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Supplementary Figures S1-S4.

Compared with PE pipes, cast iron pipes have more biofilm biomass but less bacterial activity and EPS. Corrosion products can protect bacteria from chlorination just like EPS.

We propose and experimentally demonstrate a novel switchable quadruple-wavelength CW erbium-doped fiber laser, using a linear cavity structure. It is composed of two Sagnac loops that act as cavity mirrors in the resonant cavity. The left loop consists of a 3 dB fiber coupler (FC), a squeezed polarization controller (PC), and a chirped fiber grating. The right loop consists of a 10 dB FC, the same PC and a length multimode fiber with a core diameter of 62.5 μm. The two loops based on different operation principles become two comb filters to jointly excite the multiwavelength output. On the role of the polarization hole burning effect, after adjusting the two PCs, the laser can switch flexibly to output fourteen kinds of different modes from a single wavelength to the quadruple wavelength. All lasing lines, with a narrow linewidth less than 0.28 nm, have the optical signal-to-noise ratio of more than 20 dB. The laser with good power uniformity shows better stabilities of the wavelength and peak power.

For centuries, scientists have pondered why people would help others at a cost to themselves even in the absence of expectation for future benefit. While a growing body of neuroimaging studies has suggested that the ventromedial prefrontal cortex (vmPFC) may be particularly critical for the regulation of altruistic behavior. However, evidence is still lacking in the field of neuroscience regarding the causal link between the region of vmPFC and pure altruistic behavior. In the present study, we designed a modified dictator game with a binary choice in the contexts of gain and loss that aimed to provide a simple and direct measure of participants' altruistic tendency. Using tDCS, we found that modulating the activity of vmPFC could significantly alter altruistic behaviors. Specifically, anodal stimulation of the vmPFC resulted in increasing altruistic choices compared with the cathodal stimulation, and the effect was found both in the gain and loss contexts. In addition, the subsequent inferences about others' altruistic behaviors were correlated with their own choices, and cathodal vmPFC stimulation resulted in a lower inference than sham stimulation in the gain context.

Individual attitudes and preferences are easily affected by social information. In a world where information sharing and dissemination are extremely convenient, social influence has played a greater role than in any previous era. Previous studies have suggested that the medial prefrontal cortex (mPFC) participates in mediating the tendency towards social conformity. However, the specific role of this brain area is still unknown, and it is not clear whether various types of external information influences share a mechanism. In this research, we aimed to use transcranial direct current stimulation (tDCS) to further explore the role of the mPFC in human conformity behaviour. In our experiment, the subjects received the majority opinion/expert opinion, and conformity behaviour was measured by the subject's tendency to follow this information after receiving the social information. Our research found that when social information conveys the majority opinion, cathodal stimulation of the mPFC significantly enhances the subject's consistency tendency. When social information conveys an expert opinion, stimulation of the mPFC has no significant effect on the conformity tendency of subjects. The results suggest that the mPFC plays an inhibitory role in regulating the social conformity tendency and that the activated neural circuits may vary with source when dealing with social influences.

We propose a stable multi-wavelength erbium-doped photonic crystal fiber laser at room temperature using figure-eight cavity. The physical model and theoretical mechanism are analyzed theoretically. The power changes are less than 1dB during 100 min scan. © 2020 The Author(s)

Millimeter wave technology is one of the technologies developed rapidly in recent years. The research was mainly to study the transmission of millimeter wave through textile material named silk fabric. We observed the phenomenon of sub-millimeter-wave transmission and reflection of the silk fabric, and concluded that with the number of silk fabric layers increasing, effect of scattering and absorption of the millimeter wave enhanced. The conclusion could be further employed in millimeter wave and THz imaging, dangerous goods inspection and other security application.

A label-free optical fiber biosensor based on a Mach-Zehnder interferometer for real-time bovine serum albumin (BSA) concentration detection has been proposed and experimentally demonstrated. An air microcavity has been fabricated by means of splicing a segment of microfiber between two single mode fibers (SMFs) with appropriate offset such that it acts as a microfluidic channel, where external media can directly interact with the guided light. Experimental results show a high sensitivity of -15.56 nm/(mg/mL).

We report a real-time and highly sensitive liquid level sensor based on multimode interference to acquire the level measurement of high-RI liquids, e.g. oil, which probably poses promising applications in the motor-dom. The level sensor is fabricated by fusion splicing a short section of NCF between two SMFs. Level measurement with both low-RI and high-RI liquids have been studied; it is found that the sensor shows the maximum sensitivity of ∼ 1.22 dB/mm, corresponding to a level resolution of ∼ 0. 6 μ m in the range of 0 mm to 4 mm for high-RI liquids. In addition, experimental results have demonstrated that the proposed sensor shows good performance, thus providing a liquid level sensor that is inexpensive with a very simple fabrication process.

Natural compound schweinfurthins are of considerable interest for novel therapy development because of their selective anti-proliferative activity against human cancer cells. We previously reported the isolation of highly active schweinfurthins E-H, and in the present study, mechanisms of the potent and selective anti-proliferation were investigated. We found that schweinfurthins preferentially inhibited the proliferation of PTEN deficient cancer cells by indirect inhibition of AKT phosphorylation. Mechanistically, schweinfurthins and their analogs arrested trans-Golgi-network trafficking, an intracellular vesicular trafficking system, resulting in the induction of endoplasmic reticulum stress and the suppression of both lipid raft-mediated PI3K activation and mTOR/RheB complex formation, which collectively led to an effective inhibition of mTOR/AKT signaling. The trans-Golgi-network traffic arresting effect of schweinfurthins was associated with their in vitro binding activity to oxysterol-binding proteins that are known to regulate intracellular vesicular trafficking. Moreover, schweinfurthins were found to be highly toxic toward PTEN-deficient B cell lymphoma cells, and displayed 2 orders of magnitude lower activity toward normal human peripheral blood mononuclear cells and primary fibroblasts in vitro. These results revealed a previously unrecognized role of schweinfurthins in regulating trans-Golgi-network trafficking, and linked mechanistically this cellular effect with mTOR/AKT signaling and with cancer cell survival and growth. Our findings suggest the schweinfurthin class of compounds as a novel approach to modulate oncogenic mTOR/AKT signaling for cancer treatment.

Reprogramming of immunosuppressive tumor microenvironment (TME) by targeting alternatively activated tumor associated macrophages (M2TAM), myeloid-derived suppressor cells (MDSC), and regulatory T cells (Tregs), represents a promising strategy for developing novel cancer immunotherapy. Prostaglandin E2 (PGE2), an arachidonic acid pathway metabolite and mediator of chronic inflammation, has emerged as a powerful immunosuppressor in the TME through engagement with one or more of its 4 receptors (EP1-EP4). We have developed E7046, an orally bioavailable EP4-specific antagonist and show here that E7046 has specific and potent inhibitory activity on PGE2-mediated pro-tumor myeloid cell differentiation and activation. E7046 treatment reduced the growth or even rejected established tumors in vivo in a manner dependent on both myeloid and CD8+ T cells. Furthermore, co-administration of E7046 and E7777, an IL-2-diphtheria toxin fusion protein that preferentially kills Tregs, synergistically disrupted the myeloid and Treg immunosuppressive networks, resulting in effective and durable anti-tumor immune responses in mouse tumor models. In the TME, E7046 and E7777 markedly increased ratios of CD8+granzymeB+ cytotoxic T cells (CTLs)/live Tregs and of M1-like/M2TAM, and converted a chronic inflammation phenotype into acute inflammation, shown by substantial induction of STAT1/IRF-1 and IFNγ-controlled genes. Notably, E7046 also showed synergistic anti-tumor activity when combined with anti-CTLA-4 antibodies, which have been reported to diminish intratumoral Tregs. Our studies thus reveal a specific myeloid cell differentiation-modifying activity by EP4 blockade and a novel combination of E7046 and E7777 as a means to synergistically mitigate both myeloid and Treg-derived immunosuppression for cancer treatment in preclinical models.

A multi-wavelength erbium-doped photonic crystal fiber (ED-PCF) ring laser based on nonlinear polarization rotation was demonstrated experimentally. To the best of our knowledge, this study is the first to use a polarization-dependent isolator with an ED-PCF to form an equivalent fiber filter. The intensity-dependent inhomogeneous loss induced by nonlinear polarization rotation was applied to reduce the mode competition caused by ED-PCF. A detailed theoretical analysis using the Jones matrix method to calculate the transfer function of the laser was presented. The theoretical data, which were confirmed by the experimental results, showed that a multi-wavelength with a spacing of approximately 2.26 nm was achieved by controlling the polarization controller. The proposed fiber laser with a signal-to-noise ratio higher than 40 dB achieved a low threshold power of 30 mW. Therefore, stable multi-wavelength outputs with a power fluctuation of less than 2 dB were generated at room temperature.

A flexible-rigid hopping mechanism which is inspired by the locust jumping was proposed, and its kinematic characteristics were analyzed. A series of experiments were conducted to observe locust morphology and jumping process. According to classic mechanics, the jumping process analysis was conducted to build the relationship of the locust jumping parameters. The take-off phase was divided into four stages in detail. Based on the biological observation and kinematics analysis, a mechanical model was proposed to simulate locust jumping. The forces of the flexible-rigid hopping mechanism at each stage were analyzed. The kinematic analysis using pseudo-rigid-body model was described by D-H method. It is confirmed that the proposed bionic mechanism has the similar performance as the locust hind leg in hopping. Moreover, the jumping angle which decides the jumping process was discussed, and its relation with other parameters was established. A calculation case analysis corroborated the method. The results of this paper show that the proposed bionic mechanism which is inspired by the locust hind limb has an excellent kinematics performance, which can provide a foundation for design and motion planning of the hopping robot.

Eribulin mesylate (Halaven™), a totally synthetic analog of the marine polyether macrolide halichondrin B, has recently been approved in the United States as a treatment for breast cancer. It is also currently under regulatory review in Japan and the European Union. Our continuing medicinal chemistry efforts on this scaffold have focused on oral bioavailability, brain penetration and efficacy against multidrug resistant (MDR) tumors by lowering the susceptibility of these compounds to P-glycoprotein (P-gp)-mediated drug efflux. Replacement of the 1,2-amino alcohol C32 side chain of eribulin with fragments neutral at physiologic pH led to the identification of analogs with significantly lower P-gp susceptibility. The analogs maintained low- to sub-nM potency in vitro against both sensitive and MDR cell lines. Within this series, increasing lipophilicity generally led to decreased P-gp susceptibility. In addition to potency in cell culture, these compounds showed in vivo activity in mouse xenograft models.

Novel second generation analogs of eribulin mesylate, a tubulin agent recently approved for the treatment of breast cancer, are reported. Our recent efforts have focused on expanding the target indications for this class of compounds to other tumor types. Herein, we describe the design, synthesis and evaluation of eribulin analogs active against brain tumor cell lines in vitro and corresponding brain tumor models in mice. Attenuation of basicity of the amino group(s) in the C32 side-chain region led to compounds with lower susceptibility to P-gp mediated drug efflux, allowing these compounds to permeate through the blood-brain barrier. In preclinical in vivo studies, these compounds showed significantly higher levels in the brain and cerebrospinal fluid as compared to eribulin. In addition, analogs within this series showed antitumor activity in an orthotopic murine model of human glioblastoma.

Excessive release of proinflammatory cytokines by innate immune cells is an important component of the pathogenic basis of malaria. Proinflammatory cytokines are a direct output of Toll-like receptor (TLR) activation during microbial infection. Thus, interference with TLR function is likely to render a better clinical outcome by preventing their aberrant activation and the excessive release of inflammatory mediators. Herein, we describe the protective effect and mechanism of action of E6446, a synthetic antagonist of nucleic acid-sensing TLRs, on experimental cerebral malaria (ECM) induced by Plasmodium berghei ANKA. We show that in vitro, low doses of E6446 specifically inhibited the activation of human and mouse TLR9. Tenfold higher concentrations of this compound also inhibited the human TLR8 response to single-stranded RNA. In vivo, therapy with E6446 diminished the activation of TLR9 and prevented the exacerbated cytokine response observed during acute Plasmodium infection. Furthermore, severe signs of ECM, such as limb paralysis, brain vascular leak, and death, were all prevented by oral treatment with E6446. Hence, we provide evidence that supports the involvement of nucleic acid-sensing TLRs in malaria pathogenesis and that interference with the activation of these receptors is a promising strategy to prevent deleterious inflammatory responses that mediate pathogenesis and severity of malaria.

A novel multi-wavelength fiber laser was achieved simultaneously tunable and switchable outputs of wavelength spacing with an Erbium-doped fiber amplifiers (EDFA) based on nonlinear polarization rotation (NPR) effect. We described and proved the tunable of wavelength spacing in detail by using different length of polarization maintaining fiber (PMF). The switchable outputs was simply realized an interchange among multi-wavelength operations by adjusting the polarization controller (PC) in the ring cavity. The tunable and switchable multi-wavelength fiber ring laser could stably operate in room temperature, and the peak power variations in each wavelength were measured to be less than 1dB.

An account is given of the author's several approaches to the synthesis of the parent chromophore of phytochrome (1), a protein-bound linear tetrapyrrole derivative that controls photomorphogenesis in higher plants. These studies culminated in enantioselective syntheses of both 2R- and 2S-phytochromobilin (4), as well as several (13)C-labeled derivatives designed to probe the site of Z,E-isomerization during photoexcitation. When reacted in vitro, synthetic 2R-4 and recombinant-derived phytochrome apoprotein N-C produced a protein-bound chromophore with identical difference spectra to naturally occurring 1.

Structurally simplified macrocyclic ketone analogues of halichondrin B were prepared by total synthesis and found to retain the potent cell growth inhibitory activity in vitro, stability in mouse serum, and in vivo efficacy of the natural product.

The protective effects of transient limb ischemia (TLI) induced by several cycles of intermittent pressure cuff inflation and deflation for a period have been widely investigated, however the reliability of this protocol has not been clearly verified. Our study aimed to investigate the reliability of pressure cuff induced TLI in conscious rabbits.Eight New Zealand rabbits were subjected to TLI without anesthesia. TLI consisted of 3 cycles of ischemia and reperfusion induced by inflating the cuff placed on the left lower limb to 200 mmHg for 5 minutes followed by deflating the cuff for 5 minutes. Skin color, pulse oxygen saturation (SpO2), pulse rate (PR), plethysmogram waveform (Pleth), and ultrasound detection of the blood flow in the extremity distal to the ischemic segment were observed to confirm ischemia and reperfusion during TLI. The frequency of severe limb movement during TLI was also recorded to assess the amenability of this protocol in conscious rabbits.The skin color of the extremity distal to the ischemic segment changed from bright red to dark purple after inflating the cuff to 200 mmHg, and returned to normal after cuff deflation. Pleth, PR and SpO2 disappeared during ischemia and restored during reperfusion in the monitor. Blood flow of the left posterior tibial artery was completely blocked by a pressure of 200 mmHg during ischemia, and recovered immediately after cuff deflation. The frequency of severe limb movement in supine position was higher than that in prone position (P0.05), but there was no severe limb movement that could result in disturbance to ischemia when the rabbits were placed in prone position.Pressure cuff inflating to 200 mmHg for 5 minutes and deflating for 5 minutes is a reliable regimen to induce TLI in conscious rabbits.

The discovery that circulating nucleic acid-containing complexes in the serum of autoimmune lupus patients can stimulate B cells and plasmacytoid dendritic cells via Toll-like receptors 7 and 9 suggested that agents that block these receptors might be useful therapeutics. We identified two compounds, AT791 {3-[4-(6-(3-(dimethylamino)propoxy)benzo[d]oxazol-2-yl)phenoxy]-N,N-dimethylpropan-1-amine} and E6446 {6-[3-(pyrrolidin-1-yl)propoxy)-2-(4-(3-(pyrrolidin-1-yl)propoxy)phenyl]benzo[d]oxazole}, that inhibit Toll-like receptor (TLR)7 and 9 signaling in a variety of human and mouse cell types and inhibit DNA-TLR9 interaction in vitro. When administered to mice, these compounds suppress responses to challenge doses of cytidine-phosphate-guanidine (CpG)-containing DNA, which stimulates TLR9. When given chronically in spontaneous mouse lupus models, E6446 slowed development of circulating antinuclear antibodies and had a modest effect on anti-double-stranded DNA titers but showed no observable impact on proteinuria or mortality. We discovered that the ability of AT791 and E6446 to inhibit TLR7 and 9 signaling depends on two properties: weak interaction with nucleic acids and high accumulation in the intracellular acidic compartments where TLR7 and 9 reside. Binding of the compounds to DNA prevents DNA-TLR9 interaction in vitro and modulates signaling in vivo. Our data also confirm an earlier report that this same mechanism may explain inhibition of TLR7 and 9 signaling by hydroxychloroquine (Plaquenil; Sanofi-Aventis, Bridgewater, NJ), a drug commonly prescribed to treat lupus. Thus, very different structural classes of molecules can inhibit endosomal TLRs by essentially identical mechanisms of action, suggesting a general mechanism for targeting this group of TLRs.

Covering: 1993 to 2002The synthesis of eribulin mesylate from microgram to multi-gram scale is described in this Highlight. Key coupling reactions include formation of the C30a to C1 carbon–carbon bond and macrocyclic ring closure through an intramolecular Nozaki–Hiyama–Kishi reaction.

Covering: 1993 to 2002The synthesis of eribulin mesylate from microgram to multi-gram scale is described in this Highlight. Key coupling reactions include formation of the C30a to C1 carbon–carbon bond and macrocyclic ring closure through an intramolecular Nozaki–Hiyama–Kishi reaction.

Chiral nonracemic acetylenic acids of general structure 11, prepared using the Schreiber modification of the Nicholas reaction, have been converted to β-amino acid derivatives of type 12 by a two-step sequence involving Curtius rearrangement followed by oxidative cleavage of the acetylenic bond. Amino acid derivatives 12 are excellent precursors for β-lactams of the carbapenem class, including the important antibiotics thienamycin (1) and PS-5 (4).

By addressing the relative stereochemistry of the four acyclic portions via organic synthesis, the complete relative stereochemistry of maitotoxin (MTX) has been established as 1B. The relative stereochemistry of the C.1−C.15 portion was elucidated via a two-phase approach: (1) the synthesis of the eight diastereomers possible for model C, representing the C.1−C.11 portion, and the eight diastereomers possible for model D, representing the C.11−C.15 portion, and the comparison of their proton and carbon NMR characteristics with those of MTX, concluding that 9 and 35 represent the relative stereochemistry of the corresponding portions of MTX; (2) the synthesis of the two remote diastereomers 51 and 52, and comparison of their proton and carbon NMR characteristics with those of MTX, concluding that 51 represents the relative stereochemistry of the C.1−C.15 portion of MTX. The relative stereochemistry of the C.35−C.39, C.63−C.68, and C.134−C.142 acyclic portions was established via (1) the synthesis of the ...

A multi-wavelength Erbium-doped photonic crystal fiber ring laser utilizing nonlinear polarization rotation was demonstrated by experiment. A polarization-dependent isolator with a 9m Er-doped photonic crystal fiber was used to form an equivalent fiber filter. The fiber laser without specific wavelength selection device could operate at single-wavelength, dual-wavelength, triple-wavelength and quadruple-wavelength depending on the polarization. The intensity-dependent inhomogeneous loss induced by nonlinear polarization rotation was applied to reduce the mode competition. Therefore, stable multi-wavelength output with the power fluctuation of 0.27dB was generated at room temperature. In the meantime, the tuning of wavelength could be achieved through adjusting the polarization controller. The quadruple-wavelength with a spacing of 2.2 nm was achieved, and the uniformity of multi-wavelength spectra was improved by increasing pump power. The proposed fiber laser with an extinction ratio of higher than 40 dB achieved a low threshold power of about 30 mW to realize simultaneously multi-wavelength outputs.

Dihydropyrromethenone 1b (R = p -methoxybenzyl), a potential precursor for the synthesis of phytochrome ( 3 ), has been prepared in enantiomerically pure form beginning with the homochiral acetylenic lactone 18 .

A series of eribulin analogues was evolved in silico through iterative atom-based enumeration employing a genetic algorithm-derived survival function to minimize predicted PgP-mediated drug efflux. Representatives of the virtual series were subsequently synthesized in the laboratory and tested in vitro for PgP-susceptibility. These new computer-inspired derivatives were found to exhibit high cell growth inhibitory activity and to be among the least sensitive to P-glycoprotein-mediated drug efflux in the eribulin series, thereby validating this approach to in silico molecular design.

A switchable multi-wavelength erbium-doped fiber laser based on wavelength-dependent loss with polarization has been obtained, to optimize the laser above, we have demonstrated experimentally the relationship between the laser output wavelength and the coupling ratio.

Publisher Summary This chapter focuses on the discovery and development of eribulin. Eribulin mesylate (HALAVEN) is an antitubulin antimitotic agent with distinct microtubule end-binding properties that result in inhibition of microtubule dynamics in ways that differ from those of vinblastine and paclitaxel. This agent was recently approved by the U.S. Food and Drug Administration (FDA) for use in patients with metastatic breast cancer who have previously received at least two chemotherapeutic regimens for the treatment of metastatic disease. HALAVEN represents a new and exciting treatment option that for the first time has been shown to improve overall survival in heavily pretreated women with late stage breast cancer. The path leading to the discovery and development of eribulin included close three-way collaboration among the Kishi group at Harvard University, the National Cancer Institute (NCI), and Eisai. At many points along the drug discovery path, setbacks and roadblocks arose that threatened to derail the program. Nevertheless, each of the problems was solved in turn, thereby demonstrating that a structurally complex molecule could be optimized through total synthesis to successfully deliver a marketed drug that meets all pharmacological, toxicological, and physicochemical requirements.

Homochiral acetylenic acids of general structure 10 , prepared using the Schreiber modification of the Nicholas reaction, have been converted to β-amino acid derivatives of type 11 by a two steps sequence involving Curtius rearrangement followed by oxidative cleavage of the acetylenic bond. Amino acid derivatives 11 are excellent precursors for β-lactams of the carbapenem class.

Homochiral acetylenic acid 26 , prepared using the Schreiber modification of the Nicholas reaction, has been converted to β-amino acid derivative 28 by a two step sequence involving Curtius rearrangement fallowed by oxidative clevage of the acetylenic bond. Amino acid derivative 28 was then converted to thienamycin (β12) precursor 30 by cyclization with DCC followed by epmerization.