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PubMed2006

Enhancement of cell attachment and tissue integration by a IKVAV containing multi-domain peptide.

Laminin contains a number of cell binding motifs including IKVAV and some that bind heparin. We developed a multi-domain synthetic peptide, LA2, which combines IKVAV sequences with a heparin-binding domain with the goal of improving cell attachment to otherwise non-adherent substrates. LA2 was used to coat polystyrene, ethyl vinyl acetate (EVA), expanded polytetrafluoroethylene (ePTFE), polycarbonate, titanium and stainless steel. In cell attachment studies, LA2 dramatically increased cell attachment to polystyrene and EVA compared to uncoated counterparts or those coated with SIKVAV. Similar increases were observed on ePTFE and titanium. On polystyrene, LA2 enhanced the attachment of endothelial cells, smooth muscle cells, epithelial cells, myoblasts, and osteoblast progenitor cells. Following adhesion, the cells underwent proliferation to form confluent monolayers with phenotypic morphologies. Using osteoblast progenitor cells (MC3T3 cells) grown on LA2/polystyrene, the cells exhibited an increased production of a differentiation marker, alkaline phosphatase. In vivo, LA2 improved tissue integration into ePTFE when implanted subcutaneously in rats. After 2 weeks, cells had penetrated deep into the LA2 coated ePTFE implant whereas little cell penetration was found in uncoated grafts. The implant sites exhibited little inflammation or other untoward effects. The results indicated that the LA2 peptide improved cell adhesion and tissue integration and might be useful in a number of tissue engineering applications.

Animals↗
PubMed1999

Host-induced, stage-specific virulence gene activation in Candida albicans during infection.

An understanding of the complex interactions between pathogenic microbes and their host must include the identification of gene expression patterns during infection. To detect the activation of virulence genes in the opportunistic fungal pathogen Candida albicans in vivo by host signals, we devised a reporter system that is based on FLP-mediated genetic recombination. The FLP gene, encoding the site-specific recombinase FLP, was genetically modified for expression in C. albicans and fused to the promoter of the SAP2 gene that codes for one of the secreted aspartic proteinases, which are putative virulence factors of C. albicans. The SAP2P-FLP fusion was integrated into one of the SAP2 alleles in a strain that contained a deletable marker that conferred resistance to mycophenolic acid and was flanked by direct repeats of the FLP recognition target (FRT). Using this reporter system, a transient gene induction could be monitored at the level of single cells by the mycophenolic acid-sensitive phenotype of the colonies generated from such cells after FLP-mediated marker excision. In two mouse models of disseminated candidiasis, SAP2 expression was not observed in the initial phase of infection, but the SAP2 gene was strongly induced after dissemination into deep organs. In contrast, in a mouse model of oesophageal candidiasis in which dissemination into internal organs did not occur, no SAP2 expression was detected at any time. Our results support a role of the SAP2 gene in the late stages of an infection, after fungal spread into deep tissue. This new in vivo expression technology (IVET) for a human fungal pathogen allows the detection of virulence gene induction at different stages of an infection, and therefore provides clues about the role of these genes in the disease process.

Animals↗
PubMed1998

Clinical studies and thrombin generation in patients homozygous or heterozygous for the G20210A mutation in the prothrombin gene.

A genetic variation in the prothrombin gene, the G-->A transition at nucleotide 20210, is a risk factor for venous thrombosis in heterozygotes and is associated with increased prothrombin activity. The homozygous phenotype and the extent of thrombin generation in heterozygous and homozygous subjects are unknown. We investigated a family that included 2 homozygous and 5 heterozygous carriers of the 20210 A allele. The homozygous propositus and his presumably heterozygous father suffered from deep-vein thrombosis. His presumably heterozygous mother and his homozygous sister had recurrent phlebitis at a young age. The remaining 5 affected family members are still asymptomatic. We studied thrombin generation in the family and in 22 unrelated carriers of the 20210 A allele by measuring (1) prothrombin fragment F1+2 (F1+2) as an index of ongoing thrombin generation and (2) the endogenous thrombin potential (ETP) as an index of the possible thrombin-forming capacity. Their F1+2 levels were not different from those of age-matched controls, and thus, ongoing hemostatic system activation was not detectable. A significantly increased ETP was found in the heterozygous carriers of the 20210A allele compared with the controls (527.8+/-114.9 versus 387+/-50.1 nmol/L x min, P<0.0001). In the 2 homozygotes, the ETP was almost twice (639 and 751 nmol/L x min, respectively) as high as in the controls. We conclude that homozygosity for the G20210A mutation in the prothrombin gene is associated with a severe, albeit more benign, thrombotic diathesis compared with homozygosity for deficiencies of antithrombin, protein C, or protein S. In carriers of the 20210 A allele, the pathomechanisms leading to thrombosis should be sought in the higher amounts of thrombin that may be formed once thrombin generation is triggered, rather than in ongoing thrombin generation in vivo.

Adult↗
PubMed1993

Two sibs with different phenotypes due to adjacent-1 segregation of a subtle translocation t(4;5)(p16.3;p15.3)mat.

High-resolution chromosome banding and in situ hybridization with combined cosmid and alphoid sequence probes were used to delineate a very small reciprocal translocation in a mother and her two children. The first child has a 46,XX,der(4)t(4;5)(p16.3;p15.3)mat and thus has a deletion of 4p16.3-->pter and a duplication of 5p15.3-->pter (most likely 5p15.31-->pter). Clinical findings include marked growth retardation, developmental delay, seizure disorder, microcephaly, unruly hair, broad nasal tip, downturned mouth, narrow palate, 11 pairs of ribs, mild right club foot, and a deep sacral dimple. Thus, this child has only a few non-specific manifestations of Wolf-Hirschhorn syndrome. The second child has a 46,XY,der(5)t(4;5)(p16.3;p15.3)mat; thus a deletion of 5p15.3-->pter and a duplication of 4p16.3-->pter. He has failure to thrive, developmental delay, microcephaly, sparse hair, horizontal nystagmus, short upturned nose with flared nostrils, thin lips with overhanging upper lip, long fingers and toes, and hypertonicity. Findings in the second patient are not suggestive of cri du chat syndrome (del 5p). The mother is phenotypically normal. This translocation will be useful in mapping genes and markers on the 4p and 5p chromosomal regions.

Abnormalities, Multiple↗
PubMed2003

The major clades of MADS-box genes and their role in the development and evolution of flowering plants.

MADS-box genes encode a family of transcription factors which control diverse developmental processes in flowering plants ranging from root to flower and fruit development. Sequencing of (almost) the complete Arabidopsis genome enabled the identification of (almost) all of the Arabidopsis MADS-box genes. MADS-box genes have been divided in two large groups, termed type I and type II genes. The type II genes comprise the MEF2-like genes of animals and fungi and the MIKC-type genes of plants. The majority of MIKC-type genes are of the MIKC(c)-type, which includes all plant MADS-box genes for which expression patterns or mutant phenotypes are known. By phylogeny reconstruction, almost all of the MIKC(c)-type genes can be subdivided into 12 major gene clades, each clade comprising 1-6 paralogs from Arabidopsis and putative orthologs from other seed plants. Here we first briefly describe the deep branching of the MADS-box gene tree to place the MIKC(c)-type genes into an evolutionary context. For every clade of MIKC(c)-type genes we then review what is known about its members from Arabidopsis and well-studied members from other phylogenetically informative plant species. By gene sampling and phylogeny reconstructions we provide minimal estimates for the ages of the different clades. It turns out that 7 of the 12 major gene clades, i.e., AG-, AGL6-, AGL12-, DEF+GLO- (B), GGM13- (B(s)), STMADS11- and TM3-like genes very likely existed already in the most recent common ancestor of angiosperms and gymnosperms about 300MYA. Three of the other clades, i.e., AGL2-, AGL17-, and SQUA-like genes, existed at least already in the most recent common ancestor of monocots and eudicots about 200 MYA. Only for two gene clades, AGL15-like genes (2 genes in Arabidopsis) and FLC-like genes (6 genes) members from plants other than Brassicaceae have not been reported yet. Similarly, only one ancient clade known from other flowering plant species, TM8-like genes, is not represented in Arabidopsis. These findings reveal that the diversity of MADS-box genes in Arabidopsis is rather ancient and representative for other flowering plants. Our studies may thus help to predict the set of MADS-box genes in all other flowering plants, except for relatively young paralogs. For the different gene clades we try to identify ancestral and derived gene functions and review the importance of these clades for seed plant development and evolution. We put special emphasis on gene clades for which insights into their importance has rapidly increased just recently.

Arabidopsis↗
PubMed2005

Ecotype diversity in the marine picoeukaryote Ostreococcus (Chlorophyta, Prasinophyceae).

The importance of the cyanobacteria Prochlorococcus and Synechococcus in marine ecosystems in terms of abundance and primary production can be partially explained by ecotypic differentiation. Despite the dominance of eukaryotes within photosynthetic picoplankton in many areas a similar differentiation has never been evidenced for these organisms. Here we report distinct genetic [rDNA 18S and internal transcribed spacer (ITS) sequencing], karyotypic (pulsed-field gel electrophoresis), phenotypic (pigment composition) and physiological (light-limited growth rates) traits in 12 Ostreococcus strains (Prasinophyceae) isolated from various marine environments and depths, which suggest that the concept of ecotype could also be valid for eukaryotes. Internal transcribed spacer phylogeny grouped together four deep strains isolated between 90 m and 120 m depth from different geographical origins. Three deep strains displayed larger chromosomal bands, different chromosome hybridization patterns, and an additional chlorophyll (chl) c-like pigment. Furthermore, growth rates of deep strains show severe photo-inhibition at high light intensities, while surface strains do not grow at the lowest light intensities. These features strongly suggest distinct adaptation to environmental conditions encountered at surface and the bottom of the oceanic euphotic zone, reminiscent of that described in prokaryotes.

Chlorophyll↗
PubMed2003

Repair of articular cartilage defects with osteogenic protein-1 (BMP-7) in dogs.

BACKGROUND: Articular cartilage injury has a poor prognosis for repair. Mesenchymal cells, when exposed to osteogenic proteins and other cytokines, can differentiate into cells that behave phenotypically as chondrocytes. In this study, we examined the ability of recombinant human osteogenic protein-1 (rhOP-1 or rhBMP-7) to elicit the repair of osteochondral defects in dogs. METHODS: Bilateral osteochondral defects that were 5 mm in diameter by 6 mm deep were surgically created in the medial femoral condyles of sixty-five adult dogs. rhOP-1-treated (100 mg of a 3.5-mg rhOP-1/g bovine bone-derived Type-I collagen device) and control defects (untreated or treated with 100 mg bovine bone-derived collagen implants) were evaluated grossly and histologically at six, twelve, sixteen, twenty-six, and fifty-two weeks postoperatively. The influence of protected initial weight-bearing and surgical placement of periosteal flaps was also evaluated. RESULTS: Gross and histologic grading of the defect repair indicated improvement in the rhOP-1-treated defects compared with that in the controls. Grossly, the repair tissue in the rhOP-1-treated defects was continuous with the adjacent intact cartilage and appeared translucent. By comparison, the repair tissue in the control defects was discontinuous and opaque or inhomogeneous in nature. Histologically, maturing cartilage similar in appearance to the intact articular cartilage was present in the rhOP-1-treated defects. Cartilage at the defect interface was minimally degraded. The control defects were filled primarily with fibrous tissue and fibrocartilage. Significant differences based upon treatment type were observed at twelve weeks, sixteen weeks, and for all time-periods combined (p = 0.0385, p = 0.0070, and p = 0.0026, respectively). CONCLUSION: rhOP-1 (rhBMP-7) induced hyaline cartilage-like repair of full-thickness osteochondral defects in a dog model. Differences in cartilage repair were maintained at fifty-two weeks postoperatively with no significant degradation of the rhOP-1-induced repair tissue.

Animals↗
PubMed1989

Histological inhomogeneity of colorectal adenocarcinomas.

The histological inhomogeneity of colorectal adenocarcinomas has hardly been systematically investigated up to now. Currently, however, this awareness is gaining in importance, e.g. within the framework of grading measures, for analysis of immunohistochemical results or for interpretation of flowcytometric data. Thus, 100 colon carcinomas each were semiquantitatively investigated on four different sites in terms of either homogeneous or inhomogeneous expression of histological, cytological and immunohistochemical (CEA, UEA I) criteria. Although all carcinomas contained tubular structures, there was no intraindividual uniformity but considerable inhomogeneity on the part of histological as well as cytological features. Quantitative and qualitative positivity of CEA and UEA I too, varied markedly. Our results lead to the conclusion that the phenotypic inhomogeneity of colorectal carcinoma is at least partially attributable to genetic tumor cell instability. In spite of this, there might be a trend to intra-individual localisation-related tumor cell differentiation, because several parameters showed significant differences between luminal and deep carcinoma regions.

Adenocarcinoma↗
PubMed2005

Shade tolerance, photoinhibition sensitivity and phenotypic plasticity of Ilex aquifolium in continental Mediterranean sites.

Shade tolerance, plastic phenotypic response to light and sensitivity to photoinhibition were studied in holly (Ilex aquifolium L.) seedlings transported from the field to a greenhouse and in adult trees in the field. All plants were growing in, or originated from, continental Mediterranean sites in central Spain. Seedlings tolerated moderate but not deep shade. Mortality was high and growth reduced in 1% sunlight. Survival was maximal in 12% sunlight and minimal in full sunlight, although the relative growth rate of the seedlings surviving in high light was similar to that of plants in moderate shade. Maximum photochemical efficiency at predawn was significantly lower in sun plants than in shade plants in the field, revealing chronic photoinhibition that was most pronounced in winter. Plasticity in response to available light varied according to the variable studied, being low for photosynthetic capacity and stomatal conductance, and high for specific leaf area, root:shoot ratio and leaf area ratio, particularly in seedlings. Differences in water relations and hydraulic features between sun and shade plants in the field were marginal. High water potential at the turgor loss point of field-grown plants suggested that holly is sensitive to drought during both the seedling and the adult stage. Low relative growth rates in both high and low light with low physiological plasticity in response to light indicate the existence of a stress-tolerance mechanism. We conclude that holly is a facultative understory plant in areas of oceanic and relatively mild climate, but an obligate understory plant in dry continental areas such as the study site. The impact of abandonment of traditional management practices and climate change on these Mediterranean populations is discussed.

Chlorophyll↗
PubMed1985

Degeneration of thalamic neurons in "Purkinje cell degeneration" mutant mice. I. Distribution of neuron loss.

The Purkinje cell degeneration (pcd) mutation of the mouse is an autosomal recessive allele which previous studies have shown to be the cause of rapid degeneration of nearly all cerebellar Purkinje cells between 18 and 30 postnatal days of age (P18-P30), and slowly developing, progressive losses of retinal photoreceptor cells and mitral cells of the olfactory bulb. Through examination of serial frozen sections alternately stained for Nissl substance and for degenerating neuronal processes, we have found that discrete populations of thalamic neurons degenerate rapidly between P50 and P60. Severely affected nuclei, in which a majority of neurons degenerate, include the central division of the mediodorsal nucleus, the ventral medial geniculate, posterior, posterior ventromedial, and submedial nuclei, and those portions of the ventrolateral and posteromedial nuclei which immediately surround the medial division of the ventrobasal complex. More subtle cell losses occur during the same time period in restricted portions of the lateral ventrobasal, dorsal lateral geniculate, and lateral posterior nuclei, but even at P180 these nuclei are not markedly atrophic. No common denominator among target cell populations has been established. The pcd allele affects a diverse assortment of specific relay nuclei; degeneration has not been recognized in thalamic nuclei characterized primarily or exclusively by subcortical projections or by cortical projections directed relatively selectively to superficial or deep cortical laminae. The neuronal degenerations in the thalamus are not precipitated by prior or concurrent degeneration of cortical targets or afferent sources, though striking transneuronal changes, including cell death, do develop following thalamic neuronal degeneration in this mutant. No previously described murine mutant phenotype includes the rapid degeneration of highly restricted neuronal populations beginning at these relatively advanced ages.

Aging↗
PubMed2006

Bacterial artificial chromosome transgenic analysis of dynamic expression patterns of regulator of G-protein signaling 4 during development. I. Cerebral cortex.

Signaling through G-protein-coupled receptors is modulated by a family of regulator of G protein signaling (RGS) proteins that have been implicated in several neurological and psychiatric disorders. Defining the detailed expression patterns and developmental regulation of RGS proteins has been hampered by an absence of antibodies useful for mapping. We have utilized bacterial artificial chromosome (BAC) methods to create transgenic mice that express GFP under the control of endogenous regulator of G-protein signaling 4 (RGS4) enhancer elements. This report focuses on expression patterns in the developing and mature cerebral cortex. Based on reporter distribution, RGS4 is expressed by birth in neurons across all cortical domains, but in different patterns that suggest region- and layer-specific regulation. Peak expression typically occurs before puberty, with complex down-regulation by adulthood. Deep and superficial neurons, in particular, vary in their patterns across developmental age and region and, in primary sensory cortices, layer IV neurons exhibit low or no expression of the GFP reporter. These data suggest that altering RGS4 function will produce a complex neuronal phenotype with cell- and subdomain-specificity in the cerebral cortex.

Aging↗
PubMed1988

Protective immunity in murine histoplasmosis: functional comparison of adoptively transferred T-cell clones and splenic T cells.

In this study, I examined whether a murine T-cell line and three clones that recognize Histoplasma capsulatum antigens in vitro could confer protection in vivo against a challenge of Histoplasma yeasts. C57BL/6 mice were each inoculated with 5 X 10(4) yeasts intravenously; 1 h later, 5 X 10(6) or 2 X 10(7) resting T cells were inoculated intravenously. At week 1 of infection, the T-cell line and all clones failed to reduce the number of H. capsulatum CFU in the spleens of mice compared with numbers in infected controls. Administration of recombinant interleukin 2 or cyclophosphamide to infected mice did not potentiate the functional activity in vivo of either the T-cell line or the clones. In contrast, inoculation with 2 X 10(7) CD4+ but not CD8+ cells isolated from the spleens of mice immunized with 10(6) viable yeast cells sharply diminished the number of CFU in the spleens of infected animals. Moreover, splenic CD4+ cells from immune mice transferred a delayed-type hypersensitivity response, whereas the T-cell line and clones did not. Injection Injection of an equal number of cloned T cells and CD8+ splenocytes from immune mice did not transfer resistance to infected mice. Additional studies were undertaken to determine if the ineffectiveness of cloned T cells was associated with a failure to migrate to and survive within spleens of infected mice. B6.PL Thy-1a/Cy mice, which are genetically identical to C57BL/6 mice except that T cells of the former bear Thy-1.1 rather than Thy-1.2, were inoculated with Histoplasma yeasts and then injected with immune CD4+ splenocytes or a T-cell clone. At days 1 and 7 of infection, virtually no Thy-1.2+ cells were detected in the spleens of infected mice given cloned T cells. However, the spleens of animals inoculated with immune CD4+ cells contained a small but significant (P less than 0.01) proportion of Thy-1.2+ cells at both day 1 and day 7 postinoculation of H. capsulatum. Thus, the failure of T-cell clones to transfer protection against H. capsulatum may be explained by defective trafficking or poor survival in vivo or both.

Animals↗
PubMed2002

Involvement of dipeptidyl peptidase IV in extravillous trophoblast invasion and differentiation.

Previously, we reported that dipeptidyl peptidase IV (DPPIV), a membrane-bound peptidase, was expressed on human placental cytotrophoblasts. In the present study, we focused on DPPIV expression on extravillous trophoblasts (EVTs). In the first trimester, DPPIV was expressed in the proximal part of the cell column and some EVTs located in the deep portion of the decidua and myometrium. EVTs migrating in the decidua from the cell column were negative for DPPIV. In the second and third trimesters, almost all EVTs were positive for DPPIV. Because negative DPPIV expression was associated with migration or the invasive phenotype of EVTs, using JEG-3 cells (choriocarcinoma cell line) that endogenously produce DPPIV, the influence of DPPIV on the invasive activity was examined. When a competitive inhibitor of DPPIV, diprotin A, was added in Matrigel invasion assay system, JEG-3 cells exhibited a significant enhancement of invasion. Because hypoxia is reported to reduce trophoblastic invasion, the effect of hypoxia was examined on JEG-3 cells. JEG-3 cells became less invasive with increased expression of DPPIV when cultured under hypoxic conditions (1% O(2)). These results suggest that DPPIV is important for the noninvasive EVT phenotype and the down-regulation of this enzyme was strongly associated with migration or invasive EVT phenotype.

Base Sequence↗
PubMed2005

Neurovascular phenotypes in hereditary haemorrhagic telangiectasia patients according to age. Review of 50 consecutive patients aged 1 day-60 years.

Hereditary haemorrhagic telangiectasia (HHT) is inherited as an autosomal dominant trait with varying penetrance and expressivity. Some of the most devastating consequences of this disease result from cerebral vascular malformations that manifest themselves in either arteriovenous fistulae (AVF), small nidus-type arteriovenous malformations (AVM) or micro-AVMs with a nidus less than 1 cm in size. The purpose of this study was to compare the phenotypes of CNS-manifestations of HHT with the age of the patient. The charts and angiographic films of 50 patients diagnosed with HHT according to the Curaçao criteria were retrospectively evaluated concerning age of onset of symptoms, or, if not applicable of first consultation. The files were reviewed for clinical presentation, family and personal history, while the patients' angiograms were analysed with respect to the number of lesions (single and multiple), the location (superficial supratentorial, deep supratentorial, infratentorial, and spinal), and type of lesion (fistulous AVM, nidus-type AVM, and micro-AVM). A total of 75 central nervous system manifestations of HHT were found. Lesions included seven spinal cord AVFs that were all present in the paediatric age group (mean age: 2.2 years), 34 cerebral AV fistulae, all but two affected patients were less than 6 years (mean age 3.0). Sixteen nidus type AVMs (mean age: 23.1 years) and 18 micro-AVMs (mean age: 31.8 years) were found. HHT displays an age-related penetrance of clinical manifestations. Since members of the same family can present with completely different phenotypes of this disease there seems to be no relationship between the type of mutation and the phenotype of the disease. Since there seems to be a continuum of vascular abnormalities (from large fistulous areas to small AVMs and micro-AVMs) associated with HHT, the most likely determinating factor of the HHT phenotype is the timing of the revealing event in relation to the maturity of the vessel. Presumably, the trigger of the quiescent genetical abnormality transforms a "dormant" disease into a morphologically and therefore clinically detectable one by impairing a specific vessel segment at a specific (more or less vulnerable) period of time. The nature of this triggering event is, however, as of yet unclear.

Adolescent↗
PubMed1998

Incidence and clinical manifestations of activated protein C resistance and factor V Leiden in young patients with venous thromboembolic disease in Spain.

In order to evaluate the actual incidence and clinical repercussion of activated protein C resistance (APCR) in our area, we performed a coagulation and thrombophillic study on 65 young patients diagnosed with deep vein thrombosis and 53 controls. Family and genetic study was carried out in APC-resistant patients. We found APCR in 26.15% of patients and the 77.7% of these and their relative were heterozygous for factor V Leiden. There's a clear relationship between phenotype APCR and thrombosis, and also between factor V Leiden and thrombosis.

Adolescent↗
PubMed1998

Polymorphisms of platelet membrane glycoprotein Ib associated with arterial thrombotic disease.

Platelet membrane glycoprotein Ibalpha (GPIbalpha) is a major receptor for von Willebrand factor and thrombin, which plays a key role in the initial development of thrombi. Two polymorphisms (HPA-2 and VNTR) that affect phenotype have been described in GPIbalpha. The relevance of these polymorphisms to thrombotic disease was investigated by genotypic identification in three case-control studies: 104 case patients with acute cerebrovascular disease (CVD), 101 case patients with acute coronary heart disease (CHD), 95 patients with deep venous thrombosis (DVT), and one control age-, sex-, and race-matched for each case patient. Results show that the C/B genotype of the VNTR and the HPA-2b polymorphisms of GPIbalpha are strongly associated with increased risk of coronary heart disease and cerebral vascular disease but not with deep vein thrombosis. These two polymorphisms of GPIbalpha may represent newly identified risk factors for arterial thrombotic disease, but not for venous thrombosis.

Adult↗
PubMed2025

Machine learning on multiple epigenetic features reveals H3K27Ac as a driver of gene expression prediction across patients with glioblastoma.

Epigenetic mechanisms play a crucial role in driving transcript expression and shaping the phenotypic plasticity of glioblastoma stem cells (GSCs), contributing to tumor heterogeneity and therapeutic resistance. These mechanisms dynamically regulate the expression of key oncogenic and stemness-associated genes, enabling GSCs to adapt to environmental cues and evade targeted therapies. Importantly, epigenetic reprogramming allows GSCs to transition between cellular states, including therapy-resistant mesenchymal-like phenotypes, underscoring the need for epigenetic-targeting strategies to disrupt these adaptive processes. Understanding these epigenetic drivers of gene expression provides a foundation for novel therapeutic interventions aimed at eradicating GSCs and improving glioblastoma outcomes. Using machine learning (ML), we employ cross-patient prediction of transcript expression in GSCs by combining epigenetic features from various sources, including ATAC-seq, CTCF ChIP-seq, RNAPII ChIP-seq, H3K27Ac ChIP-seq, and RNA-seq. We investigate different ML and deep learning (DL) models for this task and ultimately build our final pipeline using XGBoost. The model trained on one patient generalizes to other 11 patients with high performance. Notably, H3K27Ac alone from a single patient is sufficient to predict gene expression in all 11 patients. Furthermore, the distribution of H3K27Ac peaks across the genomes of all patients is remarkably similar. These findings suggest that GSCs share a common distributional pattern of enhancer activity characterized by H3K27Ac, which can be utilized to predict gene expression in GSCs across patients. In summary, while GSCs are known for their transcriptomic and phenotypic heterogeneity, we propose that they share a common epigenetic pattern of enhancer activation that defines their underlying transcriptomic expression pattern. This pattern can predict gene expression across patient samples, providing valuable insights into the biology of GSCs.

Glioblastoma↗
PubMed2004

An unusual clinical phenotype of Avellino corneal dystrophy associated with an Arg124His beta iG-H3 mutation in an African-American woman.

PURPOSE: To describe the clinical features, histologic changes, and genetic analysis of Avellino corneal dystrophy in an African-American woman. DESIGN: Interventional case report. METHODS: A 79-year-old African-American woman with corneal deposits consistent with Avellino corneal dystrophy was studied with histologic and genetic analysis. RESULTS: The patient had multiple crumb-like opacities in the anterior stroma of both eyes. Deep to these lesions were numerous faint, stellate lattice lesions. Corneal scraping confirmed the presence of Masson trichrome and Congo red positive subepithelial deposits. Genetic analysis revealed a heterozygous CGC/CAC change in exon 4 of the beta iG-H3 gene, resulting in an arginine to histidine substitution at codon 124. CONCLUSIONS: This case reveals several novel findings, including surface changes resembling vortex dystrophy and large granular deposits protruding through the anterior corneal surface. This is the first case described in an African-American patient.

Black or African American↗