Mean first passage time analysis reveals rate-limiting steps, parallel pathways and dead ends in a simple model of protein folding

We have analyzed dynamics on the complex free energy landscape of protein folding in the FOLD-X model, by calculating for each state of the system the mean first passage time to the folded state. The resulting kinetic map of the folding process shows that it proceeds in jumps between well-defined, local free energy minima. Closer analysis of the different local minima allows us to reveal secondary, parallel pathways as well as dead ends.Comment: 7 page

Closure theorems for orientor fields and weak convergence

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46195/1/205_2004_Article_BF00250438.pd

Dissecting the Pharmacodynamics and Pharmacokinetics of MSCs to Overcome Limitations in Their Clinical Translation

Recently, mesenchymal stromal stem cells (MSCs) have been proposed as therapeutic agents because of their promising preclinical features and good safety profile. However, their introduction into clinical practice has been associated with a suboptimal therapeutic profile. In this review, we address the biodistribution of MSCs in preclinical studies with a focus on the current understanding of the pharmacodynamics (PD) and pharmacokinetics (PK) of MSCs as key aspects to overcome unsatisfactory clinical benefits of MSC application. Beginning with evidence of MSC biodistribution and highlighting PK and PD factors, a new PK-PD model is also proposed. According to this theory, MSCs and their released factors are key players in PK, and the efficacy biomarkers are considered relevant for PD in more predictive preclinical investigations. Accounting for the PK-PD relationship in MSC translational research and proposing new models combined with better biodistribution studies could allow realization of the promise of more robust MSC clinical translation. The number of clinical trials based on MSCs that are publicly available exceeds 800; however, data regarding MSC pharmacodynamics (PD), pharmacokinetics (PK), and biodistribution are still scarce. For this reason, we dissected the PD and PK properties of MSCs, presenting factors that may influence MSC-based PK studies to then conceive a new PK-PD model that would support better and more robust MSC clinical translation

Geometric and analytic views in existence theorems for optimal control. II. Distributed and boundary controls

Existence theorems are proved for Lagrange problems of optimization in a given domain G with possibly unbounded distributed controls in G and on the boundary of G , and with functional relations on G and on the boundary represented by closed operators, not necessarily linear. The case where the functional relations are partial differential equations is emphasized. Recent work concerning the reduction or elimination of seminormality requirements is taken into account. Many examples are given.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45200/1/10957_2004_Article_BF00933208.pd

The relationship between frailty and polypharmacy in older people : A systematic review

AimsFrailty is a complex geriatric syndrome resulting in decreased physiological reserves. Frailty and polypharmacy are common in older adults and the focus of extensive studies, although little is known about the impact they may have on each other. This is the first systematic review analysing the available evidence on the relationship between frailty and polypharmacy in older adults. MethodsSystematic review of quantitative studies. A comprehensive literature search for publications in English or Spanish was performed on MEDLINE, CINAHL, the Cochrane Database and PsycINFO in September 2017 without applying restrictions on the date of publication. Studies reporting any relationship between frailty and polypharmacy in older adults were considered. ResultsA total of 25 publications were included, all of them observational studies. Evaluation of Fried's frailty criteria was the most common approach, followed by the Edmonton Frail Scale and FRAIL scale. Sixteen of 18 cross-sectional analyses and five of seven longitudinal analyses demonstrated a significant association between an increased number of medications and frailty. The causal relationship is unclear and appears to be bidirectional. Our analysis of published data suggests that polypharmacy could be a major contributor to the development of frailty. ConclusionsA reduction of polypharmacy could be a cautious strategy to prevent and manage frailty. Further research is needed to confirm the possible benefits of reducing polypharmacy in the development, reversion or delay of frailty

The Lisbon patient: Exceptional longevity with HIV suggests healthy aging as an ultimate goal for HIV care

In the context of global aging, HIV infection has become a new chronic disease and requires innovative models of care. Treating isolated comorbidities represents a useless and potentially harmful practice at advanced age. Therefore, a patient-centered approach, in which the interventions are focused on the biology and function of the individual, with understanding of the importance of securing social and home environment that provides psychosocial support, better suits unmet health needs. We present a paradigmatic case of healthy aging: the first reported HIV-infected patient who achieved 100th of life - the Lisbon patient. The construct of healthy aging, recently introduced by the World Health Organization, is the best example of this comprehensive model and could represent the fourth target of UNAIDS agenda of the end of AIDS

Effect of weaning age and diet on growth performance, caecal characteristics and potential pathogenetic microflora in rabbits

The aim of this study was to investigate the effect of age and diet at weaning on growth performances, caecal characteristics and development of potential pathogenetic microflora. The trial was carried out on 64 litters from 18 to 45 days of age comparing two weaning age (25 vs. 34 d) and two weaning diets (HF and LF) characterized, especially, by different energy, fat and starch concentration (HF: DE=11.5 MJ/kg, EE=6.2%, Starch=8.7%; LF: DE=10.1 MJ/kg DM, EE=3.1%, Starch=11.3%). At 45 d, early weaning determined a significant reduction of growth (1219 vs. 1282; P<0.01), although the solid feed intake resulted significantly higher, from 25 to 34 days of age, in early weaned rabbits (50.0 vs. 29.8 g/d; P<0.001). The age at weaning did not modify caecal traits, with the exception of pH value, that was lower in rabbits early moved to the mothers (5.53 vs. 5.83; P<0,05). Independently by age of weaning, the administration of diet HF promoted growth performance in rabbits at 45 d (1280 vs. 1222; P<0.01). Diet composition did not influence mortality rate at 34 days of age, while early weaning determined values significantly higher than those found in rabbits weaned later. The data of microbial analysis, carried out on 10 animals per diet (at 25 and 34 days of age), showed potential pathogenetic microflora development depended by the age of animal and was not affected by the composition of diets

Methodological Issues in the Clinical Validation of Biomarkers for Alzheimer&apos;s Disease : The Paradigmatic Example of CSF

The use of biomarkers is profoundly transforming medical research and practice. Their adoption has triggered major advancements in the field of Alzheimer's disease (AD) over the past years. For instance, the analysis of the cerebrospinal fluid (CSF) and neuroimaging changes indicative of neuronal loss and amyloid deposition has led to the understanding that AD is characterized by a long preclinical phase. It is also supporting the transition towards a biology-grounded framework and definition of the disease. Nevertheless, though sufficient evidence exists about the analytical validity (i.e., accuracy, reliability, and reproducibility) of the candidate AD biomarkers, their clinical validity (i.e., how well the test measures the clinical features, and the disease or treatment outcomes) and clinical utility (i.e., if and how the test improves the patient's outcomes, confirms/changes the diagnosis, identifies at-risk individuals, influences therapeutic choices) have not been fully proven. In the present review, some of the methodological issues and challenges that should be addressed in order to better appreciate the potential benefits and limitations of AD biomarkers are discussed. The ultimate goal is to stimulate a constructive discussion aimed at filling the existing gaps and more precisely defining the directions of future research. Specifically, four main aspects of the clinical validation process are addressed and applied to the most relevant CSF biomarkers: (1) the definition of reference values; (2) the identification of reference standards for the disease of interest (i.e., AD); (3) the inclusion within the diagnostic process; and (4) the statistical process supporting the whole framework

Dynamic Pricing with Finitely Many Unknown Valuations

Motivated by posted price auctions where buyers are grouped in an unknown number of latent types characterized by their private values for the good on sale, we investigate regret minimization in stochastic dynamic pricing when the distribution of buyers\u2019 private values is supported on an unknown set of points in [0, 1] of unknown cardinality K