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A computer-guided design tool to increase the efficiency of cellular conversions.

ABSTRACT: Human cell conversion technology has become an important tool for devising new cell transplantation therapies, generating disease models and testing gene therapies. However, while transcription factor over-expression-based methods have shown great promise in generating cell types in vitro, they often endure low conversion efficiency. In this context, great effort has been devoted to increasing the efficiency of current protocols and the development of computational approaches can be of great help in this endeavor. Here we introduce a computer-guided design tool that combines a computational framework for prioritizing more efficient combinations of instructive factors (IFs) of cellular conversions, called IRENE, with a transposon-based genomic integration system for efficient delivery. Particularly, IRENE relies on a stochastic gene regulatory network model that systematically prioritizes more efficient IFs by maximizing the agreement of the transcriptional and epigenetic landscapes between the converted and target cells. Our predictions substantially increased the efficiency of two established iPSC-differentiation protocols (natural killer cells and melanocytes) and established the first protocol for iPSC-derived mammary epithelial cells with high efficiency.

SUBMITTER: Jung S

PROVIDER: S-EPMC7954801 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The level of adoption of herd management information system veterinary automated management and production control program (VAMPP) Bovine and its impact on productivity of 912 specialized dairy systems with at least 5 years of information recorded was studied. Herds were classified as low (n = 389), medium (n = 343), or high (n = 180) adoption level on the basis of extent and consistency of record keeping for variables related to production, reproduction, and health. For each herd, within-year averages were obtained for six performance traits: age at first calving (AFC), days open (DO), daily milk yield (DMY), productive life (PL), incidence of clinical mastitis (MAST), and incidence of lameness (LAM). These variables were investigated with a generalized linear mixed model that included the fixed effects of the adoption level, follow-up year, and their interaction, adjusted by the fixed effects of herd size, agroecological zone, calendar period, breed group, and the random effects of variation between/within herds. A significant effect of the adoption level over all the variables was observed, except DMY and PL. The follow-up year was significant for all the variables except LAM. There were marked reductions for AFC and DO in the first 4 years of follow-up. AFC was higher and DO shorter in the low compared to medium and high level of adoption herds (p < 0.001). DMY showed a significant increasing trend (p < 0.001), regardless of the adoption level. There was higher MAST and LAM incidence in the higher adoption level (p < 0.05). The economic benefit was estimated through a stochastic simulation model using an approach based in partial budget analysis. For a herd with a medium level of adoption, the change in gross margin (GMMIS $USD) and marginal return rate (MRRMIS %) for the first 5 years of use of the system was estimated. Under these conditions, there was a GMMIS of $6890 and MRRMIS of 163%. Variation of ±10% in DMY and DO caused changes in the GMMIS of ±$1000 and ±$110, respectively, and in MRRMIS ±24% and ±4%, respectively. The trends suggest a positive influence of VAMPP in productive and reproductive traits during the first years of implementation, with less benefit for the low adoption levels.

Project description:BackgroundTuberculosis screening in psoriasis patients is complex due to the immunological alterations associated with psoriasis, the presence of comorbidities, and the effect of immunosuppressive treatment. However, it is not established whether the results of screening tests are affected by these factors in psoriasis patients.ObjectivesTo determine whether there is a change in the results of the tuberculin skin test (TST) or the interferon-gamma release assay (IGRA) in psoriasis patients living in tuberculosis (TB)-endemic area after 12 weeks of methotrexate (MTX) treatment and to investigate the association of the test results with clinical and inflammatory markers.MethodsForty-five patients were selected for a prospective single-arm self-controlled study and followed for at least 18 months. The TST, IGRA, Psoriasis Area and Severity Index (PASI), and inflammatory factors (erythrocyte sedimentation rate (ESR), C-reactive protein, interferon-gamma (IFN-γ), and tumor necrosis factor-alpha levels), were determined before and after 12 weeks of oral 15 mg per week MTX administration and compared. The associations between the IGRA and TST results were verified before and after treatment according to inflammatory factors and clinical characteristics (age, blood glucose, weight, body mass index, disease duration, and PASI).ResultsWe collected data on 25 patients who completed the full course of therapy and the follow-up. None of the patients developed TB. TST positivity was significantly elevated at week 12 (25% baseline vs 44% at week 12, P < 0.037). Three IGRAs followed the TST conversions. There was no difference between TST and IGRA pre- or posttreatment. Serum IFN-γ increased significantly in week 12 (15.95 pg/ml baseline vs 18.82 pg/ml at week 12, P < 0.005) and tended to be higher among TST-positive patients (P = 0.072). The baseline IGRA was associated with a higher ESR (P = 0.038). None of the test results were associated with clinical characteristics.ConclusionsIn addition to the classic booster effect, TST conversions in patients using MTX can occur due to an increase in IFN-γ. However, it is not possible to exclude true TST conversions. Therefore, other diagnostic methods, like IGRA or chest tomography, should be used when the TST has intermediate results.

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A computer-guided design tool to increase the efficiency of cellular conversions.

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