Interplay of network dynamics and ties heterogeneity on spreading dynamics

The structure of a network dramatically affects the spreading phenomena unfolding upon it. The contact distribution of the nodes has long been recognized as the key ingredient in influencing the outbreak events. However, limited knowledge is currently available on the role of the weight of the edges on the persistence of a pathogen. At the same time, recent works showed a strong influence of temporal network dynamics on disease spreading. In this work we provide an analytical understanding, corroborated by numerical simulations, about the conditions for infected stable state in weighted networks. In particular, we reveal the role of heterogeneity of edge weights and of the dynamic assignment of weights on the ties in the network in driving the spread of the epidemic. In this context we show that when weights are dynamically assigned to ties in the network an heterogeneous distribution is able to hamper the diffusion of the disease, contrary to what happens when weights are fixed in time.Comment: 10 pages, 10 figure

Modeling the effects of variable feeding patterns of larval ticks on the transmission of Borrelia lusitaniae and Borrelia afzelii

Spirochetes belonging to the Borrelia burgdoferi sensu lato (sl) group cause Lyme Borreliosis (LB), which is the most commonly reported vector-borne zoonosis in Europe. B. burgdorferi sl is maintained in nature in a complex cycle involving Ixodes ricinus ticks and several species of vertebrate hosts. The transmission dynamics of B. burgdorferi sl is complicated by the varying competence of animals for different genospecies of spirochetes that, in turn, vary in their capability of causing disease. In this study, a set of difference equations simplifying the complex interaction between vectors and their hosts (competent and not for Borrelia) is built to gain insights into conditions underlying the dominance of B. lusitaniae (transmitted by lizards to susceptible ticks) and the maintenance of B. afzelii (transmitted by wild rodents) observed in a study area in Tuscany, Italy. Findings, in agreement with field observations, highlight the existence of a threshold for the fraction of larvae feeding on rodents below which the persistence of B. afzelii is not possible. Furthermore, thresholds change as nonlinear functions of the expected number of nymph bites on mice, and the transmission and recovery probabilities. In conclusion, our model provided an insight into mechanisms underlying the relative frequency of different Borrelia genospecies, as observed in field studies.Comment: 14 pages, 3 figures, to be published in Theoretical Population Biolog

Advances in Alzheimer therapy: understanding pharmacological approaches to the disease

Although significant accomplishments have been made in research to understand, diagnose and treat Alzheimer's disease (AD) and its prequel, mild cognitive impairment, over the last two decades, a huge amount more remains to be achieved to impact this incurable, terminal disease that afflicts an estimated 26.6 million people worldwide. Increasing evidence indicates that early diagnosis will be fundamental to maximizing treatment benefits. Moreover, mechanistically-based, hypothesis-driven treatment strategies are now emerging to hopefully spearhead future therapy. The crossfertilization of ideas from multiple disciplines will prove key to optimize strategies and translate them to meaningful clinical utility, and forms the basis of the current issue focused on "Advances in Alzheimer therapy"

In silico modeling of the specific inhibitory potential of thiophene-2,3-dihydro-1,5-benzothiazepine against BChE in the formation of β-amyloid plaques associated with Alzheimer's disease

<p>Abstract</p> <p>Background</p> <p>Alzheimer's disease, known to be associated with the gradual loss of memory, is characterized by low concentration of acetylcholine in the hippocampus and cortex part of the brain. Inhibition of acetylcholinesterase has successfully been used as a drug target to treat Alzheimer's disease but drug resistance shown by butyrylcholinesterase remains a matter of concern in treating Alzheimer's disease. Apart from the many other reasons for Alzheimer's disease, its association with the genesis of fibrils by β-amyloid plaques is closely related to the increased activity of butyrylcholinesterase. Although few data are available on the inhibition of butyrylcholinesterase, studies have shown that that butyrylcholinesterase is a genetically validated drug target and its selective inhibition reduces the formation of β-amyloid plaques.</p> <p>Rationale</p> <p>We previously reported the inhibition of cholinesterases by 2,3-dihydro-1, 5-benzothiazepines, and considered this class of compounds as promising inhibitors for the cure of Alzheimer's disease. One compound from the same series, when substituted with a hydroxy group at C-3 in ring A and 2-thienyl moiety as ring B, showed greater activity against butyrylcholinesterase than to acetylcholinesterase. To provide insight into the binding mode of this compound (Compound A), molecular docking in combination with molecular dynamics simulation of 5000 ps in an explicit solvent system was carried out for both cholinesterases.</p> <p>Conclusion</p> <p>Molecular docking studies revealed that the potential of Compound A to inhibit cholinesterases was attributable to the cumulative effects of strong hydrogen bonds, cationic-π, π-π interactions and hydrophobic interactions. A comparison of the docking results of Compound A against both cholinesterases showed that amino acid residues in different sub-sites were engaged to stabilize the docked complex. The relatively high affinity of Compound A for butyrylcholinesterase was due to the additional hydrophobic interaction between the 2-thiophene moiety of Compound A and Ile69. The involvement of one catalytic triad residue (His438) of butyrylcholinesterase with the 3'-hydroxy group on ring A increases the selectivity of Compound A. C-C bond rotation around ring A also stabilizes and enhances the interaction of Compound A with butyrylcholinesterase. Furthermore, the classical network of hydrogen bonding interactions as formed by the catalytic triad of butyrylcholinesterase is disturbed by Compound A. This study may open a new avenue for structure-based drug design for Alzheimer's disease by considering the 3D-pharmacophoric features of the complex responsible for discriminating these two closely-related cholinesterases.</p

Advances in the therapy of Alzheimer's disease: Targeting amyloid beta and tau and perspectives for the future

Worldwide multidisciplinary translational research has led to a growing knowledge of the genetics and molecular pathogenesis of Alzheimer's disease (AD) indicating that pathophysiological brain alterations occur decades before clinical signs and symptoms of cognitive decline can be diagnosed. Consequently, therapeutic concepts and targets have been increasingly focused on early-stage illness before the onset of dementia; and distinct classes of compounds are now being tested in clinical trials. At present, there is a growing consensus that therapeutic progress in AD delaying disease progression would significantly decrease the expanding global burden. The evolving hypothesis- and evidence-based generation of new diagnostic research criteria for early-stage AD has positively impacted the development of clinical trial designs and the characterization of earlier and more specific target populations for trials in prodromal as well as in pre- and asymptomatic at-risk stages of AD

Alzheimer disease therapy-moving from amyloid-β to tau

Disease-modifying treatments for Alzheimer disease (AD) have focused mainly on reducing levels of amyloid-β (Aβ) in the brain. Some compounds have achieved this goal, but none has produced clinically meaningful results. Several methodological issues relating to clinical trials of these agents might explain this failure; an additional consideration is that the amyloid cascade hypothesis-which places amyloid plaques at the heart of AD pathogenesis-does not fully integrate a large body of data relevant to the emergence of clinical AD. Importantly, amyloid deposition is not strongly correlated with cognition in multivariate analyses, unlike hyperphosphorylated tau, neurofibrillary tangles, and synaptic and neuronal loss, which are closely associated with memory deficits. Targeting tau pathology, therefore, might be more clinically effective than Aβ-directed therapies. Furthermore, numerous immunization studies in animal models indicate that reduction of intracellular levels of tau and phosphorylated tau is possible, and is associated with improved cognitive performance. Several tau-related vaccines are in advanced preclinical stages and will soon enter clinical trials. In this article, we present a critical analysis of the failure of Aβ-directed therapies, discuss limitations of the amyloid cascade hypothesis, and suggest the potential value of tau-targeted therapy for AD