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PubMed1975

Isoaccepting lysine transfer ribonucleic acid species of Pseudomonas aeruginosa.

Pseudomonas aeruginosa tRNA was treated with iodine, CNBr and N-ethylmaleimide, three thionucleotide-specific reagents. Reaction with iodine resulted in extensive loss of acceptor activity by lysine tRNA, glutamic acid tRNA, glutamine tRNA, serine tRNA and tyrosine tRNA. CNBr treatment resulted in high loss of acceptor ability by lysine tRNA, glutamic acid tRNA and glutamine tRNA. Only the acceptor ability of tyrosine tRNA was inhibited up to 66% by N-ethylmaleimide treatment, a reagent specific for 4-thiouridine. By the combined use of benzoylated DEAE-cellulose and DEAE-Sephadex columns, lysine tRNA of Ps. aeruginosa was resolved into two isoaccepting species, a major, tRNA Lys1 and a minor, tRNALys1. Co-chromatography of 14C-labelled tRNALys1 and 3H-labelled tRNALys2 on benzoylated DEAE-cellulose at pH 4.5 gave two distinct, non-superimposable profiles for the two activity peaks, suggesting that they were separate species. The acceptor activity of these two species was inhibited by about 95% by iodine and CNBr. Both the species showed equal response to codons AAA and AAG and also for poly(A) and poly(A1,G1) suggesting that the anticodon of these species was UUU. Chemical modification of these two species by iodine did not inhibit the coding response. The two species of lysine of Ps. aeruginosa are truly redundant in that they are indistinguishable either by chemical modification or by their coding response.

Anticodon↗
PubMed2025

Genomic and Developmental Models to Predict Cognitive and Adaptive Outcomes in Autistic Children.

IMPORTANCE: Although early signs of autism are often observed between 18 and 36 months of age, there is considerable uncertainty regarding future development. Clinicians lack predictive tools to identify those who will later be diagnosed with co-occurring intellectual disability (ID). OBJECTIVE: To predict ID in children diagnosed with autism. DESIGN, SETTING, AND PARTICIPANTS: This prognostic study involved the development and validation of models integrating genetic variants and developmental milestones to predict ID. Models were trained, cross-validated, and tested for generalizability across 3 autism cohorts: Simons Foundation Powering Autism Research (SPARK), Simons Simplex Collection, and MSSNG. Autistic participants were assessed older than 6 years of age for ID. Study data were analyzed from January 2023 to July 2024. EXPOSURES: Ages at attaining early developmental milestones, occurrence of language regression, polygenic scores for cognitive ability and autism, rare copy number variants, de novo loss-of-function and missense variants impacting constrained genes. MAIN OUTCOMES AND MEASURES: The out-of-sample performance of predictive models was assessed using the area under the receiver operating characteristic curve (AUROC), positive predictive values (PPVs), and negative predictive values (NPVs). RESULTS: A total of 5633 autistic participants (4574 male [81.2%]) were included in this analysis. On average, participants were diagnosed with autism at 4 (IQR, 3-7) years of age and assessed for ID at 11 (8-14) years of age, with 1159 participants (20.6%) being diagnosed with ID. The model integrating all predictors yielded an AUROC of 0.653 (95% CI, 0.625-0.681), and this predictive performance was cross-validated and generalized across cohorts. This modest performance reflected that only a subset of individuals carried large-effect variants, high polygenic scores, or presented delayed milestones. However, combinations of genetic variants that are typically not considered clinically relevant by diagnostic laboratories achieved PPVs of 55% and correctly identified 10% of individuals developing ID. The addition of polygenic scores to developmental milestones specifically improved NPVs rather than PPVs. Notably, the ability to stratify ID probabilities using genetic variants was up to 2-fold higher in individuals with delayed milestones compared with those with typical development. CONCLUSIONS AND RELEVANCE: Results of this prognostic study suggest that the growing number of neurodevelopmental condition-associated variants cannot, in most cases, be used alone for predicting ID. However, models combining different classes of variants with developmental milestones provide clinically relevant individual-level predictions that could be useful for targeting early interventions.

Humans↗
PubMed1978

Immunochemical studies on a Mycoplasma pneumoniae polysaccharide fraction: cross-reactions with type 23 and 32 antipneumococcal rabbit sera.

Lipid-free polysaccharide fraction 2 extracted from Mycoplasma pneumoniae strain FH by Prescott et al. (J. Bacteriol. 91:2117-2115, 1966) was examined for its ability to cross-precipitate antibody from type-specific rabbit antipneumococcal sera types 1 to 34 inclusive. Cross-precipitation in type-specific pneumococcal anti-type 23 and anti-type 32 sera was examined in detail and could be attributed to a rhamnose-galactose-rich component of crude M. pneumoniae polysaccharide fraction 2 recovered from immunoprecipitates formed with anti-type 23 serum. Immunochemically isolated mycoplasma polysaccharide was found to contain glucose, galactose, rhamnose, and mannose in 1:14:5:4 molar proportions. Comparison of the ability of 6-O-alpha-L-rhamnosyl-D-glucose and free L-rhamnose to inhibit precepitation by homologous pneumococcal and heterologous mycoplasma polysaccharide antigens indicates a combining site specificity for anti-type 23 and anti-type 32 antibodies directed largely against the alpha-linked L-rhamnosyl determinants and the occurrence of alpha-L-rhamnosyl units in type 32 and M. pneumoniae polysaccharides. Hapten inhibition of the cross-precipitation of pneumococcal type 23 capsular polysaccharide in anti-type 32 serum helps to establish that cross-reactivity can be attributed to interaction of recurrent, alpha-L-rhamnosyl units of type 23 with anit-alpha-L-rhamnoside combining sites of anti-type 32 antibodies.

Antigens, Bacterial↗
PubMed1992

Variation in O-antigens, niche-specific selection and bacterial populations.

Bacterial populations usually consist of distinct clones, often apparently adapted to specific niches. A formal model is developed whereby niche-specific selection maintains the polymorphisms involved in clonal adaptation. Infrequent transfer of non-adaptive alleles to a clone is balanced by the selection for the resident adaptive allele. The model can account for the extensive polymorphism in surface antigens observed in bacteria, and also for the existence of sympatric clones of pathogenic species which differ in host range and/or mode of pathogenesis. Niche-specific selection combined with low levels of genetic transfer can also account for the high level of neutral variation in bacteria, and indirectly for their ability to respond rapidly to environmental changes.

Adaptation, Physiological↗
PubMed1992

A delayed-type hypersensitivity-inducing T-cell epitope of Semliki Forest virus mediates effective T-helper activity for antibody production.

The rational development of peptide vaccines requires the identification of both B- and T-cell epitopes. In this study, potential T-helper cell epitopes of Semliki Forest virus (SFV) were identified on the basis of their ability to induce delayed-type hypersensitivity (DTH) in mice using recombinant SFV fragments produced as hybrid proteins with beta-galactosidase in Escherichia coli and synthetic peptides coupled to beta-galactosidase. Although the tested fragments spanned almost the entire amino acid sequence of the structural proteins of SFV, only one DTH-inducing region (located between amino acid 137 and 151 of the SFV E2 membrane protein) was identified. Peptides containing this E2 region stimulated lymph node cells from SFV-primed mice in vitro. The ability of the identified T-cell epitope to induce a specific T-helper response in mice was evaluated using synthetic peptides that contained combinations of the DTH-inducing region and different previously identified linear B-cell epitopes of E2. These peptides proved able to induce an antipeptide IgG response in mice in an H-2d-restricted fashion. One of the peptides was also able to induce high titres of IgG reactive with SFV-infected cells and protected 70-100% of the peptide-immunized mice after challenge with virulent SFV. Our findings suggest that DTH and T-helper activity are mediated by different doses of the same T-cell epitope.

Animals↗
PubMed1976

[Age-specific learning ability in Japanese quails (Coturnix coturnix japonica)].

The main question of our investigation is: Do there exist age-specific learning abilities in animals? 120 QUAILS (Coturnix coturnix japonica) of 12 different age groups (between one day and 20 weeks) were tested in a combination apparatus 0y using two training methods. 60 quails were trained with decreasing (1), 60 other quails with increasing learning assistance (2). In each case the learning period lasted 5 days after which the animals were tested in a two-way choice apparatus and in a simple maze. Retention was tested 3 weeks later. - The 2 methods led to different results. In general the younger animals learnt better than the other ones when trained by method 1. No differences in learning performance between the 12 age groups were obtained by method 2.

Age Factors↗
PubMed1979

Absence of correlation between T-lymphocyte activity and development of carcinogen-induced skin tumor in mice.

Splenic lymphocytes obtained from female ICR/JCL mice, which had received combined radiation and chemical treatment for induction of skin tumors on their back skin, were tested for their ability to undergo proliferative response to non-specific mitogens as well as to allogeneic lymphocytes in vitro during 18 months after carcinogenic treatment. The treated mice, 168 in all, were divided into three groups: (a) 53 mice with no tumor, (b) 30 mice with skin papilloma, and (c) 85 mice with malignant skin tumor. Control mice, 39 in all, received no treatment. The local carcinogenic treatments used in this study induced a relatively long-lasting suppression of T-cell activities as detected by proliferative response to mitogens. Nevertheless, there was no significant difference in T-cell activities among the three groups of mice that developed (a) no tumor, (b) skin papilloma, or (c) malignant skin tumor. The results obtained with proliferative response to allogeneic lymphocytes were essentially similar. A preliminary study on the induction of cytotoxic T cells from splenic lymphocytes against allogeneic target cells in vitro also indicated that mice which developed tumors were not necessarily the ones which manifested reduced cytotoxic T-cell activity. These results suggest that reduced T-cell function was not a direct cause or not even a prerequisite for development of skin tumors in ICR mice.

Age Factors↗
PubMed1978

[Comparative studies of the oral flora in patients with cancer and precancerous lesions of the mouth mucosa].

Bacteriological smears were taken from various regions of the oral cavities of a total of 100 subjects (patients with carcinoma, non-specific ulcer or leucoplakia, and patients without pathological oral findings). The preparations were stained by the Gram procedure and differentiated according to germ count, morphology and ability to combine with dyes. Gram positive cocci prevailed in all groups. The total germ counts were greater in patients with carcinoma than in those with nonspecific ulcer and in normal subjects.

Bacteria↗
PubMed2026

Machine learning prognostic model and drug survival analysis for lung adenocarcinoma in the context of radiotherapy.

BACKGROUND: Patients with lung adenocarcinoma (LUAD) receiving radiotherapy represent an important but underexplored clinical subgroup. These patients often undergo concomitant pharmacologic treatments, yet the prognostic impact and underlying determinants of such combined regimens remain poorly understood. OBJECTIVE: This retrospective observational study aimed to develop and validate a radiotherapy-specific machine learning prognostic model for LUAD and to compare survival across concomitant pharmacologic regimens. METHODS: In this retrospective observational study, using genomic and clinical data from TCGA, a radiotherapy-specific prognostic model for LUAD was developed and validated through ten machine learning algorithms. Survival analyses were conducted across distinct concomitant pharmacologic strategies, followed by functional enrichment to elucidate molecular mechanisms underlying differential outcomes. RESULTS: Demonstrating robust prognostic abilities, the model efficiently sorted patients into high- and low-risk categories. Both treatment type and risk score independently predicted overall survival, with significant interaction effects. Low-risk patients receiving targeted or combination therapy-mainly erlotinib, gefitinib, or bevacizumab-exhibited substantially improved survival compared with those receiving conventional chemotherapy. Enrichment of "Exogenous peptide presentation," "MHC class II assembly," "Peptide-MHC II assembly," and "Symbiotic interaction" pathways indicated immune modulation and host-tumor crosstalk as key mediators of treatment efficacy. CONCLUSION: This study establishes a radiotherapy-specific prognostic model for lung adenocarcinoma, demonstrating distinct molecular and therapeutic heterogeneity and highlighting the superior survival benefit of targeted combination therapy in low-risk patients.

Humans↗
PubMed1975

Competitive ability of amylolytic bacteria in activated sludge.

Shifts were induced into the microbial community of activated sludge by the pulse addition of soluble starch. The subsequent changes of amylolytic and proteolytic microbial populations were recorded. Four amylolytic strains were isolated and characterized with regard to carrying capacity, specific surface and growth kinetics. The competitive ability of these strains was studied by means of two-member competition experiments. These experiments were analysed according to the Lotka-Volterra model and the de Wit method. The different results obtained suggest that the dominance of the amylolytic Pseudomonas sp. (code 01) is based on a combined occurrence of high amylolytic activity, large relative cell surface, high maximum specific growth rate and reduced sensitivity towards associated proteolytic populations.

Aeromonas↗
PubMed2026

Transcriptome-wide association analysis of Alzheimer's disease: construction and clinical validation of transcriptomic risk scores.

Early identification of individuals at high risk for Alzheimer's disease (AD) is crucial for disease prevention and intervention. This study aims to develop AD-specific transcriptomic risk scores (TRSs) through multi-tissue transcriptome-wide association study (TWAS) and to evaluate its clinical utility in AD diagnosis and risk prediction. Using GWAS summary statistics combined with expression quantitative trait loci (eQTL) data from 14 tissues, a multi-tissue TWAS approach was applied to identify AD-associated genes. Peripheral blood RNA expression data from the ADNI and GEO databases were used to construct the AD-specific TRSs. The associations of TRSs with AD pathological features and cognitive function were assessed in two independent cohorts. Furthermore, the diagnostic performance, differential diagnostic capability, and risk prediction efficiency of TRSs were evaluated. The TWAS identified 131 genes significantly associated with AD. The TRSs were significantly elevated in patients with AD and mild cognitive impairment (MCI) compared to cognitively normal (CN) individuals, and showed significant correlations with AD pathological markers and cognitive performance. When combined with APOE4 status, the TRSs demonstrated robust diagnostic ability for AD and MCI. When combined with age, the TRSs showed good diagnostic performance in distinguishing AD from frontotemporal dementia (FTD) (AUC = 0.86). Additionally, the TRSs effectively predicted the risk of progression to AD in non-AD individuals (HR = 1.74). The AD-specific TRSs developed in this study shows promising clinical utility in AD diagnosis, differential diagnosis, and risk prediction, providing valuable translational medical evidence for early screening and precision prevention of Alzheimer's disease.

Humans↗
PubMed2025

Predicting telomerase reverse transcriptase promoter mutation status in glioblastoma by whole-tumor multi-sequence magnetic resonance texture analysis.

OBJECTIVE: This study aimed to determine the feasibility of preoperative multi-sequence magnetic resonance texture analysis (MRTA) for predicting TERT promoter mutation status in IDH-wildtype glioblastoma (IDHwt GB). METHODS: The clinical and imaging data of 111 patients with IDHwt GB at our hospital between November 2018 and June 2023 were retrospectively analyzed as the training set, and those of 23 patients with IDHwt GB between July 2023 and November 2023 were interpreted as the validation set. We used molecular sequencing results to classify the training set into TERT promoter mutation and wildtype groups. Textural features of the whole-tumor volume were extracted, including T2-weighted imaging (T2WI), T2-fluid-attenuated inversion recovery, apparent diffusion coefficient (ADC) map, and contrast-enhanced T1-weighted imaging (CE-T1). All textural features were obtained using open-source pyradiomics. After feature selection, logistic regression was used to build prediction models, and a nomogram was generated. Finally, the model was validated using validation cohort. RESULTS: The CE-T1_Model (AUC 0.704) had a better predictive ability than the T2_Model (AUC 0.684) and ADC_Model (AUC 0.624). The MRI_Combined_Model (CE-T1, T2, and ADC texture features) (AUC 0.780) had a better predictive ability than the Clinical_Model (AUC 0.758). The Combined_Model (CE-T1, T2, ADC texture features, and clinical features) had the best predictive performance (AUC 0.871), with a sensitivity, specificity, and accuracy of 82.60 %, 83.30 %, and 80.18 %, respectively. The AUC, sensitivity, specificity, and accuracy in the validation cohort were 0.775, 86.70 %, 75.00 %, and 69.57 %, respectively. CONCLUSIONS: Whole-tumor multi-sequence MRTA can be used as non-invasive quantitative parameters to assist in the preoperative clinical prediction of TERT promoter mutation status in IDHwt GB.

Humans↗
PubMed1977

Isoelectric focus analysis of rat anti-phosphocholine antibodies.

Anti-phosphocholine (PC) antibodies in sera from four strains of rats were examined before and afterimmunization with either Streptococcus pneumoniae R36A, which contains PC as a cell wall component, or with PC-coupled keyhole limpet hemocyanin (PC-KLH). PC-specific protein was purified from pooled immune sera and shown by a combination of isoelectric focus (IEF) in acrylamide and crossed immunoelectrophoresis, as well as by molecular weight determination in NaDodSO4-acrylamide, to be immunoglobulin. An additional, small molecular weight, nonimmunoglobulin protein (pI = 7.1-7.3) was present in sera from normal and germ-free rats which had the ability to bind the C-carbohydrate of S. pneumoniae R36A, but without specificity for PC. The IEF profile of normal and immune sera showed marked sharing of bands of anti-PC antibody between individual rats as well as between strains. In addition, other anti-PC antibodies which focused between pH 8.5 and 9.5 were less regularly shared. The uniformity of IEF profile of the bulk of anti-PC antibodies in rats is most consistent with their being the products of germ line genes.

Animals↗
PubMed1976

Interactions between narcotic analgesics and benzodiazepine derivatives on behavior in the mouse.

Interactions between the benzodiazepine derivatives, diazepam and oxazepam, and the narcotic analgesics, morphine and methadone, were evaluated on locomotor activity and in the tail-flick and hot-plate tests for analgesia in the mouse. The dose-related stimulation of locomotor activity by morphine was reduced by diazepam and oxazepam at doses which alone had no effect on locomotor activity. However, only oxazepam reduced the dose-related stimulation of locomotor activity by methadone. The observed decreases produced by diazepam and oxazepam were comparable in magnitude to those produced by naloxone. Stimulation of locomotor activity by d-amphetamine was not affected by either diazepam or oxazepam. Dose-response curves for locomotor activity were also determined with morphine and methadone administered intraventricularly. As before, diazepam and naloxone given i.p. decreased the stimulation of locomotor activity produced by morphine, but only naloxone affected methadone-stimulated locomotor activity. Neither diazepam, oxazepam nor naloxone reduced the brain or plasma levels of 3H-morphine or 3H-methadone. In contrast to the results on locomotor activity, neither of these benzodiazepines significantly modified the dose-response curves of morphine or methadone in either test for analgesia. The mechanisms involved in the observed interactions on locomotor activity may be related to the influences of benzodiazepines and narcotic analgesics on motor efferent pathways summating in such a manner as to interfere with the ability of the mice to locomote. The present results demonstrate that prominent interactions occur between members of the benzodiazepine and narcotic analgesic classes; these interactions are dependent upon both the specific combination of drugs administered and upon the test procedure.

Analgesics, Opioid↗
PubMed2026

Next-generation newborn screening: feasibility of combined genetic and biochemical testing for 95 treatable inherited metabolic disorders.

INTRODUCTION: Next-generation sequencing (NGS) is gaining attention in newborn screening (NBS) for its ability to detect treatable genetic disorders, especially those without a biochemical footprint. However, NGS-NBS requires interpreting variants without phenotype information or family trio analysis. Biochemical tests, preferably in dried blood spots (DBS), are therefore useful to confirm the pathogenicity of variants identified by NGS-NBS and increase its specificity and sensitivity. OBJECTIVES: We aimed to explore the potential of combined genetic-biochemical testing for 95 treatable Inherited Metabolic Disorders (IMD) considered eligible for NGS-NBS (100 genes) previously identified by our research group. METHODS: We reviewed the Collaborative Laboratory Integrated Reports (CLIR) and carried out systematic literature reviews in PubMed and Embase to identify biochemical tests for 95 IMD. Biochemical tests conducted on DBS were differentiated from tests that require referral. RESULTS: We identified DBS-biochemical tests for 72 of the 95 IMD (77/100 genes). DBS-based biochemical tests for 55 IMD (60 genes) are already implemented in NBS. For the other 23 IMD, biochemical tests in non-DBS specimens are reported, although some are less sensitive when measured at neonatal age in presymptomatic infants. CONCLUSION: We present a comprehensive overview of current biochemical tests for 95 IMD. These tests can be used to confirm inconclusive NGS-NBS results, and combined genetic-biochemical testing is expected to improve both the negative and positive predictive values of NBS programs.

Humans↗
PubMed1976

The vasodilator--beta-blocker interaction--some determinants of its clinical success.

A number of structurally dissimilar compounds, sharing the ability to induce vasodilatation have come into clinical usefulness as antihypertensive drugs. Their successful utilisation often depends critically on an appropriate combination with diuretics and beta-blockers. Beta-blockers can specifically inhibit the reflex cardiac stimulation which otherwise may limit the tolerability and haemodynamic value of these drugs. A synergistic antihypertensive effect has been demonstrated with hydrallazine and propranolol and possibly exists with other combinations. Generally, vasodilators are not first-line drugs in chronic therapy but are best added to beta-blockers. Variations of the dose-response and the time-course of effect are stressed as being important determinants of a successful interaction.

Adrenergic beta-Antagonists↗
PubMed1978

Immunochemical studies on dextran-specific and levan-specific myeloma proteins from NZB mice.

Two dextran-specific (PC 3858 and PC 3936) and one levan-specific (PC 3660) NZB myeloma proteins were studied by quantitative precipitin and precipitin-inhibition assays. Both myeloma antidextrans were alphaD-(1 leads to 6) specific and precipitated strongly with a synthetic, linear dextran, molecular weight 35,500, and with other dextrans. The two myeloma antidextrans differed with respect to their relative reactivities with dextrans containing various proportions of alpha-D-(1 leads to 6), alpha-D-(1 leads to 4)-like, and alpha-D-(1 leads to 3)-like linkages. In inhibition assays, the two antidextran myeloma proteins behaved differently from each other, from alpha-D-(1 leads to 6)-specific BALB/c myeloma antidextrans, and from the human antidextrans previously studied. Isomalto-oligosaccharides IM3, IM4, and IM5 were all equal in inhibitory power but were only about 60% as potent as IM6 and IM7, which also inhibited equally on a molar basis. Although precipitation with linear dextran suggests that both may have groove-type sites, as previously inferred for QUPC 52, the size of their combining sites is uncertain. It is not clear whether the sites are only as big as three glucose residues with the increased inhibition by six and seven glucose residues being attributable to partial bivalence and to their ability to combine in several ways along the chain, or whether the site is as big as six glucose residues with the increment in binding by the fourth and fifth glucose residues being minimal and the sixth contributing considerable additional binding-energy. The fructan-specific myeloma protein did not react with inulin, but reacted with many levans and with perennial rye-grass levan containing only beta-D-(2 leads to 6) links. The levan-antilevan reaction was not inhibited by beta-D-(2 leads to 1)- linked oligosaccharides. The findings suggest that PC 3660 has a specificity for (2 leads to 6)-linked chains.

Animals↗
PubMed1978

Inhibition of MLC responder and stimulator function with allo-antisera in rhesus monkeys.

Ten antisera containing antibodies directed against specificities controlled by the Ia1 locus of rhesus monkeys were tested for their ability to inhibit the MLC reaction. In cultures with responding cells from the serum producer, all sera with anti-Ia1 activity depressed the stimulatory capacity of cells carrying the Ia1 antigen in question. In other responder/stimulator combinations, the stimulation-inhibition was Ia1-related for the majority of the antisera. These data provide further evidence for a possible identity (or close association on the cell membrane) between Ia1 and D locus determinants of rhesus monkeys. In addition, some sera showed an inhibitory effect also on responder cells (with cells from the serum producer as stimulators). There was no apparent relation of response inhibition to the Ia1 specificities detected by antisera.

Animals↗