Composite RNA aptamers as functional mimics of proteins

Individual RNA aptamers are often used to modulate the function of their target proteins, and multi-valent aptamers have been constructed to enhance their activity. To expand the utility of aptamers in manipulating and controlling biological processes, here we advance a general method for the design and construction of composite aptamers. The resulting molecular constructs resemble proteins in that they can form specific interactions with three or more different partners and be readily integrated into existing protein regulatory networks. As the first embodiment of this method, we created a tetra-valent aptamer that simultaneously binds to two molecules of the Drosophila protein B52 and two copies of streptavidin, thus mimicking the function of an antibody in immunochemical assays. We demonstrated that the performance of this ‘aptabody’ rivals that of a monoclonal antibody against B52 in these assays. While this study was performed in vitro and the composite aptamer we made was intended to mimic an existing protein, the same method can be used to accommodate arbitrary combinations of individual aptamers in composite molecular contexts, and these constructs can be delivered into living cells, where they are able to utilize existing cellular infrastructure for their production and processing

Phenotypic Characterization of Autoreactive B Cells—Checkpoints of B Cell Tolerance in Patients with Systemic Lupus Erythematosus

DNA-reactive B cells play a central role in systemic lupus erythematosus (SLE); DNA antibodies precede clinical disease and in established disease correlate with renal inflammation and contribute to dendritic cell activation and high levels of type 1 interferon. A number of central and peripheral B cell tolerance mechanisms designed to control the survival, differentiation and activation of autoreactive B cells are thought to be disturbed in patients with SLE. The characterization of DNA-reactive B cells has, however, been limited by their low frequency in peripheral blood. Using a tetrameric configuration of a peptide mimetope of DNA bound by pathogenic anti-DNA antibodies, we can identify B cells producing potentially pathogenic DNA-reactive antibodies. We, therefore, characterized the maturation and differentiation states of peptide, (ds) double stranded DNA cross-reactive B cells in the peripheral blood of lupus patients and correlated these with clinical disease activity. Flow cytometric analysis demonstrated a significantly higher frequency of tetramer-binding B cells in SLE patients compared to healthy controls. We demonstrated the existence of a novel tolerance checkpoint at the transition of antigen-naïve to antigen-experienced. We further demonstrate that patients with moderately active disease have more autoreactive B cells in both the antigen-naïve and antigen-experienced compartments consistent with greater impairment in B cell tolerance in both early and late checkpoints in these patients than in patients with quiescent disease. This methodology enables us to gain insight into the development and fate of DNA-reactive B cells in individual patients with SLE and paves the way ultimately to permit better and more customized therapies

Hepatic Fat Accumulation Is Modulated by the Interaction between the rs738409 Variant in the PNPLA3 Gene and the Dietary Omega6/Omega3 PUFA Intake

A single nucleotide polymorphism (SNP), the rs738409, in the patatin like phospholipase 3 gene (PNPLA3) has been recently associated with increased hepatic steatosis and ALT levels in adults and children. Given the potential role of PNPLA3 in fatty liver development, we aimed to explore whether the influence of PNPLA3 genotype on hepatic fat in obese youth might be modulated by dietary factors such as essential omega polyunsaturated fatty acids (PUFA) intake.We studied 127 children and adolescents (56 boys, 71 girls; 58 Caucasians; 30 African Americans and 39 Hispanics; mean age 14.7±3.3; mean BMI 30.7±7.2). The dietary composition was assessed by the Nutrition Data System for Research (NDS-R version 2011). The patients underwent a MRI study to assess the liver fat content (HFF%), ALT measurement and the genotyping of the rs738409 SNP by automatic sequencing.As previously observed, HFF% and ALT levels varied according to the genotype in each ethnicity. ALT levels and HFF% were significantly influenced by the interaction between genotype and omega-6/omega-3 PUFA ratio (n-6/n-3), p = 0.003 and p = 0.002, respectively. HFF% and ALT levels were, in fact, related to the n-6/n-3 consumption only in subjects homozygote for the G allele of the rs738409 (r2 = 0.45, p =  0.001 and r2 = 0.40, p = 0.006, respectively).These findings suggest that the association of a high dietary n-6/n-3 PUFA with fatty liver and liver damage in obese youths may be driven by a predisposing genotype

Period-adding bifurcations and chaos in a periodically stimulated excitable neural relaxation oscillator

This is a pre-print. The definitive version: COOMBES, S. and OSBALDESTIN, A.H., 2000. Period-adding bifurcations and chaos in a periodically stimulated excitable neural relaxation oscillator. Physical Review E, 62(3), pp.4057-4066 Part B.The response of an excitable neuron to trains of electrical spikes is relevant to the understanding of the neural code. In this paper we study a neurobiologically motivated relaxation oscillator, with appropriately identified fast and slow coordinates, that admits an explicit mathematical analysis. An application of geometric singular perturbation theory shows the existence of an attracting invariant manifold which is used to construct the Fenichel normal form for the system. This facilitates the calculation of the response of the system to pulsatile stimulation and allows the construction of a so-called extended isochronal map. The isochronal map is shown to have a single discontinuity and be of a type that can admit three types of response: mode-locked, quasi-periodic and chaotic. The bifurcation structure of the system is seen to be extremely rich and supports period-adding bifurcations separated by windows of both chaos and periodicity. A bifurcation analysis of the isochronal map is presented in conjunction with a description of the various routes to chaos in this system

Recombinant Zoster Vaccine (Shingrix): a nex gun for Rheumatologist

Herpes Zoster, or as commonly known shingles, is a debilitating painful rash occurring at any age in anyone caused by reactivation of the varicella zoster virus (VZV). The lifetime risk of HZ in the general population is around 30% HZ incidence increases with age and is estimated that 90% of adults have contracted VZV and are therefore at risk of developing HZ and that at least 1 in 3 individuals will develop the disease in their lifetime. Increased HZ incidence, attributed to a decline in immunity, is observed in elderly people and in patients using immunosuppressive medications. In light of the significant burden caused by HZ and its complications in frail patients, adopting a preventive strategy seems promising, particularly using vaccination in appropriate age and risk groups

Modelos proposicionales de las funciones cognitivas superiores: ¿Qué ganamos y qué perdemos?

This article reviews the classical imagery-propositional debate, in which sorne theorists (notably Pylyshyn) have argued that images are not really a separate type of representation but can be reduced to propositional representations, and sorne imagery researchers have refused this thesis. The authors present then two areas in cognitive science in which sorne central aspects of the debate seem to reappear: text comprehension and analogical thinking. While sorne researchers in these fields have proposed propositional models, sorne others have postulated diverse analogical representations to complement or replace propositions. Considering these more recent controversies, it is concluded that, against Pylyshyn's reductionism, there is general agreement today that different representations are needed to characterise the richness of human cognition. However, propositions are still very useful: they seem necessary for representing structured knowledge, and they constitute a powerful instrument for the formulation of unified and mechanical theories of cognition. It is also indicated that, notwithstanding this usefulness, propositional models tend to underestimate the role of other forms of representations in human cognition. The authors suggest that the idea underlying the recurrent proposals of analogical constructs in cognitive science is that psychological meaning cannot arise solely from syntactic relations between amodal arbitrary symbols. Our minds (particularly, our consciousness) afford us the possibility of having internal representations (sensorial and motor ones) akin to the ones we construct when we interact with the external environment. From this perspective, the concreteness of the mediums we employ in cognition matters a great deal, and psychological meaning cannot be accounted for unless we seriously consider the corresponding non-abstract kinds of representations

Fibromyalgia: an update on clinical characteristics, aetiopathogenesis and treatment

Fibromyalgia is characterized by chronic widespread pain, fatigue, sleep disturbances and functional symptoms. The etiopathogenesis, diagnostic criteria and classification criteria of fibromyalgia are still debated and, consequently, so are the strategies for treating this condition. Fibromyalgia is the third most frequent musculoskeletal condition, and its prevalence increases with age. However, although diagnosis has improved with the evolution of more accurate diagnostic criteria, a considerable proportion of physicians still fail to recognize the syndrome. Many factors contribute to the development of fibromyalgia in a unique manner: genetic predisposition, personal experiences, emotional\u2013cognitive factors, the mind\u2013body relationship and a biopsychological ability to cope with stress. The multiple components of the pathogenesis and maintenance of the condition necessitate a multi-modal treatment approach. Individually tailored treatment is an important consideration, with the increasing recognition that different fibromyalgia subgroups exist with different clinical characteristics. Consequently, although an evidence-based approach to fibromyalgia management is always desirable, the approach of physicians is inevitably empirical, and must have the aim of creating a strong alliance with the patient and formulating shared, realistic treatment goals