Is serine racemase(SRR) a second hit target for LRRK2-G2019S induced Parkinson's disease?

To date,at least 7 million people are suffering from Parkinson's disease(PD)worldwide,which is the second most prevalent,age-associated,and progressive neurodegenerative disorder(Tysnes and Storstein,2017).Given the accelerated global pace of aging,it becomes of fundamental importance that we start understanding the origins of neurodegeneration in order to develop effective disease modifying treatments.Most PD patients suffer from a combination of motor and nonmotor disabilities.

Exploring the contribution of the mitochondrial disulfide relay system to Parkinson’s disease:the PINK1/CHCHD4 interplay

Parkinson’s disease(PD)is a common movement disorder of the elderly caused by the degeneration of dopaminergic neurons in the substantia nigra pars compacta of the brain.Both environmental and genetic factors pointed out mitochondrial dysfunction as a major cause of neurodegeneration in PD.Pioneering studies using mitochondrial toxins revealed their ability to trigger dopaminergic cell death and irreversible parkinsonism in different animal models(Poewe et al.,2017).Typical features of mitochondrial dysfunction have been also observed in the human brain of idiopathic PD cases,showing alterations of respiratory chain complex I and IV activity,accumulation of mtDNA deletions and increased oxidative stress(Bender et al.,2006).Moreover,a number of genes found mutated in familial PD forms encode for proteins involved in the maintenance of mitochondrial homeostasis and quality control.Among these,the PINK1 gene encodes a mitochondrial serine/threonine kinase implicated in key neuroprotective functions,including mitophagy,regulation of mitochondrial transport,control of the mitochondria/endoplasmic reticulum crosstalk and calcium homeostasis(Brunelli et al.,2020).

Integration of multiple flexible electrodes for realtime detection of barrier formation with spatial resolution in a gut-on-chip system

In healthy individuals,the intestinal epithelium forms a tight barrier to prevent gut bacteria from reaching blood circulation.To study the effect of probiotics,dietary compounds and drugs on gut barrier formation and disruption,human gut epithelial and bacterial cells can be cocultured in an in vitro model called the human microbial crosstalk(HuMiX)gut-on-a-chip system.Here,we present the design,fabrication and integration of thin-film electrodes into the HuMiX platform to measure transepithelial electrical resistance(TEER)as a direct readout on barrier tightness in realtime.As various aspects of the HuMiX platform have already been set in their design,such as multiple compressible layers,uneven surfaces and nontransparent materials,a novel fabrication method was developed whereby thin-film metal electrodes were first deposited on flexible substrates and sequentially integrated with the HuMiX system via a transfer-tape approach.Moreover,to measure localized TEER along the cell culture chamber,we integrated multiple electrodes that were connected to an impedance analyzer via a multiplexer.We further developed a dynamic normalization method because the active measurement area depends on the measured TEER levels.The fabrication process and system setup can be applicable to other barrier-on-chip systems.As a proof-of-concept,we measured the barrier formation of a cancerous Caco-2 cell line in real-time,which was mapped at four spatially separated positions along the HuMiX culture area.

Global DNA methylation and transcriptional analyses of human ESC-derived cardiomyocytes

With defined culture protocol, human embryonic stem cells （hESCs） are able to generate cardiomyocytes in vitro, therefore providing a great model for human heart development, and holding great potential for car- diac disease therapies. In this study, we successfully generated a highly pure population of human cardio- myocytes （hCMs） （〉95% cTnT＋） from hESC line, which enabled us to identify and characterize an hCM-specific signature, at both the gene expression and DNA meth- ylation levels. Gene functional association network and gene-disease network analyses of these hCM-enriched genes provide new insights into the mechanisms of hCM transcriptional regulation, and stand as an informative and rich resource for investigating cardiac gene func- tions and disease mechanisms. Moreover, we show that cardiac-structural genes and cardiac-transcription fac- tors have distinct epigenetic mechanisms to regulate their gene expression, providing a better understandingof how the epigenetic machinery coordinates to regulate gene expression in different cell types.