Harnessing reductive BF2-complexation via Ru(II)-catalyzed N-O cleavage of isoxazoles.

Developed here is a highly fluorescent organic N,O bidentate BF2 complex from isoxazole in the presence of a Ru(II) catalyst. Herein, the complexation proceeds via a selective N-O cleavage of the isoxazole ring. The complex shows absorption (λmax,abs) in the range of 352-363 nm with an extinction coefficient (ε) in the range of 8000-64 000 M-1 cm-1, and fluorescence emission (λmax,em) in the range of 413-485 nm with a Stokes shift of 61-125 nm having quantum yield up to 33%. Apart from the solution state, the solid BF2 complex 2u exhibits absorption at 405 nm and strong fluorescence emission at 550 nm with a quantum yield of 26.9%.

Quantum Nonlocality: Multicopy Resource Interconvertibility and Their Asymptotic Inequivalence.

Quantum nonlocality, pioneered in Bell's seminal work and subsequently verified through a series of experiments, has drawn substantial attention due to its practical applications in various protocols. Evaluating and comparing the extent of nonlocality within distinct quantum correlations holds significant practical relevance. Within the resource theoretic framework this can be achieved by assessing the interconversion rate among different nonlocal correlations under free local operations and shared randomness. In this study we, however, present instances of quantum nonlocal correlations that are incomparable in the strongest sense. Specifically, when starting with an arbitrary many copies of one nonlocal correlation, it becomes impossible to obtain even a single copy of the other correlation, and this incomparability holds in both directions. Such incomparable quantum correlations can be obtained even in the simplest Bell scenario, which involves two parties, each having two dichotomic measurements setups. Notably, there exist an uncountable number of such incomparable correlations. Our result challenges the notion of a "unique gold coin," often referred to as the "maximally resourceful state," within the framework of the resource theory of quantum nonlocality. To this end, we provide examples of isotropic quantum correlations that cannot be distilled up to the Tsirelson point, and thus partially answer a long-standing open question in nonlocality distillation.

Photo-Induced Generation of Oxygenated Quaternary Centers via EnT Enabled Singlet O2 Addition to C3-Maleimidated Quinoxaline: A Reagent-Less Approach.

Demonstrated here is an external photo-sensitizer-free (auto-sensitized) singlet oxygen-enabled solvent-dependent tertiary hydroxylation and aryl-alkyl spiro-etherification of C3-maleimidated quinoxalines. Such "reagent-less" photo-oxygenation at Csp3-H and etherification involving Csp3-H/Csp2-H are unparalleled. Possibly, the highly π-conjugated N-H tautomer allows the substrate to get excited by irradiation, and subsequently, it attains the triplet state via ISC. This excited triplet-state sensitized molecule then transfers its energy to a triplet-state oxygen (3O2) generating reactive singlet oxygen (1O2) for hydroxylation and spirocyclization depending on the solvent used. In HFIP, the generated alkoxy radical accepts a proton via HAT giving hydroxylated product. In contrast, in an aprotic PhCl it underwent a radical addition at the ortho-position of the C2 aryl to provide spiro-ether. An unprecedented orthogonal spiro-etherification was observed via the displacement of o-substitutents for ortho (-OEt, -OMe, -F, -Cl, -Br) substituted substrates. The order of ipso substitution follows the trend -OMe>-OEt>-F>-H>-Cl>-Br. Both these oxygenation reactions can be carried out with nearly equal ease using direct sunlight without the requirement of any elaborate reaction setup. Demonstration of large-scale synthesis and a few interesting transformations have also been realized. Furthermore, several insightful control experiments and quantum chemical computations were performed to unravel the mechanism.

Investigating the role of axonal ion channel cooperativity in action potential dynamics: Studies on Hodgkin-Huxley's model.

Voltage-gated ion channels play an important role in generating action potential in neurons. These ion channels are found to be in localized cluster form on the axonal membrane surface and behave cooperatively. However, in Hodgkin & Huxley's model of action potential the ion channels are considered to function independently. According to some recent reports, the activity of an ion channel is influenced by the neighboring ion channels' activities. We have modified the Hodgkin-Huxley's model based on our previous studies on cooperativity among ion channels. Computational analysis of the proposed model shows that the initiation of the action potential, amplitude and hyperpolarization are affected significantly by the cooperative interactions among the voltage-gated ion channels present on the axonal membrane surface. These results are qualitatively supported by the existing experimental facts.

Determination and speciation of arsenic in drinking water samples by X-ray spectrometry technique.

Arsenic is ranked as the first compound in the Substance Priority List 2023 by the Agency for Toxic Substances and Disease Registry (ATSDR). The most prominent entrance to the human body is through drinking water wherein the predominant species are arsenite and arsenate. The more toxic As(III) has rigorously threatened human health worldwide; hence, speciation and separation are the need of the hour. In this article, we have reported a simple method of arsenic speciation by wavelength dispersive X-ray fluorescence (WD-XRF) spectrometer. Valence to core (VtC) electronic transitions, i.e., AsKß2,5 fluorescence lines were used for arsenic speciation. This speciation study by WD-XRF entails direct measurement of activated alumina pellets containing arsenate and arsenite species adsorbed from water sample without separation of the trivalent and pentavalent species. This is the first report wherein the X-ray technique has been explored for speciation analysis of arsenic and the biggest advantage of the method lies in its applicability to direct analysis of synthesized nanotubes or other solid-phase extraction sorbents entrapping both the arsenic species. For determination of total arsenic using activated alumina as adsorbent, the most intense AsKα1,2 analytical lines were used and the instrumental limit of detection and the lower limit of quantification were 0.23 µg/L and 0.89 µg/L, respectively. For speciation, these limits were calculated to be 50 µg/L and 200 µg/L, respectively.

Base-Induced Decarboxylative 1,1-Alkoxy Thiolation via Hydrothiolation of Vinylene Carbonate.

A base-mediated 1,1-difunctionalization of vinylene carbonate has been achieved using two different nucleophiles, namely, thiol and alcohol, with the assistance of air (O2). In alcoholic solvents, decarboxylation occurs at room temperature to provide a 1,1-difunctionalized product, where vinylene carbonate serves as an ethynol (C2) synthon in this three-component reaction. On the other hand, in acetonitrile, exclusive hydrothiolation occurs under the basic conditions at room temperature. This method offers a one-pot decarboxylative regioselective difunctionalization of vinylene carbonate at room temperature for the construction of α-alkoxy-ß-hydroxy sulfide.

Nitric oxide modulates NMDA receptor through a negative feedback mechanism and regulates the dynamical behavior of neuronal postsynaptic components.

Nitric oxide (NO) is known to be an important regulator of neurological processes in the central nervous system which acts directly on the presynaptic neuron and enhances the release of neurotransmitters like glutamate into the synaptic cleft. Calcium influx activates a cascade of biochemical reactions to influence the production of nitric oxide in the postsynaptic neuron. This has been modeled in the present work as a system of ordinary differential equations, to explore the dynamics of the interacting components and predict the dynamical behavior of the postsynaptic neuron. It has been hypothesized that nitric oxide modulates the NMDA receptor via a feedback mechanism and regulates the dynamic behavior of postsynaptic components. Results obtained by numerical analyses indicate that the biochemical system is stimulus-dependent and shows oscillations of calcium and other components within a limited range of concentration. Some of the parameters such as stimulus strength, extracellular calcium concentration, and rate of nitric oxide feedback are crucial for the dynamics of the components in the postsynaptic neuron.

Isoxazole as a nitrile synthon: en routes to the ortho-alkenylated isoxazole and benzonitrile with allyl sulfone catalyzed by Ru(II).

A Ru(II) catalyzed regioselective Heck-type C-H olefination of isoxazole with unactivated allyl phenyl sulfone is revealed. The solvent DCM offers dual sp2-sp2 C-H activation via an N-directed strategy, leading to ortho-olefinated isoxazoles with exclusive E-selectivity. On the other hand, in DCE solvent, isoxazole serves as the nitrile synthon and leads to o-olefinated benzonitrile. At a higher temperature (110 °C) in DCE, after the ortho-olefination Ru(II) mediated cleavage of isoxazoles delivered the nitrile functionality.

Photo-induced 1,2-thiohydroxylation of maleimide involving disulfide and singlet oxygen.

A visible light-driven di-functionalization of maleimide with disulfide and in situ-generated singlet oxygen offers selective 1,2-thiohydroxylation under additive-free conditions. Here the disulfide plays the dual role of photosensitizer and the coupling reagent. Notably, the hydroxyl functionality originates from the in situ generated singlet oxygen followed by HAT from H2O (moisture).

Emergent dynamics in an astrocyte-neuronal network coupledvianitric oxide.

In the brain, both neurons and glial cells work in conjunction with each other during information processing. Stimulation of neurons can induce calcium oscillations in astrocytes which in turn can affect neuronal calcium dynamics. The 'glissandi' effect is one such phenomenon, associated with a decrease in infraslow fluctuations, in which synchronized calcium oscillations propagate as a wave in hundreds of astrocytes. Nitric oxide molecules released from the astrocytes contribute to synaptic functions based on the underlying astrocyte-neuron interaction network. In this study, by defining an astrocyte-neuronal (A-N) calcium unit as an integrated circuit of one neuron and one astrocyte, we developed a minimal model of neuronal stimulus-dependent and NO-mediated emergence of calcium waves in astrocytes. Incorporating inter-unit communicationviaNO molecules, a coupled network of 1000 such A-N calcium units is developed in which multiple stable regimes were found to emerge in astrocytes. We examined the ranges of neuronal stimulus strength and the coupling strength between A-N calcium units that give rise to such dynamical behaviors. We also report that there exists a range of coupling strength, wherein units not receiving stimulus also start showing oscillations and become synchronized. Our results support the hypothesis that glissandi-like phenomena exhibiting synchronized calcium oscillations in astrocytes help in efficient synaptic transmission by reducing the energy demand of the process.

Rapid method of arsenic estimation in geological samples by WD-XRF using a novel concept of As-Pb concentration equivalence.

The presence of arsenic in ground waters of many countries has been a subject of global concern due to its toxicity. Primary sources of arsenic are geogenic, i.e. weathering and erosion of rocks and soils containing arsenic. This paper presents a rapid method for determination of arsenic in solid geological samples by wavelength dispersive X-ray fluorescence spectrometer. To achieve the best LLD (lower limit of detection), the most intense X-ray fluorescence line Kα1,2 is preferably used for determination of elemental concentrations because it pertains to the most probable transition. But the greatest challenge in arsenic estimation is the serious line overlap of AsKα1,2 lines with the equi-energy PbLα1,2 lines. By using the conventional line overlap correction methods, uncertainty and detection limits in arsenic determination are degraded to an unacceptable degree in samples which contains high lead and low arsenic concentrations. The proposed method bypasses the line overlap issue in employing a novel concept of arsenic-lead concentration equivalence factor for the cumulative peak of AsKα1,2 and PbLα1,2 fluorescence lines. The constancy of this factor for all geological matrices facilitates arsenic determination in samples universally irrespective of matrix elements. For the method validation, 22 international certified reference materials have been analysed and the results proved to be propitious wherein only one value out of 22 determinations showed relative error more than 20% of the certified values. This attests to the high accuracy of the proposed method which can effectively determine arsenic below 5 mg/kg in the presence of high lead concentration up to 1000 mg/kg.

Mn(I)-Catalyzed Preferential Electrophilic C3-Maleimidation in Quinoxaline Leading to Spirocyclization and Dehydrogenation of Succinimides.

A Mn(I)-catalyzed site-selective nondirected C3-maleimidation of quinoxaline is established. Herein, the electrophilic C3-metalation precedes over the o-directed strategy to access diversely substituted quinoxaline-appended succinimides. The products undergo PIFA-promoted C(sp2)-C(sp3) spirocyclization via π-electrons drifting from aryls and Selectfluor-mediated dehydrogenation of succinimide at room temperature.

Ca2+/Calmodulin-Dependent Protein Kinase II Disrupts the Voltage Dependency of the Voltage-Dependent Anion Channel on the Lipid Bilayer Membrane.

Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a key enzyme that plays a significant role in intracellular signaling and the modulation of mitochondrial membrane properties. It is known that the voltage-dependent anion channel (VDAC) is one of the most abundant outer mitochondrial membrane (OMM) proteins acting as a significant passageway and regulatory site for various enzymes, proteins, ions, and metabolites. Considering this, we hypothesize that VDAC could be one of the targets for CaMKII enzymatic activity. Our in vitro experiments indicate that VDAC can be phosphorylated by the CaMKII enzyme. Moreover, the bilayer electrophysiology experimental data indicate that CaMKII significantly reduces VDAC's single-channel conductivity; its open probability remains high at all the applied potentials between +60 and -60 mV, and the voltage dependency was lost, which suggests that CaMKII disrupted the VDAC's single-channel activities. Hence, we can infer that VDAC interacts with CaMKII and thus acts as a vital target for its activity. Furthermore, our findings suggest that CaMKII could play a significant role during the transport of ions and metabolites across the outer mitochondrial membrane (OMM) through VDAC and thus regulate apoptotic events.

Voltage dependent anion channel and its interaction with N-acetyl-L-Cysteine (NAC) under oxidative stress on planar lipid bilayer.

Mitochondria are the major source of Hydrogen Peroxide (H2O2), a reactive oxygen species, in the cells. The reactive oxygen species generated by the mitochondria oxidize major proteins including Voltage Dependent Anion Channel (VDAC). We were interested to know how the effect of H2O2 is countered by antioxidants present around the mitochondria. N-Acetyl-l-Cysteine (NAC) is a naturally existing antioxidant in the cells. Keeping this in view, the modulatory effect of antioxidant NAC on H2O2 oxidized VDAC has been investigated through in vitro electrophysiological studies. First, the effect of H2O2 and NAC was studied on independently incorporated single-channel VDAC. It was observed that NAC suppresses VDAC conductance with a half-maximal inhibitory concentration (IC50) of ∼1.04 µM. In contrast, H2O2 enhances VDAC conductance. Later, oxidative stress was induced by H2O2 on VDAC increased conductance with half-maximal effective concentration (EC50) of ∼302 nM. An application of 1 µM NAC on H2O2 treated (300 nM) VDAC reversed the effect of oxidation. In the next step, NAC and H2O2 were added in reverse order. When oxidative stress was induced using H2O2, reduction in conductance by NAC was 4.5 ± 0.404 nS. The change in conductance is nearly 6.3%. However, if antioxidant NAC was incubated first followed by H2O2 treatment, the conductance of VDAC was 3.09 ± 0.27 nS. The change in conductance is near 33%. Both H2O2 and NAC also affected various conducting states of VDAC. In-silico studies indicated the binding of NAC at Lysine and Glutamic acid of VDAC. Hence, NAC was found to be effective in protection of VDAC against H2O2-induced oxidative stress due to its strong binding.

Dearomative bis-functionalization of quinoxalines and bis-N-arylation of (benz)imidazoles via Cu(II)-mediated addition of boronic acids.

A Cu(OTf)2-mediated regioselective dearomative aryl-hydroxylation across the C(sp2)N bond of 2-aryl quinoxalines and bis-N-arylation of (benz)imidazoles were developed using aryl boronic acids. For the dearomative aryl-hydroxylation, the C-center should be electrophilic (ca. 0.08), the N-center nucleophilic (ca. -0.50), and the C(sp2)N bond polarized (Δe = 0.609).

A mutation in the S6 segment of the KvAP channel changes the secondary structure and alters ion channel activity in a lipid bilayer membrane.

The peptide segment S6 is known to form the inner lining of the voltage-gated K+ channel KvAP (potassium channel of archaea-bacterium, Aeropyrum pernix). In our previous work, it has been demonstrated that S6 itself can form an ion channel on a bilayer lipid membrane (BLM). In the present work, the role of a specific amino acid sequence 'LIG' in determining the secondary structure of S6 has been investigated. For this purpose, 22-residue synthetic peptides named S6-Wild (S6W) and S6-Mutant (S6M) were used. Sequences of these peptides are similar except that the two amino acids isoleucine and glycine of the wild peptide interchanged in the mutant peptide. Channel forming capabilities of both the peptides were checked electro-physiologically on BLM composed of DPhPC and cholesterol. Bilayer electrophysiological experiments showed that the conductance of S6M is higher than that of S6W. Significant differences in the current versus voltage (I-V) plot, open probability, and gating characteristics were observed. Interestingly, two sub-types of channels, S6M Type 1 and Type 2, were identified in S6M differing in conductances and open probability patterns. Circular dichroism (CD) spectroscopy indicated that the secondary structures of the two peptides are different in phosphatidyl choline/asolectin liposomes and 1% SDS detergent. Reduced helicity of S6M was also noticed in membrane mimetic liposomes and 1% SDS detergent micelles. These results are interpreted in view of the difference in hydrophobicity of the two amino acids, isoleucine and glycine. It is concluded that the 'LIG' stretch regulates the structure and pore-forming ability of the S6 peptide.

Calmodulin Modulates the Gating Properties of Voltage-Dependent Anion Channel from Rat Brain Mitochondria.

Calmodulin (CaM) is a key signaling protein that plays a decisive role in mitochondrial Ca2+ homeostasis and signaling and modulates the mitochondrial membrane properties. We propose that voltage-dependent anion channel 1 (VDAC1), one of the most abundant outer mitochondrial membrane (OMM) proteins, could be its possible target or site of action. VDAC1 is known to play a crucial role in the mitochondrial Ca2+ signaling mechanism. Bilayer electrophysiology experiments show that CaM significantly reduces VDAC1's conductivity and modulates its gating as well as permeability properties. Also, spectrofluorimetric analysis indicates the possibility of binding CaM with VDAC1. Theoretical analysis of fluorescence data shows that the aforementioned protein-protein interaction is not linear, but rather it is a complex nonlinear process. In VDAC1, CaM binding site has been predicted using various bioinformatics tools. It is proposed that CaM could interact with VDAC1's outer-loop region and regulate its gating properties. Our findings suggest that VDAC1-CaM interaction could play a crucial role in the transport of ions and metabolites through the OMM and the regulation of the mitochondrial Ca2+ signaling mechanism through alteration of VDAC1's gating and conductive properties.

Homocysteine-Thiolactone Modulates Gating of Mitochondrial Voltage-Dependent Anion Channel (VDAC) and Protects It from Induced Oxidative Stress.

The gating of the Voltage-Dependent Anion Channel (VDAC) is linked to oxidative stress through increased generation of mitochondrial ROS with increasing mitochondrial membrane potential (ΔΨm). It has been already reported that H2O2 increases the single-channel conductance of VDAC on a bilayer lipid membrane. On the other hand, homocysteine (Hcy) has been reported to induce mitochondria-mediated cell death. It is argued that the thiol-form of homocysteine, HTL could be the plausible molecule responsible for the alteration in the function of proteins, such as VDAC. It is hypothesized that HTL interacts with VDAC that causes functional abnormalities. An investigation was undertaken to study the interaction of HTL with VDAC under H2O2 induced oxidative stress through biophysical and electrophysiological methods. Fluorescence spectroscopic studies indicate that HTL interacts with VDAC, but under induced oxidative stress the effect is prevented partially. Similarly, bilayer electrophysiology studies suggest that HTL shows a reduction in VDAC single-channel conductance, but the effects are partially prevented under an oxidative environment. Gly172 and His181 are predicted through bioinformatics tools to be the most plausible binding residues of HTL in Rat VDAC. The binding of HTL and H2O2 with VDAC appears to be cooperative as per our analysis of experimental data in the light of the Hill-Langmuir equation. The binding energies are estimated to be - 4.7 kcal mol-1 and - 2.8 kcal mol-1, respectively. The present in vitro studies suggest that when mitochondrial VDAC is under oxidative stress, the effects of amino acid metabolites like HTL are suppressed.

Extracellular Signal-Regulated Kinase1 (ERK1)-Mediated Phosphorylation of Voltage-Dependent Anion Channel (VDAC) Suppresses its Conductance.

ERK1 is one of the members of the mitogen-activated protein kinases that regulate important cellular functions. VDAC is located at the outer membrane of mitochondria. Here, an interaction between VDAC and ERK1 has been studied on an artificial planar lipid bilayer using in vitro electrophysiology experiments. We report that VDAC is phosphorylated by ERK1 in the presence of Mg2+-ATP and its single-channel currents are inhibited on the artificial bilayer membrane. Treatment of Alkaline phosphatase on ERK1 phosphorylated VDAC leads to partial recovery of the single-channel VDAC currents. Later, phosphorylation of VDAC was demonstrated by Pro-Q diamond dye. Mass Spectrometric studies indicate phosphorylation of VDAC at Threonine 33, Threonine 55, and Serine 35. In a nutshell, phosphorylation of VDAC leads to the closure of the channel.

Copper(I)-Mediated Cascade Annulation via Dual C-H/C-H Activation: Access to Benzo[a]carbazolic AEEgens.

A Cu(I)-mediated cascade cyclization/annulation of unprotected o-alkynylanilines with maleimides in one pot is developed. The protocol offers sequential formation of one C-N and two C-C bonds to deliver fused benzo[a]carbazoles having free NH skeletons. The annulated products display fluorescence emission in the range of 485-502 nm with a large Stokes shift and fluorescence lifetime of ∼17 ns. The annulated 3aa displays AEE behavior in the ethanol/hexane system and possesses marigold-flower-like morphology at the aggregated state. Cell viability assays enumerate biocompatible AEEgens, while their high intracellular fluorescence depicts cell imaging applicability.