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Amide-based organic cage cavities are, in principle, ideal enzyme active site mimics. Yet, cage-promoted organocatalysis has remained elusive, in large part due to synthetic accessibility of robust and functional scaffolds. Herein, we report the acyl transfer catalysis properties of robust, hexaamide cages in organic solvent. Cage structural variation reveals that esterification catalysis with an acyl anhydride acyl carrier occurs only in bifunctional cages featuring internal pyridine motifs and two crucial antipodal carboxylic acid groups. 1H NMR data and X-ray crystallography show that the acyl carrier is rapidly activated inside the cavity as a covalent mixed-anhydride intermediate with an internal hydrogen bond. Michaelis-Menten (saturation) kinetics suggest weak binding (KM = 0.16 M) of the alcohol pronucleophile close to the internal anhydride. Finally, activation and delivery of the alcohol to the internal anhydride by the second carboxylic acid group forms ester product and releases the cage catalyst. Eyring analysis indicates a strong enthalpic stabilization of the transition state (5.5 kcal/mol) corresponding to a rate acceleration of 104 over background acylation, and an ordered, associative rate-determining attack by the alcohol, supported by DFT calculations. We conclude that internal bifunctional organocatalysis specific to the cage structural design is responsible for the enhancement over the background reaction. These results pave the way for organic-phase enzyme mimicry in self-assembled cavities with the potential for cavity elaboration to enact selective acylations.
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Molecular cages are sought after as receptors and catalysts. However, typical dynamic covalent chemistry approaches restrict the shape-persistence, solubility and stability of self-assembled organic cages. As a result, organic cages occupy a narrow chemical and functional space, and solution-phase applications and studies remain rare. We report an inâ situ trapping protocol, using Pinnick oxidation conditions, to convert soluble metastable imine assemblies to robust amide cages, and exemplify the method to access previously inaccessible organic cages. The new cages are internally functionalised with two constrained and diametrically opposed carboxylic acid groups that can distinguish between functionalised piperazines in THF. We anticipate our approach will broaden access to robust, soluble, self-assembled organic cages of an unsymmetrical or semi-flexible nature, which in turn will drive advances in solution-phase applications of molecular cages.
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Nowadays, there is tremendous growth in the Internet of Things (IoT) applications in our everyday lives. The proliferation of smart devices, sensors technology, and the Internet makes it possible to communicate between the digital and physical world seamlessly for distributed data collection, communication, and processing of several applications dynamically. However, it is a challenging task to monitor and track objects in real-time due to the distinct characteristics of the IoT system, e.g., scalability, mobility, and resource-limited nature of the devices. In this paper, we address the significant issue of IoT object tracking in real time. We propose a system called 'TrackInk' to demonstrate our idea. TrackInk will be capable of pointing toward and taking pictures of visible satellites in the night sky, including but not limited to the International Space Station (ISS) or the moon. Data will be collected from sensors to determine the system's geographical location along with its 3D orientation, allowing for the system to be moved. Additionally, TrackInk will communicate with and send data to ThingSpeak for further cloud-based systems and data analysis. Our proposed system is lightweight, highly scalable, and performs efficiently in a resource-limited environment. We discuss a detailed system's architecture and show the performance results using a real-world hardware-based experimental setup.
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Integrating symmetry-reducing methods into self-assembly methodology is desirable to efficiently realise the full potential of molecular cages as hosts and catalysts. Although techniques have been explored for metal organic (coordination) cages, rational strategies to develop low symmetry organic cages remain limited. In this article, we describe rules to program the shape and symmetry of organic cage cavities by designing edge pieces that bias the orientation of the amide linkages. We apply the rules to synthesise cages with well-defined cavities, supported by evidence from crystallography, spectroscopy and modelling. Access to low-symmetry, self-assembled organic cages such as those presented, will widen the current bottleneck preventing study of organic enzyme mimics, and provide synthetic tools for novel functional material design.
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The accuracy of both Gauge-including atomic orbital (GIAO) and continuous set of gauge transformations (CSGT) (13)C NMR spectra prediction by Density Functional Theory (DFT) at the B3LYP/6-31G** level is shown to be usefully enhanced by employing a 'fragment referencing' method for predicting chemical shifts without recourse to empirical scaling. Fragment referencing refers to a process of reducing the error in calculating a particular NMR shift by consulting a similar molecule for which the error in the calculation is easily deduced. The absolute accuracy of the chemical shifts predicted when employing fragment referencing relative to conventional techniques (e.g., using TMS or MeOH/benzene dual referencing) is demonstrated to be improved significantly for a range of substrates, which illustrates the superiority of the technique particularly for systems with similar chemical shifts arising from different chemical environments. The technique is particularly suited to molecules of relatively low molecular weight containing 'non-standard' magnetic environments, e.g., α to halogen atoms, which are poorly predicted by other methods. The simplicity and speed of the technique mean that it can be employed to resolve routine structural assignment problems that require a degree of accuracy not provided by standard incremental or hierarchically ordered spherical description of environment (HOSE) algorithms. The approach is also demonstrated to be applicable when employing the MP2 method at 6-31G**, cc-pVDZ, aug-cc-pVDZ, and cc-pVTZ levels, although none of these offer advantage in terms of accuracy of prediction over the B3LYP/6-31G** DFT method.
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The identity of the major product of Ru-catalysed alkene metathesis of two polyene substrates has been determined using density functional theory (DFT) NMR prediction, a (1)H-(1)H Total Correlated Spectroscopy (TOCSY) NMR experiment and ultimately by single-crystal X-ray crystallography. The substrates were designed as those that would potentially allow expedient access to the trans-decalin skeleton of the natural product (-)-euonyminol, but the product was found to be a bis-cyclopentenyl-ß-cyanohydrin [1-(1-hydroxycyclopent-3-en-1-yl)cyclopent-3-ene-1-carbonitrile, C11H13NO] rather than the trans-2,3,6,7-dehydrodecalin-ß-cyanohydrin.
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Alcenos/química , Ciclopentanos/química , Nitrilas/química , Catálise , Cristalografia por Raios X , Espectroscopia de Ressonância Magnética , Estrutura MolecularRESUMO
OBJECTIVE: To assess whether extracorporeal shock wave therapy increases the rate of healing in chronic decubitus ulceration. DESIGN: Double-blind randomized cross-over study. SETTING: A large, long-stay hospital specializing in the management of people with complex neurological disabilities. SUBJECTS: The total population of available patients with chronic neurological conditions and chronic decubitus ulceration who met the inclusion criteria. INTERVENTIONS: Ulcers were randomized into receiving either the extracorporeal shock wave therapy or the placebo for a four-week period, followed by a two-week 'washout' period followed by a four-week period of the cross-over treatment/ placebo. MAIN MEASURES: Measurement of the area of the ulceration. For each observation the average of three measurements were taken. RESULTS: Nine ulcers (in eight patients) were included in the study: five on the buttocks/sacrum/trochanter and four on the feet/ankles. All those with static chronic ulcers showed improved healing starting 6-8 weeks after the start of extracorporeal shock wave therapy, whether treated first with the placebo or the therapy. CONCLUSIONS: Extracorporeal shock wave therapy has a potential part to play in the treatment of chronic skin ulceration.
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Ondas de Choque de Alta Energia/uso terapêutico , Úlcera por Pressão/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença Crônica , Estudos Cross-Over , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , PlacebosRESUMO
We report reductive alkylation reactions of amines using carboxylic acids as nominal electrophiles. The two-step reaction exploits the dual reactivity of phenylsilane and involves a silane-mediated amidation followed by a Zn(OAc)2-catalyzed amide reduction. The reaction is applicable to a wide range of amines and carboxylic acids and has been demonstrated on a large scale (305 mmol of amine). The rate differential between the reduction of tertiary and secondary amide intermediates is exemplified in a convergent synthesis of the antiretroviral medicine maraviroc. Mechanistic studies demonstrate that a residual 0.5 equivalents of carboxylic acid from the amidation step is responsible for the generation of silane reductants with augmented reactivity, which allow secondary amides, previously unreactive in zinc/phenylsilane systems, to be reduced.
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Nucleophilic substitution reactions of alcohols are among the most fundamental and strategically important transformations in organic chemistry. For over half a century, these reactions have been achieved by using stoichiometric, and often hazardous, reagents to activate the otherwise unreactive alcohols. Here, we demonstrate that a specially designed phosphine oxide promotes nucleophilic substitution reactions of primary and secondary alcohols in a redox-neutral catalysis manifold that produces water as the sole by-product. The scope of the catalytic coupling process encompasses a range of acidic pronucleophiles that allow stereospecific construction of carbon-oxygen and carbon-nitrogen bonds.
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A revised pathway for the catalytic Staudinger amidation reaction is presented that involves the intervention of in situ-generated silyl esters as the species responsible for amidation.
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Amines are a fundamentally important class of biologically active compounds and the ability to manipulate their physicochemical properties through the introduction of fluorine is of paramount importance in medicinal chemistry. Current synthesis methods for the construction of fluorinated amines rely on air and moisture sensitive reagents that require special handling or harsh reductants that limit functionality. Here we report practical, catalyst-free, reductive trifluoroethylation reactions of free amines exhibiting remarkable functional group tolerance. The reactions proceed in conventional glassware without rigorous exclusion of either moisture or oxygen, and use trifluoroacetic acid as a stable and inexpensive fluorine source. The new methods provide access to a wide range of medicinally relevant functionalized tertiary ß-fluoroalkylamine cores, either through direct trifluoroethylation of secondary amines or via a three-component coupling of primary amines, aldehydes and trifluoroacetic acid. A reduction of in situ-generated silyl ester species is proposed to account for the reductive selectivity observed.
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We report a catalytic reductive alkylation reaction of primary or secondary amines with carboxylic acids. The two-phase process involves silane mediated direct amidation followed by catalytic reduction.
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This paper reviews the current state of bedside behavioral assessment in brain-damaged patients with impaired consciousness (coma, vegetative state, minimally conscious state). As misdiagnosis in this field is unfortunately very frequent, we first discuss a number of fundamental principles of clinical evaluation that should guide the assessment of consciousness in brain-damaged patients in order to avoid confusion between vegetative state and minimally conscious state. The role of standardized behavioral assessment tools is particularly stressed. The second part of this paper reviews existing behavioral assessment techniques of consciousness, showing that there are actually a large number of these scales. After a discussion of the most widely used scale, the Glasgow Coma Scale, we present several new promising tools that show higher sensitivity and reliability for detecting subtle signs of recovery of consciousness in the post-acute setting.
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Comportamento , Dano Encefálico Crônico/fisiopatologia , Dano Encefálico Crônico/psicologia , Estado de Consciência , Dano Encefálico Crônico/diagnóstico , Escala de Coma de Glasgow , Humanos , Índice de Gravidade de DoençaRESUMO
Withdrawal of nutrition and hydration, is a difficult and sensitive issue for all those working with people in the vegetative state. There are arguments against the decision to withdraw any treatment that might result in the patient deteriorating or dying. These arguments include the view that all life is worth having, that we can never be certain that the patient is not aware, and concerns that there may be new scientific developments in the future from which the patient would benefit. Others argue that the patient has no interests in life; that it is undignified, if not an assault, to insert tubes into a permanently unconscious person; that very few people would want to survive in this condition; and that it prevents loves ones from grieving. These strongly held opposing views can make clinical decision making very difficult for the clinician. Once the decision has been made to withdraw treatment then the clinician has to be certain that the patient is in the vegetative state, that there are no factors preventing the patient demonstrating awareness, that he has received expert assessment and treatment, and that the prognosis for lack of recovery is as clear as it can be. It is important to support family and staff throughout this process. The concept of withdrawal of nutrition and hydration is a sensitive issue and clinicians can expect to be considered as not acting in the patient's best interest whatever decision is taken.
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Tomada de Decisões , Hidratação , Apoio Nutricional , Estado Vegetativo Persistente , Suspensão de Tratamento , Ética Clínica , Humanos , Prognóstico , Assistência Terminal , Suspensão de Tratamento/éticaRESUMO
The request for withdrawal of nutrition and hydration from the vegetative patient is rare, but when it occurs it causes considerable anxiety for the clinical team. This anxiety is exacerbated by the need to seek a declaration from court that withdrawal of treatment would be legal. This paper discusses the process from the time of the request to the withdrawal of the tube feeding, and the actions the clinical team needs to take.
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Tomada de Decisões , Eutanásia Passiva/legislação & jurisprudência , Hidratação , Apoio Nutricional , Estado Vegetativo Persistente , Eutanásia Passiva/ética , Família , Humanos , Equipe de Assistência ao Paciente , Reino Unido , Suspensão de Tratamento/ética , Suspensão de Tratamento/legislação & jurisprudênciaRESUMO
With the emergence of tools for collaborative ontology engineering, more and more data about the creation process behind collaborative construction of ontologies is becoming available. Today, collaborative ontology engineering tools such as Collaborative Protégé offer rich and structured logs of changes, thereby opening up new challenges and opportunities to study and analyze the creation of collaboratively constructed ontologies. While there exists a plethora of visualization tools for ontologies, they have primarily been built to visualize aspects of the final product (the ontology) and not the collaborative processes behind construction (e.g. the changes made by contributors over time). To the best of our knowledge, there exists no ontology visualization tool today that focuses primarily on visualizing the history behind collaboratively constructed ontologies. Since the ontology engineering processes can influence the quality of the final ontology, we believe that visualizing process data represents an important stepping-stone towards better understanding of managing the collaborative construction of ontologies in the future. In this application paper, we present a tool - PragmatiX - which taps into structured change logs provided by tools such as Collaborative Protégé to visualize various pragmatic aspects of collaborative ontology engineering. The tool is aimed at managers and leaders of collaborative ontology engineering projects to help them in monitoring progress, in exploring issues and problems, and in tracking quality-related issues such as overrides and coordination among contributors. The paper makes the following contributions: (i) we present PragmatiX, a tool for visualizing the creation process behind collaboratively constructed ontologies (ii) we illustrate the functionality and generality of the tool by applying it to structured logs of changes of two large collaborative ontology-engineering projects and (iii) we conduct a heuristic evaluation of the tool with domain experts to uncover early design challenges and opportunities for improvement. Finally, we hope that this work sparks a new line of research on visualization tools for collaborative ontology engineering projects.
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The rehabilitation of the person with profound brain damage is a complex process requiring the skills of a true interdisciplinary team. The process is as much about the ability to: assess and diagnose; provide the optimal environment for recovery; prevent and treat secondary complications; support the family; and modify the environment as it is about a formal rehabilitation programme. Ideally these should be seamless but each contains many challenges, including the experience and skills of the observer, the ability to communicate with members of the family, and the ability to work within an interdisciplinary team.
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Lesões Encefálicas/reabilitação , Lesões Encefálicas/complicações , Lesões Encefálicas/fisiopatologia , Aconselhamento/métodos , Meio Ambiente , Família/psicologia , Humanos , Escala de Gravidade do Ferimento , Fenômenos Fisiológicos da Nutrição , Equipe de Assistência ao Paciente , Estado Vegetativo Persistente/etiologia , Estado Vegetativo Persistente/terapia , Postura/fisiologia , Recuperação de Função Fisiológica , Bexiga Urinária/fisiopatologia , Incontinência Urinária/etiologia , Incontinência Urinária/fisiopatologia , Infecções Urinárias/prevenção & controleRESUMO
Se colectaron babosas (Veronicellidae) en el Departamento de Morazán, Honduras. La digestión con jugo gástrico artificial mostró la presencia de larvas de tercer estadio morfológicamente semejantes a Angiostrongylus costaricensis. Seles inculó les inoculó en ratas (Sigmodon hispidus) con sonda gástrica. Cincuenta días después se obtuvieron los nemátodos adultos y se confirmó el diagnóstico. A pesar de que se han encontrado casos humanos de angiostrongiliasis abdominal en Honduras, nunca se había encontrado el parásito en su huésped intermediario