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The role of biologically effective dose (BED) in clinical oncology.

There are many clinical situations in which radiobiological considerations can be usefully applied and all clinicians should be aware of the potential benefits of developing a quantitative radiobiological approach to their practice. The concept of biologically effective dose (BED) in particular is useful for quantifying treatment expectations, but clinical oncologists should recognize that careful interpretation of modelling results is required before clinical decisions can be made and that there is a lack of reliable human parameters for application in some situations. Correct use of the BED concept will, in more complex treatment situations, sometimes involve the use of multiple parameters and BED calculations. Examples include: 1. Where the dose per fraction is being altered and it is possible that normal tissue tolerance may be compromised, calculations should include two or more alpha/beta ratio values, some being less than 3 Gy, in order to estimate the 'worst case scenario'. 2. A single one-point BED calculation will not be representative of the biological effect throughout a large planning target volume where there are significant 'hot spots'. Multiple BED evaluations are then indicated. 3. Where there are combinations of radiotherapy treatments or phases of treatments, these can be quantitatively assessed by the addition of BEDs, although the volume of tissue is not inherently included in the BED calculation and any high-dose region needs to be separately assessed as in point 2. 4. Allowance for tumour clonogen repopulation during therapy is required for some tumour types. 5. Different histological classes of cancers require the use of different alpha/beta ratios. Where there is reasonable doubt regarding this parameter, a suitable range should be used. The principles involved are illustrated by worked examples. Attention to detail and the examination of ranges of possible results should offer a safer guide to alternative dose fractionation schedules, although the ultimate choice will be tempered by clinical circumstances.

Dose Fractionation, Radiation↗

Spectroscopic investigation of nonbonding interactions of group-14 atoms with rare gases: the SnAr van der Waals complex.

The laser fluorescence excitation spectra of the SnAr van der Waals complex, in the vicinity of the individual fine-structure lines of the Sn 5s25p6s3P0<-- 5s25p2(3)P atomic resonance transition in the spectral region 317-270 nm are reported. Excited-state (v',0) progressions of bands built upon the individual J'<-- J" fine-structure atomic lines were observed. Because the collisional spin-orbit relaxation was slow, transitions were observed out of the lower SnAr states built upon all the J'' atomic asymptotes. The spectra were interpreted through model potential energy curves based on the isoelectronic SiAr system. Lower bounds to the dissociation energies of all lower SnAr states were determined. The binding energies of the group-13, and -14-atom-argon complexes and the effect of the spin-orbit interaction on moderating nonbonding interactions are discussed.

Journal Article↗

Electronic states of linear Au clusters supported on metal surfaces: why are they like those of a particle in a box?

Scanning tunneling spectroscopy and microscopy show that the empty states of linear Au clusters supported on a metal surface behave as if they are the states of an electron in an empty one-dimensional box. We show here that certain difficulties of this description are removed by a particle-in-a-cylinder model. This interpretation is supported by density functional calculations.

Journal Article↗

Adsorption and diffusion on a stepped surface: atomic hydrogen on Pt(211).

We present density functional theory calculations for atomic hydrogen interacting with a stepped surface, the Pt(211) surface. The calculations have been performed at the generalized gradient approximation level, using a slab representation of the surface. This is the state-of-the-art method for calculating the interaction of atoms or molecules with metal surfaces, nevertheless only few studies have used it to study atoms or molecules interacting with stepped surfaces, and none, to the best of our knowledge, have considered hydrogen interacting with stepped platinum surfaces. Our goal has been to initiate a systematic study of this topic. We have calculated the full three-dimensional potential energy surface (PES) for the H/Pt(211) system together with the vibrational band structure and vibrational eigenfunctions of H. A deep global minimum of the PES is found for bridge-bonded hydrogen on the step edge, in agreement with experimental results for the similar H/Pt(533) system. All the local vibrational excitations at the global minimum have been identified, and this will serve as a helpful guide to the interpretation of future experiments on this (or similar) system(s). Furthermore, from the calculated PES and vibrational band structure, we identify a number of consequences for the interpretation or modelling of diffusion experiments studying the coverage and directional dependence of atomic hydrogen diffusion on stepped platinum surfaces.

Journal Article↗

Molecular reorientation in hydrogen-bonding liquids: through algebraic approximately t-32 relaxation toward exponential decay.

We present a model for the description of orientational relaxation in hydrogen-bonding liquids. The model contains two relaxation parameters which regulate the intensity and efficiency of dissipation, as well as the memory function which is responsible for the short-time relaxation effects. It is shown that the librational portion of the orientational relaxation is described by an algebraic approximately t(-32) contribution, on top of which more rapid and nonmonotonous decays caused by the memory effects are superimposed. The long-time behavior of the orientational relaxation is exponential, although nondiffusional. It is governed by the rotational energy relaxation. We apply the model to interpret recent molecular dynamic simulations and polarization pump-probe experiments on HOD in liquid D(2)O [C. J. Fecko et al., J. Chem. Phys. 122, 054506 (2005)].

Journal Article↗

Origins of metabolic diversity: evolutionary divergence by sequence repetition.

Recurring patterns of primary structure have been observed in enzymes that mediate sequential metabolic reactions in bacteria. The enzymes, muconolactone Delta-isomerase [(+)-4-hydroxy-4-carboxymethylisocrotonolactone Delta(2)-Delta(3)-isomerase, EC 5.3.3.4] and beta-ketoadipate enol-lactone hydrolase [4-carboxymethylbut-3-enolide(1,4)enol-lactone-hydrolase, EC 3.1.1.24], have been coselected in bacterial populations because the isomerase can confer no nutritional advantage in the absence of the hydrolase. Similar amino acid sequences recur within the structure of the isomerase, and the amino-terminal amino acid sequence of the isomerase from Pseudomonas putida appears to be evolutionarily homologous with the corresponding sequence of a beta-ketoadipate enol-lactone hydrolase from Acinetobacter calcoaceticus. One interpretation of the sequence repetitions is that they reflect tandem duplication mutations that took place early in the evolution of the proteins. According to this view, the mutations caused elongation of structural genes and the creation of duplicated genes as the metabolic pathways evolved. A review of the sequence data calls attention to a different hypothesis: repeated amino acid sequences were introduced in the course of the proteins' evolution by substitution of copies of DNA sequences into structural genes. Our observations are interpreted on the basis of a model proposing genetic exchange between misaligned DNA sequences. The model predicts that misalignments in one chromosomal region can influence the nature of mutations in another region. Thus, as often has been observed, the mutability of a base pair will be determined by its location in a DNA sequence. Furthermore, the intrachromosomal recombination of DNA sequences may account for complex genetic modifications that occur as new pathways evolve. The model provides an interpretation of an apparent paradox, the rapid creation of new metabolic traits by bacterial genomes that are remarkably resistant to genetic drift.

Amino Acid Sequence↗

The effect of inactivity on dietary intake and energy homeostasis.

Reduced physical activity commonly occurs in patients with disease or chronic disabilities, in the elderly, and in certain patients with obesity. Surprisingly, information on the effect of inactivity on energy homeostasis is scarce and often difficult to interpret. In models of reduced physical activity, such as space flights, bed-rest and confinement, subjects frequently lose weight (< 5%), predominantly in the form of fat-free mass. In some cases this is compensated by an increase in fat mass, which means that changes in weight are poor indicators of energy balance. The extent to which spontaneous reduction in energy intake (in most studies energy intake is fixed) compensates or overcompensates for the reduction in energy expenditure (mainly physical activity and to a small extent in BMR, typically < 6%) is largely underexamined. Preliminary observations suggesting that there is a preferential selection of low-energy-dense foods (low in fat) require confirmation under carefully controlled experimental conditions. It is concluded that a comprehensive and systematic evaluation is needed to address the effects and relevance of various degrees of physical inactivity to energy homeostasis, in relation to disease and space medicine.

Anorexia↗

Changes in food habits among Pakistani immigrant women in Oslo, Norway.

OBJECTIVE: South Asians are generally known to have high prevalence of diabetes type 2 and coronary heart diseases. The Pakistani immigrant group in Norway constitute a high-risk subgroup of the population that needs a selective prevention approach. The main objective of this study was to provide information on dietary change and factors leading to these changes in Pakistani women after migration from Punjab, Pakistan to Oslo, Norway. Such information is important in designing appropriate strategies for dietary counselling. DESIGN: Twenty-five Pakistani immigrant women, recruited through the Oslo Health Study 2000-2001, participated in focus group interviews. Each group met four times, aided by a moderator and professional interpreters. A model developed by Koctürk was tested for its usefulness in analysing the dietary changes. PRECEDE was used to organise and structure the factors that were found to cause the changes. RESULTS: According to the women, life in Norway has led to several changes in meal pattern, meal composition and intake of different foods. In accordance with the Koctürk model, the cultural importance of breakfast and lunch has diminished, and dinner has become the most important meal. Meals on weekends tend to be more traditional than on working days. The study gives limited support to the hypothesis that changes occur predominantly among the accessory foods and least among staples. The focus group interviews revealed a rich variety of factors influencing dietary change: health aspects, children's preferences, work schedules, social relations, stress, traditional beliefs, climate, season and access of foods. CONCLUSION: To develop effective intervention strategies, it is vital to understand both how changes do occur and how different factors influence dietary habits. The Koctürk model was useful to structure the various foods and changes that may occur. Strategies for dietary counselling should not only include dietary advice but also focus on the multitude of factors causing dietary changes.

Adult↗

CAUSAL artificial intelligence and data-driven decision intelligence in personalized medicine: a review of healthcare informatics systems.

This review examines the integration of causal artificial intelligence (AI) and data-driven decision intelligence within healthcare informatics systems to advance personalized medicine and clinical decision-making. A narrative review methodology was employed, synthesizing interdisciplinary literature from major databases, including PubMed, Scopus, Web of Science, IEEE Xplore, and ScienceDirect. Studies focusing on causal inference, decision intelligence, and healthcare informatics applications in personalized medicine were included. Data were extracted on methodological approaches, healthcare settings, analytical techniques, and clinical applications, followed by thematic synthesis. Findings indicate that causal AI enhances clinical decision support by enabling estimation of treatment effects and simulation of intervention outcomes at the individual patient level. Integration of multimodal health data such as electronic health records, genomic data, and real-time monitoring improves prediction accuracy and supports tailored treatment strategies. Additionally, causal models improve interpretability, fostering clinician trust and facilitating transparent decision-making. Robust healthcare informatics infrastructures, including interoperable systems and data warehouses, were identified as critical enablers of causal analytics. Overall, causal AI represents a transformative advancement in healthcare analytics, supporting more informed, individualized, and evidence-based clinical decisions. Its integration within healthcare informatics systems has significant potential to improve patient outcomes and guide the future of intelligent, personalized healthcare delivery.

Precision Medicine↗

Exposure to intermittent high altitude induces different changes in adenylyl cyclase activity in hearts of young and adult Wistar rats.

This study investigates changes of adenylyl cyclase activity in the heart of young and adult Wistar rats exposed to experimental conditions simulating high altitude hypoxia as a model for interpretation of some adaptive changes of adenylyl cyclase observed in human. The exposure of rats to intermittent high altitude (IHA) hypoxia (5000 m) showed significant adaptive changes. The right ventricular weight and the ratio of right/left ventricular weights of adult rats exposed to IHA were significantly increased when compared to appropriate controls; adaptive changes of cardiac adenylyl cyclase being dependent on the age of the animals. The isoprenaline-stimulated activity was higher in the left than in the right ventricle, and in both ventricles it was higher in young rats than in adult rats. When compared to controls, isoprenaline stimulation was decreased in the right ventricles of adapted young rats and, by contrast, it was increased in the left ventricles of adapted adult rats. This decrease and increase of adenylyl cyclase activity evoked by isoprenaline was paralleled by forskolin-induced adenylyl cyclase activity in these experimental groups. It seems therefore that the changes in the pattern of total adenylyl cyclase activity observed under IHA hypoxia may at least be partially explained by the changes of beta-adrenergic receptor susceptibility following IHA hypoxia.

Adaptation, Physiological↗

Visualization of melanosome dynamics within wild-type and dilute melanocytes suggests a paradigm for myosin V function In vivo.

Unlike wild-type mouse melanocytes, where melanosomes are concentrated in dendrites and dendritic tips, melanosomes in dilute (myosin Va-) melanocytes are concentrated in the cell center. Here we sought to define the role that myosin Va plays in melanosome transport and distribution. Actin filaments that comprise a cortical shell running the length of the dendrite were found to exhibit a random orientation, suggesting that myosin Va could drive the outward spreading of melanosomes by catalyzing random walks. In contrast to this mechanism, time lapse video microscopy revealed that melanosomes undergo rapid ( approximately 1.5 microm/s) microtubule-dependent movements to the periphery and back again. This bidirectional traffic occurs in both wild-type and dilute melanocytes, but it is more obvious in dilute melanocytes because the only melanosomes in their periphery are those undergoing this movement. While providing an efficient means to transport melanosomes to the periphery, this component does not by itself result in their net accumulation there. These observations, together with previous studies showing extensive colocalization of myosin Va and melanosomes in the actin-rich periphery, suggest a mechanism in which a myosin Va-dependent interaction of melanosomes with F-actin in the periphery prevents these organelles from returning on microtubules to the cell center, causing their distal accumulation. This "capture" model is supported by the demonstration that (a) expression of the myosin Va tail domain within wild-type cells creates a dilute-like phenotype via a process involving initial colocalization of tail domains with melanosomes in the periphery, followed by an approximately 120-min, microtubule-based redistribution of melanosomes to the cell center; (b) microtubule-dependent melanosome movement appears to be damped by myosin Va; (c) intermittent, microtubule-independent, approximately 0.14 microm/s melanosome movements are seen only in wild-type melanocytes; and (d) these movements do not drive obvious spreading of melanosomes over 90 min. We conclude that long-range, bidirectional, microtubule-dependent melanosome movements, coupled with actomyosin Va-dependent capture of melanosomes in the periphery, is the predominant mechanism responsible for the centrifugal transport and peripheral accumulation of melanosomes in mouse melanocytes. This mechanism represents an alternative to straightforward transport models when interpreting other myosin V mutant phenotypes.

Actin Cytoskeleton↗

Competitive action of calcium and procaine on lobster axon. A study of the mechanism of action of certain local anesthetics.

Voltage clamp studies with the squid giant axon have shown that changes in the external calcium concentration (Frankenhaeuser and Hodgkin, 1957) shift the sodium and potassium conductance versus membrane potential curves along the potential axis. Taylor (1959) found that procaine acts primarily by reducing the sodium and, to a lesser extent, the potassium conductances. Both procaine and increased calcium also delay the turning on of the sodium conductance mechanism. Calcium and procaine have similar effects on lobster giant axon. In addition, we have observed that the magnitude of the response to procaine is influenced by the external calcium concentration. Increasing external calcium tends to reduce the effectiveness of procaine in decreasing sodium conductance. Conversely, procaine is more effective in reducing the membrane conductance if external calcium is decreased. The amplitude of the nerve action potential reflects these conductance changes in that, for example, reductions in amplitude resulting from the addition of procaine to the medium are partially restored by increasing external calcium, as was first noted by Aceves and Machne (1963). These phenomena suggest that calcium and procaine compete with one another with respect to their actions on the membrane conductance mechanism. The fact that procaine and its analogues compete with calcium for binding to phospholipids in vitro (Feinstein, 1964) suggests that the concept of competitive binding to phospholipids may provide a useful model for interpreting these data.

Animals↗

Recording of ENGs from the nerves innervating the pancreas of a dog during the intravenous glucose tolerance test.

Electroneurograms (ENGs) from the vagus nerve (VN), the splanchnic nerve (SN) and the pancreatic nerve (PN) innervating the pancreas of a dog, were recorded with chronically implanted 33-electrode spiral cuffs (cuff) before and after the pancreas were stimulated with intravenously (i.v.) administered glucose. In the cuffs platinum electrodes were arranged in three parallel spiral groups containing 11 electrodes on the inner surface. The cuffs had an inner diameter of 2 mm and a length of 18 mm. In a two-year study, the cuffs were implanted into two Beagle dogs and were also used for pancreatic stimulation, although this is not described in this paper. In the VN, the cuff was installed on the nerve at the neck, whilst in the SN, the cuff was installed on the nerve before the celiac ganglion, and in the PN, the cuff was installed on the nerve just before it enters the pancreas. Six months after implantation, when the model of interpretation of the results was developed, three recordings of ENG in each animal were conducted. The first one was conducted in the unstimulated pancreas while the second and the third were conducted 1 and 8 min after a known amount of glucose was i.v. administered. Since the results obtained in both animals were actually quite similar, we present the results obtained in one animal. To evaluate the changes in superficial activity of the nerves, elicited by the administration of glucose, the power spectra corresponding to ENGs, recorded from the nerves before and after the administration of glucose, were integrated within the band of frequencies ranging from 1 to 5 kHz. Accordingly, the magnitude of the integrated power spectrum (MIPS), corresponding to the ENG recorded from the SN before administration of glucose, was 2.863 au. One minute after glucose was administered the value fell to 2.795 au while 8 min after the administration the value returned to 2.8 au. The MIPS corresponding to the ENG recorded from the PN before the administration of glucose was 3.236 au. One minute after the administration the value fell to 2.901 au while 8 min after the administration the value rose to 3.009 au. The MIPS, corresponding to the ENG recorded from the VN before the administration of glucose, was 3.656 au. One minute after the administration the value fell to 3.565 au. Eight minutes after the administration the value rose to 3.689 au. The results show that 1 min after glucose was administered superficial activity in all three nerves was reduced while 8 min after administration the activity in the nerves returned to the same level of activity before the glucose was administered. This information could be effectively used in a further study of pancreatic innervation and its function. Moreover, the results suggest that cuffs could also be useful in recording the ENGs from other nerves of the autonomic nervous system that innervate various glands and internal organs.

Animals↗

Machine learning approaches for cancer prognosis and diagnosis via non-coding RNA: a comprehensive review.

Non-coding RNAs (ncRNAs), once considered genomic dark matter, are now established as key regulators of gene expression with widespread roles in cellular homeostasis and disease. In cancer, ncRNA expression is frequently and systematically dysregulated, and many of these molecules circulate in stable, protected form within biofluids, offering a compelling basis for non-invasive or minimally invasive diagnostic strategies. However, their clinical translation remains substantially hindered to date due to biological complexity, technical noise, and high dimensionality inherent to ncRNA expression datasets. In this context, machine learning (ML) has emerged as a powerful analytical tool to address these challenges, enabling the identification of subtle, reproducible ncRNA signatures predictive of diverse malignancies. This review critically evaluates ML-driven frameworks for cancer diagnosis and prognosis across four ncRNA subclasses, namely miRNAs, lncRNAs, circRNAs, and piRNAs, while also acknowledging the biophysical and thermodynamic models that reinforce ncRNA bioinformatics. Despite substantial methodological progress in ML-based cancer diagnosis and prognosis, key challenges persist, including tumor biological heterogeneity, limited multicenter validation, and the lack of widely adopted standardized protocols for preprocessing, normalization, and reporting workflows. Furthermore, many current ML models lack interpretability in biological or clinical context, constraining their translational utility. By synthesizing recent advances and identifying unresolved barriers, this review charts a roadmap for developing a robust, clinically actionable ncRNA biomarker platform for cancer detection. With global cancer incidence projected to exceed 35 million annual cases by 2050, validated ncRNA-ML-driven frameworks hold potential to revolutionize early-stage detection and personalized therapeutic strategies, thereby reducing the escalating socio-economic burden of cancer worldwide.

Humans↗

ALPAR: automated learning pipeline for antimicrobial resistance.

SUMMARY: The field of machine learning in antimicrobial resistance (AMR) research has experienced rapid growth, fueled by advancements in high-throughput genome sequencing and the growing capacity of computational resources. However, the complexity and lack of standardized data preparation and bioinformatic analyses present significant challenges, especially for newcomers to the domain. In response to these challenges, we introduce ALPAR (Automated Learning Pipeline for Antimicrobial Resistance), a comprehensive AMR data analysis tool covering the entire process from processing of raw genomic data to training machine learning models to interpretation of results. Our method relies on a reproducible pipeline that integrates widely used bioinformatics tools, presenting a simplified, automatic workflow specifically tailored for single-reference AMR analysis. Accepting genomic data in the form of FASTA files as input, ALPAR facilitates the generation of machine learning-ready data tables and both the training of machine learning and the execution of genome-wide association studies (GWAS) experiments. Additionally, our tool offers supplementary functionalities such as phylogeny-based analysis of the distribution of mutations, enhancing its utility for researchers. The tool has also proven its performance in competitive benchmarks, winning the 2024 CAMDA Anti-Microbial Resistance Prediction Challenge and placing third in the 2025 edition. AVAILABILITY AND IMPLEMENTATION: ALPAR is open-source and freely accessible via GitHub (https://github.com/kalininalab/ALPAR). The pipeline is fully reproducible and can be easily installed as a Conda package (https://anaconda.org/kalininalab/ALPAR).

Machine Learning↗

The compliance score as a regressor in randomized trials.

The compliance score in randomized trials is a measure of the effect of randomization on treatment received. It is in principle a group-level pretreatment variable and so can be used where individual-level measures of treatment received can produce misleading inferences. The interpretation of models with the compliance score as a regressor of interest depends on the link function. Using the identity link can lead to valid inference about the effects of treatment received even in the presence of nonrandom noncompliance; such inference is more problematic for nonlinear links. We illustrate these points with data from two randomized trials.

Bias↗

How to use participatory action research in primary care.

OBJECTIVE: The aim of the article is to demonstrate the usefulness of participatory action research (PAR) in primary care. The author used PAR firstly to develop a deeper understanding of mutual participation in the doctor-patient encounter and secondly to apply this learning in a rural cross-cultural practice setting. METHOD: PAR was done with four patient groups. Four patients with terminal illnesses formed groups with their family members, neighbours and friends. Seven meetings were held with each group over a period of 6 months. The meetings were conducted in Tsonga, which is the local vernacular. All the meetings were audio-taped. The primary question for each meeting was how the group could work together to achieve the best possible health outcome for the patient. Additionally, the author, who facilitated the meetings, kept a reflective diary, including field notes over the research period. One member of each group kept a written record of each meeting. Three free attitude interviews were conducted with the author over the research period to elicit the development of his understanding about mutual participation in the doctor-patient encounter. The recorded meetings and interviews were transcribed and translated and themes subsequently identified using the transcripts. The reflective diary was analysed similarly. A model was constructed to depict the themes and their interrelatedness. The model was interpreted and conclusions were drawn. RESULTS: The PAR process had a positive effect on the doctor-patient encounter. PAR greatly resembles a mutual participatory doctor-patient encounter. The research facilitator had certain basic tenets in order to facilitate participation. The patients who participated actively benefited most. Basic interviewing techniques were used to facilitate the mutual participation in PAR. CONCLUSIONS: PAR is very applicable in primary care. The principles of PAR such as mutual collaboration, reciprocal respect, co-learning and acting on results from the enquiry are essential in the doctor-patient relationship. Self-awareness, the ability to self-critique and reflect in a deep manner using such tools as a reflective diary are essential for nurturing the development of effective primary health care workers and consequently care structures for the patients and their families.

Cross-Cultural Comparison↗

Meiotic behavior of compound autosomes in females of Drosophila melanogaster: interchromosomal effects and the source of spontaneous nonsegregation.

In females of Drosophila melanogaster, compound autosomes enter the repulsion phase of meiosis uncommitted to a particular segregation pattern because their centromeres are not restricted to a bivalent pairing complex as a consequence of crossing over. Their distribution at anaphase, therefore, is determined by some meiotic property other than exchange pairing, a property that for many years has been associated with the concept of nonhomologous pairing. In the absence of heterologous rearrangements or a free Y chromosome, C(3L) and C(3R) are usually recovered in separate gametes, that is as products of meiotic segregation. Nevertheless, there is a regular, albeit infrequent, recovery of reciprocal meiotic products (the nonsegregational products) that are disomic and nullosomic for compound thirds. The frequency of these exceptions, which is normally between 0.5 and 5.0%, differs for the various strains examined, but remains constant for any given strain. Since previous studies have not uncovered a cause for this base level of nonsegregation, it has been referred to as the spontaneous frequency. In this study, crosses between males and females whose X chromosomes, as well as compound autosomes, are differentially marked reveal a highly significant positive correlation between the frequency of compound-autosome nonsegregation and the frequency of X-chromosome nondisjunction. However, an inverse correlation is found when the frequency of nondisjunction is related to the frequency of crossing over in the proximal region of the X-chromosome. These findings have been examined with reference to the distributive pairing and the chromocentral models and interpreted as demonstrating (1) that nonsegregational meiotic events arise primarily as a result of nonhomologous interactions, (2) that forces responsible for the segregation of nonhomologous chromosomes are properties of the chromocentral region, and (3) that these forces come into expression after the exchange processes are complete.

Animals↗