bluuebunny/crossref_metadata_2025 huggingface dataset:
A system of feed-forward cerebellar circuits that extend and diversify sensory signaling
Authors: Hariani Harsh N , Algstam A Brynn , Candler Christian T , Witteveen Isabelle F , Sidhu Jasmeen K , Balmer Timothy S
Published: January 2024

Sensory signals are processed by the cerebellum to coordinate movements. Numerous cerebellar functions are thought to require the maintenance of a sensory representation that extends beyond the input signal. Granule cells receive sensory input, but they do not prolong the signal and are thus unlikely to maintain a sensory representation for much longer than the inputs themselves. Unipolar brush cells (UBCs) are excitatory interneurons that project to granule cells and transform sensory input into prolonged increases or decreases in firing, depending on their ON or OFF UBC subtype. Further extension and diversification of the input signal could be produced by UBCs that project to one another, but whether this circuitry exists is unclear. Here we test whether UBCs innervate one another and explore how these small networks of UBCs could transform spiking patterns. We characterized two transgenic mouse lines electrophysiologically and immunohistochemically to confirm that they label ON and OFF UBC subtypes and crossed them together, revealing that ON and OFF UBCs innervate one another. A Brainbow reporter was used to label UBCs of the same ON or OFF subtype with different fluorescent proteins, which showed that UBCs innervate their own subtypes as well. Computational models predict that these feed-forward networks of UBCs extend the length of bursts or pauses and introduce delays—transformations that may be necessary for cerebellar functions from modulation of eye movements to adaptive learning across time scales.
Physiological and metabolic insights into the first cultured anaerobic representative of deep-sea Planctomycetes bacteria
Authors: Zheng Rikuan , Wang Chong , Liu Rui , Cai Ruining , Sun Chaomin
Published: January 2024

Planctomycetes bacteria are ubiquitously distributed across various biospheres and play key roles in global element cycles. However, few deep-sea Planctomycetes members have been cultivated, limiting our understanding of Planctomycetes in the deep biosphere. Here, we have successfully cultured a novel strain of Planctomycetes (strain ZRK32) from a deep-sea cold seep sediment. Our genomic, physiological, and phylogenetic analyses indicate that strain ZRK32 is a novel species, which we propose be named: Poriferisphaera heterotrophicis. We show that strain ZRK32 replicates using a budding mode of division. Based on the combined results from growth assays and transcriptomic analyses, we found that rich nutrients, or supplementation with NO3- or NH4+ promoted the growth of strain ZRK32 by facilitating energy production through the tricarboxylic acid cycle and the Embden-Meyerhof-Parnas glycolysis pathway. Moreover, supplementation with NO3- or NH4+ induced strain ZRK32 to release a bacteriophage in a chronic manner, without host cell lysis. This bacteriophage then enabled strain ZRK32, and another marine bacterium that we studied, to metabolize nitrogen through the function of auxiliary metabolic genes. Overall, these findings expand our understanding of deep-sea Planctomycetes bacteria, while highlighting their ability to metabolize nitrogen when reprogrammed by chronic viruses.
A remarkable genetic shift in a transmitted/founder virus broadens antibody responses against HIV-1
Authors: Jain Swati , Uritskiy Gherman , Mahalingam Marthandan , Batra Himanshu , Chand Subhash , Trinh Hung V , Beck Charles , Shin Woong-Hee , Alsalmi Wadad , Kijak Gustavo , Eller Leigh A , Kim Jerome , Kihara Daisuke , Tovanabutra Sodsai , Ferrari Guido , Robb Merlin L , Rao Mangala , Rao Venigalla B
Published: January 2024

A productive HIV-1 infection in humans is often established by transmission and propagation of a single transmitted/founder (T/F) virus, which then evolves into a complex mixture of variants during the lifetime of infection. An effective HIV-1 vaccine should elicit broad immune responses in order to block the entry of diverse T/F viruses. Currently, no such vaccine exists. An in-depth study of escape variants emerging under host immune pressure during very early stages of infection might provide insights into such a HIV-1 vaccine design. Here, in a rare longitudinal study involving HIV-1 infected individuals just days after infection in the absence of antiretroviral therapy, we discovered a remarkable genetic shift that resulted in near complete disappearance of the original T/F virus and appearance of a variant with H173Y mutation in the variable V2 domain of the HIV-1 envelope protein. This coincided with the disappearance of the first wave of strictly H173-specific antibodies and emergence of a second wave of Y173-specific antibodies with increased breadth. Structural analyses indicated conformational dynamism of the envelope protein which likely allowed selection of escape variants with a conformational switch in the V2 domain from an α-helix (H173) to a β-strand (Y173) and induction of broadly reactive antibody responses. This differential breadth due to a single mutational change was also recapitulated in a mouse model. Rationally designed combinatorial libraries containing 54 conformational variants of V2 domain around position 173 further demonstrated increased breadth of antibody responses elicited to diverse HIV-1 envelope proteins. These results offer new insights into designing broadly effective HIV-1 vaccines.
Hyperglycemia induced cathepsin L maturation linked to diabetic comorbidities and COVID-19 mortality
Authors: He Qiong , Zhao Miao-Miao , Li Ming-Jia , Li Xiao-Ya , Jin Jian-Min , Feng Ying-Mei , Zhang Li , Huang Wei Jin , Yang Fangyuan , Yang Jin-Kui
Published: January 2024

Diabetes, a prevalent chronic condition, significantly increases the risk of mortality from COVID-19, yet the underlying mechanisms remain elusive. Emerging evidence implicates Cathepsin L (CTSL) in diabetic complications, including nephropathy and retinopathy. Our previous research identified CTSL as a pivotal protease promoting SARS-CoV-2 infection. Here, we demonstrate elevated blood CTSL levels in individuals with diabetes, facilitating SARS-CoV-2 infection. Chronic hyperglycemia correlates positively with CTSL concentration and activity in diabetic patients, while acute hyperglycemia augments CTSL activity in healthy individuals. In vitro studies reveal high glucose, but not insulin, promotes SARS-CoV-2 infection in wild-type cells, with CTSL knockout cells displaying reduced susceptibility. Utilizing lung tissue samples from diabetic and non-diabetic patients, alongside Leprdb/dbmice and Leprdb/+mice, we illustrate increased CTSL activity in both humans and mice under diabetic conditions. Mechanistically, high glucose levels promote CTSL maturation and translocation from the endoplasmic reticulum (ER) to the lysosome via the ER-Golgi-lysosome axis. Our findings underscore the pivotal role of hyperglycemia-induced CTSL maturation in diabetic comorbidities and complications.
Fitness landscape of substrate-adaptive mutations in evolved amino acid-polyamine-organocation transporters
Authors: Karapanagioti Foteini , Atlason Úlfur Águst , Slotboom Dirk J , Poolman Bert , Obermaier Sebastian
Published: January 2024

The emergence of new protein functions is crucial for the evolution of organisms. This process has been extensively researched for soluble enzymes, but it is largely unexplored for membrane transporters, even though the ability to acquire new nutrients from a changing environment requires evolvability of transport functions. Here, we demonstrate the importance of environmental pressure in obtaining a new activity or altering a promiscuous activity in members of the amino acid-polyamine-organocation (APC)-type yeast amino acid transporters family. We identify APC members that have broader substrate spectra than previously described. Using in vivo experimental evolution, we evolve two of these transporter genes, AGP1 and PUT4, toward new substrate specificities. Single mutations on these transporters are found to be sufficient for expanding the substrate range of the proteins, while retaining the capacity to transport all original substrates. Nonetheless, each adaptive mutation comes with a distinct effect on the fitness for each of the original substrates, illustrating a trade-off between the ancestral and evolved functions. Collectively, our findings reveal how substrate-adaptive mutations in membrane transporters contribute to fitness and provide insights into how organisms can use transporter evolution to explore new ecological niches.
An arms race between 5’ppp-RNA virus and its alternative recognition receptor MDA5 in RIG-I-lost teleost fish
Authors: Geng Shang , Lv Xing , Zheng Weiwei , Xu Tianjun
Published: January 2024

The incessant arms race between viruses and hosts has led to numerous evolutionary innovations that shape life’s evolution. During this process, the interactions between viral receptors and viruses have garnered significant interest since viral receptors are cell surface proteins exploited by viruses to initiate infection. Our study sheds light on the arms race between the MDA5 receptor and 5’ppp-RNA virus in a lower vertebrate fish, Miichthys miiuy. Firstly, the frequent and independent loss events of RIG-I in vertebrates prompted us to search for alternative immune substitutes, with homology-dependent genetic compensation response (HDGCR) being the main pathway. Our further analysis suggested that MDA5 of M. miiuy and Gallus gallus, the homolog of RIG-I, can replace RIG-I in recognizing 5’ppp-RNA virus, which may lead to redundancy of RIG-I and loss from the species genome during evolution. Secondly, as an adversarial strategy, 5’ppp-RNA SCRV can utilize the m6A methylation mechanism to degrade MDA5 and weaken its antiviral immune ability, thus promoting its own replication and immune evasion. In summary, our study provides a snapshot into the interaction and coevolution between vertebrate and virus, offering valuable perspectives on the ecological and evolutionary factors that contribute to the diversity of the immune system.
Water deprivation-induced hypoxia and oxidative stress physiology responses in respiratory organs of the Indian stinging fish in near coastal zones
Authors: Pati Samar Gourav , Panda Falguni , Bal Abhipsa , Paital Biswaranjan , Sahoo Dipak Kumar
Published: January 2024

Background

Water deprivation-induced hypoxia stress (WDIHS) has been extensively investigated in numerous fish species due to their adaptation with accessory respiratory organs to respire air but this has not been studied in Indian stinging fish Heteropneustes fossilis. Data regarding WDIHS-induced metabolism in accessory respiratory organ (ARO) and gills and its relationship with oxidative stress (OS) in respiratory organs of air-breathing fish H. fossilis, are limited. So, this study aimed to investigate the effects of WDIHS (0, 3, 6, 12, and 18 h) on hydrogen peroxide (H2O2) as reactive oxygen species (ROS), OS, redox regulatory enzymes, and electron transport enzymes (ETC) in ARO and gills of H. fossilis.

Methods

Fish were exposed to air for different hours (up to 18 h) against an appropriate control, and ARO and gills were sampled. The levels of oxygen saturation in the body of the fish were assessed at various intervals during exposure to air. Protein carbonylation (PC) and thiobarbituric acid reactive substances (TBARS) were used as OS markers, H2O2 as ROS marker, and various enzymatic activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), along with the assessment of complex enzymes (I, II, III, and V) as well as the levels of ascorbic acid (AA) and the reduced glutathione (GSH) were quantified in both the tissues.

Results

Discriminant function analyses indicate a clear separation of the variables as a function of the studied parameters. The gills exhibited higher levels of GSH and H2O2 compared to ARO, while ARO showed elevated levels of PC, TBARS, AA, SOD, CAT, and GPx activities compared to the gills. The activities of GR and ETC enzymes exhibited similar levels in both the respiratory organs, namely the gills, and ARO. These organs experienced OS due to increased H2O2, TBARS, and PC levels, as observed during WDIHS. Under WDIHS conditions, the activity/level of CAT, GPx, GR, and GSH decreased in ARO, while SOD activity, along with GR, GSH, and AA levels decreased in gills. However, the activity/level of SOD and AA in ARO and CAT in gills was elevated under WDIHS. Complex II exhibited a positive correlation with WDIHS, while the other ETC enzymes (complex I, III, and V) activities had negative correlations with the WDIHS.

Discussion

The finding suggests that ARO is more susceptible to OS than gills under WDIHS. Despite both organs employ distinct redox regulatory systems to counteract this stress, their effectiveness is hampered by the inadequacy of small redox regulatory molecules and the compromised activity of the ETC, impeding their ability to effectively alleviate the stress induced by the water-deprivation condition.
Direitos humanos, assistência social e educação: enlaces de uma construção histórica
Authors: Cruz Annebelle Pena Lima Magalhães , Torres Ellen Costa Antunes , Cruz Luiz Marcelo Magalhães , Da Silva Anderson Lincoln Vital
Published: January 2024

A presente escrita como produção do conhecimento, apresenta o objetivo de abordar o contexto inicial de compreensão da temática e da relação entre Direitos Humanos e Assistência Social. Bem como, sua importância para a educação e conscientização acerca das conquistas sociais nas áreas. Justificando-se esta empreitada que aqui se descortina, por ser e ter um viés educacional e informativo, nos quais, o caminho de conhecimento ancorado na efetivação sobre os direitos conquistados, pode trazer visibilidade às lutas populares construídas ao longo dos tempos. Lutas que fazem parte de inúmeros contextos sociais, econômicos e culturais, como o direito ao trabalho, à saúde, à educação e a previdência social, que devem ser efetivados mediante as políticas públicas dos Estados, exigindo um papel ativo do governo e dos cidadãos. Como método de pesquisa, supôs a utilização de uma metodologia bibliográfica sistemática, a problematização da realidade e a realização de reflexões discursivas interdisciplinares ou transdisciplinares. Como conclusão, inferiu a importância da educação frente aos processos históricos de construção dos direitos, tornando-se fator primordial o conhecimento desse histórico de maneira a conscientizar, ampliando as esferas educativas sobre o tema. Sendo a educação e a informação sempre um papel social, quer no Direito, na Assistência Social, na Educação ou em outras áreas.
Predictors of Burden in Families of Youth Experiencing Mental Health and/or Addiction Concerns in Ontario, Canada
Authors: Levitt Emily E. , Markoulakis Roula , Weingust Staci , Dobbin Kendyl , Levitt Anthony J.
Published: January 2024

This study explored factors impacting caregiver burden (CB) in families of youth with mental health and/or addiction (MHA) issues through a cross-sectional survey of Ontario caregivers (n = 259). Zero-order correlations explored caregiver, youth, and service factors and CB. Regressions explored contributions of significant factors to the variance in CB. Barriers to services, number of youth symptoms, and waitlist status significantly predicted CB. The specific barriers that were significantly associated with CB were service costs, service availability, and youth motivation to participate in services. Tailoring interventions and policies to reduce service waitlists and barriers may alleviate CB and improve youth and family outcomes.
Reducing joint destruction due to septic arthrosis using an adenosine2A receptor agonist
Authors: Cohen Steven B. , Gill Sanjitpal S. , Baer Geoffrey S. , Leo Brian M. , Scheld W. Michael , Diduch David R.
Published: October 2003

We assessed the efficacy of a new adenosine A2A agonist ATL146e, a potent inhibitor of white blood cell chemotaxis, to reduce cartilage damage in the treatment of septic arthrosis. A live septic arthrosis model was created using Staphylococcus aureus in rabbit knees. Animals were divided into five treatment groups: (1) untreated infected control, (2) antibiotics control, and antibiotics plus ATL146e for (3) 24, (4) 48, or (5) 72 h and assessed at 1, 4, and 7 days.

Knees in all ATL146e treated animals exhibited no detectable effusion, and histologic examination revealed near normal cartilage and diminished synovial inflammatory response. Synovial WBC counts decreased with the addition of ATL146e when compared to infected and antibiotic controls. Histologic grading of osteochondral specimens demonstrated improved scores for animals treated with ATL146e compared to infected (p < 0.00004) and antibiotics controls (p < 0.05). Analysis of glycosaminoglycan content revealed significantly decreased loss of articular cartilage following infection in the ATL146e groups when compared to infected (p < 0.03) and antibiotics controls (p < 0.05).

Addition of an adenosine A2A agonist to antibiotic therapy decreases joint inflammation and articular cartilage destruction without compromising bacterial clearance in rabbit knees following intraarticular bacterial infection. The use of adenosine agonists selective to the A2A receptor to augment conventional treatment of joint sepsis may be chondroprotective and ultimately help prevent arthrosis. © 2003 Orthopaedic Research Society. Published by Elsevier Ltd. All rights reserved.
Functional activities and cellular localization of the ezrin, radixin, moesin (ERM) and RING zinc finger domains in MIR
Authors: Bornhauser Beat C , Johansson Cecilia , Lindholm Dan
Published: October 2003

Myosin regulatory light chain interacting protein (MIR) belongs to the ezrin, radixin, moesin (ERM) family of proteins involved in membrane cytoskeleton interactions and cell dynamics. MIR contains, beside the ERM domain, a RING zinc finger region. Immunocytochemistry showed that full‐length MIR and the subdomains localize differently in cells. Cell fractionation revealed a similar distribution of full‐length MIR and the RING domain protein in the Triton X‐100‐insoluble fraction. The neurite outgrowth inhibitory activity of MIR was attributed to the RING domain. MIR levels were controlled in the cells depending on the intact RING domain and proteasome activity. The dynamic regulation of MIR contributes to its effects on neurite outgrowth and cell motility.
Conditional expression of exogenous Bcl‐XS triggers apoptosis in human melanoma cells in vitro and delays growth of melanoma xenografts
Authors: Hossini Amir M , Eberle Jürgen , Fecker Lothar F , Orfanos Constantin E , Geilen Christoph C
Published: October 2003

The Bcl‐2‐related proteins Bcl‐XL and Bcl‐XS represent alternative splice products and exert opposite activities in the control of apoptosis, but their significance for melanoma is not yet clear. Applying the tetracycline‐inducible expression system Tet‐On, we found overexpression of Bcl‐XS by itself sufficient to induce apoptosis in vitro in stably transfected human melanoma cell lines. Combination with proapoptotic agents such as etoposide, pamidronate, and ceramide resulted in additive proapoptotic effects, whereas Bcl‐XL protected from apoptosis caused via CD95/Fas stimulation. In nude mice growth of melanoma xenotransplants derived from stably transfected cells was significantly reduced after induction of Bcl‐XS by doxycycline. Our results indicate that Bcl‐X proteins are of major importance for control of apoptosis in malignant melanoma.
Cervical ripening with oral misoprostol at term
Authors: Beigi A. , Kabiri M. , Zarrinkoub F.
Published: October 2003

Objectives: To determine the efficacy of 200 μg single dose oral misoprostol as a cervical priming agent at term. Methods: In this double‐blind randomized trial, 156 pregnant women requiring induction of labor with gestational age of 37–42 weeks and Bishop score ≤5, were randomized to receive either 200 μg of misoprostol or a placebo, orally. Labor was induced with intravenous oxytocin infusion 12 h after oral medication if the patient did not go into labor. The primary outcome was the change in the Bishop score 12 h after oral medication. The secondary outcomes were the timings starting from the drug administration to the onset of uterine activity, interval between oral medication and delivery, oxytocin need for induction, mode of delivery, frequency of side effects, and neonatal and maternal outcome. The chi‐square or Fisher exact test, Student's t‐test, and Mann–Whitney U‐test were used for analysis of the data. Results: There were no significant differences in maternal characteristics or indications of induction. The Bishop score 12 h after oral medication significantly improved in the misoprostol group compared with the control group [55 (70%)>8 vs. 4 (5%)>8; P<0.001]. The induction rate was significantly reduced in the misoprostol group (P<0.001). The interval between oral medication and the onset of uterine activity was significantly shorter in the misoprostol group (P<0.001). The interval between oral medication and delivery was also significantly shorter in the misoprostol group (P<0.001). The cesarean delivery rate was significantly lower in the misoprostol group (P<0.001). There were no differences between the groups with respect to the incidence of tachysystole, hyperstimulation, adverse neonatal or maternal outcome. Conclusions: Oral administration of 200 μg single dose of misoprostol is an effective agent not only for cervical priming but also for induction of labor at term. Furthermore, it reduces the rate of cesarean deliveries.
Modelling the effect of swimbladder compression on the acoustic backscattering from herring at normal or near-normal dorsal incidences
Authors: Gorska Natalia , Ona Egil
Published: October 2003

Inaccuracy in herring target strength can be an important source of bias in the acoustic assessment of several important herring stocks. New acoustic data on herring target strength (Ona et al., 2001, submitted for publication; Ona, 2003) confirm previous suggestions and evidence on a possible reduction of the size of the herring swimbladder as a result of its compression with increasing water depth. Theoretical work for a better understanding of the acoustic scattering from herring over its entire depth distribution may therefore be essential for improving abundance estimation. This study supplements the analysis, conducted by Gorska and Ona (2003) for herring averaged-backscattering cross-section. The modal-based, deformed-cylinder model (MB-DCM) solutions, presented in that paper, are used. The sensitivity of the herring backscattering cross-section in case of normal or near-normal dorsal incidences is studied with respect to frequency, contraction factors of the swimbladder dimensions and some fish morphological parameters. The study is important for a better understanding of not only the backscattering by individual fish for the dorsal incidence, but also the depth- and frequency-dependencies of the mean-backscattering cross-section. The theoretical results have been applied in the interpretation of the actual measured target-strength data on adult herring.
REVISION OF THE DISJUNCT GENUS CAMPYLANTHUS (SCROPHULARIACEAE)
Authors: HJERTSON M.
Published: October 2003

The genus Campylanthus (Scrophulariaceae) is revised and 15 species are recognized. The genus shows a markedly disjunct pattern of distribution, with two species in Macaronesia, 12 in northeastern Africa and Arabia, and one in western Pakistan. With few exceptions all have very restricted distributions. The position of the genus within the Scrophulariaceae is discussed, and it is concluded that Campylanthus is best placed as incertae sedis. Morphological aspects of the genus are discussed and a cladistic analysis including all species is presented. The analysis indicates a basal split between western and eastern species in the genus. A key, descriptions and distribution maps for all species are provided, and some lectotypes and neotypes are selected.
Ab initio reconstruction of metabolic pathways
Authors: Boyer Frédéric , Viari Alain
Published: October 2003

We propose a new formulation for the problem of ab initio metabolic pathway reconstruction. Given a set of biochemical reactions together with their substrates and products, we consider the reactions as transfers of atoms between the chemical compounds and we look for successions of reactions transferring a maximal (or preset) number of atoms between a given source and sink compound. We state this problem as the one of finding a composition of partial injections that maximizes the image size. First, we study the theoretical complexity of this problem, state some related problems and then give a practical algorithm to solve them. Finally, we present two applications of this approach to the reconstruction of the tryptophan biosynthesis pathway and to the glycolysis.

Contact: alain.viari@inrialpes.fr

*To whom correspondence should be addressed.
Exploring potential target genes of signaling pathways by
predicting conserved transcription factor binding sites
Authors: Dieterich C. , Herwig R. , Vingron M.
Published: October 2003

Many cellular signaling pathways induce gene expression by activating specific transcription factor complexes. Conventional approaches to the prediction of transcription factor binding sites lead to a notoriously high number of false discoveries. To alleviate this problem, we consider only binding sites that are conserved in man-mouse genomic sequence comparisons. We employ two alternative methods for predicting binding sites: exact matches to validated binding site sequences and weight matrix scans. We then ask the question whether there is a characteristic association between a transcription factor or set thereof to a particular group of genes. Our approach is tested on genes, which are induced in dendritic cells in response to the cells’ exposure to LPS. We chose this example because the underlying signaling pathways are well understood. We demonstrate the benefit of conserved predicted binding sites in interpreting the LPS experiment. Additionally, we find that both methods for the prediction of conserved binding sites complement one another. Finally, our results suggest a distinct role for SRF in the context of LPS-induced gene expression.

Contact: christoph.dieterich@molgen.mpg.de

*To whom correspondence should be addressed.
Probabilistic models for identifying regulation networks
Authors: Friedman Nir
Published: October 2003

Microarray-based hybridization methods techniques allow to simultaneously measure the expression level for thousands of genes. Such measurements contain information about many different aspects of gene regulation and function, and indeed this type of experiments has become a central tool in biological research. A major computational challenge is finding ways to extract new biological understanding from this wealth of data. Our goal is to uncover the causal structure of the interactions between genes, with the aim of understanding the regulatory processes that bring about the observed expression patterns. I will argue that one way of addressing this question is a Bayesian framework, where we treat the measured expression level of each gene as a random variable and each regulatory interaction as a probabilistic dependency between such variables. In my talk, I will describe an ongoing project to use Bayesian networks and extensions of them to model such dependencies.

In the talk I will explain the basic foundations of the approach, the possible choices in defining the modeling language, the methods we use to learn models from data, and finally how we interpret the learned models. This latter stage includes validation against known biology, and constructing new hypotheses about the role of unknown genes.

I will present a progression of models that capture different aspect of gene regulation, and an assessment of their performance on several large scale yeast gene expression experiments.

This is joint work with Dana Pe’er, Iftach Nachman, Aviv Regev, Gal Elidan, Eran Segel, Micha Shapira, David Botstein, and Daphne Koller.

Contact: nir@cs.huji.ac.il. http://www.cs.huji.ac.il/~nir
MCMC genome rearrangement
Authors: Miklós István
Published: October 2003

Motivation: As more and more genomes have been sequenced, genomic data is rapidly accumulating. Genome-wide mutations are believed more neutral than local mutations such as substitutions, insertions and deletions, therefore phylogenetic investigations based on inversions, transpositions and inverted transpositions are less biased by the hypothesis on neutral evolution. Although efficient algorithms exist for obtaining the inversion distance of two signed permutations, there is no reliable algorithm when both inversions and transpositions are considered. Moreover, different type of mutations happen with different rates, and it is not clear how to weight them in a distance based approach.

Results: We introduce a Markov Chain Monte Carlo method to genome rearrangement based on a stochastic model of evolution, which can estimate the number of different evolutionary events needed to sort a signed permutation. The performance of the method was tested on simulated data, and the estimated numbers of different types of mutations were reliable. Human and Drosophila mitochondrial data were also analysed with the new method. The mixing time of the Markov Chain is short both in terms of CPU times and number of proposals.

Availability: The source code in C is available on request from the author.

Contact: miklos@stats.ox.ac.uk
Reconstructing tumor genome architectures
Authors: Raphael Benjamin J. , Volik Stanislav , Collins Colin , Pevzner Pavel A.
Published: October 2003

Although cancer progression is often associated with genome rearrangements, little is known about the detailed genomic architecture of tumor genomes. The attempt to reconstruct the genomic organization of a tumor genome recently resulted in the development of the End Sequence Profiling (ESP) technique, and the application of this technique to human MCF7 tumor cells. We formulate the ESP Genome Reconstruction Problem, and develop an algorithm to solve this problem in the case of sparse ESP data. We apply our algorithm to analyze human MCF7 tumor cells, and obtain the first reconstruction of the putative architecture of human MCF7 tumor genome. Our results assist in the ongoing ESP analysis of MCF7 tumors by suggesting additional ESP experiments for the completion of a reliable reconstruction of the MCF7 tumor genome, and by focusing BAC re-sequencing efforts.

Contact: braphael@ucsd.edu

*To whom correspondence should be addressed.
The proteome and the metabolome
Authors: Thornton Janet
Published: October 2003

High throughput technology is having an immense impact on biological research and one of the major challenges today is to use all this information to understand the complex network of interactions in the cell. Not only have we seen an exponential growth in genomic sequence data, but with the advent of transcriptome and proteome technologies—in combination with structural genomics and combinatorial chemistry—the flood of new data is currently overwhelming and will only increase. In biology the sequence and structure databases (to say nothing of the small molecule data) have traditionally been separate projects—certainly within the public sector. Databases for the transcriptome and proteome data are only just coming on line. Functional data has traditionally not been captured computationally, although pathway databases are now becoming increasingly important. In this presentation I will look towards future prospects in linking bioinformatics and chemoinformatics. I will describe in detail some current work at EBI on the different worlds of the ‘proteome’ and the metabolome. It is interesting to overview the full complement of small molecules in a cell and how this reflects the metabolic enzymes. The complement of metabolic enzymes in different species will be discussed and their evolution considered.

Contact: thornton@ebi.ac.ukhttp://www.ebi.ac.uk/Information/Staff/janet.html
Neuromuscular electrical stimulation enhances fracture healing: Results of an animal model
Authors: Park Sang‐Hyun , Silva Mauricio
Published: October 2003

Neuromuscular electrical stimulation (NMES) could simulate physiological muscle functions known to be associated with the normal bone healing process. The object of the present study was to evaluate the effect of NMES on fracture healing, using an animal model. Thirty rabbits received unilateral, transverse, mid‐tibial, 3‐mm gapped osteotomies that were stabilized with double‐bar external fixators. The femoral vein was ligated to induce venous stasis. From the fourth post‐operative day, the study group was treated with 1 h daily of NMES for four weeks, while the control group was treated without NMES. For NMES, two surface electrodes were used: one above the patellar tendon and another around the lateral thigh. Callus area and mineral content at the osteotomy gap were measured, biweekly, using computerized tomographic examinations. Biomechanical properties of healing were evaluated with a torsion test, eight weeks after the index operation. Osteotomies treated with NMES exhibited 31% (p = 0.01) higher mineral content and 27% (p = 0.009) larger callus area than control osteotomies at eight weeks. The maximum torque, torsional stiffness, angular displacement at maximum torque, and energy required to failure of specimens in the study group were 62% (p = 0.006), 29% (p = 0.03), 34.6% (p = 0.008), and 124% (p < 0.0001) higher, respectively, than those in the control group at eight weeks. The results of the present study demonstrated that the use of NMES can enhance callus development and mineralization, with the consequent improvement in biomechanical properties of the healing bone. © 2003 Orthopaedic Research Society. Published by Elsevier Ltd. All rights reserved.
Ultrasound measurement of fetal size in rural Guatemala
Authors: Neufeld L.M. , Haas J.D. , Grajeda R. , Martorell R.
Published: October 2003

Objectives: To describe the fetal growth pattern of a population from rural Guatemala and determine when during gestation growth faltering becomes evident. Methods: Ultrasound examinations were conducted for 319 women. Femur length (FL), biparietal diameter (BPD), abdominal (AC) and head circumference (HC) were compared with reference values. Results: FL and AC were similar to reference values throughout gestation. BPD and HC were below the 50th percentile by 30 weeks’ gestation and below the 10th percentile later in gestation. We expected all four dimensions to show marked growth restriction during gestation. Measurement differences may explain the results but would call into question the value of cross‐study comparisons. Infants born small for gestational age were small in all measures as early as 15 weeks. Conclusions: Fetal growth faltering begins in early gestation among infants who were born small. The lack of deviation from reference data for FL and AC requires further clarification.
A pilot tagging experiment on European hake (Merluccius merluccius): methodology and preliminary results
Authors: de Pontual Hélène , Bertignac Michel , Battaglia André , Bavouzet Gérard , Moguedet Philippe , Groison Anne-Laure
Published: October 2003

European hake (Merluccius merluccius) were caught alive in the northern Bay of Biscay in June/July 2002, using a codend specially designed to avoid crushing fish and also to retain water while hauling the trawl. In all, 1307 fish were tagged with anchor T-bar tags, injected with tetracycline, then released. The length range of the tagged and marked fish varied from 13 to 58 cm, and the modal size was 28 cm, at which length they were assumed to be 2–3 years old. A mean survival rate of 68.2% was estimated. Mortality was mainly caused by stress of capture and physical damage, and depended on the size of the catch and the depth of trawling. By the end of March 2003, 32 fish and three tags had been returned to the laboratory (a 2.7% return rate), the recapture data indicating that the probability of survival after release does not depend on catch depth or depth at location of release. For combined sexes, the somatic growth rate was estimated at 0.033 ± 0.019 cm day−1 (n=15). Males and females did not differ significantly in somatic growth rate, which were, respectively, 0.028±0.018 (n=6) and 0.033 ± 0.012 cm day−1 (n=6). This pilot experiment represents the first recorded mass tagging of European hake, which is known to be a very fragile species. The preliminary results indicate that it would be possible to carry out a large-scale tagging experiment of the European stocks in order to improve assessment and subsequent management decisions.
The Death of Tiaoxi (the ‘Leaping Play’): Ritual Theatre in the Northwest of China
Authors: Holm David
Published: October 2003

This article is about one of the most depressing fieldwork situations I have ever encountered in China.
Tiaoxi, basically, is dead. Some of the old artists are still alive, but the plays themselves were performed for the last time in 1987. There is video footage, taken by a professional team from the Ministry of Culture in Beijing, but the quality can only be described as execrable. There are abundant surviving libretti in manuscript, collected by field workers during the 1950s and again during the surveys of the 1980s, but they are almost all held in the Provincial Arts Research Institute in Xi'an, and no one is allowed to see them, not even the ‘old artists’ who donated them in the first place; not even photocopies are held by the county Cultural Bureau or by the artists themselves.
A rapid method for detection of putative RNAi target genes in
genomic data
Authors: Horesh Yair , Amir Amihood , Michaeli Shulamit , Unger Ron
Published: October 2003

RNAi, inhibition of gene expression by double stranded RNA molecules, has rapidly become a powerful laboratory technique to study gene function. The effectiveness of the procedure raised the question of whether this laboratory technique may actually mimic a natural cellular control mechanism that works on similar principles. Indeed recent evidence is accumulating to suggest that RNAi is a natural control mechanism that might even serve as a primitive immune response against RNA viruses and retroposons. Three different interference scenarios seem to be utilized by various RNAi mechanisms. One of the mechanisms involves degradation of mRNA molecules. Here we suggest a method to systematically scan entire genomes simultaneously for RNAi elements and the presence of cellular genes that are degraded by these RNAi elements via exact short base-pair matching. The method is based on scanning the genomes using a suffix tree data structure that was specifically modified to identify sets of combinations of repeated and inverted repeated sequences of 20 bp or more. Initial scan suggest that a large number, about 7% of C.elegans and 3% of C.briggsae genes, have the potential to be subject to natural RNAi control. Two methods are proposed to further analyze these genes to select the cases that are more likely to be actual cases of RNAi control. One method involves looking for ESTs that can provide direct evidence that RNAi control element are indeed expressed. The other method looks for synteny between C.elegans and C.briggsae assuming that genes that might be under RNAi control in both organisms are more likely to be biological significant. Taken together, supportive evidence was found for about 70 genes to be under RNAi control. Among these genes are: transposase, hormone receptors, homeobox proteins, defensin, actins, and several types of collagens. While our method is not capable of detecting all cases of natural RNAi control, it points to a large number of potential cases that can be further verified by experimental work.

Key words: RNAi, Suffix tree, C.elegans, C.briggsae, control mechanism

Contact: ron@biocom1.ls.biu.ac.il

*To whom correspondence should be addressed.
Discovery of significant rules for classifying cancer diagnosis
data
Authors: Li Jinyan , Liu Huiqing , Ng See-Kiong , Wong Limsoon
Published: October 2003

Methods and Results: We introduce a new method to discover many diversified and significant rules from high dimensional profiling data. We also propose to aggregate the discriminating power of these rules for reliable predictions. The discovered rules are found to contain low-ranked features; these features are found to be sometimes necessary for classifiers to achieve perfect accuracy. The use of low-ranked but essential features in our method is in constrast to the prevailing use of an ad-hoc number of only top-ranked features. On a wide range of data sets, our method displayed highly competitive accuracy compared to the best performance of other kinds of classification models. In addition to accuracy, our method also provides comprehensible rules to help elucidate the translation between raw data and useful knowledge.

Supplementary information: http://sdmc.i2r.a-star.edu.sg/GEDatasets/supplementaldata/eccb2003/ECCB2003.html.

Contact: jinyan@i2r.a-star.edu.sg

*To whom correspondence should be addressed.
Finding optimal degenerate patterns in DNA sequences
Authors: Shinozaki Daisuke , Akutsu Tatsuya , Maruyama Osamu
Published: October 2003

Motivation: The problem of finding transcription factor binding sites in the upstream regions of given genes is algorithmically an interesting and challenging problem in computational biology. A degenerate pattern over a finite alphabet Σ is a sequence of subsets of Σ. A string over IUPAC nucleic acid codes is also a degenerate pattern over Σ = {A, C, G, T}, and is used as one of the major patterns modeling transcription factor binding sites in the upstream regions of genes. However, it is known that the problem of finding a degenerate pattern consistent with both positive and negative string sets is in general NP-complete. Our aim is to devise a heuristic algorithm to find a degenerate pattern which is optimal for positive and negative string sets w.r.t. a given score function.

Results: We have proposed an enumerative algorithm called SUPERPOSITION for finding optimal degenerate patterns with a pruning technique, which works with most all reasonable score functions. The performance score of the algorithm has been compared with those of other popular motif-finding algorithms YMF, MEME and AlignACE on various sets of co-regulated genes of yeast. In the computational experiment, SUPERPOSITION has outperformed the others on several gene sets.

Availability: The python script SUPERPOSITION is available at http://www.math.kyushu-u.ac.jp/~om/softwares.html

Contact: om@math.kyushu-u.ac.jp

*To whom correspondence should be addressed.
Sources of genetic and phenotypic variability
Authors: Taddei François
Published: October 2003

The availability of hundreds of genomes allows us to learn rapidly about genomic differences between micro-organisms. Comparative genomics shows that horizontal gene transfer, mutations and rearrangements are frequent events in most species. The molecular mechanisms for these events have been described in laboratory experiments and sometimes even under ‘natural conditions’. Beside, when put in different environments, a given bacterial genome shows drastic change in its profile of expression (as evidenced by transcriptomic or proteomic experiments). Thus, clearly genetic differences and variation in environmental conditions lead to phenotypic variability (i.e. as text books say genotype X environment = phenotype). However, there might be other sources of phenotypic variability as experiments show that even with a given genome in a given environment one observes phenotypic variability. Even if this was recognized already in the 50’s, the causes and consequences of this other source of phenotypic variability remain to be described presumably by developping new interdisciplinary tools.

Contact: taddei@necker.fr
The fundamental thumb‐tip force vectors produced by the muscles of the thumb
Authors: Pearlman Jonathan L. , Roach Stephanie S. , Valero‐Cuevas Francisco J.
Published: October 2003

A rigorous description of the magnitude and direction of the 3D force vector each thumb muscle produces at the thumb‐tip is necessary to understand the biomechanical consequences to pinch of a variety of paralyses and surgical procedures (such as tendon transfers). In this study, we characterized the 3D force vector each muscle produces at the thumb‐tip, and investigated if these thumb‐tip force vectors scaled linearly with tendon tension. In 13 cadaver specimens, we measured the output 3D thumb‐tip force vector produced by each tendon acting on the thumb, plus two common tendon transfers, as a function of input tendon tension. After fixing the hand to a rigid frame, we mounted the thumb by configuring it in standardized key or opposition pinch posture and coupling the thumb‐tip to a rigidly held 6 degree‐of‐freedom force/torque sensor. Linear actuators applied tension to the distal tendons of the four extrinsic thumb muscles, and to six Nylon cords reproducing the lines of action of (i) the four intrinsic thumb muscles and (ii) two alternative tendon transfers commonly used to restore thumb opposition following low median nerve palsy. Each computer‐controlled linear actuator ramped tendon tension from zero to 1/3 of predicted maximal muscle force expected at each tendon, and back to zero, while we measured the 3D force vector at the thumb‐tip. In test/re‐test trials, we saw thumb‐tip force vectors were quite sensitive to mounting procedure, but also sensitive to variations in the seating of joint surfaces. We found that: (i) some thumb‐tip force vectors act in unexpected directions (e.g., the opponens force vector is parallel to the distal phalanx), (ii) the two tendon transfers produced patently different force vectors, and (iii) for most muscles, thumb‐tip force vectors do not scale linearly with tendon tension—likely due to load‐dependent viscoelastic tendon paths, joint seating and/or bone motion. Our 3D force vector data provide the first quantitative reference descriptions of the thumb‐tip force vectors produced by all thumb muscles and two tendon transfers. We conclude that it may not be realistic to assume in biomechanical models that thumb‐tip force vectors scale linearly with tendon tensions, and that our data suggest the thumb may act as a “floating digit” affected by load‐dependent trapezium motion. © 2003 Orthopaedic Research Society. Published by Elsevier Ltd. All rights reserved.
Protein refolding assisted by self‐assembled nanogels as novel artificial molecular chaperone
Authors: Nomura Yuta , Ikeda Masahiro , Yamaguchi Nozomi , Aoyama Yasuhiro , Akiyoshi Kazunari
Published: October 2003

Molecular chaperone‐like activity for protein refolding was investigated using nanogels of self‐assembly of cholesterol‐bearing pullulan. Nanogels effectively prevented protein aggregation (i.e. carbonic anhydrase and citrate synthase) during protein refolding from GdmCl denaturation. Enzyme activity recovered in high yields upon dissociation of the gel structure in which the proteins were trapped, by the addition of cyclodextrins. The nanogels assisted protein refolding in a manner similar to the mechanism of molecular chaperones, namely by catching and releasing proteins. The nanogels acted as a host for the trapping of refolded intermediate proteins. Cyclodextrin is an effector molecule that controls the binding ability of these host nanogels to proteins. The present nanogel system was also effective at the renaturation of inclusion body of a recombinant protein of the serine protease family.