Steroid Receptor Signaling
Plant brassinosteroids signal to diverse pathways in plant physiology. These steroid hormones are perceived at the cell surface, where they bind to the receptor BRASSINOSTEROID INSENSITIVE 1 (BRI1). Santiago et al. (p. 889, published online 8 August) now show that somatic embryogenesis receptor kinase 1 (SERK1) complexes with BRI1. Together, these receptor kinases form the steroid binding site, with the hormone acting as a “molecular glue” that stabilizes the interaction. Hormone-induced heteromerization of BRI1 with SERK1 leads to the activation of the cytoplasmic signaling cascade, triggering plant growth and differentiation.
Arsenic and Populace
The solubility of arsenic in groundwater aquifers is controlled by a number of hydrologic and geochemical factors. In rural communities that rely on groundwater for drinking water, the risk from exposure may pose a public health threat, especially when groundwater pumping can increase arsenic solubility. In an effort to provide a focused assessment of risk to arsenic exposure from groundwater, Rodríguez-Lado et al. (p. 866; see the Perspective by Michael) constructed a geostatistical model that incorporates a number of factors that control arsenic solubility across China. Most of the risk centers in a few provinces—Xinjiang, Inner Mongolia, Henan, Shandong, and Jiangsu—but the total population exposed to arsenic levels above 10 micrograms per liter could be upwards of 19 million people.
Closing the Loop
Many studies have shown that protein dynamics are important to enzyme function. For example, enzyme protein movements have been shown to optimize the active site, enable binding of substrate and cofactor, and facilitate product release. Whittier et al. (p. 899) now show that in two tyrosine phosphatases, the rate of cleavage is coupled to motion of a loop. The two phosphatases have different catalytic rates; however, in both, a loop containing a catalytic residue switches between an inactive open and a catalytically competent closed state. The rates of closure are equivalent to the cleavage rates, suggesting that the leaving group tyrosine is protonated simultaneously with loop closure. Thus, tuning of the loop motion plays a regulatory role in the catalytic cycle.
Gotta Get Up to Get Down
By examining high-resolution satellite topography data of a ridge along the San Andreas Fault in California, Hurst et al. (p. 868) demonstrate how hill slope curvature may be used to infer long-term rates of tectonic uplift and erosion. Numerical modeling shows a lag phase between uplift events and changes in morphology, which, combined with the observational data, shows that topography can reveal whether landscapes are active or decaying. These fundamental relationships may help to improve seismic hazard forecasts or to interpret topographic data collected on other terrestrial planets.
Mn at Work
Biogeochemical cycling involves oxidation-reduction reactions with common metals like iron and manganese. Depending on the oxygen concentration and pH of the surrounding water, these metals—which exist in multiple oxidation states—can either accept or donate electrons; however, detecting which chemical species is dominant in these reactions often proves difficult. Using a spectrophotometric method sensitive to Mn oxidation state, Madison et al. (p. 875) show that up to 90% of the total Mn in porewater collected from sediment cores in the St. Lawrence Estuary is soluble Mn(III)—a phase traditionally assumed to be unimportant in aqueous redox reactions except in a few niche environments.
Regulating the MBT
It has been known for more than 30 years that a defined number of cell divisions in the frog embryo precede a crucial developmental event called the midblastula transition (MBT). Collart et al. (p. 893, published online 1 August) now elucidate a mechanism involved in the control of the MBT. DNA replication initiation factors are titrated out during early cell divisions, which controls the elongation of the cell cycle and the onset of zygotic transcription during the MBT.
The diterpenoid i ngenol is the core structure of a topical drug recently commercialized to treat actinic keratosis, a precancerous skin condition. Sourcing the compound from the Euphorbia plants that produce it is relatively inefficient, so Jørgensen et al. (p. 878, published online 1 August) devised a chemical synthesis starting from the comparatively simple and inexpensive monoterpene chiral (+)-3-carene. The synthetic sequence involves 14 steps—less than half as long as prior chemical routes to the target—and relies on a two-stage approach, inspired by the posited biosynthetic pathway, in which preliminary assembly of the fused ring framework precedes hydroxylation of the periphery.
HIV Detection Is a (c)GAS
Despite it being one of the most highly studied viruses, there are still many unknowns when it comes to HIV—including how it triggers the innate immune response. Gao et al. (p. 903, published 8 August) now demonstrate that the DNA sensor cyclic GMP-AMP synthase (cGAS) detects HIV infection. Reverse-transcribed HIV DNA triggers cGAS and downstream activation of antiviral immunity. Detection of HIV, as well as the retroviruses simian immunodeficiency virus and murine leukemia virus, was abrogated in mouse and human cells deficient in cGAS—suggesting that cGAS may be a critical activator of innate immunity in response to retroviral infection.
Neural Crest Development
The vertebrate neural crest is characterized by a migratory population of multipotent cells that spread out from the dorsal side of the neural tube. Many different cell types and tissues originate here, including cells of the peripheral nervous system, the adrenal medulla, melanocytes, and some skeletal cells. Dysregulation of neural crest cells can lead to defects in cell differentiation and the cell cycle, as well as to the formation of ectopic tissue, which can result in various human diseases. Takahashi et al. (p. 860) review the normal development of neural crest cells, highlighting important associations of this cell population with local environments to influence tissue interactions and function, and describe pathogenesis that results when developmental events go awry.
Next-Generation Gene Therapy
Few disciplines in contemporary clinical research have experienced the high expectations directed at the gene therapy field. However, gene therapy has been challenging to translate to the clinic, often because the therapeutic gene is expressed at insufficient levels in the patient or because the gene delivery vector integrates near proto-oncogenes, which can cause leukemia (see the Perspective by Verma). Biffi et al. (1233158, published online 11 July) and Aiuti et al. (1233151; published online 11 July) report progress on both fronts in gene therapy trials of three patients with metachromatic leukodystrophy (MLD), a neurodegenerative disorder, and three patients with Wiskott-Aldrich syndrome (WAS), an immunodeficiency disorder. Optimized lentiviral vectors were used to introduce functional MLD or WAS genes into the patients' hematopoietic stem cells (HSCs) ex vivo, and the transduced cells were then infused back into the patients, who were then monitored for up to 2 years. In both trials, the patients showed stable engraftment of the transduced HSC and high expression levels of functional MLD or WAS genes. Encouragingly, there was no evidence of lentiviral vector integration near proto-oncogenes, and the gene therapy treatment halted disease progression in most patients. A longer follow-up period will be needed to further validate efficacy and safety.
Mapping Molecular Linkers
In metal-organic framework compounds, inorganic centers (metal atoms or clusters) are linked by bidentate organic groups. Normally, the same group is used throughout the structure, but recently, synthesis with linkers bearing different functional groups has produced well-defined materials. Kong et al. (p. 882, published online 25 July) combined solid-state nuclear magnetic resonance and molecular simulations to map the distributions of linkers in these materials as random, well-mixed, or clustered.
The initial transition from a disordered solution to the formation of nuclei that grow into crystals continues to be a puzzle. Recent experiments suggested the formation of stable ordered clusters that appear prior to the formation of the first nuclei. Wallace et al. (p. 885; see the Perspective by Myerson and Trout) used molecular dynamics to look at the potential structure and dynamics of these clusters and lattice gas simulations to explore the population dynamics of the cluster populations prior to nucleation. A liquid-liquid phase separation process was observed whereby one phase becomes more concentrated in ions and becomes the precursor for nuclei to form.
Defects in α-dystroglycan lead to various congenital muscular dystrophies, and its ability to bind to extracellular matrix (ECM) is dependent on formation of a specific O-linked sugar structure. Previous efforts to understand the molecular mechanisms underlying α-dystroglycan's ability to bind to the ECM led to the identification of a phosphorylated O-mannosyl trisaccharide on α-dystroglycan and to the demonstration that addition of this residue is a prerequisite for formation of the ligand-binding motif. However, the biosynthetic pathway that leads to production of the phosphorylated O-mannosyl glycan has not been delineated. Yoshida-Moriguchi et al. (p. 896, published online 8 August) elucidate the functions of three genes recently found to cause dystroglycan-related disorders and explain the defects in the production of the phosphorylated O-mannosyl glycan that underlie the pathologies of patients with the relevant mutations.
European History at Depth
The preferential alignment of mineral grains as a result of flow direction can polarize seismic waves traveling through Earth's interior, based on velocity and direction. Zhu and Tromp (p. 871, published online 8 August) mapped this anisotropy beneath the European continent and the North Atlantic Ocean—which are products of several tectonic events across varying temporal and spatial scales—using seismic tomography. The model generated correlates well with plate motion in the region, and, compared to geodetic measurements, much of the anisotropic features are consistent with modern strain rates. Some features below Eastern Europe, however, appear to be remnants of tectonic events that occurred over 350 million years ago.