Compartmentalization Patterns Research Articles

Cerebellar Molecular Signatures in Non-Human Primates.

Cerebellar molecular signatures in primates remain largely unexplored. Here, we investigated the immunoreactivity of neuroplasticity-related molecular markers, including aldolase C (Aldoc), phospholipase C beta 3 (PLCB3), and phospholipase C beta 4 (PLCB4) in the cerebellar cortex and associated nuclei of rhesus macaque monkeys (Macaca mulatta). Our main findings are as follows: First, the cerebellar vermis in macaques exhibited striped compartmentalization for all markers, with the striped expression boundary of PLCB3 being less distinct than those of Aldoc and PLCB4. Second, the striped pattern was less pronounced in the cerebellar hemisphere compared to the vermis, with signals in the hemisphere being predominantly intense throughout. Third, distinct zonal patterns and elevated signals for Aldoc and PLCB3 were observed in the cerebellar deep nuclei. Specifically, the fastigial nucleus displayed intense Aldoc signals in both caudal and rostral regions, while the dentate nucleus displayed strong Aldoc signals in both ventral and dorsal regions. Compared to previous rodent studies, the macaque cerebellum demonstrated a higher proportion of intense signal areas and distinct compartmentalization patterns in both cortical and deep nuclei. These findings offer crucial insights into the unique molecular organization of the primate cerebellum, enhancing our understanding of the advanced neuroplasticity, cognitive, and motor capabilities in primates.

Hypoxia coordinates the spatial landscape of myeloid cells within glioblastoma to affect survival.

Myeloid cells are highly prevalent in glioblastoma (GBM), existing in a spectrum of phenotypic and activation states. We now have limited knowledge of the tumor microenvironment (TME) determinants that influence the localization and the functions of the diverse myeloid cell populations in GBM. Here, we have utilized orthogonal imaging mass cytometry with single-cell and spatial transcriptomic approaches to identify and map the various myeloid populations in the human GBM tumor microenvironment (TME). Our results show that different myeloid populations have distinct and reproducible compartmentalization patterns in the GBM TME that is driven by tissue hypoxia, regional chemokine signaling, and varied homotypic and heterotypic cellular interactions. We subsequently identified specific tumor subregions in GBM, based on composition of identified myeloid cell populations, that were linked to patient survival. Our results provide insight into the spatial organization of myeloid cell subpopulations in GBM, and how this is predictive of clinical outcome.

Compartmentalization transformation of Fe2+, Mn2+ and NH4+ in groundwater: A comparative research containing experimental medium and functional genera profiling derived from experiment data

Contamination of soluble iron (Fe2+), manganese (Mn2+), and ammonium (NH4+) in groundwater is prevalent, particularly in Northeast China. This study aims to elucidate the intricate biological and physical-chemical reactions involved in the sequential transformation of three target contaminants. Two dynamic column simulations were used to compare quartz sand filtration (QSF) system with riverbank filtration (RBF) system to assess the interactions and respective contributions of the reactions involved in transforming process. Similar pattern of transformation vertical compartmentalization in two systems along the filter depth were founded, and the Fe2+ transformation was mainly distributed in the upper part, while NH4+ and Mn2+ occurred primarily in the downstream sections. The average transformation rate of Fe2+, Mn2+ and NH4+ in RBF system was 84.52 %, 47.68 % and 67.95 %, respectively, which was 5.20 %, 11.43 % and 23.06 % higher than in QSF system. The dominant transformation process for Fe2+ in RBF involved chemical oxidation, bio-oxidation and adsorption. The lower transformation rate for Mn2+ was attributed to abiotic homogenous oxidation limitation and negative affect derived from high concentration of NH4+ with high nitrification rate in RBF system. Nitrification by Nitrosomonas and Nitrospira was critical NH4+ transformation mechanism in RBF system, while the adsorption by iron and manganese oxide and aerobic denitrification were contributed strongly to NH4+ transformation in QSF system. Furthermore, the spatial distribution of functional bacterial genera was in good consistent with the transformation compartmentalization of three target contaminants in both systems, and similar microbial community structure reflected the domestication effect of groundwater chemistry on functional bacteria.

The lateral somitic frontier: The source of multipotent somitic cells in Xenopus

The somites are embryonic structures that give rise to the axial musculoskeletal system. In amniotes vertebrates, somites are composed of multipotent somitic cells that quickly compartmentalize into a dorsal dermomyotome and a ventral sclerotome. In the somites, the dermomyotome gives rise to skeletal muscle cells (the myotome) and the dorsal dermis (the dermatome), while the sclerotome gives rise to vertebrae, ribs, and dorsal tendons (the syndetome). The compartmentalization pattern differs in anamniotes, with the establishment of a primitive myotome that begins before somite formation while the LSF (lateral somitic frontier) give rise to both the sclerotome and the dermomyotome in Xenopus. In this synthesis, we describe the contribution of the LSF in establishing somitic lineages in Xenopus and propose a model that traces the evolutionary history of somites back to ancestral precursors associated with striated skeletal muscle.

Tumor-TME Bipartite Landscape of PD-1/PD-L1 in Endometrial Cancers.

The bipartite landscape of tumor cells and stromal cells determines a tumor's response to treatment during disease management. In endometrial cancers (ECs), the mechanistic contribution of PD-L1/L2 and PD-1 signaling of the host's tumor microenvironment (TME) (CAF and immune cells) in the context of the tumor cells is elusive. To understand the tumor-stroma-immune crosstalk, we studied the compartmental pattern of PD-L1/L2 and PD-1 expression in EC tissues and their matched CAFs. Over 116 surgically resected tumors (T) and the tumor-adjacent normal tissues (N) were obtained from consented unselected consecutive patients. IHC was performed in T, N-epi-thelium, and the stromal mesenchymal environment (SME; mesenchyme) in the T and N tissues. The staining intensity and distribution patterns of PD-L1/L2 and PD-1 in the FFPE sections of T and N were evaluated by a pathologist using a standard scoring system of TPS and CPS. We tested the PD-L1/L2 and PD-1 immune landscape of tumor-TME pair and normal epithelial-stromal mesenchyme pairs from patients with different grades of disease vis-à-vis their CAF PD-L1 levels. We used qRT-PCR to determine the expressions of mRNAs, while the flow cytometry and ICC determined the level of expression of proteins. We observed higher levels of PD-L1 mRNA and protein expression in primary CAFs from the resected tumor tissue compared to the tumor-adjacent normal tissues. We also determined the expression of patients' soluble PD-L1/L2 as peripheral readouts of PD-L1/L2 and PD-1. As we evaluated the results in the context of their pathological parameters, such as grades, stages, lymphovascular invasion, percentage of myometrial invasion, and dMMR in patients, the dominance of PD-L1 expression in TME was positively correlated to the higher pathological grades of tumors, and its relationship with the dMMR. Since the neutralization of CD8-positive cytotoxic T-cells is PD-L1-dependent, our data indicate that irrespective of the PD-L1 positivity of tumor cells, the PD-L1-positive CAFs can play a critical role in bringing out an additional load of PD-L1 for an effective engagement of PD-1 within a tumor mass.

Reconstruction of Tournaisian-Viséan tectonic and climatically induced event histories of the Mobarak carbonate platform along depositional strike in the northeastern margin of Gondwana: Constraints from high-resolution cycle and sequence stratigraphy

Cyclic successions are one of the most important types of deposits in the carbonate platform of the Mississippian (Tournaisian-Viséan) in Gondwanan and Laurussian margins. The importance of climatically induced events impact on the amplitudes and frequencies of sea-level fluctuations in Mississippian of Iran is significant because the beginning, extent, duration, and significance of periods of climatically induced events in northern margin of Gondwana are not well recognized. A high-resolution sequence architecture in integration with paleoenvironmental reconstruction and foraminiferal biozonation from the Tournaisian-early Visean carbonate successions of the Mobarak Formation in Alborz basin along depositional strike (E-W- a distance of c. 340 km) suggests a mosaic-like pattern of deposition and compartmentalization of the depositional settings (homocline ramp to distally steepened ramp). According to the recognized facies, the stacking pattern of high-frequency cycles across the platform, and major accommodation events recognized on the correlated Fischer plots, six 3rd-order sequences (DS1–DS6) were identified. Detailed analysis on high-frequency cycles representing a highly variable number of shallowing-upward cycles, types, thicknesses, and facies heterogeneity along depositional strike. A combination of the episodic tectonic events along faults interacting with autocyclic processes, and inherited topographic irregularities are suggested as the driving mechanism for the cycle development. Six stages of Mobarak carbonate platform evolution based on understand the interplay of autocyclic and allocyclic controls are recognized in a hierarchical 3rd-order sequence stratigraphic framework and a chronological order: (1) early Hastarian corresponds to post-glacial transgressive episode with progressive backstepping of facies belts of early TST of DS1 throughout the region; (2) middle to late Hastarian corresponds to a major transgressional phase of DS1 following global temperature rise superimposed on different subsidence/uplift rates with the deformation of the platform along depositional strike; (3) Hastarian–Ivorian boundary corresponds to TST of DS2 with facies heterogeneity along depositional strike related to continuation of different subsidence/uplift rates. The absence of any systematic changes in the amplitude and period of cyclicity or lowstand deposits and subaerial surfaces during this phase shows the lack of influence of mid-Tournaisian glaciation and concurrent eustatic regression in northern margin of Gondwana. (4) early to middle Ivorian coincides with the RST of DS2 and TST of DS3 showing by remarkable topographic irregularities in the basin physiography and change in the position of the depocenter axis from a E–W trend to the center; (5) late Ivorian-early Moliniacian coincides with the RST of DS3 and DS4 showing by the Late Tournaisian thermal period and eustatic rise superimposed on uplift and subaerial exposure of the western part and subsidence in the central and eastern parts of the basin; (6) Moliniacian coincides with DS5-DS6 sequences showing by change from fault-related topography to major tilted fault-block topography accompanied by eustatic sea-level fall caused indirectly by the Viséan and Serpukhovian glaciations phases.

Alterations in Abundance and Compartmentalization of miRNAs in Blood Plasma Extracellular Vesicles and Extracellular Condensates during HIV/SIV Infection and Its Modulation by Antiretroviral Therapy (ART) and Delta-9-Tetrahydrocannabinol (Δ9-THC).

Alterations in Abundance and Compartmentalization of miRNAs in Blood Plasma Extracellular Vesicles and Extracellular Condensates during HIV/SIV Infection and Its Modulation by Antiretroviral Therapy (ART) and Delta-9-Tetrahydrocannabinol (Δ9-THC).

Abstract 269: PD-L1 dominated tumor-CAF-immune cell crosstalk of stromal microenvironment: Endometrial tumor vs. tumor-adjacent normal

Abstract Background: In endometrial cancers (EC), the mechanistic contribution of PD-L1/L2 and PD-1 signaling of host’s stromal microenvironment (SME) [cancer-associated fibroblast (CAF) and immune cells] in relation to the tumor (T) cells is elusive. Aim: To understand the tumor-stroma-immune crosstalk in EC, we studied the compartmental pattern of PD-L1, PD-L2, and PD-1 expression in EC tissues and their matched CAFs from both T and tumor-adjacent normal (N) tissues. Method: Over 116 surgically resected T and N tissues were obtained from consented patients with EC at the Avera Cancer Institute (March ‘16 and September ’21). IHC expression was performed in T, N-epithelium, SME (mesenchyme) in the T and N tissues. The staining intensity and distribution pattern were evaluated by a pathologist using a standard scoring system (1% cut-off value). Since fibroblasts are the most abundant cells of SME, the PD-L1 was parallelly evaluated in the multiple passages of cultured T and N derived CAFs by the qRT-PCR, flow-cytometry, and ICC. Result: The expression of 3 immune checkpoint proteins in the epithelial and mesenchyme of N was limited to only rare and focal positivity for PD-L1. The epithelial compartments of the T tissue, in contrast, had 70% positivity for PD-L1, which was independent of differentiation status, presence of TILs, or lymphovascular invasion. PD-L1 positivity was 90% of the SME of tested samples, identified predominantly in the (1) immune component, including macrophages and lymphocytes, and (2) EpCAM-/SMA+/FAP+/S100A4+ CAFs. Both PD-L1 and PD-L2 were identified by flow, ICC, and qRT-PCR in NCAF and TCAF. The overall expression of PD-L2 was found to be qualitatively and quantitatively lesser than that of PD-L1, primarily contributed by SME/stromal macrophages and lymphocytes. PD-1 expression was restricted to the SME/stromal immune components, predominantly lymphocytes. The expression for PD-L1 and PD-L2 mRNA was higher in TCAF than NCAF in successive passages, which ICC and flow cytometry confirmed. Summary: The expression of immune checkpoint proteins, PD-L1, and PD-L2, are primarily tumor-driven and associated with the endometrioid (invasive) and serous adenocarcinomas of grades II and above with myometrial invasion. The expression of PD-L1 and PD-L2 are distributed in both tumor and SME/stromal components, while PD-1 expression is exclusively SME/stromal. Citation Format: Xiaoqian Lin, Jennifer Aske, Adam Dale, Nischal Koirala, Ethan Thompson, Mary Fagerness, Natasha Flier, Paige Davies, Stacy Kehoe, Cheryl Ageton, Kris Gaster, Luis Rojas Espaillat, David Starks, Raed Sulaiman, Pradip De, Nandini Dey. PD-L1 dominated tumor-CAF-immune cell crosstalk of stromal microenvironment: Endometrial tumor vs. tumor-adjacent normal [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 269.

Dynamic compartmental computations in tuft dendrites of layer 5 neurons during motor behavior.

Tuft dendrites of layer 5 pyramidal neurons form specialized compartments important for motor learning and performance, yet their computational capabilities remain unclear. Structural-functional mapping of the tuft tree from the motor cortex during motor tasks revealed two morphologically distinct populations of layer 5 pyramidal tract neurons (PTNs) that exhibit specific tuft computational properties. Early bifurcating and large nexus PTNs showed marked tuft functional compartmentalization, representing different motor variable combinations within and between their two tuft hemi-trees. By contrast, late bifurcating and smaller nexus PTNs showed synchronous tuft activation. Dendritic structure and dynamic recruitment of the N-methyl-d-aspartate (NMDA)-spiking mechanism explained the differential compartmentalization patterns. Our findings support a morphologically dependent framework for motor computations, in which independent amplification units can be combinatorically recruited to represent different motor sequences within the same tree.

Short Communication: Co-occurring Lobaria pulmonaria and Ricasolia quercizans share green algal photobionts: Consequences for conservation

Photobiont sharing among lichens within communities is a well-documented phenomenon, especially among closely related fungal species that form photobiont-mediated guilds (Dal Grande et al. 2014; Rikkinen et al. 2002). Species of Lobaria and other closely related genera that associate with Symbiochloris reticulata are one example of a photobiont-mediated guild that have been the subject of extensive research (Dal Grande et al. 2014). In their study, Dal Grande et al. (2014) compared algal multi-locus genotypes (MLGs) at one site in Taiwan and one site in Madeira among four species of Dendriscosticta, 16 species of Lobaria, and one species of Ricasolia, and, using pairwise FST values, found the species did not associate with significantly different green algal partners when they co-occurred. Green algal symbiont sharing has also been documented between the predominantly sexually reproducing Umbilicaria spodochroa and predominantly vegetatively reproducing Lasallia pustulata (Hestmark et al 2016). Werth (2012) recovered a more complex pattern of compartmentalization in Ramalina menziesii and adjacent lichen species. Photobiont sharing may also occur with co-occurring non-lichen organisms, such as liverworts (Cornejo & Scheidegger 2016).

Light-Induced Smooth Endoplasmic Reticulum Rearrangement in a Unique Interlaced Compartmental Pattern in Macaca mulatta RPE.

PurposeTo investigate light-induced modifications of the smooth endoplasmic reticulum of the RPE in primates.MethodsEyes of three terminally anesthetized Rhesus monkeys were exposed to 5000 lux for 10 minutes or kept in the dark. Transmission electron microscopy and electron tomography were conducted on small fragments of retina sampled from different regions of the retina.ResultsRPE cells smooth endoplasmic reticulum shows a previously unknown arrangement characterized by an interlaced compartmental pattern (ICP). Electron tomograms and 3D-modelling demonstrated that the smooth endoplasmic reticulum with an ICP (ICPSER) consisted of four parallel, independent and interwoven networks of tubules arranged as interconnected coiled coils. Its architecture realized a compact labyrinthine structure of tightly packed tubules stabilized by intertubular filamentous tethers. On average, the ICPSER is present in about 14.6% of RPE cells. Although ICPSER was preferentially found in cells located in the peripheral and in the para/perifoveal retina, ICPSER cells significantly increased in number upon light exposure in the para/perifovea and in the fovea.ConclusionsAn ICPSER is apparently a unique feature to primate RPE. Its rapid appearance in the area centralis of the retina upon light exposure suggests a function related to the foveate structure of primate retina or to the diurnal habits of animals that may require additional protection from photo-oxidation or enhanced requests of visual pigments regeneration.

Principles of 3D compartmentalization of the human genome.

SUMMARYChromatin is organized in the nucleus via CTCF loops and compartmental domains. Here, we compare different cell types to identify distinct paradigms of compartmental domain formation in human tissues. We identify and quantify compartmental forces correlated with histone modifications characteristic of transcriptional activity and previously underappreciated roles for distinct compartmental domains correlated with the presence of H3K27me3 and H3K9me3, respectively. We present a computer simulation model capable of predicting compartmental organization based on the biochemical characteristics of independent chromatin features. Using this model, we show that the underlying forces responsible for compartmental domain formation in human cells are conserved and that the diverse compartmentalization patterns seen across cell types are due to differences in chromatin features. We extend these findings to Drosophila to suggest that the same principles are at work beyond humans. These results offer mechanistic insights into the fundamental forces driving the 3D organization of the genome.

Cancer-associated mutations reveal a novel role for EpCAM as an inhibitor of cathepsin-L and tumor cell invasion

BackgroundEpCAM (Epithelial cell adhesion molecule) is often dysregulated in epithelial cancers. Prior studies implicate EpCAM in the regulation of oncogenic signaling pathways and epithelial-to-mesenchymal transition. It was recently demonstrated that EpCAM contains a thyroglobulin type-1 (TY-1) domain. Multiple proteins with TY-1 domains are known to inhibit cathepsin-L (CTSL), a cysteine protease that promotes tumor cell invasion and metastasis. Analysis of human cancer sequencing studies reveals that somatic EpCAM mutations are present in up to 5.1% of tested tumors.MethodsThe Catalogue of Somatic Mutations in Cancer (COSMIC) database was queried to tabulate the position and amino acid changes of cancer associated EpCAM mutations. To determine how EpCAM mutations affect cancer biology we studied C66Y, a damaging TY-1 domain mutation identified in liver cancer, as well as 13 other cancer-associated EpCAM mutations. In vitro and in vivo models were used to determine the effect of wild type (WT) and mutant EpCAM on CTSL activity and invasion. Immunoprecipitation and localization studies tested EpCAM and CTSL protein binding and determined compartmental expression patterns of EpCAM mutants.ResultsWe demonstrate that WT EpCAM, but not C66Y EpCAM, inhibits CTSL activity in vitro, and the TY-1 domain of EpCAM is responsible for this inhibition. WT EpCAM, but not C66Y EpCAM, inhibits tumor cell invasion in vitro and lung metastases in vivo. In an extended panel of human cancer cell lines, EpCAM expression is inversely correlated with CTSL activity. Previous studies have demonstrated that EpCAM germline mutations can prevent EpCAM from being expressed at the cell surface. We demonstrate that C66Y and multiple other EpCAM cancer-associated mutations prevent surface expression of EpCAM. Cancer-associated mutations that prevent EpCAM cell surface expression abrogate the ability of EpCAM to inhibit CTSL activity and tumor cell invasion.ConclusionsThese studies reveal a novel role for EpCAM as a CTSL inhibitor, confirm the functional relevance of multiple cancer-associated EpCAM mutations, and suggest a therapeutic vulnerability in cancers harboring EpCAM mutations.

Anatomy and evolution of bioluminescent organs in the slimeheads (Teleostei: Trachichthyidae).

Bacterial bioluminescent organs in fishes have a diverse range of tissues of origin, patterns of compartmentalization, and associated light-conducting structures. The morphology of the perianal, bacterial bioluminescent organ of Aulotrachichthys prosthemius was described previously, but the light organ in other species of slimeheads, family Trachichthyidae, is poorly known. Here, we describe the anatomy of the bioluminescent organs in trachichthyids and places the evolution of this light-producing system in the context of a new phylogeny of the Trachichthyoidei to test the hypothesis that bioluminescence evolved twice in the suborder and that the light-producing component derives from the perianal ectoderm. We use gross and histological examination to provide the first description of the bioluminescent organ of Paratrachichthys and four additional species of Aulotrachichthys. Observations also strongly suggest the presence of a perianal bioluminescent organ in Sorosichthys ananasa. The updated phylogeny of the Trachichthyoidei is the first to combine morphological and DNA-sequence (11-gene fragments) evidence, and supports a monophyletic Trachichthyidae with component subfamilies Hoplostethinae and Trachichthyinae, supporting continued recognition of the family Anoplogastridae. All bioluminescent trachichthyoids share a similar bioluminescent-organ structure with elongate chambers filled with bacteria and connected to collecting ducts that, in turn, connect to superficial ducts that lead to and have lining epithelia continuous with the epidermis. In the context of the phylogeny, the bioluminescent organ of trachichthyids is inferred to have evolved as an elaboration of the proctodeum in the ancestor of Aulotrachichthys, Paratrachichthys, and Sorosichthys independently from the structurally similar cephalic bioluminescent organs in Anomalopidae and Monocentridae.

Principles of 3D Compartmentalization of the Human Genome

Chromatin is organized in the nucleus by CTCF loops and compartmental domains, the latter of which contain sequences bound by proteins capable of mediating interactions among themselves. While compartmental domains are one of the most prominent features of genome 3D organization at the chromosome scale, we lack a nuanced understanding of the different types of compartmental domains present in chromosomes and a mechanistic knowledge of the forces responsible for their formation. In this study, we compared different cell types to identify distinct paradigms of compartmental domain formation in human tissues. We identified and quantified compartmental forces correlated with histone modifications characteristic of transcriptional activity as well as previously underappreciated roles for compartmental domains correlated with the presence of H3K9me3, H3K27me3, or none of these histone modifications. We present a simple computer simulation model capable of predicting compartmental organization based on the biochemical characteristics of independent chromatin features. Using this computational model, we show that the underlying forces responsible for compartmental domain formation in human cells are conserved and that the diverse compartmentalization patterns seen across cells are due to differences in chromatin features. We extend these findings to Drosophila to suggest that the same fundamental forces are at work beyond humans. These results offer mechanistic insights into the fundamental forces driving the 3D organization of the genome.

Compartmentalized biosynthesis of mycophenolic acid

Mycophenolic acid (MPA) from filamentous fungi is the first natural product antibiotic to be isolated and crystallized, and a first-line immunosuppressive drug for organ transplantations and autoimmune diseases. However, some key biosynthetic mechanisms of such an old and important molecule have remained unclear. Here, we elucidate the MPA biosynthetic pathway that features both compartmentalized enzymatic steps and unique cooperation between biosynthetic and β-oxidation catabolism machineries based on targeted gene inactivation, feeding experiments in heterologous expression hosts, enzyme functional characterization and kinetic analysis, and microscopic observation of protein subcellular localization. Besides identification of the oxygenase MpaB' as the long-sought key enzyme responsible for the oxidative cleavage of the farnesyl side chain, we reveal the intriguing pattern of compartmentalization for the MPA biosynthetic enzymes, including the cytosolic polyketide synthase MpaC' and O-methyltransferase MpaG', the Golgi apparatus-associated prenyltransferase MpaA', the endoplasmic reticulum-bound oxygenase MpaB' and P450-hydrolase fusion enzyme MpaDE', and the peroxisomal acyl-coenzyme A (CoA) hydrolase MpaH'. The whole pathway is elegantly comediated by these compartmentalized enzymes, together with the peroxisomal β-oxidation machinery. Beyond characterizing the remaining outstanding steps of the MPA biosynthetic steps, our study highlights the importance of considering subcellular contexts and the broader cellular metabolism in natural product biosynthesis.

When a Little Bit More Makes the Difference: Expression Levels of GKRP Determines the Subcellular Localization of GK in Tanycytes.

Glucose homeostasis is performed by specialized cells types that detect and respond to changes in systemic glucose concentration. Hepatocytes, β-cells and hypothalamic tanycytes are part of the glucosensor cell types, which express several proteins involved in the glucose sensing mechanism such as GLUT2, Glucokinase (GK) and Glucokinase regulatory protein (GKRP). GK catalyzes the phosphorylation of glucose to glucose-6-phosphate (G-6P), and its activity and subcellular localization are regulated by GKRP. In liver, when glucose concentration is low, GKRP binds to GK holding it in the nucleus, while the rise in glucose concentration induces a rapid export of GK from the nucleus to the cytoplasm. In contrast, hypothalamic tanycytes display inverse compartmentalization dynamic in response to glucose: a rise in the glucose concentration drives nuclear compartmentalization of GK. The underlying mechanism responsible for differential GK subcellular localization in tanycytes has not been described yet. However, it has been suggested that relative expression between GK and GKRP might play a role. To study the effects of GKRP expression levels in the subcellular localization of GK, we used insulinoma 832/13 cells and hypothalamic tanycytes to overexpress the tanycytic sequences of Gckr. By immunocytochemistry and Western blot analysis, we observed that overexpression of GKRP, independently of the cellular context, turns GK localization to a liver-like fashion, as GK is mainly localized in the nucleus in response to low glucose. Evaluating the expression levels of GKRP in relation to GK through RT-qPCR, suggest that excess of GKRP might influence the pattern of GK subcellular localization. In this sense, we propose that the low expression of GKRP (in relation to GK) observed in tanycytes is responsible, at least in part, for the compartmentalization pattern observed in this cell type. Since GKRP behaves as a GK inhibitor, the regulation of GKRP expression levels or activity in tanycytes could be used as a therapeutic target to regulate the glucosensing activity of these cells and consequently to regulate feeding behavior.

Intra‐Arc Crustal Seismicity: Seismotectonic Implications for the Southern Andes Volcanic Zone, Chile

AbstractWe examine the intra‐arc crustal seismicity of the Andean Southern Volcanic Zone. Our aim is to resolve interseismic deformation in an active magmatic arc dominated by both margin‐parallel (Liquiñe‐Ofqui fault system, LOFS) and Andean transverse faults. Crustal seismicity provides information about the schizosphere tectonic state, delineating the geometry and kinematics of high strain domains driven by oblique‐subduction. Here, we present local seismicity based on 16‐month data collected from 34 seismometers monitoring a ~200‐km‐long section of the Southern Volcanic Zone, including the Lonquimay and Villarrica volcanoes. We located 356 crustal events with magnitudes between Mw 0.6 and Mw 3.6. Local seismicity occurs at depths down to 40 km in the forearc and consistently shallower than 12 km beneath the volcanic chain, suggesting a convex shape of the crustal seismogenic layer bottom. Focal mechanisms indicate strike‐slip faulting consistent with ENE‐WSW shortening in line with the long‐term deformation history revealed by structural geology studies. However, we find regional to local‐scale variations in the shortening axes orientation as revealed by the nature and spatial distribution of microseismicity, within three distinctive latitudinal domains. In the northernmost domain, seismicity is consistent with splay faulting at the northern termination of the LOFS; in the central domain, seismicity distributes along ENE‐ and WNW‐striking discrete faults, spatially associated with, hitherto seismic Andean transverse faults. The southernmost domain, in turn, is characterized by activity focused along a N15°E striking master branch of the LOFS. These observations indicate a complex strain compartmentalization pattern within the intra‐arc crust, where variable strike‐slip faulting dominates over dip‐slip movements.

Patterns of Invasive Growth in Malignant Gliomas—The Hippocampus Emerges as an Invasion-Spared Brain Region

BACKGROUND: Widespread infiltration of tumor cells into surrounding brain parenchyma is a hallmark of malignant gliomas, but little data exist on the overall invasion pattern of tumor cells throughout the brain. METHODS: We have studied the invasive phenotype of malignant gliomas in two invasive mouse models and patients. Tumor invasion patterns were characterized in a patient-derived xenograft mouse model using brain-wide histological analysis and magnetic resonance (MR) imaging. Findings were histologically validated in a cdkn2a−/− PDGF-β lentivirus-induced mouse glioblastoma model. Clinical verification of the results was obtained by analysis of MR images of malignant gliomas. RESULTS: Histological analysis using human-specific cellular markers revealed invasive tumors with a non-radial invasion pattern. Tumors cells accumulated in structures located far from the transplant site, such as the optic white matter and pons, whereas certain adjacent regions were spared. As such, the hippocampus was remarkably free of infiltrating tumor cells despite the extensive invasion of surrounding regions. Similarly, MR images of xenografted mouse brains displayed tumors with bihemispheric pathology, while the hippocampi appeared relatively normal. In patients, most malignant temporal lobe gliomas were located lateral to the collateral sulcus. Despite widespread pathological fluid-attenuated inversion recovery signal in the temporal lobe, 74% of the “lateral tumors” did not show signs of involvement of the amygdalo-hippocampal complex. CONCLUSIONS: Our data provide clear evidence for a compartmental pattern of invasive growth in malignant gliomas. The observed invasion patterns suggest the presence of preferred migratory paths, as well as intra-parenchymal boundaries that may be difficult for glioma cells to traverse supporting the notion of compartmental growth. In both mice and human patients, the hippocampus appears to be a brain region that is less prone to tumor invasion.

Proponent Specificity as Targeting Evolutionary Traits in Ras Isoform Mutability in Carcinogenesis

Distributional and re-distributional patterns of compartmentalization of RAS isoforms are core, persistently active abnormalities that are central/additional phenomena within mutable molecular structure and dysfunction in carcinogenesis. In such terms, ongoing transformations attributes, both within the plasmalemma and the internal membrane compartments, potentiate transformation, as further illustrated by sequestration of mutational forms of RAS. The incremental adaptation response of injured cells further conforms with the resultant dimensions of cooperating networks, rather than as linear pathways; these network organizations induce groups of neoplastic cells to further augment the effector end-target predispositions toward pre-carcinogenesis and carcinogenesis. RAS formulation is hence primarily an effector initiator and maintenance-inducing role-pattern formulator in carcinogenesis, as reflected in central metabolic pathways of cell growth promotion and proliferation.