De novo and salvage purine synthesis pathways across tissues and tumors.

Purine nucleotides are vital for RNA and DNA synthesis, signaling, metabolism, and energy homeostasis. To synthesize purines, cells use two principal routes: the de novo and salvage pathways. Traditionally, it is believed that proliferating cells predominantly rely on de novo synthesis, whereas differentiated tissues favor the salvage pathway. Unexpectedly, we find that adenine and inosine are the most effective circulating precursors for supplying purine nucleotides to tissues and tumors, while hypoxanthine is rapidly catabolized and poorly salvaged in vivo. Quantitative metabolic analysis demonstrates comparative contribution from de novo synthesis and salvage pathways in maintaining purine nucleotide pools in tumors. Notably, feeding mice nucleotides accelerates tumor growth, while inhibiting purine salvage slows down tumor progression, revealing a crucial role of the salvage pathway in tumor metabolism. These findings provide fundamental insights into how normal tissues and tumors maintain purine nucleotides and highlight the significance of purine salvage in cancer.

Stability of nucleic acid bases in concentrated sulfuric acid: Implications for the habitability of Venus' clouds.

What constitutes a habitable planet is a frontier to be explored and requires pushing the boundaries of our terracentric viewpoint for what we deem to be a habitable environment. Despite Venus' 700 K surface temperature being too hot for any plausible solvent and most organic covalent chemistry, Venus' cloud-filled atmosphere layers at 48 to 60 km above the surface hold the main requirements for life: suitable temperatures for covalent bonds; an energy source (sunlight); and a liquid solvent. Yet, the Venus clouds are widely thought to be incapable of supporting life because the droplets are composed of concentrated liquid sulfuric acid-an aggressive solvent that is assumed to rapidly destroy most biochemicals of life on Earth. Recent work, however, demonstrates that a rich organic chemistry can evolve from simple precursor molecules seeded into concentrated sulfuric acid, a result that is corroborated by domain knowledge in industry that such chemistry leads to complex molecules, including aromatics. We aim to expand the set of molecules known to be stable in concentrated sulfuric acid. Here, we show that nucleic acid bases adenine, cytosine, guanine, thymine, and uracil, as well as 2,6-diaminopurine and the "core" nucleic acid bases purine and pyrimidine, are stable in sulfuric acid in the Venus cloud temperature and sulfuric acid concentration range, using UV spectroscopy and combinations of 1D and 2D 1H 13C 15N NMR spectroscopy. The stability of nucleic acid bases in concentrated sulfuric acid advances the idea that chemistry to support life may exist in the Venus cloud particle environment.

TrieDedup: a fast trie-based deduplication algorithm to handle ambiguous bases in high-throughput sequencing.

BACKGROUND: High-throughput sequencing is a powerful tool that is extensively applied in biological studies. However, sequencers may produce low-quality bases, leading to ambiguous bases, 'N's. PCR duplicates introduced in library preparation are conventionally removed in genomics studies, and several deduplication tools have been developed for this purpose. Two identical reads may appear different due to ambiguous bases and the existing tools cannot address 'N's correctly or efficiently. RESULTS: Here we proposed and implemented TrieDedup, which uses the trie (prefix tree) data structure to compare and store sequences. TrieDedup can handle ambiguous base 'N's, and efficiently deduplicate at the level of raw sequences. We also reduced its memory usage by approximately 20% by implementing restrictedDict in Python. We benchmarked the performance of the algorithm and showed that TrieDedup can deduplicate reads up to 270-fold faster than pairwise comparison at a cost of 32-fold higher memory usage. CONCLUSIONS: The TrieDedup algorithm may facilitate PCR deduplication, barcode or UMI assignment, and repertoire diversity analysis of large-scale high-throughput sequencing datasets with its ultra-fast algorithm that can account for ambiguous bases due to sequencing errors.

Source imaging method based on diagonal covariance bases and its applications to OPM-MEG.

Magnetoencephalography (MEG) is a noninvasive imaging technique used in neuroscience and clinical research. The source estimation of MEG involves solving a highly underdetermined inverse problem, which requires additional constraints to restrict the solution space. Traditional methods tend to obscure the extent of the sources. However, an accurate estimation of the source extent is important for studying brain activity or preoperatively estimating pathogenic regions. To improve the estimation accuracy of the extended source extent, the spatial constraint of sources is employed in the Bayesian framework. For example, the source is decomposed into a linear combination of validated spatial basis functions, which is proved to improve the source imaging accuracy. In this work, we further construct the spatial properties of the source using the diagonal covariance bases (DCB), which we summarize as the source imaging method SI-DCB. In this approach, specifically, the covariance matrix of the spatial coefficients is modeled as a weighted combination of diagonal covariance basis functions. The convex analysis is used to estimate noise and model parameters under the Bayesian framework. Extensive numerical simulations showed that SI-DCB outperformed five benchmark methods in accurately estimating the location and extent of patch sources. The effectiveness of SI-DCB was verified through somatosensory stimulation experiments performed on a 31-channel OPM-MEG system. The SI-DCB correctly identified the source area where each brain response occurred. The superior performance of SI-DCB suggests that it can provide a template approach for improving the accuracy of source extent estimations under a sparse Bayesian framework.

Discovering trends in the Lewis acidity of beryllium and magnesium hydrides and fluorides with increasing clusters size.

We have reported in the last years the strong effect that Be- and Mg-containing Lewis acids have on the intrinsic properties of typical bases, which become acids upon complexation. In an effort to investigate these changes when the Be and Mg derivatives form clusters of increasing size, we have examined the behavior of the (MX2)n (M = Be, Mg; X = H, F; n = 1, 2, 3) clusters when they interact with ammonia, methanimine, hydrogen cyanide and pyridine, and with their corresponding deprotonated forms. The complexes obtained at the M06-2X/aug-cc-pVTZ level were analyzed using the MBIE energy decomposition formalism, in parallel with QTAIM, ELF, NCIPLOT and AdNDP analyses of their electron density. For n = 1 the interaction enthalpy for the different families of monomers, Be (Mg) hydrides and Be (Mg) fluorides, follows the same trend as the intrinsic basicity of the base that interacts with them. This interaction is greatly reinforced after the deprotonation of the base, resulting in a significant enhancement of the intrinsic acidity of the corresponding MX2-Base complex. For (MX2)2 clusters a further reinforcement of the interaction with the base is observed, this reinforcement being again larger for the deprotonated complexes. However, the concomitant increase of their intrinsic acidity is one order of magnitude larger for hydrides than for fluorides. Unexpectedly, the cyclic conformers (MX2)3, which are more unstable than the linear ones, become the global minima after association with the base and the same is true for the deprotonated complex. Accordingly, a further increase of the intrinsic acidity of the (MX2)3-Base complexes with respect to the (MX2)2-Base ones is observed. This effect is maximum for (MgF2)3 clusters, to the point that the (MgF2)3-Base complexes become more acidic than nitric acid, the extreme case being the cluster (MgF2)3-NCH, whose acidity is higher than that of perchloric acid.

Hydride and halide abstraction reactions behind the enhanced basicity of Be and Mg clusters with nitrogen bases.

In this study, we investigate the protonation effects on the structure, relative stability and basicity of complexes formed by the interaction of monomers and dimers of BeX2 and MgX2 (X = H, F) with NH3, CH2NH, HCN, and NC5H5 bases. Calculations were performed using the M06-2X/aug-cc-pVTZ formalism, along with QTAIM, ELF and NCI methods for electron density analysis and MBIE and LMO-EDA energy decomposition analyses for interaction enthalpies. The protonation of the MH2- and M2H4-Base complexes occurs at the negatively charged hydrogen atoms of the MH2 and M2H4 moieties through typical hydride abstraction reactions, while protonation at the N atom of the base is systematically less exothermic. The preference for the hydride transfer mechanism is directly associated with the significant exothermicity of H2 formation through the interaction between H- and H+, and the high hydride donor ability of these complexes. The basicity of both, MH2 and M2H4 compounds increases enormously upon association with the corresponding bases, with the increase exceeding 40 orders of magnitude in terms of ionization constants. Due to the smaller exothermicity of HF formation, the basicity of fluorides is lower than that of hydrides. In Be complexes, the protonation at the N atom of the base dominates over the fluoride abstraction mechanism. However, for the Mg complexes the fluoride abstraction mechanism is energetically the most favorable process, reflecting the greater facility of Mg complexes to lose F-.

Facile heterolytic bond splitting of molecular chlorine upon reactions with Lewis bases: Comparison with ICl and I2.

Formation of molecular complexes and subsequent heterolytic halogen-halogen bond splitting upon reactions of molecular Cl2 with nitrogen-containing Lewis bases (LB) are computationally studied at M06-2X/def2-TZVPD and for selected compounds at CCSD(T)/aug-cc-pvtz//CCSD/aug-cc-pvtz levels of theory. Obtained results are compared with data for ICl and I2 molecules. Reaction pathways indicate, that in case of Cl2∙LB complexes the activation energies for the heterolytic Cl-Cl bond splitting are lower than the activation energies of the homolytic splitting of Cl2 molecule into chlorine radicals. The heterolytic halogen splitting of molecular complexes of X2∙Py with formation of [XPy2]+… X 3 - $$ {\mathrm{X}}_3^{-} $$ contact ion pairs in the gas phase is slightly endothermic in case of Cl2 and I2, but slightly exothermic in the case of ICl. Formation of {[ClPy2]+… Cl 3 - $$ {\mathrm{Cl}}_3^{-} $$ }2 dimers makes the overall process exothermic. Taking into account that polar solvents favor ionic species, generation of donor-stabilized Cl+ in the presence of the Lewis bases is expected to be favorable. Thus, in polar solvents the oxidation pathway via donor-stabilized Cl+ species is viable alternative to the homolytic Cl-Cl bond breaking.

Protoporphyrin IX iron(II) revisited. An overview of the Mössbauer spectroscopic parameters of low-spin porphyrin iron(II) complexes.

Mössbauer parameters of low-spin six-coordinate [Fe(II)(Por)L2] complexes (where Por is a synthetic porphyrin; L is a nitrogenous aliphatic, an aromatic base or a heterocyclic ligand, a P-bonding ligand, CO or CN) and low-spin [Fe(Por)LX] complexes (where L and X are different ligands) are reported. A known point charge calculation approach was extended to investigate how the axial ligands and the four porphyrinato-N atoms generate the observed quadrupole splittings (ΔEQ) for the complexes. Partial quadrupole splitting (p.q.s.) and partial chemical shifts (p.c.s.) values were derived for all the axial ligands, and porphyrins reported in the literature. The values for each porphyrin are different emphasising the importance/uniqueness of the [Fe(PPIX)] moiety, (which is ubiquitous in nature). This new analysis enabled the construction of figures relating p.c.s and p.q.s values. The relationships presented in the figures indicates that strong field ligands such as CO can, and do change the sign of the electric field gradient in the [Fe(II)(Por)L2] complexes. The limiting p.q.s. value a ligand can have and still form a six-coordinate low-spin [Fe(II)(Por)L2] complex is established. It is shown that the control the porphyrin ligands exert on the low-spin Fe(II) atom limits its bonding to a defined range of axial ligands; outside this range the spin state of the iron is unstable and five-coordinate high-spin complexes are favoured. Amongst many conclusions, it was found that oxygen cannot form a stable low-spin [Fe(II)(Por)L(O2)] complex and that oxy-haemoglobin is best described as an [Fe(III)(Por)L(O2-)] complex, the iron is ferric bound to the superoxide molecule.

Carbodiimide and Isocyanate Hydroboration by a Cyclic Carbodiphosphorane Catalyst.

We report hydroboration of carbodiimide and isocyanate substrates catalyzed by a cyclic carbodiphosphorane catalyst. The cyclic carbodiphosphorane outperformed the other Lewis basic carbon species tested, including other zerovalent carbon compounds, phosphorus ylides, an N-heterocyclic carbene, and an N-heterocyclic olefin. Hydroborations of seven carbodiimides and nine isocyanates were performed at room temperature to form N-boryl formamidine and N-boryl formamide products. Intermolecular competition experiments demonstrated the selective hydroboration of alkyl isocyanates over carbodiimide and ketone substrates. DFT calculations support a proposed mechanism involving activation of pinacolborane by the carbodiphosphorane catalyst, followed by hydride transfer and B-N bond formation.

Annulation of a Methylenecyclopropane with Cyanoalkenes Catalyzed by Lewis Bases.

The annulation of a methylenecyclopropane with acyl cyanoalkenes by using DABCO or quinuclidine as a catalyst to give 2,3-dihydofurans has been developed. A stoichiometric amount of the Lewis bases promoted the isomerization of 2,3-dihydrofurans to furans. 1 H NMR spectra of the reaction in situ revealed that the methylenecyclopropane is opened by the Lewis base to form a reaction intermediate that is added to the cyanoalkenes.

Tuning Reactivities of tert-Butyllithium by the Addition of Stoichiometric Amounts of Tetrahydrofuran.

In alkyllithium chemistry the highest reactivity has historically been linked to the smallest degree of aggregation possible. Since tert-butyllithium is known to form a monomer in tetrahydrofuran solution, using just stoichiometric amounts of the lewis base to selectively form a dimeric species seemed irrational. In this study, we showed a considerable increase of the reactivity of t-BuLi when using stoichiometric amounts of THF in the non-polar solvent n-pentane in order to enable the deprotonation of simple methyl silanes and other low C-H-acidic substrates. In this context, we were able to obtain the corresponding aggregates of t-BuLi with the ligand THF in suspension and as crystalline solids and investigate them by single crystal X-ray structural analysis, in situ FTIR spectroscopy and quantum chemical calculations. Furthermore, we were able to explain the enhanced reactivity of t-BuLi with stoichiometric amounts of THF on the basis of structural features of the bridged dimer obtained under these conditions. With these findings, we present a new target in the aggregation of alkyllithium reagents: the selectively formed "frustrated" aggregates!

Synthesis of 1,3-Dibromopyrene as Precursor of 1-, 3-, 6-, and 8-Substituted Long-Axially Symmetric Pyrene Derivatives.

Pyrene derivatives bearing substituents at positions 1, 3, 6, and 8 find numerous applications, as exemplified by their use in lasers, sensors, and bioimaging probes. However, these derivatives typically have point-symmetric or short-axially symmetric structures, whereas long-axially symmetric derivatives remain underexplored because of the difficulty in obtaining their precursor, 1,3-dibromopyrene. To address this problem, we herein synthesized 1,3-dibromopyrene from 1-methoxypyrene in an overall yield (71 % over four steps) considerably exceeding those of existing methods. 1,3-Dibromopyrene was converted into 13OPA, a long-axially symmetric pyrene dye with electron-donor (alkoxy) groups at positions 1 and 3 and electron-acceptor (formyl) groups at positions 6 and 8. 13OPA exhibited photophysical properties distinct from those of its point-symmetric and short-axially symmetric isomers, featuring a broad and strongly redshifted absorption, strong fluorescence with reduced sensitivity to protic solvents, and small dipole moment change upon photoexcitation. The derivatization of 13OPA into a Schiff base and its functionalization via Lewis acid-base pairing were also demonstrated. Thus, our work expands the design scope of pyrene-based molecules, particularly those used as emitters.

A Benchmark Study of DFT-Computed p-Block Element Lewis Pair Formation Enthalpies Against Experimental Calorimetric Data.

The quantification of Lewis acidity is of fundamental and applied importance in chemistry. While the computed fluoride ion affinity (FIA) is the most widely accepted thermodynamic metric, only sparse experimental values exist. Accordingly, a benchmark of methods for computing Lewis pair formation enthalpies, also with a broader set of Lewis bases against experimental data, is missing. Herein, we evaluate different density functionals against a set of 112 experimentally determined Lewis acid/base binding enthalpies and gauge influences such as solvation correction in structure optimization. From that, we can recommend r2SCAN-3c for robust quantification of this omnipresent interaction.

Beryllium as a Base: Complexes of Be(CO)3 with HX (X=F, Cl, Br, CN, NC, CCH, OH).

Beryllium chemistry is typically governed by its electron deficient character, but in some compounds it can act as a base. In order to understand better the unusual basicity of Be, we have systematically explored the complexes of one such compound, Be(CO)3, towards several hydrogen bond donors HX (X=F, Cl, Br, CN, NC, CCH, OH). For all complexes we find three different minima, two hydrogen bonded minima (to the Be or O atoms), and one weak beryllium bonded minimum. Further characterization of the interactions using a topological analysis of the electron density and Symmetry Adapted Perturbation Theory (SAPT) provide insight into the nature of these interactions. Overall these results highlight the capability of certain beryllium compounds to act as either a weak Lewis acid or, unconventionally, a Lewis base whose basicity towards hydrogen bonding is comparable to that of π systems.

Understanding daily rhythms in weakly electric fish: the role of melatonin on the electric behavior of Brachyhypopomus gauderio.

Living organisms display molecular, physiological and behavioral rhythms synchronized with natural environmental cycles. Understanding the interaction between environment, physiology and behavior requires taking into account the complexity of natural habitats and the diversity of behavioral and physiological adaptations. Brachyhypopomus gauderio is characterized by the emission of electric organ discharges (EOD), with a very stable rate modulated by social and environmental cues. The nocturnal arousal in B. gauderio coincides with a melatonin-dependent EOD rate increase. Here, we first show a daily cycle in both the EOD basal rate (EOD-BR) and EOD-BR variability of B. gauderio in nature. We approached the understanding of the role of melatonin in this natural behavior through both behavioral pharmacology and in vitro assays. We report, for the first time in gymnotiformes, a direct effect of melatonin on the pacemaker nucleus (PN) in in vitro preparation. Melatonin treatment lowered EOD-BR in freely moving fish and PN basal rate, while increasing the variability of both. These results show that melatonin plays a key role in modulating the electric behavior of B. gauderio through its effect on rate and variability, both of which must be under a tight temporal regulation to prepare the animal for the challenging nocturnal environment.

Enantioselective Syntheses of 3,4-Dihydropyrans Employing Isochalcogenourea-Catalyzed Formal (4+2)-Cycloadditions of Allenoates.

We herein successfully demonstrate the use of chiral isochalcogenoureas as Lewis Base catalysts for a variety of (4+2)-cycloaddition reactions of allenoates and different Michael acceptors. In all cases the same structural key-motive, a dihydropyran with a (Z)-configurated exocyclic double bond could be accessed as the major regio- and diastereoisomer in an enantioselective manner. Furthermore, these chiral dihydropyrans were successfully engaged in different follow-up transformations.

Predicting Surface pH in Unbuffered Conditions for Acids, Bases, and Their Salts - A Review of Modeling Approaches and Their Performance.

Dissolution of ionizable drugs and their salts is a function of drug surface solubility driven by the surface pH, i.e., the microenvironmental pH at the solid/liquid interface, which will deviate from bulk pH when there is an acid-base reaction occurring at the solid/liquid interface. In this work, we first present a brief overview of the modeling approaches available in the literature, classified according to the rate-determining step assumed in the dissolution process. In the second part, we present and evaluate the prediction performance of two different modeling approaches for surface pH. The first method relies only on thermodynamic equilibria, while the second method accounts for transport phenomena of charged compounds through the diffusional boundary layer using the Nernst - Planck equation. Model outcomes are compared with experimental data taken from the literature and obtained during this work. In terms of surface pH predictions, the models provide identical values for weak acids or weak bases. The models' outcomes for bases are in good agreement with experimental data in acidic conditions (bulk pH 1-4), while overpredictions are observed in the 5-7 bulk pH range in a system-dependent manner. Deviations can be related to the effect of surface dissolution (also referred to as surface reaction), which may become a controlling mechanism and slow the replenishment of the unionized drug at the surface of the crystal. Surface pH predictions for acids are generally in good agreement with experiments, with a slight underestimation for some drug examples, which could be related to errors in intrinsic solubility determination or to the assumption of thermodynamic equilibrium at the surface of the drug. A good agreement is also observed for salts with the thermodynamic model except for mesylate salts, suggesting that other phenomena, not currently included in the thermodynamic equilibrium model, may determine the surface pH.

Novel naphthoquinone-1H-1,2,3-triazole hybrids: Design, synthesis and evaluation as inductors of ROS-mediated apoptosis in the MCF-7 cells.

The search for novel anticancer drugs is essential to expand treatment options, overcome drug resistance, reduce toxicity, promote innovation, and tackle the economic impact. The importance of these studies lies in their contribution to advancing cancer research and enhancing patient outcomes in the battle against cancer. Here, we developed new asymmetric hybrids containing two different naphthoquinones linked by a 1,2,3-1H-triazole nucleus, which are potential new drugs for cancer treatment. The antitumor activity of the novel compounds was tested using the breast cancer cell lines MCF-7 and MDA-MB-231, using the non-cancer cell line MCF10A as control. Our results showed that two out of twenty-two substances tested presented potential antitumor activity against the breast cancer cell lines. These potential drugs, named here 12g and 12h were effective in reducing cell viability and promoting cell death of the tumor cell lines, exhibiting minimal effects on the control cell line. The mechanism of action of the novel drugs was assessed revealing that both drugs increased reactive oxygen species production with consequent activation of the AMPK pathway. Therefore, we concluded that 12g and 12h are novel AMPK activators presenting selective antitumor effects.

Fluorescent Schiff Bases with Phenothiazine and Coumarin Moieties: Synthesis, Characterization, Photophysical, Electrochemical, Computational and Biological Studies.

We present the design and synthesis of four new schiff bases viz., two each of phenothiazine and coumarin derivatives. The structures were proposed based on FT-IR, 1H NMR, 13C NMR and mass spectral data. The photophysical, solvatochromic and electrochemical studies of all the compounds were carried out. Furthermore, theoretical studies such as density functional theory (DFT) were carried out to gain a better understanding of the compounds' intramolecular charge transfer properties and electronic structures. Good agreement was noticed between the HOMO-LUMO energy gap obtained from DFT studies and that calculated from absorption threshold wavelengths. All the compounds showed Stokes shifts in the range of 6345-11,405 cm-1. These findings showed that the new schiff bases could be considered as attractive candidates for use in the development of OLEDs, organic electrical devices and optoelectronic devices. Newly synthesized compounds were tested for biological activities. When compared to conventional standards, gallic acid and indomethacin, the schiff bases showed better antioxidant and antiinflammatory activities, respectively.

Eco-friendly optical sensor for precise detection of gold ions in diverse matrices through the integration of ß-2-hydroxybenzyl-3-methoxy-2-hydroxyazastyrene in a PVC membrane.

An environmentally conscious methodology is investigated for the precise and discerning identification of trace concentrations of gold ions in diverse matrices. A novel optical sensor membrane is proposed for the determination of Au3+ ions, utilizing the immobilization of ß-2-hydroxybenzyl-3-methoxy-2-hydroxyazastyrene (HMHS) entrapped in polyvinyl chloride (PVC). The sensor incorporates sodium tetraphenylborate (Na-TPB) as the ionic additive and dibutyl phthalate (DBP) as a plasticizer. Under optimal conditions, the suggested sensor exhibits a linear calibration response to Au3+ ions within a concentration range of 5.0 to 165 ng mL-1. Detection and quantification limits are specified as 1.5 and 4.8 ng mL-1, respectively, with a rapid response time of 5.0 min. Upon presentation, this optical sensor not only affirms high reproducibility, stability, and an extended operational lifespan but also showcases exceptional selectivity for Au3+ ions. Notably, no discernible interference is observed when assessing the potential influence of other cations and anions on Au3+ ion detection. The adaptability of this optical sensor is validated through its successful application in determining Au3+ ion concentrations across various sample types, including water, environmental, cosmetics, and soil matrices.