The Morphometrics of “Masculinity” in Human Faces

In studies of social inference and human mate preference, a wide but inconsistent array of tools for computing facial masculinity has been devised. Several of these approaches implicitly assumed that the individual expression of sexually dimorphic shape features, which we refer to as maleness, resembles facial shape features perceived as masculine. We outline a morphometric strategy for estimating separately the face shape patterns that underlie perceived masculinity and maleness, and for computing individual scores for these shape patterns. We further show how faces with different degrees of masculinity or maleness can be constructed in a geometric morphometric framework. In an application of these methods to a set of human facial photographs, we found that shape features typically perceived as masculine are wide faces with a wide inter-orbital distance, a wide nose, thin lips, and a large and massive lower face. The individual expressions of this combination of shape features—the masculinity shape scores—were the best predictor of rated masculinity among the compared methods (r = 0.5). The shape features perceived as masculine only partly resembled the average face shape difference between males and females (sexual dimorphism). Discriminant functions and Procrustes distances to the female mean shape were poor predictors of perceived masculinity.     

Life After Death: Are Autophagy Genes Involved in Cell Death and Survival During Plant Innate Immune Responses?

It has not escaped the attention of the plant disease resistance community that the vacuole is rapidly emerging as a central player in the execution of cell death. On the one hand the targeted destruction of the vacuole—from the inside out—by vacuolar processing enzymes (VPE) is required to induce PCD in pathogen-infected cells. On the other hand, an intact vacuole is vital for a functional autophagic response to ensure survival of uninfected cells. At face value, the two responses seem to represent distinct resistance mechanisms that operate at divergent branch points and their use of the vacuole merely coincidental. However, closer examination has led us to propose an interesting hypothesis that accounts for these two opposing roles of the vacuole in both VPE-mediated PCD and autophagy-dependent cell survival. During initial infection, we propose a mechanism similar to the CPY transport pathway in yeast wherein select ATG genes are needed for VPE transport, vacuolar processing and initiation of PCD. Later during infection, autophagy-specific genes are needed for autophagosome formation, sequestration of VPE preproteins and VPE degradation.     

The Role of Altered Cell–Cell Communication in Melanoma Progression

Under normal homeostasis, melanocyte growth and behaviour is tightly controlled by the surrounding keratinocytes. Keratinocytes regulate melanocyte behaviour through a complex system of paracrine growth factors and cell-cell adhesion molecules. Pathological changes, leading to development of malignant melanoma, upset this delicate homeostatic balance and can lead to altered expression of cell-cell adhesion and cell-cell communication molecules. In particular, there is a switch from the E-cadherin-mediated keratinocyte-melanocyte partnership to the N-cadherin-mediated melanoma-melanoma and melanoma-fibroblast interaction. Other changes include the alteration in the gap junctions formed between the melanocyte and keratinocyte. Changes in the connexin expression, in particular the loss of connexin 43, may result in a reduction or a loss of gap junctional activity, which is thought to contribute towards tumour progression. In the current review we describe the alterations in cell-cell adhesion and communication associated with melanoma development and progression, and discuss how a greater understanding of these processes may aid the future therapy of this disease.     

Accumulation of Self-Reactive Na?ve and Memory B Cell Reveals Sequential Defects in B Cell Tolerance Checkpoints in Sj?gren’s Syndrome

Sjögren’s syndrome (SS) is an autoimmune disease characterised by breach of self-tolerance towards nuclear antigens resulting in high affinity circulating autoantibodies. Although peripheral B cell disturbances have been described in SS, with predominance of naïve and reduction of memory B cells, the stage at which errors in B cell tolerance checkpoints accumulate in SS is unknown. Here we determined the frequency of self- and poly-reactive B cells in the circulating naïve and memory compartment of SS patients. Single CD27−IgD+ naïve, CD27+IgD+ memory unswitched and CD27+IgD− memory switched B cells were sorted by FACS from the peripheral blood of 7 SS patients. To detect the frequency of polyreactive and autoreactive clones, paired Ig V_H and V_L genes were amplified, cloned and expressed as recombinant monoclonal antibodies (rmAbs) displaying identical specificity of the original B cells. IgV_H and V_L gene usage and immunoreactivity of SS rmAbs were compared with those obtained from healthy donors (HD). From a total of 353 V_H and 293 V_L individual sequences, we obtained 114 rmAbs from circulating naïve (n = 66) and memory (n = 48) B cells of SS patients. Analysis of the Ig V gene repertoire did not show significant differences in SS vs. HD B cells. In SS patients, circulating naïve B cells (with germline V_H and V_L genes) displayed a significant accumulation of clones autoreactive against Hep-2 cells compared to HD (43.1% vs. 25%). Moreover, we demonstrated a progressive increase in the frequency of circulating anti-nuclear naïve (9.3%), memory unswitched (22.2%) and memory switched (27.3%) B cells in SS patients. Overall, these data provide novel evidence supporting the existence of both early and late defects in B cell tolerance checkpoints in patients with SS resulting in the accumulation of autoreactive naïve and memory B cells.     

The IKK Inhibitor Bay 11-7082 Induces Cell Death Independent from Inhibition of Activation of NFκB Transcription Factors

Multiple myeloma (MM) displays an NFκB activity-related gene expression signature and about 20% of primary MM samples harbor genetic alterations conducive to intrinsic NFκB signaling activation. The relevance of blocking the classical versus the alternative NFκB signaling pathway and the molecular execution mechanisms involved, however, are still poorly understood. Here, we comparatively tested NFκB activity abrogation through TPCA-1 (an IKK2 inhibitor), BAY 11-7082 (an IKK inhibitor poorly selective for IKK1 and IKK2), and MLN4924 (an NEDD8 activating enzyme (NAE)-inhibitor), and analyzed their anti-MM activity. Whereas TPCA-1 interfered selectively with activation of the classical NFκB pathway, the other two compounds inhibited classical and alternative NFκB signaling without significant discrimination. Noteworthy, whereas TPCA-1 and MLN4924 elicited rather mild anti-MM effects with slight to moderate cell death induction after 1 day BAY 11-7082 was uniformly highly toxic to MM cell lines and primary MM cells. Treatment with BAY 11-7082 induced rapid cell swelling and its initial effects were blocked by necrostatin-1 or the ROS scavenger BHA, but a lasting protective effect was not achieved even with additional blockade of caspases. Because MLN4924 inhibits the alternative NFκB pathway downstream of IKK1 at the level of p100 processing, the quite discordant effects between MLN4924 and BAY 11-7082 must thus be due to blockade of IKK1-mediated NFκB-independent necrosis-inhibitory functions or represent an off-target effect of BAY 11-7082. In accordance with the latter, we further observed that concomitant knockdown of IKK1 and IKK2 did not have any major short-term adverse effect on the viability of MM cells.     

Quantification of Biomass and Cell Motion in Human Pluripotent Stem?Cell?Colonies

Somatic cell reprogramming to pluripotency requires an immediate increase in cell proliferation and reduction in cell size. It is unknown whether proliferation and biomass controls are similarly coordinated with early events during the differentiation of pluripotent stem cells (PSCs). This impasse exists because PSCs grow in tight clusters or colonies, precluding most quantifying approaches. Here, we investigate live cell interferometry as an approach to quantify the biomass and growth of HSF1 human PSC colonies before and during retinoic acid-induced differentiation. We also provide an approach for measuring the rate and coordination of intracolony mass redistribution in HSF1 clusters using live cell interferometry images. We show that HSF1 cells grow at a consistent, exponential rate regardless of colony size and display coordinated intracolony movement that ceases with the onset of differentiation. By contrast, growth and proliferation rates show a decrease of only ∼15% decrease during early differentiation despite global changes in gene expression and previously reported changes in energy metabolism. Overall, these results suggest that cell biomass and proliferation are regulated independent of pluripotency during early differentiation, which is distinct from what occurs with successful reprogramming.     

Retinoid-X-Receptors (α/β) in Melanocytes Modulate Innate Immune Responses and Differentially Regulate Cell Survival following UV Irradiation

Understanding the molecular mechanisms of ultraviolet (UV) induced melanoma formation is becoming crucial with more reported cases each year. Expression of type II nuclear receptor Retinoid-X-Receptor α (RXRα) is lost during melanoma progression in humans. Here, we observed that in mice with melanocyte-specific ablation of RXRα and RXRβ, melanocytes attract fewer IFN-γ secreting immune cells than in wild-type mice following acute UVR exposure, via altered expression of several chemoattractive and chemorepulsive chemokines/cytokines. Reduced IFN-γ in the microenvironment alters UVR-induced apoptosis, and due to this, the survival of surrounding dermal fibroblasts is significantly decreased in mice lacking RXRα/β. Interestingly, post-UVR survival of the melanocytes themselves is enhanced in the absence of RXRα/β. Loss of RXRs α/β specifically in the melanocytes results in an endogenous shift in homeostasis of pro- and anti-apoptotic genes in these cells and enhances their survival compared to the wild type melanocytes. Therefore, RXRs modulate post-UVR survival of dermal fibroblasts in a “non-cell autonomous” manner, underscoring their role in immune surveillance, while independently mediating post-UVR melanocyte survival in a “cell autonomous” manner. Our results emphasize a novel immunomodulatory role of melanocytes in controlling survival of neighboring cell types besides controlling their own, and identifies RXRs as potential targets for therapy against UV induced melanoma.     

Cell polarity: The missing link in skeletal morphogenesis?

Despite extensive genetic analysis of the dynamic multi-phase process that transforms a small population of lateral plate mesoderm into the mature limb skeleton, the mechanisms by which signaling pathways regulate cellular behaviors to generate morphogenetic forces are not known. Recently, a series of papers have offered the intriguing possibility that regulated cell polarity fine-tunes the morphogenetic process via orienting cell axes, division planes and cell movements. Wnt5a-mediated non-canonical signaling, which may include planar cell polarity, has emerged as a common thread in the otherwise distinct signaling networks that regulate morphogenesis in each phase of limb development. These findings position the limb as a key model to elucidate how global tissue patterning pathways direct local differences in cell behavior that, in turn, generate growth and form.     

Mechanical Cell–Cell Communication in Fibrous Networks: The Importance of Network Geometry

Cells contracting in extracellular matrix (ECM) can transmit stress over long distances, communicating their position and orientation to cells many tens of micrometres away. Such phenomena are not observed when cells are seeded on substrates with linear elastic properties, such as polyacrylamide (PA) gel. The ability for fibrous substrates to support far reaching stress and strain fields has implications for many physiological processes, while the mechanical properties of ECM are central to several pathological processes, including tumour invasion and fibrosis. Theoretical models have investigated the properties of ECM in a variety of network geometries. However, the effects of network architecture on mechanical cell–cell communication have received little attention. This work investigates the effects of geometry on network mechanics, and thus the ability for cells to communicate mechanically through different networks. Cell-derived displacement fields are quantified for various network geometries while controlling for network topology, cross-link density and micromechanical properties. We find that the heterogeneity of response, fibre alignment, and substrate displacement fields are sensitive to network choice. Further, we show that certain geometries support mechanical communication over longer distances than others. As such, we predict that the choice of network geometry is important in fundamental modelling of cell–cell interactions in fibrous substrates, as well as in experimental settings, where mechanical signalling at the cellular scale plays an important role. This work thus informs the construction of theoretical models for substrate mechanics and experimental explorations of mechanical cell–cell communication.