Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “RNA guide”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,585 records · Page 88Linked to original sources
PubMed1998

Evolution of U24 and U36 snoRNAs encoded within introns of vertebrate rpL7a gene homologs: unique features of mammalian U36 variants.

U24 and U36 are members of the box C/D-containing group of antisense snoRNAs which possess long (9-21 nucleotide) conserved stretches of sequence complementarity to 18S and 28S rRNA and act as guides for the site-specific ribose methylation of rRNA. Both U24 and two variants of U36 are encoded within introns of the human and chicken rpL7a genes. We now report that an additional U36 variant is encoded within intron 4 of the human rpL7a gene and that murine homologs of the three human U36 variants are encoded within the same adjacent introns (4, 5, and 6) of the mouse rpL7a gene. We also show that, like that of the chicken, the Fugu rubripes rpL7a gene possesses only two U36-like sequences within introns 4 and 5. Whereas the two U36 variants in chicken and Fugu possess stretches of complementarity to both 18S and 28S rRNAs, it is noted that only one mammalian variant (U36b) possesses both. Unusually, the stretch of complementarity to 18S rRNA in the mammalian U36a variants and the stretch of complementarity to 28S rRNA in the mammalian U36c variants are not present, appearing to have diverged extensively from their consensus sequence. Additionally, the mammalian U36 variants show a unique heterogeneity in their potential to form a terminal stembox structure predicted for many other box C/D-containing antisense snoRNAs. Finally, the Saccharomyces cerevisiae small nuclear RNA, snR47, is shown to be homologous to the vertebrate U36 snoRNA.

Animals↗
PubMed2002

Is hepatitis C virus co-infection associated with survival in HIV-infected patients treated by combination antiretroviral therapy?

OBJECTIVE: To study whether hepatitis C virus (HCV) co-infection or the severe elevation of transaminases is associated with survival after the initiation of antiretroviral combination therapy. DESIGN: Prospective hospital-based cohort (Aquitaine Cohort). METHODS: HIV-infected adults started on an antiretroviral combination before 30 June 1999. HCV infection was defined as antibody detection or positive HCV RNA. Severe elevation of transaminases was defined as a value of aspartate or alanine aminotransferase (AST, ALT) above five times the upper limit of normal values. Survival was studied using a Cox model, including at least baseline HCV status and transaminases as a time-dependent covariate. RESULTS: Overall, 995 patients were analysed, including 576 HCV-positive individuals (58%). At baseline, HCV-positive patients were younger, more often injecting drug users and women, and had more frequently elevated transaminases. A shorter survival was associated with AIDS stage [hazard ratio (HR) versus non-AIDS 1.67; 95% confidence interval (CI) 1.03; 2.68], lower CD4 cell count (HR for 50 cells/mm3 lower 1.33; CI 1.17; 1.51), lower haemoglobin (HR for 1 g/dl lower 1.20; CI 1.07; 1.35), lower platelet count (HR for 10 000 cells/mm3 lower 1.04; CI 1.01; 1.07), and AST during follow-up (HR for > or = 200 IU/l 2.30; CI 1.32; 4.03). HCV co-infection (HR 1.20; CI 0.75; 1.92) was not statistically associated with survival. CONCLUSION: The occurrence of a severe elevation of transaminases was associated with poorer survival, although HCV was not. If liver toxicity may be treatment induced, plasma drug concentrations could guide dosage adjustments of antiretroviral treatments currently prescribed to optimize their use.

Acquired Immunodeficiency Syndrome↗
PubMed2000

Intracellular mRNA cleavage induced through activation of RNase P by nuclease-resistant external guide sequences.

Most antisense oligonucleotide experiments are performed with molecules containing RNase H-competent backbones. However, RNase H may cleave nontargeted mRNAs bound to only partially complementary oligonucleotides. Decreasing such "irrelevant cleavage" would be of critical importance to the ability of the antisense biotechnology to provide accurate assessment of gene function. RNase P is a ubiquitous endogenous cellular ribozyme whose function is to cleave the 5' terminus of precursor tRNAs to generate the mature tRNA. To recruit RNase P, complementary oligonucleotides called external guide sequences (EGS), which mimic structural features of precursor tRNA, were incorporated into an antisense 2'-O-methyl oligoribonucleotide targeted to the 3' region of the PKC-alpha mRNA. In T24 human bladder carcinoma cells, these EGSs, but not control sequences, were highly effective in downregulating PKC-alpha protein and mRNA expression. Furthermore, the downregulation is dependent on the presence of, and base sequence in, the T-loop. Similar observations were made with an EGS targeted to the bcl-xL mRNA.

3' Untranslated Regions↗
PubMed2026

Hyperprogression Upon Cemiplimab Alone or With Short Course Chemotherapy in PD-L1 ≥ 50% Non-small Cell Lung Cancer: A Biomarker Guided Multicenter International Phase 2 Trial-HYPERBOLIC Study.

BACKGROUND: Immune checkpoint inhibitor (ICI) monotherapy is the standard first-line treatment for advanced non-small cell lung cancer (NSCLC) with PD-L1 ≥ 50%; however, up to 30% of patients experience early progression or death, including cases of hyperprogressive disease (HPD). High baseline levels (≥ 30.5%) of circulating CD10- low-density neutrophils (LDNs) have been associated with increased HPD occurrence. Emerging evidence suggests that combining ICI with platinum-based chemotherapy (PCT) may mitigate the risk of HPD. Currently, no prospective studies have addressed HPD prevention in this context. PATIENTS AND METHODS: HYPERBOLIC (NCT07274384) is a phase 2, randomized, open-label, multicenter, international trial evaluating whether adding 3 cycles of PCT to first-line cemiplimab reduces HPD rate in stage IV NSCLC with PD-L1 ≥ 50% and CD10- LDNs (identified by flow cytometry as CD15⁺CD11b⁺ within the PBMC fraction, with immature cells defined by loss of CD10) ≥ 30.5%. Seventy-four patients will be randomized (1:1 ratio) to receive cemiplimab alone or cemiplimab plus 3 PCT cycles, followed by cemiplimab maintenance. Randomization will be stratified by Lung Immune Prognostic Index. The first computed tomography scan at week 7 after treatment start will assess HPD occurrence, defined as RECIST v 1.1. disease progression with a delta tumor growth rate (ΔTGR) ≥ 50% and/or TGR ratio ≥ 2. The primary endpoint will be the combined rate of HPD and early death (death within 12 weeks with no radiological evaluation). Secondary endpoints will be HPD rate according to alternative definitions, overall survival, progression free survival, objective response rate, and safety. An extensive translational research platform will include spatial transcriptomics of tumor tissue, single-cell RNA sequencing of PBMCs, circulating-free DNA and plasma factors profiling, and saliva/stool microbiome genomics and metabolomics, to longitudinally explore tumor-host dynamic interactions during treatment. CONCLUSION: to our knowledge, HYPERBOLIC is the first prospective, biomarker-driven trial investigating early treatment escalation based on HPD risk in PD-L1-high NSCLC.

CD10↗
PubMed2002

Pathogen inactivation of blood components: current status and introduction of an approach using riboflavin as a photosensitizer.

Riboflavin is a naturally occurring compound and an essential human nutrient. Studies in the 1960s and 70s showed that it could be effective, when exposed to visible or UV light, in inactivating viruses and bacteria. This suggested to us that it could act as a photosensitizer useful in the inactivation of pathogens found in blood products, because of its nucleic acid specificity and its limited tendency toward indiscriminate oxidation. The riboflavin molecule is a planar, conjugated ring structure with a sugar side chain that confers water solubility. The planar portion is capable of intercalating between the bases of DNA or RNA. Light activated riboflavin oxidizes guanine in nucleic acids, preventing replication of the pathogen's genome. Gambro BCT is developing processes using riboflavin and light to inactivate pathogens in plasma, platelet, and red cell products. We call these Pathogen Eradication Technology (PET) processes. Riboflavin is non-toxic; it must be present in the body for good health. The photo-byproducts formed in the PET processes are lumichrome and protein adducts. The photodegradation of riboflavin in the body is clearly shown by the decrease in its concentration in neonates who are treated with intense visible light to break down circulating bilirubin, which their immature livers cannot yet handle. A definitive lookback study showed no difference in cancer rates between the 55,000 children receiving this therapy in Denmark from 1977 through 1989 and nonirradiated controls. Gambro BCT is developing specific riboflavin-based PET processes for platelet concentrates, fresh frozen plasma, and packed red blood cells. In each, the process is being optimized to achieve high levels of inactivation of specific pathogens, while maintaining acceptable levels of product quality and activity. Extra- and intracellular HIV, BVDV (a model for HCV), and pseudorabies virus (a herpes virus) have been used to guide process development and validation. We have demonstrated 4 to 7 log10 reductions in the titers of these viruses, when they are spiked into blood products and irradiated in the presence of riboflavin. Porcine parvovirus, a tight-capsid, nonenveloped virus is more resistant, a finding in all experimental inactivation approaches. A range of bacteria implicated in platelet and red cell transfusion injuries and deaths, including S. aureus, E. coli, K. pneumoniae, and Y. enterocolitica, are being used to validate antibacterial efficacy. The PET platelet process involves the addition of riboflavin to platelets in plasma, illumination of the product, storage of the product and transfusion without further manipulation. The lack of toxicity of the treatment byproducts permits this ease of use. Quality of the platelets throughout storage has been assessed by pH, PO2, lactate, hypotonic shock response, morphology, glucose, and GMP-140 expression. In vitro function is well maintained. The levels seen are within the range of those reported in commonly transfused products. Radiolabeled transfusion studies of treated platelets have been carried out in primates to determine a preliminary measure of their in-vivo circulation. The in vivo recoveries and survivals of treated and control platelets did not differ. This work suggests that an endogenous photosensitizer, riboflavin, which has an extremely good safety profile, can inactivate high levels of a broad range of viruses and bacteria in platelet concentrates, fresh frozen plasma, and in red blood cells, preserving the activity and functionality of the components. Planned animal and clinical studies are expected to solidify this suggestion into a well-characterized process which can be safely and readily applied to reduce the risks of transfusion transmitted disease.

Blood Cells↗
PubMed2002

The contribution of non-invasive imaging modalities to the diagnosis of left ventricular pseudoaneurysm.

BACKGROUND: Left ventricular pseudoaneurysm (LVPA) is a rare entity characterized by a tendency to spontaneous rupture due to its morphology, a lack of myocardial fibers and fibrous tissue delineating the cavity. An early diagnosis is essential in order to guide appropriate therapy. PURPOSE: To determine the diagnostic accuracy of different imaging techniques, treatment results, and prognosis of patients (pts) with LVPA. METHODS: We evaluated the incidence of LVPA during a five-year period. The initial clinical presentation, the etiology of LVPA, time between symptom onset and diagnosis, and use of various non-invasive techniques were studied. Mean follow-up was 15 months. RESULTS: Of 19113 pts admitted to our Institute in a five-year period, LVPA was diagnosed in 11 pts (0.05%) (mean age 51 +/- 3.9 years, 8 men). The diagnosis of LVPA was confirmed by surgery in 4 pts, and by pathology in 2 pts. LVPA was an incidental finding in one asymptomatic pt, it was diagnosed in 6 pts presenting with an acute myocardial infarction (AMI) and in 4 pts presenting with LV failure. The main etiology was coronary artery disease (CAD) (9 pts), with the remaining 2 cases being post-traumatic (thoracic stab wound, surgery). LVPA location was postero-inferior in 6 patients, infero-lateral in 3 patients, and anterior in 2 patients. ECG, X-ray and TTE were performed in all cases. 6 pts had a radionuclide angiography (RNA), 3 pts had a computed tomography (CT) scan and 2 pts had a magnetic resonance imaging (MRI) study. Two-dimensional transthoracic echocardiography (TTE) provided information regarding LVPA dimensions and LV-LVPA flow. Four pts were operated (one died). Of the seven non-operated pts., 5 died. CONCLUSIONS: The clinical presentation was variable and non-specific. The most frequent cause of LVPA was MI and the most frequent location was inferior. Echocardiography offered the most reliable information when compared to ventriculography. Because clinical examination, ECG, X-ray data are non-specific for the diagnosis of LVPA, an adequate TTE study performed with a high clinical index of suspicion (especially in pts with inferior MI or thoracic trauma) could facilitate the early diagnosis of LVPA and could be relevant to outcome.

Aneurysm, False↗
PubMed1990

Kinetoplast DNA minicircles encode guide RNAs for editing of cytochrome oxidase subunit III mRNA.

Guide RNAs (gRNAs) for the editing of sites 1-8 of COIII mRNA and an "unexpected" partially edited COIII mRNA are encoded in the variable regions of specific kinetoplast DNA minicircles. The gRNAs can form 37 and 44 nucleotide perfect hybrids (allowing for G-U base pairs) with edited mRNAs. The gRNAs were detected on Northern blots and shown to have unique 5' ends situated close to the beginning of the potential base pairing with the edited mRNAs. We suggest that kinetoplast DNA minicircle molecules in general may encode gRNAs for editing of cryptogene mRNAs by a mechanism similar to that previously proposed for editing by maxicircle-encoded gRNAs.

Animals↗
PubMed2000

Antiretroviral drug resistance testing in adult HIV-1 infection: recommendations of an International AIDS Society-USA Panel.

OBJECTIVE: Assays for drug resistance testing in human immunodeficiency virus type 1 (HIV-1) infection are now available and clinical studies suggest that viral drug resistance is correlated with poor virologic response to new therapy. The International AIDS Society-USA sought to update prior recommendations to provide guidance for clinicians regarding indications for HIV-1 resistance testing. PARTICIPANTS: An International AIDS Society-USA 13-member physician panel with expertise in basic science, clinical research, and patient care involving HIV resistance to antiretroviral drugs was reconvened to provide recommendations for the clinical use of drug resistance testing. EVIDENCE AND CONSENSUS PROCESS: The full panel met regularly between January and October 1999. Resistance and resistance testing data appearing in the last decade through April 2000 and presentations at national and international research conferences were reviewed. Recommendations and considerations were developed by 100% group consensus, acknowledging that definitive data to support final recommendations are not yet available. CONCLUSIONS: Emerging data indicate that despite limitations, resistance testing should be incorporated into patient management in some settings. Resistance testing is recommended to help guide the choice of new regimens after treatment failure and for guiding therapy for pregnant women. It should be considered in treatment-naive patients with established infection, but cannot be firmly recommended in this setting. Testing also should be considered prior to initiating therapy in patients with acute HIV infection, although therapy should not be delayed pending the results. Expert interpretation is recommended given the complexity of results and assay limitations.

Adult↗
PubMed2005

The contribution of the endothelium to the development of coagulation disorders that characterize Ebola hemorrhagic fever in primates.

Recently, there have been substantial developments in the understanding of Ebola hemorrhagic fever pathogenesis, but there are still major gaps. These infections occur in underdeveloped areas of the world, and much of our knowledge of naturally occurring disease is derived from sporadic outbreaks that occurred decades in the past. Recently conducted laboratory animal studies have provided insight into Ebola pathogenesis and may help guide clinical investigations of disease using contemporary methodologies that were not available previously. A better understanding of the relevant host and viral factors that influence clinical and virologic outcome will be critical to our ability to combat this aggressive pathogen. This article reviews the most relevant information relating to the postulated pathogenesis of this disease, focusing on the role of the endothelium in contributing to the coagulation disorders that characterize Ebola hemorrhagic fever in primates. Some of the remaining and key unanswered questions relating to the role of the vascular system in the pathogenesis of this disease, that need to be addressed in further research, are highlighted.

Animals↗
PubMed1999

In vitro inducible nitric oxide synthesis inhibitors from Alismatis Rhizoma.

Bioassay-guided fractionation of an aqueous extract of Alismatis Rhizoma has furnished two inducible nitric oxide synthase (iNOS) inhibitory compounds, alismol (1) and alisol B monoacetate (2), together with an inactive triterpene, alisol C monoacetate (3). Compounds 1 and 2 inhibited nitric oxide (NO) synthesis in a dose-dependent manner in murine macrophage-like RAW 264.7 cells stimulated with interferon-gamma (IFN-gamma) plus lipopolysaccharide (LPS). The inhibitory effects of 1 and 2 on NO synthesis were partly due to suppression of iNOS mRNA expression as determined by Northern blotting.

Animals↗
PubMed2000

Discontinuing prophylaxis for opportunistic infection: guiding principles.

Several large observational studies have documented the reduced risk of opportunistic infections among recipients of potent combination antiretroviral therapy. These data raise the question of whether subjects who respond to antiretroviral therapy need to continue prophylaxis for opportunistic infection. Factors to consider when deciding whether it is safe to discontinue prophylaxis include the following: (1) the risk of developing the specific opportunistic infection; (2) the consequences of the infection (morbidity and availability of effective therapy); (3) both the short-term and long-term toxicity of the agent used for prophylaxis; (4) the potential for drug interactions between the agent used for prophylaxis and other therapies for human immunodeficiency virus infection; (5) the psychological benefit of discontinuing a treatment during the course of a chronic disease; (6) the risk of development of drug resistance during prophylaxis; and (7) costs. This article reviews current data on predicting risk of opportunistic infection, the most critical of these factors.

AIDS-Related Opportunistic Infections↗
PubMed2001

International perspectives on antiretroviral resistance. Clinical utility of resistance testing: retrospective and prospective data supporting use and current recommendations.

Data from retrospective and prospective studies support use of genotypic and phenotypic resistance assays to guide treatment changes when initial or subsequent antiretroviral regimens fail. Several retrospective studies have shown that response to antiretroviral therapy can be predicted based on genotypic analysis of HIV, with baseline genotypic evidence of resistance predicting virologic failure. Other retrospective analyses demonstrated that phenotypic drug sensitivity correlates with increased viral load suppression, particularly when virus remains sensitive to two or three drugs at initiation of the regimen. Furthermore, prospective studies such as VIRADAPT and Genotype-Assisted Antiretroviral Resistance Testing (GART) have substantiated that drug selection based on genotypic assay results yield superior viral suppression compared with empiric treatment assignment. One additional study suggested significant improvement in short-term virologic outcome when phenotypic testing was used to guide treatment selection. Based on these findings, resistance testing is currently recommended for patients with acute HIV infection, those who have failed one or more antiretroviral regimens, and pregnant women. Although these tests move toward becoming a standard of care, several research questions remain: the long-term benefit of resistance testing is not yet certain, the interpretation of specific genotypic resistance patterns needs to be better defined, and clinical cut-off points for phenotypic resistance need to be established. As these issues continue to be studied, resistance testing likely will prove a reliable tool to help plan successful ART strategies.

Anti-HIV Agents↗
PubMed2004

Impaired brain angiogenesis and neuronal apoptosis induced by conditional homozygous inactivation of vascular endothelial growth factor.

Vascular endothelial growth factor (VEGF) is essential for the differentiation of the primitive embryonic vascular system and has been implicated in the vascularization of organs. Recently, VEGF has also been proposed to play a role in neural development, neuroprotection, and adult neurogenesis. Here we have investigated the function of VEGF in the developing brain by cre-lox technology. We show that VEGF produced by the embryonic neuroectoderm is required for the vascularization and the development of the brain. Both the invasion and the directed growth of capillaries were severely impaired in the fore-, mid- and hindbrain of VEGF(lox/lox)/nestin-cre mouse embryos homozygous for a VEGF mutation in the neural tube. These observations demonstrate that VEGF, via local secretion by neural progenitors, induces brain angiogenesis and guides the growth of capillaries toward the ventricular zone. VEGF deficiency led to developmental retardation and progressive destruction of neural tissue in all brain regions. The defect was most pronounced in telencephalic structures, such as the hippocampus, and caused microcephaly. Taken together, the findings establish the critical importance of neuroectoderm-derived VEGF in the morphogenesis of the brain. VEGF acts as a key regulator of brain angiogenesis and provides instructive cues for the correct spatial organization of the vasculature.

Animals↗
PubMed2026

Comprehensive transcriptomics and proteomics analysis of neointima formation in human saphenous vein: implications for bypass graft disease.

Human saphenous veins (SVs) are widely used as grafts in coronary artery bypass (CABG) surgery but often fail due to neointima formation. Little is known, however, regarding the cellular, transcriptomic, and proteomic dynamics of neointima formation in human veins. Here, we performed transcriptomics and proteomics analysis in an ex vivo tissue culture model of neointima formation in human SVs procured for CABG surgery. Histological examination demonstrated significant elastin degradation and neointima formation (indicated by increased neointima area and neointima-to-media ratio) in SVs subjected to tissue culture. Analysis of data from 72 patients suggests that the progression of SV remodeling and neointima formation differs according to sex and body mass index, which is negatively associated with neointima formation in males only. RNA sequencing demonstrated upregulation of proinflammatory and proliferation-related genes during neointima formation and identified novel processes, including increased cellular stress and DNA damage responses, reflecting tissue trauma associated with vein harvesting. Proteomic analysis identified upregulated extracellular matrix-related and coagulation/thrombosis proteins and downregulated metabolic proteins. Spatial transcriptomics, used to infer regionally enriched gene expression, suggested dynamic alterations in fibroblast and vascular smooth muscle cell (VSMC) states during neointima formation. Specifically, we identified the emergence of HES1+ and matrix metalloproteinase 2- and 14-positive (MMP2+/MMP14+) expression in VSMCs and fibroblasts, respectively, during neointima formation. Furthermore, our data suggest that MIR647, identified through screening, maintains VSMC contractile gene expression. Our findings suggest dynamic transcriptomic and proteomic changes during neointima formation in human veins and provide useful mechanistic information for the pathogenesis of SV graft disease.NEW & NOTEWORTHY Using multiomics and spatial transcriptomics, we uncover dynamic molecular and cellular changes driving neointima proliferation in human saphenous veins, the most common conduit for bypass surgery. Our study highlights sex- and body mass index-associated differences, novel fibroblast and smooth muscle cell states, and a role for microRNA-647 in preserving vascular contractile phenotype. These findings provide new insight into the mechanisms of vein graft failure and may guide future strategies to improve coronary bypass outcomes.

Humans↗
PubMed2006

The coiled-coil domain of the Nop56/58 core protein is dispensable for sRNP assembly but is critical for archaeal box C/D sRNP-guided nucleotide methylation.

Archaeal box C/D sRNAs guide the methylation of specific nucleotides in archaeal ribosomal and tRNAs. Three Methanocaldococcus jannaschii sRNP core proteins (ribosomal protein L7, Nop56/58, and fibrillarin) bind the box C/D sRNAs to assemble the sRNP complex, and these core proteins are essential for nucleotide methylation. A distinguishing feature of the Nop56/58 core protein is the coiled-coil domain, established by alpha-helices 4 and 5, that facilitates Nop56/58 self-dimerization in vitro. The function of this coiled-coil domain has been assessed for box C/D sRNP assembly, sRNP structure, and sRNP-guided nucleotide methylation by mutating or deleting this protein domain. Protein pull-down experiments demonstrated that Nop56/58 self-dimerization and Nop56/58 dimerization with the core protein fibrillarin are mutually exclusive protein:protein interactions. Disruption of Nop56/58 homodimerization by alteration of specific amino acids or deletion of the entire coiled-coil domain had no obvious effect upon core protein binding and sRNP assembly. Site-directed mutation of the Nop56/58 homodimerization domain also had no apparent effect upon either box C/D RNP- or C'/D' RNP-guided nucleotide modification. However, deletion of this domain disrupted guided methylation from both RNP complexes. Nuclease probing of the sRNP assembled with Nop56/58 proteins mutated in the coiled-coil domain indicated that while functional complexes were assembled, box C/D and C'/D' RNPs were altered in structure. Collectively, these experiments revealed that the self-dimerization of the Nop56/58 coiled-coil domain is not required for assembly of a functional sRNP, but the coiled-coil domain is important for the establishment of wild-type box C/D and C'/D' RNP structure essential for nucleotide methylation.

Amino Acid Sequence↗
PubMed2004

New views on retinal axon development: a navigation guide.

The eye is a peripheral outpost of the central nervous system (CNS) where the retinal ganglion cells (RGCs) reside. RGC axons navigate to their targets in a remarkably stereotyped and error-free manner and it is this process of directed growth that underlies the complex organization of the adult brain. The RGCs are the only retinal neurons to project into the brain and their peripheral location makes them an unusually accessible population of projection neurons for experiments involving in vivo gene transfer, anatomical tracing, transplantation and in vitro culture. In this paper, we review recent findings that have contributed to our understanding of some of the guidance decisions that axons make in the developing visual system. We look at two choice points in the pathway, the optic nerve head (onh) and the midline chiasm, and discuss evidence that supports the idea that key molecules in guiding axon growth at these junctures are netrin-1 (onh) and ephrin-B (chiasm). In the optic tectum where RGC axon terminals are arrayed in topographic order, we present experimental evidence to suggest that in the dorso-ventral dimension, the B-type ephrins and Eph receptors are of prime importance, possibly through attractive interactions. This complements the anterior-posterior topographic mapping known to be mediated through A-type ephrin/Eph repulsive interactions. An emerging theme is that guidance molecules such as ephrin-B and netrin-1 have complex patterns of restricted expression in the pathway and play multiple and changing roles in axon guidance.

Animals↗
PubMed2026

Development and internal validation of a six-gene prognostic model based on galactose metabolism for overall survival in lung adenocarcinoma.

BACKGROUND: Lung cancer remains a leading cause of cancer incidence and mortality globally. Metabolic reprogramming promotes tumor progression and shapes an immunosuppressive tumor microenvironment. Galactose metabolism is involved in multiple malignancies, but its prognostic value in lung adenocarcinoma (LUAD) remains unclear. This study aimed to develop and internally validate a galactose metabolism-related multigene prognostic model for LUAD. METHODS: A retrospective prognostic model development and internal validation study was performed using RNA sequencing (RNA-seq) and clinical data from 585 LUAD patients in The Cancer Genome Atlas (TCGA). Differential expression, functional enrichment, univariate and multivariate Cox regression were applied to construct a prognostic gene signature. Internal validation was performed using bootstrap resampling. Model performance was evaluated by time-dependent receiver operating characteristic (ROC), C-index, calibration, and Kaplan-Meier analysis. Associations between the model and immune infiltration, immunotherapy responsiveness, and tumor stemness were also analyzed. RESULTS: A six-gene prognostic model (GALT, GANC, PGM1, GALM, B4GALT1, PGM2) was developed. The model showed good discrimination with 1-, 3-, and 5-year area under the curve (AUC) values of 0.719, 0.693, and 0.684, respectively. The low-risk group exhibited significantly longer survival, increased antitumor immune infiltration (CD8+ T cells, M1 macrophages, activated CD4+ memory T cells), higher expression of T cell proliferation-related genes, lower immune checkpoint expression, better predicted immunotherapy response, and lower tumor stemness compared with the high-risk group. CONCLUSIONS: We developed and internally validated a six-gene prognostic model for LUAD based on galactose metabolism. The model shows moderate prognostic performance and is associated with antitumor immunity and tumor stemness. It may be used for prognostic risk stratification and to guide personalized immunotherapy in LUAD.

Galactose metabolism↗
PubMed1994

Replacement of the conserved G.U with a G-C pair at the cleavage site of the Tetrahymena ribozyme decreases binding, reactivity, and fidelity.

There is a phylogenetically conserved G.U pair at the 5'-splice site of group I introns. When this is mutagenized to a G-C pair, splicing of these introns is greatly reduced. We have used a ribozyme derived from the Tetrahymena group I intron to compare the binding and reactivity of oligonucleotides that form either a G.U or a G-C pair at this position. Ribozyme binding of oligonucleotides at 42 degrees C was measured by native gel electrophoresis and equilibrium dialysis. Binding of GGCCCUCC (C(-1)P), which base-pairs with the ribozyme guide sequence to form a G-C at the cleavage site, was 10-fold weaker than the binding of GGCCCUCU (U(-1)P), which maintains the conserved G.U pair at the cleavage site. This is surprising since a terminal G-C enhances the binding between oligonucleotides by 20-fold relative to a terminal G.U. Thermal denaturation studies indicate that C(-1)P and several analogs with deoxy substitutions bind the guide-sequence oligonucleotide, GGAGGGAAA, as strongly as they bind the ribozyme. In contrast, U(-1)P binds 240-fold more strongly to the ribozyme than to GGAGGGAAA, a difference that is decreased by deoxy substitutions. Thus, while U(-1)P binds the ribozyme through a combination of base-pairing and specific 2-OH and other tertiary interactions, C(-1)P may bind by base-pairing alone. The substrate GGCCCUCCAAAAA (C(-1)S) is cleaved 100-fold more slowly than GGCCCUCUAAAAA (U(-1)S) and also has a higher propensity to be cleaved at the wrong nucleotide position.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗