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PubMed2006

How to reach linguistic consensus: a proof of convergence for the naming game.

In this paper we introduce a mathematical model of naming games. Naming games have been widely used within research on the origins and evolution of language. Despite the many interesting empirical results these studies have produced, most of this research lacks a formal elucidating theory. In this paper we show how a population of agents can reach linguistic consensus, i.e. learn to use one common language to communicate with one another. Our approach differs from existing formal work in two important ways: one, we relax the too strong assumption that an agent samples infinitely often during each time interval. This assumption is usually made to guarantee convergence of an empirical learning process to a deterministic dynamical system. Two, we provide a proof that under these new realistic conditions, our model converges to a common language for the entire population of agents. Finally the model is experimentally validated.

Biological Evolution↗

PubMed2006

Looking inside an invasion wave of cells using continuum models: proliferation is the key.

Recently, a suite of cell migration assays were conducted to investigate the migration of neural crest (NC) cells along the gut during the development of the enteric nervous system (ENS). The NC cells colonise the gastro-intestinal tract as a rostro-caudal wave. Local behaviour was shown to be controlled by position relative to the leading edge of the wavefront. The assays involved chick-quail grafting techniques allowing the total invading population to be considered as a two-species system. A two-species continuum model with logistic proliferation and a migration mechanism is developed here to simulate the chick-quail graft experiments and provide a means of looking at the processes occurring within the invasion wave. Five migration mechanisms are considered--linear diffusion, two cases of nonlinear diffusion, chemokinesis and chemotaxis. The model results agree with the experimental observations, regardless of the specific type of migration mechanism. The results show that NC cell invasion is driven by proliferation and cell motility at the leading edge of the wave. Furthermore, logistic proliferation exerts the dominant control on the system. This observation is confirmed by analysing some simplified invasion models. Once the basic experiments were mathematically replicated, the mathematical models were used in turn to make some predictions that were yet to be experimentally tested. This involved conducting a sensitivity analysis of the system by interrupting the proliferation and/or migration ability of the leading edge. Numerical results show that the system is stable against these changes. Of the three experiments suggested, one was carried out and the experimental results were concordant with the theoretical predictions. The outcome of two other suggested experiments are predicted and left for future experimental validation.

Animals↗

PubMed2006

Granulocyte-macrophage colony-stimulating factor stimulates arteriogenesis in a pig model of peripheral artery disease using clinically applicable infusion pumps.

BACKGROUND: A growing number of patients suffer from peripheral artery disease (PAD). Current therapies are often limited by the extent of vascular pathology and the occurrence of restenosis after angioplasty. The stimulatory effect of growth factor administration on collateral vessel formation (arteriogenesis) has evolved as a potential new treatment for this patient group. Granulocyte-macrophage colony-stimulating factor (GM-CSF) was shown to stimulate arteriogenesis in small-animal models and in a pilot study in patients with coronary artery disease. Although a recent clinical study demonstrated disappointing results after subcutaneous GM-CSF application in patients with PAD, we hypothesized that intra-arterial cytokine application using implantable infusion pumps might well stimulate arteriogenesis in a large-species model of peripheral vascular disease. We also aimed to compare continuous and intermittent infusion regimens and to validate experimental and clinically available measurements of collateral artery growth. METHODS: Twenty-four pigs underwent unilateral occlusion of the right femoral artery and received either GM-CSF continuously, GM-CSF intermittently, or phosphate-buffered saline (PBS). After 1 week, collateral conductance was determined under maximal vasodilatation with adenosine and by using a pump-driven extracorporal shunt system. RESULTS: Conductance showed a significant stimulatory effect of GM-CSF on arteriogenesis (collateral conductance [mL/min/mm Hg]: PBS, 37.7 +/- 5.4; GM-CSF continuous, 69.2 +/- 12.5; GM-CSF intermittent, 71.5 +/- 11.1). Flow measurements under reactive hyperemia were consistent with these results (flow occluded/non-occluded hind limb: PBS, 40.5% +/- 9.1%; GM-CSF continuous, 48.9% +/- 3.9%; GM-CSF intermittent, 48.7% +/- 4.4%). Measurements of ankle/brachial indices were not sensitive enough to detect the differences in collateral growth between the three groups. CONCLUSION: These results demonstrate the proarteriogenic properties of GM-CSF in larger animal species, revealing comparable efficacy of continuous and intermittent intra-arterial infusion. Furthermore, we provide evidence that implantable pumps offer a possible means for the intra-arterial application of growth factors. Intra-arterial application of GM-CSF might be a future treatment option for vascular occlusive disease. Finally, we show that in the peripheral circulation, pressure measurements alone have a low sensitivity to determine the effects of proarteriogenic therapy compared with flow or combined flow-pressure measurements.

Analysis of Variance↗

PubMed2005

RISUG (reversible inhibition of sperm under guidance)--an antimicrobial as male vas deferens implant for HIV free semen.

HIV transmission from the male to the female is a major health problem. A hypothesis proposing an intra vas deferens implant of an antimicrobial compound to prevent the infection spread is presented. Mechanisms of action for the inhibition could include inactivating HIV in sperms passing through the vas deferens; drug release from the implant to destroy HIV entering into semen from genital structures distal to the vas deferens; and sperm acrosome released hyaluronidase mediated reabsorption of HIV. A subcomponent of the implant flowing along sperm pathway may have a role in reducing the entry of HIV from a positive female into penile tissue. A new drug RISUG (reversible inhibition of sperm under guidance) presently undergoing clinical trials for its contraceptive effect in the male (because it disrupts the sperm acrosome by an electrical charge and pH lowering effects) has also antimicrobial action. The drug being a combination of styrene maleic anhydride (SMA) and dimethyl sulfoxide (DMSO) on being injected into the lumen of the vas deferens produces styrene maleic acid thereby lowering pH; induces electrochemical action leading to a stable electrical charge generation; releases mandelic acid; and induces acrosome reaction in sperms with consequent release of hyaluronidase and sperm inactivation. Moreover, one time administration into the lumen of the vas gives long term action. All these phenomena very well match with the needs for HIV clearance of semen and hence RISUG is here proposed as a possible candidate material for the HIV inhibiting vas deferens implant when delivered in below contraceptive threshold dosage. For experimental validation, after obtaining data on the semen HIV load under control conditions in the HIV positive males inducted into the study, 30 mg of SMA in 120 microl of DMSO (contraceptive dose being 60 mg SMA+120 microl DMSO) is to be injected into vasa deferens bilaterally. Thereafter at intervals of one month the viral load needs to be determined in semen obtained either by masturbation or in lubricant free condom at intercourse - the method of collection remaining the same throughout for a particular subject. A significant reduction in the semen viral load following RISUG administration will validate the hypothesis. Speculated reduced female to male HIV transmission is more difficult to test. Nonspecific indications will come from a population study of the incidence of RISUG treated men becoming HIV positive as compared to that in the general population.

Anti-HIV Agents↗

PubMed2005

Evolutionary and functional genomics of the Archaea.

In the past two years, archaeal genomics has achieved several breakthroughs. On the evolutionary front the most exciting development was the sequencing and analysis of the genome of Nanoarchaeum equitans, a tiny parasitic organism that has only approximately 540 genes. The genome of Nanoarchaeum shows signs of extreme rearrangement including the virtual absence of conserved operons and the presence of several split genes. Nanoarchaeum is distantly related to other archaea, and it has been proposed to represent a deep archaeal branch that is distinct from Euryarchaeota and Crenarchaeota. This would imply that many features of its gene repertoire and genome organization might be ancestral. However, additional genome analysis has provided a more conservative suggestion - that Nanoarchaeum is a highly derived euryarchaeon. Also there have been substantial developments in functional genomics, including the discovery of the elusive aminoacyl-tRNA synthetase that is involved in both the biosynthesis of cysteine and its incorporation into proteins in methanogens, and the first experimental validation of the predicted archaeal exosome.

Archaea↗

PubMed2006

In silico mining in expressed sequences of Neurospora crassa for identification and abundance of microsatellites.

In the present study, 3217 UniGene sequences of Neurospora crassa downloaded from the National Center for Biotechnology Information (NCBI) were mined for the identification of microsatellites or simple sequence repeats (SSRs). A total of 287 SSRs detected gives density of 1SSR/14.6 kb of 4187.86 kb sequences mined suggests that only 250 (7.8%) of sequences contained SSRs. Depending on the repeat units, the length of SSRs ranged from 14 to 17 bp for mono-, 14 to 48 bp for di-, 18 to 90 bp for tri-, 24 to 48 bp for tetra-, 30 for penta- and 42 to 48 bp for hexa-nucleotide repeats. Tri-nucleotide repeats were the most frequent repeat type (88.8%) followed by di-nucleotide repeats (5.9%). An attempt was also made with the help of bioinformatics approach to find out primer pairs for identified SSRs and primers were found only for 239 sequences. But, this part needs experimental validation. Annotation of SSRs containing sequences was also carried out.

Computational Biology↗

PubMed2026

Nanopore-based epigenomic profiling reveals the absence of widespread CpG methylation in the African swine fever virus genome.

DNA methylation is a critical epigenetic mechanism implicated in regulating replication and transcription in DNA viruses. However, the epigenetic landscape of African swine fever virus (ASFV), a large double-stranded DNA virus infecting pigs, remains controversial. Here, we systematically profiled the DNA methylome of the first ASFV strain isolated in Hong Kong (HK_NT_202103) using Oxford Nanopore Technologies (ONT) R10.4.1 sequencing. We employed a paired design: native whole-genome sequencing (WGS) against a methylation-free whole-genome amplification (WGA) control. Using conservative thresholds, we found no evidence of 5-methylcytosine (5mC), especially typical CpG methylation, across the viral genome. Importantly, clear CpG methylation signals were successfully detected in the host genome from WGS data, confirming the functionality of the workflow to detect 5mC at CG sites. While widespread 5mC seems absent, a small number of putative N6-methyladenine (6mA) loci were identified. A specific 6mA candidate exhibited raw ionic current disruptions and gene-level intersection with another ASFV isolate (CAS19-01/2019), although it lacked single-base consensus across different methylation callers or between the two isolates. Although our biological findings are restricted to a single isolate under specific experimental conditions, this study introduces a novel, highly rigorous ONT framework for viral epigenomics research. Furthermore, the absence of ASFV CpG methylation indicates that host CpG-depletion remains a viable strategy for viral metagenomic enrichment. Ultimately, our work offers a critical methodological baseline for ASFV surveillance and highlights the necessity of targeted experimental validation for rare viral modifications.

African Swine Fever Virus↗

PubMed2026

Trichoderma specialized metabolites in biocontrol: gene-metabolite links, ecological functions, and translational bottlenecks.

Trichoderma spp. produce a diverse repertoire of metabolites with specific activities that contribute to biocontrol through direct antagonism, ecological signalling, and modulation of plant responses. However, current knowledge remains uneven: many metabolites are chemically described, whereas fewer are supported by robust gene-metabolite associations, experimentally validated ecological functions, and realistic translational evidence. Progress in this field will depend less on expanding compound catalogues than on integrating mechanistic, ecological, and translational evidence. This review examines the specialized metabolism of Trichoderma with emphasis on biosynthetic gene clusters, regulatory networks, ecological roles, and biosafety constraints relevant to biocontrol. Major metabolite classes, including polyketides, terpenoids, peptaibols, siderophores, diketopiperazines, and volatile organic compounds, are discussed together with representative case studies for which genetic and functional evidence is available. We further propose a translational framework to distinguish metabolites with mainly descriptive support from those approaching application readiness, based on four criteria: gene-level validation, demonstrated ecological role, manageable biosafety profile, and feasible delivery/stability. This perspective helps explain why metabolite inventories continue to expand faster than field translation. Recent advances in genomics, transcriptomics, metabolomics, genome editing, and formulation science are reshaping how Trichoderma metabolites are prioritized for future development.

Biosafety↗

PubMed2026

Uncovering hidden complexity in the Apis mellifera mitotranscriptome: a polyadenylation-centered perspective.

Mitochondrial transcription is gaining increasing attention as researchers seek to better understand the full coding potential of mitochondrial DNA (mtDNA). Emerging evidence suggests that mtDNA may encode additional elements beyond classical oxidative phosphorylation genes, pointing to a more complex transcriptional architecture than previously recognized. In this study, we explored the mitochondrial transcriptome of Apis mellifera (Insecta: Hymenoptera), with a particular focus on polyadenylation-associated features. Our analysis revealed that both sense and antisense transcripts undergo polyadenylation, although transcript abundance and poly(A) tail lengths varied markedly across mitochondrial genes. Several transcripts exhibited alternative isoforms, either extended or truncated, frequently including intergenic regions. These regions may represent functional non-coding elements or structural variants rather than conventional untranslated regions (UTRs). Interestingly, some transcripts also contained non-templated nucleotide additions particularly cytosine residues immediately upstream of the poly(A) tails. Monocistronic units that included portions of downstream intergenic regions were among the most abundantly represented, suggesting a possible regulatory role for these sequences. To experimentally validate our in silico findings, we performed RT-qPCR to assess relative gene expression and applied 3' RACE-PCR to define transcript boundaries. These approaches confirmed the presence of multiple transcript isoforms and supported the involvement of polyadenylation in shaping mitochondrial RNA diversity. Together, our findings reveal a previously underappreciated level of complexity in the A. mellifera mitochondrial transcriptome and highlight the potential regulatory significance of polyadenylation dynamics and intergenic region transcription.

Animals↗

PubMed2004

Computational identification of plant microRNAs and their targets, including a stress-induced miRNA.

MicroRNAs (miRNAs) are approximately 21-nucleotide RNAs, some of which have been shown to play important gene-regulatory roles during plant development. We developed comparative genomic approaches to systematically identify both miRNAs and their targets that are conserved in Arabidopsis thaliana and rice (Oryza sativa). Twenty-three miRNA candidates, representing seven newly identified gene families, were experimentally validated in Arabidopsis, bringing the total number of reported miRNA genes to 92, representing 22 families. Nineteen newly identified target candidates were confirmed by detecting mRNA fragments diagnostic of miRNA-directed cleavage in plants. Overall, plant miRNAs have a strong propensity to target genes controlling development, particularly those of transcription factors and F-box proteins. However, plant miRNAs have conserved regulatory functions extending beyond development, in that they also target superoxide dismutases, laccases, and ATP sulfurylases. The expression of miR395, the sulfurylase-targeting miRNA, increases upon sulfate starvation, showing that miRNAs can be induced by environmental stress.

Arabidopsis↗

PubMed2006

A wiring of the human nucleolus.

Recent proteomic efforts have created an extensive inventory of the human nucleolar proteome. However, approximately 30% of the identified proteins lack functional annotation. We present an approach of assigning function to uncharacterized nucleolar proteins by data integration coupled to a machine-learning method. By assembling protein complexes, we present a first draft of the human ribosome biogenesis pathway encompassing 74 proteins and hereby assign function to 49 previously uncharacterized proteins. Moreover, the functional diversity of the nucleolus is underlined by the identification of a number of protein complexes with functions beyond ribosome biogenesis. Finally, we were able to obtain experimental evidence of nucleolar localization of 11 proteins, which were predicted by our platform to be associates of nucleolar complexes. We believe other biological organelles or systems could be "wired" in a similar fashion, integrating different types of data with high-throughput proteomics, followed by a detailed biological analysis and experimental validation.

Artificial Intelligence↗

PubMed2005

Deriving the optimal number of events for an event-related fMRI study based on the spatial extent of activation.

Event-related fMRI is a powerful tool for localising psychological functions to specific brain areas. However, the number of events required to produce stable activation maps is a poorly investigated and understood problem. Huettel and McCarthy [Huettel, S.A., McCarthy, G., 2001. The effects of single-trial averaging upon the spatial extent of fMRI activation. NeuroReport 12, 2411-2416] have shown that the spatial extent of activation increases monotonically with the number of events in an analysis. In the present paper, this result is replicated and shown to be a consequence of the cross-correlation technique used to determine active voxels and does not hold, for example, for a GLM analysis. Another analysis technique, that does not depend on goodness-of-fit to the data, is also proposed. This technique calculates an impulse response function (IRF) for each voxel, finds the best fitting haemodynamic shape to the IRF and returns an area-under-the-curve (%AUC) activation measure. Using spatial extent as a measure, asymptotic behaviour is evident after as few as 25 events for the %AUC analysis technique in a finger-tapping task with non-overlapping haemodynamic responses and for both the GLM and %AUC techniques in a similar task that allows responses to overlap. The experimental validity of the %AUC technique to identify active brain regions while minimising false positive levels is demonstrated in a group study with 25 participants.

Adult↗

PubMed2005

Computational and in vitro studies of persistent activity: edging towards cellular and synaptic mechanisms of working memory.

Persistent neural activity selective to features of an extinct stimulus has been identified as the neural correlate of working memory processes. The precise nature of the physiological substrate for this self-sustained activity is still unknown. In the last few years, this problem has gathered experimental together with computational neuroscientists in a quest to identify the cellular and network mechanisms involved. I introduce here the attractor theory framework within which current persistent activity computational models are built, and I then review the main physiological mechanisms that have been linked thereby to persistent activity and working memory. Open computational and physiological issues with these models are discussed, together with their potential experimental validation in current in vitro models of persistent activity.

Action Potentials↗

PubMed2006

Psychophysical study of the effects of topical application of menthol in healthy volunteers.

Cold hyperalgesia is a major clinical phenomenon, but validated experimental models are still lacking for humans. Topical menthol application has recently been proposed as a possible model for the study of cold pain. We characterized the psychophysical effects of 30% l-menthol in ethanol on glabrous skin in 39 healthy subjects, using a double-blind, randomized, crossover design, with ethanol as a control. Psychophysical testing included an assessment of pain thresholds and detection of mechanical, cold, and heat stimuli, and of the sensations induced by suprathreshold stimuli. Most subjects (90%) perceived a cooling sensation with menthol. Menthol decreased cold pain thresholds and enhanced pain responses to suprathreshold noxious cold stimuli, without affecting responses to other stimuli. Menthol therefore has selective effects on noxious cold processing. No subject displayed signs of skin irritation or redness. These data suggest that 30% menthol application may be a useful experimental model for studies of cold hyperalgesia in humans. The absence of local skin reactions also makes this test potentially suitable for use in patients.

Administration, Topical↗

PubMedDate not supplied

Preclinical cardiac safety assessment of pharmaceutical compounds using an integrated systems-based computer model of the heart.

Blockade of the delayed rectifier potassium channel current, I(Kr), has been associated with drug-induced QT prolongation in the electrocardiogram and life-threatening cardiac arrhythmias. However, it is increasingly clear that compound-induced interactions with multiple cardiac ion channels may significantly affect QT prolongation that would result from inhibition of only I(Kr) [Redfern, W.S., Carlsson, L., et al., 2003. Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development. Cardiovasc. Res. 58(1), 32-45]. Such an assessment may not be feasible in vitro, due to multi-factorial processes that are also time-dependent and highly non-linear. Limited preclinical data, I(Kr) hERG assay and canine Purkinje fiber (PF) action potentials (APs) [Gintant, G.A., Limberis, J.T., McDermott, J.S., Wegner, C.D., Cox, B.F., 2001. The canine Purkinje fiber: an in vitro model system for acquired long QT syndrome and drug-induced arrhythmogenesis. J. Cardiovasc. Pharmacol. 37(5), 607-618], were used for two test compounds in a systems-based modeling platform of cardiac electrophysiology [Muzikant, A.L., Penland, R.C., 2002. Models for profiling the potential QT prolongation risk of drugs. Curr. Opin. Drug. Discov. Dev. 5(1), 127-35] to: (i) convert a canine myocyte model to a PF model by training functional current parameters to the AP data; (ii) reverse engineer the compounds' effects on five channel currents other than I(Kr), predicting significant IC(50) values for I(Na+), sustained and I(Ca2+), L-type , which were subsequently experimentally validated; (iii) use the predicted (I(Na+), sustained and I(Ca2+), L-type) and measured (I(Kr)) IC(50) values to simulate dose-dependent effects of the compounds on APs in endocardial, mid-myocardial, and epicardiac ventricular cells; and (iv) integrate the three types of cellular responses into a tissue-level spatial model, which quantifiably predicted no potential for the test compounds to induce either QT prolongation or increased transmural dispersion of repolarization in a dose-dependent and reverse rate-dependent fashion, despite their inhibition of I(Kr) in vitro.

Action Potentials↗

PubMed2005

Expression, purification, and inhibition of human RET tyrosine kinase.

Tyrosine kinases are emerging as frequent targets of primary oncogenic events and therefore represent an optimal focus of therapeutical intervention. Genetic alterations that cause dysregulated activation of the RET tyrosine kinase are responsible for a significant fraction of thyroid carcinomas. In an effort towards therapeutic RET inactivation, we have developed a method for expression and purification of recombinant RET catalytic domain for structural purposes and for use in the screening of potential inhibitors of RET kinase activity. His-tagged RET kinase domain was purified from Sf9 insect cell lysate using a two-step chromatographic protocol and characterised. Purified recombinant RET phosphorylated itself and exogenous substrates at physiological pH. A specific peptide substrate, derived from RET activation loop, was identified and experimentally validated. These reagents were used to develop a rapid ELISA-based kinase assay for screening potential inhibitors. Novel RET inhibitors were identified using this assay.

Amino Acid Sequence↗

PubMed2005

ATP-regulated module (ARM) of the atrial natriuretic factor receptor guanylate cyclase.

ATP is an obligatory agent for the atrial natriuretic factor (ANF) and the type C natriuretic peptide (CNP) signaling of their respective receptor guanylate cyclases, ANF-RGC and CNP-RGC. Through a common mechanism, it binds to a defined ARM domain of the cyclase, activates the cyclase and transduces the signal into generation of the second messenger cyclic GMP. In this presentation, the authors review the ATP-regulated transduction mechanism and refine the previously simulated three-dimensional ARM model (Duda T, Yadav P, Jankowska A, Venkataraman V, Sharma RK. Three dimensional atomic model and experimental validation for the ATP-regulated module (ARM) of the atrial natriuretic factor receptor guanylate cyclase. Mol Cell Biochem 2000;214:7-14; reviewed in: Sharma RK, Yadav P, Duda T. Allosteric regulatory step and configuration of the ATP-binding pocket in atrial natriuretic factor receptor guanylate cyclase transduction mechanism. Can J Physiol Pharmacol 2001;79: 682-91; Sharma RK. Evolution of the membrane guanylate cyclase transduction system. Mol Cell Biochem 2002;230:3-30). The model depicts the ATP-binding dependent configurational changes in the ARM and supports the concept that in the first step, ATP partially activates the cyclase and primes it for the subsequent transduction steps, resulting in full activation of the cyclase.

Adenosine Triphosphate↗

PubMed2004

Proteomics in cancer cell research: an analysis of therapy resistance.

Proteomics, the global analysis of expressed cellular proteins, provides powerful tools for the detailed comparison of proteins from normal and neoplastic tissue. In particular, cancer cell culture models are suited for applying proteomics techniques, such as two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) and mass spectrometry, to identify specific protein expression profiles and/or proteins that may be associated with a defined phenotype of the cancer cells. As an instance of such an application of proteomics techniques, the detailed proteome analyses of different drug-resistant and thermoresistant cancer cell lines will be discussed. Finally, the potential roles of newly identified factors in a distinct biological mechanism have to be proven by functional studies. This experimental validation strategy will be discussed for two different factors identified by 2D-PAGE analyses of drug-resistant carcinoma cell lines, the "transporter associated with antigen presentation 1" (TAP1) and 14-3-3sigma.

Biomarkers, Tumor↗