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PubMed1989

Functional integration of the rat hippocampal tissue, transplanted into the rabbit septum.

Embryonal tissue of the rat hippocampus (E17-18) was grafted into small acute cavity within the dorsal septum of adult rabbit after interruption of septo-hippocampal connections. Histological analysis (Nissl stain), performed 6-8 weeks later, revealed surviving hippocampal grafts in 14 out of 29 grafted animals (48%). Some of the grafts were displaced into the ventricle and had only minor contact with the host septum; some others, residing in the septum, were separated from the host tissue by continuous glial scar. Six grafts (33%) were morphologically well integrated with the host septum. The grafts contained mature pyramidal neurons but their organization into layer was absent. No signs of rejection were observed in the grafts, which were not subjected to microelectrode investigation in chronic conditions. The grafts, which for 5-9 successive days were penetrated by microelectrodes, were heavily infiltrated by lymphocytes and had necrotic areas. Electrophysiological testing revealed the absence of spontaneous neuronal activity, or the presence of hypersynchronous epileptiform bursts in isolated grafts. The 4 integrated grafts, investigated electrophysiologically, contained neurons with normal spontaneous activity of two types: low-frequency discharges with complex spikes and high-frequency single spikes, sometimes with short periods of weak rhythmic modulation in the theta-range. Characteristics of spontaneous activity of the xenografted hippocampus are very close to those described in the rat hippocampus in situ. Rhythmic theta-modulation of neuronal activity appeared or increased in stability after physostigmine injection to the host, after electrical stimulation of the host's midbrain reticular formation and ventral part of diagonal band, and after multimodal sensory stimulation of the host. The frequency of theta-bursts in the grafts was identical to that of neurons of the host septum (4.5-6.5 Hz). Besides the theta-modulation sensory stimuli evoked tonic suppression or activation of discharges, phasic reactions and on-effects. Electrical stimulation of lateral septum and diagonal band evoked orthodromic and antidromic discharges of the grafted cells. Normal spontaneous and evoked activity of the grafted cells deteriorated after 5-11 successive days of microelectrode investigation. It is concluded that xenografts of nervous tissue, developing without immunosuppression, have a low rate of survival and are vulnerable to immune response after mechanical interruption of integrity of the blood-brain barrier. Nevertheless their normal activity and close functional integration with the host brain, apparently depending on development of chimeric synapses, is possible.

Action Potentials↗

PubMed2026

Human Systems Immunology in the Omics Era: Challenges, Methods, and Emerging Directions.

The human immune system is a highly complex, dynamic, and heterogeneous network shaped by genetic, environmental, and temporal influences. Advances in high-throughput omics technologies have transformed our ability to study this complexity directly and comprehensively in human cohorts. These developments have positioned systems immunology as a powerful framework for investigating coordinated immune responses, identifying regulatory mechanisms, and linking molecular patterns to clinical phenotypes. However, the analytical challenges inherent to large-scale, multimodal datasets-including batch effects, small sample sizes, high dimensionality, and substantial interindividual heterogeneity-require rigorous study design, robust statistical modeling, and thoughtful data analysis strategies. In this review, we summarize key technological foundations enabling modern human systems immunology, outline common analytical pitfalls and effective mitigation approaches, discuss data integration concepts, and highlight emerging opportunities in the field. Together, these technological and analytical advances are redefining how immune function is measured and interpreted in real-world human biology and hold significant promise for enhancing mechanistic insight, biomarker discovery, and precision medicine across immunological diseases and interventions.

Humans↗

PubMed2003

Emergence of neural integration in the head-direction system by visual supervision.

Head-direction (HD) cells in subcortical areas of the mammalian brain are tuned to a particular head direction in space; a population of such neurons forms a neural compass that may be relevant for spatial navigation. The development of neural circuits constituting the head-direction system is poorly understood. Inspired by electrophysiological experiments about the role of recurrent synaptic connections, we investigate a learning rule that teaches neurons to amplify feed-forward inputs. We simulate random head movements of a rat, during which neurons receive both visual and vestibular (head-velocity) inputs. Remarkably, as recurrent connections learn to amplify exclusively the visual inputs, a neural network emerges that performs spatio-temporal integration. That is, during head movements in darkness, neurons resemble HD cells by maintaining a fixed tuning to head direction. The proposed learning rule exhibits similarities with known forms of anti-Hebbian synaptic plasticity. We conclude that selective amplification could serve as a general principle for the synaptic development of multimodal feedback circuits in the brain.

Algorithms↗

PubMed2001

Intracardiac echocardiography.

This article describes currently available intracardiac ultrasound (ICE) technology contrasting it with intravascular ultrasound (IVUS), highlighting their differences. General and specific clinical applications, limitations and future developments of ICE are addressed. ICE is possible because lower frequency transducers (in contrast to higher frequency IVUS devices) have been miniaturized and mounted onto catheters capable of percutaneous insertion into the heart. Since the recent availability of a steerable, 5.5--10MHz phased-array catheter with full Doppler capability, these lower frequency transducers are not only capable of enhanced penetration, permitting high-resolution two-dimensional (2D) imaging but can also provide haemodynamic data. ICE facilitates electrophysiologic procedures by guiding trans-septal catheterization, enabling endocardial anatomy visualization, ensuring ablation electrode/tissue contact and promptly diagnosing procedural complications. Promising non-electrophysiologic applications include guidance of percutaneous closure of septal defects, percutaneous mitral balloon valvuloplasty and complex cardiac biopsy. Current limitations include monoplanar imaging and narrow field of view. Expanded diagnostic techniques such as tissue Doppler, multiplane, three dimensional (3D) and multimodality imaging represent future refinements. ICE is now a clinical tool. With the introduction of the newest phased-array transducer, with full Doppler capability, ICE has the potential to play an important role in diagnostic and therapeutic interventional procedures. Further refinement and miniaturization hold the key to primary operator controlled, integrated ultrasound-guided interventional devices.

Arrhythmias, Cardiac↗

PubMed1990

The detection and treatment of early breast cancer.

Early breast cancer represents an area in which advances in understanding of epidemiology, natural history, and tumor biology have merged with advances in surgery and technology to bring about some of the most significant reductions in mortality from cancer in this century. Breast cancer can be viewed as a collection of many different diseases with distinct levels of biologic behavior that are based on individual host-tumor interactions, which are in turn governed by a multitude of genetic, environmental, and hormonal variables. The key to many of the persistent questions about carcinoma of the breast and its management may lie in its earliest stages, for it is here that the origins of malignancy lie. The current multimodality approach to its detection and treatment reflects the complexity of this disease, as well as the need for a thorough understanding of all aspects of its biology. The physician involved in the management of early breast cancer must be committed to such an understanding, as well as to a rational integration of these various factors with the specific psychological and emotional makeup of the patient in order to achieve optimal results and continue advancing the frontiers of development.

Breast Neoplasms↗

PubMed1977

Difficulties in integrating child and adolescent training and service in a community mental health center.

In 1972 the Rutgers Community Mental Health Center opened as an integral component of the department of psychiatry at the new Rutgers Medical School. The center was the primary clinical facility for training and service. The philosophy of the child and adolescent services within the center emphasized community-based programs with a continuum of backup care extending into the center. A multidisciplinary multimodal approach was developed. The author discusses several of the training and service problems that developed during the first two years of the center's operation and the approaches to resolving the difficulties.

Adolescent↗

PubMed2026

DeepPlaque: a scalable multimodal platform for Aβ pathology and cell analysis in Alzheimer's disease.

Histological analysis is essential for understanding disease pathology and the microenvironment, particularly in Alzheimer's disease (AD), characterized by beta-amyloid (Aβ) plaques that exist as diffuse, fibrillar, and core species, with distinct toxicity levels. However, accurate classification of Aβ plaque types in postmortem brain tissues and profiling of surrounding cells present significant challenges. To address these challenges, we developed "DeepPlaque", an integrated system featuring "PlaqueNet", a deep learning model for automated classification of Aβ plaque species from diverse imaging platforms. DeepPlaque includes automated workflows for cellular phenotyping and proteomic profiling through targeted laser microdissection. PlaqueNet achieves expert-level accuracy (AUC > 90%) in classifying the 3 major Aβ plaque species, supporting consistent and large-scale annotation. By integrating spatial cellular phenotyping with laser microdissection, DeepPlaque enables high-throughput proteomic analysis of Aβ plaque niches, revealing that microglia are more abundant around core and fibrillar Aβ plaques, with increased expression of apolipoprotein E and amyloid precursor protein in core Aβ plaques. This customizable platform enhances the molecular and cellular characterization of Aβ plaque-associated environments, providing critical insights into AD pathology.

Alzheimer Disease↗

PubMed1998

Spatial disparity affects visual-auditory interactions in human sensorimotor processing.

Information from the auditory and visual systems converges in the nervous system with physiological and behavioral consequences. Most of our knowledge about the rules governing such convergence has been obtained in experiments where the strength or the timing of the individual auditory and visual stimuli has been varied. Relatively little attention has been paid to the spatial relationship between different modalities of stimuli in multisensory experiments. We studied saccadic reaction times of human subjects to bimodal auditory and visual stimulus presentations under two conditions: first, with the targets spatially coincident and, second, with various degrees of spatial separation or disparity. In the first experiment, we found that the saccadic reaction times were consistently shorter than would be predicted by independent processing of information about the visual and auditory targets. These results suggest convergence of multimodal information at one or more loci within the nervous system. In the second experiment, we found that saccadic latency gradually increased as spatial distance between the auditory and visual targets increased. Evidence for neural summation was found over a wide range of spatial disparities. These results suggest that multisensory information can be integrated and have significant influences on behavior over a surprisingly large range of spatial disparity.

Eye Movements↗

PubMed1993

Visual object agnosia, prosopagnosia, achromatopsia, loss of visual imagery, and autobiographical amnesia following recovery from cortical blindness: case M.H.

A number of higher visual deficits accompanied by severe retrograde autobiographical memory loss following bilateral medial occipital infarctions are described in case M.H. Assessment of M.H.'s visual object agnosia and prospagnosia suggested that he was unable to integrate the elements of a percept to form a meaningful whole. This deficit may occur at the level the percept is encoded into the visual buffer and inspected. M.H. also describes a loss of visual memories, and it is hypothesized that this may similarly be a result of an inability to integrate the elements of the visual representation (e.g. of an object or face) following its generation from long-term visual memory store into the visual buffer. M.H.'s retrograde autobiographical memory loss is postulated to be a consequence of the severe impoverishment of episodic memories that must occur when events originally stored multimodally, must be recalled without any visual component.

Adult↗

PubMed1999

The dopaminergic innervation of the avian telencephalon.

The present review provides an overview of the distribution of dopaminergic fibers and dopaminoceptive elements within the avian telencephalon, the possible interactions of dopamine (DA) with other biochemically identified systems as revealed by immunocytochemistry, and the involvement of DA in behavioral processes in birds. Primary sensory structures are largely devoid of dopaminergic fibers, DA receptors and the D1-related phosphoprotein DARPP-32, while all these dopaminergic markers gradually increase in density from the secondary sensory to the multimodal association and the limbic and motor output areas. Structures of the avian basal ganglia are most densely innervated but, in contrast to mammals, show a higher D2 than D1 receptor density. In most of the remaining telencephalon D1 receptors clearly outnumber D2 receptors. Dopaminergic fibers in the avian telencephalon often show a peculiar arrangement where fibers coil around the somata and proximal dendrites of neurons like baskets, probably providing them with a massive dopaminergic input. Basket-like innervation of DARPP-32-positive neurons seems to be most prominent in the multimodal association areas. Taken together, these anatomical findings indicate a specific role of DA in higher order learning and sensory-motor processes, while primary sensory processes are less affected. This conclusion is supported by behavioral findings which show that in birds, as in mammals, DA is specifically involved in sensory-motor integration, attention and arousal, learning and working memory. Thus, despite considerable differences in the anatomical organization of the avian and mammalian forebrain, the organization of the dopaminergic system and its behavioral functions are very similar in birds and mammals.

Afferent Pathways↗

PubMed1994

Multimodality evoked responses in the neurological assessment of the newborn.

In recent years increased attention has been devoted to evoked potentials (EP) in newborns. This paper reviews the literature and data from our research group in an attempt to assess the diagnostic and prognostic value of evoked responses in the first weeks of life and their use in different age-specific clinical conditions. The results show that EP are a very sensitive measure of the integrity of the sensory pathways. They make it possible to follow normal physiological maturation and the abnormalities of development resulting from neurological lesions. Repeated measurements of visual evoked potentials and somatosensorial evoked potential are prognostically useful in term infants, but seem much more limited in preterm newborns in predicting neurodevelopmental outcome.

Evoked Potentials↗

PubMed1998

Multimodal output mapping of human central motor representation on different spatial scales.

1. Non-invasive mapping by focal transcranial magnetic stimulation (TMS) is frequently used to investigate cortical motor function in the intact and injured human brain. We examined how TMS-derived maps relate to the underlying cortical anatomy and to cortical maps generated by functional imaging studies. 2. The centres of gravity (COGs) of TMS maps of the first dorsal intersosseus muscle (FDI) were integrated into 3-D magnetic resonance imaging (MRI) data sets in eleven subjects. In seven of these subjects the TMS-derived COGs were compared with the COG of regional cerebral blood flow increases using positron emission tomography (PET) in an index finger flexion protocol. 3. Mean TMS-derived COG projections were located on the posterior lip of the precentral gyrus and TMS-derived COG projections were in close proximity to the mean PET-derived COG, suggesting that the two methods reflect activity of similar cortical elements. 4. Criteria for a reliable assessment of the COG and the number of positions with a minimum amplitude of two-thirds of the maximum motor-evoked potential (T3Ps) were determined as a function of the number of stimuli and extension of the stimulation field. COGs and T3Ps were compared with an estimate of the size of the human motor cortex targeting alpha-motoneurons of forearm muscles. This comparison suggests that TMS can retrieve spatial information on cortical organization below the macroanatomic scale of cortical regions. 5. Finally, we studied the cortical representation of hand muscles in relation to facial and foot muscle representations and investigated hemispherical asymmetries. We did not find any evidence for a different ipsi- or contralateral representation of the mentalis muscle. Also, no difference was found between FDI representations on the dominant versus the non-dominant hemisphere.

Adult↗

PubMedDate not supplied

Image fusion of computed tomographic and magnetic resonance images for the development of a three-dimensional musculoskeletal model of the equine forelimb.

Biomechanical models that compute the lengths and forces of muscle-tendon units are broadly applicable to the study of factors that promote injury and the planning and effects of orthopedic surgical procedures in equine athletes. A three-dimensional (3D) generic musculoskeletal model of the equine forelimb comprised of bony segment, muscle-tendon, and ligament information, was developed based on high-resolution computed tomographic (CT) and T1-weighted magnetic resonance (MR) images from an isolated forelimb of a Thoroughbred racehorse. Image fusion was achieved through coregistration of CT and MR images with an image analysis program (Analyze) by adjustment of the relative position and orientation of fiducial markers visible in both modalities until the mutual information between the images was maximized. 3D surfaces of the bones and origin/insertion sites, centroid paths and volumes of the muscle-tendon and ligamentous structures were obtained from the multimodal (CT/MR) images using semiautomated and manual segmentation combined with sagittal and transverse color-cryosection anatomic images obtained from three other cadaveric equine forelimbs. Once bony and soft-tissue structures were reconstructed in the same coordinate system, data were imported to a software package for interactive musculoskeletal modeling (SIMM). The combination of integrated CT and MR acquisitions and anatomical images provided an accurate and efficient means of generating a 3D model of the musculoskeletal structures of an average-sized equine adult horse.

Animals↗

PubMed2026

Single-cell multimodal profiling of pan-cancer cell lines uncovers gene regulatory principles underlying intrinsic cell states and environmental features.

Cancer arises from genetic and epigenetic alterations that reshape chromatin, transcriptional regulation, and malignant cell states. To chart cancer-intrinsic regulatory programs, we build a pan-cancer single-cell atlas of 60 cancer cell lines spanning 16 tissue origins and 20 cancer types, comprising 240,957 snRNA-seq and 223,347 snATAC-seq profiles. Integrative analyses reveal cell-state heterogeneity, core gene-regulatory networks, and a conserved EMT axis transcending tissue of origin; copy-number analysis identifies transcription factor amplification and hyperactivation as drivers of state reprogramming. Comparing cutaneous melanoma with acral melanoma, a rare subtype underrepresented in previous studies, uncovers a universal inflammation-suppressive program in acral and an inflamed landscape in cutaneous melanoma, with JAK-STAT activity as the central discriminator. Integrating data across models and patient cohorts links tumor-intrinsic regulation to microenvironmental composition and therapeutic response. By profiling rare alongside common subtypes, this atlas offers a resource for mapping pan-cancer and subtype-specific regulatory programs shaping cell-state plasticity.

Humans↗

PubMed2004

Human cognitive ecology: an instructive framework for comparative primatology.

In this review, research on human cognitive ecology is compared with studies of the cognitive ecologies of apes-especially the common chimpanzee. The objective was to assess the feasibility of extending an activity-theory framework developed in studies of humans to an integrated approach for studying the cognitive accomplishments and skills of other primates living in the wild. Six generalizations were abstracted from studies of humans: 1) Social and material environments are arranged to facilitate production. 2) Human activity is shaped by conceptual and cultural principles that provide underlying logic for working knowledge and practice. 3) Schemata (multimodal, mental representations of procedures, strategies, and techniques) govern performance in a domain. 4) Working knowledge, skills, and social identities are co-constructed in communities of practice. 5) Rehearsal improves skilled performances, from which reputations as well as material products are derived. 6) Planning and emergence are in productive tension in human practices. These generalizations are applied to findings in the literature regarding the behavior of chimpanzees and other apes in the wild to assess the potential utility of a situated-activity approach for comparative studies of primate cognition. It is argued in the Discussion that schemata constitute a common core of higher primate intelligence. Planning, emergence, and alterations of the environment to facilitate production further characterize human and chimpanzee or gorilla behaviors to varying degrees. Less apparent in the nonhuman-primate literature is evidence of governing principles, rehearsal, and skill-based reputations or identities entailing theories of mind. Nonetheless, recent observations in the wild suggest that further research is warranted to explore the rudiments of each of these components to enhance our understanding of the ecology of primate cognition and its evolutionary history.

Animals↗

PubMed2006

Antagonizing inactivated tumor suppressor genes and activated oncogenes by a versatile transgenesis system: application in mantle cell lymphoma.

A broad range of malignant diseases, such as mantle cell lymphoma (MCL), is associated with complex genomic alterations, demanding multimodal functional testing of candidate genes. To assess such candidate disease genes, we have developed a bidirectional targeted transgenesis tool, which allows well-controlled modulation of individual gene activities within a cellular MCL system. The engineered versatile transgenesis system permits functional analysis of virtually any candidate gene: for tumor suppressor genes by complementation via integration of respective genomic DNA or for oncogenes by inactivation via integrated shRNA coding plasmids. Complementation by genomic DNA ensures wild-type (WT) regulated gene expression, whereas genomic integration of shRNA coding inserts by an advanced RNAi-strategy mediates specific knock-down of gene expression. Site-specific genomic integration of an unmodified BAC, which contains the CDKN2A/B genes absent in the MCL model system, restored CDKN2A/B expression resulting in the inhibition of cell proliferation. CCND1, strongly overexpressed in the model system, was down-regulated via shRNA expression, again inhibiting proliferation. Notably, the presented site-specific shRNA-strategy circumvents interference by IFN-response induced when using other RNAi gene knock-down methods. In conclusion, we here demonstrate that adequate restoration of a range of different gene activities yields in a desired antiproliferative effect in MCL-derived cells. By antagonizing inactivated tumor suppressor genes or activated oncogenes, the presented approach can be readily used for the functional analysis of a broad range of disease-related genetic defects.

Cell Line, Tumor↗

PubMed1996

Medication treatment strategies in the MTA Study: relevance to clinicians and researchers.

OBJECTIVE: Clinicians have difficulty applying drug research findings to clinical practice, because research protocols use methods different from those used in daily office practice settings. METHOD: To design a medication protocol for a multisite clinical trial involving 576 children with attention-deficit hyperactivity disorder (ADHD) while maintaining relevance to clinical practice, investigators from the NIMH Collaborative Multisite Multimodal Treatment Study of Children with Attention-Deficit/Hyperactivity Disorder (MTA study) developed novel medication strategies. These were designed to work either in a monomodal or multimodal format and to ensure standard approaches are used across diverse sites. Each child randomized to medication (projected N = 288) is individually titrated to his or her "best" methylphenidate dose and has individual ADHD symptoms monitored. Decision rules were developed to guide "best dose" selection, dose changes, medication changes, the management of side effects, and integration with psychosocial treatments. CONCLUSIONS: The MTA study uses a controlled method to standardize the identification of each child's "best" methylphenidate dose in a national, multisite cooperative treatment program. Although the titration protocol is complex, the study's individual dosing approach and algorithms for openly managing ADHD children's medication over time will be of interest to clinicians in office practice.

Adolescent↗

PubMed2026

Multimodal Analysis Reveals Aberrant Expression of SUMO2 and Its Significant Association With Key Mechanisms of Metabolic Pathways in Hepatocellular Carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. However, the role of small ubiquitin-like modifier 2 (SUMO2), a core member of the small ubiquitin-like modifier (SUMO) family, regarding its expression patterns and metabolism-related functions in HCC remains inadequately understood. METHODS: A multidimensional analytical framework was applied, integrating immunohistochemistry (153 HCC vs. 21 non-HCC samples), proteomics (159 paired samples), bulk transcriptomics (3240 HCC vs. 2267 non-HCC samples), single-cell RNA sequencing (RNA-seq) (10 HCC vs. 8 non-HCC samples), spatial transcriptomics, and external CRISPR/Cas9 functional genomics data. Systematic analyses included standardized mean difference (SMD), pathway enrichment, pseudotime trajectory inference, in silico knockout, cell-cell communication, metabolic flux scoring, immune infiltration, clinical correlation, drug sensitivity prediction, and molecular docking. RESULTS: At the protein level, immunohistochemistry (nuclear positivity) and external proteomic data collectively demonstrated consistent SUMO2 overexpression in HCC. Consistent upregulation was also observed at the mRNA level across large-scale cohorts. Single-cell RNA-seq and spatial transcriptomics localized SUMO2 enrichment to malignant hepatocytes and tumor-dominant regions. CRISPR-mediated SUMO2 knockout suppressed proliferation in multiple HCC cell lines. Mechanistically, high SUMO2 expression was significantly associated with metabolic reprogramming involving glycolysis/gluconeogenesis, pyruvate metabolism, and the tricarboxylic acid cycle. SUMO2-high malignant hepatocyte subpopulations exhibited enhanced activity of the macrophage migration inhibitory factor signaling axis and enhanced iron-sensor interactions. Further, the immune infiltration analysis revealed a negative correlation between SUMO2 expression and M1 macrophages and a positive correlation between follicular helper T cells and regulatory T cells. Clinically, elevated SUMO2 levels were found to be associated with adverse prognostic features. Furthermore, high SUMO2 expression was associated with increased sensitivity to dasatinib, and molecular docking simulations predicted potential binding between SUMO2 and dasatinib, with a Vina score of -8.5 kcal/mol. CONCLUSIONS: SUMO2 is aberrantly expressed at the protein, mRNA, single-cell, and spatial transcriptomic levels in HCC and is significantly associated with metabolic reprogramming and altered migration inhibitory factor (MIF)-mediated intercellular communication, suggesting its potential as a novel biomarker for diagnosis and treatment.

Humans↗