Norepinephrine (NE) is a key biogenic monoamine neurotransmitter involved in a wide range of physiological processes. However, its precise dynamics and regulation remain poorly characterized, in part due to limitations of available techniques for measuring NE in vivo. Here, we developed a family of GPCR activation-based NE (GRAB NE ) sensors with a 230% peak DF/F 0 response to NE, good photostability, nanomolar-to-micromolar sensitivities, sub-second kinetics, and high specificity. Viral-or transgenic-mediated expression of GRAB NE sensors was able to detect electrical-stimulation-evoked NE release in the locus coeruleus (LC) of mouse brain slices, looming-evoked NE release in the midbrain of live zebrafish, as well as optogenetically and behaviorally triggered NE release in the LC and hypothalamus of freely moving mice. Thus, GRAB NE sensors are robust tools for rapid and specific monitoring of in vivo NE transmission in both physiological and pathological processes.

Despite the recent success of deep-learning based semantic segmentation, deploying a pre-trained road scene segmenter to a city whose images are not presented in the training set would not achieve satisfactory performance due to dataset biases. Instead of collecting a large number of annotated images of each city of interest to train or refine the segmenter, we propose an unsupervised learning approach to adapt road scene segmenters across different cities. By utilizing Google Street View and its timemachine feature, we can collect unannotated images for each road scene at different times, so that the associated static-object priors can be extracted accordingly. By advancing a joint global and class-specific domain adversarial learning framework, adaptation of pre-trained segmenters to that city can be achieved without the need of any user annotation or interaction. We show that our method improves the performance of semantic segmentation in multiple cities across continents, while it performs favorably against state-of-the-art approaches requiring annotated training data.

Cancer immunotherapy involves blocking the interactions between the PD-1/PD-L1 immune checkpoints with antibodies. This has shown unprecedented positive outcomes in clinics. Particularly, the PD-L1 antibody therapy has shown the efficiency in blocking membrane PD-L1 and efficacy in treating some advanced carcinoma. However, this therapy has limited effects on many solid tumors, suspecting to be relevant to PD-L1 located in other cellular compartments, where they play additional roles and are associated with poor prognosis. In this review, we highlight the advances of 3 current strategies on PD-1/PD-L1 based immunotherapy, summarize cellular distribution of PD-L1, and review the versatile functions of intracellular PD-L1. The intracellular distribution and function of PD-L1 may indicate why not all antibody blockade is able to fully stop PD-L1 biological functions and effectively inhibit tumor growth. In this regard, gene silencing may have advantages over antibody blockade on suppression of PD-L1 sources and functions. Apart from cancer cells, PD-L1 silencing on host immune cells such as APC and DC can also enhance T cell immunity, leading to tumor clearance. Moreover, the molecular regulation of PD-L1 expression in cells is being elucidated, which helps identify potential therapeutic molecules to target PD-L1 production and improve clinical outcomes. Based on our understandings of PD-L1 distribution, regulation, and function, we prospect that the more effective PD-L1-based cancer immunotherapy will be combination therapies.

Recently, Mn(II)-containing nanoparticles have been explored widely as an attractive alternative to Gd(III)-based T -weighted magnetic resonance imaging (MRI) contrast agents (CAs) for cancer diagnosis. However, as far as it is known, no Mn-based MRI CAs have been reported to sensitively respond to a very weakly acidic environment (pH 6.5-7.0, i.e., the pH range in a tumor microenvironment) with satisfactory imaging performance. Here, recently devised pH-ultrasensitive Mn-based layered double hydroxide (Mn-LDH) nanoparticles with superb longitudinal relaxivity (9.48 mm s at pH 5.0 and 6.82 mm s at pH 7.0 vs 1.16 mm s at pH 7.4) are reported, which may result from the unique microstructure of Mn ions in Mn-LDH, as demonstrated by extended X-ray absorption fine structure. Further in vivo imaging reveals that Mn-LDH nanoparticles show clear MR imaging for tumor tissues in mice for 2 d post intravenous injection. Thus, this novel Mn-doped LDH nanomaterial, together with already demonstrated capacity for drug and gene delivery, is a very potential theranostic agent for cancer diagnosis and treatment.