Reporter nanoparticle that monitors its anticancer efficacy in real time
Ashish Kulkarni, Poornima Rao, Siva Natarajan, Aaron Goldman, Venkata S. Sabbisetti, Yashika Khater, Navya Korimerla, Vineethkrishna Chandrasekar, Raghunath A. Mashelkar, and Shiladitya Sengupta
The ability to identify responders and nonresponders very early during chemotherapy by direct visualization of the activity of the anticancer treatment and to switch, if necessary, to a regimen that is effective can have a significant effect on the outcome as well as quality of life. Current approaches to quantify response rely on imaging techniques that fail to detect very early responses. In the case of immunotherapy, the early anatomical readout is often discordant with the biological response. This study describes a self-reporting nanomedicine that not only delivers chemotherapy or immunotherapy to the tumor but also reports back on its efficacy in real time, thereby identifying responders and nonresponders early on. (See pp. E2104–E2113.)
Radical remodeling of the Y chromosome in a recent radiation of malaria mosquitoes
Andrew Brantley Hall, Philippos-Aris Papathanos, Atashi Sharma, Changde Cheng, Omar S. Akbari, Lauren Assour, Nicholas H. Bergman, Alessia Cagnetti, Andrea Crisanti, Tania Dottorini, Elisa Fiorentini, Roberto Galizi, Jonathan Hnath, Xiaofang Jiang, Sergey Koren, Tony Nolan, Diane Radune, Maria V. Sharakhova, Aaron Steele, Vladimir A. Timoshevskiy, Nikolai Windbichler, Simo Zhang, Matthew W. Hahn, Adam M. Phillippy, Scott J. Emrich, Igor V. Sharakhov, Zhijian Jake Tu, and Nora J. Besansky
Interest in male mosquitoes has been motivated by the potential to develop novel vector control strategies, exploiting the fact that males do not feed on blood or transmit diseases, such as malaria. However, genetic studies of male Anopheles mosquitoes have been impeded by the lack of molecular characterization of the Y chromosome. Here we show that the Anopheles gambiae Y chromosome contains a very small repertoire of genes, with massively amplified tandem arrays of a small number of satellites and transposable elements constituting the vast majority of the sequence. These genes and repeats evolve rapidly, bringing about remodeling of the Y, even among closely related species. Our study provides a long-awaited foundation for studying mosquito Y chromosome biology and evolution. (See pp. E2114–E2123.)
Genome-wide kinetics of DNA excision repair in relation to chromatin state and mutagenesis
Sheera Adar, Jinchuan Hu, Jason D. Lieb, and Aziz Sancar
Nucleotide excision repair is the sole mechanism for removing bulky adducts from the human genome, including those formed by UV radiation and chemotherapeutic drugs. We used eXcision Repair-sequencing, a genomic assay for measuring DNA repair, to map the kinetics of repair after UV treatment. These genome-wide repair maps, in turn, allowed us to infer how excision repair is influenced by DNA packaging. Active and open chromatin regions were repaired more rapidly than other genomic regions. Repair in repressed and heterochromatic regions is slower and persists for up to 2 d. Furthermore, late-repaired regions are associated with a higher level of cancer-linked somatic mutations, highlighting the importance of efficient DNA repair and linking chromatin organization to cancer mutagenesis. (See pp. E2124–E2133.)
Modeling and analysis of collective cell migration in an in vivo three-dimensional environment
Danfeng Cai, Wei Dai, Mohit Prasad, Junjie Luo, Nir S. Gov, and Denise J. Montell
Many cells travel within an organism to perform important duties in development, homeostasis, and disease. Questions remain as to why cells migrate in diverse forms: some travel as single cells, whereas others move collectively in groups of different sizes. What is also unclear is how extracellular conditions influence migration. In our study, which combines live imaging with theoretical modeling, we address these questions and reveal how both physical and chemical features of the microenvironment influence the optimum size of a migrating cell group. (See pp. E2134–E2141.)
Defects in lysosomal maturation facilitate the activation of innate sensors in systemic lupus erythematosus
Andrew J. Monteith, SunAh Kang, Eric Scott, Kai Hillman, Zenon Rajfur, Ken Jacobson, M. Joseph Costello, and Barbara J. Vilen
Activation of innate sensors by self-antigen contributes to autoimmunity, although how intracellular sensors are chronically exposed to self-antigen has remained unknown. Here, we identify a previously unidentified defect in which lupus-prone macrophages fail to mature the lysosome, promoting the accumulation of apoptotic debris-containing IgG–immune complexes (IgG-ICs). Interestingly, macrophages from other autoimmune diseases accumulate IgG-ICs, indicating that lysosomal defects may underlie multiple autoimmune diseases. Furthermore, the prolonged intracellular residency chronically activates Toll-like receptors and permeabilizes the phagolysosomal membrane, allowing activation of cytosolic sensors. These findings identify lysosomal maturation as a unique defect in MRL/lpr mice that impacts multiple events known to underlie SLE, including pathogenic cytokine secretion. (See pp. E2142–E2151.)
Anabolic actions of Notch on mature bone
Peng Liu, Yilin Ping, Meng Ma, Demao Zhang, Connie Liu, Samir Zaidi, Song Gao, Yaoting Ji, Feng Lou, Fanyuan Yu, Ping Lu, Agnes Stachnik, Mingru Bai, Chengguo Wei, Liaoran Zhang, Ke Wang, Rong Chen, Maria I. New, David W. Rowe, Tony Yuen, Li Sun, and Mone Zaidi
Notch is a critical regulator of skeletal development, but its role in remodeling of the adult skeleton is unclear. Using genetically modified mice, we show that Notch stimulates skeletal mineralization by bone-building osteoblasts. Thus, overexpression of the Notch intracellular domain in mice results in an increase in bone mass, prevents bone loss following ovariectomy and during aging, and promotes fracture healing. Notch is therefore a potential therapeutic target for conditions of bone loss, including osteoporosis. (See pp. E2152–E2161.)
Myofibroblasts are distinguished from activated skin fibroblasts by the expression of AOC3 and other associated markers
Lin-ting Hsia, Neil Ashley, Djamila Ouaret, Lai Mun Wang, Jennifer Wilding, and Walter F. Bodmer
Myofibroblasts surround the epithelial cells of the crypts that form the surface of the gut. They play an important role in controlling the normal epithelium and influence the development of colorectal and other epithelial cancers. The definition of myofibroblasts previously depended almost entirely on the expression of smooth muscle actin. We identified the surface enzyme AOC3 (amine oxidase, copper containing 3) as a new marker of myofibroblasts and as a result have discovered additional highly distinctive markers for myofibroblasts, including the transcription factor NKX2-3. The discovery of these new markers should greatly enhance the proper definition of myofibroblasts and related cell types and thus should contribute to the improved treatment of the many diseases, including cancer, that involve these cell types. (See pp. E2162–E2171.)
Output-driven feedback system control platform optimizes combinatorial therapy of tuberculosis using a macrophage cell culture model
Aleidy Silva, Bai-Yu Lee, Daniel L. Clemens, Theodore Kee, Xianting Ding, Chih-Ming Ho, and Marcus A. Horwitz
Improved regimens for treatment of tuberculosis are needed to shorten the duration of treatment and combat the emergence of drug resistance. Selection of optimized regimens requires assessment of numerous combinations of existing drugs at multiple dose levels. This requirement presents a challenge because of the exponentially large number of combinations—NM for N doses of M drugs. We show here using a high-throughput macrophage model of Mycobacterium tuberculosis infection that a feedback system control technique can determine optimal drug treatment regimens by testing a relatively small number of drug–dose combinations. In an independent assay measuring intramacrophage killing of M. tuberculosis, the optimized regimens are superior to the current standard regimen. (See pp. E2172–E2179.)
Representation of spontaneous movement by dopaminergic neurons is cell-type selective and disrupted in parkinsonism
Paul D. Dodson, Jakob K. Dreyer, Katie A. Jennings, Emilie C. J. Syed, Richard Wade-Martins, Stephanie J. Cragg, J. Paul Bolam, and Peter J. Magill
Deciphering the roles of midbrain dopaminergic neurons in the control of movement is critical not only for understanding of normal motor function but also for defining the basis of motor dysfunction in Parkinson’s disease. However the activity of these neurons generally has been considered to be unrelated to movement. Here we demonstrate that dopaminergic neurons signal the onset of spontaneous movement in a cell-type–selective manner and that these signals can be read out in transmitter and receptor activity dynamics in the striatum, one of their principal targets. Importantly, these movement-related signals were lost in a mouse model of Parkinson’s disease. Together, these data suggest that movement-related firing of dopaminergic neurons is important for precise motor control. (See pp. E2180–E2188.)
Paclitaxel-induced epithelial damage and ectopic MMP-13 expression promotes neurotoxicity in zebrafish
Thomas S. Lisse, Leah J. Middleton, Adriana D. Pellegrini, Paige B. Martin, Emily L. Spaulding, Olivia Lopes, Elizabeth A. Brochu, Erin V. Carter, Ashley Waldron, and Sandra Rieger
Paclitaxel is a widely used chemotherapeutic agent in the treatment of cancer. Although paclitaxel arrests tumor growth through stabilizing microtubules, it also causes variable peripheral neuropathy in patients. A lack of understanding of the underlying mechanisms hinders therapeutic discovery, and commonly used mammalian models have not provided conclusive evidence about the etiology of this condition. To overcome this, we developed a larval zebrafish model that permits the analysis of paclitaxel neurotoxicity in living animals. This study identifies that keratinocyte damage and ectopic expression of matrix-metalloproteinase 13 (MMP-13) contributes to paclitaxel-induced peripheral neuropathy in zebrafish. We further show that inhibition of MMP-13 improves skin defects and prevents paclitaxel neurotoxicity. Thus, this study offers a previously unidentified avenue for potential therapeutic interventions. (See pp. E2189–E2198.)
DELAY OF GERMINATION1 (DOG1) regulates both seed dormancy and flowering time through microRNA pathways
Heqiang Huo, Shouhui Wei, and Kent J. Bradford
Annual plants adapt to their environments by matching their life cycles, particularly seed germination and flowering, to the appropriate seasons. Although genetic evidence has suggested connections among genes regulating seed dormancy and flowering, specific mechanisms for such coordination are unknown. We report that a gene [DELAY OF GERMINATION1 (DOG1)] involved in determining the depth of seed dormancy, and therefore the seasonal timing of germination, also influences the timing of flowering in Arabidopsis and lettuce. We further show that this gene acts through influencing the production of microRNAs that govern the progression of developmental phase transitions through the plant life cycle, providing a molecular genetic mechanism for the coordinate adaptation of seed dormancy and flowering phenotypes to environmental conditions. (See pp. E2199–E2206.)