Biology subjects

Karki, B.

Publications and source records attributed to Karki, B..

4 recordsLinked to original sources

bioRxiv2025

Systematic contextual biases in SegmentNT relevant to all nucleotide transformer models

Recent advances in large language models (LLMs) have extended to genomic applications, yet model robustness relative to context is unclear. Here, we demonstrate two intrinsic biases (input sequence length and nucleotide position) affecting SegmentNT results, a model included with the Nucleotide Transformer that provides nucleotide-level predictions of biological features. We demonstrate that nucleotide position within the input sequence (beginning, middle, or end) alters the nature of SegmentNTs raw prediction probabilities, which can be standardized to improve prediction consistency. While longer input sequence length improves model performance, diminishing returns suggest a surprisingly small input length of [~]3,072 nucleotides might be sufficient for many applications. We further identify a 24-nucleotide periodic oscillation in SegmentNTs prediction probabilities, revealing an intrinsic bias potentially linked to the models training tokenization (6-mers) and architecture. We identify potential approaches to account for these biases and provide generalizable insights for utilizing nucleotide-resolution functional prediction models.

bioinformatics↗

bioRxiv2025

PRPS activity tunes redox homeostasis in Myc-driven lymphoma

Myc hyperactivation coordinately regulates numerous metabolic processes to drive lymphomagenesis. Here, we elucidate the temporal and functional relationships between the medley of pathways, factors, and mechanisms that cooperate to control redox homeostasis in Myc-overexpressing B cell lymphomas. We find that Myc overexpression rapidly stimulates the oxidative pentose phosphate pathway (oxPPP), nucleotide synthesis, and mitochondrial respiration, which collectively steers cellular equilibrium to a more oxidative state. We identify Myc-dependent hyperactivation of the phosphoribosyl pyrophosphate synthetase (PRPS) enzyme as a primary regulator of redox status in lymphoma cells. Mechanistically, we show that genetic inactivation of the PRPS2 isozyme, but not PRPS1, in MYC-driven lymphoma cells leads to elevated NADPH levels and reductive stress-mediated death. Employing a pharmacological screen, we demonstrate how targeting PRPS1 or PRPS2 elicits opposing sensitivity or resistance, respectively, to chemotherapeutic agents affecting the thioredoxin and glutathione network, thus providing a therapeutic blueprint for treating MYC-driven lymphomas.

cancer biology↗

bioRxiv2024

Evolutionary origins and innovations sculpting the mammalian PRPS enzyme complex

The phosphoribosyl pyrophosphate synthetase (PRPS) enzyme conducts a chokepoint reaction connecting central carbon metabolism and nucleotide production pathways, making it essential for life1,2. Here, we show that the presence of multiple PRPS-encoding genes is a hallmark trait of eukaryotes, and we trace the evolutionary origins and define the individual functions of each of the five mammalian PRPS homologs - three isozymes (one testis-restricted)3,4 and two non-enzymatic associated proteins (APs)5,6 - which we demonstrate operate together as a large molecular weight complex capable of attaining a heterogeneous array of functional multimeric configurations. Employing a repertoire of isogenic fibroblast clones in all viable individual or combinatorial assembly states, we define preferential interactions between subunits, and we show that cells lacking PRPS2, PRPSAP1, and PRPSAP2 render PRPS1 into aberrant homo-oligomeric assemblies with diminished metabolic flux and impaired proliferative capacity. We demonstrate how numerous evolutionary innovations in the duplicated genes have created specialized roles for individual complex members and identify translational control mechanisms that enable fine-tuned regulation of PRPS assembly and activity, which provide clues into the positive and negative selective pressures that facilitate metabolic flexibility and tissue specialization in advanced lifeforms. Collectively, our study demonstrates how evolution has transformed a single PRPS gene into a multimeric complex endowed with functional and regulatory features that govern cellular biochemistry.

biochemistry↗

bioRxiv2020

Vector dynamics influence spatially imperfect genetic interventions against disease

Background and objectivesGenetic engineering and similar technologies offer promising new approaches to controlling human diseases by blocking transmission from vectors. However, in spatially structured populations, imperfect coverage of the vector will leave pockets in which the parasite can persist. Yet movement by humans may disrupt this local persistence and facilitate eradication when these pockets are small, essentially distributing parasite reproduction out of unprotected areas and into areas that block its reproduction. MethodologyWe develop formal mathematical models of this process similar to standard Ross-Macdonald models, but (i) specifying spatial structure of two patches, with transmission blocked in one patch but not in the other, (ii) allowing temporary human movement (travel instead of migration), and (iii) considering two different modes of mosquito biting. ResultsWe find that there is no invariant effect of disrupting spatial structure with travel. For both biting models, travel out of the unprotected patch has different consequences than travel by visitors into the patch, but the effects are reversed between the two biting models. Conclusions and implicationsOverall, the effect of human travel on the maintenance of vector-borne diseases in structured habitats must be considered in light of the actual biology of mosquito abundances and biting dynamics. Lay summaryGenetic interventions against pathogens transmitted by insect vectors are promising methods of controlling infectious diseases. These interventions may be imperfect, leaving pockets where the parasite persists. How will human movement between protected and unprotected areas affect persistence? Mathematical models developed here show that the answer is ecology-dependent, depending on vector biting behavior.

ecology↗