bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic linkage of region containing the CREB1 gene to depressive disorders in women from families with recurrent, early‐onset, major depression
Authors: Zubenko George S. , Hughes Hugh B. , Maher Brion S. , Stiffler J. Scott , Zubenko Wendy N. , Marazita Mary L. 
Published: December 2002

AbstractThis report describes the results of a model‐free linkage analysis of six polymorphic markers, located in a 15 cM region of chromosome 2q33‐35, and unipolar Mood Disorders in 81 families identified by probands with Recurrent, Early‐Onset Major Depressive Disorder (RE‐MDD), a severe and familial form of clinical depression. Our findings reveal significant evidence of linkage of unipolar Mood Disorders to a 451 Kb region of 2q33‐34 flanked by D2S2321 and D2S2208 in these families. Increasing peak LOD scores were observed in both the single point and multipoint analyses for Mood Disorder phenotypes whose definitions embodied progressively less stringent severity criteria for inclusion in the affected group. The sex‐dependent multipoint linkage analysis of any Major or Minor Mood Disorders produced LOD scores that reached 6.331 and 6.866 at D2S2321 and D2S2208, respectively. Linkage of Mood Disorders to this region was observed exclusively among female affected relative pairs; no suggestion of linkage was observed when male affected relative pairs were analyzed. These observations imply that a sex‐specific susceptibility gene in this region contributes to the vulnerability of women in these families to the development of unipolar Mood Disorders that ranged in severity from minor to severe at the time of clinical assessment. The region between the markers that yielded the peak LOD score includes the CREB1 gene, which encodes a cAMP‐responsive element‐binding protein (CREB) that is a member of the bZIP family of transcription factors. Based on considerable clinical and preclinical evidence, CREB1 is an attractive candidate for a susceptibility gene for unipolar Mood Disorders. The sex‐specificity of the susceptibility locus identified by our study may result from reported synergistic interactions of CREB with nuclear estrogen receptors. © 2002 Wiley‐Liss, Inc.
Alcohol and genetics: New models
Authors: Crabbe John C. 
Published: December 2002

AbstractAlcoholism is a complex genetic trait; susceptibility is influenced by multiple genes of small effect. To pursue mechanistic studies, genetic animal models have been used. These models are partial, each addressing one or more of the contributing traits rather than the disease as a whole. Animal studies have modeled alcohol's rewarding effects, the development of tolerance, the pathological consequences to brain systems, and the dependence on alcohol inferred from the presence of withdrawal symptoms when the drug is removed. The classical genetic methods of inbred strain analysis and development and studies of selectively bred lines have been employed for more than 40 years. Recently, such studies have shown that a genetic tendency to experience severe withdrawal is associated with a tendency to avoid self‐administration of alcohol. Also recently, attempts to identify the specific genes conferring risk or protection from alcohol's effects have been undertaken. These studies have used mapping techniques based on gene sequence polymorphisms, studies of gene expression differences, and the use of candidate gene targeting such as creation of null mutants. Studies reviewed here have mapped quantitative trait loci (QTL) for many genes affecting alcohol sensitivity, tolerance, reward, and withdrawal severity. The furthest progress in gene mapping has been made toward one withdrawal QTL on mouse chromosome 4. Using multiple congenic strains, the gene conferring increased withdrawal severity has been isolated to a region of less than 1 centiMorgan, containing fewer than 20 genes. A strong candidate gene, coding for a multiple PS095/DLG/Z0‐1 (PDZ) binding domain zinc finger protein, cannot be excluded. Although many more such genes will be identified in the near future, their contribution to the mapped phenotype will be shown to be dependent on epistatic interactions with other risk genes, as well as genes in the animal's background. Progress in gene identification will also depend crucially on the precise description of the phenotypes being mapped so that their pleiotropic range of influence on the multi‐behavioral phenotypic syndrome can be determined. © 2002 Wiley‐Liss, Inc.
Markovian models for the developmental study of social behavior
Authors: Berchtold André , Sackett Gene 
Published: December 2002

AbstractBehavioral development involves changes in the probabilities of both social and nonsocial activities and the sequential pattern of activities over time. A number of methods have been offered for the analysis of these patterns of behavioral sequences. However, there continue to be problematic issues, including the analysis of nonstationary data; accommodation of changes in patterns within an observation period, or over repeated observations or age; and identification of differences in pattern changes between individuals or groups, and the factors responsible for these differences. In this work, we analyze data from 15 young monkeys (Macaca nemestrina) using classification and Markovian methods, including a new approach to nonstationary data called the double‐chain Markov model (DCCM). These methods allowed us to identify differences in behavior patterns that differentiate between normal subjects and those presenting developmental anomalies. Am. J. Primatol. 58:149–167, 2002. © 2002 Wiley‐Liss, Inc.
Brain alkaline intracellular pH after neonatal encephalopathy
Authors: Robertson Nicola J. , Cowan Frances M. , Cox I. Jane , Edwards A. David 
Published: December 2002

AbstractExperimental studies demonstrate an alkaline shift in brain intracellular pH (pHi) after hypoxia‐ischemia (HI). In infants with neonatal encephalopathy after HI, our aims were to assess (1) brain pHi during the first 2 weeks after birth in infants categorized according to magnetic resonance imaging (MRI) during the first 2 weeks after birth and at more than 3 months of age, and neurodevelopmental outcome at 1 year; (2) the relationship between brain pHi and lactate/creatine; and (3) duration of alkaline brain pHi. Seventy‐eight term infants with neonatal encephalopathy were studied using MR techniques. One hundred and fifty‐one studies were performed throughout the first year including 56 studies of 50 infants during the first 2 weeks after birth. pHi was calculated using phosphorus‐31 MR spectroscopy and lactate/creatine was measured using proton MRS. The mean (standard deviation [SD]) brain pHi during the first 2 weeks after birth in infants with severely abnormal versus normal MRI was 7.24 (SD, 0.17) versus 7.04 (SD, 0.05; p < 0.001); in infants who subsequently developed cerebral atrophy versus those who did not: 7.23 (SD, 0.17) versus 7.06 (SD, 0.06; p < 0.05); in infants who died or had a severe neurodevelopmental impairment versus normal outcome: 7.28 (SD, 0.15) versus 7.11 (SD, 0.09; p < 0.05). Brain alkalosis was associated with increased brain lactate/creatine (p < 0.001). pHi remained more alkaline in the severe outcome group up to 20 weeks after birth (p < 0.05). Ann Neurol 2002;52:000–000
Loss of myostatin attenuates severity of muscular dystrophy in mdx mice
Authors: Wagner Kathryn R. , McPherron Alexandra C. , Winik Nicole , Lee Se‐Jin 
Published: December 2002

AbstractMyostatin, a transforming growth factor–β family member, is a negative regulator of skeletal muscle growth. To explore the therapeutic potential of targeting myostatin in settings of muscle degeneration, we crossed myostatin null mutant mice with mdx mice, a model for Duchenne and Becker muscular dystrophy. Mdx mice lacking myostatin were stronger and more muscular than their mdx counterparts. Diaphragm muscle showed less fibrosis and fatty remodeling, suggesting improved muscle regeneration.
Primary dystonia: Is abnormal functional brain architecture linked to genotype?
Authors: Tros̆t Maja , Carbon Maren , Edwards Christine , Ma Yilong , Raymond Deborah , Mentis Marc J. , Moeller James R. , Bressman Susan B. , Eidelberg David 
Published: December 2002

AbstractThe DYT1 dystonia mutation is associated with an abnormal metabolic brain network characterized by hypermetabolism of the basal ganglia, supplementary motor area, and the cerebellum. In this study, we quantified the activity of this network in carriers of other dystonia mutations to determine whether this functional abnormality is linked to genotype. The findings suggest that the DYT1 metabolic topography is not genotype specific and may be present in carriers of other dystonia mutations.
Modeling stability in neuron and network function: the role of activity in homeostasis
Authors: Marder Eve , Prinz Astrid A. 
Published: November 2002

AbstractIndividual neurons display characteristic firing patterns determined by the number and kind of ion channels in their membranes. We describe experimental and computational studies that suggest that neurons use activity sensors to regulate the number and kind of ion channels and receptors in their membrane to maintain a stable pattern of activity and to compensate for ongoing processes of degradation, synthesis and insertion of ion channels and receptors. We show that similar neuronal and network outputs can be produced by a number of different combinations of ion channels and synapse strengths. This suggests that individual neurons of the same class may each have found an acceptable solution to a genetically determined pattern of activity, and that networks of neurons in different animals may produce similar output patterns by somewhat variable underlying mechanisms. BioEssays 24:1145–1154, 2002. © 2002 Wiley Periodicals, Inc.
Modelling the heart: insights, failures and progress
Authors: Noble Denis 
Published: November 2002

AbstractMathematical models of the heart have developed over a period of about 40 years. Cell types in all regions of the heart have been modelled and they are now being incorporated into anatomically detailed models of the whole organ. This combination is leading to the creation of the first ‘virtual organ,’ which is being used in drug discovery and testing, and in simulating the action of devices, such as cardiac defibrillators. Simulation is a necessary tool of analysis in attempting to understand biological complexity. We often learn as much from the failures as from the successes of mathematical models. It is the iterative interaction between experiment and simulation that is important. Examples are given where this process has been instrumental in some of the major advances in the field. BioEssays 24:1155–1163, 2002. © 2002 Wiley‐Periodicals, Inc.
Modeling transcriptional regulatory networks
Authors: Bolouri Hamid , Davidson Eric H. 
Published: November 2002

AbstractDevelopmental processes in complex animals are directed by a hardwired genomic regulatory code, the ultimate function of which is to set up a progression of transcriptional regulatory states in space and time. The code specifies the gene regulatory networks (GRNs) that underlie all major developmental events. Models of GRNs are required for analysis, for experimental manipulation and, most fundamentally, for comprehension of how GRNs work. To model GRNs requires knowledge of both their overall structure, which depends upon linkage amongst regulatory genes, and the modular building blocks of which GRNs are heirarchically constructed. The building blocks consist of basic transcriptional control processes executed by one or a few functionally linked genes. We show how the functions of several such building blocks can be considered in mathematical terms, and discuss resolution of GRNs by both “top down” and “bottom up” approaches. BioEssays 24:1118–1129, 2002. © 2002 Wiley‐Periodicals, Inc.
Modelling ‘evo‐devo’ with RNA
Authors: Fontana Walter 
Published: November 2002

AbstractThe folding of RNA sequences into secondary structures is a simple yet biophysically grounded model of a genotype–phenotype map. Its computational and mathematical analysis has uncovered a surprisingly rich statistical structure characterized by shape space covering, neutral networks and plastogenetic congruence. I review these concepts and discuss their evolutionary implications. BioEssays 24:1164–1177, 2002. © 2002 Wiley‐Periodicals, Inc.
The dynamics of cell cycle regulation
Authors: Tyson John J. , Csikasz‐Nagy Attila , Novak Bela 
Published: November 2002

AbstractMajor events of the cell cycle—DNA synthesis, mitosis and cell division—are regulated by a complex network of protein interactions that control the activities of cyclin‐dependent kinases. The network can be modeled by a set of nonlinear differential equations and its behavior predicted by numerical simulation. Computer simulations are necessary for detailed quantitative comparisons between theory and experiment, but they give little insight into the qualitative dynamics of the control system and how molecular interactions determine the fundamental physiological properties of cell replication. To that end, bifurcation diagrams are a useful analytical tool, providing new views of the dynamical organization of the cell cycle, the role of checkpoints in assuring the integrity of the genome, and the abnormal regulation of cell cycle events in mutants. These claims are demonstrated by an analysis of cell cycle regulation in fission yeast. BioEssays 24:1095–1109, 2002. © 2002 Wiley‐Periodicals, Inc.
What is complexity?
Authors: Adami Christoph 
Published: November 2002

AbstractArguments for or against a trend in the evolution of complexity are weakened by the lack of an unambiguous definition of complexity. Such definitions abound for both dynamical systems and biological organisms, but have drawbacks of either a conceptual or a practical nature. Physical complexity, a measure based on automata theory and information theory, is a simple and intuitive measure of the amount of information that an organism stores, in its genome, about the environment in which it evolves. It is argued that physical complexity must increase in molecular evolution of asexual organisms in a single niche if the environment does not change, due to natural selection. It is possible that complexity decreases in co‐evolving systems as well as at high mutation rates, in sexual populations, and in time‐dependent landscapes. However, it is reasoned that these factors usually help, rather than hinder, the evolution of complexity, and that a theory of physical complexity for co‐evolving species will reveal an overall trend towards higher complexity in biological evolution. BioEssays 24:1085–1094, 2002. © 2002 Wiley‐Periodicals, Inc.
Complexity of calcium signaling in synaptic spines
Authors: Franks Kevin M. , Sejnowski Terrence J. 
Published: November 2002

AbstractLong‐term potentiation and long‐term depression are thought to be cellular mechanisms contributing to learning and memory. Although the physiological phenomena have been well characterized, little consensus of their underlying molecular mechanisms has emerged. One reason for this may be the under‐appreciated complexity of the signaling pathways that can arise if key signaling molecules are discretely localized within the synapse. Recent findings suggest an unanticipated degree of structural organization at the synapse, and improved methods in cellular imaging of living tissue have provided much‐needed information about the intracellular dynamics of Ca2+, thought to be critical for both LTP and LTD. In this review, we briefly summarize some of these developments, and show that a more complete understanding of cellular signaling depends on the successful integration of traditional biochemistry and molecular biology with the spatial and temporal details of synaptic ultrastructure. Biophysically realistic computer simulations can have an important role in bridging these disciplines. BioEssays 24:1130–1144, 2002. © 2002 Wiley‐Periodicals, Inc.
Mathematical models of HIV pathogenesis and treatment
Authors: Wodarz Dominik , Nowak Martin A. 
Published: November 2002

AbstractWe review mathematical models of HIV dynamics, disease progression, and therapy. We start by introducing a basic model of virus infection and demonstrate how it was used to study HIV dynamics and to measure crucial parameters that lead to a new understanding of the disease process. We discuss the diversity threshold model as an example of the general principle that virus evolution can drive disease progression and the destruction of the immune system. Finally, we show how mathematical models can be used to understand correlates of long‐term immunological control of HIV, and to design therapy regimes that convert a progressing patient into a state of long‐term non‐progression. BioEssays 24:1178–1187, 2002. © 2002 Wiley‐Periodicals, Inc.
Stability of expanded beds during the application of crude feedstock
Authors: Lin Dong‐Qiang , Kula Maria‐Regina , Liten Alisa , Thömmes Jörg 
Published: November 2002

AbstractExpanded bed adsorption is an integrated technology that allows the introduction of a particle containing feedstock without the risk of blocking the bed. Provided a perfectly classified fluidized bed (termed expanded bed) is formed in the crude feed, a sorption performance comparable to packed beds is found. During the application of biomass containing samples to stable expanded beds an increase in bed expansion due to the higher density and viscosity of the feed is encountered. In this article it is investigated whether the expanded bed condition is also fulfilled during the transition in bed expansion from lower to higher density (i.e., from an equilibration buffer to a biomass containing feedstock). Residence time distribution analyses were performed by using model systems and a yeast suspension during this transition phase. It is shown that in systems in which the biomass does not interact with the fluidized stationary phase, the perfectly classified fluidization is maintained also during this transition phase regardless of the type of feedstock. Additional bed expansion takes place in an “ordered” manner without compromising bed stability. In case of biomass/adsorbent interactions, a deterioration in bed stability is found directly when the crude feed is loaded. © 2002 Wiley Periodicals, Inc. Biotechnol Bioeng 81: 21‐26, 2003,
Endoplasmic reticulum signaling as a determinant of recombinant protein expression
Authors: Cudna Renata E. , Dickson Alan J. 
Published: November 2002

AbstractGeneration of functional recombinant proteins requires efficient and undisturbed functioning of the ER–Golgi secretory pathway in host cells. In large‐scale production, where target proteins are highly overexpressed, this pathway can be easily congested with unfolded or misfolded proteins. Accumulating evidence suggests that, in addition to responsibility for protein processing, ER is also an important signaling compartment and a sensor of cellular stress. Two ER responses have been described to arise from the overaccumulation of proteins: unfolded protein response (UPR) and ER overload response (EOR). UPR and EOR employ various mechanisms at the transcriptional and the translational levels to deal efficiently and appropriately with encountered stress. This review will outline the molecular bases of ER functioning and stress response, highlight the relevance of ER signaling to the large‐scale cell culture productivity and discuss possible approaches to the improvement of the secretion capacities of recombinant cells. © 2002 Wiley Periodicals, Inc. Biotechnol Bioeng 81: 56–65, 2003.
Thermally triggered purification and immobilization of elastin–OPH fusions
Authors: Shimazu Mark , Mulchandani Ashok , Chen Wilfred 
Published: November 2002

AbstractA bifunctional fusion protein consisting of organophosphorus hydrolase (OPH) and elastin‐like polypeptide (ELP) was synthesized for the detoxification of organophosphorus compounds. ELPs undergo a reversible phase transition upon an increase in temperature, forming hydrophobic aggregates. This thermally triggered property of phase transition allows for a simple and rapid means of purifying the fusion protein. Over 1,300‐fold purification was achieved after only 2 cycles of inverse phase transition. The purified fusion protein showed identical kinetic properties as the native OPH with only a modest 10% increase in Km and a 5% decrease of Kcat. The ability of the ELP domain to form collapsed aggregates also improved long‐term stability of the fusion enzyme. Aggregated ELP–OPH retained nearly 100% activity over a span of three weeks. In addition to facilitating purification and stability, the ELP moiety served as a hydrophobic tag for one‐step immobilization of the fusion protein onto hydrophobic surfaces. The ELP–OPH was capable of rapidly degrading paraoxon while immobilized. The protein also retained ELP functionality of reversible phase transition thereby allowing for the regeneration of the treated surface. This technology offers a swift and convenient means for purification, immobilization, and regeneration of OPH onto a variety of hydrophobic surfaces by simple environmental triggers. © 2002 Wiley Periodicals, Inc. Biotechnol Bioeng 81: 74–79, 2003.
Unveiling steady‐state multiplicity in hybridoma cultures: The cybernetic approach
Authors: Namjoshi Abhijit Anand , Hu Wei‐Shou , Ramkrishna Doraiswami 
Published: November 2002

AbstractMammalian cells grown in suspension produce waste metabolites such as lactate, alanine, and ammonia, which reduce the yield of cell mass and the desired product on the nutrients supplied. Previous studies (Cruz et al., 1999; Europa et al., 2000; Follstad et al., 1999) have shown that the cells can be made to alter their metabolism by starving them on their nutrients in continuous cultures at low dilution rates or starting the culture as a fed‐batch. This leads to multiple steady states in continuous reactors, with some states being more favorable than others. Mathematical models that take into account the metabolic regulation that leads to these multiple steady states are invaluable tools for bioreactor control. In this article we present a cybernetic modeling strategy in which Metabolic Flux Analysis (MFA) is used to guide the cybernetic formulation. The hybridoma model presented as a result of this strategy considers the partially substitutable, partially complementary nature of glucose and glutamine. The choice of competitions within the network is guided by MFA and the model is successful in explaining the three multiple steady states observed. The cybernetic model though identified for the hybridoma experiments of Hu and others (Europa et al., 2000) seem generally applicable to mammalian systems as it captures the pathways that are common to mammalian cells grown in suspension. The model presented here could be used for start‐up strategies for continuous reactors and model‐based feedback control for maintaining high productivity of the reactor. © 2002 Wiley Periodicals, Inc. Biotechnol Bioeng 81: 80–91, 2003.
Distributed model of solid waste anaerobic digestion: Effects of leachate recirculation and pH adjustment
Authors: Vavilin Vasily A. , Rytov Sergey V. , Lokshina Ljudmila Ya. , Pavlostathis Spyros G. , Barlaz Morton A. 
Published: November 2002

AbstractA distributed model of solid waste digestion in a 1‐D bioreactor with leachate recirculation and pH adjustment was developed to analyze the balance between the rates of polymer hydrolysis/acidogenesis and methanogenesis during the anaerobic digestion of municipal solid waste (MSW). The model was calibrated on previously published experimental data generated in 2‐L reactors filled with shredded refuse and operated with leachate recirculation and neutralization. Based on model simulations, both waste degradation and methane production were stimulated when inhibition was prevented rapidly from the start, throughout the reactor volume, by leachate recirculation and neutralization. An optimal strategy to reduce the time needed for solid waste digestion is discussed. © 2002 Wiley Periodicals, Inc. Biotechnol Bioeng 81: 66–73, 2003.