No abstract

X-ray detectors are broadly utilized in medical imaging and product inspection. Halide perovskites recently demonstrate excellent performance for direct X-ray detection. However, ionic migration causes large noise and baseline drift, limiting the detection and imaging performance. Here we largely eliminate the ionic migration in cesium silver bismuth bromide (Cs 2 AgBiBr 6 ) polycrystalline wafers by introducing bismuth oxybromide (BiOBr) as heteroepitaxial passivation layers. Good lattice match between BiOBr and Cs 2 AgBiBr 6 enables complete defect passivation and suppressed ionic migration. The detector hence achieves outstanding balanced performance with a signal drifting one order of magnitude lower than all previous studies, low noise (1/ f noise free), a high sensitivity of 250 µC Gy air −1 cm –2 , and a spatial resolution of 4.9 lp mm −1 . The wafer area could be easily scaled up by the isostatic-pressing method, together with the heteroepitaxial passivation, strengthens the competitiveness of Cs 2 AgBiBr 6 -based X-ray detectors as next-generation X-ray imaging flat panels.

Nonalcoholic steatohepatitis (NASH) is a progressive disease that is often accompanied by metabolic syndrome and poses a high risk of severe liver damage. However, no effective pharmacological treatment is currently available for NASH. Here we report that CASP8 and FADD-like apoptosis regulator (CFLAR) is a key suppressor of steatohepatitis and its metabolic disorders. We provide mechanistic evidence that CFLAR directly targets the kinase MAP3K5 (also known as ASK1) and interrupts its N-terminus-mediated dimerization, thereby blocking signaling involving ASK1 and the kinase MAPK8 (also known as JNK1). Furthermore, we identified a small peptide segment in CFLAR that effectively attenuates the progression of steatohepatitis and metabolic disorders in both mice and monkeys by disrupting the N-terminus-mediated dimerization of ASK1 when the peptide is expressed from an injected adenovirus-associated virus 8-based vector. Taken together, these findings establish CFLAR as a key suppressor of steatohepatitis and indicate that the development of CFLAR-peptide-mimicking drugs and the screening of small-molecular inhibitors that specifically block ASK1 dimerization are new and feasible approaches for NASH treatment.

18F-FPPRGD2, which was approved for clinical study recently, has favorable properties for integrin targeting and showed potential for antiangiogenic therapy and early response monitoring. However, the time-consuming multiple-step synthesis may limit its widespread applications in the clinic. In this study, we developed a simple lyophilized kit for labeling PRGD2 peptide (18F-AlF-NOTA-PRGD2, denoted as 18F-alfatide) using a fluo-ride–aluminum complex that significantly simplified the labeling procedure. Methods Nine patients with a primary diagnosis of lung cancer were examined by both static and dynamic PET imaging with 18F-alfatide, and 1 tuberculosis patient was investigated using both 18F-alfatide and 18F-FDG imaging. Standardized uptake values were measured in tumors and other main organs at 30 min and 1 h after injection. Kinetic parameters were calculated by Logan graphical analysis. Immunohisto-chemistry and staining intensity quantification were performed to confirm the expression of integrin αvβ3. Results Under the optimal conditions, the whole radiosynthesis including purifica-tion was accomplished within 20 min with a decay-corrected yield of 42.1% ± 2.0% and radiochemical purity of more than 95%. 18F-alfatide PET imaging identified all tumors, with mean standardized uptake values of 2.90 ± 0.10. Tumor-to-muscle and tumor-to-blood ratios were 5.87 ± 2.02 and 2.71 ± 0.92, respectively. Conclusion 18F-alfatide can be produced with excellent radiochemical yield and purity via a simple, 1-step, lyophilized kit. PET scanning with 18F-alfatide allows specific imaging of αvβ3 expression with good contrast in lung cancer patients. This technique might be used for the assessment of angiogene-sis and for planning and response evaluation of cancer therapies that would affect angiogenesis status and integrin expression levels.

Non-alcoholic steatohepatitis (NASH) is an increasingly prevalent liver pathology that can progress from non-alcoholic fatty liver disease (NAFLD), and it is a leading cause of cirrhosis and hepatocellular carcinoma. There is currently no pharmacological therapy for NASH. Defective lysosome-mediated protein degradation is a key process that underlies steatohepatitis and a well-recognized drug target in a variety of diseases; however, whether it can serve as a therapeutic target for NAFLD and NASH remains unknown. Here we report that transmembrane BAX inhibitor motif-containing 1 (TMBIM1) is an effective suppressor of steatohepatitis and a previously unknown regulator of the multivesicular body (MVB)-lysosomal pathway. Tmbim1 expression in hepatocytes substantially inhibited high-fat diet-induced insulin resistance, hepatic steatosis and inflammation in mice. Mechanistically, Tmbim1 promoted the lysosomal degradation of toll-like receptor 4 by cooperating with the ESCRT endosomal sorting complex to facilitate MVB formation, and the ubiquitination of Tmbim1 by the E3 ubiquitin ligase Nedd4l was required for this process. We also found that overexpression of Tmbim1 in the liver effectively inhibited a severe form of NAFLD in mice and NASH progression in monkeys. Taken together, these findings could lead to the development of promising strategies to treat NASH by targeting MVB regulators to properly orchestrate the lysosome-mediated protein degradation of key mediators of the disease.

Scintillators for radiation detection are of great significance in medical imaging, security, and nondestructive inspection. The current challenge for scintillators is to simultaneously achieve high scintillation light yield, fast radioluminescence, simple film fabrication, large X‐ray attenuation efficiency as well as stable and nontoxic compositions; no previous scintillators fulfill all the above requirements. Here, metal halide Rb2AgBr3, possessing defect‐bound excitonic radioluminescence, is shown as efficient and fast scintillators. This nontoxic and stable scintillator emits from excitons bound to neutral bromine vacancies, enjoying an efficient and spin‐allowed fast emission with minimized self‐absorption. Rb2AgBr3 thus has a high light yield (25 600 photons MeV−1), fast scintillation decay time (5.31 ns), and a record value of light yield versus decay time (4821 photons MeV−1 ns−1). The close‐space sublimation method is developed for fast and scalable fabrication of oriented Rb2AgBr3 films. The scintillator film is further integrated with commercial flat‐panel imagers, and the spatial resolution reaches 10.2 line pairs per millimeter at the modulation transfer function of 0.2, doubling the resolution of conventional CsI:Tl flat‐panel detectors. The dynamic X‐ray imaging and its use to real‐time monitoring of bone movement without ghosting effect is also demonstrated.

Different emotional states lead to distinct behavioural consequences even when faced with the same challenging events. Emotions affect learning and memory capacities, but the underlying neurobiological mechanisms remain elusive. Here we establish models of learned helplessness (LHL) and learned hopefulness (LHF) by exposing animals to inescapable foot shocks or with anticipated avoidance trainings. The LHF animals show spatial memory potentiation with excitatory monosynaptic upscaling between posterior basolateral amygdale (BLP) and ventral hippocampal CA1 (vCA1), whereas the LHL show memory deficits with an attenuated BLP–vCA1 connection. Optogenetic disruption of BLP–vCA1 inputs abolishes the effects of LHF and impairs synaptic plasticity. By contrast, targeted BLP–vCA1 stimulation rescues the LHL-induced memory deficits and mimics the effects of LHF. BLP–vCA1 stimulation increases synaptic transmission and dendritic plasticity with the upregulation of CREB and intrasynaptic AMPA receptors in CA1. These findings indicate that opposite excitatory monosynaptic scaling of BLP–vCA1 controls LHF- and LHL-modulated spatial memory, revealing circuit-specific mechanisms linking emotions to memory.

The rapid one-step radiolabeling strategy by the complexation of (18)F-aluminum fluoride with NOTA-peptide conjugates was successfully applied to synthesize three dimeric RGD peptides. Among the three probes developed, (18)F-AlF-NOTA-E[PEG4-c(RGDfk)]2 with relatively low liver uptake and high tumor accumulation appears to be a promising candidate for further translational research.