Entrepreneurial workaround practices in severe institutional voids: Evidence from Kenya

Entrepreneurs in developing economies try to cope with weak or absent formal institutions – often referred to as ‘institutional voids’ – by relying extensively on intermediary organizations such as business incubators and development organizations or informal institutions such as political, kinship, or family relationships. However, in many African countries, intermediary support is limited and informal institutions are also unreliable, adding risks and costs to doing business and increasing the severity of institutional voids in the surrounding ecosystem. We investigate the practices followed by 47 commercial entrepreneurs in Kenya to ‘work around’ these severe institutional voids to achieve their goals of business creation and growth. We find that severe institutional voids stimulate the hybridization of goals to include social value creation, create a need for a more strategic orchestration of business relationships, and motivate entrepreneurs to proactively cross-brace the institutional infrastructure around them. We contribute by unveiling the important role of entrepreneurs as microinstitutional agents in developing economies and by detailing how commercial and social goals become intertwined in the context of African entrepreneurship

Successful scaling in social franchising: The case of Impact Hub

Social entrepreneurs increasingly use franchising to scale social value. Tracey and Jarvis (2007) described how social franchising is similar to commercial franchising, but also noted critical challenges arising from dual social and commercial goals. We investigate a social franchisor that overcame these challenges and describe how the social mission became the source of innovation for its business model. We show that the social mission fostered a shared identity that motivated and guided the search for adaptations to the franchise model. In particular, the shared mission-driven identity created pressure toward (1) decentralized decision-making, (2) shared governance, and (3) a new role for the franchisor as orchestrator of collaborative knowledge sharing among franchisees. Findings should help social franchisors avoid common pitfalls and suggest future research questions for social entrepreneurship and franchising scholars

An Expanded Model of Distributed Leadership in Organizational Knowledge Creation

Based on a three-year qualitative, longitudinal case study of a social venture partnership, we extend the understanding of distributed leadership in organizational knowledge creation. We develop an expanded model of distributed leadership that identifies the antecedents, different forms, and enablers of distributed leadership in knowledge creation. Our findings move beyond a static and monolithic understanding of distributed leadership to illustrate how an expanded model informs the situational leadership framework and spiral of knowledge creation across an organization's hierarchy and boundary in the context of social entrepreneurship

A simple phenotypic method for screening of MCR-1-mediated colistin resistance

Objectives: To evaluate a novel method, the colistin-MAC test, for phenotypic screening of acquired colistin resistance mediated by transferable mcr-1 resistance determinants, based on colistin MIC reduction in the presence of dipicolinic acid (DPA). Methods: The colistin-MAC test consists in a broth microdilution method, in which colistin MIC is tested in the absence or presence of DPA (900 \u3bcg/mL). Overall, 74 colistin-resistant strains of Enterobacteriaceae (65 Escherichia coli and nine other species), including 61 strains carrying mcr-1-like genes and 13 strains negative for mcr genes, were evaluated with the colistin-MAC test. The presence of mcr-1-like and mcr-2-like genes was assessed by real-time PCR and end-point PCR. For 20 strains, whole-genome sequencing data were also available. Results: A 658-fold reduction of colistin MIC in the presence of DPA was observed with 59 mcr-1-positive strains, including 53 E. coli of clinical origin, three E. coli transconjugants carrying MCR-1-encoding plasmids, one Enterobacter cloacae complex and two Citrobacter spp. Colistin MICs were unchanged, increased or at most reduced by twofold with the 13 mcr-negative colistin-resistant strains (nine E. coli and four Klebsiella pneumoniae), but also with two mcr-1-like-positive K. pneumoniae strains. Conclusions: The colistin-MAC test could be a simple phenotypic test for presumptive identification of mcr-1-positive strains among isolates of colistin-resistant E. coli, based on a 658-fold reduction of colistin MIC in the presence of DPA. Evaluation of the test with a larger number of strains, species and mcr-type resistance determinants would be of interest

CXC chemokines exhibit bactericidal activity against multidrug-resistant gram-negative pathogens

The continued rise and spread of antimicrobial resistance among bacterial pathogens pose a serious challenge to global health. Countering antimicrobial-resistant pathogens requires a multifaceted effort that includes the discovery of novel therapeutic approaches. Here, we establish the capacity of the human CXC chemokines CXCL9 and CXCL10 to kill multidrug-resistant Gram-negative bacteria, including New Delhi metallo-beta-lactamase-1-producing Klebsiella pneumoniae and colistin-resistant members of the family Enterobacteriaceae that harbor the mobile colistin resistance protein MCR-1 and thus possess phosphoethanolamine-modified lipid A. Colistin-resistant K. pneumoniae isolates affected by genetic mutation of the PmrA/PmrB two-component system, a chromosomally encoded regulator of lipopolysaccharide modification, and containing 4-amino-4-deoxy-l-arabinose-modified lipid A were also found to be susceptible to chemokine-mediated antimicrobial activity. However, loss of PhoP/PhoQ autoregulatory control, caused by disruption of the gene encoding the negative regulator MgrB, limited the bactericidal effects of CXCL9 and CXCL10 in a variable, strain-specific manner. Cumulatively, these findings provide mechanistic insight into chemokine-mediated antimicrobial activity, highlight disparities amongst determinants of colistin resistance, and suggest that chemokine-mediated bactericidal effects merit additional investigation as a therapeutic avenue for treating infections caused by multidrug-resistant pathogens

CXC chemokines exhibit bactericidal activity against multidrug-resistant gram-negative pathogens

The continued rise and spread of antimicrobial resistance among bacterial pathogens pose a serious challenge to global health. Countering antimicrobial-resistant pathogens requires a multifaceted effort that includes the discovery of novel therapeutic approaches. Here, we establish the capacity of the human CXC chemokines CXCL9 and CXCL10 to kill multidrug-resistant Gram-negative bacteria, including New Delhi metallo-beta-lactamase-1-producing Klebsiella pneumoniae and colistin-resistant members of the family Enterobacteriaceae that harbor the mobile colistin resistance protein MCR-1 and thus possess phosphoethanolamine-modified lipid A. Colistin-resistant K. pneumoniae isolates affected by genetic mutation of the PmrA/PmrB two-component system, a chromosomally encoded regulator of lipopolysaccharide modification, and containing 4-amino-4-deoxy-l-arabinose-modified lipid A were also found to be susceptible to chemokine-mediated antimicrobial activity. However, loss of PhoP/PhoQ autoregulatory control, caused by disruption of the gene encoding the negative regulator MgrB, limited the bactericidal effects of CXCL9 and CXCL10 in a variable, strain-specific manner. Cumulatively, these findings provide mechanistic insight into chemokine-mediated antimicrobial activity, highlight disparities amongst determinants of colistin resistance, and suggest that chemokine-mediated bactericidal effects merit additional investigation as a therapeutic avenue for treating infections caused by multidrug-resistant pathogens

Computer-Aided Imaging Analysis of Probe-Based Confocal Laser Endomicroscopy With Molecular Labeling and Gene Expression Identifies Markers of Response to Biological Therapy in IBD Patients: The Endo-Omics Study

Abstract Background We aimed to predict response to biologics in inflammatory bowel disease (IBD) using computerized image analysis of probe confocal laser endomicroscopy (pCLE) in vivo and assess the binding of fluorescent-labeled biologics ex vivo. Additionally, we investigated genes predictive of anti-tumor necrosis factor (TNF) response. Methods Twenty-nine patients (15 with Crohn’s disease [CD], 14 with ulcerative colitis [UC]) underwent colonoscopy with pCLE before and 12 to 14 weeks after starting anti-TNF or anti-integrin α4β7 therapy. Biopsies were taken for fluorescein isothiocyanate–labeled infliximab and vedolizumab staining and gene expression analysis. Computer-aided quantitative image analysis of pCLE was performed. Differentially expressed genes predictive of response were determined and validated in a public cohort. Results In vivo, vessel tortuosity, crypt morphology, and fluorescein leakage predicted response in UC (area under the receiver-operating characteristic curve [AUROC], 0.93; accuracy 85%, positive predictive value [PPV] 89%; negative predictive value [NPV] 75%) and CD (AUROC, 0.79; accuracy 80%; PPV 75%; NPV 83%) patients. Ex vivo, increased binding of labeled biologic at baseline predicted response in UC (UC) (AUROC, 83%; accuracy 77%; PPV 89%; NPV 50%) but not in Crohn’s disease (AUROC 58%). A total of 325 differentially expressed genes distinguished responders from nonresponders, 86 of which fell within the most enriched pathways. A panel including ACTN1, CXCL6, LAMA4, EMILIN1, CRIP2, CXCL13, and MAPKAPK2 showed good prediction of anti-TNF response (AUROC >0.7). Conclusions Higher mucosal binding of the drug target is associated with response to therapy in UC. In vivo, mucosal and microvascular changes detected by pCLE are associated with response to biologics in inflammatory bowel disease. Anti-TNF–responsive UC patients have a less inflamed and fibrotic state pretreatment. Chemotactic pathways involving CXCL6 or CXCL13 may be novel targets for therapy in nonresponders

The chlorine isotopic composition of the Moon: Insights from melt inclusions

The Moon exhibits a heavier chlorine (Cl) isotopic composition compared to the Earth. Several hypotheses have been put forward to explain this difference, based mostly on analyses of apatite in lunar samples complemented by bulk-rock data. The earliest hypothesis argued for Cl isotope fractionation during the degassing of anhydrous basaltic magmas on the Moon. Subsequently, other hypotheses emerged linking Cl isotope fractionation on the Moon with the degassing during the crystallization of the Lunar Magma Ocean (LMO). Currently, a variant of the LMO degassing model involving mixing between two end-member components, defined by early-formed cumulates, from which mare magmas were subsequently derived, and a KREEP component, which formed towards the end of the LMO crystallization, seems to reconcile some existing Cl isotope data on lunar samples. To further ascertain the history of Cl in the Moon and to investigate any evolution of Cl during magma crystallization and emplacement events, which could help resolve the chlorine isotopic variation between the Earth and the Moon, we analysed the Cl abundance and its isotopic composition in 36 olivine- and pyroxene-hosted melt inclusions (MI) in five Apollo basalts (10020, 12004, 12040, 14072 and 15016). Olivine-hosted MI have an average of 3.3 ± 1.4 ppm Cl. Higher Cl abundances (11.9 ppm on average) are measured for pyroxene-hosted MI, consistent with their formation at later stages in the crystallization of their parental melt compared to olivines. Chlorine isotopic composition (δ37) of MI in the five Apollo basalts have weighted averages of +12 ± 2.4‰ and +10.1 ± 3.2‰ for olivine- and pyroxene-hosted MI, respectively, which are statistically indistinguishable. These isotopic compositions are also similar to those measured in apatite in these lunar basalts, with the exception of sample 14072, which is known to have a distinct petrogenetic history compared to other mare basalts. Based on our dataset, we conclude that, post-MI-entrapment, no significant Cl isotopic fractionation occurred during the crystallization and subsequent eruption of the parent magma and that Cl isotopic composition of MI and apatite primarily reflect the signature of the source region of these lunar basalts. Our findings are compatible with the hypothesis that in the majority of the cases the heavy Cl isotopic signature of the Moon was acquired during the earliest stages of LMO evolution. Interestingly, MI data from 14072 suggests that Apollo 14 lunar basalts might be an exception and may have experienced post-crystallization processes, possibly metasomatism, resulting in additional Cl isotopic fractionation recorded by apatite but not melt inclusions