Upper atmospheric gravity wave details revealed in nightglow satellite imagery
Steven D. Miller, William C. Straka III, Jia Yue, Steven M. Smith, M. Joan Alexander, Lars Hoffmann, Martin Setvák, and Philip T. Partain
As an unforeseen windfall of its high sensitivity, the Day/Night Band (DNB) low-light visible sensor carried on the Suomi satellite enables global detection of gravity waves in the upper atmosphere at unprecedented subkilometric detail. On moonless nights, the observations provide all-weather viewing of waves as they modulate the nightglow layer located near the mesopause. These waves are launched by a variety of mechanisms ranging from orography to convection, intensifying fronts, and seismic and volcanic events. Wave energy is recognized as the principal driver of upper atmospheric circulation, which in turn influences tropospheric weather patterns. For lack of global observations, information about upper atmospheric wave distribution and character is limited. Here, the DNB begins to fill a critical gap. (See pp. E6728–E6735.)
Highly efficient Cas9-mediated gene drive for population modification of the malaria vector mosquito Anopheles stephensi
Valentino M. Gantz, Nijole Jasinskiene, Olga Tatarenkova, Aniko Fazekas, Vanessa M. Macias, Ethan Bier, and Anthony A. James
Malaria continues to impose enormous health and economic burdens on the developing world. Novel technologies proposed to reduce the impact of the disease include the introgression of parasite-resistance genes into mosquito populations, thereby modifying the ability of the vector to transmit the pathogens. Such genes have been developed for the human malaria parasite Plasmodium falciparum. Here we provide evidence for a highly efficient gene-drive system that can spread these antimalarial genes into a target vector population. This system exploits the nuclease activity and target-site specificity of the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) system, which, when restricted to the germ line, copies a genetic element from one chromosome to its homolog with ≥98% efficiency while maintaining the transcriptional activity of the genes being introgressed. (See pp. E6736–E6743.)
MicroRNA-3151 inactivates TP53 in BRAF-mutated human malignancies
Malori A. Lankenau, Ravi Patel, Sandya Liyanarachchi, Sophia E. Maharry, Kevin W. Hoag, Megan Duggan, Christopher J. Walker, Joseph Markowitz, William E. Carson III, Ann-Kathrin Eisfeld, and Albert de la Chapelle
Activating mutations in the B-Raf proto-oncogene serine/threonine kinase (BRAF) gene occur in many tumor types, the highest incidence being in malignant melanoma and papillary thyroid carcinoma. In patients with BRAF mutations tumor progression is more rapid than in patients without these mutations. Therapeutic strategies presently aim at inhibiting BRAF resulting in slower tumor progression; however, lasting remission is rarely accomplished. In this paper we identify the oncomiR-3151 as a downstream effector of mutated BRAF. MicroRNA-3151 (miR-3151) targets TP53 and other members of the TP53 pathway resulting in its inhibition. Simultaneous inhibition of BRAF and miR-3151 potentiates the effects on tumor cell growth. These data establish a link between mutated BRAF and the TP53 pathway, allowing novel therapeutic approaches to be considered. (See pp. E6744–E6751.)
ER trapping reveals Golgi enzymes continually revisit the ER through a recycling pathway that controls Golgi organization
Prabuddha Sengupta, Prasanna Satpute-Krishnan, Arnold Y. Seo, Dylan T. Burnette, George H. Patterson, and Jennifer Lippincott-Schwartz
Using a rapamycin-based, endoplasmic reticulum (ER) trapping scheme, modified to avoid the problem of an endogenous ER-localized FKBP-binding protein, we demonstrate that Golgi enzymes constitutively recycle back to the ER and that such recycling plays a central role in the maintenance, biogenesis, and inheritance of the Golgi apparatus in mammalian cells. We describe morphological characteristics of the retrograde carriers that ferry Golgi enzymes back to the ER and identify key molecular machinery regulating carrier formation. The study helps resolve the long-standing debate regarding the extent of Golgi enzyme trafficking back to the ER, paving the way for further investigations into the mechanistic details and functional implications of the Golgi's steady-state existence and relationship to the ER. (See pp. E6752–E6761.)
Evolution in leaps: The punctuated accumulation and loss of cultural innovations
Oren Kolodny, Nicole Creanza, and Marcus W. Feldman
The archaeological record suggests that cultural traits, as manifested in the tool repertoire, can accumulate exponentially, that technology can appear in bursts after long periods of stasis, and that dramatic cultural losses can occur. We introduce a model that accounts for this range of observations by considering a multifaceted creative process of innovation, accounting for the possibility that certain traits facilitate the invention of related traits. Further, we determine that differential distribution of tool-related knowledge, typically ignored in models, can dramatically affect the dynamics of cultural evolution, suggesting the concept of an effective cultural population size. Finally, we demonstrate that a fluctuating environment can lead to large-scale cultural losses and select for generalist tools that are useful in multiple conditions. (See pp. E6762–E6769.)
Topographical mapping of α- and β-keratins on developing chicken skin integuments: Functional interaction and evolutionary perspectives
Ping Wu, Chen Siang Ng, Jie Yan, Yung-Chih Lai, Chih-Kuan Chen, Yu-Ting Lai, Siao-Man Wu, Jiun-Jie Chen, Weiqi Luo, Randall B. Widelitz, Wen-Hsiung Li, and Cheng-Ming Chuong
Avian skin appendages include feathers, scales, claws, and beaks. They are mainly composed of α-keratins, found in all vertebrates, and β-keratins, found only in birds and reptiles. Scientists have wondered how keratins are interwoven to form different skin appendages. By studying keratin gene expression patterns in different chicken skin appendages, we found α- and β-keratin interactions crucial for appendage morphogenesis. Mutations in either α- or β-keratins can disrupt keratin expression and cause structural defects. Thus, different combinations of α- and β-keratins contribute to the structural diversity of feathers. The expansion of β-keratin genes during bird evolution might have greatly increased skin appendage diversity because it increased the possible interactions between α- and β-keratins. (See pp. E6770–E6779.)
Glucocorticoids enhance muscle endurance and ameliorate Duchenne muscular dystrophy through a defined metabolic program
Alexander Morrison-Nozik, Priti Anand, Han Zhu, Qiming Duan, Mohamad Sabeh, Domenick A. Prosdocimo, Madeleine E. Lemieux, Nikolai Nordsborg, Aaron P. Russell, Calum A. MacRae, Anthony N. Gerber, Mukesh K. Jain, and Saptarsi M. Haldar
Classic physiological studies have documented the endurance-promoting effects of glucocorticoid (GC) hormones on skeletal muscle. Pharmacologic GC therapy also improves muscle function in patients with Duchenne muscular dystrophy (DMD), a genetic muscle-wasting disease. Despite these well-established physiological and clinical observations, the molecular basis underlying the beneficial effects of GCs in skeletal muscle remains obscure. This study shows that physiological effects of GCs on muscle endurance and their therapeutic effect in DMD are mediated, in part, via activation of a potent metabolic gene called Kruppel-like factor 15 (KLF15). Importantly, KLF15 does not drive GC-mediated muscle wasting. These data shed light on the poorly understood ergogenic properties of GCs, findings that may inform steroid-sparing therapies for DMD and other muscle diseases. (See pp. E6780–E6789.)
Inhibition of host cell translation elongation by Legionella pneumophila blocks the host cell unfolded protein response
Andrew D. Hempstead and Ralph R. Isberg
The unfolded protein response (UPR) is a cellular mechanism for coping with misfolded proteins in the lumen of the endoplasmic reticulum (ER). UPR pathways are also induced in response to viral and bacterial pathogens, resulting in enhanced proinflammatory cytokine induction. Here we provide mechanistic evidence for how an intracellular pathogen is able to inhibit the IRE1 branch of the UPR by blocking host translation elongation. Given that a broad spectrum of pathogens block protein synthesis specifically at elongation rather than at other steps of translation, this may point to a common mechanism for blocking the UPR and thereby preventing enhanced proinflammatory cytokine signaling. (See pp. E6790–E6797.)
The modular and integrative functional architecture of the human brain
Maxwell A. Bertolero, B. T. Thomas Yeo, and Mark D’Esposito
Many complex networks are composed of “modules” that form an interconnected network. We sought to elucidate the nature of the brain’s modular function by testing the autonomy of the brain’s modules and the potential mechanisms underlying their interactions. By studying the brain as a large-scale complex network and measuring activity across the network during 77 cognitive tasks, we demonstrate that, despite connectivity between modules, each module appears to execute a discrete cognitive function relatively autonomously from the other modules. Moreover, brain regions with diverse connectivity across the modules appear to play a role in enabling modules to interact while remaining mostly autonomous. This generates the counterintuitive idea that regions with diverse connectivity across modules are necessary for modular biological networks. (See pp. E6798–E6807.)
CD11b+Ly6G− myeloid cells mediate mechanical inflammatory pain hypersensitivity
Nader Ghasemlou, Isaac M. Chiu, Jean-Pierre Julien, and Clifford J. Woolf
Inflammatory mediators can activate and sensitize nociceptors, specialized high-threshold nerve fibers that relay noxious signals to the spinal cord and brain to initiate pain. However, the contribution of specific immune cell types to pain in animal models of inflammation remains largely unknown. We therefore characterized the immune response in two widely used preclinical models of inflammatory pain: intraplantar injection of complete Freund’s adjuvant and plantar incisional wound. Cell-depletion strategies investigated the contribution of neutrophils, myeloid cells (including monocytes and macrophages), and T cells to pain behavior outcomes. Our results show that these two models induced quite different inflammatory processes and that targeted elimination of a subpopulation of nonneutrophil myeloid cells blocked development of mechanical hypersensitivity following incisional wounds. (See pp. E6808–E6817.)
CK2 acts as a potent negative regulator of receptor-mediated insulin release in vitro and in vivo
Mario Rossi, Inigo Ruiz de Azua, Luiz F. Barella, Wataru Sakamoto, Lu Zhu, Yinghong Cui, Huiyan Lu, Heike Rebholz, Franz M. Matschinsky, Nicolai M. Doliba, Adrian J. Butcher, Andrew B. Tobin, and Jürgen Wess
G protein-coupled receptors (GPCRs) regulate the activity of virtually all cell types including pancreatic β-cells. β-Cell M3 muscarinic receptors (M3Rs) play an essential role in maintaining proper whole-body glucose homeostasis. Activity of the M3R, like that of other GPCRs, is modulated by phosphorylation by various kinases, including GRKs and casein kinase 2 (CK2). The potential physiological relevance of M3R phosphorylation (or of GPCRs in general) by CK2 remains unknown. We here show that CK2-dependent phosphorylation of β-cell M3Rs significantly impairs M3R-mediated increases in insulin release in vitro and in vivo. Our data demonstrate, for the first time to our knowledge, the physiological relevance of CK2 phosphorylation of a GPCR and suggest the novel concept that kinases acting on β-cell GPCRs may represent therapeutic targets. (See pp. E6818–E6824.)