Social Entrepreneurship and Broader Theories: Shedding New Light on the “Bigger Picture”

This article documents the results of a research workshop bringing together six perspectives on social entrepreneurship. The idea was to challenge existing concepts of the economy, the firm, and entrepreneurship in order to shed new light on social entrepreneurship and on our existing theoretical frameworks. The first two contributions use a macro-perspective and discuss the notion of adaptive societies and the tragedies of disharmonization, respectively. Taking a management perspective, the next two focus on the limits of conventional assumptions in management theory, particularly human capital theory and resource-based view. The final two contributions follow an entrepreneurship perspective highlighting the usefulness of mobilization theory and the business model lens to social entrepreneurship. Despite this diversity, all contributions share the fact that they challenge narrow definitions of the unit of analysis in social entrepreneurship; they illustrate the aspect of social embeddedness, and they argue for an open-but-disciplined diversity of theories in social entrepreneurship research

Current and Past Immunodeficiency Are Associated with Higher Hospitalization Rates among Persons on Virologically Suppressive Antiretroviral Therapy for up to 11 Years

Background: Persons with human immunodeficiency virus (PWH) with persistently low CD4 counts despite efficacious antiretroviral therapy could have higher hospitalization risk. Methods: In 6 US and Canadian clinical cohorts, PWH with virologic suppression for ≥1 year in 2005-2015 were followed until virologic failure, loss to follow-up, death, or study end. Stratified by early (years 2-5) and long-term (years 6-11) suppression and lowest presuppression CD4 count 500 cells/μL had aIRRs of 1.44 during early suppression (95% confidence interval [CI], 1.01-2.06), and 1.67 (95% CI, 1.03-2.72) during long-term suppression. Among patients with lowest presuppression CD4 count ≥200 (56%), patients with current CD4 351-500 vs >500 cells/μL had an aIRR of 1.22 (95% CI,. 93-1.60) during early suppression and 2.09 (95% CI, 1.18-3.70) during long-term suppression. Conclusions: Virologically suppressed patients with lower CD4 counts experienced higher hospitalization rates and could potentially benefit from targeted clinical management strategies

Aggregate breakdown and dispersion of soil samples amended with sugarcane vinasse

Soil aggregation is a very complex issue related to important soil attributes and processes. The aggregate breakdown and dispersion of soil samples amended with sugarcane vinasse were evaluated using ultrasonic energy. Vinasse is an important byproduct of sugarcane industries, intensively applied to soils in Brazil as liquid fertilizer. Samples of two Oxisols and one Ultisol were used in this study. The physical and chemical characterization of soils was performed, and the 1 to 2 mm size aggregates (200 g) were packed in PVC columns (6.0 cm high and 4.0 cm internal diameter) and incubated with sugarcane vinasse under lab conditions for 1, 30 and 60 days. After incubation, aggregates were submitted to levels of ultrasonic energy, and the particle size distribution (53 to 2,000 µm, 2 to 53 µm, and < 2 µm fractions) was quantified. Mathematical equations were used to relate the mass of aggregates in each of these fractions to the applied ultrasonic energy, and parameters related to aggregate stability were then obtained. Soils showed an aggregate-hierarchy resulting in a stepwise breakdown under ultrasonic agitation. Considering this soil-aggregation hierarchy, vinasse contributed even in a short time to the bonding between and within 2 to 53 µm aggregates, mainly in the Oxisols. This may be related to organic compounds present in the vinasse, cementing soil particles. Potassium enrichment of soil samples did not contribute to soil dispersion

The Value of Rare Genetic Variation in the Prediction of Common Obesity in European Ancestry Populations

Polygenic risk scores (PRSs) aggregate the effects of genetic variants across the genome and are used to predict risk of complex diseases, such as obesity. Current PRSs only include common variants (minor allele frequency (MAF) ≥1%), whereas the contribution of rare variants in PRSs to predict disease remains unknown. Here, we examine whether augmenting the standard common variant PRS (PRScommon) with a rare variant PRS (PRSrare) improves prediction of obesity. We used genome-wide genotyped and imputed data on 451,145 European-ancestry participants of the UK Biobank, as well as whole exome sequencing (WES) data on 184,385 participants. We performed single variant analyses (for both common and rare variants) and gene-based analyses (for rare variants) for association with BMI (kg/m2), obesity (BMI ≥ 30 kg/m2), and extreme obesity (BMI ≥ 40 kg/m2). We built PRSscommon and PRSsrare using a range of methods (Clumping+Thresholding [C+T], PRS-CS, lassosum, gene-burden test). We selected the best-performing PRSs and assessed their performance in 36,757 European-ancestry unrelated participants with whole genome sequencing (WGS) data from the Trans-Omics for Precision Medicine (TOPMed) program. The best-performing PRScommon explained 10.1% of variation in BMI, and 18.3% and 22.5% of the susceptibility to obesity and extreme obesity, respectively, whereas the best-performing PRSrare explained 1.49%, and 2.97% and 3.68%, respectively. The PRSrare was associated with an increased risk of obesity and extreme obesity (ORobesity = 1.37 per SDPRS, Pobesity = 1.7x10-85; ORextremeobesity = 1.55 per SDPRS, Pextremeobesity = 3.8x10-40), which was attenuated, after adjusting for PRScommon (ORobesity = 1.08 per SDPRS, Pobesity = 9.8x10-6; ORextremeobesity= 1.09 per SDPRS, Pextremeobesity = 0.02). When PRSrare and PRScommon are combined, the increase in explained variance attributed to PRSrare was small (incremental Nagelkerke R2 = 0.24% for obesity and 0.51% for extreme obesity). Consistently, combining PRSrare to PRScommon provided little improvement to the prediction of obesity (PRSrare AUC = 0.591; PRScommon AUC = 0.708; PRScombined AUC = 0.710). In summary, while rare variants show convincing association with BMI, obesity and extreme obesity, the PRSrare provides limited improvement over PRScommon in the prediction of obesity risk, based on these large populations

Constraints on the cosmic expansion history from GWTC–3

We use 47 gravitational wave sources from the Third LIGO–Virgo–Kamioka Gravitational Wave Detector Gravitational Wave Transient Catalog (GWTC–3) to estimate the Hubble parameter H(z), including its current value, the Hubble constant H0. Each gravitational wave (GW) signal provides the luminosity distance to the source, and we estimate the corresponding redshift using two methods: the redshifted masses and a galaxy catalog. Using the binary black hole (BBH) redshifted masses, we simultaneously infer the source mass distribution and H(z). The source mass distribution displays a peak around 34 M⊙, followed by a drop-off. Assuming this mass scale does not evolve with the redshift results in a H(z) measurement, yielding ${H}_{0}={68}_{-8}^{+12}\,\mathrm{km}\ \,\ {{\rm{s}}}^{-1}\,{\mathrm{Mpc}}^{-1}$ (68% credible interval) when combined with the H0 measurement from GW170817 and its electromagnetic counterpart. This represents an improvement of 17% with respect to the H0 estimate from GWTC–1. The second method associates each GW event with its probable host galaxy in the catalog GLADE+, statistically marginalizing over the redshifts of each event's potential hosts. Assuming a fixed BBH population, we estimate a value of ${H}_{0}={68}_{-6}^{+8}\,\mathrm{km}\ \,\ {{\rm{s}}}^{-1}\,{\mathrm{Mpc}}^{-1}$ with the galaxy catalog method, an improvement of 42% with respect to our GWTC–1 result and 20% with respect to recent H0 studies using GWTC–2 events. However, we show that this result is strongly impacted by assumptions about the BBH source mass distribution; the only event which is not strongly impacted by such assumptions (and is thus informative about H0) is the well-localized event GW190814

Teleost Growth Factor Independence (gfi) Genes Differentially Regulate Successive Waves Of Hematopoiesis

Growth Factor Independence (Gfi) transcription factors play essential roles in hematopoiesis, differentially activating and repressing transcriptional programs required for hematopoietic stem/progenitor cell (HSPC) development and lineage specification. In mammals, Gfi1. a regulates hematopoietic stem cells (HSC), myeloid and lymphoid populations, while its paralog, Gfi1. b, regulates HSC, megakaryocyte and erythroid development. In zebrafish, gfi1. aa is essential for primitive hematopoiesis; however, little is known about the role of gfi1. aa in definitive hematopoiesis or about additional gfi factors in zebrafish. Here, we report the isolation and characterization of an additional hematopoietic gfi factor, gfi1. b. We show that gfi1. aa and gfi1. b are expressed in the primitive and definitive sites of hematopoiesis in zebrafish. Our functional analyses demonstrate that gfi1. aa and gfi1. b have distinct roles in regulating primitive and definitive hematopoietic progenitors, respectively. Loss of gfi1. aa silences markers of early primitive progenitors, scl and gata1. Conversely, loss of gfi1. b silences runx-1, c-myb, ikaros and cd41, indicating that gfi1. b is required for definitive hematopoiesis. We determine the epistatic relationships between the gfi factors and key hematopoietic transcription factors, demonstrating that gfi1. aa and gfi1. b join lmo2, scl, runx-1 and c-myb as critical regulators of teleost HSPC. Our studies establish a comparative paradigm for the regulation of hematopoietic lineages by gfi transcription factors. © 2012 Elsevier Inc.3732431441Amigo, J.D., Yu, M., Troadec, M.-B., Gwynn, B., Cooney, J.D., Lambert, A.J., Chi, N.C., Paw, B.H., Identification of distal cis-regulatory elements at mouse mitoferrin loci using zebrafish transgenesis (2011) Mol. Cell. Biol., 31, pp. 1344-1356Amigo, J.D., Ackermann, G.E., Cope, J.J., Yu, M., Cooney, J.D., Ma, D., Langer, N.B., Paw, B.H., The role and regulation of friend of GATA-1 (FOG-1) during blood development in the zebrafish (2009) Blood, 114, pp. 4654-4663Bolli, N., Payne, E.M., Rhodes, J., Gjini, E., Johnston, A.B., Guo, F., Lee, J.-S., Look, A.T., Cpsf1 is required for definitive HSC survival in zebrafish (2011) Blood, 117, pp. 3996-4007Burns, C.E., Traver, D., Mayhall, E., Shepard, J.L., Zon, L.I., Hematopoietic stem cell fate is established by the Notch-Runx pathway (2005) Genes Dev., 19, pp. 2331-2342Bussmann, J., Bakkers, J., Schulte-Merker, S., Early endocardial morphogenesis requires Scl/Tal1 (2007) PLoS Genet., 3, pp. e140Dan, K., Thrombocytosis in iron deficiency anemia (2005) Intern. Med., 44, pp. 1025-1026Davidson, A.J., Zon, L.I., The 'definitive' (and "primitive") guide to zebrafish hematopoiesis (2004) Oncogene, 23, pp. 7233-7246Dooley, K.A., Davidson, A.J., Zon, L.I., Zebrafish scl functions independently in hematopoietic and endothelial development (2005) Dev. Biol., 277, pp. 522-536Dufourcq, P., Rastegar, S., Strähle, U., Blader, P., Parapineal specific expression of gfi1 in the zebrafish epithalamus (2004) Gene. Expr. Patterns, 4, pp. 53-57Farr, C.J., Saiki, R.K., Erlich, H.A., McCormick, F., Marshall, C.J., Analysis of RAS gene mutations in acute myeloid leukemia by polymerase chain reaction and oligonucleotide probes (1988) Proc. Natl. Acad. Sci. USA, 85, pp. 1629-1633Ganis, J.J., Hsia, N., Trompouki, E., de Jong, J.L.O., Dibiase, A., Lambert, J.S., Jia, Z., Zon, L.I., Zebrafish globin switching occurs in two developmental stages and is controlled by the LCR (2012) Dev. Biol., 366, pp. 185-194Gering, M., Rodaway, A.R., Göttgens, B., Patient, R.K., Green, A.R., The SCL gene specifies haemangioblast development from early mesoderm (1998) EMBO J., 17, pp. 4029-4045Gilks, C.B., Bear, S.E., Grimes, H.L., Tsichlis, P.N., Progression of interleukin-2 (IL-2)-dependent rat T cell lymphoma lines to IL-2-independent growth following activation of a gene (Gfi-1) encoding a novel zinc finger protein (1993) Mol. Cell. Biol., 13, pp. 1759-1768Grimes, H.L., Chan, T.O., Zweidler-Mckay, P.A., Tong, B., Tsichlis, P.N., The Gfi-1 proto-oncoprotein contains a novel transcriptional repressor domain, SNAG, and inhibits G1 arrest induced by interleukin-2 withdrawal (1996) Mol. Cell. Biol., 16, pp. 6263-6272Hock, H., Hamblen, M.J., Rooke, H.M., Schindler, J.W., Saleque, S., Fujiwara, Y., Orkin, S.H., Gfi-1 restricts proliferation and preserves functional integrity of haematopoietic stem cells (2004) Nature, 431, pp. 1002-1007Hock, H., Hamblen, M.J., Rooke, H.M., Traver, D., Bronson, R.T., Cameron, S., Orkin, S.H., Intrinsic requirement for zinc finger transcription factor Gfi-1 in neutrophil differentiation (2003) Immunity, 18, pp. 109-120Hsu, K., Traver, D., Kutok, J.L., Hagen, A., Liu, T.-X., Paw, B.H., Rhodes, J., Look, A.T., The pu.1 promoter drives myeloid gene expression in zebrafish (2004) Blood, 104, pp. 1291-1297Karsunky, H., Zeng, H., Schmidt, T., Zevnik, B., Kluge, R., Schmid, K.W., Dührsen, U., Möröy, T., Inflammatory reactions and severe neutropenia in mice lacking the transcriptional repressor Gfi1 (2002) Nat. Genet., 30, pp. 295-300Khandanpour, C., Sharif-Askari, E., Vassen, L., Gaudreau, M.-C., Zhu, J., Paul, W.E., Okayama, T., Möröy, T., Evidence that growth factor independence 1b regulates dormancy and peripheral blood mobilization of hematopoietic stem cells (2010) Blood, 116, pp. 5149-5161Liao, E.C., Trede, N.S., Ransom, D., Zapata, A., Kieran, M., Zon, L.I., Non-cell autonomous requirement for the bloodless gene in primitive hematopoiesis of zebrafish (2002) Development, 129, pp. 649-659Lieschke, G.J., Oates, A.C., Paw, B.H., Thompson, M.A., Hall, N.E., Ward, A.C., Ho, R.K., Layton, J.E., Zebrafish SPI-1 (PU.1) marks a site of myeloid development independent of primitive erythropoiesis: implications for axial patterning (2002) Dev. Biol., 246, pp. 274-295Lin, H.-F., Traver, D., Zhu, H., Dooley, K., Paw, B.H., Zon, L.I., Handin, R.I., Analysis of thrombocyte development in CD41-GFP transgenic zebrafish (2005) Blood, 106, pp. 3803-3810Liu, F., Walmsley, M., Rodaway, A., Patient, R., Fli1 acts at the top of the transcriptional network driving blood and endothelial development (2008) Curr. Biol., 18, pp. 1234-1240Long, Q., Meng, A., Wang, H., Jessen, J.R., Farrell, M.J., Lin, S., GATA-1 expression pattern can be recapitulated in living transgenic zebrafish using GFP reporter gene (1997) Development, 124, pp. 4105-4111Lyons, S.E., Lawson, N.D., Lei, L., Bennett, P.E., Weinstein, B.M., Liu, P.P., A nonsense mutation in zebrafish gata1 causes the bloodless phenotype in vlad tepes (2002) Proc. Natl. Acad. Sci. USA, 99, pp. 5454-5459Ma, D., Zhang, J., Lin, H.-F., Italiano, J., Handin, R.I., The identification and characterization of zebrafish hematopoietic stem cells (2011) Blood, 118, pp. 289-297Meeker, N.D., Hutchinson, S.A., Ho, L., Trede, N.S., Method for isolation of PCR-ready genomic DNA from zebrafish tissues (2007) BioTechniques, 43, pp. 610-614Nilsson, R., Schultz, I.J., Pierce, E.L., Soltis, K.A., Naranuntarat, A., Ward, D.M., Baughman, J.M., Mootha, V.K., Discovery of genes essential for heme biosynthesis through large-scale gene expression analysis (2009) Cell Metab., 10, pp. 119-130Patterson, L.J., Gering, M., Patient, R., Scl is required for dorsal aorta as well as blood formation in zebrafish embryos (2005) Blood, 105, pp. 3502-3511Patterson, L.J., Gering, M., Eckfeldt, C.E., Green, A.R., Verfaillie, C.M., Ekker, S.C., Patient, R., The transcription factors Scl and Lmo2 act together during development of the hemangioblast in zebrafish (2007) Blood, 109, pp. 2389-2398Paw, B.H., Moskowitz, S.M., Uhrhammer, N., Wright, N., Kaback, M.M., Neufeld, E.F., Juvenile GM2 gangliosidosis caused by substitution of histidine for arginine at position 499 or 504 of the alpha-subunit of beta-hexosaminidase (1990) J. Biol. Chem., 265, pp. 9452-9457Pelster, B., Burggren, W.W., Disruption of hemoglobin oxygen transport does not impact oxygen-dependent physiological processes in developing embryos of zebra fish (Danio rerio) (1996) Circ. Res., 79, pp. 358-362Person, R.E., Li, F.-Q., Duan, Z., Benson, K.F., Wechsler, J., Papadaki, H.A., Eliopoulos, G., Horwitz, M., Mutations in proto-oncogene GFI1 cause human neutropenia and target ELA2 (2003) Nat. Genet., 34, pp. 308-312Postlethwait, J., Woods, I., Ngo-Hazelett, P., Yan, Y., Kelly, P., Chu, F., Huang, H., Talbot, W., Zebrafish comparative genomics and the origins of vertebrate chromosomes (2000) Genome Res., 10, p. 1890Randrianarison-Huetz, V., Laurent, B., Bardet, V., Blobe, G.C., Huetz, F., Duménil, D., Gfi-1B controls human erythroid and megakaryocytic differentiation by regulating TGF-beta signaling at the bipotent erythro-megakaryocytic progenitor stage (2010) Blood, 115, pp. 2784-2795Rhodes, J., Hagen, A., Hsu, K., Deng, M., Liu, T.-X., Look, A.T., Kanki, J.P., Interplay of pu.1 and gata1 determines myelo-erythroid progenitor cell fate in zebrafish (2005) Dev. Cell, 8, pp. 97-108Saleque, S., Cameron, S., Orkin, S.H., The zinc-finger proto-oncogene Gfi-1b is essential for development of the erythroid and megakaryocytic lineages (2002) Genes Dev., 16, pp. 301-306Schmidt, T., Karsunky, H., Gau, E., Zevnik, B., Elsässer, H.P., Möröy, T., Zinc finger protein GFI-1 has low oncogenic potential but cooperates strongly with pim and myc genes in T-cell lymphomagenesis (1998) Oncogene, 17, pp. 2661-2667Schmittgen, T.D., Livak, K.J., Analyzing real-time PCR data by the comparative C(T) method (2008) Nat. Protoc., 3, pp. 1101-1108Shaw, G.C., Cope, J.J., Li, L., Corson, K., Hersey, C., Ackermann, G.E., Gwynn, B., Paw, B.H., Mitoferrin is essential for erythroid iron assimilation (2006) Nature, 440, pp. 96-100Sood, R., English, M.A., Belele, C.L., Jin, H., Bishop, K., Haskins, R., McKinney, M.C., Liu, P.P., Development of multilineage adult hematopoiesis in the zebrafish with a runx1 truncation mutation (2010) Blood, 115, pp. 2806-2809Spooner, C.J., Cheng, J.X., Pujadas, E., Laslo, P., Singh, H., A recurrent network involving the transcription factors PU.1 and Gfi1 orchestrates innate and adaptive immune cell fates (2009) Immunity, 31, pp. 576-586Stainier, D.Y., Weinstein, B.M., Detrich, H.W., Zon, L.I., Fishman, M.C., Cloche, an early acting zebrafish gene, is required by both the endothelial and hematopoietic lineages (1995) Development, 121, pp. 3141-3150Thompson, M.A., Ransom, D.G., Pratt, S.J., MacLennan, H., Kieran, M.W., Detrich, H.W., Vail, B., Zon, L.I., The cloche and spadetail genes differentially affect hematopoiesis and vasculogenesis (1998) Dev. Biol., 197, pp. 248-269van der Meer, L.T., Jansen, J.H., van der Reijden, B.A., Gfi1 and Gfi1b: key regulators of hematopoiesis (2010) Leukemia, 24, pp. 1834-1843Wallis, D., Hamblen, M., Zhou, Y., Venken, K.J.T., Schumacher, A., Grimes, H.L., Zoghbi, H.Y., Bellen, H.J., The zinc finger transcription factor Gfi1, implicated in lymphomagenesis, is required for inner ear hair cell differentiation and survival (2003) Development, 130, pp. 221-232Wei, W., Wen, L., Huang, P., Zhang, Z., Chen, Y., Xiao, A., Huang, H., Lin, S., Gfi1.1 regulates hematopoietic lineage differentiation during zebrafish embryogenesis (2008) Cell Res., 18, pp. 677-685Wilson, N.K., Timms, R.T., Kinston, S.J., Cheng, Y.-H., Oram, S.H., Landry, J.-R., Mullender, J., Gottgens, B., Gfi1 expression is controlled by five distinct regulatory regions spread over 100 kilobases, with Scl/Tal1, Gata2, PU.1, Erg, Meis1, and Runx1 acting as upstream regulators in early hematopoietic cells (2010) Mol. Cell. Biol., 30, pp. 3853-3863Woods, I., Kelly, P., Chu, F., Ngo-Hazelett, P., Yan, Y., Huang, H., Postlethwait, J., Talbot, W., A comparative map of the zebrafish genome (2000) Genome Res., 10, p. 1903Zeng, H., Yücel, R., Kosan, C., Klein-Hitpass, L., Möröy, T., Transcription factor Gfi1 regulates self-renewal and engraftment of hematopoietic stem cells (2004) EMBO J., 23, pp. 4116-412