Shifts in the philosophy of the "state" and a growing emphasis on the "Big Society" have placed an increasing onus on a newly emerging organizational form, social enterprises, to deliver innovative ...solutions to ease societal issues. However, the question of how social enterprises manage the process of social innovation remains largely unexplored. Based on insights from both in-depth interviews and a quantitative empirical study of social enterprises, this research examines the role of stakeholder relationships in supporting the process of social innovation within social enterprises. We find that social enterprises are adept at working with their stakeholders in the ideation stage of social innovation. In contrast, they often fail to harness knowledge and expertise from their partners during the social innovation implementation phase. Consequently, we propose a social innovationstakeholder relationship matrix that provides social enterprises in particular with insight for developing stakeholder relationships to achieve their social innovation missions.
The ubiquitin-like protein ubiquilin 2 (UBQLN2) has been genetically and pathologically linked to the neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), ...but its normal cellular functions are not well understood. In a search for UBQLN2-interacting proteins, we found an enrichment of stress granule (SG) components, including ALS/FTD-linked heterogeneous ribonucleoprotein fused in sarcoma (FUS). Through the use of an optimized SG detection method, we observed UBQLN2 and its interactors at SGs. A low complexity, Sti1-like repeat region in UBQLN2 was sufficient for its localization to SGs. Functionally, UBQLN2 negatively regulated SG formation. UBQLN2 increased the dynamics of FUS–RNA interaction and promoted the fluidity of FUS–RNA complexes at a single-molecule level. This solubilizing effect corresponded to a dispersal of FUS liquid droplets in vitro and a suppression of FUS SG formation in cells. ALS-linked mutations in UBQLN2 reduced its association with FUS and impaired its function in regulating FUS–RNA complex dynamics and SG formation. These results reveal a previously unrecognized role for UBQLN2 in regulating the early stages of liquid–liquid phase separation by directly modulating the fluidity of protein–RNA complexes and the dynamics of SG formation.
Introduction
Treatment options for carbapenem-resistant Enterobacteriaceae (CRE) infections are limited and CRE infections remain associated with high clinical failure and mortality rates, ...particularly in vulnerable patient populations. A Phase 3, multinational, open-label, randomized controlled trial (TANGO II) was conducted from 2014 to 2017 to evaluate the efficacy/safety of meropenem–vaborbactam monotherapy versus best available therapy (BAT) for CRE.
Methods
A total of 77 patients with confirmed/suspected CRE infection (bacteremia, hospital-acquired/ventilator-associated bacterial pneumonia, complicated intra-abdominal infection, complicated urinary tract infection/acute pyelonephritis) were randomized, and 47 with confirmed CRE infection formed the primary analysis population (microbiologic-CRE-modified intent-to-treat, mCRE-MITT). Eligible patients were randomized 2:1 to meropenem–vaborbactam (2 g/2 g over 3 h, q8h for 7–14 days) or BAT (mono/combination therapy with polymyxins, carbapenems, aminoglycosides, tigecycline; or ceftazidime-avibactam alone). Efficacy endpoints included clinical cure, Day-28 all-cause mortality, microbiologic cure, and overall success (clinical cure + microbiologic eradication). Safety endpoints included adverse events (AEs) and laboratory findings.
Results
Within the mCRE-MITT population, cure rates were 65.6% (21/32) and 33.3% (5/15) 95% confidence interval (CI) of difference, 3.3% to 61.3%;
P
= 0.03) at End of Treatment and 59.4% (19/32) and 26.7% (4/15) (95% CI of difference, 4.6% to 60.8%;
P
= 0.02) at Test of Cure;.Day-28 all-cause mortality was 15.6% (5/32) and 33.3% (5/15) (95% CI of difference, − 44.7% to 9.3%) for meropenem–vaborbactam versus BAT, respectively. Treatment-related AEs and renal-related AEs were 24.0% (12/50) and 4.0% (2/50) for meropenem–vaborbactam versus 44.0% (11/25) and 24.0% (6/25) for BAT. Exploratory risk–benefit analyses of composite clinical failure or nephrotoxicity favored meropenem–vaborbactam versus BAT (31.3% 10/32 versus 80.0% 12/15; 95% CI of difference, − 74.6% to − 22.9%;
P
< 0.001).
Conclusions
Monotherapy with meropenem–vaborbactam for CRE infection was associated with increased clinical cure, decreased mortality, and reduced nephrotoxicity compared with BAT.
Clinical Trials Registration
NCT02168946.
Funding
The Medicines Company.
Global regulators that bind strategic metabolites allow bacteria to adapt rapidly to dynamic environments by coordinating the expression of many genes. We report an approach for determining gene ...regulation hierarchy using the regulon of the Bacillus subtilis global regulatory protein CodY as proof of principle. In theory, this approach can be used to measure the dynamics of any bacterial transcriptional regulatory network that is affected by interaction with a ligand. In B. subtilis , CodY controls dozens of genes, but the threshold activities of CodY required to regulate each gene are unknown. We hypothesized that targets of CodY are differentially regulated based on varying affinity for the protein’s many binding sites. We used RNA sequencing to determine the transcription profiles of B. subtilis strains expressing mutant CodY proteins with different levels of residual activity. In parallel, we quantified intracellular metabolites connected to central metabolism. Strains producing CodY variants F71Y, R61K, and R61H retained varying degrees of partial activity relative to the WT protein, leading to gene-specific, differential alterations in transcript abundance for the 223 identified members of the CodY regulon. Using liquid chromatography coupled to MS, we detected significant increases in branched-chain amino acids and intermediates of arginine, proline, and glutamate metabolism, as well as decreases in pyruvate and glycerate as CodY activity decreased. We conclude that a spectrum of CodY activities leads to programmed regulation of gene expression and an apparent rerouting of carbon and nitrogen metabolism, suggesting that during changes in nutrient availability, CodY prioritizes the expression of specific pathways.
We performed this study 1) to determine the prevalence of community-associated extended spectrum beta-lactamase producing Enterobacteriaceae (ESBLPE) colonization and infection in New York City ...(NYC); 2) to determine the prevalence of newly-acquired ESBLPE during travel; 3) to look for similarities in contemporaneous hospital-associated bloodstream ESBLPE and travel-associated ESBLPE.
Subjects were recruited from a travel medicine practice and consented to submit pre- and post-travel stools, which were assessed for the presence of ESBLPE. Pre-travel stools and stools submitted for culture were used to estimate the prevalence of community-associated ESBLPE. The prevalence of ESBLPE-associated urinary tract infections was calculated from available retrospective data. Hospital-associated ESBLPE were acquired from saved bloodstream isolates. All ESBLPE underwent multilocus sequence typing (MLST) and ESBL characterization.
One of 60 (1.7%) pre- or non-travel associated stool was colonized with ESBLPE. Among community-associated urine specimens, 1.3% of Escherichia coli and 1.4% of Klebsiella pneumoniae were identified as ESBLPE. Seven of 28 travelers (25.0%) acquired a new ESBLPE during travel. No similarities were found between travel-associated ESBLPE and hospital-associated ESBLPE. A range of imported ESBL genes were found, including CTX-M-14 and CTX-15.
ESBL colonization and infection were relatively low during the study period in NYC. A significant minority of travelers acquired new ESBLPE during travel.
Biofilm formation by Candida albicans poses an important therapeutic challenge in human diseases. Typically, conventional antifungal agents encounter difficulty in treating and fully eradicating ...biofilm-related infections. Novel therapeutic approaches are needed to treat recalcitrant Candida biofilms. Farnesol is a quorum-sensing molecule, which induces apoptosis, inhibits Ras protein pathways and profoundly affects the morphogenesis of C. albicans. We therefore investigated the interactions between farnesol and different classes of antifungal agents.
The combined antifungal effects of triazoles (fluconazole), polyenes (amphotericin B) and echinocandins (micafungin) with farnesol against C. albicans biofilms were assessed in vitro. Antifungal activity was determined by the XTT metabolic assay and confocal microscopy. The nature and the intensity of the interactions were assessed using the Loewe additivity model fractional inhibitory concentration (FIC) index and the Bliss independence (BI) model.
Significant synergy was found between each of the three antifungal agents and farnesol, while antagonism was not observed for any of the combinations tested. The greatest synergistic effect was found with the farnesol/micafungin combination, for which the BI-based model showed the observed effects as being 39%-52% higher than expected if the drugs had been acting independently. The FIC indices ranged from 0.49 to 0.79, indicating synergism for farnesol/micafungin and farnesol/fluconazole and no interaction for farnesol/amphotericin B. Structural changes in the biofilm correlated well with the efficacies of these combinations. The maximum combined effect was dependent on the farnesol concentration for micafungin and amphotericin B.
Farnesol exerts a synergistic or additive interaction with micafungin, fluconazole and amphotericin B against C. albicans biofilms, thus warranting further in vivo study.
Intermediate (VISA-type) vancomycin resistance in Staphylococcus aureus has been associated with a range of physiologic and genetic alterations. Previous work described the emergence of VISA-type ...resistance in two clonally-distinct series of isolates. In both series (the first belonging to MRSA clone ST8-USA300, and the second to ST5-USA100), resistance was conferred by a single mutation in yvqF (a negative regulator of the vraSR two-component system associated with vancomycin resistance). In the USA300 series, resistance was reversed by a secondary mutation in vraSR. In this study, we combined systems-level metabolomic profiling with statistical modeling techniques to discover specific, reversible metabolic alterations associated with the VISA phenotype.
Conceptualizing standard-setting organizations (SSOs) as technological arenas within which firms from different countries interact and learn, we offer insights into the interplay between firms’ ...institutional logics and their interorganizational learning outcomes. We suggest that firms’ interorganizational learning is embedded in their macrolevel country contexts, characterized by more corporatist versus less corporatist (pluralist) institutional logics. Whereas corporatism spurs coordinated approaches, pluralism engenders competitive interactions that affect the extent to which firms span organizational and technological boundaries and learn from each other. We test our theory using longitudinal analysis of 181 dyads involving 26 firms participating in 17 SSOs in the global mobile handset industry. We find that interorganizational learning, as measured by patent citations, involving corporatist firm dyads significantly increases when the dominant logic within the arena is also corporatist. By making cooperative schemas more accessible, a dominant corporatist logic also enhances interorganizational learning across technologically distant dyads. When a pluralist logic dominates the arena, corporatist dyads learn less because firms in the dyad activate a contradictory logic that decouples them from their natural processes for interorganizational learning. These findings highlight the implications of institutional logics for interorganizational learning outcomes and provide insights into how firms attend to institutional contradictions in arenas that provide opportunities for interorganizational learning.
Adopting an institutional lens, this paper examines the interaction between different levels of legal, normative and cultural-cognitive institutions on the level of innovation associated with the ...choice of alliance governance mechanism as equity or contractual. Using patent data, this paper undertakes multilevel modelling of 314 technology alliance portfolios located in Europe, North America and the Asia-Pacific region. Key findings indicate normative and cultural-cognitive institutions do affect the performance outcomes of alliances. Equity alliances provide supporting mechanisms that quell fears about organizational risk in alliances under conditions of uncertainty avoidance as the dominant cultural-cognitive frame, and hence contribute to better innovation performance. Contractual alliances are associated with higher levels of innovation under normative contexts that value collectivism rather than individualism. Contrary to expectation, the results do not support the literature of a fit between equity alliances and weak intellectual property rights protection on innovation. However, the presence of highly formalized legal processes for enforcing contracts is associated with higher levels of innovation from alliances.
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