bluuebunny/crossref_metadata_2025_split huggingface dataset:
HAPLORE: a program for haplotype reconstruction in general pedigrees without recombination
Authors: Zhang Kui , Sun Fengzhu , Zhao Hongyu 
Published: July 2004

AbstractMotivation: Haplotype reconstruction is an essential step in genetic linkage and association studies. Although many methods have been developed to estimate haplotype frequencies and reconstruct haplotypes for a sample of unrelated individuals, haplotype reconstruction in large pedigrees with a large number of genetic markers remains a challenging problem.Methods: We have developed an efficient computer program, HAPLORE (HAPLOtype REconstruction), to identify all haplotype sets that are compatible with the observed genotypes in a pedigree for tightly linked genetic markers. HAPLORE consists of three steps that can serve different needs in applications. In the first step, a set of logic rules is used to reduce the number of compatible haplotypes of each individual in the pedigree as much as possible. After this step, the haplotypes of all individuals in the pedigree can be completely or partially determined. These logic rules are applicable to completely linked markers and they can be used to impute missing data and check genotyping errors. In the second step, a haplotype-elimination algorithm similar to the genotype-elimination algorithms used in linkage analysis is applied to delete incompatible haplotypes derived from the first step. All superfluous haplotypes of the pedigree members will be excluded after this step. In the third step, the expectation-maximization (EM) algorithm combined with the partition and ligation technique is used to estimate haplotype frequencies based on the inferred haplotype configurations through the first two steps. Only compatible haplotype configurations with haplotypes having frequencies greater than a threshold are retained.Results: We test the effectiveness and the efficiency of HAPLORE using both simulated and real datasets. Our results show that, the rule-based algorithm is very efficient for completely genotyped pedigree. In this case, almost all of the families have one unique haplotype configuration. In the presence of missing data, the number of compatible haplotypes can be substantially reduced by HAPLORE, and the program will provide all possible haplotype configurations of a pedigree under different circumstances, if such multiple configurations exist. These inferred haplotype configurations, as well as the haplotype frequencies estimated by the EM algorithm, can be used in genetic linkage and association studies.Availability: The program can be downloaded from http://bioinformatics.med.yale.eduContact: hongyu.zhao@yale.edu
A Conserved Upstream Open Reading Frame Mediates Sucrose-Induced Repression of Translation[W]
Authors: Wiese Anika , Elzinga Nico , Wobbes Barry , Smeekens Sjef 
Published: July 2004

AbstractSugars have been shown to regulate transcription of numerous genes in plants. Sucrose controls translation of the group S basic region leucine zipper (bZIP)-type transcription factor ATB2/AtbZIP11 (Rook et al., 1998a). This control requires the unusually long 5′ untranslated region (UTR) of the gene. Point mutations and deletions of the 5′UTR have uncovered the sequences involved. A highly conserved upstream open reading frame (uORF) coding for 42 amino acids is essential for the repression mechanism. It is conserved in 5′UTRs of bZIP transcription factors from other Arabidopsis thaliana genes and many other plants. ATB2/AtbZIP11 is normally expressed in association with vascular tissues. Ectopic expression of a 5′UTR construct shows that the sucrose repression system is functional in all tissues. AtbZIP2 is another Arabidopsis bZIP transcription factor gene harboring the conserved uORF, which is regulated similarly via sucrose-induced repression of translation. This suggests a general function of the conserved uORF in sucrose-controlled regulation of expression. Our findings imply the operation of a sucrose-sensing pathway that controls translation of several plant bZIP transcription factor genes harboring the conserved uORF in their 5′UTRs. Target genes of such transcription factors will then be regulated in sucrose-dependent way.
Functional Divergence of Duplicated Genes Formed by Polyploidy during Arabidopsis Evolution[W]
Authors: Blanc Guillaume , Wolfe Kenneth H. 
Published: July 2004

AbstractTo study the evolutionary effects of polyploidy on plant gene functions, we analyzed functional genomics data for a large number of duplicated gene pairs formed by ancient polyploidy events in Arabidopsis thaliana. Genes retained in duplicate are not distributed evenly among Gene Ontology or Munich Information Center for Protein Sequences functional categories, which indicates a nonrandom process of gene loss. Genes involved in signal transduction and transcription have been preferentially retained, and those involved in DNA repair have been preferentially lost. Although the two members of each gene pair must originally have had identical transcription profiles, less than half of the pairs formed by the most recent polyploidy event still retain significantly correlated profiles. We identified several cases where groups of duplicated gene pairs have diverged in concert, forming two parallel networks, each containing one member of each gene pair. In these cases, the expression of each gene is strongly correlated with the other nonhomologous genes in its network but poorly correlated with its paralog in the other network. We also find that the rate of protein sequence evolution has been significantly asymmetric in &gt;20% of duplicate pairs. Together, these results suggest that functional diversification of the surviving duplicated genes is a major feature of the long-term evolution of polyploids.
A Semidominant Mutation in an Arabidopsis Mitogen-Activated Protein Kinase Phosphatase-Like Gene Compromises Cortical Microtubule Organization[W]
Authors: Naoi Kuniko , Hashimoto Takashi 
Published: July 2004

AbstractReversible protein phosphorylation regulates many cellular processes, including the dynamics and organization of the microtubule cytoskeleton, but the events mediating it are poorly understood. A semidominant phs1-1 allele of the Arabidopsis thaliana PROPYZAMIDE-HYPERSENSITIVE 1 locus exhibits phenotypes indicative of compromised cortical microtubule functions, such as left-handed helical growth of seedling roots, defective anisotropic growth at low doses of microtubule-destabilizing drugs, enhancement of the temperature-sensitive microtubule organization1-1 phenotype, and less ordered and more fragmented cortical microtubule arrays compared with the wild type. PHS1 encodes a novel protein similar to mitogen-activated protein kinase (MAPK) phosphatases. In phs1-1, a conserved Arg residue in the noncatalytic N-terminal region is exchanged with Cys, and the mutant PHS1 retained considerable phosphatase activity in vitro. In mammalian MAPK phosphatases, the corresponding region serves as a docking motif for MAPKs, and analogous Arg substitutions severely inhibit the kinase–phosphatase association. Transgenic studies indicate that the phs1-1 mutation acts dominant negatively, whereas the null phs1-2 allele is recessive embryonic lethal. We propose that the PHS1 phosphatase regulates more than one MAPK and that a subset of its target kinases is involved in the organization of cortical microtubules.
Direct Role of a Viroid RNA Motif in Mediating Directional RNA Trafficking across a Specific Cellular Boundary[W]
Authors: Qi Yijun , Peélissier Thierry , Itaya Asuka , Hunt Elizabeth , Wassenegger Michael , Ding Biao 
Published: July 2004

AbstractThe plasmodesmata and phloem form a symplasmic network that mediates direct cell–cell communication and transport throughout a plant. Selected endogenous RNAs, viral RNAs, and viroids traffic between specific cells or organs via this network. Whether an RNA itself has structural motifs to potentiate trafficking is not well understood. We have used mutational analysis to identify a motif that the noncoding Potato spindle tuber viroid RNA evolved to potentiate its efficient trafficking from the bundle sheath into mesophyll that is vital to establishing systemic infection in tobacco (Nicotiana tabacum). Surprisingly, this motif is not necessary for trafficking in the reverse direction (i.e., from the mesophyll to bundle sheath). It is not required for trafficking between other cell types either. We also found that the requirement for this motif to mediate bundle sheath-to-mesophyll trafficking is dependent on leaf developmental stages. Our results provide genetic evidence that (1) RNA structural motifs can play a direct role in mediating trafficking across a cellular boundary in a defined direction, (2) the bundle sheath–mesophyll boundary serves as a novel regulatory point for RNA trafficking between the phloem and nonvascular tissues, and (3) the symplasmic network remodels its capacity to traffic RNAs during plant development. These findings may help further studies to elucidate the interactions between RNA motifs and cellular factors that potentiate directional trafficking across specific cellular boundaries.
Allelic Variation of Gene Expression in Maize Hybrids[W]
Authors: Guo Mei , Rupe Mary A. , Zinselmeier Christopher , Habben Jeffrey , Bowen Benjamin A. , Smith Oscar S. 
Published: July 2004

AbstractAllelic expression variation of nonimprinted autosomal genes has recently been uncovered in mouse hybrids and humans. The allelic expression variation is attributed to differences in noncoding DNA sequences and does not involve epigenetic regulation or gene imprinting. This expression variation is suggested to play important roles in determining phenotypic diversity. Virtually nothing is known about such allele-specific expression variation in a hybrid plant where two alleles are compared in the same genetic context. We examined parental transcript accumulation in maize (Zea mays) hybrids using allele-specific RT-PCR analysis. Among 15 genes analyzed, 11 showed differences at the RNA level, ranging from unequal expression of the two alleles (biallelic) to expression of a single allele (monoallelic). Maternal or paternal transmission had little effect on the allele-specific transcript ratio of nearly all genes analyzed, suggesting that parent-of-origin effect was minimal. We analyzed the allelic difference in genetically contrasting hybrids and hybrids under high planting density and drought stress. Whereas a genetically improved modern hybrid expressed both alleles, a less improved old hybrid frequently showed mono-allelic expression. Furthermore, the two alleles in the hybrid responded differentially to abiotic stresses. The results of allele-specific regulation in different tissues in responding to environment and stress suggest an unequivalent function of the parental alleles in the hybrid, which may have an impact on heterosis.
JASMONATE-INSENSITIVE1Encodes a MYC Transcription Factor Essential to Discriminate between Different Jasmonate-Regulated Defense Responses in Arabidopsis[W]
Authors: Lorenzo Oscar , Chico Jose M. , Saénchez-Serrano Jose J. , Solano Roberto 
Published: July 2004

AbstractIn spite of the importance of jasmonates (JAs) as plant growth and stress regulators, the molecular components of their signaling pathway remain largely unknown. By means of a genetic screen that exploits the cross talk between ethylene (ET) and JAs, we describe the identification of several new loci involved in JA signaling and the characterization and positional cloning of one of them, JASMONATE-INSENSITIVE1 (JAI1/JIN1). JIN1 encodes AtMYC2, a nuclear-localized basic helix-loop-helix-leucine zipper transcription factor, whose expression is rapidly upregulated by JA, in a CORONATINE INSENSITIVE1–dependent manner. Gain-of-function experiments confirmed the relevance of AtMYC2 in the activation of JA signaling. AtMYC2 differentially regulates the expression of two groups of JA-induced genes. The first group includes genes involved in defense responses against pathogens and is repressed by AtMYC2. Consistently, jin1 mutants show increased resistance to necrotrophic pathogens. The second group, integrated by genes involved in JA-mediated systemic responses to wounding, is activated by AtMYC2. Conversely, Ethylene-Response-Factor1 (ERF1) positively regulates the expression of the first group of genes and represses the second. These results highlight the existence of two branches in the JA signaling pathway, antagonistically regulated by AtMYC2 and ERF1, that are coincident with the alternative responses activated by JA and ET to two different sets of stresses, namely pathogen attack and wounding.
The Activity of Antiepileptic Drugs as Histone Deacetylase Inhibitors
Authors: Eyal Sara , Yagen Boris , Sobol Eyal , Altschuler Yoram , Shmuel Miriam , Bialer Meir 
Published: July 2004

Summary:  Purpose: Valproic acid (VPA), one of the widely used antiepileptic drugs (AEDs), was recently found to inhibit histone deacetylases (HDACs). HDAC inhibitors of a wide range of structures, such as hydroxamic acids, carboxylic acids, and cyclic tetrapeptides, have various effects on transformed and nontransformed cells, including neuromodulation and neuroprotection. The aim of this study was to assess comparatively the activity of traditional and newer AEDs as HDAC inhibitors. Methods: After incubation of HeLa cells with the tested AEDs, histone hyperacetylation was assessed by immunoblotting with an antibody specific to acetylated histone H4. Direct HDAC inhibition by AEDs was estimated by using HeLa nuclear extract as an HDACs source and an acetylated lysine substrate. Results: We found that in addition to VPA, topiramate (TPM) inhibited HDACs with apparent Ki values of 2.22 ± 0.67 mM. Although levetiracetam (LEV) had no direct effect on HDACs, its major carboxylic acid metabolite in humans, 2‐pyrrolidinone‐n‐butyric acid (PBA), inhibited HDACs with Ki values of 2.25 ± 0.78 mM. The AEDs LEV, phenobarbital, phenytoin, carbamazepine, ethosuximide, gabapentin, and vigabatrin did not inhibit HDACs. The compounds that directly inhibited HDACs also induced the accumulation of acetylated histone H4 in HeLa cells. The effects of TPM and PBA on histone acetylation were significant at 0.25 mM and 1 mM, respectively. Conclusions: We found that in addition to VPA, the newer AED TPM and the major metabolite of LEV, PBA, are able to induce histone hyperacetylation in human cells, although with lower potencies than VPA.
Propofol Treatment of Refractory Status Epilepticus: A Study of 31 Episodes
Authors: Rossetti Andrea O. , Reichhart Marc D. , Schaller Marie‐Denise , Despland Paul‐André , Bogousslavsky Julien 
Published: July 2004

Summary:  Purpose: Refractory status epilepticus (RSE) is a critical medical condition with high mortality. Although propofol (PRO) is considered an alternative treatment to barbiturates for the management of RSE, only limited data are available. The aim of this study was to assess PRO effectiveness in patients with RSE. Methods: We retrospectively considered all consecutive patients with RSE admitted to the medical intensive care unit (ICU) between 1997 and 2002 treated with PRO for induction of EEG‐monitored burst suppression. Subjects with anoxic encephalopathy showing pathological N20 on somatosensory evoked potentials were excluded. Results: We studied 31 RSE episodes in 27 adults (16 men, 11 women; median age, 41.5 years). All patients received PRO, and six also subsequently thiopental (THP). Clonazepam (CZP) was administered with PRO, and other antiepileptic drugs (AEDs) concomitant with PRO and THP. RSE was successfully treated with PRO in 21 (67%) episodes and with THP after PRO in three (10%). Median PRO injection rate was 4.8 mg/kg/h (range, 2.1–13), median duration of PRO treatment was 3 days (range, 1–9), and median duration of ICU stay was 7 days (range, 2–42). In 24 episodes in which the patient survived, shivering after general anesthesia was seen in 10 episodes, transient dystonia and hyperlipemia in one each, and mild neuropsychological impairment in five. The seven deaths were not directly related to PRO use. Conclusions: PRO administered with CZP was effective in controlling most of RSE episodes, without major adverse effects. In this setting, PRO may therefore represent a valuable alternative to barbiturates. A randomized trial with these drug classes could definitively assess their respective role in RSE treatment.
Intracellular Calcium Increase in Epileptiform Activity: Modulation by Levetiracetam and Lamotrigine
Authors: Pisani Antonio , Bonsi Paola , Martella Giuseppina , De Persis Cristiano , Costa Cinzia , Pisani Francesco , Bernardi Giorgio , Calabresi Paolo 
Published: July 2004

Summary:  Purpose: Alterations in neuronal calcium (Ca2+) homeostasis are believed to play an essential role in the generation and propagation of epileptiform events. Levetiracetam (LEV) and lamotrigine (LTG), novel antiepileptic drugs (AEDs), were tested on epileptiform events and the corresponding elevations in intracellular Ca2+ concentration ([Ca2+]i) recorded from rat neocortical slices. Methods: Electrophysiological recordings were performed from single pyramidal neurons from a slice preparation. Spontaneous epileptiform events consisting of long‐lasting, repetitive paroxysmal depolarization shifts (PDSs) and interictal spike activity were induced by reducing the magnesium concentration from the solution and by adding bicuculline and 4‐aminopyridine. Simultaneously, microfluorimetric measurements of [Ca2+]i were performed. Optical imaging with Ca2+ indicators revealed a close correlation between Ca2+ transients and epileptiform events. Results: Both LEV and LTG were able to reduce both amplitude and duration of PDSs, as well as the concomitant elevation in [Ca2+]i, in a dose‐dependent fashion. Whole‐cell patch‐clamp recordings from isolated neocortical neurons revealed that LEV significantly reduced N‐, and partially P/Q‐type high‐voltage‐activated (HVA) Ca2+ currents, whereas sodium currents were unaffected. Interestingly, the inhibitory effects of LEV were mimicked and occluded by LTG or by a combination of ω‐conotoxin GVIA and ω‐agatoxin IVA, selective blockers of N‐ and P/Q‐type HVA channels, respectively, suggesting a common site of action for these AEDs. Conclusions: These results demonstrate that large, transient elevations in neuronal [Ca2+]i correlate to epileptiform discharges. The antagonistic effects of LEV and LTG on [Ca2+]i overload might represent the basis for their anticonvulsant efficacy and could preserve neuronal viability.
Serum Androgen Levels and Testicular Structure during Pubertal Maturation in Male Subjects with Epilepsy
Authors: Mikkonen Kirsi , Tapanainen Päivi , Pakarinen Arto J. , Päivänsalo Markku , Isojärvi Jouko I. T. , Vainionpää Leena K. 
Published: July 2004

Summary:  Purpose: To evaluate reproductive endocrine function in boys and young men with epilepsy taking an antiepileptic drug in a population‐based, controlled study. Methods: Seventy patients and 70 controls matched for age and pubertal stage participated in this study. Twenty‐eight patients were taking carbamazepine (CBZ); five, lamotrigine (LTG); 12, oxcarbazepine (OXC); and 25, valproate (VPA) as monotherapy for epilepsy. All subjects were examined clinically, and their medical histories were obtained. Serum reproductive hormone and sex hormone–binding globulin concentrations were measured, and testicular ultrasonography was performed. Results: Serum testosterone levels were within the normal range in young male patients with epilepsy. However, the patients taking VPA had high serum androstenedione levels at all pubertal stages. In prepuberty, their serum androstenedione values were already approximately fivefold compared with the values of the controls (8.7 nM; SD, 4.0 vs. 1.8 nM, SD, 1.0; p < 0.0003), and they were elevated in 64% of the VPA‐treated patients compared with none of the other patients, p = 0.0006. Serum sex hormone–binding globulin levels were increased, and serum dehydroepiandrosterone sulfate concentrations decreased in the pubertal patients taking CBZ. The mean testicular volumes did not differ between the patients and the controls. Conclusions: CBZ and VPA, but not LTG and OXC, are associated with changes in serum sex‐hormone levels in boys and young men with epilepsy. However, the long‐term health consequences of these reproductive endocrine changes during pubertal development remain to be established.
Unilateral Hippocampal Sclerosis with Contralateral Temporal Scalp Ictal Onset
Authors: Mintzer Scott , Cendes Fernando , Soss Jason , Andermann Frederick , Engel Jerome , Dubeau Francois , Olivier Andre , Fried Itzhak 
Published: July 2004

Summary:  Purpose: To investigate the clinical characteristics and surgical outcomes in patients with unilateral hippocampal sclerosis whose scalp ictal EEG recordings localize to the opposite temporal lobe. Methods: We retrospectively reviewed the data of all adult patients who had undergone depth electrode implantation for suspected temporal lobe epilepsy (TLE) at UCLA (1993–2000) or the Montreal Neurological Institute (1991–1998) to identify patients who had (a) unilateral hippocampal atrophy, and (b) surface ictal recordings in which the majority of seizures appeared to initiate in the opposite temporal lobe, with few or none that were concordant with the hippocampal atrophy. Results: Of 109 patients with suspected TLE who underwent depth electrode study at the two centers, five patients met the aforementioned criteria. Four of these five had very severe hippocampal atrophy, whereas the fifth had mild atrophy but extensive signal change on magnetic resonance imaging (MRI). Depth electrode recordings in four of the five patients yielded clear ictal onset in the mesial temporal lobe ipsilateral to the imaging abnormality (contralateral to apparent scalp ictal onset). One patient had an unusual bitemporal onset pattern, which was nonetheless suggestive of onset in the sclerotic hippocampus. No patient had intracranial ictal onset contralateral to the imaging abnormality. All patients underwent resection of the structurally abnormal temporal lobe. After follow‐up of ≥2 years, four (80%) of five patients were seizure free, while the fifth showed lesser improvement (class III). Conclusions: Some patients with severe hippocampal sclerosis (sometimes called a “burned‐out hippocampus”) have atypical spread of ictal discharges, resulting in apparent gross discordance between imaging and scalp ictal recordings. These patients nonetheless have excellent surgical outcomes on the whole. Whether such patients may forego intracranial recordings requires further study.