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Neurite outgrowth inhibitor A (Nogo-A) is a major player in neural development and regeneration and the target of clinical trials aiming at promoting the regeneration of the central nervous system upon traumatic and ischemic injury. In this work, we investigated the functions of Nogo-A during tooth development to determine its role in dental physiology and pathology. Using immunohistochemistry and in situ hybridization techniques, we showed that Nogo-A is highly expressed in the developing mouse teeth and, most specifically, in the ameloblasts that are responsible for the formation of enamel. Using both Nogo-Aknockout and K14-Cre;Nogo-A fl/fltransgenic mice, we showed that Nogo-A deletion in the dental epithelium leads to the formation of defective enamel. This phenotype is associated with overexpression of a set of specific genes involved in ameloblast differentiation and enamel matrix production, such as amelogenin, ameloblastinand enamelin. By characterising the interactome of Nogo-A in the dental epithelium of wild-type and mutant animals, we found that Nogo-A directly interacts with molecules important for regulating gene expression, and its deletion disturbs their cellular localisation. Furthermore, we demonstrated that inhibition of the intracellular, but not cell-surface, Nogo-A is responsible for gene expression modulation in ameloblasts. Taken together, these results reveal an unexpected function for Nogo-A in tooth enamel formation by regulating gene expression and cytodifferentiation events.

Pancreatic intraductal tubulopapillary neoplasm (ITPN) is a recently recognized intraductal neoplasm. This study aimed to clarify the clinicopathologic and molecular features of this entity, based on a multi-institutional cohort of 16 pancreatic ITPNs and associated adenocarcinomas. The genomic profiles were analyzed using histology-driven multi-regional sequencing to provide insight on tumor heterogeneity and evolution. Furthermore, an exploratory transcriptomic characterization was performed on eight invasive adenocarcinomas. The clinicopathologic parameters and molecular alterations were further analyzed based on survival indices. The main findings were as follows: 1) the concomitant adenocarcinomas, present in 75% of cases, were always molecularly associated with the intraductal components. These data definitively establish ITPN as origin of invasive pancreatic adenocarcinoma; 2) alterations restricted to infiltrative components included mutations in chromatin remodeling genes ARID2, ASXL1, and PBRM1, and ERBB2-P3H4fusion; 3) pancreatic ITPN can arise in the context of genetic syndromes, such as BRCA-germline and Peutz–Jeghers syndrome; 4) mutational profile: mutations in the classical PDAC drivers are present, but less frequently, in pancreatic ITPN; 5) novel genomic alterations were observed, including amplification of the Cyclin and NOTCHfamily genes and ERBB2, fusions involving RETand ERBB2, and RB1disruptive variation; 6) chromosomal alterations: the most common was 1q gain (75% of cases); 7) by transcriptome analysis, ITPN-associated adenocarcinomas clustered into three subtypes that correlate with the activation of signaling mechanism pathways and tumor microenvironment, displaying squamous features in their majority; and 8) TP53mutational status is a marker for adverse prognosis. ITPNs are precursor lesions of pancreatic cancer with a high malignant transformation risk. A personalized approach for patients with ITPN should recognize that such neoplasms could arise in the context of genetic syndromes. BRCAalterations, ERBB2and RETfusions, and ERBB2amplification are novel targets in precision oncology. The TP53mutation status can be used as a prognostic biomarker.

Pancreatic intraductal tubulopapillary neoplasm (ITPN) is a recently recognized intraductal neoplasm. This study aimed to clarify the clinicopathologic and molecular features of this entity, based on a multi-institutional cohort of 16 pancreatic ITPNs and associated adenocarcinomas. The genomic profiles were analyzed using histology-driven multi-regional sequencing to provide insight on tumor heterogeneity and evolution. Furthermore, an exploratory transcriptomic characterization was performed on eight invasive adenocarcinomas. The clinicopathologic parameters and molecular alterations were further analyzed based on survival indices. The main findings were as follows: 1) the concomitant adenocarcinomas, present in 75% of cases, were always molecularly associated with the intraductal components. These data definitively establish ITPN as origin of invasive pancreatic adenocarcinoma; 2) alterations restricted to infiltrative components included mutations in chromatin remodeling genes ARID2, ASXL1, and PBRM1, and ERBB2-P3H4fusion; 3) pancreatic ITPN can arise in the context of genetic syndromes, such as BRCA-germline and Peutz–Jeghers syndrome; 4) mutational profile: mutations in the classical PDAC drivers are present, but less frequently, in pancreatic ITPN; 5) novel genomic alterations were observed, including amplification of the Cyclin and NOTCHfamily genes and ERBB2, fusions involving RETand ERBB2, and RB1disruptive variation; 6) chromosomal alterations: the most common was 1q gain (75% of cases); 7) by transcriptome analysis, ITPN-associated adenocarcinomas clustered into three subtypes that correlate with the activation of signaling mechanism pathways and tumor microenvironment, displaying squamous features in their majority; and 8) TP53mutational status is a marker for adverse prognosis. ITPNs are precursor lesions of pancreatic cancer with a high malignant transformation risk. A personalized approach for patients with ITPN should recognize that such neoplasms could arise in the context of genetic syndromes. BRCAalterations, ERBB2and RETfusions, and ERBB2amplification are novel targets in precision oncology. The TP53mutation status can be used as a prognostic biomarker.

Excessive fear is a hallmark of anxiety disorders, a major cause of disease burden worldwide. Substantial evidence supports a role of prefrontal cortex-amygdala circuits in the regulation of fear and anxiety, but the molecular mechanisms that regulate their activity remain poorly understood. Here, we show that downregulation of the histone methyltransferase PRDM2 in the dorsomedial prefrontal cortex enhances fear expression by modulating fear memory consolidation. We further show that Prdm2knock-down (KD) in neurons that project from the dorsomedial prefrontal cortex to the basolateral amygdala (dmPFC-BLA) promotes increased fear expression. Prdm2KD in the dmPFC-BLA circuit also resulted in increased expression of genes involved in synaptogenesis, suggesting that Prdm2KD modulates consolidation of conditioned fear by modifying synaptic strength at dmPFC-BLA projection targets. Consistent with an enhanced synaptic efficacy, we found that dmPFC Prdm2KD increased glutamatergic release probability in the BLA and increased the activity of BLA neurons in response to fear-associated cues. Together, our findings provide a new molecular mechanism for excessive fear responses, wherein PRDM2 modulates the dmPFC -BLA circuit through specific transcriptomic changes.

Purpose: The purpose of this paper is to investigate the key drivers of coopetition by adopting a managerial and economic framework. A case of coopetition failure is investigated by means of a historical example focused on the Egyptian adventure of the Italian banks in the first decades of the XX century. Design/methodology/approach: The authors adopt a qualitative case study and a flexible pattern matching approach to develop theoretical ideas. Because the flexible pattern matching approach was adopted, the authors build the analysis on a tentative analytical framework specified a priorito provide guidance and focus. This approach allows a theory-driven research paradigm. The historical case study is mainly grounded on original sources drawn from some major banking and institutional archives. Findings: While several scholars emphasised the relevance of external drivers, the literature has paid less attention to how relational and internal drivers combine. The historical case suggests that key mechanisms supporting the success of coopetition concern planning of common goals, conflicts management, alignment and formalisation of governance. In this vein, internal and relational dimensions seem to be more relevant than environment-context dimension. In addition, the historical example shows that an intra- and inter-firm alignment is required to pursue the implementation of a coopetitive strategy. This suggests the relevance of a holistic approach to investigate coopetition. Further evidence confirms the role of governance mechanisms for the success of coopetition. Originality/value: The main contribution of this study is the re-consideration of the drivers of coopetition. In particular, the role of coopetition drivers has been investigated using a historical event: the Italian multinational banking in Egypt in the interwar years.

ABSTRACTSustainable innovation – the introduction of new products and processes that bring economic, social and environmental benefits – have a crucial role in the textile and fashion industry. However, current literature mainly focuses on new product development and the consequent environmental impacts. One of the main challenges for textile and fashion companies is how to be environmentally, socially and economically sustainable and innovative in the meantime. This paper is based on the Triple Bottom Line framework and attempts to address this gap by identifying some key success factors (KSFs) that could allow textile and fashion companies to develop product and process innovations, taking into account their social, environmental and economic outcomes. The research is based on a multiple-case study method and results show that textile and fashion companies can achieve a competitive advantage by being sustainable and innovative and when there are strong corporate values, cultural heritage and stable relationships with the territory. Besides extending the literature on sustainable, the paper highlights the main challenges and opportunities within this sector.

The outbreak of the pandemic associated with Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) led researchers to find new potential treatments, including nonpharmacological molecules such as zinc (Zn2+). Specifically, the use of Zn2+as a therapy for SARS-CoV-2 infection is based on several findings: 1) the possible role of the anti-inflammatory activity of Zn2+on the aberrant inflammatory response triggered by COronaVIrus Disease 19 (COVID-19), 2) properties of Zn2+in modulating the competitive balance between the host and the invading pathogens, and 3) the antiviral activity of Zn2+on a number of pathogens, including coronaviruses. Furthermore, Zn2+has been found to play a central role in regulating brain functioning and many disorders have been associated with Zn2+deficiency, including neurodegenerative diseases, psychiatric disorders, and brain injuries. Within this context, we carried out a narrative review to provide an overview of the evidence relating to the effects of Zn2+on the immune and nervous systems, and the therapeutic use of such micronutrients in both neurological and infective disorders, with the final goal of elucidating the possible use of Zn2+as a preventive or therapeutic intervention in COVID-19. Overall, the results from the available evidence showed that, owing to its neuroprotective properties, Zn2+supplementation could be effective not only on COVID‐19–related symptoms but also on virus replication, as well as on COVID-19–related inflammation and neurological damage. However, further clinical trials evaluating the efficacy of Zn2+as a nonpharmacological treatment of COVID-19 are required to achieve an overall improvement in outcome and prognosis.Statement of Significance: By summarizing the available literature on, and exploring the possible role of, zinc in SARS-CoV-2 infection, the present review suggests how Zn2+supplementation may be effective in COVID-19–related neurological complications.

The outbreak of the pandemic associated with Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) led researchers to find new potential treatments, including nonpharmacological molecules such as zinc (Zn2+). Specifically, the use of Zn2+as a therapy for SARS-CoV-2 infection is based on several findings: 1) the possible role of the anti-inflammatory activity of Zn2+on the aberrant inflammatory response triggered by COronaVIrus Disease 19 (COVID-19), 2) properties of Zn2+in modulating the competitive balance between the host and the invading pathogens, and 3) the antiviral activity of Zn2+on a number of pathogens, including coronaviruses. Furthermore, Zn2+has been found to play a central role in regulating brain functioning and many disorders have been associated with Zn2+deficiency, including neurodegenerative diseases, psychiatric disorders, and brain injuries. Within this context, we carried out a narrative review to provide an overview of the evidence relating to the effects of Zn2+on the immune and nervous systems, and the therapeutic use of such micronutrients in both neurological and infective disorders, with the final goal of elucidating the possible use of Zn2+as a preventive or therapeutic intervention in COVID-19. Overall, the results from the available evidence showed that, owing to its neuroprotective properties, Zn2+supplementation could be effective not only on COVID‐19–related symptoms but also on virus replication, as well as on COVID-19–related inflammation and neurological damage. However, further clinical trials evaluating the efficacy of Zn2+as a nonpharmacological treatment of COVID-19 are required to achieve an overall improvement in outcome and prognosis.

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Canonical Wnt/β-catenin signaling is an established regulator of cellular state and its critical contributions to tumor initiation, malignant tumor progression and metastasis formation have been demonstrated in various cancer types. Here, we investigated how the binding of β-catenin to the transcriptional coactivators B-cell CLL/lymphoma 9 (Bcl9) and Bcl9-Like (Bcl9L) affected mammary gland carcinogenesis in the MMTV-PyMT transgenic mouse model of metastatic breast cancer. Conditional knockout of both Bcl9and Bcl9Lresulted into tumor cell death. In contrast, disrupting the interaction of Bcl9/Bcl9L with β-catenin, either by deletion of their HD2 domains or by a point mutation in the N-terminal domain of β-catenin (D164A), diminished primary tumor growth and tumor cell proliferation and reduced tumor cell invasion and lung metastasis. In comparison, the disruption of HD1 domain-mediated binding of Bcl9/Bcl9L to Pygopus had only moderate effects. Interestingly, interfering with the β-catenin-Bcl9/Bcl9L-Pygo chain of adapters only partially impaired the transcriptional response of mammary tumor cells to Wnt3a and TGFβ treatments. Together, the results indicate that Bcl9/Bcl9L modulate but are not critically required for canonical Wnt signaling in its contribution to breast cancer growth and malignant progression, a notion consistent with the “just-right” hypothesis of Wnt-driven tumor progression.

The Sox2 transcription factor is necessary for the long‐term self‐renewal of neural stem cells (NSCs). Its mechanism of action is still poorly defined. To identify molecules regulated by Sox2, and acting in mouse NSC maintenance, we transduced, into Sox2‐deleted NSC, genes whose expression is strongly downregulated following Sox2 loss (Fos, Jun, Egr2), individually or in combination. Fos alone rescued long‐term proliferation, as shown by in vitro cell growth and clonal analysis. Furthermore, pharmacological inhibition by T‐5224 of FOS/JUN AP1 complex binding to its targets decreased cell proliferation and expression of the putative target Suppressor of cytokine signaling 3 (Socs3). Additionally, Fos requirement for efficient long‐term proliferation was demonstrated by the reduction of NSC clones capable of long‐term expansion following CRISPR/Cas9‐mediated Fos inactivation. Previous work showed that the Socs3 gene is strongly downregulated following Sox2 deletion, and its re‐expression by lentiviral transduction rescues long‐term NSC proliferation. Fos appears to be an upstream regulator of Socs3, possibly together with Jun and Egr2; indeed, Sox2 re‐expression in Sox2‐deleted NSC progressively activates both Fos and Socs3 expression; in turn, Fos transduction activates Socs3 expression. Based on available SOX2 ChIPseq and ChIA‐PET data, we propose a model whereby Sox2 is a direct activator of both Socs3 and Fos, as well as possibly Jun and Egr2; furthermore, we provide direct evidence for FOS and JUN binding on Socs3promoter, suggesting direct transcriptional regulation. These results provide the basis for developing a model of a network of interactions, regulating critical effectors of NSC proliferation and long‐term maintenance. Sox2 is necessary for long‐term neural stem cell (NSC) self‐renewal and for Socs3, Fos, Jun, and Egr2 gene expression. We previously showed that Socs3 overexpression rescues Sox2‐deleted NSC self‐renewal. Fos, Jun, and Egr2 transduction into Sox2‐deleted NSC rescues self‐renewal, Fos alone being both sufficient and necessary. Sox2 transduction upregulates Fos and Socs3 in Sox2‐deleted cells, and Fos upregulates Socs3, defining a Sox2‐dependent regulatory network.

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Natural products are a sustainable resource for drug discovery, but their identification in complex mixtures remains a daunting task. We present an automated pipeline that compares, harmonizes and ranks the annotations of LC-HRMS data by different tools. When applied to 7,400 extracts derived from 6,566 strains belonging to 86 actinomycete genera, it yielded 150,000 molecules after processing over 50 million MS features. The web-based Molecules Gateway provides a highly interactive access to experimental and calculated data for these molecules, along with the metadata related to extracts and producer strains. We show how the Molecules Gateway can be used to rapidly identify known hard to find microbial products, unreported analogs of known families and not yet described metabolites. The Molecules Gateway, which complements available repositories, contains annotated MS data, both acquired and computationally processed under an identical workflow, making it suitable for global analyses which reveal a large and untapped chemical diversity afforded by actinomycetes.

The aim of this work was to develop an innovative microemulsion with gel-like properties for the cutaneous delivery of imiquimod, an immunostimulant drug employed for the treatment of cutaneous infections and neoplastic conditions. A pseudoternary phase diagram was built using a 1/1 TPGS (d-α-tocopheryl polyethylene glycol 1000 succinate)/Transcutol mixture as surfactant system, and oleic acid as oil phase. Eight microemulsionsselected from the 1.25/8.75 oil/surfactants ratio, along the water dilution line (from 20 to 56% w/w)were characterized in terms of rheological behavior, optical properties via polarized microscopy, and supramolecular structure using X-ray scattering. Then, these formulations were loaded with imiquimod and the uptake and distribution into the skin was evaluated on full-thickness porcine skin. X-ray scattering experiments revealed the presence of disconnected drops in the case of microemulsion with 20% water content. Diluting the system up to 48% water content, the structure turned into an interconnected lamellar microemulsion, reaching a proper disconnected lamellar structure for the highest water percentages (52–56%). Upon water addition, also the rheological properties changed from nearly Newtonian fluids to gel-like structures, displaying the maximum of viscosity for the 48% water content. Skin uptake experiments demonstrated that formulation viscosity, drug loading, and surfactant concentration did not play an important role on imiquimod uptake into the skin, while the skin penetration was related instead to the microemulsion mesostructure. In fact, drug uptake became enhanced by locally lamellar interconnected structures, while it was reduced in the presence of disconnected structures, either drops or proper lamellae. Finally, the data demonstrated that mesostructure also affects the drug distribution between the epidermis and dermis. In particular, a significantly higher dermal accumulation was found when disconnected lamellar structures are present, suggesting the possibility of tuning both drug delivery and localization into the skin by modifying microemulsions composition.

Background: Cleavage Under Targets and Release Using Nuclease (CUT&RUN) is an increasingly popular technique to map genome-wide binding profiles of histone modifications, transcription factors, and co-factors. The ENCODE project and others have compiled blacklists for ChIP-seq which have been widely adopted: these lists contain regions of high and unstructured signal, regardless of cell type or protein target, indicating that these are false positives. While CUT&RUN obtains similar results to ChIP-seq, its biochemistry and subsequent data analyses are different. We found that this results in a CUT&RUN-specific set of undesired high-signal regions. Results: We compile suspect lists based on CUT&RUN data for the human and mouse genomes, identifying regions consistently called as peaks in negative controls. Using published CUT&RUN data from our and other labs, we show that the CUT&RUN suspect regions can persist even when peak calling is performed with SEACR or MACS2 against a negative control and after ENCODE blacklist removal. Moreover, we experimentally validate the CUT&RUN suspect lists by performing reiterative negative control experiments in which no specific protein is targeted, showing that they capture more than 80% of the peaks identified. Conclusions: We propose that removing these problematic regions can substantially improve peak calling in CUT&RUN experiments, resulting in more reliable datasets.

Purpose: Differently from previous works that focused on the entrepreneur and on his ability to manage social relationships, the purpose of this paper is to investigate the role of business relationships in the different stages of the life cycle of a start-up. Design/methodology/approach: Since the paper aims to explore startups’ evolutionary phenomenon, it adopts a qualitative abductive methodology, presenting an in-depth study of two innovative Italian start-ups. The research is based on two steps. In the first one, the authors collected secondary data from start-ups’ reports and documents, financial indicators (when available) and processed them to understand their background. In the second one, the authors conducted ten semi-structured interviews, including face-to-face interviews, phone interviews and video conferences. Findings: The paper presents a relationship-based life cycle model composed of four different stages, depending on the number and role of relationships developed. Indeed, since the beginning, start-ups adopt a relational approach and their evolution involves the shift from the focus on the entrepreneur to the centrality of a network approach based on interconnected relationships. The entering into a new stage of life cycle depends on relationships, mainly based on connected actors and resources shared and combined. Even if a key role is assumed by technology, the main resource is identified in the knowledge concerning the customer/user’s needs that require marketing competencies, human resources, relational capabilities. Thus, the shift from one stage to the next in the start-up’s life cycle is possible thanks to a parallel shift from a focus on the activities to a focus on those strategic and heterogeneous actors that ensure activities. Originality/value: In a traditional perspective, the start-up’s life cycle depends on activities, financial resources and revenues, as stated by previous life cycle models. In a different perspective, as depicted in our analysis, the evolution of a start-up depends on the portfolio of their business relationships. The role of business relationships is hence to facilitate the interconnections within specialized key actors, which allow start-ups to access strategic resources. These resources are essential in order to develop the activities that characterize the specific stage of the life cycle.

Human papillomavirus (HPV)-driven cutaneous squamous cell carcinoma (cSCC) is the most common cancer in immunosuppressed patients. Despite indications suggesting that HPV promotes genomic instability during cSCC development, the molecular pathways underpinning HPV-driven cSCC development remain unknown. We compared the transcriptome of HPV-driven mouse cSCC with normal skin and observed higher amounts of transcripts for Porcupine and WNT ligands in cSCC, suggesting a role for WNT signaling in cSCC progression. We confirmed increased Porcupine expression in human cSCC samples. Blocking the secretion of WNT ligands by the Porcupine inhibitor LGK974 significantly diminished initiation and progression of HPV-driven cSCC. Administration of LGK974 to mice with established cSCC resulted in differentiation of cancer cells and significant reduction of the cancer stem cell compartment. Thus, WNT/β-catenin signaling is essential for HPV-driven cSCC initiation and progression as well as for maintaining the cancer stem cell niche. Interference with WNT secretion may thus represent a promising approach for therapeutic intervention.

An innovative pH-switchable colloidal system that can be exploited for site-selective anticancer drug delivery has been generated by liposome decoration with a new novel synthetic non-peptidic oligo-arginine cell-penetration enhancer (CPE) and a quenching PEGylated counterpart that detaches from the vesicle surface under the acidic conditions of tumors. The CPE module (Arg4-DAG) is formed by four arginine units conjugated to a first-generation (G1) 2,2-bis(hydroxymethyl)propionic acid (bis-MPA)/2,2-bis(aminomethyl)propionic acid (bis-AMPA) polyester dendron terminating with 1,2-distearoyl-3-azidopropane for liposome bilayer insertion. The zeta potential of the Arg4-DAG-decorated liposomes increased up to +32 mV as the Arg4-DAG/lipids molar ratio increased. The Arg4-DAGliposome shielding at pH 7.4 was provided by methoxy-PEG5 kDa-polymethacryloyl sulfadimethoxine (mPEG5 kDa-SDM8) with 7.1 apparent pKa. Zeta potential, surface plasmon resonance and synchrotron small-angle X-ray scattering analyses showed that at pH 7.4 mPEG5 kDa-SDM8associates with polycationic Arg4-DAG-decorated liposomes yielding liposomes with neutral zeta potential. At pH 6.5, which mimics the tumor environment, mPEG5 kDa-SDM8detaches from the liposome surface yielding Arg4-DAGexposure. Flow cytometry and confocal microscopy showed a 30-fold higher HeLa cancer cell association of the Arg4-DAG-decorated liposomes compared to non-decorated liposomes. At pH 7.4, the mPEG5 kDa-SDM8-coated liposomes undergo low cell association while remarkable cell association occurred at pH 6.5, which allowed for the controlled intracellular delivery of model macromolecules and small molecules loaded in the liposome under tumor conditions.

Purpose: Even if in a traditional perspective the discovery and the exploitation of opportunities are associated to the entrepreneur’s capabilities, a relational perspective is required to better analyze the phenomenon of starting up a new venture. The growing attention to interaction with the external environment has been emerging as a precondition of the entrepreneurial processes as it creates the knowledge and the experience necessary to perceive the opportunity. The entrepreneurial opportunities are created through joint acts with others through social relationships. Shifting the attention from social to business relationships, the main aim of this paper is to investigate the discovery and the exploitation of collective entrepreneurial opportunities in starting up new business. In particular, the purpose of this paper is to analyze the role of relational proximity in the entrepreneurial journey considered as an emergent process of transforming potentiality into actuality. Design/methodology/approach: The paper applied a qualitative methodology (Dubois and Araujo, 2004) and a case study approach (Barrat et al., 2011). The case concerns the dyadic spin-off relationship between the innovative start up, ShapeMode (the generated firm), and the Milan FabLab (the generating firm) located in Lombardy Region (Italy). Findings: The emerging of collective entrepreneurial opportunities could be analyzed at two levels: the first one concerns the dyadic spin-off relationship, while the second one is founded on the business relationships that the start-up can activate with the business partners of the generating firm. The collective entrepreneurial opportunities are positive influenced by jointness of the actors and their co-evolution, founded on the shared values and goals. Research limitations/implications: Although the case study approach allowed the researcher to gain detailed information about the spin-off relationship, this effort does not measure the performance outcomes of the relationships and actions that were taken to improve the competitiveness of the start-up. Future studies would benefit from a large-scale questionnaire given to the members of the start-up and to the actors of its Entrepreneurial Network, so to analyze all of its performance implications for the start-up and the network as a whole. In addition, it could be of interest for future research to investigate the effects of collective entrepreneurial opportunities in order to examine this topic more deeply. Practical implications: From a managerial point of view, even if the growing number of start-ups has been associated to a temporary phenomenon, the development of new ventures is now consolidated. A new managerial approach is required to promote the birth and the growth of the start-ups. The development of a new venture requires to shift the attention from the collection of financial resources to the exploitation of entrepreneurial opportunities generated by interconnected business relationships. In this way a relevant attention should be recognized to the new role of organizations that can be considered as facilitators of business relationships, such as the FabLab. This paper sheds light on the relevance of the strategic networking that sustains the generation of collective entrepreneurial opportunities. The networking involves actors that belong to different geographic area and different countries but that are focused on the same business dream related to the exploitation of potentialities of digital fabrication. The policymakers should recognize the role of the FabLab as facilitator of knowledge diffusion concerning digital fabrication. Originality/value: The entrepreneurial opportunities such as the starting up of a new business and its evolution, are enacted, discovered and exploited through interconnected business relationships. In particular the main entrepreneurial opportunities are generated by the activation of business relationships with new business actors. Focusing on the dyadic spin-off relationship, the exploitation of collective entrepreneurial opportunities depends on the sharing of third actors. The business partners of the generating actor (FabLab) became business partners of the generated actor (start-up). The evolution of the generating firm (FabLab) influenced the birth and the evolution of the generated firms (start-up). The dyadic relationship allows the generated firm to discover entrepreneurial opportunities and to exploit them, accessing to the business partners of the generating firm. The effectiveness of the spin-off relationship sustains the replication of the model of new firm generation, that could benefit from the relationships of the two actors of the dyad. Moreover the strong relationships are founded on relational proximity that is characterized by the sharing of values, vision and business dreams.

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Combining zebrafish and mouse genetics, Cantù et al. identified a conserved β-catenin-associated function for BCL9 and Pygo proteins during vertebrate heart development.

Wnt signaling orchestrates gene expression via its effector, β-catenin. However, it is unknown whether β-catenin binds its target genomic regions simultaneously and how this impacts chromatin dynamics to modulate cell behavior. Using a combination of time-resolved CUT&RUN against β-catenin, ATAC-seq, and perturbation assays in different cell types, we show that Wnt/β-catenin physical targets are tissue-specific, β-catenin “moves” on different loci over time, and its association to DNA accompanies changing chromatin accessibility landscapes that determine cell behavior. In particular, Wnt/β-catenin progressively shapes the chromatin of human embryonic stem cells (hESCs) as they undergo mesodermal differentiation, a behavior that we define as “plastic.” In HEK293T cells, on the other hand, Wnt/β-catenin drives a transient chromatin opening, followed by re-establishment of the pre-stimulation state, a response that we define as “elastic.” Future experiments shall assess whether other cell communication mechanisms, in addition to Wnt signaling, are ruled by time, cellular idiosyncrasies, and chromatin constraints.

Targeting of Wnt signaling represents a promising anti-cancer therapy. However, the consequences of systemically attenuating the Wnt pathway in an adult organism are unknown. Here, we globally prevent Wnt secretion by genetically ablating Wntless. We find that preventing Wnt signaling in the entire body causes mortality due to impaired intestinal homeostasis. This is caused by the loss of intestinal stem cells. Reconstitution of Wnt/β-catenin signaling via delivery of external Wnt ligands prolongs the survival of intestinal stem cells and reveals the essential role of extra-epithelial Wnt ligands for the renewal of the intestinal epithelium. Wnt2b is a key extra-epithelial Wnt ligand capable of promoting Wnt/β-catenin signaling and intestinal homeostasis. Wnt2b is secreted by subepithelial mesenchymal cells that co-express either Gli1 or Acta2. Subepithelial mesenchymal cells expressing high levels of Wnt2b are predominantly Gli1 positive.