julilili42/papers huggingface dataset:
P012 Intestinal epithelial cells as targets of thiopurines in Inflammatory Bowel Disease paediatric patients-derived organoids
2024-01-01

Abstract Background Thiopurines, azathioprine (AZA) and mercaptopurine (MP), are immunomodulators used to maintain remission in patients with inflammatory bowel disease (IBD). Intestinal epithelial cells play a key role in the pathogenesis of IBD, however, their role as target cells for thiopurines has not been elucidated. The aim of the project is to establish an in vitro IBD model using organoids starting from intestinal biopsies of IBD paediatric patients to investigate thiopurine effects on intestinal epithelium. Methods Forty-four IBD patients (mean age 14.4 years, 21 males) were enrolled. Intestinal biopsies were used to isolate crypts and generate adult stem cell-derived organoids. The cytotoxicity of thiopurines (0.2-200 μM for 72 hours) was evaluated by CellTiter-Glo 3D assay. Gene expression was evaluated using TaqMan assays. Thiopurine metabolites were quantified by LC-MS/MS analysis. Proteomic profiles were analyzed by Q-Exactive Plus mass spectrometer, western blot and REACTOME pathway software. Statistical analysis was performed using GraphPad and R software. Results IBD patients-derived organoids were sensitive to thiopurine treatment in a dose-dependent manner with a high interpatient variability (Two-way ANOVA p-value&amp;lt;0.0001; IC50 2.24 μM for AZA (95% CI: 1.28–5.53 μM) and 2.65 μM for MP (95% CI: 1.43–8.27 μM)).A significant negative correlation was observed between the viability after thiopurine exposure and mRNA expression of candidate genes involved in thiopurine pharmacokinetics (ITPA, TPMT, PACSIN2 and NUDT15). The most abundant thiopurine metabolite measured on organoids treated with IC50 of MP was MeTIMP, with a concentration correlated with cell viability after MP exposure (p=0.0056, ρ=-0.99). Proteomic analysis on organoids treated with IC20 of thiopurines (0.2 μM) showed 45 differentially expressed proteins in common between AZA and MP (p&amp;lt;0.05). REACTOME enrichment analysis revealed as the most altered pathways: vesicular traffic, autophagy, protein ubiquitination and interferon signalling, while no proteins related to apoptosis were induced. Among these proteins, TRIM32, a ubiquitin ligase involved in STING activity, a key regulator of both interferon I expression and NF-kB activation, resulted downregulated by the treatment (t-test AZA: p=0.0006; MP: p=0.014) and its basal levels negatively correlated with viability rates after thiopurine exposure (AZA: p=0.006, ρ=-0.85; MP: p=0.002, ρ=-0.88). Organoid exposure to thiopurines also decreased p-STING/STING ratio, particularly after MP treatment (t-test p=0.025), and increased autophagy, assessed as LC3-II levels (t-test AZA: p=0.0006; MP: p=0.014). Conclusion Organoid cultures provide new insights on the mechanism of action of thiopurines in the intestinal epithelium.
Comments on the Contributions
2024-01-01

The contributions to this volume represent a broad range of aspects of proof-theoretic semantics. Some do so in the narrower, and some in the wider sense of the term. Some deal with issues I have been concerned with directly, and some tackle further problems. All of them open interesting new perspectives and develop the field in different directions. I will briefly comment on the significance of each contribution here.
Declaring Buddhism Dead in the 19th Century
2024-01-01

This paper elaborates the interaction of social ideologies and religion between the Japanese oligarchy of the first half of the Meiji era and the German Liberal Protestant Mission. The Protestant image conflict, the newly emerging science of comparative religion and social consolidation are considered in the context of the interests of both parties. German Protestant ethics and educational ideology were introduced as distinctly attractive nation-building strategies, appropriate for the purposes of the Meiji oligarchy. The parallels with the indigenous national doctrine of the Edo period enabled the ruling class to incorporate the new and Western ethical concepts, which founded their sympathy for the German Liberal Protestant mission. The influence of Liberal Protestant theology on Buddhist reformers is also discussed in relation to the mission’s activity in the 1880s and early 1890s.
Laryngeal Ultrasound for Identifying Vocal Fold Motion Impairment after Pediatric Heart Surgery
2024-01-01

Background: Due to the anatomical characteristics of the left recurrent laryngeal nerve (RLN), there is a potential risk of its intraoperative injury during pediatric cardiac surgery. This can result in vocal fold motion impairment (VFMI), leading to subsequent respiratory and feeding problems. Most commonly, VFMI occurs after surgical procedures requiring extensive aortic arch reconstruction, with the left side being more frequently affected. Usually, the VFMI is diagnosed by laryngoscopy, which is currently considered the gold standard. Laryngeal ultrasound is a promising non-invasive alternative to the laryngoscopy. The aim of our study was to assess the practicability and reliability of laryngeal ultrasound for the detection of VFMI following cardiac surgery.
4D Flow MRI Following TCPC: Comparison of Kinetic Energy in the Ventricles of Patients with Extracardiac Conduit and Lateral Tunnel
2024-01-01

Background: In this study we investigated differences in profiles of kinetic energy (KE) in the ventricles of patients with univentricular hearts after total cavopulmonary connection (TCPC) with extracardiac conduit (ECFT) or intraatrial-lateral tunnel (IAFT).
P171: Developing an approach to screening rare genetic diagnoses for amenability to bespoke genetic therapy development
2024-01-01

Rare genetic diseases are collectively common. These diseases are major contributors to pediatric morbidity and mortality, but few have specialized or targeted treatments. Proof-of-concept exists for precision genetic therapies like antisense oligonucleotides (ASOs) that are customized for an individual's specific genetic variant and/or ultra-rare condition. We hypothesize that less than 5% of genetic diagnoses in real-world patient cohorts offer the realistic prospect for precision therapy development, based on our current understanding of the associated pathomechanisms, natural history, and contemporary treatment methods.
Simulation of conductive hearing loss and its impact on distortion-product otoacoustic emissions using a hydrodynamic cochlea model
2024-01-01

Distortion-product otoacoustic emissions (DPOAEs) are sound signals in the ear canal arising from nonlinear amplification of hydrodynamic oscillations in the cochlea. The analysis of the growth behavior of DPOAE pressure as function of stimulus level offers a quantitative assessment of the mechanical state of the cochlea. However, middle-ear dysfunction directly influences DPOAEs and their diagnostic accuracy. The present work simulates the impact of middle-ear dysfunction on DPOAEs using a hydrodynamic model of the human cochlea coupled to a middle-ear model for five frequencies from f2=1 to 4 kHz. DPOAEs in the ear canal are simulated by simultaneously solving the equations of motion representing the dynamics of the middle-ear and cochlea models in the time domain. Increasing the damping and stiffness of the annular ligament in the middle-ear model introduces conductive hearing loss (CHL) of various degrees. The changes in estimated distortion-product thresholds (EDPTs) and slopes of input-output (I/O) functions derived from the simulated DPOAE growth behavior are compared to changes in the middle-ear transfer functions (METFs). Pooled over all frequencies and degrees of CHL, the relative change of the METF amplitude at f2 exhibits a linear dependency on the relative change of EDPT level while the relative change of the METF amplitude at the distortion-product frequency fDP is linearly related to the relative change of the slope. The statistically significant linear relationships of the relative changes in EDPT level and slope of the I/O functions with relative changes in the METF amplitude indicate that conductive hearing loss can be objectively quantified from the DPOAE growth behavior.
Evolution of Punishment in 21st Century: New Perspectives for Research
2024-01-01

This paper deals with a panoptic carceral state of the XXI century, whose functions are reduced to maximum social control through the wide use of imprisonment and quasiimprisonment practices and the spread of non-institutional forms of restriction of freedom (including non-punitive ones).The methodology of the research is based on works of Rusche, Kirchheimer, Melossi, Pavarini, Foucault, Cohen, Bauman, Albrecht and other scholars.Proposing the ideas of "quasi-deviant", "the carceral state" and "penological pessimism", the author analyses the priority of "protection of the society from deviants" in public policies in the XXI century, simulacraisation of measures of "protection of the society" and lowering the threshold of deviance.The aims of the research are to analyse: 1) the nature of contemporary penal practices; 2) the justification of punishment; 3) how social control spreads in the XXI century; 4) how the boundaries between imprisonment and non-institutional applications of imprisonment as well as between punishments and non-punitive forms of social control blur; 5) how the tension between "freedom" and "security" develop.The research covers such issues as 1) clarification of the content of the terms "prison policy" and "social control" in the XXI century; 2) political and economic nature of new trends in social control policies and practices; 3) global consequences on crime prevention, sentencing and prison policies; 4) probable scenarios for the evolution of social control policies in the global and national dimensions; 5) the concept of a quasi-deviant as a special new collective object of social control; 6) penological pessimism as a fundamental characteristic of social control policy and practices; 7) growing supranational nature of modern prison policy; 8) institutional violence in the XXI century.
Special issue on a 90-year journey towards light from the intramolecular universe
2024-01-01

Over the past nearly 90 years, scientists have gradually revealed the mysteries of intramolecular motion and chemical bonds through continuous research and innovation.In 1928, Irish scientist E. Synge proposed a method to overcome the limit of classical optical resolution, which laid the foundation for the subsequent development of scanning near-field optical microscopes.Near-field optical microscopy continues to push optical resolution to new records, well beyond the diffraction limit of traditional optical microscopy.By overcoming the resolution limit of classical optics, scientists have gradually achieved in-depth understanding of intramolecular motions.The combination of Raman spectroscopy and scanning near-field optical microscopy further improves the spatial resolution of chemical identification capability down to Angstrom level, and the full spatial mapping of various intrinsic vibrational modes in the intramolecular universe can be revealed.The ability of such Angstromresolved spatial resolution to determine the chemical structure of unknown molecules arouse extensive interests of researchers in the fields of chemistry, physics, materials, biology, and stimulated active research to explore the underlying super-resolution mechanisms, to interpret the experimental data, and to mature the technique for wider applications.With this special issue 'Nanospectroscopy, nanooptics and nanofabrication', we wish to highlight the rapid experimental and theoretical advances of this burgeoning
Alpha-synuclein pathology in the "weaver" mouse, a genetic model of dopaminergic denervation.
2024-01-01

Alpha-synuclein plays a pivotal role in Parkinson's disease (PD) pathogenesis, with α-synuclein aggregates/oligomers being identified as toxic species and phosphorylation at Serine 129 promoting aggregation/oligomerization. We investigated the biochemical profile of α-synuclein in the "weaver" mouse, a genetic PD model. Our results revealed increased Serine 129 phosphorylation in the midbrain, striatum, and cortex at a phase of established dopaminergic degeneration on postnatal day 100. These results indicate α-synuclein pathology already at this stage and the potential for age-related progress. Our findings confirm that the "weaver" mouse is an invaluable genetic model to study α-synuclein pathogenesis during PD progression.
Harmony via Reductions and Expansions
2024-01-01

Abstract The notion of harmony arises by considerations about the notion of assertion in the theory of meaning. When applied to rules in the format of natural deduction, harmony can be explained by making reference to certain transformations on derivations, called reductions and expansions. Reductions are a key ingredient of the proof of normalization for the calculus of natural deduction for intuitionistic logic. In this calculus, normal derivations that are closed (i.e. such that their conclusions depend on no assumption) end with an introduction rule, a fact which is referred to as the canonicity of closed normal derivations. The condition for the canonicity of normal derivations in a more general setting are discussed. The chapter ends with a brief discussion of other accounts of harmony.
Two Kinds of Difficulties
2024-01-01

Abstract Two distinct kinds of cases, going back to Crabbé and Ekman, show that the Tennant-Prawitz criterion for paradoxicality overgenerates, that is, there are derivations which are intuitively non-paradoxical but which fail to normalize. We argue that a solution to “Ekman’s paradox” consists in restricting the set of admissible reduction procedures to those that do not yield a trivial notion of identity of proofs. We then discuss a different kind of solution, due to von Plato, and recently advocated by Tennant, consisting in reformulating natural deduction elimination rules in general (or parallelized) form. Developing intuitions of Ekman we show that the adoption of general rules has the consequence of hiding redundancies within derivations. Once reductions to get rid of the hidden redundancies are devised, it is clear that the adoption of general elimination rules offers no remedy to the overgeneration of the Prawitz-Tennant analysis. In this way, we indirectly provide further support for our own solution to Ekman’s paradox.
Identity of Proofs
2024-01-01

Abstract Proof-theoretic semantics is here presented as primarily concerned with the investigation of the relationship between proofs (understood as abstract entities) and derivations (the linguistic representations of proofs). This relationship is taken to be analogous to that between names and (abstract) objects in Frege. On this conception of proof-theoretic semantics, reductions and expansions should be viewed as identity-preserving operations on derivations and thus as inducing an equivalence relation on derivations such that equivalent derivations denote the same proof. Using this equivalence on derivations it is possible to define an equivalence relation on formulas that is stricter than interderivability, called isomorphism. We argue that identity of proofs and formula isomorphism show the intensional nature of this conception of proof-theoretic semantics. Finally, this conception is compared to the one advocated by Dummett and Prawitz, which is based on a notion of validity of derivations.
Validity, Sense and Denotation in the Face of Paradoxes
2024-01-01

Abstract Which modifications does the account of PTS developed in the second chapter need to undergo for it to be applicable to languages containing paradoxical expressions? We argue that one of the basic tenets of Prawitz-Dummett PTS—namely, the definition of the correctness of an inference as validity preservation—must be given up. As a result, the proposed account of PTS is enriched by introducing a notion of sense alongside the one of denotation. Paradoxical derivations are shown to act as the proof-theoretic analog of singular terms endowed with sense but lacking a denotation. The question of which class of derivations should be regarded as having a denotation is reconsidered, and we show the consequences of the choice of different criteria of identity of proofs for the analysis of languages containing paradoxical expressions.
Towards an Intensional Notion of Harmony
2024-01-01

Abstract In this chapter we discuss how the intensional account of harmony sketched in the first chapter can be developed in a systematic way for a class of connectives whose rules are obtained in a uniform way using an inversion principle. To handle disjunction and disjunction-like connectives, the formulation of the expansions requires particular care. We discuss and compare two different ways of formulating the inversion principle and finally we investigate the prospects of developing an account of harmony for connectives whose rules do not obey inversion, pointing at the weakness of the approaches proposed in the literature so far.
Paradoxes: A Natural Deduction Approach
2024-01-01

Abstract The chapter introduces the Prawitz-Tennant analysis of paradoxes, according to which paradoxes are derivations of a contradiction which cannot be brought into normal form, due to “loops” arising in the process of reduction. After presenting Prawitz’ original formulation of Russell’s paradox, we introduce a simplified presentation of it, and then discuss the relevance of the difference between intuitionistic and classical logic and of structural properties of derivability for the Prawitz-Tennant analysis.
Introduction
2024-01-01

Abstract Over the last few years, we have witnessed a surge in protest movements around the world. As planet Earth shows its vulnerability and a global pandemic has fundamentally recalibrated the textures of our individual and collective lives, a shared concern for survival triggers individuals and groups to contest the status quo and to call for alternative solutions to the pressing issues of our time. These problems confront us with irreducible complexity, and therefore trigger a wide variety of protest responses across the political spectrum, such as the global ‘Fridays for Future’ demonstrations, or the protests against coronavirus restrictions that have found strong support, particularly among the constituencies of right-wing, populist parties. Dissenting movements, thus, can take a range of forms. At their core, however, they share a common pattern, i.e. (1) they seek to manage the irreducible complexity of reality, (2) they make normative claims about what constitutes a good life, and (3) they offer visions of transformation and hope for a future. This is the stuff of theology, and, indeed, religious and theological messages are often explicitly present in protest movements. Yet, paradoxically, within religious communities, protest is often seen either as inherently intrinsic to, or simply antithetical to, religious loyalty (or ‘faithfulness’).
Elevating MAPK Pathway Suppression with Combinatorial ERK Inhibitors
2024-01-01

Background: The advent of small molecule inhibitors specifically designed for BRAF mutations at V600, along with their downstream target MEK, marked a significant advancement in treating BRAF mutant melanoma. Despite their notable anti-tumor activity and enhanced patient survival, the rapid emergence of resistance poses a significant challenge, limiting their clinical efficacy. Various resistance mechanisms have been documented, with a common feature being the reactivation of the MAPK signaling pathway, primarily mediated by extracellular signal-regulated kinases 1 and 2 (ERK1/2). Methods: The ERK1/2 inhibitor (ERKi) ravoxertinib (GDC0994) was tested in monolayer culture on different melanoma cell lines with/without an acquired resistance to either BRAF inhibitor (BRAFi) monotherapy or its combination with a MEK inhibitor (BRAFi + MEKi). To evaluate the efficacy of the drug, we tested its short-term impact on cell viability, the induction of apoptosis via cell cycle analyses, the pathway blockade/induction via Western Blot and the long-term effect in a colony formation assay. Results: Melanoma cell lines with an acquired resistance to BRAF inhibitors or to the combination of BRAF and MEK inhibitors as well as the respective parental cells responded to long-term treatment with the ERK1/2 inhibitor by reduction of melanoma cell growth, which seemed to be independent of the sensitivity to BRAF or MEK inhibitors. Moreover, cell cycle analyses and cell viability assays revealed a distinct benefit of adding ERK1/2 inhibitor to BRAF and/or MEK inhibitors to effectively target the melanoma cells with BRAF mutation. Conclusions: In conclusion, our results show that the ERK1/2 inhibitor ravoxertinib (GDC0994) exerts only limited anti-tumor activity as a monotherapy. However, the combination of ERKi and BRAFi/MEKi causes growth inhibition and apoptosis in BRAF mutated melanoma cells irrespective of the sensitivity to BRAF or MEK inhibitors. Additional ERKi is effective especially in a chronic, long-term setting. Combinatorial treatment regimens including ERK1/2 inhibitors might be an attractive, novel therapeutic strategy in BRAF mutated melanoma cells.
Sex differences and its impact on treatment outcomes of advanced melanoma in Germany – a DeCOG study on 2032 patients of the multicenter prospective skin cancer registry ADOREG
2024-01-01

Background: The incidence of melanoma is increasing in patients of both sexes. It is known that women and men have differences in their innate and acquired immune systems. Knowing these differences, it is reasonable to hypothesize that the reagibility of the immune system and hereby the efficacy of tumor therapies might be dependent on sex. This study assessed sex-based differences in the outcome to different treatment strategies in metastatic melanoma. Methods: Patients with advanced (stage IV, AJCCv8) metastatic melanoma who were first-line treated with either PD-1-based immune checkpoint inhibition (ICI) as monotherapy or combination, or targeted therapy (TT) with BRAF plus MEK inhibitors were identified from the prospective multicenter skin cancer registry ADOREG. The study endpoints were best overall response (BOR), progression-free survival (PFS), and overall survival (OS); all endpoints were evaluated univariately and multivariately with focus on sex differences. Results: 2032 evaluable patients were identified who were treated with ICI or TT. Of those, 1274 (62.7%) were male and 758 (37.3%) were female. Median age was 66 years (range: 20-96) in the ICI cohort, and 60 years (range: 20-90) in the TT cohort. Most patients (n=1484 (73%); m: 941, f: 534) received ICI therapy; 548 patients (27%; m: 333, f: 215) were treated with TT. There were no sex-specific differences in BOR (ICI: p=0.83; TT: p=0.52), PFS (ICI: p=0.46; TT: p=0.21), and OS (ICI: p=0.20; TT: p=0.30). There were also no significant sex-specific differences in OS when patients were separately investigated by serum LDH (normal LDH: p=0.41; elevated LDH: p=0.39) or BRAF status (BRAF wt: p=0.15; BRAF mut: p=0.82). The multivariate analyses likewise showed no sex-specific differences in BOR, PFS and OS. However, LDH and ECOG were confirmed as independent influencing variables in terms of PFS and LDH, ECOG and type of therapy in terms of OS. Conclusions: There were no sex differences in first-line treatment outcomes in terms of response and survival in patients with advanced metastatic melanoma, irrespective of whether they received ICI or TT. There were also no sex differences in treatment response when BRAF status or LDH levels were measured.