Attributes of legitimate venture failure impressions

The current research investigates the effectiveness of impression management strategies available to entrepreneurs to foster social legitimacy with stakeholders following venture failure. We use a conjoint experiment to examine how different attributions of causes of failure influence the general public's legitimacy judgments. The most effective strategy proves to be the entrepreneurs distancing themselves from the failure, in that they attribute the failure to external factors that are not under the entrepreneurs' volitional control, and brought about by circumstances that are unlikely to reoccur. Our analysis also considers how the audience members' dispositional agreeableness and general self-efficacy influence judgment formation

Systemic Inflammation in Preclinical Ulcerative Colitis

Background & Aims: Preclinical ulcerative colitis is poorly defined. We aimed to characterize the preclinical systemic inflammation in ulcerative colitis, using a comprehensive set of proteins. Methods: We obtained plasma samples biobanked from individuals who developed ulcerative colitis later in life (n = 72) and matched healthy controls (n = 140) within a population-based screening cohort. We measured 92 proteins related to inflammation using a proximity extension assay. The biologic relevance of these findings was validated in an inception cohort of patients with ulcerative colitis (n = 101) and healthy controls (n = 50). To examine the influence of genetic and environmental factors on these markers, a cohort of healthy twin siblings of patients with ulcerative colitis (n = 41) and matched healthy controls (n = 37) were explored. Results: Six proteins (MMP10, CXCL9, CCL11, SLAMF1, CXCL11 and MCP-1) were up-regulated (P < .05) in preclinical ulcerative colitis compared with controls based on both univariate and multivariable models. Ingenuity Pathway Analyses identified several potential key regulators, including interleukin-1ß, tumor necrosis factor, interferon-gamma, oncostatin M, nuclear factor-¿B, interleukin-6, and interleukin-4. For validation, we built a multivariable model to predict disease in the inception cohort. The model discriminated treatment-naïve patients with ulcerative colitis from controls with leave-one-out cross-validation (area under the curve = 0.92). Consistently, MMP10, CXCL9, CXCL11, and MCP-1, but not CCL11 and SLAMF1, were significantly up-regulated among the healthy twin siblings, even though their relative abundances seemed higher in incident ulcerative colitis. Conclusions: A set of inflammatory proteins are up-regulated several years before a diagnosis of ulcerative colitis. These proteins were highly predictive of an ulcerative colitis diagnosis, and some seemed to be up-regulated already at exposure to genetic and environmental risk factors. © 2021 The Author

Truncal Adiposity is Present at Birth and in Early Childhood in South Indian Children

Objectives: muscle-thin but adipose (‘thin-fat’) body composition of south Asian adults contributes to their high risk of type 2 diabetes. Studies in Pune, India showed that this phenotype is present at birth. We aimed to determine if south Indian babies have a ‘thin-fat’ phenotype and if this persists in childhood. Design: prospective cohort study. Setting: Holdsworth Memorial Hospital, Mysore, India Subjects: children (n = 663) whose mothers were recruited from the antenatal clinics. Methods: weight, length, head, mid-upper-arm, abdominal circumferences; triceps and subscapular skinfolds were measured at birth, one and four years, and compared with white Caucasian babies born in Southampton, UK (birth), and UK and Dutch growth standards (one and four years). Results: Mysore babies were lighter (2983g vs 3472 g; –1.10 SD, CI –1.16, –1.02) and smaller in all body measurements than UK neonates (P&lt;0.001). The deficit was greatest for mid-upper- arm (–1.07 SD), head (-0.89 SD) and abdominal circumferences (–0.73 SD), and least for length (–0.25 SD) and subscapular skinfold thickness (–0.19 SD). Predictors of skinfold thickness were maternal body mass index (P&lt;0.001) and socio-economic status (P = 0.05). At four years, subscapular skinfold thickness was larger than UK (+0.18 SD, CI +0.11, +0.25; P&lt;0.001) and Dutch standards (+0.61 SD, CI +0.51, +0.71; P&lt;0.001), despite all other body measurements remaining smaller. Predictors of 4-year skinfold thickness were neonatal skinfold thickness (P = 0.001) and maternal insulin concentrations (P = 0.05). Conclusions: Mysore newborns have a ‘thin-fat’ phenotype. This may reflect the action of genes and/or the ‘maternal environment’. The phenotype persists in childhood, and may be the forerunner of a diabetogenic adult phenotype

Utilising patient-specific retinal organoids to investigate the role of SNRNP200 variants of unknown significance in severe early onset retinitis pigmentosa

Purpose : The consequence of variants in many genes implicated in retinitis pigmentosa (RP) remain unknown. This applies to SNRNP200, which encodes for a component of the spliceosome complex. To investigate the effect of SNRNP200 variants on the human retina, we generated retinal organoids (ROs) from a patient with severe early-onset RP found to harbour compound heterozygous missense variants in SNRNP200 that segregated with the disease. Methods : Computer-assisted pathogenicity programs and other tools were used to predict the pathogenicity of candidate variants detected by a 537-gene next-generation sequencing panel (MVL, Oregon, US). Induced pluripotent stem cells (iPSCs) derived from patient and control dermal fibroblasts were differentiated into ROs and maintained for up to 350 days. Western Blotting and immunohistochemical (IHC) analysis was performed using antibodies directed against SNRNP200 and retinal-specific proteins. Gene expression was analysed by qRT-PCR and retinal ultrastructure examined by transmission electron microscopy. Single cell sorting of control and patient iPSCs and ROs was performed to capture individual cells which were then subjected to RNA-Seq and bioinformatic analysis. Results : A patient-specific in vitro model of RP was generated. The emergence of retinal-specific phenotypes in ROs was confirmed by IHC and qRT-PCR. Several morphological differences in patient ROs were identified including (1) reduced neuroepithelial integrity, (2) a high number of vacuole-like inclusions within photoreceptor soma, and (3) abnormal mitochondrial morphology at later stages of differentiation. Single cell transcriptomic analysis revealed significantly significant differential gene expression between control and patient cells. Notably, multiple genes associated with immunologic signatures were upregulated, and genes associated with cell coenzyme biosynthesis, an important process for normal vision, were differentially expressed. Conclusions : Using a human RO-based model of RP we have identified patient-specific differences in gene, protein and transcriptomic expression, neuroepithelial integrity, photoreceptor morphology and ultrastructure. These data show the potential of using ROs to assess functional consequences in patients affected by variants of unknown significance

Mitochondrial efficiency in rat skeletal muscle: influence of respiration rate, substrate and muscle type.

Aim: To investigate the hypothesis that mitochondrial efficiency (i.e. P/O ratio) is higher in type I than in type II fibres during submaximal rates of respiration. Methods: Mitochondria were isolated from rat soleus and extensor digitorum longus (EDL) muscles, representing type I and type II fibres, respectively. Mitochondrial efficiency (P/O ratio) was determined with pyruvate (Pyr) or palmitoyl-L-carnitine (PC) during submaximal (constant rate of ADP infusion) and maximal (Vmax, state 3) rates of respiration and fitted to monoexponential functions. Results: There was no difference in Vmax between PC and Pyr in soleus but in EDL Vmax with PC was only 58% of that with Pyr. The activity of 3-hydroxyacyl-CoA dehydrogenase (HAD) was 3-fold higher in soleus than in EDL. P/O ratio at Vmax was 8-9% lower with PC (2.33±0.02 (soleus) and 2.30±0.02 (EDL)) than with Pyr (2.52±0.03 (soleus) and 2.54±0.03 (EDL)) but not different between the two muscles (P&gt;0.05). P/O ratio was low at low rates of respiration and increased exponentially when the rate of respiration increased. The asymptotes of the curves were similar to P/O ratio at Vmax. P/O ratio at submaximal respirations was not different between soleus and EDL neither with Pyr nor with PC. Conclusion: Mitochondrial efficiency, as determined in vitro, was not significantly different in the two fibre types neither at Vmax nor at submaximal rates of respiration. The low Vmax for PC oxidation in EDL may relate to low activity of β-oxidation.The definitive version is available at www.blackwell-synergy.co