594 research outputs found
Real-time optical manipulation of cardiac conduction in intact hearts
Optogenetics has provided new insights in cardiovascular research, leading to new methods for cardiac pacing, resynchronization therapy and cardioversion. Although these interventions have clearly demonstrated the feasibility of cardiac manipulation, current optical stimulation strategies do not take into account cardiac wave dynamics in real time. Here, we developed an allâoptical platform complemented by integrated, newly developed software to monitor and control electrical activity in intact mouse hearts. The system combined a wideâfield mesoscope with a digital projector for optogenetic activation. Cardiac functionality could be manipulated either in freeârun mode with submillisecond temporal resolution or in a closedâloop fashion: a tailored hardware and software platform allowed realâtime intervention capable of reacting within 2 ms. The methodology was applied to restore normal electrical activity after atrioventricular block, by triggering the ventricle in response to optically mapped atrial activity with appropriate timing. Realâtime intraventricular manipulation of the propagating electrical wavefront was also demonstrated, opening the prospect for realâtime resynchronization therapy and cardiac defibrillation. Furthermore, the closedâloop approach was applied to simulate a reâentrant circuit across the ventricle demonstrating the capability of our system to manipulate heart conduction with high versatility even in arrhythmogenic conditions. The development of this innovative optical methodology provides the first proofâofâconcept that a realâtime optically based stimulation can control cardiac rhythm in normal and abnormal conditions, promising a new approach for the investigation of the (patho)physiology of the heart
Tuber borchii fruit body: 2-dimensional profile and protein identification
The formation of the fruit body represents the final phase of the ectomycorrhizal fungus T. borchii life cycle. Very little is known concerning the molecular and biochemical processes involved in the fructification phase. 2-DE maps of unripe and ripe ascocarps revealed different protein expression levels and the comparison of the electropherograms led to the identification of specific proteins for each developmental phase. Associating micropreparative 2-DE to microchemical approaches, such as N-terminal sequencing and 2-D gel-electrophoresis mass-spectrometry, proteins playing pivotal roles in truffle physiology were identifie
Remotely acting SMCHD1 gene regulatory elements: in silico prediction and identification of potential regulatory variants in patients with FSHD
Background: Facioscapulohumeral dystrophy (FSHD) is commonly associated with contraction of the D4Z4 macro-satellite repeat on chromosome 4q35 (FSHD1) or mutations in the SMCHD1 gene (FSHD2). Recent studies have shown that the clinical manifestation of FSHD1 can be modified by mutations in the SMCHD1 gene within a given family. The absence of either D4Z4 contraction or SMCHD1 mutations in a small cohort of patients suggests that the disease could also be due to disruption of gene regulation. In this study, we postulated that mutations responsible for exerting a modifier effect on FSHD might reside within remotely acting regulatory elements that have the potential to interact at a distance with their cognate gene promoter via chromatin looping. To explore this postulate, genome-wide Hi-C data were used to identify genomic fragments displaying the strongest interaction with the SMCHD1 gene. These fragments were then narrowed down to shorter regions using ENCODE and FANTOM data on transcription factor binding sites and epigenetic marks characteristic of promoters, enhancers and silencers
Justice and Corporate Governance: New Insights from Rawlsian Social Contract and Senâs Capabilities Approach
By considering what we identify as a problem inherent in the ânature of the firmââthe risk of abuse of authorityâwe propound the conception of a social contract theory of the firm which is truly Rawlsian in its inspiration. Hence, we link the social contract theory of the firm (justice at firmâs level) with the general theory of justice (justice at societyâs level). Through this path, we enter the debate about whether firms can be part of Rawlsian theory of justice showing that corporate governance principles enter the âbasic structure.â Finally, we concur with Senâs aim to broaden the realm of social justice beyond what he calls the âtranscendental institutional perfectionismâ of Rawlsâ theory. We maintain the contractarian approach to justice but introduce Senâs capability concept as an element of the constitutional and post-constitutional contract model of institutions with special reference to corporate governance. Accordingly, rights over primary goods and capabilities are (constitutionally) granted by the basic institutions of society, but many capabilities have to be turned into the functionings of many stakeholders through the operation of firms understood as post-constitutional institutional domains. The constitutional contract on the distribution of primary goods and capabilities should then shape the principles of corporate governance so that at post-constitutional level anyone may achieve her/his functionings in the corporate domain by exercising such capabilities. In the absence of such a condition, post-constitutional contracts would distort the process that descends from constitutional rights and capabilities toward social outcomes
Clinical trial readiness to solve barriers to drug development in FSHD (ReSolve): protocol of a large, international, multi-center prospective study
Background Facioscapulohumeral muscular dystrophy (FSHD) is a dominantly-inherited progressive muscular dystrophy caused by de-repression of the DUX4 gene, which causes disease by a toxic-gain-of-function. As molecularly targeted drugs move from preclinical testing into human trials, it is essential that we validate clinical trial tools and methodology to facilitate the drug development process. Methods/design The primary goal of this study is to hasten drug development for FSHD by validating two novel clinical outcome assessments (COAs) and refining clinical trial strategies. We will perform an 18-month longitudinal study in 220 genetically confirmed and clinically affected participants using our FSHD Clinical Trial Research Network, comprised of 8 sites in the United States, and 3 collaborating sites in Europe. Visits occur at baseline and months 3, 12, and 18. At each visit we will collect: 1) a novel FSHD functional composite COA made up of 18 evaluator-administered motor tasks in the domains of shoulder/arm, hand, core/abdominal, leg, and balance function; and 2) electrical impedance myography as a novel muscle quality biomarker (US sites). Other COAs include 1) Domain 1 of the Motor Function Measure; 2) Reachable workspace; 3) orofacial strength using the Iowa Oral Performance Instrument; 4) lean muscle mass using dual-energy X-ray absorptiometry (DEXA); 5) strength as measured by quantitative myometry and manual muscle testing; and 6) the FSHD Health Index and other patient-reported outcomes. Plasma, DNA, RNA, and serum will be collected for future biomarker studies. We will use an industry standard multi-site training plan. We will evaluate the test-retest reliability, validity, and sensitivity to disease progression, and minimal clinically important changes of our new COAs. We will assess associations between demographic and genetic factors and the rate of disease progression to inform refinement of eligibility criteria for future clinical trials. Discussion To the best of our knowledge, this is the largest collaborative study of patients with FSHD performed in the US and Europe. The results of this study will enable more efficient clinical trial design. During the conduct of the study, relevant data will be made available for investigators or companies pursuing novel FSHD therapeutics
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