It is well established that the large array of functions that a tumour cell has to fulfil to settle as a metastasis in a distant organ requires cooperative activities between the tumour and the ...surrounding tissue and that several classes of molecules are involved, such as cell-cell and cell-matrix adhesion molecules and matrix degrading enzymes, to name only a few. Furthermore, metastasis formation requires concerted activities between tumour cells and surrounding cells as well as matrix elements and possibly concerted activities between individual molecules of the tumour cell itself. Adhesion molecules have originally been thought to be essential for the formation of multicellular organisms and to tether cells to the extracellular matrix or to neighbouring cells. CD44 transmembrane glycoproteins belong to the families of adhesion molecules and have originally been described to mediate lymphocyte homing to peripheral lymphoid tissues. It was soon recognized that the molecules, under selective conditions, may suffice to initiate metastatic spread of tumour cells. The question remained as to how a single adhesion molecule can fulfil that task. This review outlines that adhesion is by no means a passive task. Rather, ligand binding, as exemplified for CD44 and other similar adhesion molecules, initiates a cascade of events that can be started by adherence to the extracellular matrix. This leads to activation of the molecule itself, binding to additional ligands, such as growth factors and matrix degrading enzymes, complex formation with additional transmembrane molecules and association with cytoskeletal elements and signal transducing molecules. Thus, through the interplay of CD44 with its ligands and associating molecules CD44 modulates adhesiveness, motility, matrix degradation, proliferation and cell survival, features that together may well allow a tumour cell to proceed through all steps of the metastatic cascade.
Activity in the healthy brain relies on a concerted interplay of excitation (E) and inhibition (I) via balanced synaptic communication between glutamatergic and GABAergic neurons. A growing number of ...studies imply that disruption of this E/I balance is a commonality in many brain disorders; however, obtaining mechanistic insight into these disruptions, with translational value for the patient, has typically been hampered by methodological limitations. Cadherin-13 (CDH13) has been associated with autism and attention-deficit/hyperactivity disorder. CDH13 localizes at inhibitory presynapses, specifically of parvalbumin (PV) and somatostatin (SST) expressing GABAergic neurons. However, the mechanism by which CDH13 regulates the function of inhibitory synapses in human neurons remains unknown. Starting from human-induced pluripotent stem cells, we established a robust method to generate a homogenous population of SST and MEF2C (PV-precursor marker protein) expressing GABAergic neurons (iGABA) in vitro, and co-cultured these with glutamatergic neurons at defined E/I ratios on micro-electrode arrays. We identified functional network parameters that are most reliably affected by GABAergic modulation as such, and through alterations of E/I balance by reduced expression of CDH13 in iGABAs. We found that CDH13 deficiency in iGABAs decreased E/I balance by means of increased inhibition. Moreover, CDH13 interacts with Integrin-β1 and Integrin-β3, which play opposite roles in the regulation of inhibitory synaptic strength via this interaction. Taken together, this model allows for standardized investigation of the E/I balance in a human neuronal background and can be deployed to dissect the cell-type-specific contribution of disease genes to the E/I balance.
The cell-cell signaling gene
is associated with a wide spectrum of neuropsychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD), autism, and major depression.
regulates ...axonal outgrowth and synapse formation, substantiating its relevance for neurodevelopmental processes. Several studies support the influence of
on personality traits, behavior, and executive functions. However, evidence for functional effects of common gene variation in the
gene in humans is sparse. Therefore, we tested for association of a functional intronic
SNP rs2199430 with ADHD in a sample of 998 adult patients and 884 healthy controls. The Big Five personality traits were assessed by the NEO-PI-R questionnaire. Assuming that altered neural correlates of working memory and cognitive response inhibition show genotype-dependent alterations, task performance and electroencephalographic event-related potentials were measured by n-back and continuous performance (Go/NoGo) tasks. The rs2199430 genotype was not associated with adult ADHD on the categorical diagnosis level. However, rs2199430 was significantly associated with agreeableness, with minor G allele homozygotes scoring lower than A allele carriers. Whereas task performance was not affected by genotype, a significant heterosis effect limited to the ADHD group was identified for the n-back task. Heterozygotes (AG) exhibited significantly higher N200 amplitudes during both the 1-back and 2-back condition in the central electrode position Cz. Consequently, the common genetic variation of
is associated with personality traits and impacts neural processing during working memory tasks. Thus,
might contribute to symptomatic core dysfunctions of social and cognitive impairment in ADHD.
Renal cell carcinoma (RCC) are frequently chemo- and radiation resistant. Thus, there is a need for identifying biological features of these cells that could serve as alternative therapeutic targets. ...We performed suppression subtractive hybridization (SSH) on patient-matched normal renal and RCC tissue to identify variably regulated genes. 11 genes were strongly up-regulated or selectively expressed in more than one RCC tissue or cell line. Screening of filters containing cancer-related cDNAs confirmed overexpression of 3 of these genes and 3 additional genes were identified. These 14 differentially expressed genes, only 6 of which have previously been associated with RCC, are related to tumour growth/survival (EGFR, cyclin D1, insulin-like growth factor-binding protein-1 and a MLRQ sub-unit homologue of the NADH:ubiquinone oxidoreductase complex), angiogenesis (vascular endothelial growth factor, endothelial PAS domain protein-1, ceruloplasmin, angiopoietin-related protein 2) and cell adhesion/motility (protocadherin 2, cadherin 6, autotaxin, vimentin, lysyl oxidase and semaphorin G). Since some of these genes were overexpressed in 80-90% of RCC tissues, it is important to evaluate their suitability as therapeutic targets.
A
bstract
We present analytical results at four-loop level for the
β
-function of the coupling of a generic gauge group and any number of different quark representations. From this we can directly ...derive the gluino contribution to the strong coupling
β
-function of supersymmetric extensions of the Standard Model.
Summary
Background Alopecia areata (AA) is a T‐cell mediated putative autoimmune disease of hair follicles, which can be transferred by CD4+ T cells. However, whether T‐helper (Th) 1 or Th2 ...cytokines are predominant has not yet been defined.
Objectives To elucidate the importance of Th1 cells in the pathogenesis of AA we investigated the functional role of interferon (IFN)‐γ in the experimental induction of AA.
Methods AA was experimentally induced by grafting full‐thickness skin from AA‐affected C3H/HeJ mice on to C3H/HeJ mice with a targeted deletion of the Th1 cytokine IFN‐γ gene (IFNγ−/−) and on to wild‐type mice (IFNγ+/+).
Results While 90% of wild‐type mice developed AA, none of the IFNγ−/− mice exhibited hair loss. Immunohistochemistry of skin sections revealed a dense perifollicular and intrafollicular infiltrate of CD4+ and CD8+ T cells in controls, while in IFNγ−/− mice skin‐infiltrating CD8+ T cells were absent and the number of CD4+ cells was significantly reduced. Aberrant expression of major histocompatibility complex class I and II molecules in the putative immune‐privileged infrainfundibular site of the hair follicle was found to be weaker in AA‐resistant IFNγ−/− mice than in control mice with AA. Flow cytometry revealed that leucocytes of IFNγ−/− mice did not respond to the transfer of AA‐affected skin. As distinct from IFNγ+/+ mice, neither T‐cell activation markers nor Th1 cytokines were upregulated in draining lymph node cells or skin‐infiltrating leucocytes of AA‐resistant IFNγ−/− mice. However, there was no evidence for a shift towards a Th2 cytokine profile, nor for upregulation of regulatory T cells in IFNγ−/− mice.
Conclusions IFNγ−/− mice fail to activate Th1 cells in response to the transplanted (auto)antigens, which suggests an essential requirement for IFN‐γ‐mediated Th1 activation in the induction of AA.
Bronchoconstriction is a characteristic symptom of various chronic obstructive respiratory diseases such as chronic obstructive pulmonary disease and asthma. Precision-cut lung slices (PCLS) are a ...suitable ex vivo model to study physiological mechanisms of bronchoconstriction in different species. In the present study, we established an ex vivo model of bronchoconstriction in nonhuman primates (NHPs). PCLS prepared from common marmosets, cynomolgus macaques, rhesus macaques, and anubis baboons were stimulated with increasing concentrations of representative bronchoconstrictors: methacholine, histamine, serotonin, leukotriene D₄ (LTD₄), U46619, and endothelin-1. Alterations in the airway caliber were measured and compared with previously published data from rodents, guinea pigs, and humans. Methacholine induced maximal airway constriction, varying between 74 and 88% in all NHP species, whereas serotonin was ineffective. Histamine induced maximal bronchoconstriction of 77 to 90% in rhesus macaques, cynomolgus macaques, and baboons and a lesser constriction of 53% in marmosets. LTD₄ was ineffective in marmosets and rhesus macaques but induced a maximum constriction of 44 to 49% in cynomolgus macaques and baboons. U46619 and endothelin-1 caused airway constriction in all NHP species, with maximum constrictions of 65 to 91% and 70 to 81%, respectively. In conclusion, PCLS from NHPs represent a valuable ex vivo model for studying bronchoconstriction. All NHPs respond to mediators relevant to human airway disorders such as methacholine, histamine, U46619, and endothelin-1 and are insensitive to the rodent mast cell product serotonin. Only PCLS from cynomolgus macaques and baboons, however, responded also to leukotrienes, suggesting that among all compared species, these two NHPs resemble the human airway mechanisms best.
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