Cells as Active Particles in Asymmetric Potentials: Motility under External Gradients

Cell migration is a crucial event during development and in disease. Mechanical constraints and chemical gradients can contribute to the establishment of cell direction, but their respective roles remain poorly understood. Using a microfabricated topographical ratchet, we show that the nucleus dictates the direction of cell movement through mechanical guidance by its environment. We demonstrate that this direction can be tuned by combining the topographical ratchet with a biochemical gradient of fibronectin adhesion. We report competition and cooperation between the two external cues. We also quantitatively compare the measurements associated with the trajectory of a model that treats cells as fluctuating particles trapped in a periodic asymmetric potential. We show that the cell nucleus contributes to the strength of the trap, whereas cell protrusions guided by the adhesive gradients add a constant tunable bias to the direction of cell motion.     

The effect of anaerobiosis on the induced synthesis of β-galactosidase in non-growingEscherichia coli

Depending on conditions of aeration maltose and glucose were found to exhibit different effects on the inducible synthesis of β-galactosidase in aerobically grown cells ofEscherichia coli starving for an exogenous source of nitrogen; both saccharides repressed the synthesis of the enzyme under aerobic conditions, while the above-mentioned saccharides were essential for the enzyme synthesis under anaerobic conditions. The presence of maltose in the medium resulted in the repression of the enzyme synthesis in anaerobically grown cells starving for an exogenous nitrogen source under anaerobic conditions. The synthesis of β-galactosidase-specific messenger RNA was completely blocked and the synthesis of the enzyme proper considerably inhibited in aerobically grown cells incubated anaerobically in a medium without nitrogen and carbon sources.     

Genetic variability of the gene cluster CALHM1–3 in sporadic Creutzfeldt-Jakob disease

Perturbations of calcium homeostasis have been associated with several neurodegenerative disorders. A common polymorphism (rs2986017) in the CALHM1 gene, coding for a regulator of calcium homeostasis, is a genetic risk factor for the development of Alzheimer disease (AD). Although some authors failed to confirm these results, a meta-analysis has shown that this polymorphism modulates the age at disease onset. Furthermore, a recent association study has explored the genetic variability of CALHM1 gene and two adjacent paralog genes (CALHM3 and CALHM2) in an Asian population. Since several lines of evidence suggest that AD and prion diseases share pathophysiologic mechanisms, we investigated for the first time the genetic variability of the gene cluster formed by CALHM1 and its paralogs in a series of 235 sporadic Creutzfeldt-Jakob disease (sCJD) patients, and compared the genotypic and allelic frequencies with those presented in 329 controls from the same ancestry. As such, this work also represents the first association analysis of CALHM genes in sCJD. Sequencing analysis of the complete coding regions of the genes demonstrated the presence of 10 single nucleotide polymorphisms (SNP) within the CALHM genes. We observed that rs4918016-rs2986017-rs2986018 and rs41287502-rs41287500 polymorphic sites at CALHM1 were in linkage disequilibrium. We found marginal associations for sCJD risk at CALHM1 polymorphic sites rs41287502 and rs41287500 [coding for two linked missense mutations (p.(Met323Ile); (Gly282Cys)], and rs2986017 [p.(Leu86Pro)]. Interestingly, a TGG haplotype defined by the rs4918016-rs2986017-rs2986018 block was associated with sCJD. These findings underscore the need of future multinational collaborative initiatives in order to corroborate these seminal data.     

PLCγ1 promotes phase separation of T cell signaling components

The T cell receptor (TCR) pathway receives, processes, and amplifies the signal from pathogenic antigens to the activation of T cells. Although major components in this pathway have been identified, the knowledge on how individual components cooperate to effectively transduce signals remains limited. Phase separation emerges as a biophysical principle in organizing signaling molecules into liquid-like condensates. Here, we report that phospholipase Cγ1 (PLCγ1) promotes phase separation of LAT, a key adaptor protein in the TCR pathway. PLCγ1 directly cross-links LAT through its two SH2 domains. PLCγ1 also protects LAT from dephosphorylation by the phosphatase CD45 and promotes LAT-dependent ERK activation and SLP76 phosphorylation. Intriguingly, a nonmonotonic effect of PLCγ1 on LAT clustering was discovered. Computer simulations, based on patchy particles, revealed how the cluster size is regulated by protein compositions. Together, these results define a critical function of PLCγ1 in promoting phase separation of the LAT complex and TCR signal transduction.     

A positive relationship between body height and the testosterone response to physical exercise

Human male height is one of the most conspicuous sexually dimorphic, phenotypic characteristics that affect how men are perceived both by men and women, impacting mate selection and intra-sexual competition. Testosterone is a key hormone linked to morphological masculinity and advantage in intra-sexual competition. To date, there have been limited studies linking height with testosterone levels. Here, we examined the change in circulating testosterone levels after physical exercise in 97 healthy and physically active men. Our results show that there was a significant relationship between male stature and the change in testosterone levels, whereas there was no such link between body height and circulating testosterone levels. Therefore, our findings provide evidence that height may indicate male’s adaptive capabilities to physiologically mobilize their bodies when it is needed and/or beneficial.     

Syngeneic leukemia models using lentiviral transgenics

Animal models are necessary to study cancer and develop treatments. After decades of intensive research, effective treatments are available for only a few types of leukemia, while others are currently incurable. Our goal was to generate novel leukemia models in immunocompetent mice. We had achieved abilities for overexpression of multiple driving oncogenes simultaneously in normal primary cells, which can be transplanted and followed in vivo. Our experiments demonstrated the induction of primary malignant growth. Leukemia lines that model various types of leukemia, such as acute myeloid leukemia (AML) or chronic lymphocytic leukemia (CLL), were passaged robustly in congenic wild-type immunocompetent mice. These novel leukemia lines, which may complement previous models, offer the flexibility to generate tailored models of defined oncogenes of interest. The characterization of our leukemia models in immunocompetent animals can uncover the mechanisms of malignancy progression and offer a unique opportunity to stringently test anti-cancer chemotherapies.Subject terms: Cancer models, Haematopoietic stem cells, Leukaemia     

The evolution of perennially enlarged breasts in women: a critical review and a novel hypothesis

The possession of permanent, adipose breasts in women is a uniquely human trait that develops during puberty, well in advance of the first pregnancy. The adaptive role and developmental pattern of this breast morphology, unusual among primates, remains an unresolved conundrum. The evolutionary origins of this trait have been the focus of many hypotheses, which variously suggest that breasts are a product of sexual selection or of natural selection due to their putative role in assisting in nursing or as a thermoregulatory organ. Alternative hypotheses assume that permanent breasts are a by-product of other evolutionary changes. We review and evaluate these hypotheses in the light of recent literature on breast morphology, physiology, phylogeny, ontogeny, sex differences, and genetics in order to highlight their strengths and flaws and to propose a coherent perspective and a new hypothesis on the evolutionary origins of perennially enlarged breasts in women. We propose that breasts appeared as early as Homo ergaster, originally as a by-product of other coincident evolutionary processes of adaptive significance. These included an increase in subcutaneous fat tissue (SFT) in response to the demands of thermoregulatory and energy storage, and of the ontogenetic development of the evolving brain. An increase in SFT triggered an increase in oestradiol levels (E2). An increase in meat in the diet of early Homo allowed for further hormonal changes, such as greater dehydroepiandrosterone (DHEA/S) synthesis, which were crucial for brain evolution. DHEA/S is also easily converted to E2 in E2-sensitive body parts, such as breasts and gluteofemoral regions, causing fat accumulation in these regions, enabling the evolution of perennially enlarged breasts. Furthermore, it is also plausible that after enlarged breasts appeared, they were co-opted for other functions, such as attracting mates and indicating biological condition. Finally, we argue that the multifold adaptive benefits of SFT increase and hormonal changes outweighed the possible costs of perennially enlarged breasts, enabling their further development.