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Jia, T. Z.

Publications and source records attributed to Jia, T. Z..

5 recordsLinked to original sources

Language Modeling Materializes a World Model of Protein Biology

Proteins are fundamental to life. The full extent of their biology is beyond our ability to characterize with experimental approaches in the physical laboratory. Accurate digital representations could accelerate the discovery of protein biology through virtual experiments. We propose language modeling to learn unified and general representations that can be scaled to all of protein biology. Building on these representations, we develop a structure prediction model that exceeds the performance of established methods for biomolecular complex prediction across benchmarks, including for the interactions of antibodies with their targets. A simple search procedure yields high experimental success rates for the discovery of proteins with nanomolar binding affinities for both miniproteins and single-chain antibodies, a modality critical for therapeutic design. Study of the concepts in the language models representation space reveals a systematic organization aligned with the reductionist understanding of proteins developed through empirical science. Leveraging this organization, we generate a comprehensive map of protein biology encompassing over 6.8 billion sequences and 1.1 billion predicted structures, identifying connections across known and unknown biology. As a whole, this shows language modeling as a powerful substrate for representing the biology of proteins, operating across scales from the prediction and design of protein interactions at the atomic level, to identifying properties of proteins at different levels of granularity and abstraction, to the scale of mapping connections between proteins across billions of years of evolution.

bioinformatics↗

One-pot chemo-enzymatic synthesis and one-step recovery of homogeneous long-chain polyphosphates from microalgal biomass

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=193 SRC="FIGDIR/small/553819v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@1fabe18org.highwire.dtl.DTLVardef@d65a45org.highwire.dtl.DTLVardef@c09593org.highwire.dtl.DTLVardef@19c1785_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical abstractC_FLOATNO C_FIG Phosphate, an essential component of life, fertilizers, and detergents, is a finite resource that could be depleted within 70 years, while improper phosphate waste disposal in aquatic environments results in eutrophication. Despite some chemical-based methods, biological phosphorus removal using polyphosphate-accumulating organisms, such as microalgae, serves as a sustainable alternative to reclaim phosphate from wastewater. Polyphosphates have profound biological functions and biomedical applications, serving as energy stock, coagulation factors, and antiviral agents depending on their length, showing inherent value in polyphosphate recovery. Here, we leveraged the power of thermodynamic coupling and phase transitions to establish a one-pot, two-step multi-enzyme cascade to convert polydisperse polyphosphate in microalgae biomass into high-molecular-weight insoluble long-chain polyphosphates, allowing for one-step purification. We then optimzed a thermo-digestion approach to transform the 1,300-mers into shorter polyphosphates. Altogether, the processes established here enable the establishment of a sustainable P bioeconomy platform to refine microalgal biomass for biotechnological uses.

synthetic biology↗

Sensitive and specific miRNA in situ hybridization using partially methylated phosphotriester antisense DNA probes

Neutralized DNA (nDNA) is an emerging class of DNA oligonucleotides chemically synthesized with site-specific internucleoside methyl phosphotriester linkages, changing the negatively charged DNA phosphodiester backbone to a neutral methyl phosphotriester backbone. The reduction of inter-strand charge repulsion of nucleotide duplexes results in stronger binding between nDNA and other nucleic acids, and as such, nDNA has been used as a sensitive antisense probe for sequencing nucleotides. From a thermodynamic perspective due to steric effects, a hybrid duplex between DNA and partially methylated nDNA should possess higher specificity than a duplex between DNA with fully methylated nDNA, while retaining binding affinity. However, the application of nDNA for ex vivo RNA hybridization at low transcript abundance remains completely unexplored. Here, we determined that partially methylated nDNA (N4 nDNA; with 4 methylated nucleotides) probes inhibited reverse transcription of oncogenic miRNA miR-21 more efficiently than canonical DNA probes or highly methylated nDNA probes (all probes share the same sequence) and with an efficiency rivaling LNA probes. Subsequently, we performed in situ hybridization analysis using a miR-21-expressing colorectal cancer cell line (HCT116). HCT116 stained with N4 nDNA probes revealed a greater detection intensity and specificity than HCT116 stained with canonical DNA probes. Consistently, enzyme-linked immunosorbent assays revealed that miRNA hybridization efficiency of N4 nDNA probes was greater than that of canonical DNA probes at cellular transcript levels. Given that N4 nDNA probe is immune-negative and DNase I-resistant, partially methylated nDNA could be further developed to have significant applications in biotechnology and medicine.

bioengineering↗

2D-HELS-AA MS Seq: Direct sequencing of tRNA reveals its different isoforms and multiple dynamic base modifications

We report a direct method for sequencing tRNAPhe without cDNA by combining 2-dimensional hydrophobic RNA end-labeling with an anchor-based algorithm in mass spectrometry-based sequencing (2D-HELS-AA MS Seq). The entire tRNAPhe was sequenced and the identity, location and abundance of all 11 base modifications were determined. Changes in ratios of wybutosine and its depurinated form under different conditions were quantified, pointing to the ability of our technology to determine dynamic changes of nucleotide modifications. Two truncated isoforms at 3CCA tail of the tRNAPhe (75 nt CC, 80% and 74 nt C, 3%) were identified in addition to the 76 nt tRNAPhe with a full-length 3CCA tail (17%). We also discovered a new isoform with A-G transitions at both the 44 and 45 positions in the tRNAPhe variable loop.\n\nOne Sentence SummaryDirect 2D-HELS-AA MS Seq of tRNA reveals different isoforms and base modifications

biochemistry↗

A general LC/MS-based RNA sequencing method for direct analysis of multiple-base modifications in RNA mixtures

A complete understanding of the structural and functional potential of RNA requires understanding of chemical modifications and noncanonical bases; this in turn requires advances in current sequencing methods to be able to sequence not only canonical ribonucleotides, but at the same time directly sequence these nonstandard moieties. Here, we present the first direct and modification type-independent RNA sequencing method via integration of a hydrophobic end-labeling strategy with of 2-D mass-retention time LC/MS analysis to allow de novo sequencing of RNA mixtures and enhance sample usage efficiency. Our method can directly read out the complete sequence, while identifying, locating, and quantifying base modifications accurately in both single and mixed RNA samples containing multiple different modifications at single-base resolution. Our method can also quantify stoichiometry/percentage of modified RNA vs. its canonical counterpart RNA, simulating a real biological sample where modifications exist but may not be 100% at a particular site of the RNA. This method is a critical step towards fully sequencing real complex cellular RNA samples of any type and containing any modification types and can also be used in the quality control of modified therapeutic RNAs.

biochemistry↗