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Digitalisation and Industry 4.0 promote a fundamental technological disruption that requires industry, research and government institutions to revisit their roles within the innovation ecosystems. Actors in this environment need to understand value co-creation during interaction and collaboration. The purpose of this study is to investigate the triple helix collaborative capabilities in an Industry 4.0 ecosystem context. The case under study is a Finnish national publicly funded research project involving five global manufacturers, three research institutions, and several small-and medium-size enterprises (SMEs). The results demonstrate that practices related to adaptivity, experience sharing, SME co-innovation and scale up can enable the ecosystem to be managed in a dynamic way. Yet, this type of operation requires the adoption of the ecosystem approach with mutual trust, intensive collaboration and the identification of common aims among the project participants. The presented co-innovation model can be used to design innovation ecosystem projects in the future.

In image scanning microscopy, the pinhole of a confocal microscope is replaced by a detector array. The point spread function for each detector element can be interpreted as the probability density function of the signal, the peak giving the most likely origin. This thus allows a form of maximum likelihood restoration, and compensation for aberrations, with similarities to adaptive optics. As an example of an aberration, we investigate theoretically and experimentally illumination with a vortex doughnut beam. After reassignment and summation over the detector array, the point spread function is compact, and the resolution and signal level higher than in a conventional microscope.

Abstract:Since it was awarded a Round 4 Trans-Atlantic Platform Digging into Data Challenge grant in 2017, the Mapping Manuscript Migrations project has been working to develop and test a methodology to link disparate datasets from Europe and North America with the aim of providing large-scale analysis and visualizations of the history and provenance of medieval and Renaissance manuscripts.Guided by a set of research questions identified at the outset of the project, MMM developed an innovative Linked Open Data model and dataset which unifies three separate manuscript-related databases in a semantically consistent way, together with the workflows for transforming the institutional data contributions into the common structure. The dataset has been made available through a Linked Open Data service hosted by the Linked Data Finland platform and the MMM semantic portal.The aggregated data can be queried and visualized at scales ranging from a single manuscript to a total of more than 216,000 manuscripts as a group. Visualization tools developed in the portal show how the manuscripts have traveled across time and space from their place of production to their current locations, where they continue to find new audiences.The following report summarizes our methodology and results, and lays the groundwork for further research using our processes.

The Second World War (WW2) is arguably the most devastating catastrophe of human history, a topic of great interest to not only researchers but the general public. However, data about the Second World War is heterogeneous and distributed in various organizations and countries making it hard to utilize. In order to create aggregated global views of the war, a shared ontology and data infrastructure is needed to harmonize information in various data silos. This makes it possible to share data between publishers and application developers, to support data analysis in Digital Humanities research, and to develop data-driven intelligent applications. As a first step towards these goals, this article presents the WarSampo knowledge graph (KG), a shared semantic infrastructure, and a Linked Open Data (LOD) service for publishing data about WW2, with a focus on Finnish military history. The shared semantic infrastructure is based on the idea of representing war as a spatio-temporal sequence of events that soldiers, military units, and other actors participate in. The used metadata schema is an extension of CIDOC CRM, supplemented by various military history domain ontologies. With an infrastructure containing shared ontologies, maintaining the interlinked data brings upon new challenges, as one change in an ontology can propagate across several datasets that use it. To support sustainability, a repeatable automatic data transformation and linking pipeline has been created for rebuilding the whole WarSampo KG from the individual source datasets. The WarSampo KG is hosted on a data service based on W3C Semantic Web standards and best practices, including content negotiation, SPARQL API, download, automatic documentation, and other services supporting the reuse of the data. The WarSampo KG, a part of the international LOD Cloud and totalling ca. 14 million triples, is in use in nine end-user application views of the WarSampo portal, which has had over 690 000 end users since its opening in 2015.

This paper presents a new software framework, Sampo-UI, for developing user interfaces for semantic portals. The goal is to provide the end-user with multiple application perspectives to Linked Data knowledge graphs, and a two-step usage cycle based on faceted search combined with ready-to-use tooling for data analysis. For the software developer, the Sampo-UIframework makes it possible to create highly customizable, user-friendly, and responsive user interfaces using current state-of-the-art JavaScript libraries and data from SPARQL endpoints, while saving substantial coding effort. Sampo-UIis published on GitHub under the open MIT License and has been utilized in several internal and external projects. The framework has been used thus far in creating six published and five forth-coming portals, mostly related to the Cultural Heritage domain, that have had tens of thousands of end-users on the Web.

Image scanning microscopy is a technique of confocal microscopy in which the confocal pinhole is replaced by a detector array, and the image is reconstructed most straightforwardly by pixel reassignment. In the fluorescence mode, the detector array collects most of the fluorescent light, so the signal-to-noise ratio is much improved compared with confocal microscopy with a small pinhole, while the resolution is improved compared with conventional fluorescence microscopy. Here we consider two cases in which the illumination and detection point spread functions are dissimilar: illumination with a Bessel beam and multiphoton microscopy. It has been shown previously that for Bessel beam illumination in image scanning microscopy with a large array, the imaging performance is degraded. On the other hand, it is also known that the resolution of confocal microscopy is improved by Bessel beam illumination. Here we analyze image scanning microscopy with Bessel beam illumination together with a small array and show that an improvement in transverse resolution (width of the point spread function) by a factor of 1.78 compared with a conventional fluorescence microscope can be obtained. We also examine the behavior of image scanning microscopy in two- or three-photon fluorescence and for two-photon excitation also with Bessel beam illumination. The combination of the optical sectioning effect of image scanning microscopy with multiphoton microscopy reduces background from the sample surface, which can increase penetration depth. For a detector array size of two Airy units, the resolution of two-photon image scanning microscopy is a factor 1.85 better and the peak of the point spread function 2.84 times higher than in nonconfocal two-photon fluorescence. The resolution of three-photon image scanning microscopy is a factor 2.10 better, and the peak of the point spread function is 3.77 times higher than in nonconfocal three-photon fluorescence. The resolution of two-photon image scanning microscopy with Bessel beam illumination is a factor 2.13 better than in standard two-photon fluorescence. Axial resolution and optical sectioning in two-photon or three-photon fluorescence are also improved by using the image scanning modality.

Image scanning microscopy is a technique based on confocal microscopy, in which the confocal pinhole is replaced by a detector array, and the resulting image is reconstructed, usually by the process of pixel reassignment. The detector array collects most of the fluorescent light, so the signal-to-noise ratio is much improved compared with confocal microscopy with a small pinhole, while the resolution is improved compared with conventional (wide-field) microscopy. In previous studies, it has usually been assumed that pixels should be reassigned by a constant factor, to a point midway between the illumination and detection spots. Here it is shown that the peak intensity of the effective point spread function (PSF) can be further increased by 4% by a new choice of the pixel reassignment factor. For an array of two Airy units, the peak of the effective PSF is 1.90 times that of a conventional microscope, and the transverse resolution is 1.53 times better. It is confirmed that image scanning microscopy gives optical sectioning strength identical to that of a confocal microscope with a pinhole equal to the size of the detector array. However, it is shown that image scanning microscopy exhibits axial resolution superior to a confocal microscope with a pinhole the same size as the detector array. For a two-Airy-unit array, the axial resolution is 1.34 times better than in a conventional microscope for the standard reassignment factor, and 1.28 times better for the new reassignment factor. The axial resolution of a confocal microscope with a two-Airy-unit pinhole is only 1.04 times better than conventional microscopy. We also examine the signal-to-noise ratio of a point object in a uniform background (called the detectability), and show that it is 1.6 times higher than in a confocal microscope.

IMPORTANCE: The humanized monoclonal antibody atezolizumab targets programmed death-ligand 1 and has demonstrated durable single-agent activity in a subset of metastatic triple-negative breast cancers. To extend the observed activity, combinatorial approaches are being tested with standard cytotoxic chemotherapies known to induce immunogenic tumor cell death. OBJECTIVE: To examine the safety, tolerability, and preliminary clinical activity of atezolizumab plus nab-paclitaxel in metastatic triple-negative breast cancers. DESIGN, SETTING, AND PARTICIPANTS: This phase 1b multicohort study enrolled 33 women with stage IV or locally recurrent triple-negative breast cancers and 0 to 2 lines of prior chemotherapy in the metastatic setting from December 8, 2014, to April 30, 2017, at 11 sites in the United States. The median follow-up was 24.4 months (95% CI, 22.1-28.8 months). INTERVENTIONS: Patients received concurrent intravenous atezolizumab and intravenous nab-paclitaxel (minimum 4 cycles). MAIN OUTCOMES AND MEASURES: The primary end point was safety and tolerability. Secondary end points included best overall response rate by Response Evaluation Criteria in Solid Tumors, version 1.1; objective response rate; duration of response; disease control rate; progression-free survival; overall survival; and biomarker analyses. RESULTS: The 33 women had a median age of 55 years (range, 32-84 years) and received 1 or more doses of atezolizumab. All patients (100%) experienced at least 1 treatment-related adverse event, 24 patients (73%) experienced grade 3/4 adverse events, and 7 patients (21%) had grade 3/4 adverse events of special interest. No deaths were related to study treatment. The objective response rate was 39.4% (95% CI, 22.9%-57.9%), and the median duration of response was 9.1 months (95% CI, 2.0-20.9 months). The disease control rate was 51.5% (95% CI, 33.5%-69.2%). Median progression-free survival and overall survival were 5.5 months (95% CI, 5.1-7.7 months) and 14.7 months (95% CI, 10.1-not estimable), respectively. Concurrent nab-paclitaxel neither significantly changed biomarkers of the tumor immune microenvironment (programmed death-ligand 1, tumor-infiltrating lymphocytes, CD8) nor impaired atezolizumab systemic immune activation (expansion of proliferating CD8+ T cells, increase of CXCL10 chemokine). CONCLUSIONS AND RELEVANCE: In this phase 1b trial for metastatic triple-negative breast cancers, the combination of atezolizumab plus nab-paclitaxel had a manageable safety profile. Antitumor responses were observed, including in patients previously treated with a taxane. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01633970

Precise knowledge of the effective spatial resolution in a stimulated emission depletion (STED) microscopy experiment is essential for reliable interpretation of the imaging results. STED microscopy theoretically provides molecular resolution, but practically different factors limit its resolution. Because these factors are related to both the sample and the system, a reliable estimation of the resolution is not straightforward. Here we show a method based on the Fourier ring correlation (FRC), which estimates an absolute resolution value directly from any STED and, more in general, point-scanning microscopy image. The FRC-based resolution metric shows terrific sensitivity to the image signal-to-noise ratio, as well as to all sample and system dependent factors. We validated the method both on commercial and on custom-made microscopes. Since the FRC-based metric can be computed in real time, without any prior information of the system/sample, it can become a fundamental tool for (i) microscopy users to optimize the experimental conditions and (ii) microscopy specialists to optimize the system conditions.

Three Ni-Mn-Ga alloys with different chemical compositions and nonmodulated tetragonal martensitic phase (NM) were studied. In two of the alloys, the polydomain nonmodulated tetragonal phase was obtained in cubic-tetragonal martensitic phase transformation at temperatures below and above Curie point, while in the third one, NM-phase is a result of intermartensitic transformation (7M-NM). Magnetic susceptibility and differential scanning calorimetry were used to study these phase transformations. X-ray diffraction, optical polarised microscopy and mechanical testing were used to study variant rearrangement in compression. Twinning strain approximately 19% was observed for all alloys. It was found also that twinning stress is high (approximately 6–18 MPa) and the alloys did not show detectable magnetic field-induced strain. The influence of magnetic field on stress-strain curves and temperature dependencies of twinning stress are presented.

In magnetically controlled shape memory (MSM) materials defonnation can be controlled by magnetic field. It is shown that the magnetic field induced strain is directly connected with the twinning stress, i.e. mechanical stress needed to transform the sample to single variant state. In cases where the magnetically-induced stress is larger than the twinning stress, a large field-induced strain can be obtained in the magnetic field. The behaviour under mechanical stress of three single crystalline Ni-Mn-Ga alloys with different compositions was systematically investigated. The twinning stresses and deformations of these alloys and particularly their dependencies on temperatures were determined by compression tests. The present study was carried out by compression tests of the alloys in martensitic phase at different temperature. Results showed that twinning stress decreases with increasing temperature in all studied alloys.

In recent years, laser control of electrons in molecular system and condensed matter has attracted considerable attention with rapid progress in laser science and technology [. In particular, control of π-electron rotation in photo-induced chiral aromatic molecules has potential utility to the next-generation ultrafast switching devices. In this paper, we present a fundamental principle of generation of ultrafast coherent ring currents and the control in photo-induced aromatic molecules. This is based on quantum dynamics simulations of π-electron rotations and preparation of unidirectional angular momentum by ultrashort UV laser pulses properly designed. For this purpose, we adopt 2,5-dichloro [(3,6) pyrazinophane (DCPH) fixed on a surface, which is a real chiral aromatic molecule with plane chirality. Here π electrons can be rotated along the aromatic ring clockwise or counterclockwise by irradiation of a linearly polarized laser pulse with the properly designed photon polarization direction and the coherent ring current with the definite direction along the aromatic ring is prepared. This is contrast to ordinary ring current in an achiral aromatic ring molecule with degenerate electronic excited state, which is prepared by a circularly polarized laser [2]. In this case, π electrons rotate along the Z-axis of the laboratory coordinates, while for the present case electrons rotate along the z-axis in molecular Cartesian coordinates. It should be noted that signals originated from the coherent ring currents prepared by linearly polarized ultrashort UV lasers are specific to the chiral molecule of interest.

The article discusses the study on the effectiveness of the Tweed Merrifield force orthodontic technique in achieving facial balance. It details how the study was conducted involving 92 patients, three or four of whom were selected to be presented at meetings related to the technique. It compares Japanese patients with Hollywood actresses to prove superior orthodontic treatment. It concludes that the technique is effective in helping achieve facial balance.

The article presents a study on 80 Japanese patients who underwent a successful Tweed Merrifield treatment procedure involving 27 Class I, 36 Class II, and 17 Class III malocclusion cases. Considering the high FMA value of the Japanese people, an analysis of the study proposes a focus on the Incisor Mandibular Plane Angle (IMPA) rather than the FMIA. The study considers that an IMPA of 88 degrees will assure good facial esthetics, and that the Tweed Cephalometric correction Formula will be inappropriate for the high angle Japanese patient.

Natural killer (NK) cell development in the bone marrow is not fully understood. Following lineage commitment, these cells appear to advance through a series of developmental stages that are beginning to be characterized. We previously reported a selective deficiency of NK cells in a C57BL/6 mouse with a transgenic construct consisting of the cDNA for the Ly49A major histocompatibility complex (MHC) class 1–specific inhibitory receptor driven by the granzyme A gene. This mouse has few NK cells in peripheral tissues with relative preservation of other immune cells, including T and B cells. Herein we demonstrate that these mice have an accumulation of NK cells with an immature phenotype in the bone marrow, consistent with a block at a previously proposed stage in normal NK-cell development. The phenotype is associated with transgenic insertion into Atf2, the gene for the basic leucine zipper (bZIP) transcription factor family member ATF-2. Although analysis of Atf2-null NK cells shows no defect, the transgenic mice express abnormal truncated Atf2transcripts that may mediate a repressor effect because ATF2 can heterodimerize with other bZIP molecules. The defect is cell intrinsic, suggesting that certain bZIP molecules play significant roles in NK-cell development.

Early onset familial Alzheimer disease (FAD) has been associated with mutations in three genes, of which presenilin 1 (PSEN1) mutations are the most frequent. We reported previously a variant form of FAD, due to deletion of exon 9 of PSEN1, with spastic paralysis and rigidity. We describe a novel PSEN1 mutation in a family of Japanese origin with six affected individuals of both genders in two generations. The disease is characterized by presenile dementia, which is preceded by spastic paraparesis and apraxia. This mutation, which is predicted to cause a missense substitution of serine for glycine, occurred at codon 266 in exon 8 of PSEN1. The mutation was not found in 200 controls and 200 sporadic AD patients. On this basis alone, it seems this mutation is pathogenic. Our findings provide a new clue to the etiology of the familial early onset dementia. © 2002 Wiley-Liss, Inc.

Routine transplant aspiration cytology (TAC) after liver transplantation gives detailed information that concerns immunologic events in the graft. TAC can be helpful for diagnosis of acute rejection, but it also detects morphological signs of rejection without clinical correlate (“subclinical rejection”). The aim of this study was to systematically evaluate factors that influence the development of early clinical and subclinical rejection and to analyze the relevance of these early immunologic processes for the long-term course. The study includes the course of 340 patients after liver transplantation between 1988 and 1995 in whom TAC was performed routinely and who were followed for a minimum of 3 years. TAC findings were correlated with the following various clinical parameters (1) Overall early clinical rejection occurred in 17.4, subclinical rejection in 59.1, and no immune activation was seen in 23.5 of patients. (2) Incidence of early clinical and subclinical rejection was markedly influenced by type of immunosuppression. (3) Basic disease and extent of preservation injury had only a minor influence; there was a trend towards lower early rejection associated with more severe preservation damage, increased patient age, and early retransplantation. (4) Presence of early clinical or subclinical rejection was not associated with a higher incidence of chronic dysfunction. (5) Falsely indicated antirejection treatment was associated with inferior graft survival. Subclinical rejection is very frequent early after liver transplantation, requires no treatment, and has no long-term adverse effect. Incidence of early clinical rejection is mainly determined by initial immunosuppression; its occurrence has no negative long-term effects and may even be associated with a lower risk for later immunological complications. Thus, the incidence of early acute rejection is no adequate parameter for evaluating the quality of an immunosuppressive treatment protocol.

Integrin-associated protein (CD47) is a broadly expressed protein that costimulates T cells, facilitates leukocyte migration, and inhibits macrophage scavenger function. To determine the role of CD47 in regulating alloresponses, CD47+/+ or CD47−/− T cells were infused into irradiated or nonconditioned major histocompatibility complex disparate recipients. Graft-versus-host disease lethality was markedly reduced with CD47−/− T cells. Donor CD47−/− T cells failed to engraft in immunodeficient allogeneic recipients. CD47−/− marrow was unable to reconstitute heavily irradiated allogeneic or congenic immune–deficient CD47+/+ recipients. These data suggested that CD47−/− T cells and marrow cells were cleared by the innate immune system. To address this hypothesis, dye-labeled CD47−/− and CD47+/+ lymphocytes or marrow cells were infused in vivo and clearance was followed. Dye-labeled CD47−/− cells were engulfed by splenic dendritic cells and macrophages resulting in the clearance of virtually all CD47−/− lymphohematopoietic cells within 1 day after infusion. Host phagocyte-depleted CD47+/+ recipients partially accepted allogeneic CD47−/− T cells. Thus, dendritic cells and macrophages clear lymphohematopoietic cells that have downregulated CD47 density. CD47 expression may be a critical indicator for determining whether lymphohematopoietic cells will survive or be cleared.

To assess the protective effect of exogenous taurine on the central nervous system, spinal cord ischemia was induced for 60 minutes in 16 rabbits randomized into 3 groups. Group 1 (n = 5) had hypothermia targeted to 30.5°C and 10 mmol·kg-1taurine, group 2 (n = 5) had hypothermia targeted to 29.5°C, and group 3 (n = 6) had hypothermia targeted to 30°C. Group 1 was cooled to 30.6 ± 0.07°C and group 2 was cooled to 29.4 ± 0.07°C; both had total functional recovery (rabbits able to keep normal posture, to walk, and to hop) within 6 hours of reperfusion. None of the group 3 animals that were cooled to 29.9 ± 0.05°C recovered function. It was concluded that taurine combined with hypothermia protected the spinal cord from 60 minutes of ischemia at a temperature that could not otherwise ensure protection. The protective effect contributed by taurine was equivalent to 1.2°C.

The molecular mechanisms underlying target recognition during natural killing are not well understood. One approach to dissect the complexities of natural killer (NK) cell recognition is through exploitation of genetic differences among inbred mouse strains. In this study, we determined that interleukin 2–activated BALB/c-derived NK cells could not lyse Chinese hamster ovary (CHO) cells as efficiently as C57BL/6-derived NK cells, despite equivalent capacity to kill other targets. This strain-determined difference was also exhibited by freshly isolated NK cells, and was determined to be independent of host major histocompatibility haplotype. Furthermore, CHO killing did not correlate with expression of NK1.1 or 2B4 activation molecules. Genetic mapping studies revealed linkage between the locus influencing CHO killing, termed Chok, and loci encoded within the NK gene complex (NKC), suggesting that Chok encodes an NK cell receptor specific for CHO cells. In vivo assays recapitulated the in vitro data, and both studies determined that Chok regulates an NK perforin–dependent cytotoxic process. These results may have implications for the role of NK cells in xenograft rejection. Our genetic analysis suggests Chok is a single locus that affects NK cell–mediated cytotoxicity similar to other NKC loci that also regulate the complex activity of NK cells.

The initial stage of Alzheimer's disease is characterized by neuropathological alteration in the entorhinal cortex. To model one aspect of the neurodegeneration observed and to investigate anatomical changes of the hippocampus associated with unilateral entorhinal cortex lesion, excitotoxin ibotenic acid was used to produce selective unilateral neuronal loss in rat entorhinal cortex. Histological and morphometrical analyses confirmed excitotoxic lesion of the entorhinal cortex after 3 months and showed a decrease of acetylcholinesterase-stained fibers in the stratum moleculare of the dentate gyrus and the stratum radiatum of the CA3 field. This study demonstrates the importance of the entorhinal cortex in the hippocampal cholinergic function which appears to be important to memory and learning, and raises the possibility that memory deficit in Alzheimer's disease may be associated with partial neuronal loss in the entorhinal cortex.

Expression of the intercellular adhesion molecule-1 (CD54) as well as the mutations of p53 gene were studied in childhood Burkitt's lymphoma (BL). Expression of CD54 was identified in 6 of 15 fresh BL cases. Mutations of p53 gene, analyzed by polymerase chain reaction——single stranded chain polymorphism followed by sequencing, were found in 5 of 14 cases examined. Interestingly, all the cases with p53 mutation were CD54 negative. This high frequency of p53 mutation in the CD54 negative group prompted us to analyze the clinical features of these cases. Six of 15 cases died within 21 months after initiation of therapy and five of these were CD54 negative. In addition, four of these had p53 mutation. These results suggest that the lack of CD54 by BL cells may provide the background for the mutation of p53 gene to occur which could result in the transformation to a more aggressive phenotype.