Ranking and compacting binding segments of protein families using aligned pattern clusters

Background

Discovering sequence patterns with variation can unveil functions of a protein family that are important for drug discovery. Exploring protein families using existing methods such as multiple sequence alignment is computationally expensive, thus pattern search, called motif finding in Bioinformatics, is used. However, at present, combinatorial algorithms result in large sets of solutions, and probabilistic models require a richer representation of the amino acid associations. To overcome these shortcomings, we present a method for ranking and compacting these solutions in a new representation referred to as Aligned Pattern Clusters (APCs). To tackle the problem of a large solution set, our method reveals a reduced set of candidate solutions without losing any information. To address the problem of representation, our method captures the amino acid associations and conservations of the aligned patterns. Our algorithm renders a set of APCs in which a set of patterns is discovered, pruned, aligned, and synthesized from the input sequences of a protein family.

Results

Our algorithm identifies the binding or other functional segments and their embedded residues which are important drug targets from the cytochrome c and the ubiquitin protein families taken from Unitprot. The results are independently confirmed by pFam's multiple sequence alignment. For cytochrome c protein the number of resulting patterns with variations are reduced by 76.62% from the number of original patterns without variations. Furthermore, all of the top four candidate APCs correspond to the binding segments with one of each of their conserved amino acid as the binding residue. The discovered proximal APCs agree with pFam and PROSITE results. Surprisingly, the distal binding site discovered by our algorithm is not discovered by pFam nor PROSITE, but confirmed by the three-dimensional cytochrome c structure. When applied to the ubiquitin protein family, our results agree with pFam and reveals six of the seven Lysine binding residues as conserved aligned columns with entropy redundancy measure of 1.0.

Conclusion

The discovery, ranking, reduction, and representation of a set of patterns is important to avert time-consuming and expensive simulations and experimentations during proteomic study and drug discovery.

     

Inhibitory effects of biochanin A on titanium particle‐induced osteoclast activation and inflammatory bone resorption via NF‐κB and MAPK pathways

Revision operations have become a new issue after successful artificial joint replacements, and periprosthetic osteolysis leading to prosthetic loosening is the main cause of why the overactivation of osteoclasts (OCs) plays an important role. The effect of biochanin A (BCA) has been examined in osteoporosis, but no study on the role of BCA in prosthetic loosening osteolysis has been conducted yet. In this study, we utilised enzyme‐linked immunosorbent assay, computed tomography imaging, and histological analysis. Results showed that BCA downregulated the secretion levels of tumor necrosis factor‐α, interleukin‐1α (IL‐1α), and IL‐1β to suppress inflammatory responses. The secretion levels of receptor‐activated nuclear factor‐κB ligand, CTX‐1, and osteoclast‐associated receptor as well as Ti‐induced osteolysis were also reduced. BCA effectively inhibited osteoclastogenesis and suppressed hydroxyapatite resorption by downregulating OC‐related genes in vitro. Analysis of mechanisms indicated that BCA inhibited the signalling pathways of mitogen‐activated protein kinase (P38, extracellular signal‐regulated kinase, and c‐JUN N‐terminal kinase) and nuclear factor‐κB (inhibitor κB‐α and P65), thereby downregulating the expression of nuclear factor of activated T cell 1 and c‐Fos. In conclusion, BCA may be an alternative choice for the prevention of prosthetic loosening caused by OCs.     

Insect antibacterial proteins: not just for insects and against bacteria.

In response to a bacterial infection, insects launch an array of countermeasures. Among these are the antibacterial proteins, which effectively lyse bacteria or are bacteriostatic. These proteins were generally assumed to be restricted to insects, yet recent information has shown some homologous counterparts in vertebrates, including humans. Recent data have revealed that at least some of these proteins can also act against eukaryotic cells, including human infectious parasites. The latter activities have opened up new possibilities for disease control.     

Atypical B cells are part of an alternative lineage of B cells that participates in responses to vaccination and infection in humans

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PfSPZ-CVac efficacy against malaria increases from 0% to 75% when administered in the absence of erythrocyte stage parasitemia: A randomized,placebo-controlled trial with controlled human malaria infection

PfSPZ-CVac combines ‘PfSPZ Challenge’, which consists of infectious Plasmodium falciparum sporozoites (PfSPZ), with concurrent antimalarial chemoprophylaxis. In a previously-published PfSPZ-CVac study, three doses of 5.12x10⁴ PfSPZ-CVac given 28 days apart had 100% vaccine efficacy (VE) against controlled human malaria infection (CHMI) 10 weeks after the last immunization, while the same dose given as three injections five days apart had 63% VE. Here, we conducted a dose escalation trial of similarly condensed schedules. Of the groups proceeding to CHMI, the first study group received three direct venous inoculations (DVIs) of a dose of 5.12x10⁴ PfSPZ-CVac seven days apart and the next full dose group received three DVIs of a higher dose of 1.024x10⁵ PfSPZ-CVac five days apart. CHMI (3.2x10³ PfSPZ Challenge) was performed by DVI 10 weeks after the last vaccination. In both CHMI groups, transient parasitemia occurred starting seven days after each vaccination. For the seven-day interval group, the second and third vaccinations were therefore administered coincident with parasitemia from the prior vaccination. Parasitemia was associated with systemic symptoms which were severe in 25% of subjects. VE in the seven-day group was 0% (7/7 infected) and in the higher-dose, five-day group was 75% (2/8 infected). Thus, the same dose of PfSPZ-CVac previously associated with 63% VE when given on a five-day schedule in the prior study had zero VE here when given on a seven-day schedule, while a double dose given on a five-day schedule here achieved 75% VE. The relative contributions of the five-day schedule and/or the higher dose to improved VE warrant further investigation. It is notable that administration of PfSPZ-CVac on a schedule where vaccine administration coincided with blood-stage parasitemia was associated with an absence of sterile protective immunity.Clinical trials registration: {"type":"clinical-trial","attrs":{"text":"NCT02773979","term_id":"NCT02773979"}}NCT02773979.     

Canalization and adaptation in a landscape of sources and sinks

Landscapes are often spatially heterogeneous, and many species frequently confront novel environments to which they are not adapted. Whether a species becomes adapted to a novel environment, and thus undergoes niche evolution, may depend not only on the genetic architecture of the traits under selection, but also on the structure of the ecological landscape. Different models of gene architecture are used to show that complex genetic architectures tends to produce genetic canalization that slows adaptation to novel environments compared to simpler additive polygenic architectures, but that the topology of the landscape interacts with genetic architecture to influence the probability of adaptation. This interaction can lead to unexpected results, such as a greater probability of adaptation to a novel environment for a population of more highly canalized individuals than a population of less canalized individuals. The interplay between landscape structure and genetic architecture may influence the balance of evolutionary forces acting on a population, and thus whether a species is likely to adapt to the novel environments it confronts.     

Controlled In Situ Seed-Mediated Growth of Gold and Silver Nanoparticles on an Optical Fiber Platform for Plasmonic Sensing Applications

Plasmonics - This study presents an in situ growth technique to develop highly sensitive plasmonic fiber optic sensors with an excellent control over the plasmonic properties of gold (AuNPs) and...     

Thoracic splenosis. Diagnosis of a case by fine needle aspiration cytology

Fine needle aspiration cytology was used to study chest wall nodules in a patient who presented with fever, cough, pleuritic chest pain and cytomegalovirus infection and who had a previous history of abdominal trauma. The finding of splenic red pulp and white pulp in the aspirate, combined with the results of a radionucleotide liver-spleen scan, led to a diagnosis of thoracic splenosis, a relatively rare condition. Splenosis is thought to result from transplantation of splenic tissue after trauma and may provide some added protection against certain infectious conditions, both of which were present in this case.