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•Loops and channels are both promising dynamic engineering targets for altered enzymatic properties.•The relevance of loop dynamics in engineering studies highlights to address this ...property consciously.•Inspiring studies on channel engineering motivate to expand this approach to more enzymes.•The integrative use of simulation and experiment for prediction and elucidation is crucial to unlock the potential of loop and channel engineering.
Enzymes are nature’s powerful catalytic proteins to perform reactions with often outstanding activity, selectivity and specificity. Moreover, the access to non-natural functions of biocatalysts can be facilitated by enzyme engineering. While rational approaches are often focused on an enzyme’s active site, from random directed evolution we know that further functional hotspots must exist beyond the active site. Addressing flexible structural elements of these biocatalysts like loops and channels in enzyme engineering has the potential to fill this knowledge gap. The structural dynamics of enzyme catalysts are vital to promote their remarkable functions. This influences for example the access, recognition and orientation of substrates. Herein, we review recent examples of loop and channel engineering and classify them according to their use of simulation methodologies, predictions prior to engineering, the engineering methodologies themselves and discoveries found after the engineering. Thereby we highlight current possibilities and make suggestions to further unlock the potential of this yet underexplored strategy.
A mechanistic model that interprets the oxidation behavior of the diborides of Zr, Hf and Ti in the temperature range of 1000-1800 deg C was formulated. Available thermodynamic data and literature ...data for vapor pressures and diffusivities were used to evaluate the model. Good correspondence was obtained between theory and experiments for weight gain, recession and scale thickness as functions of temperature and oxygen partial pressure. At temperatures below about 1400 deg C, the rate-limiting step is the diffusion of dissolved oxygen through a film of liquid boria in capillaries at the base of the oxidation product. At higher temperatures, the boria is lost by evaporation, and the oxidation rate is limited by Knudsen diffusion of molecular oxygen through the capillaries between nearly columnar blocks of the oxide, MO2.
We review the present status in the theoretical and phenomenological understanding of charmonium and bottomonium production in heavy-ion collisions. We start by recapitulating the basic notion of ...“anomalous quarkonium suppression” in heavy-ion collisions and its recent amendments involving regeneration reactions. We then survey in some detail concepts and ingredients needed for a comprehensive approach to utilize heavy quarkonia as a probe of hot and dense matter. The theoretical discussion encompasses recent lattice QCD computations of quarkonium properties in the Quark–Gluon Plasma, their interpretations using effective potential models, inelastic rate calculations and insights from analyses of electromagnetic plasmas. We illustrate the powerful techniques of thermodynamic Green functions (
T
-matrices) to provide a general framework for implementing microscopic properties of heavy quarkonia into a kinetic theory of suppression and regeneration reactions. The theoretical concepts are tested in applications to heavy-ion reactions at SPS, RHIC and LHC. We outline perspectives for future experiments on charmonium and bottomonium production in heavy-ion collisions over a large range of energies (FAIR, RHIC-II and LHC). These are expected to provide key insights into hadronic matter under extreme conditions using quarkonium observables.
Humans and nonhuman primates are vulnerable to age- and menopause-related decline in working memory, a cognitive function reliant on the energy-demanding recurrent excitation of neurons within ...Brodmann’s Area 46 of the dorsolateral prefrontal cortex (dlPFC). Here, we tested the hypothesis that the number and morphology (straight, curved, or donut-shaped) of mitochondria in dlPFC presynaptic boutons are altered with aging and menopause in rhesus monkeys (Macaca mulatta) and that these metrics correlate with delayed response (DR) accuracy, a well-characterized measure of dlPFC-dependent working memory. Although presynaptic bouton density or size was not significantly different across groups distinguished by age or menses status, DR accuracy correlated positively with the number of total and straight mitochondria per dlPFC bouton. In contrast, DR accuracy correlated inversely with the frequency of boutons containing donut-shaped mitochondria, which exhibited smaller active zone areas and fewer docked synaptic vesicles than those with straight or curved mitochondria. We then examined the effects of estrogen administration to test whether a treatment known to improve working memory influences mitochondrial morphology. Aged ovariectomized monkeys treated with vehicle displayed significant working memory impairment and a concomitant 44% increase in presynaptic donut-shaped mitochondria, both of which were reversed with cyclic estradiol treatment. Together, our data suggest that hormone replacement therapy may benefit cognitive aging, in part by promoting mitochondrial and synaptic health in the dlPFC.
Background and Purpose- We examine the association between self-reported consumption of artificially sweetened beverages (ASB) and stroke and its subtypes, coronary heart disease, and all-cause ...mortality in a cohort of postmenopausal US women. Methods- The analytic cohort included 81 714 women from the Women's Health Initiative Observational Study, a multicenter longitudinal study of the health of 93 676 postmenopausal women of ages 50 to 79 years at baseline who enrolled in 1993 to 1998. This prospective study had a mean follow-up time of 11.9 years (SD of 5.3 years.) Participants who completed a follow-up visit 3 years after baseline were included in the study. Results- Most participants (64.1%) were infrequent consumers (never or <1/week) of ASB, with only 5.1% consuming ≥2 ASBs/day. In multivariate analyses, those consuming the highest level of ASB compared to never or rarely (<1/wk) had significantly greater likelihood of all end points (except hemorrhagic stroke), after controlling for multiple covariates. Adjusted models indicated that hazard ratios and 95% confidence intervals were 1.23 (1.02-1.47) for all stroke; 1.31 (1.06-1.63) for ischemic stroke; 1.29 (1.11-1.51) for coronary heart disease; and 1.16 (1.07-1.26) for all-cause mortality. In women with no prior history of cardiovascular disease or diabetes mellitus, high consumption of ASB was associated with more than a 2-fold increased risk of small artery occlusion ischemic stroke hazard ratio =2.44 (95% confidence interval, 1.47-4.04.) High consumption of ASBs was associated with significantly increased risk of ischemic stroke in women with body mass index ≥30; hazard ratio =2.03 (95% confidence interval, 1.38-2.98). Conclusions- Higher intake of ASB was associated with increased risk of stroke, particularly small artery occlusion subtype, coronary heart disease, and all-cause mortality. Although requiring replication, these new findings add to the potentially harmful association of consuming high quantities of ASB with these health outcomes.
Highlights • Unlike neurons in dlPFC, neurons in V1 do not lose spines with age in rhesus monkeys. • Aging decreases the proportion of thin spines in macaque dlPFC but not in V1. • Smaller dlPFC mean ...spine head diameter correlates with fewer trials to criterion on DR and DNMS tasks.
Abstract More than 5 million Americans are living with Alzheimer's disease (AD) today, and nearly two-thirds of Americans with AD are women. This sex difference may be due to the higher longevity ...women generally experience; however, increasing evidence suggests that longevity alone is not a sufficient explanation and there may be other factors at play. The Alzheimer's Association convened an expert think tank to focus on the state of the science and level of evidence around gender and biological sex differences for AD, including the knowledge gaps and areas of science that need to be more fully addressed. This article summarizes the think tank discussion, moving forward a research agenda and funding program to better understand the biological underpinnings of sex- and gender-related disparities of risk for AD.
Neurotoxic effects of brain irradiation include cognitive impairment in 50% to 90% of patients. Prior studies have suggested that donepezil, a neurotransmitter modulator, may improve cognitive ...function.
A total of 198 adult brain tumor survivors ≥ 6 months after partial- or whole-brain irradiation were randomly assigned to receive a single daily dose (5 mg for 6 weeks, 10 mg for 18 weeks) of donepezil or placebo. A cognitive test battery assessing memory, attention, language, visuomotor, verbal fluency, and executive functions was administered before random assignment and at 12 and 24 weeks. A cognitive composite score (primary outcome) and individual cognitive domains were evaluated.
Of this mostly middle-age, married, non-Hispanic white sample, 66% had primary brain tumors, 27% had brain metastases, and 8% underwent prophylactic cranial irradiation. After 24 weeks of treatment, the composite scores did not differ significantly between groups (P = .48); however, significant differences favoring donepezil were observed for memory (recognition, P = .027; discrimination, P = .007) and motor speed and dexterity (P = .016). Significant interactions between pretreatment cognitive function and treatment were found for cognitive composite (P = .01), immediate recall (P = .05), delayed recall (P = .004), attention (P = .01), visuomotor skills (P = .02), and motor speed and dexterity (P < .001), with the benefits of donepezil greater for those who were more cognitively impaired before study treatment.
Treatment with donepezil did not significantly improve the overall composite score, but it did result in modest improvements in several cognitive functions, especially among patients with greater pretreatment impairments.
We report on broadly based systematic investigations of the modeling components for open heavy-flavor diffusion and energy loss in strongly interacting matter in their application to heavy-flavor ...observables in high-energy heavy–ion collisions, conducted within an EMMI Rapid Reaction Task Force framework. Initial spectra including cold-nuclear-matter effects, a wide variety of space-time evolution models, heavy-flavor transport coefficients, and hadronization mechanisms are scrutinized in an effort to quantify pertinent uncertainties in the calculations of nuclear modification factors and elliptic flow of open heavy-flavor particles in nuclear collisions. We develop procedures for error assessments and criteria for common model components to improve quantitative estimates for the (low-momentum) heavy-flavor diffusion coefficient as a long-wavelength characteristic of QCD matter as a function of temperature, and for energy loss coefficients of high-momentum heavy-flavor particles.
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