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Results for “Functional potential”

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PubMed1999

Electrical conductivity imaging via contactless measurements.

A new imaging modality is introduced to image electrical conductivity of biological tissues via contactless measurements. This modality uses magnetic excitation to induce currents inside the body and measures the magnetic fields of the induced currents. In this study, the mathematical basis of the methodology is analyzed and numerical models are developed to simulate the imaging system. The induced currents are expressed using the A-phi formulation of the electric field where A is the magnetic vector potential and phi is the scalar potential function. It is assumed that A describes the primary magnetic vector potential that exists in the absence of the body. This assumption considerably simplifies the solution of the secondary magnetic fields caused by induced currents. In order to solve phi for objects of arbitrary conductivity distribution a three-dimensional (3-D) finite-element method (FEM) formulation is employed. A specific 7 x 7-coil system is assumed nearby the upper surface of a 10 x 10 x 5-cm conductive body. A sensitivity matrix, which relates the perturbation in measurements to the conductivity perturbations, is calculated. Singular-value decomposition of the sensitivity matrix shows various characteristics of the imaging system. Images are reconstructed using 500 voxels in the image domain, with truncated pseudoinverse. The noise level is assumed to produce a representative signal-to-noise ratio (SNR) of 80 dB. It is observed that it is possible to identify voxel perturbations (of volume 1 cm3) at 2 cm depth. However, resolution gradually decreases for deeper conductivity perturbations.

Diagnostic Imaging↗

PubMed1999

Association of Nef with the human immunodeficiency virus type 1 core.

Highly conserved among primate lentiviruses, the human immunodeficiency virus type 1 (HIV-1) Nef protein enhances viral infectivity by an unknown mechanism. Nef-defective virions are blocked at a stage of the HIV-1 life cycle between entry and reverse transcription, possibly virus uncoating. Nef is present in purified HIV-1 particles; however, it has not been determined whether Nef is specifically recruited into HIV-1 particles or whether virion-associated Nef plays a functional role in HIV-1 replication. To address the specificity and potential functionality of virion-associated Nef, we determined the subviral localization of Nef. HIV-1 cores were isolated by detergent treatment of concentrated virions followed by equilibrium density gradient sedimentation. Relative to HIV-1 virions, HIV-1 cores contained equivalent amounts of reverse transcriptase and integrase, decreased amounts of the viral matrix protein, and trace quantities of the viral transmembrane glycoprotein gp41. Examination of the particles by electron microscopy revealed cone-shaped structures characteristic of lentiviral cores. Similar quantities of proteolytically processed Nef protein were detected in gradient fractions of HIV-1 cores and intact virions. In addition, detergent-resistant subviral complexes isolated from immature HIV-1 particles contained similar quantities of Nef as untreated virions. These results demonstrate that Nef stably associates with the HIV-1 core and suggest that virion-associated Nef plays a functional role in accelerating HIV-1 replication.

Gene Products, nef↗

PubMed2005

Using a suppression subtractive library-based approach to identify tobacco genes regulated in response to short-term sulphur deficit.

Monitoring expression at the transcriptional level is an essential first step for the functional analysis of plant genes. Genes encoding proteins directly involved in sulphur metabolism constitute only a small fraction of all the genes affected by sulphur deficiency stress. Transcriptional responses to various periods of sulphur deprivation have been extensively studied in Arabidopsis thaliana; however, no corresponding data are available for Solanaceae sp. To address this problem, a subtractive library-based approach to search for tobacco genes regulated by a short-term sulphur starvation has been adopted. In this work, 38 genes were identified, of which 22 were regulated positively and 16 were regulated negatively. The transcript levels of the representative genes were monitored in four parts of the plants (mature and immature leaves, stems, and roots), which exhibited differential sulphur deficiency. Interestingly, some genes exhibit different regulation of expression in different parts of the plants. Database analysis allowed assignment of the potential function for many of the identified genes; however, the functions of a small number of genes strongly regulated by sulphur starvation remain unknown. The genes were grouped into nine functional categories, each including both up- and down-regulated genes. The possible links between the identified regulated genes and sulphur metabolism are considered, and compared where possible with expression patterns in Arabidopsis thaliana. Although no obvious regulatory genes were identified, the genes encoding proteins of unknown function remain as potential components of the regulatory processes.

Down-Regulation↗

PubMed2024

The associations between functional dyspepsia and potential risk factors: A comprehensive Mendelian randomization study.

BACKGROUND: Previous cross-sectional studies have identified multiple potential risk factors for functional dyspepsia (FD). However, the causal associations between these factors and FD remain elusive. Here we aimed to fully examine the causal relationships between these factors and FD utilizing a two-sample MR framework. METHODS: A total of 53 potential FD-related modifiable factors, including those associated with hormones, metabolism, disease, medication, sociology, psychology, lifestyle and others were obtained through a comprehensive literature review. Independent genetic variants closely linked to these factors were screened as instrumental variables from genome-wide association studies (GWASs). A total of 8875 FD cases and 320387 controls were available for the analysis. The inverse variance weighted (IVW) method was employed as the primary analytical approach to assess the relationship between genetic variants of risk factors and the FD risk. Sensitivity analyses were performed to evaluate the consistency of the findings using the weighted median model, MR-Egger and MR-PRESSO methods. RESULTS: Genetically predicted depression (OR 1.515, 95% confidence interval (CI) 1.231 to 1.865, p = 0.000088), gastroesophageal reflux disease (OR 1.320, 95%CI 1.153 to 1.511, p = 0.000057) and years of education (OR 0.926, 95%CI 0.894 to 0.958, p = 0.00001) were associated with risk for FD in univariate MR analyses. Multiple medications, alcohol consumption, poultry intake, bipolar disorder, mood swings, type 1 diabetes, elevated systolic blood pressure and lower overall health rating showed to be suggestive risk factors for FD (all p<0.05 while ≥0.00167). The positive causal relationship between depression, years of education and FD was still significant in multivariate MR analyses. CONCLUSIONS: Our comprehensive MR study demonstrated that depression and lower educational attainment were causal factors for FD at the genetic level.

Humans↗

PubMed2004

Nonlinear Krönig-Penney model.

We study the nonlinear Schrödinger equation with a periodic delta-function potential. This realizes a nonlinear Krönig-Penney model, with physical applications in the context of trapped Bose-Einstein condensate alkaly gases and in the transmission of signals in optical fibers. We find analytical solutions of zero-current Bloch states. Such wave functions have the same periodicity of the potential, and, in the linear limit, reduce to the Bloch functions of the Krönig-Penney model. We also find classes of solutions having a periodicity different from that of the external potential. We calculate the chemical potential of such states and compare it with the linear excitation spectrum.

Journal Article↗

PubMed2026

Hidden proteins encoded by non-canonical open reading frames: A review.

There is increasing evidence that translation is not limited to annotated protein-coding genes. Ribosome profiling sequencing, mass spectrometry-based proteomics, and immunopeptidomics have identified the productive translation of non-canonical open reading frames (ORFs). This suggests that the functional proteome includes not only conserved proteins but also proteins hidden in non-coding RNAs and de novo proteins. Some of these translated products are functional peptides, while others may be non-functional, potentially arising from evolutionary events. Several non-canonical ORF-encoded peptides have been found to regulate multiple physiological and pathological functions, particularly in cancer, immunity, and inflammation, indicating that they have potential as biomarkers and novel therapeutic targets. To better understand the diversity of functional peptides and translated non-canonical ORFs based on existing data, we summarize their classification according to transcriptional features and supporting evidence, including non-canonical ORFs located in ncRNAs and canonical mRNAs. This review provides a concise summary of the origin, discovery methods, and classification of non-canonical ORFs. It offers insights into the origins and functions of non-canonical ORF-encoded peptides from an evolutionary perspective, while also exploring the biological functions and regulatory mechanisms of these non-canonical ORF-encoded hidden proteins in tumorigenesis and progression.

Open Reading Frames↗

PubMed2004

Neurogenesis and neuroadaptation.

Adult neurogenesis has been established as a further mechanism of neural plasticity in the adult nervous system, and numerous studies are beginning to provide insights into the functional purposes and consequences for this new mode of neuroadaptation. These studies have approached the problem from a molecular scale, attempting to identify signaling factors that regulate stem cell function, as well as a systems or behavioral level, attempting to establish correlative and potentially causal links between neurogenesis and behavior. These two approaches have begun to reveal several potential functions for adult hippocampal neurogenesis, including adaptive roles in learning and memory, adaptation to novel environments, potential links to depression and moods, and possible responses to injury. The further implementation and convergence of these two approaches and the development of new methods to study the problem will yield further insights into both what are the many neuroadaptive roles of neurogenesis and potential means to harness it for neuroregeneration.

Adaptation, Physiological↗

PubMed2000

Evolution of N-terminal sequences of the vertebrate HOXA13 protein.

While the the role of the homeodomain in HOX function has been evaluated extensively, little attention has been given to the non-homeodomain portions of the HOX proteins. To investigate the evolution of the HOXA13 protein and to identify conserved residues in the N-terminal region of the protein with potential functional significance, N-terminal Hoxa13 coding sequences were PCR-amplified from fish, amphibian, reptile, chicken, and marsupial and eutherian mammal genomic DNA. Compared with fish HOXA13, the mammalian protein has increased in size by 35% primarily owing to the accumulation of alanine repeats and flanking segments rich in proline, glycine, or serine within the first 215 amino acids. Certain residues and amino acid motifs were strongly conserved, and several HOXA13 N-terminal domains were also shared in the paralogous HOXB 13 and HOXD13 genes; however, other conserved regions appear to be unique to HOXA13. Two domains highly conserved in HOXA13 orthologs are shared with Drosophila AbdB and other vertebrate AbdB-like proteins. Marsupial and eutherian mammalian HOXA13 proteins have three large homopolymeric alanine repeats of 14, 12, and 17-18 residues that are absent in reptiles, birds, and fish. Thus, the repeats arose after the divergence of reptiles from the lineage that would give rise to the mammals. In contrast, other short homopolymeric alanine repeats in mammalian HOXA13 have remained virtually the same length, suggesting that forces driving or limiting repeat expansion are context dependent. Consecutive stretches of identical third-base usage in alanine codons within the large repeats were found, supporting replication slippage as a mechanism for their generation. However, numerous species-specific base substitutions affecting third-base alanine repeat codon positions were observed, particularly in the largest repeat. Therefore, if the large alanine repeats were present prior to eutherian mammal development as is suggested by the opossum data, then a dynamic process of recurring replication slippage and point mutation within alanine repeat codons must be considered to reconcile these observations. This model might also explain why the alanine repeats are flanked by proline, serine, and glycine-rich sequences, and it reveals a biological mechanism that promotes increases in protein size and, potentially, acquisition of new functions.

Alanine↗

PubMed1995

Diversity and patterns of regulation of nicotinic receptor subtypes.

In our studies we explored the functional relevance of nAChR diversity, in part from the perspective of nAChR as ideal targets for regulatory influences, including those mediated via actions of ligands at other "interacting" receptors. We explored possible mechanisms for nAChR regulation and roles played by nAChR subtype and subunit diversity in those processes. We showed that regulatory factors can influence nAChR numbers at transcriptional and posttranscriptional levels and can affect nAChR function and subcellular distribution. We also demonstrated that nAChR expression can be influenced (1) by nicotinic ligands, (2) by second messengers, (3) by growth factors, (4) by agents targeting the nucleus, and (5) by agents targeting the cytoskeleton. We found common effects of some regulatory influences on more than one nAChR subtype, and we found instances where regulatory influences differ for different cell and nAChR types. Even from the very limited number of these initial studies, it is evident that nAChR subunit and subtype diversity, which alone can provide diversity in nAChR functions, localization, and ligand sensitivity, dovetails with diversity in cellular signaling mechanisms that can affect nAChR expression to amplify the potential functional plasticity of cholinoceptive cells. As examples, we discussed potential roles for nAChR diversity and regulatory plasticity in synapse remodeling and in changes in neuronal circuit conditions. These examples illustrate how nAChR diversity could play important roles in the regulation of nervous system function.

Animals↗

PubMed2002

CARPEL FACTORY, a Dicer homolog, and HEN1, a novel protein, act in microRNA metabolism in Arabidopsis thaliana.

BACKGROUND: In metazoans, microRNAs, or miRNAs, constitute a growing family of small regulatory RNAs that are usually 19-25 nucleotides in length. They are processed from longer precursor RNAs that fold into stem-loop structures by the ribonuclease Dicer and are thought to regulate gene expression by base pairing with RNAs of protein-coding genes. In Arabidopsis thaliana, mutations in CARPEL FACTORY (CAF), a Dicer homolog, and those in a novel gene, HEN1, result in similar, multifaceted developmental defects, suggesting a similar function of the two genes, possibly in miRNA metabolism. RESULTS: To investigate the potential functions of CAF and HEN1 in miRNA metabolism, we aimed to isolate miRNAs from Arabidopsis and examine their accumulation during plant development in wild-type plants and in hen1-1 and caf-1 mutant plants. We have isolated 11 miRNAs, some of which have potential homologs in tobacco, rice, and maize. The putative precursors of these miRNAs have the capacity to form stable stem-loop structures. The accumulation of these miRNAs appears to be spatially or temporally controlled in plant development, and their abundance is greatly reduced in caf-1 and hen1-1 mutants. HEN1 homologs are found in bacterial, fungal, and metazoan genomes. CONCLUSIONS: miRNAs are present in both plant and animal kingdoms. An evolutionarily conserved mechanism involving a protein, known as Dicer in animals and CAF in Arabidopsis, operates in miRNA metabolism. HEN1 is a new player in miRNA accumulation in Arabidopsis, and HEN1 homologs in metazoans may have a similar function. The developmental defects associated with caf-1 and hen1-1 mutations and the patterns of miRNA accumulation suggest that miRNAs play fundamental roles in plant development.

Amino Acid Sequence↗

PubMed1985

Acute and subchronic effects of MJ-13859, a potential antipsychotic drug, on rat brain dopaminergic function.

The potential antipsychotic drug, MJ-13859, was tested for its acute and subchronic effects on rat brain dopaminergic neurotransmission and function. This drug exhibited an IC50 for displacement of [3H]spiperone binding of 6.35 nM which was similar to trifluoperazine, a potent classical antipsychotic drug. In female rats, MJ-13859 was slightly less potent than trifluoperazine for induction of catalepsy, inhibition of stimulant-induced hyperactivity and for increasing striatal, frontal cortical and olfactory tubercule dopamine metabolism. Both drugs also blocked dopamine autoreceptors on striatal dopamine nerve endings. When administered i.p., rather than s.c., the effect of MJ-13859 on dopamine metabolism was reduced significantly. When administered to male rats, the response of dopamine metabolism to drug was reduced, but a similar inhibition of stimulated activity occurred as in female rats. These results suggest a rapid first pass metabolism of MJ-13859 in the rat and that the antistimulant effect may be partly independent of the antidopaminergic effects. Osmotic minipumps were implanted s.c. for 2 week continuous infusion of MJ-13859 at doses of 1.0 or 3.0 mg/kg/day. Unlike classical antipsychotic drugs, MJ-13859 did not cause a subsensitivity to the ability of acute haloperidol challenge (0.1 mg/kg s.c.) to increase dopamine metabolism. After allowing a 4-day drug washout period before [3H]spiperone binding assay for D2 receptors, neither the maximum binding nor Kd were altered in rats treated for 2 weeks with 3.0 mg/kg/day of MJ-13859. Haloperidol at 1.0 mg/kg/day for 2 weeks caused a 57% increase in D2 receptor maximum binding.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Identification and characterization of a functional human Ig V lambda VI germline gene.

We have isolated from a human genomic library a potentially functional and distinctive germline gene, designated IGLV6S1, that encodes for light chains of the V lambda VI subgroup. An identical germline gene was cloned from fibroblasts obtained from a patient with light-chain-associated amyloidosis (AL amyloidosis) whose serum and urine contained, respectively, a monoclonal IgG lambda VI protein and a lambda VI Bence Jones protein. Isolation and characterization of cDNA cloned from the patient's bone marrow-derived monoclonal plasma cells revealed that the nucleotide and predicted protein sequences of the rearranged gene were approximately 95% and approximately 90% homologous to those of the germline gene, respectively. The finding that the transcriptional start site for lambda VI RNA synthesis was located upstream of the putative TATA-box promoter, rather than downstream as found for the V lambda II subgroup, implies that a different transcriptional machinery controls the expression of the human V lambda VI-gene family.

Amino Acid Sequence↗

PubMedDate not supplied

Is sequence conservation in interferons due to selection for functional proteins?

The human alpha-interferon (IFN-alpha) gene family consists of at least 14 potentially functional non-allelic members; the amino acid sequences they encode differ from each other by up to approximately 20% of their residues. Human IFN-beta, which is encoded by a single gene, is distantly related to the IFN-alpha family; it differs in 67% of its residues from IFN-alpha 2. There is considerable evidence that IFN-alpha and -beta compete for the same receptors on their target cells. Comparison of 14 non-allelic human IFN-alpha sequences and the IFN-beta sequence has revealed that 37 of 166 residues are completely conserved and that several of these are arranged in clusters, for example at positions 29-33, 47-50 and 136-150. It is commonly held that evolutionary conservation of amino acids indicates that the residues in question are essential for function. To test this hypothesis in the case of IFNs, we have introduced single site-directed point mutations into the strictly conserved codons 48 and 49 of the IFN-alpha 2 gene which form part of the longest uninterrupted cluster (position 47-50). We report here that the mutant proteins, containing Tyr, Ser and Cys instead of Phe48, or His instead of Gln49, have biological activities indistinguishable from those of wild-type IFN-alpha. In addition, when Glu62, a residue conserved in all known alpha and beta IFNs of man, mouse and cattle, was replaced by Lys, antiviral activity remained unchanged.

Amino Acid Sequence↗

PubMed2005

Inositol 1,4,5-trisphosphate 3-kinases: functions and regulations.

Inositol 1,4,5-trisphosphate 3-kinase (IP3 3-kinase/IP(3)K) plays an important role in signal transduction in animal cells by phosphorylating inositol 1,4,5-trisphosphate (IP3) to inositol 1,3,4,5-tetrakisphosphate (IP(4)). Both IP(3) and IP(4) are critical second messengers which regulate calcium (Ca(2+)) homeostasis. Mammalian IP3Ks are involved in many biological processes, including brain development, memory, learning and so on. It is widely reported that Ca(2+) is a canonical second messenger in higher plants. Therefore, plant IP3K should also play a crucial role in plant development. Recently, we reported the identification of plant IP3K gene (AtIpk2beta/AtIP3K) from Arabidopsis thaliana and its characterization. Here, we summarize the molecular cloning, biochemical properties and biological functions of IP3Ks from animal, yeast and plant. This review also discusses potential functions of IP3Ks in signaling crosstalk, inositol phosphate metabolism, gene transcriptional control and so on.

Animals↗

PubMed1998

RNA structure inhibits the TRAP (trp RNA-binding attenuation protein)-RNA interaction.

TRAP (trp RNA-binding attenuation protein) regulates expression of the tryptophan biosynthetic genes in response to tryptophan in Bacillus subtilis by binding to two sites containing a series of 9 or 11 (G/U)AG triplet repeats that are generally separated by two or three spacer nucleotides. Previous mutagenesis experiments have identified three TRAP residues, Lys-37, Lys-56, and Arg-58 that are essential for RNA binding. The location of these residues on the TRAP oligomer supports the proposal that RNA binds TRAP by encircling the TRAP oligomer. In this work, we show that RNAs containing 11 GAG or UAG repeats separated by CC dinucleotide spacers (((G/U)AGCC)11) form stable structures that inhibit binding to TRAP. This conclusion is based on the effects of temperature and Mg2+ on the affinity of TRAP for RNAs with CC spacers combined with UV hyperchromicity and circular dichroism. Furthermore, introducing the base analogue 7-deazaguanosine in the ((G/U)AGCC)11 RNAs stabilized the TRAP-RNA interaction. This effect was associated with decreased stability of the RNA structure as measured by circular dichroism spectroscopy. The precise nature of the structure of the ((G/U)AGCC)11 RNAs is not known but evidence is presented that it involves noncanonical interactions. We also observed that substitution of Arg-58 with Lys further reduced the ability of TRAP to interact with structured RNAs. Since in vivo function of TRAP may involve binding to structured RNAs, we suggest a potential function for this residue, which is conserved in TRAP from three different bacilli.

Bacillus↗

PubMed2002

The neuropathological and behavioral consequences of intraspinal microglial/macrophage activation.

Activated microglia and macrophages (CNS macrophages) have been implicated in the secondary or "bystander" pathology (e.g. axon injury, demyelination) that accompanies traumatic or autoimmune injury to the brain and spinal cord. These cells also can provide neurotrophic support and promote axonal regeneration. Studying the divergent functional potential of CNS macrophages in trauma models is especially difficult due to the various degradative mechanisms that are initiated prior to or concomitant with microglial/macrophage activation (e.g. hemorrhage, edema, excitotoxicity, lipid peroxidation). To study the potential impact of activated CNS macrophages on the spinal cord parenchyma, we have characterized an in vivo model of non-traumatic spinal cord neuroinflammation. Specifically, focal activation of CNS macrophages was achieved using stereotaxic microinjections of zymosan. Although microinjection does not cause direct mechanical trauma, localized activation of macrophages with zymosan acts as an "inflammatory scalpel" causing tissue injury at and nearby the injection site. The present data reveal that activation of CNS macrophages in vivo can result in permanent axonal injury and demyelination. Moreover, the pathology can be graded and localized to specific white matter tracts to produce quantifiable behavioral deficits. Further development of this model will help to clarify the biological potential of microglia and macrophages and the molecular signals that control their function within the spinal cord.

Animals↗

PubMed1997

Protein sequence-structure compatibility criteria in terms of statistical hypothesis testing.

The assignment of query protein sequences to probable folds in a threading approach is based on the statistical analysis (learning) of structural properties of amino acids in known protein structures. We formalize the recognition problem in terms of mathematical statistics, namely statistical hypothesis testing. Our general formulation leads to various mathematical forms of a decision rule function for evaluation of the quality of a sequence-structure fit. Three criteria were derived according to a likelihood ratio approach. Two of them have new functional forms while the third happens to coincide with the mean force potential function previously derived under the additional assumption of the Boltzmann law. New decision rule functions employ (i) the Parzen estimator of a probability density and (ii) the newly introduced non-parametric statistic with known asymptotic distribution. We compared criteria efficiency by a 'structure seeks sequence' search for three highly populated template folds through a query library of non-homologous sequences of proteins with known 3D structure using residue accessibility as an environmental variable. Various criteria reflect different underlying statistical propositions and thus often recognize diverse correct sequence-structure matches. On the other hand, if an amino acid sequence is recognized as compatible with a template by each of three decision rules it appears that one can make a more reliable inference of sequence-structure relationship since almost all false positives obtained by the three criteria differ.

Algorithms↗

PubMed2002

The role of MLL in hematopoiesis and leukemia.

The MLL gene, also called HRX or ALL-1, was originally identified as a recurrent chromosomal translocation in particular subtypes of acute lymphocytic leukemia (ALL) and acute myelogenous leukemia (AML). Reciprocal rearrangements of the MLL gene are most common in infant ALL and secondary AML. Because of the unique association with infant leukemia and the intriguingly immature and mixed lineage phenotype of leukemic cells, the authors speculate that the wild-type MLL gene plays an important role early in the development of the hematopoietic system. This article reviews recent progress in understanding the function of the wild-type MLL protein, with particular consideration of potential functions within the developing hematopoietic system. Murine gain- and loss-of-function models have provided clues to the normal functions of MLL and altered functions of oncogenic MLL fusion proteins. Biochemical and genetic approaches using other model organisms have also elucidated mechanisms by which these functions are achieved.

Animals↗