Chaos–order transition in foraging behavior of ants

The study of the foraging behavior of group animals (especially ants) is of practical ecological importance, but it also contributes to the development of widely applicable optimization problem-solving techniques. Biologists have discovered that single ants exhibit low-dimensional deterministic-chaotic activities. However, the influences of the nest, ants’ physical abilities, and ants’ knowledge (or experience) on foraging behavior have received relatively little attention in studies of the collective behavior of ants. This paper provides new insights into basic mechanisms of effective foraging for social insects or group animals that have a home. We propose that the whole foraging process of ants is controlled by three successive strategies: hunting, homing, and path building. A mathematical model is developed to study this complex scheme. We show that the transition from chaotic to periodic regimes observed in our model results from an optimization scheme for group animals with a home. According to our investigation, the behavior of such insects is not represented by random but rather deterministic walks (as generated by deterministic dynamical systems, e.g., by maps) in a random environment: the animals use their intelligence and experience to guide them. The more knowledge an ant has, the higher its foraging efficiency is. When young insects join the collective to forage with old and middle-aged ants, it benefits the whole colony in the long run. The resulting strategy can even be optimal.Both experimental data analysis and mathematical modeling on the foraging behavior of group animals (especially ant colonies) have recently captured much attention due to the high level of self-organizing structures that emerge at the collective level (1–5). Random walking is a widely discussed strategy in the research literature on the foraging behavior of group animals (2, 6–8). Some ecologists maintain that especially Lévy flight schemes can appropriately be used to describe the foraging behavior (6, 7). However, some recent studies have raised doubts whether this is a valid conjecture (2, 8, 9). It is even argued that the rules of locomotion for a walker are always consistent with a purely deterministic model, rather than with a stochastic scheme (9, 10).On the other hand, in the studies on the foraging behavior of animals, the existence of homes has so far received relatively little attention. Here we argue that the existence of a home or nest influences the foraging process to a large extent. Animals are due to return to their homes because of increasing exhaustion of energy. Moreover each foraging process of an animal is also a learning process. With foraging repetition, long-term memory continues to accumulate, an animal’s knowledge about the environment of its nest gets richer, and the region that the animal is familiar with continues to enlarge. Moreover, animals’ physical ability and knowledge as determined by their age directly influence their foraging strategy. All these factors deserve close attention.There is already a rich history of research on the foraging behavior of ant colonies (see, e.g., ref. 11). In particular foraging strategies of ants were discussed in the context of solving distributed control and optimization problems. Already 30 y ago, it was proposed that Lévy flights might characterize the behavior of foraging ants (12). In 1990, Deneubourg et al. designed a well-known wide binary bridge experiment which showed that ants could mark the path followed by a trail of pheromone and find an optimal path between the nest and the food source (13). Based on similar experiments, Dorigo and coworkers (3) developed ant colony optimization algorithms which have been used for solving various difficult problems, including combinatorial optimization, object clustering, and routing selection in communication networks. A limited binary bridge experiment was presented to show that ants could even form two lanes to solve traffic flow problems on crowded branches (4).However, all these experiments were conducted in special man-designed environments, which were not identical to natural ones, so the ants’ free crawling was restricted. It was argued that unrestricted foraging ants might not perform Lévy flights. Moreover, through an experimental study on the dynamical behaviors of an isolated ant and a whole ant colony, Cole (14) discovered that the activity of an ant colony exhibited periodic behavior, whereas the behavior of a single ant showed a low-dimensional deterministic chaotic pattern. In 1993, Solé et al. (15) constructed a 1D chaotic map following Cole to describe the foraging process of an isolated ant. Nemes and Roska (16) designed a cellular neural network model to describe the synchronized oscillating pattern of activity as a result of an array of chaotic dynamic elements placed in a regular 2D grid. In 2006, Li and coworkers (17, 18) developed a chaotic ant swarm model building on Cole’s research to describe the phenomenon that the chaotic behavior of a single ant contributes to the self-organization behavior of a whole ant colony. These models have explained some relationships between the chaotic (or random) strategy, individual dynamics, and group dynamics. However, these studies ignored the possibility that the ants also use their own experience and intelligence to guide their foraging. Hence, further studies on the influences of physical ability, age, and knowledge on foraging behavior are needed to explain the biological behavior of ants in nature.The aim of this paper is to provide a novel perspective on mechanisms of effective foraging of ant colonies. We assume that the foraging process of these animals is entirely controlled by three successive strategies: hunting, homing, and path building. A mathematical model is developed to understand the whole foraging process. We discuss the influences of the special region around the nest, the size of the food source, the search range, the limitation of ants’ physical ability, and ants’ learning process with respect to foraging behavior. Our analysis suggests that group animals that have a home do not perform random walks, but rather deterministic walks in a random environment. They use their knowledge to guide them and their behavior is also influenced by their physical abilities, their age, and the existence of homes.     

Clinical Efficacy of L-Ornithine–L-Aspartate in the Management of Hepatic Encephalopathy

The clinical efficacy of both oral and parenteral L-ornithine–L-aspartate (OA) was confirmed by randomized, placebo-controlled, double-blind studies in patients with manifest hepatic encephalopathy and hyperammonemia. The drug was able to reduce high blood ammonia levels induced either by ammonium chloride or protein ingestion or existing as a clinical complication of cirrhosis per se. Furthermore, OA improved performance in Number Connection Test-A as well as mental state gradation. In contrast to the positive effects observed in patients with more advanced hepatic encephalopathy, oral OA does not seem to affect minimal hepatic encephalopathy. In a recent trial, OA decreased protein breakdown and stimulated protein synthesis in muscle. The therapy had little side effects, increasing with higher intravenously administered dosages, and was well tolerated after oral and parenteral administration.     

Attachment of phycobilisomes in an antenna–photosystem I supercomplex of cyanobacteria

Oxygenic photosynthesis is driven by photosystems I and II (PSI and PSII, respectively). Both have specific antenna complexes and the phycobilisome (PBS) is the major antenna protein complex in cyanobacteria, typically consisting of a core from which several rod-like subcomplexes protrude. PBS preferentially transfers light energy to PSII, whereas a PSI-specific antenna has not been identified. The cyanobacterium Anabaena sp. PCC 7120 has rod–core linker genes (cpcG1-cpcG2-cpcG3-cpcG4). Their products, except CpcG3, have been detected in the conventional PBS. Here we report the isolation of a supercomplex that comprises a PSI tetramer and a second, unique type of a PBS, specific to PSI. This rod-shaped PBS includes phycocyanin (PC) and CpcG3 (hereafter renamed “CpcL”), but no allophycocyanin or CpcGs. Fluorescence excitation showed efficient energy transfer from PBS to PSI. The supercomplex was analyzed by electron microscopy and single-particle averaging. In the supercomplex, one to three rod-shaped CpcL–PBSs associate to a tetrameric PSI complex. They are mostly composed of two hexameric PC units and bind at the periphery of PSI, at the interfaces of two monomers. Structural modeling indicates, based on 2D projection maps, how the PsaI, PsaL, and PsaM subunits link PSI monomers into dimers and into a rhombically shaped tetramer or “pseudotetramer.” The 3D model further shows where PBSs associate with the large subunits PsaA and PsaB of PSI. It is proposed that the alternative form of CpcL–PBS is functional in harvesting energy in a wide number of cyanobacteria, partially to facilitate the involvement of PSI in nitrogen fixation.In photosynthesis, light-harvesting antennas are essential to efficiently collect solar energy. Photosynthetic organisms have diverse antenna protein-pigment complexes, which are specifically associated with photosystems I or II (PSI or PSII, respectively) (1). Light-harvesting chlorophyll a/b-binding proteins form the peripheral antenna of PSI or PSII in green plants (2) and light-harvesting chlorophyll a/c-binding proteins are present in brown algae and related organisms (3, 4). In cyanobacteria the phycobilisome (PBS) serves as a major antenna for PSII. No specific antenna has been isolated for PSI in cyanobacteria, although PBS transfers light energy to PSI under conditions of state transition (5), a temporal energy redistribution mechanism between PSII and PSI (6, 7).Generally, the PBS is a supercomplex of rod and core subcomplexes, which consist of various phycobilin-binding proteins connected by several classes of colorless linker proteins (8). Whereas phycocyanin (PC) is the major phycobiliprotein of the rod, allophycocyanin (APC) is the major phycobiliprotein of the core cylinders. The rod–core linker cyanobacterial phycocyanin protein G (CpcG), which connects the rod to the core, plays a key role in the assembly of the PBS (9). The chromosome of the filamentous, N₂-fixing cyanobacterium Anabaena sp. PCC 7120 (hereafter “Anabaena”) bears tandem repeats of rod–core linker genes (cpcG1-cpcG2-cpcG3-cpcG4). Except for CpcG3, the products of these genes have been detected in the PBS (10–13). Only cpcG3 encodes a hydrophobic region at the C terminus, although all four copies share the sequence for the highly conserved N-terminal linker domain (Fig. S1). Given the distinct role of the hydrophobic CpcG variant protein in docking to PSI as shown in this article, the hydrophobic CpcG is hereafter renamed “CpcL.”In this study, a supercomplex comprising PSI and its specific antenna was isolated from Anabaena and biochemically and structurally characterized. We found that within the supercomplex, PSI is organized into tetramers, which were previously suggested from biochemical data (14). Single-particle electron microscopy (EM) shows that in fact they are structurally organized as a dimer of dimers. In addition, we describe a specific association of CpcL–PBS rods with the PSI pseudotetramers and discuss the role of these unique supercomplexes.     

Effects of intravenous administration of pentoxifylline in pancreatic ischaemia–reperfusion injury

Background

Therapeutic strategies to reduce the occurrence of pancreatic ischaemia–reperfusion (I–R) injury might improve outcomes in human pancreas and kidney transplantation. In addition to its haemorrheologic effects, pentoxifylline has an anti-inflammatory effect by inhibiting NF-κB activation. This group has previously demonstrated that pentoxifylline induces an anti-inflammatory response in acute pancreatitis and liver I–R models. This led to the hypothesis that pentoxifylline might reduce pancreatic and renal lesions and the systemic inflammatory response in pancreatic I–R injury. The aim of this experimental study was to evaluate the effect of pentoxifylline administration in a rat model of pancreatic I–R injury.

Methods

Pancreatic I–R was performed in Wistar rats over 1 h by clamping the splenic vessels. The animals submitted to I–R were divided into two groups: Group 1 (n = 20, control) rats received saline solution administered i.v. at 45 min after ischaemia, and Group 2 (n = 20) rats received pentoxifylline (25 mg/kg) administered i.v. at 45 min after ischaemia. Blood samples were collected to enable the determination of amylase, creatinine, tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6) and IL-10. Pancreatic malondialdehyde (MDA) content, pancreas histology and pulmonary myeloperoxidase (MPO) were also assessed.

Results

Significant reductions in serum TNF-α, IL-6 and IL-10 were observed in Group 2 compared with Group 1 (P < 0.05). No differences in pancreatic MDA content or serum amylase levels were observed between the two groups. The histologic score was significantly lower in pentoxifylline-treated animals, denoting less severe pancreatic histologic damage.

Conclusions

Pentoxifylline administration reduced the systemic inflammatory response, the pancreatic histological lesion and renal dysfunction in pancreatic I–R injury and may be a useful tool in pancreas and kidney transplantation.     

Prevalence of syphilis seropositivity in antenatal clinic clients in a teaching hospital in South–South region of Nigeria

ObjectiveTo assess the seroprevalence of syphilis among women receiving antenatal care in University of Uyo Teaching Hospital (UUTH), Uyo, Akwa Ibom State, Nigeria.MethodsBetween July 2009 to March 2010, blood samples of 415 consenting clients submitted for prevention of mother to child transmission (PMTCT) HIV screening programme were screened for syphilis antibodies using the Immunochromatographic ACON Ultra Rapid Syphilis Test Strip (ACON laboratory Inc. USA). Any positive result was repeated with another test strip (Diaspot Ultra Rapid Syphilis Test Strip, Diaspot Inc. USA).ResultsOf the 415 samples, 9 (2.2%) were syphilis seropositive and 14 (3.4%) were HIV positive. Assessment of risk factors for syphilis revealed an observed trend with increasing parity though statistically not significant (P=0.268). More than half of the syphilis positive clients believed their spouses were promiscuous.ConclusionsThere is still a substantial carriage of syphilis among antenatal clinic attendees in UUTH, Uyo. The need for routine screening is imperative. Point of care testing should conveniently be incorporated into the PMTCT programme.     

Mechanism of Anemia in Schistosoma mansoni–Infected School Children in Western Kenya

A better understanding of the mechanism of anemia associated with Schistosoma mansoni infection might provide useful information on how treatment programs are implemented to minimize schistosomiasis-associated morbidity and maximize treatment impact. We used a cross-sectional study with serum samples from 206 Kenyan school children to determine the mechanisms in S. mansoni-associated anemia. Serum ferritin and soluble transferrin receptor levels were measured by using an enzyme-linked immunosorbent assay. Results suggest that S. mansoni-infected persons are more likely (odds ratio = 3.68, 95% confidence interval = 1.33–10.1) to have levels of serum ferritin (> 100 ng/mL) that are associated with anemia of inflammation (AI) than S. mansoni-uninfected children. Our results suggest that AI is the most common form of anemia in S. mansoni infections. In contrast, the mechanism of anemia in S. mansoni-uninfected children was iron deficiency. Moreover, the prevalence of AI in the study participants demonstrated a significant trend with S. mansoni infection intensity (P < 0.001). Our results are consistent with those observed in S. japonicum-associated anemia.     

Prospective Evaluation of Quality of Life in Patients with Zollinger–Ellison Syndrome

Background  

Zollinger–Ellison syndrome (ZES) is associated with complicated ulcer disease of the upper gastrointestinal tract. While management of ZES has dramatically improved with proton pump inhibitor therapy, quality of life in medically treated patients has not been evaluated.     

Pathophysiology of cardiorenal syndrome in decompensated heart failure: Role of lung–right heart–kidney interaction

Cardiorenal syndrome (CRS) is defined as an interaction of cardiac disease with renal dysfunction that leads to diuretic resistance and renal function worsening, mainly with heart failure (HF) exacerbation.     

Utility of Atherosclerosis Imaging in the Evaluation of High-Density Lipoprotein–Raising Therapies

Decreased level of high density-lipoprotein cholesterol (HDL-C) is a rigorous predictor for future cardiovascular events. Much effort is being made to develop HDL-C–raising pharmacotherapies in the attempt to avert the pandemic of atherosclerotic disease. Important properties by which HDL-C–raising compounds are effective involve improvement of cholesterol uptake from macrophages in plaque for transport back to the liver, improvement of endothelial function, and anti-inflammatory effects. Vascular imaging can aid in the determination which HDL-C–raising compounds are effective. Ultrasound and MRI have proved suitable for assessment of structural changes of the vessel wall. Ultrasound can also be used or assessment of endothelial function. 18F-fluordeoxyglucose positron emission tomography has opened up the possibility to assess vessel wall inflammation. In this article we discuss these various imaging techniques and how they can assess efficacy as well as provide pathophysiologic information on the mechanism of action of novel HDL-C–raising drugs.     

Somatostatin–dopamine ligands in the treatment of pituitary adenomas

Somatostatin receptors (sst1–5) and dopamine receptor 2 (D2DR) are well expressed and co-localized in several human pituitary adenomas, suggesting possible functional interactions in the control of hormonal hypersecretion and tumor cell growth. The present review describes the expression and functionality of these receptors in the different classes of human pituitary adenomas. The sst2 agonists, octreotide and lanreotide, control GH hypersecretion and tumor growth in about 65% of somatotropinomas. The D2DR agonists, bromocriptine and cabergoline, control about 90% of prolactinomas. Such drugs are much less effective in the control of the others pituitary adenomas also expressing ssts and D2DR receptors. The second part summarizes the current knowledge on new chimeric compounds with sst2, sst5, and D2DR affinity. Such ligands bearing distinct ssts and DRD2 pharmacophores may synergistically produce an increased control of secretion and/or of proliferation in the different types of pituitary adenomas. The mechanisms of action of such chimeric molecules through increased binding affinities, prolonged bioavailability, ligand-induced modulation of receptors heterodimerization, are discussed.     

Role of the kallikrein–kinin system in the maturation of cardiovascular phenotype

Recent studies indicate that during early phases of life the kallikrein–kinin system (KKS) plays a role in kidney development. In the rat kidney, the spatial and temporal pattern of expression of the genes encoding for kallikrein or bradykinin (BK) B₂-receptors parallels postnatal nephrogenesis and blood flow redistribution from the inner to the outer renal cortex. Animal models with genetic dysfunction of the renal KKS show alterations in the functional maturation of the kidney, and ultimately develop salt-sensitive hypertension. Kininogen-deficient Brown Norway Katholiek rats have undetectable urinary kinin levels and show an exaggerated blood pressure sensitivity to chronic excess of salt or mineralocorticoids. Another rat model with genetic reduction in urinary kallikrein excretion is characterized by an altered pressure–natriuresis relationship, with this defect being corrected by infusion of purified rat tissue kallikrein. Knockout mice lacking the BK B₂-receptor gene show elevated blood pressure and heart rate under basal conditions and enhanced blood pressure sensitivity to salt. In rats, prenatal blockade of the BK B₂-receptor by icatibant leads to a cardiovascular phenotype similar to that of animals with genetic defects of the KKS. Delayed renal maturation is observed when high salt intake is associated with icatibant. Collectively, these findings indicate a relevant role of the KKS in the physiologic maturation of renal and cardiovascular phenotypes. Genetic or environmental factors, able to potentiate the activity of the renal KKS, could protect against the development of arterial hypertension.     

Cost-effectiveness of oral appliances in the treatment of obstructive sleep apnoea–hypopnoea

Purpose  Oral appliances (OA) are commonly prescribed for the treatment of obstructive sleep apnoea–hypopnoea (OSAH), but there is limited evidence on their cost-effectiveness. Materials and methods  A model was designed to simulate the costs and benefits of treatment of OSAH with OA or continuous positive airway pressure (CPAP) based on their effects on quality of life, motor vehicle crashes, and cardiovascular effects. The primary outcome was the incremental cost-effectiveness ratio (ICER) in terms of costs per one quality-adjusted life year (QALY) gained 5 years after treatment. Results  Compared with no treatment, OA results in $268 higher costs and an incremental QALY of 0.0899 per patient (ICER = $2,984/QALY). Compared with OA, CPAP resulted in $1,917 more costs and 0.0696 additional QALYs (ICER = $27,540/QALY). For the most part in the sensitivity analyses, CPAP remained cost-effective compared to OA, and OA remained cost-effective with respect to no treatment in almost all scenarios. Conclusions  OAs are less economically attractive than CPAP but remain a cost-effective treatment for patients who are unwilling or unable to adhere to CPAP therapy.     

Origins of specificity and affinity in antibody–protein interactions

Natural antibodies are frequently elicited to recognize diverse protein surfaces, where the sequence features of the epitopes are frequently indistinguishable from those of nonepitope protein surfaces. It is not clearly understood how the paratopes are able to recognize sequence-wise featureless epitopes and how a natural antibody repertoire with limited variants can recognize seemingly unlimited protein antigens foreign to the host immune system. In this work, computational methods were used to predict the functional paratopes with the 3D antibody variable domain structure as input. The predicted functional paratopes were reasonably validated by the hot spot residues known from experimental alanine scanning measurements. The functional paratope (hot spot) predictions on a set of 111 antibody–antigen complex structures indicate that aromatic, mostly tyrosyl, side chains constitute the major part of the predicted functional paratopes, with short-chain hydrophilic residues forming the minor portion of the predicted functional paratopes. These aromatic side chains interact mostly with the epitope main chain atoms and side-chain carbons. The functional paratopes are surrounded by favorable polar atomistic contacts in the structural paratope–epitope interfaces; more that 80% these polar contacts are electrostatically favorable and about 40% of these polar contacts form direct hydrogen bonds across the interfaces. These results indicate that a limited repertoire of antibodies bearing paratopes with diverse structural contours enriched with aromatic side chains among short-chain hydrophilic residues can recognize all sorts of protein surfaces, because the determinants for antibody recognition are common physicochemical features ubiquitously distributed over all protein surfaces.It is incompletely understood as to how functional antibodies can almost always be elicited against unlimited possibilities of protein antigens from a limited repertoire of antibodies. Antibodies provide protection against foreign protein antigens by recognizing the antigen proteins with exquisite specificity and remarkable affinity, but the principles underlying the antibody affinity and specificity remain elusive. Consequently, current antibody discoveries are by and large limited by the uncontrollable animal immune systems (1) or by the recombinant antibody libraries with relatively infinitesimal coverage of the vast combinatorial sequence space in antibody–antigen interaction interfaces (2). In developing the efficacy of a therapeutic antibody, optimizing the affinity and specificity of the antibody–antigen interaction mostly relies on selecting and screening from a large pool of random candidates. As antibodies are becoming the most prominent class of protein therapeutics (3), a better understanding of the principles governing antibody affinity and specificity will facilitate in understanding humoral immunity and in developing novel antibody-based therapeutics.Antibody paratopes are enriched with aromatic residues. Tyrosyl side chains are overpopulated on the paratopes, noticeable on solving the first structures of antibody–antigen complexes (4). Surveys thereafter showed that Tyr and Trp frequently occur in the putative binding regions of antibodies as determined from structural and sequence data (5). Recent analyses of more than 100 high-resolution antibody–antigen complexes in the Protein Data Bank (PDB) confirm a similar conclusion that aromatic residues (Tyr, Trp, and Phe) are substantially enriched in antibody paratopes (6, 7). The fundamental role of the tyrosyl side chains in antibody–antigen recognition has been demonstrated (8), with the functional antibodies selected and screened from the minimalist designs of antibody complementarity determining region (CDR) libraries with only a small subset of amino acid types (Tyr, Ala, Asp, and Ser) (9) or with binary code (Tyr and Ser) (10).Interactions involving aromatic side chains on the CDRs of antibodies with epitope residues on protein antigens have been demonstrated to contribute energetically to antibody–antigen recognition. Alanine scanning of the antibody paratope residues of the FvD1.3-hen egg white lysozyme (HEL) and FvD1.3-FvE5.2 (anti-idiotype antibody) complexes and shotgun alanine scanning assessing the energetic contributions of paratope residues to VEGF and human epidermal growth factor receptor 2 (HER2) binding indicated that around half of the hot spots (ΔΔG ≥ 1 kcal/mol) are aromatic residues (20/40) (11, 12). Double-mutant cycle experiments dissecting the residue-pair coupling energies between the epitope and paratope for the two antibody–antigen complexes also indicated the predominant energetic contribution of the aromatic side chains (9/11) in the antibody–antigen interactions (13). These energetic assessments suggest that aromatic side chains contribute a substantial portion of the affinity of the antibody–antigen complexes in general. These results are consistent with the survey indicating that aromatic residues, in particular Tyr and Trp, account for a large portion of the hot spot residues in protein–protein interactions (14, 15).Aromatic side chains interact favorably with diverse functional groups in natural amino acids, underlying the affinity and specificity of the antibody–antigen recognition through a cumulative collection of relatively weak noncovalent interactions. The aromatic side chains interact with other aromatic side chains through face-to-edge or parallel π-stacking, with positively charged side chains through the cation–π interaction, with backbone and side-chain hydrogen bond donors through hydrogen bonding to aromatic π-systems (X–H–π interaction, X = N, O, S), with alkyl carbons through the C–H–π interaction, with sulfur-containing side chains through sulfur–arene interactions, and with negative charged side chains through anion–π interactions (16, 17). Although each of the above mentioned interactions is relatively weak, on the order of a few kilocalories per mole in model systems (16, 17), the cumulative sum of the interactions involving the aromatic side chains can reasonably account for the binding energy of 12 kcal/mol for a typical antibody–antigen interaction of K_d ∼1 nM at room temperature aqueous environment. Moreover, the specific preferences of the spatial geometries for the interacting functional groups involving aromatic side chains (see refs. 16–18 and references therein) also underlie the specificity of antibody–antigen recognitions. Direct hydrogen bonds bridging across the antibody–antigen interaction interface are expected to contribute to both the binding affinity and specificity, but the removal of an interface hydrogen bond is frequently inconsequential to the binding specificity and affinity due to compensating water-mediated interactions (13). These results suggest that the 3D distribution of the paratope aromatic side chains by and large determines the affinity and specificity of the antibody–antigen interaction.Known epitopes on antigens, on the other hand, are not easily distinguishable from the solvent accessible surfaces of protein structures. A recent review of the public domain conformational epitope prediction algorithms, for which the performances were compared with an independent test set for benchmarking, shows that the conformational epitope prediction problem remain challenging, with an area under the curve (AUC) ranging from 0.567 to 0.638 and accuracy from 15.5% to 25.6% (19). This moderate success rate was attributed to incomplete understanding of the essence of the epitopes (6). It has been well accepted that the solvent accessible and protruding surface regions are more likely to be conformational epitopes (20–23) and that the epitopes encompass substantially more loop residues than α-helix and β-strand residues (23, 24). By contrast, the conclusions from various studies on the amino acid composition of conformational epitopes are not consistent (6), in large part due to the fact that the epitope amino acid composition is not particularly distinguishable from the nonantigenic solvent accessible surface area (6, 7, 22, 23, 25). The contradiction has been discussed recently (25), indicating that the physicochemical complementarity between the paratopes and the epitopes are strikingly incomparable, with overwhelmingly emphasized tyrosyl side chains in all CDR loops (25).The goal of this work is to understand how a natural repertoire of antibodies, for which the sequence and structure are relatively limited in variation, can recognize protein antigens with seemly unlimited structural and sequence diversities. An extensive examination on the monoclonal antibodies elicited with a set of model antigens has concluded that a protein antigen surface consists of overlapping conformational epitopes forming a continuum; that is, no inherent property of the protein molecule could restrict antigenic site locations on the protein surface (26). It would be conceivable that antibodies recognize a common feature shared by all protein surface sites, and as such, a relatively limited population of antibodies could recognize limitless protein antigen surfaces. That is, protein surfaces are not as diverse as one would expect by looking at the protein sequences. However, this common feature on protein surface recognizable by antibodies is not known. Although aromatic side chains are known, in principle, to be able to interact favorably with wide varieties of functional groups in natural amino acids (see above), atomic details of the paratope aromatic side chains interacting favorably with diverse epitope surfaces have not been systematically analyzed. In addition, residues with short hydrophilic side chains (Ser, Thr, Asp, and Asn) are known to be enriched alongside the aromatic side chains in the paratopes (5, 24, 27), but the roles of these short hydrophilic side chains in antibody–antigen interactions have not been systematically investigated. More importantly, it has been well accepted that only hot spot residues in an antigen combining site of an antibody, i.e., the residues in the functional paratopes, are indispensable for the antibody–antigen interaction; side chains contacting the antigen (i.e., structural paratope residues) outside the functional paratope can frequently be truncated to Cβ carbon without affecting the antibody–antigen interaction (11, 13, 15, 28). To search for the relevant protein surface features recognizable by antibodies, it is desirable to first elucidate the principles governing the interactions for the functional paratopes with the corresponding functional epitopes. Such studies require a large number of well-defined functional paratopes and functional epitopes, but only a small number have been determined with the labor-intensive alanine scanning experiment (11–13, 29). To circumvent the scarcity of the experimental data, we use computational methods to predict the functional paratopes/epitopes in antibody–protein complex structures so that the key interactions involving the hot spots in the antibody–protein interactions can be elucidated, at least to the reliable extent depending on the functional paratope prediction accuracy.In this work, we applied computational methods to predict functional paratopes on antibody variable domains and analyzed the key atomistic contact pairs in the functional paratope–epitope interfaces. Although the structural paratope–epitope interfaces can be defined from the known complex structures, the functional binding interfaces involving hot spot residues are unknown experimentally and need to be defined with computational predictions. One set of predictions was carried out with our previously published computational method [In-silico Molecular Biology Lab–protein-protein interaction (ISMBLab-PPI)], where the protein–protein interaction confidence level (PPI_CL) for protein surface atoms to participate in protein–protein interaction is strongly correlated (r² = 0.99) with the averaged burial level of the atoms in the PPI interfaces (30). Another set of predictions was carried out with a recently published random forest algorithm, prediction of antibody contacts (proABC) (31), which was trained specifically with antibody–antigen complex structures in PDB with additional information from antibody germ-line family sequences, CDR residue positions, multiple antibody sequence alignments, CDR lengths and canonical structures, and antigen volume. Both sets of predicted functional paratope–epitope interfaces consistently led to the conclusion that antibodies, with relatively limited sequence and structural diversities in the antigen binding sites, can recognize unlimited protein antigens through recognizing the common and ubiquitous physicochemical features on all protein surfaces. The implication is that a limited repertoire of antibodies bearing paratopes with diverse structural contours enriched with aromatic side chains among short-chain hydrophilic residues can recognize all sorts of protein surfaces.     

Clinico–epidemiological features of dengue fever in Saudi Arabia

ObjectiveTo highlight some clinical and epidemiological features of dengue fever.MethodsAll patients who were admitted to hospitals in Holly Mecca City, Saudi Arabia and were confirmed as dengue fever (DF) or dengue hemorrhagic fever (DHF) were included in this study. The data were collected from patient files and through direct interview with patients or their relatives. Cases were followed through their hospital stay. Routine laboratory investigations were done and diagnosis was confirmed by PCR.ResultsMost of cases admitted in stable condition (94.37%) and only one case (1.41%) died. Dengue-1 and 3 types were the prevalent dengue viruses and cases in age group 16-44 were the most frequent (70.40%). The most common symptoms was fever reported from all cases followed by headache (74.60%), myalgia and anorexia (67.60%), back pain (59.20%) and chills (54.90%). DF represented (60.57%) of the cases while DHF represented (39.43%). About half of cases had underground water tanks for human use, 5.60% had over house roof water tanks and 43.70% had both types, 16.90% of these tanks were uncovered. Approximately 70.00% of cases reported presence of small collection of water nearby houses and 46.80% reported the presence of mosquitoes within their houses.ConclusionsMost dengue fever cases might be endogenous in origin due to prevalence of mosquitoes and their breeding places within the houses and in nearby localities. Control of mosquitoes and their breeding places will contribute to prevention of dengue fever.     

Left–right dissociation of hippocampal memory processes in mice

Left–right asymmetries have likely evolved to make optimal use of bilaterian nervous systems; however, little is known about the synaptic and circuit mechanisms that support divergence of function between equivalent structures in each hemisphere. Here we examined whether lateralized hippocampal memory processing is present in mice, where hemispheric asymmetry at the CA3–CA1 pyramidal neuron synapse has recently been demonstrated, with different spine morphology, glutamate receptor content, and synaptic plasticity, depending on whether afferents originate in the left or right CA3. To address this question, we used optogenetics to acutely silence CA3 pyramidal neurons in either the left or right dorsal hippocampus while mice performed hippocampus-dependent memory tasks. We found that unilateral silencing of either the left or right CA3 was sufficient to impair short-term memory. However, a striking asymmetry emerged in long-term memory, wherein only left CA3 silencing impaired performance on an associative spatial long-term memory task, whereas right CA3 silencing had no effect. To explore whether synaptic properties intrinsic to the hippocampus might contribute to this left–right behavioral asymmetry, we investigated the expression of hippocampal long-term potentiation. Following the induction of long-term potentiation by high-frequency electrical stimulation, synapses between CA3 and CA1 pyramidal neurons were strengthened only when presynaptic input originated in the left CA3, confirming an asymmetry in synaptic properties. The dissociation of hippocampal long-term memory function between hemispheres suggests that memory is routed via distinct left–right pathways within the mouse hippocampus, and provides a promising approach to help elucidate the synaptic basis of long-term memory.Unilateral specializations may facilitate greater processing power in bilateral brain structures by using the available neuronal circuitry more effectively. Nevertheless, the nature of the mechanisms that can act within the confines of duplicate neural structures to support different cognitive functions in each hemisphere remains elusive.The hippocampus is essential for certain forms of learning and memory, both in humans (1) and in rodents (2, 3), and also plays an important role in navigation (4). The left and right mammalian hippocampi comprise the same anatomical areas and directional connectivity, and yet in the human hippocampus, task-related activity may be localized to only one hemisphere (5). This lateralization may enable the left and right hippocampus to support complementary functions in human episodic memory, with left hippocampal activity associated with an egocentric, sequential representation of space but greater activity in the right hippocampus when an allocentric representation is used (6). It has been suggested that human hippocampal asymmetry is primarily dictated by external asymmetry—namely, the left hemispheric involvement in language processing and the stronger contribution of the right hemisphere to visuospatial attention (7), supported by observations of left hippocampal dominance when semantic information is most task-relevant, compared with right hippocampal dominance when spatial information becomes more pertinent (8). However, a seminal discovery in the mouse brain suggests that left–right asymmetry may actually be a fundamental property of the mammalian hippocampus: it was found that the postsynaptic spine morphology and receptor distribution in CA1 pyramidal neurons is determined by whether the presynaptic input originates in the left or right CA3 (9, 10). Specifically, apical CA1 postsynaptic spines receiving input from the left CA3 are primarily thin and rich in GluN2B subunit-containing NMDA receptors (NMDARs); in contrast, there is a higher proportion of mushroom-shaped spines receiving right CA3 projection, and these larger spines have a lower density of GluN2B subunit-containing NMDARs (9, 10). Interestingly, synaptic plasticity also shows hemispheric asymmetry: irrespective of the hemispheric location of the CA1 neuron, GluN2B NMDAR-requiring spike timing-dependent long-term potentiation (LTP) was induced at synapses where presynaptic input originates in the left CA3, but not in the right CA3 (11).These left–right synaptic differences raise the question as to whether memory processing in mice, as in humans, might differ between the left and right hippocampus. Therefore, in this study, we asked whether acutely inactivating one part of the asymmetric CA3–CA1 network unilaterally would affect learning and memory differentially between hemispheres. To test this, we silenced excitatory cells of CA3 in either the left or the right hippocampus, and consequently also both their ipsilateral and contralateral projections to CA1, using the light-sensitive chloride pump halorhodopsin (eNpHR3.0) coexpressed with enhanced YFP (eYFP) (12).