The formation of correct synaptic structures and neuronal connections is paramount for normal brain development and a functioning adult brain. The integrin family of cell adhesion receptors and their ...ligands play essential roles in the control of several processes regulating neuronal connectivity - including neurite outgrowth, the formation and maintenance of synapses, and synaptic plasticity - that are affected in neurodevelopmental disorders, such as autism spectrum disorders (ASDs) and schizophrenia. Many ASD- and schizophrenia-associated genes are linked to alterations in the genetic code of integrins and associated signalling pathways. In non-neuronal cells, crosstalk between integrin-mediated adhesions and the actin cytoskeleton, and the regulation of integrin activity (affinity for extracellular ligands) are widely studied in healthy and pathological settings. In contrast, the roles of integrin-linked pathways in the central nervous system remains less well defined. In this Review, we will provide an overview of the known pathways that are regulated by integrin-ECM interaction in developing neurons and in adult brain. We will also describe recent advances in the identification of mechanisms that regulate integrin activity in neurons, and highlight the interesting emerging links between integrins and neurodevelopment.
The paper discusses digitising the collections of the National Library of Finland (NLF). The digitisation programme of the NLF defines the material to be digitised in the period of 2021-2024. The ...authors emphasise that digitising includes much more work than mere scanning. The process of digitising begins in the selection of material, and it includes several phases, such as revision of bibliographic records (metadata); preparation of volumes for scanning, in some cases even conservation; scanning; quality control of scanned pictures and OCR text; and long-time preservation. Digitised material is available on the digi.kansalliskirjasto.fi service and the metadata is to be found also on the finna.fi and kansalliskirjasto.finna.fi services. Making materials digital does not guarantee their availability. The out-of-copyright material is open to all users but in-copyright material requires a license from a copyright management organization. The expenses of licensing restrict the open material to the oldest part of collections. The main challenges in the near future are: guaranteeing funding for digitising, licensing and adopting new technologies; understanding the changing needs of users, particularly in the research, and diminishing the carbon footprint of the digital cultural heritage.
This report summarises the papers and discussions presented at the Scholarly Journals and Research Data Seminar organised by the Federation of Finnish Learned Societies and the Finnish Association ...for Scholarly Publishing in February 2017. Stricter policies on storing research data in repositories and opening it are now being implemented. In fact, 27 per cent of research funders now require data archiving, including the Academy of Finland. The seminar brought together funders, researchers and representatives from journals and data archives to discuss how archiving and opening data should be carried out and the role played by journals. The questions asked included: Should journals require their authors to link their text to research data or should they only encourage such action? Should journals guide their authors to use central national or international data archives or should they establish their own separate data repositories, for example in connection with the Finnish national data service IDA?
Cell adhesion to neighbouring cells and to the underlying extracellular matrix (ECM) is a fundamental requirement for the existence of multicellular organisms. As such, the formation, stability and ...dissociation of cell adhesions are subject to tight control in space and time and perturbations within the sophisticated adhesion machinery are associated with a variety of human pathologies. Here, we outline a simple protocol to monitor alterations in cell adhesion to the ECM, for example, following genetic manipulations or overexpression of a protein of interest or in response to drug treatment, using the xCELLigence real-time cell analysis (RTCA) system.
The human epidermal growth factor receptor 2 (HER2) is an oncogene targeted by several kinase inhibitors and therapeutic antibodies. While the endosomal trafficking of many other receptor tyrosine ...kinases is known to regulate their oncogenic signalling, the prevailing view on HER2 is that this receptor is predominantly retained on the cell surface. Here, we find that sortilin-related receptor 1 (SORLA; SORL1) co-precipitates with HER2 in cancer cells and regulates HER2 subcellular distribution by promoting recycling of the endosomal receptor back to the plasma membrane. SORLA protein levels in cancer cell lines and bladder cancers correlates with HER2 levels. Depletion of SORLA triggers HER2 targeting to late endosomal/lysosomal compartments and impairs HER2-driven signalling and in vivo tumour growth. SORLA silencing also disrupts normal lysosome function and sensitizes anti-HER2 therapy sensitive and resistant cancer cells to lysosome-targeting cationic amphiphilic drugs. These findings reveal potentially important SORLA-dependent endosomal trafficking-linked vulnerabilities in HER2-driven cancers.
In breast cancer, the currently approved anti‐receptor tyrosine‐protein kinase erbB‐2 (HER2) therapies do not fully meet the expected clinical goals due to therapy resistance. Identifying alternative ...HER2‐related therapeutic targets could offer a means to overcome these resistance mechanisms. We have previously demonstrated that an endosomal sorting protein, sortilin‐related receptor (SorLA), regulates the traffic and signaling of HER2 and HER3, thus promoting resistance to HER2‐targeted therapy in breast cancer. This study aims to assess the feasibility of targeting SorLA using a monoclonal antibody. Our results demonstrate that anti‐SorLA antibody (SorLA ab) alters the resistance of breast cancer cells to HER2 monoclonal antibody trastuzumab in vitro and in ovo. We found that SorLA ab and trastuzumab combination therapy also inhibits tumor cell proliferation and tumor cell density in a mouse xenograft model of HER2‐positive breast cancer. In addition, SorLA ab inhibits the proliferation of breast cancer patient‐derived explant three‐dimensional cultures. These results provide, for the first time, proof of principle that SorLA is a druggable target in breast cancer.
SorLA interacts with HER2 and HER3 and positively regulates their oncogenic signaling. Here, we report that SorLA‐targeting antibody synergizes with trastuzumab to inhibit proliferation of HER2‐amplified, trastuzumab‐resistant breast cancer cells. In addition, SorLA ab monotherapy inhibits proliferation of breast cancer patient‐derived explant cultures. These results provide proof of principle that SorLA is a druggable target in breast cancer.
Neutrophils are abundant circulating leukocytes that are rapidly recruited to sites of inflammation in an integrin-dependent fashion. Contrasting with the well-characterized regulation of integrin ...activation, mechanisms regulating integrin inactivation remain largely obscure. Using mouse neutrophils, we demonstrate in this study that the GTPase activating protein ARAP3 is a critical regulator of integrin inactivation; experiments with Chinese hamster ovary cells indicate that this is not restricted to neutrophils. Specifically, ARAP3 acts in a negative feedback loop downstream of PI3K to regulate integrin inactivation. Integrin ligand binding drives the activation of PI3K and of its effectors, including ARAP3, by outside-in signaling. ARAP3, in turn, promotes localized integrin inactivation by negative inside-out signaling. This negative feedback loop reduces integrin-mediated PI3K activity, with ARAP3 effectively switching off its own activator, while promoting turnover of substrate adhesions. In vitro, ARAP3-deficient neutrophils display defective PIP3 polarization, adhesion turnover, and transendothelial migration. In vivo, ARAP3-deficient neutrophils are characterized by a neutrophil-autonomous recruitment defect to sites of inflammation.
The purpose of this study is to examine how COVID-19-related job demands and resources have been associated with employee well-being in Nordic countries across specific occupational groups. The study ...investigated four occupational groups: (1) professional, scientific, and technical occupations in Norway (n = 301); (2) teachers in Finland (n = 315); (3) health and social service occupations in Norway (n = 267); and (4) geriatric nurses in Finland (n = 105). Hypotheses were tested using two-step hierarchical regression analysis. Work–home imbalance in Groups 1, 2, and 3, workload increase in Groups 1 and 3, and fear of infection in Groups 2 and 3 were positively related with exhaustion. A positive attitude towards digital solutions was positively related to work engagement in Groups 2 and 3. In addition, there was a significant positive relationship between COVID-19-related organizational support and work engagement in Groups 2, 3, and 4, and a negative relationship with exhaustion in Group 2. In conclusion, pandemic-related job demands and resources were differently associated with employee well-being across different occupational groups and countries. Further, organizational support may act as a supportive element for sustaining employee well-being during pandemics.
PDF
