Downregulated lncRNA LINC00908 correlates with a poor prognosis and increasing malignancy of gastric cancer.

Long non-coding RNA LINC00908 is a functional biomarker in regulating tumour progression. Its dysregulation in gastric cancer implies its potential functional role. Few studies have noted the functional role of LINC00908 in gastric cancer. The potential of LINC00908 to serve as a biomarker in gastric cancer was evaluated. A total of 113 paired gastric cancer tissues and normal tissues were collected from patients with gastric cancer. LINC00908 levels were evaluated by polymerase chain reaction, and its significance in disease progression and patients' prognosis was assessed. In vitro, the function of LINC00908 in tumour-related cellular processes was evaluated with CCK8 and Transwell assay. Significant downregulation of LINC00908 was observed in gastric cancer and was negatively associated with disease development and overall survival of patients. LINC00908 showed significant inhibitory effects on the proliferation, migration, and invasion of gastric cancer cells. Additionally, miR-627-3p was sponged by LINC00908 and therefore mediated the function of LINC00908 in gastric cancer cells. LINC00908 functioned as a prognostic biomarker and tumour suppressor of gastric cancer, providing a therapeutic target for gastric cancer.

The Drosophila blood-brain barrier invades the nervous system in a GPCR-dependent manner.

The blood-brain barrier (BBB) represents a crucial interface between the circulatory system and the brain. In Drosophila melanogaster, the BBB is composed of perineurial and subperineurial glial cells. The perineurial glial cells are small mitotically active cells forming the outermost layer of the nervous system and are engaged in nutrient uptake. The subperineurial glial cells form occluding septate junctions to prevent paracellular diffusion of macromolecules into the nervous system. To address whether the subperineurial glia just form a simple barrier or whether they establish specific contacts with both the perineurial glial cells and inner central nervous system (CNS) cells, we undertook a detailed morphological analysis. Using genetically encoded markers alongside with high-resolution laser scanning confocal microscopy and transmission electron microscopy, we identified thin cell processes extending into the perineurial layer and into the CNS cortex. Interestingly, long cell processes were observed reaching the glia ensheathing the neuropil of the central brain. GFP reconstitution experiments highlighted multiple regions of membrane contacts between subperineurial and ensheathing glia. Furthermore, we identify the G-protein-coupled receptor (GPCR) Moody as negative regulator of the growth of subperineurial cell processes. Loss of moody triggered a massive overgrowth of subperineurial cell processes into the CNS cortex and, moreover, affected the polarized localization of the xenobiotic transporter Mdr65. Finally, we found that GPCR signaling, but not septate junction formation, is responsible for controlling membrane overgrowth. Our findings support the notion that the Drosophila BBB is able to bridge the communication gap between circulation and synaptic regions of the brain by long cell processes.

Mechanisms Involved in Neuroprotective Effects of Transcranial Magnetic Stimulation.

Transcranial Magnetic Stimulation (TMS) is widely used in neurophysiology to study cortical excitability. Research over the last few decades has highlighted its added value as a potential therapeutic tool in the treatment of a broad range of psychiatric disorders. More recently, a number of studies have reported beneficial and therapeutic effects for TMS in neurodegenerative conditions and strokes. Yet, despite its recognised clinical applications and considerable research using animal models, the molecular and physiological mechanisms through which TMS exerts its beneficial and therapeutic effects remain unclear. They are thought to involve biochemical-molecular events affecting membrane potential and gene expression. In this aspect, the dopaminergic system plays a special role. This is the most directly and selectively modulated neurotransmitter system, producing an increase in the flux of dopamine (DA) in various areas of the brain after the application of repetitive TMS (rTMS). Other neurotransmitters, such as glutamate and gamma-aminobutyric acid (GABA) have shown a paradoxical response to rTMS. In this way, their levels increased in the hippocampus and striatum but decreased in the hypothalamus and remained unchanged in the mesencephalon. Similarly, there are sufficient evidence that TMS up-regulates the gene expression of BDNF (one of the main brain neurotrophins). Something similar occurs with the expression of genes such as c-Fos and zif268 that encode trophic and regenerative action neuropeptides. Consequently, the application of TMS can promote the release of molecules involved in neuronal genesis and maintenance. This capacity may mean that TMS becomes a useful therapeutic resource to antagonize processes that underlie the previously mentioned neurodegenerative conditions.

Bacterial Biotransformation of Oleic Acid: New Findings on the Formation of γ-Dodecalactone and 10-Ketostearic Acid in the Culture of Micrococcus luteus.

Microbial conversion of oleic acid (1) to form value-added industrial products has gained increasing scientific and economic interest. So far, the production of natural lactones with flavor and fragrance properties from fatty acids by non-genetically modified organisms (non-GMO) involves whole cells of bacteria catalyzing the hydration of unsaturated fatty acids as well as yeast strains responsible for further ß-oxidation processes. Development of a non-GMO process, involving a sole strain possessing both enzymatic activities, significantly lowers the costs of the process and constitutes a better method from the customers' point of view regarding biosafety issues. Twenty bacteria from the genus of Bacillus, Comamonas, Dietzia, Gordonia, Micrococcus, Pseudomonas, Rhodococcus and Streptomyces were screened for oxidative functionalization of oleic acid (1). Micrococcus luteus PCM525 was selected as the sole strain catalyzing the one-pot transformation of oleic acid (1) into natural valuable peach and strawberry-flavored γ-dodecalactone (6) used in the food, beverage, cosmetics and pharmaceutical industries. Based on the identified products formed during the process of biotransformation, we clearly established a pathway showing that oleic acid (1) is hydrated to 10-hydroxystearic acid (2), then oxidized to 10-ketostearic acid (3), giving 4-ketolauric acid (4) after three cycles of ß-oxidation, which is subsequently reduced and cyclized to γ-dodecalactone (6) (Scheme 1). Moreover, three other strains (Rhodococcus erythropolis DSM44534, Rhodococcus ruber PCM2166, Dietzia sp. DSM44016), with high concomitant activities of oleate hydratase and alcohol dehydrogenase, were identified as efficient producers of 10-ketostearic acid (3), which can be used in lubricant and detergent formulations. Considering the prevalence of γ-dodecalactone (6) and 10-ketostearic acid (3) applications and the economic benefits of sustainable management, microbial bioconversion of oleic acid (1) is an undeniably attractive approach.

Tube-like structures within the ovarian follicle of Hydrolagus colliei indicate the early origins of follicle cell processes.

Follicle cell processes (FCP) are actin-based, tube-like structures that connect the developing oocyte to the follicle cells throughout oogenesis. They were first described in Selachians (sharks) where their suggested roles were facilitating the transport of metabolites to the developing oocyte and providing structural support to the large egg cells of sharks, an early stage in the evolution of viviparity. Subsequent studies found that FCP are absent in Rajiformes (skates), suggesting that FCP may have been novel structures specific to the sharks. Here, FCP in Hydrolagus colliei, a Chimaeriform, were described. The FCP of H. colliei differ morphologically from those previously described in sharks, but as they also contain actin, they presumably play similar roles provisioning the developing oocyte and providing structural support. The presence of FCP in the order Chimaeriformes suggests that their origin predates the split of the elasmobranchs and the holocephalans.

5p and 3p Strands of miR-34 Family Members Have Differential Effects in Cell Proliferation, Migration, and Invasion in Cervical Cancer Cells.

The micro RNA (miR)-34 family is composed of 5p and 3p strands of miR-34a, miR-34b, and miR-34c. The 5p strand's expression and function is studied in cervical cancer. The 3p strand's function and regulation remain to be elucidated. To study the function of the passenger strands of miR-34 family members, we overexpressed 5p and 3p strands using a synthetic miRNA in cervical cell lines. Cell proliferation was evaluated using crystal violet. Migration and invasion were tested using transwell assays, Western blot, and zymography. Possible specific targets and cell signaling were investigated for each strand. We found that miR-34a-5p inhibited proliferation, migration, and cell invasion accompanied by matrix metalloproteinase 9 (MMP9) activity and microtubule-associated protein 2 (MAP2) protein reduction. We also found that miR-34b-5p and miR-34c-5p inhibit proliferation and migration, but not invasion. In contrast, miR-34c-5p inhibits MMP9 activity and MAP2 protein, while miR-34b-5p has no effect on these genes. Furthermore, miR-34a-3p and miR-34b-3p inhibit proliferation and migration, but not invasion, despite the later reducing MMP2 activity, while miR-34c-3p inhibit proliferation, migration, and cell invasion accompanied by MMP9 activity and MAP2 protein inhibition. The difference in cellular processes, MMP2 and MMP9 activity, and MAP2 protein inhibition by miR-34 family members suggests the participation of other regulated genes. This study provides insights into the roles of passenger strands (strand*) of the miR-34 family in cervical cancer.

Bases moleculares de la memoria y su relación con el aprendizaje / Molecular Basis of Memory and its Relation with Learning

El aprendizaje y la memoria son funciones cognitivas estudiadas históricamente desde diferentes campos del saber, de los cuales, podemos mencionar la filosofía, la psicología y las neurociencias. Aportes más recientes provienen de los desarrollos de las ciencias cognitivas y, de manera particular, de la antropología, la lingüística, la semiótica y la inteligencia artificial. En su conjunto, los aportes provenientes de estos diversos campos del conocimiento tienen incidencia importante en la educación. El aprendizaje se refiere al cambio permanente o no del comportamiento, de las ideas, los conceptos, los modelos mentales, los sentimientos, intereses, motivaciones derivados de la experiencia de los sujetos; por su parte, la memoria se refiere al proceso, por el cual ese conocimiento es codificado, almacenado y recordado. El aprendizaje y la memoria son esenciales para el funcionamiento adecuado, adaptación y supervivencia independiente de las diferentes especies animales. En esta revisión, en primer lugar, se presenta una breve reseña de los estudios más sobresalientes sobre aprendizaje y memoria, en términos generales se describen los tipos de aprendizaje y de memoria con relación a la naturaleza de la información y al tiempo de almacenamiento. En segundo lugar, se describen los procesos moleculares que explican el aprendizaje y la memoria implícita y finalmente se presentan algunas reflexiones generales desde el campo conceptual de la educación en relación con los desarrollos presentados en cuanto a la memoria y al aprendizaje...(AU)

Learning and memory are cognitive functions that have been historically studied from different fields of knowledge, namely, philosophy, psychology and neurosciences.Recent contributions come from developments on cognitive sciences and, particularly, anthropology, linguistics, semiotics and artificial intelligence as well. As a whole, contributions from these different fields of knowledge have an important impact on education. Learning refers to a continuous change regarding behavior, ideas, concepts, mental models, feelings, interests, and motivations that are derived from the individuals' experience, while memory encompasses the process by which knowledge is codified, stored and retrieved. Learning and memory are paramount for proper functioning, independent adaptation and survival of different animal species. On one hand, this review shows a brief overview of the most outstanding studies on learning and memory. In general terms, it describes the types of learning and memory in relation to the nature of information and storage time. On the other hand, it presents the molecular processes underlying learning and implicit memory. It finally describes some general reflections from the conceptual perspective on education in relation to the developments of memory and learning...(AU)

Measuring Process Dynamics and Nuclear Migration for Clones of Neural Progenitor Cells.

Neural stem and progenitor cells (NPCs) generate processes that extend from the cell body in a dynamic manner. The NPC nucleus migrates along these processes with patterns believed to be tightly coupled to mechanisms of cell cycle regulation and cell fate determination. Here, we describe a new segmentation and tracking approach that allows NPC processes and nuclei to be reliably tracked across multiple rounds of cell division in phase-contrast microscopy images. Results are presented for mouse adult and embryonic NPCs from hundreds of clones, or lineage trees, containing tens of thousands of cells and millions of segmentations. New visualization approaches allow the NPC nuclear and process features to be effectively visualized for an entire clone. Significant differences in process and nuclear dynamics were found among type A and type C adult NPCs, and also between embryonic NPCs cultured from the anterior and posterior cerebral cortex.

Valproic Acid and Other HDAC Inhibitors Upregulate FGF21 Gene Expression and Promote Process Elongation in Glia by Inhibiting HDAC2 and 3.

BACKGROUND: Fibroblast growth factor 21, a novel regulator of glucose and lipid metabolism, has robust protective properties in neurons. However, its expression and function in glia are unknown. Valproic acid, a mood stabilizer and anticonvulsant, is a histone deacetylase inhibitor and a dynamic gene regulator. We investigated whether histone deacetylase inhibition by valproic acid and other inhibitors upregulates fibroblast growth factor 21 expression and, if so, sought to identify the histone deacetylase isoform(s) involved and their role in altering glial cell morphology. METHODS: C6 glioma or primary cortical glial cultures were treated with histone deacetylase inhibitors, and fibroblast growth factor 21 levels and length of cell processes were subsequently measured. Histone deacetylase 1, 2, or 3 was also knocked down to detect which isoform was involved in regulating fibroblast growth factor 21 mRNA levels. Finally, knockdown and overexpression of fibroblast growth factor 21 were performed to determine whether it played a role in regulating cell process length. RESULTS: Treatment of C6 cells or primary glial cultures with valproic acid elevated fibroblast growth factor 21 mRNA levels, extended cell process length, and markedly increased acetylated histone-H3 levels. Other histone deacetylase inhibitors including pan- and class I-specific inhibitors, or selective knockdown of histone deacetylase 2 or 3 isoform produced similar effects. Knockdown or overexpression of fibroblast growth factor 21 significantly decreased or increased C6 cell process length, respectively. CONCLUSIONS: In glial cell line and primary glia, using pharmacological inhibition and selective gene silencing of histone deacetylases to boost fibroblast growth factor 21 mRNA levels results in elongation of cell processes. Our study provides a new mechanism via which histone deacetylase 2 and 3 participate in upregulating fibroblast growth factor 21 transcription and extending process outgrowth in glia.

Unified quantitative characterization of epithelial tissue development.

Understanding the mechanisms regulating development requires a quantitative characterization of cell divisions, rearrangements, cell size and shape changes, and apoptoses. We developed a multiscale formalism that relates the characterizations of each cell process to tissue growth and morphogenesis. Having validated the formalism on computer simulations, we quantified separately all morphogenetic events in the Drosophila dorsal thorax and wing pupal epithelia to obtain comprehensive statistical maps linking cell and tissue scale dynamics. While globally cell shape changes, rearrangements and divisions all significantly participate in tissue morphogenesis, locally, their relative participations display major variations in space and time. By blocking division we analyzed the impact of division on rearrangements, cell shape changes and tissue morphogenesis. Finally, by combining the formalism with mechanical stress measurement, we evidenced unexpected interplays between patterns of tissue elongation, cell division and stress. Our formalism provides a novel and rigorous approach to uncover mechanisms governing tissue development.

Differentiation and Cell-Cell Interactions of Neural Progenitor Cells Transplanted into Intact Adult Brain.

We studied the behavior and cell-cell interactions of embryonic brain cell from GFP-reporter mice after their transplantation into the intact adult brain. Fragments or cell suspensions of fetal neocortical cells at different stages of development were transplanted into the neocortex and striatum of adult recipients. Even in intact brain, the processes of transplanted neurons formed extensive networks in the striatum and neocortical layers I and V-VI. Processes of transplanted cells at different stages of development attained the rostral areas of the frontal cortex and some of them reached the internal capsule. However, the cells transplanted in suspension had lower process growth potency than cells from tissue fragments. Tyrosine hydroxylase fibers penetrated from the recipient brain into grafts at both early and late stages of development. Our experiments demonstrated the formation of extensive reciprocal networks between the transplanted fetal neural cells and recipient brain neurons even in intact brain.

Cellular processes involved in human epidermal cells exposed to extremely low frequency electric fields.

We observed on different tissues and organisms a biological response after exposure to pulsed low frequency and low amplitude electric or electromagnetic fields but the precise mechanism of cell response remains unknown. The aim of this publication is to understand, using bioinformatics, the biological relevance of processes involved in the modification of gene expression. The list of genes analyzed was obtained after microarray protocol realized on cultures of human epidermal explants growing on deepidermized human skin exposed to a pulsed low frequency electric field. The directed acyclic graph on a WebGestalt Gene Ontology module shows six categories under the biological process root: "biological regulation", "cellular process", "cell proliferation", "death", "metabolic process" and "response to stimulus". Enriched derived categories are coherent with the type of in vitro culture, the stimulation protocol or with the previous results showing a decrease of cell proliferation and an increase of differentiation. The Kegg module on WebGestalt has highlighted "cell cycle" and "p53 signaling pathway" as significantly involved. The Kegg website brings out interactions between FoxO, MAPK, JNK, p53, p38, PI3K/Akt, Wnt, mTor or NF-KappaB. Some genes expressed by the stimulation are known to have an exclusive function on these pathways. Analyses performed with Pathway Studio linked cell proliferation, cell differentiation, apoptosis, cell cycle, mitosis, cell death etc. with our microarrays results. Medline citation generated by the software and the fold change variation confirms a diminution of the proliferation, activation of the differentiation and a less well-defined role of apoptosis or wound healing. Wnt and DKK functional classes, DKK1, MACF1, ATF3, MME, TXNRD1, and BMP-2 genes proposed in previous publications after a manual analysis are also highlighted with other genes after Pathway Studio automatic procedure. Finally, an analysis conducted on a list of genes characterized by an accelerated regulation after extremely low frequency pulsed stimulation also confirms their role in the processes of cell proliferation and differentiation. Bioinformatics approach allows in-depth research, without the bias of pre-selection, on cellular processes involved in a huge gene list.

Emergent complexity of the cytoskeleton: from single filaments to tissue.

Despite their overwhelming complexity, living cells display a high degree of internal mechanical and functional organization which can largely be attributed to the intracellular biopolymer scaffold, the cytoskeleton. Being a very complex system far from thermodynamic equilibrium, the cytoskeleton's ability to organize is at the same time challenging and fascinating. The extensive amounts of frequently interacting cellular building blocks and their inherent multifunctionality permits highly adaptive behavior and obstructs a purely reductionist approach. Nevertheless (and despite the field's relative novelty), the physics approach has already proved to be extremely successful in revealing very fundamental concepts of cytoskeleton organization and behavior. This review aims at introducing the physics of the cytoskeleton ranging from single biopolymer filaments to multicellular organisms. Throughout this wide range of phenomena, the focus is set on the intertwined nature of the different physical scales (levels of complexity) that give rise to numerous emergent properties by means of self-organization or self-assembly.

Poster - Thur Eve - 15: Production and assessment of astatine-211 for targeted alpha therapy.

Biologically-targeted alpha-particle radiation is the basis of new and promising treatments for eliminating disseminated micrometastases and the residual microscopic malignancies that remain after surgery or radiation therapy. The short-range alpha-particles are highly cytotoxic and capable of inactivating single, isolated cancer cells which may otherwise cause recurrence. Astatine-211 is a promising alpha emitter for therapy; the 7.2 hour half-life of 211 At provides sufficient time for biological-targeting to take place. However, this radionuclide is in short supply and future treatment strategies still require extensive preclinical evaluation. The present work aims to develop technologies that (1) increase the world-wide availability of 211 At for clinical use, and (2) assess the risks of 211 At-based therapies by quantifying the activity distributions in animal models. At TRIUMF (Vancouver, BC), the feasibility of a novel generator system for 211 At is under investigation which would allow distribution of 211 At across Canada and internationally. Briefly, a longer-lived parent radionuclide of 211 At, radon-211, would be produced and allowed to decay in containment to yield 211 At in solution. Additionally, a supplementary study is underway in collaboration with the University of Washington to evaluate the sub-organ biodistributions of astatinated targeting biomolecules, with cell-level resolution. These measurements involve high resolution quantitative alpha-particle imaging in thin tissue samples and can be done for a selection of applications (eg. lymphoma, metastatic prostate cancer, etc) using animal models. The planned alpha-camera measurements are primarily designed to predict and assess the risk of toxicity associated with 211 At-based therapies and aid in developing the future clinical applications.

An Integrative Review of Mechanotransduction in Endothelial, Epithelial (Renal) and Dendritic Cells (Osteocytes).

In this review we will examine from a biomechanical and ultrastructural viewpoint how the cytoskeletal specialization of three basic cell types, endothelial cells (ECs), epithelial cells (renal tubule) and dendritic cells (osteocytes), enables the mechano-sensing of fluid flow in both their native in vivo environment and in culture, and the downstream signaling that is initiated at the molecular level in response to fluid flow. These cellular responses will be discussed in terms of basic mysteries and paradoxes encountered by each cell type. In ECs fluid shear stress (FSS) is nearly entirely attenuated by the endothelial glycocalyx that covers their apical membrane and yet FSS is communicated to both intracellular and junctional molecular components in activating a wide variety of signaling pathways. The same is true in proximal tubule (PT) cells where a dense brush border of microvilli covers the apical surface and the flow at the apical membrane is negligible. A four decade old unexplained mystery is the ability of PT epithelia to reliably reabsorb 60% of the flow entering the tubule regardless of the glomerular filtration rate. In the cortical collecting duct (CCD) the flow rates are so low that a special sensing apparatus, a primary cilia is needed to detect very small variations in tubular flow. In bone it has been a century old mystery as to how osteocytes embedded in a stiff mineralized tissue are able to sense miniscule whole tissue strains that are far smaller than the cellular level strains required to activate osteocytes in vitro.