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PubMed2001

Hemochromatosis at the intersection of classical medicine and molecular biology.

Hemochromatosis is a genetic disease of iron overload due to intestinal hyperabsorption of iron. It is one of the most prevalent autosomal recessive diseases in Caucasian populations. Hemochromatosis causes severe visceral and metabolic complications at adulthood, which include cirrhosis, diabetes, arthropathy and cardiac failure. A major breakthrough has been the discovery, in 1996, of the HFE gene which is strongly associated with the phenotypic expression of the disease. This discovery has, very quickly, provided a powerful genetic blood test which permits, in most cases, to establish the diagnosis in a non invasive way (i.e. without a liver biopsy). Hemochromatosis can be cured by repeated venesections provided the diagnosis has been detected sufficiently early. Moreover, an efficient preventive strategy can be applied to family members and should now be proposed to the general population. Finally, the identification of the HFE gene has paved the way for the identification of new iron overload entities.

Adult↗
PubMed1999

Signalling networks that cause cancer.

Cancer is caused by the stepwise accumulation of mutations that affect growth control, differentiation and survival. The view that mutations affect discrete signalling pathways, each contributing to a specific aspect of the full malignant phenotype, has proved to be too simplistic. We now know that oncogenes and tumour suppressors depend on one another for their selective advantage, and that they affect multiple pathways that intersect and overlap. The interactive nature of each genetic change has important implications for cancer therapy and for the stepwise model of carcinogenesis.

Adenomatous Polyposis Coli Protein↗
PubMedDate not supplied

The intersection of biotechnology and pharmacogenomics: health policy implications.

Increasing knowledge of the genetic basis of disease is changing the landscape of health care. Two critical aspects are growth in biotechnology and growth in personalized health care, particularly targeting medicines based on genetic information (pharmacogenomics). This paper provides an overview of the health policy implications of the integration of biotechnology and pharmacogenomics. I examine four factors that determine whether relevant technologies will be successfully adopted, using case studies for illustration. Key policy challenges include determining the appropriate role of policy in (1) providing incentives to develop socially beneficial interventions and (2) facilitating development of the evidence base.

Biotechnology↗
PubMed2026

Identification of Candidate Genes Associated with Growth Traits in Procambarus clarkii Using Whole-Genome Resequencing.

Growth is a critical economic trait in all aquaculture industries. To address issues such as germplasm degradation, a comprehensive understanding of the growth and development mechanisms, along with genetic improvement strategies, for Procambarus clarkii (P. clarkii) is urgently required. In this study, we performed whole-genome resequencing on 89 individuals from five cultured stocks to investigate growth traits (body length) and identified a total of 46,919,297 high-quality single nucleotide polymorphisms (SNPs). Based on these SNPs, we conducted principal component analysis (PCA), phylogenetic analysis, and population genetic structure analysis. Furthermore, we performed selective sweep analysis (using FST, Pi, and XP-CLR) and a genome-wide association study (GWAS) to identify genetic variants associated with growth traits. The results revealed significant genetic differentiation among the five cultured stocks, with the Ma'anshan cultured stock exhibiting the fastest linkage disequilibrium (LD) decay. Additionally, long-term aquaculture in different geographical regions resulted in distinct genetic differences among cultured stocks. Through selective sweep analysis, the intersection of FST, Pi, and XP-CLR across the five populations yielded several growth-related candidate genes: Nephrin, Somatostatin, zinc finger protein 154, and yeti. Subsequent the GWAS identified two candidate genes associated with growth traits: Cullin-associated and neddylation-dissociated protein 1 (CAND1) and Baculoviral IAP repeat-containing protein 8 (BIRC8). These genes are presumed to play pivotal roles in the growth and development of P. clarkii. Overall, our findings provide new insights into the genetic mechanisms underlying growth and development in P. clarkii, and these identified genes serve as promising candidates for further functional studies and genetic improvement of this species.

Polymorphism, Single Nucleotide↗
PubMed2006

Drosophila aging 2005/06.

Drosophila continues to be a model system of choice to study the genetics of aging. It has a short lifespan and small genome size, but nevertheless contains a complex organ and endocrine system that allows studying the role of conserved signal transduction pathways with sophisticated genetic tools. Oxidative stress and metabolic changes along with intersecting signaling systems Insulin Receptor (InR), Target of Rapamycin (TOR) and Jun N-terminal Kinase (JNK) have emerged as some of the major players in aging. Sleep and organ-specific aging has also been the subject of recent progress in understanding aging.

Aging↗
PubMed2003

How the ubiquitin-proteasome system controls transcription.

Gene transcription and ubiquitin-mediated proteolysis are two processes that have seemingly nothing in common: transcription is the first step in the life of any protein and proteolysis the last. Despite the disparate nature of these processes, a growing body of evidence indicates that ubiquitin and the proteasome are intimately involved in gene control. Here, we discuss the deep mechanistic connections between transcription and the ubiquitin-proteasome system, and highlight how the intersection of these processes tightly controls expression of the genetic information.

Animals↗
PubMed2026

Beyond Earth: Recent Advancements in Microgravity Biomedical and Genetic Research in Saudi Arabia.

Microgravity research has emerged as a rapidly evolving field at the intersection of space medicine, genomics, biotechnology, and precision medicine. Exposure to the space environment induces complex physiological and molecular adaptations that affect multiple biological systems, including immune regulation, metabolism, musculoskeletal function, and gene expression. Recent advances in genomics, multi-omics technologies, artificial intelligence, and bioengineering have substantially improved our understanding of biological adaptation to spaceflight and expanded opportunities for translational biomedical research. This review summarizes recent advances in genetic and biomedical research under microgravity conditions, with particular emphasis on molecular mechanisms, omics technologies, genome editing, microbiome research, regenerative medicine, and personalized healthcare approaches. Major experimental platforms, landmark spaceflight studies, and translational applications in infectious diseases, cancer biology, aging, tissue engineering, and pharmaceutical development are discussed. The review also highlights Saudi Arabia's emerging contributions to genomic medicine and space biosciences through initiatives such as the Saudi Human Genome Program, the Saudi Pangenome Project, the Saudi Space Agency, and the BioGravity Initiative. Recent Saudi participation in human spaceflight and microgravity-associated biomedical research is discussed within the context of Vision 2030 and national investments in biotechnology and precision medicine. Collectively, advances in microgravity research are expected to contribute to the advancement of precision medicine and facilitate the development of innovative diagnostic and therapeutic strategies with significant implications for both human space exploration and terrestrial healthcare.

Humans↗
PubMed1998

Vaccines, genes and trials.

This symposium takes place at the intersection of an acute success (the extraordinary recent developments in genetical research relevant to mycobacteria) and a chronic failure (the embarrassing failure of Bacillus Calmette-Guérin [BCG], the world's most widely used vaccine, to control tuberculosis). I will summarize the arguments that the variable efficacy of BCG is attributable, at least in part, to genetic differences in either the vaccine, the host populations or Mycobacterium tuberculosis. I will then address the problem of building upon our experience with BCG in order to develop and evaluate an improved vaccine against tuberculosis. The fact that the great burden of tuberculosis is associated with pulmonary disease in adults, much of which is associated either with reactivation of old infection or else with relatively recent reinfection, poses an immense problem for vaccine strategy and evaluation. One approach may be to vaccinate early in life, prior to initial infection with the tubercle bacillus, and then to follow up individuals for many decades. The alternative is to develop vaccines to boost appropriate protective immune mechanisms in individuals who have already been infected, and/or who have already been vaccinated (e.g. with BCG), and/or who may also have been sensitized to various environmental mycobacteria that influence the immune response to tubercle bacilli. The latter approach is novel, and may ultimately prove impossible, but its potential logistic and public health advantages are so great that it warrants serious attention by the research community before being abandoned.

Adult↗
PubMed2002

Myelodysplastic syndromes.

The myelodysplastic syndromes (MDS) are characterized by hemopoietic insufficiency associated with cytopenias leading to serious morbidity plus the additional risk of leukemic transformation. Therapeutic dilemmas exist in MDS because of the disease's multifactorial pathogenetic features, heterogeneous stages, and the patients' generally elderly ages. Underlying the cytopenias and evolutionary potential in MDS are innate stem cell lesions, cellular/cytokine-mediated stromal defects, and immunologic derangements. This article reviews the developing understanding of biologic and molecular lesions in MDS and recently available biospecific drugs that are potentially capable of abrogating these abnormalities. Dr. Peter Greenberg's discussion centers on decision-making approaches for these therapeutic options, considering the patient's clinical factors and risk-based prognostic category. One mechanism underlying the marrow failure present in a portion of MDS patients is immunologic attack on the hemopoietic stem cells. Considerable overlap exists between aplastic anemia, paroxysmal nocturnal hemoglobinuria, and subsets of MDS. Common or intersecting pathophysiologic mechanisms appear to underlie hemopoietic cell destruction and genetic instability, which are characteristic of these diseases. Treatment results and new therapeutic strategies using immune modulation, as well as the role of the immune system in possible mechanisms responsible for genetic instability in MDS, will be the subject of discussion by Dr. Neal Young. A common morphological change found within MDS marrow cells, most sensitively demonstrated by electron microscopy, is the presence of ringed sideroblasts. Such assessment shows that this abnormal mitochondrial iron accumulation is not confined to the refractory anemia with ring sideroblast (RARS) subtype of MDS and may also contribute to numerous underlying MDS pathophysiological processes. Generation of abnormal sideroblast formation appears to be due to malfunction of the mitochondrial respiratory chain, attributable to mutations of mitochondrial DNA, to which aged individuals are most vulnerable. Such dysfunction leads to accumulation of toxic ferric iron in the mitochondrial matrix. Understanding the broad biologic consequences of these derangements is the focus of the discussion by Dr. Norbert Gattermann.

Anemia, Sideroblastic↗
PubMed1987

Genetic and immunologic basis of atopic responses.

We summarize current understanding of the genetics of human diseases and of the major histocompatibility complex related factors regulating immune responsiveness. Special factors are involved in atopic diseases as a result of the intersection between the immune system, the targets in the tracheobronchial tree and the endocrine, neurologic and genetic mechanisms affecting both the effectors and the targets. The evidence from investigations of human subjects and their families and from laboratory animals for the underlying genetic and immunologic mechanisms of asthma are reviewed. The genetic control of asthma is complex. The evidence suggests a gene or genes associated with and linked to HLA. The disease phenotype may also be regulated by genetically determined levels of IgE and the outcome of the balance between immune response and immunosuppression.

Animals↗
PubMed2005

Septins: traffic control at the cytokinesis intersection.

The physical division of one cell into two requires the highly orchestrated separation of genetic and cytoplasmic contents during M phase of the cell cycle. Mitosis, the physical segregation of the genetic material of a cell into two daughter cells, has traditionally received more attention than cytokinesis, the partitioning of the cytoplasmic contents, yet clearly the two processes must be intimately co-ordinated and tightly regulated. While plant cells divide by the formation of a membranous cell barrier called the phragmoplast, animal cell division is largely driven by contraction of an actomyosin ring. However, recent evidence has suggested that membranes derived from one or more intracellular compartments are also required to break the cytoplasmic bridge connecting two dividing cells during late telophase. In this review, we focus on studies of animal cell cytokinesis that support a requirement for specific endomembrane fusion during fission, define molecular components of the membrane fusion apparatus that may be involved and point to possible roles for an emerging family of cytoskeletal proteins, the septins, in this process.

Animals↗
PubMedDate not supplied

Opportunities at the intersection of bioinformatics and health informatics: a case study.

This paper provides a "viewpoint discussion" based on a presentation made to the 2000 Symposium of the American College of Medical Informatics. It discusses potential opportunities for researchers in health informatics to become involved in the rapidly growing field of bioinformatics, using the activities of the Yale Center for Medical Informatics as a case study. One set of opportunities occurs where bioinformatics research itself intersects with the clinical world. Examples include the correlations between individual genetic variation with clinical risk factors, disease presentation, and differential response to treatment; and the implications of including genetic test results in the patient record, which raises clinical decision support issues as well as legal and ethical issues. A second set of opportunities occurs where bioinformatics research can benefit from the technologic expertise and approaches that informaticians have used extensively in the clinical arena. Examples include database organization and knowledge representation, data mining, and modeling and simulation. Microarray technology is discussed as a specific potential area for collaboration. Related questions concern how best to establish collaborations with bioscientists so that the interests and needs of both sets of researchers can be met in a synergistic fashion, and the most appropriate home for bioinformatics in an academic medical center.

Computational Biology↗
PubMed1989

The molecular basis of retinoblastomas.

Retinoblastomas and osteosarcomas in humans are associated with the homozygous inactivation of the Rb gene which maps to a locus on chromosome 13q14. This gene has been isolated as molecular clones. The gene encodes a protein of 105 kDa which is a nuclear DNA-binding phosphoprotein. The protein is not found in 15 retinoblastomas studied so far. An independent line of work examining the transforming mechanisms of the adenovirus E1A oncogene has shown that its encoded oncoprotein complexes with the Rb-encoded p105 in virus-transformed cells. This suggests that the Rb protein acts at a central intersection in the cell's growth regulatory network. Its alteration by genetic or epigenetic mechanisms appears to represent a critical event in several different pathways of tumorigenesis.

Chromosome Mapping↗
PubMed1998

Selection of very small differences in bacterial evolution.

As the Science of Biology is constantly changing due to new discoveries and advanced techniques it is essential that a systematic study of the environmental causes of natural selection on microorganisms be conducted. Very small phenotypic differences among individuals within bacterial populations arise as a result of spontaneous genetic variation, but the evolutionary importance of these small changes is frequently considered to be non-significant. Recent in vitro experiments indicate that efficient selection of these very small differences may take place in environmental compartments where a particular intensity of the selective agent is exerted. Model studies based on competition between bacterial populations only differing in one or two amino acid changes of a detoxifying antibiotic enzyme (e.g. beta-lactamase) have shown that at a narrow range of antibiotic concentrations the variant population is strongly selected over the original type, despite the extremely low phenotypic differences in antibiotic susceptibility. These selective concentrations are expected to occur in precise environmental compartments (selective compartments). Due to the high frequency of structured habitats in natural environments, the intensity of selective agents is commonly exerted along certain gradients. Each one of the points forming these gradients (or intersection among gradients) may have a particular selective ability for a specific genetic variant. Considering the environment as a composition of an extremely high number of specific selective compartments may help to understand the existence of high levels of genetic variability in natural bacterial populations. This may be one of the clues towards the unraveling of bacterial evolution.

Bacteria↗
PubMed2003

Traffic at the intersection of neurotrophic factor signaling and neurodegeneration.

Advances in understanding the biology of neurotrophic factors and their signaling pathways have provided important insights into the normal growth, differentiation and maintenance of neurons. Stimulated by neuropathological observations and genetic discoveries, studies in cell and animal models of neurodegenerative disorders have begun to clarify pathogenetic mechanisms. We examine the intersection of these research themes and identify several potential mechanisms for linking failed neurotrophic factor signaling to neurodegeneration. Studies of nerve growth factor signaling in a mouse model of Down syndrome encourage the views that neuronal dysfunction and atrophy might be linked to failed neurotrophic support and that additional studies focused on this possibility would enhance our understanding of the mechanisms of neurodegenerative disorders and their treatment.

Alzheimer Disease↗
PubMed2006

Science communication in transition: genomics hype, public engagement, education and commercialization pressures.

This essay reports on the final session of a 2-day workshop entitled 'Genetic Diversity and Science Communication', hosted by the CIHR Institute of Genetics in Toronto, April 2006. The first speaker, Timothy Caulfield, introduced the intersecting communities that promulgate a 'cycle of hype' of the timelines and expected outcomes of the Human Genome Project (HGP): scientists, the media and the public. Other actors also contribute to the overall hype, the social science and humanities communities, industry and politicians. There currently appears to be an abatement of the overblown rhetoric of the HGP. As pointed out by the second speaker, Sharon Kardia, there is broad recognition that most phenotypic traits, including disease susceptibility are multi-factorial. That said, George Davey-Smith reminded us that some direct genotype-phenotype associations may be useful for public health issues. The Mendelian randomization approach hopes to revitalize the discipline of epidemiology by strengthening causal influences about environmentally modifiable risk factors. A more realistic informational environment paves the way for greater public engagement in science policy. Two such initiatives were presented by Kardia and Jason Robert, and Peter Finegold emphasized that science education and professional development for science teachers are important components of later public engagement in science issues. However, pressures on public research institutions to commercialize and seek industry funding may have negative impacts in both encouraging scientists to inappropriately hype research and on diminishing public trust in the scientific enterprise. The latter may have a significant effect on public engagement processes, such as those proposed by Robert and Kardia.

Commerce↗
PubMed2026

Integrative multi-omics analyses suggest a candidate microbial metabolite-associated host gene network in ulcerative colitis.

Ulcerative colitis (UC) is associated with gut microbial dysbiosis, but the host molecular alterations potentially linked to microbially derived metabolites remain incompletely understood. We integrated Mendelian randomization (MR), microbial metabolite annotation, computational target prediction, colonic transcriptomics, network analysis, and machine learning. MiBioGen microbiome GWAS data were used as exposures and FinnGen Release 12 ULCERENTER as the outcome. Metabolites linked to MR-prioritized taxa were retrieved from GutMGene, and human targets were predicted using SwissTargetPrediction and SEA. UC-related genes were defined by integrating differential expression analysis and WGCNA and then intersected with predicted metabolite targets. MR prioritized one family and eight genera showing nominal genetically supported associations with UC, but none remained significant after Benjamini-Hochberg FDR correction. Three prioritized genera were linked to 15 microbe-metabolite records, corresponding to 13 unique metabolites; nine were retained for target prediction, yielding 277 unique predicted human targets. Transcriptomic analysis identified 1,530 DEGs and a 312-gene MEgrey60 module, with 273 overlapping genes, producing 1,569 unique UC-related genes. Their intersection with the 277 predicted targets yielded 47 candidate genes. Enrichment analyses highlighted mainly metabolic and lipid-related processes. Random Forest showed the highest mean AUC across the two independent external benchmarking cohorts, and SHAP prioritized EPHX1, HSD17B2, IGFBP5, and MMP10. IBDome analysis showed inflammation-associated expression differences in these genes. This study provides a genomics-informed, hypothesis-generating framework that prioritizes candidate microbe-metabolite-host relationships in UC for future experimental validation.

Humans↗