Advanced brain organoids for neuroinflammation disease modeling

Brain organoids mimic closely the embryonic human brain:Over the last decade,the development of human organoid systems has evolved rapidly.Different tissues have been modeled with organoids,such as the gut,lung,liver,kidney retina and brain.These systems have a high cellular heterogeneity,with many cell types integrated into the same system.Organoids'cellular populations interact between and amongst each other in a cellular and molecular level,which represents an advantage with respects to monolayer 2D cell culture systems.

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.

Development and Validation of a Prognostic Risk Score System for COVID-19 Inpatients:A Multi-Center Retrospective Study in China

Coronavirus disease 2019(COVID-19)has become a worldwide pandemic.Hospitalized patients of COVID-19 suffer from a high mortality rate,motivating the development of convenient and practical methods that allow clinicians to promptly identify high-risk patients.Here,we have developed a risk score using clinical data from 1479 inpatients admitted to Tongji Hospital,Wuhan,China(development cohort)and externally validated with data from two other centers:141 inpatients from Jinyintan Hospital,Wuhan,China(validation cohort 1)and 432 inpatients from The Third People’s Hospital of Shenzhen,Shenzhen,China(validation cohort 2).The risk score is based on three biomarkers that are readily available in routine blood samples and can easily be translated into a probability of death.The risk score can predict the mortality of individual patients more than 12 d in advance with more than 90%accuracy across all cohorts.Moreover,the Kaplan-Meier score shows that patients can be clearly differentiated upon admission as low,intermediate,or high risk,with an area under the curve(AUC)score of 0.9551.In summary,a simple risk score has been validated to predict death in patients infected with severe acute respiratory syndrome coronavirus 2(SARS-CoV-2);it has also been validated in independent cohorts.

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).

Data-Driven Discovery of Stochastic Differential Equations

Stochastic differential equations(SDEs)are mathematical models that are widely used to describe complex processes or phenomena perturbed by random noise from different sources.The identification of SDEs governing a system is often a challenge because of the inherent strong stochasticity of data and the complexity of the system’s dynamics.The practical utility of existing parametric approaches for identifying SDEs is usually limited by insufficient data resources.This study presents a novel framework for identifying SDEs by leveraging the sparse Bayesian learning(SBL)technique to search for a parsimonious,yet physically necessary representation from the space of candidate basis functions.More importantly,we use the analytical tractability of SBL to develop an efficient way to formulate the linear regression problem for the discovery of SDEs that requires considerably less time-series data.The effectiveness of the proposed framework is demonstrated using real data on stock and oil prices,bearing variation,and wind speed,as well as simulated data on well-known stochastic dynamical systems,including the generalized Wiener process and Langevin equation.This framework aims to assist specialists in extracting stochastic mathematical models from random phenomena in the natural sciences,economics,and engineering fields for analysis,prediction,and decision making.

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.

Apolipoprotein A-IV and its derived peptide, T55−121, improve glycemic control and increase energy expenditure

It is crucial to understand the glucose control within our bodies.Bariatric/metabolic surgeries,including laparoscopic sleeve gastrec-tomy(LSG)and Roux-en-Y gastric bypass(RYGB),provide an avenue for exploring the potential key factors involved in maintaining glucose homeostasis since these surgeries have shown promising results in improving glycemic control among patients with severe type 2 diabetes(T2D).For the first time,a markedly altered population of serum proteins in patients after LSG was discovered and analyzed through proteomics.Apolipoprotein A-IV(apoA-IV)was revealed to be increased dramatically in diabetic obese patients following LSG,and a similar effect was observed in patients after RYGB surgery.Moreover,recombinant apoA-IV protein treatment was proven to enhance insulin secretion in isolated human islets.These results showed that apoA-IV may play a crucial role in gly-cemic control in humans,potentially through enhancing insulin secretion in human islets.ApoA-IV was further shown to enhance energy expenditure and improve glucose tolerance in diabetic rodents,through stimulating glucose-dependent insulin secretion in pancreaticβcells,partially via Gαs-coupled GPCR/cAMP(G protein-coupled receptor/cyclic adenosine monophosphate)signaling.Furthermore,T55-121,truncated peptide 55-121 of apoA-IV,was discovered to mediate the function of apoA-IV.These collective findings contribute to our understanding of the relationship between apoA-IV and glycemic control,highlighting its potential as a biomarker or therapeutic target in managing and improving glucose regulation.

Non-proteolytic ubiquitination of OTULIN regulates NF-κB signaling pathway

NF-κB signaling regulates diverse processes such as cell death,inflammation,immunity,and cancer.The activity of NF-κB is controlled by methionine 1-linked linear polyubiquitin,which is assembled by the linear ubiquitin chain assembly complex(LUBAC)and the ubiquitin-conjugating enzyme UBE2L3.Recent studies found that the deubiquitinase OTULIN breaks the linear ubiquitin chain,thus inhibiting NF-κB signaling.Despite the essential role of OTULIN in NF-κB signaling has been established,the regulatory mechanism for OTULIN is not well elucidated.To discover the potential regulators of OTULIN,we analyzed the OTULIN protein complex by proteomics and revealed several OTULIN-binding proteins,including LUBAC and tripartite motif-containing protein 32(TRIM32).TRIM32 is known to activate NF-κB signaling,but the mechanism is not dear.Genetic complement experiments found that TRIM32 is upstream of OTULIN and TRIM32-mediated NF-κB activation is dependent on OTULIN.Mutagenesis of the E3 ligase domain showed that the E3 ligase activity is essential for TRIM32-mediated NF-κB activation.Further experiments found that TRIM32 conjugates polyubiquitin onto OTULIN and the polyubiquitin blocks the interaction between HOIP and OTULIN,thereby activating NF-κB signaling.Taken together,we report a novel regulatory mechanism by which TRIM32-mediated non-proteolytic ubiquitination of OTULIN impedes the access of OTULIN to the LUBAC and promotes NF-κB activation.

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.