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PubMedDate not supplied

Elucidating endometrial function in the post-genomic era.

The post-genomic era has now arrived, and science and biology are on the threshold of a transition from understanding functions of single molecules and pathways in cells, tissues and whole organisms to understanding integrative systems. The endometrium is a dynamic tissue that responds to multiple stimuli, depending on physiological and environmental conditions, including steroid hormones, an implanting conceptus, withdrawal of steroid hormones, contraceptive steroids, selective steroid hormone receptor modulators, infection, transient cell populations, and metaplastic and neoplastic agents. High throughput technologies with regard to DNA, RNA and proteins are well positioned to enable a thorough understanding of the dynamic changes and integrative systems involved in endometrial maturation, desquamation, receptivity to implantation, infertility, pregnancy maintenance and failure, inflammation and infection, and malignant transformation. This monograph reviews some of the salient features of the new technologies and summarizes current information on endometrial biology derived from these approaches.

Embryo Implantation↗

PubMed2005

Nucleocytoplasmic trafficking in plant cells.

In a eukaryotic cell, the nuclear envelope (NE) separates genetic information from the environment of biosynthesis and metabolism. Transfer of macromolecules across the NE involves the nuclear pores--large multisubunit protein complexes--and machinery that facilitates rapid, directional, and selective transport. While core elements of the transport process are conserved between kingdoms, different solutions to similar problems have also evolved. Although the structure and composition of the yeast and mammalian nuclear pore have been unraveled recently, the plant nuclear pore remains largely enigmatic. Like any other process, nucleocytoplasmic transport can be regulated. Several examples from plants are discussed that promise insights into the regulation of signaling pathways. While controlling the partitioning of cellular components, the nuclear envelope also presents an obstacle to viruses and transforming agents that need access to the genome, and different mechanisms have evolved to overcome this obstacle. Finally, the recent recognition of the importance of small RNAs for gene regulation emphasizes the need to understand small RNA nuclear export and the levels of its regulation. This review attempts to wed our molecular-mechanistic understanding of nucleocytoplasmic trafficking drawn from all model systems with the intriguing examples of regulated nucleocytoplasmic partitioning in plants.

Active Transport, Cell Nucleus↗

PubMed2005

The role of proteins of the transforming growth factor-beta superfamily in the intraovarian regulation of follicular development.

Ovarian follicular development occurs in a hierarchical manner with each follicle having a unique biochemical composition at any moment in time. It has long been understood that a precise coordination between the growth and maturation of the oocyte and adjacent follicular cells (i.e. somatic cells) is essential in order to produce an oocyte that is fully competent to undergo fertilization and embryo development. In addition to the critical endocrine signalling pathways between the hypothalamus, pituitary and ovary, it is now evident that the oocyte itself is important in influencing the microenvironment of the developing follicle by regulating, via paracrine and autocrine mechanisms, its own maturation as well as somatic cell proliferation, differentiation and ovulation rate. Several of the key oocyte-derived regulating factors are members of the transforming growth factor-beta (TGF-beta) superfamily and to date the best understood are growth differentiation factor 9 (GDF9), bone morphogenetic protein 15 (BMP15) and BMP6. Significant species differences appear to exist in the relative importance of these growth factors and much remains to be elucidated about their roles in the human ovary. More information on the roles of these factors during ovarian follicular development is likely to advance new therapeutic applications for management of fertility as well as our understanding of how better to assess oocyte quality.

Animals↗

PubMed2004

New pharmacological perspectives and therapeutic potential of PPAR-gamma agonists.

The peroxisome proliferator-activated receptor gamma (PPARgamma), a member of the nuclear hormone receptor superfamily has classically been characterized for its implications in adipocyte differentiation and fat metabolism. Recently, PPARgamma has been implicated in the pathophysiology of inflammatory and immune responses possibly through inhibition of the mitogen-activated protein kinase (MAPK) pathways or the activation of the transcription nuclear factor kappa B (NF-kappaB). Thus, these agents might also have therapeutic potential in the treatment of gastrointestinal inflammatory disorders, such as ulcerative colitis and Crohn's disease. The synthetic thiazolidinediones (TZDs), a novel class of insulin-sensitizing drugs, were the first class of compounds identified as PPARgamma ligands, and represent a significant advance in anti-diabetic therapy. However, there is less information about endogenous ligands, although the prostaglandin (PG)J(2) and the oxidized phosphatidylcholine have been suggested. Furthermore, PPARgamma ligands have been shown to be potent inhibitors of angiogenesis, a process necessary for tumor growth and metastasis, and protect against cellular transformation. Further work is needed to establish in detail the anti-proliferative and pro-differentiation mechanisms of PPARgamma activators and their efficacy in certain cancers.

Alzheimer Disease↗

PubMed1987

Afferent and efferent control of stance and gait: developmental changes in children.

Comparisons were made between the cerebral potentials (CPs) and EMG responses of leg muscles evoked by perturbation impulses during stance and gait in normal children aged from 1 to 10 years. Changes in the efferent arm of the reflex systems during development were reflected in parallel changes with age of the afferent system, expressed in the CP: in the youngest children (1-2 years of age) monosynaptic stretch reflex potentials appeared following perturbations during both stance and gait, together with a reduced level of longer latency EMG responses. The CP, too, had a profile that did not, at this early stage, differ in either condition. In children from 6 to 10 years of age, the adult pattern was reached, with the suppression of monosynaptic stretch reflexes and the early part of the CP during gait perturbation. This is interpreted as an inhibition of group I afferents at both segmental and supraspinal levels, involving suppression of both segmental stretch reflexes and group I signals to supraspinal centres. This control of afferent information had yet to be established in early infancy. The age group from 2 to 6 years showed progressive changes, with an increase in both the level and phasic nature of polysynaptic EMG responses and a corresponding transformation of the latency and shape of the CP. It is suggested that maturation of compensatory EMG responses during gait is achieved by the establishment of descending inhibition of group I afferents and facilitation of polysynaptic spinal reflexes via group II afferents.

Afferent Pathways↗

PubMed1975

Carbon-13 Nuclear Magnetic Resonance Analysis of Metabolism in Soybean Labeled by CO(2).

Fourier transform (13)C nuclear magnetic resonance spectra have been obtained of intact, fresh soybean ovules (Glycine max L. cv. Dare) harvested from pods subtended by a trifoliolate exposed to (13)CO(2) 1 to 3 days earlier. The high resolution spectra are interpreted in terms of the labeled sugars and lipids in the ovule. Comparison of the spectra taken over the 3-day period permits qualitative estimates of sugar metabolism and rates of lipid synthesis. The spectra also contain information about the distribution of labels within the lipid chains. This information leads to a method of estimating the extent to which glucose degradation in the synthesizing soybean ovule is involved in the reactions of the phosphogluconate pathway.

Journal Article↗

PubMed2026

Worldwide Innovative Network Consortium: Building a Common Global Cancer Database.

This review shares the ongoing work of the global Worldwide Innovative Network (WIN) Consortium for Precision Medicine to synthesize emerging cancer treatment data and to define the requirements for a common global cancer database that can truly support precision oncology. We performed a narrative review of emerging cancer treatment data, molecular profiling technologies, and existing clinicogenomic databases, focusing on how tumors are characterized, how subgroups are defined, and how demographic, lifestyle, and environmental factors are captured. The growth in molecular profiling technologies and the development of new targeted therapies are transforming cancer care. Tumors, regardless of tissue origin, are increasingly defined as composites of multiple, often rare, subgroups, each with distinct biology and likely response to specific therapies, based on multidimensional profiling of the tumor and its microenvironment. The solution lies in building vast databases that capture racial and ethnic diversity, reflected in genomic data, as well as diet and lifestyle factors that may have epigenetic impact on gene expression and post-translational modifications. A truly inclusive and informative data set must reflect global diversity, and there are multiple examples of demography-dependent differences in genomic signals. With members caring for and studying patients with cancer across five continents, WIN is actively exploring pathways to create a global cancer database, rich in clinical and molecular detail, granular enough for precise analysis, and large enough to power artificial intelligence-driven insights, provided appropriate data quality, validation, and governance frameworks are in place. This review surveys the current landscape and outlines practical paths forward to achieve this goal.

Humans↗

PubMed2000

Growth factors, receptors, and molecular alterations in pancreatic cancer. Putting it all together.

Because of the dismal prognosis of advanced ductal pancreatic adenocarcinoma, recent investigational strategies have focused on improved detection and therapeutic intervention in early-stage pancreatic cancer. The obvious cost constraints of screening populations at risk but with a low tumor yield will restrict screening protocols to only the highest risk groups (hereditary pancreatitis = age 50, certain hereditary pancreatic cancer kindreds). The vast majority of patients, either lacking or exhibiting an inherited predisposition to pancreatic cancer, will continue to present with disease not resectable for cure. The authors believe that the best hope for these patients lies in the further delineation of the integrative pathophysiology driving tumor growth; this would facilitate the future development of a computer program or other modality that would predict the dominant pathways driving the growth and spread of each tumor based on its "molecular profile." This article reviews the authors' current knowledge regarding the growth factors, receptors, and molecular alterations driving uncontrolled proliferation, local invasion, and metastatic spread of these tumors. The current and potential contributions of studies in cohorts with an inherited predisposition to pancreatic cancer to this pathophysiologic model are also discussed. The future strategy for incorporating this information into a working pathophysiologic road map with clinical relevance is subsequently outlined.

Adenocarcinoma↗

PubMed2004

Stabilization of thalamo-cortical long-term potentiation by the amygdala: cholinergic and transcription-dependent mechanisms.

Synaptic potentiation allows neurons to enhance excitability and store information for extended time periods. We examined the role of the amygdaloid complex, known to facilitate long-term memory encoding, to influence synaptic strength at thalamo-cortical synapses. In urethane-anaesthetized rats, theta-burst stimulation of the dorsal lateral geniculate nucleus of the thalamus induced early phase (1-2 h) long-term potentiation (LTP) of the field postsynaptic potential (fPSP) recorded in the ipsilateral primary visual cortex. Electrical stimulation (100 Hz) of the amygdala 5 min after thalamic stimulation converted early phase LTP to stable late-phase (> 4 h) LTP. This effect was not correlated with the degree of electrocorticographic activation of V1 induced by amygdala stimulation. Amygdala stimulation without thalamic theta-burst stimulation did not change thalamo-cortical fPSPs. The centrally acting cholinergic-muscarinic receptor antagonist scopolamine (1 mg/kg, i.p.), but not peripherally acting methyl-scopolamine, completely blocked the amygdala-induced conversion of early to late-phase thalamo-cortical LTP. Further, ventricular application of the transcription inhibitor anisomycin (250 micro g) reduced amygdala-induced late-phase LTP induction. These results demonstrate that the amygdaloid complex transforms time-limited synaptic enhancement of thalamo-cortical transmission into long lasting increases in synaptic strength. These processes are mediated, at least in part, by cholinergic and transcription-dependent mechanisms. These amygdaloid-induced effects provide a potential mechanism underlying long-term enhancement of sensory transmission and information encoding in thalamo-cortical networks.

Amygdala↗

PubMed2026

An embedding-based framework enables statistical testing of gene-set function hypotheses inferred by large language models.

Emerging large language models (LLMs) can infer gene functions directly from gene lists, enabling hypothesis generation without predefined gene sets. However, these LLM-derived predictions are qualitative, and principled statistical validation is lacking. Here, we develop an embedding-based statistical framework that transforms gene and function descriptions into vector representations, enabling statistical testing of gene-gene and gene-function relationships and quantitative prioritization of de novo functional hypotheses inferred by LLMs. We benchmark seven state-of-the-art embedding models using curated and retrieval-augmented literature-derived gene descriptions across diverse biological contexts. OpenAI's text-embedding-3-large and Google's gemini-embedding-001 perform best, capturing gene-gene functional relationships in 88.7-92.5% of Gene Ontology biological processes and approximately 98.6% of canonical pathways. In gene-function association analyses, these models achieve high sensitivity (95.2-98.4%) and specificity (72.7-84.3%). Through contamination analysis and evaluation using experimentally informed protein assembly gene sets, our framework distinguishes biologically meaningful LLM-inferred hypotheses from noise, outperforming confidence-based inference and conventional enrichment analysis. We further develop the open-source R package DEGEmbedR and demonstrate its utility for interpreting a drug perturbation-derived differentially expressed gene (DEG) signature lacking significant conventional enrichment results. Together, these results establish LLM-derived embeddings as a quantitative foundation for functional genomics and the statistical validation of LLM-based gene function inference.

Large Language Models↗

PubMed2004

Saccharomyces cerevisiae SSD1-V confers longevity by a Sir2p-independent mechanism.

The SSD1 gene of Saccharomyces cerevisiae is a polymorphic locus that affects diverse cellular processes including cell integrity, cell cycle progression, and growth at high temperature. We show here that the SSD1-V allele is necessary for cells to achieve extremely long life span. Furthermore, addition of SSD1-V to cells can increase longevity independently of SIR2, although SIR2 is necessary for SSD1-V cells to attain maximal life span. Past studies of yeast aging have been performed in short-lived ssd1-d strain backgrounds. We propose that SSD1-V defines a previously undescribed pathway affecting cellular longevity and suggest that future studies on longevity-promoting genes should be carried out in long-lived SSD1-V strains.

Alleles↗

PubMed1998

BioSim--a new qualitative simulation environment for molecular biology.

Traditionally, biochemical systems are modelled using kinetics and differential equations in a quantitative simulator. However, for many biological processes detailed quantitative information is not available, only qualitative or fuzzy statements about the nature of interactions. In a previous paper we have shown the applicability of qualitative reasoning methods for molecular biological regulatory processes. Now, we present a newly developed simulation environment, BioSim, that is written in Prolog using constraint logic programming techniques. The simulator combines the basic ideas of two main approaches to qualitative reasoning and integrates the contents of a molecular biology knowledge base, EcoCyc. We show that qualitative reasoning can be combined with automatic transformation of contents of genomic databases into simulation models to give an interactive modelling system that reasons about the relations and interactions of biological entities. This is demonstrated on the glycolytic pathway.

Algorithms↗

PubMed2000

Genetic heterogeneity in acute myeloid leukemia: maximizing information flow from MuLV mutagenesis studies.

The study of myeloid leukemia induced by slow transforming murine leukemia viruses (MuLV) in the laboratory mouse has led to discovery of many important genes with critical roles in regulating the growth, death, lineage determination and development of hematopoietic precursor cells. This review provides an overview of the susceptible strains and virus isolates that cause acute myeloid leukemia (AML) in mice. In addition, newer methodologies, involving the use of the polymerase chain reaction, that have been used to identify cancer genes mutated by proviral insertion in mouse models, will be discussed. As cancer is a multi-gene disease, a system in which pairs of oncogenic mutations are classified as redundant, neutral or synergistic is described. The potential to combine MuLV mutagenesis with recent advances in mouse transgenesis in order to model specific forms of myeloid leukemia or genetic pathways common in human AML will be discussed. Finally, a general strategy for maximizing these genetically rich models to foster a better understanding of AML physiology and developing therapies is proposed.

Acute Disease↗

PubMed1994

Altered expression of epidermal growth factor receptor and estrogen receptor in MCF-7 cells after single and repeated radiation exposures.

PURPOSE: Studies on radiation-induced changes in gene expression are likely to be very important in developing a better understanding of cellular responses to ionizing radiation. While there is some information on the activation of cellular signal transduction pathways after radiation, few late reacting target genes have been identified. This study focuses on the characterization of expression modulation of two critical growth regulatory genes, estrogen receptor and epidermal growth factor-receptor in malignant mammary epithelial cells in response to single and repeated ionizing radiation exposures. METHODS AND MATERIALS: MCF-7 cells were used for single radiation exposure (2-50 Gy) experiments and MCF-IR-3 cells, generated by exposure to cumulative doses of 60 Gy in 2 Gy fractions, respectively, were used to study the effects of repeated exposures. Steady-state messenger ribonucleic acid levels for estrogen receptor, epidermal growth factor-receptor, and transforming growth factor-alpha were determined by ribonucleic acid protection experiments. Estrogen receptor and epidermal growth factor-receptor protein expression was quantitated by competitive binding studies with 3H-estradiol and 125I-EGF. RESULTS: MCF-IR-3 cells showed a permanent three-fold down-regulation of the estrogen receptor messenger ribonucleic acid and protein, while epidermal growth factor-receptor was upregulated about nine-fold. Epidermal growth factor-receptor was substantially up-regulated in MCF-7 cells, at both the mRNA and protein levels, within 24 h of a single 2 Gy exposures, while there was a two-fold concomitant increase in transforming growth factor-alpha messenger ribonucleic acid expression. A decrease in estrogen receptor messenger ribonucleic acid and protein was suggested only after higher doses of single radiation exposures. CONCLUSION: Single and repeated radiation exposures modulate the expression of two critical growth promoting genes, estrogen receptor and epidermal growth factor-receptor, in MCF-7 cells. The inverse expression of estrogen receptor and epidermal growth factor-receptor established for estrogen receptor-positive malignant mammary epithelial cells is maintained in MCF-7 cells after single and repeated exposures suggesting that radiation acts through common regulatory circuits and may modulate the cellular phenotype.

Breast Neoplasms↗

PubMed2005

Modulation of motor cortex excitability by sustained peripheral stimulation: the interaction between the motor cortex and the cerebellum.

The excitability of cortical neurons in the motor cortex is determined by their membrane potential and by the level of intracortical inhibition. The excitability of the motor cortex as a whole is a function of single cell excitability, synaptic strength, and the balance between excitatory cells and inhibitory cells. It is now established that a sustained period of somatosensory stimulation increases the excitability of motor cortex areas controlling muscles in those body parts that received the stimulation prior to excitability testing. So far, it has been supposed that the sensorimotor cortex was the anatomical substrate of these excitability changes, which could represent an early change in cortical network function before structural plasticity occurs. Recent experimental studies highlight that the cerebellum, especially the interpositus nucleus, plays a key role in the adaptation of the motor cortex to repeated trains of stimulation. Interpositus neurons, which receive inputs from both sensorimotor cortex and the spinal cord, are involved in somesthetic reflex behaviors and assist the cerebral cortex in transforming sensory signals to motor-oriented commands by acting via the cerebello-thalamo-cortical projections. Moreover, climbing fibers originating in the inferior olivary complex and innervating the nucleus interpositus mediate highly integrated sensorimotor information derived from spinal modules. It appears that the interpositus nucleus is a main subcortical modulator of the excitability changes occurring in the motor cortex, which may be a substrate of early plasticity effective in motor learning and recovery from lesion.

Afferent Pathways↗

PubMed1997

Human cytotoxic T lymphocyte responses to Epstein-Barr virus infection.

Epstein-Barr virus (EBV) provides one of the most informative systems with which to study cytotoxic T lymphocyte (CTL) responses in humans. The virus establishes a highly immunogenic growth-transforming infection of B lymphocytes, associated with the coordinate expression of six virus-coded nuclear antigens (EBNAs 1, 2, 3A, 3B, 3C, -LP) and two latent membrane proteins (LMPs 1 and 2). This elicits both primary and memory CT8+ CTL responses that are markedly skewed toward HLA allele-specific epitopes drawn from the EBNA3A, 3B, 3C subset of latent proteins, with reactivities to other antigens being generally much less frequent. This hierarchy of immunodominance among the different latent proteins may at least partly reflect their differential accessibility to the HLA class I-processing pathway. Furthermore, CTLs to some of the immunodominant epitopes involve highly conserved T cell receptor (TCR) usage, a level of focusing which evidence suggests could have immunopathological consequences from cross-reactive recognition of other target structures. EBV is associated with a range of human tumors, and there is increasing interest in the possibility of targeting such malignancies using virus-specific CTLs. The dramatic reversal of EBV-driven lymphoproliferations in bone marrow transplant patients following CTL infusion demonstrates the potential of this approach, and here we discuss prospects for its extension to other EBV-positive tumors in which the immunodominant EBNA3A, 3B, 3C proteins are not expressed.

Amino Acid Sequence↗

PubMed1995

The Janus protein tyrosine kinase family and its role in cytokine signaling.

During the past 2 years, research from quite divergent areas has converged to provide the first insights into the mechanisms by which cytokines that utilize receptors of the cytokine receptor superfamily function. On the one hand, the obscure Jak family of cytoplasmic protein tyrosine kinases was independently implicated in IFN and hematopoietic growth factor signaling. Recent studies have expanded these initial observations to demonstrate that Jaks are critical to the functioning of all the receptors of the cytokine receptor superfamily. A variety of questions remain to be explored regarding the structure and function of Jaks and their interaction with receptors. It will also be important to pursue additional approaches to determine if the Jaks are necessary for various biological responses, particularly for mitogenic responses. The second major area of convergence has been the demonstration that members of the Stat family of transcription factors, initially identified in IFN-regulated gene expression, are generally involved in cytokine signaling. Clearly, a number of Stat-like activities remain to be cloned and it can be anticipated that the family contains additional members. Although a variety of genes are known to be regulated by the Stats association with IFN responses, much less is known concerning the genes regulated by the new Stats in cytokine signaling. Of particular importance is information relating to their potential contribution to mitogenic responses. From a biochemical standpoint, the Stats represent a remarkable family of proteins with regard to the ability of the modification of a single tyrosine residue to so dramatically affect cellular localization and DNA binding activity. Studies to identify the domains involved, and associated proteins that might contribute to either property, will be of considerable interest. More generally, it can hypothesized that Jaks and Stats, if important for proliferation and differentiation, may be the targets for malignant transformation. Although none of the genes map to chromosomal breakpoints that have been implicated in transformation, gain of function mutations is a likely mechanism that needs to be explored. Similarly, the Jak-Stat pathway would appear to be an excellent target for the development of drugs that affect a variety of cytokine functions.

Base Sequence↗

PubMed2003

Directional interference during bimanual coordination: is interlimb coupling mediated by afferent or efferent processes.

The role of afferent information in bimanual directional interference was studied by means of a modulation of the response-produced information in one of both limbs. In Experiment 1, visual information was either present, withdrawn, or shown with a directional transformation on a LCD screen. In Experiment 2, the technique of muscle tendon vibration was used to bias the kinesthetic afferent information associated with movement. The findings revealed strong evidence for directional interference between both limbs. Nevertheless, no evidence could be advanced that the observed interference from the right onto the left limb movement was modulated by manipulation of the afferent sources of information. It is concluded that directional interference primarily emerges at the efferent level of movement planning and organization.

Adult↗