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At least 19 recordsLinked to original sources
PubMed2026

Revealing Hidden Variables in DESI-Based Spatial Metabolomics: Solvent Composition and Tissue Type as Critical Drivers.

In the development of a desorption electrospray ionization (DESI) workflow for spatial metabolomics, we investigated the impact of two commonly used solvent systems, 90% acetonitrile (ACN) and 90% methanol (MeOH), on the spatial metabolomic profiling of various murine tissues. The performance of both solvents was evaluated across several metabolite classes (central carbon metabolites, amino acids, and fatty acids). Although the ACN-based solvent system led to higher signal intensities for small polar metabolites involved in glycolysis, the tricarboxylic acid (TCA) cycle, and amino acid metabolism, the MeOH-based solvent system provided superior signal intensities for fatty acids. These findings demonstrate that the solvent composition differentially influences metabolite extraction and ionization processes in DESI and should be carefully matched to the biological questions and metabolite classes of interest. As a proof-of-principle, the ACN solvent system was applied to a pilot study based on a rat model of renal ischemic injury, revealing region-specific metabolic changes between normoxic and ischemic conditions. Together, these results demonstrate the importance of solvent selection in DESI-based spatial metabolomics and showcase the ability of this approach to uncover spatially resolved metabolic adaptations associated with tissue injury.

Animals↗
PubMed1976

Hidden genetic variability within electromorphs in finite populations.

The amount of hidden genetic variability within electromorphs in finite populations is studied by using the infinite site model and stepwise mutation model simultaneously. A formula is developed for the bivariate probability generating function for the number of codon differences and the number of electromorph state differences between two randomly chosen cistrons. Using this formula, the distribution as well as the mean and variance of the number of codon differences between two identical or nonidentical electromorphs are studied. The distribution of the number of codon differences between two randomly chosen identical electromorphs is similar to the geometric distribution but more leptokurtic. Studies are also made on the number of codon differences between two electromorphs chosen at random one from each of two populations which have been separated for an arbitrary number of generations. It is shown that the amount of hidden genetic variability is very large if the product of effective population size and mutation rate is large.

Codon↗
PubMed2025

Simultaneous inference for generalized linear models with unmeasured confounders.

Tens of thousands of simultaneous hypothesis tests are routinely performed in genomic studies to identify differentially expressed genes. However, due to unmeasured confounders, many standard statistical approaches may be substantially biased. This paper investigates the large-scale hypothesis testing problem for multivariate generalized linear models in the presence of confounding effects. Under arbitrary confounding mechanisms, we propose a unified statistical estimation and inference framework that harnesses orthogonal structures and integrates linear projections into three key stages. It begins by disentangling marginal and uncorrelated confounding effects to recover the latent coefficients. Subsequently, latent factors and primary effects are jointly estimated through lasso-type optimization. Finally, we incorporate projected and weighted bias-correction steps for hypothesis testing. Theoretically, we establish the identification conditions of various effects and non-asymptotic error bounds. We show effective Type-I error control of asymptotic-tests as sample and response sizes approach infinity. Numerical experiments demonstrate that the proposed method controls the false discovery rate by the Benjamini-Hochberg procedure and is more powerful than alternative methods. By comparing single-cell RNA-seq counts from two groups of samples, we demonstrate the suitability of adjusting confounding effects when significant covariates are absent from the model.

Hidden variables↗
PubMed2026

Population-scale detection of methylation outliers from long-read genome sequencing.

BACKGROUND: Aberrant DNA methylation can mediate the functional effects of rare genetic variation and contribute to imprinting disorders, repeat expansion diseases, and other pathogenic regulatory mechanisms. Long-read sequencing technologies now enable genome-wide detection of CpG methylation alongside genetic variation from a single assay. However, methods for systematic identification and interpretation of methylation outliers from long-read sequencing data remain limited. METHODS: We developed METAFORA, a computational workflow for detecting methylation outlier regions from PacBio and Oxford Nanopore long-read sequencing data. METAFORA constructs population-level methylation references, segments the genome into correlated CpG blocks, infers technical and biological sources of variation through hidden factor estimation, models uncertainty due to variable depth sequencing, and computes covariate-adjusted methylation outlier scores for individual samples. We applied METAFORA across large long-read sequencing cohorts and integrated methylation outliers with multi-omic data. METAFORA is implemented as a snakemake workflow available at https://github.com/tjense25/METAFORA. RESULTS: METAFORA identified methylation outlier regions associated with rare structural variants, tandem repeat expansions, and imprinting abnormalities. We found outlier regions were enriched for molecular outliers across transcriptomic and chromatin accessibility datasets, supporting their functional relevance in gene regulation. In a representative case, METAFORA identified an imprinting defect affecting the GNAS locus associated with an STX16 deletion. CONCLUSIONS: METAFORA enables scalable detection and interpretation of methylation outliers from long-read sequencing data and provides a framework for integrating epigenetic outliers with genomic and multi-omic analyses. These approaches may improve interpretation of rare regulatory variation and support discovery of clinically relevant epigenetic abnormalities in genomic medicine.

DNA methylation↗
PubMed1978

Street heroin potency and deaths from overdose in San Antonio.

Disagreement over the mechanism of death in so-called heroin overdose has been noted in the medical literature for more than a decade. We studied the relationship between the potency of street heroin and the frequency of heroin overdose deaths in San Antonio in order to test the "pharmacologic overdose" hypothesis. We found a small, nonsignificant correlation (r=+.13) between monthly mean heroin dose and monthly number of heroin overdose deaths over a 5-year period. This low correlation contradicts findings of previous studies in Washington, D.C. and Atlanta, conducted over shorter periods of time, in which high positive correlations were found. The low correlation does not support the pharmacologic overdose hypothesis. Since there were confounding variables, the data do not refute the hypothesis. These variables include the use of alcohol and other depressants, hidden suicide, and reduced opioid drug tolerance due to institutional treatment.

Drug Packaging↗
PubMed1979

Capping of variable antigen on Trypanosoma brucei, and its immunological and biological significance.

Pathogenic trypanosomes undergo antigenic variation, whereby the glycoprotein molecules constituting the cell coat are changed, the parasite thus evading the host's immune response. On application of homologous antiserum in indirect immunofluorescence to a given variable antigen type of Trypanosoma brucei, the surface variable antigen moves to the flagellar pocket region, which overlies the Golgi apparatus. This redistribution, or capping, is temperature-dependent, occurring at 37 degrees C but not at 0-4 degree C. Patching does not occur at either temperature. Immediately after capping no homologous or heterologous variable antigen, or host plasma or blood cell antigens, can be detected by immunofluorescence on the cell surface outside the cap; only trypanosome membrane common antigens can be found. It seems unlikely for two reasons that this antibody-induced redistribution is relevant to antigenic variation. Capping of the coat requires the indirect, rather than the direct, immunofluorescent method; a single layer of antibody, in nature, would appear to be ineffective. Also, capping of variable antigen of one type is followed within 3 h by appearance of antigen of the same, and not another, type. The necessity for 2 antibody layers is usually thought of as meaning that the individual molecules of the cell surface antigen are spaced further apart than the binding sites of an individual antibody molecule, so that the necessary cross-linked lattice cannot be formed, but on T. brucei the surface variable antigen molecules are very closely packed. It is proposed that one layer of antibody is ineffective for steric reasons; the dimensions of the exposed face of each variable antigen molecule may not permit the binding of more than one molecule of immunoglobulin, or perhaps the antigen molecules are so closely packed that most of the antigenic determinants are hidden from antibodies. To test this hypothesis, an attempt was made to cap variable antigen on trypanosomes transforming in vitro from the bloodstream to the procyclic (insect midgut) stage; such forms have a much less densely packed surface coat. Patching was observed, indicative of lattice formation, but these trypanosomes did not survive the in vitro manipulation long enough to permit any possible capping. T. brucei differs structurally from most other eukaryotic cells. It has no detectable microfilaments under the plasma membrane, except at the desmosomes in the region of flagellar binding, and it also has a pellicular cortex of microtubules. Capping of its surface antigen would appear then to differ from that on mammalian cells, either in the cellular components involved or in that specialized areas of the plasma membrane are involved.

Animals↗
PubMed1992

Anti-histone autoantibodies recognize centromeric heterochromatin in metaphase chromosomes and hidden epitopes in interphase cells.

IgM autoantibodies from a subset of patients with undifferentiated rheumatic disease syndromes stained mouse kidney nuclei with a distinctive variable large-speckled (VLS) indirect immunofluorescence (IIF) pattern. However, these antibodies did not stain nuclei of tissue culture cells prepared with conventional fixation. These sera were shown to react with histone H3 by an enzyme-linked immunosorbent assay (ELISA), and adsorption with H3 reduced or eliminated the IIF reaction. Sera yielding a VLS-IIF pattern reacted in ELISA with all three H3 variants as well as the native (H3-H4)2 tetramer, but the reactive determinants were unavailable for binding when chromatin was the substrate. By IIF assay, the epitopes were exposed after treatment of tissue culture cells with 0.5 M NaCl, and were removed by 1.5 M NaCl. These sera also stained the centromeric region of metaphase chromosomes. These observations suggest that the VLS-IIF pattern is due to antibodies that recognize epitopes on constitutive heterochromatin near the centromere. The epitopes are exposed in differentiated cells but hidden in dividing cells. Histone in heterochromatin, or CENP-A, a histone-like protein in the centromere with a sequence similarity to histone H3, are candidates for the target antigen.

Autoantibodies↗
PubMed1979

Intracellular synaptic potentials of primate motor cortex neurons during voluntary movement.

An intracellular recording technique was applied to the precentral motor cortex of the unanesthetized, chronically behaving monkey. Postsynaptic potentials, responsible for an initiation of the voluntary movement, were recorded. In total, 22 pyramidal tract neurons (PTNs) and 40 non-pyramidal tract neurons (non-PTNs) were successfully penetrated in 5 monkeys while the monkey was performing a flexion-extension wrist movement after a visual cue (reaction time, 200--350 msec). The neurons showed a negative membrane potential shift of at least 30 mV for more than 30 sec. A slowly rising PSP appeared 80--180 msec after the visual cue, and was 70--180 msec prior to an onset of the movement. Spike activities were superimposed upon this slow PSP with 20--80 msec rise time and 2--6 mV depolarization (8 PTNs and 6 non-PTNs). Since these depolarizations were variable in magnitude and latency, these were considered to be summated potentials of small EPSPs and hidden IPSPs. Membrane resistance was measured from an IR drop by a hyperpolarizing current (1.2 X 10(-9) A) passed through a recording electrode, and was 3.5 +/- 1.7 Momega in 18 PTNs and 4.5 +/- 2.5 Momega in 28 non-PTNs. There was a linear relationship in PTNs between membrane resistance and antidromic latency from the pontine pyramid. Because of the time course of PSPs, their possible dendritic origins were discussed.

Animals↗
PubMedDate not supplied

Examination of microheterogeneity in grass pollen allergens.

The separation of timothy pollen extract by two-dimensional immunoblotting revealed microheterogeneity of the major allergens PhI p I and PhI p V. There was not only a diversity in size, 38 and 32 kDa for PhI p V and 37, 35, and 33 kDa for PhI p I, but also a separation into proteins of identical sizes but different pIs. Since former studies on the protein structure by amino acid analysis and N-terminal microsequencing did not reveal any differences, we examined other possibilities that might cause microheterogeneity. In allergens belonging to the PhI p I group, the variability in pI can be due to the carbohydrate structure and to the fact that charges are hidden in the interior of the protein, as shown by varying concentrations of urea. On the other hand we were not able to detect any such reasons for the existence of PhI p V isoallergens. Thus, we assume that they are stable conformational isomers of the proteins (allomorphism) or that there are only slight variations in the internal sequences of these proteins (polymorphism) causing distinct pIs.

Allergens↗
PubMed1979

The regularity of muscle spindle discharge in man.

1. The variability of discharge of thirty-nine muscle spindle afferents from the pretibial muscles of normal human subjects was determined for spike train sequences recorded with the ankle joint fixed in 25 degrees plantar flexion, during further stretch and during graded voluntary contractions of the receptor-bearing muscle. 2. In non-contracting muscles with the ankle joint in 25 degrees plantar flexion, a sustained discharge was maintained by twenty-four of the thirty-nine endings. The mean discharge frequency for the active endings was 11.1 Hz (range 4.8--22.1 Hz), the mean coefficient of variation 0.073 (range 0.021--0.183). With further stretch, the discharge of endings maintaining frequencies below 10--12 Hz became more regular. For endings maintaining higher frequencies, changes in the coefficient of variation were small and occurred in either direction. All secondary endings maintained a highly regular discharge, but, at these frequencies, there was no statistically significant difference in the variability of primary and secondary endings. 3. It is considered that these findings are comparable to those of Matthews & Stein (1969) for de-efferented feline spindle endings, and support the view that there is no functionally effective background fusimotor drive to non-contracting muscles of normal human subjects. 4. A voluntary contraction sufficient to accelerate a spindle ending invariably decreased the regularity of its afferent discharge. During voluntary contractions, coefficients of variation up to 0.345 were recorded. However, coefficients as low as 0.1 were not uncommon, and thus the absence of fusimotor drive cannot necessarily be inferred from a regular afferent discharge pattern. 5. With contractions of different strength, the increase in the coefficient of variation did not parallel the increase in discharge frequency. It is concluded that not all fusimotor influences acting on a spindle ending are translated into variability, and that measurements of the variability of discharge do not accurately reflect the level of fusimotor drive. 6. The discharge frequency of some spindle endings decreased slightly in some contractions and this was accompanied by an increase in the variability of discharge. It is suggested that contracting extrafusal muscle fibres can modulate the discharge pattern of spindle endings and contribute to the variability of discharge during a voluntary contraction. 7. In contracting muscles the irregular fusimotor-driven spindle discharge contained a 'hidden' periodicity, but this was not as extensive as has been reported for the cat. No such periodicity could be demonstrated for spindle endings in non-contracting human muscles.

Action Potentials↗
PubMed1977

[Basic patterns in the formation of sluggish schizophrenia according to epidemiologic findings].

The study is based on clinico-epidemiological data concerning sluggish schizophrenia revealed in 214 patients. Conclusions of the formation of a slowly progressive process are made by a retrospective clinical analysis of the disease from the initial period, to the ordinal transition of syndromes, up to the moment of the interview. The unification of the assessment of the present state was accomplished with the aid of a glossary of syndromes. Despite the clinical variants of sluggish schizophrenia the author established some general regularities in the development of the disease with 3 stages. In such forms of the process during the 2nd stage the clinical variability disappears and is substituted by monomorphity. The negative symptoms appear early during the first stage but during decades they may remain hidden by vividly expressed pseudoneurotic and psychopath-like syndromes.

Humans↗
PubMed2026

Hidden diversity of coronaviruses in high-altitude plateau mammals.

• Pikas and marmots from plateaus host divergent α- and β-CoVs, including the candidate subgenera Pibecovirus and Mabecovirus. • The plateau CoVs show distinctive genomic features (relocated HE gene, variable ORFs), indicating lineage-specific evolution. • High-altitude plateau ecosystems are a key yet understudied frontier of CoV evolution, warranting systematic surveillance.

Journal Article↗
PubMed1979

Smooth pursuit eye movements and optokinetic nystagmus elicited by intermittently illuminated stationary patterns.

Stationary periodic visual patterns (row of equally spaced dots or black-white stripes) of the period Ps illuminated stroboscopically with a flash frequency fs induce an apparent movement perception (sigma-movement) when slow eye movements are performed across the periodic pattern. The movement appears in the direction of the eye movements when the angular speed VE of the eyes corresponds to the following condition: Ve = k . Ps . fs [deg . s-1] (1) k is a constant and equals 1 (or exceptionally 2 or 3). The sigma-movement induces a sigma-OKN with an average angular speed of its slow phases corresponding to Eq.(1). sigma-OKN can be elicited when identical foveal or identical extrafoveal stimulus patterns are applied from flash to flash. A considerable random variability of the flash sequence does not interrupt the sigma-movement and the sigma-OKN. Both phenomena can also be elicited by a stimulus pattern with its periodicity hidden in spatial noise and this periodic pattern only becomes visible during the eye movements. It is argued that the sigma-phenomena are caused by efference copy signals of the gaze control system, which interact with the afferent signals (displacement of visual stimuli on the retina) at different levels of the afferent visual system. One interaction is supposed at a cortical level where the extrapersonal visual space is represented.

Adult↗
PubMed1992

Interassay variability of immunometric methods for thyrotropin in an external quality assessment survey: evidence that functional sensitivity is not always adequate for clinical decisions.

We investigated the ability of current immunometric methods for thyrotropin (TSH; thyroid-stimulating hormone) to distinguish between low-normal and subnormal hormone concentrations by using the data from an external quality assessment (EQA) survey in 1990. We computed the interassay (between-run) precision profiles from results from 101 laboratories, which used the five most popular kits in the survey; during the control period (one year) each laboratory assayed 4 EQA pools distributed (as hidden replicates) in five occasions. The interassay CV was relatively low (9-13%) for three pools in the normal TSH range (greater than 0.8 milli-int. unit/L) but markedly higher (30-40%, except for one more precise kit) in the subnormal range (0.2 milli-int. unit/L). We calculated the effect of the between-run variability on the diagnostic accuracy (discrimination between normal and subnormal values) for three representative TSH concentrations: 0.2, 0.4, and 0.5 milli-int. unit/L (0.3 milli-int. unit/L was considered the lower normal limit). The three concentrations were reasonably discriminated (P less than or equal to 5%), and only one kit showed a between-run CV less than 18% at 0.2 milli-int. unit/L. For the other four less-precise kits, only the higher TSH value (0.5 milli-int. unit/L) could be classified with an acceptable diagnostic reliability. With the most precise kit, one can distinguish two TSH concentrations in the 0.3-0.5 milli-int. unit/L range that differ by at least 30%; with the other kits, differences greater than 50-60% are needed for reliable discrimination. Thus many laboratories fail to achieve the functional sensitivity of a second-generation assay, even if they use immunometric methods. TSH assays with a better interassay precision in the low concentration range are needed.

Humans↗
PubMed2025

Annotation of RxLR Effectors in Oomycete Genomes.

Pathogens have evolved effector proteins to suppress host immunity and facilitate plant infections. RxLR effectors are small, secreted effector proteins with conserved RxLR and dEER amino acid motifs at the N terminus and highly variable C termini and are commonly found in oomycete species. We provide computational approaches to annotate RxLR candidate effector genes in a genome assembly in FASTA format with an available GFF file. Hidden Markov Modeling (HHM) is used in combination with regular expressions to search for RxLR and EER amino acid patterns.

Oomycetes↗
PubMed1979

Effects of some social variables on field dependence.

The effects of socio-economic status, father's absence, family size, and birth order on the field dependence of Grade 6 elementary school children in Jamaica, West Indies, were examined. To 206 boys and 212 girls from 5 urban schools the Hidden Figures Test and a questionnaire were administered. For girls, but not for boys, field independence correlated significantly and positively with socio-economic status, but significantly and negatively with father's absence. No significant relation existed for the boys. Field dependence had no significant relation with family size and birth order.

Birth Order↗
PubMed2026

Analyzing the impact of subcutaneous injection needle, device, and administration characteristics on patient pain, anxiety, and safety: a systematic literature review.

The subcutaneous (SC) injection route is a commonly used and important method for therapeutic delivery of a wide range of compounds, and needle characteristics have a significant influence on patient pain, anxiety, safety, and other outcomes. This systematic review evaluates the evidence on how needle-specific characteristics (e.g. gauge, length, tip design, wall thickness, concealment) and administration- or device-related factors can affect patient-reported outcomes and clinical safety indicators during and following SC injections. A comprehensive search was conducted in MEDLINE, PubMed, Embase, and ClinicalTrials.gov in June 2024. Studies were included if they assessed the relationship between needle characteristics and pain, anxiety, safety, or related outcomes in individuals receiving SC injections. A dual-reviewer process was used for study selection, data extraction, and quality assessment. Sixty-two studies met inclusion criteria. Evidence consistently indicated that thinner and shorter needles reduced patient-reported pain and adverse events such as bruising and bleeding. Tapered and lubricated needles, hidden or retractable needle designs, and use of autoinjectors or prefilled syringes also contributed to reduced anxiety and improved user satisfaction. However, results were heterogeneous, and many studies lacked sufficient power or single-variable evaluation of individual needle parameters, limiting definitive conclusions. Needle characteristics significantly influence patient experience and safety with SC delivery. While both clinical evidence and practical experience clearly favor thinner, shorter, and concealed needles, further standardized, high-quality research is needed to isolate and quantify the specific contributions of individual needle characteristics to optimize injection practices and support patient-centered device design.

Humans↗