Water-Controlled Keto-Enol Tautomerization of a Prebiotic Nucleobase.

Barbituric acid is believed to be a proto-RNA nucleobase that was used for biological information transfer on prebiotic earth before DNA and RNA in their present forms evolved. Nucleobases have various tautomeric forms and the relative stability of these forms is critical to their biological function. It has been shown that barbituric acid has a tri-keto form in the gas phase and an enol form in the solid state. However, its dominant tautomeric form in aqueous medium that is most relevant for biology has been investigated only to a limited extent and the findings are inconclusive. We have used multiple approaches, namely, molecular dynamics, quantum chemistry, NMR, and IR spectroscopy to determine the most stable tautomer of barbituric acid in solution. We find a delicate balance in the stability of the two tautomers, tri-keto and enol, which is tipped toward the enol as the extent of solvation by water increases.

Quantum effects in photosensitization: the case of singlet oxygen generation by thiothymines.

Photosensitization is the indirect electronic excitation of a molecule with the aid of a photosensitizer and is a bimolecular nonradiative energy transfer. In this study, we have attempted to elucidate its mechanism, and we do this by calculating rate constants of photosensitization of oxygen by thiothymines (2-thiothymine, 4-thiothymine and 2,4 dithiothymine). The rate constants have been calculated using two approaches: (a) a classical limit of Fermi's Golden Rule (FGR), and (b) a time-dependent variant of FGR, where the treatment is purely quantum mechanical. The former approach has previously been developed for bimolecular systems and has been applied to the photosensitization reactions studied here. The latter approach, however, has so far only been used for unimolecular reactions, and in this work, we describe how it can be adapted for bimolecular reactions. Experimentally, all three thiothymines are known to have significant singlet oxygen yields, which are indicative of similar rates. Rate constants calculated using the time-dependent variant of FGR are similar across all three thiothymines. While the classical approximation gives reasonable rate constants for 2-thiothymine, it severely underestimates them for 4-thiothymine and 2,4 dithiothymine, by several orders of magnitude. This work indicates the importance of quantum effects in driving photosensitization.

Pneumothorax and Pneumomediastinum Complicating Organophosphate Poisoning: A Case Series of Complications Less Understood.

Organophosphate compounds are used as insecticides in agricultural and domestic settings throughout the world. Acute organophosphorus (OP) poisoning is a major public health issue. Early diagnosis of OP poisoning and prompt atropinization can save lives. Respiratory failure may occur in patients with OP poisoning for many reasons, including aspiration of gastric contents, excessive secretions, pneumonia, and sepsis complicating acute respiratory distress syndrome. Till date, however, spontaneous pneumothorax and pneumomediastinum have not been reported in cases of OP poisoning. This report presents two similar cases of OP poisoning in which spontaneous pneumothorax and pneumomediastinum developed following OP ingestion.

Utility of early warning scores to predict mortality in COVID-19 patients: A retrospective observational study.

BACKGROUND: Coronavirus disease 2019 (COVID19) has evolved as a global pandemic. The patients with COVID-19 infection can present as mild, moderate, and severe disease forms. The reported mortality of severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) infection is around 6.6%, which is lower than that of SARS-CoV and (middle east respiratory syndrome CoV). However, the fatality rate of COVID-19 infection is higher in the geriatric age group and in patients with multiple co-morbidities. The study aimed to evaluate the utility of early warning scores (EWS) to predict mortality in patients with moderate to severe COVID-19 infection. METHODS: This retrospective study was carried out in a tertiary care institute of Uttarakhand. Demographic and clinical data of the admitted patients with moderate-to-severe COVID-19 infection were collected from the hospital record section and utilized to calculate the EWS-National early warning score (NEWS), modified early warning score (MEWS), Rapid Acute Physiology Score (RAPS), rapid emergency medicine score (REMS), and worthing physiological scoring system (WPS). RESULTS: The area under the curve for NEWS, MEWS, RAPS, REMS, and WPS was 0.813 (95% confidence interval [CI]; 0.769-0.858), 0.770 (95% CI; 0.717-0.822), 0.755 (95% CI; 0.705-0.805), 0.892 (95% CI; 0.859-0.924), and 0.892 (95% CI; 0.86-0.924), respectively. CONCLUSION: The EWS at triage can be used for early assessment of severity as well as predict mortality in patients with COVID-19 patients.

A Case of Chorea: A Rare and Unusual Complication of Hyperglycemia.

We present a case of hemichorea in a patient with nonketotic hyperglycemia (NKH), a rare presentation of hyperglycemia. A 55-year-old female with diabetes presented to the emergency department with involuntary bilateral upper and lower limb movements for five days. The patient had a serum glucose level of 358 mg/dL (19.87 mmol/L) and improved after controlling blood sugar levels. When we encounter a case of chorea in the emergency department, high blood sugar levels are an essential underlying reversible etiology to be kept in mind.

Peptide bond planarity constrains hydrogen bond geometry and influences secondary structure conformations.

An extensive database study of hydrogen bonds in different protein environments showed systematic variations in donor-acceptor-acceptor antecedent angle (H) and donor-acceptor distance. Protein environments were characterized by depth (distance of amino acids from bulk solvent), secondary structure, and whether the donor/acceptor belongs to the main chain (MC) or side chain (SC) of amino acids. The MC-MC hydrogen bonds (whether in secondary structures or not) have H angles tightly restricted to a value of around 155°, which was distinctly different from other H angles. Quantum chemical calculations attribute this characteristic MC-MC H angle to the nature of the electron density distribution around the planar peptide bond. Additional classical simulations suggest a causal link between MC-MC H angle and the conformation of secondary structures in proteins. We also showed that donor-acceptor distances are environment dependent, which has implications on protein stability. Our results redefine hydrogen bond geometries in proteins and suggest useful refinements to existing molecular mechanics force fields.

Pseudopapillary Tumor of the Pancreas: A Rare Cause of Extrahepatic Portal Hypertension.

A solid pseudopapillary tumor (SPT) of the pancreas is an uncommon neoplasm, characterized by a well-encapsulated mass, with low malignant potential. It occurs predominantly in young females. We present a case of SPT of the pancreas which presented with sinistral portal hypertension. Despite characteristic radiological findings due to its rarity, it may be missed to more common conditions like peptic ulcer disease. Delayed diagnosis can lead to complications like portal hypertension. To the best of our knowledge, in existing medical literature, SPT of the pancreas in males has rarely been described. In our case, we found that the tumor was causing extrahepatic portal hypertension which is also a very unique presentation of this tumor. Due to its vague clinical manifestations, definitive diagnosis is often a challenge hence requiring prompt investigations.

The Curious Case of Aqueous Warfarin: Structural Isomers or Distinct Excited States?

Warfarin is a potent anti-coagulant drug and is on the World Health Organization's List of Essential Medicines. Additionally, it displays fluorescence enhancement upon binding to human serum albumin, making warfarin a prototype fluorescent probe in biology. Despite its biological significance, the current structural assignment of warfarin in aqueous solution is based on indirect evidence in organic solvents. Warfarin is known to exist in different isomeric forms-open-chain, hemiketal, and anionic forms-based on the solvent and pH. Moreover, warfarin displays a dual absorption feature in several solvents, which has been employed to study the ring-chain isomerism between its open-chain and hemiketal isomers. In this study, our pH-dependent experiments on warfarin and structurally constrained warfarin derivatives in aqueous solution demonstrate that the structural assignment of warfarin solely on the basis of its absorption spectrum is erroneous. Using a combination of steady-state and time-resolved spectroscopic experiments, along with quantum chemical calculations, we assign the observed dual absorption to two distinct π → π* transitions in the 4-hydroxycoumarin moiety of warfarin. Furthermore, we unambiguously identify the isomeric form of warfarin that binds to human serum albumin in aqueous buffer.

Bend-to-Break: Curvilinear Proton Transfer in Phenol-Ammonia Clusters.

The electric field experienced by the OH group of phenol embedded in the cluster of ammonia molecules depends on the relative orientation of the ammonia molecules, and a critical field of 236 MV cm-1 is essential for the transfer of a proton from phenol to the surrounding ammonia cluster. However, exceptions to this rule were observed, which indicates that the projection of the solvent electric field over the O-H bond is not a definite descriptor of the proton transfer reaction. Therefore, a critical electric field is necessary, but it is not a sufficient condition for the proton abstraction. This, in combination with an adequate solvation of the acceptor ammonia molecule in a triple donor motif that energetically favors the proton transfer process, constitutes necessary and sufficient conditions for the spontaneous proton abstraction. The proton transfer process in phenol-(ammonia)n clusters is statistically favored to occur away from the plane of the phenyl ring and follows a curvilinear path which includes the O-H bond elongation and out-of-plane movement of the proton. Colloquially, this proton transfer can be referred to as a "bend-to-break" process.

Triplet Decay Dynamics in Sulfur-Substituted Thymine: How Position of Substitution Matters.

Sulfur-substituted analogues of thymine are of three types depending on the position of sulfur substitution: 2-thiothymine (2tThy), 4-thothymine (4tThy), and 2,4-dithiothymine (dtThy). These molecules, on photoexcitation, are known to form in their triplet state with near unity yield. Consequently, they are able to photosensitize ground state molecular oxygen to singlet oxygen, a property which makes them potential drugs for photodynamic therapy (PDT). The singlet oxygen yield is directly correlated with the triplet lifetime of the thiothymine, which in turn is governed by its triplet decay dynamics. In this work, the dependence of the triplet decay dynamics on the position of sulfur substitution is investigated by comparatively studying all three thiothymines. The topology of the triplet potential energy surface and decay mechanism of 2tThy is found to be distinctly different from 4tThy and dtThy. The fundamental reason for this is the different electronic natures of the two C═X (X = O, S) moieties in each molecule, one of which is conjugated with a C═C bond, while the other is not. Further, it is shown that the triplet lifetime of 2tThy can be increased by manipulating the energetic ordering of its molecular orbitals with unobtrusive substitutions, thus making it a better candidate for a PDT drug.

Mechanism of the Chemiluminescent Reaction between Nitric Oxide and Ozone.

The gas phase reaction of nitric oxide with ozone to give chemiluminescence is used extensively for detection of nitrogen oxides. The molecular mechanism of chemiluminescence in this reaction is not known. So far, the only chemiluminescent systems studied in depth are certain cycloperoxides, which emit light following decomposition. Given our understanding of the mechanism of chemiluminescence in those molecules, one would expect by extension that in the NO + O3 reaction the chemiluminescent species (NO2 in this case) is formed in the excited state through a reaction pathway that diverges from the ground state pathway near the transition state. A systematic search for such a pathway leads us to conclude that such a mechanism is unlikely. Instead, our study suggests that chemiluminescence in the NO + O3 reaction is due to emission from the NO2 vibronic states associated with the ground (X̃ 2A1) and first excited (à 2B2) electronic states, which are populated in the nascent NO2 produced in the reaction. The vibronic coupling between the X̃ 2A1 and à 2B2 states of NO2 is due to a conical intersection (CI), which is geometrically and energetically close to the à 2B2 minimum energy geometry and only 1.3 eV higher than ground state NO2. Further, the CI is 1.2 eV lower than the energy of the NO + O3 reactants and therefore thermodynamically accessible following the reaction. An analysis of the product energy distribution indicates that the major fraction of the reaction energy is channeled into the vibrational modes of NO2, sufficient to populate the vibronic states of NO2 around the X̃/à CI. These vibronic states show dipole-allowed emission in a frequency range that is consistent with the observed broad chemiluminescence spectrum.

Intersystem Crossing Drives Photoisomerization in o-Nitrotoluene, a Model for Photolabile Caged Compounds.

o-Nitrobenzyl (oNB) derivatives are widely used photolabile caged compounds in chemical and biological applications. The primary step in the photoinduced deprotection is an excited state intramolecular hydrogen transfer (ESIHT) leading to tautomerization of the oNB compound and subsequent release of the protecting group. The prototype molecule for studying such ESIHT is o-nitrotoluene (oNT), where hydrogen transfers from the methyl to the nitro group. Using the complete active space self-consistent field (CASSCF) method with second-order perturbative energy corrections (CASPT2), we have comprehensively investigated the photoisomerization and photo decay mechanisms in oNT. We have obtained the minimum energy crossing points (MECPs) between relevant electronic states and identified the singlet and triplet pathways. There is a barrierless path for oNT to relax to the lowest triplet state. In this T1 state, the ESIHT products are more stable than T1 oNT. Hydrogen-transfer occurs on the T1 state followed by relaxation to the ground state to give the isomerized product. A biradical intermediate proposed by previous studies is characterized to be the hydrogen-transferred T1 product. On the singlet pathway, in contrast to the triplet, the ground state tautomer is formed from the S1 oNT through a geometrically distant and energetically higher S1/S0 conical intersection. Although nonadiabatic dynamical studies are essential for determining branching ratios, our study, which considers the accessibility of different MECPs based on geometry and energy, and the magnitude of spin-orbit coupling at singlet-triplet MECPs, suggests that a significant fraction of the isomerization yield is due to the triplet channel.

Interplay between Conjugation and Size-Driven Delocalization Leads to Characteristic Properties of Substituted Thymines.

Substituted thymines, where oxygen is replaced by sulfur or selenium, affect a variety of functions in biological systems and are prospective phototherapeutic agents. In this study, we show that an interplay between two types of delocalization, one due to conjugation and the other owing to the varying size of the substituted atom, leads to distinct absorption spectra and electrophilic sites in substituted thymines. This result is supported by ab initio quantum chemical calculations and a simple particle-in-a-box model. The model explains the unexpected variation in the absorption of 2-thiothymine and 4-thiothymine and makes an unanticipated prediction about the nature of the LUMO in 2-selenothymine that is confirmed by quantum chemical calculations. Here, delocalization due to the large size of selenium dominates that due to conjugation; in essence, a 2-center delocalization exerts a greater influence on molecular properties than a 4-center delocalization. The study highlights that the widely used concept of delocalization may be affected not only by the long-established idea of double bond conjugation but also delocalization owing to the size of atoms.

Transition-Metal-Free C-H Hydroxylation of Carbonyl Compounds.

Transition metal and reductant free α-C(sp3)-H hydroxylation of carbonyl compounds are reported. This method is promoted by commercially available inexpensive KO-t-Bu and atmospheric air as an oxidant at room temperature. This unified strategy is also very facile for hydroxylation of various carbonyl compound derivatives to obtain quaternary hydroxyl compounds in excellent yield. A preliminary mechanistic investigation, supported by isotope labeling and computational studies, suggests the formation of a peroxide bond and its cleavage by in situ generated enolate.

Intramolecular cascade rearrangements of enynamine derived ketenimines: access to acyclic and cyclic amidines.

Copper-catalyzed reaction of enynamines with sulfonylazides provides acyclic and cyclic amidines. Nucleophilic addition of the tethered amino group on the in situ generated ketenimine forms a six-membered cyclic zwitterionic intermediate which facilitates migration of the tethered amino group to the C5-center giving the acyclic amidine. On the other hand, migration of a substituent on the amino group to C2- and C4-centers results in the formation of cyclic amidines. Computational studies were carried out to validate the mechanism which indicates that the product distribution of the process depends on the substitutions on the enynamine backbone.

π-Stacked Dimers of Fluorophenylacetylenes: Role of Dipole Moment.

The homodimers of singly fluorine-substituted phenylacetylenes were investigated using electronic and vibrational spectroscopic methods in combination with density functional theory calculations. The IR spectra in the acetylenic C-H stretching region show a marginal red shift for the dimers relative to the monomers. Further, the marginal red shifts indicate that the acetylenic group in all the dimers is minimally perturbed relative to the corresponding monomer. The observed spectra were assigned to a set of π-stacked structures within an energy range of 1.5 kJ mol-1, which differ in the relative orientation of the two monomers on the basis of M06-2X/aug-cc-pVTZ level calculation. The observed red shift in the acetylenic C-H stretching vibration of the dimers suggests that the antiparallel structures contribute predominantly based on a simple coupled dipole model. Energy decomposition analysis using symmetry-adapted perturbation theory indicates that dispersion plays a pivotal role in π-π stacking with appreciable contribution of electrostatics. The stabilization energies of fluorophenylacetylene dimers follow the same ordering as their dipole moments, which suggests that dipole moment enhances the ability to form π-stacked structures.

Pathways for Excited-State Nonradiative Decay of 5,6-Dihydroxyindole, a Building Block of Eumelanin.

The photophysics of 5,6-dihydroxyindole (DHI) following excitation to its lowest two optically bright states was investigated using the complete active space self-consistent field method with second-order perturbative energy corrections. There is a barrierless pathway for the molecule to relax from the second-lowest bright state (21ππ*) to the lowest bright state (11ππ*). The 11ππ* state has a conical intersection with the optically dark 11πσ* state, which further intersects with the ground state along the NH and OH stretching coordinates. Moreover, the 11ππ* has out-of-plane conical intersections with the ground state. For accessing the conical intersections with the ground state, there are energy barriers, which are higher than the available energy following vertical excitation to the lowest bright state. The nature of the calculated deactivation pathways helps interpret the experimentally estimated lifetimes of the lowest two bright states of DHI. The relatively long lifetime of the lowest excited state suggests that isolated DHI in monomeric form cannot rationalize the ultrafast deactivation property of eumelanin.

Theoretical study of structural changes in DNA under high external hydrostatic pressure.

The study of DNA under high hydrostatic pressure provides fundamental insights into the nature of interactions responsible for its structure and its remarkable stability in extreme conditions. We have investigated the structural changes in DNA under 2000 bar external pressure using electronic structure calculations and molecular dynamics simulations. Both these methods predict very small distortions in the structure; notably, the change in hydrogen bond lengths is an order of magnitude smaller than previously reported experimental values using NMR. The large discrepancy suggests further investigation into the analysis of the experimental data obtained from NMR.

Benzosultines as sulfur dioxide (SO2) donors.

In order to understand precise biological roles of sulfur dioxide (SO(2)), reliable SO(2) donors, compounds that produce SO(2) under physiological conditions, are necessary. The design and development of 1-phenyl-benzosultine as an efficient SO(2) donor is reported. This compound undergoes cycloreversion to generate SO(2) upon dissolution in aqueous buffer at 37 °C with a yield of 89% and a half-life of 39 min and shows SO(2)-like biological activity in a DNA cleavage assay.

Multidimensional treatment of stochastic solvent dynamics in photoinduced proton-coupled electron transfer processes: sequential, concerted, and complex branching mechanisms.

A theoretical approach for the multidimensional treatment of photoinduced proton-coupled electron transfer (PCET) processes in solution is presented. This methodology is based on the multistate continuum theory with an arbitrary number of diabatic electronic states representing the relevant charge distributions in a general PCET system. The active electrons and transferring proton(s) are treated quantum mechanically, and the electron-proton vibronic free energy surfaces are represented as functions of multiple scalar solvent coordinates corresponding to the single electron and proton transfer reactions involved in the PCET process. A dynamical formulation of the dielectric continuum theory is used to derive a set of coupled generalized Langevin equations of motion describing the time evolution of these collective solvent coordinates. The parameters in the Langevin equations depend on the solvent properties, such as the dielectric constants, relaxation time, and molecular moment of inertia, as well as the solute properties. The dynamics of selected intramolecular nuclear coordinates, such as the proton donor-acceptor distance or a torsional angle within the PCET complex, may also be included in this formulation. A surface hopping method in conjunction with the Langevin equations of motion is used to simulate the nonadiabatic dynamics on the multidimensional electron-proton vibronic free energy surfaces following photoexcitation. This theoretical treatment enables the description of both sequential and concerted mechanisms, as well as more complex processes involving a combination of these mechanisms. The application of this methodology to a series of model systems corresponding to collinear and orthogonal PCET illustrates fundamental aspects of these different mechanisms and elucidates the significance of proton vibrational relaxation and nonequilibrium solvent dynamics.