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A confiscated package of street drugs was characterized by the usual mass spectral (MS) and FT–IR analyses. The confiscated powder material was highly crystalline and was found to consist of two very different species, accidentally of sizes convenient for X-ray diffraction. Thus, one each was selected and redundant complete sets of data were collected at 100 K using Cu Kα radiation. The selected crystals contained: (a) 1,2-diphenyl-2-(pyrrolidin-1-yl)ethanone hydrochloride hemihydrate or 1-(2-oxo-1,2-diphenylethyl)pyrrolidin-1-ium chloride hemihydrate, C18H20NO+ ·Cl-·0.5H2O, (I), a synthetic cathinone called ‘α-D2PV’, and (b) the sugar myo-inositol, C6H12O6, (II), probably the only instance in which the drug and its diluent have been fully characterized from a single confiscated sample. Moreover, the structural details of both are rather attractive showing: (i) interesting hydrogen bonding observed in pairwise interactions by the drug molecules, mediated by the chloride counter-anions and the waters of crystallization, and (ii) π–π interactions in the case of the phenyl rings of the drug which are of two different types, namely, π–π stacking and edge-to-π. Finally, the inositol crystallizes with Z′ = 2 and the resulting diastereoisomers were examined by overlay techniques [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs) are cell derived membranous nanoparticles. EVs are important mediators of cell–cell communication via the transfer of bioactive content and as such they are being investigated for disease diagnostics as biomarkers and for potential therapeutic cargo delivery to recipient cells. However, existing methods for isolating EVs from biological samples suffer from challenges related to co‐isolation of unwanted materials such as proteins, nucleic acids, and lipoproteins. In the pursuit of improved EV isolation techniques, we introduce multimodal flowthrough chromatography (MFC) as a scalable alternative to size exclusion chromatography (SEC). The use of MFC offers significant advantages for purifying EVs, resulting in enhanced yields and increased purity with respect to protein and nucleic acid co‐isolates from conditioned 3D cell culture media. Compared to SEC, significantly higher EV yields with similar purity and preserved functionality were also obtained with MFC in 2D cell cultures. Additionally, MFC yielded EVs from serum with comparable purity to SEC and similar apolipoprotein B content. Overall, MFC presents an advancement in EV purification yielding EVs with high recovery, purity, and functionality, and offers an accessible improvement to researchers currently employing SEC. [ABSTRACT FROM AUTHOR]

Opportunities exist to reduce nitrous oxide (N2O) emissions from nitrogen (N) fertilizers using enhanced efficiency fertilizers (EEFs) and managing application timing. This study examined (1) application timing (fall/spring) and (2) fertilizer N source on N2O emissions, yield, and N uptake of Canadian hard red spring wheat (Triticum aestivum L.) in Southern Manitoba. Fertilizer N sources included granular urea and four EEF products: (1) polymer‐coated urea (environmentally smart nitrogen [ESN]); (2) urea plus nitrification inhibitor (eNtrench); (3) urea plus urease inhibitor (Limus); and (4) urea plus nitrification and urease inhibitor (SuperU). Nitrification‐inhibited products most consistently reduced N2O emissions while maintaining productivity. Compared to urea alone, urea + eNtrench was most effective in reducing cumulative N2O emissions by 47%–64% at four of six site‐years. SuperU reduced N2O emissions by 37%–57% at three of six site‐years. ESN and urea + Limus did not affect emissions in most years. Wheat yield, protein, and N uptake were unaffected by N source in five of six site‐years. Compared to spring, fall application gave greater N2O emissions by 33%–67% at three of six site‐years due to spring‐thaw emissions. Fall was inferior to spring application in wetter site years with lower yield, protein, and N uptake. Overall, nitrification‐inhibited products—either alone or with a urease inhibitor—are a promising tool to reduce N2O emissions while maintaining wheat productivity in Manitoba. However, given that there were few consistent increases in yield or protein, the additional cost of the inhibitors will be a barrier to adoption. Core Ideas: EEF products with nitrification and nitrification/urease inhibitors consistently reduced N2O emissions.Controlled release urea and urease‐inhibited urea did not reduce N2O emissions.Fall application of urea increased N2O emissions in three site‐years compared to spring application.The nitrification inhibitors applied with urea in fall or spring were effective to reduce N2O emissions.Overall, fall application decreased yield, grain protein, and N uptake in relatively wet years. [ABSTRACT FROM AUTHOR]

Introduction/Aims: Promoting regeneration after segmental nerve injury repair is a challenge, but improving angiogenesis could be beneficial. Macrophages facilitate regeneration after injury by promoting angiogenesis. Our aim in this study was to evaluate the feasibility and effects of transplanting exogenous macrophages to a segmental nerve injury. Methods: Bone marrow–derived cells were harvested from donor mice and differentiated to macrophages (BMDM), then suspended within fibrin hydrogels to facilitate BMDM transplantation. BMDM survival was characterized in vitro. The effect of this BMDM fibrin hydrogel construct at a nerve injury site was assessed using a mouse sciatic nerve gap injury. Mice were equally distributed to "fibrin+Mφ" (fibrin hydrogels containing culture medium and BMDM) or "fibrin" hydrogel control (fibrin hydrogels containing culture medium alone) groups. Flow cytometry (n = 3/group/endpoint) and immunohistochemical analysis (n = 5/group/endpoint) of the nerve gap region were performed at days 3, 5, and 7 after repair. Results: Incorporating macrophage colony‐stimulating factor (M‐CSF) improved BMDM survival and expansion. Transplanted BMDM survived for at least 7 days in a nerve gap (~40% retained at day 3 and ~15% retained at day 7). From transplantation, macrophage quantities within the nerve gap were elevated when comparing fibrin+Mφ with fibrin control (~25% vs. 3% at day 3 and ~14% vs. 6% at day 7). Endothelial cells increased by about fivefold within the nerve gap, and axonal extension into the nerve gap increased almost twofold for fibrin+Mφ compared with fibrin control. Discussion: BMDM suspended within fibrin hydrogels at a nerve gap do not impair regeneration. [ABSTRACT FROM AUTHOR]

Spinal muscular atrophy (SMA) is a leading genetic cause of infant mortality. The advent of approved treatments for this devastating condition has significantly changed SMA patients' life expectancy and quality of life. Nevertheless, these are not without limitations, and research efforts are underway to develop new approaches for improved and long‐lasting benefits for patients. Protein arginine methyltransferases (PRMTs) are emerging as druggable epigenetic targets, with several small‐molecule PRMT inhibitors already in clinical trials. From a screen of epigenetic molecules, we have identified MS023, a potent and selective type I PRMT inhibitor able to promote SMN2 exon 7 inclusion in preclinical SMA models. Treatment of SMA mice with MS023 results in amelioration of the disease phenotype, with strong synergistic amplification of the positive effect when delivered in combination with the antisense oligonucleotide nusinersen. Moreover, transcriptomic analysis revealed that MS023 treatment has minimal off‐target effects, and the added benefit is mainly due to targeting neuroinflammation. Our study warrants further clinical investigation of PRMT inhibition both as a stand‐alone and add‐on therapy for SMA. Synopsis: Spinal muscular atrophy (SMA) is a leading genetic cause of infant mortality. To address the urgent need to develop new approaches for improved and long‐lasting benefits for SMA patients, an orally available, epigenetic‐targeting small molecule was identified and tested in SMA models alone and in combination with a recently approved treatment. From a cell‐based screening of potent and selective epigenetic probes, type I protein methyltransferases inhibitor MS023 was able to promote exon 7 inclusion in SMN2 pre‐mRNA.MS023 mechanism of action entails altering the methylation pattern and binding affinity of the heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1), a negative SMN2 splicing regulator.Oral administration of MS023 improves the phenotype of SMA mice alone and enhances the effects of nusinersen when used in combination.Transcriptomic analyses revealed that targeting neuroinflammation in SMA is key to achieve the superior beneficial effects of the combinatorial treatment compared to nusinersen or MS023 alone. [ABSTRACT FROM AUTHOR]

Objective: Osteoarthritis (OA) is a leading cause of chronic pain, yet OA pain management remains poor. Age is the strongest predictor of OA development, and mechanisms driving OA pain are unclear. We undertook this study to characterize age‐associated changes in knee OA, pain‐related behaviors, and dorsal root ganglion (DRG) molecular phenotypes in mice of both sexes. Methods: Male or female C57BL/6 mice 6 or 20 months of age were evaluated for histopathologic knee OA, pain‐related behaviors, and L3–L5 DRG immune characterization via flow cytometry. DRG gene expression in older mice and humans was also examined. Results: Male mice at 20 months of age had worse cartilage degeneration than 6‐month‐old mice. Older female mouse knees showed increased cartilage degeneration but to a lesser degree than those of male mice. Older mice of both sexes had worse mechanical allodynia, knee hyperalgesia, and grip strength compared to younger mice. For both sexes, DRGs from older mice showed decreased CD45+ cells and a significant increase in F4/80+ macrophages and CD11c+ dendritic cells. Older male mouse DRGs showed increased expression of Ccl2 and Ccl5, and older female mouse DRGs showed increased Cxcr4 and Ccl3 expression compared to 6‐month‐old mouse DRGs, among other differentially expressed genes. Human DRG analysis from 6 individuals >80 years of age revealed elevated CCL2 in men compared to women, whereas CCL3 was higher in DRGs from women. Conclusion: We found that aging in male and female mice is accompanied by mild knee OA, mechanical sensitization, and changes to immune cell populations in the DRG, suggesting novel avenues for development of OA therapies. [ABSTRACT FROM AUTHOR]

Aminoindanes are a class of novel psychoactive substances (NPSs) that have become more prevalent over the past decade. GC–MS is often utilized for identifying seized drugs and is well regarded for its ability to separate mixtures. However, certain aminoindanes have similar mass spectral data and require specific gas chromatographic stationary phases for separation. Derivatization is an alternative method that can be applied to GC–MS to enhance chromatographic results, providing more selective analysis in seized‐drug identification. This study investigates derivatization techniques to provide options for forensic science laboratories in accurately identifying aminoindanes. Three derivatization reagents, N‐methyl‐bis(trifluoroacetamide) (MBTFA), heptafluorobutyric anhydride (HFBA), and ethyl chloroformate (ECF) were evaluated for the analysis of eight aminoindanes by GC–MS using two common gas chromatographic stationary phases, Rxi®‐5Sil MS and Rxi®‐1Sil MS. All three derivatization methods successfully isolated eight aminoindanes, including the isomers 4,5‐methylenedioxy‐2‐aminoindane (4,5‐MDAI), and 5,6‐methylenedioxy‐2‐aminoindane (5,6‐MDAI) that could not be differentiated prior to derivatization. Reduced peak tailing and increased abundance were observed after derivatization for all the compounds, and mass spectra of the derivatives contained individualizing fragment ions that allowed for further characterization of the aminoindanes. This excluded 4,5‐MDAI and 5,6‐MDAI as they shared the same characteristic ions and were only distinguishable by their retention times. All three derivatization techniques used in this study allow for successful characterization of the aminoindanes and give forensic science laboratories flexibility in their analysis approach when they encounter these compounds. [ABSTRACT FROM AUTHOR]

When verifying the correctness of single‐digit multiplication problems, children and adults show a robust ERP correctness effect thought to reflect similar cognitive processes across groups. Recent studies suggest that this effect is instead a modulation of the negative‐going N400 component in children, reflecting access to semantic memory, and the positive‐going P300 component in adults, reflecting stimulus categorization. However, the relative difference in ERP amplitude is the same for both components, more positive for correct than incorrect solutions, presenting a challenge to ascertaining the appropriate interpretation. Time‐frequency analysis (TFA) of the N400/P300 window provides an objective approach to dissociating these effects. TFA measured from solution onset during single‐digit multiplication verification revealed significant modulations of event‐related as theta power (3–6 Hz) in both groups. Correct trials elicit less power in children (9–12 years) and more power in adults relative to incorrect trials. These findings are consistent with modulations of the N400 and P300, respectively, where opposite effects were predicted for spectral power. The ERP results further support a reinterpretation of the multiplication correctness effect. In contrast, TFA of the N400 effect elicited to a word‐picture verification task revealed the same event‐related theta effect in both groups, with increased power for mismatched than matched pictures. Together, these findings provide evidence for a developmental shift in cognitive processing specific to the multiplication task. Models of arithmetic should account for this overlooked difference in cognitive processing between children and adults. Although previous research proposed that adults and children use the same cognitive processes to verify multiplication problems, the current results suggest otherwise. Children elicit a robust N400 effect, whereas adults show a P300 effect. Given that these components are difficult to dissociate using conventional analysis, we used time‐frequency analysis to quantify the amplitude of the ERP oscillations. Children and adults show opposite theta effects, revealing an overlooked developmental difference in multiplication. [ABSTRACT FROM AUTHOR]

Research Summary: This article introduces the concept of missed external enablement as a choice not to act on significant change in the business environment that later proves to be a meaningful accelerant for an entrepreneurial endeavor. There has been little consideration to date of such errors of omission. In response, we model the opacity and the agent intensity of enablement as fuel for inaction, leading to missed enablement. We then specify factors, such as magnitude of the miss, that strengthen or weaken the effect. As this unfolds, entrepreneurs consider how to best respond, and we model various response paths that may increase or decrease subsequent entrepreneurial action, where the path is again influenced by opacity and agent intensity. The theory generated exposes new facets of external enablement. Managerial Summary: The effects of external change are shrouded in opacity. It is therefore difficult for entrepreneurs to discern whether change benefits one's endeavor and if it does, whether the effort, time, and resources are available to capitalize on it. Hence, it is rather easy to mistakenly choose entrepreneurial inaction. Our theory addresses the complexity and richness of these dynamics as they lead to missed external enablement, and our model outlines specific ways entrepreneurs might respond when they miss out on the benefits of external change. The insights we generate highlight the effects of entrepreneurs' exposure to many changes in the business environment over time, where the actions of others coupled with one's own past interpretations of the meaning of external changes influence what follows. [ABSTRACT FROM AUTHOR]

Introduction/Aims: Repaired nerve injuries can fail to achieve functional recovery. Therapeutic options beyond surgery, such as systemic tacrolimus (FK506) and electrical stimulation (E‐stim), can improve recovery. We tested whether dual administration of FK506 and E‐stim enhances regeneration and recovery more than either therapeutic alone. Methods: Rats were randomized to four groups: E‐stim, FK506, FK506 + E‐stim, and repair alone. All groups underwent tibial nerve transection and repair. Two sets of animals were created to measure outcomes of early nerve regeneration using nerve histology (n = 36) and functional recovery (n = 42) (21‐ and 42‐day endpoints, respectively). Functional recovery was measured by behavioral analyses (walking track and grid walk) and, at the endpoint, muscle mass and force. Results: Dual E‐stim and FK506 administration produced histomorphometric measurements of nerve regeneration no different than either therapeutic alone. All treatments were superior to repair alone (FK506, P <.0001; E‐stim, P <.05; FK506 + E‐stim, P <.05). The E‐stim and FK506 + E‐stim groups had improved behavioral recovery compared with repair alone (at 6 weeks: E‐stim, P <.05; FK506 + E‐stim, P <.01). The FK506 group had improved recovery based on walking‐track analysis (at 6 weeks: P <.001) and muscle force and mass (P <.05). The concurrent use of both therapies ensured earlier functional recovery and decreased variability in functional outcomes compared with either therapy alone, suggesting a moderate benefit. Discussion: Dual administration of FK506 and E‐stim showed minimal additive effects to further improve regeneration or recovery compared with either therapy alone. The data suggest the combination of FK506 and E‐stim appears to combine the relative strengths of each therapeutic. [ABSTRACT FROM AUTHOR]

Neuroma formation following limb amputation is a prevalent and debilitating condition that can deeply affect quality of life and productivity. Several approaches exist to prevent or treat neuromas; however, no approach is either consistently reliable or surgically facile, with high rates of neuroma occurrence and/or recurrence. The present study describes the development and testing of a xenogeneic nerve cap graft made from decellularized porcine nerve. The grafts were tested in vitro for cellular removal, cytotoxicity, mechanical properties, and morphological characteristics. The grafts were then tested in rat sciatic nerve gap reconstruction and nerve amputation models for 8 weeks. Gross morphology, electrophysiology, and histopathology assessments were performed to determine the ability of the grafts to limit pathologic nerve regrowth. In vitro testing showed well decellularized and demyelinated nerve cap graft structures without any cytotoxicity from residual reagents. The grafts had a proximal socket for the proximal nerve stump and longitudinally oriented internal pores. Mechanical and surgical handling properties suggested suitability for implantation as a nerve graft. Following 8 weeks in vivo, the grafts were well integrated with the proximal and distal nerve segments without evidence of fibrotic adhesions to the surrounding tissues or bulbous outgrowth of the nerve. Electrophysiology revealed absence of nerve conduction within the remodeled nerve cap grafts and significant downstream muscle atrophy. Histologic evaluation showed well organized but limited axonal regrowth within the grafts without fibrous overgrowth or neuromatous hypercellularity. These results provide proof of concept for a novel xenograft‐based approach to neuroma prevention. [ABSTRACT FROM AUTHOR]

This article examines how modes of governance are reconfigured as a result of using algorithms in the governance process. We argue that deploying algorithmic systems creates a shift toward a special form of design‐based governance, with power exercised ex ante via choice architectures defined through protocols, requiring lower levels of commitment from governing actors. We use governance of three policy problems – speeding, disinformation, and social sharing – to illustrate what happens when algorithms are deployed to enable coordination in modes of hierarchical governance, self‐governance, and co‐governance. Our analysis shows that algorithms increase efficiency while decreasing the space for governing actors' discretion. Furthermore, we compare the effects of algorithms in each of these cases and explore sources of convergence and divergence between the governance modes. We suggest design‐based governance modes that rely on algorithmic systems might be re‐conceptualized as algorithmic governance to account for the prevalence of algorithms and the significance of their effects. [ABSTRACT FROM AUTHOR]

Rationale: Aminoindanes are one class of many new psychoactive substances that have emerged over the last decade. Analogues of 2-aminoindane (2-AI) are being encountered in crime laboratories and analytical data for most aminoindanes are limited. Interpretation and optimization of gas chromatography-mass spectrometry data will enhance reliability in characterizing aminoindanes. Methods: This study focuses on the electron ionization mass spectrometric fragmentation of eight aminoindane analogues and the gas chromatographic separation of these eight aminoindane analogues using four different column stationary phases, Rxi®-1Sil MS, Rxi®-5Sil MS, Rxi®-35Sil MS, and Rxi®-624Sil MS. Split injection (25:1) was utilized and each column had the same configuration (30 m x 25 mm x 0.25 µm), with the exception of the Rxi®-624Sil MS column (30 m x 25 mm x1.4 µm). Results: Mass spectra showed strong molecular ions for all aminoindanes, except for rasagiline that produced a uniquely abundant [M - 1] ion. Other characteristic fragmentation that was present for all the aminoindanes included indane and indene ions (m/z 115-117), the tropylium ion (m/z 91), and subsequent loss of diene to produce smaller ions that followed: phenyl (m/z 77), cyclopentadienyl (m/z 65), cyclobutadienyl (m/z 51), and cyclopropenyl (m/z 39). Conclusions: Separation of eight aminoindanes was optimized, and linear retention indices were determined for the compounds on four capillary columns. Based on the retention data, all eight aminoindanes were resolved on an Rxi®-624Sil MS column. Each aminoindane exhibited unique fragmentation ions in the mass spectra to distinguish between similar analogues. The results of this study will strengthen the analytical profiles of 2-AI and seven analogues, assisting forensic scientists in their analysis and identification of these substances. [ABSTRACT FROM AUTHOR]

Cell plasticity is a crucial hallmark leading to cancer metastasis. Upregulation of Rho/ROCK pathway drives actomyosin contractility, protrusive forces, and contributes to the occurrence of highly invasive amoeboid cells in tumors. Cancer stem cells are similarly associated with metastasis, but how these populations arise in tumors is not fully understood. Here, we show that the novel oncogene RASSF1C drives mesenchymal‐to‐amoeboid transition and stem cell attributes in breast cancer cells. Mechanistically, RASSF1C activates Rho/ROCK via SRC‐mediated RhoGDI inhibition, resulting in generation of actomyosin contractility. Moreover, we demonstrate that RASSF1C‐induced amoeboid cells display increased expression of cancer stem‐like markers such as CD133, ALDH1, and Nanog, and are accompanied by higher invasive potential in vitro and in vivo. Further, RASSF1C‐induced amoeboid cells employ extracellular vesicles to transfer the invasive phenotype to target cells and tissue. Importantly, the underlying RASSF1C‐driven biological processes concur to explain clinical data: namely, methylation of the RASSF1C promoter correlates with better survival in early‐stage breast cancer patients. Therefore, we propose the use of RASSF1 gene promoter methylation status as a biomarker for patient stratification. SYNOPSIS: The known tumour‐suppressor RASSF1A encodes an alternative transcript, RASSF1C, that acts as oncogene in human breast cancer, triggering pro‐invasive cellular features and aggressiveness via SRC/Rho/ROCK signaling. RASSF1C expression promotes mesenchymal‐to‐amoeboid transition in breast cancer cells in vitro and xenograft models in vivo.RASSF1C increases SRC kinase activity, Rho/ROCK signalling and actomyosin contractility, independently of RASSF1A.RASSF1C‐induced Rho/ROCK signaling promotes expression of cancer stem‐like markers such as Nanog, ALDH1, and CD133.RASSF1C/Rho/ROCK‐dependent amoeboid motility results in release of extracellular vesicles that transfer invasive traits to less aggressive cell types.RASSF1C promoter methylation improves stratification and prognostication of early‐stage breast cancer patients. [ABSTRACT FROM AUTHOR]

Predicting how populations may respond to climate change and anthropogenic pressures requires detailed knowledge of demographic traits, such as survival and reproduction. However, the availability of these data varies greatly across space and taxa. Therefore, it is common practice to conduct population assessments by filling in missing values from surrogate species or other populations of the same species. Using these independent surrogate values concurrently with observed data neglects the life‐history trade‐offs that connect the different aspects of a population's demography. Consequently, this approach introduces biases that could ultimately lead to erroneous management decisions.We use a Bayesian hierarchical framework to combine fragmented multi‐population data with established life‐history theory and reconstruct population‐specific demographic data across a substantial part of a species breeding range. We apply our analysis to a long‐lived colonial species, the black‐legged kittiwake Rissa tridactyla, that is classified as globally Vulnerable and is highly threatened by increasing anthropogenic pressures, including offshore renewable energy development. We then use a projection analysis to examine how the reconstructed demographic parameters may improve population assessments, compared to models that combine observed data with independent surrogate values.Demographic parameters reconstructed using a hierarchical framework can be utilised in a range of population modelling approaches. They can also be used as reference estimates to assess whether independent surrogate values are likely to over or underestimate missing demographic parameters. We show that surrogate values from independent sources are often used to fill in missing parameters that have large potential demographic impact, and that resulting biases are driven in unpredictable directions thus precluding assessments from being consistently precautionary.Synthesis and applications. Our study dramatically increases the spatial coverage of population‐specific demographic data for black‐legged kittiwakes. The reconstructed demographic parameters presented can also be used immediately to reduce uncertainty in the consenting process for offshore wind development in the United Kingdom and Ireland. More broadly, we show that the reconstruction approach used here provides a new avenue for improving evidence‐based management and policy action for animal and plant populations with fragmented and error prone demographic data. [ABSTRACT FROM AUTHOR]

Keywords: Hypermutation; H3F3A; G34; glioma; mismatch repair; molecular profiling EN Hypermutation H3F3A G34 glioma mismatch repair molecular profiling 460 463 4 03/24/21 20210401 NES 210401 INTRODUCTION Diffuse gliomas with I H3F3A i point mutations affecting histone H3.3 glycine position 34 are a distinct glioma subtype mostly occurring in the cerebral hemispheres of paediatric and young adult patients.1 These tumours have a high rate of I MGMT i promoter hypermethylation, a predictive biomarker for response to the DNA alkylating agent temozolomide (TMZ). This case supports that H3.3 p.G34-mutant gliomas should be included in studies relating to hypermutation in central nervous system tumours, and that re-sequencing of recurrent gliomas can uncover unexpected mechanisms of treatment resistance. This case of post-treatment hypermutation in a glioma with H3F3A p.G34 mutation suggests that acquired somatic hypermutation and clonal selection can contribute to therapeutic resistance and tumour progression in this glioma subtype. [Extracted from the article]

Recently, an evolving literature on the EU as a "responsive technocracy" has analysed how the growing politicization of EU-level initiatives and institutions had led to those institutions responding by, for example, adopting new legislation (Rauh, 2016, 2019). Keywords: Technocracy; EU; Agencies; Stakeholder Engagement; Participation EN Technocracy EU Agencies Stakeholder Engagement Participation 459 473 15 04/24/21 20210301 NES 210301 Introduction Regional organizations in the Global North have sought to create avenues for legitimating integrationist activities. As such, the key to democratizing EU governance may be less a matter of creating "new" institutional arrangements, than of developing the logic through which public managers at the EU level can justify and extend stakeholder engagement practices. To show this, the article analyses semi-structured interviews with 24 European Union Commission Directorates-General (DGs), civil society organizations and independent agencies, as well as stakeholder engagement strategies and engagement requirements provided in governing regulations. [Extracted from the article]

Despite advances in surgery, the reconstruction of segmental nerve injuries continues to pose challenges. In this review, current neurobiology regarding regeneration across a nerve defect is discussed in detail. Recent findings include the complex roles of nonneuronal cells in nerve defect regeneration, such as the role of the innate immune system in angiogenesis and how Schwann cells migrate within the defect. Clinically, the repair of nerve defects is still best served by using nerve autografts with the exception of small, noncritical sensory nerve defects, which can be repaired using autograft alternatives, such as processed or acellular nerve allografts. Given current clinical limits for when alternatives can be used, advanced solutions to repair nerve defects demonstrated in animals are highlighted. These highlights include alternatives designed with novel topology and materials, delivery of drugs specifically known to accelerate axon growth, and greater attention to the role of the immune system. [ABSTRACT FROM AUTHOR]

Reputation is of growing interest for the study of public bureaucracies, but a measurement that can discern between the subdimensions of reputation and is validated on real‐life audiences has remained elusive. The authors deductively build, test, and cross‐validate a survey instrument through two surveys of 2,100 key stakeholders of the European Chemicals Agency, the European Union chemicals regulator. This empirical tool measures an agency's reputation and its building blocks. This scale represents an important contribution to reputation literature, as it allows scholars to distinguish and measure which aspects of reputation public organizations are "known for" and build their claim to authority on, as well as how the profiles of public organizations differ. The authors find that direct stakeholder contact with the agency is necessary for stakeholders to be able to evaluate the separate dimensions of reputation independently. Evidence for Practice This study equips practitioners with a reputation barometer tailored to the public sector. It allows them to measure the reputation of their organization, in a differentiated fashion, among different stakeholder groups.While public organizations increasingly engage in reputation management activities, a potential caveat that emerges from our exercise is that managers might be steering in non‐astute directions. While our study shows that, as for private actors, "performance matters," procedural and moral aspects also weigh heavily in the eyes of stakeholders when it comes to public regulators.To secure a positive organizational image and the authority crucial for public agencies to operate, the performance management turn in the public sector may need to be supplemented by an enhanced organizational attention to procedural and moral aspects. [ABSTRACT FROM AUTHOR]

Background: Duchenne muscular dystrophy (DMD) is a fatal muscle‐wasting disorder caused by genetic loss of dystrophin protein. Extracellular microRNAs (ex‐miRNAs) are putative, minimally invasive biomarkers of DMD. Specific ex‐miRNAs (e.g. miR‐1, miR‐133a, miR‐206, and miR‐483) are highly up‐regulated in the serum of DMD patients and dystrophic animal models and are restored to wild‐type levels following exon skipping‐mediated dystrophin rescue in mdx mice. As such, ex‐miRNAs are promising pharmacodynamic biomarkers of exon skipping efficacy. Here, we aimed to determine the degree to which ex‐miRNA levels reflect the underlying level of dystrophin protein expression in dystrophic muscle. Methods: Candidate ex‐miRNA biomarker levels were investigated in mdx mice in which dystrophin was restored with peptide‐PMO (PPMO) exon skipping conjugates and in mdx‐XistΔhs mice that express variable amounts of dystrophin from birth as a consequence of skewed X‐chromosome inactivation. miRNA profiling was performed in mdx‐XistΔhs mice using the FirePlex methodology and key results validated by small RNA TaqMan RT‐qPCR. The muscles from each animal model were further characterized by dystrophin western blot and immunofluorescence staining. Results: The restoration of ex‐myomiR abundance observed following PPMO treatment was not recapitulated in the high dystrophin‐expressing mdx‐XistΔhs group, despite these animals expressing similar amounts of total dystrophin protein (~37% of wild‐type levels). Instead, ex‐miRNAs were present at high levels in mdx‐XistΔhs mice regardless of dystrophin expression. PPMO‐treated muscles exhibited a uniform pattern of dystrophin localization and were devoid of regenerating fibres, whereas mdx‐XistΔhs muscles showed non‐homogeneous dystrophin staining and sporadic regenerating foci. Conclusions: Uniform dystrophin expression is required to prevent ex‐miRNA release, stabilize myofiber turnover, and attenuate pathology in dystrophic muscle. [ABSTRACT FROM AUTHOR]

The volume and variety of manufactured chemicals is increasing, although little is known about the risks associated with the frequency and extent of human exposure to most chemicals. The EPA and the recent signing of the Lautenberg Act have both signaled the need for high‐throughput methods to characterize and screen chemicals based on exposure potential, such that more comprehensive toxicity research can be informed. Prior work of Mitchell et al. using multicriteria decision analysis tools to prioritize chemicals for further research is enhanced here, resulting in a high‐level chemical prioritization tool for risk‐based screening. Reliable exposure information is a key gap in currently available engineering analytics to support predictive environmental and health risk assessments. An elicitation with 32 experts informed relative prioritization of risks from chemical properties and human use factors, and the values for each chemical associated with each metric were approximated with data from EPA's CP_CAT database. Three different versions of the model were evaluated using distinct weight profiles, resulting in three different ranked chemical prioritizations with only a small degree of variation across weight profiles. Future work will aim to include greater input from human factors experts and better define qualitative metrics. [ABSTRACT FROM AUTHOR]

This symposium demonstrates the potential for throughput legitimacy as a concept for shedding empirical light on the strengths and weaknesses of multi‐level governance, as well as challenging the concept theoretically. This article introduces the symposium by conceptualizing throughput legitimacy as an 'umbrella concept', encompassing a constellation of normative criteria not necessarily empirically interrelated. It argues that in order to interrogate multi‐level governance processes in all their complexity, it makes sense for us to develop normative standards that are not naïve about the empirical realities of how power is exercised within multi‐level governance, or how it may interact with legitimacy. We argue that while throughput legitimacy has its normative limits, it can be substantively useful for these purposes. While being no replacement for input and output legitimacy, throughput legitimacy offers distinctive normative criteria—accountability, transparency, inclusiveness and openness—and points towards substantive institutional reforms. [ABSTRACT FROM AUTHOR]

Introduction: Neuroenhancing therapies are desired because repair of nerve injuries can fail to achieve recovery. We compared two neuroenhancing therapies, electrical stimulation (ES) and systemic tacrolimus (FK506), for their capabilities to enhance regeneration in the context of a rat model.Methods: Rats were randomized to four groups: ES 0.5 mA, ES 2.0 mA, FK506, and repair alone. All groups underwent tibial nerve transection and repair, and outcomes were assessed by using twice per week walking track analysis, cold allodynia response, relative muscle mass, and nerve histology.Results: Electrical stimulation and FK506 groups demonstrated improved functional recovery and myelinated axon counts distal to the repair compared with repair alone. Electrical stimulation provided improvements in nerve regeneration that were not different from optimized FK506 systemic administration.Discussion: Providing ES after nerve repair improved regeneration and recovery in rats, with minimal differences in therapeutic efficacy to FK506, further demonstrating its clinical potential to improve management of nerve injuries. [ABSTRACT FROM AUTHOR]

Although advanced materials (AdMs) are beneficial in many applications, questions remain as to whether they are more or less sustainable than the conventional materials that they may replace. Currently, there is no available tool to provide clarity to these questions. Traditional approaches for evaluating the sustainability of a chemical or material are usually not standardized, and as a result, the metrics used in sustainability measurements are subjective and often vary from assessor to assessor. Additionally, sustainability characterizations resulting from these approaches are typically presented qualitatively and are often vaguely drawn, making it difficult to confidently and transparently conclude that 1 material is more sustainable than another. This paper aims to address these gaps by enabling stakeholders involved in the production, use, or governance of AdMs to assess the sustainability of AdMs in a consistent, objective, and quantitative way using a multicriteria decision analysis (MCDA)–based model. The model proposed herein adapts a triple‐bottom‐line (TBL) framework from the Institution of Chemical Engineers (IChemE) and incorporates criteria weights identified through a stakeholder values assessment conducted by surveying AdM practitioners. Results from the stakeholder values assessment show that the perceived importance of the economic component of the TBL varies the most across stakeholders, and that practitioners providing responses from the perspective of a nongovernmental environmental advocacy group or a regulator of AdMs such as the United States Environmental Protection Agency were more likely to score and weigh economic indicators lower and environmental indicators higher compared to when responding from a business owner perspective. The resulting MCDA‐based model allows stakeholders to assess the sustainability of an AdM or AdM‐enabled product and compare it to product alternatives, predict how other stakeholders might score a product by identifying the extent to which components of the TBL are valued by other stakeholders, and identify which subcriteria contribute most to an improvement in a product's sustainability score. Integr Environ Assess Manag 2019;00:1–8. © 2019 SETAC Key Points: The multicriteria decision analysis (MCDA)–based sustainability model presented here can be used by stakeholders involved in the production, use, or governance of advanced materials (AdMs) for assessing the sustainability of an AdM or AdM‐enabled product and comparing it to product alternatives.The MCDA‐based sustainability model presented here can be used to predict how other stakeholders might score a product by identifying the extent to which components of the triple‐bottom‐line (TBL) are valued by other stakeholders.The MCDA‐based sustainability model presented here can be used to identify which subcriteria contribute most to an improvement in a product's sustainability score. [ABSTRACT FROM AUTHOR]

Rosette‐forming glioneuronal tumor (RGNT) most commonly occurs adjacent to the fourth ventricle and therefore rarely presents with epilepsy. Recent reports describe RGNT occurrence in other anatomical locations with considerable morphologic and genetic overlap with the epilepsy‐associated dysembryoplastic neuroepithelial tumor (DNET). Examples of RGNT or DNET with anaplastic change are rare, and typically occur in the setting of radiation treatment. We present the case of a 5‐year‐old girl with seizures, who underwent near total resection of a cystic temporal lobe lesion. Pathology showed morphologic and immunohistochemical features of RGNT, albeit with focally overlapping DNET‐like patterns. Resections of residual or recurrent tumor were performed 1 year and 5 years after the initial resection, but no adjuvant radiation or chemotherapy was given. Ten years after the initial resection, surveillance imaging identified new and enhancing nodules, leading to another gross total resection. This specimen showed areas similar to the original tumor, but also high‐grade foci with oligodendroglial morphology, increased cellularity, palisading necrosis, microvascular proliferation, and up to 13 mitotic figures per 10 high power fields. Ancillary studies the status by sequencing showed wild‐type of the isocitrate dehydrogenase 1 (IDH1), IDH2, and human histone 3.3 (H3F3A) genes, and BRAF studies were negative for mutation or rearrangement. Fluorescence in situ hybridization (FISH) showed codeletion of 1p and 19q limited to the high‐grade regions. By immunohistochemistry there was loss of nuclear alpha‐thalassemia mental retardation syndrome, X‐linked (ATRX) expression only in the high‐grade region. Next‐generation sequencing showed an fibroblast growth factor receptor receptor 1 (FGFR1) kinase domain internal tandem duplication in three resection specimens. ATRX mutation in the high‐grade tumor was confirmed by sequencing which showed a frameshift mutation (p.R1427fs), while the apparent 1p/19q‐codeletion by FISH was due to loss of chromosome arm 1p and only partial loss of 19q. Exceptional features of this case include the temporal lobe location, 1p/19q loss by FISH without true whole‐arm codeletion, and anaplastic transformation associated with ATRX mutation without radiation or chemotherapy. [ABSTRACT FROM AUTHOR]

Novel materials with unique or enhanced properties relative to conventional materials are being developed at an increasing rate. These materials are often referred to as advanced materials (AdMs) and they enable technological innovations that can benefit society. Despite their benefits, however, the unique characteristics of many AdMs, including many nanomaterials, are poorly understood and may pose environmental safety and occupational health (ESOH) risks that are not readily determined by traditional risk assessment methods. To assess these risks while keeping up with the pace of development, technology developers and risk assessors frequently employ risk‐screening methods that depend on a clear definition for the materials that are to be assessed (e.g., engineered nanomaterial) as well as a method for binning materials into categories for ESOH risk prioritization. The term advanced material lacks a consensus definition and associated categorization or grouping system for risk screening. In this study, we aim to establish a practitioner‐driven definition for AdMs and a practitioner‐validated framework for categorizing AdMs into conceptual groupings based on material characteristics. Results from multiple workshops and interviews with practitioners provide consistent differentiation between AdMs and conventional materials, offer functional nomenclature for application science, and provide utility for future ESOH risk assessment prioritization. The definition and categorization framework established here serve as a first step in determining if and when there is a need for specific ESOH and regulatory screening for an AdM as well as the type and extent of risk‐related information that should be collected or generated for AdMs and AdM‐enabled technologies. [ABSTRACT FROM AUTHOR]

The aim of this article is to explore the link between different notions of co‐production. It seeks to emphasise the underlying politics of co‐production in the sense of who defines co‐production, especially in relation to initial decisions concerning which specific policy areas are deemed suitable for codesigning, cocreating, or codelivering with services users or local communities. We argue that the rejection of co‐production by government may inflame political resentment and reconfirm negative pre‐existing attitudes about "the establishment." This is particularly problematic when politicians have promoted the rhetoric of "inclusive governance," "sharing power," or "delegating power" but then reject the co‐productive claims emerging from such statements. The study contributes to existing work by analysing what happens when co‐productive structures are terminated or when public protests demand the reinstitutionalisation of those relationships. We make this contribution by presenting findings from an ethnographic case study involving street trees in a large English city. We suggest these specific findings have a broader relevance. [ABSTRACT FROM AUTHOR]

This article adopts and reinvents the ethnographic approach to uncover what governing elites do, and how they respond to public disaffection. Although there is significant work on the citizens' attitudes to the governing elite (the demand side) there is little work on how elites interpret and respond to public disaffection (the supply side). It is argued here that ethnography is the best available research method for collecting data on the supply side. The article tackles longstanding stereotypes in political science about the ethnographic method and what it is good for, and highlights how the innovative and varied practices of contemporary ethnography are ideally suited to shedding light into the 'black box' of elite politics. The potential pay‐off is demonstrated with reference to important examples of elite ethnography from the margins of political science scholarship. The implications from these rich studies suggest a reorientation of how one understands the drivers of public disaffection and the role that political elites play in exacerbating cynicism and disappointment. The article concludes by pointing to the benefits to the discipline in embracing elite ethnography both to diversify the methodological toolkit in explaining the complex dynamics of disaffection, and to better enable engagement in renewed public debate about the political establishment. [ABSTRACT FROM AUTHOR]

Research Summary: We introduce a contagion model of self‐employment that relates regional cohort self‐employment to individuals' preferences for and decisions toward engaging in entrepreneurial action. We test the predictions of our model via evidence from two studies. Study 1 uses cross‐sectional data from the U.S. General Social Survey (GSS) and examines the correlation between regional cohort self‐employment and individuals' attitudes for self‐employment. Study 2 uses longitudinal data from the Household, Income, and Labour Dynamics in Australia (HILDA) survey and examines the likelihood of transitioning into self‐employment as a function of regional cohort entrepreneurship. Our results provide evidence that individuals who belong to regional cohorts with a greater proportion of entrepreneurs are more likely to express favorable attitudes toward self‐employment and to enter into self‐employment. Managerial Summary: A large literature in the social sciences indicates that people's preferences and actions are influenced by the behaviors of those around them. We find this is true when it comes to entrepreneurship. Specifically, we document that people who live in regions with higher proportions of entrepreneurs are more likely to express favorable attitudes toward self‐employment and are more likely to start new business ventures. This suggests that people embedded in environments where there is a lot of entrepreneurial activity are more likely to "catch the bug" of self‐employment, as they use already‐established entrepreneurs in the region as a roadmap for their own thinking and action. [ABSTRACT FROM AUTHOR]

Abstract: Astroblastoma is a rare and controversial glioma with variable clinical behavior. The diagnosis currently rests on histologic findings of a circumscribed glioma with astroblastomatous pseudorosettes and vascular hyalinization. Immunohistochemical studies have suggested different oncogenic drivers, such as BRAF p.V600E, but very few cases have been studied using genome‐wide methodologies. Recent genomic profiling identified a subset of CNS embryonal tumors with astroblastoma‐like morphology that harbored MN1 gene fusions, termed “CNS high‐grade neuroepithelial tumors with MN1 alteration” (CNS‐HGNET‐MN1). To further characterize the genetic alterations that drive astroblastomas, we performed targeted next‐generation sequencing (NGS) of 500 cancer‐associated genes in a series of eight cases. We correlated these findings with break‐apart fluorescence in situ hybridization (FISH) analysis of the MN1 locus and genome‐wide DNA methylation profiling. Four cases showed MN1 alteration by FISH, including two pediatric cases that lacked other pathogenic alterations, and two adult cases that harbored other cancer‐associated gene mutations or copy number alterations (eg, CDKN2A/B homozygous deletion, TP53, ATM and TERT promoter mutations). Three of these cases grouped with the CNS‐HGNET‐MN1 entity by methylation profiling. Two of four MN1 intact cases by FISH showed genetic features of either anaplastic pleomorphic xanthoastrocytoma (BRAF p.V600E mutation, CDKN2A/B homozygous deletion and TERT promoter mutation) or IDH‐wildtype glioblastoma (trisomy 7, monosomy 10, CDK4 amplification and TP53, NRAS and TERT promoter mutations) and these cases had an aggressive clinical course. Two clinically indolent cases remained unclassifiable despite multimodal molecular analysis. We conclude that astroblastoma histology is not specific for any entity including CNS‐HGNET‐MN1, and that additional genetic characterization should be considered for astroblastomas, as a number of these tumors likely contain a methylation profile or genetic alterations that suggest classification as other tumor entities. Our heterogeneous molecular findings help to explain the clinical unpredictability of astroblastoma. [ABSTRACT FROM AUTHOR]

Abstract: Shared ownership of property and resources is a longstanding challenge throughout history that has been amplifying with the increasing development of industrial and postindustrial societies. Where governments, project planners, and commercial developers seek to develop new infrastructure, industrial projects, and various other land‐and resource‐intensive tasks, veto power shared by various local stakeholders can complicate or halt progress. Risk communication has been used as an attempt to address stakeholder concerns in these contexts, but has demonstrated shortcomings. These coordination failures between project planners and stakeholders can be described as a specific kind of social dilemma that we describe as the “tragedy of the anticommons.” To overcome such dilemmas, we demonstrate how a two‐step process can directly address public mistrust of project planners and public perceptions of limited decision‐making authority. This approach is examined via two separate empirical field experiments in Portugal and Tunisia, where public resistance and anticommons problems threatened to derail emerging industrial projects. In both applications, an intervention is undertaken to address initial public resistance to such projects, where specific public stakeholders and project sponsors collectively engaged in a hypothesis‐testing process to identify and assess human and environmental health risks associated with proposed industrial facilities. These field experiments indicate that a rigorous attempt to address public mistrust and perceptions of power imbalances and change the pay‐off structure of the given dilemma may help overcome such anticommons problems in specific cases, and may potentially generate enthusiasm and support for such projects by local publics moving forward. [ABSTRACT FROM AUTHOR]

Introduction: Acellular nerve allografts (ANAs) yield less consistent favorable outcomes compared with autografts for long gap reconstructions. We evaluated whether a hybrid ANA can improve 6-cm gap reconstruction.Methods: Rat sciatic nerve was transected and repaired with either 6-cm hybrid or control ANAs. Hybrid ANAs were generated using a 1-cm cellular isograft between 2.5-cm ANAs, whereas control ANAs had no isograft. Outcomes were assessed by graft gene and marker expression (n = 4; at 4 weeks) and motor recovery and nerve histology (n = 10; at 20 weeks).Results: Hybrid ANAs modified graft gene and marker expression and promoted modest axon regeneration across the 6-cm defect compared with control ANA (P < 0.05), but yielded no muscle recovery. Control ANAs had no appreciable axon regeneration across the 6-cm defect.Discussion: A hybrid ANA confers minimal motor recovery benefits for regeneration across long gaps. Clinically, the authors will continue to reconstruct long nerve gaps with autografts. Muscle Nerve 57: 260-267, 2018. [ABSTRACT FROM AUTHOR]

Aims: Lumbar to sacral rerouting surgery can potentially allow voiding via a skin‐central nervous system‐bladder reflex pathway. Here, we assessed if this surgery was effective in treating neurogenic bladder dysfunction/sphincter in felines. Methods: Eight cats underwent spinal cord transection (SCT) at thoracic level 10/11. Unilateral L7 to S1 ventral root anastomosis was performed 1 month later in six cats. Two cats served as transection‐only controls. Electrical and manual stimulation of L6‐S1 dermatomes, and urodynamics were performed at 3, 5, 7, and 9/10 months post transection. At 9/10 months, cats were also evaluated by direct electrophysiological testing of anastomosed roots with urodynamics, then tissue collection and examination of the root anastomosis site and lumbosacral cord ventral horns for cells retrogradely labeled from tracer dye injected 2 weeks earlier into the bladder wall. Results: At 9/10 months, four of six rerouted cats exhibited increased detrusor pressure provoked by cutaneous stimulation, one cat bilaterally. Two cats presented with a voiding stream after ipsilateral cutaneous stimulation at 7 and 9 months. All six rerouted animals showed regrowth of axons from the L7 ventral horn to the bladder, although some aberrant axonal regrowth was also observed. Conclusion: L7 to S1 ventral root rerouting below the level of SCT showed successful axonal regrowth to the bladder from the L7 spinal cord segment in all rerouted animals, and induced increased detrusor pressure response to cutaneous stimulation in a subset. This feasibility study paves the way for future animal studies for bladder reinnervation. [ABSTRACT FROM AUTHOR]

ABSTRACT Providing temporally regulated glial cell line-derived neurotrophic factor (GDNF) to injured nerve can promote robust axon regeneration. However, it is poorly understood why providing highly elevated levels of GDNF to nerve can lead to axon entrapment in the zone containing elevated GDNF. This limited understanding represents an obstacle to the translation of GDNF therapies to treat nerve injuries clinically. Here, we investigated how transgenic Schwann cells (SCs) overexpressing GDNF-IRES-DsRed impact nerve regeneration. Cultured primary SCs were transduced with lentiviruses (GDNF-overexpressing transgenic SCs), one of which provides the capability to express high levels of GDNF and regulate temporal GDNF expression. These SC groups were transplanted into acellular nerve allografts (ANAs) bridging a 14 mm rat sciatic nerve defect. GDNF-overexpressing transgenic SCs expressing GDNF for as little as 1 week decreased axon regeneration across ANAs and caused extensive extracellular matrix (ECM) remodeling. To determine whether additional gene expression changes beyond GDNF transgene expression occurred in GDNF-overexpressing transgenic SCs, microarray analysis of GDNF-overexpressing transgenic SCs compared to untreated SCs was performed. Microarray analysis revealed a set of common genes regulated in transgenic SC groups expressing high levels of GDNF compared to untreated SCs. A co-culture model of GDNF-overexpressing transgenic SCs with fibroblasts (FBs) revealed differential FB ECM-related gene expression compared to untreated SCs. These data suggest a component of axon entrapment is independent of GDNF's impact on axons. Biotechnol. Bioeng. 2017;114: 2121-2130. © 2017 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Neuroma management is an unresolved problem. Biomaterials to limit unwanted axonal growth could be a tool to manage neuroma. Hyaluronic acid/carboxymethyl cellulose (HA/CMC) is an antiadhesive, biodegradable material that is nontoxic to nerve. The purpose of this study was to evaluate the efficacy of this biomaterial to limit axonal growth. Rats received a sciatic nerve transection and repair with a short conduit (5 mm) containing HA/CMC, fibrin, or nothing (empty conduit). In another study, nerve was transected and either left undisturbed or wrapped with HA/CMC around the proximal and distal ends. In a final study, nerve was transected and repaired with an HA/CMC wrap. Four weeks following the procedures, nerves were harvested and assessed using histomorphometry to measure axonal regeneration. Axonal regeneration following transection was significantly inhibited by direct axonal contact with HA/CMC, whether within a conduit or wrapped around the transected proximal nerve end. Axonal regeneration following epineurial repair was not affected by HA/CMC wrapped around nerve, demonstrating axonal growth inhibition due to direct contact of regenerating axons with HA/CMC. These studies demonstrate the efficacy of HA/CMC to limit axonal outgrowth by contact with regenerating axons. HA/CMC barriers may prove to be a tool to prevent neuroma formation by inhibiting axonal growth. © 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 568-574, 2017. [ABSTRACT FROM AUTHOR]

Research summary The endogenous formation of entrepreneurial opportunity has become an important theoretical perspective. Research to date focuses on initial opportunity creation dynamics leading to venture formation. This excludes the ongoing enactment of opportunity that takes place after venture founding. We focus on this phenomenon, arguing that opportunities must be continually reproduced through maintenance of consensus among stakeholders about their viability. If consensus fails, the objectivity of the opportunity is 'destroyed' in a process we label 'opportunity de-objectification.' We identify predictors of opportunity de-objectification and summarize their effects in propositions suitable for future empirical testing. Implications for future theory and research are also discussed. Managerial summary Previous entrepreneurship research has focused attention on the process through which opportunity ideas become objectified and perceived as external facts by entrepreneurs and their stakeholders during venture formation. While such attention is critical, we argue that venture founding marks the beginning, rather than the end, of a dynamic process in which the fact-like status of opportunities is maintained. If stakeholder consensus about opportunity viability is disrupted, it raises questions about this factual status and opens up the possibility that the opportunity is a subjective cognition of the entrepreneur rather than an objective reality. We call this phenomenon 'opportunity de-objectification,' and we identify a number of factors that precipitate it. We also suggest that entrepreneurs may reduce the likelihood of this phenomenon by managing some of the factors that induce it. Copyright © 2016 Strategic Management Society. [ABSTRACT FROM AUTHOR]

Somatic mutations of the H3F3A and HIST1H3B genes encoding the histone H3 variants, H3.3 and H3.1, were recently identified in high-grade gliomas arising in the thalamus, pons and spinal cord of children and young adults. However, the complete range of patients and locations in which these tumors arise, as well as the morphologic spectrum and associated genetic alterations remain undefined. Here, we describe a series of 47 diffuse midline gliomas with histone H3-K27M mutation. The 25 male and 22 female patients ranged in age from 2 to 65 years (median = 14). Tumors were centered not only in the pons, thalamus, and spinal cord, but also in the third ventricle, hypothalamus, pineal region and cerebellum. Patients with pontine tumors were younger (median = 7 years) than those with thalamic (median = 24 years) or spinal (median = 25 years) tumors. A wide morphologic spectrum was encountered including gliomas with giant cells, epithelioid and rhabdoid cells, primitive neuroectodermal tumor (PNET)-like foci, neuropil-like islands, pilomyxoid features, ependymal-like areas, sarcomatous transformation, ganglionic differentiation and pleomorphic xanthoastrocytoma (PXA)-like areas. In this series, histone H3-K27M mutation was mutually exclusive with IDH1 mutation and EGFR amplification, rarely co-occurred with BRAF-V600E mutation, and was commonly associated with p53 overexpression, ATRX loss (except in pontine gliomas), and monosomy 10. [ABSTRACT FROM AUTHOR]

α-Pyrrolidinovalerophenone (α-PVP), a dangerous designer drug, is now being marketed around the world as a harmless `bath salt', when in reality it is a powerful β-ketone phenethylamine stimulant. A sample of the free base from a recent law-enforcement seizure was crystallized as the HCl salt [systematic name: 1-(1-oxo-1-phenylpentan-2-yl)pyrrolidin-1-ium chloride 0.786-hydrate], C15H22NO+·Cl−·0.786H2O. In the crystal structure, the propyl chain is nearly perpendicular to both the phenyl ring and the carbonyl group. The hydrogen-bonding scheme involves the quaternary N atom, the Cl− anion and the partially occupied (0.786) water molecule, forming centrosymmetric dimers. [ABSTRACT FROM AUTHOR]

Studies of delegated agencies commonly emphasize the importance of accountability for these unelected bodies to secure authority to govern. This article argues that beyond formal accountability measures, developing legitimacy through interaction with external stakeholders is critical to agency authority. In doing so, the article makes a distinctive contribution by applying a new conceptual model based on organizational sociology and identifying multiple dimensions along which legitimacy is lost and won, and hence authority secured. The article presents original findings from a case study of how the Murray-Darling Basin Authority, an Australian water agency established in 2007, attempted to achieve 'political legitimacy'. Findings show that the Agency achieved legitimacy via appeals to common normative/ethical values and developing commonly used information and news outlets, despite facing opposition from stakeholders on the socioeconomic impact of its policies. The conclusion argues that the framework can usefully be applied to other agencies in 'wicked problem' policy areas. [ABSTRACT FROM AUTHOR]

Objective: Identification of a particular cause of meningoencephalitis can be challenging owing to the myriad bacteria, viruses, fungi, and parasites that can produce overlapping clinical phenotypes, frequently delaying diagnosis and therapy. Metagenomic deep sequencing (MDS) approaches to infectious disease diagnostics are known for their ability to identify unusual or novel viruses and thus are well suited for investigating possible etiologies of meningoencephalitis.Methods: We present the case of a 74-year-old woman with endophthalmitis followed by meningoencephalitis. MDS of her cerebrospinal fluid (CSF) was performed to identify an infectious agent.Results: Sequences aligning to Balamuthia mandrillaris ribosomal RNA genes were identified in the CSF by MDS. Polymerase chain reaction subsequently confirmed the presence of B. mandrillaris in CSF, brain tissue, and vitreous fluid from the patient's infected eye. B. mandrillaris serology and immunohistochemistry for free-living amoebas on the brain biopsy tissue were positive.Interpretation: The diagnosis was made using MDS after the patient had been hospitalized for several weeks and subjected to costly and invasive testing. MDS is a powerful diagnostic tool with the potential for rapid and unbiased pathogen identification leading to early therapeutic targeting. [ABSTRACT FROM AUTHOR]

The evaluation of opportunities to introduce new goods or services to one or more markets is an essential part of entrepreneurship, and the last decade ushered in a steady stream of studies on the topic. However, to date, this knowledge has not been systematically reviewed. The current article addresses this gap by synthesizing studies that speak to the evaluation of entrepreneurial opportunities. The review of 53 articles involves the development of a thematic framework used to organize the literature in terms of conceptual and empirical themes as well as patterns in publication trends. The insights derived culminate in an integrative framework that conceptually describes what goes on in the 'mind in the middle' as opportunity evaluation unfolds. The model illuminates a path for future research that guides improved understanding of the cognitive dynamics that lead some individuals to believe that a set of circumstances represents an attractive opportunity while others have little confidence that the same circumstances represent an opportunity at all. [ABSTRACT FROM AUTHOR]

The name `bath salts', for an emerging class of synthetic cathinones, is derived from an attempt to evade prosecution and law enforcement. These are truly illicit drugs that have psychoactive CNS (central nervous system) stimulant effects and they have seen a rise in abuse as recreational drugs in the last few years since first having been seen in Japan in 2006. The ease of synthesis and modification of specific functional groups of the parent cathinone make these drugs particularly difficult to regulate. MDPV (3,4-methylenedioxypyrovalerone) is commonly encountered as its hydrochloride salt (C16H21NO3·HCl), in either the hydrated or the anhydrous forms. This `bath salt' has various names in the US, e.g. `Super Coke', `Cloud Nine', and `Ivory Wave', to name just a few. We report here the structures of two forms of the HCl salt, one as a mixed bromide/chloride salt, C16H22NO3+·0.343Br−·0.657Cl− [systematic name: 1-(benzo[ d][1,3]dioxol-5-yl)-2-(pyrrolidin-1-ium-1-yl)pentan-1-one bromide/chloride (0.343/0.657)], and the other with the H7O3+ cation, as well as the HCl counter-ion [systematic name: hydroxonium 1-(benzo[ d][1,3]dioxol-5-yl)-2-(pyrrolidin-1-ium-1-yl)pentan-1-one dichloride, H7O3+·C16H22NO3+·2Cl−]. This is one of a very few structures (11 to be exact) in which we have a new example of a precisely determined hydroxonium cation. During the course of researching the clandestine manufacture of MDPV, we were surprised by the fact that a common precursor of this illicit stimulant is known to be the fragrant species piperonal, which is present in the fragrances of orchids, most particularly in the case of the vanilla orchid. We found that MDPV can be made by a Grignard reaction of this heliotropin. This may also explain the unexpected appearance of the bromide counter-ion in some of the salts we encountered (C16H21NO3·HBr), one of which is presented here [systematic name: 1-(benzo[ d][1,3]dioxol-5-yl)-2-(pyrrolidin-1-ium-1-yl)pentan-1-one bromide, C16H22NO3+·Br−]. Complexation of MDPV with a forensic crystallizing reagent, HAuCl4, yields the tetrachloridoaurate salt of this drug, (C16H22NO3)[AuCl4]. The heavy-metal complexing agent HAuCl4 has been used for over a century to identify common quarternary nitrogen-containing drugs via microscopic identification. Another street drug, called ethylone (3,4-methylenedioxyethylcathinone), is regularly sold and abused as its hydrochloride salt (C12H15NO3·HCl), and its structure is herein described (systematic name: N-{1-[(benzo[ d][1,3]dioxol-5-yl)carbonyl]ethyl}ethanaminium chloride, C12H16NO3+·Cl−). Marketed and sold as a `bath salt', `plant feeder', or `cleaning product', this drug is nothing more than a slight chemical modification of the banned drug methylone (3,4-methylenedioxymethcathinone). As with previously popular synthetic cathinones, the abuse of ethylone has seen a recent increase due to regulatory efforts on previous generations of cathinones that are now banned. [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs) play a significant role in cell–cell communication in numerous physiological processes and pathological conditions, and offer promise as novel biomarkers and therapeutic agents for genetic diseases. Many recent studies have described different molecular mechanisms that contribute to EV biogenesis and release from cells. However, little is known about how external stimuli such as cell culture conditions can affect the quantity and content of EVs. While N2a neuroblastoma cells cultured in serum-free (OptiMEM) conditions did not result in EVs with significant biophysical or size differences compared with cells cultured in serum-containing (pre-spun) conditions, the quantity of isolated EVs was greatly increased. Moreover, the expression levels of certain vesicular proteins (e.g. small GTPases, G-protein complexes, mRNA processing proteins and splicing factors), some of which were previously reported to be involved in EV biogenesis, were found to be differentially expressed in EVs under different culture conditions. These data, therefore, contribute to the understanding of how extracellular factors and intracellular molecular pathways affect the composition and release of EVs. [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs) have emerged as important mediators of intercellular communication in a diverse range of biological processes. For future therapeutic applications and for EV biology research in general, understanding the in vivo fate of EVs is of utmost importance. Here we studied biodistribution of EVs in mice after systemic delivery. EVs were isolated from 3 different mouse cell sources, including dendritic cells (DCs) derived from bone marrow, and labelled with a near-infrared lipophilic dye. Xenotransplantation of EVs was further carried out for cross-species comparison. The reliability of the labelling technique was confirmed by sucrose gradient fractionation, organ perfusion and further supported by immunohistochemical staining using CD63-EGFP probed vesicles. While vesicles accumulated mainly in liver, spleen, gastrointestinal tract and lungs, differences related to EV cell origin were detected. EVs accumulated in the tumour tissue of tumour-bearing mice and, after introduction of the rabies virus glycoprotein-targeting moiety, they were found more readily in acetylcholine-receptor-rich organs. In addition, the route of administration and the dose of injected EVs influenced the biodistribution pattern. This is the first extensive biodistribution investigation of EVs comparing the impact of several different variables, the results of which have implications for the design and feasibility of therapeutic studies using EVs. [ABSTRACT FROM AUTHOR]

ABSTRACT Alpha-synuclein (α-Syn) aggregates are the main component of Lewy bodies, which are the characteristic pathological feature in Parkinson's disease (PD) brain. Evidence that α-Syn aggregation can be propagated between neurones has led to the suggestion that this mechanism is responsible for the stepwise progression of PD pathology. Decreasing α-Syn expression is predicted to attenuate this process and is thus an attractive approach to delay or halt PD progression. We have used α-Syn small interfering RNA (siRNA) to reduce total and aggregated α-Syn levels in mouse brains. To achieve widespread delivery of siRNAs to the brain we have peripherally injected modified exosomes expressing Ravies virus glycoprotein loaded with siRNA. Normal mice were analyzed 3 or 7 days after injection. To evaluate whether this approach can decrease α-Syn aggregates, we repeated the treatment using transgenic mice expressing the human phosphorylation-mimic S129D α-Syn, which exhibits aggregation. In normal mice we detected significantly reduced α-Syn messenger RNA (mRNA) and protein levels throughout the brain 3 and 7 days after treatment with RVG-exosomes loaded with siRNA to α-Syn. In S129D α-Syn transgenic mice we found a decreased α-Syn mRNA and protein levels throughout the brain 7 days after injection. This resulted in significant reductions in intraneuronal protein aggregates, including in dopaminergic neurones of the substantia nigra. This study highlights the therapeutic potential of RVG-exosome delivery of siRNA to delay and reverse brain α-Syn pathological conditions. © 2014 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]