C5a-licensed phagocytes drive sterilizing immunity during systemic fungal infection.

Systemic candidiasis is a common, high-mortality, nosocomial fungal infection. Unexpectedly, it has emerged as a complication of anti-complement C5-targeted monoclonal antibody treatment, indicating a critical niche for C5 in antifungal immunity. We identified transcription of complement system genes as the top biological pathway induced in candidemic patients and as predictive of candidemia. Mechanistically, C5a-C5aR1 promoted fungal clearance and host survival in a mouse model of systemic candidiasis by stimulating phagocyte effector function and ERK- and AKT-dependent survival in infected tissues. C5ar1 ablation rewired macrophage metabolism downstream of mTOR, promoting their apoptosis and enhancing mortality through kidney injury. Besides hepatocyte-derived C5, local C5 produced intrinsically by phagocytes provided a key substrate for antifungal protection. Lower serum C5a concentrations or a C5 polymorphism that decreases leukocyte C5 expression correlated independently with poor patient outcomes. Thus, local, phagocyte-derived C5 production licenses phagocyte antimicrobial function and confers innate protection during systemic fungal infection.

Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19.

Viral pandemics, such as the one caused by SARS-CoV-2, pose an imminent threat to humanity. Because of its recent emergence, there is a paucity of information regarding viral behavior and host response following SARS-CoV-2 infection. Here we offer an in-depth analysis of the transcriptional response to SARS-CoV-2 compared with other respiratory viruses. Cell and animal models of SARS-CoV-2 infection, in addition to transcriptional and serum profiling of COVID-19 patients, consistently revealed a unique and inappropriate inflammatory response. This response is defined by low levels of type I and III interferons juxtaposed to elevated chemokines and high expression of IL-6. We propose that reduced innate antiviral defenses coupled with exuberant inflammatory cytokine production are the defining and driving features of COVID-19.

Leveraging the antiviral type I interferon system as a first line of defense against SARS-CoV-2 pathogenicity.

The emergence and spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in significant global morbidity, mortality, and societal disruption. A better understanding of virus-host interactions may potentiate therapeutic insights toward limiting this infection. Here we investigated the dynamics of the systemic response to SARS-CoV-2 in hamsters by histological analysis and transcriptional profiling. Infection resulted in consistently high levels of virus in the upper and lower respiratory tracts and sporadic occurrence in other distal tissues. A longitudinal cohort revealed a wave of inflammation, including a type I interferon (IFN-I) response, that was evident in all tissues regardless of viral presence but was insufficient to prevent disease progression. Bolstering the antiviral response with intranasal administration of recombinant IFN-I reduced viral disease, prevented transmission, and lowered inflammation in vivo. This study defines the systemic host response to SARS-CoV-2 infection and supports use of intranasal IFN-I as an effective means of early treatment.

Dengue Virus Immunity Increases Zika Virus-Induced Damage during Pregnancy.

Zika virus (ZIKV) has recently been associated with birth defects and pregnancy loss after maternal infection. Because dengue virus (DENV) and ZIKV co-circulate, understanding the role of antibody-dependent enhancement in the context of pregnancy is critical. Here, we showed that the presence of DENV-specific antibodies in ZIKV-infected pregnant mice significantly increased placental damage, fetal growth restriction, and fetal resorption. This was associated with enhanced viral replication in the placenta that coincided with an increased frequency of infected trophoblasts. ZIKV-infected human placental tissues also showed increased replication in the presence of DENV antibodies, which was reversed by FcγR blocking antibodies. Furthermore, ZIKV-mediated fetal pathogenesis was enhanced in mice in the presence of a DENV-reactive monoclonal antibody, but not in the presence of the LALA variant, indicating a dependence on FcγR engagement. Our data suggest a possible mechanism for the recent increase in severe pregnancy outcomes after ZIKV infection in DENV-endemic areas.

An Immuno-Cardiac Model for Macrophage-Mediated Inflammation in COVID-19 Hearts.

[Figure: see text].

The NF-κB Transcriptional Footprint Is Essential for SARS-CoV-2 Replication.

SARS-CoV-2, the etiological agent of COVID-19, is characterized by a delay in type I interferon (IFN-I)-mediated antiviral defenses alongside robust cytokine production. Here, we investigate the underlying molecular basis for this imbalance and implicate virus-mediated activation of NF-κB in the absence of other canonical IFN-I-related transcription factors. Epigenetic and single-cell transcriptomic analyses show a selective NF-κB signature that was most prominent in infected cells. Disruption of NF-κB signaling through the silencing of the NF-κB transcription factor p65 or p50 resulted in loss of virus replication that was rescued upon reconstitution. These findings could be further corroborated with the use of NF-κB inhibitors, which reduced SARS-CoV-2 replication in vitro. These data suggest that the robust cytokine production in response to SARS-CoV-2, despite a diminished IFN-I response, is the product of a dependency on NF-κB for viral replication. IMPORTANCE The COVID-19 pandemic has caused significant mortality and morbidity around the world. Although effective vaccines have been developed, large parts of the world remain unvaccinated while new SARS-CoV-2 variants keep emerging. Furthermore, despite extensive efforts and large-scale drug screenings, no fully effective antiviral treatment options have been discovered yet. Therefore, it is of the utmost importance to gain a better understanding of essential factors driving SARS-CoV-2 replication to be able to develop novel approaches to target SARS-CoV-2 biology.

Zika virus tropism during early infection of the testicular interstitium and its role in viral pathogenesis in the testes.

Sexual transmission and persistence of Zika virus (ZIKV) in the testes pose new challenges for controlling virus outbreaks and developing live-attenuated vaccines. It has been shown that testicular infection of ZIKV is initiated in the testicular interstitium, followed by spread of the virus in the seminiferous tubules. This leads to testicular damage and/or viral dissemination into the epididymis and eventually into semen. However, it remains unknown which cell types are targeted by ZIKV in the testicular interstitium, and what is the specific order of infectious events leading to ZIKV invasion of the seminiferous tubules. Here, we demonstrate that interstitial leukocytes expressing mir-511-3p microRNA are the initial targets of ZIKV in the testes, and infection of mir-511-3p-expressing cells in the testicular interstitium is necessary for downstream infection of the seminiferous tubules. Mir-511-3p is expressed concurrently with CD206, a marker of lineage 2 (M2) macrophages and monocyte derived dendritic cells (moDCs). Selective restriction of ZIKV infection of CD206-expressing M2 macrophages/moDCs results in the attenuation of macrophage-associated inflammatory responses in vivo and prevents the disruption of the Sertoli cell barrier in vitro. Finally, we show that targeting of viral genome for mir-511-3p significantly attenuates early ZIKV replication not only in the testes, but also in many peripheral organs, including spleen, epididymis, and pancreas. This incriminates M2 macrophages/moDCs as important targets for visceral ZIKV replication following hematogenous dissemination of the virus from the site of infection.

Dengue and Zika: The Complexities of Being Related.

Following the recent Zika virus (ZIKV) outbreak in the Americas, a major question that has arisen is how dengue virus (DENV) immunity impacts Zika virus infection and disease. A recent study (Rodriguez-Barraquer, I. et al. Science 2019;363:607-610) shows that DENV immunity is, for the most part, protective against ZIKV, but exceptions may exist.

Catalyzing Storytelling in Communication Infrastructure Theory: A Study of Local Ethnic Media.

Communication infrastructure theory (CIT) suggests that an ethnic enclave's communication infrastructure (CI) shapes the community's unique social processes that give rise to social determinants of health. A well-integrated CI in ethnic enclaves that includes community-based organizations (CBOs), local ethnic media, and resident networks is positively associated with residents' health outcomes. Through storytelling, CBOs and other community actors obtain and disseminate information, develop a sense of belonging to the community, and participate in problem-solving activities, including health-related ones. Local ethnic media can play an important role in building a network of neighborhood storytellers by catalyzing storytelling about local resources and problems. We propose three main categories of "catalyzing storytelling" by local ethnic media: 1) CBO stories, 2) geo-ethnic stories, and 3) presentation of root causes and solutions for community problems. This study examines the content of Boston Chinatown's local ethnic news media outlet, Sampan, to assess the three categories of catalyzing stories. We analyzed a total of 340 news articles and one interview with the editor. The findings showed that Sampan tells stories in all three categories. Based on our findings, we further develop the concept of catalyzing as a communication process in CIT. This new concept in CIT has practical implications for public health communication as it demonstrates a process through which local ethnic media can foster community engagement and health. Health communicators should seek opportunities to work collaboratively with local ethnic media in ways that will serve to catalyze community.

Gut microbiota and fatigue in rectal cancer patients: a cross-sectional pilot study.

CONTEXT: Although microbial-mediated disturbance of intestinal mucosal homeostasis (dysbiosis) is believed to contribute to the pathogenesis of chemotherapy and radiotherapy (CRT)-related fatigue, potential differences in the gut microbial diversity and in the abundance of gut microbial taxa between fatigued and non-fatigued patients have not been adequately examined, particularly in the rectal cancer population. PURPOSE: In this cross-sectional study, we aim to examine the differences in (a) gut microbial diversity and gut microbial abundances and (b) predicted functional pathways of the gut microbiome between rectal cancer participants with and without fatigue at the end of CRT. METHODS: Rectal cancer patients (n = 50) provided stool samples for 16S rRNA gene sequencing and symptom ratings for fatigue at the end of CRT. Gut microbiome data were analyzed using QIIME2, LEfSe, and the R statistical package. RESULTS: Fatigued (n = 35) participants showed enriched bacterial abundances of Eubacterium, Streptococcus, Adlercreutzia, and Actinomyces, as well as enriched abundances of the microbial sucrose degradation pathway, compared to non-fatigued patients at the end of CRT (n = 15). CONCLUSIONS: Differentially abundant microbial taxa were identified in fatigued and non-fatigued rectal cancer participants at the end of CRT. However, the exact role of these taxa (and identification of species) in the biology of CRT-related fatigue remains to be examined.

Communication Infrastructure in an Asian Immigrant Community.

The health benefits of having a supportive community and access to community resources are well documented and for many immigrant communities, community-based organizations (CBOs) play an important role by providing culturally competent services. The current study uses communication infrastructure theory (CIT) to examine the associations between connections to CBOs, civic engagement, and protective health behaviors within the context of Boston Chinatown's Chinese immigrant community. According to CIT, neighborhood communication resources encourage residents to engage in civic activities and health-related problem-solving behaviors. To assess these associations, data from a needs assessment survey (N = 360) were analyzed. Results showed that connections to CBOs had a positive association with total number of protective health behaviors. Civic engagement was not found to be associated with health behaviors. We also found no indirect effect of connections to CBOs on the protective health behaviors via civic engagement. These results carry important theoretical and practical implications.

Effects of Lipopolysaccharide on Oligodendrocyte Differentiation at Different Developmental Stages: an In Vitro Study.

BACKGROUND: Lipopolysaccharide (LPS) exerts cytotoxic effects on brain cells, especially on those belonging to the oligodendrocyte lineage, in preterm infants. The susceptibility of oligodendrocyte lineage cells to LPS-induced inflammation is dependent on the developmental stage. This study aimed to investigate the effect of LPS on oligodendrocyte lineage cells at different developmental stages in a microglial cell and oligodendrocyte co-culture model. METHODS: The primary cultures of oligodendrocytes and microglia cells were prepared from the forebrains of 2-day-old Sprague-Dawley rats. The oligodendrocyte progenitor cells (OPCs) co-cultured with microglial cells were treated with 0 (control), 0.01, 0.1, and 1 µg/mL LPS at the D3 stage to determine the dose of LPS that impairs oligodendrocyte differentiation. The co-culture was treated with 0.01 µg/mL LPS, which was the lowest dose that did not impair oligodendrocyte differentiation, at the developmental stages D1 (early LPS group), D3 (late LPS group), or D1 and D3 (double LPS group). On day 7 of differentiation, oligodendrocytes were subjected to neural glial antigen 2 (NG2) and myelin basic protein (MBP) immunostaining to examine the number of OPCs and mature oligodendrocytes, respectively. RESULTS: LPS dose-dependently decreased the proportion of mature oligodendrocytes (MBP+ cells) relative to the total number of cells. The number of MBP+ cells in the early LPS group was significantly lower than that in the late LPS group. Compared with those in the control group, the MBP+ cell numbers were significantly lower and the NG2+ cell numbers were significantly higher in the double LPS group, which exhibited impaired oligodendrocyte lineage cell development, on day 7 of differentiation. CONCLUSION: Repetitive LPS stimulation during development significantly inhibited brain cell development by impairing oligodendrocyte differentiation. In contrast, brain cell development was not affected in the late LPS group. These findings suggest that inflammation at the early developmental stage of oligodendrocytes increases the susceptibility of the preterm brain to inflammation-induced injury.

Protective Activity of Programmed Cell Death Protein 1 Blockade and Synergy With Caspofungin in a Murine Invasive Pulmonary Aspergillosis Model.

Pharmacological immune checkpoint blockade has revolutionized oncological therapies, and its remarkable success has sparked interest in expanding checkpoint inhibitor therapy in infectious diseases. Herein, we evaluated the efficacy of programmed cell death protein 1 (PD-1) blockade in a murine invasive pulmonary aspergillosis model. We found that, compared with isotype-treated infected control mice, anti-PD-1-treated mice had improved survival, reduced fungal burden, increased lung concentrations of proinflammatory cytokines and neutrophil-attracting chemokines, and enhanced pulmonary leukocyte accumulation. Furthermore, combined treatment with anti-PD-1 and caspofungin resulted in a significant survival benefit compared with caspofungin or anti-PD-1 therapy alone, indicating a synergistic effect between PD-1 inhibitors and immunomodulatory antifungal agents.

Atovaquone Inhibits Arbovirus Replication through the Depletion of Intracellular Nucleotides.

Arthropod-borne viruses represent a significant public health threat worldwide, yet there are few antiviral therapies or prophylaxes targeting these pathogens. In particular, the development of novel antivirals for high-risk populations such as pregnant women is essential to prevent devastating disease such as that which was experienced with the recent outbreak of Zika virus (ZIKV) in the Americas. One potential avenue to identify new and pregnancy-acceptable antiviral compounds is to repurpose well-known and widely used FDA-approved drugs. In this study, we addressed the antiviral role of atovaquone, an FDA Pregnancy Category C drug and pyrimidine biosynthesis inhibitor used for the prevention and treatment of parasitic infections. We found that atovaquone was able to inhibit ZIKV and chikungunya virus virion production in human cells and that this antiviral effect occurred early during infection at the initial steps of viral RNA replication. Moreover, we were able to complement viral replication and virion production with the addition of exogenous pyrimidine nucleosides, indicating that atovaquone functions through the inhibition of the pyrimidine biosynthesis pathway to inhibit viral replication. Finally, using an ex vivo human placental tissue model, we found that atovaquone could limit ZIKV infection in a dose-dependent manner, providing evidence that atovaquone may function as an antiviral in humans. Taken together, these studies suggest that atovaquone could be a broad-spectrum antiviral drug and a potential attractive candidate for the prophylaxis or treatment of arbovirus infection in vulnerable populations, such as pregnant women and children.IMPORTANCE The ability to protect vulnerable populations such as pregnant women and children from Zika virus and other arbovirus infections is essential to preventing the devastating complications induced by these viruses. One class of antiviral therapies may lie in known pregnancy-acceptable drugs that have the potential to mitigate arbovirus infections and disease, yet this has not been explored in detail. In this study, we show that the common antiparasitic drug atovaquone inhibits arbovirus replication through intracellular nucleotide depletion and can impair ZIKV infection in an ex vivo human placental explant model. Our study provides a novel function for atovaquone and highlights that the rediscovery of pregnancy-acceptable drugs with potential antiviral effects can be the key to better addressing the immediate need for treating viral infections and preventing potential birth complications and future disease.

P2X Antagonists Inhibit HIV-1 Productive Infection and Inflammatory Cytokines Interleukin-10 (IL-10) and IL-1ß in a Human Tonsil Explant Model.

HIV-1 causes a persistent infection of the immune system that is associated with chronic comorbidities. The mechanisms that underlie this inflammation are poorly understood. Emerging literature has implicated proinflammatory purinergic receptors and downstream signaling mediators in HIV-1 infection. This study probed whether inhibitors of purinergic receptors would reduce HIV-1 infection and HIV-1-stimulated inflammation. An ex vivo human tonsil histoculture infection model was developed to support HIV-1 productive infection and stimulated the inflammatory cytokine interleukin-1 beta (IL-1ß) and the immunosuppressive cytokine interleukin-10 (IL-10). This study tests whether inhibitors of purinergic receptors would reduce HIV-1 infection and HIV-1-stimulated inflammation. The purinergic P2X1 receptor antagonist NF449, the purinergic P2X7 receptor antagonist A438079, and azidothymidine (AZT) were tested in HIV-1-infected human tonsil explants to compare levels of inhibition of HIV-1 infection and HIV-stimulated inflammatory cytokine production. All drugs limited HIV-1 productive infection, but P2X-selective antagonists (NF449 and A438079) significantly lowered HIV-stimulated IL-10 and IL-1ß. We further observed that P2X1- and P2X7-selective antagonists can act differentially as inhibitors of both HIV-1 infection and HIV-1-stimulated inflammation. Our findings highlight the differential effects of HIV-1 on inflammation in peripheral blood compared to those in lymphoid tissue. For the first time, we demonstrate that P2X-selective antagonists act differentially as inhibitors of both HIV-1 infection and HIV-1-stimulated inflammation. Drugs that block these pathways can have independent inhibitory activities against HIV-1 infection and HIV-induced inflammation.IMPORTANCE Patients who are chronically infected with HIV-1 experience sequelae related to chronic inflammation. The mechanisms of this inflammation have not been elucidated. Here, we describe a class of drugs that target the P2X proinflammatory signaling receptors in a human tonsil explant model. This model highlights differences in HIV-1 stimulation of lymphoid tissue inflammation and peripheral blood. These drugs serve to block both HIV-1 infection and production of IL-10 and IL-1ß in lymphoid tissue, suggesting a novel approach to HIV-1 therapeutics in which both HIV-1 replication and inflammatory signaling are simultaneously targeted.

Human Monoclonal Antibodies Potently Neutralize Zika Virus and Select for Escape Mutations on the Lateral Ridge of the Envelope Protein.

The mosquito-borne Zika virus (ZIKV) has been causing epidemic outbreaks on a global scale. Virus infection can result in severe disease in humans, including microcephaly in newborns and Guillain-Barré syndrome in adults. Here, we characterized monoclonal antibodies isolated from a patient with an active Zika virus infection that potently neutralized virus infection in Vero cells at the nanogram-per-milliliter range. In addition, these antibodies enhanced internalization of virions into human leukemia K562 cells in vitro, indicating their possible ability to cause antibody-dependent enhancement of disease. Escape variants of the ZIKV MR766 strain to a potently neutralizing antibody, AC10, exhibited an amino acid substitution at residue S368 in the lateral ridge region of the envelope protein. Analysis of publicly availably ZIKV sequences revealed the S368 site to be conserved among the vast majority (97.6%) of circulating strains. We validated the importance of this residue by engineering a recombinant virus with an S368R point mutation that was unable to be fully neutralized by AC10. Four out of the 12 monoclonal antibodies tested were also unable to neutralize the virus with the S368R mutation, suggesting this region to be an important immunogenic epitope during human infection. Last, a time-of-addition infection assay further validated the escape variant and showed that all monoclonal antibodies inhibited virus binding to the cell surface. Thus, the present study demonstrates that the lateral ridge region of the envelope protein is likely an immunodominant, neutralizing epitope.IMPORTANCE Zika virus (ZIKV) is a global health threat causing severe disease in humans, including microcephaly in newborns and Guillain-Barré syndrome in adults. Here, we analyzed the human monoclonal antibody response to acute ZIKV infection and found that neutralizing antibodies could not elicit Fc-mediated immune effector functions but could potentiate antibody-dependent enhancement of disease. We further identified critical epitopes involved with neutralization by generating and characterizing escape variants by whole-genome sequencing. We demonstrate that the lateral ridge region, particularly the S368 amino acid site, is critical for neutralization by domain III-specific antibodies.

Conformer Specific Excited-State Structure of 3-Methylthioanisole.

Trans and cis conformers of 3-methylthioanisole have been spectroscopically investigated to reveal the conformer specific structural changes upon the S1(ππ*)-S0 excitation. The conformational cooling during the supersonic expansion is found to be quite efficient in the Ar carrier gas giving the trans conformational isomer exclusively in the molecular beam, whereas both trans and cis conformers are populated in the jet when the sample is carried in Ne. Using the Stark deflector, trans and cis conformers are unambiguously identified, showing the distinct Stark deflection profiles according to their sufficiently different dipole moments of 1.013 or 1.670 D, respectively. For the trans conformer, the methyl moiety on the meta-position adopting the eclipsed geometry in S0 transforms into the staggered geometry in S1 to activate a series of the CH3 torsional mode. A Hamiltonian with the one-dimensional sinusoidal torsional potential is solved using the free-rotor basis set to explain the experiment, giving the 3-fold torsional barrier of 34 and 304 cm-1 for S0 and S1, respectively. For the cis conformer, on the other hand, the CH3 torsion is little activated in the S1-S0 transition as both S0 and S1 adopt the staggered geometry at the minimum energy points. The doublet of each band of the cis conformer is ascribed to tunneling split due to the very low CH3 torsional barrier of 27 cm-1 in S0. It is found that the cis conformer undergoes a planar to pseudoplanar structural change upon the S1-S0 transition. Theoretical calculation based on the double-well model potential curve could explain the experiment quite well, suggesting that the SCH3 moiety of the cis conformer in S1 becomes out-of-plane with respect to the plane of the phenyl moiety. This implies that excited-state predissociation dynamics of trans and cis conformers of the title molecule might be different.

A novel Zika virus mouse model reveals strain specific differences in virus pathogenesis and host inflammatory immune responses.

Zika virus (ZIKV) is a mosquito borne flavivirus, which was a neglected tropical pathogen until it emerged and spread across the Pacific Area and the Americas, causing large human outbreaks associated with fetal abnormalities and neurological disease in adults. The factors that contributed to the emergence, spread and change in pathogenesis of ZIKV are not understood. We previously reported that ZIKV evades cellular antiviral responses by targeting STAT2 for degradation in human cells. In this study, we demonstrate that Stat2-/- mice are highly susceptible to ZIKV infection, recapitulate virus spread to the central nervous system (CNS), gonads and other visceral organs, and display neurological symptoms. Further, we exploit this model to compare ZIKV pathogenesis caused by a panel of ZIKV strains of a range of spatiotemporal history of isolation and representing African and Asian lineages. We observed that African ZIKV strains induce short episodes of severe neurological symptoms followed by lethality. In comparison, Asian strains manifest prolonged signs of neuronal malfunctions, occasionally causing death of the Stat2-/- mice. African ZIKV strains induced higher levels of inflammatory cytokines and markers associated with cellular infiltration in the infected brain in mice, which may explain exacerbated pathogenesis in comparison to those of the Asian lineage. Interestingly, viral RNA levels in different organs did not correlate with the pathogenicity of the different strains. Taken together, we have established a new murine model that supports ZIKV infection and demonstrate its utility in highlighting intrinsic differences in the inflammatory response induced by different ZIKV strains leading to severity of disease. This study paves the way for the future interrogation of strain-specific changes in the ZIKV genome and their contribution to viral pathogenesis.

Photodissociation Dynamics of Ortho-Substituted Thiophenols at 243 nm.

The photoinduced S-H (D) bond fission dynamics of four ortho-substituted thiophenols, 2-fluoro, 2-chloro, 2-bromo, and 2-methoxythiophenol at a pump wavelength of 243 nm, have been investigated by velocity-map imaging and high-level electronic structure calculations. The D atom images of the deuterated ortho-substituted thiophenols show much reduced X̃/à branching ratios of the cofragment radicals over that of bare thiophenol. The angular distributions of the D fragment display negative anisotropies, indicating that transition dipole moments are perpendicular to the fast dissociating S-D bond axis. Initial excitation at 243 nm occurs directly to the 1πσ* state or to the 21ππ* state followed by efficient coupling to the 1πσ* state. The calculated potential energy curves for the 1πσ* or 21ππ* excited states of the ortho-substituted thiophenols along the CCS-D torsion angle (ϕ) display minima at the nonplanar structures, whereas all of the states for bare thiophenol present minima at the planar geometries. This different topology of the ortho-substituted thiophenols in the excited states induces the wide spread of the reactive flux along the ϕ coordinate on the repulsive surface as it should experience significant torque with respect to ϕ during the fragmentation. This encourages the dissociating molecules to follow the adiabatic path at the conical intersection between the ground and the 1πσ* states at extended S-D bond lengths, giving rise to decreased X̃/à branching ratios, demonstrating that the excited-state molecular structure dictates the nonadiabatic transition probability.

Vibronic structure and predissociation dynamics of 2-methoxythiophenol (S1): The effect of intramolecular hydrogen bonding on nonadiabatic dynamics.

Vibronic spectroscopy and the S-H bond predissociation dynamics of 2-methoxythiophenol (2-MTP) in the S1 (ππ*) state have been investigated for the first time. Resonant two-photon ionization and slow-electron velocity map imaging (SEVI) spectroscopies have revealed that the S1-S0 transition of 2-MTP is accompanied with the planar to the pseudoplanar structural change along the out-of-plane ring distortion and the tilt of the methoxy moiety. The S1 vibronic bands up to their internal energy of ∼1000 cm-1 are assigned from the SEVI spectra taken via various S1 vibronic intermediate states with the aid of ab initio calculations. Intriguingly, Fermi resonances have been identified for some vibronic bands. The S-H bond breakage of 2-MTP occurs via tunneling through an adiabatic barrier under the S1/S2 conical intersection seam, and it is followed by the bifurcation into either the adiabatic or nonadiabatic channel at the S0/S2 conical intersection where the diabatic S2 state (πσ*) is unbound with respect to the S-H bond elongation coordinate, giving the excited (Ã) or ground (X̃) state of the 2-methoxythiophenoxy radical, respectively. Surprisingly, the nonadiabatic transition probability at the S0/S2 conical intersection, estimated from the velocity map ion images of the nascent D fragment from 2-MTP-d1 (2-CH3O-C6H4SD) at the S1 zero-point energy level, is found to be exceptionally high to give the X̃/à product branching ratio of 2.03 ± 0.20, which is much higher than the value of ∼0.8 estimated for the bare thiophenol at the S1 origin. It even increases to 2.33 ± 0.17 at the ν45 2 mode (101 cm-1) before it rapidly decays to 0.69 ± 0.05 at the S1 internal energy of about 2200 cm-1. This suggests that the strong intramolecular hydrogen bonding of S⋯D⋯OCH3 in 2-MTP at least in the low S1 internal energy region should play a significant role in localizing the reactive flux onto the conical intersection seam. The minimum energy pathway calculations (second-order coupled-cluster resolution of the identity or time-dependent-density functional theory) of the adiabatic S1 state suggest that the intimate dynamic interplay between the S-H bond cleavage and intramolecular hydrogen bonding could be crucial in the nonadiabatic surface hopping dynamics taking place at the conical intersection.