Concepts and Compositionality: In Search of the Brain's Language of Thought.

Imagine Genghis Khan, Aretha Franklin, and the Cleveland Cavaliers performing an opera on Maui. This silly sentence makes a serious point: As humans, we can flexibly generate and comprehend an unbounded number of complex ideas. Little is known, however, about how our brains accomplish this. Here we assemble clues from disparate areas of cognitive neuroscience, integrating recent research on language, memory, episodic simulation, and computational models of high-level cognition. Our review is framed by Fodor's classic language of thought hypothesis, according to which our minds employ an amodal, language-like system for combining and recombining simple concepts to form more complex thoughts. Here, we highlight emerging work on combinatorial processes in the brain and consider this work's relation to the language of thought. We review evidence for distinct, but complementary, contributions of map-like representations in subregions of the default mode network and sentence-like representations of conceptual relations in regions of the temporal and prefrontal cortex.

Chondrocyte deformation induces mitochondrial distortion and heterogeneous intracellular strain fields.

Chondrocyte mechanotransduction is poorly understood but may involve cell deformation and associated distortion of intracellular structures and organelles. This study quantifies the intracellular displacement and strain fields associated with chondrocyte deformation and in particular the distortion of the mitochondria network, which may have a role in mechanotransduction. Isolated articular chondrocytes were compressed in agarose constructs and simultaneously visualised using confocal microscopy. An optimised digital image correlation technique was developed to calculate the local intracellular displacement and strain fields using confocal images of fluorescently labelled mitochondria. The mitochondria formed a dynamic fibrous network or reticulum, which co-localised with microtubules and vimentin intermediate filaments. Cell deformation induced distortion of the mitochondria, which collapsed in the axis of compression with a resulting loss of volume. Compression generated heterogeneous intracellular strain fields indicating mechanical heterogeneity within the cytoplasm. The study provides evidence supporting the potential involvement of mitochondrial deformation in chondrocyte mechanotransduction, possibly involving strain-mediated release of reactive oxygen species. Furthermore the heterogeneous strain fields, which appear to be influenced by intracellular structure and organisation, may generate significant heterogeneity in mechanotransduction behaviour for cells subjected to identical levels of deformation.

Strain-dependent recovery behavior of single chondrocytes.

One of the challenges facing researchers studying chondrocyte mechanobiology is determining the range of mechanical forces pertinent to the problems they study. One possible way to deal with this problem is to quantify how the biomechanical behavior of cells varies in response to changing mechanical forces. In this study, the compressibility and recovery behaviors of single chondrocytes were determined as a function of compressive strains from 6 to 63%. Bovine articular chondrocytes from the middle and deep zones were subjected to this range of strains, and digital videocapture was used to track changes in cell dimensions during and after compression. The normalized volume change, apparent Poisson's ratio, residual strain after recovery, cell volume fraction after recovery, and characteristic recovery time constant were analyzed with respect to axial strain. Normalized volume change varied as a function of strain, demonstrating that chondrocytes exhibited compressibility. The mean Poisson's ratio of chondrocytes was found to be 0.29 +/- 0.14, and did not vary with axial strain. In contrast, residual strain, recovered volume fraction, and recovery time constant all depended on axial strain. The dependence of residual strain and recovered volume fraction on axial strain showed a change in behavior around 25-30% strain, opening up the possibility that this range of strains represents a critical value for chondrocytes. Quantifying the mechanical behavior of cells as a function of stress and strain is a potentially useful approach for identifying levels of mechanical stimulation that may be germane to normal cartilage physiology, functional tissue engineering of cartilage, and the etiopathogenesis of osteoarthritis.

Integrin-mediated mechanotransduction in IL-1 beta stimulated chondrocytes.

Mechanical loading and interleukin-1 beta (IL-1 beta) influence the release of nitric oxide (*NO) and prostaglandin E2 (PGE2) from articular chondrocytes via distinct signalling mechanisms. The exact nature of the interplay between the respective signalling pathways remains unclear. Recent studies have shown that integrins act as mechanoreceptors and may transduce extracellular stimuli into intracellular signals, thereby influencing cellular response. The current study demonstrates that the application of dynamic compression induced an inhibition of *NO and an upregulation of cell proliferation and proteoglycan synthesis in the presence and absence of IL-1 beta. PGE2 release was not affected by dynamic compression in the absence of IL-1 beta but was inhibited in the presence of the cytokine. The integrin binding peptide, GRGDSP, abolished or reversed the compression-induced alterations in all four parameters assessed in the presence and absence of IL-1 beta. The non-binding control peptide, GRADSP, had no effect. These data clearly demonstrate that the metabolic response of the chondrocytes to dynamic compression in the presence and absence of IL-1 beta, are integrin mediated.

Role of growth factors in rabbit articular cartilage repair by chondrocytes in agarose.

OBJECTIVE: Novel approaches to intervention in joint diseases consist of the replacement of diseased cartilage by in vitro engineered, viable cells or graft tissues. Two major obstacles remain to be overcome: (1) Hyaline cartilage in vitro often loses differentiated traits. (2) Grafts frequently are not integrated satisfactorily into host cartilage and/or the tissue is remodelled in situ into functionally inferior fibrocartilage. Therefore, we have explored the possibility whether chondrocytes embedded into agarose gels provided better graft tissues in a repair model of full thickness defects in rabbit joint cartilage. DESIGN: Experimental defects of knee joint cartilage was filled with articular chondrocytes cultured in agarose gels. Chondrocytes in vitro either remained unstimulated or were treated with several growth factors. Repair of the defects was assessed by histology and was scored between 0 (no healing) and 1 (perfect healing) as judged by the follwing parameters: intensity of proteoglycan staining, organization of the superficial zone, ossification at the border between repair cartilage and subchondral bone, tidemark formation in the repaired area, arrangement of chondrocytes, and integration of repair cartilage into host. RESULTS: Treatment of chondrocyte cultures with bFGF had a stabilizing effect on the differentiated state of the cells in implanted grafts whereas bone morphogenetic proteins stimulated ingrowth of subchondral bone reducing repair cartilage thickness and preventing normal tide mark formation; TGF-beta did not significantly affect evaluation parameters in comparison with untreated controls. CONCLUSION: Growth factor treatment resulted in an ambiguous quality of graft development. Only FGF had a clear beneficial effect to the graft tissues after 1 month. Further studies are required to define the precise conditions and sequence of growth factor treatment of in vitro engineered cartilage which benefits graft quality.

Quimiotaxis del neutrófilo en pacientes con periodontitis de aparición temprana / Neutrophil chemotaxis in patients with early-onset periodontitis

Se ha observado que el polimorfonuclear neutrófilo (PMN) es la célula de defensa por excelencia de las estructuras periodontales, al jugar un papel fundamental como primera línea de defensa del organismo ante el ataque bacteriano. Esta investigación se realizó para verificar si hay alteración en la función quimiotáctica de los neutrófilos en pacientes con periodontitis de aparición temprana (PAT). Se estudiaron 10 pacientes con PAT con buen estado de salud general, que no hubieran recibido terapia antibiótica en los últimos 6 meses y 10 sanos periodontal y sistémicamente, a los cuales se les tomó una muestra sanguínea de 10 cc para realizar la extracción de los PMN neutrófilos y posteriormente, la quimiotaxis bajo agarosa. El análisis estadístico realizado fue la prueba t para los datos paramétricos (edad, viabilidad, pureza y recuento) y la prueba U de Mann-Whitney para los no paramétricos (diferencial e índice quimiotáctico). Los pacientes con PAT no mostraron diferencias significativas en los valores de quimiotaxis al compararlos con los resultados de los sanos periodontalmente (p mayor 0.05). La edad promedio de los pacientes en ambos grupos fue de 23 años. Tanto la viabilidad como la pureza mínima requeridas para realizar la pureba de quimiotaxis fueron del 90 por ciento. De los resultados del presente estudio se concluye que no existe ninguna alteración en la función quimiotáctica del neutrófilo de sangre periférica de los pacientes con periodontitis de aparición temprana, sugiriéndose que, de existir alteración inmunológica en dichos pacientes, podría estar presente a otro nivel

Evidence that agarose must be internalized to stimulate mouse macrophages in vitro.

Agarose stimulation of macrophages in vitro was studied. Under conditions where agarose was ingested, stimulation was detected during 24-48 h of incubation at a time when the agarose increasingly was concentrated in the perinuclear region. Removal of extracellular agarose after 24 h when endocytosis had reached a plateau did not reduce the stimulatory effect. Preincubation for 4 days with dextran sulphate in concentrations reported to inhibit phagosome-lysosome fusion potentiated strongly the stimulatory effect. In all situations in which agarose was not internalized--in teflon tubes where the cells remain in suspension, on glass cover slips with inhibitors (2-deoxy-D-glucose, cytochalasin B), or with large, noningestible Sepharose beads--no stimulation was recorded. The possibility is discussed that stimulation of macrophages by agarose may be related to complement activation in phagosomes.