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At least 1,081 records · Page 60Linked to original sources
PubMed2005

The effect of genotyping error in sib-pair genomewide linkage scans depends crucially upon the method of analysis.

In genomewide linkage scans for complex diseases involving many loci with small genetic effects, it may be the case that no loci reach conventional statistical significance. A complementary method of evaluating linkage results, locus counting, may provide evidence for the existence of a number of genetic loci in these cases. Sib-pair study designs are often used in genomewide linkage scans, but because all genotype configurations are consistent with Mendelian inheritance, genotyping error will go largely undetected. Previous work on the effect of genotyping error has focused on a single disease locus. We considered the effect of two levels of genotyping error on genomewide evidence for linkage by using the simulated GAW 13 data. For affected sib-pair and non-parametric quantitative trait study designs, a 0.5% genotyping error rate reduced the number of independent linkage regions towards that expected under the null hypothesis of no linkage. A 2% genotyping error rate yielded less independent linkage regions than expected under the null hypothesis of no linkage. For a quantitative trait analysed using a parametric regression-based method, there was very little erosion of the linkage signal, even for error rates as high as 2%.

Data Interpretation, Statistical↗
PubMed2006

Genetic information in the diagnosis and treatment of hypertension.

Advancement in cardiovascular science should be measured by a number of new diagnostic and therapeutic options applied in clinical practice as a result of translational research. Hypertension genetics is a good example of such a successful transfer of knowledge from bench to bedside. There are genetic methods currently used as diagnostic tools in patients presenting with secondary forms of hypertension, including primary hyperaldosteronism, Cushing's syndrome, pheochromocytoma, and chronic kidney disease. Directed treatment that corrects pathophysiologic abnormalities is available for several monogenic forms of hypertension as a result of uncovering their underlying genetic mechanisms. Progress in hypertension pharmacogenetics and pharmacogenomics brings closer a perspective of personalized antihypertensive treatment and gene transfer strategies, which, although still considered as innovative approaches, may soon become options to treat, control, and, possibly, cure hypertension.

Adrenocortical Hyperfunction↗
PubMed2026

Human Umbilical Cord Mesenchymal Stem Cells in Metabolic Dysfunction-associated Fatty Liver Disease (MAFLD) Therapy: Mechanisms, Clinical Efficacy, and Future Perspectives.

There is currently no approved drug treatment for metabolic dysfunction-related fatty liver disease (MAFLD). Umbilical cord-derived mesenchymal stem cells (UC-MSCs) show therapeutic potential, but their mechanism of action is remains incompletely understood. Different from previous reviews that focused on a single pathway, this article presents three important contributions: First, it constructs an integrated "multi-target synergy network" model, clarifying how UC-MSCs coordinate and regulate the inflammatory, metabolic and fibrotic processes through the interactions between the AMPK/mTOR, Nrf2/HO-1 and TGF-β/Smad pathways; Second, it systematically assesses recent clinical trials (2022-2025), identifying several unaddressed barriers to transformation, including the lack of histological endpoint indicators, batch-to-batch differences, and the absence of dose exploration studies; Third, we integrate the latest developments from 2024 to 2025, particularly mitochondrial transfer (mediated by tunnel nanotubes and accompanied by quantitative efficacy data) and exosome circular RNA networks [Formula: see text], which have not been covered in previous reviews. Based on the above analysis, we also propose specific suggestions for standardized GMP production, mandatory genomic stability testing, and long-term safety registration. This review provides a comprehensive analysis of elaborates on the treatment of MAFLD with UC-MSCs from a mechanistic and translational perspective, based on the extensive updates of relevant literature.

Humans↗
PubMed2021

Comprehension of skin cancer genetic risk feedback in primary care patients.

Few studies have examined comprehension and miscomprehension of genetic risk feedback for moderate-risk genes in the general population. We examined the prevalence and nature of accurate and inaccurate genetic risk feedback comprehension among those who received genetic testing for melanocortin-1-receptor (MC1R) gene variants that confer moderate melanoma risk. Participants (N = 145 Albuquerque, NM) were tested as part of a randomized controlled trial. Two weeks after receiving MC1R genetic risk feedback, participants answered open-ended questions regarding their reactions to the MC1R feedback report. Participants' comprehension of their feedback (average-risk or higher-risk for melanoma) was evaluated through qualitative analysis of open-ended responses. Most participants demonstrated comprehension of their feedback results (i.e., 63% of average-risk participants [ARPs]; 51% of higher-risk participants [HRPs]). Miscomprehension was evident in fewer participants (i.e., 16% of ARPs, 11% of HRPs). A few ARPs misunderstood the purpose of testing, whereas a few HRPs reported confusion about the meaning of their risk feedback. Some participants' responses to the open-ended questions were too ambiguous to ascertain comprehension or miscomprehension (i.e., 21% of ARPs, 38% of HRPs). Taken together, these findings suggest that genetic testing feedback for MC1R risk variants is largely comprehensible to general population participants. This study adds to the work examining comprehension and usage of common, moderate risk genetic information in public health contexts. However, to maximize the utility of genetic risk information in the general population, further research is needed to investigate and address areas where common genetic risk feedback misunderstandings occur.

Genetic testing↗
PubMed2025

Small cell bladder carcinoma with a high tumor mutational burden responding to sequential cisplatin-etoposide and pembrolizumab: a case report.

Small cell carcinoma of the urinary bladder (SCCB) is a rare and aggressive malignancy with limited treatment options and a poor prognosis. We present the case of a 63-year-old man who was initially diagnosed to have non-metastatic high-grade non-muscle invasive urothelial carcinoma with sarcomatoid subtype and later developed bone metastases. A bone biopsy confirmed small cell carcinoma, and retrospective review of the original tumor revealed mixed histology comprising small cell, sarcomatoid-like, and conventional urothelial carcinoma components. The patient was treated with six cycles of cisplatin and etoposide, during which genomic profiling identified a high tumor mutational burden (22 mutations/megabase). Based on this finding, pembrolizumab was administered sequentially as monotherapy. The patient achieved a complete response that lasted for more than 1 year, but subsequently developed lymph node metastases and recurrences in bone. This case highlights the role of genomic profiling test for clinical decision-making as tumor mutational burden predicts the efficacy of immune checkpoint inhibitor therapy in SCCB. This case also underscores the urgent need for novel treatment approaches for SCCB.

Case report↗
PubMed1990

Fiber sequence heterogeneity in subgroup F adenoviruses.

The fiber gene of adenovirus type 41 was sequenced and compared to the fiber gene sequence of adenovirus type 40 (A. H. Kidd and M. J. Erasmus, 1989, Virology 172, 134-144), the other known member of subgroup F. The open reading frame, from map units 87 through 92 with transcription from the r-strand, comprised 1686 bases and was 45 bases longer than its counterpart on the Ad40 genome. The 45-base difference appears to have resulted from a block deletion on the Ad40 sequence. Apart from this one region, the Ad40 and Ad41 fiber genes showed remarkably high homology (95.6%), indicating a relatively recent evolutionary divergence. The deduced amino acid sequence of the Ad41 fiber polypeptide was analyzed according to the model of N. M. Green et al. (1983, EMBO J. 2, 1357-1365) for the structure of the adenovirus fiber. Ad41 had one more 15-residue repeat in the shaft region than Ad40, there being 22 repeat motifs. A detailed study of various Ad40 and Ad41 strains with proven genome differences indicated that the 15-amino acid difference in polypeptide length at the 14th repeat motif is a type-specific difference among the subgroup F adenoviruses. However, two uncommon Ad41 strains belonging to 2 of the 16 Ad41 genome types tested had a 15-amino acid block deletion which was different to that of the Ad40 polypeptide. The implication from this work is that the Ad40 fiber gene probably arose from its Ad41 counterpart, but the fiber gene sequences of both types of subgroup F adenovirus are so similar that genetic recombination between strains could occur with some frequency.

Adenoviruses, Human↗
PubMed1991

Linker mutation scanning of the genes encoding the adenovirus type 5 terminal protein precursor and DNA polymerase.

The replication of adenovirus DNA requires, in addition to several host factors, three virus-encoded proteins: a DNA binding protein, the precursor of the terminal protein (pTP), and a DNA polymerase (Ad pol). Ad pol and pTP form a tight complex that is necessary for the initiation step in DNA replication. To perform mutation scanning of the adenovirus type 5 pTP and Ad pol a series of in-frame linker insertions of a 12-mer oligonucleotide d(CCCATCGATGGG) were introduced into cloned viral DNA fragments containing coding sequences of these proteins. The insertions are located at recognition sites for several blunt end-cutting restriction endonucleases. Forty different sites were mutagenized and the mutated genes were transferred to a plasmid that contains the left 42% of the adenovirus genome. They were rebuilt into the viral genome by means of in vivo recombination between plasmid DNA and digested adenovirus DNA-TP complex. The resulting viral genomes were tested for viability and rescued virus was analyzed for the presence of the inserted linker oligonucleotide. This procedure resulted in recovery of a number of viable virus mutants with insertions in the pTP or Ad pol genes, all of which are phenotypically silent. The other mutations did not allow virus production. The positions of these apparent lethal codon insertion mutations were useful to identify regions of functional importance in both proteins. It can be concluded that the precursor-specific region of pTP plays an important role in virus multiplication.

Adenoviruses, Simian↗
PubMed1992

Replication capacities of natural and artificial precore stop codon mutants of hepatitis B virus: relevance of pregenome encapsidation signal.

The emergence of hepatitis B virus variants unable to express HBe protein during late stage of viral infection may represent an important mechanism of viral persistence. The molecular mechanisms responsible for the elimination of HBe expression are nonsense or frameshift mutations or initiation codon mutations in part of its coding sequence, the precore region. So far only 2 of the 29 precore amino acid codons have been found mutated to stop codons in nature, although a total of 10 codons are convertible to stop codons by single nucleotide changes. Since the HBe-coding sequence is largely overlapped by the pregenome encapsidation signal (epsilon signal), a recently found cis-acting element required for the packaging of pregenomic RNA, the absence of other potential nonsense mutants could result from their impairment of the epsilon signal. Seven such potential stop codon mutants were constructed and tested for replication capacities by transfection into a hepatoma cell line. Five mutants were replication competent, but at levels lower than that of a prevalent natural stop codon mutant. The remaining two mutants were completely defective in DNA replication, which clearly explained why these two mutants are not found in nature. Northern blot analysis revealed wild-type levels of RNA transcription by these two mutants but complete lack of packaged pregenomic RNA. Additional studies lent further support to the importance of the epsilon signal in pregenome encapsidation and suggested relaxed sequence requirements for the computer-predicted hexanucleotide bulge region as compared to the hexanucleotide loop of the signal.

Base Sequence↗
PubMed1992

Biologically active cymbidium ringspot virus satellite RNA in transgenic plants suppresses accumulation of DI RNA.

A full-length DNA copy of cymbidium ringspot virus (CyRSV) satellite RNA was cloned downstream of the bacteriophage T7 RNA polymerase promoter. In vitro transcripts were biologically active in plants when coinoculated with the helper virus or its RNA. Although the transcripts contained 7 or 29 extra nucleotides at the 3' end, the proper 3' terminus was restored in the satRNA progeny. Full-length cDNA clones of CyRSV satRNA under the control of the cauliflower mosaic virus 35S promoter and terminator were used to transform Nicotiana benthamiana plants. Integration of CyRSV satRNA sequence in the plant genome was tested by PCR amplification of DNA extracts from transformed plants and by detection of satRNA-related transcripts in total RNA extracts. Inoculation of transgenic plants with the helper virus induced replication of satRNA of the same size as the native molecule. Sequence analysis of the satRNA progeny showed that it was identical to natural CyRSV satRNA. Infected transgenic plants were not protected from apical necrosis and death by the presence of satRNA sequences. Rather, replication of satRNA was found to suppress accumulation of defective interfering RNA, which acts in the absence of satRNA as an attenuator of virus replication and disease.

Base Sequence↗
PubMed1990

Cloning of a chromosomal fragment from Lactococcus lactis subsp. lactis partially complementing Escherichia coli recA functions.

A recA-like gene was isolated from a gene library of Lactococcus lactis subsp. lactis by intergeneric complementation of an E. coli recA mutant. A plasmid was obtained which fully complemented the RecA response to DNA damaging agents and UV inducibility of prophage, but not P1 plating efficiency in an E. coli recA mutant. The cloned DNA fragment also partially complemented the rec mutation in Lc. lactis MMS36. Hybridization studies showed that there was no detectable sequence homology between the recA gene of E. coli and Lc. lactis subsp. lactis chromosomal DNA.

Bacteriophage lambda↗
PubMed1991

Cloning and characterization of the L-rhamnose regulon in Salmonella typhimurium LT2.

A Salmonella typhimurium LT2 cosmid library was constructed, and a 46-kb recombinant plasmid was isolated that could complement an Escherichia coli rha mutant. Subsequent subcloning generated a 13.6-kb ClaI restriction fragment that contained a functional regulatory element. By complementation analyses using different subclones, the approximate physical locations of rhaT, rhaC1, rhaC2, rhaB, rhaA, and rhaD were determined. The nucleotide sequence spanning the rhaB and rhaC2 genes was determined.

Amino Acid Sequence↗
PubMed1991

Native yeast telomeres are sufficient to stabilize linear DNA in Xenopus laevis oocytes.

We have constructed a linear plasmid in yeast containing the entire bovine papillomavirus genome and tested its physical stability following microinjection into stage VI oocytes of Xenopus laevis. Our results show that unmodified telomeres, in contrast to the yeast-passaged telomeres, drastically affect the stability of the injected linear plasmid. Plasmids carrying unmodified Tetrahymena thermophila telomeric sequences are rapidly degraded in oocytes. When these plasmids are passed through yeast, the telomere ends become modified by the addition of yeast telomeric sequences. These plasmids are stably maintained in X. laevis oocytes, demonstrating that yeast-modified telomeres are sufficient to prevent linear DNA degradation.

Animals↗
PubMed1994

Analysis and toxic overexpression in Escherichia coli of a staphylococcal gene encoding isoleucyl-tRNA synthetase.

We have cloned and sequenced the Staphylococcus aureus Oxford ileS gene which encodes isoleucyl-tRNA synthetase (Ile-RS), the target for the antibiotic mupirocin. The gene was identified by hybridisation to oligodeoxyribonucleotide probes derived from internal Ile-RS amino acid (aa) sequences. The 2754-bp open reading frame encodes a 918-aa protein of 105 kDa which is homologous to other known Ile-RS from Gram- bacteria, archaebacteria, yeast and protozoa. Motifs which have been implicated in the functioning of the active site are strongly conserved. The gene was engineered for high-level expression in Escherichia coli. Ile-RS overproduction was toxic to the E. coli host, the magnitude of its observed effects being strain-dependent.

Amino Acid Sequence↗
PubMed1994

Sequence and genetic analysis of multiple flagellin-encoding genes from Proteus mirabilis.

Surface-induced overproduction of flagellin is one of the hallmarks of Proteus mirabilis swarmer cell differentiation. In this study, we analyzed the nucleotide (nt) and amino acid (aa) sequences, and expression of the P. mirabilis flagellin-encoding gene (fliC) region. The nt sequence analysis of a 3567-bp region reveals three ORFs, each with homology to known Escherichia coli flagellar genes. The first ORF corresponds to fliD, the gene encoding the flagellar filament capping protein, FliD (HAP2). The second and third ORFs are highly homologous to each other and to fliC genes from many other Gram- bacteria. To distinguish between the two alleles, we have designated these genes fliC1 and fliC2. Sequences highly homologous to promoter sites for the alternate sigma factor of RNA polymerase, sigma 28, are found 5' to the start of each gene. Additionally, both fliC1 and fliC2 have a conserved direct tandem repeat (DTR) sequence upstream from the sigma 28 promoter that may have functional significance in the transcriptional control of fliC expression during swarmer cell differentiation. Both FliC1 and FliC2 were produced in E. coli, but only FliC1 could complement FliC- mutants of E. coli. Southern hybridization data indicate the presence of fliC1 and fliC2 in six distinct P. mirabilis strains, indicating that multiple flagellin-encoding genes are common in P. mirabilis. Hybridization data also suggest the presence of a third flagellin-encoding gene, fliC3, in all isolates. The possible significance of multiple fliC in swarmer cell differentiation is discussed.

Amino Acid Sequence↗
PubMed1994

Sequence analysis of the Rickettsia prowazekii gyrA gene.

The Rickettsia prowazekii (Rp) gyrA gene, which codes for a subunit of DNA gyrase in this obligate intracellular bacterium, has been isolated and characterized. Nucleotide sequence analysis revealed an open reading frame (ORF), initiating with a GTG start codon, of 2718 bp that could encode a protein of 905 amino acids (aa) with a calculated M(r) of 101,048. The Rp gyrase subunit A (GyrA), when compared to GyrA analogs of other bacterial species, exhibited 43 to 50% identity. Alignment of the Rp GyrA aa sequence with the other analogs revealed the presence of a span of additional aa within the putative DNA-binding domain. The lack of an ORF within 865 bp upstream from the Rp gyrA demonstrates a Rp gene organization different from that of characterized gyrA from other species. Despite the similarity to Escherichia coli GyrA, Rp GyrA did not complement an E. coli gyrA temperature-sensitive mutant. However, Rp gyrA was dominant to an E. coli gyrA96 nalidixic-acid-resistant (NalR) mutant, conferring Nal sensitivity when introduced into the NalR E. coli strain.

Amino Acid Sequence↗
PubMed1995

Antiviral activity and protection of cells against human immunodeficiency virus type-1 using an antisense oligodeoxyribonucleotide phosphorothioate complementary to the 5'-LTR region of the viral genome.

A COS-like monkey kidney cell line stably transfected with the plasmids pCMVgagpol-rre-r with the gag and pol genes, and pCMV rev with the rev gene of HIV-1 derived from the cDNA clone BH10, was used as a model for assessing the effectiveness of antisense (AS) constructs, A 20-mer oligodeoxyribonucleotide (oligo) phosphorothioate sequence (5'-CCG CCC CTC GCC TCT TGC CG) complementary to a portion of the 5'-long terminal repeat (5'-LTR) of the HIV-1 genome was tested for its inhibitory effects on the biologically important processes of HIV-1 replication and proliferation. We observed a concentration-dependent inhibition of HIV protein synthesis. Desitometric analysis of data from Western blot analysis showed sequence-specific and concentration-dependent oligo inhibition of p24 viral core antigen formation in the low-microM range. When lipofectin was used as a delivery vehicle, a markedly increased potentiation of the AS activity of the sequence was observed at a lower concentration (0.1 microM), following a 24-h preincubation. The AS construct specifically inhibited intracellular p24 production in chronically HIV-1-infected cells of lymphoid origin (H9/IIIB cells) by 95%, resulting in a 15-fold inhibitory effect relative to a similar sequence thiolated at only seven single-base positions. A concentration-dependent attenuation in the reverse transcriptase activity and a reduction in viral p24 level was observed in the culture supernatant of AS-pretreated HIV-1-infected phytohemagglutinin A-stimulated human cord blood mononuclear cells. Incubation of a HIV-1-infected lymphoid cell line with AS sequence resulted in a marked reduction in syncytium formation, and therefore protected cells from the cytopathic effects of the virus. Furthermore, the AS oligo did not appear to be cytotoxic in cell growth rate and colony-forming ability assays. The AS oligo described in this report is a useful new tool for the molecular analysis of HIV-1 gene expression and proliferation, and may have potential as a therapeutic agent.

Animals↗
PubMed1992

DNA damage in human white blood cells after inhalative exposure to methylenediphenyl diisocyanate (MDI)--case report.

A workplace-related inhalative exposure test in a challenge chamber was performed on an industrial worker in a methylenediphenyl diisocyanate (MDI) atmosphere from 5 to 20 ppb and the isolated white blood cell DNA was analysed by electrophoresis, anion-exchange chromatography and melting behaviour. The results of electrophoresis indicate that inhaled MDI induces double-strand breaks of DNA. Some of the DNA fragments were estimated to be in the region of 100-500 bp. Anion-exchange chromatography confirmed this finding. Following denaturation and rapid renaturation the results demonstrated that some DNA fragments are cross-linked by MDI. Comparing the melting curves before and after inhalative exposure in the challenge test chamber, genomic DNA revealed differences in the shape of the melting curve (hyperchromic effect). The results suggest that occupational MDI exposure could be associated with white blood cell DNA damage.

Administration, Inhalation↗
PubMed1988

Detection of enteroviruses using subgenomic probes of Coxsackie virus B4 by hybridization.

The objective of this research was to develop group- and type-specific probes for the detection of enteroviruses. Coxsackie virus B4 RNA was cloned, and a series of subgenomic clones were generated. Six of these clones, containing sequences from the 3' end or the 5' end of the genome, were tested for their ability to detect these viruses in a small number of infected cells employing nucleic acid hybridization technique and total cytoplasmic RNA from a panel of 11 serotypes of enteroviruses. The RNA from cells infected with Coxsackie B viruses gave characteristic and positive hybridization signals. Coxsackie B-specific probes and a control Echo 9 probe detected Coxsackie A9 and Echo 3 weakly. As little as 0.5 microgram of the RNA--which contained 10-20 ng of poly(A)-containing, virus-specific, hybridizable RNA--was sufficient to successfully conduct the assay, suggesting high sensitivity of these probes. Probes that are 3' end-specific appear to be group specific, while those that are 5' end-specific appear to be type specific among the serotypes tested.

DNA↗