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Deposition of amyloid plaques in the brains of Alzheimer's disease (AD) patients is a hallmark of the disease. AD plaques consist primarily of the beta-amyloid (Aß) peptide but can contain other factors such as lipids, proteoglycans, and chaperones. So far, it is unclear how the cellular environment modulates fibril polymorphism and how differences in fibril structure affect cell viability. The small heat-shock protein (sHSP) alpha-B-Crystallin (αBC) is abundant in brains of AD patients, and colocalizes with Aß amyloid plaques. Using solid-state NMR spectroscopy, we show that the Aß40 fibril seed structure is not replicated in the presence of the sHSP. αBC prevents the generation of a compact fibril structure and leads to the formation of a new polymorph with a dynamic N-terminus. We find that the N-terminal fuzzy coat and the stability of the C-terminal residues in the Aß40 fibril core affect the chemical and thermodynamic stability of the fibrils and influence their seeding capacity. We believe that our results yield a better understanding of how sHSP, such as αBC, that are part of the cellular environment, can affect fibril structures related to cell degeneration in amyloid diseases.
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Doença de Alzheimer , Peptídeos beta-Amiloides , Cadeia B de alfa-Cristalina , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Humanos , Cadeia B de alfa-Cristalina/química , Cadeia B de alfa-Cristalina/metabolismo , Cadeia B de alfa-Cristalina/genética , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/metabolismo , Fragmentos de Peptídeos/genética , Amiloide/química , Amiloide/metabolismoRESUMO
The self-assembly of organic amphiphilic species into various aggregates such as spherical or elongated micelles and cylinders up to the formation of lyotropic hexagonal or lamellar phases results from cooperative processes orchestrated by the hydrophobic effect, while those involving ionic inorganic polynuclear entities and nonionic organic components are still intriguing. Herein, we report on the supramolecular behavior of giant toroidal molybdenum blue-type polyoxometalate, namely, the {Mo154} species in the presence of n-octyl-ß-glucoside (C8G1), widely used as a surfactant in biochemistry. Structural investigations were carried out using a set of complementary multiscale methods including single-crystal X-ray diffraction analysis supported by molecular modeling, small-angle X-ray scattering and cryo-TEM observations. In addition, liquid NMR, viscosimetry, surface tension measurement, and isothermal titration calorimetry provided further information to decipher the complex aggregation pathway. Elucidation of the assembly process reveals a rich scenario where the presence of the large {Mo154} anion disrupts the self-assembly of the C8G1, well-known to produce micelles, and induces striking successive phase transitions from fluid-to-gel and from gel-to-fluid. Herein, intimate organic-inorganic primary interactions arising from the superchaotropic nature of the {Mo154} lead to versatile nanoscopic hybrid C8G1-{Mo154} aggregates including crystalline discrete assemblies, smectic lamellar liquid crystals, and large uni- or multilamellar vesicles where the large torus {Mo154} acts a trans-membrane component.
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Germanium is a promising basis for nanomaterials due to its low toxicity and valuable optical and electronic properties. However, germanium nanomaterials have seen little research compared to other group 14 elements due to unpredictable chemical behavior and high costs. Here, we report the dehydrocoupling of o-tolylgermanium trihydride to amorphous nanoparticles. The reaction is facilitated through reflux at 162 °C and can be accelerated with an amine base catalyst. Through cleavage of both H2 and toluene, new Ge-Ge bonds form. This results in nanoparticles consisting of crosslinked germanium with o-tolyl termination. The particles are 2-6â nm in size and have masses above approximately 3500â Da. The organic substituents are promising for further functionalization. Combined with strong absorption up to 600â nm and moderate solubility and air stability, there are numerous possibilities for future applications.
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The rotational spectrum of the molecular ion HCNH+ is revisited using double-resonance spectroscopy in an ion trap apparatus, with six transitions measured between 74 and 445 GHz. Due to the cryogenic temperature of the trap, the hyperfine splittings caused by the 14N quadrupolar nucleus were resolved for transitions up to J = 4 â 3, allowing for a refinement of the spectroscopic parameters previously reported, especially the quadrupole coupling constant eQq.
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Research has found that vaccine-promoting messages can elicit state reactance (i.e., negative emotions in response to a perceived threat to behavioral freedom), especially among individuals with high trait reactance (i.e., proneness to experiencing reactance). This can result in a lower willingness to accept vaccines. We investigated whether inoculation against reactance - that is, forewarning individuals about potentially experiencing reactance - can reduce the effects of trait reactance on vaccination willingness. Participants (N = 710) recruited through Facebook were randomly allocated to be either inoculated or not. They were then shown a message promoting a fictitious vaccine, which included either a low, medium, or high threat to freedom. Contrary to research on other health topics, inoculation was ineffective at reducing state reactance toward the vaccination message. Inoculation also did not mitigate the effects of trait reactance on vaccination willingness, and was even counterproductive in some cases. High-reactant individuals were less willing to get vaccinated than low-reactant ones, especially at high freedom threat. Conversely, high freedom threat resulted in increased vaccination willingness among low-reactant individuals. Further research is needed to understand why inoculation against reactance produces different results with vaccination, and to develop communication strategies that mitigate reactance to vaccination campaigns without compromising the positive effects of vaccine recommendations for low-reactant individuals.
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Two fundamental halocarbon ions, CH2Cl+ and CH3ClH+, were studied in the gas phase using the FELion 22-pole ion trap apparatus and the Free Electron Laser for Infrared eXperiments (FELIX) at Radboud University, Nijmegen (the Netherlands). The vibrational bands of a total of four isotopologs, CH235,37Cl+ and CH335,37ClH+, were observed in selected wavenumber regions between 500 and 2900 cm-1 and then spectroscopically assigned based on the results of anharmonic force field calculations performed at the CCSD(T) level of theory. As the infrared photodissociation spectroscopy scheme employed probes singly Ne-tagged weakly bound complexes, complementary quantum-chemical calculations of selected species were also performed. The impact of tagging on the vibrational spectra of CH2Cl+ and CH3ClH+ is found to be virtually negligible for most bands; for CH3ClH+-Ne, the observations suggest a proton-bound structural arrangement. The experimental band positions as well as the best estimate rotational molecular parameters given in this work provide a solid basis for future spectroscopic studies at high spectral resolutions.
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The ro-vibrational and pure rotational spectra of the linear ion HC3O+ have been investigated in a 4 K cryogenic ion trap instrument. For this, a novel action spectroscopic technique, called leak-out-spectroscopy (LOS, Schmid et al., J. Phys. Chem. A 2022, 126, 8111), has been utilized and characterized. In total, 45 ro-vibrational transitions within the fundamental band of the ν1 C-H stretching mode were measured with a band center at 3237.132 cm-1, as well as 34 lines from the combination band ν2 + ν4, and 41 lines tentatively identified as the combination band ν2 + ν5 + ν7, interleaved and resonant with ν1. Surprisingly, also two hot bands were detected despite the cryogenic operation temperature. Based on the novel action spectroscopy approach, a new double-resonance rotational measurement scheme was established, consisting of rotational excitation followed by vibrational excitation. Seven rotational transitions were observed between 89 and 180 GHz. Highly accurate spectroscopic parameters were extracted from a fit using all available data. In addition, a pulsed laser system has been employed to record a low resolution vibrational spectrum, in order to demonstrate the compatibility of such lasers with the LOS method.
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Mandatory and voluntary mask policies may have yet unknown social and behavioral consequences related to the effectiveness of the measure, stigmatization, and perceived fairness. Serial cross-sectional data (April 14 to May 26, 2020) from nearly 7,000 German participants demonstrate that implementing a mandatory policy increased actual compliance despite moderate acceptance; mask wearing correlated positively with other protective behaviors. A preregistered experiment (n = 925) further indicates that a voluntary policy would likely lead to insufficient compliance, would be perceived as less fair, and could intensify stigmatization. A mandatory policy appears to be an effective, fair, and socially responsible solution to curb transmissions of airborne viruses.
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Infecções por Coronavirus/prevenção & controle , Máscaras/estatística & dados numéricos , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Administração em Saúde Pública/legislação & jurisprudência , Betacoronavirus , COVID-19 , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/transmissão , Estudos Transversais , Alemanha/epidemiologia , Fidelidade a Diretrizes/estatística & dados numéricos , Humanos , Programas Obrigatórios/estatística & dados numéricos , Pneumonia Viral/epidemiologia , Pneumonia Viral/transmissão , Comportamento de Redução do Risco , SARS-CoV-2 , Comportamento Social , Programas Voluntários/estatística & dados numéricosRESUMO
BACKGROUND: People with aphasia (PWA) frequently experience difficulties in understanding longer written content such as paragraphs or books. Reading strategies are a promising approach to treat text-level reading comprehension deficits in PWA. Nevertheless, empirical evidence for their efficacy remains rare. AIMS: The primary objective of this study was to analyse the efficacy of a strategy-based intervention on text-level reading comprehension in PWA. Secondary objectives were to compare the effects of two strategy-based intervention components and to explore potential moderator effects. METHODS & PROCEDURES: A protocol was published prior to data acquisition. In a repeated measures trial, 26 German participants with chronic, post-stroke aphasia participated in a waiting period without aphasia treatment (control condition) followed by a strategy-based intervention called 'Strategiebasierte Textverständnis-Therapie bei Aphasie' (StraTexT, 14 face-to-face-sessions, twice per week, 60 min each). Two strategy combinations, Intervention Micro targeting microstructure and Intervention Macro targeting macrostructure, were applied to newspaper and magazine articles. Participants were randomly allocated to two parallel groups that received these strategy combinations in interchanged sequences. Assessments were implemented before and after each period as well as 3 and 6 months after the intervention. The primary outcome measure was text-level reading comprehension measured with the total score of a German version of the Test de Compréhension de Textes (TCT-D). Secondary outcome measures addressed the self-reported perception of reading abilities, reading activities and feelings about reading (German version of the Comprehensive Assessment of Reading in Aphasia CARA reading questionnaire) as well as selected cognitive functions. OUTCOMES & RESULTS: The per-protocol-analysis included data from 22 participants. We found significant small improvements up to 6 months post-intervention compared to pre-intervention in the TCT-D Total (d = 0.35-0.46) as well as medium to large improvements in the CARA questionnaire (d = 0.68-0.96). Up to 3 months after the intervention, treatment-induced improvements in the TCT-D Total were significantly larger than change without treatment during the control condition. There was no evidence of moderator effects. Furthermore, we found improvements in several cognitive functions. CONCLUSIONS & IMPLICATIONS: Reading strategies can lead to long-term improvements in text-level reading comprehension and in self-reported reading abilities, feelings about reading and reading activities in aphasia. In regular clinical settings, it seems reasonable to implement both Intervention Micro and Intervention Macro. It remains important to investigate participant characteristics that contribute to treatment success. WHAT THIS PAPER ADDS: What is already known on the subject Systematic reviews and multiple case studies suggest that reading strategies are a promising approach to treat text-level reading comprehension in aphasia. The efficacy of reading strategies has been demonstrated for different populations. However, to date no group study has evaluated the efficacy of reading strategies on text-level reading comprehension in people with aphasia. What this study adds This study provides the first group-level evidence about the efficacy of a systematic strategy-based intervention in 22 people with post-stroke chronic aphasia. During 14 treatment sessions, participants applied four reading strategies to newspaper and magazine articles within two intervention components called Intervention Micro and Intervention Macro (two strategies per intervention component). We found improvements in text-level reading comprehension for at least 3 months post-intervention, as well as effects on selected cognitive functions and self-reported reading abilities, thoughts and feelings about reading and the ability to engage in reading activities. What are the clinical implications of this work? The strategies and materials evaluated in this study could be used in clinical practice with people with aphasia. In order to replicate treatment effects in clinical practice, we suggest applying the strategy combination with the same protocol features (e.g., frequency, duration, homework, product orientation) as in this study, implementing Intervention Micro and Intervention Macro sequentially in either order. As treatment response was not equal in all individuals, it seems important to investigate individual features that contribute to treatment success.
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Effective science communication is challenging when scientific messages are informed by a continually updating evidence base and must often compete against misinformation. We argue that we need a new program of science communication as collective intelligence-a collaborative approach, supported by technology. This would have four key advantages over the typical model where scientists communicate as individuals: scientific messages would be informed by (a) a wider base of aggregated knowledge, (b) contributions from a diverse scientific community, (c) participatory input from stakeholders, and (d) better responsiveness to ongoing changes in the state of knowledge.
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Collagens play important roles in development and homeostasis in most higher organisms. In order to function, collagens require the specific chaperone HSP47 for proper folding and secretion. HSP47 is known to bind to the collagen triple helix, but the exact positions and numbers of binding sites are not clear. Here, we employed a collagen II peptide library to characterize high-affinity binding sites for HSP47. We show that many previously predicted binding sites have very low affinities due to the presence of a negatively charged amino acid in the binding motif. In contrast, large hydrophobic amino acids such as phenylalanine at certain positions in the collagen sequence increase binding strength. For further characterization, we determined two crystal structures of HSP47 bound to peptides containing phenylalanine or leucine. These structures deviate significantly from previously published ones in which different collagen sequences were used. They reveal local conformational rearrangements of HSP47 at the binding site to accommodate the large hydrophobic side chain from the middle strand of the collagen triple helix and, most surprisingly, possess an altered binding stoichiometry in the form of a 1:1 complex. This altered stoichiometry is explained by steric collisions with the second HSP47 molecule present in all structures determined thus far caused by the newly introduced large hydrophobic residue placed on the trailing strand. This exemplifies the importance of considering all three sites of homotrimeric collagen as independent interaction surfaces and may provide insight into the formation of higher oligomeric complexes at promiscuous collagen-binding sites.
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Colágeno/metabolismo , Proteínas de Choque Térmico HSP47/metabolismo , Sequência de Aminoácidos , Animais , Sítios de Ligação , Colágeno/química , Cristalografia por Raios X , Cães/metabolismo , Proteínas de Choque Térmico HSP47/química , Modelos Moleculares , Peptídeos/química , Peptídeos/metabolismo , Ligação Proteica , Conformação ProteicaRESUMO
A novel method of spectroscopy in ion traps termed leak-out spectroscopy (LOS) is presented. Here, mass-selected, cold ions are excited by an infrared laser. In a subsequent collision with a neutral buffer gas particle, their internal energy is then transferred to kinetic energy. As a result, these ions leak out from the ion trap and are detected. The LOS scheme is generally applicable, very sensitive, and close to background-free when operated at low temperature. The potential of this method is demonstrated and characterized here for the first time by recording the rotationally resolved spectrum of the C-H stretching vibration ν1 of linear C3H+. Besides performing high-resolution spectroscopy, this method opens up the way for analyzing the composition of trap content, for example, determining isomer ratios, by selectively expelling isomers or other isobaric ions from the trap. Likewise, LOS can be used to prepare clean samples of structural and nuclear spin isomers.
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Most democracies seek input from scientists to inform policies. This can put scientists in a position of intense scrutiny. Here we focus on situations in which scientific evidence conflicts with people's worldviews, preferences, or vested interests. These conflicts frequently play out through systematic dissemination of disinformation or the spreading of conspiracy theories, which may undermine the public's trust in the work of scientists, muddy the waters of what constitutes truth, and may prevent policy from being informed by the best available evidence. However, there are also instances in which public opposition arises from legitimate value judgments and lived experiences. In this article, we analyze the differences between politically-motivated science denial on the one hand, and justifiable public opposition on the other. We conclude with a set of recommendations on tackling misinformation and understanding the public's lived experiences to preserve legitimate democratic debate of policy.
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Misinformation about mRNA vaccination is a barrier in the global fight against the COVID-19 pandemic. Thus, authorities often rely on text-based refutations as a countermeasure. In two experiments (N = 2,444), text-based refutations effectively reduced the belief in misinformation and immunized participants against the impact of a misleading social media post. However, a follow-up (N = 817) questions the longevity of these debunking and prebunking effects. Moreover, the studies reveal potential pitfalls by showing a row of unintended effects of the refutations (lacking effect on intentions, backfire-effects among religious groups, and biased judgments when omitting information about vaccine side effects).
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Investigations into bimolecular reaction kinetics probe the details of the underlying potential energy surface (PES), which can help to validate high-level quantum chemical calculations. We utilize a combined linear Paul ion trap with a time-of-flight mass spectrometer to study isotopologue reactions between acetylene cations (C2H2 +) and two isomers of C3H4: propyne (HC3H3) and allene (H2C3H2). In a previous study [Schmid et al., Phys. Chem. Chem. Phys. 22, 20303 (2020)],1 we showed that the two isomers of C3H4 have fundamentally different reaction mechanisms. Here, we further explore the calculated PES by isotope substitution. While isotopic substitution of reactants is a standard experimental tool in the investigation of molecular reaction kinetics, the controlled environment of co-trapped, laser-cooled Ca+ ions allows the different isotopic reaction pathways to be followed in greater detail. We report branching ratios for all of the primary products of the different isotopic species. The results validate the previously proposed mechanism: propyne forms a bound reaction complex with C2H2 +, while allene and C2H2 + perform long-range charge exchange only.
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BackgroundDuring the COVID-19 pandemic, public perceptions and behaviours have had to adapt rapidly to new risk scenarios and radical behavioural restrictions.AimTo identify major drivers of acceptance of protective behaviours during the 4-week transition from virtually no COVID-19 cases to the nationwide lockdown in Germany (3-25 March 2020).MethodsA serial cross-sectional online survey was administered weekly to ca 1,000 unique individuals for four data collection rounds in March 2020 using non-probability quota samples, representative of the German adult population between 18 and 74 years in terms of ageâ¯×â¯sex and federal state (n = 3,910). Acceptance of restrictions was regressed on sociodemographic variables, time and psychological variables, e.g. trust, risk perceptions, self-efficacy. Extraction of homogenous clusters was based on knowledge and behaviour.ResultsAcceptance of restrictive policies increased with participants' age and employment in the healthcare sector; cognitive and particularly affective risk perceptions were further significant predictors. Acceptance increased over time, as trust in institutions became more relevant and trust in media became less relevant. The cluster analysis further indicated that having a higher education increased the gap between knowledge and behaviour. Trust in institutions was related to conversion of knowledge into action.ConclusionIdentifying relevant principles that increase acceptance will remain crucial to the development of strategies that help adjust behaviour to control the pandemic, possibly for years to come. Based on our findings, we provide operational recommendations for health authorities regarding data collection, health communication and outreach.
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COVID-19 , Pandemias , Adulto , Controle de Doenças Transmissíveis , Estudos Transversais , Alemanha/epidemiologia , Humanos , Pandemias/prevenção & controle , Percepção , SARS-CoV-2 , Inquéritos e Questionários , ConfiançaRESUMO
Neck pain is a frequent health complaint. Prolonged protracted malpositions of the head are associated with neck pain and headaches and could be prevented using biofeedback systems. A practical biofeedback system to detect malpositions should be realized with a simple measurement setup. To achieve this, a simple biomechanical model representing head orientation and translation relative to the thorax is introduced. To identify the parameters of this model, anthropometric data were acquired from eight healthy volunteers. In this work we determine (i) the accuracy of the proposed model when the neck length is known, (ii) the dependency of the neck length on the body height, and (iii) the impact of a wrong neck length on the models accuracy. The resulting model is able to describe the motion of the head with a maximum uncertainty of 5 mm only. To achieve this high accuracy the effective neck length must be known a priory. If however, this parameter is assumed to be a linear function of the palpable neck length, the measurement error increases. Still, the resulting accuracy can be sufficient to identify and monitor a protracted malposition of the head relative to the thorax.
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Cabeça , Pescoço , Fenômenos Biomecânicos , Humanos , Cervicalgia , Amplitude de Movimento Articular , TóraxRESUMO
Activity-based probes are valuable tools for chemical biology. However, finding probes that specifically target the active site of an enzyme remains a challenging task. Herein, we present a ligand selection strategy that allows to rapidly tailor electrophilic probes to a target of choice and showcase its application for the two cysteine proteases of SARS-CoV-2 as proof of concept. The resulting probes were specific for the active site labeling of 3CLpro and PLpro with sufficient selectivity in a live cell model as well as in the background of a native human proteome. Exploiting the probes as tools for competitive profiling of a natural product library identified salvianolic acid derivatives as promising 3CLpro inhibitors. We anticipate that our ligand selection strategy will be useful to rapidly develop customized probes and discover inhibitors for a wide range of target proteins also beyond corona virus proteases.
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Proteases 3C de Coronavírus/química , Proteases Semelhantes à Papaína de Coronavírus/química , Inibidores de Cisteína Proteinase/química , Técnicas de Sonda Molecular , Sondas Moleculares/química , SARS-CoV-2/enzimologia , Bibliotecas de Moléculas Pequenas/química , Domínio Catalítico , Proteases 3C de Coronavírus/metabolismo , Proteases Semelhantes à Papaína de Coronavírus/metabolismo , Inibidores de Cisteína Proteinase/metabolismo , Células Hep G2 , Humanos , Ligantes , Simulação de Acoplamento Molecular , Estrutura Molecular , Estudo de Prova de Conceito , Ligação Proteica , Bibliotecas de Moléculas Pequenas/metabolismo , Relação Estrutura-AtividadeRESUMO
Herein, we show how the chaotropic effect arising from reduced molybdate ions in acidified aqueous solution is able to amplify drastically weak supramolecular interactions. Time-resolved Small Angle X-ray Scattering (SAXS) analysis suggests that molybdenum-blue oligomeric species form huge aggregates in the presence of γ-cyclodextrin (γ-CD) which results in the fast formation of nanoscopic {Mo154 }-based host-guest species, while X-ray diffraction analysis reveals that the ending-point of the scenario results in an unprecedented three-component well-ordered core-shell-like motif. A similar arrangement was found by using preformed hexarhenium chalcogenide-type cluster [Re6 Te8 (CN)6 ]4- as exogenous guest. This seminal work brings better understanding of the self-assembly processes in general and gives new opportunities for practical applications in the design of complex multicomponent materials via the simplicity of the non-covalent chemistry.
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Experiments within a cryogenic 22-pole ion trap have revealed an interesting reaction dynamic phenomenon, where rovibrational excitation of an ionic molecule slows down a reaction with a neutral partner. This is demonstrated for the low-temperature hydrogen abstraction reaction c-C_{3}H_{2}^{+}+H_{2}, where excitation of the ion into the ν_{7} antisymmetric C-H stretching mode decreased the reaction rate coefficient toward the products c-C_{3}H_{3}^{+}+H. Supported by high-level quantum-chemical calculations, this observation is explained by the reaction proceeding through a c-C_{3}H_{2}^{+}-H_{2} collision complex in the entrance channel, in which the hydrogen molecule is loosely bound to the hydrogen atom of the c-C_{3}H_{2}^{+} ion. This discovery enables high-resolution vibrational action spectroscopy for c-C_{3}H_{2}^{+} and other molecular ions with similar reaction pathways. Moreover, a detailed kinetic model relating the extent of the observed product depletion signal to the rate coefficients of inelastic collisions reveals that rotational relaxation of the vibrationally excited ions is significantly faster than the rovibrational relaxation, allowing for a large fraction of the ions to be vibrationally excited. This result provides fundamental insight into the mechanism for an important class of chemical reactions, and is capable of probing the inelastic collisional dynamics of molecular ions.