Azithromycin sequential therapy plus inhaled terbutaline for Mycoplasma Pneumoniae pneumonia in children: a systematic review and meta-analysis.

BACKGROUND: An improper host immune response to Mycoplasma pneumoniae generates excessive inflammation, which leads to the impairment of pulmonary ventilation function (PVF). Azithromycin plus inhaled terbutaline has been used in the treatment of Mycoplasma pneumoniae pneumonia (MPP) in children with impaired pulmonary function, but previous randomized controlled trials (RCTs) showed inconsistent efficacy and safety. This study is aimed to firstly provide a systematic review of the combined therapy. METHODS: This study was registered at the International Prospective Register of Systematic Reviews (PROSPERO CRD42023452139). A PRISMA-compliant systematic review and meta-analysis was performed. Six English and four Chinese databases were comprehensively searched up to June, 2023. RCTs of azithromycin sequential therapy plus inhaled terbutaline were selected. The revised Cochrane risk of bias tool for randomized trials (RoB2) was used to evaluate the methodological quality of all studies, and meta-analysis was performed using Stata 15.0 with planned subgroup and sensitivity analyses. Publication bias was evaluated by a funnel plot and the Harbord' test. Certainty of evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluation recommendations. RESULTS: A total of 1,938 pediatric patients from 20 RCTs were eventually included. The results of meta-analysis showed that combined therapy was able to significantly increase total effectiveness rate (RR = 1.20, 95%CI 1.15 to 1.25), forced expiratory volume in one second (SMD = 1.14, 95%CIs, 0.98 to 1.29), the ratio of forced expiratory volume in one second/forced vital capacity (SMD = 2.16, 95%CIs, 1.46 to 2.86), peak expiratory flow (SMD = 1.17, 95%CIs, 0.91 to 1.43). The combined therapy was associated with a 23% increased risk of adverse reactions compared to azithromycin therapy alone, but no significant differences were found. Harbord regression showed no publication bias (P = 0.148). The overall quality of the evidence ranged from moderate to very low. CONCLUSIONS: This first systematic review and meta-analysis suggested that azithromycin sequential therapy plus inhaled terbutaline was safe and beneficial for children with MPP. In addition, the combined therapy represented significant improvement of PVF. Due to lack of high-quality evidence, our results should be confirmed by adequately powered RCTs in the future.

Shapeshifting Nucleophile Singly Hydrated Hydroperoxide Anion Leads to the Occurrence of the Thermodynamically Unfavored SN2 Product.

Single water molecules alone may introduce unusual features into the kinetics and dynamics of chemical reactions. The singly hydrated hydroperoxide anion, HOO-(H2O), was found to be a shapeshifting nucleophile, which can be transformed to HO- solvated by hydrogen peroxide HO-(HOOH). Herein, we performed direct dynamics simulations of its reaction with methyl iodide to investigate the effect of individual water molecules. In addition to the normal SN2 product CH3OOH, the thermodynamically unfavored proton transfer-induced HO--SN2 path (produces CH3OH) was also observed, contributing ∼4%. The simulated branching ratio of the HO--SN2 path exceeded the statistical estimation (0.6%) based on the free energy barrier difference. The occurrence of the HO--SN2 path was attributed to the shallow entrance channel well before a submerged saddle point, thus providing a region for extensive proton exchange and ultimately leading to the formation of CH3OH. In comparison, changing the leaving group from Cl to I increased the overall reaction rate as well as the proportion of the HO--SN2 path because the CH3I system has a smaller internal barrier. This work elucidates the importance of the dynamic effect introduced by a single solvent molecule to alter the product channel and kinetics of typical ion-molecule SN2 reactions.

Autophagy receptor ZmNBR1 promotes the autophagic degradation of ZmBRI1a and enhances drought tolerance in maize.

Drought stress is a crucial environmental factor that limits plant growth, development, and productivity. Autophagy of misfolded proteins can help alleviate the damage caused in plants experiencing drought. However, the mechanism of autophagy-mediated drought tolerance in plants remains largely unknown. Here, we cloned the gene for a maize (Zea mays) selective autophagy receptor, NEXT TO BRCA1 GENE 1 (ZmNBR1), and identified its role in the response to drought stress. We observed that drought stress increased the accumulation of autophagosomes. RNA sequencing and reverse transcription-quantitative polymerase chain reaction showed that ZmNBR1 is markedly induced by drought stress. ZmNBR1 overexpression enhanced drought tolerance, while its knockdown reduced drought tolerance in maize. Our results established that ZmNBR1 mediates the increase in autophagosomes and autophagic activity under drought stress. ZmNBR1 also affects the expression of genes related to autophagy under drought stress. Moreover, we determined that BRASSINOSTEROID INSENSITIVE 1A (ZmBRI1a), a brassinosteroid receptor of the BRI1-like family, interacts with ZmNBR1. Phenotype analysis showed that ZmBRI1a negatively regulates drought tolerance in maize, and genetic analysis indicated that ZmNBR1 acts upstream of ZmBRI1a in regulating drought tolerance. Furthermore, ZmNBR1 facilitates the autophagic degradation of ZmBRI1a under drought stress. Taken together, our results reveal that ZmNBR1 regulates the expression of autophagy-related genes, thereby increasing autophagic activity and promoting the autophagic degradation of ZmBRI1a under drought stress, thus enhancing drought tolerance in maize. These findings provide new insights into the autophagy degradation of brassinosteroid signaling components by the autophagy receptor NBR1 under drought stress.

Elucidating the Mechanism of Simultaneous Activation of CH4 and CO2 Mediated by Single Group 10 Metal Anions in Gas Phase.

Quantum chemistry calculations predict that besides the reported single metal anion Pt- , Ni- can also mediate the co-conversion of CO2 and CH4 to form [CH3 -M(CO2 )-H]- complex, followed by transformation to C-C coupling product [H3 CCOO-M-H]- (A), hydrogenation products [H3 C-M-OCOH]- (B) and [H3 C-M-COOH]- . For Pd- , a fourth product channel leading to PdCO2 - …CH4 becomes more competitive. For Ni- , the feed order must be CO2 first, as the weaker donor-acceptor interaction between Ni- and CH4 increases the C-H activation barrier, which is reduced by [Ni-CO2 ]- . For Ni- /Pt- , the highly exothermic products A and B are similarly stable with submerged barrier that favors B. The smaller barrier difference between A and B for Ni- suggests the C-C coupling product is more competitive in the presence of Ni- than Pt- . The charge redistribution from M- is the driving force for product B channel. This study adds our understanding of single atomic anions to activate CH4 and CO2 simultaneously.

Microsolvated Ion-Molecule SN 2 Reactions with Dual Nucleophiles Induced by Solvent Molecules.

Singly-hydrated HOO- anion was found to induce alternative nucleophile HO- via proton transfer from water molecule when reacting with CH3 Cl. To investigate the generality of this effect, the competition between the solvent-induced HO- -SN 2 pathway and the normal HOO- -SN 2 pathway is studied for the microsolvated HOO- (H2 O)n=1,2,3 +CH3 X (X=F, Cl, Br, I) reaction by quantum chemistry calculations. Incremental hydration increases the barrier heights of both pathways and enlarges the barrier difference between them, which favors the HOO- -SN 2 pathway. Interestingly, the barrier difference is insensitive to the leaving group. Calculations show that the water induced HO- -SN 2 pathway is highly suppressed when the degree of hydration increases beyond two. The differential barrier under incremental hydration can be explained by solvent molecules stabilizing the HOMO level of HO- (HOOH)(H2 O)n-1 nucleophile more than that of the HOO- (H2 O)n nucleophile. Comparison between the HO- - and HOO- -nucleophiles suggests that α-effect exists. Activation strain analysis attributes the barrier differences to stronger TS distortion of the HO- -SN 2 pathway than that of the HOO- -SN 2 pathway.

Computational Studies of Coinage Metal Anion M- + CH3X (X = F, Cl, Br, I) Reactions in Gas Phase.

We characterized the stationary points along the nucleophilic substitution (SN2), oxidative insertion (OI), halogen abstraction (XA), and proton transfer (PT) product channels of M- + CH3X (M = Cu, Ag, Au; X = F, Cl, Br, I) reactions using the CCSD(T)/aug-cc-pVTZ level of theory. In general, the reaction energies follow the order of PT > XA > SN2 > OI. The OI channel that results in oxidative insertion complex [CH3-M-X]- is most exothermic, and can be formed through a front-side attack of M on the C-X bond via a high transition state OxTS or through a SN2-mediated halogen rearrangement path via a much lower transition state invTS. The order of OxTS > invTS is inverted when changing M- to Pd, a d10 metal, because the symmetry of their HOMO orbital is different. The back-side attack SN2 pathway proceeds via typical Walden-inversion transition state that connects to pre- and post-reaction complexes. For X = Cl/Br/I, the invSN2-TS's are, in general, submerged. The shape of this M- + CH3X SN2 PES is flatter as compared to that of a main-group base like F- + CH3X, whose PES has a double-well shape. When X = Br/I, a linear halogen-bonded complex [CH3-X∙··M]- can be formed as an intermediate upon the front-side attachment of M on the halogen atom X, and it either dissociates to CH3 + MX- through halogen abstraction or bends the C-X-M angle to continue the back-side SN2 path. Natural bond orbital analysis shows a polar covalent M-X bond is formed within oxidative insertion complex [CH3-M-X]-, whereas a noncovalent M-X halogen-bond interaction exists for the [CH3-X∙··M]- complex. This work explores competing channels of the M- + CH3X reaction in the gas phase and the potential energy surface is useful in understanding the dynamic behavior of the title and analogous reactions.

Investigating the role of halogen-bonded complexes in microsolvated Y-(H2O)n + CH3I SN2 reactions.

The dynamics of bimolecular nucleophilic substitution (SN2) reactions in the gas phase are of great interest and several new mechanisms have been observed recently by theoretical studies. Here we investigate a recent-discovered SN2 reaction mechanism, called front-side complex (FSC) or halogen-bonded complex (XC) mechanism that couples the traditional front-side attack (FSA) and back-side attack (BSA) Walden-inversion mechanism. This XC-pathway begins with a front-side attack on the leaving group, then goes through a bending transition state (XTS) that is followed by Walden-inversion, and results in a configuration inverted product. We characterized the potential energy surface of the microsolvated Y-(H2O)n=0,1,2 + CH3I SN2 reaction using the B97-1/ECP/d method, where Y = HO, F, Cl, Br, and I, and n is the number of water molecules. It is found that the XCs have a deeper well depth than the back-side attack (BSA) pre-reaction complexes for HO-/F- nucleophiles, indicating that the system can easily become trapped in the halogen-bonded complex well. The barriers of both FSA- and BSA-paths increase with incremental solvation, whereas the change of XTS depends on the type of nucleophile. When Y = HO/F, the order of the barriers is BSA < XC < FSA for n = 0-2, and the order inverts to XC < BSA < FSA for n = 1 (Y = Br/I) and n = 2 (Y = Cl/Br/I), where the latter suggests an increasing participation of the halogen-bonded complex in the SN2 reactions. Comprehensive analyses on the structure, charge distribution, and energetics of XC and XTS are provided. This work indicates that the halogen-bonded complex mechanism may be common for alkyl iodides and the information on the potential energy surface is useful in understanding the dynamics behavior of the title and analogous reactions.

Consecutive methane activation mediated by single metal boride cluster anions NbB4.

Cleavage of all C-H bonds in two methane molecules by gas-phase cluster ions at room temperature is a challenging task. Herein, mass spectrometry and quantum chemical calculations have been used to identify one single metal boride cluster anions NbB4- that can activate eight C-H bonds in two methane molecules and release one H2 molecule each time under thermal collision conditions. In these consecutive reactions, the loaded Nb atoms and the support B4 units play different roles but act synergistically to activate CH4, which is responsible for the interesting reactivity of NbB4-. Moreover, there are some mechanistic differences in these two reactions, including the mechanisms for the first C-H bond activation steps, dihydrogen desorption sites, and major electron donors. This study shows that non-noble metal boride species are reactive enough to facilitate thermal C-H bond cleavages, and boron-based materials may be one kind of potential support material facilitating surface hydrogen transport.

The sequential activation of H2 and N2 mediated by the gas-phase Sc3N+ clusters: Formation of amido unit.

The activation and hydrogenation of nitrogen are central in industry and in nature. Through a combination of mass spectrometry and quantum chemical calculations, this work reports an interesting result that scandium nitride cations Sc3N+ can activate sequentially H2 and N2, and an amido unit (NH2) is formed based on density functional theory calculations, which is one of the inevitable intermediates in the N2 reduction reactions. If the activation step is reversed, i.e., sequential activation of first N2 and then H2, the reactivity decreases dramatically. An association mechanism, prevalent in some homogeneous catalysis and enzymatic mechanisms, is adopted in these gas-phase H2 and N2 activation reactions mediated by Sc3N+ cations. The mechanistic insights are important to understand the mechanism of the conversion of H2 and N2 to NH3 synthesis under ambient conditions.

Visible-Light-Enabled C-H Functionalization by a Direct Hydrogen Atom Transfer Uranyl Photocatalyst.

The development of the uranyl cation as a powerful photocatalyst is seriously delayed in comparison with the advances in its fundamental and structural chemistry. However, its characteristic high oxidative capability in the excited state ([UO2 ]2+ * (+2.6 V vs. SHE; SHE=standard hydrogen electrode) combined with blue-light absorption (hv=380-500 nm) and a long-lived fluorescence lifetime up to microseconds have reveals that the uranyl cation approaches an ideal photocatalyst for visible-light-driven organic transformations. Described herein is the successful use of uranyl nitrate as a photocatalyst to enable C(sp3 )-H activation and C-C bond formation through hydrogen atom transfer (HAT) under blue-light irradiation. In particular, this operationally simple strategy provides an appropriate approach to the synthesis of diverse and valuable diarylmethane motifs. Mechanistic studies and DFT calculations have provided insights into the detailed mechanism of the photoinduced HAT pathway. This research suggests a general platform that could popularize promising uranyl photocatalytic performance.

Paraxial models for the surface plasmon self- interference at off-axis excitation.

The surface plasmon self-interference excited by a strongly focused, linearly polarized vortex beam at off-axis illumination in a paraxial regime is analytically studied. The off-axis excitation is investigated using a geometrical model. The combination of an angular spectrum representation and homogeneous transformation is applied to derive the integral expressions of the surface plasmon polariton fields for off-axis directions both parallel and perpendicular to polarization plane, and an off-axis convergence angle is used to compute the integral. The surface plasmon excitation is represented by the relative peak intensity of the longitudinal field, while its standing wave is characterized by the full width at half-maximum of the transmitted field intensity distribution profile. Both models consistently show that even in ideal Gaussian microscopic imaging systems, self-interference degradation exists. When the off-axis angle increases, the surface plasmon interference disappears and the fields detune out of surface plasmon resonance.

Formation of Gas-Phase Formate in Thermal Reactions of Carbon Dioxide with Diatomic Iron Hydride Anions.

The hydrogenation of carbon dioxide involves the activation of the thermodynamically very stable molecule CO2 and formation of a C-H bond. Herein, we report that HCO2- and CO can be formed in the thermal reaction of CO2 with a diatomic metal hydride species, FeH- . The FeH- anions were produced by laser ablation, and the reaction with CO2 was analyzed by mass spectrometry and quantum-chemical calculations. Gas-phase HCO2- was observed directly as a product, and its formation was predicted to proceed by facile hydride transfer. The mechanism of CO2 hydrogenation in this gas-phase study parallels similar behavior of a condensed-phase iron catalyst.

Thermal Methane Conversion to Syngas Mediated by Rh1-Doped Aluminum Oxide Cluster Cations RhAl3O4.

Laser ablation generated RhAl3O4+ heteronuclear metal oxide cluster cations have been mass-selected using a quadrupole mass filter and reacted with CH4 or CD4 in a linear ion trap reactor under thermal collision conditions. The reactions have been characterized by state-of-the-art mass spectrometry and quantum chemistry calculations. The RhAl3O4+ cluster can activate four C-H bonds of a methane molecule and convert methane to syngas, an important intermediate product in methane conversion to value-added chemicals. The Rh atom is the active site for activation of the C-H bonds of methane. The high electron-withdrawing capability of Rh atom is the driving force to promote the conversion of methane to syngas. The polarity of Rh oxidation state is changed from positive to negative after the reaction. This study has provided the first example of methane conversion to syngas by heteronuclear metal oxide clusters under thermal collision conditions. Furthermore, the molecular level origin has been revealed for the condensed-phase experimental observation that trace amounts of Rh can promote the participation of lattice oxygen of chemically very inert support (Al2O3) to oxidize methane to carbon monoxide.

Iron-Carbonyl-Catalyzed Redox-Neutral [4+2] Annulation of N-H Imines and Internal Alkynes by C-H Bond Activation.

Stoichiometric C-H bond activation of arenes mediated by iron carbonyls was reported by Pauson as early as in 1965, yet the catalytic C-H transformations have not been developed. Herein, an iron-catalyzed annulation of N-H imines and internal alkynes to furnish cis-3,4-dihydroisoquinolines is described, and represents the first iron-carbonyl-catalyzed C-H activation reaction of arenes. Remarkablely, this is also the first redox-neutral [4+2] annulation of imines and alkynes proceeding by C-H activation. The reaction also features only cis stereoselectivity and excellent atom economy as neither base, nor external ligand, nor additive is required. Experimental and theoretical studies reveal an oxidative addition mechanism for C-H bond activation to afford a dinuclear ferracycle and a synergetic diiron-promoted H-transfer to the alkyne as the turnover-determining step.

Activation of Methane Promoted by Adsorption of CO on Mo2 C2 (-) Cluster Anions.

Atomic clusters are being actively studied for activation of methane, the most stable alkane molecule. While many cluster cations are very reactive with methane, the cluster anions are usually not very reactive, particularly for noble metal free anions. This study reports that the reactivity of molybdenum carbide cluster anions with methane can be much enhanced by adsorption of CO. The Mo2 C2 (-) is inert with CH4 while the CO addition product Mo2 C3 O(-) brings about dehydrogenation of CH4 under thermal collision conditions. The cluster structures and reactions are characterized by mass spectrometry, photoelectron spectroscopy, and quantum chemistry calculations, which demonstrate that the Mo2 C3 O(-) isomer with dissociated CO is reactive but the one with non-dissociated CO is unreactive. The enhancement of cluster reactivity promoted by CO adsorption in this study is compared with those of reported systems of a few carbonyl complexes.

Correlation between surrogate endpoints and overall survival in unresectable hepatocellular carcinoma patients treated with immune checkpoint inhibitors: a systematic review and meta-analysis.

This study aimed to assess the therapeutic effect of immune checkpoint inhibitors (ICIs) in patients with unresectable hepatocellular carcinoma (uHCC) and investigate the correlation between surrogate endpoints and overall survival (OS). A systematic literature search included phase I, II, and III clinical trials comparing ICIs to placebo or other therapies for uHCC treatment. Correlations between OS and surrogate endpoints were evaluated using meta-regression analyses and calculating the surrogate threshold effect (STE). The correlation analysis showed a weak association between OS and progression-free survival (PFS), with an R2 value of 0.352 (95% CI: 0.000-0.967). However, complete response (CR) exhibited a strong correlation with OS (R2 = 0.905, 95% CI: 0.728-1.000). Subgroup analyses revealed high correlations between OS and PFS, CR, stable disease (SD), and DC in phase III trials (R2: 0.827-0.922). For the ICI + IA group, significant correlations were observed between OS and SD, progressive disease (PD), and grade 3-5 immune-related adverse events (irAEs) (R2: 0.713-0.969). Analyses of the correlation between survival benefit and risk of mortality across various time points showed a strong association within the first year (R2: 0.724-0.868) but a weak association beyond one year (R2: 0.406-0.499). In ICI trials for uHCC, PFS has limited utility as a surrogate endpoint for OS, while CR exhibits a strong correlation with OS. Subgroup analyses highlight high correlations between OS and PFS, SD, and DC in phase III trials. Notably, the ICI + IA group shows significant associations between OS and SD, PD, and grade 3-5 irAEs. These findings offer valuable insights for interpreting trial outcomes and selecting appropriate endpoints in future clinical studies involving ICIs for uHCC patients.

Pectin methylesterase 31 is transcriptionally repressed by ABI5 to negatively regulate ABA-mediated inhibition of seed germination.

Pectin methylesterase (PME), a family of enzymes that catalyze the demethylation of pectin, influences seed germination. Phytohormone abscisic acid (ABA) inhibits seed germination. However, little is known about the function of PMEs in response to ABA-mediated seed germination. In this study, we found the role of PME31 in response to ABA-mediated inhibition of seed germination. The expression of PME31 is prominent in the embryo and is repressed by ABA treatment. Phenotype analysis showed that disruption of PME31 increases ABA-mediated inhibition of seed germination, whereas overexpression of PME31 attenuates this effect. Further study found that ABI5, an ABA signaling bZIP transcription factor, is identified as an upstream regulator of PME31. Genetic analysis showed that PME31 functions downstream of ABI5 in ABA-mediated seed germination. Detailed studies showed that ABI5 directly binds to the PME31 promoter and inhibits its expression. In the plants, PME31 expression is reduced by ABI5 in ABA-mediated seed germination. Taken together, PME31 is transcriptionally inhibited by ABI5 and negatively regulates ABA-mediated seed germination inhibition. These findings shed new light on the mechanisms of PMEs in response to ABA-mediated seed germination.

Frailty and in-hospital mortality in older patients with acute exacerbation of COPD: A real-world prospective cohort study.

BACKGROUND: Few evidence exists for the effect of frailty on the patients admitted with an acute exacerbation of chronic obstructive pulmonary disease (AECOPD). OBJECTIVE: We explored the link between frailty and in-hospital death in AECOPD, and whether laboratory indicators mediate this association. METHODS: This was a real-world prospective cohort study including older patients with AECOPD, consisting of two cohorts: a training set (n = 1356) and a validation set (n = 478). The independent prognostic factors, including frail status, were determined by multivariate logistic regression analysis. The relationship between frailty and in-hospital mortality was estimated by multivariable Cox regression. A nomogram was developed to provide clinicians with a quantitative tool to predict the risk of in-hospital death. Mediation analyses for frailty and in-hospital death were conducted. RESULTS: The training set included 1356 patients (aged 86.7 ± 6.6 years), and 25.0 % of them were frail. A nomogram model was created, including ten independent variables: age, sex, frailty, COPD grades, severity of exacerbation, mean arterial pressure (MAP), Charlson Comorbidity Index (CCI), Interleukin-6 (IL-6), albumin, and troponin T (TPN-T). The area under the receiver operating characteristic curve (ROCs) was 0.862 and 0.845 for the training set and validation set, respectively. Patients with frailty had a higher risk of in-hospital death than those without frailty (HR,1.83, 95%CI: 1.14, 2.94; p = 0.013). Furthermore, CRP and albumin mediated the associations between frailty and in-hospital death. CONCLUSIONS: Frailty may be an adverse prognostic factor for older patients admitted with AECOPD. CRP and albumin may be part of the immunoinflammatory mechanism between frailty and in-hospital death.

Review of the design of power ultrasonic generator for piezoelectric transducer.

The power ultrasonic generator (PUG) is the core device of power ultrasonic technology (PUT), and its performance determines the application of this technology in biomedicine, semiconductor, aerospace, and other fields. With the high demand for sensitive and accurate dynamic response in power ultrasonic applications, the design of PUG has become a hot topic in academic and industry. However, the previous reviews cannot be used as a universal technical manual for industrial applications. There are many technical difficulties in establishing a mature production system, which hinder the large-scale application of PUG for piezoelectric transducers. To enhance the performance of the dynamic matching and power control of PUG, the studies in various PUT applications have been reviewed in this article. Initially, the demand design covering the piezoelectric transducer application and parameter requirements for ultrasonic and electrical signals is overall summarized, and these parameter requirements have been recommended as the technical indicators of developing the new PUG. Then the factors affecting the power conversion circuit design are analyzed systematically to realize the foundational performance improvement of PUG. Furthermore, advantages and limitations of key control technologies have been summarized to provide some different ideas on how to realize automatic resonance tracking and adaptive power adjustment, and to optimize the power control and dynamic matching control. Finally, several research directions of PUG in the future have been prospected.

Single Solvent Molecules Induce Dual Nucleophiles in Gas-Phase Ion-Molecule Nucleophilic Substitution Reactions.

Direct dynamics simulation of singly hydrated peroxide ion reacting with CH3Cl reveals a new product channel that forms CH3OH + Cl- + HOOH, besides the traditional channel that forms CH3OOH + Cl- + H2O. This finding shows that singly hydrated peroxide ion behaves as a dual nucleophile through proton transfer between HOO-(H2O) and HO-(HOOH). Trajectory analysis attributes the occurrence of the thermodynamically and kinetically unfavored HO--induced pathway to the entrance channel dynamics, where extensive proton transfer occurs within the deep well of the prereaction complex. This study represents the first example of a single solvent molecule altering the nucleophile in a gas-phase ion-molecule nucleophilic substitution reaction, in addition to reducing the reactivity and affecting the dynamics, signifying the importance of dynamical effects of solvent molecules.