211 research outputs found
The Sublime in motion : Longinus, Freud, and embedded metaphors
This paper explores the relevance and the effect of the sublime in connection with Dionysian inspiration, Freud’s concept of the uncanny, and the interpretation of metaphorical thinking developed in the field of cognitive psychology.
Keywords Sublime. Longinus. Dionysus. Freud. Metaphors
Claudian's De raptu III 126-7. Ceres' intertextual unconscious
The intertextual models of the passage in question point to Ceres' sense of guilt for abandoning her daughter
In silico screening on the herg potassium channel
Während des Arzneistoffentwicklungsprozesses scheitern fast 35% der Arzneistoffe wegen
schlechter Absorption, Verteilung, Metabolismus, Ausscheidung und Toxizität (ADMET). Ein
wichtiger Bestandteil dieses Scheiterns ist die Interaktion mit Anti-Target Proteinen wie
Cytochrom P450, P-glycoprotein und dem hERG Kaliumkanal.
Der hERG Kaliumkanal ist in vielen verschiedenen Zellen und Geweben wie dem Herz, Nerven
und glatten Muskelzellen vorhanden. Im Herzen spielt der hERG Kanal während des
Aktionspotentials in der dritten Phase der kardialen Repolarisierung wegen der Weiterleitung des
schnellen Kalium Ausstroms (Ikr) eine wichtige Rolle. Ein Verzögern dieser Phase führt zum
Long QT Syndrom (LQTs), das eine potenziell tödliche Arrhythmie verursachen kann. Viele
Klassen von Medikamenten wurden wegen ihren Wechselwirkungen mit dem hERG Kanal in
den letzten zehn Jahren vom Markt zurĂĽckgezogen. Wie auch andere Anti-Target Proteine, ist
der hERG Kanal in der Ligandenerkennung unspezifisch, weshalb er mit vielen Klassen von
Arzneistoffen wie Psychopharmaka, Antihistaminika, Antiarrhythmika und Antibiotika
interagieren kann. Viele Studien zeigen, dass eine erhebliche Anzahl von Molekülen während
der SchlieĂźung des Kanals nicht dissoziieren und im geschlossenen Zustand des hERG Kanals
gefangen bleiben.
In dieser Studie wurden Propafenon und dessen Derivate in ein Homologie-Modell des hERG
Kanals im geschlossenen und geöffneten Zustand gedockt, um die hERG Hemmung und das
„drug trapping“ besser verstehen zu können.
Ziel war es, die Wechselwirkungen zwischen dem hERG Kanal im geschlossenen Zustand und
den Liganden zu untersuchen. Aufgrund dessen wurde eine Serie von „trapped“ Propafenon-
Derivaten im hERG Kanal, welcher sich im geschlossenen Zustand befand, mit Dock, einem
Docking Modul des Programms MOE, und GLIDE, dem Docking-Programm von Schrödinger,
gedockt. Es wurde ein svl-Skript, genannt ROTALI, verwendet, um RMSD Matrizen zu
erstellen, mit welchen die Duplikate unter den Posen, die in Bezug auf die Central Cavity
unterschiedlich positioniert waren, zu erkennen und zu löschen. In weiterer Forlge wurden die
möglichen binding modes durch agglomeratives hierarchisches Clustering identifiziert. Die
Analyse der Posen führte zur Identifizierung von zwei möglichen Binding Modes. Derselbe Prozess wurde angewandt, um eine Serie von Propafenon-Derivaten in ein Homologie-
Modell des hERG Kanals im geöffneten Zustand zu docken. Drei mögliche Binding Modes
wurden durch die agglomerative Cluster Analyse der RMSD Matrix identifiziert, welche durch
das gemeinsame Gerüst der Propafenon Derivate und jenen Aminosäuren generiert wurde, die
mit den Molekülen interagierten. Um die Flexibilität des Proteins zu berücksichtigen wurden die
Propafenon Derivate zusätzlich in acht verschiedene Schnappschüsse einer Moleküldynamik des
Homologie-Modelles des hERG Kanals im geöffneten Zustand gedockt. In diesem Fall wurden
zwei Binding Modes selektiert.
Interessanterweise war es durch das Einordnen der Posen der fĂĽnf oben genannten Cluster nach
der potenziellen Energie des R1 Substituenten, geteilt durch die Anzahl an Schweratomen,
möglich, zwischen den „Trapped“ und „non-Trapped“ Propafenon-Derivaten zu unterscheiden.
Dieser Wert war bei den „non-Trapped“ Substanzen immer höher als bei den „Trapped“
Molekülen. Der Umstand, dass dies auch bei den Vertretern des fünften Clusters möglich ist, bei
denen der R1 Substituent unterhalb der vier Phe656 zum Liegen kommt, deutet darauf hin, dass
das Phänomen des Drug-Trappings mehr auf die inhärenten Eigenschaften des R1 Substituenten
als auf seine Konformation zurĂĽckzufĂĽhren ist, wenn er mit dem hERG Kanal interagiert. Dies
könnte bedeuten, dass die Starrheit und die Sperrigkeit der Substituenten bestimmt ob
Propafenon und dessen Derivate „Trapped“ sind oder
nicht, unabhängig vom Bindemodus im hERG Kanal.During the drug development process, almost 35% of the compounds fail due to poor absorption,
distribution, metabolism, excretion and toxicity (ADMET). An important role on these failures is
played by improper interactions with antitarget proteins, such as cytocrome P450, P-glycoprotein
and the hERG potassium channel.
The hERG potassium channel is expressed in various cells and tissues, such as heart, neurons
and smooth muscle. In the heart, the hERG channel plays an important role in the third phase of
heart repolarization, due to the conduction of the rapid delayed rectifier K+ current (Ikr). A delay
of this phase of repolarization leads to a syndrome called Long QT syndrome (LQTs) which
might cause a potentially fatal arrhythmia called Torsade de Pointes (TdP). Many different
classes of compounds were withdrawn from the market in the past decade due to their interaction
with the hERG channel. Similar to other antitarget proteins, the hERG channel is polyspecific in
the ligand recognition, hence it can interact with many classes of compounds, such as
psychiatric, antihistaminic, antiarrhytmic and antimicrobial drugs. Several studies show that
some molecules do not dissociate during the channel gating and are trapped in the closed state of
the hERG channel.
In this study, propafenone and derivatives were docked into homology models of the hERG
channel in the closed and open states to shed more light on hERG inhibition and on drug
trapping.
With the aim to investigate the interactions between the hERG channel in the closed state and the
compounds investigated, a series of trapped propafenone derivatives were docked into the
homology model of the hERG channel in the closed conformation using Dock, the docking tool
of MOE, and Glide, the docking tool of Schrödinger. A svl script called ROTALI was used to
generate RMSD matrices with which the duplicate poses lying in different directions of the
central cavity were detected and deleted, thus allowing to identify possible binding modes
through agglomerative hierarchical clustering. This analysis led to the identification of two
possible binding modes.
The same process was applied to the poses obtained by docking the propafenones into a
homology model of the hERG channel in the open state. Three possible binding modes were selected through agglomerative cluster analysis of the RMSD matrix generated taking into
account the propafenone derivatives’ common scaffold and the amino acids that might interact.
Finally, in order to take into account protein flexibility, nine propafenone derivatives were
docked into eight models of the hERG channel in the open state obtained from snapshots of
molecular dynamics simulations. Clustering both according to the common scaffold RMSD and
the RMSD matrix of the amino acids interacting with the poses, two binding modes were
selected. Biological studies suggest that non-trapped propafenones hinder the hERG channel
gating with a mechanism called “foot in the door”. In four out of the five selected clusters, it is
possible to explain the “foot in the door” mechanism.
Interestingly, ranking the poses of the five clusters above-mentioned according to the potential
energy values of the R1 substituent, and according to this value divided by the number of heavy
atoms, it is possible to distinguish between trapped and non-trapped propafenones. In the nontrapped
compounds, this value is always higher than in the trapped ones. The fact that it works
also in cluster five, where the R1 substituents are placed under the ring formed by the four
Phe656, might indicate that drug trapping phenomena depend more on intrinsic properties of the
R1 susbstituent rather than on its conformation when it interacts with the hERG channel. Hence,
this might indicate that the rigidity and the bulkyness of the substituent determines whether a
propafenone derivatives is trapped or not independently of the binding mode in the hERG
channel
Una grande tradizione e una sfida per il futuro
La nascita della rivista Maia nel quadro degli studi italiani di filologia nel dopoguerra
Performance evaluation and optimal design of supermarket refrigeration systems with supermarket model "SuperSim", Part II: Model applications
This is the post-print version of the final paper published in International Journal of Refrigeration. The published article is available from the link below. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. Copyright @ 2010 Elsevier B.V.As described in Part I, the supermarket simulation software “SuperSim” with its integrated refrigeration, building and HVAC system models, can be used to evaluate, compare and optimize alternative supermarket refrigeration systems. In Part II the model was used to evaluate and compare the performance of a CO2 booster refrigeration system with that of a conventional R404A multiplex system in a supermarket application. Floating head pressure control was implemented for both systems when they were in subcritical cycles. For the CO2 system, when the system was in transcritical cycle due to higher ambient air temperature, the head pressure was optimized through extensive thermodynamic cycle analysis as a function of ambient air temperature. The performance of the CO2 booster system in the supermarket was then simulated during a one year period and compared with that of the R404A system. As a result, the system performance will benefit from a lower ambient temperature and a sizeable heat recovery for the CO2 system
Recognition and the Character of Seneca's Medea
This article examines the character and identity of Seneca's Medea. Focusing on the recognition scene at the end of the play, I investigate how Medea constructs herself both as a literary figure and as an implied human personality. The concluding scene of Seneca's Medea raises crucial questions about self-coherence and recognisability: in contrast to other moments of anagnĹŤrisis in Greco-Roman drama, it confirms the pre-existing facets of Medea's identity, rather than revealing new ones. This concept of recognition as self-confirmation is also integral to Seneca's Stoic view of human selfhood, and Medea's use of Stoic principles in this play reinforces her dual status as textual entity and quasi-person
Treatment with COLchicine in hospitalized patients affected by COVID-19: The COLVID-19 trial
Objective: To evaluate whether the addition of colchicine to standard of care (SOC) results in better outcomes in hospitalized patients with COVID-19. Design: This interventional, multicenter, randomized, phase 2 study, evaluated colchicine 1.5 mg/day added to SOC in hospitalized COVID-19 patients (COLVID-19 trial) and 227 patients were recruited. The primary outcome was the rate of critical disease in 30 days defined as need of mechanical ventilation, intensive care unit (ICU), or death. Results: 152 non-anti-SARS-CoV-2-vaccinated patients (colchicine vs controls: 77vs75, mean age 69.1±13.1 vs 67.9±15 years, 39% vs 33.3% females, respectively) were analyzed. There was no difference in co-primary end-points between patients treated with colchicine compared to controls (mechanical ventilation 5.2% vs 4%, ICU 1.3% vs 5.3%, death 9.1% vs 6.7%, overall 11 (14.3%) vs 10 (13.3%) patients, P=ns, respectively). Mean time to discharge was similar (colchicine vs controls 14.1±10.4 vs 14.7±8.1 days). Older age (>60 years, P=0.025), P/F<275 mmHg (P=0.005), AST>40 U/L (P<0.001), pre-existent heart (P=0.02), lung (P=0.003), upper-gastrointestinal (P=0.014), lower-gastrointestinal diseases (P=0.009) and cancer (P=0.008) were predictive of achieving the primary outcome. Diarrhoea (9.1% vs 0%, p=0.0031) and increased levels of AST at 6 days (76.9±91.8 vs 33.5±20.7 U/l, P=0.016) were more frequent in the colchicine group. Conclusion: Colchicine did not reduce the rate and the time to the critical stage. Colchicine was relatively safe although adverse hepatic effects require caution. We confirm that older (>60 years) patients with comorbidities are characterized by worse outcome
[Review of] M. M. Gorey, Atomism in the Aeneid: physics, politics, and cosmological disorder
Discussione del libro di Gore
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