Phenotypic plasticity and epithelial-mesenchymal transitions in cancer and normal stem cells?

Cancer stem cells (CSCs) are similar to normal stem cells in their ability to self-renew and to generate large populations of more differentiated descendants. In contrast to the hierarchical organization that is presumed to be the prevalent mode of normal tissue homeostasis, phenotypic plasticity allows cancer cells to dynamically enter into and exit from stem-cell states. The epithelial-mesenchymal transition (EMT) has been closely associated with the acquisition of both invasive and stem-cell properties in cancer cells. Thereby, EMT programs emerge as important regulators of phenotypic plasticity in cancer cells including their entrance into stem-cell states. Much is still to be learned about the regulation of EMTs through epigenetic mechanisms in cancer cells and the contributions that EMT programs make to normal tissue homeostasis.National Institutes of Health (U.S.) (Grant CA12515)National Cancer Institute (U.S.) (Grant CA12515)National Institutes of Health (U.S.) (Grant DE020817)National Cancer Institute (U.S.) (Grant DE020817

fMRI-compatible rehabilitation hand device

BACKGROUND: Functional magnetic resonance imaging (fMRI) has been widely used in studying human brain functions and neurorehabilitation. In order to develop complex and well-controlled fMRI paradigms, interfaces that can precisely control and measure output force and kinematics of the movements in human subjects are needed. Optimized state-of-the-art fMRI methods, combined with magnetic resonance (MR) compatible robotic devices for rehabilitation, can assist therapists to quantify, monitor, and improve physical rehabilitation. To achieve this goal, robotic or mechatronic devices with actuators and sensors need to be introduced into an MR environment. The common standard mechanical parts can not be used in MR environment and MR compatibility has been a tough hurdle for device developers. METHODS: This paper presents the design, fabrication and preliminary testing of a novel, one degree of freedom, MR compatible, computer controlled, variable resistance hand device that may be used in brain MR imaging during hand grip rehabilitation. We named the device MR_CHIROD (Magnetic Resonance Compatible Smart Hand Interfaced Rehabilitation Device). A novel feature of the device is the use of Electro-Rheological Fluids (ERFs) to achieve tunable and controllable resistive force generation. ERFs are fluids that experience dramatic changes in rheological properties, such as viscosity or yield stress, in the presence of an electric field. The device consists of four major subsystems: a) an ERF based resistive element; b) a gearbox; c) two handles and d) two sensors, one optical encoder and one force sensor, to measure the patient induced motion and force. The smart hand device is designed to resist up to 50% of the maximum level of gripping force of a human hand and be controlled in real time. RESULTS: Laboratory tests of the device indicate that it was able to meet its design objective to resist up to approximately 50% of the maximum handgrip force. The detailed compatibility tests demonstrated that there is neither an effect from the MR environment on the ERF properties and performance of the sensors, nor significant degradation on MR images by the introduction of the MR_CHIROD in the MR scanner. CONCLUSION: The MR compatible hand device was built to aid in the study of brain function during generation of controllable and tunable force during handgrip exercising. The device was shown to be MR compatible. To the best of our knowledge, this is the first system that utilizes ERF in MR environment

Contacts between the endoplasmic reticulum and other membranes in neurons

The cytoplasm of eukaryotic cells is compartmentalized by intracellular membranes that define subcellular organelles. One of these organelles, the endoplasmic reticulum, forms a continuous network of tubules and cisternae that extends throughout all cell compartments, including neuronal dendrites and axons. This network communicates with most other organelles by vesicular transport, and also by contacts that do not lead to fusion but allow cross-talk between adjacent bilayers. Though these membrane contacts have previously been observed in neurons, their distribution and abundance has not been systematically analyzed. Here, we have carried out such analysis. Our studies reveal new aspects of the internal structure of neurons and provide a critical complement to information about interorganelle communication emerging from functional and biochemical studies

Identification of an elaborate complex mediating postsynaptic inhibition

Inhibitory synapses dampen neuronal activity through postsynaptic hyperpolarization. The composition of the inhibitory postsynapse and the mechanistic basis of its regulation, however, remains poorly understood. We used an in vivo chemico-genetic proximity-labeling approach to discover inhibitory postsynaptic proteins. Quantitative mass spectrometry not only recapitulated known inhibitory postsynaptic proteins, but also revealed a large network of new proteins, many of which are either implicated in neurodevelopmental disorders or are of unknown function. CRISPR-depletion of one of these previously uncharacterized proteins, InSyn1, led to decreased postsynaptic inhibitory sites, reduced frequency of miniature inhibitory currents, and increased excitability in the hippocampus. Our findings uncover a rich and functionally diverse assemblage of previously unknown proteins that regulate postsynaptic inhibition and might contribute to developmental brain disorders

Human tumors instigate granulin-expressing hematopoietic cells that promote malignancy by activating stromal fibroblasts in mice

Systemic instigation is a process by which endocrine signals sent from certain tumors (instigators) stimulate BM cells (BMCs), which are mobilized into the circulation and subsequently foster the growth of otherwise indolent carcinoma cells (responders) residing at distant anatomical sites. The identity of the BMCs and their specific contribution or contributions to responder tumor growth have been elusive. Here, we have demonstrated that Scal(+)cKit(-) hematopoietic BMCs of mouse hosts bearing instigating tumors promote the growth of responding tumors that form with a myofibroblast-rich, desmoplastic stroma. Such stroma is almost always observed in malignant human adenocarcinomas and is an indicator of poor prognosis. We then identified granulin (GRN) as the most upregulated gene in instigating Scal(+)cKit(-) BMCs relative to counterpart control cells. The GRN(+) BMCs that were recruited to the responding tumors induced resident tissue fibroblasts to express genes that promoted malignant tumor progression; indeed, treatment with recombinant GRN alone was sufficient to promote desmoplastic responding tumor growth. Further, analysis of tumor tissues from a cohort of breast cancer patients revealed that high GRN expression correlated with the most aggressive triple-negative, basal-like tumor subtype and reduced patient survival. Our data suggest that GRN and the unique hematopoietic BMCs that produce it might serve as novel therapeutic targets

Prevalence of Malaria Parasite Infections among U.S.-Bound Congolese Refugees with and without Splenomegaly.

All U.S.-bound refugees from sub-Saharan Africa receive presumptive antimalarial treatment before departing for the United States. Among U.S.-bound Congolese refugees, breakthrough malaria cases and persistent splenomegaly have been reported. In response, an enhanced malaria diagnostic program was instituted. Here, we report the prevalence of plasmodial infection among 803 U.S.-bound Congolese refugees who received enhanced diagnostics. Infections by either rapid diagnostic test (RDT) or PCR were detected in 187 (23%) refugees, with 78 (10%) by RDT only, 35 (4%) by PCR only, and 74 (9%) by both. Infections identified by PCR included 103 monoinfections (87 Plasmodium falciparum, eight Plasmodium ovale, seven Plasmodium vivax, and one Plasmodium malariae) and six mixed infections. Splenomegaly was associated with malaria detectable by RDT (odds ratio: 1.8, 95% CI: 1.0-3.0), but not by PCR. Splenomegaly was not strongly associated with parasitemia, indicating that active malaria parasitemia is not necessary for splenomegaly

Understanding mechanobiology in cultured endothelium: A review of the orbital shaker method

A striking feature of atherosclerosis is its highly non-uniform distribution within the arterial tree. This has been attributed to variation in the haemodynamic wall shear stress (WSS) experienced by endothelial cells, but the WSS characteristics that are important and the mechanisms by which they lead to disease remain subjects of intensive investigation despite decades of research. In vivo evidence suggests that multidirectional WSS is highly atherogenic. This possibility is increasingly being studied by culturing endothelial cells in wells that are swirled on an orbital shaker. The method is simple and cost effective, has high throughput and permits chronic exposure, but interpretation of the results can be difficult because the fluid mechanics are complex; hitherto, their description has largely been restricted to the engineering literature. Here we review the findings of such studies, which indicate that putatively atherogenic flow characteristics occur at the centre of the well whilst atheroprotective ones occur towards the edge, and we describe simple mathematical methods for choosing experimental variables that avoid resonance, wave breaking and uncovering of the cells. We additionally summarise a large number of studies showing that endothelium cultured at the centre of the well expresses more pro-inflammatory and fewer homeostatic genes, has higher permeability, proliferation, apoptosis and senescence, and shows more endothelial-to-mesenchymal transition than endothelium at the edge. This simple method, when correctly interpreted, has the potential to greatly increase our understanding of the homeostatic and pathogenic mechanobiology of endothelial cells and may help identify new therapeutic targets in vascular disease

Small non-coding RNAs in Streptomyces coelicolor

In bacteria, small RNAs (sRNAs) make important regulatory contributions to an ever increasing number of cellular processes. To expand the repertoire of known sRNAs, we sought to identify novel sRNAs in the differentiating, multicellular bacterium Streptomyces coelicolor. We describe a combined bioinformatic and experimental approach that enabled the identification and characterization of nine novel sRNAs in S. coelicolor, including a cis-encoded antisense sRNA. We examined sRNA expression throughout the S. coelicolor developmental cycle, which progresses from vegetative mycelium formation, to aerial mycelium formation and finally sporulation. We further determined the effects of growth medium composition (rich versus minimal medium) on sRNA gene expression, and compared wild-type sRNA expression profiles with those of four developmental mutants. All but two of the sRNAs exhibited some degree of medium dependence, with three sRNAs being expressed exclusively during growth on one medium type. Unlike most sRNAs characterized thus far, several sRNA genes in S. coelicolor were expressed constitutively (apart from during late sporulation), suggesting a possible housekeeping role for these transcripts. Others were expressed at specific developmental stages, and their expression profiles were altered in response to developmental mutations. Expression of one sRNA in particular was dependent upon the sporulation-specific sigma factor σWhiG