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Wnt signaling is involved in embryo development and cancer. The binding between the DIX domains of Axin1/2, Dishevelled1/2/3, and Coiled-coil-DIX1 is essential for Wnt/β-catenin signaling. Structural and biological studies have revealed that DIX domains are polymerized through head-to-tail interface interactions, which are indispensable for activating β-catenin Wnt signaling. Although different isoforms of Dvl and Axin proteins display both redundant and specific functions in Wnt signaling, the specificity of DIX-mediated interactions remains unclear due to technical challenges. Using AlphaFold2(AF2), we predict the structures of 6 homodimers and 22 heterodimers of DIX domains without templates and compare them with the reported X-ray complex structures. PRODIGY is used to calculate the binding affinities of these DIX complexes. Our results show that the Axin2 DIX homodimer has a stronger binding affinity than the Axin1 DIX homodimer. Among Dishevelled (Dvl) proteins, the binding affinity of the Dvl1 DIX homodimer is stronger than that of Dvl2 and Dvl3. The Coiled-coil-DIX1(Ccd1) DIX homodimer shows weaker binding than the Axin1 DIX homodimer. Generally, heterodimer interactions tend to be stronger than those of homodimers. Our findings provide insights into the mechanism of the Wnt signaling pathway and highlight the potential of AF2 and PRODIGY for studying protein–protein interactions in signaling pathways. [ABSTRACT FROM AUTHOR]

Copyright of HETS Online Journal is the property of Hispanic Educational Technology Services, Inc. (HETS) and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Wnt signaling is involved in embryo development and cancer. The binding between the DIX domains of Axin1/2, Dishevelled1/2/3, and Coiled-coil-DIX1 is essential for Wnt/β-catenin signaling. Structural and biological studies have revealed that DIX domains are polymerized through head-to-tail interface interactions, which are indispensable for activating β-catenin Wnt signaling. Although different isoforms of Dvl and Axin proteins display both redundant and specific functions in Wnt signaling, the specificity of DIX-mediated interactions remains unclear due to technical challenges. Using AlphaFold2(AF2), we predict the structures of 6 homodimers and 22 heterodimers of DIX domains without templates and compare them with the reported X-ray complex structures. PRODIGY is used to calculate the binding affinities of these DIX complexes. Our results show that the Axin2 DIX homodimer has a stronger binding affinity than the Axin1 DIX homodimer. Among Dishevelled (Dvl) proteins, the binding affinity of the Dvl1 DIX homodimer is stronger than that of Dvl2 and Dvl3. The Coiled-coil-DIX1(Ccd1) DIX homodimer shows weaker binding than the Axin1 DIX homodimer. Generally, heterodimer interactions tend to be stronger than those of homodimers. Our findings provide insights into the mechanism of the Wnt signaling pathway and highlight the potential of AF2 and PRODIGY for studying protein–protein interactions in signaling pathways.

Copyright of Acta Universitatis Lodziensis: Folia Litteraria Romanica is the property of Wydawnictwo Uniwersytetu Lodzkiego and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The binding affinity of trastuzumab and pertuzumab to HER2 has been studied using both experimental and in silico methods. The experiments were conducted using the antibodies in their complete IgG form, as used in clinical therapy, and the extracellular domain of the HER2 protein in solution. This approach provides a precise, reproducible, and reliable view of the interaction between them in physicochemical conditions similar to those found in the tumoral environment. Dynamic light scattering and size exclusion chromatography coupled with tetra detection were utilized to characterize the protein complexes, measure their concentrations, and calculate the equilibrium-free binding energy, ΔGbind. In addition, PRODIGY, a QSAR-like model with excellent predictive ability, was employed to obtain in silico ΔGbind estimations. The results obtained indicate that pertuzumab exhibits a slightly higher binding affinity to HER2 than trastuzumab. The difference in binding affinity was explained based on the contribution of the different interfacial contact (IC) descriptors to the ΔGbind value estimated by the PRODIGY model. Furthermore, experiments revealed that the pertuzumab IgG antibody binds preferentially to two HER2 proteins, one per Fab fragment, while trastuzumab mainly forms a monovalent complex. This finding was interpreted based on a geometrical model that identified steric crowding in the trastuzumab–HER2 complex as compared with the pertuzumab–HER2 complex. [ABSTRACT FROM AUTHOR]

This paper aims to find details about an excellent Spanish pianist from the beginning of the 20th century who starred when she was a little child: her name was Maria Vallès. Not many news are known about her brief biography since she had a short life and little could develop and become known as a pianist. Through a research work some press articles from the first decades of the 20th century were found, which highlight the excellence of her piano performances in Spain. The aim of this research is to analyze the pedagogical codes for the training of a musical talent in Spain at the beginning of the 20th century, as well as the feminine cultural codes against a female prodigy artist, on the axis of Maria Vallès. This research was carried out according to the type of document analysis, which is one of the qualitative research types. Evidence documents regarding the prodigy phenomenon of the Spanish pianist were found. She played concerts basically in Catalonia, where she moved with her family when she was a little child. It should be also noted that she studied with one of the most prestigious pedagogues of the time, Molinari. He was her mentor and the one who introduced her to the Catalan cultural and musical life of the twenties, making her known among her peers who were also pedagogues and musicologists and the public attending her concerts. This research includes some codes for practitioners and pedagogues for the development of piano talent, in the example of Spanish pianist Maria Vallès, who was a prodigy child. [ABSTRACT FROM AUTHOR]

This paper analyses the juvenile career of Julie Andrews who was a child performer of considerable note in her native Britain during the immediate post-war period. Possessed of a remarkably developed singing voice, Andrews was feted as a musical child prodigy, and she performed widely in variety and radio as 'Britain's youngest singing star'. In an era of profound disruption, Andrews' popular image as national wunderkind served – as the myth of the child star so often it does – as a resonant cultural fiction for the articulation of deeply felt ideological concerns and the fantastic reconciliation of social and emotional anxieties. [ABSTRACT FROM AUTHOR]

Neuroenhancement aims to improve cognitive performance in typically and atypically functioning populations. However, it is currently debated whether it is also effective in exceptionally high-functioning individuals. Present theories suggest that homeostatic set points for learning and cortical plasticity limit the beneficial effects of neuroenhancement. To examine this possibility, we used transcranial random noise stimulation (tRNS) to non-invasively stimulate bilateral dorsolateral prefrontal cortices (DLPFC) of the world champion in mental calculation, G.M. TRNS did not change G.M.'s calculation performance compared to sham stimulation on an exceptionally complex arithmetic task. However, a sample of mathematicians who were not calculation prodigies (N = 6) showed reduced accuracy on a complex multiplication task in response to tRNS, relative to sham. Our findings suggest that there may be an upper limit for cognitive enhancement and that further attempts to enhance performance using tRNS (at least with the current parameters) may impair optimal functioning. The discussion of potential negative effects of brain stimulation for cognitive enhancement is critical, as it may lead to unintended impairments in different subgroups of the population.

Protein-coding genetic variants that strongly affect disease risk can yield relevant clues to disease pathogenesis. Here we report exome-sequencing analyses of 20,791 individuals with type 2 diabetes (T2D) and 24,440 non-diabetic control participants from 5 ancestries. We identify gene-level associations of rare variants (with minor allele frequencies of less than 0.5%) in 4 genes at exome-wide significance, including a series of more than 30 SLC30A8 alleles that conveys protection against T2D, and in 12 gene sets, including those corresponding to T2D drug targets (P = 6.1 × 10-3) and candidate genes from knockout mice (P = 5.2 × 10-3). Within our study, the strongest T2D gene-level signals for rare variants explain at most 25% of the heritability of the strongest common single-variant signals, and the gene-level effect sizes of the rare variants that we observed in established T2D drug targets will require 75,000-185,000 sequenced cases to achieve exome-wide significance. We propose a method to interpret these modest rare-variant associations and to incorporate these associations into future target or gene prioritization efforts.

Anhand gesammelter Pflanzenschutzhinweise und Warnmeldungen wurden Named Entity Recognition (NER) Modelle zur automatischen Erkennung und Klassifizierung von relevanten Begriffen des Gartenbaus (Kulturen, Schaderreger, Pflanzenschutzmittel, BBCH Stadium) erstellt. NER ist eine Teilaufgabe der Informationsextraktion, die darauf abzielt, benannte Entitäten, die in unstrukturiertem Text erwähnt werden, zu finden und in vordefinierte Kategorien einzuordnen. 114 Dateien mit 105737 Wörtern, davon 12295 verschiedene Wörter, wurden verwendet. Mit dem Annotationswerkzeug Prodigy wurden insgesamt 9019 Entitäten annotiert. Es wurden drei verschiedene Modelle trainiert, basierend auf spaCy, Flair und CRF. Alle drei Modelle erzielten ähnlich gute Genauigkeiten (gemittelte F-Werte), spaCy erreichte mit F1=0.8997 die höchste Genauigkeit über alle vier Klassen. Mit dem hier vorgestellten Projekt werden die Voraussetzungen geschaffen, die Inhalte der Vielzahl von Warndienstmeldungen automatisiert zu erschließen und über gezielte Abfragen und Suchvorgänge zugänglich zu machen. Der Beitrag stellt das methodische Vorgehen und einige Analyseergebnisse beispielhaft dar.

Access to commercial CD19 CAR-T cells remains limited even in wealthy countries like Canada due to clinical, logistical, and financial barriers related to centrally manufactured products. We created a non-commercial academic platform for end-to-end manufacturing of CAR-T cells within Canada’s publicly funded healthcare system. We report initial results from a single-arm, open-label study to determine the safety and efficacy of in-house manufactured CD19 CAR-T cells (entitled CLIC-1901) in participants with relapsed/refractory CD19 positive hematologic malignancies. Using a GMP compliant semi-automated, closed process on the Miltenyi Prodigy, T cells were transduced with lentiviral vector bearing a 4-1BB anti-CD19 CAR transgene and expanded. Participants underwent lymphodepletion with fludarabine and cyclophosphamide, followed by infusion of non-cryopreserved CAR-T cells. Thirty participants with non-Hodgkin’s lymphoma (n=25) or acute lymphoblastic leukemia (n=5) were infused with CLIC-1901: 21 males (70%), median age 66 (range 18-75). Time from enrollment to CLIC-1901 infusion was a median of 20 days (range 15-48). The median CLIC-1901 dose infused was 2.3 × 106 CAR-T cells/kg (range 0.13-3.6 × 106/kg). Toxicity included ≥ grade 3 cytokine release syndrome (n=2) and neurotoxicity (n=1). Median follow-up was 6.5 months. Overall response rate at day 28 was 76.7%. Median progression-free and overall survival was 6 months (95%CI 3-not estimable) and 11 months (95% 6.6-not estimable), respectively. This is the first trial of in-house manufactured CAR-T cells in Canada and demonstrates that administering fresh CLIC-1901 product is fast, safe, and efficacious. Our experience may provide helpful guidance for other jurisdictions seeking to create feasible and sustainable CAR-T cell programs in research-oriented yet resource-constrained settings.Clinical trial registrationhttps://clinicaltrials.gov/ct2/show/NCT03765177, identifier NCT03765177.

Purpose: The first objective of the study was to assess the agreement between the Stratos DR (DMS) and the GE Prodigy (GE) DXAs in determining femoral neck, total hip and lumbar spine aBMD. The second objective was to assess the potential impact of leg positioning (hip flexed at 90° or not) on lumbar spine aBMD. Methods: Forty-six individuals (n=42 women, 91.3%), with a mean age of 59.7 ± 13 years and mean BMI of 23.8 ± 4.7 kg/m², were scanned consecutively on the same day using the two devices. In a subgroup (n=30), two consecutive Stratos DR scans (with hip flexed at 90° or not) at the lumbar spine were conducted. Predictive equations for hip and lumbar spine aBMD were derived from linear regression of the data. Results: Correlation coefficients for aBMD measured with the two DXAs were characterised by an R² of 0.76 for the femoral neck, 0.89 for the total hip, and 0.86 for the lumbar spine. However, the derived equations for aBMD determination showed an intercept significantly different from 0 for hip aBMD, and a slope significantly different from 1 for lumbar spine aBMD. These results highlight a bias between the two measurements, thus requiring the determination of specific cross-calibration equations for hip and lumbar spine, femoral neck excepted. When compared with values on the Prodigy, mean aBMD on the Stratos DR was higher at the femoral neck (+4.8%, p<0.001) and total hip (+9.6%, p<0.001) and lower at L2-L4 (-8.8%, p<0.001). The coefficient of variation (CV%) for the two consecutive measures at lumbar spine (with different positioning) with the Stratos DR was 2.9%. Conclusions: The difference in aBMD measured with the two DXAs illustrates the need to define cross-calibration equations when comparing data across systems in order to avoid erroneous conclusions. [ABSTRACT FROM AUTHOR]

Although there is a rich, original archive of Phillis Wheatley's poetry about children, Wheatley's role in writing the culture of American childhood has not been widely noted. Conversely, while little can be archivally reconstructed about Wheatley's young life, popular biographies of the poet have, since the nineteenth century, placed emphasis on her childhood precocity. This essay intervenes in the first problem and deconstructs the latter, arguing that Wheatley was a major architect of American childhood who carved political interventions in childhood's pliant terms, and who pressed audaciously on its hardening racial boundaries. Placing Wheatley at the center of the early American epistemic, pedagogical, and political struggle over childhood's meaning, this essay traces the dominant racial politics of childhood that came to diminish Wheatley—as either a childlike poet or an exceptional child—in dialogue with Wheatley's own invocations of childhood, family, knowledge, and freedom in her personal writings and published work. Reading Wheatley's elegies to deceased white children beside the poem in which she casts herself—"young in life"—this essay argues that Wheatley drafted early lines in modern American childhood's recognizable form, while expanding beyond the American imagination of childhood's cognitive, social, and racial limits. [ABSTRACT FROM AUTHOR]

Observed here through the lenses of the history of mentalities and the environmental history, the meteorological phenomenon of red rain appears to have been discerned from several points of view by the medieval man. Due to its reddish colour, this peculiar rain was most often perceived as real blood. Although generally associated with a range of rather negative emotions or events, the shower of blood meant an experience felt differently by various communities: predicting death and war, blood rain could also signify the injures of the combatants, the bodily suffering of Christ, the end of the world, God’s anger and his divine punishment, or simply a natural phenomenon caused by material and physical factors. If, for the Early Middle Ages, only brief passages from chronicles inform us about these phenomena, beginning with the 12th-13th centuries a scientific discourse concerning the blood rain is formulated in Europe. In some illuminated religious manuscripts, biblical episodes depicting showers of blood and fire were represented at least since the 11th century. From the 15th century on, the iconography of the blood rain diversifies and, at the same epoch, the motif of the rain of blood appears in some private devotional books. The 16th century amplifies the means of expression on the rains of blood, through brochures and flyers, a rich compendia of prodigy, or through scientific and popular works devoted to this phenomenon. In the Renaissance, the blood rain turns into an artistic and literary motif. By looking at some biblical accounts that echoed in the medieval culture, at the discourses articulated by several chroniclers, or by trying to grasp the evolution of the learned discourse addressing the blood rain, this article aims to assess the medieval perspectives touching the phenomenon of red rain.

The binding affinity of trastuzumab and pertuzumab to HER2 has been studied using both experimental and in silico methods. The experiments were conducted using the antibodies in their complete IgG form, as used in clinical therapy, and the extracellular domain of the HER2 protein in solution. This approach provides a precise, reproducible, and reliable view of the interaction between them in physicochemical conditions similar to those found in the tumoral environment. Dynamic light scattering and size exclusion chromatography coupled with tetra detection were utilized to characterize the protein complexes, measure their concentrations, and calculate the equilibrium-free binding energy, ΔGbind. In addition, PRODIGY, a QSAR-like model with excellent predictive ability, was employed to obtain in silico ΔGbind estimations. The results obtained indicate that pertuzumab exhibits a slightly higher binding affinity to HER2 than trastuzumab. The difference in binding affinity was explained based on the contribution of the different interfacial contact (IC) descriptors to the ΔGbind value estimated by the PRODIGY model. Furthermore, experiments revealed that the pertuzumab IgG antibody binds preferentially to two HER2 proteins, one per Fab fragment, while trastuzumab mainly forms a monovalent complex. This finding was interpreted based on a geometrical model that identified steric crowding in the trastuzumab–HER2 complex as compared with the pertuzumab–HER2 complex.

Monsters, by the Latin definition of their name, are omens that portend turbulent times. The pamphlet A Relation of a terrible Monster called a Toad-fish, published in London in 1642, told of “a fiend, not a fish; at the least a monster, not an ordinary creature” which had become entangled in a fishing net and then put on display in London. The creature was described as resembling a giant toad, with a wide, toothy mouth and human characteristics of ribs, hands, and fingers. Discovery of the Thames monster instilled a sense of worry throughout the realm. The landing of the “Toad-fish” was linked in the tract to a bloody encounter that occurred between two well-known members of the British aristocracy fighting on opposing sides at the onset of the Civil War. The present paper describes how this vernacular publication was part of a flourishing of providential pamphlets in the 17th century wherein natural anomalies were invested with wider ecclesiastical and political meaning. Also undertaken herein is a review of various candidate species from which to suggest that the mysterious Toad-fish may have been another example of the angelshark’s (Squatina squatina) monstrous alter ego. This is an animal that has previously been suggested as being responsible for the ‘sea monk’ noted in several prominent natural histories of the Renaissance. [ABSTRACT FROM AUTHOR]

Efficient and cost-effective CD34+ hematopoietic stem and progenitor cell (HSPC) manufacturing processes are pivotal for the widespread accessibility of cell and gene therapies. To advance this goal, a closed and automated CD34+ HSPC manufacturing process has been developed using the Miltenyi CliniMACS Prodigy system. By leveraging this platform, a closed and automated workflow has been optimized encompassing CD34+ cell isolation, electroporation, formulation, and bag filling. The automated manufacturing process on the Miltenyi CliniMACS Prodigy system begins with automated washing, labeling, and isolation of CD34+ cells. The integration of a customized isolation protocol within the Miltenyi CliniMACS Prodigy system empowers robust and adaptable CD34+ cell isolation. This customized approach enables precise control and standardization of cellular processing, ensuring consistent yield and quality across a range of starting material variability inherent in mobilized apheresis collections. Optimization of electroporation parameters within the closed system allows efficient gene transfer while maintaining high cell viability and function. The Miltenyi CliniMACS Prodigy system allows for complete customization of electroporation parameters including number of pulses, pulse duration, voltage, and polarity. This critical step in genetic modification was optimized and seamlessly integrated into the workflow, ensuring a robust and controlled process. Formulation and bag filling stages have been tailored to accommodate a variety of bag sizes and filling volumes while upholding sterility and quality standards. This allows for the flexibility required to fill bags at a desired cell concentration, ensuring product quality across the large range of total cell numbers typically seen in autologous CD34+ HSPC therapies. The closed-system approach minimizes contamination risks and ensures the integrity of the final therapeutic product. A closed and automated CD34+ HSPC manufacturing process using the Miltenyi CliniMACS Prodigy has the potential to improve access to autologous cell therapies. By enabling manufacturing flexibility and substantially reducing operational costs, these developments pave the way for scalable and cost-effective next-generation cell therapies, further enhancing their clinical utility. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR)-engineered T cells can be highly effective in the treatment of hematological malignancies, but mostly fail in the treatment of solid tumors. Thus, approaches using 4th advanced CAR T cells secreting immunomodulatory cytokines upon CAR signaling, known as TRUCKs (" T cells redirected for universal cytokine-mediated killing "), are currently under investigation. Based on our previous development and validation of automated and closed processing for GMP-compliant manufacturing of CAR T cells, we here present the proof of feasibility for translation of this method to TRUCKs. We generated IL-18-secreting TRUCKs targeting the tumor antigen GD2 using the CliniMACS Prodigy® system using a recently described "all-in-one" lentiviral vector combining constitutive anti-GD2 CAR expression and inducible IL-18. Starting with 0.84 x 108 and 0.91 x 108 T cells after enrichment of CD4+ and CD8+ we reached 68.3-fold and 71.4-fold T cell expansion rates, respectively, in two independent runs. Transduction efficiencies of 77.7% and 55.1% was obtained, and yields of 4.5 x 109 and 3.6 x 109 engineered T cells from the two donors, respectively, within 12 days. Preclinical characterization demonstrated antigen-specific GD2-CAR mediated activation after co-cultivation with GD2-expressing target cells. The functional capacities of the clinical-scale manufactured TRUCKs were similar to TRUCKs generated in laboratory-scale and were not impeded by cryopreservation. IL-18 TRUCKs were activated in an antigen-specific manner by co-cultivation with GD2-expressing target cells indicated by an increased expression of activation markers (e.g. CD25, CD69) on both CD4+ and CD8+ T cells and an enhanced release of pro-inflammatory cytokines and cytolytic mediators (e.g. IL-2, granzyme B, IFN-γ, perforin, TNF-α). Manufactured TRUCKs showed a specific cytotoxicity towards GD2-expressing target cells indicated by lactate dehydrogenase (LDH) release, a decrease of target cell numbers, microscopic detection of cytotoxic clusters and detachment of target cells in real-time impedance measurements (xCELLigence). Following antigen-specific CAR activation of TRUCKs, CAR-triggered release IL-18 was induced, and the cytokine was biologically active, as demonstrated in migration assays revealing specific attraction of monocytes and NK cells by supernatants of TRUCKs co-cultured with GD2-expressing target cells. In conclusion, GMP-compliant manufacturing of TRUCKs is feasible and delivers high quality T cell products. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR)-engineered T cells can be highly effective in the treatment of hematological malignancies, but mostly fail in the treatment of solid tumors. Thus, approaches using 4th advanced CAR T cells secreting immunomodulatory cytokines upon CAR signaling, known as TRUCKs (“T cells redirected for universal cytokine-mediated killing”), are currently under investigation. Based on our previous development and validation of automated and closed processing for GMP-compliant manufacturing of CAR T cells, we here present the proof of feasibility for translation of this method to TRUCKs. We generated IL-18-secreting TRUCKs targeting the tumor antigen GD2 using the CliniMACS Prodigy® system using a recently described “all-in-one” lentiviral vector combining constitutive anti-GD2 CAR expression and inducible IL-18. Starting with 0.84 x 108 and 0.91 x 108 T cells after enrichment of CD4+ and CD8+ we reached 68.3-fold and 71.4-fold T cell expansion rates, respectively, in two independent runs. Transduction efficiencies of 77.7% and 55.1% was obtained, and yields of 4.5 x 109 and 3.6 x 109 engineered T cells from the two donors, respectively, within 12 days. Preclinical characterization demonstrated antigen-specific GD2-CAR mediated activation after co-cultivation with GD2-expressing target cells. The functional capacities of the clinical-scale manufactured TRUCKs were similar to TRUCKs generated in laboratory-scale and were not impeded by cryopreservation. IL-18 TRUCKs were activated in an antigen-specific manner by co-cultivation with GD2-expressing target cells indicated by an increased expression of activation markers (e.g. CD25, CD69) on both CD4+ and CD8+ T cells and an enhanced release of pro-inflammatory cytokines and cytolytic mediators (e.g. IL-2, granzyme B, IFN-γ, perforin, TNF-α). Manufactured TRUCKs showed a specific cytotoxicity towards GD2-expressing target cells indicated by lactate dehydrogenase (LDH) release, a decrease of target cell numbers, microscopic detection of cytotoxic clusters and detachment of target cells in real-time impedance measurements (xCELLigence). Following antigen-specific CAR activation of TRUCKs, CAR-triggered release IL-18 was induced, and the cytokine was biologically active, as demonstrated in migration assays revealing specific attraction of monocytes and NK cells by supernatants of TRUCKs co-cultured with GD2-expressing target cells. In conclusion, GMP-compliant manufacturing of TRUCKs is feasible and delivers high quality T cell products.

Copyright of Julius-Kühn-Archiv is the property of Julius Kuehn Institut and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Anuario Lope de Vega. Texto, Literatura, Cultura is the property of Universitat Autonoma de Barcelona and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Abstract Background Progressive multifocal leukoencephalopathy is a demyelinating CNS disorder. Reactivation of John Cunningham virus leads to oligodendrocyte infection with lysis and consequent axonal loss due to demyelination. Patients usually present with confusion and seizures. Late diagnosis and lack of adequate therapy options persistently result in permanent impairment of brain functions. Due to profound T cell depletion, impairment of T-cell function and potent immunosuppressive factors, allogeneic hematopoietic cell transplantation recipients are at high risk for JCV reactivation. To date, PML is almost universally fatal when occurring after allo-HCT. Methods To optimize therapy specificity, we enriched JCV specific T-cells out of the donor T-cell repertoire from the HLA-identical, anti-JCV-antibody positive family stem cell donor by unstimulated peripheral apheresis [1]. For this, we selected T cells responsive to five JCV peptide libraries via the Cytokine Capture System technology. It enables the enrichment of JCV specific T cells via identification of stimulus-induced interferon gamma secretion. Results Despite low frequencies of responsive T cells, we succeeded in generating a product containing 20 000 JCV reactive T cells ready for patient infusion. The adoptive cell transfer was performed without complication. Consequently, the clinical course stabilized and the patient slowly went into remission of PML with JCV negative CSF and containment of PML lesion expansion. Conclusion We report for the first time feasibility of generating T cells with possible anti-JCV activity from a seropositive family donor, a variation of virus specific T-cell therapies suitable for the post allo transplant setting. We also present the unusual case for successful treatment of PML after allo-HCT via virus specific T-cell therapy.

Observed here through the lenses of the history of mentalities and the environmental history, the meteorological phenomenon of red rain appears to have been discerned from several points of view by the medieval man. Due to its reddish colour, this peculiar rain was most often perceived as real blood. Although generally associated with a range of rather negative emotions or events, the shower of blood meant an experience felt differently by various communities: predicting death and war, blood rain could also signify the injures of the combatants, the bodily suffering of Christ, the end of the world, God's anger and his divine punishment, or simply a natural phenomenon caused by material and physical factors. If, for the Early Middle Ages, only brief passages from chronicles inform us about these phenomena, beginning with the 12th-13th centuries a scientific discourse concerning the blood rain is formulated in Europe. In some illuminated religious manuscripts, biblical episodes depicting showers of blood and fire were represented at least since the 11th century. From the 15th century on, the iconography of the blood rain diversifies and, at the same epoch, the motif of the rain of blood appears in some private devotional books. The 16th century amplifies the means of expression on the rains of blood, through brochures and flyers, a rich compendia of prodigy, or through scientific and popular works devoted to this phenomenon. In the Renaissance, the blood rain turns into an artistic and literary motif. By looking at some biblical accounts that echoed in the medieval culture, at the discourses articulated by several chroniclers, or by trying to grasp the evolution of the learned discourse addressing the blood rain, this article aims to assess the medieval perspectives touching the phenomenon of red rain. [ABSTRACT FROM AUTHOR]

Prof. Fidana Daskalova, PhD is a proven and collegially recognized specialist in the teaching of native language in kindergarten – both with her original scientific aspects on the development of the child, for his early education, for school preparation, and with the applied in the national educational practice her copyrighted works. Her works contain original theoretical analyzes with experimental solutions of philosophical and psychological cases in scientific pedagogy. Synthesized, her creative innovations here are: the principle of dichotomous opposition and order; principle of balance of freedom and order; principle of positive upbringing, principle of positive discipline; “maturation”; “super gifted”; “memes” and others. For Bulgarian pedagogy a particularly valuable ideological heritage is her message that in scientific work the leading factor should be the understanding of the positive role of observation and the inevitable need for objective experimental conditions in theorizing the researched problem. [ABSTRACT FROM AUTHOR]

Few individuals—whether scholars or laypersons—think that the words smart or intelligent suffice to characterize a person's intellectual strengths. In this article, the author reviews a set of terms commonly used to characterize intellectual strengths and then introduces the concept of synthesizing—an important but little recognized form of intellectual skill. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor T cells (CAR-T cell) targeting CD19 are effective against several subtypes of CD19-expressing hematologic malignancies. Centralized manufacturing has allowed rapid expansion of this cellular therapy, but it may be associated with treatment delays due to the required logistics. We hypothesized that point of care manufacturing of CAR-T cells on the automated CliniMACS Prodigy® device allows reproducible and fast delivery of cells for the treatment of patients with non-Hodgkin lymphoma. Here we describe cell manufacturing results and characterize the phenotype and effector function of CAR-T cells used in a phase I/II study. We utilized a lentiviral vector delivering a second-generation CD19 CAR construct with 4-1BB costimulatory domain and TNFRSF19 transmembrane domain. Our data highlight the successful generation of CAR-T cells at numbers sufficient for all patients treated, a shortened duration of production from 12 to 8 days followed by fresh infusion into patients, and the detection of CAR-T cells in patient circulation up to 1-year post-infusion.

Chimeric antigen receptor T cells (CAR-T cell) targeting CD19 are effective against several subtypes of CD19-expressing hematologic malignancies. Centralized manufacturing has allowed rapid expansion of this cellular therapy, but it may be associated with treatment delays due to the required logistics. We hypothesized that point of care manufacturing of CAR-T cells on the automated CliniMACS Prodigy® device allows reproducible and fast delivery of cells for the treatment of patients with non-Hodgkin lymphoma. Here we describe cell manufacturing results and characterize the phenotype and effector function of CAR-T cells used in a phase I/II study. We utilized a lentiviral vector delivering a second-generation CD19 CAR construct with 4-1BB costimulatory domain and TNFRSF19 transmembrane domain. Our data highlight the successful generation of CAR-T cells at numbers sufficient for all patients treated, a shortened duration of production from 12 to 8 days followed by fresh infusion into patients, and the detection of CAR-T cells in patient circulation up to 1-year post-infusion. [ABSTRACT FROM AUTHOR]

Background: Progressive multifocal leukoencephalopathy is a demyelinating CNS disorder. Reactivation of John Cunningham virus leads to oligodendrocyte infection with lysis and consequent axonal loss due to demyelination. Patients usually present with confusion and seizures. Late diagnosis and lack of adequate therapy options persistently result in permanent impairment of brain functions. Due to profound T cell depletion, impairment of T-cell function and potent immunosuppressive factors, allogeneic hematopoietic cell transplantation recipients are at high risk for JCV reactivation. To date, PML is almost universally fatal when occurring after allo-HCT.Methods: To optimize therapy specificity, we enriched JCV specific T-cells out of the donor T-cell repertoire from the HLA-identical, anti-JCV-antibody positive family stem cell donor by unstimulated peripheral apheresis [1]. For this, we selected T cells responsive to five JCV peptide libraries via the Cytokine Capture System technology. It enables the enrichment of JCV specific T cells via identification of stimulus-induced interferon gamma secretion.Results: Despite low frequencies of responsive T cells, we succeeded in generating a product containing 20 000 JCV reactive T cells ready for patient infusion. The adoptive cell transfer was performed without complication. Consequently, the clinical course stabilized and the patient slowly went into remission of PML with JCV negative CSF and containment of PML lesion expansion.Conclusion: We report for the first time feasibility of generating T cells with possible anti-JCV activity from a seropositive family donor, a variation of virus specific T-cell therapies suitable for the post allo transplant setting. We also present the unusual case for successful treatment of PML after allo-HCT via virus specific T-cell therapy. [ABSTRACT FROM AUTHOR]

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Abstract Dendritic cell (DC)-based vaccines have been successfully used for immunotherapy of cancer and infections. A major obstacle is the need for high-level class A cleanroom cGMP facilities for DC generation. The CliniMACS Prodigy® (Prodigy) represents a new platform integrating all GMP-compliant manufacturing steps in a closed system for automated production of various cellular products, notably T cells, NK cells and CD34+ cells. We now systematically tested its suitability for producing human mature monocyte-derived DCs (Mo-DCs), and optimized it by directly comparing the Prodigy approach to our established standard production of Mo-DCs from elutriated monocytes in dishes or bags. Upon step-by-step identification of an optimal cell concentration for the Prodigy's CentriCult culture chamber, the total yield (% of input CD14+ monocytes), phenotype, and functionality of mature Mo-DCs were equivalent to those generated by the standard protocol. Technician's labor time was comparable for both methods, but the Prodigy approach significantly reduced hands-on time and high-level clean room resources. In summary, using our optimized conditions for the CliniMACS Prodigy, human Mo-DCs for clinical application can be generated almost automatically in a fully closed system. A significant drawback of the Prodigy approach was, however, that due to the limited size of the CentriCult culture chamber, in contrast to our standard semi-closed elutriation approach, only one fourth of an apheresis could be processed at once. [ABSTRACT FROM AUTHOR]

Highlights • Glutamate and GABA are essential in plasticity and processing efficiency. • Cognitive impairments are linked with altered prefrontal glutamate (glu) and GABA. • We assessed glu/GABA using magnetic resonance spectroscopy in a calculation prodigy. • Prefrontal glu/GABA ratios are reduced in a calculation prodigy vs. non-prodigies. • Exceptional cognitive abilities may be reflected in non-invasive measures of glu/GABA. Abstract Alterations in excitatory and inhibitory neurotransmitters (glutamate and GABA, respectively) have been found in various neuropsychiatric disorders, but have not been examined in individuals with prodigious cognitive abilities. Understanding exceptional brain processing is critical for developing biomedical interventions for cognitive and neurodevelopmental atypicalities. We tested the 11-fold world champion in mental calculation, G.M., and compared his right middle frontal gyrus, which has been associated with mathematical prodigy, to four healthy control expert calculators, who were not prodigies. We found substantially lower frontal glutamate/GABA compared to non-prodigy controls, but not glutamate or GABA individually, measured with magnetic resonance spectroscopy. We suggest that prefrontal glutamate/GABA is a potential marker of extraordinary cognitive skills. [ABSTRACT FROM AUTHOR]

While there is a strong interest in and fascination with music prodigies, very few measurements have been conducted on this rare phenomenon and very little empirical data exist. We document the case of LN, an 11-year-old music prodigy. We tested him on his cognitive skills (non-verbal reasoning and working memory), rhythm and melody discrimination skills, sight reading, improvisation, pitch accuracy, and musical memory. The data were then compared to various controls: a group of music students of the same age group (for cognitive and discrimination skills); three university music students with perfect pitch (for pitch accuracy and musical memory); and a music prodigy of similar age who was tested almost one hundred years ago (for pitch accuracy and musical memory). This is the first study that compares the test results of a contemporary music prodigy with the rare data of a prodigy studied in the early 20th century; the results are remarkably similar. LN's results on cognitive skills confirm the exceptional working memory often associated with prodigies. Most interestingly, musical ability results revealed a phenomenal level of melody discrimination, pitch accuracy and musical memory (skills related to auditory pitch memory), but just average rhythm skills, below average sight reading ability and he was not able to improvise. This suggests the potentially important role of exceptional auditory pitch memory in the development of musical prodigies. [ABSTRACT FROM AUTHOR]

Background: CD133+ stem cells represent a promising subpopulation for innovative cell-based therapies in cardiovascular regeneration. Several clinical trials have shown remarkable beneficial effects following their intramyocardial transplantation. Yet, the purification of CD133+ stem cells is typically performed in centralized clean room facilities using semi-automatic manufacturing processes based on magnetic cell sorting (MACS®). However, this requires time-consuming and cost-intensive logistics. Methods: CD133+ stem cells were purified from patient-derived sternal bone marrow using the recently developed automatic CliniMACS Prodigy® BM-133 System (Prodigy). The entire manufacturing process, as well as the subsequent quality control of the final cell product (CP), were realized on-site and in compliance with EU guidelines for Good Manufacturing Practice. The biological activity of automatically isolated CD133+ cells was evaluated and compared to manually isolated CD133+ cells via functional assays as well as immunofluorescence microscopy. In addition, the regenerative potential of purified stem cells was assessed 3 weeks after transplantation in immunodeficient mice which had been subjected to experimental myocardial infarction. Results: We established for the first time an on-site manufacturing procedure for stem CPs intended for the treatment of ischemic heart diseases using an automatized system. On average, 0.88 × 106 viable CD133+ cells with a mean log10 depletion of 3.23 ± 0.19 of non-target cells were isolated. Furthermore, we demonstrated that these automatically isolated cells bear proliferation and differentiation capacities comparable to manually isolated cells in vitro. Moreover, the automatically generated CP shows equal cardiac regeneration potential in vivo. Conclusions: Our results indicate that the Prodigy is a powerful system for automatic manufacturing of a CD133+ CP within few hours. Compared to conventional manufacturing processes, future clinical application of this system offers multiple benefits including stable CP quality and on-site purification under reduced clean room requirements. This will allow saving of time, reduced logistics and diminished costs. [ABSTRACT FROM AUTHOR]

The purpose of this study is to examine, from a rational point of view, the story occurred in the year 42 BC and related by Pliny and Suetonius. According to these roman authors, a very young Livia Drusilla (future wife of Octavius) at the age of 15-16 years and being pregnant carried out and oomantic ceremony, in order to guess the sex of the child she was carrying and make sure it was a boy. For this purpose the narration says that she had taken a chicken egg - as a simulation of the fetus - which had been incubated within her, extra corpore, until it hatched out showing a baby-bird with an enormous red cockscomb. This image was a sign referred to the baby who was coming to life: Tiberius. In political terms, we retroactively situate the formation of this genethliacal myth in the year 2 AD, coinciding with the return of the emperor Tiberius back to Rome from his voluntary exile in Rhodes, "the golden island". This episode operates as a metaphor for a "new birth" and for its incorporation, initially unfortunate, to the political scene. [ABSTRACT FROM AUTHOR]

In Imperial times, the Roman army was confronted by prodigies, omens, divine orders and advice. Through these signs the gods addressed the soldiers. They manifested their wrath, delivered warnings about their future, were profuse in giving orders and advice and were able to be of assistance. Closely connected to the military institution, these signs could stage soldiers, their weaponry, the great symbols connected to the army. Those various testimonies demonstrate that the religious aspect proved paramount within the military institution: its members respected the word of the gods and, in their interventions, expected efficacious assistance in front of the dangers and uncertainties made multifarious by their status as soldiers.

Background: Automation of cell therapy manufacturing promises higher productivity of cell factories, more economical use of highly-trained (and costly) manufacturing staff, facilitation of processes requiring manufacturing steps at inconvenient hours, improved consistency of processing steps and other benefits. One of the most broadly disseminated engineered cell therapy products is immunomagnetically selected CD34+ hematopoietic "stem" cells (HSCs).Methods: As the clinical GMP-compliant automat CliniMACS Prodigy is being programmed to perform ever more complex sequential manufacturing steps, we developed a CD34+ selection module for comparison with the standard semi-automatic CD34 "normal scale" selection process on CliniMACS Plus, applicable for 600 × 10(6) target cells out of 60 × 10(9) total cells. Three split-validation processings with healthy donor G-CSF-mobilized apheresis products were performed; feasibility, time consumption and product quality were assessed.Results: All processes proceeded uneventfully. Prodigy runs took about 1 h longer than CliniMACS Plus runs, albeit with markedly less hands-on operator time and therefore also suitable for less experienced operators. Recovery of target cells was the same for both technologies. Although impurities, specifically T- and B-cells, were 5 ± 1.6-fold and 4 ± 0.4-fold higher in the Prodigy products (p = ns and p = 0.013 for T and B cell depletion, respectively), T cell contents per kg of a virtual recipient receiving 4 × 10(6) CD34+ cells/kg was below 10 × 10(3)/kg even in the worst Prodigy product and thus more than fivefold below the specification of CD34+ selected mismatched-donor stem cell products. The products' theoretical clinical usability is thus confirmed.Conclusions: This split validation exercise of a relatively short and simple process exemplifies the potential of automatic cell manufacturing. Automation will further gain in attractiveness when applied to more complex processes, requiring frequent interventions or handling at unfavourable working hours, such as re-targeting of T-cells. [ABSTRACT FROM AUTHOR]

Expert performance constitutes the endpoint of skill acquisition and is accompanied by widespread neuroplastic changes. To reveal common mechanisms of reorganization associated with longterm expertise in a cognitive domain (mental calculation, chess, language, memory, music without motor involvement), we used activation likelihood estimation meta-analysis and compared brain activation of experts to nonexperts. Twenty-six studies matched inclusion criteria, most of which reported an increase and not a decrease of activation foci in experts. Increased activation occurred in the left rolandic operculum (OP 4) and left primary auditory cortex and in bilateral premotor cortex in studies that used auditory stimulation. In studies with visual stimulation, experts showed enhanced activation in the right inferior parietal cortex (area PGp) and the right lingual gyrus. Experts' brain activation patterns seem to be characterized by enhanced or additional activity in domain-specific primary, association, and motor structures, confirming that learning is localized and very specialized. [ABSTRACT FROM AUTHOR]

Copyright of Ilu: Revista de Ciencias de las Religiones is the property of Universidad Complutense de Madrid and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background aims. Immunomagnetic enrichment of CD34+ hematopoietic "stem" cells (HSCs) using paramagnetic nanobead coupled CD34 antibody and immunomagnetic extraction with the CliniMACS plus system is the standard approach to generating T-cell-depleted stem cell grafts. Their clinical beneficence in selected indications is established. Even though CD34+ selected grafts are typically given in the context of a severely immunosuppressive conditioning with anti-thymocyte globulin or similar, the degree of T-cell depletion appears to affect clinical outcomes and thus in addition to CD34 cell recovery, the degree of T-cell depletion critically describes process quality. An automatic immunomagnetic cell processing system, CliniMACS Prodigy, including a protocol for fully automatic CD34+ cell selection from apheresis products, was recently developed. We performed a formal process validation to support submission of the protocol for CE release, a prerequisite for clinical use of Prodigy CD34+ products. Methods. Granulocyte-colony stimulating factor--mobilized healthy-donor apheresis products were subjected to CD34+ cell selection using Prodigy with clinical reagents and consumables and advanced beta versions of the CD34 selection software. Target and non-target cells were enumerated using sensitive flow cytometry platforms. Results. Nine successful clinical-scale CD34+ cell selections were performed. Beyond setup, no operator intervention was required. Prodigy recovered 74 ± 13% of target cells with a viability of 99.9 ± 0.05%. Per 5 x 10E6 CD34+ cells, which we consider a per-kilogram dose of HSCs, products contained 17 ± 3 x 10E3 T cells and 78 ± 22 x 10E3 B cells. Conclusions. The process for CD34 selection with Prodigy is robust and labor-saving but not time-saving. Compared with clinical CD34+ selected products concurrently generated with the predecessor technology, product properties, importantly including CD34+ cell recovery and T-cell contents, were not significantly different. The automatic system is suitable for routine clinical application. [ABSTRACT FROM AUTHOR]

Child prodigies are rare individuals with an exceptional working memory and unique attentional skills that may facilitate the attainment of professional skill levels at an age well before what is observed in the general population. Some characteristics of prodigy have been observed to be quantitatively similar to those observed in autism spectrum disorder (ASD), suggesting possible shared etiology, though objectively validated prodigies are so rare that evidence has been sparse. We performed a family-based genome-wide linkage analysis on 5 nuclear and extended families to search for genetic loci that influence the presence of both prodigy and ASD, assuming that the two traits have the same genetic etiology in the analysis model in order to find shared loci. A shared locus on chromosome 1p31-q21 reached genome-wide significance with two extended family-based linkage methods consisting of the Bayesian PPL method and the LOD score maximized over the trait parameters (i.e., MOD), yielding a simulation-based empirical significance of p = 0.000742 and p = 0.000133, respectively. Within linkage regions, we performed association analysis and assessed if copy number variants could account for the linkage signal. No evidence of specificity for either the prodigy or the ASD trait was observed. This finding suggests that a locus on chromosome 1 increases the likelihood of both prodigy and autism in these families. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The Prodigy is a new type of internal pulse generator that controls the delivery of electrical stimuli to nervous tissue. It is capable of delivering burst stimulation, which is a novel waveform that consists of closely spaced high-frequency electrical impulses delivered in packets riding on a plateau, and followed by a quiescent period. Its inception was based on mimicking burst firing in the nervous system and usually delivered by unmyelinated fibers that uniformly have a motivational affective homeostatic function. It thereby targets a multimodal salience network, even though the stimuli are delivered at the level of the spinal cord. As such, it is specifically capable of influencing the affective/attentional components of pain. Burst stimulation was initially safely applied off-label to the auditory cortex for tinnitus, and later also to the spinal cord, the somatosensory cortex for neuropathic pain, subcutaneously for failed back surgery syndrome, and cingulate cortex for addiction and tinnitus. [ABSTRACT FROM AUTHOR]

Access to commercial CD19 CAR-T cells remains limited even in wealthy countries like Canada due to clinical, logistical, and financial barriers related to centrally manufactured products. We created a non-commercial academic platform for end-to-end manufacturing of CAR-T cells within Canada's publicly funded healthcare system. We report initial results from a single-arm, open-label study to determine the safety and efficacy of in-house manufactured CD19 CAR-T cells (entitled CLIC-1901) in participants with relapsed/refractory CD19 positive hematologic malignancies. Using a GMP compliant semi-automated, closed process on the Miltenyi Prodigy, T cells were transduced with lentiviral vector bearing a 4-1BB anti-CD19 CAR transgene and expanded. Participants underwent lymphodepletion with fludarabine and cyclophosphamide, followed by infusion of non-cryopreserved CAR-T cells. Thirty participants with non-Hodgkin's lymphoma (n=25) or acute lymphoblastic leukemia (n=5) were infused with CLIC-1901: 21 males (70%), median age 66 (range 18-75). Time from enrollment to CLIC-1901 infusion was a median of 20 days (range 15-48). The median CLIC-1901 dose infused was 2.3 × 10 6 CAR-T cells/kg (range 0.13-3.6 × 10 6 /kg). Toxicity included ≥ grade 3 cytokine release syndrome (n=2) and neurotoxicity (n=1). Median follow-up was 6.5 months. Overall response rate at day 28 was 76.7%. Median progression-free and overall survival was 6 months (95%CI 3-not estimable) and 11 months (95% 6.6-not estimable), respectively. This is the first trial of in-house manufactured CAR-T cells in Canada and demonstrates that administering fresh CLIC-1901 product is fast, safe, and efficacious. Our experience may provide helpful guidance for other jurisdictions seeking to create feasible and sustainable CAR-T cell programs in research-oriented yet resource-constrained settings., Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT03765177, identifier NCT03765177., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kekre, Hay, Webb, Mallick, Balasundaram, Sigrist, Clement, Nielsen, Quizi, Yung, Brown, Dreolini, Waller, Smazynski, Gierc, Loveless, Clark, Dyer, Hogg, McCormick, Gignac, Bell, Chapman, Bond, Yong, Fung, Lockyer, Hodgson, Murphy, Subramanian, Wiebe, Yoganathan, Medynski, Vaillan, Black, McDiarmid, Kennah, Hamelin, Song, Narayanan, Rodrigo, Dupont, Hawrysh, Presseau, Thavorn, Lalu, Fergusson, Bell, Atkins, Nelson and Holt.)