Putative functions of extracellular matrix glycoproteins in secondary palate morphogenesis

Cleft palate is a common birth defect in humans. Elevation and fusion of paired palatal shelves are coordinated by growth and transcription factors, and mutations in these can cause malformations. Among the effector genes for growth factor signaling are extracellular matrix (ECM) glycoproteins. These provide substrates for cell adhesion (e.g., fibronectin, tenascins), but also regulate growth factor availability (e.g., fibrillins). Cleft palate in Bmp7 null mouse embryos is caused by a delay in palatal shelf elevation. In contrast, palatal shelves of Tgf-β3 knockout mice elevate normally, but a cleft develops due to their failure to fuse. However, nothing is known about a possible functional interaction between specific ECM proteins and Tgf-β/Bmp family members in palatogenesis. To start addressing this question, we studied the mRNA and protein distribution of relevant ECM components during secondary palate development, and compared it to growth factor expression in wildtypewild type and mutant mice. We found that fibrillin-2 (but not fibrillin-1) mRNA appeared in the mesenchyme of elevated palatal shelves adjacent to the midline epithelial cells, which were positive for Tgf-β3 mRNA. Moreover, midline epithelial cells started expressing fibronectin upon contact of the two palatal shelves. These findings support the hypothesis that fibrillin-2 and fibronectin are involved in regulating the activity of Tgf-β3 at the fusing midline. In addition, we observed that tenascin-W (but not tenascin-C) was misexpressed in palatal shelves of Bmp7-deficient mouse embryos. In contrast to tenascin-C, tenascin-W secretion was strongly induced by Bmp7 in embryonic cranial fibroblasts in vitro. These results are consistent with a putative function for tenascin-W as a target of Bmp7 signaling during palate elevation. Our results indicate that distinct ECM proteins are important for morphogenesis of the secondary palate, both as downstream effectors and as regulators of Tgf-β/Bmp activity.

Strengthening of laterality of verbal and visuospatial functions during childhood and adolescence

Cognitive functions in the child's brain develop in the context of complex adaptive processes, determined by genetic and environmental factors. Little is known about the cerebral representation of cognitive functions during development. In particular, knowledge about the development of right hemispheric (RH) functions is scarce. Considering the dynamics of brain development, localization and lateralization of cognitive functions must be expected to change with age. Twenty healthy subjects (8.6-20.5 years) were examined with fMRI and neuropsychological tests. All participants completed two fMRI tasks known to activate left hemispheric (LH) regions (language tasks) and two tasks known to involve predominantly RH areas (visual search tasks). A laterality index (LI) was computed to determine the asymmetry of activation. Group analysis revealed unilateral activation of the LH language circuitry during language tasks while visual search tasks induced a more widespread RH activation pattern in frontal, superior temporal, and occipital areas. Laterality of language increased between the ages of 8-20 in frontal (r = 0.392, P = 0.049) and temporal (r = 0.387, P = 0.051) areas. The asymmetry of visual search functions increased in frontal (r = -0.525, P = 0.009) and parietal (r = -0.439, P = 0.027) regions. A positive correlation was found between Verbal-IQ and the LI during a language task (r = 0.585, P = 0.028), while visuospatial skills correlated with LIs of visual search (r = -0.621, P = 0.018). To summarize, cognitive development is accompanied by changes in the functional representation of neuronal circuitries, with a strengthening of lateralization not only for LH but also for RH functions. Our data show that age and performance, independently, account for the increases of laterality with age.

Functions and effects of creatine in the central nervous system

Creatine kinase catalyses the reversible transphosphorylation of creatine by ATP. In the cell, creatine kinase isoenzymes are specifically localized at strategic sites of ATP consumption to efficiently regenerate ATP in situ via phosphocreatine or at sites of ATP generation to build-up a phosphocreatine pool. Accordingly, the creatine kinase/phosphocreatine system plays a key role in cellular energy buffering and energy transport, particularly in cells with high and fluctuating energy requirements like neurons. Creatine kinases are expressed in the adult and developing human brain and spinal cord, suggesting that the creatine kinase/phosphocreatine system plays a significant role in the central nervous system. Functional impairment of this system leads to a deterioration in energy metabolism, which is phenotypic for many neurodegenerative and age-related diseases. Exogenous creatine supplementation has been shown to reduce neuronal cell loss in experimental paradigms of acute and chronic neurological diseases. In line with these findings, first clinical trials have shown beneficial effects of therapeutic creatine supplementation. Furthermore, creatine was reported to promote differentiation of neuronal precursor cells that might be of importance for improving neuronal cell replacement strategies. Based on these observations there is growing interest on the effects and functions of this compound in the central nervous system. This review gives a short excursion into the basics of the creatine kinase/phosphocreatine system and aims at summarizing findings and concepts on the role of creatine kinase and creatine in the central nervous system with special emphasis on pathological conditions and the positive effects of creatine supplementation.

Expressing and Amplifying Positive Emotions Facilitate Goal Attainment in Workplace Interactions

Expressing emotions has social functions; it provides information, affects social interactions, and shapes relationships with others. Expressing positive emotions could be a strategic tool for improving goal attainment during social interactions at work. Such effects have been found in research on social contagion, impression management, and emotion work. However, expressing emotions one does not feel entails the risk of being perceived as inauthentic. This risk may well be worth taking when the emotions felt are negative, as expressing negative emotions usually has negative effects. When experiencing positive emotions, however, expressing them authentically promises benefits, and the advantage of amplifying them is not so obvious. We postulated that expressing, and amplifying, positive emotions would foster goal attainment in social interactions at work, particularly when dealing with superiors. Analyses are based on 494 interactions involving the pursuit of a goal by 113 employes. Multilevel analyses, including polynomial analyses, show that authentic display of positive emotions supported goal attainment throughout. However, amplifying felt positive emotions promoted goal attainment only in interactions with superiors, but not with colleagues. Results are discussed with regard to the importance of hierarchy for detecting, and interpreting, signs of strategic display of positive emotions.

On the signature of positive braids and adjacency for torus knots

The objects of study in this thesis are knots. More precisely, positive braid knots, which include algebraic knots and torus knots. In the first part of this thesis, we compare two classical knot invariants - the genus g and the signature σ - for positive braid knots. Our main result on positive braid knots establishes a linear lower bound for the signature in terms of the genus. In the second part of the thesis, a positive braid approach is applied to the study of the local behavior of polynomial functions from the complex affine plane to the complex numbers. After endowing polynomial function germs with a suitable topology, the adjacency problem arises: for a fixed germ f, what classes of germs g can be found arbitrarily close to f? We introduce two purely topological notions of adjacency for knots and discuss connections to algebraic notions of adjacency and the adjacency problem.

The block numerical range of analytic operator functions

We introduce the block numerical range Wn(L) of an operator function L with respect to a decomposition H = H1⊕. . .⊕Hn of the underlying Hilbert space. Our main results include the spectral inclusion property and estimates of the norm of the resolvent for analytic L . They generalise, and improve, the corresponding results for the numerical range (which is the case n = 1) since the block numerical range is contained in, and may be much smaller than, the usual numerical range. We show that refinements of the decomposition entail inclusions between the corresponding block numerical ranges and that the block numerical range of the operator matrix function L contains those of its principal subminors. For the special case of operator polynomials, we investigate the boundedness of Wn(L) and we prove a Perron-Frobenius type result for the block numerical radius of monic operator polynomials with coefficients that are positive in Hilbert lattice sense.

Patterns of positive selection in seven ant genomes

The evolution of ants is marked by remarkable adaptations that allowed the development of very complex social systems. To identify how ant-specific adaptations are associated with patterns of molecular evolution, we searched for signs of positive selection on amino-acid changes in proteins. We identified 24 functional categories of genes which were enriched for positively selected genes in the ant lineage. We also reanalyzed genome-wide datasets in bees and flies with the same methodology, to check whether positive selection was specific to ants or also present in other insects. Notably, genes implicated in immunity were enriched for positively selected genes in the three lineages, ruling out the hypothesis that the evolution of hygienic behaviors in social insects caused a major relaxation of selective pressure on immune genes. Our scan also indicated that genes implicated in neurogenesis and olfaction started to undergo increased positive selection before the evolution of sociality in Hymenoptera. Finally, the comparison between these three lineages allowed us to pinpoint molecular evolution patterns that were specific to the ant lineage. In particular, there was ant-specific recurrent positive selection on genes with mitochondrial functions, suggesting that mitochondrial activity was improved during the evolution of this lineage. This might have been an important step toward the evolution of extreme lifespan that is a hallmark of ants.

The effects of qualitatively different acute physical activity interventions in real-world settings on executive functions in preadolescent children

There is growing evidence indicating a positive effect of acute physical activity on cognitive performance in children. Most of the evidence originates, however, from studies in highly controlled laboratory settings. The aim of the present study was to investigate whether the same effects can be found in more real-world settings. We examined the effects of qualitatively different acute physical activity interventions on the three core dimensions of executive functions (updating, inhibition, shifting). In an experimental between-subject design, 219 ten to twelve year-olds were assigned to one of four conditions which varied systematically in physical activation and cognitive engagement. Executive functions were measured before and immediately after the intervention. Contrary to the hypothesis, no effects of acute physical activity with and without cognitive engagement were found on executive functions in the overall sample. Only children with higher fitness and/or higher academic achievement benefitted from the interventions in terms of their updating performance. Thus, the results indicate that it may be more difficult to attain positive effects through acute physical activity in real-world settings than in laboratory settings and that physiological and cognitive requirements may have to be adjusted to individual capacity to make an intervention effective.

Melanoma Cell-Intrinsic PD-1 Receptor Functions Promote Tumor Growth.

Therapeutic antibodies targeting programmed cell death 1 (PD-1) activate tumor-specific immunity and have shown remarkable efficacy in the treatment of melanoma. Yet, little is known about tumor cell-intrinsic PD-1 pathway effects. Here, we show that murine and human melanomas contain PD-1-expressing cancer subpopulations and demonstrate that melanoma cell-intrinsic PD-1 promotes tumorigenesis, even in mice lacking adaptive immunity. PD-1 inhibition on melanoma cells by RNAi, blocking antibodies, or mutagenesis of melanoma-PD-1 signaling motifs suppresses tumor growth in immunocompetent, immunocompromised, and PD-1-deficient tumor graft recipient mice. Conversely, melanoma-specific PD-1 overexpression enhances tumorigenicity, as does engagement of melanoma-PD-1 by its ligand, PD-L1, whereas melanoma-PD-L1 inhibition or knockout of host-PD-L1 attenuate growth of PD-1-positive melanomas. Mechanistically, the melanoma-PD-1 receptor modulates downstream effectors of mTOR signaling. Our results identify melanoma cell-intrinsic functions of the PD-1:PD-L1 axis in tumor growth and suggest that blocking melanoma-PD-1 might contribute to the striking clinical efficacy of anti-PD-1 therapy.

Cognitively engaging chronic physical activity, but not aerobic exercise, affects executive functions in primary school children: A group-randomized controlled trial

Although the positive effects of different kinds of physical activity (PA) on cognitive functioning have already been demonstrated in a variety of studies, the role of cognitive engagement in promoting children’s executive functions is still unclear. The aim of the present study was therefore to investigate the effects of two qualitatively different chronic PA interventions on executive functions in primary school children. 181 children aged between 10 and 12 years were assigned to either a 6-week physical education program with a high level of physical exertion and high cognitive engagement (team games), a physical education program with high physical exertion but low cognitive engagement (aerobic exercise), or to a physical education program with both low physical exertion and low cognitive engagement (control condition). Executive functions (updating, inhibition, shifting) and aerobic fitness (multistage 20-meter shuttle run test) were measured before and after the respective condition. Results revealed that both interventions (team games and aerobic exercise) have a positive impact on children’s aerobic fitness (4-5 % increase in estimated VO2max). Importantly, an improvement in shifting performance was found only in the team games and not in the aerobic exercise or control condition. Thus, the inclusion of cognitive engagement in PA seems to be the most promising type of chronic intervention to enhance executive functions in children, providing further evidence for the importance of the qualitative aspects of PA.

ROLE OF MIR-19A RELEASED BY INFLAMMATORY BREAST CANCER CELLS IN THE REGULATION OF DENDRITIC CELL FUNCTIONS: IN VITRO MODEL OF CROSSTALK IN THE TUMOR MICROENVIRONMENT OF INFLAMMATORY BREAST CANCER

Inflammatory breast cancer (IBC) is a rare but very aggressive form of locally advanced breast cancer (1-6% of total breast cancer patients in United States), with a 5-year overall survival rate of only 40.5%, compared with 85% of the non-IBC patients. So far, a unique molecular signature for IBC able to explain the dramatic differences in the tumor biology between IBC and non-IBC has not been identified. As immune cells in the tumor microenvironment plays an important role in regulating tumor progression, we hypothesized that tumor-associated dendritic cells (TADC) may be responsible for regulating the development of the aggressive characteristics of IBC. MiRNAs can be released into the extracellular space and mediate the intercellular communication by regulating target gene expression beyond their cells of origin. We hypothesized that miRNAs released by IBC cells can induce an increased activation status, secretion of pro-inflammatory cytokines and migration ability of TADC. In an in vitro model of IBC tumor microenvironment, we found that the co-cultured of the IBC cell line SUM-149 with immature dendritic cells (iDCSUM-149) induced a higher degree of activation and maturation of iDCSUM-149 upon stimulation with lipopolysaccharide (LPS) compared with iDCs co-cultured with the non-IBC cell line SUM-159 (iDCSUM-159), resulting in: increased expression of the costimulatory and activation markers; higher production of pro-inflammatory cytokines (TNF-a, IL-6); and 3) higher migratory ability. These differences were due to the exosome-mediated transfer of miR-19a and miR-146a from SUM-149 and SUM-159, respectively, to iDCs, causing the downregulation of the miR-19a target genes PTEN, SOCS-1 and the miR-146a target genes IRAK1, TRAF6. PTEN, SOCS-1 and IRAK1, TRAF6 are important negative and positive regulator of cytokine- and TLR-mediated activation/maturation signaling pathway in DCs. Increased levels of IL-6 induced the upregulation of miR-19a synthesis in SUM-149 cells that was associated with the induction of CD44+CD24-ALDH1+ cancer stem cells (CSCs) with epithelial-to-mesenchymal transition (EMT) characteristics. In conclusion, in IBC tumor microenvironment IL-6/miR-19a axis can represent a self-sustaining loop able to maintain a pro-inflammatory status of DCs, leading to the development of tumor cells with high metastatic potential (EMT CSCs) responsible of the poor prognosis in IBC patients.

Systematic derivation of partition functions for ligand binding to two-dimensional lattices

The Ising problem consists in finding the analytical solution of the partition function of a lattice once the interaction geometry among its elements is specified. No general analytical solution is available for this problem, except for the one-dimensional case. Using site-specific thermodynamics, it is shown that the partition function for ligand binding to a two-dimensional lattice can be obtained from those of one-dimensional lattices with known solution. The complexity of the lattice is reduced recursively by application of a contact transformation that involves a relatively small number of steps. The transformation implemented in a computer code solves the partition function of the lattice by operating on the connectivity matrix of the graph associated with it. This provides a powerful new approach to the Ising problem, and enables a systematic analysis of two-dimensional lattices that model many biologically relevant phenomena. Application of this approach to finite two-dimensional lattices with positive cooperativity indicates that the binding capacity per site diverges as Na (N = number of sites in the lattice) and experiences a phase-transition-like discontinuity in the thermodynamic limit N → ∞. The zeroes of the partition function tend to distribute on a slightly distorted unit circle in complex plane and approach the positive real axis already for a 5×5 square lattice. When the lattice has negative cooperativity, its properties mimic those of a system composed of two classes of independent sites with the apparent population of low-affinity binding sites increasing with the size of the lattice, thereby accounting for a phenomenon encountered in many ligand-receptor interactions.

New infinite families of exact sums of squares formulas, Jacobi elliptic functions, and Ramanujan’s tau function

In this paper, we give two infinite families of explicit exact formulas that generalize Jacobi’s (1829) 4 and 8 squares identities to 4n2 or 4n(n + 1) squares, respectively, without using cusp forms. Our 24 squares identity leads to a different formula for Ramanujan’s tau function τ(n), when n is odd. These results arise in the setting of Jacobi elliptic functions, Jacobi continued fractions, Hankel or Turánian determinants, Fourier series, Lambert series, inclusion/exclusion, Laplace expansion formula for determinants, and Schur functions. We have also obtained many additional infinite families of identities in this same setting that are analogous to the η-function identities in appendix I of Macdonald’s work [Macdonald, I. G. (1972) Invent. Math. 15, 91–143]. A special case of our methods yields a proof of the two conjectured [Kac, V. G. and Wakimoto, M. (1994) in Progress in Mathematics, eds. Brylinski, J.-L., Brylinski, R., Guillemin, V. & Kac, V. (Birkhäuser Boston, Boston, MA), Vol. 123, pp. 415–456] identities involving representing a positive integer by sums of 4n2 or 4n(n + 1) triangular numbers, respectively. Our 16 and 24 squares identities were originally obtained via multiple basic hypergeometric series, Gustafson’s Cℓ nonterminating 6φ5 summation theorem, and Andrews’ basic hypergeometric series proof of Jacobi’s 4 and 8 squares identities. We have (elsewhere) applied symmetry and Schur function techniques to this original approach to prove the existence of similar infinite families of sums of squares identities for n2 or n(n + 1) squares, respectively. Our sums of more than 8 squares identities are not the same as the formulas of Mathews (1895), Glaisher (1907), Ramanujan (1916), Mordell (1917, 1919), Hardy (1918, 1920), Kac and Wakimoto, and many others.

The dual functions of Fas ligand in the regulation of peripheral CD8+ and CD4+ T cells

Although Fas ligand (FasL) is well characterized for its capacity to deliver a death signal through its receptor Fas, recent work demonstrates that FasL also can receive signals facilitating antigen (Ag)-specific proliferation of CD8+ T cells. The fact that the gld mutation differentially influences the proliferative capacity of CD8+ and CD4+ T cells presented the intriguing possibility that a single molecule may play opposing roles in these two subpopulations. The present study focuses on how these positive and negative regulatory roles are balanced. We show that naive CD4+ T cells are responsive to FasL-mediated costimulation on encounter with Ag when Fas-mediated death is prevented. Thus, the machinery responsible for transducing the FasL positive reverse signal operates in both CD4+ and CD8+ T cells. Instead, differential control of FasL expression distinguishes the role of FasL in these two T cell subpopulations. FasL costimulation occurs immediately on T cell receptor ligation and correlates with the up-regulation of FasL expression on CD8+ and naive CD4+ T cells, both of which are sensitive to the FasL costimulatory signal. Conversely, FasL-initiated death occurs late in an immune response when high levels of FasL expression are maintained on CD4+ T cells that are sensitive to Fas-mediated death, but not on CD8+ T cells that are relatively insensitive to this signal. This careful orchestration of FasL expression during times of susceptibility to costimulation and conversely, to death, endows FasL with the capacity to both positively and negatively regulate the peripheral T cell compartment.

Thyroid hormone receptor-associated proteins and general positive cofactors mediate thyroid hormone receptor function in the absence of the TATA box-binding protein-associated factors of TFIID

Coactivators previously implicated in ligand-dependent activation functions by thyroid hormone receptor (TR) include p300 and CREB-binding protein (CBP), the steroid receptor coactivator-1 (SRC-1)-related family of proteins, and the multicomponent TR-associated protein (TRAP) complex. Here we show that two positive cofactors (PC2 and PC4) derived from the upstream stimulatory activity (USA) cofactor fraction act synergistically to mediate thyroid hormone (T3)-dependent activation either by TR or by a TR-TRAP complex in an in vitro system reconstituted with purified factors and DNA templates. Significantly, the TRAP-mediated enhancement of activation by TR does not require the TATA box-binding protein-associated factors of TFIID. Furthermore, neither the pleiotropic coactivators CBP and p300 nor members of the SRC-1 family were detected in either the TR-TRAP complex or the other components of the in vitro assay system. These results show that activation by TR at the level of naked DNA templates is enhanced by cooperative functions of the TRAP coactivators and the general coactivators PC2 and PC4, and they further indicate a potential functional redundancy between TRAPs and TATA box-binding protein-associated factors in TFIID. In conjunction with earlier studies on other nuclear receptor-interacting cofactors, the present study also suggests a multistep pathway, involving distinct sets of cofactors, for activation of hormone responsive genes.