Search

Circular extrachromosomal DNA (ecDNA) in patient tumors is an important driver of oncogenic gene expression, evolution of drug resistance and poor patient outcomes. Applying computational methods for the detection and reconstruction of ecDNA across a retrospective cohort of 481 medulloblastoma tumors from 465 patients, we identify circular ecDNA in 82 patients (18%). Patients with ecDNA-positive medulloblastoma were more than twice as likely to relapse and three times as likely to die within 5 years of diagnosis. A subset of tumors harbored multiple ecDNA lineages, each containing distinct amplified oncogenes. Multimodal sequencing, imaging and CRISPR inhibition experiments in medulloblastoma models reveal intratumoral heterogeneity of ecDNA copy number per cell and frequent putative 'enhancer rewiring' events on ecDNA. This study reveals the frequency and diversity of ecDNA in medulloblastoma, stratified into molecular subgroups, and suggests copy number heterogeneity and enhancer rewiring as oncogenic features of ecDNA.

Designing efficient catalysts for operating CO2 electroreduction in membrane electrode assembly (MEA) faces significant obstacles. Herein, we propose an asymmetrically coordinated Ni single‐atom catalyst featuring axial Br coordination at NiN4Br sites anchoring onto hollow Br/N co‐doped carbon nanocages, achieved through a NaBr‐assisted confined‐pyrolysis strategy. The Ni‐NBr‐C catalyst exhibits a high CO Faradaic efficiency (FECO>97 %) over the current density range of 50 to 350 mA cm−2 in the MEA device. Furthermore, Ni‐NBr‐C shows a stable cell voltage of 2.66±0.2 V while delivering a large current density of 350 mA cm−2 over an 85‐hour long‐term operation, demonstrating its potential for industrial‐scale applications. Advanced characterization techniques and theoretical calculations reveal that the coordination and doping of Br not only enhance the intrinsic activity but also highlight that the unique pore structure improves mass transfer efficiency. [ABSTRACT FROM AUTHOR]

Electrocatalytic CO2 reduction (CO2RR), an emerging sustainable energy technology to convert atmospheric CO2 into value‐added chemicals, has received extensive attention. However, the high thermodynamic stability of CO2 and the competitive hydrogen evolution reaction lead to poor catalytic performances, hardly meeting industrial application demands. Due to abundant reserves and favorable CO selectivity, zinc (Zn)‐based catalysts have been considered one of the most prospective catalysts for CO2‐to‐CO conversion. A series of advanced zinc‐based electrocatalysts, including Zn nanosheets, Zn single atoms, defective ZnO, and metallic Zn alloys, have been widely reported for CO2RR. Despite significant progress, a comprehensive and fundamental summary is still lacking. Herein, this review provides a thorough discussion of effective modulation strategies such as morphology design, doping, defect, heterointerface, alloying, facet, and single‐atom, emphasizing how these methods can influence the electronic structure and adsorption properties of intermediates, as well as the catalytic activity of Zn‐based materials. Moreover, the challenges and opportunities of Zn‐based catalysts for CO2RR are also discussed. This review is expected to promote the broader application of efficient Zn‐based catalysts in electrocatalytic CO2RR, thus contributing to a future of sustainable energy. [ABSTRACT FROM AUTHOR]

Objective: Primary health workers (PHWs) are a critical pillar of health systems but primary health care centers often struggle to attract and retain talented staff. To better understand why this is, we investigated the job preference of PHWs in a Chinese urban setting. Methods: In a discrete choice experiment, PHWs from 15 primary health care centers in Guangzhou, China, made trade-offs between several hypothetical job scenario combinations of salary, type of health institution, bianzhi (permanent post), work years required for promotion, career development and training opportunities, educational opportunities for children, and community respect. Based on the estimate of the mixed logit model, willingness to pay and policy simulations were applied to estimate the utility of each attribute. Results: Data were collected from 446 PHWs. The PHWs were willing to forgo Chinese Renminbi 2806.1 (US$ 438.5) per month to obtain better education opportunities for their children, making it the most important non-monetary factor. Their preferences were also influenced relatively more by salary, bianzhi, and community respect, than with the other attributes we tested for, work years required for promotion, career development and training opportunities, and type of health institution. Conclusion: Salary is a robust predictive factor, while three non-monetary factors (opportunities for children's education, bianzhi, and community respect) are essential in retaining health workers in primary care. [ABSTRACT FROM AUTHOR]

Background: For diabetic ulcers, the impaired response to hypoxia is a key feature associated with delayed healing. In the early phase of hypoxia, hypoxic signaling activates the AMPK system through direct phosphorylation of the PHD2 pathway, producing a significant endogenous hypoxic protective effect. Methods: Twenty Sprague-Dawley (SD) rats were randomly divided into two groups: treatment (sh-PHD2) and control (sh-Control). Using lentiviral encapsulation of PHD2-shRNA and transfection, the silencing efficiency of PHD2 expression was verified in rat dermal fibroblasts (RDF) and in rat aortic endothelial cells (RAECs). Changes in the ability of RDF and RAECs to proliferate, migrate, and in the rate of ATP production were observed and then tested after inhibition of AMPK phosphorylation using dorsomorphin. The lentiviral preparation was injected directly into the wounds of rats and wound healing was recorded periodically to calculate the healing rate. Wounded tissues were excised after 14 days and the efficiency of PHD2 silencing, as well as the expression of growth factors, was examined using molecular biology methods. Histological examination was performed to assess CD31 expression and therefore determine effects on angiogenesis. Results: Lentiviral-encapsulated PHD2-sh-RNA effectively suppressed PHD2 expression and improved the proliferation, migration, and ATP production rate of RDF and RAEC, which were restored to their previous levels after inhibition of AMPK. The rate of wound healing, vascular growth, and expression of growth factors were significantly improved in diabetic-model rats after local silencing of PHD2 expression. Conclusion: Silencing of PHD2 promoted wound healing in diabetic-model SD rats by activating AMPK phosphorylation. [ABSTRACT FROM AUTHOR]

In this work, NiMoO4 hollow nanocubes were first successfully obtained via facile solvothermal and subsequent etching process. Assembling two-dimensional NiMoO4 nanosheets into the three-dimensional framework based on Cu2O nanocubes provided outstanding nanostructure stability and excellent electrochemical property. For example, the as-prepared hollow NiMoO4 nanocubes exhibited an outstanding capacitance of 1093 F g−1 at 1 A g−1. In addition, the supercapacitor is composed of hollow NiMoO4 nanocubes as positive electrode and N-rGO as negative electrode, which showed an outstanding energy density (44.01 Wh kg−1) at a power density of 769 W kg−1 in a voltage windows of 0–1.55 V, and even maintained an energy density (23.68 Wh kg−1) at a high power density (7.7 kW kg−1). Furthermore, the device delivered a promising long-term cyclic performance of 84.7% capacitance retention after 5000 charge–discharge cycles. [ABSTRACT FROM AUTHOR]

The ability to silence the activity of genetically specified neurons in a temporally precise fashion would provide the opportunity to investigate the causal role of specific cell classes in neural computations, behaviours and pathologies. Here we show that members of the class of light-driven outward proton pumps can mediate powerful, safe, multiple-colour silencing of neural activity. The gene archaerhodopsin-3 (Arch) (1) from Halorubrum sodomense enables near-100% silencing of neurons in the awake brain when virally expressed in the mouse cortex and illuminated with yellow light. Arch mediates currents of several hundred picoamps at low light powers, and supports neural silencing currents approaching 900 pA at light powers easily achievable in vivo. Furthermore, Arch spontaneously recovers from light-dependent inactivation, unlike light-driven chloride pumps that enter long-lasting inactive states in response to light. These properties of Arch are appropriate to mediate the optical silencing of significant brain volumes over behaviourally relevant timescales. Arch function in neurons is well tolerated because pH excursions created by Arch illumination are minimized by self-limiting mechanisms to levels comparable to those mediated by channelrhodopsins (2,3) or natural spike firing. To highlight how proton pump ecological and genomic diversity may support new innovation, we show that the blue-green light-drivable proton pump from the fungus Leptosphaeria maculans (4) (Mac) can, when expressed in neurons, enable neural silencing by blue light, thus enabling alongside other developed reagents the potential for independent silencing of two neural populations by blue versus red light. Light-driven proton pumps thus represent a high-performance and extremely versatile class of 'optogenetic' voltage and ion modulator, which will broadly enable new neuro-scientific, biological, neurological and psychiatric investigations., We screened type I microbial opsins (see Supplementary Table 1) from archaebacteria, bacteria, plants and fungi for light-driven hyperpolarizing capability. (5) Mammalian codon-optimized genes were synthesized, cloned into green fluorescent [...]

Neuronal activity regulates the development and maturation of excitatory and inhibitory synapses in the mammalian brain. Several recent studies have identified signalling networks within neurons that control excitatory synapse development. [...]