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PubMed1990

The effect of reinnervation on the distribution of muscle fibre types in the tibialis anterior muscle of the mouse.

The distribution of fibre types in the tibialis anterior (TA) muscle of adult mice was examined by means of an immunohistochemical approach, using monoclonal antibodies that recognize different myosin heavy chain isoforms. As has been reported previously, the superficial portion of TA contains almost exclusively type IIB fibres and is almost entirely glycolytic in nature. Following section of the lateral popliteal nerve and rotation of the proximal stump to prevent rematching, it was found that the original pattern was virtually restored within 2 months. One possible explanation for this observation is that the activity pattern of peripheral and deep muscle fibres differs and that this aids in specification of muscle fibre type. Alternatively, the muscle fibres of the superficial portion of TA may be inherently resistant to an alteration of their phenotype with regard to expression of myosin heavy chain.

Adenosine Triphosphatases↗
PubMed1997

Differential spatial patterns of Fos induction following generalized clonic and generalized tonic seizures.

The expression of generalized clonic and generalized tonic seizures has been suggested to result from the activation of different and independent neuronal circuits. Using the induction of the c-fos protein (Fos) as a marker of neuronal activity, we identified brain structures that are differentially associated with the expression of electroconvulsive shock-induced generalized clonic and generalized tonic seizures. Expression of either seizure phenotype resulted in a similar bilaterally symmetrical increase in Fos immunoreactivity in many forebrain structures, including the bed nucleus of the stria terminalis, hippocampal dentate gyrus, amygdala, and piriform cortex, compared to controls. However, following tonic hindlimb extension (THE), the degree of labeling in specific thalamic, hypothalamic, and brain stem areas was significantly greater than that of either controls or animals exhibiting clonic seizures. While a greater number of neurons in the hypothalamus (e.g., ventromedial nucleus), subparafascicular thalamic nucleus, peripeduncular area, deep medial superior colliculus, dorsal and lateral central gray, and paralemniscal nuclei were robustly labeled following THE, noticeably fewer cells were immunoreactive following face and forelimb clonic seizure behaviors. These differences were also found to be independent of the stimulus magnitude. In animals stimulated with the same current intensity but expressing either of the two seizure phenotypes, the pattern of Fos induction was consistent with the seizure phenotype expressed. These results demonstrate that specific subsets of neurons are differentially activated following the expression of different generalized seizure behaviors and that activity in discrete mesencephalic and diencephalic structures is more frequently associated with the expression of generalized tonic seizures than with the expression of generalized clonic seizures.

Animals↗
PubMed2003

Natural selection for polymorphism in the disease resistance gene Rps2 of Arabidopsis thaliana.

Pathogen resistance is an ecologically important phenotype increasingly well understood at the molecular genetic level. In this article, we examine levels of avrRpt2-dependent resistance and Rps2 locus DNA sequence variability in a worldwide sample of 27 accessions of Arabidopsis thaliana. The rooted parsimony tree of Rps2 sequences drawn from a diverse set of ecotypes includes a deep bifurcation separating major resistance and susceptibility clades of alleles. We find evidence for selection maintaining these alleles and identify the N-terminal part of the leucine-rich repeat region as a probable target of selection. Additional protein variants are found within the two major clades and correlate well with measurable differences among ecotypes in resistance to the avirulence gene avrRpt2 of the pathogen Pseudomonas syringae. Long-lived polymorphisms have been observed for other resistance genes of A. thaliana; the Rps2 data suggest that the long-term maintenance of phenotypic variation in resistance genes may be a general phenomenon and are consistent with diversifying selection acting in concert with selection to maintain variation.

Arabidopsis↗
PubMed2005

Immunohistochemical study on distribution of mast cell phenotypes in human laryngeal mucosa: evidence for laryngeal type I allergy.

It is controversial whether or not type I allergic reactions can occur in the human laryngeal mucosa. To clarify this issue, we studied the distribution of mast cell phenotypes in the human laryngeal mucosa using the immunohistochemical staining method with antihuman tryptase and chymase antibodies. A large number of mast cells are present in the superficial layer of subepithelial connective tissue (SECT) of the epiglottis, arytenoid, and subglottis. Although mast cells containing both tryptase and chymase are predominant in the deep layer of the SECT, the majority of mast cells containing tryptase alone are located in both the epithelial layer and the superficial layer of the SECT. We conclude that the human laryngeal mucosa has the potential to induce type I allergic reaction.

Arytenoid Cartilage↗
PubMed2026

Beyond in silico prediction: multi-omics to identify a pathogenic deep intronic HNRNPK variant in Au-Kline syndrome.

Pathogenic variants in HNRNPK are associated with autosomal dominant Au-Kline syndrome (AKS, Au-Kline-Okamoto syndrome, OMIM #616580). This syndrome is characterized by developmental delay and intellectual disability, hypotonia, and distinctive facial features. Despite the use of whole-genome sequencing (WGS) as a powerful diagnostic tool, we nearly dismissed a novel intronic variant (NM_031263.4(HNRNPK):c.214-55 T > A) affecting HNRNPK splicing and function. Although commonly used bioinformatic splice prediction tools, including SpliceAI and PDIVAS, yielded inconclusive results, Face2Gene analysis indicated a high phenotypic similarity to AKS. Characteristic facial features described by Choufani et al. [1] supported the clinical diagnosis of AKS. Subsequent functional studies demonstrated aberrant splicing with intron retention, and DNA methylation profiling revealed a positive HNRNPK-specific episignature. These insights and the de novo status support an evaluation as likely pathogenic. This case report supports the relevance of facial analysis and comprehensive variant validation strategies, particularly for deep intronic variants with ambiguous in silico splicing predictions.

Journal Article↗
PubMed2003

Fulvimarina pelagi gen. nov., sp. nov., a marine bacterium that forms a deep evolutionary lineage of descent in the order "Rhizobiales".

Three brownish-yellow bacterial strains were isolated from the western Sargasso Sea by high-throughput culturing methods and characterized by polyphasic approaches. All isolates were Gram-negative, strictly aerobic, chemoheterotrophic, non-motile short rods that contained carotenoid pigments. Phylogenetic analyses based on 16S rRNA gene sequences, DNA-DNA hybridization and DNA G+C content, along with phenotypic characteristics, revealed that they belonged to the same species. The strains utilized a wide range of substrates, including pentoses, hexoses, oligosaccharides, sugar alcohols, organic acids and amino acids, as sole carbon sources. The DNA G+C content of the isolates ranged from 57.6 to 59.9 mol%. The predominant cellular fatty acid constituent was C(18 : 1)omega7c, whilst C(16 : 0), C(18 : 0) and C(19 : 0)omega8c cyclo were also abundant. The organism related most closely to these strains, as determined by 16S rDNA sequence comparison, was the recently described species Aurantimonas coralicida (93.3-93.8 % similarity). Phylogenetic analyses indicated that the strains formed a distinct and deep evolutionary lineage of descent, together with A. coralicida, within the order "Rhizobiales" of the alpha-Proteobacteria. This lineage could not be associated with any of the ten known families in the order "Rhizobiales". From polyphasic evidence, it is proposed that the strains be placed into a novel genus and species, Fulvimarina pelagi gen. nov., sp. nov. (type strain, HTCC2506(T)=ATCC BAA-666(T)=KCTC 12091(T)=DSM 15513(T)).

Microbial Sensitivity Tests↗
PubMed1985

Heterogeneity of cutaneous T-cell lymphoma. Phenotypic and ultrastructural characterization of four unusual cases.

This study characterized, by means of immunocytochemistry and electron microscopy, four cases of "unusual" cutaneous T-cell lymphoma (CTCL) other than classical mycosis fungoids and Sézary syndrome. Cases 1, 2, and 4 were diffuse lymphoma of a pleomorphic type, and Case 3 was of a mixed type. Case 4 shared a feature common to pagetoid reticulosis. A fairly large number of inflammatory cells were seen in Cases 1, 3, and 4. Functionally, the neoplastic cells of Cases 1, 3, and 4 were of a helper/inducer T-cell subset, whereas those of Case 2 were of a suppressor/cytotoxic T-cell type. Epidermotropic cells with pagetoid growth in Case 4 failed to show these specific surface phenotypes, although they still retained pan T-cell markers. Neoplastic large or intermediate-sized cells revealed a marked difference in the development of cytoplasmic organelles and their nuclear profiles, ranging from a few simple indentations (Cases 2 and 3) to forms with many deep indentations (Case 1) and highly cleaved shapes (Case 4). All of these cells, however, possessed dense-cored granules located in a portion of the cytoplasm. This study indicated the clinicopathologic and immunologic heterogeneity of CTCL, which may be classified, according to the reactivity with monoclonal antibodies and the fine structural features, into subtypes that correspond to functionally distinct subsets of T-cells and their stages or types of differentiation.

Adult↗
PubMed2003

A novel, highly viscous polysaccharide excreted by an alteromonas isolated from a deep-sea hydrothermal vent shrimp.

A deep-sea, mesophilic, aerobic, and heterotrophic microorganism, able to produce an extracellular polysaccharide, was isolated from a shrimp collected near an active hydrothermal vent of the Mid-Atlantic Ridge. On the basis of phenotypic and phylogenetic analyses and DNA/DNA relatedness, this strain could be assigned to the species Alteromonas macleodii as a variant of the fijiensis subspecies. It was selected for its ability to exhibit a swarming mucoid phenotype on specific media. The bacterium secreted, under laboratory conditions, an extremely viscous exopolysaccharide consisting of glucose, galactose as neutral sugars, and glucuronic, galacturonic acids as uronic acids, along with pyruvate and acetate as main substituents.

Alteromonas↗
PubMed2000

Neurodevelopmental profile of a new dysmorphic syndrome associated with submicroscopic partial deletion of 1p36.3.

We describe four children with dysmorphic syndrome with severe learning disability (SLD). Their chromosomes had been normal on conventional cytogenetic examination. However, screening using a multiprobe fluorescence in situ hybridisation (FISH) technique for subtelomeric abnormalities revealed a deletion of the p arm of chromosome 1. The physical features include body asymmetry, microcephaly, distinctive facies with deep-set eyes, sharply defined eye sockets, and mid-face hypoplasia; the neurodevelopmental profile was characterised by SLD, motor delay with hypotonia, markedly delayed visual maturation, and postural asymmetry together with epilepsy. This phenotype is consistent with that described for partial monosomy for 1p36.3.

Abnormalities, Multiple↗
PubMed2000

Hla-DR2-restricted responses to proteolipid protein 95-116 peptide cause autoimmune encephalitis in transgenic mice.

In multiple sclerosis (MS) patients who carry the Class II major histocompatibility (MHC) type HLA-DR2, T cells specific for amino acids 95-116 in the proteolipid protein (PLP) are activated and clonally expanded. However, it remains unclear whether these autoreactive T cells play a pathogenic role or, rather, protect against the central nervous system (CNS) damage. We have addressed this issue, using mice transgenic for the human MHC class II region carrying the HLA-DR2 (DRB1* 1502) haplotype. After stimulating cultured lymph node cells repeatedly with PLP95-116, we generated 2 HLA-DR2-restricted, PLP95-116-specific T-cell lines (TCLs) from the transgenic mice immunized with this portion of PLP. The TCLs were CD4+ and produced T-helper 1 (Th1) cytokines in response to the peptide. These TCLs were adoptively transferred into RAG-2/2 mice expressing HLA-DR2 (DRG1* 1502) molecules. Mice receiving 1 of the TCLs developed a neurological disorder manifested ataxic movement without apparent paresis on day 3, 4, or 5 after cell transfer. Histological examination revealed inflammatory foci primarily restricted to the cerebrum and cerebellum, in association with scattered demyelinating lesions in the deep cerebral cortex. These results support a pathogenic role for PLP95-116-specific T cells in HLA-DR2+ MS patients, and shed light on the possible correlation between autoimmune target epitope and disease phenotype in human CNS autoimmune diseases.

Amino Acid Sequence↗
PubMed1988

Generation of a monoclonal antibody specific for Hb G-Philadelphia [alpha 2(68)(E17)Asn----Lys beta 2] and development of an immunoassay.

A murine hybridoma was generated which secreted a monoclonal antibody (Mab) that specifically recognized the alpha 2(68)(E17)Asn----Lys beta 2 substitution of Hb G-Philadelphia. Hybridomas were produced by fusion of RBF/DnJ immune splenic lymphocytes with FOX-NY murine myeloma cells and selected in adenine-aminopterin-thymidine (AAT) medium. Culture fluids were screened by ELISA for antibody reacting with Hb G-Philadelphia but not Hb A. One such culture was cloned by limiting dilution, expanded and injected into pristane-primed, cyclophosphamide-suppressed BALB/c mice for ascites production. An enzyme-linked immunoassay was developed by conjugating hemoglobin in hemolysates or purified hemoglobins to the plastic surface of wells of a microtiter plate. The ascites fluid containing the Hb G-Philadelphia Mab was added to the wells followed by goat anti-mouse IgG conjugated with horseradish peroxidase. After the addition of substrate (tetramethylbenzidine), a deep blue color developed, signifying a positive reaction. We analyzed 58 hemolysates (17 adult, 41 cord) containing a G-variant along with 28 control hemolysates (12 cords comprising FA, FAC, FAS, FSS, FCC phenotypes; 16 adults consisting of AA, AS, SS, SC, S-beta thal, AD-Los Angeles phenotypes). Of the 58 hemolysates containing a G-variant, 53 were positive by ELISA and confirmed by radioimmunoassay (RIA). Four of the five hemolysates negative for Hb G-Philadelphia were shown to be Hb G-Montgomery by RIA. None of the control hemolysates were positive. The assay could be completed in 1 hr and represents a technological advance in hemoglobin identification.

Animals↗
PubMed2005

[Identification of a new genetic entity in the form of an autosomal dominant axonal Charcot-Marie-Tooth disease associated with periodic paralyses and pyramidal syndrome].

We report the clinical and genetic linkage analysis of eight affected patients suffering from axonal form of Charcot-Marie-Tooth disease (CMT2) with periodic paralyses and pyramidal feature. The inheritance is autosomal dominant. It was characterized by onset between the first and the second decade, distal weakness and atrophy of lower limbs. Four patients showed deep sensory loss; a periodic paralyses were also present in four patients. Genetic linkage excluded all known loci of CMT2 and other loci of clinical distinctive feature. Exclusion of these loci demonstred the distinctive phenotype of this family and assess the identification of a new genetic form.

Adolescent↗
PubMed1992

Risk for cardiovascular autonomic neuropathy is associated with the HLA-DR3/4 phenotype in type I diabetes mellitus.

OBJECTIVE: To identify risk factors for the development of cardiovascular autonomic neuropathy in patients with juvenile-onset type I diabetes mellitus. DESIGN: Cross-sectional examination of an inception cohort 15 to 21 years after the onset of diabetes. SETTING: Outpatient diabetes clinic. PATIENTS: Seventy-nine patients with type I diabetes who experienced onset of disease before 21 years of age and who were followed for 15 to 21 years. MEASUREMENTS: Autonomic nerve function was evaluated in all patients using deep breathing and tilt tests. On the basis of these tests, an index of cardiovascular autonomic neuropathy was derived and patients were classified as having intact, mildly impaired, or significantly impaired autonomic function. RESULTS: The group with significantly impaired function had a higher mean hemoglobin A1 at the time of examination than the group without impairment, yet the groups did not differ regarding glycemic control during the first decade of diabetes. The HLA-DR3/4 phenotype was present in more than 50% of the patients with significant autonomic dysfunction and conferred relative odds of 6.2 (95% CI, 1.7 to 23.3) for the development of autonomic neuropathy when compared with other HLA-DR phenotypes. Sex, percent ideal body weight, and smoking did not have a statistically significant effect on the development of autonomic neuropathy. CONCLUSIONS: The development of cardiovascular autonomic neuropathy in type I diabetes mellitus is strongly associated with the HLA-DR3/4 phenotype. Thus, genetic predisposition may play an important role in the development of this complication.

Adult↗
PubMed2016

Deletion of Indian hedgehog gene causes dominant semi-lethal Creeper trait in chicken.

The Creeper trait, a classical monogenic phenotype of chicken, is controlled by a dominant semi-lethal gene. This trait has been widely cited in the genetics and molecular biology textbooks for illustrating autosomal dominant semi-lethal inheritance over decades. However, the genetic basis of the Creeper trait remains unknown. Here we have utilized ultra-deep sequencing and extensive analysis for targeting causative mutation controlling the Creeper trait. Our results indicated that the deletion of Indian hedgehog (IHH) gene was only found in the whole-genome sequencing data of lethal embryos and Creeper chickens. Large scale segregation analysis demonstrated that the deletion of IHH was fully linked with early embryonic death and the Creeper trait. Expression analysis showed a much lower expression of IHH in Creeper than wild-type chickens. We therefore suggest the deletion of IHH to be the causative mutation for the Creeper trait in chicken. Our findings unravel the genetic basis of the longstanding Creeper phenotype mystery in chicken as the same gene also underlies bone dysplasia in human and mouse, and thus highlight the significance of IHH in animal development and human haploinsufficiency disorders.

Animals↗
PubMed1972

Repair of the lethal developmental defect in deep orange embryos of Drosophila by injection of normal egg cytoplasm.

The eggs produced by deep orange females (dor/dor) of Drosophila melanogaster have a defect that causes early death of the deep orange embryos derived from these eggs. Ovaries transplanted from deep orange females to normal female hosts continue to produce defective eggs, showing that the dor mutation directly affects an ovarian function. In heterozygous embryos (dor(+)/dor) derived from eggs of deep orange females, the presence of a paternal dor(+) gene enables normal development to occur in about half of the embryos. Thus, the egg defect caused by the dor mutation is repairable after fertilization by the action of a dor(+) gene. The deep orange egg defect has also been repaired by injection of cytoplasm from unfertilized normal eggs into deep orange embryos at the syncitial preblastoderm stage of development. About one-third of the injected deep orange embryos were able to continue their development to an advanced stage of embryogenesis. This developmental response can serve as a bioassay for the identification of the defective component in eggs of deep orange females.

Animals↗
PubMed1997

Phenotypic and phylogenetic description of an Italian isolate of "Microthrix parvicella".

"Microthrix parvicella" strain RN1 was isolated from an activated sludge treatment plant in Italy using micromanipulation techniques. The strain grows as thin unbranchedfilaments which are Gram-positive with Neisser-positive granules. The isolate was characterized by analysis of the 16S rDNA which was amplified directly from cell biomass by the polymerase chain reaction and sequenced. "Microthrix parvicella" strain RN1 presents a very high similarity (100%) with another "M. parvicella" strain recently isolated in Australia, suggesting that this micro-organism, a novel, deep branching member of the actinomycetes subphylum, is the same causing the common events of bulking and foaming phenomena in activated sludge treatment plants throughout the world.

DNA, Bacterial↗
PubMed2026

Deep visual multi-omics profiling links morphology and molecular programs in clear cell renal cell carcinoma.

Clear cell renal cell carcinoma exhibits striking intra-tumoral heterogeneity at morphological and genetic levels, complicating treatment and contributing to disease progression. CcRCCs with rhabdoid differentiation are highly aggressive tumors characterized by distinct histopathologies. However, the relationship between morphology, underlying molecular alterations, and tumor behavior remains largely unclear. Here, we present Deep Visual Multi-Omics, an approach integrating digital pathology, morphology-guided single-cell isolation, and ultra-sensitive multi-omics profiling to link cell morphologies to their molecular underpinnings. Across five tumors, we profiled ~40,000 AI-classified and expert-curated cells. We identified progressive molecular dysregulation across cells with increasing histopathological grade coexisting within heterogeneous tumors as well as distinct molecular alterations associated with aggressive rhabdoid ccRCC cells, including signatures consistent with enhanced FOXM1-driven proliferation, altered cell-matrix interactions, and a putative immunomodulatory phenotype. Notably, rhabdoid cells exhibited elevated expression of IFN-beta, PD-L1, CD38, ITGB2, and integrin signaling, suggesting that they themselves may act as a source of signals influencing the local immune microenvironment. Besides providing new insights into the biology of ccRCC and highlighting avenues for future translational studies, this illustrates the potential of Deep Visual Multi-omics to dissect cancer heterogeneity and characterize high-risk cell populations.

Humans↗
PubMed2002

Angiogenic co-operation of VEGF and stromal cell TP in endometrial carcinomas.

Vascular endothelial growth factor (VEGF) and thymidine phosphorylase (TP) are important angiogenic enzymes, inducing new blood vessel formation in many human malignancies. In this study, the immunohistochemical expression of the two molecules was analysed in a series of 121 endometrial carcinomas. VEGF was expressed exclusively in cancer cells, while TP expression was shown in cancer cells (TPcc) and in stromal cells (TPsc) of both fibroblastic and myometrial origin. In all cases, enzymatic detection was particularly evident at the invading tumour front. At this site, TPsc, but not VEGF, expression was associated with non-endometrioid-type carcinomas, high tumour grade, deep myometrial invasion, and advanced stage. VEGF, but not TP, expression was related to increased angiogenesis (p=0.01). Double stratification of the two factors, however, marked VEGF/TPsc co-expression as the most potent angiogenic phenotype (p=0.008), suggesting a synergistic function. Survival analysis revealed that VEGF and TPsc, whether expressed alone or in combination, define poor prognosis. In multivariate analysis, however, stage of disease (p<0.0001, t-ratio 4.4) and VEGF expression (p=0.01, t-ratio 2.4) were the most important prognostic variables. Furthermore, VEGF expression emerged as the only independent prognostic variable in stage I endometrial carcinomas (p=0.04, t-ratio 1.9). This was not shown for TP, probably because of its close association with histopathological parameters. In conclusion, VEGF is a major angiogenic factor in endometrial carcinomas and an independent prognostic factor in stage I endometrial disease. TP is not an effective contributor to the angiogenic process, but is associated with aggressive histological features. The two factors, when co-expressed, play a co-operative role in the induction of angiogenesis.

Biomarkers, Tumor↗