Modeling of a Broadband Microwave Composite Thin Film Absorber.

Composite thin film absorbers show superior performance and have a wide range of applications. Obtaining a broadband composite thin film absorber is a challenge. In this work, we proposed a modeling of a broadband microwave composite thin film absorber based on the impedance matching theory and equivalent circuit model of the square loop. The unit cell of the absorber was composed of metal square loops with high magnetic conductivity deposited on the polyethylene substrate, and an FR-4 (epoxy glass cloth) substrate was the spacer substrate layer. The simulation results show that the absorptivity of the absorber reached more than 90% in the frequency range of 8.7-18 GHz for TE and TM waves under normal incidence. The thickness of the designed absorber was 2.05 mm (0.059 λmax, λmax corresponds to the maximum absorption wavelength). The simulation results show that the energy distribution in the proposed absorber was mainly localized in the top metal FSS layer due to the ohmic loss of metal, and the dielectric loss played a small role in the absorption of the absorber. Our work provides a design approach to improve the efficiency of optoelectronic devices and thermal detectors and has application prospects in radar and aircraft stealth applications.

Potential of Mie-Fluorescence-Raman Lidar to Profile Chlorophyll a Concentration in Inland Waters.

Vertical distribution of phytoplankton is crucial for assessing the trophic status and primary production in inland waters. However, there is sparse information about phytoplankton vertical distribution due to the lack of sufficient measurements. Here, we report, to the best of our knowledge, the first Mie-fluorescence-Raman lidar (MFRL) measurements of continuous chlorophyll a (Chl-a) profiles as well as their parametrization in inland water. The lidar-measured Chl-a during several experiments showed good agreement with the in situ data. A case study verified that MFRL had the potential to profile the Chl-a concentration. The results revealed that the maintenance of subsurface chlorophyll maxima (SCM) was influenced by light and nutrient inputs. Furthermore, inspired by the observations from MFRL, an SCM model built upon surface Chl-a concentration and euphotic layer depth was proposed with root mean square relative difference of 16.5% compared to MFRL observations, providing the possibility to map 3D Chl-a distribution in aquatic ecosystems by integrated active-passive remote sensing technology. Profiling and modeling Chl-a concentration with MFRL are expected to be of paramount importance for monitoring inland water ecosystems and environments.

Ultralarge Pixel Array Photothermal Film based on 3D Self-Suspended Microbridge Structure for Infrared Scene Projection.

Infrared emitter is highly desirable for applications in infrared imaging and infrared stealth technology. It is also a core device in infrared scene generation. Light-driven photothermal film has attracted considerable interest due to its outstanding photothermal properties and easy fabrication. However, the existing photothermal films suffer from low photothermal conversion efficiency (PCE) as well as small sizes. The improvement of the PCE is usually achieved at the expense of dynamic frame rate. Here, this work designs and fabricates a photothermal film based on 3D self-suspended microbridge structure. Silicon (Si) microbridges are introduced into each microstructure to manipulate the thermal conductivity of the films. By optimizing the parameters of the Si microbridges, the high PCE and fast frame rate are both achieved. Moreover, the 3D structure microbridge film is 4-inch in diameter, forming an ultralarge array with over 2200 × 2200 pixels. Finally, a high PCE infrared scene projector is realized based on this photothermal film. A visible image is projected on the film, the 3D-microstructured photothermal film absorbs the visible light and emits an infrared image same as the visible one with high resolution and fast frame rate due to the excellent photothermal properties.

Backward scattering suppression in an underwater LiDAR signal processing based on CEEMDAN-fast ICA algorithm.

A new signal-processing method to realize blind source separation (BSS) in an underwater lidar-radar system based on complete ensemble empirical mode decomposition with adaptive noise (CEEMDAN) and independent component analysis (ICA) is presented in this paper. The new statistical signal processing approach can recover weak target reflections from strong backward scattering clutters in turbid water, thus greatly improve the ranging accuracy. The proposed method can overcome the common problem of ICA, i.e. the number of observations must be equal to or larger than the number of sources to be separated, therefore multiple independent observations are required, which normally is realized by repeating the measurements in identical circumstances. In the new approach, the observation matrix for ICA is constructed by CEEMDAN from a single measurement. BSS can be performed on a single measurement of the mixed source signals. The CEEMDAN-ICA method avoid the uncertainty induced by the change of measurement circumstances and reduce the errors in ICA algorithm. In addition, the new approach can also improve the detection efficiency because the number of measurement is reduced. The new approach was tested in an underwater lidar-radar system. A mirror and a white Polyvinyl chloride (PVC) plate were used as target, respectively. Without using the CEEMDAN- Fast ICA, the ranging error with the mirror was 12.5 cm at 2 m distance when the attenuation coefficient of the water was 7.1 m-1. After applying the algorithm, under the same experimental conditions, the ranging accuracy was improved to 4.33 cm. For the PVC plate, the ranging errors were 5.01 cm and 21.54 cm at 3.75 attenuation length with and without the algorithm respectively. In both cases, applying this algorithm can significantly improve the ranging accuracy.

532-nm-modulated pulse generation based on a time-delay loop and polarization rotation.

A simple and low-cost scheme of generating 532 nm modulated pulses is investigated both theoretically and experimentally. The modulator is an external cavity based on a temporal delay loop and polarization rotation that is realized by two half-wave plates. Propagating in the temporal delay loop multiple times and being outputted partially after each round trip, the intensity of the initial green laser pulse is modulated. By analyzing the polarization of the pulse in each round trip, the pulse train is modeled to simulate the waveform of the modulated pulse. This modulator is coupled with a sub-nanosecond 532-nm-laser source to verify the model of intensity modulation. In the experiment, by rotating the HWPs, modulated pulses with various temporal profiles are obtained. The fundamental modulation frequency is calculated to be 520 MHz, and the frequency of the second harmonic also exceeds 1 GHz. Such a scheme of intensity modulation can be applied in underwater detection and ranging.

Roles of Protein Disulfide Isomerase in Breast Cancer.

Protein disulfide isomerase (PDI) is the endoplasmic reticulum (ER)'s most abundant and essential enzyme and serves as the primary catalyst for protein folding. Due to its apparent role in supporting the rapid proliferation of cancer cells, the selective blockade of PDI results in apoptosis through sustained activation of UPR pathways. The functions of PDI, especially in cancers, have been extensively studied over a decade, and recent research has explored the use of PDI inhibitors in the treatment of cancers but with focus areas of other cancers, such as brain or ovarian cancer. In this review, we discuss the roles of PDI members in breast cancer and PDI inhibitors used in breast cancer research. Additionally, a few PDI members may be suggested as potential molecular targets for highly metastatic breast cancers, such as TNBC, that require more attention in future research.

Demonstration of thermal modulation using nanoscale and microscale structures for ultralarge pixel array photothermal transducers.

Large-pixel-array infrared emitters are attractive in the applications of infrared imaging and detection. However, the array scale has been restricted in traditional technologies. Here, we demonstrated a light-driven photothermal transduction approach for an ultralarge pixel array infrared emitter. A metal-black coating with nanoporous structures and a silicon (Si) layer with microgap structures were proposed to manage the thermal input and output issues. The effects of the nanoscale structures in the black coating and microscale structures in the Si layer were investigated. Remarkable thermal modulation could be obtained by adjusting the nanoscale and microscale structures. The measured stationary and transient results of the fabricated photothermal transducers agreed well with the simulated results. From the input view, due to its wide spectrum and high absorption, the black coating with nanoscale structures contributed to a 5.6-fold increase in the temperature difference compared to that without the black coating. From the output view, the microgap structures in the Si layer eliminated the in-plane thermal crosstalk. The temperature difference was increased by 340% by modulating the out-of-plane microstructures. The proposed photothermal transducer had a rising time of 0.95 ms and a falling time of 0.53 ms, ensuring a fast time response. This method is compatible with low-cost and mass manufacturing and has promising potential to achieve ultralarge-array pixels beyond ten million.

Ultrabroadband metal-black absorbers and the performance simulations based on a three-dimensional cluster-structure model.

Broadband light absorbers are attractive for their applications in photodetection and thermo-photovoltaics. Metal-black porous coatings have been experimentally proven to have broadband light absorption. However, a theoretical model is of importance for the design and fabrication of metal-black absorbers. Here we propose a three-dimensional cluster-structure model to simulate the absorption of metal-black films. Based on experimental data, a model of uniform clusters formed by nanoparticles with Gaussian random distribution in position was constructed for the gold-black absorbers. The absorption spectra were simulated with this model by finite-difference time-domain method. The gold-black absorbers were fabricated by the one-step magnetron sputtering process. The average absorption of gold-black absorbers with sputtering pressure of 50, 65 and 80 Pa were 72.34%, 87.25% and 91.08% in the visible spectral range and 81.77% (80 Pa) in 3-12 µm infrared spectrum. The high broadband absorption was attributed to the multiple scattering of incident light inside the gold-black porous structure. The simulations showed good agreements with experimental results with an error of 2.35% in visible spectrum and 1.82% in 3-12 µm infrared spectrum. To verify the applicability of this model, aluminum-black absorbers with different thicknesses were fabricated, and the absorption error between simulation and experimental results was 3.96%. This cluster model can be a good tool to design ultrabroadband absorbers based on metal-black porous structures.

The Hydroxyquinoline Analogue YUM70 Inhibits GRP78 to Induce ER Stress-Mediated Apoptosis in Pancreatic Cancer.

GRP78 (glucose-regulated protein, 78 kDa) is a key regulator of endoplasmic reticulum (ER) stress signaling. Cancer cells are highly proliferative and have high demand for protein synthesis and folding, which results in significant stress on the ER. To respond to ER stress and maintain cellular homeostasis, cells activate the unfolded protein response (UPR) that promotes either survival or apoptotic death. Cancer cells utilize the UPR to promote survival and growth. In this study, we describe the discovery of a series of novel hydroxyquinoline GRP78 inhibitors. A representative analogue, YUM70, inhibited pancreatic cancer cell growth in vitro and showed in vivo efficacy in a pancreatic cancer xenograft model with no toxicity to normal tissues. YUM70 directly bound GRP78 and inactivated its function, resulting in ER stress-mediated apoptosis. A YUM70 analogue conjugated with BODIPY showed colocalization of the compound with GRP78 in the ER. Moreover, a YUM70-PROTAC (proteolysis targeting chimera) was synthesized to force degradation of GRP78 in pancreatic cancer cells. YUM70 showed a strong synergistic cytotoxicity with topotecan and vorinostat. Together, our study demonstrates that YUM70 is a novel inducer of ER stress, with preclinical efficacy as a monotherapy or in combination with topoisomerase and HDAC inhibitors in pancreatic cancer. SIGNIFICANCE: This study identifies a novel ER stress inducer that binds GRP78 and inhibits pancreatic cancer cell growth in vitro and in vivo, demonstrating its potential as a therapeutic agent for pancreatic cancer.

A Robust Infrared Transducer of an Ultra-Large-Scale Array.

A robust micro-electro-mechanical systems (MEMS) infrared thin film transducer of an ultra-large-scale array was proposed and fabricated on a 4-inch silicon wafer. The silicon substrate and micro cavities were introduced. This novel transducer had excellent mechanical stability, time response, and state-of-the-art pixel scale. It could bear a load of 1700 g and its load pressure was improved by more than 5.24 times and time constant decreased by 50.7% compared to the traditional soft infrared thin film transducer. The array scale of its pixels exceeded 2k × 2k. The simulation and measured results of the transient temperature and radiation intensity were well consistent. Illuminated by a 532 nm laser with a frequency of 50 Hz and 50% duty cycle, the thermal decay time of the proposed transducer was 6.0 ms. A knife-edge image was utilized for spatial resolution test and the full width at half maximum (FWHM) of the proposed transducer was 24% smaller than the traditional soft one. High-resolution infrared images were generated using the proposed robust transducer. These results proved that the robust transducer was promising in infrared image generation.

SAR study of bisamides as cyclophilin a inhibitors for the development of host-targeting therapy for hepatitis C virus infection.

The therapy of chronic hepatitis C virus infections has significantly improved with the development of direct-acting antivirals (DAAs), which contain NS3/4A protease, NS5A, and NS5B polymerase inhibitors. However, mutations in specific residues in these viral target genes are associated with resistance to the DAAs. Especially inhibitors of NS3/4A protease and NS5A, such as grazoprevir and velpatasvir, have a low barrier to resistant mutations. As a result, the mutations influence the virological outcomes after DAA treatment. CypA inhibitors, as host-targeted agents, act on host factors to inhibit HCV replication, exhibiting a high resistance barrier and pan-genotype activities against HCV. Therefore, they can be developed into alternative, more effective anti-HCV agents. However, CypA inhibitors are natural products and analogs. Based on previous studies, bisamide derivatives were designed and synthesized to develop a novel class of CypA inhibitors. Bisamide derivative 7c is a promising compound with potent anti-HCV activity at subtoxic concentrations. Surface plasmon resonance experiments revealed that 7c directly binds to CypA. All these studies indicated that the derivative 7c is a potent CypA inhibitor, which can be used as a host-targeted agent in combination with other antiviral agents for anti-HCV treatment.

Performance improvement of an infrared scene generation chip by in-plane microstructures.

An infrared (IR) scene generation chip based on multi-layer thin film was demonstrated. Infrared radiation was efficiently converted from visible light energy through chip absorption. We proposed that the contradictive material parameter requirements aroused by high-spatial resolution and high-frame rate of the dynamic IR scene generator could be successfully solved by a periodical microstructure fabrication. The theoretical simulation results based on a semi-one-dimensional heat transfer model illustrated that the spatial resolution of the generated IR scene was improved using a microstructure with a low contact area ratio and high fill factor, while the thermal decay time of the chip was kept unaffected. Two infrared scene generation chips with different microstructures were fabricated by lithography and site-selective deposition. Measured by non-contact thermography, the chip with low microstructure contact area ratio (0.17) showed a higher spatial resolution (13.2 lp/mm) than that with high microstructure contact area ratio of 0.46 (8.0 lp/mm). Moreover, both chips had the same thermal decay time of 20 ms. The experimental results indicated that the proposed method is an effective and economic way to improve the performance of infrared scene generation chips.

Measurement of the thermophysical properties of self-suspended thin films based on steady-state thermography.

To measure the in-plane thermal conductivity and the infrared emissivity of thin films, a steady-state IR micro-thermography with simplified measurement procedure and new data processing method is presented in this paper. Thermal images at different optical heat intensities were collected by an IR camera. By subtracting two measurement results, the background thermal radiation was eliminated. Infrared emissivity, heat flux density and in-plane thermal conductivity were obtained by data fitting. The most important advantages of the proposed method were that the background thermal radiation was eliminated and the complicated optical absorption measurement was replaced by heat power measurement. We have performed measurements on self-suspended polyimide films with different thicknesses. For 504 nm thick film, the thermal conductivity and infrared emissivity in 7∼14 µm were 0.18 Wm-1K-1 and 0.07, respectively. The measurement uncertainty of the thermal conductivity and infrared emissivity were lower than 13% and 10%, respectively, which were much lower than the previous reported value (20%) from the steady-state method. Our measurement procedure was suitable for analyzing thin films with a wide range of thermal properties.

An objective comparison of detection and segmentation algorithms for artefacts in clinical endoscopy.

We present a comprehensive analysis of the submissions to the first edition of the Endoscopy Artefact Detection challenge (EAD). Using crowd-sourcing, this initiative is a step towards understanding the limitations of existing state-of-the-art computer vision methods applied to endoscopy and promoting the development of new approaches suitable for clinical translation. Endoscopy is a routine imaging technique for the detection, diagnosis and treatment of diseases in hollow-organs; the esophagus, stomach, colon, uterus and the bladder. However the nature of these organs prevent imaged tissues to be free of imaging artefacts such as bubbles, pixel saturation, organ specularity and debris, all of which pose substantial challenges for any quantitative analysis. Consequently, the potential for improved clinical outcomes through quantitative assessment of abnormal mucosal surface observed in endoscopy videos is presently not realized accurately. The EAD challenge promotes awareness of and addresses this key bottleneck problem by investigating methods that can accurately classify, localize and segment artefacts in endoscopy frames as critical prerequisite tasks. Using a diverse curated multi-institutional, multi-modality, multi-organ dataset of video frames, the accuracy and performance of 23 algorithms were objectively ranked for artefact detection and segmentation. The ability of methods to generalize to unseen datasets was also evaluated. The best performing methods (top 15%) propose deep learning strategies to reconcile variabilities in artefact appearance with respect to size, modality, occurrence and organ type. However, no single method outperformed across all tasks. Detailed analyses reveal the shortcomings of current training strategies and highlight the need for developing new optimal metrics to accurately quantify the clinical applicability of methods.

Molecular design, synthesis, and biological evaluation of bisamide derivatives as cyclophilin A inhibitors for HCV treatment.

Hepatitis C virus (HCV) is a major cause of end-stage liver diseases. Direct-acting antivirals (DAAs), including inhibitors of nonstructural proteins (NS3/4A protease, NS5A, and NS5B polymerase), represent key components of anti-HCV treatment. However, some DAAs are associated with increased drug resistance and undesired side effects. Previous reports have shown that bisamides could be a novel class of cyclophilin A (CypA) inhibitors for treating HCV as a member of combinational therapies. To fully elucidate structure-activity relationships of bisamide derivatives and find a better hit compound with diverse binding modes, 16 biamides were designed with the help of docking program. They were then synthesized using one-pot four-component Ugi reaction. 7e with selectivity index of more than 18.9 (50% effective concentration of 5.3 µM, but no cytotoxicity at 100 µM) and unique binding mode that could be dived into gatekeeper pocket was selected as a new hit compound. Surface plasmon resonance experiments revealed that 7e is able to bind to CypA with a KD of 3.66 µM. Taken together, these results suggest that 7e as a CypA inhibitor could be used as an alternative anti-HCV agent in combinational therapy in the future.

Inhibition of protein disulfide isomerase in glioblastoma causes marked downregulation of DNA repair and DNA damage response genes.

Aberrant overexpression of endoplasmic reticulum (ER)-resident oxidoreductase protein disulfide isomerase (PDI) plays an important role in cancer progression. In this study, we demonstrate that PDI promotes glioblastoma (GBM) cell growth and describe a class of allosteric PDI inhibitors that are selective for PDI over other PDI family members. Methods: We performed a phenotypic screening triage campaign of over 20,000 diverse compounds to identify PDI inhibitors cytotoxic to cancer cells. From this screen, BAP2 emerged as a lead compound, and we assessed BAP2-PDI interactions with gel filtration, thiol-competition assays, and site-directed mutagenesis studies. To assess selectivity, we compared BAP2 activity across several PDI family members in the PDI reductase assay. Finally, we performed in vivo studies with a mouse xenograft model of GBM combining BAP2 and the standard of care (temozolomide and radiation), and identified affected gene pathways with nascent RNA sequencing (Bru-seq). Results: BAP2 and related analogs are novel PDI inhibitors that selectively inhibit PDIA1 and PDIp. Though BAP2 contains a weak Michael acceptor, interaction with PDI relies on Histidine 256 in the b' domain of PDI, suggesting allosteric binding. Furthermore, both in vitro and in vivo, BAP2 reduces cell and tumor growth. BAP2 alters the transcription of genes involved in the unfolded protein response, ER stress, apoptosis and DNA repair response. Conclusion: These results indicate that BAP2 has anti-tumor activity and the suppressive effect on DNA repair gene expression warrants combination with DNA damaging agents to treat GBM.

RF intensity modulated mid-IR light source based on dual-frequency optical parametric oscillation.

Laser detection and ranging (Ladar)-radar uses intensity-modulated laser beam for ranging and remote sensing. It has the advantages of high spatial resolution from Ladar and immunity to atmospheric turbulence from radar, since the synthetic wavelength is in the order of meters. Intensity modulated mid-IR laser can extend the Ladar-radar concept to mid-IR spectrum. An intensity modulated mid-IR light source with tunable wavelength and modulation frequency is presented. A dual-frequency 1064 nm laser is used to pump an optical parametric oscillator with magnesium oxide doped periodically-poled lithium niobate crystal (MgO:PPLN) as the nonlinear medium. The beat note frequency of the dual-frequency pump laser can be tuned from 140 to 160 MHz. When the pump power is 13 W, the idler output power at mid-IR is 2.38 W, corresponding to a pump-idler conversion efficiency of 19.4%. The wavelength of the idler light is tuned from 3.1 to 3.8 µm by changing the temperature of the MgO:PPLN crystal. The modulation spectra of the mid-IR light are studied. The frequency stability of the beat note in mid-IR is compared with the one in the pump, which are 4.1 Hz and 3 Hz in 240 second measuring time, respectively.

Design, Synthesis, and Biological Evaluation of Novel Allosteric Protein Disulfide Isomerase Inhibitors.

Protein disulfide isomerase (PDI) is responsible for nascent protein folding in the endoplasmic reticulum (ER) and is critical for glioblastoma survival. To improve the potency of lead PDI inhibitor BAP2 (( E)-3-(3-(4-hydroxyphenyl)-3-oxoprop-1-en-1-yl)benzonitrile), we designed and synthesized 67 analogues. We determined that PDI inhibition relied on the A ring hydroxyl group of the chalcone scaffold and cLogP increase in the sulfonamide chain improved potency. Docking studies revealed that BAP2 and analogues bind to His256 in the b' domain of PDI, and mutation of His256 to Ala abolishes BAP2 analogue activity. BAP2 and optimized analogue 59 have modest thiol reactivity; however, we propose that PDI inhibition by BAP2 analogues depends on the b' domain. Importantly, analogues inhibit glioblastoma cell growth, induce ER stress, increase expression of G2M checkpoint proteins, and reduce expression of DNA repair proteins. Cumulatively, our results support inhibition of PDI as a novel strategy to treat glioblastoma.

Discovery and Mechanistic Elucidation of a Class of Protein Disulfide Isomerase Inhibitors for the Treatment of Glioblastoma.

Protein disulfide isomerase (PDI) is overexpressed in glioblastoma, the most aggressive form of brain cancer, and folds nascent proteins responsible for the progression and spread of the disease. Herein we describe a novel nanomolar PDI inhibitor, pyrimidotriazinedione 35G8, that is toxic in a panel of human glioblastoma cell lines. We performed a medium-throughput 20 000-compound screen of a diverse subset of 1 000 000 compounds to identify cytotoxic small molecules. Cytotoxic compounds were screened for PDI inhibition, and, from the screen, 35G8 emerged as the most cytotoxic inhibitor of PDI. Bromouridine labeling and sequencing (Bru-seq) of nascent RNA revealed that 35G8 induces nuclear factor-like 2 (Nrf2) antioxidant response, endoplasmic reticulum (ER) stress response, and autophagy. Specifically, 35G8 upregulated heme oxygenase 1 and solute carrier family 7 member 11 (SLC7A11) transcription and protein expression and repressed PDI target genes such as thioredoxin-interacting protein 1 (TXNIP) and early growth response 1 (EGR1). Interestingly, 35G8-induced cell death did not proceed via apoptosis or necrosis, but by a mixture of autophagy and ferroptosis. Cumulatively, our data demonstrate a mechanism for a novel PDI inhibitor as a chemical probe to validate PDI as a target for brain cancer.

Second-harmonic generation of a dual-frequency laser in a MgO:PPLN crystal.

A dual-frequency CW laser at a wavelength of 1.064 µm is frequency doubled in a MgO:PPLN nonlinear crystal. The fundamental dual-frequency laser has a tunable beat note from 125 MHz to 175 MHz. A laser-diode pumped fiber amplifier is used to amplify the dual-frequency fundamental output to a maximum power of 50 W before frequency doubling. The maximum output power of the green light is 1.75 W when the input fundamental power is 12 W, corresponding to a frequency doubling efficiency of 14.6%. After frequency doubling, green light with modulation frequencies in two bands from 125 MHz to 175 MHz and from 250 MHz to 350 MHz is achieved simultaneously. The relative intensities of the beat notes at the two bands can be adjusted by changing the relative intensities at different frequencies of the fundamental light. The spectral width and frequency stabilities of the beat notes in fundamental wave and green light are also measured, respectively. The modulated green light has potential applications in underwater ranging, communication, and imaging.