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Electrophysiology, Unplugged: Imaging Membrane Potential with Fluorescent Indicators.

Membrane potential is a fundamental biophysical property maintained by every cell on earth. In specialized cells like neurons, rapid changes in membrane potential drive the release of chemical neurotransmitters. Coordinated, rapid changes in neuronal membrane potential across large numbers of interconnected neurons form the basis for all of human cognition, sensory perception, and memory. Despite the importance of this highly orchestrated and distributed activity, the traditional method for recording membrane potential is through the use of highly invasive single-cell electrodes that offer only a small glimpse of the total activity within a system. Fluorescent dyes that change their optical properties in response to changes in biological voltage have the potential to provide a powerful complement to traditional electrode-based methods of inquiry. Voltage-sensitive fluorescent indicators would allow the direct observation of membrane potential changes, significantly expanding our ability to monitor membrane potential dynamics in living systems. Toward this end, we have initiated a program to design, synthesize, and apply voltage-sensitive fluorophores that report on membrane potential dynamics with high sensitivity and speed. The basis for this optical voltage sensing is membrane potential-dependent photoinduced electron transfer (PeT). Voltage-sensitive fluorophores, or VoltageFluors, possess a fluorophore, a conjugated molecular wire, and an aniline donor. At resting potentials, in which the cell has a hyperpolarized or negative potential relative to the outside of the cell, PeT from the aniline donor is enhanced and fluorescence is diminished. At depolarized potentials, the membrane potential decreases the rate of PeT, allowing an increase in fluorescence. We show that a number of different fluorophores, molecular wires, and aniline donors can be employed to generate fast and sensitive VoltageFluor dyes. Multiple lines of evidence point to a PeT-based mechanism for voltage sensing, delivering fast response kinetics (∼25 ns), good sensitivity (>60% Δ/), compatibility with two-photon illumination, excellent signal-to-noise, and the ability to detect neuronal and cardiac action potentials in single trials. In this Account, we provide an overview of the challenges facing the design of fluorescent voltage indicators. We trace the development of molecular wire-based fluorescent voltage indicators within our group, beginning from fluorescein-based VoltageFluor to long-wavelength indicators that use modern fluorophores like silicon rhodamine and carbofluorescein. We examine design principles for PeT-based voltage indicators, showcase the use of our recent indicators for two-photon voltage imaging in intact brains, and explore the development of hybrid indicators that can localize to genetically defined cells. Finally, we highlight outstanding challenges to and opportunities for voltage imaging.

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N,N,N Trimethyl 4 (6 phen Cell Meter™ NIR Mitocho 10 Octadecylacridine oran 3,3' Dipropylthiacarbocya Screen Quest™ Membrane 1,1' Dioctadecyl 3,3,3',3 Cell Meter™ Mitochondri Cell Meter™ JC 10 Mitoc Screen Quest™ Membrane 5 (Octadecanoylamino)fluo Screen Quest™ Membrane 1,1'-Dioctadecyl-3,3,3',3

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Metallacycle Transfer and its Link to Light-Emitting Materials and Conjugated Polymers.

Major advances in optoelectronic technologies (e. g., solar cells, organic light-emitting diodes, etc…) are prefaced by the discovery of new synthetic methodologies. In this review, the key role of the Fagan-Nugent reaction in enabling our team (and others) to gain access to new building blocks for luminescent materials and conjugated polymers bearing p-block elements will be described. The Fagan-Nugent reaction is extremely powerful as a synthetic tool since the efficient zirconium-element atom exchange involved affords a wide range of unsaturated inorganic heterocycles of controllable composition and function.

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Andarine C19H18F3N3O6� 3-O-Acetyl-17-O-tert-buty CAR,Car,Constitutive andr ∆1-Androstene-3α,17β- Rabbit Anti-O-GlcNAc tran Rabbit Anti-SEC14 like pr Androgen Receptor (Phosph Rabbit Anti-O-GlcNAc tran Rabbit Anti-SEC14 like pr Androgen Receptor Ab 1 Rabbit Anti-TFR2 Transfer Andrographolide CAS Numbe

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Photodynamic antitumor activity of Ru(ii) complexes of imidazo-phenanthroline conjugated hydroxybenzoic acid as tumor targeting photosensitizers.

Two novel Ru(ii) polypyridyl complexes bearing imidazo-phenanthroline conjugated hydroxybenzoic acid groups were designed to enhance the tumor targeting ability as photosensitizers for photodynamic therapy. [Ru(bpy)2(phcpip)] (ClO4)2 (Ru-1) and [Ru(bpy)2(ohcpip)] (ClO4)2 (Ru-2) (bpy = 2,2'-bipyridine; phcpip = 2-(3-carboxyl-4-hydroxyphenyl) imidazo [4,5-f]phenanthroline; ohcpip = 2-(2-hydroxyl-3-carboxyphenyl) imidazo [4,5-f] [1,10] phenanthroline) were synthesized and their photodynamic antitumor activities were investigated. Both complexes displayed high photocytotoxicity toward cancerous cell lines HepG2, A549, MCF-7, and MDA-MB-231, but low photocytotoxicity toward normal cell lines GES-1 and Huvec. They were mainly localized at the nucleus of HepG2 cells after 24 h incubation, arrested the cell cycle at the G2/M phase and induced cancer cell apoptosis through reactive oxygen species (ROS) mediated pathways. Tumor targeting of the complexes is attributed to stronger molecular binding to DNA.

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A theranostic agent for cancer therapy and imaging in the second near-infrared window.

Theranostic nanoparticles are integrated systems useful for simultaneous diagnosis and imaging guided delivery of therapeutic drugs, with wide ranging potential applications in the clinic. Here we developed a theranostic nanoparticle (~ 24 nm size by dynamic light scattering) p-FE-PTX-FA based on polymeric micelle encapsulating an organic dye (FE) fluorescing in the 1,000-1,700 nm second near-infrared (NIR-II) window and an anti-cancer drug paclitaxel. Folic acid (FA) was conjugated to the nanoparticles to afford specific binding to molecular folate receptors on murine breast cancer 4T1 tumor cells. the nanoparticles accumulated in 4T1 tumor through both passive and active targeting effect. Under an 808 nm laser excitation, fluorescence detection above 1,300 nm afforded a large Stokes shift, allowing targeted molecular imaging tumor with high signal to background ratios, reaching a high tumor to normal tissue signal ratio (T/NT) of (20.0 ± 2.3). Further, 4T1 tumors on mice were completed eradicated by paclitaxel released from p-FE-PTA-FA within 20 days of the first injection. Pharmacokinetics and histology studies indicated p-FE-PTX-FA had no obvious toxic side effects to major organs. This represented the first NIR-II theranostic agent developed.

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An iRGD-conjugated prodrug micelle with blood-brain-barrier penetrability for anti-glioma therapy.

Various obstacles impede the chemotherapy efficiency of glioma in clinic, such as blood brain barrier (BBB) and blood brain tumor barrier (BBTB). Ligand-mediated polymeric micelles have shown great potential for improving the efficiency of glioma treatment. Herein, we developed a disulfide bond-conjugated prodrug polymer consisted of camptothecin (CPT) and polyethylene glycol (PEG) with further modification of iRGD peptide. The polymer of CPT-S-S-PEG-COOH could self-assemble into nanosized polymeric micelles with diameter around 100 nm, and loaded with photosensitizer IR780 for combination therapy. The micelles displayed good stability with controlled drug release under physiological environment. Importantly, the iRGD modified polymeric micelles demonstrated favorable ability to cross the BBB and target glioma cells via αv β integrin and neuropilin-1-mediated ligand transportation in vitro and in vivo. The whole synthesis process is simple and the drug loading content of CPT in the [email protected] micelles was higher than 10%. Moreover, [email protected] micelles combined chemotherapy with photodynamic therapy (PDT) displayed more excellent tumor-killing capability than the other groups. Thus, both in vitro and in vivo studies suggested that the targeting prodrug system could not only effectively cross various barriers to reach at glioma site, but also significantly enhance the antitumor effect with laser irradiation. Our findings consequently suggested that [email protected] micelles with laser irradiation are a promising drug delivery system for glioma therapy.

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Hydrophobic interaction chromatography (HIC) method development and characterization of resolved drug-load variants in site-specifically conjugated pyrrolobenzodiazepine dimer-based antibody drug conjugates (PBD-ADCs).

Antibody drug conjugates (ADCs) are heterogeneous biopharmaceutical products that demand extensive characterization to ensure batch consistency, safety, and efficacy. Hydrophobic interaction chromatography (HIC) is the state-of-the-art analytical tool to monitor conjugation-related critical quality attributes (CQAs) e.g. drug-load distribution and Drug-to-Antibody Ratio (DAR). For the next generation site-specific PBD-ADCs (PBD: pyrrolobenzodiazepine dimer), denaturing RP-HPLC (reverse-phase high-performance chromatography) is the current method to determine average DAR. In this manuscript, we have utilized native HIC for the first time to understand conjugation related CQAs in PBD-ADCs. In terms of the method development, the type of stationary phase and salt, coupled with reduction of the reactive imine in the PBD drug-linker to an amine form in the sample preparation, have played a key role in achieving the best HIC resolution for the drug-load variants. The established HIC conditions resolved DAR 0, DAR 1, and two DAR 2 peaks for PBD-ADCs. Extended characterization of the DAR 2 peaks confirmed that they have retained characteristically distinct antibody Fc N-glycan distributions (Fc = Fragment crystallization region). Therefore, the results support that the HIC conditions established for PBD-ADCs is valuable in not only determining DAR values but also other important attributes including native drug-load distribution and unique DAR 2 conformations existed as a result of the N-glycan heterogeneity.

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CRKL & PTPN11 Protein Pro Rabbit Anti-Insulin Recep HSPB1 & TP53 Protein Prot Rabbit Anti-IAA (Indole-3 PPM1B & CHUK Protein Prot PTPN7 & MAPK14 Protein Pr SPP1 & F2 Protein Protein PTPRR & MAPK1 Protein Pro AKT1 & IKBKB Protein Prot Mouse Anti-Insulin(1D4:) Rabbit Anti-Integrin alph TP53 & PIAS2 Protein Prot

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Exosome-mediated siRNA delivery to suppress postoperative breast cancer metastasis.

High recurrence and metastasis of triple-negative breast cancer (TNBC) after operation is a leading cause of breast cancer related death. The pre-metastatic niche (PMN) is an environment in a secondary organ conducive to the metastasis of a primary tumor. Herein, we identify exosomes from autologous breast cancer cells that show effective lung targeting ability. Based on this, we developed the biomimetic nanoparticles (cationic bovine serum albumin (CBSA) conjugated siS100A4 and exosome membrane coated nanoparticles, CBSA/[email protected]) to improve drug delivery to the lung PMN. CBSA/[email protected] self-assembled nanoparticles formed homogeneous sizes of ~200 nm, protected siRNA from degradation, and showed excellent biocompatibility. Further in vivo studies showed that CBSA/[email protected] had a higher affinity toward lung in comparison to the CBSA/[email protected], and exhibited outstanding gene-silencing effects that significantly inhibited the growth of malignant breast cancer cells. Taken together, these results indicate that CBSA/[email protected] self-assembled nanoparticles are a promising strategy to suppress postoperative breast cancer metastasis.

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Silver Nanoparticle Conjugated Star PCL-b-AMPs Copolymer as Nanocomposite Exhibits Efficient Antibacterial Properties.

The traditional antibiotics have specific intracellular targets and disinfect in chemical ways, and the drug-resistance induced by the antibiotics has grown into an emerging threat. It is an urgent to call for novel strategies and antibacterial materials to control this situation. Herein, we report a class of silver-decorated nanocomposite [email protected] as potent nano-antibiotic, constructed by ring-opening polymerization of the monomers ε-caprolactone, Z-Lys-N-carboxyanhydrides (NCAs) and Phe-NCAs, then decorated with AgNPs, and characterized by SEM, TEM and DLS. The biological assays revealed that the nanocomposite possessed strong antibacterial efficacy against both Gram-positive and Gram-negative bacteria including clinic isolated bacteria MRSA, VRE, P. aeruginosa, and K. pneumonia, exhibiting a MIC value range in 2-8 μg/mL. Importantly, the S. aureus and P. aeruginosa treated with the nanocomposite didn't show drug-resistance even after 21th passages. Also, in vivo anti-infective assays showed that the nanocomposite was able to effectively kill bacteria in the infected viscera of mice. The study of the sterilization mechanism showed that the nanocomposite exhibited a multimodal antimicrobial mechanism, including irreversibly damaged the membrane structure, made the leakage of intracellular ions and subsequently induced generation of the reactive oxygen species (ROS), ultimately sterilized bacteria. The nanocomposite exhibit effective broad-spectrum antibacterial property and show low toxicity to the mammalian cells /animal. Overall, the [email protected] gained in this work show great potential as a highly promising antibacterial material for biomedical applications including drug-resistant bacterial infection.

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Rabbit Anti-ASB7 Polyclon Anti-Ascorbate Oxidase Pe Rabbit Anti-ASB7 Polyclon Rabbit Anti-ASB17 Polyclo Anti-Conjugated D-Asparti Rabbit Anti-ASB17 Polyclo Rabbit Anti-Eukaryotic as Rabbit Anti-D.Aspartic ac Rabbit Anti-Eukaryotic as Rabbit Anti-ASB12 Polyclo Rabbit Anti-ASB12 Polyclo Rabbit Anti-ASB7 Polyclon

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Structural characterization of bioactive compounds in Cotula cinerea extracts by ultra-high-performance liquid chromatography with photodiode array and high-resolution time-of-flight mass spectrometry detectors (UHPLC-PDA-ESI-ToF/HRMS).

Cotula cinerea of the Asteraceae family is a traditional Moroccan plant, with various biological activities such as analgesic, cytotoxic and antioxidant effects which are often related to the presence of secondary metabolites. The present work aims to screen and identify the main phytochemicals compounds of Cotula cinerea extracts.

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High density breast cance High density (188 cases 2 High density pancreatic c High density cervix cance High density esophageal c Stomach cancer high densi High density liver cancer High density stomach canc High density breast invas High density multiple org High density non small ce Colon cancer high density

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