E2393–E2402.)
In vitro system using human neurons demonstrates that varicella-zoster vaccine virus is impaired for reactivation, but not latency
Tomohiko Sadaoka, Daniel P. Depledge, Labchan Rajbhandari, Arun Venkatesan, Judith Breuer, and Jeffrey I. Cohen
The varicella vaccine is highly effective in preventing chickenpox. Although the vaccine virus is attenuated, it is unknown whether the virus is impaired for establishment of latency, for reactivation, or both. We developed an in vitro system using human neurons derived from ES cells and showed that axonal infection of neurons results in latent infection and that virus can be reactivated using Ab to NGF. Using this system, we show that the varicella vaccine is impaired for reactivation, but not latency. Although not necessarily equivalent to varicella-zoster virus (VZV) latency and reactivation in vivo, this system may be used to study the ability of other viruses, including viral vaccines, to establish latency and reactivate. (See pp. E2403–E2412.)
Covert neurofeedback without awareness shapes cortical network spontaneous connectivity
Michal Ramot, Shany Grossman, Doron Friedman, and Rafael Malach
Real-time functional MRI allows the use of well-localized, complex network activity patterns to drive neurofeedback, rather than a simple up/down regulation of a specific cortical region. We based our feedback on differential levels of activity in two high-order visual areas but misled participants to believe the feedback was random. Even without being given an explicit strategy, or having any awareness or intention of learning, our results show changes in resting-state connectivity, which are correlated with the ability to implicitly modulate interactions between neural networks to positively impact feedback. This opens up numerous possibilities for research, as well as for potential clinical intervention, even in states of altered consciousness. (See pp. E2413–E2420.)
Intrathecal gene therapy rescues a model of demyelinating peripheral neuropathy
Alexia Kagiava, Irene Sargiannidou, George Theophilidis, Christos Karaiskos, Jan Richter, Stavros Bashiardes, Natasa Schiza, Marianna Nearchou, Christina Christodoulou, Steven S. Scherer, and Kleopas A. Kleopa
Inherited demyelinating peripheral neuropathies are progressive incurable diseases caused by mutations in a variety of genes expressed by myelinating Schwann cells. A major challenge in developing effective gene therapy is to gain access to multiple nerves for cell-specific expression. Our study demonstrates for the first time, to our knowledge, that intrathecal injection of a lentiviral vector with a myelin-specific promoter can achieve targeted expression in adult myelinating Schwann cells in a widespread distribution throughout the peripheral nervous system. Furthermore, this translatable approach restored the expression of a neuropathy-associated gene and led to a phenotypic, functional, and pathological rescue of a neuropathy model. These results have important implications for further preclinical and clinical testing in this and other types of inherited demyelinating neuropathies. (See pp. E2421–E2429.)
Dominant hemisphere lateralization of cortical parasympathetic control as revealed by frontotemporal dementia
Christine C. Guo (郭聪), Virginia E. Sturm, Juan Zhou, Efstathios D. Gennatas, Andrew J. Trujillo, Alice Y. Hua, Richard Crawford, Lara Stables, Joel H. Kramer, Katherine Rankin, Robert W. Levenson, Howard J. Rosen, Bruce L. Miller, and William W. Seeley
Brain–body interactions are fundamental to physical and mental health. Here, we used a unique brain lesion model to elucidate the neural localization and lateralization of cerebro-cardiac control. Our data revealed that the salience network, an intrinsic connectivity network anchored by the anterior insula and cingulate, is crucial for maintaining basal parasympathetic outflow. Specifically, dominant hemisphere-predominant salience network damage undermined parasympathetic control of the heart. The findings suggest that balanced functional integrity of both hemispheres is vital to maintaining bodily homeostasis. (See pp. E2430–E2439.)
A descending dopamine pathway conserved from basal vertebrates to mammals
Dimitri Ryczko, Jackson J. Cone, Michael H. Alpert, Laurent Goetz, François Auclair, Catherine Dubé, Martin Parent, Mitchell F. Roitman, Simon Alford, and Réjean Dubuc
In vertebrates, the contribution of dopamine neurons to locomotor control is traditionally attributed to their ascending projections to the basal ganglia that, in turn, project down to brainstem locomotor networks. We recently discovered in lampreys that brainstem networks receive a direct descending dopaminergic input that increases locomotor output. Here, we show that this descending dopaminergic pathway is conserved in higher vertebrates. We found that dopamine is released in salamander brainstem locomotor networks, together with reticulospinal cell activation, known to trigger locomotion. Dopamine is released in rat brainstem locomotor networks, and amphetamine potentiates dopamine release in vivo. Finally, brainstem locomotor networks in human tissue contain dopaminergic terminals. Our findings have important implications for understanding the locomotor role of dopamine in vertebrates. (See pp. E2440–E2449.)
Stimulus features coded by single neurons of a macaque body category selective patch
Ivo D. Popivanov, Philippe G. Schyns, and Rufin Vogels
A fundamental and understudied question is that of the higher-level features that actually drive neuronal responses to complex images. Although previous single-unit studies developed our knowledge of the features driving face-selective regions, little is known about the feature selectivity of neurons in body-selective regions. Using a reverse correlation technique, we reveal for the first time to our knowledge the image fragments coded by single neurons of a body-selective region defined by functional imaging. We found that the neurons respond to local fragments, such as extremities (e.g. leg fragments) and curved boundaries (e.g. shoulder), tolerating position and scale changes, with evidence of opponent body coding in a few neurons. Thus, our data offer new insights on how the brain codes higher-level features. (See pp. E2450–E2459.)
In cellulo phosphorylation induces pharmacological reprogramming of maurocalcin, a cell-penetrating venom peptide
Michel Ronjat, Wei Feng, Lucie Dardevet, Yao Dong, Sawsan Al Khoury, Franck C. Chatelain, Virginie Vialla, Samir Chahboun, Florian Lesage, Hervé Darbon, Isaac N. Pessah, and Michel De Waard
Animal toxin peptides typically exhibit high affinity and selectivity for specific subclasses of cell receptors that account for their activity. Posttranslational modifications of toxin sequences may occur in the venom gland machinery, but there is no example so far of toxins being subjected to such modifications ex situ after delivery to target cells. Here, we provide evidence that the cell permeant maurocalcin (MCa), found in scorpion venom, undergoes PKA-mediated phosphorylation in cellulo, and that posttranslational modification leads to its complete pharmacological reprogramming activity toward ryanodine receptor type 1 (RyR1), a key player in Ca2+ homeostasis in excitable cells. Phosphorylation converts MCa from a potent stabilizer of RyR1 channel substates to a negative allosteric modulator that mitigates RyR1 channel Ca2+ leak. (See pp. E2460–E2468.)