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Biology subjects

Tai, C.

Publications and source records attributed to Tai, C..

4 recordsLinked to original sources

VirusImmu: a novel ensemble machine learning approach for viral immunogenicity prediction

BackgroundThe viruses threats provoke concerns regarding their sustained epidemic transmission, making the development of vaccines particularly important. In the prolonged and costly process of vaccine development, the most important initial step is to identify protective immunogens. Machine learning (ML) approaches are productive in analyzing big data such as microbial proteomes, and can remarkably reduce the cost of experimental work in developing novel vaccine candidates. ResultsWe intensively evaluated the immunogenicity prediction power of eight commonly-used ML methods by random sampling cross validation on a large dataset consisting of known viral immunogens and non-immunogens we manually curated from the public domain. XGBoost, kNN and RF showed the strongest predictive power. We then proposed a novel soft-voting based ensemble approach (VirusImmu), which demonstrated a powerful and stable capability for viral immunogenicity prediction across the test set and external test set irrespective of protein sequence length. VirusImmu was successfully applied to facilitate identifying linear B cell epitopes against African Swine Fever Virus as confirmed by indirect ELISA in vitro. ConclusionsVirusImmu exhibited tremendous potentials in predicting immunogenicity of viral protein segments. It is freely accessible at https://github.com/zhangjbig/VirusImmu.

bioinformatics↗

Pharmacological PINK1 activation ameliorates Pathology in Parkinson's Disease models

PINK1 loss-of-function mutations and exposure to mitochondrial toxins are causative for Parkinsons disease (PD) and Parkinsonism, respectively. We demonstrate that pathological -synuclein deposition, the hallmark pathology of idiopathic PD, induces mitochondrial dysfunction and impairs mitophagy, driving accumulation of the PINK1 substrate pS65-Ubiquitin (pUb) in primary neurons and in vivo. We synthesized MTK458, a brain penetrant small molecule that binds to PINK1 and stabilizes an active heterocomplex, thereby increasing mitophagy. MTK458 mediates clearance of -synuclein pathology in PFF seeding models in vitro and in vivo and reduces pUb. We developed an ultrasensitive assay to quantify pUb levels in plasma and observed an increase in pUb in PD subjects that correlates with disease progression, paralleling our observations in PD models. Our combined findings from preclinical PD models and patient biofluids suggest that pharmacological activation of PINK1 is worthy of further study as a therapeutic strategy for disease modification in PD. HighlightsO_LIDiscovery of a plasma Parkinsons Disease biomarker candidate, pS65-Ubiquitin (pUb) C_LIO_LIPlasma pUb levels correlate with disease status and progression in PD patients. C_LIO_LIIdentification of a potent, brain penetrant PINK1 activator, MTK458 C_LIO_LIMTK458 selectively activates PINK1 by stimulating dimerization and stabilization of the PINK1/TOM complex C_LIO_LIMTK458 drives clearance of -synuclein pathology and normalizes pUb in in vivo Parkinsons models C_LI

neuroscience↗

Excitatory effect of biphasic kHz field stimulation on CA1 pyramidal neurons in slices

BackgroundElectrical stimulation in the kilohertz-frequency range has been successfully used for treatment of various neurological disorders. Nevertheless, the mechanisms underlying this stimulation are poorly understood. ObjectiveTo study the effect of kilohertz-frequency electric fields on neuronal membrane biophysics we developed a reliable experimental method to measure responses of single neurons to kilohertz field stimulation in brain slice preparations. MethodsIn the submerged brain slice pyramidal neurons of the CA1 subfield were recorded in the whole-cell configuration before, during and after stimulation with an external electric field at 2kHz, 5kHz or 10 kHz. ResultsReproducible excitatory changes in rheobase and spontaneous firing were elicited during kHz-field application at all stimulating frequencies. The rheobase only decreased and spontaneous firing either was initiated in silent neurons or became more intense in previously spontaneously active neurons. Response thresholds were higher at higher frequencies. Blockade of glutamatergic synaptic transmission did not alter the magnitude of responses. Inhibitory synaptic input was not changed by kilohertz field stimulation. ConclusionkHz-frequency current applied in brain tissue has an excitatory effect on pyramidal neurons during stimulation. This effect is more prominent and occurs at a lower stimulus intensity at a frequency of 2kHz as compared to 5kHz and 10kHz.

neuroscience↗

Inhibition of amyloid formation of the Nucleoprotein of SARS-CoV-2

The SARS-CoV-2 Nucleoprotein (NCAP) functions in RNA packaging during viral replication and assembly. Computational analysis of its amino acid sequence reveals a central low-complexity domain (LCD) having sequence features akin to LCDs in other proteins known to function in liquid-liquid phase separation. Here we show that in the presence of viral RNA, NCAP, and also its LCD segment alone, form amyloid-like fibrils when undergoing liquid-liquid phase separation. Within the LCD we identified three 6-residue segments that drive amyloid fibril formation. We determined atomic structures for fibrils formed by each of the three identified segments. These structures informed our design of peptide inhibitors of NCAP fibril formation and liquid-liquid phase separation, suggesting a therapeutic route for Covid-19. One Sentence SummaryAtomic structures of amyloid-driving peptide segments from SARS-CoV-2 Nucleoprotein inform the development of Covid-19 therapeutics.

biochemistry↗