Cerebral coherence between communicators marks the emergence of meaning

How can we understand each other during communicative interactions? An influential suggestion holds that communicators are primed by each other’s behaviors, with associative mechanisms automatically coordinating the production of communicative signals and the comprehension of their meanings. An alternative suggestion posits that mutual understanding requires shared conceptualizations of a signal’s use, i.e., “conceptual pacts” that are abstracted away from specific experiences. Both accounts predict coherent neural dynamics across communicators, aligned either to the occurrence of a signal or to the dynamics of conceptual pacts. Using coherence spectral-density analysis of cerebral activity simultaneously measured in pairs of communicators, this study shows that establishing mutual understanding of novel signals synchronizes cerebral dynamics across communicators’ right temporal lobes. This interpersonal cerebral coherence occurred only within pairs with a shared communicative history, and at temporal scales independent from signals’ occurrences. These findings favor the notion that meaning emerges from shared conceptualizations of a signal’s use

Alternative splicing downstream of EMT enhances phenotypic plasticity and malignant behavior in colon cancer

Phenotypic plasticity allows carcinoma cells to transiently acquire the quasi-mesenchymal features necessary to detach from the primary mass and proceed along the invasion-metastasis cascade. A broad spectrum of epigenetic mechanisms is likely to cause the epithelial-to-mesenchymal (EMT) and mesenchymal-to-epithelial (MET) transitions necessary to allow local dissemination and distant metastasis. Here, we report on the role played by alternative splicing (AS) in eliciting phenotypic plasticity in epithelial malignancies with focus on colon cancer. By taking advantage of the coexistence of subpopulations of fully epithelial (EpCAM(hi)) and quasi-mesenchymal and highly metastatic (EpCAM(lo)) cells in conventional human cancer cell lines, we here show that the differential expression of ESRP1 and other RNA-binding proteins (RBPs) downstream of the EMT master regulator ZEB1 alters the AS pattern of a broad spectrum of targets including CD44 and NUMB, thus resulting in the generation of specific isoforms functionally associated with increased invasion and metastasis. Additional functional and clinical validation studies indicate that both the newly identified RBPs and the CD44s and NUMB2/4 splicing isoforms promote local invasion and distant metastasis and are associated with poor survival in colon cancer. The systematic elucidation of the spectrum of EMT-related RBPs and AS targets in epithelial cancers, apart from the insights in the mechanisms underlying phenotypic plasticity, will lead to the identification of novel and tumor-specific therapeutic targets

A YAP-centered mechanotransduction loop drives collective breast cancer cell invasion

Dense and aligned Collagen I fibers are associated with collective cancer invasion led by protrusive tumor cells, leader cells. In some breast tumors, a population of cancer cells (basal-like cells) maintain several epithelial characteristics and express the myoepithelial/basal cell marker Keratin 14 (K14). Emergence of leader cells and K14 expression are regarded as interconnected events triggered by Collagen I, however the underlying mechanisms remain unknown. Using breast carcinoma organoids, we show that Collagen I drives a force-dependent loop, specifically in basal-like cancer cells. The feed-forward loop is centered around the mechanotransducer Yap and independent of K14 expression. Yap promotes a transcriptional program that enhances Collagen I alignment and tension, which further activates Yap. Active Yap is detected in invading breast cancer cells in patients and required for collective invasion in 3D Collagen I and in the mammary fat pad of mice. Our work uncovers an essential function for Yap in leader cell selection during collective cancer invasion.</p

A YAP-centered mechanotransduction loop drives collective breast cancer cell invasion

Dense and aligned Collagen I fibers are associated with collective cancer invasion led by protrusive tumor cells, leader cells. In some breast tumors, a population of cancer cells (basal-like cells) maintain several epithelial characteristics and express the myoepithelial/basal cell marker Keratin 14 (K14). Emergence of leader cells and K14 expression are regarded as interconnected events triggered by Collagen I, however the underlying mechanisms remain unknown. Using breast carcinoma organoids, we show that Collagen I drives a force-dependent loop, specifically in basal-like cancer cells. The feed-forward loop is centered around the mechanotransducer Yap and independent of K14 expression. Yap promotes a transcriptional program that enhances Collagen I alignment and tension, which further activates Yap. Active Yap is detected in invading breast cancer cells in patients and required for collective invasion in 3D Collagen I and in the mammary fat pad of mice. Our work uncovers an essential function for Yap in leader cell selection during collective cancer invasion.</p

Заболевание тазобедренного сустава у детей с наследственной предрасположенностью: концептуальная модель

На основе принципов интегративной медицины, системного подхода с использованием концептуально−логического моделирования разработана единая система представлений о заболеваниях тазобедренного сустава у детей с наследственной предрасположенностью. Показано, что предлагаемый интегративный подход может служить основой для разработки диагностических и прогностических критериев развития суставов и проведения патогенетического хирургического лечения, направленного на ликвидацию или существенное снижение частоты формирования диспластического коксартроза.Based on the principles of integrative medicine, systemic approach with the use of concept of logical modelling, a uniform system of concepts about the diseases of the hip joint in children with hereditary susceptibility was worked out. It was shown that the suggested integrative approach can be used for working out diagnostic and prognostic criteria of joint development and performing pathogenetic surgery aimed at elimination or reduction in the frequency of forming dysplastic coxarthrosis

Co-cultures of colon cancer cells and cancer-associated fibroblasts recapitulate the aggressive features of mesenchymal-like colon cancer

BACKGROUND: Poor prognosis in colon cancer is associated with a high content of cancer-associated fibroblasts (CAFs) and an immunosuppressive tumor microenvironment. The relationship between these two features is incompletely understood. Here, we aimed to generate a model system for studying the interaction between cancer cells and CAFs and their effect on immune-related cytokines and T cell proliferation. METHODS: CAFs were isolated from colon cancer liver metastases and were immortalized to prolong lifespan and improve robustness and reproducibility. Established medium and matrix compositions that support the growth of patient-derived organoids were adapted to also support CAF growth. Changes in growth pattern and cellular re-organization were assessed by confocal microscopy, live cell imaging, and immunofluorescence. Single cell RNA sequencing was used to study CAF/organoid co-culture-induced phenotypic changes in both cell types. Conditioned media were used to quantify the production of immunosuppressive factors and to assess their effect on T cell proliferation. RESULTS: We developed a co-culture system in which colon cancer organoids and CAFs spontaneously organize into superstructures with a high capacity to contract and stiffen the extracellular matrix (ECM). CAF-produced collagen IV provided a basement membrane supporting cancer cell organization into glandular structures, reminiscent of human cancer histology. Single cell RNA sequencing analysis showed that CAFs induced a partial epithelial-to-mesenchymal-transition in a subpopulation of cancer cells, similar to what is observed in the mesenchymal-like consensus molecular subtype 4 (CMS4) colon cancer. CAFs in co-culture were characterized by high expression of ECM components, ECM-remodeling enzymes, glycolysis, hypoxia, and genes involved in immunosuppression. An expression signature derived from CAFs in co-culture identified a subpopulation of glycolytic myofibroblasts specifically residing in CMS1 and CMS4 colon cancer. Medium conditioned by co-cultures contained high levels of the immunosuppressive factors TGFβ1, VEGFA and lactate, and potently inhibited T cell proliferation. CONCLUSION: Co-cultures of organoids and immortalized CAFs recapitulate the histological, biophysical, and immunosuppressive features of aggressive mesenchymal-like human CRC. The model can be used to study the mechanisms of immunosuppression and to test therapeutic strategies targeting the cross-talk between CAFs and cancer cells. It can be further modified to represent distinct colon cancer subtypes and (organ-specific) microenvironments

A YAP-centered mechanotransduction loop drives collective breast cancer cell invasion

Dense and aligned Collagen I fibers are associated with collective cancer invasion led by protrusive tumor cells, leader cells. In some breast tumors, a population of cancer cells (basal-like cells) maintain several epithelial characteristics and express the myoepithelial/basal cell marker Keratin 14 (K14). Emergence of leader cells and K14 expression are regarded as interconnected events triggered by Collagen I, however the underlying mechanisms remain unknown. Using breast carcinoma organoids, we show that Collagen I drives a force-dependent loop, specifically in basal-like cancer cells. The feed-forward loop is centered around the mechanotransducer Yap and independent of K14 expression. Yap promotes a transcriptional program that enhances Collagen I alignment and tension, which further activates Yap. Active Yap is detected in invading breast cancer cells in patients and required for collective invasion in 3D Collagen I and in the mammary fat pad of mice. Our work uncovers an essential function for Yap in leader cell selection during collective cancer invasion

Business model innovation in European SMEs: thriving configurations and performance implications

For many years, Business Model Innovation (BMI) has been recognized by academics as key to improve competitiveness and innovativeness. While more than ninety percent of the large corporates conduct some degree of BMI, BMI has barely reached Small and Medium enterprises (SMEs). Increasing the use of BMI in SMEs is believed to boost the economic situation, which has become the objective of multiple innovation support programs. To substantiate the need for these programs and to guide their actions, the link between BMI and business performance requires clarification. Based on a dataset collected in 2016 by project ENVISION, this study investigates this relation by examining over five hundred European SMEs. Following a multi-method approach, this study provides evidence for the claim that BMI can enhance firm performance in different ways. Our results provide directions on how programs can be tailored to parts of the SME population that are expected to show the strongest response to raising BMI adoption.Management of Technology (MoT

Collective migration and phenotypic plasticity in cancer metastasis: Conflicting views or complementary mechanisms?

Cancer metastasis, the spread of cancer to distant organs, is the major cause of cancerrelated mortality. Hence, understanding the mechanisms underlying cancer metastasis is crucial to improve clinical interventions. Despite intensive efforts, the driving mechanisms remain ill-understood due to the difficulties posed by studying the different steps of the metastatic cascade in patients. Two established models have been proposed to underlie the driving mechanisms of metastasis are phenotypic plasticity and collective migration. Phenotypic plasticity, i.e. the capacity of the migrating cancer cell to adapt to the different cellular contexts that it encounters en route to form a metastasis, revolves around reversable transitions from epithelial to mesenchymal (EMT and MET) identities. The collective migration model denotes migrating cancer cells can overcome barriers by coordinated cooperation. Recently, these views have been integrated in a model where partial (EMT) is believed to mediate collective migration. Here, we will investigate critical assumptions of this integrated model by focusing on different steps along the invasion-metastasis cascade. Using an unsupervised approach based on complete transcriptomes, we unravel single cell EMT-related transcriptional differences in colorectal cancer cell lines and map different phenotypes on the EMT spectrum to identify E/M sub-states that might underlie collective invasion. Next, we have developed and evaluated 3D collagen models to facilitate collective migration studies both in vitro and ex vivo. Preliminary data obtained using this approach highlights how EMT induction can alter the dominating tumor migration type. Taken together, our results support a case for phenotypic plasticity and collective migration as complementary and functionally correlated mechanisms, and could serve as point of engagement for further studies aimed at clarifying the role of partial EMT in collective migration.Applied Sciences | Nanobiolog