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Results for “Phenotype modifier”

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PubMed2002

Anopheles albitarsis embryogenesis: morphological identification of major events.

Anopheles albitarsis embryogenesis was analyzed through confocal microscopy of clarified eggs. Using Drosophila melanogaster as reference system, the major morphogenetic events (blastoderm, gastrulation, germ band extension, germ band retraction, dorsal closure) were identified. The kinetics of early events is proportionally similar in both systems, but late movements (from germ band retraction on) progress slower in An. albitarsis. Major differences in An. albitarsis related to D. melanogaster were: (1) pole cells do not protrude from the blastoderm; (2) the mosquito embryo undergoes a 180 degrees rotation movement, along its longitudinal axis; (3) the head remains individualized throughout embryogenesis; (4) extraembryonary membranes surround the whole embryo. A novel kind of malaria control is under development and is based on the use of genetically modified mosquitoes. Phenotypic analysis of the embryonic development of mutants will be imposed as part of the evaluation of effectiveness and risk of employment of this strategy in the field. In order to accomplish this, knowledge of the wild type embryo is a prerequisite. Morphological studies will also serve as basis for subsequent development biology approaches.

Animals↗

PubMed2006

Molecular aspects of stromal-parenchymal interactions in malignant neoplasms.

Carcinomas are composed of parenchymal and stromal elements, and the malignant behavior is principally dictated by the cancer cells. However, the malignant tumors not merely grow into a preexisting interstitial tissue, but they actively form a new stroma and modify their composition. Thus, the tumor stroma is significantly different from that of the neighboring tissues. Cancer cells may alter their stroma by cell-to-cell contact, soluble factors or by modification of the extracellular matrix (ECM), they induce myofibroblast differentiation and govern the desmoplastic stroma reaction. On the other hand, the stromal cells (especially the myofibroblasts) are able to modify the phenotype, invasiveness, metastatic capacity of carcinomas, typically promoting the progression. Regarding pancreatic cancer, the pancreatic stellate cells (PSCs) seem to be the key elements in the cross-talk between the parenchymal cells and the desmoplastic stroma. The tumor stroma is also rich in tumor-associated macrophages (TAM), but their role in the malignant process is contradictory and may be different in various tumor types, but most studies suggest a negative impact on the tumor growth. The relationship between the parenchymal and stromal elements is highly complex, they mutually alter their characteristics. Because the neostroma of the carcinomas largely seems to promote the invasiveness of the malignant tumors, novel therapeutic strategies are being evaluated targeting the stromal elements, with some encouraging, but still fragmentary results.

Basal Cell Carcinoma↗

PubMed2026

Development and Validation of Machine Learning Models for Predicting Early Cognitive Decline Using Home Sensor-Derived Behavioral Data: Sensors in-Home for Elder Wellbeing (SINEW) Cohort Study.

BACKGROUND: As the global population continues to age, the prevalence of geriatric conditions, including dementia and frailty, is also increasing. Early identification of individuals at an elevated risk of these conditions, such as those presenting with mild cognitive impairment (MCI) or prefrailty, can provide a critical window for prompt intervention aimed at preventing or reversing disease progression. To promote such early identification, there is a burgeoning interest in the use of digital sensor technology and predictive modeling. OBJECTIVE: This study aimed to use a continuous, home-based monitoring sensor system for older adults to distinguish those exhibiting normal aging from those with MCI, early dementia, prefrailty, or frailty, and to predict their transition from normal aging to one of these conditions. METHODS: This longitudinal cohort study will recruit 200 community-dwelling adults aged ≥65 years with normal cognition or MCI at baseline. A multi-sensor system will be installed in participants' homes, including passive infrared motion sensors, door contact sensors, bed sensors, medication box sensors, wearable activity bands, and Bluetooth proximity beacons. These devices will continuously capture spatiotemporal activity patterns, mobility indicators, sleep behaviors, and medication-taking routines. Annual assessments will include standardized cognitive tests (eg, Montreal Cognitive Assessment, Mini-Mental State Examination, Rey Auditory-Verbal Learning Test, digit span, Color Trails Test, semantic fluency, Stroop), frailty measures (modified Fried phenotype, gait speed, grip strength), mental health scales, sleep quality, and psychosocial indicators. Sensor-derived features-such as gait variability, activity regularity, sleep fragmentation, and medication adherence patterns-will be integrated with clinical data to develop supervised machine learning models. Planned approaches include logistic regression, random forests, gradient boosting, and deep learning. Model performance will be evaluated using cross-validation and independent test sets. Primary metrics will include area under the receiver operating characteristic curve, sensitivity, specificity, precision, recall, and F1-score. Models will be benchmarked against gold-standard clinical diagnoses and validated using temporal subsets of the dataset. RESULTS: Enrollment for this study started in November 2019 and will continue until March 2030. As of June 2025, we have enrolled 138 participants. Full data analysis has yet to begin. CONCLUSIONS: We aim to develop a reliable and effective sensor system for in-home use that will facilitate the early detection of cognitive and physical decline. In so doing, it will add to our current understanding of digital biomarkers. It is common for older adults to seek clinical intervention only when their cognitive impairment has already reached an advanced stage. The implementation of readily deployable sensor systems within community settings presents us with opportunities for prompt intervention, which holds the potential for delaying or reversing disease progression and allowing for a greater number of functional and meaningful years.

Humans↗

PubMed1988

Genetic control of organ-reactive autoantibody production in mice by obesity (ob) diabetes (db) genes.

Inbred strains of mice exhibited genetic and sex-dependent differences in spontaneous production of organ-reactive autoantibodies detected by indirect immunofluorescence. Antitestis autoreactivity was found primarily in sera from C57BL/6J (B6) mice, whereas antigastric autoreactivity was common to both CBA/J and 129/J strains. Autoantibodies against islet cell cytoplasmic antigens (ICAs) were uniquely expressed by C57BL/KsJ (BKs) males. Introduction of the diabetes (db) mutation into these various inbred-strain backgrounds induced expression of ICA, with stronger induction observed in males. The stress imposed by the db or obesity (ob) mutation induced ICA in BKs mice at a higher frequency than in B6 mice; this differential sensitivity was somehow related to a gene linked to the H-2 complex because BKs.B6 H-2b congenic mice resembled B6 mice. The db3J mutation increased the expression of these autoantibodies in 129/J mice, which, like B6, were H-2b and therefore presumably possessed the same H-2-linked inducibility allele as BKs. Cytotoxic autoantibodies against islet cell surface antigens were only observed in C3HeB/FeJ db/db males, and their presence was correlated with beta-cell necrosis. It is concluded that db and/or ob genes appear to play an important role in the production of autoantibodies to islet cells, and sex-linked factor(s) may modify the phenotypic expression of the autoantibodies.

Animals↗

PubMed1998

Enhanced glucose-dependent insulinotropic polypeptide secretion and insulinotropic action in glucagon-like peptide 1 receptor -/- mice.

Incretins are gastrointestinal hormones that act on the pancreas to potentiate glucose-stimulated insulin secretion. Despite the physiological importance of the enteroinsular axis, disruption of glucagon-like peptide (GLP)-1 action is associated with only modest glucose intolerance in GLP-1 receptor -/- (GLP-1R -/-) mice. We show here that GLP-1R -/- mice exhibit compensatory changes in the enteroinsular axis via increased glucose-dependent insulinotropic polypeptide (GIP) secretion and enhanced GIP action. Serum GIP levels in GLP-1R -/- mice were significantly elevated versus those in +/+ control mice after an oral glucose tolerance test (369 +/- 40 vs. 236 +/- 28 pmol/l; P < or = 0.02). Furthermore, GIP perfusion of mice pancreas and isolated islets in the presence of elevated glucose concentrations elicited a significantly greater insulin response in GLP-1R -/- than in +/+ mice (P < or = 0.02-0.05). In contrast, no significant perturbation in the insulin response to perfused glucagon was detected under conditions of low (4.4 mmol/l) or high (16.6 mmol/l) glucose in GLP-1R -/- mice. Total pancreatic insulin but not glucagon content was significantly reduced in GLP-1R -/- compared with in +/+ mice (77 +/- 9 vs. 121 +/- 10 pmol/mg protein; P < or = 0.005). These observations suggest that upregulation of the GIP component of the enteroinsular axis, at the levels of GIP secretion and action, modifies the phenotype resulting from interruption of the insulinotropic activity of GLP-1 in vivo.

Animals↗

PubMed2000

Genetic modifiers of the insulin resistance phenotype in mice.

Insulin resistance can result from genetic interactions among susceptibility alleles. To identify genetic loci predisposing to insulin resistance, we used crosses between different strains of mice with a targeted null allele of the insulin receptor gene. On the genetic background of B6 mice, the insulin receptor gene mutation causes mild hyperinsulinemia. In contrast, on the genetic background of 129/Sv mice, the same mutation causes severe hyperinsulinemia, suggesting that the 129/Sv strain harbors alleles that interact with the insulin receptor mutation and predispose to insulin resistance. As a first step to identify these alleles, we generated an F2 intercross between insulin receptor heterozygous mutant mice on B6 and 129/Sv backgrounds (B6IR x 129IR) and performed a genome-wide scan with polymorphic markers at a 20-cM resolution. We report the identification of loci on chromosomes 2 (logarithm of odds [LOD] 5.58) and 10 (LOD 5.58) that show significant evidence for linkage to plasma insulin levels as a quantitative trait. These findings indicate that targeted mutations in knockout mice can be used to unravel the complex genetic interactions underlying insulin resistance.

Alleles↗

PubMed1988

Synovial fibroblasts.

Chronic synovitis refers to fibrin deposits on the surface of proliferating superficial synovial lining cells leading to villous hyperthrophy, and associated with foci of cell necrosis and infiltration of chronic inflammatory cells. The superficial synovial lining cells include fibroblast-like type B cells and macrophage-like type A cells. Fibroblast- and macrophage-like cells in the early or leading edge of pannus may represent an extension of these cells, which themselves may be nothing else than stromal fibroblasts and macrophages adapted to the particular micro-milieu prevailing at the interface of hyaluronate (HA) containing synovial fluid and richly vascularized loose connective tissue in the sublining stroma. In all three locations fibroblasts are exposed to various humoral substances, extracellular matrix (ECM) and cell-cell contacts, which may modify their phenotype and function. Therefore, one would expect differences in the fibroblasts in inflammatory and non-inflammatory synovial tissue. These changes can be best understood by considering some of the basic fibroblast properties, namely migration, substrate adherence, proliferation and synthesis and degradation of ECM.

Animals↗

PubMed1989

Biology of the vessel wall and atherosclerosis.

In humans, atherosclerotic plaques develop within pre-existing diffuse intimal thickenings. The vast majority of cells in these intimal thickenings are smooth muscle, and it is their nodular proliferation, synthesis of extracellular matrix and accumulation of intra- and extracellular lipid which results in the development of the lesion. Two of the crucial initiating or progression events in atherogenesis are the invasion of monocyte/macrophages into the vessel wall as a result of hyperlipidemia, and endothelial denudation or dysfunction with resultant platelet aggregation and release. Products from these cells interact with smooth muscle, modifying its phenotype and influencing its behaviour and response.

Arteries↗

PubMed2001

Genetic regulation of autoimmune disease: BALB/c background TGF-beta 1-deficient mice develop necroinflammatory IFN-gamma-dependent hepatitis.

Autoimmune hepatitis (AIH) in humans arises spontaneously in genetically susceptible individuals and is associated with the presence of Th1 cells in the liver. The understanding of AIH has advanced more slowly than that of other organ-specific autoimmune diseases, however, largely because of the lack of an appropriate animal model. We now describe a new mouse model characterized by spontaneous development of necroinflammatory hepatitis that is restricted by genetic background. Mice deficient in the immunomodulatory cytokine TGF-beta1 were extensively back-bred to the BALB/c background. The BALB/c background dramatically modified the phenotype of TGF-beta1(-/-) mice: specifically, BALB/c-TGF-beta1(-/-) mice developed a lethal necroinflammatory hepatitis that was not observed in TGF-beta1(-/-) mice on a different genetic background. BALB/c background TGF-beta1(-/-) livers contained large numbers of activated CD4(+) T cells that produced large quantities of IFN-gamma, but little IL-4, identifying them as Th1 cells. BALB/c background TGF-beta1(-/-)/IFN-gamma(-/-) double knockout mice, generated by cross-breeding, did not develop necroinflammatory hepatitis, demonstrating that IFN-gamma is mechanistically required for its pathogenesis. This represents the first murine model of hepatitis that develops spontaneously, is restricted by genetic background, and is dependent upon the Th1 cytokine IFN-gamma, and that thus recapitulates these important aspects of AIH.

Animals↗

PubMed1999

[Physiopathology of viral vasculitis].

Viral infections can cause vasculitides via mechanisms that remain incompletely understood but may involve circulating immune complexes or endothelial cell infection. Many viruses are capable of infecting the endothelial cells and modifying their phenotype, thus facilitating thrombosis and inflammatory cell recruitment. Although the main animal models of vasculitis are virus-induced, viruses are responsible for only a minority of cases of vasculitis in humans. However, a role of undetected viruses in vasculitides currently classified as primary cannot be completely ruled out.

Animals↗

PubMed2000

[Role of bronchial smooth muscle in inflammation].

We now have to consider the airway smooth muscle as an actor of the bronchial inflammation in asthma. In addition to its bronchoconstricting role in response to mediators secreted by the adjacent cells and tissues, that may be considered as to be passive regarding the airway inflammation, the airway smooth muscle may now be considered as pro-inflammatory, since it has the potential of synthesizing and secreting a variety of chemokines and growth factors that will favor cell proliferation, and attraction of inflammatory cells. The airway smooth muscle may modify its phenotype from a contractile to a secretory or a proliferative phenotype. These differentiation states of the bronchial smooth muscle may be studied experimentally by culturing the airway smooth muscle. The demonstration of the occurrence and/or coexistence of such differentiation states in vivo will help understand the exact role of the bronchial smooth muscle in the airway inflammation in asthma.

Animals↗

PubMed2001

[From gene to disease; 'survival' motor neuron protein and hereditary proximal spinal muscle atrophy].

The majority of patients with hereditary proximal spinal muscular atrophy (SMA) have a homozygous deletion of the survival motor neuron gene (SMN1). The number of SMN2 gene copies modifies the phenotype, which ranges from a lethal infantile disorder to an adult-onset disease causing mild impairment and disability. The SMN protein plays a role in an apparently essential cell metabolism process, the splicing of pre-mRNA in the spliceosomes. Why SMN1 deletions are only clinically expressed in motor neuron cells and not in other cell types is still unknown. DNA analysis, prenatal diagnosis and carrier testing as means of diagnosing SMA are all routinely available in the Netherlands and are currently performed at the DNA laboratory of the University of Groningen.

Adult↗

PubMed2002

Insulin-like growth factor I polymorphism and breast cancer risk in Jewish women.

BACKGROUND: Genes that confer mild or moderate susceptibility to breast cancer may be involved in the pathogenesis of sporadic breast cancer, modifying the phenotypic expression of mutant BRCA1/BRCA2 alleles. An attractive candidate is the insulin-like growth factor I, a known mitogen to mammary ductal cells in vivo and in vitro, whose serum levels were reportedly elevated in breast cancer patients. OBJECTIVE: To evaluate the contribution of the IGF-1 gene polymorphism to breast cancer risk by genotyping for a polymorphic allele size in breast cancer patients and controls. METHODS: We analyzed allele size distribution of the polymorphic CA repeat upstream of the IGF-I gene in 412 Israeli Jewish women: 268 women with breast cancer (212 sporadic and 56 carriers of either a BRCA1 or BRCA2 mutation), and 144 controls. Genotyping was accomplished by radioactive polymerase chain reaction of the relevant genomic region and size fractionation on polyacrylamide gels with subsequent autoradiography. RESULTS: Among women with breast cancer, with or without BRCA germline mutations, 196 and 198 basepair alleles were present in 4.7% (25/536 alleles), compared with 9% (26/288) controls (P = 0.02). This difference was more pronounced and significant in the non-Ashkenazi population. Conversely, the smaller size allele (176 bp) was present in the breast cancer group only (3/536, 0.6%). CONCLUSIONS: The IGF-I polymorphism may serve as a marker for breast cancer risk in the general Jewish population, in particular non-Ashkenazi Jews, but extension and confirmation of these preliminary data are needed.

Adult↗

PubMed2003

Thalassemia minor, the Gilbert mutation, and the risk of gallstones.

BACKGROUND AND OBJECTIVES: Gallstones are a frequent complication of hemolytic anemias. The association with the mutation of the A(TA)nTAA motif of the promoter of the bilirubin UDP-glucuronosyltransferase gene has also been reported to increase the risk of gallstones. We studied the prevalence of cholelithiasis in thalassemia minor and the role of the Gilbert mutation. DESIGN AND METHODS: A group of 143 women obligate carriers of beta-thalassemia, and a control group of 170 hematologically normal women were compared. In both groups serum bilirubin, total cholesterol, and alanine-aminotransferase were measured and analysis of the mutation of the UGT-1A gene was performed. On the same occasion the women underwent ultrasonography. RESULTS: Total and unconjugated bilirubin were significantly higher in beta-thalassemia heterozygotes. Carriers of thalassemia had a higher prevalence of gallstones (20.3% vs 10.6% OR=2.15). Among the control group, the prevalence of gallstones did not differ significantly in relation to UGT1-A1 genotype, while in women carriers of beta-thalassemia it increased in an allele dose-dependent fashion. As compared to the controls, the odds ratios for the development of gallstones in thalassemic women were 1.68 (95% C.I.: 0.70-4.03) for those who had the normal UGT1-A1 genotype [(TA)6/(TA)6], 2.31 (95% C.I.: 1.06-5.02) for heterozygote carriers of the mutated genotype [(TA)7/(TA)6] and 3.88 (95% C.I.: 1.31-11.55) for those homozygous for the mutated genotype [(TA)7/(TA)7]. INTERPRETATION AND CONCLUSIONS: Thalassemia minor represents a risk factor for cholelithiasis and the Gilbert mutation further increases this risk. This is an additional example of how two genotypes can interact and modify a phenotype.

Alleles↗

PubMed1992

Interleukin-3-induced up-regulation of CR3 expression on human eosinophils is inhibited by dexamethasone.

Eosinophil function is regulated by several cytokines, including interleukin-3 (IL-3), IL-5 and granulocyte-macrophage colony-stimulating factor (GM-CSF). Culture of human eosinophils with IL-3 produced a marked, dose-dependent up-regulation of CR3 expression. This was maximal after 1 day in culture and dependent on protein and RNA synthesis, as demonstrated by inhibition with cycloheximide and actinomycin D, respectively. IL-5 and GM-CSF had a similar effect on eosinophil complement receptor type 3 (CR3) expression, but the maximal response to IL-5 was always less than to IL-3 or GM-CSF. Dexamethasone inhibited the Il-3-induced up-regulation of CR3 expression in a dose-dependent manner, with an IC50 of 5 x 10(-8) M. This study demonstrates the effect of IL-3, IL-5 and GM-CSF on eosinophil CR3 expression and confirms the capacity of eosinophils to modify their phenotype through de novo protein synthesis. This process could be inhibited by physiological concentrations of glucocorticoids, thus providing an additional mechanism for their mode of action in allergic disease.

Blood Proteins↗

PubMed2004

All in the family: evidence for four new LEM-domain proteins Lem2 (NET-25), Lem3, Lem4 and Lem5 in the human genome.

LEM-domain proteins share a folded structure, the 'LEM-domain', which binds a conserved chromatin protein named BAF. Most LEM-domain proteins are found at the nuclear membrane, but some are nucleoplasmic. All characterized members of this family bind nuclear lamin filaments. We summarize the 'founding' LEM-domain proteins LAP2, emerin and MAN1 ('SANE' or 'XMAN' in Xenopus) and their emerging roles in gene regulation and nuclear assembly. These roles are placed in the context of human diseases ('laminopathies') caused by mutations in either emerin or A-type lamins. Other LEM-domain proteins might modify the phenotype or severity of human laminopathy, or cause new laminopathies. We summarize evidence that the human genome encodes at least four additional LEM-domain proteins, designated Lem2 (NET-25), Lem3, Lem4 and Lem5. Early adaptation of a consistent nomenclature, such as the "Lem" names proposed here, will facilitate rapid progress in this field. Further investigation of 'founder' and novel members of this family will be important to understand nuclear structure, and presents new opportunities to understand human disease.

Cell Nucleus↗

PubMedDate not supplied

The accumulation of extracellular matrix in the kidney: consequences on cellular function.

The mechanisms involved in the progression of chronic renal disease (CRD) have not been completely clarified. A role for hyperfiltration and increased intraglomerular pressure was proposed about twenty years ago, and experimental and clinical evidence supports, at least partially, this hypothesis. Moreover, a lot of experimental data point to the importance of different autacoids, including prostanoids, endothelial vasoactive factors, reactive oxygen species, cytokines and growth factors, in the genesis of the changes that characterize CRD. However, alternative mechanisms of progression may be involved such as the presence of abnormal extracellular matrix (ECM) proteins in kidney structures. By modifying the phenotype of renal cells, they may constitute a key factor in disease progression. Experimental studies support this hypothesis. Human mesangial cells cultured on collagen I (COLI) synthesize increased amounts of TGFss1 compared with cells cultured on collagen IV (COLIV). As a consequence of this increased TGFBeta1 synthesis, they also produce more collagens and fibronectin. Human umbilical vein endothelial cells cultured on COLI show a different pattern of endothelial vasoactive factor synthesis, compared with those on COLIV: they synthesize more endothelin-1 and less nitric oxide. Integrins and integrin-linked kinase (ILK) play a significant role in the genesis of these changes. Although an extrapolation of these data to human diseases can not be performed, they point to alternative mechanisms of chronic renal damage progression or renal dysfunction in kidney diseases. They also point to potential therapeutic targets such as integrins and ILK.

Animals↗

PubMed1991

Decrease of proliferation rate and induction of differentiation by a MYCN antisense DNA oligomer in a human neuroblastoma cell line.

The effects of an antisense oligodeoxynucleotide to codons 2-7 of the oncogene MYCN on the human neuroblastoma cell line LAN-5 were studied. Treated cells showed a decreased MYCN protein expression and synthesis by immunoperoxidase staining and immunoprecipitation. At the same time, the replication rate was inhibited, and the phenotype was modified toward a more differentiated type. Our data suggest the involvement of oncogene MYCN in both proliferative and differentiative processes.

Base Sequence↗