Identification of potent biparatopic antibodies targeting FGFR2 fusion driven cholangiocarcinoma.

Translocations involving FGFR2 gene fusions are common in cholangiocarcinoma and predict response to FGFR kinase inhibitors. However, the rate and durability of response are limited due to the emergence of resistance, typically involving acquired FGFR2 kinase domain mutations, and to sub-optimal dosing, relating to drug adverse effects. Here, we report the development of biparatopic antibodies targeting the FGFR2 extracellular domain (ECD), as candidate therapeutics. Biparatopic antibodies can overcome drawbacks of standard bivalent monoparatopic antibodies, which often show poor inhibitory or even agonist activity against oncogenic receptors. We show that oncogenic transformation by FGFR2 fusions requires an intact ECD. Moreover, by systematically generating biparatopic antibodies that target distinct epitope pairs along the FGFR2 ECD, we identified antibodies that effectively block signaling and malignant growth driven by FGFR2-fusions. Importantly, these antibodies demonstrate efficacy in vivo, synergy with FGFR inhibitors, and activity against FGFR2 fusions harboring kinase domain mutations. Thus, biparatopic antibodies may serve as new treatment options for patients with FGFR2-altered cholangiocarcinoma. Summary: We identify biparatopic FGFR2 antibodies that are effective against FGFR2 fusion driven cholangiocarcinoma.

Water-Catalyzed Formation of Reactive Oxygen Species from NO2 on a Weakly Hydrated Calcite Surface.

The interfaces of weakly hydrated mineral substrates have been shown to serve as catalytic sites for chemical reactions that may not be accessible in the gas phase or under bulk conditions. Currently known mechanisms for the formation of reactive oxygen species (ROS) from nitrogen dioxide (NO2) involve NO2 dimerization. Here, we report the formation of the ROS HONO via a mechanism involving simple adsorption of a single NO2 molecule on a weakly hydrated calcite substrate. First-principles molecular dynamics simulations coupled with enhanced sampling techniques show how an adsorbed water sublayer can enhance NO2 adsorption on calcite compared to adsorption on a bare dry substrate. On the weakly hydrated calcite surface, an interfacial electric field facilitates proton extraction from water, thus allowing HONO formation from a single adsorbed NO2, i.e., without the need for the formation of a NO2 dimer precomplex. HONO formation on calcite is kinetically more favorable than that in the gas phase, with a reaction barrier of 14 kcal/mol on the weakly hydrated calcite surface compared to 27 kcal/mol in the gas phase. Further photocatalysed HONO production by visible light and HONO dissociation are hampered on calcite, unlike the process on silica. NO2 is a significant anthropogenic pollutant, and understanding its chemistry is crucial for explaining the high ROS levels and haze formation in polluted areas or prebiotic ROS generation. These findings emphasize how mineral substrates under water-restricted hydration conditions can trigger chemical pathways that are unexpected in the gas phase or under bulk conditions.

Assessing the effect of acid and alkali treatment on a halloysite-based catalyst for dry reforming of methane.

Dry reforming of methane (DRM) has recently received wide attention owing to its outstanding performance in the reduction and conversion of CH4 and CO2 to syngas (H2 and CO). From an industrial perspective, nickel (Ni)-supported catalysts have been deemed among the most suitable catalysts for DRM owing to their low cost and high activity compared to noble metals. However, a downside of nickel catalysts is their high susceptibility to deactivation due to coke formation and sintering at high temperatures. Using appropriate supports and preparation methods plays a major role in improving the activity and stability of Ni-supported catalysts. Halloysite nanotubes (HNTs) are largely utilized in catalysis as a support for Ni owing to their abundance, low cost, and ease of preparation. The treatment of HNTs (chemical or physical) prior to doping with Ni is considered a suitable method for increasing the overall performance of the catalyst. In this study, the surface of HNTs was activated with acids (HNO3 and H2SO4) and alkalis (NaOH and Na2CO3 + NaNO3) prior to Ni doping to assess the effects of support treatment on the stability, activity, and longevity of the catalyst. Nickel catalysts on raw HNT, acid-treated HNT, and alkali-treated HNT supports were prepared via wet impregnation. A detailed characterization of the catalysts was conducted using X-ray diffraction (XRD), BET surface area analysis, scanning electron microscopy (SEM), transmission electron microscopy (TEM), solid-state nuclear magnetic resonance (ssNMR), H2-temperature programmed reduction, (H2-TPR), CO2-temperature programmed desorption (CO2-TPD), and Ni-dispersion via H2-pulse chemisorption. Our results reveal a clear alteration in the structure of HNTs after treatment, while elemental mapping shows a uniform distribution of Ni throughout all the different supports. Moreover, the supports treated with a molten salt method resulted in the overall highest CO2 and CH4 conversion among the studied catalysts and exhibited high stability over 24 hours testing.

Addressing the Effectiveness and Molecular Mechanism of the Catalytic CO2 Hydration in Aqueous Solutions by Nickel Nanoparticles.

Hydration of carbon dioxide in water solution is the rate limiting step for the CO2 mineralization process, a process which is at the base of many carbon capture and utilization (CCU) technologies aiming to convert carbon dioxide to added-value products and mitigate climate change. Here, we present a combined experimental and computational study to clarify the effectiveness and molecular mechanism by which nickel nanoparticles, NiNPs, may enhance CO2 hydration in aqueous solutions. Contrary to previous literature, our kinetic experiments recording changes of pHs, conductivity, and dissolved carbon dioxide in solution reveal a minimal effect of the NiNPs in catalyzing CO2 hydration. Our atomistic simulations indicate that the Ni metal surface can coordinate only a limited number of water molecules, leaving uncoordinated metal sites for the binding of carbon dioxide or other cations in solution. This deactivates the catalyst and limits the continuous re-formation of a hydroxyl-decorated surface, which was a key chemical step in the previously suggested Ni-catalyzed hydration mechanism of carbon dioxide in aqueous solutions. At our experimental conditions, which expand the investigation of NiNP applicability toward a wider range of scenarios for CCU, NiNPs show a limited catalytic effect on the rate of CO2 hydration. Our study also highlights the importance of the solvation regime: while Ni surfaces may accelerate carbon dioxide hydration in water restricted environments, it may not be the case in fully hydrated conditions.

Uptake and reactivity of NO2 on the hydroxylated silica surface: A source of reactive oxygen species.

We report state-of-the-art first-principles molecular dynamics results on the heterogeneous chemical uptake of NO2, a major anthropogenic pollutant, on the dry and wet hydroxylated surface of α-quartz, which is a significant component of silica-based catalysts and atmospheric dust aerosols. Our investigation spotlights an unexpected chemical pathway by which NO2 (i) can be adsorbed as HONO by deprotonation of interfacial silanols (i.e., -Si-OH group) on silica, (ii) can be barrierless converted to nitric acid, and (iii) can finally dissociated to surface bounded NO and hydroxyl gas phase radicals. This chemical pathway does not invoke any previously experimentally postulated NO2 dimerization, dimerization that is less likely to occur at low NO2 concentrations. Moreover, water significantly catalyzes the HONO formation and the dissociation of nitric acid into surface-bounded NO and OH radicals, while visible light adsorption can further promote these chemical transformations. This work highlights how water-restricted solvation regimes on common mineral substrates are likely to be a source of reactive oxygen species, and it offers a theoretical framework for further and desirable experimental efforts, aiming to better constrain trace gases/mineral interactions at different relative humidity conditions.

Epitope-engineered human hematopoietic stem cells are shielded from CD123-targeted immunotherapy.

Targeted eradication of transformed or otherwise dysregulated cells using monoclonal antibodies (mAb), antibody-drug conjugates (ADC), T cell engagers (TCE), or chimeric antigen receptor (CAR) cells is very effective for hematologic diseases. Unlike the breakthrough progress achieved for B cell malignancies, there is a pressing need to find suitable antigens for myeloid malignancies. CD123, the interleukin-3 (IL-3) receptor alpha-chain, is highly expressed in various hematological malignancies, including acute myeloid leukemia (AML). However, shared CD123 expression on healthy hematopoietic stem and progenitor cells (HSPCs) bears the risk for myelotoxicity. We demonstrate that epitope-engineered HSPCs were shielded from CD123-targeted immunotherapy but remained functional, while CD123-deficient HSPCs displayed a competitive disadvantage. Transplantation of genome-edited HSPCs could enable tumor-selective targeted immunotherapy while rebuilding a fully functional hematopoietic system. We envision that this approach is broadly applicable to other targets and cells, could render hitherto undruggable targets accessible to immunotherapy, and will allow continued posttransplant therapy, for instance, to treat minimal residual disease (MRD).

Optically Transparent Gold Nanoparticles for DSSC Counter-Electrode: An Electrochemical Characterization.

A gold nanoparticles transparent electrode was realized by chemical reduction. This work aims to compare the transparent gold nanoparticles electrode with a more commonly utilized gold-film-coated electrode in order to investigate its potential use as counter-electrode (CE) in dye-sensitized solar cells (DSSCs). A series of DSSC devices, utilizing I-/I3- and Co(III)/(II) polypyridine redox mediators [Co(dtb)3]3+/2+; dtb = 4,4'ditert-butyl-2,2'-bipyridine)], were evaluated. The investigation focused firstly on the structural characterization of the deposited gold layers and then on the electrochemical study. The novelty of the work is the realization of a gold nanoparticles CE that reached 80% of average visible transmittance. We finally examined the performance of the transparent gold nanoparticles CE in DSSC devices. A maximum power conversion efficiency (PCE) of 4.56% was obtained with a commercial I-/I3--based electrolyte, while a maximum 3.1% of PCE was obtained with the homemade Co-based electrolyte.

Laser ablation fabrication of ap-NiO/n-Si heterojunction for broadband and self-powered UV-Visible-NIR photodetection.

We report on the optoelectronic characteristics ofp-NiO/n-Si heterojunction photodiode for broadband photodetection, fabricated by depositing ap-type NiO thin film onto a commercialn-type silicon substrate using pulsed laser deposition (PLD) technique. The structural properties of the PLD-grownp-NiO material were analysed by means of x-ray diffraction and x-ray photoelectron spectroscopy, confirming its crystalline nature and revealing the presence of Ni vacancies, respectively. Hall measurements confirmed thep-type semiconducting nature of the NiO thin film having a carrier concentration of 8.4 × 1016cm-3. The current-voltage (I-V) characteristics of thep-NiO/n-Si heterojunction photodevice were investigated under different wavelengths ranging from UV to NIR. The self-bias properties under different illuminations of light were also explored systematically. Under self-bias condition, the photodiode exhibits excellent responsivities of 12.5 mA W-1, 24.6 mA W-1and 30.8 mA W-1with illumination under 365 nm, 485 nm, and 850 nm light, respectively. In addition, the time dependency of the photoresponse of the fabricated photodevice has also been investigated and discussed thoroughly.

Efficient Photocatalytic Degradation of Organic Dyes by AgNPs/TiO2/Ti3C2T x MXene Composites under UV and Solar Light.

Due to their broad applications in various industrial activities, and their well-known negative impacts on the aquatic environment, organic dyes have been continuously identified as serious threat to the quality of ecosystems. The photocatalytic degradation process in aqueous solutions has emerged as an efficient and reliable approach for the removal of organic dyes. MXenes, a new class of two-dimensional (2D) nanomaterials, possess unique chemical composition, surface functionalities, and physicochemical properties. Such characteristics enable MXenes to act as efficient catalysts or cocatalysts to photodegrade organic molecules. This work explores the application of Ti3C2T x MXene decorated with silver and palladium nanoparticles, using a simple hydrothermal treatment method, for the photocatalytic degradation of methylene blue (MB) and rhodamine B (RhB). The chemical composition of these photocatalysts, as well as their structural properties and morphology, was characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD), and X-ray photoelectron spectroscopy (XPS) techniques. The photocatalytic degradation abilities of the pristine MXene and the synthesized MXene composites were investigated under ultraviolet and solar light irradiation. A significant improvement in the photocatalytic performances was observed for all oxidized MXene composites when compared to pristine MXene, with a superior degradation efficiency achieved for AgNPs/TiO2/Ti3C2T x . This work broadens the application range of oxidized MXene composites, providing an alternative material for degrading organics dyes and wastewater treatment applications.

Uptake and hydration of sulfur dioxide on dry and wet hydroxylated silica surfaces: a computational study.

We present a first-principles molecular dynamics study on the uptake and hydration of sulfur dioxide on the dry and wet fully hydroxylated surfaces of (0001) α-quartz, which are a proxy for suspended silica dust in the atmosphere. The average adsorption energy for SO2 is about -10 kcal mol-1 on both dry and wet surfaces. The adsorption is driven by hydrogen bond formation between SO2 and the interfacial hydroxyl groups (on dry silica), or with water molecules (in the wet case). In the dry system, we report an additional electrostatic interaction between the interfacial hydroxyl oxygen and the sulfur atom, which further stabilizes the adsorbate. On dry silica, the interfacial hydroxyl group coordinates to SO2 yielding a surface bound bisulfite (Si-SO3H) complex. On the wet surface, SO2 reacts with water forming bisulfite (HSO3-), and the latter remains solvated inside the adsorbed water layer. The hydration barrier for sulfur dioxide is 1 kcal mol-1 and 3 kcal mol-1 on dry and wet silica, respectively, while for the backward reaction (i.e., bisulfite to SO2) the barrier is 6 kcal mol-1 on both surfaces. The modest backward barrier rationalizes earlier experimental findings showing no SO2 uptake on silica. These results underline the importance of the surface hydroxylation and/or adsorbed water layers for the SO2 uptake and its hydration on silica. Moreover, the hydration to bisulfite may prevent direct SO2 photochemistry and be an additional source of sulfate; this is especially relevant in atmospheres subject to a high level of suspended mineral dust, intense solar radiation and atmospheric oxidizers.

High Performance of Anion Exchange Blend Membranes Based on Novel Phosphonium Cation Polymers for All-Vanadium Redox Flow Battery Applications.

The deployment of alkaline anion exchange membranes (AEMs) in flow battery applications has the advantage of a low cationic species crossover rate. However, the alkaline stability conjugated to the low conductivity of hydroxide ions of anion exchange membranes (AEMs) still represents a major drawback for the large deployment of such technology. In this study, three types of tetraarylpolyphosphonium (pTAP)-based copolymers (namely, CP1, CP2, and CP3) are synthesized and blended with chitosan and polyvinylidene fluoride (PVDF) for the fabrication of AEMs. Chitosan, a green biopolymer, was employed as a blend to enhance the water uptake of the base ionomer matrix. It is proposed that the abundancy of hydroxyl groups in chitosan improves considerably the ionic conductivity, water transport, and ion selectivity of the membrane, together with facilitating the dispersion of the chitosan in the pTAP copolymer matrix. The purpose of blending PVDF is instead to provide stable mechanical strength to the composite blend. The chemical, mechanical, and thermal stabilities of the three fabricated composite-blend membranes (i.e., CM1, CM2, and CM3) were characterized. All the membranes exhibited a high water retaining capacity of up to 36.26% (recorded for CM2) along with a hydroxyl ion conductivity of 17.39 mS cm-1. Due to the strong interactions between pTAP copolymers, chitosan, and PVDF polymers (confirmed also by Fourier transform infrared spectroscopy), the studied anion exchange membranes are able to retain up to 97% of the original OH conductivity after 1 M KOH treatment at room temperature for 100 h. The three membranes, namely, CM1, CM2, and CM3, have vanadium ion permeabilities measured at 20 °C of 1.775 × 10-8, 1.718 × 10-8, and 1.648 × 10-8 cm2/s, respectively, which are lower than that for the commercially available Nafion. The good stability and remarkable cell performance of the composite-blend membranes reported here make them definitely excellent candidates for the future generation of vanadium redox flow batteries.

Synthesis and Characterization of a Novel Hydroquinone Sulfonate-Based Redox Active Ionic Liquid.

Introducing redox-active moieties into an ionic liquid (IL) structure is an exciting and attractive approach that has received increasing interest over recent years for a various range of energy applications. The so-called redox-active ionic liquids (RAILs) provide a highly versatile platform to potentially create multifunctional electroactive materials. Ionic liquids are molten salts consisting of ionic species, often having a melting point lower than 100 °C. Such liquids are obtained by combining a bulky asymmetric organic cation and a small anion. Here, we report on the synthesis of a novel RAIL, namely 1-butyl-3-methylimidazolium hydroquinone sulfonate ((BMIM)(HQS)). (BMIM)(HQS) was synthesized in a two-step procedure, starting by the quaternization of methylimidazole using butylchloride to produce 1-butyl-3-methylimidazolium chloride ((BMIM)(Cl)), and followed by the anion exchange reaction, where the chloride anion is exchanged with hydroquinone sulfonate. The resulting product was characterized by 1H NMR, 13C NMR, FT-IR spectroscopy, themogravimetric analysis, and differential scanning calorimetry, and shows a high stability up to 340 °C. Its electrochemical behavior was investigated using cyclic voltammetry at different temperatures and its viscosity analysis was also performed at variable temperatures. The electrochemical response of the presented RAIL was found to be temperature dependent and diffusion controlled. Overall, our results demonstrated that (BMIM)(mix of HQS and HSQ) is redox active and possesses high stability and low volatility, leading to the employment of this RAIL without any additional supporting electrolyte or additives.

Investigating the suitability of poly tetraarylphosphonium based anion exchange membranes for electrochemical applications.

Anion exchange membranes (AEMs) are becoming increasingly common in electrochemical energy conversion and storage systems around the world (EES). Proton-/cation-exchange membranes (which conduct positive charged ions such as H+ or Na+) have historically been used in many devices such as fuel cells, electrolysers, and redox flow batteries. High capital costs and the use of noble metal catalysts are two of the current major disadvantages of polymer electrolyte membrane (PEM)-based systems. AEMs may be able to overcome the limitations of conventional PEMs. As a result, polymers with anion exchange properties have recently attracted a lot of attention due to their significant benefits in terms of transitioning from a highly acidic to an alkaline environment, high kinetics for oxygen reduction and fuel oxidation in an alkaline environment, and lower cost due to the use of non-precious metals. The aim of this research was to learn more about the development of a new AEM based on poly tetraarylphosphonium ionomers (pTAP), which has high ionic conductivity, alkaline stability, thermal stability, and good mechanical properties, making it a more cost-effective and stable alternative to conventional and commercial AEMs. A simple solution casting method was used to build novel anion exchange composite membranes with controlled thicknesses using the synthesized pTAP with polysulfone (PS). To ensure their suitability for use as an electrolyte in alkaline electrochemical systems, the composite membranes were characterized using FTIR, XRD, water uptake, ionic conductivity, and alkaline stability. At 40 °C, the PS/pTAP 40/60 percent membrane had a maximum ionic conductivity of 4.2 mS/cm. The thermal and mechanical stability of the composite membranes were also examined, with no substantial weight loss observed up to 150 °C. These findings pave the way for these membranes to be used in a wide variety of electrochemical applications.

Stability of a Monoethanolamine-CO2 Zwitterion at the Vapor/Liquid Water Interface: Implications for Low Partial Pressure Carbon Capture Technologies.

The need to chemically convert CO2 at the interface of aqueous amine solutions has become particularly relevant for the development and the broad distribution of cost-effective and near-future devices for direct air capture working at low (e.g., ambient) partial pressure. Here, we have determined the stability of a CO2-monoethanolamine zwitterion and its chemical conversion into carbamate at the vapor/liquid water interface by first-principles molecular dynamics simulations coupled with a recently introduced enhanced sampling technique. Contrary to the bulk water case, our results show that both the zwitterion and carbamate ions are poorly stable at the vapor/amine aqueous interface, further stating the differences between the homogeneous and heterogeneous CO2 chemical conversion. The design of novel and cost-effective capture systems, such as those offered by amine-based scrubbing solutions, working at low (e.g., ambient) CO2 partial pressure should explore the use of novel solvents, different from aqueous mixtures, to overcome the limits of the current absorbents.

Tuning CO2 Capture at the Gas/Amine Solution Interface by Changing the Solvent Polarity.

Carbon dioxide scrubbing by aqueous amine solution is considered as a promising technology for post-combustion CO2 capture, while mitigating climate change. The lack of physicochemical details for this process, especially at the interface between the gas and the condensed phase, limits our capability in designing novel and more cost-effective scrubbing systems. Here, we present classical and first-principles molecular dynamics results on CO2 capture at the gas/amine solution interfaces using solvents of different polarities. Even if it is apolar, carbon dioxide is absorbed at the gas/monoethanolamine (MEA) aqueous solution interface, forming stable and interfacial [CO2·MEA] complexes, which are the first reaction intermediate toward the chemical conversion of CO2 to carbamate ions. We report that the stability of the interfacial [CO2·MEA] precomplex depends on the nature and polarity of the solution, as well as on the conformer population of MEA. By changing the polarity of the solvent, using chloroform, we observed a shift in the interfacial MEA population toward conformers that form more stable [CO2·MEA] complexes and, at the same time, a further stabilization of the complex induced by the solvent environment. Thus, while lowering the polarity of the solvent could decrease the solubility of MEA, at the same time, it favors conformers that are more prone to CO2 capture and mineralization. The results presented here offer a theoretical framework that helps in designing novel and more cost-effective solvents for CO2 scrubbing systems, while shedding further light on the intrinsic reaction mechanisms of interfacial environments in general.

Green Light-Responsive CO-Releasing Polymeric Materials Derived from Ring-Opening Metathesis Polymerization.

Carbon monoxide (CO) is an important biological gasotransmitter in living cells. Precise spatial and temporal control over release of CO is a major requirement for clinical application. To date, the most reported carbon monoxide releasing materials use expensive fabrication methods and require harmful and poorly designed tissue-penetrating UV irradiation to initiate the CO release precisely at infected sites. Herein, we report the first example of utilizing a green light-responsive CO-releasing polymer P synthesized via ring-opening metathesis polymerization. Both monomer M and polymer P were very stable under dark conditions and CO release was effectively triggered using minimal power and low energy wavelength irradiation (550 nm, ≤28 mW). Time-dependent density functional theory (TD-DFT) calculations were carried out to simulate the electronic transition and insight into the nature of the excitations for both L and M. TD-DFT calculations indicate that the absorption peak of M is mainly due to the excitation of the seventh singlet excited state, S7. Furthermore, stretchable materials using polytetrafluoroethylene (PTFE) strips based on P were fabricated to afford P-PTFE, which can be used as a simple, inexpensive, and portable CO storage bandage. Insignificant cytotoxicity as well as cell permeability was found for M and P against human embryonic kidney cells.

Computational aspects of anthocyanidins and anthocyanins: A review.

Anthocyanins and anthocyanidins are polyphenolic compounds, responsible for the red and blue colours in several fruits, flowers, and leaves. Their colorant properties, bioavailability and antioxidant activity, made anthocyanins and anthocyanidins largely adopted in food and pharmaceutical industries. In this body of work, we firstly introduced structure, photophysical properties, co-pigmentation, antioxidant properties, glycosylation and complexation of anthocyanins and anthocyanidins. Secondly, we reported the computational methods adopted and the main theoretical results involving either anthocyanins and anthocyanidins, ranging from the first theoretical investigation on the structure of flavylium ions to the most recent studies on anthocyanins adsorbed on TiO2. We reviewed the computational contributions to the description of molecular properties of anthocyanins and anthocyanidins, giving a particular attention to the geometries, the spectroscopic features and the complexation properties of such molecules. Nowadays, theoretical calculations represent an essential methodology to understand and predict the chemical and physical properties of anthocyanins and their derivates.

SERS and DFT study of indigo adsorbed on silver nanostructured surface.

Surface-enhanced Raman spectroscopy has emerged as a widely used tool in the identification of organic dyes in works of art. Indigo is among the most used organic pigment, its identification can therefore give important information about the provenience and the making of the investigated work of art. In this work, we combine Surface Enhanced Raman Spectroscopy (SERS) experiments with density functional theory (DFT) computations of the Raman frequencies of indigo and an indigo molecule adsorbed onto a silver surface made of 16 silver atoms. The SERS spectrum of a molecule adsorbed on a metallic surface, in fact, can differ from the corresponding Raman one. The knowledge and the comprehension of the SERS spectrum then are mandatory in dyes identification. Experimental SERS spectra were acquired using ad hoc SERS active substrates consisting of pulsed laser ablated silver nanoparticles deposited onto a polishing sheet. The polishing sheet surface roughness is able to remove some pigments grains from the surface of a work of art without damage. DFT calculations provide a good description of the observed SERS spectra, in particular, the indigo-Ag16 structure gives a better description with respect to structures where only one or two silver atoms attached to the indigo molecule are considered.

Mitochondria-localising DNA-binding biscyclometalated phenyltriazole iridium(iii) dipyridophenazene complexes: syntheses and cellular imaging properties.

Two new biscyclometalated complexes [Ir(ptzR)2(dppz)]+ (dppz = dipyridophenazene; ptzRH = 4-phenyl-1-benzyl-1,2,3-triazole (1+) and 4-phenyl-1-propyl-1,2,3-triazole (2+)) have been prepared. The hexafluorophosphate salts of these complexes have been fully characterized and, in one case, the X-ray structure of a nitrate salt was obtained. The DNA binding properties of the chloride salts of the complexes were investigated, as well as their cellular uptake by A2780 and MCF7 cell lines. Both complexes display an increase in the intensity of phosphorescence upon titration with duplex DNA, indicating the intercalation of the dppz ligand and, given that they are monocations, the complexes exhibit appreciable DNA binding affinity. Optical microscopy studies reveal that both complexes are taken up by live cancer cell lines displaying cytosol based luminescence. Colocalization studies with commercial probes show high Pearson coefficients with mitotracker dyes confirming that the new complexes specifically localize on mitochondria.

Extracellular truncated tau causes early presynaptic dysfunction associated with Alzheimer's disease and other tauopathies.

The largest part of tau secreted from AD nerve terminals and released in cerebral spinal fluid (CSF) is C-terminally truncated, soluble and unaggregated supporting potential extracellular role(s) of NH2 -derived fragments of protein on synaptic dysfunction underlying neurodegenerative tauopathies, including Alzheimer's disease (AD). Here we show that sub-toxic doses of extracellular-applied human NH2 tau 26-44 (aka NH 2 htau) -which is the minimal active moiety of neurotoxic 20-22kDa peptide accumulating in vivo at AD synapses and secreted into parenchyma- acutely provokes presynaptic deficit in K+ -evoked glutamate release on hippocampal synaptosomes along with alteration in local Ca2+ dynamics. Neuritic dystrophy, microtubules breakdown, deregulation in presynaptic proteins and loss of mitochondria located at nerve endings are detected in hippocampal cultures only after prolonged exposure to NH 2 htau. The specificity of these biological effects is supported by the lack of any significant change, either on neuronal activity or on cellular integrity, shown by administration of its reverse sequence counterpart which behaves as an inactive control, likely due to a poor conformational flexibility which makes it unable to dynamically perturb biomembrane-like environments. Our results demonstrate that one of the AD-relevant, soluble and secreted N-terminally truncated tau forms can early contribute to pathology outside of neurons causing alterations in synaptic activity at presynaptic level, independently of overt neurodegeneration.