Alternative Entry Research Articles

Anhydrous Actinide Starting Materials: Synthesis and Structural Characterization of [UCl4(Et2O)2], an Alternative Route to [UO2Cl2(THF)2]2, and Comments on the Synthesis of [ThCl4(dme)2

A new diethyl ether adduct of uranium tetrachloride, [UCl4(Et2O)2] (1), along with the previously reported mono‐etherate complex [UCl4(Et2O)]n (2), have been synthesized and characterized by powder X‐ray diffraction, elemental analysis, and in the case of 1, single crystal X‐ray diffraction. Additionally, reaction of anhydrous [UO2(OAc)2]n with HCl in Et2O/THF was found to afford the uranyl dichloride complex [UO2Cl2(THF)2]2 (3) in high purity and yield, providing an alternative and convenient entry point into anhydrous uranyl chemistry. Furthermore, comments are provided regarding the literature synthesis of [ThCl4(dme)2] via the reaction of [ThCl4(H2O)4] with Me3SiCl in dme, highlighting important considerations for the compound’s preparation in good yield.

Adenovirus-Neutralizing and Infection-Promoting Activities Measured in Serum of Human Brain Cancer Patients Treated with Oncolytic Adenovirus Ad5-∆24.RGD.

Oncolytic adenoviruses derived from human serotype 5 (Ad5) are being developed to treat cancer. Treatment efficacy could be affected by pre-existing or induced neutralizing antibodies (NAbs), in particular in repeat administration strategies. Several oncolytic adenoviruses that are currently in clinical development have modified fiber proteins to increase their infectivity. One example is Ad5-∆24.RGD, which carries a cyclic RGD peptide insert in the fiber protein to allow cell entry via integrins. The effect of anti-Ad5 NAbs on anticancer efficacy could be different for oncolytic adenoviruses with RGD-modified fibers than for unmodified Ad5-based viruses. Here, we determine pre-existing and elicited NAb titers in the serum of patients with glioblastoma who were treated by delivering Ad5-∆24.RGD to the tumor and to the surrounding tumor-infiltrated brain. We show that intracranial infusion of Ad5-∆24.RGD induced mainly neutralization of adenovirus native tropism. Infection of cells with RGD-modified virus was significantly less affected. In cerebrospinal fluid, neutralizing activity against RGD-mediated infection remained very low. Thus, the RGD-mediated alternative cell entry route allowed to bypass pre-existing and induced anti-Ad5 neutralization. Interestingly, in the course of these experiments, we discovered that the serum of most humans promotes the uptake of RGD-modified adenovirus in human cells. The until now unidentified infection-stimulating factor seems distinct from serum proteins known to promote Ad5 infection. Together, our work supports the utility of RGD-modified oncolytic adenoviruses for the treatment of cancer in humans. Since these viruses hardly induced neutralization, they seem particularly suitable for repeat administration treatments.

ISG15-LFA1 interactions in latent HIV clearance: mechanistic implications in designing antiviral therapies.

Interferon types-I/II (IFN-αβ/γ) secretions are well-established antiviral host defenses. The human immunodeficiency virus (HIV) particles are known to prevail following targeted cellular interferon secretion. CD4+ T-lymphocytes are the primary receptor targets for HIV entry, but the virus has been observed to hide (be latent) successfully in these cells through an alternate entry route via interactions with LFA1. HIV facilitates its post-entry latency-driven mode of hiding through these interactions to displace or inhibit ISG15 by forming the HIV1-LFA1 complex in lieu of ISG15-LFA1, which would at least transiently halt and bypass type-I IFN secretion. This could explain why the elimination of HIV from cellular hideouts is difficult. Hence, HIV clearance needs to be addressed to reverse its latency in LFA1+ T-lymphocytes and CD34+/CD133+ early progenitor stem cells. In the context of hematopoietic or endothelial stem-progenitor cells (HSPC/ESPC), we discuss the potential role of LFA1 in HIV permissiveness and latency in LFA1-CD34+/CD133+ versus LFA1+CD34+/CD133+ HSPCs/ESPCs. In HIV latency, the viral particles may remain engaged on the naïve-resting cells' LFA1, which are then unable to accommodate the ISG15 molecules owing to conformational changes induced upon occupation by the virus at the ISG15-LFA1 binding or interaction sites through halting of the subsequent downstream type-II IFN secretion. Viral binding to LFA1, including its transfer through activated-naïve cell-cell contacts may be a key step that needs to be addressed to prevent "transient or partial" virus-induced shutdown of type-I IFN secretion. This process allows an alternate viral entry and hideout site via LFA1. The subsequent administration of recombinant ISG15 may ensure sufficient type I/II IFN release to promote, enhance, or sustain the innate immune responses. Thus, combination antiviral therapies could potentially include exogenous ISG15 to maintain or sustain biologically and clinically relevant ISG15-LFA1 interactions. In addition to alternating with co-challenges of PKC-pro-LRA-drug modulators, this is administered post (antiretroviral therapy) and continued with periodic ART until permanent elimination of viral resurgence and latency is achieved in patients with HIV/AIDS. This triple-combination drug regimen is expected to pave the path for systemic virus clearance in vivo.

Feline Adenovirus Isolate Shows Silent Nucleotide Alterations, Alternative Receptor/Coreceptor Binding, High Resistance to Disinfectants and Antiviral Drugs, as Well as Immunomodulation.

Adenovirus (AdV) infection has been rarely documented in cats and other felids. Partial sequences of the hexon and fiber genes of a Hungarian feline adenovirus isolate (FeAdV isolate) showed a close relationship to human AdV (HAdV) type C1. Further molecular and biological characterization is reported here. Whole-genome sequencing revealed two silent mutations in the genome of the FeAdV isolate compared to a HAdV-C1 reference strain (at positions 14,096 and 15,082). Competitive antibody binding to the Coxsackie-adenovirus receptor and αvβ3 and αvβ5 integrin coreceptors inhibited the binding of the FeAdV isolate in different cell lines, but residual infections suggested alternative entry routes. The FeAdV isolate was found to be more sensitive to heat, low pH and detergents, but more resistant to alkaline and free chlorine treatments, as well as to ribavirin, stavudine and cidofovir treatments, than other human AdV types. We observed a suppression of IL-10 and TGF-β1 production during the entire course of viral replication. This immunomodulation may restore intratumoral immunity; thus, the FeAdV isolate could serve as an alternative oncolytic vector. Collectively, our results support that the Hungarian FeAdV isolate is a variant of common HAdV-C1. The cohabitation of cats with humans might result in reverse zoonotic infection. Felids appear to be susceptible to persistent and productive adenovirus infection, but further studies are needed to better understand the clinical and epidemiological implications.

Dynamin independent endocytosis is an alternative cell entry mechanism for multiple animal viruses.

Mammalian receptor-mediated endocytosis (RME) often involves at least one of three isoforms of the large GTPase dynamin (Dyn). Dyn pinches-off vesicles at the plasma membrane and mediates uptake of many viruses, although some viruses directly penetrate the plasma membrane. RME is classically interrogated by genetic and pharmacological interference, but this has been hampered by undesired effects. Here we studied virus entry in conditional genetic knock-out (KO) mouse embryonic fibroblasts lacking expression of all three dynamin isoforms (Dyn-KO-MEFs). The small canine parvovirus known to use a single receptor, transferrin receptor, strictly depended on dynamin. Larger viruses or viruses known to use multiple receptors, including alphaviruses, influenza, vesicular stomatitis, bunya, adeno, vaccinia, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and rhinoviruses infected Dyn-KO-MEFs, albeit at higher dosage than wild-type MEFs. In absence of the transmembrane protease serine subtype 2 (TMPRSS2), which normally activates the SARS-CoV-2 spike protein for plasma membrane fusion, SARS-CoV-2 infected angiotensin-converting enzyme 2 (ACE2)-expressing MEFs predominantly through dynamin- and actin-dependent endocytosis. In presence of TMPRSS2 the ancestral Wuhan-strain bypassed both dynamin-dependent and -independent endocytosis, and was less sensitive to endosome maturation inhibitors than the Omicron B1 and XBB variants, supporting the notion that the Omicron variants do not efficiently use TMPRSS2. Collectively, our study suggests that dynamin function at endocytic pits can be essential for infection with single-receptor viruses, while it is not essential but increases uptake and infection efficiency of multi-receptor viruses that otherwise rely on a functional actin network for infection.

Study on the rockburst risk of alternate exterior entry under island coal pillar

The extraction of extremely thick coal seams through slicing mining requires leaving behind several island coal pillars in the top slicing, which could lead to rockburst in the bottom slicing. This article proposed a method of alternate exterior entry (AEE) for rockburst prevention based on the stress distribution of bottom slicing. The influences of coal pillar width [Formula: see text] and stress concentration factor [Formula: see text] on stress distribution were explored using two-dimensional stress imaging. The results indicated that K value had a greater effect on stress distribution comparing with B value. Both stress relaxed and stress rate angles increased linearly with an increase in K value. In order to get the optimized location of AEE in the coal mine stress rate angle was chosen as the stress extension angle, which was further verified by field data from 1210 coal faces. Finally, numerical simulation was used to explore the optimized location of special tail entry under dip island coal pillars for rockburst prevention. It was revealed that plan first was found to be most effective due to its presence in a stress-relaxed area, thus verifying the effectiveness of the AEE method for rockburst prevention.

Accessing the Cloke-Wilson Rearrangement via Conjugate Addition of Phosphoranes to Michael Acceptors: A Route to Cyclopropanes and 5-Membered Ring Heterocycles Investigated by Density Functional and Ab Initio Theory.

Conjugate addition of unstabilized Wittig-type phosphonium ylides to 1,1-diacceptor- and 1-acceptor-substituted alkenes is investigated by density functional theory and high-level ab initio (DLPNO-CCSD(T)) calculations. The results indicate that the initial conjugate addition step should be facile with barriers predicted to be between 0 and 21 kcal mol-1. Potential intramolecular follow-up reactions include the formation of acceptor-substituted cyclopropanes as well as the formation of dihydrofuran derivatives via intramolecular SN2-type transition state structures. The barriers calculated for these potentially valuable cyclization reactions are substantial with Gibbs free energies of activation between 19 and 40 kcal mol-1. Competing reaction channels include Wittig olefination (for ketones and aldehydes), as well as Claisen condensation reactions. The reaction offers an alternative entry point to the nucleophile-catalyzed Cloke-Wilson rearrangement.

Metadynamics Study of Lipid-Mediated Antibacterial Toxin Binding to the EmrE Multiefflux Protein.

EmrE is a bacterial efflux protein in the small multidrug-resistant (SMR) family present in Escherichia coli. Due to its small size, 110 residues in each dimer subunit, it is an ideal model system to study ligand-protein-membrane interactions. Here in our work, we have calculated the free energy landscape of benzyltrimetylammonium (BTMA) and tetraphenyl phosphonium (TPP) binding to EmrE using the enhanced sampling method-multiple walker metadynamics. We estimate that the free energy of BTMA binding to EmrE is -21.2 ± 3.3 kJ/mol and for TPP is -43.6 ± 3.8 kJ/mol. BTMA passes through two metastable states to reach the binding pocket, while TPP has a more complex binding landscape with four metastable states and one main binding site. Our simulations show that the ligands interact with the membrane lipids at a distance 1 nm away from the binding site which forms a broad local minimum, consistent for both BTMA and TPP. This site can be an alternate entry point for ligands to partition from the membrane into the protein, especially for bulky and/or branched ligands. We also observed the membrane lipid and C-terminal 110HisA form salt-bridge interactions with the helix-1 residue 22LysB. Our free energy estimates and clusters are in close agreement with experimental data and give us an atomistic view of the ligand-protein-lipid interactions. Understanding the binding pathway of these ligands can guide us in future design of ligands that can alter or halt the function of EmrE.

Chronic illness as cultural disruption: The impact of chronic illness on religious and cultural practice.

The relationship between religion and health tends to be framed positively. Religion has been found to act as a coping mechanism and source of support in times of ill health. In this paper, we focus on the disruptive effect of chronic illness on religious practice and cultural engagement. Drawing on interviews with ethnic minority adults with end-stage kidney disease, who also identify as religious, we introduce the concept 'cultural disruption'. While religious practice and belief was found to provide strength and comfort we also found that chronic illness had a disruptive impact on religious and cultural practice that participants attempted to manage. To highlight the potential disruptive effect of chronic illness on religious faith and cultural engagement we identify three elements of cultural disruption-disruption to religious practice, disruption to sense of self and identity and disruption to wellbeing. We conclude by suggesting that understanding and accounting for the potential of cultural disruption when diagnosing, treating and supporting people with chronic illness offers an alternative entry point to the life-worlds of patients who identify as religious and the things that are important to them.

7,8-Dihydroxyflavone is a direct inhibitor of human and murine pyridoxal phosphatase

Vitamin B6 deficiency has been linked to cognitive impairment in human brain disorders for decades. Still, the molecular mechanisms linking vitamin B6 to these pathologies remain poorly understood, and whether vitamin B6 supplementation improves cognition is unclear as well. Pyridoxal 5’-phosphate phosphatase (PDXP), an enzyme that controls levels of pyridoxal 5’-phosphate (PLP), the co-enzymatically active form of vitamin B6, may represent an alternative therapeutic entry point into vitamin B6-associated pathologies. However, pharmacological PDXP inhibitors to test this concept are lacking. We now identify a PDXP and age-dependent decline of PLP levels in the murine hippocampus that provides a rationale for the development of PDXP inhibitors. Using a combination of small-molecule screening, protein crystallography, and biolayer interferometry, we discover, visualize, and analyze 7,8-dihydroxyflavone (7,8-DHF) as a direct and potent PDXP inhibitor. 7,8-DHF binds and reversibly inhibits PDXP with low micromolar affinity and sub-micromolar potency. In mouse hippocampal neurons, 7,8-DHF increases PLP in a PDXP-dependent manner. These findings validate PDXP as a druggable target. Of note, 7,8-DHF is a well-studied molecule in brain disorder models, although its mechanism of action is actively debated. Our discovery of 7,8-DHF as a PDXP inhibitor offers novel mechanistic insights into the controversy surrounding 7,8-DHF-mediated effects in the brain.

7,8-Dihydroxyflavone is a direct inhibitor of human and murine pyridoxal phosphatase.

Vitamin B6 deficiency has been linked to cognitive impairment in human brain disorders for decades. Still, the molecular mechanisms linking vitamin B6 to these pathologies remain poorly understood, and whether vitamin B6 supplementation improves cognition is unclear as well. Pyridoxal 5'-phosphate phosphatase (PDXP), an enzyme that controls levels of pyridoxal 5'-phosphate (PLP), the co-enzymatically active form of vitamin B6, may represent an alternative therapeutic entry point into vitamin B6-associated pathologies. However, pharmacological PDXP inhibitors to test this concept are lacking. We now identify a PDXP and age-dependent decline of PLP levels in the murine hippocampus that provides a rationale for the development of PDXP inhibitors. Using a combination of small-molecule screening, protein crystallography, and biolayer interferometry, we discover, visualize, and analyze 7,8-dihydroxyflavone (7,8-DHF) as a direct and potent PDXP inhibitor. 7,8-DHF binds and reversibly inhibits PDXP with low micromolar affinity and sub-micromolar potency. In mouse hippocampal neurons, 7,8-DHF increases PLP in a PDXP-dependent manner. These findings validate PDXP as a druggable target. Of note, 7,8-DHF is a well-studied molecule in brain disorder models, although its mechanism of action is actively debated. Our discovery of 7,8-DHF as a PDXP inhibitor offers novel mechanistic insights into the controversy surrounding 7,8-DHF-mediated effects in the brain.

RANCANGAN APLIKASI SPK PENENTUAN WALI KELAS BERDASARKAN PRESTASI GURU DENGAN METODE AHP PADA SMK JAKARTA BARAT 1

A decision support system (DSS) is the definition of a procedural model of data processing and assisting management in making decisions. Computer-based decision support systems can improve decision-making ability to solve problems that appear structured or unstructured. The Analytical Hierarchy Process (AHP) method can be used to solve the DSS problem. This method is one of the most sought-after optimal solutions among several other decision support system method options. The research was conducted at SMKN 1 West Jakarta which aimed to assist the school in selecting homeroom teachers based on the effectiveness of teachers in the learning process to students. The creation of this application is done through data collection, system design, system analysis and database design. The creation of this application program is developed using PHP, the database is MySQL. In running this application, input or alternative information is needed, namely the names of teachers, and the assessment criteria are professional values, pedagogic values, personality values, and social values. The process requirements needed are alternative data entry process, teacher data entry process and also criteria data. The result is a teacher report that is expected to help the principal to determine homeroom based on teacher achievement scores.

Synthesis and evaluation of antisense oligonucleotides prodrug with G-quadruplex assembly and lysosome escape capabilities for oncotherapy

The applications of antisense oligonucleotides (ASOs) in rare or common diseases treatment have garnered great attention in recent years. Nevertheless, challenges associated with stability and bioavailability still persist, hampering the efficiency of ASOs. This work presents an ASO prodrug with parallel G-quadruplex assembly and lysosome escape capabilities for oncotherapy. Our findings revealed that the end-assembled quadruplex structure effectively shielded the ASO from enzymatic degradation. Meanwhile, the conjugation of maleimide within the quadruplex enhanced cellular uptake, potentially offering an alternative cell entry mechanism that circumvents lysosome involvement. Notably, an optimized molecule, Mal2-G4-ASO, exhibited remarkable therapeutic effects both in vitro and in vivo. This work presents a promising avenue for enhancing the activity of nucleic acid drugs in oncotherapy and potentially other disease contexts.

Assessing the potential of transorbital and supraorbital approaches for stereotactic surgery: an anatomical feasibility study.

The Transorbital and supraorbital minimally invasive approaches have been defined to reach intraorbital structures, adjacent sinuses, skull base, and other intracranial targets in this region. These approaches reduce the possible cosmetic and brain retraction-related morbidities caused by traditional transcranial approaches. Although these pathways are being studied endoscopically, a stereotactic approach has not been defined. The Kocher`s point and its surroundings, which are traditional entry points used in stereotactic surgery create compelling trajectories, carry a potentially higher complication risk for subventricular psychosurgical and hypothalamic targets. Herein, we aimed to evaluate the supraorbital and transorbital approaches as alternative entry sites and trajectories targeting the nucleus accumbens (NAc), subcallosal cingulate gyrus (SCG), and lateral hypothalamic area (LHA), in cadavers and surgical planning station. The three-dimensional relationship of the identified trajectories within the anterior and middle cranial fossae as well as the stereotactically targeted NAc, SCG, and LHA, were demonstrated through dissection studies conducted in cadavers. To validate the accuracy of the measurements from the cadaver, trajectory planning was replicated using radiological imaging of patients without a space-occupying lesion who underwent gamma knife surgery. These measurements were compared with those from cadavers. The transorbital and supraorbital trajectories did not pass through the lateral ventricles and they can be used for subventricular targets. Additionally, the NAc and LHA can be targeted simultaneously. These trajectories pass along a broader anatomical area within the NAc due to the anatomical orientation of the nucleus. These findings suggest that these entry points may offer new opportunities for stimulating different targets in the prefrontal cortex and may serve as an approach for future clinical use.

An Exploration of Substituent Effects on the Photophysical Properties of Monobenzopentalenes.

Monobenzopentalenes have received moderate attention compared to dibenzopentalenes, yet their accessibility as stable, non-symmetric structures with diverse substituents could be interesting for materials applications, including molecular photonics. Recently, monobenzopentalene was considered computationally as a potential chromophore for singlet fission (SF) photovoltaics. To advance this compound class towards photonics applications, the excited state energetics must be characterized, computationally and experimentally. In this report we synthesized a series of stable substituted monobenzopentalenes and provided the first experimental exploration of their photophysical properties. Structural and opto-electronic characterization revealed that all derivatives showed 1H NMR shifts in the olefinic region, bond length alternation in the pentalene unit, low-intensity absorptions reflecting the ground-state antiaromatic character and in turn the symmetry forbidden HOMO-to-LUMO transitions of ~2 eV and redox amphotericity. This was also supported by computed aromaticity indices (NICS, ACID, HOMA). Accordingly, substituents did not affect the fulfilment of the energetic criterion of SF, as the computed excited-state energy levels satisfied the required E(S1)/E(T1)>2 relationship. Further spectroscopic measurements revealed a concentration dependent quenching of the excited state and population of the S2 state on the nanosecond timescale, providing initial evidence for unusual photophysics and an alternative entry point for singlet fission with monobenzopentalenes.

Gene expression profiles of precursor cells identify compounds that reduce NRP1 surface expression in macrophages: Implication for drug repositioning for COVID-19.

Coronavirus disease 2019 (COVID-19) is transitioning from a pandemic to an endemic phase through recurring mutations. Initial efforts focused on developing strategies to mitigate infection of lung epithelial cells which are the primary targets of the SARS-CoV-2 virus using the affinity of the spike protein to human ACE2 receptor. SARS-CoV-2, however, infects additional cell types present in the lung such as macrophages through the alternate entry receptor Neuropilin 1 (NRP1). Developing novel therapeutic strategies to prevent SARS-CoV-2 infection of cells crucial for immunosurveillance could thus be integral to treat post-acute sequelae of COVID-19 (PASC). Since traditional drug development process takes a long time, it is imperative to establish new strategies that can be rapidly deployed to combat the dynamic nature of COVID-19 evolution and to contribute to prevention of future pandemics. We obtained the gene expression profiles of THP-1 monocytes from L1000-based Connectivity Map using CLUE, cloud- based software platform for the analysis of perturbational datasets to identify compounds that could reduce the expression level of NRP1. Out of 33,590 compounds, we analyzed the profiles of 45 compounds for their ability to reduce NRP1 expression. We selected the top five small molecule inhibitors predicted to decrease the expression of NRP1 for validation studies. All five selected compounds showed low cytotoxicity at tested doses and their ability to reduce NRP1 surface expression was evaluated in THP-1 monocytes, THP-1-derived macrophage like cells and human peripheral blood mononuclear cell (PBMC)-derived primary macrophages. Five compounds with the largest predicted reduction of NRP1 expression decreased macrophage NRP1 surface expression measured using flow cytometry and fluorescent microscopy assays in both cell line and primary macrophages. Using our computational approach, we identified 45 compounds that could potentially decrease NRP1 surface expression in macrophages based on their effect on THP-1 monocytes. Validation studies showed that such an approach can help to identify compounds for drug repositioning in target cells that are absent in the L1000 database. Our proposed approach can be applicable for the rapid compound exploration to combat novel cell types that SARS-CoV-2 targets for infection and could provide molecular bases for the development of new drugs.

Autoantibodies in hospitalised patients with COVID-19.

CD209L and its homologous protein CD209 act as alternative entry receptors for the SARS-CoV-2 virus and are highly expressed in the virally targeted tissues. We tested for the presence and clinical features of autoantibodies targeting these receptors and compared these with autoantibodies known to be associated with COVID-19. Using banked samples (n = 118) from Johns Hopkins patients hospitalised with COVID-19, we defined autoantibodies against CD209 and CD209L by enzyme-linked immunosorbent assay (ELISA). Clinical associations of these antibodies were compared with those of patients with anti-interferon (IFN) and anti-angiotensin-converting enzyme-2 (ACE2) autoantibodies. Amongst patients hospitalised with COVID-19, 19.5% (23/118) had IgM autoantibodies against CD209L and were more likely to have coronary artery disease (44% vs 19%, P = 0.03). Antibodies against CD209 were present in 5.9% (7/118); interestingly, all 7 were male (P = 0.02). In our study, the presence of either antibody was positively associated with disease severity [OR 95% confidence interval (95% CI): 1.80 (0.69-5.03)], but the association did not reach statistical significance. In contrast, 10/118 (8.5%) had IgG autoantibodies against IFNα, and 21 (17.8%) had IgM antibodies against ACE2. These patients had significantly worse prognosis (intubation or death) and prolonged hospital stays. However, when adjusting for patient characteristics on admission, only the presence of anti-ACE2 IgM remained significant [pooled common OR (95% CI), 4.14 (1.37, 12.54)]. We describe IgM autoantibodies against CD209 and CD209L amongst patients hospitalised with COVID-19. These were not associated with disease severity. Conversely, patients with either anti-ACE2 IgM or anti-IFNα IgG antibodies had worse outcomes. Due to the small size of the study cohort, conclusions drawn should be considered cautiously.

Internationalising high–tech SMEs: Advancing a new perspective of open innovation

Choosing a foreign market entry strategy is known to be essential for firm internationalisation yet there is very little focus on the role, purpose, and value of open innovation for internationalising high–tech SMEs. A review of the international business, international entrepreneurship and international marketing literature combined with a bibliometric mapping of 2501 articles on firm internationalisation, suggests that research does not readily associate open innovation and the internationalisation of high–tech SMEs. This is regardless of open innovation's activities that can span over a firm's immediate geographical space. Thus, this study introduces new theoretical explanations and a midrange open innovation theory to advance open innovation as an alternative foreign market entry strategy especially for internationalising high–tech SMEs. This has theoretical and practical implications for academics, international business managers, and practitioners because it introduces an alternative internationalisation strategy for SMEs.

Utopian Realism

Around the turn of the nineteenth century writer, and opinion leader, Frida Stéenhoff (1865–1945), developed a theory of the future and the present of society, and argued that contemporary ideas of the social, ethical, and aesthetical were provisional, not comparable to the coming. An affinity between drama and theory, as well as investigations of peace as an idea, are distinctive features of her writing. Her play, Stridbar ungdom / Pugnacious Youth (1907), can be positioned in a tradition of peace dramas spanning from Aristophanes’ Lysistrata to Sarah Kane’s Blasted. This article studies the utopian potential of peace in Pugnacious Youth. By reading the play with Ruth Levitas’ method the Imaginary Reconstitution of Society (IROS) – suggesting that utopia is a method rather than a goal in itself – peace does not emerge negatively, as non-war, but as concrete development and possible presence. Furthermore, the division between realism and idealism when it comes to militarism and peace, as well as the realist and idealist branches of the peace movement, are problematized. In conclusion, it appears that studying ideas of peace in fiction enables an alternative entry into the actualization of its not-yet-here quality.

Comprehensive management of umbilical endometriosis using a unique laparoscopic entry portal (Darwish point) and postoperative dienogest

Umbilical endometriosis, although relatively rare, has been described with plenty of case reports and case series available in the literature. Surgical excision has been the preferred mode of treatment, with or without excision of the umbilicus. Few cases described laparoscopically assisted excision but lacked descriptions of a safe alternative non-umbilical laparoscopy entry portal, management of possible concomitant intraperitoneal lesions, and aesthetic umbilicus repair. The aim of this work is to describe a modified technique of laparoscopically assisted excision of umbilical endometriosis and treat concomitant intraperitoneal lesions via a new laparoscopic entry portal with aesthetic preservation of the umbilicus. Successful complete excision of the mass with aesthetic preservation of the umbilicus followed by 3 months of Dienogest therapy resulted in complete resolution of the mass. It is concluded that utilizing “Darwish point” for abdominal access to excise umbilical endometriosis and treat concomitant intraabdominal lesions, offers smart abdominal access with aesthetic umbilicus repair. Moreover, postoperative hormonal treatment (Dienogest) is helpful to ensure a better cure.