Challenges and Limitations of Targeting the Keap1-Nrf2 Pathway for Neurotherapeutics: Bach1 De-Repression to the Rescue
The Keap1-Nrf2 signaling axis is a validated and promising target for cellular defense and survival pathways. This minireview discusses the potential off-target effects and their impact on future drug development originating from Keap1-targeting small molecules that function as displacement activators of the redox-sensitive transcription factor Nrf2. We argue that small-molecule displacement activators, similarly to electrophiles, will release both Nrf2 and other Keap1 client proteins from the ubiquitin ligase complex. This non-specificity is likely unavoidable and may result in off-target effects during Nrf2 activation by targeting Keap1. The small molecule displacement activators may also target Kelch domains in proteins other than Keap1, causing additional off-target effects unless designed to ensure specificity for the Kelch domain only in Keap1. A potentially promising and alternative therapeutic approach to overcome this non-specificity emerging from targeting Keap1 is to inhibit the Nrf2 repressor Bach1 for constitutive activation of the Nrf2 pathway and bypass the Keap1-Nrf2 complex.
This prototype development explains the challenges encountered during the ISO/IEEE 11073 standard implementation process. The complexity of the standard and the consequent heavy requirements, which have not encouraged software engineers to adopt the standard. The developing complexity evaluation drives us to propose two possible implementation strategies that cover almost all possible use cases and eases handling the standard by non-expert users. The first one is focused on medical devices (MD) and proposes a low-memory and low-processor usage technique. It is based on message patterns that allow simple functions to generate ISO/IEEE 11073 messages and to process them easily. MD act as X73 agent. Second one is focused on more powerful device X73 manager, which do not have the MDs' memory and processor usage constraints. The protocol between Agent and Manager is point-to-point and we can distribute the functionality between devices.
Developed both implementation X73 Agent and Manager will cut developing time for applications based on ISO/EEE 11073.
Many environmental stimuli present a quasi-rhythmic structure at different timescales that the brain needs to decompose and integrate. Cortical oscillations have been proposed as instruments of sensory de-multiplexing, i.e., the parallel processing of different frequency streams in sensory signals. Yet their causal role in such a process has never been demonstrated. Here, we used a neural microcircuit model to address whether coupled theta–gamma oscillations, as observed in human auditory cortex, could underpin the multiscale sensory analysis of speech. We show that, in continuous speech, theta oscillations can flexibly track the syllabic rhythm and temporally organize the phoneme-level response of gamma neurons into a code that enables syllable identification. The tracking of slow speech fluctuations by theta oscillations, and its coupling to gamma-spiking activity both appeared as critical features for accurate speech encoding. These results demonstrate that cortical oscillations can be a key instrument of speech de-multiplexing, parsing, and encoding.
In the internal medicine wide spectrum the gastroenterology is one of the chapters, less enlightened by the scientific evidence. It does not mean that the practice of the grasntroenterology may ot be improved by the systematic use of the approaches of the evidence based medicine
The paper provides a number of proposed draft operational guidelines for technology measurement and includes a number of tentative technology definitions to be used for statistical purposes, principles for identification and classification of potentially growing technology areas, suggestions on the survey strategies and indicators. These are the key components of an internationally harmonized framework for collecting and interpreting technology data that would need to be further developed through a broader consultation process. A summary of definitions of technology already available in OECD manuals and the stocktaking results are provided in the Annex section.