Miracle-dz/UniFAR-FTUs huggingface dataset:
Design thinking and process transformation: synergy of these approaches

The new digitalization trend is a global transition to the study of customer experience. Modern conditions require the unification of the theory of business process management and the tasks facing the business. The author emphasizes that today it is necessary to manage personnel taking into account a competently built employee path in the company “Employee Experience”. The work environment and human-centered business processes create a good psychological climate, which determines how the employee will be able to solve tasks, get business results, manifest and be focused on developing their talents. Transformation and continuous improvement should change the culture of the organization, create partnerships between management and staff to ensure the success of the changes. An approach to process transformation is presented. The stages of the process transformation are presented and described in detail, where the end of the transformation is the beginning of a cycle of continuous improvement of business processes that have undergone changes. The authors emphasize that Design Thinking techniques can be used to develop and reengineer not only products (in the usual sense, as a product or service), but also in principle technology of activity as such (processes). The authors showed how CJM, HWM, CurrentFuture-Barriers, etc. can be included in the reengineering process. The presented examples of the use of Design Thinking techniques for the design of business processes can be detailed after clarifying the specifics of a particular project, supplemented by other Design Thinking techniques.
Étude du transcriptome des cellules non tumorales de l’épithélium de surface de l’ovaire des femmes porteuses d’une mutation des gènes BRCA1 et BRCA2

We analyzed the transcriptome of nine primary cultures of non-tumor ovarian surface epithelium cells (NOSE) from four non-carriers, two BRCA1 and three BRCA2 carriers, and four primary cultures of tumor ovarian cells (TOV) from three BRCA1 and one BRCA2 carriers. We identified the first molecular signatures associated with the presence of BRCA1 and BRCA2 mutations in NOSEs and the first molecular signature associated with the transformation from NOSEs to TOVs in French Canadian women carriers of BRCA1 mutation. Moreover, we localized some co-regulated chromosomal domains associated with the presence of a BRCA1 mutation in NOSE cells. Wild-type and mutated BRCA2 allelic transcripts were expressed in tumor cells from 8765delAG BRCA2 mutation carriers, with the highest level of BRCA2 transcript expression and the highest contribution of the mutated allele in cells originating from the most aggressive ovarian tumors. The observed phenotype in BRCA2-mutated cells as well as the aggressiveness of the tumor could result from a dosage effect of the BRCA2 mutated allele.
Differential cellular responses to adhesive interactions with galectin-8 and fibronectin coated substrates

The mechanisms underlying the cellular response to extracellular matrices (ECM), consisting of multiple adhesive ligands, each with distinct properties, are still poorly understood. Here we address this topic by monitoring the cellular responses to two very different extracellular adhesion molecules – fibronectin and galectin-8 – and to mixtures of the two. Fibronectin is one of the major integrin ligands, inducing cell spreading and development of focal adhesions associated with contractile stress fibers. Galectin-8 is a mammalian lectin, which specifically binds to β-galactoside residues present on some integrins, as well as to other cell surface receptors. We found marked differences in HeLa-JW cell spreading, assembly of focal adhesions and actomyosin stress fibers, and formation of adherent filopodia, on rigid flat substrates functionalized by fibronectin or galectin-8 alone, or by mixtures of these two proteins. Spreading on galectin-8 resulted in a larger projected cell area compared to that on fibronectin, by more extensive formation of filopodia, coupled with an inability to activate focal adhesion and stress fiber assembly. These differences could be partially reversed by experimental manipulations of small G-proteins of the Rho family and their downstream targets, such as formins, the Arp2/3 complex, and Rho kinase. Another factor affecting the spreading process was shown to be the enhanced physical adhesion of the cells to galectin-8, as compared to fibronectin. Notably, at least one process, the formation of adherent filopodia, was synergistically upregulated by both ligands, so filopodia development on the substrate coated with a mixture of fibronectin and galectin-8 was far more prominent than on each ligand alone.
Definition of a Small Core Transcriptional Circuit Regulated by AML1-ETO

Transcription factors regulate gene networks controlling normal hematopoiesis and are frequently deregulated in acute myeloid leukemia (AML). Critical to our understanding of the mechanism of cellular transformation by oncogenic transcription factors is the ability to define their direct gene targets. While this seems to be a straight forward task, gene network cascades can change within minutes to hours, making it difficult to distinguish direct from secondary or compensatory transcriptional changes by traditional methodologies. We describe an approach utilizing CRISPR-based genome editing to insert a degron tag into the endogenous AML1-ETO locus of Kasumi-1 cells, as well as overexpression of a degradable AML1-ETO protein in CD34+ human cord blood cells, which is a an AML1-ETO-dependent pre-leukemia model. Upon addition of a small molecule proteolysis targeting chimera (PROTAC), the AML1-ETO protein was rapidly degraded in both systems. Furthermore, by combining rapid degradation with nascent transcript analysis (PRO-seq), RNA-seq and Cut&Run, we have defined the core AML1-ETO regulatory network, which consists of fewer than 100 direct gene targets. The ability of AML1-ETO to regulate this relatively small gene pool is critical for maintaining cells in a self-renewing state, and AML1-ETO degradation set off a cascade of transcriptional events resulting in myeloid differentiation.
Ritmos circadianos e preferência pela busca de alimento de larvas de Pseudoplusia includens (Walker, 1857) (Lepidoptera: Noctuidae)

An understanding of behavior patterns that are fundamental to the biology of pest insects is a requisite for implementation of control strategies. This study aims to evaluate the circadian rhythms of Pseudoplusia includens larvae in four different natural diets. The study was conducted in laboratory for 48 hours hourly. The experimental design was randomized with four treatments (leaf discs) and ten reaplications with free choice. The treatments were: leaves of Rumex obtusifolius, Trifolium repens, Plantago lanceolata and Malus domestica. The caterpillars visited more leaves of T. repens and R. obtusifolius than the leaves of M. domestica and P. lanceolata. The searching activity lasted for the 48 hours of the observation during the 24 hours and the increase in the searching activity occurred between 16 to 21 hours.
Dissecting Autism Genetic Risk Using Single-cell RNA-seq Data

Autism spectrum disorder (autism) is a condition with strong but heterogenous genetic contribution. Recent exome and genome sequencing studies have uncovered many new risk genes through de novo variants. However, a large fraction of enrichment of de novo variants observed in cases are not accounted for by known or candidate risk genes, suggesting that the majority of risk genes are still unknown. Here we hypothesize that autism risk genes share a few common cell-type specific gene expression patterns during brain development, and such information can be quantified to improve statistical power of detecting new risk genes. We obtained large-scale single-cell RNA-seq data from human fetal brain collected through a range of developmental stages, and developed a supervised machine-learning approach “A-risk” (Autism risk), to predict the plausibility of autism risk genes across the genome. Using data from recent exome sequencing studies of autism, A-risk achieves better performance in prioritizing de novo variants than other methods, especially for genes that are less intolerant of loss of function variants. We stratified genes based on A-risk and mutation intolerance metrics to improve estimation of priors in extTADA and identified 71 candidate risk genes. In particular, CLCN4, PRKAR1B, and NR2F1 are potentially new risk genes with further support from neurodevelopmental disorders. Expression patterns of both known and candidate risk genes reveals the important role of deep-layer excitatory neurons from adult human cortex in autism etiology. With the unprecedented revolution of single-cell transcriptomics and expanding autism cohorts with exome or genome sequencing, our method will facilitate systematic discovery of novel risk genes and understanding of biological pathogenesis in autism.
A note on Valeriana jatamansi Jones (Caprifoliaceae s.l.)

The tangled arguments around the names of jatamansi drug plants are examined and the correct synonymies and typifications for Nardostachys jatamansi (D.Don) DC. and V. jatamansi Jones (both Caprifoliaceae s.l.) are provided. The conservation status of the former, and the need for further work on the subject, is briefly discussed.
Requirement of Irf6 and Esrp1/2 in frontonasal and palatal epithelium to regulate craniofacial and palate morphogenesis in mouse and zebrafish

Orofacial clefts are among the most common human congenital malformations. Irf6 and Esrp1 are two key genes important for palate development, conserved across vertebrates. In the zebrafish, we found that irf6 regulates the expression of esrp1. Using RNAscope, we detailed overlapping Irf6 and Esrp1/2 gene expression in the mouse frontonasal prominence ectoderm, lambda joint periderm, palate and lip epithelium. In the zebrafish, irf6 and esrp1/2 share expression in the pre-gastrulation periderm and the embryonic frontonasal ectoderm, oral epithelium ventral to the anterior neurocranium (ANC), and the developing stomodeum. Genetic disruption of irf6 and esrp1/2 in the zebrafish resulted in cleft of the ANC. In the esrp1/2 zebrafish mutant, cleft of the mouth opening formed and appeared to tether into the ANC cleft. Lineage tracing of the anterior cranial neural crest cells revealed that cleft of the ANC resulted not from migration defect, but from impaired chondrogenesis. Molecular analysis of the aberrant cells localized within the ANC cleft revealed that this cell population espresses sox10, col1a1 and irf6 and is adjacent to cells expressing epithelial krt4. Detailed morphogenetic analysis of mouse Irf6 mutant revealed mesenchymal defects not observed in the Esrp1/2 mutant. Analysis of breeding compound Irf6;Esrp1;Esrp2 mutant suggests that these genes interact where the triple mutant is not observed. Taken together, these studies highlight the complementary analysis of Irf6 and Esrp1/2 in mouse and zebrafish models and captured an unique aberrant embryonic cell population that contributes to cleft pathogenesis. Future work characterizing this unqiue sox10+, col1a1+, irf6+ cell population will yield additional insight into cleft pathogenesis.
Synthetic data generation with probabilistic Bayesian Networks

Bayesian Network (BN) modeling is a prominent and increasingly popular computational systems biology method. It aims to construct probabilistic networks from the large heterogeneous biological datasets that reflect the underlying networks of biological relationships. Currently, a variety of strategies exist for evaluating BN methodology performance, ranging from utilizing artificial benchmark datasets and models, to specialized biological benchmark datasets, to simulation studies that generate synthetic data from predefined network models. The latter is arguably the most comprehensive approach; however, existing implementations are typically limited by their reliance on the SEM (structural equation modeling) framework, which includes many explicit and implicit assumptions that may be unrealistic in a typical biological data analysis scenario. In this study, we develop an alternative, purely probabilistic, simulation framework that more appropriately fits with real biological data and biological network models. In conjunction, we also expand on our current understanding of the theoretical notions of causality and dependence / conditional independence in BNs and the Markov Blankets within.
Surprising amount of stasis in repetitive genome content across the Brassicales

Genome size of plants has long piqued the interest of researchers due to the vast differences among organisms. However, the mechanisms that drive size differences have yet to be fully understood. Two important contributing factors to genome size are expansions of repetitive elements, such as transposable elements (TEs), and whole-genome duplications (WGD). Although studies have found correlations between genome size and both TE abundance and polyploidy, these studies typically test for these patterns within a genus or species. The plant order Brassicales provides an excellent system to test if genome size evolution patterns are consistent across larger time scales, as there are numerous WGDs. This order is also home to one of the smallest plant genomes, Arabidopsis thaliana - chosen as the model plant system for this reason - as well as to species with very large genomes. With new methods that allow for TE characterization from low-coverage genome shotgun data and 71 taxa across the Brassicales, we find no correlation between genome size and TE content, and more surprisingly we identify no significant changes to TE landscape following WGD.
Immune Selection Pressure Contributes to Pancreatic Cancer Immune Evasion

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer death in the United States. Pancreatic tumors are minimally infiltrated by T cells and are largely refractory to immunotherapy. Accordingly, the role of T cell immunity in pancreatic cancer has been somewhat overlooked. Here, we hypothesized that immune evasion in pancreatic cancer is induced in response to T cell-based immune selection pressure, and that understanding how pancreatic tumors respond to immune attack may facilitate the development of more effective therapeutic strategies. We now provide the first evidence that T cell-dependent host immune responses induce a PDAC-derived myeloid mimicry phenomenon and stimulate immune evasion. mT3-2D cells derived from a Kras+/LSL-G12D; Trp53+/LSL-R172H; Pdx1-Cre (KPC) mouse model of pancreatic cancer were grown in immunocompetent and immunodeficient C57BL/6 mice, and analyzed to determine the impacts of adaptive immunity specifically on malignant epithelial cells as well as on whole tumors. We found that immune selection pressure, via signal transducer and activator of transcription 1 (STAT1), stimulates malignant epithelial pancreatic cells to induce the expression of genes typically expressed by myeloid cells and alters intratumoral immunosuppressive myeloid cell profiles. Targeting the Janus Kinase (JAK)/STAT signaling pathway using the FDA approved drug, ruxolitinib, overcomes these tumor-protective responses and improves anti-PD1 antibody therapeutic efficacy. These findings provide future directions for treatments that specifically disable this mechanism of resistance in PDAC.
Mast cells participate in the development of diastolic dysfunction in diabetic obese mice

Rational Heart failure with preserved ejection fraction (HFpEF) is a growing epidemiologic issue. However, to date, its pathophysiology remains poorly understood. Objective Our goal was to investigate the role of microvessel disease in the pathophysiology of diastolic dysfunction. Findings To do so, we used Leptin receptor deficient (Leprdb/db) female mice as a model of diastolic dysfunction. In these mice, the increased end diastolic pressure (EDP) signing diastolic dysfunction is associated with vascular leakage, endothelial cell activation and leucocyte infiltration. Strikingly, a RNA sequencing analysis of the cardiac vascular fraction of both Leprdb/db and control female mice confirmed endothelial dysfunction and systemic inflammation but also revealed a strong increase in several mast cell markers (notably FceR1a, Tryptase and Chymase). We then histologically confirmed an accumulation of activated mast cells in the heart of Leprdb/db mice. Importantly, mast cell degranulation inhibition reduced EDP, vascular leakage and leucocyte infiltration in Leprdb/db mice. Conclusion Mast cells play a critical role in the development of cardiac microvessel disease and diastolic dysfunction.
Nucleus accumbens melanin-concentrating hormone signaling promotes feeding in a sex-specific manner

Melanin-concentrating hormone (MCH) is an orexigenic neuropeptide produced in the lateral hypothalamus and zona incerta that increases food intake. The neuronal pathways and behavioral mechanisms mediating the orexigenic effects of MCH are poorly understood, as is the extent to which MCH-mediated feeding outcomes are sex-dependent. Here we investigate the hypothesis that MCH-producing neurons act in the nucleus accumbens shell (ACBsh) to promote feeding behavior and motivation for palatable food in a sex-dependent manner. We utilized ACBsh MCH receptor (MCH1R)-directed pharmacology as well as a dual virus chemogenetic approach to selectively activate MCH neurons that project to the ACBsh. Results reveal that both ACBsh MCH1R activation and activating ACBsh-projecting MCH neurons increase consumption of standard chow and palatable sucrose in male rats without affecting motivated operant responding for sucrose, general activity levels, or anxiety-like behavior. In contrast, food intake was not affected in female rats by either ACBsh MCH1R activation or ACBsh-projecting MCH neuron activation. To determine a mechanism for this sexual dimorphism, we investigated whether the orexigenic effect of ACBsh MCH1R activation is reduced by endogenous estradiol signaling. In ovariectomized female rats on a cyclic regimen of either estradiol (EB) or oil vehicle, ACBsh MCH1R activation increased feeding only in oil-treated rats, suggesting that EB attenuates the ability of ACBsh MCH signaling to promote food intake. Collective results show that that MCH ACBsh signaling promotes feeding in an estrogen- and sex-dependent manner, thus identifying novel neurobiological mechanisms through which MCH and female sex hormones interact to influence food intake.
PQS-Induced Outer Membrane Vesicles Enhance Biofilm Dispersion in Pseudomonas aeruginosa

Bacterial biofilms are major contributors to chronic infections in humans. Because they are recalcitrant to conventional therapy, they present a particularly difficult treatment challenge. Identifying factors involved in biofilm development can help uncover novel targets and guide the development of anti-biofilm strategies. Pseudomonas aeruginosa causes surgical site, burn wound, and hospital acquired infections, and is also associated with aggressive biofilm formation in the lungs of cystic fibrosis patients. A potent but poorly understood contributor to P. aeruginosa virulence is the ability to produce outer membrane vesicles (OMVs). OMV trafficking has been associated with cell-to-cell communication, virulence factor delivery, and the transfer of antibiotic resistance genes. Because OMVs have almost exclusively been studied using planktonic cultures, little is known about their biogenesis and function in biofilms. Our group has shown that the Pseudomonas Quinolone Signal (PQS) induces OMV formation in P. aeruginosa, and in other species, through a biophysical mechanism that is also active in biofilms. Here, we demonstrate that PQS-induced OMV production is highly dynamic during biofilm development. Interestingly, PQS and OMV synthesis are significantly elevated during dispersion, compared to attachment and maturation stages. PQS biosynthetic and receptor mutant biofilms were significantly impaired in their ability to disperse, but this phenotype could be rescued by genetic complementation or exogenous addition of PQS. Finally, we show that purified OMVs can actively degrade extracellular protein, lipid, and DNA. We therefore propose that enhanced production of PQS-induced OMVs during biofilm dispersion facilitates cell escape by coordinating the controlled degradation of biofilm matrix components. Importance Treatments that manipulate biofilm dispersion hold the potential to convert chronic drug-tolerant biofilm infections from protected sessile communities into released populations that are orders-of-magnitude more susceptible to antimicrobial treatment. However, dispersed cells often exhibit increased acute virulence and dissemination phenotypes. A thorough understanding of the dispersion process is therefore critical before this promising strategy can be effectively employed. PQS has been implicated in early biofilm development, but we hypothesized that its function as an OMV inducer may contribute at multiple stages. Here, we demonstrate that PQS and OMVs are differentially produced during Pseudomonas aeruginosa biofilm development and that effective biofilm dispersion is dependent on production of PQS-induced OMVs, which likely act as delivery vehicles for matrix degrading enzymes. These findings lay the groundwork for understanding the roles of OMVs in biofilm development and suggest a model to explain the controlled matrix degradation that accompanies biofilm dispersion in many species.
Pre-existing immunity provides a barrier to airborne transmission of influenza viruses

Human-to-human transmission of influenza viruses is a serious public health threat, yet the precise role of immunity from previous infections on the susceptibility to airborne viruses is still unknown. Using human seasonal influenza viruses in a ferret model, we examined the roles of exposure duration and heterosubtypic immunity on influenza transmission. We found that airborne transmission of seasonal influenza strains is abrogated in recipient animals with pre-existing non-neutralizing immunity, indicating that transmissibility of a given influenza virus strain should be examined in the context of ferrets that are not immunologically naïve.