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PubMed2004

Molecular phylogeny of Zygomycota based on EF-1alpha and RPB1 sequences: limitations and utility of alternative markers to rDNA.

Earlier molecular phylogenetic analyses based on nuclear small subunit ribosomal DNA (nSSU rDNA) suggest that the Zygomycota are polyphyletic within the Chytridiomycota. However, these analyses failed to resolve almost all interordinal relationships among basal fungi (Chytridiomycota and Zygomycota), due to lack of sufficient characters within the nSSU rDNA. To further elucidate the higher-level phylogeny of Zygomycota, we have sequenced partial RPB1 (DNA dependent RNA polymerase II largest subunit) and EF-1alpha (translation elongation factor 1 alpha) genes from 10 and 3 zygomycete fungi, respectively. Independent molecular phylogenetic analyses were performed based on each sequence by distance and maximum likelihood methods. Although deep phylogenetic relationships among basal fungi still remain poorly resolved using either gene, the RPB1-based phylogeny identified a novel monophyletic clade consisting of the Dimargaritales, Harpellales, and Kickxellales. This result suggests that regularly formed septa (cross walls that divide hyphae into segments) with a lenticular cavity are plesiomorphic for this clade, and indicates the importance of septal pore ultrastructure in zygomycete phylogeny. In addition, a peculiar mucoralean genus Mortierella, which was considered to be distantly related to the other Mucorales based on previous nSSU rDNA analyses, was resolved as the basal most divergence within the Mucorales, consistent with traditional phenotypic-based taxonomy. Although the taxa included in our analysis are restricted, the monophyly of each order suggested by nSSU rDNA phylogeny is supported by the present RPB1-based analysis. These results support the potential use of RPB1 as an alternative marker for fungal phylogenetic studies. Conversely, the overall fungal phylogeny based on EF-1alpha sequence is poorly resolved. A comparison of numbers of observed substitutions versus inferred substitutions within EF-1alpha indicates that this gene is much more saturated than RPB1. This result suggests that the EF-1alpha gene is unsuitable for resolving higher-level phylogenetic relationships within the Fungi.

Animals↗
PubMed2000

Ectodermal dysplasias: not only 'skin' deep.

The ectodermal dysplasias (EDs) are a large and complex nosologic group of diseases; more than 170 different pathologic clinical conditions have been identified. Despite the great number of EDs described so far, few causative genes have been identified. We review EDs in the light of the most recent molecular findings and propose a new classification of EDs integrating both molecular-genetic data and corresponding clinical findings of related diseases.

Animals↗
PubMed1999

Extraskeletal myxoid chondrosarcoma: a reappraisal of its morphologic spectrum and prognostic factors based on 117 cases.

Extraskeletal myxoid chondrosarcoma (EMC), a phenotypically and genotypically distinctive entity, has generally been viewed as a low-grade sarcoma. No studies regarding clinical and morphologic prognostic factors have been performed on a large series of cases with long-term follow-up because of the rarity and protracted clinical course of EMC. The clinical, morphologic, and immunohistochemical features of 117 previously unreported cases were studied and statistically analyzed. The male-to-female ratio was 2:1. The median patient age was 52 years (range, 6-89 years), and the median tumor size was 7 cm (range, 1.1-25 cm). All tumors occurred within the deep subcutis or deeper soft tissues, with 80% occurring in the proximal extremities or limb girdles and 20% in the trunk. Most initial tumor excisions were intralesional or marginal. Follow-up information was available in 99 cases (median, 9 years: range, 2 months-22 years). Forty-eight patients were disease-free, and 41 patients had evidence of disease (18 of these had died of disease). Ten additional patients survived, but their disease status was unknown. There were local recurrences in 40 (48%) of 83 patients, 23 (58%) of whom had multiple local recurrences. Metastases occurred in 35 (46%) of 76 patients. The estimated 5-, 10-, and 15-year survival rates were 90%, 70%, and 60%, respectively. All cases had histologic features characteristic of classical EMC, at least focally. Cellular foci devoid of myxoid matrix and reminiscent of chondroblastoma, Ewing's sarcoma, monophasic and poorly differentiated synovial sarcoma, fibrosarcoma, and rhabdoid tumor were identified in 29% cases. Older patient age, larger tumor size, and tumor location in the proximal extremity or limb girdle were adverse prognostic factors identified by multivariate analysis. Metastasis also adversely affected survival, although local recurrence did not. This study shows that EMC has a unique clinical course, including a high rate of local recurrence, prolonged survival after metastasis in some cases, and eventually a high rate of death due to tumor. These features distinguish EMC from low-grade sarcomas. This study shows that histologic grading is of no prognostic value in EMC because prognosis is dictated primarily by certain clinical features. Histologic recognition of classical EMC and cellular and solid, nonmyxoid variants is important, however, in view of EMC's distinctive biologic behavior.

Adolescent↗
PubMed1999

white anther: A petunia mutant that abolishes pollen flavonol accumulation, induces male sterility, and is complemented by a chalcone synthase transgene

A mutation in an inbred line of petunia (Petunia hybrida) produces a reduction in the deep-purple corolla pigmentation and changes the anther color from yellow to white. In addition, the mutant, designated white anther (wha), is functionally male sterile. The inability of pollen from wha plants to germinate in vitro provides a physiological basis for the lack of seed set observed in self-crosses of the mutant. Biochemical complementation with nanomolar amounts of kaempferol, a flavonol aglycone, confirms that the inability of the wha pollen to germinate is due to a lack of this essential compound. Transgenic complementation with a functional ChsA (Chalcone synthase A) cDNA suggests that the genetic lesion responsible for the wha phenotype is in Chs, the gene for the first enzyme in the flavonol biosynthesis pathway. The genetic background of the parental line, as well as the pollen phenotype, allowed us to deduce that the wha mutation is in ChsA. To our knowledge, wha is the first induced, nontransgenic Chs mutant described in petunia, and analysis of the mutation confirms earlier molecular and genetic observations that only two Chs genes (A and J) are expressed in reproductive tissues and that they are differentially regulated in corolla and anther.

Journal Article↗
PubMed1997

Expression of p67 (Munc-18), Cdk5, P-NFH and syntaxin during development of the rat cerebellum.

Cyclin-dependent kinases (cdks), which regulate the cell division cycle, have also been found in postmitotic neurons. Cdk5, isolated from neural tissue, has been shown to phosphorylate neurofilaments (NFs). Instead of cyclins, however, other neuron-specific activators of cdk5 have been identified including a 67-kD protein (p67) which is identical to a syntaxin-binding protein (n-sec-1, Munc 18) that is thought to play a role in synaptic vesicle trafficking and transmitter release. These functions for p67 are not mutually exclusive since regulation of edk5 phosphorylation of cytoskeletal proteins may modulate axonal dynamics during growth, synaptogenesis and vesicle transport. To gain further insight into the role of p67 in neural tissue, we carried out a Western blot and immunohistochemical analysis of the developing rat cerebellum using antibodies to cdk5, p67, syntaxin and phosphorylated and nonphosphorylated neurofilaments. We assumed that spatiotemporal colocalizations of antigens might correlate with proposed functions for p67. The immunoblots showed that all antigens were developmentally regulated, and increased in expression from PN2 to the adult, with p67 and cdk5 showing a close temporal correlation. Immunohistochemically, p67 colocalized with cdk5 and P-NFH in selected fiber tracts, particularly those in the deep cerebellum. For the most part, p67 also showed strong colocalization patterns with syntaxin in regions of synaptogenesis throughout development such as the molecular layer and glomeruli of the inner nuclear layer. Finally, certain fiber tracts, the afferent fibers, climbing and mossy fibers and particularly the basket cell fibers that envelop and innervate Purkinje cell somata and dendrites, displayed colocalization of cdk5 and P-NFH without expressing any p67. Given the limitations of colocalization data in defining functional relationships, the results are consistent with the hypothesis that p67 is a multifunctional protein, its activity during cerebellum development dependent upon the neuronal phenotype, its location and its state of developmental maturation.

Animals↗
PubMed1998

Development of an intrinsic P-glycoprotein-mediated doxorubicin resistance in quiescent cell layers of large, multicellular prostate tumor spheroids.

Growing multicellular prostate tumor spheroids develop quiescent cell subpopulations in central regions with features of intrinsic multicell-mediated drug resistance. Doxorubicin (dox) uptake was significantly reduced in large spheroids (diameter 400+/-70 microm), which consist predominantly of quiescent cells, as compared to small spheroids (diameter 100+/-50 microm), which consist entirely of proliferating cells. After removal of dox from the incubation medium, dox fluorescence declined more efficiently in large spheroids, which led to a decreased dox toxicity as revealed by colony-forming assays. Verapamil significantly increased dox retention in large spheroids and, consequently, augmented dox toxicity. At a depth 80 microm from the spheroid periphery, a significantly decreased dox fluorescence was observed in the deep, quiescent cell layers of large spheroids. The P-glycoprotein-mediated multidrug resistance (MDR)-reversing agents verapamil, cyclosporin A, quinidine, sodium orthovanadate and tamoxifen significantly increased dox fluorescence at this depth, whereas genistein, indomethacin, probenecid and brefeldin A, which reverse multidrug-resistance-associated protein (MRP) function, exerted no effect. Anti-P-glycoprotein immunohistochemistry of multicellular tumor spheroids revealed an increase of P-glycoprotein expression in large speroids as compared to small spheroids, which was most prominent in the Ki-67-negative, quiescent cell layers 60 to 100 microm distant from the periphery of the spheroid, indicating that the MDR phenotype is related to cell quiescence. This was corroborated by whole-cell patch-clamp experiments, where the C219 antibody, which is directed against the ATP-binding site of P-glycoprotein, significantly inhibited P-glycoprotein-associated, volume-activated chloride currents in quiescent, but not proliferating cells from multicellular tumor spheroids.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2004

Respiratory adaptations to the deep-sea hydrothermal vent environment: the case of Segonzacia mesatlantica, a crab from the Mid-Atlantic Ridge.

Segonzacia mesatlantica (Crustacea; Decapoda; Brachyura) is the only endemic crab species known from the Mid-Atlantic Ridge (MAR) hydrothermal vents. Known from all explored sites in the Atlantic, its wide distribution makes this species a model to study physiological adaptation, and specifically respiratory strategies. Native haemocyanin (Hc) comprises four non-covalent associations in equilibrium formed by monomers, hexamers, dodecamers and octadecamers made up of approximately 75 kDa polypeptide chains. Four different amino acid chains are observed with a molecular mass ranging from 75,234 to 75,972 Da. Experiments carried-out under pressure suggested that the percentage of monomer increased in the haemolymph under hypoxic condition. We have also observed a shift of the proportion of the two dodecamer series, suggesting a rapid modification of the Hc phenotype between hypoxic and hyperoxic conditions. Native Hc possesses a high oxygen affinity ( P50 = 2.2 Torr at 15 degrees C and pH 7.5), a large Bohr effect (Deltalog P50 / DeltapH approximately -2.7) and a slightly reverse temperature effect (DeltaH = +17.19 kJ mol(-1). The composition of Segonzacia haemolymph is similar to that of other littoral species except for the large enrichment in free copper and zinc. As for other species from hydrothermal vent sites, Segonzacia haemolymph possesses a higher buffer capacity than littoral species. Moreover, species from the hydrothermal vent decapods from Pacific hydrothermal vent that encounter higher CO2 content in their environment have a higher buffer capacity than Atlantic vent species. The results presented are discussed in relation with the physico-chemical characteristics of the hydrothermal vent environment.

Adaptation, Physiological↗
PubMed2025

Deep clinical and genetic analysis of 17p13.3 region: 38 pediatric patients diagnosed using next-generation sequencing and literature review.

BACKGROUND: Chromosome 17p13.3 is a region of genomic instability associated with different neurodevelopmental diseases. The malformation spectrum of 17p13.3 microdeletions ranges from an isolated lissencephaly sequence to Miller-Dieker syndrome, while 17p13.3 microduplications result in autism, learning disabilities, microcephaly and other brain malformations. This study aims to provide a more comprehensive delineation of the clinical and genetic characteristics associated with 17p13.3 alterations. METHODS: We retrospectively analyzed the next-generation sequencing (NGS) data of more than 40 thousand patients from January 2016 to December 2021 and identified 38 pediatric patients with copy-number variations (CNVs) or single-nucleotide variations (SNVs) in 17p13.3 region. Published patients with CNVs in the 17p13.3 region were also collected and we performed a Chi-square test to compare the phenotype spectrum of microdeletions and microduplications. RESULTS: Among the 27 CNV patients, 20 patients with microdeletions and 7 patients with microduplications were found. PAFAH1B1 was the most frequently deleted gene and CRK was the most frequently duplicated gene. Affected genes in 11 SNV patients included PAFAH1B1 and PRPF8. Developmental delay was the most common abnormality detected in the 38 patients (29/38, 76.3%). Of note, Case 10 presented omphalocele and Case 23 presented scoliosis, webbed neck and bone cyst, all of which were unusual variant phenotypes in this region. The Chi-square test revealed that epilepsy, lissencephaly and short stature were statistically significant with microdeletions, while behavioral abnormalities and hand and foot abnormalities were significant with microduplications (p&#x2009;<&#x2009;0.01). CONCLUSIONS: While PAFAH1B1, YWHAE and CRK are associated with major phenotypes of 17p13.3, RTN4RL1 may be involved in white matter changes and HIC1 might contribute to the occurrence of omphalocele. This study provided a comprehensive understanding of genetic information and phenotype spectrum of the 17p13.3 region.

Humans↗
PubMed1989

Distribution of corticotropin-releasing factor in the cerebellum and precerebellar nuclei of the opossum: a study utilizing immunohistochemistry, in situ hybridization histochemistry, and receptor autoradiography.

This study reports 1) a nonhomogeneous distribution of three morphologically distinct, corticotropin-releasing factor (CRF)-immunoreactive axonal phenotypes within the cerebellum of the opossum: climbing fibers, mossy fibers, and beaded fibers within the ganglionic plexus; 2) the existence of CRF binding sites within the cerebellar cortex; and 3) the distribution of CRF-containing neurons in brainstem precerebellar nuclei identified with immunohistochemistry and in situ hybridization histochemistry. CRF-immunoreactive climbing and/or mossy fibers were identified within all cerebellar lobules. The density of CRF-immunoreactive fibers was greatest in the vermis, where longitudinal bands of intensely immunoreactive climbing and mossy fibers were interspersed with regions containing fibers demonstrating lower levels of immunolabeling. CRF-immunoreactive fibers were present within all deep cerebellar nuclei. The topography of CRF-containing cerebellar fibers is discussed with respect to possible sites of origin within the brainstem. CRF-immunoreactive neurons were identified in all nuclei of the inferior olivary complex, although the number and intensity of immunostaining of CRF-containing cells varied within and among individual nuclei. CRF-immunoreactive somata were also present in brainstem nuclei known to give rise to cerebellar mossy fibers. In situ hybridization histochemistry utilizing an 35S-labeled synthetic 48-base oligodeoxynucleotide complementary to amino acids 22-37 of rat CRF proper revealed that CRF mRNA is transcribed in precerebellar nuclei. Variation in the level of CRF mRNA was detected among inferior olivary nuclei, in correspondence with variations detected in the levels of immunostaining. Data from this study suggest that variation in the level of CRF immunoreactivity detected within cerebellar afferent fibers may correlate with the level of CRF mRNA within cell bodies of origin of the projections. In vitro receptor autoradiography, utilizing 125I-Tyro-ovine CRF, revealed correspondence between CRF binding sites and CRF-immunoreactive fibers in the cerebellar cortex. Results of this study support suggestions for CRF-mediated circuitry in the cerebellum.

Animals↗
PubMed2003

The molecular genetics of the corneal dystrophies--current status.

The pertinent literature on inherited corneal diseases is reviewed in terms of the chromosomal localization and identification of the responsible genes. Disorders affecting the cornea have been mapped to human chromosome 1 (central crystalline corneal dystrophy, familial subepithelial corneal amyloidosis, early onset Fuchs dystrophy, posterior polymorphous corneal dystrophy), chromosome 4 (Bietti marginal crystalline dystrophy), chromosome 5 (lattice dystrophy types 1 and IIIA, granular corneal dystrophy types 1, 2 and 3, Thiel-Behnke corneal dystrophy), chromosome 9 (lattice dystrophy type II), chromosome 10 (Thiel-Behnke corneal dystrophy), chromosome 12 (Meesmann dystrophy), chromosome 16 (macular corneal dystrophy, fish eye disease, LCAT disease, tyrosinemia type II), chromosome 17 (Meesmann dystrophy, Stocker-Holt dystrophy), chromosome 20 (congenital hereditary endothelial corneal dystrophy types I and II, posterior polymorphous corneal dystrophy), chromosome 21 (autosomal dominant keratoconus) and the X chromosome (cornea verticillata, cornea farinata, deep filiform corneal dystrophy, keratosis follicularis spinulosa decalvans, Lisch corneal dystrophy). Mutations in nine genes (ARSC1, CHST6, COL8A2, GLA, GSN, KRT3, KRT12, M1S1and TGFBI [BIGH3]) account for some of the corneal diseases and three of them are associated with amyloid deposition in the cornea (GSN, M1S1, TGFBI) including most of the lattice corneal dystrophies (LCDs) [LCD types I, IA, II, IIIA, IIIB, IV, V, VI and VII] recognized by their lattice pattern of linear opacities. Genetic studies on inherited diseases affecting the cornea have provided insight into some of these disorders at a basic molecular level and it has become recognized that distinct clinicopathologic phenotypes can result from specific mutations in a particular gene, as well as some different mutations in the same gene. A molecular genetic understanding of inherited corneal diseases is leading to a better appreciation of the pathogenesis of these conditions and this knowledge has made it imperative to revise the classification of inherited corneal diseases.

Corneal Dystrophies, Hereditary↗
PubMed2000

Activation of annexin II and V expression, terminal differentiation, mineralization and apoptosis in human osteoarthritic cartilage.

OBJECTIVE: To test the hypothesis that terminal differentiation of chondrocytes in human osteoarthritic cartilage might lead to the failure of repair mechanisms and might cause progressive loss of structure and function of articular cartilage. DESIGN: Markers for terminally differentiated chondrocytes, such as alkaline phosphatase, annexin II, annexin V and type X collagen, were detected by immunohistochemical analysis of human normal and osteoarthritic knee cartilage from medial and lateral femoral condyles. Apoptosis in these specimens was detected using the TUNEL labeling. Mineralization and matrix vesicles were detected by alizarin red S staining and electron microscopic analysis. RESULTS: Alkaline phosphatase, annexin II, annexin V and type X collagen were expressed by chondrocytes in the upper zone of early stage and late stage human osteoarthritic cartilage. However, these proteins, which are typically expressed in hypertrophic and calcifying growth plate cartilage, were not detectable in the upper, middle and deep zones of healthy human articular cartilage. TUNEL labeling of normal and osteoarthritic human cartilage sections provided evidence that chondrocytes in the upper zone of late stage osteoarthritic cartilage undergo apoptotic changes. In addition, mineral deposits were detected in the upper zone of late stage osteoarthritic cartilage. Needle-like mineral crystals were often associated with matrix vesicles in these areas, as seen in calcifying growth plate cartilage. CONCLUSION: Human osteoarthritic chondrocytes adjacent to the joint space undergo terminal differentiation, release alkaline phosphatase-, annexin II- and annexin V-containing matrix vesicles, which initiate mineral formation, and eventually die by apoptosis. Thus, these cells resume phenotypic changes similar to terminal differentiation of chondrocytes in growth plate cartilage culminating in the destruction of articular cartilage in osteoarthritis.

Adult↗
PubMed2001

Modulation of actinorhodin biosynthesis in Streptomyces lividans by glucose repression of afsR2 gene transcription.

While the biosynthetic gene cluster encoding the pigmented antibiotic actinorhodin (ACT) is present in the two closely related bacterial species, Streptomyces lividans and Streptomyces coelicolor, it normally is expressed only in S. coelicolor-generating the deep-blue colonies responsible for the S. coelicolor name. However, multiple copies of the two regulatory genes, afsR and afsR2, activate ACT production in S. lividans, indicating that this streptomycete encodes a functional ACT biosynthetic pathway. Here we report that the occurrence of ACT biosynthesis in S. lividans is determined conditionally by the carbon source used for culture. We found that the growth of S. lividans on solid media containing glucose prevents ACT production in this species by repressing the synthesis of afsR2 mRNA; a shift to glycerol as the sole carbon source dramatically relieved this repression, leading to extensive ACT synthesis and obliterating this phenotypic distinction between S. lividans and S. coelicolor. Transcription from the afsR2 promoter during growth in glycerol was dependent on afsR gene function and was developmentally regulated, occurring specifically at the time of aerial mycelium formation and coinciding temporally with the onset of ACT production. In liquid media, where morphological differentiation does not occur, ACT production in the absence of glucose increased as S. lividans cells entered stationary phase, but unlike ACT biosynthesis on solid media, occurred by a mechanism that did not require either afsR or afsR2. Our results identify parallel medium-dependent pathways that regulate ACT biosynthesis in S. lividans and further demonstrate that the production of this antibiotic in S. lividans grown on agar can be modulated by carbon source through the regulation of afsR2 mRNA synthesis.

Anthraquinones↗
PubMed2026

Data-driven approaches in green microbiology: strategies for plant growth-promoting bacteria.

Plant growth-promoting bacteria (PGPB) are gaining attention as scalable biological solutions to enhance crop productivity and resilience. However, accurately identifying and characterizing PGPB remains challenging, particularly under variable environmental conditions where microbial functions are context-dependent and shaped by complex plant-microbe interactions. Advances in high-throughput sequencing have shifted the field from culture-dependent approaches to genome-informed strategies, enabling large-scale taxonomic and functional profiling. Although trait-based databases support the prediction of plant-beneficial genes, they capture only a fraction of the underlying biological complexity and often require labor-intensive analyses. Machine learning (ML) and deep learning (DL) have emerged as powerful tools to integrate genomic, physiological, and ecological data, enabling the prioritization of candidate strains with plant growth-promoting potential. To evaluate advances in the field, we conducted a systematic review of studies integrating ML and DL with PGPB characterization, assessing algorithm selection, performance, and target plant systems. Across 248 observations, only 6.0% of studies directly addressed PGPB screening, whereas the majority (77.4%) focused on plant disease detection, revealing a substantial gap in the application of AI to beneficial microorganisms for plant growth. Convolutional neural networks (CNNs) were the most frequently applied algorithms, largely driven by image-based phenotyping tasks. Overall, the field is constrained by limited datasets, high computational demands, and challenges in modeling multispecies and host-associated interactions. We highlight the need for integrative and interpretable ML and DL frameworks that bridge genomic data and functional validation. Such approaches represent a promising path toward scalable, data-driven discovery and deployment of bioinoculants in sustainable agriculture.

Agriculture↗
PubMed1995

Macrophages in the external muscle layers of mammalian intestines.

The literature on macrophages in the muscularis externa of mouse, rat, guinea pig, cat, dog and human gut is reviewed. In smaller mammals macrophages are regularly situated in two locations: in the serosa and at the level of Auerbach's plexus between the longitudinal and circular muscle layers. In addition a few solitary cells are present at the level of the deep muscular plexus. At the level of Auerbach's plexus the macrophages occur as a constant and regularly distributed cell population with intimate associations between macrophages and interstitial cells of Cajal. Morphologically they differ from most resident macrophages in being irregular in shape with 4-6 primary cytoplasmic processes, which branch and give a stellate appearance. They have been demonstrated with endocytotic markers (trypan red, FITC-dextran, cholera toxin), immunocytochemically with macrophage antibodies (F4/80, M1/70) and antibodies against MHC class-II antigen, GABA and cGMP. In muscularis externa of the human gut a regularly distributed cell population of macrophages is not obvious. However, a phenotypically distinct subgroup is identified by light microscopy with the pan macrophage antibodies (EBM11, C3b1 and partly by p150.95), and shows MHC class-II antigen. By electron microscopy muscularis externa macrophages, in all species investigated, appear to be endocytically downregulated, and since they are lysozyme, prostaglandine H synthase (both constitutive and activated) and acid phosphatase negative, they appear to be inactivated cells. Both origin and function of these cells are unknown. They may be immuno-competent, participate in a neuroimmune axis, tissue growth and modulation or other regulations of specific cell functions.

Animals↗
PubMed2001

Developmental dyslexia: an update on genes, brains, and environments.

The science of reading and developmental dyslexia has experienced spectacular advances during the last few years. Five aspects of this research are discussed in the article. (1) The holistic phenomenon of reading is complex. Many lower-level psychological processes (e.g., phonemic awareness, phonological decoding, ability to process stimuli rapidly and automatize this process, memory, ability to recognize words) contribute to a single act of reading. Conceptualizing the complex process of reading through its partly overlapping but partly independent components--which contribute to, but do not fully explain, the holistic process of reading--provides an excellent model for understanding complex hierarchies of higher mental functions. Those who master reading skills successfully and those who have difficulties doing so differ in a wide range of reading-related processes. The central deficit experienced by poor readers appears to be related to phonological processing (a complex hierarchy of functions related to processing phonemes), whereas characteristics of automatization processes seem to moderate the reading outcome for people whose phonological skills are weak. (2) There are new data addressing models of dyslexia in languages other than English. The most fascinating finding is that the model implicating phonological deficit as central to dyslexia, and the lack of ability to automatize as leading to troubled reading, appears to be universal, regardless of the specific language. However, there is an interaction effect between the characteristics of a particular language and the developmental model of dyslexia. In phonologically more difficult languages (e.g., English), the most pronounced weakness appears to occur in phonological processing, whereas in phonologically easier languages (e.g., German), the crucial role in the manifestation of dyslexia is played by the lack of the skills needed to achieve automatization. (3) There is abundant evidence that reading (i.e., any single act of reading as well as reading as a holistic process) is "cooked" by the brain. Although no unified brain map of reading has been developed, some specific areas of the brain have been implicated in different reading-related cognitive processes by different laboratories and on different samples. (4) Indisputable evidence has been accumulated suggesting the involvement of the genome in developmental dyslexia. As of now, specific regions of the genome have been identified as being intimately involved with a number of different reading-related processes. Today the field of developmental dyslexia is the only area of genetic studies of human abilities and disabilities in which linkages to the genome have been robustly replicated in independent laboratories. (5) Finally, evidence suggests that developmental dyslexia might be only one of the manifestations of a deep, underlying, anatomical syndrome. The comorbidity of developmental dyslexia with both internalizing and externalizing behavioral disturbances, as well as with other learning disabilities, underscores the need for wide-ranging cognitive and behavioral approaches in the remediation programs offered to dyslexic children.

Adolescent↗
PubMed1997

Manifestations in institutionalised adults with Angelman syndrome due to deletion.

Undiagnosed institutionalised patients were reviewed in an attempt to identify those with Angelman syndrome (AS). The aim was to test these patients for deletion of chromosome 15(q11-13) and to describe the adult phenotype. The selection criteria included severe intellectual disability, ataxic or hypermotoric limb movements, lack of speech, a "happy" demeanour, epilepsy, and facial appearance consistent with the diagnosis. Patients were examined, medical records perused, and patients' doctors contacted as required. Genetic tests performed included routine cytogenetics, DNA methylation analysis (with probe PW71B), and fluorescence in situ hybridisation (with probes D15S10, GABRbeta3, or SNRPN). A deletion in the AS region was detected in 11 patients (9 males and 2 females) of 22 tested. The mean age at last review (March 1996) was 31.5 years (range 24 to 36 years). Clinical assessment documented findings of large mouth and jaw with deep set eyes, and microcephaly in nine patients (two having a large head size for height). No patient was hypopigmented; 1/11 patients was fair. Outbursts of laughter occurred in all patients but infrequently in 7/11 (64%) and a constant happy demeanour was present in 5/11 (46%). All had epilepsy, with improvement in 5/11 (46%), no change in 4 (36%), and deterioration in 2 (18%). The EEG was abnormal in 10/10 patients. Ocular abnormalities were reported in 3/8 patients (37.5%) and 4/11 (36%) had developed kyphosis. Two had never walked. All nine who walked were ataxic with an awkward, clumsy, heavy, and/or lilting gait. No patient had a single word of speech but one patient could use sign language for two needs (food and drink). Our data support the concept that AS resulting from deletion is a severe neurological syndrome in adulthood. The diagnosis in adults may not be straightforward as some manifestations change with age. Kyphosis and keratoconus are two problems of older patients.

Abnormalities, Multiple↗
PubMed2003

The prognostic impact of cyclin dependent kinase inhibitors p21WAF1, p27Kip1, and p16INK4/MTS1 in adenocarcinomas of the uterine cervix: an immunohistochemical evaluation of expression patterns in population-based material from 142 patients with international federation of gynecology and obstetrics stage I and II adenocarcinoma.

BACKGROUND: The authors assessed the prognostic significance of abnormal cyclin dependent kinase inhibitor (CDKI) expression in adenocarcinomas of the uterine cervix. METHODS: Population-based, archival material from patients with International Federation of Gynecology and Obstetrics (FIGO) Stage I and II cervical adenocarcionmas from 2 5-year periods (1976-1980, n = 82 patients; 1986-1990, n = 142 patients) was examined for expression of p21(WAF1), p27(Kip1), and p16(INK4/MTS1) using immunohistochemical techniques. RESULTS: Rates of tumors with low levels of nuclear expression of p27 and p16 were lower during the period 1976-1980 (P < 0.01), suggesting bias due to unbuffered formalin. Analyses that were restricted to patients from 1986-1990 showed positive associations between all three CDKIs (P < 0.05). Low p16 expression was associated with higher FIGO stage (P = 0.01), age older than 55 years (P = 0.01), and deep invasion (P = 0.003). No significant associations with stage, age, or histopathologic parameters were found for p21 or p27. Significant associations with tumor differentiation were not seen for any CDKI. Kaplan-Meier plots showed diverging survival curves for p21 and p27 expression, but the differences were not significant. In multivariate analysis, low p27 expression and high p16 expression were strong predictors of a poor prognosis (p27: < 40% nuclear staining; P = 0.001; hazard ratio, 3.18; p16: < 40% nuclear staining; P < 0.001; hazard ratio, 0.16). Low p27 expression was of prognostic significance only if it was analyzed together with p16 expression. Further evaluation indicated that patients with different phenotypic p27/p16 combinations may have different outcomes. CONCLUSIONS: Aberrant expression patterns of CDKIs were predictors of prognosis for patients with FIGO Stage I or II cervical adenocarcinoma. Analysis of CDKI expression in this patient group may prove clinically useful.

Adenocarcinoma↗
PubMed2025

Quantitative Profiling of Histone Variants and Posttranslational Modifications by Tandem Mass Spectrometry in Arabidopsis.

Histone dynamics constitute an important layer of gene regulations associated with development and growth in multicellular eukaryotes. They also stand as key determinants of plant responses to environmental changes. Histone dynamics include the exchange of histone variants as well as post-translational modifications of their amino acid residues (such as acetylation and mono/di/trimethylation), commonly referred to as histone marks. Investigating histone dynamics with a focus on combinatorial changes occurring at their residues will greatly help unravel how plants achieve phenotypic plasticity.Mass spectrometry (MS) analysis offers unequaled resolution of the abundance of histone variants and of their marks. Indeed, relative to other techniques such as western blot or genome-wide profiling, this powerful technique allows quantifying the relative abundances of histone forms, as well as revealing coexisting marks on the same histone molecule. Yet, while MS-based histone analysis has proven efficient in several animals and other model organisms, this method stands out as more challenging in plants. One major challenge is the isolation of sufficient amounts of pure, high-quality histones, likely rendered difficult by the presence of the cell wall, for sufficiently deep and resolutive identification of histone species.In this chapter, we describe a straightforward MS-based proteomic method, implemented to characterize histone marks from Arabidopsis thaliana seedling tissues and cell culture suspensions. After acid extraction of histones, in vitro propionylation of free lysine residues, and digestion with trypsin, a treatment at highly basic pH allows obtaining sharp spectral signals of biologically relevant histone peptide forms.The method workflow described here shall be used to measure changes in histone marks between Arabidopsis thaliana genotypes, along developmental time-courses, or upon various stresses and treatments.

Histones↗