Bone-cell regulation, fleshed out: One of many medically relevant G protein–coupled receptors, parathyroid hormone receptor-1 (PTH1R) functions in the control of calcium homeostasis and bone physiology. Zhao et al. used cryo–election microscopy to observe the structure of PTH1R in a complex with a modified form of parathyroid hormone and stimulatory G protein. The structural model helps explain how parathyroid hormone interacts with its receptor and the molecular basis for receptor activation. Science , this issue p. 148

The neuroprotective effect of ceria nanoparticles in the context of brain disorders has been explained by their antioxidant effect. However, the in‐depth mechanism remains unknown. As resident immune cells in the brain, microglia exert a variety of functional reprogramming termed as polarization in response to stress stimuli. Herein, custom‐made ceria nanoparticles were developed and found to scavenge multiple reactive oxygen species with extremely high efficiency. These nanoparticles drove microglial polarization from a pro‐inflammatory phenotype to an anti‐inflammatory phenotype under pathological conditions. Pretreatment of these nanoparticles changed the microglial function from detrimental to protective for the neuronal cells by blocking the pro‐inflammatory signaling. This work not only helps to elucidate the mechanism of ceria‐nanoparticle‐mediated neuroprotection but also provides a new strategy to rebalance the immuno‐environment by switching the equilibrium of the phenotypic activation of microglia.

Accurately locating and eradicating sporadically distributed cancer cells whilst minimizing damage to adjacent normal tissues is vital in image-guided tumor ablation. In this work, we developed four heptamethine cyanine based theranostic probes, IR1–4, that demonstrated unique pH switchable near-infrared (NIR) fluorescence and photothermal efficiency. While their fluorescence quantum yields increased up to 1020-fold upon acidification from pH 7.4 to 2.4, their photothermal efficiencies decreased up to 7.1-fold concomitantly. Theoretical calculations showed that protonation of the probes in an acidic environment increased the orbital energy gaps and reduced the intramolecular charge transfer efficiency, resulting in the conversion of absorbed light energy to NIR fluorescence instead of hyperthermia. Substitutions at the terminal indole of the probes fine-tuned their pKa_fluo values to a narrow physiological pH range of 4.0–5.3. IR2, with a pKa_fluo of 4.6, not only specifically illuminated cancer cells by sensing their more acidic lysosomal lumen, but also selectively ablated cancer cells via its maximized photothermal effects in the alkaline mitochondrial matrix. As far as we are aware, these probes not only offer the highest physiological acidity triggered NIR fluorescence enhancement as small molecules, but are also the first to specifically visualize and eradicate cancer cells by sensing their altered pH values in cellular organelles. Considering that a disordered pH in organelle lumen is a common characteristic of cancer cells, these theranostic probes hold the promise to be applied in image-guided tumor ablation over a wide range of tumor subtypes.

Thrombolysis has been a standard treatment for ischemic stroke. However, only 2-7% patients benefit from it because the thrombolytic agent has to be injected within 4.5 h after the onset of symptoms to avoid the increasing risk of intracerebral hemorrhage. As the only clinically approved neuroprotective drug, edaravone (EDV) rescues ischemic brain tissues by eradicating over-produced reactive oxygen species (ROS) without the limitation of therapeutic time-window. However, EDV's short circulation half-life and inadequate cerebral uptake attenuate its therapeutic efficacy. Here we developed an EDV-encapsulated agonistic micelle (EDV-AM) to specifically deliver EDV into brain ischemia by actively tuning blood-brain barrier (BBB) permeability. The EDV-AM actively up-regulated endothelial monolayer permeability in vitro. HPLC studies showed that EDV-AM delivered more EDV into brain ischemia than free EDV after intravenous injection. Magnetic resonance imaging also demonstrated that EDV-AM more rapidly salvaged ischemic tissue than free EDV. Diffusion tensor imaging indicated the highest efficiency of EDV-AM in accelerating axonal remodeling in the ipsilesional white matter and improving functional behaviors of ischemic stroke models. The agonistic micelle holds promise to improve the therapeutic efficiency of ischemic stroke patients who miss the thrombolytic treatment.