D224V and S128Y mutation in FSHRED influence thumb movement differentially: An intricate insight gained by short-term molecular dynamics simulation

Follicle-stimulating hormone-follicle-stimulating hormone receptor (FSH-FSHR) interaction is one of the most thoroughly studied signaling pathways primarily because of being implicated in sexual reproduction in mammals by way of maintaining gonadal function and sexual fertility. Despite material advances in understanding the role of point mutations, their mechanistic basis in FSH-FSHR signaling is still confined to mystically altered behavior of sTYS335 (sulfated tyrosine) yet lacking a substantial theory. To understand the structural basis of receptor modulation, we choose two behaviorally contradicting mutations, namely S128Y (activating) and D224Y (inactivating), found in FSH receptor responsible for ovarian hyperstimulation syndrome and ovarian dysgenesis, respectively. Using short-term molecular dynamics simulations, the atomic scale investigations reveal that the binding pattern of sTYS with FSH and movement of the thumb region of FSHR show distinct contrasting patterns in the two mutants, which supposedly could be a critical factor for differential FSHR behavior in activating and inactivating mutations.     

An Ionic Current Model for Medullary Respiratory Neurons

Neurons of the mammalian medullary respiratory center have complex patterns of electrophysiological behavior. Three typical phenomena associated with these patterns are spike frequency adaptation (SFA), delayed excitation (DE), and postinhibitory rebound (PIR). Although several nuclei are associated with the medullary-pontine respiratory center, we focused on neurons from two nuclei: (1) the ventral subnucleus of the nucleus tractus solitarius (vNTS) of the dorsal respiratory group and (2) the nucleus ambiguus (NA) of the ventral respiratory group. We developed a Hodgkin-Huxley (HH) type model of the typical medullary neuron that is capable of mimicking the discharge pattern of real neurons to a very high degree. Closer examination of typical data revealed, however, that there was not one type of medullary respiratory neuron, but at least three (types A, B ₁, and B ₂). We classified these neurons based on the electrophysiologic phenomena that they exhibited (type A exhibits DE but not PIR; types B ₁ and B ₂ exhibit PIR but not DE; all types are adapting). Our objective was to relate each of these well-known phenomena to specific ionic current mechanisms. In the model, three currents directly affect the phenomena investigated: the Ca²⁺-activated K ⁺ current, I _K,Ca , controls peak and steady-state firing rates and the time constant of adaptation; the transient outward K ⁺ current, I _A, is responsible for all aspects of DE, including the dependence of delay on the magnitude and duration of conditioning hyperpolarization; and the hyperpolarization-activated current, I _h, elicits PIR and dictates its dependencies. We consider that our HH model represents a unifying structure, whereby different electrophysiological phenomena or discharge patterns can be emulated using different strengths of the component ionic membrane currents (particularly I _K,Ca , I _A, and I _h). Moreover, its predictions suggest that the electrophysiological characteristics of medullary respiratory neurons, from different areas of the brainstem and even from different species, can be modeled using the same structural framework, wherein the specific properties of individual neurons are emulated by adjusting the strengths of key ionic membrane currents in the model.     

A Framework for Automatic Adaptation of Tunable Distributed Applications

Increased platform heterogeneity and varying resource availability in distributed systems motivate the design of resource-aware applications, which ensure a desired performance level by continuously adapting their behavior to changing resource characteristics. In this paper, we describe an application-independent adaptation framework that simplifies the design of resource-aware applications. This framework eliminates the need for adaptation decisions to be explicitly programmed into the application by relying on two novel components: (1) a tunability interface, which exposes adaptation choices in the form of alternate application configurations while encapsulating core application functionality; and (2) a virtual execution environment, which emulates application execution under diverse resource availability enabling off-line collection of information about resulting behavior. Together, these components permit automatic run-time decisions on when to adapt by continuously monitoring resource conditions and application progress, and how to adapt by dynamically choosing an application configuration most appropriate for the prescribed user preference. We evaluate the framework using an interactive distributed image visualization application and a parallel image processing application. The framework permits automatic adaptation to changes in execution environment characteristics such as available network bandwidth or data arrival pattern by choosing a different application configuration that satisfies user preferences of output quality and timeliness.     

A quantitative model for metabolic intervention using gut microbes

As medicine shifts toward precision-based and personalized therapeutics, utilizing more complex biomolecules to treat increasingly difficult and rare conditions, microorganisms provide an avenue for realizing the production and processing necessary for novel drug pipelines. More so, probiotic microbes can be co-opted to deliver therapeutics by oral administration as living drugs, able to survive and safely transit the digestive tract. As living therapeutics are in their nascency, traditional pharmacokinetic–pharmacodynamic (PK–PD) models for evaluating drug candidates are not appropriate for this novel platform. Using a living therapeutic in late-stage clinical development for phenylketonuria (PKU) as a case study, we adapt traditional oral drug delivery models to properly evaluate and inform the engineering of living therapeutics. We develop the adapted for living therapeutics compartmental absorption and transit (ALT-CAT) model to provide metrics for drug efficacy across nine age groups of PKU patients and evaluate model parameters that are influenced by patient physiology, microbe selection and therapeutic production, and dosing formulations. In particular, the ALT-CAT model describes the mathematical framework to model the behavior of orally delivered engineered bacteria that act as living therapeutics by adapting similar methods that have been developed and widely-used for small molecular drug delivery and absorption.     

Primary observations on rutting behavior of the captive red goral

The rutting behavior of the red goral (Naemorhedus cranbrooki) was studied at the Breeding Center of Shanghai Zoo from September 16–November 21, 2004. Twenty‐three qualitatively distinct behavior patterns was observed. Males showed a more extensive repertoire (18 patterns, 15 carried out only by males) than did females (10 patterns, 6 carried out only by females). Smelling and licking behavior was used most by males, whereas escape was used most by females. Zoo Biol 0:1–7, 2006. © 2006 Wiley‐Liss, Inc.     

Kinetic Studies on the Inhibition of GABA-T by γ-Vinyl GABA and Taurine

γ-Aminobutyric acid transaminase (GABA-T, EC 2.6.1.19) is a pyridoxal phosphate (PLP) dependent enzyme that catalyzes the degradation of γ-aminobutyric acid. The kinetics of this reaction are studied in vitro, both in the absence, and in the presence of two inhibitors: γ-vinyl GABA (4-aminohex-5-enoic acid), and a natural product, taurine (ethylamine-2-sulfonic acid). A kinetic model that describes the transamination process is proposed. GABA-T from Pseudomonas fluorescens is inhibited by γ-vinyl GABA and taurine at concentrations of 51.0 and 78.5?mM. Both inhibitors show competitive inhibition behavior when GABA is the substrate and the inhibition constant (K_i) values for γ-vinyl GABA and taurine were found to be 26±3?mM and 68±7?mM respectively. The transamination process of α-ketoglutarate was not affected by the presence of γ-vinyl GABA, whereas, taurine was a noncompetitive inhibitor of GABA-T when α-ketoglutarate was the substrate. The inhibition dissociation constant (K_ii) for this system was found to be 96±10?mM. The Michaelis-Menten constant (K_m) in the absence of inhibition, was found to be 0.79±0.11?mM, and 0.47±0.10?mM for GABA and α-ketoglutarate respectively.     

Dual stimuli-responsive polypeptide prepared by thiol-ene click reaction of poly(l-cysteine) and N,N-dimethylaminoethyl acrylate

Stimuli-responsive polymers that can undergo conformational changes with external triggers have enabled themselves as smart materials for various utilizations, among which biodegradability is of particular importance to be engineered for biomedical application. In this study, a thermo and pH dual responsive polypeptide (N, N-dimethylaminoethyl acrylate-modified poly(l -cysteine)) (PLC-g-DMAEA) was prepared by the combination of N-carboxyanhydride ring-open polymerization and thiol-ene click chemistry. The biodegradable poly(l -cysteine) (PLC) with pendant thiol groups provided an easily clickable backbone for postmodification, which was demonstrated by reacting with a well-known monomer of N, N-dimethylaminoethyl acrylate (DMAEA) to achieve both temperature and pH responsiveness. The irreversible thermo-response of PLC-g-DMAEA could be attributed to the ordered β-sheets formed upon heating, leading to the trapped side groups with poor water accessibility. Moreover, this copolymer precipitated at pH ranging from 7.5 to 9.7, but protonation of tertiary amine groups (pH < 7.5) and salt forming of masked thiol groups (pH > 9.7) rendered it soluble in water. Our results revealed that a ready available vinyl monomer could be easily clicked onto the biodegradable PLC and its stimuli responsiveness would be reserved. Moreover, the primary and secondary structures of PLC might influence the conformation, thus leading to the unique responsive behavior of the resulted copolymer.     

Hormonal induction of spermiation,courting behavior and spawning in the southern bell frog,Litoria raniformis

We trialled the efficacy of various exogenous hormones to induce spermiation, courtship behavior, and spawning in the “endangered” southern bell frog, Litoria raniformis. Intralymphatic administration of Lucrin^®, a synthetic nonapeptide luteinizing hormone releasing hormone (LHRH), was used successfully to induce courting behaviors and ejaculation of spermatozoa in males. Various hormones, including Lucrin^®, another synthetic LHRH analog ([des‐Gly¹⁰, D‐Ala⁶]‐LHRH), human chorionic gonadotropin, progesterone, and a dopamine receptor antagonist failed to promote oviposition and spawning in females. This and earlier studies indicate that in the efficacy of hormonal induction in amphibians varies between taxa, hormones, and genders. The lack of response in females may limit the use of reproduction technology in the southern bell frog and closely related species of Australian bell frogs. Zoo Biol 29:774–782, 2010. © 2010 Wiley‐Liss, Inc.     

Prion protein—Semisynthetic prion protein (PrP) variants with posttranslational modifications

Deciphering the pathophysiologic events in prion diseases is challenging, and the role of posttranslational modifications (PTMs) such as glypidation and glycosylation remains elusive due to the lack of homogeneous protein preparations. So far, experimental studies have been limited in directly analyzing the earliest events of the conformational change of cellular prion protein (PrP^C) into scrapie prion protein (PrP^Sc) that further propagates PrP^C misfolding and aggregation at the cellular membrane, the initial site of prion infection, and PrP misfolding, by a lack of suitably modified PrP variants. PTMs of PrP, especially attachment of the glycosylphosphatidylinositol (GPI) anchor, have been shown to be crucially involved in the PrP^Sc formation. To this end, semisynthesis offers a unique possibility to understand PrP behavior invitro and invivo as it provides access to defined site‐selectively modified PrP variants. This approach relies on the production and chemoselective linkage of peptide segments, amenable to chemical modifications, with recombinantly produced protein segments. In this article, advances in understanding PrP conversion using semisynthesis as a tool to obtain homogeneous posttranslationally modified PrP will be discussed.     

Chemical Inactivation of Lipase in Organic Solvent: A Lipase from Pseudomonas aeruginosa TE3285 is More Like a Typical Serine Enzyme in an Organic Solvent than in Aqueous Media

A microbial lipase from Pseudomonas aeruginosa TE3285 was treated in anhydrous diisopropyl ether with three kinds of serine-reactive reagents, ethyl p-nitrophenyl methylphosphonate (ENMP), diisopropyl fluorophosphate (DFP), and phenylmethylsulfonyl fluoride (PMSF) to lose its catalytic activity for both transesterification in an organic solvent and ester hydrolysis in aqueous system. In contrast with the facile inactivation in an organic solvent, no or very slow inactivation was observed in an aqueous solution. The lipase was shown to behave more like a typical serine enzyme in an organic solvent than in aqueous solution with regard to the chemical inactivation by serine-reactive reagents. The unique behavior of the lipase in an organic solvent may be associated with inferfacial activation of the lipase, which is one of the most distinct characteristics of the lipase family, and the activiation of lipase could be induced by a hydrophobic interaction with an organic solvent.     

On the interaction of vanadium species with meso-2,3-dimercaptosuccinic acid

The interaction of the VO²⁺ cation with meso-2,3-dimercaptosuccinic acid (DMSA) was investigated by electron absorption spectroscopy in aqueous solution at different pH values. The spectral behavior, complemented with a spectrophotometric titration, shows the generation of a [VO(DMSA)₂]²⁻ complex in which the oxocation interacts with two pairs of deprotonated-SH groups of the acid. It was also found that DMSA rapidly reduces VO₃ ⁻ to VO²⁺, which might be chelated by an excess of the acid. DMSA can also produce the partial reduction of a V₂O₅ suspension at pH=5.2. The results of this study suggest that DMSA might be a potentially useful detoxification agent for vanadium.     

MODELS OF CHARACTER DISPLACEMENT AND THE THEORETICAL ROBUSTNESS OF TAXON CYCLES

The appropriateness of the techniques used in modeling character displacement has been the focus of vigorous debate. In this paper, the three competing methods (the coevolutionarily stable community (CSC), the evolutionarily stable strategy (ESS), and quantitative genetic recursion (QGR)) are compared in models using a common ecological setting. Specific predictions of the CSC model have been used to understand features of character displacement among Cnemidophorous lizards on islands off Mexico, Anolis lizards in the Lesser Antilles and Galápagos finches. Nonetheless, the validity of the approach has been repeatedly questioned. Conceptually the three formalisms vary in the degree to which within species variability is allowed in the models. The predictions of the CSC are found not to be robust to even small violation of its fundamental assumption of absolute species monomorphy. We show by simulation and analytical observations that the CSC is not valid under frequency dependent selection, and that the ESS is the limiting case of QGR as intraspecific phenotypic variation goes to zero. Thus the ESS and the QGR models agree closely when the between-phenotype component (BPC) of the niche width is small. However, as the BPC increases, quantitative discrepancies between ESS and QGR predictions increase, although model behavior remains qualitatively similar. A fourth approach, termed “Quantitative Genetic Optimization” (QGO) analysis, is suggested, combining advantages of both the ESS and QGR. Although all approaches support the possibility of taxon cycles, the cycle patterns predicted are qualitatively different and strongly model dependent.     

Application of Human‐Induced Pluripotent Stem Cells (hiPSCs) to Study Synaptopathy of Neurodevelopmental Disorders

Synapses are the basic structural and functional units for information processing and storage in the brain. Their diverse properties and functions ultimately underlie the complexity of human behavior. Proper development and maintenance of synapses are essential for normal functioning of the nervous system. Disruption in synaptogenesis and the consequent alteration in synaptic function have been strongly implicated to cause neurodevelopmental disorders such as autism spectrum disorders (ASDs) and schizophrenia (SCZ). The introduction of human‐induced pluripotent stem cells (hiPSCs) provides a new path to elucidate disease mechanisms and potential therapies. In this review, we will discuss the advantages and limitations of using hiPSC‐derived neurons to study synaptic disorders. Many mutations in genes encoding for proteins that regulate synaptogenesis have been identified in patients with ASDs and SCZ. We use Methyl‐CpG binding protein 2 (MECP2), SH3 and multiple ankyrin repeat domains 3 (SHANK3) and Disrupted in schizophrenia 1 (DISC1) as examples to illustrate the promise of using hiPSCs as cellular models to elucidate the mechanisms underlying disease‐related synaptopathy.     

Boosting mediated electron transfer in bioelectrochemical systems with tailored defined microbial cocultures

Bioelectrochemical systems (BES) hold great promise for sustainable energy generation via a microbial catalyst from organic matter, for example, from wastewater. To improve current generation in BES, understanding the underlying microbiology of the electrode community is essential. Electron mediator producing microorganism like Pseudomonas aeruginosa play an essential role in efficient electricity generation in BES. These microbes enable even nonelectroactive microorganism like Enterobacter aerogenes to contribute to current production. Together they form a synergistic coculture, where both contribute to community welfare. To use microbial co‐operation in BES, the physical and chemical environments provided in the natural habitats of the coculture play a crucial role. Here, we show that synergistic effects in defined cocultures of P. aeruginosa and E. aerogenes can be strongly enhanced toward high current production by adapting process parameters, like pH, temperature, oxygen demand, and substrate requirements. Especially, oxygen was identified as a major factor influencing coculture behavior and optimization of its supply could enhance electric current production over 400%. Furthermore, operating the coculture in fed‐batch mode enabled us to obtain very high current densities and to harvest electrical energy for 1 month. In this optimized condition, the coulombic efficiency of the process was boosted to 20%, which is outstanding for mediator‐based electron transfer. This study lays the foundation for a rationally designed utilization of cocultures in BES for bioenergy generation from specific wastewaters or for bioprocess sensing and for benefiting from their synergistic effects under controlled bioprocess condition.     

Preferences of invasive Ponto-Caspian and native European gammarids for zebra mussel (<Emphasis Type="Italic">Dreissena polymorpha</Emphasis>, Bivalvia) shell habitat

The migratory behavior and swimming patterns of anadromous upstream migratory fish have been poorly described in the Shibetsu River in eastern Hokkaido, Japan. In this 2004 study, we used electromyogram (EMG) transmitters and depth/ temperature (DT) loggers to compare the upstream migratory behavior of adult male chum salmon (Oncorhynchus keta) and pink salmon (O. gorbuscha) in the canalized and reconstructed segments of the Shibetsu River, where a part of canalized section was preliminary reconstructed meander to restore a more natural section. The EMG transmitter and DT logger were externally attached to the left side of the body, below the front edge of the dorsal fin. Fish of both species often migrated along the riverbanks and near the bottom of the water column, sometimes engaged in holding behavior, which was defined as cessation of swimming during their upstream migration for 5 minutes. Modal swimming depth calculated by DT loggers for chum salmon (0.2–0.4 m) was shallower than pink salmon (0.6–0.8 m). Further, modal swimming speeds measured by calibrated EMG for chum salmon (0.2–0.4 BL s⁻¹) were slower than pink salmon (1.2–1.4 BL s⁻¹). Pink salmon swam faster as well as in relatively deeper than chum salmon, suggesting that they expend more energy than chum salmon in the reconstructed segment. Based on these results, it seemed likely that the upstream migration behavior of chum and pink salmon was different with species-specific strategies.     

Overexpression of CDKN2B is involved in poor gastric cancer prognosis

The objective of this investigation is to elucidate the clinical significance of cyclin-dependent kinase inhibitor 2B (CDKN2B) expression regarding gastric cancer (GC), as well as to detect the involvement of CDKN2B expression in the clinicopathological indexes and prognosis of GC. Immunohistochemical analysis was used for identification of CDKN2B expression in GC specimens. Chi-square (χ²) test was applied to detect the association of CDKN2B expression and clinicopathological parameters of GC. The involvement of CDKN2B expression in the prognosis was analyzed via univariate and multivariate analysis. It was indicated that relative to the corresponding para-carcinoma tissues, CDKN2B expression was notably upregulated in GC specimens. Moreover, the expression of CDKN2B was strongly correlated with the differentiation (r = −0.182; P = .015), invasion (r = −0.157; P = .038), distant metastases (r = −0.196; P = .004), and TNM stage (r = −0.204; P = .005). Nevertheless, no remarkable variance was related to age, tumor loci, or sex. Kaplan-Meier survival curve and univariate analysis showed that CDKN2B overexpression predicted poorer disease-free survival (P = .007) and overall survival (P = .005) in those with GC. In addition, Cox proportional hazards regression model revealed that CDKN2B was an isolated biomarker of disease-free survival and overall survival in patients with GC. Taken together, our data demonstrated that the overexpression of CDKN2B could be an isolated factor for GC prognostic in patients. CDKN2B gene may be a useful target and new treatment for improving the prognosis of GC.     

Computation by ensemble synchronization in recurrent networks with synaptic depression

While computation by ensemble synchronization is considered to be a robust and efficient way for information processing in the cortex (C. Von der Malsburg and W. Schneider (1986) Biol. Cybern. 54: 29–40; W. Singer (1994) Inter. Rev. Neuro. 37: 153–183; J.J. Hopfield (1995) Nature 376: 33–36; E. Vaadia et al. (1995) Nature 373: 515–518), the neuronal mechanisms that might be used to achieve it are yet to be uncovered. Here we analyze a neural network model in which the computations are performed by near coincident firing of neurons in response to external inputs. This near coincident firing is enabled by activity dependent depression of inter-neuron connections. We analyze the network behavior by using a mean-field approximation, which allows predicting the network response to various inputs. We demonstrate that the network is very sensitive to temporal aspects of the inputs. In particular, periodically applied inputs of increasing frequency result in different response profiles. Moreover, applying combinations of different stimuli lead to a complex response, which cannot be easily predicted from responses to individual components. These results demonstrate that networks with synaptic depression can perform complex computations on time-dependent inputs utilizing the ability to generate temporally synchronous firing of single neurons.     

Biased distribution of single nucleotide polymorphisms (SNPs) in porcine Toll-like receptor 1 (TLR1), TLR2, TLR4, TLR5, and TLR6 genes

Toll-like receptors (TLRs) recognize various microbial components and induce immune responses. Polymorphisms in TLRs may influence their recognition of pathogen-derived molecules; swine TLRs are predicted to be associated with responses to infectious diseases such as pneumonia. In this study, we searched for single nucleotide polymorphisms (SNPs) in the coding sequences of porcine TLR1, TLR2, TLR4, TLR5, and TLR6 genes in 96 pigs from 11 breeds and elucidated 21, 11, 7, 13, and 11 SNPs, respectively, which caused amino acid substitutions in the respective TLRs. Distribution of these nonsynonymous SNPs was biased; many were located in the leucine-rich repeats, particularly in TLR1. These data demonstrated that the heterogeneity of TLR genes was preserved in various porcine breeds despite intensive breeding that was carried out for livestock improvement. It suggests that the heterogeneity in TLR genes is advantageous in increasing the possibility of survival in porcine populations.Electronic SupplementaryMaterial Supplementary material is available for this article at     

Expansin gene loss is a common occurrence during adaptation to an aquatic environment

Expansins comprise a superfamily of plant cell wall loosening proteins that can be divided into four individual families (EXPA, EXPB, EXLA and EXLB). Aside from inferred roles in a variety of plant growth and developmental traits, little is known regarding the function of specific expansin clades, for which there are at least 16 in flowering plants (angiosperms); however, there is evidence to suggest that some expansins have cell‐specific functions, in root hair and pollen tube development, for example. Recently, two duckweed genomes have been sequenced (Spirodela polyrhiza strains 7498 and 9509), revealing significantly reduced superfamily sizes. We hypothesized that there would be a correlation between expansin loss and morphological reductions seen among highly adapted aquatic species. In order to provide an answer to this question, we characterized the expansin superfamilies of the greater duckweed Spirodela, the marine eelgrass Zostera marina and the bladderwort Utricularia gibba. We discovered rampant expansin gene and clade loss among the three, including a complete absence of the EXLB family and EXPA‐VII. The most convincing correlation between morphological reduction and expansin loss was seen for Utricularia and Spirodela, which both lack root hairs and the root hair expansin clade EXPA‐X. Contrary to the pattern observed in other species, four Utricularia expansins failed to branch within any clade, suggesting that they may be the result of neofunctionalization. Last, an expansin clade previously discovered only in eudicots was identified in Spirodela, allowing us to conclude that the last common ancestor of monocots and eudicots contained a minimum of 17 expansins.