Fabrication of periodic microscale stripes of silver by laser interference induced forward transfer and their SERS properties.

The micro-stripe structure was prepared by laser interference induced forward transfer technique, composed of Ag nano-particles (NPs). The effects of the film thickness with the carbon nano-particles mixed polyimide (CNPs@PI), Ag film thickness, and laser fluence were studied on the transferred micro-stripe structure. The periodic Ag micro-stripe with good resolution was obtained in a wide range of CNPs@PI film thickness from âˆ¼0.5 to âˆ¼1.0µm for the Ag thin film âˆ¼20 nm. The distribution of the Ag NPs composing the micro-stripe was compact. Nevertheless, the average size of the transferred Ag NPs was increased from âˆ¼41 to âˆ¼197 nm with the change of the Ag donor film from âˆ¼10 to âˆ¼40 nm. With the increase of the laser fluence from 102 to 306 mJ·cm-2per-beam, the transferred Ag NPs became aggregative, improving the resolution of the corresponding micro-stripe. Finally, the transferred Ag micro-stripe exhibited the significant surface enhanced Raman scattering (SERS) property for rhodamine B (RhB). While the concentration of the RhB reached 10-10mol·L-1, the Raman characteristic peaks of the RhB were still observed clearly at 622, 1359 and 1649 cm-1. These results indicate that the transferred Ag micro-stripe has potential application as a SERS chip in drug and food detection.

Pre-sensor computing with compact multilayer optical neural network.

Moving computation units closer to sensors is becoming a promising approach to addressing bottlenecks in computing speed, power consumption, and data storage. Pre-sensor computing with optical neural networks (ONNs) allows extensive processing. However, the lack of nonlinear activation and dependence on laser input limits the computational capacity, practicality, and scalability. A compact and passive multilayer ONN (MONN) is proposed, which has two convolution layers and an inserted nonlinear layer, performing pre-sensor computations with designed passive masks and a quantum dot film for incoherent light. MONN has an optical length as short as 5 millimeters, two orders of magnitude smaller than state-of-the-art lens-based ONNs. MONN outperforms linear single-layer ONN across various vision tasks, off-loading up to 95% of computationally expensive operations into optics from electronics. Motivated by MONN, a paradigm is emerging for mobile vision, fulfilling the demands for practicality, miniaturization, and low power consumption.

A Novel Dual ATM/DNA-PK Inhibitor, XRD-0394, Potently Radiosensitizes and Potentiates PARP and Topoisomerase I Inhibitors.

A majority of patients with cancer receive radiotherapy as part of their treatment regimens whether using external beam therapy or locally-delivered radioisotopes. While often effective, some tumors are inadequately controlled with radiation and radiotherapy has significant short-term and long-term toxicities for cancer survivors. Insights into molecular mechanisms involved in cellular responses to DNA breaks introduced by radiation or other cancer therapies have been gained in recent years and approaches to manipulate these responses to enhance tumor cell killing or reduce normal tissue toxicity are of great interest. Here, we report the identification and initial characterization of XRD-0394, a potent and specific dual inhibitor of two DNA damage response kinases, ATM and DNA-PKcs. This orally bioavailable molecule demonstrates significantly enhanced tumor cell kill in the setting of therapeutic ionizing irradiation in vitro and in vivo. XRD-0394 also potentiates the effectiveness of topoisomerase I inhibitors in vitro. In addition, in cells lacking BRCA1/2 XRD-0394 shows single-agent activity and synergy in combination with PARP inhibitors. A phase Ia clinical trial (NCT05002140) with XRD-0394 in combination with radiotherapy has completed. These results provide a rationale for future clinical trials with XRD-0394 in combination with radiotherapy, PARP inhibitors, and targeted delivery of topoisomerase I inhibitors.

Spatial and Temporal Impacts of Socioeconomic and Environmental Factors on Healthcare Resources: A County-Level Bayesian Local Spatiotemporal Regression Modeling Study of Hospital Beds in Southwest China.

Comprehensive investigation on understanding geographical inequalities of healthcare resources and their influencing factors in China remains scarce. This study aimed to explore both spatial and temporal heterogeneous impacts of various socioeconomic and environmental factors on healthcare resource inequalities at a fine-scale administrative county level. We collected data on county-level hospital beds per ten thousand people to represent healthcare resources, as well as data on 32 candidate socioeconomic and environmental covariates in southwest China from 2002 to 2011. We innovatively employed a cutting-edge local spatiotemporal regression, namely, a Bayesian spatiotemporally varying coefficients (STVC) model, to simultaneously detect spatial and temporal autocorrelated nonstationarity in healthcare-covariate relationships via estimating posterior space-coefficients (SC) within each county, as well as time-coefficients (TC) over ten years. Our findings reported that in addition to socioeconomic factors, environmental factors also had significant impacts on healthcare resources inequalities at both global and local space-time scales. Globally, the personal economy was identified as the most significant explanatory factor. However, the temporal impacts of personal economy demonstrated a gradual decline, while the impacts of the regional economy and government investment showed a constant growth from 2002 to 2011. Spatially, geographical clustered regions for both hospital bed distributions and various hospital bed-covariates relationships were detected. Finally, the first spatiotemporal series of complete county-level hospital bed inequality maps in southwest China was produced. This work is expected to provide evidence-based implications for future policy making procedures to improve healthcare equalities from a spatiotemporal perspective. The employed Bayesian STVC model provides frontier insights into investigating spatiotemporal heterogeneous variables relationships embedded in broader areas such as public health, environment, and earth sciences.

A simple strategy to effectively produce d-lactate in crude glycerol-utilizing Escherichia coli.

BACKGROUND: Fed-batch fermentation has been conventionally implemented for the production of lactic acid with a high titer and high productivity. However, its operation needs a complicated control which increases the production cost. RESULTS: This issue was addressed by simplifying the production scheme. Escherichia coli was manipulated for its glycerol dissimilation and d-lactate synthesis pathways and then subjected to adaptive evolution under high crude glycerol. Batch fermentation in the two-stage mode was performed by controlling the dissolved oxygen (DO), and the evolved strain deprived of poxB enabled production of 100 g/L d-lactate with productivity of 1.85 g/L/h. To increase productivity, the producer strain was further evolved to improve its growth rate on crude glycerol. The fermentation was performed to undergo the aerobic growth with low substrate, followed by the anaerobic production with high substrate. Moreover, the intracellular redox of the strain was balanced by fulfillment of the anaerobic respiratory chain with nitrate reduction. Without controlling the DO, the microbial fermentation resulted in the homofermentative production of d-lactate (ca. 0.97 g/g) with a titer of 115 g/L and productivity of 3.29 g/L/h. CONCLUSIONS: The proposed fermentation strategy achieves the highest yield based on crude glycerol and a comparable titer and productivity as compared to the approach by fed-batch fermentation. It holds a promise to sustain the continued development of the crude glycerol-based biorefinery.

Discovery of MK-8719, a Potent O-GlcNAcase Inhibitor as a Potential Treatment for Tauopathies.

Inhibition of O-GlcNAcase (OGA) has emerged as a promising therapeutic approach to treat tau pathology in neurodegenerative diseases such as Alzheimer's disease and progressive supranuclear palsy. Beginning with carbohydrate-based lead molecules, we pursued an optimization strategy of reducing polar surface area to align the desired drug-like properties of potency, selectivity, high central nervous system (CNS) exposure, metabolic stability, favorable pharmacokinetics, and robust in vivo pharmacodynamic response. Herein, we describe the medicinal chemistry and pharmacological studies that led to the identification of (3aR,5S,6S,7R,7aR)-5-(difluoromethyl)-2-(ethylamino)-3a,6,7,7a-tetrahydro-5H-pyrano[3,2-d]thiazole-6,7-diol 42 (MK-8719), a highly potent and selective OGA inhibitor with excellent CNS penetration that has been advanced to first-in-human phase I clinical trials.

Discovery of 6-(Fluoro-(18)F)-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine ([(18)F]-MK-6240): A Positron Emission Tomography (PET) Imaging Agent for Quantification of Neurofibrillary Tangles (NFTs).

Neurofibrillary tangles (NFTs) made up of aggregated tau protein have been identified as the pathologic hallmark of several neurodegenerative diseases including Alzheimer's disease. In vivo detection of NFTs using PET imaging represents a unique opportunity to develop a pharmacodynamic tool to accelerate the discovery of new disease modifying therapeutics targeting tau pathology. Herein, we present the discovery of 6-(fluoro-(18)F)-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine, 6 ([(18)F]-MK-6240), as a novel PET tracer for detecting NFTs. 6 exhibits high specificity and selectivity for binding to NFTs, with suitable physicochemical properties and in vivo pharmacokinetics.