Different-mode power splitters based on a multi-dimension direct-binary-search algorithm.

In this work, we design, fabricate, and characterize a different-mode (waveguide-connected) power splitter ((W)PS) by what we believe to be a novel multi-dimension direct-binary-search algorithm that can significantly balance the device performance, time cost, and fabrication robustness by searching the state-dimension, rotation-dimension, shape-dimension, and size-dimension parameters. The (W)PS can simultaneously generate the fundamental transverse electric (TE0) and TE1 mode with the 1:1 output balance. Compared with the PS, the WPS can greatly shorten the adiabatic taper length between the single-mode waveguide and the grating coupler. The measured results of the different-mode (W)PS indicate that the insertion loss and crosstalk are less than 0.9 (1.3) dB and lower than -17.8 (-14.9) dB from 1540 nm to 1560 nm. In addition, based on the tunable tap couplers, the different-mode (W)PS can be extended to multiple output ports with different modes and different transmittances.

Design of OMC-Sagnac Loop Using PDMS and Different Package Structures to Improve Sensing Performance and Optimize the Ill-Conditioned Matrix.

In the process of ocean exploration, highly accurate and sensitive measurements of seawater temperature and pressure significantly impact the study of seawater's physical, chemical, and biological processes. In this paper, three different package structures, V-shape, square-shape, and semicircle-shape, are designed and fabricated, and an optical microfiber coupler combined Sagnac loop (OMCSL) is encapsulated in these structures with polydimethylsiloxane (PDMS). Then, the temperature and pressure response characteristics of the OMCSL, under different package structures, are analyzed by simulation and experiment. The experimental results show that structural change hardly affects temperature sensitivity, and square-shape has the highest pressure sensitivity. In addition, with an input error of 1% F.S., temperature and pressure errors were calculated, which shows that a semicircle-shape structure can increase the angle between lines in the sensitivity matrix method (SMM), and reduce the effect of the input error, thus optimizing the ill-conditioned matrix. Finally, this paper shows that using the machine learning method (MLM) effectively improves demodulation accuracy. In conclusion, this paper proposes to optimize the ill-conditioned matrix problem in SMM demodulation by improving sensitivity with structural optimization, which essentially explains the cause of the large errors for multiparameter cross-sensitivity. In addition, this paper proposes to use the MLM to solve the problem of large errors in the SMM, which provides a new method to solve the problem of the ill-conditioned matrix in SMM demodulation. These have practical implications for engineering an all-optical sensor that can be used for detection in the ocean environment.

Research Progress on Magneto-Refractive Magnetic Field Fiber Sensors.

The magnetic field is a vital physical quantity in nature that is closely related to human production life. Magnetic field sensors (namely magnetometers) have significant application value in scientific research, engineering applications, industrial productions, and so forth. Accompanied by the continuous development of magnetic materials and fiber-sensing technology, fiber sensors based on the Magneto-Refractive Effect (MRE) not only take advantage in compact structure, superior performance, and strong environmental adaptability but also further meet the requirement of the quasi-distributed/distributed magnetic field sensing; they manifest potential and great application value in space detection, marine environmental monitoring, etc. Consequently, the present and prevalent Magneto-Refractive Magnetic Field Fiber Sensors (MR-MFSs) are briefly summarized by this paper, proceeding from the perspective of physicochemical properties; design methods, basic performance and properties are introduced systematically as well. Furthermore, this paper also summarizes key fabrication techniques and future development trends of MR-MFSs, expecting to provide ideas and technical references for staff engaging in relevant research.

Design of an Er-doped surface plasmon resonance-photonic crystal fiber to improve magnetic field sensitivity.

In order to meet the demand for large-scale magnetic field testing, this paper proposes a D-shaped magneto-refractive photonic crystal fiber (MRPCF) based on surface plasmon resonance (SPR) by using the erbium-doped materials. The four different structures of Models A, B, C, and D are designed by changing the diameter, the position, and the number of layers of the air holes, and the corresponding magnetic field sensing characteristics are analyzed. The results show that in the magnetic field range of 5-405 mT, the magnetic field sensitivities of Models A, B, C, and D are 28 pm/mT, 48 pm/mT, 36 pm/mT, and 21 pm/mT, respectively. Meanwhile, the figure of merit (FOM) of the four MRPCF-SPR sensors is investigated, which have FOMs of 4.8 × 10-4 mT-1, 6.4 × 10-4 mT-1, 1.9 × 10-4 mT-1, 0.9 × 10-4 mT-1. Model B has higher sensitivity and larger FOM. In addition, the effect of the structural parameters of Model B on the sensing performance is also studied. By optimizing each parameter, the magnetic field sensitivity of the optimized Model B is increased to 53 pm/mT, and its magneto-refractive sensitivity and FOM are 2.27 × 10-6 RIU/mT and 6.2 × 10-4 mT-1, respectively. It shows that the magneto-refractive effect of MRPCF can be effectively enhanced by optimizing the structural design of fiber. The proposed MRPCF is an all-solid-state fiber, which solves the instability problem of the magnetic fluid-filled fiber and reduces the complexity of the fabrication process. The all-solid-state MRPCF can be used in the development of quasi-distributed optical fiber magnetic field sensors and has broad applications in the fields of geological exploration, earthquake and tsunami monitoring, and military navigation.

Contrasting influences of biogeophysical and biogeochemical impacts of historical land use on global economic inequality.

Climate change has significant implications for macro-economic growth. The impacts of greenhouse gases and anthropogenic aerosols on economies via altered annual mean temperature (AMT) have been studied. However, the economic impact of land-use and land-cover change (LULCC) is still unknown because it has both biogeochemical and biogeophysical impacts on temperature and the latter differs in latitudes and disturbed land surface types. In this work, based on multi-model simulations from the Coupled Model Intercomparison Project Phase 6, contrasting influences of biogeochemical and biogeophysical impacts of historical (1850-2014) LULCC on economies are found. Their combined effects on AMT result in warming in most countries, which harms developing economies in warm climates but benefits developed economies in cold climates. Thus, global economic inequality is increased. Besides the increased AMT by the combined effects, day-to-day temperature variability is enhanced in developing economies but reduced in developed economies, which further deteriorates global economic inequality.

Black carbon-climate interactions regulate dust burdens over India revealed during COVID-19.

India as a hotspot for air pollution has heavy black carbon (BC) and dust (DU) loadings. BC has been identified to significantly impact the Indian climate. However, whether BC-climate interactions regulate Indian DU during the premonsoon season is unclear. Here, using long-term Reanalysis data, we show that Indian DU is positively correlated to northern Indian BC while negatively correlated to southern Indian BC. We further identify the mechanism of BC-dust-climate interactions revealed during COVID-19. BC reduction in northern India due to lockdown decreases solar heating in the atmosphere and increases surface albedo of the Tibetan Plateau (TP), inducing a descending atmospheric motion. Colder air from the TP together with warmer southern Indian air heated by biomass burning BC results in easterly wind anomalies, which reduces dust transport from the Middle East and Sahara and local dust emissions. The premonsoon aerosol-climate interactions delay the outbreak of the subsequent Indian summer monsoon.

Double Trouble of Air Pollution by Anthropogenic Dust.

With urbanization worldwide in recent decades, anthropogenic dust (AD) emissions due to heavy urban construction and off-road vehicle use have been increasing. Its perturbations on urban air pollution at the global scale are still unclear. Based on observations, we found that a high urban AD optical depth is often accompanied by severe non-dust aerosol optical depth in the planetary boundary layer (PBL), both magnitudes even comparable. To investigate the causes, an AD emission inventory constrained by satellite retrievals is implemented in a global climate model. The results show that AD-induced surface radiative cooling of up to -15.9 ± 4.0 W m-2 regionally leads to reduced PBL height, which deteriorates non-dust pollution, especially over India and northern China, in addition to the tremendous direct AD contribution to pollutants. The estimated global total premature mortality due to AD is 0.8 million deaths per year and is more severe in populous regions.

The antitumor agent PBT-1 directly targets HSP90 and hnRNP A2/B1 and inhibits lung adenocarcinoma growth and metastasis.

Natural products are the major sources of currently available anticancer drugs. We recently reported that phenanthrene-based tylophorine derivative-1 (PBT-1) may be a potential antitumor agent for lung adenocarcinoma. We therefore examined the direct targets of PBT-1 and their effects in inhibiting lung adenocarcinoma. We found that PBT-1 reduced the level of Slug and inhibits the migration, invasion, and filopodia formation of lung adenocarcinoma CL1-5 cells in vitro. In addition, PBT-1 displayed in vivo antitumor and antimetastasis activities against subcutaneous and orthotopic xenografts of CL1-5 cells in nude mice. Chemical proteomics showed that heat shock protein 90 (HSP90) and heterogeneous nuclear ribonucleoproteins A2/B1 (hnRNP A2/B1) bound PBT-1 in CL1-5 cells. Inhibition of HSP90 and hnRNP A2/B1 reduced the activation of AKT and Slug expression. Taken together, these findings suggest that PBT-1 binds to HSP90 and/or hnRNP A2/B1 and initiates antitumor activities by affecting Slug- and AKT-mediated metastasis and tumorigenesis.

Cis-enone resorcylic acid lactones (RALs) as irreversible protein kinase inhibitors.

Resorcylic acid lactones (RALs) constitute a group of polyketide natural products with a large macrocyclic ring fused to resorcylic acid. Despite distinct core scaffold from all marketed kinase inhibitors, RALs bearing a cis-enone moiety have recently shown irreversible yet selective inhibition on a subset of kinases along the MAPK signaling pathway such as MEK, ERK and TAK1. The biochemical and structural studies have demonstrated that the cis-enone RALs can inhibit kinase activity by forming a covalent Michael adduct with an adequately positioned cysteine residue in the ATP binding pocket. This review discusses the mechanism of action, synthetic strategies, and structure-activity relationships (SARs) of cis-enone RALs. It is anticipated that design, synthesis and evaluation of cis-enone RALs analogs will diversify the chemical space of kinase inhibitors and facilitate the development of new leads for the treatment of various diseases such as cancer and inflammatory disorders.

Synthesis and cytotoxicity evaluation of novel pyrido[3,4-d]pyrimidine derivatives as potential anticancer agents.

A new series of 4-substituted 2-amino pyrido[3,4-d]pyrimidine derivatives has been designed and synthesized as potential anticancer agents. These compounds were prepared from a common intermediate, 4-chloro-8-methoxy pyrido[3,4-d]pyrimidin-2-amine, followed by palladium catalyzed cross-coupling reactions or nucleophilic aromatic substitutions at the C-4 position. Evaluation of the representative analogs using the US National Cancer Institute's 60 human cancer cell line (NCI 60) panel identified some of these compounds as exhibiting highly selective activities against breast cancer and renal cancer cell lines. A structure-activity relationship (SAR) study was explored to facilitate further development of this new class of compounds.

Design and synthesis of benzoazepin-2-one analogs as allosteric binders targeting the PIF pocket of PDK1.

A novel series of benzoazepin-2-ones were designed and synthesized targeting the PIF pocket of AGC protein kinases, among which a series of thioether-linked benzoazepin-2-ones were discovered to bind to the PIF pocket of 3-phosphoinositide-dependent kinase-1 (PDK1), and to displace the PIF peptide with an EC(50) values in the lower micromolar range. The structure-activity relationships (SARs) of the linker region, tail region, and distal region were explored to further optimize these novel binders which target the PIF pocket of PDK1. When tested in an in vitro PDK1 enzymatic assay using a peptide substrate, the benzodiazepin-2-ones increased the activity of the enzyme in a concentration-dependent fashion, indicating these compounds act as PDK1 allosteric activators. These new compounds may be further developed as therapeutic agents for the treatment of diseases where the PDK1-mediated AGC protein kinases are dysregulated.

Recent development of cyclic amide (pyridone/lactam) moiety containing heterocycles as protein kinase inhibitors.

Staurosporine, pyridone 6 and hydroxyfasudil are cyclic amide (pyridone/lactam) moiety containing heterocycles that are discovered/developed as potent protein kinase inhibitors targeting on the ATP (Adenosine-5'-triphosphate) binding pocket. Despite different molecular shapes (pentacycle, tetracycle and bicycle, respectively), they all bind to the residues of the hinge region at ATP binding pocket of protein kinases in a very similar manner: the cyclic amide moiety occupies the adenine region of ATP binding pocket and forms at least two hydrogen bonding interaction with the hinge region via its hydrogen bond acceptor/donor pair. Using a few examples of cyclic amide (pyridone/lactam) moiety containing heterocyclic protein kinase inhibitors, this review discusses their therapeutic application, structural basis of kinase inhibition, as well as their associated syntheses. It is anticipated that the design, synthesis and profiling of the kinase inhibitor-biased library based upon the cyclic amide (pyridone/lactam) moiety containing core scaffolds may significantly enhance the efficiency of high-throughput screenings (HTS), accelerate hit-to-lead process and improve the success rate in the development of protein kinase inhibitors for the treatment of various diseases especially cancer.

Pyrimido[5,4-e][1,2,4]triazine-5,7(1H,6H)-dione derivatives as novel small molecule chaperone amplifiers.

Pyrimido[5,4-e][1,2,4]triazine-5,7(1H,6H)-dione derivatives were investigated as novel small molecule amplifiers of heat shock factor 1 transcriptional activity. Lead optimization led to the discovery of compound 4A-13, which displayed potent HSF1 activity under mild heat stress (EC(50)=2.5microM) and significant cytoprotection in both rotenone (EC(50)=0.23microM) and oxygen-glucose deprivation cell toxicity models (80% protection at 2.5microM).

Phenanthrene-based tylophorine-1 (PBT-1) inhibits lung cancer cell growth through the Akt and NF-kappaB pathways.

Tylophorine and related natural compounds exhibit potent antitumor activities. We previously showed that PBT-1, a synthetic C9-substituted phenanthrene-based tylophorine (PBT) derivative, significantly inhibits growth of various cancer cells. In this study, we further explored the mechanisms and potential of PBT-1 as an anticancer agent. PBT-1 dose-dependently suppressed colony formation and induced cell cycle G2/M arrest and apoptosis. DNA microarray and pathway analysis showed that PBT-1 activated the apoptosis pathway and mitogen-activated protein kinase signaling. In contrast, PBT-1 suppressed the nuclear factor kappaB (NF-kappaB) pathway and focal adhesion. We further confirmed that PBT-1 suppressed Akt activation accelerated RelA degradation via IkappaB kinase-alpha and down-regulated NF-kappaB target gene expression. The reciprocal recruitment of RelA and RelB on COX-2 promoter region led to down-regulation of transcriptional activity. We conclude that PBT-1 induces cell cycle G2/M arrest and apoptosis by inactivating Akt and by inhibiting the NF-kappaB signaling pathway. PBT-1 may be a good drug candidate for anticancer chemotherapy.

Structural analogs of tylophora alkaloids may not be functional analogs.

Phenanthroindolizidine-based tylophora alkaloids have been reported to have potential antitumor, anti-immuno and, anti-inflammatory activity. The structure-activity relationships of a series of tylophora alkaloids were studied to guide future drug design. Our results indicate that although these compounds are structural analogs, their potency of cytotoxicity, selectivity against NF-kappaB signaling pathway, and their inhibitory effects against protein and nucleic acid synthesis are different. Because they do not have an identical spectrum of targets, the studied compounds are structural, but may not be functional analogs.

Antitumor agents 253. Design, synthesis, and antitumor evaluation of novel 9-substituted phenanthrene-based tylophorine derivatives as potential anticancer agents.

C9-Substituted phenanthrene-based tylophorine derivatives (PBTs) (13-36) were synthesized and evaluated as in vitro anticancer agents against the human A549 lung cancer cell line. Twelve active compounds were further examined against DU-145 (prostate), ZR-751 (breast), KB (nasopharyngeal), and KB-Vin (multidrug resistant KB subline) human cancer cell lines. They showed potent cytotoxic activity against both wild type and matched multidrug resistant KB cell lines, and displayed notable selectivity toward DU-145 (prostate) and ZR-751 (breast) cancer cell lines. The mode of action of this class may be distinctly different from that of other cancer chemotherapeutic compounds. Three PBT analogs were also evaluated in a murine model. Compound 24b showed modest in vivo antitumor activity against human A549 xenograft in nude mice as well as potent in vitro cytotoxic activity, and thus, is a promising anticancer lead compound.

Antitumor agents 252. Application of validated QSAR models to database mining: discovery of novel tylophorine derivatives as potential anticancer agents.

A combined approach of validated QSAR modeling and virtual screening was successfully applied to the discovery of novel tylophrine derivatives as anticancer agents. QSAR models have been initially developed for 52 chemically diverse phenanthrine-based tylophrine derivatives (PBTs) with known experimental EC(50) using chemical topological descriptors (calculated with the MolConnZ program) and variable selection k nearest neighbor (kNN) method. Several validation protocols have been applied to achieve robust QSAR models. The original dataset was divided into multiple training and test sets, and the models were considered acceptable only if the leave-one-out cross-validated R (2) (q (2)) values were greater than 0.5 for the training sets and the correlation coefficient R (2) values were greater than 0.6 for the test sets. Furthermore, the q (2) values for the actual dataset were shown to be significantly higher than those obtained for the same dataset with randomized target properties (Y-randomization test), indicating that models were statistically significant. Ten best models were then employed to mine a commercially available ChemDiv Database (ca. 500 K compounds) resulting in 34 consensus hits with moderate to high predicted activities. Ten structurally diverse hits were experimentally tested and eight were confirmed active with the highest experimental EC(50) of 1.8 microM implying an exceptionally high hit rate (80%). The same ten models were further applied to predict EC50 for four new PBTs, and the correlation coefficient (R (2)) between the experimental and predicted EC(50) for these compounds plus eight active consensus hits was shown to be as high as 0.57. Our studies suggest that the approach combining validated QSAR modeling and virtual screening could be successfully used as a general tool for the discovery of novel biologically active compounds.

Antitumor agents 251: synthesis, cytotoxic evaluation, and structure-activity relationship studies of phenanthrene-based tylophorine derivatives (PBTs) as a new class of antitumor agents.

Polar phenanthrene-based tylophorine derivatives (PBTs) were designed, synthesized and evaluated as potential antitumor agents. These compounds contain a core phenanthrene structure and can be synthesized efficiently in excellent yield. The newly synthesized PBTs were evaluated for cytotoxic activity against the A549 human cancer cell line. Among them, N-(2,3-methylenedioxy-6-methoxy-phenanthr-9-ylmethyl)-L-2-piperidinemethanol (34) and N-(2,3-methylenedioxy-6-methoxy-phenanthr-9-ylmethyl)-5-aminopentanol (28) showed the highest potency with IC50 values of 0.16 and 0.27 microM, respectively, which are comparable to those of currently used antitumor drugs. A structure-activity relationship (SAR) study was also explored to facilitate the further development of this new compound class.