Biology subjects

Huang, P.

Publications and source records attributed to Huang, P..

165 records · Page 10Linked to original sources

bioRxiv2017

Resting-state connectivity predicts patient-specific effects of deep brain stimulation for Parkinson’s disease

Neural circuit-based guidance for optimizing patient screening, target selection and parameter tuning for deep brain stimulation (DBS) remains limited. To this end, we propose a functional brain connectome-based modeling approach that simulates network-spreading effects of stimulating different brain regions and quantifies rectification of abnormal network topology in silico. We validate these analyses by predicting nuclei in basal-ganglia circuits as top-ranked targets for 43 local patients with Parkinsons disease and 90 patients from public database. However, individual connectome-based predictions demonstrate that globus pallidus and subthalamic nucleus (STN) constituted as the best choice for 21.1% and 19.5% of patients, respectively. Notably, the priority rank of STN significantly correlated with motor symptom severity in the local cohort. By introducing whole-brain network diffusion dynamics, these findings unfold a new dimension of brain connectomics and underscore the importance of neural network modeling for personalized DBS therapy, which warrants experimental investigation to validate its clinical utility.

neuroscience↗

bioRxiv2017

A dementia-associated risk variant near TMEM106B alters chromatin architecture and gene expression

Neurodegenerative diseases pose an extraordinary threat to the worlds aging population, yet no disease-modifying therapies are available. While genome-wide association studies (GWAS) have identified hundreds of novel risk loci for neurodegeneration, the mechanisms by which these loci influence disease risk are largely unknown. Indeed, of the many thousands of SNP-trait associations identified by GWAS over the past ~10 years, very few are understood mechanistically. Here, we investigate the association of common genetic variants at the 7p21 locus with risk for the neurodegenerative disease frontotemporal lobar degeneration. We show that variants associated with disease risk correlate with increased brain expression of the 7p21 gene TMEM106B, and no other genes. Furthermore, incremental increases in TMEM106B levels result in incremental increases in lysosomal phenotypes and cell toxicity. We then combine fine-mapping, bioinformatics, and bench-based approaches to functionally characterize all candidate causal variants at this locus. This approach identified a noncoding variant, rs1990620, which differentially recruits CTCF, influencing CTCF-mediated long-range chromatin looping interactions between multiple cis-regulatory elements, including the TMEM106B promoter. Our findings thus provide an in-depth analysis of the 7p21 locus linked by GWAS to frontotemporal lobar degeneration, nominating a causal variant and a causal mechanism for allele-specific expression and disease association at this locus. Finally, we show that genetic variants associated with risk for neurodegenerative diseases beyond frontotemporal lobar degeneration are enriched in brain CTCF-binding sites genome-wide, implicating CTCF-mediated gene regulation in risk for neurodegeneration more generally.

genetics↗

bioRxiv2017

Dissecting limiting factors of the Protein synthesis Using Recombinant Elements (PURE) system

Reconstituted cell-free protein synthesis systems such as the Protein synthesis Using Recombinant Elements (PURE) system give high-throughput and controlled access to in vitro protein synthesis. Here we show that compared to the commercial S30 crude extract based RTS 100 E. coli HY system, the PURE system has less mRNA degradation and produces ~4-fold more total protein. However the majority of these polypeptides are partially translated or inactive since the signal from firefly luciferase (Fluc) translated in PURE is only ~2/3rd of that measured using the S30 crude extract system. Both of the two systems suffer from low ribosome recycling efficiency when translating proteins from 90 kD to 220 kD. A systematic fed-batch analysis of PURE shows replenishment of 6 small molecule substrates individually or in combination prior to energy depletion increased Fluc protein yield by ~1.5 to ~2-fold, while accumulation of inorganic phosphate contributes to reaction termination. Additionally, while adding EF-P to PURE reduced total protein translated, it also increased the fraction of active product and reduced partial translated product probably by slowing down the translation process. Finally, ArfA, rather than YaeJ or PrfH, helped reduce ribosome stalling when translating Fluc and improved system productivity in a template-dependent fashion.

bioengineering↗