Molecular mechanisms creating bistable switches at cell cycle transitions

Progression through the eukaryotic cell cycle is characterized by specific transitions, where cells move irreversibly from stage i−1 of the cycle into stage i. These irreversible cell cycle transitions are regulated by underlying bistable switches, which share some common features. An inhibitory protein stalls progression, and an activatory protein promotes progression. The inhibitor and activator are locked in a double-negative feedback loop, creating a one-way toggle switch that guarantees an irreversible commitment to move forward through the cell cycle, and it opposes regression from stage i to stage i−1. In many cases, the activator is an enzyme that modifies the inhibitor in multiple steps, whereas the hypo-modified inhibitor binds strongly to the activator and resists its enzymatic activity. These interactions are the basis of a reaction motif that provides a simple and generic account of many characteristic properties of cell cycle transitions. To demonstrate this assertion, we apply the motif in detail to the G1/S transition in budding yeast and to the mitotic checkpoint in mammalian cells. Variations of the motif might support irreversible cellular decision-making in other contexts.     

TGF‐β induces SOX2 expression in a time‐dependent manner in human melanoma cells

The sry‐related high‐mobility box (SOX)‐2 protein has recently been proven to play a significant role in progression, metastasis, and clinical prognosis spanning several cancer types. Research on the role of SOX2 in melanoma is limited and currently little is known about the mechanistic function of this gene in this context. Here, we observed high expression of SOX2 in both human melanoma cell lines and primary melanomas in contrast to melanocytic nevi. This overexpression in melanoma can, in part, be explained by extra gene copy numbers of SOX2 in primary samples. Interestingly, we were able to induce SOX2 expression, mediated by SOX4, via TGF‐β1 stimulation in a time‐dependent manner. Moreover, the knockdown of SOX2 impaired TGF‐β‐induced invasiveness. This phenotype switch can be explained by SOX2‐mediated cross talk between TGF‐β and non‐canonical Wnt signaling. Thus, we propose that SOX2 is involved in the critical TGF‐β signaling pathway, which has been shown to correlate with melanoma aggressiveness and metastasis. In conclusion, we have identified a novel downstream factor of TGF‐β signaling in melanoma, which may have further implications in the clinic.     

Microbiome Composition and Function Drives Wound-Healing Impairment in the Female Genital Tract

The mechanism(s) by which bacterial communities impact susceptibility to infectious diseases, such as HIV, and maintain female genital tract (FGT) health are poorly understood. Evaluation of FGT bacteria has predominantly been limited to studies of species abundance, but not bacterial function. We therefore sought to examine the relationship of bacterial community composition and function with mucosal epithelial barrier health in the context of bacterial vaginosis (BV) using metaproteomic, metagenomic, and in vitro approaches. We found highly diverse bacterial communities dominated by Gardnerella vaginalis associated with host epithelial barrier disruption and enhanced immune activation, and low diversity communities dominated by Lactobacillus species that associated with lower Nugent scores, reduced pH, and expression of host mucosal proteins important for maintaining epithelial integrity. Importantly, proteomic signatures of disrupted epithelial integrity associated with G. vaginalis-dominated communities in the absence of clinical BV diagnosis. Because traditional clinical assessments did not capture this, it likely represents a larger underrepresented phenomenon in populations with high prevalence of G. vaginalis. We finally demonstrated that soluble products derived from G. vaginalis inhibited wound healing, while those derived from L. iners did not, providing insight into functional mechanisms by which FGT bacterial communities affect epithelial barrier integrity.     

Distributional dynamics of a specialized subterranean community oppose the classical understanding of the preferred subterranean habitats

Troglobionts are organisms that are specialized for living in a subterranean environment. These organisms reside prevalently in the deepest zones of caves and in shallow subterranean habitats, and complete their entire life cycles therein. Because troglobionts in most caves depend on organic matter resources from the surface, we hypothesized that they would also select the sections of caves nearest the surface, as long as environmental conditions were favorable. Over 1 year, we analyzed, in monthly intervals, the annual distributional dynamics of a subterranean community consisting of 17 troglobiont species, in relation to multiple environmental factors. Cumulative standardized annual species richness and diversity clearly indicated the existence of two ecotones within the cave: between soil and shallow subterranean habitats, inhabited by soil and shallow troglobionts; and between the transition and inner cave zones, where the spatial niches of shallow and deep troglobionts overlap. The mean standardized annual species richness and diversity showed inverse relationships, but both contributed to a better insight into the dynamics of subterranean fauna. Regression analyses revealed that temperatures in the range 7–10°C, high moisture content of substrate, large cross section of the cave, and high pH of substrate were the most important ecological drivers governing the spatiotemporal dynamics of troglobionts. Overall, this study shows general trends in the annual distributional dynamics of troglobionts in shallow caves and reveals that the distribution patterns of troglobionts within subterranean habitats may be more complex than commonly assumed.     

Fluid shear stress stimulates breast cancer cells to display invasive and chemoresistant phenotypes while upregulating PLAU in a 3D bioreactor

Breast cancer cells experience a range of shear stresses in the tumor microenvironment (TME). However most current in vitro three-dimensional (3D) models fail to systematically probe the effects of this biophysical stimuli on cancer cell metastasis, proliferation, and chemoresistance. To investigate the roles of shear stress within the mammary and lung pleural effusion TME, a bioreactor capable of applying shear stress to cells within a 3D extracellular matrix was designed and characterized. Breast cancer cells were encapsulated within an interpenetrating network hydrogel and subjected to shear stress of 5.4 dynes cm⁻² for 72 hr. Finite element modeling assessed shear stress profiles within the bioreactor. Cells exposed to shear stress had significantly higher cellular area and significantly lower circularity, indicating a motile phenotype. Stimulated cells were more proliferative than static controls and showed higher rates of chemoresistance to the anti-neoplastic drug paclitaxel. Fluid shear stress-induced significant upregulation of the PLAU gene and elevated urokinase activity was confirmed through zymography and activity assay. Overall, these results indicate that pulsatile shear stress promotes breast cancer cell proliferation, invasive potential, chemoresistance, and PLAU signaling.     

Biology of Bactrocera carambolae (Diptera: Tephritidae) on four hosts

Bactrocera carambolae is a quarantine pest found in Brazil, restricted to the states of Amapá, Pará and Roraima. This fruit fly can potentially cause extensive socioeconomic and environmental damage in the country, if it disperse into areas where fruit is grown for exporting. The objective of this work was to study the biology of B. carambolae on fruits of Averrhoa carambola L. (Oxalidaceae), Psidium guajava L. (Myrtaceae), Spondias mombin L. (Anacardiaceae) and Eugenia stipitata McVaugh (Myrtaceae). The following parameters were investigated: duration of egg-larva, pupal, egg-adult, pre-oviposition, oviposition and post-oviposition periods, pupal weight and viability, sex ratio, fecundity, fertility and longevity. All parameters except pupal weight, oviposition and post-oviposition period, egg fertility and sex ratio were influenced by the host plant on which the larvae were reared. The carambola fruit fly completes its development on all those hosts studied here, with the highest fecundities on A. carambola and P. guajava.