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The paper aims to investigate the thesis of the so-called Neue Mythologie within the fragment entitled “Das älteste Systemprogramm des deutschen Idealismus” [“The Oldest Systematic Program of German Idealism”]. The latter presents a revolutionary project of social pedagogy linked to the use of the aesthetic character of myth and poetry in the formation of the conscience and the intellect of the people. The program, therefore, formulates a fertile dialogue between the emancipatory potential of the Enlightenment and Jena Romanticism, in that it proposes a re-evaluation of feelings and Sinnlichkeit [sensuousness] in connection to modern rationality and freedom. The links between the rational mythology of the program and Hegelian philosophy will be explored, starting from his early writings, which are strictly concerned with the importance of a popular and sensuous religion (Volksreligion). Secondly, the work will retrace the same sensuous externalization of philosophical ideas within the relationships between art, religion and philosophy in the mature system, addressing the problem of Hegel’s change of heart regarding art and mythology between the two phases of his thought. In the end the value of symbolical mediation of concepts and idea will be established.

Crohn's disease (CD) usually affects younger individuals but delayed-onset disease is not uncommon. We studied the epidemiology, demographic profile, and clinical characteristics of patients with delayed-onset CD (disease onset >50 years) and compared them with CD in younger individuals (disease onset 20–40 years) in a tertiary care center in India. The presenting symptoms, site of involvement, and treatment profile were similar, except for weight loss, which was more often noted in young-onset CD. However, granulomatous inflammation on mucosal biopsy was twice as common in young-onset compared to delayed-onset CD. As it is thus seen less often in delayed-onset CD, this may lead to a potential delay in diagnosis and treatment.

Introduction: Wire rope isolators are often used as means of vibration isolation for the transportation of fragile machine equipment. When deployed as suspension systems in a transportation scenario, a simple spring–damper model is often used to predict the dynamic loads that act on the structure being transported. However, this simple model has proved to be too simplistic to be used in the development of an accurate numerical model that can predict the vibration levels experienced by the inner components of fragile equipment during its transportation. This paper describes the experimental tests conducted on a wire rope isolator used for the transportation of the prototype SSR1 cryomodule. Materials and methods: A hysteretic Bouc–Wen model has been used to analytically describe the force–deformation relationship of the wire rope isolators. The developed model of the isolator has been implemented in a larger model to simulate the actual transportation of the prototype SSR1 cryomodule, a section of the new PIP-II linear accelerator under construction at Fermilab. A series of multibody dynamic simulations with rigid and flexible components was used to numerically determine the acceleration of some critical components. Results and conclusions: An actual experimental transportation was simulated using two numerical models: the developed Bouc–Wen model and a conventional spring–damper model. It is shown how the Bouc–Wen formulation of the isolator characteristics drastically improves the correspondence between experimental and simulated results if compared to a spring–damper model, especially in the range of 0–30 Hz which is the most critical for transportation problems.

Understanding immune responses to SARS-CoV-2 messenger RNA (mRNA) vaccines is of great interest, principally because of the poor knowledge about the mechanisms of protection. In the present study, we analyzed longitudinally B cell and T cell memory programs against the spike (S) protein derived from ancestral SARS-CoV-2 (Wuhan-1), B.1.351 (beta), B.1.617.2 (delta) and B.1.1.529 (omicron) variants of concern (VOCs) after immunization with an mRNA-based vaccine (Pfizer). According to the magnitude of humoral responses 3 months after the first dose, we identified high and low responders. Opposite to low responders, high responders were characterized by enhanced antibody-neutralizing activity, increased frequency of central memory T cells and durable S-specific CD8+T cell responses. Reduced binding antibodies titers combined with long-term specific memory T cells that had distinct polyreactive properties were found associated with subsequent breakthrough with VOCs in low responders. These results have important implications for the design of new vaccines and new strategies for booster follow-up.

Les complications chirurgicales des tumeurs à cellules géantes (TCG) sont fréquentes, la récidive étant la cause la plus connue et la plus étudiée, mais les autres causes d’échec ont été peu investiguées Aussi nous avons mené une étude rétrospective afin de déterminer les principales causes de reprise chirurgicale des patients opérés d’une TCG, et la part respective de chacune des étiologies des reprises.

Liver transplantation (LT) from donors‐with‐HIV to recipients‐with‐HIV (HIV D+/R+) is permitted under the HOPE Act. There are only three international single‐case reports of HIV D+/R+ LT, each with limited follow‐up. We performed a prospective multicenter pilot study comparing HIV D+/R+ to donors‐without‐HIV to recipients‐with‐HIV (HIV D−/R+) LT. We quantified patient survival, graft survival, rejection, serious adverse events (SAEs), human immunodeficiency virus (HIV) breakthrough, infections, and malignancies, using Cox and negative binomial regression with inverse probability of treatment weighting. Between March 2016–July 2019, there were 45 LTs (8 simultaneous liver‐kidney) at 9 centers: 24 HIV D+/R+, 21 HIV D−/R+ (10 D− were false‐positive). The median follow‐up time was 23 months. Median recipient CD4 was 287 cells/µL with 100% on antiretroviral therapy; 56% were hepatitis C virus (HCV)‐seropositive, 13% HCV‐viremic. Weighted 1‐year survival was 83.3% versus 100.0% in D+ versus D− groups (p= .04). There were no differences in one‐year graft survival (96.0% vs. 100.0%), rejection (10.8% vs. 18.2%), HIV breakthrough (8% vs. 10%), or SAEs (all p> .05). HIV D+/R+ had more opportunistic infections, infectious hospitalizations, and cancer. In this multicenter pilot study of HIV D+/R+ LT, patient and graft survival were better than historical cohorts, however, a potential increase in infections and cancer merits further investigation. A multicenter study of HIV+ donor to HIV+ recipient liver transplantation under the HOPE Act shows that patient and graft survival were better than historical cohorts, but the possible increased incidence of infections and cancer merits further investigation.

ABSTRACTLive-cell imaging is a well-established tool to gain insights into the dynamics of autophagosome formation. We have recently generated a panel of human cancer cell lines that express HaloTagged autophagy-related (ATG) proteins from their endogenous loci, providing a highly sensitive tool to study autophagosome biogenesis. Using these cell lines in combination with automated autophagic foci tracking we dissected the molecular mechanisms of phagophore initiation and expansion. Our work supports a model in which phosphorylations by the Unc-51-Like activating Kinases (ULK1/2) and phosphoinositide 3-kinases (PI3Ks) complexes trigger the recruitment of autophagy factors to mobile ATG9A-positive vesicles transforming them into phagophores. Only a small fraction, approximately 10–20%, of these phagophores expand into autophagosomes, suggesting that autophagosome biogenesis is inefficient. Finally, we demonstrate that ATG2A recruitment commits mobile phagophores to autophagosome formation via tethering to donor membranes and promoting the conjugation of human ATG8 homologues.AbbreviationsATG: autophagy-related proteins; ULK1/2: Unc-51-Like activating Kinases; PI3Ks: Phosphoinositide 3-Kinases; ATG2A: autophagy-related protein 2A; ATG5: autophagy-related protein 5; ATG16: autophagy-related protein 16; ATG8: autophagy-related protein 8; U2OS: human bone osteosarcoma epithelial cell; LC3B: microtubule-associated protein 1A/1B Light Chain 3B; GABARAPL1: GABA type A Receptor-Associated Protein Like 1; ATG9A: autophagy-related protein 9A; ATG13: autophagy-related protein 13; SQSTM1: Sequestosome-1/p62; WIPI2: WD repeat domain, Phosphoinositide Interacting 2; PI3P: Phosphoinositide-3-phosphate.

ABSTRACTDisruption of cell cycle checkpoints has been well established as a hallmark of cancer. In particular, the G1-S transition mediated by the cyclin D-cyclin-dependent kinase 4/6 (CDK4/6) pathway is dysregulated in more than 90% of melanoma cases. Therefore, tumor cells mainly rely on the G2-M checkpoint to halt the cell cycle in order to repair DNA damage. Here, we review the promising method of cell cycle-mediated synthetic lethality for melanoma treatment, which entails exploiting somatically acquired mutations in the G1-S transition with inhibitors of the G2-M transition in order to specifically kill melanoma cells. The idea stems from the theory that melanoma cells lacking G1-S checkpoints are particularly vulnerable to mitotic catastrophe when presented with G2-M checkpoint inhibition in addition to DNA damage, whereas normal cells with intact G1-S checkpoints should theoretically be spared. This review explores the link between cell cycle dysregulation and synthetic lethality in melanoma cells and discusses potential future applications for this treatment.