Wholly synthetic molecules involving both mechanical bonds and a folded secondary structure are one of the most promising architectures for the design of functional molecular machines with ...unprecedented properties. Here, we report dynamic single-molecule force spectroscopy experiments that explore the energetic details of donor–acceptor oligorotaxane foldamers, a class of molecular switches. Themechanical breaking of the donor–acceptor interactions responsible for the folded structure shows a high constant rupture force over a broad range of loading rates, covering three orders of magnitude. In comparison with dynamic force spectroscopy performed during the past 20 y on various (bio)molecules, the near-equilibrium regime of oligorotaxanes persists at much higher loading rates, at which biomolecules have reached their kinetic regime, illustrating the very fast dynamics and remarkable rebinding capabilities of the intramolecular donor–acceptor interactions. We focused on one single interaction at a time and probed the stochastic rupture and rebinding paths. Using the Crooks fluctuation theorem, we measured the mechanical work produced during the breaking and rebinding to determine a free-energy difference, ΔG, of 6 kcal·mol−1 between the two local conformations around a single bond.
Folding is a ubiquitous process that nature uses to control the conformations of its molecular machines, allowing them to perform chemical and mechanical tasks. Over the years, chemists have ...synthesized foldamers that adopt well-defined and stable folded architectures, mimicking the control expressed by natural systems
. Mechanically interlocked molecules, such as rotaxanes and catenanes, are prototypical molecular machines that enable the controlled movement and positioning of their component parts
. Recently, combining the exquisite complexity of these two classes of molecules, donor-acceptor oligorotaxane foldamers have been synthesized, in which interactions between the mechanically interlocked component parts dictate the single-molecule assembly into a folded secondary structure
. Here we report on the mechanochemical properties of these molecules. We use atomic force microscopy-based single-molecule force spectroscopy to mechanically unfold oligorotaxanes, made of oligomeric dumbbells incorporating 1,5-dioxynaphthalene units encircled by cyclobis(paraquat-p-phenylene) rings. Real-time capture of fluctuations between unfolded and folded states reveals that the molecules exert forces of up to 50 pN against a mechanical load of up to 150 pN, and displays transition times of less than 10 μs. While the folding is at least as fast as that observed in proteins, it is remarkably more robust, thanks to the mechanically interlocked structure. Our results show that synthetic oligorotaxanes have the potential to exceed the performance of natural folding proteins.
Higher cardiorespiratory fitness (CRF) induces neuroprotective effects in the hippocampus, a key brain region for memory and learning. We investigated the association between CRF and functional ...connectivity (FC) of the hippocampus in healthy young adults. We also examined the association between hippocampal FC and neurocognitive function. Lastly, we tested whether hippocampal FC mediates the association between 2-Min Walk Test (2MWT) and neurocognitive function.
913 young adults (28.7 ± 3.7 years) from the Human Connectome Project were included in the analyses. The 2MWT performance result was used as a proxy for cardiovascular endurance. Fluid and crystalized composite neurocognitive scores were used to assess cognition. Resting-state functional MRI data were processed to measure hippocampal FC. Linear regression was used to examine the association between 2MWT, hippocampal FC, and neurocognitive outcomes after controlling for age, sex, years of education, body mass index, systolic blood pressure, and gait speed.
Better 2MWT performance was associated with greater FC between the anterior hippocampus and right posterior cingulate and left middle temporal gyrus. No associations between 2MWT and posterior hippocampal FC, whole hippocampal FC, and caudate FC (control region) were observed. Greater anterior hippocampal FC was associated with better crystalized cognition scores. Lastly, greater FC between the anterior hippocampus and right posterior cingulate mediated the association between better 2MWT scores and higher crystalized cognition scores.
Anterior hippocampal FC may be one underlying neurophysiological mechanism that promotes the association between 2MWT performance and crystalized composite cognitive function in healthy young adults.
Aging is associated with deterioration in dentate gyrus (DG) and CA3, both crucial hippocampal subfields for age susceptible memory processes such as mnemonic discrimination (MD). Meanwhile, a single ...aerobic exercise session alters DG/CA3 function and neural activity in both rats and younger adults and can elicit short‐term microstructural alterations in the hippocampus of older adults. However, our understanding of the effects of acute exercise on hippocampal subfield integrity via function and microstructure in older adults is limited. Thus, a within subject‐design was employed to determine if 20‐min of moderate to vigorous aerobic exercise alters bilateral hippocampal subfield function and microstructure using high‐resolution functional magnetic resonance imaging (fMRI) during an MD task (n = 35) and high angular resolution multi‐shell diffusion imaging (n = 31), in healthy older adults, compared to seated rest. Following the exercise condition, participants exhibited poorer MD performance, particularly when their perception of effort was higher. Exercise was also related to lower MD‐related activity within the DG/CA3 but not CA1 subfield. Finally, after controlling for whole brain gray matter diffusion, exercise was associated with lower neurite density index (NDI) within the DG/CA3. However, exercise‐related differences in DG/CA3 activity and NDI were not associated with differences in MD performance. Our results suggest moderate to vigorous aerobic exercise may temporarily inhibit MD performance, and suppress DG/CA3 MD‐related activity and NDI, potentially through neuroinflammatory/glial processes. However, additional studies are needed to confirm whether these short‐term changes in behavior and hippocampal subfield neurophysiology are beneficial and how they might relate to long‐term exercise habits.
Cyclodextrins (CDs) are cone-shaped molecular rings that have been widely employed in supramolecular/host–guest chemistry because of their low cost, high biocompatibility, stability, wide ...availability in multiple sizes, and their promiscuity for binding a range of molecular guests in water. Consequently, CD-based host–guest complexes are often employed as templates for the synthesis of mechanically bonded molecules (mechanomolecules) such as catenanes, rotaxanes, and polyrotaxanes in particular. The conical shape and cyclodirectionality of the CD “bead” gives rise to a symmetry-breaking effect when it is threaded onto a molecular “string”; even symmetrical guests are rendered asymmetric by the presence of an encircling CD host. This review focuses on the stereochemical implications of this symmetry-breaking effect in mechanomolecules, including orientational isomerism, mechanically planar chirality, and topological chirality, as well as how they support applications in regioselective and stereoselective chemical synthesis, the design of molecular machine prototypes, and the development of advanced materials.
The psychological autopsy method offers the most direct technique currently available for examining the relationship between particular antecedents and suicide. This systematic review aimed to ...examine the results of studies of suicide that used a psychological autopsy method.
A computer aided search of MEDLINE, BIDS ISI and PSYCHLIT, supplemented by reports known to the reviewers and reports identified from the reference lists of other retrieved reports. Two investigators systematically and independently examined all reports. Median proportions were determined and population attributable fractions were calculated, where possible, in cases of suicide and controls.
One hundred and fifty-four reports were identified, of which 76 met the criteria for inclusion; 54 were case series and 22 were case-control studies. The median proportion of cases with mental disorder was 91% (95 % CI 81-98%) in the case series. In the case-control studies the figure was 90% (88-95%) in the cases and 27% (14-48%) in the controls. Co-morbid mental disorder and substance abuse also preceded suicide in more cases (38%, 19-57%) than controls (6%, 0-13%). The population attributable fraction for mental disorder ranged from 47-74% in the seven studies in which it could be calculated. The effects of particular disorders and sociological variables have been insufficiently studied to draw clear conclusions.
The results indicated that mental disorder was the most strongly associated variable of those that have been studied. Further studies should focus on specific disorders and psychosocial factors. Suicide prevention strategies may be most effective if focused on the treatment of mental disorders.
An increasing proportion of cognitive difficulties are recognized to have a functional cause, the chief clinical indicator of which is internal inconsistency. When these symptoms are impairing or ...distressing, and not better explained by other disorders, this can be conceptualized as a cognitive variant of functional neurological disorder, termed functional cognitive disorder (FCD). FCD is likely very common in clinical practice but may be under-diagnosed. Clinicians in many settings make liberal use of the descriptive term mild cognitive impairment (MCI) for those with cognitive difficulties not impairing enough to qualify as dementia. However, MCI is an aetiology-neutral description, which therefore includes patients with a wide range of underlying causes. Consequently, a proportion of MCI cases are due to non-neurodegenerative processes, including FCD. Indeed, significant numbers of patients diagnosed with MCI do not 'convert' to dementia. The lack of diagnostic specificity for MCI 'non-progressors' is a weakness inherent in framing MCI primarily within a deterministic neurodegenerative pathway. It is recognized that depression, anxiety and behavioural changes can represent a prodrome to neurodegeneration; empirical data are required to explore whether the same might hold for subsets of individuals with FCD. Clinicians and researchers can improve study efficacy and patient outcomes by viewing MCI as a descriptive term with a wide differential diagnosis, including potentially reversible components such as FCD. We present a preliminary definition of functional neurological disorder-cognitive subtype, explain its position in relation to other cognitive diagnoses and emerging biomarkers, highlight clinical features that can lead to positive diagnosis (as opposed to a diagnosis of exclusion), and red flags that should prompt consideration of alternative diagnoses. In the research setting, positive identifiers of FCD will enhance our recognition of individuals who are not in a neurodegenerative prodrome, while greater use of this diagnosis in clinical practice will facilitate personalized interventions.
The relationship between gait speed and working memory is well-understood in older adults. However, it remains to be determined whether this relationship also exists in younger adults; and there is ...little known regarding the possible neural mechanism underlying the association between gait speed and working memory. The aims of this study are to determine if there is: (1) an association between gait speed and working memory performance; and (2) a mediating role of cerebellar subregion volume in the correlation between gait speed and working memory in healthy younger adults. 1054 younger adults (28.7 ± 3.6 years) from the Human Connectome Project were included in the analyses. A four-meter gait test was used to assess gait speed. The 2-back task was used to measure working memory performance accuracy and response time (RT). T1-weighted structural MRI data (obtained using Siemens 3 T MRI scanner) was used to assess cerebellar subregion volumes. Linear regression and mediation analysis were used to examine the relationships between the variables after controlling for age, sex, and education. There was no association between gait speed and 2-back working memory performance in younger adults. Greater Crus I and whole cerebellar volumes were associated with better 2-back working memory accuracy. Greater VIIIa volume was associated with faster gait speed. Greater Crus 1 and VIIIa volumes were also associated with higher fluid cognition. The present study suggests that specific subregions of the cerebellar volumes are distinctively associated with gait speed and working memory performance in healthy younger adults.
The ability to design and confer control over the kinetics of theprocesses involved in the mechanisms of artificial molecular machines is at the heart of the challenge to create ones that can carry ...out useful work on their environment, just as Nature is wont to do. As one of the more promising forerunners of prototypical artificial molecular machines, chemists have developed bistable redox-active donor–acceptor mechanically interlocked molecules (MIMs) over the past couple of decades. These bistable MIMs generally come in the form of 2rotaxanes, molecular compounds that constitute a ring mechanically interlocked around a dumbbell-shaped component, or 2catenanes, which are composed of two mechanically interlocked rings. As a result of their interlocked nature, bistable MIMs possess the inherent propensity to express controllable intramolecular, large-amplitude, and reversible motions in response to redox stimuli. In this Account, we rationalize the kinetic behavior in the ground state for a large assortment of these types of bistable MIMs, including both rotaxanes and catenanes. These structures have proven useful in a variety of applications ranging from drug delivery to molecular electronic devices. These bistable donor–acceptor MIMs can switch between two different isomeric states. The favored isomer, known as the ground-state co-conformation (GSCC) is in equilibrium with the less favored metastable state co-conformation (MSCC). The forward (k f) and backward (k b) rate constants associated with this ground-state equilibrium are intimately connected to each other through the ground-state distribution constant, K GS. Knowing the rate constants that govern the kinetics and bring about the equilibration between the MSCC and GSCC, allows researchers to understand the operation of these bistable MIMs in a device setting and apply them toward the construction of artificial molecular machines. The three biggest influences on the ground-state rate constants arise from (i) ground-state effects, the energy required to breakup the noncovalent bonding interactions that stabilize either the GSCC or MSCC, (ii) spacer effects, where the structures overcome additional barriers, either steric or electrostatic or both, en route from one co-conformation to the other, and (iii) the physical environment of the bistable MIMs. By managing all three of these effects, chemists can vary these rate constants over many orders of magnitude. We also discuss progress toward achieving mechanostereoselective motion, a key principle in the design and realization of artificial molecular machines capable of doing work at the molecular level, by the strategic implementation of free energy barriers to intramolecular motion.
Values are a central personality construct and the importance of studying them has been well established. To encourage researchers to integrate measures of values into their studies, brief and ...ultrabrief instruments were developed to recapture the 10 values measured by the 40-item Portrait Values Questionnaire (PVQ; Schwartz,
2003
). Rigorous psychometric procedures based on separate derivation (N = 38,049) and evaluation (N = 29,143) samples yielded 10- and 20-item measures of values, which proved to be successful at capturing the patterns and magnitude of correlations associated with the original PVQ. These instruments should be useful to researchers who would like to incorporate a values scale into their study but do not have the space to administer a longer measure.
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