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Conflicts and complexity in inpatient geropsychiatry.

In order to illustrate the principles and practice of inpatient geropsychiatric care, the authors present the case of a 73-year-old woman who developed a paranoid delusional syndrome associated with hypothyroidism. The roots of such care, which lie in the network of biopsychosocial losses of late life, are exemplified in their analysis of this patient's multiple medical, psychiatric and social liabilities. The interrelationships among these problems provide the rationale for integrated multidisciplinary assessment and treatment, which is the central organizational concept for geropsychiatric care. Through effective team leadership, efficient case coordination, firm and flexible interdisciplinary boundaries, and incisive prioritization of limited resources and limited options, the multidisciplinary process is shown to provide the basis for a comprehensive and, ideally, a holistic understanding of the patient's strengths and liabilities. The authors highlight this patient's dramatic benefit from such a comprehensive program of medical, psychiatric, and socioenvironmental interventions in order to indicate the fruitfulness of this complex and gratifying process.

Activities of Daily Living

Genome-wide characterization of the tomato PERK gene family and its expression profiling under abiotic stresses.

UNLABELLED: This study presents the first systematic genome-wide characterization of the proline-rich extensin-like receptor kinases (PERK) gene family in tomato (Solanum lycopersicum) and their transcriptional responses under abiotic stresses. Using the latest SL4.0/ITAG4.0 genome assembly, we identified six SlPERK genes, all harboring the conserved Ser/Thr protein kinase domain. Evolutionary and structural analyses revealed strong purifying selection (Ka/Ks&#x2009;<&#x2009;1), distinct exon-intron organizations, and the presence of stress- and hormone-responsive cis-regulatory elements in their promoters. Furthermore, post-transcriptional regulation by 57 miRNAs and complex protein-protein interaction networks were predicted. To validate their stress-responsive roles, two tomato cultivars (GMOTL-1 and Roma) were subjected to cold, heat, and salinity treatments. Quantitative RT-PCR analysis revealed cultivar-specific expression dynamics: SlPERK4 exhibited strong transient induction under cold and heat stress, while SlPERK6 was highly responsive to salinity. Notably, the GMOTL-1 cultivar displayed significantly higher and broader stress-responsive expression profiles compared to Roma, indicating a potential role of these SlPERK genes in cultivar-specific stress tolerance. These findings provide a comprehensive genomic resource and establish a critical foundation for the functional validation and molecular breeding for stress-resilience tomato cultivars. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at https://doi.org/10.1007/s13205-026-05044-y.

Abiotic stress

Integrating explainable artificial intelligence with multiomics systems biology and electronic health record data mining for personalized drug repurposing in Alzheimer's disease.

Alzheimer's disease (AD) is characterized by region- and patient-specific molecular heterogeneity, which hinders therapeutic design. In this study, we introduce PRISM-ML (PRecision-medicine using Interpretable Systems and Multiomics with Machine Learning), an open-source integrated analysis pipeline that combines interpretable machine learning with systems biology and electronic health records data mining to elucidate the molecular diversity of AD and predict promising drug repurposing opportunities. First, we integrated and harmonized transcriptomic (bulk RNA-seq) and genomic (genome-wide association study) data from 2105 brain samples, each with matched data from the same individual (1363 AD patients, 742 controls; 9 tissues), sourced from three independent studies. Random forest classifiers with SHapley Additive exPlanations identified patient-specific biomarkers; unsupervised clustering resolved 36 molecularly distinct subtissues (defined as clusters of samples within a brain tissue that share a specific expression pattern); and gene-gene coexpression networks prioritized 262 high-centrality bottleneck genes as putative regulators of dysregulated pathways. Next, knowledge graph-based drug repurposing predicted six Food and Drug Administration (FDA)-approved drugs that simultaneously target multiple bottleneck genes and multiple AD-relevant pathways. Notably, in a large US de-identified insurance-claims database (n&#x2009;=&#x2009;364&#xa0;733), exposure to promethazine, one of the candidate drugs, was associated with a 57%-62% lower incidence of AD versus an active antihistamine comparator (adjusted hazard ratio 0.38; inverse-probability weighted 0.43; both P&#x2009;<&#x2009;.001), providing real-world support for its repurposing potential. In summary, PRISM-ML, as an explainable multiomics analysis pipeline, is readily transferable to other complex diseases, advancing precision medicine.

Alzheimer Disease

Bayesian Genome-Wide Association Study of Feed Efficiency Traits in Pigs.

Feed efficiency traits are increasingly important in pig production for improving profitability and environmental sustainability. Understanding their genetic basis is crucial for uncovering underlying biological mechanisms and informing selection strategies. In this study, we analyzed residual feed intake (RFI), feed conversion ratio (FCR), and average daily feed intake (ADFI) in 201 animals. Three separate Bayesian GWASs were conducted using 29,844 SNPs in a case-control design, with the lowest and highest 15% of the phenotypic distribution selected as controls and cases (N = 30 per group), respectively, for each trait. The results confirmed the polygenic nature of the traits, identifying 4 SNPs for RFI on Sus scrofa chromosomes (SSC) 3, 13, and 15 with high posterior probability for the direction of their effects; 4 SNPs for FCR on SSC 8, 14, and 17; and 8 SNPs for ADFI on SSC 1, 2, 6, 8, and 11. A candidate gene search identified 41 potential genes involved in diverse biological processes, including feed efficiency, intestinal development, tissue remodeling and integrity, nutrient transport and absorption, metabolic homeostasis, cellular signaling, energy sensing, and neurological regulation. These genes formed a highly interconnected network, highlighting the complexity of feed efficiency and the interplay among multiple physiological, metabolic, and regulatory pathways.

Bayesian analysis

Emergence and phylogeography of the dengue vector Aedes aegypti in Southeastern Iran.

BACKGROUND: Aedes (Stegomyia) aegypti (Linnaeus) is the primary vector of dengue, chikungunya, Zika, and yellow fever viruses. Its recent detection in southeastern Iran raises public health concerns about arbovirus spread to new regions. This study provides the first genetic and phylogeographic analysis of Ae. aegypti populations from Sistan and Baluchistan Province (SBP), Iran, to infer their origin and invasion pathways. METHODS: Mitochondrial COI and ND4 genes were analysed in newly collected Ae. aegypti specimens from border areas, ports, and urban centres of SBP. Haplotype network analyses were constructed using the TCS method in PopART, and phylogenetic analyses were conducted using global reference sequences. RESULTS: Iranian specimens comprised 7 COI haplotypes (n&#x2009;=&#x2009;18) and 10 ND4 haplotypes (n&#x2009;=&#x2009;17). COI phylogeny placed Iranian specimens into two main clades, while ND4 analysis distributed them across several derived clades, mostly clustering with lineages from Latin America (Brazil, Mexico) or Africa. One Iranian specimen showed a close relationship with a Saudi Arabian sequence (bootstrap: 98%) near the basal region. Combined COI&#x2009;+&#x2009;ND4 analysis revealed a monophyletic clade of Iranian specimens with a Sri Lankan specimen, distinct from other global lineages. The global COI network (n&#x2009;=&#x2009;47) showed a star-like topology with a dominant haplotype 1 shared among 10 Iranian specimens. The ND4 network (n&#x2009;=&#x2009;31) revealed a complex topology with 18 haplotypes, where a Saudi Arabian and one Iranian specimen (~30 mutational steps) possibly represented the peripheral root. CONCLUSIONS: Detection of diverse Ae. aegypti clades confirm establishment of this vector in southeastern Iran. Results support multiple introductions and genetic connectivity with Latin America, Africa, and South Asia, pointing to an emerging invasion corridor. Continued genomic surveillance and integrated vector monitoring are urgently needed to guide prevention strategies.

Animals

Application of neural computing in pharmaceutical product development.

Neural computing technology is capable of solving problems involving complex pattern recognition. This technology is applied here to pharmaceutical product development. The most commonly used computational algorithm, the delta back-propagation network, was utilized to recognize the complex relationship between the formulation variables and the in vitro drug release parameters for a hydrophilic matrix capsule system. This new computational technique was also compared with the response surface methodology (RSM). Artificial neural network (ANN) analysis was able to predict the response values for a series of validation experiments more precisely than RSM. ANN may offer an alternative to RSM because it allows for the development of a system that can incorporate literature and experimental data to solve common problems in the pharmaceutical industry.

Algorithms

Mathematical modeling of differentiation in Dictyostelium discoideum.

Methods for the dynamic analysis of biochemical differentiation are presented. These are demonstrated in the analysis of biochemical differentiation of the carbohydrate system in D. discoideum. Procedures for simplification which are presented are projection and contraction of the system trajectory in state space and the generation of reduced equivalent dynamic metabolic networks. The importance of the hierarchical structure of differentiating systems is discussed and the concept of a dynamic embedding diagram is introduced. It is shown that complex systems must be analyzed on an epoch by epoch basis, each epoch being a period of time characterized by a constant dynamic embedding diagram, and that widely different time scales and state space scales may be necessary in different epochs. In particular there is no a priori lower limit to the time scale which may be necessary during the analysis. Some problems in mathematically defining differentiation are discussed.

Carbohydrate Metabolism

Superposition of arteriolar vasomotion waves and regulation of blood flow in skeletal muscle microcirculation.

In skin muscle microcirculation of Syrian hamsters, rhythmic diameter changes were studied along the arteriolar network, under normoxic conditions, at rest. A teflon coated-aluminum chamber was implanted in the dorsum skin of animals. The microcirculation was investigated using intravital microscopy technique. Vessel diameters were determined by a computer-assisted method. Power spectrum analysis of vasomotion recordings was carried out with Fast Fourier Transform and Autoregressive modelling. To determine vasomotion waveform spreading, cross-spectral data (amplitude and phase) were computed, using the modified periodogram method (FFT). The arterioles were classified according to Strahler's method. Order 1 vessels (diameter: 7.50 +/- 1.16 microns) showed the highest frequency, 4-15 cycles per min, and percentage amplitude in the range 60-100%. Order 2 and 3 arterioles had intermediate frequencies, and amplitude in the range 50-100%, and 15-50%, respectively. The largest order 4 vessels (diameter: 28.97 +/- 9.55 microns) had the lowest frequency, 0.3-3 cpm, and amplitude in the range 5-20%. In most networks, cross-correlation analysis revealed two groups of frequency components. Low frequency group was propagated from order 4 and 3 vessels downstream. High frequency components were transmitted upstream from order 1 and 2 arterioles. Therefore, a complex superposition of waveforms resulted from the activity of discrete points along the microvasculature. In conclusion, rhythmic diameter changes of arterioles in skeletal muscle microcirculation regulate blood flow distribution in capillary units and control tissue oxygenation.

Animals

Beyond one-to-one mappings: Modelling distributed lesion-symptom relationships with multilayer networks.

Lesion-symptom mapping is widely used to identify causal relationships between brain structures and behaviour, and has played a central role in neuropsychologically informed network models of cognition. However, even recent approaches remain constrained by a one-to-one mapping framework, which oversimplifies the complex relationships between network-level damage and cognitive deficits. In addition, the non-orthogonality of cortical and white matter damage makes it difficult to disentangle their distinct contributions. Here, we used graph-based multilayer network analysis to address these limitations and evaluate clinical relevance. Using neuroanatomical and longitudinal neuropsychological data from 252 patients who underwent awake neurosurgery for low-grade glioma, we constructed interactive, three-layer networks for each hemisphere. Layer 1 comprised neuropsychological tasks (NT), layer 2 structural disconnections (SD), and layer 3 cortical damage (CD). Nodes represented tasks, white matter tracts, and cortical parcels, respectively, whereas within-layer edges captured correlations in performance or co-occurring damage patterns. Multilayer community detection identified domain- and hemisphere-specific brain-behaviour motifs linking executive, language, and spatial functions to distinct combinations of cortical and white matter disruption, a pattern confirmed by two spatial embedding approaches. Centrality analyses revealed a continuum of mapping relationships, ranging from one-to-one to one-to-many associations, indicating that tasks such as verbal fluency are better explained by multiple disconnection mechanisms. Additional analyses uncovered many-to-one and many-to-many relationships and highlighted tracts and cortical regions with domain-general relevance. Together, these findings support a neurobiologically grounded, network-oriented account of how structural brain damage gives rise to cognitive deficits, with implications for clinical care.

Humans

Genome-wide identification of HCT gene family in sugarcane (Saccharum spp. hybrid) and characterization of putative cis-elements in gene regulation.

BACKGROUND: Sugarcane (Saccharum spp. hybrid) is a globally important crop, and its bagasse can be converted into bioethanol and other industrial products. Lignin, a core component of sugarcane cell walls, plays a crucial role in bagasse quality and lodging resistance. Shikimic acid hydroxycinnamyl transferase (HCT) is the key enzyme in lignin biosynthesis. However, the HCT gene family in sugarcane and its regulatory roles in sugarcane remain poorly understood. RESULTS: A total of 663 HCT genes (including alleles) were identified in the Saccharum hybrid R570 genome, which were classified into six groups (I-VI) and were unevenly distributed across 77 chromosomes. Bioinformatics analysis revealed that the subgroups of R570HCTs had similar gene structures, suggesting conserved functions. Moreover, the different subgroups presented unique putative cis&#x2011;element distribution patterns. Transcriptome data indicated that some R570HCTs exhibited significant spatiotemporal and tissue&#x2011;specific expression patterns. Further Pearson correlation analysis between putative cis&#x2011;element distribution and normalized expression values at the subgroup level revealed that light-responsive elements (L&#x2011;box and GA&#x2011;motif) were positively correlated with R570HCT expression, and different subgroups formed a complex regulatory network by integrating hormone response and stress elements. Importantly, this subgroup-level correlation was cross-validated by comparing the cis&#x2011;element clustering heatmap with the expression heatmap, revealing consistent enrichment patterns. CONCLUSIONS: The study's findings provide novel insights into the correlation among motifs, putative cis&#x2011;elements, and gene expression, and propose a cross-validated framework for understanding regulatory divergence among HCT subfamilies in polyploid sugarcane, serving as a hypothesis generating resource for future research on R570HCT expression.

Saccharum

Interactions and structure of the nuclear pore complex revealed by cryo-electron microscopy.

Nuclear pore complexes (NPCs) play a central role in mediating nucleocytoplasmic transport and exchange processes in eukaryotic cells. The arrangement and interactions of NPCs within amphibian nuclear envelopes have been studied using cryo-electron microscopy of unfixed and frozen hydrated specimens. The nuclear lamina in Necturus forms an orthogonal network with crossover distances which vary between 1,600 and 4,000 A and which may be related to the basic filament repeat of lamins. Furthermore, the NPCs are attached randomly within the confines of the lamin network, presumably by their nucleoplasmic rings. Image analysis of edge-on and en face projections of detergent-extracted NPCs has been combined with data on the coaxial thin rings to provide a quantitative evaluation of the triple ring model of NPC architecture proposed previously (Unwin, P. N. T., and R. Milligan. 1982. J. Cell Biol. 93:63-75). Additional details of the complex have been visualized including an intimate association of the inner spoke domains as an inner spoke ring, extensive domains within the spokes and coaxial thin rings, and interestingly, a central channel-like feature. Membrane-associated NPCs and detergent-extracted NPCs both possess peripherally located radial arms resulting in an effective diameter of approximately 1,450-1,500 A. In projection, the radial arms possess approximate mirror symmetry suggesting that they originate from both sides of the assembly. Moreover, membrane-associated NPCs are asymmetric at most radii and right-handed as viewed from the cytoplasm; detergent-extracted NPCs appear to be symmetric and have approximately 822 symmetry. Taken together, the data suggests that the framework of membrane-associated NPCs is perturbed from a symmetrical configuration, either during isolation of nuclei or by interactions with the lamina and the nuclear envelope in vivo. However, detergent extraction of nuclei appears to result in a more symmetrical alignment of components in apposing halves of the assembly.

Animals

Neural networks as a tool for utilizing laboratory information: comparison with linear discriminant analysis and with classification and regression trees.

Successful applications of neural network architecture have been described in various fields of science and technology. We have applied one such technique, error back-propagation, to a medical classification problem stemming from clinical chemistry, and we have compared the performance of two different neural networks with results obtained by conventional linear discriminant analysis or by the technique of classification and regression trees. The results obtained by the various models were tested for robustness by jackknife validation ("leave n out" method). Compared with the two other techniques, neural networks show a unique ability to detect features hidden in the input data which are not explicitly formulated as input. Thus, neural network techniques appear promising in the field of clinical chemistry, and their application, particularly in situations with complex data structures, should be investigated with more emphasis.

Alanine Transaminase

A comparative study highlights superiority of LSTM in crop genomic prediction.

We systematically evaluated three key determinants affecting prediction accuracy and the algorithm performance differences based on fifteen state-of-the-art GP methods, and found LSTM suitable for capturing additive and epistatic effects. Genomic prediction (GP) has been developed as an important method supporting crop breeding. By utilizing the phenotype values result from GP, breeders could make decisions in the seedling stage that consequently benefit for cost saving. In recent years, machine learning emerged as an efficient technology to solve modeling problems in many fields, including crop breeding. However, numerous modeling approaches have hindered the application of GP since breeders struggle to choose. Therefore, a comprehensively methodological research with guiding significance is extremely necessary. In the present study, we systematically evaluated three key determinants affecting prediction accuracy and the algorithm performance differences based on fifteen state-of-the-art GP methods. As for genomic feature processing, we found feature selection (SNP filtering approach) performed better than feature extraction (PCA method). Specifically, the feature relationship dependent methods (GBLUP, RNN, and LSTM) as well as DNN architecture showed superior performance with feature selection. Marker density analysis showed positive correlation with prediction accuracy in a limited threshold. Comparison on effect of population size demonstrated a positive correlation between trait genetic complexity and the optimal population size required. By testing fifteen modeling methods, we found LSTM network displayed superior performance, achieving the highest average STScore (0.967) across six datasets. Further research using all cell states or the latest cell states of LSTM inputs demonstrated its architecture particularly adept with capturing additive and epistatic QTL effects among SNPs. In conclusion, our findings provide basic principles for implementing GP in breeding project to maximize prediction accuracy while maintaining cost-effectiveness.

Plant Breeding

Maturation of the corneal endothelial tight junction.

Apical tight junctional formation of the rabbit corneal endothelium was examined by freeze-fracture analysis and measurement of paracellular permeability to 5(6)-carboxyfluorescein. Freeze-fracture analysis indicated that apical tight junction formation of the rabbit corneal endothelium is a dynamic process. At birth, there are few tight junctional strands present and a minimal barrier for paracellular diffusion. As the rabbit matures, a more complex network of anastomosing tight junctional strands begins to encircle the cell perimeter under the apical folds. However, even in the mature animal (3 months), there are discontinuities and free ends in the network, thus suggesting that the barrier is not complete even at this stage. Paracellular permeability measurements using 5(6)-carboxyfluorescein as a tracer corroborate these anatomic findings. Endothelial paracellular flux measurements steadily decrease as the rabbit matures from birth to young adult. This indicates that the tight junctional network is increasing in complexity and progressively limiting the flow of substances through the intercellular space.

Animals

Involvement of microtubules and microfilaments in the control of the nuclear movement during maturation of mouse oocyte.

We confirm that the centrifugal migration of the chromosomes in maturing mouse oocytes depends on a microfilament-mediated process. We investigated the role of the cytoskeleton in the germinal vesicle (GV) behavior of oocytes prevented from resuming meiosis by either activators of protein kinase A or activators of protein kinase C. A time-lapse microcinematography study demonstrates that GV immobilization by isobutylmethylxanthine (IBMX) is overcome by colcemid (COL), nocodazole (NOC), and taxol and that cytochalasin D (CCD) reversibly immobilizes the GV of oocytes treated with either IBMX + COL (or NOC) or 12-O-tetradecanoylphorbol-13-acetate (TPA), an activator of protein kinase C, known to allow a programmed GV cortical translocation. An immunofluorescence analysis shows that the disorganization of a perinuclear microtubule network is the very first cytological clue of maturation. IBMX promotes its persistence while NOC, COL, and taxol induce its immediate disappearance. It is concluded that elements of the cytoplasmic microtubular complex (CMTC) are passively involved in the control of the setting up of a "centrifugal displacement property" (CDP) by counteracting a motive force provided by the microfilament cytoskeleton. Finally, TPA induces a clearcut reorganization instead of a total disorganization of the CMTC. This reorganization is, however, sufficient to allow the microfilaments to drive the GV displacement.

Actin Cytoskeleton

Kindling in the frog: development of spontaneous epileptiform activity.

The present report is the first demonstration of the kindling phenomenon in a non-mammalian, poikilothermic species. Brief (2 sec) localized electrical stimulation was delivered to the hippocampal cortex of one hemisphere of the partially paralyzed bullfrog, Rana catesbeiana, at current levels just sufficient to elicit brief after-discharge (AD) on first application. Succeeding stimulations, once per hour, gave rise to more and more prolonged AD involving first the side stimulated (1 degree focus) and secondly the opposite hemisphere (2 degree focus). In addition to these stimulus-dependent alterations, after several hours spontaneous, paroxysmal discharges occurred in interstimulus intervals. They appeared first in the stimulated hemisphere, then as evoked spikes in the secondary hemisphere, and finally independently on the two sides. The waveshape of the spontaneous epileptiform potentials exhibited an extraordinary constancy from complex to complex which was specific to each animal. Such wave-shape coherence implies a constancy to both the anatomical substrate and the sequency of synaptic engagement each time spontaneous paroxysmal activity invades the network. The model is especially suitable for analysis of temperature-dependent biochemical events responsible for this functional transformation.

Animals

The Slovak-American "swaddling ethos": homeostat for family dynamics and cultural continuity.

This paper explores the systemic relationships among cultural ethos, family dynamics, personality configuration, and child-rearing patterns among multigeneration Slovak-Americans. The "swaddling ethos" is posited to serve as a homeostat whose regulatory function can be discerned through the analysis of family structure and process, in particular through the explication of values, affective patterns, roles, boundaries, and structural units within the family. The core of the ethos is a dependency-security complex that attaches the individual to an extended family network of obligation, indebtedness, and reciprocity (ethnic, Slovak); induces rebellion against such attachment (mainstream American); and undermines efforts toward separation-individuation, resulting in the perpetuation of an ethnic tradition.

Attitude

A Computational Workflow for Prioritizing Microbial Metabolite-Associated Host Genes in Constipation-Predominant Irritable Bowel Syndrome.

No standardized computational pipeline exists for systematically prioritizing microbial metabolite-associated host genes and protein-ligand complexes from publicly available chemical, genomic, and structural databases. This article describes an eight-stage workflow that accepts a user-defined set of gut microbiota-derived metabolites and produces a ranked shortlist of candidate metabolite-associated host genes, enriched biological pathways, and structurally prioritized protein-ligand complexes for experimental follow-up. The pipeline integrates (i) chemoinformatic metabolite profiling; (ii) multi-database candidate target prediction using protein-chemical interaction and ligand-based target-prediction tool and a molecular docking program; (iii) differential gene expression analysis of publicly available transcriptomic data; (iv) target-differentially expressed gene overlap; (v) protein-protein interaction network construction and pathway enrichment; (vi) molecular docking with a molecular docking program; (vii) 200 ns molecular dynamics simulation using a molecular dynamics engine with a protein force field used for molecular dynamics simulations; and (viii) MM-PBSA binding free-energy estimation. As a worked example, nine gut microbiota-derived or microbiota-modified metabolites representing short-chain fatty acids, bile acids, tryptophan-derived metabolites, and urolithin A were processed using the public IBS-C rectal mucosal transcriptomic dataset GSE36701. The workflow ranked 17 unique predicted metabolite-associated genes that were differentially expressed in this dataset. Docking, molecular dynamics simulation, and MM-PBSA analyses structurally prioritized five metabolite-protein complexes: lithocholic acid-VDR, lithocholic acid-NR1H4/FXR, ursodeoxycholic acid-NR1H4/FXR, tryptamine-HTR2A (simulated in an explicit 1-Palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) lipid bilayer), and urolithin A-CASP3. The protocol is designed to be adaptable to other metabolite sets, disease transcriptomic datasets, and target classes; all outputs are hypothesis-generating computational predictions that require independent transcriptomic replication, protein-level validation, and functional ligand-response assays before causal or therapeutic conclusions can be drawn.

Irritable Bowel Syndrome