Monogenic mutations in four cases of neonatal-onset watery diarrhea and a mutation review in East Asia.

Background: Infants with neonatal-onset diarrhea present with intractable diarrhea in the first few weeks of life. A monogenic mutation is one of the disease etiologies and the use of next-generation sequencing (NGS) has made it possible to screen patients for their mutations.

Main Body: We retrospectively reviewed the clinical data of four children from unrelated families, who presented with neonatal-onset, chronic, watery, non-bloody diarrhea.

Elucidating heterogeneous photocatalytic superiority of microporous porphyrin organic cage.

The investigation on the catalytic properties of porous organic cages is still in an initial stage. Herein, the reaction of cyclohexanediamine with 5,15-di[3',5'-diformyl(1,1'-biphenyl)]porphyrin affords a porphyrin tubular organic cage, PTC-1(2H). Transient absorption spectroscopy in solution reveals much prolonged triplet lifetime of PTC-1(2H) relative to monomer reference, illustrating the unique photophysical behavior of cagelike photosensitizer.

Sulfur-centered hemi-bond radicals as active intermediates in S-DNA phosphorothioate oxidation.

Phosphorothioate (PS) modifications naturally appear in bacteria and archaea genome and are widely used as antisense strategy in gene therapy. But the chemical effects of PS introduction as a redox active site into DNA (S-DNA) is still poorly understood. Herein, we perform time-resolved spectroscopy to examine the underlying mechanisms and dynamics of the PS oxidation by potent radicals in free model, in dinucleotide, and in S-oligomer.

Monitoring the Structure-Dependent Reaction Pathways of Guanine Radical Cations in Triplex DNA: Deprotonation Versus Hydration.

Exposure of DNA to one-electron oxidants leads initially to the formation of guanine radical cations (G), which may degrade by deprotonation or hydration and ultimately cause strand breaks or 8-oxoG lesions. As the structure is dramatically changed by binding of the third strand in the major groove of the target duplex, it makes the triplex an interesting DNA structure to be examined and compared with the duplex on the G degradation pathways. Here, we report for the first time the time-resolved spectroscopy study on the G reaction dynamics in triplex DNA together with the Fourier transform infrared characterization of steady-state products, from which structural effects on the reactivity of G are unraveled.

Degradation of Cytosine Radical Cations in 2'-Deoxycytidine and in i-Motif DNA: Hydrogen-Bonding Guided Pathways.

Radical cations of nucleobases are key intermediates causing genome mutation, among which cytosine C is of growing importance because the ensuing cytosine oxidation causes GC → AT transversions in DNA replication. Although the chemistry and biology of steady-state C oxidation products have been characterized, time-resolved study of initial degradation pathways of C is still at the preliminary stage. Herein, we choose i-motif, a unique C-quadruplex structure composed of hemiprotonated base pairs C(H):C, to examine C degradation in a DNA surrounding without interference of G bases.

Binding Interactions of Zinc Cationic Porphyrin with Duplex DNA: From B-DNA to Z-DNA.

Recognition of unusual left-handed Z-DNA by specific binding of small molecules is crucial for understanding biological functions in which this particular structure participates. Recent investigations indicate that zinc cationic porphyrin (ZnTMPyP4) is promising as a probe for recognizing Z-DNA due to its characteristic chiroptical properties upon binding with Z-DNA. However, binding mechanisms of the ZnTMPyP4/Z-DNA complex remain unclear.

Interaction between G-Quadruplex and Zinc Cationic Porphyrin: The Role of the Axial Water.

The interaction of ligands with G-quadruplexes has attracted considerable attention due to its importance in molecular recognition and anticancer drugs design. Here, we utilize triplet excited state as a sensitive reporter to study the binding interaction of zinc cationic porphyrin (ZnTMPyP4) with three G-quadruplexes, AG(TAG), (GTG)2, and (TGT)4. By monitoring the triplet decay dynamics of ZnTMPyP4 with transient absorption spectroscopy, the coexisted binding modes via π-π stacking of porphyrin macrocycle and the G-quartets are allowed to be identified quantitatively, which involve intercalation (25% and 36%) versus end-stacking (75% and 64%) for AG(TAG) and (GTG)2, and end-stacking (23%) versus partial intercalation (77%) for (TGT)4.

Capturing the radical ion-pair intermediate in DNA guanine oxidation.

Although the radical ion pair has been frequently invoked as a key intermediate in DNA oxidative damage reactions and photoinduced electron transfer processes, the unambiguous detection and characterization of this species remain formidable and unresolved due to its extremely unstable nature and low concentration. We use the strategy that, at cryogenic temperatures, the transient species could be sufficiently stabilized to be detectable spectroscopically. By coupling the two techniques (the cryogenic stabilization and the time-resolved laser flash photolysis spectroscopy) together, we are able to capture the ion-pair transient G⋯Cl in the chlorine radical-initiated DNA guanine (G) oxidation reaction, and provide direct evidence to ascertain the intricate type of addition/charge separation mechanism underlying guanine oxidation.

Porphyrin Bound to i-Motifs: Intercalation versus External Groove Binding.

G-rich and C-rich DNA can fold into the tetrastranded helical structures G quadruplex or C quadruplex (i-motif), which are considered to be specific drug targets for cancer therapy. A large number of small molecules (so-called ligands), which can bind and modulate the stability of G quadruplex structures, have been widely examined. Much less is known, however, about the ligand binding interactions with the C quadruplex (i-motif).

Photoinduced C-I bond homolysis of 5-iodouracil: A singlet predissociation pathway.

5-Iodouracil (5-IU) can be integrated into DNA and acts as a UV sensitive chromophore suitable for probing DNA structure and DNA-protein interactions based on the photochemical reactions of 5-IU. Here, we perform joint studies of time-resolved Fourier transform infrared (TR-FTIR) spectroscopy and ab initio calculations to examine the state-specific photochemical reaction mechanisms of the 5-IU. The fact that uracil (U) is observed in TR-FTIR spectra after 266 nm irradiation of 5-IU in acetonitrile and ascribed to the product of hydrogen abstraction by the uracil-5-yl radical (U·) provides experimental evidence for the C-I bond homolysis of 5-IU.

Gadolinium(III) Porpholactones as Efficient and Robust Singlet Oxygen Photosensitizers.

Construction of Gd(III) photosensitizers is important for designing theranostic agents owing to the unique properties arising from seven unpaired f electrons of the Gd(3+) ion. Combining these with the advantages of porpholactones with tunable NIR absorption, we herein report the synthesis of Gd(III) complexes Gd-1-4 (1, porphyrin; 2, porpholactone; 3 and 4, cis- and trans-porphodilactone, respectively) and investigated their function as singlet oxygen ((1) O2 ) photosensitizers. These Gd complexes displayed (1) O2 quantum yields (ΦΔ s) from 0.

Fluorescence Products from Terrylenediimide with Singlet Oxygen: Red, Green, and Near-Infrared Emission.

The rich photo-oxidation pathways and products of terrylenediimide (TDI) with singlet oxygen ((1)O2) have been examined by powerful computational approaches. Potential energy profiles and product fluorescence properties are characterized. A variety of new products are unraveled and predicted to emit fluorescence at both visible and near-infrared ranges, which could open the possibility for interesting applications of using TDI as a fluorescence probe for the single-molecule detection of (1)O2 and designing multicolor photoconvertible fluorophores based on (1)O2 oxidation.

Explicit Differentiation of G-Quadruplex/Ligand Interactions: Triplet Excited States as Sensitive Reporters.

We report a new transient spectral method utilizing triplet excited state as sensitive reporters to monitor and differentiate the multiplex G-quadruplex/ligand interactions in a single assay, which is a difficult task and usually requires a combination of several techniques. From a systematic study on the interactions of porphyrin (TMPyP4) with each telomeric G-quadruplex: AG3(T2AG3)3, G2T2G2TGTG2T2G2, (G4T4G4)2, and (TG4T)4, it is convincingly shown that the ligand triplet decay lifetimes are sensitive to the local bound microenvironment within G-quadruplexes, from which the coexisting binding modes of end-stacking, intercalation, and sandwich are distinguished and their respective contribution are determined. The complete scenario of mixed interaction modes is thus revealed, shedding light on the past controversial issues.

Direct observation of guanine radical cation deprotonation in G-quadruplex DNA.

Although numerous studies have been devoted to the charge transfer through double-stranded DNA (dsDNA), one of the major problems that hinder their potential applications in molecular electronics is the fast deprotonation of guanine cation (G(+•)) to form a neutral radical that can cause the termination of hole transfer. It is thus of critical importance to explore other DNA structures, among which G-quadruplexes are an emerging topic. By nanosecond laser flash photolysis, we report here the direct observation and findings of the unusual deprotonation behavior (loss of amino proton N2-H instead of imino proton N1-H) and slower (1-2 orders of magnitude) deprotonation rate of G(+•) within G-quadruplexes, compared to the case in the free base dG or dsDNA.

Physical quenching in competition with the formation of cyclobutane pyrimidine dimers in DNA photolesion.

The potential energy profiles toward formation of cyclobutane pyrimidine dimers CPD and the physical quenching after UV excitation were explored for the dinucleotide thymine dinucleoside monophosphate (TpT) using density functional theory (ωB97XD) and the time-dependent density functional theory (TD-ωB97XD). The ωB97XD functional that includes empirical dispersion correction is shown to be an appropriate method to obtain rational results for the current large reaction system of TpT. Photophysical quenching is shown to be predominant over the photochemical CPD formation.

Nonadiabatic reaction mechanisms of the O((3)P) with cyclopentene.

The reaction mechanism of the ground state oxygen atom O((3)P) with cyclopentene is investigated theoretically. The triplet and singlet potential energy surfaces are calculated at the CCSD(T)//MP2/6-311G(d,p) level and the minimum energy crossing points (MECPs) between the two surfaces are located by means of the Newton-Lagrange method, from which the complex nonadiabatic reaction pathways are revealed. Based on the theoretical results, the most probable reaction mechanism of O((3)P) with c-C5H8 is described, which agrees with the experimental results nicely, including the condensed phase experiment.

Photophysical and photochemical properties of 4-thiouracil: time-resolved IR spectroscopy and DFT studies.

Intensified research interests are posed with the thionucleobase 4-thiouracil (4-TU), due to its important biological function as site-specific photoprobe to detect RNA structures and nucleic acid-nucleic acid contacts. By means of time-resolved IR spectroscopy and density functional theory (DFT) studies, we have examined the unique photophysical and photochemical properties of 4-TU. It is shown that 4-TU absorbs UVA light and results in the triplet formation with a high quantum yield (0.

Time-resolved and mechanistic study of the photochemical uncaging reaction of the o-hydroxycinnamic caged compound.

The o-hydroxycinnamic derivatives represent efficient caged compounds that can realize quantification of delivery upon uncaging, but there has been lack of time-resolved and mechanistic studies. We used time-resolved infrared (TRIR) spectroscopy to investigate the photochemical uncaging dynamics of the prototype o-hydroxycinnamic compound, (E)-3-(2-hydroxyphenyl)-acrylic acid ethyl ester (HAAEE), leading to coumarin and ethanol upon uncaging. Taking advantage of the specific vibrational marker bands and the IR discerning capability, we have identified and distinguished two key intermediate species, the cis-isomers of HAAEE and the tetrahedral intermediate, in the transient infrared spectra, thus providing clear spectral evidence to support the intramolecular nucleophilic addition mechanism following the trans-cis photoisomerization.

Mechanism of the deamination reaction of isoguanine: a theoretical investigation.

Mechanisms of the deamination reactions of isoguanine with H2O, OH(-), and OH(-)/H2O and of protonated isoguanine (isoGH(+)) with H2O have been investigated by theoretical calculations. Eight pathways, paths A-H, have been explored and the thermodynamic properties (ΔE, ΔH, and ΔG), activation energies, enthalpies, and Gibbs energies of activation were calculated for each reaction investigated. Compared with the deamination reaction of isoguanine or protonated isoguanine (isoGH(+)) with water, the deamination reaction of isoguanine with OH(-) shows a lower Gibbs energy of activation at the rate-determining step, indicating that the deamination reaction of isoguanine is favorably to take place for the deprotonated form isoG(-) with water.

Consecutive reaction mechanism for the formation of spore photoproduct in DNA photolesion.

We have explored the potential energy profiles of TpT dinucleotides toward formation of a DNA photolesion product, spore photoproduct (SP), along the S(0), S(1), and T(1) states, by means of density functional theory and time-dependent density functional theory. Together with the spin density analysis, the consecutive mechanism for the SP formation can be established. The detailed reaction pathways have been revealed.

[2+2] Photocycloaddition reaction dynamics of triplet pyrimidines.

Taking the 266 nm excited pyrimidine (uracil or thymine) with cyclopentene as model reaction systems, we have examined the photoproduct formation dynamics from the [2 + 2] photocycloaddition reactions of triplet pyrimidines in solution and provided mechanistic insights into this important DNA photodamage reaction. By combining two compliment methods of nanosecond time-resolved transient IR and UV-vis laser flash-photolysis spectroscopy, the photoproduct formation dynamics as well as the triplet quenching kinetics are measured. Characteristic IR absorption bands due to photoproduct formation have been observed and product quantum yields are determined to be ∼0.

Competitive reaction pathways of C2Cl3 + NO via four-membered ring and bicyclic ring intermediates.

The products and mechanisms of the atmospherically and environmentally important reaction, C(2)Cl(3) + NO, are investigated comprehensively by step-scan time-resolved Fourier transform infrared emission spectroscopy and the CCSD(T)/6-311+G(d)//B3LYP/6-311G(d) level of electronic structure calculations. Vibrationally excited products of Cl(2)CO, ClNCO, CCl(3)NCO and NCO have been observed in the IR emission spectra. Cyclic intermediates are found to play important roles leading to the rich variety of the chemical transformations of the reaction.

Photodissociation and photoisomerization dynamics of CH2=CHCHO in solution.

By means of time-resolved Fourier transform infrared absorption spectroscopy, we have investigated the 193 nm photodissociation and photoisomerization dynamics of the prototype molecule of alpha,beta-enones, acrolein (CH(2)=CHCHO) in CH(3)CN solution. The primary photolysis channels and absolute branching ratios are determined. The most probable reaction mechanisms are clarified by control experiments monitoring the product yields varied with the triplet quencher addition.

Reaction mechanisms of a photo-induced [1,3] sigmatropic rearrangement via a nonadiabatic pathway.

Time-resolved Fourier transform infrared absorption spectroscopy measurements and B3LYP/cc-pVDZ calculations have been conducted to characterize the reaction dynamics of a remarkable photoinduced 1,3-Cl sigmatropic rearrangement reaction upon 193 or 266 nm excitation of the model systems acryloyl chloride (CH(2)CHCOCl) and crotonyl chloride (CH(3)CHCHCOCl) in solution. The reaction is elucidated to follow nonadiabatic pathways via two rapid ISC processes, S(1) --> T(1) and T(1) --> S(0), and the S(1)/T(1) and T(1)/S(0) surface intersections are found to play significant roles leading to the nonadiabatic pathways. The S(1) --> T(1) --> S(0) reaction pathway involving the key participation of the T(1) state is the most favorable, corresponding to the lowest energy path.

Adiabatic and nonadiabatic reaction pathways of the O(3P) with propyne.

For the reaction of O((3)P) with propyne, the product channels and mechanisms are investigated both theoretically and experimentally. Theoretically, the CCSD(T)//B3LYP/6-311G(d,p) level of calculations are performed for both the triplet and singlet potential energy surfaces and the minimum energy crossing point between the two surfaces are located with the Newton-Lagrange method. The theoretical calculations show that the reaction occurs dominantly via the O-addition rather than the H-abstraction mechanism.