The interplay between genotype, metabolic state and cofactor treatment governs phenylalanine hydroxylase function and drug response

The discovery of a pharmacological treatment for phenylketonuria (PKU) raised new questions about function and dysfunction of phenylalanine hydroxylase (PAH), the enzyme deficient in this disease. To investigate the interdependence of the genotype, the metabolic state (phenylalanine substrate) and treatment (BH4 cofactor) in the context of enzyme function in vitro and in vivo, we (i) used a fluorescence-based method for fast enzyme kinetic analyses at an expanded range of phenylalanine and BH4 concentrations, (ii) depicted PAH function as activity landscapes, (iii) retraced the analyses in eukaryotic cells, and (iv) translated this into the human system by analyzing the outcome of oral BH4 loading tests. PAH activity landscapes uncovered the optimal working range of recombinant wild-type PAH and provided new insights into PAH kinetics. They demonstrated how mutations might alter enzyme function in the space of varying substrate and cofactor concentrations. Experiments in eukaryotic cells revealed that the availability of the active PAH enzyme depends on the phenylalanine-to-BH4 ratio. Finally, evaluation of data from BH4 loading tests indicated that the patient's genotype influences the impact of the metabolic state on drug response. The results allowed for visualization and a better understanding of PAH function in the physiological and pathological state as well as in the therapeutic context of cofactor treatment. Moreover, our data underscore the need for more personalized procedures to safely identify and treat patients with BH4-responsive PAH deficienc

Pahenu1 is a mouse model for tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency and promotes analysis of the pharmacological chaperone mechanism in vivo

The recent approval of sapropterin dihydrochloride, the synthetic form of 6[R]-l-erythro-5,6,7,8-tetrahydrobiopterin (BH4), for the treatment of phenylketonuria (PKU) as the first pharmacological chaperone drug initiated a paradigm change in the treatment of monogenetic diseases. Symptomatic treatment is now replaced by a causal pharmacological therapy correcting misfolding of the defective phenylalanine hydroxylase (PAH) in numerous patients. Here, we disclose BH4 responsiveness in Pahenu1, a mouse model for PAH deficiency. Loss of function resulted from loss of PAH, a consequence of misfolding, aggregation, and accelerated degradation of the enzyme. BH4 attenuated this triad by conformational stabilization augmenting the effective PAH concentration. This led to the rescue of the biochemical phenotype and enzyme function in vivo. Combined in vitro and in vivo analyses revealed a selective pharmaceutical action of BH4 confined to the pathological metabolic state. Our data provide new molecular-level insights into the mechanisms underlying protein misfolding with loss of function and support a general model of pharmacological chaperone-induced stabilization of protein conformation to correct this intracellular phenotype. Pahenu1 will be essential for pharmaceutical drug optimization and to design individually tailored therapie

Sobre a Europa e sua lida com os outros

O artigo empreende a tentativa de refletir criticamente sobre a possibilidade de um contato não danoso com o outro, indicada sob o mote da interculturalidade, à luz do pensamento radical de Lévinas e Derrida sobre a alteridade. Essa reflexão se encontra sob a suspeita de que as filosofias ou fenomenologias da interculturalidade não dão conta da negatividade do encontro intercultural de fato com o outro irredutível, como a história do imperialismo e colonialismo europeus produziram. Para comprovar isso, eu refletirei sobre as funções, as quais o conceito de cultura assumiu nos discursos sobre a Europa. No centro da questão se encontra a comprovação de que a identificação da superioridade europeia sob o signo da cultura implica na constituição do outro como um outro ameaçador, a qual promove a brutalidade desta lida, ou seja, a história da violência – tanto interna quanto externa – da Europa. Sobre este plano de fundo eu concluo com o rascunho de alguns contornos de uma política da não-indiferença cultural, cujas raízes vejo remeterem ao pensamento de uma descolonização do imaginário da Europa

Anterior Thalamic High Frequency Band Activity Is Coupled with Theta Oscillations at Rest

Cross-frequency coupling (CFC) between slow and fast brain rhythms, in the form of phase–amplitude coupling (PAC), is proposed to enable the coordination of neural oscillatory activity required for cognitive processing. PAC has been identified in the neocortex and mesial temporal regions, varying according to the cognitive task being performed and also at rest. PAC has also been observed in the anterior thalamic nucleus (ATN) during memory processing. The thalamus is active during the resting state and has been proposed to be involved in switching between task-free cognitive states such as rest, in which attention is internally-focused, and externally-focused cognitive states, in which an individual engages with environmental stimuli. It is unknown whether PAC is an ongoing phenomenon during the resting state in the ATN, which is modulated during different cognitive states, or whether it only arises during the performance of specific tasks. We analyzed electrophysiological recordings of ATN activity during rest from seven patients who received thalamic electrodes implanted for treatment of pharmacoresistant focal epilepsy. PAC was identified between theta (4–6 Hz) phase and high frequency band (80–150 Hz) amplitude during rest in all seven patients, which diminished during engagement in tasks involving an external focus of attention. The findings are consistent with the proposal that theta–gamma coupling in the ATN is an ongoing phenomenon, which is modulated by task performance

The Violent Potential of Unconditional Claims in Conflict: Reflections on the Discourse concerning the Destruction of the Buddhas of Bamiyan

On a general level, the article analyzes how the clash of unconditional claims between secular rationales and religious narratives is prone to engender violence. To provide this discussion with material evidence, the case of the destruction of the Buddhas of Bamiyan and its media coverage is put under scrutiny. The author shows how the marker of “religious violence”, otherness, and irrationality was (re)constructed in this context. In the last analysis, the article demonstrates that a parasitic relationship obtains between an occidentalist brand of reason and its presumed other (epitomized in the gestalt of “religious violence”)