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At least 1,711 records · Page 95Linked to original sources
PubMed2025

Multi-omics analysis reveals distinct spatial compartmentalization of lung repair niches in pediatric ARDS.

BACKGROUND: Pediatric acute respiratory distress syndrome (PARDS), often triggered by viral infections, is a life-threatening condition. Despite its severity, children demonstrate significantly better survival rates and superior lung repair compared to adults. However, the mechanisms underlying this age-specific advantage remain incompletely understood. PATIENTS AND METHODS: We conducted a pilot multi-omics study of influenza-associated PARDS integrating single-cell RNA sequencing (scRNA-seq) of pediatric lung tissue and bronchoalveolar lavage fluid (BALF), spatial transcriptomics, and plasma proteomics. Analyses were harmonized with the Human Lung Cell Atlas (HLCA) reference, reanalysis of public pediatric PARDS airway scRNA-seq, and contextual comparisons to adult lethal COVID-19 lung. RESULTS: Tissue scRNA-seq and spatial data indicated outcome-linked divergence in PARDS. Survivor showed spatially restricted repair with preserved alveolar type II (AT2) cells, AT2-to-alveolar type I (AT1) differentiation signatures, and higher KRT17, whereas fatal case and adults exhibited diffuse immune activation with pro-fibrotic and pro-apoptotic signaling. In BALF, KRT17-positive airway stress–repair epithelial cells (hillock-like) increased from the acute to recovery phase, and plasma proteomics showed higher circulating KRT17 in survivors. HLCA-based label transfer strengthened cell-type definitions and enabled pediatric–adult comparisons suggesting biological and developmental differences; the adult lethal COVID-19 atlas provided a benchmark with attenuated epithelial repair and prominent collagen CTHRC1-pathologic fibroblasts. Fibroblast programs were regionally compartmentalized, with injury-enriched CTHRC1+ states versus alveolar fibroblasts in preserved areas, and showed stronger injury–homeostasis anti-correlation in fatalities. Myeloid remodeling included BALF transitions from FCN1-high inflammatory states toward FABP4-positive resident-like states, consistent with public pediatric datasets showing reduced inflammatory and interferon-stimulated gene (ISG) modules and severity-linked increases in aged neutrophils. CONCLUSIONS: This pilot multi-omics case series outlines putative pediatric lung repair niches in influenza-associated PARDS. KRT17-positive transitional epithelium, preserved AT2 differentiation, and restoration of resident-like macrophages may align with recovery, whereas diffuse immune activation and CTHRC1-enriched fibroblast programs may accompany worse outcomes. HLCA-guided annotations and adult benchmarks indicate possible age-related differences, warranting validation in larger multi-center cohorts.

Humans↗
PubMed2005

High EphA3 expressing ophthalmic trigeminal sensory axons are sensitive to ephrin-A5-Fc: implications for lobe specific axon guidance.

The ophthalmic, maxillary and mandibular axon branches of the trigeminal ganglion provide cutaneous sensory innervation to the vertebrate face. In the chick embryo, the trigeminal ganglion is bilobed, with ophthalmic axons projecting from the ophthalmic lobe, while maxillary and mandibular projections emerge from the maxillomandibular lobe. To date, target tissue specific guidance cues that discriminately guide the axon projections from the two trigeminal ganglion lobes are unknown. EphA receptor tyrosine kinases and ephrin-A ligands are excellent candidates for this process as they are known to mediate axon guidance in the developing nervous system. Accordingly, the expression of EphAs and ephrin-As was investigated at stages 13, 15, 20 of chick embryogenesis when peripheral axons from the trigeminal ganglion are pathfinding. EphA3 is expressed highly in the ophthalmic trigeminal ganglion lobe neurons in comparison to maxillomandibular trigeminal ganglion lobe neurons. Furthermore, from stages 13-20 ephrin-A2 and ephrin-A5 ligands are only localized to the mesenchyme of the first branchial arch (maxillary and mandibular processes), the target fields for maxillomandibular trigeminal ganglion axons. We found that ophthalmic and not maxillomandibular lobe axons were responsive to ephrin-A5-Fc utilizing a substratum choice assay. The implication of these results is that EphA3 forward signaling in ophthalmic sensory axons may be an important mechanism in vivo for lobe specific guidance of trigeminal ganglion ophthalmic projections.

Animals↗
PubMed1998

Key aspects of the primary sex determination mechanism are conserved across the genus Drosophila.

In D. melanogaster, a set of 'X:A numerator genes', which includes sisterlessA (sisA), determines sex by controlling the transcription of Sex-lethal (Sxl). We characterized sisA from D. pseudoobscura and D. virilis and studied the timing of sisA and Sxl expression with single cell-cycle resolution in D. virilis, both to guide structure-function studies of sisA and to help understand sex determination evolution. We found that D. virilis sisA shares 58% amino acid identity with its melanogaster ortholog. The identities confirm sisA as an atypical bZIP transcription factor. Although virilis sisA can substitute for melanogaster sisA, the protein is not fully functional in a heterologous context. The putative sisA regulatory sequence CAGGTAG is a potential 'numerator box,' since it is shared with the other strong X:A numerator gene, sisB, and its target, SxlPe. Temporal and spatial features of sisA and SxlPe expression are strikingly conserved, including rapid onset and cessation of transcription in somatic nuclei, early cessation of sisA transcription in budding pole cells and persistent high-level sisA expression in yolk nuclei. Expression of sisA and Sxl is as tightly coupled in virilis as it is in melanogaster. Taken together, these data indicate that the same primary sex determination mechanism exists throughout the genus Drosophila.

Amino Acid Sequence↗
PubMed2001

Antisense oligodeoxynucleotide-induced suppression of basal forebrain NMDA-NR1 subunits selectively impairs visual attentional performance in rats.

UNLABELLED: It is generally agreed that basal forebrain neuronal circuits contribute to the mediation of the ability to detect, select and discriminate signals, to suppress the processing of irrelevant information, and to allocate processing resources to competing tasks. Rats were trained in a task designed to assess sustained attention, or in a cued discrimination task that did not tax attentional processes. Animals were equipped with guide cannula to infuse bilaterally antisense oligodeoxynucleotides (ODNs) against the N-methyl-D-aspartate (NMDA) NR1 subunits, or missense ODNs, into the substantia innominata of the basal forebrain. Infusions of antisense or missense ODNs did not affect cued visual discrimination performance. Infusions of antisense ODNs dose-dependently impaired sustained attention performance by selectively decreasing the animals' ability to detect signals while their ability to reject nonsignal trials remained unchanged. The detrimental attentional effects of antisense infusions were maximal 24 h after the third and final infusion, and performance returned to baseline 24 h later. Missense infusions did not affect attentional performance. Separate experiments demonstrated extensive suppression of NR1 subunit immunoreactivity in the substantia innominata. Furthermore, infusions of antisense did not produce neurotoxic effects in that region as demonstrated by the Fluoro-Jade METHOD: The present data support the hypothesis that NMDA receptor (NMDAR) stimulation in the basal forebrain, largely via glutamatergic inputs originating in the prefrontal cortex, represents a necessary mechanism to activate the basal forebrain corticopetal system for mediation of attentional performance.

Animals↗
PubMed2004

Sidekick-1 is upregulated in glomeruli in HIV-associated nephropathy.

Infection of podocytes by HIV-1 induces unique changes in phenotype, which contribute to the pathogenesis of glomerular disease in HIV-associated nephropathy (HIVAN). The host genetic pathways altered by HIV-1 infection that are responsible for these phenotypic changes are largely unknown. For identifying such pathways, representational difference analysis was performed comparing cDNA from HIV-1 transgenic podocytes with nontransgenic controls. In this way, a gene named sidekick-1 (sdk-1) was cloned, a transmembrane protein of the Ig superfamily that is highly upregulated in HIV-1 transgenic podocytes. Sdk-1 and its ortholog, sidekick-2 (sdk-2), were recently shown to guide axonal terminals to specific synapses in developing neurons. Their presence and role in other organs, including the kidney, has not been described. The current study demonstrates developmental expression of both sdk-1 and sdk-2 and a tight spatial and temporal regulation of these genes in kidney. During nephrogenesis, sidekick expression was observed first in ureteric bud and ureteric bud-derived tissues in a pattern similar to other genes known to play important roles in branching morphogenesis. In adult murine renal tissue, sidekick proteins were seen in glomeruli at low levels, and expression of sdk-1 was greatly upregulated in diseased HIV-1 transgenic mouse kidneys. In a human HIVAN kidney biopsy, sidekick expression was increased in glomeruli in a pattern consistent with the mouse model. It is proposed that the dysregulation of sdk-1 protein may play an important role in HIVAN pathogenesis.

AIDS-Associated Nephropathy↗
PubMed2004

New mutation points in 23S rRNA gene associated with Helicobacter pylori resistance to clarithromycin in northeast China.

AIM: To investigate the resistance rate of Helicobacter pylori (H pylori ) to clarithromycin, metronidazole, amoxicillin and tetracycline to guide clinical practice, and to study the mechanism of H pylori resistant to clarithromycin. METHODS: Thirty H pylori strains were isolated from the mucosa of peptic ulcer, gastric tumor and chronic gastritis patients, then the minimal inhibitory concentration (MIC) to clarithromycin, metronidazole, amoxicillin and tetracycline was evaluated by E-test method. The sequence analysis of PCR fragments was conducted in 23S rRNA gene of H pylori resistant to clarithromycin to get the resistance mechanism of the bacteria. RESULTS: Among 30 H pylori strains, 7 cases were resistant to clarithromycin, 12 to metronidazole, 2 to tetracycline and no strain was found to be resistant to amoxicillin. The resistance rates were 23.3%, 40%, 6.7% and 0%, respectively. Three new mutation points were found to be related to the clarithromycin resistance in H pylori isolates, which were G2224A, C2245T and T2289C. CONCLUSION: In northeast China, H pylori shows high resistance to metronidazole, while sensitive to amoxicillin. The mechanism of resistance to clarithromycin may be related to the mutation of G2224A, C2245T and T2289C in the 23S rRNA gene.

Anti-Bacterial Agents↗
PubMed1998

Assessment of c-erbB2 and vascular endothelial growth factor mRNA expression in fine-needle aspirates from early breast carcinomas: pre-operative determination of malignant potential.

AIMS: Although axillary lymph nodes status, tumour size, hormonal-receptor status and histological grade at diagnosis are frequently used to orient the treatment of breast cancer patients, some tumours recur in patients with early stage disease. Pre-operative assessment of individual tumour characteristics, based on oncogenes and growth factors related to tumour growth, invasion or metastasis, may guide the treatment for patients with breast carcinomas. METHODS: We examine here the prognostic significance of cyclin D1, urokinase type plasminogen activator, vascular endothelial growth factor (VEGF), platelet-derived growth factor, and c-erbB2 expression in pre-operatively obtained fine-needle aspirates from breast carcinomas less than or equal to 3 cm in size. Correlation between mRNA expression of these factors and clinicopathological characteristics was analysed. RESULTS: The level of c-erbB2 mRNA expression was significantly higher in tumours with lymph node metastases than in those without lymph node metastases. VEGF mRNA expression positively correlated with the degree of angiogenesis as quantitated by immunohistological staining with a CD31 monoclonal antibody. CONCLUSIONS: Analysis of c-erbB2 and VEGF mRNA expression in fine-needle aspirates may be useful in assessing the malignant potential of individual breast carcinomas, leading to a pre-operative discrimination of a high-risk group.

Actins↗
PubMed2000

p62, a novel Xenopus laevis component of box C/D snoRNPs.

U16 belongs to the family of box C/D small nucleolar RNAs (snoRNAs) whose members participate in ribosome biogenesis, mainly acting as guides for site-specific methylation of the pre-rRNA. Like all the other members of the family, U16 is associated with a set of protein factors forming a ribonucleoprotein particle, localized in the nucleolus. So far, only a few box C/D-specific proteins are known: in Xenopus laevis, fibrillarin and p68 have been identified by UV crosslinking and shown to require the conserved boxes C and D for snoRNA interaction. In this study, we have identified an additional protein factor (p62), common to box C/D snoRNPs, that crosslinks to the internal stem region, distinct from the conserved box C/D "core motif," of U16 snoRNA. We show here that, although the absence of the core motif and, as a consequence, of fibrillarin and p68 binding prevents processing and accumulation of the snoRNA, the lack of the internal stem does not interfere with the efficient release of U16 from its host intron and only slightly affects snoRNA stability. Because this region is likely to be the binding site for p62, we propose that this protein plays an accessory role in the formation of a mature and stable U16 snoRNP particle.

Animals↗
PubMed2000

Expression of the netrin receptor UNC-5 in lamprey brain: modulation by spinal cord transection.

The sea lamprey recovers from spinal cord transection by a process that involves directionally specific regeneration of axons. The mechanisms underlying this specificity are not known, but they may involve molecular cues similar to those that guide the growth of spinal cord axons during development, such as netrins and semaphorins. To test the role of guidance cues in regeneration, we cloned netrin and its receptor UNC-5 from lamprey central nervous system (CNS) and studied their expression after spinal cord transection. In situ hybridization showed that (1) mRNA for netrin is expressed in the spinal cord, primarily in neurons of the lateral gray matter and in dorsal cells; (2) mRNA for UNC-5 is expressed in lamprey reticulospinal neurons; (3) following spinal cord transection, UNC-5 message was dramatically downregulated at two weeks, during the period of axon dieback; (4) UNC-5 message was upregulated at three weeks, when many axons are beginning to regenerate; and (5) axotomy-induced expression of UNC-5 occurred primarily in neurons whose axons regenerate poorly. Because the UNC-5 receptor is thought to mediate the chemorepellent effects of netrins, netrin signaling may play a role in limiting or channeling the regeneration of certain neurons. These data strengthen the rationale for studying the role of developmental guidance molecules in CNS regeneration.

Animals↗
PubMed1996

Clinical aspects of expression of inversion 16 chromosomal fusion transcript CBFB/MYH11 in acute myelogenous leukemia subtype M1 with abnormal bone marrow eosinophilia.

The pericentric inversion of chromosome 16 (inv(16)(p12q22)) is a characteristic karyotypic abnormality associated with acute myeloid leukemia, most commonly of the M4Eo subtype. It is increasingly appreciated as both a favorable prognostic factor and important guide to therapy. The breakpoints of the inversion have been cloned and a fusion transcript can be identified by RT-PCR. We expand upon our prior abstract of a case of AML subtype M1 with abnormal eosinophils that expressed the inversion 16 fusion transcript CBFB/MYH11. During remission, the transcript could not be detected. The patient relapsed twice during the first year after attaining a complete remission. Morphologically, the relapsed specimens were identical to the appearance of his diagnostic specimen. However, the CBFB/MYH11 fusion transcript was not detected in the relapsed specimen. We conclude that CBFB/MYH11 fusion transcript detection, as a surrogate for the favorable prognosis and treatment planning implied by inv(16) in AML M4Eo, should not be exclusively relied upon in AML M1 in the absence of prospective study of this specific (M1) category of AML. RT-PCR analysis should be correlated with cytogenetics when available and if used alone should be interpreted cautiously in cases of AML with atypical morphological features.

Aged↗
PubMed1997

Ligand-gated ion channel subunit partnerships: GABAA receptor alpha6 subunit gene inactivation inhibits delta subunit expression.

Cerebellar granule cells express six GABAA receptor subunits abundantly (alpha1, alpha6, beta2, beta3, gamma2, and delta) and assemble various pentameric receptor subtypes with unknown subunit compositions; however, the rules guiding receptor subunit assembly are unclear. Here, removal of intact alpha6 protein from cerebellar granule cells allowed perturbations in other subunit levels to be studied. Exon 8 of the mouse alpha6 subunit gene was disrupted by homologous recombination. In alpha6 -/- granule cells, the delta subunit was selectively degraded as seen by immunoprecipitation, immunocytochemistry, and immunoblot analysis with delta subunit-specific antibodies. The delta subunit mRNA was present at wild-type levels in the mutant granule cells, indicating a post-translational loss of the delta subunit. These results provide genetic evidence for a specific association between the alpha6 and delta subunits. Because in alpha6 -/- neurons the remaining alpha1, beta2/3, and gamma2 subunits cannot rescue the delta subunit, certain potential subunit combinations may not be found in wild-type cells.

Animals↗
PubMed2005

Optimization of a genotypic assay applicable to all human immunodeficiency virus type 1 protease and reverse transcriptase subtypes.

Genotypic assays are used often to guide clinicians in decisions concerning the treatment of patients. An optimized sequence-based genotypic assay was used to determine the whole protease and reverse transcriptase (RT) gene, including the gag cleavage site region and RNase H region. Since non-B subtypes are increasing in countries where subtype B was the most prevalent subtype, and treatment becomes more available in developing countries where the epidemic is characterized by a high prevalence of non-B subtypes, it was important that the genotypic test was evaluated using a panel of different subtypes. Amplification was successful for different subtypes: A, B, C, D, F, G, H, J, CRF01_AE, CRF02_AG, CRF11_cpx, CRF13_cpx and an uncharacterized recombinant sample. The detection limit of the PCR was 1000 copies/ml, except for 1 subtype C sample (PL3) and 1 CRF02_AG sample (PL8). The detection limit for these samples was 5000 copies/ml. A sequence could be obtained in both directions for most of the samples.

DNA Primers↗
PubMed2003

Sequential signaling through Notch1 and erbB receptors mediates radial glia differentiation.

Radial glia cells both generate neurons and physically guide nascent neurons to their target destination in the cortex, and as such they are essential for CNS development. It has been proposed that in the developing cerebellum, neuronal contact induces radial glia formation, however, the mechanisms involved in this process are not well understood. Here we demonstrate that neuronal induction of radial glia formation is the result of sequential signaling through Notch1 and erbB receptors. First, Notch1 activation by neuronal contact induces the glial expression of the brain lipid binding protein (BLBP) and erbB2 genes. Interestingly, two different signaling pathways mediate these effects of Notch1 on transcription, BLBP expression being dependent on Su(H), whereas erbB2 is regulated by a yet unidentified Notch1 pathway. The subsequent increase in erbB2 receptor expression makes the glia more responsive to neuronal NRG, which then induces the morphological transformation into radial glia. Thus, these results unveil some of the mechanisms underlying radial glia formation.

Animals↗
PubMed2001

Long-term RNase P-mediated inhibition of HIV-1 replication and pathogenesis.

Advances in genetic analysis and a greater understanding of human immunodeficiency virus (HIV) molecular pathogenesis have identified critical viral targets for gene interference strategies. RNase P molecules have been proposed as a novel approach for gene targeting based upon their potent catalytic activity, as well as versatile external guide sequence (EGS) which can be modified to specifically recognize almost any target mRNA. We designed a truncated EGS to specifically recognize the highly conserved U5 region of HIV-1 mRNA and mediate subsequent cleavage of hybridized mRNA by the RNase P enzyme component. The active U5-EGS (560), as well as a disabled U5 EGS (560D) control, were cloned into plasmids containing proviral constructs and transfected into a CD4(+) T cell line that was thereafter infected with HIV-1 MN. CD4(+) T cells treated with the active U5 EGS (560) were observed to maintain CD4(+) expression and did not produce HIV p24 gag antigen, form syncytia or undergo apoptosis up to 30 days after infection. Identical cells expressing the inactivated form of the U5 RNase P EGS completely down-regulated CD4 expression, produced elevated levels of HIV-1, formed large syncytia and underwent apoptosis similar to untreated cells. HIV-1 replication and related cytopathology can be effectively inhibited in CD4(+) T cells expressing a protective U5 EGS (560).

Annexin A5↗
PubMed2004

The conserved kinase UNC-51 acts with VAB-8 and UNC-14 to regulate axon outgrowth in C. elegans.

Directional cues guide growth cones. While molecules like UNC-6/netrin direct migrations along the dorsoventral axis of many organisms, it is unclear how anteroposterior guidance is achieved. We describe a physical interaction between VAB-8, a protein both necessary and sufficient for posteriorly directed migrations in C. elegans, and UNC-51, a conserved serine/threonine kinase that functions generally in axon outgrowth. We show that both proteins function in the CAN neurons to direct their axons posteriorly. Expression in the CANs of peptides predicted to interfere with interactions between UNC-51 and both VAB-8 and UNC-14, a second protein that interacts physically with UNC-51, disrupts CAN axon outgrowth. We provide genetic evidence that VAB-8 functions in an UNC-51 pathway for posteriorly directed CAN axon guidance and show that VAB-8 and UNC-14 can be targets of UNC-51 kinase activity. Taken together, our results suggest that VAB-8 and UNC-14 are substrates that mediate the function of UNC-51 in axon outgrowth.

Animals↗
PubMed2005

Specialized DNA arrays for the differentiation of pancreatic tumors.

PURPOSE: Malignant tumors of the pancreas are frequently indistinguishable from inflammatory tumors arising in the context of a chronic pancreatitis with the use of conventional imaging techniques. Thus, cytologic analysis of cells obtained by abdominal ultrasound, computed tomography, or endoscopic ultrasound-guided fine needle aspiration biopsy is required for diagnosis. However, the reliability of cytologic analyses of pancreatic fine needle aspirates remains unsatisfactory, with a diagnostic accuracy of < or =80%. The purpose of the current study was therefore to develop a novel diagnostic approach based on expression profiling of biopsy material using a specialized diagnostic cDNA array. EXPERIMENTAL DESIGN: Previous gene expression profiling studies were reevaluated to design a 558-feature diagnostic array. Minimal amounts of residual material from pancreatic cytology samples as well as surgically resected tumor and control tissue specimens were analyzed using the diagnostic array and a newly developed statistical classification system. RESULTS AND CONCLUSIONS: Our diagnostic approach resulted in 95% accurate differentiation between ductal adenocarcinomas and nonmalignant tumors of the pancreas. The diagnostic array, in conjunction with conventional diagnostic procedures, is thus suitable to significantly improve the reliability of pancreatic cancer diagnostics and can be expected to become a valuable new tool in the routine workup of suspect masses in the pancreas.

Adenocarcinoma↗
PubMed2006

VCAM-1-positive stromal cells from human bone marrow producing cytokines for B lineage progenitors and for plasma cells: SDF-1, flt3L, and BAFF.

The differentiation of B lymphocytes in the bone marrow is guided by the surrounding microenvironment determined by cytokines, adhesion molecules, and the extracellular matrix. These microenvironmental factors are mainly provided by stromal cells. In this paper, we report the identification of a VCAM-1-positive stromal cell population by flow cytometry. This population showed the expression of cell surface markers known to be present on stromal cells (CD10, CD13, CD90, CD105) and had a fibroblastoid phenotype in vitro. Single cell RT-PCR analysis of its cytokine expression pattern revealed transcripts for haematopoietic cytokines important for either the early B lymphopoiesis like flt3L or the survival of long-lived plasma cells like BAFF or both processes like SDF-1. Whereas SDF-1 transcripts were detectable in all VCAM-1-positive cells, flt3L and BAFF were only expressed by some cells suggesting the putative existence of different subpopulations with distinct functional properties. In summary, the VCAM-1-positive cell population seems to be a candidate stromal cell population supporting either developing B cells and/or long-lived plasma cells in human bone marrow.

B-Cell Activating Factor↗
PubMed2006

Role of heat-shock factor 2 in cerebral cortex formation and as a regulator of p35 expression.

Heat-shock factors (HSFs) are associated with multiple developmental processes, but their mechanisms of action in these processes remain largely enigmatic. Hsf2-null mice display gametogenesis defects and brain abnormalities characterized by enlarged ventricles. Here, we show that Hsf2-/- cerebral cortex displays mispositioning of neurons of superficial layers. HSF2 deficiency resulted in a reduced number of radial glia fibers, the architectural guides for migrating neurons, and of Cajal-Retzius cells, which secrete the positioning signal Reelin. Therefore, we focused on the radial migration signaling pathways. The levels of Reelin and Dab1 tyrosine phosphorylation were reduced, suggesting that the Reelin cascade is affected in Hsf2-/- cortices. The expression of p35, an activator of cyclin-dependent kinase 5 (Cdk5), essential for radial migration, was dependent on the amount of HSF2 in gain- and loss-of-function systems. p39, another Cdk5 activator, displayed reduced mRNA levels in Hsf2-/- cortices, which, together with the lowered p35 levels, decreased Cdk5 activity. We demonstrate in vivo binding of HSF2 to the p35 promoter and thereby identify p35 as the first target gene for HSF2 in cortical development. In conclusion, HSF2 affects cellular populations that assist in radial migration and directly regulates the expression of p35, a crucial actor of radial neuronal migration.

Animals↗